# Patent

## Title
Antiallergic agents

## Abstract

A medicament for the preventive and/or therapeutic treatment of allergic diseases and/or endometriosis and/or hysteromyoma which comprises as an active ingredient a substance selected from the group consisting of a compound represented by the following general formula (I) and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof:




wherein X represents a connecting group whose number of atoms in the main chain is 2 to 5 (said connecting group may be substituted), A represents hydrogen atom or acetyl group, E represents an aryl group which may be substituted or a hetero aryl group which may be substituted, ring Z represents an arene which may have one or more substitutents in addition to the group represented by formula —O-A wherein A has the same meaning as that defined above and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined above, or a heteroarene which may have one or more substitutents in addition to the group represented by formula —O-A wherein A has the same meaning as that defined above and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined above.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
The present application is a divisional application of U.S. application Ser. No. 10/515,623 filed Jun. 20, 2005 now abandoned, which is incorporated by reference herein in its entirety, and which is a National Stage Application of International Application No. PCT/JP03/07120, filed Jun. 5, 2003, which claims priority under the Paris Convention from Japanese Patent Application No. 2002-165148, filed Jun. 6, 2002.


FIELD OF INVENTION
The present invention relates to pharmaceutical compositions effective for preventive and/or therapeutic treatment of allergic diseases such as pollinosis, bronchial asthma, atopic dermatitis, urticaria; endometriosis, and hysteromyoma.
BACKGROUND ART
Allergic diseases are understood to be caused by production of IgE by an antigen stimulation invaded in a body, and successive release of various chemical mediators such as inflammatory cytokine, histamine, leukotriene and the like by a degranulation from an activated mast cell stimulated by a complex of the antigen and IgE, thereby constriction of airway, accentuation of vascular permeability, inflammation of skin, bronchi and the like are induced. Accordingly, antiallergic agents are understood mainly as drugs inhibiting allergic reaction type I and successively induced allergic inflammation, particularly as drugs inhibiting the production and release of the mediators from mast cells, or those as being antagonists against the aforementioned actions. At present, steroids, antihistaminic drugs, suppressants or inhibitors of the release of mediators and the like have been used as antiallergic agents. Although steroids are very effective drugs, they have a problem of side effects. Antihistaminic drugs are only for symptomatic therapies and fail to achieve radical therapy. Suppressants or inhibitors of the release of mediators are considered to have a high effectiveness. However, some of them lack immediate effectiveness or have central side effects. Accordingly, the antiallergic drugs currently available are not fully satisfactory as they are.
Patients with endometriosis are increasing in recent years, and currently, 10 to 14% of females are considered to be suffered from the disease. Endometriosis has been focused as a cause of sterility, as well as the disease lowers the quality of life of patients with severe pains during menstruation and coitus. For a treatment of the disease, a therapy by using a hormone drug has been currently applied as a pseudo menopausal therapy. However, the aforementioned therapy induces strong side effects, and it also has a risk of causing osteoporosis during a long-term administration. Therefore, at present, a drug or a method for treatment with safety and high efficacy is not available.
In recent years, it was found that mast cells exist apparently with high density in the lesion of endometriosis (American Journal of Reproductive Immunology (New York: 1998), (Denmark), Vol. 40, No. 4, p. 291-294), and that mast cells are activated to lead degranulation (Nikkei Medical, 2002, No. 415, p. 28; Fertility and Sterility, (USA), 2002, Vol. 78, No. 4, p. 782-786). Furthermore, a relation between endometriosis and allergy is strongly suggested, because interstitial hyperplasia, which is a major step of infiltration and lesion of mast cells, is significantly inhibited by the administration of a leukotriene antagonist having antiallergic action to an endometriosis model rat (Nikkei Medical, 2002, No. 415, p. 28; Fertility and Sterility, (USA), 2002, Vol. 78, No. 4, p. 782-786).
Therefore, an antiallergic drug, which strongly inhibits activation of mast cells and can be used as a therapeutic agent for radical treatment of allergic diseases, is usable as an effective therapeutic agent for endometriosis.
45% of patients with endometriosis are suffered from hysteromyoma, which suggests a relation of hysteromyoma and allergy in the same manner as endometriosis. Accordingly, it is highly probable that an antiallergic agent, which can be used as a therapeutic agent for radical treatment of allergic diseases, is useful as a therapeutic agent for hysteromyoma.
N-phenylsalicylamide derivatives are disclosed as a plant growth inhibitor in the specification of U.S. Pat. No. 4,358,443. As medicaments, said derivatives are disclosed as anti-inflammatory agents in the specification of European Patent No. 0,221,211, Japanese Patent Unexamined Publication (KOKAI) No. (Sho) 62-99329, and the specification of U.S. Pat. No. 6,117,859. Furthermore, they are disclosed as NF-κB inhibitors in the pamphlets of International Publication WO99/65499, International Publication WO02/49632, and International Publication WO02/076918, and as inhibitors against the production of cytokines in the pamphlet of International Publication WO02/051397.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide medicaments that enable radical preventive and/or therapeutic treatment of allergy by an inhibition of allergic reactions. To achieve the aforementioned object, the inventors of the present invention conducted various researches on the antiallergic actions of salicylamide derivatives which are generally believed to have low toxicity. As a result, they found that N-substituted salicylamide derivatives, particularly N-arylsalicylamide derivatives, specifically N-phenylsalicylamide derivatives wherein aniline moiety is substituted in both of 2- and 5-positions or in both of 3- and 5-positions, and N-thiazol-2-yl-salicylamide derivatives wherein thiazole ring is substituted in both of 4- and 5-positions have extremely superior activity in inhibitory action against the proliferation of mast cells, inhibitory action against the degranulation from mast cells by antigen and IgE stimulation, and inhibitory action against the production of IgE from activated B cells, and that radical preventive and/or therapeutic treatment of allergic diseases can be achieved. The inventors also conducted researches on hydroxyaryl derivatives which are analogous compounds thereof. The present invention was achieved on the basis of these findings.
The present invention thus provides:

    (1) A medicament for preventive and/or therapeutic treatment of allergic diseases and/or endometriosis and/or hysteromyoma which comprises as an active ingredient a substance selected from the group consisting of a compound represented by the following general formula (I) and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof:






wherein X represents a connecting group whose number of atoms in a main chain is 2 to 5 (said connecting group may be substituted),

    A represents hydrogen atom or acetyl group,
    E represents an aryl group which may be substituted or a heteroaryl group which may be substituted,
    ring Z represents an arene which may have one or more substitutents in addition to the group represented by formula —O-A wherein A has the same meaning as that defined above and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined above, or a heteroarene which may have one or more substitutents in addition to the group represented by formula —O-A wherein A has the same meaning as that defined above and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined above.


Examples of preferred medicaments provided by the present invention include:

    (2) the aforementioned medicament which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein X is a group selected from the following connecting group a (said group may be substituted):

[Connecting group α] The groups of the following formulas:







wherein a bond at the left end binds to ring Z and a bond at the right end binds to E;

    (3) the aforementioned medicament which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein X is a group represented by the following formula (said group may be substituted):






wherein a bond at the left end binds to ring Z and a bond at the right end binds to E;

    (4) the aforementioned medicament which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein A is a hydrogen atom;
    (5) the aforementioned medicament which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein ring Z is a C6 to C10 arene which may have one or more substitutents in addition to the group represented by formula —O-A wherein A has the same meaning as that defined in the general formula (I) and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined in the general formula (I), or a 5 to 13-membered heteroarene which may have one or more substitutents in addition to the group represented by formula —O-A wherein A has the same meaning as that defined in the general formula (I) and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined in the general formula (I);
    (6) the aforementioned medicament which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein ring Z is a ring selected from the following ring group β:

[Ring Group β] benzene ring, naphthalene ring, thiophene ring, pyridine ring, indole ring, quinoxaline ring, and carbazole ring

wherein said ring may have one or more substitutents in addition to the group represented by formula —O-A wherein A has the same meaning as that defined in the general formula (I) and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined in the general formula (I);

    (7) the aforementioned medicament which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein ring Z is a benzene ring which may have one or more substitutents in addition to the group represented by formula —O-A wherein A has the same meaning as that defined in the general formula (I) and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined in the general formula (I);
    (8) the aforementioned medicament which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein ring Z is a benzene ring which is substituted with halogen atom(s) in addition to the group represented by formula —O-A wherein A has the same meaning as that defined in the general formula (I) and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined in the general formula (I);
    (9) the aforementioned medicament which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein ring Z is a naphthalene ring which may have one or more substitutents in addition to the group represented by formula —O-A wherein A has the same meaning as that defined in the general formula (I) and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined in the general formula (I);
    (10) the aforementioned medicament which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein E is a C6 to C10 aryl group which may be substituted or a 5 to 13-membered heteroaryl group which may be substituted;
    (11) the aforementioned medicament which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein E is a phenyl group which may be substituted;
    (12) the aforementioned medicament which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein E is 3,5-bis(trifluoromethyl)phenyl group;
    (13) the aforementioned medicament which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein E is a 5-membered heteroaryl group which may be substituted.


From another aspect, the present invention provides use of each of the aforementioned substances for manufacture of the medicament according to the aforementioned (1) to (13).
The present invention further provides a method for preventive and/or therapeutic treatment of allergic diseases and/or endometriosis and/or hysteromyoma in a mammal including a human, which comprises the step of administering preventively and/or therapeutically effective amount of the aforementioned substances to a mammal including a human.
The present invention further provides:

    (1) a compound represented by the general formula (I-1) or a salt thereof, or a hydrate thereof or a solvate thereof:






wherein Z1 represents 2-hydroxyphenyl group which may be substituted in the 5-position or 2-acetoxyphenyl group which may be substituted in the 5-position, and E1 represents a phenyl group which may be substituted.

Preferably, provided is:

    (2) the compound or a salt thereof, or a hydrate thereof or a solvate thereof, wherein E1 is 2,5-bis(trifluoromethyl)phenyl group or 3,5-bis(trifluoromethyl)phenyl group, except that the following compounds are excluded:
    N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide,
    N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide,
    N-[3,5-bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide,
    N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide, and
    N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-nitrobenzamide.


More preferably, provided is:

    (3) the compound or a salt thereof, or a hydrate thereof or a solvate thereof, wherein Z1 is 2-hydroxyphenyl group which is substituted with a halogen atom in the 5-position or 2-acetoxyphenyl group which is substituted with a halogen atom in the 5-position.


Moreover, the present invention provides:

    (1) a compound represented by the general formula (I-2) or a salt thereof, or a hydrate thereof or a solvate thereof:






wherein Z2 represents 2-hydroxyphenyl group which may be substituted in the 5-position or 2-acetoxyphenyl group which may be substituted in the 5-position,

    E2 represents a 2,5-di-substituted phenyl group wherein one of said substitutents is trifluoromethyl group or a 3,5-di-substituted phenyl group wherein one of said substitutents is trifluoromethyl group, provided that the following compounds are excluded:
    5-chloro-N-[5-chloro-3-(trifluoromethyl)phenyl]-2-hydroxybenzamide,
    5-fluoro-2-hydroxy-N-[2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl]benzamide,
    5-fluoro-2-hydroxy-N-[2-(6,6,6-trifluorohexyloxy)-5-(trifluoromethyl)phenyl]-benzamide,
    5-chloro-N-[2-(4-chlorophenoxy)-5-(trifluoromethyl)phenyl]-2-hydroxybenzamide,
    5-chloro-2-hydroxy-N-[2-(4-methylphenoxy)-5-(trifluoromethyl)phenyl]benzamide,
    5-chloro-N-[2-(4-chlorophenyl)sulfanyl-5-(trifluoromethyl)phenyl]-2-hydroxybenzamide,
    5-chloro-2-hydroxy-N-[2-(1-naphthyloxy)-5-(trifluoromethyl)phenyl]benzamide, and
    5-chloro-2-hydroxy-N-[2-(2-naphthyloxy)-5-(trifluoromethyl)phenyl]benzamide.


Preferably, provided is:

    (2) the compound or a salt thereof, or a hydrate thereof or a solvate thereof, wherein Z2 is 2-hydroxyphenyl group which is substituted with a halogen atom in the 5-position or 2-acetoxyphenyl group which is substituted with a halogen atom in the 5-position.


Moreover, the present invention provides:

    (1) a compound represented by the general formula (I-3) or a salt thereof, or a hydrate thereof or a solvate thereof:






wherein Z3 represents 2-hydroxyphenyl group which may be substituted in the 5-position or 2-acetoxyphenyl group which may be substituted in the 5-position,

    E3 represents a group represented by the following formula:






wherein one of R3e2 and R3e3 represents hydrogen atom and the other represents a hydrocarbon group which may be substituted or hydroxyl group which may be substituted, and

    R3e5 represents a C2 to C6 hydrocarbon group which may be substituted.


Preferably, provided is:

    (2) the compound or a salt thereof, or a hydrate thereof or a solvate thereof, wherein Z3 is 2-hydroxyphenyl group which is substituted with a halogen atom in the 5-position or 2-acetoxyphenyl group which is substituted with a halogen atom in the 5-position.


The present invention also provides:

    (1) a compound represented by the general formula (I-4) or a salt thereof, or a hydrate thereof or a solvate thereof:






wherein Z4 represents 2-hydroxyphenyl group which may be substituted in the 5-position or 2-acetoxyphenyl group which may be substituted in the 5-position,

    E4 represents a group represented by the following formula:






wherein R4e4 represents a hydrocarbon group which may be substituted,

    R4e5 represents a halogen atom, cyano group, an acyl group which may be substituted, or a heterocyclic group which may be substituted.


Preferably, provided is:

    (2) the compound or a salt thereof, or a hydrate thereof or a solvate thereof, wherein Z4 is 2-hydroxyphenyl group which is substituted with a halogen atom in the 5-position or 2-acetoxyphenyl group which is substituted with a halogen atom in the 5-position.





BRIEF EXPLANATION OF THE DRAWINGS
FIG. 1 shows inhibitory effect of the medicament of the present invention (compound No. 50) against immediate type allergy.
FIG. 2 shows inhibitory effect of the medicament of the present invention (compound No. 50) against dermatitis with an atopic dermatitis model.



BEST MODE FOR CARRYING OUT THE INVENTION
Reference to the disclosure of the pamphlet of International Publication WO02/49632 is useful for better understanding of the present invention. The entire disclosure of the aforementioned pamphlet of International Publication WO02/49632 is incorporated by reference in the disclosures of the present specification.
The terms used in the present specification have the following meanings.
As the halogen atom, any of fluorine atom, chlorine atom, bromine atom, or iodine atom may be used unless otherwise specifically referred to.
Examples of the hydrocarbon group include, for example, an aliphatic hydrocarbon group, an aryl group, an arylene group, an aralkyl group, a bridged cyclic hydrocarbon group, a spiro cyclic hydrocarbon group, and a terpene hydrocarbon.
Examples of the aliphatic hydrocarbon group include, for example, alkyl group, alkenyl group, alkynyl group, alkylene group, alkenylene group, alkylidene group and the like which are straight chain or branched chain monovalent or bivalent acyclic hydrocarbon groups; cycloalkyl group, cycloalkenyl group, cycloalkanedienyl group, cycloalkyl-alkyl group, cycloalkylene group, and cycloalkenylene group, which are saturated or unsaturated monovalent or bivalent alicyclic hydrocarbon groups.
Examples of the alkyl group include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, neopentyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1-ethylbutyl, 1-ethyl-1-methylpropyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, and n-pentadecyl, which are C1 to C15 straight chain or branched chain alkyl groups.
Examples of the alkenyl group include, for example, vinyl, prop-1-en-1-yl, allyl, isopropenyl, but-1-en-1-yl, but-2-en-1-yl, but-3-en-1-yl, 2-methylprop-2-en-1-yl, 1-methylprop-2-en-1-yl, pent-1-en-1-yl, pent-2-en-1-yl, pent-3-en-1-yl, pent-4-en-1-yl, 3-methylbut-2-en-1-yl, 3-methylbut-3-en-1-yl, hex-1-en-1-yl, hex-2-en-1-yl, hex-3-en-1-yl, hex-4-en-1-yl, hex-5-en-1-yl, 4-methylpent-3-en-1-yl, 4-methylpent-3-en-1-yl, hept-1-en-1-yl, hept-6-en-1-yl, oct-1-en-1-yl, oct-7-en-1-yl, non-1-en-1-yl, non-8-en-1-yl, dec-1-en-1-yl, dec-9-en-1-yl, undec-1-en-1-yl, undec-10-en-1-yl, dodec-1-en-1-yl, dodec-11-en-1-yl, tridec-1-en-1-yl, tridec-12-en-1-yl, tetradec-1-en-1-yl, tetradec-13-en-1-yl, pentadec-1-en-1-yl, and pentadec-14-en-1-yl, which are C2 to C15 straight chain or branched chain alkenyl groups.
Examples of the alkynyl group include, for example, ethynyl, prop-1-yn-1-yl, prop-2-yn-1-yl, but-1-yn-1-yl, but-3-yn-1-yl, 1-methylprop-2-yn-1-yl, pent-1-yn-1-yl, pent-4-yn-1-yl, hex-1-yn-1-yl, hex-5-yn-1-yl, hept-1-yn-1-yl, hept-6-yn-1-yl, oct-1-yn-1-yl, oct-7-yn-1-yl, non-1-yn-1-yl, non-8-yn-1-yl, dec-1-yn-1-yl, dec-9-yn-1-yl, undec-1-yn-1-yl, undec-10-yn-1-yl, dodec-1-yn-1-yl, dodec-11-yn-1-yl, tridec-1-yn-1-yl, tridec-12-yn-1-yl, tetradec-1-yn-1-yl, tetradec-13-yn-1-yl, pentadec-1-yn-1-yl, and pentadec-14-yn-1-yl, which are C2 to C15 straight chain or branched chain alkynyl groups.
Examples of the alkylene group include, for example, methylene, ethylene, ethane-1,1-diyl, propane-1,3-diyl, propane-1,2-diyl, propane-2,2-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, and 1,1,4,4-tetramethylbutane-1,4-diyl group, which are C1 to C8 straight chain or branched chain alkylene groups.
Examples of the alkenylene group include, for example, ethene-1,2-diyl, propene-1,3-diyl, but-1-ene-1,4-diyl, but-2-ene-1,4-diyl, 2-methylpropene-1,3-diyl, pent-2-ene-1,5-diyl, and hex-3-ene-1,6-diyl, which are C1 to C6 straight chain or branched chain alkylene groups.
Examples of the alkylidene group include, for example, methylidene, ethylidene, propylidene, isopropylidene, butylidene, pentylidene, and hexylidene, which are C1 to C6 straight chain or branched chain alkylidene groups.
Examples of the cycloalkyl group include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, which are C3 to C8 cycloalkyl groups.
The aforementioned cycloalkyl group may be fused with benzene ring, naphthalene ring and the like, and examples include, for example, 1-indanyl, 2-indanyl, 1,2,3,4-tetrahydronaphthalen-1-yl, and 1,2,3,4-tetrahydronaphthalen-2-yl.
Examples of the cycloalkenyl group include, for example, 2-cyclopropen-1-yl, 2-cyclobuten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 1-cyclobuten-1-yl, and 1-cyclopenten-1-yl, which are C3 to C6 cycloalkenyl groups.
The aforementioned cycloalkenyl group may be fused with benzene ring, naphthalene ring and the like, and examples include, for example, 1-indanyl, 2-indanyl, 1,2,3,4-tetrahydronaphthalen-1-yl, 1,2,3,4-tetrahydronaphthalen-2-yl, 1-indenyl, and 2-indenyl.
Examples of the cycloalkanedienyl group include, for example, 2,4-cyclopentadien-1-yl, 2,4-cyclohexanedien-1-yl, and 2,5-cyclohexanedien-1-yl, which are C5 to C6 cycloalkanedienyl groups.
The aforementioned cycloalkanedienyl group may be fused with benzene ring, naphthalene ring and the like, and examples include, for example, 1-indenyl and 2-indenyl.
Examples of the cycloalkyl-alkyl group include the groups in which one hydrogen atom of the alkyl group is substituted with a cycloalkyl group, and include, for example, cyclopropylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, 3-cyclopropylpropyl, 4-cyclopropylbutyl, 5-cyclopropylpentyl, 6-cyclopropylhexyl, cyclobutylmethyl, cyclopentylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylpropyl, cyclohexylbutyl, cycloheptylmethyl, cyclooctylmethyl, and 6-cyclooctylhexyl, which are C4 to C14 cycloalkyl-alkyl groups.
Examples of the cycloalkylene group include, for example, cyclopropane-1,1-diyl, cyclopropane-1,2-diyl, cyclobutane-1,1-diyl, cyclobutane-1,2-diyl, cyclobutane-1,3-diyl, cyclopentane-1,1-diyl, cyclopentane-1,2-diyl, cyclopentane-1,3-diyl, cyclohexane-1,1-diyl, cyclohexane-1,2-diyl, cyclohexane-1,3-diyl, cyclohexane-1,4-diyl, cycloheptane-1,1-diyl, cycloheptane-1,2-diyl, cyclooctane-1,1-diyl, and cyclooctane-1,2-diyl, which are C3 to C8 cycloalkylene groups.
Examples of the cycloalkenylene group include, for example, 2-cyclopropene-1,1-diyl, 2-cyclobutene-1,1-diyl, 2-cyclopentene-1,1-diyl, 3-cyclopentene-1,1-diyl, 2-cyclohexene-1,1-diyl, 2-cyclohexene-1,2-diyl, 2-cyclohexene-1,4-diyl, 3-cyclohexene-1,1-diyl, 1-cyclobutene-1,2-diyl, 1-cyclopentene-1,2-diyl, and 1-cyclohexene-1,2-diyl, which are C3 to C6 cycloalkenylene groups.
Examples of the aryl group include a monocyclic or a fused polycyclic aromatic hydrocarbon group, and include, for example, phenyl, 1-naphthyl, 2-naphthyl, anthryl, phenanthryl, and acenaphthylenyl, which are C6 to C14 aryl groups.
The aforementioned aryl group may be fused with the aforementioned C3 to C8 cycloalkyl group, C3 to C6 cycloalkenyl group, C5 to C6 cycloalkanedienyl group or the like, and examples include, for example, 4-indanyl, 5-indanyl, 1,2,3,4-tetrahydronaphthalen-5-yl, 1,2,3,4-tetrahydronaphthalen-6-yl, 3-acenaphthenyl, 4-acenaphthenyl, inden-4-yl, inden-5-yl, inden-6-yl, inden-7-yl, 4-phenalenyl, 5-phenalenyl, 6-phenalenyl, 7-phenalenyl, 8-phenalenyl, and 9-phenalenyl.
Examples of the arylene group include, for example, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, naphthalene-1,2-diyl, naphthalene-1,3-diyl, naphthalene-1,4-diyl, naphthalene-1,5-diyl, naphthalene-1,6-diyl, naphthalene-1,7-diyl, naphthalene-1,8-diyl, naphthalene-2,3-diyl, naphthalene-2,4-diyl, naphthalene-2,5-diyl, naphthalene-2,6-diyl, naphthalene-2,7-diyl, naphthalene-2,8-diyl, and anthracene-1,4-diyl, which are C6 to C14 arylene groups.
Examples of the aralkyl group include the groups in which one hydrogen atom of the alkyl group is substituted with an aryl group, and include, for example, benzyl, 1-naphthylmethyl, 2-naphthylmethyl, anthracenylmethyl, phenanthrenylmethyl, acenaphthylenylmethyl, diphenylmethyl, 1-phenethyl, 2-phenethyl, 1-(1-naphthyl)ethyl, 1-(2-naphthyl)ethyl, 2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyl, 3-phenylpropyl, 3-(1-naphthyl)propyl, 3-(2-naphthyl)propyl, 4-phenylbutyl, 4-(1-naphthyl)butyl, 4-(2-naphthyl)butyl, 5-phenylpentyl, 5-(1-naphthyl)pentyl, 5-(2-naphthyl)pentyl, 6-phenylhexyl, 6-(1-naphthyl)hexyl, and 6-(2-naphthyl)hexyl, which are C7 to C16 aralkyl groups.
Examples of the bridged cyclic hydrocarbon group include, for example, bicyclo[2.1.0]pentyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]octyl, and adamantyl.
Examples of the spiro cyclic hydrocarbon group include, for example, spiro[3.4]octyl, and spiro[4.5]deca-1,6-dienyl.
Examples of the terpene hydrocarbon include, for example, geranyl, neryl, linalyl, phytyl, menthyl, and bornyl.
Examples of the halogenated alkyl group include the groups in which one hydrogen atom of the alkyl group is substituted with a halogen atom, and include, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl, iodomethyl, diiodomethyl, triiodomethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl, heptafluoropropyl, heptafluoroisopropyl, nonafluorobutyl, and perfluorohexyl, which are C1 to C6 straight chain or branched chain halogenated alkyl groups substituted with 1 to 13 halogen atoms.
Examples of the heterocyclic group include, for example, a monocyclic or a fused polycyclic hetero aryl group which comprises at least one atom of 1 to 3 kinds of hetero atoms selected from oxygen atom, sulfur atom, nitrogen atom and the like as ring-constituting atoms (ring forming atoms), and a monocyclic or a fused polycyclic non-aromatic heterocyclic group which comprises at least one atom of 1 to 3 kinds of hetero atoms selected from oxygen atom, sulfur atom, nitrogen atom and the like as ring-constituting atoms (ring forming atoms).
Examples of the monocyclic heteroaryl group include, for example, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, (1,2,3-oxadiazol)-4-yl, (1,2,3-oxadiazol)-5-yl, (1,2,4-oxadiazol)-3-yl, (1,2,4-oxadiazol)-5-yl, (1,2,5-oxadiazol)-3-yl, (1,2,5-oxadiazol)-4-yl, (1,3,4-oxadiazol)-2-yl, (1,3,4-oxadiazol)-5-yl, furazanyl, (1,2,3-thiadiazol)-4-yl, (1,2,3-thiadiazol)-5-yl, (1,2,4-thiadiazol)-3-yl, (1,2,4-thiadiazol)-5-yl, (1,2,5-thiadiazol)-3-yl, (1,2,5-thiadiazol)-4-yl, (1,3,4-thiadiazolyl)-2-yl, (1,3,4-thiadiazolyl)-5-yl, (1H-1,2,3-triazol)-1-yl, (1H-1,2,3-triazol)-4-yl, (1H-1,2,3-triazol)-5-yl, (2H-1,2,3-triazol)-2-yl, (2H-1,2,3-triazol)-4-yl, (1H-1,2,4-triazol)-1-yl, (1H-1,2,4-triazol)-3-yl, (1H-1,2,4-triazol)-5-yl, (4H-1,2,4-triazol)-3-yl, (4H-1,2,4-triazol)-4-yl, (1H-tetrazol)-1-yl, (1H-tetrazol)-5-yl, (2H-tetrazol)-2-yl, (2H-tetrazol)-5-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, (1,2,3-triazin)-4-yl, (1,2,3-triazin)-5-yl, (1,2,4-triazin)-3-yl, (1,2,4-triazin)-5-yl, (1,2,4-triazin)-6-yl, (1,3,5-triazin)-2-yl, 1-azepinyl, 2-azepinyl, 3-azepinyl, 4-azepinyl, (1,4-oxazepin)-2-yl, (1,4-oxazepin)-3-yl, (1,4-oxazepin)-5-yl, (1,4-oxazepin)-6-yl, (1,4-oxazepin)-7-yl, (1,4-thiazepin)-2-yl, (1,4-thiazepin)-3-yl, (1,4-thiazepin)-5-yl, (1,4-thiazepin)-6-yl, and (1,4-thiazepin)-7-yl, which are 5 to 7-membered monocyclic heteroaryl groups.
Examples of the fused polycyclic heteroaryl group include, for example, 2-benzofuranyl, 3-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl, 6-benzofuranyl, 7-benzofuranyl, 1-isobenzofuranyl, 4-isobenzofuranyl, 5-isobenzofuranyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl, 4-benzo[b]thienyl, 5-benzo[b]thienyl, 6-benzo[b]thienyl, 7-benzo[b]thienyl, 1-benzo[c]thienyl, 4-benzo[c]thienyl, 5-benzo[c]thienyl, 1-indolyl, 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, (2H-isoindol)-1-yl, (2H-isoindol)-2-yl, (2H-isoindol)-4-yl, (2H-isoindol)-5-yl, (1H-indazol)-1-yl, (1H-indazol)-3-yl, (1H-indazol)-4-yl, (1H-indazol)-5-yl, (1H-indazol)-6-yl, (1H-indazol)-7-yl, (2H-indazol)-1-yl, (2H-indazol)-2-yl, (2H-indazol)-4-yl, (2H-indazol)-5-yl, 2-benzoxazolyl, 2-benzoxazolyl, 4-benzoxazolyl, 5-benzoxazolyl, 6-benzoxazolyl, 7-benzoxazolyl, (1,2-benzisoxazol)-3-yl, (1,2-benzisoxazol)-4-yl, (1,2-benzisoxazol)-5-yl, (1,2-benzisoxazol)-6-yl, (1,2-benzisoxazol)-7-yl, (2,1-benzisoxazol)-3-yl, (2,1-benzisoxazol)-4-yl, (2,1-benzisoxazol)-5-yl, (2,1-benzisoxazol)-6-yl, (2,1-benzisoxazol)-7-yl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl, (1,2-benzisothiazol)-3-yl, (1,2-benzisothiazol)-4-yl, (1,2-benzisothiazol)-5-yl, (1,2-benzisothiazol)-6-yl, (1,2-benzisothiazol)-7-yl, (2,1-benzisothiazol)-3-yl, (2,1-benzisothiazol)-4-yl, (2,1-benzisothiazol)-5-yl, (2,1-benzisothiazol)-6-yl, (2,1-benzisothiazol)-7-yl, (1,2,3-benzoxadiazol)-4-yl, (1,2,3-benzoxadiazol)-5-yl, (1,2,3-benzoxadiazol)-6-yl, (1,2,3-benzoxadiazol)-7-yl, (2,1,3-benzoxadiazol)-4-yl, (2,1,3-benzoxadiazol)-5-yl, (1,2,3-benzothiadiazol)-4-yl, (1,2,3-benzothiadiazol)-5-yl, (1,2,3-benzothiadiazol)-6-yl, (1,2,3-benzothiadiazol)-7-yl, (2,1,3-benzothiadiazol)-4-yl, (2,1,3-benzothiadiazol)-5-yl, (1H-benzotriazol)-1-yl, (1H-benzotriazol)-4-yl, (1H-benzotriazol)-5-yl, (1H-benzotriazol)-6-yl, (1H-benzotriazol)-7-yl, (2H-benzotriazol)-2-yl, (2H-benzotriazol)-4-yl, (2H-benzotriazol)-5-yl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl, 3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl, 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 8-quinazolinyl, 2-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl, 1-phthalazinyl, 5-phthalazinyl, 6-phthalazinyl, 2-naphthyridinyl, 3-naphthyridinyl, 4-naphthyridinyl, 2-purinyl, 6-purinyl, 7-purinyl, 8-purinyl, 2-pteridinyl, 4-pteridinyl, 6-pteridinyl, 7-pteridinyl, 1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl, 9-carbazolyl, 2-(α-carbolinyl), 3-(α-carbolinyl), 4-(α-carbolinyl), 5-(α-carbolinyl), 6-(α-carbolinyl), 7-(α-carbolinyl), 8-(α-carbolinyl), 9-(α-carbolinyl), 1-(β-carbolinyl), 3-(β-carbolinyl), 4-(β-carbolinyl), 5-(β-carbolinyl), 6-(β-carbolinyl), 7-(β-carbolinyl), 8-(β-carbolinyl), 9-(β-carbolinyl), 1-(γ-carbolinyl), 2-(γ-carbolinyl), 4-(γ-carbolinyl), 5-(γ-carbolinyl), 6-(γ-carbolinyl), 7-(γ-carbolinyl), 8-(γ-carbolinyl), 9-(γ-carbolinyl), 1-acridinyl, 2-acridinyl, 3-acridinyl, 4-acridinyl, 9-acridinyl, 1-phenoxazinyl, 2-phenoxazinyl, 3-phenoxazinyl, 4-phenoxazinyl, 10-phenoxazinyl, 1-phenothiazinyl, 2-phenothiazinyl, 3-phenothiazinyl, 4-phenothiazinyl, 10-phenothiazinyl, 1-phenazinyl, 2-phenazinyl, 1-phenanthridinyl, 2-phenanthridinyl, 3-phenanthridinyl, 4-phenanthridinyl, 6-phenanthridinyl, 7-phenanthridinyl, 8-phenanthridinyl, 9-phenanthridinyl, 10-phenanthridinyl, 2-phenanthrolinyl, 3-phenanthrolinyl, 4-phenanthrolinyl, 5-phenanthrolinyl, 6-phenanthrolinyl, 7-phenanthrolinyl, 8-phenanthrolinyl, 9-phenanthrolinyl, 10-phenanthrolinyl, 1-thianthrenyl, 2-thianthrenyl, 1-indolizinyl, 2-indolizinyl, 3-indolizinyl, 5-indolizinyl, 6-indolizinyl, 7-indolizinyl, 8-indolizinyl, 1-phenoxathiinyl, 2-phenoxathiinyl, 3-phenoxathiinyl, 4-phenoxathiinyl, thieno[2,3-b]furyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, imidazo[11,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl, and 1,2,4-triazolo[4,3-a]pyridazinyl, which are 8 to 14-membered fused polycyclic heteroaryl groups.
Examples of the monocyclic non-aromatic heterocyclic group include, for example, 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-tetrahydrofuryl, 3-tetrahydrofuryl, thiolanyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 1-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 1-(2-pyrrolinyl), 1-(2-imidazolinyl), 2-(2-imidazolinyl), 1-(2-pyrazolinyl), 3-(2-pyrazolinyl), piperidino, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-homopiperidinyl, 2-tetrahydropyranyl, morpholino, (thiomorpholin)-4-yl, 1-piperazinyl, and 1-homopiperazinyl, which are 3 to 7-membered saturated or unsaturated monocyclic non-aromatic heterocyclic groups.
Examples of the fused polycyclic non-aromatic heterocyclic group include, for example, 2-quinuclidinyl, 2-chromanyl, 3-chromanyl, 4-chromanyl, 5-chromanyl, 6-chromanyl, 7-chromanyl, 8-chromanyl, 1-isochromanyl, 3-isochromanyl, 4-isochromanyl, 5-isochromanyl, 6-isochromanyl, 7-isochromanyl, 8-isochromanyl, 2-thiochromanyl, 3-thiochromanyl, 4-thiochromanyl, 5-thiochromanyl, 6-thiochromanyl, 7-thiochromanyl, 8-thiochromanyl, 1-isothiochromanyl, 3-isothiochromanyl, 4-isothiochromanyl, 5-isothiochromanyl, 6-isothiochromanyl, 7-isothiochromanyl, 8-isothiochromanyl, 1-indolinyl, 2-indolinyl, 3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl, 1-isoindolinyl, 2-isoindolinyl, 4-isoindolinyl, 5-isoindolinyl, 2-(4H-chromenyl), 3-(4H-chromenyl), 4-(4H-chromenyl), 5-(4H-chromenyl), 6-(4H-chromenyl), 7-(4H-chromenyl), 8-(4H-chromenyl), 1-isochromenyl, 3-isochromenyl, 4-isochromenyl, 5-isochromenyl, 6-isochromenyl, 7-isochromenyl, 8-isochromenyl, 1-(1H-pyrrolidinyl), 2-(1H-pyrrolidinyl), 3-(1H-pyrrolidinyl), 5-(1H-pyrrolidinyl), 6-(1H-pyrrolidinyl), and 7-(1H-pyrrolidinyl), which are 8 to 10-membered saturated or unsaturated fused polycyclic non-aromatic heterocyclic groups.
Among the aforementioned heterocyclic groups, a monocyclic or a fused polycyclic hetero aryl groups which may have 1 to 3 kinds of hetero atoms selected from oxygen atom, sulfur atom, nitrogen atom and the like, in addition to the nitrogen atom that has the bond, as ring-constituting atoms (ring forming atoms), and a monocyclic or a fused polycyclic non-aromatic heterocyclic groups which may have 1 to 3 kinds of hetero atoms selected from oxygen atom, sulfur atom, nitrogen atom and the like, in addition to the nitrogen atom that has the bond, as ring-constituting atoms (ring forming atoms) are referred to as “cyclic amino group.” Examples include, for example, 1-pyrrolidinyl, 1-imidazolidinyl, 1-pyrazolidinyl, 1-oxazolidinyl, 1-thiazolidinyl, piperidino, morpholino, 1-piperazinyl, thiomorpholin-4-yl, 1-homopiperidinyl, 1-homopiperazinyl, 2-pyrrolin-1-yl, 2-imidazolin-1-yl, 2-pyrazolin-1-yl, 1-indolinyl, 2-isoindolinyl, 1,2,3,4-tetrahydroquinolin-1-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, 1-indolyl, 1-indazolyl, and 2-isoindolyl.
The aforementioned cycloalkyl group, cycloalkenyl group, cycloalkanedienyl group, aryl group, cycloalkylene group, cycloalkenylene group, arylene group, bridged cyclic hydrocarbon group, spiro cyclic hydrocarbon group, and heterocyclic group are generically referred to as “cyclic group.” Furthermore, among said cyclic groups, particularly, aryl group, arylene group, monocyclic heteroaryl group, and fused polycyclic heteroaryl group are generically referred to as “aromatic ring group.”
Examples of the hydrocarbon-oxy group include the groups in which a hydrogen atom of the hydroxy group is substituted with a hydrocarbon group, and examples of the hydrocarbon include similar groups to the aforementioned hydrocarbon groups. Examples of the hydrocarbon-oxy group include, for example, alkoxy group (alkyl-oxy group), alkenyl-oxy group, alkynyl-oxy group, cycloalkyl-oxy group, cycloalkyl-alkyl-oxy group and the like, which are aliphatic hydrocarbon-oxy groups; aryl-oxy group; aralkyl-oxy group; and alkylene-dioxy group.
Examples of the alkoxy (alkyl-oxy group) include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, 2-methylbutoxy, 1-methylbutoxy, neopentyloxy, 1,2-dimethylpropoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy, 2-ethylbutoxy, 1-ethylbutoxy, 1-ethyl-1-methylpropoxy, n-heptyloxy, n-octyloxy, n-nonyloxy, n-decyloxy, n-undecyloxy, n-dodecyloxy, n-tridecyloxy, n-tetradecyloxy, and n-pentadecyloxy, which are C1 to C15 straight chain or branched chain alkoxy groups.
Examples of the alkenyl-oxy group include, for example, vinyloxy, (prop-1-en-1-yl)oxy, allyloxy, isopropenyloxy, (but-1-en-1-yl)oxy, (but-2-en-1-yl)oxy, (but-3-en-1-yl)oxy, (2-methylprop-2-en-1-yl)oxy, (1-methylprop-2-en-1-yl)oxy, (pent-1-en-1-yl)oxy, (pent-2-en-1-yl)oxy, (pent-3-en-1-yl)oxy, (pent-4-en-1-yl)oxy, (3-methylbut-2-en-1-yl)oxy, (3-methylbut-3-en-1-yl)oxy, (hex-1-en-1-yl)oxy, (hex-2-en-1-yl)oxy, (hex-3-en-1-yl)oxy, (hex-4-en-1-yl)oxy, (hex-5-en-1-yl)oxy, (4-methylpent-3-en-1-yl)oxy, (4-methylpent-3-en-1-yl)oxy, (hept-1-en-1-yl)oxy, (hept-6-en-1-yl)oxy, (oct-1-en-1-yl)oxy, (oct-7-en-1-yl)oxy, (non-1-en-1-yl)oxy, (non-8-en-1-yl)oxy, (dec-1-en-1-yl)oxy, (dec-9-en-1-yl)oxy, (undec-1-en-1-yl)oxy, (undec-10-en-1-yl)oxy, (dodec-1-en-1-yl)oxy, (dodec-11-en-1-yl)oxy, (tridec-1-en-1-yl)oxy, (tridec-12-en-1-yl)oxy, (tetradec-1-en-1-yl)oxy, (tetradec-13-en-1-yl)oxy, (pentadec-1-en-1-yl)oxy, and (pentadec-14-en-1-yl)oxy, which are C2 to C15 straight chain or branched chain alkenyl-oxy groups.
Examples of the alkynyl-oxy group include, for example, ethynyloxy, (prop-1-yn-1-yl)oxy, (prop-2-yn-1-yl)oxy, (but-1-yn-1-yl)oxy, (but-3-yn-1-yl)oxy, (1-methylprop-2-yn-1-yl)oxy, (pent-1-yn-1-yl)oxy, (pent-4-yn-1-yl)oxy, (hex-1-yn-1-yl)oxy, (hex-5-yn-1-yl)oxy, (hept-1-yn-1-yl)oxy, (hept-6-yn-1-yl)oxy, (oct-1-yn-1-yl)oxy, (oct-7-yn-1-yl)oxy, (non-1-yn-1-yl)oxy, (non-8-yn-1-yl)oxy, (dec-1-yn-1-yl)oxy, (dec-9-yn-1-yl)oxy, (undec-1-yn-1-yl)oxy, (undec-10-yn-1-yl)oxy, (dodec-1-yn-1-yl)oxy, (dodec-11-yn-1-yl)oxy, (tridec-1-yn-1-yl)oxy, (tridec-12-yn-1-yl)oxy, (tetradec-1-yn-1-yl)oxy, (tetradec-13-yn-1-yl)oxy, (pentadec-1-yn-1-yl)oxy, and (pentadec-14-yn-1-yl)oxy, which are C2 to C15 straight chain or branched chain alkynyl-oxy groups.
Examples of the cycloalkyl-oxy group include, for example, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy, which are C3 to C8 cycloalkyl-oxy groups.
Examples of the cycloalkyl-alkyl-oxy group include, for example, cyclopropylmethoxy, 1-cyclopropylethoxy, 2-cyclopropylethoxy, 3-cyclopropylpropoxy, 4-cyclopropylbutoxy, 5-cyclopropylpentyloxy, 6-cyclopropylhexyloxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, 2-cyclohexylethoxy, 3-cyclohexylpropoxy, 4-cyclohexylbutoxy, cycloheptylmethoxy, cyclooctylmethoxy, and 6-cyclooctylhexyloxy, which are C4 to C14 cycloalkyl-alkyl-oxy groups.
Examples of the aryl-oxy group include, for example, phenoxy, 1-naphthyloxy, 2-naphthyloxy, anthryloxy, phenanthryloxy, and acenaphthylenyloxy, which are C6 to C14 aryl-oxy groups.
Examples of the aralkyl-oxy group include, for example, benzyloxy, 1-naphthylmethoxy, 2-naphthylmethoxy, anthracenylmethoxy, phenanthrenylmethoxy, acenaphthylenylmethoxy, diphenylmethoxy, 1-phenethyloxy, 2-phenethyloxy, 1-(1-naphthyl)ethoxy, 1-(2-naphthyl)ethoxy, 2-(1-naphthyl)ethoxy, 2-(2-naphthyl)ethoxy, 3-phenylpropoxy, 3-(1-naphthyl)propoxy, 3-(2-naphthyl)propoxy, 4-phenylbutoxy, 4-(1-naphthyl)butoxy, 4-(2-naphthyl)butoxy, 5-phenylpentyloxy, 5-(1-naphthyl)pentyloxy, 5-(2-naphthyl)pentyloxy, 6-phenylhexyloxy, 6-(1-naphthyl)hexyloxy, and 6-(2-naphthyl)hexyloxy, which are C7 to C16 aralkyl-oxy groups.
Examples of the alkylenedioxy group include, for example, methylenedioxy, ethylenedioxy, 1-methylmethylenedioxy, and 1,1-dimethylmethylenedioxy.
Examples of the halogenated alkoxy group (halogenated alkyl-oxy group) include the groups in which a hydrogen atom of the hydroxy group is substituted with a halogenated alkyl group, and include, for example, fluoromethoxy, difluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, trifluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 3,3,3-trifluoropropoxy, heptafluoropropoxy, heptafluoroisopropoxy, nonafluorobutoxy, and perfluorohexyloxy, which are C1 to C6 straight chain or branched chain halogenated alkoxy groups substituted with 1 to 13 halogen atoms.
Examples of the heterocyclic-oxy group include the groups in which a hydrogen atom of the hydroxy group is substituted with a heterocyclic group, and examples of the heterocyclic ring include similar groups to the aforementioned heterocyclic groups. Examples of the heterocyclic-oxy group include, for example, a monocyclic heteroaryl-oxy group, a fused polycyclic heteroaryl-oxy group, a monocyclic non-aromatic heterocyclic-oxy group, and a fused polycyclic non-aromatic heterocyclic-oxy group.
Examples of the monocyclic heteroaryl-oxy group include, for example, 3-thienyloxy, (isoxazol-3-yl)oxy, (thiazol-4-yl)oxy, 2-pyridyloxy, 3-pyridyloxy, 4-pyridyloxy, and (pyrimidin-4-yl)oxy.
Examples of the fused polycyclic heteroaryl-oxy group include, for example, 5-indolyloxy, (benzimidazol-2-yl)oxy, 2-quinolyloxy, 3-quinolyloxy, and 4-quinolyloxy.
Examples of the monocyclic non-aromatic heterocyclic-oxy group include, for example, 3-pyrrolidinyloxy, and 4-piperidinyloxy.
Examples of the fused polycyclic non-aromatic heterocyclic-oxy group include, for example, 3-indolynyloxy, and 4-chromanyloxy.
Examples of the hydrocarbon-sulfanyl group include the groups in which a hydrogen atom of the sulfanyl group is substituted with a hydrocarbon group, and examples of the hydrocarbon include similar groups to the aforementioned hydrocarbon groups. Examples of the hydrocarbon-sulfanyl groups include, for example, alkyl-sulfanyl group, alkenyl-sulfanyl group, alkynyl-sulfanyl group, cycloalkyl-sulfanyl group, cycloalkyl-alkyl-sulfanyl group and the like, which are aliphatic hydrocarbon-sulfanyl groups; aryl-sulfanyl group, and aralkyl-sulfanyl group.
Examples of the alkyl-sulfanyl group include, for example, methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl, n-butylsulfanyl, isobutylsulfanyl, sec-butylsulfanyl, tert-butylsulfanyl, n-pentylsulfanyl, isopentylsulfanyl, (2-methylbutyl)sulfanyl, (1-methylbutyl)sulfanyl, neopentylsulfanyl, (1,2-dimethylpropyl)sulfanyl, (1-ethylpropyl)sulfanyl, n-hexylsulfanyl, (4-methylpentyl)sulfanyl, (3-methylpentyl)sulfanyl, (2-methylpentyl)sulfanyl, (1-methylpentyl)sulfanyl, (3,3-dimethylbutyl)sulfanyl, (2,2-dimethylbutyl)sulfanyl, (1,1-dimethylbutyl)sulfanyl, (1,2-dimethylbutyl)sulfanyl, (1,3-dimethylbutyl)sulfanyl, (2,3-dimethylbutyl)sulfanyl, (2-ethylbutyl)sulfanyl, (1-ethylbutyl)sulfanyl, (1-ethyl-1-methylpropyl)sulfanyl, n-heptylsulfanyl, n-octylsulfanyl, n-nonylsulfanyl, n-decylsulfanyl, n-undecylsulfanyl, n-dodecylsulfanyl, n-tridecylsulfanyl, n-tetradecylsulfanyl, and n-pentadecylsulfanyl, which are C1 to C15 straight chain or branched chain alkyl-sulfanyl groups.
Examples of the alkenyl-sulfanyl group include, for example, vinylsulfanyl, (prop-1-en-1-yl)sulfanyl, allylsulfanyl, isopropenylsulfanyl, (but-1-en-1-yl)sulfanyl, (but-2-en-1-yl)sulfanyl, (but-3-en-1-yl)sulfanyl, (2-methylprop-2-en-1-yl)sulfanyl, (1-methylprop-2-en-1-yl)sulfanyl, (pent-1-en-1-yl)sulfanyl, (pent-2-en-1-yl)sulfanyl, (pent-3-en-1-yl)sulfanyl, (pent-4-en-1-yl)sulfanyl, (3-methylbut-2-en-1-yl)sulfanyl, (3-methylbut-3-en-1-yl)sulfanyl, (hex-1-en-1-yl)sulfanyl, (hex-2-en-1-yl)sulfanyl, (hex-3-en-1-yl)sulfanyl, (hex-4-en-1-yl)sulfanyl, (hex-5-en-1-yl)sulfanyl, (4-methylpent-3-en-1-yl)sulfanyl, (4-methylpent-3-en-1-yl)sulfanyl, (hept-1-en-1-yl)sulfanyl, (hept-6-en-1-yl)sulfanyl, (oct-1-en-1-yl)sulfanyl, (oct-7-en-1-yl)sulfanyl, (non-1-en-1-yl)sulfanyl, (non-8-en-1-yl)sulfanyl, (dec-1-en-1-yl)sulfanyl, (dec-9-en-1-yl)sulfanyl, (undec-1-en-1-yl)sulfanyl, (undec-10-en-1-yl)sulfanyl, (dodec-1-en-1-yl)sulfanyl, (dodec-11-en-1-yl)sulfanyl, (tridec-1-en-1-yl)sulfanyl, (tridec-12-en-1-yl)sulfanyl, (tetradec-1-en-1-yl)sulfanyl, (tetradec-13-en-1-yl)sulfanyl, (pentadec-1-en-1-yl)sulfanyl, and (pentadec-14-en-1-yl)sulfanyl, which are C2 to C15 straight chain or branched chain alkenyl-sulfanyl groups.
Examples of the alkynyl-sulfanyl group include, for example, ethynylsulfanyl, (prop-1-yn-1-yl)sulfanyl, (prop-2-yn-1-yl)sulfanyl, (but-1-yn-1-yl)sulfanyl, (but-3-yn-1-yl)sulfanyl, (1-methylprop-2-yn-1-yl)sulfanyl, (pent-1-yn-1-yl)sulfanyl, (pent-4-yn-1-yl)sulfanyl, (hex-1-yn-1-yl)sulfanyl, (hex-5-yn-1-yl)sulfanyl, (hept-1-yn-1-yl)sulfanyl, (hept-6-yn-1-yl)sulfanyl, (oct-1-yn-1-yl)sulfanyl, (oct-7-yn-1-yl)sulfanyl, (non-1-yn-1-yl)sulfanyl, (non-8-yn-1-yl)sulfanyl, (dec-1-yn-1-yl)sulfanyl, (dec-9-yn-1-yl)sulfanyl, (undec-1-yn-1-yl)sulfanyl, (undec-10-yn-1-yl)sulfanyl, (dodec-1-yn-1-yl)sulfanyl, (dodec-11-yn-1-yl)sulfanyl, (tridec-1-yn-1-yl)sulfanyl, (tridec-12-yn-1-yl)sulfanyl, (tetradec-1-yn-1-yl)sulfanyl, (tetradec-13-yn-1-yl)sulfanyl, (pentadec-1-yn-1-yl)sulfanyl, and (pentadec-14-yn-1-yl)sulfanyl, which are C2 to C15 straight chain or branched chain alkynyl-sulfanyl groups.
Examples of the cycloalkyl-sulfanyl group include, for example, cyclopropylsulfanyl, cyclobutylsulfanyl, cyclopentylsulfanyl, cyclohexylsulfanyl, cycloheptylsulfanyl, and cyclooctylsulfanyl, which are C3 to C8 cycloalkyl-sulfanyl groups.
Examples of the cycloalkyl-alkyl-sulfanyl group include, for example, (cyclopropylmethyl)sulfanyl, (1-cyclopropylethyl)sulfanyl, (2-cyclopropylethyl)sulfanyl, (3-cyclopropylpropyl)sulfanyl, (4-cyclopropylbutyl)sulfanyl, (5-cyclopropylpentyl)sulfanyl, (6-cyclopropylhexyl)sulfanyl, (cyclobutylmethyl)sulfanyl, (cyclopentylmethyl)sulfanyl, (cyclobutylmethyl)sulfanyl, (cyclopentylmethyl)sulfanyl, (cyclohexylmethyl)sulfanyl, (2-cyclohexylethyl)sulfanyl, (3-cyclohexylpropyl)sulfanyl, (4-cyclohexylbutyl)sulfanyl, (cycloheptylmethyl)sulfanyl, (cyclooctylmethyl)sulfanyl, and (6-cyclooctylhexyl)sulfanyl, which are C4 to C14 cycloalkyl-alkyl-sulfanyl groups.
Examples of the aryl-sulfanyl group include, for example, phenylsulfanyl, 1-naphthylsulfanyl, 2-naphthylsulfanyl, anthrylsulfanyl, fenanthrylsulfanyl, and acenaphthylenylsulfanyl, which are C6 to C14 aryl-sulfanyl groups.
Examples of the aralkyl-sulfanyl group include, for example, benzylsulfanyl, (1-naphthylmethyl)sulfanyl, (2-naphthylmethyl)sulfanyl, (anthracenylmethyl)sulfanyl, (phenanthrenylmethyl)sulfanyl, (acenaphthylenylmethyl)sulfanyl, (diphenylmethyl)sulfanyl, (1-phenethyl)sulfanyl, (2-phenethyl)sulfanyl, (1-(1-naphthyl)ethyl)sulfanyl, (1-(2-naphthyl)ethyl)sulfanyl, (2-(1-naphthyl)ethyl)sulfanyl, (2-(2-naphthyl)ethyl)sulfanyl, (3-phenylpropyl)sulfanyl, (3-(1-naphthyl)propyl)sulfanyl, (3-(2-naphthyl)propyl)sulfanyl, (4-phenylbutyl)sulfanyl, (4-(1-naphthyl)butyl)sulfanyl, (4-(2-naphthyl)butyl)sulfanyl, (5-phenylpentyl)sulfanyl, (5-(1-naphthyl)pentyl)sulfanyl, (5-(2-naphthyl)pentyl)sulfanyl, (6-phenylhexyl)sulfanyl, (6-(1-naphthyl)hexyl)sulfanyl, and (6-(2-naphthyl)hexyl)sulfanyl, which are C7 to C16 aralkyl-sulfanyl groups.
Examples of the halogenated alkyl-sulfanyl group include the groups in which a hydrogen atom of the sulfanyl group is substituted with a halogenated alkyl group, and include, for example, (fluoromethyl)sulfanyl, (chloromethyl)sulfanyl, (bromomethyl)sulfanyl, (iodomethyl)sulfanyl, (difluoromethyl)sulfanyl, (trifluoromethyl)sulfanyl, (trichloromethyl)sulfanyl, (2,2,2-trifluoroethyl)sulfanyl, (pentafluoroethyl)sulfanyl, (3,3,3-trifluoropropyl)sulfanyl, (heptafluoropropyl)sulfanyl, (heptafluoroisopropyl)sulfanyl, (nonafluorobutyl)sulfanyl, and (perfluorohexyl)sulfanyl, which are C1 to C6 straight chain or branched chain halogenated alkyl-sulfanyl groups substituted with 1 to 13 halogen atoms.
Examples of the heterocyclic-sulfanyl group include the groups in which a hydrogen atom of the sulfanyl group is substituted with a heterocyclic group, and examples of the heterocyclic ring include similar groups to the aforementioned heterocyclic groups. Examples of the heterocyclic-sulfanyl group include, for example, a monocyclic heteroaryl-sulfanyl group, a fused polycyclic heteroaryl-sulfanyl group, a monocyclic non-aromatic heterocyclic-sulfanyl group, and a fused polycyclic non-aromatic heterocyclic-sulfanyl group.
Examples of the monocyclic heteroaryl-sulfanyl group include, for example, (imidazol-2-yl)sulfanyl, (1,2,4-triazol-2-yl)sulfanyl, (pyridin-2-yl)sulfanyl, (pyridin-4-yl)sulfanyl, and (pyrimidin-2-yl)sulfanyl.
Examples of the fused polycyclic heteroaryl-sulfanyl group include, for example, (benzimidazol-2-yl)sulfanyl, (quinolin-2-yl)sulfanyl, and (quinolin-4-yl)sulfanyl.
Examples of the monocyclic non-aromatic heterocyclic-sulfanyl groups include, for example, (3-pyrrolidinyl)sulfanyl, and (4-piperidinyl)sulfanyl.
Examples of the fused polycyclic non-aromatic heterocyclic-sulfanyl group include, for example, (3-indolinyl)sulfanyl, and (4-chromanyl)sulfanyl.
Examples of the acyl group include, for example, formyl group, glyoxyloyl group, thioformyl group, carbamoyl group, thiocarbamoyl group, sulfamoyl group, sulfinamoyl group, carboxy group, sulfo group, phosphono group, and groups represented by the following formulas:







wherein Ra1 and Rb1 may be the same or different and represent a hydrocarbon group or a heterocyclic group, or Ra1 and Rb1 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group.

In the definition of the aforementioned acyl group, among the groups represented by the formula (ω-1A), those groups in which Ra1 is a hydrocarbon group are referred to as “hydrocarbon-carbonyl group” whose examples include, for example, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, lauroyl, myristoryl, palmitoyl, acryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, 1-naphthoyl, 2-naphthoyl, and phenylacetyl, and those groups in which Ra1 is a heterocyclic group are referred to as “heterocyclic ring-carbonyl group” whose examples include, for example, 2-thenoyl, 3-furoyl, nicotinoyl, and isonicotinoyl.
Among the groups represented by the formula (ω-2A), those groups in which Ra1 is a hydrocarbon group are referred to as “hydrocarbon-oxy-carbonyl group” whose examples include, for example, methoxycarbonyl, ethoxycarbonyl, phenoxycarbonyl, and benzyloxycarbonyl, and those groups in which Ra1 is a heterocyclic group are referred to as “heterocyclic ring-oxy-carbonyl group” whose examples include, for example, 3-pyridyloxycarbonyl.
Among the groups represented by the formula (ω-3A), those groups in which Ra1 is a hydrocarbon group are referred to as “hydrocarbon-carbonyl-carbonyl group” whose examples include, for example, pyruvoyl, and those groups in which Ra1 is a heterocyclic group are referred to as “heterocyclic ring-carbonyl-carbonyl group.”
Among the groups represented by the formula (ω-4A), those groups in which Ra1 is a hydrocarbon group are referred to as “hydrocarbon-oxy-carbonyl-carbonyl group” whose examples include, for example, methoxalyl and ethoxalyl groups, and those groups in which Ra1 is a heterocyclic group are referred to as “heterocyclic ring-oxy-carbonyl-carbonyl group.”
Among the groups represented by the formula (ω-5A), those groups in which Ra1 is a hydrocarbon group are referred to as “hydrocarbon-sulfanyl-carbonyl group,” and those groups in which Ra1 is a heterocyclic group are referred to as “heterocyclic ring-sulfanyl-carbonyl group.”
Among the groups represented by the formula (ω-6A), those groups in which Ra1 is a hydrocarbon group are referred to as “hydrocarbon-thiocarbonyl group,” and those groups in which Ra1 is a heterocyclic group are referred to as “heterocyclic ring-thiocarbonyl group.”
Among the groups represented by the formula (ω-7A), those groups in which Ra1 is a hydrocarbon group are referred to as “hydrocarbon-oxy-thiocarbonyl group,” and those groups in which Ra1 is a heterocyclic group are referred to as “heterocyclic ring-oxy-thiocarbonyl group.”
Among the groups represented by the formula (ω-8A), those groups in which Ra1 is a hydrocarbon group are referred to as “hydrocarbon-sulfanyl-thiocarbonyl group,” and those groups in which Ra1 is a heterocyclic group are referred to as “heterocyclic ring-sulfanyl-thiocarbonyl group.”
Among the groups represented by the formula (ω-9A), those groups in which Ra1 is a hydrocarbon group are referred to as referred to as “N-hydrocarbon-carbamoyl group” whose examples include, for example, N-methylcarbamoyl group, and those groups in which Ra1 is a heterocyclic group are referred to as “N-heterocyclic ring-carbamoyl group.”
Among the groups represented by the formula (ω-10A), those groups in which both Ra1 and Rb1 are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-carbamoyl group” whose examples include, for example, N,N-dimethylcarbamoyl group, those groups in which both Ra1 and Rb1 are heterocyclic groups are referred to as “N,N-di(heterocyclic ring)-carbamoyl group,” those groups in which Ra1 is a hydrocarbon group and Rb1 is a heterocyclic group are referred to as “N-hydrocarbon-N-heterocyclic ring-substituted carbamoyl group,” and those groups in which Ra1 and Rb1 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclic amino-carbonyl group” whose examples include, for example, morpholino-carbonyl.
Among the groups represented by the formula (ω-11A), those groups in which Ra1 is a hydrocarbon group are referred to as “N-hydrocarbon-thiocarbamoyl group,” and those groups in which Ra1 is a heterocyclic group are referred to as “N-heterocyclic ring-thiocarbamoyl group.”
Among the groups represented by the formula (ω-12A), those groups in which both Ra1 and Rb1 are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-thiocarbamoyl group,” those groups in which both Ra1 and Rb1 are heterocyclic groups are referred to as “N,N-di(heterocyclic ring)-thiocarbamoyl group,” those groups in which Ra1 is a hydrocarbon group and Rb1 is a heterocyclic group are referred to as “N-hydrocarbon-N-heterocyclic ring-thiocarbamoyl group,” and those groups in which Ra1 and Rb1 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclic amino-thiocarbonyl group.”
Among the groups represented by the formula (ω-13A), those groups in which Ra1 is a hydrocarbon group are referred to as “N-hydrocarbon-sulfamoyl group,” and those groups in which Ra1 is a heterocyclic group are referred to as “N-heterocyclic ring-sulfamoyl group.”
Among the groups represented by the formula (ω-14A), those groups in which both Ra1 and Rb1 are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-sulfamoyl group” whose examples include, for example, N,N-dimethylsulfamoyl group, those groups in which both Ra1 and Rb1 are heterocyclic groups are referred to as “N,N-di(heterocyclic ring)-sulfamoyl group,” those groups in which Ra1 is a hydrocarbon group and Rb1 is a heterocyclic group are referred to as “N-hydrocarbon-N-heterocyclic ring-sulfamoyl group,” and those groups in which Ra1 and Rb1 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclic amino-sulfonyl group” whose examples include, for example 1-pyrrolylsulfonyl.
Among the groups represented by the formula (ω-15A), those groups in which Ra1 is a hydrocarbon group are referred to as “N-hydrocarbon-sulfinamoyl group,” and those groups in which Ra1 is a heterocyclic group are referred to as “N-heterocyclic ring-sulfinamoyl group.”
Among the groups represented by the formula (ω-16A), those groups in which both Ra1 and Rb1 are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-sulfinamoyl group,” those groups in which both Ra1 and Rb1 are heterocyclic groups are referred to as “N,N-di(heterocyclic ring)-sulfinamoyl group,” those groups in which Ra1 is a hydrocarbon group and Rb1 is a heterocyclic group are referred to as “N-hydrocarbon-N-heterocyclic ring-sulfinamoyl group,” and those groups in which Ra1 and Rb1 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclic amino-sulfinyl group.”
Among the groups represented by the formula (ω-17A), those groups in which Ra1 is a hydrocarbon group are referred to as “hydrocarbon-oxy-sulfonyl group,” and those groups in which Ra1 is a heterocyclic group are referred to as “heterocyclic ring-oxy-sulfonyl group.”
Among the groups represented by the formula (ω-18A), those groups in which Ra1 is a hydrocarbon group are referred to as “hydrocarbon-oxy-sulfinyl group,” and those groups in which Ra1 is a heterocyclic group are referred to as “heterocyclic ring-oxy-sulfinyl group.”
Among the groups represented by the formula (ω-19A), those groups in which both Ra1 and Rb1 are hydrocarbon groups are referred to as “O,O′-di(hydrocarbon)-phosphono group,” those groups in which both Ra1 and Rb1 are heterocyclic groups are referred to as “O,O′-di(heterocyclic ring)-phosphono group,” and those groups in which Ra1 is a hydrocarbon group and Rb1 is a heterocyclic group are referred to as “O-hydrocarbon-O′-heterocyclic ring-phosphono group.”
Among the groups represented by the formula (ω-20A), those groups in which Ra1 is a hydrocarbon group are referred to as “hydrocarbon-sulfonyl group” whose examples include, for example, methanesulfonyl and benzenesulfonyl, and those groups in which Ra1 is a heterocyclic group are referred to as “heterocyclic ring-sulfonyl group.”
Among the groups represented by the formula (ω-21A), those groups in which Ra1 is a hydrocarbon group are referred to as “hydrocarbon-sulfinyl group” whose examples include, for example, methylsulfinyl and benzenesulfinyl, and those groups in which Ra1 is a heterocyclic group are referred to as “heterocyclic ring-sulfinyl group.”
Examples of the hydrocarbon in the groups represented by the aforementioned formulas (ω-1A) through (ω-21A) include the similar groups to the aforementioned hydrocarbon group. Examples of the hydrocarbon-carbonyl group represented by the formula (ω-1A) include, for example, an alkyl-carbonyl group, an alkenyl-carbonyl group, an alkynyl-carbonyl group, a cycloalkyl-carbonyl group, a cycloalkenyl-carbonyl group, a cycloalkanedienyl-carbonyl group, a cycloalkyl-alkyl-carbonyl group, which are aliphatic hydrocarbon-carbonyl groups; an aryl-carbonyl group; an aralkyl-carbonyl group; a bridged cyclic hydrocarbon-carbonyl group; a spirocyclic hydrocarbon-carbonyl group; and a terpene family hydrocarbon-carbonyl group. In the following, groups represented by the formulas (ω-2A) through (ω-21A) are similar to those explained above.
Examples of the heterocyclic ring in the groups represented by the aforementioned formulas (ω-1A) through (ω-21A) include similar groups to the aforementioned heterocyclic group. Examples of the heterocyclic ring-carbonyl group represented by the formula (ω-1A) include, for example, a monocyclic heteroaryl-carbonyl group, a fused polycyclic heteroaryl-carbonyl group, a monocyclic non-aromatic heterocyclic ring-carbonyl group, and a fused polycyclic non-aromatic heterocyclic ring-carbonyl group. In the following, groups represented by the formulas (ω-2A) through (ω-21A) are similar to those explained above.
Examples of the cyclic amino in the groups represented by the aforementioned formulas (ω-10A) through (ω-16A) include similar groups to the aforementioned cyclic amino group.
In the present specification, when a certain functional group is defined as “which may be substituted,” the definition means that the functional group may sometimes have one or more substitutents at chemically substitutable positions, unless otherwise specifically mentioned. Kind of substitutents, number of substitutents, and the position of substitutents existing in the functional groups are not particularly limited, and when two or more substitutents exist, they may be the same or different. Examples of the substitutent existing in the functional group include, for example, halogen atoms, oxo group, thioxo group, nitro group, nitroso group, cyano group, isocyano group, cyanato group, thiocyanato group, isocyanato group, isothiocyanato group, hydroxy group, sulfanyl group, carboxy group, sulfanylcarbonyl group, oxalo group, methooxalo group, thiocarboxy group, dithiocarboxy group, carbamoyl group, thiocarbamoyl group, sulfo group, sulfamoyl group, sulfino group, sulfinamoyl group, sulfeno group, sulfenamoyl group, phosphono group, hydroxyphosphonyl group, hydrocarbon group, heterocyclic group, hydrocarbon-oxy group, heterocyclic ring-oxy group, hydrocarbon-sulfanyl group, heterocyclic ring-sulfanyl group, acyl group, amino group, hydrazino group, hydrazono group, diazenyl group, ureido group, thioureido group, guanidino group, carbamoimidoyl group (amidino group), azido group, imino group, hydroxyamino group, hydroxyimino group, aminooxy group, diazo group, semicarbazino group, semicarbazono group, allophanyl group, hydantoyl group, phosphano group, phosphoroso group, phospho group, boryl group, silyl group, stannyl group, selanyl group, oxido group and the like.
When two or more substitutents exist according to the aforementioned definition of “which may be substituted,” said two or more substitutents may combine to each other, together with atom(s) to which they bind, to form a ring. For these cyclic groups, as ring-constituting atoms (ring forming atoms), one to three kinds of one or more hetero atoms selected from oxygen atom, sulfur atom, nitrogen atom and the like may be included, and one or more substitutents may exist on the ring. The ring may be monocyclic or fused polycyclic, and aromatic or non-aromatic.
The above substitutents according to the aforementioned definition of “which may be substituted” may further be substituted with the aforementioned substitutents at the chemically substitutable positions on the substitutent. Kind of substitutents, number of substitutents, and positions of substitutents are not particularly limited, and when the substitutents are substituted with two or more substitutents, they may be the same or different. Examples of the substitutent include, for example, a halogenated alkyl-carbonyl group whose examples include, for example, trifluoroacetyl, a halogenated alkyl-sulfonyl group whose examples include, for example, trifluoromethanesulfonyl, an acyl-oxy group, an acyl-sulfanyl group, an N-hydrocarbon-amino group, an N,N-di(hydrocarbon)-amino group, an N-heterocyclic ring-amino group, an N-hydrocarbon-N-heterocyclic ring-amino group, an acyl-amino group, and a di(acyl)-amino group. Moreover, substitution on the aforementioned substitutents may be repeated multiple orders.
Examples of the acyl-oxy group include the groups in which hydrogen atom of hydroxy group is substituted with acyl group, and include, for example, formyloxy group, glyoxyloyloxy group, thioformyloxy group, carbamoloxy group, thiocarbamoyloxy group, sulfamoyloxy group, sulfinamoloxy group, carboxyoxy group, sulphooxy group, phosphonooxy group, and groups represented by the following formulas:







wherein Ra2 and Rb2 may be the same or different and represent a hydrocarbon group or a heterocyclic group, or Ra2 and Rb2 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group.

In the definition of the aforementioned acyl-oxy group, among the groups represented by the formula (ω-1B), those groups in which Ra2 is a hydrocarbon group are referred to as “hydrocarbon-carbonyl-oxy group” whose examples include, for example, acetoxy and benzoyloxy, and those groups in which Ra2 is a heterocyclic group are referred to as “heterocyclic ring-carbonyl-oxy group.”
Among the groups represented by the formula (ω-2B), those groups in which Ra2 is a hydrocarbon group are referred to as “hydrocarbon-oxy-carbonyl-oxy group,” and those groups in which Ra2 is a heterocyclic group are referred to as “heterocyclic ring-oxy-carbonyl-oxy group.”
Among the groups represented by the formula (ω-3B), those groups in which Ra2 is a hydrocarbon group are referred to as “hydrocarbon-carbonyl-carbonyl-oxy group,” and those groups in which Ra2 is a heterocyclic group are referred to as “heterocyclic ring-carbonyl-carbonyl-oxy group.”
Among the groups represented by the formula (ω-4B), those groups in which Ra2 is a hydrocarbon group are referred to as “hydrocarbon-oxy-carbonyl-carbonyl-oxy group,” and those groups in which Ra2 is a heterocyclic group are referred to as “heterocyclic ring-oxy-carbonyl-carbonyl-oxy group.”
Among the groups represented by the formula (ω-5B), those groups in which Ra2 is a hydrocarbon group are referred to as “hydrocarbon-sulfanyl-carbonyl-oxy group,” and those groups where Ra2 is a heterocyclic group are referred to as “heterocyclic ring-sulfanyl-carbonyl-oxy group.”
Among the groups represented by the formula (ω-6B), those groups in which Ra2 is a hydrocarbon group are referred to as “hydrocarbon-thiocarbonyl-oxy group,” and those groups where Ra2 is a heterocyclic group are referred to as “heterocyclic ring-thiocarbonyl-oxy group.”
Among the groups represented by the formula (ω-7B), those groups in which Ra2 is a hydrocarbon group are referred to as “hydrocarbon-oxy-thiocarbonyl-oxy group,” and those groups in which Ra2 is a heterocyclic group are referred to as “heterocyclic ring-oxy-thiocarbonyl-oxy group.”
Among the groups represented by the formula (ω-8B), those groups in which Ra2 is a hydrocarbon group are referred to as “hydrocarbon-sulfanyl-thiocarbonyl-oxy group,” and those groups wherein Ra2 is a heterocyclic group are referred to as “heterocyclic ring-sulfanyl-thiocarbonyl-oxy group.”
Among the groups represented by the formula (ω-9B), those groups in which Ra2 is a hydrocarbon group are referred to as “N-hydrocarbon-carbamoyl-oxy group,” and those groups in which Ra2 is a heterocyclic group are referred to as “N-heterocyclic ring-carbamoyl-oxy group.”
Among the groups represented by the formula (ω-10B), those groups in which both Ra2 and Rb2 are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-carbamoyl-oxy group,” those groups in which both Ra2 and Rb2 are heterocyclic groups are referred to as “N,N-di(heterocyclic ring)-carbamoyl-oxy group,” those groups in which Ra2 is a hydrocarbon group and Rb2 is a heterocyclic group are referred to as “N-hydrocarbon-N-heterocyclic ring-carbamoyl-oxy group,” and those groups in which Ra2 and Rb2 combine to each other, together with the nitrogen atom to which they bind, to form a cyclicic amino group are referred to as “cyclicamino-carbonyl-oxy group.”
Among the groups represented by the formula (ω-11B), those groups in which Ra2 is a hydrocarbon group are referred to as “N-hydrocarbon-thiocarbamoyl-oxy group,” and those groups in which Ra2 is a heterocyclic group are referred to as “N-heterocyclic ring-thiocarbamoyl-oxy group.”
Among the groups represented by the formula (ω-12B), those groups in which both Ra2 and Rb2 are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-thiocarbamoyl-oxy group,” those groups in which both Ra2 and Rb2 are heterocyclic groups are referred to as “N,N-di(heterocyclic ring)-thiocarbamoyl-oxy group,” those groups in which Ra2 is a hydrocarbon group and Rb2 is a heterocyclic group are referred to as “N-hydrocarbon-N-heterocyclic ring-thiocarbamoyl-oxy group,” and those groups in which Ra2 and Rb2 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclicamino-thiocarbonyl-oxy group.”
Among the groups represented by the formula (ω-13B), those groups in which Ra2 is a hydrocarbon group are referred to as “N-hydrocarbon-sulfamoyl-oxy group,” and those groups in which Ra2 is a heterocyclic group are referred to as “N-heterocyclic ring-sulfamoyl-oxy group.”
Among the groups represented by the formula (ω-14B), those groups in which both Ra2 and Rb2 are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-sulfamoyl-oxy group,” those groups in which both Ra2 and Rb2 are heterocyclic groups are referred to as “N,N-di(heterocyclic ring)-sulfamoyl-oxy group,” those groups in which Ra2 is a hydrocarbon group and Rb2 is a heterocyclic group are referred to as “N-hydrocarbon-N-heterocyclic ring-sulfamoyl-oxy group,” and those groups in which Ra2 and Rb2 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclic amino-sulfonyl-oxy group.”
Among the groups represented by the formula (ω-15B), those groups in which Ra2 is a hydrocarbon group are referred to as “N-hydrocarbon-sulfinamoyl-oxy group,” and those groups where Ra2 is a heterocyclic group are referred to as “N-heterocyclic ring-sulfinamoyl-oxy group.”
Among the groups represented by the formula (ω-16B), those groups in which both Ra2 and Rb2 are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-sulfinamoyl-oxy group,” those groups in which both Ra2 and Rb2 are heterocyclic groups are referred to as “N,N-di(heterocyclic ring)-sulfinamoyl-oxy group,” those groups in which Ra2 is a hydrocarbon group and Rb2 is a heterocyclic group are referred to as “N-hydrocarbon-N-heterocyclic ring-sulfinamoyl-oxy group,” and those groups in which Ra2 and Rb2 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclic amino-sulfinyl-oxy group.”
Among the groups represented by the formula (ω-17B), those groups in which Ra2 is a hydrocarbon group are referred to as “hydrocarbon-oxy-sulfonyl-oxy group,” and those groups in which Ra2 is a heterocyclic group are referred to as “heterocyclic ring-oxy-sulfonyl-oxy group.”
Among the groups represented by the formula (ω-18B), those groups in which Ra2 is a hydrocarbon group are referred to as “hydrocarbon-oxy-sulfinyl-oxy group,” those groups in which Ra2 is a heterocyclic group are referred to as “heterocyclic ring-oxy-sulfinyl-oxy group.”
Among the groups represented by the formula (ω-19B), those groups in which both Ra2 and Rb2 are hydrocarbon groups are referred to as “O,O′-di(hydrocarbon)-phosphono-oxy group,” those groups in which both Ra2 and Rb2 are heterocyclic groups are referred to as “O,O′-di(heterocyclic ring)-phosphono-oxy group,” and those groups in which Ra2 is a hydrocarbon group and Rb2 is a heterocyclic group are referred to as “O-hydrocarbon substituted-O′-heterocyclic ring substituted phophono-oxy group.”
Among the groups represented by the formula (ω-20B), those groups in which Ra2 is a hydrocarbon group are referred to as “hydrocarbon-sulfonyl-oxy group,” and those groups in which Ra2 is a heterocyclic group referred to as “heterocyclic ring-sulfonyl-oxy group.”
Among the groups represented by the formula (ω-21B), those groups in which Ra2 is a hydrocarbon group are referred to as “hydrocarbon-sulfinyl-oxy group,” and those groups in which Ra2 is a heterocyclic group are referred to as “heterocyclic ring-sulfinyl-oxy group.”
Examples of the hydrocarbon in the groups represented by the aforementioned formulas (ω-1B) through (ω-21B) include the similar groups to the aforementioned hydrocarbon group. Examples of the hydrocarbon-carbonyl-oxy group represented by the formula (ω-1B) include, for example, an alkyl-carbonyl-oxy group, an alkenyl-carbonyl-oxy group, an alkynyl-carbonyl-oxy group, a cycloalkyl-carbonyl-oxy group, a cycloalkenyl-carbonyl-oxy group, a cycloalkanedienyl-carbonyl-oxy group, and a cycloalkyl-alkyl-carbonyl-oxy group, which are aliphatic hydrocarbon-carbonyl-oxy groups; an aryl-carbonyl-oxy group; an aralkyl-carbonyl-oxy group; a bridged cyclic hydrocarbon-carbonyl-oxy group; a spirocyclic hydrocarbon-carbonyl-oxy group; and a terpene family hydrocarbon-carbonyl-oxy group. In the following, groups represented by the formulas (ω-2B) through (ω-21B) are similar to those explained above.
Examples of the heterocyclic ring in the groups represented by the aforementioned formulas (ω-1B) through (ω-21B) include similar groups to the aforementioned heterocyclic group. Examples of the heterocyclic ring-carbonyl group represented by the formula (ω-1B) include, for example, a monocyclic heteroaryl-carbonyl group, a fused polycyclic heteroaryl-carbonyl group, a monocyclic non-aromatic heterocyclic ring-carbonyl group, and a fused polycyclic non-aromatic heterocyclic ring-carbonyl group. In the following, groups represented by the formulas (ω-2B) through (ω-21B) are similar to those groups explained above.
Examples of the cyclic amino in the groups represented by the aforementioned formulas (ω-10B) through (ω-16B) include similar groups to the aforementioned cyclic amino group.
The aforementioned acyl-oxy group, hydrocarbon-oxy group, and heterocyclic-oxy group are generically referred to as “substituted oxy group.” Moreover, these substituted oxy group and hydroxy group are generically referred to as “hydroxy group which may be substituted.”
Examples of the acyl-sulfanyl group include the groups in which hydrogen atom of sulfanyl group is substituted with acyl group, and include, for example, formylsulfanyl group, glyoxyloylsulfanyl group, thioformylsulfanyl group, carbamoyloxy group, thicarbamoyloxy group, sulfamoyloxy group, sulfinamoyloxy group, carboxyoxy group, sulphooxy group, phosphonooxy group, and groups represented by the following formulas:







wherein Ra3 and Rb3 may be the same or different and represent a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, or Ra3 and Rb3 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group which may be substituted.

In the definition of the aforementioned acyl-sulfanyl group, among the groups represented by the formula (ω-1C), those groups in which Ra3 is a hydrocarbon group are referred to as “hydrocarbon-carbonyl-sulfanyl group,” and those groups in which Ra3 is a heterocyclic group are referred to as “heterocyclic ring-carbonyl-sulfanyl group.”
Among the groups represented by the formula (ω-2C), those groups in which Ra3 is a hydrocarbon group are referred to as “hydrocarbon-oxy-carbonyl-sulfanyl group,” and those groups in which Ra3 is a heterocyclic group are referred to as “heterocyclic ring-oxy-carbonyl-sulfanyl group.”
Among the groups represented by the formula (ω-3C), those groups in which Ra3 is a hydrocarbon group are referred to as “hydrocarbon-carbonyl-carbonyl-sulfanyl group,” and those groups in which Ra3 is a heterocyclic group are referred to as “heterocyclic ring-carbonyl-carbonyl-sulfanyl group.”
Among the groups represented by the formula (ω-4C), those groups in which Ra3 is a hydrocarbon group are referred to as “hydrocarbon-oxy-carbonyl-carbonyl-sulfanyl group,” and those groups in which Ra3 is a heterocyclic group are referred to as “heterocyclic ring-oxy-carbonyl-carbonyl-sulfanyl group.”
Among the groups represented by the formula (ω-5C), those groups in which Ra3 is a hydrocarbon group are referred to as “hydrocarbon-sulfanyl-carbonyl-sulfanyl group,” and those groups in which Ra3 is a heterocyclic group are referred to as “heterocyclic ring-sulfanyl-carbonyl-sulfanyl group.”
Among the groups represented by the formula (ω-6C), those groups in which Ra3 is a hydrocarbon group are referred to as “hydrocarbon-thiocarbonyl-sulfanyl group,” and those groups in which Ra3 is a heterocyclic group are referred to as “heterocyclic ring-thiocarbonyl-sulfanyl group.”
Among the groups represented by the formula (ω-7C), those groups in which Ra3 is a hydrocarbon group are referred to as “hydrocarbon-oxy-thiocarbonyl-sulfanyl group,” and those groups in which Ra3 is a heterocyclic group are referred to as “heterocyclic ring-oxy-thiocarbonyl-sulfanyl group.”
Among the groups represented by the formula (ω-8C), those groups in which Ra3 is a hydrocarbon group are referred to as “hydrocarbon-sulfanyl-thiocarbonyl-sulfanyl group,” and those groups in which Ra3 is a heterocyclic group are referred to as “heterocyclic ring-sulfanyl-thiocarbonyl-sulfanyl group.”
Among the groups represented by the formula (ω-9C), those groups in which Ra3 is a hydrocarbon group are referred to as “N-hydrocarbon-carbamoyl-sulfanyl group,” and those groups in which Ra3 is a heterocyclic group are referred to as “N-heterocyclic ring-carbamoyl-sulfanyl group.”
Among the groups represented by the formula (ω-10C), those groups in which both Ra3 and Rb3 are a hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-carbamoyl-sulfanyl group,” those groups in which both Ra3 and Rb3 are heterocyclic groups are referred to as “N,N-di(heterocyclic ring)-carbamoyl-sulfanyl group,” those groups in which Ra3 is a hydrocarbon group and Rb3 is a heterocyclic group are referred to as “N-hydrocarbon-N-heterocyclic ring-carbamoyl-sulfanyl group,” and those groups in which Ra3 and Rb3 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclicamino-carbonyl-sulfamoyl group.”
Among the groups represented by the formula (ω-11C), those groups in which Ra3 is a hydrocarbon group are referred to as “N-hydrocarbon-thiocarbamoyl-sulfanyl group,” and those groups in which Ra3 is a heterocyclic group are referred to as “N-heterocyclic ring-thiocarbamoyl-sulfanyl group.”
Among the groups represented by the formula (ω-12C), those groups in which both Ra3 and Rb3 are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-thiocarbamoyl-sulfanyl group,” those groups in which and Ra3 and Rb3 are heterocyclic groups are referred to as “N,N-di(heterocyclic ring)-thiocarbamoyl-sulfanyl group,” those groups in which Ra3 is a hydrocarbon group and Rb3 is a heterocyclic group are referred to as “N-hydrocarbon-N-heterocyclic ring-thiocarbamoyl-sulfanyl group,” and those groups in which Ra3 and Rb3 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclicamino-thiocarbonyl-sulfamoyl group.”
Among the groups represented by the formula (ω-13C), those groups in which Ra3 is a hydrocarbon group are referred to as “N-hydrocarbon-sulfamoyl-sulfanyl group,” and those groups in which Ra3 is a heterocyclic group are referred to as “N-heterocyclic ring-sulfamoyl-sulfanyl group.”
Among the groups represented by the formula (ω-14C), those groups in which both Ra3 and Rb3 are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-sulfamoyl-sulfanyl group,” those groups in which both Ra3 and Rb3 are heterocyclic groups are referred to as “N,N-di(heterocyclic ring)-sulfamoyl-sulfinyl group,” those groups in which Ra3 is a hydrocarbon group and Rb3 is a heterocyclic group are referred to as “N-hydrocarbon-N-heterocyclic ring-sulfamoyl-sulfanyl group,” and those groups in which Ra3 and Rb3 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclicamino-sulfonyl-sulfanyl group.”
Among the groups represented by the formula (ω-15C), those groups in which Ra3 is a hydrocarbon group are referred to as “N-hydrocarbon-sulfinamoyl-sulfanyl group,” and those groups in which Ra3 is a heterocyclic group are referred to as “N-heterocyclic ring-sulfinamoyl-sulfanyl group.”
Among the groups represented by the formula (ω-16C), those groups in which both Ra3 and Rb3 are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-sulfinamoyl-sulfanyl group,” those groups in which both Ra3 and Rb3 are heterocyclic groups are referred to as “N,N-di(heterocyclic ring)-sulfinamoyl-sulfanyl group,” those groups in which Ra3 is a hydrocarbon group and Rb3 is a heterocyclic group are referred to as “N-hydrocarbon-N-heterocyclic ring-sulfinamoyl-sulfanyl group,” and those groups in which Ra3 and Rb3 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclicamino-sulfanyl-sulfanyl group.”
Among the groups represented by the formula (ω-17C), those groups in which Ra3 is a hydrocarbon group are referred to as “hydrocarbon-oxy-sulfonyl-sulfanyl group,” and those groups in which Ra3 is a heterocyclic group are referred to as “heterocyclic ring-oxy-sulfonyl-sulfanyl group.”
Among the groups represented by the formula (ω-18C), those groups in which Ra3 is a hydrocarbon group are referred to as “hydrocarbon-oxy-sulfinyl-sulfanyl group,” and those groups in which Ra3 is a heterocyclic group are referred to as “heterocyclic ring-oxy-sulfinyl-sulfanyl group.”
Among the groups represented by the formula (ω-19C), those groups in which both Ra3 and Rb3 are hydrocarbon groups are referred to as “O,O′-di(hydrocarbon)-phosphono-sulfanyl group,” those groups in which both Ra3 and Rb3 are heterocyclic groups are referred to as “O,O′-di(heterocyclic ring)-phosphono-sulfanyl group,” and those groups in which Ra3 is a hydrocarbon group and Rb3 is a heterocyclic group are referred to as “O-hydrocarbon-O′-heterocyclic ring-phosphono-sulfanyl group.”
Among the groups represented by the formula (ω-20C), those groups in which Ra3 is a hydrocarbon group are referred to as “hydrocarbon-sulfonyl-sulfanyl group,” and those groups in which Ra3 is a heterocyclic group are referred to as “heterocyclic ring-sulfonyl-sulfanyl group.”
Among the groups represented by the formula (ω-21C), those groups in which Ra3 is a hydrocarbon group are referred to as “hydrocarbon-sulfinyl-sulfanyl group,” and those groups in which Ra3 is a heterocyclic group are referred to as “heterocyclic ring-sulfinyl-sulfanyl group.”
Examples of the hydrocarbon in the groups represented by the aforementioned formulas (ω-1C) through (ω-21C) include similar groups to the aforementioned hydrocarbon group. Examples of the hydrocarbon-carbonyl-sulfanyl group represented by the formula (ω-1C) include, for example, an alkyl-carbonyl-sulfanyl group, an alkenyl-carbonyl-sulfanyl group, an alkynyl-carbonyl-sulfanyl group, a cycloalkyl-carbonyl-sulfanyl group, a cycloalkenyl-carbonyl-sulfanyl group, a cycloalkanedienyl-carbonyl-sulfanyl group, a cycloalkyl-alkyl-carbonyl-sulfanyl group which are aliphatic hydrocarbon-carbonyl-sulfanyl groups; an aryl-carbonyl-sulfanyl group; an aralkyl-carbonyl-sulfanyl group; a bridged cyclic hydrocarbon-carbonyl-sulfanyl group; a spiro cyclic hydrocarbon-carbonyl-sulfanyl group; and a terpene family hydrocarbon-carbonyl-sulfanyl group. In the following, groups represented by the formulas (ω-2C) through (ω-21C) are similar to those explained above.
Examples of the heterocyclic ring in the groups represented by the aforementioned formulas (ω-1C) through (ω-21C) include similar groups to the aforementioned heterocyclic group. Examples of the heterocyclic ring-carbonyl-sulfanyl group represented by the formula (ω-1C) include, for example, a monocyclic heteroaryl-carbonyl-sulfanyl group, a fused polycyclic heteroaryl-carbonyl-sulfanyl group, a monocyclic non-aromatic heterocyclic ring-carbonyl-sulfanyl group, and a fused polycyclic non-aromatic heterocyclic ring-carbonyl-sulfanyl group. In the following, groups represented by the formula (ω-2C) through (ω-21C) are similar to those groups explained above.
Examples of the cyclic amino in the groups represented by the aforementioned formulas (ω-10C) through (ω-16C) include similar groups to the aforementioned cyclic amino group.
The aforementioned acyl-sulfanyl group, hydrocarbon-sulfanyl group, and heterocyclic-sulfanyl group are generically referred to as “substituted sulfanyl group.” Moreover, these substituted sulfanyl group and sulfanyl group are generically referred to as “sulfanyl group which may be substituted.”
Examples of the N-hydrocarbon-amino group include the groups in which one hydrogen atom of amino group is substituted with a hydrocarbon group, and include, for example, an N-alkyl-amino group, an N-alkenyl-amino group, an N-alkynyl-amino group, an N-cycloalkyl-amino group, an N-cycloalkyl-alkyl-amino group, an N-aryl-amino group, and an N-aralkyl-amino group.
Examples of the N-alkyl-amino group include, for example, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, n-pentylamino, isopentylamino, (2-methylbutyl)amino, (1-methylbutyl)amino, neopentylamino, (1,2-dimethylpropyl)amino, (1-ethylpropyl)amino, n-hexylamino, (4-methylpentyl)amino, (3-methylpentyl)amino, (2-methylpentyl)amino, (1-methylpentyl)amino, (3,3-dimethylbutyl)amino, (2,2-dimethylbutyl)amino, (1,1-dimethylbutyl)amino, (1,2-dimethylbutyl)amino, (1,3-dimethylbutyl)amino, (2,3-dimethylbutyl)amino, (2-ethylbutyl)amino, (1-ethylbutyl)amino, (1-ethyl-1-methylpropyl)amino, n-heptylamino, n-octylamino, n-nonylamino, n-decylamino, n-undecylamino, n-dodecylamino, n-tridecylamino, n-tetradecylamino, and n-pentadecylamino, which are C1 to C15 straight chain or branched chain N-alkyl amino groups.
Examples of the N-alkenyl-amino group include, for example, vinyl amino, (prop-1-en-1-yl)amino, allylamino, isopropenylamino, (but-1-en-1-yl)amino, (but-2-en-1-yl)amino, (but-3-en-1-yl)amino, (2-methylprop-2-en-1-yl)amino, (1-methylprop-2-en-1-yl)amino, (pent-1-en-1-yl)amino, (pent-2-en-1-yl)amino, (pent-3-en-1-yl)amino, (pent-4-en-1-yl)amino, (3-methylbut-2-en-1-yl)amino, (3-methylbut-3-en-1-yl)amino, (hex-1-en-1-yl)amino, (hex-2-en-1-yl)amino, (hex-3-en-1-yl)amino, (hex-4-en-1-yl)amino, (hex-5-en-1-yl)amino, (4-methylpent-3-en-1-yl)amino, (4-methylpent-3-en-1-yl)amino, (hept-1-en-1-yl)amino, (hept-6-en-1-yl)amino, (oct-1-en-1-yl)amino, (oct-7-en-1-yl)amino, (non-1-en-1-yl)amino, (non-8-en-1-yl)amino, (dec-1-en-1-yl)amino, (dec-9-en-1-yl)amino, (undec-1-en-1-yl)amino, (undec-10-en-1-yl)amino, (dodec-1-en-1-yl)amino, (dodec-11-en-1-yl)amino, (tridec-1-en-1-yl)amino, (tridec-12-en-1-yl)amino, (tetradec-1-en-1-yl)amino, (tetradec-13-en-1-yl)amino, (pentadec-1-en-1-yl)amino, and (pentadec-14-en-1-yl)amino, which are C2 to C15 straight chain or branched chain N-alkenyl amino groups.
Examples of the N-alkynyl-amino group include, for example, ethynylamino, (prop-1-yn-1-yl)amino, (prop-2-yn-1-yl)amino, (but-1-yn-1-yl)amino, (but-3-yn-1-yl)amino, (1-methylprop-2-yn-1-yl)amino, (pent-1-yn-1-yl)amino, (pent-4-yn-1-yl)amino, (hex-1-yn-1-yl)amino, (hex-5-yn-1-yl)amino, (hept-1-yn-1-yl)amino, (hept-6-yn-1-yl)amino, (oct-1-yn-1-yl)amino, (oct-7-yn-1-yl)amino, (non-1-yn-1-yl)amino, (non-8-yn-1-yl)amino, (dec-1-yn-1-yl)amino, (dec-9-yn-1-yl)amino, (undec-1-yn-1-yl)amino, (undec-10-yn-1-yl)amino, (dodec-1-yn-1-yl)amino, (dodec-11-yn-1-yl)amino, (tridec-1-yn-1-yl)amino, (tridec-12-yn-1-yl)amino, (tetradec-1-yn-1-yl)amino, (tetradec-13-yn-1-yl)amino, (pentadec-1-yn-1-yl)amino, and (pentadec-14-yn-1-yl)amino, which are C2 to C15 straight chain or branched chain N-alkynyl-amino groups.
Examples of the N-cycloalkyl-amino group include, for example, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, and cyclooctylamino, which are C3 to C8 N-cycloalkyl-amino groups.
Examples of the N-cycloalkyl-alkyl-amino group include, for example, (cyclopropylmethyl)amino, (1-cyclopropylethyl)amino, (2-cyclopropylethyl)amino, (3-cyclopropylpropyl)amino, (4-cyclopropylbutyl)amino, (5-cyclopropylpentyl)amino, (6-cyclopropylhexyl)amino, (cyclobutylmethyl)amino, (cyclopentylmethyl)amino, (cyclobutylmethyl)amino, (cyclopentylmethyl)amino, (cyclohexylmethyl)amino, (2-cyclohexylethyl)amino, (3-cyclohexylpropyl)amino, (4-cyclohexylbutyl)amino, (cycloheptylmethyl)amino, (cyclooctylmethyl)amino, and (6-cyclooctylhexyl)amino, which are C4 to C14 N-cycloalkyl-alkyl-amino groups.
Examples of the N-aryl-amino group include, for example, phenylamino, 1-naphthylamino, 2-naphtylamino, anthrylamino, phenanthrylamino, and acenaphthylenylamino, which are C6 to C14 N-mono-arylamino groups.
Examples of the N-aralkyl-amino group include, for example, benzylamino, (1-naphthylmethyl)amino, (2-naphthylmethyl)amino, (anthracenylmethyl)amino, (phenanthrenylmethyl)amino, (acenaphthylenylmethyl)amino, (diphenylmethyl)amino, (1-phenethyl)amino, (2-phenethyl)amino, (1-(1-naphthyl)ethyl)amino, (1-(2-naphthyl)ethyl)amino, (2-(1-naphthyl)ethyl)amino, (2-(2-naphthyl)ethyl)amino, (3-phenylpropyl)amino, (3-(1-naphthyl)propyl)amino, (3-(2-naphthyl)propyl)amino, (4-phenylbutyl)amino, (4-(1-naphthyl)butyl)amino, (4-(2-naphthyl)butyl)amino, (5-phenylpentyl)amino, (5-(1-naphthyl)pentyl)amino, (5-(2-naphthyl)pentyl)amino, (6-phenylhexyl)amino, (6-(1-naphthyl)hexyl)amino, and (6-(2-naphthyl)hexyl)amino, which are C7 to C16 N-aralkyl-amino groups.
Examples of the N,N-di(hydrocarbon)-amino group include the groups in which two hydrogen atoms of amino group are substituted with hydrocarbon groups, and include, for example, N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N,N-di-n-propylamino, N,N-diisopropylamino, N-allyl-N-methylamino, N-(prop-2-yn-1-yl)-N-methylamino, N,N-dicyclohexylamino, N-cyclohexyl-N-methylamino, N-cyclohexylmethylamino-N-methylamino, N,N-diphenylamino, N-methyl-N-phenylamino, N,N-dibenzylamino, and N-benzyl-N-methylamino.
Examples of the N-heterocyclic ring-amino group include the groups in which one hydrogen atom of amino group is substituted with a heterocyclic group, and include, for example, (3-pyrrolizinyl)amino, (4-piperidinyl)amino, (2-tetrahydropyranyl)amino, (3-indolinyl)amino, (4-chromanyl)amino, (3-thienyl)amino, (3-pyridyl)amino, (3-quinolyl)amino, and (5-indolyl)amino.
Examples of the N-hydrocarbon-N-heterocyclic ring-amino group include the groups in which two hydrogen atoms of amino group are substituted with hydrocarbon group and heterocyclic group respectively, and include, for example, N-methyl-N-(4-piperidinyl)amino, N-(4-chromanyl)-N-methylamino, N-methyl-N-(3-thienyl)amino, N-methyl-N-(3-pyridyl)amino, N-methyl-N-(3-quinolyl)amino.
Examples of the acyl-amino group include the groups in which one hydrogen atom of the amino group is substituted with an acyl group, and include, for example, formylamino group, glyoxyloylamino group, thioformylamino group, carbamoylamino group, thiocarbamoylamino group, sulfamoylamino group, sulfinamoylamino group, carboxyamino group, sulphoamino group, phosphonoamino group, and groups represented by the following formulas:







wherein Ra4 and Rb4 may be the same or different and represent a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, or Ra4 and Rb4 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group which may be substituted.

In the definition of the aforementioned acyl-amino group, among the groups represented by the formula (ω-1D), those groups in which Ra4 is a hydrocarbon group are referred to as “hydrocarbon-carbonyl-amino group,” and those groups in which Ra4 is a heterocyclic group are referred to as “heterocyclic ring-carbonyl-amino group.”
Among the groups represented by the formula (ω-2D), those groups in which Ra4 is a hydrocarbon group are referred to as “hydrocarbon-oxy-carbonyl-amino group,” and those groups in which Ra4 is a heterocyclic group are referred to as “heterocyclic ring-oxy-carbonyl-amino group.”
Among the groups represented by the formula (ω-3D), those groups in which Ra4 is a hydrocarbon group are referred to as “hydrocarbon-carbonyl-carbonyl-amino group,” and those groups in which Ra4 is a heterocyclic group are referred to as “heterocyclic ring-carbonyl-carbonyl-amino group.”
Among the groups represented by the formula (ω-4D), those groups in which Ra4 is a hydrocarbon group are referred to as “hydrocarbon-oxy-carbonyl-carbonyl-amino group,” and those groups in which Ra4 is a heterocyclic group are referred to as “heterocyclic ring-oxy-carbonyl-carbonyl-amino group.”
Among the groups represented by the formula (ω-5D), those groups in which Ra4 is a hydrocarbon group are referred to as “hydrocarbon-sulfanyl-carbonyl-amino group,” and those groups in which Ra4 is a heterocyclic group are referred to as “heterocyclic ring-sulfanyl-carbonyl-amino group.”
Among the groups represented by the formula (ω-6D), those groups in which Ra4 is a hydrocarbon group are referred to as “hydrocarbon-thiocarbonyl-amino group,” and those groups in which Ra4 is a heterocyclic group are referred to as “heterocyclic ring-thiocarbonyl-amino group.”
Among the groups represented by the formula (ω-7D), those groups in which Ra4 is a hydrocarbon group are referred to as “hydrocarbon-oxy-thiocarbonyl-amino group,” and those groups in which Ra4 is a heterocyclic group are referred to as “heterocyclic ring-oxy-thiocarbonyl-amino group.”
Among the groups represented by the formula (ω-8D), those groups in which Ra4 is a hydrocarbon group are referred to as “hydrocarbon-sulfanyl-thiocarbonyl-amino group,” and those groups in which Ra4 is a heterocyclic group are referred to as “heterocyclic ring-sulfanyl-thiocarbonyl-amino group.”
Among the groups represented by the formula (ω-9D), those groups in which Ra4 is a hydrocarbon group are referred to as “N-hydrocarbon-carbamoyl group,” and those groups in which Ra4 is a heterocyclic group are referred to as “N-heterocyclic ring-carbamoyl-amino group.”
Among the groups represented by the formula (ω-10D), those groups in which both Ra4 and Rb4 are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-carbamoyl-amino group,” those groups in which both Ra4 and Rb4 are heterocyclic groups are referred to as “N,N-di(heterocyclic ring)-carbamoyl-amino group,” those groups in which Ra4 is a hydrocarbon group and Rb4 is a heterocyclic group are referred to as “N-hydrocarbon-N-heterocyclic ring-carbamoyl-amino group,” and those groups in which Ra4 and Rb4 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclic amino-carbonyl-amino group.”
Among the groups represented by the formula (ω-11D), those groups in which Ra4 is a hydrocarbon group are referred to as “N-hydrocarbon-thiocarbamoyl-amino group,” and those groups in which Ra4 is a heterocyclic ring group are referred to as “N-heterocyclic-thiocarbamoyl-amino group.”
Among the groups represented by the formula (ω-12D), those groups in which both Ra4 and Rb4 are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-thiocarbamoyl-amino group,” those groups in which both Ra4 and Rb4 are heterocyclic groups are referred to as “N,N-di(heterocyclic ring)-thiocarbamoyl-amino group,” those groups in which Ra4 is a hydrocarbon group and Rb4 is a heterocyclic group are referred to as “N-hydrocarbon-N-heterocyclic ring-thiocarbamoyl-amino group,” and those groups in which Ra4 and Rb4 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclic amino-thiocarbonyl-amino group.”
Among the groups represented by the formula (ω-13D), those groups in which Ra4 is a hydrocarbon group are referred to as “N-hydrocarbon-sulfamoyl-amino group,” and those groups in which Ra4 is a heterocyclic group are referred to as “N-heterocyclic ring-sulfamoyl-amino group.”
Among the groups represented by the formula (ω-14D), those groups in which both Ra4 and Rb4 are hydrocarbon groups are referred to as “di(hydrocarbon)-sulfamoyl-amino group,” those groups in which both Ra4 and Rb4 are heterocyclic groups are referred to as “N,N-di(heterocyclic ring)-sulfamoyl-amino group,” those groups in which Ra4 is a hydrocarbon group and Rb4 is a heterocyclic group are referred to as “N-hydrocarbon-N-heterocyclic ring-sulfamoyl-amino group,” and those groups in which Ra4 and Rb4 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclic amino-sulfonyl-amino group.”
Among the groups represented by the formula (ω-15D), those groups in which Ra4 is a hydrocarbon group are referred to as “N-hydrocarbon-sulfinamoyl-amino group,” and those groups in which Ra4 is a heterocyclic group are referred to as “N-heterocyclic ring-sulfinamoyl-amino group.”
Among the groups represented by the formula (ω-16D), those groups in which both Ra4 and Rb4 are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-sulfinamoyl-amino group,” those groups in which both Ra4 and Rb4 are heterocyclic groups are referred to as “N,N-di(heterocyclic ring)-sulfinamoyl-amino group,” groups in which Ra4 is a hydrocarbon group and Rb4 is a heterocyclic group are referred to as “N-hydrocarbon-N-heterocyclic ring-sulfinamoyl-amino group,” and those groups in which Ra4 and Rb4 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclic amino-sulfinyl-amino group.”
Among the groups represented by the formula (ω-17D), those groups in which Ra4 is a hydrocarbon group are referred to as “hydrocarbon-oxy-sulfonyl-amino group,” and those groups in which Ra4 is a heterocyclic group are referred to as “heterocyclic ring-oxy-sulfoyl-amino group.”
Among the groups represented by the formula (ω-18D), those groups in which Ra4 is a hydrocarbon group are referred to as “hydrocarbon-oxy-sulfinyl-amino group,” and those groups in which Ra4 is a heterocyclic group are referred to as “heterocyclic ring-oxy-sulfinyl-amino group.”
Among the groups represented by the formula (ω-19D), those groups in which both Ra4 and Rb4 are hydrocarbon groups are referred to as “O,O′-di(hydrocarbon)-phosphono-amino group,” those groups in which both Ra4 and Rb4 are heterocyclic groups are referred to as “O,O′-di(heterocyclic ring)-phosphono-amino group,” and those groups in which Ra4 is a hydrocarbon group and Rb4 is a heterocyclic group are referred to as “O-hydrocarbon-O′-heterocyclic ring-phosphono-amino group.”
Among the groups represented by the formula (ω-20D), those groups in which Ra4 is a hydrocarbon group are referred to as “hydrocarbon-sulfonyl-amino group,” and those groups in which Ra4 is a heterocyclic group are referred to as “heterocyclic ring-sulfonyl-amino group.”
Among the groups represented by the formula (ω-21D), those groups in which Ra4 is a hydrocarbon group are referred to as “hydrocarbon-sulfinyl-amino group,” and those groups in which Ra4 is a heterocyclic group are referred to as “heterocyclic ring-sulfinyl-amino group.”
Examples of the hydrocarbon in the groups represented by the aforementioned formulas (ω-1D) through (ω-21D) include the similar groups to the aforementioned hydrocarbon group. Examples of the hydrocarbon-carbonyl-amino groups represented by the formula (ω-1D) include, for example, an alkyl-carbonyl-amino group, an alkenyl-carbonyl-amino group, an alkynyl-carbonyl-amino group, a cycloalkyl-carbonyl-amino group, a cycloalkenyl-carbonyl-amino group, a cycloalkanedienyl-carbonyl-amino group, a cycloalkyl-alkyl-carbonyl-amino group which are aliphatic hydrocarbon-carbonyl-amino groups; an aryl-carbonyl-amino group; an aralkyl-carbonyl-amino group; a bridged cyclic hydrocarbon-carbonyl-amino group; a spiro cyclic hydrocarbon-carbonyl-amino group; and a terpene family hydrocarbon-carbonyl-amino group. In the following, groups represented by the formulas (ω-2D) through (ω-21D) are similar to those explained above.
Examples of the heterocyclic ring in the groups represented by the aforementioned formulas (ω-1D) through (ω-21D) include similar groups to the aforementioned heterocyclic group. Examples of the heterocyclic ring-carbonyl-amino group represented by the formula (ω-1D) include, for example, a monocyclic heteroaryl-carbonyl-amino group, a fused polycyclic heteroaryl-carbonyl-amino group, a monocyclic non-aromatic heterocyclic-carbonyl-amino group, and a fused polycyclic non-aromatic heterocyclic-carbonyl-amino group. In the following, groups represented by the formulas (ω-2D) through (ω-21D) are similar to those groups explained above.
Examples of the cyclic amino in the groups represented by the aforementioned formulas (ω-10D) through (ω-16D) include similar groups to the aforementioned cyclic amino group.
Examples of the di(acyl)-amino group include the groups in which two hydrogen atoms of amino group are substituted with acyl groups in the definitions of the aforementioned substitutents according to “which may be substituted.” Examples include, for example, di(formyl)-amino group, di(glyoxyloyl)-amino group, di(thioformyl)-amino group, di(carbamoyl)-amino group, di(thiocarbamoyl)-amino group, di(sulfamoyl)-amino group, di(sulfinamoyl)-amino group, di(carboxy)-amino group, di(sulfo)-amino group, di(phosphono)-amino group, and groups represented by the following formulas:







wherein Ra5 and Rb5 may be the same or different and represent hydrogen atom, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, or Ra5 and Rb5 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group which may be substituted.

In the definition of aforementioned di(acyl)-amino group, among the groups represented by the formula (ω-1E), those groups in which Ra5 is a hydrocarbon group are referred to as “bis(hydrocarbon-carbonyl)-amino group,” and those groups in which Ra5 is a heterocyclic group are referred to as “bis(heterocyclic ring-carbonyl)-amino group.”
Among the groups represented by the formula (ω-2E), those groups in which Ra5 is a hydrocarbon group are referred to as “bis(hydrocarbon-oxy-carbonyl)-amino group,” and those groups in which Ra5 is a heterocyclic group are referred to as “bis(heterocyclic ring-oxy-carbonyl)-amino group.”
Among the groups represented by the formula (ω-3E), those groups in which Ra5 is a hydrocarbon group are referred to as “bis(hydrocarbon-carbonyl-carbonyl)-amino group,” and those groups in which Ra5 is a heterocyclic group are referred to as “bis(heterocyclic ring-carbonyl-carbonyl)-amino group.”
Among the groups represented by the formula (ω-4E), those groups in which Ra5 is a hydrocarbon group are referred to as “bis(hydrocarbon-oxy-carbonyl-carbonyl)-amino group,” and those groups in which Ra5 is a heterocyclic group are referred to as “bis(heterocyclic ring-oxy-carbonyl-carbonyl)-amino group.”
Among the groups represented by the formula (ω-5E), those groups in which Ra5 is a hydrocarbon group are referred to as “bis(hydrocarbon-sulfanyl-carbonyl)-amino group,” and those groups in which Ra5 is a heterocyclic group are referred to as “bis(heterocyclic ring-sulfanyl-carbonyl)-amino group.”
Among the groups represented by the formula (ω-6E), those groups in which Ra5 is a hydrocarbon group are referred to as “bis(hydrocarbon-thiocarbonyl)-amino group,” and those groups in which Ra5 is a heterocyclic group are referred to as “bis(heterocyclic ring-thiocarbonyl)-amino group.”
Among the groups represented by the formula (ω-7E), those groups in which Ra5 is a hydrocarbon group are referred to as “bis(hydrocarbon-oxy-thiocarbonyl)-amino group,” and those groups in which Ra5 is a heterocyclic group are referred to as “bis(heterocyclic ring-oxy-thiocarbonyl)-amino group.”
Among the groups represented by the formula (ω-8E), those groups in which Ra5 is a hydrocarbon group are referred to as “bis(hydrocarbon-sulfanyl-thiocarbonyl)-amino group,” and those groups in which Ra5 is a heterocyclic group are referred to as “bis(heterocyclic ring-sulfanyl-thiocarbonyl)-amino group.”
Among the groups represented by the formula (ω-9E), those groups in which Ra5 is a hydrocarbon group are referred to as “bis(N-hydrocarbon-carbamoyl)-amino group,” and those groups in which Ra5 is a heterocyclic group are referred to as “bis(N-heterocyclic ring-carbamoyl)-amino group.”
Among the groups represented by the formula (ω-10E), those groups in which both Ra5 and Rb5 are hydrocarbon groups are referred to as “bis[N,N-di(hydrocarbon)-carbamoyl]-amino group,” those groups in which both Ra5 and Rb5 are heterocyclic groups are referred to as “bis[N,N-di(heterocyclic ring)-carbamoyl]-amino group,” groups in which Ra5 is a hydrocarbon group and Rb5 is a heterocyclic group are referred to as “bis(N-hydrocarbon-N-heterocyclic ring-carbamoyl)-amino group,” and those groups in which Ra5 and Rb5 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino groups are referred to as “bis(cyclic amino-carbonyl)amino group.”
Among the groups represented by the formula (ω-11E), those groups in which Ra5 is a hydrocarbon group are referred to as “bis(N-hydrocarbon-thiocarbamoyl)-amino group,” and those groups in which Ra5 is a heterocyclic group are referred to as “bis(N-heterocyclic ring-thiocarbamoyl)-amino group.”
Among the groups represented by the formula (ω-12E), those groups in which both Ra5 and Rb5 are hydrocarbon groups are referred to as “bis[N,N-di(hydrocarbon)-thiocarbamoyl]-amino group,” those groups in which both Ra5 and Rb5 are heterocyclic groups are referred to as “bis[N,N-di(heterocyclic ring)-thiocarbamoyl]-amino group,” those groups in which Ra5 is a hydrocarbon group and Rb5 is a heterocyclic group are referred to as “bis(N-hydrocarbon-N-heterocyclic ring-thiocarbamoyl)-amino group,” and those groups in which Ra5 and Rb5 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “bis(cyclic amino-thiocarbonyl)-amino group.”
Among the groups represented by the formula (ω-13E), those groups in which Ra5 is a hydrocarbon group are referred to as “bis(N-hydrocarbon-sulfamoyl)-amino group,” and those groups in which Ra5 is a heterocyclic group are referred to as “bis(N-heterocyclic ring-sulfamoyl)-amino group.”
Among the groups represented by the formula (ω-14E), those groups in which both Ra5 and Rb5 are hydrocarbon groups are referred to as “bis[N,N-di(hydrocarbon)-sulfamoyl]-amino group,” those groups in which both Ra5 and Rb5 are heterocyclic groups are referred to as “bis[N,N-di(heterocyclic ring)-sulfamoyl]-amino group,” those groups in which Ra5 is a hydrocarbon group and Rb5 is a heterocyclic group are referred to as “bis(N-hydrocarbon-N-heterocyclic ring-sulfamoyl)-amino group,” and those groups in which Ra5 and Rb5 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “bis(cyclic amino-sulfonyl)amino group.”
Among the groups represented by the formula (ω-15E), those groups in which Ra5 is a hydrocarbon group are referred to as “bis(N-hydrocarbon-sulfinamoyl)-amino group,” and those groups in which Ra5 is a heterocyclic group are referred to as “bis(N-heterocyclic ring-sulfinamoyl)-amino group.”
Among the groups represented by the formula (ω-16E), those groups in which Ra5 and Rb5 are hydrocarbon groups are referred to as “bis[N,N-di(hydrocarbon)-sulfinamoyl]-amino group,” those groups in which Ra5 and Rb5 are heterocyclic groups are referred to as “bis[N,N-di(heterocyclic ring)-sulfinamoyl]-amino group,” those groups in which Ra5 is a hydrocarbon group and Rb5 is a heterocyclic group are referred to as “bis(N-hydrocarbon-N-heterocyclic ring-sulfinamoyl)-amino group,” and those groups in which Ra5 and Rb5 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “bis(cyclic amino-sulfinyl)amino group.”
Among the groups represented by the formula (ω-17E), those groups in which Ra5 is a hydrocarbon group are referred to as “bis(hydrocarbon-oxy-sulfonyl)-amino group,” and those groups in which Ra5 is a heterocyclic group are referred to as “bis(heterocyclic ring-oxy-sulfonyl)-amino group.”
Among the groups represented by the formula (ω-18E), those groups in which Ra5 is a hydrocarbon group are referred to as “bis(hydrocarbon-oxy-sulfinyl)-amino group,” and those groups in which Ra5 is a heterocyclic group are referred to as “bis(heterocyclic ring-oxy-sulfinyl)-amino group.”
Among the groups represented by the formula (ω-19E), those groups in which both Ra5 and Rb5 are hydrocarbon groups are referred to as “bis[O,O′-di(hydrocarbon)-phosphono]-amino group,” those groups in which both Ra5 and Rb5 are heterocyclic groups are referred to as “bis[O,O′-di(heterocyclic ring)-phosphono]-amino group,” and those groups in which Ra5 is a hydrocarbon group and Rb5 is a heterocyclic group are referred to as “bis(O-hydrocarbon-O′-heterocyclic ring-phosphono)-amino group.”
Among the groups represented by the formula (ω-20E), those groups in which Ra5 is a hydrocarbon group are referred to as “bis(hydrocarbon-sulfonyl)-amino group,” and those groups in which Ra5 is a heterocyclic group are referred to as “bis(heterocyclic ring-sulfonyl)-amino group.”
Among the groups represented by the formula (ω-21E), those groups in which Ra5 is a hydrocarbon group are referred to as “bis(hydrocarbon-sulfinyl)-amino group,” and those groups in which Ra5 is a heterocyclic group are referred to as “bis(heterocyclic ring-sulfinyl)-amino group.”
Examples of the hydrocarbon in the groups represented by the aforementioned formulas (ω-1E) through (ω-21E) include the similar groups to the aforementioned hydrocarbon group. Examples of the bis(hydrocarbon-carbonyl)-amino groups represented by the formula (ω-1E) include, for example, a bis(alkyl-carbonyl)-amino group, a bis(alkenyl-carbonyl)-amino group, a bis(alkynyl-carbonyl)-amino group, a bis(cycloalkyl-carbonyl)-amino group, a bis(cycloalkenyl-carbonyl)-amino group, a bis(cycloalkanedienyl-carbonyl)-amino group, a bis(cycloalkyl-alkyl-carbonyl)-amino group which are bis(aliphatic hydrocarbon-carbonyl)-amino groups; a bis(aryl-carbonyl)-amino group; a bis(aralkyl-carbonyl)-amino group; a bis(bridged cyclic hydrocarbon-carbonyl)-amino group; a bis(spiro cyclic hydrocarbon-carbonyl)-amino group; and a bis(terpene family hydrocarbon-carbonyl)-amino group. In the following, groups represented by the formulas (ω-2E) through (ω-21E) are similar to those explained above.
Examples of the heterocyclic ring in the groups represented by the aforementioned formulas (ω-1E) through (ω-21E) include similar groups to the aforementioned heterocyclic group. Examples of the bis(heterocyclic ring-carbonyl)-amino group represented by the formula (ω-1E) include, for example, a bis(monocyclic heteroaryl-carbonyl)-amino group, a bis(fused polycyclic heteroaryl-carbonyl)-amino group, a bis(monocyclic non-aromatic heterocyclic-carbonyl)-amino group, and a bis(fused polycyclic non-aromatic heterocyclic-carbonyl)-amino group. In the following, groups represented by the formulas (ω-2E) through (ω-21E) are similar to those groups explained above.
Examples of the cyclic amino in the groups represented by the aforementioned formulas (ω-10E) through (ω-16E) include similar groups to the aforementioned cyclic amino group.
The aforementioned acyl-amino group and di(acyl)-amino group are generically referred to as “acyl substituted amino group.” Furthermore, the aforementioned N-hydrocarbon-amino group, N,N-di(hydrocarbon)-amino group, N-heterocyclic-amino group, N-hydrocarbon-N-heterocyclic-amino group, cyclic amino group, acyl-amino group, and di(acyl)-amino group are generically referred to as “substituted amino group.”
In the following, compounds represented by the aforementioned general formula (I) are explained in details.
“Connecting group whose number of atoms of main chain is 2 to 5” in the definition of X means connecting groups wherein 2 to 5 atoms in a main chain link together between rings Z and E. The aforementioned “number of atoms of the main chain” is counted so as to minimize the number of connecting atoms existing between the rings Z and E, regardless of the presence or absence of hetero atom(s). For example, the number of atoms of 1,2-cyclopentylene is counted as 2, the number of atoms of 1,3-cyclopentylene is counted as 3, the number of atoms of 1,4-phenylene is counted as 4, and the number of atoms of 2,6-pyridine-diyl is counted as 3.
The aforementioned “connecting group whose number of atoms of main chain is 2 to 5” is formed by one functional group selected from the following group of divalent group ζ-1, or formed by combining 2 to 4 functional groups of 1 to 4 kinds selected from the following divalent group ζ-2.
[Divalent group ζ-1] the following formulas:




[Divalent group ζ-2] the following formulas:





When 2 or more divalent groups combine, each group may be the same or different.

The aforementioned “connecting group wherein the number of atoms of the main chain is 2 to 5,” is preferably a group selected from the following “connecting group α.”
[Connecting group α] the following formulas:




wherein a bond at the left end binds to ring Z and a bond at the right end binds to E.

The group represented by the following formula is most preferred:




wherein the bond at the left end binds to ring Z and the bond at the right end binds to E.

Examples of the substitutent, according to “connecting group which may be substituted” in the definition of “a connecting group whose number of atoms of the main chain is 2 to 5,” include similar groups to the substitutents in the definition of the aforementioned “which may be substituted.” A C1 to C6 alkyl group is preferred, and a methyl group is more preferred. The substitutent may combine with a substitutent of the ring E or Z, together with atoms to which they bind, to form a cyclic group which may be substituted. Examples include the compounds represented by the general formula (I) being those represented by the following formulas:




In the aforementioned general formula (I), examples of A include hydrogen atom or acetyl group, and hydrogen atom is preferred.
Examples of the “arene” in “an arene which may have one or more substitutents in addition to the group represented by formula —O-A wherein A has the same meaning as that defined above and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined above” in the definition of ring Z include a monocyclic or fused heterocyclic aromatic hydrocarbon, and include, for example, benzene ring, naphthalene ring, anthracene ring, phenanthrene ring, and acenaphylene ring. C6 to C10 arenes such as benzene ring, naphthalene ring and the like are preferred, benzene ring and naphthalene ring are more preferred, and benzene ring is most preferred.
Examples of the substitutent in the definition of “an arene which may have one or more substitutents in addition to the group represented by formula —O-A wherein A has the same meaning as that defined above and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined above” in the aforementioned definition of ring Z include similar groups to the substitutent explained for the definition “which may be substituted.” The position of substitutents existing on the arene is not particularly limited, and when two or more substitutents exist, they may be the same or different.
When “an arene which may have one or more substitutents in addition to the group represented by formula —O-A wherein A has the same meaning as that defined above and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined above” in the aforementioned definition of ring Z is “a benzene ring which may have one or more substitutents in addition to the group represented by formula —O-A wherein A has the same meaning as that defined above and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined above,” “a benzene ring which has one to three substitutents in addition to the group represented by formula —O-A wherein A has the same meaning as that defined above and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined above” is preferred, and “a benzene ring which has one substitutent in addition to the group represented by formula —O-A wherein A has the same meaning as that defined above and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined above” is more preferred. Preferred examples of said substitutents include groups selected from the following Substituent Group γ-1z. Halogen atom and tert-butyl group [(1,1-dimethyl)ethyl group] are more preferred, and halogen atom is most preferred.
[Substituent Group γ-1z] halogen atom, nitro group, cyano group, hydroxy group, methoxy group, methyl group, isopropyl group, tert-butyl group, 1,1,3,3-tetramethylbutyl group, 2-phenylethen-1-yl group, 2,2-dicyanoethen-1-yl group, 2-cyano-2-(methoxycarbonyl)ethen-1-yl group, 2-carboxy-2-cyanoethen-1-yl group, ethynyl group, phenylethynyl group, (trimethylsilyl)ethynyl group, trifluoromethyl group, pentafluoroethyl group, phenyl group, 4-(trifluoromethyl)phenyl group, 4-fluorophenyl group, 2,4-difluorophenyl group, 2-phenethyl group, 1-hydroxyethyl group, 1-(methoxyimino)ethyl group, 1-[(benzyloxy)imino]ethyl group, 2-thienyl group [thiophen-2-yl group], 3-thienyl group [thiophen-3-yl group], 1-pyrrolyl group [pyrrol-1-yl group], 2-methylthiazol-4-yl group, imidazo[1,2-a]pyridin-2-yl group, 2-pyridyl group [pyridin-2-yl group], acetyl group, isobutyryl group, piperidinocarbonyl group, 4-benzylpiperidinocarbonyl group, (pyrrol-1-yl)sulfonyl group, carboxy group, methoxycarbonyl group, N-[3,5-bis(trifluoromethyl)phenyl]carbamoyl group, N,N-dimethylcarbamoyl group, sulfamoyl group, N-[3,5-bis(trifluoromethyl)phenyl]sulfamoyl group, N,N-dimethylsulfamoyl group, amino group, N,N-dimethylamino group, acetylamino group, benzoylamino group, methanesulfonylamino group, benzenesulfonylamino group, 3-phenylureido group, (3-phenyl)thioureido group, (4-nitrophenyl)diazenyl group, and {[4-(pyridin-2-yl)sulfamoyl]phenyl}diazenyl group
When “an arene which may have one or more substitutents in addition to the group represented by formula —O-A wherein A has the same meaning as that defined above and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined above” in the aforementioned definition of ring Z is “a benzene ring which may have one or more substitutents in addition to the group represented by formula —O-A wherein A has the same meaning as that defined above and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined above,” it is most preferable that one substitutent exists and locates on the position of Rz when the following partial formula (Iz-1) in the general formula containing ring Z




is represented by the following formula (Iz-2).





At this time, said substitutents can be defined as Rz. Preferred examples of Rz include a group selected from the following Substituent Group γ-2z. Halogen atom and tert-butyl group are more preferred, and halogen atom is most preferred.

[Substituent Group γ-2z] halogen atom, nitro group, cyano group, methoxy group, methyl group, isopropyl group, tert-butyl group, 1,1,3,3-tetramethylbutyl group, 2-phenylethen-1-yl group, 2,2-dicyanoethen-1-yl group, 2-cyano-2-(methoxycarbonyl)ethen-1-yl group, 2-carboxy-2-cyanoethen-1-yl group, ethynyl group, phenylethynyl group, (trimethylsilyl)ethynyl group, trifluoromethyl group, pentafluoroethyl group, phenyl group, 4-(trifluoromethyl)phenyl group, 4-fluorophenyl group, 2,4-difluorophenyl group, 2-phenethyl group, 1-hydroxyethyl group, 1-(methoxyimino)ethyl group, 1-[(benzyloxy)imino]ethyl group, 2-thienyl group, 3-thienyl group, 1-pyrrolyl group, 2-methylthiazol-4-yl group, imidazo[1,2-a]pyridin-2-yl group, 2-pyridyl group, acetyl group, isobutyryl group, piperidinocarbonyl group, 4-benzylpiperidinocarbonyl group, (pyrrol-1-yl)sulfonyl group, carboxy group, methoxycarbonyl group, N-[3,5-bis(trifluoromethyl)phenyl]carbamoyl group, N,N-dimethylcarbamoyl group, sulfamoyl group, N-[3,5-bis(trifluoromethyl)phenyl]sulfamoyl group, N,N-dimethylsulfamoyl group, amino group, N,N-dimethylamino group, acetylamino group, benzoylamino group, methanesulfonylamino group, benzenesulfonylamino group, 3-phenylureido group, (3-phenyl)thioureido group, (4-nitrophenyl)diazenyl group, and {[4-(pyridin-2-yl)sulfamoyl]phenyl}diazenyl group

When “an arene which may have one or more substitutents in addition to the group represented by formula —O-A wherein A has the same meaning as that defined above and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined above” in the aforementioned definition of ring Z is “a naphthalene ring which may have one or more substitutents in addition to the group represented by formula —O-A wherein A has the same meaning as that defined above and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined above,” naphthalene ring is preferred.
Examples of the “hetero arene” in “a hetero arene which may have one or more substitutents in addition to the group represented by formula —O-A wherein A has the same meaning as that defined above and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined above” in the aforementioned definition of ring Z include a monocyclic or a fused polycyclic aromatic heterocyclic rings containing at least one of 1 to 3 kinds of heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom and the like as ring-constituting atoms (ring forming atoms), and include, for example, furan ring, thiophene ring, pyrrole ring, oxazole ring, isoxazole ring, thiazole ring, isothiazole ring, imidazole ring, pyrazole ring, 1,2,3-oxadiazole ring, 1,2,3-thiadiazole ring, 1,2,3-triazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, 1,2,3-triazine ring, 1,2,4-triazine ring, 1H-azepine ring, 1,4-oxepine ring, 1,4-thiazepine ring, benzofuran ring, isobenzofuran ring, benzo[b]thiophene ring, benzo[c]thiophene ring, indole ring, 2H-isoindole ring, 1H-indazole ring, 2H-indazole ring, benzoxazole ring, 1,2-benzisoxazole ring, 2,1-benzisoxazole ring, benzothiazole ring, 1,2-benzisothiazole ring, 2,1-benzisothiazole ring, 1,2,3-benzoxadiazol ring, 2,1,3-benzoxadiazol ring, 1,2,3-benzothiadiazole ring, 2,1,3-benzothiadiazole ring, 1H-benzotriazole ring, 2H-benzotriazole ring, quinoline ring, isoquinoline ring, cinnoline ring, quinazoline ring, quinoxaline ring, phthalazine ring, naphthyridine ring, 1H-1,5-benzodiazepine ring, carbazole ring, α-carboline ring, β-carboline ring, γ-carboline ring, acridine ring, phenoxazine ring, phenothiazine ring, phenazine ring, phenanthridine ring, phenanthroline ring, thianthrene ring, indolizine ring, and phenoxathiine ring, which are 5 to 14-membered monocyclic or fused polycyclic aromatic heterocyclic rings. 5 to 13-membered monocyclic or fused polycyclic aromatic heterocyclic rings are preferred, and thiophene ring, pyridine ring, indole ring, quinoxaline ring, and carbazole ring are more preferred.
Examples of the substitutent in the definition of “a hetero arene which may have one or more substitutents in addition to the group represented by formula —O-A wherein A has the same meaning as that defined above and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined above” in the aforementioned definition of ring Z include similar groups to the substitutent explained for the aforementioned definition “which may be substituted.” The position of substitutents existing on the hetero arene is not particularly limited, and when two or more substitutents exist, they may be the same or different.
Halogen atoms are preferred as the substitutent in the definition of “a hetero arene which may have one or more substitutents in addition to the group represented by formula —O-A wherein A has the same meaning as that defined above and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined above” in the aforementioned definition of ring Z.
Examples of the aryl group of “an aryl group which may be substituted” in the definition of E include similar groups to the aryl group in the definition of the aforementioned “hydrocarbon group,” and C6 to C10 aryl groups such as phenyl group, 1-naphthyl group, 2-naphthyl group and the like are preferred, and phenyl group is most preferred.
Examples of the substitutent in the definition of “an aryl group which may be substituted” in the definition of E include similar groups to the substitutent explained for the definition “which may be substituted.” The position of substitutents existing on the aryl group is not particularly limited, and when two or more substitutents exist, they may be the same or different.
When “an aryl group which may be substituted” in the aforementioned definition of E is “a phenyl group which may be substituted,” “a mono-substituted phenyl group,” “a di-substituted phenyl group,” and “a phenyl group which has three or more substitutents” are preferred, and “a di-substituted phenyl group” is more preferred.
When “an aryl group which may be substituted” in the aforementioned definition of E is “a di-substituted phenyl group,” preferred examples of the group include groups represented by the following Substituent Group δ-1e.
[Substituent Group δ-1e] 3,5-bis(trifluoromethyl)phenyl group, 3,4-propylenedioxyphenyl group, 3,5-dichlorophenyl group, 2,4-dihydroxyphenyl group, 2,5-dimethoxyphenyl group, 2-chloro-5-(trifluoromethyl)phenyl group, 3,5-bis[(1,1-dimethyl)ethyl]phenyl group, 2,5-bis(trifluoromethyl)phenyl group, 4-chloro-2-(trifluoromethyl)phenyl group, 2-fluoro-3-(trifluoromethyl)phenyl group, 4-fluoro-3-(trifluoromethyl)phenyl group, 4-chloro-3-(trifluoromethyl)phenyl group, 3-fluoro-5-(trifluoromethyl)phenyl group, 3-bromo-5-(trifluoromethyl)phenyl group, 2-fluoro-5-(trifluoromethyl)phenyl group, 4-nitro-3-(trifluoromethyl)phenyl group, 2-nitro-5-(trifluoromethyl)phenyl group, 4-cyano-3-(trifluoromethyl)phenyl group, 2-methyl-3-(trifluoromethyl)phenyl group, 4-methyl-3-(trifluoromethyl)phenyl group, 2-methyl-5-(trifluoromethyl)phenyl group, 4-methoxy-3-(trifluoromethyl)phenyl group, 3-methoxy-5-(trifluoromethyl)phenyl group, 2-methoxy-5-(trifluoromethyl)phenyl group, 2-methylsulfanyl-5-(trifluoromethyl)phenyl group, 2-(1-pyrrolidinyl)-5-(trifluoromethyl)phenyl group, 2-morpholino-5-(trifluoromethyl)phenyl group, 2-chloro-4-(trifluoromethyl)phenyl group, 2,5-dichlorophenyl group, 3,4-dichlorophenyl group, 3,5-difluorophenyl group, 3,5-dinitrophenyl group, 2,5-bis[(1,1-dimethyl)ethyl]phenyl group, 5-[(1,1-dimethyl)ethyl]-2-methoxyphenyl group, 3,5-dimethylphenyl group, 4-methoxybiphenyl-3-yl group, 3,5-dimethoxyphenyl group, 3,5-bis(methoxycarbonyl)phenyl group, 2-bromo-5-(trifluoromethyl)phenyl group, 3-methoxycarbonyl-5-(trifluoromethyl)phenyl group, 3-carboxy-5-(trifluoromethyl)phenyl group, 2-(2-naphthyloxy)-5-(trifluoromethyl)phenyl group, 2-(2,4-dichlorophenoxy)-5-(trifluoromethyl)phenyl group, 2-[4-(trifluoromethyl)piperidin-1-yl]-5-(trifluoromethyl)phenyl group, 2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl group, 2-(2-methoxyphenoxy)-5-(trifluoromethyl)phenyl group, 2-(4-chloro-3,5-dimethylphenoxy)-5-(trifluoromethyl)phenyl group, 2-piperidino-5-(trifluoromethyl)phenyl group, 2-(4-methylphenoxy)-5-(trifluoromethyl)phenyl group, 2-(4-chlorophenoxy)-5-(trifluoromethyl)phenyl group, 3,5-dicarboxyphenyl group, 5-isopropyl-2-methylphenyl group, 2,5-diethoxyphenyl group, 2,5-dimethylphenyl group, 5-chloro-2-cyano group, 5-diethylsulfamoyl-2-methoxyphenyl group, 2-chloro-5-nitrophenyl group, 2-methoxy-5-(phenylcarbamoyl)phenyl group, 5-acetylamino-2-methoxyphenyl group, 5-methoxy-2-methylphenyl group, 2,5-dibutoxyphenyl group, 2,5-diisopentyloxy group, 5-carbamoyl-2-methoxyphenyl group, 5-[(1,1-dimethyl)propyl]-2-phenoxyphenyl group, 2-hexyloxy-5-methanesulfonyl group, 5-(2,2-dimethylpropionyl)-2-methylphenyl group, 5-methoxy-2-(1-pyrrolyl)phenyl group, 5-chloro-2-(p-toluenesulfonyl)phenyl group, 2-chloro-5-(p-toluenesulfonyl)phenyl group, 2-fluoro-5-methanesulfonyl group, 2-methoxy-5-phenoxy group, 4-methylbiphenyl-3-yl group, 2-methoxy-5-(1-methyl-1-phenylethyl)phenyl group, 5-morpholino-2-nitrophenyl group, 5-fluoro-2-(1-imidazolyl)phenyl group, 2-butyl-5-nitrophenyl group, 5-[(1,1-dimethyl)]propyl-2-hydroxyphenyl group, 2-methoxy-5-methylphenyl group, 2,5-difluorophenyl group, 4-isopropyl-2-(trifluoromethyl)phenyl group, 2-nitro-4-(trifluoromethyl)phenyl group, 4-bromo-3-(trifluoromethyl)phenyl group, 4-bromo-2-(trifluoromethyl)phenyl group, 2-bromo-4-(trifluoromethyl)phenyl group, 4-fluoro-2-(trifluoromethyl)phenyl group, 4-isopropoxy-2-(trifluoromethyl)phenyl group, 4-cyano-2-(trifluoromethyl)phenyl group, 2,6-diisopropylphenyl group, 2,6-dimethylphenyl group, 3,4-dimethylphenyl group, 2,4-dichlorophenyl group, 2,3-dimethylphenyl group, indan-5-yl group, 2,4-dimethylphenyl group, 2,6-dichlorophenyl group, 4-bromo-2-(trifluoromethoxy)phenyl group, 3,4-ethylenedioxyphenyl group, 3-chloro-4-cyanophenyl group, 3-chloro-4-(trifluoromethoxy)phenyl group, 2-chloro-4-cyanophenyl group, 2,3-dichlorophenyl group, 4-isopropyl-3-methylphenyl group, 4-[(1,1-dimethyl)propyl]-2-hydroxyphenyl group, 3-chloro-2-cyanophenyl group, 2-cyano-4-methylphenyl group, 2,2-difluoro-1,3-benzodioxol-4-yl group, 2,2,3,3-tetrafluoro-1,4-benzodioxen-5-yl group, 3-chloro-4-(trifluoromethylsulfanyl)phenyl group, 2-nitro-4-(trifluoromethoxy)phenyl group, 2,2-difluoro-1,3-benzodioxol-5-yl group, 2-methyl-4-(trifluoromethoxy)phenyl group, 4-bromo-2-fluorophenyl group, 2,4-bis(methanesulfonyl)phenyl group, 2,2,3,3-tetrafluoro-1,4-benzodioxen-6-yl group, 2-benzoyl-4-chlorophenyl group, 2-bromo-4-fluorophenyl group, 3,4-dimethoxyphenyl group, 3,4-difluorophenyl group, 3-chloro-4-methoxyphenyl group, 2-chloro-4-nitrophenyl group, 2,4-difluorophenyl group, 2-benzoyl-5-methylphenyl group, 2-bromo-4-(trifluoromethoxy)phenyl group, 3,4-dihexyloxyphenyl group, 2,4-bis(trifluoromethyl)phenyl group, 4-cyano-2-(trifluoromethoxy)phenyl group, 2-(4-cyanophenoxy)-5-(trifluoromethyl)phenyl group, and 2-(4-methoxyphenoxy)-5-(trifluoromethyl)phenyl group
When “an aryl group which may be substituted” in the aforementioned definition of E is “a di-substituted phenyl group,” “a 2,5-di-substituted phenyl group,” and “a 3,5-di-substituted phenyl group” are preferred.
When “an aryl group which may be substituted” in the aforementioned definition of E is “a 2,5-di-substituted phenyl group,” preferred examples of the group include groups represented by the following Substituent Group δ-2e.
[Substituent Group δ-2e] 2,5-dimethoxyphenyl group, 2-chloro-5-(trifluoromethyl)phenyl group, 2,5-bis(trifluoromethyl)phenyl group, 2-fluoro-5-(trifluoromethyl)phenyl group, 2-nitro-5-(trifluoromethyl)phenyl group, 2-methyl-5-(trifluoromethyl)phenyl group, 2-methoxy-5-(trifluoromethyl)phenyl group, 2-methylsulfanyl-5-(trifluoromethyl)phenyl group, 2-(1-pyrrolidinyl)-5-(trifluoromethyl)phenyl group, 2-morpholino-5-(trifluoromethyl)phenyl group, 2,5-dichlorophenyl group, 2,5-bis[(1,1-dimethyl)ethyl]phenyl group, 5-[(1,1-dimethyl)ethyl]-2-methoxyphenyl group, 4-methoxybiphenyl-3-yl group, 2-bromo-5-(trifluoromethyl)phenyl group, 2-(2-naphthyloxy)-5-(trifluoromethyl)phenyl group, 2-(2,4-dichlorophenoxy)-5-(trifluoromethyl)phenyl group, 2-[4-(trifluoromethyl)piperidin-1-yl]-5-(trifluoromethyl)phenyl group, 2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl group, 2-(2-methoxyphenoxy)-5-(trifluoromethyl)phenyl group, 2-(4-chloro-3,5-dimethylphenoxy)-5-(trifluoromethyl)phenyl group, 2-piperidino-5-(trifluoromethyl)phenyl group, 2-(4-methylphenoxy)-5-(trifluoromethyl)phenyl group, 2-(4-chlorophenoxy)-5-(trifluoromethyl)phenyl group, 5-isopropyl-2-methylphenyl group, 2,5-diethoxyphenyl group, 2,5-dimethylphenyl group, 5-chloro-2-cyano group, 5-diethylsulfamoyl-2-methoxyphenyl group, 2-chloro-5-nitrophenyl group, 2-methoxy-5-(phenylcarbamoyl)phenyl group, 5-acetylamino-2-methoxyphenyl group, 5-methoxy-2-methylphenyl group, 2,5-dibutoxyphenyl group, 2,5-diisopentyloxy group, 5-carbamoyl-2-methoxyphenyl group, 5-[(1,1-dimethyl)propyl]-2-phenoxyphenyl group, 2-hexyloxy-5-methanesulfonyl group, 5-(2,2-dimethylpropionyl)-2-methylphenyl group, 5-methoxy-2-(1-pyrrolyl)phenyl group, 5-chloro-2-(p-toluenesulfonyl)phenyl group, 2-chloro-5-(p-toluenesulfonyl)phenyl group, 2-fluoro-5-methanesulfonyl group, 2-methoxy-5-phenoxy group, 2-methoxy-5-(1-methyl-1-phenylethyl)phenyl group, 5-morpholino-2-nitrophenyl group, 5-fluoro-2-(1-imidazolyl)phenyl group, 2-butyl-5-nitrophenyl group, 5-[(1,1-dimethyl)propyl]-2-hydroxyphenyl group, 2-methoxy-5-methylphenyl group, 2,5-difluorophenyl group, 2-benzoyl-5-methylphenyl group, 2-(4-cyanophenoxy)-5-(trifluoromethyl)phenyl group, and 2-(4-methoxyphenoxy)-5-(trifluoromethyl)phenyl group
When “an aryl group which may be substituted” in the aforementioned definition of E is “a 2,5-di-substituted phenyl group,” “a 2,5-di-substituted phenyl group wherein at least one of said substitutents is trifluoromethyl group” is more preferred, a group selected from the following Substituent Group δ-3e is further preferred, and 2,5-bis(trifluoromethyl)phenyl group is most preferred.
[Substituent Group δ-3e] 2-chloro-5-(trifluoromethyl)phenyl group, 2,5-bis(trifluoromethyl)phenyl group, 2-fluoro-5-(trifluoromethyl)phenyl group, 2-nitro-5-(trifluoromethyl)phenyl group, 2-methyl-5-(trifluoromethyl)phenyl group, 2-methoxy-5-(trifluoromethyl)phenyl group, 2-methylsulfanyl-5-(trifluoromethyl)phenyl group, 2-(1-pyrrolidinyl)-5-(trifluoromethyl)phenyl group, 2-morpholino-5-(trifluoromethyl)phenyl group, 2-bromo-5-(trifluoromethyl)phenyl group, 2-(2-naphthyloxy)-5-(trifluoromethyl)phenyl group, 2-(2,4-dichlorophenoxy)-5-(trifluoromethyl)phenyl group, 2-[4-(trifluoromethyl)piperidin-1-yl]-5-(trifluoromethyl)phenyl group, 2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl group, 2-(2-methoxyphenoxy)-5-(trifluoromethyl)phenyl group, 2-(4-chloro-3,5-dimethylphenoxy)-5-(trifluoromethyl)phenyl group, 2-piperidino-5-(trifluoromethyl)phenyl group, 2-(4-methylphenoxy)-5-(trifluoromethyl)phenyl group, 2-(4-chlorophenoxy)-5-(trifluoromethyl)phenyl group, 2-(4-cyanophenoxy)-5-(trifluoromethyl)phenyl group, and 2-(4-methoxyphenoxy)-5-(trifluoromethyl)phenyl group
When “an aryl group which may be substituted” in the aforementioned definition of E is “a 3,5-di-substituted phenyl group,” preferred examples of the group include groups represented by the following Substituent Group δ-4e.
[Substituent Group δ-4e] 3,5-bis(trifluoromethyl)phenyl group, 3,5-dichlorophenyl group, 3,5-bis[(1,1-dimethyl)ethyl]phenyl group, 3-fluoro-5-(trifluoromethyl)phenyl group, 3-bromo-5-(trifluoromethyl)phenyl group, 3-methoxy-5-(trifluoromethyl)phenyl group, 3,5-difluorophenyl group, 3,5-dinitrophenyl group, 3,5-dimethylphenyl group, 3,5-dimethoxyphenyl group, 3,5-bis(methoxycarbonyl)phenyl group, 3-methoxycarbonyl-5-(trifluoromethyl)phenyl group, 3-carboxy-5-(trifluoromethyl)phenyl group, and 3,5-dicarboxyphenyl group
When “an aryl group which may be substituted” in the aforementioned definition of E is “a 3,5-di-substituted phenyl group,” “a 3,5-di-substituted phenyl group wherein at least one of said substitutents is trifluoromethyl group” is more preferred, a group selected from the following Substituent Group δ-5e is further preferred, and 3,5-bis(trifluoromethyl)phenyl group is most preferred.
[Substituent Group δ-5e] 3,5-bis(trifluoromethyl)phenyl group, 3-fluoro-5-(trifluoromethyl)phenyl group, 3-bromo-5-(trifluoromethyl)phenyl group, 3-methoxy-5-(trifluoromethyl)phenyl group, 3-methoxycarbonyl-5-(trifluoromethyl)phenyl group, and 3-carboxy-5-(trifluoromethyl)phenyl group
When “an aryl group which may be substituted” in the aforementioned definition of E is “a mono-substituted phenyl group,” preferred examples of the group include groups represented by the following Substituent Group δ-6e.
[Substituent Group δ-6e] 4-methoxyphenyl group, 4-chlorophenyl group, 2-methoxyphenyl group, 2-(trifluoromethyl)phenyl group, 3-(trifluoromethyl)phenyl group, 4-(trifluoromethyl)phenyl group, 3-chlorophenyl group, biphenyl-3-yl group, 3-acetylphenyl group, 3-(acetylamino)phenyl group, 3-carbamoylphenyl group, 3-methylcarbomoylphenyl group, 4-methylphenyl group, 3-(trifluoromethoxy)phenyl group, 2-benzylphenyl group, 4-(trifluoromethoxy)phenyl group, 4-[(1,1-dimethyl)ethyl]phenyl group, 3-isopropoxyphenyl group, 4-isopropoxyphenyl group, 4-hexylphenyl group, 3-methylphenyl group, 4-cyclohexylphenyl group, 4-benzylphenyl group, 2-chlorophenyl group, 2-methylphenyl group, 4-butylphenyl group, 4-benzyloxyphenyl group, 3-benzylphenyl group, 4-hexyloxyphenyl group, 3-isopropylphenyl group, 4-cyanophenyl group, 3-cyanophenyl group, 4-(ethoxycarbonylmethyl)phenyl group, 3-(trifluoromethylsulfanyl)phenyl group, 4-(trifluoromethylsulfanyl)phenyl group, 4-(trifluoromethanesulfonyl)phenyl group, 3-ethynylphenyl group, 4-(1-methylpropyl)phenyl group, 3-benzoylphenyl group, 3-methoxyphenyl group, 4-(acetylamino)phenyl group, 4-sulfamoylphenyl group, 4-difluoromethoxy)phenyl group, 3-methylsulfanylphenyl group, 4-methanesulfonylphenyl group, 3-(butylsulfamoyl)phenyl group, 3-benzyloxyphenyl group, 4-(p-toluenesulfonylamino)phenyl group, 4-morpholinophenyl group, 3-[(1,1-dimethyl)ethyl]phenyl group, 3-(5-methylfuran-2-yl)phenyl group, 3-sulfamoylphenyl group, 3-(trifluoromethanesulfonyl)phenyl group, 3-hexyloxyphenyl group, 4-acetylphenyl group, biphenyl-2-yl group, biphenyl-4-yl group, 3-[5-phenyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl group, 3-{5-[(1,1-dimethyl)ethyl]-3-(trifluoromethyl)pyrazol-1-yl}phenyl group, 4-[3,5-bis(trifluoromethyl)pyrazol-1-yl]phenyl group, 3-[3,5-bis(trifluoromethyl)pyrazol-1-yl]phenyl group, and 4-[5-phenyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl group
When “an aryl group which may be substituted” in the aforementioned definition of E is “a phenyl group which has three or more substitutents,” preferred examples of the group include groups represented by the following Substituent Group δ-7e.
[Substituent Group δ-7e] 3,5-bis(trifluoromethyl)-2-bromophenyl group, 3,4,5-trichlorophenyl group, 3,5-dichloro-4-hydroxyphenyl group, pentafluorophenyl group, 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl group, 3,5-bis(trifluoromethyl)-2-methylphenyl group, 2,6-dichloro-4-(trifluoromethyl)phenyl group, 2,4-dimethoxy-5-(trifluoromethyl)phenyl group, 2,4-difluoro-5-(trifluoromethyl)phenyl group, 4-chloro-2-(4-chlorobenzenesulfonyl)-5-(trifluoromethyl)phenyl group, 5-chloro-2-nitro-4-(trifluoromethyl)phenyl group, 2,3-difluoro-4-(trifluoromethyl)phenyl group, 2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl group, 2,4,6-trimethylphenyl group, 2-cyano-4,5-dimethoxyphenyl group, 2,4-dichloro-5-isopropoxyphenyl group, 2,3,5-trifluorophenyl group, 2,4,5-trichlorophenyl group, and 5-ethoxy-4-fluoro-2-nitrophenyl group
When “an aryl group which may be substituted” in the aforementioned definition of E is “a naphthyl group which may be substituted,” preferred examples of the group include 1-naphthyl group, 4-methoxynaphthalen-2-yl group, and 4-hydroxy-3-methylnaphthalen-1-yl group.
Examples of the “heteroaryl group” in “a heteroaryl group which may be substituted” in the definition of E include similar groups to the “monocyclic heteroaryl group” and “fused polycyclic heteroaryl group” in the definition of the aforementioned “heterocyclic group.” A 5 to 13-membered heteroaryl group is preferred, and preferred examples of the group include thienyl group, pyrazolyl group, oxazolyl group, 1,3,4-thiadiazolyl group, pyridyl group, pyrimidinyl group, indolyl group, quinolyl group, carbazolyl group, thiazolyl group, and pyrazinyl group.
A 5-membered heteroaryl group is more preferred as the “heteroaryl group” in “a heteroaryl group which may be substituted” in the definition of E. Thienyl group, pyrazolyl group, oxazolyl group, 1,3,4-thiadiazolyl group, and thiazolyl group are further preferred, and thiazolyl group is most preferred.
Examples of the substitutent in the definition of “a heteroaryl group which may be substituted” in the aforementioned definition of E include similar groups to the substitutent explained for the definition “which may be substituted.” The position of substitutents existing on the heteroaryl group is not particularly limited, and when two or more substitutents exist, they may be the same or different.
When “a heteroaryl group which may be substituted” in the aforementioned definition of E is “a thiazolyl group which may be substituted,” “a thiazol-2-yl group which may be substituted.” “A mono-substituted thiazol-2-yl group” and “a di-substituted thiazol-2-yl group” are more preferred, and “a di-substituted thiazol-2-yl group” is further preferred.
When “a heteroaryl group which may be substituted” in the aforementioned definition of E is “a di-substituted thiazol-2-yl group,” a group selected from the following Substituent Group δ-8e is preferred, and 4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]thiazol-2-yl group is most preferred.
[Substituent Group δ-8e] 5-bromo-4-[(1,1-dimethyl)ethyl]thiazol-2-yl group, 5-bromo-4-(trifluoromethyl)thiazol-2-yl group, 5-cyano-4-[(1,1-dimethyl)ethyl]thiazol-2-yl group, 5-methylthiazol-2-yl group, 4,5-dimethylthiazol-2-yl group, 5-methyl-4-phenylthiazol-2-yl group, 5-(4-fluorophenyl)-4-methylthiazol-2-yl group, 4-methyl-5-[3-(trifluoromethyl)phenyl]thiazol-2-yl group, 4-[(1,1-dimethyl)ethyl]-5-ethylthiazol-2-yl group, 4-ethyl-5-phenylthiazol-2-yl group, 4-isopropyl-5-phenylthiazol-2-yl group, 4-butyl-5-phenylthiazol-2-yl group, 4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]thiazol-2-yl group, 4-[(1,1-dimethyl)ethyl]-5-(ethoxycarbonyl)thiazol-2-yl group, 4-[(1,1-dimethyl)ethyl]-5-piperidinothiazol-2-yl group, 4-[(1,1-dimethyl)ethyl]-5-morpholinothiazol-2-yl group, 4-[(1,1-dimethyl)ethyl]-5-(4-methylpiperazin-1-yl)thiazol-2-yl group, 4-[(1,1-dimethyl)ethyl]-5-(4-phenylpiperazin-1-yl)thiazol-2-yl group, 5-carboxymethyl-4-phenylthiazol-2-yl group, 4,5-diphenylthiazol-2-yl group, 4-benzyl-5-phenylthiazol-2-yl group, 5-phenyl-4-(trifluoromethyl)thiazol-2-yl group, 5-acetyl-4-phenylthiazol-2-yl group, 5-benzoyl-4-phenylthiazol-2-yl group, 5-ethoxycarbonyl-4-phenylthiazol-2-yl group, 5-ethoxycarbonyl-4-(pentafluorophenyl)thiazol-2-yl group, 5-methylcarbamoyl-4-phenylthiazol-2-yl group, 5-ethylcarbamoyl-4-phenylthiazol-2-yl group, 5-isopropylcarbamoyl-4-phenylthiazol-2-yl group, 5-(2-phenylethyl)carbamoyl-4-phenylthiazol-2-yl group, 5-ethoxycarbonyl-4-(trifluoromethyl)thiazol-2-yl group, 5-carboxy-4-[(1,1-dimethyl)ethyl]thiazol-2-yl group, 5-(ethoxycarbonyl)methyl-4-phenylthiazol-2-yl group, 5-carboxy-4-phenylthiazol-2-yl group, and 5-propylcarbamoyl-4-phenylthiazol-2-yl group.
When “a heteroaryl group which may be substituted” in the aforementioned definition of E is “a mono-substituted thiazol-2-yl group,” preferred examples of the group include groups represented by the following Substituent Group δ-9e.
[Substituent Group δ-9e] 4-[(1,1-dimethyl)ethyl]thiazol-2-yl group, 4-phenylthiazol-2-yl group, 4-[3,5-bis(trifluoromethyl)phenyl]thiazol-2-yl group, 4-(2,4-dichlorophenyl)thiazol-2-yl group, 4-(3,4-dichlorophenyl)thiazol-2-yl group, 4-[4-(trifluoromethyl)phenyl]thiazol-2-yl group, 4-(2,5-difluorophenyl)thiazol-2-yl group, 4-(4-methoxyphenyl)thiazol-2-yl group, 4-[3-(trifluoromethyl)phenyl]thiazol-2-yl group, and 4-(pentafluorophenyl)thiazol-2-yl group
The compounds represented by the aforementioned general formula (I-1) are explained in details.
Examples of the substitutent in the definition of “2-hydroxyphenyl group which may be substituted in the 5-position” and “2-acetoxyphenyl group which may be substituted in the 5-position” in the definition of Z1 include similar groups to the substitutent explained for the definition “which may be substituted.”
“2-Hydroxyphenyl group which is substituted in the 5-position” is preferred as the “2-hydroxyphenyl group which may be substituted in the 5-position” in the definition of Z1.
Preferred examples of the substitutent in the definition of “2-hydroxyphenyl group which may be substituted in the 5-position” and “2-hydroxyphenyl group which is substituted in the 5-position” in the definition of Z1 include a group selected from the following Substituent Group γ1-1z. A halogen atom and tert-butyl group are more preferred, and a halogen atom is most preferred.
[Substituent Group γ1-1z] a halogen atom, nitro group, cyano group, methoxy group, methyl group, isopropyl group, tert-butyl group, 1,1,3,3-tetramethylbutyl group, 2-phenylethen-1-yl group, 2,2-dicyanoethen-1-yl group, 2-cyano-2-(methoxycarbonyl)ethen-1-yl group, 2-carboxy-2-cyanoethen-1-yl group, ethynyl group, phenylethynyl group, (trimethylsilyl)ethynyl group, trifluoromethyl group, pentafluoroethyl group, phenyl group, 4-(trifluoromethyl)phenyl group, 4-fluorophenyl group, 2,4-difluorophenyl group, 2-phenethyl group, 1-hydroxyethyl group, 1-(methoxyimino)ethyl group, 1-[(benzyloxy)imino]ethyl group, 2-thienyl group, 3-thienyl group, 1-pyrrolyl group, 2-methylthiazol-4-yl group, imidazo[1,2-a]pyridin-2-yl group, 2-pyridyl group, acetyl group, isobutyryl group, piperidinocarbonyl group, 4-benzylpiperidinocarbonyl group, (pyrrol-1-yl)sulfonyl group, carboxy group, methoxycarbonyl group, N-[3,5-bis(trifluoromethyl)phenyl]carbamoyl group, N,N-dimethylcarbamoyl group, sulfamoyl group, N-[3,5-bis(trifluoromethyl)phenyl]sulfamoyl group, N,N-dimethylsulfamoyl group, amino group, N,N-dimethylamino group, acetylamino group, benzoylamino group, methanesulfonylamino group, benzenesulfonylamino group, 3-phenylureido group, (3-phenyl)thioureido group, (4-nitrophenyl)diazenyl group, and ([4-(pyridin-2-yl)sulfamoyl]phenyl)diazenyl group
“2-Acetoxyphenyl group which is substituted in the 5-position” is preferred as the “2-acetoxyphenyl group which may be substituted in the 5-position” in the definition of Z1.
A halogen atom is preferred as the substitutent in the definition of “2-acetoxyphenyl group which may be substituted in the 5-position” and “2-acetoxyphenyl group which is substituted in the 5-position” in the definition of Z1.
The definition “which may be substituted” in the definition of “a phenyl group which may be substituted” in the definition of E1 has the same meaning as “which may be substituted.”
Examples of the substitutent in the definition of “a phenyl group which may be substituted” in the definition of E1 include similar groups to the substitutents explained for the definition “which may be substituted.” A position of a substitutent existing on the phenyl group is not particularly limited, and when two or more substitutents exist, they may be the same or different.
Preferred examples of “a phenyl group which may be substituted” in the definition of E1 include 3,5-bis(trifluoromethyl)phenyl group, 2,5-bis(trifluoromethyl)phenyl group, a phenyl group which has three or more substitutents wherein at least one of said substitutents is trifluoromethyl group, and a di-substituted phenyl group wherein at least one of said substitutents is trifluoromethyl group, (provided that a 2,5-di-substituted phenyl group and a 3,5-di-substituted phenyl group are excluded as said di-substituted phenyl group.) 3,5-Bis(trifluoromethyl)phenyl group and 2,5-bis(trifluoromethyl)phenyl group are more preferred.
When “a phenyl group which may be substituted” in the definition of E1 is “a phenyl group which has three or more substitutents wherein at least one of said substitutents is trifluoromethyl group,” preferred examples of the group include groups represented by the following Substituent Group δ1-1e.
[Substituent Group δ1-1e] 3,5-bis(trifluoromethyl)-2-bromophenyl group, 3,5-bis(trifluoromethyl)-2-methylphenyl group, 2,6-dichloro-4-(trifluoromethyl)phenyl group, 2,4-dimethoxy-5-(trifluoromethyl)phenyl group, 2,4-difluoro-5-(trifluoromethyl)phenyl group, 4-chloro-2-(4-chlorobenzenesulfonyl)-5-(trifluoromethyl)phenyl group, 5-chloro-2-nitro-4-(trifluoromethyl)phenyl group, 2,3-difluoro-4-(trifluoromethyl)phenyl group, and 2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl group
When “a phenyl group which may be substituted” in the definition of E1 is “a di-substituted phenyl group wherein at least one of said substitutents is trifluoromethyl group, (provided that a 2,5-di-substituted phenyl group and a 3,5-di-substituted phenyl group are excluded from said di-substituted phenyl group)” preferred examples of the group include groups represented by the following Substituent Group δ1-2e.
[Substituent Group δ1-2e] 4-chloro-2-(trifluoromethyl)phenyl group, 2-fluoro-3-(trifluoromethyl)phenyl group, 4-fluoro-3-(trifluoromethyl)phenyl group, 4-chloro-3-(trifluoromethyl)phenyl group, 4-nitro-3-(trifluoromethyl)phenyl group, 4-cyano-3-(trifluoromethyl)phenyl group, 2-methyl-3-(trifluoromethyl)phenyl group, 4-methyl-3-(trifluoromethyl)phenyl group, 4-methoxy-3-(trifluoromethyl)phenyl group, 2-chloro-4-(trifluoromethyl)phenyl group, 4-isopropyl-2-(trifluoromethyl)phenyl group, 2-nitro-4-(trifluoromethyl)phenyl group, 4-bromo-3-(trifluoromethyl)phenyl group, 4-bromo-2-(trifluoromethyl)phenyl group, 2-bromo-4-(trifluoromethyl)phenyl group, 4-fluoro-2-(trifluoromethyl)phenyl group, 4-isopropoxy-2-(trifluoromethyl)phenyl group, 4-cyano-2-(trifluoromethyl)phenyl group, and 2,4-bis(trifluoromethyl)phenyl group
Compounds represented by the aforementioned general formula (I-2) are explained in details.
Examples of the substitutent in the definition of “2-hydroxyphenyl group which may be substituted in the 5-position” and “2-acetoxyphenyl group which may be substituted in the 5-position” in the definition of Z2 include similar groups to the substitutent explained for the definition “which may be substituted.”
“2-Hydroxyphenyl group which is substituted in the 5-position” is preferred as the “2-hydroxyphenyl group which may be substituted in the 5-position” in the definition of Z2.
A halogen atom, nitro group, methyl group, and methoxy group are preferred as the substitutent in the definition of “2-hydroxyphenyl group which may be substituted in the 5-position” and “2-hydroxyphenyl group which is substituted in the 5-position” in the definition of Z2, and a halogen atom is most preferred.
“2-Acetoxyphenyl group which is substituted in the 5-position” is preferred as the “2-acetoxyphenyl group which may be substituted in the 5-position” in the definition of Z2.
A halogen atom is preferred as the substitutent in the definition of “2-acetoxyphenyl group which may be substituted in the 5-position” and “2-acetoxyphenyl group which is substituted in the 5-position” in the definition of Z2.
Examples of the substitutent in the definition of “a 2,5-di-substituted phenyl group wherein one of said substitutents is trifluoromethyl group” and “a 3,5-di-substituted phenyl group wherein one of said substitutents is trifluoromethyl group” in the definition of E2 include similar groups to the substitutent explained for the definition “which may be substituted.”
A group selected from the following Substituent Group δ2-1e is preferred as “a 2,5-di-substituted phenyl group wherein one of said substitutents is trifluoromethyl group” in the definition of E2.
[Substituent Group δ2-1e] 2-chloro-5-(trifluoromethyl)phenyl group, 2,5-bis(trifluoromethyl)phenyl group, 2-fluoro-5-(trifluoromethyl)phenyl group, 2-nitro-5-(trifluoromethyl)phenyl group, 2-methyl-5-(trifluoromethyl)phenyl group, 2-methoxy-5-(trifluoromethyl)phenyl group, 2-methylsulfanyl-5-(trifluoromethyl)phenyl group, 2-(1-pyrrolidinyl)-5-(trifluoromethyl)phenyl group, 2-morpholino-5-(trifluoromethyl)phenyl group, 2-bromo-5-(trifluoromethyl)phenyl group, 2-(2-naphthyloxy)-5-(trifluoromethyl)phenyl group, 2-(2,4-dichlorophenoxy)-5-(trifluoromethyl)phenyl group, 2-[4-(trifluoromethyl)piperidin-1-yl]-5-(trifluoromethyl)phenyl group, 2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl group, 2-(2-methoxyphenoxy)-5-(trifluoromethyl)phenyl group, 2-(4-chloro-3,5-dimethylphenoxy)-5-(trifluoromethyl)phenyl group, 2-piperidino-5-(trifluoromethyl)phenyl group, 2-(4-methylphenoxy)-5-(trifluoromethyl)phenyl group, 2-(4-chlorophenoxy)-5-(trifluoromethyl)phenyl group, 2-(4-cyanophenoxy)-5-(trifluoromethyl)phenyl group, and 2-(4-methoxyphenoxy)-5-(trifluoromethyl)phenyl group
A group selected from the following Substituent Group δ2-2e is preferred as “a 3,5-di-substituted phenyl group wherein one of said substitutents is trifluoromethyl group” in the definition of E2.
[Substituent Group δ2-2e] 3,5-bis(trifluoromethyl)phenyl group, 3-fluoro-5-(trifluoromethyl)phenyl group, 3-bromo-5-(trifluoromethyl)phenyl group, 3-methoxy-5-(trifluoromethyl)phenyl group, 3-methoxycarbonyl-5-(trifluoromethyl)phenyl group, and 3-carboxy-5-(trifluoromethyl)phenyl group
Compounds represented by the aforementioned general formula (I-3) are explained in details.
Examples of the substitutent in the definition of “2-hydroxyphenyl group which may be substituted in the 5-position” and “2-acetoxyphenyl group which may be substituted in the 5-position” in the definition of Z3 include similar groups to the substitutent explained for the definition “which may be substituted.”
“2-Hydroxyphenyl group which is substituted in the 5-position” is preferred as the “2-hydroxyphenyl group which may be substituted in the 5-position” in the definition of Z3.
A halogen atom, nitro group, methyl group and methoxy group are preferred as the substitutent in the definition of “2-hydroxyphenyl group which may be substituted in the 5-position” and “2-hydroxyphenyl group which is substituted in the 5-position” in the definition of Z3, and a halogen atom is most preferred.
“2-Acetoxyphenyl group which is substituted in the 5-position” is preferred as the “2-acetoxyphenyl group which may be substituted in the 5-position” in the definition of Z3.
A halogen atom is preferred as the substitutent in the definition of “2-acetoxyphenyl group which may be substituted in the 5-position” and “2-acetoxyphenyl group which is substituted in the 5-position” in the definition of Z3.
Examples of the substitutent in the definition of “a hydrocarbon group which may be substituted” in the definition of R3e2 and R3e3 and “a C2 to C6 hydrocarbon group which may be substituted” in the definition of R3e5 include similar groups to the substitutent explained for the definition “which may be substituted.”
Examples of the “hydrocarbon group” in the definition of “a hydrocarbon group which may be substituted” in the definition of R3e2 and R3e3 and “a C2 to C6 hydrocarbon group which may be substituted” in the definition of R3e5 include similar groups to the “hydrocarbon group” in the aforementioned definition.
Examples of the “hydroxy group which may be substituted” in the definition of R3e2 and R3e3 include similar groups to the “hydroxy group which may be substituted” explained for the definition “which may be substituted.”
As E3, 3,5-bis[(1,1-dimethyl)ethyl]phenyl group, 2,5-bis[(1,1-dimethyl)ethyl]phenyl group, 5-[(1,1-dimethyl)ethyl]-2-methoxyphenyl group, 4-methoxybiphenyl-3-yl group, 5-[(1,1-dimethyl)propyl]-2-phenoxyphenyl group, 4-methylbiphenyl-3-yl group and 5-[(1,1-dimethyl)propyl]-2-hydroxyphenyl group are preferred, and 3,5-bis[(1,1-dimethyl)ethyl]phenyl group is more preferred.
Compounds represented by the aforementioned general formula (I-4) are explained in details.
Examples of the substitutent in the definition of “2-hydroxyphenyl group which may be substituted in the 5-position” and “2-acetoxyphenyl group which may be substituted in the 5-position” in the definition of Z4 include similar groups to the substitutent explained for the definition “which may be substituted.”
“2-Hydroxyphenyl group which is substituted in the 5-position” is preferred as the “2-hydroxyphenyl group which may be substituted in the 5-position” in the definition of Z4.
A halogen atom, phenyl group, 4-fluorophenyl group, 2,4-difluorophenyl group, 4-(trifluoromethyl)phenyl group, 1-pyrrolyl group and 2-thienyl group are preferred as the substitutent in the definition of “2-hydroxyphenyl group which may be substituted in the 5-position” and “2-hydroxyphenyl group which is substituted in the 5-position” in the definition of Z4, and a halogen atom is most preferred.
“2-Acetoxyphenyl group which is substituted in the 5-position” is preferred as the “2-acetoxyphenyl group which may be substituted in the 5-position” in the definition of Z4.
A halogen atom is preferred as the substitutent in the definition of “2-acetoxyphenyl group which may be substituted in the 5-position” and “2-acetoxyphenyl group which is substituted in the 5-position” in the definition of Z4.
Examples of the substitutent in the definition of “a hydrocarbon group which may be substituted” in the definition of R4e4, and “an acyl group which may be substituted” and “a heterocyclic group which may be substituted” in the definition of R4e5 include similar groups to the substitutent explained for the definition “which may be substituted.”
Examples of the “hydrocarbon group” in the definition of “a hydrocarbon group which may be substituted” in the definition of R4e4 include similar groups to the “hydrocarbon group” in the aforementioned definition.
Examples of the “acyl group” in the definition of “an acyl group which may be substituted” in the definition of R4e5 include similar groups to the “acyl group” in the aforementioned definition.
Examples of the “heterocyclic group” in the definition of “a heterocyclic group which may be substituted” in the definition of R4e5 include similar groups to the “heterocyclic group” in the aforementioned definition.
A group selected from the following Substituent Group δ4-1e is preferred as E4, and 4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]thiazol-2-yl group is most preferred.
[Substituent Group δ4-1e] 5-bromo-4-[(1,1-dimethyl)ethyl]thiazol-2-yl group, 5-bromo-4-(trifluoromethyl)thiazol-2-yl group, 5-cyano-4-[(1,1-dimethyl)ethyl]thiazol-2-yl group, 5-methylthiazol-2-yl group, 4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]thiazol-2-yl group, 4-[(1,1-dimethyl)ethyl]-5-(ethoxycarbonyl)thiazol-2-yl group, 4-[(1,1-dimethyl)ethyl]-5-piperidinothiazol-2-yl group, 4-[(1,1-dimethyl)ethyl]-5-morpholinothiazol-2-yl group, 4-[(1,1-dimethyl)ethyl]-5-(4-methylpiperazin-1-yl)thiazol-2-yl group, 4-[(1,1-dimethyl)ethyl]-5-(4-phenylpiperazin-1-yl)thiazol-2-yl group, 5-carboxymethyl-4-phenylthiazol-2-yl group, 5-acetyl-4-phenylthiazol-2-yl group, 5-benzoyl-4-phenylthiazol-2-yl group, 5-ethoxycarbonyl-4-phenylthiazol-2-yl group, 5-ethoxycarbonyl-4-(pentafluorophenyl)thiazol-2-yl group, 5-methylcarbamoyl-4-phenylthiazol-2-yl group, 5-ethylcarbamoyl-4-phenylthiazol-2-yl group, 5-isopropylcarbamoyl-4-phenylthiazol-2-yl group, 5-(2-phenylethyl)carbamoyl-4-phenylthiazol-2 yl group, 5-ethoxycarbonyl-4-(trifluoromethyl)thiazol-2-yl group, 5-carboxy-4-[(1,1-dimethyl)ethyl]thiazol-2-yl group, 5-carboxy-4-phenylthiazol-2-yl group, and 5-propylcarbamoyl-4-phenylthiazol-2-yl group.
Among the compound represented by the general formulas (I), (I-1), (I-2), (I-3) and (I-4), preferred compounds are those other than “substituted benzoic acid derivatives represented by the following general formula (X-1) and/or compounds represented by the following Compound Group φ-1.”




wherein R1001 represents the following general formula (X-2):





or the following general formula (X-3):





wherein each of R1003, R1004 and R1005 independently represents hydrogen atom, an alkyl group having from 1 to 6 carbons or an alkoxy group having from 1 to 6 carbons, each of R1009 and R1010 independently represents hydrogen atom, an alkyl group having from 1 to 6 carbons, or an acyl group having from 2 to 11 carbons;

    R1002 represents hydrogen atom, a lower alkyl group having from 1 to 6 carbons, which may be substituted, an aryl group having from 6 to 12 carbons, which may be substituted, a heteroaryl group having from 4 to 11 carbons, which may be substituted, an aralkyl group having from 7 to 14 carbons, which may be substituted, a heteroarylalkyl group having from 5 to 13 carbons, which may be substituted, or an acyl group having from 2 to 11 carbons;
    X1001 represents carboxy group which may be esterified or amidated.

[Compound Group φ-1]







Each compound defined by the aforementioned general formulas (I-1), (I-2), (I-3), and (I-4), or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof is novel. Uses of the compound according to the aforementioned chemical substance invention are not particularly limited.
The compounds represented by the aforementioned general formulas (I), (I-1), (I-2), (I-3) and (I-4) may form salts. Examples of pharmacologically acceptable salts include, when acidic groups exist, metal salts such as lithium salt, sodium salt, potassium salt, magnesium salt, calcium salts, or ammonium salts such as ammonium salt, methylammonium salt, dimethylammonium salt, trimethylammonium salt, dicyclohexylammonium salt, and when basic groups exist, mineral acid salts such as hydrochloride, oxalate, hydrosulfate, nitrate, phosphate, or organic acid salts such as methane sulfonate, benzene sulfonate, para-toluene sulfonate, acetate, propionate, tartrate, fumarate, maleate, malate, oxalate, succinate, citrate, benzoate, mandelate, cinnamate, lactate. Salts may sometimes be formed with amino acids such as glycine. As active ingredients of the medicament of the present invention, pharmacologically acceptable salts may also be suitably used.
The compounds or salts thereof represented by the aforementioned general formulas (I), (I-1), (I-2), (I-3) and (I-4) may exist as hydrates or solvates. As active ingredients of the medicament of the present invention, any of the aforementioned substances may be used. Furthermore, the compounds represented by the aforementioned general formulas (I), (I-1), (I-2), (I-3) and (I-4) may sometimes have one or more asymmetric carbons, and may exist as steric isomers such as optically active substance and diastereomer. As active ingredients of the medicament of the present invention, pure forms of stereoisomers, arbitrary mixture of enantiomers or diastereomers, and racemates may be used.
Furthermore, when the compounds represented by the general formulas (I), (I-1), (I-2), (I-3) and (I-4) has, for example, 2-hydroxypyridine form, the compounds may exist as 2-pyridone form which is a tautomer. As active ingredients of the medicament of the present invention, pure forms of tautomers or a mixture thereof may be used. When the compounds represented by the general formulas (I), (I-1), (I-2), (I-3) and (I-4) have olefinic double bonds, the configuration may be in either E or Z, and as active ingredients of the medicament of the present invention, geometrical isomer in either of the configurations or a mixture thereof may be used.
Examples of the compounds included in the general formulas (I), (I-1), (I-2), (I-3) and (I-4) as active ingredients of the medicaments of the present invention are shown below. However, the active ingredients of the medicaments of the present invention are not limited to the compound set out below.
The abbreviations used in the following tables have the following meanings.
Me: methyl group, Et: ethyl group.


















 










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Methods for preparation of the compounds represented by the general formulas (I), (I-1), (I-2), (I-3) and (I-4) are not particularly limited. Reference to methods described in the pamphlet of International Publication WO02/49632 is useful.
The compounds represented by the general formulas (I), (I-1), (I-2), (I-3) and (I-4) can be prepared, for example, by methods shown bellow.
<Method 1>
The compounds represented by the general formula (I), wherein X is —CONH— (the hydrogen atom on the nitrogen may be substituted) and the compounds represented by the general formulas (I-1), (I-2), (I-3) and (I-4) can be prepared, for example, by a method described in the reaction scheme 1.




wherein each of A, ring Z, and E has the same meaning as that defined in the general formula (I), A101 represents a hydrogen atom or protecting groups of hydroxy group (preferably, an alkyl group such as methyl group and the like; an aralkyl group such as benzyl group and the like; an acetyl group, an alkoxyalkyl group such as methoxymethyl group and the like; a substituted silyl group such as trimethylsilyl group or the like), each of R and R101 represents a hydrogen atom, a C1 to C6 alkyl group or the like, E101 represents E or precursor of E in the definition of the general formula (I), G represents a hydroxy group, halogen atoms (preferably, a chlorine atom), a hydrocarbon-oxy group (preferably, an aryl-oxy group which may be substituted by halogen atom), an acyl-oxy group, an imido-oxy group or the like.

(First Step)

The amide (3) can be prepared by dehydrocondensation of the carboxylic acid derivative (1) and the amine (2). This reaction is carried out at a reaction temperature of from 0° C. to 180° C., without solvent or in an aprotic solvent, in the presence of an acid halogenating agent or a dehydrocondensing agent, and in the presence or absence of a base.
As the halogenating agent, examples include, for example, thionyl chloride, thionyl bromide, sulfuryl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride or the like. When A101 is hydrogen atom, phosphorus trichloride is preferable, and when A101 is acetyl group or the like, phosphorus oxychloride is preferable. As the dehydrocondensing agent, examples include, for example, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, diphenylphosphorylazide or the like. As the base, examples include inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate or the like, or organic bases such as pyridine, triethylamine, N,N′-diethylaniline or the like. As the aprotic solvent, examples include dichloromethane, dichloroethane, chloroform, tetrahydrofuran, 1,4-dioxane, benzene, toluene, monochlorobenzene, o-dichlorobenzene, N,N′-dimethylformamide, N-methylpyrrolidone or the like, when the reaction is carried out in the presence of the acid halogenating agent, particularly, toluene, monochlorobenzene, o-dichlorobenzene are preferable.
A target compound can also be prepared, for example, by a method or similar method described in Journal of Medicinal Chemistry, (USA), 1998, Vol. 41, No. 16, p. 2939-2945, in which the acid chloride is prepared and isolated beforehand from carboxylic acid, then the result is made to react with an amine having E101.
When G is hydroxy group, the reaction condition described in Archiv der Pharmazie, (Germany), 1998, Vol. 331, No. 1, p. 3-6 can be used as a preferred reaction condition.
Kinds of carboxylic acid derivative (1) and amine (2) are not particularly limited, and new compounds synthesized by referring to well-known preparation method described in the literature or commercially available reagents can be used for the aforementioned reaction.
(Second Step)
When the amide (3) has a protecting group and/or has a favorable substitutent for functional group modification, for example, an amino group and a protected amino group or its precursor; a carboxy group and a protected carboxy group or its precursor; a hydroxy group and a protected hydroxy group or its precursor, the final target compound (4) can be prepared by a reaction for deprotection and/or functional group modification in this step. Various well-known methods can be used for the reaction. For the reaction of deprotection and functional group modification, for example, methods described in “Protective Groups in Organic Syntheses”, (USA), Theodra W. Green, Peter G. M. Wuts, Eds., Third edition, April in 1999, John Wiley & Sons, and “Handbook of Reagents for Organic Synthesis”, (USA), 4 Volumes, June in 1999, John Wiley & Sons can be used, and for the reaction of functional group modification, for example, methods described in “Palladium Reagents in Organic Syntheses”, (USA), Richard F. Heck, 1985, Academic Press, and “Palladium Reagents and Catalysts: Innovations in Organic Synthesis”, (USA), J. Tsuji, 1999, John Wiley & Sons, or the like can be used.
The aforementioned methods are applicable by appropriately combining raw materials even for the compounds wherein X is other connecting group, for example, —SO2NH—, —NHCO—, —NHSO2—, —CONHCH2—, —CONHCH2CH2—, —CONHCH2CONH—, —CONHNHCO—, —CONHNHCH2—, —COO—, —CONHNH—; wherein the hydrogen atom on said connecting group may be substituted.
In the general formula (I), when X is the formula: —CONHCH2— wherein the hydrogen atom on said connecting group may be substituted, the target compound can be prepared by using an amine represented by the formula: H2N—CH2-E101, wherein E101 has the same meaning as that defined above, instead of the amine (2).
In the general formula (I), when X is the formula: —CONHCH2CH2— wherein the hydrogen atom on said connecting group may be substituted, the target compound can be prepared by using an amine represented by the formula: H2N—CH2CH2-E101, wherein E101 has the same meaning as that defined above, instead of the amine (2).
In the general formula (I), when X is the formula: —SO2NH—, the target compound can be prepared by using a sulfonyl chloride represented by the formula: A101-O-(ring Z)-SO2Cl, wherein each of A101 and ring Z has the same meaning as that defined above, instead of the carboxylic acid derivative (1).
In the general formula (I), when X is the formula: —NHCO—, the target compound can be prepared by using an amine represented by the formula: A101-O-(ring Z)-NH2, wherein each of A101 and ring Z has the same meaning as that defined above, and a carboxylic acid represented by the formula: E101-O—COOH, wherein -E101 has the same meaning as that defined above, or a carboxylic acid chloride represented by the formula: E101-COCl, wherein -E101 has the same meaning as that defined above.
In the general formula (I), when X is the formula: —NHSO2—, wherein said connecting group may be substituted, the target compound can be prepared by using an amine represented by the formula: HO-(ring Z)-NH2, wherein ring Z has the same meaning as that defined above, and a sulfonyl chloride represented by the formula: E101SO2Cl, wherein E101 has the same meaning as that defined above.
In the general formula (I), when X is the formula: —CONHNHCO—, the target compound can be prepared by using a hydrazide represented by the formula: HO-(ring Z)-CONHNH2, wherein ring Z has the same meaning as that defined above, and a carboxylic acid chloride represented by the formula: E101-COCl, wherein -E101 has the same meaning as that defined above.
In the general formula (I), when X is the formula: —COO—, the target compound can be prepared by using a phenol derivative represented by the formula: HO-E101, wherein -E101 has the same meaning as that defined above, instead of the amine (2).
In the general formula (I), when X is the formula: —CONHNH—, the target compound can be prepared by using a hydrazine represented by the formula: H2N—NH-E101, wherein E101 has the same meaning as that defined above, instead of the amine (2).
In the general formula (I), when X is the formula: —CONHCH2CONH—, the target compound can be prepared by using an amine represented by the formula: H2N—CH2CONH-E101, wherein E101 has the same meaning as that defined above, instead of the amine (2).
The amine represented by the formula: H2N—CH2CONH-E101, can be prepared, for example, by condensation of the amine (2) and a N-protected amino acid (for example, N-(tert-butoxycarbonyl)glycine), according to the aforementioned method 1, followed by a deprotection reaction.
In the general formula (I), when X is the following formula:




wherein said connecting group may be substituted, the target compound can be prepared by using an amine represented by the following formula:





wherein ring Z has the same meaning as that defined above, and a carboxylic acid represented by the formula: E101-COOH, wherein E101 has the same meaning as that defined above, or a carboxylic acid chloride represented by the formula: E101-COCl, wherein E101 has the same meaning as that defined above.

The amine represented by the following formula:




can be prepared, for example, by a method described in the reaction scheme 1-2.





wherein ring Z has the same meaning as that defined above.

The bromoacetophenone (20) can be prepared by bromination of the acetophenone (19).
This reaction is carried out at a reaction temperature of from 0° C. to 100° C. in a solvent, in the presence of a brominating agent.
As the brominating agent, for example, phenyltrimethylammonium tribromide can preferably be used.
As the reaction solvent, any solvent can be used as long as it does not inhibit the reaction, for example, ethers such as tetrahydrofuran can be used.
The amine (21) can be prepared by reacting the bromoacetophenone (20) with thiourea.
This reaction is carried out at a reaction temperature of from 0° C. to 120° C. in a solvent.
As the reaction solvent, any solvent can be used as long as it does not inhibit the reaction, for example, alcohols such as ethanol can be used.
<Method 2>
The compounds represented by the general formula (I), wherein X is —CH2NH— can be prepared, for example, by a method described in the reaction scheme 2.




wherein each of A, ring Z, and E has the same meaning as that defined in the general formula (I).

The imine derivative of the formula (7) can be prepared by dehydrocondensation of the aldehyde (5) and the amine (6). This reaction is carried out at a reaction temperature of from 0° C. to 100° C. in a solvent, in the presence or absence of a dehydrating agent. As the dehydrating agent, examples include anhydrous magnesium sulfate, molecular sieves or the like. As the solvent, examples include inert solvent, and tetrahydrofuran, 1,4-dioxane, methanol, ethanol or the like are preferable.
The aforementioned methods are applicable by appropriately combining raw materials even for the compounds wherein X is other connecting group, for example, —CONHN═CH—, —CH═NNHCO—, —CHNNH—; wherein the hydrogen atom on said connecting group may be substituted.
In the general formula (I), when X is the formula: —CONHN═CH—, the target compound can be prepared by using a hydrazide represented by the formula: HO-(ring Z)-CONHNH2, wherein ring Z has the same meaning as that defined above, and an aldehyde represented by the formula: E-CHO, wherein E has the same meaning as that defined above.
In the general formula (I), when X is the formula: —CH═NNHCO—, the target compound can be prepared by using an aldehyde represented by the formula: HO-(ring Z)-CHO, wherein ring Z has the same meaning as that defined above, and a hydrazide represented by the formula: E-CONHNH2, wherein E has the same meaning as that defined above.
In the general formula (I), when X is the formula: —CH═NNH—, the target compound can be prepared by using an aldehyde represented by the formula: HO-(ring Z)-CHO, wherein ring Z has the same meaning as that defined above, and a hydrazine represented by the formula: E-NHNH2, wherein E has the same meaning as that defined above.
The target compound (8) can be prepared by reduction of the imine derivative (7). This reaction is carried out at a reaction temperature of from 0° C. to 100° C. in a solvent, in the presence of a reducing agent. As the reducing agent, examples include sodium borohydride, lithium borohydride or the like. As the solvent, examples include inert solvent, and tetrahydrofuran, 1,4-dioxane, methanol, ethanol or the like are preferable. This reaction can also be carried out by a method of catalytic hydrogenation. As the catalyst, examples include palladium carbon, platinum carbon, palladium hydroxide, palladium black or the like. As solvent, examples include inert solvent, and tetrahydrofuran, 1,4-dioxane, methanol, ethanol or the like are preferable. The reaction is carried out at a reaction temperature of from 0° C. to 200° C., and the hydrogen pressure may be an ordinary pressure or a positive pressure.
<Method 3>
The compounds represented by the general formula (I), wherein X is —CH═CH— (the hydrogen atom on said connecting group may be substituted), can be prepared, for example, by methods described in the reaction scheme 3-1 or the reaction scheme 3-2.




wherein each of ring Z and E has the same meaning as that defined in the general formula (I), W301 represents O,O′-di-hydrocarbon-phosphono group or triarylphosphonium group

The target compound (11) can be prepared by dehydrocondensation of the aldehyde (9-1) and the phosphorus compound (10-1). This reaction is carried out in a solvent at a reaction temperature of from 0° C. to the boiling point of the solvent, in the presence of a base. As the base, examples include inorganic base such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate or the like, or organic base such as pyridine, triethylamine, N,N-diethylaniline or the like. As the solvent, examples include inert solvent, and tetrahydrofuran, 1,4-dioxane, methanol, ethanol, water or the like are preferable.




wherein each of ring Z and E has the same meaning as that defined in the general formula (I), W302 represents halogen atoms (preferably, iodine atom and bromine atom), (trifluoromethanesulfonyl)oxy group and the like.

The target compound (11) can be prepared by reacting the halogenated compound (9-2) with the styrene compound (10-2) in the presence of a transition-metal complex catalyst. This reaction is carried out in a solvent at a reaction temperature of from 0° C. to the boiling point of the solvent, in the presence or absence of a ligand and/or a base. As the transition-metal complex catalyst, examples include palladium catalyst such as palladium acetate and dichlorobis(triphenylphosphine)palladium. As the ligand, examples include phosphine ligand such as triphenylphosphine. As the base, examples include inorganic base such as sodium carbonate, potassium carbonate, and sodium hydrogen carbonate, or organic base such as pyridine, triethylamine, and N,N-diethylaniline. As the solvent, examples include inert solvents, and N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane or the like are preferable.
<Method 4>
The compounds represented by the general formula (I), wherein X is —COCH═CH— and —COCH2CH2— (the hydrogen atom on said connecting group may be substituted), can be prepared, for example, by a method described in the reaction scheme 4.




wherein each of rings Z and E has the same meaning as that defined in the general formula (I).

The target compound enone (14) can be prepared by dehydrocondensation of the ketone (12) and the aldehyde (13). This reaction is carried out in a solvent at a reaction temperature of from 0° C. to the boiling point of the solvent, in the presence of a base. As the base, examples include inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate or the like, or organic base such as pyridine, triethylamine, N,N-diethylaniline or the like. Examples include inert solvent, and tetrahydrofuran, 1,4-dioxane, methanol, ethanol, water or the like are preferable.
Next, the target compound (15) can be prepared by reduction of the enone (14). This reaction is carried out at a reaction temperature of from 0° C. to 100° C. in solvent, in the presence of a reducing agent. As the reducing agent, examples include sodium borohydride, lithium borohydride or the like. As the solvent, examples include inert solvent, and tetrahydrofuran, 1,4-dioxane, methanol, ethanol or the like are preferable. Moreover, this reaction is carried out by a method of catalytic hydrogenation also. As the catalyst, examples include palladium carbon, platinum carbon, palladium hydroxide, palladium black or the like. As solvent, examples include inert solvent, and tetrahydrofuran, 1,4-dioxane, methanol, ethanol or the like are preferable. The reaction is carried out at a reaction temperature of from 0° C. to 200° C., and the hydrogen pressure is at normal pressure or applied pressure.
<Method 5>
The compounds represented by the general formula (I), wherein X is —NHCONH— (the hydrogen atom on said connecting group may be substituted), can be prepared, for example, by a method described in the reaction scheme 5.




wherein each of ring Z and E has the same meaning as that defined in the general formula (I).

First, the target compound urea (18) can be prepared by reacting the amine (16) with the isocyanate (17). This reaction is carried out in a solvent at a reaction temperature of from 0° C. to the boiling point of the solvent, in the presence or absence of a base. As the base, examples include inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate or the like, or organic base such as pyridine, triethylamine, N,N-diethylaniline or the like. Examples include inert solvent, and tetrahydrofuran, 1,4-dioxane, methanol, ethanol, water or the like are preferable.
<Method 6>
The compounds represented by the general formula (I), wherein X is the formula: —CONHNHCH2— (the hydrogen atom on said connecting group may be substituted), can be prepared, for example, by a method described in the reaction scheme 6.




wherein each of ring Z and E has the same meaning as that defined above, and V represents a leaving group such as halogen atom.

The target compound hydrazide (24) can be prepared by reacting the hydrazide (22) with the benzyl derivative (23).
This reaction is carried out at a reaction temperature of from 0° C. to 180° C. in a solvent, in the presence or absence of a base.
As the base, for example, organic base such as pyridine, triethylamine or the like can preferably be used.
As the reaction solvent, any solvent can be used as long as it does not inhibit the reaction, for example, halogenated solvent such as dichloromethane; ethers such as tetrahydrofuran; and hydrocarbon solvent such as toluene can be used.
<Method 7>
The compounds represented by the general formula (I), wherein X is the formula:




can be prepared, for example, by a method described in the reaction scheme 7.





wherein each of ring Z and E has the same meaning as that defined above.

The target compound 5-(benzylidene)-3-benzylthiazolidin-2,4-dione derivative (26) can be prepared by reacting the aldehyde (9-1) with the 3-benzylthiazolidin-2,4-dione derivative (25).
This reaction is carried out at a reaction temperature of from 0° C. to 180° C. in a solvent, in the presence of a catalyst. As the catalyst, for example, a mixture of piperidine/acetic acid can preferably be used. As the reaction solvent, any solvent can be used as long as it does not inhibit the reaction, for example, hydrocarbon solvent such as toluene can be used.
The 3-benzylthiazolidine-2,4-dione derivative represented by the following formula:




wherein E has the same meaning as that defined above, can be prepared, for example, by a method described in the reaction scheme 7-1.





wherein each of E and V has the same meaning as that defined above.

The target compound 3-benzylthiazolidine-2,4-dione derivative (28) can be prepared by reacting thiazolidine-2,4-dione (30) with the benzyl derivative (23).
This reaction is carried out at a reaction temperature of from 0° C. to 180° C. in a solvent, in the presence of a base. As the base, for example, inorganic base such as sodium hydroxide, potassium carbonate or the like, or organic base such as pyridine, triethylamine or the like can preferably be used.
As the reaction solvent, any solvent can be used as long as it does not inhibit the reaction, for example, water; alcohols such as ethanol or the like; halogenated solvent such as dichloromethane or the like; ethers such as tetrahydrofuran or the like; or amides such as N,N-dimethylformamide or the like can be used.
The compounds represented by the general formulas (I), (I-1), (I-2), (I-3) and (I-4) prepared by the aforementioned methods can be isolated and purified by methods widely known by those skilled in the art, for example, extraction, precipitation, fractional chromatography, fractional crystallization, suspension and washing, and recrystallization. Furthermore, each of the pharmaceutically acceptable salt of the compound of the present invention, the hydrate thereof and the solvate thereof can be prepared by methods widely known by those skilled in the art.
In the examples of the specification, preparation methods of typical compounds included in the general formulas (I), (I-1), (I-2), (I-3) and (I-4) are explained in details. Therefore, those skilled in the art can prepare any compound fall within the general formulas (I), (I-1), (I-2), (I-3) and (I-4) by referring to the explanations of the aforementioned general preparation methods and those of specific preparation methods of the examples, by choosing appropriate reaction raw materials, reaction reagents, and reaction conditions, and by adding appropriate modification and alteration of these methods, if necessary.
The compounds represented by the general formulas (I), (I-1), (I-2), (I-3), and (I-4) have antiallergic action, and accordingly, they are useful as active ingredients of the medicaments for the preventive and/or therapeutic treatment of allergic diseases. The aforementioned medicaments have inhibitory activity against the proliferation of mast cells, inhibitory activity against the production of IgE from activated B cells, and inhibitory activity against the degranulation from activated mast cells. Therefore, they can be suitably used as a suppressant against allergic reaction expression. More specifically, the medicaments of the present invention are useful for the preventive and/or therapeutic treatment of the following diseases wherein allergic reaction is believed to be involved, for example, allergic diseases such as contact dermatitis, atopic dermatitis, eczema, pruritus, pollinosis, asthma, bronchitis, urticaria, vasculitis, rhinitis, gastrointestinal symptoms, diarrhea, interstitial pneumonia, arthritis, ophthalmia, conjunctivitis, neuritis, otitis media, granulomatosis, encephalomyelitis, cystitis, laryngitis, peliosis, food allergy, insect allergy, drug allergy, metal allergy, anaphylactic shock and the like, and/or endometriosis and/or hysteromyoma.
Furthermore, in endometriosis, it is known that an adhesion of the uterus with its peripheral tissue frequently occurs due to an abnormal proliferation of endometrial tissue outside the uterus. It is known that this is caused by an inflammatory reaction by allergy and the like, and a phenomenon called as “remodeling” including fibrosis and hyperplasia of tissue as typical examples occurs (Frontiers in Bioscience, (USA), 2002, Vol. 7, the April 1 issue, p. e91-115). As for the fibrosis of tissue, it is widely known that one of the causes is a production of a large amount of collagen, which is triggered by infiltration of effecter cells and activation of proliferation of fibroblast by inflammation. This remodeling phenomenon is considered to be occurred on the basis of a mechanism common in the remodeling of cardiac muscle after myocardial infarction, the remodeling of a vessel by arteriosclerosis, the remodeling of bronchus by bronchial asthma or the like, as well as in the adhesion of a tissue in endometriosis. Accordingly, an inhibitor against the proliferation or activation of a fibroblast is considered to be useful as a therapeutic drug not only for endometriosis but for diseases in which fibrosis or remodeling of a tissue is believed to be involved, for example, myocardial infarction, arteriosclerosis, asthma, nephritis, interstitial pneumonia, pulmonary fibrosis, hepatic cirrhosis and the like.
The compounds of the present invention was found to inhibit cell proliferation of HT-1080, which is a fibrosarcoma cell having properties similar to those of fibroblast and collagen productivity, under proliferative stimulation by PDGF (platelet-derived growth factor). Therefore, they are considered to be useful as a therapeutic drug and/or a preventive drug for diseases in which fibrosis or remodeling of tissue is involved.
As the active ingredient of the medicament on the present invention, one or more kinds of substances selected from the group consisting of the compound represented by the general formulas (I), (I-1), (I-2), (I-3) and (I-4) and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof may be used. The aforementioned substance, per se, may be administered as the medicament of the present invention, however, preferably, the medicament of the present invention is provided in the form of a pharmaceutical composition comprising the aforementioned substance which is an active ingredient together with one or more pharmacologically acceptable pharmaceutical additives. In the aforementioned pharmaceutical compositions, a ratio of the active ingredient to the pharmaceutical additives is 1 weight % to 90 weight %.
The pharmaceutical compositions of the present invention may be administered as pharmaceutical compositions for oral administration, for example, granules, subtilized granules, powders, hard capsules, soft capsules, syrup, emulsion, suspension, or solution, or may be administered as pharmaceutical compositions for parenteral administration, for example, injections for intravenous administration, intramuscular administration, or subcutaneous administration, drip infusions, suppositories, percutaneous absorbent, transmucosal absorption preparations, nasal drops, ear drops, instillation, and inhalants. Preparations made as pharmaceutical compositions in a form of powder may be dissolved when necessary and used as injections or drip infusions.
For preparation of pharmaceutical compositions, solid or liquid pharmaceutical additives may be used. Pharmaceutical additives may either be organic or inorganic. When an oral solid preparation is prepared, an excipient is added to the active ingredient, and further binders, disintegrator, lubricant, colorant, corrigent are added, if necessary, to manufacture preparations in the forms of tablets, coating tablets, granules, powders, capsules and the like by ordinary procedures. Examples of the excipient include lactose, sucrose, saccharose, glucose, corn starch, starch, talc, sorbit, crystal cellulose, dextrin, kaolin, calcium carbonate, and silicon dioxide. Examples of the binder include, for example, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum Arabic, tragacanth, gelatine, shellac, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, calcium citrate, dextrin, and pectin. Examples of the lubricant include, for example, magnesium stearate, talc, polyethylene glycol, silica, and hydrogenated vegetable oil. As the coloring agent, any material can be used which are approved to be added to ordinary pharmaceuticals. As the corrigent, cocoa powder, menthol, aromatic acid, peppermint oil, d-borneol, cinnamon powder and the like can be used. These tables and granules may be applied with sugarcoating, gelatin coating, or an appropriate coating, if necessary. Preservatives, antioxidant and the like may be added, if required.
For liquid preparations for oral administration such as emulsions, syrups, suspensions, and solutions, ordinary used inactive diluents, for example, water or vegetable oil may be used. For these preparations, besides inactive diluents, adjuvants such as wetting agents, suspending aids, sweating agents, flavoring agents, coloring agents or preservatives may be blended. After a liquid preparation is manufactured, the preparation may be filled in capsules made of a absorbable substance such as gelatin. Examples of solvents or suspending agents used for the preparations of parenteral administration such as injections or suppositories include, for example, water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, and lecithin. Examples of base materials used for preparation of suppositories include, for example, cacao butter, emulsified cacao butter, lauric fat, and witepsol. Methods for preparation of the aforementioned preparations are not limited, and any method ordinarily used in the art may be used.
When the composition are prepared in the form of injections, carriers such as, for example, diluents including water, ethanol, macrogol, propylene glycol, citric acid, acetic acid, phosphoric acid, lactic acid, sodium lactate, sulfuric acid and sodium hydroxide, pH modifiers and buffer solutions including sodium citrate, sodium acetate and sodium phosphate, stabilizers such as sodium pyrosulfite, ethylenediaminetetraacetic acid, thioglycolic acid and thiolactate may be used. For the preparation, a sufficient amount of a salt, glucose, mannitol or glycerin may be blended in the preparation to manufacture an isotonic solution, and an ordinary solubilizer, a soothing agent, or a topical anesthetic may be used.
When the preparation in the form of an ointment such as a paste, a cream, and a gel is manufactured, an ordinarily used base material, a stabilizer, a wetting agent, and a preservative may be blended, if necessary, and may be prepared by mixing the components by a common method. As the base material, for example, white petrolatum, polyethylene, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicon, and bentonite may be used. As the preservative, paraoxy methyl benzoate, paraoxy ethyl benzoate, paraoxy propyl benzoate and the like may be used. When the preparation in the form of a patch is manufactured, the aforementioned ointment, cream gel, or paste and the like may be applied by a common method to an ordinary support. As the support, fabric made of cotton, span rayon, and synthetic fibersor or nonwoven fabric, and a film or a foam sheet such as made of soft vinyl chloride, polyethylene, and polyurethane and the like may be preferably used.
A dose of the medicament of the present invention is not particularly limited. For oral administration, a dose may generally be 0.01 to 5,000 mg per day for an adult as the weight of the compound of the present invention. It is preferred to increase or decrease the above dose appropriately depending on the age, pathological conditions, and symptoms of a patient. The above dose may be administered once a day or 2 to 3 times a day as divided portions with appropriate intervals, or intermittent administration for every several days may be applied. When the medicament is used as an injection, the dose may be 0.001 to 100 mg per day for an adult as the weight of the compound of the present invention.
EXAMPLES
The present invention will be explained more specifically with reference to the following examples. However the scope of the present invention is not limited to the following examples. The compound number in the following examples correspond to those in the table shown above. And the commercially available compounds, which were purchased and used for the examinations, are contained in these examples. As for such compounds, the suppliers of the reagents and the catalog code numbers are shown.
Example 1
Preparation of the Compound of Compound No. 1
Under argon atmosphere, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (it is abbreviated as WSC.HCl hereafter; 192 mg, 1 mmol) was added to a mixture of 5-bromosalicylic acid (217 mg, 1 mmol), 3,5-bis(trifluoromethyl)benzylamine (243 mg, 1 mmol), 4-dimethylaminopyridine (12 mg, 0.1 mmol) and tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give the title compound (244.8 mg, 55.4%) as a white solid.
1H-NMR(DMSO-d6): δ 4.69(2H, d, J=5.7 Hz), 6.93(1H, d, J=8.7 Hz), 7.56(1H, dd, J=8.7, 2.4 Hz), 8.02(1H, d, J=2.4 Hz), 8.06(3H, s), 9.41(1H, t, J=5.7 Hz), 12.13(1H, s).
Example 2
Preparation of the Compound of Compound No. 2
(1) 2-Acetoxy-N-(2-phenethyl)benzamide
O-Acetylsalicyloyl chloride (0.20 g, 1.00 mmol) was dissolved in benzene (8 mL). Phenethylamine (0.12 g, 1.00 mmol) and pyridine (0.3 mL) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=2:1→1:1) to give the title compound (155.5 mg, 54.9%) as a white crystal.
1H-NMR(CDCl3): δ 2.09(3H, s), 2.92(2H, t, J=6.8 Hz), 3.71(2H, q, J=6.8 Hz), 6.32(1H, brs), 7.07(1H, dd, J=8.4, 1.2 Hz), 7.23-7.35(6H, m), 7.44(1H, ddd, J=8.0, 7.6, 1.6 Hz), 7.73(1H, dd, J=7.6, 1.6 Hz).
When the preparation method described in Example 2(1) is referred in the following examples, organic bases such as pyridine, triethylamine or the like were used as the base. As the reaction solvent, solvents such as dichloromethane, tetrahydrofuran, benzene or the like were used alone or as a mixture.
(2) 2-Hydroxy-N-(2-phenethyl)benzamide
Methanol (5 mL) and 2N sodium hydroxide (0.1 mL) were added to 2-acetoxy-N-(2-phenethyl)benzamide (155.5 mg), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was crystallized (dichloromethane/hexane) to give the title compound (106.9 mg, 80.7%) as a white solid.
1H-NMR(DMSO-d6): δ 2.86(2H, t, J=7.6 Hz), 3.52(1H, q, J=7.6 Hz), 6.84-6.88(2H, m), 7.18-7.31(5H, m), 7.37(1H, ddd, J=8.4, 7.2, 1.6 Hz), 7.80(1H, dd, J=8.4, 1.6 Hz), 8.84(1H, s), 12.51(1H, s).
When the method described in Example 2(2) is referred in the following examples, inorganic bases such as sodium hydroxide, potassium carbonate or the like were used as the base. As the reaction solvent, solvents such as water, methanol, ethanol, tetrahydrofuran or the like were used alone or as a mixture.
(3) 5-Bromo-2-hydroxy-N-(2-phenethyl)benzamide (Compound No. 2)
Carbon tetrachloride (5 mL), iron powder (0.03 g) and bromine (25 μl, 0.48 mmol) were added to 2-hydroxy-N-(2-phenethyl)benzamide (79.6 mg, 0.33 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into aqueous sodium hydrogen sulfite and extracted with ethyl acetate. After the organic layer was washed with brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=5:1) to give the title compound (62 mg, 58.7%) as a white powder.
1H-NMR(DMSO-d6): δ 2.85(2H, t, J=7.6 Hz), 3.52(1H, q, J=7.6 Hz), 6.87(1H, d, J=8.8 Hz), 7.18-7.31(5H, m), 7.52(1H, dd, J=8.8, 2.4 Hz), 8.01(1H, d, J=2.4 Hz), 8.90(1H, s), 12.51(1H, s).
Example 3
Preparation of the Compound of Compound No. 3
WSC.HCl (96 mg, 0.5 mmol) was added to a solution of 5-bromosalicylic acid (109 mg, 0.5 mmol), 2-amino-5-(morpholino)carbonylindane (141 mg, 0.5 mmol) and triethylamine (70 μL, 0.5 mmol) in dichloromethane (5 mL), and the mixture was stirred at 40° C. for 1.5 hours. After cooling the reaction mixture was diluted with ethyl acetate, washed successively with 2N hydrochloric acid, water, and brine, dried over anhydrous magnesium sulfate, concentrated, and the residue was purified by column chromatography on silica gel (dichloromethane:methanol=19:1) to give the title compound (26 mg, 11.9%) as a white crystal.
1H-NMR(CDCl3): δ 2.66(1H, dd, J=16.2, 7.2 Hz), 2.82(1H, dd, J=16.2, 7.2 Hz), 3.16-3.25(2H, m), 3.43-3.86(8H, m), 4.79-4.92(1H, m), 6.88(1H, d, J=8.7 Hz), 7.14-7.15(3H, m), 7.46(1H, dd, J=8.7, 2.4 Hz), 7.74(1H, d, J=7.8 Hz), 7.84(1H, d, J=2.4 Hz).
[2-Amino-5-(morpholino)carbonylindane: Refer to “Chemical and Pharmaceutical Bulletin”, 2000, Vol. 48, p. 131.]
Example 4
The compound of Compound No. 4
This compound is a commercially available compound.
Supplier: Apin Chemicals.
Catalog code number: N 0100D.
Example 5
The Compound of Compound No. 5
This compound is a commercially available compound.
Supplier: Specs.
Catalog code number: AI-233/31581024.
Example 6
The Compound of Compound No. 6
This compound is a commercially available compound.
Supplier: Maybridge.
Catalog code number: RJC 00106.
Example 7
The Compound of Compound No. 7
This compound is a commercially available compound.
Supplier: Maybridge.
Catalog code number: BTB 13230.
Example 8
The Compound of Compound No. 8
This compound is a commercially available compound.
Supplier: Maybridge.
Catalog code number: BTB 114482.
Example 9
Preparation of the Compound of Compound No. 9
5-Chlorosalicylaldehyde (313 mg, 2 mmol) and 4-chlorobenzyltriphenylphosphonium chloride (847 mg, 2 mmol) were dissolved in N,N-dimethylfomamide (20 mL). Potassium carbonate (1.382 g, 10 mmol) dissolved in water (10 mL) was added, and the mixture was refluxed for 5 hours. After cooling, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=3:1) to give the title compound (44.6 mg, 8.4%) as a light gray solid.
1H-NMR(CDCl3): δ 5.04(1H, s), 6.74(1H, d, J=9.0 Hz), 7.05(1H, d, J=16.5 Hz), 7.10(1H, dd, J=8.4, 2.4 Hz), 7.26(1H, d, J=16.5 Hz), 7.33(2H, d, J=8.4 Hz), 7.45(2H, d, J=8.4 Hz), 7.49(1H, d, J=2.4 Hz).
Example 10
Preparation of the Compound of Compound No. 10
(1) 5-Bromo-N-(3,5-dichlorophenyl)-2-methoxybenzenesulfonamide
5-Bromo-2-methoxybenzenesulfonyl chloride (857 mg, 3 mmol) was dissolved in dichloromethane (6 mL). A solution of 3,5-dichloroaniline (510 mg, 3.15 mmol) and pyridine (261 mg, 3.3 mmol) in dichloromethane (2 mL) was added dropwise under ice cooling and argon atmosphere, and the mixture was stirred at room temperature for 6 hours. After the reaction mixture was diluted with dichloromethane, washed successively with 2N hydrochloric acid, water, and brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was crystallized from n-hexane-ethyl acetate to give 5-bromo-2-methoxy-N-(3,5-dichloro)benzenesulfonamide (900 mg, 73.0%) as a white crystal.
1H-NMR(DMSO-d6): δ 4.03(3H, s), 6.92(1H, d, J=9.0 Hz), 7.01(2H, d, J=1.8 Hz), 7.07-7.08(1H, m), 7.24(1H, brs), 7.63(1H, dd, J=8.7, 2.4 Hz), 7.99(1H, d, J=2.4 Hz).
(2) 5-Bromo-N-(3,5-dichlorophenyl)-2-hydroxybenzenesulfonamide (Compound No. 10)
A mixture of the white crystal of 5-Bromo-N-(3,5-dichlorophenyl)-2-methoxybenzenesulfonamide (206 mg, 0.5 mmol), lithium iodide (134 mg, 1 mmol) and 2,4,6-collidine (5 mL) was refluxed for 30 minutes under argon atmosphere. After cooling to room temperature, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was crystallized from n-hexane-ethyl acetate to give the title compound (90 mg, 45.3%) as a white crystal.
mp 158-159° C.
1H-NMR(DMSO-d6): δ 6.92(1H, d, J=8.7 Hz), 7.11(2H, d, J=2.1 Hz), 7.21-7.22(1H, m), 7.62(1H, dd, J=8.7, 2.7 Hz), 7.80(1H, d, J=2.4 Hz), 10.70(1H, br), 11.37(1H, br).
Example 11
Preparation of the Compound of Compound No. 11
2-Aminophenol (120 mg, 1.1 mmol) was dissolved in dichloromethane (5 mL). A solution of 3,5-bis(trifluoromethyl)benzoyl chloride (300 mg, 1.1 mmol) in dichloromethane (3 mL) and pyridine (0.5 mL) was added dropwise under ice cooling and argon atmosphere, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethanol (5 mL). 2N Sodium hydroxide (0.1 mL, 0.2 mmol) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give the title compound (288 mg, 73.6%) as a light pink crystal.
mp 183° C. (dec.).
1H-NMR(DMSO-d6): δ 6.83(1H, td, J=8.0, 1.2 Hz), 6.93(1H, dd, J=8.0, 1.2 Hz), 7.08(1H, td, J=8.0, 1.6 Hz), 7.50(1H, d, J=8.0 Hz), 8.35(2H, s), 9.61(1H, s), 10.15(1H, s).
Example 12
Preparation of the Compound of Compound No. 12
2-Amino-4-chlorophenol (316 mg, 2.2 mmol) and triethylamine (243 mg, 2.4 mmol) were dissolved in dichloromethane (8 mL). A solution of 3,5-dichlorobenzoyl chloride (419 mg, 2 mmol) in dichloromethane (2 mL) was added dropwise under ice cooling and argon atmosphere, and the mixture was stirred at room temperature for 15 hours. After the reaction mixture was diluted with ethyl acetate, washed successively with water and brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:1) to give a light brown solid. The solid was suspended and washed with n-hexane-ethyl acetate under heating at reflux to give the title compound (205 mg, 32.4%) as a white crystal.
mp 251-252° C.
1H-NMR(DMSO-d6): δ 6.93(1H, d, J=9.0 Hz), 7.11(1H, dd, J=8.7, 2.7 Hz), 7.67(2H, d, J=2.7 Hz), 7.86-7.87(1H, m), 7.97(1H, d, J=1.8 Hz), 9.85(1H, s), 10.03(1H, s).
Example 13
Preparation of the Compound of Compound No. 13
2-Amino-4-chlorophenol (287 mg, 2 mmol) and 3,5-dichlorobenzenesulfonyl chloride (540 mg, 2.2 mmol) were dissolved in dichloromethane (4 mL). Pyridine (1 mL) was added dropwise under ice cooling and argon atmosphere, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:1→1:1) to give a reddish brown solid. The solid was crystallized from n-hexane-ethyl acetate to give the title compound (445 mg, 63.1%) as a slight dark brown crystal.
mp 190-191° C.
1H-NMR(DMSO-d6): δ 6.68(1H, d, J=9.0 Hz), 7.08(1H, dd, J=8.7, 2.7 Hz), 7.17(1H, d, J=2.4 Hz), 7.70(2H, d, J=1.8 Hz), 7.95-7.96(1H, m), 10.00(1H, s), 10.06(1H, s).
Example 14
Preparation of the Compound of Compound No. 14
(1) 4-Bromo-2-[(3,5-diphenylimino)methyl]phenol
A mixture of 5-bromosalicylaldehyde (1.01 g, 5 mmol), 3,5-dichloroaniline (810 mg, 5 mmol) and ethanol (25 mL) was refluxed for 1 hour under argon atmosphere. After the reaction mixture was cooled to room temperature, the separated crystal was filtered to give the title compound (1.52 g, 88.2%) as an orange crystal.
mp 161-163° C.
1H-NMR(CDCl3): δ 6.94(1H, d, J=9.0 Hz), 7.16(2H, d, J=1.8 Hz), 7.30-7.31(1H, m), 7.47-7.53(2H, m), 8.51(1H, s).
(2) N-[(5-Bromo-2-hydroxyphenyl)methyl]-3,5-dichloroaniline (Compound No. 14)
4-Bromo-2-[(3,5-diphenylimino)methyl]phenol (1.04 g, 3 mmol) was dissolved in tetrahydrofuran (12 mL) and ethanol (6 mL). Sodium borohydride (113 mg, 3 mmol) was added under ice cooling and argon atmosphere, and the mixture was stirred at room temperature for 12 hours. Acetone (10 mL) was added to the reaction mixture. Water was added to the residue obtained by concentration under reduced pressure, and it was extracted with dichloromethane. After the dichloromethane layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give a light yellow viscous material. This was crystallized by n-hexane to give the title compound (971 mg, 93.3%) as a white crystal.
mp 125-126° C.
1H-NMR(CDCl3): δ 4.31(2H, s), 6.64(2H, d, J=1.8 Hz), 6.74-6.77(1H, m), 6.84-6.85(1H, m), 7.30-7.34(2H, m).
Example 15
The Compound of Compound No. 15
This compound is a commercially available compound.
Supplier: Sigma-Aldrich.
Catalog code number: S3203-5.
Example 16
Preparation of the Compound of Compound No. 16
A mixture of 5-chlorosalicylic acid (173 mg, 1 mmol), 3,5-bis(trifluoromethyl)-N-methylaniline (243 mg, 1 mmol), phosphorus trichloride (44 μl, 0.5 mmol) and monochlorobenzene (5 mL) was refluxed for 3 hours under argon atmosphere. After the reaction mixture was cooled to room temperature, n-hexane (50 mL) was added, and the separated crude crystal was filtered and dissolved in ethyl acetate (50 mL). After the ethyl acetate solution was washed successively with water and brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1) to give the title compound (75 mg, 18.9%) as a white crystal.
1H-NMR(CDCl3): δ 3.57(3H, s), 6.59(1H, d, J=2.4 Hz), 6.94(1H, d, J=9.0 Hz), 7.21(1H, dd, J=9.0, 2.7 Hz), 7.58(2H, s), 7.80(1H, s), 10.00(1H, brs).
When the method described in Example 16 is referred in the following examples, phosphorus trichloride was used as the acid halogenating agent. As the reaction solvent, solvents such as monochlorobenzene, toluene or the like were used.
Example 17
Preparation of the Compound of Compound No. 17
Using 5-bromosalicylic acid and 7-trifluoromethyl-1,2,3,4-tetrahydroquinoline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 42.0%.  1H-NMR(CDCl3): δ 2.08(2H, m), 2.92(2H, t, J=6.6 Hz), 3.95(2H, t, J=6.6 Hz), 6.91-6.94(2H, m), 7.14(1H, s), 7.32-7.35(2H, m), 7.40(1H, dd, J=8.7, 2.4 Hz), 10.06(1H, s).
Example 18
Preparation of the Compound of Compound No. 18
Using 2-hydroxynaphthalene-1-carboxylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 51.2%.  mp 246-248° C.  1H-NMR(DMSO-d6): δ 7.26(1H, d, J=9.3 Hz), 7.31-7.37(2H, m), 7.44-7.50(1H, m), 7.65-7.68(1H, m), 7.85-7.90(4H, m), 10.23(1H, s), 10.74(1H, s).
Example 19
Preparation of the Compound of Compound No. 19
Using 3-hydroxynaphthalene-2-carboxylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 44.3%.  mp 254-255° C.  1H-NMR(DMSO-d6): δ 7.34-7.39(3H, m), 7.49-7.54(1H, m), 7.76-7.79(1H, m), 7.89(2H, d, J=1.8 Hz), 7.92(1H, m), 8.39(1H, s), 10.75(1H, s), 11.01(1H, s).
Example 20
The Compound of Compound No. 20
This compound is a commercially available compound.
Supplier: Sigma-Aldrich.
Catalog code number: S01361-8.
Example 21
Preparation of the Compound of Compound No. 21
Using 1-hydroxynaphthalene-2-carboxylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 65.5%.  1H-NMR(DMSO-d6): δ 7.51(1H, d, J=9.0 Hz), 7.60(1H, td, J=7.8, 0.9 Hz), 7.70(1H, td, J=7.8, 0.9 Hz), 7.89(1H, s), 7.93(1H, d, J=8.4 Hz), 8.09(1H, d, J=9.0 Hz), 8.33(1H, d, J=8.7 Hz), 8.51(2H, s), 10.92(1H, s), 13.36(1H, s).
Example 22
The Compound of Compound No. 22
This compound is a commercially available compound.
Supplier: Sigma-Aldrich.
Catalog code number: S58026-0.
Example 23
The Compound of Compound No. 23
This compound is a commercially available compound.
Supplier: Sigma-Aldrich.
Catalog code number: S63263-5.
Example 24
Preparation of the Compound of Compound No. 24
5-Chloro-2-hydroxynicotinic acid (174 mg, 1 mmol), 3,5-bis(trifluoromethyl)aniline (275 mg, 1.2 mmol) and pyridine (316 mg, 4 mmol) were dissolved in tetrahydrofuran (20 mL) and dichloromethane (10 mL). Phosphorus oxychloride (0.112 ml, 1.2 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ethyl acetate (100 mL) and 0.2N hydrochloric acid (100 mL), filtered through celite after stirring for 30 minutes, and the water layer of the filtrate was extracted with ethyl acetate. After the combined ethyl acetate layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1→1:1) to give a light yellow solid. This was suspended and washed with ethanol under heating at reflux to give the title compound (183 mg, 47.6%) as a white crystal.
mp>270° C.
1H-NMR(DMSO-d6): δ 7.83(1H, s), 8.15(1H, d, J=3.3 Hz), 8.36(1H, d, J=3.0 Hz), 8.40(2H, s), 12.43(1H, s).
When the preparation method described in Example 24 is referred in the following examples, phosphorus oxychloride was used as the acid halogenating agent. Pyridine was used as the base. As the reaction solvent, solvents such as dichloromethane, tetrahydrofuran or the like were used alone or as a mixture.
Example 25
Preparation of the Compound of Compound No. 25
Using 5-chloro-2-hydroxynicotinic acid and 2-chloro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 24 gave the title compound.
Yield: 42.9%.  1H-NMR(DMSO-d6): δ 7.52(1H, dd, J=8.4, 2.1 Hz), 7.81(1H, d, J=8.4 Hz), 8.16(1H, s), 8.39(1H, d, J=2.7 Hz), 8.96(1H, d, J=2.1 Hz), 12.76(1H, s), 13.23(1H, s).
Example 26
Preparation of the Compound of Compound No. 26
Using 5-chloro-2-hydroxynicotinic acid and 3,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same operation as the Example 24 gave the title compound.
Yield: 59.1%.  1H-NMR(DMSO-d6): δ 1.29(18H, s), 7.18(1H, t, J=1.8 Hz), 7.52(2H.d, J=1.8 Hz), 8.07(1H, d, J=2.4 Hz), 8.35(1H, d, J=3.3 Hz), 11.92(1H, s), 13.10(1H, s).
Example 27
Preparation of the Compound of Compound No. 27
Using 3-hydroxypyridine-2-carboxylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 24 gave the title compound.
Yield: 45.0%.  1H-NMR(CDCl3): δ 7.40(1H, dd, J=8.4, 1.8 Hz), 7.46(1H, dd, J=8.4, 4.2 Hz), 7.68(1H, s), 8.16(1H, dd, J=4.2, 1.2 Hz), 8.25(2H, s), 10.24(1H, s), 11.42(1H, s).
Example 28
Preparation of the Compound of Compound No. 28
Under argon atmosphere, 3,5-bis(trifluoromethyl)phenylisocyanate (255 mg, 11.0 mmol) was dissolved in tetrahydrofuran (5 mL). A solution of 6-chloro-oxindole (184 mg, 1.1 mmol) in tetrahydrofuran (5 ml) and triethylamine (0.3 mL) were added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give the title compound (172.2 mg, 40.7%) as a pink solid.
1H-NMR(DMSO-d6): δ 3.97(2H, s), 7.29(1H, dd, J=8.1, 2.1 Hz), 7.41(1H, d, J=8.1 Hz), 7.88(1H, s), 8.04(1H, d, J=2.1 Hz), 8.38(2H, s), 10.93(1H, s).
Example 29
Preparation of the Compound of Compound No. 29
Using 3-hydroxyquinoxaline-2-carboxylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 2.7%.  1H-NMR(DMSO-d6): δ 7.40-7.45(2H, m), 7.69(1H, td, J=8.4, 1.5 Hz), 7.90-7.93(2H, m), 8.41(2H, s), 11.64(1H, s), 13.02(1H, s).
Example 30
The Compound of Compound No. 30
This compound is a commercially available compound.
Supplier: Sigma-Aldrich.
Catalog code number: S83846-2.
Example 31
The Compound of Compound No. 31
This compound is a commercially available compound.
Supplier: Maybridge.
Catalog code number: RDR 01818.
Example 32
Preparation of the Compound of Compound No. 32
Using 5-chlorosalicylic acid and 1-naphthylamine as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 65.0%.  1H-NMR(DMSO-d6): δ 7.09(1H, d, J=8.7 Hz), 7.51-7.61(4H, m), 7.85(1H, d, J=8.4 Hz), 7.96(1H, d, J=7.5 Hz), 7.99-8.05(2H, m), 8.13(1H, d, J=2.7 Hz), 10.88(1H, s), 12.31(1H, s).
Example 33
Preparation of the Compound of Compound No. 33
Using 5-chlorosalicylic acid and 4-methoxy-2-naphthylamine as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 84.3%.  1H-NMR(DMSO-d6): δ 3.99(3H, s), 7.05(1H, d, J=9.0 Hz), 7.30(1H, d, J=1.5 Hz), 7.39-7.45(1H, m), 7.48-7.54(2H, m), 7.83(1H, d, J=7.8 Hz), 8.00(1H, s), 8.02(1H, d, J=2.4 Hz), 8.09(1H, d, J=7.8 Hz), 10.54(1H, s), 11.88(1H, s).
Example 34
Preparation of the Compound of Compound No. 34
(1) 2-Acetoxy-5-chlorobenzoic acid
Concentrated sulfuric acid (0.08 mL) was added slowly to a mixture of 5-chlorosalicylic acid (13.35 g, 77 mmol) and acetic anhydride (20 mL). After the reaction mixture was solidified, it was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was washed with n-hexane under suspension to give the title compound (15.44 g, 93.0%) as a white crystal.
1H-NMR(DMSO-d6): δ 2.25(3H, s), 7.27(1H, d, J=8.7 Hz), 7.72(1H, dd, J=8.7, 2.7 Hz), 7.89(1H, d, J=2.7 Hz), 13.47(1H, s).
(2) 2-Acetoxy-5-chloro-N-(1-methoxynaphthalen-3-yl)benzamide (Compound No. 34)
Using 2-acetoxy-5-chlorobenzoic acid and 4-methoxy-2-naphthylamine as the raw materials, the same operation as the Example 24 gave the title compound.
Yield: 39.9%, red solid.  1H-NMR(DMSO-d6): δ 2.23(3H, s), 3.96(3H, s), 7.23(1H, d, J=1.2 Hz), 7.34(1H, d, J=8.7 Hz), 7.40(1H, dt, J=8.1, 1.2 Hz), 7.50(1H, dt, J=8.1, 1.5 Hz), 7.67(1H, dd, J=8.7, 2.7 Hz), 7.81(1H, d, J=8.7 Hz), 7.82(1H, d, J=3.0 Hz), 8.02(1H, s), 8.08(1H, d, J=8.7 Hz), 10.58(1H, s).
Example 35
Preparation of the Compound of Compound No. 35
Using 5-chlorosalicylic acid and 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid ethyl ester as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 49.6%.  1H-NMR(DMSO-d6): δ 1.32(3H, t, J=7.2 Hz), 1.74(4H, br), 2.63(2H, br), 2.75(2H, br), 4.30(2H, q, J=7.2 Hz), 7.05(1H, d, J=9.0 Hz), 7.50(1H, dd, J=8.7, 3.0 Hz), 7.92(1H, d, J=3.0 Hz), 12.23(1H, s), 13.07(1H, s).
Example 36
Preparation of the Compound of Compound No. 36
Using 5-bromosalicylic acid and 3-amino-5-phenylpyrazole as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 9.2%.  1H-NMR(DMSO-d6): δ 6.98(1H, d, J=8.8 Hz), 7.01(1H, s), 7.35(1H, t, J=7.6 Hz), 7.46(2H, t, J=7.6 Hz), 7.58(1H, dd, J=8.8, 2.8 Hz), 7.74-7.76(2H, m), 8.19(1H, s), 10.86(1H, s), 12.09(1H, s), 13.00(1H, brs).
Example 37
Preparation of the Compound of Compound No. 37
(1) 2-Amino-4,5-diethyloxazole
Propioin (1.03 g, 8.87 mmol) was dissolved in ethanol (15 mL). Cyanamide (0.75 g, 17.7 mmol) and sodium ethoxide (1.21 g, 17.7 mmol) were added, and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (dichloromethane:methanol=9:1) to give the title compound (369.2 mg, 29.7%) as an yellow amorphous.
1H-NMR(DMSO-d6): δ 1.04(3H, t, J=7.5 Hz), 1.06(3H, t, J=7.5 Hz), 2.20(2H, q, J=7.5 Hz), 2.43(2H, q, J=7.5 Hz), 6.15(2H, s).
(2) 2-Acetoxy-5-bromo-N-(4,5-diethyloxazol-2-yl)benzamide
Using 2-acetoxy-5-bromobenzoic acid and 2-amino-4,5-diethyloxazole as the raw materials, the same operation as the Example 24 gave the title compound.
Yield: 22.0%.  1H-NMR(CDCl3): δ 1.22(3H, t, J=7.5 Hz), 1.23(3H, t, J=7.5 Hz), 2.38(3H, s), 2.48(2H, q, J=7.5 Hz), 2.57(2H, q, J=7.5 Hz), 6.96(1H, d, J=8.7 Hz), 7.58(1H, dd, J=8.7, 2.7 Hz), 8.32(1H, s), 11.40(1H, br).
[2-Acetoxy-5-bromosalicylic acid: It was obtained, using 5-bromosalicylic acid and acetic anhydride as the raw materials, by the same operation as the Example 34(1) with reference to “Europian Journal of Medicinal Chemistry”, 1996, Vol. 31, p. 861-874.]
(3) 5-Bromo-N-(4,5-diethyloxazol-2-yl)-2-hydroxybenzamide (Compound No. 37)
Using 2-acetoxy-5-bromo-N-(4,5-diethyloxazol-2-yl)benzamide as the raw material, the same operation as the Example 2(2) gave the title compound.
Yield: 70.2%.  1H-NMR(CDCl3) δ: 1.25(3H, t, J=7.5 Hz), 1.26(3H, t, J=7.5 Hz), 2.52(22H, q, J=7.5 Hz), 2.60(2H, q, J=7.5 Hz), 6.84(1H, d, J=8.7 Hz), 7.43(1H, dd, J=8.7, 3.0 Hz), 8.17(1H, d, J=3.0 Hz), 11.35(1H, br), 12.83(1H, br).
Example 38
Preparation of the Compound of Compound No. 38
Using 5-bromosalicylic acid and 2-amino-4,5-diphenyloxazole as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 32.6%.  mp 188-189° C. 1H-NMR(DMSO-d6): δ 6.98(1H, d, J=8.7 Hz), 7.40-7.49(6H, m), 7.53-7.56(2H, m), 7.59-7.63(3H, m), 8.01(1H, d, J=2.4 Hz), 11.80(2H, brs).
[2-Amino-4,5-diphenyloxazole: Refer to “Zhournal Organicheskoi Khimii: Russian Journal of Organic Chemistry”, (Russia), 1980, Vol. 16, p. 2185.]
Example 39
Preparation of the Compound of Compound No. 39
(1) 2-Amino-4,5-bis(furan-2-yl)oxazole
Furoin (0.50 g, 2.60 mmol) was dissolved in ethanol (15 mL). Cyanamide (218.8 mg, 5.20 mmol) and sodium ethoxide (530.8 mg, 7.80 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (hexane:ethyl acetate=1:1→1:2) to give the title compound (175.0 mg, 31.1%) as a dark brown crystal.
1H-NMR(DMSO-d6): δ 6.59(1H, dd, J=3.3, 2.1 Hz), 6.62(1H, dd, J=3.3, 2.1 Hz), 6.73(1H, dd, J=3.3, 0.6 Hz), 6.80(1H, dd, J=3.3, 0.9 Hz), 7.05(2H, s), 7.75-7.76(2H, m).
(2) 5-Bromo-N-[4,5-bis(furan-2-yl)oxazol-2-yl]-2-hydroxybenzamide (Compound No. 39)
Using 5-bromosalicylic acid and 2-amino-4,5-bis(furan-2-yl)oxazole as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 12.9%.  1H-NMR(DMSO-d6): δ 6.65(1H, dd, J=3.6, 1.8 Hz), 6.68(1H, dd, J=3.6, 1.8 Hz), 6.75(1H, d, J=8, 7 Hz), 6.92(1H, dd, J=3.6, 0.9 Hz), 6.93(1H, d, J=3.3 Hz), 7.37(1H, dd, J=8.7, 2.7 Hz), 7.80(1H, dd, J=1.8, 0.9 Hz), 7.84(1H, dd, J=1.8, 0.9 Hz), 7.92(1H, d, J=3.0 Hz), 14.88(2H, br).
Example 40
Preparation of the Compound of Compound No. 40
(1) 2-Acetoxy-N-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)benzamide
Using O-acetylsalicyloyl chloride and 2-amino-5-(trifluoromethyl)-1,3,4-thiadiazole as the raw materials, the same operation as the Example 2(1) gave the title compound.
Yield: 51.1%.  1H-NMR(DMSO-d6): δ 2.23(3H, s), 7.32(1H, dd, J=8.0, 1.2 Hz), 7.45(1H, td, J=7.6, 1.2 Hz), 7.69(1H, td, J=8.0, 2.0 Hz), 7.87(1H, dd, J=8.0, 2.0 Hz), 13.75(1H, brs).
(2) 2-Hydroxy-N-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)benzamide (Compound No. 40)
Using 2-acetoxy-N-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)benzamide as the raw material, the same operation as the Example 2(2) gave the title compound.
Yield: 92.9%.  1H-NMR(DMSO-d6): δ 7.00(1H, td, J=8.0, 0.8 Hz), 7.06(1H, d, J=8.4 Hz), 7.51(1H, ddd, J=8.4, 7.6, 2.0 Hz), 7.92(1H, dd, J=8.0, 1.6 Hz), 12.16(1H, br).
Example 41
Preparation of the Compound of Compound No. 41
Using 5-bromosalicylic acid and 2-amino-5-trifluoromethyl-1,3,4-thiadiazole as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 80.2%.  1H-NMR(DMSO-d6): δ 7.01(1H, d, J=9.0 Hz), 7.63(1H, dd, J=8.7, 2.7 Hz), 7.97(1H, d, J=2.4 Hz).
Example 42
Preparation of the Compound of Compound No. 42
Using 5-chlorosalicylic acid and 5-amino-2-chloropyridine as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 12.2%.  1H-NMR(DMSO-d6): δ 7.04(1H, d, J=9.0 Hz), 7.49(1H, dd, J=9.0, 3.0 Hz), 7.54(1H, d, J=8.4 Hz), 7.88(1H, d, J=2.7 Hz), 8.21(1H, dd, J=8.7, 2.7 Hz), 8.74(1H, d, J=2.7 Hz), 10.62(1H, s), 11.57(1H, s).
Example 43
Preparation of the Compound of Compound No. 43
Using 5-chlorosalicylic acid and 2-amino-6-chloro-4-methoxypyrimidine as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 2.2%, white solid.  1H-NMR(DMSO-d6): δ 3.86(3H, s), 6.85(1H, s), 7.01(1H, d, J=9.0 Hz), 7.47(1H, dd, J=9.0, 3.0 Hz), 7.81(1H, d, J=3.0 Hz), 11.08(1H, s), 11.65(1H, s).
Example 44
Preparation of the Compound of Compound No. 44
Using 2-acetoxy-5-chlorobenzoic acid and 5-aminoindole as the raw materials, the same operation as the Example 24 gave the title compound.
Yield: 13.3%.  1H-NMR(DMSO-d6): δ 2.20(3H, s), 6.41(1H, t, J=2.1 Hz), 7.27-7.36(4H, m), 7.63(1H, dd, J=8.7, 2.7 Hz), 7.74(1H, d, J=2.7 Hz), 7.93(1H, s), 10.21(1H, s), 11.04(1H, s).
Example 45
The Compound of Compound No. 45
This compound is a commercially available compound.
Supplier: Peakdale.
Catalog code number: PFC-0448.
Example 46
Preparation of the Compound of Compound No. 46
Using 5-chlorosalicylic acid and 3-aminoquinoline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 4.3%.  1H-NMR(DMSO-d6): δ 7.07(1H, d, J=8.7 Hz), 7.51(1H, dd, J=9.0, 3.0 Hz), 7.61(1H, dt, J=7.8, 1.2 Hz), 7.70(1H, dt, J=7.8, 1.5 Hz), 7.98(2H, d, J=3.0 Hz), 8.01(1H, s), 8.82(1H, d, J=2.4 Hz), 10.80(1H, s), 11.74(1H, s).
Example 47
Preparation of the Compound of Compound No. 47
Using 5-chlorosalicylic acid and 3-amino-9-ethylcarbazole as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 64.6%.  1H-NMR(DMSO-d6): δ 1.33(3H, t, J=7.0 Hz), 4.46(2H, q, J=7.0 Hz), 7.04(1H, d, J=9.0 Hz), 7.21(1H, t, J=7.3 Hz), 7.45-7.52(2H, m), 7.64-7.65(2H, m), 7.70(1H, d, J=8.4, 1.9 Hz), 8.11-8.15(2H, m), 8.49(1H, d, J=1.9 Hz), 10.55(1H, s), 12.22(1H, s).
Example 48
Preparation of the Compound of Compound No. 95
Using O-acetylsalicyloyl chloride and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 2(1) gave the title compound.
Yield: 84.2%.  1H-NMR(DMSO-d6): δ 2.36(3H, s), 7.19(1H, dd, J=8.0, 1.2 Hz), 7.39(1H, td, J=7.6, 1.2 Hz), 7.57(1H, ddd, J=8.0, 7.6, 1.6 Hz), 7.65(1H, s), 7.83(1H, dd, J=8.0, 1.6 Hz), 8.11(2H, s), 8.31(1H, s).
Example 49
Preparation of the Compound of Compound No. 48
Using 2-acetoxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide (Compound No. 95) as the raw material, the same operation as the Example 2(2) gave the title compound.
Yield: 45.1%.  1H-NMR(DMSO-d6): δ 6.96-7.02(2H, m), 7.45(1H, ddd, J=8.0, 7.2, 1.6 Hz), 7.81(1H, s), 7.87(1H, dd, J=8.0, 1.6 Hz), 8.46(2H, s), 10.80(1H, s), 11.26(1H, s).
Example 50
Preparation of the Compound of Compound No. 49
Using 5-fluorosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 58.7%.  1H-NMR(DMSO-d6): δ 7.04(1H, ddd, J=9.0, 4.5, 1.2 Hz), 7.30-7.37(1H, m), 7.66(1H, ddd, J=9.0, 3.3, 1.2 Hz), 7.84(1H, s), 8.46(2H, s), 10.85(1H, s), 11.21(1H, brs).
Example 51
Preparation of the Compound of Compound No. 50
Using 5-chlorosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 85.5%.  1H-NMR(DMSO-d6): δ 7.05(1H, d, J=8.7 Hz), 7.49(1H, dd, J=8.7, 2.7 Hz), 7.85(1H, s), 7.87(1H, d, J=2.7 Hz), 8.45(2H, s), 10.85(1H, s), 11.39(1H, s).
Example 52
Preparation of the Compound of Compound No. 51
Using 5-bromosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 88.5%.  1H-NMR(DMSO-d6): δ 6.98(1H, d, J=8.8 Hz), 7.59(1H, dd, J=8.8, 2.8 Hz), 7.83(1H, s), 7.98(1H, d, J=2.8 Hz), 8.43(2H, s), 10.82(1H, s), 11.37(1H, s).
This compound was obtained also by the following preparation method.
Iron powder (30 mg, 0.54 mmol) and bromine (0.02 mL, 0.39 mmol) were added to a solution of 2-acetoxy-N-[3,5-bis(trifluoromethyl)]benzamide (Compound No. 95; 100 mg, 0.25 mmol) in carbon tetrachloride (8 mL), and the mixture was stirred at 50° C. for 4 hours. After the reaction mixture was cooled to room temperature, it was poured into aqueous NaHSO4 and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give the title compound (600 mg, 54.9%) as a white solid.
Example 53
Preparation of the Compound of Compound No. 52
Using 5-iodosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 62.2%.  1H-NMR(DMSO-d6): δ 6.86(1H, d, J=8.4 Hz), 7.74(1H, dd, J=8.7, 2.4 Hz), 7.84(1H, s), 8.13(1H, d, J=2.1 Hz), 8.84(2H, s), 10.82(1H, s), 11.41(1H, s).
Example 54
Preparation of the Compound of Compound No. 53
Using 5-nitrosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 57.2%.  1H-NMR(DMSO-d6): δ 7.18(1H, d, J=9.0 Hz), 7.86(1H, s), 8.31(1H, dd, J=9.0, 3.0 Hz), 8.45(2H, s), 8.70(1H, d, J=3.0 Hz), 11.12(1H, s).
Example 55
Preparation of the Compound of Compound No. 54
(1) 2-Benzyloxy-5-formylbenzoic acid benzyl ester
A mixture of 5-formylsalicylic acid (4.98 g, 30 mmol), benzyl bromide (15.39 g, 90 mmol), potassium carbonate (16.59 g, 120 mmol), and methyl ethyl ketone (350 mL) was refluxed for 8 hours. After cooling, the solvent was evaporated under reduced pressure. 2N Hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:1), suspended and washed with isopropyl ether under heating at reflux to give the title compound (5.98 g, 57.5%) as a white solid.
1H-NMR(CDCl3): δ 5.27(2H, s), 5.37(2H, s), 7.15(1H, d, J=9.0 Hz), 7.26-7.46(10H, m), 7.99(1H, dd, J=9.0, 2.4 Hz), 8.36(1H, d, J=2.4 Hz), 9.91(1H, s).
(2) 2-Benzyloxy-5-cyanobenzoic acid benzyl ester
A mixture of 2-benzyloxy-5-formylbenzoic acid benzyl ester (693 mg, 2 mmol), hydroxylamine hydrochloride (167 mg, 2.4 mmol), and N-methylpyrrolidone (3 mL) was stirred at 115□ for 4 hours. After the reaction mixture was cooled, 2N hydrochloric acid (5 mL) and water (30 mL) were added and the mixture was extracted with ethyl acetate. The organic layer was washed with 2N aqueous sodium hydroxide, water, and brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was suspended and washed with isopropyl ether under heating at reflux to give the title compound (527 mg, 76.7%) as a white solid.
1H-NMR(CDCl3): δ 5.23(2H, s), 5.35(2H, s), 7.08(1H, d, J=8.7 Hz), 7.33-7.43(10H, m), 7.70(1H, dd, J=8.7, 2.4 Hz), 8.13(1H, d, J=2.4 Hz).
(3) 5-Cyanosalicylic acid
Ethanol (10 mL) and tetrahydrofuran (10 mL) were added to 2-benzyloxy-5-cyanobenzoic acid benzyl ester (446 mg, 1.3 mmol) and 5% palladium on carbon (45 mg), and the mixture was hydrogenated at room temperature for 2 hours. After the insoluble matter was filtered off, the solvent was evaporated under reduced pressure to give the title compound (212 mg, 100.0%) as a white solid.
1H-NMR(DMSO-d6): δ 7.02(1H, d, J=8.7 Hz), 7.82(1H, dd, J=8.7, 2.4 Hz), 8.12(1H, d, J=2.1 Hz).
(4) N-[3,5-Bis(trifluoromethyl)phenyl]-5-cyano-2-hydroxybenzamide (Compound No. 54)
Using 5-cyanosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 16.6%.  1H-NMR(DMSO-d6): δ 7.15(1H, d, J=8.7 Hz), 7.85(1H, s), 7.86(1H, dd, J=8.7, 2.1 Hz), 8.22(1H, d, J=2.4 Hz), 8.43(2H, s), 10.93(1H, s), 12.00(1H, brs).
Example 56
Preparation of the Compound of Compound No. 55
Using 5-methylsalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 54.9%.  1H-NMR(DMSO-d6): δ 6.92(1H, d, J=8.7 Hz), 7.28(1H, dd, J=8.7, 1.8 Hz), 7.71(1H, d, J=1.8 Hz), 7.82(1H, s), 8.47(2H, s), 10.80(1H, s), 11.14(1H, s).
Example 57
Preparation of the Compound of Compound No. 56
(1) 5-[(1,1-Dimethyl)ethyl]salicylic acid
Sulfamic acid (1.76 g, 18.1 mmol) and sodium dihydrogenphosphate (7.33 g, 47 mmol) were added to a solution of 5-[(1,1-dimethyl)ethyl]-2-hydroxybenzaldehyde (2.15 g, 12.1 mmol) in 1,4-dioxane (100 mL) and water (40 mL). A solution of sodium chlorite (1.76 g, 15.5 mmol) in water (10 mL) was added to the mixture under ice cooling, and it was stirred for 1 hour. Then, sodium sulfite (1.80 g, 14.3 mmol) was added to the mixture, and it was stirred for 30 minutes. Concentrated hydrochloric acid was added to the reaction mixture, and pH was adjusted to 1. The residue obtained by evaporation of 1,4-dioxane under reduced pressure was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was washed with n-hexane under suspension to give the title compound (1.81 g, 77.4%) as a white powder.
1H-NMR(DMSO-d6): δ 1.26(9H, s), 6.90(1H, d, J=9.0 Hz), 7.58(1H, dd, J=8.7, 2.4 Hz), 7.75(1H, d, J=2.4 Hz), 11.07(1H, brs).
(2) N-[3,5-Bis(trifluoromethyl)phenyl]-5-[(1,1-dimethyl)ethyl]-2-hydroxybenzamide (Compound No. 56)
Using 5-[(1,1-dimethyl)ethyl]salicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 53.8%.  1H-NMR(DMSO-d6): δ 1.30(9H, s), 6.96(1H, d, J=8.7 Hz), 7.50(1H, dd, J=8.7, 2.4 Hz), 7.82(1H, d, J=2.4 Hz), 7.83(1H, s), 8.46(2H, s), 10.80(1H, s) 11.12(1H, s).
Example 58
Preparation of the Compound of Compound No. 78
(1) 5-Acetyl-2-benzyloxybenzoic acid methyl ester
A mixture of 5-acetylsalicylic acid methyl ester (13.59 g, 70 mmol), benzyl bromide (17.96 g, 105 mmol), potassium carbonate (19.35 g, 140 mmol) and methyl ethyl ketone (350 mL) was refluxed for 8 hours. After cooling, the solvent was evaporated under reduced pressure. 2N Hydrochloric acid was added to the residue, and it was extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated, the residue was recrystallized from isopropyl ether to give the title compound (14.20 g, 71.4%) as a white solid.
1H-NMR(CDCl3): δ 2.58(3H, s), 3.93(3H, s), 5.27(2H, s), 7.07(1H, d, J=8.7 Hz), 7.26-7.43(3H, m), 7.47-7.50(2H, m), 8.07(1H, dd, J=8.7, 2.4 Hz), 8.44(1H, d, J=2.4 Hz).
(2) 5-Acetyl-2-benzyloxybenzoic acid
5-Acetyl-2-benzyloxybenzoic acid methyl ester (5.69 g, 20 mmol) was dissolved in a mixed solvent of methanol (20 mL) and tetrahydrofuran (20 mL). 2N Sodium hydroxide (11 mL) was added dropwise, and the mixture was stirred for 8 hours. The solvent was evaporated under reduced pressure. 2N Hydrochloric acid was added to the residue, and it was extracted with dichloromethane. After the dichloromethane layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated, the residue was washed with isopropyl ether to give the title compound (4.92 g, 91.0%) as a white solid.
1H-NMR(DMSO-d6): δ 2.55(3H, s), 5.32(2H, s), 7.30-7.43(4H, m), 7.49-7.52(2H, m), 8.09(1H, dd, J=9.0, 2.7 Hz), 8.22(1H, d, J=2.4 Hz).
(3) 5-Acetyl-2-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide
Using 5-acetyl-2-benzyloxybenzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 24 gave the title compound.
Yield: 63.1%.  1H-NMR(DMSO-d6): δ 2.57(3H, s), 7.11(1H, d, J=8.7 Hz), 7.86(1H, s), 8.05(1H, dd, J=8.4, 2.1 Hz), 8.44(1H, d, J=2.1 Hz), 8.47(2H, s), 10.96(1H, s), 11.97(1H, brs).
(4) 5-Acetyl-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide (Compound No. 78)
Ethanol (6 mL) and tetrahydrofuran (72 mL) were added to 5-acetyl-2-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide (602 mg, 1.25 mmol) and 5% palladium on carbon (60 mg), and the mixture was hydrogenated at room temperature for 30 minutes. After the insoluble matter was filtered off, the solvent was evaporated under reduced pressure and the residue was recrystallized from n-hexane-ethyl acetate to give the title compound (230 mg, 47.0%) as a white solid.
1H-NMR(DMSO-d6): δ 2.59(3H, s), 5.35(2H, s), 7.32-7.36(3H, m), 7.43(1H, d, J=8.7 Hz), 7.52-7.55(2H, m), 7.82(1H, s), 8.16(1H, dd, J=8.7, 2.4 Hz), 8.25(1H, d, J=2.4 Hz), 8.31(2H, s), 10.89(1H, s).
Example 59
Preparation of the Compound of Compound No. 57
5-Acetyl-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide (Compound No. 78; 50.5 mg, 0.13 mmol) was suspended in ethanol (2 mL). Sodium borohydride (23.6 mg, 0.62 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was washed with isopropyl ether/n-hexane under suspension to give the title compound (39.7 mg, 78.3%) as a white powder.
1H-NMR(DMSO-d6): δ 1.34(3H, d, J=6.3 Hz), 4.71(1H, q, J=6.3 Hz), 5.18(1H, brs), 6.97(1H, d, J=8.4 Hz), 7.44(1H, dd, J=8.4, 2.1 Hz), 7.84(1H, s), 7.86(1H, d, J=2.1 Hz), 8.48(2H, s), 10.85(1H, s), 11.32(1H, s).
Example 60
Preparation of the Compound of Compound No. 58
5-Acetyl-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide (Compound No. 78; 100.0 mg, 0.26 mmol) was dissolved in ethanol (3 mL). Pyridine (45 μl, 0.56 mmol) and O-methylhydroxylamine hydrochloride (25.8 mg, 0.31 mmol) were added, and the mixture was refluxed for 1 hour. After cooling, the reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (hexane:ethyl acetate=4:1) to give the title compound (102.1 mg, 95.3%) as a white crystal.
1H-NMR(DMSO-d6): δ 2.19(3H, s), 3.91(3H, s), 7.05(1H, d, J=8.7 Hz), 7.77(1H, dd, J=8.7, 2.4 Hz), 7.85(1H, s), 8.09(1H, d, J=2.4 Hz), 8.47(2H, s), 10.87(1H, s), 11.48(1H, s).
Example 61
Preparation of the Compound of Compound No. 59
Using 5-acetyl-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide (Compound No. 78) and O-benzylhydroxylamine hydrochloride as the raw materials, the same operation as the Example 60 gave the title compound.
Yield: 79.9%.  1H-NMR(DMSO-d6): δ 2.24(3H, s), 5.20(2H, s), 7.04(1H, d, J=8.7 Hz), 7.29-7.47(5H, m), 7.76(1H, dd, J=8.7, 2.4 Hz), 7.85(1H, s), 8.07(1H, d, J=2.1 Hz), 8.46(2H, s), 10.87(1H, s), 11.47(1H, s).
Example 62
Preparation of the Compound of Compound No. 60
(1) 5-(2,2-Dicyanoethen-1-yl)-2-hydroxybenzoic acid
Malononitrile (132 mg, 2 mmol) was dissolved in ethanol (6 mL), and 5-formylsalicylic acid (332 mg, 2 mmol) was added. After cooling with ice bath, benzylamine (0.1 mL) was added and the mixture was stirred at room temperature for 2 hours. The separated yellow crystal was filtered and recrystallized (ethanol) to give the title compound (139.9 mg, 32.7%) as a light yellow solid.
1H-NMR(DMSO-d6): δ 7.12(1H, d, J=8.7 Hz), 8.09(1H, dd, J=8.7, 2.4 Hz), 8.41(1H, s), 8.50(1H, d, J=2.4 Hz).
(2) N-[3,5-Bis(trifluoromethyl)phenyl]-5-(2,2-dicyanoethen-1-yl)-2-hydroxybenzamide (Compound No. 60)
Using 5-(2,2-dicyanoethen-1-yl)-2-hydroxybenzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 9.1%.  1H-NMR(DMSO-d6): δ 7.13(1H, d, J=9.0 Hz), 7.83(H, s), 8.04(1H, dd, J=9.0, 2.4 Hz), 8.36(1H, s), 8.38(1H, d, J=2.4 Hz), 8.43(2H, s), 11.43(1H, s).
Example 63
Preparation of the Compound of Compound No. 62
(1) 5-[(2-Cyano-2-methoxycarbonyl)ethen-1-yl]-2-hydroxybenzoic acid
Triethylamine (0.2 ml) was added to a mixture of 5-formylsalicylic acid (332 mg, 2 mmol). Cyanoacetic acid methyl ester (198 mg, 2 mmol) and acetic acid (6 mL), and the mixture was refluxed for 5 hours. After cooling, the reaction mixture was poured into water, and the separated crystal was filtered and recrystallized (n-hexane) to give the title compound (327.7 mg, 66.3%) as a light yellow solid.
1H-NMR(DMSO-d6): δ 3.85(3H, s), 7.15(1H, d, J=8.7 Hz), 8.20(1H, dd, J=8.7, 2.4 Hz), 8.37(1H, s), 8.66(1H, d, J=2.4 Hz).
(2) 3-({N-[3,5-Bis(trifluoromethyl)phenyl]carbamoyl}-4-hydroxyphenyl)-2-cyanoacrylic acid methyl ester (Compound No. 62)
Using 5-[(2-cyano-2-methoxycarbonyl)ethen-1-yl]-2-hydroxybenzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 66.3%.  1H-NMR(DMSO-d6): δ 3.85(3H, s), 7.19(1H, d, J=9.0 Hz), 7.85(1H, s), 8.20(1H, dd, J=8.7, 2.1 Hz), 8.33(1H, s), 8.45(2H, s), 8.50(1H, d, J=2.1 Hz), 11.00(1H, s), 11.03(1H, s).
Example 64
Preparation of the Compound of Compound No. 61
3-({N-[3,5-Bis(trifluoromethyl)phenyl]carbamoyl}-4-hydroxyphenyl)-2-cyanoacrylic acid methyl ester (Compound No. 62; 50 mg, 0.11 mmol) was dissolved in ethanol (5 mL). 2N Sodium hydroxide (0.11 ml, 0.22 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was recrystallized (ethyl acetate) to give the title compound (13.5 mg, 30.4%) as a light yellow solid.
1H-NMR(DMSO-d6): δ 7.12(1H, d, J=8.4 Hz), 7.84(1H, s), 7.94(1H, dd, J=8.4, 2.1 Hz), 8.38(1H, d, J=2.1 Hz), 8.45(2H, s), 9.87(1H, s), 11.41(1H, s).
Example 65
Preparation of the Compound of Compound No. 63
A mixture of N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide (Compound No. 52; 475 mg, 1 mmol), styrene (130 mg, 1.25 mmol), palladium acetate (4.5 mg, 0.02 mmol), tris(ortho-tolyl)phosphine (12.2 mg, 0.04 mmol), diisopropylamine (388 mg, 3 mmol) and N,N-dimethylformamide (2 mL) was refluxed for 8 hours. After cooling, water was added to the reaction mixture, and it was extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated, the residue was purified by column chromatography on silica gel (n-hexane:isopropyl ether=2:1→1:1) to give the title compound (173 mg, 38.3%) as a pale yellow solid.
1H-NMR(DMSO-d6): δ 7.04(1H, d, J=8.4 Hz), 7.20-7.29(3H, m), 7.38(2H, t, J=7.5 Hz), 7.59(2H, d, J=7.5 Hz), 7.72(1H, dd, J=8.4, 2.1 Hz), 7.86(1H, s), 8.07(1H, d, J=2.1 Hz), 8.49(2H, s), 10.89(1H, s), 11.33(1H, brs).
Example 66
Preparation of the Compound of Compound No. 66
N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide (Compound No. 52; 950 mg, 2 mmol) and trimethylsilylacetylene (246 mg, 2.5 mmol) were dissolved in triethylamine (2 mL) and N,N-dimethylformamide (4 mL). Tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol) and cuprous iodide (4 mg, 0.02 mmol) were added under argon atmosphere, and the mixture was stirred at 40° C. for 2 hours. After cooling to room temperature, the reaction mixture was poured into ethyl acetate (100 mL) and 1N citric acid (100 mL), stirred, and filtered through celite. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=19:1) to give a light orange solid. This was crystallized by n-hexane to give the title compound (286 mg, 32.1%) as a white crystal.
1H-NMR(DMSO-d6): δ 0.23(9H, s), 7.00(1H, d, J=8.7 Hz), 7.54(1H, dd, J=8.7, 2.4 Hz), 7.85(1H, s), 7.98(1H, d, J=2.1 Hz), 8.46(2H, s), 10.86(1H, s), 11.69(1H, s).
Example 67
Preparation of the Compound of Compound No. 64
N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-[(trimethylsilyl)ethynyl]-benzamide (Compound No. 66; 233 mg, 0.5 mmol) was dissolved in methanol (1 mL). 2N Sodium hydroxide (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was crystallized from ethanol-water to give the title compound (67 mg, 35.9%) as a light gray crystal.
1H-NMR(DMSO-d6): δ 4.11(1H, s), 7.02(1H, d, J=8.4 Hz), 7.55(1H, dd, J=8.4, 2.1 Hz), 7.85(1H, s), 7.98(1H, d, J=2.1 Hz), 8.46(2H, s), 8.46(2H, s), 10.86(1H, s), 11.62(1H, s).
Example 68
Preparation of the Compound of Compound No. 65
Using N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide (Compound No. 52) and phenylacetylene as the raw materials, the same operation as the Example 66 gave the title compound.
Yield: 40.8%.  1H-NMR(DMSO-d6): δ 7.06(1H, d, J=8.4 Hz), 7.42-7.46(3H, m), 7.53-7.57(2H, m), 7.64(1H, dd, J=8.7, 2.1 Hz), 7.86(1H, s), 8.06(1H, d, J=2.1 Hz), 8.48(2H, s), 10.94(1H, s), 11.64(1H, brs).
Example 69
Preparation of the Compound of Compound No. 67
N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide (Compound No. 52; 200 mg, 0.42 mmol) was dissolved in 1,2-dimethoxyethane (3 mL). Tetrakis(triphenylphosphine)palladium (16 mg, 0.0014 mmol) was added under argon atmosphere, and the mixture was stirred at room temperature for 5 minutes. Then dihydroxyphenylborane (57 mg, 0.47 mmol) and 1M sodium carbonate (1.3 mL) were added and the mixture was refluxed for 2 hours. After cooling to room temperature, the reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=6:1→3:1) to give the title compound (109 mg, 61.1%) as a white crystal.
1H-NMR(DMSO-d6): δ 7.12(1H, d, J=8.7 Hz), 7.33-7.38(1H, m), 7.48(2H, t, J=7.5 Hz), 7.67-7.70(2H, m), 7.79(1H, dd, J=8.4, 2.4 Hz), 7.87(1H, s), 8.17(1H, d, J=2.4 Hz), 8.49(2H, s), 10.92(1H, s), 11.41(1H, s).
Example 70
Preparation of the Compound of Compound No. 68
Using N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-(phenylethynyl)benzamide (Compound No. 65) as the raw material, the same operation as the Example 58(4) gave the title compound.
Yield: 86.2%.  1H-NMR(DMSO-d6): δ 2.88(4H, s), 6.93(1H, d, J=8.1 Hz), 7.15-7.34(6H, m), 7.76(1H, d, J=2.4 Hz), 7.84(1H, s), 8.47(2H, s), 10.79(1H, s), 11.15(1H, s).
Example 71
Preparation of the Compound of Compound No. 69
Using 2-hydroxy-5-(trifluoromethyl)benzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 44.7%.  1H-NMR(CDCl3): δ 7.17(1H, d, J=9.0 Hz) 7.72-7.75(2H, m), 7.86(1H, s), 8.17(2H, s), 8.35(1H, s) 11.88(1H, s).
[2-Hydroxy-5-(trifluoromethyl)benzoic acid: Refer to “Chemical and Pharmaceutical Bulletin”, 1996, Vol. 44, p. 734.]
Example 72
Preparation of the Compound of Compound No. 70
Using 2-hydroxy-5-(pentafluoroethyl)benzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
1H-NMR(CDCl3): δ 7.19(1H, d, J=9.0 Hz) 7.70(1H, dd, J=8.7, 2.1 Hz), 7.81(1H, d, J=2.1 Hz), 8.17(2H, s), 8.37(1H, s), 11.92(1H, s).
s[2-Hydroxy-5-(pentafluoromethyl)benzoic acid: Refer to “Chemical and Pharmaceutical Bulletin”, 1996, Vol. 44, p. 734.]
Example 73
Preparation of the Compound of Compound No. 71
Using 2-hydroxy-5-(pyrrol-1-yl)benzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 57.8%.  1H-NMR(DMSO-d6): δ 6.27(2H, dd, J=2.4, 1.8 Hz), 7.10(1H, d, J=9.0 Hz), 7.29(2H, dd, J=2.4, 1.8 Hz), 7.66(1H, dd, J=9.0, 2.7 Hz), 7.86(1H, s), 7.98(1H, d, J=2.4 Hz), 8.47(2H, s), 10.89(1H, s), 11.24(1H, s).
Example 74
Preparation of the Compound of Compound No. 72
Using N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide (Compound No. 52) and 2-thiopheneboronic acid as the raw materials, the same operation as the Example 69 gave the title compound.
Yield: 44.4%.  1H-NMR(DMSO-d6): δ 7.08(1H, d, J=8.4 Hz), 7.14(1H, dd, J=5.4, 3.6 Hz), 7.45(1H, dd, J=3.6, 1.2 Hz), 7.51(1H, dd, J=5.1, 0.9 Hz), 7.75(1H, dd, J=8.4, 2.4 Hz), 7.59(1H, s), 8.08(1H, d, J=2.4 Hz), 8.48(2H, s), 10.91(1H, s), 11.38(1H, s).
Example 75
Preparation of the Compound of Compound No. 73
Using N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide (Compound No. 52) and 3-thiopheneboronic acid as the raw materials, the same operation as the Example 69 gave the title compound.
Yield: 38.7%.  1H-NMR(DMSO-d6): δ 7.06(1H, d, J=8.7 Hz), 7.57(1H, dd, J=4.8, 1.5 Hz), 7.66(1H, dd, J=4.8, 3.0 Hz), 7.81-7.84(2H, m), 7.86(1H, s), 8.18(1H, d, J=2.1 Hz), 8.49(2H, s), 10.90(1H, s), 11.33(1H, s).
Example 76
Preparation of the Compound of Compound No. 74
(1) 2-Benzyloxy-5-(2-bromoacetyl)-N-[3,5-bis(trifluoromethyl)phenyl]benzamide
5-Acetyl-2-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide (compound of Example 58(3); 4.81 g, 10 mmol) was dissolved in tetrahydrofuran (30 ml). Phenyltrimethylammonium tribromide (3.75 g, 10 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with aqueous sodium hydrogen sulfite, water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=4:1), and recrystallized (ethyl acetate/n-hexane) to give the title compound (2.39 g, 42.7%) as a white solid.
1H-NMR(DMSO-d6): δ 4.91(2H, s), 5.36(2H, s), 7.32-7.35(3H, m), 7.47(1H, d, J=9.0 Hz), 7.52-7.56(2H, m), 7.82(1H, s), 8.21(1H, dd, J=8.7, 2.4 Hz), 8.29(1H, d, J=2.4 Hz), 8.31(2H, s), 10.91(1H, s).
(2) 2-Benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]-5-(2-methylthiazol-4-yl)benzamide
A mixture of 2-benzyloxy-5-(2-bromoacetyl)-N-[3,5-bis(trifluoromethyl)phenyl]benzamide (280 mg, 0.5 mmol), thioacetamide (41 mg, 0.55 mmol), sodium hydrogen carbonate (50 mg, 0.6 mmol) and ethanol (15 mL) was refluxed for 1 hour. The reaction mixture was poured into water, neutralized by sodium hydrogen carbonate, and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (hexane:ethyl acetate=4:1) to give the title compound (181 mg, 67.5%) as a white solid.
1H-NMR(DMSO-d6): δ 2.72(3H, s), 5.29(2H, s), 7.33-7.36(3H, m), 7.40(1H, d, J=9.0 Hz), 7.54-7.57(2H, m), 7.81(1H, s), 7.94(1H, s), 8.12(1H, dd, J=8.7, 2.1 Hz), 8.27(1H, d, J=2.1 Hz), 8.31(2H, s), 10.86(1H, s).
(3) N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-(2-methylthiazol-4-yl)benzamide (Compound No. 74)
2-Benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]-5-(2-methylthiazol-4-yl)benzamide (160 mg, 0.3 mmol) and 10% Pd—C (240 mg) were dissolved in ethanol (10 ml) and stirred for 3.5 hours under hydrogen atmosphere. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give the title compound (103.4 mg, 79.2%) as a white solid.
1H-NMR(DMSO-d6): δ 2.72(3H, s), 7.08(1H, d, J=8.7 Hz), 7.83(1H, s), 7.85(1H, s), 8.01(1H, dd, J=8.7, 2.4 Hz), 8.42(1H, d, J=2.1 Hz), 8.50(2H, s), 10.96(1H, s), 11.40(1H, s).
Example 77
Preparation of the Compound of Compound No. 75
A mixture of 2-benzyloxy-5-(2-bromoacetyl)-N-[3,5-bis(trifluoromethyl)-phenyl]benzamide (compound of Example 58(3); 280 mg, 0.5 mmol), 2-aminopyridine (51.8 mg, 0.55 mmol), sodium hydrogen carbonate (50 mg, 0.6 mmol) and ethanol (10 mL) was refluxed for 2 hours. After cooling, the reaction mixture was poured into aqueous sodium hydrogen carbonate and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=1:2) to give a white solid (130.3 mg, 45.9%). Then, a mixture of this solid (108 mg, 0.19 mmol), 10% Pd—C (11 mg), ethanol (8 mL) and ethyl acetate (8 mL) was stirred for 7 hours under hydrogen atmosphere. The reaction mixture was filtered and the residue obtained by evaporation of the filtrate under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=1:3) to give the title compound (18.3 mg, 20.2%) as a white solid.
1H-NMR(DMSO-d6): δ 6.90(1H, dt, J=6.6, 0.9 Hz), 7.10(1H, d, J=8.7 Hz), 7.25(1H, m), 7.57(1H, d, J=9.0 Hz), 7.86(1H, s), 8.04(1H, dd, J=8.7, 2.1 Hz), 8.35(1H, s), 8.48-8.56(4H, m), 11.00(1H, s), 11.41(1H, s).
Example 78
Preparation of the Compound of Compound No. 76
(1) N-[3,5-Bis(trifluoromethyl)phenyl]-5-iodo-2-methoxymethoxybenzamide
A mixture of N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide (Compound No. 52; 4.75 g, 10 mmol), chloromethyl methyl ether (1.14 ml, 15 mmol), potassium carbonate (2.76 g, 20 mmol) and acetone (50 mL) was refluxed for 8 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=3:1), and recrystallized (n-hexane/ethyl acetate) to give the title compound (3.96 g, 76.3%) as a white solid.
1H-NMR(DMSO-d6): δ 3.38(3H, s), 5.28(2H, s), 7.12(1H, d, J=9.0 Hz), 7.81(1H, s), 7.82(1H, dd, J=8.7, 2.4 Hz), 7.88(1H, d, J=2.4 Hz), 8.40(2H, s), 10.87(1H, s).
(2) N-[3,5-Bis(trifluoromethyl)phenyl]-2-methoxymethoxy-5-(pyridin-2-yl)benzamide
N-[3,5-Bis(trifluoromethyl)phenyl]-5-iodo-2-methoxymethoxybenzamide (0.20 g, 0.39 mmol) was dissolved in N,N-dimethylformamide (8 ml). Tri-n-butyl(2-pyridyl)tin (0.13 ml, 0.41 mmol) and dichlorobis(triphenylphosphine)palladium (32.1 mg, 0.05 mmol) were added, and the mixture was stirred at 100° C. for 1.5 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=2:1→1:1) to give the title compound (37.9 mg, 20.8%) as a white powder.
1H-NMR(CDCl3): δ 3.64(3H, s), 5.53(2H, s), 7.23-7.28(1H, m), 7.36(1H, d, J=8.7 Hz), 7.65(1H, s), 7.77-7.84(2H, m), 8.20(2H, s), 8.31(1H, dd, J=8.7, 2.4 Hz), 8.68-8.70(1H, m), 8.83(1H, d, J=2.4 Hz), 10.12(1H, s).
(3) N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-(pyridin-2-yl)benzamide (Compound No. 76)
Methanol (3 ml) and concentrated hydrochloric acid (0.5 ml) were added to N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxymethoxy-5-(pyridin-2-yl)benzamide (37.9 mg, 0.08 mmol), and the mixture was refluxed for 2 hours. After cooling, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=2:1) to give the title compound (16.2 mg, 47.2%) as a white powder.
1H-NMR(DMSO-d6): δ 7.13(1H, d, J=8.4 Hz), 7.33(1H, ddd, J=7.5, 6.3, 1.2 Hz), 7.86-7.91(2H, m), 7.97(1H, d, J=7.8 Hz), 8.20(1H, dd, J=8.7, 2.1 Hz), 8.50(2H, s), 8.59(1H, d, J=2.4 Hz), 8.64-8.66(1H, m), 10.97(1H, s), 11.53(1H, s).
Example 79
Preparation of the Compound of Compound No. 77
Using 5-methoxysalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 56.8%.  1H-NMR(DMSO-d6): δ 3.77(3H, s), 6.97(1H, d, J=9.0 Hz), 7.10(1H, dd, J=9.0, 3.0 Hz), 7.43(1H, d, J=3.0 Hz), 7.84(1H, s), 8.47(2H, s), 10.84(1H, s), 10.91(1H, s).
Example 80
Preparation of the Compound of Compound No. 79
(1) 5-Acetyl-2-methoxybenzoic acid methyl ester
A mixture of 5-acetylsalicylic acid methyl ester (5.00 g, 25.7 mmol), sodium carbonate (7.10 g, 51.4 mmol) and N,N-dimethylformamide (25 mL) was cooled with ice bath. Methyl iodide (2.5 mL, 40.1 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water, neutralized by hydrochloric acid, and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was washed under suspension (isopropyl ether/n-hexane) to give the title compound (5.17 g, 96.5%) as a white crystal.
1H-NMR(CDCl3): δ 2.59(3H, s), 3.92(3H, s), 3.99(3H, s), 7.04(1H, d, J=8.7 Hz), 8.12(1H, dd, J=8.7, 2.4 Hz), 8.41(1H, d, J=2.4 Hz).
(2) 5-Isobutyryl-2-methoxybenzoic acid methyl ester
A mixture of 5-acetyl-2-methoxybenzoic acid methyl ester (0.50 g, 2.40 mmol), potassium tert-butoxide (0.81 g, 7.22 mmol) and tetrahydrofuran (10 mL) was cooled with ice bath. Methyl iodide (0.5 mL, 8.03 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, neutralized by hydrochloric acid, and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=3:1→2:1) to give the title compound (143.1 mg, 25.2%) as a light yellow oil.
1H-NMR(CDCl3): δ 1.22(6H, d, J=6.9 Hz), 3.52(1H, m), 3.92(3H, s), 3.98(3H, s), 7.05(1H, d, J=8.7 Hz), 8.13(1H, dd, J=8.7, 2.4 Hz), 8.42(1H, d, J=2.4 Hz).
(3) 5-Isobutyryl-2-methoxybenzoic acid
5-Isobutyryl-2-methoxybenzoic acid methyl ester (143.1 mg, 0.60 mmol) was dissolved in methanol (5 mL). 2N Aqueous sodium hydroxide (1 ml) was added, and the mixture was refluxed for 1 hour. After cooling, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the title compound (134 mg, yield: quantitative) as a white crystal.
1H-NMR(CDCl3): δ 1.22(6H, d, J=6.9 Hz), 3.59(1H, m), 4.15(3H, s), 7.16(1H, d, J=8.7 Hz), 8.24(1H, dd, J=8.7, 2.4 Hz), 8.73(1H, d, J=2.1 Hz).
(4) 5-Isobutyryl-N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxybenzamide
Using 5-isobutyryl-2-methoxybenzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 61.4%.  1H-NMR(CDCl3): δ 1.23(6H, d, J=6.9 Hz), 3.64(1H, m), 4.20(3H, s), 7.18(1H, d, J=8.7 Hz), 7.65(1H, s), 8.19(2H, s), 8.22(1H, dd, J=8.7, 2.1 Hz), 8.88(1H, d, J=2.1 Hz), 9.98(1H, s).
(5) N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-isobutyrylbenzamide (Compound No. 79)
A mixture of 5-isobutyryl-N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxybenzamide (143.4 mg, 0.33 mmol), 2,4,6-collidine (3 ml) and lithium iodide (53.1 mg, 0.40 mmol) was refluxed for 1 hour. After cooling, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=3:1) and crystallized (ethyl acetate/isopropyl ether) to give the title compound (90.3 mg, 65.3%) as a white crystal.
1H-NMR(DMSO-d6): δ 1.12(6H, d, J=6.9 Hz), 3.66(1H, m), 7.12(1H, d, J=8.4 Hz), 7.85(1H, s), 8.07(1H, dd, J=8.4, 2.4 Hz), 8.45(1H, d, J=2.4 Hz), 8.47(2H, s), 10.93(1H, s), 11.95(1H, brs).
Example 81
Preparation of the Compound of Compound No. 81
Using 4-hydroxyisophthalic acid 1-methyl ester and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 91.5%.  1H-NMR(DMSO-d6): δ 3.85(3H, s), 7.12(1H, d, J=8.4 Hz), 7.86(1H, s), 8.02(1H, dd, J=8.7, 2.4 Hz), 8.46-8.47(3H, m), 10.96(1H, s), 12.03(1H, brs).
[4-Hydroxyisophthalic acid 1-methyl ester: Refer to “Journal of the Chemical Society”, (England), 1956, p. 3099-3107.]
Example 82
Preparation of the Compound of Compound No. 80
N-[3,5-Bis(trifluoromethyl)phenyl]-4-hydroxyisophthalamic acid methyl ester (Compound No. 81; 2.85 g, 7 mmol) was suspended in a mixed solvent of methanol (14 mL) and tetrahydrofuran (14 mL). 2N Aqueous sodium hydroxide (14 mL) was added, and the mixture was refluxed for 2 hours. After cooling, 2N hydrochloric acid (20 ml) was added to the reaction mixture and the separated solid was filtered, washed with water, dried to give the title compound (2.68 g, 97.4%) as a white crystal.
1H-NMR(DMSO-d6): δ 7.10(1H, d, J=8.7 Hz), 7.82(1H, s), 7.86(1H, s), 8.01(1H, dd, J=8.7, 2.4 Hz), 8.47(2H, s), 8.48(1H, d, J=2.4 Hz), 10.97(1H, s), 11.98(1H, brs).
When the method described in Example 82 is referred in the following examples, inorganic bases such as sodium hydroxide, potassium carbonate or the like were used as the base. As the reaction solvent, solvents such as water, methanol, ethanol, tetrahydrofuran or the like were used alone or as a mixture.
Example 83
Preparation of the Compound of Compound No. 82
Using 4-hydroxyisophthalic acid (182 mg, 1 mmol), 3,5-bis(trifluoromethyl)-aniline (687 mg, 3 mmol), phosphorus trichloride (87 μl; 1 mmol) and toluene (10 mL), the same operation as the Example 16 gave the title compound (151 mg, 25.0%) as a white crystal.
1H-NMR(DMSO-d6): δ 7.18(1H, d, J=8.7 Hz), 7.82(1H, s), 7.86(1H, s), 8.11(1H, dd, J=8.7, 2.4 Hz), 8.50(2H, s), 8.54(2H, s), 8.56(1H, d, J=2.4 Hz), 10.79(1H, s), 10.99(1H, s), 11.84(1H, brs).
Example 84
Preparation of the Compound of Compound No. 83
(1) 4-Benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid methyl ester
Sodium hydride (60%; 1.04 g, 26 mmol) was washed with n-hexane, and suspended in N,N-dimethylformamide (100 mL). A solution of N-[3,5-bis(trifluoromethyl)phenyl]-4-hydroxyisophthalamic acid methyl ester (Compound No. 81; 8.15 g, 20 mmol) in N,N-dimethylformamide (100 mL) was added dropwise under cooling with ice bath. After the addition was finished, the mixture was stirred at room temperature for 1 hour. A solution of benzyl bromide (4.45 g, 26 mmol) in N,N-dimethylformamide (10 mL) was added, and the mixture was stirred at 60° C. for 3 hours. After cooling, the reaction mixture was poured into ice and water, and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was recrystallized (ethyl acetate/n-hexane) to give the title compound (5.38 g, 54.1%) as a white solid.
1H-NMR(DMSO-d6): δ 3.87(3H, s), 5.33(2H, s), 7.33-7.36(3H, m), 7.46(1H, d, J=8.7 Hz), 7.53-7.56(2H, m), 7.82(1H, s), 8.15(1H, dd, J=8.7, 2.1 Hz), 8.25(1H, d, J=2.1 Hz) 8.28(2H, s), 10.87(1H, s).
(2) 4-Benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid
Using 4-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid methyl ester as the raw material, the same operation as the Example 82 gave the title compound.
Yield: 79.7%.  1H-NMR(DMSO-d6): δ 5.32(2H, s), 7.32-7.34(3H, m), 7.43(1H, d, J=8.7 Hz), 7.52-7.56(2H, m), 7.81(1H, s), 8.12(1H, dd, J=8.7, 2.1 Hz), 8.22(1H, d, J=2.1 Hz), 8.28(2H, s), 10.85(1H, s), 13.81(1H, brs).
(3) 4-Benzyloxy-N3-[3,5-bis(trifluoromethyl)phenyl]-N1,N1-dimethylisophthalamide
WSC.HCl (95 mg, 0.50 mmol) was added to a solution of 4-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid (242 mg, 0.50 mmol), dimethylamine hydrochloride (41 mg, 0.50 mmol) and triethylamine (51 mg, 0.50 mmol) in tetrahydrofuran (5 mL) under ice cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with diluted hydrochloric acid, water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by chromatography on silica gel (hexane:ethyl acetate=1:4) to give the title compound (165 mg, 64.9%) as a white solid.
1H-NMR(DMSO-d6): δ 2.99(6H, s) 5.29(2H, s), 7.32-7.38(4H, m), 7.52-7.56(2H, m), 7.64(1H, dd, J=8.7, 2.1 Hz), 7.73(1H, d, J=2.1 Hz), 7.80(1H, s), 8.28(2H, s), 10.83(1H, s).
When the method described in Example 84(3) is referred in the following examples, organic bases such as pyridine, triethylamine or the like were used as the base. As the reaction solvent, solvents such as dichloromethane, tetrahydrofuran or the like were used alone or as a mixture.
(4) N3-[3,5-bis(trifluoromethyl)phenyl]-4-hydroxy-N1,N1-dimethylisophthalamide (Compound No. 83)
A solution of 4-benzyloxy-N3-[3,5-bis(trifluoromethyl)phenyl]-N1,N1-dimethyl-isophthalamide (141 mg, 0.28 mmol) and 5% Pd—C (14 mg) in a mixed solvent of ethanol (5 ml) and ethyl acetate (5 ml) was stirred at room temperature for 1 hour under hydrogen atmosphere. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give the title compound (106 mg, 91.2%) as a white solid.
1H-NMR(DMSO-d6): δ 2.98(6H, s), 7.02(1H, d, J=8.7 Hz), 7.52(1H, dd, J=8.7, 2.1 Hz), 7.84(1H, s), 7.95(1H, d, J=2.1 Hz), 8.46(2H, s), 11.10(1H, brs), 11.63(1H, brs).
Example 85
Preparation of the Compound of Compound No. 84
(1) 2-Benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]-5-(piperidine-1-carbonyl)-benzamide
Using 4-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid (compound of Example 84(2)) and piperidine as the raw materials, the same operation as the Example 84(3) gave the title compound.
Yield: 56.4%.  1H-NMR(CDCl3): δ 1.53-1.70(6H, m), 3.44(2H, brs), 3.70(2H, brs), 5.26(2H, s), 7.24(1H, d, J=8.7 Hz), 7.26(1H, s), 7.52-7.58(5H, m), 7.66(2H, s), 7.74(1H, dd, J=8.7, 2.4 Hz), 8.37(1H, d, J=2.1 Hz), 10.27(1H, s).
(2) N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-(piperidine-1-carbonyl)benzamide (Compound No. 84)
Using 2-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]-5-(piperidine-1-carbonyl)benzamide as the raw material, the same operation as the Example 84(4) gave the title compound.
Yield: 96.3%, white solid.  1H-NMR(DMSO-d6): δ 1.51(4H, brs), 1.60-1.65(2H, m), 3.47(4H, brs), 7.04(1H, d, J=8.4 Hz), 7.48(1H, dd, J=8.4, 2.1 Hz), 7.85(1H, s), 7.92(1H, d, J=2.1 Hz), 8.46(2H, s), 10.99(1H, s), 11.64(1H, brs).
Example 86
Preparation of the Compound of Compound No. 85
(1) 2-Benzyloxy-5-(4-benzylpiperidine-1-carbonyl)-N-[3,5-bis(trifluoromethyl)phenyl]-benzamide
Using 4-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid (compound of Example 84(2)) and 4-benzylpiperidine as the raw materials, the same operation as the Example 84(3) gave the title compound.
Yield: 76.7%.  1H-NMR(CD3OD): δ 1.18-1.38(2H, m), 1.67(1H, brs), 1.74(1H, brs), 1.84-1.93(1H, m), 2.60(2H, d, J=7.2 Hz), 2.83(1H, brs), 3.10(1H, brs), 3.78(1H, brs), 4.59(1H, brs), 5.34(2H, s), 7.15-7.18(3H, m), 7.24-7.28(2H, m), 7.40-7.46(4H, m), 7.57-7.63(3H, m), 7.65(1H, dd, J=8.7, 2.4 Hz), 7.96(2H, s), 8.05(1H, d, J=2.1 Hz).
(2) N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-(4-benzylpiperidine-1-carbonyl)-benzamide (Compound No. 85)
Using 2-benzyloxy-5-(4-benzylpiperidine-1-carbonyl)-N-[3,5-bis(trifluoromethyl)phenyl]-benzamide as the raw material, the same operation as the Example 84(4) gave the title compound.
Yield: 54.3%, white solid.  1H-NMR(DMSO-d6): δ 1.08-1.22(2H, m), 1.59-1.62(2H, m), 1.77-1.80(1H, m), 2.50-2.55(2H, m), 2.87(2H, brs), 3.75(1H, br), 4.39(1H, br), 7.06(1H, d, J=8.4 Hz), 7.17-7.20(3H, m), 7.28(2H, t, J=7.2 Hz), 7.49(1H, dd, J=8.4, 2.1 Hz), 7.84(1H, s), 7.93(1H, d, J=2.1 Hz), 8.47(2H, s), 10.89(1H, s), 11.65(1H, s).
Example 87
Preparation of the Compound of Compound No. 86
(1) 2-Methoxy-5-sulfamoylbenzoic acid
Methyl 2-methoxy-5-sulfamoylbenzoate (4.91 g, 20 mmol) was dissolved in methanol (30 mL). 2N Aqueous sodium hydroxide (30 mL, 60 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 2N hydrochloric acid, and the separated solid was filtered to give the title compound (4.55 g, 98.3%) as a white solid.
1H-NMR(DMSO-d6): δ 3.89(3H, s), 7.30(1H, d, J=8.7 Hz), 7.32(2H, s), 7.92(1H, dd, J=8.7, 2.7 Hz), 8.09(1H, d, J=2.7 Hz), 13.03(1H, br).
(2) N-[3,5-Bis(trifluoromethyl)phenyl]-2-methoxy-5-sulfamoylbenzamide
Using 2-methoxy-5-sulfamoylbenzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 24 gave the title compound.
Yield: 24.2%. 1H-NMR(DMSO-d6): δ 3.97(3H, s), 7.38(2H, s), 7.39(1H, d, J=8.7 Hz), 7.85(1H, s), 7.96(1H, dd, J=8.7, 2.4 Hz), 8.06(1H, d, J=2.4 Hz), 8.43(2H, s), 10.87(1H, s).
(3) N-[3,5-Bis(trifluoromethyl)phenyl]-5-dimethylsulfamoyl-2-methoxybenzamide
A suspension of N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxy-5-sulfamoylbenzamide (442 mg, 1.0 mmol), methyl iodide (710 mg, 5.0 mmol) and sodium carbonate (415 mg, 3.0 mmol) in acetonitrile (10 mL) was refluxed for 3 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was recrystallized from a mixed solvent of n-hexane and ethyl acetate (2:1) to give the title compound (207 mg, 44.1%) as a white solid.
1H-NMR(DMSO-d6): δ 2.62(6H, s), 3.99(3H, s), 7.45(1H, d, J=9.0 Hz), 7.85(1H, s), 7.91(1H, dd, J=8.7, 2.4 Hz), 7.95(1H, d, J=2.4 Hz) 8.43(2H, s), 10.90(1H, s).
(4) N-[3,5-Bis(trifluoromethyl)phenyl]-5-dimethylsulfamoyl-2-hydroxybenzamide (Compound No. 86)
Using N-[3,5-bis(trifluoromethyl)phenyl]-5-dimethylsulfamoyl-2-methoxybenzamide as the raw material, the same operation as the Example 80(5) gave the title compound.
Yield: 45.5%. 1H-NMR(DMSO-d6): δ 2.61(6H, s), 7.20(1H, d, J=8.7 Hz), 7.77(1H, dd, J=8.7, 2.1 Hz), 7.86(1H, s), 8.14(1H, d, J=2.1 Hz) 8.45(2H, s), 11.16(1H, s), 12.15(1H, br).
Example 88
Preparation of the Compound of Compound No. 87
(1) N-[3,5-Bis(trifluoromethyl)phenyl]-2-methoxy-5-(pyrrole-1-sulfonyl)benzamide
A mixture of N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxy-5-sulfamoyl-benzamide (compound of Example 87(2); 442 mg, 1 mmol), 2,5-dimethoxytetrahydrofuran (159 mg, 1.2 mmol) and acetic acid (5 mL) was refluxed for 2 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water, saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=3:2) to give the title compound (436.5 mg, 88.6%) as a white solid.
1H-NMR(DMSO-d6): δ 3.96(3H, s), 6.36(2H, dd, J=2.4, 2.1 Hz), 7.37(2H, dd, J=2.4, 2.1 Hz), 7.42(1H, d, J=9.0 Hz), 7.85(1H, s), 8.80(1H, dd, J=9.0, 2.4 Hz) 8.18(1H, d, J=2.7 Hz), 8.38(2H, s), 10.92(1H, s).
(2) N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-(pyrrole-1-sulfonyl)benzamide (Compound No. 87)
Using N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxy-5-(pyrrole-1-sulfonyl)benzamide as the raw material, the same operation as the Example 80(5) gave the title compound.
Yield: 79.4%. 1H-NMR(DMSO-d6): δ 6.36(2H, dd, J=2.4, 2.1 Hz), 7.18(1H, d, J=9.0 Hz), 7.34(2H, dd, J=2.4, 2.1 Hz), 7.86(1H, s), 7.99(1H, dd, J=9.0, 2.7 Hz) 8.31(1H, d, J=2.7 Hz), 8.42(2H, s), 10.98(1H, s).
Example 89
Preparation of the Compound of Compound No. 88
Using N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-nitrobenzamide (Compound No. 53) as the raw material, the same operation as the Example 84(4) gave the title compound.
Yield: 98.0%. 1H-NMR(DMSO-d6): δ 4.79(2H, brs), 6.76(1H, d, J=2.1 Hz), 6.76(1H, s), 7.09(1H, dd, J=2.1, 1.2 Hz), 7.80(1H, s), 8.45(2H, s), 10.30(1H, br), 10.84(1H, s).
Example 90
Preparation of the Compound of Compound No. 89
Using 5-dimethylaminosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 28.8%. 1H-NMR(DMSO-d6): δ 2.85(6H, s), 6.92(1H, d, J=9.0 Hz), 7.01(1H, dd, J=8.7, 3.0 Hz), 7.22(1H, d, J=3.0 Hz), 7.84(1H, s), 8.47(2H, s), 10.62(1H, s), 10.83(1H, s).
Example 91
Preparation of the Compound of Compound No. 90
Under argon atmosphere, a mixture of 5-amino-N-[3,5-bis(trifluoromethyl)-phenyl]-2-hydroxybenzamide (Compound No. 88; 364 mg, 1 mmol), pyridine (95 mg, 1.2 mmol) and tetrahydrofuran (10 mL) was cooled on ice. Benzoyl chloride (155 mg, 1.1 mmol) was added, and the mixture was stirred for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give the title compound (121 mg, 25.7%) as a white solid.
1H-NMR(DMSO-d6): δ 7.04(1H, d, J=8.7 Hz), 7.51-7.62(3H, m), 7.81(1H, dd, J=8.7, 2.4 Hz), 7.83(1H, s), 7.98(2H, d, J=7.2 Hz), 8.22(1H, d, J=2.4 Hz), 8.49(2H, s), 10.27(1H, s), 10.89(1H, s), 11.07(1H, s).
Example 92
Preparation of the Compound of Compound No. 91
5-Amino-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide (Compound No. 88; 100.2 mg, 0.28 mmol) was dissolved in acetonitrile (4 ml). 4-Dimethylaminopyridine (3 mg) and phenylisocyanate (30 μg, 0.28 mmol) were added, and the mixture was stirred at 60° C. for 5 minutes. The reaction mixture was concentrated and the residue was purified by chromatography on silica gel (n-hexane:ethyl acetate=1:1) to give the title compound (54.8 mg, 41.2%) as a light brown solid.
1H-NMR(DMSO-d6): δ 6.93-6.98(1H, m), 6.97(1H, d, J=9.3 Hz), 7.27(2H, t, J=7.8 Hz), 7.34-7.46(2H, m), 7.50(1H, dd, J=9.0, 2.4 Hz), 7.83(1H, s), 7.88(1H, s), 8.47(2H, s), 8.56(1H, s), 8.63(1H, s), 10.87(1H, s), 10.89(1H, s).
Example 93
Preparation of the Compound of Compound No. 92
Using 5-amino-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide (Compound No. 88) and phenylisothiocyanate as the raw materials, the same operation as the Example 92 gave the title compound.
Yield: 66.3%. 1H-NMR(DMSO-d6): δ 7.00(1H, d, J=8.4 Hz), 7.13(1H, tt, J=7.5, 1.2 Hz), 7.34(2H, t, J=7.8 Hz), 7.45-7.51(3H, m), 7.84(1H, s), 7.87(1H, d, J=2.7 Hz), 8.47(2H, s), 9.65(1H, s), 9.74(1H, s), 10.84(1H, s), 11.32(1H, s).
Example 94
Preparation of the Compound of Compound No. 93
Using 5-[(4-nitrophenyl)diazenyl]salicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 11.3%. 1H-NMR(DMSO-d6): δ 7.23(1H, d, J=9.0 Hz), 7.87(1H, s), 8.06(2H, d, J=9.0 Hz), 8.10(1H, dd, J=9.0, 2.4 Hz), 8.44(2H, d, J=9.0 Hz), 8.50(2H, s), 8.53(1H, d, J=2.4 Hz), 11.13(1H, s), 12.14(1H, br).
Example 95
Preparation of the Compound of Compound No. 94
Using 5-({[(4-pyridin-2-yl)sulfamoyl]phenyl}diazenyl)salicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 7.9%. 1H-NMR(DMSO-d6): δ 6.87(1H, t, J=6.0 Hz), 7.22(1H, d, J=8.7 Hz), 7.21-7.23(1H, m), 7.77(1H, t, J=8.4 Hz), 7.87(1H, s), 7.95-7.98(3H, m), 8.03-8.07(4H, m), 8.47(1H, d, J=2.4 Hz), 8.49(2H, s), 11.14(1H, s), 12.03(1H, br).
Example 96
Preparation of the Compound of Compound No. 96
N-[3,5-Bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (Compound No. 50; 1.51 g, 3 mmol) and pyridine (285 mg, 3.6 mmol) were dissolved in tetrahydrofuran (6 mL). Acetyl chloride (234 mg, 3.3 mmol) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure. 2 N hydrochloric acid was added to the residue, and it was extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated, the residue was recrystallized from n-hexane/ethyl acetate to give the title compound (1.06 g, 83.0%) as a white solid.
1H-NMR(DMSO-d6): δ 2.22(3H, s), 7.35(1H, d, J=9.0 Hz), 7.71(1H, dd, J=8.7, 2.7 Hz), 7.85(1H, s), 7.88(1H, d, J=2.7 Hz), 8.37(2H, s), 11.05(1H, brs).
When the method described in Example 96 is referred in the following examples, organic bases such as pyridine, triethylamine or the like were used as the base. As the reaction solvent, solvents such as dichloromethane, tetrahydrofuran, benzene or the like were used alone or as a mixture.
Example 97
Preparation of the Compound of Compound No. 97
(1) 4-Acetylamino-5-chloro-2-methoxybenzoic acid
Using 4-acetylamino-5-chloro-2-methoxybenzoic acid methyl ester as the raw material, the same operation as the Example 82 gave the title compound.
Yield: 88.0%. 1H-NMR(DMSO-d6): δ 2.16(3H, s), 3.78(3H, s), 7.72(1H, s), 7.77(1H, s), 9.57(1H, s), 12.74(1H, s).
(2) 4-Acetylamino-N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-methoxybenzamide
Using 4-acetylamino-5-chloro-2-methoxybenzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 24 gave the title compound.
Yield: 23.8%. 1H-NMR(DMSO-d6): δ 2.17(3H, s), 3.89(3H, s), 7.77-7.82(3H, m), 8.45-8.49(2H, m), 9.66(1H, s), 10.68(1H, s).
(3) 4-Acetylamino-N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (Compound No. 97)
Using 4-acetylamino-N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-methoxybenzamide as the raw material, the same operation as the Example 80(5) gave the title compound.
Yield: 72.8%. 1H-NMR(DMSO-d6): δ 2.17(3H, s), 7.75(1H, s), 7.82(1H, s), 7.95(1H, s), 8.44(2H, s), 9.45(1H, s), 11.16(1H, brs), 11.63(1H, brs).
Example 98
Preparation of the Compound of Compound No. 98
Using 4-chlorosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 55.8%. 1H-NMR(DMSO-d6): δ 7.05-7.08(2H, m), 7.84-7.87(2H, m), 8.45(2H, s), 10.84(1H, s) 11.64(1H, brs).
Example 99
Preparation of the Compound of Compound No. 99
Using 5-chlorosalicylic acid and 3,5-bis(trifluoromethyl)-2-bromoaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 14.5%. 1H-NMR(DMSO-d6): δ 7.11(1H, d, J=9.0 Hz), 7.53(1H, dd, J=9.0, 2.7 Hz), 7.91(1H, d, J=1.8 Hz), 7.98(1H, d, J=2.7 Hz), 9.03(1H, d, J=1.8 Hz), 11.26(1H, brs).
Example 100
Preparation of the Compound of Compound No. 100
Using 5-chlorosalicylic acid and 2,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 3.6%. 1H-NMR(CDCl3): δ 7.03(1H, d, J=8.7 Hz), 7.43-7.48(2H, m), 6.61(1H, d, J=8.1 Hz), 7.85(1H, d, J=8.4 Hz), 8.36(1H, br s), 8.60(1H, s), 11.31(1H, s).
Example 101
Preparation of the Compound of Compound No. 101
Using 5-bromosalicylic acid and 2,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 24.0%. 1H-NMR(DMSO-d6): δ 7.03(1H, d, J=8.7 Hz), 7.65(1H, dd, J=8.7, 2.7 Hz), 7.76(1H, d, J=8.4 Hz), 8.03(1H, d, J=8.1 Hz) 8.11(1H, d, J=2.7 Hz), 8.74(1H, s), 11.02(1H, s), 12.34(1H, s).
Example 102
Preparation of the Compound of Compound No. 102
Using 5-methylsalicylic acid and 2,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 1.5%. 1H-NMR(CDCl3): δ 2.36(3H, s), 6.97(1H, d, J=8.4 Hz), 7.23(1H, s), 7.32(1H, dd, J=8.4, 1.5 Hz), 7.57(1H, d, J=8.4 Hz), 7.83(1H, d, J=8.4 Hz), 8.46(1H, s), 8.69(1H, s), 11.19(1H, s).
Example 103
Preparation of the Compound of Compound No. 103
Using N-[2,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (Compound No. 100) and acetyl chloride as the raw materials, the same operation as the Example 96 gave the title compound.
Yield: 6.6%. 1H-NMR(CDCl3): δ 2.35(3H, s), 7.17(1H, d, J=8.7 Hz), 7.54(1H, dd, J=8.7, 2.4 Hz), 7.55(1H, d, J=8.1 Hz), 7.80(1H, d, J=8.1 Hz), 7.95(1H, d, J=2.4 Hz), 8.60(1H, s), 8.73(1H, s).
Example 104
Preparation of the Compound of Compound No. 104
Using 5-chlorosalicylic acid and 2-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 58.0%. 1H-NMR(DMSO-d6): δ 7.07(1H, d, J=8.7 Hz), 7.42(1H, t, J=7.5 Hz), 7.52(1H, dd, J=8.7, 2.7 Hz), 7.74(1H, t, J=8.1 Hz), 7.77(1H, t, J=8.1 Hz), 7.99(1H, d, J=2.7 Hz), 8.18(1H, d, J=8.1 Hz), 10.76(1H, s), 12.22(1H, s).
Example 105
Preparation of the Compound of Compound No. 105
Using 5-chlorosalicylic acid and 4-chloro-2-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 21.5%. 1H-NMR(DMSO-d6): δ 7.07(1H, d, J=8.7 Hz), 7.52(1H, dd, J=8.7, 2.7 Hz), 7.80-7.85(2H, m), 7.97(1H, d, J=2.7 Hz), 8.26(1H, d, J=8.4 Hz), 10.80(1H, s), 12.26(1H, s).
Example 106
Preparation of the Compound of Compound No. 106
Using 5-bromosalicylic acid and 3-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 50.3%. 1H-NMR(DMSO-d6): δ 6.98(1H, d, J=8.7 Hz), 7.48-7.52(1H, m), 7.59(1H, dd, J=8.7, 2.7 Hz), 7.62(1H, t, J=8.1 Hz), 7.92-7.96(1H, m), 8.02(1H, d, J=2.4 Hz), 8.20(1H, s), 10.64(1H, s), 11.60(1H, s).
Example 107
Preparation of the Compound of Compound No. 107
Using 5-chlorosalicylic acid and 2-fluoro-3-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 71.7%, white solid. 1H-NMR(DMSO-d6): δ 7.07(1H, d, J=9.0 Hz), 7.46(1H, t, J=7.8 Hz), 7.52(1H, dd, J=9.0, 2.7 Hz), 7.58(1H, t, J=7.2 Hz), 7.96(1H, d, J=2.7 Hz), 8.49(1H, t, J=7.2 Hz), 10.82(1H, s), 12.13(1H, brs).
Example 108
Preparation of the Compound of Compound No. 108
Using 5-chlorosalicylic acid and 4-fluoro-3-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 72.1%, white solid. 1H-NMR(DMSO-d6):7.03(1H, d, J=9.0 Hz), 7.48(1H, dd, J=8.7, 2.7 Hz), 7.56(1H, d, J=9.9 Hz), 7.90(1H, d, J=2.7 Hz), 7.99-8.03(1H, m), 8.21(1H, dd, J=6.6, 2.4 Hz), 10.63(1H, s), 11.58(1H, s).
Example 109
Preparation of the Compound of Compound No. 109
Using 5-bromosalicylic acid and 4-chloro-3-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 37.4%. 1H-NMR(DMSO-d6): δ 6.98(1H, d, J=8.7 Hz), 7.59(1H, dd, J=8.7, 2.4 Hz), 7.73(1H, d, J=8.7 Hz), 7.98(1H, d, J=2.4 Hz), 8.00(1H, dd, J=8.7, 2.4 Hz), 8.31(1H, d, J=2.4 Hz), 10.68(1H, s), 11.52(1H, brs).
Example 110
Preparation of the Compound of Compound No. 110
Using 5-chlorosalicylic acid and 3-fluoro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 62.0%. 1H-NMR(DMSO-d6): δ 7.04(1H, d, J=8.7 Hz), 7.42(1H, d, J=8.4 Hz), 7.48(1H, dd, J=9.0, 3.0 Hz), 7.85(1H, d, J=2.4 Hz), 7.94(1H, dd, J=11.4, 2.1 Hz), 7.99(1H, s), 10.73(1H, s), 11.46(1H, s).
Example 111
Preparation of the Compound of Compound No. 111
Using 5-bromosalicylic acid and 3-bromo-5-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 73.3%. 1H-NMR(DMSO-d6): δ 6.99(1H, d, J=9.0 Hz), 7.60(1H, dd, J=9.0, 2.4 Hz), 7.72(1H, s), 7.97(1H, d, J=2.7 Hz), 8.16(1H, s), 8.28(1H, s), 10.69(1H, s), 11.45(1H, s).
Example 112
Preparation of the Compound of Compound No. 112
Using 5-chlorosalicylic acid and 2-fluoro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 77.9%. 1H-NMR(DMSO-d6): δ 7.07(1H, d, J=9.0 Hz), 7.52(1H, dd, J=9.0, 2.7 Hz), 7.58-7.61(2H, m), 7.95(1H, d, J=2.7 Hz), 8.71(1H, d, J=7.5 Hz), 10.90(1H, s), 12.23(1H, s).
Example 113
Preparation of the Compound of Compound No. 113
Using 5-chlorosalicylic acid and 2-chloro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 49.1%. 1H-NMR(DMSO-d6): δ 7.09(1H, d, J=9.0 Hz), 7.53(1H, dd, J=9.0, 3.0 Hz), 7.55(1H, dd, J=8.4, 2.7 Hz), 7.83(1H, d, J=8.4 Hz), 7.98(1H, d, J=3.0 Hz), 8.88(1H, d, J=2.7 Hz), 11.14(1H, s), 12.39(1H, s).
Example 114
Preparation of the Compound of Compound No. 114
Using 5-bromosalicylic acid and 2-chloro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 34.2%. 1H-NMR(DMSO-d6): δ 7.04(1H, d, J=8.7 Hz), 7.56(1H, ddd, J=8.1, 2.4, 1.2 Hz), 7.64(1H, dd, J=8.7, 2.7 Hz), 7.83(1H, dd, J=8.1, 1.2 Hz), 8.11(1H, d, J=2.7 Hz), 8.87(1H, d, J=2.4 Hz), 11.12(1H, s), 12.42(1H, s).
Example 115
Preparation of the Compound of Compound No. 115
Using 5-chlorosalicylic acid and 4-nitro-3-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 44.8%. 1H-NMR(DMSO-d6): δ 7.04(1H, d, J=9.0 Hz), 7.49(1H, dd, J=9.0, 2.7 Hz), 7.81(1H, d, J=2.7 Hz), 8.23-8.24(2H, m), 8.43(1H, d, J=1.2 Hz), 11.02(1H, s), 11.30(1H, br).
Example 116
Preparation of the Compound of Compound No. 116
Using 5-chlorosalicylic acid and 2-nitro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 8.1%. 1H-NMR(DMSO-d6): δ 7.08(1H, d, J=9.0 Hz), 7.53(1H, dd, J=8.7, 2.7 Hz), 7.73(1H, dd, J=8.4, 1.8 Hz), 7.95(1H, d, J=3.0 Hz), 8.36(1H, d, J=8.7 Hz), 9.01(1H, d, J=1.8 Hz), 12.04(1H, s), 12.20(1H, s).
Example 117
Preparation of the Compound of Compound No. 117
Using 5-bromosalicylic acid and 4-cyano-3-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 49.7%. 1H-NMR(DMSO-d6): δ 6.99(1H, d, J=8.7 Hz), 7.60(1H, dd, J=8.7, 2.4 Hz), 7.92(1H, d, J=2.7 Hz), 8.16(2H, s), 8.42(1H, s), 10.93(1H, s), 11.36(1H, s).
Example 118
Preparation of the Compound of Compound No. 118
Using 5-chlorosalicylic acid and 2-methyl-3-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 14.5%. 1H-NMR(DMSO-d6): δ 2.36(3H, d, J=1.2 Hz), 7.05(1H, d, J=8.7 Hz), 7.46(1H, t, J=8.1 Hz), 7.50(1H, dd, J=8.7, 2.7 Hz), 7.60(1H, d, J=7.2 Hz), 7.99(1H, d, J=7.2 Hz), 8.00(1H, d, J=2.4 Hz), 10.43(1H, s), 12.08(1H, s).
Example 119
Preparation of the Compound of Compound No. 119
Using 5-chlorosalicylic acid and 4-methyl-3-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 80.2%. 1H-NMR(DMSO-d6): δ 7.01(1H, d, J=8.7 Hz), 7.44(1H, d, J=8.4 Hz), 7.47(1H, dd, J=9.0, 2.7 Hz), 7.84(1H, dd, J=8.4, 2.1 Hz), 7.92(1H, d, J=2.7 Hz), 8.13(1H, d, J=2.1 Hz), 10.65(1H, s), 11.68(1H, br).
Example 120
Preparation of the Compound of Compound No. 120
Using 5-chlorosalicylic acid and 2-methyl-5-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 73.3%. 1H-NMR(DMSO-d6): δ 2.39(3H, s), 7.07(1H, d, J=8.7 Hz), 7.44-7.54(3H, m), 7.99(1H, d, J=3.0 Hz), 8.43(1H, s), 10.52(1H, s), 12.17(1H, brs).
Example 121
Preparation of the Compound of Compound No. 121
Using 5-chlorosalicylic acid and 4-methoxy-3-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 79.1%. 1H-NMR(DMSO-d6): δ 3.89(3H, s), 7.02(1H, d, J=9.0 Hz), 7.30(1H, d, J=9.0 Hz), 7.48(1H, dd, J=9.0, 3.0 Hz), 7.92(1H, dd, J=9.0, 2.4 Hz), 7.96(1H, d, J=2.7 Hz), 8.04(1H, d, J=2.4 Hz), 10.47(1H, s), 11.78(1H, s).
Example 122
Preparation of the Compound of Compound No. 122
Using 5-bromosalicylic acid and 3-methoxy-5-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 58.8%. 1H-NMR(DMSO-d6): δ 3.85(3H, s), 6.98(1H, d, J=8.7 Hz), 7.03(1H, s), 7.57-7.61(2H, m), 7.77(1H, s), 8.00(1H, d, J=2.4 Hz), 10.57(1H, s), 11.56(1H, s).
Example 123
Preparation of the Compound of Compound No. 123
Using 5-bromosalicylic acid and 2-methoxy-5-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 71.3%. 1H-NMR(DMSO-d6): δ 3.99(3H, s), 7.03(1H, d, J=9.0 Hz), 7.30(1H, d, J=8.7 Hz), 7.47-7.51(1H, m), 7.61(1H, dd, J=9.0, 2.4 Hz), 8.10(1H, d, J=2.4 Hz), 8.82(1H, d, J=2.1 Hz) 11.03(1H, s), 12.19(1H, s).
Example 124
Preparation of the Compound of Compound No. 124
Using 5-chlorosalicylic acid and 2-methoxy-5-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 83.4%. 1H-NMR(DMSO-d6): δ 4.00(3H, s), 7.08(1H, d, J=9.0 Hz), 7.30(1H, d, J=8.7 Hz), 7.47-7.52(2H, m), 7.97(1H, d, J=2.7 Hz), 8.83(1H, d, J=2.4 Hz), 11.05(1H, s), 12.17(1H, s).
Example 125
Preparation of the Compound of Compound No. 125
Using 5-chlorosalicylic acid and 2-methylsulfanyl-5-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 79.2%. 1H-NMR(DMSO-d6): δ 2.57(3H, s), 7.07(1H, d, J=8.7 Hz), 7.52(1H, dd, J=8.7, 2.4 Hz), 7.55(1H, dd, J=8.4, 1.5 Hz), 7.63(1H, d, J=8.1 Hz), 8.00(1H, d, J=2.4 Hz), 8.48(1H, d, J=1.5 Hz), 10.79(1H, s), 12.26(1H, s).
Example 126
Preparation of the Compound of Compound No. 126
Using 5-bromosalicylic acid and 2-(1-pyrrolidinyl)-5-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 44.5%. 1H-NMR(DMSO-d6): δ 1.86-1.91(4H, m), 3.20-3.26(4H, m), 6.99(1H, d, J=8.7 Hz), 7.07(1H, d, J=8.7 Hz), 7.43(1H, dd, J=8.7, 2.1 Hz), 7.62(1H, dd, J=8.7, 2.4 Hz), 7.94(1H, d, J=2.1 Hz), 8.17(1H, d, J=2.4 Hz), 10.54(1H, s), 12.21(1H, s).
Example 127
Preparation of the Compound of Compound No. 127
Using 5-bromosalicylic acid and 2-morpholino-5-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 65.9%. 1H-NMR(DMSO-d6): δ 2.90(4H, dd, J=4.5, 4.2 Hz), 3.84(4H, dd, J=4.8, 4.2 Hz), 7.09(1H, d, J=8.4 Hz), 7.48(2H, s), 7.61(1H, dd, J=8.4, 2.7 Hz), 8.13(1H, d, J=2.7 Hz), 8.90(1H, s), 11.21(1H, s), 12.04(1H, s).
Example 128
Preparation of the Compound of Compound No. 128
Using 5-chlorosalicylic acid and 4-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 75.0%, white solid 1H-NMR(DMSO-d6): δ 7.04(1H, d, J=9.0 Hz), 7.48(1H, dd, J=8.7, 2.7 Hz), 7.74(2H, d, J=8.7 Hz), 7.90(1H, d, J=2.7 Hz), 7.95(2H, d, J=9.0 Hz), 10.65(1H, s), 11.59(1H, s).
Example 129
Preparation of the Compound of Compound No. 129
Using 5-bromosalicylic acid and 2-chloro-4-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 34.9%. 1H-NMR(DMSO-d6): δ 7.04(1H, d, J=8.7 Hz), 7.64(1H, dd, J=8.7, 2.7 Hz), 7.79(1H, dd, J=9.0, 2.1 Hz), 7.99(1H, d, J=2.1 Hz), 8.11(1H, d, J=2.4 Hz), 8.73(1H, d, J=9.0 Hz), 11.15(1H, s), 12.42(1H, s).
Example 130
Preparation of the Compound of Compound No. 130
Using 5-chloro-N-[2-chloro-5-(trifluoromethyl)phenyl]-2-hydroxybenzamide (Compound No. 113) and acetyl chloride as the raw materials, the same operation as the Example 96 gave the title compound.
Yield: 34.0%. 1H-NMR(CDCl3): δ 2.39(3H, s), 7.16(1H, d, J=8.7 Hz), 7.37(1H, ddd, J=8.7, 2.4, 0.6 Hz), 7.51-7.56(2H, m), 7.97(1H, d, J=3.0 Hz), 8.85(1H, s), 8.94(1H, d, J=1.8 Hz).
Example 131
Preparation of the Compound of Compound No. 131
Using 5-nitrosalicylic acid and 2-chloro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 31.1%. 1H-NMR(DMSO-d6): δ 6.98(1H, d, J=9.3 Hz), 7.52(1H, dd, J=8.4, 2.1 Hz), 7.81(1H, d, J=8.4 Hz), 8.21(1H, dd, J=9.0, 3.3 Hz), 8.82(1H, d, J=3.0 Hz), 8.93(1H, d, J=2.4 Hz), 12.18(1H, s).
Example 132
Preparation of the Compound of Compound No. 132
Using 5-methylsalicylic acid and 2-chloro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 15.8%. 1H-NMR(CDCl3): δ 2.36(3H, s), 6.95(1H, d, J=8.1 Hz), 7.26-7.31(2H, m), 7.37(1H, dd, J=8.4, 1.8 Hz), 7.56(1H, d, J=8.4 Hz), 8.65(1H, br s), 8.80(1H, d, J=1.8 Hz), 11.33(1H, br s).
Example 133
Preparation of the Compound of Compound No. 133
Using 5-methoxysalicylic acid and 2-chloro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 56.4%. 1H-NMR(DMSO-d6): δ 3.77(3H, s), 6.91(1H, d, J=9.0 Hz), 7.07(1H, dd, J=8.7, 3.0 Hz), 7.20(1H, t, J=1.8 Hz), 7.52-7.54(3H, m), 10.33(1H, s), 11.44(1H, s).
Example 134
Preparation of the Compound of Compound No. 134
Using 5-methylsalicylic acid and 4-chloro-3-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 70.4%.
1H-NMR(DMSO-d6): δ 2.29(3H, s), 6.91(1H, d, J=8.3 Hz), 7.27(1H, ddd, J=8.3, 2.2, 0.6 Hz), 7.71(1H, d, J=2.2 Hz), 7.72(1H, d, J=8.5 Hz), 8.02(1H, dd, J=8.5, 2.5 Hz), 8.33(1H, d, J=2.5 Hz), 10.64(1H, s), 11.25(1H, s).
Example 135
Preparation of the Compound of Compound No. 135
Using 5-methylsalicylic acid and 4-methyl-3-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 63.7%. 1H-NMR(DMSO-d6): δ 2.29(3H, s), 2.42(3H, s), 6.89(1H, d, J=8.4 Hz), 7.26(1H, ddd, J=8.4, 2.1, 0.6 Hz), 7.44(1H, d, J=8.1 Hz), 7.75(1H, d, J=2.1 Hz), 7.86(1H, dd, J=8.4, 1.8 Hz), 8.13(1H.d, J=2.1 Hz), 10.50(1H, s), 11.42(1H, s).
Example 136
Preparation of the Compound of Compound No. 136
Using 5-methylsalicylic acid and 2-methyl-5-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 14.2%, white solid. 1H-NMR(DMSO-d6): δ 2.29(3H, s), 2.38(3H, s), 6.94(1H, d, J=8.4 Hz), 7.27(1H, ddd, J=8.4, 2.4, 0.6 Hz), 7.44(1H, dd, J=8.1, 1.5 Hz), 7.52(1H, d, J=7.8 Hz), 7.84(1H, d, J=2.4 Hz), 8.46(1H, d, J=1.5 Hz), 10.55(1H, s), 11.72(1H, s).
Example 137
Preparation of the Compound of Compound No. 137
Using 5-methylsalicylic acid and 4-methoxy-3-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 65.1%, slightly yellow solid. 1H-NMR(DMSO-d6): δ 2.35(3H, s), 3.89(3H, s), 6.88(1H, d, J=8.4 Hz), 7.26(1H, dd, J=8.1, 1.8 Hz), 7.30(1H, d, J=8.4 Hz), 7.77(1H, d, J=2.1 Hz), 7.92(1H, dd, J=9.0, 2.7 Hz), 8.04(1H, d, J=2.7 Hz), 10.42(1H, s), 11.54(1H, s).
Example 138
Preparation of the Compound of Compound No. 138
Using 5-methylsalicylic acid and 2-methoxy-5-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 77.9%. 1H-NMR(CDCl3): δ 2.35(3H, s), 4.02(3H, s), 6.93(1H, d, J=9.0 Hz), 6.98(1H, d, J=8.4 Hz), 7.25-7.28(2H, m), 7.36(1H, ddd, J=8.4, 2.1, 0.9 Hz), 8.65(1H, br s), 8.73(1H, d, J=2.1 Hz), 11.69(1H, s).
Example 139
Preparation of the Compound of Compound No. 139
Using 5-bromosalicylic acid and aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 68.8%. mp 229-230° C. 1H-NMR(DMSO-d6): δ 6.96(1H, d, J=9.0 Hz), 7.12-7.18(1H, m), 7.35-1.41(2H, m), 7.58(1H, dd, J=8,7, 2.7 Hz), 7.67-7.71(2H, m), 8.08(1H, d, J=2.7 Hz), 10.43(1H, s), 11.87(1H, s).
Example 140
Preparation of the Compound of Compound No. 140
Using 5-bromosalicylic acid and 3-chloroaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 63.1%. mp 231-232° C. 1H-NMR(DMSO-d6): δ 6.97(1H, d, J=8.7 Hz), 7.19-7.22(1H, m), 7.38-7.43(1H, m), 7.57-7.63(2H, m), 7.91-7.92(1H, m), 8.01(1H, d, J=2.7 Hz), 10.49(1H, s), 11.64(1H, s).
Example 141
The Compound of Compound No. 141
This compound is a commercially available compound.

    Supplier: Tokyo Kasei.
    Catalog code number: B0897.


Example 142
Preparation of the Compound of Compound No. 142
Using 5-chlorosalicylic acid and 2,5-dichloroaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 10.8%. 1H-NMR(DMSO-d6): δ 7.08(1H, d, J=9.0 Hz), 7.24-7.28(1H, m), 7.50-7.54(1H, m), 7.61(1H, dd, J=9.0, 3.0 Hz), 7.97(1H, d, J=2.7 Hz), 8.58(1H, d, J=2.4 Hz), 11.02(1H, s), 12.35(1H, brs).
Example 143
Preparation of the Compound of Compound No. 143
Using 5-bromosalicylic acid and 3,4-dichloroaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 58.2%. mp 249-251° C. 1H-NMR(DMSO-d6): δ 6.97(1H, d, J=8.7 Hz), 7.57-7.70(3H, m), 7.98(1H, d, J=2.7 Hz), 8.10(1H, d, J=2.4 Hz), 10.54(1H, s), 11.55(1H, s).
Example 144
Preparation of the Compound of Compound No. 144
Using 5-bromosalicylic acid and 3,5-difluoroaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 36.3%. mp 259-261° C. 1H-NMR(DMSO-d6): δ 6.96-7.04(2H, m), 7.45-7.54(2H, m), 7.58(1H, dd, J=8.7, 2.7 Hz), 7.94(1H, d, J=2.7 Hz), 10.60(1H, s) 11.48(1H, s).
Example 145
Preparation of the Compound of Compound No. 172
Using O-acetylsalicyloyl chloride and 3,5-dichloroaniline as the raw materials, the same operation as the Example 2(1) gave the title compound.
Yield: 73.5%. mp 167-168° C. 1H-NMR(CDCl3): δ 2.35(3H, s), 7.14-7.18(2H, m), 7.35-7.40(1H, m), 7.52-7.57(3H, m), 7.81(1H, dd, J=7.8, 1.8 Hz), 8.05(1H, brs).
Example 146
Preparation of the Compound of Compound No. 145
Using 2-acetoxy-N-(3,5-dichlorophenyl)benzamide (Compound No. 172) as the raw material, the same operation as the Example 2(2) gave the title compound.
Yield: 60.3%. mp 218-219° C. 1H-NMR(DMSO-d6): δ 6.95-7.02(2H, m), 7.35-7.36(1H, m), 7.42-7.47(1H, m), 7.83-7.87(3H, m), 10.54(1H, s), 11.35(1H, s).
Example 147
Preparation of the Compound of Compound No. 146
Using 5-fluorosalicylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 33.3%. mp 258-260° C. 1H-NMR(DMSO-d6): δ 7.00-7.05(1H, m), 7.28-7.37(2H, m), 7.63(1H, dd, J=9.3, 3.3 Hz), 7.84(2H, d, J=2.1 Hz), 10.56(1H, s), 11.23(1H, s).
Example 148
Preparation of the Compound of Compound No. 147
Using 5-chlorosalicylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 41.2%. 1H-NMR(DMSO-d6): δ 7.03(1H, d, J=9.0 Hz), 7.36-7.37(1H, m), 7.48(1H, dd, J=8.7, 2.7 Hz), 7.83-7.84(3H, m), 10.56(1H, s), 11.44(1H, s).
Example 149
Preparation of the Compound of Compound No. 148
Using 5-bromosalicylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 61.6%. mp 243-244° C. 1H-NMR(DMSO-d6): δ 6.98(1H, d, J=8.7 Hz), 7.36-7.37(1H, m), 7.59(1H, dd, J=9.0, 2.4 Hz), 7.83(2H, d, J=1.8 Hz), 7.95(1H, d, J=2.4 Hz), 10.56(1H, s), 11.46(1H, s).
Example 150
Preparation of the Compound of Compound No. 149
Using 5-iodosalicylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 65.4%. mp 244-245° C. 1H-NMR(DMSO-d6): δ 6.84(1H, d, J=9.0 Hz), 7.35-7.37(1H, m), 7.72(1H, dd, J=9.0, 2.1 Hz), 7.83(2H, d, J=1.8 Hz), 8.09(1H, d, J=2.1 Hz), 10.55(1H, s), 11.45(1H, s).
Example 151
Preparation of the Compound of Compound No. 150
Using 3,5-dibromosalicylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 44.2%. mp 181-182° C. 1H-NMR(DMSO-d6): δ 7.42-7.43(1H, m), 7.80(2H, d, J=1.8 Hz), 8.03(1H, d, J=2.1 Hz), 8.17(1H, d, J=2.1 Hz), 10.82(1H, s).
Example 152
Preparation of the Compound of Compound No. 151
Using 4-chlorosalicylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 57.2%. mp 255-256° C. 1H-NMR(DMSO-d6): δ 7.03-7.06(2H, m), 7.34-7.36(1H, m), 7.82-7.85(3H,m), 10.51(1H, s), 11.70(1H, brs).
Example 153
Preparation of the Compound of Compound No. 152
Using 5-nitrosalicylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 83.1%. mp 232-233° C. 1H-NMR(DMSO-d6): δ 7.16(1H, d, J=9.6 Hz), 7.37-7.39(1H, m), 7.84(1H, d, J=2.1 Hz), 8.29(1H, dd, J=9.0, 3.0 Hz), 8.65(1H, d, J=3.0 Hz), 10.83(1H, s).
Example 154
Preparation of the Compound of Compound No. 153
Using 5-methylsalicylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 71.0%. mp 216-217° C. 1H-NMR(DMSO-d6): δ 2.28(3H, s), 6.90(1H, d, J=8.4 Hz), 7.26(1H, dd, J=8.7, 1.8 Hz), 7.34-7.36(1H, m), 7.67(1H, d, J=1.5 Hz), 7.85(2H, d, J=1.8 Hz), 10.52(1H, s), 11.15(1H, s).
Example 155
Preparation of the Compound of Compound No. 154
Using 5-methoxysalicylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 29.8%. mp 230-232° C. 1H-NMR(DMSO-d6): δ 3.76(3H, s), 6.95(1H, d, J=8.7 Hz), 7.08(1H, dd, J=9.0, 3.0 Hz), 7.35-7.36(1H, m), 7.40(1H, d, J=3.0 Hz), 7.85(2H, d, J=1.5 Hz), 10.55(1H, s), 10.95(1H, s).
Example 156
Preparation of the Compound of Compound No. 155
Using 5-bromosalicylic acid and 3,4,5-trichloroaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 78.6%. mp 297-299° C. 1H-NMR(DMSO-d6): δ 6.98(1H, d, J=9.0 Hz), 7.58(1H, dd, J=8.4, 2.4 Hz), 7.95(1H, d, J=2.4 Hz), 8.63(1H, s), 10.58(1H, s), 11.49(1H, s).
Example 157
Preparation of the Compound of Compound No. 156
Using 5-bromosalicylic acid and 3,5-dichloro-4-hydroxyaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 22.5%. 1H-NMR(DMSO-d6): δ 6.96(1H, d, J=8.7 Hz), 7.58(1H, dd, J=8.7, 2.4 Hz), 7.76(2H, s), 8.01(1H, d, J=2.4 Hz), 10.03(1H, s), 10.36(1H, s), 11.67(1H, brs).
Example 158
Preparation of the Compound of Compound No. 157
Using 5-chlorosalicylic acid and 2,3,4,5,6-pentafluoroaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 58.6%. 1H-NMR(DMSO-d6): δ 7.07(1H d, J=8.7 Hz), 7.53(1H, dd, J=8.7, 2.7 Hz), 7.91(1H, d, J=2.7 Hz), 10.38(1H, brs), 11.74(1H, brs).
Example 159
Preparation of the Compound of Compound No. 158
Using 5-bromosalicylic acid and 3,5-dinitroaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 32.2%. mp 258-260° C. 1H-NMR(DMSO-d6): δ 6.98-7.02(1H, m), 7.59-7.63(1H, m), 7.96-7.97(1H, m), 8.56-8.58(1H, m), 9.03-9.05(2H, m), 11.04(1H, s), 11.39(1H, brs).
Example 160
Preparation of the Compound of Compound No. 159
Using 5-chlorosalicylic acid and 2,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 75.7%. 1H-NMR(DMSO-d6): δ 1.27(9H, s), 1.33(9H, s), 7.04(1H, d, J=9.0 Hz), 7.26(1H, dd, J=8.4, 2.1 Hz), 7.35-7.38(2H, m), 7.49(1H, dd, J=8.7, 2.7 Hz), 8.07(1H, d, J=2.4 Hz), 10.22(1H, s), 12.38(1H, br s).
Example 161
Preparation of the Compound of Compound No. 160
Using 5-chlorosalicylic acid and 5-[(1,1-dimethyl)ethyl]-2-methoxyaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 89.5%. 1H-NMR(DMSO-d6): δ 1.28(9H, s), 3.33(3H, s), 7.01(1H, d, J=8.7 Hz), 7.05(1H, d, J=9.0 Hz), 7.11(1H, dd, J=8.7, 2.4 Hz), 7.47(1H, dd, J=9.0, 3.0 Hz), 7.99(1H, d, J=3.0 Hz), 8.49(1H, d, J=2.4 Hz), 10.78(1H, s), 12.03(1H, s).
Example 162
Preparation of the Compound of Compound No. 161
Using 5-bromosalicylic acid and 3,5-dimethylaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 58.1%. mp 188-190° C. 1H-NMR(DMSO-d6): δ 2.28(6H, s), 6.80(1H, s), 6.96(1H, d, J=8.7 Hz), 7.33(2H, s), 7.58(1H, dd, J=9.0, 2.4 Hz), 8.10(1H, d, J=2.4 Hz), 10.29(1H, s), 11.93(1H, brs).
Example 163
Preparation of the Compound of Compound No. 162
Using 5-chlorosalicylic acid and 3,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 34.1%. 1H-NMR(CDCl3): δ 1.26(18H, s), 6.99(1H, d, J=8.7 Hz), 7.29(1H, t, J=1.8 Hz), 7.39(1, dd, J=9.0, 2.4 Hz), 7.41(2H, d, J=1.5 Hz), 7.51(1H, d, J=2.1 Hz), 7.81(1H, br s), 12.01(1H, s).
Example 164
Preparation of the Compound of Compound No. 163
Using 5-bromosalicylic acid and 3,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 45.2%. 1H-NMR(DMSO-d6): δ 1.30(18H, s), 6.95(1H, d, J=8.7 Hz), 7.20(1H, t, J=1.5 Hz), 7.56(2H, d, J=1.5 Hz), 7.58(1H, dd, J=8.7, 2.4 Hz), 8.12(1H, d, J=2.7 Hz), 10.39(1H, s), 11.98(1H, s).
Example 165
Preparation of the Compound of Compound No. 164
Using 5-chlorosalicylic acid and 2-amino-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 77.5%. 1H-NMR(DMSO-d6): δ 1.23(6H, s), 1.24(6H, s), 1.64(4H, s), 2.19(3H, s), 7.13(1H, d, J=9.0 Hz), 7.20(1H, s), 7.49(1H, dd, J=8.7, 2.7 Hz), 7.67(1H, s), 8.04(1H, d, J=2.7 Hz), 10.23(1H, s), 12.26(1H, s).
Example 166
Preparation of the Compound of Compound No. 165
Using 5-chlorosalicylic acid and 3-aminobiphenyl as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 75.6%. 1H-NMR(DMSO-d6): δ 7.04(1H, d, J=8.7 Hz), 7.35-7.44(1H, m), 7.45-7.54(5H, m), 7.65-7.68(2H, m), 7.72(1H, dt, J=7.2, 2.1 Hz), 7.99(1H, d, J=3.0 Hz), 8.03(1H, m), 10.50(1H, s), 11.83(1H, brs).
Example 167
Preparation of the Compound of Compound No. 166
Using 5-chlorosalicylic acid and 3-amino-4-methoxybiphenyl as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 37.0%. 1H-NMR(DMSO-d6): δ 3.95(3H, s), 7.08(1H, d, J=8.7 Hz), 7.20(1H, d, J=8.4 Hz), 7.34(1H, t, J=7.2 Hz), 7.40-7.50(4H, m), 7.62(1H, d, J=8.7 Hz), 8.00(1H, d, J=3.0 Hz), 8.77(1H, d, J=2.1 Hz), 10.92(1H, s), 12.09(1H, s).
Example 168
Preparation of the Compound of Compound No. 167
Using 5-bromosalicylic acid and 2,5-dimethoxyaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 39.7%. 1H-NMR(DMSO-d6): δ 3.72(3H, s), 3.84(3H, s), 6.66(1H, ddd, J=9.0, 3.0, 0.6 Hz), 6.99-7.03(2H, m), 7.58(1H, ddd, J=9.0, 2.7, 0.6 Hz), 8.10(1H, dd, J=2.4, 0.6 Hz), 8.12(1H, d, J=3.0 Hz), 10.87(1H, s), 12.08(1H, s).
Example 169
Preparation of the Compound of Compound No. 168
Using 5-bromosalicylic acid and 3,5-dimethoxyaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 40.3%. mp 207-209° C. 1H-NMR(DMSO-d6): δ 3.75(6H, s), 6.30-6.32(1H, m), 6.94-6.97(3H, m), 7.57(1H, dd, J=8.7, 2.4 Hz), 8.04(1H, d, J=2.4 Hz), 10.32(1H, s), 11.78(1H, s).
Example 170
Preparation of the Compound of Compound No. 169
Using 5-chlorosalicylic acid and 3-acetylaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 80.0%. 1H-NMR(DMSO-d6): δ 2.60(3H, s), 7.03(1H, d, J=9.0 Hz), 7.49(1H, dd, J=9.0, 3.0 Hz), 7.54(1H, t, J=8.1 Hz), 7.76(1H, dq, J=7.8, 0.9 Hz), 7.96-8.00(2H, m), 8.30(1H, t, J=1.8 Hz), 10.56(1H, s), 11.75(1H, s).
Example 171
Preparation of the Compound of Compound No. 170
Using 5-bromosalicylic acid and 5-aminoisophthalic acid dimethyl ester as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 74.1%. mp 254-256° C. 1H-NMR(DMSO-d6): δ 3.92(6H, s), 6.97(1H, d, J=9.0 Hz), 7.60(1H, dd, J=9.0, 2.4 Hz), 8.06(1H, d, J=2.4 Hz), 8.24-8.25(1H, m), 8.62(2H, m), 10.71(1H, s), 11.57(1H, s).
Example 172
The Compound of Compound No. 171
This compound is a commercially available compound.

    Supplier: Maybridge.
    Catalog code number: RDR 01434


Example 173
Preparation of the Compound of Compound No. 173
Using 5-methylsalicylic acid and 2,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 61.1%. 1H-NMR(DMSO-d6): δ 1.27(9H, s), 1.33(9H, s), 2.28(3H, s), 6.89(1H, d, J=8.1 Hz), 7.24(1H, d, J=2.1 Hz), 7.27(1H, d, J=2.1 Hz), 7.32(1H, d, J=2.4 Hz), 7.37(1H, d, J=8.4 Hz), 7.88(1H, d, J=1.5 Hz), 10.15(1H, s), 11.98(1H, br s).
Example 174
Preparation of the Compound of Compound No. 174
Using N-{3,5-bis[(1,1-dimethyl)ethyl]phenyl}-5-chloro-2-hydroxybenzamide (Compound No. 162) and acetyl chloride as the raw materials, the same operation as the Example 96 gave the title compound.
Yield: 66.1%. 1H-NMR(CDCl3): δ 1.34(18H, s), 2.36(3H, s), 7.12(1H, d, J=8.4 Hz), 7.25(1H, d, J=1.5 Hz), 7.44(2H, d, J=1.2 Hz), 7.47(1H, dd, J=8.7, 2.7 Hz), 7.87(1H, d, J=2.4 Hz), 7.98(1H, s).
Example 175
Preparation of the Compound of Compound No. 175
Using 5-nitrosalicylic acid and 3,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 46.7%. 1H-NMR(CDCl3): δ 1.37(18H, s), 7.13(1H, d, J=9.3 Hz), 7.32(1H, t, J=1.8 Hz), 7.46(2H, d, J=1.8 Hz), 8.07(1H, s), 8.33(1H, dd, J=9.3, 2.1 Hz), 8.59(1H, d, J=2.4 Hz), 13.14(1H, s).
Example 176
Preparation of the Compound of Compound No. 176
Using 5-methylsalicylic acid and 3,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 16.3%. 1H-NMR(CDCl3): δ 1.35(18H, s), 2.35(3H, s), 6.94(1H, d, H=8.4 Hz), 7.23-7.28(2H, m), 7.31(1H, s), 7.42(1H, d, J=1.8 Hz), 7.88(1H, s), 11.86(1H, s).
Example 177
Preparation of the Compound of Compound No. 177
Using 5-methoxysalicylic acid and 3,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 12.7%. 1H-NMR(DMSO-d6): δ 1.30(18H, s), 3.77(3H, s), 6.91(1H, d, J=9.0 Hz), 7.07(1H, dd, J=8.7, 3.0 Hz), 7.19-7.20(1H, m), 7.52-7.54(3H, m), 10.33(1H, s), 11.44(1H, s).
Example 178
Preparation of the Compound of Compound No. 178
Using 5-chloro-N-{5-[(1,1-dimethyl)ethyl]-2-methoxyphenyl}-2-hydroxybenzamide (Compound No. 160) and acetyl chloride as the raw materials, the same operation as the Example 96 gave the title compound.
Yield: 87.5%. 1H-NMR(CDCl3): δ 1.35(9H, s), 2.37(3H, s), 3.91(3H, s), 6.86(1H, d, J=8.7 Hz), 7.12(1H, dd, J=8.7, 2.4 Hz), 7.13(1H, d, J=9.0 Hz), 7.47(1H, dd, J=9.0, 2.4 Hz), 8.02(1H, d, J=2.7 Hz), 8.66(1H, d, J=2.4 Hz), 8.93(1H, s).
Example 179
Preparation of the Compound of Compound No. 179
Using 5-methylsalicylic acid and 5-[(1,1-dimethyl)ethyl]-2-methoxyaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 84.7%. 1H-NMR(CDCl3): δ 1.35(9H, s), 2.34(3H, s), 3.93(3H, s), 6.86(1H, d, J=8.7 Hz), 6.93(1H, d, J=8.4 Hz), 7.12(1H, dd, J=8.7, 2.4 Hz), 7.24(1H, dd, J=8.4, 1.8 Hz), 7.27(1H, br s), 8.48(1H, d, J=2.4 Hz), 8.61(1H, brs), 11.95(1H, s).
Example 180
Preparation of the Compound of Compound No. 179
Using 5-bromosalicylic acid and 2-aminothiazole as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 12.0%. mp 212° C. (dec.). 1H-NMR(DMSO-d6): δ 6.94(1H, brd, J=8.0 Hz), 7.25(1H, brd, J=3.2 Hz), 7.56(2H, m), 8.05(1H, d, J=2.8 Hz).
Example 181
Preparation of the Compound of Compound No. 186
(1) 2-Amino-4-[(1,1-dimethyl)ethyl]thiazole
A mixture of 1-bromo-3,3-dimethyl-2-butanone (5.03 g, 28.1 mmol), thiourea (2.35 g, 30.9 mmol) and ethanol (30 mL) was refluxed for 1.5 hours. After cooling, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=2:1→1:1) to give the title compound (3.99 g, 90.9%) as an yellowish white powder.
1H-NMR(CDCl3): δ 1.26(9H, s), 4.96(2H, brs), 6.09(1H, s).
When the method described in Example 181(1) is referred in the following examples, solvents such as ethanol or the like were used as the reaction solvent.
(2) 2-Acetoxy-5-bromo-N-{4-[(1,1-dimethyl)ethyl]thiazol-2-yl}benzamide
Using 2-acetoxy-5-bromobenzoic acid and 2-amino-4-[(1,1-dimethyl)ethyl]thiazole as the raw materials, the same operation as the Example 24 gave the title compound.
Yield: 59.4%. 1H-NMR(CDCl3): δ 1.31(9H, s), 2.44(3H, s), 6.60(1H, s), 7.13(1H, d, J=8.4 Hz), 7.68(1H, dd, J=8.7, 2.4 Hz), 8.17(1H, d, J=2.4 Hz), 9.72(1H, brs).
(3) 5-Bromo-N-{4-[(1,1-dimethyl)ethyl]thiazol-2-yl}-2-hydroxybenzamide (Compound No. 186)
2-Acetoxy-5-bromo-N-{4-[(1,1-dimethyl)ethyl]thiazol-2-yl}benzamide (100.1 mg, 0.25 mmol) was dissolved in tetrahydrofuran (3 mL). 2N Sodium hydroxide (0.2 ml) was added, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was crystallized (isopropyl ether/n-hexane) to give the title compound (70.1 mg, 78.9%) as a white powder.
1H-NMR(DMSO-d6): δ 1.30(9H, s), 6.80(1H, brs), 6.95(1H, brs), 7.57(1H, brs), 8.06(1H, d, J=2.4 Hz), 11.82(1H, brs), 13.27(1H, brs).
Example 182
Preparation of the Compound of Compound No. 181
(1) 2-Acetoxy-5-bromo-N-(5-bromo-4-[(1,1-dimethyl)ethyl]thiazol-2-yl)benzamide
2-Acetoxy-5-bromo-N-{4-[(1,1-dimethyl)ethyl]thiazol-2-yl}benzamide (compound of Example 181(2); 0.20 g, 0.50 mmol) was dissolved in acetonitrile (10 mL). N-Bromosuccinimide (97.9 mg, 0.55 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by chromatography on silica gel (n-hexane:ethyl acetate=3:1) to give the title compound as a crude product.
(2) 5-Bromo-N-{5-bromo-4-[(1,1-dimethyl)ethyl]thiazol-2-yl}-2-hydroxybenzamide (Compound No. 181)
Using 2-acetoxy-5-bromo-N-{5-bromo-4-[(1,1-dimethyl)ethyl]thiazol-2-yl}benzamide as the raw material, the same operation as the Example 2(2) gave the title compound.
Yield: 90.9% (2 steps). 1H-NMR(DMSO-d6): δ 1.42(9H, s), 6.99(1H, d, J=8.7 Hz), 7.61(1H, dd, J=8.7, 2.7 Hz), 8.02(1H, d, J=2.4 Hz), 11.79(1H, brs), 12.00(1H, brs).
Example 183
Preparation of the Compound of Compound No. 182
Using 5-bromosalicylic acid and 2-amino-5-bromo-4-(trifluoromethyl)thiazole as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 22.4%. mp 215° C. (dec.). 1H-NMR(DMSO-d6): δ 7.00(1H, d, J=8.8 Hz), 7.61(1H, dd, J=8.8, 2.8 Hz), 7.97(1H, d, J=2.4 Hz). [2-Amino-5-bromo-4-(trifluoromethyl)thiazole: Refer to “Journal of Heterocyclic Chemistry”, (USA), 1991, Vol. 28, p. 1017.]
Example 184
Preparation of the Compound of Compound No. 183
(1) α-Bromo-pivaloylacetonitrile
Pivaloylacetonitrile (1.00 g, 7.99 mmol) was dissolved in carbon tetrachloride (15 mL). N-Bromosuccinimide (1.42 g, 7.99 mmol) was added, and the mixture was refluxed for 15 minutes. After cooling, the insoluble matter was filtered off, and the residue obtained by evaporation of the filtrate under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give the title compound (1.43 g, 87.9%) as an yellowish brown oil.
1H-NMR(CDCl3): δ 1.33(9H, s), 5.10(1H, s).
When the method described in Example 184(1) is referred in the following examples, N-bromosuccinimide was used as the brominating agent. As the reaction solvent, solvents such as carbon tetrachloride or the like were used.
(2) 2-Amino-5-cyano-4-[(1,1-dimethyl)ethyl]thiazole
Using α-bromo-pivaloylacetonitrile and thiourea as the raw materials, the same operation as the Example 181(1) gave the title compound.
Yield: 66.3%. 1H-NMR(CDCl3): δ 1.41(9H, s), 5.32(2H, s).
(3) 5-Chloro-N-{5-cyano-4-[(1,1-dimethyl)ethyl]thiazol-2-yl}-2-hydroxybenzamide (Compound No. 183)
Using 5-chlorosalicylic acid and 2-amino-5-cyano-4-[(1,1-dimethyl)-ethyl]thiazole as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 63.4%. 1H-NMR(DMSO-d6): δ 1.43(9H, s), 7.06(1H, d, J=8.7 Hz), 7.51(1H, dd, J=8.7, 3.0 Hz), 7.85(1H, d, J=2.7 Hz), 12.31(2H, br).
Example 185
Preparation of the Compound of Compound No. 184
Using 5-bromosalicylic acid and 2-amino-5-cyano-4-[(1,1-dimethyl)-ethyl]thiazole (compound of Example 184(2)) as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 61.3%. 1H-NMR(DMSO-d6): δ 1.43(9H, s), 7.00(1H, d, J=8.7 Hz), 7.62(1H, dd, J=8.7, 2.7 Hz), 7.97(1H, d, J=2.7 Hz), 11.75(1H, br), 12.43(1H, br).
Example 186
Preparation of the Compound of Compound No. 185
Using 5-bromosalicylic acid and 2-amino-5-methylthiazole as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 12.9%. 1H-NMR(DMSO-d6): δ 2.33(3H, s), 6.91(1H, d, J=7.6 Hz), 7.26(1H, s), 7.54(1H, d, J=9.6 Hz), 8.03(1H, d, J=2.8 Hz).
Example 187
Preparation of the Compound of Compound No. 187
Using 5-bromosalicylic acid and 2-amino-4,5-dimethylthiazole as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 14.4%. 1H-NMR(DMSO-d6): δ 2.18(3H, s), 2.22(3H, s), 6.89(1H, d, J=8.8 Hz), 7.51(1H, d, J=6.8 Hz), 8.02(1H, d, J=2.8 Hz), 13.23(1H, brs).
Example 188
Preparation of the Compound of Compound No. 188
Using 5-bromosalicylic acid and 2-amino-5-methyl-4-phenylthiazole as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 27.7%. mp 243-244° C. 1H-NMR(CD3OD): δ 2.47(3H, s), 6.92(1H, d, J=8.7 Hz), 7.36-7.41(1H, m), 7.44-7.50(2H, m), 7.53(1H, dd, J=9.0, 2.7 Hz), 7.57-7.61(2H, m), 8.16(1H, d, J=2.7 Hz). [2-Amino-5-methyl-4-phenylthiazole: Refer to “Yakugaku Zasshi: Journal of The Pharmaceutical Society of Japan”, 1961, Vol. 81, p. 1456.]
Example 189
Preparation of the Compound of Compound No. 189
Using (4-fluorophenyl)acetone as the raw material, the same operation as the Examples 184(1)-(3) gave the title compound.
Yield: 28.8% (3 steps).
(1) α-Bromo-(4-fluorophenyl)acetone
1H-NMR(CDCl3): δ 2.33(3H, s), 5.41(1H, s), 7.07(2H, t, J=8.7 Hz), 7.43(2H, dd, J=8.7, 5.1 Hz).
(2) 2-Amino-4-methyl-5-(4-fluorophenyl)thiazole
1H-NMR(CDCl3): δ 2.27(3H, s), 4.88(2H, s), 7.07(2H, t, J=8.7 Hz), 7.32(2H, dd, J=8.7, 5.4 Hz).
(3) 5-Bromo-N-[4-methyl-5-(4-fluorophenyl)thiazol-2-yl]-2-hydroxybenzamide (Compound No. 189)
1H-NMR(DMSO-d6): δ 2.36(3H, s), 6.95(1H, d, J=8.4 Hz), 7.33(2H, t, J=8.7 Hz), 7.52-7.59(3H, m), 8.06(1H, d, J=3.0 Hz), 12.01-13.65(2H, br).
Example 190
Preparation of the Compound of Compound No. 190
Using 3-(trifluoromethyl)phenylacetone as the raw material, the same operation as the Examples 184(1)-(3) gave the title compound.
Yield: 39.8% (3 steps).
(1) α-Bromo-3-(trifluoromethyl)phenylacetone
1H-NMR(CDCl3): δ 2.38(3H, s), 5.43(1H, s), 7.52(1H, t, J=7.8 Hz), 7.61-7.66(2H, m), 7.69-7.70(1H, m).
(2) 2-Amino-4-methyl-5-[3-(trifluoromethyl)phenyl]thiazole
1H-NMR(CDCl1): δ 2.32(3H, s), 4.95(2H, s), 7.46-7.56(3H, m), 7.59-7.61(1H, m).
(3) 5-Bromo-N-{4-methyl-5-[3-(trifluoromethyl)phenyl}thiazol-2-yl]-2-hydroxy-benzamide (Compound No. 190)
1H-NMR(DMSO-d6): δ 2.40(3H, s), 6.97(1H, d, J=8.7 Hz), 7.59(1H, dd, J=8.7, 2.4 Hz), 7.71-7.84(4H, m), (2H, m), 8.06(1H, d, J=2.4 Hz), 12.09(1H, br), 12.91-13.63(1H, br).
Example 191
Preparation of the Compound of Compound No. 191
Using 2,2-dimethyl-3-hexanone as the raw material, the same operation as the Examples 184(1)-(3) gave the title compound.
Yield: 17.0% (3 steps).
(2) 2-Amino-4-[(1,1-dimethyl)ethyl]-5-ethylthiazole
1H-NMR(CDCl3): δ 1.21(3H, t, J=7.5 Hz), 1.32(9H, s), 2.79(2H, q, J=7.5 Hz), 4.63(2H, brs).
(3) 5-Bromo-N-{4-[(1,1-dimethyl)ethyl]-5-ethylthiazol-2-yl}-2-hydroxybenzamide (Compound No. 191)
1H-NMR(CDCl3): δ 1.32(3H, t, J=7.5 Hz), 1.41(9H, s), 2.88(2H, q, J=7.5 Hz), 6.84(1H, d, J=9.0 Hz), 7.44(1H, dd, J=8.7, 2.4 Hz), 8.05(1H, d, J=2.7 Hz), 11.46(2H, br).
Example 192
Preparation of the Compound of Compound No. 192
Using 5-bromosalicylic acid and 2-amino-4-ethyl-5-phenylthiazole as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 17.4%. mp 224-225° C. 1H-NMR(DMSO-d6): δ 1.24(3H, t, J=7.6 Hz), 2.70(2H, q, J=7.6 Hz), 6.95(1H, brd, J=7.6 Hz), 7.39-7.42(1H, m), 7.45-7.51(4H, m), 7.56(1H, brd, J=8.0 Hz), 8.06(1H, d, J=2.8 Hz), 11.98(1H, brs).
Example 193
Preparation of the Compound of Compound No. 193
Using benzyl isopropyl ketone as the raw material, the same operation as the Examples 184(1)-(3) gave the title compound.
Yield: 4.4% (3 steps).
(2) 2-Amino-4-isopropyl-5-phenylthiazole
1H-NMR(CDCl3): δ 1.23(6H, d, J=6.6 Hz), 3.05(1H, m), 4.94(2H, s), 7.28-7.41(5H, m).
(3) 5-Bromo-N-(4-isopropyl-5-phenylthiazol-2-yl)-2-hydroxybenzamide (Compound No. 193)
1H-NMR(DMSO-d6): δ 1.26(6H, d, J=6.0 Hz), 3.15(1H, m), 6.98(1H, brs), 7.43-7.53(5H, m), 7.59(1H, brs), 8.08(1H, d, J=2.7 Hz), 11.90(1H, brd), 13.33(1H, brd).
Example 194
Preparation of the Compound of Compound No. 194
Using 1-phenyl-2-hexanone as the raw material, the same operation as the Examples 184(1)-(3) gave the title compound.
Yield: 52.6% (3 steps).
(1) α-Bromo-1-phenyl-2-hexanone
1H-NMR(CDCl3): δ 0.85(3H, t, J=7.2 Hz), 1.19-1.32(2H, m), 1.50-1.60(2H, m), 2.59(2H, td, J=7.5, 3.9 Hz), 5.44(1H, s), 7.34-7.45(5H, m).
(2) 2-Amino-4-butyl-5-phenylthiazole
1H-NMR(CDCl3): δ 0.89(3H, t, J=7.5 Hz), 1.28-1.41(2H, m), 1.61-1.71(2H, m), 2.56-2.61(2H, m), 4.87(2H, s), 7.25-7.40(5H, m).
(3) 5-Bromo-N-(4-butyl-5-phenylthiazol-2-yl)-2-hydroxybenzamide (Compound No. 194)
1H-NMR(DMSO-d6): δ 0.85(3H, t, J=7.2 Hz), 1.23-1.35(2H, m), 1.59-1.69(2H, m), 2.70(2H, t, J=7.2 Hz), 6.96(1H, d, J=6.9 Hz), 7.39-7.59(6H, m), 8.07(1H, d, J=2.4 Hz), 11.93(1H, br), 13.18-13.59(1H, br).
Example 195
Preparation of the Compound of Compound No. 195
(1) 4-Bromo-2,2,6,6-tetramethyl-3,5-heptanedione[α-Bromo-dipivaloylmethane]
2,2,6,6-Tetramethyl-3,5-heptanedione (dipivaloylmethane; 1.00 g, 5.42 mmol) was dissolved in carbon tetrachloride (10 mL). N-Bromosuccinimide (965.8 mg, 5.42 mmol) was added, and the mixture was refluxed for 2 hours. After cooling, the insoluble matter was filtered off, and the filtrate was evaporated under reduced pressure to give the title compound (1.42 g, quant.) as a white crystal.
1H-NMR(CDCl3): δ 1.27(18H, s), 5.67(1H, s).
When the method described in Example 195(1) is referred in the following examples, N-bromosuccinimide was used as the brominating agent. As the reaction solvent, solvents such as carbon tetrachloride or the like were used.
(2) 2-Amino-4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]thiazole
A mixture of 4-bromo-2,2,6,6-tetramethyl-3,5-heptanedione(α-bromo-dipivaloylmethane; 1.42 g, 5.40 mmol), thiourea (451.8 mg, 5.94 mmol) and ethanol (15 mL) was refluxed for 2 hours. After cooling, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was crystallized (dichloromethane/hexane) to give the title compound (1.23 g, 94.5%) as a white crystal.
1H-NMR(CDCl3): δ 1.26(9H, s), 1.29(9H, s), 5.03(2H, s).
(3) 5-Chloro-N-{4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]thiazol-2-yl}-2-hydroxybenzamide (Compound No. 195)
A mixture of 5-chlorosalicylic acid (143.6 mg, 0.83 mmol), 2-amino-4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]thiazole (200.0 mg, 0.83 mmol), phosphorus trichloride (40 μl, 0.46 mmol) and chlorobenzene (4 mL) was refluxed for 3 hours. The residue obtained by concentration of the reaction mixture under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=3:1) to give the title compound (159.1 mg, 48.4%) as a white powder.
1H-NMR(CDCl3): δ 1.33(9H, s), 1.35(9H, s), 6.99(1H, d, J=8.7 Hz), 7.43(1H, dd, J=9.0, 2.7 Hz), 7.70(1H, d, J=2.7 Hz), 10.52(2H, br).
When the method described in Example 195(3) is referred in the following examples, phosphorus trichloride was used as the acid halogenating agent. As the reaction solvent, solvents such as monochlorobenzene, toluene or the like were used.
Example 196
Preparation of the Compound of Compound No. 196
Using 5-bromosalicylic acid and 2-amino-4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]thiazole (compound of Example 195(2)) as the raw materials, the same operation as the Example 195(3) gave the title compound.
Yield: 23.8%. 1H-NMR(CDCl3): δ 1.33(9H, s), 1.35(9H, s), 6.94(1H, d, J=8, 7 Hz), 7.55(1H, dd, J=8.7, 2.1 Hz), 7.85(1H, d, J=2.1 Hz), 10.51(2H, br).
Example 197
Preparation of the Compound of Compound No. 197
Using pivaloylacetic acid ethyl ester as the raw material, the same operation as the Examples 195(1)-(3) gave the title compound.
Yield: 45.7% (3 steps).
(1) α-Bromo-pivaloylacetic acid ethyl ester
1H-NMR(CDCl3): δ 1.28(9H, s), 1.29(3H, t, J=7.2 Hz), 4.26(2H, q, J=7.2 Hz), 5.24(1H, s).
(2) 2-Amino-4-[(1,1-dimethyl)ethyl]thiazole-5-carboxylic acid ethyl ester
1H-NMR(CDCl3): δ 1.32(3H, t, J=7.2 Hz), 1.43(9H, s), 4.24(2H, q, J=7.2 Hz), 5.18(2H, s).
(3) 2-(5-Bromo-2-hydroxybenzoyl)amino-4-[(1,1-dimethyl)ethyl]thiazole-5-carboxylic acid ethyl ester (Compound No. 197)
1H-NMR(DMSO-d6): δ 1.30(3H, t, J=7.2 Hz), 1.44(9H, s), 4.27(2H, q, J=6.9 Hz), 7.00(1H, d, J=8.7 Hz), 7.63(1H, dd, J=8.7, 2.7 Hz), 8.02(1H, d, J=2.4 Hz), 11.80(1H, br), 12.12(1H, br).
Example 198
Preparation of the Compound of Compound No. 198
(1) 2-Amino-5-bromo-4-[(1,1-dimethyl)ethyl]thiazole
2-Amino-4-[(1,1-dimethyl)ethyl]thiazole (compound of Example 181(1); 0.87 g, 5.6 mmol) was dissolved in carbon tetrachloride (9 mL). N-Bromosuccinimide (1.00 g, 5.6 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Hexane was added to the reaction mixture. The insoluble matter was filtered off, and the residue obtained by evaporation of the filtrate under reduced pressure was purified by chromatography on silica gel (hexane:ethyl acetate=2:1) to give the title compound (1.23 g, 93.7%) as an yellowish gray powder.
1H-NMR(CDCl3): δ 1.39(9H, s), 4.81(2H, brs).
(2) 2-Amino-4-[(1,1-dimethyl)ethyl]-5-piperidinothiazole
A mixture of 2-amino-5-bromo-4-[(1,1-dimethyl)ethyl]thiazole (0.10 g, 0.42 mmol), piperidine (0.1 mL), potassium carbonate (0.20 g) and acetonitrile (4 mL) was refluxed for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=2:1) to give the title compound (80.7 mg, 79.3%) as an yellow crystal.
1H-NMR(CDCl3): δ 1.32(9H, s), 1.64(4H, t, J=5.7 Hz), 1.71-1.77(2H, m), 2.35(2H, brs), 2.99(2H, brs), 4.68(2H, s).
When the preparation method described in Example 198(2) is referred in the following examples, bases such as potassium carbonate or the like were used as the base. As the reaction solvent, solvents such as acetonitrile or the like were used.
(3) 2-Acetoxy-5-bromo-N-{4-[(1,1-dimethyl)ethyl]-5-piperidinothiazol-2-yl}benzamide
Under argon atmosphere, phosphorus oxychloride (46 μl, 0.50 mmol) was added to a mixture of 2-acetoxy-5-bromobenzoic acid (90.3 mg, 0.35 mmol), 2-amino-4-[(1,1-dimethyl)ethyl]-5-piperidinothiazole (80.7 mg, 0.34 mmol), pyridine (0.1 mL) and tetrahydrofuran (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=3:1) to give the title compound (84.3 mg) as a crude product.
When the preparation method described in Example 198(3) is referred in the following examples, phosphorus oxychloride was used as the acid halogenating agent. As the reaction base, pyridine was used. As the reaction solvent, solvents such as dichloromethane, tetrahydrofuran or the like were used.
(4) 5-Bromo-N-{4-[(1,1-dimethyl)ethyl]-5-piperidinothiazol-2-yl}-2-hydroxybenzamide (Compound No. 198)
2-Acetoxy-5-bromo-N-{4-[(1,1-dimethyl)ethyl]-5-piperidinothiazol-2-yl}-benzamide (crude product, 84.3 mg) was dissolved in ethanol (3 mL). 2N Aqueous sodium hydroxide (0.1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give the title compound (54.1 mg, 36.3%; 2 steps) as a white powder.
1H-NMR(CDCl3): δ 1.41(9H, s), 1.56(2H, brs), 1.67-1.74(4H, m), 2.79(4H, brs), 6.85(1H, d, J=9.0 Hz), 7.45(1H, dd, J=9.0, 2.4 Hz), 8.06(1H, d, J=2.4 Hz), 11.70(2H, br).
When the preparation method described in Example 198(4) is referred in the following examples, inorganic bases such as sodium hydroxide, potassium carbonate or the like were used as the base. As the reaction solvent, solvents such as water, methanol, ethanol, tetrahydrofuran or the like were used alone or as a mixture.
Example 199
Preparation of the Compound of Compound No. 199
Using 2-amino-5-bromo-4-[(1,1-dimethyl)ethyl]thiazole (compound of Example 198(1)) and morpholine as the raw materials, the same operation as the Examples 198(2)-(4) gave the title compound.
Yield: 17.1%.
(2) 2-Amino-4-[(1,1-dimethyl)ethyl]-5-morpholinothiazole
1H-NMR(CDCl3): δ 1.33(9H, s), 2.76(4H, brs), 3.79(4H, brs), 4.66(2H, s).
(3) 2-Acetoxy-5-bromo-N-{4-[(1,1-dimethyl)ethyl]-5-morpholinothiazol-2-yl}benzamide
The product was used for the next reaction as a crude product.
(4) 5-Bromo-N-{4-[(1,1-dimethyl)ethyl]-5-morpholinothiazol-2-yl}-2-hydroxybenzamide (Compound No. 199)
1H-NMR(CDCl1): δ 1.24(9H, s), 2.89(4H, dd, J=4.8, 4.2 Hz), 3.83(4H, dd, J=4.5, 4.2 Hz), 6.89(1H, d, J=9.0 Hz), 7.49(1H, dd, J=9.0, 2.4 Hz), 7.98(1H, d, J=2.1 Hz), 11.20(2H, br).
Example 200
Preparation of the Compound of Compound No. 200
Using 2-amino-5-bromo-4-[(1,1-dimethyl)ethyl]thiazole (compound of Example 198(1)) and 4-methylpiperazine as the raw materials, the same operation as the Examples 198(2)-(4) gave the title compound.
Yield: 6.9%.
(2) 2-Amino-4-[(1,1-dimethyl)ethyl]-5-(4-methylpiperazin-1-yl)thiazole
1H-NMR(DMSO-d6): δ 1.25(9H, s), 2.12(2H, brs), 2.19(3H, s), 2.57(2H, brs), 2.72(4H, brs), 6.51(2H, s).
(3) 2-Acetoxy-N-{4-[(1,1-dimethyl)ethyl]-5-(4-methylpiperazin-1-yl)thiazol-2-yl}-benzamide
The product was used for the next reaction as a crude product.
(4) 5-Bromo-N-{4-[(1,1-dimethyl)ethyl]-5-(4-methylpiperazin-1-yl)thiazol-2-yl}-2-hydroxybenzamide (Compound No. 200)
1H-NMR(CD3OD): δ 1.41(9H, s), 2.55(3H, s), 2.87(4H, brs), 3.03(4H, brs), 6.88(1H, d, J=8.7 Hz), 7.49(1H, dd, J=8.7, 2.7 Hz), 8.11(1H, d, J=2.7 Hz).
Example 201
Preparation of the Compound of Compound No. 201
Using 2-amino-5-bromo-4-[(1,1-dimethyl)ethyl]thiazole (compound of Example 198(1)) and 4-phenylpiperazine as the raw materials, the same operation as the Examples 198(2)-(4) gave the title compound.
Yield: 6.9%.
(2) 2-Amino-4-[(1,1-dimethyl)ethyl]-5-(4-phenylpiperazin-1-yl)thiazole
1H-NMR(CDCl3): δ 1.34(9H, s), 2.80(2H, brs), 3.03(4H, brs), 3.55(2H, brs), 4.69(2H, s), 6.88(1H, tt, J=7.2, 1.2 Hz), 6.95(2H, dd, J=9.0, 1.2 Hz), 7.28(2H, dd, J=8.7, 7.2 Hz).
(3) 2-Acetoxy-5-bromo-N-{4-[(1,1-dimethyl)ethyl]-5-(4-phenylpiperazin-1-yl)thiazol-2-yl}benzamide
The product was used for the next reaction as a crude product.
(4) 5-Bromo-N-{4-[(1,1-dimethyl)ethyl]-5-(4-phenylpiperazin-1-yl)thiazol-2-yl}-2-hydroxybenzamide (Compound No. 201)
1H-NMR(DMSO-d6): δ 1.39(9H, s), 2.97(4H, s), 3.30(4H, s), 6.82(1H, t, J=7.5 Hz), 6.97(2H, brs), 6.99(2H, t, J=7.5 Hz), 7.58(1H, brs), 8.05(1H, d, J=2.4 Hz), 11.69(1H, brs), 11.82(1H, brs).
Example 202
Preparation of the Compound of Compound No. 202
Using 5-bromosalicylic acid and 2-amino-4-phenylthiazole as the raw materials, the same operation as the Example 195(3) gave the title compound.
Yield: 16.0%. mp 239° C. (dec.). 1H-NMR(DMSO-d6): δ 7.02(1H, d, J=8.4 Hz), 7.34(1H, t, J=7.6 Hz), 7.44(2H, t, J=7.6 Hz), 7.62(1H, dd, J=8.4, 2.8 Hz), 7.67(1H, s), 7.92(2H, d, J=7.2 Hz), 8.08(111, d, J=2.8 Hz), 11.88(1H, brs), 12.05(1H, brs).
Example 203
Preparation of the Compound of Compound No. 203
(1) {2-[(5-Bromo-2-hydroxybenzoyl)amino]-4-phenylthiazol-5-yl}acetic acid methyl ester
Using 5-bromosalicylic acid and 2-amino-4-phenylthiazole-5-acetic acid methyl ester as the raw materials, the same operation as the Example 195(3) gave the title compound.
Yield: 32.1%. mp 288.5-229.5° C. 1H-NMR(DMSO-d6): δ 3.66(3H, s), 3.95(2H, s), 6.99(1H, d, J=8.0 Hz), 7.42(1H, d, J=6.0 Hz), 7.48(2H, brt, J=7.6 Hz), 7.56-7.61(3H, m), 8.07(1H, d, J=2.4 Hz), 11.85(1H, brs), 11.98(1H, brs).
(2) {2-[(5-Bromo-2-hydroxybenzoyl)amino]-4-phenylthiazol-5-yl}acetic acid (Compound No. 203)
{2-[(5-Bromo-2-hydroxybenzoyl)amino]-4-phenylthiazol-5-yl}acetic acid methyl ester (75 mg, 0.17 mmol) was dissolved in methanol (5 mL). 2N Sodium hydroxide (0.5 mL, 1 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was suspended and washed with n-hexane-ethyl acetate under heating at reflux to give the title compound (56 mg, 77.3%) as a light yellow white crystal.
mp 284-286° C. 1H-NMR(DMSO-d6): δ 3.84(2H, s), 6.98(1H, d, J=8.8 Hz), 7.42(1H, d, J=6.8 Hz), 7.49(2H, t, J=7.6 Hz), 7.58-7.61(3H, m), 8.07(1H, d, J=2.8 Hz), 12.25(H, brs).
Example 204
Preparation of the Compound of Compound No. 204
Using 5-bromosalicylic acid and 2-amino-4,5-diphenylthiazole as the raw materials, the same operation as the Example 195(3) gave the title compound.
Yield: 25.9%. mp 262-263° C. 1H-NMR(DMSO-d6): δ 7.02(1H, d, J=8.1 Hz), 7.34-7.47(10H, m), 7.63(1H, d, J=6.9 Hz), 8.08(1H, d, J=2.4 Hz), 11.88(1H, brs), 12.08(1H, brs).
[2-Amino-4,5-diphenylthiazole: Refer to “Nihon Kagaku Zasshi”, 1962, Vol. 83, p. 209.]
Example 205
Preparation of the Compound of Compound No. 205
Using 5-bromosalicylic acid and 2-amino-4-benzyl-5-phenylthiazole as the raw materials, the same operation as the Example 195(3) gave the title compound.
Yield: 28.1%. mp 198-200° C. 1H-NMR(DMSO-d6): δ 4.08(2H, s), 6.95(1H, d, J=8.8 Hz), 7.15-7.22(3H, m), 7.30(2H, t, J=7.6 Hz), 7.38-7.43(1H, m), 7.47(4H, d, J=4.4 Hz), 7.57(1H, brd, J=8.8 Hz), 8.05(1H, d, J=2.4 Hz), 11.98(1H, brs).
[2-Amino-4-benzyl-5-phenylthiazole: Refer to “Chemical and Pharmaceutical Bulletin”, 1962, Vol. 10, p. 376.]
Example 206
Preparation of the Compound of Compound No. 206
Using 5-bromosalicylic acid and 2-amino-5-phenyl-4-(trifluoromethyl)thiazole as the raw materials, the same operation as the Example 195(3) gave the title compound.
Yield: 33.2%. mp 250° C. (dec.). 1H-NMR(DMSO-d6): δ 7.02(1H, d, J=8.8 Hz), 7.51(5H, s), 7.63(1H, dd, J=8.8, 2.4 Hz), 8.02(1H, d, J=2.8 Hz), 12.38(1H, brs).
Example 207
Preparation of the Compound of Compound No. 207
Using 1-phenyl-1,3-butanedione as the raw material, the same operation as the Examples 195(1)-(3) gave the title compound.
Yield: 8.9% (3 steps).
(1) α-Bromo-1-phenyl-1,3-butanedione
1H-NMR(CDCl3): δ 2.46(3H, s), 5.62(1H, s), 7.48-7.54(2H, m), 7.64(1H, tt, J=7.5, 2.1 Hz), 7.97-8.01(2H, m).
(2) 2-Amino-5-acetyl-4-phenylthiazole
1H-NMR(DMSO-d6): δ 2.18(3H, s), 7.50-7.55(2H, m), 7.59-7.68(3H, m), 8.69(2H, brs).
(3) 5-Bromo-N-(5-acetyl-4-phenylthiazol-2-yl)-2-hydroxybenzamide (Compound No. 207)
1H-NMR(DMSO-d6): δ 2.44(3H, s), 6.99(1H, d, J=9.0 Hz), 7.55-7.71(4H, m), 7.76-7.80(2H, m), 8.01(1H, d, J=2.4 Hz), 12.36(2H, br).
Example 208
Preparation of the Compound of Compound No. 208
Using 1,3-diphenyl-1,3-propanedione as the raw material, the same operation as the Examples 195(1)-(3) gave the title compound.
Yield: 49.7%.
(1) α-Bromo-1,3-diphenyl-1,3-propanedione
1H-NMR(CDCl3): δ 6.55(1H, s), 7.45-7.50(4H, m), 7.61(2H, tt, J=7.2, 2.1 Hz), 7.98-8.01(4H, m).
(2) 2-Amino-5-benzoyl-4-phenylthiazole
1H-NMR(DMSO-d6): δ 7.04-7.18(5H, m), 7.22-7.32(3H, m), 7.35-7.38(2H, m), 8.02(2H, s).
(3) 5-Bromo-N-(5-benzoyl-4-phenylthiazol-2-yl)-2-hydroxybenzamide (Compound No. 208)
1H-NMR(DMSO-d6): δ 7.03(1H, d, J=8.7 Hz), 7.17-7.30(5H, m), 7.39-7.47(3H, m), 7.57-7.60(2H, m), 7.64(1H, dd, J=8.7, 2.7 Hz), 8.05(1H, d, J=2.4 Hz), 11.82(1H, brs), 12.35(1H, brs).
Example 209
Preparation of the Compound of Compound No. 210
Using 5-chlorosalicylic acid and 2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the raw materials, the same operation as the Example 195(3) gave the title compound.
Yield: 69.4%. 1H-NMR(DMSO-d6): δ 1.22(3H, t, J=7.5 Hz), 4.21(2H, q, J=7.5 Hz), 7.07(1H, d, J=8.7 Hz), 7.43-7.47(3H, m), 7.53(1H, dd, J=8.7, 2.4 Hz), 7.70-7.74(2H, m), 7.92(1H, d, J=3.0 Hz), 11.88(1H, br), 12.29(1H, brs).
Example 210
Preparation of the Compound of Compound No. 209
Using 5-bromosalicylic acid and 2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the raw materials, the same operation as the Example 195(3) gave the title compound.
Yield: 28.6%. mp 197-199° C. 1H-NMR(DMSO-d6): δ 1.21(3H, t, J=6.8 Hz), 4.20(2H, q, J=6.8 Hz), 7.01(1H, d, J=8.8 Hz), 7.43-7.48(3H, m), 7.63(1H, dd, J=8.8, 2.4 Hz), 7.70-7.72(2H, m), 8.04(1H, d, J=2.4 Hz), 12.33(1H, brs).
Example 211
Preparation of the Compound of Compound No. 211
Using pentafluorobenzoylacetic acid ethyl ester as the raw material, the same operation as the Examples 195-(1)-(3) gave the title compound.
Yield: 40.0% (3 steps).
(1) α-Bromo-pentafluorobenzoylacetic acid ethyl ester
It was used for the next reaction as a crude product.
(2) 2-Amino-4-(pentafluorophenyl)thiazole-5-carboxylic acid ethyl ester
1H-NMR(CDCl3): δ 1.23(3H, t, J=7.2 Hz), 4.21(2H, q, J=7.2 Hz), 5.41(2H, s).
(3) Ethyl 2-(5-bromo-2-hydroxybenzoyl)amino-4-(pentafluorophenyl)thiazole-5-carboxylate (Compound No. 211)
1H-NMR(DMSO-d6): δ 1.20(3H, t, J=7.2 Hz), 2.51(2H, q, J=7.2 Hz), 7.02(1H, d, J=8.7 Hz), 7.64(1H, dd, J=8.7, 2.7 Hz), 7.90(1H, d, J=3.0 Hz), 11.92(1H, br), 12.58(1H, br).
Example 212
Preparation of the Compound of Compound No. 212
(1) 2-(5-Bromo-2-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylic acid
Using 2-(5-bromo-2-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylic acid ethyl ester (compound No. 209) as the raw material, the same operation as the Example 82 gave the title compound.
Yield: 67.0%. 1H-NMR(DMSO-d6): δ 7.00(1H, d, J=8.8 Hz), 7.42-7.44(3H, m), 7.62(1H, dd, J=8.8, 2.4 Hz), 7.70-7.72(2H, m), 8.04(1H, d, J=2.4 Hz), 12.31(1H, brs), 12.99(1H, brs).
(2) [2-(5-Bromo-2-hydroxybenzoyl)amino-4-phenylthiazol-5-yl]-N-methylcarboxamide (Compound No. 212)
A mixture of 2-(5-bromo-2-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylic acid (0.20 g, 0.48 mmol), methylamine 40% methanol solution (0.2 ml), 1-hydroxybenzotriazole hydrate (96.7 mg, 0.72 mmol), WSC.HCl (137.2 mg, 0.72 mmol) and tetrahydrofuran (15 mL) was stirred at room temperature for 18 hours. The reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=1:2), and crystallized (dichloromethane/n-hexane) to give the title compound (87.9 mg, 42.6%) as a white powder.
1H-NMR(DMSO-d6): δ 2.70(3H, d, J=4.5 Hz), 7.02(1H, d, J=9.0 Hz), 7.40-7.48(3H, m), 7.63(1H, dd, J=9.0, 2.4 Hz), 7.68-7.71(2H, m), 8.06(1H, d, J=2.4 Hz), 8.16(1H, t, J=4.5 Hz), 11.88(1H, br), 12.15(1H, brs).
When the method described in Example 212(2) is referred in the following examples, WSC.HCl and 1-hydroxybenzotriazole hydrate were used as the dehydrocondensating agent. As the reaction solvent, solvents such as tetrahydrofuran or the like were used.
Example 213
Preparation of the Compound of Compound No. 213
Using 2-(5-bromo-2-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylic acid (compound of Example 212(1)) and 70% aqueous ethylamine solution as the raw materials, the same operation as the Example 212(2) gave the title compound.
Yield: 62.5%. 1H-NMR(DMSO-d6): δ 1.05(3H, t, J=6.9 Hz), 3.15-3.24(2H, m), 7.02(1H, d, J=8.7 Hz), 7.40-7.47(3H, m), 7.63(1H, dd, J=8.7, 3.0 Hz), 7.69-7.72(2H, m), 8.06(1H, d, J=2.4 Hz), 8.20(1H, t, J=5.4 Hz), 11.84(1H, br), 12.14(1H, brs).
Example 214
Preparation of the Compound of Compound No. 214
Using 2-(5-bromo-2-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylic acid (compound of Example 212(1)) and isopropylamine as the raw materials, the same operation as the Example 212(2) gave the title compound.
Yield: 23.9%. 1H-NMR(DMSO-d6): δ 1.07(6H, d, J=6.3 Hz), 4.02(1H, m), 7.02(1H, d, J=9.0 Hz), 7.40-7.52(3H, m), 7.64(1H, dd, J=8.7, 2.7 Hz), 7.69-7.73(2H, m), 8.06(1H, d, J=2.7 Hz), 11.89(1H, br), 12.14(1H, brs).
Example 215
Preparation of the Compound of Compound No. 215
Using 2-(5-bromo-2-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylic acid (compound of Example 212(1)) and 2-phenethylamine as the raw materials, the same operation as the Example 212(2) gave the title compound.
Yield: 62.2%. 1H-NMR(DMSO-d6): δ 2.78(2H, t, J=7.5 Hz), 3.43(2H, q, J=7.5 Hz), 7.02(1H, d, J=9.0 Hz), 7.19-7.24(3H, m), 7.27-7.33(2H, m), 7.39-7.41(3H, m), 7.61-7.65(3H, m), 8.06(1H, d, J=2.4 Hz), 8.25(1H, t, J=6.0 Hz), 11.85(1H, brs), 12.15(1H, brs).
Example 216
Preparation of the Compound of Compound No. 216
Using 5-bromosalicylic acid and 2-amino-4-(trifluoromethyl)thiazole-5-carboxylic acid ethyl ester as the raw materials, the same operation as the Example 195(3) gave the title compound.
Yield: 88.7%. 1H-NMR(DMSO-d6): δ 1.32(3H, t, J=7.2 Hz), 4.33(2H, q, J=7.2 Hz), 7.01(1H, d, J=8.7 Hz), 7.63(1H, dd, J=8.7, 2.7 Hz), 7.98(1H, d, J=2.4 Hz), 12.64(1H, br).
Example 217
Preparation of the Compound of Compound No. 217
Using 5-chloro-N-{4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]thiazol-2-yl}-2-hydroxybenzamide (compound No. 195) and acetyl chloride as the raw materials, the same operation as the Example 96 gave the title compound.
Yield: 65.3%. 1H-NMR(CDCl1): δ 1.32(9H, s), 1.33(9H,s), 2.46(3H, s), 7.22(1H, d, J=8.4 Hz), 7.56(1H, dd, J=8.7, 2.4 Hz), 8.05(1H, d, J=2.7 Hz), 9.82(1H, brs).
Example 218
Preparation of the Compound of Compound No. 218
Using 4-hydroxybiphenyl-3-carboxylic acid and 2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the raw materials, the same operation as the Example 195(3) gave the title compound.
Yield: 61.7%. mp 207-208° C. 1H-NMR(DMSO-d6): δ 1.23(3H, t, J=7.2 Hz), 4.22(2H, q, J=7.2 Hz), 7.16(1H, d, J=8.7 Hz), 7.36(1H, t, J=7.5 Hz), 7.45-7.50(5H, m), 7.69-7.76(4H, m), 7.85(1H, dd, J=8.7, 2.4 Hz), 8.31(1H, d, J=2.4 Hz), 11.73(1H, brs), 12.60(1H, brs).
[4-Hydroxybiphenyl-3-carboxylic acid: Refer to “Tetrahedron”, 1997, Vol. 53, p. 11437.]
Example 219
Preparation of the Compound of Compound No. 219
Using (4′-fluoro-4-hydroxybiphenyl)-3-carboxylic acid and 2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the raw materials, the same operation as the Example 195(3) gave the title compound.
Yield: 62.7%. mp 237-238° C. 1H-NMR(DMSO-d6): δ 1.22(3H, t, J=7.2 Hz), 4.21(2H, q, J=7.2 Hz), 7.13(1H, d, J=8.4 Hz), 7.28(2H, t, J=8.8 Hz), 7.44-7.45(3H, m), 7.71-7.75(4H, m), 7.81(1H, dd, J=8.8, 2.4 Hz), 8.27(1H, d, J=2.4 Hz), 11.67(1H, brs), 12.58(1H, brs).
[(4′-Fluoro-4-hydroxybiphenyl)-3-carboxylic acid: Refer to “Tetrahedron”, 1997, Vol. 53, p. 11437.]
Example 220
Preparation of the Compound of Compound No. 220
Using (2′,4′-difluoro-4-hydroxybiphenyl)-3-carboxylic acid and 2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the raw materials, the same operation as the Example 195(3) gave the title compound.
Yield: 45.6%. mp 206-207° C. 1H-NMR(DMSO-d6): δ 1.22(3H, t, J=7.2 Hz), 4.22(2H, q, J=7, 2 Hz), 7.17(1H, d, J=9.0 Hz), 7.21(1H, td, J=8.7, 2.4 Hz), 7.38(1H, ddd, J=11.7, 9.3, 2.4 Hz), 7.44-7.46(3H, m), 7.60-7.75(4H, m), 8.13-8.14(1H, m), 11.86(1H, brs), 12.46(1H, brs).
Example 221
Preparation of the Compound of Compound No. 221
(1) [4-Hydroxy-4′-(trifluoromethyl)biphenyl]-3-carboxylic acid
A mixture of 5-bromosalicylic acid (500 mg, 2.30 mmol), dihydroxy-4-(trifluoromethyl)phenylborane (488 mg, 2.57 mmol), palladium acetate (10 mg, 0.040 mmol) and 1M sodium carbonate (7 mL) was stirred at 80° C. for 1 hour. The reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. According to the fixed procedure, the obtained residue was methyl-esterified by trimethylsilyldiazomethane and methanol, and purified by column chromatography on silica gel (n-hexane:ethyl acetate=5:1) to give a colourless liquid (563 mg). This liquid was dissolved in methanol (10 mL). 2N Sodium hydroxide (3 mL) was added, and the mixture was stirred at 60° C. for 1 hour. After the reaction mixture was cooled to room temperature, it was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was suspended and washed with n-hexane-dichloromethane under heating at reflux to give the title compound (458 mg, 70.4%) as a white crystal.
mp 185° C. (dec). 1H-NMR(DMSO-d6): δ 7.09(1H, d, J=8.8 Hz), 7.77(2H, d, J=8.0 Hz), 7.85(2H, d, J=8.0 Hz), 7.90(1H, dd, J=8.8, 2.0 Hz), 8.10(1H, d, J=2.4 Hz), 11.80(1H, brs).
(2) 2-{[4-Hydroxy-4′-(trifluoromethyl)biphenyl]-3-carbonyl}amino-4-phenylthiazole-5-carboxylic acid ethyl ester (Compound No. 221)
Using [4-hydroxy-4′-(trifluoromethyl)biphenyl]-3-carboxylic acid and 2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the raw materials, the same operation as the Example 195(3) gave the title compound.
Yield: 41.7%. mp 236-237° C. 1H-NMR(DMSO-d6): δ 1.22(3H, t, J=7.2 Hz), 4.21(2H, q, J=7.2 Hz), 7.18(1H, d, J=8.8 Hz), 7.44-7.45(3H, m), 7.72-7.74(2H, m), 7.81(2H, d, J=8.4 Hz), 7.91(1H, dd, J=8.8, 2.4 Hz), 7.93(2H, d, J=8.4 Hz), 8.36(1H, d, J=2.4 Hz), 11.78(1H, brs), 12.62(1H, brs).
Example 222
Preparation of the Compound of Compound No. 222
Using 2-hydroxy-5-(1-pyrrolyl)benzoic acid and 2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the raw materials, the same operation as the Example 195(3) gave the title compound.
Yield: 55.0%. 1H-NMR(DMSO-d6): δ 1.22(3H, t, J=7.2 Hz), 4.22(2H, q, J=7.2 Hz), 6.26(2H, t, J=2.1 Hz), 7.13(1H, d, J=8.7 Hz), 7.32(2H, t, J=2.1 Hz), 7.43-7.47(3H, m), 7.70-7.75(3H, m), 8.09(1H, d, J=2.7 Hz), 11.58(1H, brs), 12.55(1H, brs).
Example 223
Preparation of the Compound of Compound No. 223
(1) 2-Hydroxy-5-(2-thienyl)benzoic acid
5-Bromosalicylic acid (500 mg, 2.30 mmol) was dissolved in 1,2-dimethoxyethane (5 mL). Tetrakis(triphenylphosphine)palladium (80 mg, 0.07 mmol) was added under argon atmosphere, and the mixture was stirred at room temperature for 10 minutes. Then dihydroxy-2-thienylborane (324 mg, 2.53 mmol) and 1M sodium carbonate (7 mL) were added, and the mixture was refluxed for 2 hours. After the reaction mixture was cooled to room temperature, it was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. According to the fixed procedure, the obtained residue was methyl-esterified by trimethylsilyldiazomethane and methanol, and purified by column chromatography on silica gel (n-hexane:ethyl acetate=5:1) to give an yellow liquid (277 mg). This was dissolved in methanol (5 mL). 2N Sodium hydroxide (1.5 mL) was added, and the mixture was stirred at 60° C. for 1 hour. After the reaction mixture was cooled to room temperature, it was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was crystallized from n-hexane-dichloromethane to give the title compound (58 mg, 11.5%) as a white crystal.
1H-NMR(DMSO-d6): δ 6.95(1H, d, J=8.8 Hz), 7.09(1H, dd, J=4.8, 3.6 Hz), 7.37(1H, dd, J=4.0, 1.2 Hz), 7.45(1H, dd, J=5.2, 1.2 Hz), 7.74(1H, dd, J=8.8, 2.8 Hz), 7.96(1H, d, J=2.8 Hz).
(2) 2-[2-Hydroxy-5-(2-thienyl)benzoyl]amino-4-phenylthiazole-5-carboxylic acid ethyl ester (Compound No. 223)
Using 2-hydroxy-5-(2-thienyl)benzoic acid and 2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the raw materials, the same operation as the Example 195(3) gave the title compound.
Yield: 58.2%. mp 213-214° C. 1H-NMR(DMSO-d6): δ 1.22(3H, t, J=7.2 Hz), 4.21(2H, q, J=7.2 Hz), 7.10(1H, d, J=9.2 Hz), 7.12(1H, dd, J=4.8, 3.6 Hz), 7.44-7.46(4H, m), 7.50(1H, dd, J=4.8, 1.2 Hz), 7.71-7.74(2H, m), 7.79(1H, dd, J=8.8, 2.4 Hz), 8.21(1H, d, J=2.4 Hz), 11.78(1H, brs), 12.44(1H, brs).
Example 301
Preparation of the Compound of Compound No. 301
(1) 5-Chloro-2-methoxy-β-phenylstyrene
Palladium acetate (21 mg, 7 mol %) was added to a solution of 2-bromo-4-chloroanisole (300 mg, 1.4 mmol), styrene (211 mg, 2 mmol), triethylamine (13 μL, 0.1 mmol) and triphenylphosphine (50 mg, 1.9 mmol) in acetonitrile (6 mL), and the mixture was refluxed for 8 hours under argon atmosphere. After the reaction mixture was cooled to room temperature, the solvent was concentrated under reduced pressure and the obtained residue was diluted with ethyl acetate (15 mL). After the solution was washed successively with 2N hydrochloric acid, water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=10:1) to give the title compound (118 mg, 35.6%) as a white powder.
1H-NMR(CDCl3): δ 3.85(3H, s), 6.80(1H, d, J=8.8 Hz), 7.08(1H, d, J=16.8 Hz), 7.17(1H, dd, J=8.8, 2.5 Hz), 7.20-7.42(4H, m), 7.51-7.55(3H, m).
(2) 4-Chloro-2-styrylphenol (Compound No. 301)
Under argon atmosphere, 1 mol/L boron tribromide/dichloromethane solution (0.5 mL, 0.5 mmol) was added to a solution of 5-chloro-2-methoxy-β-phenylstyrene (80 mg, 0.3 mmol) in dichloromethane (2 mL) at room temperature, and the mixture was stirred for 12 hours. The reaction mixture was diluted with ethyl acetate (15 mL), and after it was washed successively with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:1) to give the title compound (34.2 mg, 45.4%) as a white powder.
1H-NMR(CDCl3): δ 4.95 (1H, brs), 6.74(1H, d, J=8.7 Hz), 7.09(1H, dd, =8.7, 2.4 Hz), 7.10(1H, d, J=16.2 Hz), 7.28-7.39(4H, m), 7.49-7.54(3H, m).
Example 302
Preparation of the Compound of Compound No. 302
(1) (S)-2-Amino-3-phenyl-N-[3,5-bis(trifluoromethyl)phenyl]propionamide
A mixture of 3,5-bis(trifluoromethyl)aniline (0.20 g, 0.87 mmol), N-(tert-butoxycarbonyl)-L-phenylalanine (254.8 mg, 0.96 mmol), phosphorus trichloride (40 μL, 0.46 mmol) and toluene (4 mL) was stirred at 80° C. for 1.5 hours under argon atmosphere. After the reaction mixture was cooled to room temperature, it was poured into aqueous sodium hydrogen carbonate and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was crystallized by isopropyl ether/n-hexane to give the title compound (333.7 mg, 92.9%) as an yellow white powder.
1H-NMR(DMSO-d6): δ 3.13(1H, dd, J=13.8, 8.1 Hz), 3.29(1H, dd, J=13.8, 6.0 Hz), 4.37(1H, s), 7.25-7.38(5H, m), 7.86(1H, s), 8.30(2H, s), 8.48(3H, s), 11.95(1H, s).
When the method described in Example 302(1) is referred in the following examples, phosphorus trichloride was used as the acid halogenating agent. As the reaction solvent, solvents such as toluene, monochlorobenzene or the like were used.
(2) (S)-2-Acetoxy-5-chloro-N-(2-phenyl-1-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-ethyl)benzamide
WSC.HCl (184 mg, 0.96 mmol) was added to a solution of 2-acetoxy-5-chlorobenzoic acid (104 mg, 0.48 mmol), (S)-2-amino-3-phenyl-N-[3,5-bis(trifluoromethyl)phenyl]propionamide (0.20 g, 0.48 mmol) and 1-hydroxybenzotriazole (71.4 mg, 0.53 mmol) in N,N-dimethylformamide (4 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:1→2:1) to give the title compound (141.4 mg, 51.4%) as a white crystal.
1H-NMR(DMSO-d6): δ 2.05(3H, s), 3.04(1H, dd, J=13.8, 9.9 Hz), 3.19(1H, dd.J=13.8, 4.8 Hz), 4.73-4.81(1H, m), 7.22-7.35(6H, m), 7.54(1H, d, J=2.4 Hz), 7.60(1H, dd, J=8.7, 2.4 Hz), 7.81(1H, s), 8.27(2H, s), 8.91(1H, d, J=7.8 Hz), 10.81(1H, s).
When the method described in Example 302(2) is referred in the following examples, WSC.HCl and 1-hydroxybenzotriazole hydrate were used as the dehydrocondensating agent. As the reaction solvent, solvents such as N,N-dimethylformamide or the like were used.
(3) (S)-5-Chloro-2-hydroxy-N-(2-phenyl-1-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-ethyl)benzamide (Compound No. 302)
5N Aqueous sodium hydroxide (0.2 mL) was added to a solution of (S)-2-acetoxy-5-chloro-N-(2-phenyl-1-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-ethyl)benzamide (141.4 mg, 0.25 mmol) in a mixed solvent of methanol/tetrahydrofuran (2 mL+2 mL), and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was crystallized by ethyl acetate/isopropyl ether/n-hexane to give the title compound (74.4 mg, 56.8%) as a white powder.
1H-NMR(DMSO-d6): δ 3.13(1H, dd, J=13.8, 9.0 Hz), 3.26(1H, dd, J=14.1, 4.8 Hz), 4.85-4.92(1H, m), 6.95(1H, d, J=8.7 Hz), 7.19-7.23(1H, m), 7.26-7.31(4H, m), 7.45(1H, dd, J=8.7, 2.4 Hz), 7.81(1H, s), 7.97(1H, d, J=2.4 Hz), 8.26(2H, s), 9.12(1H, d, J=7.2 Hz), 10.89(1H, s), 12.01(1H, s).
When the method described in Example 302(3) is referred in the following examples, inorganic bases such as sodium hydroxide, potassium carbonate or the like were used as the base. As the reaction solvent, solvents such as water, methanol, ethanol, tetrahydrofuran or the like were used alone or as a mixture.
Example 303
Preparation of the Compound of Compound No. 303
(1) [1-({[3,5-Bis(trifluoromethyl)phenyl]amino}carbonyl)methyl]carbamic acid 1,1-dimethyl ester
Under argon atmosphere, N-(tert-butoxycarbonyl)glycine (183.5 mg, 1.05 mmol) and triethylamine (0.25 mL, 1.79 mmol) were added to a solution of 3,5-bis(trifluoromethyl)aniline (0.20 g, 0.87 mmol) in tetrahydrofuran (4 mL), and after cooling with ice bath, phosphorus oxychloride (96 μL, 1.05 mmol) was added and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1→3:2) to give the title compound (101.9 mg, 30.3%) as a white crystal.
1H-NMR(CDCl3): δ 1.49(9H, s), 3.99(2H, d, J=6.0 Hz), 5.37(1H, t, J=6.0 Hz), 7.57(1H, s), 8.00(2H, s), 9.06(1H, brs).
(2) 2-Amino-N-[3,5-bis(trifluoromethyl)phenyl]acetamide hydrochloride
4N Hydrochloric acid/ethyl acetate solution (1 mL) was added to [1-({[3,5-bis(trifluoromethyl)phenyl]amino}carbonyl)methyl]carbamic acid 1,1-dimethyl ester (101.9 mg, 0.26 mmol), and the mixture was stirred at room temperature for 1 hour. n-Hexane (15 mL) was added to the reaction mixture and the separated white solid was filtered to give the title compound (80.8 mg, 96.4%) as a white powder.
1H-NMR(CD3OD): δ 3.89(2H, s), 7.71(1H, s), 8.22(2H, s).
(3) 2-Acetoxy-5-chloro-N-({[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-methyl)benzamide
WSC.HCl (95.9 mg, 0.5 mmol) was added to a solution of 2-acetoxy-5-chlorobenzoic acid (59.1 mg, 0.28 mmol), 2-amino-N-[3,5-bis(trifluoromethyl)phenyl]acetamide hydrochloride (80.8 mg, 0.25 mmol) and 1-hydroxybenzotriazole (37.2 mg, 0.28 mmol) in N,N-dimethylformamide (3 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:2→1:1) to give the title compound (83.7 mg, 69.3%) as a white crystal.
1H-NMR(CDCl3): δ 2.40(3H, s), 4.40(2H, d, J=5.4 Hz), 7.17(1H, d.J=8.4 Hz), 7.40(1H, t, J=5.4 Hz), 7.53(1H, dd, J=8.4, 2.4 Hz), 7.62(1H, s), 7.82(1H, d, J=2.4 Hz), 8.19(2H, s), 9.20(1H, s).
(4) 5-Chloro-2-hydroxy-N-({[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-methyl)benzamide (Compound No. 303)
5N Aqueous sodium hydroxide (0.1 mL) was added to a solution of 2-acetoxy-5-chloro-N-({[3,5-bis(trifluoromethyl)phenyl]carbamoyl}methyl)benzamide (83.7 mg, 0.17 mmol) in methanol/tetrahydrofuran (2 mL+1 mL), and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1) and washed with n-hexane under suspension to give the title compound (47.7 mg, 63.7%) as a white crystal.
1H-NMR(DMSO-d6): δ 4.18(2H, d, J=5.4 Hz), 7.00(1H, d, J=9.0 Hz), 7.47(1H, dd, J=9.0, 2.7 Hz), 7.80(1H, s), 7.96(1H, d, J=2.7 Hz), 8.27(2H, s), 9.25(1H, t, J=5.4 Hz), 10.78(1H, s), 12.14(1H, s).
Example 304
Preparation of the Compound of Compound No. 304
(1) 5-Chlorosalicylhydrazide
A mixture of 5-chloro-2-hydroxybenzoic acid methyl ester (0.50 g, 2.7 mmol), hydrazine monohydrate (0.3 mL, 6.2 mmol) and ethanol (5 mL) was refluxed for 6 hours. After the reaction mixture was cooled to room temperature, n-hexane was added and the separated crystal was filtered to give the title compound (395.9 mg, 79.2%) as a white crystal.
1H-NMR(DMSO-d6): δ 6.90(1H, d, J=8.7 Hz), 7.38(1H, dd, J=8.7, 2.7 Hz), 7.85(1H, d, J=8.7 Hz), 10.23(brs).
(2) 5-Chlorosalicylic acid [3,5-bis(trifluoromethyl)benzylidene]hydrazide (Compound No. 304)
A mixture of 5-chlorosalicylhydrazide (213.9 mg, 1.2 mmol), 3,5-bis(trifluoromethyl)benzaldehyde (190 μL, 1.2 mmol), concentrated sulfuric acid (3 drops) and ethanol (5 mL) was refluxed for 30 minutes. 3,5-Bis(trifluoromethyl)benzaldehyde (100 μL, 0.61 mmol) was added and the mixture was refluxed for further 1 hour. After the reaction mixture was cooled to room temperature, it was poured into water and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine, dried over sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:1→2:1) and washed with n-hexane under suspension to give the title compound (362.6 mg, 76.8%) as a white powder.
1H-NMR(DMSO-d6): δ 7.03(1H, d, J=9.0 Hz), 7.49(1H, dd, J=9.0, 2.7 Hz), 7.86(1H, d, J=3.0 Hz), 8.20(1H, s), 8.40(2H, s), 8.59(1H, s), 11.65(1H, s), 12.14(1H, s).
Example 305
Preparation of the Compound of Compound No. 305
(1) (S)-2-Amino-4-methyl-N-[3,5-bis(trifluoromethyl)phenyl]pentanamide
Using N-(tert-butoxycarbonyl)-L-leucine and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 302(1) gave the title compound.
Yield: 25.2%. 1H-NMR(CDCl3): δ 0.98(3H, d, J=6.3 Hz), 1.01(3H, d, J=6.3 Hz), 1.39-1.48(1H, m), 1.74-1.89(2H, m), 3.55(1H, dd, J=9.9, 3.6 Hz), 7.58(1H, s), 8.12(2H, s), 10.01(1H, s).
(2) (S)-5-Chloro-2-hydroxy-N-(3-methyl-1-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-butyl)benzamide (Compound No. 305)
Using 2-acetoxy-5-chlorobenzoic acid and (S)-2-amino-4-methyl-N-[3,5-bis-(trifluoromethyl)phenyl]pentanamide as the raw materials, the same operation as the Example 302(2)-(3) gave the title compound.
Yield: 24.8% (2 steps). 1H-NMR(DMSO-d6): δ 0.95(3H, d, J=5.7 Hz), 0.97(3H, d, J=6.0 Hz), 1.65-1.84(3H, m), 4.65-4.72(1H, m), 6.98(1H, d, J=9.0 Hz), 7.47(1H, dd, J=8.7, 2.4 Hz), 7.79(1H, s), 8.06(1H, d, J=2.7 Hz), 8.32(2H, s), 9.03(1H, d, J=8.1 Hz), 10.85(1H, s), 12.20(1H, s).
Example 306
Preparation of the Compound of Compound No. 306
Using 5-chlorosalicylaldehyde and 3,5-bis(trifluoromethyl)benzhydrazide as the raw materials, the same operation as the Example 304(2) gave the title compound.
Yield: 24.7%.
1H-NMR(DMSO-d6): δ 6.97(1H, d, J=8.7 Hz), 7.34(1H, dd, J=9.0, 2.7 Hz), 7.73(1H, d, J=2.4 Hz), 8.41(1H, s), 8.59(2H, s), 8.67(1H, s), 11.07(1H, s), 12.45(1H, s).
Example 307
Preparation of the Compound of Compound No. 307
Using 5-chlorosalicylic acid and 3,5-bis(trifluoromethyl)phenethylamine as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 30.2%. 1H-NMR(CDCl3): δ 3.10(2H, t, J=6.9 Hz), 3.71-3.77(2H, m), 6.34(1H, brs), 6.95(1H, d, J=8.7 Hz), 7.23(1H, d, J=2.7 Hz), 7.36(1H, dd, J=8.7, 2.4 Hz), 7.70(2H, s), 7.80(1H, s), 12.06(1H, s).
Example 308
Preparation of the Compound of Compound No. 308
A mixture of 3-hydroxyphthalic anhydride (100 mg, 0.6 mmol), 3,5-bis(trifluoromethyl)aniline (168 mg, 0.7 mmol) and acetic acid (5 mL) was refluxed for 6 hours under argon atmosphere. After the reaction mixture was cooled to room temperature, acetic acid was evaporated under reduced pressure and the obtained residue was dissolved in ethyl acetate (15 mL). After the ethyl acetate solution was washed successively with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:1) to give the title compound (100 mg, 43.7%) as a white powder.
1H-NMR(DMSO-d6): δ 7.31(1H, d, J=8.1 Hz), 7.42(1H, d, J=7.5 Hz), 7.72(1H, dd, J=8.1, 7.5 Hz), 8.21(1H, s), 8.24(2H, s), 11.28(1H, s).
Example 309
Preparation of the Compound of Compound No. 309
3,5-Bis(trifluoromethyl)phenylisocyanate (180 μL, 1.04 mmol) was added to a solution of 2-amino-4-chlorophenol (143.6 mg, 1 mmol) in a mixed solvent of tetrahydrofuran/toluene (0.5 mL+4.5 mL), and the mixture was stirred at 100° C. for 1 hour. After the reaction mixture was cooled to room temperature, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:1) and crystallized by isopropyl ether/n-hexane to give the title compound (288.5 mg, 72.4%) as a light yellowish brown powder.
1H-NMR(DMSO-d6): δ 6.84-6.91(2H, m), 7.67(1H, s), 8.06(2H, s), 8.14(1H, d, J=2.1 Hz), 8.45(1H, s), 10.10(1H, s), 10.44(1H, s).
Example 310
Preparation of the Compound of Compound No. 310
(1) 5-Chloro-2-methoxy-β-[3,5-bis(trifluoromethyl)phenyl]styrene
A solution of sodium nitrite (57 mg, 0.8 mmol) in water (1 mL) was added to a solution of 2-amino-4-chloroanisole (131 mg, 0.8 mmol) in 48% hydrogen tetrafluoroborate (0.3 mL) under ice cooling and argon atmosphere. After the mixture was stirred at 0° C. for 1 hour, a solution of 3,5-bis(trifluoromethyl)styrene (100 mg, 0.4 mmol) in methanol (3 mL) was added and the mixture was stirred at 50° C. for 1 hour. After the reaction mixture was cooled to room temperature, the residue obtained by evaporation of the solvent under reduced pressure was diluted with ethyl acetate. After the solution was washed successively with 2N hydrochloric acid, water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=5:1) to give the title compound (52.8 mg, 33.3%) as a white powder.
1H-NMR(CDCl3): δ 3.85(3H, s), 6.80(1H, d, J=8.8 Hz), 7.08(1H, d, J=16.8 Hz), 7.17(1H, dd, J=8.8, 2.5 Hz), 7.20-7.42(4H, m), 7.51-7.55(3H, m).
(2) 4-Chloro-2-[3,5-bis(trifluoromethyl)styryl]phenol (Compound No. 310)
Using 5-chloro-2-methoxy-β-[3,5-bis(trifluoromethyl)phenyl]styrene as the raw material, the same operation as the Example 301(2) gave the title compound.
Yield: 18.1%. 1H-NMR(CDCl3): δ 5.16(1H, brs), 6.76(1H, d,J=8.4 Hz), 7.15(1H, dd, J=8.4, 2.7 Hz), 7.19(1H, d, J=16.5 Hz), 7.45(1H, d, J=15.5 Hz), 7.53(1H, d, J=2.4 Hz), 7.76(1H, s), 7.93(2H, s).
Example 311
Preparation of the Compound of Compound No. 311
Using 5-chlorosalicylic acid and 2-aminoindane as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 45.3%. 1H-NMR(DMSO-d6): δ 2.98(2H, dd, J=16.2, 5.7 Hz), 3.29(2H, dd, J=16.2, 7.5 Hz), 4.69-4.79(1H, m), 6.93(1H, d, J=8.7 Hz), 7.16-7.20(2H, m), 7.23-7.28(2H, m), 7.43(1H, dd, J=8.7, 2.4 Hz), 8.02(1H, d, J=2.4 Hz), 9.03(1H, d, J=6.9 Hz), 12.66(1H, s).
Example 312
Preparation of the Compound of Compound No. 312
(1) 4-Chloro-2-({[3,5-bis(trifluoromethyl)phenyl]imino}methyl)phenol
Using 5-chlorosalicylaldehyde and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 14(1) gave the title compound.
Yield: 76.6%. 1H-NMR(DMSO-d6): δ 7.04(1H, d, J=9.0 Hz), 7.50(1H, dd, J=9.0, 2.7 Hz), 7.80(1H, d, J=2.7 Hz), 8.01(1H, s), 8.12(2H, s), 9.03(1H, s), 12.09(1H, brs).
(2) N-[(5-Chloro-2-hydroxyphenyl)methyl]-3,5-bis(trifluoromethyl)aniline (Compound No. 312)
Using 4-chloro-2-({[3,5-bis(trifluoromethyl)phenyl]imino}methyl)phenol as the raw material, the same operation as the Example 14(2) gave the title compound.
Yield: 78.1%. 1H-NMR(CDCl3): δ 4.40(3H, s), 6.27(1H, s), 6.80(1H, d, J=8.4 Hz), 7.11(2H, s), 7.17-7.20(2H, m), 7.30(1H, s).
Example 313
Preparation of the Compound of Compound No. 313
WSC.HCl (138 mg, 0.7 mmol) was added to a solution of N-[(5-chloro-2-hydroxyphenyl)methyl]-3,5-bis(trifluoromethyl)aniline (Compound No. 312; 88.8 mg, 0.24 mmol) and acetic acid (43 mg, 0.7 mmol) in dichloromethane (2 mL) under argon atmosphere, and the mixture was stirred at room temperature for 12 hours. After the reaction mixture was diluted with ethyl acetate, washed successively with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:1) to give the title compound (69 mg, 70.4%) as a white powder.
1H-NMR(CDCl3): δ 1.92(3H, s), 4.73(2H, s), 6.54(1H, d, J=2.4 Hz), 6.95(1H, d, J=8.4 Hz), 7.22(1H, dd, J=8.7, 2.4 Hz), 7.53(2H, s), 7.99(1H, s), 9.21(1H, s).
Example 314
Preparation of the Compound of Compound No. 314
3,5-Bis(trifluoromethyl)benzoyl chloride (100 μL, 0.55 mmol) was added to a solution of 5-chlorosalicylhydrazide (compound of Example 304(1); 0.1 g, 0.53 mmol) in pyridine (3 mL) and the mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine and dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was washed with ethyl acetate/isopropyl ether/n-hexane under suspension to give the title compound (169 mg, 74.7%) as a white powder.
1H-NMR(DMSO-d6): δ 7.04(1H, d, J=9.0 Hz), 7.51(1H, dd, J=8.7, 2.4 Hz), 7.92(1H, d, J=2.4 Hz), 8.43(1H, s), 8.57(2H, s), 10.79(1H, s), 11.37(1H, s), 11.81(1H, s).
Example 315
Preparation of the Compound of Compound No. 315
A mixture of 5-chlorosalicylhydrazide (compound of Example 304(1); 0.10 g, 0.53 mmol), 3,5-bis(trifluoromethyl)benzyl bromide (120 μL, 0.65 mmol), triethylamine (0.2 mL, 1.43 mmol) and toluene (4 mL) was stirred at 100° C. for 2 hours. After the reaction mixture was cooled to room temperature, it was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine and dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:1) and crystallized by n-hexane to give the title compound (45.6 mg, 20.9%) as a white powder.
1H-NMR(CDCl3): δ 4.22(2H, d, J=4.8 Hz), 5.13(1H, q, J=4.8 Hz), 6.96(1H, d, J=8.7 Hz), 7.23(1H, d, J=2.4 Hz), 7.37(1H, dd, J=9.0, 2.4 Hz), 7.69(1H, d, J=4.8 Hz), 7.85(1H, s), 7.88(2H, s), 11.54(1H, s).
Example 316
Preparation of the Compound of Compound No. 316
A mixture of 5-chlorosalicylic acid (172.6 mg, 1 mmol), 3,5-bis(trifluoromethyl)phenol (152 μL, 1 mmol), phosphorus oxychloride (40 μL, 0.43 mmol) and xylene (3 mL) was stirred at 140° C. for 2 hours. After the reaction mixture was cooled to room temperature, it was poured into water and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine and dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=10:1→5:1) to give the title compound (53.6 mg, 13.9%) as a white crystal.
1H-NMR(CDCl3): δ 7.04(1H, d, J=9.0 Hz), 7.54(1H, dd, J=9.0, 2.7 Hz), 7.75(2H, s), 7.86(1H, s), 8.02(1H, d, J=2.7 Hz), 10.09(1H, s).
Example 317
Preparation of the Compound of Compound No. 317
WSC.HCl (30.9 mg, 0.2 mmol) was added to a solution of 5-chlorosalicylic acid (35 mg, 0.2 mmol) and 3,5-bis(trifluoromethyl)phenylhydrazine (50 mg, 0.2 mmol) in dichloromethane (2 mL) under argon atmosphere, and the mixture was stirred at room temperature for 1 hour. After the reaction mixture was diluted with ethyl acetate, washed successively with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:1) to give the title compound (56.3 mg, 69.6%) as a white powder.
1H-NMR(CDCl3): δ 6.61(1H, d, J=2.7 Hz), 6.99(1H, d, J=8.7 Hz), 7.28(2H, s), 7.41-7.45(2H, m), 7.62(1H, d, J=2.4 Hz), 8.53(1H, brs), 11.11(1H, s).
Example 318
Preparation of the Compound of Compound No. 318
(1) 2-Bromo-1-(5-chloro-2-hydroxyphenyl)ethanone
Phenyltrimethylammonium tribromide (0.44 g, 1.17 mmol) was added to a solution of 5′-chloro-2′-hydroxyacetophenone (0.20 g, 1.17 mmol) in tetrahydrofuran (6 mL) and the mixture was stirred at room temperature for 8 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine and dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=5:1) to give the title compound (220.7 mg, 75.6%) as an yellow oil.
1H-NMR(CDCl3): δ 4.41(2H, s), 7.00(1H, d, J=9.3 Hz), 7.47(1H, dd, J=8.7, 2.4 Hz), 7.71(1H, d, J=2.7 Hz), 11.63(1H, s).
(2) 2-(2-Aminothiazol-4-yl)-4-chlorophenol
A mixture of 2-bromo-1-(5-chloro-2-hydroxyphenyl)ethanone (156.9 mg, 0.63 mmol), thiourea (47.9 mg, 0.63 mmol) and ethanol (3 mL) was refluxed for 2 hours. After the reaction mixture was cooled to room temperature, it was poured into saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine and dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1) to give the title compound (98.6 mg, 64.5%) as a light yellowish white powder.
1H-NMR(DMSO-d6): δ 6.85(1H, d, J=8.7 Hz), 7.14(1H, dd, J=8.7, 3.0 Hz), 7.25(1H, s), 7.48(2H, s), 7.79(1H, d, J=3.0 Hz), 11.95(1H, s).
(3) N-[4-(5-Chloro-2-hydroxymethyl)thiazol-2-yl]-[3,5-bis(trifluoromethyl)phenyl]-benzamide (Compound No. 318)
Phosphorus trichloride (36 μL, 0.41 mmol) was added to a mixture of 2-(2-aminothiazol-4-yl)-4-chlorophenol (98.6 mg, 0.41 mmol), 3,5-bis(trifluoromethyl)benzoid acid (104.9 mg, 0.41 mmol), chlorobenzene (3 mL) and N-methyl-2-pyrrolidinone (3 mL), and the mixture was refluxed for 3 hours. After the reaction mixture was cooled to room temperature, it was poured into water and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine and dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=4:1→2:1) and washed with isopropyl ether/n-hexane under suspension to give the title compound (19.6 mg, 10.3%) as a white powder.
1H-NMR(DMSO-d6): δ 6.98(1H, d, J=8.4 Hz), 7.21(1H, dd, J=8.7, 2.7 Hz), 7.95(1H, s), 8.08(1H, d, J=2.7 Hz), 8.45(1H, s), 8.77(2H, s), 10.90(1H, s), 13.15(1H, s).
Example 319
Preparation of the Compound of Compound No. 319
(1) 3-[3,5-Bis(trifluoromethyl)benzyl]thiazolidine-2,4-dione
5N Aqueous sodium hydroxide (0.5 mL) was added to a mixture of 2,4-thiazolidinedione (198.7 mg, 1.69 mmol), 3,5-bis(trifluoromethyl)benzyl bromide (0.50 g, 1.63 mmol) and ethanol (5 mL), and the mixture was refluxed for 4 hours. After the reaction mixture was cooled to room temperature, it was poured into water and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine and dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:1→2:1) to give the title compound (405.6 mg, 72.5%) as a white crystal.
1H-NMR(CDCl3): δ 4.01(2H, s), 4.87(2H, s), 7.84(1H, s), 7.86(2H, s).
(2) 5-(5-Chloro-2-hydroxybenzylidene)-3-[3,5-bis(trifluoromethyl)benzyl]thiazolidine-2,4-dione (Compound No. 319)
A mixture of 3-[3,5-bis(trifluoromethyl)benzyl]thiazolidine-2,4-dione (0.20 g, 0.58 mmol), piperidine (3 drops), acetic acid (3 drops) and toluene (5 mL) was stirred at room temperature for 10 minutes, then 5-chlorosalicylaldehyde (92.3 mg, 0.59 mmol) was added and the mixture was refluxed for 1 hour. After the reaction mixture was cooled to room temperature, it was poured into water and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine and dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1→3:2) to give the title compound (173.2 mg, 62.0%) as a light yellow powder.
1H-NMR(DMSO-d6): δ 5.03(2H, s), 7.00(1H, d, J=9.0 Hz), 7.33(1H, d, J=2.4 Hz), 7.38(1H, dd, J=8.7, 2.7 Hz), 8.03(1H, s), 8.05(2H, s), 8.07(1H, s), 10.95(1H, s).
Example 320
Preparation of the Compound of Compound No. 320
A mixture of 3-hydroxyphthalic anhydride (33.5 mg, 0.2 mmol), 3,5-bis(trifluoromethyl)benzyl amine (62 mg, 0.2 mmol) and chlorobenzene (5 mL) was refluxed for 3 hours under argon atmosphere. After the reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure and the obtained residue was crystallized from n-hexane/ethyl acetate to give the title compound (68.5 mg, 85.2%) as a white crystal.
1H-NMR(CDCl3): δ 4.90(2H, s), 7.19(1H, dd, J=8.4, 0.6 Hz), 7.41(1H, dd, J=7.2, 0.6 Hz), 7.61(1H, dd, J=8.4, 7.2 Hz), 7.75(1H, brs), 7.82(1H, brs), 7.86(2H, s).
Example 321
Preparation of the Compound of Compound No. 321
A mixture of 5-chlorosalicylaldehyde (150 mg, 1 mmol), 3,5-bis(trifluoromethyl)phenylhydrazine (200 mg, 0.9 mmol) and methanol (5 mL) was refluxed for 1 hour under argon atmosphere. After the reaction mixture was cooled to room temperature, methanol was evaporated under reduced pressure and the obtained residue was crystallized from n-hexane/ethyl acetate to give the title compound (224 mg, 66.6%) as a white powder.
1H-NMR(CDCl3): δ 6.97(1H, d, J=8.71 Hz), 7.17(1H,d,J=2.4 Hz), 7.24(1H, dd, J=9.0, 2.7 Hz), 7.35(2H, s), 7.41(1H, s), 7.82(1H, s), 7.87(1H, s), 10.29(1H, s).
Example 322
Preparation of the Compound of Compound No. 322
Using 6-hydroxysalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 86.9%. 1H-NMR(DMSO-d6): δ 6.36(2H,d,J=8.4 Hz), 7.13(1H,t,J=8.4 Hz), 7.79(1H, s), 8.38(2H, s), 11.40(2H,brs), 11.96(1H, brs).
Example 323
Preparation of the Compound of Compound No. 323
Using 4-methylsalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 42.9%. 1H-NMR(DMSO-d6): δ 2.32(3H, s) 6.82(1H, d, J=6.6 Hz) 6.84(1H, s) 7.83(1H, s) 7.84(1H, d, J=8.5 Hz) 8.47(2H, s) 10.76(1H, s) 11.44(1H, s).
Example 324
Preparation of the Compound of Compound No. 324
Using 5-bromo-4-hydroxysalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw material, the same operation as the Example 16 gave the title compound.
Yield: 82.4%. 1H-NMR(CDCl3): δ 5.89(1H, s) 6.70(1H, s) 7.69(2H, s) 7.95(1H, s) 8.12(2H, s) 11.62(1H, s).
Example 325
Preparation of the Compound of Compound No. 325
Using 4-hydroxysalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 29.9%. 1H-NMR(DMSO-d6): δ 6.37(1H, d, J=2.5 Hz), 6.42(1H, dd, J=8.8, 2.5 Hz), 7.81(1H, s), 7.86(1H, d, J=8.5 Hz), 8.44(2H, s), 10.31(1H, s), 10.60(1H, s), 11.77(1H, s).
Example 326
Preparation of the Compound of Compound No. 326
Using 3,5-dichlorosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 44.8%. 1H-NMR(DMSO-d6): δ 7.85(1H, d, J=2.5 Hz), 7.91(1H, s), 8.01(1H, d, J=2.5 Hz), 8.42(2H, s), 11.10(1H, s).
Example 327
Preparation of the Compound of Compound No. 327
Using 3-hydroxysalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 22.7%. 1H-NMR(DMSO-d6): δ 6.81(1H, t, J=8.0 Hz), 7.01(1H, dd, J=8.0, 1.5 Hz), 7.35(1H, dd, J=8.0, 1.5 Hz), 7.84(1H, s), 8.46(2H, s), 9.56(1H, s), 10.79(1H, s), 10.90(1H, brs).
Example 328
Preparation of the Compound of Compound No. 328
Using 3-methylsalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 54.9%. 1H-NMR(DMSO-d6): δ 2.22(3H, s), 6.94(1H, t, J=7.4 Hz), 7.42(1H, d, J=7.4 Hz), 7.84-7.85(2H, m), 8.47(2H, s), 10.87(1H, s), 11.87(1H, s).
Example 329
Preparation of the Compound of Compound No. 329
Using 3-methoxysalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 34.6%. 1H-NMR(DMSO-d6): δ 3.85(3H, s), 6.94(1H, t, J=8.0 Hz), 7.20(1H, dd, J=8.0, 1.4 Hz), 7.44(1H, dd, J=8.0, 1.4 Hz), 7.84(1H, s), 8.45(2H, s), 10.82(1H, s), 10.94(1H, brs).
Example 330
Preparation of the Compound of Compound No. 330
Using 5-[(1,1,3,3-tetramethyl)butyl]salicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 64.2%. 1H-NMR(DMSO-d6): δ 0.70(9H, s), 1.35(6H, s), 1.72(2H, s), 6.95(1H, d, J=8.4 Hz), 7.50(1H, dd, J=8.0, 2.1 Hz), 7.83(1H, s), 7.84(1H, d, J=2.1 Hz), 8.46(1H, s), 10.77(1H, s), 11.20(1H, s).
Example 331
Preparation of the Compound of Compound No. 331
Using 3,5,6-trichlorosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 26.2%. 1H-NMR(DMSO-d6): δ 7.88(1H, s), 7.93(1H, s), 8.33(2H, s), 10.88(1H, s), 11.36(1H, s).
Example 332
Preparation of the Compound of Compound No. 332
Using 3,5-bis[(1,1-dimethyl)ethyl]salicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 65.0%. 1H-NMR(DMSO-d6): δ 1.34(9H, s), 1.40(9H, s), 7.49(1H, d, J=2.2 Hz), 7.82(1H, d, J=2.2 Hz), 7.91(1H, s), 8.40(2H, s), 10.82(1H, s), 12.44(1H, s).
Example 333
Preparation of the Compound of Compound No. 333
Using 6-fluorosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 35.9%. 1H-NMR(DMSO-d6): δ 6.73-6.82(2H, m), 7.32(1H, ddd, J=1.4, 8.5, 15.3 Hz), 7.83(1H, s), 8.39(2H, s), 10.50(1H, d, J=1.4 Hz), 11.11(1H, s).
Example 334
Preparation of the Compound of Compound No. 334
Using 3-chlorosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 61.3%. 1H-NMR(DMSO-d6): δ 7.05(1H, dd, J=7.6, 8.0 Hz), 7.69(1H, dd, J=1.4, 13.3 Hz), 7.90(1H, s), 7.93(1H, dd, J=1.4, 8.0 Hz), 8.44(2H, s), 11.01(1H, s), 11.92(1H, br.s).
Example 335
Preparation of the Compound of Compound No. 335
Using 4-methoxysalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 14.2%. 1H-NMR(DMSO-d6): δ 3.81(3H, s), 6.54(1H, d, J=2.5 Hz), 6.61(1H, dd, J=2.5, 8.8 Hz), 7.83(1H, s), 7.95(1H, d, J=8.8 Hz), 8.45(2H, s), 10.69(1H, s), 11.89(1H, s).
Example 336
Preparation of the Compound of Compound No. 336
Using 6-methoxysalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 63.1%. 1H-NMR(DMSO-d6): δ 3.24(3H, s), 6.03(1H, d, J=8.0 Hz), 6.05(1H, d, J=8.5 Hz), 6.71(1H, dd, J=8.2, 8.5 Hz), 7.25(1H, s), 7.88(2H, s), 9.67(1H, s), 10.31(1H, s)
Example 337
Preparation of the Compound of Compound No. 337
Using 5-amino-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide (Compound No. 88) and methanesulfonyl chloride as the raw materials, the same operation as the Example 91 gave the title compound.
Yield: 22.6%. 1H-NMR(DMSO-d6): δ 2.93(3H, s), 7.02(1H, d, J=8.4 Hz), 7.31(1H, dd, J=8.4, 2.7 Hz), 7.68(1H, d, J=2.7 Hz), 7.83(1H, s), 8.46(2H, s), 9.48(1H, s), 10.85(1H, s), 11.15(1H, s).
Example 338
Preparation of the Compound of Compound No. 338
Using 5-amino-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide (Compound No. 88) and benzenesulfonyl chloride as the raw materials, the same operation as the Example 91 gave the title compound.
Yield: 45.3%. 1H-NMR(DMSO-d6): δ 6.89(1H, d, J=8.7 Hz), 7.10(1H, dd, J=8.7, 2.7 Hz), 7.51-7.64(4H, m), 7.68-7.71(2H, m), 7.81(1H, s), 8.42(2H, s), 10.03(1H, s), 10.87(1H, s), 11.13(1H, brs).
Example 339
Preparation of the Compound of Compound No. 339
Using 5-amino-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide (Compound No. 88) and acetyl chloride as the raw materials, the same operation as the Example 91 gave the title compound.
Yield: 44.8%. 1H-NMR(DMSO-d6): δ 2.02(3H, s), 6.97(1H, d, J=8.7 Hz), 7.61(1H, dd, J=8.7, 2.7 Hz), 7.82(1H, s), 7.99(1H, d, J=2.7 Hz), 8.46(2H, s), 9.90(1H, s), 10.85(1H, s), 10.94(1H, s).
Example 340
Preparation of the Compound of Compound No. 340
Using N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxy-5-sulfamoyl-benzamide (compound of Example 87(2)) as the raw material, the same operation as the Example 80(5) gave the title compound.
Yield: 59.9%. 1H-NMR(DMSO-d6): δ 7.17(1H, d, J=8.7 Hz), 7.31(2H, s), 7.85(1H, s), 7.86(1H, dd, J=8.4, 2.4 Hz), 8.26(1H, d, J=2.7 Hz), 8.47(2H, s), 10.95(1H, s), 11.90(1H, s).
Example 341
Preparation of the Compound of Compound No. 341
Using 3-hydroxynaphthalene-2-carboxylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 46.9%. 1H-NMR(DMSO-d6): δ 7.36-7.41(2H, m), 7.50-7.55(1H, m), 7.79(1H, d, J=8.2 Hz), 7.85(1H, d, J=0.6 Hz), 7.96(1H, d, J=8.0 Hz), 8.51(2H, s), 10.98(1H, s), 11.05(1H, s).
Example 342
Preparation of the Compound of Compound No. 342
Using 2-hydroxynaphthalene-1-carboxylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 30.2%. 1H-NMR(DMSO-d6): δ 7.27(1H, d, J=8.8 Hz), 7.32-7.38(1H, m), 7.45-7.50(1H, m), 7.72(1H, d, J=8.5 Hz), 7.82-7.93(3H, m), 8.50(1H, s), 10.28(1H, s), 11.07(1H, brs).
Example 343
Preparation of the Compound of Compound No. 343
(1) 4-Bromo-3-hydroxythiophene-2-carboxylic acid
A mixture of 4-bromothiophene-2-carboxylic acid methyl ester (500 mg, 2.1 mmol), sodium hydroxide (261 mg, 6.3 mmol) in a mixed solvent of methanol/water (2.5 mL+2.5 mL) was refluxed for 2 hours. After the reaction mixture was cooled to room temperature, 2N hydrochloric acid was added to adjust pH to 1, and it was diluted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give the title compound (326 mg, 69.4%) as a red brown powder.
1H-NMR(CDCl3): δ 4.05(1H, brs), 7.40(1H, s).
(2) 4-Bromo-3-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]thiophene-2-carboxamide (Compound No. 343)
Using 4-bromo-3-hydroxythiophene-2-carboxylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 82.4%. 1H-NMR(CDCl3): δ 7.42(1H, s), 7.67(1H, brs), 7.78(1H, brs), 8.11(2H, s), 9.91(1H, brs).
Example 344
Preparation of the Compound of Compound No. 344
Using 3,5-bis(trifluoromethyl)phenylisocyanate and oxindole as the raw materials, the same operation as the Example 28 gave the title compound.
Yield: 44.8%. 1H-NMR(DMSO-d6): δ 3.98(2H, s), 7.22(1H, td, J=7.8, 1.2 Hz), 7.33-7.40(2H, m), 7.87(1H, s), 8.02(1H, d, J=7.8 Hz), 8.38(2H, s), 11.00(1H, s).
Example 345
Preparation of the Compound of Compound No. 345
Using 3,5-bis(trifluoromethyl)phenylisocyanate and 5-chlorooxindole as the raw materials, the same operation as the Example 28 gave the title compound.
Yield: 31.1%. p 1H-NMR(DMSO-d6): δ 3.99(2H, s), 7.41(1H, dd, J=8.7, 2.4 Hz), 7.47(1H, d, J=2.1 Hz), 7.87(1H, s), 8.01(1H, d, J=8.4 Hz), 8.38(2H, s), 10.93(1H, s).
Example 346
Preparation of the Compound of Compound No. 346
Using 5-chlorosalicylic acid and 3-bromo-5-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 37.1%. 1H-NMR(DMSO-d6): δ 7.03(1H, d, J=9.3 Hz), 7.48(1H, dd, J=8.7, 2.4 Hz), 7.72(1H, s), 7.84(1H, d, J=2.7 Hz), 8.16(1H, s), 8.28(1H, s), 10.69(1H, s), 11.42(1H, s).
Example 347
Preparation of the Compound of Compound No. 347
Using 5-chlorosalicylic acid and 3-methoxy-5-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 68.0%. 1H-NMR(DMSO-d6): δ 3.85(3H, s), 7.02(1H, s), 7.03(1H, d, J=8.7 Hz), 7.48(1H, dd, J=8.7, 2.7 Hz), 7.61(1H, s), 7.77(1H, s), 7.88(1H, d, J=2.7 Hz), 10.57(1H, s), 11.53(1H, s).
Example 348
Preparation of the Compound of Compound No. 348
Using 5-chlorosalicylic acid and 2-morpholino-5-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 64.80%. 1H-NMR(DMSO-d6): δ 2.90(4H, m), 3.84(4H, m), 7.15(1H, d, J=9.0 Hz), 7.48(2H, s), 7.50(1H, dd, J=9.0, 2.7 Hz), 8.00(1H, d, J=2.7 Hz), 8.91(1H, s), 11.24(1H, s), 12.05(1H, s).
Example 349
Preparation of the Compound of Compound No. 349
Using 5-chlorosalicylic acid and 2-bromo-5-(trifluoromethyl)aniline as the raw material, the same operation as the Example 16 gave the title compound.
Yield: 59.2%. 1H-NMR(DMSO-d6): δ 7.10(1H, d, J=8.7 Hz), 7.48(1H, dd, J=8.4, 2.1 Hz), 7.53(1H, dd, J=8.7, 3.0 Hz), 7.97-7.99(2H, m), 8.81(1H, d, J=2.1 Hz), 11.03(1H, s), 12.38(1H, s).
Example 350
Preparation of the Compound of Compound No. 350
Using 5-chlorosalicylic acid and 3-amino-5-(trifluoromethyl)benzoic acid methyl ester as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 67.0%. 1H-NMR(DMSO-d6): δ 3.91(3H, s), 7.02(1H, d, J=9.3 Hz), 7.43(1H, dd, J=9.0, 2.4 Hz), 7.57(1H, d, J=2.4 Hz), 8.13(1H, s), 8.23(1H, s), 8.29(1H, s), 8.36(1H, s), 11.52(1H, s).
Example 351
Preparation of the Compound of Compound No. 351
2N Aqueous sodium hydroxide (0.6 mL) was added to a mixture of 5-chloro-2-hydroxy-N-[3-methoxycarbonyl-5-(trifluoromethyl)phenyl]benzamide (Compound No. 350; 105 mg, 0.281 mmol) and methanol (2.5 mL), and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture and it was washed with ethyl acetate. After the water layer was acidified by addition of diluted hydrochloric acid, it was extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was crystallized by isopropyl ether to give the title compound (100 mg, 99.0%) as a white solid.
1H-NMR(DMSO-d6): δ 7.04(1H, d, J=9.0 Hz), 7.49(1H, dd, J=8.7, 2.7 Hz), 7.91(1H, d, J=2.7 Hz), 7.93(1H, s), 8.43(1H, s), 8.59(1H, s), 10.78(1H, s), 11.48(1H, s).
Example 352
Preparation of the Compound of Compound No. 352
Using 5-chlorosalicylic acid and 2-(2-naphthyloxy)-5-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 89.6%. 1H-NMR(CDCl3): δ 6.94(1H, d, J=9.6 Hz), 6.98(1H, d, J=9.2 Hz), 7.25-7.41(4H, m), 7.48-7.57(3H, m), 7.81(1H, d, J=6.9 Hz), 7.88(1H, d, J=6.9 Hz), 7.95(1H, d, J=8.9 Hz), 8.72(1H, s), 8.83(1H, d, J=2.0 Hz), 11.70(1H, s).
Example 353
Preparation of the Compound of Compound No. 353
Using 5-chlorosalicylic acid and 2-(2,4-dichlorophenoxy)-5-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 4.7%. 1H-NMR(CDCl1): δ 6.78(1H d, J=8.9 Hz), 7.02(1H, d, J=8.6 Hz), 7.16(1H, d, J=8.6 Hz), 7.33-7.38(3H, m), 7.42(1H, dd, J=8.6, 2.6 Hz), 7.49(1H, d, J=2.6 Hz) 7.58(1H, d, J=2.3 Hz), 8.66(1H, brs,), 8.82(1H, d, J=2.0 Hz), 11.65(1H, s).
Example 354
Preparation of the Compound of Compound No. 354
Using 5-chlorosalicylic acid and 2-[(4-trifluoromethyl)piperidino]-5-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 60.5%. 1H-NMR(CDCl3): δ 1.85-2.05(2H, m), 2.15(2H, d, J=10.9 Hz), 2.28(1H, m), 2.82(2H, t, J=11.0 Hz), 3.16(2H, d, J=12.2 Hz), 7.02(1H, d, J=8.9 Hz), 7.31(1H, d, J=8.3 Hz), 7.42(2H, m), 7.50(1H, d, J=2.6 Hz), 8.75(1H, s), 9.60(1H, s), 11.94(1H, s)
Example 355
Preparation of the Compound of Compound No. 355
Using 5-chlorosalicylic acid and 2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)-aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 94.5%. 1H-NMR(CDCl3): δ 4.58(2H, q, J=7.9 Hz), 6.99-7.05(2H, m), 7.41-7.50(3H, m), 8.63(1H, brs), 8.79(1H, d, J=2.0 Hz), 11.59(1H, s).
Example 356
Preparation of the Compound of Compound No. 356
Using 5-chlorosalicylic acid and 2-(2-methoxyphenoxy)-5-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 80.6%. 1H-NMR(DMSO-d6): δ 3.74(3H, s), 6.70(1H, d, J=8.4 Hz), 7.02(1H, d, J=8.7 Hz), 7.07(1H, dd, J=1.5, 7.8 Hz), 7.24-7.39(4H, m), 7.49(1H, dd, J=3.0, 8.7 Hz), 8.00(1H, d, J=3.0 Hz), 8.92(1H, d, J=2.1 Hz), 11.36(1H, s), 12.18(1H, s).
Example 357
Preparation of the Compound of Compound No. 357
Using 5-chlorosalicylic acid and 2-(4-chloro-3,5-dimethylphenoxy)-5-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 91.5%. 1H-NMR(DMSO-d6): δ 2.34(6H, s), 7.03(1H, d, J=8.8 Hz), 7.05(1H, d, J=8.1 Hz), 7.11(2H, s), 7.43-7.47(1H, m), 7.48(1H, dd, J=2.9, 8.8 Hz), 7.97(1H, d, J=2.6 Hz), 8.94(1H, d, J=2.2 Hz), 11.25(1H, s), 12.12(1H, s).
Example 358
Preparation of the Compound of Compound No. 358
Using 5-chlorosalicylic acid and 2-piperidino-5-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 73.7%. 1H-NMR(CDCl3): δ 1.68-1.72(2H, m), 1.80-1.88(4H, m), 2.89(4H, t, J=5.2 Hz), 7.01(1H, d, J=8.7 Hz), 7.31(1H, d, J=8.4 Hz), 7.39-7.43(2H, m), 7.55(1H, d, J=2.4 Hz), 8.73(1H, d, J=1.8 Hz), 9.71(1H, s), 12.05(1H, s)
Example 359
Preparation of the Compound of Compound No. 359
Using 5-chlorosalicylic acid and 2-(4-methylphenoxy)-5-(trifluoromethyl)-aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 67.3%. 1H-NMR(DMSO-d6): δ 2.33(3H, s), 6.93(1H, d, J=8.8 Hz), 7.03(1H, dd, J=0.5, 8.8 Hz), 7.12(2H, d, J=8.2 Hz), 7.29(2H, d, J=8.5 Hz), 7.43(1H, dd, J=2.0, 8.6 Hz), 7.48(1H, ddd, J=0.8, 2.7, 8.8 Hz), 7.98(1H, dd, J=0.8, 2.7 Hz), 8.94(1H, d, J=2.2 Hz), 11.29(1H, s), 12.15(1H, s).
Example 360
Preparation of the Compound of Compound No. 360
Using 5-chlorosalicylic acid and 2-(4-chlorophenoxy)-5-(trifluoromethyl)-aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 74.5%. 1H-NMR(DMSO-d6): δ 7.01(1H, d, J=8.8 Hz), 7.06(1H, d, J=8.5 Hz), 7.22(1H, d, J=8.5 Hz), 7.43-7.48(2H, m), 7.50(2H, d, J=8.2 Hz), 7.94(1H, dd, J=0.5, 2.7 Hz), 8.92(1H, d, J=2.2 Hz), 11.20(1H, s), 12.10(1H, s).
Example 361
Preparation of the Compound of Compound No. 361
Using 5-bromo-2-hydroxy-N-[3,5-bis(methoxycarbonyl)phenyl]benzamide (Compound No. 170) as the raw material, the same operation as the Example 351 gave the title compound.
Yield: 89.0%. 1H-NMR(DMSO-d6): δ 6.98(1H, d, J=8.7 Hz), 7.60(1H, dd, J=8.7, 2.4 Hz), 7.24(1H, dd, J=8.7, 2.7 Hz), 8.08(1H, d, J=2.7 Hz), 8.24(1H, t, J=1.5 Hz), 8.57(2H, d, J=1.2 Hz), 10.67(1H, s), 11.64(1H, s).
Example 362
Preparation of the Compound of Compound No. 362
Using 5-chlorosalicylic acid and 2-methyl-5-[(1-methyl)ethyl]aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 19.1%. 1H-NMR(CDCl3): δ 1.26(6H, d, J=6.9 Hz), 2.30(3H, s), 2.87-2.96(1H, m), 7.00(1H, d, J=8.7 Hz), 7.08(1H, dd, J=7.8, 1.8 Hz), 7.20(1H, d, J=7.8 Hz), 7.40(1H, dd, J=8.7, 2.4 Hz), 7.49(1H, d, J=2.7 Hz), 7.50(1H, s), 7.71(1H, s), 11.99(1H, s).
Example 363
Preparation of the Compound of Compound No. 363
Using 5-chlorosalicylic acid and 2,5-diethoxyaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 59.2%. 1H-NMR(DMSO-d6): δ 1.32(3H, t, J=6.9 Hz), 1.41(3H, t, J=6.9 Hz), 3.97(2H, q, J=6.9 Hz), 4.06(2H, q, J=6.9 Hz), 6.61(1H, dd, J=9.0, 3.0 Hz), 6.98(1H, d, J=8.7 Hz), 7.10(1H, d, J=8.7 Hz), 7.48(1H, dd, J=8.7, 2.7 Hz), 7.97(1H, d, J=2.7 Hz), 8.16(1H, d, J=3.0 Hz), 10.96(1H, s), 11.91(1H, s).
Example 364
Preparation of the Compound of Compound No. 364
Using 5-chlorosalicylic acid and 2,5-dimethylaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 90.5%. 1H-NMR(CDCl3): δ 2.28(3H, s), 2.35(3H, s), 6.99(1H, d, J=8.8 Hz), 7.02(1H, brs), 7.15(1H, d, J=7.7 Hz), 7.40(1H, dd, J=8.8, 2.5 Hz), 7.45(1H, brs), 7.49(1H, d, J=2.5 Hz) 7.70(1H, br), 11.96(1H, brs).
Example 365
Preparation of the Compound of Compound No. 365
Using 5-chlorosalicylic acid and 5-chloro-2-cyanoaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 90.0%. 1H-NMR(DMSO-d6): δ 7.09(1H, d, J=9.0 Hz), 7.53(1H, dd, J=8.7, 3.0 Hz), 7.82(1H, dd, J=8.7, 2.4 Hz), 7.95(1H, d, J=3.0Hz), 8.07(1H, d, J=2.4 Hz), 8.36(1H, d, J=9.0 Hz), 11.11(1H, s), 12.36(1H, s).
Example 366
Preparation of the Compound of Compound No. 366
Using 5-chlorosalicylic acid and 5-(N,N-diethylsulfamoyl)-2-methoxyaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 44.8%. 1H-NMR(CDCl3): δ 1.17(6H, t, J=7.3 Hz), 3.29(4H, q, J=7.3 Hz), 4.05(3H, s), 7.00(2H, dd, J=2.3, 8.9 Hz), 7.41(1H, dd, J=2.3, 8.9 Hz), 7.48(1H, d, J=2.6 Hz), 7.65(1H, dd, J=2.3, 8.6 Hz), 8.56(1H, br.s), 8.84(1H, d, J=2.3 Hz), 11.82(1H, s).
Example 367
Preparation of the Compound of Compound No. 367
Using 5-chlorosalicylic acid and 2-chloro-5-nitroaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 73.3%. 1H-NMR(CD3OD): δ 6.98(1H, d, J=8.6 Hz), 7.43(1H, dd, J=2.6, 8.6 Hz), 7.74(1H, d, J=8.9 Hz), 7.99(1H, dd, J=3.0, 8.9 Hz), 8.08(1H, d, J=2.6 Hz), 9.51(1H, d, J=2.6 Hz).
Example 368
Preparation of the Compound of Compound No. 368
Using 5-chlorosalicylic acid and 5-(N-phenylcarbamoyl)-2-methoxyaniline as the raw material, the same operation as the Example 16 gave the title compound.
Yield: 40.3%. 1H-NMR(DMSO-d6): δ 3.99(3H, s), 7.09(2H, dd, J=6.6, 6.9 Hz), 7.24(1H, d, J=8.6 Hz), 7.35(2H, dd, 6.9, 7.3 Hz), 7.49(1H, d, J=2.3, 8.9 Hz), 7.77(3H, d, J=8.6 Hz), 8.00(1H, s), 8.97(1H, s), 10.17(1H, s), 10.91(1H, s), 12.11(1H, s).
Example 369
Preparation of the Compound of Compound No. 369
Using 5-chlorosalicylic acid and 2,5-dimethoxyaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 73.9%. 1H-NMR(CDCl3): δ 3.82(3H, s), 3.93(3H, s), 6.66(1H, dd, J=3.0, 8.9 Hz), 6.86(1H, d, J=8.9 Hz), 6.98(1H, d, J=8.9 Hz), 7.39(1H, dd, J=2.6, 8.9 Hz), 7.47(1H, d, J=2.6 Hz), 8.08(1H, d, J=3.0 Hz), 8.60(1H, br.s), 12.03(1H, s).
Example 370
Preparation of the Compound of Compound No. 370
Using 5-chlorosalicylic acid and 5-acetylamino-2-methoxyaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 16.9%. 1H-NMR(DMSO-d6): δ 2.01(3H, s), 3.85(3H, s), 7.03(2H, t, J=9.6 Hz), 7.49(2H, dd, J=8.9, 9.2 Hz), 7.96(1H, s), 8.51(1H, s), 9.87(1H, s), 10.82(1H, s), 12.03(1H, d, J=4.0 Hz).
Example 371
Preparation of the Compound of Compound No. 371
Using 5-chlorosalicylic acid and 5-methoxy-2-methylaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 100%. 1H-NMR(CDCl3): δ 2.29(3H, s), 3.82(3H, s), 6.75(1H, dd, J=2.6, 8.2 Hz), 7.00(1H, d, J=8.9 Hz), 7.16(1H, d, J=8.6 Hz), 7.38(1H, d, 2.3 Hz), 7.41(1H, dd, J=2.3, 8.9 Hz), 7.48(1H, d, J=2.3 Hz), 7.70(1H, br.s), 11.92(1H, s).
Example 372
Preparation of the Compound of Compound No. 372
Using 5-chlorosalicylic acid and 2,5-dibutoxyaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 73.9%. 1H-NMR(CDCl3): δ 0.98(3H, t, J=7.2 Hz), 1.05(3H, t, J=7.2 Hz), 1.44-1.65(4H, m), 1.72-1.79(2H, m), 1.81-1.91(2H, m), 3.97(2H, t, J=6.3 Hz), 4.07(2H, t, J=6.3 Hz), 6.64(1H, dd, J=9.0, 3.0 Hz), 6.85(1H, d, J=9.3 Hz), 6.99(1H, d, J=9.0 Hz), 7.39(1H, dd, J=8.7, 2.4 Hz), 7.44(1H, d, J=2.7 Hz), 8.08(1H, d, J=3.0 Hz), 8.76(1H, s), 12.08(1H, s).
Example 373
Preparation of the Compound of Compound No. 373
Using 5-chlorosalicylic acid and 2,5-diisopentyloxyaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 59.7%. 1H-NMR(CDCl3): δ 0.97(6H, d, J=6.6 Hz), 1.03(6H, d, 6.6 Hz), 1.64-1.98(6H, m), 3.99(2H, t, J=6.6 Hz), 4.09(2H, t, J=6.3 Hz), 6.63(1H, dd, J=8.7, 3.0 Hz), 6.85(1H, d, J=8.7 Hz), 6.98(1H, d, J=8.7 Hz), 7.38(1H, dd, J=9.0, 2.4 Hz), 7.43(1H, d, J=2.7 Hz), 8.09(1H, d, J=3.0 Hz), 8.75(1H, s), 12.08(1H, s).
Example 374
Preparation of the Compound of Compound No. 374
Using 5-chlorosalicylic acid and 5-carbamoyl-2-methoxyaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 31.2%. 1H-NMR(CD3OD): δ 4.86(3H, s), 6.93(1H, d, J=7.6 Hz), 7.18(1H, d, J=8.6 Hz), 7.35(1H, dd, J=3.0, 7.6 Hz), 7.47(1H, dd, J=2.0, 8.6 Hz), 8.00(1H, d, J=3.0 Hz), 8.80(1H, d, J=2.0 Hz).
Example 375
Preparation of the Compound of Compound No. 375
Using 5-chlorosalicylic acid and 5-[(1,1-dimethyl)propyl]-2-phenoxyaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 65.2%. 1H-NMR(CDCl3): δ 0.69(3H, t, J=7.6 Hz), 1.29(6H, s), 1.64(2H, q, J=7.6 Hz), 6.91(1H, dd, J=1.7, 7.6 Hz), 6.96(1H, d, J=8.9 Hz), 7.03(2H, d, J=8.9 Hz), 7.10(1H, dt, J=1.7, 7.6 Hz), 7.16(1H, dt, J=1.7, 7.6 Hz), 7.40-7.31(4H, m), 8.42(1H, dd, J=2.0, 7.9 Hz), 8.53(1H, br.s) 11.94(1H, s).
Example 376
Preparation of the Compound of Compound No. 376
Using 5-chlorosalicylic acid and 2-hexyloxy-5-(methylsulfonyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 33.0%. 1H-NMR(CDCl3): δ 0.92(3H, t, J=6.9 Hz), 1.40-1.59(6H, m), 1.90-2.01(2H, m), 3.09(3H, s), 4.22(2H, t, J=6.3 Hz), 7.01(1H, d, J=8.9 Hz), 7.06(1H, d, J=8.6 Hz), 7.40-7.43(2H, m), 7.73(1H, dd, J=8.6, 2.3 Hz), 8.74(1H, brs), 8.99(1H, d, J=2.3 Hz), 11.76(1H, s).
Example 377
Preparation of the Compound of Compound No. 377
Using 5-chlorosalicylic acid and 3′-amino-2,2,4′-trimethylpropiophenone as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 44.8%. 1H-NMR(CDCl3): δ 1.38(9H, s), 2.38(3H, s), 7.01(1H, d, J=8.9 Hz), 7.31(1H, d, J=7.9 Hz), 7.42(1H, dd, J=8.9, 2.6 Hz), 7.53(1H, d, J=2.6 Hz), 7.57(1H, dd, J=7.9, 2.0 Hz), 7.83(1H, brs), 8.11(1H, d, J=2.0 Hz), 11.82(1H, s).
Example 378
Preparation of the Compound of Compound No. 378
Using 5-chlorosalicylic acid and 5-methoxy-2-(1-pyrrolyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 53.4%. 1H-NMR(CDCl3): δ 2.46(3H, s), 6.51-6.52(2H, m), 6.82-6.85(3H, m), 6.93(1H, d, J=8.9 Hz), 7.06(1H, d, J=7.9 Hz), 7.30(1H, d, J=7.9 Hz), 7.32(1H, dd, J=2.3, 8.9 Hz), 7.61(1H, s), 8.29(1H, s), 11.86(1H, br.s).
Example 379
Preparation of the Compound of Compound No. 379
Using 5-chlorosalicylic acid and 5-chloro-2-tosylaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 8.0%. 1H-NMR(CDCl3): δ 2.38(3H, s), 7.02(1H, d, J=8.9 Hz), 7.25-7.31(3H, m), 7.46(1H, dd, J=2.6, 8.9 Hz), 7.68(2H, d, J=8.6 Hz), 7.74(1H, d, J=2.3 Hz), 7.96(1H, d, J=8.6 Hz), 8.56(1H, d, J=2.0 Hz), 10.75(1H, s), 11.70(1H, s).
Example 380
Preparation of the Compound of Compound No. 380
Using 5-chlorosalicylic acid and 2-chloro-5-tosylaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 43.5%. 1H-NMR(CDCl3): δ 2.38(3H, s), 7.02(1H, d, J=8.9 Hz), 7.27(1H, d, J=7.9 Hz), 7.29(1H, dd, J=2.0, 6.6 Hz), 7.46(1H, dd, J=2.3, 8.9 Hz), 7.68(2H, d, J=8.6 Hz), 7.73(2H, d, J=2.3 Hz), 7.97(1H, d, J=8.6 Hz), 8.56(1H, d, J=2.0 Hz), 10.73(1H, s), 11.71(1H, s).
Example 381
Preparation of the Compound of Compound No. 381
Using 5-chlorosalicylic acid and 2-fluoro-5-(methylsulfonyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 28.8%. 1H-NMR(CDCl3): δ 3.12(3H, s), 7.03(1H, d, J=8.9 Hz), 7.38(1H, dd, J=8.6, 10.2 Hz), 7.45(1H, dd, J=2.3, 8.9 Hz), 7.53(1H, d, J=2.3 Hz), 7.80(1H, ddd, J=2.3, 4.6, 8.6 Hz), 8.25(1H, s), 8.98(1H, dd, J=2.3, 7.7 Hz), 11.33(1H, br.s).
Example 382
Preparation of the Compound of Compound No. 382
Using 5-chlorosalicylic acid and 2-methoxy-5-phenoxyaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 77.0%. 1H-NMR(CDCl3): δ 3.98(3H, s), 6.80(1H, d, J=8.8 Hz), 6.90(1H, d, J=8.8 Hz), 6.95-7.00(3H, m), 7.04-7.09(1H, m), 7.29-7.35(2H, m), 7.38(1H, dd, J=8.8, 2.6 Hz), 7.47(1H, d, J=2.6 Hz), 8.19(1H, d, J=2.9 Hz), 8.61(1H, brs), 11.92(1H, s).
Example 383
Preparation of the Compound of Compound No. 383
Using 5-chlorosalicylic acid and 3-amino-4-methylbiphenyl as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 47.7%. 1H-NMR(DMSO-d6): δ 2.33(3H, s), 7.06(1H, d, J=8.7 Hz), 7.43-7.52(4H, m), 7.64-7.67(2H, m), 8.04(1H, d, J=2.7 Hz), 8.19(1H, d, J=1.5 Hz), 10.40(1H, s), 12.22(1H, s).
Example 384
Preparation of the Compound of Compound No. 384
Using 5-chlorosalicylic acid and 5-(α,α-dimethylbenzyl)-2-methoxyaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 89.0%. 1H-NMR(CDCl3): δ 1.72(6H, s), 3.93(3H, s), 6.83(1H, d, J=8.8 Hz), 6.93(1H, dd, J=2.6, 8.8 Hz), 6.96(1H, d, J=9.2 Hz), 7.15-7.20(1H, m), 7.25-7.28(4H, m), 7.36(1H, dd, J=2.6, 8.8 Hz), 7.46(1H, d, J=2.6 Hz), 8.35(1H, d, J=2.6 Hz), 8.51(1H, s), 12.04(1H, s).
Example 385
Preparation of the Compound of Compound No. 385
Using 5-chlorosalicylic acid and 5-morpholino-2-nitroaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 4.1%. 1H-NMR(DMSO-d6): δ 3.46-3.52(4H, m), 3.85-3.94(4H, m), 7.03(1H, d, J=8.8 Hz), 7.47(1H, dd, J=2.9, 8.8 Hz), 7.80(1H, dd, J=2.6, 8.8 Hz), 7.82(1H, d, J=2.6 Hz), 7.88(1H, d, J=8.8 Hz), 8.20(1H, d, J=2.2 Hz), 10.70(1H, s), 11.43(1H, s)
Example 386
Preparation of the Compound of Compound No. 386
Using 5-chlorosalicylic acid and 5-fluoro-2-(1-imidazolyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 33.8%. 1H-NMR(DMSO-d6): δ 6.99(1H, d, J=8.8 Hz), 7.12-7.19(2H, m), 7.42-7.51(3H, m), 7.89(1H, d, J=2.8 Hz), 7.93(1H, d, J=1.1 Hz), 8.34(1H, dd, J=11.4, 2.8 Hz), 10.39(1H, s), 11.76(1H, brs).
Example 387
Preparation of the Compound of Compound No. 387
Using 5-chlorosalicylic acid and 2-butyl-5-nitroaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 15.3%. 1H-NMR(CDCl3): δ 0.99(3H, t, J=7.3 Hz), 1.39-1.51(2H, m), 1.59-1.73(2H, m), 2.71-2.79(2H, m), 7.03(1H, d, J=8.9 Hz), 7.41-7.49(3H, m), 7.92(1H, s), 8.07(1H, dd, J=2.3, 8.4 Hz), 8.75(1H, d, J=2.4 Hz), 11.51(1H, s).
Example 388
Preparation of the Compound of Compound No. 388
Using 5-chlorosalicylic acid and 5-[(1,1-dimethyl)propyl]-2-hydroxyaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 36.0%. 1H-NMR(CDCl3): δ 0.70(3H, t, J=7.4 Hz), 1.28(6-H, s), 1.63(2H, q, J=7.4 Hz), 6.97(1H, d, J=6.3 Hz), 7.00(1H, d, J=6.6 Hz), 7.08(1H, s), 7.14(1H, dd, J=2.5, 8.6 Hz), 7.36(1H, d, J=2.2 Hz), 7.42(1H, dd, J=2.5, 8.8 Hz), 7.57(1H, d, J=2.5 Hz), 8.28(1H, s), 11.44(1H, s).
Example 389
Preparation of the Compound of Compound No. 389
Using 5-chlorosalicylic acid and 2-methoxy-5-methylaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 74.2%. 1H-NMR(DMSO-d6): δ 2.27(3H, s), 3.85(3H, s), 6.90(1H, dd, J=9.0, 2.4 Hz), 6.98(1H, d, J=9.0 Hz), 7.05(1H, d, J=9.0 Hz), 7.47(1H, dd, J=9.0, 3.0 Hz), 7.97(1H, d, J=3.0 Hz), 8.24(1H, d, J=2.4 Hz), 10.79(1H, s), 12.03(1H, s).
Example 390
Preparation of the Compound of Compound No. 390
Using 5-chlorosalicylic acid and 2,5-difluoroaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 81.5%. 1H-NMR(DMSO-d6): δ 6.98-7.07(1H, m), 7.07(1H, d, J=9.0 Hz), 7.37-7.49(1H, m), 7.52(1H, dd, J=8.7, 3.0 Hz), 7.95(1H, d, J=2.7 Hz), 8.15-8.22(1H, m), 10.83(1H, s), 12.25(1H, s).
Example 391
Preparation of the Compound of Compound No. 391
Using 5-chlorosalicylic acid and 3,5-difluoroaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 82.0%. 1H-NMR(DMSO-d6): δ 7.00(1H, tt, J=9.3, 2.1), 7.03(1H, d, J=9.0 Hz), 7.47(1H, dd, J=7.5, 2.7 Hz), 7.49(1H, d, J=2.7 Hz), 7.51(1H, d, J=2.1 Hz), 7.82(1H, d, J=3.0 Hz), 10.63(1H, s), 11.43(1H, brs).
Example 392
Preparation of the Compound of Compound No. 392
Using 2-(5-bromo-2-hydroxybenzoyl)amino-4-[(1,1-dimethyl)ethyl]thiazole-5-carboxylic acid ethyl ester (Compound No. 197) as the raw material, the same operation as the Example 82 gave the title compound.
Yield: 85.5%. 1H-NMR(DMSO-d6): δ 1.44(9H, s), 7.00(1H, d, J=9.0 Hz), 7.62(1H, dd, J=9.0, 2.7 Hz), 8.02(1H, d, J=2.4 Hz), 11.83(1H, brs), 12.04(1H, brs), 12.98(1H, brs).
Example 393
Preparation of the Compound of Compound No. 393
Using 5-bromosalicylic acid and 2-amino-4-phenylthiazole-5-acetic acid methyl ester as the raw materials, the same operation as the Example 195(3) gave the title compound. (This compound is the compound of Example 203(1).)
Yield: 32.1%. mp 288.5-229.5° C. 1H-NMR(DMSO-d6): δ 3.66(3H, s), 3.95(2H, s), 6.99(1H, d, J=8.0 Hz), 7.42(1H, d, J=6.0 Hz), 7.48(2H, brt, J=7.6 Hz), 7.56-7.61(3H, m), 8.07(1H, d, J=2.4 Hz), 11.85(1H, brs), 11.98(1H, brs).
Example 394
Preparation of the Compound of Compound No. 394
Using 2-(5-bromo-2-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylic acid ethyl ester (Compound No. 209) as the raw material, the same operation as the Example 82 gave the title compound. (This compound is the compound of Example 212(1).)
Yield: 67.0%. 1H-NMR(DMSO-d6): δ 7.00(1H, d, J=8.8 Hz), 7.42-7.44(3H, m), 7.62(1H, dd, J=8.8, 2.4 Hz), 7.70-7.72(2H, m), 8.04(1H, d, J=2.4 Hz), 12.31(1H, brs), 12.99(1H, brs).
Example 395
Preparation of the Compound of Compound No. 395
(1) 2-Amino-4-[3,5-bis(trifluoromethyl)phenyl]thiazole
Phenyltrimethylammonium tribromide (753 mg, 2 mmol) was added to a solution of 3′,5′-bis(trifluoromethyl)acetophenone (0.51 g, 2.0 mmol) in tetrahydrofuran (5 mL) and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, ethanol (5 mL) and thiourea (152 mg, 2 mmol) were added to the residue obtained by evaporation of the solvent under reduced pressure, and the mixture was refluxed for 30 minutes. After the reaction mixture was cooled to room temperature, it was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine and dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1) and washed with n-hexane under suspension to give the title compound (520.1 mg, 83.3%) as a light yellow white crystal.
1H-NMR(CDCl3): δ 5.03(2H, s), 6.93(1H, s), 7.77(1H, s), 8.23(2H, s).
(2) 5-Chloro-2-hydroxy-N-{4-[3,5-bis(trifluoromethyl)phenyl]thiazol-2-yl}benzamide (Compound No. 395)
A mixture of 5-chlorosalicylic acid (172.6 mg, 1 mmol), 2-amino-4-[3,5-bis(trifluoromethyl)phenyl]thiazole (312.2 mg, 1 mmol), phosphorus trichloride (44 μL, 0.5 mmol) and monochlorobenzene (5 mL) was refluxed for 4 hours. After the reaction mixture was cooled to room temperature, it was poured into water and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:1→2:1) to give the title compound (109.8 mg, 23.5%) as a pale yellow white powder.
1H-NMR(DMSO-d6): δ 7.08(1H, d, J=8.7 Hz), 7.53(1H, dd, J=9.0, 3.0 Hz), 7.94(1H, d, J=3.0 Hz), 8.07(1H, s), 8.29(1H, s), 8.60(2H, s), 11.77(1H, s), 12.23(1H, s).
Example 396
Preparation of the Compound of Compound No. 396
Using 5-chlorosalicylic acid and 3-aminopyridine as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 23.2%. 1H-NMR(DMSO-d6): δ 7.02(1H, d, J=9.3 Hz), 7.42(1H, ddd, J=9.0, 4.8, 0.6 Hz), 7.47(1H, dd, J=8.7, 5.7 Hz), 7.92(1H, d, J=2.7 Hz), 8.15(1H, ddd, J=8.4, 2.4, 1.5 Hz), 8.35(1H, dd, J=7.8, 1.5 Hz), 8.86(1H, d, J=2.4 Hz), 10.70(1H, s).
Example 397
Preparation of the Compound of Compound No. 397
Using 5-chlorosalicylic acid and 2-amino-6-bromopyridine as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 12.3%. 1H-NMR(DMSO-d6): δ 7.07(1H, d, J=8.7 Hz), 7.42(1H, d, J=7.8 Hz), 7.51(1H, dd, J=8.7, 2.7 Hz), 7.82(1H, t, J=7.5 Hz), 7.94(1H, d, J=3.0 Hz), 8.24(1H, d, J=7.8 Hz), 10.95(1H, s), 11.97(1H, s).
Example 398
Preparation of the Compound of Compound No. 398
(1) 2-Acetoxy-5-chloro-N-(pyridazin-2-yl)benzamide
Using 2-acetoxy-5-chlorobenzoic acid and 2-aminopyridazine as the raw materials, the same operation as the Example 198(3) gave the title compound.
Yield: 19.7%. 1H-NMR(CDCl3): δ 2.42(3H, s), 7.19(1H, d, J=8.7 Hz), 7.54(1H, dd, J=8.7, 2.7 Hz), 8.01(1H, d, J=2.4 Hz), 8.28(1H, dd, J=2.4, 1.8 Hz), 8.42(1H, d, J=2.4 Hz), 9.09(1H, s), 9.66(1H, d, J=1.8 Hz).
(2) 5-Chloro-2-hydroxy-N-(pyridazin-2-yl)benzamide (Compound No. 398)
Using 2-acetoxy-5-chloro-N-(pyridazin-2-yl)benzamide as the raw material, the same operation as the Example 2(2) gave the title compound.
Yield: 72.6%. 1H-NMR(DMSO-d6): δ 7.09(1H, d, J=9.0 Hz), 7.52(1H, dd, J=8.7, 2.7 Hz), 7.96(1H, d, J=2.7 Hz), 8.44-8.47(2H, m), 9.49(1H, s), 10.99(1H, s), 12.04(1H, s).
Example 399
Preparation of the Compound of Compound No. 399
Using 5-bromosalicylic acid and 2-amino-5-bromopyrimidine as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 10.3%. 1H-NMR(DMSO-d6): δ 6.98(1H, d, J=8.8 Hz), 7.59(1H, dd, J=8.8, 2.4 Hz), 8.00(1H, d, J=2.8 Hz), 8.86(2H, s), 11.09(1H, s), 11.79(1H, s).
Example 400
Preparation of the Compound of Compound No. 400
Using 2-(5-bromo-2-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylic acid (Compound No. 394) and propylamine as the raw materials, the same operation as the Example 212(2) gave the title compound.
Yield: 23.1%. 1H-NMR(DMSO-d6): δ 0.82(3H, t, J=7.5 Hz), 1.39-1.51(2H, m), 3.13(2H, q, J=6.6 Hz), 7.02(1H, d, J=9.0 Hz), 7.40-7.48(3H, m), 7.63(1H, dd, J=8.7, 2.7 Hz), 7.68-7.72(2H, m), 8.06(1H, d, J=2.7 Hz), 8.18(1H, t, J=5.7 Hz), 11.87(1H, brs), 12.14(1H, brs).
Example 401
Preparation of the Compound of Compound No. 401
Using 5-chlorosalicylic acid and 2-methyl-3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 15.0%. 1H-NMR(DMSO-d6): δ 2.49(3H, s), 7.07(1H, d, J=8.7 Hz), 7.52(1H, dd, J=8.7, 2.8 Hz), 7.84(1H, s), 7.97(1H, d, J=2.8 Hz), 8.60(1H, s), 10.69(1H, brs), 12.07(1H, brs).
Example 402
Preparation of the Compound of Compound No. 402
Using 5-chlorosalicylic acid and 4-chloro-3-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 66.5%. 1H-NMR(DMSO-d6): δ 7.03(1H, d, J=8.7 Hz), 7.48(1H, dd, J=8.7, 2.7 Hz), 7.73(1H, d, J=8.7 Hz), 7.86(1H, d, J=2.4 Hz), 8.00(1H, dd, J=8.7, 2.4 Hz), 8.32(1H, d, J=2.4 Hz), 10.69(1H, s), 11.49(1H, s).
Example 403
Preparation of the Compound of Compound No. 403
Using 5-chlorosalicylic acid and 4-isopropyl-2-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 33.4%. 1H-NMR(DMSO-d6): δ 1.24(6H, d, J=6.6 Hz), 2.97-3.06(1H, m), 7.06(1H, d, J=8.7 Hz), 7.51(1H, dd, J=8.7, 2.7 Hz), 7.61(1H, s), 7.62(1H, d, J=7.5 Hz), 7.98(1H, d, J=2.7 Hz), 8.03(1H, d, J=8.1 Hz), 10.67(1H, s), 12.21(1H, s).
Example 404
Preparation of the Compound of Compound No. 404
Using 5-chlorosalicylic acid and 3-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 68.5%. 1H-NMR(DMSO-d6): δ 7.03(1H, d, J=8.6 Hz), 7.46-7.51(2H, m), 7.62(1H, t, J=7.9 Hz), 7.90(1H, d, J=3.0 Hz), 7.94(1H, d, J=9.2 Hz), 8.21(1H, s), 10.64(1H, s), 11.58(1H, brs).
Example 405
Preparation of the Compound of Compound No. 405
Using 5-chlorosalicylic acid and 2-nitro-4-(trifluoromethyl)aniline as the raw materials the same operation as the Example 16 gave the title compound.
Yield: 18.7%. 1H-NMR(DMSO-d6): δ 7.08(1H, d, J=9.0 Hz), 7.54(1H, dd, J=8.7, 2.7 Hz), 7.94(1H, d, J=2.7 Hz), 8.17(1H, dd, J=9.0, 2.4 Hz), 8.46(1H, d, J=1.8 Hz), 8.88(1H, d, J=9.0 Hz), 12.19(1H, s), 12.25(1H, s).
Example 406
Preparation of the Compound of Compound No. 406
Using 5-chlorosalicylic acid and 2,6-dichloro-4-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 22.1%. 1H-NMR(DMSO-d6): δ 7.07(1H, d, J=8.7 Hz), 7.55(1H, dd, J=8.7, 2.7 Hz), 7.99(1H, d, J=2.4 Hz), 8.10(2H, s), 10.62(1H, s), 11.88(1H, s).
Example 407
Preparation of the Compound of Compound No. 407
Using 5-chlorosalicylic acid and 4-cyano-3-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 55.8%. 1H-NMR(DMSO-d6): δ 7.04(1H, d, J=8.7 Hz), 7.49(1H, dd, J=8.7, 2.7 Hz), 7.80(1H, d, J=2.7 Hz), 8.17(2H, s), 8.43(1H, s), 10.94(1H, s), 11.34(1H, s).
Example 408
Preparation of the Compound of Compound No. 408
Using 5-chlorosalicylic acid and 4-bromo-3-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 81.2%. 1H-NMR(DMSO-d6): δ 7.03(1H, d, J=8.7 Hz), 7.48(1H, dd, J=9.0, 2.7 Hz), 7.85-7.94(3H, m), 8.31(1H, d, J=1.8 Hz), 10.67(1H, s), 11.48(1H, s).
Example 409
Preparation of the Compound of Compound No. 409
Using 5-chlorosalicylic acid and 4-bromo-2-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 41.8%. 1H-NMR(DMSO-d6): δ 7.07(1H, d, J=8.7 Hz), 7.52(1H, dd, J=9.0, 2.7 Hz), 7.93-7.97(3H, m), 8.21(1H, d, J=9.3 Hz), 10.81(1H, s), 12.28(1H, s).
Example 410
Preparation of the Compound of Compound No. 410
Using 5-chlorosalicylic acid and 2-bromo-4-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 17.6%. 1H-NMR(DMSO-d6): δ 7.10(1H, d, J=9.0 Hz), 7.53(1H, dd, J=8.7, 3.0 Hz), 7.82(1H, dd, J=9.0, 1.8 Hz), 7.98(1H, d, J=3.0 Hz), 8.11(1H, d, J=1.5 Hz), 8.67(1H, d, J=8.7 Hz), 11.05(1H, s), 12.40(1H, s).
Example 411
Preparation of the Compound of Compound No. 411
Using 5-chlorosalicylic acid and 4-fluoro-2-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 36.0%. 1H-NMR(DMSO-d6): δ 7.06(1H, d, J=9.0 Hz), 7.52(1H, dd, J=8.7, 2.7 Hz), 7.63(1H, td, J=8.7, 3.3 Hz), 7.71(1H, dd, J=8.7, 3.0 Hz), 7.97(1H, d, J=2.7 Hz), 8.11(1H, dd, J=8.7, 5.1 Hz), 10.67(1H, s), 12.20(1H, s).
Example 412
Preparation of the Compound of Compound No. 412
Using 5-chlorosalicylic acid and 4-isopropyloxy-2-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 39.2%. 1H-NMR(DMSO-d6): δ 1.29(6H, d, J=5.7 Hz), 4.67-4.79(1H, m), 7.04(1H, d, J=9.0 Hz), 7.22(1H, d, J=2.7 Hz), 7.30(1H, dd, J=8.7, 2.7 Hz), 7.51(1H, dd, J=8.7, 2.4 Hz), 7.86(1H, d, J=9.0 Hz), 7.99(1H, d, J=3.0 Hz), 10.50(1H, s), 12.18(1H, s).
Example 413
Preparation of the Compound of Compound No. 413
Using 5-chlorosalicylic acid and 2,4-dimethoxy-5-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 19.0%. 1H-NMR(CDCl3): δ 3.93(3H, s), 4.03(3H, s), 6.70(1H, s), 6.98(1H, d, J=8.9 Hz), 7.39(1H, dd, J=8.9, 2.6 Hz), 7.45(1H, d, J=2.6 Hz), 8.29(1H, brs,), 8.54(1H, s), 11.92(1H, s).
Example 414
Preparation of the Compound of Compound No. 414
Using 5-chlorosalicylic acid and 2,4-difluoro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 66.0%. 1H-NMR(DMSO-d6): δ 7.06(1H, d, J=8.8 Hz), 7.51(1H, dd, J=8.8, 2.8 Hz), 7.82(1H, t, J=10.7 Hz), 7.94(1H, d, J=2.8 Hz), 8.64(1H, d, J=8.0 Hz), 10.78(1H, s), 12.37(1H, brs).
Example 416
Preparation of the Compound of Compound No. 415
Using 5-chlorosalicylic acid and 4-cyano-2-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 24.8%. 1H-NMR(DMSO-d6): δ 7.06(1H, d, J=8.8 Hz), 7.52(1H, dd, J=2.8, 8.8 Hz), 7.94(1H, d, J=2.8 Hz), 8.17(1H, dd, J=1.8, 8.9 Hz), 8.31(1H, d, J=2.1 Hz), 8.63(1H, d, J=8.9 Hz), 11.16(1H, s), 12.45(1H, br.s).
Example 416
Preparation of the Compound of Compound No. 416
Using 5-chlorosalicylic acid and 4-chloro-2-(4-chlorobenzenesulfonyl)-5-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 8.5%. 1H-NMR(CDCl3): δ 6.98(1H, d, J=8.9 Hz), 7.13(1H, d, J=2.6 Hz), 7.22(2H, d, J=8.6 Hz), 7.34(2H, d, J=8.6 Hz), 7.40(1H, dd, J=2.3, 8.9 Hz), 7.66(1H, s), 8.71(1H, s), 8.80(1H, s), 11.42(1H, s).
Example 417
Preparation of the Compound of Compound No. 417
Using 5-chlorosalicylic acid and 5-chloro-2-nitro-4-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 22.8%. 1H-NMR(DMSO-d6): δ 7.08(1H, d, J=8.8 Hz), 7.55(1H, dd, J=8.8, 2.8 Hz), 7.93(1H, d, J=2.8 Hz), 8.52(1H, s), 9.13(1H, s), 12.38(1H, brs), 12.45(1H, s).
Example 418
Preparation of the Compound of Compound No. 418
Using 5-chlorosalicylic acid and 2,3-difluoro-4-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 21.8%. 1H-NMR(DMSO-d6): δ 7.07(1H, d, J=8.8 Hz), 7.53(1H, dd, J=2.9, 8.8 Hz), 7.66(1H, dt, J=1.8, 7.7 Hz), 7.93(1H, d, J=2.6 Hz), 8.35(1H, t, J=7.7 Hz), 11.02(1H, d, J=1.5 Hz), 12.32(1H, s).
Example 419
Preparation of the Compound of Compound No. 419
Using 5-chlorosalicylic acid and 4,4′-diamino-2,2′-bis(trifluoromethyl)biphenyl as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 35.9%. 1H-NMR(DMSO-d6): δ 7.05(2H, d, J=8.8 Hz), 7.39(2H, d, J=8.5 Hz), 7.49-7.51(2H, m), 7.91(2H, d, J=2.5 Hz), 7.99(2H, dd, J=2.0, 8.5 Hz), 8.31(2H, d, J=1.9 Hz), 10.71(2H, s), 11.54(2H, s).
Example 420
Preparation of the Compound of Compound No. 420
Using 5-chlorosalicylic acid and 2,3,5,6-tetrafluoro-4-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 42.5%. 1H-NMR(DMSO-d6): δ 7.08(1H, d, J=8.8 Hz), 7.53(1H, dd, J=2.9, 8.8 Hz), 7.89(1H, d, J=2.6 Hz), 10.65(1H, br.s), 11.76(1H, br.s).
Example 421
Preparation of the Compound of Compound No. 421
Using 5-chlorosalicylic acid and 3′-aminoacetanilide as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 22.4%. 1H-NMR(DMSO-d6): δ 2.05(3H, s), 7.01(1H, d, J=8.7 Hz), 7.24-7.39(3H, m), 7.47(1H, dd, J=9.0, 3.0 Hz), 7.97(1H, d, J=3.0 Hz), 8.03(1H, s), 10.01(1H, s), 10.41(1H, s), 11.87(1H, s).
Example 422
Preparation of the Compound of Compound No. 422
(1) 2-Acetoxy-5-chloro-N-(3-carbamoylphenyl)benzamide
Using 2-acetoxy-5-chlorobenzoic acid and 3-aminobenzamide as the raw materials, the same operation as the Example 24 gave the title compound.
Yield: 15.8%. 1H-NMR(CDCl3): δ 2.33(3H, s), 5.89(1H, brs), 6.31(1H, brs), 7.14(1H, d, J=9.0 Hz), 7.42-7.49(2H, m), 7.55-7.58(1H, m), 7.80(1H, d, J=2.7 Hz), 7.93(1H, d, J=8.1 Hz), 8.07(1H, s), 8.71(1H, s).
(2) 5-Chloro-2-hydroxy-N-(3-carbamoylphenyl)benzamide (Compound No. 422)
Using 2-acetoxy-5-chloro-N-(3-carbamoylphenyl)benzamide as the raw material, the same operation as the Example 2(2) gave the title compound.
Yield: 76.0%. 1H-NMR(DMSO-d6): δ 7.03(1H, d, J=8.7 Hz), 7.40(1H, brs), 7.45(1H, t, J=7.5 Hz), 7.48(1H, dd, J=8.7, 2.4 Hz), 7.62-7.65(1H, m), 7.86-7.89(1H, m), 7.98-7.99(2H, m), 8.15(1H, t, J=1.8 Hz), 10.51(1H, s), 11.85(1H, s).
Example 423
Preparation of the Compound of Compound No. 423
Using 5-chlorosalicylic acid and 3-amino-N-methylbenzamide as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 19.3%. 1H-NMR(DMSO-d6): δ 2.79(3H, d, J=4.5 Hz), 7.03(1H, d, J=9.0 Hz), 7.43-7.51(2H, m), 7.59(1H, dt, J=8.1, 1.5 Hz), 7.87(1H, ddd, J=8.1, 2.1, 0.9 Hz), 7.99(1H, d, J=2.4 Hz), 8.15(1H, t, J=1.8 Hz), 8.46(1H, d, J=4.2 Hz), 10.52(1H, s), 11.84(1H, s).
Example 424
Preparation of the Compound of Compound No. 424
Using 5-chlorosalicylic acid and 2,6-diisopropylaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 52.5%. 1H-NMR(DMSO-d6): δ 1.14(12H, s), 2.96-3.13(2H, m), 7.16(1H, d, J=8.7 Hz), 7.23(1H, d, J=7.5 Hz), 7.33(1H, dd, J=8.4, 6.6 Hz), 7.52(1H, dd, J=8.7, 2.4 Hz), 8.11(1H, d, J=2.4 Hz), 10.09(1H, s), 12.40(1H, s).
Example 425
Preparation of the Compound of Compound No. 425
Using 5-chlorosalicylic acid and 4-methylaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 58.6%. 1H-NMR(DMSO-d6): δ 2.29(3H, s), 7.01(1H, d, J=8.7 Hz), 7.18(1H, d, J=8.1 Hz), 7.47(1H, dd, J=8.7, 2.7 Hz), 7.58(1H, d, J=8.4 Hz), 7.98(1H, d, J=2.7 Hz), 10.35(1H, s), 11.94(1H, s).
Example 426
Preparation of the Compound of Compound No. 426
Using 5-chlorosalicylic acid and 2,6-dimethylaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 59.6%. 1H-NMR(DMSO-d6): δ 2.19(6H, s), 7.01(1H, d, J=9.0 Hz), 7.15-7.16(2H, m), 7.50(1H, dd, J=9.0, 2.7 Hz), 8.07(1H, d, J=2.7 Hz), 10.03(1H, s), 10.10(1H, s), 12.29(1H, s).
Example 427
Preparation of the Compound of Compound No. 427
Using 5-chlorosalicylic acid and 3,4-dimethylaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 68.3%. 1H-NMR(DMSO-d6): δ 2.20(3H, s), 2.23(3H, s), 7.01(1H, d, J=9.0 Hz), 7.13(1H, d, J=8.4 Hz), 7.40-7.47(2H, m), 7.47(1H, dd, J=9.0, 2.7 Hz), 7.99(1H, d, J=2.7 Hz), 10.29(1H, s), 11.97(1H, brs).
Example 428
Preparation of the Compound of Compound No. 428
Using 5-chlorosalicylic acid and 2,4,6-trimethylaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 61.0%. 1H-NMR(DMSO-d6): δ 2.14(6H, s), 2.26(3H, s), 6.95(2H, s), 7.00(1H, d, J=9.3 Hz), 7.48(1H, dd, J=8.7, 2.7 Hz), 8.09(1H, d, J=2.4 Hz), 10.03(1H, s), 12.37(1H, s).
Example 429
Preparation of the Compound of Compound No. 429
Using 5-chlorosalicylic acid and 3-(trifluoromethoxy)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 41.4%. 1H-NMR(CDCl3): δ 7.00(1H, d, J=9.0 Hz), 7.09(1H, d, J=7.5 Hz), 7.40-7.48(3H, m), 7.51(1H, d, J=2.4 Hz), 7.64(1H, s), 7.94(1H, s), 11.66(1H, s).
Example 430
Preparation of the Compound of Compound No. 430
Using 5-chlorosalicylic acid and 2-benzylaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 93.3%. 1H-NMR(CDCl3): δ 4.08(2H, s), 6.56(1H, d, J=2.5 Hz), 6.92(1H, d, J=8.8 Hz), 7.20-7.46(9H, m), 7.53(1H, brs), 7.85(1H, d, J=8.0 Hz), 12.01(1H, brs).
Example 431
Preparation of the Compound of Compound No. 431
Using 5-chlorosalicylic acid and 4-(trifluoromethoxy)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 20.4%. 1H-NMR(DMSO-d6): δ 7.03(1H, d, J=9.3 Hz), 7.39(2H, d, J=9.0 Hz), 7.48(1H, dd, J=9.0, 2.7 Hz), 7.83(2H, d, J=9.3 Hz), 7.92(1H, d, J=2.7 Hz), 10.54(1H, s), 11.78(1H, s).
Example 432
Preparation of the Compound of Compound No. 432
Using 5-chlorosalicylic acid and 2,4-dichloroaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 60.0%. 1H-NMR(DMSO-d6): δ 7.08(1H, d, J=8.7 Hz), 7.48-7.54(2H, m), 7.75(1H, d, J=2.1 Hz), 7.98(1H, d, J=2.7 Hz), 8.44(1H, d, J=8.7 Hz), 10.93(1H, s), 12.31(1H, s).
Example 433
Preparation of the Compound of Compound No. 433
Using 5-chlorosalicylic acid and 4-(tert-butyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 69.0%. 1H-NMR(DMSO-d6): δ 1.29(9H, s), 7.01(1H, d, J=8.7 Hz), 7.39(2H, d, J=8.4 Hz), 7.47(1H, dd, J=8.7, 2.7 Hz), 7.61(2H, d, J=8.4 Hz), 7.99(1H, d, J=2.4 Hz), 10.37(1H, s), 11.96(1H, s).
Example 434
Preparation of the Compound of Compound No. 434
Using 5-chlorosalicylic acid and 2,3-dimethylaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 79.5%. 1H-NMR(DMSO-d6): δ 2.14(3H, s), 2.29(3H, s), 7.03(1H, d, J=9.0 Hz), 7.06-7.15(2H, m), 7.46-7.51(2H, m), 8.05(1H, d, J=3.0 Hz), 10.32(1H, s), 12.28(1H, s).
Example 435
Preparation of the Compound of Compound No. 435
Using 5-chlorosalicylic acid and 5-aminoindane as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 80.7%. 1H-NMR(DMSO-d6): δ 1.98-2.08(2H, m), 2.81-2.89(4H, m), 7.01(1H, d, J=8.8 Hz), 7.21(1H, d, J=8.0, Hz), 7.42(1H, dd, J=8.0, 1.9 Hz), 7.48(1H, dd, J=8.8, 2.8 Hz), 7.60(1H, s), 7.99(1H d, J=2.8, Hz), 10.34(1H, s), 12.00(1H, brs).
Example 436
Preparation of the Compound of Compound No. 436
Using 5-chlorosalicylic acid and 2,4-dimethylaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 37.1%. 1H-NMR(DMSO-d6): δ 2.23(3H, s), 2.28(3H, s), 7.03(2H, d, J=8.7 Hz), 7.10(1H, s), 7.49(1H, dd, J=9.0, 2.7 Hz), 7.63(1H, d, J=8.1 Hz), 8.03(1H, d, J=2.4 Hz), 10.24(1H, s), 12.25(1H, s).
Example 437
Preparation of the Compound of Compound No. 437
Using 5-chlorosalicylic acid and 3-isopropyloxyaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 21.5%. 1H-NMR(CDCl3): δ 1.36(6H, d, J=6.0 Hz), 4.52-4.64(1H, m), 6.75(1H, ddd, J=8.4, 2.4, 0.9 Hz), 6.99(1H, d, J=8.7 Hz), 7.03(1H, ddd, J=8.1, 2.1, 0.9 Hz), 7.25-7.31(3H, m), 7.39(1H, dd, J=8.7, 2.4 Hz), 7.49(1H, d, J=2.4 Hz), 7.81(1H, s).
Example 438
Preparation of the Compound of Compound No. 438
Using 5-chlorosalicylic acid and 2,6-dichloroaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 10.3%. 1H-NMR(DMSO-d6): δ 7.05(1H, d, J=8.7 Hz), 7.43(1H, dd, J=8.7, 7.8 Hz), 7.54(1H, dd, J=9.0, 2.7 Hz), 7.62(1H, d, J=8.1 Hz), 8.05(1H, d, J=2.4 Hz), 10.52(1H, s), 12.01(1H, s).
Example 439
Preparation of the Compound of Compound No. 439
Using 5-chlorosalicylic acid and 4-isopropyloxyaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 76.8%. 1H-NMR(DMSO-d6): δ 1.26(6H, d, J=6.3 Hz), 4.52-4.64(1H, m), 6.93(2H, dt, J=9.0, 2.1 Hz), 7.46(1H, dd, J=9.0, 2.7 Hz), 7.58(2H, dt, J=9.0, 2.1 Hz), 7.99(1H, d, J=3.0 Hz), 10.36(1H, s), 11.83(1H, brs).
Example 440
Preparation of the Compound of Compound No. 440
Using 5-chlorosalicylic acid and 4-bromo-2-(trifluoromethoxy)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 59.2%. 1H-NMR(CDCl3): δ 7.01(1H, d, J=9.3 Hz), 7.42-7.52(4H, m), 8.23(1H, s), 8.31(1H, d, J=9.3 Hz), 11.35(1H, s).
Example 441
Preparation of the Compound of Compound No. 441
Using 5-chlorosalicylic acid and 4-butylaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 77.6% 1H-NMR(CDCl3): δ 0.89(3H, t, J=6.9 Hz), 1.27-1.36(6H, m), 1.56-1.64(2H, m), 2.61(2H, t, J=7.8 Hz), 6.99(1H, d, J=9.0 Hz), 7.21(2H, d, J=8.7 Hz), 7.39(1H, dd, J=9.0, 2.7 Hz), 7.44-7.49(3H, m), 7.80(1H, s), 11.96(1H, s).
Example 442
Preparation of the Compound of Compound No. 442
Using 5-chlorosalicylic acid and 3-methylaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 88.3%. 1H-NMR(CDCl3): δ 2.38(3H, s), 6.98(1H, d, J=8.8 Hz), 7.03(1H, d, J=7.4 Hz), 7.25-7.40(4H, m), 7.48(1H, d, J=2.2 Hz), 7.83(1H, brs), 11.92(1H, brs).
Example 443
Preparation of the Compound of Compound No. 443
Using 5-chlorosalicylic acid and 4-cyclohexylaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 90.6%. 1H-NMR(CDCl3): δ 1.15-1.47(5H, m), 1.56-1.87(5H, m), 2.40-2.53(2H, m), 7.01(1H, d, J=8.8 Hz), 7.21(2H, d, J=8.5 Hz), 7.47(1H, dd, J=8.8, 2.7 Hz), 7.60(2H, d, J=8.5 H), 8.00(1H, d, J=2.7 Hz), 10.36(1H, s), 11.98(1H, brs).
Example 444
Preparation of the Compound of Compound No. 444
Using 5-chlorosalicylic acid and 4-benzylaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 90.3%. 1H-NMR(DMSO-d6): δ 3.93(2H, s), 7.01(1H, d, J=9.0 Hz), 7.16-7.32(7H, m), 7.57(1H, dd, J=9.0, 2.7 Hz), 7.61(2H, d, J=8.4 Hz), 7.96(1H, d, J=2.4 Hz), 10.37(1H, s).
Example 445
Preparation of the Compound of Compound No. 445
Using 5-chlorosalicylic acid and 2-amino-4,5-dimethoxybenzonitrile as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 52.8%. 1H-NMR(DMSO-d6): δ 3.81(3H, s), 3.86(3H, s), 7.08(1H, d, J=8.7 Hz), 7.40(1H, s), 7.52(1H, dd, J=8.7, 2.7 Hz), 7.89(1H, s), 7.99(1H, d, J=3.0 Hz), 10.93(1H, s), 12.31(1H, s).
Example 446
Preparation of the Compound of Compound No. 446
Using 5-chlorosalicylic acid and 6-amino-1,4-benzodioxane as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 79.7%. 1H-NMR(DMSO-d6): δ 4.25(4H, s), 6.86(1H, d, J=8.8 Hz), 7.00(1H, d, J=8.8 Hz), 7.12(1H, dd, J=8.8, 2.5 Hz), 7.33(1H, d, J=2.5 Hz), 7.46(1H, dd, J=8.8, 2.5 Hz), 7.97(1H, d, J=2.5 Hz), 10.27(1H, s), 11.96(1H, s).
Example 447
Preparation of the Compound of Compound No. 447
Using 5-chlorosalicylic acid and 2,4-dichloro-5-(isopropyloxy)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 76.1%. 1H-NMR(DMSO-d6): δ 1.35(6H, d, J=6.0 Hz), 4.58-4.66(1H, m), 7.07(1H, d, J=9.0 Hz), 7.51(1H, dd, J=8.7, 3.0 Hz), 7.68(1H, s), 7.98(1H, d, J=3.0 Hz), 8.35(1H, s), 10.94(1H, s), 12.34(1H, s).
Example 448
Preparation of the Compound of Compound No. 448
Using 5-chlorosalicylic acid and 4-amino-2-chlorobenzonitrile as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 57.9%. 1H-NMR(DMSO-d6): δ 7.04(1H, d, J=9.0 Hz), 7.48(1H, dd, J=8.7, 2.7 Hz), 7.78(1H, d, J=2.7 Hz), 7.82(1H, dd, J=9.0, 2.1 Hz), 7.97(1H, d, J=8.7 Hz), 8.19(1H, d, J=2.1 Hz), 10.79(1H, s), 11.38(1H, s).
Example 449
Preparation of the Compound of Compound No. 449
Using 5-chlorosalicylic acid and 3-chloro-4-(trifluoromethoxy)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 50.6%. 1H-NMR(DMSO-d6): δ 7.03(1H, d, J=8.7 Hz), 7.48(1H, dd, J=8.7, 2.7 Hz), 7.60(1H, dd, J=9.0, 1.5 Hz), 7.76(1H, dd, J=9.0, 2.4 Hz), 7.85(1H, d, J=3.0 Hz), 8.13(1H, d, J=2.4 Hz), 10.61(1H, s), 11.51(1H, s).
Example 450
Preparation of the Compound of Compound No. 450
Using 5-chlorosalicylic acid and 4-amino-3-methylbenzonitrile as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 80.6%. 1H-NMR(DMSO-d6): δ 2.36(3H, s), 7.06(1H, d, J=8.7 Hz), 7.49(1H, dd, J=8.7, 2.4 Hz), 7.71(1H, dd, J=8.4, 1.8 Hz), 7.77(1H, s), 7.95(1H, d, J=3.0 Hz), 8.40(1H, d, J=8.4 Hz), 10.76(1H, s), 12.31(1H, brs).
Example 451
Preparation of the Compound of Compound No. 451
Using 5-chlorosalicylic acid and 2,3-dichloroaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 37.1%. 1H-NMR(DMSO-d6): δ 7.08(1H, d, J=9.0 Hz), 7.40-7.48(2H, m), 7.52(1H, dd, J=9.0, 2.7 Hz), 7.98(1H, d, J=2.7 Hz), 8.40(1H, dd, J=7.2, 2.4 Hz), 11.00(1H, s), 12.32(1H, s).
Example 452
Preparation of the Compound of Compound No. 452
Using 5-chlorosalicylic acid and 2-chloroaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 67.3%. 1H-NMR(DMSO-d6): δ 7.08(1H, d, J=8.7 Hz), 7.20(1H, td, J=8.1, 1.8 Hz), 7.40(1H, td, J=8.4, 1.8 Hz), 7.52(1H, dd, J=8.7, 2.7 Hz), 7.57(1H, dd, J=8.4, 1.8 Hz), 8.00(1H, d, J=2.7 Hz), 8.40(1H, dd, J=8.4, 1.8 Hz), 10.89(1H, s), 12.27(1H, s).
Example 453
Preparation of the Compound of Compound No. 453
Using 5-chlorosalicylic acid and 4-isopropyl-3-methylaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 21.6%. 1H-NMR(CDCl3): δ 1.23(6H, d, J=6.9 Hz), 2.36(3H, s), 3.12(1H, m), 6.89(1H, d, J=9.0 Hz), 7.15-7.40(5H, m), 7.48(1H, d, J=2.1 Hz), 7.83(1H, brs).
Example 454
Preparation of the Compound of Compound No. 454
Using 5-chlorosalicylic acid and 2-amino-5-[(1,1-dimethyl)propyl]phenol as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 24.9%. 1H-NMR(CDCl3): δ 0.69(3H, t, J=7.5 Hz), 1.28(6H, s), 1.63(2H, q, J=7.5 Hz), 6.98(1H, d, J=8.7 Hz), 7.01(1H, d, J=9.0 Hz), 7.06(1H, s), 7.15(1H, dd, =8.4, 2.4 Hz), 7.35(1H, d, J=2.1 Hz), 7.42(1H, dd, J=8.7, 2.4 Hz), 7.56(1H, d, J=2.4 Hz), 8.26(1H, s), 11.44(1H, s).
Example 455
Preparation of the Compound of Compound No. 455
Using 5-chlorosalicylic acid and 2-methylaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 64.7%. 1H-NMR(DMSO-d6): δ 2.28(3H, s), 7.05(1H, d, J=8.7 Hz), 7.13(1H, td, J=7.5, 1.5 Hz), 7.22-7.30(2H, m), 7.50(1H, dd, J=9.0, 2.7 Hz), 7.83(1H, d, J=7.8 Hz), 8.03(1H, d, J=3.0 Hz), 10.32(1H, s), 12.22(1H, s).
Example 456
Preparation of the Compound of Compound No. 456
Using 5-chlorosalicylic acid and 4-butylaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 82.1%. 1H-NMR(DMSO-d6): δ 0.90(3H, t, J=7.2 Hz), 1.24-1.36(2H, m), 1.50-1.60(2H, m), 2.56(2H, t, J=7.2 Hz), 7.01(1H, d, J=8.7 Hz), 7.19(2H, d, J=8.7 Hz), 7.47(1H, dd, J=8.7, 2.4 Hz), 7.59(2H, d, J=8.4 Hz), 7.98(1H, d, J=2.7 Hz), 10.36(1H, s), 11.94(1H, s).
Example 457
Preparation of the Compound of Compound No. 457
Using 5-chlorosalicylic acid and 2-amino-6-chlorobenzonitrile as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 12.7%. 1H-NMR(DMSO-d6): δ 7.09(1H, d, J=8.7 Hz), 7.52(1H, d, J=8.1 Hz), 7.53(1H, dd, J=9.0, 3.0 Hz), 7.76(1H, t, J=8.7 Hz), 7.95(1H, d, J=3.0 Hz), 8.34(1H, d, J=8.4 Hz), 11.17(1H, s), 12.39(1H, s).
Example 458
Preparation of the Compound of Compound No. 458
Using 5-chlorosalicylic acid and 2-amino-5-methylbenzonitrile as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 9.0%. 1H-NMR(CDCl3): δ 2.48(3H, s), 7.01(1H, d, J=9.0 Hz), 7.10(1H, dd, J=8.0, 0.9 Hz), 7.44(1H, d, J=9.0, 2.4 Hz), 7.56(1H, d, J=8.1 Hz), 7.62(1H, d, J=2.4 Hz), 8.22(1H, s), 8.54(1H, brs), 11.25(1H, brs).
Example 459
Preparation of the Compound of Compound No. 459
Using 5-chlorosalicylic acid and 4-benzyloxyaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 26.8%. 1H-NMR(DMSO-d6): δ 5.11(2H, s), 6.99-7.05(3H, m), 7.33-7.49(6H, m), 7.60(2H, d, J=9.0 Hz), 7.99(1H, d, J=2.7 Hz), 10.33(1H, s), 12.02(1H, s).
Example 460
Preparation of the Compound of Compound No. 460
Using 5-chlorosalicylic acid and 4-amino-2,2-difluorobenzo[1,3]dioxole as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 66.9%. 1H-NMR(DMSO-d6): δ 7.05(1H, d, J=8.8 Hz), 7.31-7.32(2H, m), 7.51(1H, dd, J=8.8, 2.8 Hz), 7.70(1H, dd, J=5.6, 3.8 Hz), 7.96(1H, d, J=2.8 Hz), 10.59(1H, s), 12.05(1H, brs).
Example 461
Preparation of the Compound of Compound No. 461
Using 5-chlorosalicylic acid and 5-amino-2,2,3,3-tetrafluoro-2,3-dihydrobenzo[1,4]dioxene as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 67.9%. 1H-NMR(CDCl3): δ 6.99-7.03(2H, m), 7.21-7.27(2H, m), 7.45(1H, dd, J=8.9, 2.5 Hz), 7.52(1H, d, J=2.5 Hz), 8.13(1H, s), 11.44(1H, s).
Example 462
Preparation of the Compound of Compound No. 462
Using 5-chlorosalicylic acid and 3-chloro-4-(trifluoromethyl)sulfanylaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 52.3%. 1H-NMR(DMSO-d6): δ 7.03(1H, d, J=8.8 Hz), 7.47(1H, dd, J=2.9, 8.8 Hz), 7.80(1H, dd, J=2.6, 8.8 Hz), 7.82(1H, d, J=2.6 Hz), 7.88(1H, d, J=8.8 Hz), 8.20(1H, d, J=2.2 Hz), 10.70(1H, s), 11.43(1H, s).
Example 463
Preparation of the Compound of Compound No. 463
Using 5-chlorosalicylic acid and 2-nitro-4-(trifluoromethoxy)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 68.4%. 1H-NMR(DMSO-d6): δ 7.07(1H, d, J=8.8 Hz), 7.52(1H, dd, J=2.6, 8.8 Hz), 7.85-7.89(1H, m), 7.93(1H, d, J=2.6 Hz), 8.17(1H, d, J=2.9 Hz), 8.67(1H, d, J=9.5 Hz), 11.92(1H, s), 12.14(1H, s).
Example 464
Preparation of the Compound of Compound No. 464
Using 5-chlorosalicylic acid and 5-amino-2,2-difluorobenzo[1,3]dioxole as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 75.8%. 1H-NMR(DMSO-d6): δ 7.02(1H, d, J=8.8 Hz), 7.42-7.43(2H, m), 7.48(1H, dd, J=8.8, 2.5 Hz), 7.90(1H, d, J=2.5 Hz), 10.54(1H, s), 11.69(1H, s).
Example 465
Preparation of the Compound of Compound No. 465
Using 5-chlorosalicylic acid and 3-benzylaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 66.4%. 1H-NMR(CDCl3): δ 3.99(2H, s), 6.97(1H, d, J=9.1 Hz), 7.06(1H, d, J=7.4 Hz), 7.18-7.48(8H, m), 7.37(1H, dd, J=9.1, 2.5 Hz), 7.45(1H, d, J=2.5 Hz), 7.80(1H, brs), 11.88(1H, s).
Example 466
Preparation of the Compound of Compound No. 466
Using 5-chlorosalicylic acid and 2-nitro-4-(trifluoromethoxy)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 40.9%. 1H-NMR(DMSO-d6): δ 2.33(3H, s), 7.05(1H, d, J=8.8 Hz), 7.25(1H, dd, J=1.8, 8.8 Hz), 7.33(1H, d, J=1.8 Hz), 7.49(1H, dd, J=2.9, 8.8 Hz), 7.97-8.00(2H, m), 10.37(1H, s), 12.15(1H, s).
Example 467
Preparation of the Compound of Compound No. 467
Using 5-chlorosalicylic acid and 2,3,5-trifluoroaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 54.2%. 1H-NMR(DMSO-d6): δ 7.06(1H, d, J=8.8 Hz), 7.28-7.37(1H, m), 7.51(1H, dd, J=2.6, 8.8 Hz), 7.92(1H, d, J=2.6 Hz), 7.98-8.04(1H, m), 10.93(1H, s), 12.27(1H, br.s)
Example 468
Preparation of the Compound of Compound No. 468
Using 5-chlorosalicylic acid and 4′-aminobenzo-15-crown-5 as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 45.1%. 1H-NMR(CDCl3): δ 3.74-3.77(8H, m), 3.90-3.92(4H, m), 4.10-4.15(4H, m), 6.83(1H, d, J=8.5 Hz), 6.96-6.99(2H, m), 7.24(1H, d, J=2.5 Hz), 7.36(1H, dd, J=2.5, 8.8 Hz), 7.53(1H, s), 8.06(1H, br.s), 11.92(1H, s).
Example 469
Preparation of the Compound of Compound No. 469
Using 5-chlorosalicylic acid and 4-bromo-2-fluoroaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 45.1%. 1H-NMR(DMSO-d6): δ 7.05(1H, d, J=8.8 Hz), 7.43-7.53(2H, m), 7.64-7.71(1H, m), 7.94(1H, d, J=1.5 Hz), 8.20(1H, dd, J=8.4, 8.8 Hz), 10.70(1H, s), 12.16(1H, s).
Example 470
Preparation of the Compound of Compound No. 470
Using 5-chlorosalicylic acid and 2,4-bis(methanesulfonyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 7.2%. 1H-NMR(CDCl1): δ 3.13(3H, s), 3.21(3H, s), 7.04(1H, d, J=8.9 Hz), 7.48(1H, dd, J=2.2, 8.9 Hz), 7.62(1H, d, J=2.2 Hz), 8.24(1H, dd, J=2.4, 9.0 Hz), 8.56(1H, d, J=2.4 Hz), 8.91(1H, d, J=8.9 Hz), 10.96(1H, s), 11.57(1H, s).
Example 471
Preparation of the Compound of Compound No. 471
A mixture of 5-chlorosalicylic acid (87 mg, 0.5 mmol), 2,2-bis(3-amino-4-methylphenyl)-1,1,1,3,3,3-hexafluoropropane (363 mg, 1 mmol), phosphorus trichloride (44 μL, 0.5 mmol) and toluene (4 mL) was refluxed for 4 hours. After the reaction mixture was cooled to, room temperature, it was purified by column chromatography on silica gel (n-hexane:ethyl acetate=5:1) to give the white title compound (16 mg, 4.9%). (The compound of Compound No. 529 described in the following Example 529 was obtained as a by-product.)
1H-NMR(DMSO-d6): δ 2.34(6H, s), 7.04(4H, d, J=8.8 Hz), 7.39(2H, d, J=8.4 Hz), 7.48(2H, dd, J=2.9, 8.8 Hz), 7.96(2H, d, J=2.9 Hz), 8.19(2H, s), 10.44(2H, s), 12.17(2H, s).
Example 472
Preparation of the Compound of Compound No. 472
Using 5-chlorosalicylic acid and 6-amino-2,2,3,3-tetrafluoro-2,3-dihydrobenzo-[1,4]dioxene as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 10.1%. 1H-NMR(DMSO-d6): δ 7.03(1H, d, J=8.8 Hz), 7.48(1H, dd, J=9.0, 2.7 Hz), 7.50(1H, d, J=9.0 Hz), 7.59(1H, dd, J=8.8, 2.2 Hz), 7.86(1H, d, J=2.7 Hz), 7.92(1H, d, J=2.2 Hz), 10.59(1H, s), 11.55(1H, s).
Example 473
Preparation of the Compound of Compound No. 473
Using 5-chlorosalicylic acid and 2-amino-5-chlorobenzophenone as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 27.6%. 1H-NMR(DMSO-d6): δ 6.96(1H, d, J=8.7 Hz), 7.43(1H, dd, J=8.7, 3.0 Hz), 7.49-7.56(3H, m), 7.64-7.75(5H, m), 8.21(1H, d, J=9.3 Hz), 11.21(1H, s), 11.83(1H, s).
Example 474
Preparation of the Compound of Compound No. 474
Using 5-chlorosalicylic acid and 2-bromo-4-fluoroaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 77.1%. 1H-NMR(DMSO-d6): δ 7.07(1H, d, J=9.0 Hz), 7.31-7.38(1H, m), 7.51(1H, dd, J=9.0, 3.0 Hz), 7.72(1H, d, J=8.1, 3.0 Hz), 8.00(1H, d, J=3.0 Hz), 8.23(1H, dd, J=9.3, 5.4 Hz), 10.70(1H, s), 12.24(1H, s).
Example 475
Preparation of the Compound of Compound No. 475
Using 5-chlorosalicylic acid and 4-hexyloxyaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 74.8%. 1H-NMR(DMSO-d6): δ 0.88(3H, t, J=6.6 Hz), 1.28-1.46(6H, m), 2.49-2.52(2H, m), 3.95(2H, t, J=6.6 Hz), 6.91-6.96(2H, m), 7.00(1H, d, J=8.8 Hz), 7.46(1H, dd, J=8.8, 2.9 Hz), 7.55-7.61(2H, m), 8.00(1H, d, J=2.9 Hz), 10.31(1H, s), 12.03(1H, s).
Example 476
Preparation of the Compound of Compound No. 476
Using 5-chlorosalicylic acid and 2,2-bis(3-aminophenyl)-1,1,1,3,3,3-hexafluoropropane as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 64.5%. 1H-NMR(DMSO-d6): δ 6.99(2H, d, J=8.8 Hz), 7.11(2H, d, J=8.0 Hz), 7.45(2H, dd, J=8.8, 2.6 Hz), 7.50(2H, t, J=8.4 Hz), 7.86(2H, d, J=2, 6 Hz), 7.88-7.91(4H, m), 10.53(2H, s), 11.56(2H, s).
Example 477
Preparation of the Compound of Compound No. 477
Using 5-chlorosalicylic acid and 2,4,5-trichloroaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 38.9%. 1H-NMR(CDCl3): δ 7.02(1H, d, J=8.6 Hz), 7.46(1H, d, J=8.6 Hz), 7.49(1H, s), 7.57(1H, s), 8.41(1H, br.s), 8.63(1H, s), 11.42(1H, s).
Example 478
Preparation of the Compound of Compound No. 478
Using 5-chlorosalicylic acid and 3-isopropylaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 55.3%. 1H-NMR(DMSO-d6): δ 1.22(6H, d, 6.9 Hz), 2.76-2.94(1H, m), 7.01(1H, d, J=8.6 Hz), 7.04(1H, d, J=7.9 Hz), 7.29(1H, t, J=7.9 Hz), 7.47(1H, dd, J=8.6, 2.6 Hz), 7.54(1H, d, J=7.9 Hz), 7.57(1H, s), 7.98(1H, d, J=2.6 Hz), 10.37(1H, s), 11.90(1H, brs).
Example 479
Preparation of the Compound of Compound No. 479
Using 5-chlorosalicylic acid and 4-aminobenzonitrile as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 45.6%. 1H-NMR(DMSO-d6): δ 7.03(1H, d, J=8.6 Hz), 7.47(1H, dd, J=8.6, 2.6 Hz), 7.83(1H, d, J=2.6 Hz), 7.84(2H, d, J=8.9 Hz), 7.92(2H, d, J=8.9 Hz), 10.71(1H, s), 11.59(1H, brs).
Example 480
Preparation of the Compound of Compound No. 480
Using 5-chlorosalicylic acid and 3-aminobenzonitrile as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 97.1%. 1H-NMR(DMSO-d6): δ 7.03(1H, d, J=8.7 Hz), 7.48(1H, dd, J=9.0, 2.7 Hz), 7.56-7.63(2H, m), 7.88(1H, d, J=2.7 Hz), 7.95-8.02(1H, m), 8.20-8.21(1H, m), 10.62(1H, s), 11.57(1H, s).
Example 481
Preparation of the Compound of Compound No. 481
Using 5-chlorosalicylic acid and 3,4-dimethoxyaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 73.3%. 1H-NMR(DMSO-d6): δ 3.75(3H, s), 3.76(3H, s), 6.95(1H, d, J=8.7 Hz), 7.01(1H, d, J=9.0 Hz), 7.24(1H, dd, J=8.7, 2.7 Hz), 7.38(1H, d, J=2.1 Hz), 7.47(1H, dd, J=8.7, 2.7 Hz), 8.00(1H, d, J=2.4 Hz), 10.30(1H, s), 12.01(1H, s).
Example 482
Preparation of the Compound of Compound No. 482
Using 5-chlorosalicylic acid and 4-aminophenylacetic acid ethyl ester as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 66.1%. 1H-NMR(DMSO-d6): δ 1.19(3H, t, J=7.5 Hz), 3.64(2H, s), 4.08(2H, q, J=7.2 Hz), 7.01(1H, d, J=8.7 Hz), 7.26(2H, d, J=8.7 Hz), 7.47(1H, dd, J=8.7, 3.0 Hz), 7.64(1H, d, J=8.4 Hz), 7.96(1H, d, J=2.4 Hz), 10.40(1H, s), 11.87(1H, s).
Example 483
Preparation of the Compound of Compound No. 483
Using 5-chlorosalicylic acid and 3-[(trifluoromethyl)sulfanyl]aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 67.1%. 1H-NMR(CDCl3): δ 7.01(1H, d, J=8.9 Hz), 7.42(1H, dd, J=8.9, 2.3 Hz), 7.47-7.53(2H, m), 7.51(1H, d, J=2.3 Hz), 7.76(1H, dt, J=7.6 Hz, 2.0 Hz), 7.88(1H, brs), 7.92(1H, s), 11.64(1H, s).
Example 484
Preparation of the Compound of Compound No. 484
Using 5-chlorosalicylic acid and 4-[(trifluoromethyl)sulfanyl]aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 63.2%. 1H-NMR(CDCl3): δ 7.01(1H, d, J=8.9 Hz), 7.43(1H, dd, J=8.9, 2.3 Hz), 7.50(1H, d, J=2.3 Hz), 7.70(4H, s), 7.90(1H, brs), 11.60(1H, s).
Example 485
Preparation of the Compound of Compound No. 485
Using 5-chlorosalicylic acid and 4-(trifluoromethanesulfonyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 38.7%. 1H-NMR(DMSO-d6): δ 7.04(1H, d, J=8.6 Hz), 7.49(1H, dd, J=8.6, 2.6 Hz), 7.80(1H, d, J=2.6 Hz), 8.12(2H, d, J=9.4 Hz), 8.17(2H, d, J=9.4 Hz), 8.16(1H, s), 10.95(1H, s), 11.37(1H, brs).
Example 486
Preparation of the Compound of Compound No. 486
Using 5-chlorosalicylic acid and 3,4-difluoroaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 75.4%. 1H-NMR(DMSO-d6): δ 7.02(1H, d, J=8.9 Hz), 7.39-7.51(3H, m), 7.85-7.93(2H, m), 10.51, (1H, s), 11.60(1H, s).
Example 487
Preparation of the Compound of Compound No. 487
Using 5-chlorosalicylic acid and 3-ethynylaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 35.8%. 1H-NMR(DMSO-d6): δ 4.22(1H, s), 7.02(1H, d, J=8.6 Hz), 7.25(1H, d, J=7.6 Hz), 7.39(1H, t, J=7.6 Hz), 7.47(1H, dd, J=8.6, 2.6 Hz), 7.70(1H, d, J=7.6 Hz), 7.89(1H, s), 7.91(1H, d, J=2.6 Hz), 10.46(1H, s), 11.69(1H, brs).
Example 488
Preparation of the Compound of Compound No. 488
Using 5-chlorosalicylic acid and 4-(sec-butyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 40.1%. 1H-NMR(DMSO-d6): δ 0.77(3H, t, 7.4 Hz), 1.19(3H, d, 6.9 Hz), 1.50-1.61(2H, m), 2.52-2.62(1H, m), 7.01(1H, d, J=8.9 Hz), 7.20(2H, d, J=8.6 Hz), 7.47(1H, dd, J=8.9, 2.6 Hz), 7.60(2H, d, J=8.6 Hz), 7.98(1H, d, J=2.6 Hz), 10.36(1H, s), 11.94(1H, brs).
Example 489
Preparation of the Compound of Compound No. 489
Using 5-chlorosalicylic acid and 3-chloro-4-methoxyaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 75.7%. 1H-NMR(CDCl3): δ 6.98(2H, t, J=9.2 Hz), 7.38-7.44(2H, m), 7.47(1H, d, J=2.6 Hz), 7.66(1H, d, J=2.6 Hz), 7.73(1H, br.s), 11.81(1H, s).
Example 490
Preparation of the Compound of Compound No. 490
Using 5-chlorosalicylic acid and 3-aminobenzophenone as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 34.3%. 1H-NMR(DMSO-d6): δ 7.02(1H, d, J=8.6 Hz), 7.48(1H, dd, J=9.1, 2.6 Hz), 7.52-7.62(4H, m), 7.68-7.79(3H, m), 7.93(1H, d, J=2.6 Hz), 8.02(1H, d, J=7.9 Hz), 8.16(1H, s), 10.60(1H, s), 11.68(1H, brs).
Example 491
Preparation of the Compound of Compound No. 491
Using 5-chlorosalicylic acid and 3-methoxyaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 23.5%. 1H-NMR(DMSO-d6): δ 3.76(3H, s), 6.69-6.75(1H, m), 7.01(1H, d, J=8.6 Hz), 7.25-7.28(2H, m), 7.39(1H, s), 7.47(1H, dd, J=8.6, 2.6 Hz), 7.94(1H, d, J=2.6 Hz), 10.39(1H, s), 11.81(1H, brs).
Example 492
Preparation of the Compound of Compound No. 492
Using 5-chlorosalicylic acid and 4′-aminoacetanilide as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 36.2%. 1H-NMR(DMSO-d6): δ 2.50(3H, s), 7.01(1H, d, J=8.6 Hz), 7.47(1H, dd, J=8.6, 2.6 Hz), 7.57(2H, d, J=9.1 Hz), 7.61(2H, d, J=9.1 Hz), 7.98(1H, d, J=2.6 Hz), 9.95(1H, s), 10.38(1H, s), 11.99(1H, brs).
Example 493
Preparation of the Compound of Compound No. 493
Using 5-chlorosalicylic acid and sulfanilamide as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 25.7%. 1H-NMR(DMSO-d6): δ 7.03(1H, d, J=8.9 Hz), 7.31(2H, s), 7.47(1H, dd, J=8.9, 2.3 Hz), 7.81(2H, d, J=8.9 Hz), 7.89(2H, d, J=8.9 Hz), 7.89(1H, d, J=2.3 Hz), 10.70(1H, s), 11.55(1H, brs).
Example 494
Preparation of the Compound of Compound No. 494
Using 5-chlorosalicylic acid and 2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol as the raw materials, the same operation as the Example 16 gave the title compound. (The compound was obtained by separation from the mixture with the compound of Compound No. 498 described in the following Example 498.)
Yield: 11.7%. 1H-NMR(DMSO-d6): δ 7.02(1H, d, J=8.6 Hz), 7.47(1H, dd, J=8.6, 2.6 Hz), 7.68(2H, d, J=8.7 Hz), 7.85(2H, d, J=8.7 Hz), 7.91(1H, d, J=2.6 Hz), 8.69(1H, s), 10.62(1H, s).
Example 495
Preparation of the Compound of Compound No. 495
Using 5-chlorosalicylic acid and 2-chloro-4-nitroaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 39.6%. 1H-NMR(CDCl3): δ 7.04(1H, d, J=8.9 Hz), 7.47(1H, dd, J=2.3, 8.9 Hz), 7.54(1H, d, J=2.3 Hz), 8.25(1H, dd, J=2.6, 8.9 Hz), 8.39(1H, d, J=2.3 Hz), 8.73(1H, d, J=9.2 Hz), 8.76(1H, br.s), 11.22(1H, s).
Example 496
Preparation of the Compound of Compound No. 496
Using 5-chlorosalicylic acid and 2,4-difluoroaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 67.8%. 1H-NMR(DMSO-d6): δ 7.05(1H, dd, J=1.7, 8.9 Hz), 7.15(1H, dt, J=1.7, 9.2 Hz), 7.41(1H, ddd, J=2.3, 8.9, 9.2 Hz), 7.51(1H, dt, J=2.3, 8.9 Hz), 7.98(1H, d, J=2.3 Hz), 8.11(1H, dd, J=8.9, 15.1 Hz), 10.59(1H, s), 12.13(1H, s).
Example 497
Preparation of the Compound of Compound No. 497
Using 5-chlorosalicylic acid and 4-(difluoromethoxy)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 85.9%. 1H-NMR(DMSO-d6): δ 7.01(1H, d, J=8.6 Hz), 7.19(1H, t, J=74.2 Hz), 7.20(2H, d, J=8.6 Hz), 7.47(1H, dd, J=8.6, 2.6 Hz), 7.74(2H, d, J=8.9 Hz), 7.94(1H, d, J=2.6 Hz), 10.47(1H, s), 11.80(1H, brs).
Example 498
Preparation of the Compound of Compound No. 498
This compound was obtained by separation from the mixture with the compound of Compound No. 494 described in the aforementioned Example 494.
Yield: 11.6%. 1H-NMR(DMSO-d6): δ 7.02(1H, d, J=8.6 Hz), 7.46(1H, dd, J=8.6, 2.3 Hz), 7.83(2H, d, J=8.1 Hz), 7.88(1H, d, J=2.3 Hz), 7.95(2H, d, J=8.1 Hz), 10.71(1H, s).
Example 499
Preparation of the Compound of Compound No. 499
Using 5-chlorosalicylic acid and 3-(methylsulfanyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 67.2%. 1-NMR(DMSO-d6): δ 2.49(3H, s), 7.00-7.05(1H, m), 7.01(1H, d, J=8.9 Hz), 7.31(1H, t, J=7.9 Hz), 7.46(1H, dd, J=8.9, 2.6 Hz), 7.44-7.49(1H, m), 7.68(1H, d, J=1.7 Hz), 7.93(1H, d, J=2.6 Hz), 10.47(1H, s).
Example 500
Preparation of the Compound of Compound No. 500
Using 5-chlorosalicylic acid and 4-methanesulfonylaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 28.6%. 1H-NMR(DMSO-d6): δ 3.20(3H, s), 7.03(1H, d, J=8.3 Hz), 7.48(1H, dd, J=8.3, 2.6 Hz), 7.87(1H, d, J=2.6 Hz), 7.92(2H, d, J=8.9 Hz), 7.98(2H, d, J=8.9 Hz), 10.75(1H, s), 11.45(1H, brs).
Example 501
Preparation of the Compound of Compound No. 501
Using 5-chlorosalicylic acid and 2-amino-4-methylbenzophenone as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 8.7%. 1H-NMR(CDCl3): δ 2.50(3H, s), 6.98(1H, d, J=8.3 Hz), 6.99(1H, d, J=7.3 Hz), 7.39(1H, dd, J=2.0, 8.6 Hz), 7.48-7.64(4H, m), 7.72(2H, d, J=7.6 Hz), 7.83(1H, d, J=2.3 Hz), 8.57(1H, s), 12.18(1H, s), 12.34(1H, br.s).
Example 502
Preparation of the Compound of Compound No. 502
Using 5-chlorosalicylic acid and 3-amino-N-butylbenzenesulfonamide as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 46.7%. 1H-NMR(DMSO-d6): δ 0.80(3H, t, J=7.3 Hz), 1.17-1.41(4H, m), 2.73-2.80(2H, m), 7.03(1H, d, J=8.9 Hz), 7.48(1H, dd, J=8.9, 2.0 Hz), 7.53-7.64(2H, m), 7.87-7.92(1H, m), 7.92(1H, d, J=2.0 Hz), 8.27(1H, s), 10.62(1H, s), 11.63(1H, s).
Example 503
Preparation of the Compound of Compound No. 503
Using 5-chlorosalicylic acid and 3-(benzyloxy)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 68.5%. 1H-NMR(DMSO-d6): δ 5.11(2H, s), 6.79-6.83(1H, m), 7.01(1H, d, J=8.9 Hz), 7.27-7.49(9H, m), 7.93(1H, d, J=3.0 Hz), 10.40(1H, s), 11.79(1H, brs).
Example 504
Preparation of the Compound of Compound No. 504
Using 5-chlorosalicylic acid and N-(4-aminophenyl)-4-methylbenzenesulfonamide as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 40.6%. 1H-NMR(DMSO-d6): δ 2.33(3H, s), 6.99(1H, d, J=8.6 Hz), 7.07(2H, d, J=8.6 Hz), 7.34(2H, d, J=8.3 Hz), 7.45(1H, dd, J=8.6, 2.1 Hz), 7.53(2H, d, J=8.6 Hz), 7.63(2H, d, J=8.3 Hz), 7.90(1H, d, J=2.1 Hz), 10.14(1H, s), 10.33(1H, s), 11.81(1H, brs).
Example 505
Preparation of the Compound of Compound No. 505
Using 5-chlorosalicylic acid and 4-(morpholino)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 29.8%. 1H-NMR(DMSO-d6): δ 3.09(4H, t, J=4.6 Hz), 3.74(4H, t, J=4.6 Hz), 6.94-7.01(3H, m), 7.46(1H, dd, J=8.9, 2.6 Hz), 7.55(2H, d, J=8.9 Hz), 8.01(1H, d, J=2.6 Hz), 10.29(1H, s), 12.10(1H, brs).
Example 506
Preparation of the Compound of Compound No. 506
Using 5-chlorosalicylic acid and 3-(tert-butyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 76.1%. 1H-NMR(CDCl3): δ 1.35(9H, s), 6.99(1H, d, J=8.9 Hz), 7.24-7.28(1H, m), 7.32-7.35(1H, m), 7.40(1H, dd, J=8.9, 2.3 Hz), 7.46-7.50(2H, m), 7.51(1H, d, J=2.3 Hz), 7.81(1H, brs), 11.94(1H, s).
Example 507
Preparation of the Compound of Compound No. 507
Using 5-chlorosalicylic acid and 3-(5-methylfuran-2-yl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 61.1%. 1H-NMR(DMSO-d6): δ 2.36(3H, s), 6.22-6.23(1H, m), 6.81(1H, d, J=3.0 Hz), 7.02(1H, d, J=8.9 Hz), 7.36-7.51(3H, m), 7.58-7.61(1H, m), 7.99-8.01(2H, m), 10.49(1H, s), 11.85(1H, brs).
Example 508
Preparation of the Compound of Compound No. 508
Using 5-chlorosalicylic acid and 3-(1-hydroxyethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 37.6%. 1H-NMR(DMSO-d6): δ 1.80(3H, d, J=6.6 Hz), 5.33(1H, q, J=6.6 Hz), 7.01(1H, d, J=8.9 Hz), 7.25(1H, d, J=7.9 Hz), 7.38(1H, t, J=7.9 Hz), 7.47(1H, dd, J=8.9, 2.3 Hz), 7.65(1H, d, J=7.9 Hz), 7.85(1H, s), 7.96(1H, d, J=2.3 Hz), 10.48(1H, s), 11.80(1H, brs).
Example 509
Preparation of the Compound of Compound No. 509
Using 5-chlorosalicylic acid and 3-aminobenzenesulfonamide as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 18.7%. 1H-NMR(DMSO-d6): δ 7.03(1H, d, J=8.9 Hz), 7.41(2H; s), 7.48(1H, dd, J=8.9, 2.6 Hz), 7.54-7.62(2H, m), 7.84-7.88(1H, m), 7.93(1H, d, J=2.6 Hz), 8.30(1H, s), 10.64(1H, s), 11.68(1H, brs).
Example 510
Preparation of the Compound of Compound No. 510
Using 5-chlorosalicylic acid and 3-(trifluoromethanesulfonyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 62.6%. 1H-NMR(DMSO-d6): δ 7.03(1H, d, J=8.6 Hz), 7.48(1H, dd, J=8.6, 2.6 Hz), 7.82-7.88(3H, m), 8.23-8.26(1H, m), 8.67(1H, s), 10.88(1H, s), 11.45(1H, brs).
Example 511
Preparation of the Compound of Compound No. 511
Using 5-chlorosalicylic acid and 2-bromo-4-(trifluoromethoxy)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 17.1%. 1H-NMR(CDCl3): δ 7.02(1H, d, J=8.9 Hz), 7.26-7.31(1H, m), 7.44(1H, dd, J=8.9, 2.6 Hz), 7.53(2H, d, J=2.6 Hz), 8.41(1H, brs,), 8.42(1H, d, J=8.9 Hz), 11.57(1H, s).
Example 512
Preparation of the Compound of Compound No. 512
Using 5-chlorosalicylic acid and 3,4-(dihexyloxy)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 60.5%. 1H-NMR(CDCl3): δ 0.91(6H, t, J=6.3 Hz), 1.34-1.61(12H, m), 1.76-1.89(4H, m), 3.97-4.04(4H, m), 6.88(1H, d, J=8.9 Hz), 6.97-7.00(2H, m), 7.22(1H, d, J=2.6 Hz), 7.38(1H, dd, J=8.9, 2.6 Hz), 7.47(1H, d, J=2.6 Hz), 7.73(1H, s), 11.97(1H, s).
Example 513
Preparation of the Compound of Compound No. 513
Using 5-chlorosalicylic acid and 3,4-dichloroaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 16.4%. 1H-NMR(DMSO-d6): δ 7.03(1H, d, J=8.7 Hz), 77.47(1H, dd, J=8.7, 2.7 Hz), 7.61-7.70(2H, m), 7.86(1H, d, J=2.7 Hz), 8.11(1H, d, J=2.1 Hz), 10.56(1H, s), 11.53(1H, s).
Example 514
Preparation of the Compound of Compound No. 514
Using 5-chlorosalicylic acid and 3-hexyloxyaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 88.2%. 1H-NMR(DMSO-d6): δ 0.89(3H, t, J=7.0 Hz), 1.28-1.47(6H, m), 1.67-1.76(2H, m), 3.95(2H, t, J=6.6 Hz), 6.69-6.73(1H, m), 7.01(1H, d, J=8.8 Hz), 7.21-7.28(2H, m), 7.39-7.40(1H, m), 7.67(1H, dd, J=8.8, 2.6 Hz), 7.94(1H, d, J=2.6 Hz), 10.34(1H, s), 11.80(1H, s).
Example 515
Preparation of the Compound of Compound No. 515
Using 5-chlorosalicylic acid and 5-ethoxy-4-fluoro-2-nitroaniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 20.2%. 1H-NMR(DMSO-d6): δ 1.43(3H, t, J=7.0 Hz), 4.27(2H, q, J=7.0 Hz), 7.07(1H, d, J=8.8 Hz), 7.52(1H, dd, J=8.8, 2.9 Hz), 7.95(1H, d, J=2.9 Hz), 8.15(1H, d, J=11.4 Hz), 8.57(1H, d, J=8.4 Hz), 12.16(1H, s), 12.26(1H, s).
Example 516
Preparation of the Compound of Compound No. 516
Using 5-chlorosalicylic acid and 4-hydroxy-3-methyl-1-naphthylamine as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 5.9%. 1H-NMR(DMSO-d6): δ 2.38(3H, s), 7.03(1H, d, J=9.3 Hz), 7.43(2H, s), 7.46(1H, d, J=2.4 Hz), 7.50-7.54(2H, m), 7.67(1H, d, J=2.1 Hz), 7.78(1H, dd, J=6.0, 2.7 Hz), 8.03(1H, brs), 8.18(1H, dd, J=6.0, 3.6 Hz), 11.98(1H, brs).
Example 517
Preparation of the Compound of Compound No. 517
This compound is a known compound.
Reference which describes the preparation method: the pamphlet of International Publication WO99/65449.
Example 518
Preparation of the Compound of Compound No. 518
This compound is a known compound.
Reference which describes the preparation method: the pamphlet of International Publication WO99/65449.
Example 519
Preparation of the Compound of Compound No. 519
This compound is a known compound.
Reference which describes the preparation method: the pamphlet of International Publication WO99/65449.
Example 520
Preparation of the Compound of Compound No. 520
This compound is a known compound.
Reference which describes the preparation method: the pamphlet of International Publication WO99/65449.
Example 521
Preparation of the Compound of Compound No. 521
This compound is a known compound.
Reference which describes the preparation method: the pamphlet of International Publication WO99/65449.
Example 522
Preparation of the Compound of Compound No. 522
This compound is a known compound.
Reference which describes the preparation method: the pamphlet of International Publication WO99/65449.
Example 523
Preparation of the Compound of Compound No. 523
This compound is a known compound.
Reference which describes the preparation method: the pamphlet of International Publication WO99/65449.
Example 524
Preparation of the Compound of Compound No. 524
Using 5-chlorosalicylic acid and 4-aminobiphenyl as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 52.4%. 1H-NMR(DMSO-d6): δ 7.03(1H, d, J=8.7 Hz), 7.33-7.38(1H, m), 7.44-7.51(3H, m), 7.67-7.72(4H, m), 7.82(2H, d, J=8.7 Hz), 7.98(1H, d, J=2.4 Hz), 10.49(1H, s), 11.84(1H, s).
Example 525
Preparation of the Compound of Compound No. 525
A mixture of 5-sulfosalicylic acid (218 mg, 1 mmol), 3,5-bis(trifluoromethyl)aniline (229 mg, 1 mmol), phosphorus trichloride (88 μL, 1 mmol) and o-xylene (5 mL) was refluxed for 3 hours. After the reaction mixture was cooled to room temperature, it was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:1) to give the title compound (29 mg, 9.2%) as a white solid.
1H-NMR(DMSO-d6): δ 7.15(1H, d, J=8.8 Hz), 7.65(2H, s), 7.73(1H, s), 7.81(1H, s), 7.82(1H, dd, J=8.7, 2.5 Hz), 8.23(1H, d, J=2.5 Hz), 8.38(2H, s), 10.87(1H, s), 11.15(1H, brs).
Example 526
Preparation of the Compound of Compound No. 526
Using 5-chlorosalicylic acid and 2,4-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 6.9%. 1H-NMR(CDCl3): δ 7.03(1H, dd, J=8.7, 0.6 Hz), 7.43-7.48(2H, m), 7.91(1H, d, J=9.0 Hz), 7.96(1H, s), 8.42(1H, s), 8.49(1H, d, J=8.7 Hz), 11.26(1H, s).
Example 527
Preparation of the Compound of Compound No. 527
Using 3-phenylsalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 64.6%. 1H-NMR(DMSO-d6): δ 7.12(1H, t, J=8.1 Hz), 7.37(1H, tt, J=7.5, 1.5 Hz), 7.43-7.48(2H, m), 7.56-7.60(3H, m), 7.91(1H, s), 8.07, (1H, dd, J=8.1, 1.5 Hz), 8.48(2H, s), 11.00(1H, s), 12.16(1H, s).
Example 528
Preparation of the Compound of Compound No. 528
Using 4-fluorosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 65.7%. 1H-NMR(DMSO-d6): δ 6.81-6.90(2H, m), 7.84(1H, s,), 7.93-7.98(1H, m,), 8.45(2H, s,), 10.78(1H, s), 11.81(1H, s,).
Example 529
Preparation of the Compound of Compound No. 529
This compound was obtained by separation from the mixture with the compound of Compound No. 471 described in the aforementioned Example 471.
Yield: 9.4%. 1H-NMR(CD3OD): δ 2.16(3H, s), 2.34(3H, s), 6.69(1H, d, J=8.2 Hz), 6.76(1H, brs) 6.95(1H, d, J=8.8 Hz), 7.02(1H, d, J=8.0 Hz), 7.15(1H, d, J=8.2 Hz), 7.29(1H, d, J=8.2 Hz), 7.37(1H, dd, J=8.8, 2.6 Hz), 7.97(1H, d, J=2.6 Hz), 7.98(1H, s).
Example 530
Preparation of the Compound of Compound No. 530
Using 5-chlorosalicylic acid and 4-amino-3-(trifluoromethoxy)benzonitrile as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 75.2%. 1H-NMR(DMSO-d6): δ 7.13(1H, d, J=8.8 Hz), 7.54(1H, dd, J=8.8, 2.6 Hz), 7.94(1H, dd, J=8.4, 1.6 Hz), 7.95(1H, d, J=2.6 Hz), 8.15(1H, t, J=1.5 Hz), 8.75(1H, d, J=8.8 Hz), 11.25(1H, s), 12.45(1H, s).
Example 531
Preparation of the Compound of Compound No. 531
Using 5-chlorosalicylic acid and 4-[2-amino-4-(trifluoromethyl)phenoxy]benzonitrile as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 11.6%. 1H-NMR(CD3OD): δ 6.88(1H, d, J=8.6 Hz), 7.19(2H, d, J=8.9 Hz), 7.24(1H, d, J=8.6 Hz), 7.33(1H, dd, J=8.8, 2.8 Hz), 7.46(1H, dd, J=8.9, 1.9 Hz), 7.76(2H, d, J=8.9 Hz), 7.98(1H, d, J=2.7 Hz), 8.96(1H, s).
Example 532
Preparation of the Compound of Compound No. 532
Using 5-chlorosalicylic acid and 3-amino-4-(4-methoxyphenoxy)-benzotrifluoride as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 88.1%.  1H-NMR(CDCl3): δ 3.85(3H, s) 6.81(1H, d, J=8.5 Hz), 6.97-7.02(3H, m), 7.08(2H, d, J=8.8 Hz), 7.30(1H, m), 7.40(1H, dd, J=8.8, 1.9 Hz), 7.45(1H, d, J=2.2 Hz), 8.70(1H, s), 8.78(1H, d, J=1.6 Hz), 11.76(1H, s).
Example 533
Preparation of the Compound of Compound No. 533
Using salicylic acid and 2,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 47.8%. 1H-NMR(CD3OD): δ 7.00-7.06(2H, m), 7.48(1H, dt, J=1.5, 7.5 Hz), 7.74(1H, d, J=8.4 Hz), 8.01-8.08(2H, m), 8.79(1H, s), 11.09(1H, s), 12.03(1H, s).
Example 534
Preparation of the Compound of Compound No. 534
(1) 2-Amino-4-(2,4-dichlorophenyl)thiazole
Using 2′,4′-dichloroacetophenone and thiourea as the raw materials, the same operation as the Example 395(1) gave the title compound.
Yield: 97.1%. 1H-NMR(CDCl3): δ 5.01(2H, s), 7.09(1H, s), 7.28(1H, dd, J=8.4, 2.1 Hz), 7.45(1H, d, J=2.1 Hz), 7.82(1H, d, J=8.4 Hz).
(2) 5-Chloro-2-hydroxy-N-[4-(2,4-dichlorophenyl)thiazol-2-yl]benzamide (Compound No. 534)
Using 5-chlorosalicylic acid and 2-amino-4-(2,4-dichlorophenyl)thiazole as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 8.0%. 1H-NMR(DMSO-d6): δ 7.08(1H, d, J=8.7 Hz), 7.50-7.55(2H, m), 7.72-7.76(2H, m), 7.91(1H, d, J=8.4 Hz), 7.95(1H, d, J=2.4 Hz), 11.87(1H, brs), 12.09(1H, brs).
Example 535
Preparation of the Compound of Compound No. 535
Using 3-isopropylsalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 99.2%. 1H-NMR(CDCl3): δ 1.26(6H, d, J=6.9 Hz), 3.44(1H, Hept, J=6.9 Hz), 6.92(1H, t, J=7.8 Hz), 7.38(1H, dd, J=8.1, 1.2 Hz), 7.44(1H, d, J=7.5 Hz), 7.69(1H, s), 8.13(3H, s), 11.88(1H, s).
Example 536
Preparation of the Compound of Compound No. 536
Bromine (14.4 μL, 0.28 mmol) and iron powder (1.7 mg, 0.03 mmol) were added to a solution of N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-3-isopropylbenzamide (Compound No. 535; 100 mg, 0.26 mmol) in carbon tetrachloride (5 mL) under argon atmosphere, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate. The ethyl acetate layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was crystallized from n-hexane/ethyl acetate to give the title compound (110 mg, 91.5%) as a white solid.
1H-NMR(CDCl3): δ 1.25(6H, d, J=6.9 Hz), 3.39(1H, Hept, J=6.9 Hz), 7.49-7.51(2H, m), 7.71(1H, brs), 8.11-8.14(3H, m), 11.81(1H, brs).
Example 537
Preparation of the Compound of Compound No. 537
N-Bromosuccinimide (88.2 mg, 0.50 mmol) was added to a solution of N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-3-methylbenzamide (Compound No. 328; 150 mg, 0.41 mmol) in a mixed solvent of methanol/water (3:1; 5 mL), and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was diluted with ethyl acetate. The ethyl acetate layer was washed with 10% aqueous sodium thiosulfate, water and brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporation under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=5:1) to give the title compound (167 mg, 91.5%) as a white powder.
1H-NMR(CDCl3): δ 2.28(3H, s), 7.47(1H, s), 7.50(1H, d, J=2.4 Hz), 7.71(1H, s), 8.08(1H, brs), 8.13(2H, s), 11.71(1H, s).
Example 538
Preparation of the Compound of Compound No. 538
(1) 1-(3-Nitrophenyl)-5-phenyl-3-(trifluoromethyl)pyrazole
A mixture of 4,4,4-trifluoro-1-phenyl-1,3-butanedione (432.3 mg, 2 mmol), 3-nitrophenylhydrazine hydrochloride (379.2 mg, 2 mmol), concentrated hydrochloric acid (0.2 mL) and ethanol (8 mL) was reflued for 2 hours. After the reaction mixture was cooled to room temperature, it was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=4:1→3:1) to give the title compound (631.5 mg, 94.7%) as a light yellowish white powder.
1H-NMR(CDCl3): δ 6.80(1H, s), 7.23-7.26(2H, m), 7.35-7.45(3H, m), 7.54(1H, t, J=8.4 Hz), 7.63(1H, ddd, J=8.1, 1.8, 1.2 Hz), 8.19-8.25(2H, m).
(2) 1-(3-Aminophenyl)-5-phenyl-3-(trifluoromethyl)pyrazole
Acetic acid (3 mL) and ethanol (2 mL) were added to 1-(3-nitrophenyl)-5-phenyl-3-(trifluoromethyl)pyrazole (0.59 g, 1.77 mmol) and 5% palladium on carbon (0.06 g), and the mixture was hydrogenated at room temperature for 2 hours under hydrogen atmosphere. After the insoluble matter was filtered off, the residue obtained by evaporation under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1) to give the title compound (491.1 mg, 91.4%) as a white solid.
1H-NMR(CDCl3): δ 3.78(2H, s), 6.54(1H, ddd, J=7.8, 1.8, 0.6 Hz), 6.65(1H, ddd, J=8.4, 2.4, 0.9 Hz), 6.73-6.75(2H, m), 7.07(1H, t, J=8.1 Hz), 7.24-7.36(5H, m).
(3) 5-Chloro-2-hydroxy-N-{3-[5-phenyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl}-benzamide (Compound No. 538)
Using 5-chlorosalicylic acid and 1-(3-aminophenyl)-5-phenyl-3-(trifluoromethyl)pyrazole as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 74.4%. 1H-NMR(CDCl3): δ 6.77(1H, s), 6.97-7.03(2H, m), 7.27-7.45(8H, m), 7.65(1H, ddd, J=8.4, 2.1, 0.9 Hz), 7.74(1H, t, J=2.1 Hz), 7.93(1H, s), 11.63(1H, s).
Example 539
Preparation of the Compound of Compound No. 539
(1) 5-(tert-Butyl)-1-(4-nitrophenyl)-3-(trifluoromethyl)pyrazole
Using 1,1,1-trifluoro-5,5-dimethyl-2,4-hexanedione and 4-nitrophenylhydrazine hydrochloride as the raw materials, the same operation as the Example 538(1) gave the title compound.
Yield: 94.7%. 1H-NMR(CDCl3): δ 1.23(9H, s), 6.51(1H, s), 7.62(2H, d, J=9.0 Hz), 8.37(2H, d, J=9.0 Hz).
(2) 1-(4-Aminophenyl)-5-(tert-butyl)-3-(trifluoromethyl)pyrazole
Using 5-(tert-butyl)-1-(4-nitrophenyl)-3-(trifluoromethyl)pyrazole as the raw material, the same operation as the Example 538(2) gave the title compound.
Yield: 98.9%. 1H-NMR(CDCl3): δ 1.20(9H, s), 4.00(2H, br), 6.40(1H, s), 6.69(2H, d, J=8.7 Hz), 7.14(2H, d, J=9.0 Hz).
(3) N-{4-[5-(tert-butyl)-3-(trifluoromethyl)pyrazol-1-yl]phenyl}-5-chloro-2-hydroxy-benzamide (Compound No. 539)
Using 5-chlorosalicylic acid and 1-(5-aminophenyl)-5-(tert-butyl)-3-(trifluoromethyl)pyrazole as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 57.6%. 1H-NMR(CDCl3): δ 1.23(9H, s), 6.47(1H, s), 7.00(1H, d, J=9.0 Hz), 7.40-7.44(3H, m), 7.57(1H, d, J=2.4 Hz), 7.72(2H, d, J=8.7 Hz), 8.15(1H, s), 11.58(1H, s).
Example 540
Preparation of the Compound of Compound No. 540
Using N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-3-phenylbenzamide (Compound No. 527), the same operation as the Example 537 gave the title compound.
Yield: 67.5%. 1H-NMR(DMSO-d6): δ 7.36-7.50(3H, m), 7.55-7.59(2H, m), 7.71(1H, d, J=2.1 Hz), 7.93(1H, brs), 8.28(1H, d, J=2.1 Hz), 8.45(2H, s), 11.06(1H, brs), 12.16(1H, brs).
Example 541
Preparation of the Compound of Compound No. 541
(1) 2-Amino-4-(3,4-dichlorophenyl)thiazole
Using 3′,4′-dichloroacetophenone and thiourea as the raw materials, the same operation as the Example 395(1) gave the title compound.
Yield: 77.8%. 1H-NMR(DMSO-d6): δ 7.17(2H, s), 7.24(1H, s), 7.62(1H, d, J=8.4 Hz), 7.78(1H, dd, J=8.7, 2.7 Hz), 8.22(1H, d, J=2.4 Hz).
(2) 5-Chloro-2-hydroxy-N-[4-(3,4-dichlorophenyl)thiazol-2-yl]benzamide (Compound No. 541)
Using 5-chlorosalicylic acid and 2-amino-4-(3,4-dichlorophenyl)thiazole as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 15.1%. 1H-NMR(DMSO-d6): δ 7.08(1H, d, J=8.7 Hz), 7.52(1H, dd, J=8.7, 2.7 Hz), 7.71(1H, d, J=8.4 Hz), 7.91(1H, d, J=1.8 Hz), 7.94(1H, s), 8.18(1H, d, J=1.5 Hz), 12.09(2H, bs).
Example 542
Preparation of the Compound of Compound No. 542
(1) 2-Amino-4-[4-(trifluoromethyl)phenyl]thiazole
Using 4′-(trifluoromethyl)acetophenone and thiourea as the raw materials, the same operation as the Example 395(1) gave the title compound.
Yield: 77.5%. 1H-NMR(DMSO-d6): δ 7.18(2H, s), 7.26(1H, s), 7.72(2H, d, J=8.4 Hz), 8.00(2H, d, J=8.1 Hz).
(2) 5-Chloro-2-hydroxy-N-{4-[4-(trifluoromethyl)phenyl]thiazol-2-yl}benzamide (Compound No. 542)
Using 5-chlorosalicylic acid and 2-amino-4-[4-(trifluoromethyl)phenyl]thiazole as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 16.0%. 1H-NMR(DMSO-d6): δ 7.09(1H, d, J=9.0 Hz), 7.53(1H, dd, J=8.7, 2.7 Hz), 7.81(2H, d, J=8.4 Hz), 7.96(1H, d, J=2.4 Hz), 7.98(1H, s), 8.16(2H, d, J=8.1 Hz), 11.91(1H, bs), 12.13(1H, bs).
Example 543
Preparation of the Compound of Compound No. 543
(1) 2-Acetoxy-N-{4-[3,5-bis(trifluoromethyl)pyrazol-1-yl]phenyl}-5-chlorobenzamide
Using 2-acetoxy-5-chlorobenzoic acid and 1-(4-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole as the raw materials, the same operation as the Example 24 gave the title compound.
Yield: 77.8%. 1H-NMR(CDCl3): δ 2.36(3H, s), 7.78(1H, s), 7.14(1H, d, J=8.7 Hz), 7.48-7.51(3H, m), 7.77(2H, d, J=9.0 Hz), 7.83(1H, d, J=2.7 Hz), 8.25(1H, s).
[1-(4-Aminophenyl)-3,5-bis(trifluoromethyl)pyrazole: Refer to “Journal of Medicinal Chemistry”, 2000, Vol. 43, No. 16, p. 2975-2981.]
(2) N-{4-[3,5-Bis(trifluoromethyl)pyrazol-1-yl]phenyl}-5-chloro-2-hydroxybenzamide (Compound No. 543)
Using 2-acetoxy-N-{4-[3,5-bis(trifluoromethyl)pyrazol-1-yl]phenyl}-5-chlorobenzamide as the raw material, the same operation as the Example 2(2) gave the title compound.
Yield: 73.1%. 1H-NMR(DMSO-d6): δ 7.04(1H, d, J=8.7 Hz), 7.48(1H, dd, J=8.7, 2.7 Hz), 7.63(2H, d, J=8.7 Hz), 7.84(1H, s), 7.89(1H, d, J=3.0 Hz), 7.94(2H, d, J=9.0 Hz), 10.65(1H, s), 11.58(1H, s).
Example 544
Preparation of the Compound of Compound No. 544
(1) 3,5-Bis(trifluoromethyl)-1-(3-nitrophenyl)pyrazole
Using hexafluoroacetylacetone and 3-nitrophenylhydrazine hydrochloride as the raw materials, the same operation as the Example 538(1) gave the title compound.
Yield: 94.0%. 1H-NMR(CDCl3): δ 7.16(1H, s), 7.77(1H, dd, J=8.7, 8.1 Hz), 7.88-7.91(1H, m), 8.42-8.45(2H, m).
(2) 1-(3-Aminophenyl)-3,5-bis(trifluoromethyl)pyrazole
Using 3,5-bis(trifluoromethyl)-1-(3-nitrophenyl)pyrazole as the raw material, the same operation as the Example 538(2) gave the title compound.
Yield: 73.1%. 1H-NMR(CDCl3): δ 3.89(2H, s), 6.77-6.87(3H, m), 7.04(1H, s), 7.26(1H, t, J=8.7 Hz).
(3) 2-Acetoxy-N-{3-[3,5-bis(trifluoromethyl)pyrazol-1-yl]phenyl}-5-chlorobenzamide
Using 2-acetoxy-5-chlorobenzoic acid and 1-(3-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole as the raw materials, the same operation as the Example 24 gave the title compound.
Yield: 84.4%. 1H-NMR(CDCl3): δ 2.33(3H, s), 7.09(1H, s), 7.11(1H, d, J=9.0 Hz), 7.30(1H, d, J=7.8 Hz), 7.45-7.52(2H, m), 7.67(1H, d, J=8.4 Hz), 7.78(1H, d, J=2.4 Hz), 7.95(1H, s), 8.29(1H, s).
(4) N-{3-[3,5-Bis(trifluoromethyl)pyrazol-1-yl]phenyl}-5-chloro-2-hydroxybenzamide (Compound No. 544)
Using 2-acetoxy-N-(3-[3,5-bis(trifluoromethyl)pyrazol-1-yl]phenyl)-5-chlorobenzamide as the raw material, the same operation as the Example 2(2) gave the title compound.
Yield: 69.9%. 1H-NMR(CDCl3): δ 7.01(1H, d, J=8.7 Hz), 7.10(1H, s), 7.34-7.37(1H, m), 7.42(1H, dd, J=8.7, 2.4 Hz), 7.50(1H, d, J=2.4 Hz), 7.56(1H, t, J=8.1 Hz), 7.69-7.73(1H, m), 7.95-7.98(2H, m), 11.57(1H, s).
Example 545
Preparation of the Compound of Compound No. 545
(1) Methyl 2-methoxy-4-phenylbenzoate
Dichlorobis(triphenylphosphine)palladium (29 mg, 0.04 mmol) was added to a solution of methyl 4-chloro-2-methoxybenzoate (904 mg, 4.5 mmol), phenylboronic acid (500 mg, 4.1 mmol) and cesium carbonate (2.7 g, 8.2 mmol) in N,N-dimethylformamide (15 mL) under argon atmosphere, and the mixture was stirred at 120° C. for 8 hours. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate. The ethyl acetate layer was washed successively with water and brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=10:1) to give the title compound (410 mg, 41.2%) as a colourless oil.
1H-NMR(CDCl3): δ 3.91(3H, s), 3.98(3H, s), 7.17(1H, d, J=1.5 Hz), 7.20(1H, dd, J=8.1, 1.5 Hz), 7.31-7.50(3H, m), 7.59-7.63(2H, m), 7.89(1H, d, J=8.1 Hz).
(2) 2-Methoxy-4-phenylbenzoic acid
2N Aqueous sodium hydroxide (5 mL) was added to a solution of methyl 2-methoxy-4-phenylbenzoate (410 mg, 1.69 mmol) in methanol (5 mL), and the mixture was refluxed for 1 hour. After the reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure. 2N hydrochloric acid was added to the obtained residue and the separated crystal was filtered to give the title compound (371 mg, 96.0%) as a crude product.
1H-NMR(DMSO-d6): δ 3.93(3H, s), 7.29(1H, dd, J=8.1, 1.5 Hz), 7.34(1H, d, J=1.5 Hz), 7.40-7.53(3H, m), 7.73-7.77(3H, m), 12.60(1H, s).
(3) N-[3,5-Bis(trifluoromethyl)phenyl]-2-methoxy-4-phenylbenzamide
Using 2-methoxy-4-phenylbenzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 97.5%. 1H-NMR(CDCl3): δ 4.19(3H, s), 7.25(1H, m), 7.38-7.53(4H, m), 7.62-7.65(3H, m), 8.12(2H, s), 8.35(1H, d, J=8.1 Hz), 10.15(1H, brs).
(4) N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-4-phenylbenzamide (Compound No. 545)
1M Boron tribromide-dichloromethane solution (0.71 mL, 0.71 mmol) was added to a solution of N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxy-4-phenylbenzamide (100 mg, 0.24 mmol) in dichloromethane (5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water and brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=5:1) to give the title compound (69.3 mg, 71.6%) as a white powder.
1H-NMR(DMSO-d6): δ 7.20(1H, dd, J=8.4.1.8 Hz), 7.30(1H, d, J=1.8 Hz), 7.39-7.51(3H, m), 7.60-7.64(3H, m), 7.70(1H, brs), 8.15(2H, s), 8.19(1H, brs), 11.59(1H, s).
Example 546
Preparation of the Compound of Compound No. 546
(1) 2-Amino-4-(2,5-difluorophenyl)thiazole
Using 2′,5′-difluoroacetophenone and thiourea as the raw materials, the same operation as the Example 395(1) gave the title compound.
Yield: 77.8%. 1H-NMR(DMSO-d6): δ 7.45(1H, d, J=2.7 Hz), 7.11-7.17(1H, m), 7.19(2H, s), 7.28-7.36(1H, m), 7.65-7.71(1H, m).
(2) 5-Chloro-2-hydroxy-N-[4-(2,5-difluorophenyl)thiazol-2-yl]benzamide (Compound No. 546)
Using 5-chlorosalicylic acid and 2-amino-4-(2,5-difluorophenyl)thiazole as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 36.5%. 1H-NMR(DMSO-d6): δ 7.09(1H, d, J=8.7 Hz), 7.22-7.30(1H, m), 7.37(1H, m), 7.53(1H, dd, J=8.7, 3.0 Hz), 7.72(1H, d, J=2.4 Hz), 7.77-7.84(1H, m), 7.94(1H, d, J=3.0 Hz), 11.89(1H, bs), 12.12(1H, bs).
Example 547
Preparation of the Compound of Compound No. 547
(1) 2-Acetoxy-4-chlorobenzoic acid
Using 4-chlorosalicylic acid, concentrated sulfuric acid and acetic anhydride as the raw materials, the same operation as the Example 34(1) gave the title compound.
Yield: 88.1%. 1H-NMR(DMSO-d6): δ 2.25(3H, s), 7.42(1H, d, J=1.8 Hz), 7.48(1H, dd, J=8.4, 2.4 Hz), 7.94(1H, d, J=8.1 Hz), 13.31(1H, s).
(2) 2-Acetoxy-N-{4-[3,5-bis(trifluoromethyl)pyrazol-1-yl]phenyl}-4-chlorobenzamide
Using 2-acetoxy-4-chlorobenzoic acid and 1-(4-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole as the raw materials, the same operation as the Example 24 gave the title compound.
Yield: 74.0%. 1H-NMR(CDCl3): δ 2.37(3H, s), 7.08(1H, s), 7.23(1H, d, J=1.8 Hz), 7.37(1H, dd, J=8.1, 2.1 Hz), 7.50(2H, d, J=8.7 Hz), 7.77(2H, d, J=8.7 Hz), 7.82(1H, d, J=8.1 Hz), 8.23(1H, s).
(3) N-{4-[3,5-Bis(trifluoromethyl)pyrazol-1-yl]phenyl}-4-chloro-2-hydroxybenzamide (Compound No. 547)
Using 2-acetoxy-N-{4-[3,5-bis(trifluoromethyl)pyrazol-1-yl]phenyl}-4-chlorobenzamide as the raw material, the same operation as the Example 2(2) gave the title compound.
Yield: 56.6%. 1H-NMR(DMSO-d6): δ 7.03-7.06(2H, m), 7.61(2H, d, J=8.7 Hz), 7.81(1H, s), 7.89-7.95(3H, m), 10.62(1H, s), 11.82(1H, s).
Example 548
Preparation of the Compound of Compound No. 548
(1) 1-(4-Nitrophenyl)-5-phenyl-3-(trifluoromethyl)pyrazole
Using 4,4,4-trifluoro-1-phenyl-1,3-butanedione and 4-nitrophenylhydrazine hydrochloride as the raw materials, the same operation as the Example 538(1) gave the title compound.
Yield: 95.2%. 1H-NMR(CDCl3): δ 6.80(1H, s), 7.22-7.26(2H, m), 7.37-7.45(3H, m), 7.51(2H, d, J=9.3 Hz), 8.22(2H, d, J=9.0 Hz).
(2) 1-(4-Aminophenyl)-5-phenyl-3-(trifluoromethyl)pyrazole
Using 1-(4-nitrophenyl)-5-phenyl-3-(trifluoromethyl)pyrazole as the raw material, the same operation as the Example 538(2) gave the title compound.
Yield: 73.0%. 1H-NMR(CDCl3): δ 3.80(2H, s), 6.62(2H, d, J=8.7 Hz), 6.72(1H, s), 7.08(2H, d, J=8.7 Hz), 7.22-7.26(2H, m), 7.30-7.33(3H, m).
(3) 5-Chloro-2-hydroxy-N-{4-[5-phenyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl}-benzamide (Compound No. 548)
Using 5-chlorosalicylic acid and 1-(4-aminophenyl)-5-phenyl-3-(trifluoromethyl)pyrazole as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 73.2%. 1H-NMR(CDCl3): δ 7.02(1H, d, J=8.7 Hz), 7.21(1H, s), 7.30-7.42(7H, m), 7.47(1H, dd, J=8.7, 2.7 Hz), 7.79(2H, d, J=8.7 Hz), 7.89(1H, d, J=2.7 Hz), 10.56(1H, s), 11.61(1H, s).
Example 549
Preparation of the Compound of Compound No. 549
(1) 2-Amino-4-(4-methoxyphenyl)thiazole
Using 4′-methoxyacetophenone and thiourea as the raw materials, the same operation as the Example 395(1) gave the title compound.
Yield: 85.2%. 1H-NMR(DMSO-d6): δ 3.76(3H, s), 6.82(1H, s), 6.92(2H, d, J=9.0 Hz), 7.01(2H, s), 7.72(2H, d, J=8.7 Hz).
(2) 5-Chloro-2-hydroxy-N-[4-(4-methoxyphenyl)thiazol-2-yl]benzamide (Compound No. 549)
Using 5-chlorosalicylic acid and 2-amino-4-(4-methoxyphenyl)thiazole as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 16.4%. 1H-NMR(DMSO-d6): δ 3.80(3H, s), 7.01(2H, d, J=9.0 Hz), 7.07(1H, d, J=8.7 Hz), 7.50-7.55(2H, m), 7.86(2H, d, J=9.0 Hz), 7.96(1H, d, J=2.7 Hz), 11.90(1H, bs), 12.04(1H, bs).
Example 550
Preparation of the Compound of Compound No. 550
(1) 2-Amino-4-[3-(trifluoromethyl)phenyl]thiazole
Using 3′-(trifluoromethyl)acetophenone and thiourea as the raw materials, the same operation as the Example 395(1) gave the title compound.
Yield: 94.1%. 1H-NMR(DMSO-d6): δ 7.19(2H, s), 7.27(1H, s), 7.61(2H, dd, J=3.9, 1.5 Hz), 8.07-8.13(2H, m).
(2) 5-Chloro-2-hydroxy-N-{4-[3-(trifluoromethyl)phenyl]thiazol-2-yl}benzamide (Compound No. 550)
Using 5-chlorosalicylic acid and 2-amino-4-[3-(trifluoromethyl)phenyl]thiazole as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 31.0%. 1H-NMR(DMSO-d6): δ 7.13(1H, d, J=8.7 Hz), 7.53(1H, dd, J=9.0, 2.7 Hz), 7.70(1H, d, J=2.4 Hz), 7.71(1H, d, J=1.2 Hz), 7.95(1H, d, J=2.7 Hz), 8.00(1H, s), 8.24-8.27(2H, m), 12.16(2H, bs).
Example 551
Preparation of the Compound of Compound No. 551
(1) 2-Amino-4-(2,3,4,5,6-pentafluorophenyl)thiazole
Using 2′,3′,4′,5′,6′-pentafluoroacetophenone and thiourea as the raw materials, the same operation as the Example 395(1) gave the title compound.
Yield: 86.7%. 1H-NMR(CDCl3): δ 5.19(2H, s), 6.83(1H, s).
(2) 5-Chloro-2-hydroxy-N-[4-(2,3,4,5,6-pentafluorophenyl)thiazol-2-yl]benzamide (Compound No. 551)
Using 5-chlorosalicylic acid and 2-amino-4-(2,3,4,5,6-pentafluorophenyl)-thiazole as the raw materials, the same operation as the Example 16 gave the title compound.
Yield: 23.8%. 1H-NMR(DMSO-d6): δ 7.08(1H, d, J=8.7 Hz), 7.53(1H, dd, J=8.7, 2.7 Hz), 7.73(1H, s), 7.93(1H, d, J=2.7 Hz), 11.85(1H, bs), 12.15(1H, bs).
Example 552
Preparation of the Compound of Compound No. 552
Iron (3 mg, 0.05 mmol) and bromine (129 μl, 2.5 mmol) were added to a solution of 2-hydroxy-N-[2,5-bis(trifluoromethyl)phenyl]benzamide (Compound No. 533; 175 mg, 0.5 mmol) in carbon tetrachloride (5 mL), and the mixture was stirred at 50° C. for 12 hours. After the reaction mixture was cooled to room temperature, it was washed with saturated aqueous sodium hydrogen carbonate, water and brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1) to give the title compound (184.2 mg, 72.7%) as a white crystal.
1H-NMR(DMSO-d6): δ 7.92-7.98(1H, m), 8.06(1H, d, J=2.1 Hz), 8.09(1H, d, J=8.4 Hz), 8.22(1H, d, J=2.1 Hz), 8.27-8.32(1H, m), 11.31(1H, s).
Example 553
Preparation of the Compound of Compound No. 553
Using 2,3-dihydroxybenzaldehyde and 3-[3,5-bis(trifluoromethyl)benzyl]-thiazolidine-2,4-dione (compound of Example 319(1)) as the raw materials, the same operation as the Example 319(2) gave the title compound.
Yield: 88.5%. 1H-NMR(DMSO-d6): δ 5.02(2H, s), 6.88(1H, d, J=7.8 Hz), 7.00-7.04(2H, m), 7.79(1H, s), 8.03(2H, s), 8.07(1H, s), 9.49(1H, s), 9.91(1H, s).
Example 554
Preparation of the Compound of Compound No. 554
A mixture of 5-chlorosalicylaldehyde (157 mg, 1 mmol), 2-amino-4-tert-amylphenyl phenyl ether (255 mg, 1 mmol) and ethanol (2 mL) was stirred at room temperature for 18 hours. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=100:1) to give the title compound (57 mg, 14.4%) as a white solid.
1H-NMR(CDCl3): δ 0.66(3H, t, J=7.5 Hz), 1.26(6H, s), 1.61(2H, q, J=7.5 Hz), 6.88-6.94(3H, m), 7.04(1H, dd, J=8.0, 1.6 Hz), 7.15-7.32(7H, m), 8.61(1H, s), 13.20(1H, s).
Example 555
Preparation of the Compound of Compound No. 555
A mixture of 4-chloro-2-({[2-phenoxy-5-(tert-amyl)phenyl]imino}-methyl)phenol (Compound No. 554; 13 mg, 0.03 mmol), sodium borohydride (1.2 mg, 0.03 mmol) and methanol (1 mL) was stirred at room temperature for 5 minutes. The residue obtained by evaporation of the solvent under reduced pressure was purified by thin layer chromatography on silica gel (n-hexane:ethyl acetate=5:1) to give the title compound (13 mg, 100%) as a colourless oil.
1H-NMR(CDCl3): δ 0.69(3H, t, J=7.6 Hz), 1.28(6H, s), 1.63(2H, q, J=7.6 Hz), 4.41(2H, s), 6.78(1H, m), 6.93-6.83(5H, m), 7.03(1H, m), 7.15(2H, m), 7.28(3H, m).
Test Example 1
Proliferation Inhibitory Test of Mast Cell Under Stimulation by SCF and IL-3
Bone marrow-derived cultured mast cells (105 cells/ml) of NC/Nga mouse were cultured with rmIL-3 (100 U/ml) and SCF (100 ng/ml) in the presence or absence of a test drug in α-Modified Eagle's Medium containing 10% of bovine fetal serum without phenol red, and then stained with trypan blue, and the number of living cells was counted. The results are shown in the following table.














Culture Time


Compound
Concentration
Number of Cell (×105/ml)












Number
(μM)
0 hr
24 hr
48 hr
72 hr















—
0
1.0
1.3
1.7
2.6


50
1
1.0
0.86
0.84
1.16



5
1.0
0.7
0.52
0.22









Test Example 2
Degranulation Inhibitory Test of Mast Cell
Anti DNP IgE was added to mouse bone marrow-derived cultured mast cells (BMCMC) which were treated beforehand with anti DNP IgE for 4 days for expression of IgE receptor. The cells were cultured for 3 days, and treated for 1 hour with or without the addition of a test substance. Then, the medium was changed to α-Modified Eagle's Medium containing 10% of bovine fetal serum without phenol red. After cultivation for 60 minutes with rmIL-3 (100 U/ml) and DNP-BSA (50 ng/ml) in the presence or absence of the test substance, the concentrations of β-hexosaminidase in the culture medium and in the cells were determined, and the progress of degranulation was measured from a ratio of the amounts. The inhibitory ratio of the degranulation by the drug was calculated when degranulation in the absence of the test substance was taken as 100%, and degranulation in the presence of anti DNP-IgE only and in the absence of the test substance was taken as 0%. The results are shown in the following table.














Compound
Inhibitory Ration of Degranulation(%)



Number
at 10 μM Drug Concentration



















50
>99



56
92



63
62



73
91



100
83



101
90



113
93



114
88



122
91



163
88



195
72










Test Example 3
IgE Production Inhibitory Test of Spleen B Cell
B cells isolated from mouse spleen were cultured with 200 U/ml of rmIL-4 and 100 ng/ml of soluble mCD40 ligand in the presence or absence of a test drug in PRMI 1640 medium containing 10% of bovine fetal serum for 9 days, and the amount of IgE in the culture medium was measured by ELISA method. The results are shown in the following table.













Concentration(μM)



Amount of IgE(ng/ml)












Compound Number
0
0.1
1.0







—
45.6
—
—



50
—
24
ND







ND = not detected






Test Example 4
Immediate Type Allergy Reaction Inhibitory Test (Ear Swelling Test)
To NC/Nga mouse sensitized by an intravenous administration of anti DNP-IgE, a diluent with a test compound for the drug administered group or that without a test drug for the control group was intraperitoneally administered. Two hours after the administration, picryl chloride dissolved in olive oil was applied to auricle to induce immediate allergy, and then swelling of the auricle was measured with passage of time for comparison of the drug administered group and the control group. The results of Compound 50 (dose: 15 mg/kg) are shown in FIG. 1.
Test Example 6
Dermatitis Inhibitory Test by Atopic Dermatitis Model Using NC/Nga Mouse
To the conventional NC/Nga mouse with the onset of severe dermatitis, an ointment containing 1% of a test substance for the drug treated group or a base material of the ointment for the control group was applied once a day, and clinical symptoms were recorded as scores with passage of day. Furthermore, the amounts of IgE in blood before and after the test were measured by ELISA. The results for Compound 50 are shown in FIG. 2.
Test Example 6
Proliferation Inhibitory Test of Fibrosarcoma (HT-1080) Under PDGF Stimulation
HT-1080 cells were cultured for 2 hours in EMEM medium containing 1% of FBS and NEAA in the presence or absence of a test substance. PDGF was added and the cells were cultured for 48 hours, and the proliferation of the cells was measured by MTT assay. The results are shown in the following table.














Inhibitory Ratio




of Proliferation(%)



Drug Concentration









Compound Number
500 nM
250 nM












50
96.6
65.4


51
97.6
62.4


67
70.9
38.5


73
84.9
52.0


63
77.9
48.3


114
95.7
48.8


163
80.8
16.9


71
83.1
57.9


56
96.9
37.5


98
59.4
26.4


196
80.2
47.3


122
51.1
32.9


195
81.7
44.7


199
24.2
26.2


201
76.2
60.3


532
91.8
42.2


552
19.4
24.0


101
80.0
53.2









INDUSTRIAL APPLICABILITY
The medicaments of the present invention are useful for the preventive and/or therapeutic treatment of allergic diseases and/or endometriosis and/or hysteromyoma.

## Claims

1. A method for the therapeutic treatment of contact dermatitis, atopic dermatitis, or otitis media, or for the therapeutic treatment of an adhesion of a tissue in endometriosis in a mammal, which comprises administering to a mammal a therapeutically effective amount of a compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof:



wherein X represents a group represented by the following formula:




wherein the bond at the left end binds to ring Z and the bond at the right end binds to E,
A represents a hydrogen atom or an acetyl group,
E represents a di-substituted phenyl group wherein at least one of said substituents is a trifluoromethyl group,
ring Z represents a benzene ring which may have one or more substituents in addition to the group represented by formula —O-A and the group represented by formula —X-E.

2. The method according to claim 1, wherein:
ring Z is a benzene ring which may have one substituent that locates on the position of Rz when the following partial formula (Iz-1) in the general formula containing ring Z




is represented by the following formula (Iz-2):

3. The method according to claim 2, wherein:
RZ is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a methoxy group, a methyl group, an isopropyl group, a tert-butyl group, a 1,1,3,3-tetramethylbutyl group, a 2-phenylethen-1-yl group, a 2,2-dicyanoethen-1-yl group, a 2-cyano-2-(methoxycarbonyl)ethen-1-yl group, a 2-carboxy-2-cyanoethen-1-yl group, an ethynyl group, a phenylethynyl group, a (trimethylsilyl)ethynyl group, a trifluoromethyl group, a pentafluoroethyl group, a phenyl group, a 4-(trifluoromethyl)phenyl group, a 4-fluorophenyl group, a 2,4-difluorophenyl group, a 2-phenethyl group, a 1-hydroxyethyl group, a 1-(methoxyimino)ethyl group, a 1-[(benzyloxy)imino]ethyl group, a 2-thienyl group, a 3-thienyl group, a 1-pyrrolyl group, a 2-methylthiazol-4-yl group, an imidazo[1,2-a]pyridin-2-yl group, a 2-pyridyl group, an acetyl group, an isobutyryl group, a piperidinocarbonyl group, a 4-benzylpiperidinocarbonyl group, a (pyrrol-1-yl)sulfonyl group, a carboxy group, a methoxycarbonyl group, an N-[3,5-bis(trifluoromethyl)phenyl]carbamoyl group, an N,N-dimethylcarbamoyl group, a sulfamoyl group, an N-[3,5-bis(trifluoromethyl)phenyl]sulfamoyl group, an N,N-dimethylsulfamoyl group, an amino group, an N,N-dimethylamino group, an acetylamino group, a benzoylamino group, a methanesulfonylamino group, a benzenesulfonylamino group, a 3-phenylureido group, a (3-phenyl)thioureido group, a (4-nitrophenyl)diazenyl group, or a {[4-(pyridin-2-yl)sulfamoyl]phenyl}diazenyl group.

4. The method according to claim 1, wherein
E is a 2-chloro-5-(trifluoromethyl)phenyl group, a 2,5-bis(trifluoromethyl)phenyl group, a 2-fluoro-5-(trifluoromethyl)phenyl group, a 2-nitro-5-(trifluoromethyl)phenyl group, a 2-methyl-5-(trifluoromethyl)phenyl group, a 2-methoxy-5-(trifluoromethyl)phenyl group, a 2-methylsulfanyl-5-(trifluoromethyl)phenyl group, a 2-(1-pyrrolidinyl)-5-(trifluoromethyl)phenyl group, a 2-morpholino-5-(trifluoromethyl)phenyl group, a 2-bromo-5-(trifluoromethyl)phenyl group, a 2-(2-naphthyloxy)-5-(trifluoromethyl)phenyl group, a 2-(2,4-dichlorophenoxy)-5-(trifluoromethyl)phenyl group, a 2-[4(trifluoromethyl)piperidin-1-yl]-5-(trifluoromethyl)phenyl group, a 2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl group, a 2-(2-methoxyphenoxy)-5-(trifluoromethyl)phenyl group, a 2-(4-chloro-3,5-dimethylphenoxy)-5-(trifluoromethyl)phenyl group, a 2-piperidino-5-(trifluoromethyl)phenyl group, a 2-(4-methylphenoxy)-5-(trifluoromethyl)phenyl group, a 2-(4-chlorophenoxy)-5-(trifluoromethyl)phenyl group, a 2-(4-cyanophenoxy)-5-(trifluoromethyl)phenyl group, a 2-(4-methoxyphenoxy)-5-(trifluoromethyl)phenyl group, a 3,5-bis(trifluoromethyl)phenyl group, a 3-fluoro-5-(trifluoromethyl)phenyl group, a 3-bromo-5-(trifluoromethyl)phenyl group, a 3-methoxy-5-(trifluoromethyl)phenyl group, a 3-methoxycarbonyl-5-(trifluoromethyl)phenyl group, or a 3-carboxy-5-(trifluoromethyl)phenyl group.

5. The method according to claim 1, wherein the mammal is a human.

6. The method according to claim 1, wherein:
ring Z is a benzene ring which may have one or more substituents selected from:
a halogen atom;
a nitro group;
a cyano group;
an alkoxy group;
an alkyl group which may be substituted with one or more substituents selected from:
a hydroxy group,
an alkoxy-imino group, and
an aralkyl-oxy-imino group;

an alkenyl group which may be substituted with one or more substituents selected from:
an aryl group,
a cyano group,
an alkyl-oxy-carbonyl group, and
a carboxy group;

an alkynyl group which may be substituted with one or more substituents selected from:
an aryl group, and
a tri(alkyl)silyl group;

a halogenated alkyl group;
an aryl group which may be substituted with one or more substituents selected from:
a halogen atom, and
a halogenated alkyl group;

an aralkyl group;
a monocyclic or a fused polycyclic heteroaryl group which may be substituted with one or more alkyl groups;
an alkyl-carbonyl group;
a monocyclic nonaromatic heterocyclic-carbonyl group which may be substituted with one or more aralkyl groups;
a monocyclic heteroaryl-sulfonyl group;
a carboxy group;
an alkyl-oxy-carbonyl group;
a carbamoyl group which may be substituted with one or more substituents selected from:
an aryl group which may be substituted with one or more halogenated alkyl
groups, and
an alkyl group;

a sulfamoyl group which may be substituted with one or more substituents selected from:
an aryl group which may be substituted with one or more halogenated alkyl
groups, and
an alkyl group;

an amino group which may be substituted with one or more substituents selected from:
an alkyl group,
an alkyl-carbonyl group,
an aryl-carbonyl group,
an alkyl-sulfonyl group, and
an aryl-sulfonyl group;

an ureido group which may be substituted with one or more aryl groups;
a thioureido group which may be substituted with one or more aryl groups;
a diazenyl group which may be substituted with one or more aryl groups wherein said aryl groups may be substituted with one or more substituents selected from:
a nitro group, and
a monocyclic heteroaryl-sulfamoyl group; and

a hydroxy group,
in addition to the group represented by formula —O-A and the group represented by formula —X-E.

7. The method according to claim 1, wherein:
ring Z is a benzene ring which may have one or more substituents selected from:
a halogen atom;
a nitro group;
a cyano group;
an alkoxy group;
an alkyl group which may be substituted with one or more substituents selected from:
a hydroxy group,
an alkoxy-imino group, and
an aralkyl-oxy-imino group;

an alkenyl group which may be substituted with one or more substituents selected from:
an aryl group,
a cyano group,
an alkyl-oxy-carbonyl group, and
a carboxy group;

an alkynyl group which may be substituted with one or more substituents selected from:
an aryl group, and
a tri(alkyl)silyl group;

a halogenated alkyl group;
an aryl group which may be substituted with one or more substituents selected from:
a halogen atom, and
a halogenated alkyl group;

an aralkyl group;
a 5 to 9-membered heteroaryl group which may be substituted with one or more alkyl groups;
an alkyl-carbonyl group;
a 6-membered nonaromatic heterocyclic-carbonyl group which may be substituted with one or more aralkyl groups;
a 5-membered heteroaryl-sulfonyl group;
a carboxy group;
an alkyl-oxy-carbonyl group;
a carbamoyl group which may be substituted with one or more substituents selected from:
an aryl group which may be substituted with one or more halogenated alkyl groups, and
an alkyl group;

a sulfamoyl group which may be substituted with one or more substituents selected from:
an aryl group which may be substituted with one or more halogenated alkyl
groups, and
an alkyl group;

an amino group which may be substituted with one or more substituents selected from:
an alkyl group,
an alkyl-carbonyl group,
an aryl-carbonyl group,
an alkyl-sulfonyl group, and
an aryl-sulfonyl group;

an ureido group which may be substituted with one or more aryl groups;
a thioureido group which may be substituted with one or more aryl groups;
a diazenyl group which may be substituted with one or more aryl groups, wherein said aryl groups may be substituted with one or more substituents selected from:
a nitro group, and
a 6-membered heteroaryl-sulfamoyl group; and

a hydroxy group,

in addition to the group represented by formula —O-A and the group represented by formula —X-E.

8. The method according to claim 1, wherein:
ring Z is a benzene ring which may have one or more substituents selected from:
a halogen atom;
a nitro group;
a cyano group;
an alkoxy group;
an alkyl group which may be substituted with one or more substituents selected from:
a hydroxy group,
an alkoxy-imino group, and
a benzyl-oxy-imino group;

an alkenyl group which may be substituted with one or more substituents selected from:
a phenyl group,
a cyano group,
an alkoxy-carbonyl group, and
a carboxy group;

an alkynyl group which may be substituted with one or more substituents selected from:
a phenyl group, and
a tri(alkyl)silyl group;

a halogenated alkyl group;
a phenyl group which may be substituted with one or more substituents selected from:
a halogen atom, and
a halogenated alkyl group;

a phenyl-alkyl group;
a monocyclic or a fused polycyclic heteroaryl group wherein said monocyclic or a fused polycyclic heteroaryl group is a 1-pyrrolyl group, a 2-pyrrolyl group, a 3-pyrrolyl group, a 2-thienyl group, a 3-thienyl group, a 2-thiazolyl group, a 4-thiazolyl group, a 5-thiazolyl group, a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group or an imidazo[1,2-a]pyridin-2-yl group, and said monocyclic or a fused polycyclic heteroaryl group may be substituted with one or more alkyl groups;
an alkyl-carbonyl group;
a monocyclic nonaromatic heterocyclic-carbonyl group wherein said monocyclic nonaromatic heterocyclic-carbonyl group is a piperidino-carbonyl group, and said monocyclic nonaromatic heterocyclic-carbonyl group may be substituted with one or more benzyl groups;
a monocyclic heteroaryl-sulfonyl group wherein said monocyclic heteroaryl-sulfonyl group is a 1-pyrrolyl-sulfonyl group, a 2-pyrrolyl-sulfonyl group or a 3-pyrrolyl-sulfonyl group;
a carboxy group;
an alkyl-oxy-carbonyl group;
a carbamoyl group which may be substituted with one or more substituents selected from:
a phenyl group which may be substituted with one or more halogenated alkyl
groups, and
an alkyl group;

a sulfamoyl group which may be substituted with one or more substituents selected from:
a phenyl group which may be substituted with one or more halogenated alkyl
groups, and
an alkyl group;

an amino group which may be substituted with one or more substituents selected from:
an alkyl group,
an alkyl-carbonyl group,
a phenyl-carbonyl group,
an alkyl-sulfonyl group, and
a phenyl-sulfonyl group;

an ureido group which may be substituted with one or more phenyl groups;
a thioureido group which may be substituted with one or more phenyl groups;
a diazenyl group which may be substituted with one or more phenyl groups wherein said phenyl groups may be substituted with one or more substituents selected from:
a nitro group, and
a monocyclic heteroaryl-sulfamoyl group wherein said monocyclic heteroaryl -sulfamoyl group is a 2-pyridyl-sulfamoyl group, a 3-pyridyl-sulfamoyl group or a 4-pyridyl-sulfamoyl group; and

a hydroxy group,

in addition to the group represented by formula —O-A and the group represented by formula —X-E.

9. The method according to claim 1, wherein:
ring Z is a benzene ring which may have one or more substituents selected from a halogen atom, a nitro group, a cyano group, a methoxy group, a methyl group, an isopropyl group, a tert-butyl group, a 1,1,3,3-tetramethylbutyl group, a 2-phenylethen-1-yl group, a 2,2-dicyanoethen-1-yl group, a 2-cyano-2-(methoxycarbonyl)ethen-1-yl group, a 2-carboxy-2-cyanoethen-1-yl group, an ethynyl group, a phenylethynyl group, a (trimethylsilyl)ethynyl group, a trifluoromethyl group, a pentafluoroethyl group, a phenyl group, a 4-(trifluoromethyl)phenyl group, a 4-fluorophenyl group, a 2,4-difluorophenyl group, a 2-phenethyl group, a 1-hydroxyethyl group, a 1-(methoxyimino)ethyl group, a 1-[(benzyloxy)imino]ethyl group, a 2-thienyl group, a 3-thienyl group, a 1-pyrrolyl group, a 2-methylthiazol-4-yl group, an imidazo[1,2-a]pyridin-2-yl group, a 2-pyridyl group, an acetyl group, an isobutyryl group, a piperidinocarbonyl group, a 4-benzylpiperidinocarbonyl group, a (pyrrol-1-yl)sulfonyl group, a carboxy group, a methoxycarbonyl group, an N-[3,5-bis(trifluoromethyl)phenyl]carbamoyl group, an N,N-dimethylcarbamoyl group, a sulfamoyl group, an N-[3,5-bis(trifluoromethyl)phenyl]sulfamoyl group, an N,N-dimethylsulfamoyl group, an amino group, an N,N-dimethylamino group, an acetylamino group, a benzoylamino group, a methanesulfonylamino group, a benzenesulfonylamino group, a 3-phenylureido group, a (3-phenyl)thioureido group, a (4-nitrophenyl)diazenyl group, and a {[4-(pyridin-2-yl)sulfamoyl]phenyl}diazenyl group.

10. The method according to claim 2, wherein:
Rz is
a hydrogen atom;
a halogen atom;
a nitro group;
a cyano group;
an alkoxy group;
an alkyl group which may be substituted with one or more substituents selected from:
a hydroxy group,
an alkoxy-imino group, and
an aralkyl-oxy-imino group;

an alkenyl group which may be substituted with one or more substituents selected from:
an aryl group,
a cyano group,
an alkyl-oxy-carbonyl group, and
a carboxy group;

an alkynyl group which may be substituted with one or more substituents selected from:
an aryl group, and
a tri(alkyl)silyl group;

a halogenated alkyl group;
an aryl group which may be substituted with one or more substituents selected from:
a halogen atom, and
a halogenated alkyl group;

an aralkyl group;
a monocyclic or a fused polycyclic heteroaryl group which may be substituted with one or more alkyl groups;
an alkyl-carbonyl group;
a monocyclic nonaromatic heterocyclic-carbonyl group which may be substituted with one or more aralkyl groups;
a monocyclic heteroaryl-sulfonyl group;
a carboxy group;
an alkyl-oxy-carbonyl group;
a carbamoyl group which may be substituted with one or more substituents selected from:
an aryl group which may be substituted with one or more halogenated alkyl
groups, and
an alkyl group;

a sulfamoyl group which may be substituted with one or more substituents selected from:
an aryl group which may be substituted with one or more halogenated alkyl
groups, and
an alkyl group;

an amino group which may be substituted with one or more substituents selected from:
an alkyl group,
an alkyl-carbonyl group,
an aryl-carbonyl group,
an alkyl-sulfonyl group, and
an aryl-sulfonyl group;

an ureido group which may be substituted with one or more aryl groups;
a thioureido group which may be substituted with one or more aryl groups;
a diazenyl group which may be substituted with one or more aryl groups wherein said aryl groups may be substituted with one or more substituents selected from:
a nitro group, and
a monocyclic heteroaryl-sulfamoyl group; or

a hydroxy group.

11. The method according to claim 2, wherein:
Rz is
a hydrogen atom;
a halogen atom;
a nitro group;
a cyano group;
an alkoxy group;
an alkyl group which may be substituted with one or more substituents selected from:
a hydroxy group,
an alkoxy-imino group, and
an aralkyl-oxy-imino group;

an alkenyl group which may be substituted with one or more substituents selected from:
an aryl group,
a cyano group,
an alkyl-oxy-carbonyl group, and
a carboxy group;

an alkynyl group which may be substituted with one or more substituents selected from:
an aryl group, and
a tri(alkyl)silyl group;

a halogenated alkyl group;
an aryl group which may be substituted with one or more substituents selected from:
a halogen atom, and
a halogenated alkyl group;

an aralkyl group;
a 5 to 9-membered heteroaryl group which may be substituted with one or more alkyl groups;
an alkyl-carbonyl group;
a 6-membered nonaromatic heterocyclic-carbonyl group which may be substituted with one or more aralkyl groups;
a 5-membered heteroaryl-sulfonyl group;
a carboxy group;
an alkyl-oxy-carbonyl group;
a carbamoyl group which may be substituted with one or more substituents selected from:
an aryl group which may be substituted with one or more halogenated alkyl
groups, and
an alkyl group;

a sulfamoyl group which may be substituted with one or more substituents selected from:
an aryl group which may be substituted with one or more halogenated alkyl
groups, and
an alkyl group;

an amino group which may be substituted with one or more substituents selected from:
an alkyl group,
an alkyl-carbonyl group,
an aryl-carbonyl group,
an alkyl-sulfonyl group, and
an aryl-sulfonyl group;

an ureido group which may be substituted with one or more aryl groups;
a thioureido group which may be substituted with one or more aryl groups;
a diazenyl group which may be substituted with one or more aryl groups wherein said aryl groups may be substituted with one or more substituents selected from:
a nitro group, and
a 6-membered heteroaryl-sulfamoyl group; and

a hydroxy group.

12. The method according to claim 2, wherein:
Rz is
a hydrogen atom;
a halogen atom;
a nitro group;
a cyano group;
an alkoxy group;
an alkyl group which may be substituted with one or more substituents selected from:
a hydroxy group,
an alkoxy-imino group, and
a benzyl-oxy-imino group;

an alkenyl group which may be substituted with one or more substituents selected from:
a phenyl group,
a cyano group,
an alkoxy-carbonyl group, and
a carboxy group;

an alkynyl group which may be substituted with one or more substituents selected from:
a phenyl group, and
a tri(alkyl)silyl group;

a halogenated alkyl group;
a phenyl group which may be substituted with one or more substituents selected from:
a halogen atom, and
a halogenated alkyl group;

a phenyl-alkyl group;
a monocyclic or a fused polycyclic heteroaryl group wherein said monocyclic or a fused polycyclic heteroaryl group is a 1-pyrrolyl group, a 2-pyrrolyl group, a 3-pyrrolyl group, a 2-thienyl group, a 3-thienyl group, a 2-thiazolyl group, a 4-thiazolyl group, a 5-thiazolyl group, a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group or an imidazo[1,2-a]pyridin-2-yl group, and said monocyclic or a fused polycyclic heteroaryl group may be substituted with one or more alkyl groups;
an alkyl-carbonyl group;
a monocyclic non-aromatic heterocyclic-carbonyl group wherein said monocyclic non-aromatic heterocyclic-carbonyl group is a piperidino-carbonyl group, and said monocyclic non-aromatic heterocyclic-carbonyl group may be substituted with one or more benzyl groups;
a monocyclic heteroaryl-sulfonyl group wherein said monocyclic heteroaryl-sulfonyl group is a 1-pyrrolyl-sulfonyl group, a 2-pyrrolyl-sulfonyl group or a 3-pyrrolyl-sulfonyl group;
a carboxy group;
an alkoxy-carbonyl group;
a carbamoyl group which may be substituted with one or more substituents selected from:
a phenyl group which may be substituted with one or more halogenated alkyl groups, and
an alkyl group;

a sulfamoyl group which may be substituted with one or more substituents selected from:
a phenyl group which may be substituted with one or more halogenated alkyl groups, and
an alkyl group;

an amino group which may be substituted with one or more substituents selected from:
an alkyl group,
an alkyl-carbonyl group,
a phenyl-carbonyl group,
an alkyl-sulfonyl group, and
a phenyl-sulfonyl group;

an ureido group which may be substituted with one or more phenyl groups;
a thioureido group which may be substituted with one or more phenyl groups;
a diazenyl group which may be substituted with one or more phenyl groups wherein said phenyl groups may be substituted with one or more substituents selected from:
a nitro group, and
a monocyclic heteroaryl-sulfamoyl group wherein said monocyclic heteroaryl -sulfamoyl group is a 2-pyridyl-sulfamoyl group, a 3-pyridyl-sulfamoyl group or a 4-pyridyl-sulfamoyl group; and

a hydroxy group.

13. The method according to claim 1, wherein:
E is a 2,5- or 3,5-di-substituted phenyl group wherein at least one of said substituents is a trifluoromethyl group, and the other substituent is selected from
a halogen atom;
a nitro group;
an alkyl group;
a halogenated alkyl group;
an alkoxy group;
a halogenated alkoxy group;
an aryl-oxy group which may be substituted with one or more substituents selected from
a halogen atom,
an alkoxy group,
an alkyl group, and
a cyano group;

an alkyl-sulfanyl group;
an alkoxy-carbonyl group;
a carboxy group; and
a monocyclic nonaromatic heterocyclic group which may be substituted with one or more halogenated alkyl group.

14. The method according to claim 13, wherein said monocyclic nonaromatic heterocyclic group is a 5 to 6-membered nonaromatic heterocyclic group.

15. The method according to claim 1, wherein:
E is a 2,5- or 3,5-di-substituted phenyl group wherein at least one of said substituents is a trifluoromethyl group, and the other substituent is selected from
a halogen atom;
a nitro group;
an alkyl group;
a halogenated alkyl group;
an alkoxy group;
a halogenated alkoxy group;
an aryl-oxy group wherein said aryl-oxy group is a phenyl-oxy group, a 1-naphthyl-oxy group or a 2-naphthyl-oxy group, and said aryl-oxy group may be substituted with one or more substituents selected from:
a halogen atom,
an alkoxy group,
an alkyl group, and
a cyano group;

an alkyl-sulfanyl group;
an alkoxy-carbonyl group;
a carboxy group; and
a monocyclic nonaromatic heterocyclic group wherein said monocyclic nonaromatic heterocyclic group is a 1-pyrrolidinyl group, a piperidino group or a morpholino group, and said monocyclic nonaromatic heterocyclic group may be substituted with one or more halogenated alkyl group.

16. The method according to claim 1, wherein
E is a 2,5- or 3,5-di-substituted phenyl group wherein at least one of said substituents is a trifluoromethyl group.