# Patent

## Title
Diarylether derivatives as antitumor agents

## Abstract

An object of the present invention is to provide a medicinal drug much improved in anti tumor activity and excellent in safety. According to the present invention, there is provided a medicinal drug containing a compound represented by the following general formula (1) or a salt thereof as an active ingredient: [Formula 1] wherein X1 represents a nitrogen atom or a group —CH═, R1 represents a group —Z—R6, in which Z represents a group —CO—, a group —CH(OH)— or the like, R6 represents a 5- to 15-membered monocyclic, dicyclic or tricyclic saturated or unsaturated heterocyclic group having 1 to 4 nitrogen atoms, oxygen atoms or sulfur atoms, R2 represents a hydrogen atom or a halogen atom, Y represents a group —O—, a group —CO—, a group —CH(OH)— or a lower alkylene group, and A represents [Formula 2] wherein R3 represents a hydrogen atom, a lower alkoxy group or the like, p represents 1 or 2, R4 represents an imidazolyl lower alkyl group or the like.

## Background
BACKGROUND OF THE INVENTION
(1) Field of the Invention
The present invention relates to a medicinal drug.
(2) Description of Related Art
Since the clinical use of nitrogen mustard as an anticancer agent was started in the 1940s for the first time in the world, numerous anticancer drugs have ever been developed. Actually, for example, antimetabolites such as 5-fluorouracil, antitumor antibiotics such as adriamycin, platinum complex such as cisplatin, and plant-derived carcinostatics such as vindesine have been subjected to clinical use.
However, most of these carcinostatics have significant side effects such as digestive disorders, myelosuppression and alopecia since they are cytotoxic also to normal cells. Due to the side effects, their range of application is limited. In addition, the therapeutic effects themselves are partial and short, in most cases.
Developments of new carcinostatics in place of these has been made; however, satisfactory results have not yet been obtained. Patent documents 1 and 2 disclose that certain kinds of compounds have fibrosing inhibitory actions. However, it is not known whether the compounds have antitumor actions.

    [Patent Document 1] WO/2006/014012
    [Patent Document 2] JP-A-2004-35475


BRIEF SUMMARY OF THE INVENTION
An object of the present invention is therefore to provide an excellent medicinal drug such as a therapeutic drug for a tumor, particularly, a therapeutic drug for a malignant tumor.
The present inventors intensively conducted studies with the view to attaining the aforementioned object. As a result, they found that a compound represented by the general formula (1) below and a salt thereof have an excellent antitumor effect. The present invention has been achieved based on the finding.
More specifically, the present invention provides medicinal drugs shown in items 1 to 58.
Item 1: An antitumor agent comprising a compound represented by the general formula (1) below or a salt thereof as an active ingredient:




wherein X1 represents a nitrogen atom or a group —CH═,

R1 represents a group —Z—R6,

Z represents a group —N(R8)—B—, a group —B—N(R8)—, a group —B0—O—, a group





a group —CO—, a group —CH(OH)—, a group N(R9a—CO—N—(R9b)—, a group —N═CH—, a group —N(R10a)—SO2—(B22a)e-, a lower alkenylene group, a group —NHCO—B1—, a group —NHCO—B2—(W)u-, a group —B0—B19a—, a group





a group





a group —SO2—N(R10b)—, a group —S—, a lower alkynylene group, a lower alkylene group, a group —N(R8d)— or a group —CO—NH—B18a—,

R8 represents a hydrogen atom, a lower alkyl group that may have a lower alkoxy group as a substituent, a lower alkanoyl group, a lower alkylsulfonyl group or a phenyl lower alkyl group,

B represents a group —CO— or a lower alkylene group,

B0 represents a lower alkylene group,

B1 represents a lower alkenylene group that may have a phenyl group as a substituent,

B2 represents a lower alkylene group that may be substituted by a group selected from the group consisting of a lower alkoxy group and a phenyl group,

R9a represents a hydrogen atom or a lower alkyl group,

R9b represents a hydrogen atom or a lower alkyl group,

R10 represents a hydrogen atom or a lower alkyl group,

B22a represents a lower alkylene group or a lower alkenylene group,

e represents 0 or 1,

B18 represents a lower alkylene group,

B19a represents a lower alkylene group,

B20a represents a lower alkylene group,

B21a represents a lower alkylene group,

k represents 2 or 3,

c represents 0 or 1,

d′ represents 0 or 1,

R10b represents a hydrogen atom or a lower alkyl group,

R8d represents a hydrogen atom or a lower alkyl group,

W represents an oxygen atom, a group —NH—, or a sulfur atom,

u represents 0 or 1,

R6 represents 5- to 15-membered monocyclic, dicyclic or tricyclic saturated or unsaturated heterocyclic group having 1 to 4 nitrogen atoms, oxygen atoms or sulfur atoms (that may have 1 to 3 substituents, which are selected from the group consisting of an oxo group; a lower alkoxy group that may have a halogen atom as a substituent; a lower alkyl group that may have a halogen atom as a substituent; a halogen atom; a lower alkylsulfonyl group; a phenyl group that may be substituted by a lower alkyl group that may have a halogen atom on the phenyl ring; a lower alkylthio group, a pyrrolyl group, a benzoyl group; a lower alkanoyl group; lower alkoxycarbonyl group; and an amino group that may have a group selected from the group consisting of a lower alkyl group and a lower alkanoyl group as a substituent, on the heterocyclic ring), an adamantly group, a naphthyl group (that may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a halogen atom, and an amino group that may have a group selected from the group consisting of a lower alkyl group and a lower alkanoyl group as a substituent, on the naphthalene ring), an alkyl group that may have a lower alkoxy group as a substituent, a cycloalkyl group that may be substituted by a group selected from the group consisting of an amino substituted lower alkyl group that may have a lower alkyl group and a lower alkyl group that may have a halogen atom as a substituent, on the cycloalkyl ring, a lower alkenyl group that may have a halogen atom as a substituent, a lower alkanoyl group, a benzoyl group (that may have 1 to 3 groups selected from the group consisting of a lower alkyl group that may have a halogen atom and halogen atom, as a substituents, on the phenyl ring), a halogen atom substituted lower alkyl group, cycloalkyl lower alkyl group or a group





R7 represents a hydrogen atom, a phenyl group, a carboxy group, a hydroxyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a phenoxy group, a lower alkoxy group that may have a halogen atom as a substituent, a lower alkylenedioxy group, an amino group that may have, as a substituent, a group selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a benzoyl group, and a cycloalkyl group, a cyano group, a lower alkanoyl group that may have a halogen atom as a substituent, a lower alkylsulfonyl group, an aminosulfonyl group, a lower alkoxycarbonyl group, a lower alkanoyloxy group, a lower alkoxycarbonyl lower alkyl group or a 5- or 6-membered saturated or unsaturated heterocyclic group having 1 to 4 nitrogen atoms, oxygen atoms, or sulfur atoms (that may have an oxo group on the heterocyclic ring),

m represents an integer from 1 to 5 (when m represents 2 to 5, two to five R7s may be identical or different) and

R2 represents a hydrogen atom, a halogen atom, or a lower alkyl group,

Y represents a group —O—, a group —N(R5)—, a group —CO—, a group —CH(OH)—, a lower alkylene group, a group —

S(O)n-, or a group —C(═N—OH)—,

R5 represents a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a benzoyl group, a phenyl lower alkyl group, or a cycloalkyl group,

n represents 0, 1, or 2,

A represents a group





or a group





p represents 1 or 2,

R3 represents a hydrogen atom, a lower alkoxy group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxycarbonyl group, a carboxy group, a group —CONR11R12, or a cyano group,

wherein R11 and R12 may be identical or different and each represent a hydrogen atom, a lower alkyl group, a cycloalkyl group, or a phenyl group, and R11 and R12, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic ring,

R4 represents an imidazolyl lower alkyl group, a 1,2,4-triazolyl lower alkyl group, a 1,2,3-triazolyl lower alkyl group, a 1,2,5-triazolyl lower alkyl group, a pyrazolyl lower alkyl group, a pyrimidinyl lower alkyl group that may have an oxo group as a substituent on the pyrimidine ring, a 3,5-dioxoisoxazolidin-4-ylidene lower alkyl group, a 1,2,4-oxadiazolyl lower alkyl group that may have a lower alkyl group as a substituent on the 1,2,4-oxadiazole ring, a thiazolidinyl lower alkyl group that may have an oxo group as a substituent on the thiazolidine ring, a group





a group





or a group -(T)1-N(R14)R15,

R13 represents a hydrogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkanoyl group that may have a halogen atom as a substituent, a lower alkoxycarbonyl group, a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, an imidazolyl lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a carboxy lower alkyl group, a benzoyl group, a morpholino-substituted lower alkanoyl group, a piperazinyl carbonyl lower alkyl group that may be substituted, on the piperazine ring, by a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, a piperazinyl lower alkanoyl group that may be substituted, on the piperazine ring, by a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, a morpholinocarbonyl-substituted lower alkyl group, or an imidazolyl lower alkanoyl group,

R13a represents a hydrogen atom or a hydroxyl group,

T represents a lower alkylene group, a group —N(R17)—B3—CO—, a group —B19—N(R18)—CO—, a group —B4—CO—, a group -Q-B5—CO—, a group —B6—N(R19)—B7—CO—, a group —CO—B8—, a group —CH(OH)—B9—, a group —CO—B10—CO—, a group —CH(OH)—B11—CO—, a group —CO—, a group —SO2—, or a group —B23a—CO—CO—,

wherein R17 represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a cycloalkylcarbonyl group, a lower alkanoyl group that may have a halogen atom as a substituent, a lower alkenyl group, an amino-substituted lower alkanoyl group that may have a lower alkyl group as a substituent, or a lower alkylsulfonyl group,

B3 represents a lower alkylene group,

B19 represents a lower alkylene group,

R18 represents a hydrogen atom or a lower alkyl group,

B4 represents a lower alkenylene group or a lower alkylene group that may have a hydroxyl group as a substituent,

Q represents an oxygen atom or a group —S(O)n- (wherein

n is the same as described above),

B5 represents a lower alkylene group,

B6 represents a lower alkylene group,

R19 represents a hydrogen atom or a lower alkanoyl group,

B7 represents a lower alkylene group,

B8 represents a lower alkylene group,

B9 represents a lower alkylene group,

B10 represents a lower alkylene group,

B11 represents a lower alkylene group,

B23a represents a lower alkylene group,

l represents 0 or 1,

R14 represents a hydrogen atom or an alkyl group that may have a hydroxyl group as a substituent,

R15 represents (2) a hydroxyl group-substituted alkyl group, (3) a cycloalkyl group that may have a group selected from the group consisting of a hydroxyl group and a lower alkyl group as a substituent, (4) a phenoxy lower alkyl group, (5) a phenyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a lower alkyl group; a lower alkoxy group that may have a halogen atom as a substituent; a halogen atom; an amino lower alkoxy group that may have a lower alkyl group as a substituent; a hydroxyl group-substituted lower alkyl group; a phenyl lower alkyl group; a lower alkynyl group; an amino group that may have a lower alkylsulfonyl group as a substituent; a lower alkylthio group; a cycloalkyl group; a phenylthio group; an adamantyl group; an anilino group that may have a halogen atom as a substituent on the phenyl ring; a lower alkoxycarbonyl group; a piperazinyl group that may have a lower alkyl group as a substituent on the piperazine ring; a pyrrolidinyl group that may have an oxo group as a substituent on the pyrrolidine ring; a lower alkanoylamino group; a cyano group; and a phenoxy group, (6) a phenoxy group, (7) a phenyl lower alkyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkoxy group that may have a halogen atom as a substituent, and a lower alkyl group, (8) a phenyl lower alkyl group that has a lower alkylenedioxy group as a substituent on the phenyl ring, (10) a lower alkoxycarbonyl-substituted lower alkyl group, (11) a carboxy-substituted lower alkyl group, (12) an amino group that may have a lower alkanoyl group as a substituent, (13) a 1,2,3,4-tetrahydroquinolyl group that may have 1 to 3 groups selected from the group consisting of an oxo group, a lower alkoxy group, and a lower alkylenedioxy group as a substituent(s) on the tetrahydroquinoline ring, (14) a cycloalkyl lower alkyl group, (15) a piperazinyl lower alkanoyl group that may be substituted, on the piperazine ring, by a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, (16) a pyridyl lower alkyl group, (17) an amino group-substituted lower alkyl group that may have a group selected from the group consisting of a lower alkyl group and a lower alkanoyl group as a substituent, (18) a lower alkoxy lower alkyl group, (19) an imidazolyl group, (20) an imidazolyl lower alkyl group, (21) a 1,2,3,4-tetrahydroisoquinolylcarbonyl-substituted lower alkyl group, (22) a piperidinylcarbonyl group that may have a group selected from the group consisting of a lower alkoxycarbonyl group, a phenyl lower alkyl group, and a furyl lower alkyl group as a substituent on the piperidine ring, (23) a thiazolidinyl lower alkanoyl group that may have an oxo group as a substituent on the thiazolidine ring, (24) a piperidinyl group that may be substituted, on the piperidine ring, by a group selected from the group consisting of a lower alkoxycarbonyl group, a phenyl lower alkyl group, a lower alkyl group, a benzoyl group, and a furyl lower alkyl group, (25) a carbonyl lower alkyl group substituted by a group





(26) a carbonyl lower alkyl group substituted by a group





(27) a group —CO—B20—N(R36)R37, (26a) a pyrrolidinyl lower alkyl group, (27a) a morpholino lower alkyl group, (28a) a phenyl lower alkenyl group, (29a) an anilinocarbonyl lower alkyl group that may have a lower alkyl group as a substituent on the phenyl ring, (30a) an indolyl group, (31a) a piperazinyl lower alkyl group that may have, as a substituent on the piperazine ring, a group selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, (32a) an amidino lower alkyl group that may have a lower alkyl group as a substituent, (33a) a fluorenyl group, (34a) a carbazolyl group that may have a lower alkyl group as a substituent on the carbazole ring, (35a) an amidino group that may have a lower alkyl group as a substituent, (36a) a piperazinyl-substituted oxalyl group that may have 1 to 3 groups selected from the group consisting of a phenyl lower alkyl group (that may have 1 to 3 groups selected from the group consisting of a lower alkylenedioxy group and a lower alkoxy group as a substituent(s) on the phenyl ring) and a pyridyl lower alkyl group as a substituent(s) on the piperazine ring, or (37a) a cyano-substituted lower alkyl group,

R34 represents an oxo group or a phenyl group,

d represents an integer from 0 to 3,

B20 represents a lower alkylene group,

R36 and R37, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic group, wherein, on the heterocyclic ring, 1 to 3 phenyl lower alkyl groups that may have a lower alkylenedioxy group on the phenyl ring, may be present as a substituent(s),

R14 and R15, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 10-membered saturated or unsaturated heterocyclic ring; or a group





wherein, on the heterocyclic ring, 1 to 3 substituents may be present which are selected from the group consisting of (28) a phenyl-substituted lower alkyl group, which has 1 to 2 phenyl groups that may be substituted by 1 to 3 groups on the phenyl ring, selected from the group consisting of a lower alkanoyl group, an amino group that may have a lower alkanoyl group as a substituent, a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxy group that may have a halogen atom as a substituent, a phenyl lower alkoxy group, a hydroxyl group, and a lower alkylenedioxy group, and that may have a pyridyl group on the lower alkyl group, (29) a carbamoyl group, (30) a pyridyl lower alkyl group that may have, as a substituent(s) on the pyridine ring, 1 to 3 groups selected from the group consisting of a hydroxyl group and a lower alkyl group that may have a hydroxyl group as a substituent, (31) a pyrrolyl lower alkyl group that may have 1 to 3 lower alkyl groups as a substituent(s) on the pyrrole ring, (32) a benzoxazolyl lower alkyl group, (33) a benzothiazolyl lower alkyl group, (34) a furyl lower alkyl group, (35) a benzoyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a cyano group, an amino group that may have a lower alkylsulfonyl group as a substituent, a halogen atom, a lower alkoxy group, a lower alkyl group that may have a halogen atom as a substituent, a thiazolidinyl lower alkyl group that may have an oxo group as a substituent on the thiazolidine ring, a thiazolidinylidene lower alkyl group that may have an oxo group as a substituent on the thiazolidine ring, and a lower alkylenedioxy group, (36) a pyrimidinyl group, (37) a pyrazinyl group, (38) a pyridyl group, (39) a lower alkoxycarbonyl group, (40) a thiazolidinyl lower alkanoyl group that may be substituted, on the thiazolidine ring, by a group selected from the group consisting of an oxo group and a group





(wherein Ra and Rb each represent a lower alkyl group), (41) a lower alkyl group that may have a group selected from the group consisting of a hydroxyl group and a halogen atom as a substituent, (42) a lower alkanoyl group that may have a halogen atom as a substituent, (43) a phenyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a carbamoyl group that may have a group selected from the group consisting of a lower alkoxy lower alkyl group and a lower alkyl group, a lower alkoxycarbonyl group, a carboxy group, a cyano group, a phenyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxy group that may have a halogen atom as a substituent, a benzoyl group that may have a halogen atom as a substituent on the phenyl ring, a phenyl lower alkyl group that may have a halogen atom as a substituent on the phenyl ring, and a hydroxyl group, (44) a phenyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, (45) a naphthyl lower alkyl group, (46) a phenoxy group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a cyano group, a lower alkyl group that may have a halogen atom as a substituent, and a lower alkoxy group that may have a halogen atom as a substituent, (47) a phenoxy lower alkyl group, (48) a phenyl lower alkoxy group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, and a lower alkoxy group that may have a halogen atom as a substituent, (49) a group —(B12CO)t-N(R20)R21, (50) a group —(CO)o-B13—N(R22)R23, (51) a 1,2,3,4-tetrahydronaphthyl-substituted lower alkyl group that may be substituted, on the 1,2,3,4-tetrahydronaphthalene ring, by 1 to 5 lower alkyl groups as a substituent(s), (52) a cycloalkyl group that may have a hydroxyl group as a substituent, (53) a piperidinyl group that may be substituted, on the piperidine ring, by 1 to 3 lower alkyl groups as a substituent(s), (54) a quinolyl lower alkyl group, (55) a 1,2,3,4-tetrazolyl lower alkyl group that may have a group selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group as a substituent on the tetrazole ring, (56) a thiazolyl lower alkyl group that may have a phenyl group as a substituent on the thiazole ring, (57) a benzoyl lower alkyl group that may have 1 to 3 groups selected from the group consisting of a lower alkoxy group and a halogen atom as a substituent(s) on the phenyl ring, (58) a piperidinyl lower alkyl group that may have a lower alkyl group as a substituent on the piperidine ring, (59) an imidazolyl group that may have 1 to 3 phenyl groups as a substituent(s) on the imidazole ring, (60) a benzimidazolyl group that may have 1 to 3 lower alkyl groups as a substituent(s) on the benzimidazole ring, (61) a pyridyl lower alkoxy group, (62) a 1,2,3,4-tetrahydroquinolyl lower alkyl group that may have an oxo group as a substituent on the tetrahydroquinoline ring, (63) a 1,3,4-oxadiazolyl lower alkyl group that may have an oxo group as a substituent on the 1,3,4-oxadizole ring, (64) a cycloalkyl lower alkyl group, (65) a tetrahydropyranyl group, (66) a thienyl lower alkyl group, (67) a pyrimidinylcarbonyl group that may have an oxo group as a substituent on the pyrimidine ring, (68) a hydroxyl group, (69) a carboxy group, (70) a lower alkoxy lower alkyl group, (71) a lower alkoxy lower alkoxy group, (72) a benzoyloxy group, (73) a lower alkoxycarbonyl lower alkoxy group, (74) a carboxy lower alkoxy group, (75) a phenoxy lower alkanoyl group, (76) a 1,2,3,4-tetrahydroquinolylcarbonyl group that may have an oxo group as a substituent on the tetrahydroquinoline ring, (77) a phenylsulfonyl group, (78) an imidazolyl lower alkanoyl group, (79) an imidazolyl lower alkyl group, (80) a pyridylcarbonyl group, (81) an imidazolylcarbonyl group, (82) a lower alkoxycarbonyl lower alkyl group, (83) a carboxy lower alkyl group, (84) a group —(O—B15)s-CO—N(R26)R27, (85) a group —N(R28)— CO—B16—N(R29)R30, (86) a group —N(R31)—B17—CO—N(R32)R33, (87) a benzoxazolyl group, (88a) a benzothienyl group, (89a) an oxo group, and (90a) a 1,2,3,4-tetrahydroquinolyl group that may have an oxo group as a substituent on the tetrahydroquinoline ring,

B12 represents a lower alkylene group,

t represents 0 or 1,

R20 and R21 may be identical or different and each represent a hydrogen atom; an amino group that may have a lower alkoxycarbonyl group as a substituent; a benzoyl group that may have 1 to 3 lower alkoxy groups as a substituent(s) on the phenyl ring; a lower alkyl group; a lower alkyl group having 1 to 2 phenyl groups that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxy group that may have a halogen atom as a substituent, and a lower alkylthio group; a phenyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a lower alkoxy group that may have a halogen atom as a substituent and a lower alkyl group that may have a halogen atom as a substituent; a lower alkoxycarbonyl group; a cycloalkyl lower alkyl group; a pyrrolidinyl lower alkyl group that may have 1 to 3 lower alkyl groups that may have a hydroxyl group as a substituent on the pyrrolidine ring; an amino-substituted lower alkyl group that may have a group selected from the group consisting of a phenyl group and a lower alkyl group as a substituent; a 1,2,3,4-tetrahydronaphthyl-substituted lower alkyl group that may have 1 to 5 lower alkyl groups as a substituent(s) on the 1,2,3,4-tetrahydronaphthalene ring; a naphthyl lower alkyl group; a pyridyl lower alkyl group; a quinolyl lower alkyl group; a 1,2,3,4-tetrazolyl lower alkyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group as a substituent(s) on the tetrazole ring; a 1,2,4-triazolyl lower alkyl group; a tetrahydrofuryl lower alkyl group that may have a hydroxyl group as a substituent on the lower alkyl group; a phenoxy lower alkyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group and a nitro group as a substituent(s) on the phenyl ring; a phenyl lower alkanoyl group; a lower alkanoyl group that may have a halogen atom as a substituent; an imidazolyl lower alkanoyl group; a lower alkoxycarbonyl lower alkyl group; a pyridyl group; or a carboxy lower alkyl group, or a cycloalkyl group; and R20 and R21, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic ring (wherein, on the heterocyclic ring, 1 to 3 substituents may be present, which are selected from the group consisting of a lower alkyl group, a phenyl group that may have 1 to 3 groups selected from the group consisting of a halogen atom and a lower alkyl group that may have a halogen atom as a substituent(s) on the phenyl ring, and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring),

o represents 0 or 1,

B13 represents a lower alkylene group,

R22 and R23 may be identical or different and each represent a hydrogen atom, a lower alkyl group, a benzoyl group that may have 1 to 3 lower alkoxy groups as a substituent(s) on the phenyl ring, a phenoxy lower alkyl group that may have a lower alkyl group as a substituent on the phenyl ring, a phenyl lower alkyl group, or a phenyl group, or R22 and R23, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic ring (wherein, on the heterocyclic ring, 1 to 3 substituents may be present, which are selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring),

B15 represents a lower alkylene group,

s represents 0 or 1,

R26 and R27 may be identical or different and each represent a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, or an imidazolyl lower alkyl group, and R26 and R27, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic ring, (wherein, on the heterocyclic ring, 1 to 3 phenyl lower alkyl groups that may have a lower alkylenedioxy group as a substituent, may be present on the phenyl ring, as a substituent(s)),

R28 represents a hydrogen atom or a lower alkyl group,

B16 represents a lower alkylene group,

R29 and R30, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic group, wherein, on the heterocyclic ring, 1 to 3 substituents may be present, which are selected from the group consisting of a lower alkyl group, a phenyl group, and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring,

R31 represents a hydrogen atom or a lower alkyl group,

B17 represents a lower alkylene group,

R32 and R33, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic group, (wherein, on the heterocyclic ring, 1 to 3 substituents may be present, which are selected from the group consisting of a lower alkyl group, a phenyl group, and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring),

provided that the aforementioned compound or a salt thereof satisfies the following requirements (i) to (v):

(i) when X1 represents a group —CH═, then R3 represents a hydrogen atom;
(ii) when X1 represents a group —CH═, l represents 1, T represents —CO—, and R14 represents a hydrogen atom or an alkyl group that may have a hydroxyl group as a substituent, R15 represents the group (24);
(iii) when X1 represents a group —CH═, l represents 1, and T represents —N(R17)—B3—CO—, R14 and R15, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 10-membered saturated or unsaturated heterocyclic ring, wherein, on the heterocyclic ring, 1 to 3 groups of (28) are present as a substituent(s);
(iv) when X1 represents a nitrogen atom, and l represents 0, or when X1 represents a nitrogen atom, l represents 1, and T represents —CO— or —SO2, R15 is not a group (5), (7), (19), or (20); and
(v) when R6 represents a cycloalkyl group that may have on the cycloalkyl ring, a substituent selected from the group consisting of an amino-substituted lower alkyl group that may have a lower alkyl group and a lower alkyl group that may have a halogen atom as a substituent, R4 represents a group -(T)l-N(R14)R15 (wherein T and l are the same as described above, and R14 and R15, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 10-membered saturated heterocyclic ring; or R14 and R15 form a group




Item 2: The antitumor agent according to item 1, comprising a compound selected from the group consisting of the compounds represented by the general formulas (1-1) to (1-7) below or a salt thereof as an active ingredient:





wherein Y3 represents a lower alkylene group.

Item 3: The antitumor agent according to item 1, comprising a compound selected from the group consisting of the compounds represented by the general formulas (1-8) to (1-14) below or a salt thereof as an active ingredient:





wherein Y3 represents a lower alkylene group.

Item 4: The antitumor agent according to item 1, comprising a compound selected from the group consisting of the compounds represented by the general formulas (1-15) to (1-21) below or a salt thereof as an active ingredient:





wherein Y3 represents a lower alkylene group.

Item 5: The antitumor agent according to item 1, comprising a compound selected from the group consisting of the compounds represented by the general formulas (1-22) to (1-28) below or a salt thereof as an active ingredient:





wherein Y3 represents a lower alkylene group.

Item 6: The antitumor agent according to item 1, comprising a compound selected from the group consisting of the compounds represented by the general formulas (1-29) to (1-35) below or a salt thereof as an active ingredient:





wherein Y3 represents a lower alkylene group.

Item 7: The antitumor agent according to item 1, comprising a compound selected from the group consisting of the compounds represented by the general formulas (1-36) to (1-42) below or a salt thereof as an active ingredient:





wherein Y3 represents a lower alkylene group.

Item 8: The antitumor agent according to item 1, comprising a compound selected from the group consisting of the compounds represented by the general formulas (1-43) to (1-49) below or a salt thereof as an active ingredient:





wherein Y3 represents a lower alkylene group.

Item 9: The antitumor agent according to item 1, comprising a compound selected from the group consisting of the compounds represented by the general formulas (1-50) to (1-56) below or a salt thereof as an active ingredient:





wherein Y3 represents a lower alkylene group.

Item 10: The antitumor agent according to item 1, comprising a compound selected from the group consisting of the compounds represented by the general formulas (1-57) to (1-63) below or a salt thereof as an active ingredient:





wherein Y3 represents a lower alkylene group.

Item 11: the antitumor agent according to item 1, comprising a compound selected from the group consisting of the compounds represented by the general formulas (1-64) to (1-70) below or a salt thereof as an active ingredient:





wherein Y3 represents a lower alkylene group, and Z1 represents a lower alkenylene group.

Item 12: The antitumor agent according to item 1, comprising a compound selected from the group consisting of the compounds represented by the general formulas (1-71) to (1-77) below or a salt thereof as an active ingredient:





wherein Y3 represents a lower alkylene group.

Item 13: The antitumor agent according to item 1, comprising a compound selected from the group consisting of the compounds represented by the general formulas (1-78) to (1-84) below or a salt thereof as an active ingredient:





wherein Y3 represents a lower alkylene group.

Item 14: The antitumor agent according to item 1, comprising a compound selected from the group consisting of the compounds represented by the general formulas (1-85) to (1-91) below or a salt thereof as an active ingredient:





wherein Y3 represents a lower alkylene group.

Item 15: The antitumor agent according to item 1, comprising a compound selected from the group consisting of the compounds represented by the general formulas (1-92) to (1-98) below or a salt thereof as an active ingredient:





wherein Y3 represents a lower alkylene group.

Item 16: The antitumor agent according to item 1, comprising a compound selected from the group consisting of the compounds represented by the general formulas (1-99) to (1-105) below or a salt thereof as an active ingredient:





wherein Y3 represents a lower alkylene group.

Item 17: The antitumor agent according to item 1, comprising a compound selected from the group consisting of the compounds represented by the general formulas (1-106) to (1-112) below or a salt thereof as an active ingredient:





wherein Y3 represents a lower alkylene group.

Item: 18 The antitumor agent according to item 1, comprising a compound selected from the group consisting of the compounds represented by the general formulas (1-113) to (1-119) below or a salt thereof as an active ingredient:





wherein Y3 represents a lower alkylene group.

Item: 19 The antitumor agent according to item 1, comprising a compound selected from the group consisting of the compounds represented by the general formulas (1-120) to (1-126) below or a salt thereof as an active ingredient:





wherein Y3 represents a lower alkylene group, and Z2 represents a lower alkynylene group.

Item: 20 The antitumor agent according to item 1, comprising a compound selected from the group consisting of the compounds represented by the general formulas (1-127) to (1-133) below or a salt thereof as an active ingredient:





wherein Y3 represents a lower alkylene group.

Item: 21 The antitumor agent according to item 1, comprising a compound selected from the group consisting of the compounds represented by the general formulas (1-134) to (1-140) below or a salt thereof as an active ingredient:





wherein Y3 represents a lower alkylene group, and

Z3 represents a lower alkylene group or a group —N(R8d)—.

Item 22: The antitumor agent according to any one of items 1 to 21, wherein Y is a group —O—.

Item 23: The antitumor agent according to any one of items 1 to 21, wherein Y is a group —N(R5)—.

Item 24: The antitumor agent according to any one of items 1 to 21, wherein Y is a group —CO—, a group —CH(OH)—, a lower alkylene group, a group —S(O)n-, or a group —C(═N—OH)—.

Item 25: The antitumor agent according to any one of items 1 to 21, wherein A is a group





Item 26: The antitumor agent according to any one of items 1 to 21, wherein A is a group





Item 27: The antitumor agent according to any one of items 1 to 21, wherein R4 represents an imidazolyl lower alkyl group, a 1,2,4-triazolyl lower alkyl group, a 1,2,3-triazolyl lower alkyl group, a 1,2,5-triazolyl lower alkyl group, a pyrazolyl lower alkyl group, a pyrimidinyl lower alkyl group that may have an oxo group as a substituent on the pyrimidine ring, a 3,5-dioxoisoxazolidin-4-ylidene lower alkyl group, a 1,2,4-oxadiazolyl lower alkyl group that may have a lower alkyl group as a substituent on the 1,2,4-oxadiazole ring, a thiazolidinyl lower alkyl group that may have an oxo group as a substituent on the thiazolidine ring, a group





or a group





Item 28: The antitumor agent according to any one of items 1 to 21, wherein R4 is a group -(T)l-N(R14)R15, and l is 0.

Item 29: The antitumor agent according to any one of items 1 to 21, wherein R4 is a group -(T)l-N(R14)R14R15, and l is 1.
Item 30: The antitumor agent according to any one of items 1 to 21, wherein R4 is a group -(T)l-N(R14)R15, l is 1, and T is a group —N(R17)—B3—CO—.
Item 31: The antitumor agent according to any one of items 1 to 21, wherein R4 is a group -(T)l-N(R14)R15, l is 1, and T is a group —B19—N(R18)—CO—.
Item 32: The antitumor agent according to any one of items 1 to 21, wherein R4 is a group -(T)l-N(R14)R15, l is 1, and T is a group —B4—CO—.
Item 33: The antitumor agent according to any one of items 1 to 21, wherein R4 is a group -(T)l-N(R14)R15, l is 1, and T is a group -Q-B5—CO—.
Item 34: The antitumor agent according to any one of items 1 to 21, wherein R4 is a group -(T)l-N(R14)R15, l is 1, and T is a group —B6—N(R19)—B7—.
Item 35: The antitumor agent according to any one of items 1 to 21, wherein R4 is a group -(T)l-N(R14)R15, l is 1, and T is a group —CO—B8—.
Item 36: The antitumor agent according to any one of Items 1 to 21, wherein R4 is a group -(T)l-N(R14)R15, l is 1, and T is a group —CH(OH)—B9—.
Item 37: The antitumor agent according to any one of items 1 to 21, wherein R4 is a group -(T)l-N(R14)R15, l is 1, and T is a group —CO—B10—CO—.
Item 38: The antitumor agent according to any one of items 1 to 21, wherein R4 is a group -(T)l-N(R14)R15, l is 1, and T is a group —CH(OH)—B11—CO—.
Item 39: The antitumor agent according to any one of items 1 to 21, wherein R4 is a group -(T)l-N(R14)R15, l is 1, and T is a group —CO—.
Item 40: The antitumor agent according to any one of items 1 to 21, wherein R4 is a group -(T)l-N(R14)R15, l is 1, and T is a group —SO2—.
Item 41: The antitumor agent according to any one of items 1 to 21, wherein R4 is a group -(T)l-N(R14)R15, l is 1, and T is a group —B23a—CO—CO—.
Item 42: The antitumor agent according to any one of items 1 to 21, wherein R4 is a group -(T)l-N(R14)R15, l is 1, and T is a lower alkylene group.
Item 43: The antitumor agent according to item 1, comprising a compound selected from the group consisting of the compounds represented by the general formulas (1-1), (1-2), (1-8), (1-9), (1-15), (1-16), (1-29), (1-30), (1-43), (1-44), (1-57), (1-58), (1-64) and (1-65) or a salt thereof as an active ingredient, wherein Y is a group —O— or a group —N(R5)—, A is a group




and

R4 is a group -(T)l-N(R14)R15.

Item 44: The antitumor agent according to item 43, wherein l is 1, and T is a group —N(R7)—B3—CO—.
Item 45: The antitumor agent according to item 43, wherein l is 1, and T is a group —B4—CO—.
Item 46: The antitumor agent according to item 43, wherein l is 1, and T is a group —CO—.
Item 47: The antitumor agent according to item 43, wherein l is 0.
Item 48: The antitumor agent according to item 1, comprising a compound selected from the group consisting of N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-methoxyphenoxy)pyridin-3-yl]-3,4-dichlorobenzamide, N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}phenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-fluorophenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-fluorophenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methoxyphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-methoxyphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-methylphenoxy)pyridin-3-yl]-3,4-dichlorobenzamide, N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, N-(6-{4-[3-(4-piperonylpiperazin-1-yl)-3-oxopropyl]phenoxy}pyridin-3-yl)-3,4-dichlorobenzenesulfonamide, N-[6-(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperazin-1-yl}phenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, N-[6-(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}phenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, N-{6-[(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}phenyl)methylamino]pyridin-3-yl}-4-trifluoromethylbenzamide, N-[6-(4-{4′-[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, N-[6-(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, N-[6-(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}-2-methylphenoxy)pyridin-3-yl]-3,4-dichlorobenzamide, N-{6-[4-(4-benzylpiperazine-1-carbonyl)phenoxy]pyridin-3-yl}-4-trifluoromethylbenzamide, N-{6-[4-(4-benzylpiperazine-1-carbonyl)phenoxy]pyridin-3-yl}-3,4-dichlorobenzamide, N-[6-({4-[3-(4-piperonylpiperazin-1-yl)-3-oxopropyl]phenyl}methylamino)pyridin-3-yl]-4-trifluoromethylbenzamide, N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-fluorophenoxy)pyridin-3-yl]-3,4-dichlorobenzamide, N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-fluorophenoxy)pyridin-3-yl]-3,4-dichlorobenzamide, N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methoxyphenoxy)pyridin-3-yl]-3,4-dichlorobenzamide, N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}phenoxy)pyridin-3-yl]-3,4-dichlorobenzamide, 1-(6-{4-[3-(4-piperonylpiperazin-1-yl)-3-oxopropyl]phenoxy}pyridin-3-yl)-3-(3,4-dichlorophenyl)-1-ethylurea, N-(6-{4-[3-(4-piperonylpiperazin-1-yl)-3-oxopropyl]phenoxy}pyridin-3-yl)-4-trifluoromethylbenzamide, N-[6-(4-{[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylrobenzamide, N-[6-(4-{4-[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}phenoxy)pyridin-3-yl]-3,4-dichlorobenzamide, N-(6-{4-[3-(4-piperonylpiperazine-1-carbonyl)piperidin-1-yl]phenoxy}pyridin-3-yl)-3,4-dichlorobenzamide, N-[6-(4-{4-[2-(4-benzylrupiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}phenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, N-{6-[(4-{4-[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}phenyl)methylamino]pyridin-3-yl}-4-trifluoromethylbenzamide, N-(6-{4-[(2-{4-[4-(4-fluorobenzoyl)phenyl]piperazin-1-yl}-2-oxoethyl)methylamino]-2-methoxyphenoxy}pyridin-3-yl)-4-trifluoromethylbenzamide, 2-(4-piperonylpiperazin-1-yl)-N-{3-methyl-4-[5-(4-trifluoromethylphenoxymethyl)pyridin-2-yloxy]phenyl}-2-oxoacetamide, N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-2-fluoro-4-trifluoromethylbenzamide, N-[6-(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}-2-methoxyphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide and 4-(3-{3-methyl-4-[5-(4-trifluoromethylbenzoylamino)-pyridin-2-yloxy]phenyl}-2-oxohexahydropyrimidin-1-yl)benzoic acid ethyl ester, or a salt thereof as an active ingredient.

Item 49: The antitumor agent according to any one of items 1 to 48, wherein a target of the antitumor agent is a malignant tumor.

Item 50: The antitumor agent according to item 49, wherein the malignant tumor is a solid tumor.

Item 51: The antitumor agent according to item 49, wherein the malignant tumor is a hematological cancer.

Item 52: The antitumor agent according to item 49, wherein the malignant tumor is lymphoma, leukemia, or myeloma.

Item 53: A method for treating or preventing tumor comprising an administration of a compound represented by the general formula (1) below or a salt thereof:





wherein X1 represents a nitrogen atom or a group —CH═,

R1 represents a group —Z—R6,

Z represents a group —N(R8)—B—, a group —B—N(R8)—, a group —B0—O—, a group





a group —CO—, a group —CH(OH)—, a group —N(R9a)—CO—N—(R9b)—, a group —N═CH—, a group —N(R10a)—SO2—(B22a) e-, a lower alkenylene group, a group —NHCO—B1—, a group —NHCO—B2—(W)u-, a group —BO—O—B19a—, a group





a group





a group —SO2—N(R10b)—, a group —S—, a lower alkynylene group, a lower alkylene group, a group —N(R8d)— or a group —CO—NH—B18a—.

R8 represents a hydrogen atom, a lower alkyl group that may have a lower alkoxy group as a substituent, a lower alkanoyl group, a lower alkylsulfonyl group or a phenyl lower alkyl group,

B represents a group —CO— or a lower alkylene group,

B0 represents a lower alkylene group,

B1 represents a lower alkenylene group that may have a phenyl group as a substituent,

B2 represents a lower alkylene group that may be substituted by a group selected from the group consisting of a lower alkoxy group and a phenyl group,

R9a represents a hydrogen atom or a lower alkyl group,

R9b represents a hydrogen atom or a lower alkyl group,

R10a represents a hydrogen atom or a lower alkyl group,

B22a represents a lower alkylene group or a lower alkenylene group,

e represents 0 or 1,

B18a represents a lower alkylene group,

B19a represents a lower alkylene group,

B20a represents a lower alkylene group,

B21a represents a lower alkylene group,

k represents 2 or 3,

c represents 0 or 1,

d′ represents 0 or 1,

R10b represents a hydrogen atom or a lower alkyl group,
R8d represents a hydrogen atom or a lower alkyl group,
W represents an oxygen atom, a group —NH—, or a sulfur atom,
u represents 0 or 1,
R6 represents 5- to 15-membered monocyclic, dicyclic or tricyclic saturated or unsaturated heterocyclic group having 1 to 4 nitrogen atoms, oxygen atoms or sulfur atoms (that may have 1 to 3 substituents, which are selected from the group consisting of an oxo group; a lower alkoxy group that may have a halogen atom as a substituent; a lower alkyl group that may have a halogen atom as a substituent; a halogen atom; a lower alkylsulfonyl group; a phenyl group that may be substituted by a lower alkyl group that may have a halogen atom on the phenyl ring; a lower alkylthio group, a pyrrolyl group, a benzoyl group; a lower alkanoyl group; lower alkoxycarbonyl group; and an amino group that may have a group selected from the group consisting of a lower alkyl group and a lower alkanoyl group as a substituent, on the heterocyclic ring), an adamantly group, a naphthyl group (that may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a halogen atom, and an amino group that may have a group selected from the group consisting of a lower alkyl group and a lower alkanoyl group as a substituent, on the naphthalene ring), an alkyl group that may have a lower alkoxy group as a substituent, a cycloalkyl group that may be substituted by a group selected from the group consisting of an amino substituted lower alkyl group that may have a lower alkyl group and a lower alkyl group that may have a halogen atom as a substituent, on the cycloalkyl ring, a lower alkenyl group that may have a halogen atom as a substituent, a lower alkanoyl group, a benzoyl group (that may have 1 to 3 groups selected from the group consisting of a lower alkyl group that may have a halogen atom and halogen atom, as a substituents, on the phenyl ring), a halogen atom substituted lower alkyl group, cycloalkyl lower alkyl group or a group




R7 represents a hydrogen atom, a phenyl group, a carboxy group, a hydroxyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a phenoxy group, a lower alkoxy group that may have a halogen atom as a substituent, a lower alkylenedioxy group, an amino group that may have, as a substituent, a group selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a benzoyl group, and a cycloalkyl group, a cyano group, a lower alkanoyl group that may have a halogen atom as a substituent, a lower alkylsulfonyl group, an aminosulfonyl group, a lower alkoxycarbonyl group, a lower alkanoyloxy group, a lower alkoxycarbonyl lower alkyl group or a 5- or 6-membered saturated or unsaturated heterocyclic group having 1 to 4 nitrogen atoms, oxygen atoms, or sulfur atoms (that may have an oxo group on the heterocyclic ring),

m represents an integer from 1 to 5 (when m represents 2 to 5, two to five R7s may be identical or different) and

R2 represents a hydrogen atom, a halogen atom, or a lower alkyl group,

Y represents a group —O—, a group —N(R5)—, a group —CO—, a group —CH(OH)—, a lower alkylene group, a group —S(O)n-, or a group —C(═N—OH)—,

R5 represents a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a benzoyl group, a phenyl lower alkyl group, or a cycloalkyl group,

n represents 0, 1, or 2,

A represents a group





or a group





p represents 1 or 2,

R3 represents a hydrogen atom, a lower alkoxy group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxycarbonyl group, a carboxy group, a group —CONR11R12, or a cyano group,

wherein R11 and R12 may be identical or different and each represent a hydrogen atom, a lower alkyl group, a cycloalkyl group, or a phenyl group, and R11 and R12, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic ring,

R4 represents an imidazolyl lower alkyl group, a 1,2,4-triazolyl lower alkyl group, a 1,2,3-triazolyl lower alkyl group, a 1,2,5-triazolyl lower alkyl group, a pyrazolyl lower alkyl group, a pyrimidinyl lower alkyl group that may have an oxo group as a substituent on the pyrimidine ring, a 3,5-dioxoisoxazolidin-4-ylidene lower alkyl group, a 1,2,4-oxadiazolyl lower alkyl group that may have a lower alkyl group as a substituent on the 1,2,4-oxadiazole ring, a thiazolidinyl lower alkyl group that may have an oxo group as a substituent on the thiazolidine ring, a group





a group





or a group -(T)1-N(R14)R15,

R13 represents a hydrogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkanoyl group that may have a halogen atom as a substituent, a lower alkoxycarbonyl group, a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, an imidazolyl lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a carboxy lower alkyl group, a benzoyl group, a morpholino-substituted lower alkanoyl group, a piperazinyl carbonyl lower alkyl group that may be substituted, on the piperazine ring, by a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, a piperazinyl lower alkanoyl group that may be substituted, on the piperazine ring, by a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, a morpholinocarbonyl-substituted lower alkyl group, or an imidazolyl lower alkanoyl group,

R13a represents a hydrogen atom or a hydroxyl group,

T represents a lower alkylene group, a group —N(R17)—B3—CO—, a group —B19—N(R18)—CO—, a group —B4—CO—, a group -Q-B5—CO—, a group —B6—N(R19)—B7—CO—, a group —CO—B8—, a group —CH(OH)—B9—, a group —CO—B10—CO—, a group —CH(OH)—B11—CO—, a group —CO—, a group —SO2—, or a group —B23a—CO—CO—,

wherein R17 represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a cycloalkylcarbonyl group, a lower alkanoyl group that may have a halogen atom as a substituent, a lower alkenyl group, an amino-substituted lower alkanoyl group that may have a lower alkyl group as a substituent, or a lower alkylsulfonyl group,

B3 represents a lower alkylene group,

B19 represents a lower alkylene group,

R18 represents a hydrogen atom or a lower alkyl group,

B4 represents a lower alkenylene group or a lower alkylene group that may have a hydroxyl group as a substituent,

Q represents an oxygen atom or a group —S(O)n- (wherein

n is the same as described above),

B5 represents a lower alkylene group,

B6 represents a lower alkylene group,

R19 represents a hydrogen atom or a lower alkanoyl group,

B7 represents a lower alkylene group,

B8 represents a lower alkylene group,

B9 represents a lower alkylene group,

B10 represents a lower alkylene group,

B11 represents a lower alkylene group,

B23a represents a lower alkylene group,

l represents 0 or 1,

R14 represents a hydrogen atom or an alkyl group that may have a hydroxyl group as a substituent,

R15 represents (2) a hydroxyl group-substituted alkyl group, (3) a cycloalkyl group that may have a group selected from the group consisting of a hydroxyl group and a lower alkyl group as a substituent, (4) a phenoxy lower alkyl group, (5) a phenyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a lower alkyl group; a lower alkoxy group that may have a halogen atom as a substituent; a halogen atom; an amino lower alkoxy group that may have a lower alkyl group as a substituent; a hydroxyl group-substituted lower alkyl group; a phenyl lower alkyl group; a lower alkynyl group; an amino group that may have a lower alkylsulfonyl group as a substituent; a lower alkylthio group; a cycloalkyl group; a phenylthio group; an adamantyl group; an anilino group that may have a halogen atom as a substituent on the phenyl ring; a lower alkoxycarbonyl group; a piperazinyl group that may have a lower alkyl group as a substituent on the piperazine ring; a pyrrolidinyl group that may have an oxo group as a substituent on the pyrrolidine ring; a lower alkanoylamino group; a cyano group; and a phenoxy group, (6) a phenoxy group, (7) a phenyl lower alkyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkoxy group that may have a halogen atom as a substituent, and a lower alkyl group, (8) a phenyl lower alkyl group that has a lower alkylenedioxy group as a substituent on the phenyl ring, (10) a lower alkoxycarbonyl-substituted lower alkyl group, (11) a carboxy-substituted lower alkyl group, (12) an amino group that may have a lower alkanoyl group as a substituent, (13) a 1,2,3,4-tetrahydroquinolyl group that may have 1 to 3 groups selected from the group consisting of an oxo group, a lower alkoxy group, and a lower alkylenedioxy group as a substituent(s) on the tetrahydroquinoline ring, (14) a cycloalkyl lower alkyl group, (15) a piperazinyl lower alkanoyl group that may be substituted, on the piperazine ring, by a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, (16) a pyridyl lower alkyl group, (17) an amino group-substituted lower alkyl group that may have a group selected from the group consisting of a lower alkyl group and a lower alkanoyl group as a substituent, (18) a lower alkoxy lower alkyl group, (19) an imidazolyl group, (20) an imidazolyl lower alkyl group, (21) a 1,2,3,4-tetrahydroisoquinolylcarbonyl-substituted lower alkyl group, (22) a piperidinylcarbonyl group that may have a group selected from the group consisting of a lower alkoxycarbonyl group, a phenyl lower alkyl group, and a furyl lower alkyl group as a substituent on the piperidine ring, (23) a thiazolidinyl lower alkanoyl group that may have an oxo group as a substituent on the thiazolidine ring, (24) a piperidinyl group that may be substituted, on the piperidine ring, by a group selected from the group consisting of a lower alkoxycarbonyl group, a phenyl lower alkyl group, a lower alkyl group, a benzoyl group, and a furyl lower alkyl group, (25) a carbonyl lower alkyl group substituted by a group





(26) a carbonyl lower alkyl group substituted by a group





27) a group —CO—B2O—N(R36)R37, (26a) a pyrrolidinyl lower alkyl group, (27a) a morpholino lower alkyl group, (28a) a phenyl lower alkenyl group, (29a) an anilinocarbonyl lower alkyl group that may have a lower alkyl group as a substituent on the phenyl ring, (30a) an indolyl group, (31a) a piperazinyl lower alkyl group that may have, as a substituent on the piperazine ring, a group selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, (32a) an amidino lower alkyl group that may have a lower alkyl group as a substituent, (33a) a fluorenyl group, (34a) a carbazolyl group that may have a lower alkyl group as a substituent on the carbazole ring, (35a) an amidino group that may have a lower alkyl group as a substituent, (36a) a piperazinyl-substituted oxalyl group that may have 1 to 3 groups selected from the group consisting of a phenyl lower alkyl group (that may have 1 to 3 groups selected from the group consisting of a lower alkylenedioxy group and a lower alkoxy group as a substituent(s) on the phenyl ring) and a pyridyl lower alkyl group as a substituent(s) on the piperazine ring, or (37a) a cyano-substituted lower alkyl group,

R34 represents an oxo group or a phenyl group,

d represents an integer from 0 to 3,

B20 represents a lower alkylene group,

R36 and R37, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic group, wherein, on the heterocyclic ring, 1 to 3 phenyl lower alkyl groups that may have a lower alkylenedioxy group on the phenyl ring, may be present as a substituent(s),

R14 and R15, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 10-membered saturated or unsaturated heterocyclic ring; or a group





wherein, on the heterocyclic ring, 1 to 3 substituents may be present which are selected from the group consisting of (28) a phenyl-substituted lower alkyl group, which has 1 to 2 phenyl groups that may be substituted by 1 to 3 groups on the phenyl ring, selected from the group consisting of a lower alkanoyl group, an amino group that may have a lower alkanoyl group as a substituent, a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxy group that may have a halogen atom as a substituent, a phenyl lower alkoxy group, a hydroxyl group, and a lower alkylenedioxy group, and that may have a pyridyl group on the lower alkyl group, (29) a carbamoyl group, (30) a pyridyl lower alkyl group that may have, as a substituent(s) on the pyridine ring, 1 to 3 groups selected from the group consisting of a hydroxyl group and a lower alkyl group that may have a hydroxyl group as a substituent, (31) a pyrrolyl lower alkyl group that may have 1 to 3 lower alkyl groups as a substituent(s) on the pyrrole ring, (32) a benzoxazolyl lower alkyl group, (33) a benzothiazolyl lower alkyl group, (34) a furyl lower alkyl group, (35) a benzoyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a cyano group, an amino group that may have a lower alkylsulfonyl group as a substituent, a halogen atom, a lower alkoxy group, a lower alkyl group that may have a halogen atom as a substituent, a thiazolidinyl lower alkyl group that may have an oxo group as a substituent on the thiazolidine ring, a thiazolidinylidene lower alkyl group that may have an oxo group as a substituent on the thiazolidine ring, and a lower alkylenedioxy group, (36) a pyrimidinyl group, (37) a pyrazinyl group, (38) a pyridyl group, (39) a lower alkoxycarbonyl group, (40) a thiazolidinyl lower alkanoyl group that may be substituted, on the thiazolidine ring, by a group selected from the group consisting of an oxo group and a group





(wherein Ra and Rb each represent a lower alkyl group), (41) a lower alkyl group that may have a group selected from the group consisting of a hydroxyl group and a halogen atom as a substituent, (42) a lower alkanoyl group that may have a halogen atom as a substituent, (43) a phenyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a carbamoyl group that may have a group selected from the group consisting of a lower alkoxy lower alkyl group and a lower alkyl group, a lower alkoxycarbonyl group, a carboxy group, a cyano group, a phenyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxy group that may have a halogen atom as a substituent, a benzoyl group that may have a halogen atom as a substituent on the phenyl ring, a phenyl lower alkyl group that may have a halogen atom as a substituent on the phenyl ring, and a hydroxyl group, (44) a phenyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, (45) a naphthyl lower alkyl group, (46) a phenoxy group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a cyano group, a lower alkyl group that may have a halogen atom as a substituent, and a lower alkoxy group that may have a halogen atom as a substituent, (47) a phenoxy lower alkyl group, (48) a phenyl lower alkoxy group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, and a lower alkoxy group that may have a halogen atom as a substituent, (49) a group —(B12CO)t-N(R20)R21, (50) a group —(CO)o-B13—N(R22)R22, (51) a 1,2,3,4-tetrahydronaphthyl-substituted lower alkyl group that may be substituted, on the 1,2,3,4-tetrahydronaphthalene ring, by 1 to 5 lower alkyl groups as a substituent(s), (52) a cycloalkyl group that may have a hydroxyl group as a substituent, (53) a piperidinyl group that may be substituted, on the piperidine ring, by 1 to 3 lower alkyl groups as a substituent(s), (54) a quinolyl lower alkyl group, (55) a 1,2,3,4-tetrazolyl lower alkyl group that may have a group selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group as a substituent on the tetrazole ring, (56) a thiazolyl lower alkyl group that may have a phenyl group as a substituent on the thiazole ring, (57) a benzoyl lower alkyl group that may have 1 to 3 groups selected from the group consisting of a lower alkoxy group and a halogen atom as a substituent(s) on the phenyl ring, (58) a piperidinyl lower alkyl group that may have a lower alkyl group as a substituent on the piperidine ring, (59) an imidazolyl group that may have 1 to 3 phenyl groups as a substituent(s) on the imidazole ring, (60) a benzimidazolyl group that may have 1 to 3 lower alkyl groups as a substituent(s) on the benzimidazole ring, (61) a pyridyl lower alkoxy group, (62) a 1,2,3,4-tetrahydroquinolyl lower alkyl group that may have an oxo group as a substituent on the tetrahydroquinoline ring, (63) a 1,3,4-oxadiazolyl lower alkyl group that may have an oxo group as a substituent on the 1,3,4-oxadizole ring, (64) a cycloalkyl lower alkyl group, (65) a tetrahydropyranyl group, (66) a thienyl lower alkyl group, (67) a pyrimidinylcarbonyl group that may have an oxo group as a substituent on the pyrimidine ring, (68) a hydroxyl group, (69) a carboxy group, (70) a lower alkoxy lower alkyl group, (71) a lower alkoxy lower alkoxy group, (72) a benzoyloxy group, (73) a lower alkoxycarbonyl lower alkoxy group, (74) a carboxy lower alkoxy group, (75) a phenoxy lower alkanoyl group, (76) a 1,2,3,4-tetrahydroquinolylcarbonyl group that may have an oxo group as a substituent on the tetrahydroquinoline ring, (77) a phenylsulfonyl group, (78) an imidazolyl lower alkanoyl group, (79) an imidazolyl lower alkyl group, (80) a pyridylcarbonyl group, (81) an imidazolylcarbonyl group, (82) a lower alkoxycarbonyl lower alkyl group, (83) a carboxy lower alkyl group, (84) a group —(O—B15)s-CO—N(R26)R27, (85) a group —N(R28)—CO—B16—N(R29)R30, (86) a group —N(R31)—B17—CO—N(R32)R33, (87) a benzoxazolyl group, (88a) a benzothienyl group, (89a) an oxo group, and (90a) a 1,2,3,4-tetrahydroquinolyl group that may have an oxo group as a substituent on the tetrahydroquinoline ring,

B12 represents a lower alkylene group,

t represents 0 or 1,

R20 and R21 may be identical or different and each represent a hydrogen atom; an amino group that may have a lower alkoxycarbonyl group as a substituent; a benzoyl group that may have 1 to 3 lower alkoxy groups as a substituent(s) on the phenyl ring; a lower alkyl group; a lower alkyl group having 1 to 2 phenyl groups that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxy group that may have a halogen atom as a substituent, and a lower alkylthio group; a phenyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a lower alkoxy group that may have a halogen atom as a substituent and a lower alkyl group that may have a halogen atom as a substituent; a lower alkoxycarbonyl group; a cycloalkyl lower alkyl group; a pyrrolidinyl lower alkyl group that may have 1 to 3 lower alkyl groups that may have a hydroxyl group as a substituent on the pyrrolidine ring; an amino-substituted lower alkyl group that may have a group selected from the group consisting of a phenyl group and a lower alkyl group as a substituent; a 1,2,3,4-tetrahydronaphthyl-substituted lower alkyl group that may have 1 to 5 lower alkyl groups as a substituent(s) on the 1,2,3,4-tetrahydronaphthalene ring; a naphthyl lower alkyl group; a pyridyl lower alkyl group; a quinolyl lower alkyl group; a 1,2,3,4-tetrazolyl lower alkyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group as a substituent(s) on the tetrazole ring; a 1,2,4-triazolyl lower alkyl group; a tetrahydrofuryl lower alkyl group that may have a hydroxyl group as a substituent on the lower alkyl group; a phenoxy lower alkyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group and a nitro group as a substituent(s) on the phenyl ring; a phenyl lower alkanoyl group; a lower alkanoyl group that may have a halogen atom as a substituent; an imidazolyl lower alkanoyl group; a lower alkoxycarbonyl lower alkyl group; a pyridyl group; or a carboxy lower alkyl group, or a cycloalkyl group; and R20 and R21, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic ring (wherein, on the heterocyclic ring, 1 to 3 substituents may be present, which are selected from the group consisting of a lower alkyl group, a phenyl group that may have 1 to 3 groups selected from the group consisting of a halogen atom and a lower alkyl group that may have a halogen atom as a substituent(s) on the phenyl ring, and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring),

o represents 0 or 1,

B13 represents a lower alkylene group,

R22 and R23 may be identical or different and each represent a hydrogen atom, a lower alkyl group, a benzoyl group that may have 1 to 3 lower alkoxy groups as a substituent(s) on the phenyl ring, a phenoxy lower alkyl group that may have a lower alkyl group as a substituent on the phenyl ring, a phenyl lower alkyl group, or a phenyl group, or R22 and R23, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic ring (wherein, on the heterocyclic ring, 1 to 3 substituents may be present, which are selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring),

B15 represents a lower alkylene group,

s represents 0 or 1,

R26 and R27 may be identical or different and each represent a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, or an imidazolyl lower alkyl group, and R26 and R27, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic ring, (wherein, on the heterocyclic ring, 1 to 3 phenyl lower alkyl groups that may have a lower alkylenedioxy group as a substituent, may be present on the phenyl ring, as a substituent(s)),

R27 represents a hydrogen atom or a lower alkyl group,

B16 represents a lower alkylene group,

R29 and R30, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic group, wherein, on the heterocyclic ring, 1 to 3 substituents may be present, which are selected from the group consisting of a lower alkyl group, a phenyl group, and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring,

R31 represents a hydrogen atom or a lower alkyl group,

B17 represents a lower alkylene group,

R32 and R33, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic group, (wherein, on the heterocyclic ring, 1 to 3 substituents may be present, which are selected from the group consisting of a lower alkyl group, a phenyl group, and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring),

provided that the aforementioned compound or a salt thereof satisfies the following requirements (i) to (v):

(i) when X1 represents a group —CH═, then R3 represents a hydrogen atom;
(ii) when X1 represents a group —CH═, l represents 1, T represents —CO—, and R14 represents a hydrogen atom or an alkyl group that may have a hydroxyl group as a substituent, R15 represents the group (24);
(iii) when X1 represents a group —CH═, l represents 1, and T represents —N(R17)—B3—CO—, R14 and R15, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 10-membered saturated or unsaturated heterocyclic ring, wherein, on the heterocyclic ring, 1 to 3 groups of (28) are present as a substituent(s);
(iv) when X1 represents a nitrogen atom, and l represents 0, or when X1 represents a nitrogen atom, l represents 1, and T represents —CO— or —SO2, R15 is not a group (5), (7), (19), or (20); and
(v) when R6 represents a cycloalkyl group that may have on the cycloalkyl ring, a substituent selected from the group consisting of an amino-substituted lower alkyl group that may have a lower alkyl group and a lower alkyl group that may have a halogen atom as a substituent, R4 represents a group -(T)l-N(R14)R15 (wherein T and l are the same as described above, and R14 and R15, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 10-membered saturated heterocyclic ring; or R14 and R15 form a group




Item 54: Use of a compound represented by the general formula (1) below or a salt thereof for manufacturing an antitumor agent:





wherein X1 represents a nitrogen atom or a group —CH═,

R1 represents a group —Z—R6,

Z represents a group —N(R8)—B—, a group —B—N(R8)—, a group —B0—O—, a group





a group —CO—, a group —CH(OH)—, a group —N(R9a)—CO—N—(R9b)—, a group —N═CH—, a group —N(R10a)—SO2—(B22a)e-, a lower alkenylene group, a group —NHCO—B1—, a group —NHCO—B2—(W)u-, a group —BO—O—B19a—, a group





a group





a group —SO2—N(R10b)—, a group —S—, a lower alkynylene group, a lower alkylene group, a group —N(R8d)— or a group —CO—NH—B18a—.

R8 represents a hydrogen atom, a lower alkyl group that may have a lower alkoxy group as a substituent, a lower alkanoyl group, a lower alkylsulfonyl group or a phenyl lower alkyl group,

B represents a group —CO— or a lower alkylene group,

B0 represents a lower alkylene group,

B1 represents a lower alkenylene group that may have a phenyl group as a substituent,

B2 represents a lower alkylene group that may be substituted by a group selected from the group consisting of a lower alkoxy group and a phenyl group,

R9a represents a hydrogen atom or a lower alkyl group,

R9b represents a hydrogen atom or a lower alkyl group,

R10a represents a hydrogen atom or a lower alkyl group,

B22a represents a lower alkylene group or a lower alkenylene group,

e represents 0 or 1,

B18a represents a lower alkylene group,

B19a represents a lower alkylene group,

B20a represents a lower alkylene group,

B21a represents a lower alkylene group,

k represents 2 or 3,

c represents 0 or 1,

d′ represents 0 or 1,

R10b represents a hydrogen atom or a lower alkyl group,

R8d represents a hydrogen atom or a lower alkyl group,

W represents an oxygen atom, a group —NH—, or a sulfur atom,

u represents 0 or 1,

R6 represents 5- to 15-membered monocyclic, dicyclic or tricyclic saturated or unsaturated heterocyclic group having 1 to 4 nitrogen atoms, oxygen atoms or sulfur atoms (that may have 1 to 3 substituents, which are selected from the group consisting of an oxo group; a lower alkoxy group that may have a halogen atom as a substituent; a lower alkyl group that may have a halogen atom as a substituent; a halogen atom; a lower alkylsulfonyl group; a phenyl group that may be substituted by a lower alkyl group that may have a halogen atom on the phenyl ring; a lower alkylthio group, a pyrrolyl group, a benzoyl group; a lower alkanoyl group; lower alkoxycarbonyl group; and an amino group that may have a group selected from the group consisting of a lower alkyl group and a lower alkanoyl group as a substituent, on the heterocyclic ring), an adamantly group, a naphthyl group (that may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a halogen atom, and an amino group that may have a group selected from the group consisting of a lower alkyl group and a lower alkanoyl group as a substituent, on the naphthalene ring), an alkyl group that may have a lower alkoxy group as a substituent, a cycloalkyl group that may be substituted by a group selected from the group consisting of an amino substituted lower alkyl group that may have a lower alkyl group and a lower alkyl group that may have a halogen atom as a substituent, on the cycloalkyl ring, a lower alkenyl group that may have a halogen atom as a substituent, a lower alkanoyl group, a benzoyl group (that may have 1 to 3 groups selected from the group consisting of a lower alkyl group that may have a halogen atom and halogen atom, as a substituents, on the phenyl ring), a halogen atom substituted lower alkyl group, cycloalkyl lower alkyl group or a group





R7 represents a hydrogen atom, a phenyl group, a carboxy group, a hydroxyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a phenoxy group, a lower alkoxy group that may have a halogen atom as a substituent, a lower alkylenedioxy group, an amino group that may have, as a substituent, a group selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a benzoyl group, and a cycloalkyl group, a cyano group, a lower alkanoyl group that may have a halogen atom as a substituent, a lower alkylsulfonyl group, an aminosulfonyl group, a lower alkoxycarbonyl group, a lower alkanoyloxy group, a lower alkoxycarbonyl lower alkyl group or a 5- or 6-membered saturated or unsaturated heterocyclic group having 1 to 4 nitrogen atoms, oxygen atoms, or sulfur atoms (that may have an oxo group on the heterocyclic ring),

m represents an integer from 1 to 5 (when m represents 2 to 5, two to five R7s may be identical or different) and

R2 represents a hydrogen atom, a halogen atom, or a lower alkyl group,

Y represents a group —O—, a group —N(R5)—, a group —CO—, a group —CH(OH)—, a lower alkylene group, a group —S(O)n-, or a group —C(═N—OH)—,

R5 represents a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a benzoyl group, a phenyl lower alkyl group, or a cycloalkyl group,

n represents 0, 1, or 2,

A represents a group





or a group





p represents 1 or 2,

R3 represents a hydrogen atom, a lower alkoxy group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxycarbonyl group, a carboxy group, a group —CONR11R12, or a cyano group,

wherein R11 and R12 may be identical or different and each represent a hydrogen atom, a lower alkyl group, a cycloalkyl group, or a phenyl group, and R11 and R12, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic ring,

R4 represents an imidazolyl lower alkyl group, a 1,2,4-triazolyl lower alkyl group, a 1,2,3-triazolyl lower alkyl group, a 1,2,5-triazolyl lower alkyl group, a pyrazolyl lower alkyl group, a pyrimidinyl lower alkyl group that may have an oxo group as a substituent on the pyrimidine ring, a 3,5-dioxoisoxazolidin-4-ylidene lower alkyl group, a 1,2,4-oxadiazolyl lower alkyl group that may have a lower alkyl group as a substituent on the 1,2,4-oxadiazole ring, a thiazolidinyl lower alkyl group that may have an oxo group as a substituent on the thiazolidine ring, a group





a group





or a group -(T)l-N(R14)R15,

R13 represents a hydrogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkanoyl group that may have a halogen atom as a substituent, a lower alkoxycarbonyl group, a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, an imidazolyl lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a carboxy lower alkyl group, a benzoyl group, a morpholino-substituted lower alkanoyl group, a piperazinyl carbonyl lower alkyl group that may be substituted, on the piperazine ring, by a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, a piperazinyl lower alkanoyl group that may be substituted, on the piperazine ring, by a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, a morpholinocarbonyl-substituted lower alkyl group, or an imidazolyl lower alkanoyl group,

R13a represents a hydrogen atom or a hydroxyl group,

T represents a lower alkylene group, a group —N(R17)—B3—CO—, a group —B19—N(R18)—CO—, a group —B4—CO—, a group Q-B5—CO—, a group —B6—N(R19)—B7—CO—, a group —CO—B8—, a group —CH(OH)—B9—, a group —CO—B10—CO—, a group —CH(OH)—B11—CO—, a group —CO—, a group —SO2—, or a group —B23a—CO—CO—,

wherein R17 represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a cycloalkylcarbonyl group, a lower alkanoyl group that may have a halogen atom as a substituent, a lower alkenyl group, an amino-substituted lower alkanoyl group that may have a lower alkyl group as a substituent, or a lower alkylsulfonyl group,

B3 represents a lower alkylene group,

B19 represents a lower alkylene group,

R18 represents a hydrogen atom or a lower alkyl group,

B4 represents a lower alkenylene group or a lower alkylene group that may have a hydroxyl group as a substituent,

Q represents an oxygen atom or a group —S(O)n- (wherein

n is the same as described above),

B5 represents a lower alkylene group,

B6 represents a lower alkylene group,

R19 represents a hydrogen atom or a lower alkanoyl group,

B7 represents a lower alkylene group,

B8 represents a lower alkylene group,

B9 represents a lower alkylene group,

B10 represents a lower alkylene group,

B11 represents a lower alkylene group,

B23a represents a lower alkylene group,

l represents 0 or 1,

R14 represents a hydrogen atom or an alkyl group that may have a hydroxyl group as a substituent,

R15 represents (2) a hydroxyl group-substituted alkyl group, (3) a cycloalkyl group that may have a group selected from the group consisting of a hydroxyl group and a lower alkyl group as a substituent, (4) a phenoxy lower alkyl group, (5) a phenyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a lower alkyl group; a lower alkoxy group that may have a halogen atom as a substituent; a halogen atom; an amino lower alkoxy group that may have a lower alkyl group as a substituent; a hydroxyl group-substituted lower alkyl group; a phenyl lower alkyl group; a lower alkynyl group; an amino group that may have a lower alkylsulfonyl group as a substituent; a lower alkylthio group; a cycloalkyl group; a phenylthio group; an adamantyl group; an anilino group that may have a halogen atom as a substituent on the phenyl ring; a lower alkoxycarbonyl group; a piperazinyl group that may have a lower alkyl group as a substituent on the piperazine ring; a pyrrolidinyl group that may have an oxo group as a substituent on the pyrrolidine ring; a lower alkanoylamino group; a cyano group; and a phenoxy group, (6) a phenoxy group, (7) a phenyl lower alkyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkoxy group that may have a halogen atom as a substituent, and a lower alkyl group, (8) a phenyl lower alkyl group that has a lower alkylenedioxy group as a substituent on the phenyl ring, (10) a lower alkoxycarbonyl-substituted lower alkyl group, (11) a carboxy-substituted lower alkyl group, (12) an amino group that may have a lower alkanoyl group as a substituent, (13) a 1,2,3,4-tetrahydroquinolyl group that may have 1 to 3 groups selected from the group consisting of an oxo group, a lower alkoxy group, and a lower alkylenedioxy group as a substituent(s) on the tetrahydroquinoline ring, (14) a cycloalkyl lower alkyl group, (15) a piperazinyl lower alkanoyl group that may be substituted, on the piperazine ring, by a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, (16) a pyridyl lower alkyl group, (17) an amino group-substituted lower alkyl group that may have a group selected from the group consisting of a lower alkyl group and a lower alkanoyl group as a substituent, (18) a lower alkoxy lower alkyl group, (19) an imidazolyl group, (20) an imidazolyl lower alkyl group, (21) a 1,2,3,4-tetrahydroisoquinolylcarbonyl-substituted lower alkyl group, (22) a piperidinylcarbonyl group that may have a group selected from the group consisting of a lower alkoxycarbonyl group, a phenyl lower alkyl group, and a furyl lower alkyl group as a substituent on the piperidine ring, (23) a thiazolidinyl lower alkanoyl group that may have an oxo group as a substituent on the thiazolidine ring, (24) a piperidinyl group that may be substituted, on the piperidine ring, by a group selected from the group consisting of a lower alkoxycarbonyl group, a phenyl lower alkyl group, a lower alkyl group, a benzoyl group, and a furyl lower alkyl group, (25) a carbonyl lower alkyl group substituted by a group





(26) a carbonyl lower alkyl group substituted by a group





27) a group —CO—B20—N(R36)R37, (26a) a pyrrolidinyl lower alkyl group, (27a) a morpholino lower alkyl group, (28a) a phenyl lower alkenyl group, (29a) an anilinocarbonyl lower alkyl group that may have a lower alkyl group as a substituent on the phenyl ring, (30a) an indolyl group, (31a) a piperazinyl lower alkyl group that may have, as a substituent on the piperazine ring, a group selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, (32a) an amidino lower alkyl group that may have a lower alkyl group as a substituent, (33a) a fluorenyl group, (34a) a carbazolyl group that may have a lower alkyl group as a substituent on the carbazole ring, (35a) an amidino group that may have a lower alkyl group as a substituent, (36a) a piperazinyl-substituted oxalyl group that may have 1 to 3 groups selected from the group consisting of a phenyl lower alkyl group (that may have 1 to 3 groups selected from the group consisting of a lower alkylenedioxy group and a lower alkoxy group as a substituent(s) on the phenyl ring) and a pyridyl lower alkyl group as a substituent(s) on the piperazine ring, or (37a) a cyano-substituted lower alkyl group,

R34 represents an Oxo group or a phenyl group,

d represents an integer from 0 to 3,

B20 represents a lower alkylene group,

R36 and R37, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic group, wherein, on the heterocyclic ring, 1 to 3 phenyl lower alkyl groups that may have a lower alkylenedioxy group on the phenyl ring, may be present as a substituent(s),

R14 and R15, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 10-membered saturated or unsaturated heterocyclic ring; or a group





wherein, on the heterocyclic ring, 1 to 3 substituents may be present which are selected from the group consisting of (28) a phenyl-substituted lower alkyl group, which has 1 to 2 phenyl groups that may be substituted by 1 to 3 groups on the phenyl ring, selected from the group consisting of a lower alkanoyl group, an amino group that may have a lower alkanoyl group as a substituent, a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxy group that may have a halogen atom as a substituent, a phenyl lower alkoxy group, a hydroxyl group, and a lower alkylenedioxy group, and that may have a pyridyl group on the lower alkyl group, (29) a carbamoyl group, (30) a pyridyl lower alkyl group that may have, as a substituent(s) on the pyridine ring, 1 to 3 groups selected from the group consisting of a hydroxyl group and a lower alkyl group that may have a hydroxyl group as a substituent, (31) a pyrrolyl lower alkyl group that may have 1 to 3 lower alkyl groups as a substituent(s) on the pyrrole ring, (32) a benzoxazolyl lower alkyl group, (33) a benzothiazolyl lower alkyl group, (34) a furyl lower alkyl group, (35) a benzoyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a cyano group, an amino group that may have a lower alkylsulfonyl group as a substituent, a halogen atom, a lower alkoxy group, a lower alkyl group that may have a halogen atom as a substituent, a thiazolidinyl lower alkyl group that may have an oxo group as a substituent on the thiazolidine ring, a thiazolidinylidene lower alkyl group that may have an oxo group as a substituent on the thiazolidine ring, and a lower alkylenedioxy group, (36) a pyrimidinyl group, (37) a pyrazinyl group, (38) a pyridyl group, (39) a lower alkoxycarbonyl group, (40) a thiazolidinyl lower alkanoyl group that may be substituted, on the thiazolidine ring, by a group selected from the group consisting of an oxo group and a group





(wherein Ra and Rb each represent a lower alkyl group), (41) a lower alkyl group that may have a group selected from the group consisting of a hydroxyl group and a halogen atom as a substituent, (42) a lower alkanoyl group that may have a halogen atom as a substituent, (43) a phenyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a carbamoyl group that may have a group selected from the group consisting of a lower alkoxy lower alkyl group and a lower alkyl group, a lower alkoxycarbonyl group, a carboxy group, a cyano group, a phenyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxy group that may have a halogen atom as a substituent, a benzoyl group that may have a halogen atom as a substituent on the phenyl ring, a phenyl lower alkyl group that may have a halogen atom as a substituent on the phenyl ring, and a hydroxyl group, (44) a phenyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, (45) a naphthyl lower alkyl group, (46) a phenoxy group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a cyano group, a lower alkyl group that may have a halogen atom as a substituent, and a lower alkoxy group that may have a halogen atom as a substituent, (47) a phenoxy lower alkyl group, (48) a phenyl lower alkoxy group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, and a lower alkoxy group that may have a halogen atom as a substituent, (49) a group —(B12CO)t-N(R20)R21, (50) a group —(CO)o-B13—N(R22)R23, (51) a 1,2,3,4-tetrahydronaphthyl-substituted lower alkyl group that may be substituted, on the 1,2,3,4-tetrahydronaphthalene ring, by 1 to 5 lower alkyl groups as a substituent(s), (52) a cycloalkyl group that may have a hydroxyl group as a substituent, (53) a piperidinyl group that may be substituted, on the piperidine ring, by 1 to 3 lower alkyl groups as a substituent(s), (54) a quinolyl lower alkyl group, (55) a 1,2,3,4-tetrazolyl lower alkyl group that may have a group selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group as a substituent on the tetrazole ring, (56) a thiazolyl lower alkyl group that may have a phenyl group as a substituent on the thiazole ring, (57) a benzoyl lower alkyl group that may have 1 to 3 groups selected from the group consisting of a lower alkoxy group and a halogen atom as a substituent(s) on the phenyl ring, (58) a piperidinyl lower alkyl group that may have a lower alkyl group as a substituent on the piperidine ring, (59) an imidazolyl group that may have 1 to 3 phenyl groups as a substituent(s) on the imidazole ring, (60) a benzimidazolyl group that may have 1 to 3 lower alkyl groups as a substituent(s) on the benzimidazole ring, (61) a pyridyl lower alkoxy group, (62) a 1,2,3,4-tetrahydroquinolyl lower alkyl group that may have an oxo group as a substituent on the tetrahydroquinoline ring, (63) a 1,3,4-oxadiazolyl lower alkyl group that may have an oxo group as a substituent on the 1,3,4-oxadizole ring, (64) a cycloalkyl lower alkyl group, (65) a tetrahydropyranyl group, (66) a thienyl lower alkyl group, (67) a pyrimidinylcarbonyl group that may have an oxo group as a substituent on the pyrimidine ring, (68) a hydroxyl group, (69) a carboxy group, (70) a lower alkoxy lower alkyl group, (71) a lower alkoxy lower alkoxy group, (72) a benzoyloxy group, (73) a lower alkoxycarbonyl lower alkoxy group, (74) a carboxy lower alkoxy group, (75) a phenoxy lower alkanoyl group, (76) a 1,2,3,4-tetrahydroquinolylcarbonyl group that may have an oxo group as a substituent on the tetrahydroquinoline ring, (77) a phenylsulfonyl group, (78) an imidazolyl lower alkanoyl group, (79) an imidazolyl lower alkyl group, (80) a pyridylcarbonyl group, (81) an imidazolylcarbonyl group, (82) a lower alkoxycarbonyl lower alkyl group, (83) a carboxy lower alkyl group, (84) a group —(O—B15)s-CO—N(R26)R27, (85) a group —N(R28)—CO—B16—N(R29)R30, (86) a group —N(R31)—B17—CO—N(R32)R33, (87) a benzoxazolyl group, (88a) a benzothienyl group, (89a) an oxo group, and (90a) a 1,2,3,4-tetrahydroquinolyl group that may have an oxo group as a substituent on the tetrahydroquinoline ring,

B12 represents a lower alkylene group,

t represents 0 or 1,

R20 and R21 may be identical or different and each represent a hydrogen atom; an amino group that may have a lower alkoxycarbonyl group as a substituent; a benzoyl group that may have 1 to 3 lower alkoxy groups as a substituent(s) on the phenyl ring; a lower alkyl group; a lower alkyl group having 1 to 2 phenyl groups that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxy group that may have a halogen atom as a substituent, and a lower alkylthio group; a phenyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a lower alkoxy group that may have a halogen atom as a substituent and a lower alkyl group that may have a halogen atom as a substituent; a lower alkoxycarbonyl group; a cycloalkyl lower alkyl group; a pyrrolidinyl lower alkyl group that may have 1 to 3 lower alkyl groups that may have a hydroxyl group as a substituent on the pyrrolidine ring; an amino-substituted lower alkyl group that may have a group selected from the group consisting of a phenyl group and a lower alkyl group as a substituent; a 1,2,3,4-tetrahydronaphthyl-substituted lower alkyl group that may have 1 to 5 lower alkyl groups as a substituent(s) on the 1,2,3,4-tetrahydronaphthalene ring; a naphthyl lower alkyl group; a pyridyl lower alkyl group; a quinolyl lower alkyl group; a 1,2,3,4-tetrazolyl lower alkyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group as a substituent(s) on the tetrazole ring; a 1,2,4-triazolyl lower alkyl group; a tetrahydrofuryl lower alkyl group that may have a hydroxyl group as a substituent on the lower alkyl group; a phenoxy lower alkyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group and a nitro group as a substituent(s) on the phenyl ring; a phenyl lower alkanoyl group; a lower alkanoyl group that may have a halogen atom as a substituent; an imidazolyl lower alkanoyl group; a lower alkoxycarbonyl lower alkyl group; a pyridyl group; or a carboxy lower alkyl group, or a cycloalkyl group; and R20 and R21, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic ring (wherein, on the heterocyclic ring, 1 to 3 substituents may be present, which are selected from the group consisting of a lower alkyl group, a phenyl group that may have 1 to 3 groups selected from the group consisting of a halogen atom and a lower alkyl group that may have a halogen atom as a substituent(s) on the phenyl ring, and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring),

o represents 0 or 1,

B13 represents a lower alkylene group,

R22 and R23 may be identical or different and each represent a hydrogen atom, a lower alkyl group, a benzoyl group that may have 1 to 3 lower alkoxy groups as a substituent(s) on the phenyl ring, a phenoxy lower alkyl group that may have a lower alkyl group as a substituent on the phenyl ring, a phenyl lower alkyl group, or a phenyl group, or R22 and R23, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic ring (wherein, on the heterocyclic ring, 1 to 3 substituents may be present, which are selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring),

B15 represents a lower alkylene group,

s represents 0 or 1,

R26 and R27 may be identical or different and each represent a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, or an imidazolyl lower alkyl group, and R26 and R27, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic ring, (wherein, on the heterocyclic ring, 1 to 3 phenyl lower alkyl groups that may have a lower alkylenedioxy group as a substituent, may be present on the phenyl ring, as a substituent(s)),

R28 represents a hydrogen atom or a lower alkyl group,

B16 represents a lower alkylene group,

R29 and R30, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic group, wherein, on the heterocyclic ring, 1 to 3 substituents may be present, which are selected from the group consisting of a lower alkyl group, a phenyl group, and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring,

R31 represents a hydrogen atom or a lower alkyl group,

B17 represents a lower alkylene group,

R32 and R33, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic group, (wherein, on the heterocyclic ring, 1 to 3 substituents may be present, which are selected from the group consisting of a lower alkyl group, a phenyl group, and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring), provided that the aforementioned compound or a salt thereof satisfies the following requirements (i) to (v):

(i) when X1 represents a group —CH═, then R3 represents a hydrogen atom;
(ii) when X1 represents a group —CH═, l represents 1, T represents —CO—, and R14 represents a hydrogen atom or an alkyl group that may have a hydroxyl group as a substituent, R15 represents the group (24);
(iii) when X1 represents a group —CH═, l represents 1, and T represents —N(R17)—B3—CO—, R14 and R15, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 10-membered saturated or unsaturated heterocyclic ring, wherein, on the heterocyclic ring, 1 to 3 groups of (28) are present as a substituent(s);
(iv) when X1 represents a nitrogen atom, and l represents 0, or when X1 represents a nitrogen atom, l represents 1, and T represents —CO— or —SO2, R15 is not a group (5), (7), (19), or (20); and
(v) when R6 represents a cycloalkyl group that may have on the cycloalkyl ring, a substituent selected from the group consisting of an amino-substituted lower alkyl group that may have a lower alkyl group and a lower alkyl group that may have a halogen atom as a substituent, R4 represents a group -(T)l-N(R14)R15 (wherein T and l are the same as described above, and R14 and R15, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 10-membered saturated heterocyclic ring; or R14 and R15 form a group




Item 55: The use according to item 54, wherein a target of the antitumor agent is a malignant tumor.

Item 56: The use according to item 55, wherein the malignant tumor is a solid tumor.

Item 57: The use according to item 55, wherein the malignant tumor is a hematological cancer.

Item 58: The use according to item 55, wherein the malignant tumor is lymphoma, leukemia, or myeloma.

Item 59: The antitumor agent according to any one of items 44 to 47, wherein R14 and R15, together with the nitrogen atom to which they bind, bind to each other, directly or via a nitrogen atom to form a 6-membered saturated heterocyclic group that is substituted, on the heterocyclic ring, by a phenyl-substituted lower alkyl group that may be substituted, on the phenyl ring, by 1 or 2 group(s), as substituent(s), selected from the group consisting of a lower alkanoyl group, an amino group that may have a lower alkanoyl group as a substituent, a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxy group that may have a halogen atom as a substituent, a phenyl lower alkoxy group, a hydroxyl group, and a lower alkylenedioxy group.

Item 60: The antitumor agent according to item 59, wherein the saturated heterocyclic group is a piperazinyl group that is substituted by a phenyl-substituted lower alkyl group that is substituted by a lower alkylenedioxy group on the phenyl ring.

Item 61: The antitumor agent according to item 59 or 60, wherein X1 is a nitrogen atom and Y is an oxygen atom.

Specific examples of individual groups shown in the general formula (1) are as follows.
Examples of the lower alkenylene group include linear or branched alkenylene groups having 2 to 6 carbon atoms and 1 to 3 double bonds such as vinylene, 1-propenylene, 1-methyl-1-propenylene, 2-methyl-1-propenylene, 2-propenylene, 2-butenylene, 1-butenylene, 3-butenylene, 2-pentenylene, 1-pentenylene, 3-pentenylene, 4-pentenylene, 1,3-butadienylene, 1,3-pentadienylene, 2-penten-4-ynylene, 2-hexenylene, 1-hexenylene, 5-hexenylene, 3-hexenylene, 4-hexenylene, 3,3-dimethyl-1-propenylene, 2-ethyl-1-propenylene, 1,3,5-hexatrienylene, 1,3-hexadienylene, and 1,4-hexadienylene groups.
Examples of the lower alkynylene group include linear or branched alkynylene groups having 2 to 6 carbon atoms and 1 to 3 triple bonds such as ethynylene, 1-propynylene, 1-methyl-1-propynylene, 2-methyl-1-propynylene, 2-propynylene, 2-butynylene, 1-butynylene, 3-butynylene, 2-pentynylene, 1-pentynylene, 3-pentynylene, 4-pentynylene, 2-pentyn-4-ynylene, 2-hexynylene, 1-hexynylene, 5-hexynylene, 3-hexynylene, 4-hexynylene, 3,3-diethyl-1-propynylene, and 2-ethyl-1-propynylene groups.
Examples of the lower alkoxy group include linear or branched alkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxyl, pentyloxy, and hexyloxy groups.
Examples of the lower alkyl group include linear or branched alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, 2,2-dimethylpropyl, 1-ethylpropyl, butyl, isobutyl, tert-butyl, isopentyl, pentyl, and hexyl groups.
Examples of the lower alkyl group which may have a lower alkoxy group as a substituent include, in addition to the above described lower alkyl groups, linear or branched alkyl groups having 1 to 6 carbon atoms which may have a linear or branched alkoxy group having 1 to 6 carbon atoms as a substituent such as methoxymethyl, 1-ethoxyethyl, 27-methoxyethyl, 2-propoxyethyl, 3-isopropoxypropyl, 4-butoxybutyl, 5-pentyloxypentyl, 6-hexyloxyhexyl, 1,1-dimethyl-2-methoxyethyl, 2-methyl-3-ethoxypropyl, and 3-methoxypropyl groups.
Examples of the lower alkanoyl group include linear or branched alkanoyl groups having 1 to 6 carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, and hexanoyl groups.
Examples of the phenyl lower alkyl group include phenylalkyl groups whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 1,1-dimethyl-2-phenylethyl, and 2-methyl-3-phenylpropyl groups.
Examples of the lower alkylene group include linear or branched alkylene groups having 1 to 6 carbon atoms such as methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethylethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene, and hexamethylene groups.
Examples of the lower alkenylene group which may have a phenyl group as a substituent include linear or branched alkenylene groups, which have 2 to 6 carbon atoms and 1 to 3 double bonds, and which may have a phenyl group as a substituent such as vinylene, 1-propenylene, 1-methyl-1-propenylene, 2-methyl-1-propenylene, 2-propenylene, 2-butenylene, 1-butenylene, 3-butenylene, 2-pentenylene, 1-pentenylene, 3-pentenylene, 4-pentenylene, 1,3-butadienylene, 1,3-pentadienylene, 2-pentene-4-ynylene, 2-hexenylene, 1-hexenylene, 5-hexenylene, 3-hexenylene, 4-hexenylene, 3,3-dimethyl-1-propenylene, 2-ethyl-1-propenylene, 1,3,5-hexatrienylene, 1,3-hexadienylene, 1,4-hexadienylene, 1-phenylvinylene, 3-phenyl-1-propenylene, 3-phenyl-1-methyl-1-propenylene, 3-phenyl-2-methyl-1-propenylene, 1-phenyl-2-propenylene, 1-phenyl-2-butenylene, 3-phenyl-1-butenylene, 1-phenyl-3-butenylene, 5-phenyl-2-pentenylene, 4-phenyl-1-pentenylene, 2-phenyl-3-pentenylene, 1-phenyl-4-pentenylene, 1-phenyl-1,3-butadienylene, 1-phenyl-1,3-pentadienylene, 1-phenyl-2-penten-4-ynylene, 1-phenyl-2-hexenylene, 3-phenyl-1-hexenylene, 4-phenyl-5-hexenylene, 6-phenyl-3-hexenylene, 5-phenyl-4-hexenylene, 1-phenyl-3,3-dimethyl-1-propenylene, 1-phenyl-2-ethyl-1-propenylene, 6-phenyl-1,3,5-hexatrienylene, 1-phenyl-1,3-hexadienylene, and 2-phenyl-1,4-hexadienylene groups.
Examples of the lower alkylene group which may be substituted with a group selected from the group consisting of a lower alkoxy group and a phenyl group include, in addition to the above described lower alkylene groups, linear or branched alkylene groups having 1 to 6 carbon atoms which may be substituted with 1 or 2 groups selected from the group consisting of a linear or branched alkoxy group having 1 to 6 carbon atoms and a phenyl group such as methoxymethylene, 2-phenylethylene, 3-ethoxytrimethylene, 1-propoxy-2-methyltrimethylene, 1-phenyl-2,2-dimethylethylene, 3-phenyl-2,2-dimethyltrimethylene, 2-butoxy-1-methyltrimethylene, phenylmethylmethylene, 2-pentyloxyethylmethylene, 4-phenyl-2-hexyloxytetramethylene, 3-phenylpentamethylene, 5-phenylhexamethylene, ethoxymethylene, 1-phenylethylene, 3-phenyltrimethylene, and 2-phenyl-1-methoxyethylene groups.
Examples of the 5- to 15-membered monocyclic, bicyclic or tricyclic saturated or unsaturated heterocyclic group which has 1 to 4 nitrogen atoms, oxygen atoms or sulfur atoms include pyrrolidinyl, piperidinyl, piperazinyl, morpholino, pyridyl, 1,2,5,6-tetrahydropyridyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 1,2,5-triazolyl, thiazolidinyl, 1,2,3,4-tetrazolyl, thienyl, quinolyl, 1,4-dihydroquinolyl, benzothiazolyl, pyrazyl, pyrimidyl, pyridazyl, 2H-pyrrolyl, pyrrolyl, 1,3,4-oxadiazolyl, tetrahydropyranyl, tetrahydrofuryl, furazanyl, carbostyryl, 3,4-dihydrocarbostyryl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, indolyl, isoindolyl, indolinyl, benzoimidazolyl, benzooxazolyl, imidazolidinyl, isoquinolyl, quinazolidinyl, quinoxalinyl, cinnolinyl, phthalazinyl, carbazoyl, acridinyl, chromanyl, isoindolinyl, isochromanyl, pyrazolyl, imidazolyl, pyrazolidinyl, phenothiazinyl, benzofuryl, 2,3-dihydrobenzo[b]furyl, benzothienyl, phenoxathiinyl, phenoxazinyl, 4H-chromenyl, 1H-indazolyl, phenazinyl, xanthenyl, thianthrenyl, 2-imidazolinyl, 2-pyrrolinyl, furyl, oxazolyl, isooxazolyl, isooxazolidinyl, thiazolyl, isothiazolyl, pyranyl, 2-thiazolinyl, 2-pyrazolinyl, quinuclidinyl, 1,4-benzooxadinyl, 3,4-dihydro-2H-1,4-benzooxadinyl, 3,4-dihydro-2H-1,4-benzothiazinyl, 1,4-benzothiazinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1,3-dithia-2,4-dihydronaphthalenyl, phenalthridinyl, 1,4-dithianaphthalenyl, dibenz[b,e]azepine, and 6,11-dihydro-5H-dibenz[b,e]azepine groups.
Examples of the halogen atom include a fluorine atom, chlorine atom, bromine atom and iodine atom.
Examples of the lower alkoxy group which may have a halogen atom as a substituent include linear or branched alkoxy groups having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, trifluoromethoxy, trichloromethoxy, chloromethoxy, bromomethoxy, fluoromethoxy, iodomethoxy, difluoromethoxy, dibromomethoxy, 2-chloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 3-chloropropoxy, 2,3-dichloropropoxy, 4,4,4-trichlorobutoxy, 4-fluorobutoxy, 5-chloropentyloxy, 3-chloro-2-methylpropoxy, 6-bromohexyloxy, and 5,6-dichlorohexyloxy groups.
Examples of the lower alkyl group which may have a halogen atom as a substituent include, in addition to the above described lower alkyl groups, linear or branched alkyl groups having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents such as trifluoromethyl, trichloromethyl, chloromethyl, bromomethyl, fluoromethyl, iodomethyl, difluoromethyl, dibromomethyl, dichloromethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 3-chloropropyl, 2,3-dichloropropyl, 4,4,4-trichlorobutyl, 4-fluorobutyl, 5-chloropentyl, 3-chloro-2-methylpropyl, 5-bromohexyl, and 5,6-dibromohexyl groups.
Examples of the lower alkylsulfonyl group include linear or branched alkylsulfonyl groups having 1 to 6 carbon atoms such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, and hexylsulfonyl groups.
Examples of the phenyl group which may be substituted, on the phenyl ring, with a lower alkyl group which may have a halogen atom include phenyl groups which may be substituted, on the phenyl ring, with 1 to 3 linear or branched alkyl groups having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms such as phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3-butylphenyl, 4-pentylphenyl, 4-hexylphenyl, 3,4-dimethylphenyl, 3,4-diethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4,5-trimethylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-(bromomethyl)phenyl, 3-(2-chloroethyl)phenyl, 4-(2,3-dichloropropyl)phenyl, 4-(4-fluorobutyl)phenyl, 3-(5-chloropentyl)phenyl, 4-(5-bromohexyl)phenyl, 4-(5,6-dibromohexyl)phenyl, 3,4-di(trifluoromethyl)phenyl, 3,4-di(4,4,4-trichlorobutyl)phenyl, 2,4-di(3-chloro-2-methylpropyl)phenyl, 2,5-di(3-chloropropyl)phenyl, 2,6-di(2,2,2-trifluoroethyl)phenyl, 3,4,5-tri(trifluoromethyl)phenyl, 4-(2,2,2-trichloroethyl)phenyl, 2-methyl-4-trifluoromethylphenyl, and 3-ethyl-4-trichloromethyl groups.
Examples of the lower alkylthio group include linear or branched alkylthio groups having 1 to 6 carbon atoms such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, tert-butylthio, pentylthio, and hexylthio groups.
Examples of the amino group which may have a group selected from the group consisting of a lower alkyl group and a lower alkanoyl group as a substituent include amino groups which may have 1 or 2 groups selected from the group consisting of linear or branched alkyl groups having 1 to 6 carbon atoms and linear or branched alkanoyl groups having 1 to 6 carbon atoms as substituents such as amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, dipentylamino, dihexylamino, N-methyl-N-ethylamino, N-ethyl-N-propylamino, N-methyl-N-butylamino, N-methyl-N-hexylamino, N-acetylamino, N-formylamino, N-propionylamino, N-butyrylamino, N-isobutyrylamino, N-pentanoylamino, N-tert-butylcarbonylamino, N-hexanoylamino, diacetylamino, N-acetyl-N-methylamino, and N-acetyl-N-ethylamino groups.
Examples of the naphthyl group which may be substituted on the naphthalene ring with 1 to 3 substituents selected from the group consisting of a lower alkyl group, a halogen atom, and an amino group which may have a group selected from the group consisting of a lower alkyl group and a lower alkanoyl group include naphthyl groups which may have, on the naphthalene ring, 1 to 3 substituents selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms, a halogen atom, and an amino group which may have 1 or 2 substituents selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms and a linear or branched alkanoyl group having 1 to 6 carbon atoms such as (1- or 2-)naphthyl, 1-methyl-(2-, 3-, 4-, 5-, 6-, 7- or 8-)naphthyl, 2-ethyl-(1-, 3-, 4-, 5-, 6-, 7- or 8-)naphthyl, 3-n-propyl-(1-, 2-, 4-, 5-, 6-, 7- or 8-)naphthyl, 4-n-butyl-(1-, 2-, 3-, 5-, 6-, 7- or 8-)naphthyl, 4-methyl-(1-, 2-, 3-, 5-, 6-, 7- or 8-)naphthyl, 5-n-pentyl-(1-, 2-, 3-, 4-, 6-, 7- or 8-)naphthyl, 6-n-hexyl-(1-, 2-, 3-, 4-, 5-, 7- or 8-)naphthyl, 1,7-dimethyl-(2-, 3-, 4-, 5-, 6- or 8-)naphthyl, 1,2,8-trimethyl-(3-, 4-, 5-, 6- or 7-)naphthyl, 1-dimethylamino-(2-, 3-, 4-, 5-, 6-, 7- or 8-)naphthyl, 2-dimethylamino-(1-, 3-, 4-, 5-, 6-, 7- or 8-)naphthyl, 3-methylamino-(1-, 2-, 4-, 5-, 6-, 7- or 8-)naphthyl, 5-amino-(1-, 2-, 3-, 4-, 6-, 7- or 8-)naphthyl, 5-dimethylamino-(1-, 2-, 3-, 4-, 6-, 7- or 8-)naphthyl, 4-(N-methyl-N-ethylamino)-(1-, 2-, 3-, 5-, 6-, 7- or 8-)naphthyl, 1-methyl-2-dimethylamino-(3-, 4-, 5-, 6-, 7- or 8-)naphthyl, 1-chloro-(2-, 3-, 4-, 5-, 6-, 7- or 8-)naphthyl, and 1-acetylamino-(2-, 3-, 4-, 5-, 6-, 7- or 8-)naphthyl groups.
Examples of the alkyl group which may have a lower alkoxy group as a substituent include, in addition to the above described lower alkyl groups which may have a lower alkoxy group as a substituent, linear or branched alkyl groups having 1 to 8 carbon atoms which may have a linear or branched alkoxy group having 1 to 6 carbon atoms as a substituent such as heptyl, 1-ethylpentyl, octyl, 7-methoxyheptyl, 1-ethoxyheptyl, 2-propoxyl-1-ethylpentyl, 3-isopropoxyoctyl, 7-butoxyheptyl, 8-pentyloxyoctyl, and 5-hexyloxy-1-ethylpentyl groups.
Examples of the amino substituted lower alkyl group which may have a lower alkyl group include linear or branched alkyl groups having 1 to 6 carbon atoms substituted with an amino group which may have 1 or 2 linear or branched alkyl groups having 1 to 6 carbon atoms such as aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 1,1-dimethyl-2-aminoethyl, 2-methyl-3-aminopropyl, methylaminomethyl, 1-ethylaminoethyl, 2-propylaminoethyl, 3-isopropylaminopropyl, 4-butylaminobutyl, 5-pentylaminopentyl, 6-hexylaminohexyl, dimethylaminomethyl, 2-diethylaminoethyl, 2-diisopropylaminoethyl, (N-ethyl-N-propylamino)methyl, and 2-(N-methyl-N-hexylamino)ethyl groups.
Examples of the cycloalkyl group include cycloalkyl groups having 3 to 16 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cycloteradecyl, cyclopentadecyl, and cyclohexadecyl groups.
Examples of the cycloalkyl group which may be substituted with a group selected from the group consisting of an amino substituted lower alkyl group which may have a lower alkyl group and a lower alkyl group which may have a halogen atom as a substituent on the cycloalkyl ring include, in addition to the above described cycloalkyl groups, cycloalkyl groups having 3 to 16 carbon atoms which may be substituted, on the cycloalkyl ring, with 1 to 3 groups selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms substituted with an amino group which may have 1 or 2 linear or branched alkyl groups having 1 to 6 carbon atoms and a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents such as 4-dimethylaminomethylcyclohexyl, 2-(aminomethyl)cyclopropyl, 3-(2-aminomethyl)cyclobutyl, 2-(1-aminoethyl)cyclopentyl, 3-(3-aminopropyl)cyclohexyl, 3-(4-aminobutyl)cycloheptyl, 4-(5-aminopentyl)cyclooctyl, 4-(6-aminohexyl)cyclohexyl, 2-(1,1-dimethyl-2-aminoethyl)cycloheptyl, 3-(2-methyl-3-aminopropyl)cyclopentyl, 3-(methylaminomethyl)cyclohexyl, 2-(1-ethylaminoethyl)cyclooctyl, 2-(2-propylaminoethyl)cyclohexyl, 3-(3-isopropylaminopropyl)cyclopentyl, 4-(4-butylaminobutyl)cycloheptyl, 2-(5-pentylaminopentyl)cyclohexyl, 2-(6-hexylaminohexyl)cyclopentyl, 3-(dimethylaminomethyl)cyclohexyl, 3-[(N-ethyl-N-propylamino)methyl]cycloheptyl, 4-[2-(N-methyl-N-hexylamino)ethyl]cyclooctyl, 4-dimethylaminomethylcyclononyl, 2-(aminomethyl)cyclodecyl, 3-(2-aminomethyl)cycloundecyl, 2-(1-aminoethyl)cyclododecyl, 3-(3-aminopropyl)cyclotridecyl, 3-(4-aminobutyl)cyclotetradecyl, 4-(5-aminopentyl)cyclopentadecyl, 4-(6-aminohexyl)cyclohexadecyl, 2-(1,1-dimethyl-2-aminoethyl)cyclononyl, 3-(2-methyl-3-aminopropyl)cyclodecyl, 3-(methylaminomethyl)cycloundecyl, 2-(1-ethylaminoethyl)cyclododecyl, 2-(2-propylaminoethyl)cyclotridecyl, 3-(3-isopropylaminopropyl)cyclotetradecyl, 4-(4-butylaminobutyl)cyclopentadecyl, 2-(5-pentylaminopentyl)cyclohexadecyl, 2-(6-hexylaminohexyl)cyclononyl, 3-(dimethylaminomethyl)cyclododecyl, 3-[(N-ethyl-N-propylamino)methyl]cyclodecyl, 4-[2-(N-methyl-N-hexylamino)ethyl]cyclohexadecyl, 2,2-dimethylcyclopropyl, and 2-trifluoromethylcyclopropyl groups.
Examples of the lower alkenyl group include linear or branched alkenyl groups having 2 to 6 carbon atoms and 1 to 3 double bonds such as vinyl, 1-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-propenyl, 2-butenyl, 1-butenyl, 3-butenyl, 2-pentenyl, 1-pentenyl, 3-pentenyl, 4-pentenyl, 1,3-butadienyl, 1,3-pentadienyl, 2-penten-4-ynyl, 2-hexenyl, 1-hexenyl, 5-hexenyl, 3-hexenyl, 4-hexenyl, 3,3-dimethyl-1-propenyl, 2-ethyl-1-propenyl, 1,3,5-hexatrienyl, 1,3-hexadienyl, and 1,4-hexadienyl groups.
Examples of the lower alkenyl group which may have a halogen atom as a substituent include, in addition to the above described lower alkenyl groups, linear or branched alkenyl groups having 2 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents and which have 1 to 3 double bonds such as 3,3,3-trifluoro-1-propenyl, 2-bromovinyl, 3-chloro-1-propenyl, 3-iodo-1-methyl-1-propenyl, 3-fluoro-2-methyl-1-propenyl, 2-butenyl, 4,4,3-trichloro-1-butenyl, 4,4-difluoro-3-butenyl, 5-fluoro-2-pentenyl, 5,5,3-tribromo-1-pentenyl, 5-chloro-3-pentenyl, 5,5,5-trifluoro-4-pentenyl, 4-chloro-1,3-butadienyl, 5-fluoro-1,3-pentadienyl, 5-bromo-2-penten-4-ynyl, 6-fluoro-2-hexenyl, 6,6,5-trifluoro-1-hexenyl, 6-chloro-5-hexenyl, 5-bromo-3-hexenyl, 6-chloro-4-hexenyl, 3,3-dimethyl-2-chloro-1-propenyl, 3-fluoro-2-ethyl-1-propenyl, 6-chloro-1,3,5-hexatrienyl, 6-bromo-1,3-hexadienyl, and 6-fluoro-1,4-hexadienyl groups.
Examples of the benzoyl group (which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkyl group which may have a halogen atom as a substituent and a halogen atom) include benzoyl groups (which may have, on the phenyl ring, with 1 to 3 substituents selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms and which may have 1 to 3 halogen atoms as substituents and a halogen atom) such as benzoyl, 3,4-difluorobenzoyl, 2-fluorobenzoyl, 3-bromobenzoyl, 4-iodobenzoyl, 4-methylbenzoyl, 2-methylbenzoyl, 3-methylbenzoyl, 2-ethylbenzoyl, 3-ethylbenzoyl, 4-ethylbenzoyl, 4-isopropylbenzoyl, 3-butylbenzoyl, 4-pentylbenzoyl, 4-hexylbenzoyl, 3,4-dimethylbenzoyl, 3,4-diethylbenzoyl, 2,4-dimethylbenzoyl, 2,5-dimethylbenzoyl, 2,6-dimethylbenzoyl, 3,4,5-trimethylbenzoyl, 2-trifluoromethylbenzoyl, 3-trifluoromethylbenzoyl, 4-trifluoromethylbenzoyl, 2-(bromomethyl)benzoyl, 3-(2-chloroethyl)benzoyl, 4-(2,3-dichloropropyl)benzoyl, 4-(4-fluorobutyl)benzoyl, 3-(5-chloropentyl)benzoyl, 4-(5-bromohexyl)benzoyl, 4-(5,6-dibromohexyl)benzoyl, 3,4-di(trifluoromethyl)benzoyl, 3,4-di(4,4,4-trichlorobutyl)benzoyl, 2,4-di(3-chloro-2-methylpropyl)benzoyl, 2,5-di(3-chloropropyl)benzoyl, 2,6-di(2,2,2-trifluoroethyl)benzoyl, 3,4,5-tri(trifluoromethyl)benzoyl, 4-(2,2,2-trichloroethyl)benzoyl, 2-methyl-4-trifluoromethylbenzoyl, 3-ethyl-4-trichloromethylbenzoyl, 2-chloro-4-trifluoromethylbenzoyl, 3-ethyl-4-fluorobenzoyl, 3-fluoro-4-trichloromethylbenzoyl, 2-methyl-3-trifluoromethyl-4-trifluoromethylbenzoyl, 3-fluorobenzoyl, 4-fluorobenzoyl, 2-bromobenzoyl, 4-bromobenzoyl, 2-iodobenzoyl, 3-iodobenzoyl, 2,3-dibromobenzoyl, 2,4-diiodobenzoyl, 2,5-difluorobenzoyl, 2,6-dichlorobenzoyl, 2,4,6-trichlorobenzoyl, 2,4-difluorobenzoyl, 3,5-difluorobenzoyl, 2,6-difluorobenzoyl, 2-chlorobenzoyl, 3-chlorobenzoyl, 4-chlorobenzoyl, 2,3-dichlorobenzoyl, 2,4-dichlorobenzoyl, 2,5-dichlorobenzoyl, 3,4-dichlorobenzoyl, 2,6-dichlorobenzoyl, 3,5-dichlorobenzoyl, 2,4,6-trifluorobenzoyl, and 2,4-difluorobenzoyl groups.
Examples of the halogen substituted lower alkyl group include linear or branched alkyl groups having 1 to 6 carbon atoms which have 1 to 3 halogen atoms as substituents such as trifluoromethyl, trichloromethyl, chloromethyl, bromomethyl, fluoromethyl, iodomethyl, difluoromethyl, dibromomethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 3-chloropropyl, 2,3-dichloropropyl, 4,4,4-trichlorobutyl, 4-fluorobutyl, 5-chloropentyl, 3-chloro-2-methylpropyl, 5-bromohexyl, and 5,6-dibromohexyl groups.
Examples of the lower alkylenedioxy group include linear or branched alkylene groups having 1 to 4 carbon atoms such as methylenedioxy, ethylenedioxy, trimethylenedioxy, and tetramethylenedioxy groups.
Examples of the amino group which may have a substituent selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a benzoyl group and a cycloalkyl group include amino groups which may have 1 or 2 substituents selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkanoyl group having 1 to 6 carbon atoms, a benzoyl group, and a cycloalkyl group having 3 to 16 carbon atoms such as amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, dipentylamino, dihexylamino, N-methyl-N-ethylamino, N-ethyl-N-propylamino, N-methyl-N-butylamino, N-methyl-N-hexylamino, N-methyl-N-acetylamino, N-acetylamino, N-formylamino, N-propionylamino, N-butyrylamino, N-isobutyrylamino, N-pentanoylamino, N-tert-butylcarbonylamino, N-hexanoylamino, N-ethyl-N-acetylamino, N-benzoylamino, N-ethyl-N-benzoylamino, N-methyl-N-benzoylamino, N-acetyl-N-benzoylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, cyclooctylamino, N-methyl-N-cyclohexylamino, N-methyl-N-cyclopentylamino, N-methyl-N-cycloheptylamino, N-cyclohexyl-N-acetylamino, N-cyclopentyl-N-benzoylamino, cyclononylamino, cyclodecylamino, cyclododecylamino, cyclotridecylamino, cyclotetradecylamino, cyclopentadecylamino, N-methyl-N-cyclohexadecylamino, N-methyl-N-cyclononylamino, N-methyl-N-cyclodecylamino, N-cycloundecyl-N-acetylamino, and N-cyclohexadecyl-N-benzoyl groups.
Examples of the lower alkanoyl group which may have a halogen atom as a substituent include, in addition to the above described lower alkanoyl groups, linear or branched alkanoyl groups having 2 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents such as 2,2,2-trifluoroacetyl, 2,2,2-trichloroacetyl, 2-chloroacetyl, 2-bromoacetyl, 2-fluoroacetyl, 2-iodoacetyl, 2,2-difluoroacetyl, 2,2-dibromoacetyl, 3,3,3-trifluoropropionyl, 3,3,3-trichloropropionyl, 3-chloropropionyl, 2,3-dichloropropionyl, 4,4,4-trichlorobutyryl, 4-fluorobutyryl, 5-chloropentanoyl, 3-chloro-2-methylpropionyl, 6-bromohexanoyl, and 5,6-dibromohexanoyl groups.
Examples of the lower alkoxycarbonyl group include linear or branched alkoxycarbonyl groups having 1 to 6 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl groups.
Examples of the lower alkanoyloxy group include linear or branched alkanoyloxy groups having 2 to 6 carbon atoms such as acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, tert-butylcarbonyloxy, and hexanoyloxy groups.
Examples of the 5- or 6-membered saturated or unsaturated heterocyclic group having 1 to 4 nitrogen atoms, oxygen atoms or sulfur atoms include pyrrolidinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino, pyridyl, 1,2,5,6-tetrahydropyridyl, thienyl, pyrazyl, pyrimidyl, pyridazyl, pyrrolyl, 2H-pyrrolyl, imidazolidinyl, pyrazolyl, imidazolyl, pyrazolidinyl, furazanyl, 2-imidazolinyl, imidazolidinyl, 2-pyrrolinyl, furyl, oxazolyl, isooxazolidinyl, isooxazolyl, thiazolyl, isothiazolyl, pyranyl, 2-pyrazolidinyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 1,2,5-triazolyl, thiazolidinyl, 2-thiazolinyl, 1,2,3,4-tetrazolyl, 1,3,4-oxadiazolyl, tetrahydropyranyl, and tetrahydrofuryl groups.
Examples of the 5- to 7-membered saturated heterocyclic ring formed by binding R11 and R12 each other, together with nitrogen atoms bound to them, through or not through a nitrogen atom, a sulfur atom or an oxygen atom, include pyrrolidinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino, and homopiperazinyl groups.
Examples of the imidazolyl lower alkyl group include imidazolylalkyl groups whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (1, 2, 4 or 5-)imidazolylmethyl, 2-[(1, 2, 4 or 5-)imidazolyl]ethyl, 1-[(1, 2, 4 or 5-)imidazolyl]ethyl, 3-[(1, 2, 4 or 5-)imidazolyl]propyl, 4-[(1, 2, 4 or 5-)imidazolyl]butyl, 5-[(1, 2, 4 or 5-)imidazolyl]pentyl, 6-[(1, 2, 4 or 5-)imidazolyl]hexyl, 1,1-dimethyl-2-[(1, 2, 4 or 5-)imidazolyl]ethyl, and 2-methyl-3-[(1, 2, 4 or 5-)imidazolyl]propyl groups.
Examples of the 1,2,4-triazolyl lower alkyl group include 1,2,4-triazolylalkyl groups whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (1, 3 or 5-)1,2,4-triazolylmethyl, 2-[(1, 3 or 5-)1,2,4-triazolyl]ethyl, 1-[(1, 3 or 5-)1,2,4-triazolyl]ethyl, 3-[(1, 3 or 5-)1,2,4-triazolyl]propyl, 4-[(1, 3 or 5-)1,2,4-triazolyl]butyl, 5-[(1, 3 or 5-)1,2,4-triazolyl]pentyl, 6-[(1, 3 or 5-)1,2,4-triazolyl]hexyl, 1,1-dimethyl-2-[(1, 3 or 5-)1,2,4-triazolyl]ethyl, and 2-methyl-3-[(1, 3 or 5-)1,2,4-triazolyl]propyl groups.
Examples of the 1,2,3-triazolyl lower alkyl group include 1,2,3-triazolylalkyl groups whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (1, 4 or 5-)1,2,3-triazolylmethyl, 2-[(1, 4 or 5-)1,2,3-triazolyl]ethyl, 1-[(1, 4 or 5-)1,2,3-triazolyl]ethyl, 3-[(1, 4 or 5-)1,2,3-triazolyl]propyl, 4-[(1, 4 or 5-)1,2,3-triazolyl]butyl, 5-[(1, 4 or 5-)1,2,3-triazolyl]pentyl, 6-[(1, 4 or 5-)1,2,3-triazolyl]hexyl, 1,1-dimethyl-2-[(1, 4 or 5-)1,2,3-triazolyl]ethyl, and 2-methyl-3-[(1, 4 or 5-)1,2,3-triazolyl]propyl groups.
Examples of the 1,2,5-triazolyl lower alkyl group include 1,2,5-triazolylalkyl groups whose alkyl moiety is a linear or branched alkyl group having 1 to 56 carbon atoms such as (1, 3 or 4-)1,2,5-triazolylmethyl, 2-[(1, 3 or 4-)1,2,5-triazolyl]ethyl, 1-[(1, 3 or 4-)1,2,5-triazolyl]ethyl, 3-[(1, 3 or 4-)1,2,5-triazolyl]propyl, 4-[(1, 3 or 4-)1,2,5-triazolyl]butyl, 5-[(1, 3 or 4-)1,2,5-triazolyl]pentyl, 6-[(1, 3 or 4-)1,2,5-triazolyl]hexyl, 1,1-dimethyl-2-[(1, 3 or 4-)1,2,5-triazolyl]ethyl, and 2-methyl-3-[(1, 3 or 4-)1,2,5-triazolyl]propyl groups.
Examples of the pyrazolyl lower alkyl group include pyrazolylalkyl groups whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (1, 3, 4 or 5-)pyrazolylmethyl, 2-[(1, 3, 4 or 5-)pyrazolyl]ethyl, 1-[(1, 3, 4 or 5-)pyrazolyl]ethyl, 3-[(1, 3, 4 or 5-)pyrazolyl]propyl, 4-[(1, 3, 4 or 5-)pyrazolyl]butyl, 5-[(1, 3, 4 or 5-)pyrazolyl]pentyl, 6-[(1, 3, 4 or 5-)pyrazolyl]hexyl, 1,1-dimethyl-2-[(1, 3, 4 or 5-)pyrazolyl]ethyl, and 2-methyl-3-[(1, 3, 4 or 5-)pyrazolyl]propyl groups.
Examples of the pyrimidinyl lower alkyl group which may have an oxo group as a substituent on the pyrimidine ring include pyrimidinylalkyl groups which may have 1 to 3 oxo groups as substituents on the pyrimidine ring and whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (2, 4, 5 or 6-)pyrimidinylmethyl, 2-[(2, 4, 5 or 6-)pyrimidinyl]ethyl, 1-[(2, 4, 5 or 6-)pyrimidinyl]ethyl, 3-[(2, 4, 5 or 6-)pyrimidinyl]propyl, 4-[(2, 4, 5 or 6-)pyrimidinyl]butyl, 5-[(2, 4, 5 or 6-)pyrimidinyl]pentyl, 6-[(2, 4, 5 or 6-)pyrimidinyl]hexyl, 1,1-dimethyl-2-[(2, 4, 5 or 6-)pyrimidinyl]ethyl, 2-methyl-3-[(2, 4, 5 or 6-)pyrimidinyl]propyl, [(1, 3, 4 or 5-)2,6-dioxopyrimidinyl]methyl, [(1, 3, 4, 5 or 6-)2-oxopyrimidinyl]methyl, [(1, 2, 4 or 5-)6-oxopyrimidinyl]methyl, [(1, 2, 5 or 6-)4-oxopyrimidinyl]methyl, [(1, 3, 5 or 6-)2,4-dioxopyrimidinyl]methyl, 2-[(4 or 6-)2,5-dioxopyrimidinyl]ethyl, 1-[(1, 3, 4 or 5-)2,6-dioxopyrimidinyl]ethyl, 3-[(1, 3 or 5-)2,4,6-trioxopyrimidinyl]propyl, 4-[(1, 3, 4 or 5-)2,6-dioxopyrimidinyl]butyl, 5-[(4 or 6-)2,5-dioxopyrimidinyl]pentyl, 6-[(1, 3, 5 or 6-)2,4-dioxopyrimidinyl]hexyl, 1,1-dimethyl-[(1, 3, 4 or 5-)2,6-dioxopyrimidinyl]ethyl, and 2-methyl-3-[(1, 3, 4 or 5-)2,6-dioxopyrimidinyl]propyl groups.
Examples of the 3,5-dioxoisoxazolidin-4-ylidene lower alkyl group include 3,5-dioxoisoxazolidin-4-ylidenealkyl groups whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as 3,5-dioxoisoxazolidin-4-ylidenemethyl, 3,5-dioxoisoxazolidin-4-ylideneethyl, 3,5-dioxoisoxazolidin-4-ylidenepropyl, 3,5-dioxoisoxazolidin-4-ylideneisopropyl, 3,5-dioxoisoxazolidin-4-ylidenebutyl, 3,5-dioxoisoxazolidin-4-ylidenepentyl, and 3,5-dioxoisoxazolidin-4-ylidenehexyl groups.
Examples of the 1,2,4-oxadiazolyl lower alkyl group which may have a lower alkyl group as a substituent on the 1,2,4-oxadiazol ring include 1,2,4-oxadiazolylalkyl groups which may have a linear or branched alkyl group having 1 to 6 carbon atoms as a substituent on the 1,2,4-oxadiazol ring and whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (3 or 5-)1,2,4-oxadiazolylmethyl, 2-[(3 or 5-)1,2,4-oxadiazolyl]ethyl, 1-[(3 or 5-)1,2,4-oxadiazolyl]ethyl, 3-[(3 or 5-)1,2,4-oxadiazolyl]propyl, 4-[(3 or 5-)1,2,4-oxadiazolyl]butyl, 5-[(3 or 5-)1,2,4-oxadiazolyl]pentyl, 6-[(3 or 5-)1,2,4-oxadiazolyl]hexyl, 1,1-dimethyl-2-[(3 or 5-)1,2,4-oxadiazolyl]ethyl, 2-methyl-3-[(3 or 5-)1,2,4-oxadiazolyl]propyl, 5-methyl-3-(1,2,4-oxadiazolyl)methyl, 3-ethyl-2-[5-(1,2,4-oxadiazolyl)]ethyl, 1-[3-propyl-5-(1,2,4-oxadiazolyl)]ethyl, 3-[5-butyl-3-(1,2,4-oxadiazolyl)]propyl, 4-[3-pentyl-5-(1,2,4-oxadiazolyl)]butyl, 5-[5-hexyl-3-(1,2,4-oxadiazolyl)]pentyl, 6-[3-methyl-5-(1,2,4-oxadiazolyl)]hexyl, 1,1-dimethyl-2-[5-isopropyl-3-(1,2,4-oxadiazolyl)]ethyl, and 2-methyl-3-[3-isobutyl-5-(1,2,4-oxadiazolyl)]propyl groups.
Examples of the thiazolydinyl lower alkyl group which may have an oxo group as a substituent on the thiazolydine ring include thiazolydinylalkyl groups which may have 1 to 3 oxo groups as substituents on the thiazolydine ring and whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (2, 3, 4 or 5-)thiazolidinylmethyl, 2-[(2, 3, 4 or 5-)thiazolidinyl]ethyl, 1-[(2, 3, 4 or 5-)thiazolidinyl]ethyl, 3-[(2, 3, 4 or 5-)thiazolidinyl]propyl, 4-[(2, 3, 4 or 5-)thiazolidinyl]butyl, 5-[(2, 3, 4 or 5-)thiazolidinyl]pentyl, 6-[(2, 3, 4 or 5-)thiazolidinyl]hexyl, 1,1-dimethyl-2-[(2, 3, 4 or 5-)thiazolidinyl]ethyl, 2-methyl-3-[(2, 3, 4 or 5-)thiazolidinyl]propyl, 2,4-dioxo-5-thiazolidinylmethyl, 2-[2-oxo-(3, 4 or 5-)thiazolidinyl]ethyl, 1-[4-oxo-(2, 3 or 5-)thiazolidinyl]ethyl, 3-[5-oxo-(2, 3 or 4-)thiazolidinyl]propyl, 4-[2,5-dioxo-(3 or 4-)thiazolidinyl]butyl, 5-[2,4,5-trioxo-3-thiazolidinyl]pentyl, 6-[4,5-dioxo-(2 or 3-)thiazolidinyl]hexyl, 1,1-dimethyl-2-[2,4-dioxo-(3 or 5-)thiazolidinyl]ethyl, 2-methyl-3-[2,4-dioxo-(3 or 5-)thiazolidinyl]propyl, and 3-[2,4-dioxo-(3 or 5-)thiazolidinyl]propyl groups.
Examples of the phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring include, in addition to the above described phenyl lower alkyl groups, phenylalkyl groups which may have a linear or branched alkylenedioxy group having 1 to 4 carbon atoms as a substituent on the phenyl ring and whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as 3,4-methylenedioxybenzyl, 3,4-trimethylenedioxybenzyl, 2-(2,3-ethylenedioxyphenyl)ethyl, 1-(3,4-trimethylenedioxyphenyl)ethyl, 3-(2,3-tetramethylenedioxyphenyl)propyl, 4-(3,4-methylenedioxyphenyl)butyl, 5-(2,3-ethylenedioxyphenyl)pentyl, 6-(3,4-trimethylenedioxyphenyl)hexyl, 1,1-dimethyl-2-(2,3-methylenedioxyphenyl)ethyl, and 2-methyl-3-(3,4-ethylenedioxyphenyl)propyl groups.
Examples of the lower alkoxycarbonyl lower alkyl group include alkoxycarbonylalkyl groups whose alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms and whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as methoxycarbonylmethyl, ethoxycarbonylmethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 1-ethoxycarbonylethyl, 3-methoxycarbonylpropyl, 3-ethoxycarbonylpropyl, 4-ethoxycarbonylbutyl, 5-isopropoxycarbonylpentyl, 6-propoxycarbonylhexyl, 1,1-dimethyl-2-butoxycarbonylethyl, 2-methyl-3-tert-butoxycarbonylpropyl, 2-pentyloxycarbonylethyl, and hexyloxycarbonylmethyl groups.
Examples of the carboxy lower alkyl group include carboxyalkyl groups whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as carboxymethyl, 2-carboxyethyl, 1-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl, 6-carboxyhexyl, 1,1-dimethyl-2-carboxyethyl, and 2-methyl-3-carboxypropyl groups.
Examples of the morpholino substituted lower alkanoyl group include morpholino substituted alkanoyl groups whose alkanoyl moiety is a linear or branched alkanoyl group having 2 to 6 carbon atoms such as 2-[(2, 3 or 4-)morpholino]acetyl group, 3-[(2, 3 or 4-)morpholino]propionyl, 2-[(2, 3 or 4-)morpholino]propionyl, 4-[(2, 3 or 4-)morpholino]butyryl, 5-[(2, 3 or 4-)morpholino]pentanoyl, 6-[(2, 3 or 4-)morpholino]hexanoyl, 2,2-dimethyl-2-[(2, 3 or 4-)morpholino]propionyl, and 2-methyl-3-[(2, 3 or 4-)morpholino]propionyl groups.
Examples of the piperazinylcarbonyl lower alkyl group which may be substituted on the piperazine ring with a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring include piperazinylcarbonylalkyl groups whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms and which may be substituted on the piperazine ring with 1 to 3 phenylalkyl groups which may have a linear or branched alkylenedioxy group having 1 to 4 carbon atoms as a substituent on the phenyl group and whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as [(1, 2 or 3-)piperazinyl]carbonylmethyl, 2-[(1, 2 or 3-)piperazinyl]carbonylethyl, 1-[(1, 2 or 3-)piperazinyl]carbonylethyl, 3-[(1, 2 or 3-)piperazinyl]carbonylpropyl, 4-[(1, 2 or 3-)piperazinyl]carbonylbutyl, 5-[(1, 2 or 3-)piperazinyl]carbonylpentyl, 6-[(1, 2 or 3-)piperazinyl]carbonylhexyl, 1,1-dimethyl-2-[(1, 2 or 3-)piperazinyl]carbonylethyl, 2-methyl-3-[(1, 2 or 3-)piperazinyl]carbonylpropyl, (4-benzyl-1-piperazinylcarbonyl)methyl, 2-[4-(2-phenylethyl)-1-piperazinylcarbonyl]ethyl, 1-[4-(3-phenylpropyl)-1-piperazinylcarbonyl]ethyl, 3-[4-(4-phenylbutyl)-1-piperazinylcarbonyl]propyl, 4-[4-(5-phenylpentyl)-1-piperazinylcarbonyl]butyl, 5-[4-(6-phenylpropyl)-1-piperazinylcarbonyl]pentyl, 6-(4-benzyl-1-piperazinylcarbonyl)hexyl, 1,1-dimethyl-2-(4-benzyl-1-piperazinylcarbonyl)ethyl, 2-methyl-3-(4-benzyl-1-piperazinylcarbonyl)propyl, [4-(3,4-methylenedioxybenzyl)-1-piperazinylcarbonyl]methyl, 2-{4-[2-(2,3-ethylenedioxyphenyl)ethyl]-1-piperazinylcarbonyl}ethyl, 1-{4-[3-(3,4-trimethylenedioxyphenyl)propyl]-1-piperazinylcarbonyl}ethyl, 3-{4-[4-(2,3-tetramethylenedioxyphenyl)butyl]-1-piperazinylcarbonyl}propyl, 4-{4-[5-(3,4-methylenedioxyphenyl)pentyl]-1-piperazinylcarbonyl}butyl, 5-{4-[3-(2,3-ethylenedioxyphenyl)propyl]-1-piperazinylcarbonyl}pentyl, 6-[4-(3,4-trimethylenedioxybenzyl)-1-piperazinylcarbonyl]hexyl, 1,1-dimethyl-2-[4-(2,3-tetramethylenedioxybenzyl)-1-piperazinylcarbonyl]ethyl, 2-methyl-3-[4-(3,4-methylenedioxybenzyl)-1-piperazinylcarbonyl]propyl, (3,4-dibenzyl-1-piperazinylcarbonyl)methyl, (3,4,5-tribenzyl-1-piperazinylcarbonyl)methyl, [2,4-di(3,4-methylenedioxybenzyl)-1-piperazinylcarbonyl]methyl, [2,4,6-tri(3,4-methylenedioxybenzyl)-1-piperazinylcarbonyl]methyl, and [3-benzyl-4-(3,4-methylenedioxybenzyl)-1-piperazinylcarbonyl]methyl groups.
Examples of the piperazinyl lower alkanoyl group which may be substituted on the piperazine ring with a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring include piperazinylalkanoyl groups whose alkanoyl moiety is a linear or branched alkanoyl group having 2 to 6 carbon atoms and which may be substituted on the piperazine ring with 1 to 3 phenylalkyl groups which may have a linear or branched alkylenedioxy group having 1 to 4 carbon atoms as a substituent on the phenyl ring and whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms, such as 2-[(1, 2 or 3-)piperazinyl]acetyl, 3-[(1, 2 or 3-)piperazinyl]propionyl, 2-[(1, 2 or 3-)piperazinyl]propionyl, 4-[(1, 2 or 3-)piperazinyl]butyryl, 5-[(1, 2 or 3-)piperazinyl]pentanoyl, 6-[(1, 2 or 3-)piperazinyl]hexanoyl, 2,2-dimethyl-3-[(1, 2 or 3-)piperazinyl]propionyl, 2-methyl-3-[(1, 2 or 3-)piperazinyl]propionyl, 2-(4-benzyl-1-piperazinyl)acetyl, 3-[4-(2-phenylethyl)-1-piperazinyl]propionyl, 2-[4-(3-phenylpropyl)-1-piperazinyl]propionyl, 4-[4-(4-phenylbutyl)-1-piperazinyl]butyryl, 5-[4-(5-phenylpentyl)-1-piperazinyl]pentanoyl, 6-[4-(6-phenylpropyl)-1-piperazinyl]hexanoyl, 6-(4-benzyl-1-piperazinyl)hexanoyl, 2,2-dimethyl-3-(4-benzyl-1-piperazinyl)propionyl, 2-methyl-3-(4-benzyl-1-piperazinyl)propionyl, 2-[4-(3,4-methylenedioxybenzyl)-1-piperazinyl]acetyl, 3-{4-[2-(2,3-ethylenedioxyphenyl)ethyl]-1-piperazinyl}propionyl, 2-{4-[3-(3,4-trimethylenedioxyphenyl)propyl]-1-piperazinyl}propionyl, 4-{4-[4-(2,3-tetramethylenedioxyphenyl)butyl]-1-piperazinyl}butyryl, 5-{4-[5-(3,4-methylenedioxyphenyl)pentyl]-1-piperazinyl}pentanoyl, 5-{4-[3-(2,3-ethylenedioxyphenyl)propyl]-1-piperazinyl}pentanoyl, 6-[4-(3,4-trimethylenedioxybenzyl)-1-piperazinyl]hexanoyl, 2,2-dimethyl-3-[4-(2,3-tetramethylenedioxybenzyl)-1-piperazinyl]propionyl, 2-methyl-3-[4-(3,4-methylenedioxybenzyl)-1-piperazinyl]propionyl, 2-(3,4-dibenzyl-1-piperazinyl)acetyl, 2-(3,4,5-tribenzyl-1-piperazinyl)acetyl, 2-[2,4-di(3,4-methylenedioxybenzyl)-1-piperazinyl]acetyl, 2-[2,4,6-tri(3,4-methylenedioxybenzyl)-1-piperazinyl]acetyl, and 2-[3-benzyl-4-(3,4-methylenedioxybenzyl)-1-piperazinyl]acetyl groups.
Examples of the morpholinocarbonyl substituted lower alkyl group include morpholinocarbonylalkyl groups whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as [(2, 3 or 4-)morpholino]carbonylmethyl, 2-[(2, 3 or 4-)morpholino]carbonylethyl, 1-[(2, 3 or 4-)morpholino]carbonylethyl, 3-[(2, 3 or 4-)morpholino]carbonylpropyl, 4-[(2, 3 or 4-)morpholino]carbonylbutyl, 5-[(2, 3 or 4-)morpholino]carbonylpentyl, 6-[(2, 3 or 4-)morpholino]carbonylhexyl, 1,1-dimethyl-2-[(2, 3 or 4-)morpholino]carbonylethyl, and 2-methyl-3-[(2, 3 or 4-)morpholino]carbonylpropyl groups.
Examples of the imidazolyl lower alkanoyl group include imidazolylalkanoyl groups whose alkanoyl moiety is a linear or branched alkanoyl group having 2 to 6 carbon atoms such as 2-[(1, 2, 4 or 5-)imidazolyl]acetyl, 3-[(1, 2, 4 or 5-)imidazolyl]propionyl, 2-[(1, 2, 4 or 5-)imidazolyl]propionyl, 4-[(1, 2, 4 or 5-)imidazolyl]butyryl, 5-[(1, 2, 4 or 5-)imidazolyl]pentanoyl, 6-[(1, 2, 4 or 5-)imidazolyl]hexanoyl, 2,2-dimethyl-3-[(1, 2, 4 or 5-)imidazolyl]propionyl, and 2-methyl-3-[(1, 2, 4 or 5-)imidazolyl]propionyl groups.
Examples of the cycloalkylcarbonyl group include cycloalkylcarbonyl groups whose cycloalkyl moiety is a cycloalkyl group having 3 to 16 carbon atoms such as cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, cyclooctylcarbonyl, cyclononylcarbonyl, cyclodecylcarbonyl, cycloundecylcarbonyl, cyclododecylcarbonyl, cyclotridecylcarbonyl, cyclotetradecylcarbonyl, cyclopentadecylcarbonyl, and cyclohexadecylcarbonyl groups.
Examples of the amino substituted lower alkanoyl group which may have a lower alkyl group as a substituent include linear or branched alkanoyl groups having 2 to 6 carbon atoms substituted with an amino group which may have 1 or 2 linear or branched alkyl groups having 1 to 6 carbon atoms as substituents such as aminoacetyl, 2-aminopropionyl, 3-aminopropionyl, 4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, 2,2-dimethyl-3-aminopropionyl, 2-methyl-3-aminopropionyl, methylaminoacetyl, 2-ethylaminopropionyl, 3-propylaminopropionyl, 3-isopropylaminopropionyl, 4-butylaminobutyryl, 5-pentylaminopentanoyl, 6-hexylaminohexanoyl, dimethylaminoacetyl, 3-diisopropylaminopropionyl, (N-ethyl-N-propylamino)acetyl, and 2-(N-methyl-N-hexylamino)acetyl groups.
Examples of the lower alkylene group which may have a hydroxyl group as a substituent include, in addition to the above described lower alkylene groups, linear or branched alkylene groups having 1 to 6 carbon atoms which may have 1 to 3 hydroxyl groups as substituents such as 1-hydroxymethylene, 2-hydroxyethylene, 1-hydroxyethylene, 2-hydroxytrimethylene, 3-hydroxytrimethylene, 1-hydroxytrimethylene, 3-hydroxy-2-methyltrimethylene, 1-hydroxy-2-methyltrimethylene, 3-hydroxy-2,2-dimethyltrimethylene, 1-hydroxy-2,2-dimethyltrimethylene, 3-hydroxy-1-methyltrimethylene, 2-hydroxy-1-methyltrimethylene, 1-hydroxymethylmethylene, hydroxymethylmethylene, 2-hydroxymethyltrimethylene, 2-hydroxymethyl-2-methyltrimethylene, (2-hydroxyethyl)methylene, (1-hydroxyethyl)methylene, 4-hydroxytetramethylene, 2-hydroxytetramethylene, 3-hydroxytetramethylene, 1-hydroxytetramethylene, 5-hydroxypentamethylene, 4-hydroxypentamethylene, 3-hydroxypentamethylene, 2-hydroxypentamethylene, 1-hydroxypentamethylene, 6-hydroxyhexamethylene, 5-hydroxyhexamethylene, 4-hydroxyhexamethylene, 3-hydroxyhexamethylene, 2-hydroxyhexamethylene, 1-hydroxyhexamethylene, 1,2-dihydroxytrimethylene, 2,2,4-trihydroxytetramethylene, 1,2,6-trihydroxyhexamethylene, and 3,4,5-trihydroxypentamethylene groups.
Examples of the alkyl group which may have a hydroxyl group as a substituent include, in addition to the above described lower alkyl groups, linear or branched alkyl groups having 1 to 16 carbon atoms which may have 1 to 3 hydroxyl groups as substituents such as heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, 1-methylhexyl, hexadecyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 1,1-dimethyl-2-hydroxyethyl, 5,5,4-trihydroxypentyl, 5-hydroxypentyl, 6-hydroxyhexyl, 1-hydroxyisopropyl, and 2-methyl-3-hydroxypropyl groups.
Examples of the hydroxyl group substituted alkyl group include linear or branched alkyl groups having 1 to 16 carbon atoms and 1 to 3 hydroxyl groups as substituents such as hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 1,1-dimethyl-2-hydroxyethyl, 5,5,4-trihydroxypentyl, 5-hydroxypentyl, 6-hydroxyhexyl, 1-hydroxyisopropyl, and 2-methyl-3-hydroxypropyl groups.
Examples of the cycloalkyl group which may have a substituent selected from the group consisting of a hydroxyl group and a lower alkyl group include, in addition to the above described cycloalkyl groups, cycloalkyl groups having 3 to 16 carbon atoms which may have 1 to 3 substituents selected from the group consisting of a hydroxyl group and a linear or branched alkyl group having 1 to 6 carbon atoms such as 2-hydroxycyclopropyl, 3-hydroxycyclobutyl, 3-hydroxycyclopentyl, 2-hydroxycyclohexyl, 4-hydroxycyclohexyl, 3-hydroxycycloheptyl, 4-hydroxycyclooctyl, 5-hydroxycyclononyl, 3-hydroxycyclodecyl, 4-hydroxycycloundecyl, 5-hydroxycyclododecyl, 6-hydroxycyclotridecyl, 7-hydroxycyclotetradecyl, 6-hydroxycyclopentadecyl, 8-hydroxycyclohexadecyl, 2,4-dihydroxycyclohexyl, 2,4,6-trihydroxycyclohexyl, 1-methylcyclopentyl, 2-ethylcyclopropyl, 3-n-propylcyclobutyl, 2-n-butylcyclohexyl, 4-n-pentylcycloheptyl, 4-n-hexylcyclooctyl, 2,3-dimethylcyclohexyl, 2,3,4-trimethylcyclohexyl, and 2-methyl-4-hydroxycyclohexyl groups.
Examples of the phenoxy lower alkyl group include phenoxyalkyl groups whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as phenoxymethyl, 2-phenoxyethyl, 1-phenoxyethyl, 3-phenoxypropyl, 4-phenoxybutyl, 1,1-dimethyl-2-phenoxyethyl, 5-phenoxypentyl, 6-phenoxyhexyl, 1-phenoxyisopropyl, and 2-methyl-3-phenoxypropyl groups.
Examples of the amino lower alkoxy group which may have a lower alkyl group as a substituent include linear or branched alkoxy groups having 1 to 6 carbon atoms substituted with an amino group which may have 1 or 2 linear or branched alkyl groups having 1 to 6 carbon atoms such as aminomethoxy, 2-aminoethoxy, 1-aminoethoxy, 3-aminopropoxy, 4-aminobutoxy, 5-aminopentyloxy, 6-aminohexyloxy, 1,1-dimethyl-2-aminoethoxy, 2-methyl-3-aminopropoxy, methylaminomethoxy, 1-ethylaminoethoxy, 2-propylaminoethoxy, 3-isopropylaminopropoxy, 4-butylaminobutoxy, 5-pentylaminopentyloxy, 6-hexylaminohexyloxy, dimethylaminomethoxy, 2-diethylaminoethoxy, 2-diisopropylaminoethoxy, (N-ethyl-N-propylamino)methoxy, and 2-(N-methyl-N-hexylamino)ethoxy groups.
Examples of the hydroxyl group substituted lower alkyl group include linear or branched alkyl groups having 1 to 6 carbon atoms which have 1 to 3 hydroxyl groups as substituents such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 1,1-dimethyl-2-hydroxyethyl, 5,5,4-trihydroxypentyl, 5-hydroxypentyl, 6-hydroxyhexyl, 1-hydroxyisopropyl, and 2-methyl-3-hydroxypropyl groups.
Examples of the amino group which may have a lower alkylsulfonyl as a substituent include amino groups which may have 1 or 2 linear or branched alkylsulfonyl groups having 1 to 6 carbon atoms as substituents such as amino, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, butylsulfonylamino, tert-butylsulfonylamino, pentylsulfonylamino, hexylsulfonylamino, dimethylsulfonylamino, diethylsulfonylamino, dipropylsulfonylamino, dibutylsulfonylamino, dipentylsulfonylamino, dihexylsulfonylamino, N-methylsulfonyl-N-ethylsulfonylamino, N-ethylsulfonyl-N-propylsulfonylamino, N-methylsulfonyl-N-butylsulfonylamino, and N-methylsulfonyl-N-hexylsulfonylamino groups.
Examples of the lower alkynyl group include linear or branched alkynyl groups having 2 to 6 carbon atoms such as ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, and 2-hexynyl groups.
Examples of the anilino group which may have a halogen atom as a substituent on the phenyl ring include anilino groups which may have 1 to 3 halogen atoms as substituents on the phenyl ring such as anilino, 2-fluoroanilino, 3-fluoroanilino, 4-fluoroanilino, 2-bromoanilino, 3-bromoanilino, 4-bromoanilino, 2-iodoanilino, 3-iodoanilino, 4-iodoanilino, 2,3-dibromoanilino, 2,4-diiodoanilino, 2,5-difluoroanilino, 2,6-dichloroanilino, 2,4,6-trichloroanilino, 2,6-difluoroanilino, 3,5-difluoroanilino, 2,6-difluoroanilino, 2-chloroanilino, 3-chloroanilino, 4-chloroanilino, 2,3-dichloroanilino, 2,4-dichloroanilino, 2,5-dichloroanilino, 3,4-dichloroanilino, 2,6-dichloroanilino, 3,5-dichloroanilino, 2,4,6-trifluoroanilino, 2,4-difluoroanilino, and 3,4-difluoroanilino groups.
Examples of the piperazinyl group which may have a lower alkyl group as a substituent on the piperazine ring include piperazinyl groups which may have 1 to 3 linear or branched alkyl groups having 1 to 6 carbon atoms as substituents on the piperazine ring such as (1-, 2- or 3-)piperazinyl, 4-methyl-(1-, 2- or 3-)piperazinyl, 2,3-dimethyl-(1- or 5-)piperazinyl, and 2,3,4-trimethyl-(1-, 5- or 6-)piperazinyl groups.
Examples of the pyrrolidinyl group which may have an oxo group as a substituent on the pyrrolidine ring include pyrrolidinyl groups which may have 1 or 2 oxo groups as substituents on the pyrrolidine ring such as (1-, 2- or 3-)pyrrolidinyl, 2-oxo-(1-, 3-, 4- or 5-)pyrrolidinyl, 3-oxo-(1-, 2-, 4- or 5-)pyrrolidinyl, 2,3-dioxo-(1-, 4- or 5-)pyrrolidinyl, and 2,5-dioxo-(1-, 3- or 4-)pyrrolidinyl groups.
Examples of the lower alkanoyl amino group include linear or branched alkanoyl amino groups having 2 to 6 carbon atoms which have 1 to 3 halogen atoms as substituents such as acetyl amino, propionyl amino, butyryl amino, pentanoyl amino, 2-methylpropionyl amino, and hexanoyl amino groups.
Examples of the phenyl group which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a lower alkyl group; a lower alkoxy group which may have a halogen atom as a substituent; a halogen atom; an amino lower alkoxy group which may have a lower alkyl group as a substituent; a hydroxyl group substituted lower alkyl group; a phenyl lower alkyl group; a lower alkynyl group; an amino group which may have a lower alkylsulfonyl group as a substituent; a lower alkylthio group; a cycloalkyl group; a phenylthio group; an adamantyl group; an anilino group which may have a halogen atom as a substituent on the phenyl ring; a lower alkoxycarbonyl group; a piperazinyl group which may have a lower alkyl group as a substituent on the piperazine ring; a lower alkanoylamino group; a cyano group; a pyrrolidinyl group which may have an oxo group as a substituent on the pyrrolidine ring; and a phenoxy group include phenyl groups which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms; a linear or branched alkoxy group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms; a halogen atom; an aminoalkoxy group whose alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms and which may have 1 or 2 linear or branched alkyl groups having 1 to 6 carbon atom as substituents; a linear or branched alkyl group having 1 to 6 carbon atoms and 1 to 3 hydroxyl groups as substituents; a phenylalkyl group whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms; a linear or branched alkynyl group having 2 to 6 carbon atoms; an amino group which may have 1 or 2 linear or branched alkylsulfonyl groups having 1 to 6 carbon atoms as substituents; a linear or branched alkylthio group having 1 to 6 carbon atoms; a cycloalkyl group having 3 to 16 carbon atoms; a phenylthio group; an adamantyl group; an anilino group which may have 1 to 3 halogen atoms as substituents on the phenyl ring; a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms; an amino group which may have 1 or 2 linear or branched alkanoyl groups having 2 to 6 carbon atoms; a cyano group; a piperazinyl group which may have 1 to 3 linear or branched alkyl groups having 1 to 6 carbon atoms as substituents on the piperazine ring; a pyrrolidinyl group which may have 1 or 2 oxo groups as substituents on the pyrrolidine ring; and a phenoxy group such as phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-isopropylphenyl, 4-isopropylphenyl, 3-butylphenyl, 4-pentylphenyl, 4-hexylphenyl, 3,4-dimethylphenyl, 3,4-diethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4,5-trimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 4-isopropoxyphenyl, 3-butoxyphenyl, 4-pentyloxyphenyl, 4-hexyloxyphenyl, 3,4-dimethoxyphenyl, 3,4-diethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-triflupromethoxyphenyl, 2-(bromomethoxy)phenyl, 3-(2-chloroethoxy)phenyl, 4-(2,3-dichloropropoxy)phenyl, 4-(4-fluorobutoxy)phenyl, 3-(5-chloropentyloxy)phenyl, 4-(5-bromohexyloxy)phenyl, 4-(5,6-dibromohexyloxy)phenyl, 3,4-di(trifluoromethoxy)phenyl, 3,4-di(4,4,4-trichlorobutoxy)phenyl, 2,4-di(3-chloro-2-methoxypropyl)phenyl, 2,5-di(3-chloropropoxy)phenyl, 2,6-di(2,2,2-trifluoroethoxy)phenyl, 3,4,5-tri(trifluoromethoxy)phenyl, 4-(2,2,2-trichloroethoxy)phenyl, 2-methyl-4-trifluoromethoxyphenyl, 3-ethyl-4-trichloromethoxyphenyl, 2-methoxy-4-trifluoromethoxyphenyl, 3-ethoxy-4-trichloromethoxyphenyl, 2-methyl-3-trifluoromethoxy-4-trifluoromethoxyphenyl, 2-phenoxyphenyl, 3-phenoxyphenyl, 4-phenoxyphenyl, 2,3-diphenoxyphenyl, 3,4-diphenoxyphenyl, 2,6-diphenoxyphenyl, 3,4,5-triphenoxyphenyl, 2-methyl-4-phenoxyphenyl, 3-ethyl-4-phenoxyphenyl, 2-methoxy-4-phenoxyphenyl, 3-ethoxy-4-phenoxyphenyl, 2-methyl-3-phenoxy-4-trifluoromethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2,6-dichlorophenyl, 3,5-dichlorophenyl, 2,4,6-trichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,5-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,6-difluorophenyl, 2,4,6-trifluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2,3-dibromophenyl, 2,4-diiodophenyl, 4-methylthiophenyl, 4-cyclohexylphenyl, 4-chloro-2-anilinophenyl, 2-(4-chloro anilino)-5-ethoxy carbonylphenyl, 4-[2-(N,N-diethylamino)ethoxy]phenyl, 4-(4-methyl-1-piperazinyl)phenyl, 4-(2-oxo-1-pyrrolidinyl)phenyl, 4-methylsulfonylaminophenyl, 4-(2-hydroxyethyl)phenyl, 4-benzylphenyl, 4-ethynylphenyl, 4-phenylthiophenyl, 4-(1-adamantyl)phenyl, 5-acetylamino-2-chlorophenyl, 2-propanoylaminophenyl, 3-cyanophenyl, 2-cyanophenyl, 4-cyanophenyl, 3,4-dicyanophenyl, and 3,4,5-tricyanophenyl groups.
Examples of the phenyl lower alkyl group which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkoxy group which may have a halogen atom as a substituent, and a lower alkyl group include, in addition to the above described phenyl lower alkyl groups, phenylalkyl groups whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms and which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a halogen atom, a linear or branched alkoxy group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents, and a linear or branched alkyl group having 1 to 6 carbon atoms such as 4-fluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-(2-fluorophenyl)ethyl, 2-(4-fluorophenyl)ethyl, 2-(4-chlorophenyl)ethyl, 3,4-dibromobenzyl, 3,4-diiodobenzyl, 2,4-difluorobenzyl, 2,5-dichlorobenzyl, 2,6-dichlorobenzyl, 3,4,5-trifluorobenzyl, 3-(4-chlorophenyl)propyl, 1-(2-bromophenyl)ethyl, 4-(3-fluorophenyl)butyl, 5-(4-iodophenyl)pentyl, 6-(4-chlorophenyl)hexyl, 1,1-dimethyl-2-(3-fluorophenyl)ethyl, 2-methyl-3-(4-chlorophenyl)propyl, 2-methylbenzyl, 2-(3-methylphenyl)ethyl, 3-(4-methylphenyl)propyl, 1-(2-ethylphenyl)ethyl, 4-(3-ethylphenyl)butyl, 5-(4-ethylphenyl)pentyl, 6-(4-isopropylphenyl)hexyl, 1,1-dimethyl-2-(3-butylphenyl)ethyl, 2-methyl-3-(4-pentylphenyl)propyl, 4-hexylbenzyl, 3,4-dimethylbenzyl, 3,4-diethylbenzyl, 2,4-dimethylbenzyl, 2,5-dimethylbenzyl, 2,6-dimethylbenzyl, 3,4,5-trimethylbenzyl, 2-methoxybenzyl, 2-(2-methoxyphenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(4-methoxyphenyl)ethyl, 4-methoxybenzyl, 1-(2-ethoxyphenyl)ethyl, 3-(3-ethoxyphenyl)propyl, 4-(4-ethoxyphenyl)butyl, 5-(4-isopropoxyphenyl)pentyl, 6-(3-butoxyphenyl)hexyl, 1,1-dimethyl-2-(4-pentyloxyphenyl)ethyl, 2-methyl-3-(4-hexyloxyphenyl)propyl, 3,4-dimethoxybenzyl, 3,4-diethoxybenzyl, 2,4-dimethoxybenzyl, 2,5-dimethoxybenzyl, 2,6-dimethoxybenzyl, 3,4,5-trimethoxybenzyl, 2-trifluoromethoxybenzyl, 3-trifluoromethoxybenzyl, 4-trifluoromethoxybenzyl, 2-[2-(bromomethoxy)phenyl]ethyl, 1-[3′-(2-chloroethoxy)phenyl]ethyl, 3-[4-(2,3-dichloropropoxy)phenyl]propyl, 4-[4-(4-fluorobutoxy)phenyl]butyl, 5-[3-(5-chloropentyloxy)phenyl]pentyl, 6-[4-(5-bromohexyloxy)phenyl]hexyl, 1,1-dimethyl-2-[4-(5,6-dibromohexyloxy)phenyl]ethyl, 3,4-di(trifluoromethoxy)benzyl, 3,4-di(4,4,4-trichlorobutoxy)benzyl, 2,4-di(3-chloro-2-methoxypropyl)benzyl, 2,5-di(3-chloropropoxy)benzyl, 2,6-di(2,2,2-trifluoroethoxy)benzyl, 3,4,5-tri(trifluoromethoxy)benzyl, 4-(2,2,2-trichloroethoxy)benzyl, 2-methyl-4-trifluoromethoxybenzyl, 3-ethyl-4-trichloromethoxybenzyl, 2-methoxy-4-trifluoromethoxybenzyl, 3-ethoxy-4-trichloromethoxybenzyl, 2-methyl-3-trifluoromethoxy-4-trifluoromethoxybenzyl, 2-chloro-3-methylbenzyl, 4-fluoro-2-trifluoromethoxybenzyl, and 3-chloro-2-methyl-4-methoxybenzyl groups.
Examples of the phenyl lower alkyl group which has a lower alkylenedioxy group as a substituent on the phenyl ring include phenylalkyl groups which have a linear or branched alkylenedioxy group having 1 to 4 carbon atoms as a substituent on the phenyl ring and whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as 3,4-methylenedioxybenzyl, 3,4-trimethylenedioxybenzyl, 2-(2,3-ethylenedioxyphenyl)ethyl, 1-(3,4-trimethylenedioxyphenyl)ethyl, 3-(2,3-tetramethylenedioxyphenyl)propyl, 4-(3,4-methylenedioxyphenyl)butyl, 5-(2,3-ethylenedioxyphenyl)pentyl, 6-(3,4-trimethylenedioxyphenyl)hexyl, 1,1-dimethyl-2-(2,3-methylenedioxyphenyl)ethyl, and 2-methyl-3-(3,4-ethylenedioxyphenyl)propyl groups.
Examples of the amino group which may have a lower alkanoyl group as a substituent include amino groups which may have a linear or branched alkanoyl group having 1 to 6 carbon atoms as a substituent such as amino, N-acetylamino, N-formylamino, N-propionylamino, N-butyrylamino, N-isobutyrylamino, N-pentanoylamino, N-tert-butylcarbonylamino, and N-hexanoylamino groups.
Examples of the 1,2,3,4-tetrahydroquinolyl group which may have, on the tetrahydroquinoline ring, 1 to 3 substituents selected from the group consisting of an oxo group, a lower alkoxy group, and a lower alkylenedioxy group include 1,2,3,4-tetrahydroquinolyl groups which may have, on the tetrahydroquinoline ring, 1 to 3 substituents selected from the group consisting of an oxo group, a linear or branched alkoxy group having 1 to 6 carbon atoms, and a linear or branched alkylenedioxy group having 1 to 4 carbon atoms such as (1, 2, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl, 2-oxo-(1, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl, 2-oxo-6,7-methylenedioxy-(1, 3, 4, 5 or 8-)1,2,3,4-tetrahydroquinolyl, 4-oxo-(1, 2, 3, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl, 2,4-dioxo-(1, 3, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl, 2,4-dioxo-6,7-methylenedioxy-(1, 3, 5 or 8-)2,3,4-tetrahydroquinolyl, 5,6-ethylenedioxy-(1, 2, 3, 4, 7 or 8-)1,2,3,4-tetrahydroquinolyl, 7,8-trimethylenedioxy-(1, 2, 3, 4, 5 or 6-)1,2,3,4-tetrahydroquinolyl, 6,7-tetramethylenedioxy-(1, 2, 3, 4, 5 or 8-)1,2,3,4-tetrahydroquinolyl, 5-methoxy-2-oxo-(1, 3, 4, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl, and 2-oxo-6,7-ethylenedioxy-(1, 3, 4, 5 or 8-)1,2,3,4-tetrahydroquinolyl groups.
Examples of the cycloalkyl lower alkyl group include cycloalkylalkyl groups having 3 to 16 carbon atoms whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as cyclopropylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 1-cyclobutylethyl, 3-cyclopentylpropyl, 4-cyclohexylbutyl, 5-cycloheptylpentyl, 6-cyclooctylhexyl, 1,1-dimethyl-2-cyclononylethyl, 2-methyl-3-cyclodecylpropyl, cycloundecylmethyl, 2-cyclododecylethyl, 1-cyclotridecylethyl, 3-cyclotetradecylpropyl, 4-cyclopentadecylbutyl, and 5-cyclohexadecylpentyl groups.
Examples of the pyridyl lower alkyl group include pyridylalkyl groups whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (2, 3 or 4-)pyridylmethyl, 2-[(2, 3 or 4-)pyridyl]ethyl, 1-[(2, 3 or 4-)pyridyl]ethyl, 3-[(2, 3 or 4-)pyridyl]propyl, 4-[(2, 3 or 4-)pyridyl]butyl, 1,1-dimethyl-2-[(2, 3 or 4-)pyridyl]ethyl, 5-[(2, 3 or 4-)pyridyl]pentyl, 6-[(2, 3 or 4-)pyridyl]hexyl, 1-[(2, 3 or 4-)pyridyl]isopropyl, and 2-methyl-3-[(2, 3 or 4-)pyridyl]propyl groups.
Examples of the amino group substituted lower alkyl group which may have a substituent selected from the group consisting of a lower alkyl group and a lower alkanoyl group include linear or branched alkyl groups having 1 to 6 carbon atoms and an amino group which may have 1 or 2 substituents selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms and a linear or branched alkanoyl group having 1 to 6 carbon atoms such as aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 1,1-dimethyl-2-aminoethyl, 2-methyl-3-aminopropyl, methylaminomethyl, 1-ethylaminoethyl, 2-propylaminoethyl, 3-isopropylaminopropyl, 4-butylaminobutyl, 5-pentylaminopentyl, 6-hexylaminohexyl, dimethylaminomethyl, 2-diisopropylaminoethyl, (N-ethyl-N-propylamino)methyl, 2-(N,N-dimethylamino)ethyl, 2-(N-methyl-N-hexylamino)ethyl, formylaminomethyl, acetylaminomethyl, 1-propionylaminoethyl, 2-acetylaminoethyl, 3-butyrylaminopropyl, 4-pentanoylaminobutyl, 5-hexanoylaminopentyl, 6-acetylaminohexyl, N-methyl-N-acetylaminomethyl, 2-(N-ethyl-N-propanoylamino)ethyl, (N-ethyl-N-butyrylamino)methyl, 2-(N-methyl-N-hexanoylamino)ethyl, and 3-(N,N-dimethylamino)propyl groups.
Examples of the lower alkoxy lower alkyl group include linear or branched alkyl groups having 1 to 6 carbon atoms which have a linear or branched alkoxy group having 1 to 6 carbon atoms, as a substituent such as methoxymethyl, 1-ethoxyethyl, 2-methoxyethyl, 2-propoxyethyl, 3-isopropoxypropyl, 4-butoxybutyl, 5-pentyloxypentyl, 6-hexyloxyhexyl, 1,1-dimethyl-2-methoxyethyl, 2-methyl-3-ethoxypropyl, and 3-methoxypropyl groups.
Examples of the 1,2,3,4-tetrahydroisoquinolylcarbonyl substituted lower alkyl group include 1,2,3,4-tetrahydroisoquinolylcarbonyl-alkyl groups whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (1, 2, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydroisoquinolylcarbonylmethyl, 2-[(1, 2, 3, 4, 5, 6, 7or 8-)1,2,3,4-tetrahydroisoquinolylcarbonyl]ethyl, 1-[((1, 2, 3, 4, 5, 6, 7 or 8-)1, 2, 3, 4-tetrahydroisoquinolylcarbonyl)ethyl, 3-[(1, 2, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydroisoquinolylcarbonyl]propyl, 4-[(1, 2, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydroisoquinolylcarbonyl]butyl, 1,1-dimethyl-2-[(1, 2, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydroisoquinolylcarbonyl]ethyl, 5-[(1, 2, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydroisoquinolylcarbonyl]pentyl, 6-[(1, 2, 3, 4, 5, 6, 7 or 8-) 1,2,3,4-tetrahydroisoquinolylcarbonyl]hexyl, 1-[(1, 2, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydroisoquinolylcarbonyl]isopropyl, and 2-methyl-3-[(1, 2, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydroisoquinolylcarbonyl]propyl groups.
Examples of the piperidinylcarbonyl group which may have, on the piperidine ring, a substituent selected from the group consisting of a lower alkoxycarbonyl group, a phenyl lower alkyl group, and a furyl lower alkyl group include piperidinylcarbonyl groups which may have, on the piperidine ring, 1 to 3 substituents selected from the group consisting of an alkoxycarbonyl group whose alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms, a phenylalkyl group whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms, and a furylalkyl group whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (1, 2, 3 or 4-)piperidinylcarbonyl, 1-benzyl-(2, 3 or 4-)piperidinylcarbonyl, 1-(2 or 3-)furylmethyl-(2, 3 or 4-)piperidinylcarbonyl, 1-(2-phenylethyl)-(2, 3 or 4-)piperidinylcarbonyl, 1-{2-[(1 or 2-)furyl]ethyl}-(2, 3 or 4-)piperidinylcarbonyl, 1-(1-phenylethyl)-(2, 3 or 4-)piperidinylcarbonyl, 1-{3-[(1 or 2-)furyl]propyl]}-(2, 3 or 4-)piperidinylcarbonyl, 1-(3-phenylpropyl)-(2, 3 or 4-)piperidinylcarbonyl, 1-{1-[(1 or 2-)furyl]ethyl]}-(2, 3 or 4-)piperidinylcarbonyl, 1-(4-phenylbutyl)-(2, 3 or 4-)piperidinylcarbonyl, 1-{4-[(1 or 2-)furyl]butyl]}-(2, 3 or 4-)piperidinylcarbonyl, 1-(5-phenylpentyl)-(2, 3 or 4-)piperidinylcarbonyl, 1-{5-[(1 or 2-)furyl]pentyl]}-(2, 3 or 4-)piperidinylcarbonyl, 1-(6-phenylhexyl)-(2, 3 or 4-)piperidinylcarbonyl, 1-{6-[(1 or 2-)furyl]hexyl]}-(2, 3 or 4-)piperidinylcarbonyl, 1,2-dibenzyl-(3, 4, 5 or 6-)piperidinylcarbonyl, 1,3-di(1 or 2-)furylmethyl-(2, 4, 5 or 6-)piperidinylcarbonyl, 1,3,5-tribenzyl-(2, 4 or 6-)piperidinylcarbonyl, 1,2,6-tri(1 or 2-)furylmethyl-(3, 4 or 5-)piperidinylcarbonyl, 1-benzyl-3-(1 or 2-)furylmethyl-(2, 4, 5 or 6-)piperidinylcarbonyl, 1-{1-[(1 or 2-)furyl]ethyl]}-(2, 3 or 4-)piperidinylcarbonyl, 1-methoxycarbonyl-(2, 3 or 4-)piperidinylcarbonyl, 1-ethoxycarbonyl-(2, 3 or 4-)piperidinylcarbonyl, 1-propoxycarbonyl-(2, 3 or 4-)piperidinylcarbonyl, 1-butoxycarbonyl-(2, 3 or 4-)piperidinylcarbonyl, 1-tert-butoxycarbonyl-(2, 3 or 4-)piperidinylcarbonyl, 1-pentyloxycarbonyl-(2, 3 or 4-)piperidinylcarbonyl, 1-hexyloxycarbonyl-(2, 3 or 4-)piperidinylcarbonyl, 1,2-dimethoxycarbonyl-(3, 4, 5 or 6-)piperidinylcarbonyl, 1,2,6-triethoxycarbonyl-(3, 4 or 5-)piperidinylcarbonyl, 1-(1 or 2-)furylmethyl-3-tert-butoxycarbonyl-(3, 4, 5 or 6-)piperidinylcarbonyl, 1-benzyl-2-methoxycarbonyl-(2, 4, 5 or 6-)piperidinylcarbonyl, and 1-(1 or 2-)furylmethyl-2,4-dimethoxycarbonyl-(3, 5 or 6-)piperidinylcarbonyl groups.
Examples of the thiazolidinyl lower alkanoyl group which may have an oxo group as a substituent on the thiazolidine ring include thiazolidinylalkanoyl groups which may have 1 to 3 oxo groups as substituents on the thiazolidine ring and whose alkanoyl moiety is a linear or branched alkanoyl group having 2 to 6 carbon atoms such as 2-[(2, 3, 4 or 5-)thiazolidinyl]acetyl, 3-[(2, 3, 4 or 5-)thiazolidinyl]propionyl, 2-[(2, 3, 4 or 5-)thiazolidinyl]propionyl, 4-[(2, 3, 4 or 5-)thiazolidinyl]butyryl, 5-[(2, 3, 4 or 5-)1,2,4-thiazolidinyl]pentanoyl, 6-[(2, 3, 4 or 5-)thiazolidinyl]hexanoyl, 2,2-dimethyl-3-[(2, 3, 4 or 5-)thiazolidinyl]propionyl, 2-methyl-3-[(2, 3, 4 or 5-)thiazolidinyl]propionyl, 2,4-dioxo-(3 or 5-)thiazolidinylacetyl, 3-[2-oxo-(3, 4 or 5-)thiazolidinyl]propionyl, 2-[4-oxo-(2, 3 or 5-)thiazolidinyl]propionyl, 4-[5-oxo-(2, 3 or 4-)thiazolidinyl]butyryl, 5-[2,5-dioxo-(3 or 4-)thiazolidinyl]pentanoyl, 6-[2,4,5-trioxo-3-thiazolidinyl]hexanoyl, 2-[4,5-dioxo-(2 or 3-)thiazolidinyl]acetyl, 2,2-dimethyl-3-[2,4-dioxo-(3 or 5-)thiazolidinyl]propionyl, and 2-methyl-3-[2,4-dioxo-(3 or 5-)thiazolidinyl]propionyl groups.
Examples of the piperidinyl group which may be substituted on the piperidine ring with a group selected from the group consisting of a lower alkoxycarbonyl group, a phenyl lower alkyl group, a lower alkyl group, a benzoyl group and a furyl lower alkyl group include piperidinyl groups which may be substituted on the piperidine ring with 1 to 3 groups selected from the group consisting of an alkoxycarbonyl group whose alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms, a phenylalkyl group whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkyl group having 1 to 6 carbon atoms, a benzoyl group, and a furylalkyl group whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (1, 2, 3 or 4-)piperidinyl, 1-benzyl-(2, 3 or 4-)piperidinyl, 1-(2 or 3-)furylmethyl-(2, 3 or 4-)piperidinyl, 1-(2-phenylethyl)-(2, 3 or 4-)piperidinyl, 1-(2-[(1 or 2-)furyl]ethyl}-(2, 3 or 4-)piperidinyl, 1-(1-phenylethyl)-(2, 3 or 4-)piperidinyl, 1-{3-[(1 or 2-)furyl]propyl]}-(2, 3 or 4-)piperidinyl, 1-(3-phenylpropyl)-(2, 3 or 4-)piperidinyl, 1-{1-[(1 or 2-)furyl]ethyl]}-(2, 3 or 4-)piperidinyl, 1-(4-phenylbutyl)-(2, 3 or 4-)piperidinyl, 1-{4-[(1 or 2-)furyl]butyl]}-(2, 3 or 4-)piperidinyl, 1-(5-phenylpentyl)-(2, 3 or 4-)piperidinyl, 1-{5-[(1 or 2-)furyl]pentyl]}-(2, 3 or 4-)piperidinyl, 1-(6-phenylhexyl)-(2, 3 or 4-)piperidinyl, 1-{6-[(1 or 2-)furyl]hexyl]}-(2, 3 or 4-)piperidinyl, 1,2-dibenzyl-(3, 4, 5 or 6-)piperidinyl, 1,3-di(1 or 2-)furylmethyl-(2, 4, 5 or 6-)piperidinyl, 1,3,5-tribenzyl-(2, 4 or 6-)piperidinyl, 1,2,6-tri(1 or 2-)furylmethyl-(3, 4 or 5-)piperidinyl, 1-benzyl-3-(1 or 2-)furylmethyl-(2, 4, 5 or 6-)piperidinyl, 1-{1-[(1 or 2-)furyl]ethyl]}-(2, 3 or 4-)piperidinyl, 1-benzoyl-(2, 3 or 4-)piperidinyl, 1,2-dibenzoyl-(3, 4, 5 or 6-)piperidinyl, 1,3,5-tribenzoyl-(2, 4 or 6-)piperidinyl, 1-methyl-(2, 3 or 4-)piperidinyl, 1-ethyl-(2, 3 or 4-)piperidinyl, 1-propyl-(2, 3 or 4-)piperidinyl, 1-isopropyl-(2, 3 or 4-)piperidinyl, 1-butyl-(2, 3 or 4-)piperidinyl, 1-isobutyl-(2, 3 or 4-)piperidinyl, 1-tert-butyl-(2, 3 or 4-)piperidinyl, 1-pentyl-(2, 3 or 4-)piperidinyl, 1-hexyl-(2, 3 or 4-)piperidinyl, 1,2-dimethyl-(3, 4, 5 or 6-)piperidinyl, 1,2,6-trimethyl-(3, 4 or 5-)piperidinyl, 1-methyl-3-benzyl-(3, 4, 5 or 6-)piperidinyl, 1-benzoyl-2-methyl-(2, 4, 5 or 6-)piperidinyl, 1-(1 or 2-)furylmethyl-2,4-dimethyl-(3, 5 or 6-)piperidinyl, 1-methoxycarbonyl-(2, 3 or 4-)piperidinyl, 1-ethoxycarbonyl-(2, 3 or 4-)piperidinyl, 1-propoxycarbonyl-(2, 3 or 4-)piperidinyl, 1-butoxycarbonyl-(2, 3 or 4-)piperidinyl, 1-tert-butoxycarbonyl-(2, 3 or 4-)piperidinyl, 1-pentyloxycarbonyl-(2, 3 or 4-)piperidinyl, 1-hexyloxycarbonyl-(2, 3 or 4-)piperidinyl, 1,2-dimethoxycarbonyl-(3, 4, 5 or 6-)piperidinyl, 1,2,6-triethoxycarbonyl-(3, 4 or 5-)piperidinyl, 1-methyl-3-tert-butoxycarbonyl-(3, 4, 5 or 6-)piperidinyl, 1-benzoyl-2-methoxycarbonyl-(2, 4, 5 or 6-)piperidinyl, 1-(1 or 2-)furylmethyl-2,4-dimethoxycarbonyl-(3, 5 or 6-)piperidinyl, and 1-benzyl-2,4-dimethoxycarbonyl-(3, 5 or 6-)piperidinyl groups.
Examples of the carbonyl lower alkyl group substituted with a group:




(hereinafter called “A group”) include A group substituted carbonylalkyl groups whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as A group substituted carbonylmethyl, 2-A group substituted carbonylethyl, 1-A group substituted carbonylethyl, 3-A group substituted carbonylpropyl, 4-A group substituted carbonylbutyl, 1,1-dimethyl-2-A group substituted carbonylethyl, 5-A group substituted carbonylpentyl, 6-A group substituted carbonylhexyl, 1-A group substituted carbonylisopropyl, and 2-methyl-3-A group substituted carbonylpropyl groups.

Examples of the carbonyl lower alkyl group substituted with a group:




wherein R34 is an oxo group or a phenyl group, and d is an integer of 0 to 3 (hereinafter called. “B group”), include B group substituted carbonylalkyl groups whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as B group substituted carbonylmethyl, 2-B group substituted carbonylethyl, 1-B group substituted carbonylethyl, 3-B group substituted carbonylpropyl, 4-B group substituted carbonylbutyl, 1,1-dimethyl-2-B group substituted carbonylethyl, 5-B group substituted carbonylpentyl, 6-B group substituted carbonylhexyl, 1-B group substituted carbonylisopropyl, and 2-methyl-3-B group substituted carbonylpropyl groups.

Examples of the pyrrolidinyl lower alkyl group include pyrrolidinylalkyl groups whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (1-, 2-, or 3-)pyrrolidinylmethyl, 2-[(1-, 2-, or 3-)pyrrolidinyl]ethyl, 1-[(1-, 2-, or 3-)pyrrolidinyl]ethyl, 3-[(1-, 2-, or 3-)pyrrolidinyl]propyl, 4-[(1-, 2-, or 3-)pyrrolidinyl]butyl, 5-[(1-, 2-, or 3-)pyrrolidinyl]pentyl, 6-[(1-, 2-, or 3-)pyrrolidinyl]hexyl, 1,1-dimethyl-2-[(1-, 2-, or 3-)pyrrolidinyl]ethyl, and 2-methyl-3-[(1-, 2-, or 3-)pyrrolidinyl]propyl groups.
Examples of the morpholino lower alkyl group include morpholinoalkyl groups whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (2-, 3- or 4-)morpholinomethyl, 2-[(2-, 3- or 4-)morpholino]ethyl, 1-[(2-, 3- or 4-)morpholino]ethyl, 3-[(2-, 3- or 4-)morpholino]propyl, 4-[(2-, 3- or 4-)morpholino]butyl, 5-[(2-, 3- or 4-)morpholino]pentyl, 6-[(2-, 3- or 4-)morpholino]hexyl, 1,1-dimethyl-2-[(2-, 3- or 4-)morpholino]ethyl, and 2-methyl-3-[(2-, 3- or 4-)morpholino]propyl groups.
Examples of the phenyl lower alkenyl group include phenylalkenyl groups whose alkenyl moiety is a linear or branched alkenyl group having 2 to 6 carbon atoms and which have 1 to 3 double bonds such as styryl, 3-phenyl-2-propenyl group (trivial name: cinnamyl group), 4-phenyl-2-butenyl, 4-phenyl-3-butenyl, 5-phenyl-4-pentenyl, 5-phenyl-3-pentenyl, 6-phenyl-5-hexenyl, 6-phenyl-4-hexenyl, 6-phenyl-3-hexenyl, 4-phenyl-1,3-butadienyl, and 6-phenyl-1,3,5-hexatrienyl groups.
Examples of the anilinocarbonyl lower alkyl group which may have a lower alkyl group as a substituent on the phenyl ring include anilinocarbonylalkyl groups whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms and which may have 1 to 3 linear or branched alkyl groups having 1 to 6 carbon atoms as substituents on the phenyl ring such as anilinocarbonylmethyl, 2-anilinocarbonylethyl, 1-anilinocarbonylethyl, 3-anilinocarbonylpropyl, 4-anilinocarbonylbutyl, 5-anilinocarbonylpentyl, 6-anilinocarbonylhexyl, 1,1-dimethyl-2-anilinocarbonylethyl, 2-methyl-3-anilinocarbonylpropyl, (4-methylanilinocarbonyl)methyl, 2-(3-methylanilinocarbonyl)ethyl, 3-(4-methylanilinocarbonyl)propyl, 1-(2-ethylanilinocarbonyl)ethyl, 4-(3-ethylanilinocarbonyl)butyl, 5-(4-ethylanilinocarbonyl)pentyl, 6-(4-isopropylanilinocarbonyl)hexyl, 1,1-dimethyl-2-(3-butylanilinocarbonyl)ethyl, 2-methyl-3-(4-pentylanilinocarbonyl)propyl, 4-hexylanilinocarbonylmethyl, 3,4-dimethylanilinocarbonylmethyl, 3,4-diethylanilinocarbonylmethyl, 2,4-dimethylanilinocarbonylmethyl, 2,5-dimethylanilinocarbonylmethyl, 2,6-dimethylanilinocarbonylmethyl, and 3,4,5-trimethylanilinocarbonylmethyl groups.
Examples of the piperazinyl lower alkyl group which may have, on the piperazine ring, a substituent selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring include piperazinylalkyl groups whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms and which may have, on the piperazine ring, 1 to 3 substituents selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms and a phenylalkyl group which may have a linear or branched alkylenedioxy group having 1 to 4 carbon atoms as a substituent on the phenyl ring and whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as [(1-, 2- or 3-)piperazinyl]methyl, 2-[(1-, 2- or 3-)piperazinyl]ethyl, 1-[(1-, 2- or 3-)piperazinyl]ethyl, 3-[(1-, 2- or 3-)piperazinyl]propyl, 4-[(1-, 2- or 3-)piperazinyl]butyl, 5-[(1-, 2- or 3-)piperazinyl]pentyl, 6-[(1-, 2- or 3-)piperazinyl]hexyl, 1,1-dimethyl-2-[(1-, 2- or 3-)piperazinyl]ethyl, 2-methyl-3-[(1-, 2- or 3-)piperazinyl]propyl, [1-methyl-(2-, 3- or 4-)piperazinyl]methyl, 2-[1-ethyl-(2-, 3- or 4-)piperazinyl]ethyl, 1-[4-propyl-(1-, 2- or 3-)piperazinyl]ethyl, 3-[3-isopropyl-(1-, 2-, 4-, 5- or 6-)piperazinyl]propyl, 4-[2-butyl-(1-, 3-, 4-, 5- or 6-)piperazinyl]butyl, 5-[1-isobutyl-(2-, 3- or 4-)piperazinyl]pentyl, 3-[4-methyl-(1-, 2- or 3-)piperazinyl]propyl, 6-[1-tert-butyl-(2-, 3- or 4-)piperazinyl]hexyl, 1,1-dimethyl-2-[4-pentyl-(1-, 2- or 3-)piperazinyl]ethyl, [1,2-dimethyl-(3-, 4-, 5- or 6-)piperazinyl]methyl, [1,2,6-trimethyl-(3-, 4- or 5-)piperazinyl]methyl, and 2-[4-(3,4-methylenedioxybenzyl)-(1-, 2- or 3-)piperazinyl]ethyl groups.
Examples of the amidino lower alkyl group which may have a lower alkyl group as a substituent include amidinoalkyl groups whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms and which may have 1 or 2 linear or branched alkyl groups having 1 to 6 carbon atoms such as amidinomethyl, 2-amidinoethyl, 1-amidinoethyl, 3-amidinopropyl, 4-amidinobutyl, 5-amidinopentyl, 6-amidinohexyl, 1,1-dimethyl-2-amidinoethyl, 2-methyl-3-amidinopropyl, N,N-dimethylamidinomethyl, 2-(N,N-dimethylamidino)ethyl, 1-(N-methylamidino)ethyl, 3-(N-ethylamidino)propyl, 4-(N-n-propylamidino)propyl, 5-(N-n-pentylamidino)pentyl, 6-(N-n-hexylamidino)hexyl, and (N-methyl-N-ethylamidino)methyl groups.
Examples of the carbazolyl group which may have a lower alkyl group as a substituent on the carbazole ring include carbazolyl groups which may have 1 to 3 linear or branched alkyl groups having 1 to 6 carbon atoms as substituents on the carbazole ring such as (1-, 2-, 3- or 4-)carbazolyl, 9-methyl-(1-, 2-, 3- or 4-)carbazolyl, 9-ethyl-(1-, 2-, 3- or 4-)carbazolyl, 1-ethyl-(2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-)carbazolyl, 2-n-propyl-(1-, 3-, 4-, 5-, 6-, 8- or 9-)carbazolyl, 3-n-butyl-(1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-)carbazolyl, 4-n-pentyl-(1-, 2-, 3-, 5-, 6-, 7-, 8- or 9-)carbazolyl, 5-n-hexyl-(1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-)carbazolyl, 6,9-dimethyl-(1-, 2-, 3-, 4-, 5-, 7- or 8-)carbazolyl, and 1,7,8-trityl-(2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-)carbazolyl groups.
Examples of the amidino group which may have a lower alkyl group as a substituent include amidino groups which may have 1 or 2 linear or branched alkyl groups having 1 to 6 carbon atoms as substituents such as amidino, N,N-dimethylamidino, N-methylamidino, N-ethylamidino, N-n-propylamidino, N-n-butylamidino, N-n-pentylamidino, N-n-hexylamidino, N,N-diethylamidino, and N-methyl-N-ethylamidino groups.
Examples of the phenyl lower alkyl group (which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkylenedioxy group and a lower alkoxy group), include, in addition to the above described phenyl lower alkyl groups, phenylalkyl groups whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms (and which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a linear or branched alkylenedioxy group having 1 to 4 carbon atoms and a linear or branched alkoxy group having 1 to 6 carbon atoms) such as 3,4-methylenedioxybenzyl, 3,4-trimethylenedioxybenzyl, 2-(2,3-ethylenedioxyphenyl)ethyl, 1-(3,4-trimethylenedioxyphenyl)ethyl, 3-(2,3-tetramethylenedioxyphenyl)propyl, 4-(3,4-methylenedioxyphenyl)butyl, 5-(2,3-ethylenedioxyphenyl)pentyl, 6-(3,4-trimethylenedioxyphenyl)hexyl, 1,1-dimethyl-2-(2,3-methylenedioxyphenyl)ethyl, 2-methyl-3-(3,4-ethylenedioxyphenyl)propyl, 2-methoxybenzyl, 2-(2-methoxyphenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(4-methoxyphenyl)ethyl, 4-methoxybenzyl, 1-(2-ethoxyphenyl)ethyl, 3-(3-ethoxyphenyl)propyl, 4-(4-ethoxyphenyl)butyl, 5-(4-isopropoxyphenyl)pentyl, 6-(3-butoxyphenyl)hexyl, 1,1-dimethyl-2-(4-pentyloxyphenyl)ethyl, 2-methyl-3-(4-hexyloxyphenyl)propyl, 3,4-dimethoxybenzyl, 3,4-diethoxybenzyl, 2,4-dimethoxybenzyl, 2,5-dimethoxybenzyl, 2,6-dimethoxybenzyl, and 3,4,5-trimethoxybenzyl groups.
Examples of the piperazinyl substituted oxalyl group which may have, on the piperazine ring, 1 to 3 substituents selected from the group consisting of a phenyl lower alkyl group (which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkylenedioxy group and a lower alkoxy group) and a pyridyl lower alkyl group include piperazinyl substituted oxalyl groups which may have, on the piperazine ring, 1 to 3 substituents selected from the group consisting of a phenylalkyl group whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms (and which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a linear or branched alkylenedioxy group having 1 to 4 carbon atoms and a linear or branched alkoxy group having 1 to 6 carbon atoms) and a pyridylalkyl group whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as 4-(3,4-methylenedioxybenzyl)-(1-, 2- or 3-)piperazinyloxalyl, 4-(2-, 3- or 4-pyridylmethyl)-(1-, 2- or 3-)piperazinyloxalyl, 4-(3,4-dimethoxybenzyl)-(1-, 2- or 3-)piperazinyloxalyl, 4-(2,3-methylenedioxybenzyl)-(1-, 2- or 3-)piperazinyloxalyl, 4-(3,4-ethylenedioxybenzyl)-(1-, 2- or 3-)piperazinyloxalyl, 4-[2-(2-, 3- or 4-pyridyl)ethyl]-(1-, 2- or 3-)piperazinyloxalyl, 4-[3-(2-, 3- or 4-pyridyl)propyl-(1-, 2- or 3-)piperazinyloxalyl, 2,4-bis(2-, 3- or 4-pyridylmethyl)-(1-, 2- or 3-)piperazinyloxalyl, 2-(3,4-methylenedioxybenzyl)-4-(2-, 3- or 4-pyridylmethyl)-(1-, 2- or 3-)piperazinyloxalyl, and 2,3,4-tri(2-, 3- or 4-pyridylmethyl)-(1-, 2- or 3-)piperazinyloxalyl groups.
Examples of the cyano substituted lower alkyl group include cyanoalkyl groups whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 3-cyanopropyl, 4-cyanobutyl, 5-cyanopentyl, 6-cyanohexyl, 1,1-dimethyl-2-cyanoethyl, and 2-methyl-3-cyanopropyl groups.
Examples of the 5- to 7-membered saturated heterocyclic ring formed by binding R36 and R37 each other, together with nitrogen atoms bound to them, through or not through a nitrogen atom, an oxygen atom, or a sulfur atom include pyrrolidinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino, and homopiperazinyl groups.
Examples of the 5- to 10-membered saturated or unsaturated heterocyclic ring formed by binding R14 and R15 each other, together with nitrogen atoms bound to them, through or not through a nitrogen atom, an oxygen atom, or a sulfur atom include 1,2,3,4,5,6-hexahydropyrimidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino, homopiperazinyl, homopiperidinyl, thiazolidinyl, 1,2,5,6-tetrahydropyridyl, pyrrolyl, pyrazolyl, imidazolyl, 2-pyrrolinyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, 1,2-dihydropyridyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2-dihydroisoquinolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, 3,4-dihydro-2H-1,4-benzooxazinyl, 3,4-dihydro-2H-1,4-benzothiazolidinyl, 1,4-benzothiazinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1,2,3,4-tetrahydrocinnolinyl, 1,2,3,4-tetrahydrophthalazinyl, 1,2,3,4-tetrahydroquinazolinyl, 1,2-dihydroquinoxalinyl, 3,4-dihydroquinoxalinyl, 1,4-dihydroquinoxalinyl, 1,2-dihydrocinnolinyl, 1,2-dihydrophthalazinyl, 3,4-dihydrophthalazinyl, 1,2-dihydroquinazolinyl, 3,4-dihydroquinazolinyl, indazolyl, indazolinyl, 6-azabicyclo[3,2,1]octyl, 3-aza-spiro[5,5]undecyl, and thiazolidinyl groups. Preferably, R14 and R15, together with the nitrogen atom to which they bind, bind to each other, directly or via a nitrogen atom to form a 6-membered saturated heterocyclic group. Most preferably, they include piperidinyl and piperazinyl groups.
Examples of the phenyl lower alkoxy group include phenylalkoxy groups whose alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms such as benzyloxy, 2-phenylethoxy, 1-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 5-phenylpentyloxy, 6-phenylhexyloxy, 1,1-dimethyl-2-phenylethoxy, and 2-methyl-3-phenylpropoxy groups.
Examples of the phenyl substituted lower alkyl group which has 1 or 2 phenyl groups which may be substituted on the phenyl ring with 1 to 3 substituents selected from the group consisting of a lower alkanoyl group, an amino group which may have a lower alkanoyl group as a substituent, a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxy group which may have a halogen atom as a substituent, a phenyl lower alkoxy group, a hydroxyl group, and a lower alkylenedioxy groups; and which may have a pyridyl group on the lower alkyl group include in addition to the above described phenyl lower alkyl groups, phenyl substituted alkyl groups which have 1 or 2 phenyls which may be substituted on the phenyl ring with 1 to 3 substituents selected from the group consisting of a linear or branched alkanoyl group having 1 to 6 carbon atoms, an amino group which may have 1 or 2 linear or branched alkanoyl groups having 1 to 6 carbon atoms as substituents, a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms, a cyano group, a nitro group, a phenyl group, a halogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents, a linear or branched alkoxy group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents, a phenylalkoxy groups whose alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms, a hydroxy group, and a linear or branched alkylenedioxy group having 1 to 4 carbon atoms; which may have a pyridyl group on the alkyl group, and whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms, such as 1-phenyl-1-(2, 3 or 4-)pyridyl methyl, 1,1-diphenylmethyl, 1,1-di(4-fluorophenyl)methyl, 1-phenyl-1-(4-methoxyphenyl)methyl, 3,4-methylenedioxybenzyl, 3,4-ethylenedioxybenzyl, 3,4-trimethylenedioxybenzyl, 2,5-difluorobenzyl, 2,4-difluorobenzyl, 3,4-difluorobenzyl, 3,5-difluorobenzyl, 2,6-difluorobenzyl, 3-trifluoromethylbenzyl, 2-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 3,4-dimethylbenzyl, 2,3-dimethylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-cyanobenzyl, 2-cyanobenzyl, 3-cyanobenzyl, 4-methoxybenzyl, 2,3-dichlorobenzyl, 2,4-dichlorobenzyl, 2,5-dichlorobenzyl, 3,4-dichlorobenzyl, 2,6-dichlorobenzyl, 4-fluorobenzyl, 3-fluorobenzyl, 2-fluorobenzyl, 4-nitrobenzyl, 3-nitrobenzyl, 2-nitrobenzyl, 3-trifluoromethoxybenzyl, 4-trifluoromethoxybenzyl, 2-trifluoromethoxybenzyl, 4-methoxycarbonylbenzyl, 3-methoxycarbonylbenzyl, 4-tert-butylbenzyl, 4-ethylbenzyl, 4-isopropylbenzyl, 4-methoxy-3-chlorobenzyl, 2-(4-methoxyphenyl)ethyl, 2-(4-fluorophenyl)ethyl, 2-(4-chlorophenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(4-methylphenyl)ethyl, 4-phenylbenzyl, 3,3-diphenylpropyl, 3-methyl-4-nitrobenzyl, 4-(4-methoxyphenyl)butyl, 2-(4-methylphenyl)ethyl, 4-tert-butoxycarbonylbenzyl, 3-chloro-6-methoxybenzyl, 4-acetylaminobenzyl, 4-nitro-3-methylbenzyl, 4-hydroxybenzyl, 3-hydroxybenzyl, 2-hydroxybenzyl, 4-tert-butyrylbenzyl, 4-benzyloxybenzyl, 4-pivaloylbenzyl, 2-(4-acetylphenyl)ethyl, 1-(3-propionylphenyl)ethyl, 3-(2-butyrylphenyl)propyl, 4-(4-pentanoylphenyl)butyl, 5-(3-hexanoylphenyl)pentyl, 6-(2,4-diacetylphenyl)hexyl, 1,1-dimethyl-2-(2,4,6-triacetylphenyl)ethyl, 2-methyl-3-(3,4-diacetylphenyl)propyl, 2-(4-aminophenyl)ethyl, 1-(3-propionylaminophenyl)ethyl, 3-(2-butyrylaminophenyl)propyl, 4-(4-pentanoylamino)phenylbutyl, 5-(hexanoylaminophenyl)pentyl, 6-(N-acetyl-N-propionylaminophenyl)hexyl, 1,1-dimethyl-2-(3,4-diaminophenyl)ethyl, 2-methyl-3-(3,4,5-triacetylaminophenyl)propyl, 2-(2-ethoxycarbonylphenyl)ethyl, 1-(3-propoxycarbonylphenyl)ethyl, 3-(4-pentyloxycarbonylphenyl)propyl, 4-(3-hexyloxycarbonylphenyl)butyl, 5-(3,4-dimethoxycarbonylphenyl)pentyl, 6-(3,4,5-triethoxycarbonylphenyl)hexyl, 1,1-dimethyl-2-(4-butoxycarbonylphenyl)ethyl, 2-methyl-3-(4-methoxycarbonylphenyl)propyl, 2-(2-cyanophenyl)ethyl, 1-(3-cyanophenyl)ethyl, 3-(4-cyanophenyl)propyl, 4-(2-cyanophenyl)butyl, 5-(3-cyanophenyl)pentyl, 6-(4-cyanophenyl)hexyl, 1,1-dimethyl-2-(2,4-dicyanophenyl)ethyl, 2-methyl-3-(2,4,6-tricyanophenyl)propyl, 2-(2-nitrophenyl)ethyl, 1-(3-nitrophenyl)ethyl, 3-(4-nitrophenyl)propyl, 4-(2-nitrophenyl)butyl, 5-(3-nitrophenyl)pentyl, 6-(4-nitrophenyl)hexyl, 1,1-dimethyl-2-(2,4-dinitrophenyl)ethyl, 2-methyl-3-(2,4,6-trinitrophenyl)propyl, 2-(2-phenylphenyl)ethyl, 1-(3-phenylphenyl)ethyl, 3-(4-phenylphenyl)propyl, 4-(2-phenylphenyl)butyl, 5-(3-phenylphenyl)pentyl, 6-(4-phenylphenyl)hexyl, 1,1-dimethyl-2-(2,4-diphenylphenyl)ethyl, 2-methyl-3-(2,4,6-triphenylphenyl)propyl, 2-(2-fluorophenyl)ethyl, 1-(3-bromophenyl)ethyl, 3-(4-iodophenyl)propyl, 4-(2-bromophenyl)butyl, 5-(3-chlorophenyl)pentyl, 6-(4-bromophenyl)hexyl, 1,1-dimethyl-2-(2,4-dichlorophenyl)ethyl, 2-methyl-3-(2,4,6-trifluorophenyl)propyl, 2-(2-ethylphenyl)ethyl; 1-(3-propylphenyl)ethyl, 3-(4-butylphenyl)propyl, 4-(2-pentylphenyl)butyl, 5-(3-hexylphenyl)pentyl, 6-(4-trifluoromethylphenyl)hexyl, 1,1-dimethyl-2-(2,4-dimethylphenyl)ethyl, 2-methyl-3-[2,4,6-tri(trifluoromethyl)phenyl]propyl, 2-(2-ethoxyphenyl)ethyl, 1-(3-propoxyphenyl)ethyl, 3-(4-butoxyphenyl)propyl, 4-(2-pentyloxyphenyl)butyl, 5-(3-hexyloxyphenyl)pentyl, 6-(4-trifluoromethoxyphenyl)hexyl, 1,1-dimethyl-2-(2,4-dimethoxyphenyl)ethyl, 2-methyl-3-[2,4,6-tri(trifluoromethoxy)phenyl]propyl, 2-(2-benzyloxyphenyl)ethyl, 1-[3-(2-phenylethoxy)phenyl]ethyl, 3-[4-(3-phenylpropoxy)phenyl]propyl, 4-[2-(4-phenylbutoxy)phenyl]butyl, 5-[3-(5-phenylpentyloxy)phenyl]pentyl, 6-[4-(6-phenylhexyloxy)phenyl]hexyl, 1,1-dimethyl-2-(2,4-dibenzyloxyphenyl)ethyl, 2-methyl-3-(2,4,6-tribenzyloxyphenyl)propyl, 2-(2-hydroxyphenyl)ethyl, 1-(3-hydroxyphenyl)ethyl, 3-(4-hydroxyphenyl)propyl, 4-(2-hydroxyphenyl)butyl, 5-(3-hydroxyphenyl)pentyl, 6-(4-hydroxyphenyl)hexyl, 1,1-dimethyl-2-(2,4-dihydroxyphenyl)ethyl, 2-methyl-3-(2,4,6-trihydroxyphenyl)propyl, 2-(3,4-methylenedioxyphenyl)ethyl, 1-(2,3-ethylenedioxyphenyl)ethyl, 3-(3,4-trimethylenedioxyphenyl)propyl, 4-(3,4-tetramethylenedioxyphenyl)butyl, 5-(3,4-methylenedioxyphenyl)pentyl, 6-(3,4-ethylenedioxyphenyl)hexyl, 1,1-dimethyl-2-(3,4-methylenedioxy)ethyl, and 2-methyl-3-(3,4-methylenedioxyphenyl)propyl groups. Preferably, they include phenyl substituted lower alkyl groups which may be substituted on the phenyl ring with group(s), as substituent(s), selected from the group consisting of a lower alkanoyl group, an amino group which may have a lower alkanoyl group as a substituent, a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxy group which may have a halogen atom as a substituent, a phenyl lower alkoxy group, a hydroxyl group, and a lower alkylenedioxy groups.
Examples of the pyridyl lower alkyl group which may have, on the pyridine ring, 1 to 3 substituents selected from the group consisting of a hydroxyl group and a lower alkyl group which may have a hydroxyl group as a substituent include, in addition to the above described pyridyl lower alkyl groups, pyridylalkyl groups which may have, on the pyridine ring, 1 to 3 substituents selected from the group consisting of a hydroxy group and a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 hydroxy groups as substituents, and whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as [2-methyl-(3, 4, 5 or 6-)pyridyl]methyl, [2-methyl-3-hydroxy-5-hydroxy methyl-(4 or 6-)pyridyl]methyl, 2-[3-ethyl-(2, 4, 5 or 6-)pyridyl]ethyl, 1-[4-propyl-(2, 3, 5 or 6-)pyridyl]ethyl, 3-[2-butyl-(3, 4, 5 or 6-)pyridyl]propyl, 4-[3-pentyl-(2, 4, 5 or 6-)pyridyl]butyl, 1,1-dimethyl-2-[4-hexyl-(2, 3, 5 or 6-)pyridyl]ethyl, 5-[2,3-dimethyl-(4, 5 or 6-)pyridyl]pentyl, 6-[2,4,6-trimethyl-(3 or 5-)pyridyl]hexyl, 1-[2-hydroxy-(2, 3, 5 or 6-)pyridyl]isopropyl, 2-methyl-3-[3-hydroxy-(2, 4, 5 or 6-)pyridyl]propyl, [2-hydroxy-(3, 4, 5 or 6-)pyridyl]methyl, 2-[3-hydroxy-(2, 4, 5 or 6-)pyridyl]ethyl, 1-[4-hydroxy-(2, 3, 5 or 6-)pyridyl]ethyl, 3-[2-hydroxy-(3, 4, 5 or 6-)pyridyl]propyl, 4-[3-hydroxy-(2, 4, 5 or 6-)pyridyl]butyl, 1,1-dimethyl-2-[4-hydroxy-(2, 3, 5 or 6-)pyridyl]ethyl, 5-[2,3-dihydroxy-(4, 5 or 6-)pyridyl]pentyl, 6-[2,4,6-trihydroxy-(3 or 5-)pyridyl]hexyl, [2-hydroxymethyl-(3, 4, 5 or 6-)pyridyl]methyl, 2-[3-(2-hydroxyethyl)-(2, 4, 5 or 6-)pyridyl]ethyl, 1-[4-(3-hydroxypropyl)-(2, 3, 5 or 6-)pyridyl]ethyl, 3-[2-(4-hydroxybutyl)-(3, 4, 5 or 6-)pyridyl]propyl, 4-[3-(5-hydroxypentyl)-(2, 4, 5 or 6-)pyridyl]butyl, 1,1-dimethyl-2-[4-(6-hydroxyhexyl)-(2, 3, 5 or 6-)pyridyl]ethyl, 5-[2,3-di(hydroxymethyl)-(4, 5 or 6-)pyridyl]pentyl, 6-[2,4,6-tri(hydroxymethyl)-(3 or 5-)pyridyl]hexyl, 1-[2-hydroxymethyl-(2, 3, 5 or 6-)pyridyl]isopropyl, 2-methyl-3-[3-(2,3-dihydroxypropyl)-(2, 4, 5 or 6-)pyridyl]propyl, [2-methyl-3-(2,2,4-trihydroxybutyl)-(4, 5 or 6-)pyridyl]methyl, and [2-methyl-5-hydroxymethyl-(3, 4 or 6-)pyridyl]methyl groups.
Examples of the pyrrolyl lower alkyl group which may have 1 to 3 lower alkyl groups as substituents on the pyrrole ring include pyrrolylalkyl groups which may have 1 to 3 linear or branched alkyl groups having 1 to 6 carbon atoms on the pyrrole ring and whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as [(1, 2 or 3-)pyrrolyl]methyl, 2-[(1, 2 or 3-)pyrrolyl]ethyl, 1-[(1, 2 or 3-)pyrrolyl]ethyl, 3-[(1, 2 or 3-)pyrrolyl]propyl, 4-[(1, 2 or 3-)pyrrolyl]butyl, 5-[(1, 2 or 3-)pyrrolyl]pentyl, 6-[(1, 2 or 3-)pyrrolyl]hexyl, 1,1-dimethyl-2-[(1, 2 or 3-)pyrrolyl]ethyl, 2-methyl-3-[(1, 2 or 3-)pyrrolyl]propyl, [1-methyl-(2 or 3-)pyrrolyl]methyl, 2-[2-ethyl-(1, 3, 4 or 5-)pyrrolyl]ethyl, 1-[3-propyl-(1, 2, 4 or 5-)pyrrolyl]ethyl, 3-[1-butyl-(2, 3 or 4-)pyrrolyl]propyl, 4-[2-pentyl-(1, 3, 4 or 5-)pyrrolyl]butyl, 5-[3-hexyl-(1, 2, 4 or 5-)pyrrolyl]pentyl, 6-[1,2-dimethyl-(3, 4 or 5-)pyrrolyl]hexyl, 1,1-dimethyl-2-[1,2,3-trimethyl-(4 or 5-)pyrrolyl]ethyl, and 2-methyl-3-[1-ethyl-2-methyl-(3, 4 or 5-)pyrrolyl]propyl groups.
Examples of the benzoxazolyl lower alkyl group include benzoxazolylalkyl groups whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as [(2, 4, 5, 6 or 7-)benzooxazolyl]methyl, 2-[(2, 4, 5, 6 or 7-)benzooxazolyl]ethyl, 1-[(2, 4, 5, 6 or 7-)benzooxazolyl]ethyl, 3-[(2, 4, 5, 6 or 7-)benzooxazolyl]propyl, 4-[(2, 4, 5, 6 or 7-)benzooxazolyl]butyl, 5-[(2, 4, 5, 6 or 7-)benzooxazolyl]pentyl, 6-[(2, 4, 5, 6 or 7-)benzooxazolyl]hexyl, 1,1-dimethyl-2-[(2, 4, 5, 6 or 7-)benzooxazolyl]ethyl, and 2-methyl-3-[(2, 4, 5, 6 or 7-)benzooxazolyl]propyl groups.
Examples of the benzothiazolyl lower alkyl group include benzothiazolylalkyl groups whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as [(2, 4, 5, 6 or 7-)benzothiazolyl]methyl, 2-[(2, 4, 5, 6 or 7-)benzothiazolyl]ethyl, 1-[(2, 4, 5, 6 or 7-)benzothiazolyl]ethyl, 3-[(2, 4, 5, 6 or 7-)benzothiazolyl]propyl, 4-[(2, 4, 5, 6 or 7-)benzothiazolyl]butyl, 5-[(2, 4, 5, 6 or 7-)benzothiazolyl]pentyl, 6-[(2, 4, 5, 6 or 7-)benzothiazolyl]hexyl, 1,1-dimethyl-2-[(2, 4, 5, 6 or 7-)benzothiazolyl]ethyl, and 2-methyl-3-[(2, 4, 5, 6 or 7-)benzothiazolyl]propyl groups.
Examples of the furyl lower alkyl group include furylalkyl groups whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as [(2 or 3-)furyl]methyl, 2-[(2 or 3-)furyl]ethyl, 1-[(2 or 3-)furyl]ethyl, 3-[(2 or 3-)furyl]propyl, 4-[(2 or 3-)furyl]butyl, 5-[(2 or 3-)furyl]pentyl, 6-[(2 or 3-)furyl]hexyl, 1,1-dimethyl-2-[(2 or 3-)furyl]ethyl, and 2-methyl-3-[(2 or 3-)furyl]propyl groups.
Examples of the thiazolidinyl lower alkyl group which may have an oxo group as a substituent on the thiazolidine ring include thiazolidinylalkyl groups which may have 1 to 3 oxo groups as substituents on the thiazolidine ring and whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (2, 3, 4 or 5-)thiazolidinylmethyl, 2-[(2, 3, 4 or 5-)thiazolidinyl]ethyl, 1-[(2, 3, 4 or 5-)thiazolidinyl]ethyl, 3-[(2, 3, 4 or 5-)thiazolidinyl]propyl, 4-[(2, 3, 4 or 5-)thiazolidinyl]butyl, 5-[(2, 3, 4 or 5-)thiazolidinyl]pentyl, 6-[(2, 3, 4 or 5-)thiazolidinyl]hexyl, 1,1-dimethyl-2-[(2, 3, 4 or 5-)thiazolidinyl]ethyl, 2-methyl-3-[(2, 3, 4 or 5-)thiazolidinyl]propyl, [2,4-dioxo-(3 or 5-)thiazolidinyl]methyl, 2-[2-oxo-(3, 4 or 5-)thiazolidinyl]ethyl, 1-[4-oxo-(2, 3 or 5-)thiazolidinyl]ethyl, 3-[2-oxo-(3, 4 or 5-)thiazolidinyl]propyl, 4-[5-oxo-(2, 3 or 4-)thiazolidinyl]butyl, 5-[2,5-dioxo-(3 or 4-)thiazolidinyl]pentyl, 6-[2,4,5-trioxo-3-thiazolidinyl]hexyl, 1-[4,5-dioxo-(2 or 3-)thiazolidinyl]ethyl, 2-[4,5-dioxo-(2- or 3-)thiazolidinyl]ethyl, 1,1-dimethyl-2-[2,4-dioxo-(3 or 5-)thiazolidinyl]ethyl, and 2-methyl-3-[2,4-dioxo-(3 or 5-)thiazolidinyl]propyl groups.
Examples of the thiazolidinylidene lower alkyl group which may have an oxo group as a substituent on the thiazolidine ring include thiazolidinylidenealkyl groups which may have 1 to 3 oxo groups as substituents on the thiazolidine ring and whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (2, 4 or 5-)thiazolidinylidenemethyl, (2, 4 or 5-)thiazolidinylideneethyl, (2, 4 or 5-)thiazolidinylidenepropyl, (2, 4 or 5-)thiazolidinylideneisopropyl, (2, 4 or 5-)thiazolidinylidenebutyl, (2, 4 or 5-)thiazolidinylidenepentyl, (2, 4 or 5-)thiazolidinylidenehexyl, 4,5-dioxo-2-thiazolidinylidenemethyl, 2,5-dioxo-4-thiazolidinylidenemethyl, 2,4-dioxo-5-thiazolidinylidenemethyl, 4-oxo-(2 or 5-)thiazolidinylideneethyl, 5-oxo-(2 or 4-)thiazolidinylidenepropyl, and 2-oxo-(4 or 5-)thiazolidinylidenebutyl groups.
Examples of the benzoyl group which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a cyano group, an amino group which may have a lower alkylsulfonyl group as a substituent, a halogen atom, a lower alkoxy group, a lower alkyl group which may have a halogen atom as a substituent, a thiazolidinyl lower alkyl group which may have an oxo group as a substituent on the thiazolidine ring, a thiazolidinylidene lower alkyl group which may have an oxo group as a substituent on the thiazolidine ring, and a lower alkylenedioxy group include benzoyl groups which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a cyano group; an amino group which may have 1 or 2 linear or branched alkylsulfonyl groups having 1 to 6 carbon atoms as substituents; a halogen atom; a linear or branched alkoxy group having 1 to 6 carbon atoms; a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents; a thiazolidinylalkyl group which may have 1 to 3 oxo groups as substituents on the thiazolidine ring and whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms; a thiazolidinylidenealkyl group which may have 1 to 3 oxo groups as substituents on the thiazolidine ring and whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms; and a linear or branched alkylenedioxy group having 1 to 4 carbon atoms such as benzoyl, 4-cyanobenzoyl, 3,4-methylenedioxybenzoyl, 2-aminobenzoyl, 3-aminobenzoyl, 4-aminobenzoyl, 3,4-diaminobenzoyl, 2,4,6-triaminobenzoyl, 4-methoxybenzoyl, 4-trifluoromethylbenzoyl, 4-chlorobenzoyl, 3,4-difluorobenzoyl, 2-fluorobenzoyl, 3-bromobenzoyl, 4-iodobenzoyl, 3,4-dimethoxybenzoyl, 4-fluorobenzoyl, 3-cyanobenzoyl, 2-cyanobenzoyl, 2,3-dicyanobenzoyl, 3,4,5-tricyanobenzoyl, 4-methylbenzoyl, 4-(2,4-dioxothiazolidinylmethyl)benzoyl, 4-(2,4-dioxothiazolidinylidenemethyl)benzoyl, 2-methylbenzoyl, 3-methylbenzoyl, 2-ethylbenzoyl, 3-ethylbenzoyl, 4-ethylbenzoyl, 4-isopropylbenzoyl, 3-butylbenzoyl, 4-pentylbenzoyl, 4-hexylbenzoyl, 3,4-dimethylbenzoyl, 3,4-diethylbenzoyl, 2,4-dimethylbenzoyl, 2,5-dimethylbenzoyl, 2,6-dimethylbenzoyl, 3,4,5-trimethylbenzoyl, 2-methoxybenzoyl, 3-methoxybenzoyl, 2-ethoxybenzoyl, 3-ethoxybenzoyl, 4-ethoxybenzoyl, 4-isopropoxybenzoyl, 3-butoxybenzoyl, 4-pentyloxybenzoyl, 4-hexyloxybenzoyl, 3,4-diethoxybenzoyl, 2,4-dimethoxybenzoyl, 2,5-dimethoxybenzoyl, 2,6-dimethoxybenzoyl, 3,4,5-trimethoxybenzoyl, 2-trifluoromethylbenzoyl, 3-trifluoromethylbenzoyl, 4-trifluoromethylbenzoyl, 2-(bromomethyl)benzoyl, 3-(2-chloroethyl)benzoyl, 4-(2,3-dichloropropyl)benzoyl, 4-(4-fluorobutyl)benzoyl, 3-(5-chloropentyl)benzoyl, 4-(5-bromohexyl)benzoyl, 4-(5,6-dibromohexyl)benzoyl, 3,4-di(trifluoromethyl)benzoyl, 3,4-di(4,4,4-trichlorobutyl)benzoyl, 2,4-di(3-chloro-2-methylpropyl)benzoyl, 2,5-di(3-chloropropyl)benzoyl, 2,6-di(2,2,2-trifluoroethyl)benzoyl, 3,4,5-tri(trifluoromethyl)benzoyl, 4-(2,2,2-trichloroethyl)benzoyl, 2-methyl-4-trifluoromethylbenzoyl, 3-ethyl-4-trichloromethylbenzoyl, 2-methoxy-4-trifluoromethylbenzoyl, 3-ethyl-4-fluorobenzoyl, 3-ethoxy-4-trichloromethylbenzoyl, 2-methyl-3-trifluoromethyl-4-trifluoromethylbenzoyl, 3-fluorobenzoyl, 4-fluorobenzoyl, 2-bromobenzoyl, 4-bromobenzoyl, 2-iodobenzoyl, 3-iodobenzoyl, 2,3-dibromobenzoyl, 2,4-diiodobenzoyl, 2,5-difluorobenzoyl, 2,6-dichlorobenzoyl, 2,4,6-trichlorobenzoyl, 2,4-difluorobenzoyl, 3,4-difluorobenzoyl, 3,5-difluorobenzoyl, 2,6-difluorobenzoyl, 2-chlorobenzoyl, 3-chlorobenzoyl, 4-chlorobenzoyl, 2,3-dichlorobenzoyl, 2,4-dichlorobenzoyl, 2,5-dichlorobenzoyl, 3,4-dichlorobenzoyl, 2,6-dichlorobenzoyl, 3,5-dichlorobenzoyl, 2,4,6-trifluorobenzoyl, 2,4-difluorobenzoyl, 3,4-difluorobenzoyl, 3,4-methylenedioxybenzoyl, 3,4-trimethylenedioxybenzoyl, 2,3-ethylenedioxybenzoyl, 3,4-trimethylenedioxybenzoyl, 2,3-tetramethylenedioxybenzoyl, 2,3-methylenedioxybenzoyl, 3,4-ethylenedioxybenzoyl, and 2-methanesulfonylaminobenzoyl groups.
Examples of the thiazolidinyl lower alkanoyl group which may be substituted on the thiazolidine ring with a group selected from the group consisting of an oxo group and a group of the formula:




wherein Ra and Rb each represent a lower alkyl group, include thiazolidinylalkanoyl groups which may be substituted on the thiazolidine ring with 1 to 3 substituents selected from the group consisting of an oxo group and a group of the formula:





wherein Ra and Rb each represent a linear or branched alkyl group having 1 to 6 carbon atoms, and whose alkanoyl moiety is a linear or branched alkanoyl group having 2 to 6 carbon atoms such as 2-[(2, 3, 4 or 5-)thiazolidinyl]acetyl, 3-[(2, 3, 4 or 5-)thiazolidinyl]propionyl, 2-[(2, 3, 4 or 5-)thiazolidinyl]propionyl, 4-[(2, 3, 4 or 5-)thiazolidinyl]butyryl, 5-[(2, 3, 4 or 5-)thiazolidinyl]pentanoyl, 6-[(2, 3, 4 or 5-)thiazolidinyl]hexanoyl, 2,2-dimethyl-3-[(2, 3, 4 or 5-)thiazolidinyl]propionyl, 2-methyl-3-[(2, 3, 4 or 5-)thiazolidinyl]propionyl, [2,4-dioxo-(3 or 5-)thiazolidinyl]acetyl, 3-[2-oxo-(3, 4 or 5-)thiazolidinyl]propionyl, 2-[4-oxo-(2, 3 or 5-)thiazolidinyl]propionyl, 4-[5-oxo-(2, 3 or 4-)thiazolidinyl]butyryl, 5-[2,5-dioxo-(3 or 4-)thiazolidinyl]pentanoyl, 6-[2,4,5-trioxo-3-thiazolidinyl]hexanoyl, 2-[4,5-dioxo-(2 or 3-)thiazolidinyl]acetyl, 2,2-dimethyl-3-[2,4-dioxo-(3 or 5-)thiazolidinyl]propionyl, 2-methyl-3-[2,4-dioxo-(3 or 5-)thiazolidinyl]propionyl, 2-[4-oxo-2-isopropylidenehydrazono-(3 or 5-)thiazolidinyl]acetyl, 2-[2-oxo-5-isopropylidenehydrazono-(3 or 4-)thiazolidinyl]acetyl, 2-[2,4-di(isopropylidenehydrazono)-(3 or 5-)thiazolidinyl]acetyl, 3-[2-methylidenehydrazono-(3, 4 or 5-)thiazolidinyl]propionyl, 2-[4-ethylidenehydrazono-(2, 3 or 5-)thiazolidinyl]propionyl, 4-[5-propylidenehydrazono-(2, 3 or 4-)thiazolidinyl]butyryl, 5-[2,5-di(isopropylidenehydrazono)-(3 or 4-)thiazolidinyl]pentanoyl, 6-[2,4,5-tri(isopropylidenehydrazono)-3-thiazolidinyl]hexanoyl, 2-[4,5-di(isopropylidenehydrazono)-(2 or 3-)thiazolidinyl]acetyl, 2,2-dimethyl-3-[4-butylidenehydrazono(2, 3 or 5-)thiazolidinyl]propionyl, 2-methyl-3-[5-pentylidene-(2, 3 or 4-)thiazolidinyl]propionyl, and 2-(hexylidenehydrazono)-(3, 4 or 5-)thiazolidinylacetyl groups.

Examples of the lower alkyl group which may have a substituent selected from the group consisting of a hydroxyl group and a halogen atom include, in addition to the above described lower alkyl groups, linear or branched alkyl groups having 1 to 6 carbon atoms which may have 1 to 3 substituents selected from the group consisting of a hydroxy group and a halogen atom such as hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 1,1-dimethyl-2-hydroxyethyl, 5,5,4-trihydroxypentyl, 5-hydroxypentyl, 6-hydroxyhexyl, 1-hydroxyisopropyl, 2-methyl-3-hydroxypropyl, trifluoromethyl, trichloromethyl, chloromethyl, bromomethyl, fluoromethyl, iodomethyl, difluoromethyl, dibromomethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 3-chloropropyl, 2,3-dichloropropyl, 4,4,4-trichlorobutyl, 4-fluorobutyl, 5-chloropentyl, 3-chloro-2-methylpropyl, 5-bromohexyl, 5,6-dibromohexyl, 2-hydroxy-3-fluoropropyl, and 2,2-dichloro-3-hydroxybutyl groups.
Examples of the carbamoyl group which may have a group selected from the group consisting of a lower alkoxy lower alkyl group and a lower alkyl group include carbamoyl groups which may have 1 or 2 groups selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms and which has a linear or branched alkoxy group having 1 to 6 carbon atoms and a linear or branched alkyl group having 1 to 6 carbon atoms such as carbamoyl, N-(2-methoxyethyl)carbamoyl, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, tert-butylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl, dibutylcarbamoyl, dipentylcarbamoyl, dihexylcarbamoyl, N-methyl-N-ethylcarbamoyl, N-ethyl-N-propylcarbamoyl, N-methyl-N-butylcarbamoyl, N-methyl-N-hexylcarbamoyl, N-(methoxymethyl)carbamoyl, N-(3-propoxypropyl)carbamoyl, N-(4-butoxybutyl)carbamoyl, N-(4-ethoxybutyl)carbamoyl, N-(5-pentyloxypentyl)carbamoyl, N-(5-methoxypentyl)carbamoyl, N-(6-hexyloxyhexyl)carbamoyl, di(2-methoxyethyl)carbamoyl, N-(2-methoxyethyl)-N-methylcarbamoyl, and N-(2-methoxyethyl)-N-ethylcarbamoyl groups.
Examples of the phenyl group which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a carbamoyl group which may have a group selected from the group consisting of a lower alkoxy lower alkyl group and a lower alkyl group, a lower alkoxycarbonyl group, a carboxy group, a cyano group, a phenyl group, a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxy group which may have a halogen atom as a substituent, a benzoyl group which may have a halogen atom as a substituent on the phenyl ring, a phenyl lower alkyl group which may have a halogen atom as a substituent on, the phenyl ring, and a hydroxyl group include phenyl groups which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a carbamoyl group which may have 1 or 2 groups selected from the group consisting of an alkoxyalkyl group whose alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms and whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms and a linear or branched alkyl group having 1 to 6 carbon atoms; a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms; a carboxy group; a cyano group; a phenyl group; a halogen atom; a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents; a linear or branched alkoxy group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents; a benzoyl group which may have 1 to 3 halogen atoms as substituents on the phenyl ring; a phenylalkyl group which may have 1 to 3 halogen atoms as substituents on the phenyl ring and whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms, and a hydroxyl group such as phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3-butylphenyl, 4-pentylphenyl, 4-hexylphenyl, 3,4-dimethylphenyl, 3,4-diethylphenyl, 2,4-dimethylphenyl, 2,3-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4,5-trimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 4-isopropoxyphenyl, 3-butoxyphenyl, 4-pentyloxyphenyl, 4-hexyloxyphenyl, 3,4-dimethoxyphenyl, 3,4-diethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-(bromomethoxy)phenyl, 3-(2-chloroethoxy)phenyl, 4-(2,3-dichloropropoxy)phenyl, 4-(4-fluorobutoxy)phenyl, 3-(5-chloropentyloxy)phenyl, 4-(5-bromohexyloxy)phenyl, 4-(5,6-dibromohexyloxy)phenyl, 3,4-di(trifluoromethoxy)phenyl, 3,4-di(4,4,4-trichlorobutoxy)phenyl, 2,4-di(3-chloro-2-methoxypropyl)phenyl, 2,5-di(3-chloropropoxy)phenyl, 2,6-di(2,2,2-trifluoroethoxy)phenyl, 3,4,5-tri(trifluoromethoxy)phenyl, 4-(2,2,2-trichloroethoxy)phenyl, 2-methyl-4-trifluoromethoxyphenyl, 3-ethyl-4-trichloromethoxyphenyl, 2-methoxy-4-trifluoromethoxyphenyl, 3-ethoxy-4-trichloromethoxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluorbmethylphenyl, 2-(bromomethyl)phenyl, 3-(2-chloroethyl)phenyl, 4-(2,3-dichloropropyl)phenyl, 4-(4-fluorobutyl)phenyl, 3-(5-chloropentyl)phenyl, 4-(5-bromohexyl)phenyl, 4-(5,6-dibromohexyl)phenyl, 3,4-di(trifluoromethyl)phenyl, 3,4-di(4,4,4-trichlorobutyl)phenyl, 2,4-di(3-chloro-2-methylpropyl)phenyl, 2,5-di(3-chloropropyl)phenyl, 2,6-di(2,2,2-trifluoroethyl)phenyl, 3,4,5-tri(trifluoromethyl)phenyl, 4-(2,2,2-trichloroethyl)phenyl, 2-methyl-4-trifluoromethylphenyl, 3-ethyl-4-trichloromethylphenyl, 2-methoxycarbonylphenyl, 3-methoxycarbonylphenyl, 4-methoxycarbonylphenyl, 2-ethoxycarbonylphenyl, 3-ethoxycarbonylphenyl, 4-ethoxycarbonylphenyl, 4-isopropoxycarbonylphenyl, 3-butoxycarbonylphenyl, 4-tert-butoxycarbonylphenyl, 4-pentyloxycarbonylphenyl, 4-hexyloxycarbonylphenyl, 3,4-dimethoxycarbonylphenyl, 3,4-diethoxycarbonylphenyl, 2,4-dimethoxycarbonylphenyl, 2,5-diethoxycarbonylphenyl, 2,6-dimethoxycarbonylphenyl, 3,4,5-triethoxycarbonylphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 3,4-dicyanophenyl, 3,5-dicyanophenyl, 2,4-dicyanophenyl, 2,5-dicyanophenyl, 2,6-dicyanophenyl, 3,4,5-tricyanophenyl, 2-phenylphenyl, 3-phenylphenyl, 4-phenylphenyl, 3,4-diphenylphenyl, 3,5-diphenylphenyl, 2,4-diphenylphenyl, 2,5-diphenylphehyl, 2,6-diphenylphenyl, 3,4,5-triphenylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2,6-dichlorophenyl, 3,5-dichlorophenyl, 2,4,6-trichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,5-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,6-difluorophenyl, 2,4,6-trifluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2,3-dibromophenyl, 2,4-diiodophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl, 3,5-dihydroxyphenyl, 2,4-dihydroxyphenyl, 2,5-dihydroxyphenyl, 2,6-dihydroxyphenyl, 3,4,5-trihydroxyphenyl, 3-benzylphenyl, 2-(2-phenylethyl)phenyl, 4-(1-phenylethyl)phenyl, 2-(3-phenylpropyl)phenyl, 3-(4-phenylbutyl)phenyl, 4-(5-phenylpentyl)phenyl, 2-(6-phenylhexyl)phenyl, 4-(1,1-dimethyl-2-phenylethyl)phenyl, 3-(2-methyl-3-phenylpropyl)phenyl, 2-(4-fluorobenzyl)phenyl, 2-methyl-5-chlorophenyl, 2-methoxy-5-chlorophenyl, 4-(4-fluorobenzoyl)phenyl, 4-(4-fluorobenzyl)phenyl, 3-(2-chlorobenzyl)phenyl, 4-(3-chlorobenzyl)phenyl, 2-(4-chlorobenzyl)phenyl, 3-[2-(4-fluorophenyl)ethyl]phenyl, 4-[2-(4-chlorophenyl)ethyl]phenyl, 2-(3,4-dibromobenzyl)phenyl, 3-(3,4-diiodobenzyl)phenyl, 4-(2,4-difluorobenzyl)phenyl, 2-(2,5-dichlorobenzyl)phenyl, 3-(2,6-dichlorobenzyl)phenyl, 4-(3,4,5-trifluorobenzyl)phenyl, 2-[3-(4-chlorophenyl)propyl]phenyl, 3-[1-(2-bromophenyl)ethyl]phenyl, 4-[4-(3-fluorophenyl)butyl]phenyl, 2-[5-(4-iodophenyl)pentyl]phenyl, 3-[6-(4-chlorophenyl)hexyl]phenyl, 2-[1,1-dimethyl-2-(3-fluorophenyl)ethyl]phenyl, 4-[2-methyl-3-(4-chlorophenyl)propyl]phenyl, 2,4-dibenzylphenyl, 2,4,6-tribenzylphenyl, 2-chloro-4-cyanophenyl, 3-hydroxy-4-phenylphenyl, 3-ethoxycarbonyl-2-benzoylphenyl, 2-benzyl-4-methyl-6-methoxyphenyl, 4-[(2-methoxyethyl)carbamoyl]phenyl, 3-(N-ethyl-N-isopropylcarbamoyl)phenyl, 4-dimethylcarbamoylphenyl, 2-carboxyphenyl, 3-carboxyphenyl, and 4-carboxyphenyl groups.
Examples of the phenyl group which has a lower alkylenedioxy group as a substituent on the phenyl ring include phenyl groups which has a linear or branched alkylenedioxy group having 1 to 4 carbon atom as a substituent on the phenyl ring such as 3,4-methylenedioxyphenyl, 3,4-trimethylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 2,3-tetramethylenedioxyphenyl, 2,3-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, and 2,3-trimethylenedioxyphenyl groups.
Examples of the naphthyl lower alkyl group include naphthylalkyl groups whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (1 or 2-)naphthylmethyl, 2-[(1 or 2-)naphthyl]ethyl, 1-[(1 or 2-)naphthyl]ethyl, 3-[(1 or 2-)naphthyl]propyl, 4-[(1 or 2-)naphthyl]butyl, 5-[(1 or 2-)naphthyl]pentyl, 6-[(1 or 2-)naphthyl]hexyl, 1,1-dimethyl-2-[(1 or 2-)naphthyl]ethyl, and 2-methyl-3-[(1 or 2-)naphthyl]propyl groups.
Examples of the phenoxy group which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a cyano group, a lower alkyl group which may have a halogen atom as a substituent, and a lower alkoxy group which may have a halogen atom as a substituent include phenoxy groups which may be substituted on the phenyl group with 1 to 3 groups selected from the group consisting of a cyano group, a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents, and a linear or branched alkoxy group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents such as phenoxy, 2-methylphenoxy, 3-methylphenyl, 4-methylphenoxy, 2-ethylphenoxy, 3-ethylphenoxy, 4-ethylphenoxy, 4-isopropylphenoxy, 3-butylphenoxy, 4-pentylphenoxy, 4-hexylphenoxy, 3,4-dimethylphenoxy, 3,4-diethylphenoxy, 2,4-dimethylphenoxy, 2,5-dimethylphenoxy, 2,6-dimethylphenoxy, 3,4,5-trimethylphenoxy, 2-methoxyphenoxy, 3-methoxyphenoxy, 4-methoxyphenoxy, 2-ethoxyphenoxy, 3-ethoxyphenoxy, 4-ethoxyphenoxy, 4-isopropoxyphenoxy, 3-butoxyphenoxy, 4-pentyloxyphenoxy, 4-hexyloxyphenoxy, 3,4-dimethoxyphenoxy, 3,4-diethoxyphenoxy, 2,4-dimethoxyphenoxy, 2,5-dimethoxyphenoxy, 2,6-dimethoxyphenoxy, 3,4,5-trimethoxyphenoxy, 2-trifluoromethoxyphenoxy, 3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, 2-(bromomethoxy)phenoxy, 3-(2-chloroethoxy)phenoxy, 4-(2,3-dichloropropoxy)phenoxy, 4-(4-fluorobutoxy)phenoxy, 3-(5-chloropentyloxy)phenoxy, 4-(5-bromohexyloxy)phenoxy, 4-(5,6-dibromohexyloxy)phenoxy, 3,4-di(trifluoromethoxy)phenoxy, 3,4-di(4,4,4-trichlorobutoxy)phenoxy, 2,4-di(3-chloro-2-methoxypropyl)phenoxy, 2,5-di(3-chloropropoxy)phenoxy, 2,6-di(2,2,2-trifluoroethoxy)phenoxy, 3,4,5-tri(trifluoromethoxy)phenoxy, 4-(2,2,2-trichloroethoxy)phenoxy, 2-methyl-4-trifluoromethoxyphenoxy, 3-ethyl-4-trichloromethoxyphenoxy, 2-methoxy-4-trifluoromethoxyphenoxy, 3-ethoxy-4-trichloromethoxyphenoxy, 2-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 4-trifluoromethylphenoxy, 2-(bromomethyl)phenoxy, 3-(2-chloroethyl)phenoxy, 4-(2,3-dichloropropyl)phenoxy, 4-(4-fluorobutyl)phenoxy, 3-(5-chloropentyl)phenoxy, 4-(5-bromohexyl)phenoxy, 4-(5,6-dibromohexyl)phenoxy, 3,4-di(trifluoromethyl)phenoxy, 3,4-di(4,4,4-trichlorobutyl)phenoxy, 2,4-di(3-chloro-2-methylpropyl)phenoxy, 2,5-di(3-chloropropyl)phenoxy, 2,6-di(2,2,2-trifluoroethyl)phenoxy, 3,4,5-tri(trifluoromethyl)phenoxy, 4-(2,2,2-trichloroethyl)phenoxy, 2-methyl-4-trifluoromethylphenoxy, 3-ethyl-4-trichloromethylphenoxy, 2-cyanophenoxy, 3-cyanophenoxy, 4-cyanophenoxy, 3,4-dicyanophenoxy, 3,5-dicyanophenoxy, 2,3-dicyanophenoxy, 2,4-dicyanophenoxy, 2,5-dicyanophenoxy, 2,6-dicyanophenoxy, 3,4,5-tricyanophenoxy, 2-cyano-4-methylphenoxy, 3-cyano-4-methoxyphenoxy, 3-cyano-5-trifluoromethylphenoxy, and 4-cyano-3-trifluoromethoxyphenoxy groups.
Examples of the phenyl lower alkoxy group which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, and a lower alkoxy group which may have a halogen atom as a substituent include, in addition to the above described phenyl lower alkoxy groups, phenylalkoxy groups which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a halogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents, and a linear or branched alkoxy group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents, and whose alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms such as 2,5-difluorobenzyloxy, 2,4-difluorobenzyloxy, 3,4-difluorobenzyloxy, 3,5-difluorobenzyloxy, 2,6-difluorobenzyloxy, 3-trifluoromethylbenzyloxy, 2-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy, 3,4-dimethoxybenzyloxy, 3,5-dimethoxybenzyloxy, 2-chlorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy, 2-methylbenzyloxy, 3-methylbenzyloxy, 4-methylbenzyloxy, 3,4-dimethylbenzyloxy, 2,3-dimethylbenzyloxy, 2-methoxybenzyloxy, 3-methoxybenzyloxy, 4-methoxybenzyloxy, 2,3-dichlorobenzyloxy, 2,4-dichlorobenzyloxy, 2,5-dichlorobenzyloxy, 3,4-dichlorobenzyloxy, 2,6-dichlorobenzyloxy, 4-fluorobenzyloxy, 3-fluorobenzyloxy, 2-fluorobenzyloxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 2-trifluoromethoxybenzyloxy, 4-tert-butylbenzyloxy, 4-ethylbenzyloxy, 4-isopropylbenzyloxy, 4-methoxy-3-chlorobenzyloxy, 2-(4-methoxyphenyl)ethoxy, 2-(4-fluorophenyl)ethoxy, 2-(4-chlorophenyl)ethoxy, 2-(3-methoxyphenyl)ethoxy, 2-(4-methylphenyl)ethoxy, 3-methyl-4-chlorobenzyloxy, 4-(4-methoxyphenyl)butoxy, 2-(4-methylphenyl)ethoxy, 4-tert-butitocybenzyloxy, 3-chloro-6-methoxybenzyloxy, 4-methoxy-3-methylbenzyloxy, 2-(2-fluorophenyl)ethoxy, 1-(3-bromophenyl)ethoxy, 3-(4-iodophenyl)propoxy, 4-(2-bromophenyl)butoxy, 5-(3-chlorophenyl)pentyloxy, 6-(4-bromophenyl)hexyloxy, 1,1-dimethyl-2-(2,4-dichlorophenyl)ethoxy, 2-methyl-3-(2,4,6-trifluorophenyl)propoxy, 2-(2-ethylphenyl)ethoxy, 1-(3-propylphenyl)ethoxy, 3-(4-butylphenyl)propoxy, 4-(2-pentylphenyl)butoxy, 5-(3-hexylphenyl)pentyloxy, 6-(4-trifluoromethylphenyl)hexyloxy, 1,1-dimethyl-2-(2,4-dimethylphenyl)ethoxy, 2-methyl-3-[2,4,6-tri(trifluoromethyl)phenyl]propoxy, 2-(2-ethoxyphenyl)ethoxy, 1-(3-propoxyphenyl)ethoxy, 3-(4-butoxyphenyl)propoxy, 4-(2-pentyloxyphenyl)butoxy, 5-(3-hexyloxyphenyl)pentyloxy, 6-(4-trifluoromethoxyphenyl)hexyloxy, 1,1-dimethyl-2-(2,4-dimethoxyphenyl)ethoxy, and 2-methyl-3-[2,4,6-tri(trifluoromethoxy)phenyl]propoxy groups.
Examples of the 1,2,3,4-tetrahydronaphthyl substituted lower alkyl group which may have 1 to 5 lower alkyl groups as substituents on the 1,2,3,4-tetrahydronaphthalene ring include 1,2,3,4-tetrahydronaphthyl substituted alkyl groups which may have 1 to 5 linear or branched alkyl groups having 1 to 6 carbon atoms as substituents on the 1,2,3,4-tetrahydronaphthalene ring, and whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (1, 2, 5 or 6-)1,2,3,4-tetrahydronaphthylmethyl, 2-[(1, 2, 5 or 6-)1,2,3,4-tetrahydronaphthyl]ethyl, 1-[(1, 2, 5 or 6-)1,2,3,4-tetrahydronaphthyl]ethyl, 3-[(1, 2, 5 or 6-)1,2,3,4-tetrahydronaphthyl]propyl, 4-[(1, 2, 5 or 6-)1,2,3,4-tetrahydronaphthyl]butyl, 5-[(1, 2, 5 or 6-)1,2,3,4-tetrahydronaphthyl]pentyl, 6-[(1, 2, 5 or 6-)1,2,3,4-tetrahydronaphthyl]hexyl, 1,1-dimethyl-2-[(1, 2, 5 or 6-)1,2,3,4-tetrahydronaphthyl]ethyl, 2-methyl-3-[(1, 2, 5 or 6-)1,2,3,4-tetrahydronaphthyl]propyl, 1,1,4,4-tetramethyl(2, 3, 5 or 6-)1,2,3,4-tetrahydronaphthylmethyl, 1,1,4,4,5-pentamethyl(2, 3, 6, 7 or 8-)1,2,3,4-tetrahydronaphthylmethyl, 1,4,4-trimethyl(2, 3, 5, 6, 7 or 8-)1,2,3,4-tetrahydronaphthylmethyl, 5,6-dimethyl(2, 3, 7 or 8-)1,2,3,4-tetrahydronaphthylmethyl, 2-[1-methyl-(1, 2, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydronaphthyl]ethyl, 1-[2-ethyl-(1, 2, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydronaphthyl]ethyl, 3-[3-propyl-(1, 2, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydronaphthyl]propyl, 4-[(4-butyl-(1, 2, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydronaphthyl]butyl, 5-[5-pentyl-(1, 2, 3, 4, 6, 7 or 8-)1,2,3,4-tetrahydronaphthyl]pentyl, 6-[6-hexyl-(1, 2, 3, 4, 5, 7 or 8-)1,2,3,4-tetrahydronaphthyl]hexyl, 1,1-dimethyl-2-[1,7-dimethyl-(1, 2, 3, 4, 5, 6 or 8-)1,2,3,4-tetrahydronaphthyl]ethyl, and 2-methyl-3-[1,1,4-trimethyl-(2, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydronaphthyl]propyl groups.
Examples of the piperidinyl group which may have 1 to 3 lower alkyl groups as substituents on the piperidine ring include piperidinyl group which may have 1 to 3 linear or branched alkyl groups having 1 to 6 carbon atoms as substituents on the piperidine ring such as (1, 2, 3 or 4-)piperidinyl, 1-methyl-(2, 3 or 4-)piperidinyl, 1-ethyl-(2, 3 or 4-)piperidinyl, 1-propyl-(2, 3 or 4-)piperidinyl, 1-isopropyl-(2, 3 or 4-)piperidinyl, 1-butyl-(2, 3 or 4-)piperidinyl, 1-isobutyl-(2, 3 or 4-)piperidinyl, 1-tert-butyl-(2, 3 or 4-)piperidinyl, 1-pentyl-(2, 3 or 4-)piperidinyl, 1-hexyl-(2, 3 or 4-)piperidinyl, 1,2-dimethyl-(3, 4, 5 or 6-)piperidinyl, and 1,2,6-trimethyl-(3, 4 or 5-)piperidinyl groups.
Examples of the quinolyl lower alkyl group include quinolylalkyl groups whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (2, 3, 4, 5, 6, 7 or 8-)quinolylmethyl, 2-[(2, 3, 4, 5, 6, 7 or 8-)quinolyl]ethyl, 1-[(2, 3, 4, 5, 6, 7 or 8-)quinolyl]ethyl, 3-[(2, 3, 4, 5, 6, 7 or 8-)quinolyl]propyl, 4-[(2, 3, 4, 5, 6, 7 or 8-)quinolyl]butyl, 5-[(2, 3, 4, 5, 6, 7 or 8-)pentyl, and 6-[(2, 3, 4, 5, 6, 7 or 8-)hexyl groups.
Examples of the 1,2,3,4-tetrazolyl lower alkyl group which may have, on the tetrazole ring, a substituent selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group include 1,2,3,4-tetrazolylalkyl groups whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms and which may have, on the tetrazole ring, a substituent selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms and a phenyl alkyl group whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms, such as [(1 or 5-)1,2,3,4-tetrazolyl]methyl, 2-[(1 or 5-)1,2,3,4-tetrazolyl]ethyl, 1-[(1 or 5-)1,2,3,4-tetrazolyl]ethyl, 3-[(1 or 5-)1,2,3,4-tetrazolyl]propyl, 4-[(1 or 5-)1,2,3,4-tetrazolyl]butyl, 5-[(1 or 5-)1,2,3,4-tetrazolyl]pentyl, 6-[(1 or 5-)1,2,3,4-tetrazolyl]hexyl, 5-[1-methyl-5-(1,2,3,4-tetrazolyl)]pentyl, 6-[1-methyl-5-(1,2,3,4-tetrazolyl)]hexyl, 5-methyl-1-(1,2,3,4-tetrazolyl)methyl, 2-[5-ethyl-1-(1,2,3,4-tetrazolyl]hexyl, 1,1-dimethyl-2-[(1 or 5-)1,2,3,4-tetrazolyl)]ethyl, 2-methyl-3-[(1 or 5-)1,2,3,4-tetrazolyl]propyl, [1-methyl-5-(1,2,3,4-tetrazolyl)]methyl, [1-ethyl-5-(1,2,3,4-tetrazolyl)]methyl, 2-[1-propyl-5-(1,2,3,4-tetrazolyl)]ethyl, 1-[1-butyl-5-(1,2,3,4-tetrazolyl)]ethyl, 3-[1-pentyl-5-(1,2,3,4-tetrazolyl)]propyl, 3-[5-propyl-1-(1,2,3,4-tetrazolyl)]propyl, 4-[5-butyl-1-(1,2,3,4-tetrazolyl)]butyl, 5-[5-pentyl-1-(1,2,3,4-tetrazolyl)]pentyl, 6-[5-hexyl-1-(1,2,3,4-tetrazolyl)]hexyl, [1-ethyl-5-(1,2,3,4-tetrazolyl)]methyl, [1-benzyl-5-(1,2,3,4-tetrazolyl)]methyl, 1-[(2-phenylethyl)-5-(1,2,3,4-tetrazolyl)]methyl, 2-[1-(3-phenylpropyl)-5-(1,2,3,4-tetrazolyl)]ethyl, 1-[1-(4-phenylbutyl)-5-(1,2,3,4-tetrazolyl)]ethyl, 3-[1-(5-phenylpentyl)-5-(1,2,3,4-tetrazolyl)]propyl, 4-[1-(6-phenylhexyl)-5-(1,2,3,4-tetrazolyl)]butyl, 5-[1-(1,1-dimethyl-2-phenylethyl)-5-(1,2,3,4-tetrazolyl)]methyl, 6-[1-(2-methyl-3-phenylpropyl)-5-(1,2,3,4-tetrazolyl)]hexyl, 5-benzyl-1-(1,2,3,4-tetrazolyl)methyl, 2-[5-(1-phenylethyl)-1-(1,2,3,4-tetrazolyl)]ethyl, 3-[5-(3-phenylpropyl)-1-(1,2,3,4-tetrazolyl)]propyl, 4-[5-(4-phenylbutyl)-1-(1,2,3,4-tetrazolyl)]butyl, 5-[5-(5-phenylpentyl)-1-(1,2,3,4-tetrazolyl)]pentyl, and 6-[5-(6-phenylhexyl)-1-(1,2,3,4-tetrazolyl)]hexyl groups.
Examples of the thiazolyl lower alkyl group which may have a phenyl group as a substituent on the thiazole ring include thiazolylalkyl groups which may have 1 or 2 phenyl groups as substituents on the thiazole ring and whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as [(2, 4 or 5-)thiazolyl]methyl, 2-[(2, 4 or 5-)thiazolyl]ethyl, 1-[(2, 4 or 5-)thiazolyl]ethyl, 3-[(2, 4 or 5-)thiazolyl]propyl, 4-[(2, 4 or 5-)thiazolyl]butyl, 5-[(2, 4 or 5-)thiazolyl]pentyl, 6-[(2, 4 or 5-)thiazolyl]hexyl, 1,1-dimethyl-2-[(2, 4 or 5-)thiazolyl]ethyl, 2-methyl-3-[(2, 4 or 5-)thiazolyl]propyl, [2-phenyl-(4 or 5-)thiazolyl]methyl, 2-[4-phenyl-(2 or 5-)thiazolyl]ethyl, 1-[5-phenyl-(2 or 4-)thiazolyl]ethyl, 3-[2-phenyl-(2 or 5-)thiazolyl]propyl, 4-(2,4-diphenyl-5-thiazolyl)butyl, 5-(2,5-diphenyl-4-thiazolyl)pentyl, 6-(4,5-diphenyl-2-thiazolyl)hexyl, 1,1-dimethyl-2-[2-phenyl-(4 or 5-)thiazolyl]ethyl, 2-methyl-3-[4-phenyl-(2 or 5-)thiazolyl]propyl, [4-phenyl-(2 or 5-)thiazolyl]methyl, [5-phenyl-(2 or 4-)thiazolyl]methyl, (2,4-diphenyl-5-thiazolyl)methyl, (2,5-diphenyl-4-thiazolyl)methyl, and (4,5-diphenyl-2-thiazolyl)methyl groups.
Examples of the benzoyl lower alkyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkoxy group and a halogen atom include benzoylalkyl groups which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a linear or branched alkoxy group having 1 to 6 carbon atoms and a halogen atom and whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as benzoylmethyl, 2-benzoylethyl, 1-benzoylethyl, 3-benzoylpropyl, 4-benzoylbutyl, 5-benzoylpentyl, 6-benzoylhexyl, 1,1-dimethyl-2-benzoylethyl, 2-methyl-3-benzoylpropyl, 4-fluorobenzoylmethyl, 2-chlorobenzoylmethyl, 3-chlorobenzoylmethyl, 4-chlorobenzoylmethyl, 2-(4-fluorobenzoyl)ethyl, 2-(4-chlorobenzoyl)ethyl, 3,4-dibromobenzoylmethyl, 3,4-diiodobenzoylmethyl, 2,4-difluorobenzoylmethyl, 2,5-dichlorobenzoylmethyl, 2,6-dichlorobenzoylmethyl, 3,4,5-trifluorobenzoylmethyl, 3-(4-chlorobenzoyl)propyl, 1-(2-bromobenzoyl)ethyl, 4-(3-fluorobenzoyl)butyl, 5-(4-iodobenzoyl)pentyl, 6-(4-chlorobenzoyl)hexyl, 1,1-dimethyl-2-(3-fluorobenzoyl)ethyl, 2-methyl-3-(4-chlorobenzoyl)propyl, 2-methoxybenzoylmethyl, 2-(3-methoxybenzoyl)ethyl, 2-(4-methoxybenzoyl)ethyl, 4-methoxybenzoylmethyl, 1-(2-ethoxybenzoyl)ethyl, 3-(3-ethoxybenzoyl)propyl, 4-(4-ethoxybenzoyl)butyl, 5-(4-isopropoxybenzoyl)pentyl, 6-(3-butoxybenzoyl)hexyl, 1,1-dimethyl-2-(4-pentyloxybenzoyl)ethyl, 2-methyl-3-(4-hexyloxybenzoyl)propyl, 3,4-dimethoxybenzoylmethyl, 3,4-diethoxybenzoylmethyl, 2,4-dimethoxybenzoylmethyl, 2,5-dimethoxybenzoylmethyl, 2,6-dimethoxybenzoylmethyl, 3,4,5-trimethoxybenzoylmethyl, 2-chloro-4-methoxybenzoylmethyl, and 3-fluoro-5-ethoxybenzoylmethyl groups.
Examples of the piperidinyl lower alkyl group which may have a lower alkyl group as a substituent on the piperidine ring include piperidinylalkyl groups which may have 1 to 3 linear or branched alkyl groups having 1 to 6 carbon atoms as substituents on the piperidine ring and whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as [(1, 2, 3 or 4-)piperidinyl]methyl, 2-[(1, 2, 3 or 4-)piperidinyl]ethyl, 1-[(1, 2, 3 or 4-)piperidinyl]ethyl, 3-[(1, 2, 3 or 4-)piperidinyl]propyl, 4-[(1, 2, 3 or 4-)piperidinyl]butyl, 5-[(1, 2, 3 or 4-)piperidinyl]pentyl, 6-[(1, 2, 3 or 4-)piperidinyl]hexyl, 1,1-dimethyl-2-[(1, 2, 3 or 4-)piperidinyl]ethyl, 2-methyl-3-[(1, 2, 3 or 4-)piperidinyl]propyl, [1-methyl-(2, 3 or 4-)piperidinyl]methyl, 2-[1-ethyl-(2, 3 or 4-)piperidinyl]ethyl, 1-[4-propyl-(1, 2 or 3-)piperidinyl]ethyl, 3-[3-isopropyl-(1, 2, 4, 5 or 6-)piperidinyl]propyl, 4-[2-butyl-(1, 3, 4, 5 or 6-)piperidinyl]butyl, 5-[1-isobutyl-(2, 3 or 4-)piperidinyl]pentyl, 6-[1-tert-butyl-(2, 3 or 4-)piperidinyl]hexyl, 1,1-dimethyl-2-[4-pentyl-(1, 2 or 3-)piperidinyl]ethyl, 2-methyl-3-[1-hexyl-(2, 3 or 4-)piperidinyl]propyl, [1,2-dimethyl-(3, 4, 5 or 6-)piperidinyl]methyl, and [1,2,6-trimethyl-(3, 4 or 5-)piperidinyl]methyl groups.
Examples of the imidazolyl group which may have 1 to 3 phenyl groups as substituents on the imidazole ring include imidazolyl groups which may have 1 to 3 phenyl groups as substituents on the imidazole ring such as 1, 2, 4 or 5-)imidazolyl, 1-phenyl-(2, 4 or 5-)imidazolyl, 2-phenyl-(1, 4 or 5-)imidazolyl, 4-phenyl-(1, 2 or 5-)imidazolyl, 5-phenyl-(1, 2 or 4-)imidazolyl, 1,2-diphenyl-(4 or 5-)imidazolyl, 2,4-diphenyl-(1 or 5-)imidazolyl, 4,5-diphenyl-(1 or 2-)imidazolyl, 2,5-diphenyl-(1 or 4-)imidazolyl, and 2,4,5-triphenyl-1-imidazolyl groups.
Examples of the benzimidazolyl group which may have 1 to 3 lower alkyl groups as substituents on the benzimidazole ring include benzimidazolyl group which may have 1 to 3 linear or branched alkyl groups having 1 to 6 carbon atoms as substituents on the benzimidazole ring such as (1, 2, 4, 5, 6 or 7-)benzimidazolyl, 1-methyl-(2, 4, 5, 6 or 7-)benzimidazolyl, 2-ethyl-(1, 4, 5, 6 or 7-)benzimidazolyl, 4-propyl-(1, 2, 5, 6 or 7-)benzimidazolyl, 5-butyl-(1, 2, 4, 6 or 7-)benzimidazolyl, 6-pentyl-(1, 2, 4, 5 or 7-)benzimidazolyl, 7-hexyl-(1, 2, 4, 5 or 6-)benzimidazolyl, 1-ethyl-(2, 4, 5, 6 or 7-)benzimidazolyl]hexyl, 1-butyl-(2, 4, 5, 6 or 7-)benzimidazolyl, 1-isopropyl-(1, 2, 4, 5, 6 or 7-)benzimidazolyl, 1,2-dimethyl-(4, 5, 6 or 7-)benzimidazolyl, 1-methyl-4-ethyl-(2, 5, 6 or 7-)benzimidazolyl, 1-propyl-5-methyl-(2, 4, 6 or 7-)benzimidazolyl, and 1,2,5-trimethyl-(2, 4, 5, 6 or 7-)benzimidazolyl groups.
Examples of the pyridyl lower alkoxy group include pyridylalkoxy groups whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (2, 3 or 4-)pyridylmethoxy, 2-[(2, 3 or 4-)pyridyl]ethoxy, 1-[(2, 3 or 4-)pyridyl]ethoxy, 3-[(2, 3 or 4-)pyridyl]propoxy, 4-[(2, 3 or 4-)pyridyl]butoxy, 1-1-dimethyl-2-[(2, 3 or 4-)pyridyl]ethoxy, 5-[(2, 3 or 4-)pyridyl]pentyloxy, 6-[(2, 3 or 4-)pyridyl]hexyloxy, 1-[(2, 3 or 4-)pyridyl]isopropoxy, and 2-methyl-3-[(2, 3 or 4-)pyridyl]propoxy groups.
Examples of the 1,2,3,4-tetrahydroquinolyl lower alkyl group which may have an oxo group as a substituent on the tetrahydroquinoline ring include 1,2,3,4-tetrahydroquinolylalkyl groups which may have 1 or 2 oxo groups as substituents on the tetrahydroquinoline ring and whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (1, 2, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolylmethyl, 2-[(1, 2, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl]ethyl, 1-[(1, 2, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl]ethyl, 3-[(1, 2, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl]propyl, 4-[(1, 2, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl]butyl, 5-[(1, 2, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl]pentyl, 6-[(1, 2, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl]hexyl, 1,1-dimethyl-2-[(1, 2, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl]ethyl, 2-methyl-3-[(1, 2, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl]propyl, [2-oxo-(1, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl]methyl, [4-oxo-(1, 2, 3, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl]methyl, [2,4-dioxo-(1, 3, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl]methyl, 2-[2-oxo-(1, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl]ethyl, 3-(4-oxo-(1, 2, 3, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl]propyl, 4-[2,4-dioxo-(1, 3, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl]butyl, 5-[2-oxo-(1, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl]pentyl, and 6-[4-oxo-(1, 2, 3, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl]hexyl groups.
Examples of the 1,3,4-oxadiazolyl lower alkyl group which may have an oxo group as a substituent on the 1,3,4-oxadiazole ring include 1,3,4-oxadiazolylalkyl groups which may have an oxo group as a substituent on the 1,3,4-oxadiazole ring and whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (2 or 5-)1,3,4-oxadiazolylmethyl, 2-[(2 or 5-)1,3,4-oxadiazolyl]ethyl, 1-[(2 or 5-)1,3,4-oxadiazolyl]ethyl, 3-[(2 or 5-)1,3,4-oxadiazolyl]propyl, 4-[(2 or 5-)1,3,4-oxadiazolyl]butyl, 5-[(2 or 5-)1,3,4-oxadiazolyl]pentyl, 6-[(2 or 5-)1,3,4-oxadiazolyl]hexyl, 1,1-dimethyl-2-[(2 or 5-)1,3,4-oxadiazolyl]ethyl, 2-methyl-3-[(2 or 5-)1,3,4-oxadiazolyl]propyl, 2-oxo-[(3 or 5-)1,3,4-oxadiazolyl]methyl, 5-oxo-[(2 or 3-)1,3,4-oxadiazolyl]methyl, 2-[2-oxo-(3 or 5-)(1,3,4-oxadiazolyl)]ethyl, 1-[5-oxo-(2 or 3-)1,3,4-oxadiazolyl]ethyl, 3-[(2 or 5-)1,3,4-oxadiazolyl]propyl, 4-[2-oxo(3 or 5-)1,3,4-oxadiazolyl]butyl, 5-[5-oxo(2 or 3-)1,3,4-oxadiazolyl]pentyl, 6-[2-oxo(3 or 5-)1,3,4-oxadiazolyl]hexyl, 1,1-dimethyl-2-[5-oxo(2 or 3-)1,3,4-oxadiazolyl]ethyl, and 2-methyl-3-[2-oxo(3 or 5-)1,3,4-oxadiazolyl]propyl groups.
Examples of the thienyl lower alkyl group include thienylalkyl groups whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (2 or 3-)thienylmethyl, 2-[(2 or 3-)thienyl]ethyl, 1-[(2 or 3-)thienyl]ethyl, 3-[(2 or 3-)thienyl]propyl, 4-[(2 or 3-)thienyl]butyl, 5-[(2 or 3-)thienyl]pentyl, 6-[(2 or 3-)thienyl]hexyl, 1,1-dimethyl-2-[(2 or 3-)thienyl]ethyl, and 2-methyl-3-[(2 or 3-)thienyl]propyl groups.
Examples of the pyrimidinylcarbonyl group which may have an oxo group as a substituent on the pyrimidine ring include pyrimidinylcarbonyl groups which may have 1 to 3 oxo groups as substituents on the pyrimidine ring such as (2, 3, 4 or 6-)pyrimidinylcarbonyl, 2,6-dioxo-(1, 3, 4 or 5-)pyrimidinylcarbonyl, 2-oxo-(1, 3, 4, 5 or 6-)pyrimidinylcarbonyl, 6-oxo-(1, 2, 3, 4 or 5-)pyrimidinylcarbonyl, 4-oxo-(1, 2, 3, 5 or 6-)pyrimidinylcarbonyl, 2,4-dioxo-(1, 3, 4 or 6-)pyrimidinylcarbonyl, and 2,4,6-trioxo-(1, 3 or 5-)pyrimidinylcarbonyl groups.
Examples of the lower alkoxy lower alkoxy group include linear or branched alkoxy groups having 1 to 6 carbon atoms which may have a linear or branched alkoxy group having 1 to 6 carbon atoms as a substituent such as methoxymethoxy, 1-ethoxyethoxy, 2-methoxyethoxy, 2-propoxyethoxy, 3-isopropoxypropoxy, 4-butbxybutoxy, 5-pentyloxypentyloxy, 6-hexyloxyhexyloxy, 1,1-dimethyl-2-methoxyethoxy, 2-methyl-3-ethoxypropoxy, and 3-methoxypropoxy groups.
Examples of the lower alkoxycarbonyl lower alkoxy group include alkoxycarbonylalkoxy groups whose two alkoxy moieties are linear or branched alkoxy groups having 1 to 6 carbon atoms such as methoxycarbonylmethoxy, ethoxycarbonylmethoxy, 2-methoxycarbonylethoxy, 2-ethoxycarbonylethoxy, 1-ethoxycarbonylethoxy, 3-methoxycarbonylpropoxy, 3-ethoxycarbonylpropoxy, 4-ethoxycarbonylbutoxy, 5-isopropoxycarbonylpentyloxy, 6-propoxycarbonylhexyloxy, 1,1-dimethyl-2-butoxycarbonylethoxy, 2-methyl-3-tert-butoxycarbonylpropoxy, 2-pentyloxycarbonylethoxy, and hexyloxycarbonylmethoxy groups.
Examples of the carboxy lower alkoxy group include carboxyalkoxy groups whose alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms such as carboxymethoxy, 2-carboxyethoxy, 1-carboxyethoxy, 3-carboxypropoxy, 4-carboxybutoxy, 5-carboxypentyloxy, 6-carboxyhexyloxy, 1,1-dimethyl-2-carboxyethoxy, and 2-methyl-3-carboxypropoxy groups.
Examples of the phenoxy lower alkanoyl group include phenoxyalkanoyl groups whose alkanoyl moiety is a linear or branched alkanoyl group having 2 to 6 carbon atoms such as 2-phenoxyacetyl, 3-phenoxypropionyl, 2-phenoxypropionyl, 4-phenoxybutyryl, 5-phenoxypentanoyl, 6-phenoxyhexanoyl, 2,2-dimethyl-2-phenoxypropionyl, and 2-methyl-3-phenoxypropionyl groups.
Examples of the 1,2,3,4-tetrahydroquinolylcarbonyl group which may have an oxo group as a substituent on the tetrahydroquinoline ring include 1,2,3,4-tettahydroquinolylcarbonyl groups which may have 1 or 2 oxo groups as substituents on the tetrahydroquinoline ring such as [(1, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl]carbonyl, [2-oxo-(1, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl]carbonyl, [4-oxo-(1, 2, 3, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl]carbonyl, and [2,4-dioxo-(1, 3, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl]carbonyl groups.
Examples of the 1,2,3,4-tetrahydroquinolyl group which may have an oxo group as a substituent on the tetrahydroquinoline ring include 1,2,3,4-tetrahydroquinolyl groups which may have 1 or 2 oxo groups as substituents on the tetrahydroquinoline ring such as (1, 2, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl, 2-oxo-(1, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl, 4-oxo-(1, 2, 3, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl, and 2,4-dioxo-(1, 3, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl groups.
Examples of the amino group which may have a lower alkoxycarbonyl group as a substituent include amino groups which may have a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms such as amino, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, isopropoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino, pentyloxycarbonylamino, and hexyloxycarbonylamino groups.
Examples of the benzoyl group which may have 1 to 3 lower alkoxy groups as substituents on the phenyl ring include benzoyl groups which may have 1 to 3 linear or branched alkoxy groups having 1 to 6 carbon atoms as substituents on the phenyl ring such as benzoyl, 2-methoxybenzoyl, 3-methoxybenzoyl, 4-methoxybenzoyl, 2-ethoxybenzoyl, 3-ethoxybenzoyl, 4-ethoxybenzoyl, 4-isopropoxybenzoyl, 3-butoxybenzoyl, 4-pentyloxybenzoyl, 4-hexyloxybenzoyl, 3,4-dimethoxybenzoyl, 3,4-diethoxybenzoyl, 2,4-dimethoxybenzoyl, 2,5-dimethoxybenzoyl, 2,6-dimethoxybenzoyl, and 3,4,5-trimethoxybenzoyl groups.
Examples of the lower alkyl group which have 1 or 2 phenyls which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxy group which may have a halogen atom as a substituent, and a lower alkylthio group include, in addition to the above described phenyl lower alkyl groups, linear or branched alkyl groups which have 1 to 6 carbon atoms and 1 to 2 phenyls which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms, a cyano group, a nitro group, a phenyl group, a halogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents, a linear or branched alkoxy group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents, and a linear or branched alkylthio group having 1 to 6 carbon atoms such as 1,1-diphenylmethyl, 1,1-di(4-fluorophenyl)methyl, 1-phenyl-1-(4-methoxyphenyl)methyl, 3,3-diphenylpropyl, 2,5-difluorobenzyl, 2,4-difluorobenzyl, 3,4-difluorobenzyl, 3,5-difluorobenzyl, 2,6-difluorobenzyl, 3-trifluoromethylbenzyl, 2-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-methylbenzyl, 37-methylbenzyl, 4-methylbenzyl, 3,4-dimethylbenzyl, 2,3-dimethylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-cyanobenzyl, 2-cyanobenzyl, 3-cyanobenzyl, 4-methoxybenzyl, 2,3-dichlorobenzyl, 2,4-dichlorobenzyl, 2,5-dichlorobenzyl, 3,4-dichlorobenzyl, 2,6-dichlorobenzyl, 4-fluorobenzyl, 3-fluorobenzyl, 2-fluorobenzyl, 4-nitrobenzyl, 3-nitrobenzyl, 2-nitrobenzyl, 3-trifluoromethoxybenzyl, 4-trifluoromethoxybenzyl, 2-trifluoromethoxybenzyl, 4-methoxycarbonylbenzyl, 3-methoxycarbonylbenzyl, 4-tert-butylbenzyl, 4-ethylbenzyl, 4-isopropylbenzyl, 4-methoxy-3-chlorobenzyl, 2-(4-methoxyphenyl)ethyl, 2-(4-fluorophenyl)ethyl, 2-(4-chlorophenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(4-methylphenyl)ethyl, 4-phenylbenzyl, 3,3-diphenylpropyl, 3-methyl-4-nitrobenzyl, 4-(4-methoxyphenyl)butyl, 2-(4-methylphenyl)ethyl, 4-tert-butitocycarbonylbenzyl, 3-chloro-6-methoxybenzyl, 4-nitro-3-methylbenzyl, 4-tert-butyrylbenzyl, 2-(2-ethoxycarbonylphenyl)ethyl, 1-(3-propoxycarbonylphenyl)ethyl, 3-(4-pentyloxycarbonylphenyl)propyl, 4-(3-hexyloxycarbonylphenyl)butyl, 5-(3,4-dimethoxycarbonylphenyl)pentyl, 6-(3,4,5-diethoxycarbonylphenyl)hexyl, 1,1-dimethyl-2-(4-butoxycarbonylphenyl)ethyl, 2-methyl-3-(4-methoxycarbonylphenyl)propyl, 2-(2-cyanophenyl)ethyl, 1-(3-cyanophenyl)ethyl, 3-(4-cyanophenyl)propyl, 4-(2-cyanophenyl)butyl, 5-(3-cyanophenyl)pentyl, 6-(4-cyanophenyl)hexyl, 1,1-dimethyl-2-(2,4-dicyanophenyl)ethyl, 2-methyl-3-(2,4,6-tricyanophenyl)propyl, 2-(2-nitrophenyl)ethyl, 1-(3-nitrophenyl)ethyl, 3-(4-nitrophenyl)propyl, 4-(2-nitrophenyl)butyl, 5-(3-nitrophenyl)pentyl, 6-(4-nitrophenyl)hexyl, 1,1-dimethyl-2-(2,4-dinitrophenyl)ethyl, 2-methyl-3-(2,4,6-trinitrophenyl)propyl, 2-(2-phenylphenyl)ethyl, 1-(3-phenylphenyl)ethyl, 3-(4-phenylphenyl)propyl, 4-(2-phenylphenyl)butyl, 5-(3-phenylphenyl)pentyl, 6-(4-phenylphenyl)hexyl, 1,1-dimethyl-2-(2,4-diphenylphenyl)ethyl, 2-methyl-3-(2,4,6-triphenylphenyl)propyl, 2-(2-fluorophenyl)ethyl, 1-(3-bromophenyl)ethyl, 3-(4-iodoruphenyl)propyl, 4-(2-bromophenyl)butyl, 5-(3-chlorophenyl)pentyl, 6-(4-bromoruphenyl)hexyl, 1,1-dimethyl-2-(2,4-dichlorophenyl)ethyl, 2-methyl-3-(2,4,6-trifluorophenyl)propyl, 2-(2-ethylphenyl)ethyl, 1-(3-propylphenyl)ethyl, 3-(4-butylphenyl)propyl, 4-(2-pentylphenyl)butyl, 5-(3-hexylphenyl)pentyl, 6-(4-trifluoromethylphenyl)hexyl, 1,1-dimethyl-2-(2,4-dimethylphenyl)ethyl, 2-methyl-3-[2,4,6-tri(trifluoromethyl)phenyl]propyl, 2-(2-ethoxyphenyl)ethyl, 1-(3-propoxyphenyl)ethyl, 3-(4-butoxyphenyl)propyl, 4-(2-pentyloxyphenyl)butyl, 5-(3-hexyloxyphenyl)pentyl, 6-(4-trifluoromethoxyphenyl)hexyl, 1,1-dimethyl-2-(2,4-dimethoxyphenyl)ethyl, 2-methyl-3-[2,4,6-tri(trifluoromethoxy)phenyl]propyl, 2-methylthiobenzyl, 3-methylthiobenzyl, 4-methylthiobenzyl, 3,4-dimethylthiobenzyl, 2,3-dimethylthiobenzyl, 2-(2-ethylthiophenyl)ethyl, 2-(4-methylthiophenyl)ethyl, 1-(3-propylthiophenyl)ethyl, 3-(4-butylthiophenyl)propyl, 4-(2-pentylthiophenyl)butyl, 5-(3-hexylthiophenyl)pentyl, 6-(4-methylthiophenyl)hexyl, 1,1-dimethyl-2-(2,4-dimethylthiophenyl)ethyl, 2-methyl-3-[2,4,6-trimethylthiophenyl]propyl, 2-methyl-4-cyanobenzyl, 3-ethoxy-4-ethoxycarbonylbenzyl, 4-phenyl-3-nitrobenzyl, 3-fluoro-4-methoxybenzyl, 4-trifluoromethyl-3-cyanobenzyl, and 3-trifluoromethoxy-3-fluorobenzyl groups.
Examples of the phenyl group which may have, on the phenyl ring, 1 to 3 groups selected from the group consisting of a lower alkoxy group which may have a halogen atom as a substituent and a lower alkyl group which may have a halogen atom as a substituent include phenyl groups which may have, on the phenyl ring, 1 to 3 groups selected from the group consisting of a linear or branched alkoxy group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents and a linear or branched alkyl group having 1 to 6 carbon atoms and which may have 1 to 3 halogen atoms as substituents such as phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3-butylphenyl, 4-pentylphenyl, 4-hexylphenyl, 3,4-dimethylphenyl, 3,4-diethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4,5-trimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxylphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 4-isopropoxyphenyl, 3-butoxyphenyl, 4-pentyloxyphenyl, 4-hexyloxyphenyl, 3,4-dimethoxyphenyl, 3,4-diethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-(bromoethoxy)phenyl, 3-(2-chloroethoxy)phenyl, 4-(2,3-dichloropropoxy)phenyl, 4-(4-fluorobutoxy)phenyl, 3-(5-chloropentyloxy)phenyl, 4-(5-bromohexyloxy)phenyl, 4-(5,6-dibromohexyloxy)phenyl, 3,4-di(trifluoromethoxy)phenyl, 3,4-di(4,4,4-trichlorobutoxy)phenyl, 2,4-di(3-chloro-2-methoxypropyl)phenyl, 2,5-di(3-chloropropoxy)phenyl, 2,6-di(2,2,2-trifluoroethoxy)phenyl, 3,4,5-tri(trifluoromethoxy)phenyl, 4-(2,2,2-trichloroethoxy)phenyl, 2-methyl-4-trifluoromethoxyphenyl, 3-ethyl-4-trichloromethoxyphenyl, 2-methoxy-4-trifluoromethoxyphenyl, 3-ethoxy-4-trichloromethoxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-(bromomethyl)phenyl, 3-(2-chloroethyl)phenyl, 4-(2,3-dichloropropyl)phenyl, 4-(4-fluorobutyl)phenyl, 3-(5-chloropentyl)phenyl, 4-(5-bromohexyl)phenyl, 4-(5,6-dibromohexyl)phenyl, 3,4-di(trifluoromethyl)phenyl, 3,4-di(4,4,4-trichlorobutyl)phenyl, 2,4-di(3-chloro-2-methylpropyl)phenyl, 2,5-di(3-chloropropyl)phenyl, 2,6-di(2,2,2-trifluoroethyl)phenyl, 3,4,5-tri(trifluoromethyl)phenyl, 4-(2,2,2-trichloroethyl)phenyl, 2-methyl-4-trifluoromethylphenyl, and 3-ethyl-4-trichloromethylphenyl groups.
Examples of the pyrrolidinyl lower alkyl group which may have, on the pyrrolidine ring, 1 to 3 lower alkyl groups which may have a hydroxyl group as a substituent include pyrrolidinylalkyl groups which may have, on the pyrrolidine ring, 1 to 3 linear or branched alkyl groups having 1 to 6 carbon atoms which may have 1 to 3 hydroxyl groups as substituents and whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as [(1, 2 or 3-)pyrrolidinyl]methyl, 2-[(1, 2 or 3-)pyrrolidinyl]ethyl, 1-[(1, 2 or 3-)pyrrolidinyl]ethyl, 3-[(1, 2 or 3-)pyrrolidinyl]propyl, 4-[(1, 2 or 3-)pyrrolidinyl]butyl, 5-[(1, 2 or 3-)pyrrolidinyl]pentyl, 6-[(1, 2 or 3-)pyrrolidinyl]hexyl, 1,1-dimethyl-2-[(1, 2 or 3-)pyrrolidinyl]ethyl, 2-methyl-3-[(1, 2 or 3-)pyrrolidinyl]propyl, [1-methyl-(2 or 3-)pyrrolidinyl]methyl, 2-[2-ethyl-(1, 3, 4 or 5-)pyrrolidinyl]ethyl, 1-[3-propyl-(1, 2, 4 or 5-)pyrrolidinyl-ethyl, 3-[1-butyl-(2 or 3-)pyrrolidinyl]propyl, 4-[2-pentyl-(1, 3, 4 or 5-)pyrrolidinyl]butyl, 5-[3-hexyl-(1, 2, 4 or 5-)pyrrolidinyl]pentyl, 6-[1,2-dimethyl-(3, 4 or 5-)pyrrolidinyl]hexyl, 1,1-dimethyl-2-[1,2,3-trimethyl-(4 or 5-)pyrrolidinyl]ethyl, 2-methyl-3-[1-ethyl-2-methyl-(3, 4 or 5-)pyrrolidinyl]propyl, [1-(2-hydroxyethyl)-(2 or 3-)pyrrolidinyl]methyl, [2-hydroxymethyl-(1, 3, 4 or 5-)pyrrolidinyl]methyl, 2-[2-hydroxymethyl-(1, 3, 4 or 5-)pyrrolidinyl]ethyl, 1-[3-(3-hydroxypropyl)-(1, 2, 4 or 5-)pyrrolidinyl]ethyl, 3-[1-(4-hydroxybutyl)-(2 or 3-)pyrrolidinyl]propyl, 4-[2-(5-hydroxypentyl)-(1, 3, 4 or 5-)pyrrolidinyl]butyl, 5-[3-(6-hydroxyhexyl)-(1, 2, 4 or 5-)pyrrolidinyl]pentyl, 6-[1,2-dihydroxymethyl-(3, 4 or 5-)pyrrolidinyl]hexyl, 1,1-dimethyl-2-[1,2,3-trihydroxymethyl-(4 or 5-)pyrrolidinyl]ethyl, 2-methyl-3-[2-(1,2-hydroxyethyl)-(1, 3, 4 or 5-)pyrrolidinyl]propyl, and [2-(2,3,4-trihydroxybutyl)-(1, 3, 4 or 5-)pyrrolidinyl]methyl groups.
Examples of the amino substituted lower alkyl group which may have a substituent selected from the group consisting of a phenyl group and a lower alkyl group include linear or branched alkyl groups having 1 to 6 carbon atoms substituted with an amino group which may have 1 or 2 substituents selected from the group consisting of a phenyl group and a linear or branched alkyl group having 1 to 6 carbon atoms such as aminomethyl, 2-aminomethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 1,1-dimethyl-2-aminoethyl, N,N-diethyl-2-aminoethyl, 2-methyl-3-aminopropyl, methylaminomethyl, 1-ethylaminoethyl, 2-propylaminoethyl, 3-isopropylaminopropyl, 4-butylaminobutyl, 5-pentylaminopentyl, 6-hexylaminohexyl, dimethylaminomethyl, 2-diisopropylaminoethyl, (N-ethyl-N-propylamino)methyl, 2-(N-methyl-N-hexylamino)ethyl, phenylaminomethyl, 1-phenylaminoethyl, 2-phenylaminoethyl, 3-phenylaminopropyl, 4-phenylaminobutyl, 5-phenylaminopentyl, 6-phenylaminohexyl, N-methyl-N-phenylaminomethyl, 2-(N-ethyl-N-phenylamino)ethyl, (N-ethyl-N-phenylamino)methyl, and 2-(N-methyl-N-phenylamino)ethyl groups.
Examples of the tetrahydrofuryl lower alkyl group which may have a hydroxyl group as a substituent on the lower alkyl group include tetrahydrofurylalkyl groups which may have a hydroxyl group as a substituent on the lower alkyl group and whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as [(2 or 3-)tetrahydrofuryl]methyl, 2-[(2 or 3-)tetrahydrofuryl]ethyl, 1-[(2 or 3-)tetrahydrofuryl]ethyl, 3-[(2 or 3-)tetrahydrofuryl]propyl, 4-[(2 or 3-)tetrahydrofuryl]butyl, 5-[(2 or 3-)tetrahydrofuryl]pentyl, 6-[(2 or 3-)tetrahydrofuryl]hexyl, 1,1-dimethyl-2-[(2 or 3-)tetrahydrofuryl]ethyl, 2-methyl-3-[(2 or 3-)tetrahydrofuryl]propyl, 1-hydroxy-1-[(2 or 3-)tetrahydrofuryl]methyl, 2-hydroxy-2-[(2 or 3-)tetrahydrofuryl]ethyl, 2-hydroxy-1-[(2 or 3-)tetrahydrofuryl]ethyl, 3-hydroxy-3-[(2 or 3-)tetrahydrotetrahydrofuryl]propyl, 4-hydroxy-4-[(2 or 3-)tetrahydrofuryl]butyl, 5-hydroxy-5-[(2 or 3-)tetrahydrofuryl]pentyl, 6-hydroxy-6-[(2 or 3-)tetrahydrofuryl]hexyl, 2-hydroxy-1,1-dimethyl-2-[(2 or 3-)tetrahydrofuryl]ethyl, and 3-hydroxy-2-methyl-3-[(2 or 3-)tetrahydrofuryl]propyl groups.
Examples of the phenoxy lower alkyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkyl group and a nitro group include, in addition to the above described phenoxy lower alkyl groups, phenoxyalkyl groups which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms and a nitro group and whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as 2-methylphenoxymethyl, 3-methylphenoxymethyl, 4-methylphenoxymethyl, 3,4-dimethylphenoxymethyl, 2,3-dimethylphenoxymethyl, 3,4,5-trimethylphenoxymethyl, 2-(2-ethylphenoxy)ethyl, 2-(3-methylphenoxy)ethyl, 2-(4-methylphenoxy)ethyl, 1-(3-propylphenoxy)ethyl, 3-(4-butylphenoxy)propyl, 4-(2-pentylphenoxy)butyl, 5-(3-hexylphenoxy)pentyl, 6-(4-methylphenoxy)hexyl, 1,1-dimethyl-2-(2,4-dimethylphenoxy)ethyl, 2-methyl-3-(2,4,6-trimethylphenoxy)propyl, 2-(4-nitro-3-methylphenoxy)ethyl, 4-nitrophenoxymethyl, 3-nitrophenoxymethyl, 2-nitrophenoxymethyl, 2-(2-nitrophenoxy)ethyl, 2-(4-nitrophenoxy)ethyl, 1-(3-nitrophenoxy)ethyl, 3-(4-nitrophenoxy)propyl, 4-(2-nitrophenoxy)butyl, 5-(3-nitrophenoxy)pentyl, 6-(4-nitrophenoxy)hexyl, 1,1-dimethyl-2-(2,4-dinitrophenoxy)ethyl, and 2-methyl-3-(2,4,6-trinitrophenoxy)propyl groups.
Examples of the phenyl lower alkanoyl group include phenylalkanoyl groups whose alkanoyl moiety is a linear or branched alkanoyl group having 2 to 6 carbon atoms such as 2-phenylacetyl, 3-phenylpropionyl, 2-phenylpropionyl, 4-phenylbutyryl, 5-phenylpentanoyl, 6-phenylhexanoyl, 2,2-dimethyl-3-phenylpropionyl, and 2-methyl-3-phenylpropionyl groups.
Examples of the phenyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a halogen atom and a lower alkyl group which may have a halogen atom include phenyl groups which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a halogen atom and a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms such as phenyl, 3,4-difluorophenyl, 2-fluorophenyl, 3-bromophenyl, 4-iodophenyl, 4-methylphenyl, 2-methylphenyl, 3-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3-butylphenyl, 4-pentylphenyl, 4-hexylphenyl, 3,4-dimethylphenyl, 3,4-diethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4,5-trimethylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-(bromomethyl)phenyl, 3-(2-chloroethyl)phenyl, 4-(2,3-dichloropropyl)phenyl, 4-(4-fluorobutyl)phenyl, 3-(5-chloropentyl)phenyl, 4-(5-bromohexyl)phenyl, 4-(5,6-dibromohexyl)phenyl, 3,4-di(trifluoromethyl)phenyl, 3,4-di(4,4,4-trichlorobutyl)phenyl, 2,4-di(3-chloro-2-methylpropyl)phenyl, 2,5-di(3-chloropropyl)phenyl, 2,6-di(2,2,2-trifluoroethyl)phenyl, 3,4,5-tri(trifluoromethyl)phenyl, 4-(2,2,2-trichloroethyl)phenyl, 2-methyl-4-trifluoromethylphenyl, 3-ethyl-4-trichloromethylphenyl, 2-chloro-4-trifluoromethylphenyl, 3-ethyl-4-fluorophenyl, 3-fluoro-4-trichloromethylphenyl, 2-methyl-3-trifluoromethyl-4-trifluoromethylphenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 2,3-dibromophenyl, 2,4-diiodophenyl, 2,5-difluorophenyl, 2,6-dichlorophenyl, 2,4,6-trichlorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, 2,6-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2,6-dichlorophenyl, 3,5-dichlorophenyl, 2,4,6-trifluorophenyl, and 2,4-difluorophenyl groups.
Examples of the 5- to 7-membered saturated heterocyclic group formed by mutually binding R20 and R21, R22 and R23, R26 and R27, R29 and R30 or R32 and R33 together with the nitrogen atoms bound to them, through or not through a nitrogen atom, an oxygen atom or a sulfur atom, include pyrrolidinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino, and homopiperazinyl groups.
Examples of the phenoxy lower alkyl group which may have, on the phenyl ring, a lower alkyl group as a substituent include, in addition to the above described phenoxy lower alkyl groups, phenoxyalkyl groups which may have, on the phenyl ring, 1 to 3 linear or branched alkyl groups having 1 to 6 carbon atoms as substituents and whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as 2-methylphenoxymethyl, 3-methylphenoxymethyl, 4-methylphenoxymethyl, 3,4-dimethylphenoxymethyl, 2,3-dimethylphenoxymethyl, 3,4,5-trimethylphenoxymethyl, 2-(2-ethylphenoxy)ethyl, 2-(4-methylphenoxy)ethyl, 1-(3-propylphenoxy)ethyl, 3-(4-butylphenoxy)propyl, 4-(2-pentylphenoxy)butyl, 5-(3-hexylphenoxy)pentyl, 6-(4-methylphenoxy)hexyl, 1,1-dimethyl-2-(2,4-dimethylphenoxy)ethyl, and 2-methyl-3-(2,4,6-trimethylphenoxy)propyl groups.
A compound represented by the general formula (I) or a salt thereof is more preferred, wherein
X1 represents a nitrogen atom or a group —CH═,
R1 represents a group —Z—R6 
Z represents a group —N(R8)—B—, a group —B—N(R8)—, a group —B0—O— or a group —N(R9a)—CO—N—(R9b)—,
R8 represents a hydrogen atom, a lower alkyl group that may have a lower alkoxy group as a substituent, a lower alkanoyl group, a lower alkylsulfonyl group or a phenyl lower alkyl group,
B represents a group —CO— or a lower alkylene group,
B0 represents a lower alkylene group,
R9a represents a hydrogen atom or a lower alkyl group,
R9b represents a hydrogen atom or a lower alkyl group,
R6 represents a group




R7 represents a halogen atom or a lower alkyl group that may have a halogen atom as a substituent,

m represents an integer of 1 or 2 (when m represents 2, two R7s may be identical or different) and

R2 represents a hydrogen atom, a halogen atom, or a lower alkyl group,

Y represents a group —O—, or a group —N(R5)—,

R5 represents a hydrogen atom, or a lower alkyl group,

A represents a group





p represents 1 or 2,

R3 represents a hydrogen atom, a lower alkoxy group, a halogen atom, or a lower alkyl group that may have a halogen atom as a substituent,

R9 represents a group -(T)l-N(R14)R15,

T represents a group —N(R17)—B3—CO—, a group —B4—CO—, or a group —CO—,

R17 represents a hydrogen atom, or a lower alkyl group,

B3 represents a lower alkylene group,

B4 represents a lower alkenylene group or a lower alkylene group that may have a hydroxyl group as a substituent,

l represents 0 or 1′,

R14 represents a hydrogen atom or an alkyl group that may have a hydroxyl group as a substituent,

R15 represents (36a) a piperazinyl-substituted oxalyl group that may have 1 to 3 groups selected from the group consisting of a phenyl lower alkyl group (that may have 1 to 3 groups selected from the group consisting of a lower alkylenedioxy group and a lower alkoxy group as a substituent(s) on the phenyl ring) and a pyridyl lower alkyl group as a substituent(s) on the piperazine ring,

R14 and R15, together with the nitrogen atom to which they bind, form a heterocyclic group which is piperidinyl or piperazinyl group,

wherein the heterocyclic ring may be substituted by a group selected from the group consisting of (28) a phenyl-substituted lower alkyl group that may be substituted by a group, on the phenyl ring, selected from the group consisting of a lower alkanoyl group, an amino group that may have a lower alkanoyl group as a substituent, a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxy group that may have a halogen atom as a substituent, a phenyl lower alkoxy group, a hydroxyl group, and a lower alkylenedioxy group (49) a group —(B12CO)t-N(R20)R21, or (84) a group —(O—B15)s-CO—N(R26)R27,

B12 represents a lower alkylene group,

t represents 0 or 1,

R20 and R21, together with the nitrogen atom to which they bind, form a saturated heterocyclic group which is piperidinyl or piperazinyl group that, on the heterocyclic ring, may be substituted by a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring,

B15 represents a lower alkylene group,

s represents 0 or 1,

R26 and R27 may be identical or different and each represent a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, or an imidazolyl lower alkyl group, and R26 and R27, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic ring, (wherein the heterocyclic ring may be substituted by 1 to 3 phenyl lower alkyl groups that may have a lower alkylenedioxy group on the phenyl ring).

For example, a compound represented by the general formula (1) or a salt thereof is further more preferred, wherein
X1 represents a nitrogen atom,
R1 represents a group —Z—R6,
Z represents a group —N(R8)—B—,
R8 represents a hydrogen atom, or a lower alkyl group that may have a lower alkoxy group as a substituent,
B represents a group —CO—,
R6 represents a group




R7 represents a halogen atom or a lower alkyl group that may have a halogen atom as a substituent,

m represents an integer of 1 or 2 (when m represents 2, two R7s may be identical or different) and

R2 represents a hydrogen atom,

Y represents a group —O—, or a group —N(R5)—,

R5 represents a hydrogen atom, or a lower alkyl group,

A represents a group





p represents 1 or 2,

R3 represents a hydrogen atom, a lower alkoxy group, a halogen atom, or a lower alkyl group that may have a halogen atom as a substituent,

R4 represents a group -(T)l-N(R14)R15,

T represents a group —N(R17)—B3—CO—, a group —B4—CO—, or a group —CO—,

R17 represents a hydrogen atom, or a lower alkyl group,

B3 represents a lower alkylene group,

B4 represents a lower alkylene group that may have a hydroxyl group as a substituent,

l represents 0 or 1,

R14 and R15, together with the nitrogen atom to which they bind, form a heterocyclic group which is piperidinyl or piperazinyl group that, on the heterocyclic ring, may be substituted by (28) a phenyl-substituted lower alkyl group that may be substituted by a lower alkylenedioxy group on the phenyl ring.

Another more preferred example is a compound represented by the general formula (1) or a salt thereof, wherein
X1 represents a nitrogen atom,
R1 represents a group —Z—R6 
Z represents a group N(R8)—B—,
R8 represents a hydrogen atom, or a lower alkyl group that may have a lower alkoxy group as a substituent,
B represents a group —CO—,
R6 represents a group




R7 represents a halogen atom or a lower alkyl group that may have a halogen atom as a substituent,

m represents an integer of 1 or 2 (when m represents 2, two R7s may be identical or different) and

R2 represents a hydrogen atom,

Y represents a group —O—, or a group —N(R5)—,

R5 represents a hydrogen atom, or a lower alkyl group,

A represents a group





represents 1 or 2,

R3 represents a hydrogen atom, a lower alkoxy group, a halogen atom, or a lower alkyl group that may have a halogen atom as a substituent,

R4 represents a group -(T)l-N(R14)R15,

R17 represents a hydrogen atom, or a lower alkyl group,

B3 represents a lower alkylene group,

B4 represents a lower alkylene group that may have a hydroxyl group as a substituent,

l represents 0,

R14 and R15, together with the nitrogen atom to which they bind, form a heterocyclic group which is piperidinyl or piperazinyl group

wherein, on the heterocyclic ring, one substituent may be present which is selected from the group consisting of (49) a group —(B12CO)t-N(R20)R21, and (84) a group —(O—B15)s-CO—N(R26)R27,

B12 represents a lower alkylene group,

t represents 0 or 1,

R20 and R21, together with the nitrogen atom to which they bind, form a saturated heterocyclic group which is piperazine or piperidine

wherein, on the heterocyclic ring, one substituent may be present which is a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring,

B15 represents a lower alkylene group,

s represents 0 or 1,

R26 and R27, together with the nitrogen atom to which they bind, bind to each other, directly or via an oxygen atom or nitrogen atom to form a 6-membered saturated heterocyclic ring, (wherein the heterocyclic ring may be substituted by 1 to 3 phenyl lower alkyl groups that may have a lower alkylenedioxy group as a substituent on the phenyl ring).

Methods for producing compounds according to the present invention will be described below.
A compound according to the present invention represented by the general formula (1), in which various groups may be used as Y, is produced, for example, in accordance with reaction formulas 1 to 4 below.




wherein, R1, R2, X1 and A are the same as described above, Y1 represents a group —O—, a group —S— or a group —NH—, and X2 represents a halogen atom.

The reaction between the compound (2) and the compound (3) is generally carried out in the presence or absence of an appropriate solvent and in the presence or absence of a basic compound.
Examples of the inert solvent to be used include aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, and diglyme, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, lower alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol, fatty acids such as acetic acid, esters such as ethyl acetate and methyl acetate, ketones such as acetone and methyl ethyl ketone, acetonitrile, pyridine, dimethylsulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, and hexamethylphosphoric acid triamide, and a mixture thereof.
Examples of the basic compound include carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and cesium carbonate, metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide, sodium hydride, potassium hydride, potassium, sodium, sodium amide, metal alcoholates such as sodium methylate, sodium ethylate, and sodium n-butoxide, and organic bases such as pyridine, imidazole, N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine, trimethylamine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), and 1,4-diazabicyclo[2.2.2]octane (DABCO), and a mixture thereof.
When the reaction is carried out in the presence of a basic compound, the basic compound is used typically in an equimolar amount to that of the compound (2) and preferably 1 to 10 times that of the compound (2) on a molar basis.
The compound (3) is used typically in at least equimolar amount to that of the compound (2) and preferably 1 to 10 times that of the compound (2) on a molar basis.
The reaction is carried out typically at −30 to 200° C., and preferably at about −30 to 150° C., and generally completed in about 5 minutes to 80 hours.
To this reaction system, an alkali metal halide such as sodium iodide or potassium iodide may be added, and a phase-transfer catalyst may be added.
Examples of the phase-transfer catalyst include quaternary ammonium salts substituted with a group selected from the group consisting of a linear or branched alkyl group having 1 to 18 carbon atoms, a phenyl alkyl group whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms and a phenyl group, such as tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium fluoride, tetrabutylammonium iodide, tetrabutylammonium hydroxide, tetrabutylammonium hydrogensulfite, tributylmethylammonium chloride, tributylbenzylammonium chloride, tetrapentylammonium chloride, tetrapentylammonium bromide, tetrahexylammonium chloride, benzyldimethyloctylammonium chloride, methyltrihexylammonium chloride, benzyldimethyloctadecanylammonium chloride, methyltridecanylammonium chloride, benzyltripropylammonium chloride, benzyltriethylammonium chloride, phenyltriethylammonium chloride, tetraethylammonium chloride, tetramethylammonium chloride; phosphonium salts substituted with a linear or branched alkyl group having 1 to 18 carbon atoms such as tetrabutylphosphonium chloride; and pyridinium salts substituted with a linear or branched alkyl group having 1 to 18 carbon atoms such as 1-dodecanylpyridinium chloride. These phase-transfer catalysts are used singly or in a combination of two types or more.
Typically the phase-transfer catalyst is used in an equimolar amount of 0.1 to 1 times that of the compound (2) and preferably 0.1 to 0.5 times that of the compound (2) on a molar basis.
A compound (1a) wherein Y1 represents a group —NH—, may be produced also by reacting a compound (2) with a compound (3) in the presence of an acid in place of a basic compound. Examples of the acid used herein include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and organic acids such as acetic acid, trifluoroacetic acid, and p-toluenesulfonic-acid. These acids are used singly or in a mixture of two types or more.
A compound (1) wherein Y represents a group —N(R5)— group, and R5 represents a group other than a hydrogen atom, may be produced from a compound (1) wherein Y represents a group —NH— in accordance with reaction formula 2.




wherein R1, R2, X1, A and X2 are the same as described above, R5a represents a lower alkyl group, phenyl lower alkyl group or cycloalkyl group, R5b represents a hydrogen atom, lower alkyl group, phenyl group or phenyl lower alkyl group, R5c represents a lower alkanoyl group or benzoyl group, RB represents a hydrogen atom or lower alkyl group, and R5b and RB may bind to each other together with carbon atoms bound to these groups to form a cycloalkyl ring, provided that the carbon number of the alkyl moiety in the group —CHRBR5b of the compound (1d) is 1 to 6.

The reaction of the compound (1b) and the compound (4) is carried out under the same conditions as in the reaction of the compound (2) and the compound (3) shown in reaction formula 1 above.
The reaction of the compound (1b) and the compound (5) is carried out, for example, in the presence of a reducing agent and in the presence or absence of an appropriate solvent. Hereinafter, this method is called “method A”.
Examples of the solvent used herein include water, lower alcohols such as, methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol, acetonitrile, fatty acids such as formic acid, and acetic acid, ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, and diglyme, aromatic hydrocarbons such as benzene, toluene, and xylene, and halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, and a mixture thereof.
Examples of the reducing agent include fatty acids and alkali metal salts thereof such as formic acid, sodium formate, and sodium acetate, hydride reducing agents such as sodium borohydride, sodium cyanoborohydride, sodium triacetyloxyborohydride, and aluminum lithium hydride, or a mixture of these hydride reducing agents, and catalytic hydrogen reducing agents such as palladium black, palladium-carbon, platinum oxide, platinum black, and Raney nickel.
In using a fatty acid or an alkali metal salt thereof such as formic acid, sodium formate, or sodium acetate as a reducing agent, the appropriate reaction temperature is typically from room temperature to about 200° C., and preferably about 50 to about 150° C. The reaction is completed generally in about 10 minutes to 10 hours. It is preferable to use a fatty acid or an alkali metal salt thereof in a large excess amount with respect to the compound (1b).
In using a hydride reducing agent, the appropriate reaction temperature is typically −80 to 100° C., and preferably −80 to 70° C. The reaction is completed generally in about 30 minutes to 60 hours. The hydride reducing agent is used typically in an equimolar amount 1 to 20 times that of the compound (1b), and preferably 1 to 6 times that of the compound (1b) on a molar basis. Especially in using aluminum lithium hydride as a hydride reducing agent, it is preferable to employ an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, or diglyme, or an aromatic hydrocarbon such as benzene, toluene, or xylene, as a solvent. To the reaction system, an amine such as trimethylamine, triethylamine, and N-ethyldiisopropylamine, or molecular sieves such as Molecular Sieves 3A (MS-3A) or Molecular Sieves 4A (MS-4A) may be added.
In using a catalytic hydrogen reducing agent, the reaction is preferably carried out in a hydrogen atmosphere typically at a normal pressure to about 20 atm, and preferably at a normal pressure to about 10 atm, or in the presence of a hydrogen donor such as formic acid, ammonium formate, cyclohexene, or hydrazine hydrate, at a temperature of typically −30 to 100° C., and preferably 0 to 60° C. The reaction is generally completed in about 1 to 12 hours. The catalytic hydrogen reducing agent is used typically in an amount of about 0.1% to 40% by weight, and preferably about 1 to 20% by weight based on the compound (1b).
In the reaction of the compound (1b) and the compound (5), the compound (5) is used typically in at least an equimolar amount to that of the compound (1b), and preferably in an equal amount to a large excess amount on a molar basis.
The reaction is carried out using a compound (5), whose RB and R5b (bound to a carbon atom) are mutually bound to form a cycloalkyl ring together with the carbon atom in the presence of a hydride reducing agent, as a starting material. In this case, in place of the compound (5), cycloalkyloxytrialkylsilane such as [(1-ethoxycyclopropyl)oxy]trimethylsilane may be used as the starting material to produce the above described compound (5) in the reaction system.
The compound (1d) may be also produced by reacting the compound (1b) with the compound (5) under the same conditions as in the reaction between the compound (1f) with hydroxylamine of the later described reaction formula 3, and then reducing the resulting compound represented by the general formula:




wherein R1, R2, X1, RB and R5b are the same as described above.

The same reaction conditions as in the method A may be applied to this reducing reaction.
The reaction of the compound (1b) and the compound (6) is carried out by a method for reacting the compound (1b) with the carboxylic acid of the compound (6) in accordance with a general reaction for producing an amide bond. This reaction may be performed by any known reaction for producing an amide bond. Specific examples of the method include: (a) a mixed acid anhydride method, specifically, a method of reacting an alkylhalocarboxylic acid with the carboxylic acid (6) to prepare a mixed acid anhydride, and then reacting the amine (1b) with the mixed acid anhydride; (b) an active ester method, specifically, a method of preparing, from the carboxylic acid (6), an active ester such as a phenyl ester, p-nitrophenyl ester, N-hydroxysuccinimide ester, or 1-hydroxybenzotriazole ester, or an active amide with benzoxazoline-2-thione, and then reacting the active ester or amide with the amine (1b); (c) a carbodiimide method, specifically, a method of condensating the carboxylic acid (6) with the amine (1b) in the presence of an activator such as dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC), or carbonyldiimidazole; (d) other methods, for example, a method of preparing a carboxylic anhydride from the carboxylic acid (6) by the action of a dehydrator such as acetic anhydride, and then reacting the carboxylic anhydride with the amine (1b), a method of reacting an ester of the carboxylic acid (6) with a lower alcohol with the amine (1b) at a high pressure and a high temperature, and a method of reacting an acid halide of the carboxylic acid (6), that is, carboxylic acid halide, with the amine (1b).
The mixed acid anhydride used in the mixed anhydride method (a) described above, which is obtained by a general Schotten-Baumann reaction, is used as it is without isolation in the reaction with the amine (2) to produce the compound of the present invention represented by the general formula (1e).
The Schotten-Baumann reaction described above is carried out in the presence of a basic compound.
Examples of the basic compound to be used include compounds commonly used in the Schotten-Baumann reaction, for example, organic bases such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-ethyldiisopropylamine, dimethylaminopyridine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), and 1,4-diazabicyclo[2.2.2]octane (DABCO), and inorganic bases including carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate, metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide, potassium hydride, sodium hydride, potassium, sodium, sodium amide, and metal alcoholates such as sodium methylate and sodium ethylate. These basic compounds are used singly or in a combination of two types or more. The reaction is carried out at typically about −20 to 100° C., and preferably about 0 to 50° C. The reaction time is about 5 minutes to 10 hours, and preferably about 5 minutes to 2 hours.
The resulting mixed acid anhydride is reacted with the amine (1b) typically at about −20 to 150° C. and preferably about 10 to 50° C. The reaction time is about 5 minutes to 10 hours and preferably about 5 minutes to 5 hours.
The mixed acid anhydride method is generally carried out in a solvent. Any solvent may be used as long as it is conventionally used in the mixed acid anhydride method. Specific examples of the solvent include halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dimethoxyethane, esters such as methyl acetate, ethyl acetate, and isopropyl acetate, and aprotic polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric acid triamide, and a mixture thereof.
Examples of the alkylhalocarboxylic acid used in the mixed acid anhydride method include methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, and isobutyl chloroformate.
In the mixed acid anhydride method, the carboxylic acid (6), alkylhalocarboxylic acid, and the amine (1b) may be preferably used in equimolar amounts to each other. However, each of alkyl halocarboxylic acid and the carboxylic acid (6) may be used 1 to 1.5 times that of the amine (1b) on a molar basis, respectively.
In the method (c) of performing a condensation reaction in the presence of an activator, the reaction is carried out in an appropriate solvent in the presence or absence of a basic compound. Any of the solvents and basic compounds used in the reaction in the methods (d) of reacting the amine (1b) with a carboxylic acid halide described below may be used for this reaction. It is appropriate to use the activator typically in at least an equimolar amount to that of the compound (1b), and preferably 1 to 5 times that of the compound (1b) on a molar basis. When WSC is used as an activator, the reaction may be carried out advantageously if 1-hydroxybenzotriazole and/or an acid such as hydrochloric acid is added to the reaction system. This reaction is carried out typically at about −20 to 180° C. and preferably at about 0 to 150° C., and completed typically in about 5 minutes to 90 hours.
When a method (d) of reacting the amine (1b) with a carboxylic acid halide is employed, the reaction is carried out in an appropriate solvent in the presence of a basic compound. Any basic compound may be used as long as it is widely known in the art. Any basic compound may be used as long as it is used in, for example, the Shotten-Baumann reaction. Examples of the solvent include, in addition to the solvents used in the mixed acid anhydride method, alcohols such as methanol, ethanol, isopropanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve, acetonitrile, pyridine, acetone, and water. The ratio of the amine (1b) to the carboxylic acid halide is not particularly limited and may be appropriately selected in a wide range. Typically, the latter one may be used in an amount at least about equimolar to that of the former one, and preferably about 1 to 5 times that of the former one on a molar basis. This reaction is carried out typically at about −20 to 180° C. and preferably at about 0 to 150° C., and completed typically in 5 minutes to 50 hours.
Further, the reaction for producing an amide bond shown in reaction formula 2 may be carried out also by reacting the carboxylic acid (6) and the amine (1b) in the presence of a condensation agent of a phosphorus compound such as triphenylphosphine, diphenylphosphinyl chloride, phenyl-N-phenylphosphoramide chloridate, diethyl chlorophosphate, diethyl cyanophosphate, diphenylphosphoric acid azide, or bis(2-oxo-3-oxazolidinyl)phosphinic chloride. The condensation agent is used singly or in a mixture of two types or more.
The reaction is carried out, in the presence of the solvent and the basic compound which are used in the method for reacting the amine (1b) with the carboxylic acid halide described above, typically at about −20 to 150° C., and preferably at about 0 to 100° C., and completed typically in 5 minutes to about 30 hours. The condensation agent and the carboxylic acid (6) each may be used approximately in at least an equimolar amount to that of the amine (1b), and preferably about 1 to 2 times that of the amine (1b) on a molar basis.
The compound (1), wherein Y represents a group —CH(OH)— or a group —C(═N—OH), is produced from a compound wherein Y represents a group —CO—, in accordance with reaction formula 3.




wherein R1, R2, X1 and A are the same as described above.

The compound (1g) is produced by reducing the compound (1f).
In the reducing reaction described above, a reducing method employing a hydride reducing agent is favorably used. Examples of the reducing agent to be used include aluminum lithium hydride, sodium borohydride, borane, diborane, and lithium borohydride-trimethoxyborane. These reducing agents are used singly or in a mixture of two types or more. The reducing agent is used typically in at least an equimolar amount to that of the compound (1f), and preferably 1 to 15 times that of the compound (1f) on a molar basis. This reducing reaction is typically carried out in an appropriate solvent, for example, water, a lower alcohol such as methanol, ethanol, or isopropanol, an ether such as tetrahydrofuran, diethyl ether, diisopropyl ether, or diglyme, or a halogenated hydrocarbon such as dichloromethane, chloroform, or carbon tetrachloride, or a mixture thereof, at about −60 to 150° C. preferably about −30 to 100° C. and generally for about 10 minutes to 40 hours. In the case where aluminum lithium hydride or borane is used as the reducing agent, it is preferable to use an anhydrous solvent such as tetrahydrofuran, diethyl ether, diisopropyl ether, or diglyme.
The compound (1h) is produced by reacting the compound (1f) and hydroxylamine in an appropriate inert solvent in the presence or absence of a basic compound.
Examples of the basic compound used herein include inorganic basic compounds such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, and potassium carbonate, fatty acid alkali metal salts such as sodium acetate, organic bases such as piperidine, piperidinium acetate, triethylamine, trimethylamine, pyridine, dimethylaniline, N-ethyldiisopropylamine, dimethylaminopyridine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), and 1,4-diazabicyclo[2.2.2]octane (DABCO). These basic compounds may be used singly or in a mixture of two types or more.
Any inert solvent may be used as long as it does not negatively affect the reaction. Examples of the inert solvent include water, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, and diglyme, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, lower alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol, fatty acids such as acetic acid, esters such as ethyl acetate and methyl acetate, ketones such as acetone and methyl ethyl ketone, acetonitrile, pyridine, dimethyl sulfoxide, N,N-dimethylformamide, and hexamethyl phosphate triamide, and a mixture thereof.
Hydroxylamine is used typically in at least an equimolar amount to that of the compound (1f), and preferably 1 to 5 times that of the compound (1f) on a molar basis. The reaction temperature is typically at room temperature to 200° C. and preferably about 50 to 150° C. The reaction is generally completed in about 5 minutes to 30 hours.
The compound (1), wherein Y represents a group —S(O)n- (n=1 or 2), is produced from a compound wherein Y represents a group —S—, in accordance with reaction formula 4.




wherein R1, R2, X1 and A are the same as described above, A16 represents a group -A or a group -A10-T2-COOR59a, T2 represents a group —N(R17)—B3—, a group —B19—N(R18)—, a group —B4—, a group -Q-B5—, a group —B6—N—(R19)—B7—, a group —CO—B10—, a group —CH(OH)—B11—, a group —B23a—CO— group, or a direct bond, wherein R17, B3, B19, R18, B4, B5, B6, R19, B7, B10 and B11 are the same as described above, A10 represents





wherein R3 and p are the same as described above, provided that a is bound to a group —S or a group —S(O)j, and b is bound to group -T2, R59a is a hydrogen atom or a lower alkyl group, and j is 1 or 2.

The reaction for converting the compound (1zzzz) into the compound (1aaaaa) is carried out in an appropriate solvent in the presence of an oxidizing agent.
Examples of the solvent include water, fatty acids such as formic acid, acetic acid, and trifluoroacetic acid, alcohols such as methanol and ethanol, and halogenated hydrocarbons such as chloroform and dichloromethane, and a mixture thereof.
Examples of the oxidizing agent include peracids such as performic acid, peracetic acid, pertrifluoroacetic acid, perbenzoic acid, m-chloroperbenzoic acid, and o-carboxyperbenzoic acid, hydrogen peroxide, sodium metaperidodate, dichromic acid, dichromates such as sodium dichromate and potassium dichromate, permanganic acid, permanganates such as sodium permanganate and potassium permanganate, and lead salts such as lead tetraacetate. These oxidizing agents are used singly or in a mixture of two types or more.
The oxidizing agent is appropriately used typically in at least an equimolar amount to that of the compound (1zzzz), and preferably 1 to 2 times that of the compound (1zzzz) on a molar basis. In the oxidizing reaction which converts a sulfur atom into a sulfonyl group (j=2), the oxidizing agent is preferably used typically in an amount at least two times that of the compound (1zzzz) and preferably 2 to 4 times that of the compound (1zzzz) on a molar basis.
The reaction is carried out at typically −10 to 150° C., and preferably about −10 to 100° C. and generally completed in about 1 to 100 hours.
The compound of the present invention represented by the general formula (1) wherein various groups may be used as A, is produced, for example, in accordance with the following reaction formulas 5 to 36.
The compound (1), wherein A represents:




wherein R4 represents an imidazolyl lower alkyl group, a 1,2,4-triazolyl lower alkyl group, a 1,2,3-triazolyl lower alkyl group, a 1,2,5-triazolyl lower alkyl group, a pyrazolyl lower alkyl group, a pyrimidinyl lower alkyl group which may have an oxo group as a substituent on the pyrimidine ring, a 1,2,4-oxadiazolyl lower alkyl group which may have an lower alkyl group as a substituent on the 1,2,4-oxadiazole ring, a thiazolidinyl lower alkyl group which may have an oxo group as a substituent on the thiazolidine ring, or a group -(T)l-NR14R15, (T is a lower alkylene group and l is 1) is produced by reacting the compound (7) with the compound (8) as shown in reaction formula 5.




wherein R1, R2 Y1 and X1 are the same as described above, A1 represents





wherein R3 and p are the same as described above, R37a represents a group —B21—X2, B21 represents a lower alkylene group, and X2 is the same as described above, and A2 represents





wherein R3 and p are the same as described above, R38 represents a group —B21—R4a, B21 is the same as described above, R4a represents an imidazolyl group, a 1,2,4-triazolyl group, a 1,2,3-triazolyl group, a 1,2,5-triazolyl group, a pyrazolyl group, a pyrimidynyl group which has an oxo group as a substituent on the pyrimidine ring, a 1,2,4-oxadiazolyl group which may have a lower alkyl group as a substituent on the 1,2,4-oxadiazole ring, a thiazolidinyl group which may have an oxo group as a substituent on the thiazolidine ring, or an —NR14R15 group, and R14 and R15 are the same as described above:

The reaction of the compound (7) with the compound (8) is carried out under the same conditions as in the reaction between the compound (2) and the compound (3) in accordance with reaction formula 1.
The compound (1), wherein A represents




wherein R4 is an imidazolyl lower alkyl group, a 1,2,4-triazolyl lower alkyl group, a 1,2,3-triazolyl lower alkyl group, a 1,2,5-triazolyl lower alkyl group, a pyrazolyl lower alkyl group, a pyrimidinyl lower alkyl group which has an oxo group as a substituent on the pyrimidine ring, a 1,2,4-oxadiazolyl lower alkyl group which may have a lower alkyl group as a substituent on the 1,2,4-oxadiazole ring, a thiazolidinyl lower alkyl group which may have an oxo group as a substituent on the thiazolidine ring, or a group -(T)l-NR14R15 (T is a lower alkylene group and l is 1)

is also produced by reacting the compound (8) with the compound (9) in accordance with reaction formula 6.





wherein R1, R2, X1 and Y1, and R4a are the same as described above, A3 represents





wherein R3 and p are the same as described above, R39 represents a —(B21)fCORA group, B21 is the same as described above, RA represents a hydrogen atom or a lower alkyl group, and f represents 0 or 1, and A4 represents





wherein R3 and p are the same as described above, R40 represents a group —(B21)fCHRAR4a, and B21, RA, f and R4a are the same as described above, provided that the alkyl moiety of the group —(B21)fCHRAR4a has not more than 6 carbon atoms.

The reaction of the compound (9) with the compound (8) is carried out under the same conditions as in the reaction between the compound (1b) and the compound (5) of reaction formula 2.
The compound (1), wherein A represents




wherein R4 represents a 3,5-dioxoisooxazolidinyl lower alkylidene group which may have an oxo group as a substituent on the 3,5-dioxoisooxazolidine ring, is produced by reacting the compound (11) with the compound (10) in accordance with reaction formula 7.





wherein R1, R2, X1 and Y are the same as described above, and

A5 represents





wherein R3 and p are the same as described above, R41 represents a group —B22 (CO2R43)(CO2R44), B22 represents a lower alkylidene group, and R43 and R44 each represent a lower alkyl group, and

A6 represents





wherein R3 and p are the same as described above, and R42 is a group represented by





wherein B22 is the same as described above.

The reaction of the compound (10) with the compound (11) is carried out under the same condition as in the reaction for converting the compound (1f) into the compound (1h) in accordance with reaction formula 3.
The compound (1), wherein A represents




wherein R4 represents





is produced from the compound (13), as shown in reaction formula 8.





wherein R1, R2, X1, Y and R13 are the same as described above,

A7 represents





wherein R3 and p are the same as described above, and

R45 represents a halogen atom,

A8 represents





wherein R3 and p are the same as described above, and

R46 represents





wherein R13 is the same as described above,

A9 represents:





wherein R3 and p are the same as described above, and

R47 represents a group





wherein R13 is the same as described above, and

A8a represents





wherein R3 and p are the same as described above, and

R46 represents a group





wherein R13 is the same as described above.

The reaction of the compound (13) with the compound (12) is carried out in an appropriate inert solvent in the presence of a basic compound.
Examples of the basic compound used herein include such as metal sodium, metal potassium, metal magnesium, sodium hydride, sodium amide, metal alcoholates such as sodium methylate, sodium ethylate, and potassium tert-butoxide, and alkyl and aryl lithiums or lithium amides such as methyl lithium, n-butyl lithium, phenyl lithium, and lithium diisopropylamide. These basic compounds are used singly or in a mixture of two types or more.
The basic compound is appropriately used typically in at least an equimolar amount to that of the compound (13), and preferably 1 to 5 times that of the compound (13) on a molar basis.
Examples of the inert solvent to be used include aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, and diglyme, aliphatic hydrocarbons such as n-hexane, heptane, and cyclohexane, halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride, dimethylsulfoxide, and N,N-dimethylformamide, and a mixture thereof.
The reaction is carried out typically at about −90 to 150° C. and preferably at about −90 to 120° C., and completed generally in about 10 minutes to 10 hours.
The compound (12) is appropriately used typically in at least an equimolar amount to that of the compound (13) and preferably 1 to 5 times that of the compound (13) on a molar basis.
The reaction for converting the compound (1l) into the compound (1m) is carried out in an appropriate inert solvent and in the presence of an acid.
Examples of the acid used herein include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and organic acids such as sulfonic acids including p-toluenesulfonic acid. These acids are used singly or in a mixture of two types or more.
The acid is preferably used typically in at least an equimolar amount to that of the compound (1l) and preferably in an equal amount to a large excess amount with respect to the compound (1l) on a molar basis.
Any solvent may be used in this reaction as long as it is used in the reaction between the compound (13) and the compound (12).
This reaction is carried out typically at room temperature to 200° C., preferably at room temperature to about 150° C., and completed generally in about 1 to 20 hours.
The reaction for converting the compound (1l) into the compound (1l′) is carried out in an appropriate solvent and in the presence of an acid and a catalyst.
Examples of the solvent used herein include water, lower alcohols such as methanol, ethanol, and isopropanol, ketones such as acetone and methyl ethyl ketone, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, ethers such as diethyl ether, dimethoxyethane, tetrahydrofuran, diisopropyl ether, diglyme, and 1,4-dioxane, aromatic hydrocarbons such as benzene, toluene, and xylene, acetonitrile, dimethyl sulfoxide, N,N-dimethylacetamide, N,N-dimethylformamide, and N-methylpyrrolidone, and a mixture thereof.
Examples of the acid used herein include inorganic acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and organic acids such as boron trifluoride diethyl etherate, formic acid, acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid.
Examples of the catalyst include alkylsilane compounds such as triethylsilane.
The acid and the catalyst described above each are used typically in an amount about 0.01 to 5 times that of the compound (1l), and preferably about 0.01 to 1 times to that of the compound (1l) on a molar basis.
The reaction is carried out at about room temperature to 200° C., and preferably about room temperature to 150° C., and completed generally in about 1 to 10 hours.
The reaction which converts the compound (1l) into the compound (1l′) may be carried out in an appropriate solvent and in the presence of a catalytic hydrogen reducing agent.
Examples of the solvent to be used include water, fatty acids such as acetic acid, alcohols such as methanol, ethanol, and isopropanol, aliphatic hydrocarbons such as n-hexane, alicyclic hydrocarbons such as cyclohexane, ethers such as diethyl ether, dimethoxyethane, tetrahydrofuran, monoglyme, diglyme, and 1,4-dioxane, esters such as methyl acetate, ethyl acetate, and butyl acetate, and aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and a mixture thereof.
Examples of the catalytic hydrogen reducing agent include palladium, palladium-black, palladium-carbon, palladium hydroxide-carbon, rhodium-alumina, platinum, platinum oxide, copper chromite, Raney nickel, and palladium acetate.
The catalytic hydrogen reducing agent is used typically in an amount of 0.01 to 1 times that of the compound (1l) on a weight basis.
The reaction favorably proceeds typically at about −20 to 100° C. and preferably at about 0 to 80° C., and completed generally in about 0.5 to 20 hours. The hydrogen pressure is typically at 1 to 10 atm.
It is preferable to add a mineral acid such as hydrochloric acid to this reaction system.
The compound (1), wherein A represents




wherein R4 represents





wherein R13 represents a group other than a hydrogen atom,

is produced from a compound wherein R13 is a hydrogen atom, in accordance with the following reaction formula 9.





wherein R1, R2, X1, Y, A10, RA, R13a and X2 are the same as described above, provided that a and b of A10 are bound to Y and a piperidinyl group, respectively,

R13b represents a lower alkyl group which may have a halogen atom as a substituent, a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, an imidazolyl lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a carboxy lower alkyl group, a piperazinylcarbonyl lower alkyl group which may be substituted, on the piperazine ring, with a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, or a morpholinocarbonyl substituted lower alkyl group,

R13c represents a lower alkanoyl group which may have a halogen atom as a substituent, a lower alkoxy carbonyl group, a benzoyl group, a morpholino substituted lower alkanoyl group, a piperazinyl lower alkanoyl group which may be substituted, on the piperazine ring, with a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring; or an imidazolyl lower alkanoyl group, and

R13d represents a hydrogen atom, a lower alkyl group which may have a halogen atom as a substituent, a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, a phenyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, an imidazolyl group, an imidazolyl lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a carboxy lower alkyl group, a piperazinylcarbonyl lower alkyl group which may be substituted, on the piperazine ring, with a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, or a morpholinocarbonyl substituted lower alkyl group, provided that the alkyl moiety of the side chain (group —CHRAR13d) of the compound (1q) has not more than 6 carbon atoms.

The reaction of the compound (1n-1) with the compound (13′) is carried out under the same conditions as in the reaction between the compound (1b) and the compound (4) in accordance with reaction formula 2.
The reaction between the compound (1n-1) and the compound (14) is carried out under the same conditions as in the reaction between the compound (1b) and the compound (6) in accordance with reaction formula 2.
The reaction between the compound (1n-1) and the compound (15) is carried out under the same conditions as in the reaction between the compound (1b) and the compound (5) of reaction formula 2.
Also, the reaction between the compound (1n-2) and the compound (13′) is carried out under the same conditions as in the reaction between the compound (1b) and the compound (4) in accordance with reaction formula 2, the reaction between the compound (1n-2) and the compound (14) is carried out under the same conditions as in the reaction between the compound (1b) and the compound (6) in accordance with reaction formula 2, and the reaction between the compound (1n-2) and the compound (15) is carried out under the same conditions as in the reaction between the compound (1b) and the compound (5) in accordance with reaction formula 2.
In reaction formula 9, the hydrolysis of the compounds (1o-1) and (1o-2) wherein R13b represents a lower alkoxycarbonyl lower alkyl group may produce the corresponding compounds (1o-1) and (1o-2) wherein R13b represents a carboxy lower alkyl group.
In reaction formula 9, the hydrolysis of compounds (1p-1) and (1p-2), wherein R13c represents a lower alkoxycarbonyl group, may produce the corresponding compounds (1p-1) and (1p-2), wherein R13c is a hydrogen atom.
The hydrolysis reaction (hereinafter, this hydrolysis reaction will be called “hydrolysis B”) may be carried out in the presence or absence of an appropriate solvent and in the presence of an acidic or basic compound.
Examples of the solvent to be used herein include water, lower alcohols such as methanol, ethanol, isopropanol, and tert-butanol, ketones such as acetone and methyl ethyl ketone, ethers such as diethyl ether, dioxane, tetrahydrofuran, monoglyme, and diglyme, fatty acids such as acetic acid and formic acid, esters such as methyl acetate and ethyl acetate, halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride, dimethylsulfoxide, N,N-dimethylformamide, and hexamethylphosphoric acid triamide, and a mixture thereof.
Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, organic acids such as formic acid, acetic acid, trifluoroacetic acid, sulfonic acids including p-toluenesulfonic acid, and Lewis acids such as boron tribromide and boron trichloride. These acids are used singly or in a mixture of two types or more.
Examples of the basic compound include carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate, and metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, and lithium hydroxide. These basic compounds are used singly or in a mixture of two types or more.
The hydrolysis reaction favorably proceeds typically at about 0 to about 200° C. and preferably at about 0 to 150° C., and is completed generally in about 10 minutes to 50 hours.
The compound (1) wherein A represents




wherein R4 represents





wherein R13 represents an imidazolyl lower alkyl group, is produced as shown in reaction formula 10 below.





wherein R1, R2, X1, Y, A10, R13a, B2, and X2 are the same as described above, provided that a and b of A10 are bound to Y and a piperidinyl group, respectively.

The reaction of the compound (1r-1) and the compound (16) and the reaction of the compound (1r-2) and the compound (16) are carried out under the same conditions as in the reaction of the compound (2) and the compound (3) shown in reaction formula 1 above.
The compound (1) wherein A represents




wherein R4 represents





wherein R13 represents a morpholino substituted lower alkanoyl group, a piperazinyl lower alkanoyl group which may be substituted on the piperazine ring with a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, or an imidazolyl lower alkanoyl group, may be produced from the corresponding compound, wherein R13 represents a lower alkanoyl group which may have a halogen atom as a substituent, as shown in reaction formula 11 below.





wherein R1, R2, X1, Y, R13a, B21 and X2 are the same as described above, and R47′ is a morpholino group, a piperazinyl group which may be substituted, on the piperazine ring, with a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, or an imidazolyl group, provided that a and b of A10 are bound to Y and a piperidinyl group, respectively.

The reaction of the compound (1t-1) and the compound (17) and the reaction of the compound (1t-2) and the compound (17) are carried out under the same conditions as in the reaction of the compound (2) and the compound (3) shown in reaction formula 1 above.
The compound (1) wherein A represents




wherein R4 represents





wherein R13 represents a piperazinylcarbonyl lower alkyl group which is substituted, on the piperazine ring, with a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, or a morpholinocarbonyl substituted lower alkyl group,

is produced from the corresponding compound wherein R13 is a carboxy group, as shown in reaction formula 12 below.





wherein R1, R2, X1, Y, A10, R13a and B21 are the same as described above, R48 is a piperazinyl group which may be substituted, on the piperazine ring, with a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, or a morpholino group, provided that a and b of A10 are bound to Y and a piperidinyl group, respectively.

The reaction of the compound (1v-1) and the compound (18) and the reaction of the compound (1v-2) and the compound (18) are carried out under the same conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula above.
The compound (1) wherein A represents




wherein R4 represents a group -(T)l-NR14R15, is produced as shown in reaction formulas 13 and 14 below.





wherein R1, R2, X1, Y, A10, X2, l, R14 and R15 are the same as described above, T1 is a lower alkylene group, a group —COB8—, a group —SO2— or a group —CH(OH)—B9—, and B8 and B9 are the same as described above, provided that, in the compounds (35) and (1pp), a and b of A10 are bound to Y and -(Tl)l, respectively.

The reaction of the compound (35) and the compound (36) is carried out under the same reaction conditions as in the reaction of the compound (2) and the compound (3) shown in reaction formula 1 above.
The compound (35) wherein l is 0 may also be produced by reacting the corresponding compound (35) with the compound (36) in an appropriate solvent in the presence of a basic compound and a catalyst.
Any solvent and basic compound may be used as long as they are used in the reaction of the compound (2) and the compound (3) shown in reaction formula 1 above.
Examples of the catalyst include various metal complexes as well as various combinations of a metal complex with a ligand. Examples of the metal complex include palladium acetate (II), tetrakis(triphenylphosphine)palladium(0), and tris(dibenzylideneacetone)dipalladium(0). Examples of the ligand include R-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (R-BINAP), S-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (S-BINAP), RAC-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (RAC-BINAP), t-butylphosphine, and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.
The catalyst is appropriately used typically in at least an equimolar amount to the compound (35) and preferably 1 to 5 times that of the compound (35) on a molar basis.
This reaction is carried out typically at about 0 to 200° C. and preferably at about 0 to 150° C., and completed generally in about 1 to 60 hours. This reaction will be hereinafter called “reaction C”.




wherein R2, X1, Y, A10, T2, R14 and R15 are the same as described above, provided that, in the compounds (37) and (1qq), a and b of A10 are bound to Y and T2, respectively, and R95 represents a group R1 or a halogen atom. The R1 used herein is the same as described above.

The reaction of the compound (37) and the compound (36) is carried out in the same reaction conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.
The compound (1) wherein A represents




wherein R4 represents a group -(T)l-NR14R15, and l represents 0,

may also be produced by the method shown in reaction formula 15.





wherein R1, R2, X1, Y, RA, X2, T, l and A10 are the same as described above,

R49 is the same group as R15 defined in (15), (22), (23), (27) and (36a),

R49a is R15 defined in (2) to (5), (7), (8), (10), (11), (13), (14), (16) to (21), (24), (25), (26), (26a), (27a), (28a), (29a), (30a), (31a), (32a), (33a), (34a), (35a), or (37a), a phenoxycarbonyl group and a lower alkylsulfonyl group,

R49b represents a hydrogen atom, an alkyl group which may have a hydroxyl group as a substituent, a phenoxy lower alkyl group, a phenyl lower alkyl group which may have, on the phenyl ring, with 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkoxy group which may have a halogen atom as a substituent, and a lower alkyl group, a phenyl group which may have, on the phenyl ring, with 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkoxy group which may have a halogen atom as a substituent, and a lower alkyl group, a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, a phenyl group which may have a lower alkylenedioxy group on the phenyl ring, a lower alkoxycarbonyl substituted lower alkyl group, a carboxy substituted lower alkyl group, a cycloalkyl lower alkyl group, a cycloalkyl group, a pyridyl lower alkyl group, a pyridyl group, an amino group substituted lower alkyl group which may have a substituent selected from the group consisting of a lower alkyl group and a lower alkanoyl group, a lower alkoxy lower alkyl group, an imidazolyl group, an imidazolyl lower alkyl group, a 1,2,3,4-tetrahydroisoquinolylcarbonyl substituted lower alkyl group, an A group-substituted carbonyl lower alkyl group, a pyrrolidinyl group, a pyrrolidinyl lower alkyl group, a morpholino group, a morpholino lower alkyl group, an anilinocarbonyl lower alkyl group which may have a lower alkyl group as a substituent on the phenyl ring, a piperazinyl group which may have, on the piperazine ring, a substituent selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, a piperazinyl lower alkyl group which may have, on the piperazine ring, a substituent selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, an amidino group which may have a lower alkyl group as a substituent, an amidino lower alkyl group which may have a lower alkyl group as a substituent, a B group substituted carbonyl lower alkyl group, or a cyano substituted lower alkyl group,

R14a represents a hydrogen atom or a lower alkyl group which may have a hydroxyl group as a substituent, and R34, d, R36, R37 and B20 are the same as described above, provided that, in the compounds (1rr), (1ss), (1ss′) and (1ss′′), a and b of A10 are bound to Y and N, respectively, and, in the compound (1ss′′), the CHRAR49b moiety of the side chain (—Y-A10N(R14a)(CHRAR49b) has not more than 6 carbon atoms.

The reaction of the compound (1rr) and the compound (38a) is carried out under the same conditions as in the reaction of the compound (1b) and the compound (4) shown in reaction formula 2 above.
The reaction of the compound (1rr) with the compound (38) is carried out under the same conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.
The reaction of the compound (1rr) with the compound (38b) is carried out under the condition similar to that of the reaction of the compound (1b) and the compound (5) shown in reaction formula 2 above.
The compound (1) wherein A represents




wherein R4 represents a group -(T)l-NR14R15, l represents 1, and T represents a group —CH(OH)—B9—,

may also be produced by the method shown in reaction formula 16 below.





wherein R1, R2, X1, A10, Y, B8, B9, R14 and R15 are the same as described above, provided that, in the compounds (1tt) and (1uu), a and b of A10 are bound to Y and B8 or B9, respectively.

The reaction which converts the compound (1tt) into the compound (1uu) is carried out under the same condition as in the reaction which converts the compound (1f) into the compound (1g) shown in reaction formula 3 above.
The compound (1) wherein A represents




wherein R4 represents a group -(T)l-NR14R15, l represents 1, and T represents a group —CH(OH)—B11, —CO—,

may also be produced by the method shown in reaction formula 17 below.





wherein R1, R2, X1, A10, Y, B10, B11, R14 and R15 are the same as described above, provided that, in the compounds (1vv) and (1ww), a and b of A10 are bound to Y and a group —COB10 or —CH(OH)B11—, respectively.

The reaction which converts the compound (1vv) into the compound (1ww) is carried out under the same conditions as in the reaction which converts the compound (1f) into the compound (1g) shown in reaction formula 3 above.
The compound (1) wherein A represents




wherein R4 is a group -(T)1NR14R15, and R14 and R15 are bound with each other to form a 5- to 10-membered saturated or unsaturated heterocyclic group which has various substituents thereon,

may be produced as shown in reaction formulas 18 to 20, 22, 24 to 31, and 34 to 36 below.





wherein R1, R2, RB, X1, Y, T, l, A10 and X2 are the same as described above, provided that a and b of A10 are bound to a group Y and a group (T)l, respectively;

R14b and R15a represent the same 5- to 10-membered saturated or unsaturated heterocyclic groups as defined in R14 and R15 above, respectively, except that each of the heterocyclic groups has at least one secondary amine thereon;

R14c and R15b represent the same 5- to 10-membered saturated or unsaturated heterocyclic groups as defined in R14 and R15 above respectively, except that each of the heterocyclic groups has at least one tertiary amine substituted with R50 thereon;

R14d and R15c represent the same 5- to 10-membered saturated or unsaturated heterocyclic group defined in R14 and R15 above, respectively, except that each of the heterocyclic groups has at least one tertiary amine substituted with R51 thereon;

R14e and R15d represent the same 5- to 10-membered saturated or unsaturated heterocyclic groups as defined in R14 and R15 above, respectively, except that each of the heterocyclic groups has at least one tertiary amine substituted with a R52(RB)CH— group thereon;

R14f and R15e represent the same 5- to 10-membered saturated or unsaturated heterocyclic groups as defined in R14 and R15 above, respectively, except that each of the heterocyclic groups has at least one tertiary amine thereon substituted with a group





wherein R50 is the same substituent for the heterocyclic ring, which is formed by binding R14 and R15 to each other, as (28), (30), (31), (32), (33), (34), (36), (37), (38), (41), (43), (44), (45), (47), (49) (provided that t is 1), (50) (provided that o is 0), (51), (52), (53), (54), (55), (56), (57), (58), (59), (60), (62), (63), (64), (65), (66), (70), (77), (79), (82), (83), (87), (88a), or (90a) described above;

R51 is the same substituent for the heterocyclic group, which is formed by binding R14 and R15 to each other, as (35), (39), (40), (42), (50) (provided that o is 1), (67), (75), (76), (77), (78), (80), (81) or (84) (provided that s is 0) described above;

R52 is a hydrogen atom, a lower alkyl group which has 1 or 2 phenyls which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkanoyl group, an amino group which may have a lower alkanoyl group as a substituent, a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxy group which may have a halogen atom as a substituent, a phenyl lower alkoxy group, a hydroxyl group, and a lower alkylenedioxy group, (the lower alkyl group optionally having a pyridyl group on the lower alkyl group), a phenyl group which may have, on the phenyl ring 1 to 3 substituents selected from the group consisting of a lower alkanoyl group, an amino group which have a lower alkanoyl group as a substituent, a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxy group which may have a halogen atom as a substituent, a phenyl lower alkoxy group, a hydroxy group, and a lower alkylenedioxy group, a pyridyl lower alkyl group which may have, on the pyridine ring, 1 to 3 substituents selected from the group consisting of a hydroxyl group and a lower alkyl group which may have a hydroxyl group as a substituent, a pyridyl group which may have, on the pyridine ring, 1 to 3 substituents selected from the group consisting of a hydroxyl group and a lower alkyl group which may have a hydroxyl group as a substituent, a pyrrolyl lower alkyl group which may have 1 to 3 lower alkyl groups as substituents on the pyrrole ring, a pyrrolyl group which may have 1 to 3 lower alkyl groups as substituents on the pyrrole ring, a benzoxazolyl lower alkyl group, a benzoxazolyl group, a benzothiazolyl lower alkyl group, a benzothiazolyl group, a furyl lower alkyl group, a furyl group, a lower alkyl group which may have a substituent selected from the group consisting of a hydroxyl group and a halogen atom, a naphthyl lower alkyl group, a naphthyl group, a phenoxy lower alkyl group, a group —B12CO—NR20R21; a group —B13NR22R23 group, a group 1,2,3,4-tetrahydronaphthyl substituted lower alkyl group which may have 1 to 5 lower alkyl groups as substituents on the 1,2,3,4-tetrahydronaphthalene ring, a 1,2,3,4-tetrahydronaphthyl group which may have 1 to 5 lower alkyl groups as substituents on the 1,2,3,4-tetrahydronaphthalene ring, a quinolyl lower alkyl group, a quinolyl group, a 1,2,3,4-tetrazolyl lower alkyl group which may have, on the tetrazole ring, a substituent selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group, a 1,2,3,4-tetrazolyl group which may have, on the tetrazole ring, a substituent selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group, a thiazolyl lower alkyl group which may have a phenyl group as a substituent on the thiazole ring, a thiazolyl group which may have a phenyl group as a substituent on the thiazole ring, a benzoyl lower alkyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkoxy group and a halogen atom, a piperidinyl lower alkyl group which may have a lower alkyl group as a substituent on the piperidine ring, a benzoyl lower alkyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkoxy group and a halogen atom, a piperidinyl group which may have a lower alkyl group on the piperidine ring, a 1,2,3,4-tetrahydroquinolyl lower alkyl group which may have an oxo group as a substituent on the tetrahydroquinoline ring, a 1,2,3,4-tetrahydroquinolyl group which may have an oxo group as a substituent on the tetrahydroquinoline ring, a 1,3,4-oxadiazolyl lower alkyl group which may have an oxo group as a substituent on the 1,3,4-oxadiazole ring, a 1,3,4-oxadiazolyl group which may have an oxo group as a substituent on the 1,3,4-oxadiazole ring, a cycloalkyl lower alkyl group, a cycloalkyl group, a thienyl lower alkyl group, a thienyl group, a lower alkoxy lower alkyl group, a carboxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, an imidazolyl lower alkyl group, or an imidazolyl group; and

RB and R52, together with carbon atoms to which they bind, may form a cycloalkyl group or a tetrahydro-4H-pyranyl group;

provided that the alkyl moiety of the R52(RB)CH— group in the compound (1aaa) has not more than six carbon atoms.

The reaction of the compound (35′) and the compound (39) is carried out under the same conditions as in the reaction of the compound (1b) with the compound (4) shown in reaction formula 2 above.
The reaction of the compound (35′) and the compound (40) is carried out under the same conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.
The reaction of the compound (35′) and the compound (41) is carried out under the same conditions as in the reaction of the compound (1b) and the compound (5) shown in reaction formula 2 above.
The reaction is carried out using a compound (41), whose RB and R52 (bound to a carbon atom) are mutually bound to form a cycloalkyl ring or a tetrahydro-4H-pyran ring together with the carbon atom in the presence of a hydride reducing agent, as a starting material. In this case, in place of the compound (41), cycloalkyloxytrialkylsilane such as [(1-ethoxycyclopropyl)oxy]trimethylsilane may be used as the starting material (to produce the above described compound (41) in the reaction system).
The reaction of the compound (35′) and the compound (42) is carried out under the same conditions as in the reaction of the compound (2) and the compound (3) shown in reaction formula 1 above.
The compound (35′) may also be produced from the compound (1yy), (1zz) or (1aaa) under the same reaction conditions as in the reaction which converts the compound (1iii′) into the compound (1hhh′) shown in reaction formula 24 below.




wherein R1, R2, X1, Y, T, l, A10 and X2 are the same as described above, provided that a and b of A10 are bound to Y and (T)l, respectively;

R14g and R15f are the same 5- to 10-membered saturated or unsaturated heterocyclic groups as defined in R14 and R15 above, respectively, except that each of the heterocyclic groups has at least one tertiary amine substituted with a lower alkoxycarbonyl group thereon; and

R14h and R15g are the same 5- to 10-membered saturated or unsaturated heterocyclic groups as defined in R14 and R15 above, respectively, except that each of the heterocyclic groups has at least one secondary amine thereon.

The reaction which converts the compound (1ccc) into the compound (1ddd) may be carried out under the same reaction conditions as in hydrolysis B as described in reaction formula 9 above.




wherein R1, R2, X1, Y, T, l and A10 are the same as described above, provided that a and b of A10 are bound to a group Y and a group (T)l, respectively, R74a represents a nitro group or a group —R1, and;

R14i and R15i are the same 5- to 10-membered saturated or unsaturated heterocyclic groups as defined in R14 and R15 above, respectively, except that each of the heterocyclic groups has at least one lower alkoxycarbonyl lower alkoxy group, lower alkoxycarbonyl group, lower alkoxycarbonyl lower alkyl group, or a group —(B12CO)t-N(R20a)R51′ thereon;

R14j and R15i are the same 5- to 10-membered saturated or unsaturated heterocyclic groups as defined in R14 and R15 above, respectively, except that each of the heterocyclic groups has at least one carboxy lower alkoxy group, carboxy group, carboxy lower alkyl group, or a group —(B12CO)t-N(R20a)R52′ group thereon;

B12 and t are the same as described above;

R20a represents a hydrogen atom, a cycloalkyl group, an amino group which may have a lower alkoxycarbonyl group as a substituent, a benzoyl group which may have 1 to 3 alkoxy groups as substituents on the phenyl ring, a lower alkyl group,

a lower alkyl group which may have, on the phenyl ring, substituents selected from the group consisting of an lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, and a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxy group which may have a halogen atom as a substituent, and a lower alkylthio group, a phenyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkoxy group which may have a halogen atom as a substituent and a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxycarbonyl group, a cycloalkyl lower alkyl group, a pyrrolidinyl lower alkyl group which may have, on the pyrrolidine ring, 1 to 3 lower alkyl groups which may have a hydroxyl group as a substituent, an amino substituted lower alkyl group which may have a substituent selected from the group consisting of a phenyl group and a lower alkyl group,

a 1,2,3,4-tetrahydronaphthyl substituted lower alkyl group which may have 1 to 5 lower alkyl groups as substituents on the 1,2,3,4-tetrahydronaphthalene ring, a naphthyl lower alkyl group, a pyridyl lower alkyl group, a quinolyl lower alkyl group, a 1,2,3,4-tetrazolyl lower alkyl group which may have, on the tetrazole ring, 1 to 3 substituents selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group, a 1,2,4-triazolyl lower alkyl group, a tetrahydrofuryl lower alkyl group which may have a hydroxyl group as a substituent on the lower alkyl group, a phenoxy lower alkyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkyl group and a nitro group, a phenyl lower alkanoyl group, a lower alkanoyl group which may have a halogen atom as a substituent, an imidazolyl lower alkanoyl group, a lower alkoxycarbonyl lower alkyl group, a pyridyl group, or a carboxy lower alkyl group;

R51′ is a lower alkdxycarbonyl group or a lower alkoxycarbonyl lower alkyl group;

R52 is a hydrogen atom or a carboxy lower alkyl group; and

R53 is a lower alkyl group.

The reaction which converts the compound (1eee) into the compound (1fff) may be carried out under the same reaction conditions as described in hydrolysis B as described in reaction formula 9 above.
The reaction of the compound (1fff) and the compound (43) may be carried out under any conditions of a typical esterification reaction. For example, the reaction is carried out in the presence of a mineral acid such as hydrochloric acid or sulfuric acid, and a halogenating agent such as thionylchloride, phosphorus oxychloride, phosphorus pentachloride, or phosphorus trichloride. The compound (43) is used in a large excess amount of that of the compound (1fff). The reaction favorably proceeds typically at about 0 to 150° C. and preferably at about 50 to 100° C., and is completed generally in about 1 to 10 hours.
The esterification reaction may be carried out using a condensation agent such as carbodiimide in the presence of a basic compound such as dimethylaminopyridine. Typical reaction conditions for producing an amide bond, which are used in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2, may also be used.
The reaction of the compound (1fff) and compound (43) is carried out in the presence of the same basic compound and the solvent as those used in the reaction of the compound (2) and the compound (3) of reaction formula 1. The reaction is carried out typically at about 0 to 100° C. and preferably at about 0 to 70° C., and completed generally in about 1 to 30 hours.
The compound (1eee) may also be produced using a halogenated lower alkyl such as methyl iodide in place of the compound (43) under the same conditions as in the reaction of the compound (2) and the compound (3) shown in reaction formula 1.




wherein R1, R2, X1, Y, A10, R13a, B21 and R53 are the same as described above, and R54 is a lower alkyl group, provided that a and b of A10 are bound to a group Y and a piperidinyl group, respectively.

The reaction which converts the compound (1ggg-1) into the compound (1v-1) and the reaction which converts the compound (1ggg-2) into the compound (1v-2) is carried out under the same reaction conditions as in hydrolysis B as described in reaction formula 9.
The reaction of the compound (1v-1) and the compound (43) and the reaction of the compound (1v-2) and the compound (43) are carried out under the same reaction conditions as in the reaction of the compound (1fff) and the compound (43) shown in reaction formula above.
The compound (1ggg-1) may also be produced using a halogenated lower alkyl such as methyl iodide in place of the compound (43) under the same conditions as in the reaction of the compound (2) and the compound (3) shown in reaction formula 1 above.
Similarly, the compound (1ggg-2) may also be produced using a halogenated lower alkyl such as methyl iodide in place of the compound (43) under the same conditions as in the reaction of the compound (2) and the compound (3) shown in reaction formula 1 above.




wherein R1, R2, X1, Y, T, l and A10 are the same as described above, provided that a and b of A10 are bound to a group Y and a group (T)l, respectively;

R14k and R15j are the same 5- to 10-membered saturated or unsaturated heterocyclic groups as defined in R14 and R15 above, respectively, except that each of the heterocyclic groups has at least one group —B21CONHNH2 (wherein B21 is the same as described above) thereon; and

R14l and R15k are the same 5- to 10-membered saturated or unsaturated heterocyclic groups as defined in R14 and R15 above, respectively, except that each of the heterocyclic groups has at least one group





thereon.

The reaction which converts the compound (1hhh) into compound (1iii) is carried out under the same conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.




wherein R1, R2, X1, Y, A10, B21 and X2 are the same as described above, provided that a and b of A10 are bound to a group Y and a group (T)l, respectively, R55 is a lower alkanoyl group, and R55a is a lower alkyl group.

The reaction of the compound (44) and the compound (45) is carried out under the same conditions as in the reaction which converts the compound (1f) into the compound (1h) shown in reaction formula 3 above.
The reaction of the compound (44a) and the compound (46) is carried out under the same conditions as in the reaction of the compound (2) and the compound (3) shown in reaction formula 1 above.
The reaction which converts the compound (47) into the compound (1rrr) is carried out under the same conditions as in the reaction which converts the compound (1f) into the compound (1h) shown in reaction formula 3 above.




wherein R1, R2, X1, Y, T, l, A10 and X2 are the same as described above, provided that a and b of A10 are bound to a group Y and a group (T)l, respectively;

R14m and R15l are the same 5- to 10-membered saturated or unsaturated heterocyclic groups as defined in R14 and R15 above, respectively, except that each of the heterocyclic groups has at least one hydroxyl group or hydroxyl group substituted lower alkyl group thereon;

R14n and R15m are the same 5- to 10-membered saturated or unsaturated heterocyclic groups as defined in R14 and R15 above, respectively, except that each of the heterocyclic groups has at least one group —OR56 thereon;

R56 represents a phenyl group which have, on the phenyl ring, with 1 to 3 substituents selected from the group consisting of a cyano group, a lower alkyl group which may have a halogen atom as a substituent, and a lower alkoxy group which may have a halogen atom as a substituent, a phenyl lower alkyl group which may have, on the phenyl ring, with 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, and a lower alkoxy group which may have a halogen atom as a substituent, a pyridyl lower alkyl group, a lower alkyl group, a lower alkoxy lower alkyl group, a benzoyl group, a lower alkoxycarbonyl lower alkyl, a carboxy lower alkyl group; or a group —B15—CO—NR26R27 group (wherein B15, R26 and R27 are the same as described above),

provided that, the R56 of the compound (48), which reacts with the heterocyclic group substituted with at least one hydroxyl group substituted lower alkyl group of the compound (1hhh′), is an unsubstituted phenyl group or a lower alkyl group.

The reaction of the compound (1hhh′) and the compound (48) is carried out under the same conditions as in the reaction of the compound (2) and the compound (3) shown in reaction formula 1 above.
The reaction which converts the compound (1iii′) into the compound (1hhh′) is carried out under the same conditions as in hydrolysis B as described in reaction formula 9 above.
The compound (1iii′) may be converted into the compound (1hhh′) by a reduction reaction. This reduction reaction is, for example, carried out in an appropriate solvent in the presence of a catalytic hydrogen reducing agent.
Examples of the solvent include water, fatty acids such as acetic acid, alcohols such as methanol, ethanol, and isopropanol, aliphatic hydrocarbons such as hexane and cyclohexane, ethers such as dioxane, tetrahydrofuran, diethyl ether, monoglyme, and diglyme, esters such as ethyl acetate and methyl acetate, aprotic polar solvents such as N,N-dimethylformamide, and a mixture thereof.
Examples of the catalytic hydrogen reducing agent include palladium, palladium black, palladium-carbon, platinum, platinum oxide, copper chromite, and Raney nickel. These reducing agents may be used singly or as a mixture of two types or more.
The catalytic hydrogen reducing agent is preferably used generally in an amount of 0.02 to 1 times that of the compound (1iii′) on a weight basis.
The reaction temperature is typically set at about −20 to 100° C. and preferably at about 0 to about 80° C. The reaction is preferably carried out at a hydrogen pressure of typically 1-10 atm, and completed generally in about 0.5 to 20 hours.




wherein R1, R2, X1, Y, T, l, A10, RA and X2 are the same as described above, provided that a and b of A10 are bound to a group Y and a group (T)l, respectively; R14o and R15n are the same 5- to 10-membered saturated or unsaturated heterocyclic groups as defined in R14 and R15 above, respectively, except that each of the heterocyclic groups has at least one group —(B12CO)tNHR20a thereon;

R14p and R15o are the same 5- to 10-membered saturated or unsaturated heterocyclic groups as defined in R14 and R15 above, respectively, except that each of the heterocyclic groups has at least one group —(B12CO)tN(R20a)R21b thereon; and

R14q and R15p are the same 5- to 10-membered saturated or unsaturated heterocyclic groups as defined in R14 and R15 above, respectively, except that each of the heterocyclic groups has at least one group —(B12CO)tN(R20a)R21c thereon;

R14r and R15q represent the same 5- to 10-membered saturated or unsaturated heterocyclic groups as defined in R14 and R15 above, respectively, except that each of the heterocyclic groups has at least one group —(B12CO)tN(R20a)(CHRAR21d) thereon,

wherein B12, t and R20a are the same as described above;

R21b represents a lower alkyl group, a cycloalkyl group, a lower alkyl group which may have 1 or 2 phenyls which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxy group which may have a halogen atom as a substituent and a lower alkylthio group, a phenyl group which may have, on the phenyl ring, 1 to 3 groups selected from the group consisting of a lower alkoxy group which may have a halogen atom as a substituent and a lower alkyl group which may have a halogen atom as a substituent, a cycloalkyl lower alkyl group, a pyrrolidinyl lower alkyl group which may have, on the pyrrolidine ring, 1 to 3 lower alkyl groups which may have a hydroxyl group as a substituent, an amino substituted lower alkyl group which may have a substituent selected from the group consisting of a phenyl group and a lower alkyl group, a 1,2,3,4-tetrahydronaphthyl substituted lower alkyl group which may have 1 to 5 lower alkyl groups as substituents on the 1,2,3,4-tetrahydronaphthalene ring, a naphthyl lower alkyl group, a pyridyl lower alkyl group, a quinolyl lower alkyl group, a 1,2,3,4-tetrazolyl lower alkyl group which may have, on the tetrazole ring, 1 to 3 substituents selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group, a 1,2,4-triazolyl lower alkyl group, a tetrahydrofuryl lower alkyl group which may have a hydroxyl group as a substituent on the lower alkyl group, a phenoxy lower alkyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkyl group and a nitro group, a lower alkoxycarbonyl lower alkyl group, a pyridyl group, or a carboxy lower alkyl group;

R21c represents a benzoyl group which may have 1 to 3 lower alkoxy groups as substituents on the phenyl ring, a lower alkoxycarbonyl group, a phenyl lower alkanoyl group, a lower alkanoyl group which may have a halogen atom as a substituent or an imidazolyl lower alkanoyl group; and

R21d represents a hydrogen atom, a lower alkyl group, a lower alkyl group which have 1 or 2 phenyl groups which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxy group which may have a halogen atom as a substituent and a lower alkylthio group, a phenyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group which may be substituted with a halogen atom, a lower alkoxy group which may be substituted with a halogen atom and a lower alkylthio group, a cycloalkyl lower alkyl group, a cycloalkyl group, a pyrrolidinyl lower alkyl group which may have, on the pyrrolidine ring, 1 to 3 lower alkyl groups which may have a hydroxyl group as a substituent, a pyrrolidinyl group which may have, on the pyrrolidine ring, 1 to 3 lower alkyl groups which may have a hydroxyl group as a substituent, an amino substituted lower alkyl group which may have a group selected from the group consisting of a phenyl group and a lower alkyl group, a 1,2,3,4-tetrahydronaphthyl substituted lower alkyl group which may have 1 to 5 lower alkyl groups as substituents on the 1,2,3,4-tetrahydronaphthalene ring, a 1,2,3,4-tetrahydronaphthyl group which may have 1 to 5 lower alkyl groups as substituents on the 1,2,3,4-tetrahydronaphthalene ring, a naphthyl lower alkyl group, a naphthyl group, a pyridyl lower alkyl group, a pyridyl group, a quinolyl lower alkyl group, a quinolyl group, a 1,2,3,4-tetrazolyl lower alkyl group which may have, on the tetrazole ring, 1 to 3 substituents selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group, a 1,2,3,4-tetrazolyl group which may have, on the tetrazole ring, 1 to 3 substituents selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group, a 1,2,4-triazolyl lower alkyl group, a 1,2,4-triazolyl group, a tetrahydrofuryl lower alkyl group which may have a hydroxyl group as a substituent on the lower alkyl group, a tetrahydrofuryl group which may have a hydroxyl group as a substituent on the lower alkyl group, a phenoxy lower alkyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkyl group and a nitro group, a lower alkoxycarbonyl lower alkyl group or a carboxy lower alkyl group;

provided that the alkyl moiety of CHRAR21d in the side chain (—(B21CO)tN(R20a)(CHRAR21d)) has not more than 6 carbon atoms.

The reaction of the compound (1uuu) with the compound (49) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (4) shown in reaction formula 2 above.
The reaction of the compound (1uuu) and the compound (51) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (5) shown in reaction formula 2 above.
The reaction of the compound (1uuu) and the compound (50) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.




wherein R1, R2, X1, Y, T, l, and A10 are the same as described above, provided that a and b of A10 are bound to Y and (T)l, respectively;

R14s and R15r represent the same 5- to 10-membered saturated or unsaturated heterocyclic groups as defined in R14 and R15 above, respectively, except that each of the heterocyclic groups has at least one group —(CO)oB13X2 thereon;

R14t and R15s represent the same 5- to 10-membered saturated or unsaturated heterocyclic groups as defined in R14 and R15 above, respectively, except that each of the heterocyclic groups has at least one group —(CO)o B13R84 thereon; and

R84 is a group —NR22R23 or an imidazolyl group (wherein B13, o, X2, R22 and R23 are the same as described above).

The reaction of the compound (1yyy) and the compound (52) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (4) shown in reaction formula 2 above.




wherein R1, R2, X1, Y, T, l, and A10 are the same as described above, provided that a and b of A10 are bound to a group Y and group (T)l, respectively;

R14s′ and R15r′ represent the same 5- to 10-membered saturated or unsaturated heterocyclic groups as defined in R14 and R15 above, respectively, except that each of the heterocyclic groups has at least one group —N(R28)—CO—B16X2 thereon; and

R14u and R15t represent the same 5- to 10-membered saturated or unsaturated heterocyclic groups as defined in R14 and R15 above, respectively, except that each of the heterocyclic groups has at least one group —N(R28)—CO—B16NR29R30 thereon;

(wherein R28, B16, X2, R29 and R30 represent the same as described above).

The reaction of the compound (1aaaa) and the compound (53) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (4) shown in reaction formula 2 above.




wherein R74a, R2, X1, Y, T, l, and A10 are the same as described above, provided that a and b of A10 are bound to a group Y and a group (T)l, respectively;

R14v and R15u represent the same 5- to 10-membered saturated or unsaturated heterocyclic groups as defined in R14 and R15 above, respectively, except that each of the heterocyclic groups has at least one group —B12COOH thereon; and

R14w and R15v represent the same 5- to 10-membered saturated or unsaturated heterocyclic groups as defined in R14 and R15 above, respectively, except that each of the heterocyclic groups has at least one group —B12CONR20R21 thereon;

(wherein B12, R20 and R21 are the same as described above).

The reaction of the compound (1cccc) and the compound (54) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.




wherein R1, R2, X1, Y, T, l, and A10 are the same as described above, provided that a and b of A10 are bound to a group Y and a group (T)l, respectively;

R14x and R15w represent the same 5- to 10-membered saturated or unsaturated heterocyclic groups as defined in R14 and R15 above, respectively, except that each of the heterocyclic groups has at least one group —O—B15COOH; and

R14y and R15x represent the same 5- to 10-membered saturated or unsaturated heterocyclic groups as defined in R14 and R15 above, respectively, except that each of the heterocyclic groups has at least one group —O—B15CONR26R27 thereon;

(wherein B15, R26 and R27 are the same as described above).

The reaction of the compound (1eeee) and the compound (55) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.




wherein R1, R2, X1, Y, T, l, and A10 are the same as described above, provided that a and b of A10 are bound to a group Y and (T)l, respectively;

R14z and R15y represent the same 5- to 10-membered saturated or unsaturated heterocyclic groups as defined in R14 and R15 above, respectively, except that each of the heterocyclic groups has at least one group —N(R31)—B17—COOH thereon; and

R14aa and R15z represent the same 5- to 10-membered saturated or unsaturated heterocyclic groups as defined in R14 and R15 above, respectively, except that each of the heterocyclic groups has at least one group —N(R31)—B17CONR32R33 thereon;

(wherein R31, B17, and R32, R33 are the same as described above).

The reaction of the compound (1gggg) and the compound (56) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6) of reaction formula 2 above.




wherein R1, R2, X1, Y, T, l, and A10 are the same as described above, provided that a and b of A10 are bound to a group Y and a group (T)l, respectively;

R14bb and R15aa represent the same 5- to 10-membered saturated or unsaturated heterocyclic groups as defined in R14 and R15 above, respectively, except that each of the heterocyclic groups has at least one group —COOH thereon; and

R14cc and R15bb represent the same 5- to 10-membered saturated or unsaturated heterocyclic groups as defined in R14 and R15 above, respectively, except that each of the heterocyclic groups has at least one group —CONR26R27 thereon;

wherein R26 and R27 are the same as described above.

The reaction of the compound (1iiii) and the compound (57) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.




wherein R1, R2, X1, Y, T, l, R14a and A10 are the same as described above, provided that a and b of A10 are bound to a group Y and a group (T)l, respectively;

h represents 0 or 1; and R57 represents a lower alkoxycarbonyl group.

The reaction which converts the compound (1kkkk) into the compound (1llll) may be carried out under the same reaction conditions as in hydrolysis B described in reaction formula 9 above.




wherein R1, R2, X1, R3, R4, Y, R11 and R12 are the same as described above, R58 represents a lower alkyl group, and g represents 0 or 1.

The reaction which converts the compound (1mmmm) into the compound (1nnnn) may be carried out under the same reaction conditions as in hydrolysis B as described in reaction formula 9 above.
The reaction of the compound (1nnnn) with the compound (58) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.




wherein R1, R2, X1, Y, T, l, A10 and X2 are the same as described above, provided that a and b of A10 are bound to a group Y and a group (T)l, respectively;

R14hh and R15gg represent the same 5- to 10-membered saturated or unsaturated heterocyclic groups as defined in R14 and R15 above, respectively, except that each of the heterocyclic groups has at least one group —(CO)o-B13NH(R22a) thereon;

R14ii and R15hh represent the same 5- to 10-membered saturated or unsaturated heterocyclic groups as defined in R14 and R15 above respectively, except that each of the heterocyclic groups has at least one group —(CO)o-B13N(R22a) thereon;

R14ii and R15hh represent the same 5- to 10-membered saturated or unsaturated heterocyclic groups as defined in R14 and R15 above, respectively, except that each of the heterocyclic groups has at least one group —(CO)o-B13N(R22a)R23b thereon;

R14kk and R15jj represent the same 5- to 10-membered saturated or unsaturated heterocyclic groups as defined in R14 and R15 above, respectively, except that each of the heterocyclic ring has at least one —(CO)o-B13N(R22a)(CHRAR23c) group thereon,

(wherein RA, B13 and o are the same as described above);

R22a is a hydrogen atom, a lower alkyl group, a benzoyl group which may have 1 to 3 lower alkoxy groups as substituents on the phenyl ring, a phenoxy lower alkyl group which may have a lower alkyl group as a substituent on the phenyl ring, a phenyl lower alkyl group or a phenyl group;

R23a represents a lower alkyl group, a phenoxy lower alkyl group which may have a lower alkyl group as a substituent on the phehyl ring, a phenyl lower alkyl group or a phenyl group;

R23b represents a benzoyl group which may have 1 to 3 lower alkoxy groups as substituents on the phenyl ring; and

R23c represents a hydrogen atom, a lower alkyl group, a phenoxy lower alkyl group which may have a lower alkyl group as a substituent on the phenyl ring, a phenyl lower alkyl group or a phenyl group; provided that the alkyl moiety of the —CHRAR23c group in the side chain (—(CO)o-B13—N(R22a)(CHRAR23c)) of the compound (1ssss) has not more than 6 carbon atoms.

The reaction of the compound (1pppp) and the compound (59) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (4) shown in reaction formula 2 above.
The reaction of the compound (1pppp) and the compound (61) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (5) shown in reaction formula 2 above.
The reaction of the compound (1pppp) and the compound (60) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.




wherein R1, R2, X1, Y, T, l, A10 and X2 are the same as described above, provided that a and b of A10 are bound to a group Y and a group (T)l, respectively;

R14ll and R15kk represent the same 5- to 10-membered saturated or unsaturated heterocyclic groups as defined in R14 and R15 above, respectively, except that each of the heterocyclic groups has at least one group —(O—B15)s-CONH(R26a) thereon;

R14mm and R15ll represent the same 5- to 10-membered saturated or unsaturated heterocyclic groups as defined in R14 and R15 above, respectively, except that each of the heterocyclic groups has at least one group —(O—B15)s-CON(R26a)(R27a) thereon;

R14nn and R15mm represent the same 5- to 10-membered saturated or unsaturated heterocyclic group as defined in R14 and R15 above, respectively, except that each of the heterocyclic rings has at least one group —(O—B15)s-CON(R26a)(CHRAR27b)
(wherein B15, s and RA are the same as described above);
R26a represents a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group or an imidazolyl lower alkyl group;
R27a represents a lower alkyl group, a phenyl lower alkyl group or an imidazolyl lower alkyl group; and
R27b represents a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, a phenyl group, an imidazolyl group or an imidazolyl lower alkyl group;
provided that the alkyl moiety of the —CHRAR27b group in the side chain (—(O—B15)s-CO(R26a)(CHRAR27b)) of the compound (1vvvv) has not more than 6 carbon atoms.
The reaction of the compound (1tttt) and the compound (62) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (4) shown in reaction formula 2 above.
The reaction of the compound (1tttt) and the compound (63) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (5) shown in reaction formula 2 above.




wherein R1, R2, X1, Y, T, l, A10, R14v, R15u, R14k and R14j are the same as described above, provided that a and b of A10 are bound to a group Y and a group (T)l, respectively;

R59 represents a lower alkyl group; and

R14oo and R15nn represent the same 5- to 10-membered saturated or unsaturated heterocyclic groups as defined in R14 and R15 above, respectively, except that each of the heterocyclic groups has at least one group —B21CONHNHCOOR59,

(wherein B21 is the same as described above).

The reaction of the compound (1cccc′) and the compound (102) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.
The reaction which converts the compound (1yyyy) into the compound (1hhh) may be carried out under the same reaction conditions as in hydrolysis B as described in reaction formula 9 above.
The compound of the present invention of the general formula (1) in which various groups are taken as R1 is produced, for example, as shown by reaction formulas 37 to 46 below.




wherein R2, X1, Y, A16, R6, R8, B21, RA and X2 are the same as described above, provided that the B21CHRA moiety of the (R6—B21CHRA—) group of the compound (1y) has hot more than 6 carbon atoms.

The reaction of the compound (19) and the compound (20) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (4) shown in reaction formula 2 above.
The reaction of the compound (19) and the compound (21) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (5) of reaction formula 2 above.
The reaction of the compound (19) and the compound (22) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6) of reaction formula 2 above.




wherein R2, X1, Y, A, R6, B, RA and X2 are the same as described above, R8a represents a lower alkyl group which may have a lower-alkoxy group as a substituent, a lower alkylsulfonyl group or a phenyl lower alkyl group, R8b represents a hydrogen atom, a phenyl group, phenyl lower alkyl group or a lower alkyl group which may have a lower alkoxy group as a substituent, and R8c represents a lower alkanoyl group, provided that the alkyl moiety of the —CHRAR8b group of the compound (1cc) has not more than 6 carbon atoms.

The reaction of the compound (1aa) and the compound (23) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (4) shown in reaction formula 2 above.
The reaction of the compound (1aa) and the compound (24) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (5) shown in reaction formula 2 above.
The reaction of the compound (1aa) and the compound (25) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.




wherein R2, X1, Y, A, B21, f, RA and R6 are the same as described above, provided that the (B21)fCHRA moiety of the side chain (—(B21)fCHRANHR6) of the compound (1ee) has not more than 6 carbon atoms.

The reaction of the compound (26) and the compound (27) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (5) shown in reaction formula 2 above.




wherein R88 represents a group —Y-A or a halogen atom, and R2, X1, Y, A, and R6 are the same as described above.

The reaction of the compound (28) and the compound (27) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.




wherein R2, X1, Y, A, R6, R8a, R8b, R8c, RA and X2 are the same as described above, provided that the alkyl moiety of the group —CHRAR8b of the compound (1hh) has not more than 6 carbon atoms.

The reaction of the compound (1ff′) and the compound (23) is carried out under the same reaction conditions similar as in the reaction of the compound (1b) and the compound (4) shown in reaction formula 2 above.
The reaction of the compound (1ff′) and the compound (24) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (5) shown in reaction formula 2 above.
The reaction of the compound (1ff′) and the compound (25) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.




wherein R2, X1, Y, A, R6 and X2 are the same as described above.

The reaction which converts the compound (30) into the compound (1jj) is carried out under the same reaction conditions as in the reaction which converts the compound (1f) into the compound (1h) shown in reaction formula 3 above.
The reaction which converts the compound (1jj) into the compound (1kk) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (5) shown in reaction formula 2 above.
The reaction of the compound (30) and the compound (32) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (4) shown in reaction formula 2 above.




wherein R2, X1, Y, A, X2 and R6 are the same as described above, B23 represents a lower alkylene group or a lower alkenylene group, and the B23—HC═CH— moiety in the side chain (R6B23—HC═CH—) of the compound (1 mm) has 1 to 3 double bonds and has not more than 6 carbon atoms.

The reaction of the compound (33) and the compound (34) is carried out in an appropriate inert solvent and in the presence of a condensation agent.
Examples of the inert solvent to be used in the above described reaction include aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, and diglyme, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, lower alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol, fatty acids such as α-dimethylaminoacetic acid and acetic acid, esters such as ethyl acetate and methyl acetate, ketones such as acetone and methyl ethyl ketone, acetonitrile, 1-methyl-2-pyrrolidone, pyridine, dimethyl sulfoxide, dimethylformamide, and hexamethylphosphoric acid triamide, and a mixture thereof.
Examples of the condensation agent include palladium complexes such as bis(benzonitrile)dichloropalladium(II).
The condensation agent is favorably used typically in an amount 0.01 to 1 times and preferably 0.01 to 0.5 times that of the compound (33) on a molar basis.
The above described reaction favorably proceeds typically at 0 to 200° C. and preferably at about room temperature to about 150° C. and is generally completed in about 10 minutes to 20 hours.
The above described reaction proceeds advantageously by adding an alkali metal salt of a fatty acid such as sodium acetate to the reaction system.




wherein R2, X1, Y, A and R6 are the same as described above.

The reaction which converts the compound (1nn) into the compound (1oo) is carried out under the same reaction conditions as in the reaction which converts the compound (1f) into the compound (1g) shown in reaction formula 3 above.
[Reaction Formula 45]




wherein A17 represents a group





wherein R2, R3, p, X1, Y, A, Bo and R6 are the same as described above.

The reaction of the compound (64) and the compound (65) is carried out in an appropriate solvent in the presence of a condensation agent.
Any solvent may be used as long as it is used in the reaction of a carboxylic acid halide with an amine (1b) of the reactions between the compound (1b) and the compound (6) (an amide bond generation reaction) shown in reaction formula 2.
Examples of the condensation agent include a mixture of an azocarboxylate (such as diethyl azodicarboxylate) and a phosphorus compound (such as triphenylphosphine).
The condensation agent is favorably used typically in at least an equimolar amount to the compound (64) and preferably 1 to 2 times that of the compound (64) on a molar basis.
The compound (65) is favorably used typically in an amount of at least an equimolar to the compound (64) and preferably 1 to 2 times that of the compound (64) on a molar basis.
The above described reaction favorably proceeds typically at 0 to 200° C., preferably at about 0 to 150° C. and is generally completed in about 1 to 10 hours.




wherein R2, X1, Y, A, and R6 are the same as described above.

The reaction of the compound (30) and the compound (66) is carried out in the presence or absence of a basic compound and preferably in the absence of the basic compound and in the presence or absence of an appropriate solvent.
Any inert solvent and basic compound may be used as long as they are used in the reaction of a carboxylic acid halide and an amine (1b) of the reactions between the compound (1b) and the compound (6) (an amide bond generation reaction) shown in reaction formula 2.
The compound (66) may be used typically in an amount of about 1 to 5 times and preferably about 1 to 3 times that of the compound (30) on a molar basis.
The above described reaction is carried out typically at 0 to 200° C. and preferably at about room temperature to 150° C. and is generally completed in about minutes to 50 hours.
A boron compound such as a boron trifluoride-diethyl ether complex may be added to the reaction system of the above described reaction.




wherein R2, X1, Y, T2, A10, R14, R15, B21, RA, X2, R6 and R59 are the same as described above, provided that a and b of A10 are bound to a group Y and a group T2, respectively.

The reaction which converts the compound (68) into the compound (71) may be carried out under the same reaction conditions as in hydrolysis B as described in reaction formula 9 above.
The reaction of the compound (71) and the compound (100) is carried out under the same reaction conditions as in the reaction of the compound (1fff) and the compound (43) shown in reaction formula 20 above.
The compound (68) may also be produced using a halogenated lower alkyl group such as methyl iodide in place of the compound (100) in the same as in the reaction of the compound (2) and the compound (3) shown in reaction formula 1 above.
The reaction which converts the compound (68) into the compound (69) may be carried out, for example, (1) by reducing the compound (68) with a catalytic hydride reducing agent in an appropriate solvent, or (2) by reducing the compound (68) with a reducing agent such as a mixture of a metal or a metal salt with an acid, or a mixture of a metal or a metal salt with an alkali metal hydroxide, a sulfide, an ammonium salt or the like, in an appropriate inert solvent.
Examples of the solvent for use in the method (1) include water, acetic acid, alcohols such as methanol, ethanol, and isopropanol, hydrocarbons such as n-hexane and cyclohexane, ethers such as dioxane, tetrahydrofuran, diethyl ether, and diethylene glycol dimethyl ether, esters such as ethyl acetate and methyl acetate, and aprotic polar solvents such as N,N-dimethylformamide, and a mixture thereof. Examples of the catalytic hydride reducing agent include palladium, palladium black, palladium-carbon, platinum-carbon, platinum, platinum oxide, copper chromite, and Raney nickel. These reducing agents may be used singly or in a mixture of two types or more. The reducing agent may be used generally in an amount 0.02 to 1 times that of the compound (68) on a weight basis. The reaction temperature is set typically at about −20 to 150° C. and preferably at about 0 to 100° C., and the hydrogen pressure is set typically at 1 to 10 atm. Generally, the above described reaction is completed in about 0.5 to 100 hours. An acid such as hydrochloric acid may be added to the reaction system.
The reducing agent for use in the method (2) is a mixture of iron, zinc, tin or stannous chloride with a mineral acid such as hydrochloric acid or sulfuric acid; or a mixture of iron, ferrous sulfate, zinc or tin with an alkali metal hydroxide such as sodium hydroxide, a sulfate such as ammonium sulfate or an ammonium salt such as ammonium hydroxide or ammonium chloride. Examples of the inert solvent include water, acetic acid, alcohols such as methanol and ethanol, and ethers such as dioxane, and a mixture thereof. The reducing reaction conditions may be chosen appropriately depending on the reducing agent to be used. For example, when stannous chloride or hydrochloric acid is used as the reducing agent, the reaction is favorably carried out advantageously at about 0 to 150° C., for about 0.5 to 10 hours. The reducing agent is used in an amount at least an equimolar to the compound (68) and typically 1 to 5 times that of the compound (68) on a molar basis.
The reaction of the compound (69) and the compound (20) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (4) shown in reaction formula 2 above.
The reaction of the compound (69) and the compound (22) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.
The reaction of the compound (69) and the compound (21) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (5) shown in reaction formula 2 above.
The reaction which converts the compound (69) into the compound (37a), the reaction which converts the compound (70a) into the compound (37d), the reaction which converts the compound (70b) into the compound (37c) and the reaction which converts the compound (70c) into the compound (37b) is carried out under the same reaction conditions as in hydrolysis B as described in reaction formula 9.
The reaction of the compound (71) and the compound (36) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2.
The reaction of the compound (69) and the compound (32) is carried out under the same reaction conditions as in the reaction of the compound (30) and the compound (32) shown in reaction formula 42 above.




wherein R2, X1, Y, A10, B3, R14, R15, RA, R74a and X2 are the same as described above;

Rc represents a group —CONR14R15 or a group —COOR59b, R59b represents a lower alkyl group or a phenyl lower alkyl group;
R17a represents a lower alkyl group, a cycloalkyl group, a lower alkyl sulfonyl group or a lower alkenyl group;
R17b represents a hydrogen atom or a lower alkyl group; and
R17c represents a cycloalkylcarbonyl group, a lower alkanoyl group which may have a halogen atom as a substituent or an amino substituted lower alkanoyl group which may have a lower alkyl group as a substituent (wherein a of A10 is bound to a group Y and b is bound to a group —NHB3—Rc, a group —N(R17a)B3—Rc, a group —N(CH(RA)(R17b))B3—Rc or a group —N(R17c)B3—Rc.
The reaction of the compound (72a) and the compound (73) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (4) shown in reaction formula 2 above
The reaction of the compound (72a) and the compound (75) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.
The reaction of the compound (72a) and the compound (74) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (5) shown in reaction formula 2 above.




wherein R2, X1, Y, A10, B3, R14 and R15 are the same as described above, R17d represents a lower alkanoyl group which has a halogen atom as a substituent, R60 represents an amino group which may be substituted with a lower alkyl group, and R61 represents an amino substituted lower alkanoyl group which may be substituted with a lower alkyl group, wherein a of A10 is bound to a group Y and b is bound to a group —N(R17d)B3—CONR14R15 or a group —NR61B3—CONR14R15.

The reaction of the compound (72e) and the compound (76) is carried out under the same reaction conditions as in the reaction of the compound (2) and the compound (3) shown in reaction formula 1 above.




wherein R2, X1, Y, R6, B21, RA and X2 are the same as described above, and A11 represents





wherein R3 and p are the same as described above, provided that the alkyl moiety in the side chain (—NHCH(RA)(B21R6) group) of the compound (78b) has not more than 6 carbon atoms.

The reaction which converts the compound (77a) into the compound (77b) is carried out under the same reaction conditions as in the reaction which converts the compound (68) into the compound (69) shown in reaction formula 47 above.
The reaction of the compound (77b) and the compound (20) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (4) shown in reaction formula 2 above.
The reaction of the compound (77b) and the compound (22) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.
The reaction of the compound (77b) and the compound (21) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (5) shown in reaction formula 2 above.




wherein R1, R2, X1, Y and A11 are the same as described above, and i represents an integer of 2 to 4.

The reaction of the compound (77c) and the compound (79) is generally called Friedel-Crafts reaction and carried out in an appropriate solvent in the presence of a Lewis acid.
Any Lewis acid may be used herein as long as it is typically used in the Friedel-Crafts reaction. Examples of the Lewis acid include aluminum chloride, zinc chloride, iron chloride, tin chloride, boron tribromide, and concentrated sulfuric acid. These Lewis acids are used singly or in a mixture of two types or more. The Lewis acid is used typically in an amount 2 to 6 times that of the compound (77c) on a molar basis.
Examples of the solvent to be used herein include aromatic hydrocarbons such as carbon disulfide, nitrobenzene, and chlorobenzene, and halogenated hydrocarbons such as dichloromethane, dichloroethane, carbon tetrachloride, and tetrachloroethane, and a mixture thereof.
The compound (7 g) is used typically in at least an equimolar amount to the compound (77c) and preferably 1 to 5 times that of the compound (77c) on a molar basis.
The above described reaction favorably proceeds typically at 0 to 120° C. and preferably at about 0 to 70° C., and is generally completed in about 0.5 to 24 hours.




wherein R2, X1, Y, R6, X2, B21 and RA are the same as described above. A12 represents a group





wherein R3 and p are the same as defined above, and R62 represents a lower alkanoyl group or a hydroxyl group substituted lower alkyl group, provided that the alkyl moiety in the side chain (—NHCH(RA)(B21R6) group) of the compound (81b) has not more than 6 carbon atoms.

The reaction which converts the compound (80a) into the compound (80b) is carried out under the same reaction conditions as in the reaction which converts the compound (68) into the compound (69) shown in reaction formula 47 above.
The reaction of the compound (80b) and the compound (20) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (4) shown in reaction formula 2 above.
The reaction of the compound (80b) and the compound (22) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.
The reaction of the compound (80b) and the compound (21) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (5) shown in reaction formula 2 above.




wherein R1, R2, X1, and Y are the same as above,

A13 represents a group





wherein R3 and p are the same as described above, and

R63a represents a lower alkanoyl group or a lower alkyl group, and

A14 represents a group





wherein R63b represents a lower alkanoyl group which is substituted with a halogen atom at the α-position or a lower alkyl group which is substituted with a halogen atom at the 2 position.

The reaction which converts the compound (80b′) into the compound (35a) is carried out in the presence of a halogenating agent in an appropriate solvent.
Examples of the halogenating agent include halogen molecules such as bromine and chlorine, iodine chloride, sulfuryl chloride, copper compounds such as cupric bromide, and N-halogenated succinic acid imides such as N-bromosuccinic acid imide and N-chlorosuccinic acid imide.
Examples of the solvent to be used herein include halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, fatty acids such as acetic acid and propionic acid, and carbon disulfide.
The halogenating agent is favorably used typically in an amount 1 to 10 times and preferably 1 to 5 times that of the compound (80b′) on a molar basis.
The above described reaction is carried out typically at 0° C. to the boiling point of the solvent and preferably at about 0 to 100° C., and completed typically for about 5 minutes to 30 hours.
When an N-halogenated succinic acid imide is used as a halogenating agent, a peroxide such as benzoyl peroxide may be added to the reaction system as a radical reaction initiator.




wherein R2, X1, Y, A10, T2, R59, R8a, R8b, R8c, X2 and RA are the same as described above, and

R64 represents a phenyl lower alkoxycarbonyl group, provided that each of the alkyl moieties in the side chain

(—N(CHRAR8b)(R64) group) of the compound (84b) and the side chain (—NH(CHRAR8b) group) of the compound (84e) has not more than 6 carbon atoms and a and b of A10 are bound to a group Y and a group T2, respectively.

The reaction of the compound (83) and the compound (23) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (4) shown in reaction formula 2 above.
The reaction of the compound (69) and the compound (82), and the reaction of the compound (83) and the compound (25) are carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.
The reaction of the compound (83) and the compound (24) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (5) shown in reaction formula 2 above.
The reactions which convert the compound (84a) into the compound (84d), the compound (84b) into the compound (84e), and the compound (84c) into the compound (84f) are carried out under the same reaction conditions as in the reaction in which the compound (1iii′) is reduced to convert into the compound (1hhh′) as described in reaction formula 24 above.




wherein R2, X1, Y, A10, B21, R74a and X2 are the same as described above, provided that a and b of A10 are bound to a group Y and a group B21, respectively.

The reaction which converts the compound (85) into the compound (7′) is carried out by reacting compound (85) with a halogenating agent in the presence or absence of an appropriate solvent.
Examples of the halogenating agent include mineral acids such as hydrochloric acid and hydrobromic acid, N,N-diethyl-1,2,2-trichlorovinyl azide, phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, sulfonyl halide compounds such as thionyl chloride, mesyl chloride, and tosyl chloride, and a mixture of carbon tetra bromide with triphenylphosphine. The sulfonyl halide compound may be used together with a basic compound.
Any basic compound may be used as long as it is used in the reaction of the compound (2) and the compound (3) shown in reaction formula 1 above.
Examples of the solvent to be used include ethers such as dioxane, tetrahydrofuran, and diethyl ether, halogenated hydrocarbons such as chloroform, methylene chloride, and carbon tetrachloride, and dimethylformamide, and a mixture thereof.
When a sulfonyl halide compound serving as a halogenating agent is used together with a basic compound, the sulfonyl halide compound is favorably used typically in at least an equimolar amount to the compound (85) and preferably 1 to 2 times that of the compound (85) on a molar basis. The basic compound is used typically in a catalytic amount of the compound (85) and preferably in a catalytic amount to an equimolar amount to the compound (85). When a halogenating agent other than sulfonyl halide compound is used, the halogenating agent is used in at least an equimolar amount to the compound (85) and typically used in a large excess amount.
The above described reaction favorably proceeds typically at room temperature to 200° C. and preferably at room temperature to 150° C., and is generally completed in about 1 to 80 hours.




wherein R74a, R2, X1, Y, A10 and B2, are the same as described above, and R65 represents a tri-lower alkyl silyl group, provided that a and b of A10 are bound to a group Y and a group B21, respectively.

Examples of the tri-lower alkyl silyl group to be used herein include trialkylsilyl groups whose alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as tert-butyldimethylsilyl, trimethylsilyl, and diethylmethylsilyl groups.
The reaction which converts the compound (86) into the compound (85) may be carried out under the same reaction conditions as in hydrolysis B as described in reaction formula 9 above.




wherein R74a, R2, X1, Y, A10, B21, R65 and X2 are the same as described above, and R66 represents a hydrogen atom, a lower alkyl group or a lower alkoxycarbonyl group, provided that a and b of A10 are bound to a group Y and a group B21, respectively, and each of the alkyl moieties in the side chain (—Y-A10-B21CH2OH) of the compound (85a) and the side chain (—Y-A10-B21CH2OR65) of the compound (86a) has not more than 6 carbon atoms.

The reaction which converts the compound (69a) into the compound (85a) is carried out under the same reaction conditions as in the reaction which converts the compound (1f) into the compound (1g) shown in reaction formula 3 above.
The reaction of the compound (85a) and the compound (101) is carried out under the same reaction conditions as in the reaction which converts the compound (2) into the compound (3) shown in reaction formula 1 above.




wherein R2, X1, Y, A10, B21, R6, RA, f, R43, R44 and X2 are the same as described above, and B21 represents a lower alkylene group, provided that a and b of A10 are bound to a group Y and a group B21′, respectively, and each of the (B21′)f-CH═C moiety in the side chain (—Y-A10-(B21′)f-CH═C(COOR43)(COOR44)) of the compound (90c) and the alkyl moiety in the side chain (—NHCH(RA)B21R6)) of the compound (90b) have not more than 6 carbon atoms, respectively.

The reaction of the compound (87) and the compound (88) is carried out under the same reaction conditions as in the reaction of the compound (1f) and a hydroxylamine shown in reaction formula 3 above.
The reaction which converts the compound (89a) into the compound (89b) is carried out under the same reaction conditions as in the reaction which converts the compound (68) into the compound (69) shown in reaction formula 47 above.
The reaction of the compound (89b) and the compound (20) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (4) shown in reaction formula 2 above.
The reaction of the compound (89b) and the compound (22) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6)shown in reaction formula 2 above.
The reaction of the compound (89b) and the compound (21) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (5) shown in reaction formula 2 above.




wherein R2, X1, Y, A10, B21′, R65, R6, B21, RA and X2 are the same as defined above, provided that a and b of A10 are bound to a group Y and a group B21′, respectively, and the alkyl moiety in the side chain (—NHCH(RA)(B21R6)) of the compound (91b) has not more than 6 carbon atoms.

The reaction which converts the compound (86a′) into the compound (86b) is carried out under the same reaction conditions as in the reaction which converts the compound (68) into the compound (69) shown in reaction formula 47 above.
The reaction of the compound (86b) and the compound (20) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (4) shown in reaction formula 2 above.
The reaction of the compound (86b) and the compound (22) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.
The reaction of the compound (86b) and the compound (21) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (5) shown in reaction formula 2 above.




wherein R2, X1, Y, A10, B21, B21′, R6, RA and X2 are the same as described above, provided that a and b of A10 are bound to a group Y and a group B21′, respectively, and the alkyl moiety in the side chain (—NHCH(RA)(B21R6)) of the compound (44c) has not more than 6 carbon atoms.

The reaction which converts the compound (92a) into the compound (92b) is carried out under the same reaction conditions as in the reaction which converts the compound (68) into the compound (69) shown in reaction formula 47 above.
The reaction of the compound (92b) and the compound (20) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (4) shown in reaction formula 2 above.
The reaction of the compound (92b) and the compound (22) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.
The reaction of the compound (92b) and the compound (21) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (5) shown in reaction formula 2 above.




wherein R2, X1, and X2 are the same as described above, R67 represents a group -A10B21CN, a group -A10-R59d a group -A10-T2-COOR59a or a group -A, R59d represents a lower alkyl group, A10, B21, T2 and R59a are the same as described above, and R68 represents a nitro group or a halogen atom.

The reaction of the compound (93) and the compound (94) is carried out under the same reaction conditions as in the reaction of the compound (2) and the compound (3) shown in reaction formula 1 above.




wherein R2, R67 and X1 are the same as described above.

The reaction which converts the compound (95a) into the compound (95b) is carried out under the same reaction conditions as in the reaction which converts the compound (68) into the compound (69) shown in reaction formula 47 above.




wherein R2, X1, Y, A7, R6, B21, RA and X2 are the same as described above, provided that the alkyl moiety in the side chain (—NHCH(RA)(B21R6)) of the compound (13b) has not more than 6 carbon atoms.

The reaction of the compound (96) and the compound (20) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (4) shown in reaction formula 2.
The reaction of the compound (96) and the compound (22) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.
The reaction of the compound (96) and the compound (21) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (5) shown in reaction formula 2 above.




wherein R2, X1, Y, B21, f, i, R6, B21, A10, RA and X2 are the same as described above, and RA′ represents a hydrogen atom or a lower alkyl group, provided that the alkyl moiety in the side chain

(—NHCH(RA)(B21R6)) in compound (98b) has not more than 6 carbon atoms, and a and b of A10 are bound to a group Y and a group (B21)f, respectively.

The reaction which converts the compound (97a) into the compound (97b) is carried out under the same reaction conditions as in the reaction which converts the compound (68) into the compound (69) shown in reaction formula 47 above.
The reaction of the compound (97b) and the compound (20) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (4) shown in reaction formula 2 above.
The reaction of the compound (97b) and the compound (22) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.
The reaction of the compound (97b) and the compound (21) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (5) shown in reaction formula 2.




wherein R1, R2, X1, Y, A10, B21, f, RA′ and A3 are the same as described above, provided that a and b of A10 are bound to a group Y and a group (B21)f, respectively.

The reaction which converts the compound (98d) into the compound (9′) may be carried out under the same reaction conditions as in hydrolysis B described in reaction formula 9 above.




wherein R1, R2, X1, Y, A3, R59, A10, B21 and f are the same as described above, T3 represents a direct bond or group B7, and B7 represents the same as described above, provided that a and b of A10 are bound to a group Y and a group (B21)f, respectively.

The reaction of the compound (9′) and the compound (99) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (5) shown in reaction formula 2 above.




wherein R3, X1, Y, A10, R14a, R49a, R49, R49b, T, l, RA and X2 are the same as described above, provided that the CHRA moiety in the side chain (—N(R14a)(CHRAR49b)) of the compound (104c) has not more than 6, a of A10 is bound to a group Y, and b of A10 is bound to a group —NR14aH, a group NR14aR49a a group —NR14aR49, or a group —NR14a(CHRAR49b).

The reaction of the compound (103) and the compound (38a) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (4) shown in reaction formula 2 above.
The reaction of the compound (103) and the compound (38) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.
The reaction of the compound (103) and the compound (38b) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (5) shown in reaction formula 2 above.




wherein R2, X1, Y and A are the same as described above.

The reaction which converts the compound (105) into the compound (19a) is carried out under the same reaction conditions as in the reaction which converts the compound (68) into the compound (69) shown in reaction formula 47 above. The compound (19a) can be subjected to the following reaction without isolation.




wherein R2, X1, Y and A10 are the same as described above, R69a represents a thiazolidinyl group which may have an oxo group as a substituent on the thiazolidine ring, R69 represents a thiazolidinylidene lower alkyl group which may have an oxo group as a substituent on the thiazolidine ring, and R70 represents a thiazolidinyl lower alkyl group which may have an oxo group as a substituent on the thiazolidine ring, provided that a of A10 is bound to a group Y and b of A10 is bound to a group —R69 or a group —R70.

The reaction of the compound (106a) and the compound (160) is carried out under the same reaction conditions as in the reaction of the compound (87) and the compound (88) shown in reaction formula 58 above.
The reaction which converts the compound (106) into the compound (19b) is carried out under the same reaction conditions as in the reaction which converts the compound (68) into the compound (69) shown in reaction formula 47 above.




wherein R2, X1, X2, A, Y1, A10, T2, R59 and R59a are the same as described above, R71 represents a group —R1 (wherein R1 is the same as described above), a nitro group or a lower alkoxycarbonyl group, X3 represents a halogen atom, and R72 represents a lower alkyl group which may have a hydroxyl group as a substituent, a nitro group, an amino group which may have a lower alkanoyl group, a carboxy lower alkyl group, a —(B21)fC(═O)RA group (wherein B21, f and RA are the same as described above), a lower alkanoyl group, a lower alkoxy group or a hydrogen atom; provided that a of A10 is bound to a group Y1 and b of A10 is bound to a group -T2 or a group —R72.

The reaction of the compound (94a) and the compound (107), and the reaction of the compound (94a) and the compound (107a) each are carried out in an appropriate solvent and in the presence of a catalyst.
Any solvent may be used herein as long as it is used in the reaction of the compound (2) and the compound (3) shown in reaction formula 1.
As the catalyst to be used herein, various metal complexes as well as various combinations of a metal complex and a ligand may be used. Examples of the metal complexes include, palladium acetate (II), tetrakis(triphenylphosphine)palladium(0), and tris(dibenzylideneacetone)dipalladium(0). Examples of the ligand include. R-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (R-BINAP), S-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (S-BINAP), RAC-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (RAC-BINAP), t-butylphosphine, and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.
Such a catalyst is favorably used typically in at least an equimolar amount to the compound (94a) and preferably 1 to 5 times that of the compound (94a) on a molar basis.
The above described reaction is carried out typically at about 0 to 200° C. and preferably at about 0 to 150° C., and generally completed in about 30 minutes to 10 hours.
When molecular sieves such as Molecular Sieves 3A (MS3A) or Molecular Sieves 4A (MS4A) or a phosphorus compound such as triphenylphosphine or tri(2-furyl)phosphine are added in the reaction system, the reaction proceeds advantageously.
The reaction of the compound (94a) and the compound (108), compound (3) or compound (110) is carried out under the same reaction conditions as in the reaction of the compound (2) and the compound (3) shown in reaction formula 1 above.
The compound (109c) wherein R71 represents a lower alkoxycarbonyl group, may be converted into the corresponding compound (109c) wherein R7 represents a carboxy group, by hydrolyzing it under the same reaction conditions as in hydrolysis B described in reaction formula 9 above.




wherein R1, R2, X1, X2, Y1, A10 and T2 are the same as described above, and Rc represents a hydrogen atom, a lower alkyl or a phenyl lower alkyl group, provided that a and b of A10 are bound to a group Y, and a group -T2, respectively.

The reaction of the compound (2) and the compound (108′) is carried out under the same reaction conditions as in the reaction of the compound (2) and the compound (3) shown in reaction formula 1 above.




wherein R2, X1, R5a, R5b, RA, R5c and X2 are the same as described above, and R73a represents a group -A10-T2-COOR59 (wherein A10, T2 and R59 are the same as described above) or a group -A (wherein A is the same as described above), provided that a of A10 is bound to a group —NH—, group —NR5a—, group —N(CHRAR5b)— or a group —NR5c—, and b of A10 is bound to a group -T2, and the alkyl moiety in the side chain (—N(R73a)(CHRAR5b)) of the compound (68d) has not more than 6 carbon atoms.

The reaction of the compound (111) and the compound (4) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (4) shown in reaction formula 2 above.
The reaction of the compound (111) and the compound (6) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.
The reaction of the compound (111) and the compound (5) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (5) shown in reaction formula 2 above.




wherein R2, X1, Y, A10, X2, R17, B3, R74a and Rc are the same as described above, provided that a of A10 is bound to a group —Y and b of A10 is bound to a group —NHR17 or a group —NR17B3Rc.

The reaction of the compound (112) and the compound (113) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (4) shown in reaction formula 2 above.




wherein R2, X1, Y, A10, T1, l, R14 and R15 are the same as described above, provided that a and b of A10 are bound to a group —Y and a group -(T1)l, respectively.

The reaction of the compound (114) and the compound (36) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (5) shown in reaction formula 2 above.
The compound (109e) in which l is 0 may also be produced by reacting the corresponding compound (114) and the compound (36) in an appropriate solvent in the presence of a basic compound and a catalyst.
The above described reaction is carried out under the same reaction conditions as in reaction C described in reaction formula 13 above.




wherein R2, X1, Y, R8, B21, R6, A10, T2, R59, RA and X2 are the same as described above, provided that the CHRAB21 moiety in the side chain (—N(R8)(CH(RA) B21R6)) of the compound (84i) has not more than 6 carbon atoms, and a and b of A10 are bound to a group —Y and a group -T2, respectively.

The reaction of the compound (84g) and the compound (20) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (4) shown in reaction formula 2 above.
The reaction of the compound (84g) and the compound (22) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.
The reaction of the compound (84g) and the compound (21) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (5) shown in reaction formula 2 above.




wherein R2, X1, Y, R8a, R8b, R8c, B, R6, A10, T2, R59, RA and X2 are the same as described above, provided that the CHRA moiety in the side chain (—NB(R6)(CH(RA)R8b)) of the compound (116b) has not more than 6 carbon atoms, and a and b of A10 are bound to a group —Y and a group -T2, respectively.

The reaction of the compound (115) and the compound (23) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (4) shown in reaction formula 2 above.
The reaction of the compound (115) and the compound (25) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.
The reaction of the compound (115) and the compound (24) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (5) shown in reaction formula 2 above.




wherein R2; X1, Y, A3, R14 and R15 are the same as described above, and A15 represents a group





wherein R73 represents a group —(B21)fCH(RA)(NR14R15), and B21, f and RA are the same as described above, provided that the (B21)fCH(RA) moiety has not more than 6 carbon atoms.

The reaction of the compound (117) and the compound (36) is carried out the same reaction conditions as in the reaction of the compound (1b) and the compound (5) shown in reaction formula 2.




wherein, R2, X1, Y, A10, T2, R6, R9a and R59 are the same as described above, provided that a and b of A10 are bound to a group —Y and a -T2 group, respectively.

The reaction of the compound (69′) and the compound (66) is carried out under the same reaction conditions as in the reaction of the compound (30) and the compound (66) shown in reaction formula 46 above.




wherein R95, R2, X1, Y, A10, T2, and R59b are the same as described above, provided that a and b of A10 are bound to a group —Y and a group -T2, respectively.

The reaction which converts the compound (120a) into the compound (120b) may be carried out under the same reaction conditions as in hydrolysis B described for reaction formula 9 above.
The reaction of the compound (120b) and the compound (100′) is carried out under the same reaction conditions as in the reaction of the compound (1fff) and the compound (43) in reaction formula 20 above.
The compound (120a) may also be produced using a lower alkyl halide such as methyl iodide in place of the compound (100′) under the same reaction conditions as in the reaction of the compound (2) and the compound (3) shown in reaction formula 1 above.




wherein R1, R2, X1, Y, A10, B5, R59a and j are the same as described above, provided that a and b of A10 are bound to a group —Y and a group —S, respectively.

The reaction which converts the compound (120c) into the compound (120d) is carried out under the same reaction conditions as in the reaction which converts the compound (1zzzz) into the compound (1aaaaa) in reaction formula 4 above.




wherein R2, X1, Y, A10, T, l, R6, X2, RA, B21 and R14a are the same as described above, and R49c represents a lower alkoxycarbonyl group, provided that a and b of A10 are bound to a group —Y and a group -(T)l, respectively.

The reaction of the compound (103) and the compound (38c) is carried out under the same reaction conditions as in the reaction of the compound (2) and the compound (3) shown in reaction formula 1 above.
The reaction which converts the compound (104d) into the compound (104e) is carried out under the same reaction conditions as in the reaction which converts the compound (68) into the compound (69) shown in reaction formula 47 above.
The reaction of the compound (104e) and the compound (20) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (4) shown in reaction formula 2 above.
The reaction of the compound (104e) and the compound (22) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.
The reaction of the compound (104e) and the compound (21) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (5) shown in reaction formula 2 above.




wherein R2, X1, Y, A3, A10, B21, f, RA and i are the same as described above, provided that a and b of A10 are bound to a group —Y and a group —(B21)f, respectively, and the moiety (B21)fC(RA) in the side chain of the compound (123a) has not more than 6 carbon atoms in total.

The reaction of the compound (121) and the compound (122) may be carried out in an appropriate solvent in the presence of an acid.
Any solvent may be used herein as long as it is used in the reaction of the compound (2) and the compound (3) shown in reaction formula 1 above.
Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and organic acids such as acetic acid, trifluoroacetic acid, and sulfonic acids including p-toluenesulfonic acid. These acids may be used singly or in a mixture of two type's or more. The acid is favorably used typically in an amount at least 0.01 to 5 times and preferably 0.01 to 2 times that of the compound (121) on a molar basis. The compound (122) is favorably used typically in at least an equimolar amount to the compound (121) and preferably 1 to 10 times that of the compound (121) on a molar basis.
The above described reaction is carried out typically at 0 to 200° C. and preferably at about 0 to 150° C. and generally completed in about 30 minutes to 10 hours.




wherein R2, X1, Y and A10 are the same as described above, and R72a represents a lower alkoxy group, provided that a of A10 is bound to a group —Y and b of A10 is bound to a group —R72 or a hydroxyl group.

The reaction which converts the compound (109f) into the compound (124) may be carried out in an appropriate solvent in the presence of an acid.
As the solvent, in addition to water, any solvent may be used herein as long as it is used in the reaction of the compound (2) and the compound (3) shown in reaction formula 1 above.
Examples of the acid include mineral acids such as hydrobromic acid, hydrochloric acid, and concentrated sulfuric acid, fatty acids such as formic acid and acetic acid, organic acids such as p-toluenesulfonic acid, Lewis acids such as aluminum chloride, zinc chloride, iron chloride, tin chloride, boron trifluoride, and boron tribromide, iodides such as sodium iodide and potassium iodide, a mixture of a Lewis acid and an iodide as described above. The acid is favorably used typically in an amount 0.1 to 5 times and preferably 0.5 to 3 times that of the compound (109f) on a molar basis.
The above described reaction is carried out typically at 0 to 150° C. and preferably at about 0 to 100° C. and generally completed in about 0.5 to 15 hours.




wherein R2, X1, Y, A10, B5, X2, R14 and R15 are the same as described above, and Q1 represents an oxygen atom or a sulfur atom, provided that a and b of A10 are bound to a group —Y and a group -Q1, respectively.

The reaction of the compound (124a) and the compound (125) is carried out under the same reaction conditions as in the reaction of the compound (2) and the compound (3) shown in reaction formula 1 above.




wherein R2, X1, Y, A10, R14a, R74a, T and l are the same as described above, and R74b represents a lower alkanoyl group or a lower alkoxycarbonyl group, provided that a and b of A10 are bound to a group —Y and a group -(T)l, respectively.

The reaction which converts the compound (109g) into the compound (109h) may be carried out under the same reaction conditions as in hydrolysis B described in reaction formula 9 above.




wherein R2, X1, Y, A10, T2, X2, R59a, B23 and R6 are the same as described above, provided that a and b of A10 are bound to —Y group and a group -T2, respectively.

The reaction of the compound (126) and the compound (34) is carried out under the same reaction conditions as in the reaction of the compound (33) and the compound (34) in reaction formula 43 above.




wherein R2, X1, Y, R74 and A10 are the same as described above, R74c represents an amino group or a group —R1 (wherein R1 is the same as described above), R75 represents a lower alkanoyl group, R76 represents a lower alkoxycarbonyl group, R77 and R78 are both lower alkoxy groups, and R79 represents a hydrogen atom or a lower alkyl group, provided that a of A10 is bound to a group —Y, and b of A10 is bound to a group —R75, a group —C(R79)═CHR76 or a group —CH(R79)CH2R76, and each of the C(R79)═CH moiety and the CH(R79)CH2 moiety has not more than 6 carbon atoms.

The reaction of the compound (128) and the compound (129) is carried out in an appropriate solvent in the presence of a basic compound.
Any conventional solvent may be used as long as it does not affect the reaction. Examples of such a solvent include ethers such as diethyl ether, dioxane, tetrahydrofuran, monoglyme, and diglyme, aromatic hydrocarbons such as benzene, toluene, and xylene, aliphatic hydrocarbons such as n-hexane, heptane, and cyclohexane, amines such as pyridine and N,N-dimethylaniline, aprotic polar solvents such as acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric acid triamide, and alcohols such as methanol, ethanol, and isopropanol, and a mixture thereof.
Examples of the basic compound include metal sodium, metal potassium, sodium hydride, sodium amide, metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide, carbonates such as sodium carbonate, potassium carbonate, and sodium bicarbonate, metal alcoholates such as sodium methylate, sodium ethylate, and potassium tert-butoxide, alkyl and aryl lithiums or lithium amides such as methyl lithium, n-butyryl lithium, phenyl lithium, and lithium diisopropylamide, and organic bases such as pyridine, piperidine, quinoline, trimethylamine, diisopropylethylamine, and N,N-dimethylaniline. These basic compounds are used singly or in a mixture of two types or more. The basic compound is favorably used typically in an amount 0.1 to 10 times and preferably 0.5 to 5 times that of the compound (128) on a molar basis.
The compound (129) is favorably used typically in at least an equimolar amount to the compound (128) and preferably 1 to 5 times that of the compound (128) on a molar basis.
The above described reaction is carried out typically at −80 to 150° C. and preferably at about −80 to 120° C. and generally completed in, about 0.5 to 40 hours.
When an organic base is used as the basic compound, the reaction advantageously proceeds by adding a lithium salt such as lithium chloride to the reaction system.
The reaction which converts the compound (130) into the compound (131) is carried out under the same reaction conditions as in the reaction which converts the compound (68) into the compound (69) shown in reaction formula 47 above.




wherein R2, X1, Y, R66 and A17 are the same as described above.

The reaction which converts the compound (28′) into the compound (64a) is carried out under the same reaction conditions as in the reaction which converts the compound (1f) into the compound (1g) shown in reaction formula 3 above.




wherein R2, X1, Y and A are the same as described above.

The reaction which converts the compound (64b) into the compound (26a) is carried out in an appropriate solvent in the presence of an oxidizing agent.
Examples of the solvent include water, fatty acids such as formic acid, acetic acid, trifluoroacetic acid, and propionic acid, esters such as ethyl acetate and methyl acetate, alcohols such as methanol, ethanol, and isopropanol, ethers such as dioxane, tetrahydrofuran, and diethyl ether, ketones such as acetone and methyl ethyl ketone, aromatic hydrocarbons such as benzene, toluene, chlorobenzene, and xylene, and halogenated hydrocarbons such as chloroform and dichloromethane, hexamethylphosphoric acid triamide, N,N-dimethylformamide, dimethyl sulfoxide, and pyridine, and a mixture thereof.
Examples of the oxidizing agent include peracids such as performic acid, peracetic acid, pertrifluoroacetic acid, perbenzoic acid, m-chloroperbenzoic acid, and o-carboxyperbenzoic acid, hydrogen peroxide, sodium metaperidodate, dichromic acid, dichromates such as sodium dichromate and potassium dichromate, manganese dioxide, permanganic acid, permanganates such as sodium permanganate and potassium permanganate, lead salts such as lead tetraacetate, silver oxide, and a Dess-Martin reagent (Dess-Martin periodinane). These oxidizing agents are used singly or in a mixture of two or more. The oxidizing agent is used typically in at least an equimolar amount to the compound (64b) and preferably 1 to 3 times that of the compound (64b) on a molar basis.
The above described reaction is carried out typically at −10 to 100° C. and preferably at about 0 to 50° C. and completed in about 30 minutes to 24 hours.




wherein R2, X1, Y, A10, B19, R18, X2, R14, R74a and R15 are the same as described above, provided that a and b of A10 are bound to a group —Y and a group —B19, respectively.

The reactions between compound (133) and the compound (134), and compound (135) and the compound (36) each are carried out under the same reaction conditions as in the reaction of the compound (2) and the compound (3) shown in reaction formula 1 above.




wherein A10, B3, R17a, R17b, RA, R17, Y1, Rc and X2 are the same as described above, and R80 represents group —Y1H or group —OR81, R81 represents a protective group of the hydroxyl group, provided that the CHRA moiety in the side chain

(—N(B3Rc)(CHRAR17b)) of the compound (108c) has not more than 6 carbon atoms, a of A10 is bound to a group —R80, and b is bound to a group —NHB3Rc, a group —N(R17a) B3Rc, a group —N(CHRAR17b)B3Rc or a group —N(R17) B3Rc.

Examples of the protective group of the hydroxyl group include a phenyl lower alkyl group, a lower alkoxy lower alkyl group, tetrahydropyranyl group, tri lower alkylsilyl group, a lower alkanoyl group, and a lower alkyl group described above.
The reaction of the compound (108a) and the compound (73) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (4) shown in reaction formula 2 above.
The reaction of the compound (108a) and the compound (75′) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.
The reaction of the compound (108a) and the compound (74) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (5) shown in reaction formula 2 above.
The reaction is carried out using a compound (74), whose RA and R17b (bound to a carbon atom) are mutually bound to form a cycloalkyl ring together with the carbon atom in the presence of a hydride reducing agent, as a starting material. In this case, in place of the compound (74), cycloalkyloxytrialkylsilane such as [(1-ethoxycyclopropyl)oxy]trimethylsilane may be used as the starting material (to produce the above described compound (74) in the reaction system).




wherein R80, A10, R17, B3, Rc, X2 and R59b are the same as described above, provided that a of A10 is bound to a group —R80 and b is bound to a group —NHR17, a group —N(R17)B3Rc or a group —N(R17)CH2CH2COOR59.

The reaction of the compound (108e) and the compound (113) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (4) shown in reaction formula 2 above.
The reaction of the compound (108e) and the compound (137) is carried out in an appropriate solvent in the presence of an acid.
Any solvent may be used as long as it is used in the reaction of the compound (2) and the compound (3) shown in reaction formula 1 above.
Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, organic acids such as acetic acid, trifluoroacetic acid, and sulfonic acids including p-toluenesulfonic acid, and Lewis acids such as aluminum chloride, zinc chloride, iron chloride, tin chloride, boron tribromide, and a boron trifluoride/diethyl ether complex. These acids may be used singly or in a mixture of two types or more. The acid is favorably used typically in an amount at least 0.01 to 5 times and preferably 0.1 to 2 times that of the compound (108e) on a molar basis. The compound (137) is favorably used typically in at least an equimolar amount to the compound (108e) and preferably 1 to 10 times that of the compound (108e) on a molar basis.
The above described reaction is carried out typically at 0 to 200° C. and preferably at about 0 to 150° C. and generally completed in about 30 minutes to 80 hours.




wherein R81 is the same as described above, R73b represents a group A10-T2-COOR59a or a group -A, and A10, T2, R59a and A are the same as described above, provided that a of A10 is bound to a group —OR81 group or a hydroxyl group, and b of A10 is bound to a group -T2.

When R81 of the starting compound (138) represents a phenyl lower alkyl group, the reaction which converts the compound (138) into the compound (139) may be carried out under the same reaction conditions as in the reduction reaction (1) (method using a catalytic hydrogen reducing agent), which is one of the reactions which convert the compound (68) into the compound (69) shown in reaction formula 47 above.
The starting compound (138), in which R81 represents a tetrahydropyranyl group or a tri-lower alkylsilyl group is converted into the compound (139), may be carried out under the same reaction conditions as in hydrolysis reaction B described in reaction formula 9 above. In the reaction which converts the compound (138) into the compound (139), hydrolysis is favorably carried out by use of an acid. The acid is favorably used typically in an amount 1 to 10 times and preferably 1 to 2 times that of the compound (138) on a molar basis.
The compound (138) in which R81 represents a tri-lower alkylsilyl group, may be treated with a fluorine compound such as tetra-n-butyl ammonium fluoride, hydrogen fluoride or cesium fluoride.
The starting compound (138) in which R81 represents a lower alkoxy lower alkyl group or a lower alkyl group, may be treated in an appropriate solvent in the presence of an acid. Examples of the solvent include water, lower alcohols such as methanol, ethanol, and isopropanol, ethers such as dioxane, tetrahydrofuran, and diethyl ether, halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride, and polar solvents such as acetonitrile, and a mixture thereof. Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, fatty acids such as formic acid and acetic acid, sulfonic acids such as p-toluenesulfonic acid, Lewis acids such as boron trifluoride, aluminum chloride, and boron tribromide, iodides such as sodium iodide and potassium iodide, and a mixture of an iodide with a Lewis acid as described above. The above described reaction is carried out typically at 0 to 200° C. and preferably at about room temperature to 150° C. and generally completed in about 0.5- to 25 hours.
Furthermore, the hydrolysis may be carried out using a basic compound under the same reaction conditions as in hydrolysis reaction B described in reaction formula 9 above. In this case, an amine such as triethylamine may be used other than the basic compounds used in hydrolysis reaction B, as the basic compound.
The material compound (138), in which R81 represents a lower alkanoyl group, is converted into the compound (139) under the same reaction conditions as in hydrolysis reaction B described in reaction formula 9 above.
The compound (138) in which R73a represents a group




a dehydration reaction takes place under the hydrolysis conditions above, with the result that the compound (138), in which the corresponding R73a represents a group





may be obtained in some cases.





wherein R80, A10, T2, R14 and R15 are the same as described above, provided that a and b of A10 are to a group —R80 and a group -T2, respectively.

The reaction of the compound (140) and the compound (36) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.




wherein Y1, A7, R13 and A9 are the same as described above.

The reaction of the compound (141) and the compound (12) is carried out under the same reaction conditions as in the reaction of the compound (13) and the compound (12) shown in reaction formula 8 above.




wherein R80, A10, B21 and f are the same as described above, provided that the alkyl moiety in the side chain (—(B21)f-CH2NH2) of the compound (144) has not more than 6 carbon atoms.

The reaction which converts the compound (143) into the compound (144) is carried out under the same reaction conditions as in the reaction using a hydride reducing agent, which is one of the reactions of the compound (1b) and the compound (5) shown in reaction formula 2.




wherein R80, A10, B19, X2, R18, R14 and R15 are the same as described above, provided that a of A10 is bound to a group —R80 and b is bound to a group —B19.

The reaction of the compound (145) and the compound (134) is carried out under the same reaction conditions as in the reaction of the compound (133) and the compound (134) shown in reaction formula 90 above.
The reaction of the compound (146) and the compound (36) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.




wherein, A10, B19, R14, R15, R80, and X2 are the same as described above, and R18a represents a lower alkyl group, provided that a and b of A10 are bound to a group —R80 and a group —B19, respectively.

The reaction of the compound (108j) and the compound (147) is carried out under the same-reaction conditions as in the reaction of the compound (1b) and the compound (4 shown in reaction formula 2 above.




wherein R2, X1, X2, X3 and R6 are the same as described above, R82 represents a lower alkyl group, and R83 represents a lower alkoxy group.

The reaction of the compound (148) and the compound (149) is carried out in an appropriate solvent in the presence of a catalyst.
Any solvent may be used herein as long as it is used in the reaction of the compound (2) and the compound (3) shown in reaction formula 1.
Examples of the catalyst include magnesium. The catalyst is favorably used typically in at least an equimolar amount to the compound (148) and preferably 1 to 5 times that of the compound (148) on a molar basis.
The above described reaction is carried out typically at 0 to 200° C. and preferably at about 0 to 150° C. and generally completed in about 30 minutes to 10 hours.




wherein A18 represents a group -A or

a group -A10-T2-COOR59b, and A, A10, T2, R59b and X3 are the same as described above.

The reaction which converts the compound (150) into the compound (107′) is carried out under the same reaction conditions as in the reaction which converts the compound (85) into the compound (7′) shown in reaction formula 55 above.




wherein R2, X1, A10, T2 and R6 are the same as described above, provided that a of A10 is bound to a —CO group, a —CH(OH) group or —CH2 group, and b of A10 is bound to a group -T2.

The reaction which converts the compound (109a′) into the compound (151) is carried out under the same reaction conditions as in the reaction using a hydride reducing agent which is one of the reactions of the compound (1b) and the compound (5) shown in reaction formula 2 above.
The reaction which converts the compound (151) into the compound (152) is carried out under the same reaction conditions as in the reaction which converts the compound (68) into the compound (69) shown in reaction formula 47 above.
The reaction of the compound (152) and the compound (22) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.
The reaction which converts the compound (153) into the compound (154) may be carried out under the same react-ion conditions as in hydrolysis B reaction described in reaction formula 9 above.




wherein R1, R2, X1, Y, A10, B6, B7 or R59 are the same as described above, and R19a represents a lower alkanoyl group, provided that a and b of A10 are bound to a group —Y and a group —B6, respectively.

The reaction of the compound (155) and the compound (156) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.




wherein R80, A10, X2, R14 and R15 are the same as described above.

The reaction of the compound (158) and the compound (36) is carried out under the same reaction conditions as the reaction of the compound (114) and the compound (36) shown in reaction formula 74 in which l is 0.




wherein R1, R2, Y, A10, R14a, h, T, l, RB, X1 and X2 are the same as described above, R85a represents a benzoyl group, R85b represents a lower alkoxy carbonyl group, a phenyl lower alkyl group, a lower alkyl group or furyl lower alkyl group, and R85c represents a hydrogen atom, a lower alkyl group, a phenyl group, phenyl lower alkyl group, a furyl group or a furyl lower alkyl group, provided that the a group —CH(RB)R85c of the compound (1bbbbb) has not more than 6 carbon atoms.

The reaction of the compound (1yyyy′) and the compound (160′) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.
The reaction of the compound (1yyyy′) and the compound (161) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (4) shown in reaction formula 2 above.
The reaction of the compound (1yyyy′) and the compound (162) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (5) shown in reaction formula 2 above.




wherein R2, B0, Y, X1, A17, R8, X2, X3 and R6 are the same as described above, R86 represents a lower alkylsulfonyl group, and R87 represents an oxygen atom or a group —N(R8)—.

The reaction of the compound (165) and the compound (163) is carried out under the same reaction conditions as in the reaction of the compound (2) and the compound (3) shown in reaction formula 1 above.
The reaction which converts the compound (165) into the compound (167) is carried out under the same reaction conditions as in the reaction which converts the compound (85) into the compound (7′) of the above described formula 55.
The reaction of the compound (166) or the compound (167) and the compound (164) is carried out under the same reaction conditions as in the reaction of the compound (2) and the compound (3) shown in reaction formula 1 above.




wherein R80 and A10 are the same as described above, R15 represents the same group as that of (5) in R15 described above.

The reaction of the compound (168) and the compound (170) is carried out under the same reaction conditions as in the reaction of the compound (30) and the compound (66) shown in reaction formula 46 above.




wherein R80, A10, T, l, R14bb, R15aa, R14cc, R15bb, R26 and R27 are the same as described above.

The reaction of the compound (171) and the compound (57) is carried out under the same reaction conditions as in the reaction of the compound (1iiii) and the compound (57) shown in reaction formula 31 above.




wherein R1, R2, X1, Y, A10, R15′ and X2 are the same as described above, and R89 represents a lower alkyl group.

The reaction of the compound (173) and the compound (170) is carried out under the same reaction conditions as in the reaction of the compound (30) and the compound (66) shown in reaction formula 46 above.
The reaction of the compound (1ddddd) and the compound (173) is carried out under the same reaction conditions as in the reaction of the compound (2) and the compound (3) shown in reaction formula 1 above.




wherein R1, R2, X1, Y, X2, B3, R14 and R15 are the same as described above, and A19 represents a group





A20 represents a group





wherein R3, p, R17, B3, R14 and R15 are the same as described above.

The reaction of the compound (174) and the compound (175) is carried out under the same reaction conditions as in the reaction of the compound (2) and the compound (3) shown in reaction formula 1 above.




wherein R1, R2, X1, and Y are the same as described above, A21 represents a group





and A22 represents a group





wherein R3, p, R17, B3, R14 and R15 are the same as described above.

The reaction which converts the compound (1ggggg) into the compound (1hhhhh) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (5) shown in reaction formula 2 in which a hydride reducing agent is used.




wherein R1; R2, X1 and Y are the same as described above,

A23 represents a group





and A24 represents a group





wherein R3 and p are the same as described above.

The reaction which converts the compound (1iiiii) into the compound (1jjjjj) is carried out under the same reaction conditions as in the reaction which converts the compound (68) into the compound (69) shown in reaction formula 47.




wherein R2, X1 and Y are the same as described above,

A25 represents a group





and A26 represents a group





wherein B4a represents a lower alkenylene group, B4b represents a lower alkylene group, and R3, p, R14 and R15 are the same as described above.

The reaction which converts the compound (1kkkkk) into the compound (1lllll) is carried out the same as in the reaction of the method (1) of the reactions which convert the compound (68) into the compound (69) shown in reaction formula 47 above.




wherein R2, X1, Y, and R59b are the same as described above, and A28 represents a group





and A27 represents a group





wherein R3, p and R59b are the same as described above.

The reaction which converts the compound (1mmmmm) into the compound (1nnnnn) is carried out under the same reaction conditions as in hydrolysis B described in reaction formula 9 above.
The reaction of the compound (1nnnnn) and the compound (100′) is carried out under the same reaction conditions as in the reaction of the compound (1fff) and the compound (43) shown in reaction formula 20 above.




wherein R2, X1, X2 and Y are the same as described above,

A29 represents a group





and A30 represents





wherein R90 represents a lower alkyl group which may have a hydroxyl group as a substituent, and R3, p and R59b are the same as described above.

The reaction of the compound (1ooooo) and the compound (176) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (4) shown in reaction formula 2 above.




wherein R2, X1, X2 and Y are the same as described above,

A31 represents a group





wherein A32 represents a group





wherein R3, p, R59b and R89 are the same as described above.

The reaction of the compound (1qqqqq) and the compound (173) is carried out under the same reaction conditions as in the reaction of the compound (2) and the compound (3) shown in reaction formula 1 above.




wherein R1, R2, X1, Y, A10, T, l, R90 and X2 are the same as described above.

R15′′ represents the group (2), (3), (4), (5), (6), (7), (8), (10), (11), (12), (13), (14), (15), (16), (17), (18), (19), (20), (21), (22), (23), (24), (25), (26), (27), (26a), (27a), (28a), (29a), (30a), (31a), (32a), (33a), (34a), (35a), (36a), or (37a), which is defined in R15 described above.

The reaction of the compound (1sssss) and the compound (176) is carried out under the same reaction conditions as in the reaction of the compound (2) and the compound (3) shown in reaction formula 1 above.




wherein R1, R2, X1, Y, A10, T and l are the same as described above,

R14AA and R15BB each represent the same 5- to 10-membered saturated or unsaturated heterocyclic group as defined in R14 and R15 described above except that the heterocyclic ring has at least one group —(B12CO)t-N(R20)—CO—B16X2 thereon,

R14CC and R15DD each represent the same 5- to 10-membered saturated or unsaturated heterocyclic group as defined in R14 and R15 described above except that the heterocyclic ring has at least one group —(B12CO)t-N(R20′)—CO—B16R91 thereon, wherein B12, t, B16 and X2 are the same as described above,

R91 represents an imidazolyl group, and

R20′ represents a hydrogen atom, a cycloalkyl group, an amino group which may have a lower alkoxycarbonyl group as a substituent, a benzoyl group which may have 1 to 3 lower alkoxy groups as substituents on the phenyl ring, a lower alkyl group, a lower alkyl group which have 1 or 2 phenyls which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxy group which may have a halogen atom as a substituent and a lower alkylthio group which may have a halogen atom as a substituent, a phenyl group which may be substituted, on the phenyl ring, with 1 to 3 groups selected from the group consisting of a lower alkoxy group which may have a halogen atom as a substituent and a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxycarbonyl group, a cycloalkyl lower alkyl group, a pyrrolidinyl lower alkyl group which may have, on the pyrrolidine ring, 1 to 3 lower alkyl groups which may have a hydroxyl group as a substituent, an amino substituted lower alkyl group which may have a substituent selected from the group consisting of a phenyl group and a lower alkyl group, a 1,2,3,4-tetrahydronaphthyl substituted lower alkyl group which may have 1 to 5 lower alkyl groups as substituents on the 1,2,3,4-tetrahydronaphthalene ring, a naphthyl lower alkyl group, a pyridyl lower alkyl group, a quinolyl lower alkyl group, a 1,2,3,4-tetrazolyl lower alkyl group which may have, on the tetrazole ring, 1 to 3 substituents selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group, a 1,2,4-triazolyl lower alkyl group, a tetrahydrofuryl lower alkyl group which may have a hydroxyl group as a substituent on the lower alkyl group, a phenoxy lower alkyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkyl group and a nitro group, a phenyl lower alkanoyl group, a lower alkanoyl group which may have a halogen atom as a substituent, an imidazolyl lower alkanoyl group, a lower alkoxycarbonyl lower alkyl group, a pyridyl group or a carboxy lower alkyl group.

The reaction of the compound (1uuuuu) and the compound (177) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (4) shown in reaction formula 2 above.




wherein X1, X2, R2, Y, A and R6 are the same as described above, and R91 represents a hydrogen atom or a lower alkyl group.

The reaction of the compound (33) and the compound (178) is carried out in an appropriate solvent in the presence of a basic compound and a catalyst.
As the solvent, an inert solvent selected from a wide range may be used. Examples of the inert solvent include water, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, 2-methoxyethanol, monoglyme, and diglyme, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, lower alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol, fatty acids such as acetic acid, esters such as ethyl acetate and methyl acetate, ketones such as acetone and methyl ethyl ketone, acetonitrile, pyridine, N-methylpyrrolidone, dimethyl sulfoxide, N,N-dimethylformamide, and hexamethylphosphoric acid triamide, and a mixture thereof.
Examples of the basic compound include carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and cesium carbonate, metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide, potassium phosphate, sodium phosphate, sodium hydride, potassium hydride, potassium, sodium, sodium amide, metal alcoholates such as sodium methylate, sodium ethylate, sodium n-butoxide, sodium tert-butoxide, and potassium tert-butoxide, alkylsilylamide alkali metal salts such as potassium bis(trimethylsilyl)amide, and organic bases such as pyridine, imidazole, N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine, trimethylamine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), and 1,4-diazabicyclo[2.2.2]octane (DABCO), and a mixture thereof.
Examples of the catalyst may include palladium compounds such as palladium acetate, bis(tributyltin)/bis(dibenzylideneacetone)palladium, copper iodide/2,2′-bipyridyl, bis(dibenzylideneacetone)palladium, copper iodide/bis(triphenylphosphine)palladium dichloride, tris(dibenzylideneacetone)dipalladium, R-tris(dibenzylideneacetone)-dipalladium, S-tris(dibenzylideneacetone)dipalladium, palladium(II) acetate, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and tetrakis(triphenylphosphine)palladium, compounds such as R-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (R-BINAP), S-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (S-BINAP), RAC-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl-(RAC-BINAP), and 2,2-bis(diphenylimidazolidinylidene), xanthene compounds such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, and borates such as tri-tert-butylphosphine tetrafluoroborate, and a mixture thereof.
The basic compound is favorably used in an amount at least 0.5 times and preferably 0.5 to 40 times that of the compound (33) on a molar basis. The catalyst is favorably used in a typical catalyst amount based on the compound (33).
The compound (178) is favorably used in an amount at least in 0.5 times and preferably 0.5 to 3 times that of the compound (33) on a molar basis.
The above described reaction is carried out typically at room temperature to 200° C., preferably at room temperature to about 150° C., and completed in about 0.5 to 20 hours.




wherein Bo, X1, R2, Y, A17, R6 and X2 are the same as described above, R92 represents a group R6—Z4— or a group R6— and Z4 represents a lower alkylene group.

The reaction of the compound (64) and the compound (179) is carried out under the same reaction conditions as in the reaction of the compound (2) and the compound (3) shown in reaction formula 1.




wherein R2, X1, Y, A and R6 are the same as described above.

The method for converting the compound (30) into the compound (1bbbbbb) is carried out by subjecting the compound (30) to diazotization to obtain a diazonium salt and reacting the diazonium salt with the compound (180).
The diazotization reaction 1) is carried out in an appropriate solvent in the presence of an acid and a diazotizing agent. Examples of the solvent to be used herein include water and acetonitrile. Examples of the acid include hydrochloric acid, hydrobromic acid, sulfuric acid, tetrafluoroboric acid, and hexafluorophosophoric acid. Examples of the diazotizing-agent include metal nitrites such as sodium nitrite and potassium nitrite, lower alkyl nitrites such as t-butyl nitrite and isoamyl nitrite.
The acid is favorably used typically in an amount about 1 to 10 times that of the compound (30) and preferably about 1 to 5 times that of the compound (30) on a molar basis. The diazotizing agent is used typically in at least about equimolar amount to the compound (30) and preferably 1 to 3 times that of the compound (30) on a molar basis.
The above described reaction is carried out typically at about 0 to 70° C. and preferably at about 0° C. to room temperature, and completed in about a few minutes to 5 hours.
The reaction of the diazonium salt obtained in the diazotination reaction and the compound (180) is carried out in the same solvent as in the diazotization reaction 1) and in the presence of a basic compound.
Any basic compound may be used herein as long as it is used in the reaction of the compound (2) and the compound (3) shown in reaction formula 1.
The basic compound is favorably used in at least an equimolar amount to the compound (30) and preferably 1 to 5 times that of the compound (30) on a molar basis.
The compound (180) is favorably used in at least an equimolar amount to the compound (30) and preferably 1 to 5 times that of the compound (30) on a molar basis.
The above described reaction is carried out typically at about 0 to 70° C., preferably at about 0° C. to room temperature, and completed in about a few minutes to 5 hours.




wherein X1, R8d, Y, A, R2 and R6 are the same as described above.

The reaction of the compound (30a) and the compound (181) may be carried out in an appropriate solvent in the presence of a basic compound and a catalyst.
Examples of the solvent used herein include water, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, 2-methoxyethanol, monoglyme, and diglyme, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, lower alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol, fatty acids such as acetic acid, esters such as ethyl acetate and methyl acetate, ketones such as acetone and methylethyl ketone, acetonitrile, pyridine, dimethylsulfoxide, N,N-dimethylformamide, and hexamethylphosphoric acid triamide, and a mixture thereof.
Examples of the basic compound include carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and cesium carbonate, metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide, sodium hydride, potassium hydride, potassium, sodium, sodium amide, metal alcoholates such as sodium methylate, sodium ethylate, sodium n-butoxide, sodium tert-butoxide, and potassium tert-butoxide, organic bases such as pyridine, imidazole, N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine, trimethylamine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), and 1,4-diazabicyclo[2.2.2]octane (DABCO), and a mixture thereof.
Examples of the catalyst include palladium compounds such as tetrakis(triphenylphosphine)palladium(0) and dichlorobis(triphenylphosphine)palladium(II), and copper compounds such as copper (II) acetate.
The basic compound is favorably used in at least an equimolar amount to the compound (30a) and preferably 1 to 5 times that of the compound (30a) on a molar basis.
The catalyst is favorably used in an amount 0.001 to 1 times and preferably 0.01 to 0.5 times that of the compound (30a) on a molar basis.
The compound (181) is favorably used in at least an equimolar amount to the compound (30a) and preferably 1 to 5 times that of the compound (30a) on a molar basis.
The above described reaction is carried out typically at −30 to 200° C. and preferably at 0 to 150° C. and generally completed in 0.5 to about 30 hours. A molecular sieve such as Molecular Sieves 3A (MS-3A), Molecular Sieves 4A (MS-4A) may be added to the reaction.




wherein R6, Z1, X1, R2, Y4 and A are the same as described above.

The reaction which converts the compound (1dddddd) into the compound (1eeeeee) is carried out in an appropriate solvent in the presence of a catalytic hydrogen reducing agent.
Examples of the solvent include water, fatty acids such as acetic acid, alcohols such as methanol, ethanol, and isopropanol, aliphatic hydrocarbons such as n-hexane, alicyclic hydrocarbons such as cyclohexane, ethers such as diethyl ether, dimethoxyethane, tetrahydrofuran, monoglyme, diglyme, and 1,4-dioxane, esters such as methyl acetate, ethyl acetate, and butyl acetate, and aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetoamide, and N-methylpyrrolidone, and a mixture thereof.
Examples of the catalytic hydrogen reducing agent include palladium, palladium-black, palladium-carbon, palladium hydroxide-carbon, rhodium-alumina, platinum, platinum oxide, copper chromite, Raney nickel, and palladium acetate.
The above described catalytic hydrogen reducing agent is used typically in an amount 0.01 to 1 times that of the compound (1dddddd) on a molar basis.
The above reaction favorably proceeds typically at about −20 to 150° C., and preferably at 0 to 100° C. and generally completed in 0.5 to 20 hours. The hydrogen pressure may be applied typically at 1 to 10 atm.




wherein R1, R2, X1, Y, A10, T and l are the same as described above; R14II and R15JJ each represent the same 5- to 10-membered saturated or unsaturated heterocyclic group as defined in R14 and R15 above, except that they have at least one phenyl group which has a lower alkoxycarbonyl group on the heterocyclic ring; R14EE and R15FF each represent the same 5- to 10-membered saturated or unsaturated heterocyclic group as defined in R14 and R15 above, except that they have at least one phenyl group which has a carboxy group on the heterocyclic ring;

R14GG and R15HH each represent the same 5- to 10-membered saturated or unsaturated heterocyclic group as defined in R14 and R15 above, except that they have, on the heterocyclic ring, at least one phenyl group which may have a carbamoyl group which may have a group selected from the group consisting of a lower alkoxy lower alkyl group and a lower alkyl group; and

R93 and R94 each represent a hydrogen atom, a lower alkyl group or a lower alkoxy lower alkyl group.

The reaction which converts the compound (1hhhhhh) into the compound (1ffffff) may be carried out the under the same reaction conditions as in the hydrolysis B described in reaction formula 9 above.
The reaction of the compound (1ffffff) and the compound (182) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.




wherein X1, R2, Y, A, X2, k, X3, R6, B20a and d′ are the same as described above.

The reaction of the compound (30) and the compound (183) is carried out under the same reaction conditions as in the reaction of the compound (30) and the compound (66) shown in reaction formula 46 above.
The reaction which converts the compound (184) into the compound (1jjjjjj) is carried out under the same reaction conditions as in the reaction of the compound (2) and the compound (3) shown in reaction formula 1 above.
The reaction of the compound (1jjjjjj) and the compound (185) is carried out under the same reaction conditions as in the reaction of the compound (2) and the compound (3) shown in reaction formula 1 above.
When the compound (185) wherein d′ represents 0, the reaction which converts the compound (1jjjjjj) into the compound (1kkkkkk) may be carried out in an appropriate solvent in the presence of a halogenated copper such as copper iodide, an alkylglycine such as N,N-dimethylglycine, or an alkali metal phosphate such as potassium phosphate.
Any solvent may be used herein as long as it is used in the reaction of the compound (2) and the compound (3) shown in reaction formula 1 above.
A halogenated copper or an alkylglycine is used in a typical catalyst amount. The alkali metal phosphate is favorably used typically in at least an equimolar amount to the compound (1jjjjjj) and preferably 1 to 5 times that of the compound (1jjjjjj) on a molar basis. The compound (185) is used in an amount typically 0.5 to 5 times and preferably 0.5 to 3 times that of the compound (1jjjjjj) on a molar basis. The above described reaction is carried out typically at room temperature to 200° C. preferably at about room temperature to 150° C. and generally completed in about 1 to 30 hours.




wherein X2, R2, X1, Y, A and R6 are the same as described above.

The reaction of the compound (33) and the compound (186) is carried out under the same reaction conditions as in the reaction of the compound (33) and the compound (178) shown in reaction formula 118 above.




wherein X1, X2, R2, Y, A, B21a, R6, and c are the same as described above.

The reaction of the compound (33) and the compound (187) is carried out under the same reaction conditions as in the reaction of the compound (33) and the compound (178) shown in reaction formula 118 above.




wherein R9a, R2, R6, X1, Y, A16, X2 and R9b are the same as described above.

The reaction of the compound (188) and the compound (189) is carried out under the same reaction conditions as in the reaction in which an amine is reacted with a carboxylic acid halide among the methods (d) in which the compound (1b) is reacted with the compound (6) shown in reaction formula 2.
The reaction of the compound (190) and the compound (191) is carried out under the same reaction conditions as in the reaction of the compound (2) and the compound (3) shown in reaction formula 1 above.




wherein R1, R2, X1, Y and A16 are the same as described above. Xa represents a halogen atom.

The reaction which converts the compound (1oooooo) into the compound (1pppppp) is carried out in an appropriate solvent in the presence of a catalytic hydrogen reducing agent and a hydrogen donor such as formic acid, ammonium formate, cyclohexene, or hydrazine hydrate.
Any solvent and catalytic hydrogen reducing agent may be used as long as they are used in the reaction which converts the compound (1dddddd) into the compound (1eeeeee) shown in reaction formula 122 above.
The catalytic hydrogen reducing agent is typically used in an amount of 0.01 to 40 wt % and preferably 0.01 to 20 wt % of the compound (1oooooo).
The hydrogen donor is used typically in at least an equimolar amount to the compound (1oooooo) and preferably 1 to 10 times that of the compound (1oooooo) on a molar basis.
The above described reaction is carried out under a hydrogen atmosphere typically at about normal pressure to 20 atm and preferably at normal pressure to 10 atm, and at a temperature of about −30 to 150° C. and preferably at about 0 to 100° C. The reaction is generally completed in about 1 to 12 hours.




wherein A10, X2, k, X3, R80 and RB are the same as described above; R94a represents a group defined as a substituent present on a heterocyclic group formed by binding R14 and R15 to each other, and include a substituent represented by (35), (40), (42), (67), (75), (76), (78), (80) or (81) in which o is 1, or (84) in which s is 0.

R94b represents a group defined as a substituent present on a heterocyclic ring formed by binding R14 and R15 to each other, and include a substituent represented by (28), (30) to (34), (36) to (39), (41), (43) to (45), (47), (52) to (60), (62) to (66), (70), (77), (79), (82), (83), (87), (88a) or (90a), a substituent represented by (49) in which t is 1, or a substituent represented by (50) in which o is 0;

and R94c represents a group defined as a substituent present on a heterocyclic ring formed by binding R14 and R15 to each other and include a substituent represented by (28), (30) to (34), (39), (41), (45), (47), (54) to (58), (62) to (64), (66), (70), (79), (82) or (83), a substituent represented by (49) in which t is 1, or a substituent represented by (50) in which o is 0; a phenyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkanoyl group, an amino group which may have a lower alkanoyl group as a substituent, a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxy group which may have a halogen atom as a substituent, a phenyl lower alkoxy group, a hydroxy group and a lower alkylenedioxy group, a pyridyl group which may have, on the pyridine ring, 1 to 3 substituents selected from the group consisting of a hydroxy group and a lower alkyl group which may have a hydroxyl group as a substituent, a pyrrolyl group which may have 1 to 3 lower alkyl groups as substituents on a pyrrolyl group, a benzoxazolyl group, a benzothiazolyl group, a furyl group, a lower alkyl group which may have a substituent selected from the group consisting of a hydroxy group and a halogen atom, a naphthyl group, a 1,2,3,4-tetrahydronaphthyl group which may have 1 to 5 lower alkyl groups as substituents on the 1,2,3,4-tetrahydronaphthalene ring, a quinolyl group, a 1,2,3,4-tetrazolyl group which may have, on the tetrazole ring, a substituent selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group; a thiazolyl group which may have a phenyl group as a substituent on the thiazole ring; a benzoyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkoxy group and a halogen atom, a piperidinyl group which may have a lower alkyl group as a substituent on the piperidine ring, a 1,2,3,4-tetrahydroquinolyl group which may have an oxo group as a substituent on the tetrahydroquinoline ring, a 1,3,4-oxadiazolyl group which may have an oxo group as a substituent on the 1,3,4 oxadiazole ring, a cycloalkyl group, a thienyl group, or an imidazolyl group.

The reaction of the compound (192) and the compound (183) is carried out under the same reaction conditions as in the reaction of the compound (30) and the compound (183) shown in reaction formula 124 above.
The reaction which converts the compound (193) into the compound (1qqqqqq) is carried out under the same reaction conditions as in the reaction which converts the compound (184) into the compound (1jjjjjj) shown in reaction formula 124 above.
The reaction of the compound (1qqqqqq) and the compound (195) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (4) shown in reaction formula 2 above.
The compound (195), in which R94b is a group represented by (36) to (38), (43), (44), (53), (59), (60), (87), (88a) or (90a), is reacted with the compound (1qqqqqq) in an appropriate solvent in the presence of a copper halide such as copper iodide, an alkylglycine such as N,N-dimethylglycine, and an alkyl metal phosphate such as potassium phosphate.
Any solvent may be used herein as long as it is used in the reaction of the compound (2) and the compound (3) shown in reaction formula 1 above. The copper halide and alkyliglycine are used in a normal catalyst amount. The alkali metal phosphate is favorably used typically in at least an equimolar amount to the compound (1qqqqqq) and preferably 1 to 5 times that of the compound (1qqqqqq) on a molar basis. The compound (195) is favorably used typically in an amount 0.5 to 5 times and preferably 0.5 to 3 times that of the compound (1qqqqqq) on a molar basis. The above described reaction is carried out typically at room temperature to 200° C. and preferably about room temperature to 150° C. and completed in about 1 to 30 hours.
The reaction of the compound (1qqqqqq) and the compound (194) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.
The reaction of the compound (1qqqqqq) and the compound (196) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (5) of the above described formula 2 above.




wherein X1, Y, A, R2, R6, B22a, e and X2 are the same as described above, and R10a′ represents a lower alkyl group.

The reaction of the compound (1uuuuuu) and the compound (197) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (4) of reaction formula 2 above.




wherein X1, Y, A, R2, R6 and X2 are the same as described above. R10b′ represents a lower alkyl group.

The reaction of the compound (1wwwwww) and the compound (197a) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (4) shown in reaction formula 2 above.




wherein R1, X1, Y, X2, R14a and R59b are the same as described above, and R96 represents a piperazinyl group which may have, on the piperazine ring, 1 to 3 substituents selected from the group consisting of a phenyl lower alkyl group (which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkylenedioxy group and a lower alkoxy group) and a pyridyl lower alkyl group.

The reaction of the compound (198) and the compound (199) is carried out under the same reaction conditions as in the reaction of the compound (2) and the compound (3) shown in reaction formula 1 above.
The reaction which converts the compound (200) into the compound (201) may be carried out under the same reaction conditions as in hydrolysis B described in reaction formula 9 above.
The reaction of the compound (201) and the compound (100′) is carried out under the same reaction conditions as in the reaction of the compound (120b) and the compound (100′) shown in reaction formula 79 above.
The reaction of the compound (201) and the compound (202) is carried out under the same reaction conditions as in the reaction of the compound (1b) and the compound (6) shown in reaction formula 2 above.
The compound (200) may also be produced by the method shown in the following reaction formula 133:




wherein R74a, R2, X1, Y. A10, R59b and X2 are the same as described above, and R14a′ represents a lower alkyl group which may have a hydroxyl group as a substituent.

The reaction of the compound (200a) and the compound (203) is carried out under the same reaction conditions as in the reaction of the compound (2) and the compound (3) shown in reaction formula 1 above.
The compound (3) may also be produced by the method of the following reaction formula 134:




wherein R80, A10, B23a, R14 and R15 are the same as described above.

The reaction which converts the compound (108l) into the compound (108m) is carried out under the same reaction conditions as in the reaction which converts the compound (1f) into the compound (1g) shown in reaction formula 3 above.




wherein R1, R2, X1, Y, A10, B23a, R14 and R15 are the same as described above.

The reaction which converts the compound (1zzzzzz) into the compound (1AAAAAA) is carried out under the same reaction conditions as in the reaction which converts the compound (64b) into the compound (26a) shown in reaction formula 89 above.
A reaction mixture containing each of the target compounds obtained by reaction formulas shown above is cooled, and thereafter, a crude reaction product can be isolated from the reaction mixture cooled by an isolation operation such as filtration, concentration, or extraction, and purified by a conventional purification operation such as column chromatography or re-crystallization.
The compound of the present invention represented by the general formula (1) includes a stereoisomer, an optical isomer, a solvate (hydrate and ethanolate, etc.)
Of the compounds of the present invention, a compound having a basic group may be easily reacted with a conventional pharmacologically acceptable acid to form a salt. Examples of such an acid include mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid, and organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, citric acid, tartaric acid, maleic acid, fumaric acid, malonic acid, and lactic acid.
Of the compounds of the present invention, a compound having an acidic group may be easily reacted with a conventional pharmacologically acceptable basic compound to form a salt. Examples of such a basic compound include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate.
Next, a medical formulation containing a compound according to the present invention as an active ingredient will be described.
The medical formulation is obtained by formulating a compound according to the present invention in the form of pharmaceutical preparation, and more specifically, prepared using a diluent or an excipient such as a filler, expander, binder, moistener, disintegrator, surfactant, or lubricant.
The form of such a medicinal formulation may be chosen from various forms depending upon the therapeutic purpose, and typical forms include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (liquids, suspensions).
The carrier to be used in forming tablets may be chosen widely from conventionally known ones. Examples of the carrier include excipients such as lactose, saccharose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, and crystalline cellulose, binders such as water, ethanol, propanol, simple syrup, a glucose solution, a starch solution, a gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, and polyvinylpyrrolidone, disintegrators such as dried starch, sodium arginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, starch, and lactose, anti-disintegrators such as saccharose, stearine, cacao butter, and hydrogenated oil, absorbefacients such as quartenary ammonium base and sodium lauryl sulfate, wetting agents such as glycerol and starch, adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicate, and lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol.
Further, tablets may be coated in a conventional manner as needed. Examples of coated tablets include sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, or double or multi-layered tablets.
The carriers to be used in forming pills may be chosen widely from the conventionally known ones. Examples of the carrier include excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, and talc, binders such as gum arabic powder, tragacanth powder, gelatin, and ethanol, and disintegrators such as laminaran and agar.
The carriers to be used in forming suppositories may be chosen widely from the conventionally known ones. Examples of the carrier include polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides.
When liquid, emulsion and suspension are prepared as injection preparations, they are preferably sterilized and controlled to be isotonic with the blood. Diluents to be used in forming these liquid, emulsion and suspension preparations may be chosen widely from the conventionally known ones. Examples of the diluents include water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid ester. In this case, the medical formulations may contain sodium chloride, glucose or glycerol in a sufficient amount to prepare isotonic solutions. Also, conventional solubilizers, buffers, analgesics, and the like, and, as necessary, coloring agents, preservatives, spices, flavors, sweets and the like, or other pharmaceuticals may be contained.
Although the amount of a compound according to the present invention contained in a medical formulation is not particularly limited and may be appropriately selected from a wide range of compounds. It is preferable that a compound according to the present invention is contained in an amount of 1 to 70 wt % in a medical formulation.
The method for administrating a medical formulation according to the present invention is not particularly limited. The medical formulation can be administered by a method determined depending upon the form of medical formulation, patient's age, sex, severity of the disease and other conditions. For example, tablets, pills, liquids, suspensions, emulsions, granules and capsules are administered orally. The injection formulations are administered singly or by mixing with a conventional fluid replacement such as a glucose solution or amino acid solution, intravenously or, as necessary, singly administered intramuscularly, intradermally, subcutaneously or intraperitoneally. Suppositories are administered into the rectum.
The dosage for the above mentioned medical formulation may be chosen appropriately depending upon the usage, patient's age, sex and severity of the disease and other conditions. Typically, 0.001 to 100 mg per kg (body weight) per day, preferably 0.001 to 50 mg per kg (body weight) per day, is administered once or in several times a day.
Since the above described dosage varies depending upon various conditions, the dosage may be smaller than the lower limit of the range described above or larger than the upper limit of the range described above.
The medicinal drug has an excellent antitumor effect and thus useful as a tumor therapeutic drug.
As a tumor upon which antitumor effect is exerted, for example, a malignant tumor and the like may be mentioned.
As such a malignant tumor, for example, a solid tumor (cancer, sarcoma and the like), blood cancers (lymphoma, leukemia, myeloma and the like) may be mentioned.
Specific examples of the malignant tumor include brain tumors of an infant such as astroglioma, malignant medulloblastoma, germ cell tumor, craniopharyngioma, and ependymoma; brain tumors of an adult such as glioma, meningioma, pituitary gland adenoma, and neurilemma; head cervix cancers such as cancer of maxillary sinus, pharyngeal cancer (nasopharyngeal carcinoma, mesopharyngeal carcinoma, hypopharyngeal carcinoma), laryngeal cancer, oral cavity cancer, labial cancer, tongue cancer, and parotoid cancer;
chest cancers and tumors, such as cellule lung cancer, non-small-cell lung cancer, chest adenoma, and mesotheliomas;
digestive organ cancers and tumors such as esophagus cancer, liver cancer, primary hepatic cancer, gallbladder cancer, bile duct cancer, stomach cancer, large bowel cancer, colonic cancer, rectal cancer, anal cancer, pancreatic cancer, and pancreas internal secretion tumor; urinary organ cancers and tumors such as penile cancer, renal pelvic/ureteral cancer, renal cell cancer, testicular tumor, prostatic cancer, bladder cancer, Wilms tumor, and urothelial cancer; gynecologic cancers and tumors such as vulvar cancer, cancer of the uterine cervix, corpus uteri cancer, endometrial cancer, uterine sarcoma, chorioma, vaginal cancer, breast cancer, ovary cancer, ovary germ cell tumor;

a soft part sarcoma of an infant and adult; tumors of bones such as osteosarcoma and Ewing tumor; cancers and tumors of the endocrine tissue such as adrenocortical cancer, thyroid cancer;

malignancy lymphoma and leukemia such as malignant lymphoma, non-Hodgkin's lymphoma, Hodgkin's disease, multiple myeloma, plasmacytic tumor, acute myelogenous leukemia, acute lymphatic leukemia, adult T cell leukemia lymphoma, chronic myelogenous leukemia, and chronic lymphatic leukemia; cancers and tumors of skin such as chronic myeloproliferative disorders, malignant melanoma, prickle cell cancer, basal cell cancer, and mycosis fungoides; and metastatic foci of tumors and cancers mentioned above. Of them, the medicinal drug of the present invention have an effect upon liver cancer, chronic myelogenous leukemia, acute myelogenous leukemia, lymphoma, and multiple myeloma.

The medical drug of the present invention has less side effects and excellent safety and is thus more excellent tumor therapeutic agent.


DETAILED DESCRIPTION OF THE INVENTION
The present invention will be explained more specifically by way of Reference Examples, Examples, Preparation Examples and Pharmacological Tests.
Reference Example 1
Production of 1-(t-butoxycarbonyl)-4-(4-hydroxyphenyl)-1,2,5,6-tetrahydropyridine
Step 1
Production of 1-(t-butoxycarbonyl)-4-[(4-methoxymethoxy)phenyl]-4-hydroxypiperidine
A solution of 1-bromo-4-methoxymethoxybenzene (5.43 g, 25.0 mmol) in tetrahydrofuran (THF) (100 mL) was stirred at −85° C., and a 2.46 M n-butyllithium hexane solution (10.2 mL, 25.0 mmol) was added dropwise to the stirred solution over 10 minutes. The resulting solution was stirred at the same temperature for 40 minutes. To the reaction solution was added dropwise for 10 minutes a solution of 1-(t-butoxycarbonyl)-4-piperidone (5.20 g, 26.0 mmol) in THF (30 mL). The temperature of the resulting solution was raised to 25° C. over 4 hours, and then the solution was stirred at that temperature for 2 hours. An aqueous solution of saturated ammonium chloride was then added to this solution. The reaction solution was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, after which the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=2:3, in ratio by volume; hereinafter the same), to thereby yield 7.63 g of the title compound.
Appearance: Colorless oil
1H NMR (CDCl3) δ 1.49 (9H, s), 1.73 (2H, d, J=12.0 Hz), 1.97 (2H, brs), 3.24 (2H, brs), 3.48 (3H, s), 4.00 (2H, brs), 5.17 (2H, s), 7.03 (2H, d, J=9.0 Hz), 7.39 (2H, d, J=9.0 Hz).
Step 2
Production of 1-(t-butoxycarbonyl)-4-(4-hydroxyphenyl)-1,2,5,6-tetrahydropyridine
To a solution of 1-(t-butoxycarbonyl)-4-[(4-methoxymethoxy)phenyl]-4-hydroxypiperidine (5.32 g, 15.8 mmol) in toluene (100 mL) was added p-toluenesulfonic acid monohydrate (0.56 g, 2.95 mmol), and the resulting solution was refluxed for 21 hours. The reaction solution was cooled to room temperature, and evaporated under reduced pressure. To this crude product were added ethanol (60 mL) and 2 M hydrochloric acid (40 mL, 80 mmol), and the resulting solution was stirred for 2 hours at 60° C. The reaction solution was again cooled to room temperature, and evaporated under reduced pressure. To the residue were added methanol (100 mL), triethylamine (9.0 mL, 64.6 mmol) and di-t-butyl dicarbonate (5.20 g, 23.8 mmol), and the resulting solution was stirred for 24 hours at room temperature. The solvent was evaporated under reduced pressure, after which to the residue was added 100 mL of ethyl acetate. Insoluble matter was removed by filtration, after which the filtrate was evaporated under reduced pressure. To the residue were added 1,4-dioxane (50 mL) and a 1 M aqueous solution of sodium hydroxide (50 mL, 50 mmol) and stirred for 14 hours at 60° C. To the resulting reaction solution was added at room temperature 2 M hydrochloric acid (25 mL, 50 mmol) to neutralize, and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated to thereby yield 4.10 g of the title compound.
Appearance: Brown amorphous
1H NMR (CDCl3) δ 1.49 (9H, s), 2.47 (2H, brs), 3.62 (2H, t, J=5.5 Hz), 4.05 (2H, brs), 5.91 (1H, brs), 6.81 (2H, d, J=9.0 Hz), 7.25 (2H, d, J=9.0 Hz).
Reference Example 2
Production of methyl 5-(4-benzylpiperazin-1-yl)-2-methoxymethoxybenzoate
To a solution of methyl 5-chloro-2-methoxymethoxybenzoate (1.45 g, 6.29 mmol) and 1-benzylpiperazine (1.66 g, 9.43 mmol) in toluene (50 mL) were added palladium acetate (28 mg, 0.126 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (157 mg, 0.252 mmol) and cesium carbonate (3.07 g, 9.43 mmol), and the resulting solution was refluxed for 3 hours. Water was added to the resulting solution, and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2), to thereby yield 400 mg of the title compound.
Appearance: Yellow oil
1H NMR (CDCl3) δ 2.59-2.62 (4H, m), 3.12-3.16 (4H, m), 3.51 (3H, s), 3.57 (2H, s), 3.88 (3H, s), 5.16 (2H, s), 7.01 (1H, dd, J=9.1 Hz, 3.1 Hz), 7.10 (1H, d, J=9.1 Hz), 7.28-7.35 (6H, m).
The following compounds were produced in the same manner as in Reference Example 2.







TABLE 1













 











Reference






Example






No.
R101
R102
R103
1H NMR (CDCl3) δ ppm





3
—CH2OCH3




—H
1.27 (3H, t, J = 7.0 Hz), 1.43- 1.48 (2H, m), 1.83 (2H, brd, J = 13.0 Hz), 1.90 (1H, m), 2.28 (2H, d, J = 7.0 Hz), 2.66 (2H, dt, J = 2.5 Hz, 12.0 Hz), 3.47 (3H, s), 3.50 (2H, brd, J = 12.0 Hz), 4.15 (2H, q, J = 7.0 Hz), 5.10 (2H, s), 6.89 (2H, d, J = 9.0 Hz), 6.95 (2H, d, J = 9.0 Hz).


 


4
—CH2OCH3




—H
1.27 (3H, t, J = 7.0 Hz), 1.57- 1.75 (2H, m), 1.82 (1H, m), 2.00 (1H, m), 2.68-2.75 (2H, m), 2.93 (1H, dd, J = 10.0 Hz, 12.0 Hz), 3.34 (1H, d, J = 12.0 Hz), 3.48 (3H, s), 3.56 (1H, brd, J = 10.0 Hz), 4.16 (2H, q, J = 7.0 Hz), 5.11 (2H, s), 6.91 (2H, d, J = 9.0 Hz), 6.96 (2H, d, J = 9.0 Hz).


 


5
—CH3




—H
1.27 (3H, t, J = 7.0 Hz), 1.91 (2H, dq, J = 3.0 Hz, 13.5 Hz), 2.02 (2H, dd, J = 13.5 Hz, 3.0 Hz), 2.38 (1H, m), 2.69 (2H, dt, J = 3.0 Hz, 12.0 Hz), 3.48 (2H, dt, J = 12.0 Hz, 3.0 Hz), 3.37 (3H, s), 4.16 (2H, q, J = 7.0 Hz), 6.83 (2H, d, J = 9.0 Hz), 6.91 (2H, d, J = 9.0 Hz).


 


6
—CH2OCH3




—CH3
1.27 (3H, t, J = 7.1 Hz), 1.82- 1.99 (4H, m), 2.22 (3H, s), 2.33- 2.42 (1H, m), 2.64-2.73 (2H, m), 3.50-3.52 (5H, m), 4.15 (2H, q, J = 7.1 Hz), 5.12 (2H, s), 6.70 (1H, dd, J = 8.9 Hz, 3.1 Hz), 6.78 (1H, d, J = 3.0 Hz), 6.95 (1H, d, J = 8.7 Hz).


 


7
—CH2OCH3




—OCH3
1.27 (3H, t, J = 7.1 Hz), 1.37- 1.47 (2H, m), 1.81-1.94 (3H, m), 2.29 (2H, d, J = 6.9 Hz), 2.64- 2.73 (2H, m), 3.51 (3H, s), 3.54 (2H, brs), 3.85 (3H, s), 4.15 (2H, q, J = 7.1 Hz), 5.13 (2H, s), 6.44 (1H, dd, J = 8.7 Hz, 2.6 Hz), 6.56 (1H, d, J = 2.6 Hz), 7.02 (1H, d, J = 8.7 Hz).


 


8
—CH2OCH3




—CH3
1.27 (3H, t, J = 7.1 Hz), 1.37- 1.49 (2H, m), 1.80-2.04 (3H, m), 2.22 (3H, s), 2.27 (2H, d, J = 6.9 Hz), 2.60-2.68 (2H, m), 3.48 (3H, s), 3.52 (2H, brs), 4.14 (2H, q, J = 7.1 Hz), 5.11 (2H, s), 6.69-6.79 (2H, m), 6.94 (1H, d, J = 8.7 Hz).
















TABLE 2













 









Reference




Example




No.
R104
1H NMR (CDCl3) δ ppm












9




1.48 (9H, s), 1.76-l.89 (4H, m), 2.78 (3H, brs), 2.81 (2H, brt, J = 12.0 Hz), 3.71 (2H, brd, J = 12.0 Hz), 4.15 (1H, brs), 6.96 (2H, d, J = 9.0 Hz), 6.98 (4H, s), 8.17 (2H, d, J =9.0 Hz).


 


10




1.49 (9H, s), 3.13 (4H, t, J = 5.0 Hz), 3.60 (4H, t, J = 5.0 Hz), 6.96-7.00 (6H, m), 8.18 (2H, d, J = 9.0 Hz).


 


11




1.79 (2H, m), 2.03 (2H, m), 2.96 (2H, m), 3.41 (3H, s), 3.51 (2H, m), 3.73 (1H, m), 4.74 (2H, s), 6.95-6.98 (6H, m), 8.17 (2H, d, J = 9.0 Hz).


 


12




1.28 (3H, t, J = 7.0 Hz), 1.90 (2H, dq, J = 4.0 Hz, 13.0 Hz), 2.05 (2H, dd, J = 13.0 Hz, 4.0 Hz), 2.45 (1H, m), 2.82 (2H, dt, J = 2.5 Hz, 12.0 Hz), 3.62 (2H, brd, J = 12.5 Hz), 4.17 (2H, q, J = 7.0 Hz), 6.95-6.98 (6H, m), 8.17 (2H, d, J = 9.0 Hz).


 


13




1.31 (3H, t, J = 7.0 Hz), 1.83 (2H, m), 2.05 (2H, m), 2.96 (1H, m), 3.07 (1H, m), 3.46 (1H, m), 3.53 (1H, m), 3.60 (1H, m), 4.16 (2H, s), 4.24 (2H, q, J = 7.0 Hz), 6.95-7.01 (6H, m), 8.17 (2H, d, J = 9.0 Hz).









Reference Example 14
Production of methyl 5-(4-benzylpiperazin-1-yl)-2-hydroxybenzoate
To a solution of 400 mg of methyl 5-(4-benzylpiperazin-1-yl)-2-methoxymethoxybenzoate (1.1 mmol) in 1,4-dioxane (20 mL) was added a solution of 4 N hydrogen chloride in 1,4-dioxane (4 mL, 16 mmol), and the resulting solution was stirred for 2 hours at 100° C. The resulting reaction solution was subjected to distillation under reduced pressure to obtain a residue. This residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1), to thereby yield 353 mg of the title compound.
Appearance: Pale yellow powder
1H NMR (CD3OD) δ 3.29-3.40 (8H, m), 3.94 (3H, s), 4.39 (2H, s), 6.91 (1H, d, J=8.9 Hz), 7.28 (1H, dd, J=8.9 Hz, 3.0 Hz), 7.42 (1H, d, J=3.0 Hz), 7.49-7.60 (5H, m).
The following compounds were produced in the same manner as in Reference Example 14.







TABLE 3













 











Reference






Example






No.
R105
R106
Form
1H NMR (solvent) δ ppm





15
—H




free
(DMSO-d6) 1.20 (3H, t, J = 7.0 Hz), 1.78 (2H, brs), 1.91 (2H, brs), 2.10 (1H, brs), 2.34 (2H, brs), 3.45 (2H, brs), 3.55 (2H, brs), 4.09 (2H, q, J = 7.0 Hz), 6.88 (2H, brs), 7.60 (2H, brs), 10.05 (1H, brs), 11.75 (1H, brs).


 


16
—H




free
(DMSO-d6) 1.20 (3H, t, J = 7.0 Hz), 1.64 (1H, brs), 1.93 (2H, brs), 2.08 (2H, brs), 3.30 (1H brs), 3.45 (2H, brs), 3.48 (2H, brs), 4.10 (2H, q, J = 7.0 Hz), 6.88 (2H, brs), 7.66 (2H, brs), 10.05 (1H, brs), 12.60 (1H, brs).


 


17
—CH3




hydro- chloride
(DMSO-d6) 1.22 (3H, t, J = 7.1 Hz), 2.03-2.13 (4H, m), 2.14 (3H, s), 2.75 (1H, brs), 3.38-3.57 (4H, m), 4.12 (2H, q, J = 7.1 Hz), 6.89 (1H, d, J = 8.6 Hz), 7.46-7.53 (2H, m), 9.99 (1H, brs).


 


18
—OCH3




free
(CDCl3) 1.27 (3H, t, J = 7.1 Hz), 1.98-2.18 (3H,.m), 2.41-2.44 (4H, m), 3.30 (2H, t, J = 12.0 Hz), 3.66 (2H, d, J = 11.9 Hz), 3.95 (3H, s), 4.15 (2H, q, J = 7.1 Hz), 6.26 (1H, brs), 6.96-7.03 (2H, m), 7.85 (1H, s).


 


19
—CH3




hydro- chloride
(DMSO-d6) 1.20 (3H, t, J = 7.1 Hz), 1.87 (4H, brs), 2.14 (4H, brs), 2.33 (2H, d, J = 6.4 Hz), 2.52 (2H, brs), 3.44 (2H, brs), 4.19 (2H, q, J = 7.1 Hz), 6.88 (1H, d, J = 8.6 Hz), 7.46-7.57 (2H, m), 9.98 (1H, brs), 12.04 (1H, brs).









Reference Example 20
Production of ethyl N-(4-hydroxyphenyl)isonipecotate
To a solution of ethyl N-(4-methoxyphenyl)-isonipecotate (2.63 g, 10 mmol) in dichloromethane (100 mL) was added a solution of 2 M boron tribromide in dichloromethane (20 mL, 40 mmol), and the resulting solution was stirred for 0.5 hours at room temperature. The resulting reaction solution was poured into ice water, then an aqueous solution of 1 M sodium hydroxide (110 mL) was added to the solution. After stirring, the resulting solution was separated. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to thereby yield 2.43 g of the title compound.
Appearance: Yellow oil
1H NMR (CDCl3) δ 1.27 (3H, t, J=7.0 Hz), 1.91 (2H, m), 2.02 (2H, brd, J=11.5 Hz), 2.38 (1H, m), 2.68 (2H, dt, J=2.0 Hz, 11.5 Hz), 3.46 (2H, dt, J=12.0 Hz, 3.0 Hz), 4.16 (2H, q, J=7.0 Hz), 4.45 (1H, brs), 6.75 (2H, d, J=9.0 Hz), 6.86 (2H, d, J=9.0 Hz).
The following compounds were produced in the same manner as in Reference Example 20.
Reference Example 21
4-(2-Fluoro-4-nitrophenoxy)phenol
1H NMR (DMSO-d6) δ 6.80-7.10 (5H, m), 8.04 (1H, ddd, J=1.4 Hz, 2.7 Hz, 9.2 Hz), 8.29 (1H, dd, J=2.7 Hz, 10.9 Hz), 9.59 (1H, s).
Reference Example 22
1-Benzyl-3-(4-hydroxyphenyl)imidazolidin-2-one
1H NMR (DMSO-d6) δ 3.18-3.40 (2H, m), 3.61-3.80 (2H, m), 4.35 (2H, s), 6.71 (2H, d, J=8.8 Hz), 7.15-7.48 (7H, m), 9.10 (1H, s).
Reference Example 23
Production of 2-(4-hydroxyphenylamino)-1-(4-piperonylpiperazin-1-yl)ethanone
To a solution of N-(4-hydroxyphenyl)glycine (11.38 g, 68.1 mmol) in N,N-dimethylformamide (DMF) (150 mL) were added under ice cooling 1-piperonylpiperazine (15.0 g, 68.1 mmol), 1-hydroxybenzotriazole monohydrate (10.43 g, 68.1 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (15.66 g, 81.7 mmol), and the resulting solution was stirred for 30 minutes under ice cooling and for 4.5 hours at room temperature. The reaction solution was concentrated under reduced pressure. To the residue was added a saturated sodium bicarbonate solution (400 mL), and extracted with ethyl acetate (400 mL). The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated, to leave the resulting product solidified in a powdered form. Ethyl acetate was added, and the resulting product was filtered off and washed with ethyl acetate, to thereby yield 18.58 g of the title compound.
Appearance: Brown powder
1H NMR (DMSO-d6) δ 2.30 (2H, brs), 2.36 (2H, brs), 3.40 (2H, s), 3.47 (4H, t, J=14.5 Hz), 4.03 (2H, d, J=7.0 Hz), 4.90 (1H, brs), 5.99 (2H, s), 6.49 (2H, d, J=8.9 Hz), 6.54 (2H, d, J=8.9 Hz), 6.75 (1H, dd, J=8.0 Hz, 1.1 Hz), 6.85 (1H, d, J=8.0 Hz), 6.87 (1H, s), 8.42 (1H, s).
The following compounds were produced in the same manner as in Reference Example 23.
Reference Example 24
6-Chloro-N-(3,4-dichlorophenyl)nicotinamide
1H NMR (CDCl3) δ 7.64 (1H, d, J=8.9 Hz), 7.72 (1H, dd, J=8.7 Hz, 2.3 Hz), 7.73 (1H, dd, J=8.3 Hz, 0.7 Hz), 8.12 (1H, d, J=2.3 Hz), 8.35 (1H, dd, J=8.3 Hz, 2.5 Hz), 8.95 (1H, dd, J=2.5 Hz, 0.7 Hz), 10.71 (1H, brs).
Reference Example 25
4-(4-Piperonylpiperazine-1-carbonyl)-1-(4-hydroxyphenyl)pyrrolidin-2-one
1H NMR (CDCl3) δ 2.43-2.45 (4H, m), 2.73-2.95 (2H, m), 3.45 (2H, s), 3.49-3.54 (4H, m), 3.65-3.72 (1H, m), 3.78-3.87 (1H, m), 4.17-4.23 (1H, m), 5.96 (2H, s), 6.71-6.80 (4H, m), 6.84-6.85 (1H, m), 7.29 (2H, d, J=8.9 Hz).







TABLE 4













 













Reference








Example








No.
Xa1
Xa2
R107
R108
Form
1H NMR (solvent) δ ppm





26
—NH—
—CH2—
—H
benzyl
free
(CDCl3) 2.46-2.48 (4H, m), 3.45 (2H, t, J = 5.0 Hz), 3.54 (2H, s), 3.68 (2H, t, J = 5.0 Hz), 3.82 (2H, s), 6.53 (2H, d, J = 8.7 Hz), 6.70 (2H, d, J = 8.7 Hz), 7.27- 7.34 (5H, m).


27
—CH2—
—CH2—
—H
benzyl
free
(CDCl3) 2.30-2.33 (2H, m), 2.41- 2.45 (2H, m), 2.55-2.60 (2H, m), 2.85- 2.91 (2H, m), 3.36-3.40 (2H, m), 3.52 (2H, s), 3.62-3.66 (2H, m), 5.10 (1H, brs), 6.74-6.77 (2H, m), 7.03 (2H, d, J = 8.6 Hz), 7.27-7.32 (5H, m).


28
—CH2—
—CH2—
—H
piperonyl
hydro- chloride
(DMSO-d6) 2.56-3.47 (10H, m), 4.01- 4.07 (1H, m), 4.18-4.48 (3H, m), 6.07 (2H, s), 6.65-6.68 (2H, m), 7.00-7.03 (4H, m), 7.21 (1H, s), 9.18 (1H, brs), 11.04 (1H, brs).


29
—O—
—CH2—
—H
piperonyl
free
(CDCl3) 2.31-2.50 (4H, m), 3.41 (2H, s), 3.52-3.72 (4H, m), 4.63 (2H, s), 5.94 (2H, s), 6.25 (1H, brs), 6.70 (2H, d, J = 9.1 Hz), 6.69-6.77 (1H, m), 6.73 (1H, s), 6.77 (2H, d, J = 9.1 Hz), 6.83 (1H, d, J = 0.9 Hz).


30
—O—
—CH2—
—H
benzyl
free
(CDCl3) 2.40-2.52 (4H, m), 3.51 (2H, s), 3.53-3.73 (4H, m), 4.63 (2H, s), 5.89 (1H, brs), 6.70 (2H, d, J = 9.2 Hz), 6.78 (2H, d, J = 9.2 Hz), 7.22-7.43 (5H, m).


31
—CH(OH)—
none
—H
benzyl
free
(CDCl3) 1.89-2.03 (1H, m), 2.21- 2.32 (1H, m), 2.32-2.57 (2H, m), 3.00- 3.18 (1H, m), 3.20-3.35 (1H, m), 3.40 (1H, d, J = 13.1 Hz), 3.46 (1H, d, J = 13.1 Hz), 3.60-3.83 (2H, m), 5.13 (1H, s), 6.71 (2H, d, J = 8.6 Hz), 7.09 (2H, d, J = 8.6 Hz), 7.18-7.35 (5H, m).


32
none
none
—H
3-pyridyl
free
(DMSO-d6) 3.18-3.35 (4H, m), 3.64 (4H, brs), 6.82 (2H, d, J = 8.4 Hz), 7.21- 7.37 (4H, m), 8.02-8.03 (1H, m), 8.32 (1H, d, J = 2.4 Hz), 9.90 (1H, brs).


33
—CH2—
—CO—
—H
—CO2C(CH3)3
free
(CDCl3) 1.44 (9H, s), 2.93-3.15 (4H, m), 3.32 (2H, t, J = 5.2 Hz), 3.50 (2H, t, J = 5.2 Hz), 3.97 (2H, s), 5.48 (1H, brs), 6.81 (2H, d, J = 8.6 Hz), 7.11 (2H, d, J = 8.6 Hz).


34
—NH—
—CH2—
—CH3
piperonyl
free
(CDCl3) 2.20 (3H, s), 2.41-2.46 (4H, m), 3.44 (4H, brs), 3.67 (2H, t, J = 4.8 Hz), 3.81 (2H, s), 4.34 (1H, brs), 4.52 (1H, brs), 5.95 (2H, s), 6.37 (1H, dd, J = 8.4 Hz, 2.6 Hz), 6.44 (1H, d, J = 2.8 Hz), 6.64 (1H, d, J = 8.4 Hz), 6.70-6.77 (2H, m), 6.85 (1H, s).









Reference Example 35
Production of ethyl(4-hydroxy-3-methylphenylamino)acetate
Potassium carbonate (5.04 g, 36.5 mmol) was added at room temperature to a solution of 4-amino-o-cresol (3.00 g, 24.4 mmol) and ethyl bromoacetate (2.70 mL, 24.4 mmol) in DMF (30 mL). The resulting solution was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), to thereby yield 5.10 g of the title compound.
Appearance: Yellow solid
1H NMR (CDCl3) δ 1.28 (3H, t, J=7.1 Hz), 2.19 (3H, s), 3.84 (2H, s), 3.95 (1H, brs), 4.22 (2H, q, J=7.1 Hz), 4.59 (1H, brs), 6.36 (1H, dd, J=8.4 Hz, 2.9 Hz), 6.44 (1H, d, J=2.9 Hz), 6.63 (1H, d, J=8.4 Hz).
The following compounds were produced in the same manner as in Reference Example 35.
Reference Example 36
Ethyl(3-hydroxyphenylamino)acetate
1H NMR (CDCl3) δ 1.30 (3H, t, J=7.1 Hz), 3.88 (2H, s), 4.25 (2H, q, J=7.1 Hz), 4.29 (1H, brs), 4.85 (1H, s), 6.08-6.10 (1H, m), 6.18-6.24 (2H, m), 7.01-7.07 (1H, m).
Reference Example 37
Benzyl(4-hydroxy-3-methoxyphenylamino)acetate
1H NMR (CDCl3) δ 3.81 (3H, s), 3.92 (2H, brs), 4.01 (1H, brs), 5.09 (1H, brs), 5.20 (2H, s), 6.11 (1H, dd, J==8.4 Hz, 2.6 Hz), 6.23 (1H, d, J=2.6 Hz), 6.76 (1H, d, J=58.4 Hz), 7.31-7.38 (5H, m).
Reference Example 38
t-Butyl[3-(4-benzyloxy-3-methylphenyl)-2-oxotetrahydropyrimidin-1-yl]acetate
1H NMR (CDCl3) δ 1.47 (9H, s), 2.04-2.21 (2H, m), 2.25 (3H, s), 3.45 (2H, t, J=5.9 Hz), 3.67 (2H, t, J=5.9 Hz), 4.04 (2H, s), 5.06 (2H, s), 6.82 (1H, d, J=8.6 Hz), 7.01 (1H, dd, J=2.6 Hz, 8.6 Hz), 7.06-7.12 (1H, m), 7.26-7.48 (5H, m).







TABLE 5













 













Reference








Example








No.
R109
R110
R111
R112
R113
1H NMR (CDCl3) δ ppm or MS





39
—CH3
—CH3
—H
—H
—H
1H NMR 1.30 (3H, t, J = 7.1 Hz), 2.14 (3H, s), 2.20 (3H, s), 3.87 (2H, s), 4.24 (2H, q, J = 7.1 Hz), 4.42 (1H, brs), 6.29 (1H, d, J = 8.6 Hz), 6.58 (1H, d, J = 8.6 Hz).


40
—F
—H
—F
—H
—H
1H NMR 1.30 (3H, t, J = 7.1 Hz), 3.85 (2H, s), 4.25 (2H, q, J = 7.1 Hz), 4.77 (1H, s), 6.37 (1H, dd, J = 7.9 Hz, 11.8 Hz), 6.73 (1H, dd, J = 7.9 Hz, 11.6 Hz).


41
—CH3
—H
—CH3
—H
—H
1H NMR 1.30 (3H, t, J = 7.1 Hz), 2.15 (3H, s), 2.19 (3H, s), 3.84 (1H, brs), 3.89 (2H, s), 4.17 (1H, s), 4.25 (2H, q, J = 7.1 Hz), 6.28 (1H, s), 6.57 (1H, s).


42
—H
—CH3
—CH3
—H
—H
MS 223 (M+)


43
—OCH3
—H
—H
—H
—H
1H NMR 1.29 (3H, t, J = 7.1 Hz), 3.82 (3H, s), 3.85 (2H, s), 4.23 (2H, q, J = 7.1 Hz), 5.26 (1H, brs), 6.11 (1H, dd, J = 8.4 Hz, 2.6 Hz), 6.25 (1H, d, J = 2.6 Hz), 6.76 (1H, d, J = 8.4 Hz).


44
—F
—H
—H
—H
—H
1H NMR 1.30 (3H, t, J = 7.1 Hz), 3.83 (2H, s), 4.08 (1H, brs), 4.24 (2H, q, J = 7.1 Hz), 4.62 (1H, d, J = 3.3 Hz), 6.30-6.41 (2H, m), 6.85 (1H, t, J = 8.9 Hz).


45
—H
—H
—H
—CH3
—CH3
1H NMR 1.20 (3H, t, J = 7.1 Hz), 1.48 (6H, s), 4.15 (2H, q, J = 7.1 Hz), 6.60-6.69 (4H, m).


46
—CH3
—H
—H
—CH3
—H
1H NMR 1.24 (3H, t, J = 7.3 Hz), 1.44 (3H, d, J = 6.9 Hz), 2.18 (3H, s), 3.80 (1H, brs), 4.03 (1H, q, J = 6.9 Hz), 4.17 (2H, q, J = 7.3 Hz), 4.25 (1H, brs), 6.37 (1H, dd, J = 8.4 Hz, 3.0 Hz), 6.45 (1H, d, J = 2.8 Hz), 6.62 (1H, d, J = 8.4 Hz).


47
—H
—H
—H
—CH3
—H
1H NMR 1.24 (3H, t, J = 7.1 Hz), 1.44 (3H, d, J = 6.7 Hz), 3.88 (1H, brs), 4.04 (1H, q, J = 6.9 Hz), 4.17 (2H, q, J = 7.1 Hz), 4.59 (1H, brs), 6.54 (2H, d, J = 8.9 Hz), 6.68 (2H, d, J = 8.9 Hz).


48
—CF3
—H
—H
—H
—H
MS 263 (M+)
















TABLE 6













 













Reference








Example








No.
R114
R115
R116
R117
R118
1H NMR (solvent) δ ppm or MS





49




—H
—H
—H
—H
1H NMR (DMSO-d6) 1.18 (3H, t, J = 7.1 Hz), 3.89 (2H, d, J = 6.2 Hz), 4.11 (2H, q, J = 7.1 Hz), 6.14 (1H, t, J = 6.2 Hz), 6.62 (2H, d, J = 8.8 Hz), 6.90 (1H, t, J = 9.0 Hz), 6.97 (2H, d, J = 8.8 Hz), 8.03 (1H, dd, J = 2.6 Hz, 9.0 Hz), 8.24 (1H, dd, J = 2.6 Hz, 10.9 Hz).


 


50




—F
—H
—F
—CH3
1H NMR (CDCl3) 1.29 (3H, t, J = 7.1 Hz), 3.07 (3H, s), 4.03 (2H, s), 4.22 (2H, q, J = 7.1 Hz), 6.22- 6.35 (2H, m), 7.15 (1H, d, J = 9.0 Hz), 8.49 (1H, dd, J = 2.8 Hz, 9.0 Hz), 9.01 (1H, d, J = 2.8 Hz).


 


51




—F
—F
—H
—CH3
1H NMR (CDCl3) 1.28 (3H, t, J = 7.1 Hz), 3.05 (3H, s), 4.06 (2H, s), 4.20 (2H, q, J = 7.1 Hz), 6.72 (1H, td, J = 2.2 Hz, 9.0 Hz), 6.90 (1H, td, J = 1.8 Hz, 9.4 Hz), 7.11 (1H, d, J = 9.0 Hz), 8.50 (1H, dd, J = 2.7 Hz, 9.0 Hz), 9.02 (1H, d, J = 2.7 Hz).


 


52




—H
—H
—H
—SO2CH3
1H NMR (CDCl3) 1.31 (3H, t, J = 7.1 Hz), 3.17 (3H, s), 4.25 (2H, q, J = 7.1 Hz), 4.47 (2H, s), 7.09 (1H, d, J = 8.9 Hz), 7.20 (2H, d, J = 8.7 Hz), 7.60 (2H, d, J = 8.9 Hz), 8.51 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.03 (1H, d, J = 2.8 Hz).


 


53




—CH3
—H
—H
—SO2CH3
1H NMR (CDCl3) 1.31 (3H, t, J = 7.1 Hz), 2.16 (3H, s), 3.17 (3H, s), 4.25 (2H, q, J = 7.1 Hz), 4.46 (2H, s), 7.07 (1H, dd, J = 9.1 Hz, 0.7 Hz), 7.08 (1H, d, J = 7.3 Hz), 7.40 (1H, d, J = 2.6 Hz), 7.44 (1H, dd, J = 7.3 Hz, 2.6 Hz), 8.50 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.01 (1H, dd, J = 2.8 Hz, 0.7 Hz).


 


54
—H
—CF3
—H
—H
—C2H5
MS 291 (M+)
















TABLE 7













 











Reference






Example






No.
R119
R120
R121
1H NMR (CDCl3) δ ppm





55
4-CF3Ph-
—H
—H
1.30 (3H, t, J = 7.1 Hz), 3.89 (2H, d, J = 4.6 Hz), 3.95 (2H, s), 4.20 (1H, brs), 4.25 (2H, q, J = 7.1 Hz), 6.62 (2H, d, J = 8.9 Hz), 6.77 (1H, d, J = 8.4 Hz), 6.97 (2H, d, J = 8.9 Hz), 7.27 (2H, d, J = 7.9 Hz), 7.39 (1H, dd, J = 8.4 Hz, 2.5 Hz), 7.54 (2H, d, J = 7.9 Hz), 8.03 (1H, d, J = 2.5 Hz).


56
4-CF3PhO—
—H
—SO2CH3
1.30 (3H, t, J = 7.1 Hz), 3.15 (3H, s), 4.23 (2H, q, J = 7.1 Hz), 4.45 (2H, s), 5.06 (2H,s), 6.99- 7.04 (3H, m), 7.16 (2H, d, J = 8.9 Hz), 7.54 (2H, d, J = 8.9 Hz), 7.56 (2H, d, J = 9.2 Hz), 7.79-7.83 (1H, m), 8.23 (1H, d, J = 2.0 Hz).


57
4-CF3PhO—
—CH3
—SO2CH3
1.30 (3H, t, J = 7.1 Hz), 2.19 (3H, s), 3.16 (3H, s), 4.24 (2H, q, J = 7.1 Hz), 4.44 (2H, s), 5.05 (2H, s), 6.96-7.07 (4H, m), 7.36 (1H, dd, J = 8.7 Hz, 2.6 Hz), 7.42 (1H, d, J = 2.3 Hz), 7.56 (2H, d, J = 8.9 Hz), 7.80 (1H, dd, J = 8.6 Hz, 2.3 Hz), 8.20 (1H, d, J = 2.3 Hz).





(Ph means a benzene ring having 1 to 4 free valences. Hereinafter Ph indicates the same meaning.)






Reference Example 58
t-Butyl(3-cyano-4-hydroxyphenylamino)acetate
MS 248 (M+)
Reference Example 59
Production of 2-[4-(2-fluoro-4-nitrophenoxy)phenoxy]-1-(4-piperonylpiperazin-1-yl)ethanone
Potassium carbonate (0.350 g, 2.53 mmol) was added to a solution of 4-(2-fluoro-4-nitrophenoxy)phenol (0.420 g, 1.69 mmol) and 1-chloroacetyl-4-piperonylpiperazine (0.500 g, 1.70 mmol) in DMF (8 mL). The resulting reaction mixture was stirred for 40 minutes at 100° C. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated, to thereby yield 0.860 of the title compound.
Appearance: Brown oil
1H NMR (CDCl3) δ 2.50-2.60 (4H, m), 3.43 (2H, s), 3.50-3.70 (4H, m), 4.71 (2H, s), 5.95 (2H, s), 6.65-6.75 (2H, m), 6.80-7.05 (6H, m), 7.94 (1H, dd, J=2.3 Hz, 9.1 Hz), 8.06 (1H, dd, J=2.3 Hz, 10.4 Hz).
The following compound was produced in the same manner as in Reference Example 59.
Reference Example 60
2-[4-(2-fluoro-4-nitrophenoxy)phenylamino]-1-(4-piperonylpiperazin-1-yl)ethanone
1H NMR (DMSO-d6) δ 2.25-2.40 (4H, m), 3.43 (2H, s), 3.45-3.50 (4H, m), 3.90 (2H, d, J=5.1 Hz), 5.75 (1H, t, J=5.1 Hz), 5.99 (2H, s), 6.70-6.75 (3H, m), 6.80-7.00 (5H, m), 8.05 (1H, ddd, J=1.4 Hz, 2.7 Hz, 10.5 Hz), 8.27 (1H, dd, J=2.7 Hz, 11.0 Hz).
Reference Example 61
Production of methyl 3-(4-benzyloxyphenylamino)-propionate
Under nitrogen, 4-benzyloxyaniline (13.0 g, 65 mmol) was dissolved by heating at 70° C., and a boron trifluoride-diethyl ether complex (0.82 mL, 6.5 mmol) was added dropwise at the same temperature to the dissolved solution. Methyl acrylate (5.85 mL, 65 mmol) was then slowly added dropwise to the resulting solution. This solution was stirred for 10 hours at 70° C. After cooling with ice, ethyl acetate was added to the reaction mixture and washed with aqueous 1 N sodium hydroxide and brine. The organic layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to thereby yield 17.5 g of the title compound.
Appearance: Brown powder
1H NMR (CDCl3) δ 2.60 (2H, t, J=6.4 Hz), 3.39 (2H, t, J=6.4 Hz), 3.69 (3H, s), 3.77 (1H, brs), 4.98 (2H, s), 6.58 (2H, d, J=8.9 Hz), 6.85 (2H, d, J=8.9 Hz), 7.30-7.44 (5H, m).
Reference Example 62
Production of ethyl 3-(4-Methoxyphenylamino)propionate
3-(4-hydroxyphenylamino)propionic acid (4.00 g, 20.5 mmol) was added to 48% hydrobromic acid (50 mL), and the resulting solution was stirred for 2.5 hours at 100° C. After concentration under reduced pressure, ethanol (10 mL) was added to the residue, and concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the residue, and extracted with dichloromethane. The dichloromethane layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby yield 1.27 g of the title compound.
Appearance: Yellow oil
1H NMR (CDCl3) δ 1.27 (3H, t, J=7.2 Hz), 2.59 (2H, t, J=6.4 Hz), 3.38 (2H, t, J=6.4 Hz), 4.15 (2H, q, J=7.2 Hz), 6.55 (2H, d, J=8.8 Hz), 6.70 (2H, d, J=8.8 Hz).
Reference Example 63
Production of ethyl[(3-fluoro-4-hydroxyphenyl)methyl-amino]acetate
Ethyl(3-fluoro-4-hydroxyphenylamino)acetate (1.06 g, 5.1 mmol) was dissolved in methanol (150 mL) and the resulting solution was cooled with ice. To the resulting solution were added aqueous 37% formaldehyde (1.5 mL), sodium triacetoxyborohydride (1 g, 16 mmol) and acetic acid (0.9 mL, 15 mmol), and then stirred at room temperature under a nitrogen atmosphere for 14 hours. The solvent was evaporated under reduced pressure. Water was added to the residue, and the resulting solution was neutralized with a saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2), to thereby yield 0.93 g of the title compound.
Appearance: Light brown oil
1H NMR (CDCl3) δ 1.24 (3H, t, J=7.1 Hz), 3.00 (3H, s), 3.98 (2H, s), 4.17 (2H, q, J=7.1 Hz), 4.68 (1H, brs), 6.31-6.52 (2H, m), 6.87 (1H, t, J=8.9 Hz).
The following compounds were produced in the same manner as in Reference Example 63.
Reference Example 64
Ethyl(methyl{4-[5-(4-trifluoromethylbenzyl)pyridin-2-yloxy]phenyl}amino)acetate
1H NMR (CDCl3) δ 1.25 (3H, t, J=7.1 Hz), 3.07 (3H, s), 3.95 (2H, s), 4.04 (2H, s), 4.18 (2H, q, J=7.1 Hz), 6.69 (2H, d, J=−9.1 Hz), 6.75 (1H, d, J=8.5 Hz), 7.00 (2H, d, J=9.1 Hz), 7.27 (2H, d, J=8.1 Hz), 7.39 (1H, dd, J=8.5 Hz, 2.5 Hz), 7.54 (2H, d, J=8.1 Hz) 8.04 (1H, d, J=2.5 Hz).
Reference Example 65
Ethyl[(4-hydroxy-2-trifluoromethylphenyl)methylamino]-acetate MS 277 (M+)







TABLE 8













 













Reference








Example








No.
R122
R123
R124
R125
M
1H NMR (CDCl3) δ ppm





66
—H
—H
—CH3
—CH3
1
3.00 (3H, s), 3.71 (3H, s), 4.01 (2H, s), 4.55 (1H, brs), 6.62 (2H, d, J = 9.2 Hz), 6.75 (2H, d, J = 9.2 Hz).


67
Benzyl
—H
—CH3
—CH3
2
2.51-2.57 (2H, m), 2.86 (3H, s), 3.56-3.62 (2H, m) 3 66 (3H, s), 5.00 (2H, s), 6.72 (2H, d, J = 9.1 Hz), 6.91 (2H, d, J = 9.1 Hz), 7.30- 7.45 (5H, m).


68
—H
—F
—C2H5
—C2H5
1
1.18 (3H, t, J = 7 1 Hz), 1.26 (3H, t, J = 7.1 Hz), 3.38 (2H, q, J = 7.1 Hz) 3.94 (2H, s), 4.19 (2H, q, J = 7.1 Hz), 4.61 (1H, brs), 630-6.35 (1H, m), 6.43 (1H, dd, J = 13.7 Hz, 3.0 Hz), 6.86 (1H, t, J = 8.9 Hz).


69
—H
—OCH3
—C2H5
—C2H5
1
1.17 (3H, t, J = 7.1 Hz), 1.25 (3H, t, J = 7.1 Hz), 3.39 (2H, q, J = 7.1 Hz), 3.85 (3H, s), 3 .95 (2H, s) 4.18 (2H, q, J = 7.1 Hz), 5.30 (1H, brs), 6.21 ( 1H, dd, J = 8.6 Hz, 2.8 Hz), 6.33 (1H, d, J = 2.8 Hz), 6.79 (1H, d, J = 8.7 Hz).


 


70




—CH3
—C2H5
—C2H5
1
1.23 (3H, t, J = 7.1 Hz), 1.28 (3H, t, J = 7.1 Hz), 2.08 (3H, s), 3.47 (2H, q, J = 7.1 Hz), 4.01 (2H, s), 4.22 (2H, q, J = 7.1 Hz) 6.40- 6.59 (2H, m), 6.81-7.00 (2H, m), 8.43 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.06 (1H, d, J = 2.8 Hz).


 


71




—CH3
—CH3
—C2H5
1
1.27 (3H, t, J = 7.1 Hz), 2.10 (3H, s), 3.08 (3H, s), 4.06 (2H, s), 4.21 (2H, q, J = 7.1 Hz), 6.50- 6.62 (2H, m), 6.85-6.99 (2H, m), 8.43 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.05 (1H, d, J = 2.8 Hz).


 


72




—OCH3
—CH3
—C2H5
1
1.27 (3H, t, J = 7.1 Hz), 3.11 (3H, s), 3.74 (3H, s), 4.07 (2H, s), 4.21 (2H, q, J = 7.1 Hz), 6.27 (1H, dd, J = 8.7 Hz, 2.8 Hz), 6.34 (1H, d, J = 2.8 Hz), 6.95-7.01 (2H, m), 8.42 (1H, dd, J = 9.2 Hz, 3.0 Hz), 9.03 (1H, d, J = 2.8 Hz).





(M means the number of the methylene groups. Hereinafter M indicates the same meaning.)













TABLE 9













 










Reference





Example





No.
R126
R127
1H NMR (CDCl3) δ ppm





73
—H
—CH3
2.41 (4H, brs), 2.88 (3H, s), 3.42 (2H, s), 3.50 (2H, brs), 3.60 (2H, brs), 3.94 (2H, s), 5.92 (2H, s), 6.55-6.69 (4H, m), 6.72 (2H, s), 6.82 (1H, s), 7.47 (1H, brs).


74
—H
—C2H5
1.05 (3H, t, J = 7.1 Hz), 2.44 (4H, brs), 3.25 (2H, q, J = 7.1 Hz), 3.46 (2H, s), 3.60 (4H, brs), 3.91 (2H, s), 5.94 (2H, s), 6.63 (4H, s), 6.72-6.74 (2H, m), 6.82 (1H, s), 7.43 (1H, brs).


 


75




—CH3
2.44 (4H, brs), 3.06 (3H, s), 3.44 (2H, s), 3.49 (2H, brs), 3.63 (2H, brs), 4.11 (2H, s), 5.94 (2H, s), 6.69-6.77 (4H, m), 6.85 (1H, s), 6.92-7.02 (3H, m), 8.41 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.04 (1H, d, J = 3.0 Hz).


 


76




—C2H5
1.20 (3H, t, J = 7.1 Hz), 2.42-2.46 (4H, m), 3.44- 3.51 (6H, m), 3.64 (2H, q, J = 7.1 Hz), 4.06 (2H, s), 5.95 (2H, s), 6.67 (2H, d, J = 9.2 Hz), 6.74 (2H, brs), 6.85 (1H, brs), 6.94 (1H, d, J = 9.1 Hz), 6.99 (2H, d, J = 9.1 Hz), 8.42 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.05 (1H, d, J = 2.8 Hz).









Reference Example 77
Production of 1-(4-piperonylpiperazin-1-yl)-2-[cyclopropyl(4-hydroxyphenyl)amino]ethanone
To a solution of 1-(4-piperonylpiperazin-1-yl)-2-(4-hydroxyphenylamino)ethanone (1.00 g, 2.7 mmol) in methanol (10 mL) were added acetic acid (1.55 mL, 27 mmol), molecular sieves 3A1/16 (1.00 g), [(1-ethoxycyclopropyl)oxy]trimethylsilane (0.653 mL, 3.2 mmol) and sodium cyanoborohydride (770 mg, 12 mmol). The resulting solution was stirred for 16 hours at 60° C. This reaction solution was filtered and concentrated, and to the residue were added ethyl acetate and water. The aqueous layer was adjusted to pH 10 using aqueous 6 N sodium hydroxide. This layer was stirred for some time, and once insoluble matter had dissolved, the ethyl acetate layer was removed, and washed with aqueous 2 N sodium hydroxide and a saturated sodium bicarbonate solution, then dried over anhydrous magnesium sulfate. The solvent was evaporated, to thereby yield 770 mg of the title compound.
Appearance: White powder
1H NMR (CDCl3) δ 0.54-0.59 (2H, m), 0.72-0.79 (2H, m), 2.39-2.45 (4H, m), 2.70-2.77 (1H, m), 3.44 (2H, s), 3.48-3.51 (2H, m), 3.57-3.60 (2H, m), 4.12 (2H, s), 5.95 (2H, s), 6.62-6.67 (2H, m), 6.74-6.85 (5H, m).
The following compound was produced in the same manner as in Reference Example 77.
Reference Example 78
Ethyl{cyclopropyl[3-methyl-4-(5-nitropyridin-2-yloxy)phenyl]amino}acetate
1H NMR (CDCl3) δ 0.66-0.72 (2H, m), 0.83-0.89 (2H, m), 1.26 (3H, t, J=7.3 Hz), 2.10 (3H, s), 2.71-2.79 (1H, m), 4.08-4.22 (4H, m), 6.77-6.82 (2H, m), 6.91-6.95 (2H, m), 8.40-8.45 (1H, m), 9.05 (1H, d, J=2.8 Hz).
Reference Example 79
Production of ethyl[(3-hydroxyphenyl)methylamino]-acetate
Potassium bicarbonate (1.42 mL, 14.19 mmol) was added to a solution of ethyl(3-hydroxyphenylamino)acetate (2.77 g, 14.19 mmol) in DMF (15 mL). To the resulting solution was further added methyl iodide (1.77 mL, 28.38 mmol), and then stirred at room temperature for 18 hours. To the resulting reaction solution was added brine (150 mL), and the obtained mixture was extracted with ethyl acetate (150 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, after which solvent was evaporated, to thereby yield 2.48 g of the title compound.
Appearance: Pale yellow oil
1H NMR (CDCl3) δ 1.24 (3H, t, J=7.1 Hz), 3.04 (3H, s), 4.03 (2H, s), 4.18 (2H, q, J=7.1 Hz), 5.17 (1H, brs), 6.17-6.27 (3H, m), 7.04-7.10 (1H, m).
The following compounds were produced in the same manner as in Reference Example 79.







TABLE 10













 












Reference







Example







No.
R128
R129
R130
R131
1H NMR (CDCl3) δ ppm or MS





80
—H
—H
—H




1H NMR 1.22 (3H, t, J = 7.1 Hz), 1.43 (3H, d, J = 7.1 Hz), 2.83 (3H, s), 4.16 (2H, q, J = 7.1 Hz), 4.33 (1H, q, J = 7.1 Hz), 4.84 (1H, brs), 6.75 (4H, s).


 


81
—CH3
—H
—H




1H NMR 1.23 (3H, t, J = 7.3 Hz), 1.42 (3H, d, J = 7.1 Hz), 2.22 (3H, s), 2.82 (3H, s), 4.08-4.21 (2H, m), 4.30 (1H, s), 4.33 (1H, q, J = 7.1 Hz), 6.58 (1H, dd, J = 8.6 Hz, 3.0 Hz), 6.65 (1H, d, J = 2.8 Hz), 6.68 (1H, d, J = 8.6 Hz).


 


82
—OCH3
—H
—H




1H NMR 1.17 (3H, t, J = 7.1 Hz), 3.39 (2H, q, J = 7.1 Hz), 3.75 (3H, s), 4.00 (2H, brs), 5.11 (1H, brs), 5.15 (2H, s), 6.21 (1H, dd, J = 8.6 Hz, 2.8 Hz), 6.27 (1H, d, J = 2.8 Hz), 6.77 (1H, d, J = 8.6 Hz), 7.27-7.37 (5H, m).


 


83
—F
—H
—F




1H NMR 1.24 (3H, t, J = 7.1 Hz), 2.92 (3H, s), 3.93 (2H, s), 4.15 (2H, q, J = 7.1 Hz), 4.96 (1H, d, J = 2.8 Hz), 6.70 (1H, d, J = 8.2 Hz, 12.9 Hz), 6.77 (1H, d, J = 8.1 Hz, 12.2 Hz).


 


84
—CH3
—H
—CH3




1H NMR 0.99 (3H, t, J = 7.1 Hz), 1.21 (3H, t, J = 7.1 Hz), 2.18 (3H, s), 2.24 (3H, s), 3.10 (2H, q, J = 7.1 Hz), 3.68 (2H, s), 4.11 (2H, q, J = 7.1 Hz), 4.47 (1H, s), 6.59 (1H, s), 6.94 (1H, s).


 


85
—H
—H
—H




1H NMR 1.26 (3H, t, J = 7.3 Hz), 1.33 (6H, s), 2.80 (3H, s), 4.18 (2H, q, J = 7.3 Hz), 5.15 (1H, brs), 6.71 (2H, d, J = 8.9 Hz), 7.00 (2H, d, J = 8.9 Hz).


 


86
—H
—CH3
—CH3




MS 237 (M+)


 


87
—CH3
—H
—CH3




1H NMR 1.24 (3H, t, J = 7.1 Hz), 2.19 (3H, s), 2.24 (3H, s), 2.79 (3H, s), 3.64 (2H, s), 4.15 (2H, q, J = 7.1 Hz), 4.45 (1H, brs), 6.59 (1H, s), 6.89 (1H, s).


 


88
—CF3
—H
—H




MS 277 (M+)


 


89
—CN
—H
—H




MS 262 (M+)
















TABLE 11













 














Reference









Example









No.
R132
R133
R134
R135
R136
M
1H NNMR (CDCl3) δ ppm





90
—H
—H
—H
—C2H5
—C2H5
1
1.24 (3H, t, J = 7.1 Hz), 1.28 (3H, t, J = 7.0 Hz), 3.48 (2H, q, J = 7.1 Hz), 4.02 (2H, s), 4.21 (2H, q, J = 7.0 Hz), 6.67 (2H, d, J = 8.9 Hz), 6.95 (1H, d, J = 9.1 Hz), 7.00 (2H, d, J = 8.9 Hz), 8.42 (1H, dd, J = 2.8 Hz, 9.1 Hz), 9.06 (1H, d, J = 2.8 Hz).


91
—H
—H
—H
—CH3
—C2H5
1
1.27 (3H, t, J = 7.2 Hz), 3.10 (3H, s), 4.07 (2H, s), 4.20 (2H, q, J = 7.2 Hz), 6.71 (2H, d, J = 9.2 Hz), 6.95 (1H, d, J = 9.1 Hz), 7.02 (2H, d, J = 9.2 Hz), 8.43 (1H, dd, J = 2.8 Hz, 9.1 Hz), 9.05 (1H, d, J = 2.8 Hz).


92
—F
—H
—H
allyl
—C2H5
1
1.29 (3H, t, J = 7.1 Hz), 4.02 (4H, brs), 4.23 (2H, q, J = 7.1 Hz), 5.21-5.30 (2H, m), 5.84-5.94 (1H, m), 6.40-6.52 (2H, m), 7.01-7.08 (2H, m), 8.47 (1H, dd, J = 8.9 Hz, 2.8 Hz), 9.03 (1H, d, J = 2.6 Hz).


93
—F
—H
—F
—C2H5
—C2H5
1
1.22 (3H, t, J = 7.1 Hz), 1.27 (3H, t, J = 7.1 Hz), 3.37 (2H, q, J = 7.1 Hz), 4.02 (2H, s), 4.20 (2H, q, J = 7.1 Hz), 6.77 (1H, dd, J = 8.1 Hz, 12.3 Hz), 6.92 (1H, dd, J = 7.3 Hz, 12.7 Hz), 7.09 (1H, d, J = 9.0 Hz), 8.49 (1H, dd, J = 2.8 Hz, 9.0 Hz), 9.02 (1H, d, J = 2.8 Hz).


94
—F
—F
—H
—CH3
—C(CH3)3
0
1.45 (9H, s), 3.26 (3H, s), 6.90-7.11 (2H, m), 7.16 (1H, d, J = 9.0 Hz), 8.53 (1H, dd, J = 2.8 Hz, 9.0 Hz), 9.01 (1H, d, J = 2.8 Hz).
















TABLE 12













 













Reference








Example








No.
R137
R138
R139
Xa3
Xa4
1H NMR (CDCl3) δ ppm





95




—H
piperonyl
none
—CH2—
2.44 (8H, brs), 2.96 (2H, s), 3.30 (3H, s), 3.38 (2H, s), 5.92 (2H, s), 6.72 (2H, brs), 6.82 (1H, s), 7.09 (1H, d, J = 9.1 Hz), 7.20 (2H, d, J = 8.9 Hz), 7.29 (2H, d, J = 8.9 Hz), 8.51 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.04 (1H, d, J = 2.8 Hz).


 


96




—H
benzyl
none
none
1.55-1.80 (3H, m), 1.81- 2.15 (3H, m), 2.23 (4H, t, J = 5.0 Hz), 3.16 (3H, s), 3.20 (4H, t, J = 5.0 Hz), 3.42 (2H, s), 3.55-3.69 (1H, m), 3.85-4.00 (1H, m), 5.36 (1H, t, J = 3.2 Hz), 6.99 (4H, s), 7.16-7.36 (5H, m).


 


97
—H
—CH3
piperonyl
—CH2—
none
2.18 (3H, s), 2.38-2.42 (4H,








m), 2.89 (3H, s), 3.41 (2H, s),








3.50 (2H, brs), 3.61 (2H, brs),








3.95 (2H, brs), 5.93 (2H, s),








6.44-6.57 (3H, m), 6.73-








6.76 (2H, m), 6.83 (1H, s).
















TABLE 13













 









Reference




Example




No.
R140
1H NMR (CDCl3) δ ppm





98
—NO2
1.07 (3H, t, J = 7.1 Hz), 2.15 (3H, s), 3.38 (3H, s), 4.19 (2H, q,




J = 7.1 Hz), 7.06-7.20 (4H, m), 8.51 (1H, dd, J = 9.1 Hz, 2.8




Hz), 8.97 (1H, d, J = 2.8 Hz).


99
4-CF3PhOCH2—
1.07 (3H, t, J = 7.1 Hz), 2.18 (3H, s), 3.36 (3H, s), 4.08 (2H, q,




J = 7.1 Hz), 5.04 (2H, s), 6.97 (1H, d, J = 8.6 Hz), 7.01-




7.13 (4H, m), 7.16 (1H, d, J = 2.3 Hz), 7.57 (2H, d, J = 8.6




Hz), 7.80 (1H, dd, J = 8.6 Hz, 2.3 Hz), 8.17 (1H, d, J = 2.3




Hz).









Reference Example 100
Production of ethyl[acetyl(3-fluoro-4-hydroxyphenyl)amino]acetate
Ethyl(3-fluoro-4-hydroxyphenylamino)acetate (0.84 g, 4 mmol) was dissolved in N,N-dimethylacetamide (4 mL). To the resulting solution was added acetyl chloride (0.6 mL, 10 mmol), and the resulting solution was stirred at room temperature for 1 hour. Water (1 mL), methanol (10 mL) and saturated sodium carbonate (10 mL) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the solution. 10% hydrochloric acid was employed to turn the solution acidic, and then the solution was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane 2:1), to thereby yield 0.84 g of the title compound.
Appearance: Colorless powder
1H NMR (CDCl3) δ 1.28 (3H, t, J=7.3 Hz), 1.94 (3H, s), 4.20 (2H, q, J=7.3 Hz), 4.32 (2H, s), 6.02 (1H, brs), 6.99-7.07 (2H, m), 7.13-7.18 (1H, m).
The following compounds were produced in the same manner as in Reference Example 100.







TABLE 14













 











Reference






Example






No.
R141
R142
M
1H NMR (CDCl3) δ ppm





101
—H
—CH3
1
1.26 (3H, t, J = 7.1 Hz), 1.92 (3H, s),






2.24 (3H, s), 4.19 (2H, q, J = 7.1 Hz),






4.32 (2H, s), 5.38 (1H, brs), 6.78 (1H, d,






J = 8.4 Hz), 7.04 (1H, dd, J = 8.4 Hz,






2.5 Hz), 7.10 (1H, d, J = 2.5 Hz).


102
—H
—H
2
1.21 (3H, t, J = 7.2 Hz), 1.83 (3H, s),






2.56 (2H, t, J = 7.4 Hz), 3.97 (2H, t, J =






7.4 Hz), 4.06 (2H, q, J = 7.2 Hz),






6.05 (1H, brs), 6.87 (2H, d, J = 8.7 Hz),






7.03 (2H, d, J = 8.7 Hz).


103
benzyl
—H
1
1.26 (3H, t, J = 7.1 Hz), 1.91 (3H, s),






4.18 (2H, q, J = 7.1 Hz), 4.33 (2H, s),






5.07 (2H, s), 6.98 (2H, d, J = 8.9 Hz),






7.26 (2H, d, J = 8.9 Hz), 7.35-7.45






(5H, m).


 


104




—H
1
1.24 (3H, t, J = 7.1 Hz), 1.89 (3H, s), 4.15 (2H, q, J = 7.1 Hz), 4.32 (2H, s), 6.95 (2H, d, J = 8.9 Hz), 7.12 (1H, t, J = 9.0 Hz), 7.27-7.32 (3H, m), 7.52- 7.60 (1H, m), 7.70-7.80 (2H, m), 7.99 (1H, s), 8.05 (1H, s).
















TABLE 15













 









Reference




Example




No.
R143
1H NMR (CDCl3) δ ppm





105
—C2H5
1.09 (3H, t, J = 7.4 Hz), 2.20 (2H, q, J = 7.4 Hz), 2.40-2.45 (4H, m),




3.43 (4H, brs), 3.61 (2H, brs), 4.47 (2H, s), 5.94 (2H, s), 6.70-6.76 (2H,




m), 6.84 (1H, s), 7.08 (1H, d, J = 9.0 Hz), 7.19 (2H, d, J = 8.7 Hz),




7.52 (2H, d, J = 8.7 Hz), 8.51 (1H, dd, J = 2.8 Hz, 9.0 Hz), 9.04 (1H,




d, J = 2.8 Hz).


106
—CH2Cl
2.40-2.48 (4H, m), 3.43 (4H, s), 3.62 (2H, brs), 3.97 (2H, s), 4.49 (2H,




s), 5.95 (2H, s), 6.70-6.77 (2H, m), 6.84 (1H, s), 7.11 (1H, d, J = 9.0




Hz), 7.23 (2H, d, J = 8.7 Hz), 7.59 (2H, d, J = 8.7 Hz), 8.52 (1H, dd,




J = 2.8 Hz, 9.0 Hz), 9.04 (1H, d, J = 2.8 Hz).


107
cyclopropyl
0.65-1.52 (5H, m), 2.43 (4H, brs), 3.43 (4H, brs), 3.61 (2H, brs),




4.50 (2H, brs), 5.95 (2H, s), 6.72-6.75 (2H, m), 6.84 (1H, s), 7.08 (1H,




d, J = 9.1 Hz), 7.20 (1H, d, J = 8.8 Hz), 7.59 (2H, d, J = 8.8 Hz),




8.50 (1H, dd, J = 2.9 Hz, 9.1 Hz), 9.04 (1H, d, J = 2.9 Hz).
















TABLE 16













 









Reference




Example




No.
R144
1H NMR (CDCl3) δ ppm





108
—H
1.44 (3H, t, J = 7.1 Hz), 4.43 (2H, q, J = 7.1 Hz), 5.05 (2H, s), 6.93 (1H, d,




J = 8.6 Hz), 7.02 (2H, d, J = 8.6 Hz), 7.17 (2H, d, J = 8.9 Hz), 7.56 (2H,




d, J = 8.4 Hz), 7.69 (2H, d, J = 8.9 Hz), 7.79 (1H, dd, J = 8.4 Hz, 2.5 Hz),




8.22 (1H, d, J = 2.5 Hz), 8.90 (1H, brs).


109
—CH3
1.44 (3H, t, J = 7.1 Hz), 2.19 (3H, s), 4.43 (2H, q, J = 7.1 Hz), 5.03 (2H,




s), 6.94 (1H, d, J = 8.4 Hz), 7.02 (2H, d, J = 8.4 Hz), 7.07 (1H, d, J = 8.6




Hz), 7.51-7.58 (4H, m), 7.78 (1H, dd, J = 8.6 Hz, 2.5 Hz), 8.20 (1H, d, J =




2.5 Hz), 8.84 (1H, brs).









Reference Example 110
Production of (6-chloropyridin-3-yl)(4-trifluoromethylphenyl)methanone
Under an argon gas flow, half of a solution of 4-bromobenzotrifluoride (1.20 g, 5.33 mmol) in THF (6 mL) was added to magnesium (156 mg, 6.41 mmol). The resulting solution was stirred, and further 1,2-dibromoethane (3 drops) was added. Once the reaction began, the balance of the 4-bromobenzotrifluoride in THF solution was added dropwise, and once dropping had finished, the resulting solution was stirred for 30 minutes at 60° C. A solution of 6-chloro-N-methoxy-N-methylnicotinamide (990 mg, 5.36 mmol) in THF (3 mL) was charged into a separate reaction vessel, into which the above reaction solution was added dropwise under an argon gas flow and ice cooling. After dropping had finished, the resulting solution was stirred for 30 minutes at room temperature, and then heated to reflux for 1 hour. The reaction solution was cooled with ice, then aqueous ammonium chloride and water were added. The resulting solution was extracted with ethyl acetate, and washed with brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to thereby yield 610 mg of the title compound.
Appearance: White powder
1H NMR (CDCl3) δ 7.52 (1H, d, J=8.3 Hz), 7.80 (2H, d, J=8.0 Hz), 7.90 (2H, d, J=8.0 Hz), 8.11 (1H, dd, J=8.3 Hz, 2.0 Hz), 8.77 (1H, d, J=2.0 Hz).
Reference Example 111
Production of ethyl 3-[4-(4-nitrophenoxy)phenyl]-propionate
To a solution of ethyl 3-(4-hydroxyphenyl)-propionate (6.00 g, 30.9 mmol) in DMF (60 mL) were added 4-fluoronitrobenzene (6.54 g, 46.3 mmol) and potassium carbonate (5.12 g, 37.1 mmol). The resulting reaction solution was stirred for 1 hour at 80° C. To the reaction solution was added water and extracted with ethyl acetate. The resulting ethyl acetate layer was washed with water and then with brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to thereby yield 9.64 g of the title compound.
Appearance: Pale yellow oil
1H NMR (CDCl3) δ 1.23 (3H, t, J=7.1 Hz), 2.62 (2H, t, J=7.7 Hz), 2.96 (2H, t, J=7.7 Hz), 4.12 (2H, q, J=7.1 Hz), 6.93-7.06 (4H, m), 7.24 (2H, d, J=8.5 Hz), 8.17 (2H, d, J=9.2 Hz).
The following compounds were produced in the same manner as in Reference Example 111.







TABLE 17













 









Reference




Example




No.
R145
1H NMR (solvent) δ ppm





112
-Ac
(DMSO-d6) 2.58(3 H, s), 7.26(2 H, d, J = 8.8 Hz), 7.40(1 H, t, J =




8.4 Hz), 8.04(2 H, d, J = 8.8 Hz), 8.15(1 H, ddd, J = 1.4 Hz,




2.6 Hz, 8.4 Hz), 8.39(1 H, dd, J = 2.6 Hz, 10.7 Hz).


113
—CH2COOCH3
(DMSO-d6) 3.63(3 H, s), 3.72(2 H, s), 7.11-7.17(3 H, m),




7.38(2 H, d, J = 8.4 Hz), 8.09(1 H, ddd, J = 1.4 Hz, 2.7 Hz, 9.1




Hz), 8.33(1 H, dd, J = 2.7 Hz, 10.2 Hz).


114
—(CH2)2COOC2H5
(CDCl3) 1.22(3 H, t, J = 7.1 Hz), 2.62(2 H, t, J = 7.6 Hz),




2.96(2 H, t, J = 7.6 Hz), 4.12(2 H, q, J = 7.1 Hz), 6.92(1 H, dd,




J = 9.0 Hz, 8.0 Hz), 6.99(2 H, d, J = 8.6 Hz), 7.24(2 H, d, J =




8.6 Hz), 7.90-8.00(1 H, m), 8.06(1 H, dd, J = 10.3 Hz, 2.7 Hz).


115
—NHAc
(DMSO-d6) 2.05(3 H, s), 7.07(1 H, t, J = 8.6 Hz), 7.16(2 H, d, J =




9.0 Hz), 7.67(2 H, d, J = 9.0 Hz), 8.06(1 H, ddd, J = 1.4 Hz,




2.7 Hz, 8.6 Hz), 8.31(1 H, dd, 2.7 Hz, 10.9 Hz), 10.06(1 H, s).


116
—SCH2COOC2H5
(CDCl3) 1.24(3 H, t, J = 7.1 Hz), 3.62(2 H, s), 4.18(2 H, q, J =




7.1 Hz), 6.95-7.05(3 H, m), 7.49(2 H, d, J = 8.8 Hz), 8.00(1 H,




ddd, J = 1.5 Hz, 2.6 Hz, 9.1 Hz), 8.08(1 H, dd, J = 2.6 Hz,




10.2 Hz).


117
—OCH3
(DMSO-d6) 3.77(3 H, s), 6.90-7.10(3 H, m), 7.16(2 H, d, J = 9.1




Hz), 8.03(1 H, ddd, J = 1.4 Hz, 2.6 Hz, 9.2 Hz), 8.27(1 H, dd, J =




2.6 Hz, 10.9 Hz).


118
—H
(CDCl3) 6.95(1 H, dd, J = 9.0 Hz, 8.0 Hz), 7.07(2 H, d, J = 7.9




Hz), 7.24(2 H, t, J = 7.9 Hz), 7.42(2 H, t, J = 7.9 Hz),




7.91-8.02(1 H, m), 8.07(1 H, dd, J = 10.3 Hz, 2.7 Hz).


119
—(CH2)3COOC2H5
(CDCl3) 1.25(3 H, t, J = 7.1 Hz), 1.88-2.03(2 H, m), 2.32(2 H, t,




J = 7.4 Hz), 2.66(2 H, t, J = 7.4 Hz), 4.12(2 H, q, J = 7.1 Hz),




6.91(1 H, dd, J = 9.0 Hz, 8.0 Hz), 6.99(2 H, d, J = 8.5 Hz),




7.22(2 H, d, J = 8.5 Hz), 7.91-7.98(1 H, m), 8.06(1 H, dd, J =




10.3 Hz, 2.7 Hz)


120
—CHO
(DMSO-d6) 7.33(2 H, d, J = 8.7 Hz), 7.47(1 H, t, J = 9.0 Hz),




8.00(2 H, d, J = 8.7 Hz), 8.16(1 H, ddd, J = 1.4 Hz, 2.7 Hz, 9.0




Hz), 8.40(1 H, dd, J = 2.7 Hz, 10.6 Hz), 9.99(1 H, s).


121
—COOC2H5
(DMSO-d6) 1.32(3 H, t, J = 7.1 Hz), 4.31(2 H, q, J = 7.1 Hz),




7.26(2 H, d, J = 8.9 Hz), 7.41(1 H, t, J = 8.4 Hz), 8.03(2 H, d, J =




8.9 Hz), 8.14(1 H, ddd, J = 1.4 Hz, 2.6 Hz, 8.4 Hz), 8.39(1 H,




dd, J = 2.6 Hz, 10.6 Hz).





(Ac means an acetyl group. Hereinafter Ac indicates the same meaning.)













TABLE 18













 










Reference





Example





No.
R146
R147
1H NMR (solvent) δ ppm





122
4-NO2




(DMSO-d6) 1.33(3 H, t, J = 7.1 Hz), 4.32(2 H, q, J = 7.1 Hz), 7.24-7.31(4 H, m), 8.05(2 H, d, J = 8.9 Hz), 8.29(2 H, d,J = 9.3 Hz).


 


123
4-NO2




(CDCl3) 3.10(3 H, s), 3.75(3 H, s), 4.10(2 H, s), 6.71(2 H, d, J = 9.2 Hz), 6.96(2 H, d, J = 9.2 Hz), 6.98(2 H, d, J = 9.2 Hz), 8.17(2 H, d, J = 9.2 Hz).


 


124
2-NO2




(CDCl3) 1.22(3 H, t, J = 7.1 Hz), 2.60(2 H, t, J = 7.7 Hz), 2.93(2 H, t, J = 7.7 Hz), 4.11(2 H, q, J = 7.1 Hz), 6.92-6.99(3 H, m), 7.13-7.23(3 H, m), 7.45(1 H, dt, J = 1.6 Hz, 8.2 Hz), 7.92(1 H, dd, J = 8.2 Hz, 1.6 Hz).


 


125
4-NO2




(CDCl3) 1.50(9 H, s), 2.53(2 H, brs), 3.66(2 H, m), 4.10 (2 H, brs), 6.05(1 H, brs), 7.02(2 H, d, J = 9.0 Hz), 7.06 (2 H, d, J = 8.5 Hz), 7.43(2 H, d, J = 8.5 Hz), 8.21(2 H, d, J = 9.0 Hz).


 


126
4-NO2




(CDCl3) 1.21(3 H, t, J = 7.1 Hz), 2.61(2 H, t, J = 7.7 Hz), 2.95(2 H, t, J = 7.7 Hz), 4.10(2 H, q, J = 7.1 Hz), 6.88-6.94(2 H, m), 6.98(2 H, d, J = 9.2 Hz), 7.08(1 H, d, J = 7.6 Hz), 7.32(1 H, t, J = 7.6 Hz), 8.18(2 H, d, J = 9.2 Hz).


 


127
4-NO2




(CDCl3) 2.58(2 H, t, J = 7.7 Hz), 2.87(2 H, t, J = 7.7 Hz), 3.62(3 H, s), 6.89-7.01(3 H, m), 7.13-7.37(3 H, m), 8.18(2 H, d, J = 9.2 Hz).
















TABLE 19













 











Reference






Example






No.
R148
R149
R150
1H NMR (CDCl3) δ ppm





128
—H
—H
—C2H5
1.41(3 H, t, J = 7.3 Hz), 4.40(2 H, q, J = 7.3 Hz),






7.09(1 H, d, J = 8.9 Hz), 7.22-7.26(2 H, m),






8.14-8.17(2 H, m), 8.52(1 H, dd, J = 8.9 Hz, 3.0 Hz), 9.04(1 H,






d, J = 3.0 Hz).


129
—H
—H
—CH3
3.94(3 H, s), 7.10(1 H, d, J = 8.9 Hz), 7.22-7.26(2 H, m),






8.13-8.16(2 H, m), 8.52(1 H, dd, J = 8.9 Hz, 2.7 Hz),






9.04(1 H, d, J = 2.7 Hz).


130
—F
—H
—CH3
3.95(3 H, s), 7.18(1 H, d, J = 8.8 Hz), 7.29-7.35(1 H, m),






7.87-7.96(2 H, m), 8.54(1 H, dd, J = 8.8 Hz, 2.6 Hz),






8.99(1 H, d, J = 2.6 Hz).


131
—F
—H
—C2H5
1.41(3 H, t, J = 7.1 Hz), 4.41(2 H, q, J = 7.1 Hz),






7.18(1 H, d, J = 9.1 .Hz), 7.29-7.35(1 H, m), 7.88-7.96(2






H, m), 8.54(1 H, dd, J = 9.1 Hz, 2.8 Hz), 8.99(1 H,






d, J = 2.8 Hz).


132
—CH3
—H
—CH3
2.21(3 H, s), 3.93(3 H, s), 7.08-7.15(2 H, m), 7.97(1 H, dd,






J = 8.4 Hz, 2.2 Hz), 8.02(1 H, d, J = 2.2 Hz), 8.52(1 H,






dd, J = 8.9 Hz, 2.7.Hz), 9.01(1 H, d, J = 2.7 Hz).


133
—OCH3
—H
—C2H5
1.41(3 H, t, J = 7.1 Hz), 3.80(3 H, s), 4.40(2 H, q, J = 7.1






Hz), 7.09(1 H, d, J = 8.9 Hz), 7.21(1 H, d, J = 8.2 Hz),






7.71-7.77(2 H, m), 8.49(1 H, dd, J = 8.9 Hz, 2.8 Hz),






8.97(1 H, a, J = 2.8 H).


134
—H
—OCH3
—CH3
3.90(3 H, s), 3.91(3 H, s), 6.77-6.81(2 H, m), 7.11(1 H, dd,






J = 9.1 Hz, 0.5 Hz), 7.91-7.95(1 H, m), 8.53(1 H, dd, J =






9.1 Hz, 2.7 Hz), 9.06(1 H, d, J = 2.7 Hz).


135
—H
—CH3
—CH3
2.64(3 H, s), 3.91(3 H, s), 7.02-7.10(3 H, m), 8.03-






8.06(1 H, m), 8.52(1 H, dd, J = 8.9 Hz, 2.7 Hz), 9.05(1 H,






dd, J = 2.7 Hz, 0.5 Hz).


136
—Cl
—H
—CH3
3.95(3 H, s), 7.17-7.20(1 H, m), 7.31(1 H, d, J = 8.6 Hz),






8.03-8.07(1 H, m), 8.20(1 H, a, J = 2.0 Hz), 8.55(1 H, dd,






J = 9.1 Hz, 2.8 Hz), 8.98(1 H, dd, J = 2.8 Hz, 0.5 Hz).


137
—F
—F
—CH3
3.97(3 H, s), 7.06-7.16(1 H, m), 7.21(1 H, dd, J = 0.3 Hz,






9.0 Hz), 7.77-7.88(1 H, m), 8.56(1 H, dd, J = 2.8 Hz, 9.0






Hz), 8.99(1 H, dd, J = 0.3 Hz, 2.8 Hz)
















TABLE 20













 











Reference






Example






No.
R151
R152
M
1H NMR (CD Cl3) δ ppm





138
—H
—CH3
2
2.64-2.70(2 H, m), 2.97-3.02(2 H, m), 3.69(3 H, s),






7.01-7.10(3 H, m), 7.26-7.30(2 H, m), 8.47(1 H, dd, J = 8.9 Hz,






2.6 Hz), 9.04(1 H, d, J = 2.6 Hz).


139
—OCH3
—C2H5
2
1.26(3 H, t, J = 7.1. Hz), 2.67(2 H, t, J = 7.5 Hz), 2.99(2 H,






t, J = 7.5 Hz), 3.74(3 H, s), 4.16(2 H, q, J = 7.1 Hz),






6.76-6.91(2 H, m), 7.02(1 H, d, J = 9.1 Hz), 7.06(1 H, d, J = 8.0






Hz), 8.45(1 H, dd, J = 9.1 Hz, 2.6 Hz), 9.01(1 H, d, J = 2.6






Hz).


140
—H
—CH3
1
3.67(2 H, s), 3.72(3 H, s), 7.04(1 H, d, J = 8.9 Hz), 7.12(2 H,






d, J = 8.6 Hz), 7.38(2 H, d, J = 8.6 Hz), 8.45-8.50(1 H, m),






9.04(1 H, d, J = 3.0 Hz).


141
—H
—C2H5
2
1.23(3 H, t, J = 7.1 Hz), 2.63(2 H, t, J = 7.8 Hz), 2.97(2 H,






t, J = 7.8 Hz), 4.11(2 H, q, J = 7.1 Hz), 7.00(1 H, d, J = 9.1






Hz), 7.06(2 H, d, J = 8.5 Hz), 7.26(2 H, d, J = 8.5 Hz),






8.45(1 H, dd, J = 9.1 Hz, 2.8 Hz), 9.02(1 H, d, J = 2.8 Hz).


142
—OCH3
—CH3
2
2.66-2.71(2 H, m), 2.97-3.02(2 H, m), 3.70(3 H, s), 3.74(3 H,






s), 6.83-6.88(2 H, m), 7.01-7.08(2 H, m), 8.45(1 H, dd, J =






9.1 Hz, 2.8 Hz), 9.01(1 H, d, J = 2.8 Hz).


143
—OC2H5
—C2H5
2
1.15(3 H, t, J = 7.0 Hz), 1.26(3 H, t, J = 7.1 Hz), 2.53-






2.72(2 H, m), 2.87-3.05(2 H, m), 3.98(2 H, q, J = 7.0 Hz),






4.15(2 H, q, J = 7.1 Hz), 6.73-6.93(2 H, m), 7.02(1 H, d, J =






9.0 Hz), 7.07(1 H, d, J = 8.0 Hz), 8.45(1 H, dd, J = 9.0 Hz,






2.8 Hz), 9.01(1 H, d, J = 2.8 Hz).


144
—F
—C2H5
2
1.26(3 H, t, J = 7.1 Hz), 2.57-2.71(2 H, m), 2.89-3.06(2 H,






m), 4.15(2 H, q, J = 7.1 Hz), 6.98-7.21(4 H, m), 8.50(1 H,






dd, J = 9.0 Hz, 2.8 Hz), 9.01(1 H, d, J = 2.8 Hz).


145
—H
—C2H5
4
1.26(3 H, t, J = 7.3 Hz), 1.60-1.80(4 H, m), 2.30-2.40(2 H,






m), 2.60-2.75(2 H, m), 4.13(2 H, q, J = 7.3 Hz), 7.01(1 H, d,






J = 9.0 Hz), 7.06(2 H, d, J = 8.6 Hz), 7.25(2 H, d, J = 8.6






Hz), 8.46(1 H, dd, J = 9.0 Hz, 3.0 Hz), 9.04(1 H, d, J = 3.0






Hz).
















TABLE 21













 











Reference






Example






No.
R153
R154
M
1H NMR (CDCl3) δ ppm or MS





146
—CH3
—H
1
1H NMR 1.32(3 H, t, J = 7.1 Hz), 2.08(3 H, s), 3.90(2 H, d, J =






5.3 Hz), 4.15-4.39 (3 H, m), 6.39-6.59(2 H, m), 6.81-7.01(2






H, m), 8.44(1 H, dd, J = 9.1 Hz, 2.8 Hz), 9.05(1 H, dd,






J = 2.8 Hz, 0.4 Hz).


147
—CH3
-Ac
1
1H NMR 1.29(3 H, t, J = 7.1 Hz), 1.99(3 H, s), 2.17(3 H, s),






4.22(2 H, q, J = 7.1 Hz), 4.38(2 H, s), 7.05-7.12(2 H, m),






7.22-7.28(2 H, m), 7.31(1 H, s), 8.50(1 H, d, J = 9.0 Hz),






9.01(1 H, s).


148
—H
—H
1
1H NMR 1.32(3 H, t, J = 7.1 Hz), 3.91(2 H, d, J = 5.4 Hz), 






4.27(2 H, q, J = 7.1 Hz), 4.37(1 H, t, J = 5.4 Hz), 6.66(2 H,






d, J = 8.9 Hz), 6.96(1 H, d, J = 9.1 Hz), 6.98(2 H, d, J = 8.9






Hz), 8.43(1 H, dd, J = 2.8 Hz, 9.1 Hz), 9.05(1 H, d, J = 2.8






Hz).


149
—H
-Ac
2
1H NMR 1.23(3 H, t, J = 7.1 Hz), 1.90(3 H, s), 2.62(2 H, t, J =






7.3 Hz), 4.03(2 H, t, J = 7.3 Hz), 4.08(2 H, q, J = 7.1 Hz),






7.10(1 H, d, J = 9.0 Hz), 7.21-7.28(4 H, m), 8.52(1 H, dd, J =






2.8 Hz, 9.0 Hz), 9.04(1 H, d, J = 2.8 Hz).


150
—F
—C2H5
1
1H NMR 1.21-1.32(6 H, m), 3.47(2 H, q, J = 7.1 Hz),






4.01(2 H, s), 4.23(2 H, q, J = 7.1 Hz), 6.38-6.49(2 H, m),






7.01-7.07(2 H, m), 8.46(1 H, dd, J = 9.1 Hz, 2.8 Hz),






9.03(1 H, d, J = 2.8 Hz).


151
—OCH3
—C2H5
1
1H NMR 1.25(3 H, t, J = 7.1 Hz), 1.28(3 H, t, J = 7.1 Hz),






3.50(2 H, q, J = 7.1 Hz), 3.72(3 H, s), 4.03(2 H, s), 4.22(2 H,






q, J = 7.1 Hz), 6.23(1 H, dd, J = 8.9 Hz, 2.8 Hz), 6.30(1 H,






d, J = 2.6 Hz), 6.95-6.99(2 H, m), 8.42(1 H, dd, J = 9.1 Hz,






2.8 Hz), 9.04(1 H, d, J = 2.8 Hz).


152
—F
—CH3
1
1H NMR 1.28(3 H, t, J = 7.1 Hz), 3.09(3 H, s), 4.06(2 H, s),






4.21(2 H, q, J = 7.1 Hz), 6.42-6.54(2 H, m), 7.03-7.10(2 H,






m), 8.47(1 H, dd, J = 9.1 Hz, 2.8 Hz), 9.03(1 H, d, J = 2.8






Hz).


153
—OCH3
—H
1
1H NMR 1.32(3 H, t, J = 7.1 Hz), 3.72(3 H, s), 3.92(2 H, d J =






5.3 Hz), 4.27(2 H, q, J = 7.1 Hz), 4.41(1 H, brt), 6.19(1 H,






dd, J = 8.4 Hz, 2.5 Hz), 6.29(1 H, d, J = 2.5 Hz), 6.96-7.00(2






H, m), 8.42(1 H, dd, J = 9.1 Hz, 2.8 Hz), 9.03(1 H, d,






J = 2.8 Hz).


154
—F
-Ac
1
1H NMR 1.30 (3 H, t, J = 7.1 Hz), 2.02(3 H, s), 4.23(2 H, q, J =






7.1 Hz), 4.38(2 H, s), 7.16-7.33(4 H, m), 8.54(1 H, dd, J =






9.1 Hz, 2.8 Hz), 9.01(1 H, dd, J = 2.8 Hz, 0.5 Hz).


155
—F
—H  
1
1H NMR 1.32(3 H, t, J = 7.1 Hz), 3.89(2 H, d, J = 5.3 Hz), 4.28(2 H, q, J = 7.1 Hz), 4.35-4.55(1 H, m), 6.31-6.50(2 H, m), 6.91-7.11(2 H, m), 8.47(1 H, dd, J = 9.1 Hz, 2.8 Hz), 9.02(1 H, dd, J = 2.8 Hz, 0.4 Hz).


156
—CF3
—CH3
1
MS 399(M+)


157
—CF3
—C2H5
1
MS 413(M+)
















TABLE 22













 














Reference









Example









No.
R155
R156
R157
R158
R159
M
1H NMR or MS





158
—H
—H
—H
—CH3
—CH3
1
1H NMR (CDCl3) δ 3.10(3 H, s),









3.74(3 H, s), 4.09(2 H, s), 6.72(2 H,









d, J = 9.1 Hz), 6.96 (1 H, d, J = 9.0









Hz), 7.03(2 H, d, J = 9.1 Hz),









8.43(1 H, dd, J = 9.0 Hz, 2.9 Hz),









9.06(1 H, d, J = 2.9 Hz).


159
—H
—H
—H
-Ac
—C2H5
1
1H NMR (DMSO-d6) δ 1.20(3 H, t,









J = 7.1 Hz), 1.87(3 H, s), 4.12(2 H,









q, J = 7.1 Hz), 4.37 (2 H, s),









7.28-7.35(3 H, m), 7.48(2 H, d, J = 8.7









Hz), 8.65(1 H, dd, J = 2.9 Hz, 9.1









Hz), 9.05 (1 H, d, J = 2.9 Hz).


160
—H
—H
—H
—CH3
—CH3
2
1H NMR (CDCl3) δ 2.59-2.64(2 H,









m), 2.96 (3 H, s), 3.67-3.72(5 H, m),









6.76(2 H, d, J = 9.1 Hz), 6.97(1 H,









d, J = 9.1 Hz), 7.05(2 H, d, J = 8.9









Hz), 8.43(1 H, dd, J = 9.1 Hz, 3.0









Hz), 9.06(1 H, d, J = 2.8 Hz).


161
—F
—H
—F
—H
—C2H5
1
1H NMR (CDCl3) δ 1.32(3 H, t, J =









7.1 Hz), 3.91(2 H, d, J = 5.5 Hz),









4.28(2 H, q, J = 7.1 Hz), 4.57-4.71(1









H, m), 6.43(1 H, dd, J = 7.9









Hz, 11.6 Hz), 6.94(1 H, dd, J = 7.0









Hz 11.0 Hz), 7.08(1 H, d, J = 9.0









Hz), 8.49(1 H, dd, J = 2.8 Hz, 9.0









Hz), 9.01(1 H, d, J = 2.8 Hz).


162
—F
—F
—H
—CH3
—C(CH3)3
0
1H NMR (CDCl3) δ 1.51(9 H, s),









3.30(3 H, s), 6.95-7.10(2 H, m),









7.21(1 H, d, J = 9.1 Hz), 8.54(1 H,









dd, J = 2.8 Hz, 9.1 Hz), 9.00(1 H,









d, J = 2.8 Hz).


163
—CH3
—H
—CH3
—C2H5
—C2H5
1
1H NMR (CDCl3) δ 1.08(3 H, t, J =









7.1 Hz), 1.24(3 H, t, J = 7.1 Hz),









2.07(3 H, s), 2.28(3 H, s), 3.21(2 H,









q, J = 7.1 Hz), 3.78(2 H, s), 4.15









(2 H, q, J = 7.1 Hz), 6.86(1 H, s),









6.95(1 H, d, J = 9.1 Hz), 7.07(1 H,









s), 8.45(1 H, dd, J = 9.1 Hz, 2.8









Hz), 9.06(1 H, d, J = 2.8 Hz).


164
—COOCH3
—H
—H
—C2H5
—C(CH3)3
1
MS 431(M+)


165
—CH3
—H
—CH3
—CH3
—C2H5
1
1H NMR (CDCl3) δ 1.27(3 H, t, J =









7.1 Hz), 2.08(3 H, s), 2.28(3 H, s),









2.89(3 H, s), 3.73(2 H, s), 4.19(2 H,









q, J = 7.1 Hz), 6.85(1 H, s), 6.96









(1 H,d, J = 9.1 Hz), 7.01(1 H, s),









8.45(1 H, dd, J = 9.1 Hz, 2.8 Hz),









9.06(1 H, d, J = 2.8 Hz).


166
—CN
—H
—H
—CH3
—C(CH3)3
1
MS 384(M+)


167
—H
—H
—CF3
—C2H5
—C2H5
1
MS 413(M+)
















TABLE 23













 










Reference





Example





No.
R160
R161
1H NMR (CDCl3) δ ppm





168
—H




1.27(3 H, t, J = 7.0 Hz), 1.41-1.48(2 H m), 1.85 (2 H, brd, J = 13.0 Hz), 1.95(1 H, m), 2.29(2 H, d, J = 7.0 Hz) 2 76(2 H, dt, J = 2.5 Hz, 12.0 Hz), 3.65 (2 H, brd, J = 12.0 Hz), 4.16(2 H, q, J = 7.0 Hz), 6.96-6.99(3 H, m), 7.03(2 H, d, J = 9.0 Hz), 8.44 (1 H, dd, J = 9.0 Hz, 3.0 Hz), 9.05(1 H, d, J = 3.0 Hz).


 


169
—H
morpholino
3.16-3.19(4 H, m), 3.86-3.89(4 H, m),





6.94-7.01 (3 H, m), 7.05-7.11(2 H, m),





8.45(1 H, dd, J = 9.2 Hz, 3.0 Hz),





9.05(1 H, d, J = 3.0 Hz).


 


170
—H




2.47-2.62(4 H, m) 2 96-3.14(4 H, m), 3.49(2 H, s), 7.11(1 H, d, J = 9.0 Hz), 7.19-7.37(7 H, m), 7.81 (2 H, d, J = 8.7 Hz), 8.52(1 H, dd, J = 9.0 Hz, 2.0 Hz), 9.02(1 H, d, J = 2.0 Hz).


 


171
—H




1.28(3 H, t, J = 7.0 Hz), 1.90(2 H, dq, J = 4.0 Hz, 11.5 Hz), 2.04(2 H, brd, J = 13.0 Hz), 2.43(1 H, m), 2.82(2 H, dt, J = 3.0 Hz, 12.0 Hz), 3.63(2 H, dt, J = 13.0 Hz, 3.0 Hz), 4.17(2 H, q, J = 7.0 Hz), 6.97-6.99(3 H, m), 7.04(2 H, d, J = 9.0 Hz), 8.44(1 H, dd, J = 9.0 Hz, 3.0 Hz), 9.05(1 H, d, J = 3.0 Hz).


 


172
—H




1.28(3 H, t, J = 7.0 Hz), 1.70(2 H, m), 1.84(1 H, m), 2.04(1 H, m), 2.69(1 H, m), 2.86(1 H, m), 3.08(1 H, dd, J = 12.0 Hz, 10.0 Hz), 3.46(1 H, brd, J = 12.0 Hz), 3.69(1 H, dd, J = 12.0 Hz, 4.0 Hz), 4.18(2 H, q, J = 7.0 Hz), 6.97-7.05(5 H, m), 8.45(1 H, dd, J = 9.0 Hz, 3.0 Hz), 9.06(1 H, d, J = 3.0 Hz).


 


173
—COOCH3




2.61-2.64(4 H, m) 3.24-3.28(4 H, m), 3.58(2 H; s), 3.68(3 H, s), 7.03-7.16(3 H, m), 7.26-7.36(5 H, m), 7.54(1 H, d, J = 2.8 Hz), 8.46(1 H, d.d, J = 9.1 Hz, 2.8 Hz), 8.97(1 H, d, J = 2.8 Hz).


 


174
—H




2.43(4 H, t, J = 5.1 Hz), 3.40(4 H, t, J = 5.1 Hz), 3.43(2 H, s), 4.46(2 H, t, J = 5.5 Hz), 4.79(1 H, t, J = 5.5 Hz), 5.95(2 H, s), 6.74(2 H, s), 6.85(1 H, s), 7.05(1 H, d, J = 9.1 Hz), 7.12(2 H, d, J = 8.4 Hz), 7.40(2 H, d, J = 8.4 Hz), 8.48(1 H, dd, J = 9.1 Hz, 2.8 Hz), 9.03(1 H, d, J = 2.8 Hz).


 


175
—CH3
—NHCOCOOC2H5
1.33(3 H, t, J = 7.1 Hz), 2.07(3 H, s),





4.32(2 H, q, J = 7.1 Hz), 7.15(1 H, d, J =





8.7 Hz), 7.27(1 H, cld, J = 9.2 Hz, 0.5





Hz), 7.63(1 H, cM, J = 8.6 Hz, 2.5 Hz),





7.71(1 H, d, J = 2.5 Hz), 8.62(1 H, dd, J =





9.1 Hz, 2 8 Hz), 9.01(1 H, dd, J = 2.8 Hz,





0.5 Hz), 10.82(1 H, brs).
















TABLE 24













 










Reference





Example


No.
R162
R163
1H NMR (solvent) δ ppm













176
—H
—Ac
(CDCl3 ) 2.60 (3H, s), 7.10-9.00 (7H, m).


177
—H
—CHO
(CDCl3) 7.14 (1H, d, J = 9.0 Hz), 7.35 (2H,





d, J = 8.7 Hz), 8.00 (2H, d, J = 8.7 Hz),





8.54 (1H, dd, J = 9.0 Hz, 1.8 Hz), 9.04 (1H,





d, J = 1.8 Hz), 10.03 (1H, s).


178
—H
—C2H5
(CDCl3) 1.28 (3H, t, J = 7.6 Hz), 2.70 (2H,





q, J = 7.6 Hz), 7.01 (1H, dd, J = 9.1 Hz,





0.7 Hz), 7.07 (2H, d, J = 8.7 Hz), 7.28 (2H,





d, J = 8.7 Hz), 8.46 (1H, dd, J = 9.1 Hz,





2.8 Hz), 9.05 (1H, dd, J = 2.8 Hz, 0.7 Hz).


179
—CH3
—CHO
(CDCl3) 2.25 (3H, s), 7.14 (1H, d, J = 8.9





Hz), 7.24 (1H, d, J = 8.2 Hz), 7.81 (1H, dd,





J = 8.2 Hz, 2.0 Hz), 7.85 (1H, s), 8.53 (1H,





dd, J = 8.9 Hz, 2.6 Hz), 9.00 (1H, d, J =





2.6 Hz), 10.00 (1H, s).


 


180
—H




(CDCl3) 1.70-1.93 (4H, m), 2.45-2.56 (2H, m), 3.22-3.36 (2H, m), 4.62 (2H, s), 7.03 (1H, d, J = 9.2 Hz), 7.12 (2H, d, J = 8.6 Hz), 7.35 (2H, d, J = 8.6 Hz), 8.47 (1H, dd, J = 9.2 Hz, 2.6 Hz), 9.04 (1H, d, J = 2.6 Hz).


 


181
—H




(CDCl3) 2.46-2.47 (4H, m), 2.77-2.99 (2H, m), 3.46 (2H, s), 3.51-3.57 (4H, m), 3.64- 3.73 (1H, m), 3.90-3.96 (1H, m), 4.30- 4.36 (1H, m), 5.96 (2H, s), 6.75-6.86 (3H, m), 7.04 (1H, d, J = 9.1 Hz), 7.17 (2H, d, J = 9.1 Hz), 7.70 (2H, d, J = 8.9 Hz), 8.48 (1H, dd, J = 2.8 Hz, 9.1 Hz), 9.03 (1H, d, J = 2.8 Hz).


 


182
—H




(CDCl3) 1.51 (9H, s), 3.80 (4H, m), 4.27 (2H, s), 7.07 (1H, d, J = 9.1 Hz), 7.21 (2H, dd, J = 6.8 Hz, 2.1 Hz), 7.38 (2H, dd, J = 6.8 Hz, 2.1 Hz), 8.49 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.04 (1H, d, J = 2.8 Hz).


 


183
—H




(CDCl3) 3.35-3.55 (4H, m), 3.96 (2H, s), 4.58 (2H, s), 5.96 (2H, s), 6.73-6.78 (2H, m), 6.81 (1H, s), 6.91 (2H, d, J = 9.1 Hz), 7.00 (1H, d, J = 9.1 Hz), 7.09 (2H, d, J = 9.1 Hz), 8.45 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.04 (1H, d, J = 2.8 Hz).


 


184
—H
—NHCONHPh
(DMSO-d6) 6.96 (1H, t, J = 6.5 Hz), 7.14 (2H, d, J = 8.8 Hz), 7.21 (1H, d, J = 9.1 Hz), 7.27 (2H, t, J = 8.3 Hz), 7.45 (2H, d, J = 8.3 Hz), 7.52 (2H, d, J = 8.8 Hz), 8.60 (1H, dd, J = 2.8 Hz, 9.1 Hz), 8.70 (1H, s), 8.77 (1H, s), 9.02 (1H, d, J = 2.8 Hz).
















TABLE 25













 












Reference







Example


No.
R164
R165
R166
M
mp (° C.) or 1H NMR (solvent) δ ppm















185
—NO2
—CH3
piperonyl
2
mp 142.0-143.0


186
—NO2
—H
benzyl
1
1H NMR (DMSO-d6) 3.36 (2H, t, J = 8.1 Hz),







3.84 (2H, t, J = 8.1 Hz), 4.40 (2H, s), 7.15-







7.25 (3H, m), 7.26-7.34 (3H, m), 7.35-







7.41 (2H, m), 7.61-7.71 (2H, m), 8.59 (1H, dd,







J = 2.9 Hz, 9.1 Hz), 9.02 (1H, d, J = 9.1 Hz).


187
—NO2
—CH3
piperonyl
1
1H NMR (DMSO-d6) 2.05 (3H, s), 3.29-







3.41 (2H, m), 3.71-3.88 (2H, m), 4.29 (2H, s),







5.60 (2H, s), 6.74-6.81 (1H, m), 6.82-6.92 (2H,







m), 7.09 (1H, d, J = 8.8 Hz), 7.21 (1H, d, J =







9.1 Hz), 7.49 (1H, d, J = 2.6 Hz, 8.8 Hz),







7.51-7.57 (1H, m), 8.60 (1H, d, J = 9.1 Hz),







9.00 (1H, d, J = 2.9 Hz).


188
—NO2
—CH3
3,4-(CH3O)2PhCH2—
2
1H NMR (CDCl3) 2.00-2.15 (2H, m),







2.14 (3H, s), 3.31 (2H, t, J = 6.0 Hz),







3.73 (2H, d, J = 6.0 Hz), 3.88 (3H, s),







3.89 (3H, s), 4.57 (2H, s), 6.83 (1H, d, J = 8.1







Hz), 6.87 (1H, dd, J = 1.9 Hz, 8.1 Hz),







6.91 (1H, d, J = 1.9 Hz), 6.98-7.06 (2H, m),







7.20 (1H, dd, J = 2.4 Hz, 8.6 Hz), 7.29 (1H, d,







J = 2.4 Hz), 8.46 (1H, dd, J = 2.8 Hz, 9.1







Hz), 9.04 (1H, d, J = 2.8 Hz).


189
—NO2
—CH3
—CH2COOC(CH3)3
2
1H NMR (CDCl3) 1.48 (9H, s), 2.12 (3H, s),







2.12-2.24 (2H, m), 3.48 (2H, t, J = 5.9 Hz),







3.77 (2H, t, J = 5.9 Hz), 4.05 (2H, s), 6.92-







7.06 (2H, m), 7.17 (1H, dd, J = 2.6 Hz, 8.6







Hz), 8.45 (1H, dd, J = 2.9 Hz, 9.1 Hz),







9.04 (1H, d, J = 2.9 Hz).


190
—Br
—CH3
piperonyl
2
1H NMR (CDCl3) 1.94-2.18 (2H, m),







2.15 (3H, s), 3.30 (2H, d, J = 6.0 Hz),







3.71 (2H, d, J = 6.0 Hz), 4.52 (2H, s),







5.95 (2H, s), 6.69-6.82 (3H, m), 6.88 (1H, s),







7.00 (1H, d, J = 8.6 Hz), 7.15 (1H, dd, J = 2.6







Hz, 8.6 Hz), 7.24 (1H, d, J = 2.6 Hz),







7.73 (1H, dd, J = 2.5 Hz, 8.6 Hz), 8.20 (1H, d,







J = 2.5 Hz).


191
—Br
—CH3
3,4-(CH3O)2PhCH2—
2
1H NMR (CDCl3) 1.95-2.11 (2H, m),







2.14 (3H, s), 3.30 (2H, t, J = 5.9 Hz),







3.70 (2H, t, J = 5.9 Hz), 3.88 (3H, s),







3.88 (3H, s), 4.56 (2H, s), 6.74-6.92 (4H, s),







7.00 (1H, d, J = 8.5 Hz), 7.15 (1H, dd, J = 2.4







Hz, 8.5 Hz), 7.24 (1H, d, J = 2.4 Hz),







7.73 (1H, dd, J = 2.6 Hz, 8.8 Hz), 8.19 (1H,







dd, J = 0.5 Hz, 2.6 Hz).
















TABLE 26













 









Reference




Example


No.
R167
1H NMR (CDCl3) δ ppm or MS












192




1H NMR 1.24 (3H, t, J = 7.1 Hz), 3.07 (3H, s), 4.05 (2H, s), 4.18 (2H, q, J = 7.1 Hz), 6.44-6.45 (1H, m), 6.49-6.53 (1H, m), 6.57-6.61 (1H, m), 6.97 (1H, d, J = 9.1 Hz), 7.25-7.31 (1H, m), 8.44 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.07 (1H, d, J = 2.8 Hz).


 


193




1H NMR 3.93 (3H, s), 7.08-7.11 (1H, m), 7.26-7.40 (1H, m), 7.51-7.57 (1H, m), 7.83-7.84 (1H, m), 7.96-8.00 (1H, m), 8.49-8.53 (1H, m), 9.02-9.03 (1H, m).


 


194




MS 488 (M+)


 


195




1H NMR 4.00 (3H, s), 7.14 (1H, d, J = 8.9 Hz), 7.37 (1H, dd, J = 8.9 Hz, 2.3 Hz), 7.67 (1H, d, J = 2.3 Hz), 7.87 (1H, d, J = 8.6 Hz), 8.04 (1H, d, J = 8.9 Hz), 8.11 (1H, dd, J = 8.6 Hz, 1.7 Hz), 8.51- 8.55 (1H, m), 8.64 (1H, brs), 9.05 (1H, d, J = 2.8 Hz).


 


196




1H NMR 4.03 (3H, s), 7.20 (1H, d, J = 9.1 Hz), 7.31 (1H, d, J = 8.1 Hz), 7.51- 7.57 (1H, m), 7.65-7.71 (1H, m), 7.94 (1H, d, J = 8.4 Hz), 8.29 (1H, d, J = 8.1 Hz), 8.55 (1H, dd, J = 9.1 Hz, 2.8 Hz), 8.99 (1H, d, J = 2.8 Hz), 9.05 (1H, d, J = 8.7 Hz).


 


197




1H NMR 1.47 (3H, t, J = 7.1 Hz), 4.49 (2H, t, J = 7.1 Hz), 7.11 (1H, d, J = 8.9 Hz), 7.42 (1H, dd, J = 9.4 Hz, 2.5 Hz), 7.52-7.58 (1H, m), 7.67 (1H, d, J = 2.5 Hz), 7.99 (1H, d, J = 8.2 Hz), 8.21 (1H, dd, J = 7.3 Hz, 1.2 Hz), 8.51 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.04-9.08 (2H, m).


 


198




1H NMR (CDCl3) 2.11 (3H, s), 2.19 (2H, t, J = 5.9 Hz), 2.34-2.50 (4H, m), 3.42 (2H, s), 3.40-3.47 (2H, m), 3.51 (2H, t, J = 5.9 Hz), 3.56-3.76 (2H, m), 3.78 (2H, t, J = 5.7 Hz), 4.20 (2H, s), 5.94 (2H, s), 6.69-6.77 (2H, m), 6.84 (1H, d, J = 1.0 Hz), 6.96-7.02 (2H, m), 7.17 (1H, dd, J = 2.6 Hz, 8.5 Hz), 7.24- 7.28 (1H, m), 8.45 (1H, dd, J = 2.8 Hz, 9.1 Hz), 9.04 (1H, d, J = 2.8 Hz).
















TABLE 27













 











Reference






Example


No.
R168
R169
M
1H NMR (solvent) δ ppm














199
—H
benzyl
2
(CDCl3) 2.36-2.45 (4H, m), 2.63-2.68 (2H, m), 2.99-






3.05 (2H, m), 3.41-3.45 (2H, m), 3.52 (2H, s), 3.64-






3.67 (2H, m), 7.01-7.11 (3H, m), 7.29-7.34 (7H, m),






8.47 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.05 (1H, d, J = 2.8






Hz).


200
—H
piperonyl
2
(CDCl3) 2.33-2.41 (4H, m), 2.62-2.67 (2H, m), 2.98-






3.04 (2H, m), 3.39-3.43 (4H, m), 3.62-3.65 (2H, m),






5.94 (2H, s), 6.73-6.77 (2H, m), 6.84 (1H, s), 7.00-






7.10 (3H, m), 7.26-7.31 (2H, m), 8.44-8.48 (1H, m),






9.03 (1H, dd, J = 3.0 Hz, 0.5 Hz).


201
—F
benzyl
0
(CDCl3) 2.49 (4H, brs), 3.49-3.56 (4H, m), 3.79 (2H,






brs), 7.15 (1H, d, J = 8.9 Hz), 7.24-7.38 (8H, m),






8.53 (1H, dd, J = 9.1 Hz, 2.8 Hz), 8.99 (1H, d, J = 2.8






Hz).


202
—H
benzyl
0
(DMSO-d6) 2.41 (4H, brs), 3.33 (2H, brs), 3.52 (4H,






brs), 7.24-7.27 (8H, m), 7.50 (2H, d, J = 7.9 Hz),






8.64 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.04 (1H, d, J = 2.8






Hz).


203
—H
4-CH3OPhCH2—
0
(CDCl3) 2.46 (4H, brs), 3.44-3.90 (4H, m), 3.49 (2H,






s), 3.81 (3H, s), 6.85-6.89 (2H, m), 7.06 (1H, d, J =






8.9 Hz), 7.18-7.27 (4H, m), 7.48-7.53 (2H, m), 8.48-






8.52 (1H, m), 9.03 (1H, d, J = 2.8 Hz).


204
—H
piperonyl
0
(CDCl3) 2.46 (4H, brs), 3.46 (2H, s), 3.52 (2H, brs),






3.77 (2H, brs), 5.95 (2H, s), 6.75 (2H, s), 6.86 (1H, s),






7.07 (1H, dd, J = 9.1 Hz, 0.5 Hz), 7.20 (2H, d, J = 8.6






Hz), 7.51 (2H, d, J = 8.6 Hz), 8.50 (1H, dd, J = 8.9






Hz, 2.8 Hz), 9.03 (1H, dd, J = 2.8 Hz, 0.5 Hz).


205
—H
3-pyridyl
0
(CDCl3) 3.27 (4H, brs), 3.84 (4H, brs), 7.08-7.12 (1H,






m), 7.21-7.27 (4H, m), 7.54-7.59 (2H, m), 8.16-






8.18 (1H, m), 8.34 (1H, brs), 8.52 (1H, dd, J = 9.1 Hz,






2.8 Hz), 9.05 (1H, dd, J = 2.8 Hz, 0.5 Hz).
















TABLE 28













 











Reference






Example


No.
Xa5
R170
M
1H NMR (CDCl3) δ ppm














206
—O—
piperonyl
1
2.43 (4H, brs), 3.42 (2H, s), 3.58 (2H, t, J = 5.0






Hz), 3.64 (2H, t, J = 5.0 Hz), 4.70 (2H, s),






5.95 (2H, s), 6.70-6.79 (2H, m), 6.84 (1H, d, J =






0.6 Hz), 7.01 (3H, d, J = 9.1 Hz), 7.09 (2H, d,






J = 9.1 Hz), 8.46 (1H, dd, J = 9.1 Hz, 2.8 Hz),






9.04 (1H, d, J = 2.8 Hz).


207
—CH(OH)—
benzyl
0
1.90-2.05 (1H, m), 2.21-2.68 (3H, m), 3.11-






3.25 (1H, m), 3.28-3.40 (1H, m), 3.45 (2H, s),






3.73 (2H, t, J = 5.1 Hz), 4.77 (1H, d, J = 6.3 Hz),






5.24 (1H, d, J = 6.3 Hz), 7.04 (1H, d, J = 8.9






Hz), 7.16 (2H, d, J = 8.7 Hz), 7.21-7.35 (5H, m),






7.38 (2H, d, J = 8.7 Hz), 8.48 (1H, dd, J = 8.9






Hz, 2.8 Hz), 9.03 (1H, d, J = 2.8 Hz).


 


208




piperonyl
1
0.65-0.70 (2H, m), 0.81-0.88 (2H, m), 2.41- 2.48 (4H, m), 2.77-2.85 (1H, m), 3.45 (2H, s), 3.49-3.52 (2H, m), 3.60-3.63 (2H, m), 4.20 (2H, s), 5.95 (2H, s), 6.71-6.78 (2H, m), 6.86 (1H, brs), 6.90-7.02 (5H, m), 8.39-8.44 (1H, m), 9.06 (1H, d, J = 2.8 Hz).


 


209
—O—
benzyl
1
2.45 (4H, t, J = 4.5 Hz), 3.52 (2H, s), 3.59 (2H, t,






J = 4.9 Hz), 3.65 (2H, t, J = 4.9 Hz), 4.70 (2H,






s), 7.00 (2H, d, J = 9.2 Hz), 7.01 (1H, d, J = 9.0






Hz), 7.08 (2H, d, J = 9.2 Hz), 7.21-7.40 (5H, m),






8.46 (1H, dd, J = 9.0 Hz, 2.8 Hz), 9.04 (1H, d,






J = 2.8 Hz).


210
—N(CH3)—
benzyl
0
2.32 (4H, brs), 3.24 (3H, s), 3.28 (4H, brs),






3.48 (2H, brs), 7.04 (1H, d, J = 9.1 Hz), 7.11 (2H,






d, J = 9.0 Hz), 7.15 (2H, d, J = 9.0 Hz), 7.22-






7.40 (5H, m), 8.48 (1H, dd, J = 9.1 Hz, 2.8 Hz),






9.04 (1H, d, J = 2.8 Hz).
















TABLE 29













 














Reference









Example






1H NMR (CDCl3)


No.
R171
R172 
Xa6
R173 
R174
R175
δ ppm or MS

















211
—NO2
—H
—N(CH3)—
—CH3
—H
—C2H5
1H NMR 1.25 (3H, t, J = 7.1 Hz), 1.50 (3H,









d, J = 7.1 Hz), 2.93 (3H, s), 4.18 (2H, q, J =









7.1 Hz), 4.48 (1H, q, J = 7.3 Hz), 6.82 (2H,









d, J = 9.2 Hz), 6.97 (1H, d, J = 9.1 Hz), 7.03









(2H, d, J = 9.0 Hz), 8.43 (1H, dd, J = 9.1









Hz, 2.8 Hz), 9.06 (1H, d, J = 2.8 Hz).


212
—NO2
—H
—N(CH3)—
—CH3
—CH3
—C2H5
1H NMR 1.24 (3H, t, J = 7.1 Hz), 1.46 (6H,









s), 2.94 (3H, s), 4.18 (2H, q, J = 7.1









Hz), 6.97 (1H, dd, J = 9.1 Hz, 0.5 Hz), 7.00-









7.08 (4H, m), 8.45 (1H, dd, J = 9.1 Hz, 3.0









Hz), 9.05 (1H, dd, J = 2.8 Hz, 0.5 Hz).


213
—NO2
—CH3
—N(CH3)—
—CH3
—H
—C2H5
1H NMR 1.26 (3H, t, J = 7.1 Hz), 1.49 (3H,









d, J = 7.3 Hz), 2.10 (3H, s), 2.91 (3H, s),









4.13-4.24 (2H, m), 4.48 (1H, q, J = 7.3 Hz),









6.64-6.68 (2H, m), 6.91-6.96 (2H, m), 8.43









(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.06 (1H, dd,









J = 2.8 Hz, 0.5 Hz).


214
—NO2
—H
none
—CH3
—CH3
—CH3
MS 316 (M+)


215
—Br
—OCH3
—CH2—
—H
—H
—C2H5
1H NMR 1.26 (3H, t, J = 7.1 Hz), 2.63-2.68









(2H, m), 2.94-3.00 (2H, m), 3.75 (3H, s),









4.15 (2H, q, J = 7.1 Hz), 6.80-6.86 (3H, m),









7.03 (1H, d, J = 7.9 Hz), 7.73 (1H, dd, J =









8.7 Hz, 2.6 Hz), 8.16 (1H, dd, J = 2.6 Hz,









0.7 Hz).


216
3,4-Cl2PhCH2NHCO—
—H
—CH2—
—H
—H
—C2H5
MS 472 (M+)


217
4-CF3PhCH2NHCO—
—H
—CH2—
—H
—H
—C2H5
MS 472 (M+)
















TABLE 30













 










Reference





Example


No.
R176
R177
1H NMR (CDCl3) δ ppm or MS













218
4-CF3PhCO—




1H NMR 1.26 (3H, t, J = 7.1 Hz), 2.64-2.69 (2H, m), 2.95-3.01 (2H, m), 3.76 (3H, s), 4.15 (2H, q, J = 7.1 Hz), 6.83-6.89 (2H, m), 7.03- 7.10 (2H, m), 7.73-7.76 (2H, m), 7.86-7.89 (2H, m), 8.21 (1H, dd, J = 8.6 Hz, 2.5 Hz), 8.55 (1H, dd, J = 2.5 Hz, 0.7 Hz).


 


219
3.4-Cl2PhNHCO—




1H NMR 1.20 (3H, t, J = 7.1 Hz), 3.44 (2H, q, J = 7.1 Hz), 3.56 (3H, s), 4.04 (2H, s), 5.17 (2H, s), 6.15- 6.18 (2H, m), 6.83 (1H, d, J = 8.7 Hz), 6.88 (1H, d, J = 8.9 Hz), 7.29-7.35 (6H, m), 7.44 (1H, dd, J = 8.7 Hz, 2.5 Hz), 7.82 (1H, d, J = 2.3 Hz), 8.10 (1H, dd, J = 8.7 Hz, 2.5 Hz), 8.59 (1H, d, J = 2.5 Hz), 8.72 (1H, brs).


 


220
3,4-Cl2PhNHCO—




MS 501 (M+)


 


221
4-CF3PhNHCO—




MS 501 (M+)


 


222
—COOC2H5
4-NO2Ph-
1H NMR 1.40 (3H, t, J = 7.1 Hz),





4.40 (2H, q, J = 7.1 Hz), 7.08 (1H,





d, J = 8.6 Hz), 7.32 (2H, d, J = 9.0





Hz), 8.31 (2H, d, J = 9.0 Hz),





8.37 (1H, dd, J = 8.6 Hz, 2.3 Hz),





8.82 (1H, d, J = 2.3 Hz).


223
4-CF3PhNHCO—
4-CHOPh-
MS 386 (M+)


 


224
—COOC2H5




1H NMR 1.39 (3H, t, J = 7.1 Hz), 2.28 (3H, s), 4.39 (2H, q, J = 7.1 Hz), 7.07 (1H, dd, J = 8.6 Hz, 0.5 Hz), 7.21 (1H, d, J = 8.9 Hz), 8.13 (1H, dd, J = 8.9 Hz, 2.8 Hz), 8.20 (1H, d, J = 2.8 Hz), 8.36 (1H, dd, J = 8.6 Hz, 2.3 Hz), 8.78 (1H, dd, J = 2.8 Hz, 0.5 Hz).





(CHOPh means a formylphenyl group. Hereinafter CHOPh indicates the same meaning.)













TABLE 31













 












Reference







Example




mp (° C.) or 1H NMR


No.
R178
R179
R180
Form
(solvent) δ ppm















225
4-CF3PhNHCO—
—CH3
—NHCOCOOC2H5
free
1H NMR (DMSO-d6)







1.33 (3H, t, J = 7.1 Hz),







2.08 (3H, s), 4.33 (2H, q,







J = 7.1 Hz), 7.12 (1H, d,







J = 8.7 Hz), 7.17 (1H, d,







J = 8.6 Hz), 7.63 (1H, dd,







J = 8.7 Hz, 2.5 Hz), 7.72-







7.75 (3H, m), 7.98 (2H, d,







J = 8.7 Hz), 8.37 (1H, dd,







J = 8.6 Hz, 2.5 Hz),







8.69 (1H, d, J = 2.5 Hz),







10.62 (1H, brs), 10.81 (1H,







brs).


 


226
3,4-Cl2PhNHCO—
—CH3




hydro- bromide
mp 132.0-134.0


 


227
—NO2
—CH3




free
1H NMR (CDCl3) 1.28 (3H, t, J = 7.1 Hz), 1.86-1.95(2H, m), 2.02- 2.06 (2H, m), 2.10 (3H, s), 2.40-2.48 (1H, m), 2.76- 2.85 (2H, m), 3.61- 3.65 (2H, m), 4.17 (2H, q, J = 7.1 Hz), 6.79-6.97 (4H, m), 8.43 (1H, dd, J = 9.1 Hz, 3.0 Hz), 9.04 (1H, d, J = 2.8 Hz).


 


228
—NO2
—OCH3




free
1H NMR (CDCl3) 1.28 (3H, t, J = 7.1 Hz), 1.41-1.50 (2H, m), 1.84- 2.04 (3H, m), 2.30 (2H, d, J = 6.9 Hz), 2.78 (2H, dd, J = 12.0 Hz, 9.7 Hz), 3.65 (2H, d, J = 12.4 Hz), 3.73 (3H, s) 4.16 (2H, q, J = 7.3 Hz), 6.53 (1H, dd, J = 8.7 Hz, 2.6 Hz), 6.59 (1H, d, J = 2.6 Hz), 6.96- 7.02 (2H, m), 8.42 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.03 (1H, d, J = 2.8 Hz).


 


229
—NO2
—CH3




free
1H NMR (CDCl3) 1.27 (3H, t, J = 7.1 Hz), 1.37-1.49 (2H, m), 1.83- 2.03 (3H, m), 2.10 (3H, s), 2.29 (2H, d, J = 6.9 Hz), 2.74 (2H, dd, J = 12.2 Hz, 10.1 Hz), 3.64 (2H, d, J = 12.4 Hz), 4.15 (2H, q, J = 7.3 Hz), 6.77-6.83 (2H, m), 6.91-6.97 (2H, m), 8.42 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.02 (1H, d, J = 2.8 Hz).
















TABLE 32













 













Reference








Example





1H NMR (CDCl3)


No.
R181
R182 
R183
R184
R185
δ ppm or MS
















230
—Br
—CH3
—H
—H




1H NMR 2.09 (3H, s), 2.41-2.45 (4H, m), 3.01 (3H, s), 3.43 (2H, s), 3.49 (2H, brs), 3.63 (2H, brs), 4.07 (2H, brs), 5.93 (2H, s), 6.51-6.56 (2H, m), 6.68-6.77 (3H, m), 6.85-6.91 (2H, m), 7.68 (1H, dd, J = 8.7 Hz, 2.5 Hz), 8.19 (1H, d, J = 2.5 Hz).


 


231
3,4-Cl2PhNHCO—
—H
—CF3
—H
—N(CH3)CH2COOC2H5
MS 541 (M+)


232
4-CF3PhNHCO—
—H
—CF3
—H
—N(CH3)CH2COOC2H5
MS 541 (M+)


233
3,4-Cl2PhCH2NHCO—
—H
—CF3
—H
—N(CH3)CH2COOC2H5
MS 555 (M+)


234
4-CF3CH2NHCO—
—H
—CF3
—H
—N(CH3)CH2COOC2H5
MS 555 (M+)


235
—Br
—F
—H
—F
—N(CH3)CH2COOC2H5
1H NMR 1.26 (3H, t,








J = 7.1 Hz), 2.99 (3H, s),








4.03 (2H, s), 4.18 (2H, q








J = 7.1 Hz), 6.76 (1H, d,








J = 8.2 Hz, 12.1 Hz),








6.84-6.95 (2H, m), 7.77








(1H, dd, J = 2.6 Hz, 8.7








Hz), 8.17 (1H, d, J = 2.6








Hz).
















TABLE 33













 












Reference







Example


No.
R186
Xa7
R187
M
1H NMR (solvent) δ ppm















236 
—COOC2H5
—CH2—
piperonyl
1
(DMSO-d6) 1.31 (3H, t, J = 7.0 Hz),







2.28 (4H, brs), 2.60-2.66 (2H, m), 2.80-







2.86 (2H, m), 3.38 (2H, s), 3.40-







3.46 (4H, m), 4.31 (2H, q, J = 7.0 Hz),







5.98 (2H, s), 6.72-6.76 (1H, m),







6.84 (2H, d, J = 8.4 Hz), 7.06-7.11 (3H,







m), 7.30 (2H, d, J = 8.4 Hz), 8.30 (1H,







dd, J = 8.6 Hz, 2.4 Hz), 8.68 (1H, d, J =







2.4 Hz).


237
—COOC2H5
none
benzyl
0
(CDCl3) 1.39 (3H, t, J = 7.3 Hz),







2.48 (4H, brs), 3.55-3.91 (6H, m),







4.38 (2H, q, J = 7.3 Hz), 6.97 (1H, d, J =







8.6 Hz), 7.17-7.19 (2H, m), 7.20-







7.34 (5H, m), 7.46-7.49 (2H, m),







8.31 (1H, dd, J = 8.6 Hz, 2.4 Hz),







8.82 (1H, d, J = 2.4 Hz).


238
—Br
—N(CH3)—
piperonyl
1
(CDCl3) 2.41-2.45 (4H, m), 3.03 (3H, s),







3.43 (2H, s), 3.47-3.51 (2H, m), 3.61-







3.65 (2H, m), 4.09 (2H, s), 5.95 (2H, s),







6.68-6.85 (6H, m), 6.96-7.02 (2H, m),







7.70 (1H, dd, J = 8.7 Hz, 2.5 Hz),







8.20 (1H, d, J = 2.5 Hz).


239
—Br
—CH2—
piperonyl
1
(CDCl3) 2.31-2.41 (4H, m), 2.59-







2.65 (2H, m), 2.95-3.00 (2H, m), 3.38-







3.42 (4H, m), 3.61-3.65 (2H, m),







5.95 (2H, s), 6.70-6.77 (2H, m), 6.81-







6.84 (2H, m), 7.01-7.06 (2H, m), 7.22-







7.27 (2H, m), 7.76 (1H, dd, J = 8.7 Hz,







2.6 Hz), 8.20-8.21 (1H, m).


240
—Br
none
benzyl
0
(CDCl3) 2.47 (4H, brs), 3.49-3.55 (6H,







m), 6.86 (1H, d, J = 8.6 Hz), 7.14 (2H,







d, J = 8.6 Hz), 7.28-7.33 (5H, m),







7.45 (2H, d, J = 8.6 Hz), 7.80 (1H, dd,







J = 8.6 Hz, 2.5 Hz), 8.22 (1H, d, J = 2.5







Hz).


241
—COOCH3
—N(CH3)—
piperonyl
1
(CDCl3) 2.41-2.45 (4H, m), 3.04 (3H, s),







3.43 (2H, s), 3.47-3.49 (2H, m),







3.63 (2H, s), 3.91 (3H, s), 4.10 (2H, s),







5.95 (2H, s), 6.69-6.75 (4H, m),







6.84 (1H, dd, J = 8.7 Hz, 0.7 Hz),







6.85 (1H, brs), 7.02 (2H, d, J = 9.2 Hz),







8.21 (1H, dd, J = 8.7 Hz, 2.5 Hz),







8.82 (1H, dd, J = 2.5 Hz, 0.7 Hz).


242
—COOC2H5
none
piperonyl
0
(CDCl3) 1.39 (3H, t, J = 7.1 Hz),







2.45 (4H, brs), 3.45 (2H, s), 3.54-







3.75 (4H, m), 4.38 (2H, q, J = 7.1 Hz),







5.95 (2H, s), 6.71-6.75 (2H, m),







6.86 (1H, s), 6.97 (1H, d, J = 8.6 Hz),







7.19 (2H, d, J = 8.6 Hz), 7.48 (2H, d, J =







8.7 Hz), 8.30 (1H, dd, J = 2.3 Hz, 8.6







Hz), 8.82 (1H, d, J = 2.3 Hz).


















TABLE 34





Reference




Example


No.
Chemical Structure
MS (M+)

















243




413


 


244




504


 


245




413


 


246




574









Reference Example 247
Production of 4-(5-nitropyridin-2-yloxy)phenylamine
To a solution of sodium hydroxide (730 mg, 18.25 mmol) in methanol was added 4-aminophenol (2.00 g, 18.32 mmol). After the resulting mixture was made to dissolve, methanol was evaporated under reduced pressure. To the residue was added DMF (20 mL), and then 2-chloro-5-nitropyridine (2.91 g, 18.35 mmol). The reaction solution was stirred for 1.5 hours at 70° C., and then concentrated under reduced pressure. Water was added to the residue, and the resulting solution was extracted with ethyl acetate. The ethyl acetate layer was washed with brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, after which solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1), to thereby yield 3.37 g of the title compound.
Appearance: Black-red powder
1H NMR (DMSO-d6) δ 5.10 (2H, s), 6.61 (2H, d, J=8.9 Hz), 6.85 (2H, d, J=8.9 Hz), 7.08 (1H, d, J=9.0 Hz), 8.55 (1H, dd, J=9.0 Hz, 3.0 Hz), 9.01 (1H, d, J=3.0 Hz).
The following compounds were produced in the same manner as in Reference Example 247.









TABLE 35





Reference




Example




No.
Chemical Structure
1H NMR (solvent) δ ppm







248




(DMSO-d6) 4.03 (2H, s), 6.96 (1H, d, J = 8.4 Hz), 7.10 (2H, d, J = 8.9 Hz), 7.17 (2H, d, J = 8.9 Hz), 7.48 (2H, d, J = 8.1 Hz), 7.66 (2H, d, J = 8.1 Hz), 7.71 (1H, dd, J = 8.4 Hz, 2.5 Hz), 8.08 (1H, d, J = 2.5 Hz), 9.12 (2H, brs).


 


249




(CDCl3) 1.47 (9H, s), 2.94 (2H, d, J = 5.1 Hz), 3.10-3.80 (9H, m), 4.62 (1H, d, J = 5.1 Hz), 7.03 (1H, d, J = 9.1 Hz), 7.10 (2H, d, J = 8.5 Hz), 7.31 (2H, d, J = 8.5 Hz), 8.46 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.01 (1H, d, J = 2.8 Hz).
















TABLE 36













 









Reference




Example




No.
R188
1H NMR (solvent) δ ppm





250
—CH2OH
(CDCl3) 4.74 (2H, s), 7.04 (1H, d, J = 8.9 Hz), 7.13-7.18 (2H,




m), 7.46 (2H, d, J = 8.3 Hz), 8.48 (1H, dd, J = 8.9 Hz, 2.6




Hz), 9.03 (1H, d, J = 2.6 Hz).


251
—(CH2)2OH
(CDCl3) 2.91 (2H, t, J = 6.6 Hz), 3.91 (2H, t, J = 6.6 Hz),




7.03 (1H, d, J = 9.2 Hz), 7.09-7.13 (2H, m), 7.32 (2H, d, J =




8.6 Hz), 8.47 (1H, dd, J = 9.2 Hz, 3.0 Hz), 9.04 (1H, d, J =




3.0 Hz).


252
—(CH2)2COOH
(CDCl3) 2.73 (2H, t, J = 7.9 Hz), 3.01 (2H, t, J = 7.9 Hz),




7.03 (1H, d, J = 8.9 Hz), 7.09 (2H, d, J = 8.6 Hz), 7.30 (2H,




d, J = 8.6 Hz), 8.47 (1H, dd, J = 9.2 Hz, 3.0 Hz), 9.04 (1H,




d, J = 2.6 Hz).


253
—(CH2)3COOH
(DMSO-d6) 2.01 (2H, dq, J = 15.0 Hz, 7.2 Hz), 2.46 (2H, t,




J = 7.2 Hz), 2.72 (2H, t, J = 7.2 Hz), 7.02 (1H, d, J = 8.6 Hz),




7.08 (2H, d, J = 8.6 Hz), 7.27 (2H, d, J = 8.6 Hz), 8.46 (1H,




dd, J = 8.6 Hz, 3.0 Hz), 9.04 (1H, d, J = 3.0 Hz).









Reference Example 254
Production of ethyl 3-[4-(3-nitrophenoxy)phenyl]-propionate
Under argon; to a solution of 3-iodonitrobenzene (3.00 g, 12.0 mmol) in pyridine (15 mL) were added ethyl 3-(4-hydroxyphenyl)propionate (2.81 g, 14.5 mmol), copper oxide (3.35 g, 42.2 mmol), and potassium carbonate (4.16 g, 30.1 mmol), and the resulting solution was heated to reflux for 40 hours. The reaction solution was concentrated under reduced pressure. Water and ethyl acetate were added to the residue, and once insoluble matter had been filtered off, and the filtrate was extracted with ethyl acetate out. The ethyl acetate layer was washed with 1 M hydrochloric acid, water and a saturated sodium bicarbonate solution, and then washed with brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1→6:1), to thereby yield 1.12 g of the title compound.
Appearance: Pale yellow oil
1H NMR (CDCl3) δ 1.23 (3H, t, J=7.1 Hz), 2.62 (2H, t, J=7.7 Hz), 2.95 (2H, t, J=7.7 Hz), 4.12 (2H, q, J=7.1 Hz), 6.96 (2H, d, J=8.6 Hz), 7.22 (2H, d, J=8.6 Hz), 7.29 (1H, dd, J=8.2 Hz, 2.3 Hz), 7.43 (1H, t, J=8.2 Hz), 7.74 (1H, s), 7.90 (1H, dd, J=8.2 Hz, 2.3 Hz).
Reference Example 255
Production of 1-(t-butoxycarbonyl)-4-[4-(4-nitrophenoxy)phenyl]piperazine
Potassium carbonate (15.7 g, 114 mmol) was added to a solution of 2-chloro-5-nitropyridine (4.50 g, 28.4 mmol) and 1-(4-hydroxyphenyl)piperazine dihydrochloride (7.13 g, 28.4 mmol) in DMF (80 mL). The resulting solution was stirred at room temperature for 8 hours. To this reaction solution was added di-t-butyl dicarbonate (6.81 g, 31.2 mmol), and stirred at room temperature for 2.5 days. To the reaction solution was charged with ethyl acetate, washed with water, and dried with anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3), to thereby yield 7.05 g of the title compound.
Appearance: Yellow needles
1H NMR (CDCl3) δ 1.49 (9H, s), 3.15 (4H, t, J=5.0 Hz), 3.59 (4H, t, J=5.0 Hz), 6.98 (2H, d, J=9.0 Hz), 7.00 (1H, d, J=9.0 Hz), 7.07 (2H, d, J=9.0 Hz), 8.45 (1H, dd, J=9.0 Hz, 2.5 Hz), 9.05 (1H, d, J=2.5 Hz).
Reference Example 256
Production of (ethyl{3-methoxy-4-[5-(4-trifluoromethylphenylcarbamoyl)pyridin-2-yloxy]phenyl}amino)acetate
Benzyl[ethyl(4-hydroxy-3-methoxyphenyl)amino]acetate (9.46 g, 30 mmol) and 6-chloro-N-(4-trifluoromethylphenyl)nicotinamide (9.02 g, 30 mmol) were dissolved in DMF (100 mL). To the resulting solution was added potassium carbonate (6.22 g, 45 mmol), and then stirred for 12 hours at 120° C. The reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate and extracted with water. The pH of the aqueous layer was adjusted from 3 to 4 with 1 M hydrochloric acid, after which the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and evaporated to thereby yield 4.2 g of the title compound.
Appearance: Brown powder
1H NMR (DMSO-d6) δ 1.19 (3H, t, J=7.1 Hz), 3.40 (2H, q, J=7.1 Hz), 3.63 (3H, s), 4.01 (2H, s), 6.17 (1H, d, J=8.9 Hz), 6.22 (1H, brs), 6.25 (1H, d, J=2.5 Hz), 6.87-6.90 (2H, m), 7.53 (2H, d, J=8.6 Hz), 7.76 (2H, d, J=8.4 Hz), 8.18 (1H, dd, J=8.7 Hz, 2.3 Hz), 8.67 (1H, d, J=2.1 Hz), 8.88 (1H, brs).
Reference Example 257
Production of ethyl methyl[2,5-difluoro-4-(5-nitropyridin-2-yloxy)phenyl]aminoacetate
To a solution of ethyl(2,5-difluoro-4-hydroxyphenyl)aminoacetate (1.1 g, 4.8 mmol) in DMF (25 mL) were added sodium bicarbonate (0.44 g, 5.2 mmol) and methyl iodide (1.69 mL, 28.6 mmol), and the resulting reaction solution was stirred for 2 days at room temperature. Water was added to the reaction mixture, and extracted with ethyl acetate. Once the ethyl acetate layer had been washed with water, the ethyl acetate layer was dried with anhydrous magnesium sulfate, and evaporated. The residue was dissolved in DMF (30 mL), and to this resulting solution were added potassium carbonate (0.72 g, 5.2 mmol) and 2-chloro-5-nitropyridine (0.79 g, 5.0 mmol). The reaction solution was stirred for 2.5 days at room temperature. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was then evaporated, and the residue was purified by silica gel chromatography (n-hexane:ethyl acetate=8:1), to thereby yield 1.41 g of the title compound.
Appearance: Yellow oil
1H NMR (CDCl3) δ 1.27 (3H, t, J=7.1 Hz), 3.01 (3H, s), 4.05 (2H, s), 4.19 (2H, q, J=7.1 Hz), 6.77 (1H, dd, J=8.2 Hz, 12.2 Hz), 6.92 (1H, dd, J=7.2 Hz, 12.8 Hz), 8.49 (1H, dd, J=2.8 Hz, 9.0 Hz), 9.02 (1H, d, J=2.8 Hz).
The following compounds were produced in the same manner as in Reference Example 257.







TABLE 37













 











Reference






Example






No.
R189
R190
R191
1H NMR (CDCl3) δ ppm





258
—NO2
—CH3
—CH3
1.27 (3H, t, J = 7.1 Hz), 2.05 (3H, s), 2.29 (3H, s),






2.87 (3H, s), 3.71 (2H, s), 4.18 (2H, q, J = 7.1 Hz),






6.87 (1H, d, J = 8.7 Hz), 6.97 (1H, dd, J = 9.1 Hz,






0.3 Hz), 7.08 (1H, d, J = 8.7 Hz), 8.45 (1H, dd,






J = 9.1 Hz, 2.8 Hz), 9.04 (1H, dd, J = 2.8 Hz,






0.3 Hz).


259
4-CF3PhCO—
—H
—C2H5
1.23 (3H, t, J = 7.1 Hz), 1.28 (3H, t, J = 7.1 Hz),






2.12 (3H, s), 3.46 (2H, q, J = 7.1 Hz), 4.01 (2H, s),






4.21 (2H, q, J = 7.1 Hz), 6.49-6.53 (2H, m), 6.92-






6.96 (2H, m), 7.73-7.77 (2H, m), 7.86-7.89 (2H,






m), 8.17 (1H, dd, J = 8.7 Hz, 2.5 Hz), 8.59 (1H,






dd, J = 2.5 Hz, 0.7 Hz).









Reference Example 260
Production of ethyl 4-{3-[3-methyl-4-(5-nitropyridin-2-yloxy)phenyl]-2-oxotetrahydropyrimidin-1-yl}benzoate
Under a nitrogen atmosphere, to a solution of ethyl 4-[3-(4-benzyloxy-3-methyl)phenyl-2-oxotetrahydropyrimidin-1-yl]benzoate (1.82 g, 3.1 mmol) in ethanol-DMF (70 mL-30 mL) was added 10% palladium-carbon (0.4 g), and the resulting solution was stirred under a hydrogen atmosphere for 4 hours at room temperature. The resulting solution was filtered through Celite, and ethanol was evaporated under reduced pressure so as to give a DMF (30 mL) solution. To this solution was addde 2-chloro-5-nitropyridine (0.52 g, 3.3 mmol) and stirred under a nitrogen atmosphere for 14 hours at room temperature, and then for 3 hours at 40° C. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=10:1), to thereby yield 1.8 g of the title compound.
Appearance: White powder
1H NMR (CDCl3) δ 1.39 (3H, t, J=7.1 Hz), 2.14 (3H, s), 2.21-2.40 (2H, m), 3.75-3.97 (4H, m), 4.36 (2H, q, J=7.1 Hz), 7.01 (1H, d, J=9.1 Hz), 7.06 (1H, d, J=8.6 Hz), 7.23 (1H, dd, J=2.6 Hz, 8.6 Hz), 7.32 (1H, d, J=2.6 Hz), 7.40-7.49 (2H, m), 7.97-8.07 (2H, m), 8.46 (1H, dd, J=2.8 Hz, 9.1 Hz), 9.04 (1H, d, J=2.8 Hz).
Reference Example 261
Production of 3-[4-(5-nitropyridin-2-ylsulfanyl)phenyl]propionic acid
To a solution of 2-chloro-5-nitropyridine (1.74 g, 11.0 mmol) and 4-mercaptohydrocinnamic acid (2.00 g, 11.0 mmol) in DMF (30 mL) was added potassium carbonate (4.55 g, 32.9 mmol), and the resulting solution was stirred for 1 hour at 80° C. To the reaction solution were added water and concentrated hydrochloric acid, and then cooled with ice. The precipitated solid matter was collected by filtration, to thereby yield 3.29 g of the title compound.
Appearance: Pale yellow powder
1H NMR (DMSO-d6) δ 2.60 (2H, t, J=7.5 Hz), 2.91 (2H, t, J=7.5 Hz), 7.07 (1H, d, J=9.0 Hz), 7.43 (2H, d, J=8.2 Hz), 7.57 (2H, d, J=8.2 Hz), 8.39 (1H, dd, J=2.8 Hz, 9.0 Hz), 9.17 (1H, d, J=2.8 Hz), 12.19 (1H, s).
Reference Example 262
Production of ethyl 3-[3-methoxy-4-(5-nitropyridin-2-ylamino)phenyl]propionate
To 2-chloro-5-nitropyridine (3.11 g, 20 mmol) were added ethyl 3-(4-amino-3-methoxyphenyl)propionate (4.38 g, 20 mmol) and acetic acid (10 mL), and the resulting solution was stirred for 13 hours at 100° C. To the reaction solution were added ethyl acetate and water. The ethyl acetate layer was separated, washed with brine, a saturated sodium bicarbonate solution and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby yield 3.78 g of the title compound.
Appearance: Yellow powder
1H NMR (CDCl3) δ 1.26 (3H, t, J=7.1 Hz), 2.61-2.67 (2H, m), 2.93-2.99 (2H, m), 3.89 (3H, s), 4.15 (2H, q, J=7.1 Hz), 6.73 (1H, d, J=9.2 Hz), 6.81-6.87 (2H, m), 7.43 (1H, brs), 7.92 (1H, d, J=8.1 Hz), 8.23 (1H, dd, J=9.2 Hz, 2.8 Hz), 9.11 (1H, d, J=2.8 Hz).
The following compounds were produced in the same manner as in Reference Example 262.







TABLE 38













 









Reference




Example




No.
R192
1H NMR (solvent) δ ppm





263
—COOC2H5
(DMSO-d6) 1.32 (3H, t, J = 7.1 Hz), 4.29 (2H, q, J = 7.1




Hz), 7.01 (1H, d, J = 9.3 Hz), 7.89 (2H, d, J = 8.9 Hz),




8.36 (1H, dd, J = 2.9 Hz, 9.3 Hz), 9.09 (1H, d, J = 2.9




Hz), 10.43 (1H, s).


264
—(CH2)2COOC2H5
(CDCl3) 1.25 (3H, t, J = 7.1 Hz), 2.64 (2H, t, J = 7.6 Hz),




2.97 (2H, t, J = 7.6 Hz), 4.14 (2H, q, J = 7.1 Hz),




6.73 (1H, d, J = 9.3 Hz), 7.20-7.40 (4H, m), 8.23 (1H, dd,




J = 2.7 Hz, 9.3 Hz), 9.07 (1H, d, J = 2.7 Hz).


 


265




(CDCl3) 1.30 (3H, t, J = 7.1 Hz), 2.77 (4H, t, J = 5.0 Hz), 3.28 (4H, t, J = 5.0 Hz), 3.28 (2H, s), 4.22 (2H, q, J = 7.1 Hz), 6.61 (1H, d, J = 9.4 Hz), 6.95 (2H, d, J = 9.0 Hz), 7.11 (1H, brs), 7.22 (2H, d, J = 9.0 Hz), 8.18 (1H, dd, J = 9.4 Hz, 2.5 Hz), 9.05 (1H, d, J = 2.5 Hz).


 


266




(CDCl3) 1.28 (3H, t, J = 7.1 Hz), 1.32-1.60 (2H, m), 1.75- 2.12 (3H, m), 2.29 (2H, d, J = 6.9 Hz), 2.77 (2H, td, J = 12.4 Hz, 2.4 Hz), 3.68 (2H, d, J = 12.4 Hz), 4.16 (2H, q, J = 7.1 Hz), 6.60 (1H, d, J = 9.2 Hz), 6.96 (2H, d, J = 8.9 Hz), 7.16 (1H, brs), 7.20 (2H, d, J = 8.9 Hz), 8.18 (1H, dd, J = 9.2 Hz, 2.6 Hz), 9.05 (1H, d, J = 2.6 Hz).









Reference Example 267
Production of 4-[(5-nitro-2-pyridyl)oxy]benzaldehyde ethylene acetal
To a solution of 4-[(5-nitro-2-pyridyl)oxy]benzaldehyde (5.00 g, 20.5 mmol) in benzene (100 mL) were added ethylene glycol (2.28 mL, 41.0 mmol) and p-toluenesulfonic acid (0.50 g), and the resulting solution was heated to reflux for 3 hours while removing water with a Dean-Stark. The reaction solution was washed with a saturated sodium bicarbonate solution, and subsequently washed with brine. The benzene layer was dried over anhydrous magnesium sulfate, and evaporated, to thereby yield 5.88 g of the title compound.
Appearance: Yellow powder
1H NMR (CDCl3) δ 4.00-4.19 (4H, m), 5.83 (1H, s), 7.00 (1H, d, J=9.0 Hz), 7.15 (2H, d, J=8.5 Hz), 7.55 (2H, d, J=8.5 Hz), 8.45 (1H, dd, J=9.0 Hz, 2.0 Hz), 9.01 (1H, d, J=2.0 Hz).
The following compound was produced in the same manner as in Reference Example 267.
Reference Example 268
4-(2-Fluoro-4-nitrophenoxybenzaldehyde ethylene acetal
1H NMR (DMSO-d6) δ 3.90-4.10 (4H, m), 5.76 (1H, s), 7.15-7.25 (3H, m), 7.54 (2H, d, J=8.7 Hz), 8.10 (1H, ddd, J=1.3 Hz, 2.7 Hz, 9.1 Hz), 8.35 (1H, dd, J=2.7 Hz, 10.8 Hz).
Reference Example 269
Production of t-butyl[4-(5-nitropyridin-2-yloxy)phenyl]carbamate
To a solution of 4-(5-nitropyridin-2-yloxy)phenylamine (2.97 g, 12.85 mmol) in THF was added di-t-butyl dicarbonate (5.60 g, 25.66 mmol), and the resulting solution was stirred under reflux for 4 hours. The reaction solution was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, evaporated, and to the resulting product was added diethyl ether. The obtained white powder was filtered, and the resulting product was washed with diethyl ether, to thereby yield 3.04 g of the title compound.
Appearance: Yellow powder
1H NMR (CDCl3) δ 1.53 (9H, s), 6.53 (1H, brs), 7.00 (1H, d, J=9.2 Hz), 7.09 (2H, d, J=8.9 Hz), 7.45 (2H, d, J=8.9 Hz), 8.46 (1H, dd, J=9.2 Hz, 3.0 Hz), 9.03 (1H, d, J=3.0 Hz).
Reference Example 270
Production of 5-[3-methyl-4-(5-nitropyridin-2-yloxy)benzylidene]thiazolidine-2,4-dione
To a solution of 3-methyl-4-(5-nitropyridin-2-yloxy)benzaldehyde (600 mg, 2.32 mmol) in toluene (35 mL) were added 2,4-thiazolidinedione (270 mg, 2.31 mmol) and piperidine acetate (135 mg, 0.93 mmol). The resulting solution was attached to a Dean Stark, and stirred under reflux for 1.5 hours. After being left to cool for 17 hours at room temperature, the precipitated yellow powder was filtered, to thereby yield 600 mg of the title compound.
Appearance: Yellow powder
1H NMR (DMSO-d6) δ 2.15 (3H, s), 7.33 (1H, d, J=8.4 Hz), 7.35 (1H, d, J=9.1 Hz), 7.52 (1H, dd, J=8.4 Hz, 2.0 Hz), 7.59 (1H, d, J=2.0 Hz), 7.79 (1H, s), 8.65 (1H, dd, J=9.1 Hz, 3.0 Hz), 9.02 (1H, d, J=3.0 Hz), 12.63 (1H, brs).
The following compounds were produced in the same manner as in Reference Example 270.







TABLE 39













 









Reference




Example




No.
R193
1H NMR (solvent) δ ppm





271




(DMSO-d6) 7.35 (1H, d, J = 9.0 Hz), 7.42 (2H, d, J = 8.6 Hz), 7.71 (2H, d, J = 8.6 Hz), 7.84 (1H, s), 8.65 (1H, dd, J = 9.0 Hz, 2.9 Hz), 9.04 (1H, d, J = 2.9 Hz), 12.64 (1H, brs).


 


272
—CH═C(COOCH3)2
(CDCl3) 3.87 (6H, s), 7.09 (1H, d, J = 9.0 Hz), 7.20 (2H, d,




J = 8.5 Hz), 7.53 (2H, d, J = 8.5 Hz), 7.77 (1H, s),




8.51 (1H, dd, J = 9.0 Hz, 2.8 Hz), 9.04 (1H, d, J = 2.8 Hz).









Reference Example 273
Production of N-[4-(2-fluoro-4-nitrophenoxy)phenyl]-N-[2-(4-piperonylpiperazin-1-yl)-2-oxyethyl]acetamide
To a solution of N-[4-(2-fluoro-4-nitrophenoxy)phenyl]acetamide (0.800 g, 2.76 mmol) in DMF (5 mL) was added 60% sodium hydride (0.118 g, 2.95 mmol). The resulting solution was stirred for 10 minutes at room temperature, after which a solution of 1-chloroacetyl-4-piperonylpiperazine (0.870 g, 2.96 mmol) in DMF (4 mL) was added to the reaction solution. The reaction solution was stirred for 2 hours at 60° C., and then for 1 hour at 100° C. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, evaporated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=5:1), to thereby yield 0.730 g of the title compound.
Appearance: Yellow oil
1H NMR (DMSO-d6) δ 1.82 (3H, s), 2.20-2.40 (4H, m), 3.30-3.50 (6H, m), 4.43 (2H, s), 5.98 (2H, s), 6.70-6.85 (3H, m), 7.20-7.30 (3H, m), 7.48 (2H, d, J=8.8 Hz), 8.12 (1H, ddd, J=1.4 Hz, 2.7 Hz, 10.5 Hz), 8.36 (1H, dd, J=2.7 Hz, 10.7 Hz).
The following compound was produced in the same manner as in Reference Example 273.
Reference Example 274
3-(4-Benzyloxy-3-methylphenyl)-1-[2-oxo-2-(4-piperonylpiperazin-1-yl)ethyl]tetrahydropyrimidin-2-one
1H NMR (DMSO-d6) δ 1.92-2.08 (2H, m), 2.15 (3H, s), 2.22-2.40 (4H, m), 3.25-3.49 (8H, m), 3.56 (2H, d, J=5.6 Hz), 4.08 (2H, s), 5.09 (2H, s), 5.97 (2H, s), 6.74 (1H, dd J=1.3 Hz, 7.9 Hz), 6.84 (1H, d, J=7.9 Hz), 6.85 (1H, d, J=1.3 Hz), 6.91 (1H, d, J=8.7 Hz), 6.95 (1H, dd, J=2.5 Hz, 8.6 Hz), 7.01 (1H, d, J=2.5 Hz), 7.28-7.34 (1H, m), 7.36-7.41 (2H, m), 7.42-7.48 (2H, m).
Reference Example 275
Production of 2-dimethylamino-N-[4-(5-nitropyridin-2-yloxy)phenyl]-N-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]acetamide
To a solution of 2-chloro-N-[4-(5-nitropyridin-2-yloxy)phenyl]-N-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]acetamide (0.300 g, 0.528 mmol) in acetonitrile (3 mL) was added at room temperature dimethylamine (0.150 mL, 1.63 mmol), and the resulting solution was stirred for 2 hours at 50° C. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, evaporated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=10:1), to thereby yield 0.270 g of the title compound.
Appearance: Yellow powder
1H NMR (CDCl3) δ 2.29 (6H, s), 2.40-2.45 (4H, m), 3.02 (2H, s), 3.40-3.46 (4H, m), 3.61 (2H, s), 4.48 (2H, s), 5.95 (2H, s), 6.70-6.77 (2H, m), 6.84 (1H, s), 7.09 (1H, d, J=9.0 Hz), 7.19 (2H, d, J=8.7 Hz), 7.51 (2H, d, J=8.7 Hz), 8.51 (1H, dd, J=2.8 Hz, 9.0 Hz), 9.04 (1H, d, J=2.8 Hz).
Reference Example 276
Production of methyl 2-[4-(5-nitropyridin-2-yloxy)phenyl]propionate
To a solution of methyl 2-[4-(5-nitropyridin-2-yloxy)phenyl]acetate (0.50 g, 1.7 mmol) in DMF (10 mL) were added 60% sodium hydride (0.153 g, 3.8 mmol) and methyl iodide (0.13 mL, 2.1 mmol), and the resulting reaction solution was stirred for 1 hour at 0° C. To the reaction solution was added saturated aqueous ammonium chloride, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated aqueous sodium chloride. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel chromatography (n-hexane:ethyl acetate=8:1), to thereby yield 0.32 g of the title compound.
Appearance: Colorless oil
1H NMR (CDCl3) δ 1.54 (3H, d, J=7.4 Hz), 3.69 (3H, s), 3.78 (1H, q, J=7.2 Hz), 7.03 (1H, d, J=9.1 Hz), 7.09-7.15 (2H, m), 7.36-7.41 (2H, m), 8.48 (1H, dd, J=9.1, 2.8 Hz), 9.05 (1H, d, J=2.8 Hz).
Reference Example 277
Production of ethyl 3-{3-methoxy-4-[methyl(5-nitropyridin-2-yl)amino]phenyl}propionate
To a solution of ethyl 3-[3-methoxy-4-(5-nitropyridin-2-ylamino)phenyl]propionate (3.70 g, 11 mmol) in DMF (60 mL) were added under ice-cooling sodium hydride (60%, 490 mg, 12 mmol) and methyl iodide (0.77 mL, 12 mmol), and the resulting reaction solution was stirred for 2 hours gradually warming up to room temperature. The reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate, washed with water and brine, and then dried with anhydrous magnesium sulfate. The solvent was evaporated, to thereby yield 4.27 g of the title compound.
Appearance: Yellow oil substance
1H NMR (CDCl3) δ 1.27 (3H, t, J=7.1 Hz), 2.66-2.71 (2H, m), 2.98-3.04 (2H, m), 3.46 (3H, s), 3.78 (3H, s), 4.17 (2H, q, J=7.1 Hz), 6.12 (1H, brd, J=9.5 Hz), 6.87-6.90 (2H, m), 7.11-7.14 (1H, m), 7.97-8.02 (1H, m), 9.11 (1H, d, J=2.7 Hz).
The following compounds were produced in the same manner as in Reference Example 277.







TABLE 40













 










Reference





Example


No.
R194
R195
1H NMR (solvent) δ ppm













278
—CH3
—COOC2H5
(DMSO-d6) 1.34 (3H, t, J = 7.1





Hz), 3.56 (3H, s), 4.34 (2H, q, J =





7.1 Hz), 6.70 (1H, d, J = 9.5 Hz),





7.55 (2H, d, J = 8.6 Hz), 8.06 (2H,





d, J = 8.6 Hz), 8.21 (1H, dd, J =





2.8 Hz, 9.5 Hz), 9.05 (1H, d, J =





2.8 Hz).


279
—CH3
—(CH2)2COOC2H5
(CDCl3) 1.26 (3H, t, J = 7.1 Hz),





2.67 (2H, t, J = 7.6 Hz), 3.01 (2H,





t, J = 7.6 Hz), 3.55 (3H, s),





4.15 (2H, q, J = 7.1 Hz), 6.32 (1H,





d, J = 9.5 Hz), 7.17 (2H, d, J = 8.3





Hz), 7.32 (2H, d, J = 8.3 Hz),





8.01 (1H, dd, J = 2.7 Hz, 9.5 Hz),





9.11 (1H, d, J = 2.7 Hz).


280
benzyl
—(CH2)2COOC2H5
(CDCl3) 1.24 (3H, t, J = 7.2 Hz),





2.64 (2H, t, J = 7.7 Hz), 2.97 (2H,





t, J = 7.7 Hz), 4.14 (2H, q, J = 7.2





Hz), 5.27 (2H, s), 6.26 (1H, d, J =





9.5 Hz), 7.06 (2H, d, J = 8.3 Hz),





7.20-7.30 (7H, m), 8.02 (1H, dd,





J = 2.7 Hz, 9.5 Hz), 9.12(1H, d,





J = 2.7 Hz).


 


281
—CH3




(CDCl3) 1.30 (3H, t, J = 7.1 Hz), 2.78 (4H, t, J = 5.0 Hz), 3.30 (2H, s), 3.31 (4H, t, J = 5.0 Hz), 3.53 (3H, s), 4.22 (2H, q, J = 7.1 Hz), 6.30 (1H, d, J = 9.5 Hz), 6.99 (2H, d, J = 8.9 Hz), 7.12 (2H, d, J = 8.9 Hz), 7.99 (1H, dd, J = 9.5 Hz, 2.8 Hz), 9.10 (1H, d, J = 2.8 Hz).


 


282
—CH3




(CDCl3) 1.28 (3H, t, J = 7.1 Hz), 1.45 (2H, qd, J = 12.2 Hz, 3.7 Hz), 1.80-2.17 (3H, m), 2.30 (2H, d, J = 6.9 Hz), 2.80 (2H, td, J = 12.2 Hz, 2.3 Hz), 3.52 (3H, s), 3.72 (2H, d, J = 12.4 Hz), 4.16 (2H, q, J = 7.1 Hz), 6.30 (1H, d, J = 9.5 Hz), 6.98 (2H, d, J = 8.9 Hz), 7.10 (2H, d, J = 8.9 Hz), 7.98 (1H, dd, J = 9.5 Hz, 2.8 Hz), 9.10 (1H, d, J = 2.8 Hz).
















TABLE 41













 









Reference




Example


No.
R196
1H NMR (CDCl3) δ ppm












283 
—(CH2)2CH3
0.93 (3H, t, J = 7.4 Hz), 1.60-1.70 (2H, m),




2.35-2.43 (4H, m), 2.66 (2H, t, J = 8.1 Hz),




3.03 (2H, t, J = 8.1 Hz), 3.42 (2H, s), 3.43-




3.45 (2H, m), 3.62-3.65 (2H, m), 3.96 (2H,




t, J = 7.7 Hz), 5.95 (2H, s), 6.16 (1H, d, J =




9.5 Hz), 6.70-6.80 (2H, m), 6.84 (1H, d, J =




1.3 Hz), 7.14 (2H, d, J = 8.3 Hz), 7.33 (2H,




d, J = 8.3 Hz), 7.96 (1H, dd, J = 2.8 Hz, 9.5




Hz), 9.08 (1H, d, J = 2.8 Hz).


284
cyclopentyl
1.30-1.40 (2H, m), 1.55-1.65 (4H, m), 1.95-




2.00 (2H, m), 2.35-2.45 (4H, m), 2.67 (2H,




t, J = 7.4 Hz), 3.04 (2H, t, J = 7.4 Hz), 3.42




(2H, s), 3.43-3.47 (2H, m), 3.55-3.68 (2H,




m), 5.18-5.28(1H, m), 5.88 (1H, d, J = 9.5




Hz), 5.95 (2H, s), 6.70-6.78 (2H, m), 6.84




(1H, s), 7.04 (2H, d, J = 8.2 Hz), 7.34 (2H,




d, J = 8.2 Hz), 7.92 (1H, dd, J = 2.8 Hz, 9.5




Hz), 9.09 (1H, d, J = 2.8 Hz).


















TABLE 42





Reference




Example


No.
Chemical Structure
1H NMR (solvent) δ ppm

















285




(CDCl3) 1.91-2.06 (2H, m), 2.27 (3H, s), 3.31-3.44 (2H, m), 3.58 (2H, t, J = 6.3 Hz), 4.69-4.85 (1H, m), 5.07 (2H, s), 6.04 (1H, s), 6.84 (1H, d, J = 10.1 Hz), 7.01 (1H, dd, J = 8.5 Hz, 2.5 Hz), 7.04 (1H, d, J = 2.5 Hz), 7.30-7.36 (1H, m), 7.37- 7.46 (4H, m).


 


286




(CDCl3) 1.96-2.11 (2H, m), 2.27 (3H, s), 3.20-3.34 (2H, m), 3.56-3.68 (2H, m), 4.50 (2H, s), 5.07 (2H, s), 5.94 (2H, s), 6.72-6.80 (2H, m), 6.84 (1H, d, J = 8.6 Hz), 6.88 (1H, d, J = 1.2 Hz), 7.04 (1H, dd, J = 2.6 Hz, 8.6 Hz), 7.11 (1H, d, J = 2.6 Hz), 7.28-7.34 (1H, m), 7.35- 7.41 (2H, m), 7.42-7.48 (2H, m).


 


287




(DMSO-d6) 3.20-3.40 (2H, m), 3.71 (3H, s), 3.64-3.83 (2H, m), 4.36 (2H, s), 6.84-6.95 (2H, m), 7.22- 7.41 (5H, m), 7.42-7.53 (2H, m).


 


288




(DMSO-d6) 2.18 (3H, s), 3.35 (2H, t, J = 8.7 Hz), 3.69-3.84 (2H, m), 5.05 (2H, s), 6.74 (1H, s), 6.93 (1H, d, J = 8.9 Hz), 7.23 (1H, dd, J = 2.8 Hz, 8.9 Hz), 7.27-7.48 (6H, m).


 


289




(CDCl3) 2.29 (3H, s), 3.28-3.39 (2H, m), 3.68-3.81 (2H, m), 4.36 (2H, s), 5.06 (2H, s), 5.95 (2H, s), 6.77 (2H, s), 6.78-6.91 (2H, m), 7.20-7.35 (2H, m), 7.36-7.51 (5H, m).


 


290




(CDCl3) 1.93-2.12 (2H, m), 2.27 (3H, s), 3.28 (2H, t, J = 5.9 Hz), 3.63 (2H, t, J = 5.9 Hz), 3.88 (6H, s), 4.55 (2H, s), 5.07 (2H, s), 6.71-6.92 (4H, m), 6.96-7.08 (1H, m), 7.11 (1H, d, J = 2.1 Hz), 7.25-7.51 (5H, m).









Reference Example 291
Production of N-[4-(5-nitropyridin-2-yloxy)phenyl]-2-(4-piperonylpiperazin-1-yl)acetamide
A solution of (4-piperonylpiperazin-1-yl)acetic acid (13.9 g, 50 mmol) was suspended in DMF (400 mL), and to the resulting suspension were added 1-hydroxybenzotriazole monohydrate (8.42 g, 55 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.5 g, 55 mmol) and 4-(5-nitropyridin-2-yloxy)phenylamine (11.6 g, 50 mmol) under ice cooling. The resulting solution was stirred for 6 hours at room temperature. The reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate, and washed with a saturated sodium bicarbonate solution and brine. The organic layer was left for standing overnight at room temperature, and the resulting precipitated crystals were collected by suction filtration, to thereby yield 12.8 g of the title compound.
Appearance: White powder
1H NMR (CDCl3) δ 2.53 (4H, brs), 2.64-2.65 (4H, m), 3.15 (2H, s), 3.46 (2H, s), 5.95 (2H, s), 6.76 (2H, brs), 6.86 (1H, s), 7.04 (1H, d, J=9.1 Hz), 7.14 (2H, d, J=8.7 Hz), 7.67 (2H, d, J=8.9 Hz), 8.47 (1H, dd, J=9.1 Hz, 2.8 Hz), 9.03 (1H, d, J=2.8 Hz), 9.24 (1H, brs).
Reference Example 292
Production of ethyl{methanesulfonyl[3-methoxy-4-(5-nitropyridin-2-yloxy)phenyl]amino}acetate
A solution of ethyl[3-methoxy-4-(5-nitropyridin-2-yloxy)phenylamino]acetate (2.43 g, 7.00 mmol) was dissolved in THF (15 mL), dichloromethane (20 mL) and DMF (10 mL), and to the resulting solution were added triethylamine (1.95 mL, 13.99 mmol), 4-dimethylaminopyridine (0.86 g, 7.00 mmol) and methanesulfonyl chloride (1.08 mL, 13.99 mmol) under ice cooling. The resulting solution was stirred for 14 hours at 30° C. Water was added to the reaction mixture, and extracted with dichloromethane. The dichloromethane layer was washed with water and brine. The dichloromethane layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2), to thereby yield 1.10 g of the title compound.
Appearance: Yellow oil
1H NMR (CDCl3) δ 1.32 (3H, t, J=7.3 Hz), 3.18 (3H, s), 3.75 (3H, s), 4.26 (2H, q, J=7.3 Hz), 4.49 (2H, s), 7.09 (1H, d, J=9.1 Hz), 7.15 (2H, d, J=1.2 Hz), 7.25 (1H, s), 8.48 (1H, dd, J=9.1 Hz, 2.8 Hz), 8.98 (1H, d, J=2.8 Hz).
The following compounds were produced in the same manner as in Reference Example 292.









TABLE 43





Reference




Example




No.
Chemical Structure
1H NMR (solvent) δ ppm or MS







293




1H NMR (DMSO-d6) 3.00 (3H, s), 5.17 (2H, s), 7.05 (1H, d, J = 8.4 Hz), 7.12 (2H, d, J = 8.9 Hz), 7.19-7.26 (4H, m), 7.67 (2H, d, J = 8.9 Hz), 7.95 (1H, dd, J = 8.4 Hz, 2.5 Hz), 8.25 (1H, d, J = 2.3 Hz), 9.69 (1H, brs).


 


294




1H NMR (CDCl3) 2.18 (3H, s), 3.04 (3H, s), 5.04 (2H, s), 6.56 (1H, brs), 6.96 (1H, d, J = 8.6 Hz), 7.01-7.09 (4H, m), 7.15 (1H, d, J = 2.6 Hz), 7.56 (2H, d, J = 8.4 Hz), 7.79 (1H, dd, J = 8.6 Hz, 2.5 Hz), 8.19 (1H, d, J = 2.5 Hz).


 


295




MS 364 (M+)









Reference Example 296
Production of 3-[4-(5-nitropyridin-2-yloxy)phenyl]-n-propanol
To a solution of 3-[4-(5-nitropyridin-2-yloxy)phenyl]propionic acid (2.64 g, 9.2 mmol) in THF (50 mL) was added dropwise a 1 M borane-THF complex THF solution (38.4 mL, 38.4 mmol) under ice cooling. The reaction solution was stirred for 2 hours at room temperature. Water was added to the reaction mixture, and extracted with ethyl acetate, and the ethyl acetate layer was washed with water and then brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, after which solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1), to thereby yield 1.17 g of the title compound.
Appearance: Green oil
1H NMR (CDCl3) δ 1.90-1.96 (2H, m), 2.73-2.79 (2H, m), δ 3.69-3.74 (2H, m), 7.00-7.09 (3H, m), 7.26-7.30 (2H, m), 8.44-8.49 (1H, m), 9.05 (1H, d, J=2.6 Hz).
Reference Example 297
Production of 2-{4-[3-(t-butyldimethylsilanyloxy)-propyl]phenoxy}-5-nitropyridine
To a solution of 3-[4-(5-nitropyridin-2-yloxy)phenyl]-n-propanol (1.17 g, 4.3 mmol) in DMF (10 mL) were added imidazole (580 mg, 8.5 mmol) and t-butylchlorodimethylsilane (640 mg, 4.2 mmol), and the resulting solution was stirred for 13 hours at room temperature. Water was added to the reaction mixture, and extracted with diethyl ether, and the diethyl ether layer was washed with water and then brine. The diethyl ether layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to thereby yield 1.14 g of the title compound.
Appearance: Pale yellow powder
1H NMR (CDCl3) δ 0.07 (6H, s), 0.92 (9H, s), 1.84-1.89 (2H, m), 2.69-2.75 (2H, m), 3.66 (2H, t, J=6.3 Hz), 6.99-7.08 (3H, m), 7.27 (2H, d, J=7.6 Hz), 8.46 (1H, dd, J=8.9 Hz, 3.0 Hz), 9.05 (1H, d, J=3.0 Hz).
The following compound was produced in the same manner as in Reference Example 297.
Reference Example 298
2-{4-[2-(t-Butyldimethylsilanyloxy)ethyl]phenoxy}-5-nitropyridine
1H NMR (CDCl3) δ 0.00 (6H, s), 0.88 (9H, s), 2.86 (2H, t, J=6.9 Hz), 3.84 (2H, t, J=6.9 Hz), 7.00 (1H, d, J=9.2 Hz), 7.05-7.08 (2H, m), 7.26-7.31 (2H, m), 8.46 (1H, dd, J=9.2 Hz, 3.0 Hz), 9.05 (1H, d, J=3.0 Hz).
Reference Example 299
Production of ethyl 4-[4-(5-nitropyridin-2-yloxy)phenyl]butanoate
To a solution of 4-[4-(5-nitropyridin-2-yloxy)phenyl]butanoic acid (9.98 g, 33.01 mmol) in dichloromethane were added ethanol (5.59 mL, 99.01 mmol), 4-dimethylaminopyridine (400 mg, 3.27 mmol), triethylamine (13.81 mL, 99.08 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.6 g, 39.65 mmol) under ice cooling, and the resulting solution was stirred for 20 minutes under ice cooling and then for 1 hour at room temperature. The reaction solution was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate, and the ethyl acetate layer was washed with 1 N hydrochloric acid, a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to thereby yield 6.77 g of the title compound.
Appearance: Colorless oil
1H NMR (CDCl3) δ 1.27 (3H, t, J=7.0 Hz), 1.99 (2H, dt, J=15.0 Hz, 7.5 Hz), 2.36 (2H, t, J=7.5 Hz), 2.70 (2H, t, J=7.5 Hz), 4.14 (2H, q, J=7.0 Hz), 7.01 (1H, d, J=9.0 Hz), 7.08 (2H, d, J=8.5 Hz), 7.26 (2H, d, J=8.5 Hz), 8.46 (1H, dd, J=9.0 Hz, 3.0 Hz), 9.04 (1H, d, J=3.0 Hz).
Reference Example 300
Production of methyl 3-[4-(5-nitropyridin-2-ylsulfanyl)phenyl]propionate
To a solution of 3-[4-(5-nitropyridin-2-ylsulfanyl)phenyl]propionic acid (86.0 g, 0.283 mmol) in DMF (1 mL) were added potassium carbonate (59.0 mg, 0.424 mmol) and methyl iodide (0.0260 mL, 0.424 mmol), and the resulting solution was stirred for 1 hour at room temperature. Water was added to the reaction mixture, and then cooled with ice. The precipitated solid matter was collected by filtration, to thereby yield 76.9 mg of the title compound.
Appearance: Light brown powder
1H NMR (DMSO-d6) δ 2.70 (2H, t, J=7.6 Hz), 2.94 (2H, t, J=7.6 Hz), 3.60 (3H, s), 7.07 (1H, d, J=8.9 Hz), 7.43 (2H, d, J=8.1 Hz), 7.57 (2H, d, J=8.1 Hz), 8.39 (1H, dd, J=2.7 Hz, 8.9 Hz), 9.17 (1H, d, J=2.7 Hz).
Reference Example 301
Production of ethyl(Z)-3-[4-(5-nitro-2-pyridyloxy)phenyl]-2-butenoate
To a suspension of 60% sodium hydride (1.28 g, 32.0 mmol) in THF (80 mL) was added dropwise a solution of triethyl phosphonoacetate (8.71 g, 38.8 mmol) in THF (40 mL) under ice cooling, and the resulting solution was stirred for 10 minutes at the same temperature. To the reaction solution was added 4-[(5-nitro-2-pyridyl)oxy]acetophenone (5.90 g, 22.8 mmol) and the resulting solution was stirred at the same temperature for 10 minutes, and then stirred at room temperature for 60 hours. To the reaction solution was added saturated ammonium chloride and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution, and then washed with brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to thereby yield 1.17 g of the title compound.
Appearance: Colorless needles
1H NMR (CDCl3) δ 1.13 (3H, t, J=7.1 Hz), 2.20 (3H, d, J=1.4 Hz), 4.02 (2H, q, J=7.1 Hz), 5.93 (1H, q, J=1.4 Hz), 7.02 (1H, d, J=9.0 Hz), 7.12 (2H, d, J=8.6 Hz), 7.29 (2H, d, J=8.6 Hz), 8.45 (1H, dd, J=9.0 Hz, 2.8 Hz), 9.03 (1H, d, J=2.8 Hz).
The following compounds were produced in the same manner as in Reference Example 301.
Reference Example 302
Ethyl(E)-3-{4-[4-(3,4-dichlorobenzoylamino)-2-fluorophenoxy]phenyl}acrylate
Melting point: 166-167° C.







TABLE 44













 










Reference





Example





No.
R197
R198
1H NMR (CDCl3) δ ppm or MS





303
—H
—H
1H NMR 1.35 (3H, t, J = 7.1 Hz), 4.28 (2H, q, J = 7.1 Hz),





6.43 (1H, d, J = 16.0 Hz), 7.09 (1H, d, J = 8.9 Hz), 7.20 (2H, d,





J = 8.7 Hz), 7.62 (2H, d, J = 8.7 Hz), 7.70 (1H, d, J = 16.0 Hz),





8.50 (1H, dd, J = 8.9 Hz, 2.5 Hz), 9.04 (1H, d, J = 2.5 Hz).


304
—H
—CH3
1H NMR 1.31 (3H, t, J = 7.1 Hz), 2.58 (3H, d, J = 1.2 Hz),





4.21 (2H, q, J = 7.1 Hz), 6.14 (1H, q, J = 1.2 Hz), 7.05 (1H, d,





J = 9.0 Hz), 7.16 (2H, d, J = 8.7 Hz), 7.55 (2H, d, J = 8.7 Hz),





8.48 (1H, dd, J = 9.0 Hz, 2.8 Hz), 9.03 (1H, d, J = 2.8 Hz).


305
—CH3
—H
MS 328 (M+)









Reference Example 306
Production of ethyl 3-[4-(5-nitropyridine-2-carbonyl)phenyl]propionate
A solution of bis(tributyltin) (1.37 g, 2.36 mmol) in toluene (7 mL) was added under an argon atmosphere to 2-chloro-5-nitropyridine (0.325 g, 2.05 mmol), bis(dibenzylideneacetone)palladium(0) (18.1 mg, 0.0315 mmol), tri(2-furyl)phosphine (29.3 mg, 0.126 mmol) and molecular sieves 4A (1.90 g), and the resulting solution was heated to reflux for 1 hour. To the reaction solution was added bis(dibenzylideneacetone)palladium(0) (27.2 mg, 0.0472 mmol) and tri(2-furyl)phosphine (43.9 mg, 0.189 mmol), and subsequently added a solution of 4-[2-ethoxycarbonyl]ethyl]benzoyl chloride (0.379 g, 1.57 mmol) in toluene (5 mL). The resulting reaction solution was stirred for 4 hours at 80° C. To the reaction solution was added saturated aqueous potassium fluoride and stirred for 0.5 hours at room temperature. Insoluble matter was then filtered off. The filtrate was extracted with ethyl acetate, and the ethyl acetate layer was washed with brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane→n-hexane:ethyl acetate=4:1), to thereby yield 0.323 g of the title compound.
Appearance: Pale yellow powder
1H NMR (CDCl3) δ 1.22 (3H, t, J=7.1 Hz), 2.65 (2H, t, J=7.7 Hz), 3.03 (2H, t, J=7.7 Hz), 4.12 (2H, q, J=7.1 Hz), 7.34 (2H, d, J=8.3 Hz), 8.00 (2H, d, J=8.3 Hz), 8.18 (1H, d, J=8.5 Hz), 8.65 (1H, dd, J=8.5 Hz, 2.6 Hz), 9.49 (1H, d, J=2.6 Hz).
Reference Example 307
Production of ethyl 3-[4-(4-aminophenoxy)phenyl]propionate
To a suspension of 5% palladium-carbon (0.50 g) in ethanol (50 mL) was added ethyl 3-[4-(4-nitrophenoxy)phenyl]propionate (5.00 g, 15.9 mmol), and the resulting solution was subjected to catalytic reduction at atmospheric pressure and at room temperature. Once the absorption of hydrogen had stopped, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure, to thereby yield 4.52 g of the title compound.
Appearance: Light brown oil
1H NMR (CDCl3) δ 1.22 (3H, t, J=7.1 Hz), 2.57 (2H, t, J=7.8 Hz), 2.88 (2H, t, J=7.8 Hz), 3.55 (2H, brs), 4.10 (2H, q, J=7.1 Hz), 6.64 (2H, d, J=8.8 Hz), 6.78-6.86 (4H, m), 7.08 (2H, d, J=8.6 Hz).
The following compounds were produced in the same manner as in Reference Example 307.







TABLE 45













 










Reference





Example No.
R199
R200
1H NMR (CDCl3) δ ppm





308
4-NH2Ph-
2-(CH2)2COOCH3
2.66 (2H, t, J = 7.8 Hz), 3.00 (2H, t, J = 7.8





Hz), 3.54 (2H, brs), 3.63 (3H, s), 6.65 (2H, d,





J = 8.8 Hz), 6.70 (1H, d, J = 8.1 Hz),





6.79 (2H, d, J = 8.8 Hz), 6.94 (1H, t, J = 8.1





Hz), 7.08 (1H, t, J = 8.1 Hz), 7.19 (1H, d, J =





8.1 Hz).


309
4-NH2Ph-
3-(CH2)2COOC2H5
1.21 (3H, t, J = 7.2 Hz), 2.56 (2H, t, J = 7.9





Hz), 2.87 (2H, t, J = 7.9 Hz), 3.54 (2H, brs),





4.10 (2H, q, J = 7.2 Hz), 6.66 (2H, d, J = 8.8





Hz), 6.70-6.76 (2H, m), 6.79-6.87 (3H, m),





7.16 (1H, t, J = 7.8 Hz).


310
2-NH2Ph-
4-(CH2)2COOC2H5
1.22 (3H, t, J = 7.2 Hz), 2.56 (2H, t, J = 7.8





Hz), 2.89 (2H, t, J = 7.8 Hz), 3.55 (2H, brs),





4.11 (2H, q, J = 7.2 Hz), 6.72 (1H, t, J = 7.8





Hz), 6.79-6.92 (4H, m), 6.93 (1H, t, J = 7.8





Hz), 7.12 (2H, d, J = 8.5 Hz).


311
4-NH2Ph-
4-COOC2H5
1.37 (3H, t, J = 7.1 Hz), 4.36 (2H, q, J = 7.1





Hz), 4.00-4.50 (2H, m), 6.78 (2H, d, J = 8.9





Hz), 6.89-6.95 (4H, m), 7.97 (2H, d, J = 8.9





Hz).


312
3-NH2Ph-
4-(CH2)2COOC2H5
1.22 (3H, t, J = 7.2 Hz), 2.59 (2H, t, J = 7.8





Hz), 2.91 (2H, t, J = 7.8 Hz), 3.65 (2H, brs),





4.12 (2H, q, J = 7.2 Hz), 6.29 (1H, t, J = 2.2





Hz), 6.32-6.41 (2H, m), 6.92 (2H, d, J = 8.6





Hz), 7.06 (1H, t, J = 8.0 Hz), 7.13 (2H, d, J =





8.6 Hz).


 


313




3-COOCH3
3.56 (2H, brs), 3.89 (3H, s), 6.80 (1H, dd, J = 8.6 Hz, 0.7 Hz), 7.11 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.25-7.29 (1H, m), 7.39-7.44 (1H, m), 7.69-7.72 (2H, m), 7.78-7.82 (1H, m).
















TABLE 46













 










Reference





Example No.
R201
Form
1H NMR (solvent) δ ppm





314
—Ac
hydrochloride
(DMSO-d6) 2.53 (3H, s), 3.30-4.20 (3H, m),





6.88 (1H, d, J = 8.8 Hz), 6.99-7.05 (3H, m),





7.22 (1H, t, J = 8.8 Hz), 7.96 (1H, d, J = 8.9 Hz).


315
—CH2COOCH3
free
(CDCl3) 3.57 (2H, s), 3.60-3.80 (5H, m),





6.41 (1H, ddd, J = 1.2 Hz, 2.6 Hz, 8.6 Hz),





6.50 (1H, dd, J = 2.6 Hz, 12.0 Hz), 6.80-





6.95 (3H, m), 7.18 (2H, d, J = 8.4 Hz).


316
—(CH2)2COOC2H5
free
(CDCl3) 1.21 (3H, t, J = 7.1 Hz), 2.56 (2H, t, J =





7.8 Hz), 2.87 (2H, t, J = 7.8 Hz), 3.66 (2H,





brs), 4.10 (2H, q, J = 7.1 Hz), 6.34-6.43 (1H,





m), 6.48 (1H, dd, J = 12.0 Hz, 2.7 Hz), 6.77-





6.93 (3H, m), 7.08 (2H, d, J = 8.7 Hz).


317
—H
free
(CDCl3) 3.66 (2H, brs), 6.35-6.44 (1H, m),





6.49 (1H, dd, J = 12.0 Hz, 2.7 Hz), 6.83-





6.96 (3H, m), 7.01 (1H, dd, J = 9.0 Hz, 8.0





Hz), 7.26 (2H, t, J = 8.0 Hz).


318
—(CH2)3COOC2H5
free
(CDCl3) 1.23 (3H, t, J = 7.1 Hz), 1.83-





1.97 (2H, m), 2.28 (2H, t, J = 7.5 Hz),





2.57 (2H, t, J = 7.6 Hz), 3.66 (2H, brs),





4.09 (2H, q, J = 7.1 Hz), 6.34-6.43 (1H, m),





6.48 (1H, dd, J = 12.0 Hz, 2.7 Hz), 6.81 (2H,





d, J = 8.5 Hz), 6.88 (1H, dd, J = 9.0 Hz, 8.0





Hz), 7.05 (2H, d, J = 8.5 Hz).


319
—COOC2H5
free
(DMSO-d6) 1.29 (3H, t, J = 7.1 Hz), 4.27 (2H,





q, J = 7.1 Hz), 5.42 (2H, brs), 6.41 (1H, dt, J =





1.6 Hz, 8.6 Hz), 6.50 (1H, dd, J = 2.5 Hz, 13.3





Hz), 6.90-7.00 (3H, m), 7.91 (2H, d, J = 9.7 Hz).


320
—NHCH2COOC2H5
free
(CDCl3) 1.29 (3H, t, J = 7.1 Hz), 3.62 (2H, s),





3.86 (2H, s), 4.12 (1H, s), 4.23 (2H, q, J = 7.1





Hz), 6.35-6.39 (1H, m), 6.48 (1H, dd, J = 2.7





Hz, 12.1 Hz), 6.55 (2H, d, J = 8.9 Hz), 6.80-





6.85 (3H, m).


321




free
(CDCl3) 3.70 (2H, brs), 3.95-4.15 (4H, m), 5.76 (1H, s), 6.38-6.42 (1H, m), 6.49 (1H, dd, J = 2.7 Hz, 14.7 Hz), 6.85-6.93 (3H, m), 7.39 (2H, d, J = 8.7 Hz).
















TABLE 47













 











Reference






Example No.
R202
R203
R204
1H NMR (CDCl3) δ ppm





322
—H
—H
—C2H5
1.38 (3H, t, J = 7.3 Hz), 4.35 (2H, q, J = 7.3 Hz),






6.82 (1H, d, J = 8.6 Hz), 7.04-7.14 (3H, m), 7.75 (1H, d,






J = 3.0 Hz), 8.01-8.04 (2H, m).


323
—H
—H
—CH3
3.30 (2H, brs), 3.89 (3H, s), 6.82 (1H, d, J = 8.6






Hz), 7.04-7.13 (3H, m), 7.75 (1H, d, J = 3.0 Hz),






8.02 (2H, dd, J = 6.6 Hz, 2.0 Hz).


324
—F
—H
—CH3
3.57 (2H, brs), 3.91 (3H, s), 6.87 (1H, d, J = 8.6 Hz),






7.10-7.23 (2H, m), 7.64 (1H, d, J = 3.0 Hz), 7.80-






7.82 (1H, m), 7.83-7.85 (1H, m).


325
—F
—H
—C2H5
1.38 (3H, t, J = 7.1 Hz), 4.37 (2H, q, J = 7.1 Hz),






6.87 (1H, d, J = 8.6 Hz), 7.12 (1H, dd, J = 8.6 Hz, 3.0






Hz), 7.15-7.22 (1H, m), 7.64 (1H, d, J = 3.0 Hz), 7.81-






7.86 (2H, m).


326
—CH3
—H
—CH3
2.29 (3H, s), 3.56 (2H, brs), 3.89 (3H, s), 6.79 (1H, d, J =






8.6 Hz), 6.92 (1H, d, J = 8.6 Hz), 7.11 (1H, dd, J = 8.6






Hz, 3.0 Hz), 7.71 (1H, d, J = 3.0 Hz), 7.85 (1H, dd, J =






8.6 Hz, 2.4 Hz), 7.94 (1H, d, J = 2.4 Hz).


327
—OCH3
—H
—C2H5
1.38 (3H, t, J = 7.1 Hz), 3.55 (2H, brs), 3.85 (3H, s),






4.37 (2H, q, J = 7.1 Hz), 6.79-6.83 (1H, m), 7.02






7.10 (2H, m), 7.63-7.67 (3H, m).


328
—H
—OCH3
—CH3
3.63 (2H, brs), 3.86 (6H, s), 6.54-6.58 (1H, m), 6.68 (1H,






d, J = 2.2 Hz), 6.81-6.84 (1H, m), 7.13 (1H, dd, J = 8.6






Hz, 3.0 Hz), 7.77 (1H, dd, J = 3.0 Hz, 0.5 Hz), 7.83 (1H,






d, J = 8.9 Hz).


329
—H
—CH3
—CH3
2.58 (3H, s), 3.63 (2H, brs), 3.86 (3H, s), 6.80-6.88 (3H,






m), 7.13 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.75 (1H, d, J =






3.0 Hz), 7.92-7.96 (1H, m).


330
—Cl
—H
—CH3
3.62 (2H, brs), 3.91 (3H, s), 6.88 (1H, d, J = 8.6 Hz),






7.08-7.15 (2H, m), 7.68 (1H, d, J = 3.0 Hz), 7.91 (1H, dd,






J = 8.6 Hz, 2.1 Hz), 8.13 (1H, d, J = 2.1 Hz).
















TABLE 48













 











Reference






Example


No.
R205
R206
M
1H NMR (CDCl3) δ ppm or MS





331
—H
—CH3
2
MS 272 (M+)


332
—OCH3
—C2H5
2
1H NMR 1.25 (3H, t, J = 7.1 Hz),






2.63 (2H, t, J = 7.5 Hz), 2.94






(2H, t, J = 7.5 Hz), 3.43 (2H, brs),






3.77 (3H, s), 4.14 (2H, q, J = 7.1






Hz), 6.71-6.86 (3H, m), 6.98 (1H,






d, J = 8.0 Hz), 7.06 (1H, dd, J =






8.6 Hz, 2.9 Hz), 7.65 (1H, d, J =






2.9 Hz).


333
—H
—CH3
1
1H NMR 3.60 (2H, s), 3.69 (3H,






s), 6.76 (1H, d, J = 8.6 Hz), 6.99-






7.10 (3H, m), 7.24-7.27 (2H, m),






7.71 (1H, d, J = 3.0 Hz).


334
—H
—C2H5
2
1H NMR 1.21 (3H, t, J = 7.1 Hz),






2.58 (2H, t, J = 7.7 Hz), 2.90 (2H,






t, J = 7.7 Hz), 4.11 (2H, q, J = 7.1






Hz), 6.72 (1H, d, J = 8.6 Hz), 6.95






(2H, d, J = 8.5 Hz), 7.05 (1H, dd,






J = 8.6 Hz, 3.0 Hz), 7.14 (2H, d,






J = 8.5 Hz), 7.68 (1H, d, J =






3.0 Hz).


335
—OCH3
—CH3
2
1H NMR 2.62-2.68 (2H, m), 2.91-






2.97 (2H, m), 3.45 (2H, brs), 3.69






(3H, s), 3.77 (3H, s), 6.74-6.79






(2H, m), 6.82 (1H, d, J = 1.8 Hz),






6.98 (1H, d, J = 7.9 Hz),






7.04-7.26 (1H, m), 7.64 (1H, d,






J = 3.0 Hz).


336
—OC2H5
—C2H5
2
1H NMR 1.20 (3H, t, J = 7.0






Hz), 1.25 (3H, t, J = 7.1 Hz), 2.51-






2.68 (2H, m), 2.81-3.01 (2H, m),






3.19-3.63 (2H, m), 3.98 (2H, q, J =






7.0 Hz), 4.14 (2H, q, J = 7.1 Hz),






6.69-6.83 (3H, m), 6.95-7.09 (2H,






m), 7.60-7.67 (1H, m).


337
—F
—C2H5
2
1H NMR 1.25 (3H, t, J = 7.1 Hz),






2.52-2.71 (2H, m), 2.86-3.02






(2H, m), 3.47 (2H, brs), 4.14






(2H, q, J = 7.1 Hz), 6.81 (1H,






d, J = 8.6 Hz), 6.93-7.04 (2H, m),






7.05-7.13 (2H, m), 7.63 (1H, d,






J = 2.9 Hz).


338
—H
—C2H5
4
1H NMR 1.25 (3H, t, J = 7.2 Hz),






1.55-1.80 (4H, m), 2.32 (2H, t,






J = 7.0 Hz), 2.60 (2H, t, J = 7.0






Hz), 3.49 (2H, brs), 4.12 (2H, q,






J = 7.2 Hz), 6.74 (1H, d, J = 8.5






Hz), 6.97 (2H, d, J = 8.5 Hz), 7.06






(1H, dd, J = 8.5 Hz, 3.0 Hz),






7.14 (2H, d, J = 8.5 Hz), 7.71






(1H, d, J = 3.0 Hz).


339
—H
—C2H5
3
1H NMR 1.26 (3H, t, J = 7.5 Hz),






1.94 (2H, dt, J = 15.0 Hz, 7.5 Hz),






2.33 (2H, t, J = 7.5 Hz), 2.63 (2H,






t, J = 7.5 Hz), 3.50 (2H, brs), 4.13






(2H, q, J = 7.0 Hz), 6.75 (1H, d,






J = 8.5 Hz), 6.98 (2H, d, J = 8.5






Hz), 7.07 (1H, dd, J = 8.5 Hz, 3.0






Hz), 7.15 (2H, d, J = 8.5 Hz), 7.72






(1H, d, J = 3.0 Hz).
















TABLE 49













 











Reference






Example






No.
Xa8
M
Form
1H NMR (solvent) δ ppm














340
—NH—
2
free
(CDCl3) 1.24 (3H, t, J = 7.1 Hz), 2.60 (2H,






t, J = 7.6 Hz), 2.90 (2H, t, J = 7.6 Hz),






3.35 (2H, brs), 4.13 (2H, q, J = 7.1 Hz),






6.16 (1H, brs), 6.77 (1H, d, J = 8.6 Hz),






6.98 (1H, dd, J = 2.9 Hz, 8.6 Hz), 7.00-






7.15 (4H, m), 7.78 (1H, d, J = 2.9 Hz).


341
—N(CH3)—
0
hydrochloride
(DMSO-d6) 1.30 (3H, t, J = 7.1 Hz),






3.43 (3H, s), 4.28 (2H, q, J = 7.1 Hz),






7.03 (1H, d, J = 9.1 Hz), 7.30 (2H, d, J =






8.6 Hz), 7.55 (1H, d, J = 9.1 Hz), 7.93 (2H,






d, J = 8.6 Hz), 8.05 (1H, s).


342
—N(CH3)—
2
free
(CDCl3) 1.24 (3H, t, J = 7.2 Hz), 2.63 (2H,






t, J = 7.7 Hz), 2.95 (2H, t, J = 7.7 Hz),






3.53 (3H, s), 4.14 (2H, q, J = 7.2 Hz),






6.52 (1H, d, J = 9.5 Hz), 7.07 (1H, dd, J =






2.7 Hz, 9.5 Hz), 7.10 (2H, d, J = 8.3 Hz),






7.22 (2H, d, J = 8.3 Hz), 7.83 (1H, d, J =






2.7 Hz).


343
—N(CH2Ph)—
2
dihydrochloride
(CDCl3) 1.22 (3H, t, J = 7.1 Hz), 2.57 (2H,






t, J = 7.7 Hz), 2.90 (2H, t, J = 7.7 Hz),






4.11 (2H, q, J = 7.1 Hz), 5.28 (2H, s),






6.65 (1H, d, J = 8.8 Hz), 7.08 (2H, d, J =






7.8 Hz), 7.15-7.24 (7H, m), 8.27 (1H, d, J =






8.8 Hz), 8.80 (1H, s).


344
—CO—
2
free
(CDCl3) 1.21 (3H, t, J = 7.1 Hz), 2.63 (2H,






t, J = 7.7 Hz), 2.98 (2H, t, J = 7.7 Hz),






4.10 (2H, q, J = 7.1 Hz), 7.18 (2H, brs),






7.27 (2H, d, J = 8.1 Hz), 7.32 (1H, d, J =






8.3 Hz), 7.88-7.99 (3H, m), 8.27 (1H, s).



























TABLE 50













 












Reference







Example


No.
R207
R208
R209
M
1H NMR (solvent) δ ppm





345
—H
—H
—C(CH3)3
0
(CDCl3) 1.51 (9H, s), 3.49 (2H, brs) 641 (1H,







brs), 6.72 (1H, d, J = 8.6 Hz), 7.00 (2H, d, J = 8.9







Hz), 7.06 (1H, dd, J = 8.6 Hz, 3 0 Hz) 7 32 (2H,







d, J = 8.9 Hz), 7.69 (1H, d, J = 3.0 Hz).


346
—H
—Ac
—C2H5
1
(CDCl3) 1.27 (3H, t, J = 7.1 Hz), 1.94 (3H, s)







3.60 (2H, brs), 4.18 (2H q, J = 7.1 Hz), 4.35 (2H,







s), 6.82 (1H, d, J = 8.6 Hz), 7.07 (2H, d, J = 8.8







Hz), 7.12 (1H, dd, J = 3.0 Hz, 8.6 Hz) 7.31 (2H,







d, J = 8.8 Hz), 7.73 (1H, d, J = 3.0 Hz),


347
—H
—Ac
—C2H5
2
(CDCl3) 1.23 (3H, t, ,J = 7.1 Hz), 1.85 (3H, s),







2.57 (2H, t, J = 7.4 Hz), 3.60 (2H, s), 3.98 (2H, t, J =







7.4 Hz), 4.07 (2H, q, J = 7.1 Hz), 6.82 (1H, d, J =







8.6 Hz), 7.08 (2H, d, J = 8.8 Hz), 7.10-7.15







(3H, m), 7.74 (1H, d, J = 3.0 Hz).


348
—CH3
—Ac
—C2H5
1
(CDCl3) 1.28 (3H, t, J = 7.1 Hz), 1.95 (3H, s),







2.23 (3H, s), 3.52 (2H, s), 4.19 (2H, q, J = 7.1 Hz),







4.34 (2H, s), 6.73 (1H, d, J = 8.6 Hz) 6.91 (1H, d,







J = 8.4 Hz), 7.05-7.15 (2H, m), 7.20 (1H, s),







7.66 (1H, s).


349
—H
—CH3
—CH3
1
(CDCl3) 3.05 (3H, s), 3.45 (2H, brs), 3.72 (3H, s),







4.05 (2H, s), 6.67 (3H, d, J = 9.0 Hz), 6.98 (2H, d,







J = 2.0 Hz), 7.04 (1H, dd, J = 8.6 Hz, 3.0 Hz),







7.69 (1H, d, J = 2.0 Hz).


350
—H
—CH3
—C2H5
1
(CDCl3) 1.25 (3H, t, J = 7.1 Hz), 3.05 (3H, s),







3.45 (2H, brs), 4.03 (2H, s), 4.18 (2H, q, J = 7.1.







Hz), 6.65-6.69 (3H, m), 6.96 (2H, d, J = 9.0 Hz),







7.04 (1H, dd, J = 2.9 Hz, 8.6 Hz), 7.69 (1H, d, J =







2.9 Hz).


351
—H
—C2H5
—C2H5
1
(CDCl3) 1.20 (3H, t, J = 7.2 Hz), 1.26 (3H, t, J =







7.2 Hz), 3.40-3.46 (4H, m), 3.99 (2H, s), 4.19 (2H,







q, J = 7.2 Hz), 6.63 (2H, d, J = 9.1 Hz), 6.67 (1H,







d, J = 8.6 Hz), 6.95 (2H, d, J = 9.1 Hz), 7.04 (1H,







dd, J = 3.2 Hz, 8.6 Hz), 7.69 (1H, d, J = 3.2 Hz).


352
—CH3
—CH3
—C2H5
1
(CDCl3) 1.26 (3H, t, J = 7.1 Hz), 2.13 (3H, s),







3.05 (3H, s), 3.41 (2H, brs), 4.02 (2H, s), 4.19 (2H,







q, J = 7.1 Hz), 6.46-6.68 (3H, m), 6.89 (1H, d, J =







8.6 Hz), 7.03 (1H, dd, J = 8.6 Hz, 3.0 Hz),







7.67 (1H, d, J = 3.0 Hz).


353
—OCH3
—CH3
—C2H5
1
(CDCl3) 1.26 (3H, t, J = 7.1 Hz), 3.07 (3H, s),







3.42 (2H, brs), 3.75 (3H, s), 4.04 (2H, s), 4.19 (2H,







q, J = 7.1 Hz), 6.24 (1H, dd, J = 8.7 Hz, 2.8 Hz),







6.33 (1H, d, J = 2.8 Hz), 6.67 (1H, d, J = 8.6 Hz),







6.95 (1H, d, J = 8.7 Hz), 7.02 (1H, dd, J = 8.6 Hz,







3.0 Hz), 7.63 (1H, d, J = 2.8 Hz).


354
—OCH3
—C2H5
—C2H5
1
(DMSO-d6) 1.13 (3H, t, J = 7.1 Hz), 1.20 (3H, t, J =







7.1 Hz), 3.41 (2H, q, J = 7.1 Hz), 3.63 (3H, s),







4.09-4.17 (4H, m), 4.81 (2H, brs), 6.11 (1H, dd, J =







8.7 Hz, 2.8 Hz), 6.26 (1H d, J = 2.8 Hz),







6.55 (1H, d, J = 8.6 Hz), 6.79 (1H, d, J = 8.7 Hz),







6.99 (1H, dd, J = 8.7 Hz, 3.0 Hz), 7.40 (1H, d, J =







2.3 Hz).
















TABLE 51













 









Reference




Example


No.
R210
1H NMR (CDCl3) δ ppm





355




1.48 (9H, s), 3.04 (4H, t, J = 5.0 Hz), 3.54 (2H, brs), 3.57 (4H, t, J = 5.0 Hz), 6.65 (2H, d, J = 9.0 Hz), 6.82 (2H, d, J = 9.0 Hz), 6.88 (4H, ABq, J = 9.0 Hz).


 


356




1.78 (2H, m), 2.03 (2H, m), 2.86 (2H, m), 3.39 (3H, s), 3.42 (2H, m), 3.52 (2H, brs), 3.70 (1H, m), 4.72 (2H; s), 6.64 (2H, d, J = 9.0 Hz), 6.82 (2H, d, J = 9.0 Hz), 6.88 (4H, ABq, J = 9.0 Hz).


 


357




1.27 (3H, t, J = 7.0 Hz), 1.88 (2H, dq, J = 3.5 Hz, 12.5 Hz), 2.03 (2h, dd, J = 12.5 Hz, 3.0 Hz), 2.40 (1H, m), 2.72 (2H, dt, J = 2.5 Hz, 12.0 Hz), 3.51-3.53 (4H, m), 4.16 (2H, q, J = 7.0 Hz), 6.65 (2H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 6.88 (4H, s).


 


358




1.48 (9H, s), 1.74 (2H, brd, J = 11.5 Hz), 1.85 (2H, m), 2.74 (2H, m), 2.77 (3H, s), 3.53 (2H, brs), 3.60 (2H, brd, J = 12.0 Hz), 4.12 (1H, brs), 6.65 (2H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 6.87 (4H, s).


 


359




1.30 (3H, t, J = 7.0 Hz), 1.81 (2H, m), 2.03 (2H, m), 2.84 (1H, m), 2.95 (1H, m), 3.35 (1H, m), 3.44 (1H, m), 3.54 (3H, m), 4.15 (2H, s), 4.23 (2H, q, J = 7.0 Hz), 6.65 (2H, d, J = 9.0 Hz), 6.82 (2H, d, J = 9.0 Hz), 6.88 (4H, s).


 


360




1.48 (9H, s), 1.60 (2H, m), 1.80 (2H, m), 2.59 (1H, m), 2.78 (2H, brs), 3.57 (2H, brs), 4.23 (2H, brs), 4.12 (1H, brs), 6.67 (2H, d, J = 9.0 Hz), 6.86 (2H, d, J = 9.0 Hz), 6.87 (2H, d, J = 9.0 Hz), 7.09 (2H, d, J = 9.0 Hz).
















TABLE 52













 










Reference





Example


No.
R211
R212
1H NMR (CDCl3) δ ppm or MS





361
—H
—Ac
1H NMR 2.50 (3H, s), 3.60 (2H, brs), 6.80-7.90 (7H, m).


 


362
—H
—NHCONHPh
1H NMR 3.55 (2H, s), 6.76 (1H, d, J = 8.6 Hz),





6.89 (1H, s), 6.95-7.02 (3H, m), 7.03-7.12 (2H, m),





7.21-7.36 (6H, m), 6.68 (1H, d, J = 2.9 Hz).


 


363
—H




1H NMR 1.70-1.90 (4H, m), 2.18 (2H, brs), 2.40- 2.50 (2H, m), 3.13-3.29 (2H, m), 4.56 (2H, s), 6.76 (1H, d, J = 8.6 Hz), 7.01 (2H, d, J = 8.6 Hz), 7.09 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.23 (2H, d, J = 8.6 Hz), 7.72 (1H, d, J = 3.0 Hz).


 


364
—H
—CH(CH3)COOCH3
MS 272 (M+)


365
—H
—C(CH3)2COOCH3
MS 286 (M+)


 


366
—H




1H NMR 1.50 (9H, s), 3.55 (2H, brs), 3.72 (2H, m), 3.78 (2H, m), 4.25 (2H, s), 6.80 (1H, d, J = 8.6 Hz), 7.08 (2H, d, J = 8.9 Hz), 7.10 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.24 (2H, d, J = 8.9 Hz), 7.72 (1H, d, J = 3.0 Hz).


 


367
—H




1H NMR 1.48 (9H, s), 3.07 (4H, brs), 3.47 (2H, brs), 3.57 (4H, t, J = 5.0 Hz), 6.72 (1H, d, J = 8.5 Hz), 6.92 (2H, d, J = 9.0 Hz), 7.00 (2H, d, J = 9.0 Hz), 7.06 (1H, dd, J = 8.5 Hz, 3.0 Hz), 7.70 (1H, d, J = 3.0 Hz).


 


368
—H




1H NMR 1.27 (3H, t, J = 7.0 Hz), 1.44 (2H, dq, J = 4.0 Hz, 12.5 Hz), 1.83 (2H, brd, J = 13.0 Hz), 1.91 (1H, m), 2.28 (2H, d, J = 7.0 Hz), 2.70 (2H, dt, J = 2.5 Hz, 12.0 Hz), 3.46 (2H, brs), 3.57 (2H, brd, J = 12.0 Hz), 4.15 (2H, q, J = 7.0 Hz), 6.69 (1H, d, J = 8.5 Hz), 6.92 (2H, d, J = 9.0 Hz), 6.97 (2H, d, J = 9.0 Hz), 7.05 (2H, dd, J = 8.5 Hz, 3.0 Hz), 7.70 (1H, d, J = 3.0 Hz).


 


369
—CH3




1H NMR 1.27 (3H, t, J = 7.1 Hz), 1.86-2.05 (4H, m), 2.14 (3H, s), 2.35-2.44 (1H, m), 2.69-2.79 (2H, m), 3.43 (2H, brs), 3.55-3.59 (2H, m), 4.16 (2H, q, J = 7.1 Hz), 6.62 (1H, d, J = 8.6 Hz), 6.74-6. 82 (2H, m), 6.89 (1H, d, J = 8.6 Hz), 7.03 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.68 (1H, d, J = 3.0 Hz).


 


370
—OCH3




1H NMR 1.27 (3H, t, J = 7.1 Hz), 1.38-1.50 (2H, m), 1.87-2.06 (3H, m), 2.29 (2H, d, J = 7.1 Hz), 2.69- 2.77 (2H, m), 3.42 (2H, brs), 3.58 (2H, d, J = 12.2 Hz), 3.75 (3H, s), 4.15 (2H, q, J = 7.1 Hz), 6.49 (1H, dd, J = 8.6 Hz, 2.6 Hz), 6.59 (1H, d, J = 2.6 Hz), 6.70 (1H, d, J = 8.6 Hz), 6.96 (1H, d, J = 8.6 Hz), 7.04 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.65 (1H, d, J = 3.0 Hz).


 


371
—CH3




1H NMR 1.27 (3H, t, J = 7.1 Hz), 1.37-1.49 (2H, m), 1.80-2.04 (3H, m), 2.13 (3H, s), 2.28 (2H, d, J = 6.9 Hz), 2.69 (2H, dd, J = 12.0 Hz, 9.9 Hz), 3.41- 3.59 (4H, m), 4.15 (2H, q, J = 7.3 Hz), 6.60 (1H, d, J = 8.6 Hz), 6.73-6.81 (2H, m), 6.88 (1H, d, J = 8.6 Hz), 7.02 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.66 (1H, d, J = 2.8 Hz).
















TABLE 53













 









Reference




Example


No.
R213
1H NMR (CDCl3) δ ppm





372




3.51 (2H, brs), 3.94-4.12 (4H, m), 5.78 (1H, s), 6.73 (1H, d, J = 8.6 Hz), 6.99-7.09 (3H, m), 7.43 (2H, d, J = 8.5 Hz), 7.70 (1H, d, J = 2.7 Hz).


 


373




0.05 (6H, s), 0.91 (9H, s), 1.77-1.88 (2H, m), 2.62- 2.68 (2H, m), 3.62-3.66 (2H, m), 6.73 (1H, d, J = 8.9 Hz), 6.95-7.17 (5H, m), 7.72 (1H, d, J = 3.0 Hz).


 


374




−0.07 (6H, s), 0.81 (9H, s), 2.73 (2H, t, J = 7.3 Hz), 3.72 (2H, t, J = 7.3 Hz), 6.66 (1H, dd, J = 8.6 Hz, 0.7 Hz), 6.88-6.92 (2H, m), 6.99 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.10 (2H, d, J = 8.6 Hz), 7.64 (1H, d, J = 3.0 Hz).


 


375
morpholino
3.09-3.13 (4H, m), 3.84-3.87 (4H, m), 6.71 (1H, d, J =




8.6 Hz), 6.90 (2H, d, J = 8.9 Hz), 7.02 (2H, d, J = 9.2




Hz), 7.05 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.69 (1H, d, J =




3.0 Hz)


 


376




3.12 (1H, dd, J = 14.2 Hz, 9.8 Hz), 3.52 (1H, dd, J = 14.2 Hz, 3.8 Hz), 3.70 (2H, s), 4.51 (1H, dd, J = 9.8 Hz, 3.8 Hz), 6.78 (1H, d, J = 8.6 Hz), 7.02 (2H, d, J = 8.6 Hz), 7.09 (1H, dd, J = 8.6 Hz, 3.1 Hz), 7.20 (2H, d, J = 8.6 Hz), 7.71 (1H, d, J = 3.1 Hz), 7.98 (1H, brs).


 


377
—CH═C(COOCH3)2
3.84 (3H, s), 3.85 (3H, s), 6.82 (1H, d, J = 8.3 Hz),




7.03 (2H, d, J = 8.9 Hz), 7.02-7.10 (1H, m), 7.42 (2H,




d, J = 8.9 Hz), 7.70-7.76 (2H, m).


 


378




1.27 (3H, t, J = 7.0 Hz), 1.88 (2H, m), 2.02 (2H, m), 2.40 (1H, m), 2.75 (2H, dt, J = 3.0 Hz, 12.0 Hz), 3.46 (2H, brs), 3.56 (2H, dt, J = 13.0 Hz, 3.0 Hz), 4.15 (2H, q, J = 7.0 Hz), 6.70 (1H, d, J = 8.5 Hz), 6.92 (2H, d, J = 9.0 Hz), 6.98 (2H, d, J = 9.0 Hz), 7.05 (1H, dd, J = 8.5 Hz, 3.0 Hz), 7.70 (1H, d, J = 3.0 Hz).


 


379




1.28 (3H, t, J = 7.0 Hz), 1.66-1.72 (2H, m), 1.82 (1H, m), 2.01 (1H, m), 2.68 (1H, m), 2.78 (1H, m), 2.99 (1H, dd, J = 12.0 Hz, 10.0 Hz), 3.39 (1H, brd, J = 12.0 Hz), 3.47 (2H, brs), 3.62 (1H, dd, J = 12.0 Hz, 4.0 Hz), 4.17 (2H, q, J = 7.0 Hz), 6.70 (1H, d, J = 8.5 Hz), 6.94 (2H, d, J = 9.0 Hz), 6.98 (2H, d, J = 9.0 Hz), 7.06 (1H, dd, J = 8.5 Hz, 3.0 Hz), 7.70 (1H, d, J = 3.0 Hz).


 


380
—CH(CH3)CH2COOC2H5
1.18 (3H, t, J = 7.2 Hz), 1.27 (3H, d, J = 7.0 Hz), 2.43-




2.60 (2H, m), 3.19-3.29 (1H, m), 3.48 (2H, brs),




4.06 (2H, q, J = 7.2 Hz), 6.72 (1H, d, J = 8.7 Hz),




6.96 (2H, d, J = 8.6 Hz), 7.05 (1H, dd, J = 8.7 Hz, 3.0




Hz), 7.16 (2H, d, J = 8.6 Hz), 7.70 (1H, d, J = 3.0 Hz).
















TABLE 54













 









Reference




Example


No.
R214 
1H NMR (CDCl3) δ ppm or MS





381




MS 460 (M+)


 


382




1H NMR 1.90-2.03 (1H, m), 2.20- 2.55 (3H, m), 3.11-3.25 (1H, m) 3.25- 3.38 (1H, m), 3.43 (2H, s), 3.57 (2H, s), 3.60-3.88 (2H, m), 4.70 (1H, d, J = 6.5 Hz), 5.18 (1H, d, J = 6.5 Hz), 6.76 (1H, d, J = 8.6 Hz), 7.02 (2H, d, J = 8.5 Hz), 7.08 (1H, dd, J = 8.5 Hz, 3.0 Hz), 7.20- 7.35 (7H, m), 7.73 (1H, dd, J = 3.1 Hz, 0.5 Hz).


 


383




1H NMR 2.25 (4H, t, J = 5.0 Hz), 3.19 (3H, s), 3.22 (4H, t, J = 5.0 Hz), 3.43 (2H, s), 3.56 (2H, brs), 6.77 (1H, d, J = 8.6 Hz), 7.00 (2H, d, J = 9.2 Hz), 7.05 (2H, d, J = 9.2 Hz), 7.09 (1H, dd, J = 8.6 Hz, 2.8 Hz), 7.17-7.35 (5H, m), 7.72 (1H, d, J = 2.8 Hz).


 


384




1H NMR 2.20 (3H, s), 3.07 (1H, dd, J = 14.2 Hz, 10.1 Hz), 3.50 (2H, brs), 3.52 (1H, dd, J = 14.2 Hz, 3.8 Hz), 4.51 (1H, dd, J = 10.1 Hz, 3.8 Hz), 6.73 (1H, d, J = 8.5 Hz), 6.90 (1H, d, J = 8.5 Hz), 7.03 (1H, dd, J = 8.5 Hz, 3.0 Hz), 7.08 (1H, dd, J = 8.5 Hz, 3.0 Hz), 7.10 (1H, d, J = 3.0 Hz), 7.67 (1H, d, J = 3.0 Hz), 8.10 (1H, brs).


 


385




1H NMR 3.62 (2H, brs), 3.97 (3H, s), 6.86 (1H, d, J = 8.6 Hz), 7.12 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.32 (1H, dd, J = 8.9 Hz, 2.5 Hz), 7.41 (1H, d, J = 2.1 Hz), 7.72-7.75 (2H, m), 7.92 (1H, d, J = 8.9 Hz), 8.02 (1H, dd, J = 8.6 Hz, 1.7 Hz), 8.56 (1H, s).


 


386




1H NMR 3.63 (2H, brs), 3.98 (3H, s), 6.90 (1H, d, J = 8.6 Hz), 6.94 (1H, d, J = 8.2 Hz), 7.15 (1H, dd, J = 8.7 Hz, 3.0 Hz), 7.54-7.57 (1H, m), 7.62-7.68 (1H, m), 7.77 (1H, d, J = 3.0 Hz), 8.18 (1H, d, J = 8.2 Hz), 8.32-8.35 (1H, m), 9.03 (1H, d, J = 8.7 Hz).


 


387




1H NMR 1.45 (3H, t, J = 7.1 Hz), 3.57 (2H, brs), 4.47 (2H, q, J = 7.1 Hz), 6.83 (1H, d, J = 8.6 Hz), 7.12 (1H, dd, J = 8.6 Hz, 3.1 Hz), 7.38 (1H, dd, J = 9.4 Hz, 2.6 Hz), 7.43-7.49 (2H, m, 7.75 (1H, d, J = 3.0 Hz), 7.89 (1H, d, J = 8.2 Hz), 8.10 (1H, dd, J = 7.3 Hz, 1.3 Hz), 8.93 (1H, d, J = 9.4 Hz).
















TABLE 55













 













Reference








Example


No.
R215
R216
R217
Xa9
Xa10
1H NMR (CDCl3) δ ppm or MS





388
—H
—CH3
piperonyl
—CH2—
—CH2—
MS 474 (M+)


389
—H
—F
benzyl
none
none
1H NMR 2.46 (4H, brs),








3.54 (6H, brs), 6.83 (1H, d, J =








8.7 Hz), 7.09 (1H, dd, J = 8.6








Hz, 3.0 Hz), 7.16-7.36 (8H, m),








7.61 (1H, d, J = 3.0 Hz).


390
—H
—OCH3
piperonyl
—CH2—
—CH2—
1H NMR 2.31-2.41 (4H, m),








2.59-2.65 (2H, m), 2.92-








2.98 (2H, m), 3.41 (4H, brs),








3.62-365 (2H, m), 3.76 (3H, s),








5.95 (2H, s), 6.71-6.79 (4H, m),








6.83-6.85 (2H, m), 6.97 (1H, d,








J = 8.1 Hz), 7.06 (1H, dd, J =








8.7 Hz, 3.0 Hz), 7.63 (1H, d, J =








2.8 Hz).


391
—H
—H
—COOC(CH3)3
—CH2—
—CH(OH)—
1H NMR 1.47 (9H, s), 2.81-








2.98 (2H, m), 301-3.20 (1H,








m), 3.29 (3H, brs), 3.39 (2H,








brs), 3.51 (2H, brs), 3.58-








3.78 (3H, m), 4.58 (1H, q, J =








7.0 Hz), 6.75 (1H, d, J = 8.8








Hz), 6.99 (2H, d, J = 8.6 Hz),








7.07 (1H, dd, J = 8.8 Hz, 3.0








Hz), 7.19 (2H, d, J = 8.6 Hz),








7.67 (1H, d, J = 3.0 Hz).


392
—CH3—
—H
piperonyl
—CH2—
—CH2—
MS 474 (M+)
















TABLE 56













 











Reference






Example


No.
R218
R219
R220
1H NMR (CDCl3) δ ppm or MS





393
—H
—H
—H
1H NMR 2.42-2.49 (4H, m), 3.42-3.48 (4H,






m), 3.66-3.72 (2H, m), 3.86 (2H, d, J = 4.3






Hz), 4.82 (1H, t, J = 4.3 Hz), 5.96 (2H, s),






6.62 (2H, d, J = 8.8 Hz), 6.68 (1H, d, J = 8.6






Hz), 6.73-6.78 (2H, m), 6.86 (1H, d, J = 1.0






Hz), 6.95 (1H, d, J = 8.8 Hz), 7.05 (1H, dd, J =






3.0 Hz, 8.6 Hz), 7.69 (1H, d, J = 3.0 Hz)


394
—H
—H
—Ac
1H NMR 1.94 (3H, s), 2.45-2.55 (4H, m),






3.45-3.70 (8H, m), 4.42 (2H, s), 5.95 (2H, s),






6.75-6.85 (3H, m, 6.92 (1H, s), 7.04 (2H, d,






J = 8.8 Hz), 7.12 (1H, dd, J = 3.0 Hz, 8.6






Hz), 7.36 (2H, d, J = 8.8 Hz), 7.72 (1H, d, J =






3.0 Hz).


395
—H
—H
—COC2H5
1H NMR 1.06 (3H, t, J = 7.5 Hz), 2.17 (2H,






q, J = 7.5 Hz), 2.40-2.45 (4H, m), 3.41 (4H,






s), 3.59 (2H, d), 4.42 (2H, s), 5.94 (2H, s),






6.70-6.75 (2H, m), 6.80-6.85 (2H, m),






7.04 (2H, d, J = 8.7 Hz), 7.11 (1H, dd, J = 3.1






Hz, 8.6 Hz), 7.36 (2H, d, J = 8.7 Hz),






7.72 (1H, d, J = 3.1 Hz).


 


396
—H
—H




1H NMR 0.60-1.55 (5H, m), 2.39 (4H, brs), 3.42 (4H1, brs), 3.55 (2H, brs), 4.46 (2H, brs), 5.94 (2H, s), 6.69-6.75 (2H, m), 6.77- 6.85 (2H, m,) 7.00-7.15 (2H, m), 7.40- 7.46 (2H, m), 7.72 (1H, s).


 


397
—H
—H
cyclopropyl
1H NMR 0.60-0.66 (2H, m), 0.77-0.83 (2H,






m), 2.42-2.44 (4H, m), 2.77-2.79 (1H, m),






3.43-3.52 (6H, m), 3.59-3.62 (2H, m),






4.16 (2H, s), 5.95 (2H, s), 6.66 (1H, d, J = 8.6






Hz), 6.75 (2H, s), 6.86-6.97 (5H, m), 7.03 (1H,






dd, J = 8.6 Hz, 2.8 Hz), 7.70 (1H, d, J = 2.8






Hz).


398
—CH3
—CH3
—C2H5
MS 517(M+)


399
—COOCH3
—H
—C2H5
MS 547(M+)
















TABLE 57













 










Reference





Example


No.
Xa11 
M
1H NMR (CDCl3) δ ppm





400
—NH—
0
2.40-2.50 (4H; m), 3.40-3.55 (6H, m), 3.68 (2H, brs),





5.95 (2H, s), 6.27 (1H, s), 6.30-6.55 (2H, m), 6.65-6.95 (5H,





m), 7.20-7.30 (2H, m).


401
—NH—
1
2.40-2.50 (4H, m), 3.35-3.45 (4H, m), 3.55-3.70 (4H, m),





3.83 (2H, d, J = 4.4 Hz), 4.72 (1H, t, J = 4.4 Hz), 5.95 (2H,





s), 6.30-6.40 (1H, m), 6.45-6.60 (3H, m),


402
—N(Ac)—
1
1.91 (3H, s), 2.40-2.50 (4H, m), 3.45-3.75 (8H, m), 4.41 (2H,





s), 5.94 (2H, s), 6.40-6.52 (2H, m), 6.70-6.75 (2H, m), 6.80-





6.95 (4H, m), 7.28 (2H, d, J = 9.0 Hz).


403
—O—
1
2.41 (4H, brs), 3.42 (2H, s), 3.50-3.80 (6H, m), 4.63 (2H, s),





5.94 (2H, s), 6.40 (1H, ddd, J = 1.2 Hz, 2.6 Hz, 7.4 Hz),





6.50 (1H, dd, J = 2.6 Hz, 12.1 Hz), 6.65-6.75 (2H, m), 6.80-





6.95 (6H, m).









Reference Example 404
Production of methyl 3-[(4-hydroxyphenyl)methylamino]-propionate
Methyl 3-[(4-benzyloxyphenyl)methylamino]-propionate (27.3 g, 91.1 mmol) was dissolved in ethanol (300 mL), and the resulting solution was cooled with ice and 10% palladium-carbon (3.0 g) was added. The resulting solution was stirred for 4.5 hours at room temperature under a hydrogen atmosphere. The reaction solution was filtered through Celite to remove insoluble matter, and the filtrate was concentrated under reduced pressure to thereby yield 19.1 g of the title compound.
Appearance: Red oil
1H NMR (CDCl3) δ 2.51-2.56 (2H, m), 2.83 (3H, brs), 3.57 (2H, brs), 3.66 (3H, s), 4.99 (1H, brs), 6.71-6.74 (4H, m).
The following compounds were produced in the same manner as in Reference Example 404.
Reference Example 405
Ethyl[acetyl(4-hydroxyphenyl)amino]acetate
1H NMR (CDCl3) δ 1.26 (3H, t, J=7.1 Hz), 1.92 (3H, s), 4.19 (2H, q, J=7.1 Hz), 4.34 (2H, s), 6.16 (1H, s), 6.87 (2H, d, J=8.8 Hz), 7.21 (2H, d, J=8.8 Hz).









TABLE 58





Reference




Example




No.
Chemical Structure
mp (° C.) or 1H NMR (CDCl3) δ ppm







406




mp 172.0-173.0


 


407




1H NMR 2.24 (3H, s), 3.25-3.39 (2H, m), 3.66-3.81 (2H, m), 4.36 (2H, s), 4.93 (1H, s), 5.95 (2H, s), 6.71 (1H, d, J = 8.6 Hz), 6.77 (2H, d, J = 0.6 Hz), 6.83 (1H, s), 7.15 (1H, dd, J = 2.8 Hz, 8.6 Hz), 7.32 (1H, d, J = 2.8 Hz).


 


408




1H NMR 1.94-2.12 (2H, m), 2.08 (3H, s), 3.29 (2H, t, J = 6.0 Hz), 3.58 (2H, t, J = 6.0 Hz), 3.89 (3H, s), 3.93 (3H, s), 4.57 (2H, s), 6.34 (1H, d, J = 8.4 Hz), 6.71 (1H, dd, J = 2.6 Hz, 8.4 Hz), 6.75-6.93 (3H, m), 6.96 (1H, d, J = 1.3 Hz), 7.61 (1H, s).


 


409




1H NMR 2.07 (3H, s), 2.09-2.18 (2H, m), 2.37-2.50 (4H, m), 3.41 (2H, s), 3.43-3.54 (4H, m), 3.54-3.68 (4H, m), 4.22 (2H, s), 5.94 (2H, s), 6.35 (1H, d, J = 8.4 Hz), 6.62- 6.77 (3H, m), 6.83 (1H, d, J = 1.1 Hz), 6.88 (1H, d, J = 2.4 Hz).


 


410




1H NMR 1.49 (9H, s), 2.07 (3H, s), 2.07-2.21 (2H, m), 3.45 (2H, t, J = 5.9 Hz), 3.61 (2H, t, J = 5.9 Hz), 4.07 (2H, s), 6.33 (1H, d, J = 8.4 Hz), 6.71 (1H, dd, J = 2.6 Hz, 8.4 Hz), 6.87 (1H, d, J = 2.6 Hz), 7.26 (1H, s).









Reference Example 411
Production of [4-(5-aminopyridin-2-yloxy)phenyl](4-piperonylpiperazin-1-yl)methanone
[4-(5-nitropyridin-2-yloxy)phenyl](4-piperonylpiperazin-1-yl)methanone (0.36 g, 0.78 mmol) was dissolved in a mixed solvent consisting of ethanol (5 mL) and THF (5 mL). To the resulting solution was added 5% platinum-carbon (0.06 g), and stirred at room temperature under a hydrogen atmosphere. Two hours later, the 5% platinum-carbon was removed by filtration, and the solvent was evaporated under reduced pressure, to thereby yield 0.32 g of the title compound.
Appearance: Pale yellow amorphous powder
1H NMR (CDCl3) δ 2.43 (4H, brs), 3.44 (2H, s), 3.58 (6H, brs), 5.95 (2H, s), 6.74 (2H, s), 6.80 (1H, d, J=8.6 Hz), 6.85 (1H, s), 7.05 (2H, d, J=8.6 Hz), 7.10 (1H, dd, J=8.6 Hz, 3.0° Hz), 7.40 (2H, d, J=8.7 Hz), 7.74 (1H, d, J=2.6 Hz).
The following compounds were produced in the same manner as in Reference Example 411.
Reference Example 412
4-[5-(4-Trifluoromethylphenoxymethyl)pyridin-2-yloxy]phenylamine
1H NMR (CDCl3) δ 3.63 (2H, brs), 5.02 (2H, s), 6.70 (2H, d, J=8.9 Hz), 6.88 (1H, d, J=8.4 Hz), 6.94 (2H, d, J=8.9 Hz), 7.01 (2H, d, J=8.6 Hz), 7.55 (2H, d, J=8.4 Hz), 7.72 (1H, dd, J=8.4 Hz, 2.5 Hz), 8.22 (1H, d, J=2.3 Hz).
Reference Example 413
3-Methyl-4-[5-(4-trifluoromethylphenoxymethyl)pyridin-2-yloxy]phenylamine
1H NMR (CDCl3) δ 2.08 (3H, s), 3.58 (2H, brs), 5.02 (2H, s), 6.65 (1H, dd, J=8.2 Hz, 2.8 Hz), 6.60 (1H, d, J=2.8 Hz), 6.83-6.87 (2H, m), 7.02 (2H, d, J=8.9 Hz), 7.56 (2H, d, J=9.1 Hz), 7.72 (1H, dd, J=8.6 Hz, 2.5 Hz), 8.21 (1H, d, J=2.5 Hz).
Reference Example 414
2-{[4-(4-Aminophenoxy)phenyl]methylamino}-1-(4-piperonylpiperazin-1-yl)ethanone
1H NMR (CDCl3) δ 2.41 (4H, t, J=5.1 Hz), 2.99 (3H, s), 3.42 (2H, s), 3.48 (2H, t, J=4.8 Hz), 3.50 (2H, brs), 3.62 (2H, t, J=4.8 Hz), 4.04 (2H, s), 5.95 (2H, s), 6.61-6.68 (4H, m), 6.73-6.88 (7H, m).
Reference Example 415
2-{[3-(5-Aminopyridin-2-yloxy)phenyl]methylamino}-1-(4-piperonylpiperazin-1-yl)ethanone
1H NMR (CDCl3) δ 2.40 (4H, t, J=4.9 Hz), 3.00 (3H, s), 3.41 (2H, s), 3.44-3.46 (2H, m), 3.51 (2H, brs), 3.59-3.61 (2H, m), 4.06 (2H, s), 5.95 (2H, s), 6.35-6.45 (3H, m), 6.70-6.74 (3H, m), 6.85 (1H, s), 7.05 (1H, dd, J=8.6 Hz, 3.1 Hz), 7.12-7.18 (1H, m), 7.73 (1H, d, J=3.1 Hz).
The following compound were produced in the same manner as in Reference Example 415.







TABLE 59













 













Reference








Example


No.
R221
R222
R223
R224
R225
1H NMR (CDCl3) δ ppm or MS





416
—H
—H
—CH3
—CH3
—CH3
1H NMR 1.25 (3H, t, J = 7.1 Hz),








1.38 (6H, s), 2.86 (3H, s), 3.50 (2H,








brs), 4.17 (2H, q, J = 7.1 Hz),








6.73 (1H, dd, J = 8.6 Hz, 0.3 Hz),








6.93 (2H, d, J = 9.1 Hz), 7.02-








7.09 (3H, m), 7.73 (1H, d, J = 3.0 Hz).


417
—F
—H
—CH3
—H
—H
1H NMR 1.26 (3H, t, J = 7.1 Hz),








3.05 (3H, s), 3.44 (2H, brs), 4.02 (2H,








s), 4.19 (2H, q, J = 7.1 Hz), 6.38-








6.51 (2H, m), 6.75 (1H, d, J = 8.6








Hz), 7.01-7.13 (2H, m), 7.63 (1H, d, J =








3.0 Hz).


418
—F
—H
—C2H5
—H
—H
1H NMR 1.16-1.30 (6H, m), 3.43 (2H,








brs), 3.43 (2H, q, J = 7.1 Hz),








3.98 (2H, s), 4.21 (2H, q, J = 7.1 Hz),








6.33-6.47 (2H, m), 6.75 (1H, d, J = 8.6








Hz), 6.99-7.09 (2H, m), 7.64 (1H, d, J =








3.0 Hz).


419
—F
—H
—(CH2)2CH3
—H
—H
1 H NMR 0.95 (3H, t, J = 7.4 Hz),








1.27 (3H, t, J = 7.3 Hz), 1.59-








1.70 (2H, m), 3.31 (2H, t, J = 7.6 z),








3.45 (2H, brs), 3.99 (2H, s), 4.20 (2H,








q, J = 7.1 Hz), 6.32-6.45 (2H, m),








6.75 (1H, dd, J = 8.7 Hz, 0.7 Hz),








7.04 (1H, t, J = 9.1 Hz), 7.05 (1H, dd,








J = 7.4 Hz, 5.8 Hz), 7.64 (1H, dd, J =








3.0 Hz, 0.7 Hz).


420
—F
—H
—Ac
—H
—H
1H NMR 1.29 (3H, t, J = 7.1 Hz),








1.98 (3H, s), 3.55 (2H, brs), 4.21 (2H,








q, J = 7.1 Hz), 4.35 (2H, s), 6.87 (1H,








d, J = 8.7 Hz), 7.10-7.29 (4H, m),








7.63 (1H, d, J = 3.0 Hz).


421
—H
—CF3
—C2H5
—H
—H
MS 383 (M+)
















TABLE 60













 










Reference





Example


No.
Xa12
R226
1H NMR (CDCl3) δ ppm





422
—O—
—CH2CN
3.54 (2H, brs), 3.72 (2H, s), 6.79 (1H, d,





J = 8.5 Hz), 7.06 (2H, d, J = 8.9 Hz),





7.09 (1H, dd, J = 8.5 Hz, 3.0 Hz),





7.30 (2H, d, J = 8.9 Hz), 7.71 (1H, d, J =





3.0 Hz).


 


423
—O—




2.41 (4H, t, J = 5.1 Hz),3.38 (4H, t, J = 5.1 Hz), 3.42 (2H, s), 3.54 (2H, brs), 4.37 (2H, d, J = 5.1 Hz), 4.72 (1H, t, J = 5.1 Hz), 5.94 (2H, s), 6.74 (2H, s), 6.77 (1H, d, J = 8.7 Hz), 6.85 (1H, s), 7.01 (2H, d, J = 8.5 Hz), 7.08 (1H, dd, J = 8.7 Hz, 3.0 Hz), 7.28 (2H, d, J = 8.5 Hz), 7.68 (1H, d, J = 2.8 Hz).


 


424
—O—




2.45-2.47 (4H, m), 2.73-2.98 (2H, m), 3.45 (2H, s), 3.49-3.72 (7H, m), 3.85- 3.91 (1H, m), 4.24-4.30 (1H, m), 5.96 (2H, s), 6.74-6.78 (3H, m), 6.86 (1H, s), 7.05-7.11 (3H, m), 7.53- 7.58 (2H, m), 7.70 (1H, d, J = 3.0 Hz).


 


425
—O—




1.35 (3H, d, J = 6.6 Hz), 2.37-2.52 (4H, m), 3.31 (1H, q, J = 6.6 Hz), 3.67- 3.72 (4H, m), 6.76 (1H, d, J = 8.6 Hz), 6.99 (2H, d, J = 8.3 Hz), 7.08 (1H, dd, J = 8.6 Hz, 2.3 Hz), 7.27 (2H, d, J = 8.4 Hz), 7.72 (1H, d, J = 3.0 Hz).


 


426
—N(CH3)—




1.30 (3H, t, J = 7.1 Hz), 2.76 (4H, t, J = 5.0 Hz), 3.24 (4H, t, J = 5.0 Hz), 3.28 (3H, s), 3.35 (4H, s), 4.21 (2H, q, J = 7.1 Hz), 6.42 (1H, dd, J = 8.8 Hz, 0.7 Hz), 6.83 (1H, dd, J = 8.8 Hz, 2.9 Hz), 6.92 (2H, d, J = 8.9 Hz), 7.10 (2H, d, J = 8.9 Hz), 7.79 (1H, dd, J = 2.9 Hz, 0.7 Hz).


 


427
—N(CH3)—




1.28 (3H, t, J = 7.1 Hz), 1.46 (2H, qd, J = 12.3 Hz, 3.6 Hz), 1.77-2.10 (3H, m), 2.29 (2H, d, J = 6.9 Hz), 2.73 (2H, td, J = 12.3 Hz, 2.4 Hz), 3.23 (2H, brs), 3.35 (3H, s), 3.63 (2H, d, J = 12.3 Hz), 4.15 (2H, q, J = 7.1 Hz), 6.41 (1H, d, J = 8.9 Hz), 6.82 (1H, dd, J = 8.9 Hz, 3.0 Hz), 6.92 (2H, d, J = 8.9 Hz), 7.09 (2H, d, J = 8.9 Hz), 7.79 (1H, d, J = 2.5 Hz).


 


428
—O—




3.28-3.42 (2H, m), 3.43-3.59 (2H, m), 3.71-3.88 (2H, m), 4.47 (2H, s), 6.73 (1H, d, J = 8.6 Hz), 7.01-7.11 (3H, m), 7.25-7.39 (5H, m), 7.51-7.59 (2H, m), 7.70 (1H, d, J = 2.9 Hz).
















TABLE 61













 










Reference





Example


No.
R227
R228
1H NMR (CDCl3) δ ppm or MS





429
—F




MS 478 (M+)


 


430
—CH3




1H NMR 1.96-2.11 (2H, m), 2.19 (3H, s), 3.29 (2H, t, J = 5.9 Hz), 3.46 (2H, s), 3.68 (2H, t, J = 5.9 Hz), 4.52 (2H, s), 5.95 (2H, s), 6.67 (1H, d, J = 8.6 Hz), 6.73-6.81 (2H, m), 6.88 (1H, s), 6.93 (1H, d, J = 8.6 Hz), 7.05 (1H, dd, J = 3.0 Hz, 8.6 Hz), 7.09 (1H, dd, J = 2.6 Hz, 8.6 Hz), 7.18-7.22 (1H, m), 7.00 (1H, d, J =3.0 Hz).


 


431
—CH3




1H NMR 1.99-2.11 (2H, m), 2.19 (3H, s), 3.29 (2H, t, J = 6.0 Hz), 3.47 (2H, s), 3.68 (2H, d, J = 6.0 Hz), 3.88 (3H, s), 3.88 (3H, s), 4.56 (2H, s), 6.68 (1H, d, J = 8.6 Hz), 6.82 (1H, d, J = 8.1 Hz), 6.86 (1H, dd, J = 1.8 Hz, 8.1 Hz), 6.91 (1H, d, J = 1.8 Hz), 6.93 (1H, d, J = 8.6 Hz), 7.05 (1H, dd, J = 3.0 Hz, 8.6 Hz), 7.09 (1H, dd, J = 2.6 Hz, 8.6 Hz), 7.19 (1H, d, J = 2.6 Hz), 7.69 (1H, d, J = 3.0 Hz).


 


432
—CH3




1H NMR 2.10-2.21 (2H, m), 2.35-2.48 (4H, m), 3.42 (2H, s), 3.43-3.54 (6H, m), 3.57-3.66 (2H, m), 3.73 (2H, t, J = 5.7 Hz), 4.21 (2H, s), 5.95 (2H, s), 6.66 (1H, d, J = 8.6 Hz), 6.69-6.77 (2H, m), 6.84 (1H, d, J = 1.2 Hz), 6.92 (1H, d, J = 8.6 Hz), 7.02-7.09 (2H, m), 7.17 (1H, d, J = 2.4 Hz), 7.69 (1H, d, J = 2.8 Hz).


 


433
—CH3




1H NMR 1.38 (3H, t, J = 7.1 Hz), 2.19 (3H, s), 2.19-2.38 (2H, m), 3.47 (2H, s), 3.73-3.93 (4H, m), 4.36 (2H, q, J = 7.1 Hz), 6.67 (1H, d, J = 8.6 Hz), 6.94 (1H, d, J = 8.6 Hz), 7.05 (1H, dd, J = 3.0 Hz, 8.6 Hz), 7.12 (1H, dd, J = 2.6 Hz, 8.6 Hz), 7.22 (1H, d, J = 2.6 Hz), 7.40-7.48 (2H, m), 7.69 (1H, d, J = 3.0 Hz), 7.95 8.04 (2H, m).


 


434
—CH3




1H NMR 1.47 (9H, s), 2.05-2.24 (5H, m), 3.34-3.54 (4H, m), 3.77 (2H, t, J = 5.8 Hz), 4.04 (2H, s), 6.65 (1H, d, J = 8.6 Hz), 6.90 (1H, d, J = 8.6 Hz), 6.99-7.10 (2H, m), 7.17 (1H, d, J = 2.4 Hz), 7.68 (1H, d, J = 3.0 Hz).
















TABLE 62













 












Reference







Example


No.
R229
Xa13
R230
Xa14
1H NMR (CDCl3) δ ppm





435
—H
—CO—
3-pyridyl
—CH2—
3.23 (4H, brs), 3.62 (2H, brs),







3.81 (4H, brs), 6.83 (1H, d, J = 8.6







Hz), 7.09 (2H, d, J 8.6 Hz),







7.12 (1H, dd, J = 8.6 Hz, 3.1 Hz),







7.20-7.21 (2H, m), 7.45 (2H, d, J = 8.7







Hz), 7.55 (1H, d, J = 3.0 Hz), 8.14-







8.17 (1H, m), 8.31-8.33 (1H, m).


436
—H
none
piperonyl
—CO—
3.37 (4H, s), 3.48 (2H, brs), 3.90 (2H,







s), 4.57 (2H, s), 5.95 (2H, s), 6.72 (1H,







dd, J = 8.5 Hz, 0.7 Hz), 6.74-







6.78 (2H, m), 6.78-6.82 (1H, m),







6.86 (2H, d, J = 9.1 Hz), 7.02 (2H, d, J =







9.1 Hz), 7.06 (1H, dd, 4 = 8.5 Hz,







2.9 Hz), 7.69 (1H, d, J = 2.9 Hz).


437
—COOCH3
none
benzyl
—CH2—
2.58-2.62 (4H, m), 3.14-3.18 (4H, m),







3.61 (2H, s), 3.65 (3H, s), 6.63 (1H, d,







J = 8.7 Hz), 6.95 (1H, d, J = 8.9 Hz),







7.12-7.18 (2H, m), 7.25-7.36 (5H, m,







7.41 (1H, d, J = 3.0 Hz), 7.51 (1H, d, J =







2.8 Hz).


438
—H
—CH2—
—COOC(CH3)3
—CH2—
1.45 (9H, s), 2.36-2.40 (4H, m), 3.40-







3.44 (4H, m), 3.47 (2H, s), 3.56 (2H,







brs), 6.76 (1H, d, J = 8.6 Hz), 6.97-







7.02 (2H, m), 7.08 (1H, dd, J = 8.6 Hz,







3.0 Hz), 7.25-7.29 (2H, m), 7.71 (1H,







d J = 3.0 Hz).


439
—H
—CO—
benzyl
—CH2—
2.38 4H, brs); 3.33 2H, brs),







3.50 (4H, brs), 5.17 (2H, brs),







6.82 (1H, d, J = 8.6 Hz), 6.96 (2H, d, J =







8.7 Hz), 7.10 (1H, dd, J = 8.6 Hz,







3.0 Hz), 7.27-7.33 (5H, m), 7.36 (2H,







d, J = 8.7 Hz), 7.57 (1H, d, J = 3.0







Hz).


440
—H
—CO—
4-CH3OPhCH2—
—CH2—
2.44 (4H, brs), 3.48 (2H, s), 3.59 (4H,







brs), 3.81 (3H, s), 6.80 (1H, dd, J =







8.6 Hz, 0.7 Hz), 6.85-6.89 (2H, m),







7.03-7.08 (2H, m), 7.11 (1H, dd, J =







8.6 Hz, 3.0 Hz), 7.21-7.26 (2H, m),







7.38-7.43 (2H, m), 7.73-7.75 (1H, m).


441
—H
—SO2—
benzyl
—CH213 
2.42-2.57 (4H, m), 2.91-3.10 (4H, m),







3.47 (2H, s), 3.63 (2H, brs), 6.83 (1H,







d, J = 8.6 Hz), 7.07-7.14 (3H, m),







7.18-7.31 (5H, m), 7.68 (2H, d, J = 8.8







Hz), 7.74 (1H, d, J = 2.0 Hz).
















TABLE 63













 













Reference








Example


No.
R231
R232
R233
R234
R235
′H NMR (CDCl3) δ ppm





442
—F
—H
—H
—H
—H
2.43-2.48 (4H, m), 3.44-3.47 (6H, m) 3.67-








3.68 (2H, m), 3.82 (2H, d, J = 4.1 Hz),








4.96 (1H, brs), 5.96 (2H, s), 6.36-6.43 (2H, m),








6.71-6.78 (3H, m), 6.86 (1H, brs), 6.97-








7.03 (1H, m), 7.06 (1H, dd, J = 8.7 Hz, 3.0








Hz), 7.63 (1H, d, J = 3.0 Hz).


443
—F
—H
—H
—H
—CH3
2.43-2.45 (4H, m), 3.01 (3H, s), 3.44 (2H, s),








3.47 (2H, brs), 3.63 (2H, brs), 4.07 (2H, s),








5.95 (2H, s), 6.39-6.50 (2H, m), 6.72-6.76 (3H,








m), 6.85 (1H, s), 7.00-7.08 (2H, m), 7.63 (1H,








dd, J = 3.0 Hz, 0.5 Hz).


444
—F
—H
—H
—H
—C2H5
1.18 (3H, t, J = 7.1 Hz), 2.43 (4H, t, J = 5.0








Hz), 3.37-3.48 (8H, m), 3.63 (2H, brs),








4.01 (2H, s), 5.95 (2H, s), 6.35-6.46 (2H, m),








6.72-6.77 (3H, m), 6.85 (1H, s), 6.99 (1H d, J =








8.9 Hz), 7.05 (1H, dd, J = 8.7 Hz, 3.0 Hz),








7.63 (1H, d, J = 3.0 Hz).


445
—F
—H
—H
—F
CH3
2.33-2.49 (4H, m), 2.93 (3H s), 3.38-3.68 (8H,








m), 4.00 (2H, s), 5.95 (2H, s), 6.71-6.77 (2H,








s), 6.78-6.82 (2H, m), 6.83-6.91 (2H, m),








7.08 (1H, dd, J = 2.9 Hz, 8.6 Hz), 7.62 (1H, d,








J = 2.9 Hz).


446
—F
—H
—H
—F
—C2H5
1.11 (3H, t, J = 7.1 Hz), 2.31-2.49 (4H, m),








3.29 (2H, q, J = 7.1 Hz), 3.41 (2H, s), 3.42-








3.69 (6H, m), 3.96 (2H, s), 6.70-6.78 (2H, m),








6.79-6.91 (4H m), 7.08 (1H, dd, J = 2.9 Hz,








8.6 Hz), 7.62 (1H, d, J = 2.9 Hz).


447
—F
—H
—F
—H
—CH3
2.36-2.52 (4H, m), 3.01 (3H, s), 3.34-3.54 (6H,








m), 3.55-3.71 (2H, m), 4.05 (2H, s), 5.95 (2H,








s), 6.18-6.29 (2H, m), 6.70-6.79 (2H, m),








6.82 (1H, d, J = 8.6 Hz), 6.85 (1H, d, J = 0.98








Hz), 7.07 (1H, dd, J = 2.9 Hz, 8.6 Hz),








7.59 (1H, d, J = 2.9 Hz).


448
—F
—F
—H
—H
—CH3
2.29-2.55 (4H, m), 2.95 (3H s), 3.30-3.75 (8H,








m), 4.01 (2H, s), 5.95 (2H, s), 6.60-6.95 (6H,








m), 7.09 (1H, dd, J = 3.0 Hz, 8.6 Hz),








7.62 (1H, d, J = 3.0 Hz).


449
—CH3
—CH3
—H
—H
—CH3
2.11 (3H, s), 2.25 (3H, s), 2.36-2.42 (4H, m),








2.66 (3H, s) 3.41 (2H, s), 3.45 (2H, brs), 3.53-








3.56 (2H, m), 3.61-3.64 (2H, m), 3.73 (2H, s),








5.95 (2H, s) 6.67 (1H, d, J = 8.7 Hz) 6.70-








6.85 (4H, m), 6.95 (1H, d, J = 8.7 Hz), 7.03-








7.08 (1H, m), 7.67 (1H, d, J = 3.0 Hz).


 


450
—CH3
—H
—H
—H




0.62-0.66 (2H, m), 0.76-0.83 (2H, m), 2.12 (3H, s), 2.40-2.46 (4H, m), 2.73-2.81 (1H, m), 3.43 (2H, s), 3.48-3.63 (4H, m), 4.15 (2H, s), 5.94 (2H, s) 6.58 (1H, d, J = 8.7 Hz), 6.68- 6.77 (4H, m), 6.87 (2H, d, J = 8.6 Hz), 7.01 (1H, dd, J = 8.7 Hz, 3.0 Hz), 7.67 (1H, d, J = 3.0 Hz).
















TABLE 64













 












Reference







Example


No.
R236
R237
R238
Xa15
1H NMR (CDCl3) δppm or MS















451
—CH3
—H
—H
—CO—
1H NMR 2.20 (3H, s), 2.48-2.54 (4H, m),







3.44 (4H, s), 3.67-3.75 (2H, m), 4.23-4.27 (2H,







m), 5.95 (2H, s), 6.68-6.78 (3H, m), 6.86 (1H,







brs), 6.95 (1H, d, J = 8.7 Hz), 7.07 (1H, dd, J =







8.6 Hz, 3.0 Hz), 7.37 (1H, dd, J = 8.7 Hz,







2.6 Hz), 7.52 (1H, d, J = 2.5 Hz), 7.66 (1H, d,







J = 3.0 Hz), 9.13 (1H, brs).


452
—CH3
—H
—CH3
—CO—
1H NMR 2.21-2.31 (7H, m), 3.28-3.40 (9H, m),







3.53 (2H, brs), 5.93 (2H, s), 6.66-6.80 (4H, m,)







6.91 (1H, d, J = 8.6 Hz), 7.03-7.12 (3H, m),







7.66 (1H, d, J = 3.0 Hz).


453
—H
—H
—SO2CH3
—CH2—
1H NMR 2.41 (4H, brs), 3.19 (3H, s), 3.34-







3.38 (2H, m), 3.42 (2H, s), 3.57-3.60 (4H, m),







4.51 (2H, s), 5.95 (2H, s), 6.70-6.77 (2H, m),







6.80 (1H, d, J = 8.6 Hz), 6.84 (1H, brs),







7.02 (2H, d, J = 8.7 Hz), 7.10 (1H, dd, J = 8.6







Hz, 3.0 Hz), 7.59 (2H, d, J = 8.7 Hz),







7.71 (1H, d, J = 3.0 Hz).


454
—CH3
—H
—SO2CH3
—CH2—
1H NMR 2.21 (3H, s), 2.41 (4H, brs), 3.20 (3H,







s), 3.34-3.38 (2H, m), 3.42 (2H, s), 3.53 (2H,







brs), 3.59-3.61 (2H, m), 4.51 (2H, s), 5.94 (2H,







s), 6.70-6.77 (3H, m), 6.83 (1H, brs), 6.90 (1H,







d, J = 8.6 Hz), 7.09 (1H, dd, J = 8.6 Hz, 3.0







Hz), 7.36 (1H, dd, J = 8.6 Hz, 2.1 Hz),







7.42 (1H, d, J = 2.3 Hz), 7.66 (1H, d, J = 3.0







Hz).


455
—CF3 
—H
—C2H5
—CH2—
MS 557 (M+)


456
—CF3
—H
—CH3
—CH2—
MS 543 (M+)


457
—CN
—H
—CH3
—CH2—
MS 500 (M+)


458
—OCH3
—H
—SO2CH3
—CH2—
1H NMR 2.48 (4H, brs), 3.26 (3H, s), 3.42-







3.66 (8H, m), 3.82 (3H, s), 4.58 (2H, s),







5.99 (2H, s), 6.77-6.79 (2H, m), 6.81-6.88 (2H,







m), 7.06-7.30 (4H, m), 7.67 (1H, d, J = 2.3







Hz).


459
—CH3
—CH3
—CH3
—CH2—
MS 503 (M+)
















TABLE 65













 











Reference






Example


No.
R239
R240
R241
1H NMR (CDCl3) δ ppm














460
—H
—CH3
—H
2.40-2.44 (4H, m), 3.00 (3H, s), 3.49 (4H, brs), 3.63 (2H, brs),






4.05 (2H, s), 5.95 (2H, s), 6.67 (1H, d, J = 8.6 Hz), 6.69 (2H, d,






J = 9.1 Hz), 6.74 (2H, brs), 6.85 (1H, brs), 6.97 (2H, d, J = 9.1






Hz), 7.03 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.68 (1H, d, J = 3.0






Hz).


461
—H
—CH3
—CH3
1.28 (3H, d, J = 6.6 Hz , 2.14-2.21 1H, m), 2.28-2.35 (2H, m)






2.47-2.49 (1H, m), 2.75 (3H, s), 3.24-3.54 (3H, m), 3.38 (2H,






s), 3.45 (2H, s), 3.78-3.84 (1H, m), 4.54 (1H, q, J = 6.8 Hz),






5.93 (2H, s), 6.68-6.75 (5H, m), 6.82 (1H, s), 6.99 (2H, d, J =






9.1 Hz), 7.05 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.69 (1H, dd, J =






3.1 Hz, 0.7 Hz).


462
—CH3
—CH3
—CH3
1.28(3H, d, J 6.6 Hz), 2.15(3H, s), 2.15-2.21(1H, in), 2.33-






2.36 (2H, m), 2.49 (1H, brs), 2.74 (3H, s), 3.25-3.55 (3H, m),






3.39 (2H, s), 3.42 (2H, s), 3.80 (1H, brs), 4.55 (1H, q, J = 6.4






Hz), 5.93 (2H, s), 6.55-6.59 (2H, m), 6.64 (1H, dd, J = 8.6 Hz,






0.5 Hz), 6.69-6.75 (2H, m), 6.83 (1H, brs), 6.90 (1H, d, J = 8.7






Hz), 7.04 (1H, dd, J = 8.7 Hz, 3.0 Hz), 7.67 (1H, dd, J = 3.0






Hz, 0.7 Hz).


463
—OCH3
—CH3
—H
2.31-2.50 (4H, m), 3.02 (3H, s), 3.31-3.57 (6H, m), 3.58-






3.70 (2H, m), 3.76 (3H, s), 4.06 (2H, s), 5.95 (2H, s), 6.24 (1H,






dd, J = 8.7 Hz, 2.8 Hz), 6.37 (1H, d, J = 2.8 Hz), 6.68 (1H, d, J =






8.6 Hz), 6.69-6.79 (2H, m), 6.85 (1H, s), 6.94 (1H, d, J = 8.7






Hz), 7.02 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.65 (1H, d, J = 3.0






Hz).


464
—OCH3
—C2H5
—H
1.18 (3H, t, J = 7.0 Hz), 2.31-2.51 (4H, m), 3.28-3.70 (10 H,






m), 3.74 (3H, s), 4.01 (2H, s), 5.95 (2H, s), 6.22 (1H, dd, J =






8.7 Hz, 2.8 Hz), 6.35 (1H, d, J = 2.8 Hz), 6.68 (1H dd, J =






8.7 Hz, 0.5 Hz), 6.69-6.79 (2H, m), 6.81-6.88 (1H, m),






6.93 (1H, d, J = 8.7 Hz), 7.03 (1H, dd, J = 8.7 Hz, 3.0 Hz),






7.65 (1H, dd, J = 3.0 Hz, 0.5 Hz).


465
—CH3
—CH3
—H
2.13 (3H, s), 2.42 (4H, t, J = 3.0 Hz), 2.99 (3H, s), 3.35-






3.57 (6H, m), 3.58-3.70 (2H, m), 4.05 (2H, s), 5.95 (2H, s),






6.53 (1H, dd, J = 8.8 Hz, 3.1 Hz), 6.57 (1H, d, J = 3.1 Hz),






6.60 (1H, d, J = 8.8 Hz), 6.71-6.78 (2H, m), 6.85 (1H, brs),






6.88 (1H, d, J = 8.7 Hz), 7.02 (1H, dd, J = 8.7 Hz, 3.0 Hz),






7.67 (1H, d, J = 3.0 Hz).


466
—CH3
—C2H5
—H
1.15 (3H, t, J = 7.0 Hz), 2.12 (3H, s), 2.42 (4H, t, J = 5.1 Hz),






3.27-3.70 (10H, m), 4.00 (2H, s), 5.95 (2H, s), 6.46-6.57 (2H,






m), 6.60 (1H, dd, J = 8.7 Hz, 0.5 Hz), 6.69-6.78 (2H, m), 6.82-






6.90 (2H, m), 7.02 (1H, dd, J = 8.7 Hz, 3.0 Hz), 7.68 (1H, dd, J =






3.0 Hz, 0.5 Hz).


467
—CH3
—Ac
—H
1.95 (3H, s), 2.23 (3H, s), 2.31-2.52 (4H, m), 3.29-3.70 (8H, m),






4.43 (2H, s), 5.94 (2H, s), 6.69-6.79 (3H, m), 6.84 (1H, s),






6.92 (1H, d, J = 8.5 Hz), 7.10 (1H, dd, J = 8.6 Hz, 3.0 Hz),






7.19 (1H, dd, J = 8.5 Hz, 2.5 Hz), 7.28 (1H, d, J = 2.2 Hz),






7.68 (1H, d, J = 2.5 Hz).
















TABLE 66













 













Reference








Example


No.
R242
R243
Xa16
M
E
1H NMR (solvent) δ ppm
















468
—OCH3
—H
—CH2—
1
1
(DMSO-d6) 2.32-2.40 (4H, m), 3.32 (2H, brs),








3.50 (4H, brs), 3.61 (3H, s), 3.88 (2H, brs),








4.88 (2H, brs), 5.44 (1H, brs), 5.99 (2H, s),








6.15 (1H, dd, J = 8.6 Hz, 2.5 Hz), 6.44 (1H, d,








J = 2.3 Hz), 6.51 (1H, d, J = 8.6 Hz), 6.71-








6.88 (4H, m), 6.98 (1H, dd, J = 8.6 Hz, 2.8








Hz), 7.40 (1H, d, J = 2.6 Hz).


469
—OCR3
—H
—CH2—
1
2
(DMSO-d6) 2.32 (2H, brs), 2.40 (2R, brs),








3.39 (2H, s), 3.49 (4H, brs), 3.61 (3H s),








3.89 (2H, brd), 4.22 (4H, s), 4.82 (2R, brs),








5.44 (1R, brt), 6.15 (1H, dd, J = 8.6 Hz, 2.5








Hz), 6.44-6.52 (2H, m), 6.70-6.81 (4H, m),








6.98 (1H, dd, J = 8.7 Hz, 3.0 Hz), 7.39 (1H, d,








J = 2.8 Hz).


470
—H
—CH3
—CH2—
2
1
(CDCl3) 2.35 (4H, tt, ,J = 5.0 Hz, 5.0 Hz),








2.52-2.58 (2R, m), 2.91 (3H, s), 3.36-3.39 (4R,








m), 3.59-3.62 (2H, m), 3.65-3.73 (4R, m),








5.93 (2H, s), 6.64-6.76 (5H, m), 6.83 (1H, d, J =








1.0 Hz), 6.97 (2H, d, J = 9.1 Hz), 7.03 (1H,








dd, J = 8.6 Hz; 3.1 Hz), 7.66 (1H, dd, J = 3.1








Hz, 0.5 Hz).


471
—CH3
—CH3
—CO—
1
1
(CDCl3) 2.12 (3R, s), 2.88-3.10 (3H, m),








3.26 (2H, t, J = 5.3 Hz), 340 (2H, brs), 3.60-








3.90 (2H, m), 4.00-4.15 (2R, m), 4.20-








4.40 (2H, m), 4.52 (2H, s), 5.95 (2H, s),








6.53 (1H, dd, J = 8.5 Hz, 3.0 Hz), 6.60 (1H, s),








6.60 (1H, d, J = 8.5 Hz), 6.71 (1H, d, J = 8.5








Hz), 6.74 (1R, s), 6.76 (1H, d, J = 8.5 Hz),








6.88 (1H, d, J = 8.8 Hz), 7.02 (1R, dd, J = 8.5








Hz, 2.8 Hz), 7.66 (1H, d, J = 2.8 Hz).


472
—OCH3
—C2H5
—CO—
1
1
(CDCl3) 1.17 (3H, t, J = 7.0 Hz), 3.20-








3.31 (2H, m), 3.40-3.60 (2H, m), 3.41 (2H, q, J =








7.0 Hz), 3.61-3.82 (2H, m), 3.74 (3R, s),








4.02 (2R, s), 4.30 (2R, s), 4.50 (2H, s),








5.95 (2R, s), 6.24 (1H, dd, J = 8.7 Hz, 2.8 Hz),








6.40 (1H, s), 6.68 (1H, d, J = 8.6 Hz),








6.70 (1H, dd, J = 7.9 Hz, 1.5 Hz), 6.76 (1H, s,








J = 1.5 Hz), 6.76 (1H, d, J = 7.9 Hz),








6.93 (1H, d, J = 8.6 Hz), 7.03 (1H, dd, J = 8.5








Hz, 2.8 Hz), 7.64 (1H, d, J = 2.8 Hz).





(E means the number of the methylene groups.


Hereinafter E indicates the same meaning.)













TABLE 67













 













Reference








Example


No.
Xa17
M
E
R244
Form
mp (° C.) or 1H NMR (CDCl3) δ ppm
















473
—CH2—
1
0
benzyl
free
1H NMR 2.33-2.43 (4H, m), 2.57-2.63








(2H, m), 2.91-2.97 (2H, m), 3.38-








3.42 (4H, m), 3.50 (2H, s), 3.62-








3.65 (2H, m), 6.75 (1H, dd, J = 8.6 Hz,








0.5 Hz), 6.95-7.00 (2H, m), 7.07 (1H,








dd, J = 8.6 Hz, 3.0 Hz), 7.15-7.20 (2H,








m), 7.28-7.33 (5H, m), 7.70 (1H, dd, J =








3.0 Hz, 0.5 Hz).


474
—CH2—
1
0
piperonyl
trihydro-
mp 179-180 dec







chloride


475
—O—
1
0
piperonyl
free
1H NMR 2.41 (4H, brs), 3.42 (2H, s),








3.48 (2H, brs), 3.50-3.70 (4H, m),








4.65 (2H, s), 5.95 (2H, s), 6.72 (1H, d, J =








8.6 Hz), 6.74 (2H, brs), 6.85 (1H,








brs, 6.91 (2H, d, J = 9.2 Hz),








7.00 (2H, d, J = 9.2 Hz), 7.06 (1H, dd,








J = 8.6 Hz, 3.0 Hz), 7.69 (1H, d, J =








3.0 Hz).


476
—O—
1
0
benzyl
free
1H NMR 2.44 (4H, t, J = 5.0 Hz),








3.51 (4H, s), 3.58 (2H, t, J = 5.0 Hz),








3.64 (2H, t, J = 5.0 Hz), 4.65 (2H, s),








6.72 (1H, d, J = 8.5 Hz), 6.92 (2H, d, J =








9.2 Hz), 7.00 (2H, d, J = 9.2 Hz),








7.06 (1H, dd, J = 8.5 Hz, 3.0 Hz),








7.22-7.35 (5H, m), 7.69 (1H, d, J = 3.0








Hz).


477
—NH—
0
1
piperonyl
free
1H NMR 2.51 (4H, brs), 2.62-2.63 (4H,








m), 3.12 (2H, s), 3.45 (2H, s), 3.52 (2H,








brs), 5.94 (2H, s), 6.74 (1H, dd, J = 8.7








Hz, 0.7 Hz), 6.75 (2H, brs), 6.85 (1H,








s), 7.03 (2H, d, J = 8.9 Hz), 7.07 (1H,








dd, J = 8.7 Hz, 3.0 Hz), 7.54 (2H, d, J =








9.1 Hz), 7.69 (1H, dd, J = 3.0 Hz,








0.7 Hz), 9.10 (1H, brs).


478
—N(CH3)—
0
1
piperonyl
free
1H NMR 2.44 (8H, brs), 2.93 (2H, s),








3.24 (3H, s), 3.38 (2H, s), 3.62 (2H,








brs), 5.92 (2H, s), 6.72 (2H, brs), 6.80-








6.84 (2H, m), 7.06 (2H, d, J = 9.1 Hz),








7.12 (1H, dd, J = 8.6 Hz, 3.1 Hz),








7.15 (2H, d, J = 8.9 Hz), 7.73 (1H, d, J =








3.0 Hz).
















TABLE 68













 











Reference






Example


No.
R245
R246
R247
1H NMR (CDCl3) δ ppm














479
—CH3
—H
—CH3
1.12 (3H, d, J = 6.3 Hz), 2.10-2.12 (1H, m), 2.47 (1H,






brs), 2.67-2.72 (1H, m), 2.80-3.11 (6H, m), 3.47-






3.60 (3H, m), 3.84-4.10 (4H, m), 5.94 (2H, s), 6.64-






6.74 (5H, m), 6.85 (1H, brs), 6.94-6.98 (2H, m), 7.00-






7.05 (1H, m), 7.68 (1H, d, J = 2.8 Hz).


480
—CH3
—CH3
—H
1.28-1.37 (3H, m), 1.94-2.03 (1H, m), 2.11-2.15 (1H, m),






2.63-2.67 (1H, m), 2.79-2.82 (1H, m), 2.95-3.00 (4H, m),






3.30-3.46 (5H, m), 4.03-4.69 (3H, m), 5.94 (2H, s),






6.66 (1H, d, J = 8.7 H), 6.68 (2H, d, J = 9.1 H), 6.74 (2H,






brs), 6.87 (1H, brs), 6.96 (2H, d, J = 9.1 Hz), 7.03 (1H,






dd, J = 8.7 Hz, 3.0 Hz), 7.68 (1H, d, J = 3.0 Hz).


481
—C2H5
—H
—CH3
1.11-1.18 (6H, m), 2.04-2.13 (1H, m), 2.45-2.47 (1H, m),






2.66-2.73 (1H, m), 2.85-3.64 (8H, m), 3.84-4.11 (4H, m),






5.94 (2H, s), 6.64-6.69 (3H, m), 6.74 (2H, brs), 6.85 (1H,






brs), 6.93-6.96 (2H, m), 7.03 (1H, dd, J = 8.7 Hz, 3.0 Hz),






7.69 (1H, d, J = 3.0 Hz).


482
—C2H5
—CH3
—H
1.15 (3H, t, J = 7.1 Hz), 1.26-1.70 (3H, m), 1.94-






2.04 (1H, m), 2.14-2.17 (1H, m), 2.63-2.67 (1H, m),






2.80 (1H, brs), 3.01-3.59 (8H, m), 3.73-4.71 (3H, m),






5.95 (2H, s), 6.63-6.70 (3H, m), 6.74 (2H, brs), 6.87 (1H,






brs), 6.95 (2H, d, J = 9.1 Hz), 7.03 (1H, dd, J = 8.6 Hz,






3.0 Hz), 7.69 (1H, dd, J = 3.0 Hz, 0.7 Hz).
















TABLE 69













 









Reference




Example


No.
R248
1H NMR (CDCl3) δ ppm












483
piperonyl
1.36-1.46 (2H, m), 1.82-1.99 (3H, m), 2.13 (3H, s), 2.28 (2H, d, J = 6.8




Hz), 2.41 (4H, brs), 2.70 (2H, t, J = 12.0 Hz), 3.41-3.76 (10 H, m),




5.94 (2H, s), 6.59-6.89 (7H, m), 7.03 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.67-




7.69 (1H, m).


484
benzyl
1.33-1.42 (2H, m), 1.82-1.98 (3H, m), 2.04 (3H, s), 2.28 (2H, d, J = 6.8




Hz), 2.41-2.45 (4H, m), 2.70 (2H, t, J = 12.0 Hz), 3.51-3.78 (10 H, m),




6.60 (1H, d, J = 8.6 Hz), 6.69-6.92 (3H, m), 7.03 (1H, dd, J = 8.6 Hz,




3.0 Hz), 7.28-7.33 (5H, m), 7.67 (1H, d, J = 2.5 Hz).
















TABLE 70













 











Reference






Example


No.
R249
R250
R251
MS (M+)














485
—H
—H
—C2H5
557


486
—H
—CH3
—CH3
557


487
—CH3
—H
—CH3
557









Reference Example 488
Production of ethyl[4-(4-amino-2-fluorophenoxy)phenylsulfanyl]acetate
To a solution of ethyl[4-(2-fluoro-4-nitrophenoxy)phenylsulfanyl]acetate (4.93 g, 14.0 mmol) in ethanol (100 mL) was added tin chloride dihydrate (9.50 g, 42.1 mmol), and the resulting solution was stirred for 8 hours at 50° C. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with 1 M hydrochloric acid, a saturated sodium bicarbonate solution, and brine, dried over anhydrous sodium sulfate, and evaporated, to thereby yield 3.45 g of the title compound.
Appearance: Brown oil
1H NMR (CDCl3) δ 1.20 (3H, t, J=7.1 Hz), 3.53 (2H, s), 3.80-4.20 (4H, m), 6.37-6.45 (1H, m), 6.49 (1H, dd, J=2.6 Hz, 12.0 Hz), 6.80-7.00 (3H, m>, 7.38 (2H, d, J=8.9 Hz).
The following compounds were produced in the same manner as in Reference Example 488.
Reference Example 489
2-{Allyl[4-(5-aminopyridin-2-yloxy)-3-fluorophenyl]amino}-1-(4-piperonylpiperazin-1-yl)ethanone
1H NMR (CDCl3) δ 2.44-2.46 (4H, m), 3.44 (4H, brs), 3.44 (2H, s), 3.83 (2H, brs), 3.98 (2H, d, J=4.8 Hz), 4.03 (2H, s), 5.16-5.30 (2H, m), 5.82-5.95 (1H, m), 5.95 (2H, s), 6.35-6.46 (2H, m), 6.71-6.74 (3H, m), 6.85-6.87 (1H, m), 6.96-7.07 (2H, m), 7.63-7.64 (1H, m).
Reference Example 490
(E)-3-[3-(5-Aminopyridin-2-yloxy)phenyl]-1-(4-piperonylpiperazin-1-yl)propenone
MS 458 (M+).
Reference Example 491
Production of methyl 3-[4-(5-aminopyridin-2-ylsulfanyl)phenyl]propionate
To a solution of methyl 3-[4-(5-nitropyridin-2-ylsulfanyl)phenyl]propionate (2.97 g, 9.33 mmol) in methanol (50 mL) were added sodium borohydride (0.590 g, 15.6 mmol) and 10% palladium-carbon (1.80 g), and the resulting solution was stirred for 24 hours at room temperature under a hydrogen atmosphere at atmospheric pressure. The reaction solution was filtered through Celite, and to the resulting filtrate was added concentrated hydrochloric acid (1.5 mL), and concentrated under reduced pressure. To the residue was added a saturated sodium bicarbonate solution, and extracted with ethyl acetate, and the ethyl acetate layer was washed with brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated, to thereby yield 2.49 g of the title compound.
Appearance: Yellow powder
1H NMR (CDCl3) δ 2.62 (2H, t, J=7.6 Hz), 2.93 (2H, t, J=7.6 Hz), 3.67 (3H, s), 6.87 (1H, dd, J=2.9 Hz, 8.4 Hz), 6.98 (1H, d, J=8.4 Hz), 7.15 (2H, d, J=8.2 Hz), 7.35 (2H, d, J=>8.2 Hz), 8.01 (1H, d, J=2.9 Hz).
Reference Example 492
Production of ethyl 3-[4-(5-aminopyridin-2-yloxy)phenyl]acrylate
To a solution of ethyl 3-[4-(5-nitropyridin-2-yloxy)phenyl]acrylate (2.02 g, 6.43 mmol) in methanol (100 mL) were added zinc (6.3 g, 96.3 mmol) and ammonium chloride (710 mg, 13.27 mmol). The resulting reaction solution was stirred for 2.5 hours under reflux, then acetic acid (5 mL) was added, and stirred for 20 minutes under reflux. Insoluble matter was filtered off through Celite, after which the filtrate was concentrated under reduced pressure. To the residue was added 5% potassium hydrogensulfate (150 mL), the mixture was extracted with dichloromethane, and the dichloromethane layer was washed with a saturated sodium bicarbonate solution and brine. The dichloromethane layer was dried over anhydrous magnesium sulfate, and evaporated, to thereby yield 1.78 g of the title compound.
Appearance: Yellow oil
1H NMR (CDCl3) δ 1.34 (3H, t, J=7.1 Hz), 3.58 (2H, brs), 4.26 (2H, q, J=7.1 Hz), 6.35 (1H, dd, J=16.0 Hz, 2.0 Hz), 6.81 (1H, d, J=8.6 Hz), 7.05 (2H, d, J=8.6 Hz), 7.10 (1H, dd, J=8.6 Hz, 3.0 Hz), 7.50 (2H, d, J=8.6 Hz), 7.66 (1H, dd, J=16.0 Hz, 3.0 Hz), 7.73 (1H, d, J=3.0 Hz).
Reference Example 493
Production of 3-(4-(5-amino-4-methylpyridin-2-yloxy)phenyl)-1-(4-piperonylpiperazin-1-yl)propan-1-one
3-(4-hydroxyphenyl)-1-(4-piperonylpiperazin-1-yl)propan-1-one (0.38 g, 1.0 mmol) was dissolved in DMF (6 mL). To the resulting solution was added 60% sodium hydride (0.05 g, 1.2 mmol) and 2-chloro-4-methyl-5-nitropyridine (0.196 g, 1.1 mmol), and the resulting reaction solution was stirred overnight at room temperature. To the reaction solution was added saturated aqueous ammonium chloride, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate), to thereby yield the intermediate product 3-(4-(4-methyl-5-nitropyridin-2-yloxy)phenyl)-1-(4-piperonylpiperazin-1-yl)propan-1-one.
The 3-(4-(4-methyl-5-nitropyridin-2-yloxy)phenyl)-1-(4-piperonylpiperazin-1-yl)propan-1-one was dissolved in a mixed solvent consisting of ethanol (4 mL) and dioxane (1 mL). To this solution was added 10% palladium-carbon (0.034 g), and the resulting solution was subjected to catalytic reduction for 8 hours at atmospheric pressure and room temperature. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (dichloromethane:methanol=20:1), to thereby yield 0.22 g of the title compound.
Appearance: Slightly yellow oil
1H NMR (CDCl3) δ 2.18 (3H, s), 2.30-2.45 (4H, m), 2.56-2.63 (2H, m), 2.91-2.97 (2H, m), 3.30-3.50 (6H, m), 3.55-3.70 (2H, m), 5.95 (2H, s), 6.65-6.80 (3H, m), 6.84 (1H, s), 6.95-7.05 (2H, m), 7.15-7.20 (2H, m), 7.64 (1H, s).
Reference Example 494
Production of ethyl 3-{4-[4-(3,4-dichlorobenzoylamino)-phenoxy]phenyl}propionate
A solution of 3,4-dichlorobenzoyl chloride (3.65 g, 17.4 mmol) was added dropwise under ice cooling to a solution of ethyl 3-[4-(4-aminophenoxy)phenyl]propionate (4.52 g, 15.9 mmol) and triethylamine (2.65 mL, 19.0 mmol) in THF (80 mL), and the resulting solution was stirred for 1 hour at the same temperature. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and evaporated. The residue was recrystallized from water-containing ethanol to thereby yield 6.67 g of the title compound.
Appearance: Colorless needles
Melting point: 139-141° C.
The following compounds were produced in the same manner as in Reference Example 494.
Reference Example 495
Ethyl 3-[4-(5-phenoxycarbonylaminopyridin-2-yloxy)phenyl]propionate
MS 406 (M+).







TABLE 71













 










Reference





Example


mp.(° C.) or


No.
Xa18
R252
1H NMR (CDCl3) δ ppm













496
p-phenylene
2-(CH2)2COOCH3
mp 117-119


497
p-phenylene
3-(CH2)2COOC2H5
mp 111-113


498
o-phenylene
4-(CH2)2COOC2H5
mp 72-73


499
m-phenylene
4-(CH2)2COOC2H5
1H NMR 1.22 (3H, t, J =





7.2 Hz), 2.59 (2H, t, J =





7.7 Hz), 2.91 (2H, t, J =





7.7 Hz), 4.10 (2H, q, J =





7.2 Hz), 6.78 (1H, dt, J =





8.1 Hz, 1.1 Hz),





6.93 (2H, d, J =8.5 Hz),





7.14 (2H, d, J = 8.5 Hz),





1H, d, J = 8.3 Hz), 7.81





(1H; brs), 7.91 (1H, d,





J = 2.1 Hz).
















TABLE 72













 










Reference





Example


No.
R253
R254
mp (° C.) or 1H NMR (solvent) δ ppm













500
—F
—H
mp 168-169


501
—H
—COOC2H5
mp 144-145


502
—F
—COOC2H5
mp 145-146


503
—F
—CH2COOCH3
mp 127-129


504
—F
—(CH2)2COOC2H5
mp 131-133


505
—F
—(CH2)3COOC2H5
mp 110-111


506
—F
—SCH2COOC2H5
1H NMR (CDCl3) 1.23 (3H, t, J = 7.1 Hz), 3.56 (2H,





s), 4.15 (2H, q, J = 7.1 Hz), 6.90 (2H, d, J = 8.7 Hz),





7.08 (1H, t, J = 8.7 Hz), 7.20-7.30 (1H, m), 7.42 (2H,





d, J = 8.7 Hz), 7.58 (1H, d, J = 8.3 Hz), 7.65-





7.80 (2H, m), 7.82 (1H, s), 7.96 (1H, d, J = 2.1 Hz).


507
—F
—NHCH2COOC2H5
1 H NMR (DMSO-d6) 1.19 (3H, t, J = 7.1 Hz),





3.87 (2H, d, J = 6.4 Hz), 4.11 (2H, q, J = 7.1 Hz),





5.93 (1H, t, J = 6.4 Hz), 6.56 (2H, d, J = 9.0 Hz),





6.81 (2H, d, J = 9.0 Hz), 6.98 (1H, t, J = 9.2 Hz),





7.44-7.47 (1H, m), 7.82-7.86 (2H, m), 7.93 (1H, dd,





J = 2.0 Hz, 8.4 Hz), 8.20 (1H, d, J = 2.0 Hz),





10.50 (1H, s).


508
—H
—Br
1H NMR (DMSO-d6) 6.96 (2H, d, J = 9.0 Hz),





7.08 (2H, d, J = 9.0 Hz), 7.55 (2H, d, J = 8.5 Hz),





7.79 (2H, d, J = 8.5 Hz), 7.83 (1H, d, J = 8.5 Hz),





7.94 (1H, dd, J = 8.5 Hz, 2.0 Hz), 8.21 (1H, d, J =





2.0 Hz), 10.44 (1H, brs).


509
—F
—Ac
mp 143


 


510
—F




1H NMR (CDCl3) 4.00-4.15 (4H, m), 5.78 (1H, s), 6.96 (2H, d, J = 8.7 Hz), 7.00-7.10 (1H, m), 7.20- 7.30 (1H, m), 7.43 (2H, d, J = 8.7 Hz), 7.57 (1H, d, J = 8.3 Hz), 7.82 (1H, s), 7.95 (1H, d, J = 2.1 Hz).
















TABLE 73













 











Reference






Example


No.
R255
R256
R257
1H NMR (CDCl3) δ ppm














511
—Cl
—Cl




3.98 (3H, s), 7.06 (1H, d, J = 8.7 Hz), 7.33-7.37 (1H, m), 7.56-7.59 (2H, m, 7.70-7.73 (1H, m), 7.80 (1H, d, J = 8.5 Hz), 7.95-8.07 (4H, m), 8.23-8.30 (2H, m), 8.60 (1H, s).


 


512
—CF3
—H




3.98 (3H, s), 7.07-7.10 (1H, m), 7.37 (1H, dd, J = 8.9 Hz, 2.3 Hz), 7.58 (1H, d, J = 2.3 Hz), 7.76- 7.82 (3H, m), 7.93-8.08 (5H, m), 8.27- 8.31 (2H, m), 8.60 (1H, s).


 


513
—Cl
—Cl




1.46 (3H, t, J = 7.1 Hz), 4.47 (2H, q, J = 7.1 Hz), 7.04 (1H, d, J = 8.7 Hz), 7.41 (1H, dd, J = 9.4 Hz, 2.5 Hz), 7.47-7.60 (3H, m), 7.70 (1H, dd, J = 8.4 Hz, 2.1 Hz), 7.82 (1H, brs), 7.94 (1H, d, J = 8.6 Hz), 7.98 (1H, d, J = 2.1 Hz), 8.14 (1H, dd, J = 7.3 Hz, 1.2 Hz), 8.20-8.27 (2H, m), 8.92 (1H, d, J = 9.4 Hz).


 


514
—CF3
—H




1.46 (3H, t, J = 7.1 Hz), 4.47 (2H, q, J = 7.1 Hz), 7.04 (1H, d, J = 8.7 Hz), 7.40 (1H, dd, J = 9.4 Hz, 2.5 Hz), 7.47-7.53 (1H, m), 7.59 (1H, d, J = 2.5 Hz), 7.75 (2H, d, J = 8.2 Hz), 7.92- 8.00 (4H, m), 8.14 (1H, dd, J = 7.3 Hz, 1.2 Hz), 8.23-8.29 (2H, m), 8.97 (1H, d, J = 9.4 Hz).


 


515
—C1
—Cl




4.00 (3H, s), 7.09 (1H, d, J = 9.6 Hz), 7.16 (1H, d, J = 8.1 Hz), 7.50- 7.57 (2H, m), 7.62-7.72 (2H, m), 7.98 (2H, d, J = 2.1 Hz), 8.15- 8.29 (4H, m), 9.01 (1H, d, J = 8.7 Hz).
















TABLE 74













 









Reference




Example


No.
R258
1H NMR (CDCl3) δ ppm












516
—COOCH3
3.91 (3H, s), 7.03 (1H, d, J = 8.9 Hz), 7.15-7.18 (2H, m),




7.58 (1H, d, J = 8.3 Hz), 7.69-7.73 (1H, m), 7.89 (1H, brs),




7.99 (1H, d, J = 2.0 Hz), 8.06-8.09 (2H, m), 8.23-8.30 (2H,




m).


517
—COOC2H5
1.39 (3H, t, J = 7.3 Hz), 4.37 (2H, q, J = 7.3 Hz), 7.02 (1H,




d, J = 8.6 Hz), 7.15-7.18 (2H, m), 7.57 (1H, d, J = 8.6 Hz);




7.70-7.73 (1H, m), 7.97-7.99 (2H, m), 8.06-8.09 (2H, m),




8.23-8.30 (2H, m).


518
—CH2COOCH3
3.63 (2H, s), 3.71 (3H, s), 6.94 (1H, d, J = 8.9 Hz), 7.07 (2H,




d, J = 8.2 Hz), 7.30 (2H, d, J = 8.6 Hz), 7.55 (1H, d, J = 8.6




Hz), 7.70 (1H, dd, J = 8.2 Hz, 2.0 Hz), 7.97-8.08 (2H, m),




8.17 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.24 (1H, d, J = 2.6 Hz).


519
—(CH2)2COOCH3
2.62-2.67 (2H, m), 2.93-2.98 (2H, m), 3.68 (3H, s), 6.93 (1H,




d, J = 8.9 Hz), 7.03-7.06 (2H, m), 7.20-7.23 (2H, m),




7.56 (1H, d, J = 8.3 Hz), 7.68-7.72 (1H, m), 7.96-7.98 (2H,




m), 8.17 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.24 (1H, d, J = 2.6




Hz).


520
—(CH2)3COOC2H5
1.26 (3H, t, J = 7.0 Hz), 1.96 (2H, dt, J = 15.0 Hz, 7.5 Hz),




2.34 (2H, t, J = 7.5 Hz), 2.66 (2H, t, J = 7.5 Hz), 4.13 (2H,




q, J = 7.0 Hz), 6.93 (1H, d, J = 8.8 Hz), 7.04 (2H, d, J = 8.6




Hz), 7.20 (2H, d, J = 8.6 Hz), 7.56 (1H, d, J = 8.3 Hz),




7.70 (1H, dd, J = 8.3 Hz, 2.0 Hz), 7.89 (1H, s), 7.98 (1H, d,




J = 2.0 Hz), 8.16 (1H, dd, J = 8.8 Hz, 2.6 Hz), 8.24 (1H, d,




J = 2.6 Hz).


521
—(CH2)4COOC2H5
1.26 (3H, t, J = 7.2 Hz), 1.60-1.75 (4H, m), 2.33 (2H, t, J =




7.0 Hz), 2.64 (2H, t, J = 7.0 Hz), 4.13 (2H, q, J = 7.2 Hz),




6.94 (1H, d, J = 8.9 Hz), 7.04 (2H, d; J = 8.5 Hz), 7.20 (2H,




d, J = 8.5 Hz), 7.58 (1H, d, J = 8.3 Hz), 7.70 (1H, dd, J =




8.3 Hz, 2.3 Hz), 7.78 (1H, brs), 7.98 (1H, d, J = 2.3 Hz),




8.16 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.24 (1H, d, J = 2.6 Hz).


522
—CH2CN
3.76 (2H, s), 7.00 (1H, d, J = 8.8 Hz), 7.16 (2H, d, J = 8.7




Hz), 7.37 (2H, d, J = 8.7 Hz), 7.58 (1H, d, J = 8.4 Hz),




7.70 (1H, dd, J = 8.4 Hz, 2.1 Hz), 7.81 (1H, s), 7.98 (1H, d,




J = 2.1 Hz), 8.20 (1H, dd, J = 8.8 Hz, 2.3 Hz), 8.25 (1H, d,




J =2.3 Hz).


523
—NHCOOC(CH3)3
1.52 (9H, s), 6.49 (1H, brs), 6.90 (1H, d, J = 8.6 Hz),




7.05 (2H, d, J = 8.9 Hz), 7.37 (2H, d, J = 8.9 Hz), 7.56 (1H,




d, J = 8.6 Hz), 7.69 (1H, dd, J = 8.6 Hz, 2.3 Hz), 7.92 (1H,




brs), 7.97 (1H, d, J = 2.3 Hz), 8.14 (1H, dd, J = 8.6 Hz, 2.6




Hz), 8.22 (1H, d, J = 2.6 Hz).


524
—CH═C(COOCH3)2
3.85 (3H, s), 3.86 (3H, s), 7.02 (1H, d, J = 8.8 Hz), 7.13 (2H,




d, J = 8.5 Hz), 7.46 (2H, d, J = 8.5 Hz), 7.59 (1H, d, J = 8.2




Hz), 7.70 (1H, dd, J = 8.2 Hz, 2.0 Hz), 7.74 (1H, s),




7.88 (1H, brs), 7.97 (1H, d, J = 2.0 Hz), 8.22 (1H, dd, J =




8.8 Hz, 2.5 Hz), 8.24 (1H, d, J = 2.5 Hz).
















TABLE 75













 











Reference






Example


No.
R259
R260
R261
1H NMR (solvent) δ ppm














525
—OCH3
—H
—COOC2H5
(CDCl3) 1.40 (3H, t, J = 7.1 Hz), 3.81 (3H, s),






4.39 (2H, q, J = 7.1 Hz), 6.99-7.02 (1H, m),






7.16 (1H, d, J = 8.1 Hz), 7.56 (1H, d, J = 8.4






Hz), 7.67-7.72 (3H, m), 7.97-8.01 (2H, m),






8.17- 8.22 (2H, m).


526
—CH3
—H
—COOCH3
(CDCl3) 2.24 (3H, s), 3.91 (3H, s), 6.97-






7.01 (1H, m), 7.07 (1H, d, J = 8.4 Hz),






7.57 (1H, d, J = 8.4 Hz), 7.69-7.73 (1H, m),






7.91 (1H, dd, J = 8.4 Hz, 2.4 Hz), 7.97-






7.99 (3H, m), 8.21-8.26 (2H, m).


527
—Cl
—H
—COOCH3
(ODCl3) 3.93 (3H, s), 7.08 (1H, d, J = 8.7 Hz),






7.26 (1H, d, J = 1.7 Hz), 7.56 (1H, d, J = 8.2






Hz), 7.69-7.73 (1H, m), 7.95-7.99 (2H, m),






8.10 (1H, brs), 8.15 (1H, d, J = 2.0 Hz), 8.22-






8.24 (1H, m), 8.27 (1H, d, J = 2.8 Hz).


528
—F
—H
—COOCH3
(CDCl3) 3.92 (3H, s), 7.07 (1H, dd, J = 7.8 Hz,






1.8 Hz), 7.25-7.31 (1H, m), 7.56 (1H, d, J = 8.4






Hz), 7.71 (1H, dd, J = 8.2 Hz, 2.1 Hz), 7.82-






7.89 (2H, m), 7.97 (1H, d, J = 2.1 Hz),






8.08 (1H, brs), 8.21-8.25 (2H, m).


529
—H
—OCH3
—COOCH3
(ODCl3) 3.83 (3H, s), 3.87 (3H, s), 6.70 (1H, dd,






J = 8.6 Hz, 2.2 Hz), 6.74 (1H, d, J = 2.2 Hz),






7.01 (1H, d, J = 8.6 Hz), 7.56 (1H, d, J = 8.1






Hz), 7.75 (1H, dd, J = 8.6 Hz, 2.2 Hz),






7.87 (1H, d, J = 8.6 Hz), 8.01 (1H, d, J = 2.2






Hz), 8.25-8.33 (3H, m).


530
—H
—CH3
—COOCH3
(ODCl3) 2.63 (3H, s), 3.91 (3H, s), 6.98-






7.05 (3H, m), 7.60 (1H, d, J = 8.4 Hz),






7.75 (1H, dd, J = 8.4 Hz, 2.2 Hz), 7.97-






8.03 (3H, m), 8.23-8.28 (1H, m), 8.30-8.32 (1H,






m).


531
—H
—COOCH3
—H
(DMSO-d66) 3.85 (3H, s), 7.17 (1H, d, J = 8.9






Hz), 7.43-7.47 (1H, m), 7.56-7.62 (2H, m),






7.78-7.86 (2H, m), 7.93-7.97 (1H, m), 8.22-






8.27 (2H, m), 8.50 (1H, d, J = 2.3 Hz),






10.60 (1H, s).
















TABLE 76













 











Reference






Example


No.
R262
R263
R264
1H NMR (CDCl3) δ ppm














532
—OCH3
—H
—COOC2H5
1.40 (3H, t, J = 7.1 Hz), 3.82 (3H, s),






4.39 (2H, q, J = 7.1 Hz), 7.00-7.03 (1H,






m), 7.17 (1H, d, J = 8.1 Hz), 7.68-






7.76 (4H, m), 8.01 (2H, d, J = 8.1 Hz),






8.16 (1H, brs), 8.22-8.25 (2H, m).


533
—OCH3
—H
—(CH2)2COOCH3
2.63-2.69 (2H, m), 2.93-2.99 (2H, m),






3.69 (3H, s), 3.74 (3H, s), 6.78-6.84 (2H,






m), 6.93 (1H, d, J = 8.7 Hz), 7.03 (1H, d,






J =8.1 Hz), 7.73 (2H, d, J = 8.1 Hz),






7.96-7.99 (3H, m), 8.14-8.20 (2H, m).


534
—CH3
—H
—COOCH3
2.25 (3H, s), 3.91 (3H, s), 6.99-7.03 (1H,






m), 7.07 (1H, d, J = 8.4 Hz), 7.75-






7.78 (2H, m), 7.88-7.92 (1H, m), 7.98-






8.01 (4H, m), 8.26-8.29 (2H, m).


535
—Cl
—H
—COOCH3
3.93 (3H, s), 7.09 (1H, d, J = 8.7 Hz),






7.24-7.27 (1H, m), 7.76 (2H, d, J = 8.7






Hz), 7.96-8.03 (4H, m), 8.16 (1H, d, J =






2.1 Hz), 8.24 (1H, d, J = 2.6 Hz),






8.29 (1H, dd, J = 8.7 Hz, 2.6 Hz).


536
—F
—H
—COOCH3
3.92 (3H, s), 7.08 (1H, d, J = 8.7 Hz),






7.26-7.32 (1H, m), 7.75 (2H, d, J = 8.4






Hz), 7.83-7.90 (2H, m), 7.98 (3H, d, J =






8.2 Hz), 8.22-8.28 (2H, m).


537
—H
—OCH3
—COOCH3
3.87 (3H, s), 3.88 (3H, s), 6.71 (1H, dd, J =






8.6 Hz, 2.2 Hz), 6.77 (1H, d, J = 2.2






Hz), 7.04 (1H, d, J = 8.9 Hz), 7.77 (2H, d,






J = 8.1 Hz), 7.88 (1H, d, J = 8.6 Hz), 8.02






(2H, d, J = 8.1 Hz), 8.17 (1H, brs), 8.29-






8.35 (2H, m).


538
—H
—CH3
—COOCH3
2.63 (3H, s), 3.91 (3H, s), 6.98-7.06 (3H,






m), 7.79 (2H, d, J = 8.1 Hz), 8.00-






8.04 (4H, m), 8.27-8.34 (2H, m).


539
—H
—COOCH3
—H
3.91 (3H, s), 6.99-7.04 (1H, m), 7.32- 7.37 (1H, m), 7.45-7.50 (1H, m, 7.74- 7.80 (3H, m), 7.86-7.90 (1H, m), 7.96- 8.01 (3H, m), 8.22-8.27 (2H, m).
















TABLE 77













 












Reference







Example


No.
R265
R266
R267
R268
1H NMR (CDCl3) δ ppm or mp (° C.)















540
—CF3
—H
—H




1H NMR 1.17 (3H, t, J = 7.1 Hz) 1.26 (3H, d, J = 7.0 Hz), 2.44-2.61 (2H, m), 3.19-3.29 (1H, m), 4.05 (2H, q, J = 7.1 Hz), 6.88 (1H, d, J = 8.8 Hz), 7.01 (2H, d, J =8.5 Hz), 7.19 (2H, d, J = 8.5 Hz), 7.68 (2H, d, J =8.3 Hz), 7.94 (2H, d, J = 8.3 Hz), 8.15 (1H, dd, J = 8.8 Hz, 2.7 Hz), 8.23 (1H, d, J = 2.7 Hz), 8.29 (1H, brs).


 


541
—Cl
—Cl
—H




1H NMR 1.17 (3H, t, J = 7.1 Hz), 1.26 (3H, d, J = 7.0 Hz), 2.43-2.60 (2H, m), 3.18-3.28 (1H, m), 4.05 (2H, q, J = 7.1 Hz), 6.85 (1H, d, J = 8.9 Hz), 6.99 (2H, d, J =8.4 Hz), 7.18 (2H, d, J = 8.4 Hz), 7.48 (1H, d, J = 8.3 Hz), 7.66 (1H, dd, J = 8.3 Hz, 2.0 Hz), 7.92 (1H, d, J = 2.0 Hz), 8.10 (1H, dd, J = 8.9 Hz, 2.7 Hz), 8.20 (1H, d, J =2.7 Hz), 8.39 (1H, brs).


 


542
—CF3
—H
—H




1H NMR 1.35 (3H, t, J = 7.1 Hz), 4.27 (2H, q, J = 7.1 Hz), 6.39 (1H, dd, J = 16.0 Hz, 2.6 Hz), 7.03 (1H, d, J = 8.9 Hz), 7.16 (2H, d, J = 8.8 Hz), 7.56 (2H, d, J = 8.8 Hz), 7.68 (1H, dd, J = 16.0 Hz, 3.2 Hz), 7.77 (2H, d, J = 8.1 Hz), 7.93 (1H, brs), 8.01 (2H, d, J = 8.1 Hz), 8.26 (1H, dd, J =8.9  Hz, 2.6 Hz) 8.29 (1H, d, J = 2.6 Hz).


 


543
—CF3
—H
—H
—CH2COOCH3
1H NMR 3.62 (2H, s), 3.70 (3H, s,)







6.94 (1H, d, J = 8.7 Hz), 7.05-7.09 (2H,







m), 7.26-7.32 (2H, m), 7.72 (2H, d, J =8.6







Hz), 7.97 (2H, d, J = 8.2 Hz), 8.17-8.26







(3H, m).


544
—CF3
—H
—H
—(CH2)2COOC2H5
1H NMR 1.25 (3H, t, J = 7.1 Hz), 2.62







(2H, t, J = 7.7 Hz), 2.95 (2H, t, J = 7.7







Hz), 4.13 (2H, q, J = 7.1 Hz), 6.94 (1H, d,







J = 8.8 Hz), 7.04 (2H, d, J = 8.6 Hz), 7.22







(2H, d, J = 8.6 Hz), 7.75 (2H, d, J = 8.3







Hz), 7.98 (2H, d, J = 8.3 Hz), 8.03 (1H,







brs), 8.19 (1H, dd, J = 8.8 Hz, 2.6 Hz),







8.26 (1H, d, J = 2.6 Hz).


 


545
—Cl
—Cl
—H




1H NMR 0.01 (3H, s), 0.89 (9H, s), 2.83 (2H, t, J = 6.9 Hz), 3.82 (2H, t, J = 6.9 Hz), 6.92 (1H, d, J = 8.9 Hz), 7.05 (2H, dd, J = 6.3 Hz, 2.0 Hz), 7.24 (2H, d, J = 8.6 Hz), 7.58 (1H, d, J = 8.3 Hz), 7.71 (1H, dd, J = 8.3 Hz, 2.0 Hz), 7.80 (1H, brs), 7.98 (1H, d, J = 2.0 Hz), 8.15-8.19 (1H, m), 8.25 (1H, d, J = 2.6 Hz).


 


546
—Cl
—Cl
—H




1H NMR 0.07 (6H, s), 0.91 (9H, s), 1.82- 1.87 (2H, m), 2.65-2.71 (2H, m), 3.63- 3.68 (2H, m), 6.92 (1H, d, J = 8.9 Hz), 7.02-7.05 (2H, m), 7.21 (2H, d, J = 8.6 Hz) 7.57 (1H, d, J = 8.3 Hz), 7.68-7.72 (1H, m), 7.86 (1H, brs), 7.97 (1H, d, J = 2.0 Hz), 8.14-8.18 (1H, m), 8.24 (1H, d, J = 2.3 Hz).


 


547
—H
—F
—CF3
—COOC2H5
mp 133-134
















TABLE 78













 













Reference








Example


No.
R269
R270
Xa19
R271
M
mp (° C.) or 1H NMR (solvent) δ ppm
















548
—Cl
—Cl
—S—
—CH3
2
mp 141-142


549
—Cl
—Cl
—NH—
—C2H5
2
mp 170-171


550
—Cl
—Cl
—N(CH3)—
—C2H5
2
1H NMR DMSO-d6) 1.17 (3H, t, J = 7.1








Hz), 2.63 (2H, t, J = 7.7 Hz), 2.85 (2H, t,








J = 7.7 Hz), 3.36 (3H, s), 4.07 (2H, d, J =








7.1 Hz), 6.56 (1H, d, J = 9.5 Hz),








7.18 (2H, d, J = 8.3 Hz), 7.27 (2H, d, J =








8.3 Hz), 7.75-7.95 (3H, m), 8.20 (1H, s),








8.47 (1H, s), 10.26 (1H, s).


551
—CF3
—H
—N(CH3)—
—C2H5
0
mp 135-136


552
—CF3
—H
—N(CH3)—
—C2H5
2
1H NMR (CDCl3) 1.26 (3H, t, J = 7.2








Hz), 2.65 (2H, t, J = 8.0 Hz), 2.97 (2H, t,








J = 8.0 Hz), 3.45 (3H, s), 4.16 (2H, q, J =








7.2 Hz), 6.57 (1H, d, J = 9.1 Hz),








7.18 (2H, d, J = 8.3 Hz), 7.24 (2H, d, J =








8.3 Hz), 7.35-7.45 (1H, m), 7.65-








7.78 (3H, m), 7.98 (2H, d, J = 8.1 Hz),








8.28 (1H, d, J = 2.5 Hz).


553
—Cl
—Cl
—N(CH2Ph)—
—C2H5
2
1H NMR (CDCl3) 1.23 (3H, t, J = 7.2








Hz), 2.61 (2H, t, J = 7.6 Hz), 2.92 (2H, t,








J = 7.6 Hz), 4.12 (2H, q, J = 7.2 Hz),








5.20 (2H, s), 6.54 (1H, d, J = 9.1 Hz),








7.10-7.30 (8H, m), 7.53 (1H, d, J = 8.4








Hz), 7.60-7.75 (3H, m), 7.94 (1H, d, J =








1.3 Hz), 8.22 (1H, d, J = 2.3 Hz).


554
—Cl
—H
—O—
—CH3
0
1H NMR (CDCl3) 3.91 (3H, s), 7.04 (1H,








d, J = 9.9 Hz), 7.17 (2H, d, J = 8.6 Hz),








7.49 (2H, d, J = 8.6 Hz), 7.79 (1H, brs),








7.83 (2H, d, J = 8.6 Hz), 8.08 (2H, d, J =








8.6 Hz), 8.27-8.29 (2H, m).


555
—CF3
—H
—O—
—C2H5
0
1H NMR (CDCl3) 1.39 (3H, t, J = 7.3








Hz), 4.37 (2H, q, J = 7.3 Hz), 7.04 (1H,








dd, J = 8.3 Hz, 1.3 Hz), 7.15-7.19 (2H,








m), 7.78 (2H, d, J = 8.3 Hz), 7.91 (1H,








brs), 8.00 (2H, d, J = 6.9 Hz), 8.07-








8.10 (2H, m), 8.27-8.31 (2H, m).


556
—H
—OCF3
—O—
—CH3
0
1H NMR (CDCl3) 3.91 (3H, s), 7.04 (1H,








d, J = 8.7 Hz), 7.16 (2H, d, J = 8.7 Hz),








7.42 (1H, d, J = 8.2 Hz), 7.53 (1H, t, J =








8.1 Hz), 7.76-7.81 (2H, m), 8.05-








8.08 (3H, m), 8.25-8.31 (2H m).


557
—H
—CF3
—O—
—C2H5
0
1H NMR CDCl3 1.39 (3H, t, J = 7.2 Hz), 4.37 (2H, q, J = 7.2 Hz), 7.40 (1H, d, J = 8.7 Hz), 7.09-7.20 (2H, m), 7.66 (1H, t, J = 7.8 Hz), 7.76-7.90 (1H, m), 8.00 (1H, brs), 8.00-8.10 (3H, m), 8.10-8.18 (1H, m), 8.20-8.35 (2H, m).
















TABLE 79













 











Reference






Example


No.
R272
R273
M
mp (° C.) or 1H NMR (CDCl3) δ ppm














558
—H
—Ac
1
mp 178-179


559
—H
—Ac
2
1H NMR 1.22 (3H, t, J = 7.2 Hz), 1.86 (3H, s), 2.58 (2H, t, J =






7.3 Hz), 3.99 (2H, t, J = 7.3 Hz), 4.07 (2H, q, J = 7.2 Hz), 7.02 (1H, d,






J = 8.9 Hz), 7.15-7.20 (4H, m), 7.58 (1H, d, J = 8.4 Hz), 7.75 (1H, dd,






J = 2.1 Hz, 8.4 Hz), 8.02 (1H, d, J = 2.1 Hz), 8.24 (1H, dd, J = 2.7 Hz,






8.9 Hz), 8.28 (1H, s), 8.32 (1H, d, J = 2.7 Hz).


560
—H
—CH3
1
1H NMR 1.26 (3H, t, J = 7.1 Hz), 3.06 (3H, s), 4.04 (2H, s), 4.18 (2H;






q, J = 7.1 Hz), 6.68 (2H, d, J = 9.1 Hz), 6.85 (1H, d, J = 8.9 Hz),






7.00 (2H, d, J = 9.1 Hz), 7.55 (1H, d, J = 8.4 Hz), 7.70 (1H, dd, J =






1.9 Hz, 8.4 Hz), 7.94 (1H, s), 7.97 (1H, d, J = 1.9 Hz), 8.10 (1H, dd, J =






2.6 Hz, 8.9 Hz), 8.21 (1H, d, J = 2.6 Hz).


561
—H
—C2H5
1
1H NMR 1.22 (3H, t, J = 7.1 Hz), 1.27 (3H, t, J = 7.1 Hz), 3.46 (2H,






q, J = 7.1 Hz), 4.01 (2H, s), 4.20 (2H; q, J = 7.1 Hz), 6.64 (2H, d, 4 =






9.1 Hz), 6.86 (1H, d, J = 8.9 Hz), 6.98 (2H, d, J = 9.1 Hz), 7.56 (1H,






d, J = 8.4 Hz), 7.70 (1H, dd, J = 1.9 Hz, 8.4 Hz), 7.82 (1H, s),






7.97 (1H, d, J = 1.9 Hz), 8.11 (1H, dd, J = 2.6 Hz, 8.9 Hz), 8.22 (1H,






d, J = 2.6 Hz).


562
—OCH3
—CH3
1
1H NMR 1.25 (3H, t, J = 7.1 Hz) 3.03 (3H, s), 3.65 (3H, s), 4.01 (2H,






s), 4.17 (2H, q, J = 7.1 Hz), 6.16 (1H, d, J = 8.7 Hz), 6.21 (1H, s),






6.76 (1H, d, J = 8.9 Hz), 6.88 (1H, d, J = 8.6 Hz), 7.43 (1H, d, J =






8.4 Hz), 7.67 (1H, d, J = 8.4 Hz), 7.94 (1H, d, J = 1.8 Hz), 8.02 (1H, d,






J = 8.9 Hz), 8.13 (1H, d, J = 2.3 Hz), 8.88 (1H, s).


563
—OCH3
—C2H5
1
1H NMR 1.21 (3H, t, J = 7.1 Hz), 1.27 (3H, t, J = 7.1 Hz), 3.44 (2H,






q, J = 7.1 Hz), 3.68 (3H, s), 3.98 (2H, s), 4.20 (2H, q, J = 7.1 Hz),






6.17 (1H, dd, J = 8.9 Hz, 3.0 Hz), 6.24 (1H, d, J = 2.8 Hz), 6.81 (1H,






d, J = 8.9 Hz), 6.91 (1H, d, J = 8.7 Hz), 7.48 (1H, d, J = 8.4 Hz),






7.68 (1H, dd, J = 8.4 Hz, 2.2 Hz), 7.96 (1H, d, J = 2.0 Hz), 8.04 (1H,






dd, J = 8.9 Hz), 2.8 Hz), 8.15 (1H, d, J = 2.3 Hz), 8.34 (1H, s).


564
—CH3
—Ac
1
1H NMR 1.26 (3H, t, J = 7.1 Hz), 1.96 (3H, s), 2.22 (3H, s), 4.20 (2H,






q, J = 7.1 Hz), 4.37 (2H, s), 6.99 (1H, d, J = 8.9 Hz), 7.07 (1H, d, J =






8.4 Hz), 7.19 (1H, dd, J = 2.4 Hz, 8.4 Hz), 7.59 (1H, d, J = 8.4 Hz),






7.72 (1H, d, J = 8.4 Hz), 7.90-8.12 (2H, m), 8.21 (1H, dd, J = 2.0 Hz,






8.4 Hz), 8.27 (1H, s).


565
—CH3
—CH3
1
1H NMR 1.26 (3H, t, J = 7.1 Hz), 2.12 (3H, s), 3.06 (3H, s), 4.04 (2H,






s), 4.20 (2H, q, J = 7.1 Hz), 6.49-6.61 (2H, m), 6.83 (1H, d, J =






8.9 Hz), 6.93 (1H, d, J = 8.5 Hz), 7.57 (1H, d, J = 8.5 Hz), 7.70 (1H,






dd, J = 8.5 Hz, 2.1 Hz), 7.73 (1H, s), 7.97 (1H, d, J = 2.1 Hz),






8.12 (1H, dd, J = 8.9 Hz, 2.8 Hz), 8.21 (1H, d, J = 2.8 Hz).


566
—F
—Ac
1
1H NMR 1.29 (3H, t, J = 7.1 Hz), 2.00 (3H, s), 4.21 (2H, q, J =






7.1 Hz), 4.37 (2H, s), 7.09 (1H, dd, J = 7.9 Hz, 1.8 Hz), 7.18-7.32 (3H,






m), 7.59 (1H, d, J = 8.4 Hz), 7.72 (1H, dd, J = 8.3 Hz, 2.1 Hz),






7.83 (1H, brs), 7.99 (1H, d, J = 2.0 Hz), 8.20-8.24 (2H, m).


567
—F
—CH3
1
1H NMR 1.27 (3H, t, J = 7.1 Hz), 3.06 (3H, s), 4.04 (2H, s), 4.20 (2H,






q, J = 7.1 Hz), 6.40-6.52 (2H, m), 6.96 (1H, d, J = 9.2 Hz), 7.07 (1H,






t, 4 = 9.1 Hz), 7.57 (1H, d, J = 8.2 Hz), 7.70 (1H, dd, J = 8.2 Hz,






2.0 Hz), 7.82 (1H, brs), 7.97 (1H, d, J = 2.1 Hz), 8.13-8.19 (2H, m).


568
—F
—C2H5
1
1H NMR 1.23 (3H, t, J = 7.1 Hz), 1.28 (3H, t, J = 7.1 Hz), 3.45 (2H,






q, J = 7.1 Hz), 4.00 (2H, s), 4.22 (2H, q, J = 7.1 Hz), 6.37-6.48 (2H,






m), 6.97 (1H, d, J = 8.7 Hz), 7.05 (1H, t, J = 9.1 Hz), 7.57 (1H, d, J =






8.4 Hz), 7.70 (1H, dd, J = 8.4 Hz, 2.2 Hz), 7.79 (1H, brs), 7.98 (1H, d,






J = 2.0 Hz), 8.13-8.20 (2H, m).
















TABLE 80













 












Reference







Example







No.
R274
R275
M
E
mp (° C.) or 1H NMR (CDCl3) δ ppm





569
—H
-Ac
1
2
mp 163-164


570
—H
-Ac
2
2
1H NMR 1.22(3 H, t, J = 7.2 Hz), 1.87(3 H, s), 2.59(2 H, t, J =







7.3 Hz), 4.00(2 H, t, J = 7.3 Hz), 4.08(2 H, q, J = 7.2 Hz),







7.03(1 H, d, J = 8.8 Hz), 7.19(4 H, s), 7.78(2 H, d, J = 8.3







Hz), 7.95(1 H, brs), 8.01(2 H, d, J = 8.3 Hz), 8.27(1 H, d, J =







8.8 Hz), 8.31(1 H, s).


571
—H
—CH3
1
1
1H NMR 3.06(3 H, s), 3.73(3 H, s), 4.07(2 H, s), 6.68(2 H, d,







J = 9.1 Hz), 6.86 (1 H, d, J = 8.9 Hz), 7.00(2 H, d, J = 9.1







Hz), 7.74(2 H, d, J = 8.0 Hz), 7.98(2 H, d, J = 8.0 Hz),







8.07(1 H, s), 8.15(1 H, dd, J = 8.9 Hz, 2.5 Hz), 8.24(1 H, d,







J = 2.5 Hz).


572
—H
—C2H5
1
2
1H NMR 1.18(3 H, t, J = 7.1 Hz), 1.25(3 H, t, J = 7.1 Hz),







3.41(2 H, q, J = 7.1 Hz), 3.98(2 H, s), 4.17(2 H, q, J = 7.1







Hz), 6.59(2 H, d, J = 9.1 Hz), 6.79(1 H, d, J = 8.7 Hz),







6.92(2 H, d, ,J = 9.1 Hz), 7.64(2 H, d, J = 8.4 Hz), 7.94(2 H,







d, J = 8.1 Hz), 8.07(1 H, dd, J = 8.9 Hz, 2.6 Hz), 8.22(1 H,







d, J = 2.8 Hz), 8.75(1 H, s).


573
—OCH3
—CH3
1
2
1H NMR 1.24(3 H, t, J = 7.1 Hz), 3.03(3 H, s), 3.65(3 H, s),







4.01(2 H, s), 4.17 (2 H, q, J = 7.1 Hz), 6.17(1 H, dd, J = 8.7







Hz, 2.6 Hz), 6.24(1 H, d, J = 2.5 Hz), 6.77(1 H, d, J = 8.9







Hz), 6.89(1 H, d, J = 8.7 Hz), 7.63(2 H, d, J = 8.3 Hz),







7.96(2 H, d, J = 8.1 Hz), 8.06(1 H, d, J = 8.7 Hz), 8.16(1 H,







d, J = 2.5 Hz), 8.91(1 H, s).


574
—OCH3
—C2H5
1
2
1H NMR 1.19 3 H, t, J = 7.1 Hz , 1.26 3 H, t, J = 7.1 Hz







3.42(2 H, q, J = 7.1 Hz), 3.64(3 H, s), 3.97(2 H, s), 4.18(2 H,







q, J = 7.1 Hz), 6.14(1 H, dd, J = 8.7 Hz, 2.8 Hz), 6.21(1 H,







d, J = 2.8 Hz), 6.76(1 H, d, J = 8.9 Hz), 6.87(1 H, d, J = 8.7







Hz), 7.62(2 H, d, J = 8.4 Hz), 7.96(2 H, d, J = 8.3 Hz),







8.05(1 H, dd, J = 8.9 Hz, 2.5 Hz), 8.18(1 H, d, J = 2.6 Hz),







9.01(1 H, s).


575
—CH3
-Ac
1
2
1H NMR 1.25(3 H, t, J = 7.0 Hz), 1.93(3 H s) 2.21(3 H, s),







4.18(2 H, q, J = 7.0 Hz), 4.35(2 H, s), 6.98(1 H, d, J = 8.7







Hz), 7.06(1 H, d, J = 8.5 Hz), 7.18(1 H, d, J = 8.5 Hz),







7.23-7.28(1 H, m), 7.75(2 H, d, J = 7.8 Hz), 8.02(2 H, d, J =







7.8 Hz), 8.22-8.33(2 H, m).


576
—CH3
—CH3
1
2
1H NMR 1.26(3 H, t, J = 7.1 Hz), 2.11(3 H, s), 3.05(3 H, s),







4.04(2 H, s), 4.19 (2 H, q, J = 7.1 Hz), 6.46-6.60(2 H, m),







6.80(1 H, d, J = 8.9 Hz), 6.91(1 H, d, J = 8.5 Hz), 7.74(2 H,







d, J = 8.4 Hz), 7.98(2 H, d, J = 8.2 Hz), 8.07(1 H, s), 8.15







(1 H, dd, J = 8.9 Hz, 2.7 Hz), 8.23(1 H, d, J = 2.7 Hz).


577
—F
-Ac
1
2
1H NMR 1.28(3 H, t, J = 7.1 Hz), 1.98(3 H, s), 4.20(2 H, q,







J = 7.1 Hz), 4.36 (2 H, s), 7.09(1 H, dd, J = 6.4 Hz, 3.5 Hz),







7.13-7.32(3 H, m), 7.77(2 H, d, J = 8.3 Hz), 8.01(2 H, d, J =







8.1 Hz), 8.12(1 H, s), 8.23-8.28(2 H, m).


578
—F
—CH3
1
2
1H NMR 1.27(3 H, t, J = 7.1 Hz), 3.07(3 H, s), 4.04(2 H, s),







4.20(2 H, q, J = 7.1 Hz), 6.41-6.53(2 H, m), 6.98(1 H, d, J =







9.7 Hz), 7.07(1 H, t, J = 9.1 Hz), 7.76 (2 H, d, J = 8.6 Hz),







7.84(1 H, s), 7.99(2 H, d, J = 8.1 Hz), 8.19-8.21(2 H, m).


579
—F
—C2H5
1
2
1H NMR 1.20-1.31(6 H, m), 3.45(2 H, q, J = 7.3 Hz),







4.00(2 H, s), 4.22(2 H, q, J = 7.1 Hz), 6.37-6.49(2 H, m),







6.97-7.09(2 H, m), 7.76-7.79(3 H, m), 7.99(2 H, d, J = 7.9







Hz), 8.19-8.21(2 H, m).









Reference Example 580
Production of ethyl 3-{4-[5-(3,4-dichlorobenzoylamino)-pyridin-2-yloxy]-3-methoxyphenyl}propionate
Under ice cooling, to a solution of ethyl 3-(4-(5-aminopyridin-2-yloxy)-3-methoxyphenyl)propionate (1.43 g, 4.5 mmol) in dichloromethane (30 mL) was added pyridine (0.44 mL, 5.4 mmol), and then 3,4-dichlorobenzoyl chloride (0.99 g, 4.7 mmol). The resulting solution was stirred for 1 hour under ice cooling, and then for 10 hours at room temperature. To the resulting reaction solution was added 10% hydrochloric acid, and extracted with dichloromethane. The dichloromethane layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated. To the residue was added diethyl ether, and stirred. The precipitates were collected by filtration. After washing with water and diethyl ether, the precipitates were air dried at 60° C., to thereby yield 0.52 g of the title compound.
Appearance: White powder
1H NMR (CDCl3) δ 1.26 (3H, t, J=7.1 Hz), 2.56-2.79 (2H, m), 2.91-3.09 (2H, m), 3.75 (3H, s), 4.15 (2H, q, J=7.1 Hz), 6.75 (3H, m), 7.10 (1H, d, J=8.0 Hz), 7.56 (1H, d, J=8.2 Hz), 7.99 (1H, d, J=8.1 Hz), 8.17 (1H, s), 8.69 (1H, d, J=9.2 Hz), 8.79 (1H, s), 9.52 (1H, brs).
The following compounds were produced in the same manner as in Reference Example 580.







TABLE 81













 











Reference






Example






No.
R276
R277
Xa20
1H NMR (CDCl3) δ ppm





581
3,4-Cl2Ph-
—H
—CO—
1.23 (3H, t, J = 7.2 Hz), 2.64 (2H, t, J = 7.6 Hz),






3.01 (2H, t, J = 7.6 Hz), 4.12 (2H, q, J = 7.2 Hz),






7.30 (2H, d, J = 8.2 Hz), 7.57 (1H, d, J = 8.3 Hz),






7.73 (1H, dd, J = 8.3 Hz, 2.2 Hz), 7.95-8.04






(3H, m), 8.09 (1H, d, J = 8.6 Hz), 8.16 (1H, brs),






8.41 (1H, dd, J = 8.6 Hz, 2.6 Hz), 8.80 (1H, d,






J = 2.6 Hz).


582
4-CF3Ph-
—OC2H5
—O—
1.22 (3H, t, J = 6.9 Hz), 1.26 (3H, t, J = 7.2 Hz),






251-2.73 (2H, m), 2.87-3.06 (2H, m), 4.02 (2H,






q, J = 6.9 Hz), 4.15 (2H, q, J = 7.2 Hz), 6.71-






6.96 (3H, m), 7.17 (1H, d, J = 7.9 Hz), 7.75 (2H,






d, J = 7.6 Hz), 8.43 (2H, d, J = 7.6 Hz), 9.15-






9.32 (1H, m), 9.42 (1H, s), 11.14 (1H, brs).


583
3,4-Cl2Ph-
—F
—O—
1.26 (3H, t, J = 7.1 Hz), 2.53-2.70 (2H, m), 2.85-






3.03 (2H, m), 4.15 (2H, q, J = 7.1 Hz), 6.97-






7.09 (3H, m), 7.10-7.19 (1H, m), 7.58 (1H, d, J =






8.3 Hz), 7.70 (1H, dd, J = 8.3 Hz, 2.1 Hz), 7.72






(1H, brs), 7.97 (1H, d, J = 2.1 Hz), 8.15-






8.23 (2H, m).


584
PhCH2O—
—H
—O—
1.25 (3H, t, J = 7.1 Hz), 2.53-2.71 (2H, m), 2.84-






3.04 (2H, m), 4.14 (2H, q, J = 7.1 Hz), 6.51-






6.64 (1H, m), 6.88 (1H, d, J = 8.8 Hz), 6.98-






7.06 (2H, m), 7.17-7.24 (2H, m), 7.30-7.43 (5H,






m), 7.87-8.02 (1H, m), 8.05 (1H, d, J = 2.5 Hz).


585
4-CF3Ph-
—F
—O—
1.26 (3H, t, J = 7.1 Hz), 2.56-2.71 (2H, m), 2.89-






3.02 (2H, m), 4.15 (2H, q, J = 7.1 Hz), 6.97-






7.08 (3H, m), 7.10-7.19 (1H, m), 7.77 (2H, d, J =






8.2 Hz), 7.82 (1H, brs), 7.99 (2H, d, J = 8.2 Hz),






8.17-8.26 (2H, m).
















TABLE 82













 













Reference








Example








No.
R278
R279
R280
R281
R282
1H NMR (CDCl3) δ ppm





586
4-CF3PhCO—
—F
—(CH2)2CH3
—H
—H
0.96 (3H, t, J = 7.3 Hz),








1.28 (3H, t, J = 7.1 Hz), 1.63-








1.74 (2H, m), 3.32 (2H, t, J =








7.6 Hz), 4.01 (2H, s),








4.21 (2H, q, J = 7.1 Hz),








6.35-6.47 (2H, m), 6.97 (1H,








d, J = 7.8 Hz), 7.01 (1H, t,








J = 8.9 Hz), 7.77 (2H, d, J =








8.2 Hz), 7.81 (1H, s),








7.99 (2H, d, J = 8.2 Hz),








8.19-8.22 (2H, m).


587
4-CF3PhCO—
—H
—CH3
—CH3
—CH3
1.25 (3H, t, J = 7.1 Hz),








1.42 (6H, s), 2.91 (3H, s),








4.18 (2H, q, J = 7.1 Hz),








6.92 (1H, d, J = 8.7 Hz),








7.00 (2H, d, J = 9.2 Hz),








7.07 (2H, d, J = 9.1 Hz),








7.77 (2H, d, J = 8.2 Hz),








7.81 (1H, s), 8.00 (2H, d, J =








8.1 Hz), 8.20 (1H, dd, J =








8.7 Hz, 2.8 Hz), 8.28 (1H, d,








J = 2.5 Hz).


588
3,4-Cl2PhSO2—
—F
—CH3
—H
—H
1.29 (3H, t, J = 7.1 Hz),








3.05 (3H, s), 4.03 (2H, s),








4.22 (2H, q, J = 7.1 Hz),








6.38-6.49 (2H, m), 6.82 (1H,








brs), 6.88 (1H, d, J = 8.7 Hz),








7.02 (1H, t, J = 8.8 Hz),








7.48 (1H, dd, J = 8.4, 1.6








Hz), 7.52 (1H, d, J = 8.4 Hz),








7.57 (1H, dd, J = 8.7 Hz, 2.6








Hz), 7.70 (1H, d, J = 2.6 Hz),








7.82 (1H, d, J = 1.8 Hz).









Reference Example 589
Production of ethyl 4-[5-(3,4-dimethylbenzoylamino)-pyridin-2-yloxy]benzoate
To a solution of ethyl 4-(5-aminopyridin-2-yloxy)benzoate (14.15 g, 54.8 mmol) in DMF (100 mL) were added 3,4-dimethylbenzoic acid (8.23 g, 54.8 mmol), 1-hydroxybenzotriazole monohydrate (8.4 g, 54.8 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (12.6 g, 65.7 mmol) under ice cooling, and then stirred for 30 minutes under ice cooling and for 17 hours at room temperature. The reaction solution was concentrated under reduced pressure. To the residue was added water (200 mL), and extracted with ethyl acetate (250 mL). The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby yield 16.15 g of the title compound.
Appearance: White powder
1H NMR (CDCl3) δ 1.39 (3H, t, J=7.1 Hz), 2.33 (6H, s), 4.37 (2H, q, J=7.1 Hz), 6.99 (1H, d, J=9.7 Hz), 7.15 (2H, d, J=8.7 Hz), 7.24 (1H, d, J=7.7 Hz), 7.59 (1H, dd, J=7.7 Hz, 2.0 Hz), 7.65 (1H, d, J=2.0 Hz), 7.90 (1H, brs), 8.07 (2H, d, J=8.7 Hz), 8.25-8.35 (2H, m).
The following compounds were produced in the same manner as in Reference Example 589.







TABLE 83













 











Reference






Example


No.
R283
R284
R285
1H NMR (CDCl3) δ ppm














590
—Cl
—Cl
—Ac
2.58 (3H, s), 7.19 (1H, d, J = 8.7 Hz), 7.22 (2H, d, J =






8.7 Hz), 6.06 (2H, s), 7.84 (1H, d, J = 8.4 Hz), 7.97 (1H,






dd, J = 8.4 Hz, 2.1 Hz), 8.01 (1H; d, J = 8.7 Hz),






8.24 (1H, d, J = 2.1 Hz), 8.28 (1H, dd, J = 8.7 Hz, 2.6






Hz), 8.56 (1H, d, J = 2.6 Hz), 10.64 (1H, brs).


591
—CN
—H
—COOCH3
3.92 (3H, s), 7.05 (1H, d, J = 8.9 Hz), 7.18 (2H, d, J =






8.6 Hz), 7.81 (2H, d, J = 8.6 Hz), 7.90 (1H, brs),






8.00 (2H, d, J = 8.6 Hz), 8.08 (2H, d, J = 8.6 Hz),






8.27 (1H, dd, J = 8.6 Hz, 2.6 Hz), 8.30 (1H, d, J = 2.3






Hz).









Reference Example 592
Production of ethyl 3-{4-[5-(3,4-dichlorobenzoylamino)-pyridin-2-yloxy]-3-ethoxyphenyl}propionate
To a solution of ethyl 3-[3-ethoxy-4-(5-nitropyridin-2-yloxy)phenyl]propionate (0.82 g, 2.3 mmol) in ethanol (40 mL) was added 10% palladium-carbon (0.15 g) under a nitrogen atmosphere, and the resulting solution was stirred under a hydrogen atmosphere at atmospheric pressure for 1 hour at room temperature. The palladium-carbon was removed by filtration, and the filtrate was concentrated. The obtained filtrate (0.58 g) was dissolved in dichloromethane (30 mL), and to the resulting solution were added pyridine (0.17 mL, 2.1 mmol) and 3,4-dichlorobenzoyl chloride (0.39 g, 1.84 mmol) under ice cooling. The resulting solution was stirred under ice cooling for 1 hour, and then stirred for 12 hours at room temperature. The reaction solution was made acidic by adding 10% hydrochloric acid, and extracted with dichloromethane. The dichloromethane layer was washed with a saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and evaporated, to thereby yield 0.94 g of the title compound.
Appearance: Yellow amorphous powder
1H NMR (CDCl3) δ 1.18 (3H, t, J=7.0 Hz), 1.26 (3H, t, J=7.1 Hz), 2.53-2.71 (2H, m), 2.86-3.01 (2H, m), 3.98 (2H, q, J=7.0 Hz), 4.15 (2H, q, J=7.1 Hz), 6.78-6.88 (2H, m), 6.95 (1H, d, J=8.8 Hz), 7.06 (1H, d, J=7.9 Hz), 7.58 (1H, d, J=8.3 Hz), 7.65-7.77 (2H, m), 7.98 (1H, d, J=2.1 Hz), 8.14 (1H, dd, J=8.8 Hz, 2.7 Hz), 8.19 (1H, d, J=2.3 Hz).
The following compound was produced in the same manner as in Reference Example 592.
Reference Example 593
N-{6-[4-(3-hydroxypropyl)phenoxy]pyridin-3-yl}-4-trifluoromethylbenzamide
1H NMR (CDCl3) δ 1.86-1.97 (2H, m), 2.70-2.75 (2H, m), 3.68-3.73 (2H, m), 6.95 (1H, d, J=8.7 Hz), 7.03-7.08 (2H, m), 7.23 (2H, d, J=8.4 Hz), 7.77 (2H, d, J=8.2 Hz), 7.84 (1H, brs), 7.99 (2H, d, J=8.2 Hz), 8.20-8.23 (1H, m), 8.26 (1H, d, J=2.6 Hz).
Reference Example 594
Production of methyl 2-(4-{5-[3-(3,4-dichlorophenyl)-ureido]pyridin-2-yloxy}phenyl)acetate
To a solution of methyl 2-[4-(5-aminopyridin-2-yloxy)phenyl]acetate (0.44 g, 1.7 mmol) in dichloro-methane (7 mL) was added 3,4-dichlorophenylisocyanate (0.353 g, 1.9 mmol), and the resulting reaction solution was stirred for 1 hour at room temperature. To the reaction solution was added diisopropyl ether. Insoluble matter was removed by filtration, to thereby yield 0.60 g of the title compound.
Appearance: White powder
1H NMR (DMSO-d6) δ 3.63 (3H, s), 3.69 (2H, s), 6.99-7.05 (3H, m), 7.26-7.30 (2H, m), 7.35 (1H, dd, J=8.8, 2.4 Hz), 7.52 (1H, d, J=8.8 Hz), 7.86 (1H, d, J=2.4 Hz), 7.98 (1H, dd, J=8.8, 2.8 Hz), 8.18 (1H, d, J=2.7 Hz), 8.91 (1H, s), 9.10 (1H, s).
The following compounds were produced in the same manner as in Reference Example 594.







TABLE 84













 









Reference




Example




No.
R286
MS (M+)





595
—H
459


596
—CH3
473
















TABLE 85













 









Reference




Example




No.
R287
1H NMR (CDCl3) δ ppm or MS





597
4-CF3Ph-
1H NMR 1.18(3 H, t, J = 7.1 Hz), 1.25(3 H, t, J = 7.1 Hz),




2.62-2.68(2 H, m), 2.96-3.01(2 H, m), 3.76(2 H, q, J = 7.1 Hz), 4.14(2 H,




q, J = 7.1 Hz), 6.17(1 H, brs), 7.05(1 H, dd, J = 8.7 Hz, 0.7 Hz),




7.11(2 H, d, J = 8.6 Hz), 7.28(2 H, d, J = 8.6 Hz), 7.40(2 H, d, J =




8.7 Hz), 7.49(2 H, d,J = 8.6 Hz), 7.63(1 H, dd, J = 8.7 Hz, 2.6 Hz),




8.14(1 H, dd, J = 2.6 Hz, 0.7 Hz).


598
3,4-Cl2Ph-
MS 501(M+)
















TABLE 86













 










Reference





Example





No.
R288
M
1H NMR (CDCl3) δ ppm





599
—H
3
1.90-2.11(2 H, m), 2.28-2.50(4 H, m), 2.51-2.72(2 H, m),





2.82-3.07(2 H, m), 3.28-3.51(4 H, m), 3.52-3.78(4 H, m), 5.25-5.40(1 H,





m), 5.96(2 H, s), 6.69-6.81(2 H, m), 6.82-6.94(2 H, m),





6.95-7.08(2 H, m), 7.09-7.26(3 H, m), 7.88-8.07(2 H, m).


600
—H
2
2.20-2.46(4 H, m), 2.52-2.70(2 H, m), 2.82-3.02(2 H, m),





3.28-3.50(4 H, m), 3.51-3.72(6 H, m), 5.52-5.71(1 H, m), 5.95(1 H, s),





6.68-6.78(2 H, m), 6.80-6.89(2 H, m), 6.91(2 H, d, J = 8.4 Hz),





7.17(2 H, d, J = 8.4 Hz), 7.36(1 H, s), 7.89-8.01(2 H, m).


601
—OCH3
3
1.85-2.08(2 H, m), 2.27-2.46(4 H, m), 2.55-2.71(2 H, m),





2.88-3.03(2 H, m), 3.30-3.46(6 H, m), 3.56(2 H, t, J = 6.3 Hz), 3.63(2 H,





t, J = 4.9 Hz), 3.71(3 H, s), 5.20-5.36(1 H, m), 5.95(2 H, s),





6.68-6.89(6 H, m), 7.00(1 H, d, J = 8.0 Hz), 7.15(1 H, s), 7.87(1 H, d, J =





2.4 Hz), 7.92(1 H, dd J = 2.8 Hz, 8.8 Hz).


602
—OCH3
2
2.25-2.49(4 H, m), 2.58-2.72(2 H, m), 2.87-3.05(2 H, m),





3.30-3.71(10 H, m), 3.7.1(3 H, s), 5.40-5.52(1 H, m), 5.95(2 H, s),





6.66-6.91(6 H, m), 7.00(1 H, d, J = 8.0 Hz), 7.07(1 H, s), 7.85-7.99





(2 H, m).


















TABLE 87





Reference




Example




No.
Chemical Structure
1H NMR (solvent) δ ppm







603




(DMSO-d6) 3.38(2 H, t, J = 6.1 Hz), 3.63(2 H, t, J = 6.1 Hz), 3.68(3 H, s), 6.27(1 H, t, J = 6.1 Hz), 6.76-6.84(2 H, m), 7.22-7.31(2 H, m), 8.41(1 H, s).


 


604




(CDCl3) 2.00-2.20(5 H, m), 3.27-3.47 (4 H, m), 3.48-3.60(2 H, m), 3.61-3.78 (2 H, m), 3.88(3 H, s), 3.89(3 H, s) 4 59 (2 H, s), 5.94-6.12(1 H, m), 6.66(1 H, d, J = 8.8 Hz), 6.83(1 H, d, J = 8.6 Hz), 6.80-6.92(3 H, m), 7.04(1 H, dd, J = 2.6 Hz, 8.6 Hz), 7.19(1 H, d, J = 2.6 Hz), 7.50(1 H, d, J = 2.8 Hz, 8.8 Hz), 7.73(1 H, s), 7.95(1 H, d, J = 2.8 Hz).


 


605




(CDCl3) 1.76-1.93(2 H, m), 2.00-2.20 (5 H, m), 3.11-3.28(2 H, m), 3.29-3.41 (2 H, m), 3.42-3.57(2 H, m), 3.60-3.78 (2 H, m), 3.87(3 H, s), 3.88(3 H, s), 4.57 (2 H, s), 5.70-5.88(1 H, m), 6.67(1 H, d, J = 8.8 Hz), 6.83(1 H, d, J = 8.6 Hz), 6.86(3 H, m), 7.04(1 H, dd, J = 2.6 Hz, 8.6 Hz), 7.17(1 H, d, J = 2.6 Hz), 7.56(1 H, dd, J = 2.8 Hz, 8.8 Hz), 7.68(1 H, s), 7.93(1 H, d, J =2.8 Hz).









Reference Example 606
Production of methyl 3-(4-{5-[3-(4-trifluoromethyl-phenyl)ureido]pyridin-2-yloxy}phenyl)propionate
Methyl 3-[4-(5-nitropyridin-2-yloxy)phenyl]propionate (1.00 g, 3.3 mmol) was dissolved in a mixed solvent consisting of THF (1 mL) and ethanol (120 mL). To the resulting solution was added 10% palladium-carbon (100 mg), and stirred for 23 hours at room temperature under a hydrogen atmosphere. The reaction solution was filtered and the filtrate was concentrated. To the residue were added THF (20 mL), triethylamine (0.917 mL, 6.6 mmol) and phenyl 4-trifluoromethylisocyanate (0.61 mL, 4.3 mmol), and the resulting solution was stirred for 20 hours at room temperature. The reaction solution was evaporated under reduced pressure. The residue was washed with ethyl acetate, to thereby yield 850 mg of the title compound.
Appearance: White powder
1H NMR (DMSO-d6) δ 2.62-2.68 (2H, m), 2.83-2.88 (2H, m), 3.60 (3H, s), 6.97-7.02 (3H, m), 7.24 (2H, d, J=8.4 Hz), 7.65-7.69 (4H, m), 7.99 (1H, dd, J=8.9 Hz, 2.8 Hz), 8.19 (1H, d, J=2.8 Hz), 8.88 (1H, s), 9.20 (1H, s).
Reference Example 607
Production of methyl 3-fluoro-4-{5-[(4-trifluoromethyl-benzylidene)amino]pyridin-2-yloxy}benzoate
Methyl 4-(5-aminopyridin-2-yloxy)-3-fluorobenzoate (2.0 g, 7.63 mmol) was dissolved in methanol (50 mL). To the resulting solution was added 4-trifluoromethylbenzaldehyde (1.04 mL, 7.63 mmol), and refluxed for 6 hours. The reaction solution was cooled to room temperature, and the resulting precipitated crystals were collected by suction filtration. The collected crystals were washed with methanol, to thereby yield 2.81 g of the title compound.
Appearance: Pale grey powder
1H NMR (DMSO-d6) δ 3.89 (3H, s), 7.32 (1H, d, J=8.7 Hz), 7.48-7.54 (1H, m), 7.85-7.92 (4H, m), 8.01 (1H, dd, J=8.7 Hz, 2.6 Hz), 8.13-8.16 (3H, m), 8.86 (1H, s).
The following compounds were produced in the same manner as in Reference Example 607.







TABLE 88













 












Reference







Example


No.
R289
R290
R291
R292
1H NMR (solvent) δ ppm















608
—CF3
—H
—H
—CH3
(DMSO-d6) 3.86 (3H, s), 7.24-7.30 (3H, m),







7.92 (2H, d, J = 8.1 Hz), 7.98-8.05 (3H, m),







8.16 (2H, d, J = 8.1 Hz), 8.24 (1H, d, J = 2.1







Hz), 8.88 (1H, s).


609
—CF3
—H
—H
—C2H5
(DMSO-d6) 1.33 (3H, t, J = 7.1 Hz), 4.32 (2H,







q, J = 7.1 Hz), 7.24-7.30 (3H, m), 7.92 (2H, d, J =







8.3 Hz), 8.00 (1H, dd, J = 8.7 Hz, 2.6 Hz),







8.02 (2H, d, J = 8.7 Hz), 8.16 (2H, d, J = 7.9







Hz), 8.24 (1H, d, J = 2.6 Hz), 8.88 (1H, s).


610
—Cl
—Cl
—F
—CH3
(DMSO-d6) 3.89 (3H, s), 7.21 (1H, d, J = 8.6







Hz), 7.48-7.54 (1H, m), 7.80-7.94 (4H, m),







7.97 (1H, dd, J = 8.7 Hz, 2.8 Hz), 8.12-







8.15 (2H, m), 8.75 (1H, s).


611
—Cl
—Cl
—F
—C2H5
(CDCl3) 1.40 (3H, t, J = 7.1 Hz), 4.39 (2H, q, J =







7.1 Hz), 7.09 (1H, d, J = 8.6 Hz), 7.26-







7.35 (1H, m), 7.55-7.57 (1H, m), 7.66-7.73 (2H,







m), 7.86-7.92 (2H, m), 8.02-8.03 (2H, m),







8.40 (1H, s).









Reference Example 612
Production of ethyl 4-{5-[1-(4-trifluoromethylphenyl)-ethylideneamino]pyridin-2-yloxy}benzoate
Ethyl 4-(5-aminopyridin-2-yloxy)benzoate (16.0 g, 62 mmol) was dissolved in toluene (300 mL). To the resulting solution were added 4-trifluoromethylacetophenone (11.7 g, 62 mmol) and (±)-camphor-10-sulfonic acid (1.08 g, 4.65 mmol), and refluxed overnight. The reaction solution was concentrated under reduced pressure, to thereby yield 26.5 g of the title compound.
Appearance: Dark green oil
1H NMR (CDCl3) δ 1.35-1.41 (3H, m), 2.34 (3H, s), 4.36 (2H, d, J=7.1 Hz), 7.01-7.31 (4H, m), 7.70-7.77 (3H, m), 8.01-8.11 (4H, m).
Reference Example 613
Production of methyl 4-[5-(4-trifluoromethylbenzyl-amino)pyridin-2-yloxy]benzoate
Methyl 4-{5-[(4-trifluoromethylbenzylidene)-amino]pyridin-2-yloxy}benzoate (2.64 g, 6.59 mmol) was suspended in methanol (25 mL), and to the resulting suspension was slowly added sodium borohydride (1.25 g, 33.0 mmol). The resulting solution was stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate, and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was washed with diethyl ether, to thereby yield 2.65 g of the title compound.
Appearance: White powder
1H NMR (CDCl3) δ 3.89 (3H, s), 4.16 (1H, brs), 4.42 (2H, s), 6.84 (1H, d, J=8.7 Hz), 7.01 (1H, dd, J=8.6 Hz, 3.0 Hz), 7.05 (2H, d, J=8.4 Hz), 7.49 (2H, d, J=8.4 Hz), 7.62 (2H, d, J=8.3 Hz), 7.67 (1H, d, J=3.1 Hz), 8.01 (2H, d, J=8.6 Hz).
The following compounds were produced in the same manner as in Reference Example 613.







TABLE 89













 













Reference








Example


No.
R293
R294
R295
R296
R297
1H NMR (CDCl3) δ ppm
















614
—CF3
—H
—H
—H
—C2H5
1.37 (3H, t, J = 7.1 Hz), 4.19 (1H, brs),








4.35 (2H, q, J = 7.1 Hz), 4.41 (2H, brs),








6.83 (1H, d, J = 8.7 Hz), 7.01 (1H, dd, J =








8.6 Hz, 3.0 Hz), 7.04 (2H, d, J = 8.6








Hz), 7.48 (2H, d, J = 8.1 Hz), 7.61 (2H,








d, J = 8.3 Hz), 7.66 (1H, d, J = 3.0 Hz),








8.02 (2H, d, J = 8.7 Hz).


615
—CF
—H
—CH3
—H
—C2H5
1.37 (3H, t, J = 7.1 Hz), 1.56 (3H, d, J =








6.8 Hz), 4.06 (1H, brs), 4.34 (2H, q, J =








7.1 Hz), 4.49 (1H, q, J = 6.6 Hz),








6.75 (1H, d, J = 8.7 Hz), 6.87 (1H, dd, J =








8.7 Hz, 3.0 Hz), 7.01 (2H, d, J = 8.6








Hz), 7.47 (2H, d, J = 8.1 Hz), 7.53 (1H,








d, J = 3.0 Hz), 7.60 (2H, d, J = 8.3 Hz),








8.00 (2H, d, J = 8.7 Hz).


616
—CF3
—H
—H
—F
—CH3
3.90 (3H, s), 4.40 (2H, brs), 6.89 (1H, d, J =








8.1 Hz), 7.03 (1H, dd, J = 8.7 Hz, 3.0








Hz), 7.15-7.21 (1H, m), 7.47 (2H, d, J =








8.1 Hz), 7.55 (1H, d, J = 3.0 Hz),








7.61 (2H, d, J = 8.1 Hz), 7.80-7.84 (2H,








m).


617
—Cl
—Cl
—H
—F
—CH3
3.91 (3H, s), 4.29 (2H, brs), 6.88 (1H, d, J =








8.7 Hz), 7.02 (1H, dd, J = 8.7 Hz, 3.0








Hz), 7.15-7.21 (2H, m), 7.41 (1H, d, J =








8.3 Hz), 7.46 (1H, d, J = 2.0 Hz),








7.53 (1H, d, J = 3.0 Hz), 7.81-7.84 (2H,








m).









Reference Example 618
Production of ethyl 3-{4-[5-(3,4-dichlorobenzylamino)-pyridin-2-yloxy]phenyl}propionate
A solution of 3,4′-dichlorobenzaldehyde (1.28 g, 7.3 mmol) was added to a solution of ethyl 3-[4-(5-aminopyridin-2-yloxy)phenyl]propionate (2.1 g, 7.3 mmol) in ethanol (20 mL), and the resulting solution was stirred for 2 hours at 40° C. To the resulting reaction solution was added sodium borohydride (0.55 g, 15.7 mmol) under ice cooling, and stirred at the same temperature for 1 hour. To the solution was added water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1), to thereby yield 2.71 g of the title compound.
Appearance: Colorless oil
1H NMR (CDCl3) δ 1.24 (3H, t, J=7.1 Hz), 2.50-2.68 (2H, m), 2.81-3.01 (2H, m), 3.71-4.20 (3H, m), 4.28 (2H, s), 6.76 (1H, d, J=8.7 Hz), 6.88-7.02 (3H, m), 7.06-7.23 (3H, m), 7.41 (1H, d, J=8.2 Hz), 7.46 (1H, d, J=2.0 Hz), 7.60 (1H, d, J=3.0 Hz).
The following compounds were produced in the same manner as in Reference Example 618.







TABLE 90













 












Reference







Example


No.
R298
R299
R300
Xa21
1H NMR (CDCl3) δ ppm















619
—CF3
—H
—H
—CH2—
1.24 (3H, t, J = 7.3 Hz), 2.60 (2H, t, J = 8.1 Hz)







2.92 (2H, t, J = 8.1 Hz), 4.13 (2H, q, J = 7.3 Hz),







4.39 (2H, s), 6.76 (1H, d, J = 8.7 Hz), 6.97 (2H, d, J =







8.4 Hz), 6.98 (1H, dd, J = 8.6 Hz, 3.1 Hz), 7.17 (2H,







d, J = 8.4 Hz), 7.47 (2H, d, J = 8.1 Hz), 7.60 (2H, d, J =







7.9 Hz), 7.61 (1H, d, J = 3.1 Hz).


620
—Cl
—Cl
—OCH3
—CH2—
1.25 (3H, t, J = 7.1 Hz), 2.65-2.74 (2H, m), 2.94 (2H,







t, J = 8.2 Hz), 3.76 (3H, s), 3.93 (1H, brs), 4.14 (2H







q, J =7.1 Hz), 4.22-4.34 (2H, m), 6.70-6.85 (3H, m),







6.85-7.02 (2H, m), 7.10-7.25 (1H m), 7.39 (1H, d, J =







8.2 Hz), 7.44 (1H, d, J = 2.0 Hz), 7.53 (1H, d, J =







2.7 Hz).


621
—CF3
—H
—OCH3
—CH2—
1.25 (3H, t, J = 7.1 Hz), 2.52-2.68 (2H, m), 2.81-







3.01 (2H, m) 3.76 (3H s), 3.93 (1H, brs), 4.14 (2H,







q, J = 7.1 Hz), 4.30-4.40 (2H, m), 6.72-6.84 (3H, m),







6.96 (1H, d, J = 8.0 Hz), 6.98 (1H, dd, J = 8.0 Hz,







3.0 Hz), 7.40 (2H, d, J = 8.0 Hz), 7.55 (1H, d, J =







3.0 Hz), 7.59 (2H, d, J = 8.0 Hz).


622
—Cl
—Cl
—OC2H5
—CH2—
1.18 (3H, t, J = 7.0 Hz), 1.25 (3H, t, J = 7.1 Hz),







2.52-2.69 (2H, m), 2.82-3.00 (2H, m), 3.81-4.02 (3H,







m), 4.14 (2H, q, J = 7.1 Hz), 4.27 (2H, d, J =







4.7 Hz), 6.72-6.82 (3H, m), 6.93-7.02 (2H, m), 7.18







(1H, dd, J = 8.2 Hz, 2.0 Hz), 7.39 (1H, d, J = 8.4 Hz),







7.45 (1H, d, J = 2.0 Hz), 7.52 (1H, d, J = 3.0 Hz).


623
—CF3
—H
—OC2H5
—CH2—
1.18 (3H, t, J = 7.0 Hz), 1.25 (3H, t, J = 7.1 Hz),







2.51-2.72 (2H, m), 2.83-3.01 (2H, m), 3.87-4.06 (3H,







m), 4.16 (2H, q, J = 7.1 Hz), 4.30-4.42 (2H, m), 6.72-







6.83 (3H, m), 6.94-7.02 (2H, m), 7.46 (2H, d, J =







8.1 Hz), 7.54 (1H, d, J = 3.0 Hz), 7.59 (2H, d, J =







8.1 Hz).


624
—Cl
—Cl
—F
—CH2—
1.12-1.35 (3H, m), 2.50-2.74 (2H, m), 2.93 (2H, t, J =







7.7 Hz), 3.95 (1H, brs), 4.05-4.20 (2H, m), 4.27







(2H, s), 6.82 (1H, d, J = 8.4 Hz), 6.90-7.15 (4H, m),







7.18 (1H, dd, J = 8.4 Hz, 2.0 Hz), 7.35-7.60 (3H, m).


625
—CF3
—H
—F
—CH2—
1.13-1.35 (3H, m), 2.65-2.70 (2H, m), 2.93 (2H, t, J =







7.7 Hz), 4.01 (1H, brs), 4.05-4.23 (2H, m),







4.37 (2H, s), 6.82 (1H, d, J = 8.8Hz), 6.90-7.15 (4H,







m), 7.37-7.55 (3H, m) 7.55-7.70 (2H, m).


626
—Cl
—Cl
—H
—N(Ac)—
1.27 (3H, t, J = 7.1 Hz), 1.94 (3H, s), 4.10 (1H, brs),







4.19 (2H, q, J = 7.1 Hz), 4.31 (2H, s), 4.34 (2H, s),







6.84 (1H, d, J = 8.5 Hz), 7.00 (1H, dd, J = 8.5 Hz,







3.0 Hz), 7.06 (2H, d, J = 8.7 Hz), 7.20 (1H, dd, J =







8.2 Hz, 2.2 Hz), 7.31 (2H, d, J = 8.7 Hz), 7.42 (1H, d,







J = 8.2 Hz), 7.47 (1H, d, J = 2.2 Hz), 7.62 (1H, d, J =







3.0 Hz).


627
—CF3
—H
—H
—N(Ac)—
1.27 (3H, t, J = 7.1 Hz), 1.93 (3H, s) 4.15 (1H, brs),







4.18 (2H, q, J = 7.1 Hz), 4.34 (2H, s), 4.35-4.50 (2H,







m), 6.83 (1H, d, J = 8.6 Hz), 7.01 (1H, dd, J =







8.6 Hz, 3.0 Hz), 7.06 (2H, d, J = 8.9 Hz), 7.31 (2H, d,







J = 8.9 Hz), 7.48 (2H, d, J = 8.1 Hz), 7.62 (2H, d, J =







8.1 Hz), 7.64 (1H, d, J = 3.6 Hz).









Reference Example 628
Production of ethyl 3-(4-{5-[benzyloxycarbonyl(2-methoxyethyl)amino]pyridin-2-yloxy}phenyl)propionate
Under a nitrogen atmosphere, to a solution of ethyl 3-[4-(5-benzyloxycarbonylaminopyridin-2-yloxy)phenyl]propionate (1.7 g, 4.0 mmol) in DMF (50 mL) was added 60% sodium hydride (0.19 g, 4.9 mmol) under ice cooling, and the resulting solution was stirred for 35 minutes at the same temperature. 2-Bromoethylmethyl ether (0.4 mL, 4.2 mmol) was added dropwise to the solution. The reaction solution was stirred for 2 hours under ice cooling, and then stirred for 2 days at room temperature. To the reaction solution was added water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1), to thereby yield 1.6 g of the title compound.
Appearance: Pale yellow oil
1H NMR (CDCl3) δ 1.25 (3H, t, J=7.1 Hz), 2.57-2.70 (2H, m), 2.89-3.02 (2H, m), 3.52 (2H, t, J=5.4 Hz), 3.79 (2H, t, J=5.4 Hz), 4.14 (2H, q, J=7.1 Hz), 5.14 (2H, brs), 6.87 (1H, d, J=8.7 Hz), 6.89-7.10 (2H, m), 7.11-7.41 (7H, m), 7.47-7.69 (1H, m), 8.10 (1H, brs).
The following compounds were produced in the same manner as in Reference Example 628.
Reference Example 629
Ethyl[(4-{5-[(3,4-dichlorophenyl)methylamino]pyridin-2-yloxy}-2-trifluoromethylphenyl)ethylamino]acetate
MS 541 (M+)







TABLE 91













 










Reference





Example


No.
R301
R302
1H NMR (CDCl3) δ ppm or MS













630
4-CF3PhCH2—
–(CH2)2OCH3
1H NMR 1.24 (3H, t, J = 7.1 Hz), 2.54-





2.67 (2H, m), 2.76-2.98 (2H, m), 4.13 (2H, q, J =





7.1 Hz), 4.61 (2H, s), 6.76 (1H, d, J = 8.9 Hz),





6.93-7.01 (2H, m), 7.07 (1H, dd, J = 8.9 Hz, 3.3





Hz), 7.12-7.20 (2H, m), 7.33 (2H, d, J = 8.0





Hz), 7.56 (2H, d, J = 8.0 Hz), 7.65 (1H, d, J =





2.9 Hz).


631
4-CF3PhCH2—
—C2H5
1H NMR 1.09-1.32 (6H, m), 2.53-2.66 (2H, m),





2.84-2.98 (2H, m), 3.45 (2H, q, J = 7.1 Hz),





4.13 (2H, q, J = 7.1 Hz), 4.49 (2H, s), 6.77 (1H,





d, J = 8.5 Hz), 6.93-7.01 (2H, m), 7.02-





7.09 (1H, m), 7.12-7.20 (2H, m), 7.11-7.39 (2H,





m), 7.53-7.61 (2H, m), 7.66 (1H, d, J = 3.0 Hz).


632
PhCH2OCO—
—C2H5
1H NMR 1.15 (3H, t, J = 7.1 Hz), 1.25 (3H, t, J =





7.1 Hz), 2.54-2.71 (2H, m), 2.83-3.04 (2H, m),





3.69 (2H, q, J = 7.1 Hz), 4.14 (2H, q, J = 7.1





Hz), 5.14 (2H, brs), 6.88 (1H, d, J = 8.7 Hz),





7.02-7.11 (2H, m), 7.18-7.40 (7H, m), 7.44-





7.59 (1H, m), 7.98-8.08 (1H, m).


633
4-CF3PhCH2—
—SO2CH3
MS 522(M+)


634
3,4-Cl2PhCH2—
—SO2CH3
MS 522(M+)


635
3,4-Cl2Ph-
—CH3
MS 444(M+)









Reference Example 636
Production of ethyl 3-{4-[5-(2-methoxyethylamino)-pyridin-2-yloxy]phenyl}propionate
To a solution of ethyl 3-(4-{5[benzyloxycarbonyl(2-methoxyethyl)amino]pyridin-2-yloxy}phenyl}propionate (1.82 g, 3.8 mmol) in ethanol-ethyl acetate (10 mL-10 mL) was added under a nitrogen atmosphere 10% palladium-carbon (0.2 g), and the resulting solution was stirred for 3 hours under a hydrogen atmosphere at atmospheric pressure. The palladium-carbon was filtered off through Celite, and the filtrate was evaporated to yield 1.23 g of the title compound.
Appearance: Blue oil
1H NMR (CDCl3) δ 1.24 (3H, t, J=7.1 Hz), 2.55-2.68 (2H, m), 2.87-2.98 (2H, m), 3.20-3.31 (2H, m), 3.56-3.66 (2H, m), 4.13 (2H, q, J=7.1 Hz), 6.77 (1H, d, J=8.7 Hz), 6.93-7.01 (2H, m), 7.03 (1H, dd, J=8.7 Hz, 3.0 Hz), 7.13-7.22 (2H, m), 7.66 (1H, d, J=3.0 Hz).
The following compound was produced in the same manner as in Reference Example 636.
Reference Example 637
Ethyl 3-[4-(5-ethylaminopyridin-2-yloxy)phenyl]-propionate
1H NMR (CDCl3) δ 1.29-1.32 (6H, m), 2.55-2.67 (2H, m), 2.87-2.99 (2H, m), 3.14 (2H, q, J=7.1 Hz), 4.13 (2H, q, J=7.1 Hz), 6.77 (1H, d, J=8.7 Hz), 6.89-7.02 (3H, m), 7.09-7.25 (3H, m), 7.63 (1H, d, J=3.0 Hz).
Reference Example 638
Production of ethyl 3-(3-methoxy-4-{5-[methyl-(4-trifluoromethylbenzyl)amino]pyridin-2-yloxy}phenyl)-propionate
To a solution of ethyl 3-{3-methoxy-4-[5-(4-trifluoromethylbenzylamino]pyridin-2-yloxy}phenyl}-propionate (0.8 g, 1.7 mmol) in methanol (15 mL) were added a 37% aqueous formaldehyde solution (0.38 mL, 5.1 mmol) and acetic acid (0.1 mL, 1.7 mmol). The reaction solution was stirred for 30 minutes at room temperature. After that, sodium cyanoborohydride (0.24 g, 3.4 mmol) was added to the reaction solution under ice cooling, and the mixture was stirred under ice cooling for 40 minutes. To the reaction solution was added water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1), to thereby yield 0.62 g of the title compound.
Appearance: Pale yellow oil
1H NMR (CDCl3) δ 1.25 (3H, t, J=7.1 Hz), 2.52-2.70 (2H, m), 2.87-3.02 (5H, m), 3.77 (3H, s), 4.14 (2H, q, J=7.1 Hz), 4.40-4.50 (2H, m), 6.74-6.86 ((3H, m), 6.97 (1H, d, J=8.0 Hz), 7.11 (1H, dd, J=8.9 Hz, 3.2 Hz), 7.34 (2H, d, J=8.1 Hz), 7.57 (2H, d, J=8.1 Hz), 7.65 (1H, d, J=3.2 Hz).
The following compounds were produced in the same manner as in Reference Example 638.







TABLE 92













 











Reference






Example






No.
R303
R304
R305
1H NMR (CD Cl3) δ ppm





639
—H
—CH3
—CH3
3.07(3 H, s), 3.89(3 H, s), 4.56(2 H, s), 6.87(1 H, d, J =






8.9 Hz), 7.06(2 H, d, J = 8.6 Hz), 7.13(1 H, dd, J = 8.9






Hz, 3.3 Hz), 7.35(2 H, d, J = 8.1 Hz), 7.60(2 H, d, J =






8.3 Hz), 7.75(1 H, d, J = 3.1 Hz), 8.02(2 H, d, J = 8.6






Hz).


640
—H
—C2H5
—C2H5
1.24(3 H, t, J = 7.1 Hz), 1.37(3 H, t, J = 7.1 Hz),






3.49(2 H, q, J = 7.1 Hz), 4.35(2 H, q, J = 7.1 Hz),






4 53(2 H, s), 6.84(1 H, d, J = 8.9 Hz), 7.05(2 H, d, J =






8.6 Hz), 7.06(1 H, dd, J = 8.9 Hz, 3.1 Hz), 7.36(2 H, d,






J = 8.4 Hz), 7.58(2 H, d, J = 8.3 Hz), 7.69(1 H, d, J =






3.1 Hz), 8.02(2 H, d, J = 8.6 Hz).


641
—CH3
—CH3
—C2H5
1.38(3 H, t, J = 7.1 Hz), 1.59(3 H, d, J = 6.9 Hz),






2.74(3 H, s), 4.36(2 H, q, J = 7.1 Hz), 4.49(1 H, q, J =






6.9 Hz), 6.89(1 H, d, J = 8.9 Hz), 7.08 (2 H, d, J = 8.9






Hz), 7.24(1 H, dd, J = 8.9 Hz, 3.1 Hz), 7.43(2 H, d, J =






8.6 Hz), 7.61(2 H, d, J = 8.3 Hz), 7.84(1 H, d, J = 3.1






Hz), 8.03(2 H, d, J = 8.9 Hz).
















TABLE 93













 











Reference






Example






No.
R306
R307
Xa22
1H NMR (CDCl3) δ ppm





642
—CH3
—H
—CH2—
1.24(3 H, t, J = 7.1 Hz), 2.60(2 H, t, J = 7.8 Hz),






2.92(2 H, t, J = 7.8 Hz), 3.02(3 H, s), 4.12(2 H, q, J =






7.1 Hz), 4.51(2 H, s), 6.79(1 H, d, J = 8.9 Hz),






6.97(2 H, d, J = 8.4 Hz), 7.10(1 H, dd, J = 8.9 Hz, 3.3






Hz), 7.17(2 H, d, J = 8.3 Hz), 7.34(2 H, d, J = 8.1 Hz),






7.58(2 H, d, J = 8.3 Hz), 7.69(1 H, d, J = 3.1 Hz).


643
−CH3
—H
—N(Ac)-
1.27(3 H, t, J = 7.1 Hz), 1.94(3 H, s), 3.06(3 H, s),






4.18(2 H, q, J = 7.1 Hz), 4.34(2 H, s), 4.55(2 H, s),






6.87(1 H, d, J = 8.9 Hz), 7.07(2 H, d, J = 83 Hz),






7.13(1 H, dd, J = 8.9 Hz, 3.1 Hz), 7.31(2 H, d, J = 8.7






Hz), 7.35(2 H, d, J = 8.0 Hz), 7.59(2 H, d, J = 8.0 Hz),






7.72(1 H, d, J = 3.1 Hz).


644
—CH3
—F
—CH2—
1.25(3 H, t, J = 7.1 Hz), 2.55-2.70(2 H, m), 2.93(2 H, t,






J = 7.9 Hz), 3.00(3 H, s), 4.13(2 H, q, J = 7.1 Hz),






4.49(2 H, s), 6.86(1 H, d, J = 8.9 Hz), 6.90-7.16(4 H,






m), 7.33(2 H, d, J = 8.1 Hz), 7.57(2 H, d, J = 8.1 Hz),






7.62(1 H, d, J = 3.2 Hz).


645
—CH3
—OC2H5
—CH2—
1.19(3 H, t, J = 7.0 Hz), 1.25(3 H, t, J = 7.1 Hz),






2.50-2.69(2 H, m), 2.81-2.99(2 H, m), 2.98(3 H, s), 3.98(2 H,






q, J = 7.0 Hz), 4.14(2 H, q, J = 7.1 Hz), 4.48(2 H, s),






6.68-6.88(3 H, m), 7.00(1 H, d, J = 8.0 Hz), 7.11(1 H,






dd, J = 8.0 Hz, 3.0 Hz), 7.33(2 H, d, J = 8.0 Hz),






7.56(2 H, d, J = 8.0 Hz), 7.64(1 H, d, J = 3.0 Hz).


646
—C2H5
—F
—CH2—
1.19(3 H, t, J = 7.1 Hz), 1.10-1.35(3 H, m),






2.50-2.70(2 H, m), 2.93 (2 H, t, J = 8.0 Hz), 3.43(2 H, q, J =






7.1 Hz), 4.02-4.22(2 H, m), 4.47 (2 H, s), 6.83(1 H, d, J =






9.0 Hz), 6.88-7.15(4 H, m), 7.34(2 H, d, J = 8.0 Hz),






7.41-7.70(3 H, m).


647
—C2H5
—OCH3
—CH2—
1.18(3 H, t, J = 7.0 Hz), 1.25(3 H, t, J = 7.1 Hz),






2.57-2.68(2 H, m), 2.88-2.99(2 H, m), 3.42(2 H, q, J = 7.0






Hz), 3.77(3 H, s), 4.14(2 H, q, 4 7.1 Hz),






4.42-4.50(2 H, m), 6.72-6.86((3 H, m), 6.97(1 H, d, J = 8.0






Hz), 7.05(1 H, 4d, J = 9.0 Hz, 3.2 Hz), 7.30-7.38(2 H,






m), 7.51-7.59 (2 H, m), 7.60(1 H, d, J = 3.2 Hz).


648
—C2H5
—OC2H5
—CH2—
1.17(3 H, t, J = 7.0 Hz), 1.18(3 H, t, J = 7.0 Hz),






1.25(3 H, t, J = 7.1 Hz), 2.55-2.69(2 H, m),






2.84-2.98(2 H, m), 3.42(2 H, q, J = 7.1 Hz), 3.97(2 H, q, J =






7.0 Hz), 4.13(2 H, q, J = 7.0 Hz), 4.46(2 H, s),






6.71-6.82(3 H, m), 6.99(1 H, d, J = 8.0 Hz), 7.05(1 H, dd, J =






8.9 Hz, 3.1 Hz), 7.34(2 H, d, J = 8.0 Hz), 7.55(2 H,






d, J = 8.0 Hz), 7.59(1 H, d, J = 3.1 Hz).
















TABLE 94













 











Reference






Example






No.
R308
R309
Xa23
1H NMR (CD Cl3) δ ppm





649
—CH3
—H
—N(Ac)-
1.27(3 H, t, J = 7.1 Hz), 1.94(3 H, s); 3.03(3 H, s),






4.19(2 H, q, J = 7.1 Hz), 4.34(2 H, s), 4.43(2 H, s),






6 87(1 H, d, J = 9.0 Hz), 7.03-7.11(1 H, m),






7.07(2 H d, J = 8.7 Hz), 7.13(1 H, dd, J = 9.0 Hz,






3.1 Hz), 7.27-7.35(1 H, m), 7.31(2 H, d, J = 8.7 Hz),






7.40(1 H, d, J = 8.2 Hz), 7.71(1 H, d, J = 3.1 Hz).


650
—CH3
—F
—CH2—
1.15-1.30(3 H, m), 2.53-2.70(2 H, m), 2.93(2 H, t, J =






7.9 Hz), 2.97(3 H, s), 4.02-4.20(2 H, m), 4.37(2 H,






s), 6.86(1 H, d, J = 8.9 Hz), 6.91-7.18(5 H, m),






7.32(1 H, d, J = 2.0 Hz), 7.38(1 H, d, J = 8.2 Hz),






7.61(1 H, d, J = 2.9 Hz).


651
—CH3
—OCH3
—CH2—
1.25(3 H, t, J = 7.1 Hz), 2.55-2.75(2 H, m),






2.85-3.05(2 H, m), 2.95(3 H, s), 3.77(3 H, s), 4.14(2 H, q,






J = 7.1 Hz), 4.36(2 H, s), 6.71-6.88(3 H, m),






6.98(1 H, d, J = 8.1 Hz), 7.00-7.15(2 H, m),






7.32(1 H, d, J = 2.0 Hz), 7.38(1 H, d, J = 8.1 Hz),






7.64(1 H, d, J = 3.1 Hz).


652
—CH3
—OC2H5
—CH2—
1.19(3 H, t, J = 7.0 Hz), 1.25(3 H, t, J = 7.1 Hz),






2.55-2.72(2 H, m), 2.84-3.01(5 H, m), 3.98(2 H, q, J =






7.0 Hz), 4.14(2 H, q, 4 7.1 Hz), 4.29-4.40(2 H,






m), 6.74-6.83(3 H, m), 7.00(1 H, d, J = 8.0 Hz),






7.06(1 H, dd, J = 8.2 Hz, 2.0 Hz), 7.10(1 H, dd, J =






9.0 Hz, 3.2 Hz), 7.31(1 H, d, J = 2.0 Hz), 7.37(1 H,






d, J = 8.2 Hz), 7.63(1 H, d, J = 3.2 Hz).


653
—C2H5
—F
—CH2—
1.17(3 H, t, J = 7.1 Hz), 1.20-1.30(3 H, m),






2.50-2.72(2 H, m), 2.93(2 H, t, J = 7.8 Hz), 3.40(2 H, q, J =






7.1 Hz), 4.00-4.22(2 H, m), 4.36(2 H, s), 6.83(1 H,






d, J = 8.9 Hz), 6.85-7.15(5 H, m), 7.28-7.32(1 H, m),






7.37(1 H, d, J = 8.2 Hz), 7.56(1 H, d, J = 3.2 Hz).


654
—C2H5
—OCH3
—CH2—
1.16(3 H, t, J = 7.1 Hz), 1.21-1.35(3 H, m),






2.50-2.75(2 H, m), 2.82-3.05(2 H, m), 3.39(2 H, q, J = 7.1






Hz), 3.77(3 H, s), 4.05-4.25 (2 H, m), 4.35(2 H, s),






6.68-6.88(3 H, m), 6.90-7.00(1 H, m), 7.00-7.11(2 H,






m), 7.31(1 H, d, J = 2.0 Hz), 7.37(1 H, d, J = 8.2






Hz), 7.59(1 H, d, J = 3.0 Hz).


655
—C2H5
—OC2H5
—CH2—
1.11-1.22(6 H, m), 1.25(3 H, t, J = 7.1 Hz),






2.56-2.67(2 H, m), 2.86-2.97(2 H, m), 3.39(2 H, q, J = 7.1






Hz), 3.97(2 H, q, J = 7.0 Hz), 4.14(2 H, q, J = 7.1






Hz), 4.34(2 H, s), 6.736.82(3 H, m), 6.99 (1 H, d, J =






8.0 Hz), 7.02-7.10(2 H, m), 7.32(1 H, d, J = 1.9






Hz), 7.36(1 H, d, J = 8.2 Hz), 7.58(1 H, d, J = 3.1






Hz).









Reference Example 656
Production of ethyl 3-(4-(5-(3,4-dichlorophenylamino)pyridin-2-yloxy)phenyl)propionate
Triethylamine (1.2 mL, 8.4 mmol) was added to a suspension of ethyl 3-(4-(5-aminopyridin-2-yloxy)phenyl)propionate (1.2 g, 4.2 mmol), 3,4-dichlorophenylboronic acid (1.6 g, 8.4 mmol), anhydrous copper acetate (0.762 g, 4.2 mmol) and molecular sieves 4A (5 g) in dichloromethane (24 mL), and the resulting reaction solution was stirred overnight at room temperature. After the resulting solution was filtered through Celite, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1), to thereby yield 1.5 g of the title compound.
Appearance: Slightly brown solid
1H NMR (CDCl3) δ 1.25 (3H, t, J=7.1 Hz), 2.60-2.66 (2H, m), 2.93-2.99 (2H, m), 4.14 (2H, q, J=7.1 Hz), 5.52 (1H, brs), 6.71 (1H, dd, J=8.7 Hz, 2.7 Hz), 6.90 (1H, d, J=8.7 Hz), 6.97 (1H, d, J=2.7 Hz), 7.04-7.08 (2H, m), 7.21-7.26 (3H, m), 7.49 (1H, dd, J=8.7 Hz, 2.9 Hz), 8.01 (1H, d, J=2.8 Hz).
The following compound was produced in the same manner as in Reference Example 656.
Reference Example 657
Ethyl({4-[5-(3,4-dichlorophenylamino)pyridin-2-yloxy]-2-trifluoromethylphenyl}ethylamino)acetate
MS 527 (M+)
Reference Example 658
Production of ethyl 4-[3-(4-benzyloxy-3-methyl)phenyl-2-oxotetrahydropyrimidin-1-yl]benzoate
Under a nitrogen atmosphere, to a solution of 1-(4-benzyloxy-3-methyl)phenyltetrahydropyrimidin-2-one (0.5 g, 1.7 mmol) in dioxane (5 mL) were added copper (I) iodide (16 mg, 0.08 mmol) and N,N-dimethylglycine hydrochloride (47 mg, 0.34 mmol). The resulting solution was stirred for 5 minutes, and then ethyl 4-iodobenzoate (0.39 g, 1.4 mmol) and potassium (III) phosphate (1.04 g, 4.9 mmol) were added to the reaction mixture. The resulting solution was stirred for 20 hours at 100° C., after which the resulting solution was sprinkled with silica gel. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=3:1→dichloromethane:methanol=40:1), to thereby yield 0.43 g of the title compound.
Appearance: White powder
1H NMR (DMSO-d6) δ 1.30 (3H, t, J=7.1 Hz), 2.08-2.22 (5H, m), 3.66 (2H, t, J=5.9 Hz), 3.81 (2H, t, J=5.9 Hz), 4.28 (2H, q, J=7.1 Hz), 5.10 (2H, s), 6.86-7.14 (3H, m), 7.26-7.51 (7H, m), 7.82-7.92 (2H, m).
Reference Example 659
Production of ethyl(E)-3-(3-methoxy-4-{5-[2-(4-trifluoromethylphenyl)vinyl]pyridin-2-yloxy}phenyl)propionate
To ethyl 3-[4-(5-bromopyridin-2-yloxy)-3-methoxyphenyl]propionate (610 mg, 1.6 mmol) were added 4-trifluoromethylstyrene (0.332 mL, 2.2 mmol), dichlorobis(benzonitrile)palladium(II) (33 mg, 0.082 mmol), N,N-dimethylglycine hydrochloride (17 mg, 0.16 mmol), sodium acetate (263 mg, 3.2 mmol) and N-methylpyrrolidone (5 mL) under an argon atmosphere. The resulting solution was stirred under an argon atmosphere for 17 hours at 130° C. To the reaction solution was added ethyl acetate and filtered. The filtrate was washed with water, and then dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), to thereby yield 500 mg of the title compound.
Appearance: Pale yellow oil
1H NMR (CDCl3) δ 1.27 (3H, t, J=7.1 Hz), 2.64-2.69 (2H, m), 2.95-3.01 (2H, m), 3.76 (3H, s), 4.05 (2H, q, J=7.1 Hz), 6.71-6.88 (2H, m), 6.95 (1H, d, J=8.6 Hz), 6.98-7.08 (2H, m), 7.11 (1H, d, J=16.5 Hz), 7.56-7.63 (4H, m), 7.87-7.91 (1H, m), 8.23 (1H, d, J=2.3 Hz).
The following compound was produced in the same manner as in Reference Example 659.
Reference Example 660
Ethyl 3-(4-{5-[(E)-2-(3,4-dichlorophenyl)vinyl]pyridin-2-yloxy}-3-methoxyphenyl)propionate
1H NMR (CDCl3) δ 1.26 (3H, t, J=7.1 Hz), 2.63-2.69 (2H, m), 2.94-3.00 (2H, m), 3.76 (3H, s), 4.15 (2H, q, J=7.1 Hz), 6.81-6.90 (3H, m), 6.93 (1H, d, J=8.6 Hz), 6.99 (1H, d, J=15.3 Hz), 7.06 (1H, d, J=9.1 Hz), 7.27-7.31 (1H, m), 7.40 (1H, d, J=8.2 Hz), 7.55 (1H, d, J=2.0 Hz), 7.82-7.86 (1H, m), 8.19 (1H, d, J=2.5 Hz).
Reference Example 661
Production of ethyl{4-[4-(3,4-dichlorobenzoylamino)-2-fluorophenoxy]benzenesulfonyl}acetate
To a solution of ethyl{4-[4-(3,4-dichlorobenzoylamino)-2-fluorophenoxy]phenylsulfanyl}-acetate (1.20 g, 2.43 mmol) in dichloromethane (20 mL) was added m-chloroperbenzoic acid (1.45 g, 6.06 mmol) at 0° C. The resulting solution was stirred for 2 hours at room temperature. To the reaction solution was added methanol and stirred for some time. To the resulting solution was then added water, and extracted with dichloromethane. The dichloromethane layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and evaporated. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1), to thereby yield 1.28 g of the title compound.
Appearance: Yellow amorphous powder
1H NMR (CDCl3) δ 1.22 (3H, t, J=7.1 Hz), 4.11 (2H, s), 4.16 (2H, q, J=7.1 Hz), 7.06 (2H, d, J=8.9 Hz), 7.19 (1H, t, J=8.7 Hz), 7.30 (1H, d, J=8.7 Hz), 7.59 (1H, d, J=8.3 Hz), 7.71 (1H, dd, J=2.0 Hz, 8.3 Hz), 7.75-7.85 (1H, m), 7.86-7.95 (3H, m), 7.98 (1H, d, J=2.0 Hz).
Reference Example 662
Production of methyl 3-{4-[5-(3,4-dichlorobenzoyl-amino)pyridine-2-sulfinyl]phenyl}propionate
To a solution of methyl 3-{4-[5-(3,4-=dichlorobenzoylamino)pyridin-2-ylsulfanyl]phenyl}propionate (1.00 g, 2.17 mmol) in dichloromethane (20 mL) was added m-chloroperbenzoic acid (0.620 g, 2.60 mmol) at 0° C. The resulting solution was stirred for 1 hour at 0° C. To the reaction solution was added methanol and stirred for some time. To the resulting solution was then added water, and extracted with dichloromethane. The dichloromethane layer was washed with water, a saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and evaporated. The obtained residue was recrystallized from ethanol 3 times, to thereby yield 0.790 g of the title compound.
Appearance: White powder
Melting point: 164-166° C.
Reference Example 663
Production of methyl 3-{4-[5-(3,4-dichlorobenzoyl-amino)pyridine-2-sulfonyl]phenyl}propionate
To a solution of methyl 3-{4-[5-(3,4-dichlorobenzoylamino)pyridin-2-ylsulfanyl]phenyl}-propionate (1.00 g, 2.17 mmol) in dichloromethane (20 mL) was added m-chloroperbenzoic acid (1.29 g, 5.42 mmol) at 0° C. The resulting solution was stirred for 1.5 hours at 0° C. To the reaction solution was added methanol and stirred for some time. To the resulting solution was then added water, and extracted with dichloromethane. The dichloromethane layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated. The obtained residue was recrystallized from ethanol, to thereby yield 0.890 g of the title compound.
Appearance: White powder
Melting point: 165-166° C.
Reference Example 664
Production of ethyl{4-[4-(3,4-dichlorobenzoylamino)-2-fluorophenoxy]benzenesulphenyl}acetate
To a solution of ethyl{4-[4-(3,4-dichloro-benzoylamino)-2-fluorophenoxy]phenylsulfanyl}acetate (0.800 g, 1.61 mmol) in methanol (20 mL) was added a 31% hydrogen peroxide solution (2.08 mL, 18.5 mmol). The resulting solution was refluxed for 16 hours. The reaction solution was cooled with ice, and the resulting precipitated solid was collected by filtration, to thereby yield 0.651 g of the title compound.
Appearance: White powder
1H NMR (DMSO-d6) δ 1.13 (3H, t, J=7.1 Hz), 3.90-4.10 (4H, m), 7.14 (2H, d, J=8.8 Hz), 7.34 (1H, t, J=9.0 Hz), 7.55-7.65 (1H, m), 7.72 (2H, d, J=8.8 Hz), 7.84 (1H, d, J=8.4 Hz), 7.90-8.00 (2H, m), 8.22 (1H, d, J=2.0 Hz), 10.63 (1H, s).
Reference Example 665
Production of ethyl 3-(4-{5-[4-(trifluoromethyl)phenyl-carbomoyl]pyridin-2-yloxy}phenyl)butyrate
To a suspension of 60% sodium hydride (0.133 g, 3.3 mmol) in THF (6 mL) was added dropwise triethylphosphono acetate (0.53 mL, 2.7 mmol) under ice cooling, and the resulting solution was stirred for 1 hour at room temperature. To the reaction solution was added a solution of 6-(4-acetylphenoxy)-N-[4-(trifluoromethyl]phenyl]nicotinamide (0.53 g, 1.3 mmol) in THF (6 mL), and the resulting solution was stirred for 10 hours at 60° C. To the reaction solution was added saturated aqueous ammonium chloride, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1), to thereby yield 0.57 g of the intermediate product ethyl 3-(4-{5-[4-(trifluoromethyl)phenyl-carbamoyl]pyridin-2-yloxy}phenyl)-2-butenoate.
10% palladium-carbon (0.057 g) was suspended in a mixed solvent consisting of ethanol (8 mL) and dioxane (2 mL), and to this suspension was added ethyl 3-(4-{5-[4-(trifluoromethyl)phenylcarbamoyl]pyridin-2-yloxy}phenyl)-2-butenoate (0.57 g, 1.2 mmol). The resulting product was subjected to catalytic reduction at atmospheric pressure and room temperature. Once the absorption of hydrogen had stopped, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure, to thereby yield 0.56 g of the title compound.
Appearance: White solid
1H NMR (CDCl3) δ 1.21 (3H, t, J=7.1 Hz), 1.33 (3H, d, J=7.0 Hz), 2.51-2.67 (2H, m), 3.28-3.37 (1H, m), 4.10 (2H, q, J=7.1 Hz), 7.00 (1H, d, J=8.6 Hz), 7.07-7.12 (2H, m), 7.26-7.31 (2H, m), 7.60-7.65 (2H, m), 7.73-7.77 (2H, m), 7.81 (1H, brs), 8.21 (1H, dd, J=8.6, 2.6 Hz), 8.68 (1H, d, J=2.3 Hz).
The following compound was produced in the same manner as in Reference Example 665.
Reference Example 666
Ethyl 2-methyl-3-{4-[5-(4-trifluoromethylphenyl-carbamoyl)pyridin-2-yloxy]phenyl}propionate
MS 472 (M+)
Reference Example 667
Production of 3,4-dichloro-N-{6-[4-(N-hydroxy-carbamimidoylmethyl)phenoxy]pyridin-3-yl}benzamide
To a solution of 3,4-dichloro-N-[6-(4-cyanomethylphenoxy)pyridin-3-yl]benzamide (700 mg, 1.76 mmol) in ethanol (30 mL) were added water (2 mL), hydroxylamine (420 mg, 12.71 mmol) and potassium carbonate (1.76 g, 12.73 mmol). Under argon, the resulting solution was stirred under reflux for 4 hours. The resulting reaction solution was concentrated under reduced pressure. To the residue was added water, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=10:1), to thereby yield 510 mg of the title compound.
Appearance: White powder
1H NMR (DMSO-d6) δ 3.27 (2H, s), 5.41 (2H, brs), 7.03 (2H, d, J=8.4 Hz), 7.05 (1H, d, J=8.8 Hz), 7.31 (2H, d, J=8.4 Hz), 7.84 (1H, d, J=8.4 Hz), 7.94 (1H, dd, J=8.4 Hz, 2.0 Hz), 8.18 (1H, dd, J=8.8 Hz, 2.6 Hz), 8.22 (1H, d, J=2.0 Hz), 8.46 (1H, d, J=2.6 Hz), 8.88 (1H, s), 10.53 (1H, s).
Reference Example 668
Production of 3,4-dichloro-N-{6-[4-(N-acetoxy-carbamimidoylmethyl)phenoxy]pyridin-3-yl}benzamide
To a solution of 3,4-dichloro-N-{6-[4-(N-hydroxycarbamimidoylmethyl)phenoxy]pyridin-3-yl}benzamide (510 mg, 1.18 mmol) in dioxane (8 mL) was added potassium carbonate (163 mg, 1.18 mmol). While stirring under ice cooling, to the resulting solution was added dropwise acetyl chloride (0.084 mL, 1.18 mmol), and the resulting solution was stirred for 15 minutes at room temperature. To the reaction solution was added THF (10 mL), and then water, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, evaporated. The residue was washed with ethyl acetate to yield 340 mg of the title compound.
Appearance: White powder
1H NMR (DMSO-d6) δ 2.05 (3H, s), 3.35 (2H, s), 6.43 (2H, brs), 7.06 (1H, d, J=9.0 Hz), 7.06 (2H, d, J=8.6 Hz), 7.36 (2H, d, J=8.6 Hz), 7.84 (1H, d, J=8.3 Hz), 7.94 (1H, dd, J=8.3 Hz, 2.0 Hz), 8.18 (1H, dd, J=9.0 Hz, 2.5 Hz), 8.22 (1H, d, J=2.0 Hz), 8.47 (1H, d, J=2.5 Hz), 10.54 (1H, s).
Reference Example 66.9
Production of 4-{4-[4-(3,4-dichlorobenzoylamino)-2-fluorophenoxy]phenyl}-4-oxobutyric acid
To a suspension consisting of 3,4-dichloro-3′-fluoro-4′-phenoxybenzanilide (5.05 g, 13.4 mmol) and succinic anhydride (1.48 g, 14.8 mmol) in 1,2-dichloroethane (25 mL) was added aluminum chloride (6.26 g, 47.0 mmol) under ice cooling, and the resulting mixture was stirred at the same temperature for 5 minutes, and then at room temperature for 1.5 hours. The resulting reaction solution was poured into ice water, and the resulting solid was collected by filtration. To the solid was added 50% aqueous acetone (200 mL), and the resulting solution was refluxed for 0.5 hours, then cooled. The obtained solid was collected by filtration, to thereby yield 6.30 g of the title compound.
Appearance: White powder
Melting point: 205-208° C.
Reference Example 670
Production of ethyl 3-{4-[hydroxy(5-nitro-2-pyridyl)-methyl]phenyl}propionate
To a solution of ethyl 3-[4-(5-nitropyridine-2-carbonyl)phenyl]propionate (1.52 g, 4.63 mmol) in dichloromethane (15 mL) and ethanol (15 mL) was added sodium borohydride (0.175 g, 4.63 mmol) under ice cooling, and the resulting solution was stirred at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was dissolved in water and ethyl acetate. To the solution was added acetic acid and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), to thereby yield 0.264 g of the title compound.
Appearance: Brown powder
1H NMR (CDCl3) δ 1.19 (3H, t, J=7.2 Hz), 2.56 (2H, t, J=7.8 Hz), 2.91 (2H, t, J=7.8 Hz), 4.09 (2H, q, J=7.2 Hz), 4.35 (1H, brs), 5.84 (1H, s), 7.17 (2H, d, J=8.1 Hz), 7.26 (2H, d, J=8.1 Hz), 7.46 (1H, d, J=8.7 Hz), 8.40 (1H, dd, J=8.7 Hz, 2.5 Hz), 9.36 (1H, d, J=2.5 Hz).
The following compound was produced in the same manner as in Reference Example 670.
Reference Example 671
t-Butyl 4-[2-hydroxy-3-(4-hydroxyphenyl)propionyl]-piperazine-1-carboxylate
1H NMR (CDCl3) δ 1.47 (9H, s), 1.62 (1H, brs), 2.85 (2H, d, J=6.0 Hz), 3.00-3.80 (8H, m), 4.56 (1H, t, J=6.0 Hz), 5.35 (1H, brs), 6.74 (2H, d, J 8.4 Hz), 7.06 (2H, d, J=8.4 Hz).
Reference Example 672
Production of ethyl 3-(4-{5-[bis(3,4-dichlorobenzoyl)-amino]-2-pyridylmethyl}phenyl)propionate
To a suspension of 10% palladium-carbon (27 mg) in ethanol (5 mL) were added a solution of ethyl 3-{4-[hydroxy(5-nitro-2-pyridyl)-methyl]phenyl}propionate (0.264 g, 0.799 mmol) and 0.5 M hydrogen chloride in ethanol (2 mL), and the resulting solution was subjected to catalytic reduction at atmospheric pressure at 50° C. Once the absorption of hydrogen had stopped, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was suspended in THF (5 mL), and triethylamine (0.267 mL, 2.40 mmol) was added. To the solution was added dropwise a solution of 3,4-dichlorobenzoyl chloride (0.255 g, 0.879 mmol) in THF (1 mL) under ice cooling, and stirred for 1 hour at the same temperature. To the resulting solution was added water and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to thereby yield 0.177 g of the title compound.
Appearance: Pale yellow oil
1H NMR (CDCl3) δ 1.20 (3H, t, J=7.2 Hz), 2.56 (2H, t, J=7.8 Hz), 2.89 (2H, t, J=7.8 Hz), 4.09 (2H, q, J=7.2 Hz), 6.99 (1H, s), 7.17 (2H, d, J=8.2 Hz), 7.35 (2H, d, J=8.2 Hz), 7.42 (1H, d, J=8.6 Hz), 7.43-7.56 (2H, m), 7.63 (1H, dd, J=8.6 Hz, 2.1 Hz), 7.85-7.94 (2H, m), 8.15 (1H, d, J=2.0 Hz), 8.20-8.32 (2H, m), 8.57 (1H, d, J=2.5 Hz).
Reference Example 673
Production of ethyl 3-(4-(5-(N-(4-(trifluoromethyl)-phenyl)sulfamoyl)pyridin-2-yloxy)phenyl)propionate
To a solution of ethyl 3-(4-(3-bromo-5-(N-(4-(trifluoromethyl)phenyl)sulfamoyl)pyridin-2-yloxy)phenyl)propionate (0.41 g, 0.7 mmol) in ethanol (10 mL) were added 10% palladium-carbon (0.041 g) and ammonium formate (0.226 g, 3.6 mmol), and the resulting solution was heated to reflux for 2 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was then purified by silica gel chromatography (n-hexane:ethyl acetate=4:1), to thereby yield 0.28 g of the title compound.
Appearance: White solid
1H NMR (CDCl3) δ 1.24 (3H, t, J=7.1 Hz), 2.60-2.66 (2H, m), 2.93-2.99 (2H, m), 4.14 (2H, q, J=7.1 Hz), 6.95 (1H, d, J=8.8 Hz), 7.01-7.05 (2H, m), 7.20-7.26 (3H, m), 7.50-7.54 (3H, m), 8.03 (1H, dd, J=8.8 Hz, 2.6 Hz), 8.59 (1H, d, J=2.6 Hz).
Reference Example 674
Production of 1-(4-methoxyphenyl)imidazolin-2-one
To a suspension of 1-(2-chloroethyl)-3-(4-methoxyphenyl)urea (7.0 g, 30.6 mmol) in t-butanol (120 mL) was added potassium t-butoxide (6.4 g, 57.0 mmol) under a nitrogen atmosphere. The resulting solution was stirred for 10 minutes, and then potassium t-butoxide (3.0 g, 26.7 mmol) was added. This solution was stirred for 10 minutes, and then potassium t-butoxide (4.3 g, 38.3 mmol) was added. The resulting solution was stirred for 16 hours at room temperature. The pH was adjusted to between 2 and 3 with 10% hydrochloric acid, and the solvent was evaporated under reduced pressure. To the residue were added water (100 mL) and ethyl acetate (100 mL), and stirred for 1 hour at room temperature. Resulting precipitates were filtered, washed with diethyl ether, and then dried under reduced pressure, to thereby yield 5.1 g of the title compound.
Appearance: White powder
1H NMR (DMSO-d6) δ 3.29-3.44 (2H, m), 3.70 (3H, s), 3.71-3.88 (2H, m), 6.77 (1H, s), 6.81-6.95 (2H, m), 7.35-7.50 (2H, m).
The following compounds were produced in the same manner as in Reference Example 674.
Reference Example 675
1-(4-Benzyloxy-3-methylphenyl)tetrahydropyrimidin-2-one
1H NMR (DMSO-d6) δ 1.81-1.96 (2H, m), 2.16 (3H, s), 3.11-3.25 (2H, m), 3.51 (2H, t, J=5.6 Hz), 5.09 (2H, s), 6.42 (1H, s), 6.91 (1H, d, J=8.7 Hz), 6.98 (1H, dd, J=2.6 Hz, 8.7 Hz), 7.04 (1H, d, J=2.6 Hz), 7.28-7.34 (1H, m), 7.36-7.41 (2H, m), 7.42-7.48 (2H, m).







TABLE 95













 










Reference





Example


No.
R310
M
mp (°C.) or 1H NMR (CDCl3) δ ppm













676
—H
1
mp 162.0-163.0


677
—H
2
mp 179.0-180.0


678
—OCH3
1
1H NMR 2.29-2.45 (4H, m), 2.59-2.69 (2H, m), 2.91-3.04 (2H, m),





3.34-3.47 (4H, m), 3.53-1.69 (4H, m), 3.75 (3H, s), 3.85-3.96 (2H,





m), 4.58 (1H, s), 5.95 (2H, s), 6.69-6.78 (2H, m), 6.79-6.89 (3H,





m), 6.91 (1H, d, J = 9.0 Hz), 7.02 (1H, d, J = 8.0 Hz), 7.99 (1H, d,





J = 2.9 Hz), 8.25 (1H, dd, J = 2.9 Hz, 9.0 Hz).


679
—OCH3
2
mp 140.0-141.5
















TABLE 96













 









Reference




Example


No.
M
1H NMR (CDCl3) δ ppm












680
1
1.98-2.14 (2H, m), 2.18 (3H, s), 3.30 (2H, d, J = 6.0 Hz), 3.51-3.66 (2H, m), 3.67-




3.78 (2H, m), 3.80-4.05 (8H, m), 4.57 (2H, s), 4.79 (1H, s), 6.78-6.94 (4H, m),




6.99 (1H, d, J = 8.6 Hz), 7.13 (1H, dd, J = 2.6 Hz, 8.6 Hz), 7.22 (1H, d, J = 2.6 Hz),




8.05 (1H, d, J = 2.9 Hz), 8.22 (1H, dd, J = 2.9 Hz, 9.0 Hz).


681
2
1.91-2.15 (4H, m), 2.18 (3H, s), 3.18-3.36 (2H, m), 3.37-3.51 (2H, m), 3.58-3.78 (2H,




m), 3.88 (3H, s), 3.88 (3H, s), 4.56 (2H, s), 4.89 (1H, s), 6.76-6.94 (4H, m), 7.00 (1H,




d, J = 8.7 Hz), 7.13 (1H, dd, J = 2.6 Hz, 8.7 Hz), 7.23 (1H, d, J = 2.6 Hz),




7.67 (1H, dd, J = 2.8 Hz, 8.8 Hz), 8.08 (1H, d, J = 2.8 Hz).









Reference Example 682
Production of 3-{4-[4-(3,4-dichlorobenzoylamino)-phenoxy]phenyl}propionic acid
To a solution of ethyl 3-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}propionate (6.00 g, 13.1 mmol) in THF (60 mL) and ethanol (30 mL) were added 5 M aqueous sodium hydroxide (3.14 mL, 15.7 mmol) and water (30 mL) and the resulting solution was refluxed for 1 hour. The reaction solution was cooled with ice. To the reaction solution were added 5 M hydrochloric acid (4.0 mL, 20.0 mmol) and water (100 mL). The obtained solid was collected by filtration, and recrystallized from water-containing acetone, to thereby yield 5.60 g of the title compound.
Appearance: White powder
Melting point: 188-190° C.
The following compounds were produced in the same manner as in Reference Example 682.







TABLE 97













 









Reference




Example


No.
R311
1H NMR (solvent) δ ppm or MS












683




1H NMR (CDCl3) 1.51 (3H, d, J = 7.1 Hz), 2.12 (3H, s), 2.91 (3H, s), 4.49 (1H, q, J = 7.1 Hz), 6.71- 6.75 (2H, m), 6.95-7.00 (2H, m), 8.45 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.04 (1H, dd, J = 2.8 Hz, 0.5 Hz).


 


684




MS 300 (M+)


 


685




1H NMR (DMSO-d6) 7.39 (1H, td, J = 2.0 Hz, 8.9 Hz), 7.50 (1H, d, J = 9.0 Hz), 7.78 (1H, td, J = 2.1 Hz, 8.9 Hz), 8.70 (1H, dd, J = 2.8 Hz, 9.0 Hz), 9.04 (1H, d, J = 2.8 Hz), 11.35-11.91 (1H, m).


 


686




1H NMR (CDCl3) 2.72-2.77 (2H, m), 2.98-3.03 (2H, m), 3.74 (3H, s), 6.85-6.89 (2H, m), 7.03 (1H, d, J = 9.1 Hz), 7.06-7.09 (1H, m), 8.45 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.01. (1H, d, J = 2.8 Hz).


 


687




1H NMR (DMSO-d6) 2.52 (2H, t, J = 7.6 Hz), 2.80 (2H, t, J = 7.6 Hz), 6.86 (1H, d, J = 9.4 Hz), 7.21 (2H, d, J = 8.5 Hz), 7.58 (2H, d, J = 8.5 Hz), 8.26 (1H, dd, J = 2.9 Hz, 9.4 Hz), 9.01 (1H, d, J = 2.9 Hz), 10.06 (1H, s).


 


688




1H NMR (DMSO-d6) 2.96 (3H, s), 4.09 (2H, s), 6.44- 6.49 (2H, m), 6.56 (1H, dd, J = 8.3 Hz, 2.4 Hz), 7.15 (1H, d, J = 9.1 Hz), 7.20-7.26 (1H, m), 8.59 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.05 (1H, d, J = 2.8 Hz).


 


689




1H NMR (CDCl3) 1.53 (3H, d, J = 7.1 Hz), 2.93 (3H, s), 4.51 (1H, q, J = 7.1 Hz); 6.87 (2H, d, J = 9.2 Hz), 6.98 (1H, d, J = 9.1 Hz), 7.05 (2H, d, J = 9.1 Hz), 8.44 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.05 (1H, d, J = 2.6 Hz).


 


690




1H NMR (CDCl3) 2.63-2.69 (2H, m), 2.97 (3H, s), 3.68 (2H, t, J = 7.1 Hz), 6.81 (2H, d, J = 9.1 Hz), 6.98 (1H, d, J = 9.1 Hz), 7.05 (2H, d, J = 9.2 Hz), 8.44 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.06 (1H, d, J = 2.8 Hz).


 


691




1H NMR (DMSO-d6) 3.55 (3H, s), 6.67 (1H, d, J = 9.5 Hz), 7.52 (2H, d, J = 8.5 Hz), 8.04 (2H, d, J = 8.5 Hz), 8.21 (1H, dd, J = 2.8 Hz, 9.5 Hz), 9.05 (1H, d, J = 2.8 Hz), 13.10 (1H, brs).


 


692




1H NMR (DMSO-d6) 1.28-1.32 (2H, m), 1.75- 1.79 (3H, m), 2.01 (3H, s), 2.19 (2H, d, J = 6.8 Hz), 2.65 (2H, t, J = 12.0 Hz), 3.65 (2H, d, J = 12.4 Hz), 6.80-6.96 (3H, m), 7.15 (1H, d, J = 9.2 Hz), 8.58 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.01 (1H, d, J = 2.8 Hz), 10.71 (1H, brs).


 


693




MS 306 (M+)
















TABLE 98













 













Reference








Example



No.
R312
R313
R314
R315
R316
1H NMR (solvent) δ ppm





694
—F
—H
—H
—H
—CH3
(CDCl3) 3.09 (3H, s), 4.12 (2H, s), 6.45-








6.57 (2H, m), 7.05-7.12 (2H, m), 8.47 (1H, dd,








J = 9.1 Hz, 2.8 Hz), 9.02 (1H, dd, J = 2.8 Hz,








0.7 Hz).


695
—F
—H
—H
—H
—C2H5
(CDCl3) 1.25 (3H, t, J = 7.1 Hz), 3.47 (2H, q,








J = 7.1 Hz), 4.06 (2H, s), 6.42-6.53 (2H, m),








7.04-7.10 (2H, m), 8.47 (1H, dd, J = 9.1 Hz,








2.8 Hz), 9.02 (1H, dd, J = 2.8 Hz, 0.5 Hz).


696
—F
—H
—H
—H
allyl
(CDCl3) 4.03 (2H, d, J = 5.0 Hz), 4.09 (2H,








s), 5.25-5.32 (2H, m), 5.82-5.96 (1H, m),








6.44-6.56 (2H, m), 7.04-7.10 (2H, m),








8.47 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.02 (1H,








d, J = 2.6 Hz).


697
—F
—H
—H
—F
—CH3
(DMSO-d6) 2.94 (3H, s), 4.04 (3H, s),








6.92 (1H, dd, J = 8.5 Hz, 12.9 Hz), 7.30 (1H,








dd, J = 7.5 Hz, 13.7 Hz), 7.35 (1H, d, J =








9.1 Hz), 8.63 (1H, dd, d = 2.8 Hz, 9.1 Hz),








9.04 (1H, d, J = 2.8 Hz), 12.41-12.82 (1H,








m).


698
—F
—H
—H
—F
—C2H5
(DMSO-d6) 1.10 (3H, t, J = 7.0 Hz), 3.12-








3.48 (2H, m), 4.01 (2H, s), 6.90 (1H, dd, J =








8.4 Hz, 13.1 Hz), 7.29 (1H, dd, J = 7.6 Hz,








13.7 Hz), 7.35 (1H, d, J = 9.0 Hz), 8.63 (1H,








dd, J = 2.8 Hz, 9.0 Hz), 9.04 (1H, d, J = 2.8 Hz),








12.41-12.70 (1H, m).


699
—F
—H
—F
—H
—CH3
(DMSO-d6) 2.96 (3H, s), 4.26 (2H, s), 6.41-








6.61 (2H, m), 7.43 (1H, d, J = 9.1 Hz),








8.65 (1H, dd, J = 2.8 Hz, 9.1 Hz), 9.05 (1H,








d, J = 2.8 Hz), 12.56-12.90 (1H, m).


700
—CH3
—CH3
—H
—H
—CH3
(CDCl3) 2.07 (3H, s), 2.32 (3H, s), 2.85 (3H,








s), 3.76 (2H, s), 6.91 (1H, d, J = 8.7 Hz),








7.00 (1H, dd, J = 9.1 Hz, 0.6 Hz), 7.09 (1H,








d, J = 8.7 Hz), 8.46 (1H, dd, J = 9.1 Hz, 2.8 Hz),








9.04 (1H, dd, J = 2.8 Hz, 0.6 Hz).


701
—CH3
—H
—H
—CH3
—C2H5
(DMSO-d6) 0.98 (3H, t, J = 7.1 Hz),








1.98 (3H, s), 2.20 (3H, s), 3.09








(2H, q, J = 7.1 Hz),








3.70 (2H, s), 6.91 (1H, s), 7.06 (1H, s),








7.18 (1H, d, J = 9.1 Hz), 8.59 (1H, dd, J = 9.1 Hz,








2.9 Hz), 9.03 (1H, d, J = 2.9 Hz),








12.30 (1H, brs).


702
—H
—H
—H
—H
—SO2CH3
(DMSO-d6) 3.17 (3H, s), 4.43 (2H, s),








7.29 (2H, d, J = 8.7 Hz), 7.31 (1H, d, J = 9.1 Hz),








7.55 (2H, d, J = 8.9 Hz), 8.64 (1H, dd, J =








9.1 Hz, 2.8 Hz), 9.05 (1H, d, J = 2.8 Hz).


703
—CH3
—H
—H
—H
—SO2CH3
(DMSO-d6) 2.09 (3H, s), 3.11 (3H, s),








4.42 (2H, s), 7.20 (1H, d, J = 8.6 Hz),








7.31 (1H, d, J = 9.1 Hz), 7.37 (1H, dd, J = 8.6 Hz,








2.5 Hz), 7.44 (1H, d, J = 2.3 Hz),








8.64 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.03 (1H,








d, J = 2.8 Hz), 12.88 (1H, brs).
















TABLE 99













 














Reference









Example



No.
R317
R318
R319
R320
R321
R322
1H NMR (solvent) δ ppm or MS





704
—NO2
—H
—CH3
—H
—CH3
—CH3
MS 331 (M+)


705
—NO2
—H
—CF3
—H
—H
—CH3
MS 371 (M+)


706
—NO2
—H
—CF3
—H
—H
—C2H5
MS 385 (M+)


707
—NO2
—CH3
—H
—CF3
—H
—CH3
MS 385 (M+)


708
—NO2
—H
—F
—F
—H
—CH3
1H NMR (DMSO-d6)









2.98 (3H, s), 4.05 (2H, s),









6.64-6.88 (1H, m), 6.96-7.20









(1H, m), 7.38 (1H, d, J = 9.1 Hz),









8.64 (1H, dd, J = 2.7 Hz,









9.1 Hz), 9.04 (1H, d, J = 2.7 Hz),









12.24-12.95 (1H, m).


709
—NO2
—H
—OCH3
—H
—H
—SO2CH3
1H NMR (DMSO-d6)









3.16 (3H, s), 3.70 (3H, s),









4.45 (2H, s), 7.10-7.30 (4H,









m), 8.61 (1H, dd, J = 9.1 Hz,









2.8 Hz), 9.02 (1H, d, J = 2.8 Hz),









12.97 (1H, brs).


710
—Br
—H
—F
—H
—F
—CH3
1H NMR (DMSO-d6)









2.92 (3H, s), 4.01 (2H, s),









6.80-6.93 (1H, m), 7.11 (1H, d,









J = 8.8 Hz), 7.14-7.26 (1H,









m), 8.06 (1H, dd, J = 2.6 Hz,









8.8 Hz), 8.25 (1H, d, J = 2.6 Hz),









12.18-12.89 (1H, m).


711
4-CF3PhCH2—
—H
—H
—H
—H
—CH3
1H NMR (CDCl3) 3.04 (3H, s),









3.93 (2H, s), 4.04 (2H, s),









6.69 (2H, d, J = 9.1 Hz),









6.70 (1H, d, J = 8.5 Hz),









6.97 (2H, d, J = 9.1 Hz),









7.25 (2H, d, J = 8.6 Hz),









7.39 (1H, dd, J = 8.5 Hz, 2.5 Hz),









7.52 (2H, d, J = 8.6 Hz),









8.09 (1H, d, J = 2.5 Hz),









11.26 (1H, brs).


712
4-CF3PhOCH2—
—H
—H
—H
—H
—SO2CH3
1H NMR (DMSO-d6)









3.11 (3H, s), 4.40 (2H, s),









5.18 (2H, s), 7.12 (1H, d, J =









8.9 Hz), 7.15-7.23 (4H, m),









7.49 (2H, d, J = 8.9 Hz),









7.67 (2H, d, J = 8.6 Hz),









7.98 (1H, dd, J = 8.4 Hz, 2.5 Hz),









8.28 (1H, d, J = 2.0 Hz),









12.41 (1H, brs).


713
4-CF3PhOCH2—
—H
—CH3
—H
—H
—SO2CH3
1H NMR (DMSO-d6)









2.06 (3H, s), 3.18 (3H, s),









3.89 (2H, s), 5.15 (2H, s), 7.02









(1H, d, J = 8.4 Hz), 7.07 (1H,









d, J = 8.6 Hz), 7.21 (2H, d, J =









8.4 Hz), 7.44 (1H, dd, J = 8.6 Hz,









2.6 Hz), 7.49 (1H, d, J =









2.3 Hz), 7.67 (2H, d, J = 8.9 Hz),









7.95 (1H, dd, J = 8.4 Hz,









2.5 Hz), 8.24 (1H, d, J = 2.5 Hz).
















TABLE 100













 










Reference





Example



No.
R323
R324
1H NMR (solvent) δ ppm





714
—H
—H
(DMSO-d6) 3.35 (1H, brs), 3.84 (2H, s), 6.63 (2H, d, J = 8.9 Hz),





6.96 (2H, d, J = 8.9 Hz), 7.14 (1H, d, J = 9.1 Hz), 8.59 (1H, dd, J =





2.9 Hz, 9.1 Hz), 9.05 (1H, d, J = 2.9 Hz).


715
—H
—CH3
(CDCl3) 3.09 (3H, s), 4.11 (2H, s), 6.74 (2H, d, J = 9.1 Hz),





6.97 (1H, dd, J = 9.1 Hz, 0.5 Hz), 7.04 (2H, d, J = 9.1 Hz),





8.43 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.04 (1H, dd, J = 2.8 Hz, 0.5 Hz).


716
—H
—C2H5
(CDCl3) 1.24 (3H, t, J = 7.1 Hz), 3.48 (2H, q, J = 7.1 Hz),





4.07 (2H, s), 6.73 (2H, d, J = 9.2 Hz), 6.98 (1H, d, J = 9.1 Hz),





7.04 (2H, d, J = 9.2 Hz), 8.44 (1H, dd, J = 9.1 Hz, 2.8 Hz),





9.05 (1H, d, J = 2.8 Hz).


717
—OCH3
—H
(DMSO-d6) 3.62 (3H, s), 3.83 (2H, s), 6.13 (1H, dd, J = 8.6 Hz,





2.5 Hz), 6.41 (1H, d, J = 2.5 Hz), 6.90 (1H, d, J = 8.6 Hz),





7.09 (1H, d, J = 8.6 Hz), 8.54 (1H, dd, J = 9.1 Hz, 3.0 Hz),





9.00 (1H, d, J =3.0 Hz).


718
—OCH3
—CH3
(DMSO-d6) 3.00 (3H, s), 3.65 (3H, s), 4.12 (2H, s), 6.21 (1H, dd,





J = 8.8 Hz, 2.8 Hz), 6.39 (1H, d, J = 2.8 Hz), 6.96 (1H, d, J =





8.8 Hz), 7.11 (1H, d, J = 9.1 Hz), 8.54 (1H, dd, J = 9.1 Hz, 2.8 Hz),





9.00 (1H, d, J = 2.8 Hz), 12.57 (1H, s).


719
—OCH3
—C2H5
(DMSO-d6) 1.13 (3H, t, J = 7.0 Hz), 3.42 (2H, q, J = 7.0 Hz),





3.64 (3H, s), 4.05 (2H, s), 6.14 (1H, dd, J = 8.8 Hz, 2.8 Hz),





6.31 (1H, d, J = 2.8 Hz), 6.95 (1H, d, J = 8.8 Hz), 7.12 (1H, d, J =





9.1 Hz), 8.53 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.00 (1H, d, J = 2.8 Hz),





12.59 (1H, brs).


720
—CH3
—Ac
(DMSO-d6) 1.86 (3H, s), 2.08 (3H, s), 4.26 (2H, s), 7.05-7.50 (4H,





m), 8.63 (1H, dd, J = 9.1 Hz, 2.9 Hz), 9.02 (1H, dd, J = 2.9 Hz,





0.4 Hz), 12.72 (1H, brs).


721
—CH3
—H
(CDCl3) 2.09 (3H, s), 3.98 (2H, s), 5.26 (1H, brs), 6.50-6.55 (2H,





m), 6.92 (1H, d, J = 8.4 Hz), 6.98 (1H, d, J = 8.1 Hz), 8.45 (1H,





dd, J = 8.1 Hz, 2.8 Hz), 9.04 (1H, d, J = 2.8 Hz).


722
—CH3
—CH3
(DMSO-d6) 1.99 (3H, s), 2.97 (3H, s), 4.09 (2H, s), 6.52 (1H, dd,





J = 8.8 Hz, 3.0 Hz), 6.59 (1H, d, J = 3.0 Hz), 6.92 (1H, d, J =





8.8 Hz), 7.13 (1H, dd, J = 9.1 Hz, 0.3 Hz), 8.57 (1H, dd, J = 9.1 Hz,





2.9 Hz), 9.01 (1H, d, J = 2.9 Hz), 12.54 (1H, brs).


723
—CH3
—C2H5
(DMSO-d6) 1.11 (3H, t, J = 7.0 Hz), 1.98 (3H, s), 3.89 (2H, q, J =





7.0 Hz), 4.02 (2H, s), 6.44 (1H, dd, J = 8.8 Hz, 2.9 Hz), 6.51 (1H,





d, J = 2.9 Hz), 6.90 (1H, d, J = 8.8 Hz), 7.13 (1H, d, J = 9.1 Hz),





8.56 (1H, dd, J = 9.1 Hz, 2.9 Hz), 9.0 1 (1H, d, J = 2.9 Hz),





12.53 (1H, brs).


 


724
—CH3




(DMSO-d6) 0.54-0.59 (2H, m), 0.80-0.87 (2H, m), 2.02 (3H, s), 2.64-2.71 (1H, m), 4.11 (2H, s), 6.77-6.81 (1H, m), 6.85 (1H, d, J = 2.8 Hz), 6.96 (1H, d, J = 8.7 Hz), 7.17 (1H, dd, J = 9.2 Hz, 0.5 Hz), 8.59 (1H, dd, J = 9.1 Hz, 3.0 Hz), 9.04 (1H, dd, J = 3.0 Hz, 0.5 Hz), 12.56 (1H, brs).


 


725
—F
—H
(DMSO-d6) 3.82 (2H, s), 6.43 (1H, dd, J = 8.7 Hz, 2.8 Hz),





6.53 (1H, dd, J = 13.4 Hz, 2.6 Hz), 7.07 (1H, t, J = 8.9 Hz),





7.28 (1H, dd, J = 9.1 Hz, 0.5 Hz), 8.61 (1H, dd, J = 9.1 Hz, 2.8 Hz),





9.03 (1H, dd, J = 2.8 Hz, 0.5 Hz).
















TABLE 101













 










Reference





Example


mp (° C.) or 1H NMR (solvent)


No.
R325
R326
δ ppm





726
4-NO2Ph-
4-N(CH3)CH2COOH
1H NMR (CDCl3) 3.10 (3H, s),





4.13 (2H, s), 6.74 (2H, d, J = 9.2 Hz),





6.95 (2H, d, J = 9.2 Hz),





7.00 (2H, d, J = 9.2 Hz), 8.17 (2H,





d, J = 9.2 Hz).


 


727




2-(CH2)2COOH
mp 157-159


 


728




3-(CH2)2COOH
mp 192-194


 


729




4-(CH2)2COOH
1H NMR (CDCl3) 2.67 (2H, t, J = 7.7 Hz), 2.94 (2H, t, J = 7.7 Hz), 6.78 (1H, dd, J = 8.2 Hz, 1.2 Hz), 6.97 (2H, d, J = 8.6 Hz), 7.02- 7.19 (2H, m), 7.20 (2H, d, J = 8.6 Hz), 7.48 (1H, d, J = 8.3 Hz), 7.56 (1H, dd, J = 8.3 Hz, 2.1 Hz), 7.84 (1H, d, J = 2.1 Hz), 8.38 (1H, brs), 8.49 (1H, dd, J = 8.3 Hz, 2.1 Hz), 10.46 (1H, brs).


 


730




4-(CH2)2COOH
1H NMR (CDCl3) 2.67 (2H, t, J = 7.6 Hz), 2.93 (2H, t, J = 7.6 Hz), 6.78 (1H, dt, J = 8.1 Hz, 1.2 Hz), 6.95 (2H, d, J = 8.5 Hz), 7.16 (2H, d, J = 8.5 Hz), 7.22-7.34 (3H, m), 7.53 (1H, d, J = 8.3 Hz), 7.64 (1H, dd, J = 8.3 Hz, 2.1 Hz), 7.73 (1H, brs), 7.90 (1H, d, J = 2.1 Hz), 10.23 (1H, brs).


 


731




4-(CH2)2COOH
1H NMR (DMSO-d6) 1.05 (3H, t, J = 7.1 Hz), 2.56 (2H, t, J = 7.6 Hz), 2.84 (2H, t, J = 7.6 Hz), 3.64 (2H q, J = 7.1 Hz), 7.05-7.10 (3H, m), 7.28 (2H, d, J = 8.6 Hz), 7.45 (2H, brs), 7.76-7.80 (2H, m), 8.08 (1H, dd J = 2.8 Hz, 0.5 Hz), 8.27 (1H, brs), 12.10 (1H, brs).


 


732




4-(CH2)2COOH
1H NMR (DMSO-d6) 1.06 (3H, t, J = 7.1 Hz), 2.53-2.59 (2H, m), 2.81-2.87 (2H, m), 3.67 (2H, q, J = 7.1 Hz), 7.05-7.10 (3H, m), 7.29 (2H, d, J = 8.7 Hz), 7.56 (2H, d, J = 8.7 Hz), 7.66 (2H, d, J = 8.7 Hz), 7.78 (1H, dd, J = 8.6 Hz, 2.8 Hz), 8.09 (1H, d, J = 2.8 Hz), 8.41 (1H, brs), 12.14 (1H, brs).
















TABLE 102













 












Reference







Example



No.
R327
Xa24
M
Form
mp (° C.) or 1H NMR (DMSO-d6) δ ppm





733
—H
none
0
free
mp 252-255


734
—F
none
0
free
mp 257-259


735
—F
none
1
free
mp 204-206


736
—F
none
2
free
mp 173-174


737
—F
none
3
free
mp 175-177


738
—F
—S—
1
Na
1H NMR 3.86 (2H, s), 6.86 (2H, d, J = 8.7 Hz),






salt
7.15 (1H, t, J = 9.0 Hz), 7.25 (2H, d, J = 8.7 Hz),







7.55 (1H, d, J = 9.0 Hz), 7.80 (1H, d, J = 8.4 Hz),







7.91 (1H, dd, J = 2.4 Hz, 13.3 Hz), 7.98 (1H, dd,







J = 2.0 Hz, 8.4 Hz), 8.25 (1H, d, J = 2.0 Hz).


739
—F
—SO—
1
free
1H NMR 3.79 (1H, d, J = 14.3 Hz), 3.97 (1H, d,







J = 14.3 Hz), 7.12 (2H, d, J = 8.8 Hz), 7.33 (1H, t,







J = 9.1 Hz), 7.55-7.65 (1H, m), 7.71 (2H, d, J =







8.8 Hz), 7.84 (1H, d, J = 8.4 Hz), 7.90-7.95 (2H,







m), 8.20 (1H, d, J = 2.0 Hz), 10.63 (1H, s),







13.20 (1H, brs).


740
—F
—SO2—
1
free
mp 214-216


741
—F
—N(Ac)—
1
free
1H NMR 1.80 (3H, s), 4.22 (2H, s), 7.00 (1H, d, J =







8.9 Hz), 7.25-7.30 (1H, m), 7.38 (2H, d, J = 8.9 Hz),







7.50-7.60 (1H, m), 7.84 (1H, d, J = 8.4 Hz),







7.90-7.96 (2H, m), 8.21 (1H, d, J = 2.0 Hz),







10.61 (1H, s), 12.68 (1H, s).


742
—F




0
free
mp 241-243










(—SO— means a group of





and —SO2— means a group of





.


Hereinafter —SO— and —SO2— indicate the same meanings.)













TABLE 103













 












Reference







Example



No.
R328
R329
Xa25
M
mp (° C.) or 1H NMR (DMSO-d6) δ ppm





743
—Cl
—Cl
—CO—
2
1H NMR 2.60 (2H, t, J = 7.6 Hz), 2.91 (2H, t,







J = 7.6 Hz), 7.39 (2H, d, J = 8.2 Hz), 7.82-







8.20 (4H, m), 8.07 (1H, d, J = 8.6 Hz),







8.25 (1H, dd, J = 7.5 Hz, 2.1 Hz), 8.45 (1H,







dd, J = 8.6 Hz, 2.5 Hz), 9.03 (1H, d, J = 2.5 Hz),







10.91 (1H, s), 12.16 (1H, brs).


744
—Cl
—Cl
—S—
2
mp 201-202


745
—Cl
—Cl
—SO—
2
mp 202-205


746
—Cl
—Cl
—SO2—
2
mp 172-173


747
—Cl
—Cl
—NH—
2
1H NMR 2.76 (2H, t, J = 7.6 Hz), 3.20-3.40







(2H, m), 6.86 (1H, d, J = 8.8 Hz), 7.12 (2H, d,







J = 8.3 Hz), 7.52 (2H, d, J = 8.3 Hz),







7.83 (1H, d, J =8.4 Hz), 7.90-7.96 (2H, m),







8.21 (1H, d, J =1.3 Hz), 8.45 (1H, d, J = 2.4 Hz),







9.03 (1H, brs), 10.37 (1H, s), 12.11 (1H,







brs).


748
—Cl
—Cl
—N(CH3)—
2
mp 158-160


749
—CF3
—H
—N(CH3)—
0
mp 240-243


750
—CF3
—H
—N(CH3)—
2
1H NMR 2.57 (2H, t, J = 7.5 Hz), 2.84 (2H, t,







J = 7.5 Hz), 3.38 (3H, s), 6.61 (1H, d, J = 9.1 Hz),







7.22 (2H, d, J = 8.3 Hz), 7.29 (2H, d, J =







8.3 Hz), 7.80-7.85 (1H, m), 7.91 (2H, d, J =







8.3 Hz), 8.15 (2H, d, J = 8.3 Hz), 8.51 (1H, d,







J = 2.5 Hz), 10.42 (1H, s), 12.10 (1H, brs).


751
—Cl
—Cl
—N(CH2Ph)-
2
1H NMR 2.53 (2H, t, J = 7.9 Hz), 2.80 (2H, t,







J = 7.9 Hz), 5.21 (2H, s), 6.63 (1H, d, J = 9.1 Hz),







7.15-7.30 (9 H, m), 7.75-7.95 (3H, m),







8.19 (1H, d, J = 2.1 Hz), 8.45 (1H, d, J = 2.5 Hz),







10.34 (1H, s), 12.10 (1H, brs).
















TABLE 104













 












Reference







Example



No.
R330
R331
R332
M
mp (° C.) or 1H NMR (DMSO-d6) δ ppm





752
—H
—CN
—H
0
1H NMR 7.18-7.21 (3H, m), 7.98 (2H, d, J = 8.2 Hz),







8.05 (2H, d, J = 8.9 Hz), 8.13 (2H, d, J = 8.2 Hz),







8.28 (1H, dd, J = 8.6 Hz, 2.6 Hz), 8.57 (1H, d, J = 2.6 Hz),







10.70 (1H, s), 12.87 (1H, brs).


753
—Cl
—Cl
—H
0
1H NMR 7.17-7.22 (3H, m), 7.85 (1H, d, J = 8.2 Hz),







7.94-8.01 (3H, m), 8.23-8.29 (2H, m), 8.55 (1H, d, J = 2.6 Hz),







10.01 (1H, s), 12.87 (1H, brs).


754
—H
—Cl
—H
0
1H NMR 7.16-7.21 (3H, m), 7.63 (2H, d, J = 8.6 Hz),







7.97-8.02 (4H, m), 8.28 (1H, dd, J = 8.6 Hz, 2.6 Hz),







8.57 (1H, d, J = 2.6 Hz), 10.53 (1H, s), 12.86 (1H, brs).


755
—H
—CF3
—H
0
1H NMR 7.18-7.22 (3H, m), 7.93-8.00 (4H, m), 8.18 (2H,







d, J = 8.4 Hz), 8.30 (1H, dd, J = 8.9 Hz, 2.7 Hz),







8.58 (1H, d, J = 2.7 Hz), 10.69 (1H, s), 12.91 (1H, brs).


756
—CH3
—CH3
—H
0
1H NMR 2.30 (3H, s), 2.31 (3H, s), 7.16 (1H, d, J = 8.9 Hz),







7.18 (2H, d, J = 8.7 Hz), 7.31 (1H, d, J = 7.6 Hz),







7.72 (1H, d, J = 7.6 Hz), 7.77 (1H, s), 7.98 (2H, d, J = 8.7 Hz),







8.28 (1H, dd, J = 8.9 Hz, 2.7 Hz), 8.58 (1H, d, J =







2.7 Hz), 10.35 (1H, s), 12.88 (1H, brs).


757
—CF3
—H
—F
0
mp 238-239


758
—OCF3
—H
—H
0
1H NMR 7.18-7.22 (3H, m), 7.61-7.81 (2H, m), 7.89-







8.06 (4H, m), 8.28 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.57 (1H,







d, J = 2.3 Hz), 10.62 (1H, s), 12.95 (1H, brs).


759
—CF3
—H
—H
0
1H NMR 7.11-7.22 (3H, m), 7.70-7.85 (1H, m), 7.90-







8.05 (3H, m), 8.2-8.35 (3H, m), 8.56 (1H, d, J = 2.4 Hz),







10.70 (1H, s), 12.90 (1H, brs).


760
—H
—CF3
—H
1
1H NMR 3.59 (2H, s), 7.04-7.10 (3H, m), 7.27-7.33 (2H,







m), 7.94 (2H, d, J = 8.4 Hz), 8.17 (2H, d, J = 8.1 Hz),







8.21-8.25 (1H, m), 8.51 (1H, d, J = 2.6 Hz), 10.64 (1H, s),







12.43 (1H, brs).


761
—Cl
—Cl
—H
1
1H NMR 3.59 (2H, s), 7.04-7.09 (3H, m), 7.27-7.32 (2H,







m), 7.83 (1H, d, J = 8.4 Hz), 7.95 (1H, dd, J = 8.4 Hz, 2.1 Hz),







8.18-8.23 (2H, m), 8.48 (1H, d, J = 2.6 Hz),







10.55 (1H, s), 12.37 (1H, brs).


762
—Cl
—Cl
—H
2
1H NMR 2.51-2.58 (2H, m), 2.81-2.86 (2H, m), 7.01-







7.06 (3H, m), 7.26 (2H, d, J = 8.6 Hz), 7.84 (1H, d, J =







8.4 Hz), 7.93-7.97 (1H, m), 8.16-8.23 (2H, m), 8.47 (1H,







d, J = 2.7 Hz), 10.54 (1H, s), 12.13 (1H, brs).


763
—H
—CF3
—H
2
1H NMR 2.56 (2H, t, J = 7.5 Hz), 2.84 (2H, t, J = 7.5 Hz),







7.03 (2H, d, J = 8.6 Hz), 7.05 (1H, d, J = 8.8 Hz),







7.27 (2H, d, J = 8.6 Hz), 7.93 (2H, d, J = 8.2 Hz),







8.17 (2H, d, J = 8.2 Hz), 8.21 (1H, dd, J = 8.8 Hz, 2.6 Hz),







8.50 (1H, d, J = 2.6 Hz), 10.63 (1H, s), 12.16 (1H, s).
















TABLE 105













 











Reference






Example



No.
R333
R334
M
1H NMR (DMSO-d6) δ ppm





764
—OCH3
—H
0
3.76 (3H, s), 7.09 (1H, d, J = 8.9 Hz), 7.23 (1H, d, J = 8.1 Hz),






7.59-7.63 (2H, m), 7.84 (1H, d, J = 8.4 Hz), 7.93-






7.96 (1H, m), 8.16-8.22 (2H, m), 8.39 (1H, d, J = 2.7 Hz),






10.53 (1H, s), 13.00 (1H, brs).


765
—H
—OCH3
0
3.80 (3H, s), 6.69 (1H, dd, J = 8.4 Hz, 2.2 Hz), 6.90 (1H, d, J =






2.2 Hz), 7.17 (1H, d, J = 8.9 Hz), 7.73 (1H, d, J = 8.4 Hz),






7.85 (1H, d, J = 8.4 Hz), 7.97 (1H, dd, J = 8.4 Hz, 2.2 Hz),






8.23-8.28 (2H, m), 8.56 (1H, d, J = 2.4 Hz), 10.62 (1H, s),






12.56 (1H, brs).


766
—CH3
—H
0
2.18 (3H, s), 7.09-7.16 (2H, m), 7.79-7.97 (4H, m), 8.21-






8.26 (2H, m), 8.47 (1H, d, J = 2.2 Hz), 10.57 (1H, s),






12.86 (1H, brs).


767
—H
—CH3
0
2.53 (3H, s), 6.97-7.04 (2H, m), 7.16 (1H, d, J = 8.7 Hz),






7.77-7.98 (3H, m), 8.23-8.27 (2H, m), 8.54 (1H, d, J = 2.6 Hz),






10.62 (1H, s), 12.79 (1H, brs).


768
—F
—H
0
7.24 (1H, d, J = 8.9 Hz), 7.39-7.45 (1H, m), 7.70-8.05 (4H,






m), 8.23-8.28 (2H, m), 8.46 (1H, d, J = 2.6 Hz), 10.64 (1H,






s), 13.55 (1H, brs).


769
—Cl
—H
0
7.25 (1H, d, J = 8.9 Hz), 7.39 (1H, d, J = 8.6 Hz), 7.84 (1H,






d, J = 8.4 Hz), 7.93-7.97 (2H, m), 8.06 (1H, d, J = 2.0 Hz),






8.22 (1H, d, J = 2.0 Hz), 8.25-8.29 (1H, m), 8.47 (1H, d, J =






2.6 Hz), 10.61 (1H, s), 13.31 (1H, brs).


770
—OCH3
—H
2
2.50-2.65 (2H, m), 2.71-2.92 (2H, m), 3.67 (3H, s), 6.81 (1H,






dd, J = 8.1 Hz, 1.9 Hz), 6.95 (1H, d, J = 8.9 Hz), 6.99-






7.05 (2H, m), 7.82 (1H, d, J = 8.4 Hz), 7.93 (1H, dd, J = 8.4 Hz,






2.0 Hz), 8.10 (1H, dd, J = 8.9 Hz, 2.7 Hz), 8.20 (1H, d, J =






2.0 Hz), 8.35 (1H, m), 10.47 (1H, s), 12.15 (1H, brs).


771
—OC2H5
—H
2
1.06 (3H, t, J = 7.0 Hz), 2.51-2.62 (2H, m), 2.74-2.88 (2H,






m), 3.94 (2H, q, J = 7.0 Hz), 6.80 (1H, dd, J = 8.1 Hz, 1.8 Hz),






6.92-7.04 (3H, m), 7.82 (1H, d, J = 8.4 Hz), 7.93 (1H,






dd, J = 8.4 Hz, 2.0 Hz), 8.11 (1H, dd, J = 8.9 Hz, 2.7 Hz),






8.20 (1H, d, J = 2.0 Hz), 8.36 (1H, d, J = 2.7 Hz), 10.47 (1H,






s), 12.14 (1H, brs).


772
—F
—H
2
2.50-2.67 (2H, m), 2.75-2.93 (2H, m), 7.03-7.29 (4H, m),






7.82 (1H, d, J = 8.4 Hz), 7.93 (1H, dd, J = 8.4 Hz, 2.0 Hz),






8.12-8.24 (2H, m), 8.39 (1H, d, J = 2.5 Hz), 10.53 (1H, s),






12.18 (1H, brs).
















TABLE 106













 











Reference






Example



No.
R335
R336 
M
1H NMR (DMSO-d6) δ ppm





773
—OCH3
—H
0
3.76 (3H, s), 7.10 (1H, d, J = 8.9 Hz), 7.23 (1H, d, J = 8.1 Hz),






7.59-7.64 (2H, m), 7.93 (2H, d, J = 8.1 Hz), 8.15-






8.23 (3H, m), 8.42 (1H, d, J = 2.2 Hz), 10.60 (1H, s),






13.00 (1H, brs).


774
—H
—OCH3
0
3.80 (3H, s), 6.69 (1H, dd, J = 8.6 Hz, 2.2 Hz), 6.90 (1H, d,






J = 2.2 Hz), 7.17 (1H, d, J = 8.6 Hz), 7.73 (1H, d, J = 8.4 Hz),






7.95 (2H, d, J = 8.4 Hz), 8.18 (2H, d, J = 8.4 Hz),






8.29 (1H, dd, J = 8.6 Hz, 2.7 Hz), 8.58 (1H, d, J = 2.7 Hz),






10.69 (1H, s), 12.51 (1H, brs).


775
—CH3
—H
0
1.99 (3H, s), 7.09-7.17 (2H, m), 7.79-7.83 (1H, m), 7.91-






7.95 (3H, m), 8.12-8.18 (2H, m), 8.27 (1H, dd, J = 8.9 Hz,






2.7 Hz), 8.49 (1H, d, J = 2.7 Hz), 10.64 (1H, s), 12.87 (1H,






brs).


776
—H
—CH3
0
2.54 (3H, s), 6.98-7.05 (2H, m), 7.17 (1H, d, J = 8.7 Hz),






7.87-7.97 (3H, m), 8.13-8.19 (2H, m), 8.26-8.30 (1H, m),






8.57 (1H, d, J = 2.8 Hz), 10.70 (1H, s), 12.81 (1H, brs).


777
—F
—H
0
7.26 (1H, d, J = 8.9 Hz), 7.40-7.46 (1H, m), 7.82-7.85 (2H,






m), 7.94 (2H, d, J = 8.2 Hz), 8.17 (2H, d, J = 8.2 Hz),






8.30 (1H, dd, J = 8.9 Hz, 2.1 Hz), 8.49 (1H, d, J = 2.1 Hz),






10.70 (1H, s), 13.39 (1H, brs).


778
—Cl
—H
0
7.14 (1H, d, J = 8.9 Hz), 7.19 (1H, d, J = 8.2 Hz), 7.82-






7.86 (1H, m), 7.92 (2H, d, J = 8.4 Hz), 7.96 (1H, d, J = 1.8 Hz),






8.20 (2H, d, J = 8.2 Hz), 8.29 (1H, dd, J = 8.9 Hz, 2.6 Hz),






8.47 (1H, d, J = 2.6 Hz), 10.86 (1H, s).


779
—OCH3
—H
2
2.57-2.63 (2H, m), 2.83-2.89 (2H, m), 3.69 (3H, s), 6.84 (1H,






dd, J = 8.1 Hz, 1.8 Hz), 6.97 (1H, d, J = 8.9 Hz), 7.01-






7.04 (2H, m), 7.92 (2H, d, J = 8.4 Hz), 8.14-8.18 (3H, m),






8.40 (1H, d, J = 2.5 Hz), 10.58 (1H, s).


780
—OC2H5
—H
2
1.06 (3H, t, J = 7.0 Hz), 2.47-2.67 (2H, m), 2.72-2.91 (2H,






m), 3.94 (2H, q, J = 7.0 Hz), 6.80 (1H, dd, J = 8.0 Hz, 1.8 Hz),






6.94-7.05 (3H, m), 7.91 (2H, d, J = 8.3 Hz), 8.09-






8.19 (3H, m), 8.38 (1H, d, J = 2.6 Hz), 10.55 (1H, s),






12.14 (1H, brs)


781
—F
—H
2
2.49-2.63 (2H, m), 2.71-2.93 (2H, m), 7.09 (1H, dd, J = 8.3 Hz,






1.5 Hz), 7.14 (1H, d, J = 8.9 Hz), 7.17-7.28 (2H, m),






7.92 (2H, d, J = 8.2 Hz), 8.15 (2H, d, J = 8.2 Hz), 8.21 (1H,






dd, J = 8.9 Hz, 2.7 Hz), 8.38-8.44 (1H, m), 10.60 (1H, s),






12.17 (1H, brs).
















TABLE 107













 











Reference






Example



No.
R337
R338
R339
1H NMR (DMSO-d6) δ ppm





782
—Cl
—Cl




7.20 (1H, d, J = 8.7 Hz), 7.40 (1H, dd, J = 8.7 Hz, 2.3 Hz), 7.60-7.67 (1H, m), 7.82- 8.03 (4H, m), 8.15 (1H, d, J = 8.9 Hz), 8.26- 8.32 (2H, m), 8.56-8.60 (2H, m), 10.78 (1H, s).


 


783
—CF3
—H




7.18 (1H, d, J = 8.7 Hz), 7.36 (1H, dd, J = 8.7 Hz, 2.3 Hz), 7.63 (1H, d, J = 2.0 Hz), 7.84-8.11 (5 H, m), 8.23 (2H, d, J = 8.1 Hz), 8.34 (1H, dd, J = 8.9 Hz, 2.5 Hz), 8.54- 8.60 (2H, m), 10.98 (1H, s).


 


784
—Cl
—Cl




7.19 (1H, d, J = 8.7 Hz), 7.47 (1H, dd, J = 9.4 Hz, 2.5 Hz), 7.57-7.63 (1H, m), 7.73 (1H, d, J = 2.5 Hz), 7.85 (1H, d, J = 8.4 Hz), 7.96 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.10-8.14 (2H, m), 8.23-8.28 (2H, m), 8.52 (1H, d, J = 2.5 Hz), 8.92 (1H, d, J = 9.4 Hz), 10.60 (1H, s), 13.20 (1H, brs).


 


785
—CF3
—H




7.20 (1H, d, J = 8.7 Hz), 7.48 (1H, dd, J = 9.4 Hz, 2.6 Hz), 7.57-7.63 (1H, m), 7.73 (1H, d, J = 2.5 Hz), 7.94 (2H, d, J = 8.2 Hz), 8.11-8.19 (4H, m), 8.29 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.55 (1H, d, J = 2.5 Hz), 8.93 (1H, d, J = 9.4 Hz), 10.68 (1H, s), 13.21 (1H, brs).


 


786
—Cl
—Cl




7.24 (1H, d, J = 8.1 Hz), 7.32 (1H, d, J = 8.7 Hz), 7.58-7.64 (1H, m), 7.69-7.77 (1H, m), 7.85 (1H, d, J = 8.4 Hz), 7.97 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.06-8.12 (1H, m), 8.20- 8.23 (2H, m), 8.30 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.48 (1H, d, J = 2.6 Hz), 9.02 (1H, d, J = 8.7 Hz), 10.63 (1H, s), 13.11 (1H, brs).


 


787
—Cl
—Cl




7.17 (1H, d, J = 8.9 Hz), 7.38-7.43 (1H, m), 7.53-7.59 (2H, m), 7.76-7.86 (2H, m), 7.93- 7.97 (1H, m), 8.22-8.27 (2H, m), 8.51 (1H, d, J = 2.0 Hz), 10.60 (1H, s), 13.15 (1H, brs).
















TABLE 108













 










Reference





Example



No.
R340
R341
1H NMR (solvent) δ ppm





788
—H
—Ac
(DMSO-d6) 1.85 (3H, s), 4.26 (2H, s), 7.13 (1H, d, J = 8.8 Hz),





7.19 (2H, d, J = 8.7 Hz), 7.42 (2H, d, J = 8.7 Hz), 7.85 (1H, d, J =





8.4 Hz), 7.95 (1H, dd, J = 1.9 Hz, 8.4 Hz), 8.20-8.24 (2H, m),





8.51 (1H, d, J = 2.5 Hz), 12.77 (1H, brs).


789
—H
—CH3
(DMSO-d6) 2.98 (3H, s), 4.01 (2H, s), 6.65 (1H, d, J = 9.1 Hz),





6.90-6.95 (3H, m), 7.82 (1H, d, J = 8.4 Hz), 7.94 (1H, dd, J = 2.1 Hz,





8.4 Hz), 8.13 (1H, dd, J = 2.7 Hz, 8.9 Hz), 8.22 (1H, d, J = 2.1 Hz),





8.43 (1H, d, J = 2.7 Hz), 10.54 (1H, s).


790
—H
—C2H5
(DMSO-d6) 1.11 (3H, t, d = 7.1 Hz), 3.39 (2H, q, J = 7.1 Hz),





4.01 (2H, s), 6.58 (2H, d, J = 9.1 Hz), 6.90-6.95 (3H, m), 7.81 (1H,





d, J = 8.4 Hz), 7.92 (1H, dd, J = 2.0 Hz, 8.4 Hz), 8.11 (1H, dd, J =





2.7 Hz, 8.9 Hz), 8.19 (1H, d, J = 2.0 Hz), 8.41 (1H, d, J = 2.7 Hz),





10.48 (1H, s), 12.53 (1H, brs).


791
—OCH3
—CH3
(DMSO-d6) 3.01 (3H, s), 3.67 (3H, s), 4.12 (2H, s), 6.20 (1H, dd, J =





8.7 Hz, 2.8 Hz), 6.39 (1H, d, J = 2.8 Hz), 6.85-6.94 (2H, m),





7.83 (1H, d, J = 8.4 Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.1 Hz),





8.08 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.21 (1H, d, J = 2.0 Hz),





8.36 (1H, d, J = 2.5 Hz), 10.47 (1H, s), 12.58 (1H, brs).


792
—OCH3
—C2H5
(DMSO-d6) 1.15 (3H, t, J = 7.1 Hz), 3.43 (2H, q, J = 7.1 Hz),





3.65 (3H, s), 4.06 (2H, s), 6.13 (1H, dd, J = 8.7 Hz, 2.6 Hz),





6.30 (1H, d, J = 2.6 Hz), 6.87-6.91 (2H, m), 7.83 (1H, d, J = 8.4 Hz),





7.94 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.08 (1H, dd, J = 8.9 Hz,





2.6 Hz), 8.21 (1H, d, J = 2.0 Hz), 8.36 (1H, d, J = 2.6 Hz),





10.48 (1H, s), 12.58 (1H, brs).


793
—CH3
—Ac
(DMSO-d6) 1.84 (3H, s), 2.11 (3H, s), 4.23 (2H, s), 7.05-7.10 (2H,





m), 7.20-7.25 (1H, m), 7.32 (1H, d, J = 2.2 Hz), 7.75-7.85 (1H, m),





7.92 (1H, dd, J = 2.2 Hz, 8.4 Hz), 8.10-8.20 (2H, m), 8.43 (1H, d, J =





2.6 Hz), 10.53 (1H, s), 12.66 (1H, brs).


794
—CH3
—CH3
(DMSO-d6) 2.01 (3H, s), 2.97 (3H, s), 4.07 (2H, s), 6.49 (1H, dd, J =





8.8 Hz, 3.0 Hz), 6.57 (1H, d, J = 3.0 Hz), 6.85 (1H, d, J = 8.8 Hz),





6.90 (1H, d, J = 8.9 Hz), 7.82 (1H, d, J = 8.4 Hz), 7.93 (1H,





dd, J = 8.4 Hz, 2.0 Hz), 8.11 (1H, dd, J = 8.9 Hz, 2.7 Hz),





8.20 (1H, d, J = 2.0 Hz), 8.39 (1H, d, J = 2.7 Hz), 10.47 (1H, s),





12.51 (1H, brs).


795
—F
—Ac
(CDCl3 + DMSO-d6) 1.99 (3H, s), 4.35 (2H, s), 7.03 (1H, d, J = 8.9 Hz),





7.21-7.31 (3H, m), 7.57 (1H, d, J = 8.4 Hz), 7.90 (1H, dd, J =





8.4 Hz, 2.1 Hz), 8.19 (1H, d, J = 2.0 Hz), 8.32 (1H, dd, J = 8.9 Hz,





2.6 Hz), 8.46 (1H, d, J = 2.5 Hz), 10.12 (1H, s).


796
—F
—CH3
(CDCl3 + DMSO-d6) 3.04 (3H, s), 3.98 (2H, s), 6.40-6.49 (2H, m),





6.90 (1H, d, J = 8.9 Hz), 7.02 (1H, t, J = 8.7 Hz), 7.52 (1H, d, J =





8.4 Hz), 7.85 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.14 (1H, d, J = 2.0 Hz),





8.23 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.34 (1H, d, J = 2.5 Hz),





9.77 (1H, s).


797
—F
—C2H5
(CDCl3) 1.26 (3H, t, J = 7.1 Hz), 3.44 (2H, q, J = 7.1 Hz),





4.03 (2H, s), 6.39-6.52 (2H, m), 6.96 (1H, d, J = 9.7 Hz), 7.06 (1H,





t, J = 8.9 Hz), 7.55 (1H, d, J = 8.4 Hz), 7.69 (1H, dd, J = 8.6 Hz,





2.1 Hz), 7.96-7.97 (2H, m), 8.15-8.18 (2H, m).
















TABLE 109













 










Reference





Example



No.
R342
R343
1H NMR (solvent) δ ppm





798
—H
—Ac
(DMSO-d6) 1.85 (3H, s), 4.26 (2H, s), 7.13 (1H, d, J = 8.8 Hz),





7.18 (2H, d, J = 8.7 Hz), 7.42 (2H, d, J = 8.7 Hz), 7.94 (2H, d,





J = 8.2 Hz), 8.16 (2H, d, J = 8.2 Hz), 8.25 (1H, dd, J = 2.5 Hz,





8.8 Hz), 8.54 (1H, d, J = 2.5 Hz), 10.66 (1H, s),





12.70 (1H, brs).


799
—H
—CH3
(DMSO-d6) 2.99 (3H, s), 4.09 (2H, s), 6.67 (2H, d, J = 9.0 Hz),





6.96 (3H, d, J = 9.0 Hz), 7.93 (2H, d, J = 8.2 Hz), 8.16 (2H, d,





J = 8.2 Hz), 8.12-8.20 (1H, m), 8.46 (1H, d, J = 2.3 Hz),





10.59 (1H, s), 12.58 (1H, brs).


800
—H
—C2H5
(DMSO-d6) 1.13 (3H, t, J = 7.1 Hz) 3.38 (2H, q, J = 7.1 Hz),





4.00 (2H, s), 6.65 (1H, d, J = 8.9 Hz), 6.73 (1H, d, J = 8.9 Hz),





6.92-6.97 (3H, m), 7.93 (2H, d, J = 8.1 Hz), 8.15-8.18 (3H,





m), 8.46 (1H, s), 10.59 (1H, s).


801
—OCH3
—CH3
(DMSO-d6) 3.01 (3H, s), 3.67 (3H, s), 4.12 (2H, s), 6.20 (1H,





dd, J = 8.7 Hz, 2.6 Hz), 6.39 (1H, d, J = 2.5 Hz), 6.83-





6.95 (2H, m), 7.93 (2H, d, J = 8.3 Hz), 8.09-8.17 (3H, m),





8.38 (1H, d, J = 2.6 Hz), 10.56 (1H, s), 12.58 (1H, brs).


802
—OCH2
—C2H5
(DMSO-d6) 1.15 (3H, t, J = 7.1 Hz), 3.43 (2H, q, J = 7.1 Hz),





3.66 (3H, s), 4.06 (2H, s), 6.14 (1H, dd, J = 8.7 Hz, 2.6 Hz),





6.31 (1H, d, J = 2.8 Hz), 6.88-6.92 (2H, m), 7.93 (2H, d, J =





8.4 Hz), 8.09-8.17 (3H, m), 8.39 (1H, d, J = 2.5 Hz),





10.55 (1H, s), 12.59 (1H, brs).


803
—CH3
—Ac
(DMSO-d6) 1.84 (3H, s), 2.11 (3H, s), 4.23 (2H, s), 7.05-





7.10 (2H, m), 7.23 (1H, dd, J = 2.4 Hz, 8.5 Hz), 7.33 (1H, d, J =





2.4 Hz), 7.86 (1H, d, J = 8.3 Hz), 7.91 (2H, d, J = 8.3 Hz),





8.14 (2H, d, J = 8.3 Hz), 8.20 (1H, dd, J = 2.7 Hz, 8.9 Hz),





8.45 (1H, d, J = 2.7 Hz), 10.61 (1H, s), 12.67 (1H, brs).


804
—CH3
—CH3
(DMSO-d6) 2.01 (3H, s), 2.97 (3H, s), 4.06 (2H, s), 6.49 (1H,





dd, J = 8.8 Hz, 3.1 Hz), 6.57 (1H, d, J = 2.9 Hz), 6.85 (1H, d,





J = 8.8 Hz), 6.91 (1H, d, J = 8.9 Hz), 7.91 (2H, d, J = 8.3 Hz),





8.04-8.23 (3H, m), 8.41 (1H, d, J = 2.6 Hz), 10.56 (1H, s),





12.11-12.98 (1H, m).


805
—F
—Ac
(CDCl3) 1.96 (3H, s), 4.32 (2H, s), 7.09-7.31 (4H, m), 7.75 (2H,





d, J = 8.4 Hz), 8.02 (2H, d, J = 8.3 Hz), 8.20 (1H, d, J = 2.6 Hz),





8.40 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.44 (1H, s).


806
—F
—CH3
(CDCl3 + DMSO-d6) 3.08 (3H, s), 4.02 (2H, s), 6.47-6.52 (2H,





m), 6.92 (1H, d, J = 8.7 Hz), 7.06 (1H, t, J = 9.0 Hz),





7.73 (2H, d, J = 8.4 Hz), 8.11 (2H, d, J = 8.4 Hz), 8.26 (1H,





dd, J = 8.7 Hz, 2.5 Hz), 8.39 (1H, d, J = 2.5 Hz), 9.76 (1H,





s).


807
—F
—C2H5
(CDCl3 + DMSO-d6) 1.23 (3H, t, J = 7.1 Hz), 3.45 (2H, q, J =





7.1 Hz), 3.97 (2H, s), 6.39-6.48 (2H, m), 6.91 (1H, d, J = 8.7 Hz),





7.04 (1H, t, J = 9.1 Hz), 7.73 (2H, d, J = 7.9 Hz),





8.12 (2H, d, J = 7.9 Hz), 8.25 (1H, d, J = 9.1 Hz), 8.42 (1H, d,





J = 2.5 Hz), 9.92 (1H, s).


808
—F
—(CH2)2CH3
(CDCl3 + DMSO-d6) 0.96 (3H, t, J = 7.2 Hz), 1.61-1.72 (2H,





m), 3.33 (2H, t, J = 7.6 Hz), 3.99 (2H, s), 6.37-6.48 (2H, m),





6.93 (1H, d, J = 8.8 Hz), 7.04 (1H, t, J = 9.1 Hz), 7.73 (2H, d,





J = 8.1 Hz), 8.09 (2H, d, J = 8.1 Hz), 8.26 (1H, dd, J = 8.9 Hz),





2.6 Hz), 8.36 (1H, d, J = 2.5 Hz), 9.45 (1H, s).
















TABLE 110













 











Reference






Example



No.
R344
R345
R346
1H NMR (solvent) δ ppm





809
—Cl
—Cl
—N(Ac)(CH2)2COOH
(DMSO-d6) 1.71 (3H, s), 2.39 (2H, t, J =






7.5 Hz), 3.78 (2H, t, J = 7.5 Hz), 7.08 (1H,






d, J = 8.8 Hz), 7.14 (2H, d, J = 8.6 Hz),






7.31 (2H, d, J = 8.6 Hz), 7.80 (1H, d, J =






8.4 Hz), 7.91 (1H, dd, J = 2.1 Hz, 8.4 Hz),






8.15-8.21 (2H, m), 8.49 (1H, d, J = 2.5 Hz),






10.55 (1H, s), 12.20 (1H, brs)


810
—CF3
—H
—N(Ac)(CH2)2COOH
(DMSO-d6) 1.71 (3H, s), 2.40 (2H, t, J =






7.3 Hz), 3.78 (2H, t, J = 7.3 Hz), 7.09 (1H,






d, J = 8.7 Hz), 7.14 (2H, d, S = 8.1 Hz),






7.31 (2H, d, J = 8.1 Hz), 7.90 (2H, d, J =






8.1 Hz), 8.12 (2H, d, J = 8.1 Hz), 8.21 (1H,






d, J = 8.7 Hz), 8.52 (1H, s), 10.63 (1H, s),






12.25 (1H, brs).


811
—Cl
—Cl
—CH(CH3)CH2COOH
(CDCl3− CD3OD) 1.26 (3H, d, J = 7.0 Hz),






2.42-2.61 (2H, m), 3.17-3.28 (1H, m),






6.84 (1H, d, J = 8.9 Hz), 6.98 (2H, d, J =






8.5 Hz), 7.20 (2H, d, J = 8.5 Hz), 7.50 (1H,






d, J = 8.4 Hz), 7.73 (1H, dd, J = 8.5 Hz,






2.1 Hz), 8.01 (1H, d, J = 2.1 Hz), 8.14 (1H,






d, J = 2.7 Hz), 8.26 (1H, dd, J = 8.9 Hz,






2.7 Hz).


812
—CF3
—H
—CH(CH3)CH2COOH
(CDCl3− CD3OD) 1.28 (3H, d, J = 7.0 Hz),






2.44-2.61 (2H, m), 3.18-3.29 (1H, m),






6.88 (1H, d, J = 8.9 Hz), 7.00 (2H, d, J =






8.5 Hz), 7.20 (2H, d, J = 8.5 Hz), 7.70 (2H,






d, J = 8.2 Hz), 7.99 (2H, d, J = 8.2 Hz),






8.17 (1H, d, J = 2.6 Hz), 8.28 (1H, dd, J =






8.9 Hz, 2.6 Hz).


813
—CF3
—H
—CH═CHCOOH
(DMSO-d6) 6.49 (1H, d, J = 16.0 Hz),





trans
7.15 (3H, d, J = 8.8 Hz), 7.61 (1H, d, J =






16.0 Hz), 7.74 (2H, d, J = 8.8 Hz),






7.94 (2H, d, J = 8.3 Hz), 8.17 (2H, d, J =






8.3 Hz), 8.26 (1H, dd, J = 8.8 Hz, 2.7 Hz),






8.55 (1H, d, J = 2.7 Hz), 10.67 (1H, s),






12.36 (1H, s).


 


814
—CF3
—H




(CDCl3) 1.34 (6 H, s), 2.79 (3H, s), 6.98 (1H, d, J = 8.9 Hz), 7.10 (2H, d, J = 8.9 Hz), 7.21 (2H, d, J = 9.1 Hz), 7.76 (2H, d, J = 8.2 Hz), 8.01 (2H, d, J = 8.1 Hz), 8.10 (1H, brs), 8.24 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.31 (1H, d, J = 2.3 Hz).
















TABLE 111













 













Reference








Example



No.
R347
R348
R349
R350
M
1H NMR (solvent) δ ppm





815
—Cl
—Cl
—H
—F
0
(DMSO-d6) 4.29 (2H, d, J = 5.6 Hz), 6.46 (1H, t, J =








5.9 Hz), 6.94 (1H, d, J = 8.7 Hz), 7.15 (1H, dd, J =








8.7 Hz, 3.0 Hz), 7.20 (1H, d, J = 8.3 Hz),








7.36 (1H, dd, J = 8.3 Hz, 1.8 Hz), 7.47 (1H, d, J =








2.8 Hz), 7.59 (1H, d, J = 8.3 Hz), 7.63 (1H, d, J =








2.0 Hz), 7.72-7.77 (2H, m).


816
—CF3
—H
—H
—F
0
(DMSO-d6) 4.37 (2H, d, J = 5.3 Hz), 6.47 (1H,








brs), 6.89 (1H, d, J = 8.7 Hz), 7.06-7.12 (1H, m),








7.13 (1H, dd, J = 8.7 Hz, 3.0 Hz), 7.45 (1H, d, J =








3.0 Hz), 7.58 (2H, d, J = 8.1 Hz), 7.65-7.69 (2H,








m), 7.70 (2H, d, J = 8.1 Hz).


817
—CF3
—H
—CH3
—H
0
(DMSO-d6) 3.03 (3H, s), 4.66 (2H, s), 6.82 (2H, d,








J = 8.7 Hz), 6.87 (1H, d, J = 8.9 Hz), 7.29 (1H, dd,








J = 8.9 Hz, 3.3 Hz), 7.45 (2H, d, J = 8.1 Hz),








7.68-7.72 (3H, m), 7.82 (2H, d, J = 8.7 Hz).


818
—CF3
—H
—C2H5
—H
0
(DMSO-d6) 1.13 (3H, t, J = 7.1 Hz), 3.49 (2H, q, J =








7.1 Hz), 4.61 (2H, s), 6.81 (2H, d, J = 8.6 Hz),








6.84 (1H, d, J = 8.9 Hz), 7.22 (1H, dd, J = 8.9 Hz,








3.3 Hz), 7.47 (2H, d, J = 8.1 Hz), 7.62 (1H, d, J =








3.3 Hz), 7.70 (2H, d, J = 8.3 Hz), 7.80 (2H, d, J =








8.7 Hz).


819
—Cl
—Cl
—CH3
—OCH3 
2
(CDCl3) 2.66 (2H, t, J = 7.7 Hz), 2.93 (2H, t, J =








7.7 Hz), 2.95 (3H, s), 3.75 (3H, s), 4.35 (2H, s),








6.68-6.88 (3H, m), 6.90-7.00 (1H, m), 7.00-








7.17 (2H, m), 7.31 (1H, d, J = 2.0 Hz), 7.37 (1H, d,








J = 8.2 Hz), 7.65 (1H, d, J = 3.0 Hz), 8.21 (1H,








brs).


820
—CF3
—H
—CH3
—OCH3
2
(DMSO-d6) 2.41-2.62 (2H, m), 2.69-2.85 (2H, m),








2.96 (3H, s), 3.64 (3H, s), 4.58 (2H, s), 6.70-








6.79 (2H, m), 6.88 (1H, d, J = 8.0 Hz), 6.95 (1H, d,








J = 1.8 Hz), 7.25 (1H, dd, J = 9.2 Hz, 3.2 Hz),








7.42 (2H, d, J = 8.0 Hz), 7.52 (1H, d, J = 3.2 Hz),








7.67 (2H, d, J = 8.0 Hz), 11.64-12.51 (1H, m).


821
—Cl
—Cl
—CH3
—OC2H5
2
(DMSO-d6) 1.03 (3H, t, J = 7.0 Hz), 2.53 (2H, t, J =








7.6 Hz), 2.78 (2H, t J = 7.6 Hz), 3.89 (2H, q, J =








7.0 Hz), 4.49 (2H, s), 6.70-6.80 (2H, m),








6.88 (1H, d, J = 8.0 Hz), 6.92 (1H, d, J = 1.9 Hz),








7.19 (1H, dd, J = 8.3 Hz, 2.0 Hz), 7.26 (1H, dd, J =








9.0 Hz, 3.2 Hz), 7.45 (1H, dd, J = 2.0 Hz),








7.52 (1H, d, J = 3.2 Hz), 7.56 (1H, d, J = 8.3 Hz),








11.81-12.30 (1H, m).


822
—Cl
—Cl
—CH3
—F
2
(DMSO-d6) 2.55 (2H, t, J = 7.6 Hz), 2.80 (2H, t, J =








7.6 Hz), 2.96 (3H, s), 4.50 (2H, s), 6.92 (1H, d, J =








8.9 Hz), 7.00-7.22 (4H, m), 7.22-7.38 (1H, m),








7.38-7.40 (1H, m), 7.40-7.55 (2H, m), 12.10 (1H,








brs).


823
—Cl
—Cl
—C2H5
—F
2
(CDCl3) 1.17 (3H, t, J = 7.0 Hz), 2.66 (2H, t, J =








7.7 Hz), 2.93 (2H, t, J = 7.7 Hz), 3.40 (2H, q, J =








7.0 Hz), 4.36 (2H, s), 6.72-6.86 (1H, m), 6.90-








7.15 (5 H, m), 727-7.35 (1H, m), 7.36 (1H, d, J =








8.2 Hz), 7.59 (1H, d, J = 3.2 Hz).
















TABLE 112













 












Reference







Example



No.
R351
R352
R353
R354
1H NMR (solvent) δ ppm















824
—CF3
—H
—CH3
—H
(DMSO-d6) 2.50-2.54 (2H, m), 2.79 (2H, t, J = 7.6 Hz),







3.02 (3H, s), 4.64 (2H, s), 6.86 (1H, d, J = 8.9 Hz),







6.89 (2H, d, J = 8.4 Hz), 7.19 (2H, d, J = 8.7 Hz),







7.29 (1H, dd, J = 8.9 Hz, 3.3 Hz), 7.44 (2H, d, J = 7.9 Hz),







7.69 (2H, d, J = 7.9 Hz), 7.64 (1H, d, J = 3.1 Hz).


825
—CF3
—H
—CH3
—OC2H5
(DMSO-d6) 1.03 (3H, t, J = 7.0 Hz), 2.47-2.59 (2H, m),







2.71-2.83 (2H, m), 2.97 (3H, s), 3.89 (2H, q, J = 7.0 Hz),







4.59 (2H, s), 6.69-6.79 (2H, m), 6.88 (1H, d, J =







8.0 Hz), 6.91 (1H, d, J = 1.9 Hz), 7.26 (1H, dd, J = 9.0 Hz,







3.1 Hz), 7.41 (2H, d, J = 8.0 Hz), 7.52 (1H, d, J =







3.1 Hz), 7.66 (2H, d, J = 8.0 Hz), 11.85-12.31 (1H, m),


826
—CF3
—H
—CH3
—F
(CDCl3) 2.67 (2H, t, J = 7.7 Hz), 2.94 (2H, t, J = 7.7 Hz),







3.00 (3H, s), 4.49 (2H, s), 6.86 (1H, d, J = 8.9 Hz),







6.90-7.16 (4H, m), 7.33 (2H, d, J = 8.1 Hz), 7.57 (2H,







d, J = 8.1 Hz), 7.64 (1H, d, J = 3.1 Hz).


827
—CF3
—H
—C2H5
—H
(DMSO-d6) 1.11 (3H, t, J = 7.0 Hz), 2.42-2.57 (2H, m),







2.71-2.82 (2H, m), 3.47 (2H, q, J = 7.0 Hz), 4.58 (2H,







s), 6.82 (1H, d, J = 8.9 Hz), 6.84-6.91 (2H, m), 7.13-







7.21 (2H, m), 7.20 (1H, dd, J = 8.9 Hz, 3.1 Hz),







7.45 (2H, d, J = 8.1 Hz), 7.57 (1H, d, J = 3.1 Hz),







7.68 (2H, d, J = 8.1 Hz), 12.06 (1H, brs).


828
—Cl
—Cl
—C2H5
—OCH3
(CDCl3) 1.16 (3H, t, J = 7.1 Hz), 2.55-2.78 (2H, m),







2.94 (2H, t, J = 7.7 Hz), 3.39 (2H, q, J = 7.1 Hz),







3.77 (3H, s), 4.35 (2H, s), 6.70-6.88 (3H, m), 6.92-







7.13 (3H, m), 7.32 (1H, d, J = 2.0 Hz), 7.36 (1H, d, J =







8.2 Hz), 7.59 (1H, d, J = 3.1 Hz).


829
—CF3
—H
—C2H5
—OCH3
(DMSO-d6) 1.09 (3H, t, J = 7.0 Hz), 2.48-2.61 (2H, m),







2.72-2.86 (2H, m), 3.40 (2H, q, J = 7.0 Hz), 3.64 (3H,







s), 4.54 (2H, s), 6.73 (1H, d, J = 9.0 Hz), 6.74 (1H, dd,







J = 8.0 Hz, 1.9 Hz), 6.87 (1H, d, J = 8.0 Hz), 6.95 (1H,







d, J = 1.9 Hz), 7.18 (2H, dd, J = 9.0 Hz, 3.2 Hz), 7.39-







7.49 (3H, m), 7.62-7.71 (2H, m), 11.90-12.31 (1H, m).


830
—Cl
—Cl
—C2H5
—OC2H 5
(DMSO-d6) 0.95-1.11 (6 H, m), 2.41-2.57 (2H, m),







2.77 (2H, t, J = 7.7 Hz), 3.29-3.47 (2H, m), 3.88 (2H, q,







J = 7.0 Hz), 4.44 (2H, s), 6.73 (1H, dd, J = 8.0 Hz, 1.9 Hz),







6.74 (1H, d, J = 9.0 Hz), 6.88 (1H, d, J = 8.0 Hz),







6.91 (1H, d, J = 1.9 Hz), 7.15-7.24 (2H, m), 7.41-7.48







(2H, m), 7.55 (1H, d, J = 8.2 Hz), 11.60-12.50 (1H, m).


831
—CF3
—H
—C2H5
—OC2H5
(DMSO-d6) 1.02 (3H, t, J = 7.0 Hz), 1.08 (3H, t, J =







7.0 Hz), 2.46-2.59 (2H, m), 2.71-2.83 (2H, m),







3.43 (2H, q, J = 7.0 Hz), 3.89 (2H, q, J = 7.0 Hz),







6.69-6.78 (2H, m), 6.87 (1H, d, J = 8.0 Hz), 6.91 (1H,







d, J = 1.8 Hz), 7.19 (1H, dd, J = 9.0 Hz, 3.2 Hz), 7.39-







7.49 (3H, m), 7.61-7.69 (2H, m), 11.92-12.22 (1H, m).


832
—CF3
—H
—C2H5
—F
(CDCl3) 1.19 (3H, t, J = 7.1 Hz), 2.67 (2H, t, J = 7.7 Hz),







2.93 (2H, t, J = 7.7 Hz), 3.43 (2H, q, J = 7.1 Hz),







4.48 (2H, s), 6.83 (1H, d, J = 9.0 Hz), 6.90-7.20 (4H,







m), 7.34 (2H, d, J = 8.2 Hz), 7.50-7.65 (3H, m)
















TABLE 113













 














Reference









Example


No.
R355
R356
R357
R358
R359
Form
1NMR (solvent) δ ppm





833
—CF3
—H
—CH3
—H
—COOH
free
(DMSO-d6) 1.45 (3H, d, J = 6.8 Hz),









4.61 (1H, dt, J = 6.8 Hz, 6,8 Hz),









6.85 (1H, d, J = 8.6 Hz), 6.97 (2H, d,









J = 8,7 Hz), 7.04 (1H, dd, J = 8.7









Hz, 3.0 Hz), 7.51 (1H, d, J = 3.0









Hz), 7.62 (2H, d, J = 8.3 Hz), 7.70









(2H, d, J = 8.3 Hz), 7.89 (2H, d,









J = 8.9 Hz), 12.79 (1H, brs).


834
—CF3
—H
—CH3
—CH3
—COOH
free
(DMSO-d6) 1.54 (3H, d, J = 6.8 Hz),









2.73 (3H, s), 5.23 (1H, q, J = 6.8









Hz), 7.00 (1H, d, J = 8.9 Hz), 7.05









(2H, d, J = 8.7 Hz), 7.46 (1H, dd,









J = 9.1 Hz, 3.3 Hz), 7.54 (2H, d,









J = 8.1 Hz), 7.72 (2H, d, J = 8.4 Hz),









7.84 (1H, d, J = 3.3 Hz), 7.93 (2H, d,









J = 8.6 Hz)


 


835
—CF3
—H
—H
—CH3




dihydro- chloride
 (DMSO-d6) 1.81 (3H, s), 3.05 (3H, s), 4.22 (2H, s), 4.67 (2H, s), 6.95 (1H, d, J = 8.7 Hz), 7.04 (2H, d, J = 8.6 Hz), 7.28-7.40 (1H, m), 7.35 (2H, d, J = 8.6 Hz), 7.45 (2H, d, J = 8.1 Hz), 7.62-7.80 (1H, m), 7.70 (2H, d, J = 8.1 Hz).


 


836
—Cl
—Cl
—H
—CH3




dihydro- chloride
 (CDCl3) 1.81 (3H, s), 3.02 (3H, s), 4.23 (2H, s), 4.57 (2H, s), 6.95 (1H, d, J = 8.8 Hz), 7.04 (2H, d, J = 8.7 Hz), 7.22 (1H, dd, J = 8.2 Hz, 2.0 Hz), 7.32-7.40 (1H, m), 7.35 (2H, d, J = 8.7 Hz), 7.51 (1H, d, J = 2.0 Hz), 7.59 (1H, d, J = 8.2 Hz), 7.71 (1H, d, J = 3.0 Hz).


 


837
—CF3
—H
—H
—(CH2)2OCH3
—(CH2)2COOH
free
(DMSO-d6) 2.43-2.57 (2H, m),









2.71-2.82 (2H, m), 3.25 (3H, s),









3.48-3.58 (2H, m), 3.59-3.68 (2H,









m), 4.66 (2H, s), 6.80 (1H, d, J = 8.9









Hz), 6.83-6.90 (2H, m), 7.11-7.25









(3H, m), 7.44 (2H, d, J = 8.0 Hz),









7.56 (1H, d, J = 3.1 Hz), 7.67 (2H, d,









J = 8.0 Hz), 12.09 (1H, brs).
















TABLE 114













 













Reference








Example


No.
R360
R361
R362
Xa26
Xa27
1H NMR (solvent) δ ppm or MS





838
—Cl
—Cl
—OCH3
—CH═CH—
—CH2—
1H NMR (DMSO-d6) 2.57-2.63 (2H,






(trans)

m), 2.83-2.88 (2H, m), 3.68 (3H, s),








6.84 (1H, dd, J = 8.1 Hz, 1.7 Hz),








6.98-7.05 (3H, m), 7.20 (1H, d,








J = 16.5 Hz), 7.36 (1H, d, J = 16.5








Hz), 7.54-7.65 (2H, m), 7.87 (1H, d,








J = 1.8 Hz), 8.07-8.11 (1H, m), 8.22








(1H, d, J = 2.1 Hz), 12.20 (1H, brs).


839
—CF3
—H
—OCH3
—CH═CH—
—CH2—
1H NMR (DMSO-d6) 2.58-2.63 (2H,






(trans)

m), 2.83-2.89 (2H, m), 3.68 (3H, s),








6.82-6.86 (1H, m), 6.99-7.06 (3H,








m), 7.31 (1H, d, J = 16.5 Hz), 7.41








(1H, d, J = 16.5 Hz), 7.71-7.81 (4H,








m), 8.15 (1H, dd, J = 8.7 Hz, 2.5








Hz), 8.27 (1H, d, J = 2.1 Hz), 12.18








(1H, brs).


840
—CF3
—H
—OCH3
—CO—
—CH2—
1H NMR (DMSO-d6) 2.57-2.63 (2H,








m), 2.83-2.89 (2H, m), 3.70 (3H, s),








6.86 (1H, dd, J = 8.1 Hz, 2.0 Hz),








7.06-7.15 (3H, m), 7.90-7.97 (4H,








m), 8.18-8.22 (1H, m), 8.50 (1H, dd,








J = 2.5 Hz, 0.7 Hz), 12.19 (1H, brs).


841
—CF3
—H
—CH3
—CO—
—N(C2H5)—
1H NMR (CDCl3) 1.23 (3H, t,








J = 7.1 Hz), 2.12 (3H, s), 3.46 (2H,








q, J = 7.1 Hz), 4.04 (2H, s), 5.77








(1H, brs), 6.55-6.59 (2H, m), 6.97








(2H, d, J = 8.7 Hz), 7.73-7.89 (4H,








m), 8.17-8.21 (1H, m), 8.58 (1H, d,








J = 2.3 Hz).


842
—Cl
—Cl
—H
—NHCONH—
none
MS 431 (M+)
















TABLE 115













 











Reference






Example


No.
R363
R364
Form
1H NMR (solvent) δ ppm





843
—H




hydro- chloride
 (DMSO-d6) 2.94 (3H, s), 3.10-3.59 (7H, m), 4.02-4.39 (5H, m), 6.07 (2H, s), 6.68 (2H, d, J = 9.1 Hz), 6.74-7.06 (5H, m), 7.25 (1H, brs), 8.23 (1H, dd, J = 8.7 Hz, 2.3 Hz), 8.65 (1H, d, J = 2.3 Hz), 11.23 (1H, brs).


 


844
—H
—NO2
free
(CDCl3) 7.13 (1H, d, J = 8.5 Hz),






7.35 (2H, d, J = 9.1 Hz), 8.33 (2H, d,






J = 9.1 Hz), 8.41 (1H, dd, J = 8.5






Hz, 2.5 Hz), 8.89 (1H, d, J = 2.5






Hz).


 


845
—H




free
(DMSO-d6) 2.47 (4H, brs), 3.31-3.53 (6H, m), 7.16 (1H, d, J = 8.6 Hz), 7.23-7.34 (7H, m), 7.45-7.48 (2H, m), 8.31 (1H, dd, J = 8.6 Hz, 2.4 Hz), 8.68 (1H, d, J = 2.4 Hz), 13.20 (1H, brs).


 


846
—H




free
(DMSO-d6) 3.36-3.55 (8H, m), 3.58 (2H, s), 6.00 (2H, s), 6.78-6.92 (3H, m), 7.17 (1H, d, J = 8.6 Hz), 7.26 (2H, d, J = 8.6 Hz), 7.48 (2H, d, J = 8.4 Hz), 8.31 (1H, dd, J = 2.3 Hz, 8.6 Hz), 8.68 (1H, d, J = 2.2 Hz).


 


847
—H




free
(DMSO-d6) 2.50 (4H, brs), 2.63-2.68 (2H, m), 2.81-2.86 (2H, m), 3.48-3.61 (6H, m), 6.01 (2H, s), 6.81-6.90 (2H, m), 6.96 (1H, s), 7.06-7.10 (3H, m), 7.30 (2H, d, J = 8.6 Hz), 8.25-8.33 (1H, m), 8.66 (1H, d, J = 2.7 Hz), 12.58 (1H, brs).


 


848
—CH3
—NO2
free
(DMSO-d6) 2.22 (3H, s), 7.28 (1H,






dd, J = 8.6 Hz, 0.7 Hz), 7.40 (1H, d,






J = 8.9 Hz), 8.14 (1H, dd, J = 8.9






Hz, 2.8 Hz), 8.28 (1H, d, J = 2.6






Hz), 8.36 (1H, dd, J = 8.6 Hz, 2.3






Hz), 8.65 (1H, dd, J = 2.3 Hz, 0.7






Hz).
















TABLE 116













 











Reference






Example


No.
R365
R366
R367
1H NMR (solvent) δ ppm





849
—NO2
—CH3
—H
(DMSO-d6) 2.06 (3H, s), 7.14 (1H,






d, J = 8.6 Hz), 7.26 (1H, d, J = 9.1






Hz), 7.64 (1H, dd, J = 8.7 Hz, 2.5






Hz), 7.74 (1H, d, J = 2.5 Hz), 8.62






(1H, dd, J = 9.1 Hz, 3.0 Hz), 9.02






(1H, d, J = 2.8 Hz), 10.75 (1H, brs).


850
—NO2
—CH3
—CH3
(DMSO-d6) 2.09 (3H, s), 3.26 (3H,






s), 7.20-7.36 (4H, m), 8.64 (1H, dd,






J = 9.1 Hz, 2.8 Hz), 9.03 (1H, d,






J = 2.6 Hz).


851
4-CF3PhNHCO—
—CH3
—H
(DMSO-d6) 2.08 (3H, s), 7.11 (1H,






d, J = 8.7 Hz), 7.16 (1H, d, J = 8.7






Hz), 7.64 (1H, dd, J = 8.7 Hz, 2.5






Hz), 7.72-7.75 (3H, m), 7.98 (2H, d,






J = 8.6 Hz), 8.37 (1H, dd, J = 8.7






Hz, 2.5 Hz), 8.69 (1H, d, J = 2.5






Hz), 10.62 (1H, brs), 10.74 (1H, brs).


852
4-CF3PhOCH2—
—H
—H
(DMSO-d6) 5.17 (2H, s), 7.06 (1H,






d, J = 8.4 Hz), 7.13 (2H, d, J = 8.9






Hz), 7.21 (2H, d, J = 8.6 Hz), 7.67






(2H, d, J = 8.4 Hz), 7.79 (2H, d,






J = 9.1 Hz), 7.95 (1H, dd, J = 8.4






Hz, 2.5 Hz), 8.25 (1H, d, J = 2.0






Hz), 10.78 (1H, brs).


853
4-CF3PhOCH2—
—CH3
—H
(CDCl3) 2.18 (3H, s), 5.05 (2H, s),






7.01-7.08 (5H, m), 7.51-7.58 (4H,






m), 7.83-7.87 (1H, m), 8.20 (1H, d,






J = 2.1 Hz), 9.02 (1H, brs).


854
4-CF3PhOCH2—
—CH3
—CH3
(DMSO-d6) 2.09 (3H, s), 3.25 (3H,






s), 5.17 (2H, s), 7.10 (1H, d, J = 8.4






Hz), 7.11 (1H, d, J = 8.4 Hz),






7.17-7.23 (3H, m), 7.32 (1H, d,






J = 2.3 Hz), 7.67 (2H, d, J = 8.7 Hz),






7.98 (1H, dd, J = 8.4 Hz, 2.3 Hz),






8.24 (1H, d, J = 2.3 Hz).
















TABLE 117













 











Reference






Example


No.
R368
R369
R370
1H NMR (solvent) δ ppm





855
3,4-Cl2PhSO2NH—
—F
—CH3
(DMSO-d6) 2.96 (3H, s), 4.11 (2H,






s), 6.43 (1H, dd, J = 8.9 Hz, 2.1 Hz),






6.58 (1H, dd, J = 14.4 Hz, 3.0 Hz),






6.97-7.02 (2H, m), 7.53 (1H, dd,






J = 8.9 Hz, 2.8 Hz), 7.63 (1H, dd,






J = 8.4 Hz, 2.1 Hz), 7.77 (1H, d,






J = 2.5 Hz), 7.86 (1H, d, J = 8.6 Hz),






7.88 (1H, d, J = 2.1 Hz), 10.40 (1H,






s), 12.61 (1H, brs).


856
3,4-Cl2PhNHCO—
—OCH3
—C2H5
(CDCl3) 1.26 (3H, t, J = 7.1 Hz),






3.45 (2H, q, J = 7.1 Hz), 3.69 (3H,






s), 4.08 (2H, s), 6.24 (1H, dd, J = 8.7






Hz, 2.8 Hz), 6.31 (1H, d, J = 2.6






Hz), 6.95 (1H, d, J = 8.7 Hz), 7.00






(1H, d, J = 8.7 Hz), 7.29-7.50 (1H,






m), 7.55 (1H, dd, J = 8.9 Hz, 2.5






Hz), 7.88 (1H, d, J = 8.24 (1H, dd,






J = 8.7 Hz, 2.5 Hz), 8.56 (1H, brs),






8.73 (1H, d, J = 2.0 Hz).









Reference Example 857
Production of 3-{4-[5-(3,4-dichlorobenzylmethylamino)-pyridin-2-yloxy]phenyl}propionic acid
To a solution of ethyl 3-{4-[5-(3,4-dichlorobenzylamino)pyridin-2-yloxy]phenyl}propionate (1.63 g, 3.7 mmol) in ethanol (30 mL) were added 37% aqueous formaldehyde (2.0 mL, 22 mmol) and acetic acid (0.21 mL, 3.7 mmol), and the resulting solution was stirred at room temperature for 1 hour. To this solution was then added sodium cyanoborohydride (0.46 g, 7.3 mmol) at 0° C., and the resulting solution was stirred at the same temperature for 1 hour. To this solution was added water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to thereby yield 1.55 g of ethyl 3-{4-[5-(3,4-dichlorobenzylmethylamino)-pyridin-2-yloxy]phenyl}propionate. This product was dissolved in ethanol (40 mL), and to the resulting solution was added 10% aqueous sodium hydroxide (2.7 mL, 6.7 mmol) and stirred at room temperature for 2 hours. The resulting solution was then acidified by adding 10% hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated, to thereby yield 1.44 g of the title compound.
Appearance: Colorless oil
1H NMR (DMSO-d6) δ 2.38-2.60 (2H, m), 2.78 (2H, t, J=7.6 Hz), 4.52 (2H, s), 6.81-6.92 (3H, m), 7.12-7.23 (3H, m), 7.28 (1H, dd, J=8.9 Hz, 3.3 Hz), 7.48 (1H, d, J=1.9 Hz), 7.57 (1H, d, J=8.2 Hz), 7.63 (1H, d, J=3.3 Hz), 11.70-12.40 (1H, m).
The following compound was produced in the same manner as in Reference Example 857.
Reference Example 858
3-(4-{5-[(3,4-Dichlorobenzyl)ethylamino]pyridin-2-yloxy}phenyl)propionic acid
1H NMR (DMSO-d6) δ 1.09 (3H, t, J=6.9 Hz), 2.37-2.59 (2H, m), 2.64-2.83 (2H, m), 3.45 (2H, q, J=6.9 Hz), 4.48 (2H, s), 6.82 (1H, d, J=8.9 Hz), 6.85-6.92 (2H, m), 7.12-7.25 (4H, m), 7.48 (1H, d, J=1.8 Hz), 7.54-7.61 (2H, m), 11.77-12.38 (1H, m).
Reference Example 859
Production of N-[2-(4-formylphenoxy)-5-pyridyl]-3,4-dichlorobenzamide
To a solution of 4-[(5-amino-2-pyridyl)oxy]benzaldehyde ethylene acetal (5.27 g, 20.4 mmol) and triethylamine (3.41 mL, 24.5 mmol) in THF (80 mL) was added dropwise a solution of 3,4-dichlorobenzoyl chloride (4.49 g, 21.4 mmol) in THF (30 mL) under ice cooling. The resulting solution was stirred for 2 hours at the same temperature. The reaction solution was concentrated under reduced pressure, to the residue, 80% acetic acid (55 mL) was added, and the mixture was heated at 80° C. with stirring for 1 hour. The reaction solution was concentrated under reduced pressure and to the residue was added water, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The obtained solid was recrystallized from isopropanol, to thereby yield 5.63 g of the title compound.
Appearance: Pale yellow powder
1H NMR (CDCl3) δ 7.05 (1H, d, J=8.7 Hz), 7.24 (2H, d, J=8.7 Hz), 7.57 (1H, d, J=8.4 Hz), 7.70 (1H, dd, J=8.4 Hz, 2.1 Hz), 7.82-7.93 (3H, m), 7.97 (1H, d, J=2.1 Hz), 8.25 (1H, dd, J=8.7 Hz, 2.7 Hz), 8.29 (1H, d, J=2.7 Hz), 9.96 (1H, s).
Reference Example 860
Production of ethyl{4-[5-(3,4-dichlorobenzoylamino)-pyridin-2-yloxy]benzylamino}acetate
A solution of N-[2-(4-formylphenoxy)-5-pyridyl]-3,4-dichlorobenzamide (1.00 g, 2.58 mmol), glycine ethyl ester hydrochloride (0.400 g, 2.84 mmol) and sodium acetate (0.230 g, 2.84 mmol) in methanol (20 mL) was stirred for 30 minutes at 60° C. The reaction solution was cooled with ice, and then sodium cyanoborohydride (0.180 g, 2.84 mmol) was added. The resulting solution was stirred at the same temperature for 1 hour. To the reaction solution was added 5 M hydrochloric acid (2 mL) and concentrated under reduced pressure. To the residue was added a saturated sodium bicarbonate solution, and extracted with dichloromethane. The dichloromethane layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:2), to thereby yield 0.752 g of the title compound.
Appearance: Yellow oil
1H NMR (CDCl3) δ 1.27 (3H, t, J=7.1 Hz), 3.43 (2H, s), 3.81 (2H, s), 4.2.0 (2H, q, J=7.1 Hz), 6.95 (1H, d, J=8.8 Hz), 7.09 (2H, d, J=8.5 Hz), 7.36 (2H, d, J=8.5 Hz), 7.57 (1H, d, J=8.3 Hz), 7.71 (1H, dd, J=2.1 Hz, 8.3 Hz), 7.84 (1H, s), 7.98 (1H, d, J=2.1 Hz), 8.18 (1H, dd, J=2.7 Hz, 8.8 Hz), 8.24 (1H, d, J=2.7 Hz).
Reference Example 861
Production of (acetyl{4-[5-(3,4-dichlorobenzoylamino)-pyridin-2-yloxy]benzyl}amino)acetic acid
To a solution of ethyl{4-[5-(3,4-dichloro-benzoylamino)pyridin-2-yloxy]benzylamino}acetate (0.811 g, 1.59 mmol) in dichloromethane (5 mL) were added triethylamine (0.332 mL, 2.39 mmol) and acetyl chloride (0.136 mL, 1.91 mmol) at room temperature. The resulting solution was stirred for 1 hour at the same temperature. To the reaction solution was added water, and extracted with dichloromethane. The dichloromethane layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated, to thereby yield 0.785 g of residue. This residue was dissolved in ethanol (5 mL). To the resulting solution was added 5 M aqueous sodium hydroxide (0.350 mL, 1.75 mmol) at room temperature and stirred at the same temperature for 14 hours. To the resulting reaction solution were added 5 M hydrochloric acid (0.400 mL) and water, and extracted with dichloromethane. The dichloromethane layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated, to thereby yield 0.776 g of the title compound.
Appearance: White amorphous powder
1H NMR (DMSO-d6 at 375 K) δ 2.10 (3H, s), 4.02 (2H, s), 4.60 (2H, s), 7.03 (1H, d, J=8.8 Hz), 7.11 (2H, d, J=8.2 Hz), 7.32 (2H, d, J=8.2 Hz), 7.7.8 (1H, d, J=8.4 Hz), 7.97 (1H, dd, J=2.1 Hz, 8.4 Hz), 8.10-8.30 (2H, m), 8.53 (1H, d, J=2.6 Hz), 10.23 (1H, s).
Reference Example 862
Production of 1-(4-piperonylpiperazin-1-yl)-2-{methyl-[3-methyl-4-(5-nitropyridin-2-yloxy)phenyl]amino}-ethanone
To a solution of {methyl[3-methyl-4-(5-nitropyridin-2-yloxy)phenyl]amino}acetic acid (0.93 g, 2.9 mmol) in DMF (40 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.67 g, 3.5 mmol), 1-hydroxybenzotriazole monohydrate (0.54 g, 3.5 mmol), and 1-piperonylpiperazine (0.68 g, 3.08 mmol). The reaction mixture was stirred for 15 hours at room temperature under a nitrogen atmosphere. To the resulting solution was added water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→dichloromethane methanol=100:1), to thereby yield 1.2 g of the title compound.
Appearance: Yellow powder
Melting point: 142-143° C.
The following compounds were produced in the same manner as in Reference Example 862.







TABLE 118













 












Reference







Example


No.
R371
R372
Xa28
Xa29
1H NMR (CDCl3) δ ppm





863
—CH3
—CH3
—CH2—
—CO—
2.09 (3H, s), 3.04 (3H, s), 3.22-3.39







(2H, m), 3.60-3.90 (2H, m), 4.11







(2H, s), 4.19-4.40 (2H, m), 4.53 (2H,







s), 5.95 (2H, s), 6.51-6.62 (2H, m),







6.68-6.80 (3H, m), 6.92 (1H, d,







J = 8.6 Hz), 6.94 (1H, d, J = 9.0 Hz),







8.42 (1H, dd, J = 9.0 Hz, 2.6 Hz),







9.04 (1H, d, J = 2.6 Hz).


864
—OCH3
—C2H5
—CH2—
—CO—
1.21 (3H, t, J = 6.7 Hz), 3.20-3.33







(2H, m), 3.46 (2H, q, J = 6.7 Hz),







3.71 (3H, s), 3.65-3.85 (2H, m), 4.07







(2H, s), 4.29 (2H, s), 4.52 (2H, s),







5.96 (2H, s), 6.23 (1H, dd, J = 8.7







Hz, 2.6 Hz), 6.39 (1H, d, J = 2.6







Hz), 6.65-6.85 (3H, m), 6.97 (2H, d,







J = 8.7 Hz), 8.41 (1H, dd, J = 9.0







Hz, 2.8 Hz), 9.02 (1H, d, J = 2.8







Hz).


865
—H
—CH3
—CH2—
—CH(CH3)—
1.12-1.16 (3H, m), 2.08-2.16 (1H,







m), 2.46-2.53 (1H, m), 2.71-2.73







(1H, m), 2.85-3.48 (6H, m),







3.54-3.59 (1H, m), 3.84-4.19 (4H,







m), 5.94 (2H, s), 6.68-6.74 (4H, m),







6.85 (1H, brs), 6.94 (1H, d, J = 9.1







Hz), 7.01 (2H, d, J = 8.9 Hz), 8.41







(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.05







(1H, d, J = 2.8 Hz).


866
—H
—C2H5
—CH2—
—CH(CH3)—
1.13-1.28 (6H, m), 2.08-2.16 (1H,







m), 2.47-2.50 (1H, m), 2.71-2.75







(1H, m), 2.86-3.35 (3H, m),







3.41-3.49 (2H, m), 3.58-3.62 (1H,







m), 3.85-4.16 (4H, m), 5.94 (2H, s),







6.67 (2H, d, J = 9.1 Hz), 6.74 (2H,







brs), 6.85 (1H, brs), 6.94 (1H, d,







J = 9.1 Hz), 6.99 (2H, d, J = 9.1 Hz),







8.41 (1H, dd, J = 9.1 Hz, 3.0 Hz),







9.05 (1H, d, J = 2.5 Hz).


867
—H
—CH3
—CH(CH3)—
—CH2—
1.29-1.40 (3H, m), 1.96-2.06 (1H,







m), 2.17 (1H, brs), 2.65-2.70 (1H,







m), 2.81-2.86 (1H, m), 2.96-3.06







(4H, m), 3.32-3.49 (3H, m),







3.97-4.71 (3H, m), 5.95 (2H, s), 6.70







(2H, d, J = 9.2 Hz), 6.74-6.75 (2H,







m), 6.87 (1H, brs), 6.94 (1H, dd,







J = 9.1 Hz, 0.5 Hz), 7.01 (2H, d,







J = 9.2 Hz), 8.41 (1H, dd, J = 9.1







Hz, 2.8 Hz), 9.05 (1H, dd, J = 2.8







Hz, 0.5 Hz).


868
—H
—C2H5
—CH(CH3)—
—CH2—
1.20 (3H, t, J = 7.1 Hz), 1.26-1.40







(3H, m), 1.98-2.05 (1H, m),







2.16-2.17 (1H, m), 2.65-2.69 (1H,







m), 2.81-2.85 (1H, m), 3.02-3.56







(6H, m), 4.03-4.71 (3H, m), 5.94







(2H, s), 6.66 (2H, d, J = 9.2 H),







6.74-6.75 (2H, m), 6.87 (1H, brs),







6.94 (1H, dd, J = 9.1 Hz, 0.7 Hz),







6.99 (2H, d, J = 9.1 Hz), 8.41 (1H,







dd, J = 9.1 Hz, 2.8 Hz), 9.05 (1H,







dd, J = 2.8 Hz, 0.7 Hz).
















TABLE 119













 











Reference






Example



1H NMR (solvent) δ ppm


No.
R373
R374
R375
or MS





869
—COOCH3
—H
—C2H5
MS 577 (M+).


870
—OCH3
—H
—H
1H NMR (DMSO-d6)






2.32-2.40 (4H, m), 3.42






(2H, s), 3.50 (4H, brs),






3.63 (3H, s), 3.92 (2H, d,






J = 4.6 Hz), 5.65 (1H, t,






J = 4.8 Hz), 5.99 (2H, s),






6.22 (1H, dd, J = 8.6 Hz,






2.5 Hz), 6.51 (1H, d,






J = 2.5 Hz), 6.76 (1H,






dd, J = 7.9 Hz, 1.5 Hz),






6.84-6.91 (3H, m), 7.07






(1H, dd, J = 9.1 Hz, 0.5






Hz), 8.54 (1H, dd,






J = 9.1 Hz, 2.8 Hz), 9.00






(1H, dd, J = 2.8 Hz, 0.5






Hz).


871
—OCH3
—H
—CH3
1H NMR (CDCl3)






2.35-2.52 (4H, m), 3.07






(3H, s), 3.44 (2H, s),






3.41-3.55 (2H, m),






3.56-3.70 (2H, m), 3.73






(3H, s), 5.95 (2H, s),






6.24 (1H, dd, J = 8.8 Hz,






2.8 Hz), 6.35 (1H, d,






J = 2.8 Hz), 6.64-6.79






(2H, m), 6.85 (1H, s),






6.89-7.04 (2H, m), 8.41






(1H, dd, J = 9.1 Hz, 2.8






Hz), 9.03 (1H, d, J = 2.8






Hz).


872
—OCH3
—H
—C2H5
1H NMR (CDCl3) 1.22






(3H, t, J = 7.0 Hz),






2.33-2.52 (4H, m),






3.49-3.58 (6H, m),






3.59-3.69 (2H, m), 3.72






(3H, s), 4.06 (2H, s),






5.95 (2H, s), 6.22 (1H,






dd, J = 8.8 Hz, 2.7 Hz),






6.33 (1H, d, J = 2.7 Hz),






6.69-6.79 (2H, m), 6.85






(1H, s), 6.95 (1H, d,






J = 9.1 Hz), 6.96 (1H, d,






J = 8.8 Hz), 8.41 (1H,






dd, J = 9.1 Hz, 2.8 Hz),






9.04 (1H, d, J = 2.8 Hz).


873
—CH3
—H
—H
1H NMR (CDCl3) 2.08






(3H, s), 2.43-2.48 (4H,






m), 3.45-3.48 (4H, m),






3.67-3.71 (2H, m), 3.86






(2H, d, J = 4.1 Hz), 4.93






(1H, t, J = 4.1 Hz), 5.96






(2H, s), 6.47-6.52 (2H,






m), 6.71-6.78 (2H, m),






6.86-6.96 (3H, m), 8.44






(1H, dd, J = 9.1 Hz, 2.8






Hz), 9.05 (1H, d, J = 2.8






Hz).


874
—CH3
—H
—Ac
1H NMR (CDCl3) 1.98






(3H, s), 2.16 (3H, s),






2.32-2.51 (4H, m),






3.35-3.48 (4H, m),






3.53-3.69 (2H, m), 4.46






(2H, s), 5.95 (2H, s),






6.65-6.79 (2H, m), 6.85






(1H, s), 7.08 (2H, d,






J = 8.7 Hz), 7.27-7.34






(1H, m), 7.35-7.42 (1H,






m), 8.51 (1H, dd, J = 9.0






Hz, 2.8 Hz), 9.02 (1H,






dd, J = 2.8 Hz, 0.3 Hz).


875
—CH3
—H
—C2H5
1H NMR (CDCl3) 1.20






(3H, t, J = 7.1 Hz), 2.08






(3H, s), 2.37-2.55 (4H,






m), 3.37-3.72 (8H, m),






4.05 (2H, s), 5.95 (2H,






s), 6.42-6.58 (2H, m),






6.63-6.79 (2H, m),






6.81-6.99 (3H, m), 8.42






(1H, dd, J = 9.1 Hz, 2.8






Hz), 9.05 (1H, d, J = 2.8






Hz).


 


876
—CH3
—H




 1H NMR (CDCl3) 0.64-0.69 (2H, m), 0.80-0.87 (2H, m), 2.09 (3H, s), 2.41-2.49 (4H, m), 2.76-2.84 (1H, m), 3.44 (2H, s), 3.49-3.52 (2H, m), 3.60-3.64 (2H, m), 4.18 (2H, s), 5.95 (2H, s), 6.71-6.93 (7H, m), 8.39-8.44 (1H, m), 9.05-9.06 (1H, m).


 


877
—CH3
—CH3
—CH3
1H NMR (CDCl3) 2.05






(3H, s), 2.28 (3H, s),






2.37-2.43 (4H, m), 2.72






(3H, s), 3.42 (2H, s),






3.52-3.56 (2H, m),






3.62-3.65 (2H, m), 3.77






(2H, s), 5.95 (2H, s),






6.71-6.77 (2H, m),






6.85-6.90 (2H, m),






6.97-7.06 (2H, m), 8.45






(1H, dd, J = 9.1 Hz, 3.0






Hz), 9.04 (1H, dd,






J = 3.0 Hz, 0.5 Hz).
















TABLE 120













 












Reference







Example




1H NMR (solvent) δ ppm


No.
R376
R377
R378
R379
or MS





878
—CH3
—H
—CH3
—C2H5
MS 547 (M+)


879
—F
—H
—H
—H
1H NMR (CDCl3)







2.44-2.49 (4H, m),







3.43-3.45 (2H, m), 3.45







(2H, s), 3.68-3.71 (2H,







m), 3.84 (2H, d, J = 4.1







Hz), 5.12 (1H, brs), 5.96







(2H, s), 6.40-6.45 (2H,







m), 6.71-6.80 (2H, m),







6.85 (1H, brs), 7.02 (1H,







t, J = 8.5 Hz), 7.05 (1H,







dd, J = 9.1 Hz, 0.5 Hz),







8.46 (1H, dd, J = 9.1 Hz,







2.8 Hz), 9.02 (1H, dd,







J = 2.8 Hz, 0.7 Hz).


880
—F
—H
—H
—CH3
1H NMR (CDCl3) 2.44







(4H, brs), 3.06 (3H, s),







3.45 (2H, s), 3.45-3.47







(2H, m), 3.62-3.64 (2H,







m), 4.11 (2H, s), 5.95







(2H, s), 6.40-6.51 (2H,







m), 6.71-6.78 (2H, m),







6.85 (1H, brs), 7.04 (1H,







d, J = 9.1 Hz), 7.05 (1H,







t, J = 8.9 Hz), 8.46 (1H,







dd, J = 9.1 Hz, 2.8 Hz),







9.02 (1H, d, J = 2.3 Hz)


881
—F
—H
—H
—C2H5
1H NMR (CDCl3) 1.22







(3H, t, J = 7.2 Hz), 2.45







(4H, brs), 3.40-3.49 (4H,







m), 3.45 (2H, s), 3.65







(2H, brs), 4.05 (2H, s),







5.95 (2H, s), 6.37-6.46







(2H, m), 6.74-6.75 (2H,







m), 6.86 (1H, brs),







6.99-7.06 (2H, m), 8.45







(1H, dd, J = 9.1 Hz, 2.8







Hz), 9.03 (1H, d, J = 2.5







Hz).


882
—F
—H
—H
allyl
1H NMR (CDCl3) 2.46







(4H, brs), 3.45 (2H, s),







3.48 (2H, brs), 3.65 (2H,







brs), 4.00 (2H, d, J = 5.0







Hz), 4.07 (2H, s),







5.19-5.29 (2H, m),







5.82-5.94 (1H, m), 5.95







(2H, s), 6.37-6.47 (2H,







m), 6.71-6.78 (2H, m),







6.86-6.87 (1H, m),







6.98-7.05 (2H, m), 8.45







(1H, dd, J = 9.1 Hz, 2.8







Hz), 9.02 (1H, dd,







J = 2.8 Hz, 0.5 Hz)


883
—F
—H
—F
—CH3
1H NMR (CDCl3)







2.33-2.49 (4H, m), 2.99







(3H, s), 3.43 (2H, s),







3.37-3.50 (2H, m),







3.51-3.68 (2H, m), 4.10







(2H, s), 5.95 (2H, s),







6.69-6.78 (2H, m), 6.81







(1H, dd, J = 8.2 Hz, 12.1







Hz), 6.85 (1H, d,







J = 0.96 Hz), 6.90 (1H,







dd, J = 7.1 Hz, 12.8 Hz),







7.09 (1H, d, J = 9.1 Hz),







8.49 (1H, dd, J = 2.8 Hz,







9.0 Hz), 9.01 (1H, d,







J = 2.8 Hz).


884
—F
—H
—F
—C2H5
1H NMR (CDCl3) 1.17







(3H, t, J = 7.1 Hz),







2.30-2.52 (4H, m), 3.35







(2H, q, J = 7.1 Hz),







3.37-3.70 (6H, m), 4.04







(2H, s), 5.95 (2H, s),







6.68-6.78 (2H, m), 6.82







(1H, dd, J = 8.0 Hz, 12.1







Hz), 6.83-6.88 (1H, m),







6.91 (1H, dd, J = 7.2







Hz, 12.5 Hz), 7.09 (1H,







d, J = 9.0 Hz), 8.49 (1H,







dd, J = 2.8 Hz, 9.0 Hz),







9.02 (1H, d, J = 2.8 Hz).


885
—F
—F
—H
—CH3
1H NMR (CDCl3)







2.20-2.45 (4H, m), 2.91







(3H, s), 3.34-3.53 (6H,







m), 4.31 (2H, s), 5.98







(2H, s), 6.47 (2H, d,







J = 11.8 Hz), 6.70-6.79







(1H, m), 6.80-6.91 (2H,







m), 7.42 (1H, d, J = 9.1







Hz), 8.64 (1H, dd,







J = 2.8 Hz, 9.1 Hz), 9.05







(1H, d, J = 2.8 Hz).


886
—CH3
—H
—CH3
—CH3
MS 533 (M+)


887
—CF3
—H
—H
—C2H5
MS 587 (M+)


888
—CF3
—H
—H
—CH3
MS 573 (M+)


889
—H
—F
—F
—CH3
1H NMR (CDCl3)







2.30-2.52 (4H, m), 3.01







(3H, s), 3.43 (2H, s),







3.38-3.71 (4H, m), 4.10







(2H, s), 5.95 (2H, s),







6.65-6.81 (3H, m),







6.82-6.96 (2H, m), 7.10







(1H, d, J = 9.1 Hz), 8.49







(1H, dd, J = 2.8 Hz, 9.1







Hz), 9.01 (1H, d, J = 2.8







Hz).
















TABLE 121













 












Reference







Example




mp (° C.) or 1H NMR (CDCl3)


No.
R380
R381
Xa30
R382
δ ppm





890
—CH3
—CH3
—CH2—
benzyl
1H NMR 2.12 (3H, s), 2.40-2.55 (4H,







m), 3.04 (3H, s), 3.45-3.55 (2H, m),







3.54 (2H, s), 3.60-3.70 (2H, m), 4.10







(2H, s), 6.50-6.61 (2H, m), 6.91 (1H,







d, J = 8.5 Hz), 6.92 (1H, d, J = 9.1







Hz), 7.22-7.40 (5H, m), 8.42 (1H,







dd, J = 9.1 Hz, 2.8 Hz), 9.05 (1H, d,







J = 2.8 Hz).


891
—CH3
—C2H5
—CH2—
benzyl
mp 134-136


892
—H
—CH3
—CH2CH2—
piperonyl
1H NMR 2.23-2.41 (4H, m),







2.56-2.61 (2H, m), 2.97 (3H, s),







3.39-3.42 (4H, m), 3.60-3.64 (2H,







m), 3.71-3.76 (2H, m), 5.94 (2H, s),







6.72-6.76 (5H, m), 6.83 (1H, brs),







6.97 (1H, d, J = 9.1 Hz), 7.02 (1H, d,







J = 9.1 Hz), 8.43 (1H, dd, J = 9.1







Hz, 2.8 Hz), 9.04 (1H, d, J = 2.8







Hz).


893
—CH3
—CH3
—CH(CH3)—
piperonyl
1H NMR 1.31 (3H, d, J = 6.6 Hz),







2.11 (3H, s), 2.17-2.49 (4H, m), 2.78







(3H, s), 3.31-3.56 (3H, m), 3.39 (2H,







s), 3.77(1H, brs), 4.57 (1H, q, J = 6.6







Hz), 5.94 (2H, s), 6.60-6.63 (2H, m),







6.68-6.75 (2H, m), 6.83 (1H, brs),







6.93-6.98 (2H, m), 8.44 (1H, dd,







J = 9.1 Hz, 2.8 Hz), 9.05 (1H, d,







J = 2.8 Hz).


894
—H
—CH3
—CH(CH3)—
piperonyl
1H NMR 1.32 (3H, d, J = 6.6 Hz),







2.19-2.50 (4H, m), 2.80 (3H, s),







3.30-3.56 (3H, m), 3.32 (2H, s), 3.78







(1H, brs), 4.58 (1H, q, J = 6.6 Hz),







5.93 (2H, s), 6.68-6.82 (3H, m), 6.77







(2H, d, J '2 9.1 Hz), 6.98 (1H, dd,







J = 8.6 Hz, 0.5 Hz), 7.04 (2H, d,







J = 9.2 Hz), 8.44 (1H, dd, J = 9.1







Hz, 2.8 Hz), 9.05 (1H, dd, J = 2.8







Hz, 0.5 Hz).


895
—CH3
—H
—CO—
piperonyl
1H NMR 2.15 (3H, s), 2.49-2.55 (4H,







m), 3.45 (2H, s), 3.71-3.75 (2H, m),







4.25-4.28 (2H, m), 5.96 (2H, s), 6.75







(2H, brs), 6.86 (1H, brs), 7.04 (1H,







d, J = 9.1 Hz), 7.06 (1H, d, J = 8.6







Hz), 7.49 (1H, dd, J = 8.7 Hz, 2.6







Hz), 7.61 (1H, d, J = 2.5 Hz), 8.48







(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.02







(1H, d, J = 2.8 Hz), 9.23 (1H, brs).


896
—CH3
—CH3
—CO—
piperonyl
1H NMR 2.15 (3H, s), 2.25-2.33 (4H,







m), 3.33-3.42 (9H, m), 5.93 (2H, s),







6.66-6.79 (3H, m,) 7.04-7.21 (4H,







m), 8.51 (1H, dd, J = 9.1 Hz, 2.8







Hz), 8.99 (1H, dd, J = 2.8 Hz, 0.5







Hz).
















TABLE 122













 









Reference




Example


No.
R383
1H NMR (CDCl3) δ ppm or MS





897




MS 502 (M+)


 


898




1H NMR 2.44 (4H, brs), 3.07 (3H, s), 3.44 (2H, s), 3.47-3.51 (2H, m), 3.62-3.66 (2H, m), 4.12 (2H, s), 5.95 (2H, s), 6.67-6.75 (4H, m), 6.86 (1H, s), 6.93-6.99 (4H, m), 8.16 (2H, d, J = 9.2 Hz).


 


899




1H NMR 2.42 (4H, t, J = 4.9 Hz), 3.04 (3H, s), 3.42 (2H, s), 3.44 (2H, t, J = 4.9 Hz), 3.62 (2H, t, J = 4.9 Hz), 4.11 (2H, s), 5.95 (2H, s), 6.42-6.44 (1H, m), 6.50-6.51 (1H, m), 6.54-6.58 (1H, m), 6.70-6.77 (2H, m), 6.84 (1H, m), 6.96 (1H, d, J = 9.1 Hz), 7.24-7.30 (1H, m), 8.43 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.08 (1H, d, J = 2.8 Hz).


 


900




1H NMR 2.44 (4H, brs), 3.44 (2H, s), 3.55 (2H, brs), 3.73 (2H, brs), 5.95 (2H, s), 6.74 (2H, s), 6.85 (1H, s), 6.86 (1H, d, J = 8.6 Hz), 7.14 (2H, d, J = 8.6 Hz), 7.46 (2H, d, J = 8.6 Hz), 7.79 (1H, dd, J = 8.7 Hz, 2.5 Hz), 8.22 (1H, d, J = 2.5 Hz).


 


901




MS 508 (M+)


 


902




MS 587 (M+)


 


903




1H NMR 2.31-2.50 (4H, m), 2.96 (3H, s), 3.42 (2H, s), 3.40-3.52 (2H, m), 3.53-3.67 (2H, m), 4.05 (2H, s), 5.95 (2H, s), 6.65-6.95 (6H, m), 7.77 (1H, dd, J = 2.5 Hz, 8.7 Hz), 8.16 (1H, dd, J = 0.5 Hz, 2.5 Hz).
















TABLE 123













 









Reference




Example


No.
R384
1H NMR (CDCl3) δ ppm





904
—H
2.29-2.34 (4H, m), 3.15 (3H, s), 3.34-3.43 (6H,




m), 4.63 (2H, s), 5.98 (2H, s), 6.72-6.76 (1H, m),




6.83-6.86 (2H, m), 7.27 (2H, d, J = 8.9 Hz), 7.31




(1H, d, J = 9.3 Hz), 7.54 (2H, d, J = 8.9 Hz),




8.64 (1H, dd, J = 9.2 Hz, 2.8 Hz), 9.05 (1H, d,




J = 2.8 Hz).


905
—CH3
2.15 (3H, s), 2.42-2.43 (4H, m), 3.22 (3H, s),




3.39-3.41 (2H, m), 3.43 (2H, s), 3.61-3.63 (2H,




m), 4.56 (2H, s), 5.94 (2H, s), 6.70-6.77 (2H, m),




6.84 (1H, brs), 7.06 (1H, d, J = 8.2 Hz), 7.07




(1H, d, J = 9.1 Hz), 7.48-7.52 (2H, m), 8.49 (1H,




dd, J = 9.1 Hz, 2.8 Hz), 9.01 (1H, d, J = 2.8 Hz).


906
—OCH3
2.42-2.46 (4H, m), 3.24 (3H, s), 3.40 (2H, brs),




3.43 (2H, s), 3.63 (2H, brs), 3.74 (3H, s), 4.58




(2H, s), 5.94 (2H, s), 6.70-6.77 (2H, m), 6.84




(1H, s), 7.06-7.14 (2H, m), 7.23-7.28 (1H, m),




7.32 (1H, d, J = 2.3 Hz), 8.47 (1H, dd, J = 9.1




Hz, 2.8 Hz), 8.98 (1H, d, J = 2.8 Hz).
















TABLE 124













 









Reference




Example


No.
R385
1H NMR (CDCl3) δ ppm





907
piperonyl
1.33-1.46 (2H, m), 1.86-2.00 (3H, m), 2.10 (3H,




s), 2.29 (2H, d, J = 6.8 Hz), 2.39-2.43 (4H, m),




2.75 (2H, t, J = 12.2 Hz), 3.40-3.48 (4H, m),




3.62-3.66 (4H, m), 5.94 (2H, s), 6.73-6.85 (5H,




m), 6.91-6.96 (2H, m), 8.43 (1H, dd, J = 9.1 Hz,




3.0 Hz), 9.04 (1H, d, J = 2.8 Hz).


908
benzyl
1.35-1.46 (2H, m), 1.86-2.00 (3H, m), 2.10 (3H,




s), 2.29 (2H, d, J = 6.8 Hz), 2.41-2.45 (4H, m),




2.75 (2H, t, J = 12.2 Hz), 3.47-3.53 (4H, m),




3.61-3.65 (4H, m), 6.79-6.96 (4H, m), 7.24-7.33




(5H, m), 8.43 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.05




(1H, d, J = 2.8 Hz).









Reference Example 909
Production of (4-benzylpiperazin-1-yl){4-[methyl(5-nitropyridin-2-yl)amino]phenyl}methanone
To a solution of 4-[methyl-(5-nitropyridin-2-yl)amino]benzoic acid (0.800 g, 2.93 mmol) and 1-benzylpiperazine (0.542 g, 3.08 mmol) in DMF (15 mL) were added triethylamine (1.02 mL, 7.32 mmol) and diethyl cyanophosphonate (0.593 mL, 3.52 mmol), and the resulting solution was stirred for 3 hours. To the resulting reaction solution was added water and extracted with ethyl-acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate), to thereby yield 1.25 g of the title compound.
Appearance: Yellow amorphous powder
1H NMR (CDCl3) δ 2.25-2.65 (4H, m), 3.49 (2H, brs), 3.56 (2H, s), 3.57 (3H, s), 3.81 (2H, brs), 6.43 (1H, d, J=9.5 Hz), 7.25-7.35 (7H, m), 7.53 (2H, d, J=8.4 Hz), 8.06 (1H, dd, J=2.8 Hz, 9.5 Hz), 9.12 (1H, d, J=2.8 Hz).
The following compounds were produced in the same manner as in Reference Example 909.







TABLE 125













 












Reference







Example


No.
Xa31
R386
Xa32
M
1H NMR (DMSO-d6) δ ppm















910
—NH—
—H
—CH2—
1
2.20-2.30 (4H, m), 2.59 (2H, t, J = 7.3 Hz),







2.78 (2H, t, J = 7.3 Hz), 3.35 (2H, s), 3.36-







3.45 (4H, m), 5.98 (2H, s), 6.72 (1H, dd, J = 1.3







Hz, 7.9 Hz), 6.80-6.90 (3H, m), 7.21 (2H, d, J =







8.4 Hz), 7.57 (2H, d, J = 8.4 Hz), 8.26 (1H, dd, J =







2.9 Hz, 9.3 Hz), 9.01 (1H, d, J = 2.9 Hz),







10.06 (1H, s).


911
—O—
—H
—NH—
1
2.32 (2H, brs), 2.39 (2H, brs), 3.41 (2H, s),







3.50 (4H, brs), 3.91 (2H, d, J = 5.2 Hz); 5.68 (1H,







t, J = 5.2 Hz), 5.99 (2H, s), 6.70 (2H, d, J = 8.9







Hz), 6.74-6.77 (1H, m), 6.83-6.88 (2H, m),







6.94 (2H, d, J = 8.9 Hz), 7.11 (1H, d, J = 9.1 Hz),







8.56 (1H, dd, J = 2.9 Hz, 9.1 Hz), 9.02 (1H, d, J =







2.9 Hz).


912
—O—
—OCH3
—NH—
2
2.48 (2H, brs), 2.49 (2H, brs), 3.39 (2H, s),







3.50 (4H, brs), 3.63 (3H, s), 3.92 (2H, d, J = 4.8







Hz), 4.22 (4H, s), 5.65 (1H, brt), 6.22 (1H, dd, J =







8.6 Hz, 2.5 Hz), 6.51 (1H, d, J = 2.5 Hz), 6.73-







6.81 (3H, m), 6.89 (1H, d, J = 8.6 Hz), 7.07 (1H,







d, J = 9.1 Hz), 8.54 (1H, dd, J = 9.1 Hz, 2.8 Hz),







9.00 (1H, d, J = 2.8 Hz).









Reference Example 913
Production of N-[4-(5-nitropyridin-2-yloxy)phenyl]-N-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]acetamide
To a solution of ethyl{acetyl[4-(5-nitropyridin-2-yloxy)phenyl]amino}acetate (2.30 g, 6.40 mmol) in ethanol (50 mL) was added 5 M aqueous sodium hydroxide (1.92 mL, 9.60 mmol), and the resulting solution was stirred at room temperature for 30 minutes. To this reaction solution were added 5 M hydrochloric acid (2 mL) and water, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, evaporated, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1), to thereby yield 1.68 g of an oil. To a solution of this oil in DMF (10 mL) were added 1-piperonylpiperazine (1.29 g, 5.86 mmol), triethylamine (1.85 mL, 13.3 mmol) and diethyl cyanophosphonate (1.07 mL, 6.36 mmol), and the resulting solution was stirred for 1 hour at room temperature. To this reaction solution was added water and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, evaporated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1), to thereby yield 2.21 g of the title compound.
Appearance: Yellow amorphous powder
1H NMR (CDCl3) δ 1.98 (3H, s), 2.40-2.50 (4H, m), 3.40-3.45 (4H, m), 3.62 (2H, brs), 4.48 (2H, s), 5.94 (2H, s), 6.70-6.76 (2H, m), 6.85 (1H, s), 7.09 (1H, d, J=9.1 Hz), 7.20 (2H, d, J=8.7 Hz), 7.51 (2H, d, J=8.7 Hz), 8.51 (1H, dd, J=2.8 Hz, 9.1 Hz), 9.04 (1H, d, J=2.8 Hz).
The following compounds were produced in the same manner as in Reference Example 913.







TABLE 126













 










Reference





Example


No.
R387
R388
MS (M+)













914
—CH3
—CH3
587


915
—H
—C2H5
587









Reference Example 916
Production of 3-[3-methoxy-4-(5-nitropyridin-2-yloxy)phenyl]-1-(4-piperonylpiperazin-1-yl)propan-1-one
3-[3-methoxy-4-(5-nitropyridin-2-yloxy)phenyl]propionic acid (3.18 g, 10 mmol) was dissolved in dichloromethane (30 mL). To the resulting solution were added thionyl chloride (0.88 mL, 12 mmol) and DMF (1 drop), and refluxed for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (20 mL). To the resulting solution were added triethylamine (1.67 mL, 12 mmol) and a solution of 1-piperonylpiperazine (2.20 g, 10 mmol) in dichloromethane (30 mL) under ice cooling, and the resulting solution was stirred for 1 hour at 0° C. The resulting reaction solution was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was recrystallized from ethyl acetate, to thereby yield 4.95 g of the title compound.
Appearance: Pale yellow powder
1H NMR (CDCl3) δ 2.33-2.42 (4H, m), 2.63-2.69 (2H, m), 2.97-3.03 (2H, m), 3.42 (4H, brs), 3.62-3.66 (2H, m), 3.74 (3H, s), 5.95 (2H, s), 6.73-6.75 (2H, m), 6.85-6.90 (3H, m), 7.04 (1H, d, J=9.1 Hz), 7.06 (1H, d, J=7.9 Hz), 8.45 (1H, dd, J=9.1 Hz, 2.8 Hz), 9.01 (1H, d, J=2.8 Hz).
The following compound was produced in the same manner as in Reference Example 916.
Reference Example 917
6-Chloro-N-(4-trifluoromethylphenyl)nicotinamide
1H NMR (DMSO-d6) δ7.74 (1H, d, J=8.4 Hz), 7.76 (2H, d, J=8.7 Hz), 8.00 (2H, d, J=8.7 Hz), 8.38 (1H, dd, J=8.7 Hz, 2.5 Hz), 8.97 (1H, d, J=2.5 Hz), 10.80 (1H, brs).
Reference Example 918
Production of 3-{3-methoxy-4-[methyl(5-nitropyridin-2-yl)amino]phenyl}-1-(4-piperonylpiperazin-1-yl)propan-1-one
To a solution of ethyl 3-{3-methoxy-4-[methyl-(5-nitropyridin-2-yl)amino]phenyl}propionate (3.85 g, 11 mmol) in ethanol (80 mL) was added 2 N aqueous sodium hydroxide (6.4 mL, 13 mmol), and the resulting solution was stirred at room temperature for 2.5 hours. To the resulting reaction solution was added 6 N hydrochloric acid (2.2 mL, 13 mmol), and the solvent was removed under reduced pressure. To the residue were added THF (80 mL) and N,N′carbonyldiimidazole (2.08 g, 13 mmol), and the resulting solution was stirred at room temperature for 3 hours. To the resulting reaction solution were added 1-piperonylpiperazine (2.60 g, 12 mmol) and DMF (40 mL), and stirred at room temperature for 21 hours. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate), to thereby yield 4.59 g of the title compound.
Appearance: Yellow powder
1H NMR (CDCl3) δ 2.36-2.43 (4H, m), 2.64-2.70 (2H, m), 2.99-3.05 (2H, m), 3.42-3.46 (7H, m), 3.63-3.67 (2H, m), 3.77 (3H, s), 5.95 (2H, s), 6.12 (1H, brd, J=9.1 Hz), 6.70-6.77 (2H, m), 6.85-6.90 (3H, m), 7.12 (1H, d, J=8.1 Hz), 7.97-8.01 (1H, m), 9.11 (1H, d, J=2.6 Hz).
Reference Example 919
Production of 5-{methyl[2-oxo-2-(4-piperonylpiperazin-1-yl)ethyl]amino}-2-(5-nitropyridin-2-yloxy)-benzonitrile
To a solution of t-butyl 2-((3-cyano-4-(5-nitropyridin-2-yloxy)phenyl)(methyl)amino)acetate (1.2 g, 3.1 mmol) in dichloromethane (12 mL) was added trifluoroacetic acid (12 mL), and the resulting reaction solution was stirred at room temperature for 5 hours. The solvent was evaporated, and water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated, to thereby yield crude 2-((3-cyano-4-(5-nitropyridin-2-yloxy)phenyl)(methyl)amino)-acetic acid. To a solution of this compound in DMF (24 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (659 mg, 3.4 mmol), 1-hydroxybenzotriazole monohydrate (526 mg, 3.4 mmol) and 1-piperonylpiperazine (757 mg, 3.4 mmol), and the resulting reaction solution was stirred for 8 hours at room temperature. Water was added to the reaction solution and extracted with ethyl acetate. The ethyl acetate layer was then washed with, in order, saturated aqueous sodium bicarbonate solution, water and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel chromatography (ethyl acetate), to thereby yield 412 g of the title compound.
Appearance: Yellow amorphous powder
1H NMR (CDCl3) δ 2.40-2.55 (4H, m), 3.09 (3H, s), 3.45-3.50 (4H, m), 3.55-3.70 (2H, m), 4.14 (2H, s), 5.95 (2H, s), 6.70-6.80 (2H, m), 6.80-6.95 (3H, m), 7.10-7.20 (2H, m), 8.50 (1H, dd, J=9.1 Hz, 2.8 Hz), 8.99 (1H, d, J=2.8 Hz).
Reference Example 920
Production of 2-{(2,3-difluoro-4-t-butoxycarbonyl-amino)phenoxy}-5-nitropyridine
To a solution of {2,3-difluoro-4-(5-nitropyridin-2-yloxy)}benzoic acid (1.22 g, 4.1 mmol) in t-butanol (50 mL) were added diphenylphosphorylazide (0.98 mL, 4.5 mmol) and triethylamine (0.63 mL, 4.5 mmol), and the resulting solution was refluxed for 4 hours under a nitrogen atmosphere. After cooling, water was added to the reaction solution and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1), to thereby yield 1.2 g of the title compound.
Appearance: White powder
1H NMR (CDCl3) δ 1.54 (9H, s), 6.59-6.78 (1H, m), 6.90-7.04 (1H, m), 7.13 (1H, d, J=9.0 Hz), 7.84-8.02 (1H, m), 8.51 (1H, dd, J=2.8 Hz, 9.0 Hz), 8.99 (1H, d, J=2.8 Hz).
Reference Example 921
Production of 3,4-dichloro-N-[3-fluoro-4-(4-formylphenoxy)phenyl]benzamide
3,4-Dichloro-N-[4-(4-[1,3]dioxsolane-2-ylphenoxy)-3-fluorophenyl]benzamide (17.4 g, 38.9 mmol) was added to 80% acetic acid, and the resulting solution was stirred for 1.5 hours at 80° C. The reaction solution was concentrated under reduced pressure, wherein the obtained residue was recrystallized from 80% ethanol to thereby yield 12.8 g of the title compound.
Appearance: Pale yellow powder
1H NMR (DMSO-d6) δ 7.13 (2H, d, J=8.6 Hz), 3.40 (1H, t, J=9.0 Hz), 7.63 (1H, d, J=9.0 Hz), 7.85 (1H, d, J=8.4 Hz), 7.90-8.00 (4H, m), 8.22 (1H, d, J=1.9 Hz), 9.93 (1H, s), 10.67 (1H, s).
Reference Example 922
Production of N-[6-(4-aminophenoxy)pyridin-3-yl]-3,4-dichlorobenzamide dihydrochloride
t-Butyl{4-[5-(3,4-dichlorobenzoylamino)-pyridin-2-yloxy]phenyl}carbamate (4.31 g, 9.09 mmol) was dissolved in a mixed solution of chloroform-methanol-ethyl acetate. The resulting solution was concentrated to a volume of about 20 mL. To the residue solution was added a solution of 4 N hydrogen chloride in ethyl acetate (70 mL), and left to cool for 2 hours at room temperature. The precipitated white powder was filtered, and washed with ethyl acetate, to thereby yield 4.04 g of the title compound.
Appearance: White powder
1H NMR (DMSO-d6) δ 5.20 (2H, brs), 7.14 (1H, d, J=8.5 Hz), 7.25 (2H, d, J=8.9 Hz), 7.42 (2H, d, J=8.9 Hz), 7.84 (1H, d, J=8.5 Hz), 7.97 (1H, dd, J=8.5 Hz, 2.0 Hz), 8.24 (1H, dd, J=8.5 Hz, 2.6 Hz), 8.25 (1H, d, J=2.0 Hz), 8.51 (1H, d, J=2.6 Hz), 10.65 (1H, s).
The following compounds were produced in the same manner as in Reference Example 922.







TABLE 127













 













Reference








Example





1H NMR (CDCl3) δ ppm or


No.
R389
R390
R391
R392
R393
MS
















923
—F
—H
—F
—H
—CH3
1H NMR 2.83 (3H, d, J = 5.2








Hz), 3.90-4.05 (1H, m), 6.18-








6.27 (2H, m), 7.15 (1H, d, J =








9.0 Hz), 8.49 (1H, dd, J = 2.8








Hz, 9.0 Hz), 9.02 (1H, d, J =








2.8 Hz).


924
—F
—F
—H
—H
—CH3
1H NMR 2.92 (3H, d, J = 3.8








Hz), 3.90-4.16 (1H, m),








6.46 (1H, td, J = 22 Hz, 8.8








Hz), 6.89 (1H, td, J = 2.4 Hz,








7.8 Hz), 7.08 (1H, d, J = 9.0








Hz), 8.49 (1H, dd, J = 2.8 Hz,








9.0 Hz), 9.02 (1H, d, J = 28








Hz).


925
—COOCH3
—H
—H
—CH2COOH
—C2H5
MS 375(M+)









Reference Example 926
Production of 4-(tetrahydropyran-2-yloxy)benzylamine
To a solution of lithium aluminum hydride (2.66 g, 70 mmol) in THF (2.00 mL) was added dropwise under ice cooling a solution of 4-(tetrahydropyran-2-yloxy)benzonitrile in THF (70 mL). The resulting solution was then refluxed for 1 hour. The resulting reaction solution was again cooled with ice, and then to the solution was added dropwise, in order, water (2.66 mL), 1 N aqueous sodium hydroxide (2.66 mL) and water (7.98 mL). Insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure, after which the residue was purified by silica gel column chromatography (chloroform methanol 7:1), to thereby yield 11.41 g of the title compound.
Appearance: Colorless oil
1H NMR (CDCl3) δ 1.56 (2H, s), 1.45-1.78 (3H, m), 1.78-2.12 (3H, m), 3.53-3.66 (1H, m), 3.80 (2H, s), 3.84-3.99 (1H, m), 5.41 (1H, t, J=3.2 Hz), 7.02 (2H, d, J=8.7 Hz), 7.22 (2H, d, J=8.7 Hz).
Reference Example 927
Production of 4-(2-fluoro-4-nitrophenoxy)phenylamine hydrochloride
N-[4-(2-fluoro-4-nitrophenoxy)phenyl]-acetamide (1.00 g, 3.45 mmol) was added to 6 M hydrochloric acid (10 mL), and the resulting solution was refluxed for 2 hours. The resulting reaction solution was concentrated under reduced pressure, to thereby yield 0.910 g of the title compound.
Appearance: Pale yellow powder
1H-NMR (DMSO-d6) δ 3.40-4.00 (2H, m), 7.18 (1H, t, J=8.7 Hz), 7.24 (2H, d, J=8.9 Hz), 7.32 (2H, d, J=8.9 Hz), 8.10 (1H, ddd, J=1.4 Hz, 2.6 Hz, 8.9 Hz), 8.35 (1H, dd, J=2.6 Hz, 10.8 Hz).
Reference Example 928
Production of {4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]phenyl}carbamate phenyl ester
To a suspension of N-[6-(4-aminophenoxy)pyridin-3-yl]-3,4-dichlorobenzamide dihydrochloride (700 mg, 1.57 mmol) in THF (20 mL) was added triethylamine (1.1 mL, 7.89 mmol). To the resulting solution was then added dropwise phenyl chlorocarbonate (0.39 mL, 3.14 mmol) under ice cooling. The resulting reaction solution was stirred for 1 hour at room temperature. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated, whereupon the residue solidified into a powder. The powder was filtered, and washed with diethyl ether, to thereby yield 470 mg of the title compound.
Appearance: White powder
1H NMR (DMSO-d6) δ 7.04 (1H, d, J=8.9 Hz), 7.11 (2H, d, J=8.9 Hz), 7.19-7.31 (3H, m), 7.38-7.49 (2H, m), 7.53 (2H, d, J=8.0 Hz), 7.84 (1H, d, J=8.4 Hz), 7.95 (1H, dd, J=8.4 Hz, 2.0 Hz), 8.18 (1H, dd, J=8.9 Hz, 2.2 Hz), 8.22 (1H, d, J=2.0 Hz), 8.47 (1H, d, J=2.2 Hz), 10.26 (1H, s), 10.54 (1H, s).
The following compounds were produced in the same manner as in Reference Example 928.







TABLE 128













 










Reference





Example


No.
R394
M
1H NMR (solvent) δ ppm













929




0
(DMSO-d6) 7.08 (1H, t, J = 8.7 Hz), 7.15-7.30 (5H, m), 7.35-7.50 (2H, m), 7.60 (2H, d, J = 8.9 Hz), 8.07 (1H, dd, J = 1.1 Hz, 9.0 Hz), 8.31 (1H, dd, J = 2.6 Hz, 10.9 Hz), 10.36 (1H, s).


 


930




0
(CDCl3) 1.50-1.80 (3H, m), 1.80-2.15 (3H, m), 3.55- 3.67 (1H, m), 3.85-4.00 (1H, m), 5.37 (1H, t, J = 3.3 Hz), 6.83 (1H, brs), 7.03 (2H, d, J = 9.1 Hz) 7.14-7.30 (3H, m); 7.30-7.47 (4H, m).


 


931




1
(CDCl3) 1.50-1.79 (3H, m), 1.79-2.15 (3H, m), 3.55- 3.60 (1H, m), 3.82-4.00 (1H, m), 3.39 (2H, d, J = 6.0 Hz), 5.26 (1H, brs), 5.42 (1H, t, J = 3.1 Hz), 7.05 (2H, d, J = 8.7 Hz), 7.27 (2H, d, J = 8.7 Hz), 7.10-7.40 (5H, m).









Reference Example 932
Production of 4-piperonylpiperazine-1-carboxylic acid 4-(2-fluoro-4-nitrophenoxy)phenyl]amide
To a solution of [4-(2-fluoro-4-nitrophenoxy)phenyl]carbamate phenyl ester (0.700 g, 1.90 mmol) in DMF (15 mL) was added 1-piperonylpiperazine (0.460 g, 2.09 mmol), and the resulting solution was stirred for 2 hours at room temperature water was added to the resulting reaction solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, and evaporated, to thereby yield 0.939 g of the title compound.
Appearance: Yellow oil
1H NMR (DMSO-d6) δ 2.30-2.40 (4H, m), 3.35-3.50 (6H, m), 6.00 (2H, s), 6.70-6.90 (2H, m), 7.00-7.15 (2H, m), 7.55 (2H, d, J=9.1 Hz), 8.05-8.10 (1H, m), 8.30 (1H, dd, J=2.8 Hz, 10.9 Hz), 9.31 (1H, s).
The following compounds were produced in the same manner as in Reference Example 932.
Reference Example 933
Ethyl 3-(4-{5-[3-(3,4-dichlorophenyl)-3-ethylureido]-pyridin-2-yloxy}phenyl)propionate
MS 501 (M+).







TABLE 129













 










Reference





Example


No.
R395
M
1H NMR (CDCl3) δ ppm













934
benzyl
0
1.50-1.87 (3H, m), 1.87-2.15 (3H, m), 2.48 (4H, t, J = 5.1 Hz),





3.48 (4H, t, J = 5.1 Hz), 3.54 (2H, s), 3.50-3.65 (1H, m), 3.85-





4.00 (1H, m), 5.34 (1H, t, J = 3.2 Hz), 6.21 (1H, brs), 6.98 (2H,





d, J = 8.9 Hz), 7.22 (2H, d, J = 8.9 Hz), 7.25-7.38 (5H, m).


935
piperonyl
1
1.48-1.77 (3H, m), 1.77-2.11 (3H, m), 2.40 (4H, t, J = 5.0 Hz),





3.36 (4H, t, J = 5.0 Hz), 3.41 (2H, s), 3.50-1.67 (1H, m), 3.81-





3.96 (1H, m), 4.34 (2H, d, J = 5.1 Hz), 4.61 (1H, t, J =5.1 Hz),





5.40 (1H, t, J = 3.2 Hz), 5.94 (2H, s), 6.74 (2H, s), 6.84 (1H, s),





7.00 (2H, d, J = 8.6 Hz), 7.22 (2H, d, J = 8.6 Hz).









Reference Example 936
Production of 4-piperonylpiperazine-1-carboxylic acid 4-hydroxybenzylamide
To a solution of 4-piperonylpiperazine-1-carboxylic acid 4-(tetrahydropyran-2-yloxy)benzylamide (1.1 g, 2.43 mmol) in methanol (50 mL) was added p-toluenesulfonic acid monohydrate (1.0 g, 5.26 mmol), and the resulting solution was stirred for 1 hour at room temperature. The resulting reaction solution was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated, to thereby yield 330 mg of the title compound.
Appearance: White powder
1H NMR (CDCl3) δ 2.41 (4H, t, J=5.0 Hz), 3.37 (4H, t, J=5.0 Hz), 3.42 (2H, s), 4.32 (2H, d, J=5.2 Hz), 4.68 (1H, t, J=5.2 Hz), 5.94 (2H, s), 6.15 (1H, brs), 6.70-6.80 (2H, m), 6.75 (2H, d, J=8.6 Hz), 6.84 (1H, s), 7.13 (2H, d, J=8.6 Hz).
The following compound was produced in the same manner as in Reference Example 936.
Reference Example 937
4-Benzylpiperazine-1-carboxylic acid (4-hydroxyphenyl)methylamide hydrochloride
1H NMR (DMSO-d6) δ 2.69-2.91 (2H, m), 3.03 (3H, s), 2.92-3.23 (4H, m), 3.68 (2H, d, J=13.7 Hz), 4.26 (2H, s), 6.75 (2H, d, J=8.7 Hz), 6.98 (2H, d, J=8.7 Hz), 7.45 (3H, brs), 7.54 (2H, brs), 9.52 (1H, s).
Reference Example 938
Production of 3,4-dichloro-N-{6-[4-(3-hydroxypropyl)-phenoxy]pyridin-3-yl}benzamide
To 2-{4-[3-(t-butyldimethylsilanyloxy)propyl]phenoxy}-5-nitropyridine (950 mg, 1.8 mmol) were added acetic acid (10 mL) and water (5 mL), and the resulting solution was stirred for 1 hour at room temperature. The resulting reaction solution was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was recrystallized from ethyl acetate, to thereby yield 520 mg of the title compound.
Appearance: White prisms
1H NMR (DMSO-d6) δ 1.70-1.78 (2H, m), 2.59-2.65 (2H, m), 3.32-3.47 (2H, m), 4.46-4.49 (1H, m), 7.00-7.05 (3H, m), 7.23 (2H, d, J=8.2 Hz), 7.84 (1H, d, J=8.2 Hz), 7.95 (1H, dd, J=8.3 Hz, 2.0 Hz), 8.16-8.22 (2H, m), 8.48 (1H, d, J=2.6 Hz), 10.54 (1H, s).
The following compound was produced in the same manner as in Reference Example 938.
Reference Example 939
3,4-Dichloro-N-{6-[4-(2-hydroxyethyl)phenoxy]pyridin-3-yl}benzamide
1H NMR (DMSO-d6) δ 2.73 (2H, t, J=6.9 Hz), 3.59-3.66 (2H, m), 4.65 (1H, t, J=5.3 Hz), 7.00-7.06 (3H, m), 7.25 (2H, d, J=8.3 Hz), 7.84 (1H, d, J=8.3 Hz), 7.95 (1H, dd, J=8.3 Hz, 2.0 Hz), 8.16-8.23 (2H, m), 8.47 (1H, d, J=2.6 Hz), 10.54 (1H, s).
Reference Example 940
Production of 3,4-dichloro-N-{6-[4-(5-hydroxypentyl)-phenoxy]pyridin-3-yl}benzamide
To a solution of ethyl 5-{4-[5-(3,4-dichloro-benzoylamino)pyridin-2-yloxy]phenyl}pentanoate (8.79 g, 18.0 mmol) in THF (140 mL) was added sodium borohydride (3.14 g, 144 mmol), and the resulting solution was refluxed for 3 hours under a nitrogen atmosphere. The resulting reaction solution was cooled with ice, and treated with 1 N hydrochloric acid. The resulting solution was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:2), to thereby yield 7.07 g of the title compound.
Appearance: White powder
1H NMR (CDCl3) δ 1.25-1.75 (7H, m), 2.62 (2H, t, J=7.6 Hz), 3.65 (2H, t, J=6.6 Hz), 6.92 (1H, d, J=8.5 Hz), 7.02 (2H, d, J=8.5 Hz), 7.19 (2H, d, J=8.5 Hz), 7.56 (1H, d, J=8.5 Hz), 7.69 (1H, dd, J=8.5 Hz, 2.0 Hz), 7.93 (1H, s), 7.97 (1H, d, J=2.0 Hz), 8.15 (1H, dd, J=8.5 Hz, 2.5 Hz), 8.22 (1H, d, J=2.5 Hz).
The following compounds were produced in the same manner as in Reference Example 940.







TABLE 130













 









Reference




Example


No.
M
mp (° C.)












941
1
162-163


942
2
104-105


943
3
111-113


944
4
102-104
















TABLE 131













 











Reference






Example


No.
R396
R397
M
1H NMR (DMSO-d6) δ ppm














945
—Cl
—Cl
1
4.49 (2H, d, J = 5.6 Hz), 5.17 (1H, brs), 7.03-7.08 (3H, m),






7.35 (2H, d, J = 8.6 Hz), 7.84 (1H, d, J = 8.6 Hz), 7.93-






7.97 (1H, m), 8.17-8.22 (2H, m), 8.47 (1H, d, J = 2.6 Hz),






10.53 (1H, s).


946
—CF3
—H
1
4.50 (2H, d, J = 5.7 Hz), 5.18 (1H, t, J = 5.7 Hz), 7.04-






7.09 (3H, m), 7.35 (2H, d, J = 8.4 Hz), 7.93 (2H, d, J = 8.4






Hz), 8.15-8.24 (3H, m), 8.50 (1H, d, J = 2.7 Hz), 10.61 (1H,






s).


947
—Cl
—Cl
4
1.35-1.70 (4H, m), 2.59 (2H, t, J = 7.5 Hz), 3.42 (2H, q, J =






6.0 Hz), 4.37 (1H, t, J = 5.5 Hz), 7.02 (2H, d, J = 8.2 Hz),






7.04 (1H, d, J = 8.6 Hz), 7.22 (2H, d, J = 8.2 Hz), 7.84 (1H,






d, J = 8.2 Hz), 7.94 (1H, dd, J = 8.2 Hz, 2.0 Hz), 8.18 (1H,






dd, J = 8.9 Hz, 2.6 Hz), 8.22 (1H, d, J = 2.0 Hz), 8.47 (1H,






d, J = 2.6 Hz), 10.53 (1H, s).









Reference Example 948
Production of 4-cyano-N-[6-(4-hydroxymethylphenoxy)-pyridin-3-yl]benzamide
A suspension of 4-[5-(4-cyanobenzoylamino)-pyridin-2-yloxy]benzoic acid (1.80 g, 5.01 mmol) in THF (20 mL) was cooled with ice-common salt, and to the solution was added triethylamine (0.77 mL, 5.51 mmol), and then ethyl chlorformate (0.53 mL, 5.51 mmol). The resulting solution was stirred at room temperature. Thirty minutes later, the reaction solution was filtered and insoluble matter was removed. The resulting filtrate was poured while stirring under ice cooling into an aqueous solution of sodium borohydride (0.95 g, 25.05 mmol) in 80% methanol (40 mL). After stirring for 30 minutes at room temperature, water (200 mL) was added to the reaction solution. The obtained mixture was extracted with ethyl acetate (200 mL). The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was recrystallized from a mixed solution of ethyl acetate-n-hexane, to thereby yield 1.26 g of the title compound.
Appearance: Slightly yellow powder
1H NMR (DMSO-d6) δ 4.50 (2H, d, J=5.3 Hz), 5.19 (1H, t, J=5.6 Hz), 7.04-7.09 (3H, m), 7.35 (2H, d, J=8.6 Hz), 8.04 (2H, d, J=8.9 Hz), 8.12 (2H, d, J=8.6 Hz), 8.21 (1H, dd, J=8.9 Hz, 2.6 Hz), 8.49 (1H, d, J=2.3 Hz), 11.63 (1H, s).
The following compounds were produced in the same manner as in Reference Example 948.
Reference Example 949
4-Chloro-N-[6-(4-hydroxymethylphenoxy)pyridin-3-yl]benzamide
1H NMR (DMSO-d6) δ 4.50 (2H, d, J=5.3 Hz), 5.18 (1H, t, J=5.6 Hz), 7.03-7.08 (3H, m), 7.35 (2H, d, J=8.6 Hz), 7.63 (2H, d, J=8.6 Hz), 8.00 (2H, d, J=8.6 Hz), 8.20 (1H, dd, J=8.9 Hz, 2.6 Hz), 8.48 (1H, d, J=2.3 Hz), 10.46 (1H, s).







TABLE 132













 










Reference





Example


No.
R398
R399
1H NMR (CDC13) δ ppm













950
—H
—NO2
4.71 (2H, s), 7.05 (1H, d, J = 8.4 Hz), 7.25 (2H, d, J = 8.9 Hz), 7.83 (1H, dd, J = 8.3 Hz, 2.3 Hz), 8.19 (1H, d, J = 2.5 Hz), 8.27 (2H, d, J = 8.9 Hz).


 


951
—CH3
—NO2
2.30 (4H, brs), 4.67 (2H, s), 7.02 (1H, d, J = 8.41 Hz,), 7.12 (1H, d, J = 8.90 Hz), 7.80 (1H, dd, J = 8.41 Hz, 2.47 Hz), 8.05-8.17 (3H, m).


 


952
—H




2.45 (4H, brs), 3.45 (2H, s), 3.57 (2H, brs), 3.69 (2H, brs), 4.67 (2H, s), 5.95 (2H, s), 6.74-6.77 (2H, m), 6.85 (1H, s), 6.94 (1H, d, J = 8.4 Hz), 7.14 (2H, d, J  8.4 Hz), 7.44 (2H, d, J = 8.4 Hz), 7.76 (1H, dd, J = 2.5 Hz, 8.4 Hz), 8.16 (1H, d, J = 2.5 Hz).


 


953
—H




1.96 (1H, brs), 2.40-2.44 (4H, m), 3.02 (3H, s), 3.43 (2H, brs), 3.47- 3.49 (2H, m), 3.62 (2H, brs), 4.07 (2H, s), 4.62 (2H, s), 5.94 (2H, s), 6.68- 6.77 (4H, m), 6.81 (1H, d, J = 8.6 Hz), 6.85 (1H, brs), 6.99 (2H, d, J = 9.2 Hz), 7.66 (1H, dd, J = 8.4 Hz, 2.5 Hz), 8.13 (1H, d, J = 2.5 Hz).


 


954
—H




1.75-2.01 (1H, m), 2.22-2.50 (4H, m), 2.51-2.70 (2H, m), 2.88-3.07 (2H, m), 3.30-3.51 (4H, m), 3.52-3.78 (2H, m), 4.67 (2H, s), 5.96 (2H, s), 6.69- 6.81 (2H, m), 6.83-6.88 (1H, m), 6.91 (1H, d, J = 8.4 Hz), 7.01-7.11 (2H, m), 7.19-7.29 (2H, m), 7.74 (1H, dd, J = 2.5 Hz, 8.4 Hz), 8.16 (1H, dd, J = 0.5 Hz, 2.5 Hz).









Reference Example 955
Production of 2-[4-(1-bromoethyl)phenoxy]-5-nitropyridine
2-(4-ethylphenoxy)-5-nitropyridine (7.33 g, 30 mmol) was dissolved in carbon tetrachloride (100 mL), and to the resulting solution were added N-bromosuccimide (5.34 g, 30 mmol) and benzoyl peroxide (0.73 g, 3 mmol). This solution was refluxed overnight under a nitrogen atmosphere. The reaction solution was allowed to cool, after which insoluble matter was removed by filtration. The resulting filtrate was washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to thereby yield 1.34 g of the title compound.
Appearance: White powder
1H NMR (CDCl3) δ 2.08 (3H, d, J=6.9 Hz), 5.26 (1H, q, J=6.9 Hz), 7.05 (1H, d, J=9.1 Hz), 7.15 (2H, d, J=8.6 Hz), 7.53 (2H, d, J=8.7 Hz), 8.49 (1H, dd, J=9.1 Hz, 2.8 Hz), 9.04 (1H, d, J=2.8 Hz).
Reference Example 956
Production of N-[6-(4-chloromethylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide
To a solution of N-[6-(4-hydroxymethylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide (3.06 g, 7.9 mmol) in dichloromethane (90 mL) was added thionyl chloride (1.7 mL, 23.3 mmol), and the resulting solution was stirred for 4 hours at room temperature. To the residue was added a saturated sodium bicarbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was washed with diethyl ether, to thereby yield 2.95 g of the title compound.
Appearance: White powder
1H NMR (CDCl3) δ 4.61 (2H, s), 7.00 (1H, d, J=8.9 Hz), 7.11-7.14 (2H, m), 7.41-7.44 (2H, m), 7.77 (2H, d, J=8.4 Hz), 7.89 (1H, brs), 8.00 (2H, d, J=8.4 Hz), 8.22-8.28 (2H, m).
The following compounds were produced in the same manner as in Reference Example 956.
Reference Example 957
3,4-Dichloro-N-[4-(4-chloromethylphenoxy)-3-fluorophenyl]benzamide
1H NMR (CDCl3) δ 4.58 (2H, s), 6.95 (2H, d, J=8.6 Hz), 7.10 (1H, t, J=8.6 Hz), 7.20-7.30 (1H, m), 7.30-7.40 (3H, m), 7.59 (1H, d, J=8.3 Hz), 7.65-7.78 (2H, m), 7.96 (1H, d, J=2.1 Hz).







TABLE 133













 










Reference





Example No.
R400
R401
1H NMR (CDCl3) δ ppm





958
—NO2
CH2Cl
4.63 (2H, s), 7.06 (1H, d, J = 8.9





Hz), 7.16 (2H, dd, J = 6.6 Hz, 2.0





Hz), 7.47 (2H, d, J = 8.3 Hz),





8.47-8.51 (1H, m), 9.04 (1H, d, J =





2.6 Hz)


959
3,4-
—CH2Cl
4.59 (2H, s), 6.95 (1H, d, J = 8.9



Cl2PhCONH—

Hz), 7.10 (2H, d, J = 8.6 Hz), 7.40





(2H, d, J = 8.6 Hz), 7.54 (1H, d, J =





8.2 Hz), 7.71-7.75 (1H, m), 7.99





(1H, d, J = 2.3 Hz), 8.18-8.22





(2H, m), 8.30 (1H, d, J = 2.6 Hz).


960
4-CNPhCONH—
—CH2Cl
4.60 (2H, s), 6.99 (1H, d, J = 8.9





Hz), 7.12 (2H, d, J = 8.6 Hz), 7.42





(2H, d, J = 8.6 Hz), 7.79 (2H, d, J =





8.3 Hz), 7.97-8.00 (3H, m), 8.21





(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.27





(1H, d, J = 2.6 Hz).


961
4-ClPhCONH—
—CH2Cl
4.61 (2H, s), 6.99 (1H, d, J = 9.6





Hz), 7.12 (2H, d, J = 8.3 Hz), 7.42





(2H, d, J = 8.3 Hz), 7.48 (2H, d, J =





8.3 Hz), 7.75 (1H, brs), 7.85 (2H, d,





J = 8.3 Hz), 8.20-8.25 (2H, m).


 


962
—CH2Cl




2.41-2.45 (4H, m), 3.03 (3H, s), 3.43 (2H, brs), 3.49 (2H, brs), 3.63 (2H, brs), 4.08 (2H, s), 4.54 (2H, s), 5.94 (2H, s), 6.70 (2H, d, J = 9.2 Hz), 6.73-6.77 (2H, m), 6.82 (1H, d, J = 8.6 Hz), 6.85 (1H, brs), 7.00 (2H, d, J = 9.2 Hz), 7.67 (1H, dd, J = 8.6 Hz, 2.5 Hz), 8.15 (1H, d, J = 2.5 Hz).





(CNPh means a cyanophenyl group. Hereinafter CNPh indicates the same meaning.)






Reference Example 963
Production of 3,4-dichloro-N-{6-[4-(5-chloropentyl)-phenoxy]pyridin-3-yl}benzamide hydrochloride
To 3,4-dichloro-N-{6-[4-(5-hydroxypentyl)-phenoxy]pyridin-3-yl}benzamide (6.83 g, 15.34 mmol) was added thionyl chloride (35 mL). The resulting solution was stirred for 20 minutes at room temperature, followed by stirring for 1 hour at 50° C. Excess thionyl chloride was evaporated, after which to the resulting residue was added ethyl acetate (100 mL). The obtained white powder was filtered, and washed with ethyl acetate, to thereby yield 6.98 g of the title compound.
Appearance: White powder
1H NMR (DMSO-d6) δ 1.33-1.50 (2H, m), 1.50-1.68 (2H, m), 1.68-1.85 (2H, m), 2.59 (2H, t, J=7.6 Hz), 3.64 (2H, t, J=6.6 Hz), 7.02 (2H, d, J=8.5 Hz), 7.03 (1H, d, J=9.0 Hz), 7.23 (2H, d, J=8.5 Hz), 7.83 (1H, d, J=8.5 Hz), 7.97 (1H, dd, J=8.5 Hz, 2.0 Hz), 8.20 (1H, dd, J=9.0 Hz, 2.5 Hz), 8.25 (1H, d, J=2.0 Hz), 8.50 (1H, d, J=2.5 Hz), 10.63 (1H, s).
The following compounds were produced in the same manner as in Reference Example 963.







TABLE 134













 












Reference







Example No.
R402
R403
M
Form
1H NMR (solvent) δ ppm





964
—Cl
—Cl
2
free
(CDCl3) 3.04-3.10 (2H, m), 3.69-3.75 (2H,







m), 6.95 (1H, d, J = 8.6 Hz), 7.06-7.09 (2H,







m), 7.24 (2H, d, J = 8.2 Hz), 7.56 (1H, d, J =







8.2 Hz), 7.69 (1H, dd, J = 8.2 Hz, 2.0 Hz),







7.93 (1H, brs), 7.97 (1H, d, J = 2.0 Hz), 8.15-







8.19 (1H, m), 8.24 (1H, d, J = 2.6 Hz).


965
—Cl
—Cl
3
free
(CDCl3) 2.04-2.12 (2H, m), 2.76-2.81 (2H,







m), 3.53-3.58 (2H, m), 6.94 (1H, d, J = 8.9







Hz), 7.04-7.07 (2H, m), 7.20-7.26 (2H, m),







7.56 (1H, d, J = 8.1 Hz), 7.70 (1H, dd, J =







8.4 Hz, 2.2 Hz), 7.90 (1H, brs), 7.97 (1H, d,







J = 2.2 Hz), 8.14-8.18 (1H, m), 8.24 (1H, d,







J = 2.7 Hz).


966
—CF3
—H
3
free
(CDCl3) 2.04-2.14 (2H, m), 2.75-2.81 (2H,







m), 3.53-3.57 (2H, m), 6.93 (1H, d, J = 8.7







Hz), 7.03-7.07 (2H, m), 7.20-7.23 (2H, m),







7.73 (2H, d, J = 8.2 Hz), 7.97 (2H, d, J = 8.2







Hz), 8.09 (1H, brs), 8.16-8.21 (1H, m),







8.25 (1H, d, J = 2.6 Hz).


967
—Cl
—Cl
4
hydrochloride
(DMSO-d6) 1.60-1.85 (4H, m), 2.62 (2H, t, J =







6.3 Hz), 3.68 (2H, t, J = 6.3 Hz), 7.03 (2H,







d, J = 8.5 Hz), 7.04 (1H, d, J = 9.0 Hz),







7.24 (2H, d, J = 8.5 Hz), 7.83 (1H, d, J = 8.6







Hz), 7.97 (1H, dd, J = 8.6 Hz, 2.0 Hz),







8.20 (1H, dd, J = 9.0 Hz, 2.7 Hz), 8.25 (1H,







d, J = 2.2 Hz), 8.50 (1H, d, J = 2.7 Hz),







10.64 (1H, s).









Reference Example 968
Production of N-{6-[4-(2-bromoacetyl)phenoxy]pyridin-3-yl}-3,4-dichlorobenzamide
N-[6-(4-acetylphenoxy)pyridin-3-yl}-3,4-dichlorobenzamide (4.0 g, 10 mmol) was dissolved in chloroform (200 mL). To the resulting solution was added copper bromide (5.76 g, 25 mmol), and refluxed overnight. The resulting reaction solution was filtered, and the filtrate was washed with saturated sodium thiosulfate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. To the filtered product from the earlier step was added ethyl acetate, and washed with saturated sodium thiosulfate water and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residues were combined for purification by silica gel column chromatography (n-hexane:ethyl acetate=3:1), to thereby yield 1.86 g of the title compound.
Appearance: White powder
1H NMR (CDCl3) δ 4.43 (2H, s), 7.06 (1H, d, J=8.7 Hz), 7.21 (2H, d, J=8.9 Hz), 7.57 (1H, d, J=8.4 Hz), 7.72 (1H, dd, J=8.4 Hz, 2.0 Hz), 7.99 (1H, d, J=2.0 Hz), 8.03 (2H, d, J=8.9 Hz), 8.09 (1H, brs), 8.27 (1H, dd, J=8.7 Hz, 2.8 Hz), 8.32 (1H, d, J=2.2 Hz).
The following compound was produced in the same manner as in Reference Example 968.
Reference Example 969
N-{4-[4-(2-Bromoacetyl)phenoxy]-3-fluorophenyl}-3,4-dichlorobenzamide
1H NMR (DMSO-D6) δ 4.88 (2H, s), 7.06 (2H, d, J=8.9 Hz), 7.30-7.50 (1H, m), 7.60-7.70 (1H, m), 7.80-8.20 (5H, m), 8.22 (1H, d, J=2.0 Hz), 10.67 (1H, brs).
Reference Example 970
Production of 4′-[4-(3-bromopropyl)phenoxy]-3,4-dichloro-3′-fluorobenzanilide
To a suspension of 3,4-dichloro-3′-fluoro-4′-[4-(3-hydroxypropyl)phenoxy]benzanilide (2.32 g, 5.34 mmol) in dichloromethane (46 mL) were added carbon tetrabromide (2.13 g, 6.41 mmol) and triphenylphosphine (1.54 g, 5.88 mmol), and the resulting solution was stirred for 12 hours at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to thereby yield 2.41 g of the title compound.
Appearance: White powder
1H NMR (CDCl3) δ 2.08-2.11 (2H, m), 2.73 (2H, t, J=7.3 Hz), 3.38 (2H, t, J=6.5 Hz), 6.88 (2H, d, J=8.5 Hz), 7.02 (1H, dd, J=9.0 Hz, 8.0 Hz), 7.13 (2H, d, J=8.5 Hz), 7.17-7.28 (1H, m), 7.54 (1H, d, J=8.3 Hz), 7.60-7.74 (2H, m), 7.85 (1H, brs), 7.93 (1H, d, J=2.0 Hz).
The following compounds were produced in the same manner as in Reference Example 970.







TABLE 135













 









Reference




Example No.
M
1H NMR (CDCl3) δ ppm





971
2
3.13 (2H, t, J = 7.5 Hz), 3.55 (2H, t, J = 7.5 Hz),




6.91 (2H, d, J = 6.6 Hz), 7.08 (1H, t, J = 8.7 Hz),




7.15 (2H, d, J = 6.6 Hz), 7.18-7.25 (1H, m), 7.56 (1H,




d, J = 8.3 Hz), 7.65-7.75 (2H, m), 7.90-8.00 (2H, m).


972
4
1.67-1.79 (2H, m), 1.81-1.94 (2H, m), 2.60 (2H, t, J =




7.5 Hz), 3.40 (2H, t, J = 6.6 Hz), 6.88 (2H, d, J = 8.6




Hz), 7.02 (1H, dd, J = 9.0 Hz, 8.0 Hz), 7.11 (2H, d,




J = 8.6 Hz), 7.14-7.21 (1H, m), 7.55 (1H, d, J = 8.3




Hz), 7.60-7.73 (2H, m), 7.78 (1H, brs), 7.93 (1H, d,




J = 1.9 Hz).









Reference Example 973
Production of t-butyl 4-[4-(5-nitropyridin-2-yloxy)benzyl]piperazine-1-carboxylate
To a solution of 2-(4-chloromethylphenoxy)-5-nitropyridine (12.32 g, 47 mmol) in DMF (120 mL) were added triethylamine (19.4 mL, 140 mmol) and t-butyl piperazine-1-carboxylate 11.27 g, 61 mmol), and the resulting solution was stirred for 3 hours at 50° C. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1), to thereby yield 11.26 g of the title compound.
Appearance: Yellow powder
1H NMR (CDCl3) δ 1.46 (9H, s), 2.40-2.44 (4H, m), 3.43-3.46 (4H, m), 3.54 (2H, s), 7.04 (1H, d, J=8.9 Hz), 7.09-7.14 (2H, m), 7.38-7.44 (2H, m), 8.48 (1H, dd, J=8.9 Hz, 2.8 Hz), 9.05 (1H, d, J=2.8 Hz).
The following compound was produced in the same manner as in Reference Example 973.
Reference Example 974
4-{1-[4-(5-Nitropyridin-2-yloxy)phenyl]ethyl}morpholine
1H NMR (CDCl3) δ 1.38 (3H, d, J=6.8 Hz), 2.36-2.54 (4H, m), 3.37 (1H, q, J=6.8 Hz), 3.69-3.72 (4H, m), 7.02 (1H, dd, J=9.1 Hz, 0.5 Hz), 7.11 (2H, d, J=8.6 Hz), 7.40 (2H, d, J=8.5 Hz), 8.47 (1H, dd, J=9.1 Hz, 2.8 Hz), 9.06 (1H, dd, J=2.8 Hz, 0.5 Hz).
Reference Example 975
Production of methanesulfonic acid 6-(4-nitrophenoxy)-pyridin-3-ylmethyl ester
[6-(4-nitrophenoxy)pyridin-3-yl]methanol (6.1 g, 24.8 mmol) was dissolved in dichloromethane (150 mL), and to the resulting solution was added triethylamine (4.15 mL, 29.8 mmol) under ice cooling. To the resulting solution was added dropwise methanesulfonic acid chloride (2.11 mL, 27.3 mmol), and then stirred under a nitrogen atmosphere for 30 minutes at 0° C. The reaction solution was washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. To the residue was added a mixed solvent (50 mL) of n-hexane ethyl acetate=1:1. The precipitated crystals were removed by suction filtration, to thereby yield 7.9 g of the title compound.
Appearance: White powder
1H NMR (CDCl3) δ 3.04 (3H, s), 5.23 (2H, s), 7.09 (1H, d, J=8.4 Hz), 7.29 (2H, d, J=9.1 Hz), 7.88 (1H, dd, J=8.4 Hz, 2.5 Hz), 8.23 (1H, d, J=2.3 Hz), 8.28 (2H, d, J=9.1 Hz).
The following compounds were produced in the same manner as in Reference Example 975.







TABLE 136













 










Reference





Example No.
R404
R405
1H NMR (CDCl3) δ ppm





976
—CH3
—NO2
2.29 (3H, s), 3.03 (3H, s), 5.22 (2H, s),





7.08 (1H, dd, J = 8.4 Hz, 0.5 Hz), 7.18 (1H,





d, J = 8.9 Hz), 7.86 (1H, dd, J = 8.4 Hz, 2.5





Hz), 8.11 (1H, dd, J = 8.9 Hz, 2.8 Hz),





8.17 (1H, dd, J = 2.5 Hz, 0.5 Hz), 8.19 (1H,





d, J = 2.8 Hz).


 


977
—H




2.65 (4H, brs), 3.01 (3H, s), 3.65-3.75 (6H, m), 5.22 (2H, s), 5.97 (2H, s), 6.79 (2H, s), 6.92 (1H, s), 7.00 (1H, d, J = 8.4 Hz), 7.18 (2H, d, J = 8.6 Hz), 7.47 (2H, d, J = 8.7 Hz), 7.81 (1H, dd, J = 2.5 Hz, 8.4 Hz), 8.20 (1H, d, J = 2.0 Hz).









Reference Example 978
Production of 2-(4-nitrophenoxy)-5-(4-trifluoromethyl-phenoxymethyl)pyridine
Methanesulfonic acid 6-(4-nitrophenoxy)-pyridin-3-ylmethyl ester (4.86 g, 15 mmol) was dissolved in DMF (250 mL), and to the resulting solution were added 4-hydroxybenzotrifluoride (2.92 g, 18 mmol) and potassium carbonate (3.11 g, 22.5 mmol). The resulting solution was stirred under a nitrogen atmosphere for 1 hour at 50° C. The reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate, and washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane methanol=80:1), to thereby yield 5.8 g of the title compound.
Appearance: Pale yellow powder
1H NMR (CDCl3) δ 5.09 (2H, s), 7.02-7.10 (3H, m), 7.26-7.31 (2H, m), 7.56-7.59 (2H, m), 7.88 (1H, dd, J=8.4 Hz, 2.5 Hz), 8.25-8.31 (3H, m).
The following compound was produced in the same manner as in Reference Example 978.
Reference Example 979
2-(2-Methyl-4-nitrophenoxy)-5-(4-trifluoromethyl-phenoxymethyl)pyridine
1H NMR (CDCl3) δ 2.31 (3H, s), 5.07 (2H, s), 7.03 (2H, d, J=8.6 Hz), 7.08 (1H, d, J=8.4 Hz), 7.17 (1H, d, J=8.9 Hz), 7.57 (2H, d, J=8.4 Hz), 7.87 (1H, dd, J=8.4 Hz, 2.5 Hz), 8.10 (1H, dd, J=8.9 Hz, 2.8 Hz), 8.18 (1H, d, J=2.6 Hz), 8.21 (1H, d, J=2.5 Hz).
Example 1
Production of N-{6-[4-(4-benzylpiperazine-1-carbonyl)-phenoxy]pyridin-3-yl}-4-trifluoromethylbenzamide
To a solution of 4-[5-(4-trifluoromethyl-benzoylamino)pyridin-2-yloxy]benzoic acid (1.19 g, 2.3 mmol) in DMF (30 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (530 mg, 2.8 mmol), 1-hydroxybenzotriazole monohydrate (370 mg, 2.7 mmol) and benzylpiperazine (0.475 mL, 2.7 mmol) under ice cooling. The resulting solution was stirred for 1 day gradually warming up to room temperature. To the residue was added a saturated sodium bicarbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (methanol:chloroform=1:19), to thereby yield 800 mg of the title compound.
Appearance: White needles
1H NMR (CDCl3) δ 2.46 (4H, brs), 3.55 (2H, s), 3.72 (4H, brs), 6.96 (1H, d, J=8.9 Hz), 7.10-7.13 (2H, m), 7.28-7.40 (7H, m), 7.74 (2H, d, J=8.3 Hz), 8.02 (2H, d, J=8.3 Hz), 8.16-8.21 (1H, m), 8.32 (1H, d, J=2.6 Hz), 8.53 (1H, brs).
The following compounds were produced in the same manner as in Example 1.







TABLE 137













 











Example






No.
R501
R502
Form
mp (° C.)





2
—H
—CH3
hydrochloride
175-176


3
—H
benzyl
hydrochloride
187-189


4
—H
piperonyl
free
182-183


5
—H
—COOC(CH3)3
free
217-220


6
—H
-Ac
free
152-154


7
—H
—(CH2)2OH
hydrochloride
153-155


8
—F
benzyl
free
172-173


9
—F
piperonyl
free
170-171
















TABLE 138













 











Example






No.
R503
R504
Form
mp (° C.)





10
—H
morpholino
free
189-192


11
—F
morpholino
free
203-204


 


12
—F




free
210-211


 


13
—F




hydrochloride
233-235


 


14
—F




hydrochloride
247-249


 


15
—H




free
174-175


 


16
—H




hydrochloride
213-216
















TABLE 139













 










Example





No.
R505
R506
1H NMR (DMSO-d6) δ ppm





17
—CH3
—NHAc
1.92 (3H, s), 2.17 (3H, s), 7.13





(1H, d, J = 8.2 Hz), 7.14 (1H, d,





J = 8.9 Hz), 7.74 (1H, dd,





J = 8.2 Hz, 2.2 Hz), 7.84 (1H, d,





J = 8.2 Hz), 7.84 (1H, d, J = 2.2





Hz), 7.95 (1H, dd, J = 8.2 Hz,





2.2 Hz), 8.22 (1H, d, J = 2.2





Hz), 8.23 (1H, dd, J = 8.9 Hz,





2.6 Hz), 8.46 (1H, d, J = 2.6





Hz), 9.89 (1H, s), 10.24 (1H, s),





10.57 (1H, s).


18
—H
cyclopropyl
0.51-0.60 (2H, m), 0.66-0.74





(2H, m), 2.80-2.89 (1H, m),





7.10-7.20 (3H, m), 7.81-7.89





(3H, m), 7.95 (1H, dd, J = 8.4





Hz, 2.1 Hz), 8.19-8.28 (2H, m),





8.42 (1H, brd), 8.52 (1H, d,





J = 2.7 Hz), 10.59 (1H, s).


19
—H
cyclohexyl
1.06-1.19 (1H, m), 1.21-1.36





(4H, m), 1.55-1.65 (1H, m),





1.69-1.78 (2H, m), 1.78-1.87





(2H, m), 3.69-3.80 (1H, m),





7.10-7.20 (3H, m), 7.85 (1H, d,





J = 8.4 Hz), 7.86-7.92 (2H, m),





7.95 (1H, dd, J = 8.4 Hz, 2.1





Hz), 8.17 (1H, brd), 8.20-8.29





(2H, m), 8.52 (1H, d, J = 2.7





Hz), 10.58 (1H, s).


20
—H
cyclopentyl
1.46-1.60 (4H, m), 1.63-1.76





(2H, m), 1.82-1.94 (2H, m),





4.17-4.28 (1H, m), 7.10-7.20





(3H, m), 7.85 (1H, d, J = 8.4





Hz), 7.87-7.92 (2H, m), 7.95





(1H, dd, J = 8.4 Hz, 2.1 Hz),





8.19-8.28 (3H, m), 8.52 (1H, d,





J = 2.6 Hz), 10.58 (1H, s).


21
—H
cycloheptyl
1.36-1.71 (10H, m), 1.80-1.90





(2H, m), 3.88-4.00 (1H, m),





7.10-7.20 (3H, m), 7.85 (1H, d,





J = 8.4 Hz), 7.86-7.92 (2H, m),





7.95 (1H, dd, J = 8.4 Hz, 2.1





Hz), 8.17-8.28 (3H, m), 8.51





(1H, d, J = 2.6 Hz), 10.58 (1H,





s).


22
—H
cyclododecanyl
1.20-1.57 (20H, m), 1.61-1.63





(2H, m), 4.08-4.21 (1H, m),





7.10-7.21 (3H, m), 7.85 (1H, d,





J = 8.4 Hz), 7.88-7.92 (2H, m),





7.95 (1H, dd, J = 8.4 Hz, 2.1





Hz), 8.09 (1H, brd), 8.20-8.29





(2H, m), 8.51 (1H, d, J = 2.7





Hz), 10.58 (1H, s).


23
—H
cyclooctyl
1.44-1.65 (8H, m), 1.65-1.80





(6H, m), 3.98-4.09 (1H, m),





7.10-7.20 (3H, m), 7.85 (1H, d,





J = 8.4 Hz), 7.88-7.92 (2H, m),





7.95 (1H, dd, J = 8.4 Hz, 2.1





Hz), 8.17-8.27 (3H, m), 8.51





(1H, d, J = 2.7 Hz), 10.58 (1H,





s).


24
—H
cyclopropyl-methyl
0.19-0.26 (2H, m), 0.38-0.47





(2H, m), 0.99-1.09 (1H, m),





3.12-3.19 (2H, m), 7.12-7.21





(3H, m), 7.85 (1H, d, J = 8.4





Hz), 7.89-7.94 (2H, m), 7.95





(1H, dd, J = 8.4 Hz, 2.1 Hz),





8.21-8.29 (2H, m), 8.53 (1H, d,





J = 2.8 Hz), 8.54 (1H, brt),





10.60 (1H, s).


25
—H
—(CH2)2NHAc
1.81 (3H, s), 3.15-3.24 (2H, m),





3.24-3.33 (2H, m), 7.10-7.20





(3H, m), 7.80-8.00 (5H, m),





8.20-8.26 (2H, m), 8.48 (1H,





brt), 8.52 (1H, d, J = 2.6 Hz),





10.59 (1H, s).
















TABLE 140













 










Example





No.
R507
Form
1H NMR (solvent) δ ppm or MS





26
morpholino
hydro-
1H NMR (DMSO-d6) 3.50-3.65 (8 H, m), 7.13-




chloride
7.19 (3 H, m), 7.47 (2 H, d, J = 8.6 Hz), 7.84 (1 H, d, J =





8.2 Hz), 7.97 (1 H, dd, J = 8.3 Hz, 2.0 Hz), 8.23-





8.27 (2 H, m), 8.54 (1 H, d, J = 2.6 Hz), 10.63 (1 H, s).


 


27




free
1H NMR (CDCl3) 1.81-1.95 (2 H, m), 2.59-2.77 (4 H, m), 3.51-3.57 (4 H, m), 3.75 (2 H, brs), 5.94 (2 H, s), 6.71-6.75 (2 H, m), 6.83-6.93 (2 H, m), 7.05-7.10 (2 H, m), 7.32-7.37 (2 H, m), 7.54 (1 H, d, J = 8.2 Hz), 7.79 (1 H, dd, J = 8.3 Hz, 2.0 Hz), 8.06-8.10 (2 H, m), 8.30 (1 H, s), 8.96 (1 H, s).


 


28




free
MS 574 (M+)


 


29




free
MS 611 (M+)


 


30
—NH(CH2)2OCH3
free
1H NMR (DMSO-d6) 3.32 (3 H, s), 3.39-3.48 (4 H, m),





7.15-7.20 (3 H, m), 7.85 (1 H, d, J = 8.3 Hz), 7.86-





7.92 (2 H, m), 7.95 (1 H, dd, J = 8.4 Hz, 2.1 Hz), 8.20-





8.26 (2 H, m), 8.50 (1 H, brt), 8.52 (1 H, d, J = 2.5 Hz),





10.59 (1 H, s).


 


31




free
MS 601 (M+ − 1)


 


32




free
1H NMR (DMSO-d6) 0.86-0.99 (2 H, m), 1.10- 1.27 (3 H, m), 1.50-1.65 (2 H, m), 1.65-1.78 (4 H, m), 3.06-3.15 (2 H, m), 7.11-7.22 (3 H, m), 7.85 (1 H, d, J = 8.4 Hz), 7.88-7.92 (2 H, m), 7.95 (1 H, dd, J = 8.4 Hz, 2.1 Hz), 8.20-8.28 (2 H, m), 8.40 (1 H, brt), 8.52 (1 H, d, J = 2.7 Hz), 10.58 (1 H, s).


 


33
—NH(CH2)2OPh
free
1H NMR (DMSO-d6) 3.63 (2 H, t, J = 5.8 Hz),





4.12 (2 H, t, J = 5.9 Hz), 6.90-7.01 (3 H, m), 7.13-





7.24 (3 H, m), 7.26-7.35 (2 H, m), 7.85 (1 H, d, J = 8.4





Hz), 7.90-8.00 (3 H, m), 8.20-8.30 (2 H, m), 8.52 (1 H,





d, J = 2.6 Hz), 8.69 (1 H, brt), 10.59 (1 H, s).


 


34




free
MS 574 (M+)


 


35




free
1H NMR (CDCl3) 1.80-1.96 (2 H, m), 2.61-2.79 (4 H, m), 3.45-3.57 (2 H, m), 3.62-3.67 (2 H, m), 3.75- 3.77 (2 H, m), 6.94 (1 H, d, J = 8.6 Hz), 7.08-7.13 (2 H, m), 7.24-7.41 (7 H, m), 7.56 (1 H, d, J = 8.6 Hz), 7.76 (1 H, dd, J = 8.6 Hz, 2.0 Hz), 8.04 (1 H, d, J = 2.0 Hz), 8.07-8.14 (1 H, m), 8.29 (1 H, d, J = 2.0 Hz), 8.39 (1 H, s).
















TABLE 141













 









Example




No.
R508
Property





36




mp 221-224° C.


 


37




mp 228-230° C.


 


38




mp 193-194° C.


 


39
—N(CH3)COOC(CH3)3
1H NMR (CDCl3) δ 1.47 (9 H, s), 1.45-1.81 (4 H, m),




2.73 (3 H, s), 2.90 (2 H, brs), 4.10 (2 H, brs), 4.75 (1 H,




brs), 6.95 (1 H, d, J = 8.7 Hz), 7.11 (2 H, d, J = 8.7




Hz), 7.39 (2 H, d, J = 8.7 Hz), 7.55 (1 H, d, J = 8.2




Hz), 7.77 (1 H, dd, J = 8.2 Hz, 2.0 Hz), 8.05 (1 H, d, J =




2.0 Hz), 8.14 (1 H, dd, J = 8.7 Hz, 2.6 Hz),




8.30 (1 H, d, J = 2.6 Hz), 8.77 (1 H, s).


40
—OPh
MS 560 (M+ − 1)


41
4-CF3OPhO—
MS 629 (M+)


42
4-CF3OPhO—
MS 644 (M+ − 1)


43
4-CNPhO—
MS 586 (M+)


44
—C2H5
MS 496 (M+ − 1)


45
—COOC2H5
1H NMR (CDCl3) δ 1.27 (3 H, t, J = 7.0 Hz),




1.73 (2 H, brs), 1.95 (2 H, brs), 2.58 (1 H, m), 3.08 (2 H,




brs), 3.86 (1 H, brs), 4.16 (2 H, q, J = 7.0 Hz),




4.50 (1 H, brs), 6.97 (1 H, d, J = 9.0 Hz), 7.12 (2 H, d,




J = 8.5 Hz), 7.40 (2 H, d, J = 8.5 Hz), 7.57 (1 H, d, J =




8.5 Hz), 7.75 (1 H, dd, J = 8.5 Hz, 2.0 Hz),




8.03 (1 H, d, J = 2.0 Hz), 8.16 (1 H, dd, J = 9.0 Hz,




3.0 Hz), 8.30 (1 H, d, J = 3.0 Hz), 8.34 (1 H, brs).


46
—(CH2)2N(CH3)Ph
MS 602 (M+)


47
2-FPhCH2O—
MS 592 (M+ − 1)


48
PhCH2O—
MS 574 (M+ − 1)


49
cyclohexyl
MS 550 (M+ − 1)


50
4-ClPh-
MS 580 (M+ + 1)


51
-Ph
MS 544 (M+ − 1)


52
—CHPh2
MS 635 (M+)


53
2-NH2PhCO—
MS 587 (M+ − 1)


54
4-CH3OPhCONH—
MS 617 (M+ − 1)


55
—NHCOPh
MS 587 (M+ − 1)


56
4-CF3PhCH2O—
mp 186-187° C.


57
4-ClPhCH2O—
mp 176-177° C.
















TABLE 142













 









Example




No.
R509
MS





58




580 (M+ − 1)


 


59




610 (M+ − 1)


 


60




580 (M+ − 1)


 


61




598 (M+ − 1)


 


62




592 (M+ − 1)


 


63
Ph(CH2)2N(CH3)—
600 (M+ − 2)


64
Ph2CH(CH2)2N(CH3)—
691 (M+ − 1)


65
4-CH3SPh(CH2)2N(CH3)—
648 (M+)


 


66




678 (M+ + H)


 


67




613 (M+ + H)


 


68
4-CH3OPh(CH2)4N(CH3)—
660 (M+)


69
4-CH3Ph(CH2)2N(CH3)—
617 (M+ + H)


70
PhO(CH2)2N(CH3)—
618 (M+)


71
PhN(CH3)(CH2)2N(CH3)—
631 (M+)


72




608 (M+)


73
—O(CH2)2Ph
588 (M+ − 1)


 


74




575 (M+ − 1)


 


75




576 (M+)


 


76
4-ClPhCH2—
594 (M+ + 1)


 


77
4-CF3PhNH—
644 (M+)
















TABLE 143













 











Example





No.
R510
MS















78
4-CH3PhO(CH2)2N(CH3)—
633 (M+ + H)



79
Ph(CH2)3N(CH3)—
616 (M+)



80
2-phenylmorpholino
630 (M+)



81
4-CH3PhCH2—
572 (M+ − 1)



82
morpholino
554 (M+)



83
4-CH3OPhCH2O—
606 (M+ + H)



84
3-ClPhCH2O—
608 (M+ − 1)



85
2-ClPhCH2O—
608 (M+ − 1)



86
3,4-Cl2PhCH2O—
644 (M+ + 1)



87
3-CH3OPhCH2O—
604 (M+ − 1)



88
3,5-(CH3O)2PhCH2O—
634 (M+ − 1)



89
4-CH3PhCH2O—
588 (M+ − 1)



90
3-CH3PhCH2O—
588 (M+ − 1)



91
2-CH3PhCH2O—
588 (M+ − 1)



92
3,4-(CH3)2PhCH2O—
602 (M+ − 1)



93
4-FPhCH2O—
592 (M+ − 1)



94
3-FPhCH2O—
592 (M+ − 1)



95
3,5-F2PhCH2O—
610 (M+ − 1)



96
2-CF3PhCH2O—
642 (M+ − 1)



97
4-CF3OPhCH2O—
658 (M+ − 1)



98
3-CF3OPhCH2O—
658 (M+ − 1)



99
2-CF3OPhCH2O—
658 (M+ − 1)



 



100




638 (M+ − 1)

















TABLE 144













 









Example




No.
R511 
mp (° C.) or 1H NMR (CDCl3) δ ppm





101




mp 218-220


 


102




mp 227-231


 


103




1H NMR 1.09-1.30 (1 H, m), 1.60- 1.87 (4 H, m), 2.55-2.95 (4 H, m), 3.80 (1 H, brs), 4.59 (1 H, brs), 6.92 (1 H, d, J = 8.7 Hz), 7.05-7.35 (9 H, m), 7.71 (2 H, d, J = 8.6 Hz), 8.04 (2 H, d, J = 8.1 Hz), 8.14 (1 H, dd, J = 8.9 Hz, 2.6 Hz), 8.34 (1 H, d, J = 2.6 Hz), 8.99 (1 H, s).


 


104




1H NMR 1.27 (3 H, t, J = 7.0 Hz), 1.74 (2 H, brs), 1.95 (2 H, brs), 2.58 (1 H, m), 3.08 (2 H, brs), 3.92 (1 H, brs), 4.17 (2 H, q, J = 7.0 Hz), 4.51 (1 H, brs), 7.01 (1 H, d, J = 9.0 Hz), 7.16 (2 H, d, J = 8.5 Hz), 7.44 (2 H, d, J = 8.5 Hz), 7.78 (2 H, d, J = 8.0 Hz), 7.88 (1 H, brs), 8.01 (2 H, d, J = 8.0 Hz), 8.24 (1 H, dd, J = 9.0 Hz, 3.0 Hz), 8.32 (1 H, d, J = 3.0 Hz)


 


105




1H NMR 1.46 (9 H, s), 1.50-1.90 (4 H, m), 2.35-3.00 (2 H, m), 2.89 (3 H, s), 4.10- 4.70 (3 H, m), 6.99 (1 H, d, J = 8.7 Hz), 7.14 (2 H, d, J = 8.3 Hz), 7.40 (2 H, d, J = 8.3 Hz), 7.76 (2 H, d, J = 8.1 Hz), 8.03 (2 H, d, J = 8.1 Hz), 8.22 (1 H, dd, J = 8.7 Hz, 2.6 Hz), 8.33 (1 H, d, J = 2.6 Hz), 8.34 (1 H, brs).
















TABLE 145













 









Example




No.
R512
1H NMR (CDCl3) δ ppm or MS





106
4-CH3OPhCH(Ph)-
MS 665 (M+ − 1)


107
4-CH3OPhCOCH2—
1H NMR 2.63 (4 H, brs), 3.65 (4 H, brs), 3.82 (2 H,




s), 3.88 (3 H, s), 6.92-6.98 (3 H, m), 7.12 (2 H, d, J =




8.7 Hz), 7.41 (2 H, d, J = 8.7 Hz), 7.56 (1 H, d, J =




8.2 Hz), 7.75 (1 H, dd, J = 8.2 Hz, 2.1 Hz),




7.97 (2 H, d, J = 8.9 Hz), 8.03 (1 H, d, J = 2.0 Hz),




8.16 (1 H, dd, J = 8.9 Hz, 2.8 Hz), 8.30 (1 H, d, J =




2.8 Hz), 8.39 (1 H, s).


108
4-ClPhCOCH2—
1H NMR 2.63 (4 H, brs), 3.66 (4 H, brs), 3.83 (2 H,




s), 6.97 (1 H, d, J = 8.7 Hz), 7.13 (2 H, d, J = 8.6




Hz), 7.39-7.47 (4 H, m), 7.56 (1 H, d, J = 8.4 Hz),




7.74 (1 H, dd, J = 8.2 Hz, 2.1 Hz), 7.94 (2 H, d, J =




8.6 Hz), 8.02 (1 H, d, J = 2.0 Hz), 8.16 (1 H, dd, J =




8.7 Hz, 2.8 Hz), 8.30 (1 H, d, J = 2.8 Hz), 8.37 (1 H




s).


109
3-pyridyl
1H NMR 3.20 (4 H, brs), 3.78 (4 H, brs), 6.93 (1 H, d,




J = 8.7 Hz), 7.11 (2 H, d, J = 8.6 Hz), 7.19-




7.21 (2 H, m), 7.39 (2 H, d, J = 8.6 Hz), 7.46 (1 H, d,




J = 8.4 Hz), 7.76 (1 H, dd, J = 8.4 Hz, 2.0 Hz),




8.03 (1 H, d, J = 2.0 Hz), 8.11-8.25 (3 H, m),




8.36 (1 H, d, J = 2.5 Hz), 9.81 (1 H, s).


110
—CH2CONHPh
MS 603 (M+)


111
2-pyridyl
MS 547 (M+)


112
4-pyridyl
MS 547 (M+)


 


113




MS 548 (M+)


 


114




MS 548 (M+)


 


115
—(CH2)4Ph
MS 603 (M+ + H)


116
—CH(C2H5)2
MS 540 (M+)


117
—CH(CH3)2
MS 511 (M+ − 1)


118
—(CH2)2N(CH3)2
MS 540 (M+ − 1)
















TABLE 146













 












Example







No.
R513
R514
R515
R516
MS (M+)





119
—F
—H
—H
—H
564


120
—Cl
—H
—H
—H
582


121
—CF3
—H
—H
—H
614


122
—OCH3
—H
—H
—H
576


123
—CH3
—H
—H
—H
560


124
—H
—CF3
—H
—H
614


125
—H
—Cl
—H
—H
582


126
—H
—OCH3
—H
—H
576


127
—H
—CH3
—H
—H
560


128
—H
—H
—CN
—H
571


129
—H
—H
—OCF3
—H
630


130
—H
—H
—CO2C(CH3)3
—H
646


131
—H
—H
—F
—H
564


132
—H
—H
—Cl
—H
580


133
—H
—H
—OCH3
—H
576


134
—H
—H
—CH3
—H
560


135
—H
—H
—CF3
—H
614


136
—H
—H
-Ph
—H
622


137
—Cl
—Cl
—H
—H
616


138
—CH3
—CH3
—H
—H
574


139
—H
—CH3
—CH3
—H
574


140
—F
—H
—F
—H
582


141
—OCH3
—H
—H
—Cl
612
















TABLE 147













 











Example






No.
R517
R518
R519
mp (° C.) or 1H NMR (CDCl3) δ ppm





142
—H
—H
—H
1H NMR 3.20 (4 H, brs), 3.79 (4 H, brs), 6.89-






6.96 (3 H, m), 7.00 (1 H, d, J = 8.9 Hz), 7.14-7.19 (2 H,






m), 7.27-7.33 (2 H, m), 7.43-7.48 (2 H, m), 7.76 (2 H,






d, J = 8.1 Hz), 8.02 (2 H, d, J = 8.1 Hz), 8.23 (1 H, dd,






J = 8.9 Hz, 2.7 Hz), 8.31-8.34 (2 H, m).


143
—F
—H
—H
mp 193-194


144
—Cl
—H
—H
1H NMR 3.07 (4 H, brs), 3.82 (4 H, brs), 7.00-






7.06 (3 H, m), 7.18 (2 H, d, J = 8.4 Hz), 7.22-7.26 (1 H,






m), 7.38-7.41 (1 H, m), 7.48 (2 H, d, J = 8.6 Hz),






7.77 (2 H, d, J = 8.1 Hz), 8.04 (2 H, d, J = 8.1 Hz),






8.24 (1 H, dd, J = 8.9 Hz, 2.4 Hz), 8.30 (1 H, brs),






8.35 (1 H, d, J = 2.4 Hz).


145
—H
—Cl
—H
1H NMR 3.19 (4 H, brs), 3.76 (4 H, brs), 6.77-






6.81 (1 H, m), 6.86-6.88 (2 H, m), 6.99 (1 H, d, J = 8.9






Hz), 7.13-7.22 (3 H, m), 7.40-7.45 (2 H, m), 7.73 (2 H,






d, J = 8.4 Hz), 8.02 (2 H, d, J = 8.4 Hz), 8.21 (1 H, dd,






J = 8.9 Hz, 2.7 Hz), 8.34 (1 H, d, J = 2.7 Hz),






8.56 (1 H, s).


146
—H
—CH3
—H
1H NMR 2.31 (3 H, s), 3.15 (4 H, brs), 3.74 (4 H, brs),






6.71-6.73 (3 H, m), 6.97 (1 H, d, J = 8.9 Hz), 7.11-






7.18 (3 H, m), 7.42 (2 H, d, J = 8.1 Hz), 7.72 (2 H, d, J =






8.1 Hz), 8.01 (2 H, d, J = 8.1 Hz), 8.18-8.21 (1 H,






m), 8.34 (1 H, brs), 8.54 (1 H, brs).


147
—H
—OCH3
—H
1H NMR 3.07 (4 H, brs), 3.73 (4 H, brs), 3.88 (3 H, s),






6.88-7.08 (5 H, m), 7.13-7.17 (2 H, m), 7.42-7.47 (2 H,






m), 7.75 (2 H, d, J = 8.4 Hz), 8.03 (2 H, d, J = 7.8






Hz), 8.21 (1 H, dd, J = 8.9 Hz, 2.4 Hz), 8.34 (1 H, d, J =






2.4 Hz), 8.45 (1 H, brs).


148
—H
—CF3
—H
mp 174-177


149
—H
—H
—OH
mp 241-242


150
—H
—H
—OCH3
1H NMR 3.06 (4 H, brs), 3.63-3.91 (7 H, m), 6.83-






6.93 (4 H, m), 6.99 (1 H, d, J = 8.6 Hz), 7.15 (2 H, d, J =






8.4 Hz), 7.44 (2 H, d, J = 8.4 Hz), 7.75 (2 H, d, J =






8.4 Hz), 8.02 (2 H, d, J = 8.1 Hz), 8.22 (1 H, dd, J =






8.9 Hz, 2.4 Hz), 8.33 (1 H, d, J = 2.4 Hz), 8.40 (1 H,






brs).


151
—H
—H
—CN
1H NMR 3.23 (4 H, brs), 3.79 (4 H, brs), 7.01 (1 H, d, J =






8.9 Hz), 7.12-7.19 (5 H, m), 7.33-7.39 (1 H, m),






7.43-7.48 (2 H, m), 7.74 (2 H, d, J = 8.4 Hz), 8.02 (2 H,






d, J = 8.4 Hz), 8.23 (1 H, dd, J = 8.9 Hz, 2.7 Hz),






8.35 (1 H, d, J = 2.7 Hz), 8.47 (1 H, s).
















TABLE 148













 










Example





No.
R520
R521
1H NMR (solvent) δ ppm or MS





152
—H
piperonyl
1H NMR (CDCl3) 2.38-2.45 (4 H, m),





3.45 (2 H, s), 3.49-3.74 (4 H, m), 5.95 (2 H,





s), 6.74 (2 H, s), 6.85 (1 H, s), 6.97 (1 H, d, J =





8.6 Hz), 7.10 (2 H, d, J = 8.9 Hz),





7.41 (2 H, d, J = 8.9 Hz), 7.58 (1 H, d, J =





8.3 Hz), 7.74 (1 H, dd, J = 8.3 Hz, 2.0 Hz),





8.02 (1 H, d, J = 2.3 Hz), 8.13-8.20 (2 H, m),





8.29 (1 H, d, J = 2.6 Hz).


153
—H
—COOCH(CH3)3
1H NMR (DMSO-d6) 1.41 (9 H, s), 3.39-





3.50 (8 H, m), 7.13-7.19 (3 H, m), 7.45-





7.48 (2 H, m), 7.84 (1 H, d, J = 8.4 Hz),





7.95 (1 H, dd, J = 8.4 Hz, 2.1 Hz), 8.21-





8.26 (2 H, m), 8.52 (1 H, d, J = 2.3 Hz),





10.58 (1 H, s).


154
—H
2-naphthylmethyl
MS 611 (M+ + 1)


 


155
—H




MS 671 (M+ + 1)


 


156
—H
1-naphthylmethyl
MS 611 (M+ + 1)


157
—CH3
3,4-(CH3O)2PhCH2—
MS 633 (M+ + 1)


 


158
—H




MS 631 (M+ − 1)


 


159
—H
—CH(CH3)Ph
MS 573 (M+ − 1)


 


160
—H




MS 637 (M+)


161
—H
(4-FPh)2CH—
MS 671 (M+ − 1)


162
—H
—(CH2)3CH3
MS 526 (M+)


163
—H
—(CH2)3Ph
MS 588 (M+)


164
—H
cyclopentyl
MS 538 (M+)


165
—H
cycloheptyl
MS 565 (M+ − 1)
















TABLE 149













 











Example





No.
R522
MS







166




567 (M+)



 



167




581 (M+)



 



168




583 (M+)



 



169




567 (M+)



 



170
4-pyridylmethyl
561 (M+)



171
2-pyridylmethyl
562 (M+ + H)



 



172




643 (M+ + H)



 



173




580 (M+)



 



174




643 (M+)

















TABLE 150













 










Example





No.
R523
R524
mp (° C.) or 1H NMR (solvent) δ ppm





175
—H
3-pyridyl
1H NMR (CDCl3) 3.21 (4 H, brs), 3.78 (4 H, brs),





6.98 (1 H, d, J = 8.7 Hz), 7.13-7.21 (4 H, m), 7.41-





7.44 (2 H, m), 7.70 (2 H, d, J = 8.1 Hz), 8.02 (2 H, d, J =





8.1 Hz), 8.12-8.14 (1 H, m), 8.20-8.27 (2 H, m),





8.35 (1 H, d, J = 2.6 Hz), 8.99 (1 H, s).


176
—H
2-pyridyl
mp 222-224


177
—F
3-pyridyl
1H NMR (CDCl3) 3.21 (4 H, brs), 3.79 (4 H, brs),





7.05 (1 H, d, J = 8.4 Hz), 7.20-7.30 (5 H, m), 7.71 (2 H,





d, J = 8.2 Hz), 8.00 (2 H, d, J = 8.2 Hz), 8.14 (1 H,





brs), 8.21-8.25 (3 H, m), 8.78 (1 H, s).


 


178
—H




mp 205-206


 


179
—H




1H NMR (DMSO-d6) 2.38 (4 H, brs), 2.43 (2 H, t, J = 7.5 Hz), 2.86 (2 H, t, J = 7.5 Hz), 3.41 (2 H, s), 3.45 (4 H, brs), 6.80 (1 H, d, J = 7.9 Hz), 7.06 (1 H, d, J = 7.9 Hz), 7.10 (1 H, s), 7.15 (1 H, d, J = 8.8 Hz), 7.17 (2 H, d, J = 8.4 Hz), 7.44 (2 H, d, J = 8.4 Hz), 7.94 (2 H, d, J = 8.0 Hz), 8.17 (2 H, d, J = 8.0 Hz), 8.26 (1 H, dd, J = 8.8 Hz, 2.6 Hz), 8.54 (1 H, d, J = 2.6 Hz), 10.06 (1 H, s), 10.68 (1 H, s).


 


180
—H




1H NMR (CDCl3) 1.71-2.05 (4 H, m), 2.58 (4 H, brs), 3.16 (2 H, s), 3.36-3.53 (4 H, m), 3.55 (2 H, brs), 3.74 (2 H, brs), 7.00 (1 H, d, J = 8.9 Hz), 7.14 (2 H, d, J = 8.6 Hz), 7.42 (2 H, d, J = 8.6 Hz), 7.76 (2 H, d, J = 8.1 Hz), 8.04 (2 H, d, J = 8.1 Hz), 8.26 (1 H, dd, J = 8.9 Hz, 2.6 Hz), 8.34 (1 H, d, J = 2.6 Hz), 8.50 (1 H, s).


 


181
—H
—COOC(CH3)3
1H NMR (CDCl3) 1.48 (9 H, s), 3.45 (4 H, brs),





3.58 (4 H, brs), 6.99 (1 H, d, J = 8.7 Hz), 7.15 (2 H, d, J =





8.7 Hz), 7.41 (2 H, d, J = 8.7 Hz), 7.74 (2 H, d, J =





8.2 Hz), 8.02 (2 H, d, J = 8.2 Hz), 8.21 (1 H, dd, J =





8.7 Hz, 2.6 Hz), 8.33 (1 H, d, J = 2.6 Hz), 8.43 (1 H,





brs).


182
—H
—CH2COOC2H5
1H NMR (CDCl3) 1.28 (3 H, t, J = 7.1 Hz), 2.61 (4 H,





brs), 3.26 (2 H, s), 3.57 (2 H, brs), 3.78 (2 H, brs),





4.19 (2 H, q, J = 7.1 Hz), 6.97 (1 H, d, J = 8.7 Hz),





7.12 (2 H, d, J = 8.7 Hz), 7.40 (2 H, d, J = 8.7 Hz),





7.74 (2 H, d, J = 8.1 Hz), 8.03 (2 H, d, J = 8.1 Hz),





8.19 (1 H, dd, J = 8.7 Hz, 2.6 Hz), 8.33 (1 H, d, J = 2.6





Hz), 8.61 (1 H, brs).


183
—H
—CH2CONHNHCOOC(CH3)3
1H NMR (CDCl3) 1.46 (9 H, s), 2.60 (4 H, brs),





3.17 (2 H, s), 3.67 (4 H, brs), 6.48 (1 H, brs), 7.00 (1 H,





d, J = 8.7 Hz), 7.14 (2 H, d, J = 8.5 Hz), 7.41 (2 H, d, J =





8.5 Hz), 7.75 (2 H, d, J = 8.1 Hz), 8.02 (2 H, d, J =





8.1 Hz), 8.24 (1 H, dd, J = 8.7 Hz, 2.6 Hz), 8.33 (1 H,





d, J = 2.6 Hz), 8.53 (2 H, s).
















TABLE 151













 














Example






mp (° C.) or 1H NMR


No.
R525
R526
R527
R528
R529
Form
(solvent) δ ppm





184
—Cl
—Cl
—H
—F
3-pyridyl
free
1H NMR (CDCl) 3.21 (4 H,









brs), 3.79 (4 H, brs),









7.02 (1 H, d, J = 8.7 Hz),









7.18-7.28 (5 H, m), 7.49 (1 H,









d, J = 8.2 Hz), 7.74 (1 H, dd,









J = 8.2 Hz, 1.7 Hz),









8.00 (1 H, d, J = 1.7 Hz),









8.13 (1 H, brs), 8.17-8.21 (1 H,









m), 8.26 (2 H, d, J = 2.3 Hz),









9.33 (1 H, brs).


185
—H
—Cl
—H
—H
4-CNPhCH2—
free
mp 199-201


186
—OCF3
—H
—H
—H
3-pyridyl-
free
1H NMR (CDCl3) 2.43-







methyl

2.55 (4 H, m), 3.43-3.71 (6 H,









m), 6.90 (1 H, d, J = 8.7 Hz),









7.05-7.08 (2 H, m), 7.25-









7.46 (5 H, m), 7.66-7.69 (1 H,









m), 7.82-7.88 (2 H, m),









8.15 (1 H, dd, J = 8.9 Hz, 2.8









Hz), 8.36 (1 H, d, J = 2.5 Hz),









8.48 (1 H, dd, J = 4.8 Hz, 1.7









Hz), 8.51 (1 H, d, J = 1.7 Hz),









9.84 (1 H, s).


187
—CF3
—H
—H
—H
4-CNPhCH2—
free
mp 193-197


188
—F
—H
—CF3
—H
4-CNPhCH2—
oxalate
mp 136-139


189
—CH3
—CH3
—H
—H
—COOC(CH3)3
free
1H NMR (CDCl3) 1.48 (9 H,









s), 2.34 (6 H, s), 3.46 (4 H,









brs), 3.60 (4 H, brs), 6.99 (1 H,









d, J = 8.7 Hz), 7.14-7.17









(2 H, m), 7.23-7.26 (1 H, m),









7.42-7.47 (2 H, m), 7.61 (1 H,









dd, J = 7.8 Hz, 2.0 Hz), 7.67









(1 H, d, J = 2.0 Hz), 7.93









(1 H, brs), 8.25-8.31 (2 H, m).
















TABLE 152













 













Example








No.
R530
R531
R532
R533
R534
MS





190
—Cl
—H
—H
—H
—H
594 (M+)


191
—OCH3
—H
—H
—H
—H
590 (M+)


192
—CH3
—H
—H
—H
—H
574 (M+)


193
—F
—H
—H
—H
—H
578 (M+)


194
—NO2
—H
—H
—H
—H
603 (M+ − 2)


195
—CF3
—H
—H
—H
—H
628 (M+)


196
—OCF3
—H
—H
—H
—H
645 (M+ + 1)


197
—H
—Cl
—H
—H
—H
595 (M+ + 1)


198
—H
—F
—H
—H
—H
579 (M+ + 1)


199
—H
—NO2
—H
—H
—H
605 (M+)


200
—H
—CF3
—H
—H
—H
628 (M+)


201
—H
—OCF3
—H
—H
—H
644 (M+)


202
—H
—COOCH3
—H
—H
—H
618 (M+)


203
—H
—H
—Cl
—H
—H
594 (M+)


204
—H
—H
—F
—H
—H
578 (M+)


205
—H
—H
—NO2
—H
—H
605 (M+)


206
—H
—H
—COOCH3
—H
—H
618 (M+)


207
—H
—H
-Ph
—H
—H
636 (M+)


208
—H
—H
—C2H5
—H
—H
588 (M+)


209
—Cl
—Cl
—H
—H
—H
630 (M+)


210
—Cl
—H
—Cl
—H
—H
630 (M+)


211
—H
—F
—H
—F
—H
596 (M+)


212
—H
—OCH3
—H
—OCH3
—H
622 (M+ + 2)


213
—F
—H
—F
—H
—H
596 (M+)


214
—H
—Cl
—Cl
—H
—H
630 (M+)


215
—F
—H
—H
—H
—F
596 (M+)


216
—Cl
—H
—H
—H
—Cl
630 (M+)


217
—F
—H
—H
—F
—H
596 (M+)


218
—Cl
—H
—H
—Cl
—H
629 (M+ + 1)


219
—H
—Cl
—OCH3
—H
—H
624 (M+)
















TABLE 153













 












Example







No.
R535
R536
R537
R538
mp (° C.) or 1H NMR (CDCl3) δ ppm





220
—Cl
—Cl
—H
—H
mp 164-166


221
—Cl
—Cl
—F
—H
1H NMR 2.46 (4 H, brs), 3.39-3.82 (6 H, m), 7.00 (1 H,







d, J = 8.9 Hz), 7.13-7.33 (8 H, m), 7.52 (1 H, d, J =







8.4 Hz), 7.72 (1 H, dd, J = 8.4 Hz, 2.0 Hz), 8.00 (1 H,







d, J = 2.0 Hz), 8.15 (1 H, dd, J = 8.9 Hz, 2.6 Hz),







8.23 (1 H, d, J = 2.6 Hz), 8.61 (1 H, brs).


222
—CF3
—H
—F
—H
1H NMR 2.44 (4 H, brs), 3.42-3.78 (6 H, m), 6.97 (1 H,







d, J = 8.7 Hz), 7.09-7.36 (8 H, m), 7.66 (2 H, d, J =







8.1 Hz), 7.96 (2 H, d, J = 8.1 Hz), 8.16 (1 H, dd, J =







8.7 Hz, 2.5 Hz), 8.26 (1 H, d, J = 2.5 Hz), 9.04 (1 H,







brs).


223
—Cl
—Cl
—Cl
—H
1H NMR 2.47 (4 H, brs), 3.42-3.83 (6 H, m), 7.00 (1 H,







d, J = 8.9 Hz), 7.17 (1 H, d, J = 8.2 Hz), 7.25-







7.33 (6 H, m), 7.46 (1 H, d, J = 1.8 Hz), 7.53 (1 H, d, J =







8.4 Hz), 7.74 (1 H, dd, J = 8.4 Hz, 2.1 Hz),







8.01 (1 H, d, J = 2.1 Hz), 8.17 (1 H, dd, J = 8.9 Hz,







2.6 Hz), 8.25 (1 H, d, J = 2.6 Hz), 8.64 (1 H, brs).


224
—CF3
—H
—Cl
—H
1H NMR 2.47 (4 H, brs), 3.42-3.82 (6 H, m), 7.02 (1 H,







d, J = 8.9 Hz), 7.19 (1 H, d, J = 8.4 Hz), 7.27-







7.33 (6 H, m), 7.47 (1 H, d, J = 1.8 Hz), 7.73 (2 H, d, J =







8.4 Hz), 8.00 (2 H, d, J = 7.9 Hz), 8.20-8.26 (2 H,







m), 8.46 (1 H, brs).


225
—Cl
—Cl
—CH3
—H
1H NMR 2.15 (3 H, s), 2.45 (4 H, brs), 3.46-3.75 (6 H,







m), 6.85 (1 H, d, J = 8.9 Hz), 6.95 (1 H, d, J = 8.4







Hz), 7.13-7.33 (7 H, m), 7.50 (1 H, d, J = 8.6 Hz),







7.75 (1 H, dd, J = 8.4 Hz, 2.2 Hz), 8.03 (1 H, d, J =







2.2 Hz), 8.08 (1 H, dd, J = 8.9 Hz, 3.0 Hz), 8.27 (1 H,







d, J = 3.0 Hz), 9.06 (1 H, s).


226
—CF3
—H
—CH3
—H
1H NMR 2.17 (3 H, s), 2.44 (4 H, brs), 3.40-3.82 (6 H,







m), 6.88 (1 H, d, J = 8.9 Hz), 6.98 (1 H, d, J = 8.1







Hz), 7.14-7.18 (1 H, m), 7.23-7.33 (6 H, m), 7.70 (2 H,







d, J = 8.4 Hz), 8.01 (2 H, d, J = 8.1 Hz), 8.15 (1 H,







dd, J = 8.9 Hz, 2.7 Hz), 8.30 (1 H, d, J = 2.7 Hz),







8.90 (1 H, brs).


227
—Cl
—Cl
—OCH3
—H
mp 197-199


228
—CF3
—H
—OCH3
—H
mp 152-154


229
—Cl
—Cl
—H
—CH3
mp 182-183


230
—CF3
—H
—H
—CH3
mp 188-190


231
—Cl
—Cl
—H
—OCH3
mp 196-198


232
—CF3
—H
—H
—OCH3
1H NMR 2.32-2.50 (4 H, m), 3.30 (2 H, brs), 3.53 (2 H,







s), 3.70-3.81 (5 H, m), 6.61-6.65 (2 H, m), 6.91 (1 H, d,







J = 8.9 Hz), 7.11-7.15 (1 H, m), 7.26-7.36 (5 H, m),







7.72 (2 H, d, J = 8.4 Hz), 8.05-8.13 (3 H, m),







8.36 (1 H, d, J = 2.4 Hz), 9.07 (1 H, s).
















TABLE 154













 













Example








No.
R539
R540
R541
R542
Form
mp (° C.) or 1H NMR (solvent) δ ppm





233
—CF3
—H
—H
—H
hydro-
1H NMR (DMSO-d6) 2.90-3.70 (6 H, m), 3.80-







chloride
4.60 (2 H, m), 4.24 (2 H, brs), 6.07 (2 H, s),








6.98 (1 H, d, J = 8.0 Hz), 7.05 (1 H, dd, J = 8.0








Hz, 1.5 Hz), 7.16 (1 H, d, J = 8.7 Hz), 7.20 (2 H,








d, J = 8.6 Hz), 7.27 (1 H, s), 7.52 (2 H, d, J = 8.6








Hz), 7.93 (2 H, d, J = 8.3 Hz), 8.21 (2 H, d, J =








8.3 Hz), 8.30 (1 H, dd, J = 8.7 Hz, 2.6 Hz),








8.60 (1 H, d, J = 2.6 Hz), 10.80 (1 H, s).


234
—Cl
—Cl
—F
—H
free
1H NMR (CDCl3) 2.42 (4 H, brs), 3.37-3.79 (6 H,








m), 5.94 (2 H, s), 6.70-6.77 (2 H, m), 6.84 (1 H,








brs), 6.96 (1 H, d, J = 8.7 Hz), 7.10-7.22 (3 H,








m), 7.47 (1 H, d, J = 8.2 Hz), 7.72 (1 H, dd, J =








8.2 Hz, 2.0 Hz), 7.99 (1 H, d, J = 2.0 Hz),








8.12 (1 H, dd, J = 8.9 Hz, 2.6 Hz), 8.25 (1 H, d, J =








2.6 Hz), 9.14 (1 H, brs).


235
—CF3
—H
—F
—H
free
1H NMR (CDCl3) 2.41 (4 H, brs), 3.37-3.79 (6 H,








m), 5.94 (2 H, s), 6.69-6.76 (2 H, m), 6.84 (1 H, s),








6.99 (1 H, d, J = 8.9 Hz), 7.10-7.26 (3 H, m),








7.67 (2 H, d, J = 8.1 Hz), 7.97 (2 H, d, J = 8.1








Hz), 8.17 (1 H, dd, J = 8.9 Hz, 2.5 Hz), 8.26 (1 H,








d, J = 2.5 Hz), 8.89 (1 H, brs).


236
—Cl
—Cl
—Cl
—H
free
1H NMR (CDCl3) 2.45 (4 H, brs), 3.38-3.81 (6 H,








m), 5.95 (2 H, s), 6.71-6.78 (2 H, m), 6.85 (1 H, s),








7.01 (1 H, d, J = 8.7 Hz), 7.17-7.30 (2 H, m),








7.45-7.47 (1 H, m), 7.54 (1 H, d, J = 8.4 Hz),








7.70-7.74 (1 H, m), 8.00 (1 H, d, J = 1.8 Hz),








8.17 (1 H, dd, J = 8.9 Hz, 2.6 Hz), 8.24 (1 H, d, J =








2.6 Hz), 8.48 (1 H, s).


237
—CF3
—H
—Cl
—H
free
1H NMR (CDCl3) 2.45 (4 H, brs), 3.40-3.81 (6 H,








m), 5.95 (2 H, s), 6.71-6.77 (2 H, m), 6.85 (1 H, s),








7.03 (1 H, d, J = 8.6 Hz), 7.20 (1 H, d, J = 8.2








Hz), 7.28-7.31 (1 H, m), 7.48 (1 H, d, J = 2.0 Hz),








7.74 (2 H, d, J = 8.4 Hz), 8.00 (2 H, d, J = 8.2








Hz), 8.21-8.26 (2 H, m), 8.34 (1 H, brs).


238
—CF3
—H
—CH3
—H
free
1H NMR (CDCl3) 2.16 (3 H, s), 2.42 (4 H, brs),








3.44-3.70 (6 H, m), 5.94 (2 H, s), 6.70-6.77 (2 H,








m), 6.85-6.89 (2 H, m), 6.97 (1 H, d, J = 8.4 Hz),








7.14-7.23 (2 H, m), 7.69 (2 H, d, J = 8.1 Hz),








8.01 (2 H, d, J = 8.1 Hz), 8.13-8.17 (1 H, m),








8.30 (1 H, d, J = 2.7 Hz), 8.97 (1 H, brs).


239
—Cl
—Cl
—OCH3
—H
free
mp 194-196


240
—CF3
—H
—OCH3
—H
free
mp 134-136


241
—CF3
—H
—H
—Ch3
free
mp 199-201


242
—CF3
—H
—H
—OCH3
free
mp 192-193
















TABLE 155













 











Example






No.
R543
R544
R545
1H NMR (CDCl3) δppm





243
—Cl
—Cl
benzyl
2.39-2.62(4 H, m), 3.42-3.91(6 H, m), 6.94(1 H,






d, J = 8.9 Hz), 7.28-7.33(6 H, m), 7.41(1 H, dd,






J = 8.4 Hz, 1.6 Hz), 7.50-7.53(2 H, m), 7.72-






7.75(2 H, m), 7.81-7.84(2 H, m), 8.02(1 H, d, J =






2.1 Hz), 8.14(1 H, dd, J = 8.9 Hz, 2.7 Hz),






8.28(1 H, d, J = 2.7 Hz), 8.66(1 H, s).


244
—Cl
—Cl
piperonyl
2.41-2.74(4 H, m), 3.42-3.91(6 H, m), 5.94(2 H,






s), 6.73(2 H, brs), 6.84(1 H, brs), 6.97(1 H, d, J =






8.9 Hz), 7.29-7.33(1 H, m), 7.42(1 H, d, J =






8.2 Hz), 7.52-7.57(2 H, m), 7.71-7.85(4 H, m),






8.02(1 H, d, J = 2.0 Hz), 8.18(1 H, dd, J = 8.9






Hz, 2.8 Hz), 8.28(1 H, d, J = 2.8 Hz), 8.48(1 H,






brs).


245
—Cl
—Cl
3-pyridyl
3.25(4 H, brs), 3.82(4 H, brs), 7.01(1 H, d, J =






8.7 Hz), 7.21-7.22(2 H, m), 7.35(1 H, dd, J =






8.9 Hz, 2.3 Hz), 7.47-7.50(1 H, m), 7.52-






7.56(2 H, m), 7.74(1 H, dd, J = 8.2 Hz, 2.0 Hz),






7.80(1 H, d, J = 8.6 Hz), 7.86-7.91(2 H, m),






8.01(1 H, d, J = 2.0 Hz), 8.13-8.15(1 H, m),






8.18-8.22(1 H, m), 8.29-8.31(2 H, m), 8.42(1 H,






brs).


246
—CF3
—H
benzyl
2.35-2.58(4 H, m), 3.37-3.87(6 H, m), 6.96(1 H,






d, J = 8.9 Hz), 7.28-7.34(6 H, m), 7.41(1 H, dd,






J = 8.4 Hz, 1.5 Hz), 7.52(1 H, d, J = 2.0 Hz),






7.64-7.76(3 H, m), 7.83(2 H, d, J = 9.1 Hz),






8.00(2 H, d, J = 8.2 Hz), 8.19(1 H, dd, J = 8.9






Hz, 2.6 Hz), 8.30(1 H, d, J = 2.6 Hz), 8.68(1 H,






brs).


247
—CF3
—H
piperonyl
2.30-2.58(4 H, m), 3.35-3.87(6 H, m), 5.94(2 H,






s), 6.70-6.l77(2 H, m), 6.85(1 H, brs), 6.95(1 H,






d, J = 8.7 Hz), 7.31(1 H, dd, J = 8.9 Hz, 2.1






Hz), 7.39(1 H, d, J = 8.4 Hz), 7.51(1 H, brs),






7.66-7.83(5 H, m), 7.99(2 H, d, J = 8.1 Hz),






8.17(1 H, dd, J = 8.7 Hz, 2.3 Hz), 8.30(1 H,






brs), 8.89(1 H, brs).


248
—CF3
—H
3-pyridyl
3.22(4 H, brs), 3.79(4 H, brs), 6.99(1 H, d, J =






8.7 Hz), 7.17-7.23(2 H, m), 7.33(1 H, dd, J =






8.9 Hz, 2.3 Hz), 7.45(1 H, dd, J = 8.4 Hz, 1.5






Hz), 7.54(1 H, d, J = 2.3 Hz), 7.66(2 H, d, J =






8.4 Hz), 7.76-7.86(3 H, m), 7.99(2 H, d, J = 8.1






Hz), 8.13(1 H, brs), 8.21-8.25(1 H, m), 8.28(1 H,






brs), 8.33(1 H, d, J = 2.5 Hz), 9.13(1 H, s).
















TABLE 156













 











Example






No.
R546 
R547
R548
1H NMR (CDCl3) δppm





249
—Cl
—Cl
benzyl
2.27-2.34(2 H, m), 2.58-2.61(2 H, m), 3.20-






3.29(2 H, m), 3.53(2 H, s), 3.90-3.99(2 H, m),






6.91(1 H, d, J = 8.7 Hz), 7.29-7.32(7 H, m), 7.39-






7.45(1 H, m), 7.53-7.56(2 H, m), 7.71-7.81(3 H,






m), 8.00-8.04(2 H, m), 8.25(1 H, d, J = 2.6 Hz),






8.47(1 H, s).


250
—Cl
—Cl
piperonyl
2.25-2.31(2 H, m), 2.55-2.59(2 H, m), 3.22(2 H,






brs), 3.44(2 H, s), 3.86-4.01(2 H, m), 5.94(2 H, s),






6.69-6.76(2 H, m), 6.84-6.91(2 H, m), 7.25-






7.29(2 H, m), 7.38-7.44(1 H, m), 7.52-7.55(2 H,






m), 7.71-7.80(3 H, m), 7.97-8.03(2 H, m),






8.24(1 H, d, J = 2.8 Hz), 8.60(1 H, s).


251
—CF3
—H
benzyl
2.27-2.34(2 H, m), 2.57-2.61(2 H, m), 3.23-






3.25(2 H, m), 3.53(2 H, s), 3.89-3.98(2 H, m),






6.96(1 H, d, J = 8.7 Hz), 7.27-7.31(7 H, m), 7.40-






7.45(1 H, m), 7.55(1 H, d, J = 2.3 Hz), 7.72-7.83






(4 H, m), 8.00(2 H, d, J = 8.1 Hz), 8.12(1 H, dd, J =






8.9 Hz, 2.8 Hz), 8.30(1 H, d, J = 2.6 Hz),






8.40(1 H, brs).


252
—CF3
—H
piperonyl
2.25-2.31(2 H, m), 2.55-2.58(2 H, m), 3.23(2 H,






m), 3.43(2 H, s), 3.85-4.00(4 H, m), 5.94(2 H, s),






6.70-6.76(2 H, m), 6.84(1 H, s), 6.96(1 H, d, J =






8.9 Hz), 7.28-7.31(2 H, m), 7.40-7.46(1 H, m),






7.55(1 H, d, J = 2.5 Hz), 7.72-7.83(4 H, m),






8.00(2 H, d, J = 7.9 Hz), 8.12(1 H, dd, J = 8.9






Hz, 2.6 Hz), 8.30(1 H, d, J = 2.6 Hz), 8.44(1 H,






brs).
















TABLE 157













 














Example









No.
R549
R550
R551
R552
R553
Form
1H NMR (solvent) δppm





253
—CF3
—H
—CH3
—H
3-pyridyl
free
(CDCl3) 3.06(3 H, s), 3.22(4 H, brs),









3.81(4 H, brs), 4.55(2 H, s), 6.87(1 H,









d, J = 8.9 Hz), 7.09(2 H, d, J = 8.7









Hz), 7.14(1 H, dd, J = 8.9 Hz, 3.3









Hz), 7.19-7.21(2 H, m), 7.35(2 H, d,









J = 7.9 Hz), 7.44(2 H, d, J = 8.7









Hz), 7.60(2 H, d, J = 8.1 Hz),









7.74(1 H, d, J = 3.0 Hz), 8.14-









8.17(1 H, m), 8.31-8.33(1 H, m).


254
—CF3
—H
—H
—F
benzyl
free
(CDCl3) 2.46(4 H, brs), 3.54(6 H,









brs), 4.11(1 H, brs), 4.38(2 H, brs),









6.85(1 H, d, J = 8.7 Hz), 7.01(1 H,









dd, J = 8.7 Hz, 3.1 Hz), 7.16-









7.25(3 H, m), 7.28-7.33(5 H, m),









7.46(2 H, d, J = 8.1 Hz), 7.52(1 H, d,









J = 2.6 Hz), 7.60(2 H, d, J = 8.1 Hz).


255
—CF3
—H
—CH3
—H
piperonyl
hydro-
(DMSO-d6) 2.49-2.52(2 H, m),








chloride
3.06(5 H, brs), 3.35(4 H, brs),









4.22(2 H, brs), 4.68(2 H, brs),









6.07(2 H, s), 6.94-7.05(5 H, m),









7.23(1 H, brs), 7.32(1 H, dd, J = 8.9









Hz, 3.3 Hz), 7.43-7.46(4 H, m),









7.69-7.72(3 H, m), 11.23(1 H, brs).


256
—Cl
—Cl
—H
—F
benzyl
free
(CDCl3) 2.47(4 H, brs), 3.49-









3.68(6 H, m), 4.29(2 H, s), 6.86(1 H,









d, J = 8.7 Hz), 7.01(1 H, dd, J = 8.7









Hz, 3.0 Hz), 7.17-7.22(4 H, m),









7.32(5 H, brs), 7.41(1 H, d, J = 8.3









Hz), 7.45(1 H, d, J = 1.8 Hz),









7.51(1 H, d, J = 3.0 Hz).


257
—CF3
—H
—CH3
—H
4-CH3OPhCH2—
hydro-
(DMSO-d6) 2.49-2.52(2 H, m),








chloride
3.06(5 H, brs), 3.32-3.38(4 H, m),









3.78(3 H, s), 4.27(2 H, d, J = 4.1









Hz), 4.68(2 H, brs), 6.96(1 H, d, J =









8.9 Hz), 7.00-7.05(4 H, m), 7.32(1 H,









dd, J = 8.9 Hz, 3.3 Hz), 7.43-









7.49(6 H, m), 7.68-7.72(3 H, m),









10.72(1 H, brs).


258
—CF3
—H
—CH3
—H
4-pyridyl-
hydro-
(DMSO-d6) 2.49-2.52(2 H, m), 3.05-







methyl
chloride
3.44(9H, m), 4.26(2 H, brs),









4.68(2 H, brs), 6.96(1 H, d, J = 8.9









Hz), 7.03(2 H, d, J = 8.7 Hz),









7.32(1 H, dd, J = 8.9 Hz, 3.3 Hz),









7.42-7.47(4 H, m), 7.68-7.72(5 H,









m), 8.71(2 H, dd, J = 4.6 Hz, 1.5









Hz).
















TABLE 158













 












Example







No.
R554
R555
R556
Form
1H NMR (solvent) δppm





259
—CH3
—H
benzyl
hydro-
(DMSO-d6) 1.44(3 H, d, J = 6.8 Hz), 2.44-






chloride
2.52(2 H, m), 3.08-3.15(2 H, m), 3.30-3.38(4 H,







m), 4.33(2 H, brs), 4.55-4.62(1 H, m), 6.51(1 H,







d, J = 6.3 Hz), 6.82(1 H, d, J = 8.7 Hz),







6.97(2 H, d, J = 8.7 Hz), 7.04(1 H, dd, J = 8.7







Hz, 3.0 Hz), 7.41(2 H, d, J = 8.6 Hz), 7.45-







7.47(4 H, m), 7.57(2 H, brs), 7.61(2 H, d, J = 8.3







Hz), 7.69(2 H, d, J = 8.4 Hz), 10.99(1 H, brs).


260
—CH3
—CH3
benzyl
free
(CDCl3) 1.58(3 H, d, J = 6.9 Hz), 2.46(4 H, brs),







2.72(3 H, s), 3.46-3.53(6 H, m), 4.97(1 H, q, J =







6.9 Hz), 6.86(1 H, d, J = 8.9 Hz), 7.07(2 H, d, J =







8.6 Hz), 7.23(1 H, dd, J = 8.9 Hz, 3.3 Hz),







7.27-7.36(5 H, m), 7.40(2 H, d, J = 8.6 Hz),







7.43(2 H, d, J = 7.3 Hz), 7.60(2 H, d, J = 8.3







Hz), 7.82(1 H, d, J = 3.3 Hz).


261
—CH3
—CH3
piperonyl
free
(CDCl3) 1.58(3 H, d, J = 6.9 Hz), 2.43(4 H, brs),







2.72(3 H, s), 3.44(2 H, s), 3.48-3.68(4 H, m),







4.97(1 H, q, J = 6.9 Hz), 5.95(2 H, s), 6.74(2 H,







brs), 6.85(1 H, brs), 6.87(1 H, d, J = 9.1 Hz),







7.07(2 H, d, J = 8.7 Hz), 7.23(1 H, dd, J = 8.9







Hz, 3.3 Hz), 7.40(2 H, d, J = 8.6 Hz), 7.43(2 H,







d, J = 7.9 Hz), 7.60(2 H, d, J = 8.3 Hz),







7.82(1 H, d, J = 3.1 Hz).


262
—CH3
—H
piperonyl
hydro-
(DMSO-d6) 1.44(3 H, d, J = 6.8 Hz), 2.49-






chloride
2.52(2 H, m), 3.01-3.06(2 H, m), 3.29-3.45(4 H,







m), 4.23(2 H, brs), 4.58-4.62(1 H, m), 6.07(2 H,







s), 6.51(1 H, d, J = 6.6 Hz), 6.82(1 H, d, J = 8.7







Hz), 6.96-6.99(4 H, m), 7.04(1 H, dd, J = 8.7







Hz, 3.0 Hz), 7.20(1 H, brs), 7.41(2 H, d, J = 8.6







Hz), 7.46(1 H, d, J = 3.0 Hz), 7.61(2 H, d, J =







8.3 Hz), 7.69(2 H, d, J = 8.4 Hz), 10.99(1 H,







brs).


263
—H
—C2H5
benzyl
hydro-
(DMSO-d6) 1.14(3 H, d, J = 6.9 Hz), 2.50-






chloride
2.51(2 H, m), 3.11(2 H, brs), 3.35(4 H, brs),







3.51(2 H, q, J = 6.9 Hz), 4.33(2 H, brs),







4.63(2 H, brs), 6.94(1 H, d, J = 8.9 Hz),







7.03(2 H, d, J = 8.6 Hz), 7.25(1 H, dd, J = 8.9







Hz, 3.3 Hz), 7.42-7.48(7 H, m), 7.57(2 H, brs),







7.62(1 H, d, J = 3.1 Hz), 7.70(2 H, d, J = 8.1







Hz), 11.03(1 H, brs).


264
—H
—C2H5
piperonyl
hydro-
(DMSO-d6) 1.14(3 H, d, J = 6.9 Hz), 2.50-






chloride
2.51(2 H, m), 3.06(2 H, brs), 3.36(4 H, brs),







3.52(2 H, q, J = 6.9 Hz), 4.22(2 H,brs),







4.64(2 H, brs), 6.07(2 H, s), 6.94(1 H, d, J = 8.9







Hz), 6.99(2 H, brs), 7.03(2 H, d, J = 8.6 Hz),







7.23(1 H, brs), 7.25(1 H, dd, J = 8.9 Hz, 3.3







Hz), 7.42-7.49(4 H, m), 7.62(1 H, d, J = 3.1







Hz), 7.71(2 H, d, J = 8.1 Hz), 11.29(1 H, brs).
















TABLE 159













 










Example





No.
R557
R558
1H NMR (solvent) δppm





265
3,4-Cl2PhCONH—




(CDCl3) 2.39-2.49(4 H, m), 3.39- 3.79(6 H, m), 6.87(1 H, d, J = 8.9 Hz), 7.06-7.15(3 H, m), 7.27- 7.37(6 H, m), 7.51(1 H, d, J = 8.4 Hz), 7.74-7.78(1 H, m), 8.01- 8.05(2 H, m), 8.28(1 H, d, J = 2.6 Hz), 9.10(1 H, brs).


 


266
3,4-Cl2PhCONH—




(CDCl3) 2.37-2.48(4 H, m), 3.43- 3.75(6 H, m), 5.94(2 H, s), 6.70- 6.77(2 H, m), 6.84(1 H, brs), 6.92(1 H, d, J = 8.9 Hz), 7.09- 7.17(3 H, m), 7.34-7.40(1 H, m), 7.55(1 H, d, J = 8.4 Hz), 7.73- 7.77(1 H, m), 8.04(1 H, d, J = 2.1 Hz), 8.09(1 H, dd, J = 8.9 Hz, 2.8 Hz), 8.28(1 H, d, J = 2.8 Hz), 8.63(1 H, brs).


 


267
4-CF3PhCH2N(CH3)—




(DMSO-d6) 3.03-3.13(5 H, m), 4.69-4.75(3 H, m), 6.88-6.98(3 H, m), 7.06(2 H, d, J = 8.6 Hz), 7.16- 7.23(2 H, m), 7.33(1 H, dd, J = 9.1 Hz, 3.1 Hz), 7.46(2 H, d, J = 8.3 Hz), 7.69-7.73(3 H, m), 7.91(2 H, d, J = 8.7 Hz), 8.61(1 H, d, J = 8.1 Hz), 10.35(1 H, brs).


 


268
4-CF3PhCH2N(CH3)—




(DMSO-d6) 2.89-3.06(2 H, m), 3.06(3 H, s), 4.61-4.72(3 H, m), 5.96(2 H, s), 6.50(1 H, s), 6.84(1 H, s), 6.97(1 H, d, J = 8.9 Hz), 7.06(2 H, d, J = 8.7 Hz), 7.33(1 H, dd, J = 8.9 Hz, 3.3 Hz), 7.46(2 H, d, J = 8.1 Hz), 7.69-7.73(3 H, m), 7.89(2 H, d, J = 8.7 Hz), 8.56(1 H, d, J = 8.3 Hz), 10.15(1 H, brs).


 


269
3,4-Cl2PhCONH—




(CDCl3) 2.28-2.30(2 H, m), 2.58- 2.60(2 H, m), 3.25-3.29(2 H, m), 3.44(2 H, s), 3.92-3.98(2 H, m), 5.94(2 H, s), 6.73(2 H, s), 6.84(1 H, s), 6.96(1 H, d, J = 8.7 Hz), 7.14(1 H, d, J ==0 7.8 Hz), 7.37(1 H d, J = 7.8 Hz), 7.50-7.59(3 H, m), 7.73(1 H, dd, J = 8.2 Hz, 2.1 Hz), 7.83(1 H, dd, J = 7.6 Hz, 3.0 Hz), 8.03(1 H, d, J = 2.1 Hz), 8.06- 8.13(2 H, m), 8.17(1 H, s), 8.24(1 H, d, J = 3.0 Hz).
















TABLE 160













 














Example






mp (° C.) or 1H NMR


No.
R559
R560
Xb1
Xb2
R561
Form
(DMSO-d6) δppm





270
—Cl
—Cl
—O—




piperonyl
free
1H NMR (at 375 K) 2.00(3 H, brs), 2.30- 2.38(4 H, m), 3.34-3.43(6 H, m), 4.12(2 H, s), 4.51(2 H, brs), 5.91(2 H, s), 6.73(1 H, d, J = 7.9 Hz), 6.77(1 H, d, J = 7.9 Hz), 6.81(1 H, s), 6.98(1 H, d, J = 8.8 Hz), 7.05(2 H, d, J = 8.2 Hz), 7.26(2 H, d, J = 8.2 Hz), 7.73(1 H, d, J = 8.4 Hz), 7.91(1 H, dd, J = 2.1 Hz, 8.4 Hz), 8.12- 8.18(3 H, m), 8.48(1 H, d, J = 2.6 Hz), 10.17(1 H, s).


 


271
—Cl
—Cl
—O—




benzyl
free
1H NMR (at 375 K) 2.00(3 H, brs), 2.33- 2.40(4 H, m), 3.38-3.42(4 H, m), 3.49- 3.53(2 H, m), 4.13(2 H, s), 4.51(2 H, brs), 698(1 H, d, J = 8.8 Hz), 7.02-7.10(2 H, m), 7.16-7.30(7 H, m), 7.73(1 H, d, J = 8.4 Hz), 7.91(1 H, dd, J = 8.4 Hz, 2.1 Hz), 8.11-8.17(2 H, m), 8.48(1 H, d, J = 2.5 Hz), 10.17(1 H, s).


 


272
—CF3
—H
—O—
—CH═CH—
benzyl
free
1H NMR 2.39(4 H, brs), 3.52(2 H, s),






(trans)


3.58(2 H, brs), 3.71(2 H, brs), 7.13(1 H, d,









J = 8.9 Hz), 7.14(2 H, d, J = 8.7 Hz),









7.24(1 H, d, J = 15.3 Hz), 7.18-7.41(5 H,









m), 7.50(1 H, d, J = 15.3 Hz), 7.76(2 H, d,









J = 8.7 Hz), 7.94(2 H, d, J = 8.3 Hz),









8.17(2 H, d, J = 8.3 Hz), 8.25(1 H, dd, J =









8.9 Hz, 2.7 Hz), 8.54(1 H, d, J = 2.7 Hz),









10.66(1 H, s).


273
—CF3
—H
—O—
—CH═CH—
piperonyl
free
1H NMR 2.37(4 H, brs), 3.42(2 H, s),






(trans)


3.58(2 H, brs), 3.70(2 H, brs), 5.99(2 H, s),









6.76(1 H, dd,J = 8.0 Hz, 2.4Hz),









6.85(1 H, d, J = 8.0 Hz), 6.88(1 H, d, J =









1.5 Hz), 7.13(1 H, d, J = 8.9 Hz),









7.14(2 H, d, J = 8.7 Hz), 7.20(1 H, d, J =









15.4 Hz), 7.50(1 H, d, J = 15.4 Hz),









7.76(2 H, d, J = 8.7 Hz), 7.94(2 H, d, J =









8.2 Hz), 8.17(2 H, d, J = 8.2 Hz),









8.25(1 H, dd, J = 8.9 Hz, 2.6 Hz), 8.54









(1 H, d, J = 2.6 Hz), 10.65(1 H, s).


274
—CF3
—H
—N(CH3)—
none
piperonyl
dihydro-
1H NMR 2.98-3.12(2 H, m), 3.12-








chloride
3.36(2 H, m), 3.50(3 H, s), 3.71-4.68(6 H,









m), 6.06(2 H, s), 6.93-7.06(3 H, m),









7.26(1 H, s), 7.42(2 H, d, J = 8.3 Hz),









7.53(2 H, d, J = 8.3 Hz), 7.92(2 H, d, J =









8.3 Hz), 8.12(1 H, d, J = 9.2 Hz),









8.20(2 H, d, J = 8.3 Hz), 8.67(1 H, s),









10.79(1 H, s), 11.47(1 H, brs).


275
—CF3
—H
—N(CH3)—
none
benzyl
free
mp 213-214
















TABLE 161













 











Example



mp (° C.) or 1H NMR (CDCl3)


No.
R562
R563
R564
δppm





276
—Cl
—Cl




1H NMR 1.62-1.80(2 H, m), 1.82- 1.87(2 H, m), 2.71(1 H, dt, J = 3 Hz, 11.0 Hz), 2.84(1 H, brs), 2.94(1 H, t, J = 11.0 Hz), 3.55- 3.70(10 H, m), 6.89(1 H, d, J = 9.0 Hz), 6.93(2 H, dd, J = 7.0 Hz, 2.0 Hz), 7.02(2 H, dd, J = 7.0 Hz, 2.0 Hz), 7.56(1 H, d, J = 8.0 Hz), 7.71(1 H, dd, J = 9.0 Hz, 2.0 Hz), 7.99(1 H, d, J = 2.0 Hz), 2.0 Hz), 7.99(1 H, d, J = 2.0 Hz), 8.10(1 H, s), 8.15(1 H, dd, J = 9.0 Hz, 2.5 Hz), 8.25(1 H, d, J = 2.5 Hz).


 


277
—Cl
—Cl




1H NMR 2.38-2.42(4 H, m), 2.62- 2.67(4 H, m), 3.14-3.17(4 H, m), 3.22(2 H, s), 3.42(2 H, s), 3.61- 3.63(4 H, m), 5.95(2 H, s), 6.70- 6.75(2 H, m), 7.03(2 H, d, J = 8.0 Hz), 7.55(1 H, d, J = 8.0 Hz), 7.70(1 H, brs), 7.73(2 H, d, J = 8.0 Hz), 8.01(1 H, s), 8.15(1 H, brd, J = 9.0 Hz), 8.27(1 H, d, J = 2.5 Hz).


 


278
—Cl
—Cl




1H NMR 2.40-2.45(4 H, m), 2.60- 2.64(4 H, m), 3.13(4 H, brs), 3.20(2 H, brs), 3.48(2 H, brs), 3.62(4 H, brs), 6.85-6.91(3 H, m), 7.01(2 H, d, J = 8.0 Hz), 7.26- 7.32(5 H, m), 7.52(1 H, d, J = 8.5 Hz), 7.70(1 H, brs), 7.74(1 H, dd, J = 8.5 Hz, 2.0 Hz), 8.03(1 H, d, J = 2.0 Hz), 8.15(1 H, brd, J = 9.0, Hz), 8.29(1 H, d, J = 2.5 Hz).


 


279
—H
—CF3




mp 180-183


 


280
—H
—CF3




mp 197-199


 


281
—H
—CF3




mp 133-135
















TABLE 162













 










Example





No.
R565
Form
mp (° C.)





282




free
108-110


 


283




free
136-138


 


284




free
133-136


 


285




free
147-151


 


286




dihydrochloride
180-183


 


287




free
111-113


 


288




free
111-113


 


289




free
246-249


 


290




free
148-151


 


291




free
120-121
















TABLE 163













 










Example





No.
R566
Form
mp (° C.)





292




free
 83-86


 


293




free
130-133


 


294




free
145-146


 


295




trihydro- chloride
180-185


 


296




free
184-186


 


297




free
173-176


 


298




free
181-183


 


299




free
166-170
















TABLE 164













 









Example




No.
R567
mp (° C.)





300




102-104


 


301




106-109


 


302




261-264


 


303




173-175


 


304




164-166


 


305




158-160


 


306




174-176


 


307




206-207


 


308




165-166


 


309




164-167


 


310




188-190


 


311




130-132
















TABLE 165













 










Example





No.
R568
R569
mp (° C.) or 1H NMR (CDCl3) δppm





312
—H




mp 166-167


 


313
—H




mp 157-158


 


314
—H




mp 218-219


 


315




benzyl
1H NMR 0.25-0.31(2 H, m), 0.61- 0.69(2 H, m), 2.67-2.73(1 H, m), 2.86(4 H, brs), 3.18(4 H, brs), 3.83(2 H, s), 6.80-6.92(3 H, m), 7.16-7.62(8 H, m), 8.11(2 H, d, J = 8.1 Hz), 8.39(1 H, dd, J = 8.9 Hz, 2.6 Hz), 8.45(1 H, d, J = 2.5 Hz), 10.23(1 H, s), 10.93(1 H, brs).


 


316
—CONHPh
benzyl
1H NMR 3.07(4 H, brs), 3.26(4 H,





brs), 3.98(2 H, s), 6.83-7.59(14 H,





m), 7.65(2 H, d, J = 8.3 Hz),





8.06(2 H, d, J = 8.1 Hz), 8.37(1 H,





d, J = 2.6 Hz), 8.49(1 H, dd, J =





8.9 Hz, 2.6 Hz), 9.30(1 H, s),





9.71(1 H, brs).


 


317




benzyl
1H NMR 1.87(4 H, brs), 2.72(4 H, brs), 3.19(4 H, brs), 3.40(4 H, brs), 3.69(2 H, s), 6.58(1 H, d, J = 8.7 Hz), 6.80(1 H, s), 6.92(1 H, d, J = 9.2 Hz), 7.02(1 H, d, J = 8.9 Hz), 7.26-7.34(5 H, m), 7.57(2 H, d, J = 7.9 Hz), 7.90(1 H, d, J = 7.1 Hz), 8.05(2 H, d, J = 8.1 Hz), 8.40(1 H, s), 9.73(1 H, s).
















TABLE 166













 












Example







No.
Xb3
Xb4
Xb5
R570
mp (° C.) or 1H NMR (CDCl3) δppm





318
—O—








benzyl
mp 162-163


 


319
—O—








piperonyl
mp 136-137


 


320
—O—




—O—
none
mp 176-177


 


321
—N(CH3)—












1H NMR 2.43(4 H, brs), 2.67(4 H, t, J = 4.8 Hz), 3.22(4 H, t, J = 4.8 Hz), 3.24(2 H, s), 3.42(3 H, s), 3.52(2 H, s), 3.63(4 H, brs), 6.46 (1 H, d, J = 9.1 Hz), 6.95(2 H, d, J = 8.9 Hz), 7.15(2 H, d, J = 8.9 Hz), 7.20-7.40(5 H, m), 7.65-7.80(2 H, m), 7.74(2 H, d, J = 8.2 Hz), 7.98(2 H, d, J = 8.2 Hz), 8.26(1 H, d, J = 2.5 Hz).


 


322
—N(CH3)—








piperonyl
1H NMR 2.41(4 H, brs), 2.67(4 H, t, J = 4.8 Hz), 3.22(4 H, t, J = 5.1 Hz), 3.24(2 H, s), 3.42(5 H, s), 3.62(4 H, t, J = 4.5 Hz), 5.94(2 H, s), 6.46(1 H, d, J = 9.1 Hz), 6.74(2 H, s), 6.85(1 H, s), 6.95(2 H, d, J = 8.9 Hz), 7.15(2 H, d, J = 8.9 Hz), 7.65-7.75(1 H, m), 7.74(2 H, d, J = 8.1 Hz), 7.83(1 H, brs), 7.99(2 H, d, J = 8.1 Hz), 8.26(1 H,d, J = 2.5 Hz).


 


323
—N(CH3)—








benzyl
1H NMR 1.31-1.52(2 H, m), 1.88(2 H, d, J = 12.3 Hz), 1.88-2.15(1 H, m), 2.29(2 H, d, J = 6.7 Hz), 2.44(4 H, t, J = 5.1 Hz), 2.76(2 H, t, J = 11.2 Hz), 3.42(3 H, s), 3.49(2 H, t, J = 4.9 Hz), 3.53(2 H, s), 3.59-3.78(4 H, m), 6.47(1 H, d, J = 9.1 Hz), 6.96(2 H, d, J = 8.9 Hz), 7.13 (2 H, d, J = 8.9 Hz), 7.20-7.41(5 H, m), 7.61- 7.78(2 H, m), 7.75(2 H, d, J = 8.1 Hz), 7.98 (2 H, d, J = 8.1 Hz), 8.25(1 H, d, J = 2.3 Hz).


 


324
—N(CH3)—








piperonyl
1H NMR 1.30-1.51(2 H, m), 1.88(2 H, d, J = 2.9 Hz), 1.98-2.11(1 H, m), 2.29(2 H, d, J = 6.7 Hz), 2.41(4 H, m), 2.76(2 H, t, J = 11.2 Hz), 3.42(3 H, s), 3.43(2 H, s), 3.49(2 H, t, J = 4.8 Hz), 3.55-3.78(4 H, m), 5.95(2 H, s), 6.47(1 H, d, J = 9.0 Hz), 6.74(2 H, s), 6.86(1 H, s), 6.96(2 H, d, J = 8.9 Hz), 7.13(2 H, d, J = 8.9 Hz), 7.70(1 H, brs), 7.71(1 H, dd, J = 9.0 Hz, 2.7 Hz), 7.75(2 H, d, J = 8.2 Hz), 7.99(2 H, d, J = 8.2 Hz), 8.26(1 H, d, J = 2.7 Hz).
















TABLE 167













 












Example







No.
Xb6
M
R571
Form
δmp (° C.) or 1H NMR





325
—N(Ac)—
1




hydro- chloride
mp 214-216


 


326
—N(Ac)—
1




free
1H NMR (DMSO-d6) δ 1.77(3 H,s), 2.25-2.34(4 H, m), 3.30-3.50(6 H, m), 4.40 (2 H, s), 6.97(2 H, d, J = 8.8 Hz), 7.22-7.35(6 H, m), 7.36(2 H, d, J = 8.8 Hz), 7.53- 7.59(1 H, m), 7.84(1 H, d, J = 8.3 Hz), 7.89-7.95(2 H, m), 8.20(1 H, d, J = 2.2 Hz), 10.61(1 H, s).


 


327
none
1




free
mp 178-179


 


328
none
1
morpholino
free
mp 196-198


 


329
none
1




free
mp 197-198


 


330
none
3
morpholino
free
mp 144-146


 


331
none
3




hydro- chloride
mp 194-196


 


332
none
3




hydro- chloride
mp 205-206


 


333
—S—
1




free
1H NMR (CDCl3) δ 2.35- 2.45(4 H, m), 3.42(2 H, s), 3.42-3.48(2 H, m), 3.58(2 H, brs), 3.65(2 H, s), 5.94(2 H, s), 6.72-6.75(2 H, m), 6.84(1 H, d, J = 1.1 Hz), 6.89(2 H, d, J = 8.8 Hz), 7.00-7.10(1 H, m), 7.19-7.25(1 H, m), 7.42(2 H, d, J = 8.8 Hz), 7.58(1 H, d, J = 8.3 Hz), 7.65-7.76(2 H, m), 7.98(1 H, s), 7.99(1 H, s).


 


334
—SO—
1




free
mp 133-135


 


335
—SO2—
1




free
mp 125-128


 


336
CH═CH— (trans)
0




free
mp 169-171
















TABLE 168













 










Example





No.
R572
R573
1H NMR (solvent) δppm





337
4-CF3Ph-
benzyl
(CDCl3) 2.30-2.34(2 H, m), 2.39-2.43(2 H, m),





3.46-3.49(4 H, m), 3.62-3.66(2 H, m), 3.69(2 H,





s), 6.94(1 H, d, J = 8.7 Hz), 7.03-7.08(2 H, m),





7.19-7.35(7 H, m), 7.75(2 H, d, J = 8.2 Hz),





8.00(2 H, d, J = 8.2 Hz), 8.21(1 H, dd, J = 8.7





Hz, 2.8 Hz), 8.26(1 H, s), 8.29(1 H, d, J = 2.8





Hz).


338
4-CF3Ph-
piperonyl
(CDCl3) 2.28-2.32(2 H, m), 2.36-2.39(2 H, m),





3.39(2 H, s), 3.45-3.49(2 H, m), 3.60-3.64(2 H,





m), 3.68(2 H, s), 5.94(2 H, s), 6.69-6.76(2 H, m),





6.83(1 H, brs), 6.92(1 H, d, J = 8.7 Hz), 7.01-





7.06(2 H, m), 7.17-7.22(2 H, m), 7.72(2 H, d, J =





8.4 Hz), 8.00(2 H, d, J = 8.1 Hz), 8.17-8.21(1 H,





m), 8.29(1 H, d, J = 2.6 Hz), 8.49(1 H, brs).


339
3,4-Cl2Ph-
benzyl
(CDCl3) 2.31-2.34(2 H, m), 2.38-2.42(2 H, m),





3.46-3.50(4 H, m), 3.62-3.65(2 H, m), 3.69(2 H,





s), 6.90(1 H, d, J = 8.9 Hz), 7.00-7.05(2 H, m),





7.17-7.23(2 H, m), 7.28-7.35(5 H, m), 7.54(1 H, d,





J = 8.2 Hz), 7.73(1 H, dd, J = 8.4 Hz, 2.1 Hz),





7.99(1 H, d, J = 2.1 Hz), 8.12-8.17(1 H, m),





8.28(1 H, d, J = 2.8 Hz), 8.44(1 H, brs).


340
3,4-Cl2Ph-
3-pyridyl
(CDCl3) 3.02-3.06(2 H, m), 3.13-3.17(2 H, m),





3.63-3.67(2 H, m), 3.76-3.82(4 H, m), 6.91(1 H, d,





J = 8.9 Hz), 7.02-7.07(2 H, m), 7.17-7.24(4 H,





m), 7.52(1 H, d, J = 8.4 Hz), 7.73-7.76(1 H, m),





8.01(1 H, d, J = 2.0 Hz), 8.11-8.13(1 H, m),





8.18(1 H,dd, J = 8.9 Hz, 2.8 Hz), 8.23-8.25(2 H,





m), 8.95(1 H, brs).


341
3,4-Cl2Ph-
piperonyl
(CDCl3) 2.28-2.39(4 H, m), 3.39(2 H, s), 3.46-





3.49(2 H, m), 3.60-3.64(2 H, m), 3.69(2 H, s)





5.94(2 H, s), 6.69-6.76(2 H, m), 6.82-6.83(1 H,





m), 6.89(1 H, d, J = 8.9 Hz), 6.99-7.04(2 H, m),





7.15-7.21(2 H, m), 7.53(1 H, d, J = 8.4 Hz), 7.71-





7.75(1 H, m), 7.99(1 H, d, J = 2.1 Hz), 8.14(1 H,





dd, J = 8.9 Hz, 2.6 Hz), 8.28(1 H, d, J = 2.6 Hz),





8.56(1 H, s).


342
3,4-Cl2PhNH—
piperonyl
(DMSO-d6) 2.20-2.35(4 H, m), 3.38(2 H, s), 3.40-





3.55(4 H, m), 3.69(2 H, s), 5.98(2 H, s), 6.70-





6.76(1 H, m), 6.76-6.86(2 H, m), 6.97-7.00(3 H,





m), 7.02-7.24(2 H, m), 7.35(1 H, dd, J = 8.8 Hz,





2.5 Hz), 7.52(1 H, d, J = 8.8 Hz), 7.86(1 H, d, J =





2.5 Hz), 7.98(1 H, dd, J = 8.8 Hz, 2.8 Hz),





8.19(1 H, d, J = 2.6 Hz), 8.89(1 H, s), 9.08(1 H,





s).
















TABLE 169













 









Example




No.
R574
1H NMR (DMSO-d6) δppm or MS





343
—H
1H NMR 2.33(2 H, t, J = 7.7 Hz), 2.77(2 H, t, J = 7.7 Hz),




6.75(1 H, brs), 6.87(2 H, d, J = 8.6 Hz), 7.15-7.23(3 H, m),




7.28(1 H, brs), 7.54(1 H, d, J = 8.7 Hz), 7.85(1 H, d, J = 8.4




Hz), 7.89(1 H, dd, J = 13.2 Hz, 2.4 Hz), 7.94(1 H, dd, J = 8.4




Hz, 2.0 Hz), 8.21(1 H, d, J = 2.0 Hz), 10.57(1 H, s).


344
—CH3
MS 460(M+)


345
—C2H5
1H NMR 0.97(3 H, t, J = 7.2 Hz), 2.32(2 H, t, J = 7.8 Hz),




2.77(2 H, t, J = 7.8 Hz), 3.00-3.08(2 H, m), 6.87(2 H, d, J = 8.6




Hz), 7.14-7.21(3 H, m), 7.54(1 H, d, J = 9.8 Hz), 7.78(1 H, brt),




7.85(1 H, d, J = 8.4 Hz), 7.89(1 H, dd, J = 13.2 Hz, 2.3 Hz),




7.94(1 H, dd, J = 8.4 Hz, 2.1 Hz), 8.21(1 H, d, J = 2.1 Hz),




10.57(1 H, s).


346
—CH(CH3)2
1H NMR 1.00(6 H, d, J = 6.6 Hz), 2.30(2 H, t, J = 7.7 Hz),




2.77(2 H, t, J = 7.7 Hz), 3.75-3.86(1 H, m), 6.87(2 H, d, J = 8.6




Hz), 7.13-7.20(3 H, m), 7.54(1 H, d, J = 8.9 Hz), 7.65(1 H,




brd), 7.85(1 H, d, J = 8.4 Hz), 7.89(1 H, dd, J = 13.1 Hz, 2.5




Hz), 7.94(1 H, dd, J = 8.4 Hz, 2.1 Hz), 8.22(1 H, d, J = 2.1




Hz), 10.58(1 H, s).


347
—CH2CH(CH3)2
1H NMR 0.78(6 H, d, J = 6.7 Hz), 1.56-1.68(1 H, m), 2.36(2 H,




t, J = 7.6 Hz), 2.78(2 H, t, J = 7.6 Hz), 2.81-2.87(2 H, m),




6.87(2 H, d, J = 8.6 Hz), 7.10-7.22(3 H, m), 7.54(1 H, d, J =




8.9 Hz), 7.77(1 H, brt), 7.85(1 H, d, J = 8.4 Hz), 7.89(1 H, dd, J =




13.2 Hz, 2.4 Hz), 7.94(1 H, dd, J = 8.4 Hz, 2.1 Hz),




8.21(1 H, d, J = 2.1 Hz), 10.57(1 H, s).


348
—(CH2)3CH3
1H NMR 0.84(3 H, t, J = 7.3 Hz), 1.15-1.27(2 H, m), 1.27-




1.38(2 H, m), 2.33(2 H, t, J = 7.7 Hz), 2.77(2 H, t, J = 7.7 Hz),




2.97-3.05(2 H, m), 6.87(2 H, d, J = 8.6 Hz), 7.11-7.21(3 H, m),




7.50-7.58(1 H, m), 7.74(1 H, brt), 7.85(1 H, d, J = 8.4 Hz), 7.89




(1 H, dd, J = 13.2 Hz, 2.4Hz), 7.94(1 H, dd, J = 8.4 Hz, 2.1




Hz), 8.21(1 H, d, J = 2.1 Hz), 10.57(1 H, s).


349
cyclopropyl
1H NMR 0.26-0.37(2 H, m), 0.51-0.63(2 H, m), 2.29(2 H, t, J =




7.7 Hz), 2.53-2.61(1 H, m), 2.76(2 H, t, J = 7.7 Hz), 6.87(2 H,




d, J = 8.6 Hz), 7.10-7.23(3 H, m), 7.54(1 H, d, J = 8.6 Hz),




7.80-8.00(4 H, m), 8.21(1 H, d, J = 2.1 Hz), 10.57(1 H, s).


350
cyclopentyl
1H NMR 1.21-1.34(2 H, m), 1.41-1.51(2 H, m), 1.51-1.63(2 H,




m), 1.68-1.80(2 H, m), 2.31(2 H, t, J = 7.7 Hz), 2.76(2 H, t, J =




7.7 Hz), 3.90-3.99(1 H, m), 6.87(2 H, d, J = 8.6 Hz), 7.14-




7.21(3 H, m), 7.50-7.57(1 H, m), 7.72(1 H, brd), 7.85(1 H, d, J =




8.4 Hz), 7.89(1 H, dd, J = 13.2 Hz, 2.4 Hz), 7.94(1 H, dd, J =




8.4 Hz, 2.1 Hz), 8.22(1 H, d, J = 2.1 Hz), 10.58(1 H, s).


351
cyclohexyl
1H NMR 1.00-1.15(3 H, m), 1.15-1.28(2 H, m), 1.48-1.58(1 H,




m), 1.58-1.70(4 H, m), 2.31(2 H, t, J = 7.6 Hz), 2.77(2 H, t, J =




7.6 Hz), 3.44-3.53(1 H, m), 6.87(2 H, d, J = 8.6 Hz), 7.11-




7.23(3 H, m), 7.50-7.57(1 H, m), 7.62(1 H, brd), 7.85(1 H, d, J =




8.4 Hz), 7.89(1 H, dd, J = 13.2 Hz, 2.4 Hz), 7.94(1 H, dd, J =




8.4 Hz, 2.1 Hz), 8.21(1 H, d, J = 2.1 Hz), 10.57(1 H, s).
















TABLE 170













 









Example




No.
R575
1H NMR (DMSO-d6) δ ppm





352
cycloheptyl
1.28-1.40 (4 H, m), 1.40-1.61 (6 H, m), 1.63-1.77 (2 H, m),




2.31 (2 H, t, J = 7.6 Hz), 2.76 (2 H, t, J = 7.6 Hz), 3.64-




3.74 (1 H, m), 6.87 (2 H, d, J = 8.6 Hz), 7.11-7.23 (3 H, m),




7.54 (1 H, d, J = 9.1 Hz), 7.67 (1 H, brd), 7.85 (1 H, d, J = 8.4 Hz),




7.89 (1 H, dd, J = 13.2 Hz, 2.4 Hz), 7.94 (1 H, dd,




J = 8.4 Hz, 2.1 Hz), 8.21 (1 H, d, J = 2.1 Hz), 10.57 (1 H, s).


353
cyclooctyl
1.30-1.65 (14 H, m), 2.31 (2 H, t, J = 7.6 Hz), 2.76 (2 H, t,




J = 7.6 Hz), 3.69-3.80 (1 H, m), 6.87 (2 H, d, J = 8.6 Hz),




7.10-7.22 (3 H, m), 7.54 (1 H, d, J = 8.9 Hz), 7.65 (1 H, brd),




7.85 (1 H, d, J = 8.4 Hz), 7.89 (1 H, dd, J = 13.2 Hz, 2.3 Hz),




7.94 (1 H, dd, J = 8.4 Hz, 2.0 Hz), 8.21 (1 H, d, J = 2.0 Hz),




10.57 (1 H, s).


354
cyclododecanyl
1.10-1.41 (20 H, m), 1.41-1.54 (2 H, m), 2.32 (2 H, t, J = 7.5 Hz),




2.77 (2 H, t, J = 7.5 Hz), 3.79-3.88 (1 H, m), 6.86 (2 H,




d, J = 8.6 Hz), 7.10-7.21 (3 H, m), 7.48-7.57 (2 H, m),




7.85 (1 H, d, J = 8.4 Hz), 7.89 (1 H, dd, J = 13.1 Hz,




2.5 Hz), 7.94 (1 H, dd, J = 8.4 Hz, 2.1 Hz), 8.21 (1 H, d,




J = 2.1 Hz), 10.58 (1 H, s).


355
cyclopropylmethyl
0.06-0.16 (2 H, m), 0.28-0.42 (2 H, m), 0.78-0.90 (1 H, m),




2.35 (2 H, t, J = 7.7 Hz), 2.78 (2 H, t, J = 7.7 Hz), 2.84-




2.97 (2 H, m), 6.87 (2 H, d, J = 8.5 Hz), 7.12-7.27 (3 H, m),




7.54 (1 H, d, J = 8.8 Hz), 7.85 (1 H, d, J = 8.4 Hz), 7.87 (1 H,




brt), 7.89 (1 H, dd, J = 13.2 Hz, 2.3 Hz), 7.94 (1 H, dd,




J = 8.4 Hz, 2.0 Hz), 8.21 (1 H, d, J = 2.0 Hz), 10.57 (1 H, s).


356
cyclohexylmethyl
0.71-0.86 (2 H, m), 1.03-1.20 (3 H, m), 1.22-1.34 (1 H, m),




1.50-1.69 (5 H, m), 2.35 (2 H, t, J = 7.6 Hz), 2.78 (2 H, t,




J = 7.6 Hz), 2.80-2.90 (2 H, m), 6.86 (2 H, d, J = 8.6 Hz), 7.12-




7.23 (3 H, m), 7.54 (1 H, d, J = 8.9 Hz), 7.73 (1 H, brt),




7.85 (1 H, d, J = 8.4 Hz), 7.89 (1 H, dd, J = 13.2 Hz,




2.4 Hz), 7.94 (1 H, dd, J = 8.4 Hz, 2.1 Hz), 8.21 (1 H, d,




J = 2.1 Hz), 10.57 (1 H, s).


357
piperonyl
2.41 (2 H, t, J = 7.6 Hz), 2.81 (2 H, t, J = 7.6 Hz), 4.15 (2 H,




d, J = 5.9 Hz), 5.96 (2 H, s), 6.63 (1 H, d, J = 8.0 Hz),




6.74 (1 H, d, J = 1.4 Hz), 6.80 (1 H, d, J = 8.0 Hz), 6.87 (2 H,




d, J = 8.8 Hz), 7.14-7.23 (3 H, m), 7.54 (1 H, d, J = 9.8 Hz),




7.85 (1 H, d, J = 8.4 Hz), 7.89 (1 H, dd, J = 13.2 Hz, 2.4 Hz),




7.94 (1 H, dd, J = 8.4 Hz, 2.1 Hz), 8.22 (1 H, d, J = 2.1 Hz),




8.25 (1 H, brt), 8.40-8.46 (2 H, m), 10.58 (1 H, s).


358
—CH(CH3)Ph
1.30 (3 H, d, J = 7.0 Hz), 2.40 (2 H, t, J = 7.5 Hz), 2.78 (2 H,




t, J = 7.5 Hz), 3.86-3.96 (1 H, m), 6.82-6.99 (2 H, m), 7.12-




7.24 (6 H, m), 7.24-7.31 (2 H, m), 7.55 (1 H, dd, J = 8.9 Hz,




1.2 Hz), 7.85 (1 H, d, J = 8.4 Hz), 7.90 (1 H, dd, J = 13.2 Hz,




2.5 Hz), 7.94 (1 H, dd, J = 8.4 Hz, 2.1 Hz), 8.22 (1 H, d,




J = 2.1 Hz), 8.24 (1 H, brd), 10.59 (1 H, s).
















TABLE 171













 









Example




No.
R576
1H NMR (DMSO-d6) δ ppm or MS





359
2-pyridylmethyl
MS 537(M+)


360
3-pyridylmethyl
1H NMR 2.44 (2 H, t, J = 7.6 Hz), 2.82 (2 H, t, J = 7.6 Hz),




4.27 (2 H, d, J = 5.9 Hz), 6.86 (2 H, dd, J = 6.7 Hz,




1.9 Hz), 7.14-7.22 (3 H, m), 7.25-7.32 (1 H, m), 7.46-




7.58 (2 H, m), 7.85 (1 H, d, J = 8.4 Hz), 7.90 (1 H, dd,




J = 13.2 Hz, 2.5 Hz), 7.94 (1 H, dd, J = 8.4 Hz, 2.1 Hz),




8.22 (1 H, d, J = 2.1 Hz), 8.38 (1 H, brt), 8.40-8.46 (2 H,




m), 10.58 (1 H, s).


361
4-pyridylmethyl
MS 537(M+)


362
—(CH2)2NHAc
1H NMR 1.78 (3 H, s), 2.34 (2 H, t, J = 7.8 Hz),




2.78 (2 H, t, J = 7.8 Hz), 2.96-3.10 (4 H, m), 6.83-




6.91 (2 H, m), 7.14-7.23 (3 H, m), 7.54 (1 H, dd, J = 8.9 Hz,




1.3 Hz), 7.80-7.98 (5 H, m), 8.21 (1 H, d, J = 2.1 Hz),




10.58 (1 H, s).


363
—CH(CH3)(CH2)4CH3
1H NMR 0.84 (3 H, t, J = 7.0 Hz), 0.96 (3 H, d, J = 6.6 Hz),




1.08-1.34 (8 H, m), 2.32 (2 H, t, J = 7.2 Hz),




2.77 (2 H, t, J = 7.2 Hz), 3.65-3.76 (1 H, m), 6.82-




6.89 (2 H, m), 7.12-7.21 (3 H, m), 7.50-7.60 (2 H, m),




7.85 (1 H, d, J = 8.4 Hz), 7.89 (1 H, dd, J = 13.2 Hz,




2.5 Hz), 7.94 (1 H, dd, J = 8.3 Hz, 2.1 Hz), 8.21 (1 H, d,




J = 2.1 Hz), 10.58 (1 H, s).


364
—(CH2)2OCH3
1H NMR 2.35 (2 H, t, J = 7.7 Hz), 2.77 (2 H, t, J = 7.7 Hz),




3.13-3.22 (2 H, m), 3.22 (3 H, s), 3.29 (2 H, t,




J = 5.8 Hz), 6.82-6.92 (2 H, m), 7.13-7.23 (3 H, m),




7.54 (1 H, d, J = 8.9 Hz), 7.85 (1 H, d, J = 8.4 Hz), 7.85-




7.92 (2 H, m), 7.94 (1 H, dd, J = 8.4 Hz, 2.0 Hz),




8.21 (1 H, d, J = 2.0 Hz), 10.57 (1 H, s).


 


365




MS 554(M+)


 


366




MS 619(M+)
















TABLE 172













 










Example


mp (° C.)


No.
R577
R578
or MS





367
—H
morpholino
mp 160-162


368
—F
morpholino
mp 150-151


 


369
—F




MS 657 (M + + H)


 


370
—F




MS 646 (M + − 1)


 


371
—F
4-CH3OPh(CH2)2N(C2H5)—
MS 608 (M +)


372
—F
4-CH3OPhCH2N(C2H5)—
MS 594 (M +)


373
—F
3,4-
MS 638 (M +)




(CH3O)2PhCH2N(CH2CH2CH3)—
















TABLE 173













 









Example




No.
R579
1H NMR (DMSO-d6) δ ppm





374
Ph-
2.39-2.49 (2 H, m), 2.78-2.88 (2 H, m), 4.18-4.30 (2 H, m),




6.87 (2 H, d, J = 8.6 Hz), 7.02-7.33 (8 H, m), 7.55 (1 H, d, J = 8.9 Hz),




7.85 (1 H, d, J = 8.4 Hz), 7.90 (1 H, dd, J = 13.2 Hz, 2.4 Hz),




7.94 (1 H, dd, J = 8.4 Hz, 2.0 Hz), 8.22 (1 H, d, J = 2.0 Hz),




8.32 (1 H, brt), 10.58 (1 H, s).


375
4-FPh-
2.43 (2 H, t, J = 7.6 Hz), 2.82 (2 H, t, J = 7.6 Hz), 4.22 (2 H, d,




J = 5.9 Hz), 6.87 (2 H, d, J = 8.6 Hz), 7.04-7.12 (2 H, m), 7.12-




7.24 (5 H, m), 7.55 (1 H, d, J = 9.0 Hz), 7.85 (1 H, d, J = 8.4 Hz),




7.90 (1 H, dd, J = 13.2 Hz, 2.4 Hz), 7.94 (1 H, dd, J = 8.4 Hz, 2.1 Hz),




8.22 (1 H, d, J = 2.1 Hz), 8.32 (1 H, brt), 10.58 (1 H, s).


376
3,4-(CH3O)2Ph-
2.42 (2 H, t, J = 7.6 Hz), 2.82 (2 H, t, J = 7.6 Hz), 3.70 (3 H, s),




3.71 (3 H, s), 4.18 (2 H, d, J = 5.8 Hz), 6.67 (1 H, d, J = 8.4 Hz),




6.77-6.90 (4 H, m), 7.15-7.23 (3 H, m), 7.55 (1 H, d, J = 9.0 Hz),




7.85 (1 H, d, J = 8.4 Hz), 7.89 (1 H, dd, J = 13.2 Hz, 2.4 Hz),




7.94 (1 H, dd, J = 8.4 Hz, 2.1 Hz), 8.21 (1 H, d, J = 2.0 Hz),




8.25 (1 H, brt), 10.58 (1 H, s).


377
2-ClPh-
2.48 (2 H, t, J = 7.5 Hz), 2.83 (2 H, t, J = 7.5 Hz), 4.30 (2 H, d,




J = 5.9 Hz), 6.88 (2 H, d, J = 8.6 Hz), 7.08-7.15 (1 H, m), 7.15-




7.32 (5 H, m), 7.38-7.46 (1 H, m), 7.51-7.59 (1 H, m), 7.85 (1 H, d,




J = 8.4 Hz), 7.90 (1 H, dd, J = 13.2 Hz, 2.4 Hz), 7.94 (1 H, dd,




J = 8.4 Hz, 2.1 Hz), 8.22 (1 H, d, J = 2.0 Hz), 8.34 (1 H, brt), 10.58




(1 H, s).


378
3-ClPh-
2.45 (2 H, t, J = 7.5 Hz), 2.83 (2 H, t, J = 7.5 Hz), 4.25 (2 H, d,




J = 6.0 Hz), 6.87 (2 H, d, J = 8.6 Hz), 7.07-7.12 (1 H, m), 7.12-




7.21 (3 H, m), 7.21-7.25 (1 H, m), 7.25-7.33 (2 H, m), 7.55 (1 H, d,




J = 9.0 Hz), 7.85 (1 H, d, J = 8.4 Hz), 7.90 (1 H, dd, J = 13.2 Hz,




2.4 Hz), 7.94 (1 H, dd, J = 8.4 Hz, 2.1 Hz), 8.22 (1 H, d, J = 2.1 Hz),




8.37 (1 H, brt), 10.58 (1 H, s).


379
4-ClPh-
2.44 (2 H, t, J = 7.5 Hz), 2.82 (2 H, t, J = 7.5 Hz), 4.22 (2 H, d,




J = 6.0 Hz), 6.87 (2 H, d, J = 8.6 Hz), 7.14 (2 H, d, J = 8.4 Hz),




7.16-7.22 (3 H, m), 7.29-7.34 (2 H, m), 7.55 (1 H, d, J = 8.1 Hz),




7.85 (1 H, d, J = 8.4 Hz), 7.90 (1 H, dd, J = 13.2 Hz, 2.5 Hz),




7.94 (1 H, dd, J = 8.4 Hz, 2.1 Hz), 8.21 (1 H, d, J = 2.1 Hz),




8.34 (1 H, brt), 10.58 (1 H, s).


380
2-CH3Ph-
2.21 (3 H, s), 2.44 (2 H, t, J = 7.5 Hz), 2.82 (2 H, t, J = 7.5 Hz),




4.21 (2 H, d, J = 5.7 Hz), 6.87 (2 H, d, J = 8.6 Hz), 7.00-7.07 (1 H,




m), 7.07-7.23 (6 H, m), 7.55 (1 H, d, J = 9.0 Hz), 7.85 (1 H, d,




J = 8.4 Hz), 7.90 (1 H, dd, J = 13.2 Hz, 2.4 Hz), 7.94 (1 H, dd, 




J = 8.4 Hz, 2.1 Hz), 8.16 (1 H, brt), 8.22 (1 H, d, , J = 2.1 Hz),




10.58 (1 H, s).


381
4-CH3OPh-
2.41 (2 H, t, J = 7.6 Hz), 2.81 (2 H, t, J = 7.6 Hz), 3.71 (3 H, s),




4.17 (2 H, d, J = 5.8 Hz), 6.80-6.91 (4 H, m), 7.07 (2 H, d, J = 8.5 Hz),




7.13-7.25 (3 H, m), 7.55 (1 H, d, J = 8.5 Hz), 7.85 (1 H, d,




J = 8.4 Hz), 7.90 (1 H, dd, J = 13.2 Hz, 2.4 Hz), 7.94 (1 H, dd,




J = 8.4 Hz, 2.1 Hz), 8.21 (1 H, d, J = 2.1 Hz), 8.24 (1 H, brt),




10.58 (1 H, s).
















TABLE 174













 









Example




No.
R580
1H NMR (DMSO-d6) δ ppm





382
Ph-
2.33 (2 H, t, J = 7.7 Hz), 2.66 (2 H, t, J = 7.3 Hz), 2.77 (2 H,




t, J = 7.7 Hz), 3.20-3.29 (2 H, m), 6.87 (2 H, d, J = 8.6 Hz),




7.12-7.22 (6 H, m), 7.23-7.30 (2 H, m), 7.54 (1 H, dd,




J = 8.9 Hz, 1.1 Hz), 7.85 (1 H, d, J = 8.4 Hz), 7.85-7.91 (2 H,




m), 7.94 (1 H, dd, J = 8.4 Hz, 2.1 Hz), 8.21 (1 H, d, J = 2.1 Hz),




10.57 (1 H, s).


383
4-FPh-
2.33 (2 H, t, J = 7.7 Hz), 2.65 (2 H, t, J = 7.2 Hz), 2.76 (2 H,




t, J = 7.7 Hz), 3.30-3.37 (2 H, m), 6.87 (2 H, d, J = 8.5 Hz),




7.04-7.11 (2 H, m), 7.13-7.22 (5 H, m), 7.54 (1 H, d, J = 9.1 Hz),




7.85 (1 H, d, J = 8.4 Hz), 7.80-7.92 (2 H, m), 7.94 (1 H,




dd, J = 8.4 Hz, 2.0 Hz), 8.21 (1 H, d, J = 2.0 Hz),




10.58 (1 H, s).


384
4-ClPh-
2.32 (2 H, t, J = 7.6 Hz), 2.66 (2 H, t, J = 7.1 Hz), 2.76 (2 H,




t, J = 7.6 Hz), 3.18-3.27 (2 H, m), 6.87 (2 H, d, J = 8.5 Hz),




7.10-7.22 (5 H, m), 7.31 (2 H, d, J = 8.3 Hz), 7.54 (1 H, d,




J = 8.9 Hz), 7.84 (1 H, d, J = 8.4 Hz), 7.85-7.92 (2 H, m),




7.94 (1 H, dd, J = 8.4 Hz, 2.0 Hz), 8.21 (1 H, d, J = 2.0 Hz),




10.57 (1 H, s).


385
3-CH3OPh-
2.33 (2 H, t, J = 7.7 Hz), 2.64 (2 H, t, J = 7.3 Hz), 2.78 (2 H,




t, J = 7.7 Hz), 3.18-3.27 (2 H, m), 3.72 (3 H, s), 6.70-




6.78 (3 H, m), 6.87 (2 H, d, J = 8.6 Hz), 7.12-7.23 (4 H, m),




7.54 (1 H, dd, J = 8.9 Hz, 1.2 Hz), 7.85 (1 H, d, J = 8.4 Hz),




7.85-7.92 (2 H, m), 7.94 (1 H, dd, J = 8.4 Hz, 2.1 Hz),




8.21 (1 H, d, J = 2.0 Hz), 10.57 (1 H, s).


386
4-CH3OPh-
2.33 (2 H, t, J = 7.6 Hz), 2.59 (2 H, t, J = 7.2 Hz), 2.77 (2 H,




t, J = 7.6 Hz), 3.16-3.24 (2 H, m), 3.71 (3 H, s), 6.83 (2 H, d,




J = 8.5 Hz), 6.87 (2 H, d, J = 8.5 Hz), 7.07 (2 H, d, J = 8.4 Hz),




7.13-7.23 (3 H, m), 7.54 (1 H, d, J = 8.5 Hz), 7.80-




7.98 (4 H, m), 8.21 (1 H, d, J = 1.8 Hz), 10.57 (1 H, s).


387
PhO—
2.38 (2 H, t, J = 7.7 Hz), 2.79 (2 H, t, J = 7.7 Hz), 3.38-




3.43 (2 H, m), 3.94 (2 H, t, J = 5.7 Hz), 6.79-6.85 (2 H, m),




6.89-6.96 (3 H, m), 7.12-7.20 (3 H, m), 7.23-7.31 (2 H, m),




7.50-7.57 (1 H, m), 7.85 (1 H, d, J = 8.4 Hz), 7.89 (1 H, dd,




J = 13.2 Hz, 2.4 Hz), 8.10 (1 h, brt), 8.22 (1 H, d, J = 2.1 Hz),




10.58 (1 H, s).


388
PhCH2—
1.60-1.70 (2 H, m), 2.36 (2 H, t, J = 7.4 Hz), 2.49-2.55 (2 H,




m), 2.79 (2 H, t, J = 7.4 Hz), 3.00-3.08 (2 H, m), 6.83-




6.90 (2 H, m), 7.10-7.21 (6 H, m), 7.21-7.29 (2 H, m),




7.53 (1 H, d, J = 8.9 Hz), 7.89-7.92 (3 H, m), 8.21 (1 H, d,




J = 2.1 Hz), 10.57 (1 H, s).
















TABLE 175













 









Example




No.
R581
MS





389
—CHPh2
681 (M+ + 1)


390
—NHCOPh
633 (M+)


391
—O(CH2)2Ph
634 (M+)


392
—(CH2)2N(CH3)Ph
647 (M+)


 


393




675 (M+)


 


394
morpholino
599 (M+)


 


395




626 (M+)


 


396
cyclohexyl
596 (M+)


 


397




656 (M+)


 


398




626 (M+)


 


399
4-CH3OPhCONH—
664 (M+ + 1)


 


400




644 (M+)


 


401




620 (M+ − 1)


 


402




623 (M+ + 2)
















TABLE 176













 










Example





No.
R582
R583
Property





403
—H
4-CF3OPhNH—
mp 91-95° C.


404
—F
4-CF3OPhNH—
mp 145-147° C.


405
—H
4-CF3PhO—
mp 118-121° C.


406
—H
4-CF3OPhO—
mp 126-127° C.


407
—F
4-CF3PhO—
mp 129-134° C.


408
—H
4-CNPhO—
mp 148-149° C.


409
—F
4-CNPhO—
mp 147-150° C.


410
—F
4-CF3OPhO—
1H NMR (CDCl3) δ 1.69-1.85 (4 H, m), 2.62 (2 H,





t, J = 7.5 Hz), 2.90 (2 H, t, J = 7.5 Hz), 3.36 (1 H,





m), 3.57-3.67 (3 H, m), 4.47 (1 H, m), 6.85-





6.90 (4 H, m), 7.00 (1 H, t, J = 8.5 Hz), 7.10 (2 H,





d, J = 8.5 Hz), 7.13 (2 H, d, J = 8.5 Hz),





7.30 (1 H, brd, J = 8.5 Hz), 7.52 (1 H, d, J = 8.5 Hz),





7.69-7.75 (2 H, m), 7.98 (1 H, d, J = 2.0 Hz),





8.80 (1 H, s).


411
—F
PhO—
MS 606 (M+)


412
—F
4-ClPhCH2—
MS 638 (M+)


413
—F
4-CH3PhCH2—
MS 618 (M+)


414
—F
4-ClPh-
MS 626 (M+)


415
—F
Ph-
MS 590 (M+)


416
—F
2-NH2PhCO—
MS 633 (M+)
















TABLE 177













 











Example



mp (° C.)


No.
R584
R585
Form
or MS





417
—F
—H
free
MS 543 (M+)


418
—F
—(CH2)2OPh
free
MS 664 (M+ + H)


419
—F
—(CH2)2Ph
free
MS 648 (M+ + H)


420
—F
—(CH2)2N(C2H5)2
free
MS 643 (M+ + H)


421
—H
—(CH2)2Ph
fumarate
mp 148-151


422
—F
—(CH2)3Ph
free
MS 661 (M+)


423
—F
—(CH2)2CHPh2
free
MS 737 (M+)


 


424
—F




free
MS 638 (M+)


 


425
—F
4-CH3SPh(CH2)2—
free
MS 692 (M+ − 1)


426
—F
4-CH3PhO(CH2)2—
free
MS 678 (M+ + H)


 


427
—F




free
MS 723 (M+ + H)


 


428
—F
4-CH3OPh(CH2)4—
free
MS 705 (M+)


 


429
—F




free
MS 658 (M+ + H)


 


430
—F
4-CH3Ph(CH2)2—
free
MS 661 (M+)


431
—F
—(CH2)2N(CH3)Ph
free
MS 676 (M+)


 


432
—F




free
MS 653 (M+)
















TABLE 178













 













Example





mp (° C.)


No.
R586
R587
R588
R589
R590
or MS





433
—H
—H
—H
—CF3
—H
mp 124-126


434
—F
—H
—H
—CF3
—H
mp 132-134


435
—F
—H
—H
—Cl
—H
MS 654 (M+)


436
—F
—F
—H
—H
—H
MS 638 (M+)


437
—F
—H
—H
—H
—H
MS 620 (M+)


438
—F
—H
—H
—OCH3
—H
MS 651 (M+ + H)


439
—F
—H
—Cl
—H
—H
MS 656 (M+)


440
—F
—Cl
—H
—H
—H
MS 654 (M)


441
—F
—H
—Cl
—Cl
—H
MS 690 (M+)


442
—F
—H
—OCH3
—H
—H
MS 650 (M+)


443
—F
—H
—OCH3
—H
—OCH3
MS 680 (M+)


444
—F
—H
—H
—CH3
—H
MS 635 (M+ + H)


445
—F
—H
—CH3
—H
—H
MS 636 (M+ + 2)


446
—F
—CH3
—H
—H
—H
MS 635 (M+ + H)


447
—F
—H
—CH3
—CH3
—H
MS 648 (M+)


448
—F
—H
—H
—F
—H
MS 638 (M+)


449
—F
—H
—F
—H
—H
MS 638 (M+)


450
—F
—H
—F
—H
—F
MS 656 (M+)


451
—F
—CF3
—H
—H
—H
MS 688 (M+)


452
—F
—H
—H
—OCF3
—H
MS 705 (M+ + H)


453
—F
—H
—OCF3
—H
—H
MS 704 (M+)


454
—F
—OCF3
—H
—H
—H
MS 704 (M+)


455
—F
—H
—Cl
—OCH3
—H
MS 685 (M+ + H)
















TABLE 179













 










Example





No.
R591
R592
Property





456
—H
—CH2CONHPh
1H NMR (CDCl3) δ 2.45 (2 H, brt, J = 5.0 Hz),





2.55 (2 H, brt, J = 5.0 Hz), 2.63 (2 H, t, J = 7.5 Hz),





2.96 (2 H, t, J = 7.5 Hz), 3.11 (2 H, s),





3.47 (2 H, brs), 3.70 (2 H, brs), 6.93 (2 H, d, J = 8.5 Hz),





6.98 (2 H, d, J = 8.5 Hz), 7.13 (1 H, t, J = 8.5 Hz),





7.15 (2 H, d, J = 8.5 Hz), 7.34 (2 H, t, J = 8.5 Hz),





7.52-7.59 (5 H, m), 7.73 (1 H, dd, J = 8.5 Hz,





2.0 Hz), 7.99 (1 H, d, J = 2.0 Hz), 8.28 (1 H, s),





8.92 (1 H, s).


457
—F
—CH2CONHPh
1H NMR (CDCl3) δ 2.39 (2 H, brs), 2.51 (2 H, brs),





2.61 (2 H, t, J = 7.5 Hz), 2.93 (2 H, t, J = 7.5 Hz),





3.08 (2 H, s), 3.43 (2 H, brs), 3.67 (2 H, brs),





6.88 (2 H, d, J = 8.5 Hz), 7.03 (1 H, t, J = 8.5 Hz),





7.11-7.15 (3 H, m), 7.30-7.35 (3 H, m), 7.51-





7.54 (3 H, m), 7.70 (1 H, dd, J = 9.0 Hz, 2.0 Hz),





7.74 (1 H, dd, J = 8.5 Hz, 2.0 Hz), 8.00 (1 H, d,





J = 2.0 Hz), 8.74 (1 H, s), 8.93 (1 H, s).


458
—F
—(CH2)3Ph
MS 633 (M+)


459
—F
—(CH2)4Ph
MS 647 (M+)


460
—F
—CH(C2H5)2
MS 586 (M+ + 1)


461
—F
—CH(CH3)2
MS 556 (M+ − 1)


462
—F
—(CH2)3CH3
MS 571 (M+)


463
—F
—(CH2)2N(CH3)2
MS 585 (M+ − 1)


464
—F
—COOC(CH3)3
mp 155-157° C.


465
—F
—CH2COPh
MS 633 (M+)


466
—H
3-pyridyl
mp 153-155° C.


467
—F
3-pyridyl
mp 183-185° C.


468
—F
2-pyridyl
MS 591 (M+ − 1)


469
—F
4-pyridyl
MS 592 (M+)


 


470
—F




MS 593 (M+)


 


471
—F




MS 593 (M+)
















TABLE 180













 










Example





No.
R593
R594
MS





472
—CH3
benzyl
619 (M+)


473
2-pyridylmethyl
—H
606 (M+)


474
3-pyridylmethyl
—H
606 (M+)


475
4-pyridylmethyl
—H
605 (M+ − 1)


476
cyclopentyl
—H
583 (M+)


477
cycloheptyl
—H
611 (M+)


 


478




—H
612 (M+)


 


479




—H
627 (M+ + H)


 


480




—H
628 (M+)


 


481




—H
612 (M+)


 


482
2-quinolylmethyl
—H
657 (M+ + H)


 


483




—H
686 (M+ − 1)


 


484




—H
625 (M+)


 


485




—H
688 (M+)
















TABLE 181













 












Example




mp (° C.)


No.
R595
R596
R597
Form
or MS





486
—H
—H
—COOC(CH3)3
free
mp 188-189


487
—H
—H
—CH3
free
mp 189-191


488
—H
—H
benzyl
fumarate
mp 190-192


489
—F
—H
—(CH2)2Ph
hydrochloride
mp 191-200


490
—F
—H
piperonyl
hydrochloride
mp 226-228


491
—F
—H




free
MS 714 (M+ − 1)


492
—F
—H
1-naphthylmethyl
free
MS 655 (M+)


493
—F
—CH3
3,4-(CH3O)2PhCH2—
free
MS 679 (M+)


494
—F
—H




free
MS 678 (M+ + 1)


495
—F
—H
—CH(CH3)Ph
free
MS 619 (M+)


496
—F
—H




free
MS 682 (M+)


497
—F
—H
(4-FPh)2CH—
free
MS 717 (M+)


498
—F
—H
4-CH3OPhCH(Ph)—
free
MS 711 (M+)
















TABLE 182













 














Example






mp (° C.)


No.
R598
R599
R600
R601
R602
Form
or MS





499
—F
—H
—H
—OCF3
—H
hydrochloride
mp 118-121


500
—F
—H
—H
—CN
—H
free
mp 190-192


501
—F
—H
—H
—OCF3
—H
hydrochloride
mp 148-149


502
—H
—H
—H
—CN
—H
free
mp 186-188


503
—F
—CF3
—H
—H
—H
free
MS 659 (M+)


504
—F
—H
—CF3
—H
—H
free
MS 659 (M+)


505
—F
—H
—H
—COOC(CH3)3
—H
free
MS 691 (M+)


506
—F
—H
—H
—F
—H
free
MS 609 (M+)


507
—F
—OCH3
—H
—H
—H
free
MS 621 (M+)


508
—F
—Cl
—H
—H
—H
free
MS 625 (M+)


509
—F
—H
—H
—Cl
—H
free
MS 627 (M+)


510
—F
—H
—Cl
—H
—H
free
MS 625 (M+)


511
—F
—Cl
—Cl
—H
—H
free
MS 661 (M+)


512
—F
—H
—H
—OCH3
—H
free
MS 621 (M+)


513
—F
—H
—OCH3
—H
—H
free
MS 621 (M+)


514
—F
—H
—H
—CH3
—H
free
MS 605 (M+)


515
—F
—H
—CH3
—H
—H
free
MS 605 (M+)


516
—F
—CH3
—H
—H
—H
free
MS 605 (M+)


517
—F
—CH3
—CH3
—H
—H
free
MS 619 (M+)


518
—F
—H
—CH3
—CH3
—H
free
MS 619 (M+)


519
—F
—H
—H
—CF3
—H
free
MS 659 (M+)


520
—F
—H
—H
—Ph
—H
free
MS 667 (M+)


521
—F
—F
—H
—H
—H
free
MS 609 (M+)


522
—F
—F
—H
—F
—H
free
MS 627 (M+)


523
—F
—OCH3
—H
—H
—Cl
free
MS 657 (M+)
















TABLE 183













 














Example






mp (° C.)


No.
R603
R604
R605
R606
R607
Form
or MS





524
—H
—H
—H
—H
—H
fumarate
mp 168-170


525
—H
—H
—Cl
—H
—H
free
MS 638 (M+ − 1)


526
—H
—Cl
—H
—H
—H
free
MS 639 (M+)


527
—Cl
—H
—H
—H
—H
free
MS 641 (M+ + 2)


528
—Cl
—Cl
—H
—H
—H
free
MS 675 (M+ + 2)


529
—Cl
—H
—Cl
—H
—H
free
MS 673 (M+)


530
—Cl
—H
—H
—Cl
—H
free
MS 673 (M+)


531
—H
—Cl
—Cl
—H
—H
free
MS 676 (M+ + 3)


532
—H
—OCH3
—H
—H
—H
free
MS 635 (M+)


533
—OCH3
—H
—H
—H
—H
free
MS 635 (M+)


534
—H
—OCH3
—H
—OCH3
—H
free
MS 665 (M+)


535
—H
—CH3
—H
—H
—H
free
MS 619 (M+)


536
—CH3
—H
—H
—H
—H
free
MS 619 (M+)


537
—H
—CH3
—CH3
—H
—H
free
MS 633 (M+)


538
—H
—H
—F
—H
—H
free
MS 623 (M+)


539
—H
—F
—H
—H
—H
free
MS 623 (M+)


540
—F
—H
—H
—H
—H
free
MS 623 (M+)


541
—F
—H
—F
—H
—H
free
MS 641 (M+)


542
—F
—H
—H
—H
—F
free
MS 641 (M+)


543
—H
—H
—NO2
—H
—H
free
MS 650 (M+)


544
—H
—NO2
—H
—H
—H
free
MS 650 (M+)


545
—NO2
—H
—H
—H
—H
free
MS 650 (M+)


546
—H
—CF3
—H
—H
—H
free
MS 673 (M+)


547
—H
—H
—CN
—H
—H
free
MS 630 (M+)


548
—H
—OCF3
—H
—H
—H
free
MS 689 (M+)


549
—H
—H
—COOCH3
—H
—H
free
MS 664 (M+ + 1)


550
—H
—H
—C(CH3)3
—H
—H
free
MS 661 (M+)


551
—H
—H
—OCH2Ph
—H
—H
free
MS 710 (M+ − 1)


552
—H
—H
—Ph
—H
—H
free
MS 681 (M+)


553
—Cl
—H
—H
—H
—Cl
free
MS 675 (M+ + 2)


554
—F
—H
—H
—H
—H
free
MS 641 (M+)


555
—H
—F
—H
—H
—H
free
MS 641 (M+)


556
—H
—H
—CF3
—H
—H
free
MS 674 (M+ + 1)


557
—H
—H
—OCF3
—H
—H
free
MS 689 (M+)


558
—OCF3
—H
—H
—H
—H
free
MS 689 (M+)


559
—H
—COOCH3
—H
—H
—H
free
MS 663 (M+)


560
—H
—H
—C2H5
—H
—H
free
MS 633 (M+)


561
—H
—H
—CH(CH3)2
—H
—H
free
MS 647 (M+)


562
—H
—Cl
—OCH3
—H
—H
free
MS 669 (M+)
















TABLE 184













 












Example




mp (° C.) or


No.
R608
R609
R610
Form
1H NMR (solvent) δ ppm





563
—H
—CH3
piperonyl
free
mp 147-149


564
—H
—H
piperonyl
free
mp 138-140


565
—H
—CH3
benzyl
free
mp 150-152


566
—H
—H
benzyl
free
1H NMR (CDCl3) 2.34-2.42 (4 H,







m), 2.58-2.64 (2 H, m), 2.91-







2.96 (2 H, m), 3.40-3.43 (2 H, m),







3.51 (2 H, s), 3.60-3.64 (2 H, m),







6.93 (1 H, d, J = 8.9 Hz), 7.01-







7.04 (2 H, m), 7.20 (2 H, d, J = 8.6 Hz),







7.27-7.33 (5 H, m), 7.56 (1 H,







d, J = 8.3 Hz), 7.71-7.75 (1 H, m),







8.00 (1 H, d, J = 2.0 Hz), 8.16-







8.27 (3 H, m).


567
—OCH3
—H
piperonyl
free
mp 142.0-144.5


568
—F
—H
piperonyl
free
mp 156.5-157.5


569
—H
—H
—COOC(CH3)3
free
1H NMR (CDCl3) 1.46 (9 H, s),







2.62-2.67 (2 H, m), 2.96-3.01 (2 H,







m), 3.33-3.39 (6 H, m), 3.57-







3.60 (2 H, m), 6.94-6.97 (1 H, m),







7.05 (2 H, d, J = 8.4 Hz), 7.23 (2 H,







d, J = 8.4 Hz), 7.57 (1 H, d,







J = 8.1 Hz), 7.71-7.75 (1 H, m), 8.00







(1 H, d, J = 2.2 Hz), 8.13 (1 H,







brs), 8.21-8.24 (2 H, m).


570
—OC2H5
—H
piperonyl
oxalate
1H NMR (DMSO-d6) 1.06 (3 H, t,







J = 6.9 Hz), 2.39-2.86 (8 H, m),







3.40-3.60 (4 H, m), 3.65 (2 H, s),







3.70-5.20 (4 H, m), 6.00 (2 H, s),







6.76-6.84 (2 H, m), 6.85-7.02 (5 H,







m), 7.82 (1 H, d, J = 8.4 Hz),







7.92 (1 H, m), 8.03 (1 H, m),







8.20 (1 H, d, J = 2.0 Hz), 8.35 (1 H,







d, J = 2.5 Hz), 10.47 (1 H, s).
















TABLE 185













 












Example




mp (° C.) or


No.
R611
R612
R613
Form
1H NMR (CDCl3) δppm





571
—H
—CH3
piperonyl
hydro-
mp 218-220






chloride


572
—H
—CH3
benzyl
free
mp 142-144


573
—OCH3
—H
benzyl
free
1H NMR 2.34-2.40 (4H, m), 2.58-







2.63 (2H, m), 2.89-2.94 (2H, m),







3.39-3.42 (2H, m), 3.50 (2H, s),







3.58-3.61 (2H, m), 3.70 (3H, s),







6.75-6.80 (2H, m), 6.91 (1H, d, J =







8.7 Hz), 7.00 (1H, d, J = 7.9 Hz),







7.24-7.35 (5H, m), 7.69 (2H, d, J =







8.1 Hz), 7.98 (2H, d, J = 8.1 Hz),







8.14-8.18 (1H, m), 8.23 (1H, d, J =







2.3 Hz), 8.59 (1H, s).


574
—OCH3
—H
piperonyl
free
1H NMR 2.31-2.37 (4H, m), 2.57-







2.63 (2H, m), 2.88-2.94 (2H, m),







3.37-3.41 (4H, m), 3.57-3.60 (2H,







m), 3.70 (3H, s), 5.93 (2H, s), 6.69-







6.80 (4H, m), 6.84 (1H, brs),







6.90 (1H, d, J = 8.9 Hz), 7.00 (1H,







d, J = 7.9 Hz), 7.69 (2H, d, J = 8.1







Hz), 7.98 (2H, d, J = 8.1 Hz), 8.14-







8.19 (1H, m), 8.24 (1H, d, J = 2.5







Hz), 8.67 (1H, s).


575
—F
—H
piperonyl
free
mp 170.5-171.0


576
—H
—H
—COOC(CH3)3
free
1H NMR 1.46 (9H, s), 2.66 (2H, t, J =







6.5 Hz), 2.97 (2H, t, J = 6.5 Hz),







3.25-3.48 (6H, m), 3.51-3.65 (2H,







m), 6.95 (1H, d, J = 9.7 Hz),







7.04 (2H, d, J = 8.4 Hz), 7.22 (2H,







d, J = 8.4 Hz), 7.75 (2H, d, J = 8.2







Hz), 8.01 (2H, d, J = 8.2 Hz), 8.18-







8.33 (3H, m).


577
—OC2H5
—H
piperonyl
hydro-
mp 147.5-149.0






chloride
















TABLE 186













 













Example





mp (° C.) or


No.
R614
R615
R616
Xb7
Form
1H NMR





578
—Cl
—Cl
morpholino
—O—
free
1H NMR (CDCl3) δ








2.60-2.66 (2H, m), 2.96-








3.02 (2H, m), 3.37-








3.41 (2H, m), 3.55-








3.64 (6H, m), 6.96 (1H,








d, J = 8.4 Hz), 7.06 (2H,








d, J = 8.6 Hz), 7.23-








7.26 (2H, m), 7.58 (1H,








d, J = 8.4 Hz), 7.70-








7.74 (1H, m), 7.86 (1H,








brs), 7.99 (1H, d, J = 1.9








Hz), 8.19-8.25 (2H, m).


 


579
—Cl
—Cl




—NH—
free
mp 141-142


 


580
—Cl
—Cl




—S—
free
mp 169-170


 


581
—Cl
—Cl




—SO2—
free
mp 154-156


 


582
—CF3
—H




—N(CH3)—
free
mp 175-176


 


583
—Cl
—Cl




—N(CH2Ph)—
free
mp 171-173


 


584
—Cl
—Cl




—N(CH2Ph)—
free
mp 144-146


 


585
—Cl
—Cl




—CO—
free
mp 129-132


 


586
—Cl
—Cl




—O—
free
mp 208-210


 


587
—Cl
—Cl
—NH(CH2)2OPh
—O—
free
mp 129-132


 


588
—Cl
—Cl




—SO—
oxalate
mp 128-130
















TABLE 187













 












Example







No.
R617
R618
Xb8
R619
1H NMR (CDCl3) δppm





589
—Cl
—Cl
—CH═CH—
piperonyl
2.33-2.42 (4H, m), 2.62-2.68 (2H, m),





(trans)

2.96-3.01 (2H, m), 3.40-3.44 (4H, m),







3.62-3.66 (2H, m), 3.76 (3H, s), 5.95 (2H,







s), 6.71-6.77 (2H, m), 6.82-7.07 (7H, m),







7.28-7.32 (1H, m), 7.38-7.46 (1H, m),







7.57 (1H, d, J = 2.0 Hz), 7.83-7.87 (1H,







m), 8.19 (1H, d, J = 2.3 Hz).


590
—CF3
—H
—CH═CH—
piperonyl
2.33-2.42 (4H, m), 2.62-2.68 (2H, m),





(trans)

2.96-3.02 (2H, m), 3.40-3.43 (4H, m),







3.63-3.66 (2H, m), 3.76 (3H, s), 5.94 (2H,







s) 6.71-6.79 (2H, m), 6.82-6.89 (3H, m),







6.95 (1H, d, J = 8.7 Hz), 7.00 (1H, d, J =







16.5 Hz), 7.05-7.14 (2H, m), 7.55-7.62







(4H, m), 7.86-7.90 (1H, m), 8.22 (1H, d, J =







2.3 Hz).


591
—CF3
—H
—CO—
benzyl
2.38-2.43 (4H, m), 2.63-2.68 (2H, m),







2.97-3.02 (2H, m), 3.43 (2H, brs),







3.51 (2H, s), 3.65 (2H, brs), 3.76 (3H, s),







6.84-6.89 (2H, m), 7.04-7.09 (2H, m),







7.27-7.31 (5H, m), 7.73-7.88 (4H, m),







8.19-8.22 (1H, m), 8.55 (1H, brs).


592
—CF3
—H
—CO—
piperonyl
2.35-2.39 (4H, m), 2.62-2.68 (2H, m),







2.96-3.02 (2H, m), 3.41-3.44 (4H, m),







3.62-3.65 (2H, m), 3.76 (3H, s), 5.95 (2H,







s), 6.74-6.89 (5H, m), 7.04-7.09 (2H, m),







7.73-7.88 (4H, m), 8.19-8.22 (1H, m),







8.55 (1H, brs).


593
—CF3
—H
—CO—
3-pyridyl
2.69-2.75 (2H, m), 3.01-3.06 (2H, m),







3.14-3.20 (4H, m), 3.59-3.62 (2H, m),







3.77 (3H, s), 3.80-3.84 (2H, m), 6.86-6.92







(2H, m), 7.04-7.11 (2H, m), 7.18-7.20 (2H,







m), 7.75 (2H, d, J = 8.4 Hz), 7.87 (2H, d, J =







8.1 Hz), 8.15 (1H, t, J = 3.0 Hz), 8.20







(1H, dd, J = 8.7 Hz, 2.3 Hz), 8.30 (1H, t,







J = 1.8 Hz), 8.53 (1H, d, J = 2.3 Hz).
















TABLE 188













 











Example






No.
R620
R621
M
1H NMR (solvent) δppm





594
3,4-Cl2PhNHCON(C2H5)—
4-pyridyl-
2
(CDCl3) 1.16 (3H, t, J = 7.1 Hz), 2.35-




methyl

2.45 (4H, m), 2.62-2.67 (2H, m), 2.97-






3.03 (2H, m), 3.42-3.46 (2H, m),






3.51 (2H, s), 3.64-3.68 (2H, m),






3.73 (2H, q, J = 7.1 Hz), 6.07 (1H, d, J =






5.0 Hz), 7.04 (1H, d, J = 8.7 Hz),






7.09-7.14 (3H, m), 7.25-7.30 (5H, m),






7.52 (1H, d, J = 2.6 Hz), 7.61 (1H, dd, J =






8.7 Hz, 2.6 Hz), 8.11 (1H, d, J = 2.6






Hz), 8.54 (2H, d, 4 = 5.9 Hz).


595
4-CF3PhNHCON(C2H5)—
piperonyl
2
(CDCl3) 1.18 (3H, t, J = 7.1 Hz), 2.32-






2.41 (4H, m), 2.61-2.67 (2H, m), 2.97






3.03 (2H, m), 3.39-3.43 (4H, m), 3.61-






3.65 (2H, m), 3.75 (2H, q, J = 7.1 Hz),






5.94 (2H, s), 6.15 (1H, brs), 6.72






6.76 (2H, m), 6.83 (1H, d, J = 0.7 Hz),






7.05 (1H, dd, J = 8.7 Hz, 0.5 Hz),






7.11 (2H, d, J = 8.6 Hz), 7.29 (2H, d, J =






8.6 Hz), 7.40 (2H, d, J = 8.6 Hz),






7.49 (2H, d, 4 = 8.7 Hz), 7.63 (1H, dd, J =






8.7 Hz, 2.8 Hz), 8.14 (1H, dd, J =






2.8 Hz, 0.5 Hz).


596
4-CF3PhNHCON(C2H5)—
4-pyridyl-
2
(CDCl3) 1.18 (3H, t, J = 7.1 Hz), 2.35-




methyl

2.45 (4H, m), 2.62-2.68 (2H, m), 2.98-






3.03 (2H, m), 3.42-3.46 (2H, m),






3.51 (2H, s), 3.66 (2H, t, J = 5.0 Hz),






3.75 (2H, q, J = 7.1 Hz), 6.18 (1H, brs),






7.05 (1H, dd, J = 8.7 Hz, 0.5 Hz),






7.11 (2H, d, J = 8.4 Hz), 7.25-7.31 (4H,






m), 7.40 (2H, d, J = 8.7 Hz), 7.49 (2H,






d, J = 8.7 Hz), 7.63 (1H, dd, J = 8.7






Hz, 2.8 Hz), 8.13 (1H, dd, J = 2.6 Hz,






0.5 Hz), 8.53-8.55 (2H, m).


597
4-CF3PhNHCON(C2H5)—
2-pyridyl
2
(CDCl3) 1.17 (3H, t, J = 7.1 Hz), 2.68-






2.74 (2H, m), 3.02-3.07 (2H, m), 3.46-






3.53 (6H, m), 3.70-3.78 (4H, m),






6.12 (1H, brs), 6.62-6.67 (2H, m),






7.04 (1H, d, J = 8.7 Hz), 7.12 (2H, d, J =






8.6 Hz), 7.31 (2H, d, J = 8.6 Hz),






7.40 (2H, d, J = 8.7 Hz), 7.45-7.52 (3H,






m), 7.60 (1H, dd, J = 8.7 Hz, 2.6 Hz),






8.07 (1H, d, J = 2.5 Hz), 8.16-8.19 (1H,






m).
















TABLE 189













 












Example




mp (° C.) or


No.
R622
R623
R624
R625
1H NMR (CDCl3) δppm





598
—Cl
—Cl
—H




mp 169-171


 


599
—Cl
—Cl
—H




mp 158-160


 


600
—Cl
—Cl
—H




mp 183-186


 


601
—CF3
—H
—F




1H NMR 3.00 (3H, s), 3.20- 3.36 (2H, m), 3.57-3.80 (2H, m), 4.07 (2H, s), 4.14-4.34 (2H, m), 4.51 (2H, s), 5.94 (2H, s), 6.32- 6.50 (2H, m), 6.65-6.80 (3H, m), 6.92 (1H, d, J = 9.4 Hz), 7.02 (1H, t, J = 8.8 Hz), 7.71 (2H, d, J = 8.1 Hz), 7.98 (2H, d, J = 8.1 Hz), 8.10-8.20 (1H, m), 8.18 (1H, s), 8.30 (1H, s).


 


602
—CF3
—H
—H




1H NMR 1.45 (6H, s), 2.14 (2H, brs), 2.33 (2H, brs), 2.87 (3H, s), 3.32 (2H, s), 3.63 (2H, brs), 3.92 (2H, brs), 5.93 (2H, s), 6.68- 6.75 (2H, m), 6.82 (1H, d, J = 1.0 Hz), 6.92 (2H, d, J = 9.2 Hz), 6.93 (1H, d, J = 9.1 Hz), 7.00 (2H, d, J = 9.2 Hz), 7.77 (2H, d, J = 8.1 Hz), 7.81 (1H, s), 8.00 (2H, d, J = 8.1 Hz), 8.19 (1H, dd, J = 8.7 Hz, 2.8 Hz), 8.26 (1H, d, J = 2.1 Hz).


 


603
—CF3
—H
—OCH3




1H NMR 1.33-1.45 (2H, m), 1.82-1.96 (3H, m), 2.28 (2H, d, J = 6.8 Hz), 2.39-2.41 (4H, m), 2.72 (2H, t, J = 10.1 Hz), 3.43 (2H, s), 3.48 (2H, brs), 3.57- 3.62 (4H, m), 3.72 (3H, s), 5.95 (2H, s), 6.48 (1H, dd, J = 8.7 Hz, 2.5 Hz), 6.56 (1H, d, J = 2.5 Hz), 6.71-6.77 (2H, m), 6.86 (2H, d, J = 8.6 Hz), 6.97 (1H, d, J = 8.6 Hz), 7.70 (2H, d, J = 8.4 Hz), 8.00 (2H, d, J = 8.1 Hz), 8.13 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.22 (1H, d, J = 2.5 Hz), 8.40 (1H, s).
















TABLE 190













 












Example




mp (° C.) or


No.
R626
R627
R628
R629
1H NMR (DMSO-d6) δppm















604
—CF3
—H
—CH3
—OC2H5
1H NMR 1.03 (3H, t, J = 6.9 Hz), 2.52-2.68 (6H, m),







3.89 (2H, q, J = 6.9 Hz), 4.00-5.90 (4H, m), 6.01 (2H,







s), 6.74 (1H, dd, J = 8.0 Hz, 1.8 Hz), 6.76 (1H, d, J =







8.9 Hz), 6.82 (1H, dd, J = 8.0 Hz, 1.3 Hz), 6.84-







6.97 (4H, m), 7.26 (1H, dd, J = 9.0 Hz, 3.1 Hz),







7.41 (2H, d, J = 8.0 Hz), 7.50 (1H, d, J = 3.1 Hz),







7.65 (2H, d, J = 8.0 Hz).


605
—CF3
—H
—C2H5
—OC2H5
1H NMR 1.02 (3H, t, J = 6.9 Hz), 1.08 (3H, t, J =







6.9 Hz), 2.53-2.84 (8H, m), 3.43 (2H, q, J = 6.9 Hz),







3.46-3.62 (4H, m), 3.72 (2H, s), 3.88 (2H, q, J =







6.9 Hz), 4.30-5.90 (4H, m), 6.01 (2H, s), 6.69-







6.78 (2H, m), 6.82 (1H, dd, J = 8.0 Hz, 1.4 Hz), 6.83-







6.97 (4H, m), 7.19 (1H, dd, J = 9.0 Hz, 3.1 Hz), 7.37-







7.48 (3H, m), 7.65 (2H, d, J = 8.1 Hz).


606
—Cl
—Cl
—CH3
—H
1H NMR 2.48-2.67 (6H, m), 2.68-2.82 (2H, m)







2.98 (3H, s) 3.37-3.62 (4H, m), 3.70 (2H, s), 4.50-







5.90 (4H, m), 6.01 (2H, s), 6.78-6.95 (6H, m), 7.13-







7.23 (3H, m), 7.28 (1H, dd, J = 9.0 Hz, 3.3 Hz),







7.48 (1H, d, J = 2.0 Hz), 7.57 (1H, d, J = 8.3 Hz),







7.61 (1H, d, J = 3.1 Hz).


607
—Cl
—Cl
—C2H5
—H
1H NMR 1.09 (3H, t, J = 6.9 Hz), 2.48-2.66 (6H, m),







2.69-2.82 (2H, m), 3.35-3.59 (6H, m), 3.67 (2H, s),







4.00-5.90 (4H, m), 6.00 (2H, s), 6.76-6.94 (6H, m),







7.13-7.25 (4H, m), 7.47 (1H, d, J = 1.9 Hz), 7.52-







7.61 (2H, m).


608
—CF3
—H
—CH3
—F
1H NMR 2.50-2.72 (6H, m), 2.72-2.88 (2H, m),







2.98 (3H, s), 3.32-3.61 (4H, m) 3.70 (2H, brs),







4.67 (2H, s), 6.00 (2H, s), 6.80 (1H, dd, J = 7.9 Hz,







1.4 Hz), 6.85-6.95 (3H, m), 6.98-7.11 (2H, m) 7.11-







7.22 (1H, m), 7.29 (1H, dd, J = 9.0 Hz, 3.1 Hz),







7.41 (2H, d, J = 8.0 Hz), 7.50 (1H, d, J = 3.1 Hz),







7.66 (2H, d, J = 8.0 Hz).


609
—Cl
—Cl
—C2H5
—F
1H NMR 1.00-1.20 (3H, m), 2.46-2.72 (6H, m), 2.72-







2.89 (2H, m), 3.29-3.61 (6H, m), 3.71 (2H, brs),







4.46 (2H, s), 6.01 (2H, s), 6.81 (1H, dd, J = 8.0 Hz,







1.4 Hz), 6.85-6.95 (3H, m), 6.98-7.11 (2H, m), 7.13-







7.28 (3H, m), 7.45 (1H, d, J = 3.1 Hz), 7.46 (1H, d, J =







1.9 Hz), 7.56 (1H, d, J = 8.3 Hz).


610
—Cl
—Cl
—CH3
—OC2H5
1H NMR 1.02 (3H, t, J = 6.9 Hz), 2.42-2.81 (8H, m),







2.94 (3H, s), 3.00-4.30 (10H, m), 4.49 (2H, s),







6.00 (2H, s), 6.71-6.83 (3H, m), 6.84-6.95 (4H, m),







7.18 (1H, dd, J = 8.3 Hz, 2.0 Hz), 7.26 (1H, dd, J =







9.0 Hz, 3.2 Hz), 7.44 (1H, d, J = 2.0 Hz), 7.50 (1H, d, J =







3.0 Hz), 7.55 (1H, d, J = 8.3 Hz).


611
—Cl
—Cl
—C2H5
—OC2H5
1H NMR 1.01 (3H, t, J = 7.0 Hz), 1.06 (3H, t, J =







7.0 Hz), 2.40-2.83 (8H, m), 2.90-4.50 (14H, m),







6.00 (2H, s), 6.70-6.82 (3H, m), 6.84-6.95 (4H, m),







7.15-7.24 (2H, m), 7.39-7.48 (2H, m), 7.55 (1H, d, J =







8.3 Hz).


612
—Cl
—Cl
—C2H5
—OCH3
mp 91.0-96.5 dec


613
—CF3
—H
—C2H5
—F
mp 104-107
















TABLE 191













 











Example






No.
R630
R631
Form
1H NMR (solvent) δppm





614
—H
piperonyl
free
(CDCl3) 2.30-2.34 (2H, m), 2.36-2.40 (2H,






m), 2.56-2.62 (2H, m), 2.91-2.96 (2H, m),






3.01 (3H, s), 3.37-3.40 (4H, m), 3.60-






3.64 (2H, m), 4.50 (2H, s), 5.94 (2H, s), 6.72-






6.73 (2H, m), 6.80 (1H, d, J = 8.9 Hz),






6.84 (1H, brs), 6.98 (2H, d, J = 8.6 Hz),






7.11 (1H, dd, J = 8.9 Hz, 3.3 Hz), 7.18 (2H,






d, J = 8.4 Hz), 7.34 (2H, d, J = 7.9 Hz),






7.58 (2H, d, J = 8.3 Hz), 7.70 (1H, d, J = 3.3






Hz).


615
—H
3-pyridyl
free
(CDCl3) 2.63-2.69 (2H, m), 2.95-3.01 (5H,






m), 3.08-3.18 (4H, m), 3.54-3.58 (2H, m),






3.78-3.81 (2H, m), 4.50 (2H, s), 6.79 (1H, d,






J = 8.9 Hz), 6.99 (2H, d, J = 8.6 Hz),






7.10 (1H, dd, 4 = 8.9 Hz, 3.1 Hz), 7.17-






7.22 (4H, m), 7.34 (2H, d, 4 = 8.1 Hz),






7.58 (2H, d, J = 7.9 Hz), 7.67 (1H, d, J = 2.8






Hz), 8.12-8.14 (1H, m), 8.29-8.30 (1H, m).


616
—H
4-pyridylmethyl
free
(CDCl3) 2.33 (2H, t, J = 5.0 Hz), 2.41 (2H, t,






J = 5.1 Hz), 2.57-2.63 (2H, m), 2.92-






2.97 (2H, m), 3.02 (3H, s), 3.41 (2H, t, J =






5.0 Hz), 3.50 (2H, s), 3.65 (2H, t, J = 5.1






Hz), 4.51 (2H, s), 6.80 (1H, d, J = 8.9 Hz),






6.98 (2H, d, J = 8.4 Hz), 7.11 (1H, dd, J =






8.9 Hz, 3.1 Hz), 7.18 (2H, d, J = 8.4 Hz),






7.27 (2H, d, J = 5.6 Hz), 7.34 (2H, d, J = 8.3






Hz), 7.58 (2H, d, J = 8.3 Hz), 7.69 (1H, d, J =






3.1 Hz), 8.55 (2H, d, J = 5.8 Hz).


617
—H
benzyl
hydrochloride
(DMSO-d6) 2.64-2.69 (2H, m), 2.75-






2.81 (2H, m), 2.92-3.02 (5H, m), 3.23-






3.32 (2H, m), 3.41-3.51 (2H, m), 4.02-






4.08 (1H, m), 4.31 (2H, brs), 4.43-4.48 (1H,






m) 4.64 (2H, brs), 6.86 (1H, d, J = 9.1 Hz),






6.90 (2H, d, J = 8.6 Hz), 7.20 (2H, d, J = 8.4






Hz), 7.29 (1H, dd, J = 9.1 Hz, 3.1 Hz), 7.42-






7.47 (5H, m), 7.56-7.57 (2H, m), 7.62 (1H, d,






J = 3.1 Hz), 7.69 (2H, d, J = 8.1 Hz),






11.08 (1H, brs).


618
—OCH3
piperonyl
hydrochloride
(DMSO-d6) 2.59-3.09 (6H, m), 2.97 (3H, s),






3.16-3.61 (4H, m), 3.65 (3H, s), 3.97-






4.13 (1H, m), 4.14-4.28 (2H, m), 4.38-






4.51 (1H, m), 4.58 (2H, s), 6.06 (2H, s), 6.72-






6.80 (2H, m), 6.89 (1H, d, J = 8.0 Hz), 6.93-






7.03 (3H, m), 7.18 (1H, s), 7.26 (1H, dd, J =






9.0 Hz, 3.2 Hz), 7.42 (2H, d, J = 8.0 Hz),






7.49 (1H, d, J = 3.1 Hz), 7.67 (2H, d, J = 8.0






Hz), 10.81 (1H, brs).
















TABLE 192













 













Example








No.
R632
R633
R634
R635
Form
1H NMR (DMSO-d6) δppm





619
—CF3
—H
—C2H5
—H
TsOH
1.11 (3H, t, J = 6.9 Hz), 2.28 (3H, s),







salt
2.54-3.02 (7H, m), 3.17-3.48 (3H, m),








3.47 (2H, q, J = 6.9 Hz), 3.97-4.12 (1H,








m), 4.15-4.31 (2H, m), 4.38-4.52 (1H,








m), 4.58 (2H, s), 6.07 (2H, s), 6.78-








7.26 (11H, m), 7.39-7.49 (4H, m),








7.53 (1H, d, J = 3.1 Hz), 7.68 (2H, d, J =








8.2 Hz), 9.45-9.69 (1H, m).


620
—CF3
—H
—(CH2)2OCH3
—H
TsOH
2.27 (3H, s), 2.52-3.03 (7H, m),







salt
3.24 (3H, s), 3.17-3.70 (10H, m), 3.95-








4.13 (1H, m), 4.15-4.32 (2H, m), 4.36-








4.54 (1H, m), 4.66 (2H, s), 6.07 (2H, s),








6.80 (1H, d, J = 8.9 Hz), 6.83-7.07 (5H,








m), 7.10 (2H, d, J = 7.8 Hz), 7.13








7.26 (3H, m), 7.37-7.49 (4H, m),








7.52 (1H, d, J = 3.1 Hz), 7.67 (2H, d, J =








8.1 Hz), 9.46-9.69 (1H, m).


621
—Cl
—Cl
—CH3
—OCH3
hydro-
2.60-3.15 (7H, m), 2.94 (3H, s), 3.15-







chloride
3.38 (2H, m), 3.38-3.60 (1H, m),








3.65 (3H, s), 4.07 (1H, d, J = 15.7 Hz),








4.20 (2H, brs), 4.38-4.60 (1H, m), 4.48








(2H, s), 6.06 (2H, s), 6.73-6.81 (2H, m),








6.90 (1H, d, J = 8.0 Hz), 6.93-7.05 (3H,








m), 7.16-7.24 (2H, m), 7.29 (1H, dd, J =








8.9 Hz, 3.2 Hz), 7.47 (1H, d, J = 1.9








Hz), 7.50 (1H, d, J = 3.1 Hz), 7.56 (1H,








d, J = 8.2 Hz), 11.10 (1H, brs).


622
—Cl
—Cl
—CH3
—F
hydro-
2.58-3.17 (7H, m), 2.96 (3H, s), 3.18-







chloride
3.38 (2H, m), 3.38-3.70 (1H, m), 4.00-








4.18 (1H, m), 4.20 (2H, brs), 4.33








4.60 (1H, m), 4.50 (2H, s), 6.06 (2H, s),








6.92 (1H, d, J = 9.0 Hz), 6.95-7.14 (4H,








m), 7.16-7.25 (3H, m), 7.31 (1H, dd, J =








9.0 Hz, 3.1 Hz), 7.47 (1H, d, J = 1.9








Hz), 7.51 (1H, d, J = 3.1 Hz), 7.56 (1H,








d, J = 8.2 Hz), 11.10 (1H, brs).


623
—CF3
—H
—C2H5
—OCH3
hydro-
1.09 (3H, t, J = 6.9 Hz), 2.58-3.11 (8H,







chloride
m), 3.15-3.58 (4H, m), 3.64 (3H, s),








3.94-4.12 (1H, m), 4.14-4.28 (2H, m),








4.36-4.50 (1H, m), 4.54 (2H, s), 6.69-








6.79 (2H, m), 6.88 (1H, d, J = 8.0 Hz),








6.92-7.02 (3H, m), 7.12-7.24 (2H, m),








7.37-7.49 (3H, m), 7.67 (2H, d, J = 8.1








Hz), 10.77 (1H, brs).





(TsOH means a p-toluenesulfonic acid. Hereinafter TsOH indicates the same meaning)













TABLE 193













 















Example







mp (° C.) or


No.
R636
R637
R638
R639
R640
R641
Form
1H NMR





624
Ya2
—H
—H
Ya1
—H
—H
hydrochloride
1H NMR (DMSO-d6) δ 2.56-










2.72 (2H, m), 2.73-2.94 (3H,










m), 2.96-3.10 (1H, m), 3.12-










3.52 (4H, m), 3.91-4.07 (1H,










m), 4.10-4.26 (2H, m), 4.33










4.48 (1H, m), 6.05 (2H, s),










6.82 (1H, d, J = 8.2 Hz),










6.89-7.02 (4H, m), 7.09 (1H,










t, J = 7.6 Hz), 7.14-7.25 (2H,










m), 7.35 (1H, d, J = 7.6 Hz),










7.74 (2H, d, J = 9.0 Hz),










7.81 (1H, d, J = 8.4 Hz),










7.94 (1H, dd, J = 8.4 Hz, 2.1










Hz), 8.22 (1H, d, J = 2.1 Hz),










10.45 (1H, s), 11.15 (1H,










brs).


625
Ya2
—H
—H
—H
Ya1
—H
oxalate
mp 134-143


626
—H
—H
Ya2
—H
—H
Ya1
fumarate
mp 123-126


627
—H
Ya2
—H
—H
—H
Ya1
hydrochloride
mp 141-153










In the above-mentioned Table, Ya1 means a group of








and Ya2 means a group of



















TABLE 194













 









Example

MS


No.
R642
(M+ + H)





628




540


 


629




574


 


630
morpholino
528


 


631




574


 


632




673


 


633




513


 


634




543


 


635




632


 


636




555


 


637




689


 


638




655


 


639




626
















TABLE 195













 












Example


MS



No.
R643
R644
(M+ + H)







640
—CH3
cyclohexyl
554



641
—H
cyclohexyl
540



642
—C2H5
—Ph
562



643
—CH3
4-CH3Ph—
562



644
—H
cycloheptyl
554



645
—H
cyclooctyl
569



646
—H
benzyl
548



647
—H
2-ClPhCH2—
584



648
—H
3-ClPhCH2—
584



649
—H
4-ClPhCH2—
584



650
—CH3
Ph(CH2)2—
577



651
—CH3
3,4-(CH3O)2PhCH2—
623



652
—CH3
benzyl
562



653
—C2H5
benzyl
576



654
—H
PhOCH2CH(CH3)—
593



655
—C2H5
cyclohexyl
569



656
—H
—C2H5
486



657
—H
-(CH2)2CH3
500



658
—H
-(CH2)2OCH3
516



659
—C2H5
cyclohexylmethyl
583



660
—H
4-CH3OPhCH2—
578



661
—H
4-CH3OPh(CH2)2—
593



662
—H
4-CF3OPhCH2—
632



663
—H
4-CF3OPh—
618



664
—H
4-ClPh(CH2)2—
598



665
—H
piperonyl
592



666
—H
—(CH2)2OPh
579



667
—H
cyclopentyl
527



668
—H
cyclohexylmethyl
554



669
—H
4-hydroxycyclohexan-1-yl
556



670
—H
4-FPhCH2—
566



671
—H
—CH(CH3)Ph
562



672
—H
—(CH2)3Ph
576



673
—H
—Ph
534



674
—H
4-CH3OPh—
564



675
—H
—(CH2)2Ph
562



676
—H
3-PhOPh—
627



677
—H
4-PhOPh—
627



678
—H
2-CH3OPh(CH2)2—
593



679
—H
2-FPh(CH2)2—
580

















TABLE 196













 












Example


MS



No.
R645
R646
(M+ + H)







680
—H




632



 



681
—H
—CH(CH3)2
501



 



682
—CH3




578



 



683
—(CH2)2OH
—(CH2)2OH
547



684
—CH3
—(CH2)2N(CH3)2
544



685
—H
—(CH2)3CH3
515



686
—H
cyclopropyl
499



687
—H
2-pyridylmethyl
550



688
—H
3-pyridylmethyl
550



689
—H
—CH2CH(CH3)2
515



690
—H
cyclopropylmethyl
513



 



691
—H




567



 



692
—H




570



 



693
—H




572

















TABLE 197













 












Example






No.
R647
R648
1H NMR or MS







694
—H
4-CF3OPhO—
MS 702 (M+ + H)



695
—H
benzyl
MS 617 (M+ + H)



696
—OH
4-ClPh—
MS 654 (M+ + H)



697
—H
—H
MS 526 (M+ + H)



698
—H
—Ph
MS 602 (M+ + H)



699
—H
piperonyl
1H NMR (CDCl3) δ 1.11-1.16 (5H,






m), 1.65-1.71 (3H, m), 2.48 (2H, d, J =






6.4 Hz), 2.54-2.58 (1H, m), 2.95-






3.04 (1H, m), 3.35 (2H, q, J = 7.1 Hz),






3.84-3.89 (1H, m), 4.01 (2H, s), 4.52-






4.57 (1H, m), 5.93 (2H, s), 6.56






6.63 (4H, m), 6.73 (1H, d, J = 7.8 Hz),






6.79 (1H, d, J = 8.7 Hz), 6.92 (2H, d,






J = 9.1 Hz), 7.52 (1H, d, J = 8.4 Hz),






7.72 (1H, dd, J = 8.4 Hz, 2.0 Hz),






7.99 (1H, d, J = 2.0 Hz), 8.04 (1H, dd,






J = 8.9 Hz, 2.8 Hz), 8.26 (1H, d, J =






2.5 Hz), 8.56 (1H, brs).



 



700
—H




MS 610 (M+ + H)



 



701
—H
4-CH3OPhCONH—
MS 676 (M+ + H)



702
—H
—N(CH3)CH2Ph
MS 646 (M+ + H)



703
—H
4-CH3PhO
MS 690 (M+ + H)





(CH2)2N(CH3)—



704
—OH
—Ph
MS 619 (M+ + H)



705
—H
4-CNPhO—
MS 644 (M+ + H)



706
—H
2-ClPhCH2—
MS 653 (M+ + H)



707
—CH2(CH2)3CH2—
MS 595 (M+ + H)

















TABLE 198













 














Example









No.
R649
R650
R651
R652
R653
M
1H NMR (solvent) δppm





708
—Cl
—Cl
—CH3
—CONH2
—H
1
(DMSO-d6) 1.79-2.02 (4H, m), 2.96 (3H,









s), 3.37-3.67 (3H, m), 4.19 (2H, s), 6.61-









6.70 (2H, m), 6.89-6.95 (3H, m),









7.83 (1H, d, J = 8.4 Hz), 7.94 (1H, dd, J =









8.4 Hz, 2.0 Hz), 8.13 (1H, dd, J = 8.9









Hz, 2.6 Hz), 8.22 (1H, d, J = 2.0 Hz),









8.43 (1H, d, J = 2.6 Hz), 10.51 (1H, s).


709
—Cl
—Cl
—CH3
—H
benzyl
2
(CDCl3) 1.18-1.26 (2H, m), 1.57 (3H,









brs), 1.58-1.74 (2H, m), 2.49-2.58 (2H,









m), 3.83 (1H, d, J = 13.5 Hz), 4.08 (2H,









s), 4.56 (1H, d, J = 13.5 Hz), 6.40 (1H, d,









J = 8.9 Hz), 6.67 (2H, d, J = 9.1 Hz),









6.98 (2H, d, J = 9.1 Hz), 7.12-7.32 (5H,









m), 7.56 (1H, d, J = 8.4 Hz), 7.71 (1H,









dd, J = 8.4 Hz, 2.1 Hz), 7.98 (1H, d, J =









2.1 Hz), 8.03-8.10 (2H, m), 8.24 (1H, d, J =









2.6 Hz).


710
—CF3
—H
—C2H5
—H
piperonyl
2
(CDCl3) 1.12-1.17 (5H, m), 1.64-









1.71 (3H, m), 2.48 (2H, d, J = 6.6 Hz),









2.53-2.58 (1H, m), 2.94-3.03 (1H, m),









3.37 (2H, q, J = 7.1 Hz), 3.84-3.89 (1H,









m), 4.01 (2H, s), 4.53-4.58 (1H, m),









5.93 (2H, s), 6.56-6.63 (4H, m), 6.73 (1H,









d, J = 7.8 Hz), 6.82 (1H, d, J = 8.9 Hz),









6.95 (2H, d, J = 9.1 Hz), 7.72 (2H, d, J =









8.3 Hz), 7.99 (2H, d, J = 8.1 Hz),









8.10 (1H, dd, J = 8.9 Hz, 2.8 Hz),









8.27 (1H, d, J = 2.6 Hz), 8.37 (1H, brs).


711
—Cl
—Cl
—CH3
—H
piperonyl
2
(CDCl3) 1.03-1.17 (2H, m), 1.64-1.74









(3H, m), 2.46-2.57 (3H, m), 2.97-3.04









(4H, m), 3.80-3.85 (1H, m), 4.07 (2H, s),









4.51-4.55 (1H, m), 5.92 (2H, s), 6.56









6.63 (4H, m), 6.73 (1H, d, J = 7.8 Hz),









6.79 (1H, d, J = 8.9 Hz), 6.94 (2H, d, J =









8.9 Hz), 7.52 (1H, d, J = 8.4 Hz), 7.71









(1H, dd, J = 8.4 Hz, 2.1 Hz), 7.98 (1H,









d, J = 2.1 Hz), 8.04 (1H, d, J = 8.9 Hz),









8.25 (1H, d, J = 2.3 Hz), 8.49 (1H, brs).


712
—CF3
—H
—CH3
—H
piperonyl
2
(CDCl3) 1.09-1.17 (2H, m), 1.67-









1.70 (3H, m), 2.47-2.52 (3H, m), 2.94-









3.03 (4H, m), 3.80-3.85 (1H, m),









4.06 (2H, s), 4.50-4.55 (1H, m), 5.92 (2H,









s), 6.55-6.65 (4H, m), 6.73 (1H, d, J = 7.9









Hz), 6.81 (1H, d, J = 8.9 Hz), 6.95 (2H,









d, J = 8.9 Hz), 7.70 (2H, d, J = 8.1 Hz),









7.99 (2H, d, J = 8.1 Hz), 8.09 (1H, dd, J =









8.9 Hz, 2.1 Hz), 8.26 (1H, d, J = 2.6









Hz), 8.48 (1H, brs).
















TABLE 199













 











Example






No.
R654
R655
R656
1H NMR (solvent) δppm





713
—OCH3
—CH3




(CDCl3) 2.38-2.43 (4H, m), 2.95 (3H, s), 3.40 (2H, s), 3.47.-3.58 (4H, m), 3.63 (3H, s), 4.05 (2H, s), 4.24 (4H, s), 6.12 (1H, dd, J = 8.7 Hz, 2.6 Hz), 6.21 (1H, d, J = 2.6 Hz), 6.74-6.87 (5H, m), 7.44 (1H, d, J = 8.4 Hz), 7.69 (1H, dd, J = 8.4 Hz, 2.0 Hz), 7.96 (1H, d, J = 2.0 Hz), 8.02 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.19 (1H, d, J = 2.6 Hz), 9.00 (1H, s).


 


714
—F
—CH3
3-furylmethyl
(DMSO-d6) 2.32 (2H, brs), 2.41 (2H, brs),






2.93 (3H, s), 3.37 (2H, s), 3.44 (4H, brs),






4.29 (2H, s), 6.40-6.44 (2H, m), 6.56 (1H,






dd, J = 14.5 Hz, 2.8 Hz), 7.01-7.08 (2H,






m), 7.58 (1H, s), 7.62 (1H, s), 7.84 (1H, d, J =






8.4 Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.0






Hz), 8.16 (1H, dd, J = 8.9 Hz, 2.8 Hz),






8.22 (1H, d, J = 2.0 Hz), 8.39 (1H, d, J =






2.6 Hz), 10.53 (1H, s).


 


715
—F
—CH3




(DMSO-d6) 2.30 (2H, brs), 2.39 (2H, brs), 2.93 (3H, s), 3.38 (2H, s), 3.44 (4H, brs), 4.22 (4H, s), 4.28 (2H, s), 6.41 (1H, dd, J = 8.6 Hz, 2.2. Hz), 6.56 (1H, dd, J = 14.4 Hz, 2.8 Hz), 6.76-6.81 (3H, m), 7.01-7.08 (2H, m), 7.84 (1H, d, J = 8.4 Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.16 (1H, dd, J = 8.9 Hz, 2.8 Hz), 8.22 (1H, d, J = 2.0 Hz), 8.39 (1H, d, J = 2.5 Hz), 10.53 (1H, s).


 


716
—H
—CH3
3-furylmethyl
(CDCl3) 2.42 (4H, brs), 2.97 (3H, s),






3.40 (2H, s), 3.50 (2H, brs), 3.61 (2H, brs),






4.07 (2H, s), 6.38 (1H, d, J = 1.5 Hz),






6.63 (2H, d, J = 9.1 Hz), 6.80 (1H, d, J =






8.9 Hz), 6.95 (2H, d, J = 9.1 Hz), 7.34 (1H,






s), 7.40 (1H, t, J = 1.5 Hz), 7.52 (1H, d, J =






8.4 Hz), 7.70 (1H, dd, J = 8.4 Hz, 2.0 Hz),






7.97 (1H, d, J = 2.0 Hz), 8.04 (1H, dd, J =






8.9 Hz, 2.6 Hz), 8.24 (1H, d, J = 2.6 Hz),






8.42 (1H, s).


717
—OCH3
—CH3
3-furylmethyl
(CDCl3) 2.40-2.44 (4H, m), 2.96 (3H, s),






3.39 (2H, s), 3.49-3.63 (4H, m), 3.63 (3H, s),






4.06 (2H, s), 6.12 (1H, dd, J = 8.7 Hz, 2.6






Hz) 6.22 (1H, d, J = 2.5 Hz), 6.38 (1H, s),






6.76 (1H, d, J = 8.7 Hz), 6.86 (1H, d, J =






8.7 Hz), 7.33-7.47 (3H, m), 7.69 (1H, dd, J =






8.4 Hz, 2.0 Hz), 7.96-8.04 (2H, m),






8.20 (1H, d, J = 2.3 Hz), 8.92 (1H, s).
















TABLE 200













 











Example






No.
R657
R658
R659
Property





718
—CH3
—CH3
3-furylmethyl
mp 116.5-118.0° C.


 


719
—H
—C2H5




MS 606(M+ + H)


 


720
—H
—C2H5




MS 645(M+ + H)


 


721
—H
—C2H5




1H NMR (CDCl3) δ 1.16 (3 H, t, J = 7.1 Hz), 3.04 (4 H, brs), 3.40 (2 H, q, J = 7.1 Hz), 3.66-3.76 (4 H, m), 4.07 (2 H, s), 5.91 (2 H, s), 6.36 (1 H, dd, J = 8.4 Hz, 2.5 Hz), 6.55 (1 H, d, J = 2.3 Hz), 6.66 (2 H, d, J = 9.1 Hz), 6.73 (1 H, d, J = 8.4 Hz), 6.83 (1 H, d, J = 8.9 Hz), 6.96 (2 H, d, J = 8.9 Hz), 7.54 (1 H, d, J = 8.4 Hz), 7.71 (1 H, dd, J = 8.4 Hz, 2.1 Hz), 7.98 (1 H, d, J = 2.1 Hz), 8.07 (1 H, dd, J = 8.9 Hz, 2.6 Hz), 8.22 (1 H, brs), 8.24 (1 H, d, J = 2.5 Hz).


 


722
—H
—CH3




1H NMR (CDCl3) δ 3.00-3.03 (7 H, m), 3.64 (2 H, brs), 3.75 (2 H, brs), 4.12 (2 H, s), 5.91 (2 H, s), 6.36 (1 H, dd, J = 8.4 Hz, 2.5 Hz), 6.55 (1 H, d, J = 2.3 Hz), 6.68 (2 H, d, J = 9.1 Hz), 6.73 (1 H, d, J = 8.4 Hz), 6.83 (1 H, d, J = 8.9 Hz), 6.98 (2 H, d, J = 9.1 Hz), 7.54 (1 H, d, J = 8.4 Hz), 7.71 (1 H, dd, J = 8.4 Hz, 2.1 Hz), 7.98 (1 H, d, J = 2.1 Hz), 8.07 (1 H, dd, J = 8.9 Hz, 2.8 Hz), 8.22 (1 H, brs), 8.23 (1 H, d, J = 3.0 Hz).


 


723
—H
—C2H5




1H NMR (DMSO-d6) δ 1.11 (3 H, t, J = 7.1 Hz), 2.31 (2 H, brs), 2.38 (2 H, brs), 3.22-3.58 (8 H, m), 4.16 (2 H, s), 4.21 (4 H, s), 6.56 (2 H, d, J = 9.0 Hz), 6.71-6.85 (3 H, m), 6.90 (2 H, d, J = 9.0 Hz), 6.93 (1 H, d, J = 8.9 Hz), 7.83 (1 H, d, J = 8.4 Hz), 7.95 (1 H, dd, J = 8.4 Hz, 2.0 Hz), 8.12 (1 H, dd, J = 8.9 Hz, 2.6 Hz), 8.22 (1 H, d, J = 2.0 Hz), 8.43 (1 H, d, J = 2.6 Hz), 10.51 (1 H, s).


 


724
—H
—C2H5




1H NMR (CDCl3) δ 1.13 (3 H, t, J = 7.0 Hz, 2.10-2.25 (2 H, m), 2.42 (4 H, brs), 3.34 (2 H, q, J = 7.0 Hz), 3.42 (2 H, s), 3.50 (2 H, brs), 3.61 (2 H, brs), 4.01 (2 H, s), 4.11-4.31 (4 H, m), 6.59 (2 H, d, J = 9.2 Hz), 6.79 (1 H, d, J = 8.9 Hz), 6.82-6.98 (5 H, m), 7.51 (1 H, d, J = 8.4 Hz), 7.70 (1 H, dd, J = 8.4 Hz, 2.0 Hz), 7.98 (1 H, d, J = 2.8 Hz), 8.03 (1 H, dd, J = 8.9 Hz, 2.8 Hz), 8.24 (1 H, d, J = 2.8 Hz), 8.54 (1 H, s).
















TABLE 201













 











Example






No.
R660
R661
R662
mp (° C.) or 1H NMR (solvent) δ ppm





725
—CH3
—Ac
piperonyl
mp 216-217


726
—CH3
—Ac
benzyl
1H NMR (DMSO-d6) 1.82 (3 H, s), 2.09 (3 H,






s), 2.28-2.36 (4 H, m), 3.35-3.50 (6 H, m),






4.44 (2 H, s), 7.05-7.10 (2 H, m), 7.20-7.32 (7 H,






m, 7.82 (1 H, d, J = 8.5 Hz), 7.92 (1 H, dd, J =






1.9 Hz, 8.5 Hz), 8.15-8.20 (2 H, m), 8.42 (1 H,






d, J = 2.5 Hz), 10.53 (1 H, s).


727
—H
—C2H5
3-pyridyl
1H NMR (DMSO-d6) 1.13 (3 H, t, J = 7.1 Hz),






3.21 (2 H, brs), 3.29 (2 H, brs), 3.37 (2 H, q, J =






7.1 Hz), 3.51-3.78 (4 H, m), 4.26 (2 H, s),






6.60 (2 H, d, J = 9.0 Hz), 6.92 (2 H, d, J = 9.0






Hz), 6.94 (1 H, d, J = 8.9 Hz), 7.23 (1 H, dd, J =






8.5 Hz, 4.6 Hz), 7.36 (1 H, dd, J = 8.5 Hz,






1.6 Hz), 7.83 (1 H, d, J = 8.5 Hz), 7.94 (1 H,






dd, J = 8.5 Hz, 2.0 Hz), 8.03 (1 H, d, J = 4.6






Hz), 8.12 (1 H, dd, J = 8.9 Hz, 2.8 Hz),






8.22 (1 H, d, J = 2.0 Hz), 8.34 (1 H, d, J = 2.8






Hz), 8.43 (1 H, d, J = 2.8 Hz), 10.51 (1 H, s).


728
—F
—C2H5
piperonyl
mp 149-151


729
—F
—CH3
piperonyl
mp 199-201


730
—F
—Ac
piperonyl
mp 233-235


731
—OCH3
—CH3
piperonyl
1H NMR (CDCl3) 2.41-2.43 (4 H, m),






3.02 (3 H, s), 3.42 (2 H, s), 3.49-3.62 (4 H, m),






3.72 (3 H, s), 4.08 (2 H, s), 5.95 (2 H, s),






6.21 (1 H, dd, J = 8.7 Hz, 2.6 Hz), 6.32 (1 H, d,






J = 2.8 Hz), 6.73-6.77 (2 H, m), 6.84 (2 H, t, J =






4.5 Hz), 6.95 (1 H, d, J = 8.7 Hz), 7.54 (1 H,






d, J = 8.4 Hz), 7.70 (1 H, dd, J = 8.2 Hz, 2.0






Hz), 7.97 (2 H, d, J = 2.0 Hz), 8.05-8.09 (1 H,






m), 8.19 (1 H, d, J = 2.5 Hz).


732
—H
—CH3
3-pyridylmetyl
1H NMR (CDCl3) 2.40-2.42 (4 H, m),






2.93 (3 H, s), 3.44 (2 H, s), 3.48-3.58 (4 H, m),






4.06 (2 H, s), 6.58 (2 H, d, J = 9.1 Hz),






6.74 (1 H, d, J = 8.9 Hz), 6.90 (2 H, d, J = 9.1






Hz), 7.25-7.30 (1 H, m), 7.43 (1 H, d, J = 8.4






Hz), 7.66-7.73 (2 H, m), 7.97 (1 H, d, J = 2.0






Hz), 8.03 (1 H, dd, J = 8.9 Hz, 2.6 Hz),






8.25 (1 H, d, J = 2.5 Hz), 8.47-8.51 (2 H, m),






9.59 (1 H, s).


 


733
—H
—CH3




1H NMR (DMSO-d6) 2.96 (3 H, s), 3.07-3.15 (4 H, m), 3.59 (4 H, brs), 3.83 (2 H, s), 4.31 (2 H, s), 6.66 (2 H, d, J = 9.1 Hz), 6.88-6.95 (5 H, m, 7.05-7.13 (4 H, m), 7.20-7.24 (2 H, m), 7.83 (1 H, d, J = 8.4 Hz), 7.95 (1 H, dd, J = 8.4 Hz, 2.0 Hz), 8.12 (1 H, dd, J = 8.9 Hz, 2.8 Hz), 8.22 (1 H, d, J = 2.0 Hz), 8.43 (1 H, d, J = 2.5 Hz), 10.50 (1 H, s).
















TABLE 202













 










Example





No.
R663
R664
MS or 1H NMR





734
—H
—CHPh2
MS 694(M+ + H)


735
—H
3-CH3OPh-
MS 634(M+ + H)


736
—H
4-CH3OPh-
MS 634(M+ + H)


737
—H
3,4- (CH3)2Ph-
MS 632(M+ + H)


738
—H
2,3-Cl2Ph-
MS 673(M+ + H)


739
—H
2,4-F2Ph-
MS 640(M+ + H)


740
—H
2-CH3OPh-
MS 634(M+ + H)


741
—H
3-CF3Ph-
MS 671(M+ + H)


742
—H
2-ClPh-
MS 639(M+ + H)


743
—H
4-CF3Ph-
MS 671(M+ + H)


744
—H
-Ph
MS 604(M+ + H)


745
—H
2-pyridylmethyl
MS 619(M+ + H)


746
—H
2-pyridyl
MS 605(M+ + H)


747
—H
—(CH2)3Ph
MS 646(M+ + H)


748
—H
—(CH2)4Ph
MS 660(M+ + H)


749
—H
—(CH2)2N (CH3)2
MS 599(M+ + H)


750
—H
cyclopentyl
MS 596(M+ + H)


 


751
—H




MS 625(M+ + H)


 


752
—H




MS 641(M+ + H)


 


753
—H
—CH (CH3)Ph
MS 634(M+ + H)


754
—H
—(CH2)2Ph
MS 632(M+ + H)


755
—H
—CH2CONHPh
MS 661(M+ + H)


756
—H
—(CH2)3N (CH3)2
MS 613(M+ + H)


 


757
—H




MS 639(M+ + H)


 


758
—H
—CH3
MS 542(M+ + H)


759
—OCH3
—H
1H NMR (CDCl3) δ 1.26 (3 H, t, J = 6.9 Hz),





2.70 (1 H, brs), 2.82-2.87 (4 H, m), 3.33 (2 H,





q, J = 6.9 Hz), 3.49-3.57 (4 H, m), 3.62 (3 H,





s), 4.00 (2 H, s), 6.09 (1 H, d, J = 8.7 Hz),





6.20 (1 H, s), 6.73 (1 H, d, J = 8.7 Hz),





6.83 (1 H, d, J = 8.6 Hz), 7.42 (1 H, d, J = 8.3





Hz), 7.70 (1 H, d, J = 7.4 Hz), 7.97-8.03 (2 H,





m), 8.23 (1 H, s), 9.26 (1 H, brs).
















TABLE 203













 











Example






No.
R665 
R666
Form
1H NMR (DMSO-d6) δ ppm





760
—Ac
piperonyl
hydro-
1.84 (3 H, s), 2.83-3.14 (2 H, m), 3.23-3.32 (2 H,





chloride
m), 4.02 (1 H, d, J = 13.6 Hz), 4.18-4.27 (2 H,






m), 4.40 (1 H, d, J = 13.6 Hz), 4.50-4.60 (2 H,






m), 6.07 (2 H, s), 6.96-7.03 (2 H, m),






7.10-7.25 (4 H, m), 7.43 (2 H, d, J = 8.8 Hz),






7.85 (1 H, d, J = 8.4 Hz), 7.98 (1 H, dd, J = 2.0






Hz, 8.4 Hz), 8.24 (1 H, dd, J = 2.6 Hz, 8.9 Hz),






8.26 (1 H, d, J = 2.0 Hz), 8.54 (1 H, d, J = 2.6






Hz), 10.69 (1 H, s), 11.07 (1 H, brs).


761
—Ac
benzyl
hydro-
1.84 (3 H, s), 2.90-3.17 (2 H, m), 3.23-3.35 (2 H,





chloride
m), 4.03 (1 H, d, J = 14.4 Hz), 4.28-4.43 (3 H,






m), 4.50-4.62 (2 H, m), 7.13 (1 H, d, J = 8.8 Hz),






7.17 (2 H, d, J = 8.8 Hz), 7.40-7.50 (5 H, m),






7.58-7.62 (2 H, m), 7.85 (1 H, d, J = 8.4 Hz),






8.00 (1 H, dd, J = 2.0 Hz, 8.4 Hz),






8.20-8.29 (2 H, m), 8.54 (1 H, d, J = 2.6 Hz),






10.70 (1 H, s), 11.21 (1 H, brs).


762
—C2H5
3-furylmethyl
trihydro-
1.11 (3 H, t, J = 7.1 Hz), 2.75-3.30 (3 H, m),





chloride
3.30-3.50 (2 H, m), 3.40 (2 H, q, J = 7.1 Hz),






3.51-3.72 (1 H, m), 3.95-4.15 (1 H, m), 4.22 (2 H,






s), 4.30-4.62 (3 H, m), 6.80-6.85 (1 H, m),






6.89 (2 H, d, J = 8.9 Hz), 7.00 (1 H, d, J = 8.9






Hz), 7.0 1 (2 H, d, J = 8.9 Hz), 7.70-7.80 (1 H,






m), 7.84 (1 H, d, J = 8.5 Hz), 7.88 (1 H, s),






7.99 (1 H, dd, J = 8.5 Hz, 2.0 Hz), 8.19 (1 H, dd,






J = 8.9 Hz, 2.7 Hz), 8.27 (1 H, d, J = 2.0 Hz),






8.50 (1 H, d, J = 2.7 Hz), 10.69 (1 H, s).


763
—C2H5
4-pyridylmethyl
tetrahydro-
1.11 (3 H, t, J = 7.0 Hz), 3.00-3.60 (6 H, m),





chloride
3.41 (2 H, q, J = 7.0 Hz), 3.90 (2 H, brs),






4.42 (2 H, brs), 4.63 (2 H, brs), 6.82 (2 H, d, J =






8.8 Hz), 6.98 (3 H, d, J = 8.8 Hz), 7.84 (1 H, d, J =






8.4 Hz), 7.98 (1 H, dd, J = 8.4 Hz, 2.0 Hz),






8.17 (1 H, dd, J = 8.9 Hz, 2.6 Hz), 8.22-8.39 (3






H, m), 8.49 (1 H, d, J = 2.5 Hz), 8.99 (2 H,






d, J = 6.2 Hz), 10.67 (1 H, s).


 


764
—CH3




dihydro- chloride
2.94 (3 H, s), 2.80-3.22 (3 H, m), 3.22-3.70 (3 H, m), 3.95-4.60 (6 H, m), 6.68 (2 H, d, J = 9.1 Hz), 6.92 (2 H, d, J = 9.1 Hz), 6.95 (1 H, d, J = 8.9 Hz), 7.79 (1 H, dd, J = 8.4 Hz, 1.6 Hz), 7.84 (1 H, d, J = 8.4 Hz), 7.96 (1 H, dd, J = 8.4 Hz, 2.0 Hz), 8.14 (1 H, dd, J = 8.9 Hz, 2.3 Hz), 8.20 (1 H, d, J = 8.4 Hz), 8.24 (1 H, d, J = 2.0 Hz), 8.40 (1 H, d, J = 1.6 Hz), 8.44 (1 H, d, J = 2.3 Hz), 9.51 (1 H, s), 10.57 (1 H, s).
















TABLE 204













 













Example








No.
R667
R668
R669
R670
R671
mp (° C.) or 1H NMR (solvent) δ ppm





765
—Cl
—Cl
—H
—CH3
piperonyl
mp 198-200


766
—Cl
—Cl
—H
—C2H5
benzyl
1H NMR (DMSO-d6) 1.12 (3 H, t, J =








7.1 Hz), 2.98 (4 H, brs), 3.34 (2 H, q, J =








7.1 Hz), 3.20-3.50 (2 H, m),








3.67 (2 H, brs), 4.10 (2 H, brs),








4.23 (2 H, s), 6.11 (2 H, s), 6.59 (2 H, d,








J = 9.2 Hz), 6.91 (2 H, d, J = 9.2 Hz),








6.94 (1 H, d, J = 8.9 Hz), 7.45 (5 H, s),








7.84 (1 H, d, J = 8.4 Hz), 7.94 (1 H,








dd, J = 8.4 Hz, 2.6 Hz), 8.12 (1 H,








dd, J = 8.9 Hz, 2.6 Hz), 8.22 (1 H, d,








J = 2.0 Hz), 8.43 (1 H, d, J = 2.6 Hz),








10.51 (1 H, s).


 


767
—Cl
—Cl
—H
—CH3




1H NMR (DMSO-d6) 2.94 (3 H, s), 3.05 (4 H, brs), 3.40 (2 H, brs), 3.63 (2 H, brs), 4.04 (2 H, brs), 4.26 (4 H, s), 4.31 (2 H, brs), 6.09 (2 H, s), 6.65 (2 H, d, J = 9.1 Hz), 6.82-7.06 (6 H, m), 7.84 (1 H, d, J = 8.4 Hz), 7.94 (1 H, dd, J = 8.4 Hz, 2.0 Hz), 8.12 (1 H, dd, J = 8.8 Hz, 2.5 Hz), 8.22 (1 H, d, J = 2.0 Hz), 8.43 (1 H, d, J = 2.5 Hz), 10.51 (1 H, s).


 


768
—Cl
—Cl
—OCH3
—C2H5
piperonyl
mp 172-177


769
—CF3
—H
—H
—C2H5
benzyl
1H NMR (CDCl3 + CD3OD) 1.13 (3 H,








t, J = 6.9 Hz), 3.08 (4 H, brs),








3.36 (2 H, q, J = 6.9 Hz), 3.85 (4 H,








brs), 4.09 (2 H, s), 4.18 (2 H, s), 6.31








(2 H, s), 6.73 (2 H, d, J = 8.9 Hz),








6.87 (1 H, d, J = 9.2 Hz), 6.98 (2 H, d,








J = 8.9 Hz), 7.40-7.44 (5 H, m),








7.73 (2 H, d, J = 8.4 Hz), 8.07 (2 H, d,








J = 8.3 Hz), 8.27 (2 H, d, J = 7.4 Hz),








9.63 (1 H, s).


 


770
—CF3
—H
—H
—CH3




1H NMR (DMSO-d6) 2.94 (3 H, s), 2.95 (4 H, brs), 3.33 (4 H, brs), 4.03 (2 H, brs), 4.26 (4 H, s), 4.31 (2 H, brs), 6.09 (2 H, s), 6.65 (2 H, d, J = 9.2 Hz), 6.85-7.03 (6 H, m, 7.93 (2 H, d, J = 8.2 Hz), 8.14 (1 H, dd, J = 8.9 Hz, 2.5 Hz), 8.16 (2 H, d, J = 8.2 Hz), 8.45 (1 H, d, J = 2.5 Hz), 10.59 (1 H, s).
















TABLE 205













 











Example






No.
R672
R673
R674
mp (° C.) or 1H NMR (solvent) δ ppm





771
—H
—Ac
benzyl
mp 161-162


772
—CH3
—Ac
piperonyl
1H NMR (DMSO-d6) 1.82 (3 H, s), 2.10 (3 H, s),






2.23-2.36 (4 H, m), 3.33-3.45 (6 H, m), 4.44 (2 H,






s), 5.96 (2 H, s), 6.72 (1 H, d, J = 8.0 Hz),






6.82 (1 H, d, J = 8.0 Hz), 6.84 (1 H, s), 7.02-7.10 (2






H, m), 7.23 (1 H, d, J = 8.6 Hz), 7.33 (1 H,






s), 7.91 (2 H, d, J = 8.4 Hz), 8.14 (2 H, d, J = 8.4






Hz), 8.20 (1 H, d, J = 8.6 Hz), 8.45 (1 H, s),






10.60 (1 H, s).


773
—CH3
—Ac
benzyl
1H NMR (DMSO-d6) 1.82 (3 H, s), 2.10 (3 H, s),






2.30-2.37 (4 H, m), 3.35-3.45 (4 H, m), 3.47 (2 H,






s), 4.44 (2 H, s), 7.03-7.10 (2 H, m), 7.20-7.35 (7






H, m), 7.91 (2 H, d, J = 8.4 Hz), 8.14 (2 H,






d, J = 8.4 Hz), 8.21 (1 H, dd, J = 2.5 Hz, 8.9






Hz), 8.45 (1 H, d, J = 2.5 Hz), 10.60 (1 H, s).


774
—H
—C2H5
piperonyl
mp 178-180


775
—F
—C2H5
piperonyl
mp 170-172


776
—F
—CH3
piperonyl
mp 220-221


777
—OCH3
—CH3
piperonyl
1H NMR (CDCl3) 2.38-2.42 (4 H, m), 2.96 (3 H,






s), 3.41 (2 H, s), 3.47-3.58 (4 H, m), 3.64 (3 H, s),






4.05 (2 H, s), 5.94 (2 H, s), 6.13 (1 H, dd, J = 8.9






Hz, 2.8 Hz), 6.24 (1 H, d, J = 2.8 Hz), 6.70-6.89 (5






H, m), 7.64 (2 H, d, J = 8.3 Hz), 7.96 (2 H,






d, J = 8.1 Hz), 8.06 (1 H, dd, J = 8.9 Hz, 2.6






Hz), 8.20 (1 H, d, J = 2.6 Hz), 8.93 (1 H, s).


 


778
—OCH3
—CH3




1H NMR (CDCl3) 2.38-2.42 (4 H, m), 2.96 (3 H, s), 3.40 (2 H, s), 3.47-3.57 (4 H, m), 3.98 (3 H, s), 4.05 (2 H, s), 4.24 (4 H, s), 6.13 (1 H, dd, J = 8.9 Hz, 2.8 Hz), 6.23 (1 H, d, J = 2.6 Hz), 6.73-6.88 (5 H, m), 7.63 (2 H, d, J = 8.3 Hz), 7.97 (2 H, d, J = 8.1 Hz), 8.07 (1 H, dd, J = 8.9 Hz, 2.6 Hz), 8.20 (1 H, d, J = 2.5 Hz), 9.11 (1 H, s).


 


779
—F
—CH3




1H NMR (DMSO-d6) 2.30 (2 H, brs), 2.39 (2 H, brs), 2.93 (3 H, s), 3.38 (2 H, s), 3.44 (4 H, brs), 4.22 (4 H, s), 4.28 (2 H, s), 6.40-6.43 (1 H, m), 6.56 (1 H, dd, J = 14.2 Hz, 2.6 Hz), 6.73-6.81 (3 H, m), 7.02-7.08 (2 H, m), 7.93 (2 H, d, J = 8.6 Hz), 8.14-8.21 (3 H, m), 8.49 (1 H, d, J = 2.6 Hz), 10.61 (1 H, s).


 


780
—F
—CH3
3-furylmethyl
1H NMR (DMSO-d6) 2.32 (2 H, s), 2.41 (2 H, s),






2.93 (3 H, s), 3.37 (2 H, s), 3.44 (4 H, brs),






4.29 (2 H, s), 6.40-6.44 (2 H, m), 6.55 (1 H, dd, J =






14.5 Hz, 2.8 Hz), 7.02-7.08 (2 H, m), 7.58-7.62 (2






H, m), 7.93 (2 H, d, J = 8.4 Hz), 8.14-8.21 (3






H, m), 8.41 (1 H, d, J = 2.6 Hz),






10.61 (1 H, s).
















TABLE 206













 











Example






No.
R675
R676
R677
mp (° C.) or 1H NMR (solvent) δ ppm





781
—OCH3
—C2H5




1H NMR (CDCl3) 1.16 (3 H, t, J = 6.9 Hz), 2.38-2.43 (4 H, m), 3.33-3.62 (8 H, m), 3.66 (3 H, s), 4.02 (2 H, s), 4.26 (4 H, s), 6.14 (1 H, dd, J = 8.7 Hz, 2.6 Hz), 6.25 (1 H, d, J = 2.6 Hz), 6.75-6.90 (5 H, m), 7.66 (2 H, d, J = 8.3 Hz), 8.01 (2 H, d, J = 8.3 Hz), 8.09 (1 H, dd, J = 9.1 Hz, 2.8 Hz), 8.26 (1 H, d, J = 2.6 Hz), 9.19 (1 H, s).


 


782
—F
—Ac
piperonyl
1H NMR (DMSO-d6) 1.88 (3 H, s), 2.33 (4 H, brs),






3.40 (2 H, s), 3.40 (4 H, brs), 4.50 (2 H, s),






5.99 (2 H, s), 6.73-6.76 (1 H, m), 6.83-6.86 (2 H,






m), 7.21 (1 H, d, J = 8.9 Hz), 7.32-7.49 (3 H, m),






7.94 (2 H, d, J = 8.3 Hz), 8.16 (2 H, d, J = 8.1






Hz), 8.25 (1 H, dd, J = 8.9 Hz, 2.6 Hz), 8.46 (1 H,






d, J = 2.6 Hz), 10.66 (1 H, s).


783
—H
—CH3
3-furylmethyl
1H NMR (CDCl3) 2.44 (4 H, brs), 2.99 (3 H, s),






3.40 (2 H, s), 3.50 (2 H, t, J = 4.9 Hz), 3.62 (2 H,






t, J = 4.9 Hz), 4.07 (2 H, s), 6.38 (1 H, d, J = 1.0






Hz), 6.67 (2 H, d, J = 9.1 Hz), 6.84 (1 H, d, J =






8.8 Hz), 6.98 (2 H, d, J = 9.1 Hz), 7.34 (1 H, s),






7.40 (1 H, t, J = 1.6 Hz), 7.73 (2 H, d, J = 8.2 Hz),






7.99 (2 H, d, J = 8.2 Hz), 8.11 (1 H, dd, J = 8.8






Hz, 2.6 Hz), 8.24 (1 H, s), 8.25 (1 H, d, J = 2.6






Hz).


784
—OCH3
—C2H5
3-furylmethyl
mp 174-176


785
—OCH3
—CH3
3-furylmethyl
mp 160-164


786
—CH3
—CH3
—COOC (CH3)3
1H NMR (CDCl3) 1.47 (9 H, s), 2.12 (3 H, s),






3.01 (3 H, s), 3.30-3.71 (8 H, m), 4.09 (2 H, s),






6.44-6.66 (2 H, m), 6.83 (1 H, d, J = 8.9 Hz),






6.93 (1 H, d, J = 8.4 Hz), 7.75 (2 H, d, J = 8.1






Hz), 7.94 (1 H, s), 7.99 (2 H, d, J = 8.1 Hz),






8.15 (1 H, d, J = 9.2 Hz), 8.22 (1 H, s).


 


787
—H
—C2H5




1H NMR (CDCl3) 1.18 (3 H, t, J = 7.1 Hz), 3.03 (4 H, brs), 3.43 (2 H, q, J = 7.1 Hz), 3.67-3.77 (4 H, m), 4.08 (2 H, s), 5.91 (2 H, s), 6.36 (1 H, dd, J = 8.4 Hz, 2.3 Hz), 6.55 (1 H, d, J = 2.5 Hz), 6.68-6.75 (3 H, m), 6.87 (1 H, d, J = 8.7 Hz), 7.00 (2 H, d, J = 8.9 Hz), 7.75 (2 H, d, J = 8.4 Hz), 7.98 (1 H, brs), 7.99 (2 H, d, J = 8.3 Hz), 8.13 (1 H, dd, J = 8.7 Hz, 2.6 Hz), 8.25 (1 H, d, J = 2.6 Hz)
















TABLE 207













 












Example







No.
R678
R679
R680
Form
mp (° C.) or 1H NMR (solvent) δ ppm





788
—F
—(CH2)2CH3
piperonyl
free
1H NMR (CDCl3) 0.94 (3 H, t, J = 7.3







Hz), 1.58-1.69 (2 H, m), 2.45 (4 H,







brs), 3.29 (2 H, t, J = 7.6 Hz),







3.45 (2 H, s), 3.49 (2 H, brs), 3.64 (2 H,







brs), 4.05 (2 H, s), 5.95 (2 H, s),







6.34-6.44 (2 H, m), 6.75 (2 H, s), 6.86 (1 H,







s), 6.96 (1 H, d, J = 8.9 Hz), 7.03 (1 H,







t, J = 9.1 Hz), 7.76 (2 H, d, J = 8.2







Hz), 7.86 (1 H, brs), 8.00 (2 H, d, J =







8.1 Hz), 8.16-8.22 (2 H, m).


 


789
—H
—CH3




free
1H NMR (CDCl3) 3.02 (7 H, brs), 3.64 (2 H, brs), 3.75 (2 H, brs), 4.12 (2 H, s), 5.91 (2 H, s), 6.36 (1 H, dd, J = 8.4 Hz, 2.5 Hz), 6.55 (1 H, d, J = 2.5 Hz), 6.70 (2 H, d, J = 9.1 Hz), 6.73 (1 H, d, J = 8.3 Hz), 6.85 (1 H, d, J = 8.9 Hz), 6.99 (2 H, d, J = 9.2 Hz), 7.73 (2 H, d, J = 8.3 Hz), 7.98 (2 H, d, J = 8.3 Hz), 8.12 (1 H, dd, J = 9.1 Hz, 2.8 Hz), 8.15 (1 H, brs), 8.24 (1 H, d, J = 2.5 Hz).


 


790
—OCH3
—CH3
4- (4-FPhCO)Ph-
free
1H NMR (CDCl3) 3.03 (3 H, s),







3.39 (4 H, brs), 3.70 (3 H, s), 3.71-3.79 (4







H, m), 4.14 (2 H, s), 6.23 (1 H,







dd, J = 8.9 Hz, 2.8 Hz), 6.36 (1 H, d,







J = 2.6 Hz), 6.81-6.96 (4 H, m),







7.09-7.17 (2 H, m), 7.68 (2 H, d, J = 8.4







Hz), 7.72-7.78 (4 H, m), 7.99 (2 H, d, J =







8.3 Hz), 8.09 (1 H, dd, J = 8.9 Hz,







2.8 Hz), 8.21 (1 H, d, J = 2.6 Hz),







8.53 (1 H, s).


791
—OCH3
—C2H5
4- (4-FPhCO)Ph-
free
1H NMR (CDCl3) 1.17 (3 H, t, J = 6.9







Hz), 3.37-3.42 (6 H, m), 3.67 (3 H, s),







3.71-3.76 (4 H, m), 4.08 (2 H, s),







6.19 (1 H, dd, J = 8.9 Hz, 2.8 Hz),







6.33 (1 H, d, J = 2.6 Hz),







6.77-6.92 (4 H, m), 7.09-7.15 (2 H, m),







7.64 (2 H, d, J = 8.3 Hz), 7.71-7.77 (4







H, m), 7.98 (2 H, d, J = 8.1







Hz), 8.07 (1 H, dd, J = 8.9 Hz, 2.6







Hz), 8.23 (1 H, d, J = 2.6 Hz),







8.83 (1 H, s).


792
—CH3
—CH3
3-furylmethyl
hydro-
mp 158.5-161.0






chloride
















TABLE 208













 











Example






No.
R681
R682
R683
1H NMR (DMSO-d6) δ ppm





793
—Cl
—Cl
piperonyl
1.74 (3 H, s), 2.19-2.34 (4 H, m), 2.54 (2 H, t, J = 7.7






Hz), 3.32-3.46 (6 H, m), 3.76 (2 H, t, J = 7.7 Hz),






5.96 (2 H, s), 6.72 (1 H, d, J = 7.9 Hz), 6.77-6.85 (2 H,






m), 7.11 (1 H, d, J = 8.8 Hz), 7.17 (2 H, d, J = 8.6 Hz),






7.31 (2 H, d, J = 8.6 Hz), 7.83 (1 H, d, J = 8.4 Hz),






7.93 (1 H, dd, J = 8.4 Hz, 2.1 Hz), 8.17-8.25 (2 H, m,






8.51 (1 H, d, J = 2.4 Hz), 10.57 (1 H, s).


794
—Cl
—Cl
benzyl
1.74 (3 H, s), 2.25-2.37 (4 H, m), 2.54 (2 H, t, J = 7.7






Hz), 3.36-3.42 (4 H, m), 3.46 (2 H, s), 3.76 (2 H, t, J =






7.7 Hz), 7.11 (1 H, d, J = 8.8 Hz), 7.16 (2 H, d, J = 8.6






Hz), 7.20-7.31 (5 H, m), 7.34 (2 H, d, J = 8.6 Hz),






7.83 (1 H, d, J = 8.4 Hz), 7.93 (1 H, dd, J = 8.4 Hz, 2.1






Hz), 8.19-8.25 (2 H, m), 8.51 (1 H, d, J = 2.5 Hz),






10.57 (1 H, s).


795
—CF3
—H
piperonyl
1.74 (3 H, s), 2.20-2.35 (4 H, m), 2.54 (2 H, t, J = 7.7






Hz), 3.34-3.42 (6 H, m), 3.76 (2 H, t, J = 7.7 Hz),






5.96 (2 H, s), 6.72 (1 H, d, J = 7.8 Hz), 6.78-6.86 (2 H,






m), 7.12 (1 H, d, J = 8.8 Hz), 7.17 (2 H, d, J = 8.5 Hz),






7.35 (2 H, d, J = 8.5 Hz), 7.92 (2 H, d, J = 8.2 Hz),






8.15 (2 H, d, J = 8.2 Hz), 8.24 (1 H, dd, J = 8.8 Hz, 2.5






Hz), 8.54 (1 H, d, J = 2.5 Hz), 10.65 (1 H, s).


796
—CF3
—H
benzyl
1.74 (3 H, s), 2.18-2.36 (4 H, m), 2.54 (2 H, t, J = 7.7






Hz), 3.35-3.45 (4 H, m), 3.46 (2 H, s), 3.76 (2 H, t, J =






7.7 Hz), 7.12 (1 H, d, J = 8.8 Hz), 7.17 (2 H, d, J = 8.6






Hz), 7.20-7.33 (5 H, m), 7.34 (2 H, d, J = 8.6 Hz),






7.92 (2 H, d, J = 8.3 Hz), 8.15 (2 H, d, J = 8.3 Hz),






8.24 (1 H, dd, J = 8.8 Hz, 2.5 Hz), 8.54 (1 H, d, J = 2.5






Hz), 10.65 (1 H, s).
















TABLE 209













 











Example






No.
R684
R685
R686
1H NMR (DMSO-d6) δ ppm





797
—Cl
—Cl
benzyl
1.80 (3 H, s), 3.02 (3 H, s), 2.70-3.40 (5 H, m),






3.41-3.68 (1 H, m), 3.88-4.10 (1 H, m), 4.32 (2 H, brs), 4.25-






4.50 (1 H, m), 4.50 (2 H, d, J = 3.8 Hz), 4.57 (2 H, s), 6.94






(1 H, d, J = 8.9 Hz), 7.02 (2 H, d, J = 8.7 Hz), 7.22 (1 H,






dd, J = 8.2 Hz, 2.0 Hz), 7.34 (1 H, dd, J = 8.9 Hz, 3.2 Hz),






7.36 (2 H, d, J = 8.7 Hz), 7.42-7.49 (3 H, m), 7.50 (1 H, d,






J = 2.0 Hz), 7.55-7.64 (1 H, m), 7.62 (2 H, d, J = 8.2 Hz),






7.66 (1 H, d, J = 6.1 Hz).


798
—Cl
—Cl
piperonyl
1.81 (3 H, s), 2.75-3.40 (5 H, m), 3.02 (3 H, s),






3.43-3.67 (1 H, m), 3.90-4.10 (1 H, m), 4.22 (2 H, brs), 4.30-






4.50 (1 H, m), 4.50 (2 H, d, J = 4.6 Hz), 4.57 (2 H, s), 6.07






(2 H, s), 6.94 (2 H, d, J = 8.8 Hz), 6.97-7.07 (1 H, m), 7.02






(2 H, d, J = 8.9 Hz), 7.22 (1 H, dd, J = 8.3 Hz, 1.8 Hz),






7.24 (1 H, s), 7.34 (1 H, dd, J = 8.8 Hz, 3.0 Hz), 7.36 (2 H, d,






J = 8.9 Hz), 7.50 (1 H, d, J = 1.8 Hz), 7.60 (1 H, d, J = 8.3 Hz),






7.67 (1 H, d, J = 3.0 Hz).


799
—CF3
—H
benzyl
1.80 (3 H, s), 3.05 (3 H, s), 2.70-3.40 (5 H, m),






3.41-3.68 (1 H, m), 3.90-4.08 (1 H, m), 4.22-4.45 (1 H, m), 4.32






(2 H, brs), 4.50 (2 H, d, J = 3.5 Hz), 4.67 (2 H, s), 6.94 (1 H,






d, J = 8.9 Hz), 7.02 (2 H, d, J = 8.8 Hz), 7.34 (1 H, dd,






J = 8.9 Hz, 3.3 Hz), 7.36 (2 H, d, J = 8.8 Hz), 7.39-7.50






(5 H, m), 7.54-7.64 (2 H, m), 7.67 (1 H, d, J = 3.3 Hz), 7.70






(2 H, d, J = 8.1 Hz).


800
—CF3
—H
piperonyl
1.80 (3 H, s), 2.70-3.40 (5 H, m), 3.05 (3 H, s),






3.43-3.65 (1 H, m), 3.90-4.09 (1 H, m), 4.22 (2 H, s), 4.29-






4.48 (1 H, m), 4.50 (2 H, d, J = 4.8 Hz), 4.67 (2 H, s), 6.07






(2 H, s), 6.94 (1 H, d, J = 8.9 Hz), 7.00 (2 H, d, J = 7.0 Hz),






7.02 (2 H, d, J = 8.8 Hz), 7.24 (1 H, d, J = 1.1 Hz), 7.35






(1 H, dd, J = 8.9 Hz, 2.3 Hz), 7.36 (2 H, d, J = 8.8 Hz),






7.45 (2 H, d, J = 8.1 Hz), 7.67 (1 H, d, J = 3.3 Hz), 7.70






(2 H, d, J = 8.1 Hz).
















TABLE 210













 











Example






No.
R687
R688
R689
1H NMR (CDCl3) δ ppm





801
4-CF3PhCO—
—CH3
—C2H5
1.19 (3 H, t, J = 7.1 Hz), 2.11 (3 H, s),






2.42-2.45 (4 H, m), 3.39-3.53 (6 H, m),






3.63-3.66 (2 H, m), 4.04 (2 H, s), 5.95 (2 H, s),






6.50-6.54 (2 H, m), 6.71-6.77 (2 H, m),






6.85 (1 H, s), 6.90-6.95 (2 H, m), 7.75 (2 H, d,






J = 8.2 Hz), 7.87 (2 H, d, J = 8.1 Hz),






8.17 (1 H, dd, J = 8.7 Hz, 2.5 Hz),






8.59 (1 H, d, J = 2.0 Hz).


802
3,4-Cl2PhNHCO—
—OCH3
—C2H5
1.19 (5 H, t, J = 7.1 Hz), 2.42 (4 H, brs),






3.42 (2 H, q, J = 7.1 Hz), 3.43 (2 H, s),






3.51 (2 H, s), 3.62 (2 H, brs), 3.68 (3 H, s),






4.04 (2 H, s), 5.95 (2 H, s), 6.17 (1 H, dd, J =






8.7 Hz, 2.6 Hz), 6.28 (1 H, d, J = 2.6 Hz),






6.73-6.74 (2 H, m), 6.85 (1 H, brs), 6.88 (1 H,






d, J = 8.6 Hz), 6.90 (1 H, d, J = 8.7 Hz),






7.37 (1 H, d, J = 8.7 Hz), 7.47 (1 H, dd, J =






8.7 Hz, 2.5 Hz), 7.86 (1 H, d, J = 2.5 Hz),






8.11 (1 H, dd, J = 8.6 Hz, 2.5 Hz),






8.31 (1 H, brs), 8.58 (1 H, d, J = 2.3 Hz).


803
4-CF3PhNHCO—
—OCH3
—C2H5
1.19 (3 H, t, J = 7.1 Hz), 2.42 (4 H, brs),






3.38-3.47 (4 H, m), 3.51 (2 H, brs), 3.62 (2 H,






brs), 3.68 (3 H, s), 4.05 (2 H, s), 5.94 (2 H,






s), 6.17 (1 H, dd, J = 8.7 Hz, 2.8 Hz),






6.29 (1 H, d, J = 2.8 Hz), 6.73-6.74 (2 H, m),






6.84 (1 H, brs), 6.89 (1 H, d, J = 8.7 Hz),






6.91 (1 H, d, J = 8.7 Hz), 7.58 (2 H, d, J =






8.7 Hz), 7.76 (2 H, d, J = 8.7 Hz), 8.13 (1 H,






dd, J = 8.7 Hz, 2.5 Hz), 8.44 (1 H, brs),






8.64 (1 H, d, J = 2.5 Hz).


804
3,4-Cl2PhNHCONH—
—CONHCH3
—C2H5
1.07 (3 H, t, J = 7.0 Hz), 2.30-2.45 (4 H, m),






2.85 (3 H, d, J = 4.9 Hz), 3.33 (2 H, q, J =






7.0 Hz), 3.38 (2 H, s), 3.38-3.50 (2 H, m),






3.50-3.65 (2 H, m), 4.01 (2 H, s), 5.95 (2 H,






s), 6.55-6.65 (1 H, m), 6.69-6.84 (5 H, m),






7.14 (1 H, d, J = 3.1 Hz), 7.25-7.35 (2 H, m),






7.35-7.45 (1 H, m), 7.65 (1 H, d, J = 1.5 Hz),






7.72 (1 H, d, J = 2.6 Hz), 7.84 (1 H, dd, J =






8.9 Hz, 2.7 Hz), 8.02 (1 H, s), 8.61 (1 H, s).


805
4-CF3PhCH2—
—H
—CH3
2.42 (4 H, t, J = 5.1 Hz), 3.02 (3 H, s),






3.43 (2 H, s), 3.48 (2 H, brs), 3.63 (2 H, brs),






3.95 (2 H, s), 4.06 (2 H, s), 5.94 (2 H, s),






6.70 (2 H, d, J = 9.0 Hz), 6.73 (2 H, s),






6.74 (1 H, d, J = 10.0 Hz), 6.84 (1 H, s),






7.00 (2 H, d, J = 9.0 Hz), 7.27 (2 H, d, J =






8.1 Hz), 7.38 (1 H, dd, J = 8.4 Hz, 2.5 Hz),






7.54 (2 H, d, J = 8.1 Hz), 8.03 (1 H, d, J =






2.5 Hz).
















TABLE 211













 












Example







No.
R690
R691
R692
R693
1H NMR (solvent) δ ppm





806
4-CF3PhNHCO—
—CH3
—H
piperonyl
(CDCl3) 2.17 (3 H, s), 2.49-2.54 (4 H,







m), 3.45 (2 H, s), 3.71-3.75 (2 H, m),







4.26 (2 H, brs), 5.96 (2 H, s), 6.75 (2 H,







brs), 6.86 (1 H, brs), 7.02 (1 H, d, J =







8.7 Hz), 7.06 (1 H, d, J = 8.7 Hz),







7.47 (1 H, dd, J = 8.7 Hz, 2.5 Hz),







7.58 (1 H, d, J = 2.3 Hz), 7.63 (2 H, d,







J = 8.4 Hz), 7.75 (2 H, d, J = 8.3 Hz),







7.84 (1 H, brs), 8.22 (1 H, dd, J = 8.7







Hz, 2.6 Hz), 8.64 (1 H, d, J = 2.5 Hz),







9.20 (1 H, brs).


807
4-CF3PhOCH2—
—H
—H
piperonyl
(CDCl3) 2.51-2.54 (4 H, m), 3.45 (2 H,







s), 3.71-3.75 (2 H, m), 4.27-4.29 (2 H,







m), 5.05 (2 H, s), 5.95 (2 H, s),







6.85 (2 H, brs), 6.86 (1 H, brs),







6.96 (1 H, d, J = 8.4 Hz), 7.02 (2 H, d,







J = 8.6 Hz), 7.14 (2 H, d, J = 8.9 Hz),







7.56 (2 H, d, J = 8.6 Hz), 7.64 (2 H, d,







J = 8.9 Hz), 7.78 (1 H, dd, J = 8.4 Hz,







2.3 Hz), 8.22 (1 H, d, J = 2.3 Hz),







9.21 (1 H, brs).


808
4-CF3PhOCH2—
—H
—H
4-pyridylmethyl
(CDCl3) 2.52-2.58 (4 H, m), 3.55 (2 H,







s), 3.74-3.77 (2 H, m), 4.29-4.32 (2 H,







m), 5.04 (2 H, s), 6.96 (1 H, d, J = 8.4







Hz), 7.02 (2 H, d, J = 8.4 Hz),







7.15 (2 H, d, J = 8.9 Hz),







7.26-7.30 (2 H, m), 7.56 (2 H, d, J = 8.6







Hz), 7.64 (2 H, d, J = 9.1 Hz),







7.78 (1 H, dd, J = 8.6 Hz, 2.5 Hz),







8.22 (1 H, d, J = 2.0 Hz),







8.56-8.58 (2 H, m), 9.24 (1 H, brs).


809
4-CF3PhOCH2—
—CH3
—CH3
piperonyl
a mixture of the rotational isomers







(DMSO-d6) 2.07-2.43 (7 H, m),







3.24-3.57 (11 H, m), 5.17 (2 H, brs),







5.95-5.99 (2 H, m), 6.66-6.89 (3 H, m),







7.07-7.12 (2 H, m), 7.16-7.37 (4 H, m),







7.66 (2 H, d, J = 8.4 Hz),







7.85-8.00 (1 H, m), 8.22 (1 H, d, J = 2.0







Hz).


810
4-CF3PhOCH2—
—CH3
—CH3
3,4-
a mixture of the rotational isomers






(CH3O)2PhCH2—
(DMSO-d6) 2.07-2.43 (7 H, m),







3.26-3.75 (15 H, m), 5.17 (2 H, brs),







6.70-6.91 (3 H, m), 7.07-7.12 (2 H, m),







7.16-7.37 (4 H, m), 7.66 (2 H, d, J = 8.9







Hz), 7.95-8.00 (1 H, m), 8.22 (1 H, d, J =







2.0 Hz).
















TABLE 212













 









Example




No.
R694
1H NMR (CDCl3) δ ppm





811
piperonyl
2.18 (3 H, s), 2.49-2.54 (4 H, m), 3.45 (2 H, s), 3.70-3.74 (2 H,




m), 4.23-4.27 (2 H, m), 5.03 (2 H, s), 5.95 (2 H, s), 6.71




6.78 (2 H, m), 6.86 (1 H, brs), 6.92 (1 H, d, J = 8.6 Hz),




7.00-7.06 (3 H, m), 7.44 (1 H, dd, J = 8.7 Hz, 2.6 Hz),




7.54-7.58 (3 H, m), 7.77 (1 H, dd, J = 8.6 Hz, 2.5 Hz), 8.20 (1 H, d,




J = 2.3 Hz), 9.20 (1 H, brs).


812
3,4- (CH3O)2PhCH2—
2.18 (3 H, s), 2.50-2.55 (4 H, m), 3.48 (2 H, s), 3.71-3.75 (2 H,




m), 3.88 (3 H, s), 3.90 (3 H, s), 4.24-4.28 (2 H, m), 5.03 (2 H, s),




6.79-6.86 (2 H, m), 6.88 (1 H, brs), 6.93 (1 H, d, J = 8.4 Hz),




7.00-7.06 (3 H, m), 7.44 (1 H, dd, J = 8.6 Hz, 2.6 Hz),




7.54-7.58 (3 H, m), 7.77 (1 H, dd, J = 8.4 Hz, 2.5 Hz), 8.20 (1 H, d,




J = 2.5 Hz), 9.19 (1 H, brs).


813
4-pyridylmethyl
2.18 (3 H, s), 2.52-2.58 (4 H, m), 3.55 (2 H, s), 3.73-3.77 (2 H,




m), 4.27-4.31 (2 H, m), 5.03 (2 H, s), 6.93 (1 H, d, J = 8.4 Hz),




7.00-7.06 (3 H, m), 7.28 (2 H, d, J = 5.9 Hz), 7.44 (1 H, dd, J =




8.7 Hz, 2.6 Hz), 7.54-7.57 (3 H, m), 7.77 (1 H, dd, J = 8.4 Hz,




2.3 Hz), 8.19 (1 H, d, J = 2.1 Hz), 8.56 (2 H, d, J = 5.9 Hz),




9.23 (1 H, brs).
















TABLE 213













 










Example





No.
R695
R696
1H NMR (CDCl3) δ ppm





814
—H
piperonyl
2.42 (4 H, brs), 3.21 (3 H, s), 3.37 (2 H, brs), 3.42 (2 H,





s), 3.62 (2 H, brs), 4.54 (2 H, s), 5.06 (2 H, s), 5.94 (2 H,





s), 6.70-6.77 (2 H, m), 6.83 (1 H, brs), 6.98-7.04 (3 H,





m), 7.14 (2 H, d, J = 8.7 Hz), 7.56 (2 H, d, J = 8.7





Hz), 7.62 (2 H, d, J = 8.9 Hz), 7.81 (1 H, dd, J = 8.4





Hz, 2.3 Hz), 8.23 (1 H, d, J = 2.1 Hz).


815
—H
4-pyridylmethyl
2.48 (4 H, brs), 3.21 (3 H, s), 3.41 (2 H, brs), 3.53 (2 H,





s), 3.65 (2 H, brs), 4.55 (2 H, s), 5.06 (2 H, s), 7.01 (1 H,





d, J = 8.2 Hz), 7.03 (2 H, d, J = 8.4 Hz), 7.14 (2 H, d,





J = 8.9 Hz), 7.26-7.28 (2 H, m), 7.57 (2 H, d, J = 8.7





Hz), 7.62 (2 H, d, J = 8.7 Hz), 7.81 (1 H, dd, J = 8.4





Hz, 2.3 Hz), 8.23 (1 H, d, J = 2.1 Hz), 8.56 (2 H, d, J =





5.6 Hz).


816
—CH3
piperonyl
2.18 (3 H, s), 2.41-2.44 (4 H, m), 3.22 (3 H, s),





3.36-3.39 (2 H, m), 3.43 (2 H, s), 3.60-3.64 (2 H, m),





4.54 (2 H, s), 5.05 (2 H, s), 5.94 (2 H, s), 6.73-6.74 (2 H,





m), 6.84 (1 H, brs), 6.97 (1 H, d, J = 8. 4 Hz),





7.02 (1 H, d, J = 8.6 Hz), 7.04 (2 H, d, J = 8.6 Hz),





7.45 (1 H, dd, J = 8.6 Hz, 2.6 Hz), 7.49 (1 H, d, J =





2.5 Hz), 7.56 (2 H, d, J = 8.4 Hz), 7.80 (1 H, dd, J =





8.6 Hz, 2.5 Hz), 8.20 (1 H, d, J = 2.0 Hz).


817
—CH3
3,4- (CH3O)2PhCH2—
2.18 (3 H, s), 2.44 (4 H, brs), 3.22 (3 H, s),





3.38-3.40 (2 H, m), 3.46 (2 H, s), 3.63-3.65 (2 H, m),





3.87 (3 H, s), 3.89 (3 H, s), 4.55 (2 H, s), 5.04 (2 H, s),





6.81 (2 H, brs), 6.87 (1 H, brs), 6.98 (1 H, d, J = 8.6





Hz), 7.02 (1 H, d, J = 8.4 Hz), 7.04 (2 H, d, J = 8.4





Hz), 7.45 (1 H, dd, J = 8.6 Hz, 2.6 Hz), 7.49 (1 H, d, J =





2.6 Hz), 7.56 (2 H, d, J = 8.4 Hz), 7.80 (1 H, dd, J =





8.4 Hz, 2.5 Hz), 8.20 (1 H, d, J = 2.3 Hz).
















TABLE 214













 










Example





No.
R697
R698
mp (° C.)





818
4-CF3PhCO—




207.0-209.0


 


819
4-CF3PhCO—




237.0-238.0


 


820
3,4-Cl2PhSO2—




115.0-116.0


 


821
3,4-Cl2PhNHCO—
—CH2CONHPh
147.0-148.0


 


822
3,4-Cl2PhNHCO—




207.0-208.0
















TABLE 215













 









Example




No.
R699
1H NMR or MS





823




1H NMR (DMSO-d6) δ 1.40-1.80 (2 H, m), 1.80-2.10 (2 H, m), 2.93 (3 H, s), 3.15-3.50 (2 H, m), 3.60-3.90 (2 H, 3 m), 4.31 (2 H, s), 4.60-4.70 (1 H, m), 6.35-6.45 (1 H, m), 6.54 (1 H, dd, J = 14.4 Hz, 2.6 Hz), 6.96-7.11 (4 H, m), 7.27-7.31 (2 H, m), 7.52 (1 H, dd, J = 8.7 Hz, 2.7 Hz), 7.63 (1 H, dd, J = 8.5 Hz, 2.1 Hz), 7.76 (1 H, d, J = 2.7 Hz), 7.84-7.88 (2 H, m), 10.39 (1 H, brs).


 


824




MS 682 (M+ + H)


 


825




MS 618 (M+ + H)


 


826
—N[CH2CH(CH3)2]2
MS 611 (M+ + H)


 


827




MS 571 (M+ + H)


 


828




MS 635 (M+ + H)


 


829
—N[(CH2)3N(CH3)2]2
MS 669 (M+ + H)


 


830




MS 645 (M+ + H)


 


831




MS 712 (M+ + H)


 


832




MS 665 (M+ + H)


 


833




MS 595 (M+ + H)


 


834




MS 764 (M+ + H)
















TABLE 216













 









Example




No.
R699
MS (M+ + H)





835




635


 


836




714


 


837




581


 


838
4-CF3OPhCH2NH—
673


 


839




553


 


840
—NH(CH2)5OH
585


841
—NHCH(CH3)COOCH3
585


842
3,5-F2PhCH2N(C2H5)—
653


843
4-CH3PhNHCOCH2N(CH3)—
660


844
3,4-(CH3O)2PhCH2N(C2H5)—
677


845
4-CH3PhCH2N(C2H5)—
631


 


846




614


 


847




686


 


848
3,4-Cl2Ph-
714


 


849




695


 


850




734


 


851
—N(CH2Ph)CH2CH2CN
642


852
—N(C2H5)CH(CH3)2
569


853
—NHC(CH3)2CH2Ph
631


854
3-CNPhNH—
600


855
3,5-F2PhNH—
611
















TABLE 217













 









Ex-




am-


ple



No.
R701
MS (M+ + H)





856




700


 


857




652


 


858




583


 


859




662


 


860




665


 


861




659


 


862




673


 


863




702


 


864




674


 


865




674


 


866




666
















TABLE 218













 









Example




No.
R702
MS (M+ + H)





867




698


 


868




639


 


869




639


 


870




673


 


871




610


 


872




596


 


873




555


 


874




569


 


875




663


 


876




692
















TABLE 219













 












Example




MS


No.
R703
R704
R705
R706
(M+ + H)





877
—H
—H
—OCF3
—H
659


878
—H
—H
—CH3
—H
589


879
—OCH3
—OCH3
—H
—H
635


880
—H
—H
—SCH3
—H
621


881
—CH(CH3)2
—H
—H
—H
617


882
—H
—H
cyclohexyl
—H
657


883
—NHPh
—H
—Cl
—H
702


884
4-ClPhNH—
—H
—H
—COOC2H5
774


885
—H
—H
—O(CH2)2N(C2H5)2
—H
690


 


886
—H
—H




—H
673


 


887
—H
—H




—H
658


 


888
—H
—H
—NHSO2CH3
—H
668


889
—H
—H
—(CH2)OH
—H
619


890
—H
—H
—(CH2)4CH3
—H
645


891
—H
—H
benzyl
—H
665


892
—H
—H
—SPh
—H
683


 


893
—H
—H




—H
709
















TABLE 220













 











Example






No.
R707
R708
R709 
1H NMR (CDCl3) δ ppm





894
4-CF3Ph-
—CH3
piperonyl
1.34-1.42 (2 H, m), 1.80-1.98 (3 H, m), 2.03 (3 H,






s), 2.29 (2 H, d, J = 6.6 Hz), 2.41 (4 H, brs),






2.65 (2 H, t, J = 12.0 Hz), 3.43 (2 H, s), 3.49-






3.65 (6 H, m), 5.94 (2 H, s), 6.69-6.87 (8 H, m),






7.56 (1 H, dd, J = 8.9 Hz, 2.8 Hz), 7.68 (2 H, d, J =






8.6 Hz), 7.76-7.85 (3 H, m).


895
3,4-Cl2Ph-
—CH3
piperonyl
1.34-1.39 (2 H, m), 1.79-1.98 (3 H, m), 2.04 (3 H,






s), 2.29 (2 H, d, J = 6.6 Hz), 2.41 (4 H, brs),






2.64 (2 H, t, J = 11.9 Hz), 3.43 (2 H, s), 3.49-






3.65 (6 H, m), 5.94 (2 H, s), 6.70-6.88 (7 H, m),






7.45-7.50 (3 H, m), 7.55 (1 H, dd,






J = 8.9 Hz, 2.8 Hz),






7.78-7.82 (2 H, m).


896
4-CF3Ph-
—CH3
benzyl
1.34-1.43 (2 H, m), 1.80-2.01 (3 H, m), 2.03 (3 H,






s), 2.29 (2 H, d, J = 6.6 Hz), 2.43 (4 H, brs),






2.65 (2 H, t, J = 12.0 Hz), 3.49-3.65 (8 H, m),






6.70-6.76 (3 H, m), 6.86 (1 H, d, J = 8.7 Hz),






7.26-7.32 (6 H, m), 7.55 (1 H, dd,






J = 8.7 Hz, 2.6 Hz),






7.68 (2 H, d, J = 8.6 Hz), 7.76 (1 H, d, J =






2.8 Hz), 7.84 (2 H, d, J = 8.4 Hz).


897
3,4-Cl2Ph-
—CH3
benzyl
1.27-1.39 (2 H, m), 1.79-2.01 (3 H, m), 2.04 (3 H,






s), 2.29 (2 H, d, J = 6.8 Hz), 2.43 (4 H, brs),






2.64 (2 H, t, J = 11.9 Hz), 3.53-3.66 (8 H, m),






6.69-6.76 (3 H, m), 6.86 (1 H, d, J = 8.7 Hz),






7.29-7.32 (6 H, m), 7.44-7.50 (2 H, m), 7.55 (1 H,






dd, J = 8.7 Hz, 2.6 Hz), 7.79-7.82 (2 H, m).


898
4-CF3Ph-
—H
3,4-Cl2Ph-
1.34-1.46 (2 H, m), 1.83-2.02 (3 H, m), 2.34 (2 H,






d, J = 6.8 Hz), 2.67 (2 H, t, J = 12.0 Hz), 3.15-






3.17 (4 H, m), 3.55-3.65 (4 H, m), 3.78-3.80 (2 H,






m), 6.72-6.97 (7 H, m), 7.26-7.31 (2 H, m), 7.56






(1 H, dd, J = 8.9 Hz, 2.8 Hz), 7.70 (2 H, d, J =






8.24 Hz), 7.78-7.86 (3 H, m).


899
4-CF3Ph-
—H
3,4-CF3Ph-
1.35-1.47 (2 H, m), 1.83-2.02 (3 H, m), 2.36 (2 H,






d, J = 6.8 Hz), 2.67 (2 H, t, J = 12.0 Hz), 3.28-






3.30 (4 H, m), 3.57 (2 H, d,






J = 12.2 Hz),






3.68 (2 H, brs), 3.82 (2 H, brs), 6.76 (1 H, d, J =






8.7 Hz), 6.87-6.96 (7 H, m), 7.50 (2 H, d,






J = 8.6 Hz),






7.56 (1 H, dd, J = 8.9 Hz, 2.8 Hz), 7.69 (2 H,






d, J = 8.4 Hz), 7.80-7.86 (3 H, m).


900
3,4-Cl2Ph-
—H
4-CF3Ph-
1.34-1.47 (2 H, m), 1.83-2.02 (3 H, m), 2.35 (2 H,






d, J = 6.8 Hz), 2.68 (2 H, t, J = 12.0 Hz), 3.29-






3.31 (4 H, m), 3.58 (2 H, d, J = 12.2 Hz),






3.68 (2 H, brs), 3.83 (2 H, brs), 6.79 (1 H, d, J =






8.7 Hz), 6.88-6.98 (7 H, m), 7.50-7.59 (5 H, m),






7.79 (1 H, d, J = 2.8 Hz), 7.83-7.84 (1 H, m).
















TABLE 221













 











Example






No.
R710
R711
R712
1H NMR (CDCl3) δ ppm





901
3,4-Cl2Ph-
—H
3,4-Cl2Ph-
1.34-1.46 (2 H, m), 1.82-2.02 (3 H, m), 2.35 (2 H, d,






J = 6.6 Hz), 2.66 (2 H, t, J = 12.0 Hz), 3.16-






3.17 (4 H, m), 3.57 (2 H, d, J = 12.2 Hz), 3.65 (2 H,






brs), 3.80 (2 H, brs), 6.72-6.78 (2 H, m), 6.87-






6.97 (6 H, m), 7.29 (1 H, d, J = 8.9 Hz), 7.49 (2 H,






s), 7.57 (1 H, dd, J = 8.7 Hz, 2.6 Hz), 7.81-






7.84 (2 H, m).


902
4-CF3Ph-
—CH3
3,4-Cl2Ph-
1.34-1.46 (2 H, m), 1.82-2.01






(3 H, m), 2.03 (3 H,






s), 2.35 (2 H, d, J = 6.8 Hz),






2.67 (2 H, t, J = 12.0 Hz),






3.15-3.17 (4 H, m), 3.58 (2 H, d, J = 12.2 Hz),






3.65 (2 H, brs), 3.79 (2 H, brs), 6.70-6.76 (4 H, m),






6.86 (1 H, d, J = 8.6 Hz), 6.96 (1 H, d, J = 2.8 Hz),






7.29 (1 H, d, J = 8.7 Hz), 7.53-7.57 (1 H, m),






7.68 (2 H, d, J = 8.2 Hz), 7.77 (1 H, d, J = 2.5 Hz),






7.84 (2 H, d, J = 8.2 Hz), 8.05 (1 H, s).


903
4-CF3Ph-
—H
piperonyl
1.27-1.41 (2 H, m), 1.83-2.05 (3 H, m), 2.29 (2 H, d,






J = 6.8 Hz), 2.40-2.44 (4 H, m), 2.66-2.75 (2 H,






m), 3.44-3.56 (4 H, m), 3.65-3.74 (4 H, m),






5.95 (2 H, s), 6.75-6.99 (8 H, m), 7.57 (1 H, dd, J =






8.9 Hz, 2.8 Hz), 7.71-7.74 (4 H, m), 7.85 (2 H, d, J =






= 8.2 Hz).


904
3,4-Cl2Ph-
—H
benzyl
1.31-1.40 (2 H, m), 1.80-2.05 (3 H, m), 2.29 (2 H, d,






J = 6.8 Hz), 2.62-2.71 (2 H, m), 3.53-3.58 (6 H,






m), 3.66 (2 H, brs), 6.79 (1 H, d, J = 8.7 Hz), 6.88-






6.98 (4 H, m), 7.31 (5 H, brs), 7.50 (2 H, s), 7.56






(1 H, dd, J = 8.9 Hz, 2.8 Hz), 7.77-7.84 (3 H, m).


905
4-CF3Ph-
—H
benzyl
1.30-1.43 (2 H, m), 1.80-2.04 (3 H, m), 2.28 (2 H, d,






J = 6.8 Hz), 2.42-2.46 (4 H, m), 2.62-2.70 (2 H,






m), 3.47-3.58 (6 H, m), 3.66 (2 H, brs), 6.78 (1 H, d,






J = 8.7 Hz), 6.87-6.97 (4 H, m), 7.26-7.32 (6 H,






m), 7.56 (1 H, dd, J = 8.9 Hz, 2.8 Hz), 7.68-






7.77 (3 H, m), 7.83-7.86 (2 H, m).


906
3,4-Cl2Ph-
—H
piperonyl
1.33-1.39 (2 H, m), 1.79-2.00 (3 H, m) 2.30 (2 H, d,






J = 6.8 Hz), 2.42-2.44 (4 H, m), 2.65 (2 H, t, J =






10.4 Hz), 3.43 (2 H, s), 3.49-3.57 (4 H, m),






3.65 (2 H, brs), 5.94 (2 H, s), 6.74-6.77 (3 H, m),






6.84-6.97 (5 H, m), 7.49-7.59 (3 H, m), 7.81-






7.85 (3 H, m).


907
4-CF3Ph-
—OCH3
piperonyl
1.33-1.44 (2 H, m), 1.82-1.95 (3 H, m), 2.29 (2 H, d),






J = 6.8 Hz), 2.41 (4 H, brs), 2.70 (2 H, t, J = 12.2 Hz),






3.43-3.64 (8 H, m), 3.67 (3 H, s), 5.94 (2 H, s),






6.46 (1 H, dd, J = 8.7 Hz, 2.6 Hz), 6.54 (1 H, d, J =






2.5 Hz, 6.70-6.78 (4 H, m), 6.85 (1 H, s),






6.92 (1 H, d, J = 8.6 Hz), 7.55 (1 H, dd, J = 8.7 Hz,






2.6 Hz), 7.67 (2 H, d, J = 8.4 Hz), 7.74 (1 H, d,






J = 2.6 Hz), 7.84 (2 H, d, J = 8.2 Hz).
















TABLE 222













 











Example






No.
R713
R714
R715
1H NMR (CDCl3) δ ppm





908
3,4-Cl2Ph-
—H
benzyl
1.76-1.99 (4 H, m), 2.45-2.73 (7 H, m), 3.53 (4 H,






brs), 3.66 (4 H, brs), 6.75 (1 H, d, J = 8.7 Hz),






6.87-6.97 (4 H, m), 7.29-7.59 (9H, m), 7.83 (2 H,






d, J = 2.0 Hz).


909
4-CF3Ph-
—H
benzyl
1.77-1.99 (4 H, m), 2.45 (4 H, brs), 2.53-2.76 (3 H,






m), 3.54 (4 H, brs), 3.65-3.69 (4 H, m), 6.81 (1 H,






d, J = 8.7 Hz), 6.90-6.99 (4 H, m), 7.28-7.34 (6 H,






m), 7.57 (1 H, dd, J = 8.9 Hz, 2.8 Hz), 7.71-






7.75 (3 H, m), 7.85 (2 H, d, J = 8.2 Hz).


910
4-CF3Ph-
—CH3
piperonyl
1.75-1.96 (4 H, m), 2.04 (3 H, s), 2.44 (4 H, brs),






2.53-2.73 (3 H, m), 3.43 (2 H, s), 3.53 (2 H, brs),






3.63 (4 H, brs), 5.94 (2 H, s), 6.70-6.89 (8 H, m),






7.56 (1 H, dd, J = 8.9 Hz, 2.8 Hz), 7.67 (2 H, d, J =






8.6 Hz), 7.78 (1 H, d, J = 2.6 Hz), 7.84 (2 H, d,






J = 8.2 Hz).


911
4-CF3Ph-
—CH3
benzyl
1.75-2.02 (4 H, m), 2.03 (3 H, s), 2.45 (4 H, brs),






2.55-2.72 (3 H, m), 3.53 (4 H, brs), 3.66 (4 H, brs),






6.72-6.77 (3 H, m), 6.87 (1 H,






d, J = 8.6 Hz),






7.25-7.31 (6 H, m), 7.56 (1 H, dd, J = 8.7 Hz, 2.6 Hz),






7.66 (2 H, d, J = 8.2 Hz), 7.78-7.86 (3 H, m).


912
3,4-Cl2Ph-
—CH3
piperonyl
1.76-1.98 (4 H, m), 2.04 (3 H, s), 2.44 (4 H, brs),






2.54-2.72 (3 H, m), 3.43 (2 H, s), 3.54 (2 H, brs),






3.63-3.67 (4 H, m), 5.94 (2 H, s), 6.70-6.89 (8 H,






m), 7.44-7.59 (3 H, m), 7.80 (2 H, J = 2.0 Hz).


913
3,4-Cl2Ph-
—CH3
benzyl
1.77-1.97 (4 H, m), 2.07 (3 H, s), 2.45 (4 H, brs),






2.53-2.75 (3 H, m), 3.54 (4 H, brs), 3.66 (4 H, brs),






6.75-6.81 (3 H, m), 6.90 (1 H, d, J = 8.6 Hz),






7.26-7.33 (6 H, m), 7.51-7.58 (3 H, m), 7.72 (1 H,






d, J = 2.6 Hz), 7.79 (1 H, s).


914
3,4-Cl2Ph-
—H
piperonyl
1.76-1.99 (4 H, m), 2.44 (4 H, brs), 2.54-2.74 (3 H,






m), 3.43 (2 H, s), 3.54 (2 H, brs), 3.63-3.67 (4 H,






m), 5.94 (2 H, s), 6.74-6.98 (8 H, m), 7.45-






7.59 (3 H, m), 7.81-7.84 (3 H, m).


915
4-CF3Ph-
—H
piperonyl
1.76-1.80 (2 H, m), 1.91-1.95 (2 H, m), 2.43 (4 H,






brs), 2.59-2.73 (3 H, m), 3.43 (2 H, s), 3.54 (2 H,






brs), 3.62 (4 H, brs), 5.94 (2 H, s), 6.72-6.75 (3 H,






m), 6.84-6.96 (5 H, m), 7.57 (1 H, dd, J = 8.7 Hz,






2.8 Hz), 7.66 (2 H, d, J = 8.4 Hz), 7.82-7.87 (4 H,






m).
















TABLE 223













 











Example






No.
R716
R717
M
1H NMR (CDCl3) δ ppm





916
—H
piperonyl
1
1.31-1.45 (2 H, m), 1.82-2.02 (3 H, m), 2.33 (2 H, d, J =






6.8 Hz), 2.43 (4 H, brs), 2.69 (2 H, t, J = 12.0 Hz),






3.43 (2 H, s), 3.51-3.67 (6 H, m), 5.93 (2 H, s), 6.73-






6.99 (8 H, m), 7.28 (2 H, d, J = 8.6 Hz), 7.50 (2 H, d, J =






8.6 Hz), 8.28 (1 H, d, J = 2.1 Hz), 8.43 (1 H, d, J = 2.1 Hz).


917
—H
benzyl
1
1.34-1.44 (2 H, m), 1.82-2.00 (3 H, m), 2.32 (2 H, d, J =






6.8 Hz), 2.43-2.47 (4 H, m), 2.69 (2 H, t, J = 12.0 Hz),






3.51-3.67 (8 H, m), 6.88 (2 H, d,






J = 9.2 Hz), 6.98 (2 H,






d, J = 9.2 Hz), 7.25-7.32 (8 H, m), 7.50 (2 H, d, J = 8.6 Hz),






8.28 (1 H, d, J = 2.3 Hz),






8.43 (1 H, d, J = 2.1 Hz).


918
—CH3
piperonyl
1
1.31-1.45 (2 H, m), 1.82-2.00 (3 H, m), 2.02 (3 H, s),






2.33 (2 H, d, J = 6.8 Hz), 2.43 (4 H, brs), 2.68 (2 H, t, J =






11.9 Hz), 3.41-3.67 (8 H, m), 5.92 (2 H, s), 6.73-






6.92 (7 H, m), 7.25-7.30 (2 H, m), 7.50 (2 H, d, J = 8.6 Hz),






8.30 (1 H, d, J = 2.3 Hz), 8.41 (1 H, d, J = 2.3 Hz).


919
—CH3
benzyl
1
1.37-1.40 (2 H, m), 1.83-2.01 (3 H, m), 2.03 (3 H, s),






2.31 (2 H, d, J = 6.9 Hz), 2.43-2.47 (4 H, m), 2.70 (2 H, t,






J = 12.0 Hz), 3.51-3.67 (8 H, m), 6.74-6.80 (2 H, m),






6.91 (1 H, d, J = 8.6 Hz), 7.24-7.33 (8 H, m), 7.52 (2 H,






d, J = 8.4 Hz), 8.29 (1 H, d,






J = 2.1 Hz), 8.42 (1 H, d, J = 2.3 Hz).


920
—H
piperonyl
0
1.79-2.03 (4 H, m), 2.45 (4 H, brs), 2.57-2.76 (3 H, m),






3.44 (2 H, s), 3.55 (2 H, brs), 3.66 (4 H, brs), 5.94 (2 H, s),






6.72-6.78 (2 H, m), 6.85-7.00 (6 H, m), 7.28 (2 H, d, J =






8.6 Hz), 7.50 (2 H, d, J = 8.6 Hz), 8.28 (1 H, d, J = 2.1 Hz),






8.42 (1 H, d, J = 2.1 Hz).
















TABLE 224













 










Example





No.
R718
R719
1H NMR (CDCl3) δ ppm





921
3,4-Cl2Ph-
piperonyl
1.37-1.44 (2 H, m), 1.81-2.02 (3 H, m), 2.30 (2 H, d, J = 6.8 Hz),





2.42 (4 H, brs), 2.69 (2 H, t, J = 11.9 Hz), 3.43 (2 H, s),





3.43-3.65 (6 H, m), 3.68 (3 H, s), 5.94 (2 H, s), 6.46 (1 H, dd,





J = 8.7 Hz, 2.5 Hz), 6.54 (1 H, d, J = 2.3 Hz), 6.73-





6.76 (3 H, m), 6.85 (1 H, s), 6.93 (1 H, d, J = 8.6 Hz), 7.44-





7.57 (3 H, m), 7.79-7.83 (3 H, m).


922
4-CF3Ph-
benzyl
1.37-1.44 (2 H, m), 1.81-2.02 (3 H, m), 2.29 (2 H, d, J = 6.8 Hz),





2.42-2.46 (4 H, m), 2.69 (2 H, t, J = 12.0 Hz), 3.48-





3.63 (8 H, m), 3.67 (3 H, s), 6.46 (1 H, dd, J = 8.7 Hz, 2.6 Hz),





6.54 (1 H, d, J = 2.6 Hz), 6.75 (1 H, d, J = 8.9 Hz),





6.92 (1 H, d, J = 8.7 Hz), 7.26-7.36 (6 H, m), 7.54 (1 H, dd,





J = 8.7 Hz, 2.8 Hz), 7.67 (2 H, d, J = 8.6 Hz), 7.75 (1 H, d,





J = 2.8 Hz), 7.83 (2 H, d, J = 8.1 Hz).


923
3,4-Cl2Ph-
benzyl
1.37-1.44 (2 H, m), 1.81-2.02 (3 H, m), 2.30 (2 H, d, J = 6.8 Hz),





2.42-2.46 (4 H, m), 2.69 (2 H, t, J = 11.9 Hz), 3.50-





3.66 (8 H, m), 3.67 (3 H, s), 6.45 (1 H, dd, J = 8.7 Hz, 2.5 Hz),





6.54 (1 H, d, J = 2.5 Hz), 6.74 (1 H, d, J = 8.7 Hz),





6.93 (1 H, d, J = 8.6 Hz), 7.26-7.32 (5 H, m), 7.43-7.56 (3 H,





m), 7.79-7.83 (3 H, m).
















TABLE 225













 









Example




No.
R720
1H NMR (CDCl3) δ ppm





924
benzyl
1.63-1.77 (2 H, m), 1.81-1.98 (2 H, m), 2.44 (4 H, brs), 2.53-2.72 (3 H, m),




3.53 (4 H, brs), 3.65-3.69 (4 H, m), 6.90-7.04 (5 H, m), 7.26-7.33 (5 H, m),




7.74 (2 H, d, J = 8.2 Hz), 7.99 (2 H, d, J = 8.2 Hz), 8.14-8.19 (2 H, m),




8.27 (1 H, d, J = 2.6 Hz).


925
piperonyl
1.64-1.77 (2 H, m), 1.89-1.97 (2 H, m), 2.39-2.41 (4 H, m), 2.56-2.75 (3 H,




m), 3.43 (2 H, s), 3.52-3.69 (6 H, m), 5.94 (2 H, s), 6.70-6.77 (2 H, m), 6.85-




7.04 (6 H, m), 7.74 (2 H, d, J = 8.2 Hz), 7.99 (2 H, d, J = 8.2 Hz), 8.14-




8.18 (2 H, m), 8.27 (1 H, d, J = 2.5 Hz).









The following compounds were made in the same manner as in Reference Example 918.







TABLE 226













 












Example







No.
R721
Xb9
R722
M
1H NMR (CDCl3) δ ppm





926
4-CF3Ph-
—CH2—
benzyl
1
2.38-2.44 (4 H, m), 2.63-2.68 (2 H, m), 2.89-







2.95 (2 H, m), 3.45-3.49 (2 H, m), 3.52 (2 H,







s), 3.64-3.68 (2 H, m), 6.85 (1 H, d, J = 8.9 Hz),







6.93-6.98 (2 H, m), 7.08-7.13 (2 H, m),







7.28-7.36 (5 H, m), 7.44-7.51 (4 H, m), 7.96







(1 H, d, J = 2.5 Hz), 8.00-8.04 (1 H, m),







8.14 (1 H, s), 8.18 (1 H, s).


927
3,4-Cl2Ph-
—CH(CH3)—
piperonyl
0
1.47 (3 H, d, J = 6.8 Hz), 2.00-2.15 (1 H, m),







2.25-2.50 (3 H, m), 3.36 (2 H, s), 3.36-







3.80 (4 H, m), 3.98 (1 H, q, J = 6.8 Hz),







5.93 (2 H, s), 6.65-6.75 (2 H, m), 6.79 (1 H, d,







J = 1.2 Hz), 6.89 (1 H, d, J = 8.8 Hz), 7.02-







7.06 (2 H, m), 7.16-7.33 (4 H, m), 7.57 (1 H, d,







J = 2.4 Hz), 7.91 (1 H, d, J = 2.7 Hz),







8.00 (1 H, brs), 8.05-8.10 (2 H, m).


928
3,4-Cl2Ph-
—C(CH3)2—
piperonyl
0
1.55 (6 H, s), 1.80-2.15 (2 H, m), 2.20-







2.55 (2 H, m), 2.95-3.20 (2 H, m), 3.31 (2 H,







s), 3.50-3.90 (2 H, m), 5.91 (2 H, s), 6.60-







6.72 (2 H, m), 6.76 (1 H, d, J = 1.3 Hz),







6.90 (1 H, d, J = 8.9 Hz), 7.07-7.33 (6 H, m),







7.58 (1 H, d, J = 2.4 Hz), 7.88 (1 H, d, J =







2.7 Hz), 8.09-8.11 (2 H, m), 8.17 (1 H, dd, J =







8.9 Hz, 2.8 Hz).
















TABLE 227













 









Example




No.
R723
1H NMR (CDCl3) δ ppm





929
benzyl
2.33-2.55 (4 H, m), 3.36-3.79 (6 H, m), 6.89 (1 H, d, J = 8.7 Hz), 7.07-




7.15 (3 H, m), 7.24-7.38 (6 H, m), 7.67-7.70 (2 H, m), 8.00 (2 H, d, J = 7.9 Hz),




8.09-8.13 (1 H, m), 8.32 (1 H, d, J = 2.3 Hz), 9.05 (1 H, brs).


930
piperonyl
2.36-2.44 (4 H, m), 3.37-3.76 (6 H, m), 5.93 (2 H, s), 6.69-6.75 (2 H, m),




6.83 (1 H, brs), 6.86 (1 H, d, J = 8.7 Hz), 7.04-7.06 (2 H, m), 7.10-




7.14 (1 H, m), 7.27-7.36 (1 H, m), 7.65 (2 H, d, J = 8.4 Hz), 7.99 (2 H, d, J =




8.1 Hz), 8.07-8.12 (1 H, m), 8.34 (1 H, d, J = 2.6 Hz), 9.41 (1 H, s).
















TABLE 228













 









Example




No.
R724
1H NMR (CDCl3) δ ppm





931
4-CF3PhCH2N(SO2CH3)—
2.31-2.41 (4 H, m), 2.58-2.64 (2 H, m), 2.94-2.97 (2 H, m),




2.99 (3 H, s), 3.38-3.41 (4 H, m), 3.60-3.65 (2 H, m),




4.85 (2 H, s), 5.94 (2 H, s), 6.65-6.75 (2 H, m), 6.83-




6.87 (2 H, m), 6.95-7.05 (2 H, m), 7.20-7.30 (2 H, m), 7.38-




7.41 (2 H, m), 7.52 (1 H, dd, J = 8.8 Hz, 2.8 Hz), 7.54-




7.57 (2 H, m), 8.04 (1 H, d, J = 2.3 Hz).


932
3,4-Cl2PhCH2N(SO2CH3)—
2.25-2.45 (4 H, m), 2.59-2.65 (2 H, m), 2.94-3.05 (5 H, m),




3.30-3.45 (4 H, m), 3.55-3.70 (2 H, m), 4.74 (2 H, s),




5.95 (2 H, s), 6.65-6.80 (2 H, m), 6.84-6.89 (2 H, m), 7.02-




7.15 (3 H, m), 7.23-7.30 (3 H, m), 7.30-7.40 (2 H, m),




8.03 (1 H, d, J = 2.7 Hz).


933
3,4-Cl2PhCH2NHCO—
2.25-2.45 (4 H, m), 2.59-2.65 (2 H, m), 2.94-3.00 (2 H, m),




3.37-3.41 (4 H, m), 3.59-3.65 (2 H, m), 4.58 (2 H, d, J =5.9 Hz),




5.94 (2 H, s), 6.50-6.65 (1 H, m), 6.65-6.80 (2 H, m),




6.84 (1 H, s), 6.94 (1 H, d, J = 8.6 Hz), 7.03-7.06 (2 H, m),




7.17 (1 H, dd, J = 8.2 Hz, 2.0 Hz), 7.22-7.26 (2 H, m),




7.38-7.42 (2 H, m), 8.14 (1 H, dd, J = 8.6 Hz, 2.5 Hz),




8.57 (1 H, d, J. 2.3 Hz).


934
3,4-Cl2PhNHCON(C2H5)—
1.17 (3 H, t, J = 7.1 Hz), 2.32-2.42 (4 H, m), 2.61-




2.67 (2 H, m), 2.97-3.03 (2 H, m), 3.39-3.43 (4 H, m), 3.61-




3.65 (2 H, m), 3.74 (2 H, q, J = 7.1 Hz), 5.94 (2 H, s),




6.00 (1 H, brs), 6.70-6.85 (3 H, m), 7.05 (1 H, d, J = 8.7 Hz),




7.09-7.13 (3 H, m), 7.26-7.31 (3 H, m), 7.52 (1 H, d, J =




2.5 Hz), 7.61 (1 H, dd, J = 8.7 Hz, 2.8 Hz), 8.12 (1 H, d,




J = 2.4 Hz).


935
3,4-Cl2PhN(CH3)—
2.25-2.45 (4 H, m), 2.59-2.65 (2 H, m), 2.95-3.00 (2 H, m),




3.25 (3 H, s), 3.38-3.42 (4 H, m), 3.61-3.65 (2 H, m),




5.94 (2 H, s), 6.55-6.65 (1 H, m), 6.65-6.80 (2 H, m), 6.80-




6.85 (2 H, m), 6.89-6.93 (1 H, m), 7.06-7.10 (2 H, m), 7.20-




7.27 (3 H, m), 7.45-7.50 (1 H, m), 8.01 (1 H, d, J = 2.4 Hz).


936
3,4-Cl2PhNH—
2.31-2.41 (4 H, m), 2.59-2.65 (2 H, m), 2.94-3.00 (2 H, m),




3.37-3.41 (4 H, m), 3.61-3.65 (2 H, m), 5.61 (1 H, brs),




5.94 (2 H, s), 6.69-6.80 (3 H, m), 6.84 (1 H, s), 6.90 (1 H, d,




J = 8.7 Hz), 6.96 (1 H, d, J = 2.7 Hz), 7.04-7.07 (2 H, m),




7.21-7.25 (3 H, m), 7.49 (1 H, dd, J = 8.7 Hz, 2.9 Hz),




8.00 (1 H, d, J = 2.8 Hz).


937
4-CF3PhCH2NHCO—
2.31-2.40 (4 H, m), 2.59-2.65 (2 H, m), 2.95-3.01 (2 H, m),




3.38-3.41 (4 H, m), 3.60-3.64 (2 H, m), 4.70 (2 H, d, J =5.8 Hz),




5.94 (2 H, s), 6.35-6.50 (1 H, m), 6.70-6.77 (2 H, m),




6.84 (1 H, s), 6.95 (1 H, d, J = 8.6 Hz), 7.03-7.07 (2 H, m),




7.23-7.26 (2 H, m), 7.44-7.47 (2 H, m), 7.59-7.62 (2 H, m),




8.14 (1 H, dd, J = 8.6 Hz, 2.5 Hz), 8.57 (1 H, d, J = 2.4 Hz).


938
3,4-Cl2PhN(C2H5)CONH—
1.17 (3 H, t, J = 7.1 Hz), 2.30-2.40 (4 H, m), 2.57-




2.63 (2 H, m), 2.92-2.98 (2 H, m), 3.37-3.40 (4 H, m), 3.60-




3.64 (2 H, m), 3.77 (2 H, q, J = 7.1 Hz), 5.94 (2 H, s), 6.65-




6.80 (2 H, m), 6.81-6.85 (2 H, m), 6.98-7.00 (2 H, m), 7.17-




7.21 (3 H, m), 7.45 (1 H, d, J = 2.4 Hz), 7.57 (1 H, d, J =




8.5 Hz), 7.85-7.91 (2 H, m).
















TABLE 229













 










Example





No.
R725
R726
1H NMR (CDCl3) δ ppm





939
3,4-Cl2PhNHCO—
—CH3
2.30-2.50 (4 H, m), 2.78 (3 H, s), 3.42 (2 H, s), 3.50-





3.65 (4 H, m), 3.82 (2 H, s), 5.95 (2 H, s), 6.65-





6.75 (2 H, m), 6.85 (1 H, s), 7.05 (1 H, d, J = 8.6 Hz),





7.26-7.30 (1 H, m), 7.39-7.43 (2 H, m), 7.49-





7.53 (2 H, m), 7.88 (1 H, d, J = 2.4 Hz), 8.24 (1 H,





dd, J = 8.6 Hz, 2.5 Hz), 8.31 (1 H, brs), 8.66 (1 H,





d, J = 2.4 Hz).


940
4-CF3PhNHCO—
—CH3
2.30-2.45 (4 H, m), 2.78 (3 H, s), 3.41 (2 H, s), 3.55-





3.59 (4 H, m), 3.82 (2 H, s), 5.94 (2 H, s), 6.65-





6.80 (2 H, m), 6.85 (1 H, s), 7.05 (1 H, d, J = 8.6 Hz),





7.26-7.30 (1 H, m), 7.41 (1 H, d, J = 2.8 Hz),





7.51 (1 H; d, J = 8.8 Hz), 7.59-7.63 (2 H, m), 7.77-





7.80 (2 H, m), 8.26 (1 H, dd, J = 8.6 Hz, 2.5 Hz),





8.54 (1 H, brs), 8.66 (1 H, d, J = 2.2 Hz).


941
3,4-Cl2PhCH2NHCO—
—CH3
2.30-2.45 (4 H, m), 2.80 (3 H, s), 3.42 (2 H, s), 3.50-





3.65 (4 H, m), 3.81 (2 H, s), 4.59 (2 H, d, J = 5.9 Hz),





5.95 (2 H, s), 6.50-6.60 (1 H, m), 6.65-





6.80 (2 H, m), 6.85 (1 H, s), 7.01 (1 H, d, J = 8.6 Hz),





7.18 (1 H, dd, J = 8.2 Hz, 2.0 Hz), 7.30 (1 H,





dd, J = 8.8 Hz, 2.7 Hz), 7.39-7.43 (3 H, m),





7.54 (1 H, d, J = 8.8 Hz), 8.18 (1 H, dd, J = 8.6 Hz,





2.5 Hz), 8.56 (1 H, d, J = 2.4 Hz).


942
4-CF3PhCH2NHCO—
—CH3
2.30-2.45 (4 H, m), 2.80 (3 H, s), 3.42 (2 H, s), 3.50-





3.65 (4 H, m), 3.81 (2 H, s), 4.70 (2 H, d, J = 5.9 Hz),





5.94 (2 H, s), 6.50-6.65 (1 H, m), 6.70-





6.80 (2 H, m), 6.85 (1 H, s), 7.00 (1 H, d, J = 8.6 Hz),





7.29 (1 H, dd, J = 8.8 Hz, 2.7 Hz), 7.39-





7.62 (6 H, m), 8.18 (1 H, dd, J = 8.6 Hz, 2.5 Hz),





8.57 (1 H, d, J = 2.4 Hz).


943
3,4-Cl2PhN(CH3)—
—C2H5
1.02 (3 H, t, J = 7.1 Hz), 2.35-2.40 (4 H, m),





3.22 (2 H, q, J = 7.1 Hz), 3.27 (3 H, s), 3.40 (2 H, s),





3.45-3.60 (4 H, m), 3.85 (2 H, s), 5.94 (2 H, s),





6.64 (1 H, dd, J = 8.9 Hz, 2.9 Hz), 6.65-6.75 (2 H,





m), 6.84 (1 H, s), 6.90 (1 H, d, J = 2.8 Hz),





6.96 (1 H, d, J = 8.7 Hz), 7.22-7.26 (1 H, m), 7.26-





7.35 (1 H, m), 7.42 (1 H, d, J = 2.8 Hz), 7.50 (1 H,





dd, J = 8.7 Hz, 2.9 Hz), 7.66 (1 H, d, J = 8.8 Hz),





8.00 (1 H, d, J = 2.6 Hz).
















TABLE 230













 














Example









No.
R727
R728
R729
R730
R731
Xb10
1H NMR (CDCl3) δ ppm





944
—Cl
—Cl
—CH3
—CH3
—H
—N(CH3)—
2.30 (6 H, s), 2.32-2.45 (4 H, m),









2.83 (3 H, s), 3.30-3.45 (4 H, m), 3.55-









3.70 (2 H, m), 3.83 (2 H, s), 5.94 (2 H, s),









6.69-6.76 (4 H, m), 6.83 (1 H, s),









6.96 (1 H, d, J = 8.6 Hz), 7.40 (1 H, d, J =









8.7 Hz), 7.50 (1 H, dd, J 8.8 Hz,









2.5 Hz), 7.87 (1 H, d, J = 2.4 Hz),









8.19 (1 H, dd, J = 8.6 Hz, 2.5 Hz),









8.3 1 (1 H, brs), 8.68 (1 H, d, J = 2.2









Hz).


945
—CF3
—H
—CH3
—CH3
—H
—N(CH3)—
2.30-2.45 (10 H, m), 2.86 (3 H, s), 3.30-









3.45 (4 H, m), 3.55-3.70 (2 H, m),









3.84 (2 H, s), 5.94 (2 H, s), 6.65-









6.78 (4 H, m), 6.84 (1 H, s), 6.99 (1 H, d,









J = 8.6 Hz), 7.60-7.65 (2 H, m), 7.70-









7.78 (2 H, m), 8.07 (1 H, brs), 8.21 (1 H,









dd, J = 8.6 Hz, 2.6 Hz), 8.70 (1 H, d, J =









2.5 Hz).


946
—CF3
—H
—H
—H
—H
—CH(CH3)—
1.30-1.36 (3 H, m), 2.10-2.40 (4 H, m),









2.47-2.67 (2 H, m), 3.25-3.45 (5 H, m),









3.50-3.65 (2 H, m), 5.93 (2 H, s), 6.65-









6.75 (2 H, m), 6.83 (1 H, d, J = 0.9 Hz),









7.01 (1 H, dd, J = 8.6 Hz, 0.6 Hz),









7.06-7.15 (2 H, m), 7.25-7.30 (2 H, m),









7.60-7.64 (2 H, m), 7.74-7.78 (2 H, m),









8.14 (1 H, brs), 8.22 (1 H, dd, J = 8.6









Hz, 2.6 Hz), 8.67-8.68 (1 H, m).


947
—CF3
—H
—H
—H
—CH3
—CH2—
1.14-1.17 (3 H, m), 1.95-2.10 (1 H, m),









2.15-2.45 (3 H, m), 2.55-2.70 (1 H, m),









3.45-3.70 (2 H, m), 5.92-5.94 (2 H, m),









6.65-6.85 (3 H, m), 6.95-7.06 (3 H, m),









7.10-7.30 (2 H, m), 7.59-7.63 (2 H, m),









7.75-7.79 (2 H, m), 8.24 (1 H, dd, J =









8.6 Hz, 2.6 Hz), 8.40 (1 H, brs),









8.71 (1 H, d, J = 2.4 Hz).
















TABLE 231













 









Example No.
R732
1H NMR (DMSO-d6) δ ppm





948
—Br
2.20-2.35 (4 H, m), 2.59-2.65 (2 H, m), 2.79-2.85 (2 H, m), 3.20-3.60 (6 H,




m), 5.99 (2 H, s), 6.73-6.77 (1 H, m), 6.83-6.86 (2 H, m), 7.07-7.10 (2 H, m),




7.27-7.34 (4 H, m), 7.62-7.65 (2 H, m), 8.44-8.48 (2 H, m), 10.90 (1 H, brs).


949
—H
2.20-2.35 (4 H, m), 2.59-2.65 (2 H, m), 2.78-2.84 (2 H, m), 3.38-3.44 (6 H,




m), 5.98 (2 H, s), 6.72-6.76 (1 H, m), 6.82-6.86 (2 H, m), 7.04-7.08 (2 H, m),




7.17 (1 H, d, J = 8.8 Hz), 7.26-7.33 (4 H, m), 7.61-7.65 (2 H, m), 8.17 (1 H,




dd, J = 8.7 Hz, 2.6 Hz), 8.55 (1 H, d, J = 2.6 Hz), 10.98 (1 H, brs).









Example 950
Production of 3,4-dichloro-N-{6-[4-(4-phenethylpiperazine-1-carbonyl)phenoxy]pyridin-3-yl}benzamide
To a solution of ethyl 4-(5-aminopyridin-2-yloxy)benzoate (690 mg, 2.7 mmol) in THF (10 mL) were added triethylamine (0.73 mL, 5.3 mmol) and 3,4-dichlorobenzoyl chloride (570 mg, 2.7 mmol) under ice cooling, and the resulting solution was stirred for 1 hour under ice cooling. This reaction solution was concentrated under reduced pressure, and to the residue was added ethyl acetate. The resulting solution was washed with water, 1 N hydrochloric acid and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was washed, when hot, with n-hexane:dichloromethane=1:2. The product was dissolved in THF (20 mL). To the residue was added 1 N aqueous sodium hydroxide (2.9 mL, 2.9 mmol), and this solution was stirred for 5 hours at 100° C. THF was evaporated, and the aqueous layer was made to have a pH of 3 with 1 N hydrochloric acid. Precipitated matter was collected by filtration, and dried. The resulting product was dissolved in bMF (10 mL), and 1-phenethylpiperazine (200 mg, 1.1 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (240 mg, 1.3 mmol) and 1-hydroxybenzotriazole monohydrate (170 mg, 1.3 mmol) were added to the solution. The resulting solution was stirred for 1 day at room temperature. This reaction solution was concentrated under reduced pressure, and to the residue was added chloroform. The resulting solution was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (methanol:chloroform=1:99), to thereby yield 310 mg of the title compound.
Appearance: White Powder
1H NMR (CDCl3) δ 2.54 (4H, brs), 2.62-2.68 (2H, m), 2.79-2.85 (2H, m), 3.60-3.73 (4H, m), 6.95 (1H, d, J=8.9 Hz), 7.09-7.23 (5H, m), 7.27-7.33 (2H, m), 7.37-7.41 (2H, m), 7.55 (1H, d, J=8.3 Hz), 7.74-7.78 (1H, m), 8.04 (1H, d, J=2.0 Hz), 8.11-8.15 (1H, m), 8.31 (1H, d, J=2.6 Hz), 8.57 (1H, brs).
The following compounds were produced in the same manner as in Example 950.







TABLE 232













 













Example








No.
R733
R734
R735
R736
R737
MS (M+ + H)





951
—CH3
—F
—H
—H
4-CNPhCH2—
550


952
—H
—F
—F
—H
4-CNPhCH2—
554


953
—H
—Cl
—H
—Cl
4-CNPhCH2—
586


954
—H
—OCF3
—H
—H
4-CNPhCH2—
602


955
—CH3
—F
—H
—H
2-pyridylmethyl
526


956
—H
—CH3
—CH3
—H
2-pyridylmethyl
522


957
—H
—F
—F
—H
2-pyridylmethyl
530


958
—H
—Cl
—H
—Cl
2-pyridylmethyl
530


959
—H
—CF3
—H
—H
2-pyridylmethyl
562


960
—H
—H
—Cl
—H
2-pyridylmethyl
528


961
—H
—CF3
—H
—F
2-pyridylmethyl
580


962
—H
—OCF3
—H
—H
2-pyridylmethyl
578


963
—CH3
—F
—H
—H
3-pyridylmethyl
526


964
—H
—CH3
—CH3
—H
3-pyridylmethyl
522


965
—H
—F
—F
—H
3-pyridylmethyl
530


966
—H
—Cl
—H
—Cl
3-pyridylmethyl
562


967
—H
—CF3
—H
—H
3-pyridylmethyl
562


968
—H
—H
—Cl
—H
3-pyridylmethyl
528


969
—H
—CF3
—H
—F
3-pyridylmethyl
580


970
—CH3
—F
—H
—H
4-pyridylmethyl
526


971
—H
—CH3
—CH3
—H
4-pyridylmethyl
522


972
—H
—F
—F
—H
4-pyridylmethyl
530


973
—H
—Cl
—H
—Cl
4-pyridylmethyl
562


974
—H
—CF3
—H
—H
4-pyridylmethyl
562


975
—H
—H
—Cl
—H
4-pyridylmethyl
528


976
—H
—CF3
—H
—F
4-pyridylmethyl
580


977
—H
—OCF3
—H
—H
4-pyridylmethyl
578


978
—CH3
—F
—H
—H
piperonyl
569


979
—H
—CH3
—CH3
—H
piperonyl
565


980
—H
—F
—F
—H
piperonyl
573


981
—H
—Cl
—H
—Cl
piperonyl
605


982
—H
—CF3
—H
—H
piperonyl
605


983
—H
—CF3
—H
—F
piperonyl
623
















TABLE 233













 













Example








No.
R738
R739
R740
R741
R742
MS (M+ + H)
















984
—H
—OCF3
—H
—H
piperonyl
621


985
—H
—CH3
—CH3
—H
benzyl
521


986
—H
—F
—F
—H
benzyl
529


987
—CH3
—F
—H
—H
4-AcNHPhCH2—
582


988
—H
—CH3
—CH3
—H
4-ACNHPhCH2—
578


989
—H
—F
—F
—H
4-AcNHPhCH2—
586


990
—H
—Cl
—H
—Cl
4-AcNHPhCH2—
618


991
—H
—CF3
—H
—H
4-AcNHPhCH2—
618


992
—H
—H
—Cl
—H
4-AcNHPhCH2—
584


993
—H
—CF3
—H
—F
4-AcNHPhCH2—
636


994
—H
—OCF3
—H
—H
4-AcNHPhCH2—
634


995
—CH3
—F
—H
—H
2,3-(CH3)2PhCH2—
553


996
—H
—CH3
—CH3
—H
2,3-(CH3)2PhCH2—
549


997
—H
—F
—F
—H
2,3-(CH3)2PhCH2—
557


998
—H
—Cl
—H
—Cl
2,3-(CH3)2PhCH2—
589


999
—H
—CF3
—H
—H
2,3-(CH3)2PhCH2—
589


1000
—H
—H
—Cl
—H
2,3-(CH3)2PhCH2—
555


1001
—H
—CF3
—H
—F
2,3-(CH3)2PhCH2—
607


1002
—H
—OCF3
—H
—H
2,3-(CH3)2PhCH2—
605


1003
—CH3
—F
—H
—H
3-furylmethyl
515


1004
—H
—CH3
—CH3
—H
3-furylmethyl
511


1005
—H
—F
—F
—H
3-furylmethyl
519


1006
—H
—Cl
—H
—Cl
3-furylmethyl
551


1007
—H
—CF3
—H
—H
3-furylmethyl
551


1008
—H
—H
—Cl
—H
3-furylmethyl
517


1009
—H
—Cl
—Cl
—H
3-furylmethyl
551


1010
—H
—CF3
—H
—F
3-furylmethyl
569


1011
—H
—OCF3
—H
—H
3-furylmethyl
567


1012
—CH3
—F
—H
—H
3-pyridyl
512


1013
—H
—CH3
—CH3
—H
3-pyridyl
508


1014
—H
—F
—F
—H
3-pyridyl
516


1015
—H
—Cl
—H
—Cl
3-pyridyl
548


1016
—H
—CF3
—H
—H
3-pyridyl
548


1017
—H
—CF3
—H
—F
3-pyridyl
566


1018
—H
—OCF3
—H
—H
3-pyridyl
564
















TABLE 234













 












Example No.
R743
R744
R745
R746
MS (M+ + H)





1019
—CH3
—F
—H
—H
519


1020
—H
—CH3
—CH3
—H
515


1021
—H
—F
—F
—H
523


1022
—H
—Cl
—H
—Cl
555


1023
—H
—CF3
—H
—H
555


1024
—H
—H
—Cl
—H
521


1025
—H
—Cl
—Cl
—H
555


1026
—H
—CF3
—H
—F
573


1027
—H
—OCF3
—H
—H
571
















TABLE 235













 









Example No.
R747
MS (M+ + H)





1028
4-CNPhCH2—
544


1029
2-pyridylmethyl
520


1030
3-pyridylmethyl
520


1031
4-pyridylmethyl
520


1032
4-AcNHPhCH2—
576


1033
2,3-(CH3)2PhCH2—
547


1034
3-furylmethyl
509


 


1035




513









Example 1036
Production of 2-{3-methyl-4-[5-(4-trifluoromethylbenzoyl)pyridin-2-yloxy]phenylamino}-1-(4-piperonylpiperazin-1-yl)ethanone
To a solution of 2-chloro-5-(4-trifluoromethylbenzoyl)pyridine (1.00 g, 3.5 mmol) in DMF (30 mL) were added N-(4-hydroxy-3-methylphenyl)glycine ethyl ester (0.81 g, 3.9 mmol), cesium carbonate (1.71 g, 5.2 mmol) and copper (I) iodide (200 mg, 1.05 mmol), and the resulting solution was stirred for 3.5 hours at 60° C. under an argon atmosphere. The resulting reaction solution was filtered and concentrated. To the residue was added water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), to thereby yield 1.20 g of a yellow oil. The yellow oil was dissolved in THF (23 mL), and to the solution was added 1 M aqueous sodium hydroxide (3.9 mL, 3.9 mmol). The resulting solution was stirred for 3 hours at room temperature. This reaction solution was cooled with ice, and made to have a pH of 1 with 6 M hydrochloric acid. The resulting solution was extracted with ethyl acetate, and the ethyl acetate layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, to thereby yield 1.04 g of a yellow oil. This yellow oil was dissolved in DMF (20 mL), and to the resulting solution were added 1-piperonylpiperazine (530 mg, 2.4 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (560 mg, 2.9 mmol) and 1-hydroxybenzotriazole monohydrate (390 mg, 2.6 mmol), and the resulting solution was stirred for 15 hours at room temperature. The reaction solution was concentrated under reduced pressure, and to the residue was added water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:2→ethyl acetate), to thereby yield 280 mg of a yellow oil. To this oil was added diethyl ether and left to stand. Precipitated matter, was collected by filtration, to thereby yield 220 mg of the title compound.
Appearance: Yellow powder
1H NMR (CDCl3) δ 2.11 (3H, s), 2.43-2.48 (4H, m), 3.45-3.48 (4H, m), 3.67-3.71 (2H, m), 3.86 (2H, d, J=4.1 Hz), 4.90 (1H, t, J=4.1 Hz), 5.96 (2H, s), 6.49-6.53 (2H, m), 6.71-6.78 (2H, m), 6.86-6.97 (3H, m), 7.75 (2H, d, J=8.1 Hz), 7.87 (2H, d, J=8.1 Hz), 8.18 (1H, dd, J=8.7 Hz, 2.5 Hz), 8.58 (1H, d, J=2.1 Hz).
The following compound was produced in the same manner as in Example 1036.
Example 1037
6-(4-{[2-(4-Piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2,5-difluorophenoxy)-N-(4-trifluoromethylphenyl)nicotinamide hydrobromide
Melting point: 224.5-226.0° C.
Example 1038
Production of N-(6-{2-methyl-4-[methyl-(2-oxo-2-piperazin-1-ylethyl)amino]phenoxy}pyridin-3-yl)-3,4-dichlorobenzamide
To a solution of methyl{4-[5-(3,4-dichlorobenzoylamino)-pyridin-2-yloxy]-3-methylphenyl}aminoacetic acid (1.59 g, 3.5 mmol) in DMF (60 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.79 g, 4.1 mmol), 1-hydroxybenzotriazole monohydrate (0.63 g, 4.1 mmol), and 1-t-butyloxycarbonylpiperazine (0.68 g, 3.6 mmol). The resulting solution was stirred for 15 hours at room temperature under a nitrogen atmosphere. Water was added to the solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and then the ethyl acetate layer was dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→3:2), to thereby yield an amide product. This amide product was dissolved in THF (20 mL). To the solution was then added 10% hydrochloric acid (10 mL), and the resulting solution was stirred for 14 hours at room temperature. To this reaction solution was added a saturated sodium bicarbonate solution to make the solution neutral, and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=50:1→20:1), to thereby yield 0.38 g of the title compound.
Appearance: Colorless amorphous powder
1H NMR (CDCl3) δ 2.10 (3H, s), 2.75-2.94 (4H, m), 2.99 (3H, s), 3.40-3.70 (4H, m), 4.08 (2H, s), 6.46-6.59 (2H, m), 6.79 (1H, d, J=8.9 Hz), 6.89 (1H, d, J=8.6 Hz), 7.55 (1H, d, J=8.4 Hz), 7.71 (1H, dd, J=8.4 Hz, 2.1 Hz), 7.98 (1H, d, J=2.1 Hz), 8.03-8.14 (2H, m), 8.23 (1H, d, J=2.6 Hz).
Example 1039
Production of N-(6-{4-[3-(4-piperonylpiperazin-1-yl)-3-oxopropyl]phenoxy}pyridin-3-yl)-4-trifluoromethylbenzamide
To a solution of 3-[4-(5-aminopyridin-2-yloxy)phenyl]-1-(4-piperonylpiperazin-1-yl)propan-1-one trihydrochloride (200 mg, 0.35 mmol) in THF (4 mL) were added triethylamine (0.243 mL, 1.8 mmol) and 4-trifluoromethylbenzoyl chloride (0.055 mL, 0.37 mmol), and the resulting solution was stirred for 1 hour at room temperature. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over anhydrous magnesium sulfate, evaporated, and the residue was recrystallized from diethyl ether, to thereby yield 170 mg of the title compound.
Appearance: White powder
Melting point: 140-141° C.
1H NMR (CDCl3) δ 2.32-2.40 (4H, m), 2.59-2.65 (2H, m), 2.93-2.99 (2H, m), 3.41 (4H, brs), 3.60-3.64 (2H, m), 5.94 (2H, s), 6.71-6.77 (2H, m), 6.85 (1H, s), 6.96 (1H, d, J=8.9 Hz), 7.05 (2H, d, J=8.4 Hz), 7.22 (2H, d, J=8.4 Hz), 7.76 (2H, d, J=8.4 Hz), 8.01 (2H, d, J=8.4 Hz), 8.11-8.14 (1H, m), 8.23 (1H, dd, J=8.9 Hz, 2.7 Hz), 8.28 (1H, d, J=2.7 Hz).
A crude titled product (77.4 g) obtained using the same procedures was recrystallized from ethyl acetate (400 mL), to thereby yield 49.66 g of the title compound.
Appearance: White powder; Melting point: 142-144° C.
The following compounds were produced in the same manner as in Example 1039.







TABLE 236













 











Example






No.
Xb11
Xb12
R748
mp (° C.) or 1H NMR





1040








—COOC(CH3)3
mp 197-199


 


1041








—OCH2OCH3
mp 152-154


 


1042








—COOC2H5
mp 189-190


 


1043








—N(CH3)COOC(CH3)3
mp 146-147


 


1044








—COOC(CH3)3
mp 192-193


 


1045








—OCH2COOC2H5
1H NMR (CDCl3) δ 1.30 (3 H, t, J = 7.0 Hz), 1.75-1.81 (2 H, m), 2.03 (2 H, brs), 2.85-2.90 (2 H, m), 3.45-3.49 (2 H, m), 3.56 (1 H, m), 4.15 (2 H, s), 4.23 (2 H, q, J = 7.0 Hz), 6.90-6.95 (6 H, m), 7.50-7.53 (3 H, m), 7.69 (1 H, dd, J = 8.5 Hz, 2.0 Hz), 7.95 (1 H, d, J = 2.0 Hz), 8.04 (1 H, brs).
















TABLE 237













 














Example









No.
R749
R750
R751
Xb13
M
Form
mp (° C.) or 1H NMR





1046
—Cl
—Cl
—F
—N(Ac)—
1
free
1H NMR (DMSO-d6) δ 1.78 (3 H,









s), 2.22-2.38 (4 H, m), 3.30-









3.50 (6 H, m), 4.41 (2 H, s),









5.98 (2 H, s), 6.74 (1 H, d, J = 8.1









Hz), 6.80-6.86 (2 H, m), 6.98 (2 H,









d, J = 8.8 Hz), 7.29 (1 H, t, J =









9.2 Hz), 7.38 (2 H, d, J = 8.8 Hz),









7.58 (1 H, d, J = 9.2 Hz),









7.84 (1 H, d, J 8.4 Hz), 7.90-









7.96 (2 H, m), 8.21 (1 H, d, J = 1.8









Hz), 10.61 (1 H, s).


1047
—Cl
—Cl
—F
—NH—
0
free
mp 224-228


1048
—Cl
—Cl
—F
—NH—
1
dihydrochloride
mp 174-178


1049
—CF3
—H
—H
—N(CH3)—
1
free
1H NMR (ODCl3) δ 2.45 (4 H,









brs), 3.03 (3 H, s), 3.46 (2 H, s),









3.52 (2 H, brs), 3.64 (2 H, brs),









4.08 (2 H, s), 5.95 (2 H, s),









6.67 (2 H, d, J = 9.1 Hz), 6.74-









6.78 (2 H, m), 6.87 (1 H, s), 6.92-









6.97 (4 H, m), 7.52 (2 H, d, J = 8.9









Hz), 7.74-7.81 (3 H, m), 7.98 (2 H,









d, J = 8.2 Hz).


1050
—Cl
—Cl
—H
—N(CH3)—
1
free
1H NMR (CDCl3) δ 2.49 (4 H,









brs), 3.02 (3 H, s), 3.50 (2 H, s),









3.55 (2 H, brs), 3.66 (2 H, brs),









4.08 (2 H, s), 5.96 (2 H, s),









6.67 (2 H, d, J = 9.1 Hz), 6.74-









6.78 (2 H, m), 6.88-6.96 (5 H, m),









7.50 (2 H, d, J = 8.9 Hz),









7.56 (1 H, d, J = 8.4 Hz),









7.70 (1 H, dd, J = 8.4 Hz, 2.1 Hz),









7.83 (1 H, s), 7.97 (1 H, d, J = 2.1









Hz).


1051
—Cl
—Cl
—F
—O—
1
hydrochloride
1H NMR (DMSO-d6) δ 2.83-









2.95 (1 H, m), 2.97-3.12 (2 H, m),









3.23-3.56 (3 H, m), 3.95-4.06 (1 H,









m), 4.18-4.29 (2 H, m), 4.33-









4.44 (1 H, m), 4.75-4.92 (2 H, m),









6.07 (2 H, s), 6.90-6.96 (4 H, m),









6.97-7.04 (2 H, m), 7.11 (1 H, t, J =









9.1 Hz), 7.15-7.22 (1 H, m),









7.52 (1 H, d, J = 9.1 Hz), 7.84









(1 H, d, J = 8.4 Hz), 7.88 (1 H, d,









J = 13.3 Hz), 7.94 (1 H, dd, J =









8.4 Hz, 1.9 Hz), 8.23 (1 H, d, J =









1.9 Hz), 10.60 (1 H, s), 11.10 (1 H,









brs).
















TABLE 238













 










Example





No.
R752
R753
mp (° C.) or 1H NMR (CDCl3) δ ppm





1052
4-ClPh-
benzyl
mp 187-190


1053
3-ClPh-
benzyl
1H NMR 2.38 (4 H, brs), 3.34-3.71 (6 H, m), 6.86 (1 H,





d, J = 8.8 Hz), 7.00-7.05 (2 H, m), 7.19-7.36 (8 H, m),





7.43-7.47 (1 H, m), 7.69-7.73 (1 H, m), 7.83 (1 H, t, J =





1.8 Hz), 8.08 (1 H, dd, J = 8.8 Hz, 2.8 Hz), 8.24 (1 H,





d, J = 2.6 Hz), 8.5 1 (1 H, brs).


1054
4-CH3Ph-
4-CH3OPhCH2—
1H NMR 2.32-2.50 (7 H, m), 3.44-3.79 (9 H, m), 6.84-





6.92 (3 H, m), 7.06-7.11 (2 H, m), 7.20-7.23 (4 H, m),





7.34-7.39 (2 H, m), 7.79 (2 H, d, J = 8.3 Hz), 8.16-





8.21 (1 H, m), 8.35 (1 H, d, J = 2.8 Hz), 8.76 (1 H, brs).


1055
2-naphthyl
4-CH3OPhCH2—
1H NMR 2.41 (4 H, bra), 3.46-3.80 (6 H, m), 3.81 (3 H,





s), 6.83-6.90 (2 H, m), 6.95 (1 H, d, J = 8.7 Hz),





7.10 (2 H, d, J = 8.7 Hz), 7.22 (2 H, d, J = 8.6 Hz),





7.38 (2 H, d, J = 8.7 Hz), 7.52-7.63 (2 H, m), 7.88-





7.97 (4 H, m), 8.27 (1 H, dd, J = 8.7 Hz, 2.8 Hz),





8.41-8.43 (2 H, m), 8.80 (1 H, brs).


1056
4-ClPh-
4-CH3OPhCH2—
1H NMR 2.43 (4 H, brs), 3.48-3.77 (6 H, m), 3.80 (3 H,





s), 6.83-6.89 (2 H, m), 6.96 (1 H, d, J = 8.9 Hz), 7.10-





7.15 (2 H, m), 7.22 (2 H, d, J = 8.6 Hz), 7.38-7.48 (4 H,





m), 7.82-7.87 (2 H, m), 8.17-8.21 (2 H, m), 8.30 (1 H,





d, J = 2.6 Hz).


1057
3-ClPh-
4-CH3OPhCH2—
1H NMR 2.41 (4 H, brs), 3.46-3.76 (6 H, m), 3.79 (3 H,





s), 6.83-6.89 (3 H, m), 7.05 (2 H, d, J = 8.4 Hz),





7.21 (2 H, d, J = 8.6 Hz), 7.31-7.48 (4 H, m), 7.77 (1 H,





d, J = 7.8 Hz), 7.90 (1 H, s), 8.08-8.12 (1 H, m),





8.35 (1 H, d, J = 2.5 Hz), 9.26 (1 H, brs).


1058
4-CF3OPh-
benzyl
mp 152-153


1059
2,4-Cl2Ph-
benzyl
mp 196-197


1060
2,3-F2Ph-
benzyl
mp 172-175


1061
4-ClPh-
piperonyl
1H NMR 2.45 (4 H, brs), 3.45 (2 H, s), 3.45-3.75 (4 H,





m), 5.95 (2 H, s), 6.74-6.77 (2 H, m), 6.86 (1 H, a),





6.99 (1 H, d, J = 8.9 Hz), 7.14 (2 H, d, 4 8.7 Hz),





7.42-7.51 (4 H, m), 7.84 (2 H, d, J = 8.7 Hz), 7.91 (1 H,





brs), 8.22 (1 H, dd, J = 8.7 Hz, 2.8 Hz), 8.29 (1 H, d,





2.1 Hz)


1062
4-ClPh-
3-pyridyl
1H NMR 3.24 (4 H, brs), 3.49-3.82 (4 H, m), 7.02 (1 H,





d, J = 8.7 Hz), 7.16-7.24 (4 H, m), 7.48 (2 H, d, J =





8.9 Hz), 7.49 (2 H, d, J = 8.7 Hz), 7.85 (2 H, d, J = 8.7





Hz), 8.04 (1 H, brs), 8.15-8.17 (1 H, m), 8.24 (1 H, dd,





J = 8.7 Hz, 2.8 Hz), 8.31-8.32 (2 H, m).
















TABLE 239













 












Example







No.
R754
R755
Xb14
Form
Property





1063
3-CF3OPh-
benzyl
—CO—
maleate
mp 155-157° C.


1064
3,5-Cl2Ph-
benzyl
—CO—
dihydrochloride
1H NMR (DMSO-d6) δ 3.15-







3.54 (8 H, m), 4.36 (2 H, s),







7.15-7.22 (3 H, m), 7.47-







7.60 (7 H, m), 7.90-7.91 (1 H,







m), 8.00 (1 H, s), 8.01 (1 H, s),







8.22-8.27 (1 H, m), 8.54 (1 H,







d, J = 2.2 Hz), 10.69 (1 H, s).


1065
PhCH═CH—
benzyl
—CO—
free
MS 518(M+)



(trans)


1066
PhCH═CH—
piperonyl
—CO—
free
1H NMR (CDCl3) δ 2.45 (4 H,



(trans)



brs), 3.44 (2 H, s), 3.52 (2 H,







brs), 3.76 (2 H, brs), 5.95







(2 H, s), 6.60 (1 H, d, J = 15.5







Hz), 6.74-6.77 (2 H, m),







6.85 (1 H, s), 6.95 (1 H, d, J =







8.7 Hz), 7.12 (2 H, d, J = 8.6







Hz), 7.38-7.45 (511, m), 7.53-







7.56 (211, m), 7.74 (1 H, brs),







7.77 (1 H, d, J = 15.5 Hz),







8.21 (1 H, d, J = 8.4 Hz),







8.25 (1 H, d, J = 2.5 Hz).


1067
PhCH═CH—
3-pyridyl
—CO—
free
1H NMR (CDCl3) δ 3.20 (4 H,



(trans)



brs), 3.79 (4 H, brs),







6.67 (1 H, d, J = 15.7 Hz),







6.92 (1 H, d, J = 8.7 Hz),







7.10-7.21 (4 H, m), 7.33-







7.46 (7 H, m), 7.73 (1 H, d, J =







15.7 Hz), 8.11-8.31 (4 H, m),







9.30 (1 H, s).


1068
3,4-Cl2Ph-
benzyl
—SO2—
hydrochloride
mp 253-256° C.


1069
4-CF3Ph-
benzyl
—SO2—
hydrochloride
mp 249-251° C.
















TABLE 240













 












Example







No.
R756
R757
Xb15
M
1H NMR (solvent) δ ppm





1070
3,4-
benzyl
—CH(OH)—
0
(CDCl3) 1.95-2.15 (1 H, m), 2.15-2.40 (3 H,







m), 3.42 (2 H, s), 3.49 (4 H, brs), 5.42 (1 H, d,







J = 6.6 Hz), 5.61 (1 H, d, J = 6.6 Hz),







7.08 (1 H, d, J = 8.9 Hz), 7.09 (2 H, d, J = 8.6







Hz), 7.15-7.43 (5 H, m), 7.38 (2 H, d, J = 8.6







Hz), 7.85 (1 H, d, J = 8.4 Hz), 7.95 (1 H, dd, J =







8.4 Hz, 2.0 Hz), 8.20 (1 H, dd, J = 8.9 Hz,







2.7 Hz), 8.23 (1 H, d, J = 2.3 Hz), 8.50 (1 H,







d, J = 2.7 Hz), 10.57 (1 H, s).


1071
4-CF3Ph-
benzyl
—CH(OH)—
0
(CDCl3) 1.90-2.05 (1 H, m), 2.22-2.57 (3 H,







m), 3.10-3.40 (2 H, m), 3.44 (2 H, s), 3.58-.







3.85 (2 H, m), 4.75 (1 H, d, J = 6.4 Hz),







5.21 (1 H, d, J 6.4 Hz), 6.96 (1 H, d, J = 8.9







Hz), 7.12 (2 H, d, J = 8.6 Hz), 7.20-7.38 (5 H,







m), 7.32 (2 H, d, J = 8.6 Hz), 7.78 (2 H, d, J =







8.1 Hz), 7.92 (1 H, brs), 8.00 (2 H, d, J = 8.1







Hz), 8.22 (1 H, dd, J = 8.9 Hz, 2.5 Hz),







8.29 (1 H, d, J = 2.5 Hz).


1072
4-CF3Ph-
piperonyl
—O—
1
(DMSO-d6) 2.32 (2 H, brs), 2.40 (2 H, brs),







3.41 (2 H, s), 3.46 (4 H, brs), 4.81 (2 H, s),







5.99 (2 H, s), 6.73-6.88 (3 H, m), 6.94 (2 H, d, J =







9.2 Hz), 7.02 (1 H, d, J = 8.7 Hz), 7.05 (2 H,







d, J = 9.2 Hz), 7.93 (2 H, d, J = 8.4 Hz), 8.16







(2 H, d, J = 8.4 Hz), 8.19 (1 H, dd, J = 8.7







Hz, 2.7 Hz), 8.47 (1 H, d, J = 2.7 Hz),







10.60 (1 H, s).


1073
4-CF3Ph-
benzyl
—O—
1
(CDCl3) 2.35-2.53 (4 H, m), 3.51 (2 H, s),







3.56 (2 H, t, J = 5.0 Hz), 3.62 (2 H, t, J = 5.0







Hz), 4.64 (2 H, s), 6.90 (1 H, d, J = 8.8 Hz),







6.92 (2 H, d, J = 9.0 Hz), 7.04 (2 H, d, J = 9.0







Hz), 7.21-7.41 (5 H, m), 7.73 (2 H, d, J = 8.1







Hz), 8.00 (2 H, d, J = 8.1 Hz), 8.18 (1 H, dd, J =







8.8 Hz, 2.6 Hz), 8.27 (1 H, d, J = 2.6 Hz),







8.32 (1 H, brs).


1074
3-ClPh-
piperonyl
none
2
(CDCl3) 2.31-2.38 (4 H, m), 2.58-2.64 (2 H,







m), 2.90-2.96 (2 H, m), 3.37-3.40 (4 H, m),







3.59-3.62 (2 H, m), 5.94 (2 H, s), 6.70-







6.77 (2 H, m), 6.84 (1 H, a), 6.92 (1 H, d, J =







8.9 Hz), 7.03 (2 H, d, J = 8.4 Hz), 7.20 (2 H,







d, J = 8.4 Hz), 7.38-7.44 (1 H, m), 7.50-







7.54 (1 H, m), 7.77 (1 H, d, J = 7.8 Hz), 7.87-







7.88 (1 H, m), 8.21 (1 H, dd, J = 8.9 Hz, 2.7







Hz), 8.28 (1 H, d, J = 2.7 Hz), 8.36 (1 H, s).
















TABLE 241













 









Example




No.
R758
mp (° C.) or 1H NMR





1075
3-ClPh-
1H NMR (CDCl3) δ 2.33-2.38 (4 H, m), 2.55-2.61 (2 H, m), 2.86-




2.91 (2 H, m), 3.37-3.41 (2 H, m), 3.49 (2 H, s), 3.56-3.60 (2 H, m),




6.87 (1 H, d, J = 8.9 Hz), 6.97-7.01 (2 H, m), 7.14 (2 H, d, J = 8.6 Hz),




7.25-7.37 (6 H, m), 7.45-7.48 (1 H, m), 7.75-7.79 (1 H, m), 7.87 (1 H, t, J =




1.8 Hz), 8.18 (1 H, dd, J = 8.9 Hz, 2.8 Hz), 8.32 (1 H, d, J = 2.8 Hz),




9.06 (1 H, brs).


1076
4-ClPh-
mp 136-139


1077
2-ClPh-
1H NMR (CDCl3) δ 2.32-2.41 (4 H, m), 2.56-2.61 (2 H, m), 2.90-




2.96 (2 H, m), 3.37-3.41 (2 H, m), 3.50 (2 H, s), 3.58-3.61 (2 H, m),




6.92 (1.H, d, J = 8.7 Hz), 7.03 (2 H, d, J = 8.4 Hz), 7.19-7.43 (10 H, m),




7.69-7.72 (1 H, m), 8.21-8.27 (3 H, m).


1078
Ph-
1H NMR (CDCl3) δ 2.36 (4 H, brs), 2.56-2.61 (2 H, m), 2.89-2.95 (2 H,




m), 3.36-3.41 (2 H, m), 3.49 (2 H, s), 3.58-3.62 (2 H, m), 6.99 (1 H, d, J =




8.7 Hz), 7.01 (2 H, d, J = 8.1 Hz), 7.18 (2 H, d, J = 8.1 Hz), 7.26-




7.55 (8 H, m), 7.87 (2 H, d, J = 6.6 Hz), 8.20 (1 H, d, J = 8.7 Hz),




8.28 (1 H, brs), 8.50 (1 H, brs).


1079
4-CNPh-
1H NMR (CDCl3) δ 2.33-2.41 (4 H, m, 2.56-2.62 (2 H, m), 2.87




2.92 (2 H, m), 3.38-3.42 (2 H, m), 3.50 (2 H, s), 3.56-3.60 (2 H, m),




6.91 (1 H, d, J = 8.9 Hz), 6.98-7.01 (2 H, m), 7.14-7.19 (2 H, m), 7.25-




7.35 (5 H, m), 7.71-7.75 (2 H, m), 7.99-8.02 (2 H, m), 8.17-8.29 (2 H, m),




8.75-8.97 (1 H, m).


1080
3-CH3OPh-
1H NMR (CDCl3) δ 2.33-2.41 (4 H, m), 2.56-2.62 (2 H, m), 2.90




2.95 (2 H, m), 3.38-3.42 (2 H, m), 3.51 (2 H, s), 3.60-3.63 (2 H, m),




3.83 (3 H, s), 6.90 (1 H, d, J = 8.7 Hz), 7.00-7.09 (3 H, m), 7.18 (2 H, d, J =




8.6 Hz), 7.26-7.44 (8 H, m), 8.19-8.23 (1 H, m), 8.29 (1 H, d, J = 2.8




Hz), 8.48 (1 H, brs).


1081
4-CH3Ph-
1H NMR (CDCl3) δ 2.33-2.40 (7 H, m), 2.56-2.62 (2 H, m), 2.90-




2.95 (2 H, m), 3.38-3.41 (2 H, m), 3.49 (2 H, s), 3.59-3.62 (2 H, m),




6.89 (1 H, d, J 8.7 Hz), 7.01 (2 H,d, J = 8.6 Hz), 7.16-7.32 (9 H, m),




7.78 (2 H, d, J = 8.2 Hz), 8.18-8.22 (1 H, m), 8.27 (1 H, d, J = 2.6 Hz),




8.33-8.44 (1 H, m).


1082
2-CH3Ph-
1H NMR (CDCl3) δ 2.32-2.40 (4 H, m), 2.48 (3 H, s), 2.55-2.60 (2 H, m),




2.89-2.95 (2 H, m), 3.37-3.40 (2 H, m), 3.50 (2 H, s), 3.57-3.60 (2 H, m),




6.89-6.92 (1 H, m), 7.00-7.05 (2 H, m), 7.18-7.47 (10 H, m), 7.45 (1 H, d,




J = 2.2 Hz), 8.04 (1 H, brs), 8.23-8.25 (2 H, m).


1083
4-CH3OPh-
1H NMR (CDCl3) δ 2.31-2.38 (4 H, m), 2.54-2.60 (2 H, m), 2.87-




2.93 (2 H, m); 3.37-3.40 (2 H, m), 3.48 (2 H, s), 3.58-3.61 (2 H, m),




3.82 (3 H, s), 6.84-6.90 (3 H, m), 6.99 (2 H, d, J = 8.4 Hz), 7.15 (2 H, d, J =




8.6 Hz), 7.25-7.32 (5 H, m), 7.85 (2 H, d, J = 8.9 Hz), 8.17 (1 H, dd, J =




8.9 Hz, 2.7 Hz), 8.28 (1 H, d, J = 2.7 Hz), 8.73 (1 H, brs).


1084
2-CH3OPh-
1H NMR (CDCl3) δ 2.33-2.42 (4 H, m), 2.58-2.64 (2 H, m), 2.93-




2.99 (2 H, m), 3.38-3.42 (2 H, m), 3.49 (2 H, s), 3.61-3.65 (2 H, m),




8.23-8.29 (3 H, m), 9.76 (1 H, s).


1085
2-naphthyl
mp 156-159


1086
4-CF3Ph-
1H NMR (DMSO-d6) δ 2.30-2.32 (4 H, m), 2.59-2.65 (2 H, m), 2.79-




2.84 (2 H, m), 3.44-3.47 (6 H, m), 7.02 (2 H, d, J = 8.6 Hz), 7.05 (1 H, d,




J = 9.1 Hz), 7.25-7.35 (7 H, m), 7.93 (2 H, d, J = 8.3 Hz), 8.16 (2 H, d, J =




8.3 Hz), 8.21 (1 H, dd, J = 8.9 Hz, 2.6 Hz), 8.49 (1 H, d, J = 2.6 Hz),




10.62 (1 H, brs).
















TABLE 242













 











Example






No.
R759
R760
Form
mp (° C.) or 1H NMR





1087
4-CF3OPh-
benzyl
maleate
mp 144-146


1088
3-CF3OPh-
benzyl
maleate
mp 125-128


1089
4-CF3OPh-
piperonyl
free
mp 187-190


1090
2-CF3OPh-
piperonyl
free
1H NMR (CDCl3) δ 2.31-2.39 (4 H, m), 2.57-






2.63 (2 H, m), 2.91-2.97 (2 H, m), 3.37-






3.40 (4 H, m), 3.58-3.62 (2 H, m), 5.93 (2 H, s),






6.70-6.76 (2 H, m), 6.84 (1 H, s), 6.93 (1 H, d, J =






8.9 Hz), 7.03-7.07 (2 H, m), 7.19-7.23 (2 H,






m), 7.32-7.36 (1 H, m), 7.40-7.46 (1 H, m),






7.53-7.59 (1 H, m), 7.99-8.03 (1 H, m),






8.20 (1 H, dd, J = 8.9 Hz, 2.7 Hz), 8.27 (1 H, d,






J = 2.7 Hz), 8.55 (1 H, brs).


1091
3-CF3OPh-
piperonyl
free
1H NMR (CDCl3) δ 2.30-2.36 (4 H, m), 2.55-






2.61 (2 H, m), 2.86-2.92 (2 H, m), 3.37






3.40 (4 H, m), 3.56-3.60 (2 H, m), 5.93 (2 H, s),






6.69-6.76 (2 H, m), 6.83 (1 H, s), 6.88-6.92 (1 H,






m), 6.98-7.02 (2 H, m), 7.14-7.18 (2 H, m),






7.36-7.40 (1 H, m), 7.44-7.52 (1 H, m), 7.78-






7.85 (2 H, m), 8.19 (1 H, dd, J = 8.9 Hz, 2.7






Hz), 8.29-8.31 (1 H, m), 8.78-8.92 (1 H, m).


1092
3,5-Cl2Ph-
piperonyl
dihydro-
1H NMR (DMSO-d6) δ 2.69-3.33 (10 H, m),





chloride
3.99-4.11 (1 H, m), 4.23 (2 H, s), 4.44-4.49 (1 H,






m), 6.07 (2 H, s), 6.97-7.07 (5 H, m), 7.20-






7.30 (3 H, m), 7.89-8.00 (1 H, m), 8.00 (2 H, d, J =






1.8 Hz), 8.19 (1 H, dd, J = 8.9 Hz, 2.6 Hz),






8.48 (1 H, d, J = 2.3 Hz), 10.64 (1 H, s).


1093
PhCH═CH—
piperonyl
free
1H NMR (CDCl3) δ 2.05-3.38 (9 H, m), 3.69-



(trans)


4.71 (5 H, m), 5.96 (2 H, s), 6.72-6.79 (2 H, m),






6.95-7.05 (4 H, m), 7.13-7.23 (3 H, m), 7.35-






7.37 (3 H, m), 7.51-7.5.4 (2 H, m), 7.70-






7.76 (1 H, m), 8.41 (1 H, d, J 2.3 Hz),






8.50 (1 H, d, J = 8.7 Hz), 8.95 (1 H, brs).


1094
2-naphthyl
piperonyl
free
1H NMR (CDCl3) δ 2.28-2.34 (4 H, m), 2.55-






2.61 (2 H, m), 2.89-2.95 (2 H, m), 3.38 (4 H,






brs), 3.58 (2 H, brs), 5.92 (2 H, s), 6.69-






6.76 (2 H, m), 6.83 (1 H, s), 6.92 (1 H, d, J = 8.6






Hz), 7.02 (2 H, d, J = 8.4 Hz), 7.18 (2 H, d, J =






8.4 Hz), 7.51-7.61 (2 H, m), 7.86-7.94 (4 H, m),






8.27 (1 H, dd, J = 8.6 Hz, 2.7 Hz), 8.33-






8.38 (2 H, m), 8.55 (1 H, brs).


1095
4-ClPh-
piperonyl
free
1H NMR (CDCl3) δ 2.31-2.41 (4 H, m), 2.59-






2.65 (2 H, m), 2.94-3.00 (2 H, m), 3.38-






3.41 (4 H, m), 3.63 (2 H, brs), 5.94 (2 H, s), 6.71-






6.77 (2 H, m), 6.85 (1 H, s), 6.95 (1 H, d, J = 8.9






Hz), 7.05 (2 H, d, J = 8.4 Hz), 7.23 (2 H, d, J =






8.4 Hz), 7.48 (2 H, d, J = 8.6 Hz), 7.82-






7.89 (3 H, m), 8.19-8.25 (2 H, m).
















TABLE 243













 













Example








No.
R761
R762
R763
R764
R765
1H NMR (CDCl3) δ ppm





1096
4-CF3Ph-
—H
—H
—OH
—COOC(CH3)3
1.44 (9 H, s), 2.82-3.00 (2 H, m),








3.00-3.80 (9 H, m), 4.60 (1 H, t, J =








6.5 Hz), 6.97 (1 H, d, J = 8.8 Hz),








7.06 (2 H, d, J = 8.6 Hz), 7.24 (2 H,








d, J = 8.6 Hz), 7.75 (2 H, d, J = 8.1








Hz), 8.00 (2 H, d, J = 8.1 Hz),








8.07 (1 H, brs), 8.18 (1 H, d, J = 2.6








Hz), 8.27 (1 H, dd, J = 8.8 Hz, 2.6








Hz).


1097
4-CF3Ph-
—H
—CH3
—H
piperonyl
2.32 (3 H, s), 2.32-2.40 (4 H, m),








2.59-2.64 (2 H, m), 2.93-2.98 (2 H,








m), 3.30-3.45 (4 H, m), 3.55-








3.70 (2 H, m), 5.94 (2 H, s), 6.65-








6.75 (2 H, m), 6.82-6.84 (2 H, m),








7.03-7.07 (2 H, m), 7.20-7.24 (2 H,








m), 7.72 (1 H, brs), 7.75-7.79 (2 H,








m), 8.00-8.04 (2 H, m), 8.30 (1 H, s).


1098
4-CF3Ph-
—CH3
—H
—H
piperonyl
2.31-2.40 (4 H, m), 2.47 (3 H, s),








2.59-2.65 (2 H, m), 2.94-3.00 (2 H,








m), 3.38-3.41 (4 H, m), 3.60-








3. 65 (2 H, m), 5.94 (2 H, s), 6.68-








6.77 (3 H, m), 6.84 (1 H, s), 7.04-








7.08 (2 H, m), 7.20-7.24 (2 H, m),








7.63 (1 H, brs), 7.77-7.80 (2 H, m),








7.99-8.11 (3 H, m).


1099
3,4-
—CH3
—H
—H
piperonyl
2.25-2.40 (4 H, m), 2.45 (3 H, s),



Cl2Ph-




2.58-2.64 (2 H, m), 2.92-2.98 (2 H,








m), 3.38-3.41 (4 H, m), 3.60-








3.64 (2 H, m), 5.94 (2 H, s), 6.66-








6.76 (3 H, m), 6.84 (1 H, s), 7.03-








7.07 (2 H, m), 7.18-7.22 (2 H, m),








7.59 (1 H, d, J = 8.3 Hz), 7.67 (1 H,








brs), 7.72 (1 H, dd, J = 8.4 Hz, 2.0








Hz), 7.98-8.02 (2 H, m).


1100
3,4-
—H
—CH3
—H
piperonyl
2.31 (3 H, s), 2.31-2.40 (4 H, m),



Cl2Ph-




2.58-2.64 (2 H, m), 2.92-2.98 (2 H,








m), 3.37-3.41 (4 H, m), 3.60-








3.64 (2 H, m), 5.94 (2 H, s), 6.65-








6.75 (2 H, m), 6.80-6.84 (2 H, m),








7.03-7.06 (2 H, m), 7.20-7.24 (2 H,








m), 7.58 (1 H, d, J = 8.3 Hz),








7.64 (1 H, brs), 7.73 (1 H, dd, J =








8.3 Hz, 1.8 Hz), 8.01 (1 H, d, J =








1.9 Hz), 8.26 (1 H, s).
















TABLE 244













 












Example







No.
R766
R767
R768
R769
mp (° C.) or 1H NMR (solvent) δ ppm





1101
4-CF3Ph-
—H
—H
—Ac
mp 189-191


1102
3,4-Cl2Ph-
—H
—H
—COC2H5
mp 204-206


1103
3,4-Cl2Ph-
—H
—H
—H
mp 188-189


 


1104
3,4-Cl2Ph-
—H
—H




1H NMR (DMSO-d6) 0.60-0.70 (2 H, m), 0.75- 0.80 (2 H, m), 1.42 (1 H, m), 2.25-2.35 (4 H, m), 3.35-3.45 (6 H, m), 4.49 (2 H, s), 5.98 (2 H, s), 6.74 (1 H, d, J = 7.9 Hz), 6.84 (1 H, d, J = 7.9 Hz), 6.86 (1 H, s), 7.12 (1 H, d, J = 8.8 Hz), 7.18 (2 H, d, J = 8.6 Hz), 7.47 (2 H, d, J = 8.6 Hz), 7.84 (1 H, d, J = 8.4 Hz), 7.95 (1 H, dd, J = 8.4 Hz, 2.0 Hz), 8.20-8.23 (2 H, m), 8.5 1 (1 H, d, J = 2.5 Hz), 10.58 (1 H, s).


 


1105
4-CF3Ph-
—H
—H
—CH3
H NMR (DMSO-d6) 2.31-2.39 (4 H, m),







2.94 (3 H, s), 3.31 (2 H, s), 3.42 (4 H, brs),







4.24 (2 H, s), 5.99 (2 H, s), 6.64 (2 H, d, J = 9.1







Hz), 6.76 (1 H, dd, J = 7.9 Hz, 1.2 Hz), 6.84-







6.96 (5 H, m), 7.93 (2 H, d, J = 8.3 Hz),







8.13 (1 H, s), 8.16 (2 H, d, J = 8.6 Hz), 8.45 (1 H,







d, J = 2.5 Hz), 10.58 (1 H, s).


 


1106
3,4-Cl2Ph-
—H
—H




1H NMR (CDCl3) 0.57-0.62 (2 H, m), 0.75- 0.82 (2 H, m), 2.37-2.49 (4 H, m), 2.70-2.74 (1 H, m), 3.45 (2 H, s), 3.49-3.59 (4 H, m), 4.17 (2 H, s), 5.95 (2 H, s), 6.74-6.94 (8 H, m), 7.49 (1 H, d, J = 8.2 Hz), 7.67-7.71 (1 H, m), 7.95 (1 H, d, J = 2.1 Hz), 8.00 (1 H, dd, J = 8.9 Hz, 2.6 Hz), 8.24 (1 H, d, J 2.6 Hz), 8.59 (1 H, brs).


 


1107
4-CF3Ph-
—H
—H




1H NMR (CDCl3) 0.57-0.62 (2 H, m), 0.74- 0.81 (2 H, m), 2.35-2.47 (4 H, m), 2.66-2.74 (1 H, m), 3.44 (2 H, s), 3.47-3.57 (4 H, m), 4.16 (2 H, s), 5.94 (2 H, s), 6.70-6.94 (8 H, m), 7.66 (2 H, d, J = 8.2 Hz), 7.95 (2 H, d, J = 8.0 Hz), 8.04 (1 H, dd, J = 8.9 Hz, 2.6 Hz), 8.25 (1 H, d, J = 2.6 Hz), 8.80 (1 H, s).


 


1108
4-CF3Ph-
—CH3
—CH3
—CH3
1H NMR (CDCl3) 2.09 (3 H, s), 2.26 (3 H, s),







2.39 (4 H, brs), 2.67 (3 H, s), 3.41 (2 H, s), 3.53







3.63 (4 H, m), 3.74 (2 H, s), 5.94 (2 H, s), 6.71-







6.77 (2 H, m), 6.85-6.90 (3 H, m), 6.98 (1 H, d, J =







8.7 Hz), 7.75 (2 H, d, J = 8.2 Hz), 7.98-8.01







(3 H, m), 8.18 (1 H, dd, J = 8.9 Hz, 2.8 Hz),







8.25 (1 H, d, J = 2.3 Hz).


1109
3,4-Cl2Ph-
—CH3
—CH3
—CH3
1H NMR (CDCl3) 2.09 (3 H, s), 2.25 (3 H, s),







2.37-2.40 (4 H, m), 2.66 (3 H, s), 3.41 (2 H, s),







3.53-3.63 (4 H, m), 3.73 (2 H, s), 5.94 (2 H, s),







6.70-6.77 (2 H, m), 6.84-6.89 (3 H, m), 6.96 (1 H,







d, J = 8.7 Hz), 7.56 (1 H, d, J = 8.2 Hz), 7.70-







7.74 (1 H, m), 7.99 (1 H, d, J = 2.0 Hz), 8.10-







8.16 (2 H, m), 8.24 (1 H, d, J = 2.8 Hz).
















TABLE 245













 












Example







No.
R770
R771
R772
Form
mp (° C.) or 1H NMR (solvent) δ ppm





1110
4-CF3Ph-
—OCH3
—C2H5
free
mp 142.6-146.5


1111
4-CF3Ph-
—CH3
—C2H5
hydrochloride
mp 173-175 dec


1112
3,4-Cl2Ph-
—CH3
—C2H5
hydrochloride
mp 168.5-171.0


1113
2,3-Cl2Ph-
—CH3
—CH3
free
1H NMR (CDCl3) 2.12 (3H, s),







2.41-2.45 (4H, m), 3.01 (3H, s), 3.43







(2H, s), 3.50 (2H, s), 3.63 (2H, brs),







4.07 (2H, s), 5.95 (2H, s), 6.52-6.58







(2H, m), 6.71-6.77 (2H, m), 6.81-6.93







(3H, m), 7.32 (1H, t, J = 7.8 Hz), 7.56-







7.61 (2H, m), 7.68 (1H, brs), 8.16 (1H,







dd, J = 8.7 Hz, 2.8 Hz), 8.20 (1H, d,







J = 2.2 Hz).


1114
3,4-Cl2Ph-
—OCH3
—H
free
1H NMR (DMSO-d6) 2.32-2.40 (4H,







m), 3.42 (2H, s), 3.51 (4H, brs), 3.63







(3H, s), 3.91 (2H, d, J = 4.8 Hz), 5.54







(1H, t, J = 4.8 Hz), 5.99 (2H, s), 6.21







(1H, dd, J = 8.6 Hz, 2.5 Hz), 6.50 (1H,







d, J = 2.5 Hz), 6.76 (1H, dd, J = 7.9







Hz, 1.5 Hz), 6.82-6.88 (4H, m), 7.82







(1H, d, J = 8.4 Hz), 7.94 (1H, dd,







J = 8.4 Hz, 2.0 Hz), 8.07 (1H, dd,







J = 8.9 Hz, 2.6 Hz), 8.21 (1H, d,







J = 2.2 Hz), 8.37 (1H, d, J = 2.5 Hz),







10.44 (1H, s).


1115
4-CF3Ph-
—OCH3
—H
free
1H NMR (CDCl3) 2.32-2.40 (4H, m),







3.42 (2H, s), 3.50 (4H, brs), 3.63 (3H,







s), 3.91 (2H, d, J = 4.6 Hz), 5.55 (1H,







brt), 5.99 (2H, s), 6.20 (1H, dd, J = 8.6







Hz, 2.5 Hz), 6.49 (1H, d, J = 2.3 Hz),







6.74-6.88 (5H, m), 7.92 (2H, d, J = 8.4







Hz), 8.07-8.17 (3H, m), 8.38 (1H, d,







J = 2.3 Hz), 10.53 (1H, s).


 


1116
4-CF3Ph-
—CH3




free
 1H NMR (CDCl3) 0.59-0.64 (2H, m), 0.76-0.82 (2H, m), 2.08 (3H, s), 2.37-2.47 (4H, m), 2.69-2.77 (1H, m), 3.44 (2H, s), 3.48-3.59 (4H, m), 4.16 (2H, s), 5.94 (2H, s), 6.67-6.77 (5H, m), 6.86 (2H, d, J = 8.6 Hz), 7.70 (2H, d, J = 8.2 Hz), 7.97 (2H, d, J = 8.1 Hz), 8.08 (1H, dd, J = 8.9 Hz, 2.8 Hz), 8.23 (1H, d, J = 2.8 Hz), 8.39 (1H, brs).


 


1117
3,4-Cl2Ph-
—CH3




free
 1H NMR (CDCl3) 0.59-0.65 (2H, m), 0.76-0.83 (2H, m), 2.08 (3H, s), 2.38-2.48 (4H, m), 2.71-2.78 (1H, m), 3.44 (2H, s), 3.49-3.59 (4H, m), 4.17 (2H, s), 5.95 (2H, s), 6.67-6.77 (5H, m), 6.85-6.88 (2H, m), 7.53 (1H, d, J = 8.2 Hz), 7.68-7.72 (1H, m), 7.96 (1H, d, J = 2.0 Hz), 8.02-8.07 (1H, m), 8.22-8.26 (2H, m).


 


1118




—CH3
—CH3
free
 1H NMR (CDCl3) 0.83-0.85 (2H, m), 1.07-1.08 (2H, m), 1.46-1.63 (1H, m), 2.10 (3H, s), 2.41-2.44 (4H, m), 3.00 (3H, s), 3.43 (2H, s), 3.47-3.49 (2H, m), 3.63 (2H, brs), 4.06 (2H, s), 5.94 (2H, s), 6.51-6.55 (2H, m), 6.70-6.77 (3H, m), 6.85 (1H, brs), 6.89 (1H, d, J = 8.4 Hz), 7.44-7.64 (1H, m), 8.01-8.04 (1H, m), 8.08 (1H, d, J = 2.3 Hz).
















TABLE 246













 












Example







No.
R773
R774 
R775
Form
1H NMR (solvent) δ ppm





1119




—CH3
—CH3
hydrochloride
(DMSO-d6) 2.01 (3H, s), 2.80-3.18 (3H, m), 2.93 (3H, s), 3.35 (2H, s), 3.38-3.62 (1H, m), 3.95-4.50 (4H, m), 4.27 (2H, s), 6.08 (2H, s), 6.49 (1H, dd, J = 8.7 Hz, 2.7 Hz), 6.58 (1H, d, J = 2.7 Hz), 6.83 (1H, d, J = 8.7 Hz), 6.92 (1H, d, J = 8.9 Hz), 7.02 (2H, s), 7.21 (1H, s), 7.74 (1H, d, J = 8.4 Hz), 7.90 (1H, d, J = 8.4 Hz), 7.88-7.95 (1H, m), 8.11 (1H, dd, J = 8.9 Hz, 2.7 Hz), 8.36 (1H, d, J = 2.7 Hz), 10.71 (1H, s).


 


1120




—CH3
—CH3
free
 (CDCl3) 2.11 (3H, s), 2.42 (4H, brs), 3.00 (3H, s), 3.43 (2H, s), 3.47-3.49 (2H, m), 3.63 (2H, brs), 4.07 (2H, s), 5.95 (2H, s), 6.01 (2H, s), 6.37 (1H, d, J = 15.2 Hz), 6.52-6.56 (2H, m), 6.74-6.85 (5H, m), 6.91 (1H, d, J = 8.6 Hz), 7.00-7.02 (2H, m), 7.49 (1H, brs), 7.65 (1H, d, J = 15.3 Hz), 8.16-8.17 (2H, m).


 


1121




—CH3
—CH3
free
 (CDCl3) 2.09 (3H, s), 2.42-2.43 (4H, m), 3.00 (3H, s), 3.43 (2H, s), 3.47-3.50 (2H, m), 3.63 (2H, brs), 4.08 (2H, s), 5.95 (2H, s), 6.49-6.61 (3H, m), 6.70-6.91 (6H, m), 7.01-7.03 (2H, m), 7.63 (1H, d, J = 15.3 Hz), 7.98 (1H, brs), 8.16-8.19 (2H, m).


 


1122




—CH3
—CH3
free
 (CDCl3) 2.17 (3H, s), 2.43 (4H, brs), 2.82 (3H, s), 3.01 (3H, s), 3.44 (2H, s), 3.50 (2H, brs), 3.63 (2H, brs), 4.08 (2H, s), 5.95 (2H, s), 6.53-6.57 (2H, m), 6.74 (2H, brs), 6.81 (1H, d, J = 8.9 Hz), 6.85 (1H, s), 6.92 (1H, d, J = 8.6 Hz), 7.52 (1H, brs), 7.73 (2H, d, J = 8.3 Hz), 8.04-8.09 (3H, m), 8.18 (1H, d, J = 2.8 Hz).


 


1123
4-CF3Ph-
—F
allyl
free
(CDCl3) 2.45 (4H, brs), 3.45 (2H, s),







3.45 (2H, brs), 3.64 (2H, brs), 3.99







(2H, d, J = 5.1 Hz), 4.05 (2H, s),







5.18-5.28 (2H, m), 5.83-5.93 (1H,







m), 5.95 (2H, s), 6.36-6.47 (2H, m),







6.75 (2H, s), 6.86-6.87 (1H, m), 6.96







(1H, d, J = 9.1 Hz), 7.03 (1H, t,







J = 8.9 Hz), 7.75-7.78 (3H, m), 7.99







(2H, d, J = 8.1 Hz), 8.15-8.22 (2H,







m).


 


1124




—CH3
—CH3
free
 (CDCl3) 0.83-0.87 (1H, m), 1.19-1.22 (7H, m), 1.37-1.42 (1H, m), 2.10 (3H, s), 2.41-2.44 (4H, m), 3.00 (3H, s), 3.43 (2H, s), 3.48 (2H, brs), 3.63 (2H, brs), 4.06 (2H, s), 5.94 (2H, s), 6.51-6.56 (2H, m), 6.70-6.77 (3H, m), 6.85-6.91 (2H, m), 7.40 (1H, brs), 8.05-8.06 (2H, m).
















TABLE 247













 













Example








No.
R776
R777
R778
R779
M
mp (° C.) or 1H NMR





1125
4-CF3Ph-
—F
—F
—CH3
1
mp 160.0-161.5


1126
3,4-Cl2Ph-
—F
—F
—CH3
1
mp 207-209


1127
4-CF3Ph-
—F
—F
—C2H5
1
1H NMR (DMSO-d6) δ 1.07 (3H, t, J = 7.0








Hz), 2.20-2.41 (4H, m), 3.20-3.30 (2H, m),








3.39 (2H, s), 3.39-3.52 (4H, m), 4.11 (2H, s),








5.97 (2H, s), 6.71-6.76 (1H, m), 6.78-6.88 (3H,








m), 7.09-7.19 (2H, m), 7.92 (2H, d, J = 8.4








Hz), 8.15 (2H, d, J = 8.4 Hz), 8.20 (1H, dd,








J = 2.7 Hz, 9.0 Hz), 8.42 (1H, d, J = 2.7 Hz).


1128
3,4-Cl2Ph-
—CH3
—CH3
—C2H5
1
1H NMR (DMSO-d6) δ 0.95 (3H, t, J = 7.0








Hz), 2.01 (3H, s), 2.19 (3H, s), 2.20-2.40 (4H,








m), 3.00 (2H, q, J = 7.0 Hz), 3.30-3.55 (6H,








m), 3.79 (2H, s), 5.98 (2H, s), 6.74 (1H, dd,








J = 7.9 Hz, 1.4 Hz), 6.82-6.86 (3H, m), 6.97








(1H, d, J = 8.9 Hz), 7.05 (1H, s), 7.84 (1H, d,








J = 8.4 Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.0 Hz),








8.15 (1H, dd, J = 8.9 Hz, 2.7 Hz), 8.21 (1H, d,








J = 2.0 Hz), 8.42 (1H, d, J = 2.6 Hz), 10.51








(1H, brs).


1129
4-CF3Ph-
—CH3
—CH3
—C2H5
1
1H NMR (DMSO-d6) δ 0.95 (3H, t, J = 7.0








Hz), 2.02 (3H, s), 2.19 (3H, s), 2.20-2.40 (4H,








m), 3.00 (2H, q, J = 7.0 Hz), 3.30-3.60 (6H,








m), 3.79 (2H, s), 5.98 (2H, s), 6.74 (1H, d,








J = 7.9 Hz), 6.82-6.85 (3H, m), 6.98 (1H, d,








J = 8.6 Hz), 7.05 (1H, s), 7.91-7.95 (2H, m),








8.14-8.20 (3H, m), 8.44 (1H, d, J = 1.8 Hz),








10.59 (1H, brs).


1130
4-CF3Ph-
—OCH3
—H
—H
2
1H NMR (CDCl3) δ 2.44 (4H, brs), 3.43 (4H,








brs), 3.49 (2H, s), 3.66 (3H, s), 3.83 (2H, brs),








4.25 (4H, s), 4.67 (1H, brs), 6.10 (1H, dd,








J = 8.6 Hz, 2.5 Hz), 6.23 (1H, d, J = 2.5 Hz),








6.75-6.96 (5H, m), 7.67 (2H, d, J = 8.3 Hz),








7.96 (2H, d, J = 8.1 Hz), 8.10 (1H, dd, J = 8.9








Hz, 2.6 Hz), 8.20-8.24 (1H, m), 8.56 (1H, s).
















TABLE 248













 












Example




mp (° C.) or 1H NMR (solvent) δ


No.
R780
R781
R782
R783
ppm





1131




—CH3
—H
—H
1H NMR (CDCl3) 2.13 (3H, s), 2.43 (4H, t, J = 4.8 Hz), 3.02 (3H, s), 3.44 (2H, s), 3.50 (2H, brs), 3.64 (2H, brs), 4.08 (2H, s), 5.94 (2H, s), 6.53-6.58 (2H, m), 6.74 (2H, brs), 6.83 (1H, d, J = 8.9 Hz), 6.85 (1H, s), 6.93 (1H, d, J = 8.4 Hz), 7.42 (1H, dd, J = 8.9 Hz, 2.0 Hz), 7.50 (1H, d, J = 8.9 Hz), 7.53 (1H, s), 7.69 (1H, d, J = 1.8 Hz), 8.19 (1H, dd, J = 8.9 Hz, 2.8 Hz), 8.26 (1H, brs), 8.31 (1H, d, J = 2.6 Hz).


 


1132
3,4-Cl2Ph-
—F
—F
—H
mp 203.5-204.5


1133
4-CF3Ph-
—F
—F
—H
mp 230.0-231.5


1134
4-ClPh-
—CH3
—H
—H
1H NMR (CDCl3) 2.08 (3H, s), 2.42







(4H, brs), 2.97 (3H, s), 3.43 (2H, s),







3.49 (2H, brs), 3.60 (2H, brs), 4.05







(2H, s), 5.94 (2H, s), 6.48-6.52 (2H,







m), 6.74-6.89 (5H, m), 7.41 (2H, d,







J = 8.6 Hz), 7.80 (2H, d, J = 8.4 Hz),







8.08 (1H, dd, J = 8.9 Hz, 2.8 Hz),







8.21 (1H, d, J = 2.6 Hz), 8.29 (1H,







s).


 


1135




—CH3
—H
—H
 1H NMR (CDCl3) 2.11 (3H, s), 2.43-2.44 (4H, m), 3.00 (3H, s), 3.43 (2H, s), 3.47-3.49 (2H, m), 3.63 (2H, brs), 4.07 (2H, s), 5.95 (2H, s), 6.51-6.57 (2H, m), 6.69-6.93 (6H, m), 7.19 (1H, dd, J = 8.7 Hz, 7.5 Hz), 7.35-7.38 (2H, m), 7.55 (1H, brs), 7.86 (1H, d, J = 15.8 Hz), 8.17-8.20 (2H, m).


 


1136




—CH3
—H
—H
 1H NMR (CDCl3) 2.10 (3H, s), 2.43 (4H, brs), 3.00 (3H, s), 3.43 (2H, s), 3.50 (2H, brs), 3.64 (2H, brs), 4.07 (2H, s), 5.95 (2H, s), 6.50-6.56 (2H, m), 6.67-6.92 (6H, m), 7.07-7.19 (2H, m), 7.31-7.36 (1H, m), 7.47-7.52 (1H, m), 7.73 (1H, brs), 7.80 (1H, d, J = 15.7 Hz), 8.14-8.20 (2H, m).


 


1137




—CH3
—H
—H
 1H NMR (CDCl3) 2.11 (3H, s), 2.41-2.44 (4H, m), 3.00 (3H, s), 3.43 (2H, s), 3.47-3.49 (2H, m), 3.63 (2H, brs), 4.06 (2H, s), 5.94 (2H, s), 6.09 (1H, d, J = 14.7 Hz), 6.51-6.56 (2H, m), 6.70-6.96 (7H, m), 7.30-7.55 (7H, m), 8.14 (1H, d, J = 2.5 Hz), 8.14 (1H, brs).


 


1138
4-CF3Ph-
—F
—H
—F
mp 169.0-170.0


1139
3,4-Cl2Ph-
—F
—H
—F
mp 138.0-139.0
















TABLE 249













 











Example






No.
R784
R785
R786
1H NMR (solvent) δ ppm





1140
3,4-Cl2Ph-
—CH3
—CH3
(DMSO-d6) 2.00 (3H, s), 2.93 (3H, s), 3.23 (1H, brs),






3.36 (1H, brs), 3.63 (1H, brs), 3.72 (1H, brs), 4.07 (1H,






s), 4.27 (1H, s), 4.29 (2H, s), 4.47 (2H, s), 5.99 (2H, s),






6.43-6.63 (2H, m), 6.77 (1H, dd, J = 8.0 Hz, 1.5 Hz),






6.77-6.88 (2H, m), 6.82 (1H, d, J = 8.8 Hz), 6.90 (1H, d,






J = 8.6 Hz), 7.83 (1H, d, J = 8.4 Hz), 7.94 (1H, dd,






J = 8.4 Hz, 2.0 Hz), 8.12 (1H, dd, J = 8.8 Hz, 2.6






Hz), 8.21 (1H, d, J = 2.0 Hz), 8.40 (1H, d, J = 2.6 Hz),






10.48 (1H, s).


1141
4-CF3Ph-
—CH3
—CH3
(CDCl3) 2.10 (3H, s), 2.90-3.06 (3H, m), 3.20-3.34 (2H,






m), 3.62-3.84 (2H, m), 4.08 (2H, s), 4.20-4.33 (2H, m),






4.52 (2H, s), 5.95 (2H, s), 6.53 (1H, dd, J = 8.6 Hz, 3.0






Hz), 6.58 (1H, d, J = 3.0 Hz), 6.67-6.79 (3H, m), 6.82






(1H, d, J = 8.9 Hz), 6.91 (1H, d, J = 8.1 Hz), 7.74






(2H, d, J = 8.2 Hz), 7.99 (2H, d, J = 8.2 Hz), 8.10






(1H, s), 8.15 (1H, dd, J = 9.2 Hz, 2.3 Hz), 8.22 (1H, d,






J = 2.3 Hz).


1142
3,4-Cl2Ph-
—OCH3
—C2H5
(CDCl3) 1.17 (3H, t, J = 6.4 Hz), 3.17-3.30 (2H, m),






3.32-3.52 (2H, m), 3.70 (3H, s), 3.62-3.86 (2H, m), 4.03






(2H, s), 4.29 (2H, s), 4.50 (2H, s), 5.95 (2H, s), 6.22






(1H, d, J = 8.9 Hz), 6.37 (1H, s), 6.70 (1H, d, J = 8.2






Hz), 6.75 (1H, s), 6.76 (1H, d, J = 8.9 Hz), 6.86 (1H, d,






J = 8.9 Hz), 6.94 (1H, d, J = 8.7 Hz), 7.54 (1H, d,






J = 8.4 Hz), 7.70 (1H, dd, J = 8.4 Hz, 2.0 Hz), 7.98 (1H,






d, J = 2.0 Hz), 8.08 (1H, s), 8.08 (1H, dd, J = 8.9 Hz,






2.3 Hz), 8.20 (1H, d, J = 2.3 Hz).


1143
4-CF3Ph-
—OCH3
—C2H5
(CDCl3) 1.18 (3H, t, J = 6.7 Hz), 3.16-3.33 (2H, m),






3.33-3.50 (2H, m), 3.72 (2H, s), 3.62-3.85 (3H, m), 4.04






(2H, s), 4.29 (2H, s), 4.50 (2H, s), 5.95 (2H, s), 6.23






(1H, dd, J = 8.7 Hz, 2.8 Hz), 6.38 (1H, s), 6.71 (1H, d,






J = 8.1 Hz), 6.76 (1H, s), 6.76 (1H, d, J = 8.7 Hz), 6.88






(1H, d, J = 8.7 Hz), 6.95 (1H, d, J = 8.7 Hz), 7.74 (2H,






d, J = 8.0 Hz), 7.99 (2H, d, J = 8.0 Hz), 8.03 (1H, s),






8.13 (1H, dd, J = 8.7 Hz, 2.4 Hz), 8.21 (1H, d, J = 2.4






Hz).
















TABLE 250













 













Example








No.
R787
R788
Xb16
Xb17
Form
1H NMR (solvent) δ ppm





1144
4-CF3Ph-
—H
—N(CH3)—
—CH(CH3)—
free
(CDCl3) 1.30 (3H, d, J = 6.3 Hz),








2.16-2.48 (4H, m), 2.77 (3H, s),








3.26-3.56 (3H, m), 3.39 (2H, s), 3.78








(1H, brs), 4.56 (1H, q, J = 6.6 Hz),








5.92 (2H, s), 6.68-6.77 (4H, m), 6.82








(1H, s), 6.91 (1H, d, J = 8.9 Hz),








7.04 (2H, d, J = 9.1 Hz), 7.76 (2H, d,








J = 8.2 Hz), 7.90 (1H, brs), 7.99 (2H,








d, J = 8.1 Hz), 8.17 (1H, dd, J = 8.9








Hz, 2.6 Hz), 8.25 (1H, d, J = 2.6








Hz).


1145
4-CF3Ph-
—CH3
—N(CH3)—
—CH(CH3)—
free
(CDCl3) 1.29 (3H, d, J = 6.6 Hz),








2.14 (3H, s), 2.14-2.22 (1H, m),








2.29-2.35 (2H, m), 2.48 (1H, brs),








2.76 (3H, s), 3.26-3.56 (3H, m), 3.39








(2H, s), 3.78 (1H, brs), 4.57 (1H, q,








J = 6.6 Hz), 5.93 (2H, s), 6.58-6.62








(2H, m), 6.68-6.75 (2H, m), 6.83








(1H, brs), 6.86 (1H, d, J = 8.9 Hz),








6.95 (1H, d, J = 9.2 Hz), 7.76 (2H, d,








J = 8.3 Hz), 7.90 (1H, brs), 7.99 (2H,








d, J = 8.3 Hz), 8.16 (1H, dd, J = 8.9








Hz, 2.8 Hz), 8.23 (1H, d, J = 2.5








Hz).


1146
3,4-Cl2Ph-
—H
—CH2—
—NH—
hydrochloride
(DMSO-d6) 2.78-3.10 (2H, m),








3.10-3.35 (4H, m), 4.00-4.19 (2H,








m), 4.18-4.32 (4H, m), 6.07 (2H, s),








6.95-7.10 (3H, m), 7.06 (2H, d, J =








8.6 Hz), 7.23 (1H, s), 7.30 (2H, d,








J = 8.6 Hz), 7.39 (1H, t, J = 5.5 Hz),








7.84 (1H, d, J = 8.4 Hz), 7.97 (1H,








dd, J = 8.4 Hz, 2.0 Hz), 8.19 (1H,








dd, J = 8.7 Hz, 2.6 Hz), 8.25 (1H, d,








J = 2.0 Hz), 8.48 (1H, d, J = 2.6 Hz),








10.62 (1H, s).


1147
4-CF3Ph-
—H
—CH2—
—NH—
hydrochloride
(DMSO-d6) 2.80-3.05 (2H, m),








3.11-3.38 (4H, m), 4.00-4.35 (4H,








m), 4.24 (2H, s), 6.07 (2H, s), 6.98








(1H, d, J = 8.7 Hz), 6.92-7.10 (2H,








m), 7.06 (2H, d, J = 8.6 Hz), 7.24








(1H, d, J = 1.3 Hz), 7.30 (2H, d,








J = 8.6 Hz), 7.35-7.45 (1H, m), 7.93








(2H, d, J = 8.3 Hz), 8.19 (2H, d,








J = 8.3 Hz), 8.22 (1H, dd, J = 8.7








Hz, 2.5 Hz), 8.51 (1H, d, J = 2.5








Hz), 10.70 (1H, s).
















TABLE 251













 











Example






No.
R789
R790
R791
1H NMR (solvent) δ ppm





1148
4-CF3Ph-
—CH3
—H
(CDCl3) 2.17 (3H, s), 2.50-2.55 (4H, m), 3.46 (2H, s),






3.71-3.74 (2H, m), 4.26 (2H, brs), 5.95 (2H, s),






6.74-6.75 (2H, m), 6.86 (1H, brs), 6.91-6.95 (1H, m),






7.04 (1H, d, J = 8.7 Hz), 7.43 (1H, dd, J = 8.7 Hz, 2.5






Hz), 7.56 (1H, d, J = 2.3 Hz), 7.76 (2H, d, J = 8.4 Hz),






7.94 (1H, brs), 7.99 (2H, d, J = 8.1 Hz), 8.20-8.23 (2H,






m), 9.17 (1H, brs).


1149
3,4-Cl2Ph-
—CH3
—H
(CDCl3) 2.18 (3H, s), 2.50-2.56 (4H, m), 3.47 (2H, s),






3.72-3.75 (2H, m), 4.25-4.29 (2H, m), 5.96 (2H, s), 6.75






(2H, m), 6.86 (1H, brs), 6.93 (1H, d, J = 8.7 Hz), 7.04






(1H, d, J = 8.7 Hz), 7.44 (1H, dd, J = 8.7 Hz, 2.6 Hz),






7.56-7.57 (1H, m), 7.58 (1H, d, J = 8.3 Hz), 7.70 (1H,






brs), 7.71 (1H, dd, J = 8.3 Hz, 2.1 Hz), 7.98 (1H, d,






J = 2.1 Hz), 8.15-8.47 (1H, m), 10.54 (1H, brs).


1150
3,4-Cl2Ph-
—CH3
—CH3
(DMSO-d6) 2.10-2.49 (7H, m), 3.26-3.57 (9H, m),






5.96-5.99 (2H, m), 6.69-6.89 (3H, m), 7.05-7.11 (2H,






m), 7.16-7.28 (1H, m), 7.30-7.37 (1H, m), 7.84 (1H, d,






J = 8.4 Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.18-8.22






(2H, m), 8.42-8.47 (1H, m), 10.54 (1H, brs).


1151
4-CF3Ph-
—CH3
—CH3
(DMSO-d6) 2.10-2.46 (7H, m), 3.26-3.57 (9H, m),






5.96-6.00 (2H, m), 6.69-6.89 (3H, m), 7.06-7.12 (2H,






m), 7.17-7.29 (1H, m), 7.31-7.37 (3H, m), 7.94 (1H, d,






J = 8.6 Hz), 8.16 (2H, d, J = 8.6 Hz), 8.21-8.25 (2H, m),






8.45-8.49 (1H, m), 10.61 (1H, brs).


1152
4-CF3Ph-
—H
—SO2CH3
(CDCl3) 2.45 (4H, brs), 3.19 (3H, s), 3.39 (2H, brs),






3.46 (2H, s), 3.62 (2H, brs), 4.52 (2H, s), 5.94 (2H, s),






6.74 (2H, brs), 6.84 (1H, brs), 7.00 (1H, d, J = 8.7 Hz),






7.10 (2H, d, J = 8.7 Hz), 7.57 (2H, d, J = 8.7 Hz), 7.75






(2H, d, J = 8.1 Hz), 8.00 (2H, d, J = 8.1 Hz), 8.15-8.24






(2H, m), 8.31 (1H, brs).


1153
3,4-Cl2Ph-
—CH3
—SO2CH3
(CDCl3) 2.16 (3H, s), 2.46 (4H, brs), 3.20 (3H, s), 3.40






(2H, brs), 3.47 (2H, s), 3.63 (2H, brs), 4.52 (2H, s), 5.94






(2H, s), 6.70-6.77 (2H, m), 6.83 (1H, brs), 6.95 (1H, d,






J = 9.1 Hz), 6.99 (1H, d, J = 8.7 Hz), 7.38-7.57 (3H, m),






7.71 (1H, dd, J = 8.4 Hz, 2.0 Hz), 7.97 (1H, d, J = 2.0






Hz), 8.11 (1H, brs), 8.17 (1H, dd, J = 8.9 Hz, 2.6 Hz),






8.25 (1H, d, J = 2.6 Hz).


1154
4-CF3Ph-
—CH3
—SO2CH3
(CDCl3) 2.18 (3H, s), 2.42-2.46 (4H, m), 3.21 (3H, s),






3.39-3.40 (2H, m), 3.44 (2H, s), 3.62 (2H, brs), 4.53






(2H, s), 5.94 (2H, s), 6.70-6.77 (2H, m), 6.84 (1H, brs),






6.96-7.03 (2H, m), 7.41-7.46 (2H, m), 7.76 (2H, d,






J = 8.2 Hz), 7.98-8.01 (3H, m), 8.21 (1H, dd, J = 8.7 Hz,






2.8 Hz), 8.26 (1H, d, J = 2.3 Hz).


1155
3,4-Cl2Ph-
—H
—SO2CH3
(CDCl3) 2.41-2.45 (4H, m), 3.19 (3H, s), 3.38 (2H, brs),






3.44 (2H, s), 3.61 (2H, brs), 4.52 (2H, s), 5.94 (2H, s),






6.72-6.74 (2H, m), 6.83 (1H, brs), 6.98 (1H, d, J = 8.7






Hz), 7.09 (2H, d, J = 8.7 Hz), 7.55 (1H, d, J = 8.4 Hz),






7.56 (2H, d, J = 8.7 Hz), 7.72 (1H, dd, J = 8.4 Hz, 2.1






Hz), 7.98 (1H, d, J = 2.1 Hz), 8.18 (1H, dd, J = 8.7 Hz,






2.8 Hz), 8.27 (1H, brs), 8.30 (1H, d, J = 2.1 Hz).
















TABLE 252













 











Example






No.
R792
R793
R794
1H NMR (CDCl3) δ ppm





1156
4-CF3Ph-
—H
—CH3
1.21 (3H, t, J = 6.8 Hz), 2.05-2.14 (1H, m), 2.44-2.51 (1H,






m), 2.70-2.74 (1H, m), 2.83-3.32 (6H, m), 3.55-3.59 (1H,






m), 3.84-4.08 (4H, m), 5.94 (2H, s), 6.66 (2H, d, J = 8.9






Hz), 6.74 (2H, brs), 6.81-6.85 (2H, m), 6.97 (2H, d, J = 8.4






Hz), 7.72 (2H, d, J = 8.3 Hz), 7.98 (2H, d, J = 8.3 Hz),






8.11 (1H, d, J = 9.1 Hz), 8.25 (1H, d, J = 2.5 Hz), 8.31






(1H, brs).


1157
4-CF3Ph-
—CH3
—H
1.26-1.39 (3H, m), 1.99-2.04 (1H, m), 2.13-2.17 (1H, m),






2.64-2.67 (1H, m), 2.79-2.83 (1H, m), 2.98 (4H, brs),






3.31-3.53 (3H, m), 3.97-4.66 (3H, m), 5.95 (2H, s), 6.64






(2H, d, J = 9.1 Hz), 6.74 (2H, brs), 6.82 (1H, d, J = 8.9






Hz), 6.87 (1H, brs), 6.96 (2H, d, J = 9.1 Hz), 7.71 (2H, d,






J = 7.9 Hz), 7.98 (2H, d, J = 8.3 Hz), 8.10 (1H, dd, J = 8.9






Hz, 2.5 Hz), 8.25 (1H, d, J = 2.5 Hz), 8.40 (1H, brs).


1158
3,4-Cl2Ph-
—H
—CH3
1.21 (3H, t, J = 6.8 Hz), 2.07-2.14 (1H, m), 2.43-2.52 (1H,






m), 2.70 (1H, brs), 2.83-3.32 (6H, m), 3.55-3.60 (1H, m),






3.83-4.08 (4H, m), 5.94 (2H, s), 6.64 (2H, d, J = 9.1 Hz),






6.74 (2H, brs), 6.81 (1H, d, J = 8.9 Hz), 6.85 (1H, brs),






6.96 (2H, d, J = 8.7 Hz), 7.53 (1H, d, J = 8.4 Hz), 7.71






(1H, dd, J = 8.3 Hz, 2.1 Hz), 7.98 (1H, d, J = 2.0 Hz), 8.05






(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.24 (1H, d, J = 2.5 Hz), 8.31






(1H, brs).


1159
3,4-Cl2Ph-
—CH3
—H
1.26-1.39 (3H, m), 1.99-2.17 (2H, m), 2.64-2.68 (1H, m),






2.79-2.84 (1H, m), 2.99 (4H, brs), 3.31-3.54 (3H, m),






4.01-4.68 (3H, m), 5.95 (2H, s), 6.64 (2H, d, J = 9.1 Hz),






6.74 (2H, brs), 6.81 (1H, d, J = 8.9 Hz), 6.87 (1H, brs),






6.96 (2H, d, J = 8.9 Hz), 7.53 (1H, d, J = 8.4 Hz), 7.71






(1H, dd, J = 8.4 Hz, 2.0 Hz), 7.98 (1H, d, J = 2.0 Hz), 8.06






(1H, dd, J = 8.9 Hz, 2.5 Hz), 8.24 (1H, d, J = 2.3 Hz), 8.26






(1H, brs).
















TABLE 253













 











Example






No.
R795
R796
R797
1H NMR (CDCl3) δ ppm





1160
3,4-Cl2Ph-
—H
—CH3
1.16-1.19 (6H, m), 2.04-2.14 (1H, m), 2.43-2.52 (1H, m),






2.66-2.74 (1H, m), 2.83-3.36 (5H, m), 3.59-3.63 (1H, m),






3.84-4.08 (4H, m), 5.94 (2H, s), 6.59 (2H, d, J = 8.9 Hz),






6.74 (2H, brs), 6.79 (1H, d, J = 8.9 Hz), 6.85 (1H, brs), 6.92






(2H, d, J = 8.9 Hz), 7.50 (1H, d, J = 8.4 Hz), 7.71 (1H, dd,






J = 8.4 Hz, 2.1 Hz), 7.98 (1H, d, J = 2.0 Hz), 8.03 (1H, dd,






J = 8.9 Hz, 2.6 Hz), 8.25 (1H, d, J = 2.3 Hz), 8.64 (1H, brs).


1161
4-CF3Ph-
—H
—CH3
1.09-1.15 (6H, m), 2.04-2.13 (1H, m), 2.43-2.51 (1H, m),






2.66-2.74 (1H, m), 2.83-3.38 (5H, m), 3.58-3.63 (1H, m),






3.84-4.08 (4H, m), 5.94 (2H, s), 6.61 (2H, d, J = 8.9 Hz),






6.74 (2H, brs), 6.81 (1H, d, J = 8.9 Hz), 6.85 (1H, brs), 6.94






(2H, d, J = 8.3 Hz), 7.71 (2H, d, J = 7.8 Hz), 7.99 (2H, d,






J = 8.1 Hz), 8.10 (1H, d, J = 9.1 Hz), 8.26 (1H, d, J = 2.5






Hz), 8.50 (1H, brs).


1162
3,4-Cl2Ph-
—CH3
—H
1.15 (3H, t, J = 7.1 Hz), 1.26-1.43 (3H, m), 2.00 (1H, brs),






2.13 (1H, brs), 2.64-2.68 (1H, m), 2.79-2.83 (1H, m),






3.02-4.68 (9H, m), 5.95 (2H, s), 6.61 (2H, d, J = 9.1 Hz),






6.74 (2H, brs), 6.81 (1H, d, J = 8.7 Hz), 6.87 (1H, brs), 6.94






(2H, d, J = 8.9 Hz), 7.53 (1H, d, J = 8.4 Hz), 7.71 (1H, dd,






J = 8.4 Hz, 2.1 Hz), 7.99 (1H, d, J = 2.0 Hz), 8.06 (1H, d,






J = 8.9 Hz), 8.25 (1H, d, J = 2.6 Hz), 8.32 (1H, brs).


1163
4-CF3Ph-
—CH3
—H
1.15 (3H, t, J = 6.9 Hz), 1.26-1.39 (3H, m), 1.99 (1H, brs),






2.13 (1H, brs), 2.63-2.67 (1H, m), 2.79-2.83 (1H, m),






3.00-4.67 (9H, m), 5.95 (2H, s), 6.61 (2H, d, J = 8.4 Hz),






6.74 (2H, brs), 6.82 (1H, d, J = 8.7 Hz), 6.87 (1H, brs), 6.95






(2H, d, J = 8.9 Hz), 7.71 (2H, d, J = 7.9 Hz), 7.99 (2H, d,






J = 8.1 Hz), 8.10 (1H, d, J = 8.3 Hz), 8.27 (1H, d, J = 2.5






Hz), 8.38 (1H, brs).
















TABLE 254













 










Example





No.
R798
R799
1H NMR (CDCl3) δ ppm





1164
4-CF3Ph—
—H
2.52 (4H, brs), 2.64 (4H, brs), 3.12 (2H, s), 3.45 (2H, brs), 5.94 (2H,





s), 6.75 (2H, brs), 6.86 (1H, brs), 6.95 (1H, d, J = 8.7 Hz), 7.11 (2H,





d, J = 8.9 Hz), 7.60 (2H, d, J = 8.9 Hz), 7.76 (2H, d, J = 8.3 Hz),





7.98 (1H, brs), 8.00 (2H, d, J = 8.3 Hz), 8.21 (1H, dd, J = 8.9 Hz,





2.8 Hz), 8.26 (1H, d, J = 2.5 Hz), 9.16 (1H, brs).


1165
3,4-Cl2Ph-
—H
2.52 (4H, brs), 2.62-2.64 (4H, m), 3.12 (2H, s), 3.45 (2H, brs), 5.95





(2H, s), 6.75 (2H, brs), 6.86 (1H, brs), 6.94 (1H, d, J = 8.7 Hz), 7.10





(2H, d, J = 8.9 Hz), 7.57 (1H, d, J = 8.4 Hz), 7.59 (2H, d, J = 8.9





Hz), 7.72 (1H, dd, J = 8.4 Hz, 2.1 Hz), 7.99 (2H, brs), 8.17 (1H, dd,





J = 8.9 Hz, 2.8 Hz), 8.25 (1H, d, J = 2.8 Hz), 9.17 (1H, brs).


1166
3,4-Cl2Ph-
—CH3
2.44 (8H, brs), 2.95 (2H, s), 3.26 (3H, s), 3.39 (2H, s), 5.92 (2H, s),





6.71 (2H, brs), 6.81 (1H, brs), 7.02 (1H, d, J = 8.7 Hz), 7.14-7.22





(4H, m), 7.58 (1H, d, J = 8.4 Hz), 7.77 (1H, dd, J = 8.4 Hz, 2.1 Hz),





8.05 (1H, d, J = 2.1 Hz), 8.27 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.32





(1H, d, J = 2.6 Hz), 8.33 (1H, brs).


1167
4-CF3Ph-
—CH3
2.50 (8H, brs), 2.95 (2H, s), 3.24 (3H, s), 3.47 (2H, s), 5.92 (2H, s),





6.72 (2H, brs), 6.81 (1H, brs), 7.02 (1H, d, J = 8.7 Hz), 7.13-7.21





(4H, m), 7.74 (2H, d, J = 8.4 Hz), 8.05 (2H, d, J = 8.1 Hz), 8.30





(1H, dd, J = 8.9 Hz, 2.5 Hz), 8.35 (1H, d, J = 2.3 Hz), 8.61 (1H,





brs).
















TABLE 255













 












Example







No.
R800
R801
M
Form
1H NMR (solvent) δ ppm





1168
3,4-Cl2Ph-
piperonyl
2
hydrochloride
(DMSO-d6) 2.60-2.61 (2H, m),







2.75-3.08 (6H, m), 3.22-3.60 (5H,







m), 4.03 (1H, d, J = 13.9 Hz), 4.20







(2H, d, J = 4.3 Hz), 4.46 (1H, d,







J = 13.9 Hz), 6.06 (2H, s), 6.73 (2H,







d, J = 8.9 Hz), 6.93-6.99 (5H, m),







7.20 (1H, brs), 7.83 (1H, d, J = 8.4







Hz), 7.96 (1H, dd, J = 8.4 Hz, 2.1







Hz), 8.14 (1H, dd, J = 8.9 Hz, 2.6







Hz), 8.23 (1H, d, J = 2.0 Hz), 8.45







(1H, d, J = 2.6 Hz), 10.57 (1H, brs),







11.00 (1H, brs).


1169
4-CF3Ph-
piperonyl
2
hydrochloride
(DMSO-d6) 2.60-2.62 (2H, m),







2.88-3.08 (6H, m), 3.23-3.60 (5H,







m), 4.01-4.06 (1H, m), 4.20-4.21







(2H, m), 4.43-4.49 (1H, m), 6.07







(2H, s), 6.73 (2H, d, J = 8.6 Hz),







6.94-6.99 (5H, m), 7.20 (1H, brs),







7.93 (2H, d, J = 8.2 Hz), 8.14-8.19







(3H, m), 8.47 (1H, d, J = 2.5 Hz),







10.64 (1H, brs), 11.00 (1H, brs).


1170
4-CF3Ph-
benzyl
0
free
(CDCl3) 2.25 (4H, t, J = 4.9 Hz),







3.19 (3H, s), 3.23 (4H, t, J = 4.9 Hz),







3.43 (2H, s), 6.95 (1H, d, J = 8.7







Hz), 7.08 (4H, s), 7.20-7.32 (5H, m),







7.75 (2H, d, J = 8.0 Hz), 8.02 (2H, d,







J = 8.0 Hz), 8.24 (1H, dd, J = 8.7







Hz, 2.5 Hz), 8.31 (1H, d, J = 2.5







Hz), 8.34 (1H, s).


1171
3,4-Cl2Ph-
benzyl
0
hydrochloride
(DMSO-d6) 2.70-3.00 (2H, m), 3.14







(3H, s), 2.95-3.30 (4H, m), 3.72 (2H,







d, J = 13.7 Hz), 4.29 (2H, s), 7.08







(1H, d, J = 8.7 Hz), 7.11 (2H, d,







J = 8.9 Hz), 7.23 (2H, d, J = 8.9 Hz),







7.39-7.48 (3H, m), 7.51-7.60 (2H,







m), 7.84 (1H, d, J = 8.5 Hz), 7.97







(1H, dd, J = 8.5 Hz, 2.0 Hz), 8.22







(1H, dd, J = 8.7 Hz, 2.6 Hz), 8.25







(1H, d, J = 20 Hz), 8.53 (1H, d,







J = 2.6 Hz), 10.67 (1H, s).
















TABLE 256













 











Example






No.
R802
R803
R804
1H NMR (CDCl3) δ ppm





1172
3,4-Cl2Ph-
—H
—CH3
2.34 (3H, s), 2.34-2.50 (4H, m), 2.78 (3H, s), 3.42 (2H, s),






3.50-3.70 (4H, m), 3.80 (2H, s), 5.95 (2H, s), 6.70-6.80






(2H, m), 6.85-6.89 (2H, m), 7.26-7.35 (1H, m), 7.40 (1H,






d, J = 2.8 Hz), 7.51 (1H, d, J = 8.9 Hz), 7.57-7.61 (2H, m),






7.74 (1H, dd, J = 8.3 Hz, 2.0 Hz), 8.01 (1H, d, J = 2.0 Hz),






8.29 (1H, s).


1173
4-CF3Ph-
—H
—CH3
2.36 (3H, s), 2.36-2.50 (4H, m), 2.79 (3H, s), 3.42 (2H, s),






3.50-3.65 (4H, m), 3.80 (2H, s), 5.94 (2H, s), 6.70-6.75






(2H, m), 6.85-6.90 (2H, m), 7.30 (1H, dd, J = 8.8 Hz, 2.7






Hz), 7.40 (1H, d, J = 2.8 Hz), 7.51 (1H, d, J = 8.8 Hz),






7.68 (1H, brs), 7.76-7.80 (2H, m), 8.01-8.04 (2H, m), 8.34






(1H, s).


1174
3,4-Cl2Ph-
—CH3
—H
2.30-2.44 (4H, m), 2.44 (3H, s), 2.79 (3H, s), 3.42 (2H, s),






3.50-3.65 (4H, m), 3.80 (2H, s), 5.95 (2H, s), 6.65-6.81






(3H, m), 6.85 (1H, s), 7.29 (1H, dd, J = 8.8 Hz, 2.8 Hz),






7.41 (1H, d, J = 2.7 Hz), 7.49 (1H, d, J = 8.8 Hz), 7.59






(1H, d, J = 8.3 Hz), 7.67 (1H, brs), 7.72 (1H, dd, J = 8.3






Hz, 2.1 Hz), 8.00 (1H, d, J = 2.0 Hz), 8.09 (1H, d, J = 8.7






Hz).


1175
4-CF3Ph-
—CH3
—H
 2.35-2.45 (4H, m), 2.45 (3H, s), 2.79 (3H, s), 3.42 (2H, s),






3.50-3.65 (4H, m), 3.80 (2H, s), 5.95 (2H, s), 6.65-6.82






(2H, m), 6.85 (1H, s), 7.30 (1H, dd, J = 8.8 Hz, 2.8 Hz),






7.41 (1H, d, J = 2.8 Hz), 7.50 (1H, d, J = 8.8 Hz), 7.72






(1H, brs), 7.77-7.80 (2H, m), 8.00-8.03 (2H, m), 8.15 (1H,






d, J = 8.6 Hz).
















TABLE 257













 













Example








No.
R805
R806
R807
R808
Form
1H NMR (DMSO-d6) δ ppm





1176
3,4-Cl2Ph-
—H
—H




free
3.14 (1H, dd, J = 14.0 Hz, 9.4 Hz), 3.40 (1H, dd, J = 14.0 Hz, 4.5 Hz), 4.93 (1H, dd, J = 9.4 Hz, 4.5 Hz), 7.07 (1H, d, J = 8.9 Hz), 7.07 (2H, d, J = 8.4 Hz), 7.29 (2H, d, J = 8.4 Hz), 7.84 (1H, d, J = 8.4 Hz), 7.95 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.20 (1H, dd, J = 8.9 Hz, 2.5 Hz), 8.22 (1H, d, J = 2.0 Hz), 8.48 (1H, d, J = 2.5 Hz), 10.56 (1H, s), 12.06 (1H, s).


 


1177
4-CF3OPh-
—CH3
—H




hydrochloride
2.09 (3H, s), 3.09 (1H, dd, J = 14.3 Hz, 9.6 Hz), 3.40 (1H, dd, J = 14.3 Hz, 4.3 Hz), 4.93 (1H, dd, J = 9.6 Hz, 4.3 Hz), 6.99 (1H, d, J = 8.1 Hz), 7.02 (1H, d, J = 8.9 Hz), 7.12 (1H, d, J = 8.1 Hz), 7.20 (1H, s), 7.55 (2H, d, J = 8.8 Hz), 8.10 (2H, d, J = 8.8 Hz), 8.20 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.44 (1H, d, J = 2.6 Hz), 10.54 (1H, s), 12.10 (1H, s).


 


1178
3,4-Cl2Ph-
—H
—CH3
morpholino
hydrochloride
1.70 (3H, d, J = 6.9 Hz), 2.94-3.01








(2H, m), 3.63-4.02 (6H, m), 4.50








(1H, t, J = 6.6 Hz), 7.13 (1H, d,








J = 9.1 Hz), 7.23 (2H, d, J = 8.7 Hz),








7.64 (2H, d, J = 8.7 Hz), 7.85 (1H, d,








J = 8.4 Hz), 7.96 (1H, dd, J = 8.4








Hz, 2.2 Hz), 8.23 (1H, dd, J = 8.9








Hz, 2.6 Hz), 8.24 (1H, d, J = 2.1








Hz), 8.54 (1H, d, J = 2.1 Hz), 10.63








(1H, brs), 10.89 (1H, brs).


1179
4-CF3Ph-
—H
—CH3
morpholino
hydrochloride
1.72 (3H, d, J = 6.6 Hz), 2.92 (2H,








brs), 3.35 (2H, brs), 3.69-3.99 (4H,








m), 4.49 (1H, brs), 7.14 (1H, d,








J = 8.7 Hz), 7.22 (2H, d, J = 8.3 Hz),








7.69 (2H, d, J = 8.3 Hz), 7.94 (2H, d,








J = 8.3 Hz), 8.20 (2H, d, J = 8.1 Hz),








8.28 (1H, d, J = 8.9 Hz), 8.58 (1H,








brs), 10.77 (1H, brs), 11.47 (1H, brs).


1180
Ph-
—H
—CH3
morpholino
hydrochloride
1.70 (3H, d, J = 6.8 Hz), 2.94 (2H,








brs), 3.38-3.43 (2H, m), 3.62-4.02








(4H, m), 4.50 (1H, t, J = 6.6 Hz),








7.12 (1H, d, J = 8.7 Hz), 7.22 (2H, d,








J = 8.6 Hz), 7.52-7.65 (5H, m),








7.96-8.00 (2H, m), 8.26 (1H, dd,








J = 8.7 Hz, 2.8 Hz), 8.56 (1H, d,








J = 2.8 Hz), 10.47 (1H, brs), 10.91








(1H, brs).


















TABLE 258





Example




No.
Chemical stracture
mp (° C.)







1181




203.0-204.0


 


1182




186.0-187.0


 


1183




165.0-166.0


 


1184




122.0-124.0


 


1185




155.0-157.0


 


1186




182.0-183.5


 


1187




117.0-118.0


 


1188




160.0-161.0
















TABLE 259













 












Example







No.
R809
R810
R811
Xb18
1H NMR (CDCl3) δ ppm





1189
4-CF3Ph-
—COOCH3
benzyl
—O—
2.62 (4H, brs), 3.23 (4H, brs), 3.58







(2H, s), 3.67 (3H, s), 6.95 (1H, d,







J = 9.7 Hz), 7.06-7.14 (2H, m),







7.26-7.36 (5H, m), 7.49 (1H, d,







J = 2.3 Hz), 7.74 (2H, d, J = 8.3 Hz),







7.87 (1H, s), 7.98 (2H, d, J = 8.1







Hz), 8.16-8.18 (2H, m).


1190
3,4-Cl2Ph-
—H
—COOC(CH3)3
—O—
1.49 (9H, s), 3.11 (4H, t, J = 4.8 Hz),







3.58 (4H, t, J = 4.8 Hz), 6.92 (1H, d,







J = 9.0 Hz), 6.96 (2H, d, J = 8.5 Hz),







7.06 (2H, d, J = 8.5 Hz), 7.58 (1H, d,







J = 8.5 Hz), 7.70 (1H, dd, J = 8.5







Hz, 2.0 Hz), 7.74 (1H, brs), 7.98







(1H, d, J = 2.0 Hz), 8.15 (1H, brd,







J = 9.0 Hz), 8.24 (1H, d, J = 2.5 Hz).


1191
4-CF3Ph-
—H
—COOC(CH3)3
—O—
1.49 (2H, s), 3.11 (4H, t, J = 5.0 Hz),







3.58 (4H, t, J = 5.0 Hz), 6.93 (1H, d,







J = 9.0 Hz), 6.96 (2H, d, J = 9.0 Hz),







7.06 (2H, d, J = 9.0 Hz), 7.77 (2H, d,







J = 8.0 Hz), 7.82 (2H, brs), 7.99 (2H,







d, J = 8.0 Hz), 8.19 (1H, dd, J = 9.0







Hz, 2.5 Hz), 8.25 (1H, d, J = 2.5







Hz).


1192
4-CF3Ph-
—H
—CH2COOC2H5
—N(CH3)—
1.30 (3H, t, J = 7.1 Hz), 2.77 (4H, t,







J = 5.0 Hz), 3.28 (4H, t, J = 5.0 Hz),







3.29 (2H, s), 3.42 (3H, s), 4.22 (2H,







q, J = 7.1 Hz), 6.47 (1H, d, J = 9.2







Hz), 6.96 (2H, d, J = 9.0 Hz), 7.15







(2H, d, J = 9.0 Hz), 7.69 (1H, brs),







7.70 (1H, d, J = 2.5 Hz), 7.74 (2H, d,







J = 8.1 Hz), 7.98 (2H, d, J = 8.1 Hz),







8.26 (1H, d, J = 2.5 Hz).
















TABLE 260













 












Example







No.
R812
R813
Xb19
Xb20
1H NMR (solvent) δ ppm





1193
3,4-Cl2Ph-
—COOC(CH3)3
—CO—
—CH2—
(CDCl3) 1.51 (9 H, s), 3.75 (2 H, m),







3.79 (2 H, m), 4.26 (2 H, s), 6.98 (1 H, d,







J = 8.8 Hz), 7.14 (2 H, dd, J = 6.9 Hz,







2.1 Hz), 7.28 (2 H, dd, J = 6.9 Hz, 2.1 Hz),







7.58 (1 H, d, J = 8.3 Hz), 7.72 (1 H,







dd, J = 8.3 Hz, 2.1 Hz), 7.99 (1 H, d,







J = 2.1 Hz), 8.13 (1 H, dd, J = 8.8 Hz,







2.7 Hz), 8.29 (1 H, d, J = 2.7 Hz).


1194
3,4-Cl2Ph-
piperonyl
—CH2—
—CO—
(DMSO-d6) 3.22-3.50 (4 H, m),







3.84 (2 H, s), 4.50 (2 H, s), 6.00 (2 H, s),







6.77 (1 H, dd, J = 8.0 Hz, 1.4 Hz),







6.84 (1 H, d, J = 1.4 Hz), 6.87 (1 H, d,







J = 8.0 Hz), 6.98 (2 H, d, J = 8.6 Hz),







6.97-7.06 (3 H, m), 7.84 (1 H, d, J = 8.4 Hz),







7.94 (1 H, dd, J = 8.4 Hz, 2.0 Hz), 







8.15 (1 H, dd, J = 8.9 Hz, 2.8 Hz),







8.22 (1 H, d, J = 2.0 Hz), 8.44 (1 H, d,







J = 2.3 Hz), 10.51 (1 H, s).


1195
4-CF3Ph-
piperonyl
—CH2—
—CO—
(DMSO-d6) 3.27-3.40 (2 H, m), 3.40-







3.50 (2 H, m), 3.85 (2 H, s), 4.50 (2 H, s),







6.00 (2 H, s), 6.77 (1 H, dd, J = 7.9 Hz,







1.5 Hz), 6.84 (1 H, d, J = 1.5 Hz),







6.88 (1 H, d, J = 7.9 Hz), 6.95-7.07 (5 H,







m), 7.93 (2 H, d, J = 8.1 Hz), 8.16 (2 H,







d, J = 8.1 Hz), 8.17 (1 H, dd, J = 8.8 Hz,







2.5 Hz), 8.46 (1 H, d, J = 2.5 Hz),







10.60 (1 H, s).
















TABLE 261













 











Example






No.
R814
R815
Xb21
1H NMR (CDCl3) δ ppm





1196
3,4-Cl2Ph-
—COOC2H5
—O—
1.28 (3 H, t, J = 7.0 Hz), 1.88-1.93 (2 H, m),






2.03 (2 H, brd, J = 10.0 Hz), 2.42 (1 H, m),






2.78 (1 H, t, J = 10.5 Hz), 3.59 (2 H, dt,






J = 12.5 Hz, 3.5 Hz), 4.16 (2 H, q, J = 7.0 Hz),






6.90 (1 H, d, J = 9.0 Hz), 6.95 (2 H, d, J = 9.0 Hz),






7.03 (2 H, d, J = 9.0 Hz), 7.58 (1 H, d,






J = 8.5 Hz), 7.70 (1 H, brs), 7.71 (1 H, dd, J = 8.5 Hz,






2.0 Hz), 7.98 (1 H, d, J = 2.0 Hz),






8.14 (1 H, dd, J = 9.0 Hz, 2.5 Hz), 8.24 (1 H, d,






J = 2.5 Hz).


1197
3,4-Cl2Ph-
—CH2COOC2H5
—O—
1.27 (3 H, t, J = 7.0 Hz), 1.40-1.46 (2 H, m),






1.82 (2 H, brd, J = 13.0 Hz), 1.90 (1 H, m),






2.27 (2 H, d, J = 7.0 Hz), 2.69 (2 H, brt,






J = 13.0 Hz), 3.57 (2 H, brd, J = 12.0 Hz), 4.15






(2 H, q, J = 7.0 Hz), 6.83 (1 H, d, J = 9.0 Hz),






6.90 (2 H, d, J = 9.0 Hz), 6.97 (2 H, d, J = 9.0 Hz),






7.49 (1 H, d, J = 8.5 Hz), 7.68 (1 H, dd,






J = 8.5 Hz, 2.0 Hz), 7.95 (1 H, d, J = 2.0 Hz),






8.10 (1 H, dd, J = 9.0 Hz, 2.5 Hz), 8.21 (1 H, d,






J = 2.5 Hz), 8.48 (1 H, brs).


1198
4-CF3Ph-
—CH2COOC2H5
—N(CH3)—
1.28 (3 H, t, J = 7.1 Hz), 1.46 (2 H, qd, J = 12.2 Hz,






3.4 Hz), 1.86 (2 H, d, J = 13.5 Hz), 1.85-






2.10 (1 H, m), 2.30 (2 H, d, J = 7.1 Hz),






2.76 (2 H, td, J = 12.2 Hz, 2.2 Hz), 3.42 (3 H,






s), 3.68 (2 H, d, J = 12.2 Hz), 4.16 (2 H, q,






J = 7.1 Hz), 6.46 (1 H, d, J = 9.0 Hz), 6.96 (2 H, d,






J = 8.9 Hz), 7.13 (2 H, d, J = 8.9 Hz), 7.72 (1 H,






dd, J = 9.0 Hz, 2.5 Hz), 7.73 (1 H, d, J = 2.5 Hz),






7.74 (2 H, d, J = 8.2 Hz), 7.98 (2 H, d,






J = 8.2 Hz), 8.26 (1 H, d, J = 2.5 Hz).


1199
4-CF3Ph-
—CH2COOC2H5
—O—
1.28 (3 H, t, J = 7.0 Hz), 1.44 (2 H, dq, J = 3.5 Hz,






12.0 Hz), 1.84 (2 H, brd, J = 13.0 Hz),






1.93 (1 H, m), 2.29 (2 H, d, J = 7.0 Hz),






2.73 (2 H, dt, J = 2.5 Hz, 12.0 Hz), 3.61 (2 H,






brd, J = 12.0 Hz), 4.15 (2 H, q, J = 7.0 Hz),






6.91 (1 H, d, J = 9.0 Hz), 6.96 (2 H, d, J = 9.0 Hz),






7.04 (2 H, d, J = 9.0 Hz), 7.74 (1 H, brs),






7.77 (2 H, d, J = 8.5 Hz), 7.99 (2 H, d, J = 8.5 Hz),






8.18 (1 H, dd, J = 9.0 Hz, 2.5 Hz),






8.25 (1 H, d, J = 2.5 Hz).


1200
4-CF3Ph-
—COOC2H5
—O—
1.26 (3 H, t, J = 7.1 Hz), 1.77-1.98 (4 H, m),






2.35-2.43 (1 H, m), 2.68-2.76 (2 H, m), 3.51-






3.55 (2 H, m), 4.14 (2 H, q, J = 7.1 Hz),






6.78 (1 H, d, J = 8.9 Hz), 6.85-6.95 (4 H, m),






7.61 (2 H, d, J = 8.2 Hz), 7.93 (2 H, d, J = 8.1 Hz),






8.09 (1 H, dd, J = 8.9 Hz, 2.6 Hz),






8.25 (1 H, d, J = 2.6 Hz), 9.00 (1 H, s).
















TABLE 262













 











Example






No.
R816
R817
R818
1H NMR (CDCl3) δ ppm





1201
4-CF3Ph-
—CH3




1.34-1.43 (2 H, m), 1.80-1.98 (3 H, m), 2.10 (3 H, s), 2.26 (2 H, d, J = 6.8 Hz), 2.38-2.44 (4 H, m), 2.66 (2 H, t, J = 12.2 Hz), 3.46-3.63 (8 H, m), 6.72-6.81 (3 H, m), 6.90 (1 H, d, J = 8.6 Hz), 7.26- 7.33 (5 H, m), 7.70 (2 H, d, J = 8.2 Hz), 8.00 (2 H, d, J = 8.1 Hz), 8.15 (1 H, dd, J = 8.9 Hz, 2.8 Hz), 8.25 (1 H, d, J = 2.5 Hz), 8.60 (1 H, s).


 


1202
4-CF3Ph-
—CH3




1.31-1.43 (2 H, m), 1.79-1.98 (3 H, m), 2.11 (3 H, s), 2.26 (2 H, d, J = 6.8 Hz), 2.36-2.39 (4 H, m), 2.66 (2 H, t, J = 12.0 Hz), 3.42 (2 H, s), 3.45-3.61 (6 H, m), 6.70-6.92 (7 H, m), 7.70 (2 H, d, J = 8.2 Hz), 7.99 (2 H, d, J = 8.1 Hz), 8.15 (1 H, dd, J = 8.9 Hz, 2.8 Hz), 8.25 (1 H, d, J = 2.5 Hz), 8.55 (1 H, s).


 


1203
3,4-Cl2Ph-
—CH3




1.29-1.41 (2 H, m), 1.77-1.98 (3 H, m), 2.09 (3 H, s), 2.26 (2 H, d, J = 6.8 Hz), 2.34-2.40 (4 H, m), 2.62 (2 H, t, J = 12.0 Hz), 3.41 (2 H, s), 3.46-3.60 (6 H, m), 6.70-6.90 (7 H, m), 7.49 (1 H, d, J = 8.4 Hz), 7.73 (1 H, dd, J = 8.2 Hz, 2.0 Hz), 7.99 (1 H, d, J = 2.0 Hz), 8.12 (1 H, dd, J = 8.9 Hz, 2.6 Hz), 8.25 (1 H, d, J = 2.6 Hz), 8.99 (1 H, s).


 


1204
3,4-Cl2Ph-
—CH3




1.29-1.41 (2 H, m), 1.77-1.98 (3 H, m), 2.09 (3 H, s), 2.26 (2 H, d, J = 6.8 Hz), 2.37-2.44 (4 H, m), 2.63 (2 H, t, J = 11.9 Hz), 3.48-3.63 (8 H, m), 6.70-6.78 (2 H, m), 6.88 (1 H, d, J = 8.6 Hz), 7.26- 7.33 (6 H, m), 7.48 (1 H, d, J = 8.4 Hz), 7.72 (1 H, dd, J = 8.4 Hz, 2.1 Hz), 7.99 (1 H, d, J = 2.1 Hz), 8.12 (1 H, dd, J = 8.9 Hz, 2.6 Hz), 8.26 (1 H, d, J = 2.6 Hz), 9.03 (1 H, s).


 


1205
4-CF3Ph-
—OCH3
—OC2H5
1.27 (3 H, t, J = 7.1 Hz), 1.39-1.42 (2 H,






m), 1.80-1.85 (3 H, m), 2.28 (2 H, d,






J = 6.9 Hz), 2.70 (3 H, t, J = 10.1 Hz),






3.56 (2 H, d, J = 12.2 Hz), 3.66 (3 H, s),






4.14 (2 H, q, J = 7.3 Hz), 6.43 (1 H, dd,






J = 8.7 Hz, 2.5 Hz), 6.51 (1 H, d, J = 2.5 Hz),






6.78 (1 H, d, J = 8.9 Hz), 6.90 (1 H,






d, J = 8.7 Hz), 7.63 (2 H, d, J = 8.6 Hz),






7.96 (2 H, d, J = 8.2 Hz), 8.08 (1 H, dd,






J = 8.9 Hz, 2.6 Hz), 8.18 (1 H, d, J = 2.6 Hz),






8.95 (1 H, s).
















TABLE 263













 










Example
R819
R820
mp (° C.) or 1H NMR (solvent) δppm





1206
3,4-
morpholino
1H NMR (DMSO-d6) 3.07-3.10(4 H, m), 3.73-



Cl2Ph-

3.77(4 H, m), 6.96-7.04(5 H, m), 7.83(1 H, d, J =





8.2 Hz), 7.94(1 H, dd, J = 8.2 Hz, 2.0 Hz),





8.15(1 H, dd, J = 8.9 Hz, 2.6 Hz), 8.22(1 H, d, J =





2.0 Hz), 8.45(1 H, d, J = 2.6 Hz), 8.;22(1 H, d, J =





2.0 Hz), 8.45(1 H, d, J = 2.6 Hz), 10.51(1 H,





brs).


 


1207
3,4- Cl2Ph-




1H NMR (CDCl3) 1.72-1.90(4 H, m), 2.40- 2.53(2 H, m), 3.20-3.32(2 H, m), 4.58(2 H, s), 6.95(1 H, d, J = 8.9 Hz), 7.08(2 H, d, J = 8.6 Hz), 7.27(2 H, d, J = 8.6 Hz), 7.58(1 H, d, J = 8.6 Hz), 7.73(1 H, dd, J = 8.6 Hz, 2.0 Hz), 8.01(1 H, d, J = 2.0 Hz), 8.11(1 H , s), 8.19(1 H, dd, J = 8.9 Hz, 2.3 Hz), 8.28(1 H, d, J = 2.3 Hz).


 


1208
4-CF3Ph-
—NHCONHPh
mp 240.0-240.5


 


1209
3,4- Cl2Ph-




1H NMR (CDCl3) 1.28(3 H, t, J = 7.0 Hz), 1.60- 1.70(2 H, m), 1.83(1 H, m), 2.03(1 H, m), 2.69(1 H, m), 2.82(1 H, brt, J = 12.0 Hz), 3.03(1 H, dd, J = 12.0 Hz, 10.0 Hz),3.42(1 H, brd, J = 12.0 Hz), 3.65(1 H, brd, J = 12.0 Hz), 41.7(2 H, q, J = 7.0 Hz), 6.90(1 H, d, J = 9.0 Hz), 6.97(2 H, d, J = 9.0 Hz), 7.03(2 H, d, J = 9.0 Hz), 7.58(1 H, d, J = 8.5 Hz), 7.70(1 H, dd, J = 8.5 Hz, 2.0 Hz), 7.75(1 H, s), 7.97(1 H, d, J = 2.0 Hz), 8.14(1 H, brd, J = 9.0 Hz), 8.23(1 H, d, J = 2.5 Hz).


 


1210
3,4- Cl2Ph-




1H NMR (DMSO-d6) 2.33-2.38(4 H, m), 2.65- 2.83(2 H, m), 3.41(2 H, s), 3.45-3.57(4 H, m), 3.65-3.75(1 H, m), 3.91-4.08(2 H, m), 6.00(2 H, s), 6.76(1 H, dd, J = 1.5 Hz, 8.1 Hz), 6.84- 6.88(2 H, m), 7.07(1 H, d, J = 8.9 Hz), 7.14(2 H, d, J = 8.9 Hz), 7.67(2 H, d, J = 9.1 Hz), 7.85(1 H, d, J = 8.4 Hz), 7.95(1 H, dd, J = 2.0 Hz, 8.4 Hz), 8.19(1 H, dd, J = 2.6 Hz, 8.9 Hz), 8.23(1 H, d, J = 2.1 Hz), 8.47(1 H, d, J = 2.6 Hz), 10.56(1 H, s).


 


1211
4-CF3Ph-




1H NMR (DMSO-d6) 2.33-2.38(4 H, m), 2.65- 2.83(2 H, m), 3.41(2 H, s), 3.51(4 H, brs), 3.65- 3.75(1 H, m), 3.91-4.08(2 H, m), 5.99(2 H, s), 6.76(1 H, dd, J = 1.3 Hz, 7.9 Hz), 6.84-6.88(2 H, m), ), 7.08(1 H, d, J = 8.9 Hz), 7.15(2 H, d, J = 6.9 Hz), 7.68(2 H, d, J = 6.9 Hz), 7.94(2 H, d, J = 8.6 Hz), 8.17(2 H, d, J = 8.1 Hz), 8.23(1 H, dd, J = 2.6 Hz, 8.9 Hz), 8.50(1 H, d, J = 2.6 Hz), 10.64(1 H, s).
















TABLE 264













 









Example




No.
R821
1H NMR (DMSO-d6) δ ppm





1212
3,4-Cl2Ph-
2.25-2.33 (4 H, m), 2.92 (3 H, s), 3.36 (2 H, s), 3.42 (4 H, brs), 4.23 (2 H, s),




5.98 (2 H, s), 6.29-6.32 (2 H, m), 6.42-6.45 (1 H, m), 6.70-6.74 (1 H, m),




6.80-6.84 (2 H, m), 6.97 (1 H, d, J = 8.9 Hz), 7.11-7.17 (1 H, m),




7.84 (1 H, d, J = 8.4 Hz), 7.95 (1 H, dd, J = 8.4 Hz, 2.0 Hz), 8.16-




8.22 (2 H, m), 8.52 (1 H, d, J = 2.5 Hz), 10.55 (1 H, s).


1213
4-CF3Ph-
2.26-2.33 (4 H, m), 2.92 (3 H, s), 3.37-3.41 (6 H, m), 4.23 (2 H, s),




5.98 (2 H, s), 6.29-6.34 (2 H, m), 6.42-6.45 (1 H, m), 6.70-6.74 (1 H, m),




6.80-6.84 (2 H, m), 6.98 (1 H, d, J = 8.9 Hz), 7.11-7.17 (1 H, m),




7.93 (2 H, d, J = 8.3 Hz), 8.16 (2 H, d, J = 8.1 Hz), 8.21 (1 H, dd,




J = 8.9 Hz, 2.6 Hz), 8.54 (1 H, d, J = 2.3 Hz), 10.63 (1 H, s).
















TABLE 265













 













Example








No.
R822
R823
Xb22
M
Form
1H NMR (solvent) δ ppm





1214
—CH3
piperonyl
—N(CH3)—
1
free
(CDCl3) 1.90 (3 H, s), 2.41-2.45 (4 H, m),








3.03 (3 H, s), 3.43 (2 H, s), 3.49( 2 H, brs),








3.63 (2 H, brs), 4.09 (2 H, s), 4.77 (2 H, s),








5.95 (2 H, s), 6.70 (2 H, d, J = 9.1 Hz),








6.74-6.75 (2 H, m), 6.81-6.85 (2 H, m),








7.00 (2 H, d, J = 9.1 Hz), 7.04 (1 H, dd,








J = 8.4 Hz, 2.1 Hz), 7.24 (1 H, dd, J = 8.7 Hz,








2.87 Hz), 7.31 (1 H, d, J = 2.1 Hz),








7.35 (1 H, d, J = 8.1 Hz), 7.83 (1 H, d,








J = 2.6 Hz).


1215
—C2H5
piperonyl
—N(CH3)—
1
free
(CDCl3) 1.08 (3 H, t, J = 7.4 Hz),








2.07 (2 H, q, J = 7.4 Hz), 2.41-2.45 (4 H,








m), 3.03 (3 H, s), 3.43 (2 H, s), 3.48 (2 H,








brs), 3.63 (2 H, brs), 4.09 (2 H, s),








4.77 (2 H, s), 5.95 (2 H, s), 6.70 (2 H, d,








J = 9.2 Hz), 6.73-6.74 (2 H, m), 6.82 (1 H,








d, J = 8.7 Hz), 6.85 (1 H, brs), 7.00 (2 H,








d, J = 9.1 Hz), 7.04 (1 H, dd, J = 8.3 Hz,








2.0 Hz), 7.22 (1 H, dd, J = 8.7 Hz, 2.8 Hz),








7.30 (1 H, d, J = 2.0 Hz), 7.34 (1 H,








d, J = 8.3 Hz), 7.82 (1 H, d, J = 2.5 Hz).


1216
—CH3
benzyl
none
0
hydro-
(DMSO-d6) 1.87 (3 H, s), 3.14 (2 H, brs),







chloride
3.37 (6 H, brs), 4.35 (2 H, s), 4.85 (2 H, s),








7.13 (1 H, d, J = 8.9 Hz), 7.22 (2 H, d,








J = 8.4 Hz), 7.41-7.58 (10 H, m), 7.80 (1 H,








dd, J = 8.9 Hz, 2.6 Hz), 8.03 (1 H, d,








J = 2.6 Hz), 10.88 (1 H, brs).









Example 1217
Production of 1H-indole-2-carboxylic acid {6-[4-(2,4-dioxothiazolidine-5-ylmethyl)-2-methylphenoxy]pyridin-3-yl}amide
To a solution of 5-[4-(5-aminopyridin-2-yloxy)-3-methylbenzyl]thiazolidine-2,4-dione (150 mg, 0.46 mmol) in DMF (5 mL) were added indole-2-carboxylic acid (74 mg, 0.46 mmol), 1-hydroxybenzotriazole monohydrate (70 mg, 0.46 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (110 mg, 0.57 mmol), and the resulting solution was stirred for 5 days at room temperature. This reaction solution was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, evaporated, and the residue was then purified by silica gel column chromatography (chloroform:methanol=30:1). To the obtained powdery substance was added ethanol, the resulting solution was filtered and the filtrate was washed with ethanol, to thereby yield 100 mg of the title compound.
Appearance: White powder
1H NMR (DMSO-d6) δ 2.10 (3H, s), 3.09 (1H, dd, J=14.2 Hz, 9.7 Hz), 3.40 (1H, dd, J=14.2 Hz, 4.2 Hz), 4.94 (1H, dd, J=9.7 Hz, 4.2 Hz), 6.99 (1H, d, J=8.2 Hz), 7.04 (1H, d, J=8.9 Hz), 7.05-7.16 (2H, m), 7.20 (1H, s), 7.24 (1H, dd, J=7.0 Hz, 1.0 Hz), 7.39 (1H, d, J=1.6 Hz), 7.46 (1H, d, J=8.2 Hz), 7.68 (1H, d, J=7.7 Hz), 8.21 (1H, dd, J=8.9 Hz, 2.8 Hz), 8.49 (1H, d, J=2.8 Hz), 10.37 (1H, s), 11.80 (1H, s), 12.09 (1H, s).
The following compounds were produced in the same manner as in Example 1217.







TABLE 266













 











Example






No.
R824
R825
Form
1H NMR (solvent) δ ppm





1218
3,4-(CH3)2Ph-
4-CH3OPhCH2—
free
(CDCl3) 2.34 (6 H, s), 2.45 (4 H, brs),






3.45 (2 H, s), 3.47-3.79 (4 H, m),






3.81 (3 H, s), 6.83-6.89 (2 H, m),






6.97 (1 H, d, J = 8.9 Hz), 7.11-7.16 (2 H,






m), 7.21-7.26 (3 H, m), 7.41-7.46 (2 H,






m), 7.59-7.62 (1 H, m), 7.67 (1 H, d,






J = 1.9 Hz), 7.92 (1 H, brs), 8.23-8.30 (1 H,






m), 8.31 (1 H, d, J = 2.4 Hz).


1219
2-(CH3)2NPh-
benzyl
trihydro-
(DMSO-d6) 3.07 (6 H, s), 3.17-3.48 (8 H,





chloride
m), 4.35 (2 H, s), 7.16-7.21 (3 H, m),






7.41-7.54 (6 H, m), 7.59-7.70 (4 H, m),






7.92 (1 H, d, J = 7.1 Hz), 8.27 (1 H, dd,






J = 2.8 Hz, 8.7 Hz), 8.55 (1 H, d, J = 2.1 Hz),






11.30 (1 H, s).


1220
3,5-(CH3)2Ph-
benzyl
hydro-
(DMSO-d6) 2.36 (6 H, s), 3.00-3.20 (2 H,





chloride
m), 3.20-3.40 (2 H, m), 3.47 (2 H, brs),






4.40 (2 H, brs), 4.33 (2 H, s), 7.13 (1 H, d,






J = 8.9 Hz), 7.19 (2 H, d, J = 8.6 Hz),






7.24 (1 H, s), 7.40-7.70 (7 H, m),






7.51 (2 H, d, J = 8.6 Hz), 8.26 (1 H, dd,






J = 8.9 Hz, 2.6 Hz), 8.56 (1 H, d, J = 2.6 Hz),






10.41 (1 H, s).


1221
2,3-(CH3O)2Ph-
benzyl
hydro-
(DMSO-d6) 3.00-3.65 (6 H, m), 3.80 (3 H,





chloride
s), 3.86 (3 H, s), 4.20 (2 H, brs), 4.33 (2 H,






brs), 7.09-7.25 (6 H, m), 7.40-7.80 (7 H,






m), 8.23 (1 H, dd, J = 8.9 Hz, 2.3 Hz),






8.52 (1 H, d, J = 2.3 Hz), 10.43 (1 H, s).


1222
4-(CH3)2NPh-
benzyl
free
(CDCl3) 2.48 (4 H, brs), 3.06 (6 H, s),






3.55 (2 H, s), 3.70 (4 H, brs), 6.71 (2 H, d,






J = 9.0 Hz), 6.96 (1 H, d, J = 9.6 Hz),






7.13 (2 H, d, J = 8.7 Hz), 7.20-7.38 (5 H,






m), 7.43 (2 H, d, J = 8.7 Hz), 7.71 (1 H,






brs), 7.78 (2 H, d, J = 9.0 Hz), 8.20-






8.30 (2 H, m).


1223
1-naphthyl
benzyl
free
(DMSO-d6) 2.41 (4 H, brs), 3.51 (4 H,






brs), 3.52 (2 H, s), 7.17 (3 H, d, J = 8.7 Hz),






7.21-7.38 (5 H, m), 7.44 (2 H, d,






J = 8.7 Hz), 7.55-7.69 (3 H, m), 7.80 (1 H, d,






J = 6.4 Hz), 7.98-8.06 (1 H, m), 8.10






(1 H, d, J = 8.1 Hz), 8.18-8.27 (1 H, m),






8.32 (1 H, dd, J = 8.7 Hz, 2.6 Hz),






8.58 (1 H, d, J = 2.6 Hz), 10.76 (1 H, s).
















TABLE 267













 










Example


mp


No.
R826
Form
(° C.)





1224




maleate
172-175


 


1225




maleate
143-146


 


1226




free
187-189


 


1227




free
191-192


 


1228




maleate
180-182


 


1229
2,5-(CF3)2Ph-
dihydro-
152-156




chloride


1230
2,5-F2Ph-
maleate
182-184


1231
2,3-Cl2Ph-
free
195-196


1232
3-PhOPh-
free
171-172


1233
3-CF3Ph-
dihydro-
146-146




chloride
















TABLE 268













 












Example




MS


No.
R827
R828
R829
R830
(M+ + H)





1234
—H
—H
—H
—H
532


1235
—H
—H
—OCH3
—H
562


1236
—H
—H
—Cl
—H
566


1237
—H
—H
—F
—H
550


1238
—CH3
—H
—H
—H
546


1239
—H
—H
—Br
—H
612


1240
—H
—H
—CH3
—H
546


1241
—H
—H
—OCF3
—H
616


1242
—H
—OCH3
—H
—H
562


1243
—H
—Cl
—H
—H
566


1244
—H
—H
—H
—OCH3
562


1245
—H
—Cl
—H
—Cl
600


1246
—H
—H
—H
—Cl
566


1247
—H
—H
—OCH3
—OCH3
592
















TABLE 269













 














Example






MS


No.
R831
R832
R833
R834
R835
M
(M+ + H)





1248
—H
—H
—H
—H
—H
0
532


1249
—H
—H
—H
—H
—H
2
560


1250
—H
—H
—H
—H
—H
1
546


1251
—H
—H
—Cl
—H
—H
1
580


1252
—H
—CH3
—H
—H
—H
1
560


1253
—H
—CH3
—CH3
—H
—H
1
574


1254
—H
—CH3
—OCH3
—H
—H
1
590


1255
—H
—CH3
—F
—H
—H
1
578


1256
—H
—CH3
—C(CH3)3
—H
—H
1
616


1257
—H
—CH3
—CH3
—H
—CH3
1
588


1258
—H
—CH3
—Br
—H
—F
1
658


1259
—H
—CH3
—H
—H
—F
1
578


1260
—H
—CH3
—C2H5
—H
—H
1
588


1261
—H
—H
—F
—H
—H
1
564


1262
—H
—H
—H
—F
—H
1
564


1263
—CH3
—H
—H
—H
—H
1
560


1264
—H
—H
—OCH3
—H
—H
1
576


1265
—H
—H
—H
—H
—CH3
1
560


1266
—H
—H
—CH3
—H
—H
1
560


1267
—H
—H
—Br
—H
—H
1
626
















TABLE 270













 









Example




No.
R836
1H NMR (solvent) δ ppm





1268
3-CNPh-
(CDCl3) 2.37-2.44 (4 H, m), 2.57-2.63 (2 H, m), 2.88-2.95 (2 H, m),




3.42-3.45 (2 H, m), 3.55 (2 H, s), 3.60-3.64 (2 H, m), 6.90 (1 H, d,




J = 8.9 Hz), 7.00 (2 H, d, J = 8.6 Hz), 7.16 (2 H, d, J = 8.6 Hz), 7.25-




7.31 (5 H, m), 7.54-7.76 (1 H, m) 7.76-7.80 (1 H, m), 8.19-8.26 (3 H,




m), 8.37 (1 H, d, J = 2.6 Hz), 9.41 (1 H, brs).


1269
2-CNPh-
(CDCl3) 2.35-2.45 (4 H, m), 2.60-2.66 (2 H, m), 2.95-3.01 (2 H, m),




3.40-3.44 (2 H, m), 3.52 (2 H, s), 3.63-3.67 (2 H, m), 7.05-7.13 (3 H, m),




7.23-7.32 (8 H, m), 7.69-7.80 (3 H, m), 7.93-7.96 (2 H, m), 8.23 (1 H, d,




J = 2.5 Hz).


1270
3-N(CH3)2Ph-
(CDCl3) 2.35-2.44 (4 H, m), 2.57-2.62 (2 H, m), 2.91-2.98 (8 H, m),




3.39-3.43 (2 H, m), 3.53 (2 H, s), 3.62-3.65 (2 H, m), 6.84-6.92 (2 H, m),




7.02 (2 H, d, J = 8.6 Hz), 7.11 (1 H, d, J = 7.9 Hz), 7.19 (2 H, d, J = 8.6 Hz),




7.25-7.35 (7 H, m), 8.22-8.37 (3 H, m).


1271
3-CH3Ph-
(CDCl3) 2.36-2.46 (7 H, m), 2.57-2.63 (2 H, m), 2.91-2.97 (2 H, m),




3.40-3.44 (2 H, m), 3.56 (2 H, s), 3.62-3.66 (2 H, m), 6.91 (1 H, d,




J = 8.9 Hz), 7.00-7.05 (2 H, m), 7.19 (2 H, d, J = 8.6 Hz), 7.25-7.35 (7 H,




m), 7.66-7.71 (2 H, m), 8.23-8.31 (2 H, m), 8.43 (1 H, brs).


1272
3,4-(CH3)2Ph-
(CDCl3) 2.31 (3 H, s), 2.32 (3 H, s), 2.36-2.46 (4 H, m), 2.58-2.64 (2 H,




m), 2.92-2.98 (2 H, m), 3.41-3.44 (2 H, m), 3.56 (2 H, s), 3.63-3.67 (2 H,




m), 6.90-6.94 (1 H, m), 7.03 (2 H, d, J = 8.4 Hz), 7.19-7.37 (8 H, m),




7.58-7.73 (2 H, m), 8.21-8.28 (3 H, m).


1273
2-FPh-
(DMSO-d6) 2.28-2.31 (4 H, m), 2.59-2.64 (2 H, m), 2.78-2.84 (2 H, m),




3.44-3.47 (6 H, m), 7.01 (2 H, d, J = 8.4 Hz), 7.02-7.05 (1 H, m),




7.26 (2 H, d, J = 8.4 Hz), 7.31-7.40 (7 H, m), 7.51-7.61 (1 H, m), 7.64-




7.72 (1 H, m), 8.18 (1 H, dd, J = 8.9 Hz, 2.6 Hz), 8.45 (1 H, d, J = 2.5 Hz),




10.54 (1 H, brs).


1274
3-FPh-
(DMSO-d6) 2.30 (4 H, brs), 2.62 (2 H, brs), 2.81 (2 H, brs), 3.47 (6 H,




brs), 7.03 (3 H, brs), 7.25-7.30 (7 H, m), 7.47 (1 H, brs), 7.60 (1 H, d,




J = 6.1 Hz), 7.77-7.81 (2 H, m), 8.20 (1 H, d, J = 7.6 Hz), 8.49 (1 H, brs),




10.46 (1 H, brs).


1275
4-FPh-
(DMSO-d6) 2.28-2.30 (4 H, m), 2.58-2.64 (2 H, m), 2.77-2.83 (2 H, m),




3.43-3.46 (6 H, m), 7.00 (2 H, d, J = 8.6 Hz), 7.02 (1 H, d, J = 8.7 Hz),




7.25 (2 H, d, J = 8.6 Hz), 7.29-7.40 (7 H, m), 8.01-8.06 (2 H, m),




8.18 (1 H, dd, J = 8.7 Hz, 2.6 Hz), 8.46 (1 H, d, J = 2.5 Hz),




10.39 (1 H, brs).


1276
4-AcPh-
(DMSO-d6) 2.28-2.32 (4 H, m), 2.59-2.65 (5 H, m), 2.79-2.84 (2 H, m),




3.44-3.47 (6 H, m), 6.99-7.06 (3 H, m), 7.27-7.36 (7 H, m), 8.09 (4 H,




brs), 8.21 (1 H, dd, J = 8.9 Hz, 2.8 Hz), 8.50 (1 H, d, J = 2.6 Hz),




10.56 (1 H, brs).


1277
3,4-F2Ph-
(DMSO-d6) 2.28-2.32 (4 H, m), 2.59-2.65 (2 H, m), 2.79-2.84 (2 H, m),




3.44-3.47 (6 H, m), 7.01 (2 H, d, J = 8.4 Hz), 7.04 (1 H, d, J = 8.7 Hz),




7.27 (2 H, d, J = 8.4 Hz), 7.31-7.36 (5 H, m), 7.59-7.69 (1 H, m), 7.85-




7.89 (1 H, m), 8.00-8.07 (1 H, m), 8.18 (1 H, dd, J = 8.9 Hz, 2.6 Hz),




8.46 (1 H, d, J = 2.5 Hz), 10.46 (1 H, brs).
















TABLE 271













 













Example








No.
R837
R838
R839
R840
R841
1H NMR (solvent) δ ppm or MS





1278
—H
—F
—H
—F
—H
1H NMR (DMSO-d6) 2.29-








2.32 (4 H, m), 2.59-2.65 (2 H, m),








2.79-2.85 (2 H, m), 3.44-3.48 (6 H,








m), 7.00-7.06 (3 H, m), 7.25-








7.36 (7 H, m), 7.51-7.59 (1 H, m),








7.67-7.71 (2 H, m), 8.19 (1 H, dd,








J = 8.7 Hz, 2.6 Hz), 8.48 (1 H, d,








J = 2.5 Hz), 10.51 (1 H, brs).


1279
—H
—H
—SO2NH2
—H
—H
1H NMR (DMSO-d6) 2.25-








2.35 (4 H, m), 2.60-2.66 (2 H, m),








2.74-2.85 (2 H, m), 3.31 (2 H, s),








3.40-3.50 (4 H, m), 7.00-7.06 (3 H,








m), 7.25-7.34 (7 H, m), 7.53 (2 H, s),








7.97 (2 H, d, J = 8.6 Hz), 8.12 (2 H,








d, J = 8.6 Hz), 8.21 (1 H, dd,








J = 8.9 Hz, 2.7 Hz), 8.49 (1 H, d,








J = 2.7 Hz), 10.56 (1 H, s).


1280
—H
—H
—NHAc
—H
—H
MS 576 (M+ − 1)


1281
—F
—H
—CF3
—H
—H
MS 607 (M+ + H)


1282
—COOC2H5
—H
—H
—H
—H
MS 593 (M+ + 1)


1283
—Cl
—Cl
—H
—H
—H
MS 590 (M+ + 2)


1284
—H
—H
—COOCH3
—H
—H
MS 579 (M+ + H)


1285
—OCH3
—H
—OCH3
—H
—H
MS 580 (M+)


1286
—Cl
—H
—Cl
—H
—H
MS 589 (M+)


1287
—CH3
—H
—CH3
—H
—H
MS 548 (M+)


1288
—F
—H
—F
—H
—H
MS 557 (M+ + H)


1289
—H
—OCH3
—OCH3
—H
—H
MS 580 (M+)


1290
—CF3
—H
—H
—H
—H
MS 589 (M+ + 1)


1291
—H
—CF3
—H
—H
—H
MS 588 (M+)


1292
—H
—COOCH3
—H
—H
—H
MS 579 (M+ + 1)


1293
—F
—H
—H
—H
—F
MS 557 (M+ + 1)


1294
—F
—F
—H
—H
—H
MS 557 (M+ + H)


1295
—CF3
—H
—H
—CF3
—H
MS 656 (M+)


1296
—H
—F
—H
—CF3
—H
MS 606 (M+)


1297
—F
—CF3
—H
—H
—H
MS 607 (M+ + H)


1298
—F
—H
—H
—CF3
—H
MS 607 (M+ + 1)


1299
—CH3
—H
—H
—CH3
—H
MS 549 (M+ + 1)


1300
—F
—H
—H
—F
—H
MS 557 (M+ + H)


1301
—Cl
—H
—F
—H
—H
MS 572 (M+)


1302
—H
—OAc
—H
—H
—H
MS 579 (M+ + 1)


1303
—OCF3
—H
—H
—H
—H
MS 604 (M+)
















TABLE 272













 













Example








No.
R842
R843
R844
R845
R846
1H NMR or MS





1304
—H
—CF3
—F
—H
—H
MS 607 (M+ + 1)


1305
—OCH3
—H
—H
—OCH3
—H
MS 580 (M+)


1306
—Cl
—H
—H
—Cl
—H
MS 590 (M+ + 1)


1307
—CH3
—H
—H
—F
—H
MS 552 (M+)


1308
—N(CH3)2
—H
—H
—H
—H
MS 564 (M+ + H)


1309
—OCH3
—H
—H
—H
—OCH3
MS 581 (M+ + H)


1310
—H
—OPh
—H
—H
—H
MS 613 (M+ + H)


1311
—H
—OCH3
—H
—OCH3
—H
MS 581 (M+ + H)


1312
—H
—Cl
—H
—Cl
—H
MS 589 (M+ + H)


1313
—H
—CH3
—H
—CH3
—H
MS 549 (M+ + H)


1314
—OCH3
—OCH3
—H
—H
—H
MS 581 (M+ + H)


1315
—CH3
—CH3
—H
—H
—H
MS 549 (M+ + H)


1316
—CH3
—F
—H
—H
—H
MS 553 (M+ + H)


1317
—H
—H
—N(CH3)2
—H
—H
MS 564 (M+ + H)


1318
—H
—CF3
—H
—CF3
—H
MS 656 (M+)


1319
—Cl
—H
—H
—CF3
—H
MS 622 (M+)


1320
—H
—CH3
—NHAc
—H
—H
MS 591 (M+)


1321
—H
—Cl
—NHAc
—H
—H
MS 611 (M+)


1322
—H
—OCH3
—NHAc
—H
—H
MS 607 (M+)


1323
—H
—NHAc
—CH3
—H
—H
MS 591 (M+)


1324
—H
—NHAc
—Cl
—H
—H
MS 611 (M+)


1325
—H
—NHAc
—OCH3
—H
—H
MS 607 (M+)


1326
—H
—NHAc
—F
—H
—H
MS 595 (M+)


1327
—H
—CH3
—NHCOPh
—H
—H
MS 653 (M+)


1328
—H
—Cl
—NHCOPh
—H
—H
MS 673 (M+)


1329
—H
—OCH3
—NHCOPh
—H
—H
MS 669 (M+)


1330
—H
—NHCOPh
—CH3
—H
—H
MS 653 (M+)


1331
—H
—NHCOPh
—Cl
—H
—H
MS 673 (M+)


1332
—H
—NHCOPh
—OCH3
—H
—H
MS 669 (M+)


1333
—H
—NHCOPh
—F
—H
—H
MS 657 (M+)


1334
—COOH
—H
—Cl
—Cl
—H
1H NMR (DMSO-d6) δ








2.42 (4 H, brs), 2.62 (2 H, t,








J = 7.1 Hz), 2.81 (2 H, t,








J = 7.1 Hz), 3.33 (1 H, brs),








3.47 (4 H, brs), 3.60 (2 H, s),








7.00 (2 H, d, J = 8.6 Hz),








7.02 (1 H, d, J = 4.7 Hz),








7.26 (2 H, d, J = 8.6 Hz),








7.28-7.38 (5 H, m), 7.94 (1 H,








s), 8.05 (1 H, s), 8.10 (1 H,








dd, J = 8.7 Hz, 2.8 Hz),








8.36 (1 H, d, J = 2.8 Hz),








10.68 (1 H, s).
















TABLE 273













 













Example








No.
R847
R848
R849
R850
R851
MS





1335
—H
—H
—H
—H
—H
546 (M+)


1336
—H
—OCH3
—H
—H
—H
577 (M+ + H)


1337
—Cl
—H
—H
—H
—H
581 (M+ + H)


1338
—H
—Cl
—H
—H
—H
581 (M+ + H)


1339
—H
—H
—Cl
—H
—H
581 (M+ + H)


1340
—F
—H
—H
—H
—H
565 (M+ + H)


1341
—H
—F
—H
—H
—H
565 (M+ + H)


1342
—H
—H
—F
—H
—H
565 (M+ + H)


1343
—H
—H
—N(CH3)2
—H
—H
590 (M+ + 1)


1344
—H
—OCH3
—OCH3
—H
—H
606 (M+)


1345
—Cl
—H
—H
—H
—Cl
615 (M+ + 1)


1346
—H
—Cl
—Cl
—H
—H
615 (M+ + H)


1347
—F
—H
—H
—H
—F
583 (M+ + H)


1348
—H
—F
—H
—F
—H
583 (M+ + H)












1349
—H
—OCH2O—
—H
—H
591 (M+ + H)













1350
—H
—OCH3
—H
—OCH3
—H
607 (M+ + H)


1351
—H
—H
—CH3
—H
—H
561 (M+ + H)


1352
—H
—CF3
—H
—H
—H
615 (M+ + H)


1353
—H
—H
—OCH3
—H
—H
577 (M+ + 1)


1354
—OCH3
—OCH3
—H
—H
—H
606 (M+)


1355
—OCH3
—H
—H
—OCH3
—H
607 (M+ + 1)


1356
—H
—OCH3
—OCH3
—OCH3
—H
637 (M+ + 1)
















TABLE 274













 









Example




No.
R852
1H NMR (solvent) δ ppm





1357




(CDCl3) 1.68-1.86 (2 H, m), 1.91-2.03 (2 H, m), 2.12 (3 H, s), 2.34- 2.40 (2 H, m), 2.40-2.46 (2 H, m), 2.48-2.56 (1 H, m), 2.62 (2 H, t, J = 7.9 Hz), 2.66-2.75 (1 H, m), 2.96 (2 H, t, J = 7.9 Hz), 3.08- 3.18 (1 H, m), 3.38-3.45 (2 H, m), 3.51 (2 H, s), 3.59-3.69 (2 H, m), 3.88-3.97 (1 H, m), 4.59-4.69 (1 H, m), 6.89 (1 H, d, J = 9.7 Hz), 7.02 (2 H, d, J = 8.4 Hz), 7.22 (2 H, d, J = 8.4 Hz), 7.25-7.31 (1 H, m), 7.31-7.38 (4 H, m), 7.54 (1 H, brs), 8.08-8.16 (2 H, m).


 


1358




(CDCl3) 2.05-2.18 (1 H, m), 2.32-2.40 (2 H, m), 2.40-2.47 (2 H, m), 2.49-2.56 (1 H, m), 2.63 (2 H, t, J = 7.9 Hz), 2.80-2.90 (1 H, m), 2.90-3.02 (3 H, m), 3.36-3.46 (2 H, m), 3.51 (2 H, s), 3.60-3.70 (2 H, m), 4.64-4.70 (1 H, m), 6.88-7.02 (3 H, m), 7.04 (2 H, d, J = 8.4 Hz), 7.09-7.15 (1 H, m), 7.15-7.22 (1 H, m), 7.22-7.25 (1 H, m), 7.25-7.30 (2 H, m), 7.30-7.38 (4 H, m), 8.14 (1 H, dd, J = 8.8, 2.8 Hz), 8.25 (1 H, d, J = 2.8 Hz), 8.54 (1 H, brs).


 


1359
—CH2OCH3
(CDCl3) 2.30-2.38 (2 H, m), 2.38-2.45 (2 H, m), 2.62 (2 H, t, J = 7.9 Hz),




2.96 (2 H, t, J = 7.9 Hz), 3.35-3.43 (2 H, m), 3.50 (2 H, s),




3.52 (3 H, s), 3.58-3.68 (2 H, m), 4.04 (2 H, s), 6.90 (1 H, d, J = 8.8 Hz),




7.03 (2 H, d, J = 8.4 Hz), 7.22 (2 H, d, J = 8.4 Hz), 7.25-




7.29 (1 H, m), 7.29-7.37 (4 H, m), 8.14 (1 H, dd, J = 8.8, 2.8 Hz),




8.18-8.25 (2 H, m).


1360
—CH3
(CDCl3) 2.18 (3 H, s), 2.32-2.39 (2 H, m), 2.39-2.45 (2 H, m),




2.61 (2 H, t, J = 7.9 Hz), 2.95 (2 H, t, J = 7.9 Hz), 3.36-3.44 (2 H,




m), 3.50 (2 H, s), 3.60-3.68 (2 H, m), 6.85-6.92 (1 H, m), 7.02 (2 H,




d, J = 8.4 Hz), 7.21 (2 H, d, J = 8.4 Hz), 7.25-7.30 (1 H, m), 7.30-




7.35 (4 H, m), 7.38 (1 H, brs), 8.06-8.15 (2 H, m).


1361
—C(CH3)3
(CDCl3) 1.32 (9 H, s), 2.32-2.38 (2 H, m), 2.38-2.44 (2 H, m),




2.62 (2 H, t, J = 7.9 Hz), 2.96 (2 H, t, J = 7.9 Hz), 3.37-3.43 (2 H,




m), 3.50 (2 H, s), 3.60-3.69 (2 H, m), 6.87 (1 H, d, J = 9.8 Hz),




7.02 (2 H, d, J = 8.4 Hz), 7.22 (2 H, d, J = 8.4 Hz), 7.25-7.30 (1 H,




m), 7.30-7.37 (5 H, m), 8.07-8.15 (2 H, m).


1362
—(CH2)2OPh
(DMSO-d6) 2.23-2.33 (4 H, m), 2.56-2.67 (2 H, m), 2.73-2.86 (4 H,




m), 3.37-3.50 (6 H, m), 4.26 (2 H, t, J = 6.0 Hz), 6.90-6.96 (3 H, m),




6.96-7.02 (3 H, m), 7.20-7.35 (9 H, m), 8.07 (1 H, dd, J = 8.8,




2.7 Hz), 8.33 (1 H, d, J = 2.7 Hz), 10.23 (1 H, s).


1363
3-CH3OPhOCH2—
(DMSO-d6) 2.23-2.34 (4 H, m), 2.58-2.68 (2 H, m), 2.76-2.85 (2 H,




m), 3.38-3.50 (6 H, m), 3.74 (3 H, s), 4.68 (2 H, s), 6.51-6.62 (3 H,




m), 6.95-7.04 (3 H, m), 7.18-7.28 (4 H, m), 7.28-7.37 (4 H, m),




8.09 (1 H, dd, J = 8.9, 2.7 Hz), 8.36 (1 H, d, J = 2.7 Hz),




10.22 (1 H, s).


1364
3-CH3PhOCH2—
(DMSO-d6) 2.23-2.34 (7 H, m), 2.56-2.66 (2 H, m), 2.74-2.84 (2 H,




m), 3.37-3.50 (6 H, m), 4.67 (2 H, s), 6.75-6.81 (2 H, m), 6.81-




6.88 (1 H, m), 6.96-7.03 (3 H, m), 7.14-7.21 (1 H, m), 7.21-7.28 (3 H,




m), 7.28-7.36 (4 H, m), 8.09 (1 H, dd, J = 8.9, 2.7 Hz), 8.36 (1 H, d,




J = 2.7 Hz), 10.21 (1 H, s).


1365
4-CH3PhOCH2—
(DMSO-d6) 2.23 (3 H, s), 2.26-2.32 (4 H, m), 2.57-2.65 (2 H, m),




2.73-2.83 (2 H, m), 3.36-3.50 (6 H, m), 4.65 (2 H, s), 6.90 (2 H, d,




J = 8.5 Hz), 6.95-7.02 (3 H, m), 7.11 (2 H, d, J = 8.5 Hz), 7.20-




7.29 (3 H, m), 7.29-7.35 (4 H, m), 8.08 (1 H, dd, J = 8.9, 2.7 Hz),




8.36 (1 H, d, J = 2.7 Hz), 10.21 (1 H, s).
















TABLE 275













 









Example




No.
R853
1H NMR (DMSO-d6) δ ppm or MS





1366
PhOCH2—
1H NMR 2.23-2.34 (4 H, m), 2.57-2.65 (2 H, m), 2.76-




2.85 (2 H, m), 3.38-3.50 (6 H, m), 4.70 (2 H, s), 6.92-




7.05 (6 H, m), 7.20-7.27 (3 H, m), 7.27-7.38 (6 H, m),




8.09 (1 H, dd, J = 8.9, 2.7 Hz), 8.36 (1 H, d, J = 2.7 Hz),




10.24 (1 H, s).


1367
4-CH3PhCH2—
1H NMR 2.21-2.32 (7 H, m), 2.56-2.65 (2 H, m), 2.73-




2.82 (2 H, m), 3.37-3.49 (6 H, m), 3.58 (2 H, s), 6.92-




7.00 (3 H, m), 7.09-7.16 (2 H, m), 7.19-7.21 (2 H, m), 7.21-




7.27 (3 H, m), 7.27-7.35 (4 H, m), 8.04 (1 H, dd, J = 8.9,




2.7 Hz), 8.30 (1 H, d, J = 2.7 Hz), 10.27 (1 H, s).


1368
4-ClPhCH2—
1H NMR 2.21-2.32 (4 H, m), 2.55-2.65 (2 H, m), 2.73-




2.82 (2 H, m), 3.38-3.49 (6 H, m), 3.66 (2 H, s), 6.93-




7.00 (3 H, m), 7.20-7.26 (3 H, m), 7.26-7.35 (6 H, m), 7.35-




7.42 (2 H, m), 8.04 (1 H, dd, J = 8.9, 2.7 Hz), 8.30 (1 H, d,




J = 2.7 Hz), 10.33 (1 H, s).


1369
4-CH3OPhCH2—
1H NMR 2.22-2.33 (4 H, m), 2.56-2.65 (2 H, m), 2.75-




2.83 (2 H, m), 3.38-3.50 (6 H, m), 3.56 (2 H, s), 3.73 (3 H, s),




6.84-6.90 (2 H, m), 6.92-7.00 (3 H, m), 7.19-7.28 (5 H, m),




7.28-7.36 (4 H, m), 8.04 (1 H, dd, J = 8.9, 2.7 Hz),




8.30 (1 H, d, J = 2.7 Hz), 10.25 (1 H, s).


1370
4-FPhCH2—
1H NMR 2.23-2.32 (4 H, m), 2.56-2.65 (2 H, m), 2.75-




2.84 (2 H, m), 3.39-3.50 (6 H, m), 3.64 (2 H, s), 6.93-




7.00 (3 H, m), 7.11-7.19 (2 H, m), 7.21-7.29 (3 H, m), 7.29-




7.40 (6 H, m), 8.04 (1 H, dd, J = 8.9, 2.7 Hz), 8.30 (1 H, d,




J = 2.7 Hz), 10.31 (1 H, s).


1371
benzyl
1H NMR 2.22-2.33 (4 H, m), 2.56-2.67 (2 H, m), 2.72-




2.84 (2 H, m), 3.37-3.50 (6 H, m), 3.64 (2 H, s), 6.90-




7.00 (3 H, m), 7.20-7.29 (4 H, m), 7.29-7.38 (8 H, m),




8.05 (1 H, dd, J = 8.8, 2.7 Hz), 8.31 (1 H, d, J = 2.7 Hz),




10.32 (1 H, s).


1372
—(CH2)3Ph
MS 563 (M+ + 1)


1373
—(CH2)2CH3
MS 487 (M+ + 1)


1374
—CH(CH3)2
MS 486 (M+)


1375
cyclopentyl
MS 512 (M+)


 


1376




MS 630 (M+)


 


1377
—(CH2)2Ph
MS 549 (M+ + H)


1378
2-furyl
MS 511 (M+ + H)


1379
2-thienyl
MS 527 (M+ + H)


1380
2-thenyl
MS 541 (M+ + H)


1381
cyclohexyl
MS 527 (M+ + H)


1382
cycloheptyl
MS 541 (M+ + H)


1383
cyclopentylmethyl
MS 527 (M+ + H)


1384
cyclohexylmethyl
MS 541 (M+ + H)


1385
2-Ch3OPhOCH2—
MS 581 (M+ + 1)
















TABLE 276







 








 









Example




No.
R854
MS





1386




584 (M+ + 1)


 


1387




582 (M+ + 1)


 


1388




587 (M+ + H)


 


1389




547 (M+)


 


1390




547 (M+)


 


1391




561 (M+ + 1)


 


1392
2-CH3PhOCH2—
565 (M+ + H)


1393
2-ClPhOCH2—
585 (M+)


1394
3-ClPhOCH2—
585 (M+ + H)


1395
4-CNPhOCH2—
575 (M+)


 


1396




595 (M+ + H)


 


1397
3,4,5-(CH3O)3PhOCH2—
641 (M+ + 1)


 


1398




556 (M+ + 1)


 


1399




556 (M+ + H)


 


1400




590 (M+ + H)


 


1401




567 (M+)


 


1402




556 (M+)
















TABLE 277







 








 









Example




No.
R855
MS





1403




566 (M+ − 1)


 


1404




559 (M+)


 


1405




562 (M+ + H)


 


1406




528 (M+ + 1)


 


1407
2-quinolyl 
571 (M+)


1408
3-quinolyl
572 (M+ + H)


1409
4-quinolyl
571 (M+)


1410
6-quinolyl
571 (M+)


1411
1-isoquinolyl
571 (M+)


1412
3-isoquinolyl
572 (M+ + H)


 


1413




560 (M+)


 


1414




590 (M+)


 


1415
3,4-Cl2PhCH2—
603 (M+ + H)


1416
2-CH3OPhCH2—
564 (M+)


1417
—CH(CH2Ph)NHAc
605 (M+)


 


1418




557 (M+)


 


1419
—CH2NHAc
515 (M+)


1420
—CH(CH3)NHAc
529 (M+)


1421
—CH(CH2Ph)NHCOPh
667 (M+)


 


1422




619 (M+)


 


1423
—CH2NHCOPh
577 (M+)
















TABLE 278







 








 









Example




No.
R856
MS





1424
—CH(CH3)NHCOPh
591 (M+)


1425
2-pyridyl
522 (M+ + H)


1426
3-pyridyl
522 (M+ + H)


1427
4-pyridyl
522 (M+ + H)


1428
1-naphthyl
571 (M+ + H)


 


1429




551 (M+)


 


1430
2-pyrrolyl
509 (M+)


1431
3-pyridylmethyl 
536 (M+ + H)


1432
3-furyl
510 (M+)


1433
3-thienyl
526 (M+)


1434
3-thenyl
541 (M+ + H)


 


1435




592 (M+)


 


1436
3-CH3PhCH2—
549 (M+ + H)


1437
3-ClPhCH2—
569 (M+ + H)


1438
2-FPhCH2—
553 (M+ + H)


1439
3-FPhCH2—
553 (M+ + H)


1440
2,5-(CH3O)2PhCH2—
594 (M+)


1441
2,4-Cl2PhCH2—
603 (M+ + H)


1442
2,6-Cl2PhCH2—
602 (M+)


1443
3,4,5-(CH3O)3PhCH2—
624 (M+)


1444
CH(OCH3)Ph
564 (M+)


 


1445




622 (M+)


 


1446




588 (M+ + H)


 


1447




659 (M+)


 


1448




589 (M+)
















TABLE 279







 








 









Example




No.
R857
MS





1449




589 (M+)


 


1450




590 (M+ + H)


 


1451




573 (M++ H)


 


1452
4-CH3OPhO(CH2)2—
595 (M+ + H)


1453
4-CH3OPh(CH2)2—
579 (M+ + H)


1454
3,4,5-(CH3O)3Ph(CH2)2—
638 (M+)


1455
2,4-Cl2PhOCH2—
618 (M+)


1456
PhSCH2—
567 (M+ + H)


1457
—(CH2)2COPh
577 (M+ + H)


 


1458




573 (M+)


 


1459




588 (M+ + H)


 


1460




590 (M+ + H)


 


1461




594 (M+ + H)


 


1462




578 (M+ + H)


 


1463




573 (M+)


 


1464
4—CH3OPh(CH2)3—
593 (M+ + H)


 


1465




576 (M+)
















TABLE 280







 








 









Example




No.
R858
mp (° C.) or 1H NMR (DMSO-d6) δ ppm





1466
2,5-F2Ph-
mp 173-176


 


1467




mp 181-182


 


1468




mp 199-201


 


1469
2,3-Cl2Ph-
mp 149-151


1470
2,4-Cl2Ph-
1H NMR 2.54 (4 H, brs), 2.64 (2 H, t, J = 7.5 Hz), 2.81 (2 H, t, J =




7.5 Hz), 3.51 (4 H, brs), 3.65 (2 H, brs), 6.01 (2 H, s), 6.81 (1 H,




d, J = 8.0 Hz), 6.89 (1 H, d, J = 8.0 Hz), 6.92 (1 H, s), 7.01 (2 H,




d, J = 8.5 Hz), 7.04 (1 H, d, J = 9.0 Hz), 7.26 (2 H, d, J = 8.5 Hz),




7.57 (1 H, dd, J = 8.5 Hz, 2.0 Hz), 7.65 (1 H, d, J = 8.5 Hz),




7.78 (1 H, d, J = 2.0 Hz), 8.15 (1 H, dd, J = 9.0 Hz, 2.5 Hz),




8.41 (1 H, d, J = 2.5 Hz), 10.69 (1 H, s).


1471
2,5-(CF3)2Ph-
1H NMR 2.54 (4 H, brs), 2.64 (2 H, t, J = 7.5 Hz), 2.81 (2 H, t, J =




7.5 Hz), 3.49 (4 H, brs), 3.59 (2 H, brs), 6.00 (2 H, s), 6.79 (1 H,




d, J = 8.0 Hz), 6.88 (1 H, d, J = 8.0 Hz), 6.90 (1 H, s), 7.02 (2 H,




d, J = 8.5 Hz), 7.05 (1 H, d, J = 9.0 Hz), 7.27 (2 H, d, J = 8.5 Hz),




8.12-8.14 (3 H, m), 8.21 (1 H, s), 8.37 (1 H, d, J = 2.5 Hz),




10.84 (1 H, s).


1472
3-CF3Ph-
1H NMR 2.54 (4 H, brs), 2.64 (2 H, t, J = 7.5 Hz), 2.82 (2 H, t, J =




7.5 Hz), 3.51 (4 H, brs), 3.63 (2 H, brs), 6.01 (2 H, s), 6.81 (1 H,




d, J = 8.0 Hz), 6.89 (1 H, d, J = 8.0 Hz), 6.92 (1 H, s), 7.02 (2 H,




d, J = 8.5 Hz), 7.05 (1 H, d, J = 9.0 Hz), 7.27 (2 H, d, J = 8.5 Hz),




7.80 (1 H, t, J = 8.0 Hz), 7.99 (1 H, d, J = 8.0 Hz),




8.19 (1 H, dd, J = 9.0 Hz, 2.5 Hz), 8.27 (1 H, d, J = 8.0 Hz),




8.30 (1 H, s), 8.48 (1 H, d, J = 2.5 Hz), 10.61 (1 H, s).


1473
2,3-F2Ph-
1H NMR 2.54 (4 H, brs), 2.64 (2 H, t, J = 7.5 Hz), 2.81 (2 H, t, J =




7.5 Hz), 3.51 (4 H, brs), 3.62 (2 H, brs), 6.01 (2 H, s), 6.80 (1 H,




d, J = 8.0 Hz), 6.89 (1 H, d, J = 8.0 Hz), 6.92 (1 H, s), 7.02 (2 H,




d, J = 8.5 Hz), 7.04 (1 H, d, J = 9.0 Hz), 7.26 (2 H, d, J = 8.5 Hz),




7.36 (1 H, m), 7.50 (1 H, m), 7.60 (1 H, m), 8.16 (1 H, dd, J =




9.0 Hz, 2.5 Hz), 8.43 (1 H, d, J = 2.5 Hz), 10.67 (1 H, s).
















TABLE 281







 








 











Example






No.
R859
Xb23
Form
mp (° C.) or 1H NMR (solvent) δ ppm





1474




—N(Ac)—
free
mp 142-144


 


1475
3,4-F2Ph-
—CH2—
free
1H NMR (CDCl3) 2.31-2.40 (4 H, m), 2.59-






2.65 (2 H, m), 2.92-2.98 (2 H, m), 3.38-3.41 (4 H,






m), 3.60-3.64 (2 H, m), 5.94 (2 H, s), 6.70-






6.77 (2 H, m), 6.84 (1 H, s), 6.94 (1 H, d, J = 8.9 Hz),






7.01-7.07 (2 H, m), 7.19-7.24 (2 H, m),






7.29-7.33 (1 H, m), 7.62-7.68 (1 H, m), 7.74-






7.81 (1 H, m), 8.01 (1 H, brs), 8.16-8.20 (1 H, m),






8.24 (1 H, d, J = 2.2 Hz).


 


1476




—CH2—
hydro- chloride
1H NMR (DMSO-d6) 2.60-2.98 (6 H, m), 3.01- 3.15 (1 H, m), 3.26 (2 H, t, J = 15.0 Hz), 3.46- 3.59 (1 H, m), 4.00-4.11 (1 H, m), 4.15-4.27 (2 H, m), 4.30-4.51 (1 H, m), 6.05 (2 H, s), 6.97 (1 H, d, J = 7.9 Hz), 6.98-7.09 (4 H, m), 7.20- 7.31 (3 H, m), 7.97 (1 H, d, J = 8.4 Hz), 8.11- 8.23 (3 H, m), 8.50 (1 H, d, J = 2.7 Hz), 10.78 (1 H, s), 11.38 (1 H, brs).


 


1477




—CH2—
hydro- chloride
1H NMR (DMSO-d6) 2.60-2.99 (6 H, m), 3.01- 3.17 (1 H, m), 3.25 (2 H, t, J = 15.0 Hz), 3.48- 3.60 (1 H, m), 4.00-4.12 (1 H, m), 4.15-4.28 (2 H, m), 4.39-4.51 (1 H, m), 6.05 (2 H, s), 6.96 (1 H, d, J = 8.8 Hz), 6.99-7.08 (4 H, m), 7.19- 7.31 (3 H, m), 7.55 (1 H, t, J = 7.8 Hz), 7.90- 8.04 (2 H, m), 8.16 (1 H, dd, J = 8.8 Hz, 2.7 Hz), 8.43 (1 H, d, J = 2.7 Hz), 10.82 (1 H, s), 11.44 (1 H, brs).


 


1478




—CH2—
hydro- chloride
mp 213-215


 


1479




—CH2—
trihydro- chloride
1H NMR (DMSO-d6) 2.69-3.40 (15 H, m), 3.99- 4.49 (5 H, m), 6.07 (2 H, s), 6.97-7.09 (5 H, m), 7.21-7.30 (3 H, m), 7.43-7.47 (1 H, m), 7.65- 7.70 (2 H, m), 7.91 (1 H, d, J = 9.4 Hz), 8.21 (1 H, dd, J = 8.9 Hz, 2.6 Hz), 8.48 (1 H, d, J = 2.1 Hz), 11.23 (1 H, s).


 


1480
3-PhOPh-
—CH2—
hydro- chloride
1H NMR (DMSOd6) 2.60-3.09 (7 H, m), 3.18-






3.31 (2 H, m), 3.38-3.50 (1 H, m), 4.08 (1 H, d, J =






14.0 Hz), 4.22 (2 H, brs), 4.45 (1 H, d, J =






14.0 Hz), 6.07 (2 H, s), 6.90-7.08 (7 H, m), 7.15-






7.26 (5 H, m), 7.44 (2 H, t, J = 7.9 Hz), 7.56 (1 H,






t, J = 7.9 Hz), 7.61 (1 H, s), 7.79 (1 H, d, J = 7.6 Hz),






8.19 (1 H, dd, J = 8.9 Hz, 2.6 Hz),






8.45 (1 H, d, J = 2.6 Hz), 10.45 (1 H, s), 10.90-






11.20 (1 H, m).
















TABLE 282







 








 












Example







No.
R860
R861 
Xb24
Form
mp (° C.) or 1H NMR (solvent) δ ppm





1481
1-naphthyl
—H
—CH2—
hydro-
1H NMR (DMSO-d6) 2.50-






chloride
3.60 (10 H, m), 4.00-4.20 (1 H, m),







4.22 (2 H, s), 4.35-4.51 (1 H, m),







6.07 (2 H, s), 6.91-7.08 (2 H, m),







7.04 (2 H, d, J = 8.6 Hz), 7.08 (1 H,







d, J = 8.9 Hz), 7.21 (1 H, s), 7.39







(2 H, d, J = 8.6 Hz), 7.55-7.67 (3 H,







m), 7.79 (1 H, d, J = 7.1 Hz), 7.98-







8.05 (1 H, m), 8.10 (1 H, d, J = 8.2 Hz),







8.16-8.22 (1 H, m), 8.26 (1 H,







dd, J = 8.9 Hz, 2.5 Hz), 8.54 (1 H, d,







J = 2.5 Hz), 10.72 (1 H, s)


 


1482




—CH3
—N(CH3)—
free
1H NMR (CDCl3) 2.13 (3 H, s), 2.43 (4 H, t, J = 4.8 Hz), 3.01 (3 H, s), 3.44 (2 H, s), 3.45-3.56 (2 H, m), 3.56-3.70 (2 H, m), 4.08 (2 H, s), 4.09 (3 H, s), 5.95 (2 H, s), 6.51-6.60 (2 H, m), 6.72-6.76 (2 H, m), 6.82 (1 H, d, J = 8.9 Hz), 6.85 (1 H, s), 6.92 (1 H, d, J = 8.4 Hz), 7.04 (1 H, s), 7.14- 7.23 (1 H, m), 7.28-7.40 (1 H, m), 7.42 (1 H, d, J = 7.9 Hz), 7.67 (1 H, d, J = 7.9 Hz), 7.94 (1 H, s), 8.14 (1 H, dd, J = 8.9 Hz, 2.8 Hz), 8.22 (1 H, d, J = 2.8 Hz).


 


1483
3,5-(CH3)2Ph-
—H
—CH2—
hydro-
H NMR (DMSO-d6) 2.36 (6 H, s),






chloride
2.60-3.60 (10 H, m), 4.00-4.60 (2 H,







m), 4.29 (2 H, s), 6.07 (2 H, s), 6.85-







7.10 (5 H, m), 7.22 (2 H, s), 7.27 (2 H,







d, J = 8.5 Hz), 7.57 (2 H, s), 8.19







(1 H, dd, J = 8.9 Hz, 2.7 Hz), 8.48







(1 H, d, J = 2.7 Hz), 10.34 (1 H, s).


 


1484




—CH3
—N(CH3)—
free
mp 143-144


 


1485




—CH3
—N(CH3)—
free
mp 163-165


 


1486




—CH3
—N(CH3)—
free
mp 224-227 dec


 


1487




—CH3
—N(CH3)—
free
mp 131-134
















TABLE 283







 








 












Example







No.
R862
R863
Xb25
Form
1H NMR (solvent) δ ppm





1488
2,3-(CH3O)2Ph-
—H
—CH2—
hydro-
(DMSO-d6) 3.80 (3 H, s), 3.86 (3 H, s),






chloride
2.60-3.60 (10 H, m), 4.00-4.20 (1 H, m),







4.22 (2 H, s), 4.40-4.55 (1 H, m), 6.07 (2 H,







s), 6.90-7.30 (11 H, m), 8.18 (1 H, dd, J =







8.8 Hz, 2.6 Hz), 8.45 (1 H, d, J = 2.6 Hz),







10.37 (1 H, s).


 


1489




—CH3
—N(CH3)—
free
(CDCl3) 2.12 (3 H, s), 2.35-2.50 (4 H, m), 3.01 (3 H, s), 3.43 (2 H, s), 3.45-3.55 (2 H, m), 3.57-3.70 (2 H, m), 4.07 (2 H, s) 5.95 (2 H, s), 6.40 (2 H, t, J = 2.2 Hz), 6.50-6.59 (2 H, m), 6.74 (2 H, s), 6.81 (1 H, d, J = 8.9 Hz), 6.85 (1 H, s), 6.92 (1 H, d, J = 8.6 Hz), 7.17 (2 H, t, J = 2.2 Hz), 7.49 (2 H, d, J = 8.8 Hz), 7.90 (1 H, brs), 7.95 (2 H, d, J = 8.8 Hz), 8.15 (1 H, dd, J = 8.9 Hz, 2.3 Hz), 8.22 (1 H, d, J = 2.3 Hz).


 


1490




—CH3
—N(CH3)—
free
(CDCl3) 2.04 (3 H, s), 2.39-2.46 (4 H, m), 2.94 (3 H, s), 3.43-3.51 (4 H, m), 3.59- 3.63 (2 H, m), 4.05 (2 H, s), 5.94 (2 H, s), 6.41-6.48 (2 H, m), 6.67-6.84 (6 H, m), 7.44 (1 H, d, J = 4.1 Hz), 8.01 (1 H, dd, J = 8.9 Hz, 2.6 Hz), 8.17 (1 H, d, J = 2.6 Hz), 8.82 (1 H, brs).


 


1491




—CH3
—N(CH3)—
maleate
(DMSO-d6) 2.01 (3 H, s), 2.50 (4 H, brs), 2.93 (3 H, s), 3.33 (4 H, brs), 4.03 (2 H, s), 4.29 (2 H, s), 6.06 (2 H, s), 6.10 (2 H, s), 6.48 (1 H, dd, J = 8.9 Hz, 2.8 Hz), 6.56 (1 H, s), 6.81-7.01 (6 H, m), 7.43- 7.53 (2 H, m), 7.57 ( 1 H, dd, J = 5.9 Hz, 3.6 Hz), 7.77 (1 H, dd, J = 5.8 Hz, 3.6 Hz), 7.88 (1 H, d, J = 15.7 Hz), 8.11 (1 H, dd, J = 8.7 Hz, 2.5 Hz), 8.36 (1 H, d, J = 2.6 Hz), 10.42 (1 H, s).


 


1492
4-(CH3)2NPh-
—H
—CH2—
free
(CDCl3) 2.33 (2 H, t, J = 5.0 Hz), 2.39 (2 H,







t, J = 5.0 Hz), 2.61 (2 H, t, J = 7.5 Hz),







2.97 (2 H, t, J = 7.5 Hz), 3.05 (6 H, s),







3.32-3.45 (2 H, m), 3.41 (2 H, s), 3.63 (2 H,







t, J = 5.0 Hz), 5.94 (2 H, s), 6.70 (2 H, d, J =







9.0 Hz), 6.74 (2 H, s), 6.85 (1 H, s),







6.92 (1 H, d, J = 9.0 Hz), 7.04 (2 H, d, J =







8.6 Hz), 7.22 (2 H, d, J = 8.6 Hz),







7.72 (1 H, s), 7.78 (2 H, d, J = 9.0 Hz),







8.21 (1 H, d, J = 2.8 Hz), 8.23 (1 H, dd, J =







8.6 Hz, 2.8 Hz).


1493
2,4-Cl2PhOCH2—
—CH3
—N(CH3)—
free
(CDCl3) 2.11 (3 H, s), 2.42 (4 H, brs),







3.00 (3 H, s), 3.43 (2 H, s), 3.49 (2 H, brs),







3.63 (2 H, brs), 4.07 (2 H, s), 4.62 (2 H, s),







5.94 (2 H, s), 6.54 (1 H, dd, J = 11.1 Hz,







2.3 Hz), 6.74-6.92 (6 H, m), 7.24 (1 H, dd,







J = 8.7 Hz, 2.5 Hz), 7.43 (1 H, d, J = 2.5 Hz),







8.06 (1 H, dd, J = 8.9 Hz, 2.8 Hz),







8.23 (1 H, d, J = 2.6 Hz), 8.55 (1 H, s).
















TABLE 284







 








 













Example





mp (° C.) or 1H NMR (solvent)


No.
R864
R865
Xb26
Xb27
Form
δ ppm





1494




—CH3
—N(CH3)—
—CH2—
free
1H NMR (CDCl3) 2.10 (3 H, s), 2.45 (4 H, brs), 3.01 (3 H, s), 3.45 (2 H, s), 3.51 (2 H, brs), 3.64 (2 H, brs), 4.08 (2 H, s), 5.95 (2 H, s), 6.51-6.59 (3 H, m), 6.75- 6.92 (5 H, m), 7.33 (1 H, d, J = 8.3 Hz), 7.45 (1 H, d, J = 8.4 Hz), 7.61-7.76 (3 H, m), 8.16 (1 H, d, J = 8.9 Hz), 8.18 (1 H, s).


 


1495




—CH3
—N(CH3)—
—CH2—
free
1H NMR (CDCl3) 2.09 (3 H, s), 2.34-2.48 (4 H, m), 2.98 (3 H, s), 3.42 (2 H, s), 3.40-3.55 (2 H, m), 3.55-3.70 (2 H, m), 3.84 (3 H, s), 4.06 (2 H, s), 5.94 (2 H, s), 6.46- 6.55 (2 H, m), 6.67-6.76 (2 H, m), 6.77 (1 H, d, J = 8.9 Hz), 6.85 (1 H, s), 6.89 (1 H, d, J = 8.5 Hz), 6.93- 6.98 (1 H, m), 6.97 (1 H, dd, J = 8.9 Hz, 2.3 Hz), 7.04 (1 H, d, J = 2.3 Hz), 7.30 (1 H, d, J = 8.9 Hz), 8.11 (1 H, dd, J = 8.9 Hz, 2.5 Hz), 8.22 (1 H, s), 8.25 (1 H, d, J = 2.5 Hz), 9.45 (1 H, s).


 


1496
3,4-(CH3)2Ph-
—H
—CH2—
—CH2—
free
1H NMR (CDCl3) 2.31-2.38 (10 H, m), 2.57-2.63 (2 H, m), 2.91- 2.97 (2 H, m), 3.37-3.40 (4 H, m), 3.59-3.63 (2 H, m), 5.93 (2 H, s), 6.70-6.77 (2 H, m), 6.84 (1 H, s), 6.91 (1 H, d, J = 8.9 Hz), 7.00-7.05 (2 H, m), 7.17-7.22 (3 H, m), 7.60 (1 H, dd, J = 7.8 Hz, 1.9 Hz), 7.66 (1 H, d, J = 1.9 Hz), 8.16- 8.26 (3 H, m).


 


1497




—H
—CH2—
—CH2—
free
1H NMR (DMSO-d6) 2.41 (4 H, brs), 2.62 (2 H, t, J = 7.5 Hz), 2.81 (2 H, t, J = 7.5 Hz), 3.32 (1 H, brs), 3.47 (4 H, brs), 3.52 (2 H, s), 6.00 (2 H, s), 6.78 (1 H, d, J = 8.0 Hz), 6.87 (1 H, d, J = 8.0 Hz), 6.88 (1 H, d, J = 2.0 Hz), 7.00 (2 H, d, J = 8.5 Hz), 7.03 (1 H, d, J = 8.9 Hz), 7.26 (2 H, d, J = 8.5 Hz), 7.94 (1 H, s), 8.05 (1 H, s), 8.10 (1 H, dd, J = 8.9 Hz, 2.6 Hz), 8.36 (1 H, d, J = 2.6 Hz), 10.72 (1 H, s).


 


1498




—CH3
—N(CH3)—
—CH2—
hydro- chloride
mp 145.0-148.0


 


1499




—CH3
—N(CH3)—
—CO—
free
mp 269.0-272.0
















TABLE 285







 








 












Example







No.
R866
R867
R868
Form
1H NMR (solvent) δ ppm





1500
3,4-Cl2Ph-
—CH3




hydro- chloride
(DMSO-d6) 2.08 (3 H, s), 3.09 (1 H, dd, J = 14.2 Hz, 9.7 Hz), 3.40 (1 H, dd, J = 14.2 Hz, 4.2 Hz), 4.93 (1 H, dd, J = 9.7 Hz, 4.2 Hz), 7.00 (1 H, d, J = 8.3 Hz), 7.02 (1 H, d, J = 8.9 Hz), 7.11 (1 H, dd, J = 8.3 Hz, 2.0 Hz), 7.20 (1 H, d, J = 2.0 Hz), 7.83 (1 H, d, J = 8.4 Hz), 7.95 (1 H, dd, J = 8.4 Hz, 2.0 Hz), 8.18 (1 H, dd, J = 8.9 Hz, 2.5 Hz), 8.23 (1 H, d, J = 2.0 Hz), 8.44 (1 H, d, J = 2.5 Hz), 10.57 (1 H, s), 12.08 (1 H, s).


 


1501
4-CF3Ph-
—CH3




free
(DMSO-d6) 2.09 (3 H, s), 3.09 (1 H, dd, J = 14.1 Hz, 9.6 Hz), 3.40 (1 H, dd, J = 14.1 Hz, 4.3 Hz), 4.93 (1 H, dd, J = 9.6 Hz, 4.3 Hz), 6.99 (1 H, d, J = 8.2 Hz), 7.03 (1 H, d, J = 8.9 Hz), 7.12 (1 H, dd, J = 8.2 Hz, 2.0 Hz), 7.20 (1 H, d, J = 2.0 Hz), 7.93 (2 H, d, J = 8.2 Hz), 8.16 (2 H, d, J = 8.2 Hz), 8.20 (1 H, dd, J = 8.9 Hz, 2.5 Hz), 8.45 (1 H, d, J = 2.5 Hz), 10.60 (1 H, s), 12.07 (1 H, s).


 


1502
3-CF3Ph-
—H




free
(CDCl3) 1.28 (3 H, t, J = 7.0 Hz), 1.46 (2 H, dq, J = 4.0 Hz, 12.5 Hz), 1.85 (2 H, brd, J = 12.5 Hz), 1.93 (1 H, m), 2.73 (2 H, dt, J = 2.5 Hz, 12.0 Hz), Hz), 3.61 (2 H, brd, J = 12.0 Hz), 4.15 (2 H, q, J = 7.0 Hz), 6.90 (1 H, d, J = 9.0 Hz), 6.96 (2 H, d, J = 9.0 Hz), 7.03 (2 H, d, J = 9.0 Hz), 7.65 (1 H, t, J = 8.0 Hz), 7.83 (1 H, d, J = 8.0 Hz), 7.86 (1 H, brs), 8.07 (1 H, d, J = 8.0 Hz), 8.14 (1 H, brs), 8.18 (1 H, dd, J = 9.0 Hz, 2.5 Hz), 8.27 (1 H, d, J = 2.5 Hz).









Example 1503
Production of N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide
To a suspension of 1-(4-piperonylpiperazin-1-yl)-2-{methyl-[3-methyl-4-(5-nitropyridin-2-yloxy)phenyl]amino}ethanone (2.65 g, 5.10 mmol) in ethyl acetate (50 mL) was added 5% platinum-carbon (0.20 g) under a nitrogen atmosphere, and the resulting mixture was stirred for 11 hours under a hydrogen atmosphere. The platinum-carbon was separated off by filtration using Celite. To a solution of the resulting filtrate in ethyl acetate was added triethylamine (0.78 mL, 5.61 mmol) under ice cooling, and then to the resulting solution was added 4-(trifluoromethyl)benzoyl chloride (0.80 mL, 5.36 mmol). This reaction solution was stirred for 16 hours, and then added a saturated sodium bicarbonate solution. The resulting solution was stirred at room temperature, and after 20 minutes, extracted with ethyl acetate. The ethyl acetate layer was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from acetone-diethyl ether, to thereby yield 3.03 g of the title compound.
Appearance: Pale yellow powder
Melting point: 153.0-154.5° C.; 1H NMR (CDCl3) δ 2.12 (3H, s), 2.31-2.52 (4H, m), 3.01 (3H, s), 3.38-3.72 (6H, m), 4.07 (2H, s), 5.95 (2H, s), 6.49-6.61 (2H, m), 6.69-6.78 (2H, m), 6.79-6.88 (2H, m), 6.92 (1H, d, J=8.6 Hz), 7.76 (2H, d, J=8.3 Hz), 7.81-7.90 (1H, m), 7.99 (2H, d, J=8.3 Hz), 8.13 (1H, dd, J=8.8 Hz, 2.6 Hz), 8.23 (1H, d, J=2.6 Hz).
A crude titled product (5.00 g, 7.6 mmol) obtained using the same procedures was recrystallized from ethanol (15 mL), to thereby yield 3.90 g of the title compound.
Appearance: Pale yellow powder
Melting point: 156-158° C.
The following compounds were produced in the same manner as in Example 1503.
Example 1504
N-{6-[2-methyl-4-(2-oxo-3-piperonylimidazolidin-1-yl)phenoxy]pyridin-3-yl}-4-trifluoromethylbenzamide
mp 188.0-189.0° C.







TABLE 286







 








 















Example







mp (° C.) or 1H NMR


No.
R869
R870
R871
R872
R873
M
Form
(solvent) δ ppm


1505
—Cl
—Cl
cyclopentyl
—H
piperonyl
2
oxalate
mp 135-139





1506
—Cl
—Cl
—(CH2)2CH3
—H
piperonyl
2
free
1H NMR (DMSO-d6)










0.86 (3 H, t, J = 7.5 Hz),










1.56 (2 H, q, J = 7.5 Hz),










2.27 (2 H, brs), 2.64 (2 H, t,










J = 7.4 Hz), 2.83 (2 H, t, J =










7.4 Hz), 3.37-3.48 (6 H, m),










3.84 (2 H, t, J = 7.5 Hz),










5.98 (2 H, s), 6.36 (1 H, d, J =










9.1 Hz), 6.74 (1 H, d, J =










7.9 Hz), 6.83 (1 H, d, J =










7.9 Hz), 6.86 (1 H, s),










7.16 (2 H, d, J = 8.2 Hz),










7.30 (2 H, d, J = 8.2 Hz),










7.70 (1 H, dd, 9.1 Hz,










2.6 Hz), 7.81 (1 H, d, J =










8.4 Hz), 7.93 (1 H, dd, J =










8.4 Hz, 1.9 Hz), 8.19 (1 H,










d, J = 1.9 Hz), 8.43 (1 H, d,










J = 2.6 Hz), 10.27 (1 H, s).


1507
—Cl
—Cl
—CH3
—OCH3
piperonyl
2
free
1H NMR (CDCl3) 2.34-










2.41 (4 H, m), 2.62-2.68 (2 H,










m), 2.95-3.01 (2 H, m),










3.34 (3 H, s), 3.38-3.45 (4 H,










m), 3.62-3.65 (2 H, m),










3.75 (3 H, s), 5.94 (2 H, s),










6.25 (1 H, d, J = 9.2 Hz),










6.70-6.84 (5 H, m), 7.12 (1 H,










d, J = 7.6 Hz), 7.53 (1 H, d,










J = 8.2 Hz), 7.67-7.72 (2 H,










m), 7.97 (2 H, d, J = 2.0 Hz),










8.24 (1 H, d, J = 2.5 Hz).


1508
—CF3
—H
—CH3
—OCH3
piperonyl
2
free
1H NMR (CDCl3) 2.36-










2.37 (4 H, m), 2.62-2.67 (2 H,










m), 2.94-2.99 (2 H, m),










3.28-3.45 (7 H, m), 3.60-










3.64 (2 H, m), 3.74 (3 H, s),










5.93 (2 H, s), 6.25 (1 H, d, J =










9.1 Hz), 6.70-6.84 (5 H,










m), 7.11 (1 H, d, J = 7.6 Hz),










7.67-7.75 (3 H, m),










7.97 (2 H, d, J = 7.9 Hz),










8.16-8.32 (2 H, m).


1509
—Cl
—Cl
—CH3
—H
benzyl
0
oxalate
mp 228-230
















TABLE 287







 








 














Example






mp (° C.) or 1H NMR


No.
R874
R875
R876
R877
R878
Form
(solvent) δ ppm

















1510
—Cl
—Cl
—H




piperonyl
dioxalate
1H NMR (DMSO-d6) 2.36- 2.50 (4 H, m), 2.73 (6 H, s), 3.42-3.56 (6 H, m), 3.94 (2 H, s), 4.56 (2 H, s), 5.98 (2 H, s), 6.76 (1 H, d, J = 8.0 Hz), 6.85 (1 H, d, J = 8.0 Hz), 6.88 (1 H, s), 7.13 (1 H, d, J = 8.9 Hz), 7.23 (2 H, d; J = 8.8 Hz), 7.45 (2 H, d, J = 8.8 Hz), 7.83 (1 H, d, J = 8.4 Hz), 7.93 (1 H, dd, J = 8.4 Hz, 2.0 Hz), 8.20-8.25 (2 H, m), 8.52 (1 H, d, J = 2.7 Hz), 10.63 (1 H, s).


 


1511
—CF3
—H
—CH3
—H
piperonyl
free
1H NMR (CDCl3) 2.11 (3 H,









s), 2.42-2.48 (4 H, m), 3.45-









3.48 (4 H, m), 3.66-3.70 (2 H,









m), 3.86 (2 H, s), 4.83 (1 H,









brs), 5.96 (2 H, s), 6.46-









6.52 (2 H, m), 6.71-6.78 (2 H,









m), 6.83-6.91 (3 H, m), 7.75-









7.82 (3 H, m), 7.99 (2 H, d, J =









8.1 Hz), 8.16 (1 H, dd, J =









8.9 Hz, 2.8 Hz), 8.22 (1 H, d,









J = 2.8 Hz).


1512
—Cl
—Cl
—CH3
—CH3
piperonyl
hydro-
mp 183-185 dec








chloride



1513
—CF3
—H
—CH3
—C2H5
benzyl
maleate
mp 165-167


1514
—Cl
—Cl
—CH3
—C2H5
benzyl
free
mp 102-105


1515
—CF3
—H
—CH3
—CH3
benzyl
free
mp 110-111


1516
—Cl
—Cl
—CH3
—CH3
benzyl
free
mp 111-113
















TABLE 288







 








 










Example





No.
R879
Form
mp (° C.) or MS





1517
3,4-Cl2Ph-
maleate
mp 203-205


1518
3-PhOPh-
free
MS 686 (M+ + H)


1519
3,5-Cl2Ph-
free
MS 662 (M+ + H)


1520
3,5-(CH3)2Ph-
free
MS 622 (M+ + H)


1521
2,3-(CH3)2Ph-
free
MS 622 (M+ + H)


1522
2,3-Cl2Ph-
free
MS 662 (M+ + H)


1523
1-naphthyl
free
MS 644 (M+ + H)


1524
2,4-(CH3)2Ph-
free
MS 622 (M+ + H)


1525
3,4-(CH3)2Ph-
free
MS 622 (M+ + H)


1526
3,4-F2Ph-
free
MS 630 (M+ + H)


1527
3-CF3Ph-
free
MS 663 (M+ + H)


1528
3-CF3OPh-
free
MS 678 (M+ + H)


1529
4-CF3OPh-
free
MS 678 (M+ + H)


1530
3-ClPhOCH2—
free
MS 658 (M+ + H)


1531
2-quinolyl
free
MS 645 (M+ + H)


1532
4-quinolyl
free
MS 645 (M+ + H)


1533
1-isoquinolyl
free
MS 645 (M+ + H)


1534
3-isoquinolyl 
free
MS 645 (M+ + H)


1535
3,4-Cl2PhCH2—
free
MS 676 (M+ + H)


1536
2,4-Cl2PhCH2—
free
MS 676 (M+ + H)


1537
3,5-(CF3)2Ph-
free
MS 731 (M+ + H)


1538
2,4-Cl2PhOCH2—
free
MS 691 (M+ + H)


1539
4-CH3OPh-
free
MS 624 (M+ + H)


1540
4-CH3PhCH2—
free
MS 622 (M+ + H)


1541
PhOCH2—
free
MS 624 (M+ + H)


1542
3-pyridyl
free
MS 595 (M+ + H)


1543
—CH(CH3)2
free
MS 560 (M+ + H)


1544
cyclopentyl
free
MS 586 (M+ + H)


1545
cyclohexyl
free
MS 600 (M+ + H)


1546
cycloheptyl
free
MS 614 (M+ + H)


1547
cycloheptylmethyl
free
MS 628 (M+ + H)


1548
3-CH3Ph-
free
MS 608 (M+ + H)


1549
3-(CH3)2NPh-
free
MS 637 (M+ + H)


1550
4-(CH3)2NPh-
free
MS 637 (M+ + H)


1551
2,5-(CH3)2Ph-
free
MS 622 (M+ + H)


1552
—CH(CH3)Ph
free
MS 622 (M+ + H)


1553
—C(CH3)3
free
MS 574 (M+ + H)
















TABLE 289







 








 









Example




No.
R880
MS (M+ + H)





1554




626


 


1555




681


 


1556




681


 


1557




663


 


1558




646


 


1559




677


 


1560




661


 


1561




621


 


1562




601


 


1563




660


 


1564




661


 


1565




702
















TABLE 290







 








 









Example




No.
R881
MS (M+ + H)





1566




660


 


1567




679


 


1568




672


 


1569




759


 


1570




680


 


1571




651


 


1572




584


 


1573




616


 


1574




601


 


1575




601


 


1576




662


 


1577




704


 


1578




660
















TABLE 291













 
















Example










No.
Xb28
R882
R883
R884
R885
R886
MS (M+ + H)







1579
—NH—
—H
—H
—H
—H
—H
634



1580
—O—
—H
—H
—H
—H
—H
634



1581
—O—
—H
—H
—H
—H
—OCH3
664



1582
—NH—
—H
—H
—OCH3
—H
—H
663



1583
—NH—
—H
—H
—Cl
—H
—H
667



1584
—NH—
—H
—H
—F
—H
—H
651



1585
—N(CH3)—
—H
—H
—H
—H
—H
647



1586
—S—
—H
—H
—H
—H
—H
650



1587
—NH—
—H
—H
—Br
—H
—H
711



1588
—NH—
—H
—H
—CH3
—H
—H
648



1589
—NH—
—H
—H
—OCF3
—H
—H
717



1590
—NH—
—H
—OCH3
—H
—H
—H
664



1591
—NH—
—H
—Cl
—H
—H
—H
667



1592
—NH—
—H
—H
—H
—OCH3
—H
663



1593
—NH—
—H
—Cl
—H
—Cl
—H
701



1594
—NH—
—H
—H
—H
—Cl
—H
667



1595
—NH—
—H
—H
—OCH3
—OCH3
—H
693



1596
—O—
—CH3
—H
—H
—H
—H
648



1597
—O—
—H
—H
—OCH3
—H
—H
664



1598
—O—
—H
—H
—Cl
—H
—H
668

















TABLE 292













 













Example








No.
R887
R888
R889
R890
R891
MS (M+ + H)





1599
—H
—OCH3
—H
—H
—H
650


1600
—H
—H
—OCH3
—H
—H
650


1601
—H
—Cl
—H
—H
—H
654


1602
—F
—H
—H
—H
—H
638


1603
—H
—F
—H
—H
—H
638


1604
—OCH3
—OCH3
—H
—H
—H
680


1605
—OCH3
—H
—H
—OCH3
—H
680


1606
—H
—OCH3
—OCH3
—H
—H
680


1607
—Cl
—H
—H
—H
—Cl
688


1608
—H
—Cl
—Cl
—H
—H
688


1609
—F
—H
—H
—H
—F
656


1610
—H
—F
—H
—F
—H
656












1611
—H
—OCH2O—
—H
—H
664













1612
—H
—OCH3
—OCH3
—OCH3
—H
711


1613
—H
—OCH3
—H
—OCH3
—H
681


1614
—H
—CF3
—H
—H
—H
689









Example 1615
Production of 3,4-dichloro-N-[6-(2-fluoro-4-{methyl[2-oxo-2-(4-piperonylpiperazin-1-yl)ethyl]amino}phenoxy)pyridin-3-yl]benzenesulfonamide
To a solution of 2-{[4-(5-aminopyridin-2-yloxy)-3-fluorophenyl]methylamino}-1-(4-piperonylpiperazin-1-yl)ethanone (15.85 g, 1.9 mmol) in dichloromethane (150 mL) were added 3,4-dichlorobenzenesulfonyl chloride (12.92 g, 1.9 mmol) and pyridine (11 mL, 12.4 mmol), and the resulting solution was stirred for 1 hour at room temperature. Water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from ethanol, to thereby yield 5.6 g of the title compound.
Appearance: White powder; Melting point: 185.6-187.0° C.;
1H NMR (CDCl3) δ 2.45 (4H, t, J=4.6 Hz), 3.01 (3H, s), 3.44 (2H, s), 3.47 (2H, brs), 3.64 (2H, brs), 4.07 (2H, s), 5.95 (2H, s), 6.33-6.44 (2H, m), 6.71-6.78 (2H, m), 6.84-6.87 (2H, m), 6.98 (1H, t, J=9.1 Hz), 7.47 (1H, dd, J=8.4 Hz, 2.0 Hz), 7.51 (2H, dd, J=8.4 Hz, 2.8 Hz), 7.68 (1H, d, J=2.1 Hz), 7.83 (1H, d, J=1.8 Hz); MS 701 (M+).
The following compounds were produced in the same manner as in Example 1615.







TABLE 293













 













Example








No.
R892
R893
R894
R895
M
1H NMR (solvent) δppm





1616
—CH3
—H
—H
benzyl
2
(CDCl3) 2.29-2.37(2 H, m), 2.37-2.45(5 H, m),








2.61(2 H, t, J = 7.9 Hz), 2.95(2 H, t, J = 7.9








Hz), 3.35-3.42(2 H, m), 3.50(2 H, s), 3.59-








3.68(2 H, m), 6.58(1 H, brs), 6.83(1 H, d, J =








8.8 Hz), 7.00(2 H, d, J = 8.4 Hz), 7.18-








7.38(9 H, m), .755-7.63(3 H, m), 7.68(1 H, d, J =








2.8 Hz).


1617
—CF3
—H
—H
benzyl
0
(CDCl3) 2.46(4 H, brs), 3.54(2 H, s), 3.54(2 H,








brs), 3.79(2 H, brs), 6.88(1 H, d, J = 8.7 Hz),








7.10(2 H, d, J = 8.6 Hz), 7.28-7.33(5 H, m),








7.42(2 H, d, J = 8.6 Hz), 7.59(1 H, dd, J = 8.7








Hz, 2.8 Hz), 7.73(2 H, d, J = 8.4 Hz), 7.74(1 H,








s), 7.86(2 H, d, J = 8.4 Hz).


1618
—CF3
—H
—CH3
piperonyl
2
(DMSO-d6) 1.96(3 H, s), 2.20-2.40(4 H, m),








2.56-2.62(2 H, m), 2.73-2.78(2 H, m),








3.32(2 H, s), 3.37-3.43(4 H, m), 5.99(2 H, s),








6.74(1 H, dd, J = 7.9 Hz, 1.3 Hz), 6.82-








6.93(4 H, m), 7.05(1 H, dd, J = 8.2 Hz, 1.9 Hz),








7.12(1 H, s), 7.52(1 H, dd, J = 8.8 Hz, 2.7 Hz),








7.73(1 H, d, J = 2.7 Hz), 7.89-7.98(4 H, m),








10.45(1 H, brs).


1619
—Cl
—Cl
—OCH3
piperonyl
2
(DMSO-d6) 2.20-2.40(4 H, m), 2.58-2.64(2 H,








m), 2.75-2.81(2 H, m), 3.37-3.43(6 H, m),








3.60(3 H, s), 5.97(2 H, s), 6.70-7.00(7 H, m),








7.47(1 H, dd, J = 8.8 Hz, 2.8 Hz), 7.61(1 H, dd,








J = 8.5 Hz, 2.1 Hz), 7.68(1 H, d, J = 2.6 Hz),








7.82-7.86(2 H, m), 10.32(1 H, brs).


1620
—CF3
—H
—OCH3
piperonyl
2
(DMSO-d6) 2.20-2.40(4 H, m), 2.55-2.70(2 H,








m), 2.75-2.85(2 H, m), 3.30-3.50(6 H, m),








3.58(3 H, s), 5.97(2 H, s), 6.71-7.00(7 H, m),








7.47(1 H, dd, J = 8.8 Hz, 2.7 Hz), 7.67(1 H, d,








J = 2.7 Hz), 7.87-7.98(4 H, m), 10.40(1 H,








brs).


1621
—Cl
—Cl
—CH3
piperonyl
2
(DMSO-d6) 1.97(3 H, s), 2.20-2.35(4 H, m),








2.56-2.62(2 H, m), 2.73-2.79(2 H, m), 3.37-








3.50(6 H, m), 5.98(2 H, s), 6.72-6.76(1 H, m),








6.82-6.94(4 H, m), 7.00-7.13(2 H, m), 7.52(1 H,








dd, J = 8.8 Hz, 2.8 Hz), 7.62(1 H, dd, J = 8.4








Hz, 2.1 Hz), 7.72(1 H, d, J = 2.6 Hz), 7.83(1 H,








d, J = 2.1 Hz), 7.85(1 H, d, J = 8.5 Hz),








10.36(1 H, brs).


1622
—CF3
—H
—F
piperonyl
2
(DMSO-d6) 2.20-2.35(4 H, m), 2.60-2.66(2 H,








m), 2.78-2.84(2 H, m), 3.39(2 H, s), 3.42-








3.50(4 H, m), 5.99(2 H, s), 6.72-6.76(1 H, m),








6.83-6.86(2 H, m), 7.03-7.24(4 H, m), 7.55(1 H,








dd, J = 8.8 Hz, 2.7 Hz), 7.75(1 H, d, J = 2.7








Hz), 7.90-7.99(4 H, m), 10.52(1 H, brs).
















TABLE 294













 











Example



mp (° C.) or 1H NMR (solvent)


No.
R896
R897
R898
δppm





1623
—CF3
—H




mp 208.0-209.0


 


1624
—Cl
—Cl




1H NMR (CDCl3) 1.70(1 H, brs), 2.42(4 H, t, J = 5.1 Hz), 3.39(4 H, t, J = 5.1 Hz), 3.43(2 H, s), 4.38(2 H, d, J = 5.4 Hz), 4.80(1 H, t, J = 5.4 Hz), 5.94(2 H, s), 6.73(2 H, s), 6.84(1 H, s), 6.86(1 H, d, J = 8.5 Hz), 7.00(2 H, d, J = 8.6 Hz), 7.27(2 H, d, J = 8.6 Hz), 7.51(2 H, d, J = 2.5 Hz), 7.58(1 H, dd, J = 8.7 Hz, 2.7 Hz), 7.73(1 H, dd, J = 2.7 Hz, 0.7 Hz), 7.83(1 H, t, J = 2.5 Hz).


 


1625
—Cl
—Cl




1H NMR (DMSO-d6) 2.20- 2.35(4 H, m), 2.56-2.62(2 H, m), 2.77-2.82(2 H, m), 3.30-3.50(6 H, m), 5.98(2 H, s), 6.70-6.80(1 H, m), 6.82-6.90(3 H, m), 6.93- 6.97(2 H, m), 7.05-7.10(1 H, m), 7.24-7.35(1 H, m), 7.54(1 H, dd, J = 8.8 Hz, 2.8 Hz), 7.64(1 H, dd, J = 8.5 Hz, 2.0 Hz), 7.80(1 H, d, J = 2.8 Hz), 7.86(1 H, d, J = 8.4 Hz), 7.89(1 H, d, J = 2.0 Hz), 10.43(1 H, brs).


 


1626
—CF3
—H




1H NMR (DMSO-d6) 2.20- 2.30(4 H, m), 2.55-2.61(2 H, m), 2.76-2.82(2 H, m), 3.30-3.40(6 H, m), 5.98(2 H, s), 6.70-6.80(1 H, m), 6.82-6.95(5 H, m), 7.05(1 H, d, J = 7.7 Hz), 7.23-7.30(1 H, m), 7.54(1 H, dd, J = 8.8 Hz, 2.8 Hz), 7.80(1 H, d, J = 2.8 Hz), 7.90- 7.99(4 H, m), 10.52(1 H, brs).


 


1627
—Cl
—Cl




1H NMR (DMSO-d6) 2.25- 2.45(4 H, m), 3.42(2 H, s), 3.50- 3.75(4 H, m), 5.99(2 H, s), 6.75- 6.80(1 H, m), 6.83-6.88(2 H, m), 7.00(1 H, d, J = 8.8 Hz), 7.05- 7.10(1 H, m), 7.25-7.29(1 H, m), 7.35-7.65(6 H, m), 7.80(1 H, d, J = 2.7 Hz), 7.86(1 H, d, J = 8.4 Hz), 7.90(1 H, d, J = 2.1 Hz), 10.44 (1 H, brs).
















TABLE 295













 











Example






No.
R899
R900
M
mp (° C.) or 1H NMR (DMSO-d6) δppm





1628
4-CF3Ph-
piperonyl
2
1H NMR 1.89-2.06(5 H, m), 3.17-3.31(2 H,






m), 3.52-3.71(2 H, m), 4.39(2 H, s), 5.98(2 H,






m), 6.75(1 H, dd, J = 1.2 Hz, 7.9 Hz),






6.83(1 H, d, J = 1.2 Hz), 6.86(1 H, d, J = 7.9






Hz), 6.92(1 H, d, J = 8.6 Hz), 6.95(1 H, d, J =






8.8 Hz), 7.09(1 H, dd, J = 2.5 Hz, 8.6 Hz),






7.18(1 H, d, J = 2.5 Hz), 7.53(1 H, dd, J = 2.8






Hz, 8.8 Hz), 7.75(1 , d, J = 2.8 Hz),






7.90(2 H, d, J = 8.4 Hz), 7.96(2 H, d, J = 8.4






Hz), 10.47(1 H, s).


1629
3,4-Cl2Ph-
piperonyl
2
1H NMR (1.89-2.09(5 H, m), 3.19-3.33(2 H,






m), 3.50-3.71(2 H, m), 4.39(2 H, s), 5.98(2 H,






s), 6.73-6.78(1 H, m), 6.83(1 H, d, J = 1.3






Hz), 6.86(1 H, d, J = 7.9 Hz), 6.93(1 H, d, J =






8.6 Hz), 6.97(1 H, d, J = 8.8 Hz), 7.10(1 H, d,






J = 2.4 Hz, 8.6 Hz), 7.19(1 H, d, J = 2.4 Hz),






7.53(1 H, dd, J = 2.7 Hz, 8.8 Hz), 7.62(1 H,






dd, J = 2.1 Hz, 8.4 Hz), 7.75(1 H, d, J = 2.7






Hz), 7.83(1 H, d, J = 2.1 Hz), 7.85(1 H, d, J =






8.4 Hz), 10.37(1 H, s).


1630
4-CF3Ph-
piperonyl
1
mp 163.0-164.0


1631
3,4-Cl2Ph-
piperonyl
1
mp 190.5-191.0


1632
4-CF3Ph-
3,4-(CH3O)2PhCH2—
2
mp 141.0-143.0


1633
3,4-Cl2Ph-
3,4-(CH3O)2PhCH2—
2
mp 135.0-136.0


 


1634
3,4-Cl2Ph-




2
mp 181.0-183.0
















TABLE 296













 











Example
R901
R902
M
1H NMR (CDCl3) δppm





1635
3,4-Cl2Ph-
—CH3
0
1.27(3 H, t, J = 7.1 Hz), 1.84-2.05(4 H, m), 2.06(3 H, s),






2.40-2.48(1 H, m), 2.71-2.81(2 H, m), 3.56-3.61(2 H, m),






4.16(2 H, q, J = 7.1 Hz), 6.74-6.79(3 H, m), 6.89(1 H, d, J =






8.6 Hz), 7.47-7.57(4 H, m), 7.76-7.79(2 H, m).


1636
4-CF3Ph-
—CH3
0
1.27(3 H, t, J = 7.1 Hz), 1.84-2.00(4 H, m), 2.03(3 H, s),






2.42-2.51(1 H, m), 2.70-2.79(2 H, m), 3.55-3.60(2 H, m),






4.16(2 H, q, J = 7.1 Hz), 6.68-6.78(3 H, m), 6.87(1 H, d, J =






8.6 Hz), 7.55(1 H, dd, J = 8.7 Hz, 2.6 Hz), 7.67(2 H, d, J =






8.2 Hz), 7.79-7.84(3 H, m), 8.10(1 H, s).


1637
3,4-Cl2Ph-
—H
1
1.27(3 H, t, J = 7.1 Hz), 1.39-1.48(2 H, m), 1.81-1.92(3 H,






m), 2.29(2 H, d, J = 6.9 Hz), 2.71(2 H, dd, J = 12.2 Hz, 9.9






Hz), 3.59(2 H, d, J = 12.4 Hz), 4.15(2 H, q, J = 7.3 Hz),






6.78(1 H, d, J = 8.7 Hz), 6.90-6.98(4 H, m), 7.50(2 H, d, J =






1.2 Hz), 7.55(1 H, dd, J = 8.7 Hz, 2.6 Hz), 7.78-7.81(3 H,






m).


1638
4-CF3Ph-
—H
1
1.27(3 H, t, J = 7.1 Hz), 1.36-1.48(2 H, m), 1.81-1.92(3 H,






m), 2.29(2 H, d, J = 6.9 Hz), 2.70(2 H, dd, J = 12.2 Hz, 9.9






Hz), 3.59(2 H, d, J = 12.2 Hz), 4.15(2 H, q, J = 7.3 Hz),






6.75(1 H, d, J = 8.9 Hz), 6.89-6.97(4 H, m), 7.55(1 H, dd, J =






8.7 Hz, 2.6 Hz), 7.68(2 H, d, J = 8.7 Hz), 7.79-7.85(4 H,






m).


1639
4-CF3Ph-
—OCH3
1
1.27(3 H, t, J = 7.1 Hz), 1.30-1.48(2 H, m), 1.82-2.05(3 H,






m), 2.29(2 H, d, J = 6.9 Hz), 2.69-2.77(2 H, m), 3.60(2 H, d,






J = 12.2 Hz), 3.68(3 H, s), 4.15(2 H, q, J = 7.1 Hz),






6.48(1 H, dd, J = 8.6 Hz, 2.5 Hz), 6.56(1 H, d, J = 2.6 Hz),






6.76(1 H, d, J = 8.7 Hz), 6.94(1 H, d, J = 8.7 Hz), 7.54(1 H,






dd, J = 8.7 Hz, 2.8 z), 7.66-7.73(4 H, m), 7.83(2 H, d, J =






8.2 Hz).


1640
3,4-Cl2Ph-
—OCH3
1
1.28(3 H, t, J = 7.1 Hz), 1.30-1.48(2 H, m), 1.82-2.05(3 H,






m), 2.29(2 H, d, J = 6.9 Hz), 2.73(2 H, t, J = 12.0 Hz),






3.60(2 H, d, J = 12.2 Hz), 3.69(3 H, s), 4.16(2 H, q, J = 7.1






Hz), 5.29(2 H, s), 6.48(1 H, dd, J = 8.7 Hz, 2.6 Hz),






6.56(1 H, d, J = 2.6 Hz), 6.77(1 H, d, J = 8.7 Hz), 6.94(1 H,






d, J = 8.6 Hz), 7.46-7.75(3 H, m), 7.79-7.80(3 H, m).


1641
4-CF3Ph-
—H
0
1.27(3 H, t, J = 7.1 Hz), 1.81-1.94(2 H, m), 2.00-2.05(2 H,






m), 2.40-2.54(1 H, m), 2.71-2.82(2 H, m), 3.56-3.60(2 H, m),






4.16(2 H, q, J = 7.1 Hz), 6.78(1 H, d, J = 8.9 Hz), 6.90-






6.99(5 H, m), 7.56(1 H, dd, J = 8.9 Hz, 2.8 z), 7.70(2 H, d, J =






8.4 Hz), 7.77(1 H, d, J = 2.8 Hz), 7.84(2 H, d, J = 8.2 Hz).


1642
3,4-Cl2Ph-
—H
0
1.27(3 H, t, J = 7.3 Hz), 1.89-1.94(2 H, m), 2.01-2.05(2 H,






m), 2.38-2.54(1 H, m), 2.72-2.82(2 H, m), 3.56-3.61(2 H, m),






4.16(2 H, q, J = 7.1 Hz), 6.80(1 H, d, J = 8.7 Hz), 6.91-






7.00(4 H, m), 7.26(1 H, brs), 7.51-7.58(3 H, m), 7.77(1 H, d,






J = 2.8 Hz), 7.82(1 H, s).
















TABLE 297













 











Example






No.
R903
R904
M
1H NMR (CDCl3) δppm





1643
4-CF3Ph-
—CH3
1
1.27(3 H, t, J = 7.1 Hz), 1.38-1.43(2 H, m), 1.80-






2.01(3 H, m), 2.02(3 H, s), 2.29(2 H, d, J = 6.9 Hz),






2.69(2 H, t, J = 12.0 Hz), 3.58(2 H, d, J = 12.0 Hz),






4.15(2 H, q, J = 7.3 Hz), 6.67-6.87(4 H, m), 7.53-






7.68(3 H, m), 7.79-7.84(4 H, m).


1644
3,4-Cl2Ph-
—CH3
1
1.27(3 H, t, J = 7.1 Hz), 1.30-1.48(2 H, m), 1.80-






2.04(3 H, m), 2.05(3 H, s), 2.29(2 H, d, J = 6.9 Hz),






2.69(2 H, t, J = 12.0 Hz), 3.58(2 H, d, J = 12.0 Hz),






4.15(2 H, q, J = 7.1 Hz), 6.71-6.79(3 H, m), 6.88(1 H, d, J =






8.6 Hz), 7.49-7.57(4 H, m), 7.77(2 H, d, J = 2.8 Hz).
















TABLE 298













 












Example







No.
R905
R906
R907
Form
mp (° C.)





1645
4-CF3Ph-
—H
—CH3
hydrochloride
189.0-191.0


1646
3,4-Cl2Ph-
—H
—CH3
free
180.0-182.0


1647
4-CF3Ph-
—CH3
—H
free
129.5-131.0


1648
3,4-Cl2Ph-
—CH3
—H
free
129.0-130.0
















TABLE 299













 










Example





No.
R908
R909
1H NMR (DMSO-d6) δppm





1649




—F
2.20-2.35(4 H, m), 2.60-2.66(2 H, m), 2.77-2.83(2 H, m), 3.39(2 H, s), 3.39-3.50(4 H, m), 5.99(2 H, s), 6.65-6.76(1 H, m), 6.83-6.86(2 H, m), 7.01-7.25(4 H, m), 7.30-7.40(1 H, m), 7.55(1 H, dd, J = 8.8 Hz, 2.8 Hz), 7.72(1 H, dd, J = 8.7 Hz, 2.6 Hz), 7.78(1 H, d, J = 2.3 Hz), 8.00-8.05(1 H, m), 10.65(1 H, brs).


 


1650




—CH3
1.94(3 H, s), 2.20-2.35(4 H, m), 2.56-2.61(2 H, m), 2.72- 2.78(2 H, m), 3.38(2 H, s), 3.38-3.50(4 H, m), 5.98(2 H, s), 6.72-6.75(1 H, m), 6.82-6.91(4 H, m), 7.03-7.12(2 H m), 7.30-7.45(1 H, m), 7.52(1 H, dd, J = 8.8 Hz, 2.2 Hz), 7.71(1 H, dd, J = 8.7 Hz, 2.1 Hz), 7.78(1 H, d, J = 2.7 Hz), 7.98-8.04(1 H, m), 10.58(1 H, brs).


 


1651
3,4-Cl2Ph-
—H
2.20-2.35(4 H, m), 2.57-2.63(2 H, m), 2.76-2.82(2 H, m),





3.39(2 H, s), 3.39-3.43(4 H, m), 5.99(2 H, s), 6.70-6.76(1 H,





m), 6.82-6.86(2 H, m), 6.93-6.98(3 H, m), 7.22-7.26(2 H, m),





7.51-7.55(1 H, m), 7.63(1 H, dd, J = 8.5 Hz, 2.0 Hz),





7.79(1 H, d, J = 2.7 Hz), 7.86(1 H, d, J = 8.5 Hz), 7.88(1 H,





d, J = 2.1 Hz), 10.41(1 H, brs).


1652
4-CF3Ph-
—H
2.20-2.35(4 H, m), 2.57-2.63(2 H, m), 2.76-2.82(2 H, m),





3.32(2 H, s), 3.32-3.50(4 H, m), 5.98(2 H, s), 6.70-6.76(1 H,





m), 6.82-6.86(2 H, m), 6.92-6.98(3 H, m), 7.22-7.25(2 H, m),





7.52(1 H, dd, J = 8.8 Hz, 2.8 Hz), 7.78(1 H, d, J = 2.7 Hz),





7.90-7.99(4 H, m), 10.50(1 H, brs).


1653
3,4-Cl2Ph-
—F
2.20-2.35(4 H, m), 2.60-2.66(2 H, m), 2.78-2.84(2 H, m),





3.39(2 H, s), 3.42-3.50(4 H, m), 5.99(2 H, s), 6.70-6.7(1 H,





m), 6.82-6.86(2 H, m), 7.04-7.30(4 H, m), 7.55(1 H, dd, J =





8.8 Hz, 2.8 Hz), 7.63(1 H, dd, J = 8.5 Hz, 2.2 Hz), 7.75(1 H,





d, J = 2.6 Hz), 7.85(1 H, d, J = 8.5 Hz), 7.88(1 H, d, J = 2.1





Hz), 10.43(1 H, brs).
















TABLE 300













 












Example







No.
R910
R911
R912
R913
mp (° C.) or 1H NMR (solvent) δppm





1654
4-CF3Ph-
—F
—H
—CH3
mp 186.0-188.0


1655
3,4-Cl2Ph-
—F
—H
—C2H5
mp 157.3-160.1


1656
4-CF3Ph-
—F
—H
—C2H5
mp 173.0-176.8


1657
4-CF3Ph-
—OCH3
—H
—C2H5
mp 179.0-181.0


1658
3,4-Cl2Ph-
—OCH3
—H
—C2H5
mp 175.0-176.0


1659
4-CF3Ph-
—CH3
—H
—CH3
mp 170.0-172.0


1660
3,4-Cl2Ph-
—CH3
—H
—CH3
mp 170.0-173.0


1661
3,4-Cl2Ph-
—H
—H
—CH3
mp 135.0-137.0


1662
4-CF3Ph-
—H
—H
—CH3
mp 189.0-190.0


1663
4-CF3Ph-
—F
—F
—CH3
mp 159.5-160.0


1664
3,4-Cl2Ph-
—F
—F
—CH3
mp 136.0-137.0


1665
Ph-
—H
—H
—CH3
1H NMR (CDCl3) 2.41-2.45(4 H, m), 3.01(3 H,







s), 3.43(2 H, s), 3.47-3.49(2 H, m), 3.63(2 H,







brs), 4.07(2 H, s), 5.95(2 H, s), 6.63(1 H, brs),







6.66(2 H, d, J = 9.1 Hz), 6.71-6.77(3 H, m),







6.85(1 H, brs), 6.93(2 H, d, J = 9.1 Hz), 7.42-







7.59(4 H, m), 7.68-7.73(3 H, m).


1666
—(CH2)3CH3
—H
—H
—CH3
1H NMR (CDCl3) 0.93(3 H, t, J = 7.3 Hz),







1.36-1.50(2 H, m), 1.75-1.87(2 H, m), 2.41-







2.45(4 H, m), 3.01-3.06(5 H, m), 3.44(2 H, s),







3.47-3.49(2 H, m), 3.63(2 H, brs), 4.09(2 H, s),







5.95(2 H, s), 6.37(1 H, brs), 6.69(2 H, d, J =







9.1 Hz), 6.72-6.77(2 H, m), 6.82-6.96(2 H, m),







6.99(2 H, d, J = 9.1 Hz), 7.65(1 H, dd, J = 8.7







Hz, 2.8 H), 8.00(1 H, d, J = 2.8 Hz).


1667
4-CH3Ph-
—H
—H
—CH3
1H NMR (CDCl3) 2.39(3 H, s), 2.41-2.44(4 H,







m), 3.01(3 H, s), 3.43(2 H, s), 3.47-3.49(2 H,







m), 3.62(2 H, brs), 4.07(2 H, s), 5.95(2 H, s),







6.46-6.51(1 H, m), 6.66(2 H, d, J = 8.9 Hz),







6.70-6.77(3 H, m), 6.85(1 H, brs), 6.94(2 H, d,







J = 8.9 Hz), 7.23(2 H, d, J = 8.1 Hz),







7.50(1 H, dd, J = 8.2 Hz, 2.8 Hz), 7.58(2 H, d,







J = 8.4 Hz), 7.66(1 H, d, J = 2.6 Hz).


 


1668




—F
—H
—CH3
1H NMR (DMSO-d6) 2.25-2.45(4 H, m), 2.91(3 H, s), 3.42(6 H, brs), 4.26(2 H, s), 5.99(2 H, s), 6.30-6.40(1 H, m), 6.45-6.55(1 H, m), 6.74-6.77(1 H, m), 6.83-7.05(4 H, m), 7.30-7.45(1 H, m), 7.51(1 H, dd, J = 8.9 Hz, 2.8 Hz), 7.71(1 H, dd, J = 8.7 Hz, 2.5 Hz), 7.79(1 H, d, J = 2.7 Hz), 8.02(1 H, dd, J = 8.9 Hz, 5.9 Hz), 10.60(1 H, brs).


 


1669
3,4-Cl2Ph-
—COOCH3
—H
—C2H5
1H NMR (DMSO-d6) 1.11(3 H, t, J = 7.0 Hz),







2.20-2.5(4 H, m), 3.30-3.50(11 H, m),







4.22(2 H, s), 5.99(2 H, s), 6.75-7.00(7 H, m),







7.45-7.55(1 H, m), 7.60-7.70(2 H, m), 7.83-







7.87(2 H, m), 10.31(1 H, brs).
















TABLE 301













 












Example







No.
R914
R915
R916
R917
1H NMR (solvent) δppm





1670




—F
—CH3
—H
(DMSO-d6) 2.23(3 H, s), 2.25-2.45(4 H, m), 2.91(3 H, s), 3.41(6 H, brs), 3.83(3 H, s), 4.25(2 H, s), 5.99(2 H, s), 6.30-6.40(1 H, m), 6.45-6.55(1 H, m), 6.75-6.77(1 H, m), 6.83- 6.99(4 H, m), 7.07(1 H, d, J = 8.5 Hz), 7.30- 7.40(1 H, m), 7.48(1 H, d, J = 1.9 Hz), 7.51(1 H, dd, J = 8.8 Hz, 2.7 Hz), 7.74(1 H, d, J = 2.6 Hz), 9.85(1 H, brs).


 


1671
3,4-Cl2Ph-
—CH3
—CH3
—CH3
(CDCl3) 1.28(3 H, d, J = 6.6 Hz), 2.05(3 H,







s), 2.08-2.21(1 H, m), 2.33(2 H, brs),







2.50(1 H, brs), 2.75(3 H, s), 3.29-3.57(3 H,







m), 3.38(2 H, s), 3.77(1 H, brs), 4.55(1 H, q, J =







6.6 Hz), 5.94(2 H, s), 6.56-6.59(2 H, m),







6.68-6.75(2 H, m), 6.79-6.82(2 H, m), 6.89-







6.93(1 H, m), 7.51-7.52(2 H, m), 7.57(1 H, dd,







J = 8.9 Hz, 2.8 Hz), 7.71(1 H, dd, J = 2.8 Hz,







0.5 Hz), 7.79(1 H, dd, J = 1.7 Hz, 0.8 Hz).


1672
4-CF3Ph-
—CH3
—CH3
—CH3
(CDCl3) 1.28(3 H, d, J = 6.4 Hz), 2.07(3 H,







s), 2.17-2.20(1 H, m), 2.33-2.36(2 H, m),







2.47-2.49(1 H, m), 2.75(3 H, s), 3.28-







3.30(1 H, m), 3.38(2 H, s), 3.38-3.50(1 H, m),







3.52-3.56(1 H, m), 3.77-3.82(1 H, m),







4.55(1 H, q, J = 6.6 Hz), 5.94(2 H, s), 6.55-







6.59(2 H, m), 6.68-6.75(2 H, m), 6.78-







6.82(2 H, m), 6.89-6.92(1 H, m), 7.57(1 H, dd,







J = 8.7 Hz, 2.8 Hz), 7.70(1 H, dd, J = 2.8 Hz,







0.5 Hz), 7.73(2 H, d, J = 8.3 Hz), 7.85(2 H, d,







J = 8.3 Hz).


 


1673




—F
—CH3
—H
(DMSO-d6) 2.20-2.50(4 H, m), 2.91(3 H, s), 3.35-3.50(6 H, m), 4.26(2 H, s), 5.99(2 H, s), 6.20-6.30(1 H, m), 6.45-6.55(1 H, m), 6.75- 6.80(1 H, m), 6.84-7.01(4 H, m), 7.52(1 H, dd, J = 8.8 Hz, 2.7 Hz), 7.79(1 H, d, J = 2.8 Hz), 7.97(1 H, dd, J = 8.2 Hz, 1.5 Hz), 8.09(1 H, d, J = 8.2 Hz), 8.29(1 H, d, J = 1.5 Hz), 10.80(1 H, brs).


 


1674
4-PhOPh-
—F
—CH3
—H
(DMSO-d6) 2.20-2.45(4 H, m), 2.92(3 H, s),







3.35-3.50(6 H, m), 4.26(2 H, s), 5.99(2 H, s),







6.35-6.45(1 H, m), 6.45-6.60(1 H, m),







6.76(1 H, d, J = 7.9 Hz), 6.83-6.87(2 H, m),







6.93-7.14(6 H, m), 7.20-7.30(1 H, m), 7.43-







7.55(3 H, m), 7.68-7.74(3 H, m), 10.17(1 H,







brs).


1675
3,4-Cl2Ph-
—CF3
—C2H5
—H
(DMSO-d6) 1.11(3 H, t, J = 6.9 Hz), 2.25-







2.45(4 H, m), 3.35-3.55(8 H, m), 4.27(2 H, s),







5.99(2 H, s), 6.67-6.88(5 H, m), 6.94-







7.05(2 H, m), 7.52(1 H, dd, J = 8.8 Hz, 2.8







Hz), 7.63(1 H, dd, J = 8.4 Hz, 2.2 Hz),







7.75(1 H, d, J = 2.7 Hz), 7.83-7.87(2 H, m),







10.38(1 H, brs).
















TABLE 302













 














Example









No.
R918
R919
R920
R921
R922
Form
Property





1676
4-CF3Ph-
—F
—F
—H
—CH3
free
mp 199.0-200.0° C.


1677
3,4-Cl2Ph-
—F
—F
—H
—CH3
free
mp 198.0-199.0° C.


1678
4-CF3Ph-
—F
—H
—F
—CH3
free
mp 176.0-177.0° C.


1679
3,4-Cl2Ph-
—F
—H
—F
—CH3
free
mp 115.0-116.0° C.


1680
4-CF3Ph-
—F
—H
—F
—C2H5
free
mp 173.0-174.0° C.


1681
3,4-Cl2Ph-
—F
—H
—F
—C2H5
free
mp 156.0-157.0° C.


1682
3,4-Cl2Ph-
—CH3
—H
—CH3
—C2H5
hydro-
1H NMR (DMSO-d6) δ 0.95(3 H, t,








chloride
J = 7.0 Hz), 1.97(3 H, s), 2.28(3 H,









s), 2.70-4.40(14 H, m), 6.07(2 H, s),









6.86(1 H, brs), 6.93-7.10(3 H, m),









7.20-7.40(2 H, m), 7.56(1 H, dd, J =









8.8 Hz, 2.7 Hz), 7.66(1 H, dd, J =









8.5 Hz, 2.1 Hz), 7.78(1 H, d, J =









2.6 Hz), 7.85-7.88(2 H, m),









10.55(1 H, brs), 11.47(1 H, brs).


1683
4-CF3Ph-
—CH3
—H
—CH3
—C2H5
free
1H NMR (DMSO-d6) δ 0.92(3 H, t,









J = 7.0 Hz), 1.91(3 H, s), 2.16(3 H,









s), 2.20-2.40(4 H, m), 2.98(2 H, q, J =









7.0 Hz), 3.30-3.50(6 H, m),









3.77(2 H, s), 5.98(2 H, s), 6.72-









6.76(2 H, m), 6.82-6.90(3 H, m),









7.01(1 H, s), 7.51(1 H, dd, J = 8.8









Hz, 2.8 Hz), 7.75(1 H, d, J = 2.7









Hz), 7.89-7.99(4 H, m), 10.45(1 H,









brs).


1684
3,4-Cl2Ph-
—F
—H
—H
—H
hydro-
1H NMR (DMSO-d6) δ 2.75-








chloride
3.65(7 H, m), 3.85-4.55(6 H, m),









6.08(2 H, s), 6.47-6.50(1 H, m),









6.59(1 H, dd, J = 13.5 Hz, 2.6 Hz),









6.92-7.01(4 H, m), 7.20(1 H, s),









7.52(1 H, dd, J = 8.7 Hz, 2.6 Hz),









7.64(1 H, dd ,J = 8.4 Hz, 2.1 Hz),









7.76(1 H, d, J = 2.5 Hz), 7.86(1 H,









d, J = 8.6 Hz), 7.89(1 H, d, J = 2.2









Hz), 10.45(1 H, s), 10.90(1 H, brs).


1685
4-
—H
—H
—H
—CH3
free
MS 646(M+ + H)



CH3OPh-


1686
1-naphthyl
—H
—H
—H
—CH3
free
MS 666(M+ + H)


1687
2-naphthyl
—H
—H
—H
—CH3
free
MS 666(M+ + H)


1688
2-CH3Ph-
—H
—H
—H
—CH3
free
MS 630(M+ + H)


1689
4-FPh-
—H
—H
—H
—CH3
free
MS 634(M+ + H)


1690
2-CF3Ph-
—H
—H
—H
—CH3
free
MS 684(M+ + H)


1691
2-ClPh-
—H
—H
—H
—CH3
free
MS 650(M+ + H)
















TABLE 303













 












Example






No.
R923
R924
MS (M+ + H)







1692
2-thienyl
—H
622



1693
2-CF3OPh-
—H
700



1694
3-CF3OPh-
—H
700



1695
3-CH3OPh-
—H
646



1696
3-FPh-
—H
634



1697
2,3-Cl2Ph-
—H
684



1698
3-CF3Ph-
—H
684



1699
4-CF3OPh-
—H
700



1700
4-biphenylyl
—H
692



1701
3,4-(CH3O)2Ph-
—H
676



1702
2,5-(CH3O)2Ph-
—H
676



1703
3-CH3Ph-
—H
630



1704
2,5-Cl2Ph-
—H
684



1705
3-ClPh-
—H
650



1706
2,4-Cl2Ph-
—H
684



1707
2,3,4-Cl3Ph-
—H
720



1708
—C2H5
—H
568



1709
2,6-Cl2Ph-
—H
684



1710
4-CH3OOPh-
—F
664



1711
4-ClPh-
—F
668



1712
1-naphthyl
—F
684



1713
2-naphthyl
—F
684



1714
2-CH3Ph-
—F
648



1715
4-FPh-
—F
652



1716
2-CF3Ph-
—F
702



1717
2-thienyl
—F
640



1718
2-ClPh-
—F
668



1719
2-CF3OPh-
—F
718



1720
3-CF3OPh-
—F
718



1721
2-CNPh-
—F
660



1722
3-CH3OPh-
—F
664



1723
3-FPh-
—F
652



1724
2,3-Cl2Ph-
—F
702



1725
3-CF3Ph-
—F
702



1726
4-CF3OPh-
—F
718



1727
4-biphenylyl
—F
710



1728
3,4-(CH3O)2Ph-
—F
694



1729
2,5-(CH3O)2Ph-
—F
694

















TABLE 304













 












Example






No.
R925
R926
MS (M+ + H)







1730
3-CH3Ph-
—F
648



1731
2,5-Cl2Ph-
—F
702



1732
3-ClPh-
—F
668



1733
2,4-Cl2Ph-
—F
702



1734
—CH3
—F
572



1735
2,3,4-Cl3Ph-
—F
738



1736
—(CH2)3CH3
—F
614



1737
—C2H5
—F
586



1738
2,6-Cl2Ph-
—F
702



1739
4-CH3OPh-
—CH3
660



1740
4-ClPh-
—CH3
664



1741
1-naphthyl
—CH3
680



1742
2-naphthyl
—CH3
680



1743
2-CH3Ph-
—CH3
644



1744
4-FPh-
—CH3
648



1745
2-CF3Ph-
—CH3
698



1746
2-thienyl
—CH3
636



1747
2-ClPh-
—CH3
664



1748
2-CF3OPh-
—CH3
714



1749
2-CNPh-
—CH3
656



1750
3-CH3OPh-
—CH3
660



1751
3-FPh-
—CH3
648



1752
2,3-Cl2Ph-
—CH3
698



1753
3-CF3Ph-
—CH3
698



1754
4-CF3OPh-
—CH3
714



1755
4-biphenylyl
—CH3
706



1756
3,4-(CH3O)2Ph-
—CH3
690



1757
2,5-(CH3O)2Ph-
—CH3
690



1758
3-CH3Ph-
—CH3
644



1759
2,5-Cl2Ph-
—CH3
698



1760
3-ClPh-
—CH3
664



1761
2,4-Cl2Ph-
—CH3
698



1762
—CH3
—CH3
568



1763
2,3,4-Cl3Ph-
—CH3
734



1764
—(CH2)3CH3
—CH3
610



1765
—C2H5
—CH3
582



1766
2,6-Cl2Ph-
—CH3
698



1767
2,4,5-Cl3Ph-
—H
719

















TABLE 305













 












Example






No.
R927
R928
MS (M+ + H)







1768
2,4,6-(CH3)3Ph-
—H
658



1769
4-C2H5Ph-
—H
644



1770
2,5-(CH3)2Ph-
—H
644



1771
2-FPh-
—H
634



1772
2,4,6-(CH3)3Ph-
—F
676



1773
4-CH3Ph-
—F
648



1774
4-C2H5Ph-
—F
662



1775
2,5-(CH3)2Ph-
—F
662



1776
2-FPh-
—F
652



1777
2,4,5-Cl3Ph-
—CH3
732



1778
2,4,6-(CH3)3Ph-
—CH3
672



1779
4-CH3Ph-
—CH3
644



1780
4-C2H5Ph-
—CH3
658



1781
2,5-(CH3)2Ph-
—CH3
658



1782
2-FPh-
—CH3
648



1783
4-BrPh-
—H
696



1784
—CH(CH3)2
—H
582



1785
8-quinolyl
—H
667



1786
3-CNPh-
—H
641



1787
4-PhOPh-
—H
708



1788
3-BrPh-
—H
696



1789
4-CNPh-
—H
641



1790
2,4-F2Ph-
—H
652



1791
4-BrPh-
—F
714



1792
—CH(CH3)2
—F
600



1793
8-quinolyl
—F
685



1794
3-CNPh-
—F
659



1795
4-CNPh-
—F
659



1796
2,4-F2Ph-
—F
670



1797
4-BrPh-
—CH3
710



1798
—CH(CH3)2
—CH3
596



1799
8-quinolyl
—CH3
681



1800
3-CNPh-
—CH3
655



1801
3-BrPh-
—CH3
710



1802
4-CNPh-
—CH3
655



1803
2,4-F2ph-
—CH3
666



1804
2,4,6-Cl3Ph-
—H
720



1805
2,4,6-Cl3Ph-
—F
738

















TABLE 306













 












Example






No.
R929
R930
MS (M+ + H)







1806
2,4,5-Cl3Ph-
—F
738



1807
2,4,6-Cl3Ph-
—CH3
734



1808
Ph-
—F
634



1809
Ph-
—CH3
630



1810
2,5-F2Ph-
—F
670



1811
2,5-F2Ph-
—CH3
666



1812
2,6-F2Ph-
—CH3
666



1813
3,4-F2Ph-
—CH3
666



1814
2,6-F2Ph-
—H
652



1815
3,4-F2Ph-
—H
652



1816
2,6-F2Ph-
—F
670



1817
3,4-F2Ph-
—F
670



1818
—CH3
—H
554



 



1819




—H
680



 



1820




—H
660



 



1821




—F
698



 



1822




—CH3
694



 



1823




—CH3
674



 



1824




—H
718



 



1825




—H
668



 



1826




—H
698



 



1827




—H
718

















TABLE 307























Example






No.
R931
R932
MS (M+ + H)







1828




—H
675



 



1829




—H
686



 



1830




—H
742



 



1831




—H
672



 



1832




—H
660



 



1833




—H
688



 



1834




—F
716



 



1835




—F
736



 



1836




—F
718



 



1837




—F
678



 



1838




—F
747



 



1839




—F
706



 



1840




—CH3
712

















TABLE 308













 












Example






No.
R933
R934
MS (M+ + H)







1841




—CH3
732



 



1842




—CH3
689



 



1843




—CH3
700



 



1844




—CH3
714



 



1845




—CH3
674



 



1846




—CH3
743



 



1847




—CH3
702



 



1848




—H
700



 



1849




—H
709



 



1850




—H
680



 



1851




—H
674



 



1852




—H
698

















TABLE 309













 












Example






No.
R935
R936
MS (M+ + H)







1853




—H
682



 



1854




—H
710



 



1855




—H
707



 



1856




—F
727



 



1857




—F
698



 



1858




—F
692



 



1859




—F
716



 



1860




—F
700



 



1861




—F
728



 



1862




—F
725



 



1863




—CH3
723

















TABLE 310













 












Example






No.
R937
R938
MS (M+ + H)







1864




—CH3
694



 



1865




—CH3
688



 



1866




—CH3
712



 



1867




—CH3
696



 



1868




—CH3
724



 



1869




—CH3
721



 



1870




—H
730



 



1871




—F
736



 



1872




—F
704



 



1873




—CH3
732



 



1874




—CH3
682



 



1875




—H
668

















TABLE 311













 












Example






No.
R939
R940
MS (M+ + H)







1876




—H
660



 



1877




—H
664



 



1878




—H
648



 



1879




—H
664



 



1880




—H
714



 



1881




—H
664



 



1882




—F
678



 



1883




—F
682



 



1884




—F
666



 



1885




—F
682



 



1886




—F
686



 



1887




—CH3
682



 



1888




—F
682

















TABLE 312













 












Example






No.
R941
R942
MS (M+ + H)







1889




—CH3
674



 



1890




—CH3
678



 



1891




—CH3
662



 



1892




—CH3
678



 



1893




—CH3
728



 



1894




—CH3
678



 



1895




—F
732



 



1896




—F
760



 



1897




—CH3
756



 



1898
3-BrPh-
—F
714



1899
4-PhOPh-
—CH3
722



 



1900




—F
690



 



1901




—CH3
686

















TABLE 313













 












Example






No.
R943
R944
MS (M+ + H)







1902




—H
678



 



1903




—H
658



 



1904




—H
700



 



1905




—H
700



 



1906




—H
674



 



1907




—H
620



 



1908




—F
696



 



1909




—F
676



 



1910




—F
718



 



1911




—F
718



 



1912




—F
692



 



1913




—F
638

















TABLE 314













 












Example






No.
R945
R946
MS (M+ + H)







1914




—CH3
692



 



1915




—CH3
672



 



1916




—CH3
714



 



1917




—CH3
714



 



1918




—CH3
688



 



1919




—CH3
634



 



1920




—H
673



 



1921
vinyl
—H
566



1922
—(CH2)3Cl
—H
616



1923
cyclohexylmethyl
—H
636



 



1924




—F
691



 



1925
vinyl
—F
584



1926
—(CH2)3Cl
—F
634



1927
cyclohexylmethyl
—F
654



 



1928




—CH3
687



 



1929
vinyl
—CH3
580



1930
—(CH2)3Cl
—CH3
630



1931
cyclohexylmethyl
—CH3
650



1932
2-BrPh-
—H
696



 



1933




—H
656

















TABLE 315













 









Example




No.
R947
MS (M+ + H)





1934
3,5-Cl2Ph
684


 


1935




683


 


1936




682


 


1937




702


 


1938




687


 


1939




681


 


1940




723


 


1941
5-isoquinolyl
667


1942
—CH2CF3
622


 


1943




688


 


1944




668


 


1945




635


 


1946




690


 


1947




690
















TABLE 316













 












Example






No.
R948
R949
MS (M+ + H)







1948
—CH2Cl
—H
588



 



1949




—H
702



 



1950




—H
660



 



1951




—H
694



 



1952




—H
680



 



1953




—H
726



 



1954
benzyl
—H
630



1955
PhCH═CH—
—H
642



1956
—(CH2)2CH3
—H
582



1957
2-BrPh-
—F
714



 



1958




—F
674



 



1959
3,5-Cl2Ph
—F
702



 



1960




—F
701



 



1961




—F
700



 



1962




—F
720



 



1963




—F
705



 



1964




—F
699



 



1965




—F
741

















TABLE 317













 









Example




No.
R950
MS (M+ + H)





1966
5-isoquinolyl
685


1967
—CH2CF3
640


 


1968




706


 


1969




686


 


1970




653


 


1971




694


 


1972




708


 


1973




708


 


1974
—CH2Cl
606


 


1975




720


 


1976




678


 


1977




712


 


1978




698


 


1979




744


 


1980
benzyl
648


1981
PhCH═CH—
660
















TABLE 318













 












Example






No.
R951
R952
MS (M+ + H)







1982
—(CH2)2CH3
—F
600



1983
2-BrPh-
—CH3
710



 



1984




—CH3
670



 



1985
3,5-Cl2Ph
—CH3
698



 



1986




—CH3
697



 



1987




—CH3
696



 



1988




—CH3
716



 



1989




—CH3
701



 



1990




—CH3
695



 



1991




—CH3
737



 



1992
5-isoquinolyl
—CH3
681



1993
—CH2CF3
—CH3
636



 



1994




—CH3
702



 



1995




—CH3
682



 



1996




—CH3
649

















TABLE 319













 












Example






No.
R953
R954
MS (M+ + H)







1997




—CH3
690



 



1998




—CH3
704



 



1999




—CH3
704



 



2000
—CH2Cl
—CH3
602



 



2001




—CH3
716



 



2002




—CH3
674



 



2003




—CH3
708



 



2004




—CH3
694



 



2005




—CH3
740



 



2006
benzyl
—CH3
644



2007
—CHCl2
—CH3
636



2008
PhCH═CH—
—CH3
656



2009
—(CH2)2CH3
—CH3
596



2010
2,3,4-F3Ph-
—H
670



2011
2,3,4-F3Ph-
—F
688



2012
2,3,4-F3Ph-
—CH3
684

















TABLE 320













 












Example







No.
R955
R956
R957
Xb29
1H NMR (solvent) δppm





2013
3,4-Cl2Ph-
—CH3
—H
—CO—
(CDCl3) 2.12 (3 H, s), 2.50-2.52 (4 H, m),







3.45 (2 H, s), 3.72 (2 H, brs), 4.24 (2 H, brs),







5.95 (2 H, s), 6.71-6.78 (2 H, m), 6.85-6.89 (2 H,







m), 7.00 (1 H, d, J = 8.6 Hz), 7.42 (1 H, dd, J =







8.6 Hz, 2.5 Hz), 7.52-7.55 (3 H, m), 7.60 (1 H,







dd, J = 8.7 Hz, 2.8 Hz), 7.70 (1 H, d, J = 2.6







Hz), 7.79 (1 H, brs), 9.17 (1 H, brs).


2014
4-CF3Ph-
—CH3
—H
—CO—
(CDCl3) 2.10 (3 H, s), 2.50-2.54 (4 H, m),







3.45 (2 H, s), 3.70-3.73 (2 H, m), 4.23 (2 H, brs),







5.95 (2 H, s), 6.71-6.78 (2 H, m), 6.83-6.87 (2 H,







m), 6.99 (1 H, d, J = 8.6 Hz), 7.42(1 H, dd, J =







8.6 Hz, 2.6 Hz), 7.54 (1 H, d, J = 2.5 Hz),







7.60 (1 H, dd, J = 8.7 Hz, 3.3 Hz), 7.70 (1 H, d,







J = 3.3 Hz), 7.72 (2 H, d, J = 8.9 Hz), 7.85(2 H,







d, J = 8.3 Hz), 9.18 (1 H, brs).


2015
3,4-Cl2Ph-
—CH3
—CH3
—CO—
(CDCl3) 2.12 (3 H, brs), 2.20-2.50 (4 H, m),







3.27-3.46 (9 H, m), 5.95-5.96 (2 H, m), 6.66-







6.77 (3 H, m), 6.85-7.04 (2 H, m), 7.08-7.22







(2 H, m), 7.51-7.53 (2 H, m), 7.55-7.72 (2 H, m),







7.78-7.80 (1 H, m).


2016
4-CF3Ph-
—CH3
—CH3
—CO—
(DMSO-d6) 2.11 (3 H, s), 2.19-2.51 (4 H, m),







3.28-3.71 (9 H, m), 5.96 (2 H, s), 6.65-6.78 (3 H,







m), 6.85-7.04 (2 H, m), 7.08-7.22 (2 H, m), 7.57-







7.65 (1 H, m), 7.70-7.73 (3 H, m), 7.84-7.87 (2 H,







m).


2017
3,4-Cl2Ph-
—H
—SO2CH3
—CH2—
(CDCl3) 2.42 (4 H, brs), 3.20 (3 H, s), 3.37-







3.39 (2 H, m), 3.42 (2 H, s), 3.61 (2 H, brs),







4.54 (2 H, s), 5.95 (2 H, s), 6.70-6.77 (2 H, m),







6.83 (1 H, brs), 6.93 (1 H, d, J = 8.6 Hz),







7.08 (2 H, d, J = 8.9 Hz), 7.53-7.54 (2 H, m),







7.58-7.63 (3 H, m), 7.77 (1 H, d, J = 2.6 Hz),







7.88 (1 H, d, J = 1.0 Hz).


2018
4-CF3Ph-
—H
—SO2CH3
—CH2—
(CDCl3) 2.42 (4 H, brs), 3.19 (3 H, s), 3.37 (2 H,







brs), 3.42 (2 H, s), 3.61 (2 H, brs), 4.53 (2 H, s),







5.95 (2 H, s), 6.73-6.77 (2 H, m), 6.83 (1 H, brs),







6.92 (1 H, d, J = 8.7 Hz), 7.08(2 H, d, J = 8.7







Hz), 7.59 (2 H, d, J = 8.7 Hz), 7.61 (1 H, dd, J =







8.7 Hz, 2.8 Hz), 7.73-7.76 (3 H, m), 7.87 (2 H,







d, J = 8.6 Hz).


2019
3,4-Cl2Ph-
—CH3
—SO2CH3
—CH2—
(CDCl3) 2.12 (3 H, s), 2.42 (4 H, brs), 3.21 (3 H,







s), 3.83 (2 H, brs), 3.42 (2 H, s), 3.61 (2 H, brs),







4.53 (2 H, s), 5.95 (2 H, s), 6.70-6.77 (2 H, m),







6.83 (1 H, brs), 6.91 (1 H, d, J = 8.7 Hz),







6.98 (1 H, d, J = 8.4 Hz), 7.40-7.50 (2 H, m),







7.53-7.56 (2 H, m), 7.60 (1 H, dd, J = 8.7 Hz,







2.8 Hz), 7.71 (1 H, d, J = 2.3 Hz), 7.80 (1 H, dd,







J = 1.7 Hz, 0.8 Hz).
















TABLE 321







 








 











Example






No.
R958
R959
R960
1H NMR (solvent) δ ppm





2020
4-CF3Ph-
—CH3
—SO2CH3
(CDCl3) 2.10 (3 H, s), 2.40-2.42 (4 H, m), 3.20 (3 H, s),






3.37 (2 H, brs), 3.42 (2 H, s), 3.60 (2 H, brs), 4.53 (2 H,






s), 5.94 (2 H, s), 6.69-6.76 (2 H, m), 6.83 (1 H, brs),






6.87 (1 H, d, J = 8.7 Hz), 6.96 (1 H, d, J = 8.4 Hz),






7.40 (1 H, d, J = 8.6 Hz), 7.44 (1 H, brs), 7.59 (1 H, dd,






J = 8.7 Hz, 2.8 Hz), 7.72 (2 H, d, J = 8.2 Hz),






7.73 (1 H, d, J = 2.8 Hz), 7.86 (2 H, d, J = 8.2 Hz).


2021
4-CF3Ph-
—CF3
—C2H5
(DMSO-d6) 1.11 (3 H, t, J = 6.9 Hz), 2.25-2.45 (4 H,






m), 3.35-3.55 (8 H, m), 4.26 (2 H, s), 5.99 (2 H, s), 6.67-






7.04 (7 H, m), 7.52 (1 H, dd, J = 8.8 Hz, 2.8 Hz),






7.74 (1 H, d, J = 2.6 Hz), 7.88-7.98 (4 H, m), 10.48 (1 H,






brs).


 


2022




—CF3
—C2H5
(DMSO-d6) 1.11 (3 H, t, J = 6.9 Hz), 2.25-2.45 (4 H, m), 3.35-3.55 (8 H, m), 4.26 (2 H, s), 5.99 (2 H, s), 6.67- 7.03 (7 H, m), 7.30-7.45 (1 H, m), 7.52 (1 H, dd, J = 8.8 Hz, 2.6 Hz), 7.71 (1 H, dd, J = 8.7 Hz, 2.5 Hz), 7.79 (1 H, d, J = 2.7 Hz), 7.99-8.05 (1 H, m), 10.61 (1 H, brs).


 


2023
3,4-Cl2Ph-
—CF3
—CH3
(DMSO-d6) 2.20-2.45 (4 H, m), 2.97 (3 H, s), 3.40-






3.55 (6 H, m), 4.34 (2 H, s), 5.99 (2 H, s), 6.70-6.80 (2 H,






m), 6.83-6.88 (3 H, m), 6.97 (1 H, d, J = 8.8 Hz), 7.03-






7.07 (1 H, m), 7.52 (1 H, dd, J = 8.8 Hz, 2.8 Hz),






7.63 (1 H, dd, J = 8.6 Hz, 2.2 Hz), 7.75 (1 H, d, J = 2.7






Hz), 7.83-7.87 (2 H, m), 10.39 (1 H, brs).


 


2024




—CF3
—CH3
(DMSO-d6) 2.25-2.50 (4 H, m), 2.97 (3 H, s), 3.35- 3.55 (6 H, m), 4.34 (2 H, s), 5.99 (2 H, s), 6.74-7.05 (7 H, m), 7.30-7.45 (1 H, m), 7.52 (1 H, dd, J = 8.8 Hz, 2.7 Hz), 7.71 (1 H, dd, J = 8.7 Hz, 2.5 Hz), 7.80 (1 H, d, J = 2.7 Hz), 8.00-8.06 (1 H, m), 10.61 (1 H, brs).


 


2025
3,4-Cl2Ph-
—CN
—CH3
(DMSO-d6) 2.25-2.50 (4 H, m), 2.94 (3 H, s), 3.35-






3.50 (6 H, m), 4.33 (2 H, s), 5.99 (2 H, s), 6.74-7.11 (7 H,






m), 7.50-7.65 (2 H, m), 7.78 (1 H, d, J = 2.6 Hz),






7.83 (1 H, d, J = 8.5 Hz), 7.89 (1 H, d, J = 1.5 Hz),






10.45 (1 H, brs).


2026
4-CF3Ph-
—OCH3
—SO2CH3
(CDCl3) 2.43 (4 H, brs), 3.20 (3 H, s), 3.38 (2 H, brs),






3.43 (2 H, s), 3.61 (2 H, brs), 3.68 (3 H, s), 4.54 (2 H, s),






5.94 (2 H, s), 6.73-6.76 (2 H, m), 6.80-6.90 (2 H, m),






7.04 (1 H, d, J = 8.4 Hz), 7.15-7.19 (1 H, m), 7.24-






7.26 (1 H, m), 7.57 (1 H, dd, J = 8.7 Hz, 2.8 Hz), 7.70-






7.72 (4 H, m), 7.85 (2 H, d, J = 8.2 Hz).


2027
3,4-Cl2Ph-
—OCH3
—SO3CH3
(CDCl3) 2.43 (4 H, brs), 3.21 (3 H, s), 3.37 (2 H, brs),






3.43 (2 H, s), 3.61 (2 H, brs), 3.71 (3 H, s), 4.54 (2 H, s),






5.95 (2 H, s), 6.73-6.77 (2 H, m), 6.83 (1 H, s), 6.92 (1 H,






d, J = 8.7 Hz), 7.06 (1 H, d, J = 8.6 Hz), 7.18 (1 H, dd,






J = 8.4 Hz, 2.3 Hz), 7.25 (2 H, s), 7.52 (2 H, s),






7.57 (1 H, dd, J = 8.7 Hz, 2.8 Hz), 7.70 (1 H, d, J = 2.6






Hz), 7.81 (1 H, s).
















TABLE 322







 








 













Example








No.
R961
R962
R963
R964
R965
1H NMR (DMSO-d6) δ ppm





2028
3,4-Cl2Ph-
—CH3
—H
—CH3
—CH3
1.93 (3 H, s), 2.16 (3 H, s), 2.20-2.40 (4 H,








m), 2.63 (3 H, s), 3.39 (2 H, s), 3.39-








3.50 (4 H, m), 3.74 (2 H, s), 5.99 (2 H,








s), 6.72-6.92 (5 H, m), 6.98 (1 H, s), 7.51 (1 








H, dd, J = 8.8 Hz, 2.4 Hz), 7.63 (1 H, dd,








J = 8.5 Hz, 1.4 Hz), 7.73 (1 H, d, J =








2.6 Hz), 7.82-7.87 (2 H, m), 10.35 (1 H,








brs).


 


2029




—CH3
—H
—CH3
—CH3
1.90 (3 H, s), 2.15 (3 H, s), 2.25-2.40 (4 H, m), 2.62 (3 H, s), 3.38 (2 H, s), 3.38- 3.50 (4 H, m), 3.73 (2 H,s ), 5.98 (2 H, s), 6.72-6.76 (2 H, m), 6.82-6.88 (3 H, m), 6.97 (1 H, s), 7.30-7.45 (1 H, m), 7.51 (1 H, dd, J = 8.8 Hz, 2.7 Hz), 7.72 (1 H, dd, J = 8.7 Hz, 2.6 Hz), 7.78 (1 H, d, J = 2.8 Hz), 7.98-8.04 (1 H, m ), 10.56 (1 H, brs).


 


2030
3,4-Cl2Ph-
—H
—CF3
—H
—C2H5
0.92 (3 H, t, J = 7.1 Hz), 2.20-2.40 (4 H,








m), 3.11 (2 H, q, J = 7.1 Hz), 3.35-








3.50 (6 H, m), 3.83 (2 H, s), 5.98 (2 H, s),








6.70-6.90 (3 H, m), 7.05 (1 H, d, J = 8.8








Hz), 7.32-7.36 (2 H, m), 7.56-7.75 (3 H, m),








7.81-7.91 (3 H, m), 10.48 (1 H, brs).









Example 2031
N-{4-[4-(4-benzenesulfonylpiperazin-1-yl)phenoxy]phenyl}-3,4-dichlorobenzamide
Melting point: 191-192° C.
The following compounds were produced in the same manner as in Reference Example 292.







TABLE 323













 









Example No.
R966
1H NMR (CDCl3) δ ppm





2032
—CH3
2.41 (4H, brs), 3.20 (3H, s), 3.36 (2H, brs), 3.42 (2H, s), 3.59 (2H, brs), 3.66 (3H, s), 4.50




(2H, s), 5.94 (2H, s), 6.70-6.76 (2H, m), 6.83 (1H, s), 6.93 (1H, d, J = 8.7 Hz), 6.99-7.04




(2H, m), 7.13 (1H, dd, J = 8.4 Hz, 2.1 Hz), 7.51 (1H, d, J = 2.3 Hz), 7.69 (1H, dd, J = 8.4




Hz, 2.1 Hz), 7.95 (1H, d, J = 2.1 Hz), 8.12 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.23 (1H, d, J = 2.6




Hz), 8.53 (1H, s).


2033
—C2H5
1.37 (3H, t, J = 7.4 Hz), 2.42 (4H, brs), 3.38-3.46 (6H, m), 3.60 (2H, brs), 3.71 (3H, s), 4.53




(2H, s), 5.94 (2H, s), 6.70-6.77 (2H, m), 6.84 (1H, s), 6.97 (1H, d, J = 8.7 Hz), 7.06 (1H, d,




J = 8.6 Hz), 7.14-7.18 (1H, m), 7.26 (1H, s), 7.55 (1H, d, J = 8.4 Hz), 7.71 (1H, dd, J = 8.4




Hz, 2.1 Hz), 7.98 (1H, d, J = 2.1 Hz), 8.16-8.23 (3H, m).









Example 2034
Production of t-butyl 4-{4-[5-(3,4-dichlorobenzoyl-amino)pyridin-2-yloxy]phenylcarbamoyl}piperidine-1-carboxylate
To a solution of N-[6-(4-aminophenoxy)pyridin-3-yl]-3,4-dichlorobenzamide dihydrochloride (1.0 g, 2.24 mmol) in DMF (15 mL) were added, piperidine-1,4-dicarboxylic acid mono-t-butyl ester (510 mg, 2.22 mmol), triethylamine (0.94 mL, 6.74 mmol), 1-hydroxybenzotriazole monohydrate (350 mg, 2.29 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (514 mg, 2.68 mmol) under ice cooling. The resulting solution was then stirred under ice cooling for 1 hour, and at room temperature for 17 hours. This reaction solution was concentrated under reduced pressure. The residue was diluted with water and ethyl acetate, whereupon a white powder was precipitated. The white powder was filtered, then washed with water, and subsequently washed with ethyl acetate, to thereby yield 1.04 g of the title compound.
Appearance: White powder
1H NMR (DMSO-d6) δ 1.41 (9H, s), 1.35-1.50 (2H, m), 1.70-1.85 (2H, m), 2.40-2.60 (1H, m), 2.65-2.90 (2H, m), 3.90-4.11 (2H, m), 7.03 (1H, d, J=8.9 Hz), 7.06 (2H, d, J=8.9 Hz), 7.62 (2H, d, J=8.9 Hz), 7.84 (1H, d, J=8.5 Hz), 7.94 (1H, dd, J=8.5 Hz, 2.0 Hz), 8.17 (1H, dd, J=8.9 Hz, 2.6 Hz), 8.22 (1H, d, J=2.0 Hz), 8.46 (1H, d, J=2.6 Hz), 9.96 (1H, s), 10.54 (1H, s).
The following compound was produced in the same manner as in Example 2034.
Example 2035
3,4-Dichloro-N-(6-{4-[2-(2,4-dioxothiazolidine-5-yl)-acetylamino]phenoxy}pyridin-3-yl)benzamide
1H NMR (DMSO-d6) δ 3.07 (1H, dd, J=16.5 Hz, 8.9 Hz), 3.24 (1H, dd, J=16.5 Hz, 4.0 Hz), 4.73 (1H, dd, J=9.0 Hz, 4.0 Hz), 7.04 (1H, d, J=8.9 Hz), 7.08 (2H, d, J=8.9 Hz), 7.58 (2H, d, J=8.9 Hz), 7.84 (1H, d, J=8.2 Hz), 7.94 (1H, dd, J=8.2 Hz, 2.0 Hz), 8.18 (1H, dd, J=8.9 Hz, 2.6 Hz), 8.22 (1H, d, J=2.0 Hz), 8.46 (1H, d, J=2.6 Hz), 10.21 (1H, s), 10.53 (1H, s), 12.00 (1H, s).
Example 2036
Production of 3,4-dichloro-N-(6-{4-[4-piperonyl-piperazin-1-ylmethyl]phenoxy}pyridin-3-yl)benzamide
To a solution of 3,4-dichloro-N-[6-(4-piperazin-1-ylmethylphenoxy)pyridin-3-yl]benzamide (300 mg, 0.66 mmol) in DMF (10 mL) were added piperonylic acid (120 mg, 0.72 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (140 mg, 0.73 mmol) and 1-hydroxybenzotriazole monohydrate (100 mg, 0.74 mmol) under ice cooling. The resulting reaction solution was stirred overnight at room temperature. To the residue was added a saturated sodium bicarbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated, to thereby yield 110 mg of the title compound.
Appearance: White powder
1H NMR (CDCl3) δ 2.46 (4H, brs), 3.53 (2H, s), 3.60 (4H, brs), 5.99 (2H, s), 6.79 (1H, d, J=7.9 Hz), 6.85-6.96 (3H, m), 7.08 (2H, d, J=8.6 Hz), 7.33 (2H, d, J=8.3 Hz), 7.54 (1H, d, J=8.3 Hz), 7.69-7.73 (1H, m), 7.99 (1H, d, J=2.3 Hz), 8.16-8.21 (1H, m), 8.27-8.30 (2H, m).
The following compounds were produced in the same manner as in Example 2036.







TABLE 324







 








 












Example







No.
R967
R968
Xb30
R969
mp (° C. ) or 1H NMR (solvent) δ ppm





2037
—CF3
—H
—CO—




1H NMR (DMSO-d6) 3.52 (4 H, brs), 3.60 (4 H, brs), 5.57 (1 H, s), 7.17 (1 H, d, J = 8.9 Hz), 7.20 (2 H, d, J = 8.9 Hz), 7.51 (2 H, d, J = 8.4 Hz), 7.95 (2 H, d, J = 8.1 Hz), 8.17 (2 H, d, J = 8.1 Hz), 8.27 (1 H, dd, J = 8.9 Hz, 2.6 Hz), 8.55 (1 H, d, J = 2.6 Hz), 10.69 (1 H, brs), 11.18 (1 H, brs), 11.32 (1 H, brs).


 


2038
—Cl
—Cl
—CH2—




mp 250-251


 


2039
—CF3
—H
—CH2—
2-CNPh-
mp 189-192


2040
—CF3
—H
—CH2—
4-pyridyl
mp 122-124


2041
—CF3
—H
—CH2—
3-pyridyl
mp 167-168


2042
—CF3
—H
—CH2—
2-pyridyl
mp 189-191


 


2043
—CF3
—H
—CH2—




1H NMR (DMSO-d6) 2.45 (4 H, brs), 3.36 (2 H, s), 3.54-4.18 (4 H, m), 7.09 (3 H, d, J = 8.9 Hz), 7.36 (2 H, d, J = 8.4 Hz), 7.59 (1 H, brs), 7.72 (1 H, s), 7.94 (2 H, d, J = 8.4 Hz), 8.18 (2 H, d, J = 8.4 Hz), 8.24 (1 H, dd, J = 8.9 Hz, 2.6 Hz), 8.53 (1 H, d, J = 2.6 Hz), 10.67 (1 H, s),  12.48 (1 H, brs).


 


2044
—CF3
—H
—CH2—




1H NMR (CDCl3 + CD3OD) 2.98- 3.15 (5 H, m), 3.34-3.47 (1 H, m), 3.61- 3.76 (4 H, m), 4.18 (2 H, s), 4.57 (1 H, dd, J = 10.2 Hz, 3.1 Hz), 7.04 (1 H, d, J = 8.7 Hz), 7.19 (2 H, d, J = 8.6 Hz), 7.49 (2 H, d, J = 8.6 Hz), 7.79 (2 H, d, J = 8.3 Hz), 8.11 (2 H, d, J = 8.1 Hz ), 8.25 (1 H, dd, J = 8.9 Hz, 2.8 Hz), 8.52 (1 H, d, J = 2.3 Hz).


 


2045
—CF3
—H
—(CH2)3—




1H NMR (CDCl3) 1.81-1.89 (2 H, m), 2.40-2.45 (6 H, m), 2.62-2.68 (2 H, m), 3.61 (4 H, brs), 5.98 (2 H, s), 6.76-6.93 (4 H, m), 7.03 (2 H, d, J = 8.4 Hz), 7.19 (2 H, d, J = 8.4 Hz), 7.68 (2 H, d, J = 8.4 Hz), 7.99 (2 H, d, J = 8.3 Hz), 8.18-8.23 (1 H, m), 8.30 (1 H, d, J = 2.6 Hz ), 8.73 (1 H, s).


 


2046
—CF3
—H
—(CH2)3—
3,4-(CH3O)2Ph-
1H NMR (CDCl3) 1.78-1.89 (2 H, m),







2.39-2.45 (6 H, m), 2.63-2.68 (2 H, m),







3.62 (4 H, brs), 3.85 (3 H, s), 3.89 (3 H, s),







6.82-6.85 (1 H, m), 6.91-6.95 (3 H, m),







7.01-7.06 (2 H, m), 7.18-7.23 (2 H, m),







7.70 (2 H, d, J = 8.2 Hz), 7.99 (2 H, d, J =







8.2 Hz), 8.20-8.24 (1 H, m), 8.29 (1 H, d, J =







2.6 Hz), 8.51 (1 H, brs).
















TABLE 325







 








 













Example








No.
R970
R971
R972
M
Form
1H NMR (solvent) δ ppm





2047
—CF3
—H




1
free
(DMSO-d6) 1.94 (6 H, s), 2.49- 2.51 (4 H, m), 2.76-2.93 (1 H, m), 3.17-3.51 (7 H, m), 4.20 (1 H, dd, J = 10.4 Hz, 3.0 Hz), 7.09-7.13 (3 H, m), 7.42 (2 H, brs), 7.94 (2 H, d, J = 8.4 Hz), 8.16-8.26 (3 H, m), 8.54 (1 H, d, J = 2.5 Hz), 10.67 (1 H, s), 11.68 (1 H, brs).


 


2048
—CF3
—H




1
free
(CDCl3 + CD3OD) 2.46-2.59 (4 H, m), 3.16 (1 H, dd, J = 14.2 Hz, 9.4 Hz), 3.32 (4 H, brs), 3.51 (1 H, dd, J = 14.0 Hz, 3.8 Hz), 3.79 (2 H, brs), 4.50 (1 H, dd, J = 9.4 Hz, 4.0 Hz), 6.93 (1 H, d, J = 8.9 Hz), 7.06 (2 H, d, J = 8.4 Hz), 7.26-7.46 (6 H, m), 7.72 (2 H, d, J = 8.3 Hz), 8.05 (2 H,  d, J = 8.1 Hz), 8.27 (1 H, d, J = 2.1 Hz), 8.33 (1 H, dd, J = 8.9 Hz, 2.8 Hz).


 


2049
—CF3
—H




1
free
(DMSO-d6) 2.49-2.52 (4 H, m), 3.34-3.40 (4 H, m), 3.57 (2 H, s), 7.06-7.10 (3 H, m), 7.36 (2 H, d, J = 8.6 Hz), 7.54 (2 H, d, J = 8.1 Hz), 7.67 (2 H, d, J = 8.4 Hz), 7.79 (1 H, s), 7.94 (2 H, d, J = 8.6 Hz), 8.15- 8.25 (3 H, m), 8.51 (1 H, d, J = 2.8 Hz), 10.64 (1 H, s).


 


2050
—CF3
—H
4-pyridyl
3
hydro-
(DMSO-d6) 2.04 (2 H, brs), 2.63-







chloride
2.69 (2 H, m), 3.10-3.59 (9 H, m),








4.54 (1 H, brs), 7.05-7.08 (3 H, m),








7.28 (2 H, d, J = 8.2 Hz), 7.45 (2 H,








d, J = 4.9 Hz), 7.94 (2 H, d, J = 8.2








Hz), 8.18-8.26 (3 H, m), 8.53 (1 H, d,








J = 2.3 Hz), 8.70 (2 H, d, J = 5.4








Hz), 10.72 (1 H, s), 11.27 (1 H, brs).


2051
—Cl
—Cl
3,4-F2Ph-
1
free
(CDCl3) 2.46 (4 H, brs), 3.47-








3.72 (6 H, m), 6.91 (1 H, d, J = 8.9








Hz), 7.05-7.33 (7 H, m), 7.50 (1 H, d,








J = 8.4 Hz), 7.71 (1 H, dd, J = 8.4








Hz, 2.1 Hz), 7.97 (1 H, d, J = 2.1








Hz), 8.14-8.18 (1 H, m), 8.28 (1 H,








d, J = 2.6 Hz), 8.68 (1 H, s).


















TABLE 326





Ex-




am-




ple




No.
Chemical stracture
mp (° C.) or 1H NMR







2052




mp 171-173


 


2053




mp 116-118


 


2054




mp 133-135


 


2055




1H NMR (CDCl3) δ 2.39 (2 H, brs), 2.55 (2 H, brs), 3.00 (3 H, s), 3.35 (2 H, brs), 3.51 (2 H, s), 3.79 (2 H, brs), 4.40 (2 H, s), 6.82 (1 H, d, J = 8.9 Hz), 6.99-7.13 (4 H, m), 7.25-7.29 (5 H, m), 7.32 (1 H, d, J = 1.8 Hz), 7.39 (1 H, d, J = 3.3 Hz), 8.68-8.70 (2 H, m).









Example 2056
Production of N-{6-[4-(4-chloroacetylpiperazino)phenoxy]-3-pyridyl}-4-(trifluoromethyl)benzamide
To a solution of N-[6-(4-piperazinophenoxy)-3-pyridyl]-4-(trifluoromethyl)benzamide (885 mg, 2.00 mmol) in DMF (20 mL) were added triethylamine (0.418 mL, 3.00 mmol) and chloroacetyl chloride (0.191 g, 2.40 mmol), and the resulting reaction solution was stirred for 10 minutes at room temperature. To this reaction solution was added ethyl acetate. The resulting solution was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, to thereby yield 1.00 g of the title compound.
Appearance: White powder
1H NMR (CDCl3) δ 3.17 (2H, t, J=5.0 Hz), 3.22 (2H, t, J=5.0 Hz), 3.70 (2H, t, J=5.0 Hz), 3.80 (2H, t, J=5.0 Hz), 6.95 (1H, d, J=9.0 Hz), 6.97 (2H, d, J=9.0 Hz), 7.08 (2H, d, J=9.0 Hz), 7.77 (1H, brs), 7.78 (2H, d, J=8.0 Hz), 7.99 (2H, d, J=8.0 Hz), 8.20 (1H, dd, J=9.0 Hz, 2.5 Hz), 8.26 (1H, d, J=2.5 Hz).
The following compounds were produced in the same manner as in Example 2056.







TABLE 327







 








 












Example







No.
R973
R974
Xb31
R975
mp (° C.) or 1H NMR (solvent) δ ppm





2057
—CF3
—H
—CO—
4-CNPh-
1H NMR (DMSO-d6) 3.29-3.69 (8 H, m), 7.14-







7.20 (3 H, m), 7.49 (2 H, d, J = 8.6 Hz),







7.63 (2 H, d, J = 8.1 Hz), 7.93-7.95 (4 H, m),







8.17 (2 H, d, J = 8.1 Hz), 8.27 (1 H, dd, J =







8.9 Hz, 2.4 Hz), 8.55 (1 H, d, J =







2.4 Hz), 10.66 (1 H, s).


2058
—CF3
—H
—CO—
—CH3
1H NMR (CDCl3) 2.13 (3 H, s), 3.35-3.90 (8 H,







m), 7.02 (1 H, d, J = 8.8 Hz), 7.17 (2 H, d, J =







8.6 Hz), 7.44 (2 H, d, J = 8.6 Hz), 7.75 (2 H, d, J =







8.1 Hz), 8.02 (2 H, d, J = 8.1 Hz), 8.25 (1 H,







dd, J = 8.8 Hz, 2.5 Hz), 8.33 (1 H, d, J = 2.5







Hz), 8.38 (1 H, brs).


2059
—Cl
—Cl
—CH2—
-Ph
1H NMR (CDCl3) 2.08-2.55 (4 H, m), 3.43-







3.45 (2 H, m), 3.55 (2 H, s), 3.79-3.81 (2 H, m),







6.96 (1 H, d, J = 8.9 Hz), 7.07-7.12 (2 H, m),







7.33-7.46 (7 H, m), 7.57 (1 H, d, J = 8.6 Hz),







7.69-7.73 (1 H, m), 7.94-7.99 (2 H, m), 8.17-







8.21 (1 H, m), 8.27 (1 H, d, J = 2.6 Hz).


2060
—Cl
—Cl
—CH2—
4-CNPh-
1H NMR (CDCl3) 2.44 (2 H, brs), 2.58 (2 H,







brs), 3.39 (2 H, brs), 3.56 (2 H, s), 3.81 (2 H,







brs), 6.96 (1 H, d, J = 8.9 Hz), 7.08-7.12 (2 H,







m), 7.34 (2 H, d, J = 8.4 Hz), 7.48-7.51 (2 H, m),







7.57 (1 H, d, J = 8.4 Hz), 7.69-7.77 (3 H, m),







7.95 (1 H, brs), 7.98 (1 H, d, J = 2.0 Hz), 8.14-







8.21 (1 H, m), 8.27 (1 H, d, J = 2.3 Hz),


2061
—CF3
—H
—CH2—
4-CNPh-
mp 167-168


2062
—CF3
—H
—CH2—
-Ph
1H NMR (CDCl3) 2.41-2.53 (4 H, m), 3.43 (2 H,







brs), 3.53 (2 H, s), 3.78 (2 H, brs), 6.95 (1 H, d, J =







8.9 Hz), 7.06-7.11 (2 H, m), 7.33-7.41 (7 H,







m), 7.71 (2 H, d, J = 8.4 Hz), 7.99 (2 H, d, J =







8.4 Hz), 8.23 (1 H, dd, J = 8.9 Hz, 2.7 Hz),







8.31 (1 H, d, J = 2.7 Hz), 8.39 (1 H, s).


2063
—CF3
—H
—CH2—
3,4-F2Ph-
mp 130-133


2064
—CF3
—H
—CH2—
3-CNPh-
1H NMR (CDCl3) 2.43 (2 H, brs), 2.56 (2 H,







brs), 3.39 (2 H, brs), 3.55 (2 H, s), 3.79 (2 H,







brs), 6.97 (1 H, d, J = 8.9 Hz), 7.07-7.12 (2 H,







m), 7.32-7.37 (2 H, m), 7.50-7.77 (6 H, m),







8.00 (2 H, d, J = 8.1 Hz), 8.07 (1 H, brs),







8.23 (1 H, dd, J = 8.9 Hz, 2.7 Hz), 8.28 (1 H, d,







J = 2.7 Hz).


2065
—CF3
—H
—CH2—
4-CH3Ph-
mp 193-194


2066
—CF3
—H
—CH2—
4-ClPh-
mp 176-178


2067
—CF3
—H
—CH2—
4-CH3OPh-
mp 190-191
















TABLE 328







 








 











Example






No.
R976
R977
M
1H NMR (CDCl3) δ ppm





2068
3,4-
-Ph
1
2.38 (2 H, brs), 2.53 (2 H, brs), 2.99 (3 H, s),



Cl2PhCH2N(CH3)—


3.42 (2 H, brs), 3.50 (2 H, s), 3.79 (2 H, brs),






4.39 (2 H, s), 6.81 (1 H, d, J = 8.9 Hz), 6.99-






7.12 (4 H, m), 7.26-7.39 (9 H, m), 7.69 (1 H, d,






J = 3.1 Hz).


2069
3,4-
4-CNPh-
1
2.39 (2 H, brs), 2.55 (2 H, brs), 3.01 (3 H, s),



Cl2PhCH2N(CH3)—


3.35 (2 H, brs), 3.51 (2 H, s), 3.79 (2 H, brs),






4.40 (2 H, s), 6.82 (1 H, d, J = 8.9 Hz), 6.99-






7.13 (4 H, m), 7.25-7.33 (3 H, m), 7.39 (1 H, d, J =






8.1 Hz), 7.48-7.52 (2 H, m), 7.69-7.73 (3 H,






m).


2070
3,4-
4-ClPh
1
2.34-2.59 (4 H, m), 3.00 (3 H, s), 3.36 (2 H, brs),



Cl2PhCH2N(CH3)—


3.52 (2 H, s), 3.83 (2 H, brs), 4.40 (2 H, s),






6.82 (1 H, d, J = 8.9 Hz), 6.98-7.13 (4 H, m),






7.25-7.41 (8 H, m), 7.70 (1 H, d, J = 3.3 Hz).


2071
3,4-
3,4-F2Ph-
1
2.33-2.57 (4 H, m), 3.00 (3 H, s), 3.37-3.51 (4 H,



Cl2PhCH2N(CH3)—


m), 3.75 (2 H, brs), 4.40 (2 H, s), 6.82 (1 H, d, J =






8.9 Hz), 7.00-7.32 (10 H, m), 7.39 (1 H, d, J =






8.1 Hz), 7.69 (1 H, d, J = 3.1 Hz).


2072
4-CF3PhCONH—
-Ph
3
1.78-1.89 (2 H, m), 2.39-2.49 (6 H, m),






2.66 (2 H, t, J = 7.6 Hz), 3.44 (2 H, brs),






3.79 (2 H, brs), 6.94 (1 H, d, J = 8.7 Hz), 7.02-






7.07 (2 H, m), 7.18-7.23 (2 H, m), 7.35-






7.42 (5 H, m), 7.72 (2 H, d, J = 8.2 Hz),






7.99 (2 H, d, J = 8.1 Hz), 8.19-8.29 (3 H, m).


2073
4-CF3PhCONH—
4-CNPh-
3
1.79-1.90 (2 H, m), 2.41-2.69 (8 H, m),






3.39 (2 H, brs), 3.81 (2 H, brs), 6.95 (1 H, d, J =






8.9 Hz), 7.02-7.07 (2 H, m), 7.18-7.23 (2 H, m),






7.49 (2 H, d, J = 7.9 Hz), 7.69-7.77 (4 H, m),






8.00 (2 H, d, J = 8.1 Hz), 8.06 (1 H, brs),






8.21 (1 H, dd, J = 8.9 Hz, 2.6 Hz), 8.28 (1 H, d,






J = 2.6 Hz).


2074
4-CF3PhCONH—
3,4-F2Ph-
3
1.81-1.87 (2 H, m), 2.41-2.69 (8 H, m), 3.47-






3.76 (4 H, m), 6.95 (1 H, d, J = 8.7 Hz), 7.02-






7.07 (2 H, m), 7.11-7.28 (5 H, m), 7.75 (2 H, d, J =






8.4 Hz), 7.99-8.06 (3 H, m), 8.19-8.23 (1 H,






m), 8.28 (1 H, d, J = 2.6 Hz).
















TABLE 329







 








 











Example






No.
Xb32
Xb33
R978
mp (° C.) or 1H NMR (solvent) δ ppm





2075








—COPh
mp 136-138


 


2076








4-CH3OPhCO—
mp 161-162


 


2077








4-CF3PhCO—
mp 143-144


 


2078












mp 163-165


 


2079








4-ClPhCO—
mp 147-151


 


2080








—N(CH3)COPh
mp 231-232


 


2081








—N(CH3)COCH2Cl
1H NMR (CDCl3) 1.70-1.76 (2 H, m), 1.80- 1.90 (2 H, m), 2.80-2.88 (2 H, m), 2.98 (3 H, s), 3.56-3.68 (2 H, m), 4.10 (2 H, s), 4.57 (1 H, m), 6.94-6.99 (6 H, m), 7.53-7.58 (3 H, m), 7.69-7.71 (2 H, m), 7.97 (1 H, d, J = 2.0 Hz).


 


2082








—COCH2Cl
1H NMR (DMSO-d6) 3.08 (2 H, m), 3.14 (2 H, m), 3.61 (4 H, m), 4.44 (2 H, s), 6.93- 7.02 (6 H, m), 7.71 (2 H, d, J = 9.0 Hz), 7.82 (1 H, d, J = 8.5 Hz), 7.93 (1 H, dd, J = 8.5 Hz, 2.0 Hz), 8.21 (1 H, d, J = 2.0 Hz), 10.39 (1 H, s).


 


2083








—COCH2Cl
1H NMR (CDCl3) 1.66 (1 H, m), 1.74 (1 H, m), 1.91-1.98 (2 H, m), 2.72-2.77 (2 H, m), 3.24 (1 H, m), 3.99 (1 H, brd, J = 13.0 Hz), 4.11 (2 H, s), 4.73 (1 H, brd, J = 13.0 Hz), 6.96 (2 H, d, J = 8.5 Hz), 7.02 (2 H, d, J = 9.0 Hz), 7.15 (2 H, d, J = 8.5 Hz), 7.56- 7.79 (3 H, m), 7.71 (1 H, dd, J = 8.5 Hz, 2.0  Hz), 7.90 (1 H, brs), 7.98 (1 H, d, J = 2.0 Hz).
















TABLE 330







 








 














Example






mp (° C.) or


No.
R979
R980
Xb34
Xb35
Xb36
R981
MS





2084
3,4- Cl2Ph-
—H
none
none




—N(CH3)COCH2Ph
MS 616 (M+)


 


2085
4-CF3Ph-
—CH3
—N(CH3)—
—CH2—




4-CNPhCO—
mp 131-132


 


2086
4-CF3Ph-
—CH3
—N(CH3)—
—CH2—








mp 143-145
















TABLE 331







 








 











Example






No.
R982
Xb37
R983
Property





2087
—H




—Ac
mp 138-140° C.


 


2088
—F




—N(CH3)COCH2Ph
MS 661 (M+)


 


2089
—H




—COCH2Cl
1H NMR (CDCl3) δ 2.62 (2 H, t, J = 7.6 Hz), 2.95 (2 H, t, J = 7.6 Hz), 3.31-3.73 (8 H, m), 4.05 (2 H, s), 6.91 (2 H, d, J = 8.5 Hz), 6.97 (2 H, d, J = 8.9 Hz), 7.15 (2 H, d, J = 8.5 Hz), 7.49-7.60 (3 H, m), 7.68 (1 H, dd, J = 8.3 Hz, 2.1 Hz), 7.91 (1 H, brs), 7.95 (1 H, d, J = 2.1 Hz).
















TABLE 332







 








 









Example




No.
R984
mp (° C.)





2090
2-pyridyl
217-218


2091
3-pyridyl
191-192


2092
4-pyridyl
204-205
















TABLE 333







 








 









Example




No.
R985
mp (° C) or 1H NMR (CDCl3) δ ppm





2093
-Ph
mp 185-186


2094
—CH2Cl
a mixture of the rotational isomers 1H NMR 2.57 (0.4 H, brs), 2.65 (0.6 H, brs), 3.74 (0.6 H, t, J = 6.0 Hz), 3.85 (0.4 H, t, J = 6.0 Hz), 4.13 (0.8 H, s), 4.15 (1.2 H, s), 4.22 (1.2 H, m), 4.25 (0.8 H, m), 5.89 (0.4 H, brs), 6.04 (0.6 H, brs), 6.98 (2 H, d, J = 8.5 Hz), 7.04 (2 H, d, J = 9.0 Hz), 7.34 (2 H, dd, J = 8.5 Hz, 4.0 Hz), 7.56- 7.60 (3 H, m ), 7.71 (1 H, dd, J = 8.5 Hz, 2.0 Hz), 7.89 (1 H, brs), 7.89 (1 H, d, J = 2.0 Hz).









Example 2095
Production of 1-{4-[4-(3,4-dichlorobenzoylamino)-phenoxy]phenyl}-4-benzoyloxypiperidine
To a solution of 1-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}-4-hydroxypiperidine (200 mg, 0.44 mmol) in dichloromethane (8 mL) were added with triethylamine (0.091 mL, 0.65 mmol), benzoyl chloride (74 mg, 0.53 mmol) and 4-(dimethylamino)pyridine (3 mg, 0.025 mmol), and the resulting solution was stirred for 2.5 days at room temperature. This reaction solution was purified by silica gel column chromatography (methanol:dichloromethane=7:93), to thereby yield 80 mg of the title compound.
Appearance: White powder
Melting point: 188-190° C.
Example 2096
Production of 3,4-dichloro-N-(6-{4-[[2-oxo-2-(4-piperonylpiperazin-1-yl)ethyl](2,2,2-trifluoroacetyl)amino]phenoxy}pyridin-3-yl)benzamide
To a solution of 3,4-dichloro-N-(6-{4-[2-oxo-2-(4-piperonylpiperazin-1-yl)ethylamino]phenoxy}pyridin-3-yl)benzamide (0.152 g, 0.239 mmol) in THF (5 mL) were added triethylamine (0.0500 mL, 0.359 mmol) and trifluoroacetic anhydride (0.0410 mL, 0.2.87 mmol), and the resulting solution was stirred for 6 hours. Water was added to the resulting reaction solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to yield a solid. This solid was recrystallized from methanol, to thereby yield 28.8 mg of the title compound.
Appearance: White powder
Melting point: 211-213° C.
The following compound was produced in the same manner as in Example 2096.
Example 2097
N-[6-(4-Acetyl[2-oxo-2-(4-piperonylpiperazin-1-yl)ethyl]amino}-2-methoxyphenoxy)pyridin-3-yl]-3,4-dichlorobenzamide
1H NMR (CDCl3) δ 1.90 (3H, s), 2.28 (2H, brs), 2.38 (2H, brs), 3.37 (4H, brs), 3.49 (2H, brs), 3.67 (3H, s), 4.43 (2H, s), 5.93 (2H, s), 6.68-6.75 (2H, m), 6.82 (1H, s), 6.91-6.97 (2H, m), 7.07-7.10 (2H, m), 7.53 (1H, d, J=8.4 Hz), 7.76 (1H, dd, J=8.4 Hz, 2.0 Hz), 8.05 (1H, d, J=2.0 Hz), 8.20 (1H, dd, J=8.9 Hz, 2.8 Hz), 8.37 (1H, d, J=2.6 Hz), 9.26 (1H, s).
Example 2098
Production of N-[6-(benzoyl{4-[3-oxo-3-(4-piperonylpiperazin-1-yl)propyl]phenyl}amino)pyridin-3-yl]-3,4-dichlorobenzamide monooxalate
To a solution of 3,4-dichloro-N-(6-{4-[3-oxo-3-(4-piperonylpiperazin-1-yl)propyl]phenylamino}-pyridin-3-yl)benzamide (250 mg, 0.395 mmol) in THF (5 mL) were added triethylamine (0.132 mL, 0.949 mmol) and benzoyl chloride (0.0550 mL, 0.474 mmol), and the resulting solution was stirred for 7 hours at room temperature. Water was added to the resulting reaction solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol 10:1) to yield 0.300 g of a free form. To this free form were added isopropanol (5 mL) and oxalic acid dihydrate (100 mg, 0.793 mmol), and the resulting solution was dissolved under heat. The solvent was evaporated, and the resulting solid was recrystallized from isopropanol, to thereby yield 80.0 mg of the title compound.
Appearance: Yellow powder
Melting point: 140-143° C.
The following compound was produced in the same manner as in Example 2098.
Example 2099
N-[6-(Acetyl{4-[3-oxo-3-(4-piperonylpiperazin-1-yl)propyl]phenyl}amino)pyridin-3-yl]-3,4-dichlorobenzamide
Melting point: 150-165° C.
1H NMR (DMSO-d6) δ 1.98 (3H, s), 2.62-2.98 (7H, m), 3.04 (1H, t, J=12.1 Hz), 3.26 (2H, t, J=14.7 Hz), 3.35-3.50 (2H, m), 4.06 (1H, d, J=13.8 Hz), 4.13-4.26 (2H, m), 4.44 (1H, d, J=13.8 Hz), 6.07 (2H, s), 6.95-7.02 (2H, m), 7.20-7.24 (3H, m), 7.28 (2H, d, J=8.3 Hz), 7.52 (1H, d, J=8.9 Hz), 7.85 (1H, d, J=8.4 Hz), 7.96 (1H, dd, J=2.0 Hz, 8.4 Hz), 8.23-8.26 (2H, m), 8.77 (1H, s), 10.77 (1H, s), 11.10 (1H, brs).
Example 2100
Production of 6-{4-[3-(4-piperonylpiperazin-1-yl)-3-oxopropyl]phenoxy}-N-(3,4-dichlorophenyl)nicotinamide
To a solution of 6-{4-[3-(4-piperonylpiperazin-1-yl)-3-oxopropyl]phenoxy}nicotinic acid (1.23 g, 2.5 mmol) in THF (35 mL) was added N,N′-carbonyldiimidazole (540 mg, 3.3 mmol), and the resulting solution was stirred for 30 minutes at room temperature. The resulting reaction solution was concentrated under reduced pressure, and to the residue was added 3,4-dichloroaniline (4.07 g, 25 mmol). The resulting solution was stirred for 3 days at room temperature. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and the resulting product was recrystallized from diethyl ether, to thereby yield 510 mg of the title compound.
Appearance: White powder
1H NMR (CDCl3) δ 2.33 (4H, brs), 2.59-2.65 (2H, m), 2.91-2.97 (2H, m), 3.40 (4H, brs), 3.59 (2H, s), 5.94 (2H, s), 6.70-6.76 (2H, m), 6.83 (1H, s), 6.96-7.06 (3H, m), 7.20-7.26 (2H, m), 7.40 (1H, d, J=8.6 Hz), 7.50-7.54 (1H, m), 7.86 (1H, d, J=1.8 Hz), 8.18-8.22 (1H, m), 8.44 (1H, brs), 8.66 (1H, brs).
The following compounds were produced in the same manner as in Example 2100.







TABLE 334













 












Example No.
R986
Xb38
Xb39
R987
mp (° C.) or 1H NMR (CDCl3) δ ppm





2101
3,4-Cl2Ph-
none
none
benzyl
mp 206-207


2102
4-CF3Ph-
none
none
benzyl
1H NMR 2.44 (4H, brs), 3.53-3.70 (6H,







m), 6.93 (1H, d, J = 8.4 Hz), 7.11-







7.14 (2H, m), 7.27-7.40 (7H, m),







7.56 (2H, d, J = 8.9 Hz), 7.83 (2H, d, J =







8.4 Hz), 8.23-8.27 (1H, m), 8.71 (1H,







d, J = 2.4 Hz), 9.39 (1H, brs).


2103
4-CF3Ph-
—N(CH3)—
—CH2—
piperonyl
1H NMR 2.42 (4H, brs), 3.03 (3H, s),







3.43-3.52 (4H, m), 3.60 (2H, brs),







4.10 (2H, s), 5.95 (2H, s), 6.66-6.77 (4H,







m), 6.85 (1H, brs), 6.89 (1H, d, J = 8.6







Hz), 6.98 (2H, d, J = 6.6 Hz), 7.60 (2H,







d, J = 8.4 Hz), 7.76 (2H, d, J = 8.4 Hz),







8.14 (1H, dd, J = 8.6 Hz, 2.6 Hz),







8.33 (1H, brs), 8.63 (1H, brs).


2104
3,4-Cl2Ph-
—N(CH3)—
—CH2—
piperonyl
1H NMR 2.42-2.44 (4H, m), 3.05 (3H,







s), 3.44 (2H, brs), 3.47-3.57 (2H, m),







3.63 (2H, brs), 4.11 (2H, s), 5.95 (2H, s),







6.68-6.74 (4H, m), 6.85 (1H, brs), 6.92







(1H, d, J = 8.9 Hz), 7.00 (2H, d, J = 8.7







Hz), 7.42-7.44 (2H, m), 7.80-7.86 (1H,







m), 7.87 (1H, d, J = 2.1 Hz), 8.13 (1H,







dd, J = 8.7 Hz, 2.6 Hz), 8.63 (1H, d, J =







2.1 Hz).


2105
4-CF3Ph-
none
none
piperonyl
1H NMR 2.71 (4H, brs), 3.46-3.92 (6H,







m), 5.91 (2H, s), 6.65-6.73 (2H, m),







6.81 (1H, d, J = 1.5 Hz), 7.01 (1H, d, J =







9.1 Hz), 7.14 (2H, d, J = 8.7 Hz),







7.43 (2H, d, J = 8.7 Hz), 7.60 (2H, d, J =







8.6 Hz), 7.82 (2H, d, J = 8.6 Hz),







8.29 (1H, dd, J = 2.6 Hz, 8.6 Hz),







8.71 (1H, d, J = 2.1 Hz), 8.87 (1H, brs).









Example 2106
Production of (4-benzylpiperazin-1-yl){4-[5-(3,4-dichlorophenylsulfanyl)pyridin-2-yloxy]phenyl}methanone
To a solution of [4-(5-aminopyridin-2-yloxy)phenyl](4-benzylpiperazin-1-yl)methanone (0.73 g, 1.88 mmol) in concentrated sulfuric acid (0.38 mL)-water (1.1 mL) were added dropwise a solution of sodium nitrate (0.13 g, 1.88 mmol) in water (0.6 mL) under ice cooling. The reaction mixture was stirred for 10 minutes. This reaction mixture was added to a solution of 3,4-dichlorobenzenethiol (0.24 mL, 1.88 mmol) in 2 N aqueous sodium hydroxide (2 mL) under cooling with ice. Water was added to the resulting reaction solution, and extracted with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel chromatography (dichloromethane:methanol=80:1), to thereby yield 0.1 g of the title compound.
Appearance: Yellow oil
1H NMR (CDCl3) δ 2.49 (4H, brs), 3.56 (2H, s), 3.56 (2H, brs), 3.78 (2H, brs), 6.99 (1H, d, J=8.9 Hz), 7.20 (2H, d, J=8.7 Hz), 7.25-7.39 (5H, m), 7.46 (1H, dd, J=8.2 Hz, 2.0 Hz), 7.47 (2H, d, J=8.7 Hz), 7.56 (1H, d, J=8.2 Hz), 7.76 (1H, d, J=2.0 Hz), 7.86 (1H, dd, J=8.9 Hz, 2.5 Hz), 8.50 (1H, d, J=2.5 Hz).
The following compound was produced in the same manner as in Example 2106.
Example 2107
2-({4-[5-(3,4-Dichlorophenylsulfanyl)pyridin-2-yloxy]-3-methoxyphenyl}ethylamino)-1-(4-piperonylpiperazin-1-yl)ethanone
1H NMR (CDCl3) δ 1.20 (3H, t, J=7.0 Hz), 2.43 (4H, t, J=4.9 Hz), 3.43 (2H, s), 3.35-3.50 (2H, m), 3.49-3.60 (2H, m), 3.60-3.70 (2H, m), 3.73 (3H, s), 4.05 (2H, s), 5.95 (2H, s), 6.22 (1H, dd, J=8.9 Hz, 2.7 Hz), 6.35 (1H, d, J=2.7 Hz), 6.70-6.76 (2H, m), 6.85 (1H, s), 6.90 (1H, d, J=9.0 Hz), 6.98 (1H, d, J=8.8 Hz), 7.46 (1H, dd, J=8.2 Hz, 2.0 Hz), 7.55 (1H, d, J=8.2 Hz), 7.75 (1H, d, J=2.0 Hz), 7.78 (1H, dd, J=9.0 Hz, 2.5 Hz), 8.49 (1H, d, J=2.5 Hz).
Example 2108
Production of 1-(6-{4-[3-(4-piperonylpiperazin-1-yl)-3-oxopropyl]phenoxy}pyridin-3-yl)-3-(3,4-dichlorophenyl)urea
To a solution of 3-[4-(5-aminopyridin-2-yloxy)phenyl]-1-(4-piperonylpiperazin-1-yl)propane-1-one (600 mg, 1.3 mmol) in toluene (20 mL) were added ethyldiisopropylamine (0.454 mL, 2.6 mmol) and 3,4-dichlorophenylisocyanate (270 mg, 1.4 mmol), and the resulting solution was stirred for 1 day under reflux. The reaction solution was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:chloroform=1:19), and then recrystallized from ethyl acetate to thereby yield 280 mg of the title compound.
Appearance: Pale yellow powder
1H NMR (CDCl3) δ 2.37-2.39 (4H, m), 2.61-2.67 (2H, m), 2.89-2.94 (2H, m), 3.41-3.47 (4H, m), 3.61-3.65 (2H, m), 5.94 (2H, s), 6.69-6.83 (4H, m), 6.95 (2H, d, J=8.4 Hz), 7.10-7.26 (4H, m), 7.49 (1H, d, J=2.3 Hz), 7.93-7.96 (2H, m), 8.1-5 (1H, s), 8.21 (1H, s).
The following compounds were produced in the same manner as in Example 2108.







TABLE 335













 









Example No.
R988
1H NMR (solvent) δ ppm





2109




(DMSO-d6) 1.13 (3H, t, J = 6.9 Hz), 2.20-2.60 (1H, m), 2.75-3.20 (2H, m), 3.20-3.65 (7H, m), 3.64 (3H, s), 4.05- 4.52 (4H, m), 6.07 (2H, brs), 6.10 (1H, dd, J = 8.8 Hz, 2.7 Hz), 6.27 (1H, brs), 6.80 (1H, d, J = 8.6 Hz), 6.84 (1H, d, J = 8.6 Hz), 7.01 (2H, brs), 7.19 (1H, brs), 7.33 (1H, dd, J = 8.9 Hz, 2.6 Hz), 7.51 (1H, d, J = 8.9 Hz), 7.85 (1H, dd, J = 8.9 Hz, 2.6 Hz), 7.86 (1H, d, J = 2.6 Hz), 8.07 (1H, d, J = 2.6 Hz), 8.94 (1H, s), 9.28 (1H, s).


 


2110




(CDCl3) 1.14 (3H, t, J = 7.0 Hz), 2.35- 2.55 (4H, m), 3.38 (2H, q, J = 7.0 Hz), 3.44 (2H, s), 3.45-3.55 (2H, m), 3.60 (3H, s), 3.60-3.75 (2H, m), 4.02 (2H, s), 5.95 (2H, s), 6.60-6.80 (4H, m), 6.85 (1H, s), 6.92 (1H, d, J = 8.9 Hz), 7.00- 7.15 (2H, m), 7.22 (1H, d, J = 8.7 Hz), 7.45 (1H, d, J = 2.3 Hz), 7.75-7.85 (2H, m), 7.95 (1H, s), 7.97 (1H, s).


 


2111




(CDCl3) 1.09 (3H, t, J = 7.1 Hz), 2.35- 2.45 (4H, m), 3.10 (2H, q, J = 7.1 Hz), 3.43 (2H, s), 3.55-3.65 (4H, m), 3.85 (2H, s), 5.95 (2H, s), 6.70-6.80 (2H, m), 6.85 (1H, s), 6.90 (1H, d, J = 8.8 Hz), 7.05-7.35 (4H, m), 7.46 (1H, d, J = 8.8 Hz), 7.53 (1H, d, J = 2.4 Hz), 7.79 (1H, brs), 7.85 (1H, brs), 7.93 (1H, d, J = 2.6 Hz), 7.99 (1H, dd, J = 8.8 Hz, 2.8 Hz).


 


2112




(CDCl3) 1.44 (9H, s), 1.96 (3H, s), 2.10- 2.30 (2H, m), 3.42-3.61 (2H, m), 3.62- 3.78 (2H, m), 4.04 (2H, s), 6.58 (1H, d, J = 8.8 Hz), 6.60 (1H, d, J = 8.5 Hz), 6.91 (1H, dd, J = 2.6 Hz, 8.5 Hz), 7.00 (1H, d, J = 2.6 Hz), 7.31 (1H, d, J = 8.8 Hz), 7.36 (1H, dd, J = 2.3 Hz, 8.8 Hz), 7.69 (1H, d, J = 2.3 Hz), 7.79 (1H, dd, J = 2.8 Hz, 8.8 Hz), 7.91 (1H, d, J = 2.8 Hz), 7.93 (1H, s), 8.05 (1H, s).









Example 2113
Production of 4-piperonylpiperazine-1-carboxylic acid {(4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]phenyl}amide hydrochloride
To a solution of {4-[5-(3,4-dichlorobenzoyl-amino)pyridin-2-yloxy]phenyl}-carbamic acid phenyl ester (320 mg, 0.65 mmol) in DMF (4 mL) was added 1-piperonylpiperazine (285 mg, 1.29 mmol), and the resulting solution was stirred for 17 hours at room temperature. This reaction solution was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was then purified by silica gel column chromatography (dichloromethane:methanol=25:1). The obtained residue was dissolved in a mixed solvent of ethanol-ethyl acetate. To the resulting solution was added a solution of 4 N hydrogen chloride in ethyl acetate to bring the pH to 3. The precipitated white powder was then filtered off and washed with ethanol, to thereby yield 330 mg of the title compound.
Appearance: White powder
1H NMR (DMSO-d6) δ 2.85-3.09 (2H, m), 3.20-3.50 (4H, m), 4.12-4.38 (4H, m), 6.08 (2H, s), 7.02 (2H, d, J=9.0 Hz), 6.93-7.12 (3H, m), 7.28 (1H, d, J=1.5 Hz), 7.49 (2H, d, J=9.0 Hz), 7.83 (1H, d, J=8.5 Hz), 7.97 (1H, dd, J=8.5 Hz, 2.0 Hz), 8.19 (1H, dd, J=8.8 Hz, 2.6 Hz), 8.25 (1H, d, J=2.0 Hz), 8.50 (1H, d, J=2.6 Hz), 8.92 (1H, s), 10.63 (1H, s)
The following compound was produced in the same manner as in Example 2113.
Example 2114
4-Benzylpiperazine-1-carboxylic acid {4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]phenyl}amide hydrochloride
1H NMR (DMSO-d6) δ 2.90-3.20 (2H, m), 3.22-3.45 (4H, m), 4.27 (2H, d, J=13.6 Hz), 4.35 (2H, d, J=5.0 Hz), 7.02 (1H, d, J=8.9 Hz), 7.03 (2H, d, J=8.9 Hz), 7.41-7.52 (3H, m), 7.48 (2H, d, J=8.9 Hz), 7.55-7.69 (2H, m), 7.84 (1H, d, J=8.4 Hz), 7.97 (1H, dd, J=8.4 Hz, 2.0 Hz), 8.19 (1H, dd, J=8.9 Hz, 2.6 Hz), 8.25 (1H, d, J=2.0 Hz), 8.49 (1H, d, J=2.6 Hz), 8.90 (1H, s), 10.62 (1H, s).
Example 2115
Production of 2-[(4-{5-[(3,4-dichlorobenzylidene)-amino]pyridin-2-yloxy}phenyl)methylamino]-1-(4-piperonylpiperazin-1-yl)ethanone
2-{[(4-(5-aminopyridin-2-yloxy)phenyl]methylamino}-1-(4-piperonylpiperazin-1-yl)ethanone (7.80 g, 16.4 mmol) was dissolved in methanol (400 mL), and to the resulting solution was added 3,4-dichlorobenzaldehyde (2.87 g, 16.4 mmol). This solution was refluxed for 16 hours. The resulting reaction solution was concentrated under reduced pressure, to thereby yield 10.4 g of the title compound.
Appearance: Brown oil
1H NMR (CDCl3) δ 2.44 (4H, brs), 3.03 (3H, s), 3.44-3.45 (2H, m), 3.50 (2H, brs), 3.63 (2H, brs), 4.09 (2H, s), 5.94 (2H, s), 6.65-6.77 (4H, m), 6.84-6.88 (2H, m), 7.03 (2H, d, J=9.1 Hz), 7.54 (1H, d, J=8.3 Hz), 7.58 (1H, dd, J=8.9 Hz, 2.8 Hz), 7.70 (1H, dd, J=8.4 Hz, 2.0 Hz), 8.00 (1H, d, J=2.0 Hz), 8.10 (1H, d, J=2.8 Hz), 8.39 (1H, s).
The following compounds were produced in the same manner as in Example 2115.







TABLE 336







 








 













Example








No.
R989
R990
R991
Xb40
M
1H NMR (solvent) δ ppm





2116
3,4-
—H
benzyl
none
0
(DMSO-d6) 2.41 (4 H, brs), 3.34-3.51 (6 H, m),



Cl2Ph




7.19 (1 H, d, J = 8.7 Hz), 7.20 (2 H, d, J = 7.9








Hz), 7.29-7.33 (5 H, m), 7.45 (2 H, d, J = 7.9








Hz), 7.81 (1 H, d, J = 8.3 Hz), 7.91-7.96 (2 H,








m), 8.15 (1 H, brs), 8.18 (1 H, d, J = 2.6 Hz),








8.75 (1 H, s).


2117
3,4-
—H
benzyl
none
2
(DMSO-d6) 2.30 (4 H, brs), 2.60-2.62 (2 H,



Cl2Ph




m), 2.79-2.85 (2 H, m), 3.44-3.48 (6 H, m),








7.05 (2 H, d, J = 8.4 Hz), 7.09 (1 H, d, J = 8.7








Hz), 7.25-7.36 (7 H, m), 7.81 (1 H, d, J = 8.2








Hz), 7.88-7.93 (2 H, m), 8.13-8.14 (2 H, m),








8.74 (1 H, s).


2118
4-
—H
benzyl
none
0
(CDCl3) 2.47 (4 H, brs), 3.55 (2 H, brs),



CF3Ph-




3.55 (2 H, s), 3.79 (2 H, brs), 7.00 (1 H, d, J =








8.7 Hz), 7.18 (2 H, d, J = 8.6 Hz), 7.22-








7.40 (5 H, m), 7.47 (2 H, d, J = 8.6 Hz),








7.67 (1 H, dd, J = 8.7 Hz, 2.6 Hz), 7.74 (2 H,








d, J = 8.1 Hz), 8.03 (2 H, d, J = 8.1 Hz),








8.14 (1 H, d, J = 2.6 Hz), 8.54 (1 H, s).


2119
4-
—H
piperonyl
—N(CH3)—
1
(CDCl3) 2.45 (4 H, brs), 3.04 (3 H, s), 3.45-



CF3Ph-




3.51 (4 H, m), 3.65 (2 H, s), 4.09 (2 H, s),








5.95 (2 H, s), 6.71-6.74 (4 H, m), 6.86-








6.89 (2 H, m), 7.04 (2 H, d, J = 9.1 Hz),








7.61 (1 H, dd, J = 8.7 Hz, 2.6 Hz), 7.73 (2 H,








d, J = 8.3 Hz), 8.01 (2 H, d, J = 8.4 Hz),








8.14 (1 H, d, J = 2.6 Hz), 8.53 (1 H, s).


2120
4-
—F
benzyl
none
0
(CDCl3) 2.49 (4 H, brs), 3.43-3.75 (6 H, m),



CF3Ph-




7.07 (1 H, d, J = 8.6 Hz), 7.29-7.34 (8 H, m),








7.69 (1 H, dd, J = 8.7 Hz, 2.8 Hz), 7.74 (2 H,








d, J = 8.3 Hz), 8.02 (2 H, d, J = 8.3 Hz),








8.05 (1 H, d, J = 2.6 Hz), 8.53 (1 H, s).


2121
3,4-
—H
piperonyl
—N(CH3)—
2
(CDCl3) 2.34-2.41 (4 H, m), 2.55-2.61 (2 H,



Cl2Ph




m), 2.95 (3 H, s), 3.41 (4 H, brs), 3.61-








3.65 (2 H, m), 3.68-3.76 (2 H, m), 5.94 (2 H, s),








6.70-6.77 (4 H, m), 6.84 (1 H, d, J = 1.0 Hz),








6.89 (1 H, dd, J = 8.7 Hz, 0.5 Hz), 7.04 (2 H,








d, J = 9.2 Hz), 7.55 (1 H, d, J = 8.3 Hz),








7.60 (1 H, dd, J = 8.7 Hz, 2.8 Hz), 7.71 (1 H,








dd, J = 8.3 Hz, 2.0 Hz), 8.01 (1 H, d, J = 1.8








Hz), 8.11 (1 H, dd, J = 2.8 Hz, 0.5 Hz),








8.40 (1 H, brs).


2122
4-
—H
piperonyl
—N(CH3)—
2
(CDCl3) 2.34-2.41 (4 H, m), 2.55-2.61 (2 H,



CF3Ph




m), 2.95 (3 H, s), 3.39-3.42 (4 H, m), 3.61-








3.64 (2 H, m), 3.68-3.76 (2 H, m), 5.94 (2 H, s),








6.70-6.77 (4 H, m), 6.84 (1 H, d, J = 0.8 Hz),








6.90 (1 H, dd, J = 8.7 Hz, 0.7 Hz), 7.05 (2 H, d, J =








9.2 Hz), 7.63 (1 H, dd, J = 8.7 Hz, 2.8 Hz),








7.73 (2 H, d, J = 8.3 Hz), 8.01 (2 H, d, J = 8.6








Hz), 8.13 (1 H, dd, J = 2.8 Hz, 0.7 Hz),








8.53 (1 H, brs).
















TABLE 337







 








 










Example





No.
R992
R993
1H NMR (CDCl3) δ ppm





2123
3,4-Cl2Ph-
—H
2.43 (4 H, brs), 3.22 (3 H, s), 3.38 (2 H, brs), 3.43 (2 H, s), 3.62 (2 H,





brs), 4.55 (2 H, s), 5.95 (2 H, s), 6.74 (2 H, brs), 6.84 (1 H, brs),





7.01 (1 H, d, J = 8.6 Hz), 7.15 (2 H, d, J = 8.7 Hz), 7.57 (1 H, d, J =





8.3 Hz), 7.61-7.68 (3 H, m), 7.72 (1 H, dd, J = 8.3 Hz, 1.8 Hz),





8.03 (1 H, d, J = 1.8 Hz), 8.11 (1 H, d, J = 2.8 Hz), 8.42 (1 H, brs).


2124
3,4-Cl2Ph-
—CH3
2.20 (3 H, s), 2.42-2.43 (4 H, m), 3.23 (3 H, s), 3.38 (2 H, brs),





3.43 (2 H, s), 3.62 (2 H, brs), 4.54 (2 H, s), 5.94 (2 H, s), 6.70-





6.77 (2 H, m), 6.84 (1 H, brs), 6.97 (1 H, dd, J = 8.7 Hz, 0.5 Hz),





7.05 (1 H, d, J = 8.6 Hz), 7.43-7.49 (2 H, m), 7.55 (1 H, d, J = 8.2





Hz), 7.62-7.66 (1 H, m), 7.69-7.74 (1 H, m), 8.01 (1 H, d, J = 2.0





Hz), 8.07 (1 H, d, J = 2.1 Hz), 8.40 (1 H, brs).


2125
4-CF3Ph-
—CH3
2.20 (3 H, s), 2.41-2.43 (4 H, m), 3.23 (3 H, s), 3.38 (2 H, brs),





3.43 (2 H, s), 3.60 (2 H, brs), 4.55 (2 H, s), 5.95 (2 H, s), 6.73-





6.74 (2 H, m), 6.84 (1 H, brs), 6.98 (1 H, d, J = 8.7 Hz), 7.05 (1 H, d,





J = 8.4 Hz), 7.43-7.49 (2 H, m), 7.65-7.75 (3 H, m), 8.00-8.10 (3 H,





m), 8.53 (1 H, brs).


2126
4-CF3Ph-
—OCH3
2.43 (4 H, brs), 3.24 (3 H, s), 3.39 (2 H, brs), 3.43 (2 H, s), 3.63 (2 H,





brs), 3.77 (3 H, s), 4.57 (2 H, s), 5.94 (2 H, s), 6.73-6.77 (2 H, m),





6.84 (1 H, s), 7.02 (1 H, d, J = 8.6 Hz), 7.13 (1 H, d, J = 8.4 Hz),





7.22 (1 H, dd, J = 8.4 Hz, 2.3 Hz), 7.30 (1 H, d, J = 2.3 Hz),





7.66 (1 H, dd, J = 8.7 Hz, 2.8 Hz), 7.73 (2 H, d, J = 8.1 Hz),





8.01 (2 H, d, J = 8.1 Hz), 8.08 (1 H, d, J = 2.5 Hz), 8.53 (1 H, s).
















TABLE 338







 








 










Example





No.
R994
R995
1H NMR (solvent) δ ppm





2127
3,4-Cl2Ph-
—H
(CDCl3) 2.20 (3 H, s), 2.49-2.55 (4 H, m), 3.45 (2 H, s), 3.71-





3.75 (2 H, m), 4.25-4.29 (2 H, m), 5.95 (2 H, s), 6.75 (2 H, brs),





6.86 (1 H, brs), 6.92 (1 H, d, J = 8.6 Hz), 7.06 (1 H, d, J = 8.6





Hz), 7.44 (1 H, dd, J = 8.6 Hz, 2.6 Hz), 7.53-7.65 (3 H, m),





7.70 (1 H, dd, J = 8.2 Hz, 2.0 Hz), 8.01 (1 H, d, J = 1.8 Hz),





8.07 (1 H, d, J = 2.8 Hz), 8.40 (1 H, brs), 9.17 (1 H, brs).


2128
4-CF3Ph-
—H
(CDCl3) 2.20 (3 H, s), 2.49-2.55 (4 H, m), 3.45 (2 H, s), 3.71-





3.75 (2 H, m), 4.25-4.28 (2 H, m), 5.95 (2 H, s), 6.75 (2 H, brs),





6.86 (1 H, brs), 6.93 (1 H, d, J = 8.7 Hz), 7.07 (1 H, d, J = 8.7





Hz), 7.45 (1 H, dd, J = 8.7 Hz, 2.6 Hz), 7.58 (1 H, d, J = 2.5





Hz), 7.65 (1 H, dd, J = 8.6 Hz, 2.6 Hz), 7.73 (2 H, d, J = 8.2





Hz), 8.01 (2 H, d, J = 8.1 Hz), 8.10 (1 H, d, J = 2.8 Hz),





8.53 (1 H, s), 9.19 (1 H, brs).


2129
3,4-Cl2Ph-
—CH3
a mixture of the rotational isomers





(DMSO-d6) 2.10-2.44 (7 H, m), 3.16-3.57 (9 H, m), 5.96-





5.99 (2 H, m), 6.67-6.89 (3 H, m), 7.09-7.26 (3 H, m), 7.29-





7.38 (1 H, m), 7.81 (1 H, d, J = 8.41 Hz), 7.89-7.96 (2 H, m),





8.10-8.15 (2 H, m), 8.74 (1 H, s).


2130
4-CF3Ph-
—CH3
a mixture of rotational isomers





(DMSO-d6) 2.11-2.44 (7 H, m), 3.18-3.57 (9 H, m), 5.96-





6.00 (2 H, m), 6.67-6.90 (3 H, m), 7.09-7.27 (3 H, m), 7.29-





7.38 (1 H, m), 7.90 (2 H, d, J = 8.24 Hz), 7.95-8.00 (1 H, m),





8.11-8.16 (3 H, m), 8.85 (1 H, s).
















TABLE 339













 










Example





No.
R996
R997
1H NMR (CDCl3) δ ppm





2131
—H




1.46 (9 H, s), 2.41-2.45 (4 H, m), 3.43-3.47 (4 H, m), 3.53 (2 H, s), 6.96 (1 H, d, J = 8.7 Hz), 7.08- 7.14 (2 H, m), 7.36 (2 H, d, J = 8.4 Hz), 7.55 (1 H, d, J = 8.2 Hz), 7.63 (1 H, dd, J = 8.7 Hz, 2.6 Hz), 7.71 (1 H, dd, J = 2.0 Hz), 8.01 (1 H, d, J = 1.8 Hz), 8.11-8.12 (1 H, m), 8.41 (1 H, s).


 


2132
—CH3




2.19 (3 H, s), 3.12 (1 H, dd, J = 14.0 Hz, 9.9 Hz), 3.55 (1 H, dd, J = 14.0 Hz, 3.8 Hz), 4.54 (1 H, dd, J = 9.9 Hz, 3.8 Hz), 6.95 (1 H, d, J = 8.7 Hz), 7.04 (1 H, d, J = 8.1 Hz), 7.12 (1 H, dd, J = 8.1 Hz, 2.1 Hz), 7.16 (1 H, d, J = 2.1 Hz), 7.56 (1 H, d, J = 8.4 Hz), 7.64 (1 H, dd, J = 8.7 Hz, 2.3 Hz), 7.71 (1 H, dd, J = 8.4 Hz, 1.8 Hz), 8.02 (1 H, d, J = 1.8 Hz), 8.08 (1 H, d, J = 2.3 Hz), 8.18 (1 H, brs), 8.41 (1 H, s).









Example 2133
Production of 3-({4-[5-(3,4-dichlorobenzylamino)-pyridin-2-yloxy]phenyl}methylamino)-1-(4-piperonylpiperazin-1-yl)propane-1-one
3-[(4-{5-(3,4-dichlorobenzylidene)pyridin-2-yloxy}phenyl)methylamino]-1-(4-piperonylpiperazin-1-yl)propane-1-one (3.88 g, 6.0 mmol) was dissolved in a mixed solvent of methanol (150 mL) and THF (50 mL). To the resulting solution was slowly added sodium borohydride (1.13 g, 30.0 mmol) and that resulting solution was stirred for 13 hours at room temperature. This reaction solution was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate, and washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was then purified by silica gel column chromatography (dichloromethane:methanol=40:1), to thereby yield 3.60 g of the title compound.
Appearance: White powder
1H NMR (CDCl3) δ 2.32-2.39 (4H, m), 2.52-2.57 (2H, m), 2.91 (3H, s), 3.36-3.40 (4H, m), 3.59-3.63 (2H, m), 3.66-3.71 (2H, m), 3.97 (1H, brs), 4.27 (2H, d, J=5.0 Hz), 5.94 (2H, s), 6.65-6.76 (5H, m), 6.83 (1H, d, J=1.0 Hz), 6.94 (1H, dd, J=8.9 Hz, 3.0 Hz), 6.97 (2H, d, J=9.2 Hz), 7.18 (1H, dd, J=8.3 Hz, 2.0 Hz), 7.40 (1H, d, J=8.4 Hz), 7.45 (1H, d, J=2.0 Hz), 7.56 (1H, d, J=2.5 Hz); MS 647 (M+).
The following compounds were produced in the same manner as in Example 2133.







TABLE 340













 












Example







No.
R998
R999
Xb41
M
1H NMR (solvent) δ ppm





2134
4-CF3Ph-
piperonyl
—N(CH3)—
1
(CDCl3) 2.42 (4 H, brs), 2.99 (3 H, s), 3.43-







3.49 (4 H, m), 3.62 (2 H, brs), 4.04 (2 H, s),







4.37 (2 H, s), 5.95 (2 H, s), 6.67-6.75 (5 H, m),







6.86 (1 H, brs), 6.92-6.97 (3 H, m), 7.47 (2 H, d,







J = 7.9 Hz), 7.58-7.61 (3 H, m).


2135
4-CF3Ph-
piperonyl
—N(CH3)—
2
(CDCl3) 2.32-2.39 (4 H, m), 2.52-2.57 (2 H, m),







2.91 (3 H, s), 3.36-3.39 (4 H, m), 3.59-3.63 (2 H,







m), 3.66-3.71 (2 H, m), 4.00 (1 H, brs),







4.37 (2 H, d, J = 4.3 Hz), 5.94 (2 H, s), 6.66-







6.76 (5 H, m), 6.83 (1 H, d, J = 1.0 Hz),







6.95 (1 H, dd, J = 8.9 Hz, 3.0 Hz), 6.97 (2 H, d,







J = 9.1 Hz), 7.46 (2 H, d, J = 8.1 Hz), 7.57-







7.61 (3 H, m).


2136
3,4-Cl2Ph-
piperonyl
—N(CH3)—
1
(CDCl3) 2.39-2.43 (4 H, m), 2.99 (3 H, s),







3.42 (2 H, brs), 3.46-3.50 (2 H, m), 3.60-







3.62 (2 H, m), 3.97 (1 H, t, J = 5.8 Hz),







4.05 (2 H, s), 4.26 (2 H, d, J = 5.8 Hz),







5.95 (2 H, s), 6.65-6.77 (5 H, m), 6.85 (1 H, brs),







6.93 (1 H, dd, J = 8.6 Hz, 3.1 Hz), 6.96 (2 H, d,







J = 9.1 Hz), 7.18 (1 H, dd, J = 8.3 Hz, 2.1







Hz), 7.40 (1 H, d, J = 8.3 Hz), 7.45 (1 H, d, J =







2.1 Hz), 7.57 (1 H, d, J = 2.8 Hz)


2137
3,4-Cl2Ph-
benzyl
none
2
(DMSO-d6) 2.26-2.28 (4 H, m), 2.57 (2 H, t, J =







7.9 Hz), 2.76 (2 H, t, J = 7.9 Hz), 3.40-







3.46 (6 H, m), 4.28 (2 H, d, J = 5.9 Hz),







6.36 (1 H, t, J = 6.1 Hz), 6.77 (1 H, d, J = 8.7







Hz), 6.85 (2 H, d, J = 8.3 Hz), 7.09 (1 H, dd, J =







8.7 Hz, 3.0 Hz), 7.17 (2 H, d, J = 8.4 Hz),







7.24-7.37 (6 H, m), 7.50 (1 H, d, J = 3.0 Hz),







7.58 (1 H, d, J = 8.3 Hz), 7.62 (1 H, d, J = 1.8







Hz).


2138
3,4-Cl2Ph-
benzyl
none
0
(DMSO-d6) 2.38 (4 H, brs), 3.33-3.50 (6 H, m),







4.30 (2 H, d, J = 6.3 Hz), 6.47 (1 H, t, J = 6.3







Hz), 6.87 (1 H, d, J = 8.7 Hz), 6.97 (2 H, d, J =







8.6 Hz), 7.12 (1 H, dd, J = 8.7 Hz, 3.0 Hz),







7.25-7.39 (8 H, m), 7.56 (1 H, d, J = 3.0 Hz),







7.58-7.64 (2 H, m).


2139
4-CF3Ph-
benzyl
none
0
(CDCl3) 2.45 (4 H, brs), 3.52 (2 H, brs),







3.53 (2 H, s), 3.73 (2 H, brs), 4.16 (1 H, brs),







4.41 (2 H, s), 6.80 (1 H, d, J = 8.7 Hz),







6.99 (1 H, dd, J = 8.7 Hz, 3.0 Hz), 7.03 (2 H, d,







J = 8.5 Hz), 7.20-7.37 (5 H, m), 7.38 (2 H, d, J =







8.5 Hz), 7.48 (2 H, d, J = 8.1 Hz), 7.61 (2 H,







d, J = 8.1 Hz), 7.64 (1 H, d, J = 3.0 Hz).
















TABLE 341













 










Example





No.
R1000
R1001
1H NMR (CDCl3) δ ppm





2140
3,4-Cl2Ph-
—H
2.41 (4 H, brs), 3.19 (3 H, s), 3.33-3.35 (2 H, m), 3.42 (2 H, s),





3.60 (2 H, brs), 4.08 (1 H, brs), 4.30 (2 H, d, J = 5.3 Hz),





4.50 (2 H, s), 5.95 (2 H, s), 6.73-6.74 (2 H, m), 6.80-6.84 (2 H,





m), 6.99 (1 H, dd, J = 8.6 Hz, 3.1 Hz), 7.02 (2 H, d, J = 8.7





Hz), 7.20 (1 H, dd, J = 8.3 Hz, 2.0 Hz), 7.42 (1 H, d, J = 8.3





Hz), 7.66 (1 H, d, J = 2.1 Hz), 7.54 (2 H, d, J = 8.9 Hz),





7.60 (1 H, d, J = 2.8 Hz).


2141
3,4-Cl2Ph-
—CH3
2.19 (3 H, s), 2.41 (4 H, brs), 3.19 (3 H, s), 3.35 (2 H, brs),





3.41 (2 H, s), 3.60 (2 H, brs), 4.07-4.15 (1 H, m), 4.27 (2 H, s),





4.50 (2 H, s), 5.93 (2 H, s), 6.69-6.78 (3 H, m), 6.83 (1 H, brs),





6.88 (1 H, d, J = 8.6 Hz), 6.98 (1 H, dd, J = 8.7 Hz, 3.0 Hz),





7.17-7.20 (1 H, m), 7.34-7.44 (4 H, m), 7.53 (1 H, d, J = 3.0





Hz).


2142
4-CF3Ph-
—CH3
2.20 (3 H, s), 2.41 (4 H, brs), 3.19 (3 H, s), 3.35-3.37 (2 H, m),





3.41 (2 H, s), 3.60-3.62 (2 H, m), 4.15 (1 H, brs), 4.38 (2 H, s),





4.50 (2 H, s), 5.94 (2 H, s), 6.73 (2 H, brs), 6.76 (1 H, d, J = 8.7





Hz), 6.83 (1 H, brs), 6.88 (1 H, d, J = 8.6 Hz), 7.00 (1 H, dd, J =





8.7 Hz, 3.0 Hz), 7.36 (1 H, dd, J= 8.6 Hz, 2.6 Hz), 7.42 (1 H,





d, J = 2.5 Hz), 7.47 (2 H, d, J = 8.1 Hz), 7.56 (1 H, d, J = 2.8





Hz), 7.59 (2 H, d, J = 8.1 Hz).


2143
4-CF3Ph-
—OCH3
2.41 (4 H, brs), 3.21 (3 H, s), 3.36 (2 H, brs), 3.42 (2 H, s),





3.60 (2 H, brs), 3.76 (3 H, s), 4.09 (1 H, brs), 4.37 (2 H, s),





4.52 (2 H, s), 5.94 (2 H, s), 6.70-6.83 (4 H, m), 6.97-7.02 (2 H,





m), 7.12-7.16 (1 H, m), 7.23-7.26 (1 H, m), 7.44-7.60 (5 H, m).
















TABLE 342













 










Example





No.
R1002
R1003
1H NMR (solvent) δ ppm





2144
3,4-Cl2Ph-
—H
(CDCl3) 2.17 (3 H, s), 2.48-2.53 (4 H, m), 3.44 (2 H, s), 3.69-





3.73 (2 H, m), 3.97 (1 H, brs), 4.23-4.27 (4 H, m), 5.95 (2 H, s), 6.70-





6.74 (3 H, m), 6.85 (1 H, brs), 6.94 (1 H, d, J = 8.7 Hz), 6.96 (1 H,





dd, J = 8.7 Hz, 3.1 Hz), 7.18 (1 H, dd, J = 8.2 Hz, 2.0 Hz),





7.36 (1 H, dd, J = 8.7 Hz, 2.5 Hz), 7.40 (1 H, d, J = 8.2 Hz),





7.45 (1 H, d, J = 2.1 Hz), 7.51 (1 H, d, J = 2.3 Hz), 7.55 (1 H, d, J =





3.0 Hz), 9.11 (1 H, brs).


2145
4-CF3Ph-
—H
(CDCl3) 2.19 (3 H, s), 2.48-2.53 (4 H, m), 3.44 (2 H, s), 3.70-





3.73 (2 H, m), 4.00 (1 H, brs), 4.23-4.27 (2 H, m), 4.37 (2 H, s),





5.95 (2 H, s), 6.72 (1 H, d, J = 8.7 Hz), 6.74-6.77 (2 H, m), 6.85 (1 H,





brs), 6.94 (1 H, d, J = 8.7 Hz), 6.97 (1 H, dd, J = 8.7 Hz, 3.1 Hz),





7.37 (1 H, dd, J = 8.7 Hz, 2.6 Hz), 7.47 (2 H, d, J = 8.4 Hz),





7.51 (1 H, d, J = 2.5 Hz), 7.57 (1 H, d, J = 3.1 Hz), 7.60 (2 H, d, J =





8.1 Hz), 9.11 (1 H, brs).


2146
3,4-Cl2Ph-
—CH3
a mixture of the rotational isomers





(DMSO-d6) 2.25-2.42 (7 H, m), 3.22-3.55 (9 H, m), 4.27 (2 H, d, J =





6.27 Hz), 5.77-5.99 (2 H, m), 6.38 (1 H, t, J = 6.27 Hz), 6.65-





6.90 (5 H, m), 7.06-7.14 (2 H, m), 7.22-7.28 (1 H, m), 7.32-7.36 (1 H,





m), 7.46 (1 H, d, J = 2.80 Hz), 7.56-7.61 (2 H, m).


2147
4-CF3Ph-
—CH3
a mixture of the rotational isomers





(DMSO-d6) 2.24-2.41 (7 H, m), 3.20-3.54 (9 H, m), 4.34-4.36 (2 H,





m), 5.95-5.98 (2 H, m), 6.38-6.41 (1 H, m), 6.65-6.88 (5 H, m), 7.03-





7.13 (2 H, m), 7.21-7.27 (1 H, m), 7.45 (1 H, d, J = 2.64 Hz),





7.55 (2 H, d, J = 7.75 Hz), 7.67 (2 H, d, J = 7.75 Hz).
















TABLE 343













 










Example





No.
R1004
R1005
1H NMR (CDCl3) δ ppm





2148
—H




1.45 (9 H, s), 2.37-2.40 (4 H, m), 3.40-3.44 (4 H, m), 3.47 (2 H, s), 4.28 (2 H, s), 6.77 (1 H, d, J = 8.7 Hz), 6.95-7.01 (3 H, m), 7.17-7.21 (1 H, m), 7.26- 7.29 (2 H, m), 7.41 (1 H, d, J = 8.1 Hz), 7.45 (1 H, d, J = 1.8 Hz), 7.60 (1 H, d, J = 3.0 Hz).


 


2149
—CH3




2.19 (3 H, s), 3.05 (1 H, dd, J = 14.0 Hz, 10.0 Hz), 3.50 (1 H, dd, J = 14.0 Hz, 3.8 Hz), 4.02 (1 H, brs), 4.27 (2 H, s), 4.49 (1 H, dd, J = 10.0 Hz, 3.8 Hz), 6.73 (1 H, d, J = 8.7 Hz), 6.99 (1 H, d, J = 8.2 Hz), 6.97 (1 H, dd, J = 8.7 Hz, 2.9 Hz), 7.02 (1 H, dd, J = 8.2 Hz, 2.0 Hz), 7.09 (1 H, d, J = 2.0 Hz), 7.18 (1 H, dd, J = 8.2 Hz, 2.0 Hz), 7.41 (1 H, d, J = 8.2 Hz), 7.45 (1 H, d, J = 2.0 Hz), 7.55 (1 H, d, J = 2.9 Hz), 8.61 (1 H, brs).









Example 2150
Production of 1-(4-benzylpiperazin-1-yl)-3-(4-{5-(piperonylamino)pyridin-2-yloxy}phenyl)propane-1-one
3-[4-(5-aminopyridin-2-yloxy)phenyl]-1-(4-piperonylpiperazin-1-yl)propane-1-one (1.04 g, 2.5 mmol) was dissolved in methanol (25 mL). To the resulting solution was added piperonal (0.39 g, 2.63 mmol), and this solution was refluxed overnight. The resulting reaction solution was cooled with ice, and then sodium borohydride (0.28 g, 7.50 mmol) was added. The resulting solution was stirred for 2 hours at room temperature. This reaction solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate, and washed with water, saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was then purified by silica gel column chromatography (ethyl acetate), to thereby yield 0.80 g of the title compound.
Appearance: Yellow oil
1H NMR (DMSO-d6) δ 2.28 (4H, brs), 2.57 (2H, t, J=7.9 Hz), 2.76 (2H, t, J=7.9 Hz), 3.40-3.46 (6H, m), 4.15 (2H, d, J=6.1 Hz), 5.97 (2H, s), 6.21 (1H, t, J=6.1 Hz), 6.76 (1H, d, J=8.6 Hz), 6.82-6.86 (4H, m), 6.92 (1H, brs), 7.08 (1H, dd, J=8.7 Hz, 3.0 Hz), 7.17 (2H, d, J=8.4 Hz), 7.24-7.32 (5H, m), 7.51 (1H, d, J=3.0 Hz).
The following compounds were produced in the same manner as in Example 2150.







TABLE 344













 













Example








No.
R1006
R1007
R1008 
Xb42
M
1H NMR (solvent) δ ppm





2151
4-CF3Ph-
—CH3
piperonyl
—N(C2H5)—
1
(CDCl3) 1.15 (3 H, t, J = 7.1 Hz),








2.11 (3 H, s), 2.30-2.50 (4 H, m),








3.39 (2 H, q, J = 7.1 Hz), 3.42 (2 H, s),








3.42-3.55 (2 H, m) 3.56-3.70 (2 H, m),








3.80-4.05 (1 H, m), 3.99 (2 H, s),








4.36 (2 H, s), 5.94 (2 H, s), 6.44-








6.55 (2 H, m), 6.58-6.64 (1 H, m), 6.69-








6.78 (2 H, m), 6.80-6.89 (2 H, m),








6.94 (1 H, dd, J = 8.8 Hz, 3.1 Hz),








7.46 (2 H, d, J = 8.0 Hz), 7.55-








7.63 (3 H, m).


2152
3,4-Cl2Ph-
—CH3
piperonyl
—N(C2H5)—
1
(CDCl3) 1.15 (3 H, t, J = 7.1 Hz),








2.11 (3 H, s), 2.32-2.49 (4 H, m),








3.39 (2 H, q, J = 7.1 Hz), 3.42 (2 H, s),








3.44-3.55 (2 H, m), 3.56-3.69 (2 H, m),








3.79-3.94 (1 H, m), 3.99 (2 H, s), 4.15-








4.30 (2 H, m), 5.94 (2 H, s), 6.50 (1 H,








dd, J = 8.5 Hz, 3.0 Hz), 6.54 (1 H, d, J =








3.0 Hz), 6.58-6.65 (1 H, m), 6.69-








6.78 (2 H, m), 6.82-6.88 (2 H, m),








6.92 (1 H, dd, J = 8.8 Hz, 3.0 Hz),








7.18 (1 H, dd, J = 8.2 Hz, 2.0 Hz),








7.40 (1 H, d, J = 8.2 Hz), 7.45 (1 H, d,








J = 2.0 Hz), 7.57 (1 H, d, J = 3.0 Hz).


2153
4-CF3Ph-
—H
benzyl
none
2
(DMSO-d6) 2.28 (4 H, brs), 2.54-








2.60 (2 H, m), 2.73-2.79 (2 H, m), 3.42-








3.46 (6 H, m), 4.37 (2 H, d, J = 5.9 Hz),








6.41 (1 H, t, J = 6.1 Hz), 6.77 (1 H, d, J =








8.7 Hz), 6.84 (2 H, d, J = 8.6 Hz),








7.08 (1 H, dd, J = 8.7 Hz, 3.0 Hz),








7.17 (2 H, d, J = 8.6 Hz), 7.22-








7.35 (5 H, m), 7.50 (1 H, d, J = 3.0 Hz),








7.58 (2 H, d, J = 7.9 Hz), 7.69 (2 H, d,








J = 7.9 Hz).


2154
4-ClPh-
—H
benzyl
none
2
(DMSO-d6) 2.28 (4 H, t, J = 4.8 Hz),








2.57 (2 H, t, J = 7.3 Hz), 2.76 (2 H, t, J =








7.3 Hz), 3.38-3.46 (6 H, m),








4.25 (2 H, d, J = 6.1 Hz), 6.32 (1 H, t, J =








6.1 Hz), 6.76 (1 H, d, J = 8.6 Hz),








6.84 (2 H, d, J = 8.6 Hz), 7.07 (1 H, dd,








J = 8.7 Hz, 3.1 Hz), 7.17 (2 H, d, J =








8.6 Hz), 7.24-7.32 (5 H, m), 7.38 (4 H,








brs), 7.50 (1 H, d, J = 3.1 Hz).


2155
3,4-F2Ph-
—H
benzyl
none
2
(DMSO-d6) 2.26-2.28 (4 H, m), 2.57-








2.60 (2 H, m), 2.73-2.79 (2 H, m), 3.37-








3.46 (6 H, m), 4.25 (2 H, d, J = 5.8








Hz), 6.32 (1 H, t, J = 5.8 Hz), 6.77








(1 H, d, J = 8.6 Hz), 6.84 (2 H, d, J =








8.3 Hz), 7.08 (1 H, dd, J = 8.6 Hz, 3.0








Hz), 7.17 (2 H, d, J = 8.4 Hz), 7.22-








7.43 (8 H, m), 7.50 (1 H, d, J = 3.1 Hz).
















TABLE 345













 













Example





mp (° C.) or 1H NMR (solvent)


No.
R1009
R1010
R1011
Xb43
M
δ ppm





2156
4-CF3Ph-
—CH3
piperonyl
—N(CH3)—
1
1H NMR (CDCl3) 2.12 (3 H, s),








2.42 (4 H, t, J = 5.0 Hz), 2.98 (3 H,








s), 3.41-3.55 (4 H, m), 3.56-








3.67 (2 H, m), 3.77-3.99 (1 H, m),








4.04 (2 H, s), 4.36 (2 H, s),








5.94 (2 H, s), 6.52 (1 H, dd, J = 8.7








Hz, 3.0 Hz), 6.56 (1 H, d, J = 3.0








Hz), 6.59-6.64 (1 H, m), 6.69-








6.78 (2 H, m), 6.85 (1 H, s),








6.87 (1 H, d, J = 8.7 Hz), 6.93 (1 H,








dd, J = 8.8 Hz, 3.0 Hz), 7.46 (2 H,








d, J = 8.0 Hz), 7.54-7.63 (3 H, m).


2157
3,4-Cl2Ph-
—CH3
piperonyl
—N(CH3)—
1
mp 132-134


2158
4-CF3Ph-
—CH3
piperonyl
—N(Ac)—
1
1H NMR (CDCl3) 1.94 (3 H, s),








2.09 (3 H, s), 2.30-2.50 (4 H, m),








3.29-3.51 (4 H, m), 3.52-3.69 (2 H,








m), 3.92-4.17 (1 H, m), 4.29-








4.51 (4 H, m), 5.94 (2 H, s), 6.69-








6.77 (2 H, m), 6.78 (1 H, d, J = 8.7








Hz), 6.81-6.86 (1 H, m), 6.91 (1 H,








d, J = 8.5 Hz), 7.01 (1 H, dd, J =








8.7 Hz, 3.1 Hz), 7.18 (1 H, dd, J =








8.5 Hz, 2.5 Hz), 7.28 (1 H, d, J =








2.5 Hz), 7.48 (2 H, d, J = 8.1 Hz),








7.56-7.64 (3 H, m).


2159
3,4-Cl2Ph-
—CH3
piperonyl
—N(Ac)—
1
1H NMR (CDCl3) 1.95 (3 H, s),








2.07 (3 H, s), 2.30-2.51 (4 H, m),








3.29-3.50 (4 H, m), 3.51-3.71 (2 H,








m), 3.92-4.18 (1 H, m), 4.29 (2 H,








s), 4.42 (2 H, s), 5.94 (2 H, s), 6.69-








6.78 (3 H, m), 6.82-6.87 (1 H, m),








6.91 (1 H, d, J = 8.5 Hz), 7.00 (1 H,








dd, J = 8.7, 3.0 Hz), 7.14-








7.23 (2 H, m), 7.26-7.31 (1 H, m),








7.41 (1 H, d, J = 8.2 Hz),








7.46 (1 H, d, J = 2.0 Hz), 7.57 (1 H,








d, J = 3.0 Hz).


2160
Ph-
—H
benzyl
none
2
1H NMR (DMSO-d6) 2.27 (4 H,








brs), 2.54-2.60 (2 H, m), 2.73-








2.79 (2 H, m), 3.40-3.46 (6 H, m),








4.25 (2 H, d, J = 5.9 Hz), 6.28 (1 H,








t, J = 5.9 Hz), 6.76 (1 H, d, J = 8.7








Hz), 6.84 (2 H, d, J = 8.4 Hz), 7.09








(1 H, dd, J = 8.7 Hz, 3.0 Hz), 7.17








(2 H, d, J = 8.7 Hz), 7.23-7.38








(10 H, m), 7.52 (1 H, d, J = 3.0








Hz).


2161
4-CF3Ph-
—OCH3
piperonyl
—N(CH3)—
1
mp 102-103


2162
3,4-Cl2Ph-
—OCH3
piperonyl
—N(CH3)—
1
mp 145-146


2163
4-CF3Ph-
—OCH3
piperonyl
—N(C2H5)—
1
mp 160.0-160.5


2164
3,4-Cl2Ph-
—OCH3
piperonyl
—N(C2H5)—
1
mp 133-134


2165
3,4-Cl2Ph-
—F
piperonyl
—N(CH3)—
1
mp 134-137
















TABLE 346













 












Example







No.
R1012
R1013
Xb44
M
mp (° C.) or 1H NMR (CDCl3) δ ppm





2166
4-CF3Ph-
—OCH3
none
2
1H NMR 2.38-2.44 (4 H, m), 2.56-2.67 (2 H,







m), 2.88-2.99 (2 H, m), 3.31-3.45 (2 H, m),







3.40 (2 H, s), 3.57-3.69 (2 H, m), 3.76 (3 H,







s), 3.80-4.06 (1 H, m), 4.37 (2 H, s),







5.94 (2 H, s), 6.68-6.81 (4 H, m), 6.83-







6.87 (2 H, m), 6.96 (1 H, d, J = 8.0 Hz),







6.98 (1 H, dd, J = 8.7 Hz, 3.0 Hz),







7.46 (2 H, d, J = 8.0 Hz), 7.54 (1 H, d, J =







2.6 Hz), 7.59 (2 H, d, J = 8.0 Hz).


2167
4-CF3Ph-
—F
—N(C2H5)—
1
mp 106-107


2168
4-CF3Ph-
—F
—N(CH3)—
1
mp 163-164


2169
3,4-Cl2Ph-
—F
—N(C2H5)—
1
mp 107.5-109.0


2170
4-CF3Ph-
—H
—N(SO2CH3)—
1
1H NMR 2.41 (4 H, brs), 3.18 (3 H, s),







3.35 (2 H, brs), 3.42 (2 H, s), 3.62 (2 H, brs),







4.14 (1 H, brs), 4.41 (2 H, brs), 4.50 (2 H, s),







5.94 (2 H, s), 6.70-6.76 (2 H, m), 6.80-







6.83 (2 H, m), 6.98-7.04 (3 H, m), 7.47-







7.56 (4 H, m), 7.60-7.63 (3 H, m).









Example 2171
Production of 1-(4-benzylpiperazin-1-yl)-3-[4-(5-dibenzylaminopyridin-2-yloxy)phenyl]propane-1-one
3-[4-(5-aminopyridin-2-yloxy)phenyl]-1-(4-benzylpiperazin-1-yl)propane-1-one (1.0 g, 2.4 mmol) was dissolved in DMF (30 mL). To this solution were added potassium carbonate (0.73 g, 5.28 mmol), sodium iodide (0.76 g, 5.04 mmol) and benzyl bromide (0.60 mL, 5.04 mmol), and the resulting solution was stirred at room temperature overnight. This reaction solution was concentrated under reduced pressure. The residue was diluted with chloroform, and washed with water, saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was then purified by silica gel column chromatography (chloroform methanol=80:1), to thereby yield 0.67 g of the title compound.
Appearance: Yellow oil
1H NMR (DMSO-d6) δ 2.27 (4H, brs), 2.50-2.59 (2H, m), 2.73-2.78 (2H, m), 3.37-3.45 (6H, m), 4.68 (4H, s), 6.78 (1H, d, J=8.9 Hz), 6.85 (2H, d, J=8.4 Hz), 7.17 (2H; d, J=8.6 Hz), 7.20-7.36 (16H, m), 7.54 (1H, d, J=3.1 Hz).
Example 2172
Production of 2-[(4-{5-[(3,4-dichlorobenzyl)-ethylamino]pyridin-2-yloxy}phenyl)methylamino]-1-(4-piperonylpiperazin-1-yl)ethanone
2-({4-[5-(3,4-dichlorobenzylamino)pyridin-2-yloxy]phenyl}methylamino)-1-(4-piperonylpiperazin-1-yl)ethanone (1.59 g, 2.5 mmol) was dissolved in dichloroethane (80 mL). To this solution were added acetoaldehyde (1.40 mL, 25.0 mmol) and sodium triacetyloxy borohydride (1.59 mL, 7.5 mmol) under ice cooling. To the resulting solution was added dropwise acetic acid (0.43 mL, 7.5 mmol), and this solution was stirred at room temperature for 16 hours. The resulting reaction solution was washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was then purified by silica gel column chromatography (chloroform:methanol=50:1). The obtained solid was recrystallized from ethanol, to thereby yield 0.65 g of the title compound.
Appearance: White powder
1H NMR (CDCl3) δ 1.17 (3H, t, J=7.1 Hz), 2.41 (4H, brs), 2.99 (3H, s), 3.36-3.44 (4H, m), 3.48 (2H, brs), 3.62 (2H, brs), 4.04 (2H, s), 4.35 (2H, s), 5.95 (2H, s), 6.67-6.77 (5H, m), 6.85 (1H, brs), 6.97 (2H, d, J=9.1 Hz), 7.01 (1H, dd, J=8.9 Hz, 3.1 Hz), 7.07 (1H, dd, J=8.2 Hz, 2.0 Hz), 7.32 (1H, d, J=2.0 Hz), 7.37 (1H, d, J=8.3 Hz), 7.63 (1H, d, J=3.0 Hz); MS 661 (M+).
The following compounds were produced in the same manner as in Example 2172.







TABLE 347













 













Example








No.
R1014
R1015
R1016
Xb45
M
1H NMR (CDCl3) δ ppm





2173
4-CF3Ph-
—H
piperonyl
—N(CH3)—
1
2.44 (4 H, brs), 2.99 (6 H, s), 3.39-








3.62 (6 H, m), 4.04 (2 H, s), 4.48 (2 H,








s), 5.95 (2 H, s), 6.62-6.78 (5 H, m),








6.86 (1 H, brs), 6.97 (2 H, d, J = 9.1








Hz), 7.08 (1 H, dd, J = 8.9 Hz, 3.1








Hz), 7.34 (2 H, d, J = 7.9 Hz),








7.57 (2 H, d, J = 8.1 Hz), 7.69 (1 H, d, J =








3.1 Hz).


2174
3,4-Cl2Ph-
—H
piperonyl
—N(CH3)—
2
2.32-2.40 (4 H, m), 2.53-2.58 (2 H, m),








2.92 (3 H, s), 2.97 (3 H, s), 3.37-








3.40 (4 H, m), 3.59-3.63 (2 H, m), 3.66-








3.72 (2 H, m), 4.37 (2 H, s), 5.94 (2 H,








s), 6.66-6.76 (5 H, m), 6.83 (1 H, d, J =








1.0 Hz), 6.98 (2 H, d, J = 9.1 Hz),








7.04-7.11 (2 H, m), 7.32 (1 H, d, J = 2.0








Hz), 7.38 (1 H, d, J = 8.3 Hz),








7.67 (1 H, d, J = 3.1 Hz).


2175
4-CF3Ph-
—H
piperonyl
—N(CH3)—
2
2.32-2.39 (4 H, m), 2.52-2.57 (2 H, m),








2.92 (3 H, s), 2.99 (3 H, s), 3.36-








3.40 (4 H, m), 3.59-3.63 (2 H, m), 3.66-








3.72 (2 H, m), 4.48 (2 H, s), 5.94 (2 H,








s), 6.67-6.76 (5 H, m), 6.83 (1 H, d, J =








1.0 Hz), 6.98 (2 H, d, J = 9.2 Hz),








7.09 (1 H, dd, J = 9.1 Hz, 3.1 Hz),








7.34 (2 H, d, J = 7.9 Hz), 7.57 (2 H, d,








J = 8.1 Hz), 7.68 (1 H, d, J = 2.8 Hz).


2176
3,4-Cl2Ph-
—H
piperonyl
—N(CH3)—
1
2.40-2.44 (4 H, m), 2.96 (3 H, s),








3.00 (3 H, s), 3.43 (2 H, brs), 3.49 (2 H,








brs), 3.62 (2 H, brs), 4.05 (2 H, s),








4.36 (2 H, s), 5.95 (2 H, s), 6.67-








6.77 (5 H, m), 6.85 (1 H, brs), 6.97 (2 H,








d, J = 9.1 Hz), 7.06 (1 H, dd, J = 8.3








Hz, 1.7 Hz), 7.07 (1 H, dd, J = 8.9 Hz,








3.1 Hz), 7.32 (1 H, d, J = 2.0 Hz),








7.38 (1 H, d, J = 8.3 Hz), 7.69 (1 H, d, J =








3.1 Hz).


2177
4-CF3Ph-
—F
benzyl
none
0
2.46 (4 H, brs), 3.02 (3 H, s), 3.54 (6 H,








brs), 4.52 (2 H, s), 6.89 (1 H, d, J = 8.9








Hz), 7.14 (1 H, dd, J = 8.9 Hz, 3.1








Hz), 7.17-7.21 (2 H, m), 7.28-7.35








(8 H, m), 7.58 (2 H, d, J = 8.1 Hz),








7.62 (1 H, d, J = 2.8 Hz).


2178
3,4-Cl2Ph-
—F
benzyl
none
0
2.47 (4 H, brs), 3.00 (3 H, s), 3.55-








3.73 (6 H, m), 4.40 (2 H, s), 6.89 (1 H, d,








J = 8.9 Hz), 7.06 (1 H, dd, J = 8.2 Hz,








1.7 Hz), 7.14 (1 H, dd, J = 8.9 Hz, 3.1








Hz), 7.17-7.22 (3 H, m), 7.28-7.33 (6 H,








m), 7.39 (1 H, d, J = 8.3 Hz), 7.61 (1 H,








d, J = 3.3 Hz).
















TABLE 348













 












Example




mp (° C.) or 1H NMR (DMSO-d6)


No.
R1017
R1018
R1019
Form
δ ppm





2179
4-CF3Ph-
—CH3
—C2H5
fumarate
mp 157-159 dec


2180
3,4-Cl2Ph-
—CH3
—C2H5
fumarate
mp 148-151 dec


2181
4-CF3Ph-
—CH3
—CH3
fumarate
mp 151-154


2182
3,4-Cl2Ph-
—CH3
—CH3
hydrochloride
mp 139-142


2183
4-CF3Ph-
—CH3
—Ac
hydrochloride
mp 199.5-201.5


2184
3,4-Cl2Ph-
—CH3
—Ac
hydrochloride
mp 188.5-190.0


2185
4-CF3Ph-
—OCH3
—CH3
oxalate
1H NMR 2.48-2.81 (4 H, m),







2.93 (3 H, s), 2.94 (3 H, s), 3.36-







3.85 (9 H, m), 4.25 (2 H, s), 4.56







(2 H, s), 6.01 (2 H, s), 6.12 (1 H, dd,







J = 8.8 Hz, 2.8 Hz), 6.29 (1 H, d,







J = 2.8 Hz), 6.66 (1 H, d, J = 9.0







Hz), 6.77 (1 H, d, J = 8.8 Hz),







6.79-6.98 (3 H, m), 7.22 (1 H, dd, J =







9.0 Hz, 3.2 Hz), 7.42 (2 H, d, J =







8.1 Hz), 7.52 (1 H, d, J = 3.2







Hz), 7.67 (2 H, d, J = 8.1 Hz).


2186
3,4-Cl2Ph-
—OCH3
—CH3
hydrochloride
1H NMR 2.75-3.18 (8 H, m), 3.21-







3.42 (2 H, m), 3.63 (3 H, s), 3.83-







4.52 (10 H, m), 6.06 (2 H, s),







6.16 (1 H, dd, J = 8.8 Hz, 2.7 Hz),







6.34 (1 H, d, J = 2.7 Hz), 6.68 (1 H,







d, J = 9.0 Hz), 6.79 (1 H, d, J =







8.8 Hz), 6.94-7.06 (2 H, m), 7.16-







7.24 (2 H, m), 7.27 (1 H, dd, J =







9.0 Hz, 3.2 Hz), 7.47 (1 H, d, J =







2.0 Hz), 7.53 (1 H, d, J = 3.2 Hz),







7.56 (1 H, d, J = 8.2 Hz), 10.91-







11.26 (1 H, m).


2187
4-CF3Ph-
—OCH3
—C2H5
fumarate
mp 159-162


2188
3,4-Cl2Ph-
—OCH3
—C2H5
fumarate
mp 154-157


2189
4-CF3Ph-
—F
—CH3
hydrobromide
mp 211-212


2190
3,4-Cl2Ph-
—F
—CH3
hydrobromide
mp 206.5-207.0


2191
4-CF3Ph-
—F
—C2H5
hydrobromide
mp 151.0-152.5


2192
3,4-Cl2Ph-
—F
—C2H5
hydrobromide
mp 172.5-174.5
















TABLE 349













 













Example








No.
R1020
R1021
R1022
M
Form
1H NMR (DMSO-d6) δ ppm





2193
Ph-
—CH3
—H
2
dihydro-
2.50-3.07 (10 H, m), 3.22-3.31 (2 H, m),







chloride
3.45-3.50 (1 H, m), 4.03-4.08 (1 H, m),








4.30 (2 H, d, J = 3.8 Hz), 4.42-4.55 (3 H,








m), 6.85-6.92 (3 H, m), 7.19-7.26 (5 H, m),








7.30-7.35 (3 H, m), 7.45-7.47 (3 H, m),








7.58-7.60 (2 H, m), 7.66 (1 H, d, J = 2.8








Hz), 11.33 (2 H, brs).


2194
3,4-Cl2Ph-
—CH3
—H
0
dihydro-
2.50-2.51 (2 H, m), 3.03 (3 H, s), 3.13-







chloride
3.48 (6 H, m), 4.34-4.37 (2 H, m), 4.58 (2 H,








s), 6.97 (1 H, d, J = 8.9 Hz), 7.04 (2 H, d, J =








8.4 Hz), 7.23 (1 H, dd, J = 8.4 Hz, 1.5








Hz), 7.34 (1 H, dd, J = 8.9 Hz, 3.1 Hz),








7.44-7.47 (5 H, m), 7.51 (1 H, d, J = 1.5








Hz), 7.58-7.61 (3 H, m), 7.70 (1 H, d, J =








3.3 Hz), 11.52 (2 H, brs).


2195
4-CF3Ph-
—CH3
—H
0
dihydro-
3.06 (3 H, s), 3.00-3.20 (2 H, m), 3.20-







chloride
3.40 (2 H, m), 3.45 (2 H, brs), 4.20-








4.50 (2 H, m), 4.34 (2 H, s), 4.69 (2 H, s),








6.97 (1 H, d, J = 8.9 Hz), 7.04 (2 H, d, J =








8.8 Hz), 7.33 (1 H, dd, J = 8.9 Hz, 3.1








Hz), 7.41-7.49 (7 H, m), 7.55-7.68 (2 H,








m), 7.70 (1 H, d, J = 3.1 Hz), 7.71 (2 H, d,








J = 8.0 Hz).


2196
3,4-Cl2Ph-
—CH3
—H
2
dihydro-
2.49-3.07 (10 H, m), 3.23-3.27 (2 H, m),







chloride
3.45-3.55 (1 H, m), 4.03-4.08 (1 H, m),








4.30 (2 H, d, J = 4.3 Hz), 4.42-4.47 (1 H,








m), 4.54 (2 H, s), 6.87 (1 H, d, J = 9.1 Hz),








6.90 (2 H, d, J = 8.6 Hz), 7.19-7.23 (3 H,








m), 7.32 (1 H, dd, J = 8.9 Hz, 3.3 Hz),








7.45-7.50 (4 H, m), 7.57-7.64 (4 H, m),








11.33 (2 H, brs).


2197
4-CF3Ph-
—C2H5
—F
0
hydro-
1.21 (3 H, t, J = 6.9 Hz), 2.50-2.51 (2 H,







chloride
m), 3.14-3.38 (6 H, m), 3.49 (2 H, q, J =








6.9 Hz), 4.34 (2 H, brs), 4.61 (2 H, brs),








6.98 (1 H, d, J = 8.9 Hz), 7.25-7.29 (3 H,








m), 7.42-7.50 (7 H, m), 7.58 (2 H, brs),








7.69 (2 H, d, J = 8.1 Hz), 11.12 (1 H, brs).


2198
3,4-Cl2Ph-
—C2H5
—F
0
hydro-
1.10 (3 H, t, J = 7.0 Hz), 2.49-2.52 (2 H,







chloride
m), 3.13 (2 H, brs), 3.32-3.58 (6 H, m),








4.33 (2 H, brs), 4.50 (2 H, brs), 6.99 (1 H, d,








J = 9.1 Hz), 7.20-7.31 (4 H, m), 7.42-7.57








(6 H, m), 7.58-7.60 (3 H, m), 11.14 (1 H,








brs).
















TABLE 350













 













Example








No.
R1023
R1024
R1025
M
Form
mp (° C.) or 1H NMR (solvent) δ ppm





2199
3,4-Cl2Ph-
—H
—CH3
2
free
1H NMR (CDCl3) 1.17 (3 H, t, J =








7.1 Hz), 2.32-2.39 (4 H, m), 2.52-








2.57 (2 H, m), 2.91 (3 H, s), 3.36-








3.44 (6 H, m), 3.59-3.63 (2 H, m),








3.66-3.71 (2 H, m), 4.35 (2 H, s), 5.95








(2 H, s), 6.67-6.76 (5 H, m), 6.83 (1 H,








d, J = 1.0 Hz), 6.98 (2 H, d, J = 9.1








Hz), 7.03 (1 H, dd, J = 9.1 Hz, 3.3








Hz), 7.07 (1 H, dd, J = 8.9 Hz, 2.1








Hz), 7.32 (1 H, d, J = 2.0 Hz),








7.47 (1 H, d, J = 8.3 Hz), 7.62 (1 H, d,








J = 3.1 Hz).


2200
4-CF3Ph-
—H
—CH3
2
free
1H NMR (CDCl3) 1.19 (3 H, t, J =








7.1 Hz), 2.32-2.38 (4 H, m), 2.52-








2.57 (2 H, m), 2.91 (3 H, s), 3.36-








3.47 (6 H, m), 3.59-3.63 (2 H, m),








3.66-3.71 (2 H, m), 4.47 (2 H, s), 5.94








(2 H, s), 6.67-6.76 (5 H, m), 6.83 (1 H,








d, J = 1.0 Hz), 6.97 (2 H, d, J = 9.2








Hz), 7.03 (1 H, dd, J = 9.1 Hz, 3.1








Hz), 7.35 (2 H, d, J = 7.9 Hz),








7.56 (2 H, d, J = 7.9 Hz), 7.63 (1 H, d,








J = 2.8 Hz).


2201
3,4-Cl2Ph-
—CH3
—CH3
1
hydrochloride
mp 167-170 dec


2202
4-CF3Ph-
—CH3
—Ac
1
hydrochloride
mp 186-189


2203
3,4-Cl2Ph-
—CH3
—Ac
1
hydrochloride
mp 188.5-191.0


2204
4-CF3Ph-
—OCH3
—CH3
1
oxalate
1H NMR (DMSO-d6) 1.08 (3 H, t, J =








7.0 Hz), 2.50-2.81 (4 H, m), 2.93 (3 H,








s), 3.41 (2 H, q, J = 7.0 Hz), 3.33-








3.72 (7 H, m), 3.77 (2 H, s), 4.25 (2 H,








s), 4.52 (2 H, s), 6.01 (2 H, s),








6.12 (1 H, dd, J = 8.8 Hz, 2.7 Hz),








6.28 (1 H, d, J = 2.7 Hz), 6.64 (1 H,








d, J = 9.0 Hz), 6.76 (1 H, d, J = 8.7








Hz), 6.80-6.94 (2 H, m), 6.97 (1 H,








brs), 7.15 (1 H, dd, J = 9.0 Hz, 3.2








Hz), 7.34-7.50 (3 H, m), 7.66 (2 H, d,








J = 8.1 Hz).


2205
3,4-Cl2Ph-
—OCH3
—CH3
1
hydrochloride
1H NMR (DMSO-d6) 1.06 (3 H, t, J =








6.9 Hz), 2.75-3.16 (5 H, m), 3.21-








3.48 (4 H, m), 3.62 (3 H, s), 3.71-








4.52 (10 H, m), 6.06 (2 H, s), 6.16 (1 H,








dd, J = 8.8 Hz, 2.7 Hz), 6.34 (1 H, d,








J = 2.7 Hz), 6.67 (1 H, d, J = 8.9 Hz),








6.78 (1 H, d, J = 8.8 Hz), 6.94-7.06








(2 H, m), 7.13-7.28 (3 H, m), 7.41-








7.52 (2 H, m), 7.56 (1 H, d, J = 8.3








Hz), 10.83-11.19 (1 H, m).
















TABLE 351













 












Example







No.
R1026 
R1027 
R1028 
Form
mp (° C.)





2206
4-CF3Ph-
—CH3
—C2H5
oxalate
126-128


2207
3,4-Cl2Ph-
—CH3
—C2H5
oxalate
111-113


2208
4-CF3Ph-
—CH3
—C2H5
oxalate
120-123


2209
4-CF3Ph-
—OCH3
—CH3
hydrobromide
205-208


2210
3,4-Cl2Ph-
—OCH3
—C2H5
hydrobromide
133-135


2211
4-CF3Ph-
—F
—CH3
hydrobromide
203-205


2212
3,4-Cl2Ph-
—F
—CH3
hydrobromide
185-188


2213
4-CF3Ph-
—F
—C2H5
oxalate
121.0-122.5


2214
3,4-Cl2Ph-
—F
—C2H5
hydrobromide
165.0-166.5
















TABLE 352













 










Example





No.
R1029
R1030
1H NMR (CDCl3) δ ppm





2215
—H




1.45 (9 H, s), 2.39-2.43 (4 H, m), 3.01 (3 H, s), 3.41-3.44 (4 H, m), 3.50 (2 H, s), 4.41 (2 H, s), 6.82 (1 H, d, J = 8.9 Hz), 7.01 (2 H, d, J = 8.4 Hz), 7.08-7.13 (2 H, m), 7.27-7.41 (4 H, m), 7.70 (1 H, d, J = 8.6 Hz).


 


2216
—CH3




2.20 (3 H, s), 2.98 (3 H, s), 3.06 (1 H, dd, J = 14.0 Hz, 10.1 Hz), 3.52 (1 H, dd, J = 14.0 Hz, 3.8 Hz), 4.38 (2 H, s), 4.50 (1 H, dd, J = 10.1 Hz, 3.8 Hz), 6.77 (1 H, d, J = 8.9 Hz), 6.91 (1 H, d, J = 8.3 Hz), 7.03 (1 H, dd, J = 8.3 Hz, 2.1 Hz), 7.05-7.16 (3 H, m), 7.32 (1 H, d, J = 2.1 Hz), 7.39 (1 H, d, J = 8.3 Hz), 7.67 (1 H, d, J = 3.1 Hz).
















TABLE 353













 











Example






No.
R1031
R1032
R1033
1H NMR (CDCl3) δ ppm





2217
3,4-Cl2Ph-
—CH3
—H
2.41 (4 H, brs), 3.02 (3 H, s), 3.19 (3 H, s), 3.36 (2 H,






brs), 3.42 (2 H, s), 3.60 (2 H, brs), 4.41 (2 H, s),






4.51 (2 H, s), 5.95 (2 H, s), 6.73-6.77 (2 H, m), 6.84-






6.87 (2 H, m), 7.03 (2 H, d, J = 8.9 Hz), 7.07 (1 H,






dd, J = 8.3 Hz, 2.0 Hz), 7.12 (1 H, dd, J = 8.9 Hz,






3.1 Hz), 7.33 (1 H, d, J = 2.0 Hz), 7.40 (1 H, d, J =






8.3 Hz), 7.59 (2 H, d, J = 8.9 Hz), 7.69 (1 H, d, J =






3.1 Hz).


2218
3,4-Cl2Ph-
—C2H5
—H
1.21 (3 H, t, J = 7.1 Hz), 2.41 (4 H, brs), 3.18 (3 H,






s), 3.36 (2 H, brs), 3.42 (2 H, s), 3.46 (2 H, q, J = 7.1






Hz), 3.60 (2 H, brs), 4.40 (2 H, s), 4.50 (2 H, s),






5.94 (2 H, s), 6.73-6.77 (2 H, m), 6.81-6.84 (2 H, m),






7.01-7.10 (4 H, m), 7.33 (1 H, d, J = 2.0 Hz),






7.39 (1 H, d, J = 8.3 Hz), 7.54 (2 H, d, J = 9.1 Hz),






7.64 (1 H, d, J = 3.0 Hz).


2219
4-CF3Ph-
—CH3
—H
2.41 (4 H, brs), 3.05 (3 H, s), 3.19 (3 H, s), 3.34-






3.36 (2 H, m), 3.42 (2 H, s), 3.60 (2 H, brs), 4.50 (2 H,






s), 4.54 (2 H, s), 5.95 (2 H, s), 6.73-6.74 (2 H, m),






6.83 (1 H, brs), 6.85 (1 H, d, J = 8.9 Hz), 7.03 (2 H,






d, J = 8.9 Hz), 7.13 (1 H, dd, J = 8.9 Hz, 3.3 Hz),






7.34 (2 H, d, J = 7.9 Hz), 7.54 (2 H, d, J = 8.9 Hz),






7.59 (2 H, d, J = 8.1 Hz), 7.70 (1 H, d, J = 3.1 Hz).


2220
4-CF3Ph-
—C2H5
—H
1.22 (3 H, t, J = 7.1 Hz), 2.41 (4 H, brs), 3.19 (3 H,






s), 3.35 (2 H, brs), 3.42 (2 H, s), 3.48 (2 H, q, J = 7.1






Hz), 3.60 (2 H, brs), 4.50 (2 H, s), 4.52 (2 H, s),






5.95 (2 H, s), 6.70-6.77 (2 H, m), 6.82 (1 H, d, J =






8.7 Hz), 6.84 (1 H, brs), 7.02 (2 H, d, J = 8.9 Hz),






7.07 (1 H, dd, J = 8.9 Hz, 3.1 Hz), 7.36 (2 H, d, J =






7.9 Hz), 7.54 (2 H, d, J = 8.9 Hz), 7.58 (2 H, d, J =






8.1 Hz), 7.65 (1 H, d, J = 3.0 Hz).


2221
3,4-Cl2Ph-
—CH3
—CH3
2.21 (3 H, s), 2.42 (4 H, brs), 3.00 (3 H, s), 3.21 (3 H,






s), 3.34-3.38 (2 H, m), 3.42 (2 H, s), 3.59-3.62 (2 H,






m), 4.39 (2 H, s), 4.51 (2 H, s), 5.95 (2 H, s), 6.73-






6.77 (2 H, m), 6.80-6.83 (2 H, m), 6.91 (1 H, d, J =






8.6 Hz), 7.06 (1 H, dd, J = 8.2 Hz, 2.1 Hz),






7.12 (1 H, dd, J = 8.9 Hz, 3.1 Hz), 7.32-7.44 (4 H,






m), 7.65 (1 H, d, J = 3.1 Hz).


2222
4-CF3Ph-
—CH3
—CH3
2.21 (3 H, s), 2.42 (4 H, brs), 3.02 (3 H, s), 3.20 (3 H,






s), 3.34-3.38 (2 H, m), 3.42 (2 H, s), 3.58-3.62 (2 H,






m), 4.51 (4 H, brs), 5.94 (2 H, s), 6.70-6.76 (2 H, m),






6.79-6.83 (2 H, m), 6.90 (1 H, d, J = 8.6 Hz),






7.12 (1 H, dd, J = 8.9 Hz, 3.3 Hz), 7.32-7.39 (3 H,






m), 7.43 (1 H, d, J = 2.5 Hz), 7.58 (2 H, d, J = 8.1






Hz), 7.66 (1 H, d, J = 3.0 Hz).
















TABLE 354













 











Example






No.
R1034
R1035
R1036
1H NMR (CDCl3) δppm





2223
3,4-Cl2Ph-
—C2H5
—CH3
1.19(3 H, t, J = 7.1 Hz), 2.21(3 H, s), 2.41(4 H, brs),






3.20(3H, s), 3.34-3.37(2 H, m), 3.42(2 H, s),






3.43(2 H, q, J = 7.1 Hz), 3.58-3.62(2 H, m),






4.38(2 H, s), 4.50(2 H, s), 5.95(2 H, s), 6.70-






6.77(2 H, m), 6.79(1 H, d, J = 8.9 Hz), 6.83(1 H, d,






J = 0.8 Hz), 6.91(1 H, d, J = 8.6 Hz), 7.04-7.09(2 H,






m), 7.32-7.43(4 H, m), 7.60(1 H, d, J = 3.0 Hz).


2224
4-CF3Ph-
—C2H5
—CH3
1.21(3 H, t, J = 7.1 Hz), 2.21(3 H, s), 2.41(4 H, brs),






3.20(3 H, s), 3.34-3.37(2 H, m), 3.42(2 H, s),






3.46(2 H, q, J = 7.1 Hz), 3.58-3.62(2 H, m),






4.50(4 H, brs), 5.94(2 H, s), 6.70-6.74(2 H, m),






6.78(1 H, d, J = 9.2 Hz), 6.83(1 H, brs), 6.90(1 H, d,






J = 8.6 Hz), 7.04-7.08(1 H, m), 7.34-7.43(4 H, m),






7.57(1 H, d, J = 8.1 Hz), 7.60(1 H, d, J = 3.0 Hz).


2225
4-CF3Ph-
—CH3
—OCH3
2.42(4 H, brs), 3.01(3 H, s), 3.21(3 H, s), 3.37(2 H,






brs), 3.42(2 H, s), 3.61(2 H, brs), 3.78(3 H, s),






4.27(2 H, s), 4.53(2 H, s), 5.94(2 H, s), 6.72-






6.76(2 H, m), 6.84(2 H, d, J = 8.4 Hz), 7.00(1 H, d,






J = 8.4 Hz), 7.10-7.16(2 H, m), 7.24-7.26(1 H, m),






7.33(2 H, d, J = 8.1 Hz), 7.57(2 H, d, J = 7.9 Hz),






7.62(1 H, d, J = 3.0 Hz).


2226
4-CF3Ph-
—C2H5
—OCH3
1.20(3 H, t, J = 6.9 Hz), 2.42(4 H, brs), 3.21(3 H, s),






3.36(2 H, brs), 3.40-3.48(4 H, m), 3.61(2 H, brs),






3.77(3 H, s), 4.48(2 H, s), 4.52(2 H, s), 5.94(2 H, s),






6.73-6.76(2 H, m), 6.81-6.85(2 H, m), 6.99(1 H, d, J =






8.6 Hz), 7.07(1 H, dd, J = 9.1 Hz, 3.3 Hz),






7.14(1 H, dd, J = 8.4 Hz, 2.3 Hz), 7.24(1 H, d, J =






2.5 Hz), 7.34(2 H, d, J = 8.1 Hz), 7.54-7.57(3 H, m).
















TABLE 355













 











Example






No.
R1037
R1038
R1039
1H NMR (solvent) δppm





2227
3,4-Cl2Ph-
—CH3
—H
(CDCl3) 2.20(3 H, s), 2.48-2.54(4 H, m), 2.97(3 H, s),






3.44(2 H, s), 3.70-3.73(2 H, m), 4.23-4.27(2 H, m),






4.37(2 H, s), 5.95(2 H, s), 6.73-6.77(3 H, m), 6.85(1 H,






brs), 6.95(1 H, d, J = 8.6 Hz), 7.06(1 H, dd, J = 8.2






Hz, 2.0 Hz), 7.10(1 H, dd, J = 8.9 Hz, 3.1 Hz),






7.32(1 H, d, J = 2.0 Hz), 7.37(1 H, dd, J = 8.6 Hz, 2.6






Hz), 7.38(1 H, d, J = 8.2 Hz), 7.52(1 H, d, J = 2.5






Hz), 7.66(1 H, d, J = 2.8 Hz), 9.12(1 H, brs).


2228
4-CF3Ph-
—CH3
—H
(CDCl3) 2.20(3 H, s), 2.48-2.54(4 H, m), 3.00(3 H, s),






3.44(2 H, s), 3.72(2 H, t, J = 5.0 Hz), 4.23-4.27(2 H,






m), 4.49(2 H, s), 5.95(2 H, s), 6.73-6.77(3 H, m),






6.85(1 H, brs), 6.95(1 H, d, J = 8.7 Hz), 7.10(1 H, dd,






J = 8.9 Hz, 3.3 Hz), 7.32-7.39(3 H, m), 7.52(1 H, d, J =






2.5 Hz), 7.57(2 H, d, J = 8.1 Hz), 7.67(1 H, d, J =






3.3 Hz), 9.12(1 H, brs).


2229
3,4-Cl2Ph-
—C2H5
—H
(CDCl3) 1.18(3 H, t, J = 7.1 Hz), 2.20(3 H, s), 2.48-






2.53(4 H, m), 3.41(2 H, q, J = 7.1 Hz), 3.44(2 H, s),






3.70-3.73(2 H, m), 4.23-4.27(2 H, m), 4.36(2 H, s),






5.95(2 H, s), 6.72-6.77(3 H, m), 6.85(1 H, brs),






6.95(1 H, d, J = 8.6 Hz), 7.02-7.09(2 H, m), 7.32-






7.39(3 H, m), 7.51(1 H, d, J = 2.6 Hz), 7.60(1 H, d, J =






3.1 Hz), 9.12(1 H, brs).


2230
4-CF3Ph-
—C2H5
—H
(CDCl3) 1.19(3 H, t, J = 7.1 Hz), 2.20(3 H, s), 2.48-






2.53(4 H, m), 3.43(2 H, q, J = 7.1 Hz), 3.44(2 H, s),






3.70-3.73(2 H, m), 4.23-4.27(2 H, m), 4.48(2 H, s),






5.95(2 H, s), 6.71-6.77(3 H, m), 6.85(1 H, brs),






6.95(1 H, d, J = 8.7 Hz), 7.04(1 H, dd, J = 8.9 Hz, 3.1






Hz), 7.32-7.38(3 H, m), 7.51(1 H, d, J = 2.5 Hz),






7.56(2 H, d, J = 8.1 Hz), 7.61(1 H, d, J = 3.1 Hz),






9.11(1 H, brs).


2231
3,4-Cl2Ph-
—C2H5
—CH3
a mixture of the rotational isomers






(DMSO-d6) 1.09(3 H, t, J = 6.93 Hz), 2.29-2.42(7 H,






m), 3.22-3.54(11 H, m), 4.48(2 H, s), 5.97-5.99(2 H,






m), 6.64-6.94(5 H, m), 7.07-7.27(4 H, m), 7.46-






7.59(3 H, m).


2232
4-CF3Ph-
—C2H5
—CH3
a mixture of the rotational isomers






(DMSO-d6) 1.12(3 H, t, J = 6.93 Hz), 2.07-2.42(7 H,






m), 3.22-3.55(11 H, m), 4.59(2 H, s), 5.97-5.99(2 H,






m), 6.65-6.94(5 H, m), 7.07-7.18(1 H, m), 7.23-






7.29(2 H, m), 7.44(2 H, d, J = 8.08 Hz), 7.53(1 H, d, J =






3.13 Hz), 7.67(2 H, d, J = 8.41 Hz).
















TABLE 356













 









Example




No.
R1040
1H NMR (DMSO-d6) δppm





2233
3,4-Cl2Ph-
a mixture of the rotational isomers




2.09-2.12(3 H, m), 2.66-4.53(18 H, m), 6.05-6.08(2 H, m), 6.88-




6.93(2 H, m), 6.96-7.11(3 H, m), 7.19-7.25(3 H, m), 7.32-7.36(1 H, m),




7.48(1 H, d, J = 2.1 Hz), 7.55-7.60(2 H, m), 11.35(1 H, brs).


2234
4-CF3Ph-
a mixture of the rotational isomers




2.10-2.12(3 H, m), 2.66-4.64(18 H, m), 6.05-6.08(2 H, m), 6.87-




6.92(2 H, m), 6.96-7.11(3 H, m), 7.18-7.25(2 H, m), 7.30-7.35(1 H, m),




7.43(2 H, d, J = 8.1 Hz), 7.60-7.61(1 H, m), 7.68(2 H, d, J = 8.2 Hz),




11.27(1 H, brs).









Example 2235
Production of (4-{5-[benzyl-(3,4-dichlorobenzyl)-amino]pyridin-2-yloxy}(4-benzylpiperazin-1-yl)methanone
(4-benzylpiperazin-1-yl){4-[5-(3,4-dichlorobenzylamino)pyridin-2-yloxy]phenyl}methanone (1.09 g, 2.0 mmol) was dissolved in DMF (30 mL). To this solution were added potassium carbonate (0.28 g, 2.0 mmol) and benzyl bromide (0.24 mL, 2.0 mmol), and the resulting solution was stirred at room temperature for 2 hours, then subsequently stirred for 1 hour at 70° C. To the resulting solution were further added potassium carbonate (0.03 g, 0.2 mmol) and benzyl bromide (0.02 mL, 0.2 mmol), and this solution was stirred for 3 hours at 70° C. To the resulting solution were again added potassium carbonate (0.03 g, 0.2 mmol), benzyl bromide (0.02 mL, 0.2 mmol) and sodium iodide (0.15 g, 1.0 mmol), and this solution was stirred for overnight at 70° C. The resulting reaction solution was concentrated under reduced pressure. The residue was diluted with chloroform, and this solution was washed with water, saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was then purified by silica gel column chromatography (ethyl acetate), to thereby yield 0.64 g of the title compound.
Appearance: Pale yellow oil
1H NMR (CDCl3) δ 2.37 (4H, brs), 3.28-3.50 (6H, m), 4.71 (2H, s), 4.73 (2H, s), 6.90 (1H, d, J=8.9 Hz), 6.99 (2H, d, J=8.6 Hz), 7.22-7.37 (14H, m), 7.52 (1H, d, J=2.0 Hz), 7.58-7.61 (2H, m).
The following compounds were produced in the same manner as in Example 2235.







TABLE 357













 











Example






No.
R1041
R1042
R1043
1H NMR (CDCl3) δppm





2236
3,4-Cl2PhCON(CH3)—
—OCH3
—C2H5
1.19(3 H, t, J = 7.1 Hz), 2.42(4 H, t, J = 4.8






Hz), 3.30-3.55(4 H, m), 3.43(2 H, s),






3.44(3 H, s), 3.58-3.70(2 H, m), 3.67(3 H, s),






4.03(2 H, s), 5.95(2 H, s), 6.19(1 H, dd, J =






8.8 Hz, 2.8 Hz), 6.30(1 H, d, J = 2.8 Hz),






6.70-6.75(2 H, m), 6.79(1 H, d, J = 8.9 Hz),






6.85(1 H, s), 6.92(1 H, d, J = 8.8 Hz), 7.05






(1 H, dd, J = 8.1 Hz, 2.0 Hz), 7.27(1 H, d, J =






8.1 Hz), 7.35(1 H, dd, J = 8.9 Hz, 2.6






Hz), 7.41(1 H, d, J = 2.0 Hz), 7.80(1 H, d, J =






2.6 Hz).


2237
4-CF3PhCON(CH3)—
—CH3
—CH3
1.97(3 H, s), 2.43(4 H, t, J = 5.0 Hz),






3.00(3 H, s), 3.44(2 H, s), 3.47(3 H, s), 3.42-






3.57(2 H, m), 3.63(2 H, brs), 4.06(2 H, s),






5.95(2 H, s), 6.44-6.55(2 H, m), 6.67-






6.79(3 H, m), 6.82-6.90(2 H, m), 7.40-






7.47(1 H, m), 7.37(2 H, d, J = 8.1 Hz), 7.48






(2 H, d, J = 8.1 Hz), 7.81(1 H, brs).


2238
4-CF3PhCON(CH3)—
—OCH3
—C2H5
1.18(3 H, t, J = 7.1 Hz), 2.41(4 H, t, J = 4.9






Hz), 3.40(2 H, q, J = 7.1 Hz), 3.42(2 H, t, J =






3.5 Hz), 3.47(3 H, s), 3.42-3.59(2 H, m),






3.63(5 H, s), 4.02(2 H, s), 5.95(2 H, s),






6.18(1 H, dd, J = 8.7 Hz, 2.8 Hz), 6.28(1 H,






d, J = 2.8 Hz), 6.69-6.78(2 H, m), 6.77(1 H,






d, J = 8.8 Hz), 6.85(1 H, s), 6.90(1 H, d, J =






8.7 Hz), 7.35(1 H, d, J = 8.8 Hz), 7.38(2 H,






d, J = 8.4 Hz), 7.48(2 H, d, J = 8.4 Hz),






7.79(1 H, brs).


2239
3,4-Cl2PhN(CH3)CO—
—OCH3
—C2H5
1.18(3 H, t, J = 7.1 Hz), 2.42(4 H, t, J = 5.0






Hz), 3.42(2 H, s), 3.43(2 H, q, J = 7.1 Hz),






3.45(3 H, s), 3.55(2 H, brs), 3.65(5 H, brs),






4.02(2 H, s), 5.95(2 H, s), 6.19(1 H, dd, J =






8.7 Hz, 2.8 Hz), 6.29(1 H, d, J = 2.8 Hz),






6.71-6.74(3 H, m), 6.85(1 H, brs), 6.87(1 H,






dd, J = 8.6 Hz, 2.5 Hz), 6.92(1 H, d, J =






8.7 Hz), 7.20(1 H, d, J = 2.5 Hz), 7.32(1 H,






d, J = 8.4 Hz), 7.64(1 H, dd, J = 8.6 Hz,






2.3 Hz), 8.05(1 H, d, J = 1.8 Hz).


2240
3,4-Cl2PhSO2N(CH3)—
—F
—CH3
2.44(2 H, brs), 3.03(3 H, s), 3.19(3 H, s),






3.44(2 H, brs), 3.47(2 H, brs), 3.62(2 H,






brs), 4.08(2 H, brs), 4.08(2 H, s), 5.95(2 H,






s), 6.41(1 H, dd, J = 8.2 Hz, 3.1 Hz), 6.42-






6.50(1 H, m), 6.70-6.79(2 H, m), 6.85(1 H,






brs), 6.90(1 H, d, J = 8.7 Hz), 7.04(1 H, t, J =






7.8 Hz), 7.34(1 H, dd, J = 8.4 Hz, 2.2






Hz), 7.50(1 H, dd, J = 8.7 Hz, 2.8 Hz),






7.56(1 H, d, J = 8.4 Hz), 7.72(1 H, d, J =






2.2 Hz), 7.77(1 H, d, J = 2.8 Hz).
















TABLE 358













 












Example







No.
R1044
R1045
Xb46
Form
mp (° C.) or 1H NMR





2241
4-CF3PhCON(CH3)—
—CH3
—N(SO2CH3)—
free
1H NMR (CDCl3) δ







2.05(3 H, s), 2.42(4 H, brs),







3.20(3 H, s), 3.34-3.37(2 H,







m), 3.42(2 H, s), 3.48(3 H,







s), 3.59-3.61(2 H, m),







4.52(2 H, s), 5.95(2 H, s),







6.70-6.77(2 H, m), 6.84(1 H,







brs), 6.86(1 H, d, J = 8.7







Hz), 6.97(1 H, d, J = 8.1







Hz), 7.37-7.51(7 H, m),







7.79(1 H, brs).


2242
3,4-Cl3PhCON(CH3)—
—CH3
—N(SO2CH3)—
free
1H NMR (CDCl3) δ







2.09(3 H, s), 2.42(4 H, brs),







3.21(3 H, s), 3.37(2 H, brs),







3.43(2 H, s), 3.46(3 H, s),







3.61(2 H, brs), 4.52(2 H, s),







5.95(2 H, s), 6.70-6.80(2 H,







m), 6.84(1 H, brs), 6.89(1 H,







d, J = 8.7 Hz), 6.99(1 H, d,







J = 8.4 Hz), 7.09(1 H, dd, J =







8.2 Hz, 1.8 Hz), 7.29(1 H,







d, J = 8.2 Hz), 7.38(1 H, d,







J = 2.0 Hz), 7.42-7.46(3 H,







m), 7.80(1 H, d, J = 2.5







Hz).


 


2243




—H
—CH2—
free
mp 133.0-134.0


 


2244




—H
—CH2—
free
mp 117.0-118.0


 


2245
4-CF3PhN(CH3)SO2—
—H
—CH2—
free
1H NMR (CDCl3) δ2.33-







2.41(4 H, m), 2.63(2 H, t, J =







7.3 Hz), 2.99(2 H, t, J =







7.3 Hz), 3.22(3 H, s),







3.40(4 H, brs), 3.61-







3.64(2 H, m), 5.93(2 H, s),







6.69-6.76(2 H, m), 6.84(1 H,







s), 6.94(1 H, d, J = 8.7 Hz),







7.06(2 H, d, J = 8.6 Hz),







7.27-7.31(4 H, m), 7.59(2 H,







d, J = 8.4 Hz), 7.71(1 H, dd,







J = 8.7 Hz, 2.6 Hz),







8.37(1 H, d, J = 2.6 Hz).


2246
F3CCH═CHCON(CH3)—
—CH3
—N(CH3)—
hydro-
mp 161.0-164.0






chloride
















TABLE 359













 









Example




No.
R1046
1H NMR (solvent) δppm





2247
3,4-Cl2PhCON(CH3)—
a mixture of the rotational isomers




(DMSO-d6) 1.93(3 H, brs), 2.08-2.42(4 H, m), 3.21-




3.56(12 H, m), 5.97-5.99(2 H, m), 6.66-6.89(3 H, m), 6.90-




7.07(2 H, m), 7.13-7.32(3 H, m), 7.48-7.54(2 H, m), 7.85-




7.89(2 H, m).


2248
4-CF3PhCON(CH3)—
a mixture of the rotational isomers




(DMSO-d6) 1.87(3 H, brs), 2.07-2.41(4 H, m), 3.20-




3.55(12 H, m), 5.97-5.99(2 H, m), 6.66-6.89(3 H, m), 6.98-




7.04(2 H, m), 7.12-7.21(1 H, m), 7.24-7.30(1 H, m), 7.47(2 H,




brs), 7.61-7.64(2 H, m), 7.86-7.89(2 H, m).


2249
3,4-Cl2PhSO2N(CH3)—
(CDCl3) 2.17(3 H, s), 2.23-2.53(4 H, m), 3.21(3 H, brs), 3.32-




3.82(9 H, m), 5.93-5.95(2 H, m), 6.65-6.78(3 H, m), 6.85-




6.95(1 H, m0, 7.02-7.06(1 H, m), 7.07-7.18(2 H, m), 7.38-




7.42(1 H, m), 7.53-7.58(2 H, m), 7.67-7.68(1 H, m), 7.78-




7.80(1 H, m).


2250
4-CF3PhSO2N(CH3)—
a mixture of the rotational isomers




(DMSO-d6) 2.07-2.43(7 H, m), 3.16-3.56(12 H, m), 6.67-




6.70(2 H, m), 6.76-6.89(3 H, m), 7.05-7.36(4 H, m), 7.61-




7.66(1 H, m), 7.77-7.80(2 H, m), 7.91-7.80(3 H, m).


2251
4-CF3PhSO2N(C2H5)—
(CDCl3) 1.13(3 H, t, J = 7.1 Hz), 2.18(3 H, s), 2.23-2.52(4 H,




m), 3.32-3.66(11 H, m), 5.93-5.95(2 H, m), 6.66-6.95(4 H,




m), 7.04-7.19(3 H, m), 7.46(1 H, dd, J = 8.7 Hz, 2.6 Hz),




7.73-7.80(5 H, m).
















TABLE 360













 











Example






No.
R1047
R1048
R1049
1H NMR (CDCl3) δppm





2252
4-CF3Ph-
—H
benzyl
1.34-1.46(2 H, m), 1.85-2.03(3 H, m), 2.29(2 H, d,






J = 6.8 Hz), 2.43(4 H, brs), 2.73(2 H, t, J = 12.0






Hz), 3.19(3 H, s), 3.47-3.65(8 H, m), 6.83(1 H, d, J =






8.7 Hz), 6.92-7.03(4 H, m), 7.26-7.33(5 H, m),






7.48(1 H, dd, J = 8.9 Hz, 2.8 Hz), 7.70-7.78(5 H,






m).


2253
3.4-Cl2Ph-
—H
piperonyl
1.33-1.46(2 H, m), 1.85-2.04(3 H, m), 2.29(2 H, d,






J = 6.8 Hz), 2.39-2.42(4 H, m), 2.74(2 H, t, J =






12.2 Hz), 3.19(3 H, s), 3.43(2 H, s), 3.46-3.64(6 H,






m), 5.94(2 H, s), 6.70-6.77(2 H, m), 6.83(2 H, d, J =






8.9 Hz), 6.92-7.03(4 H, m), 7.38(1 H, dd, J = 8.4






Hz, 2.1 Hz), 7.49(1 H, dd, J = 9.9 Hz, 2.8 Hz),






7.56(1 H, d, J = 8.4 Hz), 7.70(1 H, d, J = 2.1 Hz),






7.81(1 H, d, J = 2.3 Hz).


2254
4-CF3Ph-
—H
piperonyl
1.34-1.46(4 H, m), 1.85-2.02(3 H, m), 2.28(2 H, d,






J = 6.8 Hz), 2.39-2.42(4 H, m), 2.74(2 H, t, J =






12.0 Hz), 3.20(3 H, s), 3.43(2 H, s), 3.46-3.64(6H,






m), 5.94(2 H, s), 6.70-6.77(2 H, m), 6.81-7.03(6 H,






m), 7.49(1 H, dd, J = 8.7 Hz, 2.8 Hz), 7.71-






7.78(5 H, m).


2255
4-CF3Ph-
—OCH3
benzyl
1.31-1.42(2 H, m), 1.86-2.00(3 H, m), 2.29(2 H, d,






J = 6.8 Hz), 2.42-2.45(4 H, m), 2.76(2 H, t, J =






12.0 Hz), 3.19(3 H, s), 3.49-3.69(8 H, m), 3.75(3 H,






s), 6.51(1 H, dd, J = 8.7 Hz, 2.5 Hz), 6.59(1 H, d, J =






2.5 Hz), 6.83(1 H, d, J = 8.7 Hz), 6.98(1 H, d, J =






8.7 Hz), 7.26-7.33(5 H, m), 7.47(1 H, dd, J = 8.9






Hz, 2.8 Hz), 7.69-7.75(5 H, m).


2256
3,4-Cl2Ph-
—H
benzyl
1.39-1.42(2 H, m), 1.84-2.02(3 H, m), 2.28(2 H, d,






J = 6.8 Hz), 2.41-2.45(4 H, m), 2.73(2 H, t, J =






12.2 Hz), 3.19(3 H, s), 3.48-3.95(8 H, m), 6.83(1 H,






d, J = 8.7 Hz), 6.92-7.03(4 H, m), 7.27-7.39(6 H,






m), 7.48(1 H, dd, J = 8.7 Hz, 2.8 Hz), 7.55(1 H, d,






J = 8.4 Hz), 7.70(1 H, d, J = 2.1 Hz), 7.81(1 H, d,






J = 2.3 Hz).


2257
3,4-Cl2Ph-
—OCH3
benzyl
1.34-1.42(2 H, m), 1.82-2.00(3 H, m), 2.29(2 H, d,






J = 6.8 Hz), 2.41-2.45(4 H, m), 2.76(2 H, t, J =






12.2 Hz), 3.19(3 H, s), 3.49-3.65(8 H, m), 3.75(3 H,






s), 6.51(1 H, dd, J = 8.7 Hz, 2.6 Hz), 6.58(1 H, d, J =






2.6 Hz), 6.84(1 H, d, J = 8.7 Hz), 6.98(1 H, d, J =






8.6 Hz), 7.26-7.39(6 H, m), 7.46(1 H, dd, J = 8.7






Hz, 2.6 Hz), 7.54(1 H, d, J = 8.4 Hz), 7.69(1 H, d,






J = 2.0 Hz), 7.78(1 H, d, J = 2.5 Hz).
















TABLE 361













 










Example





No.
R1050
R1051
1H NMR (CDCl3) δppm





2258
4-CF3PhN(CH3)SO2—
—H
1.34-1.46(2 H, m), 1.85-2.00(3 H, m), 2.28(2 H, d, J =





6.8 Hz), 2.39-2.43(4 H, m), 2.75(2 H, t, J = 12.2





Hz), 3.21(3 H, s), 3.43(2 H, s), 3.46-3.64(6 H, m),





5.94(2 H, s), 6.70-6.77(2 H, m), 6.85-7.02(6 H, m),





7.26-7.31(2 H, m), 7.59(2 H, d, J = 8.6 Hz), 7.67(1 H,





dd, J = 8.7 Hz, 2.6 Hz), 8.39(1 H, d, J = 2.1 Hz).


2259
4-CF3PhSO2N(C2H5)—
—OCH3
1.11(3 H, t, J = 7.1 Hz), 1.30-1.42(2 H, m), 1.85-





2.00(3 H, m), 2.29(2 H, d, J = 6.8 Hz), 2.39-2.44(4 H,





m), 2.76(2 H, t, J = 12.2 Hz), 3.40-3.70(10 H, m),





3.75(3 H, s), 5.94(2 H, s), 6.51(1 H, dd, J = 8.7 Hz,





2.6 Hz), 6.59(1 H, d, J = 2.6 Hz), 6.74-6.87(4 H, m),





6.99(1 H, d, J = 8.7 Hz), 7.37-7.48(2 H, m), 7.54(1 H,





d, J = 8.4 Hz), 7.73-7.75(2 H, m).


2260
4-CF3PhSO2N(C2H5)—
—H
1.11(3 H, t, J = 7.1 Hz), 1.35-1.47(2 H, m), 1.85-





2.00(3 H, m), 2.29(2 H, d, J = 6.8 Hz), 2.40-2.42(4 H,





m), 2.74(2 H, t, J = 12.0 Hz), 3.42-3.48(4 H, m),





3.57-3.64(6 H, m), 5.94(2 H, s), 6.74-6.77(2 H, m),





6.82-7.04(6 H, m), 7.41(1 H, dd, J = 8.7 Hz, 2.8 Hz),





7.72-7.94(5 H, m).


2261
4-CF3PhSO2N(CH3)—
—OCH3
1.39-1.47(2 H, m), 1.86-2.00(3 H, m), 2.29(2 H, d, J =





6.8 Hz), 2.41(4 H, brs), 2.76(2 H, t, J = 12.0 Hz),





3.19(3 H, s), 3.43(2 H, s), 3.48(2 H, brs), 3.60(4 H,





brs), 3.64(3 H, s), 5.93(2 H, s), 6.51(1 H, dd, J = 8.7





Hz, 2.5 Hz), 6.59(1 H, d, J = 2.5 Hz), 6.74-6.84(4 H,





m), 6.98(1 H, d, J = 8.6 Hz), 7.46(1 H, dd, J = 8.7





Hz, 2.6 Hz), 7.69-7.76(5 H, m).


2262
4-CF3PhN(CH3)SO2—
—CH3
1.34-1.45(2 H, m), 1.85-2.01(3 H, m), 2.07(3 H, s),





2.29(2 H, d, J = 6.8 Hz), 2.41-2.43(4 H, m), 2.73(2 H,





t, J = 12.0 Hz), 3.22(3 H, s), 3.43(2 H, s), 3.46-





3.77(6 H, m), 5.94(2 H, s), 6.74-6.94(7 H, m),





7.29(2 H, d, J = 8.2 Hz), 7.58(2 H, d, J = 8.4 Hz),





7.68(1 H, dd, J = 8.7 Hz, 2.6 Hz), 8.38(1 H, d, J =





2.5 Hz).


2263
3,4-Cl2PhSO2N(CH3)—
—CH3
1.38-1.41(2 H, m), 1.84-1.98(3 H, m), 2.11(3 H, s),





2.29(2 H, d, J = 6.8 Hz), 2.41(4 H, brs), 2.72(2 H, t, J =





12.0 Hz), 3.19(3 H, s), 3.43-3.64(8 H, m), 5.94(2 H,





s), 6.74-6.85(6 H, m), 6.93(1 H, d, J = 8.6 Hz),





7.39(1 H, dd, J = 8.4 Hz, 2.1 Hz), 7.49(1 H, dd, J =





8.7 Hz, 2.8 Hz), 7.56(1 H, d, J = 8.4 Hz), 7.67(1 H,





d, J = 2.0 Hz), 7.78(1 H, d, J = 2.3 Hz).


2264
3,4-Cl2PhSO2N(CH3)—
—OCH3
1.39-1.47(2 H, m), 1.85-2.02(3 H, m), 2.29(2 H, d, J =





6.8 Hz), 2.39-2.44(4 H, m), 2.76(2 H, t, J = 12.2





Hz), 3.19(3 H, s), 3.43(2 H, s), 3.49(2 H, brs), 3.59-





3.73(4 H, m), 3.75(3 H, s), 5.94(2 H, s), 6.51(1 H, dd,





J = 8.7 Hz, 2.6 Hz), 6.59(1 H, d, J = 2.6 Hz), 6.74-





6.85(4 H, m), 6.98(1 H, d, J = 8.6 Hz), 7.38(1 H, dd,





J = 8.2 Hz, 2.0 Hz), 7.46(1 H, dd, J = 8.7 Hz, 2.8





Hz), 7.55(1 H, d, J = 8.4 Hz), 7.69(1 H, d, J = 2.1





Hz), 7.78(1 H, d, J = 2.8 Hz).
















TABLE 362













 










Example





No.
Xb47
R1052
1H NMR (CDCl3) δppm





2265
—CO—




2.33(2 H, d, J = 5.1 Hz), 2.38(2 H, d, J = 5.1 Hz), 2.60(2 H, t, J = 5.1 Hz), 2.96(2 H, t, J = 8.0 Hz), 3.33-3.46(2 H, m), 3.40(2 H, s), 3.47(3 H, s), 3.62(2 H, t, J = 2.0 Hz), 5.94(2 H, s), 6.67- 6.79(2 H, m), 6.83(1 H, d, J = 8.7 Hz), 6.84(1 H, s), 6.99(2 H, d, J = 8.4 Hz), 7.22(2 H, d, J = 8.4 Hz), 7.34-7.45(1 H, m), 7.40(2 H, d, J = 8.2 Hz), 7.50(2 H, d, J = 8.2 Hz), 7.85(1 H, brs).


 


2266
—CO—




3.17(3 H, s), 3.21(3 H, s), 3.48(3 H, s), 6.70(1 H, d, J = 8.7 Hz), 6.72-6.84(6 H, m), 6.95(1 H, t, J = 7.4 Hz), 7.07(2 H, t, J = 7.8 Hz), 7.31-7.45(3 H, m), 7.46- 7.58(2 H, m), 7.79-7.92(1 H, m).


 


2267
—SO2—




1.78-2.04(4 H, m), 2.11(3 H, s), 2.44 (4 H, brs), 2.53-2.76(3 H, m), 3.19(3 H, s), 3.53(4 H, brs), 3.67(4 H, brs), 6.76- 6.81(3 H, m), 6.93(1 H, d, J = 8.6 Hz), 7.26-7.33(5 H, m), 7.49(1 H, dd, J = 8.9 Hz, 2.8 Hz), 7.70-7.79(5 H, m).
















TABLE 363













 










Example





No.
R1053
Form
1H NMR (DMSO-d6) δppm





2268
—CH3
free
2.39(4 H, brs), 3.32-3.51(9 H, m), 7.08(1 H, d, J = 8.7 Hz),





7.09(2 H, d, J = 8.4 Hz), 7.25-7.31(6 H, m), 7.41(2 H, d, J =





8.6 Hz), 7.55-7.58(2 H, m), 7.87(1 H, dd, J = 8.7 Hz, 2.8 Hz),





8.03(1 H, brs).


2269
benzyl
hydro-
3.12-3.43(8 H, m), 4.33(2 H, s), 5.09(2 H, s), 7.02(1 H, d, J =




chloride
8.7 Hz), 7.07(2 H, d, J = 7.8 Hz), 7.26-7.33(6 H, m), 7.45-





7.48(5 H, m), 7.55-7.58(3 H, m), 7.67(1 H, brs), 7.77(1 H, d, J =





8.7 Hz), 7.85(1 H, brs), 11.09(1 H, brs).









Example 2270
Production of 1-(t-butoxycarbonyl)-4-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}-4-hydroxypiperidine
To a solution of N-[4-(4-bromophenoxy)phenyl]-3,4-dichlorobenzamide (4.94 g, 11.3 mmol) in THF (100 mL) was stirred at −85° C., and added a solution of 2.46 M n-butyl lithium hexane (9.65 mL, 23.7 mmol) dropwise over 10 minutes. Upon stirring for 20 minutes at the same temperature, crystals were precipitated. To this reaction solution was added a solution of 1-(t-butoxycarbonyl)-4-piperidone (2.48 g, 12.4 mmol) in THF (20 mL). The temperature of the solution was raised over 3 hours to −40° C., and then aqueous saturated ammonium chloride was added to the solution. The resulting reaction solution was extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was then evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=2:3 to 1:1), to yield 2.30 g of a white powder. These crystals were washed with ether, to thereby yield 1.80 g of the title compound.
Appearance: White powder
Melting point: 208-209° C.
Example 2271
Production of 1-(t-butoxycarbonyl)-4-(4-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}-1,2,5,6-tetrahydropyridine
To a solution of 1-(t-butoxycarbonyl)-4-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}-4-hydroxypiperidine (1.56 g, 2.80 mmol) in toluene (32 mL) was added p-toluenesulfonic acid hydrate (53 mg, 0.28 mmol), and the resulting solution was refluxed for 18 hours. The resulting reaction solution was purified by silica gel column chromatography (dichloromethane methanol=20:1), to thereby yield 1.35 g of the title compound.
Appearance: White powder
Melting point: 173-174° C.
Example 2272
Production of 1-{4-[4-(3,4-dichlorobenzoylamino)-phenoxy]phenyl}-4-hydroxypiperidine
To a solution of 1-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}-4-(methoxymethoxy)piperidine (5.50 g, 11.0 mmol) in ethanol (110 mL) was added 2 M hydrochloric acid (55 mL, 110 mmol), and the resulting solution was stirred for 8 hours at 60° C. To the resulting reaction solution was added potassium carbonate (16 g) at room temperature, and the solvent was evaporated under reduced pressure. Water (200 mL) was added to the residue. Precipitated crystals were collected by filtration, to thereby yield 5.0 g of the title compound.
Appearance: Pale brown powder
Melting point: 178-180° C.
Example 2273
Production of 1-(3-{4-[4-(3,4-dichlorobenzoylamino)-phenoxy]phenyl}propionyl)piperazine monohydrochloride
To a solution of 1-(t-butoxycarbonyl)-4-(3-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}-propionyl)piperazine (2.40 g, 4.01 mmol) in dichloromethane (24 mL) was added trifluoroacetic acid (12 mL) under ice cooling, and the resulting solution was stirred for 3 hours at the same temperature. The solvent was evaporated. To the residue was added acetone (5 mL), and then added a saturated sodium bicarbonate solution to make the solution basic. The formed solids were collected by filtration and dried, whereby 2.00 g of a white powder free form was obtained. This free form (0.500 g) was dissolved in ethanol (10 mL) and 5 M hydrochloric acid (0.4 mL) by heating. The solvent was then evaporated, and the obtained solid was recrystallized from isopropanol, to thereby yield 0.388 g of the title compound.
Appearance: White powder
Melting point: 127-130° C.
The following compounds were produced in the same manner as in Example 2273.







TABLE 364













 











Example






No.
R1054
R1055
Form
mp (° C.) or 1H NMR (solvent) δppm





2274
—F




hydro- chloride
mp 149-151


 


2275
—H




free
mp 198-199


 


2276
—H




free
mp 170-174


 


2277
—H




free
1H NMR (CDCl3) 2.43-2.46(2 H, m), 3.11(2 H, t, J = 5.5 Hz), 3.53(2 H, q, J = 3 Hz), 6.10(1 H, m), 6.97(2 H, d, J = 8.5 Hz), 7.04(2 H, d, J = 9.0 Hz), 7.36(2 H, d, J = 8.5 Hz), 7.56-7.59(3 H, m), 7.68-7.69(2 H, m), 7.97(1 H, d, J = 2.0 Hz).


 


2278
—H




free
1H NMR (DMSO-d6) 1.32-1.36(2 H, m), 1.85-1.91(2 H, m), 2.32(3 H, s), 2.45(1 H, m), 2.66-2.71(2 H, m), 3.54-3.56(2 H, m), 4.13(1 H, m), 6.89-6.97(6 H, m), 7.65- 7.71(3 H, m), 7.82(1 H, d, J = 8.5 Hz), 7.93(1 H, dd, J = 8.5 Hz, 2.0 Hz), 8.21(1 H, d, J = 2.0 Hz), 10.36(1 H, s).


 


2279
—H




free
1H NMR (CDCl3) 1.63(2 H, m), 1.83(2 H, brd, J = 14.0 Hz), 2.61(1 H, m), 2.75(2 H, dt, J = 2.5 Hz, 12.0 Hz), 3.20(2 H, brd, J = 12.0 Hz), 6.95(2 H, d, J = 8.5 Hz), 7.03(2 H, d, J = 9.0 Hz), 7.19(2 H, d, J = 8.5 Hz), 7.55(1 H, d, J = 8.0 Hz), 7.58(2 H, d, J = 8.5 Hz), 7.69(1 H, dd, J = 8.0 Hz, 2.0 Hz), 7.69(1 H, brs), 7.97(1 H, d, J = 2.0 Hz).
















TABLE 365













 












Example







No.
R1056
Xb48
Xb49
Form
1H NMR (solvent) δppm





2280
3,4-Cl2Ph-
none
—CO—
trifluoro-
(DMSO-d6) 3.56(2 H, brs), 3.87(2 H, m),






acetate
3.92(2 H, brs), 7.14(1 H, d, J = 8.8 Hz),







7.20(2 H, dd, J = 6.7 Hz, 2.2 Hz),







7.35((2 H, dd, J = 6.7 Hz, 2.2 Hz),







7.85(1 H, d, J = 8.4 Hz), 7.95(1 H, dd, J =







8.4 Hz, 2.1 Hz), 8.22(1 H, dd, J = 8.8







Hz, 2.7 Hz), 8.23(1 H, d, J = 2.1 Hz),







8.51(1 H, d, J = 2.7 Hz), 9.30(2 H, brs),







10.59(1 H, s).


2281
4-CF3Ph-
none
—CH2—
free
(CDCl3) 3.07(4 H, t, J = 5.0 Hz),







3.15(4 H, t, J = 5.0 Hz), 6.92(1 H, d, J =







9.0 Hz), 6.96(2 H, d, J = 9.0 Hz),







7.06(2 H, d, J = 9.0 Hz), 7.77(1 H, brs),







7.78(2 H, d, J = 8.0 Hz), 7.99(2 H, d, J =







8.0 Hz), 8.19(1 H, brd, J = 9.0 Hz),







8.25(1 H, d, J = 2.5 Hz).


2282
3,4-Cl2Ph-
none
—CH2—
free
(CDCl3) 3.18(4 H, dd, J = 5.5 Hz, 2.5







Hz), 3.16(4 H, dd, J = 5.5 Hz, 2.5 Hz),







6.90(1 H, d, J = 9.0 Hz), 6.95(2 H, d, J =







9.0 Hz), 7.05(2 H, d, J = 9.0 Hz),







7.58(1 H, d, J = 8.5 Hz), 7.71(1 H, dd, J =







8.5 Hz, 2.0 Hz), 7.88(1 H, brs),







7.98(1 H, d, J = 2.0 Hz), 8.16(1 H, dd, J =







9.0 Hz, 2.5 Hz), 8.24(1 H, d, J = 2.5







Hz).


2283
3,4-Cl2Ph-
—CH2—
—CH2—
free
(DMSO-d6) 2.45-2.47(4 H, m), 2.88-







2.92(4 H, m), 3.49(2 H, s), 7.05-







7.09(3 H, m), 7.33(2 H, d, J = 8.6 Hz),







7.84(1 H, d, J = 8.6 Hz), 7.95-7.99(1 H,







m), 8.18-8.25(2 H, m), 8.51(1 H, d, J =







2.6 Hz), 10.62(1 H, s).


2284
3,4-Cl2Ph-
—CO—
—CH2—
free
(DMSO-d6) 2.69(4 H, brs), 3.40(4 H,







brs), 7.12-7.17(3 H, s), 7.41-7.44(2 H,







m), 7.84(1 H, d, J = 8.4 Hz), 7.96(1 H,







dd, J = 8.4 Hz, 2.2 Hz), 8.21-8.26(2 H,







m), 8.52(1 H, d, J = 2.7 Hz), 10.62(1 H,







brs).


2285
4-CF3Ph-
—CH2—
—CH2—
free
(DMSO-d6) 2.44-2.46(4 H, m), 2.89-







2.92(4 H, m), 3.49(2 H, s), 4.79(1 H,







brs), 7.06-7.09(3 H, m), 7.33(2 H, d, J =







8.6 Hz), 7.94(2 H, d, J = 8.1 Hz), 8.16-







8.25(3 H, m), 8.52(1 H, d, J = 2.7 Hz),







10.65(1 H, s).


2286
3,4-(CH3)2Ph-
—CO—
—CH2—
free
(DMSO-d6) 2.29(3 H, s), 2.30(3 H, s),







2.73(4 H, brs), 3.44(4 H, brs), 7.09-







7.16(3 H, m), 7.29(1 H, d, J = 7.9 Hz),







7.40-7.44(2 H, m), 7.69-7.72(1 H, m),







7.75(1 H, brs), 8.22-8.26(1 H, m),







8.53(1 H, d, J = 2.8 Hz), 10.31(1 H, s).
















TABLE 366













 











Example






No.
R1057
Xb50
M
1H NMR (solvent) δppm





2287
3,4-Cl2PhCH2N(CH3)—
none
1
(DMSO-d6) 2.51-2.54(4 H, m), 3.00(3 H, s),






3.06-3.08(4 H, m), 3.50(2 H, s), 4.55(2 H, s),






6.88(1 H, d, J = 8.9 Hz), 6.94(2 H, d, J =






8.4 Hz), 7.19-7.32(4 H, m), 7.49(1 H, d, J =






1.5 Hz), 7.58(1 H, d, J = 8.2 Hz), 7.64(1 H,






d, J = 3.1 Hz), 8.73(1 H, brs).


2288
4-CF3PhCONH—
none
3
(CDCl3) 1.77-1.96(6 H, m), 2.35-2.44(6 H,






m), 2.61-2.66(2 H, m), 6.92(1 H, d, J = 8.6






Hz), 7.01-7.05(2 H, m), 7.17-7.23(2 H, m),






7.74(2 H, d, J = 8.4 Hz), 8.00(2 H, d, J = 8.4






Hz), 8.21(1 H, dd, J = 8.6 Hz, 2.6 Hz), 8.27-






8.28(2 H, m).


2289
3,4-Cl2PhCONH—
—CO—
2
(DMSO-d6) 2.59-2.69(6 H, m), 2.79-






2.85(2 H, m), 3.37-3.43(4 H, m), 4.31(1 H,






brs), 7.00-7.06(3 H, m), 7.27(2 H, d, J = 8.6






Hz), 7.84(1 H, d, J = 8.4 Hz), 7.95(1 H, dd,






J = 8.4 Hz, 2.1 Hz), 8.16-8.22(2 H, m),






8.46(1 H, d, J = 2.3 Hz), 10.54(1 H, s).


2290
4-CF3PhCONH—
—COCO—
1
(CDCl3) 1.69(1 H, brs), 2.51(2 H, t, J = 5.1






Hz), 2.77(2 H, t, J = 5.1 Hz), 3.15(2 H, t, J =






5.1 Hz), 3.53(2 H, t, 5.1 Hz), 4.05(2 H, s),






6.98(1 H, d, J = 8.7 Hz), 7.11(2 H, d, J = 8.5






Hz), 7.29(2 H, d, J = 8.5 Hz), 7.76(2 H, d, J =






8.2 Hz), 7.99(2 H, d, J = 8.2 Hz),






8.01(1 H, brs), 8.21(1 H, dd, J = 8.7 Hz, 2.7






Hz), 8.25(1 H, d, J = 2.7 Hz).









Example 2291
[3-(4-{5-[3-(3,4-Dichlorophenyl)ureido]pyridin-2-yloxy}-3-methylphenyl)-2-oxotetrahydropyrimidin-1-yl]acetic acid
1H NMR (DMSO-d6) δ 1.87-2.15 (5H, m), 3.25-3.47 (2H, m), 3.58-3.75 (2H, m), 3.95 (2H, s), 6.82-7.00 (2H, m), 7.01-7.12 (1H, m), 7.17 (1H, d, J=2.4 Hz), 7.29-7.32 (1H, m), 7.50 (1H, d, J=8.8 Hz), 7.85 (1H, d, J=2.4 Hz), 7.89-8.02 (1H, m), 8.11 (1H, d, J=2.7 Hz), 8.95 (1H, s), 9.17 (1H, s), 12.50 (1H, s).
The following compounds were produced in the same manner as in Reference Example 922.







TABLE 367













 










Example





No.
R1058
R1059
1H NMR (DMSO-d6) δppm





2292
3,4-Cl2Ph-




1.40-1.65(2 H, m), 1.95-2.18(2 H, m), 2.40- 2.65(3 H, m), 3.00(2 H, brs), 3.25(1 H, brs), 3.85(1 H, brs), 4.40(1 H, brs), 7.15(1 H, d, J = 9.0 Hz), 7.19(2 H, d, J = 8.7 Hz), 7.43(2 H, d, J = 8.7 Hz), 7.84(1 H, d, J = 8.4 Hz), 7.99(1 H, dd, J = 8.4 Hz, 2.0 Hz), 8.22-8.30(2 H, m), 8.56(1 H, d, J = 2.0 Hz), 10.71(1 H, s).


 


2293
3,4-Cl2Ph-




1.70-2.05(4 H, m), 2.60-2.80(1 H, m), 2.80- 3.05(2 H, m), 3.44(2 H, d, J = 7.1 Hz), 7.03(1 H, d, J = 8.7 Hz), 7.07(2 H, d, J = 8.9 Hz), 7.65(2 H, d, J = 8.9 Hz), 7.84(1 H, d, J = 8.4 Hz), 7.98(1 H, dd, J = 8.4 Hz, 2.0 Hz), 8.20(1 H, dd, J = 8.7 Hz, 2.7 Hz), 8.26(1 H, d, J = 2.0 Hz), 8.50(1 H, d, J = 2.7 Hz), 10.22(1 H, s), 10.65(1 H, s).


 


2294
4-CF3Ph-




1.75-1.90(2 H, m), 1.95-2.30(2 H, m), 2.84(3 H, s), 2.70-3.15(2 H, m), 3.20-3.42(2 H, m), 4.55(1 H, brs), 6.51(1 H, brs), 7.16(1 H, d, J = 8.8 Hz), 7.17(2 H, d, J = 8.4 Hz), 7.47(2 H, d, J = 8.4 Hz), 7.94(2 H, d, J = 8.1 Hz), 8.22(2 H, d, J = 8.1 Hz), 8.31(1 H, dd, J = 8.8 Hz, 2.6 Hz), 8.60(1 H, d ,J = 2.6 Hz), 10.84(1 H, s).
















TABLE 368













 













Example








No.
R1060
R1061
Xb51
M
Form
1H NMR (solvent) δppm





2295
—H
—H
none
0
dihydro-
(DMSO-d6) 3.16(4 H, brs), 3.75(4 H,







chloride
brs), 7.16(1 H, d, J = 8.9 Hz),








7.19(2 H, d, J = 8.7 Hz), 7.53(2 H, d,








J = 8.7 Hz), 7.93(2 H, d, J = 8.1 Hz),








8.21(2 H, d, J = 8.1 Hz), 8.30(1 H, dd,








J = 8.9 Hz, 2.5 Hz), 8.60(1 H, d, J =








2.5 Hz), 10.81(1 H, s).


2296
—H
—H
none
2
dihydro-
(DMSO-d6) 2.68(1 H, d, J = 6.5 Hz),







chloride
2.71(1 H, d, J = 8.4 Hz), 2.82(1 H, d, J =








8.4 Hz), 2.84(1 H, d, J = 6.5 Hz),








3.04(4 H, brs), 3.70(4 H, t, J = 5.0








Hz), 7.03(2 H, d, J = 8.6 Hz),








7.05(1 H, d, J = 8.9 Hz), 7.29(2 H, d, J =








8.6 Hz), 7.41(1 H, brs), 7.92(2 H, d,








J = 8.5 Hz), 8.21(2 H, d, J = 8.5 Hz),








8.25(1 H, dd, J = 8.9 Hz, 2.8 Hz),








8.54(1 H, d, J = 2.8 Hz), 10.80(1 H, s).


2297
—CH3
—H
—N(CH3)—
1
free
(CDCl3) 2.11(3 H, s), 2.74-2.96(4 H,








m), 3.01(3 H, s), 3.39-3.70(4 H, m),








4.08(2 H, s), 6.54(1 H, dd, J = 8.6 Hz,








3.0 Hz), 6.57(1 H, d, J = 3.0 Hz), 6.81








(1 H, d, J = 8.9 Hz), 6.91(1 H, d, J =








8.6 Hz), 7.75(2 H, d, J = 8.2 Hz),








7.93-8.02(3 H, m), 8.13(1 H, dd, J =








8.9 Hz, 2.7 Hz), 8.24(1 H, d, J = 2.7








Hz).


2298
—H
—CH2CONHNH2
none
0
trihydro-
(DMSO-d6) 3.42(4 H, brs), 3.75(4 H,







chloride
brs), 4.21(2 H, s), 7.17(1 H, d, J = 8.8








Hz), 7.21(2 H, d, J = 8.6 Hz), 7.53








(2 H, d, J = 8.6 Hz), 7.94(2 H, d, J =








8.1 Hz), 8.22(2 H, d, J = 8.1 Hz),








8.31(1 H, dd, J = 8.8 Hz, 2.6 Hz),








8.62(1 H, d, J = 2.6 Hz), 10.87(1 H,








s).









Example 2299
Production of 1-(3-{4-[4-(3,4-dichlorobenzoylamino)-phenoxy]phenyl}propionyl)-4-piperonylpiperazine monohydrochloride
To a suspension consisting of 1-(3-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}propionyl)-piperazine (0.500 g, 1.00 mmol) and diisopropyl-ethylamine (0.262 mL, 1.50<mmol) in acetonitrile (12 mL) was added piperonyl chloride (0.188 g, 1.10 mmol), and the resulting solution was heated to reflux for 1.5 hours. Water was added to this reaction solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1), to thereby yield 0.486 g of a free form. This free form was dissolved in ethanol (10 mL) and 5 M hydrochloric acid (0.3 mL) by heating. The solvent was then evaporated, and the obtained solid was recrystallized from 90% ethanol (17.5 mL), to thereby yield 0.322 g of the title compound.
Appearance: White powder
Melting point: 221-224° C.
A crude titled product (9.95 g, 14.9 mmol) obtained using the same procedures was recrystallized from 80% ethanol (350 mL), to thereby yield 9.37 g of the title compound.
Appearance: White powder
Melting point: 232-234° C.
The following compounds were produced in the same manner as in Example 2299.







TABLE 369













 













Example





mp (° C.) or 1H NMR


No.
R1062
Xb52
Xb53
R1063
Form
(CDCl3) δppm





2300
—H
—(CH2)2—
—CO—
—(CH2)2Ph
hydro-
mp 205-207







chloride


2301
—H
—(CH2)2—
—CO—
—(CH2)2OH
hydro-
mp 101-105







chloride


2302
—H
—(CH2)2—
—CO—
—(CH2)2Ph
1⁄2
mp 156-159







fumarate


2303
—F
—(CH2)2—
—CO—
4-CH3PhCH2—
free
mp 105-107


2304
—F
—(CH2)2—
—CO—
4-CH3OPhCH2—
free
mp 137-139


2305
—F
—(CH2)2—
—CO—
2-CF3PhCH2—
free
mp 130-132


2306
—F
—(CH2)2—
—CO—
2-naphthyl-
hydro-
mp 172-175






methyl
chloride


2307
—H
—(CH2)2—
—CO—
—CH2COOC2H5
free
1H NMR 1.25 (3H, t, J = 7.1








Hz), 2.39-2.53 (4H, m),








2.58 (2H, t, J = 7.8 Hz),








2.90 (2H, t, J = 7.8 Hz),








3.19 (2H, s), 3.36-3.48 (2H, m),








3.58-3.69 (2H, m), 4.16 (2H, q,








J = 7.1 Hz), 6.89 (2H, d, J =








8.6 Hz), 6.96 (2H, d, J = 8.9








Hz), 7.12 (2H, d, J = 8.6 Hz),








7.47-7.59 (3H, m), 7.69 (1H,








dd, J = 8.3 Hz, 2.1 Hz), 7.96








(1H, d, J = 2.1 Hz), 8.14 (1H,








brs).


2308
—H
none
—CO—
—(CH2)2Ph
hydro-
mp 210-218







chloride


2309
—H
none
none
—(CH2)2Ph
free
mp 214-215


2310
—H
none
none
benzyl
free
mp 189-190


2311
—H
none
none
—(CH2)3Cl
free
1H NMR 2.00 (2H, m),








2.56 (2H, t, J = 7.0 Hz), 2.62-








2.64 (4H, m), 3.16-3.18 (4H,








m), 3.64 (2H, t, J = 7.0 Hz),








6.92 (2H, d, J = 7.0 Hz), 6.95-








6.98 (4H, m), 7.52 (2H, d, J =








9.0 Hz), 7.57 (1H, d, J = 8.0








Hz), 7.69 (1H, dd, J = 8.0 Hz,








2.0 Hz), 7.70 (1H, s), 7.96 (1H,








d, J = 2.0 Hz).


2312
—H
none
none
—CH2COOC2H5
free
1H NMR 1.30 (3H, t, J = 7.0








Hz), 2.76 (4H, t, J = 5.0 Hz),








3.21 (4H, t, J = 5.0 Hz),








3.28 (2H, s), 4.21 (2H, q, J =








7.0 Hz), 6.91-6.98 (6H, m),








7.52 (2H, d, J = 9.0 Hz),








7.57 (1H, d, J = 8.5 Hz), 7.69








(1H, dd, J = 8.5 Hz, 2.0 Hz),








7.72 (1H, brs), 7.96 (1H, d, J =








2.0 Hz).
















TABLE 370













 









Example




No.
R1064
mp (° C.) or 1H NMR (CDCl3) δppm





2313




mp 189-195


 


2314




1H NMR 2.60 (2H, brs), 2.85 (2H, m), 3.31 (2H, m), 3.39 (2H, s), 3.76 (3H, s), 6.00 (1H, brs), 6.95 (2H, d, J = 8.5 Hz), 7.03 (2H, d, J = 8.5 Hz), 7.34 (2H, d, J = 8.5 Hz), 7.57 (2H, d, J = 8.5 Hz), 7.57 (1H, brs), 7.70 (1H, d, J = 7.0 Hz), 7.75 (1H, brs), 7.97 (1H, s).


 


2315




1H NMR 1.28 (3H, t, J = 7.0 Hz), 1.60-1.70 (2H, m), 1.93-1.96 (2H, m), 2.46 (3H, s), 2.60-2.72 (3H, m), 3.37 (2H, s), 3.64-3.66 (2H, m), 4.20 (2H, q, J = 7.0 Hz), 6.93-6.98 (6H, m), 7.52 (2H, m), 7.57 (1H, d, J = 8.5 Hz), 7.68-7.70 (2H, m), 7.96 (1H, d, J = 2.0 Hz).


 


2316




1H NMR 1.29 (3H, t, J = 7.0 Hz), 1.81-1.88 (4H, m), 2.30 (2H, brt, J = 11.0 Hz), 2.49 (1H, m), 3.06 (2H, brd, J = 11.0 Hz), 4.21 (2H, q, J = 7.0 Hz), 6.94 (2H, d, J = 8.5 Hz), 7.01 (2H, d, J = 9.0 Hz), 7.18 (2H, d, J = 8.5 Hz), 7.55-7.68 (3H, m), 7.69 (1H, d, J = 2.0 Hz), 7.75 (1H, brs), 7.97 (1H, d, J = 2.0 Hz).


 


2317




1H NMR 2.04 (2H, m), 2.56 (2H, brs), 2.62 (2H, t, J = 7.0 Hz), 2.72 (2H, t, J = 5.5 Hz), 3.17 (2H, brs), 3.64 (2H, t, J = 6.5 Hz), 6.02 (1H, brs), 6.96 (2H, d, J = 9.0 Hz), 7.04 (2H, d, J = 9.0 Hz), 7.36 (2H, d, J = 9.0 Hz), 7.58 (3H, m), 7.70 (1H, dd, J = 8.5 Hz, 2.0 Hz), 7.77 (1H, brs), 7.98 (1H, d, J = 2.0 Hz).
















TABLE 371













 










Example





No.
R1065
R1066
1H NMR (solvent) δppm





2318
4-CF3Ph-
—(CH2)2Ph
(DMSO-d6) 2.31-2.60 (6H, m), 2.67-2.81 (2H,





m), 3.51 (4H, brs), 7.16 (1H, d, J = 8.8 Hz),





7.17 (2H, d, J = 8.5 Hz), 7.10-7.33 (5H, m),





7.44 (2H, d, J = 8.5 Hz), 7.94 (2H, d, J = 8.2 Hz),





8.17 (2H, d, J = 8.2 Hz), 8.26 (1H, dd, J = 8.8





Hz, 2.6 Hz), 8.55 (1H, d, J = 2.6 Hz), 10.67 (1H,





s).


2319
3,4-Cl2Ph-
4-CNPhCH2—
(CDCl3) 2.46 (4H, brs), 3.59 (2H, s), 3.75 (4H,





brs), 6.97 (1H, d, J = 8.9 Hz), 7.11-7.14 (2H, m),





7.40-7.43 (2H, m), 7.46 (2H, d, J = 7.8 Hz),





7.56-7.65 (3H, m), 7.72-7.76 (1H, m), 8.02 (1H,





d, J = 2.2 Hz), 8.16 (1H, dd, J = 8.9 Hz, 2.7 Hz),





8.27 (1H, brs), 8.30 (1H, d, J = 2.7 Hz).


2320
3,4-Cl2Ph-
—CH2COPh
(CDCl3) 2.65 (4H, brs), 3.60-3.82 (4H, m),





3.89 (2H, s), 6.99 (1H, d, J = 8.7 Hz), 7.15 (2H,





d, J = 8.6 Hz), 7.43-7.50 (4H, m), 7.56-7.60 (2H,





m), 7.72-7.76 (1H, m), 7.97-8.02 (3H, m), 8.13-





8.21 (2H, m), 8.30 (1H, d, J = 2.5 Hz).


2321
3,4-Cl2Ph-
3,4-(CH3)2PhCH2—
(CDCl3) 2.25 (3H, s), 2.26 (3H, s), 2.44 (4H, brs),





3.47 (2H, s), 3.73 (4H, brs), 6.89 (1H, d, J = 8.9





Hz), 7.01-7.10 (5H m) 7.32-7.36 (2H, m),





7.51 (1H, d, J = 8.4 Hz), 7.74-7.78 (1H, m),





8.05 (1H, d, J = 8.1 Hz), 8.09 (1H, dd, J = 8.8





Hz, 2.7 Hz), 8.30 (1H, d, J = 2.7 Hz), 9.06 (1H,





brs).


2322
3,4-Cl2Ph-
4-C(CH3)3COPhCH2—
(CDCl3) 1.36 (9H, s), 2.48 (4H, brs), 3.58 (2H, s),





3.70 (4H, brs), 6.96 (1H, d, J = 8.7 Hz), 7.11-





7.14 (2H, m), 7.39-7.43 (4H, m), 7.57 (1H, d, J =





8.4 Hz), 7.69 (2H, d, J = 8.3 Hz), 7.73-7.77 (1H,





m), 8.03 (1H, d, J = 2.0 Hz), 8.15 (1H, dd, J =





8.9 Hz, 2.7 Hz), 8.30 (1H, d, J = 2.7 Hz),





8.37 (1H, brs).


2323
3,4-Cl2Ph-
4-PhCH2OPhCH2—
(CDCl3) 2.45 (4H, brs), 3.49 (2H, s), 3.73 (4H,





brs), 5.06 (2H, s), 6.92-6.98 (3H, m), 7.11-





7.15 (2H, m), 7.23 (2H, d, J = 8.6 Hz), 7.32-





7.46 (7H, m), 7.57 (1H, d, J = 8.1 Hz), 7.75 (1H,





dd, J = 8.4 Hz, 2.2 Hz), 8.03 (1H, d, J = 2.2 Hz),





8.16 (1H, dd, J = 8.9 Hz, 2.7 Hz), 8.26 (1H, brs),





8.29 (1H, d, J = 2.7 Hz).


2324
3,4-Cl2Ph-
4-C(CH3)3PhCH2—
(CDCl3) 1.32 (9H, s), 2.48 (4H, brs), 3.53 (2H, s),





3.70 (4H, brs), 6.98 (1H, d, J = 8.4 Hz), 7.13 (2H,





d, J = 8.6 Hz), 7.21-7.27 (2H, m), 7.36 (2H, d, J =





8.4 Hz), 7.43 (2H, d, J = 8.6 Hz), 7.59 (1H, d, J =





8.1 Hz), 7.72-7.76 (1H, m), 8.02 (1H, d, J = 2.2





Hz), 8.13 (1H brs), 8.16-8.20 (1H, m), 8.30 (1H,





d, J = 2.2 Hz).


2325
3,4-Cl2Ph-
3-CH3PhCH2—
(CDCl3) 2.36 (3H, s), 2.47 (4H, brs), 3.52 (2H, s),





3.74 (4H, brs), 6.97 (1H, d, J = 8.7 Hz), 7.08-





7.26 (6H, m), 7.41-7.44 (2H, m), 7.58 (1H, d, J =





8.4 Hz), 7.76 (1H, dd, J = 8.4 Hz, 2.1 Hz),





8.04 (1H, d, J = 2.1 Hz), 8.14-8.19 (1H, m),





8.26 (1H, brs), 8.30 (1H, d, J = 2.2 Hz).
















TABLE 372













 










Example





No.
R1067
R1068
1H NMR (CDCl3) δppm





2326
3,4-Cl2Ph-
4-CH(CH3)2PhCH2—
1.25 (6H, d, J = 7.3 Hz), 2.46 (4H, brs), 2.85-





2.96 (1H, m), 3.52 (2H, s), 3.75 (4H, brs),





6.95 (1H, d, J = 8.9 Hz), 7.10-7.13 (2H, m), 7.17-





7.26 (4H, m), 7.38-7.42 (2H, m), 7.57 (1H, d, J =





8.1 Hz), 7.75 (1H, dd, J = 8.4 Hz, 2.2 Hz),





8.04 (1H, d, J = 2.2 Hz), 8.14 (1H, dd, J = 8.9 Hz,





2.7 Hz), 8.30 (1H, d, J = 2.7 Hz), 8.41 (1H, brs).


2327
3,4-Cl2Ph-
4-CH3PhCH2—
2.34 (3H, s), 2.45 (4H, brs), 3.51 (2H, s), 3.73 (4H,





brs), 6.93 (1H, d, J = 8.7 Hz), 7.07-7.22 (6H, m),





7.35-7.38 (2H, m), 7.54 (1H, d, J = 8.4 Hz),





7.77 (1H, dd, J = 8.4 Hz, 2.2 Hz), 8.05 (1H, d, J =





2.2 Hz), 8.12 (1H, dd, J = 8.9 Hz, 2.7 Hz),





8.30 (1H, d, J = 2.7 Hz), 8.82 (1H, s).


2328
3,4-Cl2Ph-
3,4-F2PhCH2—
2.45 (4H, brs), 3.49-3.73 (6H, m), 6.96 (1H, d, J =





8.7 Hz), 7.01-7.23 (5H, m), 7.39-7.42 (2H, m),





7.56 (1H, d, J = 8.4 Hz), 7.76 (1H, dd, J = 8.4 Hz,





2.1 Hz), 8.03 (1H, d, J = 2.1 Hz), 8.17 (1H, dd, J =





8.7 Hz, 2.7 Hz), 8.30 (1H, d, J = 2.7 Hz),





8.50 (1H, s).


2329
3,4-Cl2Ph-
4-CH3OPhCH2—
2.43 (4H, brs), 3.48 (2H, s), 3.73 (4H, brs),





3.81 (3H, s), 6.85-6.93 (3H, m), 7.06-7.10 (2H, m),





7.21-7.24 (2H, m) 7.34-7.37 (2H, m), 7.53 (1H, d,





J = 8.4 Hz), 7.77 (1H, dd, J = 8.4 Hz, 2.1 Hz),





8.05 (1H, d, J = 2.1 Hz), 8.10 (1H, dd, J = 8.9 Hz,





2.7 Hz), 8.30 (1H, d, J = 2.7 Hz), 8.90 (1H, s).


2330
4-CF3Ph-
4-CF3PhCH2—
2.48 (4H, brs), 3.60 (2H, s), 3.70 (4H, brs),





7.00 (1H, d, J = 8.9 Hz), 7.12-7.17 (2H, m), 7.41-





7.48 (4H, m), 7.60 (2H, d, J = 7.9 Hz), 7.77 (2H,





d, J = 8.1 Hz), 8.02 (2H, d, J = 8.1 Hz), 8.14 (1H,





brs), 8.19-8.24 (1H, m), 8.32 (1H, d, J = 2.3 Hz).


2331
4-CF3Ph-
3,4-(CH3)2PhCH2—
2.25 (3H, s), 2.26 (3H, s), 2.45 (4H, brs), 3.47 (2H,





s), 3.40-3.90 (4H, m), 6.98 (1H, d, J = 8.7 Hz),





6.97-7.10 (3H, m), 7.13 (2H, d, J = 8.7 Hz),





7.42 (2H, d, J = 8.7 Hz), 7.76 (2H, d, J = 8.1 Hz),





8.02 (2H, d, J = 8.1 Hz), 8.18 (1H, brs), 8.20 (1H,





dd, J = 8.7 Hz, 2.5 Hz), 8.31 (1H, d, J = 2.5 Hz).


2332
4-CF3Ph-
3-CH3PhCH2—
2.35 (3H, s), 2.46 (4H, brs), 3.35-3.90 (4H, m),





3.50 (2H, s), 6.98 (1H, d, J = 8.9 Hz), 7.12 (2H, d,





J = 8.6 Hz), 7.05-7.30 (4H, m), 7.41 (2H, d, J =





8.6 Hz), 7.76 (2H, d, J = 8.1 Hz), 8.02 (2H, d, J =





8.1 Hz), 8.19 (1H, dd, J = 8.9 Hz, 2.6 Hz),





8.28 (1H, brs), 8.31 (1H, d, J = 2.6 Hz).


2333
4-CF3Ph-
4-CH3PhCH2—
2.34 (3H, s), 2.44 (4H, brs), 3.50 (2H, s), 3.35-





3.85 (4H, m), 6.97 (1H, d, J = 8.9 Hz), 7.12 (2H,





d, J = 8.8 Hz), 7.12 (2H, d, J = 8.1 Hz), 7.20 (2H,





d, J = 8.1 Hz), 7.40 (2H, d, J = 8.8 Hz), 7.75 (2H,





d, J = 8.1 Hz), 8.02 (2H, d, J = 8.1 Hz), 8.18 (1H,





dd, J = 8.9 Hz, 2.5 Hz), 8.32 (1H, d, J = 2.5 Hz),





8.38 (1H, s).
















TABLE 373













 










Example





No.
R1069
R1070
1H NMR (CDCl3) δppm





2334
3,4-Cl2Ph-
3-CH3OPhCH2—
2.47 (4H, brs), 3.46-3.82 (6H, m), 3.86 (3H, s),





6.80-6.84 (1H, m), 6.88-6.92 (2H, m) 6.95 (1H, d,





J = 8.8 Hz), 7.10-7.13 (2H, m), 7.23 (1H, d, J = 8.1





Hz), 7.38-7.41 (2H, m), 7.56 (1H, d, J = 8.3 Hz),





7.73-7.77 (1H, m), 8.04 (1H, d, J = 2.1 Hz), 8.12-





8.16 (1H, m), 8.29 (1H, d, J = 2.7 Hz), 8.44 (1H,





brs).


2335
3,4-Cl2Ph-
2-quinolylmethyl
2.58 (4H, brs), 3.58-3.76 (4H, m), 3.88 (2H, s),





6.94 (1H, d, J = 8.8 Hz), 7.11 (2H, d, J = 8.4 Hz),





7.40 (2H, d, J = 8.6 Hz), 7.51-7.57 (2H, m),





7.62 (1H, d, J = 8.4 Hz), 7.68-7.84 (3H, m),





8.04 (1H, d, J = 2.1 Hz), 8.07 (1H, d, J = 8.6 Hz),





8.12-8.17 (2H, m), 8.29 (1H, d, J = 2.5 Hz),





8.65 (1H, brs).


2336
3,4-Cl2Ph-
4-CF3PhCH2—
2.47 (4H, brs), 3.44-3.85 (6H, m), 6.98 (1H, d, J =





8.9 Hz), 7.11-7.16 (2H, m), 7.39-7.48 (4H, m),





7.56-7.61 (3H, m), 7.75 (1H, dd, J = 8.4 Hz, 2.1





Hz), 8.02 (1H, d, J = 2.1 Hz), 8.14-8.18 (1H, m),





8.24 (1H, brs), 8.30 (1H, d, J = 2.6 Hz).


2337
3,4-Cl2Ph-
4-CF3OPhCH2—
2.46 (4H, brs), 3.46-3.84 (6H, m), 6.96 (1H, d, J =





8.9 Hz), 7.10-7.20 (4H, m), 7.34-7.41 (4H, m),





7.56 (1H, d, J = 8.4 Hz), 7.76 (1H, dd, J = 8.4 Hz,





2.1 Hz), 8.03 (1H, d, J = 2.1 Hz), 8.11-8.16 (1H,





m), 8.30 (1H, d, J = 2.5 Hz), 8.49 (1H, brs).


2338
3,4-Cl2Ph-
PhO(CH2)2—
2.60 (4H, brs), 2.85 (2H, t, J = 5.4 Hz), 3.53-





3.75 (4H, m), 4.12 (2H, t, J = 5.4 Hz), 6.88-





6.99 (4H, m), 7.06-7.13 (2H, m), 7.25-7.37 (4H, m),





7.51 (1H, d, J = 8.4 Hz), 7.77 (1H, dd, J = 8.4 Hz,





2.1 Hz), 8.05 (1H, d, J = 2.1 Hz), 8.07-8.12 (1H,





m), 8.32 (1H, d, J = 2.6 Hz), 9.10 (1H, brs).


2339
4-CF3Ph-
4-CNPhCH2—
2.45 (4H, brs), 3.58 (2H, s), 3.63 (4H, brs),





6.98 (1H, d, J = 8.8 Hz), 7.13 (2H, d, J = 8.7 Hz),





7.41 (2H, d, J = 8.7 Hz), 7.46 (2H, d, J = 8.1 Hz),





7.62 (2H, d, J = 8.1 Hz), 7.75 (2H, d, J = 8.1 Hz),





8.01 (2H, d, J = 8.1 Hz), 8.20 (1H, dd, J = 8.8 Hz,





2.6 Hz), 8.28 (1H, brs), 8.33 (1H, d, J = 2.6 Hz).


2340
4-CF3Ph-
3,4-F2PhCH2—
2.44 (4H, brs), 3.48 (2H, s), 3.64 (4H, brs),





6.98 (1H, d, J = 8.9 Hz), 6.97-7.25 (3H, m),





7.12 (2H, d, J = 8.7 Hz), 7.41 (2H, d, J = 8.7 Hz),





7.75 (2H, d, J = 8.0 Hz), 8.01 (2H, d, J = 8.0 Hz),





8.19 (1H, dd, J = 8.9 Hz, 2.3 Hz), 8.30 (1H, brs),





8.32 (1H, d, J = 2.3 Hz).


2341
4-CF3Ph-
4-CH3OPhCH2—
2.43 (4H, brs), 3.48 (2H, s), 3.60 (4H, brs),





3.80 (3H, s), 6.86 (2H, d, J = 8.7 Hz), 6.96 (1H, d,





J = 8.7 Hz), 7.11 (2H, d, J = 8.7 Hz), 7.22 (2H, d,





J = 8.7 Hz), 7.38 (2H, d, J = 8.7 Hz), 7.74 (2H, d,





J = 8.1 Hz), 8.02 (2H, d, J = 8.1 Hz), 8.17 (1H, dd,





J = 8.7 Hz, 2.4 Hz), 8.32 (1H, d, J = 2.4 Hz),





8.52 (1H, s).
















TABLE 374













 










Example


mp (° C.) or


No.
R1071
R1072
1H NMR (CDCl3) δppm





2342
3,4-(CH3)2Ph-
4-CNPhCH2—
1H NMR 2.33 (6H, s), 2.45 (4H, brs), 3.58 (2H,





s), 3.64 (4H, brs), 6.97 (1H, d, J = 8.7 Hz),





7.11-7.16 (2H, m), 7.24 (1H, d, J = 7.6 Hz),





7.41-7.47 (4H, m), 7.58-7.67 (4H, m), 7.94





(1H, brs), 8.24 (1H, dd, J = 8.7 Hz, 2.7 Hz),





8.31 (1H, d, J = 2.7 Hz).


2343
3,4-(CH3)2Ph-
3,4-F2PhCH2—
1H NMR 2.34 (6H, s), 2.45 (4H, brs), 3.48 (2H,





s), 3.65 (4H, brs), 6.98 (1H, d, J = 8.9 Hz),





7.03-7.23 (6H, m), 7.41-7.46 (2H, m), 7.59-





7.62 (1H, m), 7.67 (1H, d, J = 1.8 Hz), 7.95





(1H, brs), 8.26 (1H, dd, J = 8.9 Hz, 2.7 Hz),





8.31 (1H, d, J = 2.7 Hz).


2344
4-CF3Ph-
3-CH3OPhCH2—
mp 118-120


2345
4-CF3Ph-
2-quinolylmethyl
1H NMR 2.56 (4H, brs), 3.43-3.81 (4H, m),





3.87 (2H, s), 6.94 (1H, d, J = 8.9 Hz), 7.08-





7.13 (2H, m), 7.35-7.40 (2H, m), 7.51-7.57 (1H,





m), 7.61 (1H, d, J = 8.4 Hz), 7.68-7.74 (3H,





m), 7.81-7.84 (1H, m), 8.01-8.20 (5H, m),





8.33 (1H, d, J = 2.7 Hz), 8.94 (1H, s).


2346
4-CF3Ph-
PhO(CH2)2—
mp 161-162


 


2347
4-CF3Ph-




1H NMR 2.48 (4H, brs), 3.55 (2H, brs), 3.66 (2H, s), 3.75 (2H, brs), 6.97 (1H, d, J = 8.7 Hz), 7.12 (2H, d, J = 8.4 Hz), 7.32- 7.43 (1H, m), 7.41 (2H, d, J = 8.4 Hz), 7.55 (1H, d, J = 8.4 Hz), 7.70-7.80 (1H, m), 7.75 (2H, d, J = 8.1 Hz), 8.02 (2H, d, J = 8.1 Hz), 8.10 (1H, s), 8.20 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.32 (1H, d, J = 2.6 Hz), 8.41 (1H, s).
















TABLE 375













 










Example





No.
R1073
R1074
1H NMR (CDCl3) δppm





2348
3,4-Cl2Ph-
2,6-F2PhCH2—
2.42 (4H, brs), 2.54-2.60 (2H, m), 2.83-2.88 (2H,





m), 3.38-3.42 (2H, m), 3.55-3.58 (2H, m),





3.69 (2H, s), 6.85-6.98 (5H, m), 7.12 (2H, d, J =





8.6 Hz), 7.19-7.31 (1H, m), 7.48 (1H, d, J = 8.4





Hz), 7.74 (1H, dd, J = 8.4 Hz, 2.1 Hz), 7.99 (1H,





d, J = 2.1 Hz), 8.14-8.18 (1H, m), 8.30 (1H, d, J =





2.8 Hz), 9.19 (1H, brs).


2349
3,4-Cl2Ph-
4-CF3PhCH2—
2.33-2.41 (4H, m), 2.59-2.65 (2H, m), 2.92-





2.97 (2H, m), 3.40-3.44 (2H, m), 3.55 (2H, s),





3.61-3.64 (2H, m), 6.93 (1H, d, J = 8.8 Hz),





7.02-7.06 (2H, m), 7.20 (2H, d, J = 8.6 Hz),





7.44 (2H, d, J = 8.4 Hz), 7.54-7.60 (3H, m),





7.74 (1H, dd, J = 8.4 Hz, 2.2 Hz), 8.01 (1H, d, J =





2.2 Hz), 8.17-8.21 (1H, m), 8.28 (1H, d, J =





2.6 Hz), 8.44 (1H, brs).


 


2350
4-CF3Ph-




2.28 (2H, t, J = 4.9 Hz), 2.43 (2H, t, J = 4.9 Hz), 2.61 (2H, t, J = 7.5 Hz), 2.96 (2H, t, J = 7.5 Hz), 3.30 (2H, t, J = 4.9 Hz), 3.59 (2H, s), 3.63 (2H, t, J = 4.9 Hz), 6.96 (1H, d, J = 8.3 Hz), 7.04 (2H, d, J = 8.5 Hz), 7.21 (2H, d, J = 8.5 Hz), 7.36 (1H, dd, J = 8.5 Hz, 1.5 Hz), 7.53 (1H, d, J = 8.4 Hz), 7.73 (1H, brs), 7.75 (2H, d, J = 8.3 Hz), 8.01 (1H, s), 8.02 (2H, d, J = 8.3 Hz), 8.25 (1H, s), 8.27 (1H, dd, J = 8.3 Hz, 2.6 Hz), 8.58 (1H, s).


 


2351
3,4-Cl2Ph-
3,4-F2PhCH2—
2.31-2.40 (4H, m), 2.60-2.65 (2H, m), 2.93-





2.99 (2H, m), 3.39-3.45 (4H, m), 3.61-3.65 (2H,





m), 6.95 (1H, d, J = 8.8 Hz), 7.03-7.24 (7H, m),





7.57 (1H, d, J = 8.3 Hz), 7.73 (1H, dd, J = 8.4





Hz, 2.1 Hz), 8.00 (1H, d, J = 2.1 Hz), 8.10 (1H,





brs), 8.16-8.20 (1H, m), 8.26 (1H, d, J = 2.3





Hz).


2352
3,4-Cl2Ph-
3,5-F2PhCH2—
2.32-2.38 (4H, m), 2.58-2.64 (2H, m), 2.89-





2.94 (2H, m), 3.40-3.46 (4H, m), 3.59-3.62 (2H,





m), 6.66-6.74 (1H, m), 6.85-7.03 (5H, m),





7.17 (2H, d, J = 8.6 Hz), 7.52 (1H, d, J = 8.2





Hz), 7.71-7.75 (1H, m), 7.99 (1H, d, J = 2.0 Hz),





8.16-8.20 (1H, m), 8.28 (1H, d, J = 2.6 Hz),





8.77 (1H, brs).
















TABLE 376













 











Example






No.
R1075
Xb54
R1076
1H NMR (CDCl3) δppm





2353
3,4-Cl2Ph-
—CO—
—CH3
3.03 (2H, t, J = 5.2 Hz), 3.39 (2H, s), 3.51 (2H, s),






3.76 (2H, t, J = 5.2 Hz), 3.77 (3H, s), 6.98 (1H, d, J =






8.9 Hz), 7.15 (2H, dd, J = 8.8 Hz, 2.1 Hz),






7.30 (2H, dd, J = 8.8 Hz, 2.1 Hz), 7.59 (1H, d, J =






8.4 Hz), 7.72 (1H, dd, J = 8.4 Hz, 2.1 Hz),






7.99 (1H, d, J = 2.1 Hz), 8.15 (1H, dd, J = 8.9 Hz,






2.7 Hz), 8.29 (1H, d, J = 2.7 Hz).


2354
3,4-Cl2Ph-
—CH2—
—CH3
2.75 (4H, t, J = 5.0 Hz), 3.23 (4H, t, J = 5.0 Hz),






3.30 (2H, s), 3.75 (3H, s), 6.90 (1H, d, J = 9.0 Hz),






6.95 (2H, d, J = 9.0 Hz), 7.04 (2H, d, J = 9.0 Hz),






7.58 (1H, d, J = 8.5 Hz), 7.70 (1H, dd, J = 8.5 Hz,






2.0 Hz), 7.76 (1H, brs), 7.98 (1H, d, J = 2.0 Hz),






8.15 (1H, dd, J = 9.0 Hz, 3.0 Hz), 8.23 (1H, d, J =






3.0 Hz).


2355
3,4-Cl2Ph-
—CH2—
—C2H5
1.31 (3H, t, J = 7.0 Hz), 2.75 (4H, t, J = 5.0 Hz),






3.23 (4H, t, J = 5.0 Hz), 3.28 (2H, s), 4.21 (2H, q, J =






7.0 Hz), 6.90 (1H, d, J = 9.0 Hz), 6.95 (2H, d, J =






9.0 Hz), 7.04 (2H, d, J = 9.0 Hz), 7.57 (1H, d, J =






8.5 Hz), 7.71 (1H, dd, J = 8.5 Hz, 2.0 Hz),






7.88 (1H, brs), 7.98 (1H, d, J = 2.0 Hz), 8.15 (1H,






dd, J = 9.0 Hz, 2.5 Hz), 8.24 (1H, d, J = 2.5 Hz).


2356
4-CF3Ph-
—CH2—
—CH3
2.75 (4H, t, J = 5.0 Hz), 3.24 (4H, t, J = 5.0 Hz),






3.30 (2H, s), 3.75 (3H, s), 6.92 (1H, d, J = 9.0 Hz),






6.96 (2H, d, J = 9.0 Hz), 7.06 (2H, d, J = 9.0 Hz),






7.74 (1H, brs), 7.78 (2H, d, J = 8.0 Hz), 7.99 (2H, d,






J = 8.0 Hz), 8.19 (1H, dd, J = 9.0 Hz, 2.5 Hz), 8.25






(1H, d, J = 2.5 Hz).









Example 2357
Production of 3,4-dichloro-N-[6-(4-{4-[(3,4-difluorobenzyl)methylamino]piperidine-1-carbonyl}phenoxy)pyridin-3-yl]benzamide
3,4-dichloro-N-{6-[4-(4-methylamino-piperidine-1-carbonyl)phenoxy]pyridin-3-yl}benzamide dihydrochloride (114 mg, 0.2 mmol) was dissolved in DMF (3 mL). To the resulting solution were added 4-bromomethyl-1,2-difluorobenzene (31 μl, 0.24 mmol) and potassium carbonate (111 mg, 0.8 mmol), and this solution was stirred for 4 hours at room temperature. The resulting reaction solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. This residue was purified by silica gel column chromatography (chloroform:methanol=50:1), to thereby yield 60 mg of the title compound.
Appearance: White powder
1H NMR (CDCl3) δ 1.64 (4H, brs), 1.84 (2H, brs), 2.20 (3H, s), 2.65-2.90 (3H, m), 3.54 (2H, s), 6.95-7.08 (4H, m), 7.13 (2H, d, J=9.3 Hz), 7.41 (2H, d, J=9.2 Hz), 7.57 (1H, d, J=8.4 Hz), 7.75 (1H, dd, J=8.4 Hz, 2.0 Hz), 8.03 (1H, d, J=2.0 Hz), 8.15 (1H, dd, J=8.9 Hz, 2.8 Hz), 8.30 (1H, brs), 8.31 (1H, d, J=2.2 Hz).
The following compounds were produced in the same manner as in Example 2357.







TABLE 377













 









Example




No.
R1077
1H NMR (CDCl3) δppm





2358
2,4-F2Ph-
1.66 (4H, brs), 1.91 (2H, brs), 2.25 (3H, s), 2.73-3.08 (3H, m),




3.63 (2H, s), 6.75-6.89 (3H, m), 6.97 (1H, d, J = 8.7 Hz), 7.13 (2H,




d, J = 9.2 Hz), 7.42 (2H, d, J = 9.2 Hz), 7.57 (1H, d, J = 8.3 Hz),




7.76 (1H, dd, J = 8.3 Hz, 2.1 Hz), 8.04 (1H, d, J = 2.1 Hz),




8.16 (1H, dd, J = 8.9 Hz, 2.8 Hz), 8.31 (1H, d, J = 2.3 Hz), 8.37




(1H, brs).


2359
2,5-F2Ph-
1.72 (4H, brs), 1.88 (2H, brs), 2.25 (3H, s), 2.67-2.96 (3H, m),




3.62 (2H, s), 6.85-7.02 (3H, m), 7.09-7.23 (3H, m), 7.39 (2H, d, J =




8.9 Hz), 7.55 (1H, d, J = 8.3 Hz), 7.77 (1H, dd, J = 8.4 Hz, 2.1




Hz), 8.05 (1H, d, J = 2.1 Hz), 8.12 (1H, dd, J = 8.9 Hz, 2.8 Hz),




8.31 (1H, d, J = 2.6 Hz), 8.66 (1H, brs).


2360
4-CH(CH3)2Ph-
1.25 (6H, d, J = 6.9 Hz), 1.57-2.21 (7H, m), 2.66-3.07 (4H, m),




3.56 (2H, s), 3.90 (1H, brs), 4.66 (1H, brs), 6.90 (1H, d, J = 8.9




Hz), 7.04-7.10 (2H, m), 7.16-7.25 (4H, m), 7.31-7.36 (2H, m),




7.50 (1H, d, J = 8.4 Hz), 7.77 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.06-




8.10 (2H, m), 8.33 (1H, d, J = 2.5 Hz), 9.37 (1H, s).


2361
4-C(CH3)3Ph-
1.32 (9H, s), 1.58 (2H, brs), 1.89 (2H, brs), 2.22 (3H, s), 2.62-




3.10 (3H, m), 3.57 (2H, s), 3.92 (1H, brs), 4.69 (1H, brs),




6.92 (1H, d, J = 8.6 Hz), 7.06-7.11 (2H, m), 7.22-7.25 (2H, m),




7.32-7.37 (4H, m), 7.53 (1H, d, J = 8.6 Hz), 7.78 (1H, dd, J = 8.4




Hz, 2.2 Hz), 8.07 (1H, d, J = 2.2 Hz), 8.11 (1H, d, J = 2.7 Hz),




8.32 (1H, d, J = 2.7 Hz), 9.07 (1H, brs).
















TABLE 378













 









Example




No.
R1078
1H NMR (CDCl3) δppm





2362
4-CNPh-
1.54 (1H, brs), 1.86 (3H, brs), 2.20 (3H, s), 2.64-3.04 (3H, m), 3.64 (2H,




s), 3.91 (1H, brs), 4.69 (1H, brs), 6.91 (1H, d, J = 8.9 Hz), 7.05-7.10 (2H,




m), 7.32-7.37 (2H, m), 7.45 (2H, d, J = 8.4 Hz), 7.50 (1H, d, J = 8.4 Hz),




7.59-7.62 (2H, m), 7.75-7.79 (1H, m), 8.05 (1H, d, J = 2.0 Hz), 8.10 (1H,




dd, J = 8.9 Hz, 2.7 Hz), 8.35 (1H, d, J = 2.7 Hz), 9.31 (1H, brs).


2363
Ph-
1.55 (2H, brs), 1.87 (2H, brs), 2.22 (3H, s), 2.61-2.80 (2H, m), 2.90 (1H,




brs), 3.60 (2H, s), 3.93 (1H, brs), 4.72 (1H, brs), 6.98 (1H, d, J = 8.9 Hz),




7.14 (2H, d, J = 8.7 Hz), 7.18-7.37 (5H, m), 7.43 (2H, d, J = 8.7 Hz),




7.58 (1H, d, J = 8.4 Hz), 7.75 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.02 (1H, d, J =




2.0 Hz), 8.16 (1H, dd, J = 8.9 Hz, 2.4 Hz), 8.19 (1H, brs), 8.30 (1H, d,




J = 2.4 Hz).


2364
2-ClPh-
1.50 (2H, brs), 1.90 (2H, brs), 2.26 (3H, s), 2.68-2.85 (2H, m), 2.98 (1H,




brs), 3.70 (2H, s), 3.95 (1H, brs), 4.75 (1H brs), 6.98 (1H, d, J = 8.7 Hz),




7.14 (2H, d, J = 8.5 Hz), 7.15-7.30 (2H, m), 7.34 (1H, dd, J = 7.2 Hz, 2.0




Hz), 7.43 (2H, d, J = 8.5 Hz), 7.47 (1H, dd, J = 7.2 Hz, 2.0 Hz),




7.58 (1H, d, J = 8.4 Hz), 7.75 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.04 (1H, d, J =




2.0 Hz), 8.16 (1H, dd, J = 8.7 Hz, 2.8 Hz), 8.31 (1H, d, J = 2.8 Hz),




8.32 (1H, brs).


2365
3-ClPh-
1.50 (2H, brs), 1.87 (2H, brs), 2.21 (3H, s), 2.55-3.20 (3H, m), 3.57 (2H,




s), 3.95 (1H, brs), 4.70 (1H, brs), 6.99 (1H, d, J = 8.8 Hz), 7.14 (2H, d, J =




8.7 Hz), 7.15-7.28 (3H, m), 7.33 (1H, brs), 7.44 (2H, d, J = 8.7 Hz),




7.59 (1H, d, J = 8.4 Hz), 7.74 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8 02 (1H, d, J =




2.0 Hz), 8.09 (1H, brs), 8.17 (1H, dd, J = 8.8 Hz, 2.8 Hz), 8.30 (1H, d,




J = 2.8 Hz).


2366
3,4-Cl2Ph-
1.50 (2H, brs), 1.85 (2H, brs), 2.20 (3H, s), 2.60-3.15 (3H, m), 3.54 (2H,




s), 3.95 (1H, brs), 4.70 (1H, brs), 6.97 (1H, d, J = 8.9 Hz), 7.13 (2H, d, J =




8.6 Hz), 7.10-7.19 (1H, m), 7.36 (1H, s), 7.41 (2H, d, J = 8.6 Hz), 7.35-




7.47 (1H, m), 7.57 (1H, d, J = 8.4 Hz), 7.75 (1H, dd, J = 8.4 Hz, 2.1 Hz),




8.03 (1H, d, J = 2.1 Hz), 8.14 (1H, dd, J = 8.9 Hz, 2.5 Hz), 8.30 (1H, d, J =




2.5 Hz), 8.40 (1H, s).


2367
2,3-Cl2Ph-
1.60 (2H, brs), 1.90 (2H, brs), 2.26 (3H, s), 2.65-3.20 (3H, m), 3.72 (2H,




s), 3.90 (1H, brs), 4.72 (1H, brs), 6.97 (1H, d, J = 8.8 Hz), 7.13 (2H, d, J =




8.6 Hz), 7.20 (1H, d, J = 8.0 Hz), 7.36 (1H, dd, J = 8.0 Hz, 1.5 Hz),




7.42 (2H, d, J = 8.6 Hz), 7.37-7.46 (1H, m), 7.57 (1H, d, J = 8.2 Hz),




7.75 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.04 (1H, d, J = 2.0 Hz), 8.14 (1H, dd,




J = 8.8 Hz, 2.7 Hz), 8.30 (1H, d, J = 2.7 Hz), 8.38 (1H, brs).


2368
2-FPh-
1.55 (2H, brs), 1.85 (2H, brs), 2.25 (3H, s), 2.50-3.20 (3H, m), 3.65 (2H,




s), 3.95 (1H, brs), 4.70 (1H, brs), 6.97 (1H, d, J = 8.8 Hz), 6.95-7.17 (2H,




m), 7.13 (2H, d, J = 8.7 Hz), 7.18-7.29 (1H, m), 7.32-7.45 (1H, m),




7.42 (2H, d, J = 8.7 Hz), 7.57 (1H, d, J = 8 2 Hz), 7.75 (1H, dd, J = 8.2




Hz, 2.1 Hz), 8.04 (1H, d, J = 2.1 Hz), 8.14 (1H, dd, J = 8.8 Hz, 2.5 Hz),




8.30 (1H, d, J = 2.5 Hz), 8.34 (1H, brs).


2369
2-CH3Ph-
1.67 (4H, brs), 1.89 (2H, brs), 2.19 (3H, s), 2.36 (3H, s), 2.67-2.96 (3H,




m), 3.57 (2H, s), 6.96 (1H, d, J = 8.7 Hz), 7.07-7.26 (6H, m), 7.41 (2H, d,




J = 8.1 Hz), 7.57 (1H, d, J = 8.4 Hz), 7.77 (1H, dd, J = 8.4 Hz, 2.0 Hz),




8.05 (1H, d, J = 2.0 Hz), 8.14 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.31 (1H, d, J =




2.6 Hz), 8.51 (1H brs).
















TABLE 379













 










Example





No.
R1079
Form
1H NMR (solvent) δppm





2370
3,5-(CH3O)2Ph-
hydro-
(DMSO-d6) 1.67-1.93 (2H, m), 2.08-2.30 (2H, m),




chloride
2.61 (3H, d, J = 4.8 Hz), 2.95 (1H, brs), 3.31-3.75 (4H,





m), 3.77 (6H, s), 4.02-4.18 (1H, m), 4.31-4.45 (1H, m),





6.57 (1H, t, J = 2.0 Hz), 6.83 (2H, d, J = 2.0 Hz),





7.16 (1H, d, J = 8.7 Hz), 7.20 (2H, d, J = 8.6 Hz),





7.49 (2H, d, J = 8.6 Hz), 7.85 (1H, d, J = 8.4 Hz),





7.97 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.24 (1H, d, J = 2.1





Hz), 8.24 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.55 (1H, d, J =





2.6 Hz), 10.64 (1H, brs).


2371
3-CH3OPh-
free
(CDCl3) 1.60 (2H, brs), 1.87 (2H, brs), 2.23 (3H, s), 2.52-





3.20 (3H, m), 3.58 (2H, s), 3.81 (3H, s), 3.95 (1H, brs),





4.70 (1H, brs), 6.75-6.90 (3H, m), 6.97 (1H, d, J = 8.9





Hz), 7.13 (2H, d, J = 8.6 Hz), 7.21 (1H, d, J = 8.0 Hz),





7.41 (2H, d, J = 8.6 Hz), 7.57 (1H, d, J = 8.4 Hz),





7.75 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.04 (1H, d, J = 2.0





Hz), 8.14 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.30 (1H, d, J =





2.6 Hz), 8.36 (1H, brs).


2372
3-CH3Ph-
free
(CDCl3) 1.61 (4H, brs), 1.88 (2H, brs), 2.22 (3H, s),





2.35 (3H, s), 2.68-3.01 (3H, m), 3.56 (2H, s), 6.98 (1H, d,





J = 8.9 Hz), 7.06-7.29 (6H, m), 7.42 (2H, d, J = 8.6 Hz),





7.58 (1H, d, J = 8.2 Hz), 7.76 (1H, dd, J = 8.3 Hz, 2.0





Hz), 8.04 (1H, d, J = 2.0 Hz), 8.16 (1H, dd, J = 8.9 Hz,





2.6 Hz), 8.31 (1H, d, J = 2.3 Hz), 8.38 (1H, brs).


2373
3,5-F2Ph-
free
(CDCl3) 1.42-1.96 (4H, m), 2.21 (3H, s), 2.65-3.10 (3H,





m), 3.56 (2H, s), 3.90 (1H, brs), 4.68 (1H, brs), 6.64-





6.70 (1H, m), 6.85-6.92 (3H, m), 7.04-7.09 (2H, m), 7.31-





7.36 (2H, m), 7.50 (1H, d, J = 8.4 Hz), 7.74-7.79 (1H,





m), 8.05-8.10 (2H, m), 8.33 (1H, d, J = 2.5 Hz), 9.30





(1H, brs).


2374
3,4-(CH3)2Ph-
free
(CDCl3) 1.59 (4H, brs), 1.90-1.98 (2H, m), 2.22 (3H, s),





2.25 (3H, s), 2.26 (3H, s), 2.67-2.97 (3H, m), 3.59 (2H, s),





6.99 (1H, d, J = 8.7 Hz), 7.05-7.10 (3H, m), 7.15 (2H, d,





J = 9.4 Hz), 7.44 (2H, d, J = 9.4 Hz), 7.59 (1H, d, J =





8.3 Hz), 7.74 (1H, dd, J = 8.3 Hz, 2.2 Hz), 8.02 (1H, d, J =





2.0 Hz), 8.03 (1H, brs), 8.18 (1H, dd, J = 8.7 Hz, 2.8





Hz), 8.31 (1H, d, J = 2.8 Hz).


2375
3-FPh-
free
(CDCl3) 1.59-1.85 (6H, m), 2.22 (3H, s), 2.67-2.99 (3H,





m), 3.59 (2H, s), 6.94-6.97 (2H, m), 7.05-7.13 (5H, m),





7.39 (2H, d, J = 8.4 Hz), 7.56 (1H, d, J = 8.4 Hz),





7.77 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.05 (1H, d, J = 2.0





Hz), 8.13 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.31 (1H, d, J =





2.5 Hz), 8.63 (1H, brs).


2376
2,6-F2Ph-
free
(CDCl3) 1.65 (4H, brs), 1.81-1.91 (2H, m), 2.28 (3H, s),





2.69-3.03 (3H, m), 3.69 (2H, s), 6.83-6.92 (3H, m),





6.99 (1H, d, J = 8.9 Hz), 7.15 (2H, d, J = 9.2 Hz),





7.44 (2H, d, J = 9.2 Hz), 7.59 (1H, d, J = 8.4 Hz),





7.75 (1H, dd, J = 8.4 Hz, 2.2 Hz), 8.03 (1H, d, J = 2.2





Hz), 8.17 (1H, brs), 8.18 (1H, dd, J = 8.7 Hz, 2.8 Hz),





8.31 (1H, d, J = 2.6 Hz).
















TABLE 380













 









Example




No.
R1080
mp (° C.) or MS





2377
4-CF3OPh-
mp 180-181


2378
2-NO2Ph-
MS 634 (M+ + H)


2379
3-NO2Ph-
MS 634 (M+ + H)


2380
4-NO2Ph-
MS 634 (M+ + H)


2381
2-CF3Ph-
MS 657 (M+ + H)


2382
3-CF3Ph-
MS 657 (M+ + H)


2383
4-CF3Ph-
MS 657 (M+ + H)


2384
2-CF3OPh-
MS 673 (M+ + H)


 


2385




MS 647 (M+ + H)


 


2386
4-biphenylyl
MS 665 (M+ + H)


 


2387




MS 647 (M+ + H)


 


2388




MS 699 (M+ + H)


 


2389
2-pyridyl
MS 590 (M+ + H)


2390
2-quinolyl
MS 640 (M+ + H)


 


2391




MS 671 (M+ + H)


 


2392




MS 609 (M+ + H)


 


2393
2,4-Cl2Ph-
MS 657 (M+ + H)


2394
2,5-Cl2Ph-
MS 657 (M+ + H)


2395
2,6-Cl2Ph-
MS 657 (M+ + H)
















TABLE 381













 












Example







No.
R1081
Xb55
Xb56
R1082
mp (° C.) or MS





2396
—H
none
none
Ph-
mp 155-158


2397
—F
—(CH2)2—
—CO—
Ph-
MS 634 (M+ + H)


2398
—F
—(CH2)2—
—CO—
2-ClPh-
MS 668 (M+ + 1)


2399
—F
—(CH2)2—
—CO—
3-ClPh-
MS 668 (M+ + H)


2400
—F
—(CH2)2—
—CO—
4-ClPh-
MS 668 (M+ + H)


2401
—F
—(CH2)2—
—CO—
2,3-Cl2Ph-
MS 702 (M+ + 1)


2402
—F
—(CH2)2—
—CO—
2,4-Cl2Ph-
MS 701 (M+)


2403
—F
—(CH2)2—
—CO—
2,5-Cl2Ph-
MS 702 (M+ + 1)


2404
—F
—(CH2)2—
—CO—
2,6-Cl2Ph-
MS 702 (M+ + H)


2405
—F
—(CH2)2—
—CO—
3,4-Cl2Ph-
MS 703 (M+)


2406
—F
—(CH2)2—
—CO—
3-pyridyl
MS 634 (M+)


2407
—F
—(CH2)2—
—CO—
2-quinolyl
MS 685 (M+ + H)


 


2408
—F
—(CH2)2—
—CO—




MS 716 (M+ + H)


 


2409
—F
—(CH2)2—
—CO—




MS 654 (M+ + H)


 


2410
—F
—(CH2)2—
—CO—




MS 730 (M+ + H)


 


2411
—F
—(CH2)2—
—CO—
3-CH3OPh-
MS 662 (M+ − 1)


2412
—F
—(CH2)2—
—CO—
3,5-(CH3O)2Ph-
MS 693 (M+)


2413
—F
—(CH2)2—
—CO—
2-CH3Ph-
MS 648 (M+ + H)


2414
—F
—(CH2)2—
—CO—
3-CH3Ph-
MS 648 (M+ + H)


2415
—F
—(CH2)2—
—CO—
4-CH3Ph-
MS 648 (M+ + H)


2416
—F
—(CH2)2—
—CO—
3,4-(CH3)2Ph-
MS 662 (M+ + 1)


2417
—F
—(CH2)2—
—CO—
2-FPh-
MS 652 (M+ + H)


2418
—F
—(CH2)2—
—CO—
3-FPh-
MS 652 (M+ + H)


2419
—F
—(CH2)2—
—CO—
4-FPh-
MS 652 (M+ + 1)


2420
—F
—(CH2)2—
—CO—
2,4-F2Ph-
MS 670 (M+ + H)


2421
—F
—(CH2)2—
—CO—
2,5-F2Ph-
MS 670 (M+ + H)


2422
—F
—(CH2)2—
—CO—
2,6-F2Ph-
MS 671 (M+ + 2)


2423
—F
—(CH2)2—
—CO—
3,4-F2Ph-
MS 670 (M+ + H)


2424
—F
—(CH2)2—
—CO—
3,5-F2Ph-
MS 670 (M+ + H)
















TABLE 382













 









Example




No.
R1083
MS





2425
2-NO2Ph-
679 (M+ + H)


2426
3-NO2Ph-
678 (M+)


2427
4-NO2Ph-
679 (M+ + H)


2428
2-CF3Ph-
701 (M+ )


2429
3-CF3Ph-
702 (M+ + H)


2430
4-CF3Ph-
701 (M+)


2431
4-CNPh-
659 (M+ + H)


2432
2-CF3OPh-
718 (M+ + H)


2433
3-CF3OPh-
718 (M+ + H)


2434
4-CF3OPh-
718 (M+ + H)


 


2435




692 (M+ + H)


 


2436
4-biphenylyl
710 (M+ + H)


 


2437




692 (M+ + H)


 


2438
4-C2H5Ph-
662 (M+ + H)


2439
4-CH(CH3)2Ph-
676 (M+ + H)


2440
4-C(CH3)3Ph-
690 (M+ + H)


 


2441




744 (M+ + H)


 


2442
2-naphthyl
684 (M+ + H)


2443
2-pyridyl
635 (M+ + H)









Example 2444
Production of 1-(4-piperonylpiperazin-1-yl)-2-{4-[5-(4-trifluoromethylphenoxymethyl)pyridin-2-yloxy]-phenylamino}ethanone
4-[5-(4-trifluoromethylphenoxymethyl)pyridin-2-yloxy]phenylamine (4.50 g, 12.5 mmol) was dissolved in DMF (150 mL). To the resulting solution were added potassium carbonate (2.60 g, 18.8 mmol) and sodium iodide (1.87 g, 12.5 mmol), and then to this solution was added 2-chloro-1-(4-piperonylpiperazin-1-yl)ethanone (4.21 g, 12.5 mmol). The resulting solution was stirred for 11 hours under a nitrogen atmosphere at 80° C. The resulting reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate and washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=80:1), to thereby yield 5.2 g of the title compound.
Appearance: White powder
1H NMR (CDCl3) δ 2.44-2.46 (4H, m), 3.43-3.47 (4H, m), 3.69 (2H, t, J=5.0 Hz), 3.86 (2H, s), 4.91 (1H, brs), 5.02 (2H, s), 5.94 (2H, s), 6.64 (2H, d, J=8.9 Hz), 6.74-6.75 (2H, m), 6.85-6.89 (2H, m), 6.96-7.03 (4H, m), 7.55 (2H, d, J=8.4 Hz), 7.72 (1H, dd, J=8.4 Hz, 2.5 Hz), 8.22 (1H, d, J=2.0 Hz).
Example 2445
Production of N-{6-[4-(4-thiazole-2-ylmethylpiperazine-1-carbonyl)phenoxy]pyridin-3-yl}-4-trifluoromethyl-benzamide
To a suspension of N-{6-[4-(piperazine-1-carbonyl)phenoxy]pyridin-3-yl}-4-trifluoromethyl-benzamide dihydrochloride (400 mg, 0.74 mmol) in 1,2-dichloroethane (20 mL) were added 2-formylthiazole (125 mg, 1.10 mmol) and triethylamine (0.21 mL, 1.50 mmol). After the resulting solution was stirred at room temperature for 30 minutes, sodium triacetyloxy borohydride (312 mg, 1.47 mmol) was added under ice cooling. The reaction mixture was stirred at the same temperature for 30 minutes and at room temperature for 1 hour. Acetic acid (0.085 mL, 1.48 mmol) was added to the reaction mixture, and stirred at room temperature for 17 hours. The reaction mixture was poured into ice water, and extracted with chloroform. The chloroform layer was washed with a saturated sodium bicarbonate solution and brine, and dried over anhydrous magnesium sulfate. A significant part of the solvent was evaporated. The white precipitate was then filtered off and washed with ethyl acetate, to thereby yield 293 mg of the title compound.
Appearance: White powder
1H NMR (DMSO-d6) δ 2.55 (4H, brs), 3.55 (4H, brs), 3.90 (2H, s), 7.15 (1H, d, J=8.7 Hz), 7.16 (2H, d, J=8.6 Hz), 7.45 (2H, d, J=8.6 Hz), 7.68 (1H, d, J=3.2 Hz), 7.73 (1H, d, J=3.2 Hz), 7.94 (2H, d, J=8.1 Hz), 8.17 (2H, d, J=8.1 Hz), 8.26 (1H, dd, J=8.7 Hz, 2.3 Hz), 8.55 (1H, d, J=2.3 Hz), 10.68 (1H, s).
The following compounds were produced in the same manner as in Example 2445.







TABLE 383













 










Example





No.
R1084
R1085
1H NMR (solvent) δppm





2446
3,4-Cl2Ph-
3,4-(CH3)2Ph-
(CDCl3) 2.27 (3H, s), 2.29 (3H, s), 2.42 (4H, brs),





3.49 (2H, s), 3.70 (4H, brs), 6.90 (1H, d, J = 8.9 Hz),





7.05-7.10 (5H, m), 7.34-7.36. (2H, m), 7.50 (1H, d, J =





8.4 Hz), 7.75-7.79 (1H, m), 8.00-8.14 (2H, m), 8.33 (1H,





d, J = 2.7 Hz), 9.30 (1H, brs).


2447
4-CF3Ph-
2-FPh-
(CDCl3) 2.50 (4H, brs), 3.55 (2H, brs), 3.70 (2H, brs),





3.62 (2H, s), 6.98 (1H, d, J = 8.8 Hz), 6.95-7.17 (2H, m),





7.12 (2H, d, J = 8.7 Hz), 7.20-7.41 (2H, m), 7.40 (2H, d,





J = 8.7 Hz), 7.76 (2H, d, J = 8.2 Hz), 8.02 (2H, d, J =





8.2 Hz), 8.19 (1H, dd, J = 8.8 Hz, 2.8 Hz), 8.31 (1H, s),





8.32 (1H, d, J = 2.8 Hz).


2448
4-CF3Ph-
3-pyridyl
(CDCl3) 2.46 (4H, brs), 3.55 (2H, s), 3.58-3.73 (4H, m),





6.97 (1H, d, J = 8.7 Hz), 7.10-7.15 (2H, m), 7.25-





7.30 (1H, m), 7.38-7.43 (2H, m), 7.65-7.69 (1H, m),





7.74 (2H, d, J = 8.1 Hz), 8.03 (2H, d, J = 8.1 Hz), 8.19-





8.23 (1H, m), 8.32 (1H, d, J = 2.3 Hz), 8.51-8.53 (1H,





m), 8.54 (1H, d, J = 1.5 Hz), 8.62 (1H, brs).


2449
4-CF3Ph-
cyclohexyl
(DMSO-d6) 0.60-1.90 (11H, m), 2.10 (2H, d, J = 7.2





Hz), 2.34 (4H, brs), 3.50 (4H, brs), 7.15 (1H, d, J = 8.8





Hz), 7.16 (2H, d, J = 8.7 Hz), 7.43 (2H, d, J = 8.7 Hz),





7.94 (2H, d, J = 8.1 Hz), 8.17 (2H, d, J = 8.1 Hz),





8.26 (1H, dd, J = 8.8 Hz, 2.7 Hz), 8.55 (1H, d, J = 2.7





Hz), 10.66 (1H, s).


2450
4-CF3Ph-
3-furyl
(CDCl3) 2.46 (4H, brs), 3.42 (2H, s), 3.40-3.90 (4H, m),





6.39 (1H, brs), 6.98 (1H, d, J = 8.9 Hz), 7.13 (2H, d, J =





8.7 Hz), 7.34 (1H, brs), 7.33-7.42 (1H, m), 7.41 (2H, d, J =





8.7 Hz), 7.76 (2H, d, J = 8.1 Hz), 8.02 (2H, d, J = 8.1





Hz), 8.20 (1H, dd, J = 8.9 Hz, 2.5 Hz), 8.29 (1H, s),





8.32 (1H, d, J = 2.5 Hz).


2451
4-CF3Ph-
4-pyridyl
(CDCl3) 2.45 (4H, brs), 3.41-3.81 (6H, m), 6.95 (1H, d, J =





8.9 Hz), 7.08-7.13 (2H, m), 7.28 (2H, d, J = 5.9 Hz),





7.35-7.40 (2H, m), 7.70 (2H, d, J = 8.4 Hz), 8.02 (2H, d,





J = 8.4 Hz), 8.21 (1H, dd, J = 8.9 Hz, 2.7 Hz), 8.33 (1H,





d, J = 2.7 Hz), 8.53-8.55 (2H, m), 9.02 (1H, s).


2452
4-CF3Ph-
2-furyl
(CDCl3) 2.50 (4H, brs), 3.59 (2H, s), 3.73 (4H, brs),





6.23 (1H, d, J = 3.0 Hz), 6.33 (1H, dd, J = 3.0 Hz, 2.0





Hz), 6.99 (1H, d, J = 8.9 Hz), 7.13 (2H, d, J = 8.8 Hz),





7.41 (2H, d, J = 8.8 Hz), 7.35-7.48 (1H, m), 7.76 (2H, d,





J = 8.1 Hz), 8.02 (2H, d, J = 8.1 Hz), 8.20 (1H, dd, J =





8.9 Hz, 2.5 Hz), 8.24 (1H, brs), 8.32 (1H, d, J = 2.5 Hz)


2453
4-CF3Ph-
4-NO2Ph-
(CDCl3) 2.48 (4H, brs), 3.63 (2H, s), 3.73 (4H, brs),





7.00 (1H, d, J = 8.8 Hz), 7.14 (2H, d, J = 8.7 Hz),





7.43 (2H, d, J = 8.7 Hz), 7.53 (2H, d, J = 8.4 Hz),





7.76 (2H, d, J = 8.0 Hz), 8.01 (2H, d, J = 8.0 Hz),





8.15 (1H, brs), 8.20 (2H, d, J = 8.4 Hz), 8.21 (1H, dd, J =





8.8 Hz, 2.5 Hz), 8.32 (1H, d, J = 2.5 Hz).
















TABLE 384













 










Example





No.
R1086
R1087
mp (° C.) or 1H NMR (solvent) δ ppm





2454
4-CF3Ph-




1H NMR (CDCl3) 2.43(4 H, brs), 3.46(2 H, s), 3.55(4 H, brs), 3.65 (3 H, s), 5.95-6.08(2 H, m), 6.61(1 H, t, J = 2.2 Hz), 6.98(1 H, d, J = 8.9 Hz), 7.13(2 H, d, J = 8.8 Hz), 7.41(2 H, d, J = 8.8 Hz), 7.76(2 H, d, J = 8.1 Hz), 8.02(2 H, d, J = 8.1 Hz), 8.20(1 H, dd, J = 8.9 Hz, 2.5 Hz), 8.25(1 H, brs), 8.31(1 H, d, J = 2.5 Hz).


 


2455
4-CF3Ph-
2-pyridyl
mp 175-176


2456
4-CF3Ph-
4-OHPh-
1H NMR (DMSO-d6) 2.36(4 H, brs), 3.32(2 H, s),





3.49(4 H, brs), 6.70(2 H, d, J = 8.4 Hz), 7.09(2 H, d, J =





8.4 Hz), 7.15(1 H, d, J = 8.9 Hz), 7.16(2 H, d, J = 8.6





Hz), 7.43(2 H, d, J = 8.6 Hz), 7.94(2 H, d, J = 8.0 Hz),





8.17(2 H, d, J = 8.0 Hz), 8.26(1 H, dd, J = 8.9 Hz, 2.5





Hz), 8.54(1 H, d, J = 2.5 Hz), 9.27(1 H, s), 10.66(1 H, s).


2457
4-CF3Ph-
2-OHPh-
1H NMR (CDCl3) 2.59(4 H, brs), 3.68(4 H, brs),





3.75(2 H, s), 6.72-6.88(2 H, m), 6.92-7.10(1 H, m),





7.01(1 H, d, J = 8.8 Hz), 7.15(2 H, d, J = 8.8 Hz),





7.10-7.25(1 H, m), 7.44(2 H, d, J = 8.8 Hz), 7.76(2 H, d, J =





8.1 Hz), 8.01(2 H, d, J = 8.1 Hz), 8.12(1 H, brs),





8.22(1 H, dd, J = 8.8 Hz, 2.3 Hz), 8.31(1 H, d, J = 2.3





Hz).


2458
4-CF3Ph-
4-AcNHPh-
1H NMR (DMSO-d6) 2.02(3 H, s), 2.38(4 H, brs),





3.45(2 H, s), 3.45 (4 H, brs), 7.15(1 H, d, J = 8.9 Hz),





7.16(2 H, d, J = 8.6 Hz), 7.22(2 H, d, J = 8.4 Hz),





7.44(2 H, d, J = 8.6 Hz), 7.52(2 H, d, J = 8.4 Hz),





7.94(2 H, d, J = 8.1 Hz), 8.17(2 H, d, J = 8.1 Hz),





8.26(1 H, dd, J = 8.9 Hz, 2.6 Hz), 8.54(1 H, d, J = 2.6





Hz), 9.90(1 H, s), 10.66(1 H, s).


2459
4-CF3Ph-
2,3-(CH3)2Ph-
1H NMR (CDCl3) 2.25(3 H, s), 2.28(3 H, s), 2.42(4 H,





brs), 3.47(2 H, s), 3.67(4 H, brs), 6.95(1 H, d, J = 8.7





Hz), 6.95-7.12(3 H, m), 7.10 (2 H, d, J = 8.6 Hz),





7.38(2 H, d, J = 8.6 Hz), 7.73(2 H, d, J = 8.1 Hz),





8.00(2 H, d, J = 8.1 Hz), 8.17(1 H, dd, J = 8.7 Hz, 2.7





Hz), 8.30 (1 H, d, J = 2.7 Hz), 8.43(1 H, s).


2460
4-CF3Ph-
3-thienyl
1H NMR (CDCl3) 2.45(4 H, brs), 3.55(2 H, brs),





3.56(2 H, s), 3.72 (2 H, brs), 6.97(1 H, d, J = 8.9 Hz),





7.05(1 H, dd, J = 5.0 Hz, 1.1 Hz), 7.08-7.17(1 H, m),





7.12(2 H, d, J = 8.7 Hz), 7.29(1 H, dd, J = 5.0 Hz, 3.0





Hz), 7.39(2 H, d, J = 8.7 Hz), 7.75(2 H, d, J = 8.1 Hz),





8.02(2 H, d, J = 8.1 Hz), 8.19(1 H, dd, J = 8.9 Hz, 2.8





Hz), 8.32(1 H, d, J = 2.8 Hz), 8.41(1 H, brs).


2461
3,4-Cl2Ph-
3-pyridyl
1H NMR (CDCl3) 2.46(4 H, brs), 3.46(2 H, s),





3.55-3.80(4 H, m), 6.96(1 H, d, J = 8.9 Hz), 7.12(2 H, d, J =





8.4 Hz), 7.26-7.30(1 H, m), 7.40(2 H, d, J = 8.4 Hz),





7.56(1 H, d, J = 8.4 Hz), 7.65-7.78(2 H, m), 8.04(1 H, d,





J = 2.2 Hz), 8.16(1 H, dd, J = 8.9 Hz, 2.7 Hz), 8.29(1 H,





d, J = 2.2 Hz), 8.51-8.56(2 H, m), 8.61(1 H, brs).
















TABLE 385













 











Example






No.
R1088
R1089
Form
1H NMR (solvent) δ ppm





2462
4-CF3Ph-
cyclopropyl
free
(CDCl3) 0.11(2 H, dd, J = 10.5 Hz, 4.5






Hz), 0.54(2 H, dd, J = 12.5 Hz, 6.5 Hz),






0.77-0.93(1 H, m), 2.29(2 H, d, J = 6.5 Hz),






2.52(4 H, brs), 3.55(2 H, brs), 3.75(2 H,






brs), 6.98(1 H, d, J = 8.9 Hz), 7.14(2 H, d,






J = 8.7 Hz), 7.42(2 H, d, J = 8.7 Hz),






7.76(2 H, d, J = 8.1 Hz), 8.03(2 H, d, J =






8.1 Hz), 8.20 (1 H, dd, J = 8.9 Hz, 2.5 Hz),






8.33(1 H, d, J = 2.5 Hz), 8.36 (1 H, brs).


2463
4-CF3Ph-
3-OHPh-
hydro-
(DMSO-d6) 2.90-3.70(6 H, m),





chloride
3.90-4.20(2 H, m), 4.24 (2 H, d, J = 3.9 Hz),






6.86(1 H, dd, J = 8.1 Hz, 1.7 Hz), 6.97






(1 H, brs), 7.01(1 H, d, 4 7.7 Hz),






7.16(1 H, d, J = 8.9 Hz), 7.20(2 H, d, J =






8.6 Hz), 7.25(1 H, t, J = 7.7 Hz), 7.52 (2 H,






d, J = 8.6 Hz), 7.94(2 H, d, J = 8.1 Hz),






8.20(2 H, d, J = 8.1 Hz), 8.29(1 H, dd, J =






8.9 Hz, 2.5 Hz), 8.58(1 H, d, J = 2.5 Hz),






10.77(1 H, s).


2464
4-CF3Ph-
—C(CH3)3
free
(CDCl3) 0.88(9 H, s), 2.09(2 H, s), 2.52(4 H,






brs), 3.49(2 H, brs), 3.68(2 H,brs),






6.97(1 H, d, J = 8.8 Hz), 7.12(2 H, d, J =






8.5 Hz), 7.39(2 H, d, J = 8.5 Hz), 7.75(2 H,






d, J = 8.1 Hz), 8.03(2 H, d, J = 8.1 Hz),






8.19(1 H, dd, J = 8.8 Hz, 2.5 Hz), 8.33(1 H,






d, J = 2.5 Hz), 8.47(1 H, s).


 


2465
4-CF3Ph-




free
(CDCl3) 2.42(3 H, s), 2.59(4 H, brs), 3.48-3.76(4 H, m), 3.91(2 H, s), 4.56(2 H, s), 7.00(1 H, d, J = 8.9 Hz), 7.13(2 H, d, J = 8.7 Hz), 7.39(2 H, d, J = 8.6 Hz), 7.71(2 H, d, J = 8.3 Hz), 7.79(1 H, s), 8.00(2 H, d, J = 8.1 Hz), 8.22-8.29(2 H, m), 8.81(1 H, brs).


 


2466
4-CF3Ph-




free
(CDCl3) 2.55(3 H, s), 2.35-2.70(4 H, m), 3.66(2 H, s), 3.40-3.95(4 H, m), 6.98(1 H, d, J = 8.7 Hz), 7.05(1 H, d, J = 7.6 Hz), 7.12(2 H, d, J = 8.5 Hz), 7.22(1 H, d, J = 7.6 Hz), 7.42(2 H, d, J = 8.5 Hz), 7.56(1 H, t, J = 7.6 Hz), 7.75 (2 H, d, J = 8.2 Hz), 8.02(2 H, d, J = 8.2 Hz), 8.21(1 H, dd, J = 8.7 Hz, 2.8 Hz), 8.31(1 H, d, J = 2.8 Hz), 8.38(1 H, s).


 


2467
3,4-Cl2Ph-
4-AcNHPh-
free
(DMSO-d6) 2.02(3 H, s), 2.38(4 H, brs),






3.44(2 H, s), 3.55 (4 H, brs), 7.14(1 H, d, J =






8.8 Hz), 7.16(2 H, d, J = 8.7 Hz),






7.21(2 H, d, J = 8.4 Hz), 7.43(2 H, d, J =






8.7 Hz), 7.52 (2 H, d, J = 8.4 Hz), 7.84(1 H,






d, J = 8.4 Hz), 7.95(1 H, dd, J = 8.4 Hz,






2.0 Hz), 8.22(1 H, d, J = 2.0 Hz), 8.23(1 H,






dd, J = 8.8 Hz, 2.6 Hz), 8.51(1 H, d, J =






2.6 Hz), 9.90(1 H, s), 10.59(1 H, s).
















TABLE 386













 













Example








No.
Xb57
R1090
R1091
Xb58
Form
1H NMR (solvent) δ ppm





2468
—NH—
—H




—CH2—
trihydro- cloride
(DMSO-d6) 2.60-3.20(7 H, m), 3.22-3.60(3 H, m), 3.71(3 H, s), 4.10(1 H, d, J = 13.2 Hz), 4.30 (2 H, d, J = 4.8 Hz), 4.48(1 H, d, J = 13.2 Hz), 6.05(1 H, t, J = 2.5 Hz), 6.32(1 H, dd, J = 3.6 Hz, 1.9 Hz), 6.87(1 H, t, J = 2.5 Hz), 7.04(2 H, d, J = 8.4 Hz), 7.06 (1 H, d, J = 8.8 Hz), 7.29(2 H, d, J = 8.4 Hz), 7.93(2 H, d, J = 8.5 Hz), 8.19(2 H, d, J = 8.5 Hz), 8.22 (1 H, dd, J = 8.8 Hz, 2.6 Hz), 8.51(1 H, d, J = 2.6 Hz), 10.70(1 H, s).


 


2469
—NH—
—H
3-furylmethyl
—CH2—
free
(CDCl3) 2.25-2.45(4 H, m),








2.60(2 H, t, J = 7.7 Hz),








2.93(2 H, t, J = 7.7 Hz), 3.37








(2 H, s), 3.40(2 H, t, J 5.0 Hz),








3.60 (2 H, t, J = 5.0 Hz), 6.37








(1 H, d, J = 1.5 Hz), 6.93(1 H, d,








J = 8.8 Hz), 7.02(2 H, d, J = 8.6








Hz), 7.19(2 H, d, J = 8.6 Hz),








7.33(1 H, s), 7.39(1 H, t, J = 1.5








Hz), 7.73(2 H, d, J = 8.1 Hz),








8.01(2 H, d, J = 8.1 Hz),








8.21(1 H, dd, J = 8.8 Hz, 2.6








Hz), 8.28(1 H, d, J = 2.6 Hz),








8.46(1 H, s).


2470
—NH—
—H
furfuryl
—CH2—
free
(CDCl3) 2.31-2.52(4 H, m),








2.60(2 H, t, J = 7.2 Hz),








2.93(2 H, t, J = 7.2 Hz), 3.43








(2 H, t, J = 5.0 Hz), 3.55(2 H, s),








3.63 (2 H, t, J = 5.0 Hz),








6.21(1 H, d, J = 2.6 Hz),








6.32(1 H, d, J = 3.0 Hz),








6.94(1 H, d, J = 8.9 Hz),








7.02(2 H, d, J = 8.5 Hz),








7.19(2 H, d, J = 8.5 Hz),








7.38(1 H, d, J = 2.8 Hz),








7.74(2 H, d, J = 8.0 Hz), 8.00








(2 H, d, J = 8.0 Hz), 8.21(1 H, dd,








J = 8.9 Hz, 2.5 Hz), 8.28(1 H, d,








J = 2.5 Hz), 8.35(1 H, s).


2471
none
—CH3
piperonyl
—N(CH3)—
free
(CDCl3) 2.12(3 H, s),








2.42-2.45(4 H, m), 3.03(3 H, s),








3.44(2 H, s), 3.47-3.52(2 H, m),








3.62-3.65(2 H, m), 4.09(2 H, s),








5.95 (2 H, s), 6.54-6.59(2 H, m),








6.71-6.77 (2 H, m), 6.85(1 H, s),








6.92-6.96(2 H, m), 7.75(2 H, d, J =








8.4 Hz), 7.87(2 H, d, J = 8.1








Hz), 8.17(1 H, dd, J = 8.6 Hz,








2.5 Hz), 8.58(1 H d J = 2.1 Hz).
















TABLE 387













 












Example







No.
R1092
Xb59
Xb60
R1093
1H NMR (DMSO-d6) δ ppm





2472
3,4-Cl2Ph-
—NH—
none
benzyl
1.55-1.82(4 H, m) 1.96(2 H, t, J =







10.5 Hz), 2.21-2.40(1 H, m),







2.87(2 H, d, J = 10.5 Hz), 3.47(2 H,







s), 7.02(1 H, d, J = 8.9 Hz),







7.05(2 H, d, J = 9.1 Hz),







7.18-7.42(5 H, m), 7.62(2 H, d, J = 9.1







Hz, 7.84(1 H, d, J = 8.4 Hz),







7.94(1 H, dd, J = 8.4 Hz, 2.0 Hz),







8.17(1 H, dd, J = 8.9 Hz, 2.6 Hz),







8.22(1 H, d, J = 2.0 Hz), 8.46(1 H,







d, J = 2.6 Hz), 9.89(1 H, s),







10.53(1 H, s).


2473
3,4-Cl2Ph-
—NH—
none
3-furylmethyl
1.55-1.85(4 H, m), 1.85-2.07(2 H,







m), 2.18-2.40(1 H, m),







2.80-3.00(2 H, m), 3.32(2 H, s), 6.44(1 H,







s), 7.02(1 H, d, J = 8.9 Hz),







7.05(2 H, d, J = 8.9 Hz), 7.57(1 H,







s) 7.57-7.66(1 H, m), 7.62(2 H, d, J =







8.9 Hz), 7.84(1 H, d, J = 8.4 Hz),







7.94(1 H, dd, J = 8.4 Hz, 2.0 Hz),







8.17(1 H, dd, J = 8.9 Hz, 2.6 Hz),







8.22(1 H, d, J = 2.0 Hz), 8.45(1 H,







d, J = 2.6 Hz), 9.89(1 H, s),







10.54(1 H, s).


2474
4-CF3Ph-
none
—N(CH3)—
benzyl
1.50-2.30(6 H, m), 2.84(5 H, brs),







3.44(2 H, brs), 4.27(1 H, brs),







7.16(3 H, d, J = 8.6 Hz),







7.18-7.39(5 H, m), 7.41(2 H, d, J = 8.5







Hz), 7.95(2 H, d, J = 8.1 Hz),







8.17(2 H, d, J = 8.1 Hz), 8.27(1 H,







dd, J = 8.9 Hz, 2.5 Hz), 8.56 (1 H,







d, J = 2.5 Hz), 10.68(1 H, s).


2475
4-CF3Ph-
none
—N(CH3)—
3-furylmethyl
1.50-2.20(6 H, m), 2.83(3 H, s),







2.72-3.02(2 H, m), 3.30(2 H, d, J =







3.5 Hz), 4.28(1 H, brs), 6.41(1 H, s),







7.15(1 H, d, J = 8.8 Hz), 7.16(2 H,







d, J = 8.4 Hz), 7.41(2 H, d, J = 8.4







Hz), 7.53 (1 H, s), 7.60(1 H, s),







7.95(2 H, d, J = 8.1 Hz), 8.17(2 H,







d, J = 8.1 Hz), 8.27(1 H, dd, J = 8.8







Hz, 2.5 Hz), 8.55(1 H, d, J = 2.5







Hz), 10.68 (1 H, s).
















TABLE 388













 









Example




No.
R1094
1H NMR (CDCl3) δ ppm





2476
cyclohexyl
1.00-1.40(5 H, m), 1.52-1.70(1 H, m), 1.70-1.92(4 H, m), 2.21-2.40(1 H,




m), 2.57 (4 H, brs), 3.52(2 H, brs),3.73(2 H, brs), 6.98(1 H, d, J = 8.9




Hz), 7.13(2 H, d, J = 8.8 Hz), 7.41(2 H, d, J = 8.8 Hz), 7.76(2 H, d, J =




8.2 Hz), 8.03(2 H, d, J = 8.2 Hz), 8.19 (1 H, dd, J = 8.9 Hz, 2.5 Hz),




8.33(1 H, d, J = 2.5 Hz), 8.36(1 H, brs).


 


2477




1.40-1.85(4 H, m), 2.38-2.60(1 H, m), 2.57(4 H, brs), 3.38(2 H, t, J = 11.0 Hz), 3.72 (4 H, brs), 4.03(2 H, dd, J = 11.0 Hz, 3.5 Hz), 7.00(1 H, d, J = 8.7 Hz), 7.15(2 H, d, J = 8.7 Hz), 7.43(2 H, d, J = 8.7 Hz), 7.77(2 H, d, J = 8.5 Hz), 8.02(2 H, d, J = 8.5 Hz), 8.16(1 H, brs), 8.21(1 H, dd, J = 8.7 Hz, 2.5 Hz), 8.32(1 H, d, J = 2.5 Hz).


 


2478
cyclopropyl
0.33-0.58(4 H, m), 1.45-1.72(1 H, m), 2.62(4 H, brs), 3.49(2 H, brs),




3.68(2 H, brs), 7.00(1 H, d, J = 8.9 Hz), 7.15(2 H, d, J = 8.4 Hz),




7.43(2 H, d, J = 8.4 Hz), 7.77(2 H, d, J = 8.4 Hz), 8.02(2 H, d, J = 8.4




Hz), 8.21(1 H, s), 8.21(1 H, dd, J = 8.9 Hz, 2.6 Hz), 8.33(1 H, d, J = 2.6




Hz).


















TABLE 389





Example




No.
Chemical structure
1H NMR (solvent) δ ppm







2479




(DMSO-d6) 2.77-3.10(2 H, m), 3.17-3.63(4 H, m), 3.71-3.89(1 H, m), 4.18(2 H, s), 4.24(2 H, s), 4.27-4.44(1 H, m), 6.07(2 H, s), 6.92-7.06(2 H, m), 7.09(3 H, d, J = 8.6 Hz), 7.22(1 H, s), 7.28(2 H, d, J = 8.6 Hz), 7.92(2 H, d, J = 8.0 Hz), 8.18(2 H, d, J = 8.0 Hz), 8.24(1 H, dd, J = 8.8 Hz, 2.5 Hz), 8.53(1 H, d, J = 2.5 Hz), 10.69(1 H, s).


 


2480




(CDCl3) 2.25-2.52(4 H, m), 2.77-2.95 (2 H, m), 3.12-3.29(1 H, m), 3.29-3.46 (1 H, m), 3.41(2 H, s), 3.43-3.59(1 H, m), 3.65-3.84(2 H, m), 5.30(1 H, brs), 5.92 (2 H, s), 6.73(2 H, s), 6.84(1 H, s), 6.95 (1 H, d, J = 9.0 Hz), 7.05(2 H, d, J = 8.4 Hz), 7.23(2 H, d, J = 8.4 Hz), 7.75(2 H, d, J = 8.1 Hz), 7.98(2 H, d, J = 8.1 Hz), 8.03(1 H, brs), 8.20(1 H, dd, J = 9.0 Hz, 2.5 Hz), 8.22(1 H, s).


 


2481




(CDCl3) 1.32-1.44(2 H, m), 1.83-2.02 (3 H, m), 2.30(2 H, d, J = 6.8 Hz), 2.42-2.47(4 H, m), 2.69(2 H, t, J = 12.0 Hz), 3.48-3.66(8 H, m), 6.86-6.99(6 H, m), 7.25-7.32(7 H, m), 7.50(2 H, d, J = 8.6 Hz), 7.98(1 H, dd, J = 8.7 Hz, 2.6 Hz), 8.59(1 H, d, J = 2.0 Hz).









Example 2482
Production of N-(6-{4-[4-((1S,2S)-2-hydroxy-cyclohexyl)piperazine-1-carbonyl]phenoxy}pyridin-3-yl)-4-trifluoromethylbenzamide
To a solution of N-{6-[4-(piperazine-1-carbonyl)phenoxy]-pyridin-3-yl}-4-trifluoromethyl-benzamide (430 mg, 0.91 mmol) in methanol was added 1,2-epoxycyclohexane (180 mg, 1.83 mmol), and the resulting solution was stirred for 1 day under reflux. The resulting reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=35:1), and then ethyl acetate was added. The precipitated white powder was filtered off and washed with ethyl acetate, to thereby yield 284 mg of the title compound.
Appearance: White powder
1H NMR (CDCl3) δ 1.03-1.38 (4H, m), 1.42-1.88 (3H, m), 2.06-2.35 (2H, m), 2.31 (2H, brs), 2.74 (2H, brs), 3.30-4.00 (6H, m), 7.00 (1H, d, J=8.9 Hz), 7.15 (2H, d, J=8.7 Hz), 7.43 (2H, d, J=8.7 Hz), 7.77 (2H, d, J=8.1 Hz), 8.02 (2H, d, J=8.1 Hz), 8.21 (1H, brs), 8.22 (1H, dd, J=8.9 Hz, 2.7 Hz), 8.33 (1H, d, J=2.7 Hz).
Example 2483
Production of 3,4-dichloro-N-[6-({4-[3-oxo-3-(4-piperonylpiperazin-1-yl)propyl]phenyl}methylamino)-pyridin-3-yl]benzamide dioxalate
To a solution of 3,4-dichloro-N-(6-{4-[3-oxo-3-(4-piperonylpiperazin-1-yl)propyl]phenylamino}pyridin-3-yl)benzamide (250 mg, 0.395 mmol) in methanol (3 mL) were added acetic acid (0.500 mL) and 37% aqueous formaldehyde (0.640 mL, 7.89 mmol), and the resulting solution was stirred for 30 minutes at 50° C. To the reaction solution was added sodium cyanoborohydride (0.160 g, 2.55 mmol) at room temperature, and stirred for 8 hours at 50° C. Water was added to the reaction solution and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=10:1), to yield a free form. This free form was dissolved in isopropanol (5 mL) and oxalic acid dihydrate (7.0 mg, 0.555 mmol) by heating. The solvent was evaporated, and the resulting solid was recrystallized from isopropanol, to thereby yield 0.193 g of the title compound.
Appearance: Pale yellow powder
Melting point: 127-129° C.
The following compound was produced in the same manner as in Example 2483.
Example 2484
2-(Ethyl{4-[5-(4-trifluoromethylphenoxymethyl)pyridin-2-yloxy]phenyl}amino)-1-(4-piperonylpiperazin-1-yl)ethanone
1H NMR (CDCl3) δ 1.18 (3H, t, j 7.1 Hz), 2.41-2.44 (4H, m), 3.39-3.47 (4H, m), 3.51 (2H, brs), 3.64 (2H, brs), 4.03 (2H, s), 5.03 (2H, s), 5.94 (2H, s), 6.68 (2H, d, J=19.1 Hz), 6.73-6.74 (2H, m), 6.85-6.88 (2H, m), 6.99 (2H, d, J=9.1 Hz), 7.01 (2H, d, J=8.4 Hz), 7.55 (2H, d, J=8.7 Hz), 7.71 (1H, dd, J=8.6° Hz, 2.5 Hz), 8.22 (1H, d, J=2.3 Hz).
Example 2485
Production of 3,4-dichloro-N-[6-(4-thiomorpholine-4-ylmethylphenoxy)pyridin-3-yl]benzamide monohydrochloride
3,4-dichloro-N-[6-(4-chloromethylphenoxy)-pyridin-3-yl]benzamide (0.61 g, 1.5 mmol) was dissolved in DMF (5 mL). To the resulting solution were added triethylamine (0.84 mL, 6.0 mmol) and thiomorpholine (0.15 mL, 1.5 mmol), and this solution was stirred overnight at 40° C. The resulting reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate and washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate and evaporated. This residue was purified by silica gel column chromatography (chloroform:methanol=80:1). The obtained solid (0.56 g, 1.18 mmol) was dissolved in ethyl acetate (50 mL), and a solution of 4 N hydrogen chloride in ethyl acetate (0.295 mL, 1.18 mmol) was added, and this solution was stirred for 1 hour at room temperature. The precipitated crystals were collected by suction filtration, and recrystallized from methanol, to thereby yield 0.38 g of the title compound.
Appearance: White powder
1H NMR (DMSO-d6) δ 2.80-2.83 (2H, m), 3.09-3.17 (4H, m), 3.61 (2H, m), 4.35 (2H, s), 7.14 (1H, d, J=8.9 Hz), 7.21 (2H, d, J=8.3 Hz), 7.60 (2H, d, J=8.3 Hz), 7.85 (1H, d, J=8.6 Hz), 7.96 (1H, dd, J=8.3 Hz, 2.0 Hz), 8.23 (1H, dd, J=8.9 Hz, 2.6 Hz), 8.24 (1H, d, J=2.0 Hz), 8.53 (1H, d, J=2.6 Hz), 10.45 (1H, brs), 10.62 (1H, brs).
The following compounds were produced in the same manner as in Example 2485.
Example 2486
3,4-Dichloro-N-(4-{4-[1-(3-imidazole-1-ylpropyl)-1,2,3,6-tetrahydropyridine-4-yl]phenoxy}phenyl)-benzamide
Melting point: 169-171° C.







TABLE 390













 












Example







No.
R1095
Xb61
R1096
Form
mp (° C.)





2487
—F
—CH2—
benzyl
dihydro-
178-179






chloride


2488
—F
—CH2—
piperonyl
dihydro-
192-195






chloride


2489
—F
—(CH2)2—
benzyl
dihydro-
208-210






chloride


2490
—F
—(CH2)2—
piperonyl
dihydro-
202-205






chloride


2491
—F
—(CH2)3—
benzyl
dihydro-
260-262






chloride


2492
—F
—(CH2)3—
piperonyl
dihydro-
258-260






chloride


2493
—F
—(CH2)4—
benzyl
dihydro-
245-248






chloride


2494
—F
—(CH2)4—
piperonyl
dihydro-
256-258






chloride


 


2495
—H
none




free
172-173


 


2496
—H
none




free
131-134
















TABLE 391













 












Example






No.
M
Form
mp (° C.)







2497
1
hydrochloride
165-168



2498
2
free
143-144



2499
3
oxalate
173-175



2500
4
hydrochloride
226-228

















TABLE 392













 









Example




No.
M
mp (° C.)





2501
1
183-185


2502
4
141-143
















TABLE 393













 












Example







No.
R1097
R1098
M
Form
1H NMR (solvent) δ ppm





2503
3,4-Cl2Ph-
piperidino
1
free
(CDCl3) 1.42-1.58(6 H, m), 2.36-2.38(4 H,







m), 3.44(2 H, s), 6.86(1 H, d, J = 8.9 Hz),







6.99(2 H, dd, J 6.6 Hz, 2.0 Hz), 7.26







7.31(2 H, m), 7;47(1 H, d, J = 8.3 Hz),







7.67(1 H, dd, J = 8.3 Hz, 2.0 Hz),







7.94(1 H, d, J = 2.3 Hz), 8.10(1 H, dd, J =







8.9 Hz, 2.6 Hz), 8.21(1 H, d, J = 2.6 Hz),







8.69(1 H, brs).


2504
3,4-Cl2Ph-
piperidino
3
dihydro-
(DMSO-d6) 1.67-1.77(6 H, m), 1.99-2.10






chloride
(2 H, m), 2.61-3.05 (6 H, m), 3.40-3.43(2 H,







m), 6.01(1 H, brs), 7.04-7.08(3 H, m),







7.28(9 H d, J = 8.6 Hz), 7.84(1 H, d, J =







8.4 Hz), 7.96-8.00 (1 H, m), 8.198.23(1 H,







m), 8.26(1 H, d, J = 1.9 Hz), 8.51 (1 H, d, J =







2.7 Hz), 10.24(1 H, brs), 10.67(1 H, s).


2505
3,4-Cl2Ph-
piperidino
4
free
(CDCl3) 1.40-1.50(2 H, m), 1.50-1.75(8 H,







m), 2.25-2.50 (6 H, m), 2.63(2 H, t, J = 7.0







Hz), 6.93(1 H, d, J = 9.0 Hz), 7.03(2 H, d,







J = 8.5 Hz), 7.19(2 H, d, J = 8.5 Hz),







7.58(1 H, d, J = 8.5 Hz), 7.71(1 H, dd, J =







8.5 Hz, 2.0 Hz) 7 82(1 H, s), 7.98(1 H, d, J =







2.0 Hz), 8.16(1 H, dd, J = 9.0 Hz, 3.0







Hz), 8.25(1 H, d, J = 3.0 Hz).


2506
3,4-Cl2Ph-
piperidino
5
free
(CDCl3) 1.20-1.80(12 H, m), 2.31(2 H, t, J =







7.8 Hz), 2.40 (4 H, brs), 2.61(2 H, t, J =







7.8 Hz), 6.94(1 H, d, J = 8.8 Hz), 7.04(2 H,







d, J = 8.4 Hz), 7.20(2 H, d, J = 8.4 Hz),







7.58(1 H, d, J = 8.2 Hz), 7.72(1 H, s),







7.71(1 H, dd, J = 8.2 Hz, 2.0 Hz),







7.98(1 H, d, J = 2.3 Hz), 8.16(1 H, dd, J =







8.8 Hz, 2.8 Hz), 8.24(1 H, d, J = 2.8 Hz).


2507
4-CF3Ph-
morpholino
1
free
(DMSO-d6) 2.37(4 H, t, J = 4.6 Hz), 3.46







(2 H, s), 3.59(4 H, t, J = 4.6 Hz), 7.07(3 H,







d, J = 8.6 Hz), 7.33(2 H, d, J = 8.6 Hz),







7.93(2 H, d, J = 8.6 Hz), 8.15-8.24(3 H, m),







8.51(1 H, d, J = 2.6 Hz), 10.63(1 H, s).


2508
3,4-Cl2Ph-
morpholino
1
free
(CDCl3) 2.56(4 H, t, J = 4.6 Hz), 3.60(2 H,







s), 3.82(4 H, t, J = 4 6 Hz), 7.05(1 H, d, J =







8.6 Hz), 7.18(2 H, dd, J = 6.6 Hz, 2.0 Hz),







7.45(2 H, d, J = 8.6 Hz), 7.67(1 H, d, J =







8.6 Hz), 7.80(1 H, dd, J = 8.3 Hz, 2.0 Hz),







7.99(1 H, brs), 8.07(1 H, d, J = 2.0 Hz),







8.25-8.29(1 H, m), 8.35(1 H, d, J = 2.6 Hz).


2509
3,4-Cl2Ph-
morpholino
2
free
(CDCl3) 2.54-2.85(8 H, m), 3.74-3.78(4 H,







m), 6.95(1 H, d, J = 8.9 Hz) 7 04-7.07(2 H,







m), 7.22-7.26(2 H, m), 7.58-1 H, d, J = 8.6







Hz), 7.68-7.72(1 H, m), 7.79(1 H, brs),







7.98(1 H, d, J = 2.0 Hz), 8.17(1 H, dd, J =







8.9 Hz, 2.6 Hz), 8.24(1 H, d, J = 2.6 Hz).


2510
3,4-Cl2Ph-
morpholino
3
free
(CDCl3) 1.78-1.83(2 H, m), 2.34-2.45(6 H,







m), 2.60-2.66 (2 H, m), 3.70-3.73(4 H, m),







6.88(1 H, d, J = 8.6 Hz), 7.00 (2 H, d, J =







8.6 Hz), 7.18(2 H, d, J = 8.6 Hz), 7.51(1 H,







d, J = 8.6 Hz), 7.667.70(1 H, m), 7.94(1 H,







d, J = 2.2 Hz), 8.108.14(1 H, m), 8.22(1 H,







d, J = 2.7 Hz), 8.40(1 H, brs).
















TABLE 394













 











Example






No.
R1099
M
Form
1H NMR (solvent) δ ppm





2511
morpholino
4
dihydro-
(DMSO-d6) 1.55-1.90(4 H, m), 2.63(2 H, t, J = 7.2 Hz),





chloride
2.90-3.20(4 H, m), 3.30-3.50(2 H, m), 3.79(2 H, t, J = 11.2






Hz), 3.93(2 H, s), 7.04(2 H, d, J = 8.2 Hz), 7.05(1 H, d, J =






9 0 Hz), 7.26(2 H, d, J = 8.2 Hz), 7.84(1 H, d, J = 8.2 Hz),






7198(1 H, dd, J = 8.2 Hz, 2.0 Hz), 8.20(1 H dd J = 9.0






Hz, 2.7 Hz), 8.25(1 H, d, J = 2.0 Hz), 8.50(1 H, d, J = 2.7






Hz), 10.65(1 H, s).


2512
morpholino
5
free
(CDCl3) 1.30-1.45(2 H, m), 1.45-1.75(4 H, m), 2.33(2 H, t,






J = 7.2 Hz), 2.44(4 H, t, J = 4.6 Hz), 2.62(2 H, t, J = 7.7






Hz), 3.72(4 H, t, J = 4.6 Hz), 6.94(1 H, d, 4 9.0 Hz),






7.04(2 H, d, J = 8.5 Hz), 7.20(2 H, d, J = 8.5 Hz)






7.58(1 H, d, J = 8.2 Hz), 7.65-7.75(2 H, m), 7.98(1 H, d, J =






2.0 Hz), 8.16 (1 H, dd, J = 9.0 Hz, 2.6 Hz), 8.24(1 H, d,






J = 2.6 Hz).


 


2513




3
free
(CDCl3) 1.97-2.03(2 H, m), 2.67(2 H, t, 4 7.6 Hz), 3.68-3.73(2 H, m), 3.88(2 H, s), 6.95(1 H, d, J = 8.9 Hz), 7.05(2 H, d, J = 8.6 Hz), 7.21(2 H, d, J = 8.6 Hz) 7.56(1 H, d, J = 8.3 Hz), 7.69-7.74(2 H, m), 7.98(1 H, d, J = 2.3 Hz), 8.14-8.18(1 H, m), 8.23(1 H, d, J = 3.0 Hz).


 


2514




1
free
(DMSO-d6) 5.20(2 H, s), 6.91(1 H, s), 7.07(1 H, d, J = 8.6 Hz), 7.10(2 H, d, J = 8.6 Hz), 7.22(1 H, s), 7.31(2 H, d, J = 8.6 Hz), 7.77(1 H, s), 7.84 (1 H, d, J = 8.6 Hz), 7.94(1 H, dd, J = 8.6 Hz, 2.0 Hz), 8.19(1 H, dd, J = 8.6 Hz, 2.3 Hz), 8.22(1 H, d, J = 2.0 Hz), 8.46(1 H, d, J = 2.3 Hz), 10.57 (1 H, s).


 


2515




1
hydro- chloride
(DMSO-d6) 5.48(2 H, s), 7.09(1 H, d, J = 8.5 Hz), 7.12(2 H, d, J = 8.6 Hz), 7.38(2 H, d, J = 8.6 Hz), 7.83(1 H, d, J = 8.5 Hz), 7.98(1 H, dd J = 8.5 Hz, 2.0 Hz), 8.23(1 H, dd, J = 8.5 Hz, 2.3 Hz), 8.26(1 H, s), 8.26(1 H, d, J = 2.0 Hz), 8.51(1 H, d, J = 2.3 Hz), 9.05(1 H, s), 10.70(1 H, s).


 


2516




1
free
(DMSO-d6) 5.63(2 H, d, J = 8.6 Hz), 7.09(1 H, d, J = 8.6 Hz), 7.11(2 H, d, J = 8.6 Hz), 7.36(2 H, d, J = 8.6 Hz), 7.76(1 H, d, J = 1.0 Hz), 7.84(1 H, d, J = 8.3 Hz), 7.94(1 H, dd, J = 8.3 Hz, 2.0 Hz), 8.20(1 H, dd, J = 8.6 Hz, 2.6 Hz) 8.23(2 H, s), 8.46(1 H, d, J = 2.6 Hz), 10.55(1 H, s).


 


2517




1
hydro- chloride
(DMSO-d6) 5.66(2 H, s), 7.09(1 H, d, J = 8.6 Hz, 7.10(2 H, d, J = 8.6 Hz), 7.32(2 H, d, J = 8.6 Hz), 7.83(2 H, s), 7.83(1 H, d, J = 8.5 Hz), 7.96 (1 H, dd, J = 8.5 Hz, 2.0 Hz), 8.21(1 H, dd, J = 8.5 Hz, 2.3 Hz), 8.23(1 H, d, J = 2.0 Hz), 8.47(1 H, d, J = 2.3 Hz), 10.61(1 H, s).


 


2518




1
hydro- chloride
(DMSO-d6) 5.34(2 H, s), 6.28(1 H, t, J = 2.0 Hz), 7.06(1 H, d, J = 9.0 Hz), 7.07(2 H, d, J = 8.6 Hz), 7.26(2 H, d, J = 8.6 Hz), 7.47(1 H, d, J = 2.0 Hz), 7.83(1 H, d, J = 8.6 Hz), 7.85(1 H, d, J = 2.0 Hz), 7.96(1 H, dd, J = 8.6 Hz, 2.0 Hz), 8.20(1 H, dd, J = 9.0 Hz, 2.6 Hz), 8.23(1 H, d, J = 2.0 Hz), 8.47(1 H, d, J = 2.6 Hz), 10.61(1 H, s).


 


2519




2
free
(CDCl3) 3.04(2 H, t, J = 7.0 Hz), 4.17(2 H, t, J = 7.0 Hz), 6.87(1 H, t, J = 1.3 Hz), 6.94(1 H, d, J = 8.7 Hz), 7.02(1 H, brs), 7.05(4 H, s), 7.30(1 H, brs), 7.56(1 H, d, J = 8.3 Hz), 7.75(1 H, dd, J = 8.3 Hz, 2.1 Hz), 8.03(1 H, d, J = 2.1 Hz), 8.17(1 H, dd, J = 8.7 Hz, 2.3 Hz), 8.23(1 H, d, J = 2.3 Hz), 8.6 1(1 H, brs).
















TABLE 395













 










Example





No.
R1100
R1101
1H NMR (solvent) δ ppm





2520
4-ClPh-
piperonyl
(CDCl3) 2.48(8 H, brs), 3.42(2 H, s),3.50(2 H, s), 5.93(2 H,





s), 6.74 (2 H, s), 6.85(1 H, s), 6.94(1 H, d, J = 8.6 Hz),





7.07(2 H, d, J = 8.6 Hz), 7.33(2 H, d, J = 8.6 Hz), 7.49(2 H,





d, J = 8.6 Hz), 7.73(1 H, brs), 7.82(2 H, d, J = 8.6 Hz),





8.18-8.24(2 H, m).


2521
4-CNPh-
piperonyl
(CDCl3) 2.48(8 H, brs), 3.42(2 H, s), 3.51(2 H, s), 5.93(2 H,





s), 6.73-6.74(2 H, m), 6.85(1 H, s), 6.96(1 H, d, J = 8.9 Hz),





7.07(2 H, d, J = 8.6 Hz), 7.34(2 H, d, J = 8.6 Hz),





7.79-7.82(3 H, m), 7.99(2 H, d, J = 8.2 Hz), 8.19(1 H, dd, J =





8.9 Hz, 2.6 Hz), 8.26(1 H, d, J = 2.6 Hz).


2522
3,4-Cl2Ph-
benzyl
(CDCl3) 2.51(8 H, brs), 3.52(2 H, s), 3.53(2 H, s), 6.95(1 H,





d, J = 8.9 Hz), 7.07(2 H, d, J = 8.2 Hz), 7.26-7.36(7 H, m),





7.59(1 H, d, J = 8.6 Hz), 7.69-7.73(2 H, ml), 7.99(1 H, d, J =





2.0 Hz), 8.18(1 H, dd, J = 8.9 Hz, 2.6 Hz), 8.25(1 H, d, J =





2.6 Hz).


2523
3,4-Cl2Ph-
—COOC(CH3)3
(CDCl3) 1.46(9 H, s), 2.40(4 H, t, J = 5.0 Hz), 3.43(4 H, t, J =





5.0 Hz), 3.50(2 H, s), 6.95(1 H, d, J = 8.9 Hz), 7.08(2 H,





d, J = 8.6 Hz), 7.34 (2 H, d, J = 8.6 Hz), 7.57(1 H, d, J =





8.3 Hz), 7.70-7.74(1 H, m), 8.00 (1 H, d, J = 2.0 Hz),





8.07(1 H, brs), 8.17-8.21(1 H, m), 8.27(1 H, d, J = 2.6 Hz).


2524
3,4-Cl2Ph-
—C2H5
(CDCl3) 1.08(3 H, t, J = 7.3 Hz), 2.38-2.49(10 H, m),





3.48(2 H, s), 6.88(1 H, d, J = 8.9 Hz), 7.01(2 H, d, J = 8.3





Hz), 7.30(2 H, d, J = 8.6 Hz), 7.49(1 H, d, J = 8.3 Hz),





7.66-7.70(1 H, m), 7.95(1 H, d, J = 2.0 Hz), 8.13(1 H, dd, J =





8.9 Hz, 2.6 Hz), 8.23(1 H, d, J = 2.6 Hz), 8.58 (1 H, brs).


2525
3,4-Cl2Ph-
-Ph
(CDCl3) 2.64(4 H, t, J = 5.0 Hz), 3.22(4 H, t, J = 5.0 Hz),





3.57(2 H, s), 6.83-6.88(1 H, m), 6.92-6.99(3 H, m),





7.10(2 H, d, J = 8.6 Hz), 7.23-7.29(2 H, m), 7.39(2 H, d, J =





8.6 Hz), 7.59(1 H, d, J = 8.6 Hz), 7.71(1 H, dd, J = 8.3





Hz, 2.0 Hz), 7.76(1 H, s), 7.99(1 H, d, J = 2.0 Hz),





8.19(1 H, dd, J = 8.6 Hz, 2.6 Hz), 8.26(1 H, d, J = 2.6 Hz).


2526
4-CF3Ph-
—COOC(CH3)3
(DMSO-d6) 1.40(9 H, s), 2.32-2.36(4 H, m), 3.30-3.35(4 H,





m), 3.49 (2 H, s), 7.06-7.09(3 H, m), 7.32-7.36(2 H, m),





7.94(2 H, d, J = 8.4 Hz), 8.18(2 H, d, J = 8.1 Hz), 8.24(1 H,





dd, J = 8.9 Hz, 2.7 Hz), 8.52 (1 H, d, J = 2.7 Hz),





10.64(1 H, s).


2527
3,4-Cl2Ph
—CH3
(CDCl3) 2.27(3 H, s), 2.45(8 H, brs), 3.47(2 H, s), 6.87(1 H,





d, J = 8.9 Hz), 6.99-7.03(2 H, m), 7.27-7.31(2 H, m),





7.48(1 H, dd, J = 8.3 Hz, 2.6 Hz), 7.68(1 H, dd, J = 8.6





Hz, 2.0 Hz), 7.94(1 H, d, J = 2.0 Hz), 8.12(1 H, dd, J = 8.9





Hz, 2.6 Hz), 8.23(1 H, d, J = 2.6 Hz), 8.76(1 H, brs).


2528
3,4-Cl2Ph-
piperonyl
(CDCl3) 2.47(8 H, brs), 3.42(2 H, s), 3.49(2 H, s), 5.93(2 H,





s), 6.73 (2 H, d, J = 0.7 Hz), 6.84(1 H, s), 6.91(1 H, d, J =





8.9 Hz), 7.04(2 H, d, J = 8.6 Hz), 7.31(2 H, d, J = 8.6 Hz),





7.53(1 H, d, J = 8.2 Hz), 7.70 (1 H, dd, J = 8.3 Hz, 2.0





Hz), 7.97(1 H, d, J = 2.3 Hz), 8.138.18(1 H, m), 8.24(2 H,





d, J = 2.6 Hz).
















TABLE 396













 












Example







No.
R1102
Xb62
R1103
Form
1H NMR (solvent) δ ppm





2529
3,4-Cl2Ph-
—(CH2)2—
piperonyl
free
(CDCl3) 1.97-2.01(2 H, m),







2.85-2.90(8 H, m), 3.68(2 H, s),







3.75(2 H, s), 5;95(2 H, s),







6.74-6.84(2 H, m), 6.94-6.97(2 H, m),







7.08(2 H, d, J = 8.6 Hz),







7.41(2 H, d, J = 8.6 Hz),.







7.57(1 H, d, J = 8.6 Hz),







7.75(1 H, dd, J = 8.6 Hz, 2.3







Hz), 8.01-8.02(2 H, m), 8.20(1 H,







dd, J = 8.9 Hz, 2.6 Hz),







8.31(1 H, d, J = 2.6 Hz).


2530
3,4-Cl2Ph-
—(CH2)2—
benzyl
trihydro-
(DMSO-d6) 2.25(2 H, brs), 3.38






chloride
(4 H, brs), 3.78(4 H, brs), 4.38







(4 H, s), 7.127.22(3 H, m),







7.46-7.48(3 H, m), 7.62-7.67 (4 H, m),







7.84(1 H, d, J = 8.6 Hz), 7.98







(1 H, dd, J = 8.6 Hz, 2.0 Hz),







8.22-8.27(2 H, m), 8.55 (1 H, d, J =







2.6 Hz), 10.68(1 H, s).


2531
3,4-Cl2Ph-
—CO—
benzyl
free
(CDCl3) 2.66(2 H, t, J 5.9 Hz),







3.22-3.25(4 H, m), 3.55(2 H, s),







4.60(2 H, s), 6.95(1 H, d, J = 8.9







Hz), 7.08(2 H, d, J = 8.6 Hz),







7.23-7.35(7 H, m), 7.56(1 H, d, J =







8.3 Hz, 7.72(1 H, dd, J = 2.0







Hz, 8.6 Hz), 8.00(1 H, d, J = 2.0







Hz), 8.10(1 H, s), 8.18(1 H, dd, J =







2.6 Hz, 8.6 Hz), 8.28 (1 H, d, J =







2.6 Hz).


 


2532
4-CF3Ph-
—CH2—




free
(CDCl3) 2.6 1(4 H, brs), 3.38(4 H, brs), 3.55(2 H, s), 6.85-6.94(3 H, m), 7.06-7.14 (4 H, m), 7.36(2 H, d, J = 8.3 Hz), 7.64(2 H, d, J = 8.3 Hz), 7.70-7.75(4 H, m), 7.99 (2 H, t, J = 8.3 Hz), 8.24(1 H, dd, J = 8.7 Hz, 2.5 Hz), 8.40(1 H, d, J = 2.6 Hz), 9.19 (1 H, s).


 


2533
4-CF3Ph-
—CH2—




free
(CDCl3) 2.58-2.62(4 H, m), 3.14-3.17(4 H, m), 3.54(2 H, s), 3.86(2 H, s), 6.83-7.14 (11 H, m), 7.36(2 H, d, J = 8.4 Hz), 7.71 (2 H, d, J = 8.3 Hz), 7.96(2 H, d, J = 8.1 Hz), 8.15-8.26(3 H, m).
















TABLE 397













 











Example






No.
R1104
R1105
M
1H NMR (CDCl3) δ ppm





2534
3,4-Cl2Ph-
—CH3
2
2.30(3 H, s), 2.50-2.81(12 H, m), 6.86(1 H, d, J =






8.6 Hz), 6.98 (2 H, d, J = 8.6 Hz), 7.18(2 H, d, J =






8.3 Hz), 7.47(1 H, d, J = 8.3 Hz), 7.67(1 H, dd, J =






8.3 Hz, 2.0 Hz), 7.94(1 H, d, J = 2.0 Hz), 8.11(1 H,






dd, J = 8.9 Hz, 2.6 Hz), 8.21(1 H, d, J = 2.6 Hz),






8.66 (1 H, brs).


2535
3,4-Cl2Ph-
piperonyl
2
2.51-2.83(12 H, m), 3.43(2 H, s), 5.93(2 H, s), 6.74






(2 H, d, J = 1.0 Hz), 6.86-7.03(4 H, m), 7.20(2 H, d,






J = 8.3 Hz), 7.53(1 H, d, J = 8.6 Hz), 7.68-7.72






(1 H, m), 7.97(1 H, d, J = 2.0 Hz), 8.15(1 H, dd,






J = 8.9 Hz, 2.6 Hz), 8.23(2 H, d, J = 2.6 Hz).


2536
3,4-Cl2Ph-
—CH3
3
1.78-1.84(2 H, m), 2.29(3 H, s), 2.36-2.48(10 H, m),






2.59-2.65 (2 H, m), 6.89(1 H, d, J = 8.4 Hz),






7.00(2 H, d, J = 8.4 Hz), 7.18 (2 H, d, J = 8.4 Hz),






7.52(1 H, d, J = 8.6 Hz), 7.67-7.71(1 H,m),






7.96(1 H, d, J = 2.2 Hz), 8.11-8.15(1 H, m),






8.23(1 H, d, J = 2.7 Hz), 8.31(1 H, brs).


2537
3,4-Cl2Ph-
piperonyl
3
1.78-1.84(2 H, m), 2.36-2.47(10 H, m), 2.60-2.65






(2 H, m), 3.41 (2 H, s), 5.93(2 H, s), 6.73(2 H, d, J =






0.8 Hz), 6.85(1 H, s), 6.91 (1 H, d, J = 8.9 Hz),






7.02(2 H, d, J = 8.4 Hz), 7.19(2 H, d, J = 8.6 Hz),






7.55(1 H, d, J = 8.1 Hz), 7.68-7.71(1 H, m),






7.96-7.97(2 H, m), 8.14-8.17(1 H, m), 8.23(1 H, d, J =






2.7 Hz).


2538
4-CF3Ph-
—COOC(CH3)3—
3
1.46(9 H,.s), 1.78-1.89(2 H, m), 2.36-2.42(6 H, m),






2.62-2.68 (2 H, m), 3.42-3.45(4 H, m), 6.94(1 H, d,






J = 8.9 Hz), 7.01-7.06 (2 H, m), 7.18-7.23(2 H, m),






7.76(2 H, d, J = 8.2 Hz), 7.99-8.03 (3 H, m),






8.22(1 H, dd, J = 8.9 Hz, 2.6 Hz), 8.28(1 H, d, J =






2.6 Hz).


2539
3,4-Cl2Ph-
—CH3
4
1.50-1.80(4 H, m), 2.32(3 H, s), 2.38(2 H, t, J = 7.3






Hz), 2.30-2.70(8 H, m), 2.64(2 H, t, J = 7.3 Hz),






6.94(1 H, d, J = 8.8 Hz), 7.03(2 H, d, J = 8.2 Hz),






7.19(2 H, d, J = 8.2 Hz), 7.58(1 H, d, J = 8.2 Hz),






7.72(1 H, dd, J = 8.2 Hz, 2.0 Hz), 7.84(1 H, s),






8.00(1 H, d, J = 2.0 Hz), 8.18(1 H, dd, J = 8.8 Hz,






2.6 Hz), 8.26 (1 H, d, J = 2.6 Hz).


2540
3,4-Cl2Ph-
benzyl
4
1.45-1.75(4 H, m), 2.36(2 H, t, J = 7.5 Hz),






2.30-2.65(8 H, m), 2.62(2 H, t, J = 7.7 Hz), 3.51(2 H, s),






6.92(1 H, d, J = 8.6 Hz), 7.03(2 H, d, J = 8.6 Hz),






7.19(2 H, d, J = 8.6 Hz), 7.15-7.40(5 H, m),






7.57(1 H, d, J = 8.2 Hz), 7.71(1 H, dd, J = 8.2 Hz,






2.0 Hz), 7.85(1 H, s), 7.98(1 H, d, 4 2.0 Hz),






8.16(1 H, dd, J = 8.6 Hz, 2.5 Hz), 8.24(1 H, d, J =






2.5 Hz).


2541
3,4-Cl2Ph-
benzyl
5
1.25-1.45(2 H, m), 1.45-1.75(4 H, m), 2.34(2 H, t, J =






7.7 Hz), 2.30-2.70(8 H, m), 2.61(2 H, t, J = 7.7






Hz), 3.51(2 H, s), 6.93(1 H, d, J = 8.7 Hz),






7.03(2 H, d, J = 8.6 Hz), 7.19(2 H, d, J = 8.6 Hz),






7.20-7.40(5 H, m), 7.58(1 H, d, J = 8.3 Hz),






7.70(1 H, dd, J = 8.3 Hz, 2.0 Hz), 7.71(1 H, d, J =






2.0 Hz), 7.98(1 H, d, J = 2.0 Hz), 8.16(1 H, dd, J =






8.7 Hz, 2.6 Hz), 8.24(1 H, d, J = 2.6 Hz).
















TABLE 398













 











Example






No.
R1106
R1107
Form
1H NMR (DMSO-d6) δ ppm





2542
3,4-Cl2Ph-
—H
hydro-
1.12(3 H, d, J = 6.3 Hz), 2.75-3.03(2 H,





chloride
m), 3.24-3.39(2 H, m), 378-3.98(3 H, m),






4.31(2 H, brs) 7.13(1 H, d, J = 8.6 Hz),






7.20 (2 H, d, J = 8.3 Hz), 7.63(2 H, d, J =






8.3 Hz), 7.84(1 H, d, J = 8.2 Hz),






7.98(1 H, dd, J = 8.2 Hz, 2.6 Hz),






8.24(1 H, dd, J = 8.9 Hz, 2.6 Hz),






8.25(1 H, d, J = 2.0 Hz), 8.55(1 H, d, J = 






2.6 Hz), 10.67(1 H, brs), 11.10(1 H, brs).


2543
3,4-Cl2Ph-
—O(CH2)3CH3
hydro-
0.87(3 H, t, J = 7.3 Hz), 1.22-1.36(2 H,





chloride
m), 1.41-1.51(2 H, m), 2.90-3.07(2 H, m),






3.23-3.50(611, m), 3.80-3.88(1 H, m),






3.99-4.02(2 H, m), 4.35(2 H, brs),






7.13(1 H, d, J = 8.9 Hz), 7.21 (2 H, d, J =






8.6 Hz), 7.63(2 H, d, J = 8.3 Hz),






7.84(1 H, d, J = 8.6 Hz), 7.97(1 H, dd, J =






8.3 Hz, 2.0 Hz), 8.24(1 H, dd, J = 8.9 Hz,






2.6 Hz), 8.25(1 H, d, J = 2.0 Hz),






8.54(1 H, d, J = 2.6 Hz), 10.66(1 H, brs),






11.17(1 H, brs).


2544
3,4-Cl2Ph-
piperidino
dihydro-
1.38-1.77(6 H, m), 2.92-3.10(5 H, m),





chloride
3.22-3.33(4 H, m), 3.47-3.51(1 H, m),






3.97-4.06(2 H, m), 4.27-4.55(3 H, m), 7.13






(1 H, d, J = 8.9 Hz), 7.21(2 H, d, J = 8.6






Hz), 7.67(2 H, d, J = 8.6 Hz), 7.84(1 H, d,






J = 8.6 Hz), 7.99(1 H, dd, J = 8.2 Hz, 2.0






Hz), 8.26(1 H, dd, J = 8.6 Hz, 3.0 Hz),






8.28(1 H, d, J = 2.3 Hz), 8.57(1 H, d, J =






2.6 Hz), 10.27(1 H, brs), 10.74(1 H, brs),






11.91 (1 H, brs).


2545
4-CF3Ph-
—H
hydro-
1.12(3 H, d, J = 6.1 Hz), 2.68-2.80(1 H,





chloride
m), 2.983.06(1 H, m), 3.24-3.28(2 H, m),






3.80-3.90(3 H, m), 4.31(2 H, brs),






7.14(1 H, d, J = 8.7 Hz), 7.21(2 H, d, J =






8.4 Hz), 7.64(2 H, d, J = 8.1 Hz),






7.93(2 H, d, J = 8.4 Hz), 8.19(2 H, d, J =






8.2 Hz), 8.27(1 H, dd, J = 8.9 Hz, 2.6






Hz), 8.57(1 H, d, J = 2.6 Hz), 10.75(1 H,






brs), 11.19(1 H, brs).


2546
4-CF3Ph-
—OCH
hydro-
2.92-3.12(2 H, m), 3.26(3 H, s), 3.34-3.47





chloride
(4 H, m), 3.80-4.02 (3 H, m), 4.34(2 H,






brs), 7.14(1 H, d, J = 8.9 Hz), 7.21(2 H, d,






J = 8.6 Hz), 7.63(2 H, d, J = 8.2 Hz),






7.94(2 H, d, J = 8.4 Hz), 8.18 (2 H, d, J =






8.1 Hz), 8.27(1 H, dd, J 8.7 Hz, 2.6






Hz), 8.57(1 H, d, J = 2.6 Hz), 10.73(1 H,






brs), 11.13(1 H, brs).


2547
3,4-Cl2Ph-
—OCH3
hydro-
2.92-3.11(2 H, m), 3.26(3 H, s), 3.31-3.52





chloride
(4 H, m), 3.79-3.87 (1 H, m), 3.95-4.04






(2 H, m), 4.34(2 H, brs), 7.14(1 H, d, J =






8.9 Hz), 7.21(2 H, d, J = 8.6 Hz),






7.62(2 H, d, J = 8.6 Hz), 7.84(1 H, d, J =






8.4 Hz), 7.97(1 H, dd, J = 8.4 Hz, 2.2






Hz), 8.24-8.26(2 H, m), 8.54(1 H, d, J =






2.6 Hz), 10.66(1 H, brs), 11.02(1 H, brs).
















TABLE 399







 








 











Example






No.
R1108
M
Form
1H NMR (solvent) δppm





2548




5
free
(CDCl3) 1.30-1.45 (2H, m), 1.45-1.75 (4H, m), 2.30 (3H, s), 2.25-2.40 (2H, m), 2.49 (8H, brs), 2.62 (2H, t, J = 7.5 Hz), 6.94 (1H, d, J = 8.9 Hz), 7.04 (2H, d, J = 8.6 Hz), 7.20 (2H, d, J = 8.6 Hz), 7.59 (1H, d, J = 8.2 Hz), 7.65-7.75 (2H, m), 7.98 (1H, d, J = 2.0 Hz), 8.17 (1H, dd, J = 8.9 Hz, 3.0 Hz), 8.24 (1H, d, J = 3.0 Hz).


 


2549




1
hydro- chloride
(DMSO-d6) 1.13 (6H, d, J = 6.6 Hz), 2.66-2.76 (2H, m), 3.25-3.34 (2H, m), 3.91-3.99 (2H, m), 4.30 (2H, s), 7.14 (1H, d, J = 8.6 Hz), 7.21 (2H, d, J = 8.6 Hz), 7.62 (2H, d, J = 8.3 Hz), 7.85 (1H, d, J = 8.6 Hz), 7.97 (1H, dd, J = 8.6 Hz, 2.0 Hz), 8.24 (.1H, dd, J = 8.6 Hz, 3.0 Hz), 8.25 (1H, d, J = 2.3 Hz), 8.55 (1H, d, J = 2.6 Hz), 10.65 (1H, brs), 10.96 (1H, brs).


 


2550




1
hydro- chloride
(DMSO-d6) 1.11 (3H, d, J = 6.3 Hz), 1.40 (3H, d, J = 6.9 Hz), 2.67-2.75 (1H, m), 3.10 (2H, m), 3.25- 3.33 (1H, m), 4.02-4.32 (4H, m), 7.14 (1H, d, J = 8.9 Hz), 7.21 (2H, d, J = 8.3 Hz), 7.65 (2H, d, J = 8.6 Hz), 7.85 (1H, d, J = 8.2 Hz), 7.97 (1H, dd, J = 8.6 Hz, 2.0 Hz), 8.21-8.26 (2H, m), 8.54 (1H, d, J = 2.3 Hz), 10.46 (1H, brs), 10.64 (1H, brs).









Example 2551
Production of 1-(3-{4-[4-(3,4-dichlorobenzoylamino)-phenoxy]phenyl}propionyl)-4-[2-(morpholino)acetyl]-piperazine
To a solution of 1-chloroacetyl-4-(3-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}propionyl)-piperazine (0.515 g, 0.896 mmol) and diisopropylethylamine (0.234 mL, 1.34 mmol) in acetonitrile (11 mL) was added morpholine (0.117 mL, 1.34 mmol), and the resulting solution was refluxed for 1 hour. This reaction solution was concentrated under reduced pressure. To the residue was added a saturated sodium bicarbonate solution, and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, and evaporated. The obtained solid was recrystallized from water-containing acetone, to thereby yield 0.441 g of the title compound.
Appearance: White powder
Melting point: 187-190° C.
The following compounds were produced in the same manner as in Example 2551.







TABLE 400







 








 










Example





No.
R1109
Form
mp (° C.) or 1H NMR





2552
—COCH2N(C2H5)2
3/2 oxalate
mp 107-118


2553
—COCH2NHCH2Ph
hydrochloride
mp 199-202


2554
—COCH2N(C2H5)CH2Ph
fumarate
1H NMR (DMSO-d6) δ 0.99 (3H, t, J =





7.1 Hz), 2.56-2.70 (2H, m), 2.73





2.86 (2H, m), 3.09-3.50 (12H, m),





3.59 (2H, s), 6.61 (2H, s), 6.91 (2H, d, J =





8.0 Hz), 6.98 (2H, d, J = 9.0 Hz),





7.14-7.37 (7H, m), 7.74 (2H, d, J = 9.0





Hz), 7.81 (1H, d, J = 8.4 Hz), 7.92 (1H,





dd, J = 8.4 Hz, 2.1 Hz), 8.20 (1H, d, J =





2.1 Hz), 10.39 (1H, s), 13.09 (2H,





brs).


 


2555




dihydrochloride
mp 173-176


 


2556
—COCH2N(C2H5)Ph
free
mp 140-143
















TABLE 401







 








 









Example




No.
R1110
mp (° C.)





2557




206-210


 


2558




154-156


 


2559
morpholino
177-178


 


2560




204-206


 


2561
—N(CH3)CH2Ph
182-184
















TABLE 402







 








 









Example




No.
R1111
mp (° C.)





2562




151-152


 


2563
morpholino
177-178


 


2564




146-147
















TABLE 403







 








 









Example




No.
R1112
mp (° C.)





2565
morpholino
195-197


 


2566




146-148


 


2567




173-176


 


2568




150-153
















TABLE 404







 








 










Example





No.
R1113
Form
mp (° C.)





2569




dihydrochloride
152-155


 


2570




dihydrochloride
181-185


 


2571
morpholino
hydrochloride
146-150
















TABLE 405







 








 









Example




No.
R1114
mp (° C.)





2572
morpholino
157-160


 


2573




241-243


 


2574




193-196


 


2575




180-182
















TABLE 406







 








 











Example






No.
R1115
Xb63
R1116
mp (° C.) or 1H NMR





2576
3,4-Cl2Ph—
none
morpholino
1H NMR (DMSO-d6) δ 2.50-






2.53 (4H, m), 3.55-3.61 (4H,






m), 3.82 (2H, s), 7.20 (1H, d, J =






8.7 Hz), 7.21 (2H, d, J = 8.1






Hz), 7.85 (1H, d, J = 8.4 Hz),






7.96 (1H, dd, J = 8.4 Hz, 1.2






Hz), 8.06 (2H, d, J = 8.4 Hz),






8.23 (1H, d, J = 1.5 Hz), 8.27 (1H, dd, J = 8.9 Hz, 2.8 Hz), 8.55 (1H, d, J = 2.8 Hz), 10.61 (1H, brs).


 


2577
4-CF3Ph—








mp 179-181


 


2578
4-CF3Ph—








mp 172-174


 


2579
4-CF3Ph—




morpholino
mp 144-146


 


2580
4-CF3Ph—




—N(CH3)CH2Ph
mp 188-190


 


2581
4-CF3Ph—








mp 192-193









The following compound was produced in the same manner as in Reference Example 860.
Example 2582
1-{4-[5-(3,4-Dichlorobenzoylamino)pyridin-2-yloxy]benzyl}piperazine-4-carboxylic acid ethyl ester
Appearance: Pale yellow oil
1H NMR (CDCl3) δ 1.25 (3H, t, J=7.0 Hz), 1.76 (2H, m), 1.77 (2H, m), 2.03 (2H, t, J=11.5 Hz), 2.28 (1H, m), 2.87 (2H, brd, J=11.5 Hz), 3.48 (2H, s), 4.13 (2H, q, J=7.0 Hz), 6.94 (1H, d, J=9.0 Hz), 7.06 (2H, d, J=8.5 Hz), 7.33 (2H, d, J=9.0 Hz), 7.57 (1H, d, J=8.5 Hz), 7.70 (1H, dd, J=8.5 Hz, 2.0 Hz), 7.88 (1H, brs), 7.97 (1H, d, J=2.0 Hz), 8.17 (1H, dd, J=9.0 Hz, 3.0 Hz), 8.24 (1H, d, J=3.0 Hz).
Example 2583
Production of 3,4-dichloro-N-{6-[4-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)phenoxy]pyridin-3-yl}benzamide
To uracil (200 mg, 1.8 mmol) was added hexamethyldisilazane (5 mL), and the resulting solution was stirred for 5.5 hours at 150° C. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in a solution of acetonitrile (10 mL)-THF (5 mL), and to this solution were added 3,4-dichloro-N-[6-(4-chloromethylphenoxy)pyridin-3-yl]benzamide (500 mg, 1.2 mmol) and tin tetrachloride (3 drops). The resulting solution was refluxed for 2.5 hours. To this reaction solution was added methanol (1 mL), and the resulting solution was stirred for 30 minutes at room temperature. The resulting reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol:chloroform=1:99→3:97), to thereby yield 20 mg of the title compound.
Appearance: White powder
1H NMR (DMSO-d6) δ 4.88 (2H, s), 5.61 (1H, dd, J=7.9 Hz, 2.3 Hz), 7.07-7.13 (3H, m), 7.35 (2H, d, J=8.6 Hz), 7.79-7.85 (2H, m), 7.95 (1H, dd, J=8.6 Hz, 2.0 Hz), 8.18 (1H, d, J=2.6 Hz), 8.22 (1H, d, J=2.0 Hz), 8.47 (1H, d, J=2.6 Hz), 10.55 (1H, s), 11.33 (1H, s);
MS: m/z 482 (M+).
Example 2584
Production of N-{6-[4-(4-benzyl-2-oxopiperazin-1-ylmethyl)phenoxy]pyridin-3-yl}-3,4-dichlorobenzamide dihydrochloride
To a solution of 4-benzylpiperazin-2-one (0.56 g, 2.95 mmol) in DMF (10 mL) was added 60% sodium hydride (0.12 g, 2.95 mmol), and this solution was stirred at room temperature for 30 minutes. 2-(4-chloromethylphenoxy)-5-nitropyridine (0.78 g, 2.95 mmol) was added to the reaction mixture, and the mixture was stirred for 1 hour at room temperature. To this mixture was added brine (50 mL), and extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The remaining oil was dissolved in ethyl acetate (5 mL), and to the resulting solution was added iron powder (0.33 g, 5.89 mmol). This solution was stirred for 2 hours at room temperature. The resulting reaction solution was concentrated under reduced pressure, and a saturated sodium bicarbonate solution (50 mL) was added to the residue. The obtained mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated. The remaining oil was dissolved in THF (10 mL). To the resulting solution were added triethylamine (0.21 mL, 1.47 mmol) and 3,4-dichlorobenzoyl chloride (0.31 mL, 1.47 mmol), and this solution was stirred at room temperature for 2 hours. A saturated sodium bicarbonate solution (50 mL) was added to the solution, and extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=40:1). The obtained oil was dissolved in ethyl acetate (5 mL), and to the resulting solution was added a solution of 4 N hydrogen chloride in ethyl acetate (1.5 mL, 6 mmol). The formed white powder was collected by suction filtration, to thereby yield 0.045 g of the title compound.
Appearance: White powder
1H NMR (DMSO-d6) δ 3.54 (4H, m), 3.86 (2H, brs), 4.42 (2H, s), 4.59 (2H, brs), 7.06-7.12 (3H, m), 7.34 (2H, d, J=8.6 Hz), 7.48-7.51 (3H, m), 7.57-7.60 (2H, m), 7.84 (1H, d, J=8.6 Hz), 7.97 (1H, dd, J=2.0 Hz, 8.3 Hz), 8.18-8.24 (2H, m), 8.49 (1H, d, J=2.6 Hz), 10.61 (1H, s).
The following compound was produced in the same manner as in Reference Example 656.
Example 2585
2-({4-[5-(3,4-Dichlorophenylamino)pyridin-2-yloxy]-2-trifluoromethylphenyl}ethylamino)-1-(4-piperonylpiperazin-1-yl)ethanone
1H NMR (CDCl3) δ 1.02 (3H, t, J=7.1 Hz), 2.30-2.45 (4H, m), 3.22 (2H, q, J=7.1 Hz), 3.40 (2H, s), 3.45-3.65 (4H, m), 3.85 (2H, s), 5.57 (1H, brs), 5.94 (2H, s), 6.65-6.80 (3H, m), 6.85 (1H, s), 6.95 (1H, d, J=8.7 Hz), 7.00 (1H, d, J=2.7 Hz), 7.29-7.31 (2H, m), 7.39 (1H, d, J=2.7 Hz), 7.53 (1H, dd, J=8.7 Hz, 2.9 Hz), 7.64 (1H, d, J=8.8 Hz), 7.99 (1H, d, J=2.7 Hz).
The following compounds were produced in the same manner as in Reference Example 658.







TABLE 407













 











Example No.
R1117
R1118
M
mp (° C.) or 1H NMR (DMSO-d6) δ ppm





2586
4-CF3Ph-
—H
2
1H NMR 2.14-2.30 (2H, m), 2.62-3.12 (7H, m), 3.20-3.58 (3H,






m), 3.77 (2H, t, J = 5.9 Hz), 3.81-4.15 (3H, m), 4.16-4.32 (2H,






m), 4.49-4.57 (1H, m), 6.08 (2H, s), 6.96-7.09 (5H, m), 7.21 (1H,






s), 7.29 (2H, d, J = 8.5 Hz), 7.58 (2H, d, J = 8.5 Hz), 7.70 (2H, d,






J = 8.8 Hz), 7.86 (1H, dd, J = 2.8 Hz, 8.8 Hz), 8.13 (1H, d,






J = 2.8 Hz), 10.78-11.01 (1H, m).


2587
3,4-Cl2Ph-
—H
2
mp 182.0-183.0


2588
3-CF3Ph-
—H
1
mp 200.0-203.0


2589
4-CF3Ph-
—OCH3
1
mp 153.0-154.0


2590
3,4-Cl2Ph-
—OCH3
1
mp 169.0-171.0


2591
4-CF3Ph-
—OCH3
2
mp 134.0-136.0


2592
3,4-Cl2Ph-
—OCH3
2
mp 130.0-132.0
















TABLE 408













 










Example No.
R1119
M
mp (° C.) or 1H NMR (DMSO-d6) δ ppm





2593
4-CF3Ph-
1
1H NMR 1.90-2.06 (2H, m), 2.07 (3H, s), 3.18-3.32 (2H, m),





3.55-3.70 (2H, m), 3.73 (3H, s), 3.74 (3H, s), 3.91-4.12 (4H,





m), 4.43 (2H, s), 4.49-4.93 (1H, m), 6.81 (1H, dd, J = 1.8 Hz,





8.1 Hz), 6.88 (1H, d, J = 1.8 Hz), 6.92 (1H, d, J = 8.1 Hz), 6.97





(1H, d, J = 8.5 Hz), 7.06 (1H, d, J = 9.0 Hz), 7.12 (1H, dd, J =





2.4 Hz, 8.5 Hz), 7.21 (1H, d, J = 2.4 Hz), 7.71 (2H, d, J = 8.9





Hz), 7.83 (2H, d, J = 8.9 Hz), 8.19 (1H, dd, J = 2.9 Hz, 9.0 Hz),





8.27 (1H, d, J = 2.9 Hz).


2594
3,4-Cl2Ph-
1
mp 146.0-148.0


2595
3,4-Cl2Ph-
2
1H NMR 1.91-2.11 (5H, m), 2.12-2.24 (2H, m), 3.19-3.32 (2H,





m), 3.58-3.83 (10H, m), 3.85-4.22 (3H, m), 4.42 (2H, s), 6.81





(1H, dd, J = 1.8 Hz, 8.1 Hz), 6.87 (1H, d, J = 1.8 Hz), 6.91 (1H,





d, J = 8.1 Hz), 6.94-7.02 (2H, m), 7.12 (1H, dd, J = 2.5 Hz, 8.6





Hz), 7.21 (1H, d, J = 2.5 Hz), 7.35 (1H, dd, J = 2.5 Hz, 8.8 Hz),





7.57 (1H, d, J = 8.8 Hz), 7.66 (1H, d, J = 2.5 Hz), 7.82 (1H, dd,





J = 2.5 Hz, 8.8 Hz), 8.07 (1H, d, J = 2.5 Hz).









Example 2596
Production of 3-(4-{5-[4-(3,4-dichlorophenyl)piperazin-1-yl]pyridin-2-yloxy}phenyl)-1-(4-pipeonylpiperazin-1-yl)propane-1-one
To a solution of 3-[4-(5-bromopyridin-2-yloxy)phenyl]-1-(4-piperonylpiperazin-1-yl)propane-1-one (359 mg, 0.69 mmol) and 1-(3,4-dichlorophenyl)-piperazine (206 mg, 0.89 mmol) in toluene (16 mL) were added with Pd2(dba)3 (25 mg, 0.027 mmol), Xantphos (32 mg, 0.055 mmol) and sodium t-butoxide (99 mg, 1.03 mmol), and the resulting solution was refluxed under an argon atmosphere for 3 hours. The solution was left to cool, water was added to this reaction mixture. The resulting solution was extracted with dichloromethane, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane methanol=30:1), to thereby yield 236 mg of the title compound.
Appearance: Pale yellow powder
1H NMR (CDCl3) δ 2.31-2.40 (4H, m), 2.58-2.64 (2H, m), 2.92-2.98 (2H, m), 3.23-3.38 (8H, m), 3.41 (4H, brs), 3.63 (2H, t, J=4.9 Hz), 5.94 (2H, s), 6.72-6.73 (2H, m), 6.78 (1H, dd, J=8.9 Hz, 2.8 Hz), 6.84-6.90 (2H, m), 6.99-7.06 (3H, m), 7.19-7.24 (3H, m), 7.32 (1H, dd, J=9.4 Hz, 3.1 Hz), 7.88 (1H, d, J=3.0 Hz). Tris(dibenzylideneacetone)dipalladium is abbreviated to Pd2(dba)3. Hereinafter, the same. 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene is abbreviated to Xantphos. Hereinafter the same.
The following compounds were produced in the same manner as in Example 2596.







TABLE 409







 








 











Example






No.
R1120
R1121 
Xb64
1H NMR (CDCl3) δppm





2597
4-CF3PhCH2—
—H
—CH2—
2.31-2.38 (4H, m), 2.60-2.64 (6H, m), 2.95 (2H, t, J =






7.3 Hz), 3.11-3.15 (4H, m), 3.40 (4H, brs),






3.61 (4H, brs), 5.93 (2H, s), 6.73 (2H, s), 6.83 (2H,






d, J = 9.1 Hz), 6.99 (2H, d, J = 8.4 Hz), 7.19 (2H,






d, J = 8.4 Hz), 7.29 (1H, dd, J = 8.9 Hz, 3.1 Hz),






7.47 (2H, d, J = 8.2 Hz), 7.58 (2H, d, J = 8.1 Hz),






7.83 (1H, d, J = 3.0 Hz).


2598
3,4-Cl2Ph—
—CH3
—N(CH3)—
2.13 (3H, s), 2.40-2.44 (4H, m), 3.00 (3H, s), 3.18-






3.38 (8H, m), 3.43 (2H, s), 3.49 (2H, brs), 3.63 (2H,






brs), 4.06 (2H, s), 5.94 (2H, s), 6.52-6.57 (2H, m),






6.69-6.91 (6H, m), 7.00 (1H, d, J = 3.0 Hz), 7.26-






7.32 (2H, m), 7.86 (1H, d, J = 2.8 Hz).


2599
4-CF3Ph—
—CH3
—N(CH3)—
2.13 (3H, s), 2.41-2.44 (4H, m), 3.00 (3H, s), 3.20-






3.24 (4H, m), 3.34-3.43 (6H, m), 3.49 (2H, brs),






3.63 (2H, brs), 4.06 (2H, s), 5.94 (2H, s), 6.52-






6.58 (2H, m), 6.70-6.77 (3H, m), 6.85-6.98 (4H, m),






7.31 (1H, dd, J = 9.1 Hz, 3.1 Hz), 7.50 (2H, d, J =






8.6 Hz), 7.87 (1H, d, J = 2.6 Hz).


2600
4-CF3Ph—
—H
—CH2—
2.31-2.40 (4H, m), 2.61 (2H, t, J = 7.3 Hz),






2.96 (2H, t, J = 7.3 Hz), 3.23-3.27 (4H, m), 3.38-






3.45 (8H, m), 3.63 (2H, t, J = 4.8 Hz), 5.94 (2H, s),






6.70-6.76 (2H, m), 6.84-7.06 (6H, m), 7.19-






7.26 (2H, m), 7.36 (1H, dd, J = 8.9 Hz, 3.1 Hz),






7.51 (2H, d, J = 8.9 Hz), 7.89 (1H, d, J = 3.0 Hz).









The following compounds were produced in the same manner as in Reference Example 659.







TABLE 410







 








 












Example







No.
R1122
Xb65
Xb66
R1123
1H NMR (CDCl3) δppm





2601
4-CF3Ph—
—N(CH3)—
—CH2—
piperonyl
2.41-2.44 (4H, m), 3.03 (3H, s), 3.43 (2H,







s), 3.47-3.50 (2H, m), 3.61-3.65 (2H, m),







4.09 (2H, s), 5.93 (2H, s), 6.68-6.77 (4H,







m), 6.83-6.86 (2H, m) 6.99 (1H, d, J =







16.5 Hz), 7.00-7.06 (2H, m), 7.10 (1H, d,







J = 16.5 Hz), 7.54-7.61 (4H, m), 7.84 (1H,







dd, J = 8.6 Hz, 2.5 Hz), 8.26 (1H, d, J =







2.5 Hz).


2602
3,4-Cl2Ph—
—N(CH3)—
—CH2—
piperonyl
2.42-2.45 (4H, m), 3.04 (3H, s), 3.44 (2H,







s), 3.48-3.52 (2H, m), 3.62-3.66 (2H, m),







4.09 (2H, s), 5.95 (2H, s), 6.68-6.86 (6H,







m), 6.94 (1H, d, J = 17.3 Hz), 6.99-







7.04 (3H, m), 7.31 (1H, dd, J = 8.4 Hz, 2.0







Hz), 7.42 (1H, d, J = 8.4 Hz), 7.57 (1H, d,







J = 2.0 Hz), 7.82 (1H, d, J = 8.4 Hz),







8.24 (1H, brs).


2603
4-CF3Ph—
—CH2—
—CH2—
piperonyl
2.32-2.41 (4H, m), 2.60-2.66 (2H, m),







2.96-3.01 (2H, m), 3.39-3.43 (4H, m),







3.62-3.66 (2H, m), 5.95 (2H, s), 6.70-







6.77 (2H, m), 6.84-6.85 (1H, m), 6.93 (1H,







d, J = 8.6 Hz), 7.00-7.09 (3H, m),







7.12 (1H, d, J = 16.5 Hz), 7.23-7.27 (2H,







m), 7.56-7.64 (4H, m), 7.90 (1H, dd, J =







8.7 Hz, 2.6 Hz), 8.27 (1H, d, J = 2.6 Hz).


2604
4-CF3Ph—
none
none
benzyl
2.47 (4H, brs), 3.55-3.77 (6H, m),







6.97 (1H, d, J = 8.6 Hz), 7.05 (1H, d, J =







16.3 Hz), 7.10-7.27 (3H, m), 7.28-







7.34 (5H, m), 7.45-7.50 (2H, m), 7.57-







7.64 (4H, m), 7.93 (1H, dd, J = 8.6 Hz, 2.4







Hz), 8.29 (1H, d, J = 2.4 Hz).


2605
3,4-Cl2Ph—
none
none
benzyl
2.52 (4H, brs), 3.49-3.90 (6H, m), 6.89-







6.98 (2H, m), 7.03 (1H, d, J = 16.5 Hz),







7.15-7.20 (2H, m), 7.30-7.50 (9H, m),







7.58 (1H, d, J = 2.1 Hz), 7.90 (1H, dd, J =







8.7 Hz, 2.5 Hz), 8.26 (1H, d, J = 2.5 Hz).
















TABLE 411







 








 










Example





No.
R1124
Form
1H NMR (solvent) δppm





2606
piperonyl
hydrobromide
(DMSO-d6) 1.89-2.06 (2H, m), 2.06 (3H, s),





3.18-3.35 (2H, m), 3.57-3.71 (2H, m), 4.40 (2H,





s), 4.42-4.80 (1H, m, 5.99 (2H, s), 6.77 (1H, dd,





J = 1.6 Hz, 7.9 Hz), 6.84 (1H, d, J = 1.6 Hz),





6.87 (1H, d, J = 7.9 Hz), 7.01 (1H, d, J = 8.6





Hz), 7.07 (1H, d, J = 8.6 Hz), 7.13 (1H, dd, J =





2.5 Hz, 8.6 Hz), 7.23 (1H, d, J = 2.5 Hz),





7.32 (1H, d, J = 16.5 Hz), 7.42 (1H, d, J = 16.5





Hz), 7.72 (2H, d, J = 8.5 Hz), 7.79 (2H, d, J =





8.5 Hz), 8.19 (1H, dd, J = 2.4 Hz, 8.6 Hz),





8.30 (1H, d, J = 2.4 Hz).


2607
3,4-
free
(CDCl3) 1.99-2.14 (2H, m), 2.18 (3H, s), 3.22-



(CH3O)2PhCH2—

3.38 (2H, m), 3.63-3.79 (2H, m), 3.89 (3H, s),





3.90 (3H, s), 4.57 (2H, s), 6.76-6.95 (4H, m),





6.97-7.20 (4H, m), 7.51-7.67 (4H, m), 7.88 (1H,





dd, J = 2.5 Hz, 8.6 Hz), 8.27 (1H, d, J = 2.5





Hz).









Example 2608
Production of 1-(3,4-dimethoxybenzyl)-3-{3-methyl-4-[5-(4-trifluoromethylphenylethynyl)pyridin-2-yloxy]phenyl}tetrahydropyrimidin-2-one
To a solution of 1-[4-(5-bromopyridin-2-yloxy)-3-methylphenyl]-3-(3,4-dimethoxybenzyl)tetrahydropyrimidin-2-one (0.3 g, 0.59 mmol) in N-methylpyrrolidone (10 mL) were added bis(triphenylphosphine)palladium dichloride (20 mg, 0.03 mmol), copper iodide (11 mg, 0.059 mmol), 4-ethynyl-α,α,α-trifluorotoluene (0.14 mL, 0.88 mmol) and triethylamine (0.14 mL, 10 mmol) under a nitrogen atmosphere. The resulting solution was stirred for 3 hours at 110 to 120° C. After being left to cool, water was added to the reaction solution. The resulting solution was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then evaporated, and the residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1→1:1), to thereby yield 0.28 g of the title compound.
Appearance: Pale brown amorphous powder
1H NMR (CDCl3) δ 1.97-2.15 (2H, m), 2.16 (3H, s), 3.31 (2H, t, J=6.0 Hz), 3.72 (2H, t, J=6.0 Hz), 3.88 (3H, s), 3.89 (3H, s), 4.57 (2H, s), 6.72-6.95 (5H, m), 7.04 (1H, d, J=8.6 Hz), 7.17 (1H, dd, J=2.6 Hz, 8.6 Hz), 7.55-7.68 (4H, m), 7.78 (1H, dd, J=2.3 Hz, 8.6 Hz), 8.36 (1H, d, J=2.3 Hz).
Example 2609
Production of 3-(3-methyl-4-{5-[2-oxo-2-(4-trifluoromethylphenyl)ethyl]pyridin-2-yloxy}phenyl)-1-piperonyltetrahydropyrimidin-2-one hydrobromide
To a solution of 3-[4-(5-bromopyridin-2-yloxy)-3-methylphenyl]-1-piperonyltetrahydropyrimidin-2-one (0.11 g, 0.22 mmol) in toluene (10 mL) were added Pd2(dba)3 (10 mg, 0.01 mmol) and Xantphos (15 mg, 0.03 mmol) under a nitrogen atmosphere. The resulting solution was stirred for 5 minutes, and then 4′-(trifluoromethyl)acetophenone (63 mg, 0.33 mmol) and potassium bis(trimethylsilyl)amide (66 mg, 0.33 mmol) were added to the reaction % solution. The resulting solution was stirred at 70 to 80° C. for 30 minutes, and left to cool. Water was added to the reaction solution, and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→1:1), to yield 50 mg of a free form. To this free form was added an equivalent amount of hydrobromic acid, to thereby yield 50 mg of the title compound.
Appearance: Colorless amorphous powder
1H NMR (DMSO-d6) δ 1.85-2.10 (2H, m), 2.06 (3H, s), 3.14-3.47 (2H, m), 3.50-3.76 (2H, m), 4.40 (2H, s), 4.49 (2H, s), 4.70-5.40 (1H, m), 5.98 (2H, s), 6.70-6.80 (1H, m), 6.81-6.90 (2H, m), 6.90-7.04 (2H, m), 7.12 (1H, d, J=2.2 Hz, 8.6 Hz), 7.18-7.26 (1H, m), 7.72 (1H, dd, J=2.2 Hz, 8.5 Hz), 7.93 (2H, d, J=8.2 Hz), 7.95-8.02 (1H, m), 8.24 (2H, d, J=8.2 Hz).
The following compounds were produced in the same manner as in Example 2609.







TABLE 412







 








 










Example





No.
R1125
R1126
1H NMR (CDCl3) δppm





2610
3,4-Cl2Ph—
piperonyl
1.82-2.10 (2H, m), 2.07 (3H, s), 3.12-3.32 (2H, m),





3.53-3.72 (2H, m), 4.40 (2H, s), 4.45 (2H, s), 4.80-





5.40 (1H, m), 5.99 (2H, s), 6.71-6.80 (1H, m), 6.81-





6.90 (2H, m), 6.98 (2H, dd, J = 2.4 Hz, 8.5 Hz),





7.12 (1H, dd, J = 2.4 Hz, 8.5 Hz), 7.21 (1H, d, J = 2.4





Hz), 7.70 (1H, dd, J = 2.2Hz, 8.4 Hz), 7.84 (1H, d, J =





8.4 Hz), 7.96 (1H, d, J = 2.2 Hz), 8.00 (1H, dd, J =





2.0 Hz, 8.4 Hz), 8.25 (1H, d, J = 2.0 Hz).


2611
4-CF3Ph—
3,4-(CH3O)2Ph—
1.87-2.11 (5H, m), 3.15-3.32 (2H, m), 3.43-3.71 (3H,





m), 3.74 (3H, s), 3.75 (3H, s), 4.44 (2H, s), 4.51 (2H, s),





6.78-6.86 (1H, m), 6.87-6.91 (1H, m), 6.93 (1H, d, J =





8.5 Hz), 6.99 (1H, d, J = 8.5 Hz), 7.00 (1H, d, J = 8.5





Hz), 7.14 (1H, dd, J = 2.4 Hz, 8.5 Hz), 7.19-7.25 (1H,





m), 7.73 (1H, dd J = 2.4 Hz, 8.5 Hz), 7.94 (1H, d, J =





8.3 Hz), 7.97-8.01 (1H, m), 8.25 (1H, d, J = 8.3 Hz).
















TABLE 413







 








 









Example

mp (° C.) or


No.
R1127
1H NMR (solvent) δppm





2612




1H NMR (CDCl3) 2.44 (4H, brs), 3.44 (2H, s), 3.54 (2H, brs), 3.73 (2H, brs), 4.29 (2H, s), 5.94 (2H, s), 6.74 (2H, s), 6.85 (1H, s), 6.94 (1H, d, J = 8.4 Hz), 7.16 (2H, d, J = 8.6 Hz), 7.45 (2H, d, J = 8.6 Hz), 7.63 (1H, dd, J = 8.4 Hz, 2.5 Hz), 7.76 (2H, d, J = 8.1 Hz), 8.07 (1H, d, J = 2.5 Hz), 8.11 (2H, d, J = 8.1 Hz).


 


2613




1H NMR (DMSO-d6) 2.31 (3H, s), 2.76- 3.45 (9H, m), 3.69-4.57 (8H, m), 6.07 (2H, s), 6.81-7.22 (6H, m), 7.74 (1H, dd, J = 2.2 Hz, 8.4 Hz), 7.89-8.00 (2H, m), 8.24 (1H, d, J = 8.4 Hz), 9.49-9.79 (1H, m).


 


2614




mp 164.0-166.0









The following compounds were produced in the same manner as in Reference Example 111.







TABLE 414







 








 











Example





No.
Xb67
1H NMR (solvent) δppm






2615
—N(CH3)—
2.42-2.45 (4H, m), 3.05 (3H, s), 3.44 (2H, s), 3.47-3.51 (2H, m), 3.62-





3.65 (2H, m), 4.11 (2H, s), 5.95 (2H, s), 6.69-6.77 (4H, m), 6.85 (1H,





s), 6.97 (1H, d, J = 8.7 Hz), 7.01-7.07 (2H, m), 7.75 (2H, d, J = 8.4





Hz), 7.87 (2H, d, J = 8.1 Hz), 8.17 (1H, dd, J = 8.7 Hz, 2.3 Hz),





8.58 (1H, d, J = 2.3 Hz).



2616
—CH2—
2.32-2.41 (4H, m), 2.61-2.67 (2H, m), 2.97-3.03 (2H, m), 3.41-





3.43 (4H, m), 3.62-3.66 (2H, m), 5.95 (2H, s), 6.70-6.77 (2H, m),





6.84 (1H, s), 7.03-7.13 (3H, m), 7.28-7.32 (2H, m), 7.76 (2H, d, J = 8.1





Hz), 7.88 (2H, d, J = 8.1 Hz), 8.22 (1H, dd, J = 8.6 Hz, 2.4 Hz),





8.58 (1H, d, J = 2.4 Hz).
















TABLE 415







 








 










Example





No.
R1128
R1129
1H NMR (CDCl3) δppm





2617
—H
—CH2COOC2H5
1.27 (3H, t, J = 7.1 Hz), 1.34-1.48 (2H, m), 1.81-1.99 (3H,





m), 2.29 (2H, d, J = 6.9 Hz), 2.73 (2H, t, J = 12.2 Hz),





3.63 (2H, d, J = 12.2 Hz), 4.15 (2H, q, J = 7.3 Hz), 6.91-





7.01 (4H, m), 7.18-7.26 (3H, m), 7.54 (2H, d, J = 8.9 Hz),





8.26 (1H, d, J = 2.3 Hz), 8.43 (1H, d, J = 2.3 Hz).


2618
—CH3
—CH2COOC2H5
1.28 (3H, t, J = 7.1 Hz), 1.30-1.39 (2H, m), 1.80-1.96 (3H,





m), 2.07 (3H, s), 2.29 (2H, d, J = 6.9 Hz), 2.70 (2H, t, J =





12.0 Hz), 3.61 (2H, d, J = 12.4 Hz), 4.17 (2H, q, J = 7.3





Hz), 6.74-6.78 (2H, m), 6.92 (1H, d, J = 8.6 Hz), 7.20-





7.26 (3H, m), 7.52 (2H, d, J = 8.4 Hz), 8.28 (1H, d, J = 2.3





Hz), 8.41 (1H, d, J = 2.3 Hz).


2619
—H
—COOC2H5
1.27 (3H, t, J = 7.1 Hz), 1.92-2.00 (2H, m), 2.01-2.05 (2H,





m), 2.38-2.47 (1H, m), 2.74-2.84 (2H, m), 3.59-3.63 (2H,





m), 4.15 (2H, q, J = 7.1 Hz), 6.93-7.02 (4H, m), 7.17-





7.26 (3H, m), 7.54 (2H, d, J = 8.4 Hz), 8.26 (1H, d, J = 2.3





Hz), 8.43 (1H, d, J = 2.3 Hz).
















TABLE 416













 










Example





No.
R1130
R1131
mp (° C.) or 1H NMR (DMSO-d6) δppm





2620
4-CF3Ph-
piperonyl
mp 129.0-130.5


2621
4-CF3Ph-
3,4-(CH3O)2PhCH2—
mp 130.0-132.0


2622
3,4-Cl2Ph-
3,4-(CH3O)2PhCH2—
1H NMR 1.85-2.14(5 H, m), 3.13-3.33( 2 H,





m), 3.58-3.71(2 H, m), 3.73(3 H, s), 3.74(3 H,





s), 4.12-4.78(3 H, m), 6.73-6.94(3 H, m),





7.04(1 H, d, J = 8.6 Hz), 7.11-7.20(2 H, m),





7.25(1 H, d, J = 2.4 Hz), 7.61(1 H, d, J = 8.8





Hz), 7.71(1 H, dd, J = 2.4 Hz, 8.8 Hz),





8.11(1 H, d, J = 2.4 Hz), 8.34(1 H, dd J = 2.4





Hz, 8.8 Hz), 8.66(1 H, d, J = 2.4 Hz),





10.53(1 H, s).









Example 2623
Production of 2-[4-(3-{4-[4-(3,4-dichlorobenzoylamino)-phenoxy]phenyl}propionyl)piperazin-1-yl]acetic acid hydrochloride
To a solution of ethyl 2-[4-(3-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}propionyl)piperazin-1-yl]acetate (0.493° g, 0.843 mmol) in THF (5 mL) and ethanol (5 mL) were added 5 M aqueous sodium hydroxide (0.253 mL, 1.27 mmol) and water (1 mL), and the resulting solution was refluxed for 1 hour. This reaction solution was concentrated under reduced pressure, and the residue was dissolved in 50% aqueous ethanol. To the resulting solution was added 5 M hydrochloric acid (0.253 mL, 1.27 mmol), and the obtained solid was collected by filtration. To this solid was dissolved in ethanol (10 mL) and 5 M hydrochloric acid (0.3 mL) by heating. The solvent was then evaporated, and the obtained solid was recrystallized from ethanol-diethyl ether, to thereby yield 0.381 g of the title compound.
Appearance: White powder
Melting point: 215-218° C.
The following compounds were produced in the same manner as in Example 2623.







TABLE 417













 









Example




No.
R1132
1H NMR (solvent) δppm





2624




(DMSO-d6) 2.71-2.73(4 H, m), 3.12-3.14(4 H, m), 3.21(2 H, s), 6.91-6.98(6 H, m), 7.71(2 H, dd, J = 7.0 Hz, 2.0 Hz), 7.82(1 H, d, J = 8.0 Hz), 7.93(1 H, dd, J = 8.0 Hz, 2.0 Hz), 8.21(1 H, d, J = 2.0 Hz), 10.38(1 H, s).


 


2625




(CDCl3) 2.68(2 H, m), 3.05(2 H, m), 3.35(2 H, s), 3.49(2 H, m), 6.00(1 H, m), 6.98(2 H, d, J = 8.5 Hz), 7.05(2 H, d, J = 8.5 Hz), 7.35(2 H, d, J = 8.5 Hz), 7.58(2 H, d, J = 8.5 Hz), 7.58(1 H, brs), 7.77(2 H, m), 7.97(1 H, s).


 


2626




(DMSO-d6) 1.60-1.70(2 H, m), 1.85-1.90(2 H, m), 2.50(1 H, m), 2.65-2.73(2 H, m), 3.55(2 H, brd, J = 12.5 Hz), 6.90-6.98(6 H, m), 7.71(2 H, d, J = 9.0 Hz), 7.81(1 H, d, J = 8.5 Hz), 7.93(1 H, dd, J = 8.5 Hz, 2.0 Hz), 8.21(1 H, d, J = 2.0 Hz), 10.37(1 H, s), 12.20(1 H, brs).


 


2627




(DMSO-d6) 1.51-1.58(2 H, m), 1.90-1.95(2 H, m), 2.78-2.82(2 H, m), 3.43(2 H, m), 3.52(1 H, m), 3.92(2 H, s), 6.89-6.98(6 H, m), 7.70(2 H, d, J = 9.0 Hz), 7.82(1 H, d, J = 8.5 Hz), 7.93(1 H, dd, J = 8.5 Hz, 2.0 Hz), 8.21(1 H, d, J = 2.0 Hz), 10.40(1 H, s).


 


2628




(DMSO-d6) 1.59-1.66(2 H, m), 1.94-1.97(2 H, m), 2.54(3 H, s), 3.62(2 H, t, J = 11.0 Hz), 2.98(1 H, m), 3.29(2 H, s), 3.67- 3.70(2 H, m), 6.90-6.99(6 H, m), 7.71(2 H, ,d J = 9.0 Hz), 7.82(1 H, d, J = 8.5 Hz), 7.93(1 H, dd, J = 8.5 Hz, 2.0 Hz), 8.21(1 H, d, J = 2.0 Hz), 10.39(1 H, s).


 


2629




(CDCl3) 1.80-1.83(4 H, m), 2.61-2.65(3 H, m), 3.24(2 H, s), 3.25(2 H, brd, J = 11.0 Hz), 6.94(2 H, d, J = 8.5 Hz), 7.03(2 H, d, J = 9.0 Hz), 7.25(2 H, d, J = 8.5 Hz), 7.76(2 H, d, J = 9.0 Hz), 7.83(1 H, d, J = 8.5 Hz), 7.94(1 H, dd, J = 8.5 Hz, 2.0 Hz), 8.21(1 H, d, J = 2.0 Hz), 10.41(1 H, s).
















TABLE 418













 












Example







No.
R1133
Xb68
Xb69
M
1H NMR (DMSO-d6) δppm





2630
4-CF3Ph-
—N(CH3)—
none
1
1.20-1.45(2 H, m), 1.70-1.95(3 H, m),







2.20(2 H, d, J = 6.6 Hz), 2.67(2 H, t, J = 12.4







Hz), 3.32(3 H, s), 3.67(2 H, d, J = 12.4 Hz),







6.42(1 H, d, J = 9.1 Hz), 6.99(2 H, d, J = 8.9







Hz), 7.11(2 H, d, J = 8.9 Hz), 7.73(1 H, dd, J =







9.1 Hz, 2.3 Hz), 7.90(2 H, d, J = 8.2 Hz),







8.15(2 H, d, J = 8.2 Hz), 8.46(1 H, d, J = 2.3







Hz), 10.33(1 H, s).


2631
3.4-Cl2Ph-
—O—
—CH2—
0
1.57(2 H, brs), 1.81(2 H, brs), 2.00(2 H, brs),







2.23(1 H, brs), 2.77(2 H, brs), 3.44(2 H, brs),







7.05(1 H, d, J = 9.0 Hz), 7.07(2 H, d, J = 8.5







Hz), 7.35(2 H, d, J = 8.5 Hz), 7.84(1 H, d, J =







8.5 Hz), 7.95(1 H, d, J = 8.5 Hz), 8.20(1 H,







dd, J = 9.0 Hz, 3.0 Hz), 8.22(1 H, d, J = 2.0







Hz), 8.49(1 H, d, J = 3.0 Hz), 10.56(1 H, s),







12.15(1 H, brs).


2632
3,4-Cl2Ph-
—O—
—CO—
0
1.52(2 H, m), 1.86(2 H, brs), 2.52(1 H, m),







3.10(2 H, brs), 3.65(1 H, brs), 4.31(1 H, brs),







7.15(1 H, d, J = 9.0 Hz), 7.16(2 H, d, J = 8.5







Hz), 7.43(2 H, d, J = 8.5 Hz), 7.84(2 H, d, J =







8.5 Hz), 7.95(1 H, dd, J = 8.5 Hz, 2.0 Hz),







8.23(1 H, d, J = 2.0 Hz), 8.24(1 H, dd, J = 9.0







Hz, 3.0 Hz), 8.52(1 H, d, J = 3.0 Hz),







10.60(1 H, s).


2633
4-CF3Ph-
—O—
—CO—
0
1.52(2 H, m), 1.86(2 H, brs), 2.54(1 H, m),







3.05(2 H, brs), 3.63(1 H, brs), 4.31(1 H, brs),







7.15(1 H, d, J = 9.0 Hz), 7.16(2 H, d, J = 8.5







Hz), 7.44(2 H, d, J = 8.5 Hz), 7.94(2 H, d, J =







8.5 Hz), 8.17(2 H, d, J = 8.5 Hz), 8.27(1 H,







dd, J = 9.0 Hz, 2.5 Hz), 8.55(1 H, d, J = 2.5







Hz), 10.67(1 H, s).


2634
3,4-Cl2Ph-
—O—
none
0
1.63-1.71(2 H, m), 1.92(2 H, brd, J = 10.0







Hz), 2.74(2 H, t, J = 11.5 Hz), 3.58(2 H, brd,







J = 12.5 Hz), 6.96( 1 H, d J = 9.0 Hz),







6.98(4 H, s), 7.83(1 H, d,J = 8.5 Hz),







7.94(1 H, dd, J = 8.5 Hz, 2.0 Hz), 8.14(1 H,







dd, J = 9.0 Hz, 2.5 Hz), 8.21(1 H, d, J = 2.0







Hz), 8.44(1 H, d, J = 2.5 Hz), 10.50(1 H, s),







12.20(1 H, brs).


2635
3,4-Cl2Ph-
—O—
none
1
1.31-1.34(2 H, m), 1.77(2 H, brd, J = 11.5







Hz), 2.20(2 H, t, J = 6.5 Hz), 2.64(2 H, brt, J =







10.5 Hz), 3.61(2 H, brd, J = 12.5 Hz),







6.96(1 H, d, J = 9.0 Hz), 6.96(4 H, s), 7.83







(1 H, d, J = 8.5 Hz), 7.94(1 H, dd, J = 8.5 Hz,







2.0 Hz), 8.14(1 H, dd, J = 9.0 Hz, 2.5 Hz),







8.21(1 H, d, J = 2.0 Hz), 8.44(1 H, d, J = 2.5







Hz), 10.50(1 H, s), 12.06(1 H, brs).
















TABLE 419













 












Example







No.
R1134
Xb70
Xb71
Xb72
1H NMR (DMSO-d6) δppm





2636
4-CF3Ph-
—O—
—CO—
—CH2—
3.30(4 H, brs), 3.77(4 H, brs), 3.99(2 H,







s), 7.17(1 H, d, J = 8.8 Hz), 7.21(2 H, d,







J = 8.6 Hz), 7.51(2 H, d, J = 8.6 Hz),







7.94(2 H, d, J = 8.0 Hz), 8.20(2 H, d, J =







8.0 Hz), 8.29(1 H, dd, J = 8.8 Hz, 2.6







Hz), 8.59(1 H, d, J = 2.6 Hz), 10.79(1 H,







s).


2637
3,4-Cl2Ph-
—O—
none
—CH2—
2.71(4 H, t, J = 5.0 Hz), 3.13(2 H, s),







3.14(4 H, t, J = 5.0 Hz), 6.96-7.00(5 H,







m), 7.82(1 H, d, J = 8.5 Hz), 7.96(1 H,







dd, J = 8.5 Hz, 2.0 Hz), 8.16(1 H, dd, J =







9.0 Hz, 2.5 Hz), 8.24(1 H, d, J = 2.0







Hz), 8.37(1 H, s) ,8.46(1 H, d, J = 2.5







Hz), 10.62(1 H, brs).


2638
4-CF3Ph-
—N(CH3)—
none
—CH2—
2.64(4 H, brs), 2.95(2 H, s), 3.15(4 H,







brs), 3.33(3 H, s), 6.42(1 H, d, J = 9.1







Hz), 6.99(2 H, d, J = 8.9 Hz), 7.13(2 H,







d, J = 8.9 Hz), 7.75(1 H, dd, J = 9.1 Hz,







2.5 Hz), 7.89(2 H, d, J = 8.2 Hz),







8.17(2 H, d, J = 8.2 Hz), 8.49(1 H, d, J =







2.5 Hz), 10.46(1 H, s).


2639
4-CF3Ph-
—O—
none
—CH2—
2.72(4 H, t, J = 5.0 Hz), 3.15(4 H, t, J =







5.0 Hz), 3.20(2 H, s), 6.96-7.01(5 H,







m), 7.93(2 H, d, J = 8.5 Hz), 8.16(2 H, d,







J = 8.5 Hz), 8.18(1 H, dd, J = 8.0 Hz, 2.5







Hz), 8.46(1 H, d, J = 2.5 Hz), 10.60(1 H,







s).


2640
3,4-Cl2Ph-
—O—
none
—CO—
3.13(2 H, brs), 3.17(2 H, s), 3.48(2 H,







brs), 3.71(2 H, brs), 7.12(1 H, d, J = 8.9







Hz), 7.15(2 H, dd, J = 6.8 Hz, 2.1 Hz),







7.36(2 H, dd, J = 6.8 Hz, 2.1 Hz),







7.84(1 H, d, J = 8.4 Hz), 7.95(1 H, dd, J =







8.4 Hz, 2.1 Hz), 8.22(1 H, dd, J = 8.9







Hz, 2.7 Hz), 8.23(1 H, d, J = 2.1 Hz),







8.49(1 H, d, J = 2.7 Hz), 10.58(1 H, s).
















TABLE 420













 













Example





1H NMR (solvent)


No.
R1135
Xb73
Xb74
Xb75
R1136
δppm





2641
4-CF3PhCO—
none
none
none
benzyl
(CD3OD) 3.47(8 H,








brs), 4.43(2 H, s), 6.96








(1 H, d, J = 8.9 Hz),








7.14(1 H, d, J = 8.9








Hz), 7.30(1 H, dd, J =








8.9 Hz, 3.0 Hz), 7.51-








7.59(6 H, m), 7.82(2 H,








d, J = 8.3 Hz), 8.12-








8.18(3 H, m), 8.36(1 H,








d, J = 2.5 Hz).


2642
3,4-Cl2PhSO2—
—N(C2H5)—
—CH2—
—CO—
piperonyl
(DMSO-d6) 1.11(3 H, t,








J = 7.0 Hz), 2.20-2.45








(4 H, m), 3.30-3.55(8 H,








m), 4.22(2 H, s), 5.99








(2 H, s), 6.70-7.00(7 H,








m), 7.40-7.50(1 H, m),








7.55-7.60(1 H, m),








7.66(1 H, d, J = 2.7








Hz), 7.84(1 H,d, J =








8.4 Hz), 7.88(1 H, d, J =








2.1 Hz), 01.27(1 H,








brs), 12.51(1 H, brs).


2643
3,4-Cl2PhNHCO—
—N(C2H5)—
—CH2—
—CO—
piperonyl
(DMSO-d6) 1.13(3 H, t,








J = 7.0 Hz), 2.20-2.50








(4 H, m), 3.30-3.60(8 H,








m), 4.21(2 H, s), 5.99








(2 H, s), 6.60-7.05(7 H,








m), 7.30-7.40(1 H, m),








7.47(1 H, d, J = 8.8








Hz), 7.65-7.85(1 H, m),








7.90(1 H, d, J = 2.3








Hz), 8.06(1 H, d, J =








2.6 Hz), 9.80(2 H, brs),








12.40(1 H, brs).
















TABLE 421













 












Example







No.
R1137
R1138
R1139
R1140
1H NMR (solvent) δppm





2644
3,4-Cl2Ph-
—H
—H
—COOH
(CDCl3) 1.80(1 H, m), 1.86-1.94(3 H,







m), 2.82(1 H, m), 3.14(2 H, m), 3.32







(2 H, m), 6.94(1 H, d, J = 9.0 Hz),







7.06(4 H, s), 7.57(1 H, d, J = 8.5 Hz),







7.72(1 H, d, J = 8.5 Hz), 7.93(1 H,







brs), 7.99(1 H, s), 8.18(1 H, brd, J =







9.0 Hz), 8.26(1 H, d, J = 2.5 Hz).


2645
4-CF3Ph-
—H
—CH2COOH
—H
(CDCl3) 1.44-1.50(2 H, m), 1.90(2 H,







brd, J = 13.5 Hz), 1.94(1 H, m), 2.36







(2 H, d, J = 7.0 Hz), 2.75(2 H, dt, J =







2.5 Hz, 12.0 Hz), 3.63(2 H, brd, J =







12.0 Hz), 6.92(1 H, d, J = 9.0 Hz),







6.97(2 H, d, J = 9.0 Hz), 7.04(2 H, d,







J = 9.0 Hz), 7.72(1 H, s), 7.78(2 H, d,







J = 8.0 Hz), 7.99(2 H, d, J = 8.0 Hz),







8.19(1 H, dd, J = 9.0 Hz, 2.5 Hz),







8.25(1 H, d, J = 2.5 Hz).


2646
3-CF3Ph-
—H
—CH2COOH
—H
(CDCl3) 1.46-1.49(2 H, m), 1.89(2 H,







brd,J '2 15.0 Hz), 1.95(1 H, m),







2.3692 H, d, J = 7.0 Hz), 2.74(2 H, dt,







J = 2.0 Hz, 12.0 Hz), 3.63(2 H, brd,







J = 12.0 Hz), 6.92(1 H, d, J = 9.0







Hz), 6.97(2 H, d, J = 9.0 Hz), 7.05







(2 H, d, J = 9.0 Hz), 7.66(1 H, t, J =







7.5 Hz), 7.73(2 H, brs), 7.84(1 H, d, J =







7.5 Hz), 8.07(1 H, d, J = 7.5 Hz),







8.14(1 H, brs), 8.17(1 H, dd, J = 9.0







Hz, 2.5 Hz), 8.27(1 H, d, J = 2.5 Hz).


2647
4-CF3Ph-
—OCH3
—CH2COOH
—H
(DMSO-d6) 1.31-1.36(2 H, m), 1.77-







1.81(3 H, m), 2.21(2 H, d, J = 7.4







Hz), 2.68-2.75(2 H, m), 3.64(2 H,







brs), 3.68(3 H, s), 6.52(1 H, brs),







6.68(1 H, brs), 6.89-6.96(2 H, m),







7.92(2 H, d, J = 8.4 Hz), 8.09-







8.17(3 H, m), 8.38(1 H, d, J = 2.5







Hz), 10.54(1 H, s), 12.10(1 H, brs).


2648
4-CF3Ph-
—H
—COOH
—H
(CDCl3 + CD3OD) 1.82-1.96(2 H, m),







2.04-2.09(2 H, m), 2.38-2.48(1 H,







m), 2.74-2.84(2 H, m), 3.52-3.61(2 H,







m), 6.86(1 H, dd, J = 8.9 Hz, 0.5







Hz), 6.96-7.05(4 H, m), 7.69-







7.76(2 H, m), 8.06(2 H, d, J = 8.1







Hz), 8.16(1 H, d, J = 8.1 Hz), 8.23-







8.33(2 H, m).
















TABLE 422













 










Example





No.
R1141
R1142
1H NMR (DMSO-d6) δppm





2649
4-CF3Ph-
—CH3
1.41(2 H, brs), 1.84-1.96(3 H, m), 1.97(3 H, s), 2.22(2 H, d, J =





6.6 Hz), 2.55-2.75(2 H, m), 3.58(2 H, d, J = 11.9 Hz), 6.72-





7.11(4 H, m), 7.52(1 H, dd, J = 8.9 Hz, 2.8 Hz), 7.74(1 H, d, J =





2.6 Hz), 7.89-7.99(4 H, m), 10.49(1 H, s), 12.14(1 H, brs).


2650
3,4-Cl2Ph-
—CH3
1.38(2 H, brs), 1.82-1.96(3 H, m), 1.97(3 H, s), 2.22(2 H, d, J =





6.4 Hz), 2.55-2.75(2 H, m), 3.59(2 H, d, J = 11.9 Hz), 6.88-





6.91(4 H, m), 7.51(1 H, dd, J = 8.7 Hz, 2.5 Hz), 7.63(1 H, dd, J =





8.4 Hz, 2.1 Hz), 7.74(1 H, d, J = 2.8 Hz), 7.83-7.87(2 H, m),





10.38(1 H, s), 12.12(1 H, brs).


2651
3.4-Cl2Ph-
—H
1.30-1.37(2 H, m), 1.75-1.91(3 H, m), 2.20(2 H, d, J = 6.9 Hz),





2.51-2.62(2 H, m), 3.60(2 H, d, J = 12.0 Hz), 6.87-6.94(5 H,





m), 7.50(1 H, dd, J = 8.7 Hz, 2.8 Hz), 7.62(1 H, dd, J = 8.6





Hz, 2.3 Hz), 7.77(1 H, d, J = 2.8 Hz), 7.84-7.89(2 H, m),





10.39(1 H, s), 12.09(1 H, brs).


2652
4-CF3Ph-
—H
1.29-1.33(2 H, m), 1.74-1.91(3 H, m), 2.19(2 H, d, J = 6.8 Hz),





2.63-2.75(2 H, m), 3.59(2 H, d, J = 12.2 Hz), 6.86-6.93(5 H,





m), 7.50(1 H, dd, J = 8.9 Hz, 2.8 Hz), 7.77(1 H, d, J = 2.6 Hz),





7.89-7.99(4 H, m), 10.47(1 H, s), 12.09(1 H, brs).


2653
4-CF3Ph-
—OCH3
1.41(2 H, brs), 1.81-1.85(3 H, m), 2.25(2 H, d, J = 6.4 Hz),





2.55-2.79(2 H, m), 3.64(3 H, s), 3.68(2 H, brs), 6.73-6.95(4 H,





m), 7.51(1 H, dd, J = 8.7 Hz, 2.5 Hz), 7.73(1 H, d, J = 2.6 Hz),





7.92-8.02(4 H, m), 10.45(1 H, s), 12.14(1 H, brs).


2654
3,4-Cl2Ph-
—OCH3
1.42(2 H, brs), 1.79-1.91(3 H, m), 2.23(2 H, d, J = 6.6 Hz),





2.76-2.83(2 H, m), 3.63(5 H, brs), 6.63-6.98(4 H, m), 7.48(1 H,





dd, J = 8.7 Hz, 2.6 Hz), 7.63(1 H, dd, J = 8.4 Hz, 2.0 Hz),





7.71(1 H, d, J = 2.8 Hz), 7.85-7.88(2 H, m), 10.36(1 H, s),





12.33(1 H, brs).
















TABLE 423













 










Example





No.
R1143
R1144
1H NMR (DMSO-d6) δppm





2655
4-CF3Ph-
—CH3
1.81-1.99(4 H, m), 2.00(3 H, s), 2.41-2.44(1 H, m), 2.75(2 H,





brs), 3.58(2 H, d, J = 12.2 Hz), 6.91-7.20(4 H, m), 7.53(1 H,





dd, J = 8.9 Hz, 2.6 Hz), 7.75(1 H, d, J = 2.6 Hz), 7.90-





7.99(4 H, m), 10.52(1 H, s), 12.41(1 H, brs).


2656
3,4-Cl2Ph-
—CH3
1.63-1.71(2 H, m), 1.91-1.94(2 H, m), 1.95(3 H, s), 2.41-





2.48(1 H, m), 2.75-2.80(2 H, m), 3.58(2 H, d, J = 12.9 Hz),





6.85-6.89(3 H, m), 7.50(1 H, dd, J = 8.7 Hz, 2.6 Hz), 7.68-





7.79(2 H, m), 7.81-7.98(4 H, m), 10.43(1 H, s), 12.35(1 H,





brs).


2657
3,4-Cl2Ph-
—H
1.74(2 H, brs), 1.93-1.98(2 H, m), 2.49-2.51(2 H, m),





2.88(1 H, brs), 3.55-3.60(2 H, m), 6.90-7.01(5 H, m), 7.50-





7.89(5 H, m), 10.41(1 H, s), 12.13(1 H, brs).


2658
4-CF3Ph-
—H
1.66-1.71(2 H, m), 1.88-1.92(2 H, m), 2.34-2.42(1 H, m),





2.68-2.76(2 H, m), 3.56(2 H, d, J = 12.4 Hz), 6.85-6.92(5 H,





m), 7.48(1 H, d, J = 2.8 Hz), 7.51(1 H, d, J = 2.8 Hz), 7.77-





7.99(4 H, m), 10.47(1 H, s), 12.21(1 H, s).
















TABLE 424













 










Example





No.
R1145
R1146
1H NMR (DMSO-d6) δppm





2659
—H
—CH2COOH
1.26-1.32(2 H, m), 1.74-1.91(3 H, m), 2.20(2 H, d, J = 6.6





Hz), 2.66(2 H, t, J = 11.0 H), 3.63(2 H, d, J = 12.5 Hz),





6.93-7.03(4 H, m), 7.13-7.35(2 H, m), 7.65(2 H, d, J = 8.6





Hz), 8.42(1 H, d, J = 2.3 Hz), 8.47(1 H, d, J = 2.3 Hz),





11.00(1 H, s), 12.07(1 H, brs).


2660
—CH3
—CH2COOH
1.30-1.41(2 H, m), 1.80-2.00(3 H, m), 1.99(3 H, s), 2.20(2 H,





d, J = 6.6 Hz), 2.68-2.76(2 H, m), 3.62(2 H, d, J = 12.2 Hz),





6.88-6.96(3 H, m), 7.33(2 H, d, J = 8.2 Hz), 7.65(2 H, d, J =





8.6 Hz), 8.44(2 H, s), 11.00(1 H, s), 12.10(1 H, brs).


2661
—H
—COOH
1.63-1.70(2 H, m), 1.88-1.92(2 H, m), 2.41-2.45(1 H, m),





2.71-2.79(2 H, m), 3.61(2 H, d, J = 12.5 Hz), 6.93-7.00(4 H,





m), 7.31(2 H, d, J = 8.6 Hz), 7.63(2 H, d, J = 8.7 Hz), 8.40-





8.47(2 H, m), 10.63(1 H, s), 12.21(1 H, s).
















TABLE 425













 









Example




No.
R1147
1H NMR (DMSO-d6) δppm





2662
4-CF3PhCO—
2.08(3 H, s), 2.09-2.32(2 H, m), 3.65-3.93(4 H, m), 7.01(1 H, d, J =




8.6 Hz), 7.06(1 H, d, J = 8.9 Hz), 7.19(1 H, dd, J = 2.6 Hz, 8.6 Hz),




7.29(1 H, d, J = 2.6 Hz), 7.42-7.51(2 H, m), 7.81-7.98(4 H, m),




8.10-8.18(2 H, m), 8.21(1 H, dd, J = 2.6 Hz, 8.9 Hz), 8.43(1 H, d, J =




2.6 Hz), 10.60(1 H, s), 12.60-12.91(1 H, m).


2663
3,4-Cl2PhSO2—
1.99(3 H, s), 2.07-2.31(2 H, m), 3.60-3.91(4 H, m), 6.97(1 H, d, J =




8.5 Hz), 6.98(1 H, d, J = 8.8 Hz), 7.16(1 H, dd, J = 2.4 Hz, 8.5 Hz),




7.25(1 H, d, J = 2.2 Hz), 7.40-7.51(2 H, m), 7.54(1 H, dd, J = 2.8




Hz, 8.8 Hz), 7.62(1 H, dd, J = 2.2 Hz, 8.5 Hz), 7.75(1 H, d, J = 2.8




Hz), 7.79-7.93(4 H, m).









Example 2664
Production of (4-{5-[(4-trifluoromethylphenylamino)-methyl]-pyridin-2-yloxy}phenyl)(4-piperonylpiperazin-1-yl)methanone
Methanesulfonic acid 6-[4-(4-piperonylpiperazine-1-carbonyl)phenoxy]pyridin-3-yl ester (0.433 g, 0.824 mmol) and 4-trifluoromethyl phenylamine (0.310 mL, 2.47 mmol) were mixed together, and the resulting mixture was stirred for 2 hours at 100° C. The formed yellow mass was stirred together with a saturated sodium bicarbonate solution, ethyl acetate and THF (20 ml of each). The organic layer was collected, washed with brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=50:1), to thereby yield 0.236 g of the title compound.
Appearance: Pale yellow amorphous powder
1H NMR (CDCl3) δ 2.44 (4H, brs), 3.45 (2H, s), 3.57 (2H, brs), 3.75 (2H, brs), 4.30-4.35 (1H, m), 4.36 (2H, s), 5.95 (2H, s), 6.63 (2H, d, J=8.7 Hz), 6.74-6.77 (2H, m), 6.85 (1H, s), 6.93 (1H, d, J=8.4 Hz), 7.15 (2H, d, J=8.4 Hz), 7.39-7.47 (4H, m), 7.71 (1H, dd, J=2.5 Hz, 8.4 Hz), 8.18 (1H, d, J=2.3 Hz).
The following compounds were produced in the same manner as in Example 2664.







TABLE 426













 












Example







No.
R1148
Xb76
Xb77
Form
1NMR (solvent) δppm





2665
3,4-Cl2Ph-
—N(CH3)—
—CH2—
free
(CDCl3) 2.42-2.44(4 H, m), 3.03(3 H, s),







3.43(2 H, brs), 3.49-3.50(2 H, m),







3.63(2 H, brs), 4.08(2 H, s), 4.94(2 H, s),







5.94(2 H, s), 6.70(2 H, d, J = 9.2 Hz),







6.74(2 H, brs), 6.80(1 H, dd, J = 8.9 Hz,







2.8 Hz), 6.83-6.86(2 H, m), 7.01(2 H, d,







J = 9.1 Hz), 7.05(1 H, d, J = 2.8 Hz),







7.32(1 H, d, J = 8.9 Hz), 7.86(1 H, dd, J =







8.6 Hz, 2.5 Hz), 8.19(1 H, d, J = 1.8







Hz).


2666
4-CF3Ph-
—N(CH3)—
—CH2—
free
(CDCl3) 2.41-2.44(4 H, m), 3.03(3 H, s),







3.43(2 H, brs), 3.49(2 H, brs), 3.63(2 H,







brs), .408(2 H, s), 5.02(2 H, s), 5.95(2 H,







s), 6.69-6.74(4 H, m), 6.85-6.88(2 H, m),







7.00-7.03(4 H, m), 7.56(2 H, d, J = 8.6







Hz), 7.72(1 H, dd, J = 8.6 Hz, 2.5 Hz),







8.22(1 H, d, J = 2.3 Hz).


2667
4-CF3Ph-
none
none
hydro-
(DMSO-d6) 3.10-3.42( 8 H, m), 4.24(2 H,






chloride
brs), 5.20(2 H, s), 6.07(2 H, s), 6.97-







7.04(2 H, m), 7.15(1 H, d, J = 8.6 Hz),







7.21-7.24(5 H, m), 7.52(2 H, d, J = 8.6







Hz), 7.68(2 H, d, J = 8.7 Hz), 8.01(1 H,







dd, J = 2.5 Hz, 8.4 Hz), 8.29(1 H, d, J =







2.3 Hz), 11.00(1 H, brs).









Example 2668
Production of 2-(methyl-{4-[5-(5-trifluoromethyl-pyridin-2-yloxymethyl)pyridin-2-yloxy]phenyl}amino)-1-(4-piperonylpiperazin-1-yl)ethanone
2-{[4-(5-hydroxymethylpyridin-2-yloxy)phenyl]methylamino}-1-(4-piperonylpiperazin-1-yl)ethanone (0.98 g, 2.0 mmol) was dissolved in DMF (30 mL). To the resulting solution was added 60% sodium hydride (60%, 88 mg, 2.2 mmol) under ice cooling, and this solution was stirred for 30 minutes at 0° C. To the reaction solution was added 2-chloro-5-(trifluoromethyl)pyridine (0.36 g, 2.0 mol), and this solution was stirred under a nitrogen atmosphere for 3 hours at 60° C. The resulting reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate, and this solution was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane ethyl acetate=1:5), to thereby yield 0.68 g of the title compound.
Appearance: White powder
1H NMR (CDCl3) δ 2.41-2.44 (4H, m), 3.02 (3H, s), 3.43 (2H, s), 3.48 (2H, brs), 3.63 (2H, brs), 4.08 (2H, s), 5.37 (2H, s), 5.94 (2H, s), 6.68-6.77 (4H, m), 6.81-6.84 (3H, m), 7.00 (2H, d, J=9.1 Hz), 7.72-7.79 (2H, m), 8.27 (1H, d, J=2.3 Hz), 8.44 (1H, brs).
The following compounds were produced in the same manner as in Example 2668.







TABLE 427













 









Example No.
R1149
mp (° C.)





2669
4-CF3Ph-
165.0-166.0


2670
3-CF3Ph-
163.0-165.0


2671
3,4-Cl2Ph-
160.0-161.5









Example 2672
3,4-dichloro-N-{6-[4-(3,5-dioxoisoxazolidine-4-ylidenemethyl)phenoxy]pyridin-3-yl}benzamide
To a solution of hydroxylamine hydrochloride (500 mg, 1.0 mmol) in water (0.2 mL) were added sodium carbonate (1.05 g, 9.91 mmol) and a solution of 2-{4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]benzylidene}malonic acid dimethyl ester (500 mg, 1.0 mmol) in THF (5 mL). To the resulting solution was subsequently added methanol (5 mL) and stirred for 8 hours at 60° C. The reaction solution was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1). To the resulting white precipitate was added ethyl acetate, filtered, and the filtrate was washed with diethyl ether, to thereby yield 105 mg of the title compound.
Appearance: White powder
1H NMR (DMSO-d6) δ 7.12 (1H, d, J=8.9 Hz), 7.14 (2H, d, J=8.8 Hz), 7.63 (2H, d, J=8.8 Hz), 7.84 (1H, d, J=58.4 Hz), 7.95 (1H, dd, J=8.4 Hz, 2.0 Hz), 8.15 (1H, s), 8.22 (1H, dd, J=8.9 Hz, 2.6 Hz), 8.22 (1H, d, J=2.0 Hz), 8.51 (1H, d, J=2.6 Hz), 10.57 (1H, s), 11.16 (1H, s).
Example 2673
Production of 3,4-dichloro-N-{6-[4-(5-methyl-[1,2,4]oxadiazol-3-ylmethyl)phenoxy]pyridin-3-yl}benzamide monohydrochloride
To 3,4-dichloro-N-{6-[4-(N-acetoxycarbamimidoylmethyl)phenoxy]pyridin-3-yl}benzamide (340 mg, 0.788 mmol) was added acetic acid (4 mL), and the resulting solution was stirred under reflux for 10 minutes. This reaction solution was concentrated under reduced pressure. To the residue was added a saturated sodium bicarbonate solution, and the resulting solution was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (chloroform:methanol=40:1), and the obtained reside was dissolved in ethyl acetate (5 mL). To this solution was added a solution of 4 N hydrogen chloride in ethyl acetate until the compound no longer precipitated out. The obtained white powder was filtered, and washed with diethyl ether, to thereby yield 154 mg of the title compound.
Appearance: White powder
1H NMR (DMSO-d6) δ 2.55 (3H, s), 4.05 (2H, s), 7.07 (1H, d, J=8.7 Hz), 7.07 (2H, d, J=8.6 Hz), 7.33 (2H, d, J=8.6 Hz), 7.83 (1H, d, J=8.4 Hz), 7.96 (1H, dd, J=8.4 Hz, 2.0 Hz), 8.21 (1H, dd, J=8.7 Hz, 2.6 Hz), 8.24 (1H, d, J=2.0 Hz), 8.48 (1H, d, J=2.6 Hz), 10.62 (1H, s).
Example 2674
Production of 1-(3-{4-[5-(3,4-dichlorobenzoylamino)-2-pyridylmethyl]phenyl}propionyl)-4-piperonylpiperazine monohydrochloride
To a solution of ethyl 3-(4-{5-[bis(3,4-dichlorobenzoyl)amino]-2-pyridylmethyl}phenyl)propionate (177 mg, 0.281 mmol) in THF (5 mL) and ethanol (5 mL) were added 5 M aqueous sodium hydroxide (0.0929 mL, 0.463 mmol) and water (1 mL), and the resulting solution was refluxed for 1 hour. To this reaction solution was added 5 M hydrochloric acid (0.12 mL), and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was dissolved in DMF (3 mL), and to the resulting solution were then added 1-piperonylpiperazine (102 mg, 0.463 mmol), triethylamine (0.137 mL, 0.983 mmol) and diethyl cyanophosphonate (0.0703 mL, 463 mmol), and stirred for 1.5 hours at room temperature. Water was added to the resulting reaction solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=70:1→40:1→20:1), to thereby yield 44.1 mg of a free form. This free form was dissolved in ethanol (5 mL) and 5 M hydrochloric acid (0.03 mL) by heating. The solvent was then evaporated, and the obtained solid was recrystallized from water-containing isopropanol, to thereby yield 19.6 mg of the title compound.
Appearance: Pale yellow powder
Melting point: 181-183° C.
Example 2675
Production of N-(6-{4-[4-(5-oxo-4,5-dihydro-[1,3,4]oxadiazole-2-ylmethyl)piperazine-1-carbonyl]-phenoxy}pyridin-3-yl)-4-trifluoromethylbenzamide monooxalate
To a suspension of N-{6-[4-(4-hydrazinocarbonylmethylpiperazine-1-carbonyl)phenoxy]pyridin-3-yl}-4-trifluoromethylbenzamide trihydrochloride (300 mg, 0.46 mmol) in THF (7 mL) was added triethylamine (0.29 mL, 2.08 mmol), and the resulting solution was stirred for 10 minutes at room temperature. To the solution was added N,N′-carbonyldiimidazole (97 mg, 0.60 mmol) under ice cooling, and the resulting solution was stirred for 1 hour at room temperature. The reaction solution was concentrated under reduced pressure. To the residue was added a saturated sodium bicarbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was then purified by silica gel column chromatography (chloroform methanol=15:1). The obtained residue was dissolved in ethanol, and to the resulting solution was added oxalic acid. Ethanol was evaporated under reduced pressure, after which the solidified white substance was filtered, and washed with diethyl ether, to thereby yield 140 mg of the title compound.
Appearance: White powder
1H NMR (DMSO-d6) δ 2.31-2.69 (4H, m), 3.53 (2H, s), 3.53 (4H, brs), 7.16 (1H, d, J=8.9 Hz), 7.17 (2H, d, J=8.5 Hz), 7.45 (2H, d, J=8.5 Hz), 7.94 (2H, d, J=8.1 Hz), 8.17 (2H, d, J=8.1 Hz), 8.26 (1H, dd, J=8.9 Hz, 2.7 Hz), 8.55 (1H, d, J=2.7 Hz), 10.67 (1H, s), 12.27 (1H, s).
Example 2676
Production of 4-(4-{4-[4-(3,4-dichlorobenzoylamino)-2-fluorophenoxy]phenyl}-4-hydroxybutyryl)morpholine
To a suspension of 4-(4-{4-[4-(3,4-dichlorobenzoylamino)-2-fluorophenoxy]phenyl}-4-oxobutyryl)morpholine (1.00 g, 1.83 mmol) in THF (20 mL) and methanol (5 mL) was added sodium borohydride (0.0694 g, 1.83 mmol), and the resulting solution was stirred for 1 hour at room temperature. To this reaction solution were added water and saturated aqueous ammonium chloride, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1). The obtained solid was recrystallized from water-containing isopropanol, to thereby yield 0.850 g of the title compound.
Appearance: White powder
Melting point: 108-111° C.
The following compounds were produced in the same manner as in Example 2676.







TABLE 428













 










Example





No.
R1150
Form
mp (° C.)





2677
morpholino
free
142-145


 


2678




free
150-152


 


2679




hydro- chloride
197-199


 


2680




hydro- chloride
222-225
















TABLE 429













 











Example






No.
Xb78
R1151
Form
mp (° C.) or 1H NMR





2681
—O—




free
1H NMR (DMSO-d6) δ 2.38- 2.54(6 H, m), 3.58(4 H, t, J = 4.5 Hz), 4.73-4.77(1 H, m), 5.06(1 H, d, J = 3.8 Hz), 7.04-7.07(3 H, m), 7.38(2 H, d, J = 8.4 Hz), 7.84(1 H, d, J = 8.4 Hz), 7.95(1 H, dd, J = 8.4 Hz, 1.2 Hz), 8.22(1 H, d, J = 2.0 Hz), 8.19(1 H, dd, J = 8.9 Hz, 2.8 Hz), 8.48(1 H, d, J = 2.6 Hz), 10.55(1 H, brs).


 


2682
—CH(OH)—




oxalate
mp 102-108
















TABLE 430













 










Example





No.
R1152
Xb79
1H NMR (CDCl3) δppm





2683
—OCH3
—CH2—
2.30-2.39(4 H, m), 2.57-2.62(2 H, m), 2.90-2.95(2 H, m), 3.36-





3.43(4 H, m), 3.58-3.61(2 H, m), 3.70(3 H, s), 5.83(1 H, s),





5.93(2 H, s), 6.69-6.88(6 H, m), 6.99(1 H, d, J = 8.1 Hz), 7.47-





7.62(5 H, m), 8.07(1 H, d, J = 2.3 Hz).


2684
—H
N(CH3)—
2.38-2.43(4 H, m), 2.99(3 H, s), 3.42-3.60(6 H, m), 4.05(2 H, s),





5.77(1 H, s), 5.94(2 H, s), 6.64-6.84(6 H, m), 6.93-6.99(2 H, m),





7.47(2 H, d, J = 8.1 Hz), 7.53-7.59(3 H, m) ,8.10(1 H, d, J = 2.1





Hz).









Example 2685
Production of {6-[4-(4-piperonylpiperazin-1-ylmethyl)phenoxy]pyridin-3-ylmethyl}-(4-trifluoromethylphenyl)amine
To a suspension of lithium aluminum hydride (0.106 g, 2.80 mmol) in THF (10 mL) was added dropwise a solution of 6-[4-(4-piperonylpiperazine-1-carbonyl)-phenoxy]-N-(4-trifluoromethylphenyl)nicotinamide (0.423 g, 0.700 mmol) in THF (10 mL) under ice cooled stirring. Once the entire amount was added dropwise, the solution temperature was slowly raised, and stirred under reflux, for 2 hours. After cooling, ice water (50 mL) was added to the solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane methanol 40:1), to thereby yield 0.125 g of the title compound.
Appearance: Pale Yellow oil
MS 576 (M+)
The following compounds were produced in the same manner as in Example 2685.
Example 2686
N-[6-(2-fluoro-4-{methyl[2-(4-piperonylpiperazin-1-yl)ethyl]amino}phenoxy)pyridin-3-yl]-3,4-dichlorobenzenesulfonamide
1H NMR (CDCl3) δ 2.50-2.55 (10H, m), 2.92 (3H, s), 3.41-3.45 (4H, m), 5.93 (2H, s), 6.39-6.49 (2H, m), 6.73-6.74 (2H, m), 6.84-6.89 (2H, m), 6.99 (1H, t, J=9.1 Hz), 7.42-7.70 (4H, m), 7.81 (1H, brs).
Example 2687
Production of 3-(3-methyl-4-{5-[2-(4-trifluoromethyl-phenyl)ethyl]pyridin-2-yloxy}phenyl)-1-piperonyl-tetrahydropyrimidin-2-one hydrobromide
To a solution of 3-(3-methyl-4-{5-[(E)-2-(4-trifluoromethylphenyl)vinyl]pyridin-2-yloxy}phenyl)-1-piperonyltetrahydropyrimidin-2-one (0.16 g, 0.27 mmol) in ethyl acetate (15 mL) was added 5% platinum-carbon (0.05 g) under a nitrogen atmosphere, and the resulting solution was then stirred under a hydrogen atmosphere for 4.5 hours at room temperature. The resulting reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:=n-hexane 1:4-1:2), and to the resulting product was added hydrobromide, to thereby yield 50 mg of the title compound.
Appearance: Colorless amorphous powder
1H NMR (DMSO-d6) δ 1.85-2.09 (5H, m), 2.77-3.02 (4H, m), 3.15-3.33 (2H, m), 3.55-3.70 (2H, m), 3.75-4.15 (1H, m), 4.40 (2H, s), 5.99 (2H, s), 6.76 (1H, dd, J=1.5 Hz, 7.8 Hz), 6.80-6.98 (4H, m), 7.10 (1H, dd, J=2.6 Hz, 8.5 Hz), 7.19 (1H, d, J=2.6 Hz), 7.44 (2H, d, J=8.1 Hz), 7.62 (2H, d, J=8.1 Hz), 7.71 (1H, dd, J=2.4 Hz, 8.4 Hz), 7.91 (1H, d, J=2.4 Hz).
The following compounds were produced in the same manner as in Reference Example 673.







TABLE 431













 











Example No.
R1153 
R1154
M
1H NMR (CDCl3) δ ppm





2688
—H
piperonyl
1
1.31-1.45 (2H, m), 1.84-2.02 (3H, m), 2.30 (2H, d, J = 6.8 Hz),






2.41-2.43 (4H, m), 2.72 (2H, t, J = 12.2 Hz), 3.43 (2H, s), 3.44-






3.65 (6H, m), 5.95 (2H, s), 6.71-6.77 (2H, m), 6.85-7.00 (6H, m),






7.21-7.26 (3H, m), 7.51 (2H, d, J = 8.6 Hz), 7.98 (1H, dd, J = 8.7






Hz, 2.6 Hz), 8.60 (1H, d, J = 2.6 Hz).


2689
—H
—H
1
1.38-1.46 (2H, m), 1.84-2.00 (3H, m), 2.31 (2H, d, J = 6.8 Hz),






2.71 (2H, t, J = 12.2 Hz), 2.86-2.89 (4H, m), 3.48-3.63 (7H, m),






6.86-6.99 (5H, m), 7.23-7.29 (3H, m), 7.49 (2H, d, J = 8.4 Hz),






7.97 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.60 (1H, d, J = 2.1 Hz).


2690
—CH3
piperonyl
1
1.36-1.40 (2H, m), 1.82-2.02 (3H, m), 2.03 (3H, s), 2.30 (2H, d, J =






6.8 Hz), 2.41-2.43 (4H, m), 2.68 (2H, t, J = 12.0 Hz), 3.43 (2H, s),






3.49-3.65 (6H, m), 5.94 (2H, s), 6.74-6.89 (8H, m), 7.24 (2H, d, J =






8.2 Hz), 7.49 (2H, d, J = 8.6 Hz), 7.99 (1H, dd, J = 8.7 Hz, 2.5 Hz),






8.58 (1H, d, J = 2.1 Hz).


2691
—H
piperonyl
0
1.78-2.03 (4H, m), 2.46 (4H, brs), 2.55-2.77 (3H, m), 3.46 (2H, s),






3.55 (2H, brs), 3.67 (4H, brs), 5.95 (2H, s), 6.75-6.78 (2H, m),






6.85-7.01 (6H, m), 7.21-7.26 (3H, m), 7.52 (2H, d, J = 8.6 Hz),






7.98 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.60 (1H, d, J = 2.5 Hz).









Example 2692
Production of 1-[3-(4-{1-[5-(3,4-dichlorobenzoylamino)-2-pyridyl]-1-hydroxyimino}methylphenyl)propionyl]-4-piperonylpiperazine
To a solution of 1-(3-{4-[5-(3,4-dichloro-benzoylamino)pyridine-2-carbonyl]phenyl}propionyl)-4-piperonylpiperazine (0.330 g, 0.511 mmol) in pyridine (7 mL) was added hydroxylamine hydrochloride (53.3 mg, 0.767 mmol), and the resulting solution was refluxed for 0.5 hours. The reaction solution was concentrated under reduced pressure, and to the residue was added brine. This solution was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=15:1), whereby 0.225 g of the title compound was obtained as a mixture of the syn form and the anti form (1:1) of the oxime.
Appearance: Colorless amorphous powder
1H NMR (CDCl3) δ 2.21-2.39 (4H, m), 2.49-2.60 (2H, m), 2.78-2.90 (2H, m), 3.29-3.44 (4H, m), 3.55 (2H, s), 5.90 (2H, s), 6.62-6.73 (2H, m), 6.80 (1H, s), 7.07 (1H, d, J=7.7 Hz), 7.12 (1H, d, J=7.7 Hz), 7.15-7.30 (2.5H, m), 7.39 (0.5H, d, J=8.4 Hz), 7.42 (0.5H, d, J=8.4 Hz), 7.45-7.51 (0.5H, m), 7.62-7.74 (1H, m), 7.94 (0.5H, d, J=2.0 Hz), 7.99 (0.5H, d, J=2.0 Hz), 8.09-8.28 (1H, m), 8.62 (0.5H, s), 8.85 (0.5H, s), 9.40 (0.5H, brs), 9.62 (0.5H, brs), 10.21 (0.5H, brs), 13.85 (0.5H, brs).
Example 2693
Production of 4-(2-oxo-3-{4-[5-(4-trifluoromethyl-benzoylamino)pyridin-2-yloxy]phenyl}propionyl)-piperazine-1-carboxylic acid t-butyl ester
To a solution of 4-(2-hydroxy-3-{4-[5-(4-trifluoromethylbenzoylamino)pyridin-2-yloxy]phenyl}propionyl)piperazine-1-carboxylic acid t-butyl ester (0.58 g, 0.94 mmol) in dichloromethane (4 mL) was added a Dess-Martin reagent (0.8 g, 1.89 mmol), and the resulting solution was then stirred under a nitrogen gas flow for 4 hours at room temperature. The reaction solution was concentrated under reduced pressure. To the residue was added 1 N aqueous sodium hydroxide (50 mL), and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel chromatography (dichloromethane:methanol=50:1), to thereby yield 0.31 g of the title compound.
Appearance: Yellow powder
1H NMR (CDCl3) δ 1.41 (9H, s), 2.99-3.22 (4H, m), 3.25-3.41 (2H, m), 3.42-3.60 (2H, m), 4.04 (2H, s), 6.97 (1H, d, J=8.9 Hz), 7.10 (2H, d, J=8.4 Hz), 7.27 (2H, d, J=8.4 Hz), 7.73 (2H, d, J=8.0 Hz), 7.99 (2H, d, J=8.0 Hz), 8.13 (1H, d, J=2.8 Hz), 8.30 (1H, dd, J=8.9 Hz, 2.8 Hz), 8.45 (1H, brs).
Example 2694
Production of 3,4-dichloro-N-{3-fluoro-4-[4-(1-hydroxy-2-morpholine-4-ylethyl)phenoxy]phenyl}benzamide
3,4-Dichloro-N-{3-fluoro-4-[4-(1-hydroxy-2-morpholine-4-ylethyl)phenoxy]phenyl}benzamide (37.4 g) was recrystallized from ethanol (700 mL) to yield 34.34 g of the title compound.
Appearance: White powder
Melting point: 175-176° C.
Example 2695
Production of N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-fluorophenoxy)pyridin-3-yl]-3,4-dichlorobenzenesulfonamide
N-[6-(4-{2-(4-Piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-fluorophenoxy)pyridin-3-yl]-3,4-dichlorobenzenesulfonamide (8.15 g) was recrystallized from ethanol (60 mL) to yield 7.78 g of the title compound.
Appearance: White powder
Melting point: 163-166° C.
Example 2696
Production of N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide
N-[6-(4-{[2-(4-Piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide (5.1 g, 7.7 mmol) was recrystallized from acetone (15 mL) to yield 3.7 g of the title compound.
Appearance: White powder
Melting point: 128-131° C.
Example 2697
Production of N-{6-[4-(4-benzylpiperazine-1-carbonyl)phenoxy]pyridin-3-yl}-4-trifluoromethyl-benzamide
N-{[6-[4-(4-Benzylpiperazine-1-carbonyl)-phenoxy]pyridin-3-yl}-4-trifluoromethylbenzamide (78.86 g) was recrystallized from ethanol (530 mL) to yield 96.66 g of the title compound.
Appearance: White needles
Melting point: 177.6-179.2° C.
Example 2698
Production of N-(6-{4-[4-(2-oxo-1,2,3,4-tetrahydro-quinoline-6-ylmethyl)piperazine-1-carbonyl]phenoxy}-pyridin-3-yl)-4-trifluoromethylbenzamide
To a solution of 4-[5-(4-trifluoromethylbenzoylamino)pyridin-2-yloxy]benzoic acid (4.30 g, 10.7 mmol) in DMF (150 mL) were added 1-(2-oxo-1,2,3,4-tetrahydroquinoline-6-ylmethyl)-piperazine (2.6 g, 10.7 mmol), 1-hydroxybenzotriazole monohydrate (1.64 g, 10.7 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.46 g, 12.8 mmol) under ice cooling, and the resulting solution was stirred for 1 hour under ice cooling and for 17 hours at room temperature. This reaction solution was concentrated under reduced pressure. To the residue was added a saturated sodium bicarbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was recrystallized from ethyl acetate, to thereby yield 5.24 g of the title compound.
Appearance: White powder
Melting point: 250.5-252.5° C.
Example 2699
Production of N-(6-{4-[4-(4-benzylpiperidine-1-carbonyl)piperazine-1-carbonyl]phenoxy}pyridin-3-yl)-3,4-dichlorobenzamide
To a solution of 1-{4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]benzoyl}piperidine-4-carboxylic acid (4.5 g, 8.8 mmol) in DMF (88 mL) were added 1-benzylpiperazine (1.83 mL, 10.5 mmol), 1-hydroxybenzotriazole monohydrate (1.61 g, 10.5 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.02 g, 10.5 mmol) under ice cooling, and the resulting solution was stirred overnight at room temperature. To this reaction solution was added a saturated sodium bicarbonate solution, and the resulting solution was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was recrystallized from isopropyl alcohol (700 mL), to thereby yield 3.2 g of the title compound.
Appearance: White powder
Melting point: 223-225° C.
Example 2700
Production of N-[6-(4-{[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide
To a suspension of 1-(4-benzylpiperazin-1-yl)-2-{methyl[3-methyl-4-(5-nitropyridin-2-yloxy)phenyl]amino}ethanone (2.85 g, 6.0 mmol) in ethyl acetate (30 mL) was added 5% platinum-carbon (0.30 g) under a nitrogen atmosphere, and the resulting solution was stirred for 3 hours at 40° C. under a hydrogen atmosphere. The platinum-carbon was separated off with Celite, and the filtrate was concentrated. The residue was dissolved in THF (30 mL), and to this solution was added triethylamine (1.26 mL, 9.1 mmol) under ice cooling. To the resulting solution was then added dropwise 4-(trifluoromethyl)benzoyl chloride (1.16 mL, 7.8 mmol). This reaction solution was stirred overnight, then a saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, and then dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1). The resulting product was then recrystallized from a mixed solvent consisting of diisopropyl ether-acetone, to thereby yield 1.37 g of the title compound.
Appearance: White powder
Melting point: 112-113° C.
Example 2701
Production of (4-benzylpiperazin-1-yl)(4-{5-[methyl(4-trifluoromethylbenzyl)amino]pyridin-2-yloxy}phenyl)-methanone
To a solution of (4-benzylpiperazin-1-yl){4-[5-(4-trifluoromethylbenzylamino)pyridin-2-yloxy]phenyl}methanone (5.40 g, 9.88 mmol) in methanol (150 mL) were added 37% aqueous formaldehyde (2.8 mL), sodium cyanoborohydride (1.86 g, 29.6 mmol) and acetic acid (1.7 mL) under ice cooling, and the resulting solution was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure. Water was added to the residue, and this solution was neutralized with a saturated sodium bicarbonate solution, and extracted with chloroform. The organic layer was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform:methanol=60:1). To the resulting product was then added a solution of 4 M hydrogen chloride in ethyl acetate until the resulting solution had a pH of 1. The precipitates were collected by filtration and recrystallized from ethanol (80 mL), to thereby yield 2.5 g of the title compound.
Appearance: White powder
Melting point: 180-183.5° C.
Example 2702
Production of 4-piperonylpiperazine-1-carboxyl 4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]benzylamide hydrochloride
To a solution of 4-piperonylpiperazine-1-carboxyl 4-(5-aminopyridin 2-yloxy)benzylamide (2.48 g, 5.4 mmol) in THF (50 mL) were added triethylamine (0.9 mL, 6.5 mmol) and 3,4-dichlorobenzoyl chloride (1.13 g, 5.4 mmol) under ice cooling, and the resulting solution was stirred under ice cooling for 10 minutes. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=25:1) to yield 2.97 g of a white powder. This white powder was dissolved in ethanol (45 mL), and to the resulting solution was added a solution of 4 M hydrogen chloride in ethyl acetate until the solution had a pH of 1. The precipitates were collected by filtration and recrystallized from 83% ethanol (36 mL), to thereby yield 2.72 g of the title compound.
Appearance: White powder
Melting point: 243.5-246.5° C.
Example 2703
Production of N-[6-(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzenesulfonamide
N-[6-(4-{4-[2-(4-Piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzenesulfonamide (1.35 g) was recrystallized from ethanol (20 mL) to yield 1.23 g of the title compound.
Appearance: White powder
Melting point: 156-158° C.
Example 2704
Production of N-(6-{4-[4-(4-piperonylpiperazine-1-carbonyl)piperidin-1-yl]phenoxy}pyridin-3-yl)-3,4-dichlorobenzenesulfonamide
N-(6-{4-[4-(4-Piperonylpiperidine-1-carbonyl)piperidin-1-yl]phenoxy}pyridin-3-yl)-3,4-dichlorobenzenesulfonamide (1.95 g) was recrystallized from ethanol (35 mL) to yield 1.70 g of the title compound.
Appearance: White powder
Melting point: 130-133° C.
Example 2705
Production of N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide
N-[6-(4-{[2-(4-Piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide (0.86 g, 1.30 mmol) was recrystallized from a mixed solvent of acetone (3 mL) diethyl ether (4 mL) and n-hexane (1 mL) to yield 0.72 g of the title compound.
Appearance: Pale yellow powder
Melting point: 154-155° C.
Example 2706
Production of N-(6-{4-[4-(4-benzylpiperazine-1-carbonyl)piperidin-1-yl]phenoxy}pyridin-3-yl)-4-trifluoromethylbenzensulfonamide
N-(6-{4-[4-(4-Benzylpiperidin-1-carbonyl)piperidin-1-yl]phenoxy}pyridin-3-yl)-4-trifluoromethylbenzensulfonamide (1.55 g) was recrystallized from ethanol (60 mL) to yield 1.41 g of the title compound.
Appearance: White powder
Melting point: 199-201° C.
Example 2707
Production of N-[6-(4-{4-[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}-2-methylphenoxy)pyridin-3-yl]-3,4-dichlorobenzenesulfonamide
To a solution of (1-{4-[5-(3,4-dichlorobenzenesulfonylamino)pyridin-2-yloxy]-3-methylphenyl}piperidine-4-yl)acetic acid (1.70 g, 3.1 mmol) and 1-benzylpiperazine (0.71 g, 4.0 mmol) in DMF (40 mL) were added triethylamine (1.08 mL, 7.8 mmol) and diethyl cyanophosphonate (0.76 g, 4.3 mmol) under ice cooling, and the resulting solution was stirred for 1 hour under ice cooling. To this reaction solution was added a saturated sodium bicarbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=40:1), after which the resulting product was recrystallized from ethanol, to thereby yield 1.61 g of the title compound.
Appearance: White needles
Melting point: 151-155° C.
Example 2708
Production of N-[6-(4-{[2-(4-benzothiazole-6-ylmethylpiperazin-1-yl)-2-oxoethyl]methylamino}-phenoxy)pyridin-3-yl]-3,4-dichlorobenzamide dihydrochloride
To a solution of ({4-[5-(3,4-dichlorobenzoyl-amino)pyridin-2-yloxy]phenyl}methylamino)acetic acid (1.02 g, 2.3 mmol) and 1-(benzothiazole-6-ylmethyl)-piperazine (0.58 g, 2.5 mmol) in DMF (15 mL) were added triethylamine (0.95 mL, 6.9 mmol) and diethyl cyanophosphonate (0.447 mL, 2.7 mmol) under ice cooling, and the resulting solution was stirred for 30 minutes under ice cooling and for 45 minutes at room temperature. Water was added to the solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1) to obtain 1.28 g of a white powder. This white powder was dissolved in ethanol (15 mL), and to the resulting solution was added a solution of 4 M hydrogen chloride in ethyl acetate until the resulting solution had a pH of 1. The precipitates were collected by filtration and recrystallized from 85% ethanol (30 mL), to thereby yield 1.06 g of the title compound.
Appearance: White powder
Melting point: 202-223° C.
Example 2709
Production of 3,4-dichloro-N-{6-[4-({2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)piperazin-1-yl]-2-oxoethyl}methylamino)phenoxy]pyridin-3-yl}benzamide maleate
To a solution of ({4-[5-(3,4-dichlorobenzoyl-amino)pyridin-2-yloxy]phenyl}methylamino)acetic acid (2.50 g, 5.6 mmol) in DMF (55 mL) were added 1-(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)piperazine (1.7 g, 7.3 mmol), 1-hydroxybenzotriazole monohydrate (0.86 g, 5.6 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.29 g, 6.7 mmol) under ice cooling, and the resulting solution was stirred for 30 minutes under ice cooling and for 17 hours at room temperature. This reaction solution was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was dissolved in ethanol (30 mL). To the resulting solution was added maleic acid (0.32 g, 2.7 mmol), and this solution was left to stand. The precipitates were collected by filtration, to thereby yield 1.45 g of the title compound.
Appearance: Pale yellow powder
Melting point: 188-190° C.
Example 2710
Production of N-(6-{4-[4-(4-benzylpiperazine-1-carbonyl)piperidin-1-yl]phenoxy}pyridin-3-yl)-3,4-dichlorobenzenesulfonamide
N-(6-{4-[4-(4-Benzylpiperazine-1-carbonyl)piperidin-1-yl]phenoxy}pyridin-3-yl)-3,4-dichlorobenzenesulfonamide (0.79 g) was recrystallized from ethanol (15 mL) to yield 0.67 g of the title compound.
Appearance: White powder
Melting point: 185-189° C.
Example 2711
Production of N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-pyrrole-1-ylbenzamide
N-[6-(4-{[2-(4-Piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-pyrrole-1-ylbenzamide (2.49 g) was recrystallized from a mixed solvent consisting of acetone (20 mL) and diethyl ether (30 mL) to yield 2.26 g of the title compound.
Appearance: Pale yellow powder
Melting point: 163.1-166.5° C.
Example 2712
Production of N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-fluorophenoxy)pyridin-3-yl]-4-trifluoromethylbenzenesulfonamide
N-[6-(4-{[2-(4-Piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-fluorophenoxy)pyridin-3-yl]-4-trifluoromethylbenzenesulfonamide (8.18 g) was recrystallized from a mixed solvent consisting of ethyl acetate (70 mL) and n-hexane (20 mL) to yield 6.93 g of the title compound.
Appearance: White powder
Melting point: 177.8-180.1° C.
Example 2713
Production of 6-(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl]-2-methylphenoxy}pyridine-3-sulfonyl-(4-trifluoromethylphenyl)amide
6-(4-{4-[2-(4-Piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl]-2-methylphenoxy}pyridine-3-sulfonyl-(4-trifluoromethylphenyl)amide (1.50 g) was recrystallized from ethanol (20 mL) to yield 1.40 g of the title compound.
Appearance: White powder
Melting point: 156-160° C.
Example 2714
Production of N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide
N-[6-(4-{[2-(4-Piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide (2.1 g, 3.2 mmol) was heated to dissolve in acetone (5 mL), and to the resulting solution was then added diethyl ether (10 mL), whereby recrystallization yielded 2.0 g of the title compound.
Appearance: White powder
Melting point: 113-116° C.
Example 2715
Production of 3,4-dichloro-N-{3-fluoro-4-[4-(1-hydroxy-2-morpholine-4-ylethyl)phenoxy]phenyl}benzamide
3,4-Dichloro-N-{3-fluoro-4-[4-(1-hydroxy-2-morpholine-4-ylethyl)phenoxy]phenyl}benzamide (5 g) was recrystallized from ethyl acetate-n-hexane to yield 4.73 g of the title compound.
Appearance: White powder
Melting point: 169-170° C.
Example 2716
Production of N-(6-{4-[4-(4-piperonylpiperazine-1-carbonyl)piperidine-1-carbonyl]phenoxy}pyridin-3-yl)-3,4-dichlorobenzamide
To a solution of 1-{4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]benzoyl}piperidine-4-carboxylic acid (7.96 g, 15.5 mmol) in DMF (160 mL) were added 1-piperonylpiperazine (3.75 g, 17.6 mmol), 1-hydroxybenzotriazole monohydrate (2.85 g, 18.6 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.56 g, 18.6 mmol) under ice cooling, and the resulting solution was stirred for overnight at room temperature. This reaction solution was concentrated under reduced pressure. To the residue were added water and ethyl acetate, and the resulting solution was vigorously stirred. The resulting precipitates were collected by filtration and recrystallized from a dichloromethane-methanol mixed solvent, to thereby yield 7.36 g of the title compound.
Appearance: White powder
Melting point: 236-238° C.
Example 2717
Production of N-{6-[(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}phenyl)methylamino]-pyridin-3-yl}-4-trifluoromethylbenzamide
To a solution of [1-(4-{methyl[5-(4-trifluoromethylbenzoylamino)pyridin-2-yl]amino}phenyl)piperidine-4-yl]acetic acid (0.80 g, 1.6 mmol) in DMF (10 mL) were added 1-piperonylpiperazine (0.41 g, 1.9 mmol), 1-hydroxybenzotriazole monohydrate (0.24 g, 1.6 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.39 g, 2.0 mmol) under ice cooling, and the resulting solution was stirred for 3 hours at room temperature. This reaction solution was concentrated under reduced pressure. To the residue was added a saturated sodium bicarbonate solution, and extracted with dichloromethane. The dichloromethane layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1). The resulting product was then recrystallized from a mixed solvent consisting of 95% ethanol-dichloromethane, to thereby yield 1.05 g of the title compound.
Appearance: White powder
Melting point: 210-212° C.
Formulation Example 1
100 g of the N-[6-(4-{4-[2-(piperonyl-piperazin-1-yl)-2-oxoethyl]piperidin-1-yl}phenoxy)-pyridin-3-yl]-4-trifluoromethylbenzamide obtained in Example 319, 40 g of Avicel (Tradename, manufactured by Asahi Kasei Corporation), 30 g of cornstarch and 2 g of magnesium stearate were mixed and ground together. The resulting mixture was then formed into a sugar-coated R 10-mm-tablets using a pestle. The obtained tablets were coated with a film coating agent containing 10 g of TC-5 (Tradename, manufactured by Shin-Etsu Chemical Co., Ltd., hydroxypropylmethyl cellulose), 3 g of polyethylene glycol 6000, 40 g of castor oil and a suitable amount of ethanol, to thereby prepare a film-coated tablet.
Pharmacological Test 1
Anti-Cancer Effect (In-Vitro) on Cancer Cells
Anti-proliferative effect of test compounds on human hepatic cancer cells (HuH-7), human lung cancer cells (EBC-1), human colorectal cancer cells (HCT116), human prostatic cancer cells (22Rv1), human pancreatic cancer cells (MIA PaCa-2), human stomach cancer cells (MKN45), human breast cancer cells (ZR-75-1) was checked by a sulforhodamine B method in accordance with Skehan P et al. (J. Natl. Cancer Inst. 1990 Jul. 4; 82(13): 1107-12). Explanation will be made taking HuH-7 cells as an example.
HuH-7 cells were seeded on DMEM medium (Dulbeco's modified Eagle Medium) containing 10% fetal bovine serum of a 96-well microplate and cultured at 37° C. for 24 hours in the presence of 5% carbon dioxide gas (CO2). Thereafter, a test compound was added to the wells and the cells were cultured for a further 5 days. After the cultivation, trichloro acetic acid was added to the wells so as to obtain a final concentration of 10%. The microplate was allowed to stand still at 4° C. for one hour to fix the cells on the wells. The microplate was washed with water to remove the medium and trichloroacetic acid and dried in the air. After the air-dry, the microplate was stored at 4° C. until it was stained with sulforhodamine B.
To each of the wells, a 1% aqueous acetic acid solution containing 0.4% sulforhodamine B was added and the wells were allowed to stand still at room temperature for 20 to 30 minutes. After the supernatant was removed, each well was washed with the 1% aqueous acetic acid solution and a 10 mM aqueous Tris (Tris hydroxyaminomethane) solution was add to each well and stirred. In this manner, the dye taken in the cell was eluted. Subsequently, OD (optical density) was measured at a measurement wavelength of 492 nm and a reference wavelength of 690 nm to obtain the difference (A) in OD thus measured. Furthermore, the OD of a control well (containing no cells) was measured at a measurement wavelength of 492 nm and a reference wavelength of 690 nm to obtain the difference (B) in OD. The difference (A−B) was regarded as the cell proliferation activity of each of the wells.
Anti-proliferative effect of test compounds on human chronic myelogenous leukemia cells (KU812) was determined by an MTT assay in accordance with the method described in Singh A K et al. (Cancer Lett. 1996 Oct. 1; 107(1): 109-15). To describe more specifically, KU812 cells were seeded on RPMI 1640 medium containing 10% fetal bovine serum of a 96-well microplate, cultured at 37° C. for 24 hours in the presence of a 5% carbon dioxide gas (CO2). Thereafter, a test compound was added to the wells and the cells were cultured for a further 5 days. After the incubation, 10 μl of 5 mg/mL MTT (3-(4,5-dimethyl)-2,5-diphenyltetrazolium bromide) was added to the wells. After the cells were cultured for 4 hours, 100 μl of 0.01N HCl containing 10% SDS (sodium dodecyl sulfate) was added to the wells, which was further cultured overnight. Subsequently, OD was measured at a measurement wavelength of 570 nm and a reference wavelength of 690 nm to obtain the difference (A) in OD. Furthermore, OD of a control well (containing no cells) was measured at a measurement wavelength of 570 nm and a reference wavelength of 690 nm to obtain the difference (B) in OD. The difference (A−B) was regarded as the cell proliferation activity of each of the wells.
The cell proliferation activity (T) at the time a test compound was added was compared to that (C) of the control (containing no test compound) and the cell proliferation suppression activity (T/C) of the test compound was computationally obtained. Based on this, the concentration (IC50) of the test compound at which the proliferation of 50% of the cells was inhibited, that is, the concentration of the test compound providing T/C=0.5, was obtained.















TABLE 432










MIA






HuH-7
EBC-1
HCT116
22Rv1
PaCa-2
MKN45
ZR-75-1
KU812



IC50
IC50
IC50
IC50
IC50
IC50
IC50
IC50


Example No.
(nM)
(nM)
(nM)
(nM)
(nM)
(nM)
(nM)
(nM)























276
<100
<1000
<1000
<1000
<100
<1000
<1000
<100


322
<100
<100
<100
<100
<100
<100
<100
<100


582
<100
<100
<100
<1000
<100
<1000
<1000
<100


940
<100
<100
<1000
<1000
<100
<100
<1000
<100


1039
<100
<100
<100
<100
<100
<100
<1000
<100


1049
<100
<100
<100
<100
<100
<1000
<100
<100


1202
<100
<100
<100
<100
<100
<100
<100
<100


1503
<100
<100
<100
<100
<100
<100
<100
<100


2228
<100
<100
<1000
<1000
<100
<1000
<1000
<100









Pharmacological Test 2

Anti-Cancer Effect (In-Vitro) on Hepatic Cancer Cells HuH-7

Human hepatic cancer cells HuH-7 were transplanted into SCID mice (a group of 6 female mice). Anti-tumor effect of test compounds according to the present invention was checked. To describe more specifically, the cancer cells were cultured in advance and a cell suspension solution containing the cancer cells in a concentration of 2.5×107 cells/mL was prepared. Then, 0.2 mL of the cell suspension solution was injected into the right axillary region of each of the mice to transplant the cancer cells. In this manner, cancer-bearing mice were prepared. When the tumor grew up to a diameter of 5 mm or more, the mice were divided into groups based on tumor volume. From the following day after the grouping, a 5% gum arabic suspension solution containing a test compound was orally administrated once a day for consecutive 9 days. To a control group, a 5% gum arabic suspension solution was administrated. Next day after completion of administration, the volume of a tumor was measured. The ratio in volume of a tumor at the time of grouping relative to that measured next day after completion of administration was calculated to obtain a relative tumor volume of each group. Then, the ratio (T/C %) in relative tumor volume of a control group to a test group (administrated with a test compound) was calculated and used as an index of the effect.

Relative tumor volume=tumor volume measured on the next day of completion of administration/tumor volume measured at the time of grouping

(T/C %)=(an average value of relative tumor volume of test compound administration group)/(an average value of relative tumor volume of a control group)×100












TABLE 433








Applied dose




Compound
(mg/kg/day)
T/C %




















Example 811
30
<50



Example 1202
100
<50



Example 1503
100
<50










Pharmacological Test 3

Anti-Proliferative effect of test compounds on human renal cancer cells (Caki-2) was checked in the same manner as in Pharmacological test 1 in accordance with the sulforhodamine B method of Skehan P et al.
In addition, anti-proliferative effect of test compounds on human acute myelogenous leukemia cells (KG-1), human Burkitt's lymphoma cells (Daudi), human lymphoma cells (U937) and human multiple myeloma cells (IM-9) was checked by the MTT assay in the same manner as in Pharmacological test 1 in accordance with Singh A K et al. (Cancer Lett. 1996 Oct. 1; 107(1): 109-15).
IC50 values of human renal cancer cells (Caki-2), human acute myelogenous leukemia cells (KG-1) and human multiple myeloma, cells (IM-9) are shown in Table 434.
The cell proliferation activity of each of the test compounds on human Burkitt's lymphoma cells (Daudi) and human lymphoma cells (U937) was compared to that of a control (containing no test compounds) to obtain cell proliferation suppression activities (T/C) of each test compound. The results are shown in Table 435.












TABLE 434








Caki-2
IM-9
KG-1




IC50
IC50
IC50



Example No.
(nM)
(nM)
(nM)





















276
<1000
<1000
<100



322
<100
<100
<100



582
<1000
<100
<100



940
<1000
<100
<100



1039
<100
<100
<100



1049
<100
<100
<100



1202
<100
<100
<100



1503
<100
<100
<100



2228
<100
<100
<100






















TABLE 435








Applied






dose
Daudi
U937



Example No.
(nM)
(T/C %)
(T/C %)





















322
10
<70
<70



1202
10
<70
<70



1503
10
<70
<70

## Claims

1. A method for treating a tumor comprising administering, to a patient in need thereof, an effective amount of a compound represented by the general formula (2) or a salt thereof:



wherein
X1 represents a nitrogen atom or a group —CH═,
R8 represents a hydrogen atom, a lower alkyl group that may have a lower alkoxy group as a substituent, a lower alkanoyl group, a lower alkylsulfonyl group, or a phenyl lower alkyl group,
B represents a group —CO— or a lower alkylene group,
R7 represents a hydrogen atom, a phenyl group, a carboxy group, a hydroxyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a phenoxy group, a lower alkoxy group that may have a halogen atom as a substituent, a lower alkylenedioxy group, an amino group that may have a group, as a substituent, selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a benzoyl group and a cycloalkyl group, a cyano group, a lower alkanoyl group that may have a halogen atom as a substituent, a lower alkylsulfonyl group, an aminosulfonyl group, a lower alkoxycarbonyl group, a lower alkanoyloxy group, a lower alkoxycarbonyl lower alkyl group, or a 5- or 6-membered saturated or unsaturated heterocyclic group having 1 to 4 nitrogen atoms, oxygen atoms, or sulfur atoms (wherein said heterocyclic ring may be substituted by an oxo group),
m represents an integer between 1 and 5, wherein when m represents 2 to 5, two to five R7s may be identical or different,
R2 represents a hydrogen atom, a halogen atom, or a lower alkyl group,
p represents 1 or 2,
R3 represents a hydrogen atom, a lower alkoxy group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxycarbonyl group, a carboxy group, a group —CONR11R12, or a cyano group,
each of R11 and R12, which are identical or different, represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, or a phenyl group; or R11 and R12, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, a sulfur atom, or an oxygen atom to form a 5- to 7-membered saturated heterocyclic ring,
T represents a lower alkylene group, a group —N(R17)—B3—CO—, a group —B19—N(R18)—CO—, a group —B4—CO—, a group -Q-B5—CO—, a group —B6—N(R19)—B7—CO—, a group —CO—B8—, a group —CH(OH)—B9—, a group —CO—B10—CO—, a group —CH(OH)—B11—CO—, a group —CO—, a group —SO2—, or a group —B23a—CO—CO—,
R17 represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a cycloalkylcarbonyl group, a lower alkanoyl group that may have a halogen atom as a substituent, a lower alkenyl group, an amino-substituted lower alkanoyl group that may have a lower alkyl group as a substituent, or a lower alkylsulfonyl group,
B3 represents a lower alkylene group,
B19 represents a lower alkylene group,

R18 represents a hydrogen atom or a lower alkyl group,
B4 represents a lower alkenylene group, or a lower alkylene group that may have a hydroxyl group as a substituent,
Q represents an oxygen atom or a group —S(O)n- (wherein n has the same meaning as described above),
B5 represents a lower alkylene group,
B6 represents a lower alkylene group,
R19 represents a hydrogen atom or a lower alkanoyl group,
B7 represents a lower alkylene group,
B8 represents a lower alkylene group,
B9 represents a lower alkylene group,
B10 represents a lower alkylene group,
B11 represents a lower alkylene group,
B23a represents a lower alkylene group,
I represents 0 or 1,
R14 and R15, together with the nitrogen atom to which they bind, form a piperidinyl group or a piperazinyl group, wherein a substituent on the piperidinyl group or the piperazinyl group represents a phenyl-substituted lower alkyl group, which may have a pyridyl group on the lower alkyl group, having 1 to 2 phenyl groups that may be substituted by 1 to 3 groups, as substituent on the phenyl ring, selected from the group consisting of a lower alkanoyl group, an amino group that may have a lower alkanoyl group as a substituent, a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxy group that may have a halogen atom as a substituent, a phenyl lower alkoxy group, a hydroxyl group, and a lower alkylenedioxy group;
wherein tumor is at least one tumor chosen from liver cancer, non-small-cell lung cancer, large bowel cancer, pancreatic cancer, stomach cancer, breast cancer, prostatic cancer, acute myelogenous leukemia, chronic myelogenous leukemia, multiple myeloma, and non-Hodgkin's lymphoma.

2. A method according to claim 1, for treating a tumor comprising administering, to a patient in need thereof, an effective amount of an aromatic compound selected from the group consisting of:
N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-methoxyphenoxy)pyridin-3-yl]-3,4-dichlorobenzamide,
N-{2-[4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl]-2-oxoethyl{-N-{4-[(5-{methyl[4-(trifluoromethyl)benzyl]amino}pyridin-2-yl)oxy]phenyl}acetamide,
N-(6-{4-[3-(4-piperonylpiperazin-1-yl)-3-oxopropyl]phenoxy}pyridin-3-yl)-4-trifluoromethylbenzamide,
N-[4-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}phenoxy)phenyl]-4-trifluoromethylbenzamide,
N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-methoxyphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide,
N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, and
N-[6-(4-{[4-(4-pivaloylbenzyl)piperazin-1-yl]oxomethyl}phenoxy)pyridin-3-yl]-3,4-dichlorobenzamide,
or a salt thereof.

3. A method for treating a tumor comprising administering, to a patient in need thereof, an effective amount of an aromatic compound selected from the group consisting of:
3,4-dichloro-N-(6-{4-[3-(morpholin-4-ylcarbonyl)piperidin-1-yl]phenoxy}pyridin-3-yl)benzamide,
N-(6-{[4-(4-{2-[4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl]-2-oxoethyl}piperazin-1-yl)phenyl](methyl)amino}pyridin-3-yl)-4-(trifluoromethyl)benzamide,
N-{6-[(4-{3-[4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl]-3-oxopropyl}phenyl)(methyl)amino]pyridin-3-yl}-4-(trifluoromethyl)benzamide,
2-[4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl]-N-{3-methyl-4-[(5-{[4-(trifluoromethyl)phenoxy]methyl}pyridin-2-yl)oxy]phenyl}-2-oxoacetamide,
6-{4-[{2-[4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl]-2-oxoethyl}(methyl)amino]-3-(trifluoromethyl)phenoxy}-N-[4-(trifluoromethyl)phenyl]pyridine-3-carboxamide,
N-(6-{4-[3-(4-piperonylpiperazin-1-yl)-3-oxopropyl]phenoxy}pyridin-3-yl)-4-trifluoromethylbenzamide,
N-(4-{4-[{2-[4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl]-2-oxoethyl}(methyl)amino]phenoxy}phenyl)-4-(trifluoromethyl)benzamide,
N-{6-[4-(4-{2-[4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl]-2-oxoethyl}piperidin-1-yl)-2-methylphenoxy]pyridin-3-yl}-4-(trifluoromethyl)benzamide,
N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide,
2-[4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl]-N-{3-methyl-4-[(5-{methyl[4-(trifluoromethyl)benzyl]amino}pyridin-2-yl)oxy]phenyl}-2-oxoacetamide,
or a salt thereof;
wherein tumor is at least one tumor chosen from liver cancer, non-small-cell lung cancer, large bowel cancer, pancreatic cancer, stomach cancer, breast cancer, prostatic cancer, acute myleogenous leukemia, chronic myelogenous leukemia, multiple myeloma, and non-Hodgkin's lymphoma.

4. The method according to any one of claims 1-3, wherein the tumor is at least one solid tumor chosen from liver cancer, non-small-cell lung cancer, large bowel cancer, pancreatic cancer, stomach cancer, breast cancer, and prostatic cancer.

5. The method according to any one of claims 1-3, wherein the tumor is at least one hematological cancer chosen from acute myelogenous leukemia, chronic myelogenous leukemia, and multiple myeloma.

6. The method according to any one of claims 1-3, wherein the tumor is non-Hodgkin's lymphoma.