# Patent

## Title
N,N-substituted 3-aminopyrrolidine compounds useful as monoamines reuptake inhibitors

## Abstract

The present invention provides a pyrrolidine compound of General Formula (1)




or a salt thereof, wherein R101 and R102 are each independently a phenyl group or a pyridyl group, the phenyl group or the pyridyl group may have one or more substituents selected from halogen atoms and lower alkyl groups optionally substituted with one or more halogen atoms, etc. The pyrrolidine compound or a salt thereof of the present invention is usable to produce a pharmaceutical preparation having a wider therapeutic spectrum and being capable of exhibiting sufficient therapeutic effects after short-term administration.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a Divisional of U.S. application Ser. No. 13/792,791, filed Mar. 3, 2013 (now allowed); which is a Continuation of U.S. application Ser. No. 13/298,336, filed Nov. 17, 2011 (now U.S. Pat. No. 8,420,623); which is a Divisional Application of U.S. application Ser. No. 11/914,183, filed Sep. 29, 2008 (now U.S. Pat. No. 8,084,442); which is a National Stage Entry of PCT/JP2006/309988, filed May 12, 2006, claiming priority from Japanese Application No. 2005-141230, filed May 13, 2005; the contents of all of which are incorporated herein by reference in their entirety.


TECHNICAL FIELD
The present invention relates to a pyrrolidine compound.
BACKGROUND OF THE INVENTION
Three types of monoamines, known as serotonin, norepinephrine and dopamine, act as neurotransmitters in organisms. Therefore, pharmaceuticals having a monoamine reuptake inhibitory effect are widely used as therapeutic pharmaceuticals for diseases of the central and peripheral nervous systems.
Many of the pharmaceuticals used to date for treating depression selectively inhibit norepinephrine or serotonin reuptake. Examples of such pharmaceuticals include imipramine (a first-generation antidepressant), maprotiline (a second-generation antidepressant), selective serotonin-uptake inhibitors such as fluoxetine (SSRI, third-generation antidepressants), serotonin and/or norepinephrine reuptake inhibitors such as venlafaxine (SNRI, fourth-generation-antidepressants), and the like (see Sadanori Miura, Rinshoseishinyakuri (Japanese Journal of Clinical Psychopharmacology), 2000, 3: 311-318).
However, it takes at least three weeks for these pharmaceuticals to exhibit their therapeutic effects and furthermore, these pharmaceuticals fail to exhibit sufficient effects in about 30% of patients suffering from depression (see Phil Skolnick, European Journal of Pharmacology, 2001, 375: 31-40).
DISCLOSURE OF THE INVENTION
An object of the invention is to provide a pharmaceutical preparation having a wider therapeutic spectrum than known antidepressants, and being capable of exhibiting sufficient therapeutic effects after short-term administration.
The present inventors carried out extensive research to achieve the above object and found that a pyrrolidine compound represented by formula (1) below can be used to produce such a desired pharmaceutical preparation. The present invention has been accomplished based on this finding.
The present invention provides a pyrrolidine compound, a composition comprising said compound, an agent comprising said compound, a use of said compound, a method for treating a disorder, and a process for producing said compound, as described in Items 1 to 14 below.
Item 1. A pyrrolidine compound of General Formula (1)




or a salt thereof,

wherein R101 and R102 are each independently one of the following groups (1) to (86):

(1) a phenyl group,

(2) a pyridyl group,

(3) a benzothienyl group,

(4) an indolyl group,

(5) a 2,3-dihydro-1H-indenyl group,

(6) a naphthyl group,

(7) a benzofuryl group,

(8) a quinolyl group,

(9) a thiazolyl group,

(10) a pyrimidinyl group,

(11) a pyrazinyl group,

(12) a benzothiazolyl group,

(13) a thieno[3,2-b]pyridyl group,

(14) a thienyl group,

(15) a cycloalkyl group,

(16) a tetrahydropyranyl group,

(17) a pyrrolyl group,

(18) a 2,4-dihydro-1,3-benzodioxinyl group,

(19) a 2,3-dihydrobenzofuryl group,

(20) a 9H-fluorenyl group,

(21) a pyrazolyl group,

(22) a pyridazinyl group,

(23) an indolinyl group,

(24) a thieno[2,3-b]pyridyl group,

(25) a thieno[3,2-d]pyrimidinyl group,

(26) a thieno[3,2-e]pyrimidinyl group,

(27) a 1H-pyrazolo[3,4-b]pyridyl group,

(28) an isoquinolyl group,

(29) a 2,3-dihydro-1,4-benzoxadinyl group,

(30) a quinoxalinyl group,

(31) a quinazolinyl group,

(32) a 1,2,3,4-tetrahydroquinolyl group,

(33) a cycloalkyl lower alkyl group,

(34) a lower alkylthio lower alkyl group,

(35) an amino-substituted lower alkyl group optionally substituted with one or two lower alkyl groups on the amino group,

(36) a phenoxy lower alkyl group,

(37) a pyridyloxy lower alkyl group,

(38) a lower alkynyl group,

(39) a phenyl lower alkenyl group,

(40) a 1,3-benzodioxolyl group,

(41) a 2,3-dihydro-1,4-benzodioxinyl group,

(42) a 3,4-dihydro-1,5-benzodioxepinyl group,

(43) a dihydropyridyl group,

(44) a 1,2-dihydroquinolyl group,

(45) a 1,2,3,4-tetrahydroisoquinolyl group,

(46) a benzoxazolyl group,

(47) a benzoisothiazolyl group,

(48) an indazolyl group,

(49) a benzoimidazolyl group,

(50) an imidazolyl group,

(51) a 1,2,3,4-tetrahydronaphthyl lower alkyl group,

(52) an imidazo[1,2-a]pyridyl lower alkyl group,

(53) a thiazolyl lower alkyl group,

(54) a tetrahydropyranyl lower alkyl group,

(55) a piperidyl lower alkyl group,

(56) a diphenyl lower alkoxy-substituted lower alkyl group,

(57) a lower alkoxycarbonyl-substituted lower alkyl group,

(58) a phenyl lower alkoxycarbonyl-substituted lower alkyl group,

(59) a hydroxy-substituted lower alkyl group,

(60) a lower alkoxy lower alkyl group,

(61) a carboxy lower alkyl group,

(62) a carbamoyl-substituted lower alkyl group optionally substituted with one or two lower alkyl groups on the carbamoyl group,

(63) a lower alkenyl group,

(64) a morpholinylcarbonyl lower alkyl group,

(65) a benzoyl lower alkyl group,

(66) a phenylthio lower alkyl group,

(67) a naphthylthio lower alkyl group,

(68) a cycloalkylthio lower alkyl group,

(69) a pyridylthio lower alkyl group,

(70) a pyrimidinylthio lower alkyl group,

(71) a furylthio lower alkyl group,

(72) a thienylthio lower alkyl group,

(73) a 1,3,4-thiadiazolylthio lower alkyl group,

(74) a benzimidazolylthio lower alkyl group,

(75) a benzthiazolylthio lower alkyl group,

(76) a tetrazolylthio lower alkyl group,

(77) a benzoxazolylthio lower alkyl group,

(78) a thiazolylthio lower alkyl group,

(79) an imidazolylthio lower alkyl group,

(80) an amino-substituted lower alkylthio lower alkyl group optionally substituted with one or two lower alkyl groups on the amino group,

(81) a phenyl-substituted lower alkylthio lower alkyl group,

(82) a furyl-substituted lower alkylthio lower alkyl group,

(83) a pyridyl-substituted lower alkylthio lower alkyl group,

(84) a hydroxy-substituted lower alkylthio lower alkyl group,

(85) a phenoxy-substituted lower alkylthio lower alkyl group, and

(86) a lower alkoxycarbonyl-substituted lower alkylthio lower alkyl group,

and each of the groups (1) to (32), (37), (39) to (56), (64) to (79), (81) to (83) and (85) may have one or more substituents selected from the following (1-1) to (1-37) on the cycloalkyl, aromatic or heterocyclic ring:

(1-1) halogen atoms,

(1-2) lower alkylthio groups optionally substituted with one or more halogen atoms,

(1-3) lower alkyl groups optionally substituted with one or more halogen atoms,

(1-4) lower alkoxy groups optionally substituted with one or more halogen atoms,

(1-5) nitro group,

(1-6) lower alkoxycarbonyl groups,

(1-7) amino groups optionally substituted with one or two lower alkyl groups,

(1-8) lower alkylsulfonyl groups,

(1-9) cyano group,

(1-10) carboxy group,

(1-11) hydroxy group,

(1-12) thienyl groups,

(1-13) oxazolyl groups,

(1-14) naphthyl groups,

(1-15) benzoyl group,

(1-16) phenoxy groups optionally substituted with one to three halogen atoms on the phenyl ring,

(1-17) phenyl lower alkoxy groups,

(1-18) lower alkanoyl groups,

(1-19) phenyl groups optionally substituted on the phenyl ring with one to five substituents selected from the group consisting of halogen atoms, lower alkoxy groups, cyano group, lower alkanoyl groups and lower alkyl groups,

(1-20) phenyl lower alkyl groups,

(1-21) cyano lower alkyl groups,

(1-22) 5 to 7-membered saturated heterocyclic group-substituted sulfonyl groups, the heterocyclic group containing on the heterocyclic ring one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur,

(1-23) thiazolyl groups optionally substituted with one or two lower alkyl groups on the thiazole ring,

(1-24) imidazolyl groups,

(1-25) amino lower alkyl groups optionally substituted with one or two lower alkyl groups on the amino group,

(1-26) pyrrolidinyl lower alkoxy groups,

(1-27) isoxazolyl groups,

(1-28) cycloalkylcarbonyl groups,

(1-29) naphthyloxy groups,

(1-30) pyridyl groups,

(1-31) furyl groups,

(1-32) phenylthio group,

(1-33) oxo group,

(1-34) carbamoyl group,

(1-35) 5 to 7-membered saturated heterocyclic groups containing one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, the heterocyclic group optionally being substituted with one to three substituents selected from the group consisting of oxo group; lower alkyl groups; lower alkanoyl groups; phenyl lower alkyl groups; phenyl groups optionally substituted on the phenyl ring with one to three members selected from the group consisting of halogen atoms and lower alkoxy groups; and pyridyl groups,

(1-36) oxido group and

(1-37) lower alkoxido groups,

with the proviso that R101 and R102 are not simultaneously unsubstituted phenyl.

Item 2. A pyrrolidine compound of General Formula (1) or a salt thereof according to Item 1, wherein
R101 is
(1) a phenyl group,
(3) a benzothienyl group,
(4) an indolyl group,
(5) a 2,3-dihydro-1H-indenyl group,
(6) a naphthyl group,
(7) a benzofuryl group,
(8) a quinolyl group,
(12) a benzothiazolyl group,
(18) a 2,4-dihydro-1,3-benzodioxinyl group,
(19) a 2,3-dihydrobenzofuryl group,
(20) a 9H-fluorenyl group,
(23) an indolinyl group,
(28) an isoquinolyl group,
(29) a 2,3-dihydro-1,4-benzoxadinyl group,
(30) a quinoxalinyl group,
(31) a quinazolinyl group,
(32) a 1,2,3,4-tetrahydroquinolyl group,
(40) a 1,3-benzodioxolyl group,
(41) a 2,3-dihydro-1,4-benzodioxinyl group,
(42) a 3,4-dihydro-1,5-benzodioxepinyl group,
(44) a 1,2-dihydroquinolyl group,
(45) a 1,2,3,4-tetrahydroisoquinolyl group,
(46) a benzoxazolyl group,
(47) a benzoisothiazolyl group,
(48) an indazolyl group or
(49) a benzoimidazolyl group,
and each of which may have on the aromatic or heterocyclic ring one to three substituents selected from the groups (1-1) to (1-37) as defined in Item 1.
Item 3. A pyrrolidine compound of General Formula (1) or a salt thereof according to Item 2, wherein
R101 is
(1) a phenyl group or
(3) a benzothienyl group,
and each of which may have on the aromatic or heterocyclic ring one to three substituents selected from the group consisting of (1-1) halogen atoms and (1-3) lower alkyl groups optionally substituted with one to three halogen atoms.
Item 4. A pyrrolidine compound of General Formula (1) or a salt thereof according to Item 3, wherein
R102 is
(1) a phenyl group,
(2) a pyridyl group,
(9) a thiazolyl group,
(10) a pyrimidinyl group,
(11) a pyrazinyl group
(14) a thienyl group,
(48) an indazolyl group,
(59) a hydroxy-substituted lower alkyl group or
(60) a lower alkoxy lower alkyl group,
and each of the groups (1), (2), (9), (10), (11), (14) and (48) may have on the aromatic or heterocyclic ring one to three substituents selected from the groups (1-1) to (1-37) as defined in Item 1.
Item 5. A pyrrolidine compound of General Formula (1) or a salt thereof according to Item 4, wherein
R101 is
a monohalophenyl group, a dihalophenyl group or a phenyl group substituted with one halogen atom and one lower alkyl group,
R102 is
(1) a phenyl group,
(2) a pyridyl group,
(9) a thiazolyl group,
(10) a pyrimidinyl group,
(11) a pyrazinyl group,
(14) a thienyl group,
(48) an indazolyl group,
(59) a hydroxy-substituted lower alkyl group or
(60) a lower alkoxy lower alkyl group,
and each of the groups (1), (2), (9), (10), (11), (14) and (48) may have on the aromatic or heterocyclic ring one or two substituents selected from the group consisting of (1-1) halogen atoms, (1-3) lower alkyl groups optionally substituted with one or more halogen atoms, and (1-9) cyano group.
Item 6. A pyrrolidine compound of General Formula (1) or a salt thereof according to Item 5 selected from the group consisting of:

    (4-chlorophenyl)phenyl-(S)-pyrrolidin-3-ylamine,
    (4-fluorophenyl)phenyl-(S)-pyrrolidin-3-ylamine,
    (3,4-difluorophenyl)phenyl-(S)-pyrrolidin-3-ylamine,
    bis-(4-fluorophenyl)-(S)-pyrrolidin-3-ylamine,
    (3,4-difluorophenyl)-(4-fluorophenyl)-(S)-pyrrolidin-3-ylamine,
    (3-chloro-4-fluorophenyl)-(S)-pyrrolidin-3-yl-p-tolylamine,
    4-[(S)-(4-fluoro-3-methylphenyl)pyrrolidin-3-ylamino]-benzonitrile,
    bis-(3-fluorophenyl)-(S)-pyrrolidin-3-ylamine,
    (3-chloro-4-fluorophenyl)-(S)-pyrrolidin-3-ylthiazol-2-ylamine,
    (4-fluorophenyl)-(S)-pyrrolidin-3-ylthiazol-2-ylamine,
    (3,4-dichlorophenyl)-(S)-pyrrolidin-3-ylthiazol-2-ylamine,
    (3,4-dichlorophenyl)pyrimidin-5-yl-(S)-pyrrolidin-3-ylamine,
    (3-chloro-4-fluorophenyl)pyrazin-2-yl-(S)-pyrrolidin-3-ylamine,
    (3-chloro-4-fluorophenyl)-(5-chloropyridin-2-yl)-(S)-pyrrolidin-3-ylamine,
    (3-chloro-4-fluorophenyl)pyridin-2-yl-(S)-pyrrolidin-3-ylamine,
    (3-chloro-4-fluorophenyl)pyridin-3-yl-(S)-pyrrolidin-3-ylamine,
    (3-chloro-4-fluorophenyl)-(6-fluoropyridin-3-yl)-(S)-pyrrolidin-3-ylamine,
    (3,4-dichlorophenyl)pyridin-3-yl-(S)-pyrrolidin-3-ylamine,
    (3-chloro-4-fluorophenyl)-(S)-pyrrolidin-3-ylthiophen-3-ylamine,
    (3-chloro-4-fluorophenyl)-(5-fluoropyridin-3-yl)-(S)-pyrrolidin-3-ylamine,
    (4-fluoro-3-methylphenyl)-(5-fluoropyridin-3-yl)-(S)-pyrrolidin-3-ylamine,
    2-[(S)-(3-chloro-4-fluorophenyl)pyrrolidin-3-ylamino]ethanol,
    1-[(S)-(3-chloro-4-fluorophenyl)pyrrolidin-3-ylamino]-2-methyl-propan-2-ol,
    (3-chloro-4-fluorophenyl)-(2-methoxyethyl)-(S)-pyrrolidin-3-ylamine,
    3-[(S)-(3-chloro-4-fluorophenyl)pyrrolidin-3-ylamino]-propan-1-ol,
    (3-chloro-4-fluorophenyl)-(3-methoxypropyl)-(S)-pyrrolidin-3-ylamine,
    (3-chloro-4-fluorophenyl)-(1-methyl-1H-indazol-5-yl)-(S)-pyrrolidin-3-ylamine,
    benzo[b]thiophen-6-yl-(S)-pyrrolidin-3-ylthiophen-3-ylamine, and
    benzo[b]thiophen-5-yl-(S)-pyrrolidin-3-ylthiophen-3-ylamine.


Item 7. A pharmaceutical composition comprising a pyrrolidine compound of General Formula (1) or a salt thereof according to Item 1 as an active ingredient and a pharmaceutically acceptable carrier.
Item 8. A prophylactic and/or therapeutic agent for disorders caused by reduced neurotransmission of serotonin, norepinephrine or dopamine, comprising as an active ingredient a pyrrolidine compound of General Formula (1) or a salt thereof according to Item 1.
Item 9. A prophylactic and/or therapeutic agent according to Item 8, wherein the disorder is selected from the group consisting of hypertension; depression; anxiety disorders; fear; posttraumatic stress syndrome; acute stress syndrome; avoidant personality disorders; body dysmorphic disorder; precocious ejaculation; eating disorders; obesity; chemical dependencies to alcohol, cocaine, heroin, phenobarbital, nicotine and benzodiazepines; cluster headache; migraine; pain disorder; Alzheimer's disease; obsessive-compulsive disorders; panic disorders; memory disorders; Parkinson's disease; endocrine disorders; vascular spasm; cerebellar ataxia; gastrointestinal tract disorders; negative syndrome of schizophrenia; premenstrual syndrome; fibromyalgia syndrome; stress incontinence; Tourette's syndrome; trichotillomania; kleptomania; male impotence; attention deficit hyperactivity disorder (ADHD); chronic paroxysmal hemicrania; chronic fatigue; cataplexy; sleep apnea syndrome and headache.
Item 10. A prophylactic and/or therapeutic agent according to Item 8, wherein the disorder is selected from the group consisting of:
depressions selected from the group consisting of major depression; bipolar 1 disorder; bipolar 2 disorder; mixed episode; dysthymic disorders; rapid cycler; atypical depression; seasonal affective disorders; postpartum depression; minor depression; recurrent brief depressive disorder; intractable depression/chronic depression; double depression; alcohol-induced mood disorders; mixed anxiety & depressive disorders; depressions induced by various physical disorders selected from the group consisting of Cushing's disease, hypothyroidism, hyperparathyroidism syndrome, Addison's disease, amenorrhea and lactation syndrome, Parkinson's disease, Alzheimer's disease, intracerebral bleeding, diabetes, chronic fatigue syndrome and cancers; depression of the middle-aged; senile depression; depression of children and adolescents; depression induced by interferons; depression induced by adjustment disorder; and anxieties selected from the group consisting of anxiety induced by adjustment disorder and anxiety induced by neuropathy selected from the group consisting of head trauma, brain infection and inner ear injury.
Item 11. Use of a pyrrolidine compound of General Formula (1) or a salt thereof according to any one of Items 1 to 6 as a drug.
Item 12. Use of a pyrrolidine compound of General Formula (1) or a salt thereof according to any one of Items 1 to 6 as a serotonin reuptake inhibitor and/or a norepinephrine reuptake inhibitor and/or a dopamine reuptake inhibitor.
Item 13. A method for treating or preventing disorders caused by reduced neurotransmission of serotonin, norepinephrine or dopamine, comprising administering a pyrrolidine compound of General Formula (1) or a salt thereof according to any one of Items 1 to 6 to human or animal.
Item 14. A process for producing a pyrrolidine compound of General Formula (1):




or a salt thereof, wherein R101 and R102 are defined above in Item 1,

the process comprising
(1) subjecting a compound of General Formula (2)




wherein R101 and R102 are as defined above in Item 1, and R112 is an amino-protecting group to an elimination reaction to remove the amino protecting group.

Preferred embodiments of the pyrrolidine compound (1) include compounds represented by General Formula (1)




and salts thereof,

wherein R101 is

(1) a phenyl group,

(3) a benzothienyl group,

(4) an indolyl group,

(5) a 2,3-dihydro-1H-indenyl group,

(6) a naphthyl group,

(7) a benzofuryl group,

(8) a quinolyl group,

(12) a benzothiazolyl group,

(18) a 2,4-dihydro-1,3-benzodioxinyl group,

(19) a 2,3-dihydrobenzofuryl group,

(20) a 9H-fluorenyl group,

(23) an indolinyl group,

(28) an isoquinolyl group,

(29) a 2,3-dihydro-1,4-benzoxadinyl group,

(30) a quinoxalinyl group,

(31) a quinazolinyl group,

(32) a 1,2,3,4-tetrahydroquinolyl group,

(40) a 1,3-benzodioxolyl group,

(41) a 2,3-dihydro-1,4-benzodioxinyl group,

(42) a 3,4-dihydro-1,5-benzodioxepinyl group,

(44) a 1,2-dihydroquinolyl group,

(45) a 1,2,3,4-tetrahydroisoquinolyl group,

(46) a benzoxazolyl group,

(47) a benzoisothiazolyl group,

(48) an indazolyl group or

(49) a benzoimidazolyl group,

and each of which may have on the aromatic or heterocyclic ring one to five (preferably one to three) substituents selected from the following (1-1) to (1-37):

(1-1) halogen atoms,

(1-2) lower alkylthio groups optionally substituted with one or more (preferably one to three) halogen atoms,

(1-3) lower alkyl groups optionally substituted with one or more (preferably one to three) halogen atoms,

(1-4) lower alkoxy groups optionally substituted with one or more (preferably one to four) halogen atoms,

(1-5) nitro group,

(1-6) lower alkoxycarbonyl groups,

(1-7) amino groups optionally substituted with one or two lower alkyl groups,

(1-8) lower alkylsulfonyl groups,

(1-9) cyano group,

(1-10) carboxy group,

(1-11) hydroxy group,

(1-12) thienyl groups,

(1-13) oxazolyl groups,

(1-14) naphthyl groups,

(1-15) benzoyl group,

(1-16) phenoxy groups optionally substituted with one to three halogen atoms on phenyl ring,

(1-17) phenyl lower alkoxy groups,

(1-18) lower alkanoyl groups,

(1-19) phenyl groups optionally substituted on the phenyl ring with one to five (preferably one to three) substituents selected from the group consisting of halogen atoms, lower alkoxy groups, cyano group, lower alkanoyl groups and lower alkyl groups,

(1-20) phenyl lower alkyl groups,

(1-21) cyano lower alkyl groups,

(1-22) 5 to 7-membered saturated heterocyclic group-substituted sulfonyl groups, the heterocyclic group containing on the heterocyclic ring one or two nitrogen atoms (preferably piperidylsulfonyl),

(1-23) thiazolyl groups optionally substituted with one or two lower alkyl groups on the thiazole ring,

(1-24) imidazolyl groups,

(1-25) amino lower alkyl groups optionally substituted with one or two lower alkyl groups on the amino group,

(1-26) pyrrolidinyl lower alkoxy groups,

(1-27) isoxazolyl groups,

(1-28) cycloalkylcarbonyl groups,

(1-29) naphthyloxy groups,

(1-30) pyridyl groups,

(1-31) furyl groups,

(1-32) phenylthio group,

(1-33) oxo group,

(1-34) carbamoyl group,

(1-35) 5 to 7-membered saturated heterocyclic groups containing one or two nitrogen atoms (preferably pyrrolidinyl, piperazinyl or piperidyl), the heterocyclic group optionally being substituted with one to three substituents selected from the group consisting of oxo group; lower alkyl groups; lower alkanoyl, groups; phenyl lower alkyl groups; phenyl groups optionally substituted with one to three members selected from the group consisting of halogen atoms and lower alkoxy groups; and pyridyl groups,

(1-36) oxido group and

(1-37) lower alkoxido groups,

with the proviso that R101 and R102 are not simultaneously unsubstituted phenyl.

More preferred embodiments of the pyrrolidine compound (1) include compounds represented by General Formula (1)




and salts thereof,

wherein R101 is

(1) a phenyl group or (3) a benzothienyl group,

and each of which may have on the aromatic or heterocyclic ring one or two substituents selected from the group consisting of (1-1) halogen atoms and (1-3) lower alkyl groups optionally substituted with one to three halogen atoms, and

R102 is

(1) a phenyl group,

(2) a pyridyl group,

(3) a benzothienyl group,

(4) an indolyl group,

(5) a 2,3-dihydro-1H-indenyl group,

(6) a naphthyl group,

(7) a benzofuryl group,

(8) a quinolyl group,

(9) a thiazolyl group,

(10) a pyrimidinyl group,

(11) a pyrazinyl group,

(12) a benzothiazolyl group,

(13) a thieno[3,2-b]pyridyl group,

(14) a thienyl group,

(15) a cycloalkyl group,

(16) a tetrahydropyranyl group,

(17) a pyrrolyl group,

(18) a 2,4-dihydro-1,3-benzodioxinyl group,

(19) a 2,3-dihydrobenzofuryl group,

(20) a 9H-fluorenyl group,

(21) a pyrazolyl group,

(22) a pyridazinyl group,

(23) an indolinyl group,

(24) a thieno[2,3-b]pyridyl group,

(25) a thieno[3,2-d]pyrimidinyl group,

(26) a thieno[3,2-e]pyrimidinyl group,

(27) a 1H-pyrazolo[3,4-b]pyridyl group,

(28) an isoquinolyl group,

(29) a 2,3-dihydro-1,4-benzoxadinyl group,

(30) a quinoxalinyl group,

(31) a quinazolinyl group,

(32) a 1,2,3,4-tetrahydroquinolyl group,

(40) a 1,3-benzodioxolyl group,

(41) a 2,3-dihydro-1,4-benzodioxinyl group,

(42) a 3,4-dihydro-1,5-benzodioxepinyl group,

(43) a dihydropyridyl group,

(44) a 1,2-dihydroquinolyl group,

(45) a 1,2,3,4-tetrahydroisoquinolyl group,

(46) a benzoxazolyl group,

(47) a benzoisothiazolyl group,

(48) an indazolyl group,

(49) a benzoimidazolyl group,

(50) an imidazolyl group,

(59) a hydroxy-substituted lower alkyl group or

(60) a lower alkoxy lower alkyl group

and each of groups (1) to (50) may have on the aromatic or heterocyclic ring one to five (preferably one to three) substituents selected from the following (1-1) to (1-37):

(1-1) halogen atoms,

(1-2) lower alkylthio groups optionally substituted with one or more (preferably one to three) halogen atoms,

(1-3) lower alkyl groups optionally substituted with one or more (preferably one to three) halogen atoms,

(1-4) lower alkoxy groups optionally substituted with one or more (preferably one to four) halogen atoms,

(1-5) nitro group,

(1-6) lower alkoxycarbonyl groups,

(1-7) amino groups optionally substituted with one or two lower alkyl groups,

(1-8) lower alkylsulfonyl groups,

(1-9) cyano group,

(1-10) carboxy group,

(1-11) hydroxy group,

(1-12) thienyl groups,

(1-13) oxazolyl groups,

(1-14) naphthyl groups,

(1-15) benzoyl group,

(1-16) phenoxy groups optionally substituted with one to three halogen atoms on phenyl ring,

(1-17) phenyl lower alkoxy groups,

(1-18) lower alkanoyl groups,

(1-19) phenyl groups optionally substituted on the phenyl ring with one to five (preferably one to three) substituents selected from the group consisting of halogen atoms, lower alkoxy groups, cyano group, lower alkanoyl groups and lower alkyl groups,

(1-20) phenyl lower alkyl groups,

(1-21) cyano lower alkyl groups,

(1-22) 5 to 7-membered saturated heterocyclic group-substituted sulfonyl groups, the heterocyclic group containing on the heterocyclic ring one or two nitrogen atoms (preferably piperidylsulfonyl),

(1-23) thiazolyl groups optionally substituted with one or two lower alkyl groups on the thiazole ring,

(1-24) imidazolyl groups,

(1-25) amino lower alkyl groups optionally substituted with one or two lower alkyl groups on the amino group,

(1-26) pyrrolidinyl lower alkoxy groups,

(1-27) isoxazolyl groups,

(1-28) cycloalkylcarbonyl groups,

(1-29) naphthyloxy groups,

(1-30) pyridyl groups,

(1-31) furyl groups,

(1-32) phenylthio group,

(1-33) oxo group,

(1-34) carbamoyl group,

(1-35) 5 to 7-membered saturated heterocyclic groups containing one or two nitrogen atoms (preferably pyrrolidinyl, piperazinyl or piperidyl), the heterocyclic group optionally being substituted with one to three substituents selected from the group consisting of oxo group; lower alkyl groups; lower alkanoyl groups; phenyl lower alkyl groups; phenyl groups optionally substituted with one to three members selected from the group consisting of halogen atoms and lower alkoxy groups; and pyridyl groups,

(1-36) oxido group and

(1-37) lower alkoxido groups,

with the proviso that R101 and R102 are not simultaneously unsubstituted phenyl.

Particularly preferred embodiments of the pyrrolidine compound (1) include compounds represented by General Formula (1)




and salts thereof,

wherein R101 is

(1) a phenyl group substituted on the phenyl ring with one or two substituents selected from the group consisting of (1-1) halogen atoms and (1-3) lower alkyl groups optionally substituted with one to three halogen atoms, and

R102 is

(1) a phenyl group,

(2) a pyridyl group,

(9) a thiazolyl group,

(10) a pyrimidinyl group,

(11) a pyrazinyl group,

(14) a thienyl group,

(48) an indazolyl group,

(59) a hydroxy-substituted lower alkyl group or

(60) a lower alkoxy lower alkyl group,

and each of the groups (1), (2), (9), (10), (11), (14) and (48) may have on the aromatic or heterocyclic ring one or two substituents selected from the group consisting of

(1-1) halogen atoms,

(1-3) lower alkyl groups optionally substituted with one to three halogen atoms and

(1-9) cyano group.

Examples of particularly preferable pyrrolidine compounds of the present invention are as follows:

    (4-chlorophenyl)phenyl-(S)-pyrrolidin-3-ylamine,
    (4-fluorophenyl)phenyl-(S)-pyrrolidin-3-ylamine,
    (3,4-difluorophenyl)phenyl-(S)-pyrrolidin-3-ylamine,
    bis-(4-fluorophenyl)-(S)-pyrrolidin-3-ylamine,
    (3,4-difluorophenyl)-(4-fluorophenyl)-(S)-pyrrolidin-3-ylamine,
    (3-chloro-4-fluorophenyl)-(S)-pyrrolidin-3-yl-p-tolylamine,
    4-[(S)-(4-fluoro-3-methylphenyl)pyrrolidin-3-ylamino]-benzonitrile,
    bis-(3-fluorophenyl)-(S)-pyrrolidin-3-ylamine,
    (3-chloro-4-fluorophenyl)-(S)-pyrrolidin-3-ylthiazol-2-ylamine,
    (4-fluorophenyl)-(S)-pyrrolidin-3-ylthiazol-2-ylamine,
    (3,4-dichlorophenyl)-(S)-pyrrolidin-3-ylthiazol-2-ylamine,
    (3,4-dichlorophenyl)pyrimidin-5-yl-(S)-pyrrolidin-3-ylamine,
    (3-chloro-4-fluorophenyl)pyrazin-2-yl-(S)-pyrrolidin-3-ylamine,
    (3-chloro-4-fluorophenyl)-(5-chloropyridin-2-yl)-(S)-pyrrolidin-3-ylamine,
    (3-chloro-4-fluorophenyl)pyridin-2-yl-(S)-pyrrolidin-3-ylamine,
    (3-chloro-4-fluorophenyl)pyridin-3-yl-(S)-pyrrolidin-3-ylamine,
    (3-chloro-4-fluorophenyl)-(6-fluoropyridin-3-yl)-(S)-pyrrolidin-3-ylamine,
    (3,4-dichlorophenyl)pyridin-3-yl-(S)-pyrrolidin-3-ylamine,
    (3-chloro-4-fluorophenyl)-(S)-pyrrolidin-3-ylthiophen-3-ylamine,
    (3-chloro-4-fluorophenyl)-(5-fluoropyridin-3-yl)-(S)-pyrrolidin-3-ylamine,
    (4-fluoro-3-methylphenyl)-(5-fluoropyridin-3-yl)-(S)-pyrrolidin-3-ylamine,
    2-[(S)-(3-chloro-4-fluorophenyl)pyrrolidin-3-ylamino]ethanol,
    1-[(S)-(3-chloro-4-fluorophenyl)pyrrolidin-3-ylamino]-2-methyl-propan-2-ol,
    (3-chloro-4-fluorophenyl)-(2-methoxyethyl)-(S)-pyrrolidin-3-ylamine,
    3-[(S)-(3-chloro-4-fluorophenyl)pyrrolidin-3-ylamino]-propan-1-ol,
    (3-chloro-4-fluorophenyl)-(3-methoxypropyl)-(S)-pyrrolidin-3-ylamine,
    (3-chloro-4-fluorophenyl)-(1-methyl-1H-indazol-5-yl)-(S)-pyrrolidin-3-ylamine,
    benzo[b]thiophen-6-yl-(S)-pyrrolidin-3-ylthiophen-3-ylamine, and
    benzo[b]thiophen-5-yl-(S)-pyrrolidin-3-ylthiophen-3-ylamine.


Specific examples of groups in General Formula (1) are as follows.
Examples of halogen atoms include fluorine, chlorine, bromine, and iodine.
Examples of lower alkylthio groups optionally substituted with one or more halogen atoms include straight or branched C1-6 alkylthio groups optionally substituted with one to three halogen atoms, such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, sec-butylthio, n-pentylthio, isopentylthio, neopentylthio, n-hexylthio, isohexylthio, 3-methylpenthylthio, trifluoromethylthio, trichloromethylthio, chloromethylthio, bromomethylthio, fluoromethylthio, iodomethylthio, difluoromethylthio, dibromomethylthio, 2-chloroethylthio, 2,2,2-trifluoroethylthio, 2,2,2-trichloroethylthio, 3-chloropropylthio, 2,3-dichloropropylthio, 4,4,4-trichlorobutylthio, 4-fluorobutylthio, 5-chloropentylthio, 3-chloro-2-methylpropylthio, 5-bromohexylthio, 5,6-dibromohexylthio, etc.
Examples of lower alkyl groups optionally substituted with one or more halogen atoms include straight or branched C1-6 alkyl groups optionally substituted with one to four halogen atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl, trifluoromethyl, trichloromethyl, chloromethyl, bromomethyl, fluoramethyl, 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-dibramohexyl, 1,1,2,2-tetrafluoroethyl, etc.
Examples of lower alkoxy groups optionally substituted with one or more halogen atoms include straight or branched C1-6 alkoxy groups optionally substituted with one to four halogen atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, 3-methylpentyloxy, 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, 5-bromohexyloxy, 5,6-dibromohexyloxy, 1,1,2,2-tetrafluoroethoxy, etc.
Examples of lower alkoxycarbonyl groups include alkoxycarbonyl groups wherein the alkoxy moiety is a straight or branched C1-6 alkoxy group, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl, n-pentyloxycarbonyl, neopentyloxycarbonyl, n-hexyloxycarbonyl, isohexyloxycarbonyl, 3-methylpentyloxycarbonyl, etc.
Examples of lower alkyl groups include straight or branched C1-6 alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl, etc.
Examples of lower alkanoyl groups include a straight or branched C1-6 alkanoyl group such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, hexanoyl, etc.
Examples of lower alkylsulfonyl groups include straight or branched C1-6 alkyl sulfonyl groups, such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl, sec-butylsulfonyl, n-pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl, n-hexylsulfonyl, isohexylsulfonyl, 3-methylpentylsulfonyl, etc.
Examples of phenoxy groups optionally substituted with one to three halogen atoms on the phenyl ring include phenoxy, 2-fluorophenoxy, 3-fluorophenoxy, 4-fluorophenoxy, 2-chlorophenoxy, 3-chlorophenoxy, 4-chlorophenoxy, 2-bromophenoxy, 3-bromophenoxy, 4-bromophenoxy, 2-iodophenoxy, 3-iodophenoxy, 4-iodophenoxy, 2,3-difluorophenoxy, 3,4-difluorophenoxy, 3,5-difluorophenoxy, 2,4-difluorophenoxy, 2,6-difluorophenoxy, 2,3-dichlorophenoxy, 3,4-dichlorophenoxy, 3,5-dichlorophenoxy, 2,4-dichlorophenoxy, 2,6-dichlorophenoxy, 3,4,5-trifluorophenoxy, 3,4,5-trichlorophenoxy, 2,4,6-trifluorophenoxy, 2,4,6-trichlorophenoxy, 2-fluoro-4-bromophenoxy, 4-chloro-3-fluorophenoxy, 2,3,4-trichlorophenoxy, etc.
Examples of phenyl lower alkoxy groups include phenylalkoxy groups wherein the alkoxy moiety is a straight or branched C1-6 alkoxy group, such as benzyloxy, 2-phenylethoxy, 1-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 5-phenylpentyloxy, 6-phenylhexyloxy, 1,1-dimethyl-2-phenylethoxy, 2-methyl-3-phenylpropoxy, etc.
Examples of phenyl lower alkyl groups include phenylalkyl groups wherein the alkyl moiety is a straight or branched C1-6 alkyl group, such as benzyl, 1-phenethyl, 2-phenethyl, 3-phenylpropyl, 2-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 4-phenylpentyl, 6-phenylhexyl, 2-methyl-3-phenylpropyl, 1,1-dimethyl-2-phenylethyl, etc.
Examples of cyano lower alkyl groups include cyanoalkyl groups wherein the alkyl moiety is a straight or branched C1-6 alkyl group, such as cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 3-cyanopropyl, 4-cyanobutyl, 1,1-dimethyl-2-cyanoethyl, 5-cyanopentyl, 6-cyanohexyl, 1-cyanoisopropyl, 2-methyl-3-cyanopropyl, etc.
Examples of thiazolyl groups optionally substituted with one or two lower alkyl groups on the thiazole ring include thiazolyl groups optionally substituted with one or two straight or branched C1-6 alkyl groups on the thiazole ring, such as (2-, 4-, or 5-)thiazolyl, 2-methyl-(4-, or 5-)thiazolyl, 4-methyl-(2- or 5-)thiazolyl, 2-ethyl-(4- or 5-)thiazolyl, 4-n-propyl-(2- or 5-)thiazolyl, 5-n-butyl-(2- or 4-)thiazolyl, 2-n-pentyl-(4- or 5-) thiazolyl, 4-n-hexyl-(2- or 5-)thiazolyl, 2,4-dimethyl-5-thiazolyl, etc.
Examples of amino lower alkyl groups optionally substituted with one or two lower alkyl groups on an amino group include aminoalkyl groups wherein the alkyl moiety is a straight or branched C1-6 alkyl group and which are optionally substituted on an amino group with one or two straight or branched C1-6 alkyl groups; 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, 2-ethylaminoethyl, 3-propylaminopropyl, 3-isopropylaminopropyl, 4-butylaminobutyl, 5-pentylaminopentyl, 6-hexylaminohexyl, 2-dimethylaminoethyl, 2-diisopropylaminopropyl, 3-dimethylaminopropyl, diisopropylaminomethyl, 3-diisopropylaminopropyl, (N-ethyl-N-propylamino)methyl, 2-(N-methyl-N-hexylamino)methyl, etc.
Examples of pyrrolidinyl lower alkoxy groups include pyrrolidinyl alkoxy groups wherein the alkoxy moiety is a straight or branched alkoxy group, such as (1-, 2-, or 3-) pyrrolydinyl methoxy, 2-[(1-, 2-, or 3-)pyrrolydinyl]ethoxy, 1-[(1-, 2-, or 3-)pyrrolydinyl]ethoxy, 3-[(1-, 2-, or 3-) pyrrolydinyl]propoxy, 4-[(1-, 2-, or 3-)pyrrolydinyl]butoxy, 5-[(1-, 2-, or 3-)pyrrolydinyl]pentyloxy, 6-[(1-, 2-, or 3-) pyrrolydinyl]hexyloxy, 1,1-dimethyl-2-[(1-, 2-, or 3-) pyrrolydinyl]ethoxy, 2-methyl-3-[(1-, 2-, or 3-) pyrrolydinyl]propoxy, etc.
Examples of cycloalkyl groups include C3-8 cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.
Examples of cycloalkylcarbonyl groups include cycloalkylcarbonyl groups wherein the cycloalkyl moiety is a C3-8 cycloalkyl group, such as cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, cyclooctylcarbonyl, etc.
Examples of lower alkoxy groups include straight or branched C1-6 alkoxy groups, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, 3-methylpentyloxy, etc.
Examples of lower alkylthio groups include straight or branched C1-6 alkylthio groups such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, sec-butylthio, n-pentylthio, isopentylthio, neopentylthio, n-hexylthio, isohexylthio, 3-methylpentylthio, etc.
Examples of phenyl groups optionally substituted on the phenyl ring with one to three members selected from the group consisting of halogen atoms and lower alkoxy groups include phenyl groups optionally substituted on the phenyl ring with one to three members selected from the group consisting of halogen atoms and straight or branched C1-6 alkoxy groups, such as phenyl, 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-methoxy-4-fluorophenyl, 4-fluorophenyl, 2,5-difluorophenyl, 2,4-difluorophenyl, 3,4-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-fluorophenyl, 2-fluorophenyl, 3-bromophenyl, 4-iodophenyl, 2-bromophenyl, 4-bromophenyl, 3,5-dichlorophenyl, 2,4,6-trifluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-iodophenyl, 3-iodophenyl, 2,3-dibromophenyl, 2,4-diiodophenyl, 2,4,6-trichlorophenyl, etc.
Examples of 5- to 7-membered saturated heterocyclic groups containing on the heterocyclic ring one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur include pyrrolidinyl, piperazinyl, piperidinyl, morpholino, thiomorpholino, homopiperazinyl, homopiperidinyl, imidazolidinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, isothiazolidinyl and pyrazolidinyl.
Examples of the above-mentioned heterocyclic groups substituted with one to three members selected from the group consisting of oxo group; lower alkyl groups; lower alkanoyl groups; phenyl lower alkyl groups; phenyl groups optionally substituted on the phenyl ring with one to three members selected from the group consisting of halogen atoms and lower alkoxy groups; and pyridyl groups:
include the above-mentioned heterocyclic groups substituted with one to three members selected from the group consisting of oxo groups; straight or branched C1-6 alkyl groups; straight or branched C1-6 alkanoyl groups; phenyl alkyl groups wherein the alkyl moiety is a straight or branched C1-6 alkyl group; phenyl groups optionally substituted on the phenyl ring with one to three members selected from the group consisting of halogen atoms and straight or branched C1-6 alkoxy groups; and pyridyl groups;
such as 2-oxo-(1-, 3-, 4-, or 5-)pyrrolidinyl, 2-oxo-(1-, 3-, 4-, 5-, or 6-)piperazinyl, 4-methyl-(1-, 2-, or 3-) piperazinyl, 4-acetyl-(1-, 2-, or 3-)piperazinyl, 4-ethyl-(1-, 2-, or 3-)piperazinyl, 2-methyl-(1-, 2-, 3-, 4-, or 5-) pyrrolidinyl, 2-methyl-(1-, 2-, 3-, 4-, 5-, or 6-)piperidinyl, 2,4-dimethyl-(1-, 2-, 3-, 5-, or 6-)piperidinyl, 3-methyl-(1-, 2-, 3-, 4-, or 5-)pyrrolidinyl, 2,3,4-trimethyl-(1-, 2-, 3-, 5-, or 6-)piperazinyl, 4-acetyl-3-methyl-(1-, 2-, 3-, 5-, or 6-) piperazinyl, 3-methyl-(2-, 3-, 4-, 5-, or 6-)morpholino, 2-acetyl-(2-, 3-, 4-, 5-, or 6-)morpholino, 4-(2-phenylethyl)-(1-, 2-, or 3-)piperazinyl, 4-(3,4-dichlorophenyl)-(1-, 2-, 3-, or 4-) piperazinyl, 4-(4-methoxyphenyl)-(1-, 2-, or 3-)piperazinyl, 4-(2-chlorophenyl)-(1-, 2-, or 3-)piperazinyl, 4-[(2-, 3-, or 4-) pyridyl]-(1-, 2-, or 3-)piperazinyl, 4-phenyl-(1-, 2-, or 3-) piperazinyl, 4-benzyl-(1-, 2-, or 3-)piperidinyl, 4-(3,4-dichlorophenyl)-(1-, 2-, or 3-)morpholino, 2-(4-methoxyphenyl)-(1-, 2-, 3-, 4-, or 5-)pyrrolidinyl, 4-(2-chlorophenyl)-(1-, 2-, or 3-)piperidinyl, 4-[(2-, 3-, or 4-) pyridyl]-(1-, 2-, or 3-) piperidinyl, 4-phenyl-(1-, 2-, or 3-) piperidinyl, 4-phenyl-3-methyl-(1-, 2-, 3-, 5-, or 6-) piperazinyl, 4-[(2-, 3-, or 4-) pyridyl]-2-acetyl-(1-, 2-, 3-, 5-, or 6-)piperazinyl, etc.
Examples of cycloalkyl lower alkyl groups include cycloalkyl alkyl groups wherein the cycloalkyl moiety is a C3-8 cycloalkyl group and the alkyl moiety is a straight or branched C1-6 alkyl group, such as cyclopropylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 1-cyclobutylethyl, cyclopentylmethyl, 3-cyclopentylpropyl, 4-cyclohexylbutyl, 5-cycloheptylpentyl, 6-cyclooctylhexyl, 1,1-dimethyl-2-cyclohexylethyl, 2-methyl-3-cyclopropylpropyl, etc.
Examples of lower alkylthio lower alkyl groups include alkylthioalkyl groups wherein the alkylthio moiety is a straight or branched C1-6 alkylthio group and the alkyl moiety is a straight or branched C1-6 alkyl group, such as methylthiomethyl, 2-methylthioethyl, 1-ethylthioethyl, 2-ethylthioethyl, 3-n-butylthiopropyl; 4-n-propylthiobutyl, 1,1-dimethyl-2-n-pentylthioethyl, 5-n-hexylthiopentyl, 6-methylthiohexyl, 1-ethylthioisopropyl, 2-methyl-3-methylthiopropyl, etc.
Examples of phenoxy lower alkyl groups include phenoxy alkyl groups wherein the alkyl moiety is a straight or branched C1-6 alkyl group, such as phenoxymethyl, 1-phenoxyethyl, 2-phenoxyethyl, 3-phenoxypropyl, 2-phenoxypropyl, 4-phenoxybutyl, 5-phenoxypentyl, 4-phenoxypentyl, 6-phenoxyhexyl, 2-methyl-3-phenoxypropyl, 1,1-dimethyl-2-phenoxyethyl, etc.
Examples of pyridyloxy lower alkyl groups include pyridyloxyalkyl groups wherein the alkyl moiety is a straight or branched C1-6 alkyl group, such as [2-, 3-, or 4-]pyridyloxy]methyl, 1-[2-, 3-, or 4-]pyridyloxy]ethyl, 2-[2-, 3-, or 4-]pyridyloxy]ethyl, 3-[2-, 3-, or 4-]pyridyloxy]propyl, 2-[2-, 3-, or 4-]pyridyloxy]propyl, 4-[2-, 3-, or 4-]pyridyloxy]butyl, 5-[2-, 3-, or 4-]pyridyloxy]pentyl, 4-[2-, 3-, or 4-]pyridyloxy]pentyl, 6-[2-, 3-, or 4-]pyridyloxy]hexyl, 2-methyl-3-[2-, 3-, or 4-]pyridyloxy]propyl, 1,1-dimethyl-2-[2-, 3-, or 4-]pyridyloxy]ethyl, etc.
Examples of lower alkynyl groups include C2-6 straight or branched alkynyl groups, such as ethynyl, (1- or 2-) propynyl, 1-methyl-(1- or 2-)propynyl, 1-ethyl-(1- or 2-)propynyl, (1-, 2- or 3-)butynyl and (1-, 2-, 3- or 4-)pentynyl, (1-, 2-, 3-, 4- or 5-)hexynyl, etc.
Examples of phenyl lower alkenyl groups include phenylalkenyl groups containing one to three double bonds wherein the alkenyl moiety is a straight or branched C2-6 alkenyl group, such as styryl, 3-phenyl-2-propenyl (trivial name: cinnamyl), 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, 6-phenyl-1,3,5-hexatrienyl, etc.
Examples of cycloalkyl lower alkyl groups include cycloalkyl alkyl groups wherein the cycloalkyl moiety is a C3-8 cycloalkyl group as defined above and the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of lower alkylthio lower alkyl groups include alkylthio alkyl groups wherein the alkylthio moiety is a straight or branched C1-6 alkylthio group as defined above and the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of amino-substituted lower alkyl groups optionally substituted with one or two lower alkyl groups on the amino group include amino-substituted alkyl groups optionally substituted with one or two straight or branched C1-6 alkyl groups on the amino group wherein the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of phenoxy lower alkyl groups include phenoxy alkyl groups wherein the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of pyridyloxy lower alkyl groups include pyridyloxy alkyl groups wherein the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of 1,2,3,4-tetrahydronaphthyl lower alkyl groups include 1,2,3,4-tetrahydronaphthyl alkyl groups wherein the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of imidazo[1,2-a]pyridyl lower alkyl groups include imidazo[1,2-a]pyridyl alkyl groups wherein the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of thiazolyl lower alkyl groups include thiazolyl alkyl groups wherein the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of tetrahydropyranyl lower alkyl groups include tetrahydropyranyl alkyl groups wherein the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of piperidyl lower alkyl groups include piperidyl alkyl groups wherein the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of diphenyl lower alkoxy-substituted lower alkyl groups include diphenyl alkoxy-substituted alkyl groups wherein the alkoxy moiety is a straight or branched C1-6 alkoxy group as defined above and the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of lower alkoxycarbonyl-substituted lower alkyl groups include alkoxycarbonyl-substituted alkyl groups wherein the alkoxy moiety is a straight or branched C1-6 alkoxy group as defined above and the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of phenyl lower alkoxycarbonyl-substituted lower alkyl groups include phenyl alkoxycarbonyl-substituted alkyl groups wherein the alkoxy moiety is a straight or branched C1-6 alkoxy group as defined above and the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of hydroxy-substituted lower alkyl groups include hydroxy-substituted alkyl groups wherein the alkyl moiety is a straight or branched C1-4 alkyl group as defined above having 1 to 3 hydroxy groups, such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl, 3,4-dihydroxybutyl, 5-hydroxypentyl, 4-hydroxypentyl, 6-hydroxyhexyl, 2,2-dimethyl-3-hydroxypropyl, 1,1-dimethyl-2-hydroxyethyl, 2,3,4-trihydroxybutyl, etc.
Examples of lower alkoxy lower alkyl groups include alkoxy alkyl groups wherein the alkoxy moiety is a straight or branched C1-6 alkoxy group as defined above and the alkyl moiety is a straight or branched C1-6 alkyl group as defined above, such as methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxypropyl, 3-methoxypropyl, 3-ethoxypropyl, 3-propoxypropyl, 4-methoxybutyl, 3-methoxybutyl, 5-methoxypentyl, 4-ethoxypentyl, 6-methoxyhexyl, 2,2-dimethyl-3-methoxypropyl, 1,1-dimethyl-2-methoxyethyl etc.
Examples of carboxy lower alkyl groups include carboxy alkyl groups wherein the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of carbamoyl-substituted lower alkyl groups optionally substituted with one or two lower alkyl groups on the carbamoyl group include carbamoyl-substituted alkyl groups optionally substituted with one or two straight or branched C1-6 alkyl groups on the carbamoyl group wherein the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of morpholinylcarbonyl lower alkyl groups include morpholinylcarbonyl alkyl groups wherein the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of benzoyl lower alkyl groups include benzoyl alkyl groups wherein the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of phenylthio lower alkyl groups include phenylthio alkyl groups wherein the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of naphthylthio lower alkyl groups include naphthylthio alkyl groups wherein the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of cycloalkylthio lower alkyl groups include cycloalkylthio alkyl groups wherein the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of pyridylthio lower alkyl groups include pyridylthio alkyl groups wherein the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of pyrimidinylthio lower alkyl groups include pyrimidinylthio alkyl groups wherein the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of furylthio lower alkyl groups include furylthio alkyl groups wherein the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of thienylthio lower alkyl groups include thienylthio alkyl groups wherein the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of 1,3,4-thiadiazolylthio lower alkyl groups include 1,3,4-thiadiazolylthio alkyl groups wherein the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of benzimidazolylthio lower alkyl groups include benzimidazolylthio alkyl groups wherein the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of benzthiazolylthio lower alkyl groups include benzthiazolylthio alkyl groups wherein the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of tetrazolylthio lower alkyl groups include tetrazolylthio alkyl groups wherein the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of benzoxazolylthio lower alkyl groups include benzoxazolylthio alkyl groups wherein the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of thiazolylthio lower alkyl groups include thiazolylthio alkyl groups wherein the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of imidazolylthio lower alkyl groups include imidazolylthio alkyl groups wherein the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of amino-substituted lower alkylthio lower alkyl groups optionally substituted with one or two lower alkyl groups on the amino group include amino-substituted alkylthio alkyl groups optionally substituted with one or two straight or branched C1-6 alkyl groups on the amino group wherein the alkylthio moiety is a straight or branched C1-6 alkylthio group as defined above and the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of phenyl-substituted lower alkylthio lower alkyl groups include phenyl-substituted alkylthio alkyl groups wherein the alkylthio moiety is a straight or branched C1-6 alkylthio group as defined above and the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of furyl-substituted lower alkylthio lower alkyl groups include furyl-substituted alkylthio alkyl groups wherein the alkylthio moiety is a straight or branched C1-6 alkylthio group as defined above and the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of pyridyl-substituted lower alkylthio lower alkyl groups include pyridyl-substituted alkylthio alkyl groups wherein the alkylthio moiety is a straight or branched C1-6 alkylthio group as defined above and the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of hydroxy-substituted lower alkylthio lower alkyl groups include hydroxy-substituted alkylthio alkyl groups wherein the alkylthio moiety is a straight or branched C1-6 alkylthio group as defined above and the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of phenoxy-substituted lower alkylthio lower alkyl groups include phenoxy-substituted alkylthio alkyl groups wherein the alkylthio moiety is a straight or branched C1-6 alkylthio group as defined above and the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of lower alkoxycarbonyl-substituted lower alkylthio lower alkyl groups include alkoxycarbonyl-substituted alkylthio alkyl groups wherein the alkoxy moiety is a straight or branched C1-6 alkoxy group as defined above, the alkylthio moiety is a straight or branched C1-6 alkylthio group as defined above and the alkyl moiety is a straight or branched C1-6 alkyl group as defined above.
Examples of lower alkenyl groups include straight or branched C2-6 alkenyl groups, such as vinyl, 1-propenyl, allyl, 1-methylallyl, (1-, 2- or 3-)butenyl, (1-, 2-, 3- or 4-) pentenyl and (1-, 2-, 3-, 4- or 5-)hexenyl.
Examples of dihydropyridyl groups include 1,2-dihydropyridyl, 3,4-dihydropyridyl and the like.
Examples of 5- to 7-membered saturated heterocyclic group-substituted sulfonyl groups, the heterocyclic group containing one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, include pyrrolidinylsulfonyl, piperazinylsulfonyl, piperidinylsulfonyl, morpholinosulfonyl, thiomorpholinosulfonyl, homopiperazinylsulfonyl, homopiperidinylsulfonyl, imidazolidinylsulfonyl, thiazolidinylsulfonyl, isothiazolidinylsulfonyl, oxazolidinylsulfonyl, isoxazolidinylsulfonyl, isothiazolidinylsulfonyl, pyrazolidinylsulfonyl, etc.
Examples of lower alkoxido groups include straight or branched C1-6 alkoxido groups, such as methoxido, ethoxido, etc.
The pyrrolidine compounds represented by General Formula (1) can be produced by various methods, and for example, by a method according to the following Reaction Scheme 1.




wherein R101 and R102 are as defined above, and R112 is an amino-protecting group.

The pyrrolidine compound (1) can be prepared by subjecting a compound (2) to an elimination reaction to remove the amino-protecting group.
Examples of amino-protecting groups usable herein include lower alkoxycarbonyl groups, lower alkanoyl groups, aryloxy carbonyl groups, aryl-substituted lower alkyl groups, etc.
Examples of lower alkoxycarbonyl groups include straight or branched C1-6 alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.
Examples of lower alkanoyl groups include straight or branched C1-6 alkanoyl groups, such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, hexanoyl, etc.
Examples of aryloxycarbonyl groups include phenoxy carbonyl groups optionally substituted with one to three substituents; naphthyloxy carbonyl groups optionally substituted with one to three substituents; etc. Examples of substituents for aryl groups include methyl, ethyl, propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, 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-cloroethyl, 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-dichlorohexyl, 3-hydroxy-2-chloropropyl, or like straight or branched C1-6 alkyl groups optionally substituted with one to three members selected from the group consisting of halogen atoms and a hydroxyl group; methoxy, ethoxy, propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, hydroxymethoxy, 2-hydroxyethoxy, 1-hydroxyethoxy, 3-hydroxypropoxy, 2,3-dihydroxypropoxy, 4-hydroxybutoxy, 1,1-dimethyl-2-hydroxyethoxy, 5,5,4-trihydroxypentyloxy, 5-hydroxypentyloxy, 6-hydroxyhexyloxy, 1-hydroxyisopropoxy, 2-methyl-3-hydroxypropoxy, 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, 5-bromohexyloxy; 5,6-dichlorohexyloxy, 3-hydroxy-2-chloropropoxy, or like straight or branched C1-6 alkoxy groups optionally substituted with one to three members selected from the group consisting of halogen atoms and a hydroxyl group; halogen atoms such as fluorine, bromine, chlorine, and iodine; etc. When two or more substituents are present, the substituents may be the same or different.
Examples of aryl-substituted lower alkyl groups include benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 1,1-dimethyl-2-phenylethyl, 2-methyl-3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl, 2-(α-naphthyl)ethyl, 1-(β-naphthyl)ethyl, 3-α-naphthyl)propyl, 4-(β-naphthyl)butyl, 5-(α-naphthyl)pentyl, 6-(β-naphthyl)hexyl, 1,1-dimethyl-2-(α-naphthyl)ethyl, 2-methyl-3-(β-naphthyl)propyl, like phenyl-substituted straight or branched C1-6 alkyl groups optionally substituted with one to three substituents; or like naphtyl-substituted straight or branched C1-6 alkyl groups optionally substituted with one to three substituents. Examples of substituents for aryl groups include methyl, ethyl, propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, 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-dichlorohexyl, 3-hydroxy-2-chloropropyl, or like straight or branched C1-6 alkyl groups optionally substituted with one to three members selected from the group consisting of halogen atoms and a hydroxyl group; methoxy, ethoxy, propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, hydroxymethoxy, 2-hydroxyethoxy, 1-hydroxyethoxy, 3-hydroxypropoxy, 2,3-dihydroxypropoxy, 4-hydroxybutoxy, 1,1-dimethyl-2-hydroxyethoxy, 5,5,4-trihydroxypentyloxy, 5-hydroxypentyloxy, 6-hydroxyhexyloxy, 1-hydroxyisopropoxy, 2-methyl-3-hydroxypropoxy, 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, 5-bromohexyloxy, 5,6-dichlorohexyloxy, 3-hydroxy-2-chloropropoxy, or like straight or branched C1-6 alkoxy groups optionally substituted with one to three members selected from the group consisting of halogen atoms and a hydroxyl group; halogen atoms such as fluorine, bromine, chlorine, and iodine; etc. When two or more substituents are present, the substituents may be the same or different.
The reaction for producing compound (1) from compound (2) is carried out in a suitable solvent or without solvent in the presence of an acid or basic compound. This reaction is referred to as “Reaction A” hereinafter.
Examples of useful solvents 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; aliphatic 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; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrolidone; dimethyl sulfoxide; hexamethylphosphoric triamide; and mixtures of such solvents.
Examples of useful acids include mineral acids such as hydrochloric acid, sulfuric acid and hydrobromic acid; and organic acids such as formic acid, acetic acid, trifluoroacetic acid and p-toluenesulfonic acid.
Examples of useful basic compounds include carbonates such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate and potassium hydrogencarbonate; and metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide and lithium hydroxide.
An acid or basic compound is usually used in an amount of at least about 1 mole, and preferably about 1 to about 10 moles, per mole of compound (2). However, an acid may also be used in a large excess relative to compound (2).
The reaction advantageously proceeds usually at about 0 to about 200° C., and preferably at about 0 to about 150° C., and usually finishes in about 10 minutes to about 30 hours.
When R112 of compound (2) is an aryl-substituted lower alkyl group, it is also possible to produce compound (1) by the reduction of such compound (2).
The reduction reaction can be carried out, for example, by catalytic hydrogenation in a suitable solvent in the presence of a catalyst.
Examples of useful solvents 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 ethylene glycol dimethyl ether; esters such as ethyl acetate and methyl acetate; aprotic polar solvents such as dimethylformamide; and mixtures of such solvents.
Examples of useful catalysts include palladium, palladium black, palladium carbon, platinum, platinum oxide, copper chromite, Raney nickel and mixtures thereof. A catalyst is preferably used in an amount of about 0.02 to about 1 times by weight of compound (2).
The reaction temperature for the reduction reaction is usually about −20 to about 100° C., and preferably about 0 to about 80° C., and the hydrogen pressure is usually from 1 to 10 atm. The reaction usually finishes in about 0.5 to about 20 hours.
When R112 of compound (2) is an aryl-substituted lower alkyl group, compound (2) can be reacted to form compound (1) by steps of (i) treating compound (2) with a dealkylating agent in a suitable solvent; and (ii) heating the resulting compound in a suitable solvent.
The solvent for use in the reaction of step (i) may be the same as any solvent used for reaction (A).
Examples of useful dealkylating agents include formic esters such as 1-chloroethyl chloroformate, ethyl chloroformate and tert-butyl chloroformate. A dealkylating agent is usually used in an amount of at least about 1 mole of compound (2), and preferably about 1 mole to about 10 moles, per mole of compound (2).
The reaction advantageously proceeds usually at about 0 to about 150° C., and preferably at room temperature to about 100° C., and usually completes in about 1 to about 25 hours.
Examples of solvents for use in step (ii) include alcohols such as methanol, ethanol and isopropanol. Heating is conducted usually at about 0 to about 150° C., and preferably at room temperature to about 100° C. for about 1 to about 10 hours.
The compound of General Formula (2) used as a starting material can be easily produced, for example, by the process shown by Reaction Scheme 2:




wherein R101, R102 and R112 are the same as above.

The reaction of compound (3) with compound (4) is carried out, for example, without solvent or in a suitable solvent in the presence of a reducing agent.
For the reaction, compound (4) is usually used in an amount of at least about 1 mole per mole of compound (3), and preferably equivalent to a large excess relative to compound (3).
Examples of useful solvents include water; lower alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol and ethylene glycol; acetonitrile; aliphatic 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; halogenated hydrocarbons such as dichloromethane, dichloroethane and carbon tetrachloride; and mixtures of such solvents.
Examples of reducing agents include aliphatic acids such as formic acid; aliphatic acid alkali metal salts such as sodium formate; hydride reducing agents such as sodium boronhydride, sodium cyanoborohydride, sodium triacetoxyborohydride, aluminium lithium hydride or mixtures of such hydride reducing agents; catalytic hydrogenation reducing agents such as palladium black, palladium carbon, platinum oxide, platinum black and Raney nickel.
When an aliphatic acid or aliphatic acid alkali metal salt is used as a reducing agent, a suitable temperature is usually from room temperature to about 200° C., and preferably from about 50 to about 150° C. The reaction usually completes in about 10 minutes to about 10 hours. The aliphatic acid or aliphatic acid alkali metal salt is preferably used in a large excess relative to compound (3).
When a hydride reducing agent is used as a reducing agent, a suitable reaction temperature is usually from about −80 to about 100° C., and preferably about −80 to about 70° C. The reaction usually finishes in about 30 minutes to about 60 hours. The hydride reducing agent is usually used in an amount of about 1 to about 20 moles per mole of compound (3), and preferably about 1 to about 6 moles per mole of compound (3). Especially when aluminium lithium hydride is used as a hydride reducing agent, it is preferable to use ethers, such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme, and aromatic hydrocarbons, such as benzene, toluene and xylene, or mixtures of such solvents as solvents. To the reaction system of the reaction may be added amine(s) such as trimethylamine, triethylamine and N-ethyldiisopropyl amine or molecular sieves such as molecular sieves of the type 3A (MS-3A) and molecular sieves of the type 4A (MS-4A).
When a catalytic hydrogenation reducing agent is used as a reducing agent, the reaction is usually carried out at about −30 to about 100° C., and preferably about 0 to about 60° C., in a hydrogen atmosphere of about atmospheric pressure to about 20 atm, and preferably about atmospheric pressure to about 10 atm, or in the presence of a hydrogen donor such as formic acid, ammonium formate, cyclohexene and hydrazine hydrate. The reaction usually finishes in about 1 to about 12 hours. The catalytic hydrogenation reducing agent is usually used in an amount of about 0.1 to about 40 wt %, and preferably about 1 to about 20 wt %, of compound (3).




wherein R101, R102 and R112 are the same as above; R113 represents a lower alkylsulfonyloxy group, a phenylsulfonyloxy group optionally substituted on the phenyl ring with one or more lower alkyl groups, or a halogen atom.

The lower alkylsulfonyloxy group is a group consisting of a C1-6 alkyl group and a sulfonyloxy group, examples of which include methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy, butanesulfonyloxy, pentanesulfonyloxy and hexanesulfonyloxy.
Examples of phenylsulfonyloxy groups optionally substituted on the phenyl ring with one or more lower alkyl groups are benzene sulfonyloxy groups which may be substituted with one to three straight or branched C1-6 alkyl groups, such as benzenesulfonyloxy, o-toluenesulfonyloxy, m-toluenesulfonyloxy, p-toluenesulfonyloxy, 2-ethylbenzenesulfonyloxy, 3-ethylbenzenesulfonyloxy, 4-ethylbenzenesulfonyloxy, 2-propylbenzenesulfonyloxy, 3-propylbenzenesulfonyloxy, 4-propylbenzenesulfonyloxy, 2,3-dimethylbenzenesulfonyloxy, 2,4-dimethylbenzenesulfonyloxy and 2,4,6-trimethylbenzenesulfonyloxy.
Examples of halogen atoms include fluorine, bromine, chlorine and iodine atoms.
The reaction of compound (4) with compound (5) is carried out in a suitable solvent in the presence of a basic compound.
Examples of useful inert solvents 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; aliphatic 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, dimethylsulfoxide, N,N-dimethylformamide and hexamethyl phosphoramide; and mixtures of such solvents.
Examples of basic compounds include carbonates such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate and cesium carbonate; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide; phosphates such as potassium phosphate and sodium phosphate; alkali metal hydrides such as sodium hydride and potassium hydride; alkali metals such as potassium and sodium; sodium amide; metal alcoholates such as sodium methylate, sodium ethylate and 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 mixtures of such basic compounds.
Compound (5) is usually used in an amount of at least about 0.1 mole per mole of compound (4), and preferably about 0.1 to about 10 moles per mole of compound (4).
A basic compound is usually used in an amount of at least about 1 mole per mole of compound (4), and preferably about 1 to about 10 moles per mole of compound (4).
For the reaction, compound (4) may be used in a large excess instead of adding a basic compound.
Alkali metal halogen compound(s), such as sodium iodide and potassium iodide, may be added to the reaction system of the reaction.
The reaction is usually carried out at about 0 to about 200° C., and preferably about 0 to about 150° C., and usually completes in about 5 minutes to about 80 hours.




wherein R101, R102 and R112 are the same as above, and X represents a halogen atom.

The reaction between compounds (6) and (7) and the reaction between compounds (8) and (9) are carried out under the same conditions as in the reaction between compounds (5) and (4) shown by Reaction Scheme 3.
When R101 or R102 of compound (6) represents any of the groups shown by (1) to (14), (17) to (32) and (40) to (50), the reaction between compound (6) and compound (7) is carried out in a suitable solvent in the presence of a basic compound and catalyst. Similarly, when R101 or R102 of compound (8) represents any of the groups shown by (1) to (14), (17) to (32) and (40) to (50), the reaction between compound (8) and compound (9) is carried out in a suitable solvent in the presence of a basic compound and catalyst.
The solvent and basic compound for use in the reaction may each be the same as those used for the reaction between compounds (5) and (4) shown by Reaction Scheme 3.
Examples of catalysts include palladium compounds such as palladium acetate, bis(tributyl tin)/bis(dibenzylideneacetone)palladium, copper iodide/2,2′-bipyridyl, bis(dibenzylideneacetone)palladium, tris(dibenzylideneacetone)dipalladium, [1,1′-bis(diphenyl phosphino)ferrocene]dichloropalladium(II) and tetrakis(triphenyl phosphine)palladium; binaphthyl compounds such as R-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl(R-BINAP), S-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl(S-BINAP), and RAC-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl(RAC-BINAP); xanthene compounds such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; borates such as tri-tert-butylphosphine tetrafluoroborate; 2,2-bis(diphenyl imidazolidinylidene); and mixtures thereof.
A basic compound is usually used in an amount of at least about 0.5 mole per mole of compound (6) or (8), and preferably about 0.5 to about 40 moles per mole of compound (6) or (8).
A catalyst may be used in a usual catalytic amount for compound (6) or (8).
Compounds (7) and (9) are usually used in amounts of at least about 0.5 mole per mole of compounds (6) and (8), respectively, and preferably about 0.5 to about 3 moles per mole of compounds (6) and (8).
These reactions advantageously proceed usually at room temperature to about 200° C., and preferably at room temperature to about 150° C., and usually complete in about 0.5 to about 20 hours.
When R101 or R102 of compound (6) represents any of the groups shown by (1) to (14), (17) to (32) and (40) to (50), the reaction between compound (6) and compound (7) is carried out in a suitable solvent in the presence of a basic compound, copper iodide and ethylene glycol. Similarly, when R101 or R102 of compound (8) represents any of the groups shown by (1) to (14), (17) to (32) and (40) to (50), the reaction between compound (8) and compound (9) is carried out in a suitable solvent in the presence of a basic compound, copper iodide and ethylene glycol.
The solvent and basic compound for use in the reaction may each be the same as those used for the reaction between compounds (5) and (4) shown by Reaction Scheme 3.
Copper iodide and ethylene glycol may each be used usually in an amount of about 0.01 to 3 moles, and preferably about 0.05 to about 1 mole, per mole of compound (6) or (7).
Compounds (7) and (9) are usually used in amounts of at least about 1 mole per mole of compounds (6) and (8), respectively, and preferably about 1 to about 2 moles per mole of compounds (6) and (8).
These reactions advantageously proceed usually at room temperature to about 200° C., and preferably at room temperature to about 150° C., and usually completes in about 0.5 to about 50 hours.
When R101 or R102 of compound (6) represents any of the groups shown by (1) to (14), (17) to (32) and (40) to (50), the reaction between compound (6) and compound (7) is carried out in a suitable solvent in the presence of a silane compound such as sodium bis(trimethylsilyl)amide. Similarly, when R101 or R102 of compound (8) represents any of the groups shown by (1) to (14), (17) to (32) and (40) to (50), the reaction between compound (8) and compound (9) is carried out in a suitable solvent in the presence of a silane compound such as sodium bis(trimethylsilyl)amide.
The solvent for use in the reaction may be the same as that used for the reaction between compounds (5) and (4) shown by Reaction Scheme 3.
A silane compound is usually used in an amount of about 0.1 to about 3 moles, and preferably about 0.1 to about 2 moles, per mole of compound (6) or (7).
Compounds (7) and (9) are usually used in amounts of at least about 1 mole per mole of compounds (6) and (8), respectively, and preferably about 1 to about 2 moles per mole of compounds (6) and (8).
These reactions advantageously proceed usually at about 0 to about 200° C., and preferably at about 0 to about 150° C., and usually finishes in about 0.5 to about 20 hours.
Depending on the kind of compound (7) used, the reaction of compound (6) and compound (7) produces, instead of compound (8), compound (10) shown below:




wherein R101 and R112 are the same as above.





wherein R101 and X are the same as above, R108 represents any of the groups shown by (1-1) to (1-37) as defined in General Formula (1), R110 and R111 are linked together to form, together with the nitrogen atom to which they are bound, 5 to 7-membered one nitrogen atom-containing saturated heterocyclic groups which may have one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, the heterocyclic group optionally being substituted with one to three substituents selected from the group consisting of oxo group; lower alkyl groups; lower alkanoyl groups; phenyl lower alkyl groups; phenyl groups optionally substituted on the phenyl ring with one to three members selected from the group consisting of halogen atoms and lower alkoxy groups; and pyridyl groups, and b′ represents an integer from 0 to 3.

Examples of 5- to 7-membered one nitrogen atom-containing saturated heterocyclic groups which may have one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur include pyrrolidinyl, piperazinyl, piperidinyl, morpholino, thiomorpholino, homopiperazinyl, homopiperidinyl, imidazolidinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, isothiazolidinyl and pyrazolidinyl.
Examples of the above-mentioned heterocyclic groups substituted with one to three members selected from the group consisting of oxo group; lower alkyl groups; lower alkanoyl groups; phenyl lower alkyl groups; phenyl groups optionally substituted on the phenyl ring with one to three members selected from the group consisting of halogen atoms and lower alkoxy groups; and pyridyl groups:
include the above-mentioned heterocyclic groups substituted with one to three members selected from the group consisting of oxo groups; straight or branched C1-6 alkyl groups; straight or branched C1-6 alkanoyl groups; phenyl alkyl groups wherein the alkyl moiety is a straight or branched C1-6 alkyl group; phenyl groups optionally substituted on the phenyl ring with one to three members selected from the group consisting of halogen atoms and straight or branched C1-6 alkoxy groups; and pyridyl groups;
such as 2-oxo-(1-, 3-, 4-, or 5-)pyrrolidinyl, 2-oxo-(1-, 3-, 4-, 5-, or 6-)piperazinyl, 4-methyl-(1-, 2-, or 3-) piperazinyl, 4-acetyl-(1-, 2-, or 3-)piperazinyl, 4-ethyl-(1-, 2-, or 3-)piperazinyl, 2-methyl-(1-, 2-, 3-, 4-, or 5-) pyrrolidinyl, 2-methyl-(1-, 2-, 3-, 4-, 5-, or 6-)piperidinyl, 2,4-dimethyl-(1-, 2-, 3-, 5-, or 6-)piperidinyl, 3-methyl-(1-, 2-, 3-, 4-, or 5-)pyrrolidinyl, 2,3,4-trimethyl-(1-, 2-, 3-, 5-, or 6-)piperazinyl, 4-acetyl-3-methyl-(1-, 2-, 3-, 5-, or 6-) piperazinyl, 3-methyl-(2-, 3-, 4-, 5-, or 6-)morpholino, 2-10 acetyl-(2-, 3-, 4-, 5-, or 6-)morpholino, 4-(2-phenylethyl)-(1-, 2-, or 3-)piperazinyl, 4-(3,4-dichlorophenyl)-(1-, 2-, 3-, or 4-) piperazinyl, 4-(4-methoxyphenyl)-(1-, 2-, or 3-)piperazinyl, 4-(2-chlorophenyl)-(1-, 2-, or 3-)piperazinyl, 4-[(2-, 3-, or 4-) pyridyl]-(1-, 2-, or 3-)piperazinyl, 4-phenyl-(1-, 2-, or 3-) piperazinyl, 4-benzyl-(1-, 2-, or 3-)piperidinyl, 4-(3,4-dichlorophenyl)-(1-, 2-, or 3-)morpholino, 2-(4-methoxyphenyl)-(1-, 2-, 3-, 4-, or 5-)pyrrolidinyl, 4-(2-chlorophenyl)-(1-, 2-, or 3-)piperidinyl, 4-[(2-, 3-, or 4-) pyridyl]-(1-, 2-, or 3-) piperidinyl, 4-phenyl-(1-, 2-, or 3-) piperidinyl, 4-phenyl-3-methyl-(1-, 2-, 3-, 5-, or 6-) piperazinyl, 4-[(2-, 3-, or 4-) pyridyl]-2-acetyl-(1-, 2-, 3-, 5-, or 6-)piperazinyl, etc.
The reaction between compound (11) and compound (12) is carried out under the same conditions as in the reaction between compounds (6) and (7) shown by Reaction Scheme 4.




wherein R101, R108, b′ and X are the same as above.

Compound (14) is produced by reacting compound (11) with a metal cyanide compound in a suitable solvent in the presence of a catalyst.
Examples of metal cyanide compounds include sodium cyanide, potassium cyanide, zinc cyanide, copper cyanide, etc.
The solvent and catalyst for use in the reaction may each be the same as those used for the reaction between compounds (6) and (7) shown by Reaction Scheme 4. The catalyst may be used in a usual catalytic amount for compound (11).
The metal cyanide compound is usually used in an amount of at least about 1 mole per mole of compound (11), and preferably about 1 to about 3 moles per mole of compound (11).
The reaction advantageously proceeds usually at room temperature to about 200° C., and preferably at room temperature to about 150° C., and usually completes in about 0.5 to about 20 hours.




wherein R101, R108, b′ and X are the same as above, and R114 represents any of the groups shown by (1-3), (1-12), (1-14), (1-19), (1-23), (1-30), and (1-31) in General Formula (1).

The reaction between compound (11) and compound (15) is carried out under the same conditions as in the reaction between compounds (6) and (7) shown by Reaction Scheme 4.




wherein R101 and R112 are the same as above; R115 represents a phenyl group, phenyl lower alkyl group, cycloalkyl group, cycloalkyl lower alkyl group, lower alkylthio lower alkyl group, amino-substituted lower alkyl group optionally substituted on the amino group with one or two lower alkyl groups, phenoxy lower alkyl group, or pyridyl lower alkyl group; and R116 represents a hydrogen atom or lower alkyl group. R115 and R116 may alternatively be linked together to form a cycloalkyl group, provided that the total number of carbon atoms of the portion CH(R116)(R115) in the side chain —(R101)CH(R116)(R115) of compound (18) does not exceed 6.

The reaction between compound (8) and compound (17) is carried out under the same conditions as in the reaction between compounds (3) and (4) shown by Reaction Scheme 2, except for using compound (17) usually in an amount of at least 1 mole per mole of compound (8), and preferably 1 to 5 moles per mole of compound (8).




wherein R101, and R112 are the same as above; a′ represents an integer from 0 to 4; R103 represents any of the groups shown by (1-1) to (1-37) as defined in General Formula (1), R117 represents a lower alkoxycarbonyl group; and R118 represents a carboxy group.

Compound (20) is produced by the hydrolysis of compound (19).
The hydrolysis of compound (19) is carried out in a suitable solvent or without solvent in the presence of an acid or basic compound.
Examples of useful solvents 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; aliphatic 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 hexamethylphosphortriamide; and mixtures of such solvents.
Examples of acids include mineral acids such as hydrochloric acid, sulfuric acid and hydrobromic acid; and organic acids such as formic acid, acetic acid and sulfonic acids such as trifluoroacetic acid and p-toluenesulfonic acid. Such acids may be used singly or in combination.
Examples of basic compounds include carbonates such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate and potassium hydrogencarbonate; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide; and other like basic compounds. Such basic compounds may be used singly or in combination.
The hydrolysis reaction advantageously proceeds usually at about 0 to about 200° C., preferably about 0 to about 150° C., and usually finishes in about 10 minutes to about 30 hours.
Compound (19) is produced by reacting compound (20) with the compound shown by General Formula (21):

R119OH  (21)

wherein R119 represents a lower alkyl group.

Conditions usually selected for esterification reactions are applicable to the reaction between compounds (20) and (21). For example, the reaction between compounds (20) and (21) can be carried out in the presence of a mineral acid such as hydrochloric acid and sulfuric acid; or a halogenating agent such as thionyl chloride, phosphorus oxychloride, phosphorus pentachloride and phosphorus trichloride. Compound (21) is used in a large excess relative to compound (20). The reaction advantageously proceeds usually at about 0 to about 150° C., and preferably about 50 to about 100° C., and usually completes in about 1 to about 10 hours.




wherein R101, R103, a′ and R112 are the same as above; R120 represents a lower alkylthio group; and R121 represents a lower alkylsulfonyl group.

The reaction for producing compound (23) from compound (22) is carried out in a suitable solvent in the presence of an oxidizing agent.
Examples of useful solvents include water; aliphatic acids such as formic acid, acetic acid and trifluoroacetic acid; alcohols such as methanol and ethanol; halogenated hydrocarbons such as chloroform and dichloromethane; and mixtures of such solvents.
Examples of useful oxidizing agents include peracids such as performic acid, peracetic acid, pertrifluoroacetic acid, peroxybenzoic acids, m-chloroperoxybenzoic acid and o-carboxyperoxybenzoic acid; hydrogen peroxide; sodium metaperiodate; dichromates such as dichromic acid, sodium dichromate and potassium dichromate; permanganates such as permanganic acid, sodium permanganate and potassium permanganate; lead salts such as lead tetraacetate.
An oxidizing agent is usually used in an amount of at least about 2 moles per mole of compound (22), and preferably about 2 to 4 moles per mole of compound (22).
The reaction is usually carried out at about −10 to about 150° C., preferably at about −10 to about 100° C., and usually finishes in about 1 to about 10 hours.




wherein R101 and R112 are the same as above; R122 represents a lower alkyl group having one or more halogen atoms; R123 represents an amino-substituted lower alkyl group optionally substituted on the amino group with one or two lower alkyl groups; and R123a represents an amino group optionally substituted on the amino group with one or two lower alkyl groups.

The reaction between compound (24) and compound (25) is carried out under the same conditions as in the reaction between compounds (5) and (4) shown by Reaction Scheme 3.
Compounds (7) and (9) used as starting materials can be easily produced, for example, by the process shown in Reaction Scheme below:




wherein X is the same as above, and R124 represents a lower alkyl group having one or more halogen atoms.

The reaction between compound (27) and compound (28) is carried out under the same conditions as in the reaction between compounds (5) and (4) shown by Reaction Scheme 3.
Compound (8) as a starting material can be produced, for example, by the process shown by Reaction Scheme 13 below:




wherein R103, a′, X and R112 are the same as above.

The reaction for producing compound (31) from compound (30) is carried out, for example, without solvent or in a suitable solvent in the presence of a reducing agent.
Examples of useful solvents include water; lower alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol and ethylene glycol; acetonitrile; aliphatic 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; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride; and mixtures of such solvents.
Examples of a reducing agent include catalytic hydrogenation reducing agents such as palladium black, palladium carbon, platinum oxide, platinum black and Raney nickel, and the like.
A catalytic hydrogenation reducing agent is usually used in an amount of about 0.1 to 40 wt %, and preferably about 0.1 to about 20 wt %, of compound (30).
The reaction advantageously proceeds by adding basic compound(s) such as sodium hydroxide to the reaction system of the reaction.
The reaction is usually carried out at about −30 to about 100° C., and preferably at about 0 to about 60° C., in a hydrogen atmosphere of atmospheric pressure to about 20 atm, and preferably atmospheric pressure to about 10 atm. The reaction usually finishes in about 1 to about 12 hours.
Compounds (3), (5) and (6) used as starting materials can be easily produced by, for example, Reaction Scheme shown below:




wherein R112 and X are the same as above, and R125 represents an oxo group, a group represented by R113, or an amino group, R113 being the same as above.

The reaction between compounds (32) and (33) is carried out under the same conditions as in the reaction between compounds (5) and (4) shown by Reaction Scheme 3 above.
Compound (4) used as a starting material is easily produced, for example, by the process shown by Reaction Scheme below:




wherein R101, R102 and X are the same as the above.

The reaction of compound (35) with compound (9) is carried under the same conditions as described in connection with the reaction of compound (6) with compound (7) shown in Reaction Scheme 4.
Compounds (2), (B), (13), (14), (16), (18), (19), (20), (23) and (26) each of whose R112 is a hydrogen atom, can be produced by replacing R112 with a hydrogen atom in compounds (3), (5), (6), (8), (11), (19), (20), (22) and (24), which are used as starting materials in each reaction shown by Reaction Schemes 2-11, using the thus-obtained compound as a starting material, and reacting the starting material under the same conditions as in the reactions shown by Reaction Schemes 2-11.
If an optically active substance is used as a starting material (compounds (5), (6), (8), (11), (19), (20), (22) and (24)) in the reactions shown by Reaction Schemes 3-11, optically active compounds (2), (8), (13), (14), (16), (18), (19), (20), (23) and (26) can be produced by reacting the compound under the same conditions as in the reaction shown by Reaction Schemes 3-11.
It is also possible to produce compound (1) of the present invention by using compound (2), (8), (13), (14), (16), (18), (19), (20), (23) or (26) produced in the reactions of Reaction Schemes 2-11 as a starting material in the reaction of Reaction Scheme 1 without isolating it.
Each of the objective compounds obtained according to such an above reaction scheme can be isolated and purified from the reaction mixture by, for example, after cooling the reaction mixture, performing an isolation procedure such as filtration, concentration, extraction, etc., to separate a crude reaction product, and then subjecting the crude reaction product to a standard purification procedure such as column chromatography, recrystallization, etc.
The compound of General Formula (1) according to the present invention includes stereoisomers and optical isomers thereof.
Among the starting compounds and object pyrrolidine compound of the present invention, those having a basic group or groups may be suitable to form salts with common pharmaceutically acceptable acids. Examples of such acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and other inorganic acids; methansulfonic acid, p-toluenesulfonic acid, acetic acid, citric acid, tartaric acid, maleic acid, fumaric acid, malic acid, lactic acid and other organic acids, etc.
Among the starting compounds and object pyrrolidine compound of the present invention, those having an acidic group or groups may be suitable to form salts with common pharmaceutically acceptable basic compounds. Examples of such basic compounds include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, etc.
In addition, compounds in the form in which solvate (for example, hydrate, ethanolate, etc.) was added to the starting compounds and object compound shown in each of the reaction formulae are included in each of the general formaulae.
Pharmaceutical preparations containing the compound of the present invention as an active ingredient are explained below.
Such pharmaceutical preparations are obtained by formulating the compound of the present invention into standard pharmaceutical preparations, using typically employed diluents and/or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, etc.
The form of such pharmaceutical preparations can be selected from various forms according to the purpose of therapy. Typical examples include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.) and the like.
To form tablets, any of various known carriers can be used, including, for example, lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and other excipients; water, ethanol, propanol, simple syrup, glucose solutions, starch solutions, gelatin solutions, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders; dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogencarbonate, calcium carbonate, fatty acid esters of polyoxyethylenesorbitan, sodium laurylsulfate, stearic acid monoglycerides, starch, lactose and other disintegrants; white sugar, stearin, cacao butter, hydrogenated oils and other disintegration inhibitors; quaternary ammonium bases, sodium lauryl sulfate and other absorption promoters; glycerol, starch and other wetting agents; starch, lactose, kaolin, bentonite, colloidal silicic acid and other adsorbents; purified talc, stearates, boric acid powder, polyethylene glycol and other lubricants; etc.
Such tablets may be coated with typical coating materials as required, to prepare, for example, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double- or multi-layered tablets, etc.
To form pills, any of various known carriers can be used, including, for example, glucose, lactose, starch, cacao butter, hydrogenated vegetable oils, kaolin, talc and other excipients; gum arabic powder, tragacanth powder, gelatin, ethanol and other binders; laminaran, agar and other disintegrants; etc.
To form suppositories, any of various known carriers can be used, including, for example, polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides, etc.
To form an injection, a solution, emulsion or suspension is sterilized and preferably made isotonic to blood. Any of various known widely used diluents can be employed to prepare the solution, emulsion or suspension. Examples of such diluents include water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, fatty acid esters of polyoxyethylene sorbitan, etc. In this case, the pharmaceutical preparation may contain sodium chloride, glucose or glycerol in an amount sufficient to prepare an isotonic solution, and may contain typical solubilizers, buffers, analgesic agents, etc., and further, if necessary, coloring agents, preservatives, flavors, sweetening agents, etc., and/or other medicines.
The proportion of the compound of the present invention in the pharmaceutical preparation is not limited and can be suitably selected from a wide range. It is usually preferable that the pharmaceutical preparation contain the compound of the present invention in a proportion of 1 to 70 wt. %.
The route of administration of the pharmaceutical preparation of the present invention is not limited, and the preparation is administered by a route suitable to the form of the preparation, patient's age and sex, status of the disease, and other conditions. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally. Injections are intravenously administered singly or as mixed with typical injection transfusions such as glucose solutions, amino acid solutions or the like, or singly administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally, as required. Suppositories are administered intrarectally.
The dosage of the pharmaceutical preparation is suitably selected according to the method of use, patient's age and sex, severity of the disease, and other conditions, and is usually about 0.001 to about 100 mg/kg body weight/day, and preferably 0.001 to 50 mg/kg body weight/day, in single or divided doses.
Since the dosage varies depending on various conditions, a dosage smaller than the above range may be sufficient or a dosage larger than the above range may be required.
Effect of the Invention
The pyrrolidine compound of the present invention has an effect of inhibiting reuptake of one, two, or three kinds of monoamines (i.e., serotonin, norepinephrine, dopamine).
The pyrrolidine compound of the present invention exhibits significantly stronger uptake inhibitory activity to one of these three monoamines than known compounds having uptake inhibitory activity to monoamines in vitro or ex vivo experiments. In the microdialysis study, the pyrrolidine compound of the present invention also exhibits significantly stronger effects for increasing one of these three monoamines in the rat brain than, known compounds having uptake inhibitory activity to monoamines.
The pyrrolidine compound of the present invention has wider spectrum for the medical treatment than known antidepressants.
The pyrrolidine compound of the present invention exhibits sufficient therapeutic effects even after short-term administration.
The pyrrolidine compound of the present invention has excellent bioavailability, little metabolic enzyme inhibitive activity in the liver, little side effects, and is very safe.
The pyrrolidine compound of the present invention exhibits strong activity in a mouse forced-swimming test/tail suspension test, which is used for screening for antidepressants. The pyrrolidine compound of the present invention also exhibits strong activity in the rat forced-swimming test, which is used for screening for antidepressants. The pyrrolidine compound of the present invention also exhibits strong activity in the reserpine-induced hypothermia model, which is used for screening for antidepressants
The pyrrolidine compound of the present invention also exhibits strong activity in the mouse marble-burying behavior test, and a conditioned fear stress model, which are a anxiety- or stress-related disease models.
The pyrrolidine compound of the present invention has an effect of inhibiting reuptake of one, two, or three kinds of monoamines (i.e., serotonin, norepinephrine, dopamine), and therefore is effective for treating various disorders caused by reduced neurotransmission of serotonin, norepinephrine or dopamine.
Examples of such diseases include hypertension, depressions (e.g., major depression, bipolar 1 disorder, bipolar 2 disorder, mixed episode, dysthymic disorders, rapid cycler, atypical depression, seasonal affective disorders, postpartum depression, minor depression, recurrent brief depressive disorder, intractable depression/chronic depression, double depression, alcohol-induced mood disorders, mixed anxiety & depressive disorders; depressions induced by various physical disorders such as Cushing's disease, hypothyroidism, hyperparathyroidism syndrome, Addison's disease, amenorrhea and lactation syndrome, Parkinson's disease, Alzheimer's disease, intracerebral bleeding, diabetes, chronic fatigue syndrome and cancers; depression of the middle-aged, senile depression, depression of children and adolescents, depression induced by medicines such as interferons), depression induced by adjustment disorder, anxiety induced by adjustment disorder, anxiety induced by various physical disorders (e.g. neuropathy (head trauma, brain infection, inner ear injury), cardiovascular disturbance (cardiac arrest, abnormal cardiac rhythm), endocrine disorder (adrenal hyperfunctio, cachexia exophthalmica), breathing problem (asthma, chronic obstructive pulmonary disease)), generalized anxiety disorders, fears (e.g., agoraphobia, social phobia, and simple phobias), posttraumatic stress syndrome, acute stress syndrome, avoidant personality disorders, body dysmorphic disorde, precocious ejaculation, eating disorders (e.g., anorexia nervosa and bulimia nervosa), obesity, chemical dependencies (e.g., to alcohol, cocaine, heroin, phenobarbital, nicotine, and benzodiazepines), cluster headache, migraine, pain disorder, Alzheimer's disease, obsessive-compulsive disorders, panic disorders, memory disorders (e.g., dementia, amnestic disorder, and age-related cognitive decline (ARCD)), Parkinson's disease (e.g., dementia caused by Parkinson's disease, neuroleptic agent induced Parkinson's syndrome, tardive dyskinesia), endocrine disorders (e.g., hyperprolactinaemia), vascular spasm (in particular, in the blood circulatory system in the cerebrum), cerebellar ataxia, gastrointestinal tract disorders (including change in movement and secretion), negative syndrome of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette's syndrome, trichotillomania, kleptomania, male impotence, attention deficit hyperactivity disorder (ADHD), chronic paroxysmal hemicrania, chronic fatigue, cataplexy, sleep apnea syndrome and headache (related to angiopathy).


BEST MODE FOR CARRYING OUT THE INVENTION
Preparation Example, Reference Examples, Examples, and Pharmacological Test Examples are explained below.
Preparation Example 1
The compound of the present invention (100 g), 40 g of Avicel (trade name, manufactured by Asahi Kasei Corporation), 30 g of cornstarch, and 2 g of magnesium stearate were mixed, ground, and then subjected to tableting using a punch of 10.0 mm in diameter for sugar-coating tablets. The thus-obtained tablets were coated using a film-coating agent comprising 10 g of TC-5 (trade name, Shin-Etsu Chemical Co., Ltd., hydroxypropyl methylcellulose), 3 g of polyethylene glucol 6000, 40 g of castor oil, and a suitable amount of ethanol, producing film-coated tables having the above-mentioned ingredients.
Reference Example 1
Synthesis of 3-[(3,4-dichlorophenyl)-(4-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester
Sodium hydride (0.19 g, 60% in oil) was added to 10 ml of dimethyl sulfoxide (DMSO) and stirred at 60° C. for one hour. Subsequently, 1.0 g of (3,4-dichlorophenyl)-(4-fluorophenyl)amine was added to the mixture and stirred at 60° C. for one hour. A DMSO solution containing 2.0 g of 3-(toluene-4-sulfonyloxy)pyrrolidine-1-carboxylic acid tert-butyl ester was gradually added to the mixture and stirred at 60° C. for 15 hours. Ethyl acetate was added to the reaction solution. The solution was then washed with water, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1). The eluent solvent was distilled off under reduced pressure to thereby obtain 0.29 g of oily brown 3-[(3,4-dichlorophenyl)-(4-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester.
1H-NMR (CDCl3) δ ppm:
1.43 (9H, s), 1.74-1.92 (1H, m), 2.04-2.22 (1H, m), 3.10-3.35 (3H, m), 3.61-3.85 (1H, m), 4.31-4.48 (1H, m), 6.42 (1H, dd=2.9 Hz, J=8.9 Hz), 6.67 (1H, d, J=2.8 Hz), 6.90-7.22 (5H, m).
Reference Example 2
Synthesis of 3(S)-[(3,4-dichlorophenyl)phenylamino]pyrrolidine-1-carboxylic acid tert-butyl ester
Sodium hydride (0.36 g, 60% in oil) was added to 20 ml of dimethyl sulfoxide (DMSO) and stirred at 60° C. for one hour. Subsequently, 2.0 g of 3,4-dichlorophenyl-phenylamine was added to the mixture and stirred at 60° C. for one hour. A DMSO solution containing 1.5 g of 3(R)-methanesulfonyloxypyrrolidine-1-carboxylic acid tert-butyl ester was gradually added to the mixture and stirred at 60° C. for 15 hours. Ethyl acetate was added to the reaction solution, and the reaction solution was then washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1). The eluent solvent was distilled off under reduced pressure to thereby obtain 0.13 g of light brown amorphous solid 3(S)-[(3,4-dichlorophenyl)phenylamino]pyrrolidine 1-carboxylic acid tert-butyl ester.
1H-NMR (CDCl2) δ ppm:
1.42 (9H, s), 1.73-1.93 (1H, m), 2.05-2.23 (1H, m), 3.10-3.36 (3H, m), 3.61-3.83 (1H, m), 4.33-4.50 (1H, m), 6.48 (1H, dd, J=2.9 Hz, J=10.3 Hz), 6.74 (1H, d, J=2.8 Hz), 6.96-7.07 (2H, m), 7.16-7.34 (2H, m), 7.35-7.46 (2H, m).
Reference Example 3
Synthesis of ((S)-1-benzylpyrrolidin-3-yl)-(3-fluorophenyl)amine
A toluene solution containing 2.2 g of (S)-1-benzylpyrrolidin-3-ylamine (12.5 mmol), 2.2 g of 3-bromofluorobenzene (12.5 mmol), 0.31 g of 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP, 0.51 mmol), 0.14 g of bis(dibenzylideneacetone)palladium (Pd(dba)2, 0.22 mmol), and 1.3 g of sodium tert-butoxide (13.2 mmol) was heated under reflux under a nitrogen atmosphere for 3 hours. The reaction solution was filtered to remove insoluble matter, and ethyl acetate and water were added to the filtrate to separate the solution into layers. The organic layer was washed with water, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1→1:1). The eluent solvent was distilled off under reduced pressure to thereby obtain 3.0 g of oily colorless ((S)-1-benzylpyrrolidin-3-yl)-(3-fluorophenyl)amine.
1H-NMR (CDCl2) δ ppm:
1.59-1.78 (2H, m), 2.21-2.38 (1H, m), 2.39-2.50 (1H, m), 2.55 (1H, dd, J=3.3 Hz, J=9.7 Hz), 2.71-2.85 (2H, m), 3.63 (2H, s), 3.90-4.10 (1H, m), 6.24 (1H, dt, J=2.3 Hz, J=11.6 Hz), 6.29-6.41 (2H, m), 7.02-7.11 (1H, m), 7.21-7.39 (5H, m).
Reference Example 4
Synthesis of ((S)-1-benzylpyrrolidin-3-yl)-phenylamine
((S)-1-benzylpyrrolidin-3-yl)-phenylamine was synthesized using (S)-1-benzylpyrrolidin-3-ylamine and bromobenzene in the same manner as in Reference Example 3.
Oily Brown Substance
1H-NMR (CDCl3) δ ppm:
1.56-1.78 (2H, m), 2.22-2.39 (1H, m), 2.41-2.58 (1H, m), 2.70-2.84 (2H, m), 3.63 (2H, s), 4.01 (1H, s), 6.57 (2H, d, J=8.5 Hz), 6.64-6.73 (1H, m), 7.11-7.19 (2H, m), 7.21-7.36 (5H, m).
Reference Example 5
Synthesis of ((S)-1-benzylpyrrolidin-3-yl)-(3-fluorophenyl)-(4-trifluoromethylphenyl)amine
A toluene solution containing 0.7 g of ((S)-1-benzylpyrrolidin-3-yl)-(3-fluorophenyl)amine (2.6 mmol), 0.59 g of 4-bromobenzotrifluoride (2.6 mmol), 65 mg of BINAP (0.1 mmol), 23 mg of palladium acetate (0.1 mmol) and 0.28 g of sodium tert-butoxide (2.9 mmol) was heated under reflux under a nitrogen atmosphere for 3 hours. The reaction solution was filtered to remove insoluble matter, and ethyl acetate and water were added to the filtrate to separate the solution into layers. The organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1→10:1). The eluent solvent was distilled off under reduced pressure to thereby obtain 0.48 g of oily colorless ((S)-1-benzylpyrrolidin-3-yl)-(3-fluorophenyl)-(4-trifluoromethylphenyl)amine.
1H-NMR(CDCl3) δ ppm:
1.82-2.01 (1H, m), 2.17-2.31 (1H, m), 2.61-2.78 (3H, m), 3.45 (1H, d, J=12.9 Hz), 3.64 (1H, d, J=12.9 Hz), 4.55 (1H, m), 6.78-6.86 (3H, m), 6.88-6.96 (2H, m), 7.19-7.36 (6H, m).
Reference Example 6
Synthesis of 3(S)-(3-chloro-4-fluorophenylamino)pyrrolidine-1-carboxylic acid tert-butyl ester
To a 50 ml of toluene solution containing 5.0 g of 3(S)-aminopyrrolidine-1-carboxylic acid tert-butyl ester (27 mmol) and 5.7 g of 4-bromo-2-chloro-1-fluorobenzene (27 mmol) were added 1.7 g of BINAP (2.7 mmol), 0.30 g of palladium acetate (1.3 mmol) and 3.5 g of sodium tert-butoxide (36 mmol). The mixture was heated under reflux under a nitrogen atmosphere for 8 hours, and then cooled to room temperature. Water was added to the reaction solution, and extraction with ethyl acetate was performed. After drying over sodium sulfate and concentration under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1). The solvent was distilled off under reduced pressure, and the residue was recrystallized from diethyl ether to thereby obtain 4.76 g of white powdery 3(S)-(3-chloro-4-fluorophenylamino)pyrrolidine-1-carboxylic acid tert-butyl ester.
1H-NMR (CDCl3) δ ppm:
1.47 (9H, s), 1.78-1.96 (1H, m), 2.10-2.28 (1H, m), 2.10-2.28 (1H, m), 3.11-3.30 (1H, m), 3.30-3.56 (2H, m), 3.57-3.79 (2H, m), 3.85-4.03 (1H, m), 6.38-6.47 (1H, m), 6.60 (1H, dd, J=6.0 Hz, J=2.9 Hz), 6.90-7.00 (1H, m).
Reference Example 7
Synthesis of 3(S)-(3-chloro-4-fluorophenylamino)pyrrolidine-1-carboxylic acid tert-butyl ester
To a 50 ml of isopropyl alcohol solution containing 15.0 g of 3(S)-aminopyrrolidine-1-carboxylic acid tert-butyl ester (80.5 mmol) and 24.8 g of 2-chloro-1-fluoro-4-iodobenzene (96.7 mmol) were added 1.54 g of copper (I) iodide (8.1 mmol), 9.0 ml of ethylene glycol (10.1 mmol) and 34.2 g of potassium phosphate (161 mmol), and heated under reflux under a nitrogen atmosphere for 46 hours. The reaction solution was cooled to room temperature and filtered using Celite. The substance remained in the filter was washed with ethyl acetate and the filtrate was concentrated under reduced pressure together with the washings, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1). The solvent was distilled off under reduced pressure, and the residue was recrystallized from diethyl ether to thereby obtain 15.9 g of white powdery 3(S)-(3-chloro-4-fluorophenylamino)pyrrolidine-1-carboxylic acid tert-butyl ester.
1H-NMR (CDCl3) δ ppm:
1.47 (9H, s), 1.78-1.96 (1H, m), 2.10-2.28 (1H, m), 2.10-2.28 (1H, m), 3.11-3.30 (1H, m), 3.30-3.56 (2H, m), 3.57-3.79 (2H, m), 3.85-4.03 (1H, m), 6.38-6.47 (1H, m), 6.60 (1H, dd, J=6.0 Hz, J=2.9 Hz), 6.90-7.00 (1H, m).
Reference Example 8
Synthesis of 3(S)-(3-cyanophenylamino)pyrrolidine-1-carboxylic acid tert-butyl ester
To a toluene solution (7 ml) containing 2.82 g of 3(S)-aminopyrrolidine-1-carboxylic acid tert-butyl ester (15 mmol) and 1.82 g of 3-bromobenzonitrile (10 mmol) were added 68.5 mg of BINAP (0.11 mmol), 22.5 mg of palladium acetate (0.1 mmol) and 3.91 g of cesium carbonate (12 mmol). The mixture was heated under reflux under a nitrogen atmosphere for 8 hours. After cooling to room temperature, water was added to the reaction solution, and extraction with dichloromethane was performed. After drying over sodium sulfate and concentration under reduced pressure, the residue was then purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 1.56 g of light yellow powdery 3(S)-(3-cyanophenylamino)pyrrolidine-1-carboxylic acid tert-butyl ester.
1H-NMR (CDCl3) δ ppm:
1.46 (9H, s), 1.8-2.0 (1H, m), 2.1-2.3 (1H, m), 3.1-3.6 (3H, m), 3.6-3.8 (1H, m), 3.9-4.1 (2H, m), 6.7-6.9 (2H, m), 6.99 (1H, d, J=7.6 Hz), 7.23 (1H, dd, J=7.6 Hz, J=8.4 Hz).
Reference Example 9
Synthesis of 3(S)-(3-chloro-4-methoxyphenylamino)pyrrolidine-1-carboxylic acid tert-butyl ester
To a 5 ml of toluene solution containing 0.20 g of 3(S)-aminopyrrolidine-1-carboxylic acid tert-butyl ester (1.1 mmol) and 0.238 g of 2-chloro-3-bromoanisole (1.1 mmol) were added 67.0 mg of BINAP (0.11 mmol), 24 mg of tris(dibenzylideneacetone)dipalladium (0.027 mmol) and 144 mg of sodium tert-butoxide (1.5 mmol). The mixture was heated under reflux under a nitrogen atmosphere at 100° C. for one hour. After cooling to room temperature, the reaction solution was filtered using Celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1→3:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 0.28 g of light yellow amorphous solid 3(S)-(3-chloro-4-methoxyphenylamino)pyrrolidine-1-carboxylic acid tert-butyl ester.
1H-NMR (CDCl3) δ ppm:
1.47 (9H, s), 1.80-1.90 (1H, m), 2.10-2.20 (1H, m), 3.10-3.25 (1H, m), 3.38-3.75 (3H, m), 3.83 (3H, s), 3.92-3.96 (1H, m), 6.47 (1H, dd, J=2.8 Hz, J=8.8 Hz), 6.67 (1H, d, J=2.8 Hz), 6.81 (1H, d, J=8.8 Hz).
Reference Example 10
Synthesis of 3(S)-(4-methoxyphenylamino)pyrrolidine-1-carboxylic acid tert-butyl ester
To a 10 ml of ethanol solution containing 0.28 g of 3(S)-(3-chloro-4-methoxyphenylamino)pyrrolidine-1-carboxylic acid tert-butyl ester were added a 0.2 ml of a 5 N sodium hydroxide solution and 0.1 g of 10% palladium carbon. Catalytic reduction was conducted at room temperature and atmospheric pressure (ordinary pressure). The reaction solution was filtered using Celite and concentrated under reduced pressure. Water was added to the residue, and extraction with dichloromethane was performed. The extract was dried over magnesium sulfate and concentrated to dryness under reduced pressure to thereby obtain 0.25 g of yellow amorphous solid 3(S)-(4-methoxyphenylamino)pyrrolidine-1-carboxylic acid tert-butyl ester.
1H-NMR (CDCl3) δ ppm:
1.46 (9H, s), 1.79-1.88 (1H, m), 2.10-2.22 (1H, m), 3.12-3.25 (1H, n), 3.30-3.52 (3H, m), 3.60-3.75 (4H, m), 3.88-4.00 (1H, m), 6.50-6.58 (2H, m), 6.72-6.80 (2H, m).
Reference Example 11
Synthesis of 3(S)-[bis-(3-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester
To a 10 ml of toluene solution containing 1.0 g of 3(S)-aminopyrrolidine-1-carboxylic acid tert-butyl ester (5.3 mmol) and 2.3 g of 3-bromo-1-fluorobenzene (13 mmol) were added 32 mg of tri-tert-butylphosphine.tetrafluoroborate (0.11 mmol), 24 mg of palladium acetate (0.11 mmol) and 1.5 g of sodium tert-butoxide (16 mmol). The mixture was heated under reflux under a nitrogen atmosphere for 8 hours. After cooling to room temperature, water was added to the reaction solution, and extraction with ethyl acetate was conducted. After drying over sodium sulfate and concentration under reduced pressure, the residue was then purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 1.56 g of oily yellow 3(S)-[bis-(3-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester.
1H-NMR (CDCl3) δ ppm:
1.43 (9H, s), 1.78-1.95 (1H, m), 2.02-2.26 (1H, m), 3.12-3.39 (3H, m), 3.65-3.83 (1H, m), 4.35-4.51 (1H, m), 6.61 (2H, dt, J=2.1 Hz, J=11.0 Hz), 6.61-6.68 (2H, m), 6.77 (2H, t, J=8.0 Hz), 7.18-7.31 (2H, m).
Reference Example 12
Synthesis of 3(S)-[(3,4-dichlorophenyl)-thiazole-2-ylamino]pyrrolidine-1-carboxylic acid tert-butyl ester
To a 150 ml of toluene solution containing 20.0 g of 3(S)-(3,4-dichlorophenylamino)pyrrolidine-1-carboxylic acid tert-butyl ester (60.4 mmol) and 15.0 g of 2-bromothiazole (91.5 mmol) were added 1.86 g. of tri-tert-butylphosphine.tetrafluoroborate (6.4 mmol), 2.88 g of tris(dibenzylideneacetone)dipalladium (3.15 mmol) and 11.6 g of sodium tert-butoxide (120 mmol). The mixture was heated under reflux under a nitrogen atmosphere for 9 hours. The reaction solution was cooled to room temperature and filtered using Celite. Water was added to the filtrate, and extraction with ethyl acetate was conducted. After drying over sodium sulfate and concentration under reduced pressure, the residue was then purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 7.94 g of yellow powdery 3(S)-[(3,4-dichlorophenyl)-thiazol-2-ylamino]pyrrolidine-1-carboxylic acid tert-butyl ester.
1H-NMR (CDCl3) δ ppm:
1.43 (9H, s), 1.83-2.03 (1H, m), 2.11-2.35 (1H, m), 3.18-3.42 (3H, m), 3.73-3.87 (1H, m), 4.97-5.09 (1H, m), 6.53 (1H, d, J=3.5 Hz), 7.14 (1H, dd, J=2.5 Hz, J=8.5 Hz), 7.22 (1H, brs), 7.39 (1H, d, J=2.5 Hz), 7.56 (1H, brd, J=8.5 Hz).
Reference Example 13
Synthesis of 3(S)-[(3-chloro-4-fluorophenyl)pyridin-3-ylamino]pyrrolidine-1-carboxylic acid tert-butyl ester
To a 10 ml of toluene solution containing 1.0 g of 3(S)-(3-chloro-4-fluorophenylamino)pyrrolidine-1-carboxylic acid tert-butyl ester (3.2 mmol) and 0.75 g of 3-bromopyridine (4.75 mmol) were added 50 mg of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (XANTPHOS, 0.09 mmol), 21.4 mg of palladium acetate (0.10 mmol) and 11.6 g of sodium tert-butoxide (120 mmol). The mixture was heated under reflux under a nitrogen atmosphere for 9 hours. After cooling to room temperature, the reaction solution was filtered using Celite. Water was added to the filtrate, and extraction with ethyl acetate was conducted. After drying over sodium sulfate and concentration under reduced pressure, the residue was then purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1). The purified product was concentrated under reduced pressure to thereby obtain 1.14 g of oily light yellow 3(S)-[(3-chloro-4-fluorophenyl)pyridin-3-ylamino]pyrrolidine-1-carboxylic acid tert-butyl ester.
1H-NMR (CDCl3) δ ppm:
1.43 (9H, s), 1.79-1.98 (1H, m), 2.08-2.29 (1H, m), 3.12-3.41 (3H, m), 3.65-3.85 (1H, m), 4.38-4.51 (1H, m), 6.83-6.91 (1H, m), 7.00-7.23 (4H, m [including 7.04 ppm (dd, J=2.7 Hz, J=6.4 Hz)]), 8.14 (1H, s), 8.22 (1H, d, J=4.4 Hz).
Reference Example 14
Synthesis of 3(S)-[(3-chloro-4-fluorophenyl)cyclohexyl amino]pyrrolidine-1-carboxylic acid tert-butyl ester
A 3 ml of acetic acid solution containing 0.60 g of 3(S)-[(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (1.9 mmol) and 0.56 g of cyclohexanone (5.7 mmol) was stirred at room temperature over night. To the mixture was added 1.21 g of sodium triacetoxyborohydride (5.7 mmol), followed by stirring at room temperature for 8 hours. Dichloromethane was added to the reaction solution, the reaction solution was washed with water and an aqueous saturated sodium hydrogencarbonate solution, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1). The solvent was distilled off from the purified product under reduced pressure to thereby obtain 0.24 g of oily colorless 3-[(S)-(3-chloro-4-fluorophenyl)cyclohexylamino]pyrrolidine-1-carboxylic acid tert-butyl ester.
1H-NMR (CDCl3) δ ppm:
0.81-1.32 (6H, m), 1.44 (9H, s), 1.60-2.00 (6H, m), 2.79-2.93 (1H, m), 2.98-3.10 (1H, m), 3.16-3.31 (1H, m), 3.35-3.70 (2H, m), 3.35-3.70 (2H, m), 3.85-4.07 (1H, m), 6.85-7.13 (3H, m).
Reference Example 15
Synthesis of 3(S)-[(4-carboxyphenyl)-(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester
To an ethanol solution containing 1.7 g of 3(S)-[(3-chloro-4-fluorophenyl)-(4-ethoxycarbonylphenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (3.7 mmol) was added 6 ml of a 5 N sodium hydroxide solution, followed by stirring at room temperature for 15 hours. Dichloromethane and acetic acid were added to the reaction solution to make the reaction solution acidic. After washing with water three times and with an aqueous saturated sodium hydrogencarbonate solution once, the solvent was distilled off under reduced pressure to thereby obtain 1.50 g of white powdery 3(S)-[(4-carboxyphenyl)-(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester.
1H-NMR (DMSO-d6) δ ppm:
1.33 (9H, s), 1.72-1.88 (1H, m), 2.06-2.26 (1H, m), 2.99-3.23 (3H, m), 3.61 (1H, dd, J=6.4 Hz, J=11.3 Hz), 4.53-4.69 (1H, m), 6.57-6.65 (2H, m), 7.19-7.28 (1H, m), 7.46-7.58 (2H, m), 7.68-7.78 (2H, m), 12.3 (1H, brs).
Reference Example 16
Synthesis of 3(S)-[(3-chloro-4-fluorophenyl)-(4-methanesulfonylphenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester
To a dichloromethane solution containing 0.45 g of 3(S)-[(3-chloro-4-fluorophenyl)-(4-methanesulfanillphenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 mmol) was added 0.54 g of metachloroperoxybenzoic acid (3.1 mmol) at 0° C., followed by stirring at 0° C. for 2 hours. The reaction solution was washed with water and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Subsequently, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1→1:1). The solvent was distilled off from the purified product under reduced pressure to thereby obtain 0.42 g of oily light yellow 3(S)-[(3-chloro-4-fluorophenyl)-(4-methanesulfonylphenyl)amino]pyrrolidine 1-carboxylic acid tert-butyl ester.
1H-NMR (CDCl3) δ ppm:
1.43 (9H, s), 1.80-1.91 (1H, m), 2.11-2.29 (1H, m), 3.01 (3H, s), 3.16-3.40 (3H, m), 3.70-3.86 (1H, m), 4.49-4.61 (1H, m), 6.62 (2H, d, J=9.0 Hz), 7.03 (1H, ddd, J=2.6 Hz, J=4.1 Hz, J=8.6 Hz), 7.01-7.06 (1H, m), 7.19-7.23 (1H, m), 7.24-7.31 (1H, m), 7.66-7.74 (2H, m).
Reference Example 17
Synthesis of 3(S)-[(3-chloro-4-fluorophenyl)-(6-cyanopyridin-2-yl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester
3(S)-[(6-bromopyridin-2-yl)-(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 1.06 mmol), zinc cyanide (250 mg, 2.12 mmol) and tetrakis(triphenylphosphine)palladium (122 mg, 0.106 mmol) were suspended in 8 ml of dimethylformamide (DMF), followed by stirring under a nitrogen atmosphere at 110° C. for 9 hours. After cooling to room temperature, ethyl acetate and water were added to the reaction solution to separate the solution into layers. The organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1→3:1). The solvent was distilled off from the purified product under reduced pressure to thereby obtain 398 mg of oily colorless 3(S)-((3-chloro-4-fluorophenyl)-(6-cyanopyridin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester.
1H-NMR (CDCl3) δ ppm:
1.44 (9H, s), 1.74-1.84 (1H, m), 2.03-2.24 (1H, m), 3.08-3.32 (3H, m), 3.76-3.86 (1H, m), 5.28-5.38 (1H, m), 6.21 (1H, d, J=8.7 Hz), 7.04-7.11 (2H, m), 7.23-7.42 (3H, m).
Reference Example 18
Synthesis of 3(S)-{(3-chloro-4-fluorophenyl)-[5-(4-fluorophenyl)pyridin-2-yl]amino}pyrrolidine-1-carboxylic acid tert-butyl ester
3(S)-[(5-bromopyridin-2-yl)-(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 0.64 mmol), 4-fluorophenylboric acid (98 mg, 0.7 mmol), tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol) and a 2 M aqueous sodium carbonate solution (0.83 ml) were added to toluene (3 ml), followed by stirring under a nitrogen atmosphere at 100° C. for 10 hours. After cooling to room temperature, ethyl acetate and water were added to the reaction solution to separate the reaction solution into layers. The organic layer was washed with saturated saline, followed by drying over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1). The solvent was distilled off from the purified product under reduced pressure to thereby obtain 2.55 mg of white solid 3(S)-{(3-chloro-4-fluorophenyl)-[5-(4-fluorophenyl)pyridin-2-yl]amino}pyrrolidine-1-carboxylic acid tert-butyl ester.
1H-NMR (CDCl3) δ ppm:
1.44 (9H, s), 1.78-1.89 (1H, m), 2.05-2.23 (1H, m), 3.07-3.31 (3H, m), 3.85 (1H, dd, J=7.1, 10.8 Hz), 5.31-5.42 (1H, m), 6.08 (1H, d, J=8.8 Hz), 7.06-7.14 (3H, m), 7.20-7.28 (2H, m), 7.41-7.50 (3H, m), 8.37-8.41 (1H, m).
Reference Example 19
Synthesis of 3(S)-[(3-chloro-4-fluorophenyl)-(4-thiophene-3-ylphenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester
Using 3(S)-[(4-bromophenyl)-(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester and 3-thiopheneboric acid, 3(S)-[(3-chloro-4-fluorophenyl)-(4-thiophene-3-ylphenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester was synthesized in the same manner as in Reference Example 9.
Oily Colorless Substance
1H-NMR (CDCl3) δ ppm:
1.43 (9H, s), 1.83-1.88 (1H, m), 2.05-2.20 (1H, m), 3.18-3.31 (3H, m), 3.63-3.84 (1H, m), 4.40-4.51 (1H, m), 6.71-6.80 (1H, m), 6.85-6.88 (2H, m), 6.94 (1H, dd, J=2.8 Hz, J=6.4 Hz), 7.05-7.10 (1H, m), 7.30-7.45 (3H, m), 7.50-7.55 (2H, m).
Reference Example 20
Synthesis of (S)-{(3-chloro-4-fluorophenyl)-[6-(4-methylpiperazin-1-yl)pyridin-2-yl]amino}pyrrolidine-1-carboxylic acid tert-butyl ester
3(S)-[(6-bromopyridin-2-yl)-(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 0.43 mmol), 1-methylpiperazine (0.61 ml, 0.55 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (XANTPHOS, 12 mg, 0.02 mmol), tris(dibenzylideneacetone)dipalladium (9 mg, 0.01 mmol) and sodium t-butoxide (61 mg, 0.63 mmol) were added to toluene (5 ml), followed by stirring under a nitrogen atmosphere at 100° C. for 8 hours. Insoluble matter was removed by filtration, and the resultant filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1). The solvent was distilled off from the purified product under reduced pressure to thereby obtain 102 mg of oily colorless (S)-{(3-chloro-4-fluorophenyl)-[6-(4-methylpiperazin-1-yl)pyridin-2-yl]amino}pyrrolidine-1-carboxylic acid tert-butyl ester.
1H-NMR (CDCl3) δ ppm:
1.44 (9H, s), 1.74-1.89 (1H, m), 2.03-2.21 (1H, m), 2.36 (3H, s), 2.51-2.55 (4H, m), 3.08-3.31 (3H, m), 3.54 (4H, brs), 3.64-3.90 (1H, m), 5.10-5.23 (1H, m), 5.32 (1H, d, J=8.1 Hz), 6.01 (1H, d, J=8.1 Hz), 7.03-7.08 (1H, m), 7.19-7.25 (3H, m).
Reference Example 21
Synthesis of 3(S)-[(3-chloro-4-fluorophenyl)-(4-piperidin-1-ylphenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester
Using 3(S)-[(4-bromophenyl)-(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester and piperidine, 3(S)-[(3-chloro-4-fluorophenyl)-(4-piperidin-1-ylphenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester was synthesized in the same manner as in Reference Example 11.
Oily Colorless Substance
1H-NMR (CDCl3) δ ppm:
1.43 (9H, s), 1.55-1.62 (2H, m), 1.68-1.73 (4H, m), 1.74-1.90 (1H, m), 2.02-2.18 (1H, m), 3.16-3.29 (7H, m), 3.61-3.81 (1H, m), 4.23-4.38 (1H, m), 6.40-6.46 (1H, m), 6.59-6.62 (1H, m), 6.86-6.92 (5H, m).
Reference Example 22
Synthesis of 3(S)-[(3-chloro-4-cyanophenyl)-(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester
To an anhydrous toluene solution containing 3(S)-[(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (0.50 g, 1.6 mmol) and 2-chloro-4-fluorobenzonitrile (0.30 g, 1.9 mmol) was added a 1.45 ml tetrahydrofuran solution containing sodium bis(trimethylsilyl)amide (1.1 M) using a syringe. The mixture was heated under reflux under a nitrogen atmosphere for 8 hours and cooled to room temperature. Water was added to the reaction solution, and extraction with diethyl ether was conducted. After drying over sodium sulfate and concentration under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 0.56 g of white amorphous solid 3(S)-[(3-chloro-4-cyanophenyl)-(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester.
1H-NMR (CDCl3) δ ppm:
1.43 (9H, s), 1.76-1.93 (1H, m), 2.11-2.27 (1H, m), 3.15-3.39 (3H, m), 3.66-3.87 (1H, m), 4.39-4.55 (1H, m), 6.42 (1H, dd, J=2.5 Hz, J=9.0 Hz), 6.57 (1H, d, J=2.5 Hz), 6.98-7.04 (1H, m), 7.20 (1H, dd, J=2.5 Hz, J=6.5 Hz), 7.23-7.32 (1H, m), 7.40 (1H, d, J=8.5 Hz).
Reference Example 23
Synthesis of 2-(4-chlorobutoxy)pyridine
To a DMF solution (110 ml) containing 2-pyridinol (10 g, 105 mmol) and 1-bromo-4-chlorobutane (36 ml, 315 mmol) was added potassium carbonate (16 g, 116 mmol), followed by stirring at room temperature for 8 hours. Water (300 ml) was added to the reaction solution, and extraction with ethyl acetate (300 ml) was then conducted. The organic layer was washed with water (300 ml) twice and dried over magnesium sulfate. The solvent was distilled off, under reduced pressure, and the residue was then purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1). The purified product was concentrated under reduced pressure to thereby obtain 3.32 g of oily colorless 2-(4-chlorobutoxy)pyridine.
Reference Example 24
Synthesis of 3(S)-[4-(pyridin-2-yloxy)butylamino]pyrrolidine-1-carboxylic acid tert-butyl ester
3(S)-aminopyrrolidine-1-carboxylic acid tert-butyl ester (0.93 g, 5.0 mmol), 2-(4-chlorobutoxy)pyridine (0.93 g, 5.0 mmol), potassium carbonate (0.83 g, 6.0 mmol) and sodium iodide (0.83 g, 5.5 mmol) were suspended in acetonitrile (20 ml) and heated under reflux for 24 hours. After cooling to room temperature, water (50 ml) was added to the reaction solution and extraction with ethyl acetate (50 ml) was conducted. The organic layer was washed with water twice and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was then purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1). The purified product was concentrated under reduced pressure to thereby obtain 372 mg of oily colorless 3(S)-[4-(pyridin-2-yloxy)butylamino]pyrrolidine-1-carboxylic acid tert-butyl ester.
1H-NMR (CDCl3) δ ppm:
1.46 (9H, s), 1.5-1.9 (6H, m), 1.95-2.15 (1H, m), 2.68 (2H, t, J=7 Hz), 2.95-3.15 (1H, m), 3.25-3.65 (4H, m), 4.30 (2H, t, J=6.5 Hz), 6.71 (1H, d, J=8.5 Hz), 6.85 (1H, dd, J=5.5 Hz, J=6.5 Hz), 7.5-7.65 (1H, m), 8.14 (1H, dd, J=2 Hz, J=5 Hz).
Reference Example 25
Synthesis of 3(S)-[(3-chloro-4-fluorophenyl)-(3-chloropropyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester
3(S)-[(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (3 g, 9.5 mmol), 1-bromo-3-chloropropane (4.7 ml, 48 mmol) and potassium carbonate (1.97 g, 14.3 mmol) were suspended in N-methylpyrrolidone (NMP, 15 ml), followed by stirring at 100° C. for 8 hours. After cooling to room temperature, water was added to the reaction solution, and extraction with ethyl acetate was conducted. After drying the organic layer over sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), and the purified product was concentrated under reduced pressure to thereby obtain 1.0 g of oily colorless 3(S)-[(3-chloro-4-fluorophenyl)-(3-chloropropyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester.
1H-NMR (CDCl3) δ ppm:
1.46 (9H, s), 1.7-2.1 (4H, m), 3.1-3.35 (4H, m), 3.35-3.7 (4H, m), 3.8-4.1 (1H, m), 6.7-6.9 (1H, m), 6.9-7.1 (2H, m).
Reference Example 26
Synthesis of 3(S)-[(3-chloro-4-fluorophenyl)-(3-dimethylamino propyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester
3(S)-[(3-chloro-4-fluorophenyl)-(3-chloropropyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (0.5 g, 1.24 mmol), 50% dimethylamine solution (1 ml) and sodium iodide (0.37 g, 2.5 mmol) were suspended in DMF (3 ml), followed by stirring at 60° C. for 4 hours. After cooling to room temperature, water was added to the reaction solution, and extraction with ethyl acetate was conducted. The organic layer was dried over sodium sulfate, and the solvent was then distilled off under reduced pressure. The residue was purified with basic silica gel column chromatography (ethyl acetate), and the purified product was then concentrated under reduced pressure to thereby obtain 0.36 g of oily colorless 3(S)-[(3-chloro-4-fluorophenyl)-(3-dimethylamino propyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester.
1H-NMR (CDCl3) δ ppm:
1.46 (9H, s), 1.5-1.75 (4H, m), 1.75-2.1 (2H, m), 2.19 (6H, s), 3.0-3.3 (4H, m), 3.3-3.75 (2H, m), 3.8-4.2 (1H, m), 6.6-6.8 (1H, m), 6.8-7.1 (2H, m).
The compounds shown below were produced in the same manners as in the above Reference Examples.







TABLE 1













 













Ref. Ex.








No.
R1
R2
R3
R4
R5
NMR





27
—H
—H
—H
—H
—H
1H-NMR (CDCl3) δ ppm








1.46 (9H, s), 1.85-1.95 (1H, m), 2.15-2.23 (1H, m), 3.18-3.26 (1H, m),








3.39-3.51 (2H, m), 3.62-3.75 (2H, m), 4.00-4.05 (1H, m), 6.60 (2H, d,








J = 7.8 Hz), 6.69-6.73 (1H, m), 7.15-7.20 (2H, m).


28
—H
—H
—OCH3
—H
—H
1H-NMR (CDCl3) δ ppm








1.46 (9H, s), 1.79-1.88 (1H, m), 2.10-2.22 (1H, m), 3.12-3.25 (1H, m),








3.30-3.52 (3H, m), 3.60-3.75 (4H, m), 3.88-4.00 (1H, m), 6.50-6.58








(2H, m), 6.72-6.80 (2H, m).


29
—H
—H
—CH3
—H
—H
1H-NMR (CDCl3) δ ppm








1.46 (9H, s), 1.80-1.92 (1H, m), 2.10-2.22 (1H, m), 2.24 (3H, s), 3.15-








3.23 1H, m), 3.35-3.75 (4H, m), 3.95-4.05 (1H, m), 6.51-6.55 (2H, m),








6.95-7.05 (2H, m).


30
—H
—H
—OCH3
—Cl
—H
1H-NMR (CDCl3) δ ppm








1.47 (9H, s), 1.80-1.90 (1H, m), 2.10-2.20 (1H, m), 3.10-3.25 (1H, m),








3.38-3.75 (3H, m), 3.83 (3H, s), 3.92-3.96 (1H, m), 6.47 (1H, dd, J = 2.8,








8.8 Hz), 6.67 (1H, d, J = 2.8 Hz), 6.81 (1H, d, J = 8.8 Hz).


31
—H
—H
—F
—H
—H
1H-NMR (CDCl3) δ ppm








1.46 (9H, s), 1.75-1.82 (1H, m), 2.00-2.24 (1H, m), 3.03-3.79 (5H, m),








3.80-4.05 (1H, m), 6.51-6.57 (2H, m), 6.90 (2H, dd, J = 8.5 Hz, 8.5 Hz).


32
—H
—H
—H
—F
—H
1.47 (9H, S), 1.80-1.99 (1H, m), 2.10-2.26 (1H, m ), 3.11-3.35 (1H, m),








3.38-3.57 (2H, m), 3.61-3.77 (1H, m), 3.79-3.91 (1H, m), 3.94-








4.08 (1H, m), 6.29 (1H, dt, J = 2.3 Hz and 11.4 Hz), 6.33-6.39 (1H, m),








6.40-6.47 (1H, m), 7.04-7.16 (1H, m)


33
—H
—H
—F
—Cl
—H
1H-NMR (CDCl3) δ ppm








1.47 (9H, s), 1.78-1.96 (1H, m), 2.10-2.28 (1H, m), 2.10-2.28 (1H, m),








3.11-3.30 (1H, m), 3.30-3.56 (2H, m), 3.57-3.79 (2H, m), 3.85-4.03 (1H,








m), 6.38-6.47 (1H, m), 6.60 (1H, dd, J = 6.0 Hz and 2.9 Hz), 6.90-7.00 








(1H, m)


34
—H
—H
—F
—CH3
—H
1H-NMR (CDCl3) δ ppm








1.46 (9H, s), 1.7-1.9 (1H, m), 2.1-2.2 (1H, m), 2.21 (3H, s), 3.1-3.3 (1H,








m), 3.3-3.8 (4H, m), 3.8-4.1 (1H, m), 6.3-6.5 (2H, m), 6.83 (1H, dd, J =








8.9 Hz, J = 8.9 Hz)


35
—H
—H
—H
—CN
—H
1H-NMR (CDCl3) δ ppm








1.46 (9H, s), 1.8-2.0 (1H, m), 2.1-2.3 (1H, m), 3.1-3.6 (3H, m), 3.6-3.8








(1H, m), 3.9-4.1 (2H, m), 6.7-6.9 (2H, m), 6.99 (1H, d, J = 7.6 Hz), 7.23








(1H, dd, J = 7.6 Hz, J = 8.4 Hz)


36
—H
—H
—F
—CF3
—H
1H-NMR (CDCl3) δ ppm








1.47 (9H, s), 1.76-1.96 (1H, m), 2.11-2.27 (1H, m), 3.13-3.32 (1H, m),








3.37-3.53 (2H, m), 3.61-3.84 (2H, m), 3.92-4.06 (1H, m), 6.66-6.76








(2H, m), 7.02 (1H, dd, J = 9.5 Hz, 9.5 Hz).


37
—H
—H
—Cl
—Cl
—H
1H-NMR (CDCl3) δ ppm








1.47 (9H, s), 1.80-1.92 (1H, brs), 2.11-2.26 (1H, m), 3.15-3.30 (1H, m),








3.40-3.55 (2H, m), 3.60-3.75 (1H, m), 3.79-3.89 (1H, m), 3.91-4.04








(1H, m), 6.42 (1H, dd, J = 2.7 Hz and 8.7 Hz), 6.66 (1H, d, J = 2.7 Hz),








7.19 (1H, d, J = 8.6 Hz)
















TABLE 2













 









Ref. Ex. 




No.
R1
NMR





38




1H-NMR (CDCl3) δ ppm 1.20-1.30 (2H, m), 1.46 (9H, s), 1.50-1.70 (5H, m), 1.80-1.92 (2H, m), 2.05-2.12 (1H, m), 2.92-3.05 (1H, m), 3.06-3.15 (1H, m), 3.25-3.65 (4H, m).


 


39




1H-NMR (CDCl3) δ ppm 1.00-1.30 (5H, m), 1.46 (9H, s), 1.47-1.96 (6H, m), 2.00-2.10 (1H, m), 2.40-2.50 (1H, m), 2.91-3.02 (1H, m), 3.25-3.35 (1H, m), 3.38-3.65 (3H, m).


 


40




1H-NMR (CDCl3) δ ppm 1.47 (9H, s), 1.8-2.0 (1H, m), 2.1-2.3 (1H, m), 3.1-3.3 (1H, m), 3.4-3.6 (2H, m), 3.6-3.8 (2H, m), 3.9-4.1 (1H, m), 6.88 (1H, d, J = 8.3 Hz), 7.0-7.2 (1H, m), 6.8-7.1 (2H, m), 7.9-8.0 (1H, m), 8.03 (1H, s)


 


41




1H-NMR (CDCl3) δ ppm 1.47 (9H, s), 1.82-2.00 (1H, m), 2.18-2.32 (1H, m), 3.14-3.37 (1H, m), 3.39-3.56 (2H, m), 3.73 (1H, dd, J = 6.0 Hz, 11.5 Hz), 4.37-4.52 (1H, m), 4.59-4.71 (1H, m), 7.84 (1H, d, J = 2.5 Hz), 7.90 (1H, d, J = 1.0 Hz), 8.00 (1H, brs).


 


42




1H-NMR (CDCl3) δ ppm 1.46 (9H, s), 1.79-1.95 (1H, m), 1.97-2.24 (3H, m), 2.82 (4H, dd, J = 7.5 Hz, 14.5 Hz), 3.13-3.29 (1H, m), 3.36-3.81 (4H, m), 3.95-4.08 (1H, m), 6.42 (1H, dd, J = 2.0 Hz, 8.0 Hz), 6.52 (1H, brs), 7.04 (1H, d, J = 8.0 Hz).


 


43




1H-NMR (CDCl3) δ ppm 1.46 (9H, s), 1.73-2.01 (1H, m), 2.15-2.31 (1H, m), 3.12-3.35 (1H, m), 3.38-3.59 (2H, m), 3.65-3.79 (1H, m), 4.27-4.42 (1H, m), 4.48-4.65 (1H, m), 6.35-6.42 (1H, m), 6.56-6.64 (1H, m), 7.38-7.46 (1H, m), 8.04-8.15 (2H, m)


 


44




1H-NMR (CDCl3) δ ppm 1.46 (9H, s), 1.55-1.71 (1H, m), 1.74-2.01 (1H, m), 2.16-2.29 (1H, m), 3.19-3.36 J = 2.2 Hz and 8.6 Hz), 6.99 (1H, d, J = 2.2 Hz), 7.13-7.21 (1H, m), 7.35-7.43 (1H, m), 7.59-7.68 (1H, m)


 


45




1H-NMR (CDCl3) δ ppm 1.46 (9H, s), 1.88-2.01 (1H, m), 2.19-2.29 (1H, m), 3.20-3.36 (1H, m), 3.41-3.59 (2H, m), 3.68-3.90 (2H, m), 4.03-4.18 (1H, m), 6.69 (1H, dd, J = 2.1 Hz and 8.6 Hz), 7.03 (1H, d, J = 2.0 Hz), 7.11 (1H, d, J = 5.2 Hz), 7.17 (1H, d, J = 5.3 Hz), 7.59 (1H, d, J = 8.4 Hz)
















TABLE 3













 













Ref. Ex.








No.
R1
R2
R3
R4
R5
NMR





46
—H
—H
—C1
—C1
—H
1H-NMR (CDCl3) δ ppm








1.42 (9H, s), 1.73-1.93 (1H, m), 2.05-2.23 (1H, m), 3.10-3.36 (3H, m),








3.61-3.83 (1H, m), 4.33-4.50 (1H, m), 6.48 (1H, dd, J = 2.9 Hz and








J = 10.3 Hz), 6.74 (1H, d, J = 2.8 Hz), 6.96-7.07 (2H, m), 7.16-7.34 (2H,








m), 7.35-7.46 (2H, m).


47
—H
—H
—SCH3
—H
—H
1H-NMR (CDCl3) δ ppm








1.42 (9H, s), 1.75-1.92 (1H, m), 2.00-2.20 (1H, m), 2.46 (3H, s), 3.09-








3.33 (3H, m), 3.62-3.83 (1H, m), 4.38-4.55 (1H, m), 6.77-6.88 (4H, m),








6.97-7.08 (1H, m), 7.18-7.33 (4H, m)


48
—H
—H
—C1
—H
—H
1H-NMR (CDCl3) δ ppm








1.42 (9H, s), 1.78-1.87 (1H, m), 2.05-2.16 (1H, m), 3.13-3.27 (3H, m),








3.68-3.79 (1H, m), 4.39-4.45 (1H, m), 6.68-6.75 (2H, m), 6.90 (2H, d,








J = 7.7 Hz), 7.05-7.15 (1H, m), 7.16-7.25 (2H, m), 7.30-7.40 (2H, m).


49
—H
—H
—H
—C1
—C1
1H-NMR (CDCl3) δ ppm








1.36-1.49 (9H, m), 1.80-1.98 (1H, m), 2.03-2.29 (1H, m), 3.19-3.41








(3H, m), 3.64-3.89 (1H, m), 4.44-4.59 (1H, m), 6.52 (2H, d,








J = 8.2 Hz), 6.74-6.85 (1H, m), 7.12-7.33 (4H, m), 7.46-7.52 (1H, m)


50
—H
—H
—OCF3
—H
—H
1H-NMR (CDCl3) δ ppm








1.42 (9H, s), 1.76-1.91 (1H, m), 2.02-2.21 (1H, m), 3.08-3.86 (4H, m),








4.38-4.53 (1H, m), 6.76 (2H, d, J = 9.0 Hz), 6.90-6.96 (2H, m), 7.03-7.22








(3H, m), 7.29-7.40 (2H, m)


51
—H
—H
—CO2CH3
—H
—H
1H-NMR (CDCl3) δ ppm








1.42 (9H, s), 1.73-1.92 (1H, m), 2.08-2.28 (1H, m), 3.12-3.34 (3H, m),








3.69-3.88 (4H, m with s at Φ3.84), 4.49-4.65 (1H, m), 6.50-6.59 (2H,








m, ), 7.08-7.16 (2H, m), 7.31-7.51 (3H, m), 7.82 (2H, d, J = 6.1 Hz)


52
—H
—C1
—H
—C1
—H
1H-NMR (CDCl3) δ ppm








1.42 (9H, s), 1.73-1.89 (1H, m), 2.02-2.21 (1H, m), 3.09-3.33 (3H, m),








3.62-3.85 (1H, m), 4.35-4.45 (1H, m), 6.42 (2H, d, J = 1.6 Hz),








6.74 (1H, s), 7.02-7.11 (2H, m), 7.30-7.50 (3H, m)


53
—H
—H
—NO2
—H
—H
1H-NMR (CDCl3) δ ppm








1.42 (9H, s), 1.78-1.95 (1H, m), 2.09-2.28 (1H, m), 3.10-3.38 (3H, m),








3.71-3.92 (1H, m), 4.52-4.69 (1H, m), 6.48-6.55 (2H, m), 7.08-7.18








(2H, m), 7.39-7.58 (3H, m), 8.04 (2H, d, J = 8.1 Hz)


54
—H
—H
—CH3
—H
—H
1H-NMR (CDCl3) δ ppm








1.42 (9H, s), 1.80-1.85 (1H, m), 2.00-2.15 (1H, m), 2.34 (3H, s), 3.18-








3.25 (3H, m), 3.65-3.80 (1H, m), 4.40-4.50 (1H, m), 6.73 (2H, d,








J = 8.1 Hz), 6.85-6.90 (3H, m), 7.10-7.26 (4H, m).


55
—H
—H
—CHO
—H
—H
1H-NMR (CDCl3) δ ppm








1.42 (9H, s), 1.80-1.88 (1H, m), 2.10-2.20 (1H, m), 3.15-3.30 (3H, m),








3.70-3.85 (1H, m), 4.55-4.65 (1H, m), 6.59 (2H, d, J = 8.4 Hz), 7.10-7.15








(2H, m), 7.40-7.60 (3H, m), 7.60-7.70 (2H, m), 9.75 (1H, s).


56
—H
—H
—Br
—H
—H
1H-NMR (CDCl3) δ ppm








1.41 (9H, s), 1.80-1.88 (1H, m), 2.05-2.20 (1H, m), 3.15-3.30 (3H, m),








3.65-3.75 (1H, m), 4.38-4.46 (1H, m), 6.65 (2H, d, J = 8.9 Hz), 6.94 (2H,








d, J = 8.5 Hz), 7.10-7.40 (5H, m).


57
—H
—H
—OCH3
—C1
—H
1H-NMR (CDCl3) δ ppm








1.43 (9H, s), 1.80-1.88 (1H, m), 2.05-2.15 (1H, m), 3.15-3.30 (3H, m),








3.65-3.80 (1H, m), 3.90 (3H, s), 4.38-4.44 (1H, m), 6.65-6.70 (2H, m),








6.82-6.90 (3H, m), 7.07 (1H, s), 7.15-7.25 (2H, m).
















TABLE 4













 













Ref. Ex.








No.
R1
R2
R3
R4
R5
NMR





58
—H
—H
—OCH3
—H
—H
1H-NMR (CDCl3) δ ppm








1.42 (9H, s), 1.80-1.86 (1H, m), 2.00-2.12 (1H, m), 3.15-3.26 (3H,








m), 3.65-3.78 (1H, m), 3.82 (3H, s), 4.40-4.50 (1H, m), 6.63 (2H, d,








J = 7.6 Hz), 6.75-6.80 (1H, m), 6.86-6.95 (2H, m), 7.00 (2H, d,








J = 7.6 Hz), 7.10-7.20 (2H, m).


59
—H
—H
—OC2H5
—C1
—H
1H-NMR (CDCl3) δ ppm








1.43 (9H, s), 1.47 (3H, t, J = 7.0 Hz), 1.75-1.92 (1H, m), 2.01-2.21








(1H, m), 3.11-3.36 (3H, m), 3.64-3.83 (1H, m), 4.10 (2H, q,








J = 7.0 Hz), 4.36-4.51 (1H, m), 6.67-6.74 (2H, m), 6.83-6.93 (3H,








m), 7.04-7.08 (2H, m), 7.14-7.27 (2H, m . . .


60
—H
—H
—OC3H7
—C1
—H
1H-NMR (CDCl3) δ ppm








1.08 (3H, t, J = 7.4 Hz), 1.43 (9H, s), 1.79-1.95 (1H, m), 1.96-2.20








(1H, m), 3.15-3.38 (3H, m), 3.60-3.85 (1H, m), 3.98 (2H, t,








J = 6.5 Hz), 4.37-4.51 (1H, m), 6.66-6.73 (2H, m), 6.81-6.93 (3H,








m), 7.03-7.09 (1H, m), 7.14-7.28 (2H, m)


61
—H
—H
—F
—CH3 
—H
1H-NMR (CDCl3) δ ppm








1.43 (9H, s), 1.7-1.9 (1H, m), 2.0-2.2 (1H, m), 2.24 (3H, s), 3.1-3.4








(3H, m), 3.6-3.8 (1H, m), 4.4-4.6 (1H, m), 6.69 (2H, d, J = 7.9








Hz), 6.7-7.1 (4H, m), 7.1-7.3 (2H, m)


62
—H
—OCH3
—F
—F
—H
1H-NMR (CDCl3) δ ppm








1.43 (9H, s), 1.7-1.9 (1H, m), 2.0-2.2 (1H, m), 3.1-3.4 (3H, m), 3.6-








3.8 (1H, m), 3.76 (3H, s), 4.3-4.5 (1H, m), 6.0-6.3 (2H, m), 6.92








(2H, d, J = 7.5 Hz), 7.0-7.2 (1H, m), 7.2-7.4 (2H, m)


63
—H
—H
—F
—H
—H
1H-NMR (CDCl3) δ ppm








1.42 (9H, s), 1.75-1.92 (1H, m), 2.00-2.24 (1H, m), 3.10-3.32 (3H,








m), 3.61-3.83 (1H, m), 4.41-4.53 (1H, m), 6.72 (2H, d, J = 8.2 Hz),








6.85-7.10 (5H, m), 7.16-7.28 (2H, m)


64
—H
—H
—H
—H
—Cl
1H-NMR (CDCl3) δ ppm








1.30-1.50 (total 9H, m with two ss at δ1.41 and 1.44), 1.79-1.96








(1H, m), 2.06-2.32 (1H, m), 3.12-3.41 (3H, m), 3.64-3.91 (1H, m),








4.41-4.60 (1H, m), 6.52 (2H, d, J = 8.2 Hz), 6.70-6.81 (1H, m), 7.21-








7.41 (5H, m), 7.47-7.58 (1H, m)


65
—H
—H
—H
—Cl
—H
1H-NMR (CDCl3) δ ppm








1.43 (9H, s), 1.78-1.88 (1H, m), 2.07-2.20 (1H, m), 3.15-3.31 (3H,








m), 3.65-3.74 (1H, m), 4.40-4.51 (1H, m), 6.55 (2H, dd, J = 1.2 Hz








and 4.8 Hz), 6.67 (1H, t, J = 1.2 Hz), 6.80-6.85 (1H, m), 6.98-7.03








(1H, m), 7.07-7.14 (1H, m), 7.21-7.28 (1H, m), 7.34-7.43 (1H, m)
















TABLE 5













 


















Ref. 













Ex.













No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
R10
NMR





66
—H
—H
—Cl
—Cl
—H
—H
—H
—F
—H
—H
1H-NMR (CDCl3) δ ppm













1.43 (9H, s), 1.73-1.91 (1H, m), 2.01-2.21 (1H, m), 3.09-3.38













(3H, m), 3.60-3.82 (1H, m), 4.29-4.48 (1H, m), 6.41 (1H, dd,













J = 2.9 Hz and J = 8.9 Hz), 6.67 (1H, d, J = 2.8 Hz), 6.90-7.22 













(5H, m)


67
—H
—H
—Cl
—Cl
—H
—F
—H
—H
—H
—H
1H-NMR (CDCl3) δ ppm













1.42 (9H, s), 1.73-1.92 (1H, m), 2.05-2.28 (1H, m), 3.12-3.35













(3H, m), 3.63-3.86 (1H, m), 4.35-4.51 (1H, m), 6.39 (1H,













dd, J = 2.9 Hz and 9.0 Hz), 6.66 (1H, d, J = 2.7 Hz), 7.08-7.28 













(4H, m), 7.31-7.45 (1H, m)


68
—H
—H
—H
—F
—H
—H
—H
—Cl
—H
—H
1H-NMR (CDCl3) δ ppm













1.43 (9H, s), 1.74-1.91 (1H, m), 2.02-2.21 (1H, m), 3.10-3.35













(3H, m), 3.62-3.82 (1H, m), 4.39-4.51 (1H, m), 6.39 (1H,













dt, J = 1.4 Hz and J = 11.7 Hz), 6.47 (1H, d, J = 8.3 Hz), 6.55-













6.65 (1H, m), 6.89-6.98 (2H, m), 7.09-7.21 (1H, m), 7.29-7.38 













(2H, m)


69
—H
—H
—H
—F
—H
—H
—H
—F
—H
—H
1H-NMR (CDCl3) δ ppm













1.43 (9H, s), 1.74-1.92 (1H, m), 2.06-2.29 (1H, m), 3.08-3.89













4H, m), 4.35-4.51 (1H, m), 6.27 (1H, dt, J = 2.3 Hz and













J = 12.3 Hz), 6.35 (1H, d, J = 7.0 Hz), 6.41-6.53 (1H, m), 7.01-













7.21 (5H, m)


70
—H
—H
—H
—F
—H
—H
—H
—SCH3
—H
—H
1H-NMR (CDCl3) δ ppm













1.43 (9H, s), 1.75-1.91 (1H, m), 2.01-2.21 (1H, m), 2.50 (1H, s),













3.11-3.32 (3H, m), 3.63-3.83 (1H, m) 4.38-4.51 (1H, m), 6.34













(1H, dt, J = 2.3 Hz and J = 12.1 Hz), 6.42 (1H, d, J = 8.4 Hz), 













6.48-6.58 (1H, m), 6.92-7.01 (2H, m), 7.05-7.18 (1H, m), 7.22-













7.31 (2H, m)


71
—H
—H
—F
—H
—H
—H
—H
—Cl
—H
—H
1H-NMR (CDCl3) δ ppm













1.42 (9H, s), 1.75-1.92 (1H, m), 2.01-2.20 (1H, m), 3.10-3.33













(3H, m), 3.61-3.81 (1H, m), 4.32-4.99 (1H, m), 6.61 (2H, d,













J = 8.8 Hz), 6.94-7.19 (6H, m)


72
—H
—H
—F
—H
—H
—H
—H
—F
—H
—H
1H-NMR (CDCl3) δ ppm













1.42 (9H, s), 1.80-1.88 (1H, m), 2.00-2.15 (1H, m), 3.10-3.30













(3H, m), 3.60-3.75 (1H, m), 4.30-4.38 (1H, m), 6.75-6.85 (4H,













m), 6.90-7.00 (4H, m).


73
—H
—H
—H
—F
—H
—H
—F
—H
—H
—H
1H-NMR (CDCl3) δ ppm













1.43 (9H, s), 1.78-1.95 (1H, m), 2.02-2.26 (1H, m), 3.12-3.39













(3H, m), 3.65-3.83 (1H, m), 4.35-4.51 (1H, m), 6.61













(2H, dt, J = 2.1 Hz and J = 11.0 Hz), 6.61-6.68 (2H, m), 6.77 













(2H, t, J = 8.0 Hz), 7.18-7.31 (2H, m)


74
—H
—H
—F
—Cl
—H
—H
—F
—H
—H
—H
1H-NMR (CDCl3) δ ppm













1.43 (9H, s), 1.75-1.92 (1H, m), 2.02-2.35 (1H, m), 3.12-3.38













(3H, m), 3.63-3.85 (1H, m), 4.35-4.50 (1H, m), 6.38 (1H, dt,













J = 2.3 Hz and 11.7 Hz), 6.90 (1H, ddd, J = 4.2 Hz, J = 4.2 Hz 













and J = 8.8 Hz), 7.08 (1H, dd, J = 2.6 Hz and J = 6.5 Hz), 7.11- 













7.22 (1H, m)


75
—H
—H
—F
—CH3
—H
—H
—CH3
—F
—H
—H
1H-NMR (CDCl3) δ ppm













1.43 (9H, s), 1.8-2.0 (1H, m), 2.0-2.2 (1H, m), 2.21 (6H, s), 3.1-













3.4 (3H, m), 3.6-3.8 (1H, m), 4.3-4.5 (1H, m), 6.6-6.7 (4H, m),













6.8-7.0 (2H, m)


76
—H
—H
—F
—CH3
—H
—H
—F
—H
—H
—H
1H-NMR (CDCl3) δ ppm













1.43 (9H, s), 1.7-1.9 (1H, m), 2.0-2.2 (1H, m), 2.27 (3H, s),













3.1-3.4 (3H, m), 3.6-3.8 (1H, m), 4.3-4.5 (1H, m), 6.26 (1H, d,













J = 12.4 Hz), 6.3-6.5 (2H, m), 6.8-7.2 (4H, m)
















TABLE 6





























Ref. Ex.













No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
R10
NMR





77
—H
—H
—F
—Cl
—H
—H
—CH3
—H
—H
—H
1H-NMR (CDCl3) δ ppm













1.43 (9H, s), 1.7-1.9 (1H, m), 2.0-2.2 (1H, m), 2.40













(3H, s) 3.1-3.4 (3H, m) 3.6-3.8 (1H, m), 4.3-4.5 (1H,













m), 6.6-6.8 (3H, m), 6.85 (1H, d, J = 6.4 Hz), 6.92













(1H, d, J = 7.3 Hz), 6.9-7.1 (1H, m), 7.1-7.3 (1H, m)


78
—H
—H
—H
—F
—H
—H
—CH3
—H
—H
—H
1H-NMR (CDCl3) δ ppm













1.43 (9H, s), 1.7-1.9 (1H, m), 2.0-2.2 (1H, m), 2.34













(3H, s), 3.1-3.4 (3H, m), 3.6-3.8 (1H, m), 4.3-4.5 (1H,













m), 6.33 (1H, d, J = 12.2 Hz), 6.42 (1H, d, J = 8.3













Hz), 6.4-6.6 (1H, m), 6.8-6.9 (2H, m), 7.0-7.2 (2H, m),













7.2-7.3 (1H, m)


79
—H
—H
—F
—CH3
—H
—H
—H
—F
—H
—H
1H-NMR (CDCl3) δ ppm













1.43 (9H, s), 1.7-1.9 (1H, m), 2.0-2.2 (1H, m), 2.22













(3H, s), 3.1-3.4 (3H, m), 3.6-3.8 (1H, m), 4.3-4.5 (1H,













m), 6.6-6.8 (4H, m), 6.8-7.1 (3H, m)


80
—H
—H
—H
—CH3
—H
—H
—H
—F
—H
—H
1H-NMR (CDCl3) δ ppm













1.43 (9H, s), 1.7-1.9 (1H, m), 2.0-2.2 (1H, m), 2.27













(3H, s), 3.1-3.4 (3H, m), 3.6-3.8 (1H, m), 4.4-4.6 (1H,













m), 6.54 (2H, d, J = 6.5 Hz), 6.74 (1H, d, J = 7.1 Hz),













6.8-7.2 (5H, m)


81
—H
—H
—H
—F
—H
—H
—H
—CH3
—H
—H
1H-NMR (CDCl3) δ ppm













1.42 (9H, s), 1.7-1.9 (1H, m), 2.0-2.2 (1H, m), 2.38













(3H, s), 3.1-3.4 (3H, m), 3.6-3.8 (1H, m), 4.3-4.5 (1H,













m), 6.28 (1H, d, J = 12.5 Hz), 6.3-6.5 (2H, m), 6.96













(2H, d, J = 8.2 Hz), 7.0-7.3 (3H, m)


82
—H
—H
—CH3
—Cl
—H
—H
—F
—H
—H
—H
1H-NMR (CDCl3) δ ppm













1.43 (9H, s), 1.7-1.9 (1H, m), 2.0-2.2 (1H, m), 2.37













(3H, s), 3.1-3.4 (3H, m), 3.6-3.8 (1H, m), 4.3-4.5 (1H,













m), 6.38 (1H, d, J = 11.9 Hz), 6.46 (1H, d, J = 8.3













Hz), 6.57 (1H, dd, J = 8.1 Hz, 7.8 Hz), 6.82 (1H, d, J = 













8.1 Hz), 7.02 (1H, s), 7.1-7.3 (2H, m)


83
—H
—H
—Cl
—CH3
—H
—H
—F
—H
—H
—H
1H-NMR (CDCl3) δ ppm













1.43 (9H, s), 1.7-1.9 (1H, m), 2.0-2.2 (1H, m), 2.35













(3H, s), 3.1-3.4 (3H, m), 3.6-3.8 (1H, m), 4.3-4.5 (1H,













m), 6.36 (1H, d, J = 11.9 Hz), 6.43 (1H, d, J = 8.3













Hz), 6.55 (1H, dd, J = 8.0 Hz, 8.1 Hz), 6.80 (1H, d, J = 













8.3 Hz), 6.89 (1H, s), 7.1-7.2 (1H, m), 7.3-7.4 (1H, m)


84
—H
—H
—F
—Cl
—H
—H
—Cl
—F
—H
—H
1H-NMR (CDCl3) δ ppm













1.75-1.92 (1H, m), 2.03-2.22 (1H, m), 3.11-3.39 (3H,













m), 3.61-3.79 (1H, m), 4.26-4.42 (1H, m), 6.42-6.75













2H, m), 6.87-6.91 (2H, m), 7.06 (1H, dd, J = 8.5 Hz,













8.5 Hz).


85
—H
—H
—H
—F
—H
—H
—CN
—H
—H
—H
1H-NMR (CDCl3) δ ppm













1.43 (9H, s), 1.8-1.9 (1H, m), 2.1-2.3 (1H, m), 3.1-3.4













(3H, m), 3.6-3.8 (1H, m), 4.4-4.5 (1H, m), 6.68 (1H, d,













J = 10.2 Hz), 6.75 (1H, d, J = 8.0 Hz), 6.9-7.0 (3H, m),













7.1-7.4 (3H, m)
















TABLE 7













 


















Ref. Ex.













No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
R10
NMR





86
—H
—H
—F
—Cl
—H
—H
—CN
—H
—H
—H
1H-NMR (CDCl3) δ ppm













1.44 (9H, s), 1.7-1.9 (1H, m), 2.0-2.2 (1H, m), 3.1-3.4













(3H, m), 3.6-3.8 (1H, m), 4.3-4.5 (1H, m), 6.7-6.9













(2H, m), 6.9-7.0 (1H, m), 7.0-7.4 (4H, m),


87
—H
—H
—F
—Cl
—H
—H
—H
—OCH3
—H
—H
1H-NMR (CDCl3) δ ppm













1.43 (9H, s), 1.75-1.91 (1H, m), 2.02-2.18 (1H, m),













3.11-3.35 (3H, m), 3.60-3.79 (1H, m), 3.83 (3H, s),













4.29-4.42 (1H, m), 6.44 (1H, dt, J = 3.5 Hz and













J = 8.9 Hz), 6.61 (1H, dd, J = 2.8 Hz and J = 6.1 Hz), 6.86-













7.01 (5H, m)


88
—H
—H
—F
—Cl
—H
—H
—H
—CH3
—H
—H
1H-NMR (CDCl3) δ ppm













1.43 (9H, s), 1.75-1.91 (1H, m), 2.02-2.20 (1H, m),













2.37 (1H, s), 3.11-3.38 (3H, m), 3.60-3.83 (1H, m),













4.29-4.49 (1H, m), 6.56 (1H, dt, J = 3.6 Hz and













J = 9.0 Hz), 6.74 (1H, dd, J = 2.9 Hz and J = 6.3 Hz), 6.86













(2H, d, J = 8.3 Hz), 6.91-7.02 (1H, m), 7.11-7.21 (2H, m)


89
—H
—H
—F
—Cl
—H
—H
—H
—OC2H5
—H
—H
1H-NMR (CDCl3) δ ppm













1.32-1.50 (12H, m, with s at δ1.42 and t at δ 1.43,













J = 7.0 Hz), 1.74-1.91 (1H, m), 2.01-2.18 (1H, m),













3.10-3.32 (3H, m), 3.58-3.81 (1H, m), 4.06 (2H, q,













J = 7.0 Hz), 4.28-4.42 (1H, m), 6.44 (1H, dt, J = 3.2 Hz













and J = 9.0 Hz), 6.61 (1H, dd, J = 2.9 Hz and J = 6.1 Hz),













6.84-7.01 (5H, m) with at δ6.96, J = 2.5 Hz)


90
—H
—H
—F
—Cl
—H
—H
—H
—C2H5
—H
—H
1H-NMR (CDCl3) δ ppm













1.25 (3H, t, J = 7.5 Hz), 1.43 (9H, s), 1.72-1.91 (1H,













m), 2.00-2.20 (1H, m), 2.64 (2H, q, J = 7.5 Hz), 3.10-













3.46 (3H, m), 3.60-3.81 (1H, m), 4.30-4.49 (1H, m),













6.53-6.61 (1H, m), 6.76 (1H, dd, J = 2.9 Hz and













J = 6.3 Hz), 6.87 (1H, d, J = 8.2 Hz), 6.91-7.03 (1H, m),













7.12-7.22 (2H, m)


91
—H
—H
—F
—Cl
—H
—H
—H
—CO2C2H5
—H
—H
1H-NMR (CDCl3) δ ppm













1.35 (3H, t, J = 7.1 Hz), 1.43 (9H, s), 1.78-1.95 (1H,













m), 2.09-2.27 (1H, m), 3.11-3.39 3H, m), 3.69-













3.85 (1H, m), 4.32 (2H, q, J = 7.1 Hz, 4.93-4.61 (1H,













m), 6.57 (2H, d, J = 8.9 Hz), 6.96-7.04 (1H, m), 7.14-













7.29 (2H, m), 7.81-7.94 (2H, m)


92
—H
—H
—F
—Cl
—H
—H
—H
—CO2H
—H
—H
1H-NMR (CDCl3) δ ppm













1.33 (9H, s), 1.72-1.88 (1H, m), 2.06-2.26 (1H, m),













2.99-3.23 (3H, m), 3.61 (1H, dd, J = 6.4 Hz and













J = 11.3 Hz), 4.53-4.69 (1H, m), 6.57-6.65 (2H, m),













7.19-7.28 (1H, m), 7.46-7.58 (2H, m), 7.68-7.78 (2H,













m), 12.3 (1H, brs)


93
—H
—H
—CH3
—H
—H
—H
—H
—F
—H
—H
1H-NMR (CDCl3) δ ppm













1.42 (9H, s), 1.74-1.92 (1H, m), 2.00-2.20 (1H, m),













2.30 (3H, s), 3.13-3.32 (3H, m), 3.62-3.80 (1H, m),













4.33-4.48 (1H, m), 6.74 (2H, d, J = 8.5 Hz), 6.80-6.88













(2H, m), 6.90-7.02 (2H, m), 7.03-7.13 (2H, m).
















TABLE 8













 


















Ref. EX.













No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
R10
NMR





















94
—H
—H
—F
—Cl
—H
—H
—H
—N(CH3)2
—H
—H
1H-NMR (CDCl3) δ ppm













1.43 (9H, s), 1.70-1.87 (1H, m), 2.00-2.13 (1H, m),













2.97 (6H, s), 3.10-3.29 (3H, m), 3.59-3.77 (1H, m),













4.28-4.38 (1H, m), 6.41 (1H, dt, J = 3.4, 9.1 Hz), 6.57-













6.61 (1H, m), 6.68-6.72 (2H, m), 6.84-6.94 (3H, m).


95
—H
—H
—F
—Cl
—H
—H
—H
—CN
—H
—H
1H-NMR (CDCl3) δ ppm













1.43 (9H, s), 1.79-1.92 (1H, m), 2.09-2.17 (1H, m),













3.11-3.32 (3H, m), 3.70-3.89 (1H, m), 4.45-4.53 (1H,













m), 6.56 (2H, d, J = 9.0 Hz), 7.02 (1H, ddd, J = 2.6, 4.2,













8.7 Hz)), 7.18-7.28 (2H, m), 7.43 (2H, d, J = 7.9 Hz).


96
—H
—H
—F
—Cl
—H
—H
—H
—CF3
—H
—H
1H-NMR (CDCl3) δ ppm













1.43 (9H, s), 1.78-1.90 (1H, m), 2.09-2.23 (1H, m),













3.12-3.34 (3H, m), 3.65-3.80 (1H, m), 4.40-4.52 (1H,













m), 6.64 (2H, d, J = 8.8 Hz), 7.02 (1H, ddd, J = 2.7, 4.1,













8.6 Hz), 7.15-7.25 (2H, m), 7.42 (2H, d, J = 7.7 Hz).


97
—H
—H
—F
—Cl
—H
—H
—OCH3
—H
—H
—H
1H-NMR (CDCl3) δ ppm













1.43 (9H, s), 1.82-1.90 (1H, m), 2.04-2.18 (1H, m),













3.15-3.32 (3H, m), 3.65-3.80 (1H, m), 3.76 (3H, s),













4.33-4.43 (1H, m), 6.35 (1H, t, J = 2.3 Hz), 6.59 (1H,













dd, J = 1.8, 8.2 Hz), 6.74-6.79 (1H, m), 6.95 (1H, dd,













J = 2.7, 6.4 Hz), 7.02-7.10 (1H, m), 7.15-7.22 (1H, m).


98
—H
—H
—F
—Cl
—H
—H
—OC2H5
—H
—H
—H
1H-NMR (CDCl3) δ ppm













1.38 (3H, t, J = 7.0 Hz), 1.43 (9H, s), 1.80-1.90 (1H,













m), 2.03-2.18 (1H, m), 3.16-3.32 (3H, m), 3.60-3.69













(1H, m), 3.96 (2H, q, J = 7.0), 4.31-4.41 (1H, m), 6.37













(1H, t, J = 2.2 Hz), 6.41 (1H, dd, J = 1.58, 8.0 Hz), 6.59













(1H, d, J = 8.1 Hz), 6.75 (1H, ddd, J = 2.9, 3.9, 8.8 Hz),













6.93 (1H, dd, J = 2.8, 6.4 Hz), 7.00-7.08 (1H, m), 7.14-













7.25 (1H, m).


99
—H
—H
—F
—Cl
—H
—H
—SCH3
—H
—H
—H
1H-NMR (CDCl3) δ ppm













1.43 (9H, s), 1.78-1.92 (1H, m), 2.04-2.20 (1H, m),













2.44 (3H, s), 3.11-3.33 (3H, m), 3.60-3.80 (1H, m),













4.31-4.45 (1H, m), 6.57 (1H, ddd, J = 0.8, 2.3, 8.1 Hz),













6.70 (1H, t, 1.9 Hz), 6.76 (1H, ddd, J = 2.8, 4.0,













8.9 Hz), 6.90-6.96 (2H, m), 7.03-7.11 (1H, m), 7.16-













7.23 (1H, m).


100
—H
—H
—F
—CH3
—H
—H
—H
—NO2
—H
—H
1H-NMR (CDCl3) δ ppm













1.43 (9H, s), 1.80-1.90 (1H, m), 2.01-2.20 (1H, m),













2.31 (3H, s), 3.18-3.38 (3H, m), 3.70-3.88 (1H, m),













4.50-4.59 (1H, m), 6.50 (2H, d, J = 9.5 Hz), 6.85-6.97













(2H, m), 7.07-7.15 (1H, m), 8.03 (2H, d, J = 7.9 Hz).


101
—H
—H
—F
—CH3
—H
—H
—H
—CN
—H
—H
1H-NMR (CDCl3) δ ppm













1.43 (9H, s), 1.81-1.93 (1H, m), 2.08-2.20 (1H, m),













2.35 (3H, s), 3.18-3.30 (3H, m), 3.65-3.78 (1H, m),













4.45-4.55 (1H, m), 6.50 (2H, d, J = 9.5 Hz), 6.83-6.99













(2H, m), 7.03-7.15 (1H, m), 7.32-7.43 (2H, m).
















TABLE 9













 


















Ref. Ex.













No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
R10
NMR





102
—H
—H
—F
—CH3
—H
—H
—CH3
—H
—H
—H
1H-NMR (CDCl3) δ ppm













1.43 (9H, s), 1.79-1.90 (1H, m), 2.00-2.18 (1H, m),













2.24 (3H, s), 2.27 (3H, s), 3.12-3.30 (3H, m), 3.62-













3.71 (1H, m), 4.39-4.50 (1H, m), 6.50-6.52 (2H, m),













6.68-6.72 (1H, m), 6.77-6.84 (2H, m), 6.93-7.01 (1H,













m), 7.06-7.11 (1H, m)


103
—H
—H
—F
—Cl
—H
—H
—H
—C3H7
—H
—H
1H-NMR (CDCl3) δ ppm













0.96 (3H, t, J = 7.3 Hz), 1.43 (9H, s), 1.61-1.70 (2H,













m), 1.76-1.89 (1H, m), 2.01-2.18 (1H, m), 2.51-2.65













(2H, m), 3.11-3.35 (3H, m), 3.62-3.82 (1H, m), 4.31-













4.43 (1H, m), 6.55-6.59 (1H, m), 6.76 (1H, dd,













J = 2.9 Hz and 6.3 Hz), 6.86 (2H, d, J = 8.2 Hz), 6.97













(1H, q, J = 9.1 Hz), 7.11-7.19 (2H, m)


104
—H
—H
—F
—Cl
—H
—H
—H
—C(CH3)3
—H
—H
1H-NMR (CDCl3) δ ppm













1.31 (9H, s), 1.43 (9H, s), 1.78-1.89 (1H, m), 2.02-













2.19 (1H, m), 3.11-3.34 (3H, m), 3.62-3.80 (1H, m),













4.32-4.45 (1H, m), 6.59-6.65 (1H, m), 6.79-6.88 (2H,













m with dd at δ6.81, J = 2.8 Hz and 6.3 Hz), 6.99 (1H, q,













J = 8.9 Hz), 7.29-7.38 (2H, m)


105
—H
—H
—F
—Cl
—H
—H
—H
—SCH3
—H
—H
1H-NMR (CDCl3) δ ppm













1.43 (9H, s), 1.79-1.89 (1H, m), 2.03-2.09 (1H, m),













2.51 (3H, s), 3.13-3.34 (3H, m), 3.63-3.80 (1H, m),













6.65-6.69 (1H, m), 6.80-6.86 (3H, m), 7.02 (1H, q,













J = 8.8 Hz), 7.21-7.27 (2H, m)


106
—H
—H
—F
—Cl
—H
—H
—H
—SO2CH3
—H
—H
1H-NMR (CDCl3) δ ppm













1.43 (9H, s), 1.80-1.91 (1H, m), 2.11-2.29 (1H, m),













3.01 (3H, s), 3.16-3.40 (3H, m), 3.70-3.86 (1H, m),













4.49-4.61 (1H, m), 6.62 (2H, d, J = 9.0 Hz), 7.03 (1H,













ddd, J = 2.6 Hz, 4.1 Hz and 8.6 Hz), 7.01-7.06 (1H, m),













7.19-7.23 (1H, m), 7.24-7.31 (1H, m), 7.66-7.74 (2H, m)


107
—H
—H
—H
—SCH3
—H
—H
—H
—F
—H
—H
1H-NMR (CDCl3) δ ppm













1.43 (9H, s), 1.78-1.91 (1H, m), 2.02-2.18 (1H, m),













2.40 (3H, s), 3.11-3.30 (3H, m), 3.71-3.80 (1H, m),













4.35-4.50 (1H, m), 6.45 (1H, dd, J = 2.0, 8.1 Hz), 6.56













(1H, brs), 6.75 (1H, d, J = 7.9 Hz), 6.97-7.15 (5H, m).


108
—H
—H
—H
—NO2
—H
—H
—CH3
—F
—H
—H
1H-NMR (CDCl3) δ ppm













1.43 (9H, s), 1.78-1.91 (1H, m), 2.08-2.23 (1H, m),













2.29 (3H, s), 3.14-3.33 (3H, m), 3.71-3.82 (1H, m),













4.45-4.55 (1H, m), 6.75-6.84 (1H, m), 6.89-6.99 (2H,













m), 7.03-7.28 (2H, m), 7.41-7.55 (1H, m), 7.55-7.58













(1H, m).


109
—H
—H
—F
—CH3
—H
—H
—OCH3
—H
—H
—H
1H-NMR (CDCl3) δ ppm













1.43 (9H, s), 1.78-1.90 (1H, m), 2.02-2.19 (1H, m),













2.24 (3H, s), 3.13-3.30 (3H, m), 3.63-3.82 (1H, m),













3.73 (3H, s), 4.39-4.52 (1H, m), 6.19 (1H, s), 6.25-













6.28 (1H, m), 6.38-6.41 (1H, m), 6.80-6.91 (2H, m),













6.92-7.06 (1H, m), 7.07-7.13 (1H, m).
















TABLE 10













 


















Ref. Ex.













No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
R10
NMR





110
—H
—H
—Cl
—Cl
—H
—H
—F
—H
—H
—H
1H-NMR (CDCl3) δ ppm













1.43 (9H, s), 1.78-1.92 (1H, m), 2.03-2.23 (1H, m), 













3.12-3.36 (3H, m), 3.61-3.82 (1H, m), 4.31-4.50 (1H, 













m), 6.57 (1H, dt, J = 2.2 Hz and 10.7 Hz), 6.61-6.66 













(1H, m), 6.69 (1H, dd, J = 2.7 Hz and 8.7 Hz),













6.75-6.85 (1H, m), 6.95 (1H, d, J = 2.7 Hz),













7.19-7.39 (2H, m)


 


111
—H
—H
—F
—Cl
—H
—H
—H




—H
—H
1H-NMR (CDCl3) δ ppm 1.43 (9H, s), 1.59-1.75 (3H, m), 1.79-1.92 (3H, m),  1.95-2.15 (2H, m), 3.11-3.32 (3H, m), 3.58-3.79 (2H,  m), 3.89-3.99 (1H, m), 4.30-4.43 (1H, m), 5.30 (1H, s),  6.43-6.44 (1H, m), 6.62-6.67 (1H, m), 6.85-6.97 (3H,  m), 7.02-7.10 (2H, m)


 


112
—H
—H
—F
—CF3
—H
—H
—Cl
—F
—H
—H
1H-NMR (CDCl3) δ ppm













1.43 (9H, s), 1.76-1.91 (1H, m), 2.03-2.09 (1H, m), 













3.11-3.37 (3H, m), 3.61-3.79 (1H, m), 4.32-4.45 (1H, 













m), 6.73-6.79 (1H, m), 6, 93-6.98 (2H, m), 7.01-7.04 













(1H, m), 7.05-7.16 (2H, m)
















TABLE 11













 

















Ref. Ex.












No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
NMR





113
—H
—H
—H
—H
—H
—H
—H
—H
—H
1H-NMR (CDCl3) δ ppm












1.42 (9H, s), 1.68-1.72 (1H, m), 1.99-2.21 (1H, m), 












3.06-3.31 (3H, m), 3.83 (1H, dd, J = 7.2 Hz and 10.7 












Hz), 5.32-5.49 (1H, m), 5.96 (1H, d, J = 6.0 Hz), 












6.52-6.65 (1H, m), 7.10-7.29 (3H, m), 7.31-7.52 












(3H, m), 8.15-8.23 (1H, m)


114
—H
—F
—H
—H
—H
—H
—H
—H
—H
1H-NMR (CDCl3) δ ppm












1.43 (9H, s), 1.75-1.94 (1H, m), 2.09-2.38 (1H, m), 












3.12-3.49 (3H, m), 3.70-3.85 (1H, m), 4.40-4.60 












(1H, m), 6.49-6.61 (2H, m), 6.68-6.79 (1H, m), 












7.16-7.31 (3H, m), 8.27 (1H, s), 8.36-8.44 (1H, m)


115
—H
—Cl
—F
—H
—H
—H
—H
—H
—H
1H-NMR (CDCl3) δ ppm












1.45 (9H, s), 1.70-1.89 (1H, m), 2.02-2.25 (1H, m), 












3.04-3.49 (3H, m), 3.84 (1H, dd, J = 7.1 Hz and 10.8 












Hz), 5.30-5.49 (1H, m), 6.02 (1H, d, J = 8.6 Hz), 












6.58-6.72 (1H, m), 7.02-7.39 (4H, m), 8.16-8.28 












(1H, m)


116
—H
—H
—H
—H
—H
—CH3
—H
—H
—H
1H-NMR (CDCl3) δ ppm












1.43 (9H, s), 1.68-1.89 (1H, m), 2.00-2.20 (1H, m), 












2.43 (3H, d, J = 4.6 Hz), 3.09-3.30 (3H, m), 












3.72-3.95 (1H, m), 5.39-5.58 (1H, m), 5.74 (1H, d, 












J = 8.5 Hz), 6.33-6.53 (1H, m), 7.05-7.20 (3H, m), 












7.29-7.50 31H, m)


117
—H
—H
—H
—H
—H
—H
—CH3
—H
—H
1H-NMR (CDCl3) δ ppm












1.42 (9H, s), 1.68-1.85 (1H, m), 1.95-2.20 (4H, m 












with s at δ 2.17), 3.03-3.31 (3H, m), 3.75-3.88 (1H, 












m), 5.24-5.47 (1H, m), 5.92 (1H, d, J = 8.6 Hz), 












7.07 (1H, d, J = 8.6 Hz), 7.11-7.19 (2H, m), 












7.29-7.31 (3H, m), 8.00 (1H, d, J = 5.2 Hz)


118
—H
—H
—H
—H
—H
—H
—H
—CH3
—H
1H-NMR (CDCl3) δ ppm












1.42 (9H, s), 1.65-1.87 (1H, m), 1.95-2.12 (1H, m), 












2.17 (3H, s), 3.05-3.31 (3H, m), 3.78-3.88 (1H, m), 












5.21-5.45 (1H, m), 5.92 (1H, d, J = 8.6 Hz), 7.07 












(1H, d, J = 8.6 Hz), 7.10-7.20 (2H, m), 7.28-7.31 












(3H, m), 7.96-8.05 (1H, m)


119
—H
—Cl
—F
—H
—H
—H
—CH3
—H
—H
1H-NMR (CDCl3) δ ppm












1.43 (9H, s), 1.69-1.71 (1H, m), 1.90-2.10 (1H, m), 












2.19 (3H, s), 3.01-3.36 (3H, m), 3.76-3.86 (1H, m), 












5.19-5.36 (1H, m), 5.96 (1H, d, J = 8.6 Hz), 












7.01-7.06 (1H, m), 7.07-7.17 (2H, m), 7.18-7.26 












(2H, m), 8.01 (1H, d, J = 12.5 Hz)


120
—H
—Cl
—F
—H
—H
—H
—H
—CH3
—H
1H-NMR (CDCl3) δ ppm












1.43 (9H, s), 1.68-1.81 (1H, m), 2.02-2.20 (4H, m 












with s at δ 2.12), 3.04-3.32 (3H, m), 3.78-3.84 (1H, 












m), 5.29-5.42 (1H, m), 5.80 (1H, s), 6.40-6.53 (1H, 












m), 7.02-7.10 (1H, m), 7.11-7.25 (2H, m), 8.05 (1H, 












d, J = 5.0 Hz and 12.2 Hz)
















TABLE 12













 

















Ref. Ex.












No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
NMR





121
—H
—Cl
—F
—H
—H
—CH3
—H
—H
—H
1H-NMR (CDCl3) δ ppm












1.44 (9H, s), 1.68-1.82 (1H, m), 2.00-2.19 (1H, 












m), 2.39-2.49 (3H, m), 3.02-3.37 (3H, m), 












3.74-3.84 (1H, m), 5.32-5.51 (1H, m), 5.70-5.81 












(1H, m), 6.41-6.57 (1H, m), 7.04 (1H, ddd, 












J = 2.6 Hz, 4.3 Hz and 8.7 Hz), 7.10-7.30 (3H, 












m)


122
—H
—Cl
—F
—H
—H
—H
—Cl
—H
—H
1H-NMR (CDCl3) δ ppm












1.43 (9H, s), 1.62-1.82 (1H, m), 2.01-2.22 (1H, 












m), 3.03-3.31 (3H, m), 3.79 (1H, dd, J = 7.0, 












10.8 Hz), 5.21-5.27 (1H, m), 5.96 (1H, d, 












J = 9.0 Hz), 7.04 (1H, ddd, J = 2.6, 4.2, 8.6), 












7.20-7.26 (4H, m), 8.12-8.14 (1H, m).


123
—H
—CF3
—F
—H
—H
—H
—H
—H
—H
1H-NMR (CDCl3) δ ppm












1.43 (9H, s), 1.63-1.79 (1H, m), 2.02-2.26 (1H, 












m), 3.03-3.35 (3H, m), 3.84 (1H, dd, J = 7.0 Hz, 












11.0 Hz), 5.30-5.41 (1H, m), 5.97 (1H, d, 












J = 8.5 Hz), 6.62-6.73 (1H, m), 7.26-7.47 (4H, 












m), 8.18-8.26 (1H, m).


124
—H
—CH3
—F
—H
—H
—H
—Cl
—H
—H
1H-NMR (CDCl3) δ ppm












1.43 (9H, s), 1.68-1.82 (1H, m), 2.00-2.19 (1H, 












m), 2.29 (3H, s), 3.10-3.29 (3H, m), 3.79 (1H, 












dd, J = 7.1, 10.8 Hz), 5.15-5.32 (1H, m), 5.93 












(1H, d, J = 9.1 Hz), 6.90-6.99 (2H, m), 












7.01-7.21 (2H, m), 8.11-8.12 (1H, m).


125
—H
—H
—F
—H
—H
—H
—Cl
—H
—H
1H-NMR (CDCl3) δ ppm












1.42 (9H, s), 1.73-1.82 (1H, m), 2.00-2.17 (1H, 












m), 3.06-3.29 (3H, m), 3.79 (1H, dd, J = 7.1, 












10.8 Hz), 5.15-5.32 (1H, m), 5.92 (1H, d, 












J = 9.0 Hz), 7.07-7.27 (5H, m), 8.12 (1H, d, 












J = 4.7).


126
—H
—Cl
—F
—H
—H
—H
—H
—CF3
—H
1H-NMR (CDCl3) δ ppm












1.43 (9H, s), 1.7-1.9 (1H, m), 2.0-2.2 (1H, m), 












3.0-3.4 (3H, m), 3.7-3.9 (1H, m), 5.2-5.4 (1H, 












m), 6.15 (1H, s), 6.82 (1H, d, J = 5.0 Hz), 












7.0-7.1 (1H, m), 7.2-7.4 (2H, m), 8.3-8.4 (1H, 












m)


127
—H
—Cl
—F
—H
—H
—OCH3
—H
—H
—H
1H-NMR (CDCl3) δ ppm












1.43 (9H, s), 1.7-1.9 (1H, m), 2.0-2.2 (1H, m), 












3.1-3.4 (3H, m), 3.7-3.9 (1H, m), 3.90 (3H, s), 












5.1-5.3 (1H, m), 5.51 (1H, d, J = 8.1 Hz), 6.09 












(1H, d, J = 8.3 Hz), 7.0-7.1 (1H, m), 7.2-7.4 












(3H, m)
















TABLE 13













 

















Ref. Ex.












No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
NMR





128
—H
—Cl
—F
—H
—H
—H
—H
—H
—H
1H-NMR (CDCl3) δ ppm












1.43 (9H, s), 1.79-1.98 (1H, m), 2.08-2.29 (1H, m), 












3.12-3.41 (3H, m), 3.65-3.85 (1H, m), 4.38-4.51 












(1H, m), 6.83-6.91 (1H, m), 7.00-7.23 (4H, m with 












dd at δ 7.04, J = 2.7 Hz and J = 6.4 Hz), 8.14 (1H, 












s), 8.22 (1H, d, J = 4.4 Hz)


129
—H
—CH3
—F
—H
—H
—H
—H
—H
—H
1H-NMR (CDCl3) δ ppm












1.43 (9H, s), 1.7-1.9 (1H, m), 2.0-2.2 (1H, m), 2.26 












(3H, s), 3.1-3.4 (3H, m), 3.6-3.8 (1H, m), 4.3-4.5 












(1H, m), 6.8-7.1 (5H, m), 7.9-8.1 (2H, m)


130
—H
—H
—H
—H
—H
—H
—F
—H
—H
1H-NMR (CDCl3) δ ppm












1.43 (9H, s), 1.73-1.96 (1H, m), 2.01-2.29 (1H, m), 












3.11-3.40 (3H, m), 3.64-3.86 (1H, m), 4.37-4.56 












(1H, m), 6.79-6.94 (3H, m), 7.02-7.15 (1H, m), 












7.19-7.40 (3H, m), 7.80 (1H, brs)


131
—H
—Cl
—F
—H
—H
—H
—OCH3
—H
—H
1H-NMR (CDCl3) δ ppm












1.43 (9H, s), 1.7-1.9 (1H, m), 2.0-2.2 (1H, m), 












3.1-3.4 (3H, m), 3.6-3.8 (1H, m), 3.96 (3H, s), 












4.3-4.5 (1H, m), 6.50 (1H, d, J = 9.0 Hz), 6.67 (1H, 












d, J = 6.0 Hz), 6.78 (1H, d, J = 8.8 Hz), 6.9-7.0 (1H, 












m), 7.26 (1H, d, J = 8.8 Hz), 7.92 (1H, s)


132
—H
—Cl
—H
—H
—H
—H
—H
—H
—H
1H-NMR (CDCl3) δ ppm












1.41 (9H, s), 1.7-1.9 (1H, m), 2.1-2.3 (1H, m), 












3.1-3.4 (3H, m), 3.7-3.9 (1H, m), 4.4-4.6 (1H, m), 












6.71 (1H, d, J = 6.9 Hz), 6.83 (1H, s), 7.03 (1H, dd, 












J = 6.9 Hz, J = 7.8 Hz), 7.1-7.3 (2H, m), 8.24 (1H, 












s), 8.36 (1H, s)
















TABLE 14













 

















Ref. Ex.












No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
NMR





133
—H
—F
—F
—H
—H
—H
—H
—H
—H
1H-NMR (CDCl3) δ ppm












1.43 (9H, s), 1.8-2.0 (1H, m), 2.1-2.3 (1H, m), 












3.1-3.4 (3H, m), 3.6-3.8 (1H, m), 4.4-4.5 (1H, 












m), 6.6-6.7 (1H, m), 6.7-6.9 (1H, m), 7.0-7.3 












(3H, m), 8.16 (1H, d, J = 6.6 Hz), 8.25 (1H, s)


134
—H
—F
—Cl
—H
—H
—H
—H
—H
—H
1H-NMR (CDCl3) δ ppm












1.42 (9H, s), 1.8-1.9 (1H, m), 2.1-2.3 (1H, m), 












3.1-3.4 (3H, m), 3.7-3.9 (1H, m), 4.4-4.5 (1H, 












m), 6.47 (1H, d, J = 8.1 Hz), 6.54 (1H, d, 












J = 11.2 Hz), 7.2-7.4 (3H, m), 8.30 (1H, s), 8.45 












(1H, s)


135
—H
—Cl
—Cl
—H
—H
—H
—H
—H
—H
1H-NMR (CDCl3) δ ppm












1.43 (9H, s), 1.8-1.9 (1H, m), 2.1-2.3 (1H, m), 












3.1-3.4 (3H, m), 3.7-3.9 (1H, m), 4.4-4.5 (1H, 












m), 6.63 (1H, d, J = 8.7 Hz), 6.90 (1H, s), 












7.2-7.4 (3H, m), 8.27 (1H, s), 8.41 (1H, s)


136
—H
—CF3
—F
—H
—H
—H
—H
—H
—H
1H-NMR (CDCl3) δ ppm












1.43 (9H, s), 1.74-1.94 (1H, m), 2.06-2.28 (1H, 












m), 3.12-3.38 (3H, m), 3.65-3.82 (1H, m), 












4.38-4.56 (1H, m), 7.01-7.25 (5H, m), 8.16 (1H, 












s), 8.28 (1H, d, J = 4.5 Hz).


137
—H
—H
—F
—H
—H
—H
—H
—H
—H
1H-NMR (CDCl3) δ ppm












1.43 (9H, s), 1.79-1.97 (1H, m), 2.03-2.23 (1H, 












m), 3.11-3.29 (3H, m), 3.63-3.79 (1H, m), 












4.38-4.50 (1H, m), 6.83-6.92 (1H, m), 7.01-7.12 












(5H, m), 8.01-8.10 (2H, m).
















TABLE 15













 

















Ref. Ex.












No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
NMR





138
—H
—H
—H
—H
—H
—H
—H
—H
—H
1H-NMR (CDCl3) δ ppm












1.42 (9H, s), 1.77-1.92 (1H, m), 1.95-2.27 (1H, m), 












3.10-3.38 (3H, m), 3.68-3.89 (1H, m), 4.41-4.61 (1H, 












m), 6.32-6.40 (2H, m), 7.08-7.15 (2H, m), 7.38-7.54 












(3H, m), 8.12-8.22 (1H, m)


139
—H
—Cl
—F
—H
—H
—H
—H
—H
—H
1H-NMR (CDCl3) δ ppm












1.43 (9H, s), 1.73-1.95 (1H, m), 2.07-2.27 (1H, m), 












3.12-3.38 (3H, m), 3.65-3.84 (1H, m), 4.41-4.61 (1H, 












m), 6.32-6.41 (2H, m), 6.99-7.08 (1H, m), 7.18-7.32 












(2H, m with dd at δ 7.21, J = 2.5 Hz and J = 6.6 Hz), 












8.12-8.31 (2H, m)


140
—H
—Cl
—F
—H
—H
—H
—H
—CH3
—H
1H-NMR (CDCl3) δ ppm












1.43 (9H, s), 1.8-2.0 (1H, m), 2.1-2.3 (1H, m), 2.40 












(3H, s), 3.1-3.4 (3H, m), 3.7-3.9 (1H, m), 4.4-4.6 (1H, 












m), 6.1-6.3 (2H, m), 6.9-7.1 (1H, m), 7.1-7.3 (2H, m), 












8.12 (1H, d, J = 5.0 Hz)
















TABLE 16













 














Ref. Ex.









No.
R1
R2
R3
R4
R5
R6
NMR





141
—H
—H
—F
—H
—H




1H-NMR (CDCl3) δ ppm 0.80-1.36 (6H, m), 1.44 (9H, s), 1.61-1.99 (6H, m), 2.75-2.93 (1H,  m), 2.96-3.09 (1H, m), 3.15-3.31 (1H, m), 3.33-3.68 (2H, m),  3.87-4.07 (1H, m), 6.86-6.98 (2H, m), 6.98-7.07 (2H, m)


 


142
—H
—H
—F
—H
—H




1H-NMR (CDCl3) δ ppm 1.44 (9H, s), 1.61-1.81 (3H, m), 1.89-2.01 (1H, m), 2.95-3.70 (7H,  m), 3.88-4.01 (1H, m), 6.88-7.10 (4H, m)


 


143
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δ ppm 1.19-1.74 (18H, m with s at δ 1.46), 1.89-2.02 (1H, m), 2.97-3.63  5H, m), 3.71-3.91 (1H, m), 6.89-7.07 (2H, m), 7.10 (1H, d, J = 6.4  Hz)


 


144
—H
—H
—F
—H
—H




1H-NMR (CDCl3) δ ppm 1.43 (9H, s), 1.8-2.0 (1H, m), 2.0-2.2 (1H, rn), 3.1-3.4 (3H, m),  3.6-3.8 (1H, m), 4.2-4.4 (1H, m), 5.95 (2H, s), 6.4-6.5 (2H, m),  6.6-6.8 (3H, m), 6.8-7.0 (2H, m)


 


145
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δ ppm 1.44 (9H, s), 1.7-1.9 (1H, m), 2.0-2.2 (1H, m), 3.1-3.4 (3H, m),  3.6-3.8 (1H, m), 4.2-4.4 (1H, m), 6.00 (2H, s), 6.4-6.5 (3H, m), 6.66  (1H, d, J = 6.2 Hz), 6.7-7.0 (2H, m)


 


146
—H
—H
—H
—F
—H




1H-NMR (CDCl3) δ ppm 1.43 (9H, s), 1.8-1.9 (1H, m), 2.0-2.2 (1H, m), 3.1-3.4 (3H, m),  3.6-3.8 (1H, m), 4.3-4.5 (1H, m), 6.02. (2H, s), 6.27 (1H, d, J = 12.6  Hz), 6.37 (1H, d, J = 8.5 Hz), 6.4-6.5 (1H, m), 6.5-6.7 (2H, m),  6.8-6.9 (1H, m), 7.0-7.2 (1H, m)


 


147
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δ ppm 1.43 (9H, s), 1.78-1.90 (1H, m), 2.04-2.16 (3H, m), 2.79-2.95 (4H,  m), 3.13-3.32 (3H, m), 3.61-3.80 (1H, m), 4.27-4.45 1H, m),  6.50-6.57 (1H, m), 6.61-6.79 (2H, m), 6.83 (1H, s), 6.88-7.02 (1H,  m), 7.13-7.22 (1H, m).


 


148
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δ ppm 1.45 (9H, s), 1.7-1.9 (1H, m), 2.0-2.2 (1H, m), 3.1-3.4 (3H, m),  3.6-3.8 (1H, m), 4.27 (4H, s), 4.3-4.5 (1H, m), 6.4-6.6 (3H, m), 6.68  (1H, d, J = 6.2 Hz), 6.84 (1H, dd, J = 9.1 Hz, J = 9.1 Hz), 6.9-7.0  (1H, m)


 


149
—H
—H
—H
—H
—H




1H-NMR (CDCl3) δ ppm:  1.41 (9H, s), 1.8-2.0 (1H, m), 2.05-2.3 (1H, m), 3.1-3.4 (3H, m),  3.7-3.95 (1H, m), 4.5-4.7 (1H, m), 6.85-7.0 (3H, m), 7.08 (1H, dd,  J = 7, 7 Hz), 7.2-7.5 (5H, m), 7.6-7.8 (3H, m).


 


150
—H
—H
—H
—H
—H




1H-NMR (CDCl3) δ ppm:  1.40 (9H, d, J = 4.5 Hz), 1.65-1.9 (1H, m), 2.0-2.25 (1H, m),  3.05-3.4 (3H, m), 3.7-4.0 (1H, m), 4.6-4.8 (1H, m), 6.54 (2H, d,  J = 8 Hz), 6.65-6.8 (1H, m), 7.0-7.25 (2H, m), 7.31 (1H, d, J = 7  Hz), 7.35-7.6 (3H, m), 7.75-8.0 (3H, m).
















TABLE 17













 














Ref. Ex.









No.
R1
R2
R3
R4
R5
R6
NMR





151
—H
—H
—H
—H
—H




H-NMR (CDCl3) δ ppm:  1.40 (9H, s), 1.75-2.0 (1H, m), 2.0-2.25 (1H, m), 3.1-3.4 (3H, m),  3.65-3.9 (1H, m), 4.45-4.65 (1H, m), 6.65 (2H, d, J = 8 Hz), 6.7-6.85  (2H, m), 7.00 (1H, dd, J = 2, 8.5 Hz), 7.1-7.25 (2H, m), 7.34 (1H, d,  J = 2 Hz), 7.50 (1H, dd, J = 3.5, 8.5 Hz), 7.65 (1H, bs).


 


152
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δ ppm 1.40 (9H, s), 1.7-1.9 (1H, rn), 2.1-2.3 (1H, m), 3.1-3.4 (3H, m),  3.6-3.9 (1H, m), 4.3-4.5 (1H, m), 6.4-6.6 (1H, m), 6.64 (1H, s), 6.76  (1H, d, J = 7.4 Hz), 6.8-7.1 (2H, m), 7.31 (1H, s), 7.52 (1H, dd,  J = 8.9 Hz, J = 9.0 Hz), 7.67 (1H, s)


 


153
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δ ppm 1.41 (9H, s), 1.7-1.9 (1H, m), 2.1-2.3 (1H, m), 3.1-3.4 (3H, m),  3.6-3.8 (1H, m), 4.3-4.5 (1H, m), 6.5-6.7 (1H, m), 6.76 (1H, d,  J = 6.2 Hz), 6.9-7.1 (2H, m), 7.2-7.3 (1H, m), 7.4-7.6 (2H, m),  7.8-7.9 (1H, m)


 


154
—H
—H
—H
—H
—H




1H-NMR (CDCl3) δ ppm:  1.41 (9H, s), 1.8-2.0 (1H, m), 2.0-2.25 (1H, m), 3.1-3.4 (3H, m),  3.65-3.95 (1H, m), 4.4-4.65 (1H, m), 6.82 (2H, dd, J = 1, 8.5 Hz),  6.95 (2H, dd, J = 2, 8.5 Hz), 7.15-7.3 (3H, m), 7.36 (1H, d, J = 5.5  Hz), 7.47 (1H, d, J = 2 Hz), 7.73 (1H, dd, J = 2.5, 8.5 Hz).


 


155
—H
—H
—H
—H
—H




1H-NMR (CDCl3) δ ppm:  1.41 (9H, s), 1.75-1.95 (1H, m), 2.0-2.25 (1H, m), 3.1-3.4 (3H, m),  3.7-3.95 (1H, m), 4.5-4.75 (1H, m), 6.59 (2H, d, J = 8 Hz), 6.7-6.8  (1H, m), 7.05-7.25 (4H, m), 7.3-7.5 (2H, m), 7.86 (1H, d, J = 8 Hz).


 


156
—H
—H
—H
—H
—H




1H-NMR (CDCl3) δ ppm:  1.40 (9H, s), 1.75-2.0 (1H, m), 2.0-2.25 (1H, m), 3.1-3.4 (3H, m),  3.7-3.9 (1H, m), 4.45-4.65 (1H, m), 6.76 (2H, d, J = 8 Hz), 6.89 (1H,  dd, J = 7.5, 7.5 Hz), 6.99 (1H, dd, J = 2.5, 8.5 Hz), 7.15-7.3 (3H, m),  7.4-7.5 (2H, m), 7.82 (1H, dd, J = 3.5, 8.5 Hz).


 


157
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δ ppm:  1.41 (9H, s), 1.75-2.0 (1H, m), 2.0-2.25 (1H, m), 3.15-3.4 (3H, m),  3.65-3.9 (1H, m), 4.35-4.55 (1H, m), 6.55-6.7 (1H, m), 6.82 (1H, dd,  J = 3, 6.5 Hz), 6.85-7.1 (2H, m), 7.30 (1H, d, J = 5.5 Hz), 7.41 (1H,  d, J = 5.5 Hz), 7.48 (1H, d, J = 2 Hz), 7.76 (1H. d, J = 9 Hz).
















TABLE 18













 














Ref. Ex.









No.
R1
R2
R3
R4
R5
R6
NMR





158
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δ ppm:  1.41 (9H, s), 1.68 (9H, s), 1.7-1.95 (1H, m), 2.0-2.2  (1H, m), 3.1-3.3 (3H, m), 3.65-3.9 (1H, m), 4.4-4.6  (1H, m), 6.26 (1H, d, J = 4 Hz), 6.35-6.45 (1H, m),  6.60 (1H, dd, J = 3, 6 Hz), 6.8-6.95 (1H, m), 6.99 (1H,  d, J = 7.5 Hz), 7.25-7.4 (1H, m), 7.53 (1H, br), 8.15  (1H, d, J = 8.5 Hz).


 


159
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δ ppm:  1.41 (9H, s), 1.63 (9H, s), 1.8-2.0 (1H, m), 2.0-2.25  (1H, m), 3.15-3.4 (3H, m), 3.65-3.85 (1H, m),  4.35-4.45 (1H, m), 6.5-6.65 (2H, m), 6.6-6.8 (1H, m),  6.86 (1H, dd, J = 2, 8.5 Hz), 6.9-7.0 (1H, m), 7.45-7.55  (1H, m), 7.55-7.65 (1H, m), 7.86 (1H, br).


 


160
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δ ppm:  1.17 (18H. d, J = 7.5 Hz), 1.40 (9H, s), 1.71 (3H, qq,  J = 7.5, 7.5 Hz), 1.75-1.95 (1H, m), 2.0-2.25 (1H, m),  3.05-3.35 (3H, m), 3.65-3.95 (1H, m), 4.4-4.6 (1H, m),  6.35-6.5 (1H, m), 6.6-6.75 (1H, m), 6.8-6.95 (1H, m),  7.0-7.3 (4H, m), 7.52 (1H, d, J = 8 Hz).


 


161
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δ ppm 1.42 (9H, s), 1.8-2.0 (1H, m), 2.1-2.3 (1H, m), 3.2-3.5  (3H, m), 3.7-3.9 (1H, m), 4.4-4.6 (1H, m), 6.8-7.0 (1H,  m), 7.0-7.2 (2H, m), 7.4-7.8 (4H, m), 8.02 (1H, d,  J = 8.2 Hz), 8.41 (1H, s)


 


162
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δ ppm 1.45 (9H, s), 1.90 (3H, s), 2.1-2.2 (1H, m), 2.2-2.3 (1H,  m), 3.2-3.5 (3H, m), 3.8-4.0 (1H, m), 4.8-5.0 (1H, m),  6.8-7.0 (1H, m), 7.0-7.1 (2H, m), 7.3-7.5 (1H, m),  7.5-7.7 (2H, m), 7.76 (1H, d, J = 5.9 Hz), 7.9-8.0 (1H,  m)


 


163
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δ ppm:  1.39 (9H, d, J = 7.5 Hz), 1.65-1.85 (1H, m), 1.95-2.2  (1H, m), 3.05-3.35 (3H, m), 3.6-3.95 (1H, m), 4.5-4.75  (1H, m), 6.25-6.4 (1H, m), 6.57 (1H, dd, J = 3, 6 Hz),  6.75-7.0 (1H, m), 7.3-7.45 (2H, m), 7.78 (1H, dd,  J = 7.5. 7.5 Hz), 8.05-8.25 (2H, m), 8.95 (1H, d, J = 3.5  Hz).


 


164
—H
—H
—H
—H
—H




1H-NMR (CDCl3) δ ppm:  1.39 (9H, d, J = 6 Hz), 1.65-1.85 (1H, m), 1.95-2.25  (1H, m), 3.05-3.35 (3H, m), 3.7-3.95 (1H, m), 4.6-4.8  (1H, m), 6.54 (2H, d, J = 8 Hz), 6.65-6.8 (1H, m),  7.05-7.2 (2H, m), 7.3-7.45 (2H, m), 7.77 (1H, dd,  J = 7.5, 7.5 Hz), 8.1-8.25 (2H, m), 8.93 (1H, d, J = 3.5  Hz).


 


165
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δ ppm 1.40 (9H, s), 1.7-1.9 (1H, m), 2.0-2.3 (1H, m), 3.1-3.4  (3H, m), 3.7-3.9 (1H, m), 4.5-4.8 (1H, m), 6.3-6.5 (1H,  m), 6.5-6.7 (1H, m), 6.8-7.0 (1H, m), 7.5-7.8 (3H, m),  8.08 (1H, d, J = 6.7 Hz), 8.37 (1H, s), 9.28 (1H, s)
















TABLE 19













 














Ref. Ex.









No.
R1
R2
R3
R4
R5
R6
NMR





166
—H
—H
—H
—H
—H




1H-NMR (CDCl3) δ ppm 1.43 (9H, s), 1.8-2.0 (1H, m), 2.1-2.4 (1H, m), 3.1-3.4  (3H, m), 3.7-3.9 (1H, m), 5.3-5.5 (1H, m), 7.0-7.1 (1H,  m), 7.2-7.4 (3H, m), 7.45 (1H, d, J = 7.7 Hz), 7.4-7.6  (3H, m), 7.61 (1H, dd, J = 8.2 Hz, J = 8.5 Hz)


 


167
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δ ppm 1.44 (9H, s), 1.8-2.0 (1H, m), 2.2-2.4 (1H, m), 3.2-3.5  (3H, m), 3.8-4.0 (1H, m), 5.2-5.4 (1H, m), 7.0-7.4 (4H,  m), 7.40 (1H, d, J = 8.6 Hz), 7.50 (1H, d, J = 7.7 Hz),  7.62 (1H, dd, J = 8.2 Hz, J = 8.6 Hz)


 


168
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δ ppm 1.43 (9H, s), 1.8-2.0 (1H, m), 2.2-2.4 (1H, m), 3.2-3.5  (3H, m), 3.80 (3H, s), 3.8-4.0 (1H, m), 5.2-5.4 (1H, m),  6.92 (1H, d, J = 8.6 Hz), 7.03 (1H, s), 7.1-7.3 (2H, m),  7.39 (1H, d, J = 8.6 Hz), 7.52 (1H, dd, J = 9.0 Hz, J = 9.0  Hz)


 


169
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δ ppm 1.44 (9H, s), 1.9-2.1 (1H, m), 2.1-2.3 (1H, m), 3.2-3.4  (3H, m), 3.7-3.9 (1H, m), 4.6-4.8 (1H, m), 6.77 (1H, d,  J = 5.6 Hz), 7.1-7.2 (2H, m), 7.29 (1H, d, J = 6.4 Hz),  7.37 (1H, d, J = 5.6 Hz), 7.45 (1H, d, J = 5.6 Hz), 8.49  (1H, d, J = 5.6 Hz)


 


170
—H
—H
—H
—F
—H




1H-NMR (CDCl3) δ ppm 1.43 (9H, s), 1.82-2.00 (1H, m), 2.03-2.25 (1H, m),  3.10-3.39 (3H, m), 4.32-4.50 (1H, m), 6.37 (1H, dt,  J = 2.3 Hz and 12.2 Hz), 6.41-6.57 (2H, m), 6.76 (1H,  dd, J = 1.4 Hz and J = 5.1 Hz), 6.96 (1H, dd, J = 1.4 Hz  and J = 3.1 Hz), 7.06-7.18 (1H, m . . .


 


171
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δ ppm 1.11 (18H, d, J = 7.4 Hz), 1.43 (9H, s), 1.77-2.21 (2H,  m), 3.07-3.35 (3H, m), 3.59-3.82 (1H, m), 4.26-4.42  (1H, m), 5.97-6.02 (1H, m), 6.43-6.58 (2H, m),  6.62-6.70 (1H, m), 6.76 (1H, s), 6.83-6.95 (1H, m)
















TABLE 20













 














Ref. Ex.









No.
R1
R2
R3
R4
R5
R6
NMR





172
—H
—H
—Cl
—Cl
—H




1H-NMR (CDCl3) δ ppm 1.42 (9H, s), 1.81-2.011 (1H, m), 2.03-2.31 (1H, m),  2.23 (3H, d, J = 1.0 Hz), 3.12-3.38 (3H, m), 3.69-3.85  (1H, m), 4.89-5.01 (1H, m), 6.85 (1H, brs), 7.11 (1H,  dd, J = 2.5 Hz, 8.5 Hz), 7.37 (1H, d, J = 2.5 Hz),  7.51-7.54 (1H, m)


 


173
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δ ppm 1.43 (9H, s), 1.81-2.00 (1H, m), 2.10-2.40 (1H, m),  3.11-3.41 (3H, m), 3.68-3.88 (1H, m), 4.99-5.13 (1H,  m), 6.51 (1H, d, J = 3.5 Hz), 7.12-7.31 (3H, m), 7.35  (1H, dd, J = 6.5 Hz and J = 2.5 Hz)


 


174
—H
—H
—Cl
—Cl
—H




1H-NMR (CDCl3) δ ppm 1.43 (9H, s), 1.83-2.03 (1H, m), 2.11-2.35 (1H, m),  3.18-3.42 (3H, m), 3.73-3.87 (1H, m), 4.97-5.09 (1H,  m), 6.53 (1H, d, J = 3.5 Hz), 7.14 (1H, dd, J = 2.5 Hz,  8.5 Hz), 7, 22 (1H, brs), 7.39 (1H, d, J = 2.5 Hz), 7.56  (1H, brd, J = 8.5 Hz)


 


175
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δ ppm 1.42 (9H, s), 1.80-2.03 (1H, m), 2.08-2.22 (1H, m),  2.22 (3H, s), 3.13-3.38 (3H, m), 3.68-3.85 (1H, m),  4.98 (1H, tt, J = 6.5 Hz, 6.5 Hz), 6.84 (1H, brs),  7.11-7.23 (2H, m), 7.33 (1H, dd, J = 2.5 Hz, 6.5 Hz)


 


176
—H
—H
—F
—H
—H




1H-NMR (CDCl3) δ ppm 1.42 (9H, s), 1.76-2.03 (1H, m), 2.08-2.33 (1H, m),  3.08-3.42 (3H, m), 3.71-3.87 (1H, m), 5.03-5.20 (1H,  m), 6.47 (1H, d, J = 3.5 Hz), 7.11-7.32 (5H, m)


 


177
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δ ppm 1.43 (9H, s), 1.80-2.00 (1H, m), 2.10-2.31 (1H, m),  3.18-3.42 (3H, m), 3.63-3.80 (1H, m), 4.38-4.50 (1H,  m), 6.95-7.05 (1H, m), 7.14-7.30 (2H, m with dd at δ  7.17, J = 2.6 Hz and 6.4 Hz), 8.12 (2H, s), 8.72 (1H, s)


 


178
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δ ppm 1.44 (9H, s), 1.70-1.90 (1H, m), 2.02-2.21 (1H, m),  3.09-3.41 (3H, m), 3.75-3.90 (1H, m), 5.21-5.38 (1H,  m), 6.62 (1H, s), 6.99-7.09 (1H, m), 7.15-7.29 (2H, m),  8.21-8.41 (2H, m)


 


179
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δ ppm 1.43 (9H, s), 1.7-1.9 (1H, m), 2.1-2.3 (1H, m), 2.53  (3H, s), 3.1-3.4 (3H, m), 3.7-3.9 (1H, m), 5.3-5.5 (1H,  m), 5.56 (1H, d, J = 5.7 Hz), 7.0-7.1 (1H, m), 7.2-7.3  (2H, m), 7.91 (1H, d, J = 5.7 Hz)
















TABLE 21













 














Ref. Ex.









No.
R1
R2
R3
R4
R5
R6
NMR





180
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δ ppm 1.43 (9H, s), 1.71-1.90 (1H, m), 2.01-2.25 (1H, m),  3.08-3.40 (3H, m), 3.71-3.89 (1H, m), 5.12-5.39 (1H,  m), 7.05-7.13 (1H, m), 7.23-7.33 (2H, m), 7.49 (1H, s),  7.90 (1H, s), 8.09 (1H, s)


 


181
—H
—H
—F
—H
—H




1H-NMR (CDCl3) δ ppm 1.43 (9H, s), 1.69-1.87 (1H, m), 2.00-2.21 (1H, m),  3.05-3.34 (3H, m), 3.71-3.87 (1H, m), 5.13-5.27 (1H,  m), 7.17 (4H, d, J = 5.5 Hz), 7.44 (1H, s), 7.85 (1H, s),  8.08 (1H, s).


 


182
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δ ppm 1.40 (9H, s), 1.8-1.9 (1H, m), 2.0-2.2 (1H, m), 3.1-3.4  (3H, m), 3.6-3.8 (1H, m), 4.2-4.4 (1H, m), 6.5-6.6 (1H,  m), 6.62 (1H, dd, J = 10.0 Hz, J = 9.8 Hz), 6.72 (1H, d,  J = 6.0 Hz), 6.9-7.1 (1H, m), 7.2-7.3 (2H, m), 13.17  (1H, brs)


 


183
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δ ppm 1.44 (9H, s), 1.7-1.9 (1H, m), 2.0-2.2 (1H, m), 3.0-3.4  (3H, m), 3.6-3.8 (1H, m), 4.2-4.4 (1H, m), 4.9-5.3 (2H,  m), 6.4-6.5 (1H, m), 6.6-6.7 (2H, m), 6.7-7.1 (3H, m),  7.2-7.4 (5H, m)
















TABLE 22













 









Ref. Ex.




No.
R1
NMR





184




1H-NMR (CDCl3) δ ppm: 1.47 (9H, s), 2.04 (1H, br), 2.15-2.35 (1H, m),  3.2-3.4 (1H, m), 3.4-3.6 (2H, m), 3.65-3.95 (2H, m), 4.17 (1H, br), 6.81  (1H, d, J = 2.3 Hz), 6.86 (1H, dd, J = 2.4, 8.7 Hz), 7.15-7.3 (1H, m), 7.37  (1H, dd, J = 7.8, 7.8 Hz), 7.55-7.7 (3H, m).


 


185




1H-NMR (CDCl3) δ pprn: 1.47 (9H, s), 1.91 (1H, br), 2.1-2.3 (1H, m),  3.1-3.35 (1H, m), 3.35-3.85 (4H, m), 4.05 (1H, br), 6.55-6.7 (2H, m),  6.77 (1H, d, J = 2.3 Hz), 7.31 (1H, d, J = 8.8 Hz), 7.54 (1H, d, J = 2.0 Hz).


 


186




1H-NMR (CDCl3) δ ppm: 1.47 (9H, s), 1.93 (1H, br), 2.15-2.3 (1H, m),  3.15-3.4 (1H, m), 3.4-3.6 (2H, m), 3.65-3.85 (1H, m), 3.85-4.0 (1H, m),  4.0-4.2 (1H, m), 6.75 (1H, dd, J = 2.1, 8.7 Hz), 6.9-7.0 (2H, m), 7.60 (1H,  d, J = 8.6 Hz).


 


187




1H-NMR (CDCl3) δ ppm: 1.47 (9H, s), 1.85-2.05 (1H, m), 2.15-2.35 (1H,  m), 3.2-3.4 (1H, m), 3.4-3.6 (2H, m), 3.65-3.9 (2H, m), 4.16 (1H, br), 6.76  (1H, dd, J = 2, 2, 8.6 Hz), 6.96 (1H, d, J = 2.3 Hz), 7.26 (1H, s), 7.59 (1H, d, J = 8.6 Hz).


 


188




1H-NMR (CDCl3) δ ppm: 1.47 (9H, s), 1.85-2.0 (1H, m), 2.1-2.3 (1H, m),  2.36 (3H, d, J = 1.1 Hz), 3.1-3.35 (1H, m), 3.4-3.6 (2H,, m), 3.65-3.85  (2H, m), 4.0-4.2 (1H, m), 6.71 (1H, dd, J = 2.2, 8.6 Hz), 6.76 (1H, d,  J = 0.8 Hz), 7.01 (1H, d, J = 2.1 Hz), 7.49 (1H, d, J = 8.6 Hz).


 


189




1H-NMR (CDCl3) δ ppm: 1.47 (9H, s), 1.85-2.0 (1H, m), 2.15-2.3 (1H,  m), 2.37 (3H, s), 3.15-3.35 (1H, m), 3.4-3.6 (2H, m), 3.65-3.85 (2H, m),  4.05-4.25 (1H, m), 6.72 (1H, dd, J = 2.2, 8.6 Hz), 6.85 (1H, d, J = 2.1 Hz), 7.03 (1H, s), 7.61 (1H, d, J = 8.5 Hz).


 


190




1H-NMR (CDCl3) δ ppm: 1.65 (9H, s), 2.04 (1H, br), 2.1-2.3 (1H, m),  3.15-3.35 (1H, m), 3.35-3.6 (2H, m), 3.6-3.8 (1H, m), 3.8-3.95 (1H, m),  3.95-4.1 (1H, m), 6.71 (1H, d, J = 1.9 Hz), 6.90 (1H, d, J = 1.5 Hz), 7.15  (1H, d, J = 5.5 Hz), 7.30 (1H, d, J = 5.7 Hz).


 


191




1H-NMR (CDCl3) δ ppm: 1.47 (9H, s), 1.9-2.1 (1H, m), 2.05-2.35 (1H,  m), 3.2-3.65 (3H, m), 3.65-3.9 (1H, m), 4.0-4.3 (2H, m), 6.53 (1H, d,  J = 7.4 Hz), 7.15-7.4 (4H, m).


 


192




1H-NMR (CDCl3) δ ppm: 1.47 (9H, s), 1.91 (1H, br), 2.0-2.3 (1H, m),  2.51 (3H, d, J = 0.9 Hz), 3.15-3.35 (1H, m), 3.35-3.6 (2H, m), 3.6-3.85  (2H, m), 4.07 (1H, br), 6.62 (1H, dd, J = 2.2, 8.5 Hz), 6.80 (1H, s), 6.93  (1H, d, J = 2.1 Hz), 7.42 (1H, d, J = 8.5 Hz).
















TABLE 23













 









Ref. Ex.




No.
R1
NMR





193




1H-NMR (CDCl3) δ ppm: 1.47 (9H, s), 1.97 (1H, br), 2.15-2.3 (1H, m),  3.15-3.4 (1H, m), 3.4-3.6 (2H, m), 3.65-3.85 (1H, m), 4.0-4.25 (2H, m),  6.70 (1H, dd, J = 2.0, 8.7 Hz), 6.96 (1H, d, J = 1.5 Hz), 7.79 (1H, d,  J = 8.7 Hz), 8.65 (1H, s).


 


194




1H-NMR (CDCl3) δ ppm: 1.47 (9H, s), 1.8-2.0 (1H, m), 2.15-2.35 (1H,  m), 3.15-3.6 (3H, m), 3.7-3.85 (1H, m), 4.4-4.65 (2H, m), 6.43 (1H, d,  J = 8.6 Hz), 7.07 (2H, s), 7.76 (1H, d, J = 8.6 Hz).


 


195




1H-NMR (CDCl3) δ ppm: 1.47 (9H, s), 1.93 (1H, br), 2.17-2.29 (1H, m),  3.27 (1H, br), 3.49 (2H, br), 3.69 (3H, s), 3.92 (2H, br), 4.08 (1H, br),  6.69 (1H, d, J = 9.6 Hz), 6.71 (1H, d, J = 2.9 Hz), 6.91 (1H, dd, J = 9.0  Hz), 7.23 (1H, d, J = 2.9, 9.0 Hz), 7.55 (1H, d, J = 9.6 Hz).
















TABLE 24













 













Ref. Ex.








No.
R1
R2
R3
R4
R5
NMR





196
—H
—H
—F
—F
—H
1H-NMR (CDCl3) δ ppm; 1.47 (9H, s), 1.76-1.95 (1H, m), 2.09-2.25 








(1H, m), 3.11-3.32 (1H, m), 3.36-3.56 (2H, m), 3.58-3.78 (2H, m), 








3.85-4.03 (1H, m), 6.19-6.30 (1H, m), 6.34-6.43 (1H, m), 6.96 (1H, dd, 








J = 9.0, 19.0 Hz)


197
—H
—Cl
—H
—Cl
—H
1H-NMR (CDCl3) δ ppm: 1.47 (9H, s), 1.77-1.95 (1H, m), 2.02-2.27 








(1H, m), 3.15-3.75 (3H, m), 3.87-4.02 (2H, m), 6.45-6.46 (2H, m), 








6.68-6.70 (1H, m).


198
—H
—H
—Cl
—CH3
—H
1H-NMR (DMSO-d6) δ ppm: 1.39 (9H, s), 1.64-1.85 (1H, m), 








2.00-2.18 (1H, m), 2.21 (3H, s), 2.97-3.10 (1H, m), 3.22-3.39 (2H, m), 








3.42-3.60 (1H, m), 3.78-3.96 (1H, m), 5.89 (1H, d, J = 6.8 Hz), 6.43 








(1H, dd, J = 8.6, 2.5 Hz), 6.55 (1H, d, J = 2.5 Hz), 7.06 (1H, d, J = 8.6 








Hz).


199
—H
—OCH3
—F
—F
—H
1H-NMR (DMSO-d6) δ ppm: 1.39 (9H, s), 1.60-1.82 (1H, m), 








1.93-2.17 (1H, m), 2.92-3.10 (1H, m), 3.20-3.44 (1H, m), 3.48-3.57 








(1H, m), 3.75 (3H, s), 3.80-4.00 (1H, m), 6.01-6.19 (2H, m).


200
—H
—F
—F
—F
—H
1H-NMR (CDCl3) δ ppm: 1.47 (9H, s), 1.74-1.92 (1H, m), 2.08-2.21 








(1H, m), 3.08-3.28 (1H, m), 3.33-3.51 (2H, m), 3.61-3.95 (2H, m), 








6.08-6.21 (2H, m).


201
—H
—F
—Cl
—F
—H
1H-NMR (CDCl3) δ ppm: 1.45 (9H, s), 1.78-1.93 (1H, m), 2.03-2.24 








(1H, m), 3.09-3, 31 (1H, m), 3.36-3.52 (2H, m), 3.60-3.75 (1H, m), 








3.85-4.08 (1H, m), 6.15-6.24 (2H, m).


202
—H
—H
—CH3
—F
—H
1H-NMR (CDCl3) δ ppm: 1.46 (9H, s), 1.87 (1H, br), 2.14-2, 23 (1H, 








m), 2.15 (3H, d, J = 1.4 Hz), 3.21 (1H, br), 3.45 (2H, br), 3.68 (2H, br), 








3.97 (1H, br), 6.26-6.31 (2H, m), 6.95 (1H, dd, J = 8.5, 10.7 Hz).


203
—H
—H
—Cl
—H
—H
1H-NMR (CDCl3) δ ppm 1.46 (9H, s), 1.78-1.96 (1H, m), 2.10-2.20 








(1H, m), 3.11-3.30 (1H, m), 3.40-3.56 (2H, m), 3.60-3.80 (2H, m), 








3.85-4.03 (1H, m), 6.52 (2H, d, J = 8.7 Hz), 7.12 (1H, d, 8.7 Hz)
















TABLE 25













 


















Ref. Ex.













No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
R10
NMR





204
—H
—H
—F
—Cl
—H
—CH3
—H
—F
—H
—H
1H-NMR (CDCl3) δppm; {1.42 (s), 1.44 (s)













total 9H, 1:1}, 1.71-1.89 (1H, m), 2.03-













2.19 (1H, m), 2.08 (3H, s), 3.12-3.36 (3H,













m), 3.61-3.82(1H, m), 4.32-4.45 (1H, m),













6.23-6.29 (1H, m), 6.46 (1H, dd, J = 3.0,













6.0 Hz), 6.86-7.07 (4H, m)


205
—H
—H
—F
—F
—H
—H
—F
—F
—H
—H
1H-NMR (CDCl3) δppm; 1.43(9H, s), 1.73-













1.92(1H, m), 2.00-2.22(1H, m), 3.11-













3.36(3H, m), 3.59-3.78 (1H, m), 4.25-













4.41(1H, m), 6.51-6.72(4H, m), 7.09(2H,













dd, J = 8.5, 18.0 Hz)
















TABLE 26













 

















Ref. Ex.












No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
NMR





206
—H
—Cl
—Cl
—H
—H
—H
—H
—H
—H
1H-NMR (CDCl3) δppm; 1.43 (9H, s), 1.79-1.90












(1H, m), 2.10-2.20 (1H, m), 3.15-3.33 (3H, m),












3.67-3.84 (1H, m), 4.39-4.52 (1H, m), 6.63 (1H, dd,












J = 2.7, 8.8 Hz), 6.89 (1H, d, J = 2.7 Hz), 7.24-7.32












(3H, m), 8.28 (1H, brs), 8.42 (1H, brs).


207
—H
—Cl
—F
—H
—H
—H
—H
—H
—CH3
1H-NMR (CDCl3) δppm; 1.44 (9H, s), 1.74-1.89












(1H, m), 2.04-2.20 (1H, m), 2.12 (3H, s), 3.13-3.21












(1H, m), 3.24-3.38 (2H, m), 3.69-3.85 (1H, m),












4.39-4.55 (1H, m), 6.25-6.36 (1H, m), 6.52 (1H, dd,












J = 3.1, 6.0 Hz), 6.90-6.98 (1H, m), 7.25-7.28 (1H,












m), 8.30 (1H, s), 8.48 (1H, d, J = 4.8 Hz).


208
—H
—Cl
—Cl
—H
—H
—H
—H
—H
—CH3
1H-NMR (CDCl3) δppm; 1.43 (9H, s), 1.70-1.86












(1H, m), 2.04-2.28 (1H, m), 2.12 (3H, s), 3.14-3.21












(1H, m), 3.23-3.35 (2H, m), 3.68-3.84 (1H, m),












4.43-4.51-5.35 (1H, m), 6.29 (1H, d, 8.7 Hz), 6.56












(1H, d, J = 2.9 Hz), 7.16-7.20 (1H, m), 7.27-7.30 (1H,












m), 8.29 (1H, s), 8.50 (1H, d, J = 4.7 Hz).
















TABLE 27













 

















Ref. Ex.












No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
NMR





209
—H
—Cl
—H
—Cl
—H
—H
—H
—H
—H
1H-NMR (CDCl3) δppm: 1.43 (9H, s), 1.72-1.89












(1H, m), 2.08-2.24 (1H, m), 3.09-3.32 (3H, m),












3.67-3.84 (1H, m), 4.38-4.52 (1H, m), 6.52-6.53












(2H, m), 6.87-6.89 (1H, m), 7.35-7.40 (2H, m),












8.34-8.35 (1H, m), 8.54-8.56 (1H, m).


210
—H
—CH3
—Cl
—H
—H
—H
—H
—H
—H
1H-NMR (CDCl3) δppm: 1.43 (9H, s), 1.79-1.92












(1H, m), 2.04-2.22 (1H, m), 2.34 (3H, s), 3.15-3.38












(3H, m), 6.76 (1H, dd, J = 8.4, 2.5 Hz), 6.85 (1H, d,












J = 2.5 Hz), 6.97-7.05 (1H, m), 6.87-6.89 (1H, dd, J =












8.4, 4.6 Hz), 7.27-7.35 (1H, m), 8.09-8.145 (1H,












m), 8.18 (1H, d, J = 3.8 Hz).


211
—H
—Cl
—F
—H
—H
—H
—H
—F
—H
1H-NMR (CDCl3) δppm: 1.43 (9H, s), 1.8-1.95












(1H, m), 2.05-2.3 (1H, m), 3.15-3.4 (3H, m),












3.65-3.8 (1H, m), 4.35-4.5 (1H, m), 6.59 (1H, d,












J = 10.2 Hz), 6.95-7.05 (1H, m), 7.1-7.3 (2H, m),












7.84 (1H, br), 7.96 (1H, d, J = 2.1 Hz).


212
—H
—CH3
—F
—H
—H
—H
—H
—F
—H
1H-NMR (CDCl3) δppm: 1.43 (9H, s), 1.8-1.95












(1H, m), 2.05-2.25 (1H, m), 2.29 (3H, s), 3.15-












3.35 (3H, m), 3.65-3.8 (1H, m), 4.35-4.5 (1H,












m), 6.45-6.55 (1H, m), 6.85-6.95 (2H, m), 7.0-












7.15 (1H, m), 7.79 (1H, br), 7.87 (1H, d, J =












1.9 Hz).


213
—H
—H
—F
—H
—H
—H
—H
—F
—H
1H-NMR (CDCl3) δppm: 1.43 (9H, s), 1.8-1.95












(1H, m), 2.05-2.25 (1H, m), 3.1-3.35 (3H, m),












3.65-3.8 (1H, m), 4.35-4.5 (1H, m), 6.45-6.55












(1H, m), 7.05-7.2 (4H, m), 7.80 (1H, br), 7.88












(1H, d, J = 2.1 Hz).
















TABLE 28













 

















Ref. Ex.












No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
NMR





214
—H
—Cl
—F
—H
—H
—H
—H
—F
—H
1H-NMR (CDCl3) δppm: 1.43 (9H, s), 1.8-1.95












(1H, m), 2.05-2.3 (1H, m), 3.15-3.4 (3H, m),












3.65-3.8 (1H, m), 4.35-4.5 (1H, m), 6.59 (1H, d,












J = 10.2 Hz), 6.95-7.05 (1H, m), 7.1-7.3 (2H,












m), 7.84 (1H, br), 7.96 (1H, d, J = 2.1 Hz).


215
—H
—CH3
—F
—H
—H
—H
—H
—F
—H
1H-NMR (CDCl3) δppm: 1.43 (9H, s), 1.8-1.95












(1H, m), 2.05-2.25 (1H, m), 2.29 (3H, s), 3.15-












3.35 (3H, m), 3.65-3.8 (1H, m), 4.35-4.5 (1H,












m), 6.45-6.55 (1H, m), 6.85-6.95 (2H, m), 7.0-












7.15 (1H, m), 7.79 (1H, br), 7.87 (1H, d, J =












1.9 Hz).


216
—H
—H
—F
—H
—H
—H
—H
—F
—H
1H-NMR (CDCl3) δppm: 1.43 (9H, s), 1.8-1.95












(1H, m), 2.05-2.25 (1H, m), 3.1-3.35 (3H, m),












3.65-3.8 (1H, m), 4.35-4.5 (1H, m), 6.45-6.55












(1H, m), 7.05-7.2 (4H, m), 7.80 (1H, br), 7.88












(1H, d, J = 2.1 Hz).
















TABLE 29













 














Ref. Ex.









No.
R1
R2
R3
R4
R5
R6
NMR





217
—H
—H
—Cl
—Cl
—H




1H-NMR (CDCl3) δppm: 1.43 (9H, s), 1.75-1.89 (1H, m), 2.03-2.20 (1H, m), 3.08-3.33 (3H, m), 3.80 (1H, dd, J = 7.1, 10.9 Hz), 5.17-5.29 (1H, m), 6.00 (1H, d, J = 9.0 Hz), 7.03 (1H, dd, J = 2.4, 8.4 Hz), 7.25 (1H, dd, J = 2.2, 9.0 Hz), 7.29 (1H, d, J = 2.2 Hz), 7.52-7.57 (1H, dd, J = 4.7, 8.3 Hz), 8.13 (1H, d, J = 4.7 Hz).


 


218
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δppm: 1.44 (9H, s), 1.80-2.21 (2H, m), 3.20-3.47 (3H, m), 3.57-3.78 (1H, m), 4.68-4.74 (1H, m), 6.85-7.03 (4H, m), 7.55-7.59 (1H, m), 8.29-8.32 (1H, m).


 


219
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δppm: 1.44 (9H, s), 1.71-1.89 (1H, m), 2.04-2.28 (1H, m), 3.10-3.34 (3H, m), 3.85 (1H, dd, J = 7.5, 10.3 Hz), 5.35-5.43 (1H, m), 6.08 (1H, d, J = 8.8 Hz), 7.07-7.12 (1H, m), 7.2- 7.36 (5H, m), 7.46-7.51 (2H, m), 8.42 (1H, d, J = 5.9 Hz).


 


220
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δppm: 1.43 (9H, s), 1.80-1.93 (1H, m), 2.05-2.21 (1H, m), 3.14-3.35 (3H, m), 3.67-3.82 (1H, m), 4.35-4.46 (1H, m), 5.36 (1H, d, J = 10.8 Hz), 6.05 (1H, d, J = 17.4 Hz), 6.75 (1H, dd, J = 10.8, 17.4 Hz), 6.83-6.89 (1H, m), 7.02-7.19 (3H, m), 7.24 (1H, d, J = 8.6 Hz), 8.09 (1H, s).


 


221
—H
—H
—Cl
—Cl
—H




1H-NMR (CDCl3) δppm: 1.32 (9H, s), 1.75-1.89 (1H, m), 2.08-2.20 (1H, m), 3.07-3.32 (3H, m), 3.67-3.81 (1H, m), 3.97 (3H, s), 4.38-4.46 (1H, m), 6.42 (1H, dd, J = 2.9, 9.0 Hz), 6.66 (1H, d, J = 2.9 Hz), 6.81 (1H, dd, J = 3.1, 8.4 Hz), 7.17 (1H, d, J = 6.8 Hz), 7.30 (1H, dd, J = 2.7, 8.8 Hz), 7.94 (1H, d, 2.3 Hz).


 


222
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δppm: 1.43 (9H, s), 1.80-1.93 (1H, m), 2.15-2.20 (1H, m), 2.29 (3H, s), 3.18-3.39 (3H, m), 3.63-3.77 (1H, m), 4.41 (1H, brs), 6.85- 6.91 (2H, m), 7.03-7.07 (1H, m), 7.11-7.18 (1H, m), 7.73 (1H, brs).


 


223
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δppm: 1.43 (9H, s), 1.78-1.92 (1H, m), 2.09-2.36 (1H, m), 2.55 (3H, s), 3.15-3.32 (3H, m), 3.68-3.99 (1H, m), 5.31-5.52 (1H, m), 6.24 (1H, d, J = 9.2 Hz), 6.96 (1H, d, J = 9.2 Hz), 7.06 (1H, ddd, J = 2.6, 4.2, 8.6 Hz), 7.15-7.27 (1H, m), 7.55-7.59 (1H, m).


 


224
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δppm: 1.43 (9H, s), 1.78-1.97 (1H, m), 2.08-2.36 (1H, m), 3.12-3.32 (3H, m), 3.67-3.96 (1H, m), 4.05 (3H, s), 5.14-5.33 (1H, m), 6.39 (1H, d, J = 9.6 Hz), 6.72 (1H, d, J = 9.6 Hz), 7.07 (1H, ddd, J = 2.6, 4.2, 8.6 Hz), 7.11-7.32 (2H, m).
















TABLE 30













 














Ref. Ex.









No.
R1
R2
R3
R4
R5
R6
NMR





225
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δppm: 1.43 (9H, s), 1.81-1.95 (1H, m), 2.10-2.35 (1H, m), 3.12-3.30 (3H, m), 3.74-3.95 (1H, m), 5.34-5.45 (1H, m), 6.31 (1H, d, J = 9.4 Hz), 7.06-7.10 (2H, m), 7.21-7.33 (2H, m).


 


226
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δppm: 1.43 (9H, s), 1.84-1.99 (1H, m), 2.10-2.29 (1H, m), 3.12-3.38 (3H, m), 3.70-3.76 (1H, m), 4.36-4.45 (1H, m), 7.02 (1H, ddd, J = 2.7, 4.1, 8.6 Hz), 7.20 (1H, dd, J = 2.5, 6.4 Hz), 7.21-7.28 (1H, m), 7.97 (2H, m).


 


227
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δppm: 1.44 (9H, s), 1.80-1.95 (1H, m), 2.04-2.20 (1H, m), 3.20-3.40 (3H, m), 3.70 (6H, s), 3.77-3.88 (1H, m), 5.21-5.30 (1H, m), 5.46 (1H, s), 7.02 (1H, ddd, J = 2.5, 4.3, 8.7 Hz), 7.13-7.19 (1H, m), 7.24 (1H, dd, J = 2.4, 6.6 Hz).


 


228
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δppm: 1.43 (9H, s), 1.70-1.88 (1H, m), 1.97-2.20 (1H, m), 3.07-3.30 (3H, m), 3.72-3.82 (1H, m), 3.83 (3H, s), 3.96 (3H, s), 4.86 (1H, s), 5,37-5.41 (1H, m), 7.05 (1H, ddd, J = 2.6, 4.2, 8.7 Hz), 7.21-7.31 (2H, m).


 


229
—H
—H
—F
—H
—H




1H-NMR (CDCl3) δppm: 1.43 (9H, s), 1.86-1.96 (1H, m), 2.16-2.28 (1H, m), 3.10-3.35 (3H, m), 3.72-3.77 (1H,.m), 4.41-4.51 (1H, m), 7.09-7.17 (4H, m), 8.07 (2H, s), 8.64 (1H, s).


 


230
—H
—H
—F
—CH3
—H




1H-NMR (CDCl3) δppm: 1.43 (9H, s), 1.85-1.97 (1H, m), 2.05-2.28 (1H, m), 2.29 (3H, s), 3.20- 3.35 (3H, m), 3.70-3.78 (1H, m), 4.43-4.47 (1H, m), 6.89-7.97 (2H, m), 7.06-7.13 (1H, m), 8.06 (2H, s), 8.63 (1H, s).


 


231
—H
—H
—Cl
—Cl
—H




1H-NMR (CDCl3) δppm: 1.43 (9H, s), 1.81-1.96 (1H, m), 2.10-2.31 (1H, m), 3.15-3.39 (3H, m), 3.63-3.78 (1H, m), 4.37-4.45 (1H, m), 6.90 (1H, dd, J = 2.5, 8.6 Hz), 7.16 (1H, d, J = 2.4 Hz), 7.51 (1H, d, J = 8.3 Hz), 8.05 (2H, s).


 


232
—H
—H
—F
—H
—H




1H-NMR (CDCl3) δppm: 1.42 (9H, s), 1.78-1.93 (1H, m), 2.10-2.26 (1H, m), 3.09-3.37 (3H, m), 3.63-3.70 (1H, m), 4.37-4.45 (1H, m), 7.07-7.29 (4H, m), 7.92 (2H, s).


 


233
—H
—H
—F
—CH3
—H




1H-NMR (CDCl3) δppm: 1.43 (9H, s), 1.81-1.95 (1H, m), 2,05-2.27 (1H, m), 2.29 (3H, s), 3.19- 3.43 (3H, m), 3.65-3.80 (1H, m), 4.35-4.43 (1H, m), 6.90-6.97 (2H, m), 7.07-7.13 (1H, m), 7.91 (2H, s).
















TABLE 31













 














Ref. Ex.









No.
R1
R2
R3
R4
R5
R6
NMR





234
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δppm: 1.44 (9H, s), 1.74-1.90 (1H, m), 2.08-2.26 (1H, m), 3.09-3.35 (3H, m), 3.78- 3.88 (1H, m), 5.20-5.35 (1H, m), 6.92 (1H, d, J = 4.8 Hz), 7.04 (1H, ddd, J = 2.5, 4.2, 8.7 Hz), 7.20- 7.25 (2H, m), 8.47 (1H, d, J = 4.6 Hz).


 


235
—H
—H
—Cl
—Cl
—H




1H-NMR (CDCl3) δppm: 1.43 (9H, s), 1.77-1.88 (1H, m), 2.05-2.28 (1H, m), 2.52 (3H, s), 3.15-3.33 (3H, m), 3.70-3.90 (1H, m), 5.28-5.43 (1H, m), 5.60 (1H, d, J = 6.0 Hz), 7.03 (1H, dd, J = 2.4, 8.5 Hz), 7.29 (1H, d, J = 2.4 Hz), 7.58 (1H, d, J = 8.3 Hz), 7.90 (1H, d, J = 6.0 Hz).


 


236
—H
—H
—Cl
—Cl
—H




1H-NMR (CDCl3) δppm: 1.44 (9H, s), 1.75-1.88 (1H, m), 2.05-2.20 (1H, m), 3.12-3.36 (3H, m), 3.77- 3.87 (1H, m), 5.24-5.34 (1H, m), 6.62 (1H, brs), 7.02 (1H, dd, J = 2.4, 8.5 Hz), 7.27 (1H, d, J = 2.4 Hz), 7.51 (1H, dd, J = 4.1, 8.4 Hz), 8.32 (2H, brs).


 


237
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δppm: 1.44 (9H, s), 1.87-1.96 (1H, m), 2.04-2.20 (1H, m), 3.15-3.39 (3H, m), 3.61 (3H, s), 3.72-3.84 (1H, m), 4.77-4.86 (1H, m), 6.96 (1H, ddd, J = 2.6, 4.3, 8.7 Hz), 7.06 (1H, dd, J = 2.6, 8.5 Hz), 7.11 (1H, dd, J = 2.6, 6.6 Hz), 7.65 (1H, brs), 7.79 (1H, d, J = 4.4 Hz).


 


238
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δppm: 1.42 (9H, s), 1.90-2.20 (2H, m), 2.00 (3H, s), 2.48 (3H, s), 3.22-3.45 (3H, m), 3.61-3.82 (1H, m), 4.67-4.76 (1H, m), 6.80-6.84 (1H, m), 6.95-7.02 (1H, m), 7.08 (1H, t, J = 8.6 Hz), 8.04 (1H, d, J = 5.2 Hz).


 


239
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δppm: 1.44 (9H, s), 1.78-1.86 (1H, m), 2.05-2.24 (1H, m), 3.08-3.31 (3H, m), 3.80 (1H, dd, J = 7.0, 9.0 Hz), 5.17-5.23 (1H, m), 7.10 (1H, ddd, J = 2.6, 3.9, 8.7 Hz), 7.26-7.32 (3H, m), 7.88 (1H, s).


 


240
—H
—H
—Cl
—Cl
—H




1H-NMR (CDCl3) δppm: 1.44 (9H, s), 1.77-1.87 (1H, m), 2.04-2.21 (1H, m), 3.11-3.35 (3H, m), 3.75- 3.86 (1H, m), 5.14-5.23 (1H, m), 7.07 (1H, dd, J = 2,4, 8,5 Hz), 7.33 (1H, d, J = 2.4 Hz), 7.51 (1H, d, J = 1.1 Hz), 7.58 (1H, dd, J = 3.9, 8.2 Hz), 7.90 (1H, s), 8.09 (1H, s).


 


241
—H
—H
—Cl
—Cl
—H




1H-NMR (CDCl3) δppm: 1.44 (9H, s), 1.73-1.80 (1H, m), 2.01-2.18 (1H, m), 3.03-3.33 (3H, m), 3.81 (1H, dd, J = 6.1, 10.7 Hz), 5.13-5.22 (1H, m), 6.06 (1H, dd, J = 3.4, 9.2 Hz), 7.02 (1H, dd, J = 2.4, 8.4 Hz), 7.06-7.12 (1H, m), 7.28 (1H, d, J = 2.4 Hz), 7.50-7.55 (1H, m), 8.06 (1H, brs).
















TABLE 32













 














Ref. Ex.









No.
R1
R2
R3
R4
R5
R6
NMR





242
—H
—H
—Cl
—Cl
—H




1H-NMR (CDCl3) δppm: 1.43 (9H, s), 1.75-1.84 (1H, m), 2.04-2.18 (1H, m), 3.03-3.33 (3H, m), 3.77-3.85 (1H, m), 5.29-5.38 (1H, m), 5.68 (1H, dd, J = 2.1, 12.0 Hz), 6.38-6.46 (1H, m), 7.03 (1H, dd, J = 2.4, 8.5 Hz), 7.29 (1H, d, J = 2.3 Hz), 7.54-7.59 (1H, m), 8.10- 8.18 (1H, m).


 


243
—H
—H
—Cl
—Cl
—H




1H-NMR (CDCl3) δppm: 1.43 (9H, s), 1.72-1.86 (1H, m), 2.04-2.22 (1H, m), 3.08-3.33 (3H, m), 3.83 (1H, dd, J = 7.1, 10.8 Hz), 5.28-5.37 (1H, m), 6.04 (1H, d, J = 8.6 Hz), 6.63-6.68 (1H, m), 7.03 (1H, dd, J = 2.4, 8.5 Hz), 7.27-7.35 (2H, m), 7.51-7.56 (1H, m), 8.17-8.22 (1H, m).


 


244
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δppm: 1.44 (9H, s), 1.73-1.90 (1H, m), 2.05-2.22 (1H, m), 3.08-3.34 (3H, m), 3.82 (1H, dd, J = 7.2, 10.7 Hz), 5.16-5.25 (1H, m), 7.08-7.14 (1H, m), 7.27-7.33 (2H, m), 7.49 (1H, s), 7.89 (1H, brs), 8.09 (1H, brs).


 


245
—H
—H
—Cl
—Cl
—H




1H-NMR (CDCl3) δppm: 1.44 (9H, s), 1.76-1.89 (1H, m), 2.05-2.28 (1H, m), 3.10-3.35 (3H, m), 3.77-3.87 (1H, m), 5.14-5.25 (1H, m), 7.08 (1H, dd, J = 2.4, 8.5 Hz), 7.34 (1H, d, J = 2.3 Hz), 7.52 (1H, s), 7.59 (1H, dd, J = 4.0, 8.2 Hz), 8.10 (1H, brs), 8.66 (1H, brs).


 


246
—H
—H
—Cl
—Cl
—H




1H-NMR (CDCl3) δppm: 1.44 (9H, s), 1.75-1.86 (1H, m), 2.09-2.28 (1H, m), 3.12-3.34 (3H, m), 3.80 (1H, dd, 7.1, 10.0 Hz), 5.13-5.24 (1H, m), 7.07 (1H, dd, J = 2.4, 8.5 Hz), 7.32-7.34 (2H, m), 7.59 (1H, d, J = 8.0 Hz), 8.49 (1H, s).


 


247
—H
—H
—Cl
—Cl
—H




1H-NMR (CDCl3) δppm: 1.43 (9H, s), 1.82-1.95 (1H, m), 2.09-2.25 (1H, m), 3.13-3.37 (3H, m), 3.70-3.80 (1H, m), 4.41-4.50 (1H, m), 6.86 (1H, dd, J = 2.5, 8.6 Hz), 7.13 (1H, d, J = 2.5 Hz), 7.48 (1H, d, J = 8.8 Hz), 8.22 (2H, s), 8.82 (1H, s).


 


248
—H
—H
—Cl
—Cl
—H




1H-NMR (CDCl3) δppm: 1.44 (9H, s), 1.74-1.88 (1H, m), 2.05-2.20 (1H, m), 3.10-3.38 (3H, m), 3.77-3.87 (1H, m), 5.22-5.34 (1H, m), 6.63 (1H, brs), 7.02 (1H, dd, J = 2.4, 8.5 Hz), 7.28 (1H, d, J = 2.4 Hz), 7.51 (1H, dd, J = 4.3, 8.4 Hz), 8.32 (2H, brs).


 


249
—H
—H
—Cl
—Cl
—H




1H-NMR (CDCl3) δppm: 1.43 (9H, s), 1.79-1.90 (1H, m), 2.04-2.27 (1H, m), 3.14-3.36 (3H, m), 3.67-3.80 (1H, m), 4.36-4.45 (1H, m), 6.89 (1H, dd, J = 2.5, 8.5 Hz), 7.16 (1H, d, J = 2.3 Hz), 7.51 (1H, d, J = 8.4 Hz), 8.05 (1H, brs).


 


250
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δppm: 1.43 (9H, s), .1.80-1.98 (1H, m), 2.11-2.28 (1H, m), 3.15-3.39 (3H, m), 3.68-3.78 (1H, m), 4.36-4.45 (1H, m), 6.99-7.05 (1H, m), 7.18- 7.27 (2H, m), 7.97 (2H, s).
















TABLE 33













 














Ref. Ex.









No.
R1
R2
R3
R4
R5
R6
NMR





251
—H
—H
—F
—F
—H




1H-NMR (CDCl3) δppm: 1.43(9H, s), 1.79-1.97(1H, m), 2.01-2.22(1H, m), 3.08-3.38(3H, m), 3.60-3.78 (1H, m), 4.25-4.41(1H, m), 6.42-6.62(2H, m), 6.66(1H, dd, J = 1.5, 5.0 Hz), 6.78(1H, dd, J = 1.5, 3.0 Hz), 6.91-7.07(1H, m), 7.30 (1H, d, J = 3.0 Hz)


 


252
—H
—H
—Cl
—CH3
—H




1H-NMR (CDCl3) δppm: 1.43 (9H, s), 1.78-1.97 (1H, m), 2.03-2.20 (1H, m), 2.29 (3H, s), 3.18-3.38 (3H, m), 3.61- 3.82 (1H, m), 4.34-4.43 (1H, m), 6.54-6.73 (4H, m), 7.11- 7.30 (2H, m).


 


253
—H
—Cl
—H
—Cl
—H




1H-NMR (CDCl3) δppm: 1.44 (9H, s), 1.78-1.94 (1H, m), 2.04-2.20 (1H, m), 3.13-3.34 (3H, m), 3.67-3.80 (1H, m), 4.29-4.45 (1H, m), 6.48 (2H, d, J = 1.7 Hz), 6.72-6.83 (2H, m), 7.04 (1H, dd, J = 3.1, 1.7 Hz), 7.37-7.42 (1H, m).


 


254
—H
—H
—F
—H
—H




1H-NMR (CDCl3) δppm: 1.43 (9H, s), 1.82-2.00 (1H, m), 2.01-2.23 (1H, m), 3.10-3.40 (3H, m), 3.61-3.79 (1H, m), 4.26-4.42 (1H, m), 6.41-6.44 (1H, m), 6.50 (1H, dd, J = 1.5, 5.0 Hz), 6.89-7.02 (4H, m), 7.18 (1 h, brs)


 


255
—H
—H
—Cl
—Cl
—H




1H-NMR (CDCl3) δppm: 1.43 (9H, s), 1.81-1.98 (1H, m), 2.05-2.24 (1H, m), 3.12-3.38 (3H, m), 3.63-3.82 (1H, m), 4.30-4.46 (1H, m), 6.50 (1H, dd, J = 3.0, 9.0 Hz), 6.72-6.76 (2H, m), 6.96 (1H, dd, J = 1.5, 3.0 Hz), 7.20 (1H, brd, J = 9.5 Hz), 7.36 (1H, brs)


 


256
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δppm: 1.27-1.52 (11H, m), 1.62-1.82 (3H, m), 1.90-2.05 (1H, m), 2.95-3.69 (7H, m), 3.85-4.05 (3H, m), 6.95-7.00 (1H, m), 7.00-7.16 (2H, m).


 


257
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δppm: 1.15-1.35 (2H, m), 1.46 (9H, s), 1.52-1.73 (3H, m), 1.76-2.05 (2H, m), 2.91 (2H, d, J = 6.7 Hz), 3.08-3.35 (4H, m), 3.35-3.65 (2H, m), 3.80-4.00 (3H, m), 6.76-6.88 (1H, m), 6.95-7.10 (2H, m).


 


258
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δppm: 1.42 (9H, s), 1.8-1.95 (1H, m), 2.1-2.25 (1H, m), 3.15-3.35 (3H, m), 3.65-3.85 (1H, m), 4.45-4.6 (1H, m), 6.7-6.8 (1H, m), 6.9-7.0 (2H, m), 7.0- 7.1 (1H, m), 7.21 (1H, s), 7.31 (1H, d, J = 1.7 Hz), 7.65- 7.8 (1H, m).


 


259
—H
—H
—H
—H
—H




1H-NMR (CDCl3) δppm: 1.42 (9H, s), 1.8-1.95 (1H, m), 2.1-2.25 (1H, m), 3.15-3.35 (3H, m), 3.65-3.9 (1H, m), 4.45-4.6 (1H, m), 6.85-7.0 (3H, m), 7.05-7.2 (2H, m), 7.25-7.4 (3H, m), 7.6-7.75 (1H, m).


 


260
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δppm: 1.42 (9H, s), 1.8-2.0 (1H, m), 2.1-2.3 (1H, m), 3.15-3.4 (3H, m), 3.65-3.85 (1H, m), 4.4-4.6 (1H, m), 6.65-6.75 (1H, m), 6.86 (1H, dd, J = 2.9, 6.3 Hz), 6.95 (1H, dd, J = 2.2, 8.6 Hz), 6.95-7.1 (1H, m), 7.35 (1H, s), 7.42 (1H, d, J = 2.1 Hz), 7.74 (1H, d, J = 8.6 Hz).
















TABLE 34













 














Ref. Ex.









No.
R1
R2
R3
R4
R5
R6
NMR





261
—H
—H
—H
—H
—H




1H-NMR (CDCl3) δppm: 1.41 (9H, s), 1.8-2.0 (1H, m), 2.05-2.3 (1H, m), 3.15-3.4 (3H, m), 3.7-3.9 (1H, m), 4.5-4.7 (1H, m), 6.8-6.9 (2H, m), 6.9-7.1 (2H, m), 7.2-7.35 (3H, m), 7.42 (1H, d, J = 2.1 Hz), 7.65-7.75 (1H, m).


 


262
—H
—H
—F
—H
—H




1H-NMR (CDCl3) δppm: 1.42 (9H, s), 1.8-2.0 (1H, m), 2.05-2.3 (1H, m), 3.15-3.4 (3H, m), 3.7-3.85 (1H, m), 4.45-4.6 (1H, m), 6.80 (1H, dd, J = 2.3, 8.8 Hz), 6.9-7.1 (4H, m), 7.2-7.35 (2H, m), 7.62 (1H, d, J = 8.6 Hz).


 


263
—H
—H
—F
—H
—H




1H-NMR (CDCl3) δppm: 1.43 (9H, s), 1.8-1.95 (1H, m), 2.05-2.25 (1H, m), 3.1-3.4 (3H, m), 3.65-3.9 (1H, m), 4.4-4.6 (1H, m), 6.82 (1H, dd, J = 2.0, 8.8 Hz), 6.95-7.2 (6H, m), 7.55-7.7 (1H, m).


 


264
—H
—H
—H
—H
—H




1H-NMR (CDCl3) δppm: 1.41 (9H, s), 1.8-1.95 (1H, m), 2.05-2.25 (1H, m), 2.42 (3H, d, J = 0.6 Hz), 3.15-3.35 (3H, m), 3.7-3.9 (1H, m), 4.45-4.65 (1H, m), 6.75-6.85 (2H, m), 6.9-7.05 (3H, m), 7.15-7.3 (2H, m), 7.45 (1H, d, J = 1.9 Hz), 7.63 (1H, dd, J = 3.9, 8.5 Hz).


 


265
—H
—H
—H
—H
—H




1H-NMR (CDCl3) δppm: 1.40 (9H, d, J = 2.9 Hz), 1.8- 1.95 (1H, m), 2.05-2.25 (1H, m), 2.39 (3H, d, J = 0.8 Hz), 3.15-3.35 (3H, m), 3.7-3.9 (1H, m), 4.45- 4.65 (1H, m), 6.65-6.75 (2H, m), 6.8-6.9 (1H, m), 7.01 (1H, dd, J = 1.8, 8.5 Hz), 7.11 (1H, bs), 7.15- 7.3 (2H, m), 7.39 (1H, d, J = 1.9 Hz), 7.81 (1H, dd, J = 3.6, 8.4 Hz).


 


266
—H
—H
—H
—H
—H




1H-NMR (CDCl3) δppm: 1.42 (9H, s), 1.8-1.95 (1H, m), 2.05-2.25 (1H, m), 3.15-3.35 (3H, m), 3.7-3.9 (1H, m), 4.45-4.6 (1H, m), 6.87 (1H, d, J = 1.9 Hz), 6.93 (2H, dd, J = 1.0, 8.5 Hz), 7.05-7.15 (1H, m), 7.23 (1H, s), 7.25-7.4 (4H, m).


 


267
—H
—H
—H
—H
—H




1H-NMR (CDCl3) δppm: 1.41 (9H, s), 1.75-1.95 (1H, m), 2.0-2.2 (1H, m), 2.57 (3H, s), 3.15-3.35 (3H, m), 3.7-3.9 (1H, m), 4.45-4.6 (1H, m), 6.75 (2H, d, J = 7.8 Hz), 6.8-7.0 (3H, m), 7.15-7.3 (2H, m), 7.39 (1H, d, J = 1.7 Hz), 7.58 (1H, dd, J = 3.8, 8.2 Hz).


 


268
—H
—H
—F
—H
—H




1H-NMR (CDCl3) δppm: 1.42 (9H, s), 1.75-1.95 (1H, m), 2.0-2.2 (1H, m), 2.55 (3H, d, J = 1.0 Hz), 3.15- 3.35 (3H, m), 3.657-3.85 (1H, m), 4.35-4.55 (1H, m), 6.75-6.9 (4H, m), 6.9-7.05 (2H, m), 7.26 (1H, s), 7.51 (1H, d, J = 8.6 Hz).
















TABLE 35













 














Ref. Ex.









No.
R1
R2
R3
R4
R5
R6
NMR





269
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δppm: 1.44 (9H, s), 1.8-1.95 (1H, m), 2.1-2.3 (1H, m), 3.15-3.4 (3H, m), 3.7- 3.9 (1H, m), 4.45-4.6 (1H, m), 6.71 (1H, dd, J = 2.1, 8.9 Hz), 6.9-7.05 (1H, m), 7.1-7.3 (3H, m), 7.81 (1H, d, J = 8.8 Hz), 8.72 (1H, s).


 


270
—H
—H
—H
—H
—H




1H-NMR (CDCl3) δppm: 1.43 (9H, s), 1.8-2.0 (1H, m), 2.1-2.25 (1H, m), 3.15-3.35 (3H, m), 3.75- 3.95 (1H, m), 4.5-4.65 (1H, m), 6.69 (1H, dd, J = 2.2, 8.9 Hz), 7.05-7.15 (3H, m), 7.3-7.4 (1H, m), 7.4-7.5 (2H, m), 7.76 (1H, d, J = 7.7 Hz), 8.68 (1H, bs).


 


271
—H
—H
—F
—H
—H




1H-NMR (CDCl3) δppm: 1.43 (9H, s), 1.8-1.95 (1H, m), 2.1-2.3 (1H, m), 3.1-3.35 (3H, m), 33- 3.9 (1H, m), 4.5-4.65 (1H, m), 6.65 (1H, dd, J = 2.2, 9.0 Hz), 7.05-7.2 (5H, m), 7.75 (1H, d, J = 8.3 Hz), 8.67(1H, s).


 


272
—H
—H
—H
—H
—H




1H-NMR (CDCl3)δppm: 1.43 (9H, s), 1.7-1.9 (1H, m), 2.05-2.25 (1H, m), 3.1-3.35 (3H, m), 3.8-3.95 (1H, m), 5.4-5.55 (1H, m), 6.03 (1H, d, J = 8.9 Hz), 7.0-7.05 (1H, m), 7.05-7.1 (1H, m), 7.1- 7.2 (2H, m), 7.35-7.55 (3H, m), 7.58 (1H, d, J = 8.9 Hz).


 


273
—H
—H
—F
—H
—H




1H-NMR (CDCl3) δppm: 1.43 (9H, s), 1.7-1.9 (1H, m), 2.05-2.25 (1H, m), 3.05-3.35 (3H, m), 3.8- 3.95 (1H, m), 5.4-5.55 (1H, m), 6.02 (1H, d, J = 8.9 Hz), 7.0-7.2 (6H, m), 7.60 (1H, d, J = 8.8 Hz).


 


274
—H
—H
—H
—H
—H




1H-NMR (CDCl3) δppm: 1.43 (9H, s), 1.7-1.9 (1H, m), 2.05-2.25 (1H, m), 3.1-3.35 (3H, m), 3.8-3.95 (1H, m), 5.4-5.55 (1H, m), 6.06 (1H, d, J = 9.0 Hz), 7.15-7.2 (2H, m), 7.3-7.55 (4H, m), 7.55- 7.65 (1H, m), 7.67 (1H, d, J = 10.0 Hz).□


 


275
—H
—H
—F
—Cl
—H




1H-NMR(CDCl3) δppm; 1.43(9H, s), 1.85-2.00(1H, m), 2.08-2.26(1H, m), 3.16-3.40(3H, m), 3.68-3.90 (1H, m), 4.50-4.61(1H, m), 6.88-6.96(1H, m), 7.05- 7.20(4H, m), 7.35(1H, dd, J = 4.2, 8.3 Hz), 7.88- 8.05(2H, m), 8.76 (1H, d, J = 2.9 Hz)


 


276
—H
—H
—F
—CH3
—H




1H-NMR (CDCl3) δppm: 1.43 (9H, s), 1.75- 1.88(1H, m), 2.12 (1H, br), 2.28 (3H, s), 2.85 (2H, t, J = 6,6 Hz), 3.10 (3H, s), 3.19-3.28 (3H, m), 3.48 (2H, t, J = 6.6 Hz), 3.69-3.83 (1H, m), 4.49-4.55 (1H, m), 6.22 (1H, d, J = 12.3 Hz), 6.49 (1H, dd, J = 8.1, 8.6 Hz), 6.87-6.95 (2H, m), 7,03- 7.09 (1H, m), 7.87 (1H, dd, J = 8.7, 8.7 Hz).


 


277
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δppm: 1.41 (9H, s), 1.83-1.95 (1H, m), 2.15 (1H, br), 3.22-3.34 (3H, m), 3.69- 3.85 (1H, m), 4.06 (3H, s), 4.47 (1H, br), 6.65- 6.70 (1H, m), 6.85 (1H, dd, J = 2.8, 6.3 Hz), 6.90 (1H, d, J = 8.8 Hz), 6.99-7.05 (1H, m), 7.17 (1H, dd, J = 2.5, 8.9 Hz), 7.26-7.27 (1H, m), 7.77-7.90 (2H, m).
















TABLE 36













 














Ref. Ex.









No.
R1
R2
R3
R4
R5
R6
NMR





278
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δppm: 1.43(9H, s), 1.78- 1.90 (1H, m), 2.04-2.17 (1H, m), 2.66 (2H, dd, J = 6.7, 7.7 Hz), 2.86 (2H, dd, J = 6.7, 7.7 Hz), 3.19-3.29 (3H, m), 3.36 (3H, s), 3.66- 3.78 (1H, m), 4.35-4.41 (1H, m), 6.60 (1H, ddd, J = 3.0, 3.8, 9.0 Hz), 6.75-6.78 (2H, m), 6.86 (1H, dd, J = 1.9, 8.6 Hz), 6.93-7.02 (2H, m).


 


279
—H
—H
—F
—H
—H




1H-NMR (CDCl3) δppm: 1.43 (9H, s), 1.78- 1.91 (1H, m), 2.05-2.17 (1H, m), 2.62 (2H, dd, J = 6.1, 8.3 Hz), 2.82 (2H, dd, J = 6.1, 8.3 Hz), 3.26 (3H, br , 3.33 (3H, s), 3.69-3.79 (1H, m), 4.41 (1H, br), 6.62 (1H, br), 6.72 (1H, dd, J = 2.5, 8.7 Hz), 6.84-6.91 (3H, m), 6.93-7.03 (2H, m).


 


280
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δppm: 1.41 (9H, s), 1.81- 1.93 (1H, m), 2.13-2.18 (1H, m), 3.24-3.31 (3H, m), 3.67-3.81 (1H, m), 3.72 (3H, s), 4.41-4.45 (1H, m), 6.62-6.67 (1H, m), 6.73 (1H, d, J = 9.4 Hz), 6.81 (1H, dd, J = 2.7, 6.2 Hz), 6.82-7.05 (1H, m), 7.14-7.18 (2H, m), 7.27-7.32 (1H, m), 7.59 (1H, d, J = 9.4 Hz).


 


281
—H
—H
—CH3
—F
—H




1H-NMR (CDCl3) δppm: 1.43(9H, s), 1.78- 1.91 (1H, m), 2.08-2.18 (1H, m), 2.18 (3H, s), 2.66 (2H, dd, J = 6.6, 7.6, Hz), 2.86 (2H, dd, J = 6.6, 7.6 Hz), 3.18-3.27 (3H, m), 3.36 (3H, s), 3.68-3.78 (1H, m), 4.38-4.44 (1H, m), 6.36-6.43 (2H, m), 6.79 (1H, d, J = 2.2 Hz), 6.87-7.02 (3H, m).


 


282
—H
—H
—CH3
—F
—H




1H-NMR (CDCl3) δppm: 1.41 (9H, s), 1.60- 1.72 (1H, m), 2.15 (1H, br), 2.20 (3H, s), 3.24-3.32 (3H, m), 3.72 (3FI, s), 3.75-3.81 (1H, m), 4.46 (1H, br), 6.40-6.45 (2H, m), 6.72 (1H, d, J = 9.5 Hz), 7.02 (1H, br), 7.18- 7.21 (2H, m), 7.31-7.34 (1H, m), 7.58 (1H, dd, J = 2.9, 9.4 Hz).


 


283
—H
—H
—F
—CH3
—H




1H-NMR (CDCl3) δppm. 1.43 (9H s), 1.78- 1.90 (1H, m), 2.02-2.13 (1H, m), 2.24 (3H, s), 2.62 (2H, dd, J = 5.4,(8.0, Hz), 2.79-2.84 (2H, m), 3.19-3.29 (3H, m), 3.32 (3H, s), 3.98-3.79 (1H, m), 4.35-4.46 (1H, m), 6.58 (1H, br), 6.70-6.76 (3H, m), 6.84-6.99 (2H, m).


 


284
—H
—H
—F
—CH3
—H




1H-NMR (CDCl3) δppm: 1.42 (9H, s), 1.80- 1.92 (1H, m), 2.08-2.18 (1H, m), 2.24 (3H, s), 3.24-3.31 (3H, m), 3.69 (3H, s), 3.75-3.81 (1H, m), 4.44 (1H, br), 6.69 (1H, d, J = 9.4 Hz), 6.74-6.79 (2H, m), 6.96-7.01 (3H, m), 7.21-6.79 (1H, m), 7.55 (1H, d, J = 9.4 Hz).
















TABLE 37













 














Ref. Ex.









No.
R1
R2
R3
R4
R5
R6
NMR





285
—H
—H
—F
—Cl
—H




1H-NMR (CDCl3) δppm: 1.42 (9H, s), 1.77-1.82 (1H, m), 2.06-2.10 (1H, m), 2.72-2.80 (2H, m), 2.86-2.91 (2H, m), 3.15-3.27 (3H, m), 3.64- 3.73 (1H, m), 3.78 (3H, s), 4.34 (1H, br), 5.09 (2H, br), 6.53-6.89 (7H, m), 6.97-7.00 (1H, m), 7.14-7.17 (2H, m).


 


286
—H
—H
—F
—H
—H




1H-NMR (CDCl3) δppm: 1.42 (9H, s), 1.61-1.73 (1H, m), 1.90-2.00 (1H, m), 2.74 (2H, dd, J = 5.8, 7.9 Hz), 2.87 (2H, dd, J = 5.8, 7.9 Hz), 3.10- 3.23 (3H, m), 3.56-3.68 (1H, m), 3.77 (3H, s), 4.23-4.28 (1H, m), 4.81 (1H, d, J = 15.5 Hz), 5.02 (1H, d, J = 15.5 Hz), 6.12 (1H, d, J = .2.3 Hz), 6.37 (1H, d, J = 8.4 Hz), 6.72-6.99 (9H, m).


 


287
—H
—H
—CH3
—F
—H




1H-NMR (CDCl3) δppm: 1.42 (9H s), 1.76-1.86 (1H, m), 2.04-2.11 (1H, m), 2.18 (3H, s), 2.75-2.79 (2H, m), 2.88- 2.93 (2H, m), 3.13-3.25 (3H, m), 3.66-3.76 (1H, m), 3.78 (3H, s), 4.34- 4.38 (1H, m), 5.09 (2H, s), 6.36 (2H, m), 6.70-6.74 (2H, m), 6.83-6.91 (3H, m), 6.99 (1H, br), 7.17 (1H, d, J = 8.6 Hz).


 


288
—H
—H
—F
—CH3
—H




1H-NMR (CDCl3) δppm: 1.42 (9H, s), 1.76-1.85 (1H, m), 2.01-2.09 (1H, m), 2.22 (3H, s), 2.71-2.75 (2H, m), 2.84-2.88 (2H, m), 3.13-3.28 (3H, m), 3.63-3.75 (1H, m), 3.77 (3H, s), 4.33-4.37 (1H, m), 5.06 (2H, s), 6.47- 6.53 (2H, m), 6.69-6.85 (5H, m), 6.91-6.95 (1H, m), 7.14 (2H, d, J = 8.5 Hz).
















TABLE 38













 










Ref. Ex.





No.
R1
R6
NMR





289








1H-NMR (CDCl3) δppm: 1.41 (9H, s), 1.8-2.0 (1H, m), 2.1- 2.3 (1H, m), 3.15-3.4 (3H, m), 3.7-3.9 (1H, m), 4.45-4.6 (1H, m), 7.0-7.1 (2H, m), 7.1-7.2 (1H, m), 7.28 (1H, s), 7.45 (1H, d, J = 1.6 Hz), 7.75-7.8 (1H, m), 8.1-8.3 (2H, m).


 


290








1H-NMR (CDCl3) δppm: 1.42 (9H, s), 1.8-2.0 (1H, m), 2.1- 2.3 (1H, m), 3.15-3.4 (3H, m), 3.7-3.9 (1H, m), 4.5-4.7 (1H, m), 6.78 (1H, dd, J = 2.0, 8.9 Hz), 7.28 (1H, s), 7.3-7.4 (2H, m), 7.86 (1H, d, J = 9.4 Hz), 8.37 (1H, s), 8.45-8.55 (1H, m), 8.75 (1H, s).


 


291








1H-NMR (CDCl3) δppm: 1.40 (9H, s), 1.8-2.0 (1H, m), 2.1- 2.3 (1H, m), 3.15-3.4 (3H, m), 3.7-3.9 (1H, m), 4.5-4.65 (1H, m), 6.95-7.2 (3H, m), 7.38 (1H, s), 7.53 (1H, d, J = 2.0 Hz), 7.75-7.9 (1H, m), 8.05-8.2 (2H, m).


 


292








1H-NMR (CDCl3) δppm: 1.40 (9H, s), 1.8-2.0 (1H, m), 2.1- 2.3 (1H, m), 3.1-3.4 (3H, m), 3.7-3.9 (1H, m), 4.45-4.6 (1H, m), 6.45-6.6 (1H, m), 7.09 (1H, dd, J = 1.9, 8.4 Hz), 7.38 (1H, d, J = 5.4 Hz), 7.54 (1H, d, J = 5.4 Hz), 7.65 (1H, d, J = 1.7 Hz), 7.8-7.95 (3H, m).


 


293








1H-NMR (CDCl3) δppm: 1.42 (9H, s), 1.8-2.0 (1H, m), 2.1- 2.3 (1H, m), 3.1-3.4 (3H, m), 3.7-3.9 (1H, m), 4.45-4.6 (1H, m), 6.45-6.6 (1H, m), 7.07 (1H, dd, J = 2.0, 8.4 Hz), 7.3-7.4 (1H, m), 7.55 (1H, d, J = 5.4 Hz), 7.59 (1H, d, J = 2.0 Hz), 7.8-7.9 (2H, m), 7.96 (1H, d, J = 5.4 Hz).


 


294








1H-NMR (CDCl3) δppm: 1.40 (9H, s), 1.8-2.0 (1H, m), 2.1- 2.3 (1H, m), 3.1-3.4 (3H, m), 3.7-3.9 (1H, m), 4.45-4.6 (1H, (m, 6.5-6.65 (1H, m), 7.18 (1H, dd, J = 1.9, 8.5 Hz), 7.40 (1H, s), 7.59 (1H, d, J = 1.7 Hz), 7.8-8.0 (3H, m).









Example 1
Synthesis of (3,4-dichlorophenyl)phenylpyrrolidin-3-ylamine dihydrochloride
An acetic acid solution (15 ml) containing 3-oxopyrrolidine-1-carboxylic acid tert-butyl ester (0.67 g) and (3,4-dichlorophenyl)phenylamine (0.94 g) was stirred at room temperature over night. To the mixture was added 1.5 g of sodium triacetoxyborohydride, followed by stirring at room temperature for 8 hours. Dichloromethane was added to the reaction solution and washed with water, followed by drying over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was then purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1). The solvent was distilled off from the purified product under reduced pressure, and the residue was dissolved in 1 N hydrochloric acid-ethanol and heated under reflux for one hour. The reaction solution was concentrated to dryness to thereby obtain 50 mg of brown amorphous solid (3,4-dichlorophenyl)phenylpyrrolidin-3-ylamine dihydrochloride.
1H-NMR (DMSO-d6) δ ppm:
1.50-1.68 (1H, m), 2.10-2.29 (1H, m), 2.74-2.90 (1H, m), 3.02-3.22 (2H, m), 3.51-3.66 (1H, m), 4.61-4.79 (1H, m), 6.58 (1H, dd, J=2.9 Hz, J=9.0 Hz), 6.87 (1H, d, J=2.9 Hz), 7.13-7.19 (2H, m), 7.29-7.44 (2H, m), 7.45-7.54 (2H, m), 9.03 (2H, brs).
Example 2
Synthesis of (S)-(3,4-dichlorophenyl)phenylpyrrolidin-3-ylamine.dihydrochloride
3(S)-[(3,4-dichlorophenyl)phenylamino]pyrrolidine-1-carboxylic acid tert-butyl ester (0.13 g) was dissolved in 1 N hydrochloric acid-ethanol and heated under reflux for one hour. The reaction solution was concentrated to dryness to thereby obtain 0.11 g of brown amorphous solid 3(S)-(3,4-dichlorophenyl)phenylpyrrolidin-3-ylamine hydrochloride.
1H-NMR (DMSO-d6) δ ppm:
1.50-1.68 (1H, m), 2.10-2.29 (1H, m), 2.75-2.90 (1H, m), 3.02-3.23 (2H, m), 3.51-3.65 (1H, m), 4.60-4.80 (1H, m), 6.58 (1H, dd, J=2.9 Hz, J=9.0 Hz), 6.87 (1H, d, J=2.9 Hz), 7.12-7.19 (2H, m), 7.29-7.44 (2H, m), 7.45-7.54 (2H, m), 9.05 (2H, brs).
Example 3
Synthesis of (3-fluorophenyl)-(S)-pyrrolidin-3-yl-(4-trifluoromethylphenyl)amine difumarate
To a 1,2-dichloromethane solution (1 ml) containing ((S)-1-benzylpyrrolidin-3-yl)-(3-fluorophenyl)-(4-trifluoromethylphenyl)amine (0.48 g, 1.1 mmol) was added 1-chloroethyl chloroformate (0.82 g, 5.8 mmol). The mixture was stirred at room temperature for 15 hours and heated under reflux for 3 hours. The solvent was distilled off under reduced pressure, and 5 ml methanol was then added to the residue and heated under reflux for 3 hours. After distilling the solvent off under reduced pressure, the residue was then dissolved in dichloromethane and washed with an aqueous saturated sodium hydrogencarbonate solution. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in ethanol, fumaric acid (128 mg, 1.1 mmol) was then added thereto, giving a uniform solution. The solvent was distilled off under reduced pressure, and the crystals produced by adding dichloromethane to the residue were separated by filtration and dried, giving 0.24 g of light brown powdery (3-fluorophenyl)-(S)-pyrrolidin-3-yl-(4-trifluoromethylphenyl)amine difumarate.
Melting point 144.0-146.2° C.
Example 4
Synthesis of (3-chloro-4-fluorophenyl)-(4-methanesulfonylphenyl)-(S)-pyrrolidin-3-ylamine hydrochloride
3(S)-[(3-chloro-4-fluorophenyl)-(4-methanesulfonylphenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (0.42 g, 0.9 mmol) was added to 4 N hydrochloric acid/ethyl acetate, followed by stirring at room temperature for one hour. The reaction solution was concentrated to dryness under reduced pressure to thereby obtain 0.35 g of white powdery (3-chloro-4-fluorophenyl)-(4-methanesulfonylphenyl)-(S)-pyrrolidin-3-ylamine hydrochloride.
1H-NMR (DMSO-d6) δ ppm:
1.56-1.68 (1H, m), 2.19-2.29 (1H, m), 2.82-2.94 (1H, m), 3.08 (3H, s), 3.10-3.20 (2H, m), 3.57-3.68 (1H, m), 4.70-4.85 (1H, m), 6.69-6.75 (2H, m), 7.32-7.37 (1H, m), 7.58-7.64 (1H, m), 7.65-7.69 (3H, m), 9.10-9.45 (2H, m).
Example 5
Synthesis of (3-chloro-4-fluorophenyl)-[4-(pyridin-2-yloxy)butyl]-(S)-pyrrolidin-3-ylamine difumarate
To a toluene solution (4 ml) containing 3(S)-[4-(pyridin-2-yloxy)butylamino]pyrrolidine-1-carboxylic acid tert-butyl ester (0.2 g, 0.6 mmol) and 4-bromo-2-chloro-1-fluorobenzene (0.8 ml, 0.65 mmol) were added tri-tert-butylphosphine.tetrafluoroborate (14 mg, 0.05 mmol), tris(dibenzylideneacetone)dipalladium (11 mg, 0.012 mmol) and sodium tert-butoxide (110 mg, 1.2 mmol) and heated under reflux under a nitrogen atmosphere for 12 hours. After cooling to room temperature, water was added to the reaction solution, and extraction with ethyl acetate was conducted. The extract was dried over magnesium sulfate and concentrated under reduced pressure, and the residue was then purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1). The solvent was distilled off from the purified product under reduced pressure. The residue was dissolved in 0.4 ml dichloromethane, and trifluoroacetic acid (0.06 ml, 0.8 mmol) was added thereto, followed by stirring at room temperature for 3 hours. After concentrating under reduced pressure, the residue was purified by HPLC. After collecting objective fractions, the solvent was distilled off under reduced pressure, and 10% aqueous potassium carbonate solution was added to the residue, followed by extraction with dichloromethane. The extract was dried over magnesium sulfate and concentrated under reduced pressure, and an ethanol solution containing fumaric acid (8.1 mg) was added to the residue (ethanol solution) to thereby obtain a uniform solution. After concentration under reduced pressure, water (3 ml) was added to the residue, followed by freeze-drying to thereby obtain 19 mg of white solid (3-chloro-4-fluorophenyl)-[4-(pyridin-2-yloxy)butyl]-(S)-pyrrolidin-3-ylamine difumarate.
1H-NMR (DMSO-d6) δ ppm:
1.45-1.55 (2H, m), 1.65-1.8 (2H, m), 1.8-1.95 (1H, m), 2.05-2.15 (1H, m), 2.6-4.05 (11H, m), 4.25 (2H, t, J=6.5 Hz), 4.3-4.4 (1H, m), 6.55 (4H, s), 6.77 (1H, d, J=8.5 Hz), 6.8-6.9 (1H, m), 6.9-7.0 (1H, m), 7.03 (1H, dd, J=3 Hz, J=6.5 Hz), 7.22 (1H, dd, J=9 Hz, J=9 Hz), 7.65-7.7 (1H, m), 8.1-8.15 (1H, m).
Example 6
Synthesis of (3-chloro-4-fluorophenyl)-(3-methylsulfanylpropyl)-(S)-pyrrolidin-3-ylamine hydrochloride
An acetic acid solution (3 ml) containing 3(S)-[(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (0.60 g, 1.9 mmol) and 3-methylthiopropionic aldehyde (0.6 g, 5.7 mmol) was stirred at room temperature over night. Sodium triacetoxy borohydride (0.81 g, 3.8 mmol) was added to the mixture, followed by stirring at room temperature for 15 hours. Dichloromethane was added to the reaction solution, and the reaction solution was washed with water and an aqueous saturated sodium hydrogencarbonate solution, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was then dissolved in 1 N hydrochloric acid-ethanol (10 ml) and heated under reflux for one hour. The reaction solution was concentrated to dryness to thereby obtain 0.16 g of yellow amorphous solid (3-chloro-4-fluorophenyl)-(3-methylsulfanyl propyl)-(S)-pyrrolidin-3-ylamine hydrochloride.
1H-NMR (DMSO-d6) δ ppm:
1.52-1.70 (2H, m), 1.80-2.18 (including 5H, m [2.07 ppm(s)]), 2.40-2.51 (2H, m), 2.84-3.49 (6H, m), 4.29-4.49 (1H, m), 6.85-6.95 (1H, m), 7.05-7.35 (2H, m), 9.30-9.79 (2H, m).
Example 7
Synthesis of (3-chloro-4-fluorophenyl)pyridin-3-yl-(S)-pyrrolidin-3-ylamine dimethanesulfonate
To a dichloromethane solution (100 ml) containing 3(S)-[(3-chloro-4-fluorophenyl)pyridin-3-ylamino]pyrrolidine-1-carboxylic acid tert-butyl ester (16.0 g, 41 mmol) was added trifluoroacetic acid (20 ml), followed by stirring at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and an aqueous saturated sodium hydrogencarbonate solution was added to the residue to make the residue alkaline, followed by extraction with dichloromethane. The extract was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by basic silica gel column chromatography (dichloromethane:methanol=10:1). The solvent was distilled off from the purified product under reduced pressure. To an ethanol solution containing the residue was added methanesulfonic acid (9.2 g), and the solvent was then distilled off under reduced pressure. The residue was recrystallized from ethanol to thereby obtain 16.9 g of white powdery (3-chloro-4-fluorophenyl)pyridin-3-yl-(S)-pyrrolidin-3-ylamine dimethanesulfonate.
Melting point 194.0-195.0° C.
The compounds of Example 8 to 1180 shown in the below Tables can be prepared in the same manners as in the above Examples, using corresponding starting compounds. In the following Tables, compounds with the physical properties, such as crystalline form, m.p. (melting point), salt, 1H-NMR and MS (mass spectrum), were produced actually.







TABLE 39













 














Ex. No.
R1
R2
R3
R4
R5
M.p. (° C.)
Salt





8
—H
—H
—Cl
—H
—H
173.7-175.0
Fumarate


9
—Cl
—Cl 
—H
—H
—H
160.3-162.6
Fumarate


10
—H
—Cl 
—H
—H
—H
144.2-146.7
Fumarate
















TABLE 40













 














Ex. No.
R1
R2
R3
R4
R5
NMR
Salt





11
—H
—H
—Cl
—Cl
—H
1H-NMR (DMSO-d6) δppm
2 Hydro-








1.50-1.68 (1H, m), 2.10-2.29 (1H, m), 2.74-2.90 (1H, m),
chloride








3.02-3.22 (2H, m), 3.51-3.66 (1H, m), 4.61-4.79 (1H, m),









6.58 (1H, dd, J = 2.9 Hz and 9.0 Hz), 6.87 (1H, d, J = 2.9 Hz),









7.13-7.19 (2H, m), 7.29-7.44(2H, m), 7.45-7.54 (2H, m),



12
—H
—H
—Cl
—Cl
—H
1H-NMR (DMSO-d6) δppm
Fumarate








1.49-1.68 (1H, m), 2.05-2.25 (1H, m), 2.69-2.82 (1H, m),









2.92-3.15 (2H, m), 3.44-3.60 (1H, m), 4.55-4.74 (1H, m),









6.44(2H, s), 6.57 (1H, dd, J = 2.9 Hz and 9.0 Hz), 6.85 (1H, d,









J = 2.8 Hz), 7.11-7.21 (2H, m), 7.29-7.41 (2H, m), 7.43-7.54









(2H, m)
















TABLE 41













 



















Ex. No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
R10
M.p. (° C.)
Salt





13
—H
—H
—F
—H
—H
—H
—H
—F
—H
—H
155.4-156.4
Fumarate


14
—H
—H
—F
—H
—H
—H
—H
—Cl
—Cl
—H
178.7-180.1
Fumarate


15
—H
—H
—H
—H
—F
—H
—H
—Cl
—Cl
—H
156.6-158.7
Fumarate


16
—H
—F
—H
—H
—H
—H
—Cl
—Cl
—H
—H
156.4-158.5
Fumarate
















TABLE 42













 















Ex. No.
R1
R2
R3
R4
R5
M.p. (° C.)

Salt





17
—H
—H
—Cl
—H
—H
152.0-153.0

Fumarate


18
—H
—Cl
—Cl
—H
—H
144.0-147.9

Fumarate


19
—H
—H
—SCH3
—H
—H
152.9-155.5

Fumarate


20
—H
—H
—F
—H
—H
143.0-145.0

Fumarate


21
—Cl
—H
—H
—H
—H
138.1-141.8

Fumarate


22
—H
—H
—CH3
—H
—H
141.7-143-8

Fumarate


23
—Cl
—Cl
—H
—H
—H
130.2-132.2

Fumarate


24
—H
—H
—OCF3
—H
—H
131.2-133.6

Fumarate


25
—H
—Cl
—H
—H
—H
146.6-149.1

Fumarate


26
—H
—H
—CF3
—H
—H
120.3-124.6

Fumarate


27
—H
—H
—OCH3
—H
—H
137.5-139.2

Fumarate


28
—H
—H
—NO2
—H
—H
153.0-135.5

Fumarate


29
—H
—OCH3
—H
—H
—H
135.3-140.7

Fumarate


30
—H
—H
—CO2CH3
—H
—H
147.5-149.0

Fumarate


31
—H
—Cl
—H
—Cl
—H
164.8-166.8

Fumarate


32
—H
—H
—Br
—H
—H
156-158

Fumarate


33
—H
—H
—SO2CH3
—H
—H
184.5-185.8
(dec.)
Fumarate


34
—H
—F
—F
—H
—H
137.5-138.5

Fumarate


35
—H
—H
—CN
—H
—H
146.7-149.6

Fumarate


36
—H
—Cl
—OCH3
—H
—H
142-144

Fumarate


37
—H
—H
—H
—F
—H
144.2-145.2

Fumarate


38
—H
—F
—Cl
—H
—H
155.4-158.4

Fumarate


39
—H
—Cl
—OC2H5
—H
—H
135.0-137.2

Fumarate


40
—H
—Cl
—OC3H7
—H
—H
129.6-132.4

Fumarate
















TABLE 43













 














Ex. No.
R1
R2
R3
R4
R5
NMR
Salt





41
—H
—Cl
—Cl
—H
—H
1H-NMR (DMSO-d6) δppm
Hydrochloride








1.50-1.68 (1H, m), 2.10-2.29 (1H, m), 2.75-2.90









(1H, m), 3.02-3.23 (2H, m), 3.51-3.65 (1H, m),









4.60-4.80 (1H, m), 6.58 (1H, dd, J = 2.9 Hz and









9.0 Hz), 6.87 (1H, d, J = 2.9 Hz), 7.12-7.19 (2H, m),









7.29-7.44 (2H, m), 7.45-7.54 (2H, m), 9.05 (2H,









brs)



42
—H
—H
—NH2
—H
—H
1H-NMR (DMSO-d6) δppm
2 Hydro-








1.52-1.69 (1H, m), 2.09-2.24 (1H, m), 2.71-2.86
chloride








(1H, m), 3.00-3.21 (2H, m), 3.48-3.62 (1H, m),









4.52-4.75 (1H, m), 6.82-6.90 (2H, m), 6.98-7.08









(2H, m), 7.14-7.23 (1H, m), 7.24-7.32 (2H, m),









7.35-7.44 (2H, m), 9.30-10.9 (5H, m)



43
—H
—H
—N(CH3)2
—H
—H
1H-NMR (DMSO-d6) δppm
2 Hydro-








1.50-1.70 (1H, m), 2.09-2.27 (1H, m), 2.69-2.87
chloride








(1H, m), 2.92-3.24 (8H, m with sat δ3.01), 4.60-









4.77 (1H, m), 6.83 (2H, d, J = 8.6 Hz), 6.90-7.20









(3H, m), 7.22-7.70 (4H, m), 9.12-9.60 (2H, m)



44
—H
—Cl
—F
—H
—H
1H-NMR (DMSO-d6) δppm
Fumarate








1.50-1.68 (1H, m), 2.05-2.20 (1H, m), 2.72-2.86









(1H, m), 2.96-3.13 (2H, m), 3.43-3.57 (1H, m),









4.52-4.69 (1H, m), 6.45 (2H, s), 6.77-6.86 (1H,









m), 6.97 (2H, d, J = 8.2 Hz),7.05 (1H, dd, J = 2.8 Hz









and 6.4 Hz), 7.09-7.17 (1H, m), 7.26-7.41 (3H, m)



45
—H
—H
—CO2H
—H
—H
1H-NMR (DMSO-d6) δppm
Hydrochloride








1.50-1.70 (1H, m), 2.14-2.30 (1H, m), 2.70-2.90









(1H, m), 2.99-3.22 (2H, m), 3.51-3.70 (1H, m),









4.69-4.89 (1H, m), 6.54-6.64 (2H, m), 7.19-7.29









(2H, m), 7.38-7.48 (1H, m), 7.49-7.59 (2H, m),









7.68-7.79 (2H, m), 9.34(2H, brs), 12.32 (1H, brs)



46
—H
—CH3
—F
—H
—H
1H-NMR (DMSO-d6) δppm
Fumarate








1.5-1.7 (1H, m), 2.0-2.2 (1H, m), 2.20 (3H, s),









2.7-2.9 (1H, m), 3.0-3.2 (2H, m), 3.5-3.6 (1H, m),









4.5-4.7 (1H, m), 6.44 (2H, s), 6.6-6.8 (2H, m),









6.8-6.9 (2H, m), 6.9-7.0 (1H, m), 7.0-7.3 (3H, m)



47
—H
—F
—F
—OCH3
—H
1H-NMR (DMSO-d6) δppm
Fumarate








1.5-1.7 (1H, m), 2.0-2.2 (1H, m), 2.7-2.9 (1H, m),









3.0-3.2 (2H, m), 3.5-3.7 (1H, m), 3.77 (3H, s),









4.6-4.8 (1H, m), 6.2-6.4 (2H, m), 6.47 (2H, s),









7.00 (2H, d, J = 7.6 Hz), 7.15 (1H, dd, J = 7.3 Hz,









J = 7.3 Hz), 7.3-7.5 (2H, m)
















TABLE 44













 



















Ex. No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
R10
M.p. (° C.)
Salt





48
—H
—H
—F
—H
—H
—H
—H
—F
—H
—H
156.0-157.0
Fumarate


49
—H
—H
—F
—H
—H
—H
—H
—Cl
—Cl
—H
170.5-171.8
Fumarate


50
—H
—H
—H
—H
—F
—H
—H
—Cl
—Cl
—H
133.1-135.8
Fumarate


51
—H
—H
—Cl
—H
—H
—H
—F
—H
—H
—H
154.3-155.6
Fumarate


52
—H
—H
—F
—H
—H
—H
—F
—H
—H
—H
143.2-144.4
Fumarate


53
—H
—H
—CF3
—H
—H
—H
—F
—H
—H
—H
144.0-146.2
2 Fumarate


54
—H
—H
—SCH3
—H
—H
—H
—F
—H
—H
—H
161.1-163.2
Fumarate


55
—H
—H
—F
—H
—H
—H
—H
—Cl
—H
—H
174.1-176.2
Fumarate


56
—H
—H
—F
—H
—H
—H
—F
—F
—H
—H
148.6-151.3
Fumarate


57
—H
—H
—F
—H
—H
—H
—Cl
—F
—H
—H
176.7-178.4
Fumarate


58
—H
—H
—F
—H
—H
—H
—F
—Cl
—H
—H
163.1-164.1
Fumarate


59
—H
—H
—H
—F
—H
—H
—Cl
—F
—H
—H
149.0-152.0
Fumarate


60
—H
—CH3
—H
—H
—H
—H
—H
—F
—H
—H
142-143
Fumarate


61
—H
—Cl
—F
—H
—H
—H
—H
—OCH3
—H
—H
133.1-135.1
Fumarate


62
—H
—H
—CH3
—H
—H
—H
—Cl
—F
—H
—H
144.0-146.0
Fumarate


63
—H
—Cl
—F
—H
—H
—H
—H
—OC2H5
—H
—H
138.0-141.0
Fumarate


64
—H
—H
—SCH3
—H
—H
—H
—H
—F
—Cl
—H
136.7-139.0
Fumarate


65
—H
—H
—C3H7
—H
—H
—H
—H
—F
—Cl
—H
136.6-138.0
Fumarate


66
—H
—H
—C(CH3)3
—H
—H
—H
—H
—F
—Cl
—H
132.0-134.8
Fumarate


67
—H
—Cl
—F
—H
—H
—H
—Cl
—F
—H
—H
165-167
Fumarate


68
—H
—H
—F
—Cl
—H
—H
—H
—OH
—H
—H
191.5-194.5
Fumarate


69
—H
—H
—F
—H
—H
—H
—H
—CH3
—H
—H
145-148
Fumarate
















TABLE 45













 




















Ex. No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
R10
M.p. (° C.)

Salt





70
—H
—H
—Br
—H
—H
—H
—H
—F
—Cl
—H
141-143

Fumarate


71
—H
—H
-3-THIENYL
—H
—H
—H
—Cl
—F
—H
—H
158-160

Fumarate


72
—H
—CF3
—F
—H
—H
—H
—H
—F
—Cl
—H
105-108

2 Fumarate


73
—H
—H
—CN
—H
—H
—H
—Cl
—F
—H
—H
174-175

Fumarate


74
—H
—H
—CF3
—H
—H
—H
—Cl
—F
—H
—H
169-170

Fumarate


75
—H
—H
—N(CH3)2
—H
—H
—H
—Cl
—F
—H
—H
153-154

Fumarate


76
—H
—OCH3
—H
—H
—H
—H
—Cl
—F
—H
—H
135-137

Fumarate


77
—H
—OC2H5
—H
—H
—H
—H
—Cl
—F
—H
—H
155-156

Fumarate


78
—H
—H
—NO2
—H
—H
—H
—CH3
—F
—H
—H
162-164

Fumarate


79
—H
—H
—CN
—H
—H
—H
—CH3
—F
—H
—H
169-170

Fumarate


80
—H
—CH3
—H
—H
—H
—H
—CH3
—F
—H
—H
129-130

Fumarate


81
—H
—H
—F
—H
—H
—H
—SCH3
—H
—H
—H
156-158

Fumarate


82
—H
—NO2
—H
—H
—H
—H
—CH3
—F
—H
—H
108-110

Fumarate


83
—H
—OCH3
—H
—H
—H
—H
—H
—F
—CH3
—H
140-142

Fumarate


84
—H
—H
—OC2H5
—H
—H
—H
—H
—F
—CH3
—H
112-113

Fumarate


85
—H
—F
—H
—H
—H
—H
—F
—H
—H
—H
149.0-153.0
(dec.)
Fumarate


86
—H
—SCH3
—H
—H
—H
—H
—Cl
—F
—H
—H
143-144

Fumarate
















TABLE 46













 



















Ex. No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
R10
M.p. (° C.)
Salt





87
—H
—H




—H
—H
—H
—H
—F
—Cl
—H
199-203
3 Hydro- chloride


 


88
—H
—H




—H
—H
—H
—Cl
—F
—H
—H
108-110
Fumarate


 


89
—H
—H




—H
—H
—H
—H
—F
—Cl
—H
198-201
3 Hydro- chloride


 


90
—H
—H




—H
—H
—H
—H
—F
—Cl
—H
115-117
















TABLE 47













 



















Ex.














No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
R10
NMR
Salt





91
—H
—F
—H
—H
—H
—H
—Cl
—Cl
—H
—H
1H-NMR (DMSO-d6) δppm1.49-1.69 (1H, m), 2.03- 
Fumarate













2.22 (1H, m), 2.73-2.86 (1H, m), 2.92-3.10 (2H, m), 














3.42-3.58 (1H, m), 4.54-4.72 (1H, m), 6.73-6.91














(3H, m with dd at δ6.82, J = 2.7 Hz and 














8.8 Hz, and dt at δ6.88, J = 2.4 Hz and 11.1 Hz), 














6.93-7.01 (1H, m), 7.14 (1H, d, J = 2.7 Hz), 














7.32-7.43 (1H, m), 7.51 (1H, d, J = 8.8 Hz)



92
—H
—CH3
—F
—H
—H
—H
—CH3
—F
—H
—H
1H-NMR (DMSO-d6) δppm
Fumarate













1.5-1.7 (1H, m), 2.0-2.2 (1H, m), 2.17 (6H, s), 2.7-2.9 














(1H, m), 3.0-3.2 (2H, m), 3.5-3.6 (1H, m), 4.5-4.7 (1H, 














m), 6.44 (2H, s), 6.7-6.9 (4H, m), 7.05 (2H, dd, J = 9.1 














Hz, J = 9.1 Hz)



93
—H
—F
—H
—H
—H
—H
—CH3
—F
—H
—H
1H-NMR (DMSO-d6) δppm
Fumarate













1.5-1.7 (1H, m), 2.0-2.2 (1H, m), 2.23 (3H, s), 2.7-2.9 














(1H, m), 3.0-3.2 (2H, m), 3.5-3.6 (1H, m), 4.5-4.7 (1H, 














m), 6.3-6.6 (3H, m), 6.44 (2H, s), 7.0-7.2 (3H, m), 7.22














(1H, dd, J = 9.2 Hz, J = 8.9 Hz)



94
—H
—CH3
—H
—H
—H
—H
—Cl
—F
—H
—H
1H-NMR (DMSO-d6) δppm1
Fumarate













.5-1.7 (1H, m), 2.0-2.2 (1H, m), 2.27 (3H, s), 2.7-2.9 














(1H, m), 3.0-3.2 (2H, m), 3.5-3.6 (1H, m), 4.5-4.7 (1H, 














m), 6.45 (2H, s), 6.7-7.1 (5H, m), 7.2-7.4 (2H, m)



95
—H
—CH3
—H
—H
—H
—H
—F
—H
—H
—H
1H-NMR (DMSO-d6) δppm
Fumarate













1.5-1.7 (1H, m), 2.0-2.2 (1H, m), 2.30 (3H, s), 2.7-2.9 














(1H, m), 3.0-3.2 (2H, m), 3.5-3.6 (1H, m), 4.5-4.7 (1H, 














m), 6.3-6.6 (3H, m), 6.43 (2H, s), 6.8-7.0 (2H, m), 














7.1-7.3 (2H, m), 7.33 (1H, dd, J = 7.7 Hz, J = 7.7 Hz)



96
—H
—H
—F
—H
—H
—H
—CH3
—F
—H
—H
1H-NMR (DMSO-d6) δppm
Fumarate













1.5-1.7 (1H, m), 2.0-2.2 (1H, m), 2.48 (3H, s), 2.7-2.9 














(1H, m), 3.0-3.2 (2H, m), 3.5-3.6 (1H, m), 4.5-4.7 (1H, 














m), 6.43 (2H, s), 6.7-6.9 (4H, m), 7.0-7.2 (3H, m)
















TABLE 48













 



















Ex. 














No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
R10
NMR
Salt





 97
—H
—H
—CH3
—H
—H
—H
—F
—H
—H
—H
1H-NMR (DMSO-d6) δppm
Fuma-













1.5-1.7 (1H, m), 2.0-2.2 (1H, m), 2,33 (3H, s), 2.7-2.9 
rate













(1H, m), 3.0-3.2 (2H, m), 3.5-3.6 (1H, m), 4.5-4.7 (1H, 














m), 6.3-6.6 (3H, m), 6.43 (2H, s), 7.05 (2H, d, J = 8.1 














Hz), 7.1-7.2 (1H, m), 7.28 (2H, d, J = 8.1 Hz)



 98
—H
—Cl
—CH3
—H
—H
—H
—F
—H
—H
—H
1H-NMR (DMSO-d6) δppm
Fuma-













1.5-1.7 (1H, m), 2.0-2.2 (1H, m), 2,32 (3H, s), 2.7-2.9 
rate













(1H, m), 3.0-3.2 (2H, m), 3.5-3.6 (1H, m), 4.5-4.7 (1H, 














m), 6.4-6.7 (3H, m), 6.43 (2H, s), 6.98 (1H, d, J = 8.1 














Hz), 7.16 (1H, s), 7.2-7.3 (1H, m), 7.38 (1H, d, J = 8.1 














Hz)



 99
—H
—Cl
—F
—H
—H
—H
—H
—C2H5
—H
—H
1H-NMR (DMSO-d6) δppm
Fuma-













1.18 (3H, t, J = 7.6 Hz), 1.49-1.68 (1H, m), 2.01-2.19 
rate













(1H, m), 2.60 (2H, q, J = 7.6 Hz), 2.69-2.81 (1H, m), 














2.92-3.14 (2H, m), 3.40-3.55 (1H, m), 4.50-4.69 (1H, 














m), 6.44 (2H, s), 6.63-6.71 (1H, m), 6.89 (1H, dd, J = 














2.8 Hz and 6.3 Hz), 7.00 (2H, d, J = 8.3 Hz), 7.19-














7.29 (2H, m)



100
—H
—F
—H
—H
—H
—H
—CH3
—Cl
—H
—H
1H-NMR (DMSO-d6) δppm
Fuma-













1.5-1.7 (1H, m), 2.0-2.2 (1H, m), 2,30 (3H, s), 2.7-2.9 
rate













(1H, m), 3.0-3.2 (2H, m), 3.5-3.6 (1H, m), 4.5-4.7 (1H, 














m), 6.4-6.7 (3H, m), 6.46 (2H, s), 6.93 (1H, d, J = 8.5 














Hz), 7.12 (1H, s), 7.2-7.3 (1H, m), 7.43 (1H, d, J = 8.5 














Hz)



101
—H
—F
—H
—H
—H
—H
—CN
—H
—H
—H
1H-NMR (DMSO-d6) δppm
Fuma-













1.5-1.7 (1H, m), 2.1-2.3 (1H, m), 2.8-3.0 (1H, m), 3.0- 
rate













3.2 (2H, m), 3.5-3.7 (1H, m), 4.6-4.8 (1H, m), 6.48 














(2H, s), 6.7-7.0 (3H, m), 7.1-7.2 (1H, m), 7.3-7.5 (4H, 














m)



102
—H
—H
—F
—Cl
—H
—H
—CN
—H
—H
—H
1H-NMR (DMSO-d6) δppm
Fuma-













1.5-1.7 (1H, m), 2.0-2.2 (1H, m), 2.7-2.9 (1H, m), 3.0- 
rate













3.2 (2H, m), 3.6-3.8 (1H, m), 4.6-4.8 (1H, m), 6.44 














(2H, s), 6.93 (1H, d, J = 8.4 Hz), 7.1-7.2 (1H, m), 7.19 














(1H, s), 7.27 (1H, d, J = 7.6 Hz), 7.37 (1H, dd, J = 7.6 














Hz, J = 8.2 Hz), 7.4-7.6 (2H, m)
















TABLE 49













 



















Ex.














No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
R10
NMR
Salt





103
—H
—H
—CO2C2H5
—H
—H
—H
—Cl
—F
—H
—H
1H-NMR (DMSO-d6) δppm 1.26 (3H, t,
Hydro-













J = 7.1 Hz), 1.55-1.68 (1H, m), 2.18-2.29
chloride













(1H, m), 2.83-2.92 (1H, m), 3.07-3.19 (2H,














m), 3.58-3.68 (1H, m), 4.23 (2H, q, J = 7.1














Hz), 4.71-4.82 (1H, m), 6.65 (2H, d, J = 9.0














Hz), 7.28-7.34 (1H, m), 7.55-7.64 (2H, m), 














7.76 (2H, d, J = 9.0 Hz), 8.90-9.51 (2H, br)



104
—H
—H
—CO2H
—H
—H
—H
—Cl
—F
—H
—H
1H-NMR (DMSO-d6) δppm 1.52-1.70
Hydro-













(1H, m), 2.15-2.21 (1H, m), 2.81-2.92 
chloride













(1H, m), 3.06-3.18 (2H, m), 3.53-3.67














(1H, m), 4.65-4.80 (1H, m), 6.64














(1H, d, J = 9.0 Hz), 7.25-7.33 (1H, m),














7.52-7.62 (2H, m), 7.75 (2H, d, J = 9.0 Hz),














8.50-10.50 (1H, br), 11.00-13.00 (2H, br)



105
—H
—H
—SO2CH3
—H
—H
—H
—Cl
—F
—H
—H
1H-NMR (DMSO-d6) δppm 1.56-1.68
Hydro-













(1H, m), 2.19-2.29 (1H, m),
chloride













2.82-2.94 (1H, m), 3.08 (3H, s),














3.10-3.20 (2H, m), 3.57-3.68 (1H, m),














4.70-4.85 (1H, m), 6.69-6.75 (2H, m),














7.32-7.37 (1H, m), 7.58-7.64 (1H, m),














7.65-7.69 (3H, m), 9.10-9.45 (2H, m)



106
—H
—H
—N(CH3)2
—H
—H
—H
—CH3
—F
—H
—H
1H-NMR (DMSO-d6) δppm 1.52-1.70
2 Hydro-













(1H, m), 2.08-2.25 (1H, m), 2.24 (3H, s),
chloride













2.73-2.87 (1H, m), 3.03 (6H, s), 3.02-3.19














(2H, m), 3.50-3.67 (1H, m), 4.65-4.76














(1H, m), 6.73 (2H, d, J = 9.1 Hz), 7.00-7.20














(2H, m), 7.25 (1H, t, J = 9.1 Hz), 7.56 (2H,














d, J = 7.2 Hz), 9.47 (1H, brs), 9.58 (1H, brs).
















TABLE 50













 


















Ex.













No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
R10
NMR





107
—H
—Cl
—F
—H
—H
—H
—H




—H
—H
1H-NMR (CDCl3) δppm 1.56-1.86 (5H, m), 2.17-2.30 (1H, m), 2.96 (1H, dd, J = 7.4, 11.5 Hz), 3.08-3.21 (6H, m), 3.52 (1H, dd, J = 6.8, 11.4 Hz), 4.58-4.72 (1H, m), 6.62 (2H, d, J = 9.0 Hz), 7.02-7.09 (1H, m), 7.21-7.30 (2H, m), 7.59 (2H, d, J = 9.0 Hz).
















TABLE 51













 
















Ex. No.
R1
R2
R3
R4
R5
R6
M.p. (° C.)

Salt





108
—H
—Cl
—F
—H
—H




126-129




 


109
—H
—H
—H
—H
—H




141-142

Fumarate


 


110
—H
—H
—H
—H
—H




148-150

Fumarate


 


111
—H
—Cl
—F
—H
—H




144-146
(dec.)
Fumarate


 


112
—H
—H
—F
—Cl
—H




168-170

Fumarate


 


113
—H
—H
—H
—H
—H




133-135

Fumarate


 


114
—H
—H
—F
—H
—H




131.6-133.3

Fumarate


 


115
—H
—H
—F
—H
—H




133.2-135.6

Fumarate


 


116
—H
—H
—H
—H
—H




158-160

Hydrochloride
















TABLE 52













 















Ex.










No.
R1
R2
R3
R4
R5
R6
NMR
Salt





117
—H
—H
—F
—H
—H




1H-NMR (DMSO-d6) δppm 1.5-1.7 (1H, m), 2.0-2.2 (1H, m), 2.7-2.9 (1H, m), 3.0-3.2 (2H, m), 3.4-3.5 (1H, m), 4.4-4.6 (1H, m), 6.02 (2H, s), 6.43 (2H, s), 6.54 (1H, d, J = 8.2 Hz), 6.69 (1H, s), 6.7- 6.8 (2H, m), 6.90 (1H, d, J = 8.2 Hz), 7.0-7.1 (2H, m)
Fumarate


 


118
—H
—H
—F
—Cl
—H




1H-NMR (DMSO-d6) δppm 1.5-1.7 (1H, m), 2.0-2.2 (1H, m), 2.7-2.9 (1H, m), 3.0-3.2 (2H, m), 3.5-3.6 (1H, m), 4.5-4.7 (1H, m), 6.06 (2H, s), 6.44 (2H, s), 6.5-6.7 (2H, m), 6.7-6.8 (2H, m), 6.96 (1H, d, J = 8.2 Hz), 7.12 (1H, s), 7.1-7.3 (1H, m)
Fumarate


 


119
—H
—H
—H
—F
—H




1H-NMR (DMSO-d6) δppm 1.5-1.7 (1H, m), 2.0-2.2 (1H, m), 2.7-2.9 (1H, m), 2.9-3.1 (2H, m), 3.4-3.6 (1H, m), 4.5-4.7 (1H, m), 6.08 (2H, s), 6.3- 6.5 (3H, m), 6.44 (2H, s), 6.67 (1H, d, J = 8.1 Hz), 6.82 (1H, s), 6.99 (1H, d, J = 8.1 Hz), 7.0-7.2 (1H, m)
Fumarate


 


120
—H
—H
—F
—Cl
—H




1H-NMR (DMSO-d6) δppm 1.5-1.7 (1H, m), 2.0-2.2 (1H, m), 2.7-2.9 (1H, m), 3.0-3.2 (2H, m), 3.4-3.6 (1H, m), 4.24 (4H, s), 4.5-4.7 (1H, m), 6.45 (2H, s), 6.5-6.7 (2H, m), 6.70 (1H, s), 6.7-6.8 (1H, m), 6.91 (1H, d, J = 8.5 Hz), 7.20 (1H, dd, J = 9.1 Hz, J = 9.1 Hz)
Fumarate


 


121
—H
—H
—F
—Cl
—H




1H-NMR (DMSO-d6) δppm 1.5-4.7 (1H, m), 2.1-2.3 (1H, m), 2.7-2.9 (1H, m), 3.0-3.2 (2H, m), 3.5-3.7 (1H, m), 4.6-4.8 (1H, m), 6.45 (2H, s), 6.9- 7.0 (1H, m), 7.08 (1H, d, J = 8.5 Hz), 7.23 (1H, dd, J = 9.1 Hz, J = 9.1 Hz), 7.42 (1H, d, J = 5.4 Hz), 7.66 (1H, s), 7.80 (1H, d, J = 5.4 Hz), 8.02(1H, d, J = 8.5 Hz)
Fumarate


 


122
—H
—H
—F
—Cl
—H




1H-NMR (DMSO-d6) δppm 1.5-1.7 (1H, m), 2.1-2.3 (1H, m), 2.7-2.9 (1H, m), 3.0-3.2 (2H, m), 3.5-3.7 (1H, m), 4.6-4.8 (1H, m), 6.46 (2H, s), 6.5- 6.6 (1H, m), 6.7-6.8 (1H, m), 6.96 (1H, d, J = 2.2 Hz), 7.09 (1H, d, J = 8.7 Hz), 7.18 (1H, dd, J = 9.1 Hz, J = 9.1 Hz), 7.50 (1H, d, J = 2.2 Hz), 7.67 (1H, d, J = 8.7 Hz), 8.05 (1H, d, J = 2.2 Hz)
Fumarate
















TABLE 53













 














Ex.









No.
R1
R2
R3
R4
R5
R6
NMR





123
—H
—Cl
—F
—H
—H




1H-NMR (CDCl3) δppm 1.7-1.9 (2H, m), 2.0-2.25 (1H, m), 2.8-3.0 (3H, m), 3.05-3.25 (1H, m), 4.35-4.6 (1H, m), 6.24 (1H, d, J = 1 Hz), 6.4-6.5 (1H, m), 6.65- 6.75 (1H, m), 6.8-7.0 (2H, m), 7.1-7.2 (1H, m),7.22 (1H, d, J = 7.5 Hz), 7.36 (1H, d, J = 8 Hz), 8.43 (1H, br).


 


124
—H
—H
—H
—H
—H




1H-NMR (CDCl3) δppm 1.68 (1H, br), 1.8-1.95 (1H, m), 2.0-2.2 (1H, m), 2.86 (2H, t, J = 7.5 Hz), 2.99 (1H, dd, J = 5.5, 12 Hz), 3.13 (1H, dd, J = 6.5, 11.5 Hz), 4.5-4.6 (1H, m), 6.2-6.3 (1H, m), 6.6-6.75 (3H, m), 6.92 (1H, d, J = 7.5 Hz), 7.05-7.25 (4H, m), 7.35 (1H, d, J = 8 Hz), 8.34 (1H, br).


 


125
—H
—Cl
—F
—H
—H




1H-NMR (CDCl3) δppm 1.65-1.9 (2H, m), 2.0-2.2 (1H, m), 2.8-3.0 (3H, m), 3.05-3.2 (1H, m), 4.25-4.4 (1H, m), 6.4-6.5 (1H, m), 6.57 (1H, d, J = 3H), 6.67 (1H, dd, J = 3, 6 Hz), 6.75-6.85 (1H, m), 6.90 (1H, dd, J = 9, 9 Hz), 7.13 (1H, s), 7.2-7.3 (1H, m), 7.64 (1H, d, J = 8.5 Hz), 8.38 (1H, br).


 


126
—H
—Cl
—F
—H
—H




1H-NMR(CDCl3) δppm 1.74-1.91(1H, m), 2.03-2.18(1H, m), 2.82-3.00(3H, m), 3.14(1H, dd, J = 6.5 Hz,11.5 Hz), 4.30-4.40(1H, m), 6.39-6.46(1H, m), 6.55(1H, d, J = 3.0 Hz), 6.63(1H, dd, J = 3.0 Hz, 3.0 Hz), 6.83-6.91 (1H, m), 7.18-7.41(3H, m), 8.50 (1H, br)
















TABLE 54













 















Ex.










No.
R1
R2
R3
R4
R5
R6
NMR
Salt





127
—H
—H
—H
—H
—H




1H-NMR (DMSO-d6) δppm 1.4-1.6 (1H, m), 2.05-2.25 (1H, m), 2.8-2.95 (1H, m), 3.0-3.2 (2H, m), 3.55-3.7 (1H, m), 4.8-5.0 (1H, m), 6.47 (2H, s), 6.53 (2H, d, J = 8 Hz), 6.68 (1H, dd, J = 7.5, 7.5 Hz), 7.0-7.2 (2H, m), 7.4-7.7 (4H, m), 7.7-7.85 (1H, m), 8.02 (2H, d, J = 7.5, 7.5 Hz).
Fumarate


 


128
—H
—H
—F
—Cl
—H




1H-NMR (DMSO-d6) δppm 1.35-1.55 (1H, m), 2.0-2.2 (1H, m), 2.25-5.45 (8H, m), 6.3- 6.45 (1H, m), 6.48 (2H, s), 6.77 (1H, dd, J = 3, 6 Hz), 7.14 (1H, dd, J = 9, 9 Hz), 7.55 (1H, dd, J = 4, 8.5 Hz), 7.62 (1H, dd, J = 1, 7.5 Hz), 7.88 (1H, dd, J = 7.5, 7.5 Hz), 8.12 (1H, d, J = 8.5 Hz), 8.22 (1H, d, J = 8 Hz), 8.96 (1H, dd, J = 1.5, 4 Hz).
Fumarate


 


129
—H
—H
—H
—H
—H




1H-NMR (DMSO-d6) δppm 1.45-1.8 (1H, m), 1.95-2.25 (1H, m), 2.6-4.8 (8H, m), 6.44 (2H, s), 6.67 (2H, d, J = 8 Hz), 6.77 (1H, dd, J = 7.5, 7.5 Hz), 6.96 (1H, dd, J = 1, 2 Hz), 7.06 (1H, dd, J = 2, 8.5 Hz), 7.16 (2H, dd, J = 7.5, 8.5 Hz), 7.47 (1H, d, J = 2 Hz), 7.65 (1H, d, J = 8.5 Hz), 8.04 (1H, d, J = 2 Hz).
Fumarate
















TABLE 55













 















Ex. No.
R1
R2
R3
R4
R5
R6
M.p. (° C.)
Salt





130
—H
—Cl
—F
—H
—H




183-186
Hydrochloride


 


131
—H
—Cl
—F
—H
—H




128.0-129.9
Fumarate


 


132
—H
—H
—F
—H
—H




172-176
2 Hydrochloride


 


133
—H
—Cl
—F
—H
—H




183-186
2 Hydrochloride


 


134
—H
—Cl
—Cl
—H
—H




209-211
2Methanesulfonate


 


135
—H
—Cl
—Cl
—H
—H




193-195
2Methanesulfonate


 


136
—H
—Cl
—Cl
—H
—H




122-126
2 Hydrochloride


 


137
—H
—Cl
—F
—H
—H




137.0-140.0
Fumarate


 


138
—H
—H
—F
—H
—H




115-119 (dec.)
Fumarate


 


139
—H
—Cl
—F
—H
—H




162.0-164.0
Fumarate
















TABLE 56













 















Ex.










No.
R1
R2
R3
R4
R5
R6
NMR
Salt


















140
—H
—CH3
—F
—H
—H




H-NMR (DMSO-d6) δ ppm 1.8-2.0 (1H, m), 2.2-2.4 (1H, m), 2.27 (3H, s), 3.1-3.3 (3H, m), 3.5-3.7 (1H, m), 4.8-5.0 (1H, m), 6.79 (1H, d, J = 3.7 Hz), 7.23 (1H, d, J = 3.7 Hz), 7.3-7.4 (1H, m), 7.43 (1H, d, J = 7.5 Hz), 9.25 (1H, brs), 9.44 (1H, brs)
2 Hydro- chloride


 


141
—H
—Cl
—F
—H
—H




1H-NMR (DMSO-d6) δ ppm 1.79-1.98 (1H, m), 2.14- 2.33 (1H, m), 2.19 (3H, d, J = 1.0 HZ), 2.98-3.39 (2H, m), 3.46-3.63 (1H, m), 4.71-4.90 (1H, m), 6.93 (1H, d, J =1.0 Hz), 7.50-7.65 (2H, m), 7.84 (1H, dd, J = 2.5 Hz, 6.5 Hz), 9.05 (1H, br), 9.24 (1H, br).
2 Hydro- chloride


 


142
—H
—Cl
—F
—H
—H




1H-NMR (DMSO-d6) δ ppm 1.55-1.72 (1H, m), 2.05-2.29 (1H, m), 2.82-2.95 (1H, m), 3.02-3.14 (2H, m), 3.51-3.65 (1H, m), 4.65-4.83 (1H, m), 6.51 (4H, s), 7.20-7.29 (1H, m), 7.46-7.60 (2H, m with dd, J = 2.6 Hz and 6.7 Hz), 8.24 (2H, s), 8.68 (1H, s),
2 Fum- arate


 


143
—H
—Cl
—F
—H
—H




H-NMR (DMSO-d6) δ ppm 1.6-1.7 (1H, m), 2.1-2.2 (1H, m), 2.57 (3H, s), 2.9-3.1 (1H, m), 3.1-3.2 (2H, m), 3.6-3.8 (1H, m), 5.2-5.4 (1H, m), 5.87 (1H, d, J = 6.1 Hz), 7.4-7.5 (1H, m), 7.65 (1H, dd, J = 8.9 Hz, J = 8.9 Hz), 7.8-7.9 (1H, m), 8.01 (1H, d, J = 6.1 Hz), 9.39 (1H, brs), 9.59 (1H, brs)
2 Hydro- chloride


 


144
—H
—Cl
—F
—H
—H




1H-NMR (DMSO-d6) δ ppm 1.66-1.88 (1H, m), 2.10-2.29 (1H, m), 2.96-3.30 (3H, m), 3.48-3.64 (1H, m), 4.95-5.09 (1H, m), 7.38-7.49 (1H, m), 7.53 (1H, d, J = 1.5 Hz), 7.55-7.66 (1H, m), 7.7 (1H, dd, J = 2.5 Hz and 6.8 Hz), 7.94 (1H, d, J = 2.7 Hz), 8.19-8.26 (1H, m), 9.30 (1H, brs), 9.62 (1H, brs)
2 Hydro- chloride
















TABLE 57













 















Ex.










No.
R1
R2
R3
R4
R5
R6
NMR
Salt


















145
—H
—Cl
—F
—H
—H




H-NMR (DMSO-d6) δ ppm 1.8-2.0 (1H, m), 2.2-2.4 (1H, m), 3.1-3.4 (3H, m), 3.5-3.7 (1H, m), 5.0-5.2 (1H, m), 7.11 (1H, dd, J = 7.3 Hz, J = 7.7 Hz), 7.32 (1H, dd, J = 7.3 Hz, J = 8.2 Hz), 7.6-7.8 (4H, m), 7.9-8.1 (1H, m), 9.22 (1H, brs), 9.46 (1H, brs)
2 Hydro- chloride


 


146
—H
—Cl
—F
—H
—H




H-NMR (DMSO-d6) δ ppm 1.8-2.0 (1H, m), 2.2-2.4 (1H, m), 2.57 (3H, s), 3.1-3.4 (3H, m), 3.5-3.7 (1H, m), 3.72 (3H, s), 4.9-5.1 (1H, m), 6.92 (1H, d, J = 8.8 Hz), 7.31 (1H, s), 7.52 (1H, d, J = 8.8 Hz), 7.6-7.7 (2H, m), 7.9-8.1 (1H, m), 9.17 (1H, brs), 9.42 (1H, brs)
2 Hydro- chloride


 


147
—H
—H
—H
—H
—H




H-NMR (DMSO-d6) δ ppm 1.8-2.0 (1H, m), 2.2-2.4 (1H, m), 3.1-3.4 (3H, m), 3.6-3.7 (1H, m), 5.0-5.2 (1H, m), 7.08 (1H, dd, J = 7.2 Hz, J = 7.9 Hz), 7.31 (1H, dd, J = 7.2 Hz, J = 8.2 Hz), 7.5-7.8 (7H, m), 9.28 (1H, brs), 9.50 (1H, brs)
2 Hydro- chloride


 


148
—H
—Cl
—F
—H
—H




H-NMR (DMSO-d6) δ ppm 1.6-1.8 (1H, m), 2.3-2.4 (1H, m), 2.9-3.1 (1H, m), 3.1-3.2 (2H, m), 3.7-3.8 (1H, m), 5.1-5.2 (1H, m), 7.39 (1H, d, J = 7.2 Hz), 7.55 (1H, d, J = 5.7 Hz), 7.7-7.8 (2H, m), 8.08 (1H, d, J = 7.2 Hz), 8.22 (1H, d, J = 5.7 Hz), 8.69 (1H, d, J = 7.0 Hz), 9.43 (1H, brs), 9.59 (1H, brs)
2 Hydro- chloride
















TABLE 58













 















Ex.










No.
R1
R2
R3
R4
R5
R6
NMR
Salt


















149
—H
—Cl
—F
—H
—H




1H-NMR (DMSO-d6) δ ppm 1.6-1.8 (1H, m), 2.2-2.4 (1H, m), 2.9-3.1 (1H, m), 3.1-3.3 (2H, m), 3.6-3.8 (1H, m), 4.8-5.0 (1H, m), 7.3-7.4 (1H, m), 7.56 (1H, dd, J = 9.0 Hz, J = 9.0 Hz), 7.6-7.7 (1H, m), 7.7-7.9 (2H, m), 8.08 (1H, d, J = 7.8 Hz), 8.22 (1H, d, J = 8.4 Hz), 8.27 (1H, s), 8.67 (1H, s), 9.57(1H, brs), 9.64 (1H, brs)
2 Hydro- chloride


 


150
—H
—Cl
—F
—H
—H




H-NMR (DMSO-d6) δ ppm 1.82 (3H, s), 1.9-2.1 (1H, m), 2.2-2.3 (1H, m), 3.1-3.2 (1H, m), 3.2-3.3 (1H, m), 3.4-3.5 (1H, m), 3.6-3.8 (1H, m), 4.9-5.0 (1H, m), 7.0-7.1 (1H, m), 7.3-7.4 (2H, m), 7.4-7.5 (1H, m), 7.68 (1H, dd, J = 8.0 Hz, J = 8.3 Hz), 7.81 (1H, d, J = 7.2 Hz), 7.92 (1H, d, J = 8.3 Hz), 8.04 (1H, s), 8.94 (1H, brs), 9.11 (1H, brs)
2 Hydro- chloride


 


151
—H
—CH3
—F
—H
—H




H-NMR (CDCl3) δ ppm 1.8-2.0 (1H, m), 2.32 (3H, s), 2.4-2.5 (1H, m), 3.1-3.3 (1H, m), 3.4-3.5 (1H, m), 3.5-3.7 (1H, m), 4.1-4.3 (1H, m), 5.2- 5.4 (1H, m), 7.0-7.3 (3H, m), 7.5-7.7 (2H, m), 7.89 (1H, d, J = 7.9 Hz), 8.04 (1H, s), 8.47 (1H, d, J = 8.3 Hz), 8.87 (1H, s), 9.72 (1H, brs), 10.28 (1H, brs)
2 Hydro- chloride


 


152
—H
—Cl
—F
—H
—H




1H-NMR (DMSO-d6) δ ppm 1.6-1.8 (1H, m), 2.2-2.4 (1H, m), 2.9-3.1 (1H, m), 3.1-3.3 (2H, m), 3.6-3.8 (1H, m), 4.8-5.0 (1H, m), 6.3-6.4 (1H, m), 6.48 (2H, s), 6.7-6.8 (1H, m), 7.15 (1H, dd, J = 9.0 Hz, J = 9.0 Hz), 7.6-7.8 (3H, m), 8.1-8.3 (1H, m), 8.51 (1H, s), 9.41 (1H, s)
Fumarate
















TABLE 59













 


















Ex. No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
M.p. (° C.)
Salt





153
—H
—H
—H
—H
—H
—H
—H
—H
—H
208.0-211.0
2 Hydrochloride












(dec.)



154
—H
—Cl
—F
—H
—H
—H
—H
—H
—H
152.4-154.4
Fumarate


155
—H
—Cl
—F
—H
—H
—H
—CH3
—H
—H
141.8-143.1
Fumarate


156
—H
—Cl
—F
—H
—H
—H
—H
—CH3
—H
138.6-140.2
Fumarate


157
—H
—Cl
—F
—H
—H
—H
—H
—H
—H
207.0-208.0
2Methanesulfonate


158
—H
—Cl
—F
—H
—H
—H
-3-THIENYL
—H
—H
148-151
2 Hydrochloride


159
—H
—Cl
—F
—H
—H
—H
-4-PYRIDYL
—H
—H
157-158
3 Hydrochloride


160
—H
—Cl
—F
—H
—H
—H
—C6H5
—H
—H
150-153
2 Hydrochloride


161
—H
—Cl
—F
—H
—H
—H
—H
—H
—F
83-85
2 Hydrochloride


162
—H
—Cl
—F
—H
—H
—H
—H
—F
—H
150-153
2 Hydrochloride


163
—H
—Cl
—F
—H
—H
—H
—CF3
—H
—H
87-89
Hydrochloride


164
—H
—Cl
—F
—H
—H
—H
—H
—OCH3
—H
153-156
2 Hydrochloride


165
—H
—Cl
—F
—H
—H
—Br
—H
—H
—H
220-223
Hydrochloride


166
—H
—Cl
—F
—H
—H
—Cl
—H
—H
—H
219-220
Hydrochloride


167
—H
—Cl
—F
—H
—H
—H
—C2H5
—H
—H
112-115
Fumarate


168
—H
—Cl
—F
—H
—H
-2-THIENYL
—H
—H
—H
 98-103
Hydrochloride


169
—H
—Cl
—F
—H
—H
-3-THIENYL
—H
—H
—H
95-98
Hydrochloride


170
—H
—Cl
—F
—H
—H
—H
—H
—Cl
—H
125-128
2 Hydrochloride


171
—H
—Cl
—Cl
—H
—H
—H
—F
—H
—H
111-115
2 Hydrochloride


172
—H
—Cl
—Cl
—H
—H
—H
—Br
—H
—H
115-118
2 Hydrochloride


173
—H
—Cl
—Cl
—H
—H
—H
—H
—H
—F
75-80
2 Hydrochloride


174
—H
—Cl
—Cl
—H
—H
—H
—H
—F
—H
125-128
2 Hydrochloride
















TABLE 60













 


















Ex. No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
M.p. (° C.)
Salt





175
—H
—Cl
—Cl
—H
—H
—H
—H
—OCH3
—H
160-165
2 Hydrochloride


176
—H
—Cl
—F
—H
—H
—H
—CN
—H
—H
211-213
Hydrochloride


177
—H
—Cl
—Cl
—H
—H
—H
—CN
—H
—H
126-130
2 Hydrochloride


178
—H
—Cl
—Cl
—H
—H
—H
—H
—CH3
—H
204-207
2 Hydrochloride


179
—H
—Cl
—Cl
—H
—H
—H
—CF3
—H
—H
100-105
2 Hydrochloride


180
—H
—Cl
—Cl
—H
—H
—OCH3
—H
—H
—H
190-195
2 Hydrochloride


181
—H
—Cl
—Cl
—H
—H
—H
—H
—CN
—H
135-138
2 Hydrochloride


182
—H
—Cl
—F
—H
—H
—H
—Cl
—H
—H
163-165
Fumarate


183
—H
—Cl
—F
—H
—H
—H
—Cl
—H
—H
190-191
2 Hydrochloride


184
—H
—H
—F
—H
—H
—H
—Cl
—H
—H
95-97
Fumarate


185
—H
—CH3
—F
—H
—H
—H
—Cl
—H
—H
156-157
Fumarate


186
—H
—Cl
—F
—H
—H
—H
—Br
—H
—H
159-160
Fumarate


187
—H
—H
—F
—H
—H
—H
—H
—H
—H
226-228
2 Hydrochloride


188
—H
—H
—Cl
—Cl
—H
—H
—H
—H
—H
135-138
2 Hydrochloride


189
—H
—H
—Cl
—Cl
—H
—H
—Cl
—H
—H
123-125
2 Hydrochloride


190
—H
—H
—F
—Cl
—H
—H
-3-FURYL
—H
—H
157-160
2 Hydrochloride


191
—H
—H
—F
—Cl
—H
—H
-2-THIENYL
—H
—H
152-155
2 Hydrochloride


192
—H
—H
—F
—Cl
—H
—H
—F
—H
—H
115-120
2 Hydrochloride
















TABLE 61













 


















Ex. No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
M.p. (° C.)
Salt





193
—H
—Cl
—F
—H
—H
—H




—H
—H
143-145
2 Hydro- chloride


 


194
—H
—Cl
—F
—H
—H
—H




—H
—H
145-146
2 Hydro- chloride


 


195
—H
—Cl
—F
—H
—H
—H




—H
—H
113-116
2 Hydro- chloride


 


196
—H
—Cl
—F
—H
—H
—H




—H
—H
128-130
2 Hydro- chloride


 


197
—H
—Cl
—F
—H
—H
—H




—H
—H
116-120
2 Hydro- chloride


 


198
—H
—H
—F
—H
—H
—H




—H
—H
132-135
2 Hydro- chloride


 


199
—H
—Cl
—F
—H
—H
—H




—H
—H
142-145
3 Hydro- chloride


 


200
—H
—Cl
—F
—H
—H
—H




—H
—H
212-215
4 Hydro- chloride


 


201
—H
—Cl
—F
—H
—H
—H




—H
—H
208-211
4 Hydro- chloride


 


202
—H
—Cl
—F
—H
—H
—H




—H
—H
200-203
3 Hydro- chloride
















TABLE 62













 


















Ex. No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
M.p. (° C.)
Salt





203
—H
—Cl
—F
—H
—H
—H




—H
—H
160-162
4 Hydro- chloride


 


204
—H
—Cl
—F
—H
—H
—H




—H
—H
167-170
2 Hydro- chloride


 


205
—H
—Cl
—F
—H
—H
—H




—H
—H
200-203
3 Hydro- chloride


 


206
—H
—Cl
—F
—H
—H
—H




—H
—H
243-246
3 Hydro- chloride


 


207
—H
—Cl
—F
—H
—H
—H




—H
—H
145-147
4 Hydro- chloride


 


208
—H
—H
—F
—Cl
—H
—H




—H
—H
143-145
3 Hydro- chloride


 


209
—H
—H
—F
—H
—H
—H




—H
—H
131-133
3 Hydro- chloride


 


210
—H
—H
—F
—Cl
—H
—H




—H
—H
184-186
3 Hydro- chloride


 


211
—H
—H
—F
—Cl
—H
—H




—H
—H
160-162
3 Hydro- chloride


 


212
—H
—H
—F
—Cl
—H
—H




—H
—H
133-135
2 Hydro- chloride
















TABLE 63













 


















Ex. No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
M.p. (° C.)
Salt





213
—H
—Cl
—F
—H
—H
—H




—H
—H
128-131
2 Hydro- chloride


 


214
—H
—Cl
—F
—H
—H
—H




—H
—H
164-166
2 Hydro- chloride
















TABLE 64













 


















Ex. No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
M.p. (° C.)
Salt





215
—H
—Cl
—F
—H
—H




—H
—H
—H
181-183
4 Hydro- chloride
















TABLE 65













 


















Ex.













No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
NMR
Salt





















216
—H
—Cl
—F
—H
—H
—H
—H
—H
—H
1H-NMR (DMSO-d6) δ ppm
2 Hydro-












1.59-1.82 (1H, m), 2.11-2.35 (1H, m), 2.85-3.28 (3H, m),
chloride












3.50-3.71 (1H, m), 5.01-5.21 (1H, m), 6.25-6.46 (1H, m),













6.82-6.92 (1H, m), 7.33-7.50 (1H, m), 7.55-7.70 (2H, m),













7.74 (1H, dd, J = 2.4 Hz and 6.7 Hz), 8.11-8.21 (1H,













m), 9.20-9.75 (2H, m)



217
—H
—H
—H
—H
—H
—CH3
—H
—H
—H
1H-NMR (DMSO-d6) δ ppm
Hydro-












1.60-1.79 (1H, m), 2.13-2.30 (1H, m), 2.50 (1H, s), 2.86-3.02
chloride












(1H, m), 3.05-3.20 (2H, m), 3.59-3.64 (1H, m), 5.29-5.45













(1H, m), 5.80-6.00 (1H, m), 6.68 (1H, d, J = 7.2 Hz), 7.32













(1H, d, J = 7.2 Hz), 7.41-7.51 (2H, m), 7.53-7.61 (2H,













m), 9.49 (2H, brs)



218
—H
—H
—H
—H
—H
—H
—CH3
—H
—H
1H-NMR (DMSO-d6) δ ppm
2 Hydro-












1.61-1.79 (1H, m), 2.19 (3H, s), 2.23-2.39 (1H, m), 2.85-
chloride












3.20 (3H, m), 3.59-3.74 (1H, m), 5.05-5.22 (1H, m), 6.20-6.40













(1H, m), 7.32-7.41 (2H, m), 7.46-7.62 (4H, m), 7.94-7.99 (1H,













m), 9.30-9.65 (2H, br)



219
—H
—H
—H
—H
—H
—H
—H
—CH3
—H
1H-NMR (DMSO-d6) δ ppm
2 Hydro-












1.60-1.80 (1H, m), 2.19 (3H, s), 2.24-2.48 (1H, m), 2.81-3.00
chloride












(1H, m), 3.02-3.19 (2H, m), 3.58-3.64 (1H, m), 6.30 (1H, d,













J = 8.8 Hz), 7.32-7.42 (2H, m), 7.49-7.68 (4H, m), 7.93-













8.01 (1H, m), 9.50 (2H, brs)



220
—H
—Cl
—F
—H
—H
—CH3
—H
—H
—H
1H-NMR (DMSO-d6) δ ppm
Fumarate












1.52-1.76 (1H, m), 1.92-2.18 (1H, m), 2.32 (3H, s), 2.90-













3.22 (3H, m), 3.50-3.72 (1H, m), 5.05-5.25 (1H, m), 5.72-













5.90 (1H, m), 6.35-6.70 (3H, m), 7.11-7.75 (3H, m)



221
—H
—CF3
—F
—H
—H
—H
—H
—H
—H
1H-NMR (DMSO-d6) δ ppm
2 Hydro-












1.65-1.83 (1H, m), 2.16-2.31 (1H, m), 3.00-3.31 (3H, m),
chloride












3.52-3.67 (1H, m), 5.03-5.16 (1H, m), 6.25 (1H, d, J =













8.5 Hz), 6.80-6.85 (1H, m), 7.52-7.59 (1H, m), 7.67-7.81













(1H, m), 7.84 (1H, d, J = 6.5 Hz), 8.19-8.22













(1H, m), 9.07 (1H, br), 9.34 (1H, br).
















TABLE 66













 


















Ex.













No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
NMR
Salt





222
—H
—Cl
—F
—Cl
—H
—H
—H
—CF3
—H
H-NMR (DMSO-d6) δ ppm 1.7-1.8 (1H, m),
2 Hydro-












2.1-2.3 (1H, m), 3.0-3.2 (2H, m), 3.2-3.3 (1H,
chloride












m), 3.5-3.7 (1H, m), 5.1-5.2 (1H, m), 6.24 (1H, s), 7.03













(1H, d, J = 5.3 Hz), 7.4-7.5 (1H, m), 7.63 (1H, dd,













J = 9.0 Hz, J = 9.0 Hz), 7.7-7.8 (1H, m), 8.47 













(1H, d, J = 5.3 Hz), 9.21 (1H, brs), 9.53 (1H, brs)



223
—H
—Cl
—F
—H
—H
—OCH3
—H
—H
—H
H-NMR (DMSO-d6) δ ppm 1.6-1.7 (1H, m),
2 Hydro-












2.1-2.2 (1H, m), 2.9-3.1 (1H, m), 3.1-3.2 (2H, m),
chloride












3.6-3.8 (1H, m), 3.85 (3H, s), 5.1-5.2 (1H, m), 5.52













(1H, d, J = 8.0 Hz), 6.12 (1H, d, J = 7.8 Hz), 7.3-7.4 (2H,













m), 7.5-7.7 (2H, m), 9.25 (1H, brs), 9.45 (1H, brs)



224
—H
—CH3
—F
—H
—H
—H
—H
—H
—Cl
H-NMR (CDCl3) δ ppm 2.1-2.4 (2H, m), 2.23
2 Hydro-












(3H, s), 3.2-3.3 (1H, m), 3.4-3.6 (2H, m), 3.6-3.8 
chloride












(1H, m), 4.7- 4.9 (1H, m), 6.7-7.1 (4H, m), 7.57













(1H, d, J = 7.1 Hz), 8.52 (1H, d, J = 3.9 Hz), 9.53













(1H, brs), 10.10 (1H, brs)



225
—H
—CH3
—F
—H
—H
—H
—H
—H
—H
H-NMR (CDCl3) δ ppm 1.8-2.0 (1H, m), 2.35
2 Hydro-












(3H, s), 2.5-2.7 (1H, m), 3.1-3.4 (2H, m), 3.4-3.6
chloride












(1H, m), 4.1-4.3 (1H, m), 5.3-5.5 (1H, m), 6.47 (1H, d,













J = 8.9 Hz), 7.05 (1H, s), 7.2-7.4 (3H, m), 7.78 (1H, dd,













J = 8.9 Hz, J = 7.6 Hz), 8.25 (1H, d, J = 4.7 Hz), 9.51













(1H, brs), 10.39 (1H, brs)



226
—H
—H
—F
—H
—H
—H
—CH3
—H
—H
H-NMR (CDCl3) δ ppm 1.8-2.0 (1H, m), 2.31
2 Hydro-












(3H, s), 2.35 (3H, s), 2.6-2.7 (1H, m), 3.1-3.3 (1H, m),
chloride












3.3-3.4 (1H, m), 3.4-3.6 (1H, m), 4.1-4.3 (1H, m), 













5.3-5.5 (1H, m), 6.42 (1H, d, J = 9.3 Hz), 













7.1-7.4 (3H, m), 7.61 (1H, d, J = 9.3 Hz),













8.04 (1H, s), 9.51 (1H, brs), 10.47 (1H, brs)



227
—H
—CH3
—F
—H
—H
—CH3
—H
—H
—H
H-NMR (CDCl3) δ ppm 1.8-2.0 (1H, m), 2.36 (3H, s),
2 Hydro-












2.4-2.5 (1H, m), 2.92 (3H, s), 3.2-3.4 (2H, m), 3.4-3.6
chloride












(1H, m), 4.1-4.3 (1H, m), 6.0-6.1 (1H, m), 6.20 (1H,













d, J = 8.9 Hz), 6.73 (1H, d, J = 7.1 Hz), 7.1-7.3 (3H,













m), 7.5-7.7 (1H, m), 9.29 (1H, brs), 10.98 (1H, brs)
















TABLE 67













 


















Ex.













No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
NMR
Salt





















228
—H
—CH3
—F
—H
—H
—OCH3
—H
—H
—H
H-NMR (CDCl3) δ ppm 1.9-2.1 (1H, m), 2.26 (3H, s),
2 Hydro-












2.2-2.4 (1H, m), 3.2-3.5 (3H, m), 3.8-3.9 (1H, m),
chloride












3.90 (3H, s), 5.0-5.2 (1H, m), 5.58 (1H, d, J = 8.1













Hz), 6.08 (1H, d, J = 8.0 Hz), 6.9-7.1 (3H, m),













7.22 (1H, dd, J = 8.0 Hz, J = 8.1 Hz), 9.74 (1H, brs),













10.18 (1H, brs)



229
—H
—CH3
—F
—H
—H
—H
—H
—CH3
—H
H-NMR (CDCl3) δ ppm 1.9-2.0 (1H, m), 2.31
2 Hydro-












(3H, s), 2.37 (3H, s), 2.6-2.7 (1H, m), 3.1-3.3
chloride












(1H, m), 3.3-3.4 (1H, m), 3.4-3.6 (1H, m), 4.1-4.3













(1H, m), 5.4-5.6 (1H, m), 6.18 (1H, s), 6.84 (1H, d,













J = 6.3 Hz), 7.2-7.4 (3H, m), 8.11 (1H, d, J = 6.3 Hz),













9.55 (1H, brs), 10.64 (1H, brs)



230
—H
—CH3
—F
—H
—H
—H
—H
—H
—CH3 
H-NMR (CDCl3) δ ppm 1.96 (3H, s), 2.0-2.1
2 Hydro-












(1H, m), 2.27 (3H, s), 2.4-2.6 (1H, m), 3.4-
chloride












3.7 (3H, m), 3.8-4.0 (1H, m), 5.3-5.5 (1H, m), 7.0-7.3













(3H, m), 7.3-7.5 (1H, m), 7.89 (1H, d, J = 7.0 Hz), 













8.50 (1H, d, J = 5.1 Hz), 9.77 (1H, brs), 10.39 (1H, brs)



231
—H
—Cl
—F
—H
—H
—H
—Cl
—H
—Cl
1H-NMR (CDCl3) δ ppm













1.65-1.81 (1H, m), 1.99-2.09 (1H, m), 2.81-3.11 (4H, m),













4.50-4.61 (1H, m), 6.80-6.87 (1H, m), 7.00 (1H, dd, J =













2.8, 6.4 Hz), 7.05 (1H, t, d, J = 8.7 Hz), 7.61 (1H, d = 2.3













Hz), 8.26 (1H, d, J = 2.3 Hz).



232
—H
—Cl
—F
—H
—H
—H
—CN
—H
—H
1H-NMR (CDCl3) δ ppm













1.63-1.77 (1H, m), 2.01-2.15 (1H, m), 2.78-2.96 (3H, m),













3.28-3.35 (1H, m), 5.02-5.16 (1H, m), 6.03 (1H, d, J = 9.0













Hz), 7.02-7.10 (1H, m), 7.24-7.32 (2H, m), 7.44 (1H, dd,













J = 2.3, 9.0 Hz), 8.46 (1H, d, J = 2.3 Hz).



233
—H
—Cl
—F
—H
—H
—CN
—H
—H
—H
1H-NMR (CDCl3) δ ppm













1.82-1.95 (1H, m), 2.19-2.25 (1H, m), 3.11-3.29 (3H, m),













3.62-3.70 (1H, m), 5.01-5.11 (1H, m), 6.27 (1H, d, J = 8.8













Hz), 7.06 (1H, d, J = 7.3 Hz), 7.10-7.15 (1H, m), 7.23-7.31













(2H, m), 7.39 (1H, dd, J = 7.3, 8.8 Hz).
















TABLE 68













 


















Ex.













No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
NMR
Salt





















234
—H
—Cl
—Cl
—H
—H
—H
—H
—Cl
—H
1H-NMR (DMSO-d6) δ ppm 1.68-1.82 (1H, m), 2.11-2.24
2 Hydro-












(1H, m), 3.01-3.14 (2H, m), 3.15-3.29 (1H, m), 3.48-3.65
chloride












(1H, m), 4.98-5.10 (1H, m), 6.21 (1H, s), 6.88 (1H, d,













J = 5.4 Hz), 7.35-7.40 (1H, m), 7.76 (1H, d, J = 1.7 Hz),













7.82 (1H, d, J = 8.4 Hz), 8.21 (1H, d, J = 5.4 Hz), 9.19













(1H, brs), 9.55 (1H, brs).



235
—H
—Cl
—F
—H
—H
—H
—H
—H
—Cl
1H-NMR (CDCl3) δ ppm 1.74 (1H, brs), 2.30 (1H, brs),
Hydro-












3.34 (1H, brs), 3.55 (2H, brs), 3.73 (1H, brs), 4.79
chloride












(1H, brs), 6.90-7.13 (4H, m), 7.60 (1H, d, J = 7.7













Hz), 8.58 (1H, s), 9.48 (1H, brs), 10.38 (1H, brs).



236
—H
—Cl
—F
—H
—H
—H
-3-
—H
—H
1H-NMR (DMSO-d6) δ ppm 1.65-1.90 (1H, m), 2.13-2.31
2 Hydro-









PYRIDYL


(1H, m), 2.99-3.28 (3H, m), 3.58-3.72 (1H, m), 5.13-5.28
chloride












(1H, m), 6.26 (1H, d, J = 9.0 Hz), 7.45 (1H, ddd,













J = 2.6, 4.3, 8.6 Hz), 7.65 (1H, t, J = 9.0 Hz), 7.76 (1H, dd, 













J = 2.5, 6.7 Hz), 8.02 (1H, dd, J = 2.5, 9.0 Hz), 













8.11 (1H, dd, J = 5.7, 8.1 Hz), 8.78-8.87













(3H, m), 9.25 (1H, s), 9.60 (1H, brs), 9.85 (1H, brs).
















TABLE 69













 


















Ex. No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
M.p. (° C.)
Salt





237
—H
—Cl
—F
—H
—H
—H
—H
—H
—H
194.0-195.0
2Methanesulfonate


238
—H
—Cl
—F
—H
—H
—H
—C6H5
—H
—H
158-161
2 Hydrochloride


239
—H
—Cl
—F
—H
—H
—H
—F
—H
—H
75-80
2 Hydrochloride


240
—H
—Cl
—F
—H
—H
—H
—F
—H
—H
121-123
Fumarate


241
—H
—Cl
—Cl
—H
—H
—H
—CN
—H
—H
150-155
2 Hydrochloride


242
—H
—Cl
—Cl
—H
—H
—H
—H
—H
—H
108-110
Hydrochloride


243
—H
—H
—F
—H
—H
—H
—H
—H
—H
232-234
2 Hydrochloride


244
—H
—Cl
—F
—H
—H
—H
—Cl
—H
—H
136-137
Fumarate


245
—H
—Cl
—F
—H
—H
—H
—H
-4-PYRIDYL
—H
200-205
3 Hydrochloride
















TABLE 70













 


















Ex. No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
M.p.(° C.)
Salt





246
—H
—Cl
—F
—H
—H
—H
—H




—H
252-257
4 Hydro- chloride


 


247
—H
—H
—F
—Cl
—H
—H




—H
—H
223-225
3 Hydro- chloride


 


248
—H
—H
—F
—Cl
—H
—H




—H
—H
155-157
2 Hydro- chloride
















TABLE 71













 


















Ex.













No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
NMR
Salt





249
—H
—H
—H
—H
—H
—H
—H
—H
—H
1H-NMR (DMSO-d6) δppm 1.50-1.70 (1H, m),
Fumarate












2.10-2.31(1H, m), 2.75-2.90 (1H, m), 3.00-3.22













(2H, m), 3.51-3.68 (1H, m), 4.60-4.80 (1H, m), 













6.47 (2H, s), 7.01-7.10 (2H, m), 7.13-7.30 (3H, m), 













7.32-7.45 (2H, m), 8.07 (1H, d, J = 2.7 Hz), 8.13













(1H, dd, J = 1.4 Hz and 4.5 Hz)



250
—H
—Cl
—F
—H
—H
—H
—H
—H
—H
1H-NMR (DMSO-d6) δppm 1.51-1.74 (1H, m),
2 Hydro-












2.13-2.35 (1H, m), 2.80-2.99 (1H, m), 3.01-3.20
chloride












(2H, m), 3.52-3.72 (1H, m), 4.75-4.94 (1H, m), 













7.39-7.48 (1H, m), 7.59-7.69 (2H, m), 7.71-7.81 













(2H, m), 8.19-8.29 (2H, m)



251
—H
—F
—H
—H
—H
—H
—H
—H
—H
1H-NMR (DMSO-d6) δppm 1.62-1.81 (1H, m),
2 Hydro-












2.20-2.37 (1H, m), 2.88-3.24 (3H, m), 3.56-3.72
chloride












(1H, m), 5.10-5.27 (1H, m), 6.27 (1H, d, J = 8.6













Hz), 6.82-6.92 (1H, m), 7.37 (2H, d, J = 7.1 Hz), 













7.49-7.72 (4H, m with d at δ7.58, J = 7.6 Hz), 8.15 













(1H, dd, J = 1.2 Hz and 5.6 Hz), 9.30-9.80 (2H, m)



252
—H
—H
—H
—H
—H
—H
—F
—H
—H
1H-NMR (DMSO-d6) δppm 1.50-1.71 (1H, m),
Hydro-












2.05-2.28 (1H, m), 2.75-2.92 (1H, m), 3.00-3.24
chloride












(2H, m), 3.45-3.62 (1H, m), 4.52-4.78 (1H, m), 6.86- 













6.98 (2H, m), 7.01-7.11 (1H, m), 7.15 (1H, dd, J = 3.4













Hz and 7.2 Hz), 7.28-7.39 (2H, m), 7.48-7.62













(1H, m), 7.84-7.93 (1H, m), 9.20-9.80 (2H, m)



253
—H
—CH3
—F
—H
—H
—H
—H
—H
—H
1H-NMR (DMSO-d6) δppm 1.5-1.7 (1H, m), 2.0-
2Methane-












2.2 (1H, m), 2.27 (3H, s), 2.36 (6H, s), 2.8-3.0
sulfonate












(1H, m), 3.0-3.3 (2H, m), 3.6-3.7 (1H, m), 4.7-4.9 













(1H, m), 7.2-7.4 (3H, m), 7.55 (1H, d, J = 8.9 Hz), 













7.75 (1H, d, J = 8.9 Hz), 8.14 (1H, s), 













8.22 (1H, d, J = 5.1 Hz), 8.83 (2H, brs)



254
—H
—Cl
—F
—H
—H
—H
—OCH3
—H
—H
1H-NMR (DMSO-d6) δppm 1.5-1.7 (1H, m), 2.1-2.2
Fumarate












(1H, m), 2.7-2.9 (1H, m), 3.0-3.2 (2H, m), 3.5-3.6













(1H, m), 3.86 (3H, s), 4.6-4.7 (1H, m), 6.46 (2H, s),













6.5-6.7 (1H, m), 6.85 (1H, d, J = 9.1 Hz), 6.90 (1H, d,













J = 8.7 Hz), 7.21 (1H, dd, J = 9.1 Hz, J = 9.1 Hz), 7.56













(1H, d, J = 8.7 Hz), 8.03 (1H, s)
















TABLE 72













 


















Ex.













No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
NMR
Salt





255
—H
—F
—F
—H
—H
—H
—H
—H
—H
H-NMR (DMSO-d6) δppm 1.6-1.8 (1H, m), 2.2-2.3
2 Hydro-












(1H, m), 2.9-3.0 (1H, m), 3.0-3.2 (2H, m), 3.6-3.8
chloride












(1H, m), 4.8-4.9 (1H, m), 7.23 (1H, d, J = 8.7 Hz),













7.5-7.8 (4H, m), 8.21 (1H, s), 8.36 (1H, d, J =













5.1 Hz), 9.49 (1H, brs), 9.55 (1H, brs)



256
—H
—Cl
—Cl
—H
—H
—H
—H
—H
—H
H-NMR (DMSO-d6) δppm 1.6-1.8 (1H, m), 2.2-2.3
2 Hydro-












(1H, m), 2.9-3.0 (1H, m), 3.1-3.2 (2H, m), 3.6-3.8
chloride












(1H, m), 4.8-4.9 (1H, m), 7.26 (1H, d, J = 8.6 Hz),













7.6-7.8 (4H, m), 8.32 (1H, s), 8.34 (1H, d, J =













4.6 Hz), 9.38 (1H, brs), 9.50 (1H, brs)



257
—H
—CF3
—F
—H
—H
—H
—H
—H
—H
1H-NMR (DMSO-d6) δppm 1.52-1.72 (1H, m), 2.19-
2 Hydro-












2.35 (1H, m), 2.84-3.01 (1H, m), 3.05-3.21 (2H, m),
chloride












3.59-3.73 (1H, m), 4.81-4.94 (1H, m), 7.61 (1H, dd,













J = 2.0 Hz, 8.5 Hz), 7.71-7.76 (3H, m), 7.82 (1H, d, J =













7.0 Hz), 8.26-8.29 (2H, m), 9.40 (1H, br), 9.50 (1H, br).



258
—H
—Cl
—H
—H
—H
—H
—H
—H
—H
H-NMR (DMSO-d6) δppm 1.6-1.8 (1H, m), 2.2-2.3
2 Hydro-












(1H, m), 2.8-2.9 (1H, m), 3.0-3.2 (2H, m), 3.5-3.7
chloride












(1H, m), 4.8-5.0 (1H, m), 7.29 (1H, d, J = 7.8 Hz), 7.47













(1H, s), 7.5-7.7 (3H, m), 7.76 (1H, d, J = 8.9 Hz), 8.21













(1H, s), 8.29 (1H, d, J = 5.3 Hz), 9.5-9.8 (2H, br)



259
—H
—Cl
—F
—H
—H
—H
—H
—Br
—H
H-NMR (DMSO-d6) δppm 1.5-1.7 (1H, m), 2.1-2.3
2 Hydro-












(1H, m), 2.8-3.0 (1H, m), 3.0-3.2 (2H, m), 3.5-3.7
chloride












(1H, m), 4.7-4.9 (1H, m), 7.2-7.4 (1H, m), 7.50 (1H, s),













7.56 (1H, dd, J = 9.0 Hz, J = 9.0 Hz), 7.6-7.7 (1H, m),













7.97 (1H, s), 8.23 (1H, s), 9.41 (1H, brs), 9.51 (1H, brs)
















TABLE 73













 


















Ex.













No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
NMR
Salt





260
—H
—Cl
—F
—H
—H
—H
—H
—COC6H5
—H
H-NMR (DMSO-d6) δppm 1.6-1.8 (1H, m), 2.2-2.4
2 Hydro-












(1H, m), 2.9-3.0 (1H, m), 3.1-3.2 (2H, m), 3.5-3.7
chloride












(1H, m), 4.8-5.0 (1H, m), 7.3-7.4 (1H, m), 7.5-7.9













(8H, m), 8.37 (1H, s), 8.39 (1H, s), 9.4-9.7 (2H, br)



261
—H
—Cl
—F
—H
—H
—H
—H
—C6H5
—H
H-NMR (DMSO-d6) δppm 1.6-1.8 (1H, m), 2.2-
2 Hydro-












2.4 (1H, m), 2.9-3.0 (1H, m), 3.1-3.2 (2H, 
chloride












m), 3.6-3.8 (1H, m), 4.9-5.1 (1H, m), 7.4-7.5













(1H, m), 7.5-7.6 (3H, m), 7.62 (1H, dd, J = 8.9













Hz, J = 8.9 Hz), 7.7-7.8 (1H, m), 7.79













(2H, d, J = 8.3 Hz), 7.87 (1H, s), 8.00 (1H, s), 













8.57 (1H, s), 9.46 (1H, brs), 9.58 (1H, brs)



262
—H
—Cl
—F
—H
—H
—H
—H
—SCH3
—H
H-NMR (DMSO-d6) δppm 1.5-1.7 (1H, m), 2.1-2.3
2 Hydro-












(1H, m), 2.55 (3H, s), 2.8-3.0 (1H, m), 3.0-3.2
chloride












(2H, m), 3.5-3.7 (1H, m), 4.7-4.9 (1H, m), 7.2-7.3













(1H, m), 7.33 (1H, s), 7.5-7.6 (2H, m), 7.81













(1H, s), 8.10 (1H, s), 9.22 (1H, brs), 9.36 (1H, brs)



263
—H
—Cl
—F
—H
—H
—H
—H
—SC6H5
—H
H-NMR (DMSO-d6) δppm 1.5-1.7 (1H, m), 2.1-2.3
2 Hydro-












(1H, m), 2.8-2.9 (1H, m), 3.0-3.2 (2H, m), 3.5-3.7
chloride












(1H, m), 4.7-4.9 (1H, m), 6.77 (1H, s), 7.2-7.3 (1H, 













m), 7.40 (5H, s), 7.4-7.6 (2H, m), 8.01 (1H, s), 8.08













(1H, s), 9.38 (1H, brs), 9.46 (1H, brs)



264
—H
—Cl
—F
—H
—H
—H
—Cl
—Cl
—H
H-NMR (DMSO-d6) δppm 1.5-1.7 (1H, m), 2.1-2.3
2 Hydro-












(1H, m), 2.8-2.9 (1H, m), 3.0-3.2 (2H, m), 3.5-3.7
chloride












(1H, m), 4.7-4.9 (1H, m), 7.2-7.4 (1H, m), 7.44 (1H,













s), 7.54 (1H, dd, J = 9.0 Hz, J = 9.0 Hz), 7.6-7.7













(1H, m), 7.75 (1H, s), 9.36 (2H, brs)
















TABLE 74













 


















Ex.













No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
NMR
Salt





















265
—H
—Cl
—F
—H
—H
—H
—H
—C2H5
—H
H-NMR (DMSO-d6) δppm 1.16 (3H, t, J = 7.0 Hz),
2 Hydro-












1.5-1.7 (1H, m), 2.2-2.3 (1H, m), 2.69 (2H, q, J =
chloride












7.0 Hz), 2.8-2.9 (1H, m), 3.0-3.2 (2H, m), 3.5-3.7













(1H, m), 4.8-5.0 (1H, m), 7.2-7.3 (1H, m), 7.59













(1H, s), 7.6-7.7 (2H, m), 7.95 (1H, s), 8.19 (1H, s),













9.42 (1H, brs), 9.55 (1H, brs)



266
—H
—Cl
—F
—H
—H
—H
—H
—Cl
—H
H-NMR (DMSO-d6) δppm 1.5-1.7 (1H, m), 2.1-2.3
2 Hydro-












(1H, m), 2.8-2.9 (1H, m), 3.0-3.2 (2H, m), 3.5-3.7
chloride












(1H, m), 4.7-4.9 (1H, m), 7.2-7.3 (1H, m), 7.33













(1H, s), 7.55 (1H, dd, J = 9.0 Hz, J = 9.0 Hz), 













7.6-7.7 (1H, m), 7.92 (1H, s), 8.13













(1H, s), 9.44 (1H, brs), 9.53 (1H, brs)



267
—H
—Cl
—F
—H
—H
—H
—H
—CN
—H
H-NMR (DMSO-d6) δppm 1.5-1.7 (1H, m), 2.1-2.3
2Methane-












(1H, m), 2.44 (6H, s), 2.8-3.0 (1H, m), 3.1-3.2 (2H,
sulfonate












m), 3.6-3.8 (1H, m), 4.7-4.9 (1H, m), 7.2-7.3 (1H, m),













7.5-7.7 (2H, m), 7.67 (1H, s), 8.17 (1H, s), 8.45 













(1H, s), 8.79 (1H, brs), 8.84 (1H, brs)



268
—H
—Cl
—F
—H
—H
—H
—CN
—H
—H
1H-NMR (DMSO-d6) δppm 1.60-1.78 (1H, m),
2 Hydro-












2.18-2.32 (1H, m), 2.83-2.99 (1H, m), 3.05-3.19
chloride












(2H, m), 3.55-3.70 (1H, m), 4.75-4.87 (1H, m), 7.05













(1H, dd, J = 3.0, 8.9 Hz), 7.32-7.43 (1H, m), 7.64













(1H, t, J = 9.0 Hz), 7.74 (1H, dd, J = 2.5, 6.7 Hz), 













7.78 (1H, d, J = 8.9 Hz), 8.03 (1H, d, J =













2.9 Hz), 9.25 (1H, brs), 9.38 (1H, brs).



269
—H
—Cl
—F
—H
—H
—H
—CN
—H
—H
1H-NMR (CDCl3) δppm 1.67-1.81 (1H, m),













2.10-2.25 (1H, m), 2.83-2.89 (1H, m), 2.90-3.00 (2H,













m), 3.27-3.34 (1H, m), 4.35-4.52 (1H, m), 6.86 (1H, 













dd, J = 3.0, 5.4 Hz), 7.05-7.10 (1H, m), 7.23-7.28 (1H, 













m), 7.30 (1H, d, J = 8.8 Hz), 7.44 (1H, d, J = 8.8 Hz), 













8.00 (1H, d, J = 3.0 Hz).
















TABLE 75













 


















Ex.













No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
NMR
Salt





270
—H
—Cl
—Cl
—H
—H
—H
—CN
—H
—H
1H-NMR (CDCl3) δppm 1.70-1.82 (1H, m), 2.11-2.25













(1H, m), 2.83-2.90 (1H, m), 2.94-3.00 (2H, m), 3.26-3.33













(1H, m), 4.35-4.50 (1H, m), 6.90 (1H, dd, J = 3.0,













8.8 Hz), 7.04 (1H, dd, J = 2.4, 8.5 Hz), 7.28 (1H, d,













J = 2.8 Hz), 7.45 (1H, d, J = 8.8 Hz), 7.59













(1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 2.8 Hz).



271
—H
—H
—Cl
—F
—H
—H
—H
—H
—H
H-NMR (DMSO-d6) δppm 1.6-1.8 (1H, m), 2.2-2.3
2Methane-












(1H, m), 2.36 (6H, s), 2.9-3.0 (1H, m), 3.1-3.3 (2H, m),
sulfonate












3.6-3.8 (1H, m), 4.8-4.9 (1H, m), 7.09 (1H, d, J = 8.5













Hz), 7.4-7.5 (1H, m), 7.7-7.9 (3H, m), 8.30 (1H, s), 8.36













(1H, d, J = 6.1 Hz), 8.76 (1H, brs), 8.84 (1H, brs)
















TABLE 76













 

















Ex. No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
NMR





272
—H
—Cl
—F
—H
—H
—H
—H




—H
1H-NMR (CDCl3) ppm 1.67-1.81 (1H, m), 2.08-2.19 (1H, m), 2.87-3.00 (3H, m), 3.24-3.31 (1H, m), 4.40-4.48 (1H, m), 6.95-7.05 (1H, m), 7.16-7.24 (3H, m), 7.61 (2H, d, J = 8.3 Hz), 7.74 (2H, d, J = 8.3 Hz), 8.12 (1H, d, J = 2.6 Hz), 8.43 (1H, d, J = 1.5 Hz).
















TABLE 77













 


















Ex. No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
M.p. (° C.)
Salt





273
—H
—Cl
—Cl
—H
—H
—H
—H
—H
—H
229-231
2 Hydro-













chloride
















TABLE 78













 


















Ex. No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
NMR
Salt





274
—H
—H
—H
—H
—H
—H
—H
—H
—H
1H-NMR (DMSO-d6) δppm1.52-1.71 (1H, m),
Hydro-












2.21-2.39 (1H, m), 2.40-2.99 (1H, m), 3.00-3.25
chloride












(2H, m), 3.61-3.78 (1H, m), 4.98-5.12 (1H, m),













6.55-7.10 (2H, m), 7.35-7.45 (2H, m), 7.53-7.71













(3H, m), 8.22-8.38 (2H, m), 9.80 (2H, brs),













14.45 (1H, brs)



275
—H
—Cl
—F
—H
—H
—H
—H
—H
—H
1H-NMR (DMSO-d6) δppm
2 Hydro-












1.56-1.76 (1H, m), 2.20-2.38 (1H, m), 2.89-3.02
chloride












(1H, m), 3.03-3.20 (2H, m), 3.60-3.75 (1H, m),













4.94-5.11 (1H, m), 6.70-7.15 (2H, m), 7.41-7.53













(1H, m), 7.66-7.76 (1H, m), 7.85 (1H, dd,













J = 2.5 Hz and 6.9 Hz), 8.33 (2H, d, J = 7.0 Hz),













9.44-9.80 (2H, m)



276
—H
—Cl
—F
—H
—H
—H
—CH3 
—H
—H
H-NMR (DMSO-d6) δppm
2 Hydro-












1.6-1.8 (1H, m), 2.2-2.4 (1H, m), 2.50 (3H, s),
chloride












2.8-3.0 (1H, m), 3.1-3.2 (2H, m), 3.6-3.8 (1H,













m), 4.9-5.1 (1H, m), 6.4-7.0 (2H, m), 7.4-7.5













(1H, m), 7.69 (1H, dd, J = 9.0 Hz, J = 9.0 Hz),













7.8-7.9 (1H, m), 8.20 (1H, d, J = 5.5 Hz), 9.54













(1H, brs), 9.70 (1H, brs)
















TABLE 79













 















Ex. No.
R1
R2
R3
R4
R5
R6
M.p. (° C.)
Salt





277
—H
—H
—H
—H
—H




124.7-126.7
Fumarate


 


278
—H
—Cl
—F
—H
—H




135.0-136.0
Fumarate


 


279
—H
—F
—H
—H
—H




139.0-141.0
Fumarate
















TABLE 80













 















Ex. No.
R1
R2
R3
R4
R5
R6
NMR
Salt





280
—H
—H
—F
—H
—H




1H-NMR (DMSO-d6) δppm 0.99-1.50 (2H, m), 1.51-2.20 (4H, m), 2.80-3.65  (7H, m), 3.60-3.99 (2H, m), 4.10-4.81(1H, m), 7.01-7.99 (4H, m), 9.15-9.90 (2H, m)
Hydrochloride
















TABLE 81













 















Ex. No.
R1
R2
R3
R4
R5
R6
NMR
Salt





281
—H
—Cl
—F
—H
—H




1H-NMR (DMSO-d6) δppm 1.68-1.83 (1H, m), 2.05-2.22 (1H, m), 2.75- 3.20 (3H, m), 3.41-3.59 (1H, m), 4.51-4.72 (1H, m), 5.80-5.90 (1H, m), 6.57-6.65 (1H, m), 6.69-6.79 (2H, m), 6.80-6.88 (1H, m), 7.09- 7.19 (1H, m), 9.10-9.50 (2H, m), 11.05 (1H, brs)
2 Hydro- chloride


 


282
—H
—Cl
—F
—H
—H




1H-NMR (DMSO-d6) δppm 1.6-1.8 (1H, m), 2.1-2.2 (1H, m), 2.8-3.0 (1H, m), 3.1-3.3 (2H, m), 3.4-3.6 (1H, m), 4.6-4.7 (1H, m), 6.56 (1H, d, J = 9.6 Hz), 6.7-6.8 (1H, m), 6.94 (1H, d, J = 9.2 Hz), 7.25 (1H, dd, J = 9.2 Hz, J = 9.0 Hz), 7.43 (1H, d, J = 9.6 Hz), 7.58 (1H, s), 8.90 (2H, brs)
2 Hydro- bromide


 


283
—H
—Cl
—F
—H
—H




1H-NMR (DMSO-d6) δppm 1.6-1.8 (1H, m), 2.1-2.2 (1H, m), 2.8-3.0 (1H, m), 3.0-3.2 (2H, m), 3.4-3.6 (1H, m), 4.54.7 (1H, m), 5.04 (1H, d, J = 14.5 Hz), 5.12 (1H, d, J = 14.5 Hz), 6.48 (2H, s), 6.49 (1H, d, J = 9.5 Hz), 6.6-6.7 (1H, m), 6.8-6.9 (1H, m), 7.1-7.5 (7H, m), 7.94 (1H, s)
Fumarate


 


284
—H
—Cl
—F
—H
—H




1H-NMR (DMSO-d6) δppm 1.6-1.8 (1H, m), 2.1-2.2 (1H, m), 2.8-3.0 (1H, m), 3.0-3.2 (2H, m), 3.42 (3H, s), 3,4-3.6 (1H, m), 4.5-4.7 (1H, m), 6.46 (1H, d, J = 9.5 Hz), 6.6-6.7 (1H, m), 6.8-6.9 (1H, m), 7.22 (1H, dd, J = 9.1 Hz, J = 9.1 Hz), 7.30 (1H, d, J = 9.5 Hz), 7.87 (1H, s), 9.42 (1H, brs), 9.49 (1H, brs)
2 Hydro- chloride


 


285
—H
—Cl
—F
—H
—H




1H-NMR (CDCl3) δppm: 1.65-2.0 (2H, m), 2.05-2.25 (1H, m), 2.7-3.05 (3H, m), 3.1-3.3 (1H, m), 4.4-4.55 (1H, m), 6.4-6.55 (1H, m), 6.65-6.75 (1H, m), 6.86 (1H, dd, J = 9, 9 Hz), 7.0-7.1 (2H, m), 7.1-7.45 (4H, m), 8.51 (1H, br).
















TABLE 82













 











Ex. No.
R2
R6
NMR
Salt





286








1H-NMR (DMSO-d6) δppm 1.56-1.76 (1H, m), 2.01-2.17 (2H, m), 2.21-2.35 (1H, m), 2.76-3.01 (5H, m), 3.05-3.25 (2H, m), 3.59-3.74 (1H, m), 4.794.91 (1H, m), 7.07 (1H, dd, J = 1.5 Hz, 7.5 Hz), 7.20 (1H, s), 7.42-7.53 (2H, m), 7.70-7.76 (1H, m), 8.06 (1H, d, J = 3.0 Hz), 8.19 (1H, d, J = 5.0 Hz), 9.46 (1H, br), 9.52 (1H, br).
2 Hydro- chloride


 


287








1H-NMR (DMSO-d6) δppm 1.62-1.81 (1H, m), 1.99-2.15 (2H, m), 2.20-2.37 (1H, m), 2.84-3.21 (7H, m), 3.57-3.73 (1H, m), 5.10-5.26 (1H, m), 6.38 (1H, d, J = 8.5 Hz), 6.90 (1H, dd, J = 6.5 Hz, 6.5 Hz), 7.11 (1H, dd, J = 1.5 Hz, 8.0 Hz), 7.24 (1H, s), 7.44 (1H, d, J = 8.0 Hz),7.68 (1H, dd, J = 7.5 Hz,7.5 Hz), 8.12 (1H, dd, J = 1.5 Hz, 5.5 Hz), 9.42 (1H, br), 9.51 (1H, br).
2 Hydro- chloride


 


288








1H-NMR (DMSO-d6) δppm 1.64-1.85 (1H, m), 1.99-2.25 (3H, m), 2.85-3.28 (7H, m), 3.47-3.63 (1H, m), 5.02-5.15 (1H, m), 7.09 (1H, dd, J = 2.0 Hz,8.0 Hz), 7.22 (1H, s), 7.38-7.43 (2H, m), 7.88 (1H, d, J = 2.5 Hz), 8.19-8.21 (1H, m), 9.26 (1H, br), 9.54 (1H, br).
2 Hydro- chloride


 


289








1H-NMR (DMSO-d6) δppm 1.66-1.71 (1H, m), 2.15-2.25 (1H, m), 2.82-2.91 (1H, m), 3.01-3.14 (2H, m), 3.54-3.62 (1H, m), 4.70-4.85 (1H, m), 6.47 (2H, s), 7.09 (1H, dd, J = 1.9 Hz and 8.5 Hz), 7.12-7.16 (1H, m), 7.20-7.26 (1H, m), 7.45 (1H, d, J = 5.4 Hz), 7.77 (1H, d, J = 5.4 Hz), 7.85-7.88 (1H, m), 7.91 (1H, d, J = 8.5 Hz), 8.04-8.09 (2H, m)
Fumarate


 


290








1H-NMR (DMSO-d6) δppm: 1.55-1.8 (1H, m), 2.1- 2.35 (1H, m), 2.75-4.5 (7H, m), 4.65-4.9 (1H, m), 6.46 (2H, s), 7.09 (1H, dd, J = 2.5, 9 Hz), 7.2-7.35 (2H, m), 7.35-7.55 (2H, m), 7.60 (1H, d, J = 2 Hz), 7.75-7.95 (3H, m), 8.1-8.25 (2H, m).
Fumarate


 


291








1H-NMR (DMSO-d6) δppm: 1.45-1.7 (1H, m), 2.1- 2.3 (1H, m), 2.6-4.3 (7H, m), 4.75-4.95 (1H, m), 6.48 (2H, s), 6.85-6.95 (1H, m), 7.1-7.25 (2H, m), 7.25-7.4 (1H, m), 7,51 (1H, dd, J = 7.5, 7.5 Hz), 7.78 (1H, d, J = 5.5 Hz), 7.85-8.0 (2H, m), 8.10 (1H, d, J = 8 Hz).
Fumarate


 


292








1H-NMR (DMSO-d6) δppm: 1.4-1.7 (1H, m), 2.0- 2.3 (1H, m), 2.6-4.65 (7H, m), 4.85-5.0 (1H, m), 6.49 (2H, s), 6.8-6.9 (1H, m), 7.12 (1H, dd, J = 4.5, 8.5), 7.45-7.7 (4H, m), 7.77 (1H, d, J = 8 Hz), 7.84 (1H, d, J = 3 Hz), 7.91 (1H, dd, J = 1, 4.5 Hz), 7.99- 8.1 (2H, m).
Fumarate
















TABLE 83













 











Ex. No.
R2
R6
NMR
Salt





293








1H-NMR (DMSO-d6) δppm: 1.55-1.75 (1H, m), 2.15-2.3 (1H, m), 2.55-4.55 (7H, m), 4.75-4.9 (1H, m), 6.48 (2H, s), 6.95- 7.05 (1H, m), 7.1-725 (1H, m), 7.38 (1H, d, J = 7.5 Hz), 7.45-7.6 (2H, m), 7.75 (1H, d, J = 5.51-tz), 7.85-8.05 (3H, m).
Fumarate


 


294








1H-NMR (DMSO-d6) δppm 1.59-1.69. (1H, m), 2.21-2.49 (1H, m), 2.82-3.24 (3H, m), 3.61-3.75 (1H, m), 4.84-5.02 (1H, m), 7.90 (1H, d, J = 2.0 Hz), 7.92 (1H, d, J = 5.5 Hz), 8.14 (1H, d, J = 2.8 Hz), 8.19 (1H, d, J = 5.5 Hz), 8.24 (1H, d, J = 8.5 Hz)
2 Hydro- chloride


 


295








1H-NMR (CDCl3) δppm: 1.7-1.9 (2H, m), 2.16 (1H, dt, J = 7.5, 7.5 Hz), 2.85-3.0 (3H, m), 321 (1H, dd, J = 6.5, 11.5 Hz), 4.45 (1H, tt, J = 6.5, 6.5 Hz), 6.77 (1H, dd, J = 1, 2 Hz), 6.8-6.9 (1H, m), 7.0-7.1 (2H, m), 7.38 (1H, d, J = 2 Hz), 7.55 (1H, d, J = 8.5 Hz), 7.68 (1H, d, J = 2 Hz), 7.99 (1H, dd, J = 1.5, 4.5 Hz), 8.04 (1H, d, J = 3 Hz).



 


296








1H-NMR (CDCl3) δppm: 1.75-1.95 (1H, m), 2.05- 2.4 (2H, m), 2.88 (2H, t, J = 7.5 Hz), 2.98 (1H, dd, J = 5.5, 11.5 Hz), 3.17 (1H, dd, J = 6.5, 12 Hz), 3.83 (3H, s), 4.35-4.5 (1H, m), 6.48 (1H, dd, J = 0.5, 3 Hz), 6.75-6.85 (1H, m), 6.9-7.05 (2H, m), 7.11 (1H, d, J = 3 Hz), 7.3-7.45 (2H, m), 7.92 (1H, dd, J = 1.5, 4.5 Hz), 8.03 (1H, d, J = 3 Hz).



 


297








1H-NMR (DMSO-d6) δ ppm: 1.3-1.65 (1H, m), 2.0-225 (1H, m), 2.6-5.65 (8H, m), 6.46 (2H, s), 6.54 (2H, d, J = 8 Hz), 6.71 (1H, dd, J = 7.5, 7.5 Hz), 7.12 (2H, dd, J = 7.5, 8.5 Hz), 7.52 (1H, dd, J = 4, 8.5 Hz), 7.59 (1H, dd, J = 1, 7.5 Hz), 7.87 (1H, dd, J = 7.5, 8.5 Hz), 8.09 (1H, d, J = 8.5 Hz), 8.15-8.25 (1H, m), 8.93 (1H, dd, J = 1.5, 4 Hz).
Fumarate


 


298








1H-NMR (DMSO-d6) δppm: 1.55-1.75 (1H, m), 2.15-2.35 (1H, m), 2.6-5.75 (8H, m), 6.50 (2H, s), 6.95-7.05 (1H, m), 7.1-72 (1H, m), 7.3-7.5 (3H, m), 7.9-8.0 (3H, m), 8.0-8.1 (1H, m).
Fumarate


 


299








1H-NMR (DMSO-d6) δppm: 1.65-1.85 (1H, m), 2.15-2.35 (1H, m), 2.85-3.05 (1H, m), 3.05-3.3 (2H, m), 3.5-3.7 (1H, m), 4.7-4.9 (1H, m), 6.9- 7.05 (2H, m), 7.38 (2H, d, J = 5.5 Hz), 7.55 (2H, d, J = 1.5 Hz), 7.76 (2H, d, J = 5.5 Hz), 7.91 (2H, d, J = 8.5 Hz), 9.28 (1H, br), 9.50 (1 H, br).
Hydro- chloride


 


300








1H-NMR (DMSO-d6) δppm: 1.65-1.85 (1H, m), 2.15-2.35 (1H, m), 2.8-3.05 (1H, m), 3.05-3.25 (2H, m), 3.35-3.8 (1H, m), 4.75-4.9 (1H, m), 6.9- 7.0 (2H, m), 7.39 (2H, d, J = 5.5 Hz), 7.64 (2H, d, J = 5.5 Hz), 7.70 (2H, s), 7.79 (2H, d, J = 8.5 Hz), 9.24 (1H, br), 9.43 (1H, br).
Hydro- chloride
















TABLE 84













 
















Ex. No.
R1
R2
R3
R4
R5
R6
M.p. (° C.)

Salt





301
—H
—Cl
—F
—H
—H
-cyclo-C6H11
194.9-196.1
(dec.)
Hydrochloride


302
—H
—Cl
—F
—H
—H
—CH2-cyclo-C6H11
158.5-161.0

Hydrochloride
















TABLE 85













 















Ex. No.
R1
R2
R3
R4
R5
R6
NMR
Salt





303
—H
—Cl
—F
—H
—H
-cyclo-C6H11
1H-NMR (DMSO-d6) δppm
Fumarate









0.80-1.09 (3H, m), 1.15-1.38 (2H, m), 1.42-1.58










(2H, m), 1.60-1.87 (5H, m), 1.88-2.05 (1H, m),










2.81-3.12 (3H, m), 3.12-3.29 (1H, m), 4.09-4.25










(1H, m), 7.00-7.10 (1H, m), 7.20 (1H, dd,










J = 2.6 Hz and 6.7 Hz), 7.24-7.34 (1H, m),



304
—H
—H
—F
—H
—H
-cyclo-C6H11
1H-NMR (DMSO-d6) δppm
Hydrochloride









0.59-1.55 (8H, m), 1.58-2.43 (5H, m), 2.81-4.11










(4H, m), 4.40-5.22 (1H, m), 7.00-8.20 (4H, m),










9.25-10.45 (2H, m)



305
—H
—Cl
—F
—H
—H
—(CH2)3SCH3
1H-NMR (DMSO-d6) δppm
Hydrochloride









1.52-1.70 (2H, m), 1.80-2.18 (5H, m with s at










δ2.07), 2.40-2.51 (2H, m), 2.84-3.49 (6H, m),










4.29-4.49 (1H, m), 6.85-6.95 (1H, m), 7.05-7.35










(2H, m), 9.30-9.79 (2H, m)



306
—H
—Cl
—F
—H
—H
-cyclo-C5H9
1H-NMR (DMSO-d6) δppm
Hydrochloride









1.15-1.88 (9H, m), 1.95-2.18 (1H, m), 2.71-3.49










(4H, m), 3.60-3.85 (1H, m), 4.35-4.55 (1H, m),










7.05-7.55 (3H, m), 9.01-9.45 (2H, m)



307
—H
—Cl
—F
—H
—H
—(CH2)3NHCH3
1H-NMR (DMSO-d6) δppm
3 Hydro-









1.5-3.5 (14H, m), 3.7-3.9 (1H, m), 4.1-4.6
chloride









(2H, m), 5-5.75 (1H, brs), 6.8-7.1 (1H, m), 7.1-










7.3 (2H, m), 8.7-9.7 (2H, m)



308
—H
—Cl
—F
—H
—H
—(CH2)3N(CH3)2
1H-NMR (DMSO-d6) δppm
3 Hydro-









1.7-2.3 (3H, m), 2.70 (3H, s), 2.72 (3H, s),
chloride









2.9-3.4 (8H, m), 4.38(1H, m), 6.8-7.0 (1H, m),










7.1-7.2 1H, m), 7.28 (1H, t, J = 9.1 Hz), 9.2-9.4










(1H, brs), 9.6-9.8 (1H, brs), 10.3-10.6 (1H, brs)
















TABLE 86













 















Ex. No.
R1
R2
R3
R4
R5
R6
NMR
Salt





309
—H
—Cl
—F
—H
—H
—(CH2)2OC6H5
1H-NMR (DMSO-d6) δppm: 1.85-2.1
2 Hydro-









(1H, m), 2.1-2.3 (1H, m), 2.95-3.25
chloride









(2H, m), 3.25-3.55 (2H, m), 3.67 (2H,










t, J = 5.5 Hz), 3.85-4.1 (3H, m), 4.4-4.6










(2H, m), 6.8-7.0 (4H, m), 7.1-7.2 (1H,










m), 7.2-7.35 (3H, m), 9.43 (1H, br),










9.60 (1H, br).



 


310
—H
—Cl
—F
—H
—H




1H-NMR (DMSO-d6) δppm: 1.8-1.95 (3H, m), 2.05-2.15 (1H, m), 2.6-3.95 (11H, m), 4.07 (2H, t, J = 6 Hz), 4.35- 4.45 (1H, m), 6.57 (4H, s), 6.9-6.95 (1H, m), 7.12 (1H, dd, J = 3, 6.5 Hz), 7.26 (1H, dd, J = 9, 9 Hz), 7.32 (1H, dd, J = 4.5, 8.5 Hz), 7.38 (1H, dd, J = 1.5, 8.5 Hz), 8.17 (1H, dd, J = 3.5, 3.5 Hz), 8.31 (1H, d, J = 3 Hz).
2 Fumarate


 


311
—H
—Cl
—F
—H
—H




1H-NMR (DMSO-d6) δppm: 1.45-1.55 (2H, m), 1.65-1.8 (2H, m), 1.8-1.95 (1H, m), 2.05-2.15 (1H, m), 2.6-4.05 (11H, m), 4.25 (2H, t, J = 6.5 Hz), 4.3- 4.4 (1H, m), 6.55 (4H, s), 6.77 (1H, d, J = 8.5 Hz), 6.8-6.9 (1H, m), 6.9-7.0 (1H, m), 7.03 (1H, dd, J = 3, 6.5 Hz), 7.22 (1H, dd, J = 9, 9 Hz), 7.65-7.7 (1H, m), 8.1-8.15 (1H, m).
2 Fumarate
















TABLE 87













 













Ex. No.
R1
R2
R3
R4
R5
MS (M + 1)





312
—H
—H
—OC2H5
—H
—H
283


313
—CH3
—H
—H
—H
—H
253


314
—H
—H
—CF3
—H
—H
307


315
—H
—H
—CN
—H
—H
264


316
—H
—NO2
—H
—H
—H
284


317
—H
—H
—NO2
—H
—H
284


318
—H
—H
—N(CH3)2
—H
—H
282


319
—H
—CH3
—H
—H
—H
253


320
—OCH3
—H
—H
—H
—H
269


321
—H
—OCH3
—H
—H
—H
269


322
—H
—OC2H5
—H
—H
—H
283


323
—H
—OCF3
—H
—H
—H
323


324
—H
—SCH3
—H
—H
—H
285


325
—H
—N(CH3)2
—H
—H
—H
282


326
—CN
—H
—H
—H
—H
264


327
—H
—H
—SCH3
—H
—H
285


328
—H
—CF3
—H
—H
—H
307


329
—CH3
—H
—F
—H
—H
271


330
—H
—CF3
—Cl
—H
—H
341


331
—H
—H
—CH3
—H
—H
253


332
—H
—Cl
—H
—Cl
—H
307


333
—H
—H
—COC6H5
—H
—H
343


334
—H
—H
—CH(CH3)2
—H
—H
281


335
—H
—H
—OC6H5
—H
—H
331


336
—H
—H
—OC6H13
—H
—H
339


337
—H
—H
—C2H5
—H
—H
267


338
—H
—H
—OCH2C6H5
—H
—H
345


339
—H
—CF3
—F
—H
—H
325


340
—H
—CF3
—H
—CF3
—H
375


341
—H
—H
—OCH3
—H
—H
269


342
—CH3
—CH3
—H
—H
—H
267


343
—C2H5
—H
—H
—H
—H
267


344
—H
—F
—H
—H
—OCH3
287


345
—H
—H
—COCH3
—H
—H
281


346
—H
—COCH3
—H
—H
—H
281


347
—CH3
—H
—Cl
—H
—H
287


348
—H
—Cl
—Cl
—H
—H
307
















TABLE 88













 













Ex. No.
R1
R2
R3
R4
R5
MS (M + 1)





349
—H
—F
—F
—H
—H
275


350
—H
—F
—H
—F
—H
275


351
—H
—H
—CF3
—F
—H
325


352
—H
—CF3
—H
—F
—H
325


353
—H
—CF3
—CH3
—H
—H
321


354
—H
—SCF3
—H
—H
—H
339


355
—H
—CF3
—OCH3
—H
—H
337


356
—H
—CH3
—N(CH3)2
—CH3
—H
310


357
—H
—CH(CH3)2
—H
—H
—H
281


358
—H
—H
—SC2H5
—H
—H
299


359
—H
—H
—N(C2H5)2
—H
—H
310


360
—H
—OCH(CH3)2
—H
—H
—H
297


361
—H
—F
—H
—Cl
—H
291


362
—H
—CH3
—H
—CH3
—H



363
—H
—F
—CH3
—H
—H
271


364
—H
—F
—Cl
—H
—H
291


365
—H
—C6H5
—H
—H
—H
315


366
—H
—F
—H
—H
—H
257


367
—H
—Cl
—CH3
—H
—H
287


368
—H
—F
—F
—F
—H
293


369
—H
—F
—H
—H
—CH3
271


370
—F
—H
—H
—CH3
—H
271


371
—H
—F
—OCH3
—H
—H
287


372
—H
—CH3
—Cl
—H
—H
287


373
—H
—H
—C3H7
—H
—H
281


374
—OCH3
—H
—H
—CH3
—H
283


375
—CH3
—Cl
—H
—H
—H
287


376
—H
—H
—CH2C6H5
—H
—H
329


377
—H
—Cl
—H
—H
—OCH3
303


378
—CH3
—F
—CH3
—H
—H
285


379
—H
—CH2CH2CN
—H
—H
—H
292


380
—H
—H
—CH2CH2CN
—H
—H
292


381
—H
—Cl
—H
—H
—CH3
287


382
—H
—OCHF2
—H
—H
—H
305


383
—H
—C2H5
—H
—H
—H
267


384
—H
—F
—OCH3
—F
—H
305


385
—CH3
—H
—CH3
—H
—H
267
















TABLE 89













 













Ex. No.
R1
R2
R3
R4
R5
MS (M + 1)





386
—H
—F
—F
—OCH3
—H
305


387
—H
—Cl
—H
—H
—H
273


388
—CH3
—H
—H
—CH3
—H
267


389
—H
—CH3
—CH3
—H
—H
267


390
—H
—OCH3
—OCH3
—OCH3
—H
329


391
—H
—CN
—F
—H
—H
282


392
—CH(CH3)2
—H
—H
—CH3
—H
295


393
—H
—H
—COC2H5
—H
—H
295


394
—H
—H
—CF3
—H
—F
325


395
—F
—H
—CF3
—F
—H
343


396
—H
—CO2C2H5 
—Cl
—H
—H
345


397
—CH2C6H5
—H
—H
—H
—H
329


398
—H
—CH3
—OCH3
—H
—H
283


399
—H
—H
—C6H5
—H
—H
315


400
—H
—Cl
—CN
—H
—H
298


401
—H
—CH3
—F
—CH3
—H
285


402
—H
—H
—OCF2CHF2
—H
—H
355


403
—H
—H
—OH
—H
—H
255
















TABLE 90













 













Ex. No.
R1
R2
R3
R4
R5
MS (M + 1)





404
—H
—H




—H
—H
322


 


405
—H




—H
—H
—H
336


 


406
—H
—H




—H
—H
306


 


407
—H
—H




—H
—H
305


 


408
—H
—H




—H
—H
352


 


409
—H
—H




—H
—H
306


 


410
—H
—H




—H
—H
307


 


411
—H




—H
—H
—H
349
















TABLE 91













 


















Ex. No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
R10
MS (M + 1)





412
—H
—Cl
—F
—H
—H
—H
—H
—OC2H5
—H
—H
335


413
—H
—Cl
—F
—H
—H
—CH3
—H
—H
—H
—H
305


414
—H
—Cl
—F
—H
—H
—H
—H
—CF3
—H
—H
359


415
—H
—Cl
—F
—H
—H
—H
—H
—CN
—H
—H
316


416
—H
—Cl
—F
—H
—H
—H
—H
—N(CH3)2
—H
—H
334


417
—H
—Cl
—F
—H
—H
—H
—CH3
—H
—H
—H
305


418
—H
—Cl
—F
—H
—H
—H
—CO2C2H5
—H
—H
—H
363


419
—H
—Cl
—F
—H
—H
—OCH3
—H
—H
—H
—H
321


420
—H
—Cl
—F
—H
—H
—H
—OCH3
—H
—H
—H
321


421
—H
—Cl
—F
—H
—H
—H
—OC2H5
—H
—H
—H
335


422
—H
—Cl
—F
—H
—H
—H
—OCF3
—H
—H
—H
375


423
—H
—Cl
—F
—H
—H
—H
—SCH3
—H
—H
—H
337


424
—H
—CH3
—F
—H
—H
—H
—H
—OC2H5
—H
—H
315


425
—H
—CH3
—F
—H
—H
—CH3
—H
—H
—H
—H
285


426
—H
—CH3
—F
—H
—H
—H
—H
—CF3
—H
—H
339


427
—H
—CH3
—F
—H
—H
—H
—H
—CN
—H
—H
296


428
—H
—CH3
—F
—H
—H
—H
—NO2
—H
—H
—H
316


429
—H
—CH3
—F
—H
—H
—H
—H
—NO2
—H
—H
316


430
—H
—CH3
—F
—H
—H
—H
—H
—N(CH3)2
—H
—H
314


431
—H
—CH3
—F
—H
—H
—H
—CH3
—H
—H
—H
285


432
—H
—CH3
—F
—H
—H
—OCH3
—H
—H
—H
—H
301


433
—H
—CH3
—F
—H
—H
—H
—OCH3
—H
—H
—H
301


434
—H
—CH3
—F
—H
—H
—H
—OC2H5
—H
—H
—H
315


435
—H
—CH3
—F
—H
—H
—H
—OCF3
—H
—H
—H
355


436
—H
—CH3
—F
—H
—H
—H
—SCH3
—H
—H
—H
317


437
—H
—H
—F
—H
—H
—H
—H
—OC2H5
—H
—H
301


438
—CH3
—H
—H
—H
—H
—H
—H
—F
—H
—H
271


439
—H
—H
—CF3
—H
—H
—H
—H
—F
—H
—H
325


440
—H
—H
—F
—H
—H
—H
—H
—CN
—H
—H
282


441
—H
—NO2
—H
—H
—H
—H
—H
—F
—H
—H
302


442
—H
—H
—NO2
—H
—H
—H
—H
—F
—H
—H
302


443
—H
—H
—N(CH3)2
—H
—H
—H
—H
—F
—H
—H
300


444
—H
—CH3
—H
—H
—H
—H
—H
—F
—H
—H
271


445
—OCH3
—H
—H
—H
—H
—H
—H
—F
—H
—H
287


446
—H
—OCH3
—H
—H
—H
—H
—H
—F
—H
—H
287
















TABLE 92













 


















Ex. No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
R10
MS (M + 1)





447
—H
—OC2H5
—H
—H
—H
—H
—H
—F
—H
—H
301


448
—H
—OCF3
—H
—H
—H
—H
—H
—F
—H
—H
341


449
—H
—SCH3
—H
—H
—H
—H
—H
—F
—H
—H
303


450
—H
—N(CH3)2
—H
—H
—H
—H
—Cl
—F
—H
—H
334


451
—H
—Cl
—F
—H
—H
—CN
—H
—H
—H
—H
316


452
—H
—Cl
—F
—H
—H
—H
—H
—SCH3
—H
—H
337


453
—H
—N(CH3)2
—H
—H
—H
—H
—CH3
—F
—H
—H
314


454
—H
—CH3
—F
—H
—H
—H
—H
—SCH3
—H
—H
317


455
—H
—N(CH3)2
—H
—H
—H
—H
—H
—F
—H
—H
300


456
—H
—H
—F
—H
—H
—H
—H
—SCH3
—H
—H
303
















TABLE 93













 














Ex. No.
R1
R2
R3
R4
R5
R6
MS (M + 1)





457
—H
—H
—H
—H
—H




283


 


458
—H
—H
—H
—H
—H




283


 


459
—H
—H
—H
—H
—H




319


 


460
—H
—Cl
—F
—H
—H




349


 


461
—H
—H
—H
—H
—H




297


 


462
—H
—CH3
—F
—H
—H




329


 


463
—H
—H
—F
—H
—H




315


 


464
—H
—H
—H
—H
—H




369


 


465
—H
—H
—H
—H
—H




311


 


466
—H
—H
—H
—H
—H




369


 


467
—H
—H
—H
—H
—H




293
















TABLE 94













 














Ex. No.
R1
R2
R3
R4
R5
R6
MS (M + 1)





468
—H
—H
—H
—H
—H




289


 


469
—H
—H
—H
—H
—H




289


 


470
—H
—H
—H
—H
—H




319


 


471
—H
—H
—H
—H
—H




307


 


472
—H
—H
—H
—H
—H




327


 


473
—H
—H
—H
—H
—H




281


 


474
—H
—H
—H
—H
—H




279


 


475
—H
—Cl
—F
—H
—H




347


 


476
—H
—H
—H
—H
—H




295


 


477
—H
—CH3
—F
—H
—H




327


 


478
—H
—H
—F
—H
—H




313
















TABLE 95













 














Ex. No.
R1
R2
R3
R4
R5
R6
MS (M + 1)





479
—H
—H
—H
—H
—H




295


 


480
—H
—Cl
—F
—H
—H




297


 


481
—H
—Cl
—F
—H
—H




394


 


482
—H
—H
—H
—H
—H




321


 


483
—H
—H
—H
—H
—H




246


 


484
—H
—Cl
—F
—H
—H




298


 


485
—H
—CH3
—F
—H
—H




278


 


486
—H
—H
—H
—H
—H




243


 


487
—H
—H
—F
—H
—H




261
















TABLE 96













 














Ex. No.
R1
R2
R3
R4
R5
R6
MS(M + 1)





488
—H
—H
—H
—H
—H




255


 


489
—H
—Cl
—F
—H
—H




307


 


490
—H
—CH3
—F
—H
—H




287


 


491
—H
—H
—F
—H
—H




273


 


492
—H
—CH3
—F
—H
—H




303


 


493
—H
—H
—H
—H
—H




317


 


494
—H
—Cl
—F
—H
—H




369


 


495
—H
—CH3
—F
—H
—H




349
















TABLE 97













 














Ex. No.
R1
R2
R3
R4
R5
R6
MS(M + 1)





496
—H
—H
—H
—H
—H




241


 


497
—H
—Cl
—F
—H
—H




293


 


498
—H
—CH3
—F
—H
—H




273


 


499
—H
—H
—H
—H
—H




269


 


500
—H
—H
—F
—H
—H




287


 


501
—H
—CH3
—F
—H
—H




301


 


502
—H
—Cl
—F
—H
—H




321


 


503
—H
—H
—H
—H
—H




283


 


504
—H
—Cl
—F
—H
—H




335


 


505
—H
—H
—F
—H
—H




301


 


506
—H
—CH3
—F
—H
—H




315
















TABLE 98













 














Ex. No.
R1
R2
R3
R4
R5
R6
MS(M + 1)





507
—H
—H
—H
—H
—H




269


 


508
—H
—Cl
—F
—H
—H




321


 


509
—H
—CH3
—F
—H
—H




301


 


510
—H
—H
—F
—H
—H




287


 


511
—H
—Cl
—F
—H
—H




361


 


512
—H
—CH3
—F
—H
—H




341


 


513
—H
—H
—F
—H
—H




327


 


514
—H
—H
—H
—H
—H




301


 


515
—H
—Cl
—F
—H
—H




353


 


516
—H
—CH3
—F
—H
—H




333
















TABLE 99













 














Ex. No.
R1
R2
R3
R4
R5
R6
MS(M + 1)





517
—H
—H
—F
—H
—H




319


 


518
—H
—H
—H
—H
—H




287


 


519
—H
—Cl
—F
—H
—H




339


 


520
—H
—CH3
—F
—H
—H




319


 


521
—H
—H
—F
—H
—H




305


 


522
—H
—Cl
—F
—H
—H




411


 


523
—H
—CH3
—F
—H
—H




391
















TABLE 100













 














Ex. No.
R1
R2
R3
R4
R5
R6
MS (M + 1)





524
—H
—Cl
—F
—H
—H




353


 


525
—H
—H
—H
—H
—H




337


 


526
—H
—CH3
—F
—H
—H




369


 


527
—H
—H
—F
—H
—H




399


 


528
—H
—CH3
—F
—H
—H




413


 


529
—H
—H
—H
—H
—H




241


 


530
—H
—CH3
—F
—H
—H




273


 


531
—H
—H
—F
—H
—H




259


 


532
—H
—Cl
—F
—H
—H




293
















TABLE 101













 














Ex. No.
R1
R2
R3
R4
R5
R6
MS (M + 1)





533
—H
—H
—H
—H
—H




241


 


534
—H
—Cl
—F
—H
—H




293


 


535
—H
—CH3
—F
—H
—H




273


 


536
—H
—H
—F
—H
—H




259


 


537
—H
—H
—H
—H
—H




269


 


538
—H
—Cl
—F
—H
—H




321


 


539
—H
—CH3
—F
—H
—H




301


 


540
—H
—H
—F
—H
—H




287


 


541
—H
—H
—H
—H
—H




271


 


542
—H
—Cl
—F
—H
—H




323


 


543
—H
—CH3
—F
—H
—H




303
















TABLE 102













 














Ex. No.
R1
R2
R3
R4
R5
R6
MS(M + 1)





544
—H
—H
—F
—H
—H




289


 


545
—H
—H
—H
—H
—H




322


 


546
—H
—H
—H
—H
—H




296


 


547
—H
—Cl
—F
—H
—H




348


 


548
—H
—CH3
—F
—H
—H




328


 


549
—H
—H
—F
—H
—H




314


 


550
—H
—H
—H
—H
—H




326


 


551
—H
—Cl
—F
—H
—H




378


 


552
—H
—CH3
—F
—H
—H




358


 


553
—H
—H
—F
—H
—H




344


 


554
—H
—H
—H
—H
—H




310
















TABLE 103













 














Ex. No.
R1
R2
R3
R4
R5
R6
MS(M + 1)





555
—H
—H
—H
—H
—H




296


 


556
—H
—H
—H
—H
—H




296


 


557
—H
—H
—H
—H
—H




296


 


558
—H
—Cl
—F
—H
—H




348


 


559
—H
—CH3
—F
—H
—H




328


 


560
—H
—H
—F
—H
—H




314


 


561
—H
—H
—H
—H
—H




297


 


562
—H
—Cl
—F
—H
—H




349


 


563
—H
—CH3
—F
—H
—H




329


 


564
—H
—H
—F
—H
—H




315


 


565
—H
—H
—H
—H
—H




311
















TABLE 104













 














Ex. No.
R1
R2
R3
R4
R5
R6
MS(M + 1)





566
—H
—Cl
—F
—H
—H




363


 


567
—H
—CH3
—F
—H
—H




343


 


568
—H
—H
—F
—H
—H




329


 


569
—H
—H
—F
—H
—H




315


 


570
—H
—Cl
—F
—H
—H




363


 


571
—H
—CH3
—F
—H
—H




343


 


572
—H
—H
—F
—H
—H




329


 


573
—H
—H
—H
—H
—H




387


 


574
—H
—Cl
—F
—H
—H




439
















TABLE 105













 














Ex. No.
R1
R2
R3
R4
R5
R6
MS(M + 1)





575
—H
—CH3
—F
—H
—H




419


 


576
—H
—H
—H
—H
—H




322


 


577
—H
—Cl
—F
—H
—H




374


 


578
—H
—CH3
—F
—H
—H




354


 


579
—H
—H
—F
—H
—H




340


 


580
—H
—H
—H
—H
—H




290


 


581
—H
—Cl
—F
—H
—H




342


 


582
—H
—CH3
—F
—H
—H




322


 


583
—H
—H
—F
—H
—H




308
















TABLE 106













 














Ex. No.
R1
R2
R3
R4
R5
R6
MS(M + 1)





584
—H
—H
—H
—H
—H




290


 


585
—H
—H
—F
—H
—H




308


 


586
—H
—Cl
—F
—H
—H




342


 


587
—H
—H
—H
—H
—H




290


 


588
—H
—H
—H
—H
—H




304


 


589
—H
—H
—H
—H
—H




310


 


590
—H
—H
—H
—H
—H




354


 


591
—H
—H
—H
—H
—H




291


 


592
—H
—Cl
—F
—H
—H




343


 


593
—H
—CH3
—F
—H
—H




323


 


594
—H
—H
—H
—H
—H




291
















TABLE 107













 














Ex. No.
R1
R2
R3
R4
R5
R6
MS(M + 1)





595
—H
—H
—H
—H
—H




367


 


596
—H
—Cl
—F
—H
—H




419


 


597
—H
—CH3
—F
—H
—H




399


 


598
—H
—H
—F
—H
—H




385
















TABLE 108













 

















Ex. No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
MS (M + 1)





599
—H
—Cl
—F
—H
—H
—H
—NO2
—H
—H
337


600
—H
—Cl
—F
—H
—H
—H
—CO2CH3
—H
—H
350


601
—H
—Cl
—F
—H
—H
—H
—H
—H
—CF3
360


602
—H
—Cl
—F
—H
—H
—H
—Cl
—H
—H
326


603
—H
—Cl
—F
—H
—H
—H
—H
—H
—Cl
326


604
—H
—Cl
—F
—H
—H
—OCH3
—H
—H
—H
322


605
—H
—Cl
—F
—H
—H
—H
—H
—H
—H
292


606
—H
—Cl
—F
—H
—H
—H
—CH3
—H
—H
306


607
—H
—Cl
—F
—H
—H
—H
—H
—CH3
—H
306


608
—H
—Cl
—F
—H
—H
—H
—H
—CF3
—H
360


609
—H
—Cl
—F
—H
—H
—CH3
—H
—H
—H
306


610
—H
—Cl
—F
—H
—H
—H
—CF3
—H
—H
360


611
—H
—H
—H
—H
—H
—H
—NO2
—H
—H
285


612
—H
—H
—H
—H
—H
—H
—CO2CH3
—H
—H
298


613
—H
—H
—H
—H
—H
—H
—H
—H
—CF3
308


614
—H
—H
—H
—H
—H
—H
—Cl
—H
—H
274


615
—H
—H
—H
—H
—H
—H
—H
—H
—Cl
274


616
—H
—H
—H
—H
—H
—H
—H
—H
—H
240


617
—H
—H
—H
—H
—H
—H
—CH3
—H
—H
254


618
—H
—H
—H
—H
—H
—H
—H
—CH3
—H
254


619
—H
—H
—H
—H
—H
—H
—H
—CF3
—H
308


620
—H
—H
—H
—H
—H
—CH3
—H
—H
—H
254


621
—H
—H
—H
—H
—H
—OCH3
—H
—H
—H
270


622
—H
—H
—H
—H
—H
—H
—H
—H
—CH3
254


623
—H
—H
—H
—H
—H
—H
—CF3
—H
—H
308


624
—H
—CH3
—F
—H
—H
—H
—NO2
—H
—H
317


625
—H
—CH3
—F
—H
—H
—H
—CO2CH3
—H
—H
330


626
—H
—CH3
—F
—H
—H
—H
—H
—H
—CF3
340


627
—H
—CH3
—F
—H
—H
—H
—H
—H
—NO2
317


628
—H
—CH3
—F
—H
—H
—H
—Cl
—H
—H
306


629
—H
—CH3
—F
—H
—H
—H
—H
—H
—Cl
306


630
—H
—CH3
—F
—H
—H
—H
—H
—H
—H
272


631
—H
—CH3
—F
—H
—H
—H
—CH3
—H
—H
286


632
—H
—CH3
—F
—H
—H
—H
—H
—CH3
—H
286


633
—H
—CH3
—F
—H
—H
—H
—H
—CF3
—H
340


634
—H
—CH3
—F
—H
—H
—CH3
—H
—H
—H
286


635
—H
—CH3
—F
—H
—H
—OCH3
—H
—H
—H
302
















TABLE 109













 

















Ex. No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
MS (M + 1)





636
—H
—CH3
—F
—H
—H
—H
—H
—H
—CH3
286


637
—H
—CH3
—F
—H
—H
—H
—CF3
—H
—H
340


638
—H
—H
—F
—H
—H
—H
—NO2
—H
—H
303


639
—H
—H
—F
—H
—H
—H
—CO2CH3
—H
—H
316


640
—H
—H
—F
—H
—H
—H
—H
—H
—CF3
326


641
—H
—H
—F
—H
—H
—H
—Cl
—H
—H
292


642
—H
—H
—F
—H
—H
—H
—H
—H
—Cl
292


643
—H
—H
—F
—H
—H
—H
—H
—H
—H
258


644
—H
—H
—F
—H
—H
—H
—CH3
—H
—H
272


645
—H
—H
—F
—H
—H
—H
—H
—CH3
—H
272


646
—H
—H
—F
—H
—H
—H
—H
—CF3
—H
326


647
—H
—H
—F
—H
—H
—CH3
—H
—H
—H
272


648
—H
—H
—F
—H
—H
—OCH3
—H
—H
—H
288


649
—H
—H
—F
—H
—H
—H
—CF3
—H
—H
326


650
—H
—Cl
—F
—H
—H
—CH3
—H
—CF3
—H
374


651
—H
—Cl
—F
—H
—H
—H
—H
—NO2
—H
337


652
—H
—Cl
—F
—H
—H
—H
—H
—OCH3
—H
322


653
—H
—Cl
—F
—H
—H
—H
—H
—C2H5
—H
320


654
—H
—H
—H
—H
—H
—CH3
—H
—CF3
—H
322


655
—H
—H
—H
—H
—H
—H
—H
—NO2
—H
285


656
—H
—H
—H
—H
—H
—H
—H
—OCH3
—H
270


657
—H
—H
—H
—H
—H
—H
—H
—C2H5
—H
268


658
—H
—CH3
—F
—H
—H
—CH3
—H
—CF3
—H
354


659
—H
—CH3
—F
—H
—H
—H
—H
—NO2
—H
317


660
—H
—CH3
—F
—H
—H
—H
—H
—OCH3
—H
302


661
—H
—CH3
—F
—H
—H
—H
—H
—C2H5
—H
300


662
—H
—H
—F
—H
—H
—CH3
—H
—CF3
—H
340


663
—H
—H
—F
—H
—H
—H
—H
—NO2
—H
303


664
—H
—H
—F
—H
—H
—H
—H
—OCH3
—H
288


665
—H
—H
—F
—H
—H
—H
—H
—C2H5
—H
286
















TABLE 110













 

















Ex. No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
MS (M + 1)





666
—H
—H
—H
—H
—H
—H
—H




—H
309
















TABLE 111













 

















Ex. No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
MS (M + 1)





667
—H
—Cl
—F
—H
—H
—H
—H
—H
—H
292


668
—H
—H
—H
—H
—H
—H
—H
—H
—H
240


669
—H
—H
—H
—H
—H
—H
—NO2
—H
—H
285


670
—H
—H
—H
—H
—H
—CH3
—CH3
—H
—H
268


671
—H
—CH3
—F
—H
—H
—H
—H
—H
—H
272


672
—H
—CH3
—F
—H
—H
—H
—NO2
—H
—H
317


673
—H
—H
—F
—H
—H
—H
—H
—H
—H
258


674
—H
—H
—F
—H
—H
—H
—NO2
—H
—H
303


675
—H
—H
—F
—H
—H
—CH3
—CH3
—H
—H
286


676
—H
—Cl
—F
—H
—H
—H
—CH3
—H
—H
306


677
—H
—Cl
—F
—H
—H
—H
—OCH3
—H
—H
322


678
—H
—Cl
—F
—H
—H
—H
—H
—OCH3
—H
322


679
—H
—H
—H
—H
—H
—H
—CH3
—H
—H
254


680
—H
—H
—H
—H
—H
—H
—H
—OCH3
—H
270


681
—H
—CH3
—F
—H
—H
—H
—CH3
—H
—H
286


682
—H
—CH3
—F
—H
—H
—H
—H
—OCH3
—H
302


683
—H
—H
—F
—H
—H
—H
—CH3
—H
—H
272


684
—H
—H
—F
—H
—H
—H
—H
—OCH3
—H
288


685
—H
—H
—OC2H5
—H
—H
—H
—H
—H
—H
284


686
—CH3
—H
—H
—H
—H
—H
—H
—H
—H
254


687
—H
—H
—CF3
—H
—H
—H
—H
—H
—H
308


688
—H
—H
—CN
—H
—H
—H
—H
—H
—H
265


689
—H
—NO2
—H
—H
—H
—H
—H
—H
—H
285


690
—H
—H
—NO2
—H
—H
—H
—H
—H
—H
285


691
—H
—H
—N(CH3)2
—H
—H
—H
—H
—H
—H
283


692
—H
—CF3
—H
—H
—H
—H
—H
—H
—H
308


693
—CH3
—H
—F
—H
—H
—H
—H
—H
—H
272


694
—H
—CF3
—Cl
—H
—H
—H
—H
—H
—H
342


695
—H
—H
—CH3
—H
—H
—H
—H
—H
—H
254


696
—H
—H
—C(CH3)3
—H
—H
—H
—H
—H
—H
296


697
—H
—Cl
—H
—Cl
—H
—H
—H
—H
—H
308


698
—H
—H
—SCH3
—H
—H
—H
—H
—H
—H
286


699
—H
—H
—COC6H5
—H
—H
—H
—H
—H
—H
344


700
—H
—H
—CH(CH3)2
—H
—H
—H
—H
—H
—H
282


701
—H
—H
—OC6H5
—H
—H
—H
—H
—H
—H
332


702
—H
—H
—OC6H13
—H
—H
—H
—H
—H
—H
340


703
—H
—H
—C6H13
—H
—H
—H
—H
—H
—H
324


704
—H
—H
—C2H5
—H
—H
—H
—H
—H
—H
268
















TABLE 112













 

















Ex. No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
MS (M + 1)





705
—H
—H
—OCH2C6H5 
—H
—H
—H
—H
—H
—H
346


706
—H
—CF3
—F
—H
—H
—H
—H
—H
—H
326


707
—H
—CF3
—H
—CF3
—H
—H
—H
—H
—H
376


708
—H
—OCH3
—H
—H
—OCH3
—H
—H
—H
—H
300


709
—Cl
—H
—H
—H
—H
—H
—H
—H
—H
274


710
—H
—H
—OCH3
—H
—H
—H
—H
—H
—H
270


711
—CH3
—CH3
—H
—H
—H
—H
—H
—H
—H
268


712
—C2H5
—H
—H
—H
—H
—H
—H
—H
—H
268


713
—H
—F
—H
—H
—OCH3
—H
—H
—H
—H
288


714
—H
—H
—COCH3
—H
—H
—H
—H
—H
—H
282


715
—H
—COCH3
—H
—H
—H
—H
—H
—H
—H
282


716
—CH3
—H
—Cl
—H
—H
—H
—H
—H
—H
288


717
—H
—Cl
—Cl
—H
—H
—H
—H
—H
—H
308


718
—H
—F
—F
—H
—H
—H
—H
—H
—H
276


719
—H
—F
—H
—F
—H
—H
—H
—H
—H
276


720
—H
—H
—CF3
—F
—H
—H
—H
—H
—H
326


721
—H
—CF3
—H
—F
—H
—H
—H
—H
—H
326


722
—H
—CF3
—CH3
—H
—H
—H
—H
—H
—H
322


723
—H
—SCF3
—H
—H
—H
—H
—H
—H
—H
340


724
—H
—CF3
—OCH3
—H
—H
—H
—H
—H
—H
338


725
—H
—CH3
—N(CH3)2
—CH3
—H
—H
—H
—H
—H
311


726
—H
—CH(CH3)2
—H
—H
—H
—H
—H
—H
—H
282


727
—H
—H
—SC2H5
—H
—H
—H
—H
—H
—H
300


728
—H
—H
—N(C2H5)2
—H
—H
—H
—H
—H
—H
311


729
—H
—OCH(CH3)2
—H
—H
—H
—H
—H
—H
—H
298


730
—H
—H
—OCHF2
—H
—H
—H
—H
—H
—H
306


731
—H
—F
—H
—Cl
—H
—H
—H
—H
—H
292


732
—H
—CH3
—OCH3
—CH3
—H
—H
—H
—H
—H
298


733
—H
—CH3
—H
—CH3
—H
—H
—H
—H
—H
268


734
—H
—F
—CH3
—H
—H
—H
—H
—H
—H
272


735
—H
—F
—Cl
—H
—H
—H
—H
—H
—H
292


736
—H
—C6H5
—H
—H
—H
—H
—H
—H
—H
316


737
—H
—F
—H
—H
—H
—H
—H
—H
—H
258


738
—H
—Cl
—CH3
—H
—H
—H
—H
—H
—H
288


739
—H
—F
—F
—F
—H
—H
—H
—H
—H
294


740
—H
—F
—H
—H
—CH3
—H
—H
—H
—H
272


741
—F
—H
—H
—CH3
—H
—H
—H
—H
—H
272


742
—H
—F
—OCH3
—H
—H
—H
—H
—H
—H
288
















TABLE 113













 

















Ex. No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
MS (M + 1)





743
—H
—CH3
—Cl
—H
—H
—H
—H
—H
—H
288


744
—H
—H
—C3H7
—H
—H
—H
—H
—H
—H
282


745
—OCH3
—H
—H
—CH3
—H
—H
—H
—H
—H
284


746
—CH3
—Cl
—H
—H
—H
—H
—H
—H
—H
288


747
—H
—H
—CH2C6H5
—H
—H
—H
—H
—H
—H
330


748
—H
—Cl
—H
—H
—OCH3
—H
—H
—H
—H
304


749
—CH3
—F
—CH3
—H
—H
—H
—H
—H
—H
286


750
—H
—CH2CH2CN
—H
—H
—H
—H
—H
—H
—H
293


751
—H
—H
—CH2CH2CN
—H
—H
—H
—H
—H
—H
293


752
—H
—Cl
—H
—H
—CH3
—H
—H
—H
—H
288


753
—H
—OCHF2
—H
—H
—H
—H
—H
—H
—H
306


754
—H
—C2H5
—H
—H
—H
—H
—H
—H
—H
268


755
—H
—F
—OCH3
—F
—H
—H
—H
—H
—H
306


756
—H
—F
—F
—H
—OCH3
—H
—H
—H
—H
306


757
—CH3
—H
—CH3
—H
—H
—H
—H
—H
—H
268


758
—H
—F
—F
—OCH3
—H
—H
—H
—H
—H
306


759
—H
—OCH3
—OCH3
—H
—H
—H
—H
—H
—H
300


760
—H
—Cl
—H
—H
—H
—H
—H
—H
—H
274


761
—CH3
—H
—H
—CH3
—H
—H
—H
—H
—H
268


762
—H
—CH3
—CH3
—H
—H
—H
—H
—H
—H
268


763
—H
—CN
—F
—H
—H
—H
—H
—H
—H
283


764
—CH(CH3)2
—H
—H
—CH3
—H
—H
—H
—H
—H
296


765
—H
—NO2
—F
—H
—H
—H
—H
—H
—H
303


766
—CH2C6H5
—H
—H
—H
—H
—H
—H
—H
—H
330


767
—H
—CH3
—OCH3
—H
—H
—H
—H
—H
—H
284


768
—H
—H
—C6H5
—H
—H
—H
—H
—H
—H
316


769
—H
—Cl
—CN
—H
—H
—H
—H
—H
—H
299


770
—H
—CH3
—F
—CH3
—H
—H
—H
—H
—H
286


771
—H
—H
—OCF2CHF2
—H
—H
—H
—H
—H
—H
356


772
—H
—H
—OH
—H
—H
—H
—H
—H
—H
256
















TABLE 114













 

















Ex. No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
MS (M + 1)





773
—H




—H
—H
—H
—H
—H
—H
—H
337


 


774
—H
—H




—H
—H
—H
—H
—H
—H
307


 


775
—H
—H




—H
—H
—H
—H
—H
—H
353


 


776
—H
—H




—H
—H
—H
—H
—H
—H
308


 


777
—H




—H
—H
—H
—H
—H
—H
—H
350
















TABLE 115













 









Ex. No.
R1
MS (M + 1)





778




296


 


779




298


 


780




290


 


781




311


 


782




290


 


783




284


 


784




294


 


785




312


 


786




291


 


787




292


 


788




311
















TABLE 116













 











Ex. No.
R1
MS (M + 1)







789




284



 



790




282



 



791




305



 



792




370



 



793




370



 



794




320



 



795




320



 



796




323



 



797




308



 



798




328



 



799




280

















TABLE 117













 









Ex. No.
R1
MS (M + 1)





800




279


 


801




353


 


802




355


 


803




310


 


804




297


 


805




297
















TABLE 118













 

















Ex. No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
MS (M + 1)





806
—H
—Cl
—F
—H
—H
—H
—H
—CH3
—H
306


807
—H
—Cl
—F
—H
—H
—H
-2-PYRIDYL
-2-PYRIDYL
—H
446


808
—H
—H
—H
—H
—H
—H
—H
—CH3
—H
254


809
—H
—H
—H
—H
—H
—H
—H
—H
—CH3
254


810
—H
—H
—H
—H
—H
—H
-2-PYRIDYL
-2-PYRIDYL
—H
394


811
—H
—CH3
—F
—H
—H
—H
—H
—CH3
—H
286


812
—H
—CH3
—F
—H
—H
—H
-2-PYRIDYL
-2-PYRIDYL
—H
426


813
—H
—H
—F
—H
—H
—H
-2-PYRIDYL
-2-PYRIDYL
—H
412
















TABLE 119













 































MS


Ex.











(M +


No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
R10
R11
1)





814
—H
—Cl
—F
—H
—H
—H
—H
—H
—H
—H
—H
342


815
—H
—H
—H
—H
—H
—H
—H
—H
—H
—H
—H
290


816
—H
—CH3
—F
—H
—H
—H
—H
—H
—H
—H
—H
322


817
—H
—H
—F
—H
—H
—H
—H
—H
—H
—H
—H
308
















TABLE 120













 



















Ex. No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
R10
R11
MS (M + 1)





818
—H
—Cl
—F
—H
—H
—CH3
—H
—H
—H
—H
—H
356


819
—H
—Cl
—F
—H
—H
—H
—H
—H
—H
—H
—H
342


820
—H
—Cl
—F
—H
—H
—H
—H
—H
—H
—CF3
—H
410


821
—H
—Cl
—F
—H
—H
—C6H5
—H
—H
—H
—H
—H
418


822
—H
—Cl
—F
—H
—H
—H
—H
—H
—H
—Cl
—H
376


823
—H
—Cl
—F
—H
—H
—CF3
—H
—H
—H
—H
—H
410


824
—H
—Cl
—F
—H
—H
—H
—H
—H
—H
—H
—CF3
410


825
—H
—H
—H
—H
—H
—CH3
—H
—H
—H
—H
—H
304


826
—H
—H
—H
—H
—H
—H
—H
—H
—H
—H
—H
290


827
—H
—H
—H
—H
—H
—H
—H
—H
—H
—CF3
—H
358


828
—H
—H
—H
—H
—H
—C6H5
—H
—H
—H
—H
—H
366


829
—H
—H
—H
—H
—H
—H
—H
—H
—H
—Cl
—H
324


830
—H
—H
—H
—H
—H
—CF3
—H
—H
—H
—H
—H
358


831
—H
—H
—H
—H
—H
—H
—H
—H
—H
—H
—CF3
358


832
—H
—CH3
—F
—H
—H
—CH3
—H
—H
—H
—H
—H
336


833
—H
—CH3
—F
—H
—H
—H
—H
—H
—H
—H
—H
322


834
—H
—CH3
—F
—H
—H
—H
—H
—H
—H
—CF3
—H
390


835
—H
—CH3
—F
—H
—H
—C6H5
—H
—H
—H
—H
—H
398


836
—H
—CH3
—F
—H
—H
—H
—H
—H
—H
—Cl
—H
356


837
—H
—CH3
—F
—H
—H
—CF3
—H
—H
—H
—H
—H
390


838
—H
—CH3
—F
—H
—H
—H
—H
—H
—H
—H
—CF3
390


839
—H
—H
—F
—H
—H
—CH3
—H
—H
—H
—H
—H
322


840
—H
—H
—F
—H
—H
—H
—H
—H
—H
—H
—H
308


841
—H
—H
—F
—H
—H
—H
—H
—H
—H
—CF3
—H
376


842
—H
—H
—F
—H
—H
—C6H5
—H
—H
—H
—H
—H
384


843
—H
—H
—F
—H
—H
—H
—H
—H
—H
—Cl
—H
342


844
—H
—H
—F
—H
—H
—CF3
—H
—H
—H
—H
—H
376


845
—H
—H
—F
—H
—H
—H
—H
—H
—H
—H
—CF3
376


846
—H
—Cl
—F
—H
—H
—H
—H
—H
—CF3
—H
—H
410


847
—H
—H
—H
—H
—H
—H
—H
—H
—F
—H
—F
326


848
—H
—H
—H
—H
—H
—H
—H
—H
—CF3
—H
—H
358


849
—H
—CH3
—F
—H
—H
—H
—H
—H
—F
—H
—F
358


850
—H
—CH3
—F
—H
—H
—H
—H
—H
—CF3
—H
—H
390


851
—H
—H
—F
—H
—H
—H
—H
—H
—F
—H
—F
344


852
—H
—H
—F
—H
—H
—H
—H
—H
—CF3
—H
—H
376


853
—H
—H
—H
—H
—H
—OCH3
—H
—H
—H
—H
—H
320
















TABLE 121













 



















Ex. No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
R10
R11
MS (M + 1)





854
—H
—H
—F
—Cl
—H
—H
—H
—H
—H
—H
—H
342


855
—H
—H
—F
—Cl
—H
—CH3
—H
—H
—H
—H
—H
356


856
—H
—H
—F
—Cl
—H
—OCH3
—H
—H
—H
—H
—H
372


857
—H
—H
—F
—Cl
—H
—H
—CH3
—H
—H
—H
—H
356


858
—H
—H
—F
—Cl
—H
—H
—H
—NO2
—H
—H
—F
405


859
—H
—H
—F
—Cl
—H
—CH2C6H5
—H
—H
—H
—H
—H
432


860
—H
—H
—F
—Cl
—H
—H
—H
—H
—OCH3
—H
—H
372


861
—H
—H
—F
—Cl
—H
—H
—OCH3
—H
—H
—H
—H
372


862
—H
—H
—F
—Cl
—H
—H
—H
—H
—H
—OCH3
—H
372


863
—H
—H
—H
—H
—H
—H
—H
—H
—H
—H
—H
290


864
—H
—H
—H
—H
—H
—CH3
—H
—H
—H
—H
—H
304


865
—H
—H
—H
—H
—H
—OCH3
—H
—H
—H
—H
—H
320


866
—H
—H
—H
—H
—H
—H
—CH3
—H
—H
—H
—H
304


867
—H
—H
—H
—H
—H
—H
—H
—NO2
—H
—H
—F
353


868
—H
—H
—H
—H
—H
—CH2C6H5
—H
—H
—H
—H
—H
380


869
—H
—H
—H
—H
—H
—H
—H
—H
—OCH3
—H
—H
320


870
—H
—H
—H
—H
—H
—H
—OCH3
—H
—H
—H
—H
320


871
—H
—H
—H
—H
—H
—H
—H
—H
—H
—OCH3
—H
320


872
—H
—H
—F
—CH3
—H
—H
—H
—H
—H
—H
—H
322


873
—H
—H
—F
—CH3
—H
—CH3
—H
—H
—H
—H
—H
336


874
—H
—H
—F
—CH3
—H
—OCH3
—H
—H
—H
—H
—H
352


875
—H
—H
—F
—CH3
—H
—H
—CH3
—H
—H
—H
—H
336


876
—H
—H
—F
—CH3
—H
—H
—H
—NO2
—H
—H
—F
385


877
—H
—H
—F
—CH3
—H
—H
—H
—H
—OCH3
—H
—H
352


878
—H
—H
—F
—CH3
—H
—H
—H
—H
—H
—OCH3
—H
352


879
—H
—H
—F
—H
—H
—H
—H
—H
—H
—H
—H
308


880
—H
—H
—F
—H
—H
—CH3
—H
—H
—H
—H
—H
322


881
—H
—H
—F
—H
—H
—OCH3
—H
—H
—H
—H
—H
338


882
—H
—H
—F
—H
—H
—H
—CH3
—H
—H
—H
—H
322


883
—H
—H
—F
—H
—H
—H
—H
—NO2
—H
—H
—F
371


884
—H
—H
—F
—H
—H
—H
—H
—H
—OCH3
—H
—H
338


885
—H
—H
—F
—H
—H
—H
—OCH3
—H
—H
—H
—H
338


886
—H
—H
—F
—H
—H
—H
—H
—H
—H
—OCH3
—H
338


887
—H
—H
—H
—H
—H
—H
—OC2H5
—H
—H
—H
—H
334
















TABLE 122













 





















MS


Ex.






(M +


No.
R1
R2
R3
R4
R5
R6
1)





888
—H
—H
—F
—H
—H




297


 


889
—H
—H
—F
—Cl
—H
—CH2C≡CH
253


 


890
—H
—H
—F
—Cl
—H




415


 


891
—H
—H
—F
—Cl
—H




345


 


892
—H
—H
—F
—Cl
—H




346
















TABLE 123













 















Ex. No.
R1
R2
R3
R4
R5
R6
NMR
Salt





893
—H
—H
—F
—Cl
—H




1H-NMR (DMSO-d6) δ ppm: 1.55-1.75 (1H, m), 2.2-2.35 (1H, m), 2.38 (6H, s), 2.85-3.0 (1H, m), 3.1-3.2 (2H, m), 3.6- 3.75 (1H, m), 4.17 (1H, br), 4.77 (1H, tt, J = 7.7, 7.7 Hz), 7.21 (1H, dt, J = 4.0, 7.1 Hz), 7.25-7.35 (1H, m), 7.55-7.65 (2H, m), 7.86 (1H, bs), 8.14 (1H, d, J = 2.3 Hz), 8.76 (2H, br).
2-Methanesulfonate


 


894
—H
—H
—F
—Cl
—H




1H-NMR (DMSO-d6) δ ppm: 1.55-1.75 (1H, m), 2.15-2.3 (1H, m), 2.8-3.0 (1H, m), 3.05-3.2 (2H, m), 3.61 (1H, dd, J = 7.1, 11.8), 4.74 (1H, tt, J = 7.5, 7.5 Hz), 7.10 (1H, ddd, J = 2.4, 2.4, 12.0 Hz), 7.25-7.35 (1H, m), 7.45-7.65 (2H, m), 7.82 (1H, s), 8.05 (1H, d, J = 2.2 Hz), 9.1-9.55 (2H, m).
Hydrochloride


 


895
—H
—H
—F
—CH3
—H




1H-NMR (DMSO-d6) δ ppm: 1.55-1.75 (1H, m), 2.15-2.35 (4H, m), 2.75-2.95 (1H, m), 3.0-3.2 (2H, m), 3.55-3.7 (1H, m), 4.76 (1H, tt, J = 7.6, 7.6 Hz), 5.38 (1H, br), 7.05-7.25 (2H, m), 7.25-7.4 (2H, m), 7.75 (1H, dd, J = 1.2, 2.3 Hz), 8.07 (1H, d, J = 1.8 Hz), 9.43 (2H, br).
2 Hydrochloride


 


896
—H
—H
—F
—Cl
—H




1H-NMR (DMSO-d6) δ ppm: 1.55-1.75 (1H, m), 2.15-2.3 (1H, m), 2.8-3.0 (1H, m), 3.0-3.2 (2H, m), 3.55-3.7 (1H, m), 4.75 (1H, tt, J = 7.6, 7.6 Hz), 5.04 (1H, br), 6.9-7.05 (1H, m), 7.3-7.5 (2H, m), 7.62 (1H, dd, J = 9.0, 9.0 Hz), 7.71 (1H, dd, J = 2.4, 6.7 Hz), 7.95-8.15 (2H, m), 9.40 (2H, br).
2 Hydrochloride
















TABLE 124













 















Ex. No.
R1
R2
R3
R4
R5
R6
NMR
Salt





897
—H
—H
—F
—Cl
—H




1H-NMR (DMSO-d6) δ ppm: 1.5-1.7 (1H, m), 2.15-2.3 (1H, m), 2.8-2.95 (1H, m), 3.0-3.2 (2H, m), 3.5-3.65 (1H, m), 4.39 (1H, br), 4.70 (1H, tt, J = 7.8, 7.8 Hz), 6.68 (1H, d, J = 11.3 Hz), 7.35-7.45 (1H, m), 7.46 (1H, s), 7.61 (1H, dd, J = 9.0, 9.0 Hz), 7.71 (1H, dd, J = 2.6, 6.8 Hz), 7.95-8.05 (1H, m), 9.27 (2H, br).
2 Hydro- chloride


 


898
—H
—H
—F
—Cl
—H




1H-NMR (DMSO-d6) δ ppm: 1.55-1.75 (1H, m), 2.05-2.3 (1H, m), 2.8-3.0 (1H, m), 3.05-3.3 (2H, m), 3.5-3.7 (1H, m), 4.78 (1H, tt, J = 7.3, 7.3 Hz), 6.8-6.9 (1H, m), 7.1-7.2 (2H, m), 7.34 (1H, dd, J = 9.0, 9.0 Hz), 7.44 (1H, d, J = 2.1 Hz), 7.97 (1H, s), 8.08 (1H, d, J = 8.7 Hz), 9.29 (1H, br), 9.44 (1H, br).
Hydro- chloride


 


899
—H
—H
—F
—H
—H




1H-NMR (DMSO-d6) δ ppm: 1.55-1.75 (1H, m), 2.1-2.25 (1H, m), 2.85-3.05 (1H, m), 3.1-3.25 (2H, m), 3.6-3.75 (1H, m), 3.8-5.0 (1H, m), 5.28 (1H, tt, J = 8.2, 8.2 Hz), 6.06 (1H, d, J = 8.9 Hz), 7.22 (1H, d, J = 5.9 Hz), 7.35-7.5 (5H, m), 7.85 (1H, d, J = 8.9 Hz), 9.34 (2H, br).
2 Hydro- chloride


 


900
—H
—H
—H
—H
—H




1H-NMR (DMSO-d6) δ ppm: 1.55-1.8 (1H, m), 2.2-2.35 (1H, m), 2.8-2.95 (1H, m), 3.0-3.25 (2H, m), 3.6-3.75 (1H, m), 4.10 (1H, br), 4.75-4.9 (1H, m), 6.68 (1H, dd, J = 2.1, 8.9 Hz), 7.15-7.3 (2H, m), 7.3-7.45 (1H, m), 7.45-7.6 (3H, m), 7.93 (1H, d, J = 8.9 Hz), 8.87 (1H, s), 9.26 (1H, br), 9.38 (1H, br).
2 Hydro- chloride
















TABLE 125













 















Ex. No.
R1
R2
R3
R4
R5
R6
NMR
Salt





901
—H
—H
—F
—H
—H




1H-NMR (DMSO-d6) δ ppm: 1.6-1.75 (1H, m), 2.2-2.35 (1H, m), 2.8-2.95 (1H, m), 3.05-3.25 (2H, m), 3.6-3.75 (1H, m), 4.47 (1H, br), 4.80 (1H, tt, J = 7.6, 7.6 Hz), 6.66 (1H, dd, J = 2.2, 8.9 Hz), 7.25-7.4 (4H, m), 7.48 (1H, d, J = 1.8 Hz), 7.92 (1H, d, J = 9.0 Hz), 8.85 (1H, s), 9.34 (1H, br), 9.45 (1H, br).
2 Hydrochloride


 


902
—H
—H
—H
—H
—H




1H-NMR (DMSO-d6) δ ppm: 1.6-1.75 (1H, m), 2.15-2.3 (1H, m), 2.90 (1H, dd, J = 8.0, 11.6 Hz), 3.05-3.2 (2H, m), 3.62 (1H, dd, J = 6.9, 11.6 Hz), 4.7-4.85 (1H, m), 6.92 (1H, d, J = 1.8 Hz), 7.04 (2H, d, J = 7.7 Hz), 7.17 (1H, dd, J = 7.3, 7.3 Hz), 7.35-7.45 (3H, m), 7.63 (1H, d, J = 1.3 Hz), 7.76 (1H, d, J = 5.5 Hz), 9.23 (2H, br).
Hydrochloride


 


903
—H
—H
—H
—H
—H




1H-NMR (DMSO-d6) δ ppm: 1.6-1.75 (1H, m), 2.1-2.25 (1H, m), 2.55 (3H, d, J = 0.9 Hz), 2.8-2.95 (1H, m), 3.0-3.25 (2H, m), 3.5-3.65 (1H, m), 4.72 (1H, tt, J = 7.3, 7.3 Hz), 6.80 (2H, d, J = 7.7 Hz), 6.85-7.0 (2H, m), 7.10 (1H, s), 7.2-7.3 (2H, m), 7.63 (1H, d, J = 1.9 Hz), 7.69 (1H, d, J = 8.5 Hz), 9.17 (1H, br), 9.34 (1H, br).
Hydrochloride


 


904
—H
—H
—F
—H
—H




1H-NMR (DMSO-d6) δ ppm: 1.6-1.75 (1H, m), 2.1-2.25 (1H, m), 2.53 (3H, d, J = 0.7 Hz), 2.8-2.95 (1H, m), 3.0-3.25 (2H, m), 3.5-3.65 (1H, m), 4.69 (1H, tt, J = 7.1, 7.1 Hz), 6.86 (1H, dd, J = 2.1, 8.5 Hz), 6.9- 7.05 (2H, m), 7.05 (1H, s), 7.1-7.2 (2H, m), 7.54 (1H, d, J = 1.9 Hz), 7.62 (1H, d, J = 8.6 Hz), 9.30 (1H, br), 9.45 (1H, br).
Hydrochloride
















TABLE 126













 















Ex.










No.
R1
R2
R3
R4
R5
R6
NMR
Salt





905
—H
—H
—CH3
—F
—H




1H-NMR (DMSO-d6) δ ppm: 1.58-1.71 (1H, m), 2.12 (3H, s), 2.19-2.23 (1H, m), 2.55 (2H, dd, J = 7.0, 8.0 Hz, with DMSO-d6), 2.78-2.89 (1H, m), 2.86 (2H, dd, J = 7.0, 8.0 Hz), 3.08-3.22 (2H, m), 3.27 (3H, s), 3.48-3.62 (1H, m, with H2O), 4.59-4.69 (1H, m), 6.44 (1H, dd, J = 2.3, 8.3 Hz), 6.52 (1H, dd, J = 2.3, 12.8 Hz), 7.02-7.16 (4H, m), 9.34 (2H, br). 
Hydrochloride


 


906
—H
—H
—CH3
—F
—H




1H-NMR (DMSO-d6) δ ppm: 1.59-1.72 (1H, m), 2.13 (3H, d, J = 0.86 Hz), 2.17-2.27 (1H, m), 2.82-2.91 (1H, m), 3.09-3.20 (2H, m), 3.61-3.63 (1H, m, with H2O), 3.63 (3H, s), 4.66-4.73 (1H, m), 6.47 (1H, dd, J = 2.3, 8.5 Hz), 6.58 (1H, dd, J = 2.3, 12.6 Hz), 6.65 (1H, d, J = 9.5 Hz), 7.11 (1H, dd, J = 8.5, 8.9 Hz), 7.36 (1H, dd, J = 2.5, 8.9 Hz), 7.56-7.60 (2H, m), 7.89 (1H, d, J = 9.5 Hz), 9.33 (1H, br), 9.41 (1H, br).
Hydrochloride


 


907
—H
—H
—F
—CH3
—H




1H-NMR (DMSO-d6) δ ppm: 1.59-1.72 (1H, m), 2.09-2.19 (1H, m), 2.19 (3H, d, J = 1.4 Hz), 2.48-2.51 (2H, m, with DMSO-d6), 2.78-2.90 (1H, m), 2.81 (2H, dd, J = 6.8, 8.0 Hz), 3.09-3.19 (2H, m), 3.22 (3H, s), 3.40-3.54 (1H, m, with H2O), 4.56-4.66 (1H, m), 6.75-6.80 (1H, m), 6.83-6.85 (2H, m), 6.90 (1H, dd, J = 2.6, 6.8 Hz), 7.02-7.11 (2H, m), 9.29 (1H, br), 9.40 (1H, br).
Hydrochloride


 


908
—H
—H
—F
—CH3
—H




1H-NMR (DMSO-d6) δ ppm: 1.62-1.75 (1H, m), 2.14-2.26 (1H, m), 2.20 (3H, d, J = 1.6 Hz), 2.85-2.95 (1H, m), 3.11- 3.43 (2H, m), 3.53-3.69 (1H, m, with H2O), 3.59 (3H, s), 4.64-4.73 (1H, m), 6.61 (1H, d, J = 9.4 Hz), 6.82-6.87 (1H, m), 6.95 (1H, dd, J = 2.6, 6.8 Hz), 7.11 (1H, dd, J = 9.0, 9.1 Hz), 7.16 (1H, dd, J = 2.6, 9.1 Hz), 7.38 (1H, d, J = 2.6 Hz), 7.48 (1H, d, J = 9.1 Hz), 7.86 (1H, d, J = 9.4 Hz), 9.35 (1H, br), 9.48 (1H, br).
Hydrochloride
















TABLE 127













 















Ex. No.
R1
R2
R3
R4
R5
R6
NMR
Salt





909
—H
—H
—F
—CH3
—H




1H-NMR (DMSO-d6) δ ppm: 1.58-1.71 (1H, m), 2.08-2.17 (1H, m), 2.17 (3H, d, J = 1.5 Hz), 2.42 (2H, dd, J = 6.9, 8.0 Hz), 2.81-2.89 (1H, m), 2.83 (2H, dd, J = 6.9, 8.0 Hz), 3.08-3.14 (2H, m), 3.16- 3.56 (1H, m, with H2O), 4.52-4.61 (1H, m), 6.63-6.69 (1H, m), 6.79 (1H, dd, J = 2.6, 6.9 Hz), 6.84-6.86 (3H, m), 7.02 (1H, dd, J = 9.1, 9.1 Hz), 9.17 (1H, br), 9.29 (1H, br), 10.07 (1H, s).
Hydrochloride


 


910
—H
—H
—F
—CH3
—H




1H-NMR (DMSO-d6) δ ppm: 1.56-1.69 (1H, m), 2.16-2.65 (1H, m), 2.63 (3H, d, J = 1.5 Hz), 2.78-2.89 (1H, m), 2.83 (2H, dd, J = 6.5, 6.5 Hz), 2.96 (3H, s), 3.07-3.19 (2H, m), 3.37-3.45 (2H, m, with H2O), 3.56-3.66 (1H, m), 4.71-4.80 (1H, m), 6.41 (1H, d, J = 2.4 Hz), 6.47 (1H, dd, J = 2.4, 8.7 Hz), 7.07-7.12 (1H, m), 7.20 (1H, dd, J = 2.4, 7.0 Hz), 7.29 (1H, dd, J = 8.9, 9.2 Hz), 7.64 (1H, d, J = 8.7 Hz), 9.11 (1H, br), 9.19 (1H, br).
Hydrochloride


 


911
—H
—H
—F
—Cl
—H




1H-NMR (DMSO-d6) δ ppm: 1.58-1.71 (1H, m), 2.15-2.22 (1H, m), 2.55 (2H, dd, J = 6.4, 8.3 Hz), 2.81-2.89 (1H, m), 2.86 (2H, dd, J = 6.4, 8.3 Hz), 3.12-3.27 (2H, m), 3.26 (3H, s), 3.55 (1H, dd, J = 6.9, 11.7 Hz), 4.60-4.70 (1H, m), 6.69 (1H, ddd, J = 3.0, 3.9, 9.1 Hz), 6.93 (1H, dd, J = 3.0, 6.3 Hz), 7.03-7.06 (2H, m), 7.15 (1H, d, J = 9.3 Hz), 7.27 (1H, dd, J = 9.1, 9.1 Hz), 9.17 (2H, br).
Hydrochloride


 


912
—H
—H
—F
—Cl
—H




1H-NMR (DMSO-d6) δ ppm: 1.62-1.72 (1H, m), 2.17-2.27 (1H, m), 2.83-2.94 (1H,m ), 3.12-3.19 (1H, m), 3.54-3.60 (1H, m), 3.63 (3H, s), 4.67-4.77 (1H, m), 6.66 (1H, d, J = 9.5 Hz), 6.74 (1H, ddd, J = 3.1, 3.8, 9.1 Hz), 6.99 (1H, dd,  J = 3.1, 6.3 Hz), 7.29 (1H, dd, J = 9.1, 9.1 Hz), 7.37 (1H, dd, J = 2.6, 8.9 Hz), 7.56- 7.60 (2H, m), 7.88 (1H, d, J = 9.5 Hz), 9.13 (1H, br), 9.21 (1H, br).
Hydrochloride
















TABLE 128













 















Ex. No.
R1
R2
R3
R4
R5
R6
NMR
Salt





913
—H
—Cl
—F
—H
—H




1H-NMR (DMSO-d6) δ ppm: 1.65-1.82 (1H, m), 2.19- 2.40 (1H, m), 2.90-3.10 (1H, m), 3.10-3.20 (2H, m), 3.65- 3.80 (1H, m), 4.80-4.90 (1H, m), 7.30-7.45 (2H, m), 7.52 (1H, d, J = 2.5 Hz), 7.55-7.69 (2H, m), 7.88 (1H, dd, J = 8.4, 5.1 Hz), 8.15 (1H, d, J = 9.4 Hz), 8.83 (1H, d, J = 8.4 Hz), 8.94 (1H, d, J = 4.1 Hz), 9.45 (1H, bs), 9.62 (1H, bs)
2 Hydrochloride


 


914
—H
—H
—F
—Cl
—H




1H-NMR (DMSO-d6) δ ppm: 1.56-1.70 (1H, m), 2.12-2.22 (1H,m), 2.46 (2H, dd, J =  7.1, 8.0 Hz), 2.80-2.90 (1H, m), 2.88 (2H, dd, J = 7.1, 8.0 Hz), 3.09-3.16 (2H, m), 3.50- 3.60 (1H, m), 4.58-4.68 (1H, m), 6.61 (1H, ddd, J = 3.4, 3.5, 9.1 Hz), 6.86 (1H, dd, J = 2.9, 6.3 Hz), 6.91-7.00 (3H, m), 7.23 (1H, dd, J = 9.1, 9.1 Hz), 8.80 (2 H, br), 10.19 (1H, s).
2 Trifluoroacetate


 


915
—H
—H
—F
—H
—H




1H-NMR (DMSO-d6) δ ppm: 1.59-1.66 (1H, m), 2.10-2.20 (1H, m), 2.43 (2H, dd, J =  7.0, 8.1 Hz), 2.84 (2H, dd, J = 7.0, 8.1 Hz), 2.84-2.92 (1H, m), 3.11-3.21 (2H, m), 3.47- 3.55 (1H, m), 4.54-4.64 (1H, m), 6.79-6.89 (5H, m), 7.09 (2H, dd, J = 8.8, 8.9 Hz), 8.71 (2H, br), 10.10 (1H, s).
2 Trifluoroacetate
















TABLE 129













 















Ex. No.
R1
R2
R3
R4
R5
R6
NMR
Salt





916
—H
—H
—F
—H
—H




1H-NMR (DMSO-d6) δ ppm: 1.60-1.71 (1H, m), 2.12-2.22 (1H, m), 2.49-2.54 (2H, m, with DMSO-d6), 2.82 (2H, dd, J = 7.4, 8.0), 2.84-2.91 (1H, m), 3.12-3.16 (2H, m), 3.23 (3H, s), 3.45-3.55 (1H, m), 4.56-4.65 (1H, m), 6.87-6.95 (4H, m), 7.06 (1H, d, J = 9.4 Hz), 7.14 (2H, dd, J = 8.8, 8.9 Hz), 8.67 (2H, br).
Hydrochloride


 


917
—H
—H
—F
—H
—H




1H-NMR (DMSO-d6) δ ppm: 1.58-1.73 (1H, m), 2.10-2.31 (1H, m), 2.41 (2H, dd, J = 7.0, 8.0 Hz), 2.80 (2H, dd, J = 7.0, 8.0 Hz), 2.82-3.14 (1H, m), 3.14 (2H, br), 3.46-3.56 (1H, m), 4.54-4.62 (1H, m), 6.31 (1H, d, J = 2.2 Hz), 6.47 (1H, dd, J = 2.2, 8.1 Hz), 7.01-7.10 (3H, m), 7.21 (2H, dd, J = 8.7, 8.8 Hz), 8.83 (2H, br), 9.88 (1H, s).
Hydrochloride


 


918
—H
—F
—CH3
—H
—H




1H-NMR (DMSO-d6) δ ppm: 1.60-1.70 (1H, m), 2.10 (3H, s), 2.13-2.21 (1H, m), 2.43- 2.48 (2H, m), 2.79-2.90 (1H, m), 2.87 (2H, dd, J = 7.1, 8.0 Hz), 3.11 (2H, br), 3.48-3.55 (1H, m), 4.56-4.66 (1H, m), 6.37 (1H, dd, J = 2.4, 8.4 Hz), 6.44 (1H, dd, J = 2.4, 13.0 Hz), 6.90-7.08 (4H, m), 9.22 (1H, br), 9.32 (1H, br), 10.19 (1H, s).
Hydrochloride
















TABLE 130













 















Ex. No.
R1
R2
R3
R4
R5
R6
NMR
Salt





919
—H
—CH3
—F
—H
—H




1H-NMR (DMSO-d6) δ ppm: 1.53- 1.65 (1H, m), 2.14-2.21 (1H, m), 2.14 (3H, d, J = 1.6 Hz), 2.44-2.49 (2H, m, with DMSO-d6), 2.63-2.69 (2H, m), 2.85 (1H, dd, J = 7.8, 11.6 Hz), 3.13-3.17 (2H, m), 3.28 (3H,
Hydrochloride









s), 3.59 (1H, dd, J = 6.9, 11.6 Hz),










4.57-4.67 (1H, m), 6.33-6.39 (1H,










m), 6.51 (1H, dd, J = 3.1, 6.4 Hz),










6.91-6.97 (2H, m), 7.15 (1H, d, J =










8.1 Hz), 7.38 (1H, t, J = 8.1 Hz),










9.03 (2H, br).



 


920
—H
—Cl
—F
—H
—H




1H-NMR (DMSO-d6) δ ppm: 1.58- 1.71 (1H, m), 2.15-2.25 (1H, m), 2.82-2.92 (1H, m), 3.11-3.16 (2H, m), 3.37 (3H, s, with H2O), 3.54- 3.60 (1H, m), 4.65-4.74 (1H, m),
2Hydrochloride









6.54 (1H, d, J = 9.6 Hz), 6.64-6.69










(1H, m), 6.93 (1H, dd, J = 2.9, 6.3










Hz), 7.22-7.30 (2H, m), 7.37 (1H,










d, J = 8.7 Hz), 7.53 (1H, d, J = 2.2










Hz), 7.88 (1H, d, J = 9.6 Hz), 9.04










(1H, br), 9.13 (1H, br), 11.86 (1H,










s).
















TABLE 131













 















Ex. No.
R1
R2
R3
R4
R5
R6
NMR
Salt





921
—H
—H
—F
—Cl
—H




1H-NMR (DMSO-d6) δ ppm: 1.18-1.35 (2H, m), 1.66-1.90 (3H, m), 1.95-2.12 (1H, m), 2.88-3.46 (7H, m), 3.83 (2H,  dd, J = 3.2, 11.1 Hz), 4.18-4.36 (1H,  brs), 7.11-7.30 (1H, m), 7.30-7.50 (2H,  m), 9.25-9.65 (2H, br).
Hydrochloride


 


922
—H
—H
—F
—Cl
—H 




1H-NMR (DMSO-d6) δ ppm: 1.08-1.29 (2H, m), 1.45-1.70 (3H, m), 1.79-2.14 (2H, m), 2.85-3.40 (8H, m), 3.73-3.85 (2H, m), 4.28-4.46 (1H, m), 6.91-7.08
Hydrochloride









(1H, m), 7.11-7.35 (2H, m), 9.00-9.85










(2H, m).



 


923
—H
—H
—Cl
—CH3
—H




1H-NMR (DMSO-d6) δ ppm: 1.57-1.75 (1H, m), 2.19-2.35 (1H, m), 2.37 (3H,  s), 2.83-2.96 (1H, m), 3.00-3.19 (2H,  m), 3.58-3.74 (1H, m), 4.80-4.95 (1H,  m), 7.22 (1H, dd, J = 8.4, 2.4 Hz), 7.40 
2Hydrochbride









(1H, d, J = 2.4 Hz), 7.55-7.66 (2H, m), 










7.77 (1H, dd, J = 8.9, 5.3 Hz), 8.17 (1H, 










J = 2.7 Hz), 8.24 (1H, d, J = 5.3 Hz), 










9.62 (2H, br).



 


924
—H
—H
—F
—Cl
—H




1H-NMR (DMSO-d6) δ ppm: 1.76-1.93 (6H, m), 2.07-2.09 (1H, m), 2.94 (1H, br), 3.10 (1H, br), 3.13 (2H, s), 3.34- 3.71 (6H, m, with H2O), 4.36-4.42 (1H,
Hydrochloride









m), 7.02-7.07 (1H, m), 7.24-7.51 (5H,










m), 7.77 (2H, br), 9.06 (1H, br), 9.40










(1H, br).
















TABLE 132













 















Ex. No.
R1
R2
R3
R4
R5
R6
m.p. (° C.)
Salt





925
—H
—H
—F
—H
—H




195.5-198.5
2Hydrochloride


 


926
—H
—H
—Cl
—Cl
—H




102-105
Hydrochloride


 


927
—H
—H
—Cl
—Cl
—H




119-122
2Hydrochloride


 


928
—H
—H
—Cl
—Cl
—H




123-124
2Hydrochloride


 


929
—H
—H
—Cl
—Cl
—H




191-193
Hydrochloride


 


930
—H
—H
—F
—Cl
—H




150-156
2Hydrochloride


 


931
—H
—F
—F
—H
—H




153-155
Fumarate


 


932
—H
—Cl
—H
—Cl
—H




174.7-176.7
2Hydrochloride


 


933
—H
—H
—H
—H
—H




  227-228.5
2Hydrochloride


 


934
—H
—H
—H
—H
—H




241.5-243.5
2Hydrochloride
















TABLE 133













 















Ex No.
R1
R2
R3
R4
R5
R6
m.p. (° C.)
Salt





935
—H
—H
—F
—H
—H




133-135
Fumarate


 


936
—H
—Cl
—Cl
—H
—H




134-136
Fumarate


 


937
—H
—F
—F
—H
—H




138-141
Fumarate


 


938
—H
—H
—Cl 
—CH3
—H




110.3-111.9
Fumarate


 


939
—H
—Cl 
—H
—Cl
—H




179.2-181.1
Fumarate


 


940
—H
—H
—F
—Cl
—H




203.5-206  
Hydrochloride


 


941
—H
—H
—H
—H
—H




141-144
Fumarate


 


942
—H
—H
—H
—H
—H




135-161
Fumarate


 


943
—H
—H
—H
—H
—H




155-156
Hydrochloride
















TABLE 134













 















Ex. No.
R1
R2
R3
R4
R5
R6
m.p. (° C.)
Salt





944
—H
—H
—H
—H
—H




160-180
Hydrochloride


 


945
—H
—H
—F
—H
—H




155.5-164.5
Hydrochloride


 


946
—H
—H
—F
—H
—H




  161-167.5
Hydrochloride
















TABLE 135













 











Ex No. 
R1
R6
NMR
Salt





947








1H-NMR (DMSO-d6) δ ppm: 1.6-1.8 (1H, m), 2.25-  2.4 (1H, m), 2.85-3.0 (1H, m), 3.0-3.2 (2H, m), 3.25- 4.45 (2H, m), 4.9-5.0 (1H, m), 7.45 (1H, dd, J = 1.8, 8.5 Hz), 7.58 (1H, dd, J = 2.3, 8.8 Hz), 7.72 (1H, dd,  J = 5.3, 8.8 Hz), 7.98 (1H, d, J = 8.5 Hz), 8.08 (1H,  s), 8.16 (1H, d, J = 1.6 Hz), 8.22 (1H, d, J = 2.8 Hz), 
2Hydrochloride





8.25 (1H, d, J = 5.0 Hz), 9.45 (1H, br), 9.58 (1H, br).



 


948








1H-NMR (DMSO-d6) δ ppm: 1.6-1.8 (1H, m), 2.25- 2.4 (1H, m), 2.85-3.25 (3H, m), 3.6-3.8 (1H, m),  4.97 (1H, tt, J = 7.7, 7.7 Hz), 7.32 (1H, dd, J = 1.7,  8.6 Hz), 7.65-7.8 (2H, m), 8.16 (1H, s), 8.3-8.4 (3H,  m), 9.17 (1H, d, J = 0.7 Hz), 9.3-9.8 (2H, m).
2Hydrochloride


 


949








1H-NMR (DMSO-d6) δ ppm: 1.55-1.75 (1H, m), 2.25-  2.4 (1H, m), 2.7-5.3 (1H, br), 2.85-3.0 (1H, m), 3.05- 3.25 (2H, m), 3.65-3.8 (1H, m), 4.95 (1H, tt, J = 7.7, 7.7 Hz), 7.45 (1H, dd, J = 1.9, 8.6 Hz), 7.55-7.6 (1H, m), 7.74 (1H, dd, J = 5.3, 8.8 Hz), 7.81 (1H, d,  J = 1.8 Hz), 8.09 (1H, s), 8.19 (1H, d, J = 2.8 Hz), 
2Hydrochloride





8.23 (1H, d, J = 5.2 Hz), 8.33 (1H, d, J = 8.6 Hz), 






9.44 (1, br), 9.62 (1H, br).



 


950








1H-NMR (DMSO-d6) δ ppm: 1.55-1.75 (1H, m), 2.2- 2.35 (1H, m), 2.8-3.0 (1H, m), 3.0-3.25 (2H, m), 3.55-3.75 (1H, m), 4.35-5.5 (2H, m), 7.20 (1H, d, J = 12.2 Hz), 7.28 (1H, dd, J = 1.8, 8.5 Hz), 7.55 (1H, d,  J = 5.4 Hz), 7.7-7.8 (1H, m), 7.91 (1H, d, J = 5.4 Hz),
2Hydrochloride





8.0-8.1 (2H, m), 8.10 (1H, d, J = 2.2 Hz), 9.32 (1H,






br), 9.47 (1H, br).



 


951








1H-NMR (DMSO-d6) δ ppm: 1.55-1.8 (1H, m), 2.2- 2.35 (1H, m), 2.8-3.0 (1H, m), 3.0-3.2 (2H, m), 3.6- 3.75 (1H, m), 4.3-5.0 (2H, m), 7.1-7.25 (1H, m), 7.27 (1H, dd, J = 2.0, 8.5 Hz), 7.51 (1H, d, J = 5.5 Hz), 7.76 (1H, d, J = 1.1 Hz), 7.87 (1H, d, J =
2Hydrochloride





1.9 Hz), 7.91 (1H, d, J = 5.4 Hz), 8.08 (1H, d, J =






2.2 Hz), 8.20 (1H, d, J = 8.5 Hz), 9.27 (1H, br), 9.43






(1H, br).



 


952








1H-NMR (DMSO-d6) δ ppm: 1.6-1.75 (1H, m), 2.2- 2.35 (1H, m), 2.85-3.0 (1H, m), 3.0-3.2 (2H, m), 3.6-3.15 (1H, m), 4.32 (1H, br), 4.85 (1H, tt, J = 7.7, 7.7 Hz), 7.19 (1H, ddd, J = 2.4, 2.4, 12.0 Hz), 7.37 (1H, dd, J = 1.9, 8.5 Hz), 7.8-7.85 (1H, m), 7.92 (1H, d, J = 8.5 Hz), 8.02 (1H, s), 8.05-8.15 (2H, m), 9.21
2Hydrochloride





(1H, br), 9.33 (1H, br).
















TABLE 136













 















Ex. No.
R1
R2
R3
R4
R5
R6
m.p. (° C.)
Salt





953
—H
—H
—Cl
—Cl
—H




96-98
2Hydrochloride


 


954
—H
—H
—Cl
—Cl
—H




126-129
2Hydrochloride


 


955
—H
—H
—Cl
—Cl
—H




139-143
2Hydrochloride


 


956
—H
—H
—Cl
—Cl
—H




117-120
2Hydrochloride


 


957
—H
—H
—Cl
—Cl
—H




155-159
Hydrochloride


 


958
—H
—H
—F
—Cl
—H




101-103
Hydrochloride


 


959
—H
—H
—F
—Cl
—H




157-160
Hydrochloride


 


960
—H
—H
—Cl
—Cl
—H




151-153
2Hydrochbride


 


961
—H
—H
—Cl
—Cl
—H




96-98
Hydrochloride


 


962
—H
—H
—F
—Cl
—H




119-123
2Hydrochloride


 


963
—H
—H
—Cl
—Cl
—H




120-124
2Hydrochloride
















TABLE 137













 















Ex. No.
R1
R2
R3
R4
R5
R6
NMR
Salt





964
—H
—Cl
—F
—H
—H
—(CH2)2OCH(C6H5)2
1H-NMR (CDCl3) δ ppm; 1.99-2.18 (2H, m),
—









3.13-3.34 (2H, m), 3.38-3.3.47 (7H, m),










4.23-4.35 (1H, m), 5.25 (1H, s), 6.71-6.78










(1H, m), 6.92-7.00 (2H, m), 7.18-7.33










(10H, m)



965
—H
—Cl
—F
—H
—H
—CH2CO2C2H5
1H-NMR (DMSO-d6) δ ppm; 1.15 (3H, t, J =
Hydrochloride









7.1 Hz), 2.05-2.36 (2H, m), 3.04-3.22 (1H,










m), 3.22-3.72 (4H, m), 3.71-4.50 (3H, m),










5.34 (1H, brs), 7.52-7.69 (2H, m), 7.87-










7.98 (1H, m), 9.10-9.70 (2H, m).



966
—H
—Cl
—F
—H
—H
—(CH2)2OH
1H-NMR (CDCl3) δ ppm; 1.25 (1H, s), 1.80-
—









1.94 (1H, m), 2.04-2.19 (1H, m), 2.97-3.74










(9H, m), 4.05-4.14 (1H, m), 6.76 (1H, ddd,










J = 8.9, 3.6, 2.9 Hz), 6.92 (1H, dd, J = 6.2,










2.9 Hz), 7.03 (1H, dd, J = 8.9, 8.8 Hz)



967
—H
—Cl
—F
—H
—H
—CH2C(CH3)2OH
1H-NMR (DMSO-d6) δ ppm; 1.01 (3H, s),
Oxalate









1.04 (3H, s), 1.88-2.15 (2H, m), 3.03-3.22










(4H, m), 3.22-3.45 (2H, m), 3.45-3.55 (5H,










m; including 1H, quint at 4.30), 7.01-7.10










(1H, m), 7.23 (1H, t, J = 9.1 Hz), 7.25-7.32










(1H, m).



968
—H
—Cl
—F
—H
—H
—(CH2)2OCH3
1H-NMR (DMSO-d6) δ ppm; 1.82-2.00
Hydrochloride









(1H, m), 2.06-2.20 (1H, m), 2.90-3.19 (2H,










m), 3.24 (3H, s), 3.26-3.50 (6H, m), 4.44










(1H, quint, J = 8.2 Hz), 6.89 (1H, td, J =










3.3, 9.1 Hz), 7.07 (1H, dd, J = 3.3, 9.1 Hz),










7.25 (1H, t, J = 9.1 Hz), 9.34 (1H, br), 9.52










(1H, br).



969
—H
—Cl
—F
—H
—H
—CH2CO2H
1H-NMR (DMSO-d6) δ ppm; 2.05-2.34 (2H, 
Hydrochloride









m), 2.80-4.40 (5H, m), 5.22 (1H, brs), 7.51-










7.71 (2H, m), 7.89 (1H, dd, J = 1.8, 5.3










Hz), 7.15-7.65 (2H, br), 9.85-11.65 (2H,










br).



970
—H
—Cl
—F
—H
—H
—CH2CONH2




971
—H
—Cl
—F
—H
—H
—CH2CONHCH3
1H-NMR (DMSO-d6) δ ppm; 2.09-2.31 (2H,
Hydrochloride









m), 2.63 (3H, d, J = 4.6 Hz), 3.05-3.25 (1H,










m), 3.25-3.54 (3H, m), 3.54-3.79 (1H, m),










5.27 (1H, brs), 7.50-7.70 (2H, m), 7.80-










7.97 (1H, m), 8.92 (1H, brs), 9.36-9.85










(2H, m), 9.80-11.10 (1H, br).
















TABLE 138













 















Ex. No.
R1
R2
R3
R4
R5
R6
NMR
Salt





972
—H
—Cl
—F
—H
—H
—CH2CON(CH3)2
1H-NMR (DMSO-d6) δ ppm; 2.07-2.40 (2H,
Hydrochloride









m), 2.89 (3H, s), 2.90 (3H, s), 3.02-3.24










(1H, m), 324-3.83 (4H, m), 5.63 (1H, brs),










7.53-7.69 (2H, m), 7.83-7.93 (1H, m), 9.32-










9.75 (2H, m), 9.82-10.50 (1H, m).



973
—H
—Cl
—F
—H
—H
—CH2CH═CH2
1H-NMR (DMSO-d6) δ ppm; 1.76-1.95 (1H,
Hydrochloride









m), 2.10-2.25 (1H, m), 2.85-3.02 (1H, m),










3.02-3.19 (1H, m), 3.25-3.50 (2H, m), 3.89










(2H, brs), 4.59 (1H, quint, J = 7.8 Hz),










5.05-5.20 (2H, m), 5.76-5.94 (1H, m), 6.69-










6.82 (1H, m), 6.88-6.97 (1H, m), 7.23 (1H,










t, J = 9.2 Hz), 8.90-9.95 (2H, br).



974
—H
—Cl
—F
—H
—H
—(CH2)3OH
1H-NMR (DMSO-d6) δ ppm; 1.49-2.79 (2H,
Hydrochloride









m), 1.81-2.04 (2H, m), 2.05-2.20 (1H, m),










2.82-3.20 (2H, m), 3.20-3.50 (6H, m), 4.33-










4.52 (1H, m), 6.84-7.04 (1H, m), 7.04-7.21










(1H, m), 7.22-7.35 (1H, m), 9.15-9.75 (2H,










m).



975
—H
—Cl
—F
—H
—H
—(CH2)2C(CH3)2OH




976
—H
—Cl
—F
—H
—H
—(CH2)3OCH3
1H-NMR (DMSO-d6) δ ppm; 1.55-1.72 (2H,
Oxalate









m), 1.80-1.99 (1H, m), 2.04-220 (1H, m),










2.93 (1H, dd, J = 9.4, 11.6 Hz), 3.05-3.50










(10H, m), 4.40 (1H, quint, J = 7.9 Hz),










5.25-8.20 (6H, m; including 6.80-6.90 (1H,










m), 7.00-7.10 (1H, m), and 7.26 (1H, t, J =










9.1 Hz).
















TABLE 139













 















Ex No.
R1
R2
R3
R4
R5
R6
NMR
Salt





977
—H
—Cl 
—F
—H
—H




1H-NMR (CDCl3) δ ppm; 1.58-1.71 (1H, m), 2.03-2.18 (2H, m), 2.79 (1H, dd, J = 11.2, 4.3 Hz), 2.91 (1H, ddd, J = 11.2, 8.2, 6.2 Hz), 3.03-3.15 (2H, m), 4.25-4.35 (1H, m), 6.88- 6.92 (1H, m), 6.97-7.15 (3H, m), 7.25 (1H, dd,
—









J = 8.7, 8.7 Hz), 7.49 (1H, ddd, J = 8.7, 4.2,










2.6 Hz), 7.66 (1H, dd, J = 6.5, 2.6 Hz)



 


978
—H
—Cl 
—F
—H
—H




1H-NMR (CDCl3) δ ppm; 1.59 (1H, s), 1.66-1.81 (1H, m), 2.00-2.16 (1H, m), 2.83-2.93 (3H, m), 3.12 (1H, dd, J = 11.5, 6.6 Hz), 3.22 (1H, t, J =8.7 Hz), 4.20-4.31 (1H, m), 4.62 (1H, t, J =
—









8.7 Hz), 6.44 (1H, ddd, J = 9.1, 3.6,










3.0 Hz), 6.62 (1H, dd, J = 6.2, 3.0 Hz),










6.75-6.85 (2H, m), 6.86-6.94 (2H, m)



 


979
—H
—Cl 
—F
—H
—H








 


980
—H
—Cl 
—F
—H
—H




1H-NMR (CDCl3) δ ppm; 1.64-1.84 (2H, m), 2.07-2.19 (1H, m), 2.87-3.02 (3H, m), 3.21 (1H, dd, J = 11.5, 6.7 Hz), 4.34-4.44 (1H, m), 6.81 (1H, ddd, J = 8.9, 4.1, 2.8 Hz), 6.90-6.95 (2H, m), 7.00 (1H, dd, J = 6.5, 2.8 Hz), 7.07 (1H, dd, J = 8.9, 8.7 Hz), 7.30-7.34 (1H, m), 7.39-7.45 (2H, m), 7.49-7.61 (4H, m)
Oxa- late


 


981
—H
—Cl 
—F
—H
—H




1H-NMR (CDCl3) δ ppm; 1.66-1.82 (1H, m), 1.98-2.12 (1H, m), 2.83-3.20 (5H, m), 3.40- 3.52 (4H, m), 4.02-4.15 (1H, m), 5.23 (1H, s), 6.67 (1H, ddd, J = 8.9, 3.6, 3.0 Hz), 6.89 (1H, dd, J = 6.2, 3.0 Hz), 6.96 (1H, dd, J = 8.9, 8.8 Hz), 7.16-7.21 (4H, m), 7.25-7.32 (4H, m)
—


 


982
—H
—Cl 
—F
—H
—H




1H-NMR (CDCl3) δ ppm; 1.67-1.82 (1H, m), 1.98-2.13 (1H, m), 2.83-3.20 (4H, m), 3.24 (1H, br), 3.40-3.52 (4H, m), 4.03-4.15 (1H, m), 5.26 (1H, s), 6.67 (1H, ddd, J = 9.0, 3.6, 3.0 Hz), 6.89 (1H, dd, J = 6.2, 3.0 Hz), 6.91-7.05 (5H, m), 7.20-7.29 (4H, m)
—
















TABLE 140













 















Ex. No.
R1
R2
R3
R4
R5
R6
NMR
Salt





983
—H
—Cl
—F
—H
—H




1H-NMR (CDCl3) δ ppm; 1.68-1.82 (2H, m), 2.03-2.17 (1H, m), 2.83-2.95 (3H, m), 3.16 (1H, dd, J = 11.6, 6.7 Hz), 4.25-4.35 (1H, m), 6.58 (1H, ddd, J = 9.0, 3.9, 2.9 Hz), 6.78 (1H, dd, J = 6.3, 2.9 Hz), 6.94-7.06 (7H, m), 7.09-
Oxa- late









7.16 (1H, m), 7.32-7.40 (2H, m)



 


984
—H
—Cl
—F
—H
—H




1H-NMR (CDCl3) δ ppm; 1.67-1.90 (2H, m), 2.04-2.18 (1H, m), 2.80-3.01 (3H, m), 3.05- 3.30 (1H, m), 4.20-4.44 (1H, m), 6.58-6.69 (1H, m), 6.78-6.82 (1H, m), 6.84-7.00 (7H, m), 7.27-7.34 (2H, m)
—


 


985
—H
—Cl
—F
—H
—H




1H-NMR (CDCl3) δ ppm; 1.66-1.80 (2H, m), 2.02-2.17 (1H, m), 2.80-2.95 (3H, m), 3.03- 3.26 (1H, m), 4.24-4.37 (1H, m), 6.54-6.62 (1H, m), 6.74-6.81 (1H, m), 6.83-7.10 (9H, m)
—
















TABLE 141













 















Ex No.
R1
R2
R3
R4
R5
R6
NMR
Salt





986
—H
—Cl
—F
—H
—H




1H-NMR (CDCl3) δ ppm; 1.70-1.84 (2H, m), 2.06-2.20 (1H, m), 2.86-2.98 (3H, m), 3.18-2.26 (1H, m), 4.33-4.45 (1H, m), 6.78-6.85 (1H, m), 6.87-6.94 (2H, m), 6.98-7.02 (1H, m), 7.04-7.16 (3H, m), 7.43-7.55 (4H, m)
—


 


987
—H
—Cl
—F
—H
—H




1H-NMR (CDCl3) δ ppm; 1.68 (1H, s), 1.69-1.83 (1H, m), 2.04-2.20 (1H, m), 2.75-2.97 (3H, m), 3.22 (1H, dd, J = 11.5, 6.8 Hz), 4.34-4.45 (1H, m), 6.84 (1H, ddd, J = 8.8, 4.1, 2.7 Hz), 6.85- 6.92 (2H, m), 7.03 (1H, dd, J = 6.5, 2.7 Hz), 7.10 (1H, dd, J = 8.8, 8.7 Hz), 7.34-7.41 (2H, m), 7.43-7.52 (4H, m)
—


 


988
—H
—Cl
—F
—H
—H





2Trifluoroacetate


 


989
—H
—Cl
—F
—H
—H




1H-NMR (CDCl3) δ ppm; 1.85-2.1 (1H, m), 2.15-2.35 (1H, m), 2.35-2.95 (1H, m), 3.14 (1H, br), 3.33 (2H, br), 3.59 (1H, br), 4.55-4.8 (1H, m), 6.8- 6.95 (1H, m), 7.01 (1H, dd, J = 2.7,
2Trifluoroacetate









6.3 Hz), 7.05-7.2 (2H, m), 7.55 (1H,










d, J = 2.0 Hz), 8.06 (1H, d, J = 8.8 Hz),










8.97 (1H, s), 9.86 (2H, br).



 


990
—H
—Cl
—F
—H
—H




1H-NMR (DMSO-d6) δ ppm ;1.6-1.8 (1H, m), 2.15-2.3 (1H, m), 2.85-3.0 (1H, m), 3.05-3.25 (2H, m), 3.55-3.7 (1H, m), 4.03 (3H, s), 4.76 (1H, tt, J = 7.2, 7.2 Hz), 5.28 (1H, br), 6.8-6.9 (1H, br), 6.8-6.9 (1H, m), 7.08 (1H,
2Hydrochloride









dd, J = 2.9, 6.4 Hz), 7.32 (1H, dd, J =










9.0, 9.0 Hz), 7.44 (1H, s), 7.71 (1H, d,










J = 8.6 Hz), 8.01 (1H, s), 9.36 (1H,










br), 9.52 (1H, br).
















TABLE 142













 















Ex. No.
R1
R2
R3
R4
R5
R6
NMR
Salt





991
—H
—Cl
—F
—H
—H




1H-NMR (DMSO-d6) δ ppm; 1.5-1.75 (1H, m), 2.1-2.3 (1H, m), 2.75-2.95 (1H, m), 2.95-3.25 (2H, m), 3.45-3.65 (1H, m), 3.65-4.35 (4H, m), 4.72 (1H, tt, J = 7.2, 7.2 Hz), 6.59 (1H, ddd, J = 3.5, 3.5, 9.1 Hz), 6.79 (1H, dd, J = 3.0, 6.3 Hz),
Hydrochloride









7.1-7.25 (2H, m), 7.67 (1H, d, J =










1.5 Hz), 7.75 (1H, d, J = 8.8 Hz), 8.08










(1H, d, J = 0.4 Hz), 9.31 (1H, br), 9.42










(1H, br).



 


992
—H
—Cl
—F
—H
—H








 


993
—H
—Cl
—F
—H
—H








 


994
—H
—Cl
—F
—H
—H




1H-NMR (CDCl3) δ ppm; 1.85-2.05 (1H, m), 2.2-2.35 (1H, m), 3.1-3.25 (1H, m), 3.25-3.4 (2H, m), 3.55-3.7 (1H, m), 4.79 (1H, tt, J = 6.8, 6.8 Hz), 6.60 (1H, ddd,  J = 3.4, 3.4, 9.0 Hz), 6.76 (1H, dd, J = 3.0, 6.0 Hz), 6.95 (1H, dd, J = 8.8, 8.8 Hz),
2Trifluoroacetate









7.25-7.45 (4H, m), 7.85 (1H, dd, J = 1.2,










7.6 Hz), 9.07 (1H, br), 9.24 (1H, br),










10.44 (1H, br).



 


995
—H
—Cl
—F
—H
—H




1H-NMR (CDCl3) δ ppm; 1.8-2.05 (4H, m), 2.15-2.35 (1H, m), 3.0-3.2 (1H, m), 3.25-3.45 (2H, m), 3.5-3.7 (1H, m), 4.64 (1H, tt, J = 6.8, 6.8 Hz), 6.46 (1H, ddd,  J = 3.4, 3.4, 9.1 Hz), 6.60 (1H, dd, J = 3.0, 6.1 Hz), 6.96 (1H, dd, J = 8.8, 8.8 Hz),
2Ttifluoroacetate









7.05-7.15 (2H, m), 8.85-965 (2H, m),










10.42 (1H, br).
















TABLE 143













 















Ex. No.
R1
R2
R3
R4
R5
R6
NMR
Salt





996
—H
—Cl
—F
—H
—H








 


997
—H
—Cl
—F
—H
—H




1H-NMR (CDCl3) δ ppm; 2.05-2.2 (1H, m), 2.2-2.35 (1H, m), 2.44 (3H, d, J = 1.0 Hz), 3.15-3.45 (3H, m), 3.5-3.7 (1H, m), 4.59 (1H, tt, J = 6.6, 6.6 Hz), 6.55-6.65 (2H,
2Trifluoroacetate









m), 6.69 (1H, ddd, J = 3.4, 9.0 Hz), 6.84










(1H, dd, J = 3.0, 6.1 Hz), 7.00 (1H, dd, J =










8.7, 8.7 Hz), 9.14 (2H, br), 9.52 (1H, br).



 


998
—H
—Cl
—F
—H
—H




1H-NMR (DMSO-d6) δ ppm ;1.6-1.75 (1H, m), 2.05-2.2 (1H, m), 2.39 (3H, d, J = 0.7 Hz), 2.86 (1H, dd, J = 7.4, 11.5 Hz), 2.95-3.15 (2H, m), 3.50 (1H, dd, J = 7.0,
Fumarate









11.5 Hz), 3.65-6.1 (4H, m), 6.46 (2H, s),










6.50 (1H, s), 6.7-6.85 (1H, m), 6.9-7.0










(2H, m), 7.27 (1H, dd, J = 9.1, 9.1 Hz).



 


999
—H
—Cl
—F
—H
—H





2Trifluoroacetate
















TABLE 144













 











Ex. No.
R1
R6
NMR
Salt





1000








1H-NMR (DMSO-d6) δ ppm; 1.7-1.85 (1H, m), 2.15-2.3 (1H, m), 2.9-3.2 (3H, m), 3.63 (1H, dd, J = 7.0, 11.5 Hz), 4.73 (1H, tt, J = 7.3, 7.3 Hz), 6.47 (2H, s), 6.82 (1H, dd, J = 1.4, 5.1 Hz), 6.95 (1H, dd, J = 2.4, 9.0 Hz), 7.26 (1H, dd, J = 1.4, 3.1 Hz), 7.25-7.35 (2H, m), 7.35-7.45 (1H, m), 7.59 (1H, dd,
Fumarate





J = 3.1, 5.1 Hz), 7.7-7.8 (3H, m), 10.3 (3H, br).



 


1001








1H-NMR (DMSO-d6) δ ppm; 1.6-1.9 (1H, m), 2.0-2.35 (1H, m), 2.65-5.55 (8H, m), 6.48 (2H, s), 6.68 (1H, dd, J = 1.4, 5.1 Hz), 6.92 (1H, dd, J = 2.1, 8.6 Hz), 7.04 (1H, dd, J = 1.4, 3.0 Hz), 7.35 (1H, d, J = 5.5 Hz), 7.50 (1H, dd, J = 3.1, 5.1 Hz), 7.55-7.65 (2H, m), 7.75 (1H, d, J = 8.6 Hz).
Fumarate


 


1002








1H-NMR (DMSO-d6) δ ppm; 1.55-1.9 (1H, m), 2.0-2.25 (1H, m), 2.3-5.45 (8H, m), 6.48 (2H, s), 6.59 (1H, dd, J = 1.4, 5.1 Hz), 6.92 (1H, dd, J = 1.4, 3.0 Hz), 6.99 (1H, dd, J = 2.2, 8.7 Hz), 7.38 (1H, d, J = 5.4 Hz), 7.45 (1H, dd, J = 3.1, 5.1 Hz), 7.54 (1H, d, J = 2.1 Hz), 7.75 (1H, d, J = 5.4 Hz), 
Fumarate





7.91 (1H, d, J = 8.6 Hz).
















TABLE 145













 














Ex. No. 
R1
R2
R3
R4
R5
R6
MS(M + 1)





1003
—H
—Cl
—F
—H
—H
—(CH2)2CO2CH3



1004
—H
—Cl
—F
—H
—H
—(CH2)2CO2C2H5



1005
—H
—Cl
—F
—H
—H
—(CH2)2CO2CH2C6H5



1006
—H
—Cl
—F
—H
—H
—(CH2)2CON(CH3)2
314


1007
—H
—Cl
—F
—H
—H
—(CH2)2COCH3



1008
—H
—Cl
—F
—H
—H
—(CH2)2COC2H5



1009
—H
—Cl
—F
—H
—H
—(CH2)2COC6H5



1010
—H
—Cl
—F
—H
—H
—(CH2)2CH(OH)CH3



1011
—H
—Cl
—F
—H
—H
—(CH2)2CH(OH)C2H5



1012
—H
—Cl
—F
—H
—H
—(CH2)2CH(OH)C8H5



1013
—H
—Cl
—F
—H
—H
—(CH2)2CH(OH)(CH3)2



1014
—H
—Cl
—F
—H
—H
—(CH2)3SC6H5
365


1015
—H
—Cl
—F
—H
—H
—(CH2)3S(CH2)2N(C2H5)2



1016
—H
—Cl
—F
—H
—H
—(CH2)3S(CH2)2CH3
331


1017
—H
—Cl
—F
—H
—H
—(CH2)3SCH2C8H5
379


1018
—H
—Cl
—F
—H
—H
—(CH2)3S(CH2)2C6H5
393


1019
—H
—Cl
—F
—H
—H
—(CH2)3S(CH2)2NH2



1020
—H
—Cl
—F
—H
—H
—(CH2)3SC2H5



1021
—H
—Cl
—F
—H
—H
—(CH2)3S(CH2)2OH
333


1022
—H
—Cl
—F
—H
—H
—(CH2)3S(CH2)2CO2CH3
375


1023
—H
—Cl
—F
—H
—H
—(CH2)3SCH2CO2CH3
361


1024
—H
—Cl
—F
—H
—H
—(CH2)3S-cyclo-C5H9
357


1025
—H
—Cl
—F
—H
—H
—(CH2)3S-cyclo-C6H11
371


1026
—H
—Cl
—F
—H
—H
—(CH2)3S(CH2)3C6H5
407


1027
—H
—Cl
—F
—H
—H
—(CH2)3S(CH2)2OC6H5
409
















TABLE 146













 














Ex. No.
R1
R2
R3
R4
R5
R6
MS(M + 1)





1028
—H
—Cl
—F
—H
—H







 


1029
—H
—Cl
—F
—H
—H




380


 


1030
—H
—Cl
—F
—H
—H




379


 


1031
—H
—Cl
—F
—H
—H




399


 


1032
—H
—Cl
—F
—H
—H







 


1033
—H
—Cl
—F
—H
—H







 


1034
—H
—Cl
—F
—H
—H




422


 


1035
—H
—Cl
—F
—H
—H







 


1036
—H
—Cl
—F
—H
—H







 


1037
—H
—Cl
—F
—H
—H




395
















TABLE 147













 














Ex. No.
R1
R2
R3
R4
R5
R6
MS(M + 1)





1038
—H
—Cl
—F
—H
—H







 


1039
—H
—Cl
—F
—H
—H




366


 


1040
—H
—Cl
—F
—H
—H




366


 


1041
—H
—Cl
—F
—H
—H




395


 


1042
—H
—Cl
—F
—H
—H




367


 


1043
—H
—Cl
—F
—H
—H




387


 


1044
—H
—Cl
—F
—H
—H




369


 


1045
—H
—Cl
—F
—H
—H




405


 


1046
—H
—Cl
—F
—H
—H




422


 


1047
—H
—Cl
—F
—H
—H




433
















TABLE 148













 














Ex. No.
R1
R2
R3
R4
R5
R6
MS(M + 1)





1048
—H
—Cl
—F
—H
—H




406


 


1049
—H
—Cl
—F
—H
—H







 


1050
—H
—C1
—F
—H
—H




369


 


1051
—H
—Cl
—F
—H
—H







 


1052
—H
—Cl
—F
—H
—H




369


 


1053
—H
—Cl
—F
—H
—H







 


1054
—H
—Cl
—F
—H
—H




386


 


1055
—H
—Cl
—F
—H
—H







 


1056
—H
—Cl
—F
—H
—H




371


 


1057
—H
—Cl
—F
—H
—H




409
















TABLE 149













 














Ex. No.
R1
R2
R3 
R4
R5
R6
MS(M + 1)





1058
—H
—Cl
—F
—H
—H




413


 


1059
—H
—Cl
—F
—H
—H




393


 


1060
—H
—Cl
—F
—H
—H







 


1061
—H
—Cl
—F
—H
—H




















TABLE 150













 

















Ex. No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
MS(M + 1)





1062
—H
—H
—CF3
—H
—H
—H
—H
—F
—H
326


1063
—H
—H
—N(CH3)2
—H
—H
—H
—H
—F
—H
301


1064
—H
—OCH3
—H
—H
—H
—H
—H
—F
—H
288


1065
—H
—OC2H5
—H
—H
—H
—H
—H
—F
—H
302


1066
—H
—SCH3
—H
—H
—H
—H
—H
—F
—H
304


1067
—H
—CF3
—Cl
—H
—H
—H
—H
—F
—H
360


1068
—H
—H
—CH3
—H
—H
—H
—H
—F
—H
272


1069
—Cl
—Cl
—H
—H
—H
—H
—H
—F
—H



1070
—H
—H
—SCH3
—H
—H
—H
—H
—F
—H
304


1071
—H
—H
—CH(CH3)2
—H
—H
—H
—H
—F
—H
300


1072
—H
—H
—OC6H5
—H
—H
—H
—H
—F
—H
350


1073
—H
—H
—C2H5
—H
—H
—H
—H
—F
—H
286


1074
—H
—CF3
—F
—H
—H
—H
—H
—F
—H
344


1075
—F
—CF3
—H
—H
—H
—H
—H
—F
—H



1076
—Cl
—H
—H
—H
—H
—H
—H
—F
—H
292


1077
—H
—H
—OCH3
—H
—H
—H
—H
—F
—H
288


1078
—CH3
—CH3
—H
—H
—H
—H
—H
—F
—H
286


1079
—C2H5
—H
—H
—H
—H
—H
—H
—F
—H
286


1080
—H
—Cl
—Cl
—H
—H
—H
—H
—F
—H
326


1081
—H
—F
—F
—H
—H
—H
—H
—F
—H
294


1082
—H
—F
—H
—F
—H
—H
—H
—F
—H
294


1083
—H
—H
—CF3
—F
—H
—H
—H
—F
—H
344


1084
—CF3
—F
—H
—H
—H
—H
—H
—F
—H



1085
—F
—H
—CF3
—H
—H
—H
—H
—F
—H
344


1086
—H
—CF3
—H
—F
—H
—H
—H
—F
—H
344


1087
—H
—CF3
—CH3
—H
—H
—H
—H
—F
—H
340


1088
—H
—CF3
—OCH3
—H
—H
—H
—H
—F
—H
356


1089
—H
—CH3
—N(CH3)2
—CH3
—H
—H
—H
—F
—H
329


1090
—H
—CH(CH3)2
—H
—H
—H
—H
—H
—F
—H
300


1091
—H
—F
—Br
—H
—H
—H
—H
—F
—H



1092
—H
—F
—H
—Cl
—H
—H
—H
—F
—H
310


1093
—H
—CH3
—OCH3
—CH3
—H
—H
—H
—F
—H
316


1094
—H
—CH3
—H
—CH3
—H
—H
—H
—F
—H
286
















TABLE 151













 

















Ex. No.
R1
R2
R3
R4
R5
R6
R7
R8
R9
MS(M + 1)





1095
—H
—F
—CH3
—H
—H
—H
—H
—F
—H
290


1096
—H
—F
—Cl
—H
—H
—H
—H
—F
—H
310


1097
—H
—F
—F
—H
—F
—H
—H
—F
—H



1098
—F
—H
—F
—H
—H
—H
—H
—F
—H



1099
—H
—F
—H
—H
—F
—H
—H
—F
—H
294


1100
—H
—F
—H
—H
—H
—H
—H
—F
—H
276


1101
—H
—Cl
—CH3
—H
—H
—H
—H
—F
—H
306


1102
—H
—F
—F
—F
—H
—H
—H
—F
—H
312


1103
—F
—F
—H
—H
—H
—H
—H
—F
—H
294


1104
—H
—F
—OCH3
—H
—H
—H
—H
—F
—H
306


1105
—H
—CH3
—Cl
—H
—H
—H
—H
—F
—H
306


1106
—H
—H
—C3H7
—H
—H
—H
—H
—F
—H
300


1107
—H
—C2H5
—H
—H
—H
—H
—H
—F
—H



1108
—H
—OCH3
—OCH3
—H
—H
—H
—H
—F
—H
318


1109
—H
—Cl
—H
—H
—H
—H
—H
—F
—H
292


1110
—H
—CH3
—CH3
—H
—H
—H
—H
—F
—H
286


1111
—H
—CH3
—OCH3
—H
—H
—H
—H
—F
—H
302


1112
—H
—CH3
—F
—CH3
—H
—H
—H
—F
—H
304


1113
—H
—H
—Cl
—H
—H
—H
—H
—F
—H
292


1114
—H
—H
—H
—H
—H
—H
—H
—F
—H
258


1115
—H
—H
—F
—H
—H
—H
—H
—F
—H
276


1116
—H
—H




—H
—H
—H
—H
—F
—H
341


 


1117
—H
—H




—H
—H
—H
—H
—F
—H
325


 


1118
—H




—H
—H
—H
—H
—H
—F
—H
















TABLE 152













 










Ex. No.
R1
R6
MS(M + 1)





1119








293


 


1120








259


 


1121








260


 


1122








309


 


1123








309


 


1124











 


1125








260


 


1126








323


 


1127








309


 


1128
























TABLE 153













 










Ex No.
R1
R6
MS(M + 1)





1129








314


 


1130








309


 


1131








310


 


1132








288


 


1133











 


1134











 


1135








320


 


1136








264


 


1137








265


 


1138
























TABLE 154













 










Ex.


MS


No.
R1
R6
(M + 1)





1139











 


1140








288


 


1141








323


 


1142








377


 


1143








315


 


1144








323


 


1145











 


1146








339


 


1147








377


 


1148
























TABLE 155













 










Ex. No.
R1
R6
MS(M + 1)





1149











 


1150








314


 


1151








316


 


1152








308


 


1153








329


 


1154








308


 


1155








302


 


1156








330


 


1157








309


 


1158








310
















TABLE 156













 










Ex.


MS


No.
R1
R6
(M + 1)





1159








329


 


1160








302


 


1161








300


 


1162








323


 


1163








338


 


1164








341


 


1165








326


 


1166








346


 


1167








314


 


1168








298
















TABLE 157













 










Ex.


MS


No.
R1
R6
(M + 1)





1169








315


 


1170








339


 


1171








353


 


1172











 


1173








298
















TABLE 158













 














Ex.






MS


No. 
R1
R2
R3
R4
R5
R6
(M + 1)





1174
—H
—Cl
—F
—H
—H




344


 


1175
—H
—Cl
—F
—H
—H




332


 


1176
—H
—Cl
—F
—H
—H




340
















TABLE 159













 















Ex. No.
R1
R2
R3
R4
R5
R6
NMR
salt





1177
—H
—H
—F
—Cl
—H




1H-NMR (DMSO-d6) δ ppm: 1.55-1.75  (1H, m), 2.1-2.25 (1H, m), 2.8-2.95 (1H, m), 3.0-3.25 (2H, m), 3.5-3.65 (1H, m), 4.19 (3H, s), 4.64 (1H, tt, J = 7.3, 7.3 Hz), 5.01 (1H, br), 6.60 (1H, ddd, J = 3.5, 3.5,
2Hydrochloride









9.1 Hz), 6.81 (1H, dd, J = 3.0, 6.3 Hz), 6.96










(1H, dd, J = 2.0, 9.0 Hz), 7.22 (1H, dd, J =










9.1, 9.1 Hz), 7.61 (1H, d, J = 1.5 Hz), 7.68










(1H, d, J = 9.0 Hz), 8.39 (1H, s), 9.28 (1H,










br), 9.39 (1H, br).



 


1178
—H
—H
—F
—Cl
—H




1H-NMR (DMSO-d6) δ ppm: 1.6-1.75  (1H, m), 2.1-2.3 (1H, m), 2.8-3.0 (1H, m), 3.05-3.25 (2H, m), 3.5-3.65 (1H, m), 4.18 (3H, s), 4.72 (1H, tt, J = 7.3, 7.3 Hz), 5.88 (1H, br), 6.67 (1H, dd, J = 1.9, 8.9 Hz),
2Hydrochloride









6.8-6.9 (1H, m), 7.07 (1H, dd, J = 2.9,










6.4 Hz), 7.25-7.4 (2H, m), 7.73 (1H, dd, 










J = 0.3, 8.9 Hz), 8.42 (1H, s), 9.43 (1H, 










br), 9.56 (1H, br).



 


1179
—H
—H
—H
—H
—H




1H-NMR (DMSO-d6) δ ppm: 1.6-1.8 (1H, m), 2.1-2.25 (1H, m), 2.8-2.95 (1H, m), 3.0-3.25 (2H, m), 3.5-3.65 (1H, m), 4.0- 4.5 (4H, m), 4.70 (1H, tt, J = 7.3, 7.3 Hz), 6.70 (2H, d, J = 7.9 Hz), 6.80 (1H, dd, J =
2Hydrochloride









7.3, 7.3 Hz), 6.92 (1H, dd, J = 2.0, 9.0 Hz),










7.1-7.25 (2H, m), 7.55 (1H, d, J = 1.4 Hz),










7.64 (1H, d, J = 9.0 Hz), 8.36 (1H, s), 9.30










(1H, br), 9.47 (1H, br).



 


1180
—H
—H
—H
—H
—H




1H-NMR (DMSO-d6) δ ppm: 1.6-1.8 (1H, m), 2.1-2.25 (1H, m), 2.8-3.0 (1H, m), 3.0-3.25 (2H, m), 3.5-3.65 (1H, m), 4.15 (3H, s), 4.22 (1H, br), 4.73 (1H, tt, J = 7.3, 7.3 Hz), 6.60 (1H, dd, J = 1.8, 8.9 Hz), 6.91
2Hydrochloride









(2H, d, J = 7.6 Hz), 7.02 (1H, dd, J = 7.3,










7.3 Hz), 7.22 (1H, s), 7.25-7.4 (2H, m),










7.66 (1H, d, J = 8.9 Hz), 8.37 (1H, s), 9.26










(1H, br), 9.42 (1H, br).









Pharmacological Test 1

Evaluation of Inhibitory Activity of Test Compound on Serotonin (5-HT) Uptake into Rat Brain Synaptosome

Male Wistar rats were decapitated and the brains were removed and the frontal cortices were dissected. The separated frontal cortices were homogenized in 20 volumes as weight of 0.32 M sucrose solution by a Potter-type homogenizer. The homogenate was centrifuged at 1000 g at 4° C. for 10 minutes, and the supernatant was then centrifuged at 20000 g at 4° C. for 20 minutes. The pellet was resuspended in incubation buffer (20 mM HEPES buffer (pH 7.4)) containing 10 mM glucose, 145 mM sodium chloride, 4.5 mM potassium chloride, 1.2 mM magnesium chloride, and 1.5 mM calcium chloride) and used as crude synaptosome fractions.
The uptake reaction mixture was suspended in a final volume of 200 μl containing pargyline (final concentration of 10 μM) and sodium ascorbate (final concentration of 0.2 mg/ml) in each well of 96-well-round-bottom-plate.
Solvent, unlabeled 5-HT, and serial diluted test compounds were added in each well, and synaptosome fraction of 1/10 volume of the final volume were added. After a 10 min preincubation at 37° C., the uptake was initiated by the addition of tritium-labeled 5-HT solution (final concentration of 8 nM) at 37° C. The uptake was stopped after 10 minutes by filtration under vacuum through a 96-well glass fiber filter plate. After washing the filter with cold physiological saline and drying up, Microscint-O (Perkin-Elmer) was added, and remained radioactivity on the filter was measured.
The total uptake activity with only solvent was determined as 100%, and the nonspecific uptake activity with unlabeled 5-HT (final concentration of 10 μM) was determined as 0%. The 50% inhibitory concentrations were calculated based on the concentrations of the test compounds and their inhibitory activities. Table 160 shows the results.










TABLE 160








50% inhibittory concentration



Test Compound
(nM)









Compound of Example 5
1.6



Compound of Example 7
3.0



Compound of Example 19
0.7



Compound of Example 40
0.8



Compound of Example 73
0.6



Compound of Example 90
1.2



Compound of Example 114
0.8



Compound of Example 131
0.6



Compound of Example 145
0.6



Compound of Example 149
1.2



Compound of Example 151
0.8



Compound of Example 154
0.8



Compound of Example 268
0.8



Compound of Example 278
2.2



Compound of Example 306
1.4



Compound of Example 894
2.6



Compound of Example 895
3.0



Compound of Example 896
2.5



Compound of Example 899
0.7



Compound of Example 900
1.5



Compound of Example 901
0.7



Compound of Example 903
1.2



Compound of Example 912
1.0



Compound of Example 913
0.8



Compound of Example 917
0.7



Compound of Example 930
0.8



Compound of Example 934
1.8



Compound of Example 961
2.8



Compound of Example 963
1.0



Compound of Example 967
0.9



Compound of Example 989
0.6










Pharmacological Test 2

Evaluation of Inhibitory Activity of Test Compound on Norepinephrine (NE) Uptake into Rat Brain Synaptosome

Male Wistar rats were decapitated and the brains were removed and the hippocampi were dissected. The separated hippocampi were homogenized in 20 volumes as weight of 0.32 M sucrose solution by a Potter-type homogenizer. The homogenate was centrifuged at 1000 g at 4° C. for 10 minutes, and the supernatant was then centrifuged at 20000 g at 4° C. for 20 minutes. The pellet was resuspended in incubation buffer (20 mM HEPES buffer (pH 7.4)) containing 10 mM glucose, 145 mM sodium chloride, 4.5 mM potassium chloride, 1.2 mM magnesium chloride, and 1.5 mM calcium chloride) and used as crude synaptosome fraction.
The uptake reaction mixture was suspended in final volume of 200 μl containing pargyline (final concentration of 10 μM) and sodium ascorbate (final concentration of 0.2 mg/ml) in each well of 96-well-round-bottom-plate.
Solvent, unlabeled NE, and serial diluted test compounds were added to each well, and synaptosome fraction of 1/10 volume of the final volume were added. After 10 minutes preincubation at 37° C., the uptake was initiated by the addition of tritium-labeled NE solution (final concentration of 12 nM) at 37° C. The uptake was stopped after 10 minutes by filtration under vacuum through a 96-well glass fiber filter plate. After washing the filter with cold physiological saline and drying up, Microscint-0 (Perkin-Elmer) was added, and remained radioactivity on the filter was measured.
The total uptake activity with only solvent was determined as 100%, and the nonspecific uptake activity with unlabeled NE (final concentration of 10 μM) was determined as 0%. The 50% inhibitory concentrations were calculated based on the concentrations of the test compounds and their inhibitory activities. Table 161 shows the results.








TABLE 161





Test Compound
50% inhibitory concentration (nM)







Compound of Example 1
0.6


Compound of Example 7
0.4


Compound of Example 20
0.8


Compound of Example 22
2.2


Compound of Example 44
0.4


Compound of Example 90
0.7


Compound of Example 98
0.3


Compound of Example 114
0.4


Compound of Example 116
0.1


Compound of Example 131
0.2


Compound of Example 154
0.2


Compound of Example 188
0.1


Compound of Example 223
0.2


Compound of Example 242
0.2


Compound of Example 244
0.5


Compound of Example 256
0.1


Compound of Example 278
0.3


Compound of Example 289
0.1


Compound of Example 306
0.8


Compound of Example 894
0.3


Compound of Example 895
0.5


Compound of Example 896
0.9


Compound of Example 900
0.6


Compound of Example 903
0.7


Compound of Example 913
0.8


Compound of Example 922
0.5


Compound of Example 930
1.0


Compound of Example 951
0.5


Compound of Example 961
0.7


Compound of Example 963
0.8


Compound of Example 967
0.1


Compound of Example 989
0.3


Compound of Example 990
0.8


Compound of Example 1000
0.4


Compound of Example 1001
0.1


Compound of Example 1002
0.1









Pharmacological Test 3

Evaluation of Inhibitory Activity of Test Compound on Dopamine (DA) into Rat Brain Synaptosome

Male Wistar rats were decapitated and the brains were removed and the striata were dissected. The separated striata were homogenized in 20 volumes as weight of 0.32 M sucrose solution by a Potter-type homogenizer. The homogenate was centrifuged at 1000 g at 4° C. for 10 minutes, and the supernatant was then centrifuged at 20000 g at 4° C. for 20 minutes. The pellet was resuspended in incubation buffer (20 mM HEPES buffer (pH 7.4)) containing 10 mM glucose, 145 mM sodium chloride, 4.5 mM potassium chloride, 1.2 mM magnesium chloride, and 1.5 mM calcium chloride) and used as crude synaptosome fraction.
The uptake reaction mixture was suspended in a final volume of 200 μl containing pargyline (final concentration of 10 μM) and sodium ascorbate (final concentration of 0.2 mg/ml) in each well of 96-well-round-bottom-plate.
Solvent, unlabeled DA, and serial diluted test compounds were added in each well, and synaptosome fraction of 1/10 volume of the final volume were added. After 10-min preincubation at 37° C., the uptake was initiated by the addition of tritium labeled DA solution (final concentration of 2 nM) at 37° C. The uptake was stopped after 10 minutes by filtration under vacuum through a 96-well glass fiber filter plate. After washing the filter with cold physiological saline and drying up, Microscint-0 (Perkin-Elmer) was added and remained radioactivity on the filter was measured.
The uptake activity with only solvent was determined as 100%, and the nonspecific uptake activity with unlabeled DA (final concentration of 10 μM) was determined as 0%. The 50% inhibitory concentrations were calculated based on the concentrations of the test compounds and their inhibitory activities. Table 162 shows the results.








TABLE 162





Test Compound
50% inhibitory concentration (nM)
















Compound of Example 7
45.0


Compound of Example 44
8.7


Compound of Example 46
9.3


Compound of Example 73
9.0


Compound of Example 90
4.8


Compound of Example 114
32.5


Compound of Example 116
8.9


Compound of Example 154
9.2


Compound of Example 200
3.8


Compound of Example 201
4.3


Compound of Example 268
6.5


Compound of Example 270
8.2


Compound of Example 272
30.0


Compound of Example 273
32.9


Compound of Example 278
34.7


Compound of Example 289
30.6


Compound of Example 294
24.0


Compound of Example 299
48.6


Compound of Example 300
9.6


Compound of Example 894
9.4


Compound of Example 895
38.0


Compound of Example 912
30.2


Compound of Example 913
6.5


Compound of Example 930
6.8


Compound of Example 951
29.8


Compound of Example 961
9.6


Compound of Example 963
47.1


Compound of Example 967
25.4


Compound of Example 989
5.8


Compound of Example 990
26.0


Compound of Example 1001
16.4


Compound of Example 1002
32.9









Pharmacological Test 4

Forced-Swimming Test

Forced-swimming test was conducted based on the method of Porsolt, R. D., et al. (Porsolt, R. D., et al., Behavioural despair in mice: A primary screening test for antidepressants. Arch. Int. Pharmacodyn., 229, pp 327-336 (1977) with a modification.
The test compound was suspended in a 5% gum arabic/physiological saline solution (w/v) and then orally administered to male ICR mice (provided by Clea Japan Inc., 5 to 6 weeks old). One hour after administration, the mice were dropped into a tank containing 9.5 cm water maintained at 21 to 25° C. Then, the mice were forced to swim for 6 minutes. During the last four minutes of the test, the period of time the mice were not moving was measured (i.e., immobility time). The analysis and measurement of the immobility time was conducted using a SCANET MV-20 AQ system (product name of Melquest Co., Ltd.).
In this test, the test compound treated animal exhibited reduction of immobility time. Therefore it is clear that the test compound is effective as an antidepressant.

## Claims

1. A method for treating fibromyalgia syndrome, comprising administering to a subject in need thereof an effective amount of a pyrrolidine compound of General Formula (1)



or a salt thereof to human or animal,
wherein R101 is (1) phenyl group, and R102 is one of the following groups (1) to (86):
(1) a phenyl group,
(2) a pyridyl group,
(3) a benzothienyl group,
(4) an indolyl group,
(5) a 2,3-dihydro-1H-indenyl group,
(6) a naphthyl group,
(7) a benzofuryl group,
(8) a quinolyl group,
(9) a thiazolyl group,
(10) a pyrimidinyl group,
(11) a pyrazinyl group,
(12) a benzothiazolyl group,
(13) a thieno[3,2-b]pyridyl group,
(14) a thienyl group,
(15) a cycloalkyl group,
(16) a tetrahydropyranyl group,
(17) a pyrrolyl group,
(18) a 2,4-dihydro-1,3-benzodioxinyl group,
(19) a 2,3-dihydrobenzofuryl group,
(20) a 9H-fluorenyl group,
(21) a pyrazolyl group,
(22) a pyridazinyl group,
(23) an indolinyl group,
(24) a thieno[2,3-b]pyridyl group,
(25) a thieno[3,2-d]pyrimidinyl group,
(26) a thieno[3,2-e]pyrimidinyl group,
(27) a 1H-pyrazolo[3,4-b]pyridyl group,
(28) an isoquinolyl group,
(29) a 2,3-dihydro-1,4-benzoxadinyl group,
(30) a quinoxalinyl group,
(32) a 1,2,3,4-tetrahydroquinolyl group,
(33) a cycloalkyl lower alkyl group,
(34) a lower alkylthio lower alkyl group,
(35) an amino-substituted lower alkyl group optionally substituted with one or two lower alkyl groups on the amino group,
(36) a phenoxy lower alkyl group,
(37) a pyridyloxy lower alkyl group,
(38) a lower alkynyl group,
(39) a phenyl lower alkenyl group,
(40) a 1,3-benzodioxolyl group,
(41) a 2,3-dihydro-1,4-benzodioxinyl group,
(42) a 3,4-dihydro-1,5-benzodioxepinyl group,
(43) a dihydropyridyl group,
(44) a 1,2-dihydroquinolyl group,
(45) a 1,2,3,4-tetrahydroisoquinolyl group,
(46) a benzoxazolyl group,
(47) a benzoisothiazolyl group,
(48) an indazolyl group,
(49) a benzoimidazolyl group,
(50) an imidazolyl group,
(51) a 1,2,3,4-tetrahydronaphthyl lower alkyl group,
(54) a tetrahydropyranyl lower alkyl group,
(55) a piperidyl lower alkyl group,
(56) a diphenyl lower alkoxy-substituted lower alkyl group,
(57) a lower alkoxycarbonyl-substituted lower alkyl group,
(58) a phenyl lower alkoxycarbonyl-substituted lower alkyl group,
(59) a hydroxy-substituted lower alkyl group,
(60) a lower alkoxy lower alkyl group,
(61) a carboxy lower alkyl group,
(62) a carbamoyl-substituted lower alkyl group optionally substituted with one or two lower alkyl groups on the carbamoyl group,
(63) a lower alkenyl group,
(64) a morpholinylcarbonyl lower alkyl group,
(65) a benzoyl lower alkyl group,
(66) a phenylthio lower alkyl group,
(67) a naphthylthio lower alkyl group,
(68) a cycloalkylthio lower alkyl group,
(69) a pyridylthio lower alkyl group,
(70) a pyrimidinylthio lower alkyl group,
(71) a furylthio lower alkyl group,
(72) a thienylthio lower alkyl group,
(73) a 1,3,4-thiadiazolylthio lower alkyl group,
(74) a benzimidazolylthio lower alkyl group,
(75) a benzthiazolylthio lower alkyl group,
(76) a tetrazolylthio lower alkyl group,
(77) a benzoxazolylthio lower alkyl group,
(78) a thiazolylthio lower alkyl group,
(79) an imidazolylthio lower alkyl group,
(80) an amino-substituted lower alkylthio lower alkyl group optionally substituted with one or two lower alkyl groups on the amino group,
(81) a phenyl-substituted lower alkylthio lower alkyl group,
(82) a furyl-substituted lower alkylthio lower alkyl group,
(83) a pyridyl-substituted lower alkylthio lower alkyl group,
(84) a hydroxy-substituted lower alkylthio lower alkyl group,
(85) a phenoxy-substituted lower alkylthio lower alkyl group, and
(86) a lower alkoxycarbonyl-substituted lower alkylthio lower alkyl group,
and each of the groups (1) to (32), (37), (39) to (56), (64) to (79), (81) to (83) and (85) may have one or more substituents selected from the following (1-1) to (1-37) on the cycloalkyl, aromatic or heterocyclic ring:
(1-1) halogen atoms,
(1-2) lower alkylthio groups optionally substituted with one or more halogen atoms,
(1-3) lower alkyl groups optionally substituted with one or more halogen atoms,
(1-4) lower alkoxy groups optionally substituted with one or more halogen atoms,
(1-5) nitro group,
(1-6) lower alkoxycarbonyl groups,
(1-7) amino groups optionally substituted with one or two lower alkyl groups,
(1-8) lower alkylsulfonyl groups,
(1-9) cyano group,
(1-10) carboxy group,
(1-11) hydroxy group,
(1-12) thienyl groups,
(1-13) oxazolyl groups,
(1-14) naphthyl groups,
(1-15) benzoyl group,
(1-16) phenoxy groups optionally substituted with one to three halogen atoms on the phenyl ring,
(1-17) phenyl lower alkoxy groups,
(1-18) lower alkanoyl groups,
(1-19) phenyl groups optionally substituted on the phenyl ring with one to five substituents selected from the group consisting of halogen atoms, lower alkoxy groups, cyano group, lower alkanoyl groups and lower alkyl groups,
(1-20) phenyl lower alkyl groups,
(1-21) cyano lower alkyl groups,
(1-22) 5 to 7-membered saturated heterocyclic group-substituted sulfonyl groups, the heterocyclic group containing on the heterocyclic ring one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur,
(1-23) thiazolyl groups optionally substituted with one or two lower alkyl groups on the thiazole ring,
(1-24) imidazolyl groups,
(1-25) amino lower alkyl groups optionally substituted with one or two lower alkyl groups on the amino group,
(1-26) pyrrolidinyl lower alkoxy groups,
(1-27) isoxazolyl groups,
(1-28) cycloalkylcarbonyl groups,
(1-29) naphthyloxy groups,
(1-30) pyridyl groups,
(1-31) furyl groups,
(1-32) phenylthio group,
(1-33) oxo group,
(1-34) carbamoyl group,
(1-35) 5 to 7-membered saturated heterocyclic groups containing one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, the heterocyclic group optionally being substituted with one to three substituents selected from the group consisting of oxo group; lower alkyl groups; lower alkanoyl groups; phenyl lower alkyl groups; phenyl groups optionally substituted on the phenyl ring with one to three members selected from the group consisting of halogen atoms and lower alkoxy groups; and pyridyl groups,
(1-36) oxido group and
(1-37) lower alkoxido groups,
with the proviso that R101 and R102 are not simultaneously unsubstituted phenyl.

2. A process for producing a pyrrolidine compound of General Formula (1) of claim 1:



or a salt thereof,
the process comprising
(1) subjecting a compound of General Formula (2)




wherein R101 and R102 are as defined in claim 1, and R112 is an amino-protecting group to an elimination reaction to remove the amino protecting group.

3. A method for treating fibromyalgia syndrome according to claim 1, wherein in the pyrrolidine compound of General Formula (1) or a salt thereof,
R101 is (1) a phenyl group that may have on the phenyl ring one to three substituents selected from the groups (1-1) to (1-37).

4. A method for treating fibromyalgia syndrome according to claim 3, wherein in the pyrrolidine compound of General Formula (1) or a salt thereof,
R101 is (1) a phenyl group that may have on the phenyl ring one to three substituents selected from the group consisting of (1-1) halogen atoms and (1-3) lower alkyl groups optionally substituted with one to three halogen atoms.

5. A method for treating fibromyalgia syndrome according to claim 4, wherein in the pyrrolidine compound of General Formula (1) or a salt thereof,
R102 is
(1) a phenyl group,
(2) a pyridyl group,
(9) a thiazolyl group,
(10) a pyrimidinyl group,
(11) a pyrazinyl group,
(14) a thienyl group,
(48) an indazolyl group,
(59) a hydroxy-substituted lower alkyl group or
(60) a lower alkoxy lower alkyl group,
and each of the groups (1), (2), (9), (10), (11), (14) and (48) may have on the phenyl or heterocyclic ring one to three substituents selected from the groups (1-1) to (1-37).

6. A method for treating fibromyalgia syndrome according to claim 5, wherein in the pyrrolidine compound of General Formula (1) or a salt thereof,
R101 is a monohalophenyl group, a dihalophenyl group or a phenyl group substituted with one halogen atom and one lower alkyl group,
R102 is
(1) a phenyl group,
(2) a pyridyl group,
(9) a thiazolyl group,
(10) a pyrimidinyl group,
(11) a pyrazinyl group,
(14) a thienyl group,
(48) an indazolyl group,
(59) a hydroxy-substituted lower alkyl group or
(60) a lower alkoxy lower alkyl group,
and each of the groups (1), (2), (9), (10), (11), (14) and (48) may have on the phenyl or heterocyclic ring one or two substituents selected from the group consisting of (1-1) halogen atoms, (1-3) lower alkyl groups optionally substituted with one or more halogen atoms, and (1-9) cyano group.

7. A method for treating fibromyalgia syndrome according to claim 5, wherein the pyrrolidine compound of General Formula (1) or a salt thereof is selected from the group consisting of:
(4-chlorophenyl)phenyl-(S)-pyrrolidin-3-ylamine,
(4-fluorophenyl)phenyl-(S)-pyrrolidin-3-ylamine,
(3,4-difluorophenyl)phenyl-(S)-pyrrolidin-3-ylamine,
bis-(4-fluorophenyl)-(S)-pyrrolidin-3-ylamine,
(3,4-difluorophenyl)-(4-fluorophenyl)-(S)-pyrrolidin-3-ylamine,
(3-chloro-4-fluorophenyl)-(S)-pyrrolidin-3-yl-p-tolylamine,
4-[(S)-(4-fluoro-3-methylphenyl)pyrrolidin-3-ylamino]-benzonitrile,
bis-(3-fluorophenyl)-(S)-pyrrolidin-3-ylamine,
(3-chloro-4-fluorophenyl)-(S)-pyrrolidin-3-ylthiazol-2-ylamine,
(4-fluorophenyl)-(S)-pyrrolidin-3-ylthiazol-2-ylamine,
(3,4-dichlorophenyl)-(S)-pyrrolidin-3-ylthiazol-2-ylamine,
(3,4-dichlorophenyl)pyrimidin-5-yl-(S)-pyrrolidin-3-ylamine,
(3-chloro-4-fluorophenyl)pyrazin-2-yl-(S)-pyrrolidin-3-ylamine,
(3-chloro-4-fluorophenyl)-(5-chloropyridin-2-yl)-(S)-pyrrolidin-3-ylamine,
(3-chloro-4-fluorophenyl)pyridin-2-yl-(S)-pyrrolidin-3-ylamine,
(3-chloro-4-fluorophenyl)pyridin-3-yl-(S)-pyrrolidin-3-ylamine,
(3-chloro-4-fluorophenyl)-(6-fluoropyridin-3-yl)-(S)-pyrrolidin-3-ylamine,
(3,4-dichlorophenyl)pyridin-3-yl-(S)-pyrrolidin-3-ylamine,
(3-chloro-4-fluorophenyl)-(S)-pyrrolidin-3-ylthiophen-3-ylamine,
(3-chloro-4-fluorophenyl)-(5-fluoropyridin-3-yl)-(S)-pyrrolidin-3-ylamine,
(4-fluoro-3-methylphenyl)-(5-fluoropyridin-3-yl)-(S)-pyrrolidin-3-ylamine,
2-[(S)-(3-chloro-4-fluorophenyl)pyrrolidin-3-ylamino]ethanol,
1-[(S)-(3-chloro-4-fluorophenyl)pyrrolidin-3-ylamino]-2-methyl-propan-2-ol,
(3-chloro-4-fluorophenyl)-(2-methoxyethyl)-(S)-pyrrolidin-3-ylamine,
3-[(S)-(3-chloro-4-fluorophenyl)pyrrolidin-3-ylamino]-propan-1-ol,
(3-chloro-4-fluorophenyl)-(3-methoxypropyl)-(S)-pyrrolidin-3-ylamine,
(3-chloro-4-fluorophenyl)-(1-methyl-1H-indazol-5-yl)-(S)-pyrrolidin-3-ylamine, and
the salts thereof.