CA2450400A1 - Medicinal compositions - Google Patents

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Publication number
CA2450400A1
CA2450400A1 CA002450400A CA2450400A CA2450400A1 CA 2450400 A1 CA2450400 A1 CA 2450400A1 CA 002450400 A CA002450400 A CA 002450400A CA 2450400 A CA2450400 A CA 2450400A CA 2450400 A1 CA2450400 A1 CA 2450400A1
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Canada
Prior art keywords
group
pyridyl
thiazol
methylphenyl
alkyl
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Abandoned
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CA002450400A
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French (fr)
Inventor
Shigenori Ohkawa
Ken-Ichi Naruo
Shigeru Morimoto
Yoshinori Nagase
Seiji Miwatashi
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Takeda Pharmaceutical Co Ltd
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Individual
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Abstract

Prevention/treatment for pain and/or suppression of the activation and/or inhibition of the formation of osteoclasts by using a p38MAP kinase inhibitor and/or a TNF-.alpha. production inhibitor. A method of relieving a P450-inhibiotry effect of a compound having a pyridyl group or its salt characterized by introducing a substituent into the .alpha.-position of the nitrogen atom in the pyridyl group of the above compound or its salt, or for relieving a P450-inhibiotry effect of a compound having a pyridyl group and an aromatic hydrocarbyl group or its salt characterized by introducing a polar group into the aromatic hydrocarbyl group of the above compound or its salt.

Description

DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

NOTE : Pour les tomes additionels, veuillez contacter 1e Bureau canadien des brevets JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME

NOTE: For additional volumes, please contact the Canadian Patent Office NOM DU FICHIER / FILE NAME
NOTE POUR LE TOME / VOLUME NOTE:

DESCRIPTION
MEDICINAh COMPOSITIONS
Technical Field The present invention relates to an agent for the prophylaxis or treatment of pain or an agent for the suppression of activation or inhibition of formation of osteoclast, which contains a p38 MAP kinase inhibitor and/or a TNF-c production inhibitor.
Background Art io Cytokines such as TNF-c, (tumor necrosis factor-a,), IL-1 (interleukin-1) and the like are biological substances, which are produced by a variety of cells such as monocyte or macrophage in response to infection and other cellular stress (Koj, A., Biochim. Biophys. Acta, 1317, 84-94 (1996)).
Is Although these cytokines play important roles in the immune response when they are present at an appropriate amount, it is thought that the overproduction is associated with a variety of inflammatory diseases (Dinarello, C.A., Curr. Opin.
Immunol., 3, 941-948 (1991)). p38 MAP kinase which was cloned 2o as a homologue of MAP kinase is involved in the control of production of these cytokines and signal transduction system coupled with receptors, and there is a possibility that the inhibition of p38 MAP kinase provides a drug for treating inflammatory diseases (Stein, B., Anderson, D., Annual Report 25 in Medicinal Chemistry, edited by Bristol, J.A., Academic Press, vo1.31, pages 289-298, 1996).
As compounds having a p38 MAP kinase inhibitory activity, imidazole derivatives are described in JP-T 7-50317 (WO
93/14081) and axazole derivatives are described in JP-T 9-so 505055 (WO 95/13067), respectively.
On the other hand, as thiazole compounds, the following compounds are known:
1) 1,3-thiazole derivatives represented by the formula:

S

wherein R1 represents a cycloalkyl group, a cyclic amino group, an amino group optionally having, as substituents, 1 or 2 lower alkyl, phenyl, acetyl or lower alkoxycarbonylacetyl, an alkyl group optionally having, as substituents, hydroxyl, carboxyl or lower alkoxycarbonyl, or a phenyl group optionally having, as substituents, carboxyl, 2-carboxyethenyl or 2-carboxy-1-propenyl, RZ represents a pyridyl group optionally having, as substituents, lower alkyl, R3 represents a phenyl io group optionally having, as substituents, lower alkoxy, lower alkyl, hydroxyl, halogen or methylenedioxy, or salts thereof, which have analgesic, antipyretic, anti-inflammatory, anti-ulcerative, thromboxane A2 (TXAZ) synthase-inhibitory, and platelet coagulation-inhibitory activities (JP-A 60-58981), 15 2) 1,3-thiazole derivatives represented by the formula:

S
/ R

wherein R1 represents an alkyl group, an alkenyl group, an aryl group, an aralkyl group, a cycloalkyl group, a heterocyclic group employing carbon as an attachment point or an amino 2o group optionally having substituents, R2 represents a pyridyl group optionally substituted with alkyl group(s), R3 represents a phenyl group optionally having substituents, or salts thereof, which have analgesic, antipyretic, anti-inflammatory, anti-ulcerative, TXAZ synthase-inhibitory, and platelet 2s coagulation-inhibitory activities (JP-A 61-10580), 3) 1,3-thiazole derivatives represented by the formula:

S
1 /~-R, wherein R1 represents an alkyl group, an alkenyl group, an aryl group, an aralkyl group, a cycloalkyl group, a heterocyclic group employing carbon as an attachment point or an amino group optionally having substituents, R2 represents a pyridyl group optionally substituted with alkyl group(s), R3 represents an aryl group optionally having substituents, or salts thereof, which have analgesic, antipyretic, anti-inflammatory, anti-ulcerative, TXA2 synthase-inhibitory, and platelet coagulation-inhibitory activities (USP 4,612,321), io 4) a compound of the formula S
4 R3 ~ /~R2 R ( ~ N
Rs ~ N
Rs wherein R1 represents an optionally substituted phenyl, R2 represents C1_6 alkyl or (CHZ) nAr, n represents 0-2, Ar represents an optionally substituted phenyl, R3 represents a hydrogen or Cl_9 alkyl, R4 represents a hydrogen, Cl_4 alkyl and the like, R5 represents a hydrogen or C1_4 alkyl, R6 represents a hydrogen, C1_4 alkyl and the like, or a salt thereof, having an inhibitory activity of gastric acid secretion (JP-T 7-503023, wo93/15071), 20 5) a compound of the formula R2 S N NR5Rs /~-N
R~ N Ra wherein R~ represents pyridyl and the like, RZ represents phenyl and the like, R3 and R9 represent a hydrogen or methyl, RS represents methyl and the like, and R6 represents a hydrogen, 2s methyl and the like, or a salt thereof, which is an antiinflammatory agent and antiallergic agent (DE-A-3601411), 6) a compound of the formula 3~ ~>-NHS02R
R ''~N
wherein R1 represents a lower alkyl substituted by halogen, R2 represents pyridyl and the like, and R3 represents phenyl and the like, or a salt thereof, having an antiinflammatory, antipyretic, analgesic and antiallergic activity (JP-A-5-70446), and 7) a thiazole compound of the formula R~ N
-R
R2 ~S
wherein R represents a lower alkyl group; a lower haloalkyl group; a lower hydroxyalkyl group; a lower alkoxy(lower)alkyl group; an aralkyloxy(lower)alkyl group and the like, R1 represents a cycloalkyl group optionally substituted by lower alkyl groups) and the like, and R2 represents an optionally I5 substituted aryl group and the like, or a pharmaceutically acceptable salt thereof, having a selective inhibitory activity of TNF-a production and/or IFN-r production (JP-A-11-49762).
W000/64894 describes that an optionally N-oxidized compound represented by the formula:
N~ ~
I
R2~z~Y ~ X ( ) ~ ,~R, wherein R~ represents a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino group optionally 25 having substituents or an acyl group, RZ represents an aromatic group optionally having substituents, R3 represents a hydrogen atom, a pyridyl group optionally having substituents or an aromatic hydrocarbon group optionally having substituents, X represents an oxygen atom or an optionally oxidized sulfur atom, Y represents a bond, an oxygen atom, an optionally oxidized sulfur atom or a group represented by the formula: NR4 (Wherein R4 represents a hydrogen atom, a hydrocarbon group optionally having substituents or an acyl group) and To Z represents a bond or a divalent acyclic hydrocarbon group optionally having substituents, or a salt thereof, has a superior p38 MAP kinase inhibitory activity and TNF-a, inhibitory activity and is useful as a prophylactic or therapeutic agent for p38 MAP kinase related diseases and TNF-15 a, related diseases .
W000/63204 describes that a compound of the formula WARS
N' \ Z
-R

wherein 2o a is N or C;
b is CH when a is N, or 0 when a is C;
- denotes a single or a double bond dependent upon whether the azole ring is an imidazole or an oxazole ring;
25 Z is N or CH;
W is -NR6-Y-, -0- or -S-, where R6 is a hydrogen atom, Cl_4 alkyl group, C3-8 cycloalkyl group, C3_$ cycloalkyl-Cl_3 alkyl group, C6-le aryl group, C3_18 heteroaryl group, C~_19 aralkyl group or C4_19 heteroaralkyl group, and -Y- is Cl_4 alkylene group or a bond;
R2 is phenyl group, optionally substituted by ane or more substituents selected from the group consisting of a halogen atom, trifluoromethyl, cyano, amido, thioamido, carboxylate, thiocarboxylate, C1_4 alkoxy, C1_4 alkyl, amino, and mono- or di-C1_4 alkylamino;
R3 is a hydrogen atom, a halogen atom, Cl_lo alkyl group, Cl_4 io alkenyl group, C3-to cycloalkyl group, C3-le heterocycloalkyl group, C6_le aryl group, C3-1g heteroaryl group or -CH=N-NH-C(NH)NH2, (each of which is optionally substituted by 1 to 4 substituents selected from Cl_4 alkyl optionally substituted by hydroxy, halogen atom, is halo-substituted-C1-9 alkyl, hydroxy, C1_4 alkoxy, C1_9 alkylthio, carboxy, carbonyl optionally substituted by Cl_6 alkyl or C1_6 alkoxy, amino, mono- or di-C1_q alkylamino and 5 to 7 membered N-heterocyclic group optionally further containing heteroatom(s));
ao R5 is C6_lB aryl group, C3_lg heteroaryl group or C3_1z cycloalkyl group each of which is optionally substituted by 1 to 4 substituents selected from C1_Q alkyl, halogen, halo-substitued-Cl_4 alkyl, hydroxy, Cl_9 alkoxy, C1-9 alkylthio, amino, mono- or di-C1_4 alkylamino and 5 to 7 25 membered N-heterocyclic group optionally further containing heteroatom(s), or a salt thereof has a p38 MAP kinase inhibitory activity and is useful as a prophylactic or therapeutic agent of rheumatoid arthritis and the like.
so WO01/10865 describes that a 1,3-thiazole compound, which is a compound represented by the formula S
/~'.'R~ (Iaa) wherein R1 is a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino group optionally having substituents or s an aryl group, R2 is a 4-pyridyl group having substituents free of aromatic group, and R3 is an aromatic group optionally having substituents, and the like, wherein the 5-position is substituted by a 4-pyridyl Zo group having substituents free of aromatic group, which is other than N-[4-(3,5-dimethylphenyl)-5-(2-hydroxy-4-pyridyl)-1,3-thiazol-2-yl]acetamide and 4-[2-(acetylamino)-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl acetate, or a salt thereof, and a 1,3-thiazole compound, which is a compound 1s represented by the formula ...2a K S
/>--'R~a ( Ibb) N
wherein Rla is a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino group optionally having substituents or 2o an acyl group, RZa is a pyridyl group having a substituent free of an aromatic group at the position next to the nitrogen atom of the pyridyl group, and R3a is an aromatic group optionally having substituents and the Zs like, wherein the 5-position is substituted by a pyridyl group having substituents free of aromatic group next to the nitrogen atom of the pyridyl group, which is other than N-[4-(3,5-dimethylphenyl)-5-(2-hydroxy-4-pyridyl)-1,3-thiazol-2-yl]acetamide and 4-[2-(acetylamino)-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl acetate, and a salt thereof have superior p38MAP kinase inhibitory action or TNF-a inhibitory action, and are useful as prophylactic or therapeutic agents of p38 MAP kinase related diseases or TNF-a related diseases.
s Disclosure of the Invention The present invention aims at providing a prophylactic or therapeutic agent of pain or an activation suppressant or formation inhibitor of osteoclast, which contains a p38 MAP
1o kinase inhibitor and/or a TNF-a production inhibitor.
In view of the above-mentioned object, the present inventors have conducted intensive studies and found that a p38 MAP kinase inhibitor and/or a TNF-a production inhibitor used as a prophylactic or therapeutic agent of diseases such Is as rheumatism, arthritis and the like unexpectedly has/have a superior prophylactic or therapeutic effect on pain, suppresses) activation of osteoclast and inhibits) formation of osteoclast. Based on this finding, the present inventors have further studied and completed the present invention.
2o Accordingly, the present invention provides [1) an agent for the prophylaxis or treatment of pain and/or suppression of activation and/or inhibition of formation of osteoclast, which contains a p38 MAP kinase inhibitor and/or a TNF-a production inhibitor, 2s [2] ~e agent of [1] for the prophylaxis or treatment of pain, which contains a p38 MAP kinase inhibitor and/or a TNF-a production inhibitor, [3] the agent of [1) for the suppression of activation and/or inhibition of formation of osteoclast, which contains a p38 3o MAp kinase inhibitor and/or a TNF-a production inhibitor, [4) the agent of [1], wherein the p38 MAP kinase inhibitor and/or the TNF-a production inhibitor are/is a 1,3-thiazole compound substituted at the 5-position by a pyridyl group optionally having substituents, or a salt thereof or a prodrug thereof, [5] the agent of [1], wherein the p38 MAP kinase inhibitor and/or the TNF-a production inhibitor are/is a compound represented by the formula:

S
fIa) wherein R1 represents a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino group optionally having substituents or an acyl group;
Rz represents a pyridyl group optionally having substituents; and R3 represents an aromatic group optionally having 15 substituents, a salt thereof or a prodrug thereof, [6] the agent of [1], wherein the p38 MAP kinase inhibitor and/or the TNF-a production inhibitor are/is an optionally N-oxidized compound represented by the formula:
N
ao RzeiZwYe I / Xa ( I I ) / R~a Rsa N
wherein Rla represents a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino group 25 optionally having substituents or an acyl group;
R2a represents an aromatic group optionally having substituents;
R3a represents a hydrogen atom, a pyridyl group optionally having substituents or an aromatic hydrocarbon group optionally having substituents;
Xa represents an oxygen atom or an optionally oxidized sulfur atom;
s Ya represents a bond, an oxygen atom, an optionally oxidized sulfur atom or a group represented by the formula: NR4a (wherein RQa represents a hydrogen atom, a hydrocarbon group optionally having substituents or an acyl group); and io Z$ represents a bond or a divalent acyclic hydrocarbon group optionally having substituents, or a salt thereof, or a prodrug thereof, [7] the agent of [1], wherein the p38 MAP kinase inhibitor and/or the TNF-a, production inhibitor are/is a compound is represented by the formula w /R5b b NI \ zb (III) a R3b R
2b wherein a is N or C;
b is CH when a is N, or O when a is C;
20 _ denotes a single or a double bond dependent upon whether the azole ring is an imidazole ring or an oxazole ring;
Zb is N oz CH;
Wb is -NRsb-Yb-, -O- or -S-.
25 where R6b is a hydrogen atom, Cl_4 alkyl group, C3_$
cycloalkyl group, C3_$ cycloalkyl-Cl_3 alkyl group, C6-ie aryl group, C3-1g heteroaryl group, C~_19 aralkyl group or C4-19 heteroaralkyl group, and -Yb- is Cl_4 alkylene group or a bond;
R2b is phenyl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, trifluoromethyl, cyano, amido, thioamido, carboxylate, thiocarboxylate, C1_9 alkoxy, C1_4 alkyl, amino, and mono- or di-C1_4 alkylamino;
R3b is a hydrogen atom, a halogen atom, C1-to alkyl group, C2_9 alkenyl group, C3-to cycloalkyl group, C3_1~
heterocycloalkyl group, C6_le aryl group, C3_lg heteroaryl io group or -CH=N-NH-C (NH) NH2 (wherein Cl-to alkyl group, C2_4 alkenyl group, C3_lo cycloalkyl group, C3_ls heterocycloalkyl group, C6_1$ aryl group, C3_18 heteroaryl group and -CH=N-NH-C(NH)NH2 are each optionally substituted by 1 to 4 substituents selected from the 15 group consisting of C1_4 alkyl optionally substituted by hydroxy, halogen atom, halo-substituted-C1_4 alkyl, hydroxy, C1_4 alkoxy, C1_4 alkylthio, carboxy, carbonyl optionally substituted by C1-s alkyl or C1_6 alkoxy, amino, mono- or di-C1_4 alkylamino and 5- to 7- membered N-2o heterocyclic group optionally further containing heteroatom(s)); and RSb is C6_18 aryl group, C3_l8 heteroaryl group or C3_lz cycloalkyl group each of which is optionally substituted by 1 to 4 substituents selected from the group consisting of C~_4 alkyl, halogen, halo-substitued-C,__4 alkyl, hydroxy, C,__4 alkoxy, C1_4 alkylthio, amino, mono-or di-C1_4 alkylamino and 5- to 7-membered N-heterocyclic group optionally further containing heteroatom(s), or a salt thereof or a prodrug thereof, 30 [g] the agent of [1], wherein the p38 MAP kinase inhibitor and/or the TNF-a production inhibitor is a 1,3-thiazole compound (IV) substituted at the 5-position by a 4-pyridyl group having substituents free of aromatic group, or a salt thereof or a prodrug thereof, [9] the agent of [8], wherein the 1,3-thiazole compound is a compound represented by the formula S
~~-'-[~~c (IVa) N
wherein R1° is a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino group optionally having substituents or an acyl group;
1° R2° is a 4-pyridyl group having substituents free of aromatic group; and R3° is an aromatic group optionally having substituents, or a salt thereof, [10] the agent of [1], wherein the p38 MAP kinase inhibitor 15 and/or the TNF-a, production inhibitor is a 1,3-thiazole compound (V) substituted at the 5-position by a pyridyl group having substituents free of aromatic group at a position next to a nitrogen atom of the pyridyl group, or a salt thereof, or a prodrug thereof, 2° [11] the agent of [10], wherein the 1,3-thiazole compound is a compound represented by the formula .,2d t'( S
/~"R~d (Va) Rd N
wherein Rld is a hydrogen atom, a hydrocarbon group optionally 25 having substituents, a heterocyclic group optionally having substituents, an amino group optionally having substituents or an acyl group;
RZd is a pyridyl group having substituents free of aromatic group at a position next to a nitrogen atom of the pyridyl group; and R3d is an aromatic group optionally having substituents, or a salt thereof, [12] the agent of [1], wherein the p38 MAP kinase inhibitor and/or the TNF-a production inhibitor are/is a 1,3-thiazole compound (VI) substituted at the 5-position by a 4-pyridyl group having substituents free of aromatic group at a position next to a nitrogen atom of the 4-pyridyl group, or a salt thereof or a prodrug thereof, so [13] the agent of [1], wherein the p38 MAP kinase inhibitor and/or the TNF-a production inhibitor are/is N-[5-(2-benzoylamino-4-pyridyl)-4-(3,5-dimethylphenyl)-1,3-thiazol-2-yl]acetamide, N-[5-(2-benzylamino-4-pyridyl)-4-(3,5-dimethylphenyl)-1,3-is thiazol-2-y1]acetamide, N-[4-[4-(4-methoxyphenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide, N- [4- [2- (4-fluorophenyl) -4- (3-methylphenyl) -l, 3-thiazol-5-yl] -2-pyridyl]phenylacetamide, 2o N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl)phenylacetamide, N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide, N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-25 pyridyl]phenylacetamide, N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide, N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide, 3o N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide, N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-(4-methoxyphenyl)propionamide, N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-4-phenylbutyramide, N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide, s N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide, N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide, N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-io 3-phenylpropionamide, N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide, N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide, .ts N- [4- [4- (3-methylphenyl) -2- (4-methylthiophenyl) -1, 3-thiazol-5-yl]-2-pyridyl]benzamide, N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide, N-benzyl-N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-2o pyridyl]amine, N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine, N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine, 2s N-benzyl-N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]amine, N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine, N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-3o pyridyl]-N-(3-phenylpropyl)amine, N-benzyl-N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine, N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N- ( 2-phenylethyl ) amine , N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine, N-benzyl-N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine, N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine, N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine, 1o N- [4- [4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) -1, 3-thiazol-5-yl]-2-pyridyl]benzamide, N- [ 4- [ 4- ( 3-methylphenyl ) -2- ( 4-methylsul fonylphenyl ) -1, 3-thiazol-5-yl]-2-pyridyl]phenylacetamide, N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-zs thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide, N-benzyl-N- [4- [4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) -1,3-thiazol-5-yl]-2-pyridyl]amine, N- [4- [4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) -1, 3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine, 2o N- [,~_ [g- (3-methylphenyl) -2- (4-methylsulfonylphenyl) -1, 3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine, N- ( 4-f luorobenzyl ) -N- [ 4- [ 4- ( 3-methylphenyl ) -2- ( 4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine, ( S ) -N- [ 4- ( 3-methylphenyl ) -5- ( 2- ( 1-phenylethylamino ) -4-2s pyridyl)-1,3-thiazol-2-yl]nicotinamide, (R) -N- [4- (3-methylphenyl) -5- (2- (1-phenylethylamino) -4-pyridyl)-1,3-thiazol-2-yl]nicotinamide, (S) -N- [4- (3-methylphenyl) -5- (2- (1-phenylethylamino) -4-pyridyl)-1,3-thiazol-2-yl]-2-rnethylnicotinamide, 30 (R) -N- [4- (3-rnethylphenyl) -5- (2- (1-phenylethylamino) -4-pyridyl)-1,3-thiazol-2-yl]-2-methylnicotinamide, (S) -N- [4- (3-methylphenyl) -5- (2- (1-phenylethylamino) -4-pyridyl)-1,3-thiazol-2-yl]-2-chloronicotinamide, (R) -N- [4- (3-methylphenyl) -5- (2- (1-phenylethylamino) -4-pyridyl)-1,3-thiazol-2-yl]-2-chloronicotinamide, ( S ) -N- [ 4- ( 3-methylphenyl ) -5- ( 2- ( 1-phenylethylamino ) -4-pyridyl)-1,3-thiazol-2-yl]-2-methoxynicotinamide, (R) -N- [4- (3-methylphenyl) -5- (2- (1-phenylethylamino) -4-pyridyl)-1,3-thiazol-2-yl]-2-methoxynicotinamide, N-[5-(2-benzylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]nicotinamide, N-[5-(2-benzylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-io 2-yl]-2-methoxynicotinamide, N-[5-(2-benzylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]-2-chloronicotinamide, N-[5-(2-benzylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]-2-methylnicotinamide, i5 N-[5- (2-benzoylamino-4-pyridyl) -4- (3-methylphenyl) -1, 3-thiazol-2-yl]nicotinamide, N-[5-(2-benzoylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]-2-methylnicotinamide, N-[5-(2-benzoylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-2o thiazol-2-yl]-2-chloronicotinamide, N-[5-(2-benzoylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]-2-methoxynicotinamide, (S)-N-(1-phenylethyl)-4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine, 2s (R) -N- (1-phenylethyl) -4- [2-ethyl-4- (3-methylphenyl) -1, 3-thiazol-5-yl]-2-pyridylamine, (S)-N-(1-phenylethyl)-4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridylamine, (R)-N-(1-phenylethyl)-4-[4-(3-methylphenyl)-2-propyl-1,3-3o thiazol-5-yl]-2-pyridylamine, (S) -N- (1-phenylethyl) -4- [2-butyl-4- (3-methylphenyl) -1, 3-thiazol-5-yl]-2-pyridylamine, (R)-N-(1-phenylethyl)-4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine, ( S ) -N- ( 1-phenylethyl ) -4- [ 4- ( 3-methylphenyl ) -2- ( 4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridylamine, (R) -N- (1-phenylethyl) -4- [4- (3-methylphenyl) -2- (4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridylamine, ( S ) -N- ( 1-phenylethyl ) -4- [ 4- ( 3-methylphenyl ) -2- ( 4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine, (R) -N- (1-phenylethyl) -4- [4- (3-methylphenyl) -2- (4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine, i o ( S ) -N- ( 1-phenylethyl ) -4- [ 2- ( 4-f luorophenyl ) -4- ( 3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine, (R) -N- ( 1-phenylethyl ) -4- [ 2- ( 4-f luorophenyl ) -4- ( 3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine, or a salt thereof, 15 [14] the agent of [3], which is an agent for the prophylaxis or treatment of (1) postmenopausal or senile primary osteoporosis, (2) secondary osteoporosis caused by inflammation, blood system malignant disease, endocrine disorder or administration of pharmaceutical agent, (3) bone 20 or joint tissue destruction or deforming associated with bone metastasis of tumor or rheumatism, (4) Paget's disease or (5) hypercalcemia, [15] a method for the prophylaxis or treatment of pain, which comprises administering an effective amount of p38 MAP kinase 25 inhibitor and/or the TNF-a, production inhibitor to a mammal, [16] a method for the suppression of activation and/or inhibition of formation of osteoclast, which comprises administering an effective amount of p38 MAP kinase inhibitor and/or the TNF-a, production inhibitor to a mammal, so [17] a method for the prophylaxis or treatment of (1) postmenopausal or senile primary osteoporosis, (2) secondary osteoporosis caused by inflammation, blood system malignant disease, endocrine disorder or administration of pharmaceutical agent, (3) bone or joint tissue destruction or deforming associated with bone metastasis of tumor or rheumatism, (4) Paget's disease or (5) hypercalcemia, which comprises administering an effective amount of p38 MAP kinase inhibitor and/or the TNF-a production inhibitor to a mammal, [18] use of a p38 MAP kinase inhibitor and/or the TNF-a production inhibitor for the production of an agent for the prophylaxis or treatment of pain, [19] use of a p38 MAP kinase inhibitor and/or the TNF-a, zo production inhibitor for the production of an agent for the suppression of activation and/or inhibition of formation of osteoclast, and [20] use of a p38 MAP kinase inhibitor and/or the TNF-a production inhibitor for the production of an agent for the 15 prophylaxis or treatment of (1) postmenopausal or senile primary osteoporosis, (2) secondary osteoporosis caused by inflammation, blood system malignant disease, endocrine disorder or administration of pharmaceutical agent, (3) bone or joint tissue destruction or deforming associated with bone 2o metastasis of tumor or rheumatism, (4) Paget's disease or (5) hypercalcemia, [21] a method for reducing a P450 inhibitory action of a compound containing a pyridyl group or a salt thereof, which comprises introducing a substituent into the a-position of a 25 nitrogen atom of the pyridyl group of the compound or a salt thereof, [22] a method for reducing a P450 inhibitory action of a compound containing a pyridyl group and an aromatic hydrocarbon group, or a salt thereof, which comprises 3o introducing a polar group into the aromatic hydrocarbon group of the compound or a salt thereof, [23] the method of [22], further comprising introducing a substituent into the a-position of a nitrogen atom of the pyridyl group, [24] the method of [21] or [22], wherein the P450 is CYP2C9, CYP2D6 or CYP3A4, [25] the method of [21] or [23], wherein the substituent is 1 s to 3 selected from (i) halogen atom, (ii) Cl_s alkyl group, C2-s alkenyl group, C2_s alkynyl group, C3_s cycloalkyl group, Cs_14 aryl group and C~_ls aralkyl group [these groups may have 1 to 5 substituents selected from a group io consisting of oxo, halogen atom, C1_3 alkylenedioxy, nitro, cyano, optionally halogenated C1_s alkyl, optionally halogenated C2_s alkenyl, carboxy C2_s alkenyl, optionally halogenated C2_s alkynyl , optionally halogenated C3_s cycloalkyl , Cs_lg aryl , optionally halogenated Cl_8 alkoxy, Cl_s alkoxy-carbonyl-Cl-s Is alkoxy, hydroxy, Cs_14 aryloxy, C~_ls aralkyloxy, mercapto, optionally halogenated C1_s alkylthio, Cs_14 arylthio, C~_ls aralkylthio, amino, mono-C1_s alkylamino, mono-Cs_14 arylamino, di-C1_s alkylamino, di-Cs_14 arylamino, formyl, carboxy, Cl_s alkyl-carbonyl, C3_s cycloalkyl-carbonyl, C1_s alkoxy-carbonyl, Cs-i4 aryl-carbonyl, C~_ls aralkyl-carbonyl, Cs-i4 aryloxy-carbonyl, C?_ls aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, carbamoyl, thiocarbamoyl, mono-C1_s alkyl-carbamoyl, di-C1-s alkyl-carbamoyl, Cs_14 aryl-carbamoyl, 5- or 6-membered heterocyclic carbamoyl, C1_s alkylsulfonyl, Cs_19 arylsulfonyl, 2s C,_s alkylsulfinyl, Cs_,4 arylsulfinyl, formylamino, C,_-s alkyl-carbonylamino, Cs_24 aryl-carbonylamino, Cl_s alkoxy-carbonylamino, Cl-s alkylsulfonylamino, Cs_14 arylsulfonylamino, Cz-6 alkyl-carbonyloxy, Cs-lg aryl-carbonyloxy, Cl_s alkoxy-carbonyloxy, mono-Cl_s alkyl-carbamoyloxy, di-C1_s alkyl-3o carbamoyloxy, Cs_lq aryl-carbamoyloxy, nicotinoyloxy, 5- to 7-membered saturated cyclic amino containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, besides one nitrogen atom and carbon atom (this cyclic amino may have substituents selected from the group consisting of Cl_6 alkyl, C6_19 aryl, Cl_6 alkyl-carbonyl, 5- to 10-membered aromatic heterocyclic group and oxo), and 5-to 10-membered aromatic heterocyclic group, containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, besides carbon atom, sulfo, sulfamoyl, sulfinamoyl and sulfenamoyl (substituent group A)], (iii) 5- to 14-membered heterocyclic group containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from nitrogen atom, io sulfur atom and oxygen atom, besides carbon atom, which may have 1 to 3 substituents selected from substituent group A, (iv) aryl group represented by the formula: -(C=O)-R5, -(C=0)-ORS , - ( C=O) -NRSR6 , - ( C=S ) -NARS or -S02-R' wherein RS is (1) hydrogen atom, (2) C1_6 alkyl group, Cz-s i5 alkenyl group, CZ_6 alkynyl group, C3_6 cycloalkyl group, C6-is aryl group or C~_16 aralkyl group, which may have 1 to 3 substituents selected from substituent group A or (3) 5- to 14-membered heterocyclic group containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from nitrogen atom, sulfur atom Zo and oxygen atom, besides carbon atom, which may have 1 to 3 substituents selected from substituent group A, R6 is hydrogen atom or C1-6 alkyl group, and R' is (1) C1-6 alkyl group, CZ-6 alkenyl group, C2_6 alkynyl group, C3_6 cycloalkyl group, C6-14 aryl group or C~-16 aralkyl group, which may have 1 to 3 2s substituents selected from substituent group A or (3) 5- to 14-membered heterocyclic group containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, besides carbon atom, which may have 1 to 3 substituents selected from substituent group A, 30 (v) amino group (this amino group may have 1 or 2 substituents selected from ( 1 ) Cl_6 alkyl group, CZ-6 alkenyl group, CZ-6 alkynyl group, C3_6 cycloalkyl group, C6-is aryl group or C~_ls aralkyl group, which may have 1 to 3 substituents selected from substituent group A, (2) 5- to 14-membered heterocyclic group containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, besides carbon atom, which may have 1 to 3 substituents selected from substituent group A, and (3) acyl group shown by the above-mentioned (iv)), (vi) 5- to 7-membered non-aromatic cyclic amino group containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, besides one io nitrogen atom and carbon atom, (this cyclic amino group may have 1 to 3 substituents selected from Cl_6 alkyl, C6_1q aryl, C1_ 6 alkyl-carbonyl, 5- to 10-membered aromatic heterocyclic group and oxo ) , and (vii) Cl_6 alkoxy group, Cs-14 aryloxy group and C~_16 aralkyloxy 15 group, which may have 1 to 3 substituents selected from substituent group A, [26] the method of [22], wherein the polar group is 1 to 3 selected from (1) halogen atom, (2) hydroxy, (3) amino optionally having 1 or 2 substituents selected from a 2o substituent selected from substituent group A and acyl shown by the above-mentioned ( iv ) , ( 4 ) nitro , ( 5 ) carboxy , ( 6 ) formyl, (7) C1_6 alkoxy optionally having 1 to 3 substituents selected from substituent group A, (8) C1_6 alkoxy-carbonyl optionally having 1 to 3 substituents selected from 25 substituent group A, ( 9 ) cyano and ( 10 ) C,__s alkyl or C6_, 4 aryl having 1 to 3 groups from the above-mentioned (1)-(9) as substituents.
The present invention further relates to [27] the agent of [1], wherein the p38 MAP kinase inhibitor so and/or the TNF-a, production inhibitor are/is an optionally N-oxidized compound represented by the formula:

/~
S
~~Rtm Rzm N ( Im) wherein ring C is a 4-pyrimidinyl group optionally having substituents;
Rlm is a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino group optionally having substituents or an aryl group; and io Rzm is an aromatic group optionally having substituents, or a salt thereof, or a prodrug thereof.
[28] The agent of [27], wherein the compound (Im) is an optionally N-oxidized compound represented by the formula:
R3n~wn2"
i5 N~N
S
~~Rtn Rzn N (Iri) wherein Z° is a bond, -NR~n- (R°n is a hydrogen atom or a hydrocarbon group optionally having substituents), an oxygen atom or 2o an optionally oxidized sulfur atom;
W° is a bond or a divalent hydrocarbon group optionally having substituents;
Rln is a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally 25 having substituents, an amino group optionally having substituents or an acyl group;

R2n is an aromatic group optionally having substituents; and R3° is a hydrogen atom, a hydrocarbon group optionally having substituents or a heterocyclic group optionally having substituents, or a salt thereof.
[29] The agent of [28], wherein both Wn and Zn are each a bond.
[30] The agent of [27], wherein the compound (Im) is an optionally N-oxidized compound represented by the formula:
R3f~WfN~R4f 1o N~N
S
1f ~r , N~R (If' ) wherein Wf is a bond or a divalent hydrocarbon group optionally having substituents;
is Rlf is a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino group optionally having substituents or an acyl group;
R2f is an aromatic group optionally having substituents;
2o Rsf is a hydrocarbon group optionally having substituents or a heterocyclic group optionally having substituents; and R4f is a hydrogen atom or a hydrocarbon group optionally having substituents, or a salt thereof.
2s [31] The agent of [30], wherein the compound (If') is an optionally N-oxidized compound represented by the formula:

R~
1g (Ig' ) wherein R1g is a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino group optionally having substituents or an acyl group;
RZg is an aromatic group optionally having substituents;
R3g is a hydrocarbon group optionally having substituents or I° a heterocyclic group optionally having substituents; and R4g is a hydrogen atom or a hydrocarbon group optionally having substituents, or a salt thereof.
[32] The agent of [30], wherein the compound (If') is an 15 optionally N-oxidized compound represented by the formula:
R3\N~R4n N~N
S
\ 1n RZn ~ N~R (Ih' ) wherein 2o Rih is a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino group optionally having substituents or an acyl group;
R2'' is an aromatic group optionally having substituents;
R3h is a hydrocarbon group optionally having substituents or a heterocyclic group optionally having substituents; and R4h is a hydrogen atom or a hydrocarbon group optionally having substituents, or a salt thereof.
While the p38 MAP kinase inhibitor and/or the TNF-a, production inhibitor to be used in the present invention are/is not particularly limited as long as the inhibitors) has(ve) a p38 MAP kinase inhibitory activity and/or a TNF-a io production inhibitory activity, and exemplified by, for example, the following compounds (I)-(VII) and the like.
( compound ( I ) ) (1) a 1,3-thiazole compound substituted at the 5-position by a pyridyl group optionally having substituents or a salt thereof, I5 (2) a 1,3-thiazole compound substituted at the 5-position by a pyridyl group optionally having substituents or a salt thereof, excluding a compound of the formula Ar N H
\~--N-R
~'S
N /
wherein Ar is an unsubstituted or substituted aryl group 2o bonded to a thiazole ring by a carbon atom of an aromatic ring, and R is a hydrogen atom, an acyl group, or a monovalent aromatic group having not more than 10 carbon atoms, which is bonded to a nitrogen atom by a carbon atom of the aromatic ring, and a salt thereof, 25 (3) the compound of (1) or (2), wherein the 1,3-thiazole compound is a 1,3-thiazole compound substituted at the 4-position by an aromatic group optionally having substituents, (4) the compound of (1) or (2), wherein the 1,3-thiazole compound is a 1,3-thiazole compound substituted at the 2-3o position by an aryl group optionally having substituents or an amino group optionally having substituents, (5) the compound of (1) or (2), wherein the 1,3-thiazole compound is a compound of the formula Rz S
(Ia) wherein R1 represents a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino group optionally having substituents or an acyl group;
R2 represents a pyridyl group optionally having substituents;
z o and R3 represents an aromatic group optionally having substituents, or a salt thereof, (6) the compound of (5), wherein R1 is (i) a hydrogen atom, zs (ii) a C1_lo alkyl group, a CZ-s alkenyl group, a C2_s alkynyl group, a C3-s cycloalkyl group, a C6-is aryl group or a C~_ls aralkyl group [these groups may have substituents selected from the group (substituent group A) consisting of oxo, halogen atom, C1-3 alkylenedioxy, nitro, cyano, optionally 2o halogenated C1_s alkyl, optionally halogenated CZ-s alkenyl, carboxy C2_s alkenyl, optionally halogenated CZ_s alkynyl, optionally halogenated C3-s cycloalkyl, Cs_1ø aryl, optionally halogenated Cz_$ alkoxy, C,-s alkoxy-carbonyl-C,_s alkoxy, hydroxy, Cs_14 aryloxy, C~-is aralkyloxy, mercapto, optionally halogenated 2s Ci-s alkylthio, Cs_19 arylthio, C~_ls aralkylthio, amino, mono-C1_s alkylamino, mono-Cs-14 arylamino, di-Cl_s alkylamino, di-Cs_19 arylamino, formyl, carboxy, C1_s alkyl-carbonyl, C3_s cycloalkyl-carbonyl, Cl_s alkoxy-carbonyl, Cs_19 aryl-carbonyl, C~_ls aralkyl-carbonyl, Cs_19 aryloxy-carbonyl, C~_ls aralkyloxy-3o carbonyl, 5 or 6 membered heterocyclic carbonyl, carbamoyl, thiocarbamoyl, mono-C1-s alkyl-carbamoyl, di-C1_s alkyl-carbamoyl, Cs-14 aryl-carbamoyl, 5 or 6 membered heterocyclic carbamoyl, C1_ s alkylsulfonyl, Cs-is arylsulfonyl, Cl_s alkylsulfinyl, C6_14 arylsulfinyl, formylamino, C1_s alkyl-carbonylamino, Cs_14 aryl-carbonylamino, C1_s alkaxy-carbonylamino, C1_s alkylsulfonylamino, Cs-is arylsulfonylamino, Cl_s alkyl-carbonyloxy, Cs_14 aryl-carbonyloxy, C1_s alkoxy-carbonyloxy, mono-C1_s alkyl-carbamoyloxy, di-C1_s alkyl-carbamoyloxy, Cs_14 aryl-carbamoyloxy, nicotinoyloxy, 5 to 7 membered saturated cyclic amino optionally having 1 to 4 of one or two kinds of heteroatom(s) selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to one nitrogen atom and carbon atoms (this cyclic amino may have substituents selected from the group consisting of Cl_s alkyl, Cs_14 aryl, C1_s alkyl-carbonyl, 5 to 10 membered aromatic heterocyclic group and oxo), 5 to 10 i5 membered aromatic heterocyclic group containing 1 to 4 of one or two kinds of heteroatom(s) selected from a nitrogen atom, a sulfur atom and an oxygen atom, in addition to carbon atoms, sulfo, sulfamoyl, sulfinamoyl and sulfenamoyl], (iii) a monovalent heterocyclic group obtained by removing one arbitrary hydrogen atom from a 5 to 14 membered heterocycle containing 1 to 4 of one or two kinds of heteroatom(s) selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms optionally having substituents selected from the above-mentioned substituent 25 group A, (iv) an acyl group represented by the formula:
- ( C=0 ) -R~ , - ( C=0 ) -ORS , - ( C=O ) -NRSRs , - ( C=S ) -NHRS o r - S02-R' wherein R5 represents (a) a hydrogen atom, (b) a Cl-s alkyl group, a C2_s alkenyl group, a C2_s alkynyl group, a C3_s cycloalkyl group, a Cs_lq aryl group or a C~-is aralkyl group as defined in the above (ii) or (c) a heterocyclic group as defined in the above (iii), Rs represents a hydrogen atom or a C1-s alkyl group, R' represents (a) a C1_s alkyl group, a C2_s alkenyl group, a C2_6 alkynyl group, a C3_6 cycloalkyl group, a C6_14 aryl group or a C~_16 aralkyl group as defined in the above (ii), or (b) a heterocyclic group as defined in the above (iii) , s (v) an amino group (this amino group may have substituents selected from the group consisting of (a) a C1-6 alkyl group, a C2-6 alkenyl group, a C2_6 alkynyl group, a C3_6 cycloalkyl group, a C6-1q aryl group or a C~_16 aralkyl group as defined in the above (ii), (b) a heterocyclic group as defined in the above io (iii) , (c) an acyl group as defined in the above (iv) , and (d) a C1_6 alkylidene group optionally having substituents selected from the above substituent group A), or (vi) a 5 to 7 membered non-aromatic cyclic amino group optionally containing 1 to 4 of one or two kinds of is heteroatom(s) selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to one nitrogen atom and carbon atoms (this cyclic amino group may have substituents selected from the group consisting of Cl_6 alkyl, Cs_l9 aryl, Cl_6 alkyl-carbonyl, 5 to 10 membered aromatic heterocyclic group and 2° oxo) ;
R2 represents a pyridyl group optionally having substituents selected from the above substituent group A; and R3 represents (a) a C6_14 monocyclic or fused polycyclic aromatic hydrocarbon group optionally having substituents 2s selected from the substituent group A or (b) a monovalent aromatic heterocyclic group obtained by removing one arbitrary hydrogen atom from a 5 to 14 membered aromatic heterocycle containing 1 to 4 of one or two kinds of heteroatom(s) selected from a nitrogen atom, a sulfur atom and an oxygen 3o atom in addition to carbon atoms, said 5 to 14 membered aromatic heterocycle optionally having substituents selected from the substituent group A, (7) the compound of (5), wherein R1 is (a) a Cs_19 aryl group (preferably Cs-to aryl) optionally having 1 to 5 substituents selected from halogen atom, optionally halogenated C1_s alkyl, carboxy C2_s alkenyl, optionally halogenated C1_s alkoxy, Cl_s alkoxy-carbonyl-Cl_s alkoxy, hydroxy, amino, mono- or di-C1_s alkylamino, carboxy, Cl_s alkoxy-carbonyl , mono- or di-Cl_s alkyl-carbamoyl , Cs_14 aryl-carbonylamino, C1_3 alkylenedioxy, Cl_s alkylthio, Cs_14 arylthio, Cl_s alkylsulfinyl, Cs_14 arylsulfinyl, C1-s alkylsulfonyl, Cs_19 arylsulfonyl and vitro, io (b) a C1_8 alkyl group optionally having 1 to 5 substituents selected from halogen atom, optionally halogenated C1_s alkyl, carboxy C2_s alkenyl, optionally halogenated Cl_s alkoxy, C1-s alkoxy-carbonyl-C1_s alkoxy, hydroxy, amino, mono- or di-C1-s alkylamino, carboxy, C1_s alkoxy-carbonyl, mono- or di-C1_s 15 alkyl-carbamoyl and Cs_19 aryl-carbonylamino, (c) a C3_s cycloalkyl group (e. g., cyclohexyl) optionally having 1 to 5 substituents selected from halogen atom, optionally halogenated Cl_s alkyl, carboxy C2_s alkenyl, optionally halogenated Cl-s alkoxy, C1_s alkoxy-carbonyl-Cl_s alkoxy, hydroxy, 2o amino, mono- or di-Cl-s alkylamino, carboxy, C1_s alkoxy-carbonyl, mono- or di-Cl_s alkyl-carbamoyl and Cs_19 aryl-carbonylamino, (d) a C~_ls aralkyl group (e. g. , phenyl-Cl_s alkyl group) , (e) a 5 to 10 membered aromatic heterocyclic group containing 1 to 4 of one or two kinds of heteroatom(s) selected from a 25 nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms (e. g., 5 or 6 membered aromatic heterocyclic group such as pyridyl, thienyl and the like), (f) a 5 to 10 membered non-aromatic heterocyclic group containing 1 or 2 of one or two kinds of heteroatom(s) so selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, said 5 to 10 membered non-aromatic heterocyclic group may have Cs_1q aryl (e. g., phenyl), C1_s alkyl-carbonyl or oxo (e. g., 5 or 6 membered non-aromatic cyclic amino group such as piperidino, piperazino and the like) , (g) an amino group optionally having 1 or 2 substituents selected from the group consisting of the following (1) to (7) [ ( 1 ) Cl_s alkyl , ( 2 ) C6_l~ aryl , ( f ) C~_ls aralkyl , ( 4 ) 5 or 6 membered heterocyclic group containing 1 or 2 heteroatom(s) selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms ( a . g . , pyridyl ) , ( 5 ) Cl_s alkyl-carbonyl, C3_s cycloalkyl-carbonyl, C6_14 aryl-carbonyl, io C~_ls aralkyl-carbonyl, Cl_s alkyl-carbamoyl or 5 or 6 membered heterocyclic carbonyl group, each optionally having 1 to 3 substituents selected from halogen atom, Cl_s alkyl, Cl_s alkoxy, carboxy, C1_s alkoxy-carbonyl, cyano, tetrazine and the like, ( 6 ) Cs_14 aryl-carbamoyl group optionally having 1 to 3 IS substituents selected from halogen atom, Cl_s alkyl , Cl_s alkoxy, carboxy, C1_s alkoxy-carbonyl, cyano, nitro, mono- or di-Cl-s alkylamino and the like and (7) di-Cl_s alkylamino-C1-s alkylidene~, or (h) a carboxy group, 20 ( 8 ) the compound of ( 5 ) , wherein R1 is a Cs_14 aryl group optionally having C1_s alkylsulfonyl, (9) the compound of (5), wherein R2 is a ~-pyridyl group optionally having substituents, (10) the compound of (5) , wherein R3 is a Cs_lfl aryl group 25 optionally having substituents, (11) the compound of (5), wherein R3 is a phenyl group optionally having substituents, ( 12 ) the compound of ( 5 ) , wherein R3 is a Cs_14 aryl group optionally having substituents selected from the group so consisting of halogen atom, C1_3 alkylenedioxy, optionally halogenated Cl_s alkyl, carboxy C2_s alkenyl, optionally halogenated Cl_e alkoxy, carboxy Cl_8 alkoxy, hydroxy, Cs-i4 aryloxy, C1_6 alkoxy-carbonyl, C1_s alkyl-carbonyloxy, mono- or di-Cl_6 alkylamino and Cl_6 alkoxy-carbonyl-Cl_6 alkoxy, (13) the compound of (5), wherein R3 is a phenyl group optionally having substituents selected from the group consisting of halogen atom and C1_6 alkyl group, (14) the compound of (5), wherein R1 is (a) an amino group optionally having 1 or 2 acyl groups represented by the formula: - (C=0) -RS or - (C=0) -NRSR6 wherein each symbol is as defined above, (b) C6_1~ aryl group optionally having 1 to 5 substituents selected from C~_6 alkylthio, C6_lg arylthio, Cl-s to alkylsulfinyl, C6_14 arylsulfinyl, Cl_6 alkylsulfonyl, C6_14 arylsulfonyl and carboxy or (c) C1_6 alkyl group optionally substituted by halogen atom, R2 is a pyridyl group, and R3 is a C6-14 aryl group optionally having 1 to 5 substituents Is selected from halogen atom, optionally halogenated C1_6 alkyl, optionally halogenated C1_6 alkoxy and carboxy, (15) the compound of (5) , wherein R1 is (i) Cl_$ alkyl, C3_6 cycloalkyl or C6_14 aryl, each optionally having 1 to 5 substituents selected from halogen atom, 20 optionally halogenated C1_s alkyl, carboxy C2_6 alkenyl, optionally halogenated C1_6 alkoxy, C1_6 alkoxy-carbonyl-Cl_s alkoxy, hydroxy, amino, mono- or di-C1_6 alkylamino, carboxy, Cl_6 alkoxy-carbonyl, mono- or di-Cl_6 alkyl-carbamoyl and C6-is aryl-carbonylamino, 25 (ii) a 5 membered heterocyclic group, (iii) an amino group optionally having 1 or 2 substituents selected from (a) C1_6 alkyl, (b) C6_14 aryl, (c) C~_ls aralkyl, (d) 6 membered heterocyclic group and (e) C1_6 alkyl-carbonyl, cycloalkyl-carbonyl, C6_19 aryl-carbonyl, C~_16 aralkyl-3o carbonyl, C1_6 alkyl-carbamoyl or 5 or 6 membered heterocyclic carbonyl, each optionally having 1 to 3 substituents selected from halogen atom, C1_6 alkyl, Cl_6 alkoxy, carboxy and C1_s alkoxy-carbonyl, or an amino group optionally having di-C1_s alkylamino-C1-6 alkylidene, (iv) a 5 or 6 membered non-aromatic cyclic amino group optionally substituted by C1_6 alkyl-carbonyl or oxo, or (v) a carboxy group;
RZ is a pyridyl group; and R3 is a C6-to aryl group optionally having 1 to 3 substituents selected from halogen atom, C1_3 alkylenedioxy, optionally halogenated C1_6 alkyl, carboxy C2_6 alkenyl, optionally halogenated Cl_$ alkoxy, hydroxy, C~_16 aralkyloxy and Cl_6 alkyl-zo carbonyloxy (two adjacent alkyl groups as substituents may be bonded to form a 5 membered non-aromatic carbon ring), (16) the compound of (5), wherein Rl is a C6-is aryl group optionally having C1_6 alkylsulfonyl, R2 is a pyridyl group, and R3 is a C6-19 aryl group optionally having halogen atom (s) , i5 (17) N-ethyl- [4- (4-methoxyphenyl) -5- (4-pyridyl) -1, 3-thiazol-2-yl]amine (Reference Example A 23-269), N-propyl-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (Reference Example A 23-276), N-butyl-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-2o yl]amine (Reference Example A 23-280), N-benzyl-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (Reference Example A 23-281), N-propyl-[4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (Reference Example A 23-290), 25 N-isopropyl-[4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (Reference Example A 23-291), N-[4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]-N'-phenylurea (Reference Example A 23-296), ~-[[[4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-so yl]amino]carbonyl]benzoic acid (Reference Example A 23-299), methyl 4-[2-[4-(methylthio)phenyl]-5-(4-pyridyl)-1,3-thiazol-4-yl]phenyl ether (Reference Example A 23-300), 4-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]phenyl methyl sulfide (Reference Example A 23-302), 4-[4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]phenyl methyl sulfoxide (Reference Example A 23-303), 4-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]phenyl methyl sulfoxide (Reference Example A 23-305), 4-[4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]phenyl methyl sulfone (Reference Example A 23-306), 4-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]phenyl methyl sulfone (Reference Example A 23-308), l0 4-[4-(4-fluorophenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]phenyl methyl sulfide (Reference Example A 23-309), 4-[4-(4-chlorophenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]phenyl methyl sulfide (Reference Example A 23-310), 4-[4-(4-fluorophenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]phenyl is methyl sulfoxide (Reference Example A 23-311), 4-[4-(4-chlorophenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]phenyl methyl sulfoxide (Reference Example A 23-312), 4-[4-(4-fluorophenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]phenyl methyl sulfone (Reference Example A 23-313), 20 4-[4-(4-chlorophenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]phenyl methyl sulfone (Reference Example A 23-314), N-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]-N'-phenylurea (Reference Example A 23-315), 2-hydroxy-N-[4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-25 yl]propionamide (Reference Example A 23-325), 4-[4-(3,4-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]phenyl methyl sulfide (Reference Example A 23-326), 4-[4-(3,4-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]phenyl methyl sulfoxide (Reference Example A 23-327), so 4- [4- (3, 4-dimethylphenyl) -5- (4-pyridyl) -1, 3-thiazol-2-yl]phenyl methyl sulfone (Reference Example A 23-328), 2-hydroxy-N-[4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]acetamide (Reference Example A 23-329), 4-[[[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amino]carbonyl]benzoic acid (Reference Example A 23-337), 3-[[[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amino]carbonyl]benzoic acid (Reference Example A 23-342), 4-(4-fluorophenyl)-2-phenyl-5-(4-pyridyl)-1,3-thiazole (Reference Example A 44-1), methyl 4-[4-(3-methylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]phenyl sulfide (Reference Example A 44-7), methyl 4-[4-(3-methylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-Io yl]phenyl sulfoxide (Reference Example A 44-8), methyl 4-[4-(3-methylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]phenyl sulfone (Reference Example A 44-26), or a salt thereof, As "acyl group", for example, there are an acyl group 1s represented by the formula:
- ( C=O ) -RS , - ( C=O ) -ORS , - ( C=O ) -NRSR6 , - ( C=S ) -NHRS o r - S OZ-R' (wherein RS represents a hydrogen atom, a hydrocarbon group optionally having substituents or a heterocyclic group optionally having substituents, R6 represents a hydrogen atom 20 or a C1_6 alkyl, R' represents a hydrocarbon group optionally having substituents or a heterocyclic group optionally having substituents) and the like.
In the aforementioned formula, as "hydrocarbon group" of "hydrocarbon group optionally having substituents" represented 25 by RS, for example, there are an acyclic or cyclic hydrocarbon group (for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl and the like) and the like. Among them, acyclic or cyclic hydrocarbon groups having 1 to 16 carbon atoms) are preferable.
so As "alkyl", for example, C1_6 alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like) and the like are preferable.
As "alkenyl", for example, C2_6 alkenyl (for example, vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl and the like) and the like are preferable.
As "alkynyl", for example, CZ_6 alkynyl (for example, ethynyl, propargyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-hexynyl and the like) and the like are preferable.
As "cycloalkyl", for example, C3_6 cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like) and the like are preferable.
io As "aryl", for example, C6_ls aryl (for example, phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and the like) and the like are preferable.
As "aralkyl", for example, C~_16 aralkyl (for example, 15 benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl and the like) and the like are preferable.
As "substituents" of "hydrocarbon group optionally having 2° substituents" represented by R5, for example, there are oxo, halogen atom (for example, fluorine, chlorine, bromine, iodine and the like) , Cl_3 alkylenedioxy (for example, methylenedioxy, ethylenedioxy and the like), nitro, cyano, optionally halogenated C1_6 alkyl, optionally halogenated CZ_6 alkenyl, 25 carboxy C2_6 alkenyl (for example, 2-carboxyethenyl, 2-carboxy-2-methylethenyl and the like), optionally halogenated C2_s alkynyl , optionally halogenated C3_6 cycloalkyl , C6_, 9 aryl ( for example, phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and the like), optionally so halogenated Cl_8 alkoxy, C1_6 alkoxy-carbonyl-C1_6 alkoxy (for example, ethoxycarbonylmethyloxy and the like), hydroxy, C6_19 aryloxy (for example, phenyloxy, 1-naphthyloxy, 2-naphthyloxy and the like) , C~_16 aralkyloxy (for example, benzyloxy, phenethyloxy and the like), mercapto, optionally halogenated C1_6 alkylthio, C6_14 arylthio (for example, phenylthio, 1-naphthylthio, 2-naphthylthio and the like), C~_16 aralkylthio (for example, benzylthio, phenethylthio and the like), amino, s mono-C1_6 alkylamino (for example, methylamino, ethylamino and the like), mono-C6_14 arylamino (for example, phenylamino, 1-naphthylamino, 2-naphthylamino and the like), di-C1_6 alkylamino (for example, dimethylamino, diethylamino, ethylmethylamino and the like), di-C6_14 arylamino (for example, diphenylamino io and the like), formyl, carboxy, carboxy-CZ_6 alkenyl, carboxy-C1_6 alkyl, C1_6 alkyl-carbonyl (for example, acetyl, propionyl and the like), C3_6 cycloalkyl-carbonyl (for example, cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl and the like) , C1_6 alkoxy-carbonyl (for example, is methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like), C6_14 aryl-carbonyl (for example, benzoyl, 1-naphthoyl, 2-naphthoyl and the like), C~_16 aralkyl-carbonyl (for example, phenylacetyl, 3-phenylpropionyl and the like) , C6_14 aryloxy-carbonyl (for example, phenoxycarbonyl and 2o the like) , C~_16 aralkyloxy-carbonyl (for example, benzyloxycarbonyl, phenethyloxycarbonyl and the like), 5 or 6 membered heterocyclic carbonyl (for example, nicotinoyl, isonicotinoyl, thenoyl, furoyl, morpholinocarbonyl, thiomorpholinocarbonyl, piperazin-1-ylcarbonyl, pyrrolidin-1-2s ylcarbonyl and the like), carbamoyl, thiocarbamoyl, mono-C,_6 alkyl-carbamoyl (for example, methylcarbamoyl, ethylcarbamoyl and the like), di-C1_6 alkyl-carbamoyl (for example, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl and the like) , mono- or di-C6_19 aryl-carbamoyl (for example, so phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl and the like), mono- or di-5 or 6 membered heterocyclic carbamoyl (for example, 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl and the like) , C1-6 alkylsulfonyl (for example, methylsulfonyl, ethylsulfonyl and the like) , Cl-6 alkylsulfinyl (for example, methylsulfinyl, ethylsulfinyl and the like), C6-i4 arylsulfonyl (for example, phenylsulfonyl, 1-naphthylsulfonyl, 2-s naphthylsulfonyl and the like) , C6_14 arylsulfinyl (for example, phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl and the like), formylamino, C1_6 alkyl-carbonylamino (for example, acetylamino and the like), C6_14 aryl-carbonylamino (for example, benzoylamino, naphthoylamino and the like), C1_6 alkoxy-io carbonylamino (for example, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino and the like), C1_6 alkylsulfonylamino (for example, methylsulfonylamino, ethylsulfonylamino and the like), C6_1Q
arylsulfonylamino (for example, phenylsulfonylamino, 2-Is naphthylsulfonylamino, 1-naphthylsulfonylamino and the like), C1_6 alkyl-carbonyloxy (for example, acetoxy, propionyloxy and the like), C6_14 aryl-carbonyloxy (for example, benzoyloxy, naphthylcarbonyloxy and the like), C1_6 alkoxy-carbonyloxy (for example, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy and the like), mono-C1_s alkyl-carbamoyloxy (for example, methylcarbamoyloxy, ethylcarbamoyloxy and the like), di-C1_6 alkyl-carbamoyloxy (for example, dimethylcarbamoyloxy, diethylcarbamoyloxy and the like), C6_~4 aryl-carbamoyloxy (for example, phenylcarbamoyloxy, 2s naphthylcarbamoyloxy and the like), nicotinoyloxy, 5 to 7 membered saturated cyclic amino optionally having substituents, to 10 membered aromatic heterocyclic group (for example, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-3Q isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl and the like), sulfo and the like.

The "hydrocarbon group" may have 1 to 5, preferably 1 to 3 aforementioned substituents at a substitutable position and, when the number of substituents is 2 or more, respective substituents may be the same or different.
As aforementioned "optionally halogenated C1_s alkyl", for example, there are C1_s alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like) and the like optionally having 1 to 5, preferably 1 to 3 halogen atoms) (for example, fluorine, to chlorine, bromine, iodine and the like). Examples thereof are methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, z5 pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl and the like.
As the aforementioned "optionally halogenated CZ_s alkenyl", for example, there are CZ_s alkenyl (for example, vinyl, propenyl, isopropenyl, 2-buten-1-yl, 4-penten-1-yl, 5-Zo hexen-1-yl) and the like optionally having 1 to 5, preferably 1 to 3 halogen atoms) (for example, fluorine, chlorine, bromine, iodine and the like).
As the aforementioned "optionally halogenated CZ_s alkynyl", there are C2_s alkynyl (for example, 2-butyn-1-y1, 4-ZS pentyn-1-yl, 5-hexyn-1-yl and the like) and the like optionally having 1 to 5, preferably 1 to 3 halogen atoms) (for example, fluorine, chlorine, bromine, iodine and the like).
As the aforementioned "optionally halogenated C3_s so cycloalkyl", fox example, there are C3_s cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like) and the like optionally having 1 to 5, preferably 1 to 3 halogen atoms) (for example, fluorine, chlorine, bromine, iodine and the like). Examples thereof are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dichlorocyclohexyl, 2,2,3,3-tetrafluorocyclopentyl, 4-chlorocyclohexyl and the like.
As the aforementioned "optionally halogenated C1_8 alkoxy", for example, there are C1_g alkoxy (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like) and the like optionally having 1 to 5, preferably 1 to 3 halogen atoms) (for example, fluorine, la chlorine, bromine, iodine and the like). Examples thereof are methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like.
15 As the aforementioned "optionally halogenated C1_s alkylthio", for example, there are C1_6 alkylthio (fox example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio and the like) and the like optionally having 1 to 5, preferably 1 to 3 halogen atoms) 2o (for example, fluorine, chlorine, bromine, iodine and the like). Examples thereof are methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio and the like.
2s As "5 to 7 membered saturated cyclic amino" of the aforementioned "5 to 7 membered saturated cyclic amino optionally having substituents", there are 5 to 7 membered saturated cyclic amino optionally containing 1 to 4 of one or two kinds of heteroatom(s)selected from a nitrogen atom, a 3o sulfur atom and an oxygen atom in addition to one nitrogen atom and carbon atoms and examples thereof are pyrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, thiomorpholino, hexahydroazepin-1-yl and the like.

As "substituents" of the "5 to 7 membered saturated cyclic amino optionally having substituents", for example, there are 1 to 3 C1_6 alkyl (for example, methyl, ethyl, propyl, isoprppyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, s hexyl and the like) , C6-is aryl (for example, phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and the like), C1_6 alkyl-carbonyl (for example, acetyl, propionyl and the like), 5 to 10 membered aromatic heterocyclic group (for example, 2-thienyl, 3-thienyl, 2-io pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl and the like), oxo and the Zs like.
As "heterocyclic group" of "heterocyclic group optionally having substituents" represented by R5, for example, there is a monovalent group obtained by removing one arbitrary hydrogen atom from a 5 to 14 membered (monocyclic, bicyclic or Zo tricyclic) heterocycle containing 1 to 4 of one or two kinds of heteroatom(s) selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, preferably (i) a 5 to 14 membered (preferably 5 to 10 membered) aromatic heterocycle, (ii) a 5 to 10 membered non-aromatic heterocycle Zs or (iii) a 7 to 10 membered bridged heterocycle.
As the aforementioned "5 to 14 membered (preferably 5 to membered) aromatic heterocycle", there are an aromatic heterocycle such as thiophene, benzo[b]thiophene, benzo[b]furan, benzimidazole, benzoxazole, benzothiazole, 3o benzisothiazole, naphtho[2,3-b]thiophene, furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, 4H-quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, ~-carboline, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, isoxazole, furazan, phenoxazine and the like, and a ring formed by fusing these rings (preferably monocyclic) with one or more (preferably 1 to 2) aromatic rings) (fox example, benzene ring and the like).
As the aforementioned "5 to 10 membered non-aromatic heterocycle", for example, there are pyrrolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, so thiomorpholine, dioxazole, oxadiazoline, thiadiazoline, triazoline, thiadiazole, dithiazole and the like.
As the aforementioned "7 to 10 membered bridged heterocycle", for example, there are quinuclidine, 7-azabicyclo[2.2.1]heptane and the like.
Is The "heterocyclic group" is preferably a 5 to 14 membered (preferably 5 to 10 membered) (monocyclic or bicyclic) heterocyclic group containing preferably 1 to 4 of one or two kinds of heteroatom(s) selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms. More 2o particularly, examples thereof are an aromatic heterocyclic group such as 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl,, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, pyrazinyl, 2-pyrimidinyl, 4-2$ pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl and the like, and a non-aromatic heterocyclic group such as 1-pyrrolidinyl, 2-3o pyrrolidinyl, 3-pyrrolidinyl, 2-imidazolinyl, 4-imidazolinyl, 2-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl, morpholino, thiomorpholino and the like.

Among them, for example, a 5 or 6 membered heterocyclic group containing 1 to 3 heteroatom(s) selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms is further preferable. More particularly, examples thereof are 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-imidazolinyl, 4-imidazolinyl, 2-pyrazolidinyl, 3-pyrazolidinyl, 4-?o pyrazolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl, morpholino, thiomorpholino and the like.
As "substituents" of "heterocyclic group optionally having substituents", for example, there are the same Is "substituents" as substituents of "hydrocarbon group optionally having substituents" represented by R~.
The "heterocyclic group" may have 1 to 5, preferably 1 to 3 aforementioned substituents at a substitutable position and, when the number of substituents is 2 or more, respective ao substituents may be the same or different.
As "C1_6 alkyl" represented by R6, for example, there are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.
As "hydrocarbon group optionally having substituents" and 25 "heterocyclic group optionally having substituents"
represented by R', for example, there are the aforementioned "hydrocarbon group optionally having substituents" and "heterocyclic group optionally having substituents"
represented by R5, respectively.
so As "hydrocarbon group optionally having substituents"
represented by R1, for example, "hydrocarbon group optionally having substituents" represented by RS can be mentioned.
As "heterocyclic group optionally having substituents"

represented by R1, for example, "heterocyclic group optionally having substituents" represented by R5 can be mentioned.
As "amino group optionally having substituents"
represented by R1, for example, there are (1) an amino group optionally having 1 or 2 substituents and (2) a cyclic amino group optionally having substituents, and the like.
As "substituents" of "amino group optionally having 1 or 2 substituents" of the aforementioned (1), for example, there are a hydrocarbon group optionally having substituents, a io heterocyclic group optionally having substituents, an acyl group, an alkylidene group optionally having substituents, and the like. As these "hydrocarbon group optionally having substituents" and "heterocyclic group optionally having substituents", there are the same "hydrocarbon group i5 optionally having substituents" and "heterocyclic group optionally having substituents" as those represented by RS
described above, respectively.
As "alkylidene group" of "alkylidene group optionally having substituents", for example, there are a C1_s alkylidene 2o group (for example, methylidene, ethylidene, gropylidene and the like) and the like. As "substituents" of "alkylidene group optionally having substituents", there are 1 to 5, preferably 1 to 3 same substituents as "substituents" of "hydrocarbon group optionally having substituents" represented by R5.
25 When the number of the aforementioned "substituents" of "amino group optionally having 1 or 2 substituents" is 2, respective substituents may be the same or different.
As "cyclic amino group" of "cyclic amino group optionally having substituents" of the aforementioned (2), there are a 5 3o to 7 membered non-aromatic cyclic amino group optionally containing 1 to 4 of one or two kinds of heteroatom(s) selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to one nitrogen atom and carbon atoms. More particularly, examples thereof are pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, thiomorpholino, hexahydroazepin-1-yl, imidazolidin-1-yl, 2,3-dihydro-1H-imidazol-1-yl, tetrahydro-1(2H)-pyrimidinyl, 3,6-dihydro-1(2H)-pyrimidinyl, 3,4-dihydro-1(2H)-pyrimidinyl and the like. As "substituents"
of "cyclic amino optionally having substituents", there are 1 to 3 of the same ones as "substituents" of "5 to 7 membered saturated cyclic amino group optionally having substituents"
which were described in detail as "substituents" of Io "hydrocarbon group optionally having substituents" represented by R5.
Examples of the 5 to 7 membered non-aromatic cyclic amino group having one oxo, there are 2-oxoirnidazolidin-1-yl, 2-oxo-2,3-dihydro-1H-imidazol-1-yl, 2-oxotetrahydro-1(2H)-15 pyrimidinyl, 2-oxo-3,6-dihydro-1(2H)-pyrimidinyl, 2-oxo-3,4-dihydro-1(2H)-pyrimidinyl, 2-oxopyrrolidin-1-yl, 2-oxopiperidino, 2-oxopiperazin-1-yl, 3-oxopiperazin-1-yl, 2-oxo-2,3,4,5,6,7-hexahydroazepin-1-yl and the like.
As R1, an amino group optionally having substituents and 2o an aryl group optionally having substituents are preferable.
As further preferable example of the "amino group optionally having substituents" is an amino group optionally having 1 or 2 acyl groups represented by the formula:
- (C=O) -R5, - (C=O) -ORS, - (C=O) -NR5R6, - (C=S) -NHR5 or -SOz-R' 25 [wherein respective symbols represent the same meanings as described above].
More preferable example is an amino group optionally having 1 or 2 acyl groups represented by the formula:
-C(C=O)-RS or -(C=O)-NRSR6 [wherein respective symbols represent 3o the same meanings as described above].
As the "aryl group optionally having substituents", for example, there is preferably a C6_14 aryl group (preferably a phenyl group and the like) optionally having 1 to 5 substituents selected from C1_6 alkylthio, C6_14 arylthio, Cl_s alkylsulfinyl, C6_i4 arylsulfinyl, Cl_6 alkylsulfonyl, C6_la arylsulfonyl and carboxy.
Particularly, as Ri, there are mentioned (1) C6_14 aryl group (preferably C6_lo aryl) optionally having 1 to 5 substituents selected from halogen atom, optionally halogenated C1_6 alkyl, carboxy C2_6 alkenyl, optionally halogenated Cl_s alkoxy, C1_6 alkoxy-carbonyl-Cl_6 alkoxy, hydroxy, amino, mono- or di-C1_6 alkylamino, carboxy, C1_6 alkoxy-carbonyl, 1o mono- or di-Cl_6 alkyl-carbamoyl, C6-14 aryl-carbonylamino, C1_3 alkylenedioxy, Cl_6 alkylthio, C6_14 arylthio, C1_6 alkylsulfinyl, Cs-is arylsulfinyl, Cl_6 alkylsulfonyl, C6_14 arylsulfonyl, nitro and the like, (2) C1_8 alkyl group optionally having 1 to 5 substituents 15 selected from halogen atom, optionally halogenated C1_6 alkyl, carboxy C2_6 alkenyl, optionally halogenated Cl_6 alkoxy, Gl_s alkoxy-carbonyl-Cz_6 alkoxy, hydroxy, amino, mono- or di-C1_s alkylamino, carboxy, C1_6 alkoxy-carbonyl, mono- or di-C1_s alkyl-carbamoyl and Cs_14 aryl-carbonylamino, 2o (3) C3_6 cycloalkyl group (e. g., cyclohexyl) optionally having 1 to 5 substituents selected from halogen atom, optionally halogenated Cl_6 alkyl, carboxy C2_6 alkenyl, optionally halogenated Cl_6 alkoxy, C1_6 alkoxy-carbonyl-C1_6 alkoxy, hydroxy, amino, mono- or di-C1_6 alkylamino, carboxy, C1_6 alkoxy-carbonyl, 2s mono- or di-C,_s alkyl-carbamoyl and C6_,q aryl-carbonylamino, (4) C~_,6 aralkyl group (e.g. , phenyl-C1_6 alkyl group) , (5) 5 to 10 membered aromatic heterocyclic group containing 1 to 4 of one or two kinds of heteroatom(s) selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to so carbon atoms (e. g., 5 or 6 membered aromatic heterocyclic group such as pyridyl, thienyl and the like), (6) 5 to 10 membered non-aromatic heterocyclic group containing 1 or 2 of one or two kinds of heteroatom(s) selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, which may have Cs-is aryl (e.g., phenyl), C1_s alkyl-carbonyl or oxo, such as 5 or 6 membered non=aromatic cyclic amino group (e. g., piperidino, piperazino and the like), (7) amino group optionally having 1 or 2 substituents selected from the group consisting of the following 1 ) to 7 ) [ 1 ) Cl_s alkyl , 2 ) Cs-is aryl , 3 ) C~_ls aralkyl , 4 ) a 5 or 6 membered heterocyclic group (e.g., pyridyl) containing I or 2 so heteroatom(s) selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, 5) C1_s alkyl-carbonyl, C3_s cycloalkyl-carbonyl, Cs_14 aryl-carbonyl, C~_ls aralkyl-carbonyl, C1-s alkyl-carbamoyl or 5 or 6 membered heterocyclic carbonyl group, each optionally having 1 to 3 15 substituents selected from halogen atom, C1_s alkyl, C1_s alkoxy, carboxy, C1-s alkoxy-carbonyl, cyano, tetrazine and the like, 6) Cs_14 aryl-carbamoyl group optionally having 1 to 3 substituents selected from halogen atom, Cl_s alkyl, Cl_s alkoxy, carboxy, Cl_s alkoxy-carbonyl, cyano, nitro, mono- or di-C1_s alkylamino and 2o the like , 7 ) di-Cl_s alkylamino-C1_s alkylidene ] , or ( 8 ) carboxy group and the like are preferable.
As the "pyridyl group" of the "pyridyl group optionally having substituents" represented by R2, 1-, 2-, 3- or 4-pyridyl group is used.
25 As the "substituents" of the "pyridyl group optionally having substituents" represented by R2, for example, those similar to the "substituents" of the "hydrocarbon group optionally having substituents" represented by the aforementioned RS are used.
sa The "pyridyl group" may have 1 to 5, preferably 1 to 3, substituents such as those mentioned above at substitutable position(s). When the number of substituent is 2 or more, the respective substituents may be the same or different. In addition, the nitrogen atom in the ring of the "pyridyl group"
may be N-oxidized.
R2 is preferably a pyridyl group optionally having substituents (e.g., 3-pyridyl group, 4-pyridyl group and the like, preferably 4-pyridyl group).
As R2, pyridyl group optionally having 1 or 2 substituents selected from the group consisting of C1_6 alkyl (e. g. , methyl) , hydroxy and Cl_s alkyl-carbonyloxy (e.g. , acetyloxy) and the like are preferable.
io As the "aromatic group" of "aromatic group optionally having substituents" represented by R3, for example, there are an aromatic hydrocarbon group and an aromatic heterocyclic group.
As the "aromatic hydrocarbon group", examples thereof i5 include a C6-14 monocyclic or fused polycyclic (bicyclic or tricyclic) aromatic hydrocarbon group. As examples, there are a C6_14 aryl group and the like such as phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and the like.
2° As the "aromatic heterocyclic group", there are 5 to 14 membered (preferably 5 to 10 membered)(monocyclic or bicyclic) aromatic heterocyclic groups containing preferably 1 to 4 of one or two kinds of heteroatom(s) selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon 2s atoms and the like and, more particularly, an aromatic heterocyclic group such as 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, pyrazinyl, 2-3o pyrimidinyl, 4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl and the like.
As the "substituents" of the "aromatic group optionally having substituents", there are 1 to 5, preferably 1 to 3 same substituents as "substituents" of "hydrocarbon group optionally having substituents" represented by the aforementioned R5. When the number of substituents is 2 or more, respective substituents may be the same or different.
The adjacent two substituents may form a 4 to 7 membered non-aromatic carbon ring. Preferably, it is a 5 membered non-io aromatic carbon ring.
R3 is preferably a C6-to aryl group optionally having substituents. More preferably, it is a phenyl group optionally having substituents. The substituent of the Cs-to aryl group and phenyl group is preferably 1 to 3 i5 substituents selected from halogen atom, C1-3 alkylenedioxy, optionally halogenated Cl_6 alkyl, carboxy C2_6 alkenyl, C3_s cycloalkyl, optionally halogenated Cl_B alkoxy, hydroxy, C7_ls aralkyloxy, C1_6 alkyl-carbonyloxy arid carboxy, particularly preferably, is optionally halogenated C1_6 alkyl (e.g., C1-s 2o alkyl such as methyl, ethyl and the like), optionally halogenated Cl_B alkoxy (e. g. , C1_3 alkoxy such as methoxy, ethoxy and the like). The two adjacent alkyl groups as substituents may be bonded to form a 5 membered non-aromatic carbon ring.
25 The compound (I) preferably does not include a compound of the formula Ar N H
\?--N-R
(Iaa) N
wherein Ar is an unsubstituted or substituted aryl group bonded to a thiazole ring by a carbon atom of the aromatic 3o ring, and R is a hydrogen atom, acyl group, or a monovalent aromatic group having not more than 10 carbon atoms, which is bonded to a nitrogen atom by a carbon atom of the aromatic ring.
As the compound (I) , for example, compound (Ia) is preferable.
As compound (Ia), the following compounds of (A)-(B) and the like are preferable.
(A) A compound (Ia) wherein R1 is (a) an amino group which may have 1 or 2 acyl groups of the formula: - (C=O) -R~ or i° -(C=O)-NRSR6 wherein each symbol is as defined above or (b) a C6_19 aryl group optionally having 1 to 5 substituents selected from C1_6 alkylthio, C6-i4 arylthio, Cl_6 alkylsulfinyl, C6_14 arylsulfinyl, C1_6 alkylsulfonyl, C6_14 arylsulfonyl and carboxy and the like;
RZ is pyridyl group optionally having 1 to 5 substituents selected from C1_6~alkyl, hydroxy and C1_6 alkyl-carbonyloxy; and R3 is a C6_14 aryl group optionally having 1 to 5 substituents selected from halogen atom, optionally halogenated C1_s alkyl, optionally halogenated C1_6 alkoxy and carboxy.
2° (B) A compound (Ia) wherein R1 is (i) Cl_$ alkyl, C3-6 cycloalkyl or Cs-14 aryl (preferably C6-to aryl) , each optionally having 1 to 5 substituents selected from halogen atom, optionally halogenated C1-6 alkyl , carboxy C2_6 alkenyl , optionally halogenated Cl_6 alkoxy, C1_6 alkoxy-carbonyl-C,__6 alkoxy, hydroxy, 25 wino, mono- or di-C,_6 alkylamino, carboxy, C,_6 alkoxy-carbonyl, mono- or di-Cl_6 alkyl-carbamoyl and C6-19 aryl-carbonyl amino, (ii) a 5 membered heterocyclic group, (iii) an amino group optionally having 1 or 2 substituents selected from ( 1 ) C1_6 alkyl , ( 2 ) C6_19 aryl , (3 ) C~_16 aralkyl , (4) 6 membered heterocyclic group and (5) C1_6 alkyl-carbonyl, C3-6 cycloalkyl-carbonyl, C6_19 aryl-carbonyl, C~_16 aralkyl-carbonyl, C1_6 alkyl-carbamoyl or 5 or 6 membered heterocyclic carbonyl, each optionally having 1 to 3 substituents selected from halogen atom, C1-s alkyl, C1_s alkoxy, carboxy and C1-s alkoxy-carbonyl, or an amino group optionally having di-C1_s alkylamino-Cl_s alkylidene, (iv) a 5 or 6 membered non-aromatic cyclic amino group optionally substituted by C1_6 alkyl-carbonyl or oxo, or (v) a carboxy group;
RZ is a pyridyl group optionally having 1 to 3 substituents selected from Cl_s alkyl, hydroxy and C1_s alkyl-carbonyloxy;
R3 is a Cs_lo aryl group optionally having 1 to 3 substituents io selected from halogen atom, C1_3 alkylenedioxy, optionally halogenated Cl_s alkyl, carboxy C2_s alkenyl, optionally halogenated C1_8 alkoxy, hydroxy, C~_ls aralkyloxy and Cl_s alkyl-carbonyloxy (two adjacent alkyl groups as substituents may be bonded to form a 5 membered non-aromatic carbon ring).
i5 Moreover, preferable examples of compound (I) and compound (Ia) include:
[4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (Reference Example A 13-14), [4-phenyl-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (Reference Zo Example A 13-15), N-methyl [4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (Reference Example A 13-16), N-methyl [4-phenyl-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (Reference Example A 13-47), Zs N-methyl [4-(4-fluorophenyl)-5-(4-pyridyl)-I,3-thiazol-2-yl]amine (Reference Example A 13-&9), N-methyl [4-(4-chlorophenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (Reference Example A 13-70), N-methyl [4-(4-bromophenyl)-5-(4-pyridyl)-1,3-thiazol-2-so yl]amine (Reference Example A 13-71), 2-phenyl-N-[4-phenyl-5-(4-pyridyl)-1,3-thiazol-2-yl]acetamide (Reference Example A 23-29), 3-phenyl-N-[4-phenyl-5-(4-pyridyl)-1,3-thiazol-2-yl]propionamide (Reference Example A 23-30), N-[4-(3-chlorophenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]acetamide (Reference Example A 23-49), N-[4-(3-chlorophenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]propionamide (Reference Example A 23-50), N-[4-(3-methylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]acetamide (Reference Example A 23-51), N-[4-(3-methylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl)propionamide (Reference Example A 23-52), [4- (3-chlorophenyl) -5- (4-pyridyl) -1, 3-thiazol-2-yl] amine (Reference Example A 23-59), [4-(3-methylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (Reference Example A 23-60), [4-(4-chlorophenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine 15 (Reference Example A 23-61), [4-(4-methylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (Reference Example A 23-62), N-[4-phenyl-5-(4-pyridyl)-1,3-thiazol-2-yl]acetamide (Reference Example A 23-71), Z° N-phenyl-[4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (Reference Example A 23-80), N-[4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]nicotinamide (Reference Example A 23-101), N-[4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-2s yl]isonicotinamide (Reference Example A 23-102), [4-(3,4-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (Reference Example A 23-125), N-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]acetamide (Reference Example A 23-128), so [4-(2-naphthyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (Reference Example A 23-144), N-ethyl-N'-[4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]urea (Reference Example A 23-156), N-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]isonicotinamide (Reference Example A 23-200), N-ethyl-[4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (Reference Example A 23-269), s N-propyl-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (Reference Example A 23-276), N-butyl-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (Reference Example A 23-280), N-benzyl-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-zo yl]pine (Reference Example A 23-281), N-propyl-[4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (Reference Example A 23-290), N-isopropyl-[4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (Reference Example A 23-291), zs N-[4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]-N'-phenylurea (Reference Example A 23-296), 4-([[4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amino]carbonyl]benzoic acid (Reference Example A 23-299), methyl 4-[2-[4-(methylthio)phenyl]-5-(4-pyridyl)-1,3-thiazol-20 4-yl]phenyl ether (Reference Example A 23-300), 4-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]phenyl methyl sulfide (Reference Example A 23-302), 4-[4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]phenyl methyl sulfoxide (Reference Example A 23-303), zs 4-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]phenyl methyl sulfoxide (Reference Example A 23-305), 4-[4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]phenyl methyl sulfone (Reference Example A 23-306), 4-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-3o yl]phenyl methyl sulfone (Reference Example A 23-308), 4-[4-(4-fluorophenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]phenyl methyl sulfide (Reference Example A 23-309), 4-[4-(4-chlorophenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]phenyl methyl sulfide (Reference Example A 23-310), 4-[4-(4-fluorophenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]phenyl methyl sulfoxide (Reference Example A 23-311), 4-[4-(4-chlorophenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]phenyl methyl sulfoxide (Reference Example A 23-312), 4-[4-(4-fluorophenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]phenyl methyl sulfone (Reference Example A 23-313), 4-[4-(4-chlorophenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]phenyl methyl sulfone (Reference Example A 23-314), 1o N-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]-N'-phenylurea (Reference Example A 23-315), 2-hydroxy-N-[4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]propionamide (Reference Example A 23-325), 4-[4-(3,4-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-is yl]phenyl methyl sulfide (Reference Example A 23-326), 4-[4-(3,4-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]phenyl methyl sulfoxide (Reference Example A 23-327), 4-[4-(3,4-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]phenyl methyl sulfone (Reference Example A 23-328), 20 2-hydroxy-N- [4- (4-methoxyphenyl) -5- (4-pyridyl) -1, 3-thiazol-2-yl]acetamide (Reference Example A 23-329), 4-[[[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amino]carbonyl)benzoic acid (Reference Example A 23-337), 3-[[[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-25 yl]amino]carbonyl]benzoic acid (Reference Example A 23-342), salts thereof and the like.
Preferable examples of compound (I) and compound (Ia) further include 4-(4-fluorophenyl)-2-phenyl-5-(4-pyridyl)-1,3-thiazole (Reference Example A 44-1), methyl 4-[4-(3-30 methylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]phenyl sulfide (Reference Example A 44-7), methyl 4-[4-(3-methylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]phenyl sulfoxide (Reference Example A 44-8), methyl 4-[4-(3-methylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]phenyl sulfone (Reference Example A 44-26) and the like.
Furthermore, as compound (I) and (Ia), (S) -N- [4- (3-methylphenyl) -5- (2- (1-phenylethylamino) -4-s pyridyl)-1,3-thiazol-2-yl]nicotinamide, (R) -N- [4- (3-methylphenyl) -5- (2- (1-phenylethylamino) -4-pyridyl)-1,3-thiazol-2-yl]nicotinamide, (S) -N- [4- (3-methylphenyl) -5- (2- (1-phenylethylamino) -4-pyridyl)-1,3-thiazol-2-yl]-2-methylnicotinamide, io (R) -N- [4- (3-methylphenyl) -5- (2- ( 1-phenylethylamino) -4-pyridyl)-1,3-thiazol-2-yl]-2-methylnicotinamide, (S) -N- [4- (3-methylphenyl) -5- (2- (1-phenylethylamino) -4-pyridyl)-1,3-thiazol-2-yl]-2-chloronicotinamide, (R) -N- [4- (3-methylphenyl) -5- (2- (1-phenylethylamino) -4-is pyridyl)-1,3-thiazol-2-yl]-2-chloronicotinamide, ( S ) -N- [ 4- ( 3-methylphenyl ) -5- ( 2- ( 1-phenylethylamino ) -4-pyridyl)-1,3-thiazol-2-yl]-2-methoxynicotinamide, (R) -N- [ 4- ( 3-methylphenyl ) -5- ( 2- ( 1-phenylethylamino ) -4-pyridyl)-1,3-thiazol-2-yl]-2-methoxynicotinamide, 2o N-[5-(2-benzylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]nicotinamide, N-[5-(2-benzylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]-2-methoxynicotinamide, N-[5-(2-benzylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2s 2-yl]-2-chloronicotinamide, N-[5-(2-benzylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]-2-methylnicotinamide, N-[5-(2-benzoylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]nicotinamide, 3o N-[5-(2-benzoylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]-2-methylnicotinamide, N-[5-(2-benzoylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]-2-chloronicotinamide, N-[5-(2-benzoylarnino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]-2-methoxynicotinamide, (S)-N-(1-phenylethyl)-4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine, (R)-N-(1-phenylethyl)-4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine, (S)-N-(1-phenylethyl)-4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridylamine, (R) -N- (1-phenylethyl) -4- [4- (3-methylphenyl) -2-propyl-1, 3-i° thiazol-5-yl]-2-pyridylamine, (S) -N- (1-phenylethyl) -4- [2-butyl-4- (3-methylphenyl) -1, 3-thiazol-5-yl]-2-pyridylamine, (R) -N- ( 1-phenylethyl ) -4- [ 2-butyl-4- ( 3-methylphenyl ) -1, 3-thiazol-5-yl]-2-pyridylamine, is ( S ) -N- ( 1-phenylethyl ) -4- [ 4- ( 3-methylphenyl ) -2- ( 4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridylamine, (R) -N- (1-phenylethyl) -4- [4- (3-methylphenyl) -2- (4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridylamine, ( S ) -N- ( 1-phenylethyl ) -4- [ 4- ( 3-methylphenyl ) -2- ( 4-2° methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine, ( R) -N- ( 1-phenylethyl ) -4- [ 4- ( 3-methylphenyl ) -2- ( 4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine, ( S ) -N- ( 1-phenylethyl ) -4- [ 2- ( 4-f luorophenyl ) -4- ( 3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine, 25 (R) -N- ( 1-phenylethyl ) -4- [ 2- ( 4-f luorophenyl ) -4- ( 3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine, salts thereof and the like are preferable.
As the salt of Compounds (I) and (Ia), for example, there are a metal salt, ammonium salt, a salt with an organic base, 3o a salt with an inorganic acid, a salt with an organic acid, a salt with basic or acidic amino acid and the like. As a suitable metal salt, there are alkali metal salt such as sodium salt, potassium salt and the like; alkaline earth metal salt such as calcium salt, magnesium salt, barium salt and the like; aluminum salt and the like. As a suitable example of a salt with an organic base, for example, there are salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine and the like. As a suitable example of a salt with an inorganic acid, for example, there are salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. As a suitable example of a salt with an organic acid, for example, there are salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, malefic acid, citric acid, succinic acid, malic acid, z5 methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. As a suitable example of a salt with a basic amino acid, for example, there are salts with arginine, lysine, ornithine and the like. As a suitable example of a salt with an acidic amino acid, for example, there are salts 2o with aspartic acid, glutamic acid and the like.
Among them, pharmaceutically acceptable salts are preferable. For example, when a compound has an acidic functional group therein, there are inorganic salts such as alkali metal salts (for example, sodium salt, potassium salt 25 and the like), alkaline earth metal salts (for example, calcium salt, magnesium salt, barium salt and the like), ammonium salts and the like and, when a compound has a basic functional group therein, there are salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, so sulfuric acid, phosphoric acid and the like, and salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, malefi c acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
A process for producing Compound (I) including Compound (Ia) will be described below. Compound (I) can be obtained according to the methods described in W001/10865, JP-A-60-58981, JP-A-61-10580, JP-T 7-503023, WO 93/15071, DE-A-3601411, JP-A-5-70446 and the like, a method similar to these methods and the like.
When Compound (I) is present as a configurational isomer, diastereomer, conformer or the like, each can be optionally to isolated by the above separation and purification means. In addition, Compound (I) is in the form of its racemate, they can be separated into S- and R-forms by any conventional optical resolution.
When Compound (I) includes stereoisomers, both the 15 isomers alone and mixtures of each isomers are included in the scope of the present invention.
In addition, Compound (I) may be hydrated or anhydrous.
Compound (I) may be labeled with an isotope (for example, sH~ iaC, 35~) or the like.
[compound (II)]
(1) an optionally N-oxidized compound represented by the formula:
RZaiZwYe ( I I
to z5 wherein Rla represents a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino group optionally having substituents or an acyl group, RZa represents an aromatic group optionally having substituents, 3o Rsa represents a hydrogen atom, a pyridyl group optionally having substituents or an aromatic hydrocarbon group optionally having substituents, Xa represents an oxygen atom or an optionally oxidized sulfur atom, Ya represents a bond, an oxygen atom, an optionally oxidized sulfur atom or a group~represented by the formula: NR4a (wherein Røa represents a hydrogen atom, a hydrocarbon group optionally having substituents or an acyl group) and Za represents a bond ar a divalent acyclic hydrocarbon group optionally having substituents, or a salt thereof, (2) the compound according to (1), wherein Za is a divalent acyclic hydrocarbon group optionally having substituents, (3) the compound according to (1), which is a compound represented by the formula:
(p1 i s Z' a R2a wherein n represents 0 or 1, and other symbols are as defined in (1), or a salt thereof, ( 4 ) the compound according to ( 1 ) or ( 3 ) , wherein Rla represents 2° (i) a hydrogen atom, (ii) a C,__6 alkyl group, a C2_6 alkenyl group, a C2_6 alkynyl group, a C3_6 cycloalkyl group, a C6_z4 aryl group or a C~_ls aralkyl group [these groups may have substituents selected from the group (substituent group A) consisting of oxo, 25 halogen atom, C1_3 alkylenedioxy, vitro, cyano, optionally halogenated C1_6 alkyl, optionally halogenated CZ_6 alkenyl, carboxy CZ_6 alkenyl, optionally halogenated CZ_6 alkynyl, optionally halogenated C3_6 cycloalkyl, C6_l~ aryl, optionally halogenated Cl_B alkoxy, C1_6 alkoxy-carbonyl-C1_6 alkoxy, hydroxy, Cs-14 aryloxy, C~_ls aralkyloxy, mercapto, optionally halogenated Cl_s alkylthio, Cs_14 arylthio, C~_ls aralkylthio, amino, mono-C1_s alkylamino, mono-Cs_1Q
arylamino, di-C1_s alkylamino, di-Cs_14 arylamino, formyl, carboxy, Cl_s alkyl-carbonyl, C3_s cycloalkyl-carbonyl, Cl_s alkoxy-carbonyl, Cs_19 aryl-carbonyl, C~_ls aralkyl-carbonyl, Cs_19 aryloxy-carbonyl, C~_ls aralkyloxy-carbonyl, 5 or 6 membered heterocyclic carbonyl, carbamoyl, thiocarbamoyl, mono-C1_s alkyl-carbamoyl, di-C1_s alkyl-carbamoyl, Cs_14 aryl-carbamoyl, 5 to or 6 membered heterocyclic carbamoyl, Cl_s alkylsulfonyl, Cs_14 arylsulfonyl, C1_s alkylsulfinyl, Cs_14 arylsulfinyl, formylamino, Cl_s alkyl-carbonylamino, Cs-14 aryl-carbonylamino, Cl_s alkoxy-carbonylamino, C1_s alkylsulfonylamino, Cs_z9 arylsulfonylamino, Cl_s alkyl-carbonyloxy, Cs_14 aryl-carbonyloxy, C1_s alkoxy-z5 carbonyloxy, mono-Cl_s alkyl-carbamoyloxy, di-Cl_s alkyl-carbamoyloxy, Cs_14 aryl-carbamoyloxy, nicotinoyloxy, 5 to 7 membered saturated cyclic amino optionally having 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to one nitrogen 2o atom and carbon atoms (this cyclic amino may have substituents selected from the group consisting of Cl_s alkyl, Cs_14 aryl, G1-s alkyl-carbonyl, 5 to 10 membered aromatic heterocyclic group and oxo), 5 to 10 membered aromatic heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected 25 from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, sulfo, sulfamoyl, sulfinamoyl and sulfenamoyl]
(iii) a 5 to 14 membered heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, so a sulfur atom and an oxygen atom in addition to carbon atoms optionally having substituents selected from the substituent group A, (iv) an acyl group represented by the formula:

- ( C=O ) -R5a ~ _ ( C=0 ) -ORsa , - ( C=O ) -NRsaR6a ~ - ( C=$ ) -NHRSa O r -S02-R7a (wherein Rsa represents (1) a hydrogen atom, (2) a Cl_s alkyl group, an C2_s alkenyl group, an C2_s alkynyl group, a C3_s cycloalkyl group, a Cs_1q aryl group or a C~_16 aralkyl group optionally having substituents selected from the substituent group A or (3) a 5 to 14 membered heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in io addition to carbon atoms optionally having substituents selected from the substituent group A, Rsa represents a hydrogen atom or a C1-s alkyl group, R'a represents ( 1 ) a Cl_s alkyl group, a C2_s alkenyl group, a C2_s alkynyl group, a C3_s cycloalkyl group, a Cs_19 aryl group or a C~_ls aralkyl group zs optionally having substituents selected from the substituent group A or (2) a 5 to 14 membered heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms optionally having substituents 2o selected from the substituent group A), (v) an amino group (this amino group may have substituents selected from the group consisting of (1) a C1-s alkyl group, a CZ_s alkenyl group, a CZ_s alkynyl group, a C3-s cycloalkyl group, a Cs-i4 aryl group or a C~_ls aralkyl group optionally having 2s substituents selected from the substituent group A, (2) a 5 to 14 membered heterocyclic group containing 1. to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms optionally having substituents selected from the substituent group A, (3) 3o an acyl group as defined in the (iv) , and (4) a C1-s alkylidene group optionally having substituents selected from the substituent group A), or (vi) a 5 to 7 membered non-aromatic cyclic amino group optionally containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to one nitrogen atom and carbon atoms (this cyclic amino may have substituents selected from the group consisting of Cl_6 alkyl, C6_14 aryl, Cl_6 alkyl-carbonyl, 5 to 10 membered aromatic heterocyclic group and oxo);
R2a represents (1) a C6_19 monocyclic or fused polycyclic aromatic hydrocarbon group optionally having substituents selected from the substituent group A or (2) a 5 to 14 so membered aromatic heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, optionally having substituents selected from the substituent group A;
z5 R3a represents (1) a hydrogen atom, (2) a pyridyl group optionally having substituents selected from the substituent group A, or (3) a C6_19 monocyclic or fused polycyclic aromatic hydrocarbon group optionally having substituents selected from the substituent group A;
2o Xa represents O, S, SO or S02;
Ya represents a bond, O, S, S0, S02 or a group represented by the formula : NR4a (wherein R4a represents ( 1 ) a hydrogen atom, (2) a C1_6 alkyl group, a CZ_6 alkenyl group, a C2_6 alkynyl group, a C3_6 cycloalkyl group, a C6-14 aryl group or 25 a C~-,6 aralkyl group optionally having substituents selected from the substituent group A or (3) an acyl group as defined in the (iv) ) .
Za represents a bond, a C1_15 alkylene group, a C2-is alkenylene group or a CZ-is alkynylene group optionally having 3o substituents selected from the substituent group A, (5) the compound according to (1), wherein Rla is an amino group optionally having substituents, ( 6 ) the compound according to ( 1 ) , wherein Rla i s ( i ) a Cl_s alkyl group, (ii) a C6_14 aryl group optionally substituted with substituents selected from C1_6 alkylthio, C1_6 alkylsulfonyl and halogen atom, or (iii) an amino group optionally having 1 or 2 acyl groups represented by the formula: -(C=O)-Rsa' (wherein Rsa ~ represents ( 1 ) a Cl_6 alkyl group, (2 ) a C6_14 aryl group or (3) a 5 to 14 membered heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an. oxygen atom in addition to carbon atoms), (?) the compound according to (1), wherein Rla is an amino 1o group optionally having 1 or 2 acyl groups represented by - (C=O) -Rya" (wherein R5a" represents (1) a C6_14 aryl group or (2) a 5 to 14 membered heterocyclic.group containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms), 15 ( 8 ) the compound according to ( 1 ) , wherein R2a is a C6_14 aryl group optionally having substituents, ( 9 ) the compound according to ( 1 ) , wherein RZa i s a C6_19 aryl group optionally substituted with halogen atom or C1_6 alkoxy, or a 5 to 14 membered aromatic heterocyclic group containing 1 2o to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, ( 10 ) the compound according to ( 1 ) , wherein R2a is a C6_l9 aryl group, or a 5 to 14 membered heterocyclic group containing 1 25 to 4 heteroatoms of one or two kinds selected from nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, ( 11 ) the compound according to ( 1 ) , wherein R3a is a C6_19 aryl group optionally having substituents, 30 ( 12 ) the compound according to ( 1 ) , wherein R3a is a C6_19 aryl group optionally substituted with one or two C~_6 alkyl or C1_s alkoxy groups, (13) the compound according to (1), wherein Xa is an optionally oxidized sulfur atom, (14) the compound according to (1), wherein Xa is a sulfur atom, (15) the compound according to (1), wherein Ya is an oxygen atom or a group represented by the formula: NR4a (wherein R4a is as defined in (1)), (16) the compound according to (1), wherein Ya is an oxygen atom, an optionally oxidized sulfur atom or a group represented by the formula: NR9a~ (wherein R4a~ represents a Cl_s alkyl group), io (17) the compound according to (1), wherein Ya is O, NH or S, (18) the compound according to (1), wherein Za is a lower alkylene group optionally having substituents, (19) the compound according to (1), wherein Z$ is a bond or a C1_s alkylene group optionally having oxo, is (20) the compound according to (1) , wherein Rla is (i) a C1-s alkyl group, (ii) a Cs-is aryl group optionally substituted with Cl_s alkylthio, C2_s sulfonyl and halogen atom, or (iii) an amino group optionally having 1 or 2 acyl groups represented by the formula: - (C=O) -Rsa' (wherein Rsa' represents (1) a C1_s alkyl Zo group , ( 2 ) a Cs_19 aryl group or ( 3 ) a 5 to 14 membered heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms;
RZa is a Cs_14 aryl group optionally substituted with 2s halogen atom or C1-s alkoxy, or a 5 to 14 membered aromatic heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms;
R3a is a Cs_14 aryl group optionally substituted with 1 or 30 2 C1-s alkyl or C1_s alkoxy groups;
Xa is a sulfur atom;
Ya is an oxygen atom, an optionally oxidized sulfur atom or a group represented by the formula: NR4a' (wherein R4a, represents a C1_6 alkyl group) ;
Za is a Cl_6 alkylene group optionally having oxo or Cs_s alkyl or a bond, (21) the compound according to (1) , wherein Rla is an amino group optionally having 1 or 2 acyl groups represented by - (C=O) -Rsa" (wherein RSa" represents (1) a C6_14 aryl group or (2) a 5 to 14 membered heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms);
1o Raa is a C6_1q aryl group or a 5 to 14 membered aromatic heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms;
R3a is a C6-19 aryl group optionally substituted with 1 or I5 2 C1-6 alkyl or C1-6 alkoxy groups ;
Xa is a sulfur atom; Ya is 0, NH or S; Za is a bond or a C1_6 alkylene group optionally having oxo, (22) N- [5- (2-benzoylamino-4-pyridyl) -4- (3, 5-dimethylphenyl)-1,3-thiazol-2-yl]acetamide (Reference Example D Compound No.9), N-[5-(2-benzylamino-4-pyridyl)-4-(3,5-dimethylphenyl)-1,3-thiazol-2-yl]acetamide (Reference Example D Compound No.lO), N-[4-[4-(4-methoxyphenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide (Reference Example D Compound No.l3), 25 N- [ 4- [ 2- ( 4-f luorophenyl ) -4- ( 3-methylphenyl ) -1, 3-thiazol-5-yl ] -2-pyridyl]phenylacetamide (Reference Example D Compound No.l4), N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide (Reference Example D Compound No.l5-2), N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-3o pyridyl]phenylacetamide (Reference Example D Compound No.l5-3), N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide (Reference Example D Compound No.l5-4), N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide (Reference Example D Compound No.l5-6), N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (Reference Example D Compound No.l6-1), N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide (Reference Example D Compound No.l6-2), N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-(4-methoxyphenyl)propionamide (Reference Example D Compound No.l6-3), Zo N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-4-phenylbutyramide (Reference Example D Compound No.l6-5), N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide (Reference Example D Compound No.l6-7), N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-i5 pyridyl]-3-phenylpropionamide (Reference Example D Compound No . 16-8 ) , N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (Reference Example D Compound No.l6-9), N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-20 3-phenylpropionamide (Reference Example D Compound No. l6-10), N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (Reference Example D Compound No. l6-11), N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide (Reference Example D Compound 25 No .16-12 ) , N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (Reference Example D Compound No.l6-15) , N- [4- [4- (3-methylphenyl) -2- (4-methylthiophenyl) -1, 3-thiazol-5-so yl]-2-pyridyl]-3-phenylpropionamide (Reference Example D
Compound No. l6-16), N-benzyl-N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine (Reference Example D Compound No.l9-2), N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine (Reference Example D Compound No.l9-3), N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine (Reference Example D Compound No.l9-4), N-benzyl-N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]amine (Reference Example D Compound No.l9-5), N-[4-(4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine (Reference Example D Compound No . 19-6 ) , io N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine (Reference Example D Compound No.l9-7), N-benzyl-N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine (Reference Example D Compound No.l9-8), is N-(4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2- phenylethyl)amine (Reference Example D Compound No.l9-9), N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine (Reference Example D Compound No.l9-10) , 2o N-benzyl-N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine (Reference Example D Compound No. l9-17), N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine (Reference Example D
25 Compound No. l9-18), N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine (Reference Example D
Compound No. l9-19), N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-so thiazol-5-yl]-2-pyridyl]benzamide (Reference Example D
Compound No.20), N- [4- [4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) -1, 3-thiazol-5-yl]-2-pyridyl]phenylacetamide (Reference Example D

Compound No.21-1), N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide (Reference Example D Compound No.21-2), N-benzyl-N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine (Reference Example D
Compound No.21-5), N- [4- [4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) -1, 3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine (Reference 2° Example D Compound No.21-6), N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl)-2-pyridyl]-N-(2-phenylethyl)amine (Reference Example Compound No.25-1), N- (4-fluorobenzyl) -N- [4- [4- (3-methylphenyl) -2- (4-15 methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine (Reference Example D Compound No.25-2), or salts thereof, In the aforementioned formula, Rla represents a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino 2° group optionally having substituents or acyl group.
As "acyl group" represented by Rla, for example, there are an acyl group represented by the formula: -(C=0)-Rsa, - (C=0) -ORsa, - (C=O) -NRSaRsa, - (C=S) -NHRsa or -S02-Rya (wherein Rsa represents a hydrogen atom, a hydrocarbon group optionally 2s having substituents or a heterocyclic group optionally having substituents, R6a represents a hydrogen atom or a C1_6 alkyl, R'a represents a hydrocarbon group optionally having substituents or a heterocyclic group optionally having substituents) and the like.
so In the aforementioned formula, as "hydrocarbon group"
represented by R5a of "hydrocarbon group optionally having substituents", for example, there are an acyclic or cyclic hydrocarbon group (for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl and the like) and the like. Among them, C1_ls acyclic or cyclic hydrocarbon groups are preferable.
As "alkyl", for example, C1-s alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-s butyl, pentyl, hexyl and the like) is preferable and, in particular, C1_3 alkyl (for example, methyl, ethyl, propyl and isopropyl) and the like are preferable.
As "alkenyl", for example, CZ_s alkenyl (for example, vinyl, a11y1, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-To methyl-2-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl and the like) and the like are preferable.
As "alkynyl", for example, CZ_s alkynyl (for example, ethynyl, propargyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-hexynyl and the like) and the like are preferable.
is As "cycloalkyl", for example, C3_s cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like) and the like are preferable.
As "aryl" , for example, Cs-24 aryl (for example, phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-2o biphenylyl, 2-anthryl and the like) and the like are preferable.
As "aralkyl", for example, C~_ls aralkyl (for example, benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-2s phenylbutyl, 5-phenylpentyl and the like) and the like are preferable.
As "substituents" of "hydrocarbon group optionally having substituents" represented by Rsa, for example, there are oxo, halogen atom (for example, fluorine, chlorine, bromine, iodine so and the like), C1_3 alkylenedioxy (for example, methylenedioxy, ethylenedioxy and the like), nitro, cyano, optionally halogenated C1_s alkyl, optionally halogenated CZ_s alkenyl, carboxy Cz_s alkenyl (for example, 2-carboxyethenyl, 2-carboxy-2-methylethenyl and the like), optionally halogenated C2_s alkynyl, optionally halogenated C3_s cycloalkyl, Cs_14 aryl (for example, phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and the like), optionally halogenated Cl_$ alkoxy, Cl_s alkoxy-carbonyl-C1_s alkoxy (for example, ethoxycarbonylmethyloxy and the like), hydroxy, Cs_1~
aryloxy (for example, phenyloxy, 1-naphthyloxy, 2-naphthyloxy and the like) , C~_ls aralkyloxy (for example, benzyloxy, phenethyloxy and the like), mercapto, optionally halogenated Zo C1-s alkylthio, Cs_19 arylthio (for example, phenylthio, 1-naphthylthio, 2-naphthylthio and the like), C~_ls aralkylthio (for example, benzylthio, phenethylthio and the like), amino, mono-C1_s alkylamino (for example, methylamino, ethylamino and the like), mono-Cs_14 arylamino (for example, phenylamino, 1-Zs naphthylamino, 2-naphthylamino and the like), di-C1_s alkylamino (for example, dimethylamino, diethylamino, ethylmethylamino and the like) , di-Cs_14 arylamino (for example, diphenylamino and the like), formyl, carboxy, C1_s alkyl-carbonyl (for example, acetyl, propionyl and the like), C3_s cycloalkyl-carbonyl (for 2o example, cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl and the like), C1_s alkoxy-carbonyl (fox example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like), Cs-14 aryl-carbonyl (for example, benzoyl, 1-naphthoyl, 2-naphthoyl and the like), C~_ls 25 aralkyl-carbonyl (for example, phenylacetyl, 3-phenylpropionyl and the like) , Cs-14 aryloxy-carbonyl (for example, phenoxycarbonyl and the like), C~-is aralkyloxy-carbonyl (for example, benzyloxycarbonyl, phenethyloxycarbonyl and the like), or 6 membered heterocyclic carbonyl (for example, nicotinoyl, so isonicotinoyl, thenoyl, furoyl, morpholinocarbonyl, thiomorpholinocarbonyl, piperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl and the like), carbamoyl, thiocarbamoyl, mono-C1_s alkyl-carbamoyl (for example, methylcarbamoyl, ethylcarbamoyl and the like), di-C1_s alkyl-carbamoyl (for example, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl and the like), Cs_14 aryl-carbamoyl (for example, phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl and the like), 5 or 6 membered heterocyclic carbamoyl (for example, 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl and the like), C1-s alkylsulfonyl (for example, methylsulfonyl, ethylsulfonyl and the like) , Cs_14 arylsulfonyl (for example, phenylsulfonyl, 1-io naphthylsulfonyl, 2-naphthylsulfonyl and the like), C1_s alkylsulfinyl (for example, methylsulfinyl, ethylsulfinyl and the like), Cs_1q arylsulfinyl (for example, phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl and the like), formylamino, C1_s alkyl-carbonylamino (for example, acetylamino i5 and the like) , Cs_14 aryl-carbonylamino (for example, benzoylamino, naphthoylamino and the like), C1_6 alkoxy-carbonylamino (for example, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino and the like) , Cl_s alkylsulfonylamino (for example, 2o methylsulfonylamino, ethylsulfonylamino and the like), Cs_14 arylsulfonylamino (for example, phenylsulfonylamino, 2-naphthylsulfonylamino, 1-naphthylsulfonylamino and the like), C1_s alkyl-carbonyloxy (for example, acetoxy, propionyloxy and the like), Cs_19 aryl-carbonyloxy (for example, benzoyloxy, 25 naphthylcarbonyloxy and the like), C,_s alkoxy-carbonyloxy (for example, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy and the like), mono-C1_s alkyl-carbamoyloxy (for example, methylcarbamoyloxy, ethylcarbamoyloxy and the like), di-C1_s alkyl-carbamoyloxy (for 3o example, dimethylcarbamoyloxy, diethylcarbamoyloxy and the like), Cs_19 aryl-carbamoyloxy (for example, phenylcarbamoyloxy, naphthylcarbamoyloxy and the like), nicotinoyloxy, 5 to 7 membered saturated cyclic amino optionally having substituents, to 10 membered aromatic heterocyclic group (for example, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, ~-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl and the like), sulfo, sulfamoyl, sulfinamoyl, sulfenamoyl and the like.
The "hydrocarbon group" may have 1 to 5, preferably 1 to 3 aforementioned substituents at a substitutable position and, when the number of substituents is 2 or more, respective substituents may be the same or different.
As aforementioned "optionally halogenated C1_6 alkyl", for example, there are C1-6 alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like) and the like optionally having 1 to 5, preferably 1 to 3 halogen atoms (for example, fluorine, chlorine, bromine, iodine and the like). Examples thereof are methyl, chloromethyl, difluoromethyl, trichloromethyl, 2o trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl and the like.
As the aforementioned "optionally halogenated CZ_6 alkenyl", for example, there are C2_6 alkenyl (for example, vinyl, propenyl, isopropenyl, 2-buten-1-yl, 4-penten-1-yl, 5-hexen-1-yl) and the like optionally having 1 to 5, preferably 1 to 3 halogen atoms (for example, fluorine, chlorine, bromine, 3o iodine and the like).
As the aforementioned "optionally halogenated C2_s alkynyl", there are CZ-6 alkynyl (for example, 2-butyn-1-yl, 4-pentyn-1-yl, 5-hexyn-1-yl and the like) and the like optionally having 1 to 5, preferably 1 to 3 halogen atoms (for example, fluorine, chlorine, bromine, iodine and the like).
As the aforementioned "optionally halogenated C3_s cycloalkyl", for example, there are C3_6 cycloalkyl (for example, s cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like) and the like optionally having 1 to 5, preferably 1 to 3 halogen atoms (for example, fluorine, chlorine, bromine, iodine and the like). Examples thereof are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dichlorocyclohexyl, so 2,2,3,3-tetrafluorocyclopentyl, 4-chlorocychohexyl and the like.
As the aforementioned "optionally halogenated C1-$ alkoxy", for example, there axe C1_e alkoxy (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, Is hexyloxy and the like) and the like optionally having 1 to 5, preferably 1 to 3 halogen atoms (for example, fluorine, chlorine, bromine, iodine and the like). Examples thereof are methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-20 trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like.
As the aforementioned "optionally halogenated C1-s alkylthio", for example, there are C1_6 alkylthio (for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, 2s sec-butylthio, tert-butylthio and the like) and the like optionally having 1 to 5, preferably 1 to 3 halogen atoms (for example, fluorine, chlorine, bromine, iodine and the like).
Examples thereof are methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, 3o butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio and the like.
As "5 to 7 membered saturated cyclic amino" of the aforementioned "5 to 7 membered saturated cyclic amino optionally having substituents", there are 5 to 7 membered saturated cyclic amino optionally containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to one nitrogen atom and carbon atoms and examples thereof are pyrrolidin-1-yl, piperidino, piperazin-1-y1, morpholino, thiomorpholino, hexahydroazepin-1-yl and the like.
As "substituents" of the "5 to 7 membered saturated cyclic amino optionally having substituents", for example, io there are 1 to 3 C1_6 alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like) , C6_14 aryl (for example, phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and the like), C1_6 alkyl-carbonyl (for example, acetyl, i5 propionyl and the like), 5 to 10 membered aromatic heterocyclic group (for example, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl, 20 2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl; 2-benzo[b]furanyl, 3-benzo[b]furanyl and the like), oxo and the like.
As "heterocyclic group" of "heterocyclic group optionally having substituents" represented by RSa, for example, there is 25 a monovalent group obtained by removing one arbitrary hydrogen atom from a 5 to 14 membered (monocyclic, bicyclic or tricyclic) heterocycle containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, preferably (i) a 5 to 30 14 membered (preferably 5 to 10 membered, particularly preferably 5 to 6 membered) aromatic heterocycle, (ii) a 5 to membered (preferably 5 to 6 membered) non-aromatic heterocycle or (iii) a 7 to 10 membered bridged heterocycle.

As the aforementioned "5 to 14 membered (preferably 5 to membered) aromatic heterocycle", there are an aromatic heterocycle such as thiophene, benzo[b]thiophene, benzo[b]furan, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, 4H-quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, io (3-carboline, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, isoxazole, furazan, phenoxazine and the like, and a ring formed by fusing these rings (preferably monocyclic) with 1 or a plurality (preferably 1 to 2) of aromatic rings (for example, benzene ring and the like).
As the aforementioned "5 to 10 membered non-aromatic heterocycle", for example, there are pyrrolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, thiomorpholine, dioxazole, oxadiazoline, thiadiazoline, triazoline, thiadiazole, dithiazole and the like.
2o As the aforementioned "7 to 10 membered bridged heterocycle", for example, there are quinuclidine, 7-azabicyclo[2.2.1]heptane and the like.
The "heterocyclic group" is preferably a 5 to 14 membered (preferably 5 to 10 membered) (monocyclic or bicyclic) heterocyclic group containing preferably 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms. More particularly, examples thereof are an aromatic heterocyclic group such as 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-so pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl and the like, and a non-aromatic heterocyclic group such as 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-imidazolinyl, 4-imidazolinyl, 2-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl, morpholino, thiomorpholino and the like.
Among them, for example, a 5 or 6 membered heterocyclic z° group containing 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms is further preferable. More particularly, examples thereof are 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, pyrazinyl, 2-pyrimidinyl, 3-15 pyrrolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-imidazolinyl, 4-imidazolinyl, 2-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl, morpholino, 2o thiomorpholino and the like.
As "substituents" of "heterocyclic group optionally having substituents", for example, there are the same "substituents" as substituents of "hydrocarbon group optionally having substituents" represented by Rsa.
25 The "heterocyclic group" may have 1 to 5, preferably 1 to 3 aforementioned substituents at a substitutable position and, when the number of substituents is 2 or mare, respective substituents may be the same or different.
As "C1_6 alkyl" represented by R6a, for example, there are 3o methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.
As "hydrocarbon group optionally having substituents" and "heterocyclic group optionally having substituents"

represented by R'a, for example, there are the aforementioned "hydrocarbon group optionally having substituents" and "heterocyclic group optionally having substituents"
represented by RSa, respectively.
As "hydrocarbon group optionally having substituents" and "heterocyclic group optionally having substituents"
represented by Rla, for example, there are the aforementioned "hydrocarbon group optionally having substituents" and - "heterocyclic group optionally having substituents"
so represented by RSa, respectively.
As "amino group optionally having substituents"
represented by Rla, for example, there are (1) an amino group optionally having 1 or 2 substituents and (2) a cyclic amino group optionally having substituents and the like.
1s As "substituents" of "amino group optionally having 1 or 2 substituents" of the aforementioned (1), for example, there are a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an aryl group, an alkylidene group optionally having substituents and zo the like. As these "hydrocarbon group optionally having substituents" and "heterocyclic group optionally having substituents", there are the same "hydrocarbon group optionally having substituents" and "heterocyclic group optionally having substituents" as those represented by Rsa z5 described above, respectively. As the "acyl group", there is the same "acyl group" as that by represented by Rla as described above.
As "alkylidene group" of "alkylidene group optionally having substituents", for example, there are a C1_6 alkylidene 3o group (for example, methylidene, ethylidene, propylidene and the like) and the like. As "substituents" of "alkylidene group optionally having substituents", there are 1 to 5, preferably 1 to 3 same substituents as "substituents" of "hydrocarbon group optionally having substituents" represented by Rsa.
When the number of the aforementioned "substituents" of "amino group optionally having 1 or 2 substituents" is 2, respective substituents may be the same or different.
As "cyclic amino group" of "cyclic amino group optionally having substituents" of the aforementioned (2), there are a 5 to 7 membered non-aromatic cyclic amino group optionally containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in io addition to one nitrogen atom and carbon atoms. More particularly, examples thereof are pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, thiomorpholino, hexahydroazepin-1-yl, imidazolidin-1-yl, 2,3-dihydro-1H-imidazol-1-yl, tetrahydro-1(2H)-pyrimidinyl, 3,6-dihydro-1(2H)-pyrimidinyl, 15 3~4-dihydro-1(2H)-pyrimidinyl and the like. As "substituents"
of "cyclic amino optionally having substituents", there are l to 3 of the same ones as "substituents" of "5 to 7 membered saturated cyclic amino group" which were described in detail as "substituents" of "hydrocarbon group optionally having 2o substituents" represented by Rsa.
Examples of the 5 to 7 membered non-aromatic cyclic amino group having 1 oxo, there are 2-oxoimidazolidin-1-yl, 2-oxo-2,3-dihydro-1H-imidazol-1-yl, 2-oxotetrahydro-1(2H)-pyrimidinyl, 2-oxo-3,6-dihydro-1(2H)-pyrimidinyl, 2-oxo-3,4-25 dihydro-1(2H)-pyrimidinyl, 2-oxopyrrolidin-1-yl, 2-oxopiperidino, 2-oxopiperazin-1-yl, 3-oxopiperazin-1-yl, 2-oxo-2,3,4,5,6,7-hexahydroazepin-1-yl and the like.
As Rla, an amino group optionally having substituents, an aryl group optionally having substituents and an alkyl group 30 optionally having substituents and the like are preferable.
As further preferable example of the "amino group optionally having substituents" is an amino group optionally having 1 or 2 acyl groups represented by the formula:

- ( C=0 ) -Rsa ~ - ( C=0 ) -ORSa ~ - ( C=0 ) -NR5aRsa ~ - ( C=S ) -NHRSa o r -S OZ-R7a [wherein respective symbols represent the same meanings as described above]. Particularly preferable example is an amino group optionally having 1 or 2 acyl groups represented by the s . formula: -C (C=O) -Rsa or - (C=0) -NR5aRsa [wherein respective symbols represent the same meanings as described above].
As the "aryl group optionally having substituents", for example, there is preferably a Cs_14 aryl group (preferably a phenyl group and the like) optionally having 1 to 5 to substituents selected from Cl_s alkylthio, Cs_1q arylthio, Cl_s alkylsulfinyl, Cs_14 arylsulfinyl, Cl_s alkylsulfonyl, Cs_14 arylsulfonyl and carboxy.
As the "alkyl group optionally having substituents", for example, a C1_s alkyl group (for example, methyl, ethyl, propyl, is isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like) optionally substituted with 1 to 3 substituents selected from halogen atom, Cl_s alkoxy, hydroxy, carboxy and C1_s alkoxy-carbonyl and the like are preferable, and particularly Cl-3 alkyl groups such as methyl, ethyl and the like is preferable.
2o Among them, as Rla, (i) C1_s alkyl group (for example, C1_4 alkyl group such as methyl, ethyl, propyl, butyl), (ii) a Cs_14 aryl group (for example, a phenyl group) optionally substituted with substituents selected from C1_s alkylthio (for example, methylthio), C1_s alkylsulfonyl (for example, Zs methylsulfonyl) and halogen atom (for example, chlorine atom, fluorine atom) or (iii) an amino group optionally having 1 or 2 acyl groups represented by the formula: -(C=O)-R5a' (wherein Rsa' represents (1) a C1_s alkyl group (for example, Cl_3 alkyl group such as methyl) , (2) a Cs_14 aryl group (for example, a so phenyl group) or (3) a 5 to 14 membered heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms (for example, a 5 to 6 membered heterocyclic group containing 1 to 2 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms such as pyridyl group) are preferable. As Rsa, and Rsa", a phenyl group or a pyridyl group is suitable.
s In the aforementioned formula, R2a represents an aromatic group optionally having substituents.
As "aromatic group" of "aromatic group optionally having substituents" represented by R2a, for example, there are an aromatic hydrocarbon group, an aromatic heterocyclic group and to the like.
As the "aromatic hydrocarbon group", examples thereof include a C6_14 monocyclic or fused polycyclic (bicyclic or tricyclic) aromatic hydrocarbon group, etc. As examples, there are a C6_la aryl group and the like such as phenyl, 1-naphthyl, is 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and the like and, further preferably, a C6_lo aryl group and the like (for example, phenyl, 1-naphthyl, 2-naphthyl and the like, preferably phenyl and the like).
As the "aromatic heterocyclic group", there is a 2o monovalent group obtained by removing one arbitrary hydrogen atom from 5 to 14 membered (preferably 5 to 10 membered) aromatic heterocycle containing 1 to 4 heteroatoms of one or two kinds selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atoms.
2s As the aforementioned "5 to 14 membered (preferably 5 to membered) aromatic heterocycle", for example, there are an aromatic heterocycle such as thiophene, benzo[b]thiophene, benzo[b]furan, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, pyrrole, 3o imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, 4H-quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, (3-carboline, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, isoxazole, furazan, phenoxazine and the like, and a ring formed by fusing these rings (preferably monocycle) with 1 or a plurality of (preferably 1 or 2) aromatic rings (for example, benzene ring and the like).
As the "aromatic heterocyclic group", there are preferably a 5 to 14 membered (preferably 5 to 10 membered)(monocyclic or bicyclic) aromatic heterocyclic group containing preferably 1 to 4 heteroatoms of one or two kinds io selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms and the like and, more particularly, there are an aromatic heterocyclic group such as 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-15 quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b)furanyl, 3-2o benzo[b]furanyl and the like.
As "substituents" of "aromatic group optionally having substituents", there are 1 to 5, preferably 1 to 3 same substituents as "substituents" of "hydrocarbon group optionally having substituents" represented by Rsa. When the 25 number of substituents is 2 or more, respective substituents may be the same or different.
As RZa, (1) a C6-14 aryl group optionally having substituents and (2) a 5 to 14 membered aromatic heterocyclic group containing 1 to 4 heteroatoms of one or two kinds so selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms are preferable and, among them, (1) a C6-14 aryl group (for example, phenyl group, naphthyl group) optionally substituted with halogen atom (for example, chlorine atom, fluorine atom) or Cl_6 alkoxy (for example, methoxy), (2) a 5 to 14 membered aromatic heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an s oxygen atom in addition to carbon atoms (for example, a 5 to 6 membered aromatic heterocyclic group containing 1 to 2 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms such as pyridyl group, thienyl group) and the like are preferable and, in io particular, a phenyl group, a pyridyl group and the like are suitable.
In the aforementioned formula, R3a represents a hydrogen atom, a pyridyl group optionally having substituents or an aromatic hydrocarbon group optionally having substituents.
is As "substituents" of "pyridyl group optionally having substituents" represented by R3a, there are the same substituents as "substituents" of "hydrocarbon group optionally having substituents" represented by Rsa.
The "pyridyl group" may, for example, have 1 to 5, 2o preferably 1 to 3 aforementioned substituents at substitutable positions and, when the number of substituents is 2 or more, respective substituents may be the same or different. In addition; an intracyclic nitrogen atom may be N-oxidized.
As "aromatic hydrocarbon group" of "aromatic hydrocarbon 2s group optionally having substituents" represented by R3a, there is the same aromatic hydrocarbon group as "aromatic hydrocarbon group" of "aromatic group optionally having substituents" represented by RZa and, preferably, there are a Cs-14 aryl group and the like such as phenyl, 1-naphthyl, 2-3o naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and the like and, further preferably, a C6-to aryl group and the like (for example, phenyl, 1-naphthyl, f-naphthyl and the like, preferably phenyl and the like) and the like. As "substituents" of "aromatic hydrocarbon group optionally having substituents" represented by R3a, there are the same substituents as substituents of "aromatic group optionally having substituents" represented by R2a.
As R3a, a C6-14 aryl group optionally having substituents is preferable and, among them, a C6_1q aryl group optionally substituted with 1 or 2 C1-6 alkyl (for example, methyl, ethyl and the like) or C1_6 alkoxy groups (for example, methoxy, ethoxy and the like) is preferable and, in particular, a to phenyl group optionally substituted with 1 or 2 C1_6 alkyl or C1-6 alkoxy groups (for example, 3-methoxyphenyl, 2-methylphenyl, 2,4-dimethylphenyl and the like) is suitable.
In the aforementioned formula, Xa represents an oxygen atom or an optionally oxidized sulfur atom.
Is As "optionally oxidized sulfur atom" represented by Xa, there are S, SO and SO2.
As Xa, there is preferably an optionally oxidized sulfur atom. Further preferably, it is S.
In the aforementioned formula, Ya represents a bond, an 2° oxygen atom, an optionally oxidized sulfur atom or the formula NR4a (wherein R9a represents a.hydrogen atom, a hydrocarbon group optionally having substituents or an acyl group).
As "optionally oxidized sulfur atom" represented by Ya, there are S, SO and SO2.
25 As "hydrocarbon group optionally having substituents"
represented by R4a, for example, there is the same group as "hydrocarbon group optionally having substituents" represented by RSa. Among them, a C1-6 alkyl group such as methyl, ethyl and the like and, in particular, a C1_3 alkyl group such as methyl 30 and the like is preferable.
As "acyl group" represented by R4a, there is the same group as "acyl group" represented by Rla.
As Ya, an oxygen atom, an optionally oxidized sulfur atom, a group represented by the formula NR4a (wherein R4a represents the same meaning as that described above) and the like are preferable and, among them, an oxygen atom, an optionally oxidized sulfur atom, a group represented by the formula NR'a' (R4a' represents a hydrogen atom or a C1_s alkyl group) and the like are preferable and, further, an oxygen atom, S, 502, NH, N(CH3) and the like are preferable and, in particular, O or NH
is suitable.
In the aforementioned formula, Za represents a bond or a io divalent acyclic hydrocarbon group optionally having substituents.
As "divalent acyclic hydrocarbon group" of "divalent acyclic hydrocarbon group optionally having substituents"
represented by Za, for example, there are a C1_15 alkylene group 15 (for example, methylene, ethylene, propylene, butylene, pentamethylene, hexamethylene, heptamethylene, octamethylene and the like, preferably a C1_s alkylene group and the like), a CZ_ls alkenylene group (for example, vinylene, propenylene, 1-butenylene, 2-butenylene, 1-pentenylene, 2-pentenylene, 3-2o pentenylene and the like) , a CZ_ls alkynylene group (ethynylene, propynylene, 1-butynylene, 2-butynylene, 1-pentynylene, 2-pentynylene, 3-pentynylene and the like) and the like, preferably, a C1_ls alkylene group, particularly preferably, a Cz_s alkylene group and the like. As "substituents" of 25 "divalent acyclic hydrocarbon group optionally having substituents" represented by Za, for example, there are the same substituents as "substituents" of "hydrocarbon group optionally having substituents" represented by Rsa.
As Za, a lower alkylene group optionally having C1_3 alkyl 30 (for example, methyl), oxo and the like (for example, a C1-s alkylene group such as methylene, ethylene, propylene and the like, in particular, a C1_3 alkylene group) is preferable and, among them, a C1_s alkylene group optionally having oxo (for example, a C1_3 alkylene group such as methylene, ethylene, propylene, in particular, methylene) is suitable.
More particularly, as Za, -CH2-, - (CHZ) z-, - (CH2) 3-, -CO-, -CHZCO-, - (CH2) ZCO-, -CH (CH3) - and the like are used and, in .
particular, -CHZ-, -CO- and the like are suitable.
A nitrogen atom in Compound (II) may be N-oxidized. For example, a nitrogen atom which is a constituent atom of 4-pyridyl group as a substituent at 5-position of a ring represented by the formula:
X
N
wherein a symbol in the formula represents the same meaning as that described above, may be N-oxidized. As Compound (II), for example, a compound represented by the formula:
~~~ n a a R2a/ZwYa I / X
/~Rla Rsa N
15 wherein n represents 0 or 1, and other symbols represents the same meanings as those described above, or salts thereof are preferable.
As Compound (II), compounds shown by the following (A) to (F) are preferably used.
20 (A) Compound (II) wherein Rla is an amino group optionally having substituents, RZa is a C6-is aryl group optionally having substituents, R3a is a C6_14 aryl group optionally having substituents, X is a sulfur atom, Y is an oxygen atom or a group represented by the formula NR4a (wherein Rqa represents 2s the same meaning as that described above) or (and) Z is a lower alkylene group optionally having substituents.
(B) Compound (II) wherein Rla is (i) a C1_6 alkyl group (for example, a C1_4 alkyl group such as methyl, ethyl, propyl, butyl and the like), (ii) a C6-19 aryl group (for example, a phenyl group) optionally substituted with substituents selected from C1_6 alkylthio (for example, methylthio) , Cl_6 alkylsulfonyl (for example, methylsulfonyl) and halogen atom (for example, chlorine atom, fluorine atom), or (iii) an amino group optionally having 1 or 2 acyl groups represented by the formula: - (C=O) -Rsa' [wherein Rsa' represents to (1) a C1-6 alkyl group (for example, C1_3 alkyl group such as methyl and the like) , (2) a C6_14 aryl group (for example, a phenyl group) or (3) a 5 to 14 membered heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in 15 addition to carbon atoms (for example, a 5 to 6 membered heterocyclic group containing 1 to 2 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms such as a pyridyl group);
R2a is a C6_14 aryl group (for example, a phenyl group, a 2o naphthyl group) optionally substituted with halogen atom (for example, chlorine atom, fluorine atom) or C1_6 alkoxy (for example, methoxy), or a 5 to 14 membered aromatic heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen 25 atom in addition to carbon atoms (for example, a 5 to 6 membered aromatic heterocyclic group containing 1 to 2 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms such as a pyridyl group, a thienyl group and the like);
3o Rsa is a C6_14 aryl group (particularly, a phenyl group) optionally substituted with 1 or 2 C1_6 alkyl (for example, methyl) or Cl_6 alkoxy groups (for example, methoxy) ;
Xa is a sulfur atom;

Ya is an oxygen atom, an optionally oxidized sulfur atom or a group represented by the formula NR4a' (Raa, is a hydrogen atom or a C1_6 alkyl group) (in particular, an oxygen atom, S, SO2, NH, N (CH3) and the like) ;
Za is a C1_6 alkylene group (in particular, a Cl_3 alkylene group) optionally having oxo or Cl-6 alkyl (for example, C1-s alkyl such as methyl) or a bond.
(C) Compound (II) wherein Rla is an amino group optionally having 1 or 2 acyl groups represented by the formula 1o - (C=O) -Rsa" (wherein Rsa" represents (1) a C6_19 aryl group (for example, phenyl group) or (2) a 5 to 14 membered heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms (for example, a 5 to 6 Z5 membered heterocyclic group containing 1 to 2 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms such as a pyridyl group);
R2a is a C6-19 aryl group (for example, a phenyl group) or a 5 to 14 membered aromatic heterocyclic group containing 1 to 20 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms (for example, a 5 to 6 membered aromatic heterocyclic group containing 1 to 2 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon 2s atoms such as a pyridyl group);
R3a is a C6_l4 aryl group (in particular, a phenyl group) optionally substituted with 1 or 2 C1_6 alkyl (for example, methyl) or Cl_6 alkoxy groups (for example, methoxy) ;
Xa is a sulfur atom;
30 Ya is 0, NH or S;
Za is a bond or a C1-6 alkylene group optionally having oxo (in particular, a C1-3 alkylene group, such as methylene, ethylene and the like).

(D) Compound (II) prepared in Reference Examples D 1-79.
(E) [4-(3,5-dimethylphenyl)-5-(2-phenylmethyloxy-4-pyridyl)-1,3-thiazol-2-yl]amine (Reference Example D Compound No. 1), N-[4-[2-benzoylamino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (Reference Example D Compound No. 2), N-[4-(4-methoxyphenyl)-5-[2-[(3-pyridylcarbonylamino)]-4-pyridyl]-1,3-thiazol-2-yl]nicotinamide (Reference Example D
Compound No . 3 ) , N-[4-[2-amino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]-2-lo pyridyl]benzamide (Reference Example D Compound No. 4), N-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (Reference Example D Compound No. 5), N-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzylamine (Reference Example D Compound No. 6), i5 N-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide hydrochloride (Reference Example D Compound No. 7) , N-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzylamine dihydrochloride (Reference Example D
2o Compound No . 8 ) .
(F) N- [5- [2-benzoylamino-4-pyridyl) -4- (3, 5-dimethylphenyl) -1,3-thiazol-2-yl]acetamide (Reference Example D Compound No.
9) .
N-[5-(2-benzylamino-4-pyridyl)-4-(3,5-dimethylphenyl)-1,3-2s thiazol-2-yl]acetamide (Reference Example D Compound No. 10), N-[4-[4-(4-methoxyphenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide (Reference Example D Compound No. 13), N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide (Reference Example D Compound No:
30 14 ) , N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide (Reference Example D Compound No. 15-2) , N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide (Reference Example D Compound No. 15-3) , N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-s pyridyl]phenylacetamide (Reference Example D Compound No. 15-4) , N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide (Reference Example D Compound No.
15-6 ) , io N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (Reference Example D Compound No. 16-1), N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide (Reference Example D Compound No. 16-2), N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-is 3-(4-methoxyphenyl)propionamide (Reference Example D Compound No. 16-3), N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-4-phenylbutyramide (Reference Example D Compound No. 16-5), N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-2o pyridyl]benzamide (Reference Example D Compound No. 16-7), N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide (Reference Example D Compound No.
16-8 ) , N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-2s pyridyl]benzamide (Reference Example D Compound No. 16-9), N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide (Reference Example D Compound No. 16-10), N- [4- [2- (4-fluorophenyl) -4- (3-methylphenyl) -1, 3-thiazol-5-yl] -2-pyridyl]benzamide (Reference Example D Compound No. 16-11), 3o N- [4- [2- (4-fluorophenyl) -4- (3-methylphenyl) -1, 3-thiazol-5-yl] -2-pyridyl]-3-phenylpropionamide (Reference Example D Compound No. 16-12), N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (Reference Example D Compound No. 16-15) , N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide (Reference Example D
s Compound No. 16-16), N-benzyl-N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine (Reference Example D Compound No. 19-2), N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N- (2-phenylethyl) amine (Reference Example D Compound No. 19-3) , to N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine (Reference Example D Compound No. 19-4) , N-benzyl-N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]amine (Reference Example D Compound No. 19-5), is N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine (Reference Example D Compound No . 19-6 ) , N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine (Reference Example D Compound zo No . 19-7 ) , N-benzyl-N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine (Reference Example D Compound No. 19-8), N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine (Reference Example D Compound No. 19-9), 2s N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine (Reference Example D Compound No. 19-10) , N-benzyl-N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine (Reference Example D Compound No.
30 1g-17 ) .
N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine (Reference Example D
Compound No. 19-18), N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine (Reference Example D
Compound No. 19-19), N- [4- [4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) -l, 3-s thiazol-5-yl]-2-pyridyl]benzamide (Reference Example D
Compound No. 20), N- [ 4- [ 4- ( 3-methylphenyl ) -2- ( 4-methylsu if onylphenyl ) -1, 3-thiazol-5-yl]-2-pyridyl]phenylacetamide (Reference Example D
Compound No. 21-1), i o N- [ 4- [ 4- ( 3-methylphenyl ) -2- ( 4-methylsulf onylphenyl ) -1, 3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide (Reference Example D Compound No. 21-2), N-benzyl-N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine (Reference Example D
is Compound No. 21-5), N- [4- [4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) -1, 3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine (Reference Example D Compound No. 21-6), N- [4- [4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) -1, 3-2o thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine (Reference Example D Compound No. 25-1), N- ( 4-f luorobenzyl ) -N- [ 4- [ 4- ( 3-methylphenyl ) -2- ( 4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine (Reference Example D Compound No. 25-2).
2s As a salt of Compound (II), for example, there are a metal salt, ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with basic or acidic amino acid and the like. As a suitable metal salt, there are alkali metal salts such as sodium salt, 3o potassium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt, barium salt and the like;
aluminum salt and the like. As a suitable example of a salt with an organic base, for example, there are salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine and the like. As a suitable example of a salt with an inorganic acid, for example, there are salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. As a suitable example of a salt with an organic acid, for example, there are salts with formic acid, acetic acid, trifluoroacetic acid, io phthalic acid, fumaric acid, oxalic acid, tartaric acid, malefic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. As a suitable example of a salt with a basic amino acid, for example, there are salts with arginine, is lysine, ornithine and the like. As a suitable example of a salt with an acidic amino acid, for example, there are salts with aspartic acid, glutamic acid and the like.
Among them, pharmaceutically acceptable salts are preferable. For example, when a compound has an acidic 2o functional group therein, there are inorganic salts such as alkali metal salts (for example, sodium salt, potassium salt and the like), alkaline earth metal salts (for example, calcium salt, magnesium salt, barium salt and the like), ammonium salts and the like and, when a compound has a basic 2s functional group therein, there are salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, and salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, malefic acid, citric acid, succinic 3o acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
The compound (II) and a salt thereof can be produced according to the method described in WO00/64894.

In the above-mentioned formulas, Rla, R2a, R3a, Xa, Ya and Za are each correspond to Rl, R2, R3, X, Y and Z, described in WO00/64894.
[Compound (III)) A compound represented by the formula /R5b b N' \ Zb a~
R3b R2b wherein a is N or C;
b is CH when a is N, or O when a is C;
_ denotes a single or a double bond dependent upon whether the azole ring is an imidazole or an oxazole ring;
Zb is N or CH;
Wb 1 S -NR6b-Yb- , -O- or -S- , i5 where R6b is a hydrogen atom, Cl_4 alkyl group, C3_g cycloalkyl group, C3-8 cycloalkyl-C1_3 alkyl group, C6_lB
aryl group, C3-lg heteroaryl group, C~_19 aralkyl group or Cq-1g heteroaralkyl group, and -Yb- is C1_q alkylene group or a bond;
2° R2b 1S phenyl group, optionally substituted by one or more substituents selected from a halogen atom, trifluoromethyl, cyano, amido, thioamido, carboxylate, thiocarboxylate, C1_q alkoxy, Cl_4 alkyl, amino, and mono-or di-Cl-4 alkylamino;
2s R3b is a hydrogen atom, a halogen atom, C1_lo alkyl group, C2_9 alkenyl group, C3-to cycloalkyl group, C3_18 heterocycloalkyl group, C6_1$ aryl group, C3_1$ heteroaryl group or -CH=N-NH-C (NH) NHZ (wherein Cl-to alkyl group, C2_4 alkenyl group, C3_lo cycloalkyl group, C3-is heterocycloalkyl group, C6_18 aryl group, C3_18 heteroaryl group and -CH=N-NH-C(NH)NHZ are each optionally substituted by 1 to 4 substituents selected from C1_4 alkyl optionally substituted by hydroxy, halogen atom, halo-substituted-Cl_4 alkyl, hydroxy, Cl_4 alkoxy, Cl_4 alkylthio, carboxy, carbonyl optionally substituted by Cl_6 alkyl or Cl_6 alkoxy, amino, mono- or di-Cl_4 alkylamino and 5 to 7 membered N-heterocyclic group io optionally further containing heteroatom(s));
Rsb is C6_18 aryl group, C3_1$ heteroaryl group or C3_lz cycloalkyl group each of which is optionally substituted by 1 to 4 substituents selected from C1_9 alkyl, halogen, halo-substitued-C1_4 alkyl, hydroxy, Cl_4 alkoxy, Cl_4 15 alkylthio, amino, mono- or di-C1_4 alkylamino and 5 to 7 membered N-heterocyclic group optionally further containing heteroatom(s), or a salt thereof.
The compound (III) and a salt thereof can be produced according to WO00/63204, and specifically, the compounds Zo produced in Examples can be used.
In the above-mentioned formulas, RZb, Rsb. Rsb. Rsb, Zb and Wb respectively correspond to RZ, R3, Rs, R6, Z and W described in WO00/63204, pages 1-2.
25 [compound (IV) , (V) and (VI) ]
[1] A 1,3-thiazole compound (IV) of which 5-position is substituted with a 4-pyridyl group having a substituent including no aromatic group, or a salt thereof;
[2] A compound as defined in [1] which is a compound 3o represented by the formula:
R~
S
~~R1c (IVa) R N

wherein R1° represents a hydrogen atom, a hydrocarbon group optionally having a substituent, a heterocyclic group optionally having a substituent, an amino group optionally having a substituent or an acyl group, R2° represents a 4-pyridyl group having a substituent including no aromatic group, and R3° represents an aromatic group optionally having a substituent, or a salt thereof;
[3] A 1,3-thiazole compound (V) of which 5-position is substituted with a pyridyl group having a substituent to including no aromatic group, at a position adjacent to a nitrogen atom of the pyridyl group, or a salt thereof;
[4) A compound represented by the formula:
Ft2d S
/~R~d (va) N
wherein Rld represents a hydrogen atom, a hydrocarbon group i5 optionally having a substituent, a heterocyclic group optionally having a substituent, an amino group optionally having a substituent or an acyl group, RZd represents a pyridyl group having a substituent including no aromatic group, at a position adjacent to a nitrogen atom of the 2o pyridyl group, and R3d represents an aromatic group optionally having a substituent, or a salt thereof;
[5] A 1,3-thiazole compound (VI) of which 5-position is substituted with a 4-pyridyl group having a substituent including no aromatic group, at a position adjacent to a 25 nitrogen atom of the 4-pyridyl group, or a salt thereof;
[6] A compound as defined in any one of [1) to [5]
wherein the substituent including no aromatic group is a halogen atom, C1_3 alkylenedioxy, nitro, cyano, C1_6 alkyl which may be halogenated, C2_6 alkenyl which may be 3o halogenated, carboxy CZ_6 alkenyl, C2_6 alkynyl which may be halogenated, C3-g cycloalkyl which may be halogenated, C3_$

cycloalkyl-G1_s alkyl, C1_B alkoxy which may be halogenated, C1_s alkoxy-carbonyl-C1_s alkoxy, hydroxy, mercapto, C1_s alkylthio which may be halogenated, amino, mono-C1_s alkylamino, di-C1_s alkylamino, C3_e cycloalkylamino, C3_$
cycloalkyl-C1_s alkylamino, N-C3_e cycloalkyl-N-C1_s alkylamino, formyl, carboxy, carboxy-C2_s alkenyl, carboxy-C1_s alkyl, C1_s alkyl-carbonyl which may be halogenated, C3_8 cycloalkyl-carbonyl optionally substituted by C1_s alkyl, C1_s alkoxy-carbonyl, carbamoyl, thiocarbamoyl, mono-C1_s alkyl-carbamoyl, io di-C1_s alkyl-carbamoyl, C1_s alkylsulfonyl, C1_s alkylsulfinyl, formylamino, C1_s alkyl-carbonylamino, C3_B cycloalkyl-carbonylamino which may be substituted by C1_s alkyl, C1-s alkoxy-carbonylamino, C1_s alkylsulfonylamino, C1_s alkyl-carbonyloxy, C1_s alkoxy-carbonyloxy, mono-C1_s alkyl-15 carbamoyloxy, di-C1_s alkyl-carbamoyloxy, 5- to 7-membered aliphatic heterocyclic group containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms (this aliphatic heterocyclic group optionally has a substituent 2o selected from C1_s alkyl, C1_s alkyl-carbonyl and oxo) , sulfo, sulfamoyl, sulfinamoyl, sulfenamoyl or a group obtained by connecting 2 to 3 of these substituents (e.g. , (i) C1_s alkyl, (ii) amino, (iii) C1_s alkylamino, (iv) C3_$ cycloalkylamino, (v) 5- to 7-membered aliphatic 25 heterocyclic amino containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, (vi) C1_6 alkyl-carbonyl amino, (vii) C3_8 cycloalkyl-carbonylamino or (viii) 5- to 7-membered aliphatic heterocyclic-carbonyl amino so containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, which is substituted, respectively, by a substituent selected from the group consisting of a halogen atom, cyano, hydroxy, C1_s alkoxy, C1_s alkylthio, C1_s alkylsulfinyl, C1_s alkylsulfonyl, C3_8 cycloalkyl, 5- to 7-membered aliphatic heterocyclic group containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, C1_s alkyl-carbonyl, 5- to 7-membered aliphatic heterocyclic-carbonyl containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, C3_$ cycloalkoxy, 5- to 7-io membered aliphatic heterocyclic-oxy containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, C1_s alkylamino, C1_s alkoxy-carbonyl, C3_8 cycloalkoxy-carbonyl, 5- to 7-membered aliphatic heterocyclic-oxycarbonyl 15 containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, etc.);
[7] A compound as defined in [2] or [4] wherein (1) the hydrocarbon group optionally having a 2o substituent is a Cl_s alkyl group, a C2_s alkenyl group, a CZ_s alkynyl group, a C3_B cycloalkyl group, a Cs_14 aryl group or a C7_ls aralkyl group, optionally having a substituent selected from Group A of substituents consisting of oxo, a halogen atom, C1_3 alkylenedioxy, nitro, cyano, Cl_s alkyl which may be ZS halogenated, C2_s alkenyl which may be halogenated, carboxy C2_s alkenyl, CZ_s alkynyl which may be halogenated, C3_g cycloalkyl which may be halogenated, C3_e cycloalkyl-C1_s alkyl, Cs_14 aryl, C1_a alkoxy which may be halogenated, C1_s alkoxy-carbonyl-C1_s alkoxy, hydroxy, Cs_14 aryloxy, C~_ls aralkyloxy, so mercapto, C1_s alkylthio which may be halogenated, Cs-i4 arylthio, C~_ls aralkylthio, amino, mono-C1_s alkylamino, mono-Cs-i4 arylamino, di-C1_s alkylamino, C3_$ cycloalkylamino, di-Cs_ is arylamino, C3_$ cycloalkyl-C1_s alkylamino, N-C3-$

cycloalkyl-N-C1_6 alkylamino, formyl, carboxy, C1_6 alkyl-carbonyl which may be halogenated, C3_8 cycloalkyl-carbonyl optionally substituted by Cl_6 alkyl, C1_6 alkoxy-carbonyl, C6_ 14 aryl-carbonyl, C~_16 aralkyl-carbonyl, C6_14 aryloxy-carbonyl, C~-is aralkyloxy-carbonyl, 5- to 7-membered heterocyclic carbonyl containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, carbamoyl, thiocarbamoyl, mono-C1_6 alkyl-carbamoyl , di-C1_6 alkyl-carbamoyl , mono-C6-is io aryl-carbamoyl, di-C6_la aryl-carbamoyl, 5- to 7-membered heterocyclic carbamoyl containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, C1_6 alkylsulfonyl, C6_1q arylsulfonyl, C1_6 alkylsulfinyl, C6_14 arylsulfinyl, Is formylamino, C1_6 alkyl-carbonylamino, C3_$ cycloalkyl-carbonylamino optionally substituted by C1_6 alkyl , C6_14 aryl-carbonylamino, C1_6 alkoxy-carbonylamino, C1-s alkylsulfonylamino, C6_14 arylsulfonylamino, C1_6 alkyl-carbonyloxy, C6-is aryl-carbonyloxy, C1_6 alkoxy-carbonyloxy, 2o mono-C1_6 alkyl-carbamoyloxy, di-C1_6 alkyl-carbamoyloxy, mono-Cs-14 aryl-carbamoyloxy, di-C6_14 aryl-carbamoyloxy, nicotinoyloxy, isonicotinoyloxy, 5- to 10-membered heterocyclic group containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and 2s an oxygen atom in addition to carbon atoms (this heterocyclic group optionally has a substituent selected from C1_6 alkyl, C6_14 aryl, C1_6 alkyl-carbonyl which may be halogenated, 5- to 10-membered aromatic heterocyclic group containing 1 to 4 of l or 2 kinds of hetero atoms selected from a nitrogen atom, a so sulfur atom and an oxygen atom in addition to carbon atoms and oxo), sulfo, sulfamoyl, sulfinamoyl, sulfenamoyl and a group formed by connecting 2 to 3 of these substituents (e. g., (i) C1_6 alkyl, (ii) C6_14 aryl, (iii) amino, (iv) C1-s alkylamino, (v) C3_B cycloalkylamino, (vi) C6-is arylamino, (vii) 5- to 7-membered heterocyclic amino containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, (viii) C1-6 alkyl-carbonylamino, (ix) C3_$ cycloalkyl-carbonylamino, (x) C6_14 aryl-carbonyl amino or (xi) 5- to 7-membered heterocyclic-carbonyl amino containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, Io which is substituted, respectively, by a substituent selected from the group consistirig of a halogen atom, cyano, hydroxy, C1-6 alkoxy, C6-i4 aryloxy, C1_6 alkylthio, C6_19 arylthio, C1-s alkylsulfinyl, C6_14 arylsulfinyl, C1-6 alkylsulfonyl, C6-la arylsulfonyl, C3_g cycloalkyl, 5- to 7-membered heterocyclic I5 group containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, C6_1Q aryl, C1-6 alkyl-carbonyl, 5- to 7-membered heterocyclic-carbonyl containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen 2o atom, a sulfur atom and an oxygen atom in addition to carbon atoms, C6_19 aryl-carbonyl, C3_$ cycloalkoxy, 5- to 7-membered heterocyclic-oxy containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, C1_6 alkylamino, C6-19 25 arylamino, C,__6 alkoxy-carbonyl, 5- to 7-membered heterocyclic-oxycarbonyl containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, C6-is aryloxycarbonyl, etc.) 30 (2) the heterocyclic group optionally having a substituent is a 5- to 14-membered heterocyclic group containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, which optionally has a substituent selected from Group A of substituents, (3) the acyl group is an acyl group of the formula: -( C-O ) -R5~ ~ - ( C=O ) -ORSc ~ - ( C=O ) -NRs~Rs~ ~ - ( C=S ) _NHRS°
, - ( C=0 ) _ s N (ORS) Rs~, _ (C=S) -NHORS° or -SOZ-R'° (wherein R5~
represents ( 1 ) a hydrogen atom, ( 2 ) a C1_6 alkyl group, a CZ_6 alkenyl group, a CZ_6 alkynyl group, a C3_8 cycloalkyl group, a C6-14 aryl group or a C~_16 aralkyl group, optionally having a substituent selected from Group A of substituents, or (3) a l0 5- to 14-membered heterocyclic group containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, which optionally has a substituent selected from Group A of substituents, R6° represents a hydrogen atom or a C1-6 alkyl is group, and R'° represents (1) a C1_6 alkyl group, a CZ_s alkenyl group, a CZ_6 alkynyl group, a C3-8 cycloalkyl group, a C6_19 aryl group or a C~-16 aralkyl group, optionally having a substituent selected from Group A of substituents, or (2) a 5- to 14-membered heterocyclic group containing 1 to 4 of 1 20 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, which optionally has a substituent selected from Group A of substituents), (4) the amino group optionally having a substituent is 2s (i) an amino group optionally having 1 or 2 substituents selected from the group consisting of (1) a C1-s alkyl group, a CZ_6 alkenyl group, a CZ_6 alkynyl group, a C3_$
cycloalkyl group, a C6-is aryl group and a C~_16 aralkyl group, optionally having a substituent selected from Group A of 3o substituents, (2) a 5- to 14-membered heterocyclic group containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, which optionally have a substituent selected from Group A of substituents, (3) an acyl group of the formula: - (C=O) -RS~, - (C=O) -ORS, - (C=0) -NRS~Rs°, - (C=S) -NHRS°, - (C=O) -N (ORS) Rs~, - (C=S) -NHOR5~ or -S02-R'°
(wherein each symbol is as defined above) , and (4) a C1_6 alkylidene group optionally having a substituent selected from Group A
of substituents, or (ii) a 5- to 7-membered non-aromatic cyclic amino group optionally containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen to atom in addition to one nitrogen atom and carbon atoms, which optionally has a substituent selected from the group consisting of C1-6 alkyl, C6_14 aryl, C1_6 alkyl-carbonyl which may be halogenated, C1_6 alkoxy-carbonyl, 5- to 10-membered aromatic heterocyclic group containing 1 to 4 of 1 or 2 kinds 15 of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, and oxo, (5) the substituent containing no aromatic group is a halogen atom, C1-3 alkylenedioxy, nitro, cyano, C1_6 alkyl which may be halogenated, CZ-6 alkenyl which may be 2o halogenated, carboxy C2_6 alkenyl, C2-6 alkynyl which may be halogenated, C3_a cycloalkyl which may be halogenated, C3_g cycloalkyl-C1-6 alkyl, C1_$ alkoxy which may be halogenated, C1-6 alkoxy-carbonyl-C1_6 alkoxy, hydroxy, mercapto, C1-s alkylthio which may be halogenated, amino, mono-C1_s 2s alkylamino, di-C,_-6 alkylamino, C3_$ cycloalkylamino, C3_8 cycloalkyl-C1-6 alkylamino, N-C3_$ cycloalkyl-N-C1_6 alkylamino, formyl, carboxy, carboxy-CZ_6 alkenyl, carboxy-C1_6 alkyl, C1_s alkyl-carbonyl which may be halogenated, C3_8 cycloalkyl-carbonyl optionally substituted by C1_6 alkyl, C1-6 alkoxy-so carbonyl, carbamoyl, thiocarbamoyl, mono-C1_6 alkyl-carbamoyl, di-Cl_6 alkyl-carbamoyl, C1_6 alkylsulfonyl, C1-6 alkylsulfinyl, formylamino, C1-6 alkyl-carbonylamino, C3_$ cycloalkyl-carbonylamino which may be substituted by C1_6 alkyl, C1_s alkoxy-carbonylamino, C1_s alkylsulfonylamino, C1_s alkyl-carbonyloxy, C1_s alkoxy-carbonyloxy, mono-C1-s alkylcarbamoyloxy, di-C1_s alkyl-carbamoyloxy, 5- to 7-membered aliphatic heterocyclic group containing 1 to 4 of 1 s or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms (this aliphatic heterocyclic group optionally has a substituent selected from C1_s alkyl, C1_s alkyl-carbonyl and oxo), sulfo, sulfamoyl, sulfinamoyl, sulfenamoyl or a group so obtained by connecting 2 to 3 of these substituents (e. g., (i) C1_s alkyl, (ii) amino, (iii) C1_s alkylamino, (iv) C3_e cycloalkylamino, (v) 5- to 7-membered aliphatic heterocyclic amino containing 1 to 4 of 1 or 2 kinds of he'tero atoms selected from a nitrogen atom, a sulfur atom and an oxygen is atom in addition to carbon atoms, (vi) Cl_s alkyl-carbonyl amino, (vii) C3-a cycloalkyl-carbonylamino or (viii) 5- to 7-membered aliphatic heterocyclic-carbonyl amino containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, which is substituted, respectively, by a substituent selected from the group consisting of a halogen atom, cyano, hydroxy, Cl_s alkoxy, C1_s alkylthio, C1_s alkylsulfinyl, C1_s alkylsulfonyl, C3-8 cycloalkyl, 5- to 7-membered aliphatic heterocyclic group containing 1 to 4 of 1 or 2 kinds of 2s hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, C1_s alkyl-carbonyl, 5- to 7-membered aliphatic heterocyclic-carbonyl containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in 3o addition to carbon atoms, C3_B cycloalkoxy, 5- to 7-membered aliphatic heterocyclic-oxy containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, C1_s alkylamino, C1_6 alkoxy-carbonyl, C3_$ cycloalkoxy-carbonyl, 5-to 7-membered aliphatic heterocyclic-oxycarbonyl containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon s atoms, etc.), (6) the aromatic group optionally having a substituent is 1) a C6-14 mono-cyclic or fused poly-cyclic aromatic hydrocarbon group optionally having a substituent selected from Group A of substituents, or 2) a 5- to 14-membered to aromatic heterocyclic group containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms;
[8] A compound as defined in j2] or [4] wherein R1°
represents (i) a hydrogen atom, (ii) a Cl_6 alkyl group is optionally substituted by a substituent selected from the group consisting of a halogen atom, C1_6 alkoxy-carbonyl, carboxy, cyano, C1-6 alkylthio, C1_6 alkylsulfinyl, Cl_s alkylsulfonyl, hydroxy, C1-6 alkoxy and C1_6 alkyl-carbonyl, (iii) a C6-is aryl group optionally having a substituent 2o selected from the group consisting of a halogen atom and a group of the formula: -S (C)n-Rlf (wherein Ref represents a C1-s alkyl group, and n represents an integer of 0 to 2), (iv) a C~_15 aralkyl group, (v) an amino group optionally having one or two substituents selected from 1) C1_6 alkyl, 2) C1_6 alkyl-2s carbonyl, 3) 5- to 7-membered heterocyclic-carbonyl containing 1 to 4 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, in addition to carbon atoms, optionally substituted with a halogen atom, CI_6 alkyl or C1_~ alkoxy, 4) C6_z4 aryl-so carbamoyl, 5) C1_6 alkyl-carbamoyl which may be halogenated, 6) C1_6 alkoxy-carbonyl which may be halogenated, 7) C1-s alkoxy-carbamoyl and 8) C6_19 aryloxy-carbamoyl, (vi) a 5- to 10-membered heterocyclic group containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, optionally substituted by oxo, C1_6 alkyl, C6_14 aryl or Cl_s alkoxy-carbonyl, (vii) an acyl group represented by the s formula: - (C=O) -R5d~ (wherein RSd~ represents a hydrogen atom, a C1_6 alkyl group which may be halogenated or a C6_14 aryl group which may be halogenated), or (viii) an acyl group represented by the formula: - (C=0) -ORsd~ (wherein Rsa-represents a hydrogen atom or a C1_6 alkyl group);
to [g] A compound as defined in [2] or [4] wherein the substituent having no aromatic group is (1) a Cl_6 alkyl group (this C1_6 alkyl may be substituted by a halogen atom, cyano, hydroxy, C3_8 cycloalkyl or 5- to 7-membered aliphatic heterocyclic group containing 1 Is to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms), (2) a halogen atom, (3) an amino group optionally having a substituent selected from the group consisting of the following 1) to 7);
20 1) a C1_6 alkyl group (this C1_6 alkyl group may be substituted by a halogen atom, cyano, hydroxy, C3_e cycloalkyl or 5- to 7-membered aliphatic heterocyclic group having 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms), zs 2) a C3_e cycloalkyl group, 3) a C1_6 alkyl-carbonyl group (this C1_6 alkyl-carbonyl group may be substituted by a halogen atom, cyano, hydroxy, C3_a cycloalkyl or 5- to 7-membered aliphatic heterocyclic group having 1 to 4 hetero atoms selected from a nitrogen 3o atom, an oxygen atom and a sulfur atom in addition to carbon atoms ) , 4 ) a Cl-6 alkoxy-carbonyl group, 5) a C3_$ cycloalkyl-carbonyl group optionally substituted by C1_s alkyl , 6) a S- to 7-membered saturated heterocyclic group having 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms (this saturated heterocyclic group may be substituted by C1-s alkyl or C1_s alkyl-carbonyl) , 7) a 5- to 7-membered saturated heterocyclic-carbonyl group having 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon to atoms (this saturated heterocyclic-carbonyl group may be substituted by C1_s alkyl or C1_s alkyl-carbonyl) (4) a 5- to 7-membered saturated cyclic amino group optionally further containing 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in I5 addition to carbon atoms and one nitrogen atom (this saturated cyclic amino group may be substituted by C1_s alkyl or C1-s alkyl-carbonyl) , (5) a hydroxy group, or (&) a Cl_s alkyl-carbonyloxy group.
20 [10] A compound as defined in [2] or (4] wherein R3 is (1) a Cs-i4 aryl group or (2) a 5- to 14-membered aromatic heterocyclic group preferably containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, which 25 optionally has substituents selected from the group consisting of C~-s alkyl which may be halogenated, C1-s alkoxy, a halogen atom, carboxyl, C1_s alkoxy-carbonyl, cyano, C1-s alkylthio and C1_s alkylsulfonyl;
[11] A compound as defined in [3] which is a compound 30 of the formula:
Rze S
/~"-R1e (VIa) wherein Rle represents ( i ) a hydrogen atom, ( i i ) a C1_s alkyl group optionally substituted by a substituent selected from the group consisting of a halogen atom, C1_s alkoxy-carbonyl, carboxy, cyano, C1_s alkylthio, C1_s alkylsulfinyl, C1-s alkylsulfonyl, hydroxy, C1_s alkoxy and C1_s alkyl-carbonyl, (iii) a Cs_14 aryl group optionally having a substituent selected from the group consisting of a halogen atom and a group of the formula: -S (O) n-Rlf (Rif represents a C1_s alkyl group, and n represents an integer of 0 to 2) , (iv) a C~_ls to aralkyl group, (v) an amino group optionally having one or two substituents selected from 1) C1_s alkyl, 2) Cl_s alkyl-carbonyl, 3) C1_s alkoxy-carbonyl, 4) 5- to 7-membered heterocyclic-carbonyl containing 1 to 4 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom 15 and a sulfur atom in addition to carbon atoms, optionally substituted with a halogen atom, C1_s alkyl or C1_s alkoxy, 5) Cs_19 aryl-carbamoyl, 6) C1_s alkyl-carbamoyl which may be halogenated, 7) Cz_s alkoxy-carbonyl which may be halogenated, 8 ) C1_s alkoxy-carbamoyl and 9 ) Cs_14 aryloxy-carbamoyl , (vi ) a 20 5- to 10-membered heterocyclic group containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, optionally substituted by oxo, C1_s alkyl, Cs_14 aryl, C1_s alkyl-carbonyl or C~_s alkoxy-carbonyl, (vii) an acyl group 2s represented by the formula: - (C=O) -R5d~ (wherein Rsa~
represents a hydrogen atom, a C1_s alkyl group which may be halogenated or a Cs_14 aryl group which may be halogenated), or (viii) an acyl group represented by the formula: -(C=O)-ORSd~ (wherein Rsd~ represents a hydrogen atom or C1_s alkyl 3o group ) , RZe represents a pyridyl group (preferably 4-pyridyl group which may be N-oxidized) having, at the position adjacent to a nitrogen atom of the pyridyl group, a substituent selected from the group consisting of (1) a Cl_6 alkyl group (this C1_6 alkyl group may be substituted by a halogen atom, cyano, hydroxy, C3_g cycloalkyl or a 5- to 7-membered aliphatic heterocyclic group containing hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms), ( 2 ) a halogen atom, (3) an amino group optionally having a substituent selected from the group consisting of the following 1) to 7);
io 1) a C1_6 alkyl group (this C1_6 alkyl group may be substituted by a halogen atom, cyano, hydroxy, C3_$ cycloalkyl or a 5- to 7-membered aliphatic heterocyclic group having 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms), is 2) a C3_e cycloalkyl group, 3) a C1_6 alkyl-carbonyl group (this C1_6 alkyl-carbonyl group may be substituted by a halogen atom, cyano, hydroxy, C3_$ cycloalkyl or a 5- to 7-membered aliphatic heterocyclic group having 1 to 4 hetero atoms selected from a nitrogen 2o atom, an oxygen atom and a sulfur atom in addition to carbon atoms ) , 4) a C1_6 alkoxy-carbonyl group, 5) a C3_8 cycloalkyl-carbonyl group optionally substituted by C1_6 alkyl, -25 6) a 5- to 7-membered aliphatic heterocyclic group having 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms (this aliphatic heterocyclic group may be substituted by C1_s alkyl or C1_6 alkyl-carbonyl) , so 7) a 5- to 7-membered aliphatic heterocyclic-carbonyl group having 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms (this aliphatic heterocyclic-carbonyl group may be substituted by C1_s alkyl or C1_s alkyl-carbonyl) , (4) a 5- to 7-membered saturated cyclic amino group optionally further containing 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms and one nitrogen atom (this saturated cyclic amino group may be substituted by C1_s alkyl or C1_s alkyl-carbonyl) , (5) a hydroxy group, and (6) a C1_s alkyl-carbonyloxy group, particularly from to the group consisting of (1) to (4) above, and R3e represents ( 1 ) a Cs_19 aryl group or ( 2 ) a 5- to 14-membered aromatic heterocyclic group containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, is which optionally has a substituent selected from the group consisting of C1-s alkyl which may be halogenated, C1_s alkoxy, a halogen atom, carboxyl, C1_s alkoxy-carbonyl, cyano, C1_s alkylthio and C1_s alkylsulfonyl, or a salt thereof;
[12] A compound as defined in [11] wherein the pyridyl Zo group is a 4-pyridyl group;
[13] A compound as defined in [11] wherein Rle is a C1_s alkyl group optionally having a substituent selected from the group consisting of a halogen atom, hydroxy, C1_s alkoxy, C1_s alkylthio, C1_s alkylsulfinyl and C1_s alkylsulfonyl, RZe is a 2s 4-pyridyl group having a C,__s alkyl-carbonyl-amino group or a C3-8 cycloalkylamino group at the position adjacent to a nitrogen atom of the 4-pyridyl group, R3e is a Cs_14 aryl group which optionally has a substituent selected from the group consisting of C1_s alkyl and a halogen atom;
[ 14 ] A compound as def fined in [ 11 ] wherein Rle is a C1_3 alkyl group optionally having a substituent selected from the group consisting of a halogen atom, hydroxy, C1_s alkoxy, C1_s alkylthio, C1_s alkylsulfinyl and C1-s alkylsulfonyl, RZe is a 4-pyridyl group having a C1_3 alkyl-carbonyl-amino group or a C3_e cycloalkylamino group at the position adjacent to a nitrogen atom of the 4-pyridyl group, R3e is a phenyl group which optionally has methyl or a chlorine atom;
[15] A compound as defined in [5] which is 5-[2-(tert-butoxycarbonylamino)-4-pyridyl]-2-ethyl-4-(3-methylphenyl)-1,3-thiazole (Reference Example H 3), [4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]amine (Reference Example H 7-4), io 2-ethyl-5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazole (Reference Example H 11), 5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-2-[4-(methylthio)phenyl]-1,3-thiazole (Reference Example H 15), 4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-2-[4-i5 (methylthio)phenyl]-1,3-thiazole (Reference Example H 16-1), 4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine (Reference Example H 22), N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]acetamide (Reference Example H 29-2), 2o N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-y1]-2-pyridyl]propionamide (Reference Example H 29-4), N-[4-[4-(3-chlorophenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl]acetamide (Reference Example H 30-1), N-[4-[4-(3-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-2-2s pyridyl]acetamide (Reference Example H 30-2), N-[4-[4-(3-chlorophenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]acetamide (Reference Example H 30-3), N-[4-[4-(3-chlorophenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl]propionamide (Reference Example H 30-7), 3o N-[4-[4-(3-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl)-2-pyridyl]propionamide (Reference Example H 30-8), N-[4-[4-(3-chlorophenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]propionamide (Reference Example H 30-9), N-cyclohexyl-4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine (Reference Example H 36-4), N-cyclohexyl-4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine (Reference Example H 36-5), N-cyclopentyl-4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine (Reference Example H 36-6), N-cyclopentyl-4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine io (Reference Example H 36-7), 4-[4-(3-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-N-cyclohexyl-2-pyridylamine (Reference Example H 36-10), 4-[4-(3-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-N-cyclopentyl-2-pyridylamine (Reference Example H 36-11), is N- [ 4- ( 3-methylphenyl ) -5- ( 2-methyl-4-pyridyl ) -1 , 3-thiazol-2-yl]acetamide (Reference Example H 39), N-[4-(3,5-dimethylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]nicotinamide (Reference Example H 42-1), 6-chloro-N-[4-(3,5-dimethylphenyl)-5-(2-methyl-4-2o pyridyl)-1,3-thiazol-2-yl]nicotinamide (Reference Example H
44-3) , N-[4-(3,5-dimethylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]-6-methylnicotinamide (Reference Example H 46-3), N-[4-(3,5-dimethylphenyl)-5-(2-methyl-4-pyridyl)-1,3~-25 thiazol-2-yl]-6-methoxynicotinamide (Reference Example H 48-3) , 4- ( 3-methylphenyl ) -5- ( 2-methyl-4-pyridyl ) -2- ( 4-methylsulfinylphenyl)-1,3-thiazole (Reference Example H 54), 4- (3-methylphenyl) -5- (2-methyl-4-pyridyl) -2- (4-so methylsulfonylphenyl)-1,3-thiazole (Reference Example H 57), 5- (2-fluoro-4-pyridyl) -4- (3-methylphenyl) -2- (4-methylsulfonylphenyl)-1,3-thiazole (Reference Example H 58-4), N-[4-[4-(3-chlorophenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]acetamide (Reference Example H
58-6), N- (4- [4- (3-chlorophenyl) -2- (4-methylsulfonylphenyl) -1,3-thiazol-5-yl]-2-pyridyl]propionamide (Reference Example H
s 58-~ ) .
N-[4-[4-(3-chlorophenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]pivalamide (Reference Example H
58-8) , or a salt thereof;
[16] A pro-drug of a compound as claimed in any one as defined in [1] to [5];
In this specification, as the "acyl group", for example, a acyl group represented by the formula: -(C=O)-RS°, -(C=O)-1s ORS~~ _ (C=p) _NRS~Rsc~ - (C=S) -NHRS°, - (C=O) -N (ORS°) R6~, - (C=S) _ NHORS° or -S02-R'° wherein RS° represents a hydrogen atom, a hydrocarbon group optionally having a substituent or a heterocyclic group optionally having a substituent, R6°
represents a hydrogen atom or a C1-6 alkyl group, and R'°
2o represents a hydrocarbon group optionally having a substituent or a heterocyclic group optionally having a substituent, etc. are exemplified.
In the above-described formulae, as the ~hydrocarbon group" of the ~hydrocarbon group optionally having a 25 substituent" represented by RS°, for example, a chain or cyclic hydrocarbon group (e. g., alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl and the like), etc. are exemplified.
Of them, a chain or cyclic hydrocarbon group having 1 to 16 carbon atoms, etc. are preferable.
so As the ~alkyl", for example, a Ci_6 alkyl group (e. g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl;
tert-butyl, pentyl, hexyl and the like), etc. are preferable.
As the "alkenyl", for example, a C2_6 alkenyl group (e.g., vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl and the like), etc. are preferable.
As the ~alkynyl", for example, a C2_6 alkynyl group (e. g., ethynyl, propargyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-hexynyl and the like), etc. are preferable.
As the ~cycloalkyl", for example, a C3_$ cycloalkyl group (e. g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like), etc. are preferable.
io As the "aryl" , fox example , a C6_14 aryl group (e . g . , phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and the like), etc. are preferable.
As the ~aralkyl", for example, a C~_16 aralkyl group (e. g., ben~yl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 15 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl and the like), etc. are preferable.
As the "substituent" of the "hydrocarbon group optionally having a substituent" represented by R5°, the 2o substituent selected from Group A of substituents consisting of, for example, oxo, a halogen atom (e. g., fluorine, chlorine, bromine, iodine and the like), C1-3 alkylenedioxy (e. g., methylenedioxy, ethylenedioxy and the like), vitro, cyano, C1_6 alkyl which may be halogenated, C2_6 alkenyl which 25 may be halogenated, carboxy C2_6 alkenyl (e.g., 2-carboxyethenyl, 2-carboxy-2-methylethenyl and the like), CZ-s alkynyl which may be halogenated, C3_$ cycloalkyl which may be halogenated, C3_$ cycloalkyl-C1_6 alkyl, C6_14 aryl (e.g. , phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 30 4-biphenylyl, 2-anthryl and the like), C1_$ alkoxy which may be halogenated, C1_6 alkoxy-carbonyl-C1_6 alkoxy (e, g. , ethoxycarbonylmethyloxy and the like), hydroxy, C6_19 aryloxy (e. g., phenyloxy, 1-naphthyloxy, 2-naphthyloxy and the like), C~_ls aralkyloxy (e. g., benzyloxy, phenethyloxy and the like), mercapto, C1_s alkylthio which may be halogenated, Cs_14 arylthio (e. g., phenylthio, 1-naphthylthio, 2-naphthylthio and the like). C~-is aralkylthio (e. g., benzylthio, phenethylthio and the like), amino, mono-C1_s alkylamino (e. g., methylamino, ethylamino and the like), mono-Cs_14 arylamino (e.g., phenylamino, 1-naphthylamino, 2-naphthylamino and the like), di-C1_s alkylamino (e. g., dimethylamino, diethylamino, ethylmethylamino and the like), C3_$ cycloalkylamino (e. g., s~ cyclopentylamino, cyclohexylamino and the like), di-Cs_14 arylamino (e. g., diphenylamino and the like), C3_B cycloalkyl-C1_s alkylamino (e. g., cyclopentylmethylamino, cyclohexylmethylamino, cyclopentylethylamino, cyclohexylethylamino and the like) , N-C3_$ cycloalkyl-N-C1_s z5 alkylamino (N-cyclopentyl-N-methylamino, N-cyclohexyl-N-methylamino, N-cyclopentyl-N-ethylamino, N-cyclohexyl-N-ethylamino and the like), formyl, carboxy, carboxy-C2-s alkenyl, carboxy-C1_s alkyl, Cl_s alkyl-carbonyl which may be halogenated (e. g., acetyl, propionyl, pivaloyl and the like), C3_$ cycloalkyl-carbonyl optionally substituted by Cl_s alkyl such as methyl, ethyl, etc. (e. g., cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, 1-methyl-cyclohexyl-carbonyl and the like), C1_s alkoxy-carbonyl (e. g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-2s butoxycarbonyl and the like), Cs_,4 aryl-carbonyl (e. g., benzoyl, 1-naphthoyl, 2-naphthoyl and the like), C~_ls aralkyl-carbonyl (e.g., phenylacetyl, 3-phenylpropionyl and the like), Cs-is aryloxy-carbonyl (e.g., phenoxycarbonyl and the like), C~_ls aralkyloxy-carbonyl (e. g., benzyloxycarbonyl, so phenethyloxycarbonyl and the like), 5- to 7-membered heterocyclic carbonyl containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms (e. g., nicotinoyl, isonicotinoyl, thenoyl, furoyl, morpholinocarbonyl, thiomorpholinocarbonyl, piperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl and the like), carbamoyl, thiocarbamoyl, mono-C1_s alkyl-carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, and the like), di-C1-6 alkyl-carbamoyl (e. g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl and the like), mono-or di-C6_14 aryl-carbamoyl (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl and the like), mono-or di- 5- to 7-membered heterocyclic carbamoyl containing 1 io to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms (e.g., 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl and the like) , C1_6 alkylsulfonyl (e.g. , methylsulfonyl, i5 ethylsulfonyl and the like) , C1_6 alkylsulfinyl (e. g. , methylsulfinyl, ethylsulfinyl and the like), C6_ia arylsulfonyl (e.g., phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl and the like) , C6-i4 arylsulfinyl (e.g. , phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl and 2° the like) , formylamino, C1_6 alkyl-carbonylamino (e. g. , acetylamino, propionylamino, pivaloylamino and the like), C3-$
cycloalkyl-carbonylamino optionally substituted by C1-6 alkyl (e. g., cyclopropylcarbonylamino, cyclopentylcarbonylamino, cyclohexylcarbonylamino and the like), C6-14 aryl-2s carbonylamino (e.g., benzoylamino, naphthoylamino and the like), C1_6 alkoxy-carbonylamino (e. g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino and the like), C1_6 alkylsulfonylamino (e. g., methylsulfonylamino, ethylsulfonylamino and the like), 3o Cs-14 arylsulfonylamino (e.g., phenylsulfonylamino, 2-naphthylsulfonylamino, 1-naphthylsulfonylamino and the like), C1_6 alkyl-carbonyloxy (e.g., acetoxy, propionyloxy and the like) , C6_14 aryl-carbonyloxy (e.g. , benzoyloxy, naphthylcarbonyloxy and the like), C1_s alkoxy-carbonyloxy (e. g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy and the like), mono-C1-s alkyl-carbamoyloxy (e. g., methylcarbamoyloxy, ethylcarbamoyloxy and the like), di-C1_s alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy, diethylcarbamoyloxy and the like), mono- or di-Cs_14 aryl-carbamoyloxy (e. g., phenylcarbamoyloxy, naphthylcarbamoyloxy and the like), nicotinoyloxy, isonicotinoyloxy, 5- to 10-membered io heterocyclic group containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, which may have a substituent (e. g. 5- to 7-membered aliphatic heterocyclic group, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo(b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl and the like) optionally having a substituent, 2o sulfo, sulfamoyl, sulfinamoyl, sulfenamoyl, a group obtained by connecting two or more (e. g., 2 to 3) of these substituents (e. g. , (i) C1_s alkyl, (ii) Cs-19 aryl, (iii) amino, (iv) C1_s alkylamino, (v) C3-$ cycloalkylamino, (vi) Cs-ia arylamino, (vii) 5- to 7-membered heterocyclic amino containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, (viii) C1_s alkyl-carbonyl amino, (ix) C3-a cycloalkyl-carbonylamino, (x) Cs_14 aryl-carbonylamino or (xi) 5- to 7-membered heterocyclic-carbonyl so amino containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, which is optionally substituted, respectively, by a substituent selected from the group consisting of a halogen atom, cyano, hydroxy, C1_s alkoxy, Cs_la aryloxy, C1_s alkylthio, Cs_14 arylthio, C1-s alkylsulfinyl, Cs-14 arylsulfinyl, C1_s alkylsulfonyl, Cs_14 arylsulfonyl, C3_$ cycloalkyl, 5- to 7-membered heterocyclic group containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, Cs-14 aryl, C1_s alkyl-carbonyl, 5- to 7-membered heterocyclic-carbonyl containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen zo atom, a sulfur atom and an oxygen atom in addition to carbon atoms, Cs_19 aryl-carbonyl, C3_8 cycloalkoxy, 5- to 7-membered heterocyclic-oxy containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, C1_s alkylamino, Cs_la is arylamino, C1_s alkoxy-carbonyl, C3_8 cycloalkoxy-carbonyl, 5-to 7-membered heterocyclic-oxycarbonyl containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, Cs_19 aryloxycarbonyl, etc.) and the like, and the like can be Z° mentioned.
The above-mentioned "hydrocarbon group" may have, for example, the 1 to 5, preferably 1 to 3 above-mentioned substituents at substitutable positions, and when the number of the substituent is 2 or more, they may be the same or 25 different.
As the above-mentioned "C1_s alkyl which may be halogenated", for example, C1_s alkyl (e. g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like) which may have 1 to 5, preferably 30 1 to 3 halogen atoms (e. g., fluorine, chlorine, bromine, iodine and the like), etc. are exemplified. As specific examples thereof, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl, etc. are s exemplified.
As the above-mentioned "C2_6 alkenyl which may be halogenated", for example, C2_6 alkenyl (e. g., vinyl, propenyl, isopropenyl, 2-buten-1-yl, 4-penten-1-yl, 5-hexen-1-yl and the like) which may have 1 to 5, preferably 1 to 3 halogen io atoms (e.g., fluorine, chlorine, bromine, iodine and the like), etc. are exemplified.
As the above-mentioned "C2_6 alkynyl which may be halogenated", for example, C2_6 alkynyl (e.g., 2-butyn-1-yl, 4-pentyn-1-yl, 5-hexyn-1-yl and the like) which may have 1 to is 5, preferably 1 to 3 halogen atoms (e. g., fluorine, chlorine, bromine, iodine and the like), etc. are exemplified.
As the above-mentioned "C3_8 cycloalkyl which may be halogenated", for example, C3_B cycloalkyl (e. g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like) which may 2o have 1 to 5, preferably 1 to 3 halogen atoms (e. g., fluorine, chlorine, bromine, iodine and the like), etc. are exemplified.
As specific examples thereof, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dichlorocyclohexyl, 2,2,3,3-tetrafluorocyclopentyl, 4-chlorocyclohexyl, etc. are 2s exemplified.
As the above-mentioned "C1_8 alkoxy which maybe halogenated", for example, C1_$ alkoxy (e. g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like) which may have 1 to 5, preferably 1 to so 3 halogen atoms (e. g., fluorine, chlorine, bromine, iodine and the like), etc. are exemplified. As specific examples thereof, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc. are exemplified.
As the above-mentioned "C1_s alkylthio which may be halogenated", for example, C1_s alkylthio (e. g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio and the like) which may have 1 to 5, preferably 1 to 3 halogen atoms (e. g., fluorine, chlorine, bromine, iodine and the like), etc. are exemplified. As specific examples thereof, methylthio, difluoromethylthio, io trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio, etc. are exemplified.
As the "5- to 7-membered aliphatic heterocyclic group"
of the above-mentioned "5- to 7-membered aliphatic is heterocyclic group optionally having a substituent", for example, 5- to 7-membered aliphatic heterocyclic group containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms are exemplified, and as specific 2o examples thereof, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl, 3-piperazinyl, 4-piperazinyl, morpholino, 2-morpholinyl, 3-morpholinyl, thiomorpholino, 2-thiomorpholinyl, 3-25 thiomorpholinyl, hexahydroazepin-1-yl, etc. are exemplified.
As the "substituent" of the above-mentioned "5- to 7-membered aliphatic heterocyclic group optionally having a substituent", for example, 1 to 3 of C1_s alkyl (e. g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-3o butyl, pentyl, hexyl and the like) , Cs-is aryl (e. g. , phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and the like), C1-s alkyl-carbonyl (e. g., acetyl, propionyl and the like) which may be halogenated, C1-s alkoxy-carbonyl (e. g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl), 5- to 10-membered aromatic heterocyclic group (e.g., 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl and the like), oxo, etc.
are exemplified.
to As the "heterocyclic group" of the "heterocyclic group optionally having a substituent" represented by R5, for example, a 5- to 14-membered (monocyclic, bicyclic or tricyclic) heterocyclic ring which contains 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms are exemplified, preferably, mono-valent groups obtained by removing any one hydrogen atom from (i) a 5- to 14-membered (preferably, 5- to 10-membered) aromatic heterocyclic ring, (ii) a 5- to 10-membered non-aromatic heterocyclic ring or (iii) a 7- to 10-membered bridged heterocyclic ring, etc. are exemplified.
As the above-mentioned "5- to 14-membered (preferably, 5- to 10-membered) aromatic heterocyclic ring", for example, an aromatic heterocyclic ring such as thiophene, benzo[b]thiophene, benzo[b]furan, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, 4H-quinolidine, isoquinoline, quinoline, phthalazine, 3o naphthylidine, quinoxaline, quinazoline, cinnoline, carbazole, ~-carboline, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, isoxazole, furazane, phenoxazine and the like, or rings formed by fusing these rings (preferably, monocyclic ring) with 1 or plural (preferably, 1 or 2) aromatic rings (for example, benzene ring and the like), etc. are exemplified.
As the above-mentioned ~5- to 10-membered non-aromatic s heterocyclic ring", for example, pyrrolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, thiomorpholine, dioxazole, oxadiazoline, thiadiazoline, triazoline, thiadiazole, dithiazole, etc. are exemplified.
As the above-mentioned "7- to 10-membered bridged 1o heterocyclic ring", for example, quinuclidine, 7-azabicyclo [2.2.1) heptane, etc. are exemplified.
The above-mentioned "heterocyclic group" is preferably a 5- to 14-membered (preferably, 5- to 10-membered) (monocyclic or bicyclic) heterocyclic group which contains is preferably 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms. Specifically, an aromatic heterocyclic group such as, for example, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 20 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, pirazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isooxazolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3-2s benzo[b)thienyl, 2-benzo[bJfuranyl, 3-benzo[b]furanyl and the like, and aliphatic heterocyclic groups such as, for example, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 3-oxazolidinyl, 1-imidazolidinyl, 2-imidazolinyl, 4-imidazolinyl, 2-pyrazolidinyl, 3-pyrazolidinyl, 4-so pyrazolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl, morpholino, thiomorpholin0 and the like, etc. are exemplified.
Of them, for example, a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms are further preferable. Specifically, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, pirazinyl, 2-pyrimidinyl, 3-pyrrolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isooxazolyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 3-oxazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 2-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidyl, 3-1o piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl, morpholino, thiomorpholino, etc. are exemplified.
As the ~substituent" of the above-mentioned ~heterocyclic group optionally having a substituent", for example, the same moieties as for the ~substituent" of the i5 above-mentioned "hydrocarbon group optionally having a substituent" represented by RS°, etc. are exemplified.
The above-mentioned "heterocyclic group" may have, for example, 1 to 5, preferably 1 to 3 of the above-mentioned substituents at substitutable positions, and when the number 20 of the substituent is 2 or more, they may be the same or different.
As the ~C1_6 alkyl group" represented by R6°, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. are exemplified.
25 As the "hydrocarbon group optionally having a substituent" and ~heterocyclic group optionally having a substituent" represented by R'°, for example, the above-mentioned "hydrocarbon group optionally having a substituent"
and ~heterocyclic group optionally having a substituent"
3o represented by RS° are exemplified, respectively.
As the "hydrocarbon group optionally having a substituent" represented by R1° and Rld, for example, the "hydrocarbon group optionally having a substituent"

represented by RS° is exemplified.
As the ~heterocyclic group optionally having a substituent" represented by R1~ and Rld, for example, the "heterocyclic group optionally having a substituent"
represented by RS° is exemplified.
As the ~amino group optionally having a substituent"
represented by Rl~ and Rld, (1) an amino group optionally having 1 or 2 substituents and (2) a cyclic amino group optionally having a substituent are exemplified.
to As the ~substituent" of the above-mentioned ~(1) amino group optionally having 1 or 2 substituents", for example, a hydrocarbon group optionally having a substituent, a heterocyclic group optionally having a substituent, an acyl group, an alkylidene group optionally having a substituent, is etc. are exemplified. As the "hydrocarbon group optionally having a substituent" and ~heterocyclic group optionally having a substituent", for example, the same moieties as for the above-mentioned ~hydrocarbon group optionally having a substituent" and "heterocyclic group optionally having a 2o substituent" represented by RS are exemplified, respectively.
As the ~alkylidene group" of the above-mentioned ~alkylidene group optionally having a substituent", for example, C1-6 alkylidene (e. g., methylidene, ethylidene, propylidene and the like), etc. are exemplified. As the 25 ~substituent" of the above-mentioned "alkylidene group optionally having a substituent", for example, 1 to 5, preferably 1 to 3 of the same moieties as for the "substituent" of the above-mentioned "hydrocarbon group optionally having a substituent" represented by RS° are so exemplified.
When the number of the ~substituent" of the above-mentioned ~amino group optionally having 1 or 2 substituents"
is two, these substituents may be the same or different.

As the ~cyclic amino group" of the above-mentioned ~(2) cyclic amino group optionally having a substituent", a 5- to 7-membered non-aromatic cyclic amino group (saturated cyclic amino group) which may contain 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to one nitrogen atom and carbon atoms are exemplified, and as specific examples thereof, 1-pyrrolidinyl, piperidino, 1-piperazinyl, morpholino, thiomorpholino, hexahydroazepin-1-yl, imidazolidin-1-yl, 2,3-io dihydro-1(1H)-imidazolyl, tetrahydro-1(2H)-pyrimidinyl, 3,6-dihydro-1(2H)-pyrimidinyl, 3,4-dihydro-1(2H)-pyrimidinyl, etc.
are exemplified. As the "substituent" of the "cyclic amino group optionally having a substituent", for example, 1 to 3 of the same moieties as for the ~substituent" of the ~5- to 7-membered aliphatic heterocyclic group optionally having a substituent" described in detail as the "substituent" of the "hydrocarbon group optionally having a substituent"
represented by RS°.
As specific examples of the 5- to 7-membered non-2o aromatic cyclic amino group having one oxo, for example, 2-oxoimidazolidin-1-yl, 2-oxo-2,3-dihydro-1H-imidazol-1-y1, 2-oxoteterahydro-1(2H)-pyrimidinyl, 2-oxo-3,6-dihydro-1(2H)-pyrimidinyl, 2-oxo-3,4-dihydro-1(2H)-pyrimidinyl, 2-oxopyrrolidin-1-yl, 2-oxopiperidino, 2-oxopiperazin-1-yl, 3-oxopiperazin-1-yl, 2-oxo-2,3,4,5,6,7-hexahydroazepin-1-yl, etc. are exemplified.
R1° or Rld is preferably an alkyl group optionally having a substituent, an aryl group optionally having a substituent, an amino group optionally having a substituent, 3o a heterocyclic group optionally having a substituent, an acyl group represented by the formula: -(C=O)-R5° (wherein RS° is as defined above), an acyl group represented by the formula:
- (C=O) -ORS° (wherein RS~ is as defined above) , or the like.

As the "alkyl group optionally having a substituent", for example, a C1_s alkyl group (preferably, methyl, ethyl, propyl, butyl and the like) optionally having 1 to 5 substituents selected from a halogen atom, carboxy, hydroxy, Ci-s alkoxy, C1-s alkoxy-carbonyl, C1_s alkylthio, C1_s alkylsulfinyl, C1_s alkylsulfonyl, and the like, etc. are preferably exemplified.
As the above-mentioned ~aryl group optionally having a substituent", for example, a Cs_14 aryl group (preferably, io phenyl and the like) optionally having 1 to 5 substituents selected from a halogen atom, C1_s alkylthio, Cs_19 arylthio, C1_s alkylsulfinyl, Cs_14 arylsulfinyl, C1_s alkylsulfonyl, Cs-i4 arylsulfonyl, carboxy and the like, etc. are preferably exemplified.
As the above-mentioned ~amino group optionally having a substituent", an amino group optionally having 1 or 2 acyl represented by the formula: - (C=0) -RS°, - (C=O) -ORS°, - (C=0) -NRS°Rs~, - (C=S) -NHRS°, - (C=O) -N (ORS) Rs°, -(C=S) -NHORS° or -S02-R'° (wherein each symbol is as defined above), etc. are 2o preferably exemplified.
Further preferably, R1° is an amino group optionally having 1 or 2 acyls represented by the formula: -(C=O)-RS° or - (C=O) -NR5°Rs° (wherein each symbol is as defined above) , etc.
are exemplified.
2s As the ~heterocyclic group" of the ~heterocyclic group optionally having a substituent", for example, a 5- to 14-membered (monocyclic, bicyclic or tricyclic) heterocyclic group which contain 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen 3o atom in addition to carbon atoms are used, and of them, a 5-to 7-membered aromatic heterocyclic group, a 5- to 10-membered non-aromatic heterocyclic group, etc. are preferable.
As the "substituent" of the "heterocyclic group optionally having a substituent", for example, an oxo group, a C1_6 alkyl group (a.g. , methyl, ethyl, etc. ) , a C6-i4 aryl group (e. g., phenyl, etc.), a C1_6 alkyl-carbonyl group (e. g., acetyl, etc.), a C1_6 alkoxy-carbonyl group (e. g., s methoxycarbonyl, ethoxycarbonyl, etc.) and the like are used, and the number of substituents is 1 to 3.
As RS' of the "acyl group represented by the formula:-(C=O)-RS'", a hydrogen atom, a hydrocarbon group optionally having a substituent and an aromatic heterocyclic group io optionally having a substituent are preferable, and particularly, (1) a hydrogen atom, (2) a C1_6 alkyl group which may be halogenated (e. g., methyl, ethyl, propyl, trifluoromethyl, etc.), (3) a C6_14 aryl group which may be halogenated (e. g., phenyl, naphthyl, fluorophenyl, is chlorophenyl, etc.), (4)a 5- to 7-membered aromatic heterocyclic group (e. g., pyridyl, thienyl, pyrrolyl, furyl, pyridazinyl, pyrimidinyl, etc.) which rnay be substituted by a halogen atom (e. g., fluorine, chlorine, bromine, etc.), optionally halogenated C1_6 alkyl (e. g., methyl, ethyl, propyl, 2o trifluoromethyl, etc.), C1_6 alkoxy group (e. g., methoxy, ethoxy, propoxy, butoxy, etc.), and the like are preferable.
As RS' of the "acyl group represented by the formula:-(C=O)-ORS'", a hydrogen atom and a hydrocarbon group optionally substituted are preferable, and particularly, a 25 hydrogen atom and a C,__6 alkyl group (e. g., methyl, ethyl, propyl, etc.), and the like are preferable.
As R1' or Rld, (i) a hydrogen atom, (ii) a C1_6 alkyl group optionally substituted by a substituent selected from the group consisting of a halogen atom, C1_6 alkoxy-carbonyl, so carboxy, cyano, C1_6 alkylthio, C1_6 alkylsulfinyl, C1-s alkylsulfonyl, hydroxy, C1_6 alkoxy and Cl-6 alkyl-carbonyl, (iii) a C6_14 aryl group optionally having a substituent selected from the group consisting of a halogen atom and a group of the formula: -S (O) n-Rlf (Rif represents a C1_s alkyl group, and n represents an integer of 0 to 2) , (iv) a C~_ls aralkyl group, (v) an amino group optionally having one or two substituents selected from (1) C1_s alkyl, (2) Cl_s alkyl-carbonyl, (3)5- to 7-membered heterocyclic-carbonyl containing 1 to 4 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms, optionally substituted with a halogen atom, C1_s alkyl or C1_s alkoxy, (4) Cs_14 aryl-Io carbamoyl, (5) C1_s alkyl-carbamoyl which may be halogenated, (6) C1_s alkoxy-carbonyl which may be halogenated, (7) C1_s alkoxy-carbamoyl and (8) Cs_19 aryloxy-carbamvyl, (vi) a 5- to 10-membered heterocyclic group containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur 15 atom and an oxygen atom in addition to carbon atoms, optionally substituted by oxo, C1_s alkyl, Cs_~4 aryl, C1_s alkoxy-carbonyl or C1_s alkyl-carbonyl, (vii) an acyl group represented by the formula: - (C=O) -Rsd (wherein Rsd represents a hydrogen atom, a C1_s alkyl group which may be halogenated 20 or a Cs_14 aryl group which may be halogenated) , or (viii) an acyl group represented by the formula:-(C=O)-ORsd (wherein Rsa represents a hydrogen atom or a C1_s alkyl group), and the like are suitable.
As the C1_s alkyl group represented by Rl~ or Rld, for 25 example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. are used, and particularly, C1_4 alkyl groups such as methyl, ethyl, propyl, butyl and the like are preferable.
As the halogen atom which is a substituent of the C1-s 3o alkyl group represented by R1° or Rld, for example, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom and the like are preferable.
As the C1-s alkoxy-carbonyl which is a substituent of the C1_s alkyl group represented by R1' or Rld, for example, methoxycarbonyl, ethoxycarbonyl and the like are preferable.
As the C1_6 alkylthio which is a substituent of the C1_s alkyl group represented by Rl' or Rld, for example, methylthio, ethylthio and the like are preferable.
As the C1_s alkylsulfinyl which is a substituent of the C1_s alkyl group represented by R1' or Rld, for example, methylsulfinyl, ethylsulfinyl and the like are preferable.
As the C1_s alkylsulfonyl which is a substituent of the io Ci-s alkyl group represented by R1' or Rld, for example, methylsulfonyl, ethylsulfonyl and the like are preferable.
As the C1_s alkoxy which is a substituent of the C1_s alkyl group represented by Rl' or Rld, for example, methoxy, ethoxy, propoxy and the like are preferable.
i5 As the C1_6 alkyl-carbonyl which is a substituent of the C1_s alkyl group represented by R1' or Rld, for example, acetyl, propionyl and the like are preferable.
As the C1_s alkyl group represented by Rlf, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, 2o tert-butyl, pentyl, hexyl, etc. are used, and of them, C1_9 alkyl groups such as methyl, ethyl, propyl, butyl and the like are preferable, and methyl is particularly preferable.
As the Cs_14 aryl group represented by R1' or Rld, for example, phenyl, naphthyl, etc. are preferable, and of them, 25 phenyl is particularly preferable.
As the halogen atom which is a substituent of the Cs-19 aryl group represented by R1' or Rld, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom are used.
As the C~_15 aralkyl group represented by R1' or Rld, for so example, phenyl-C1_3 alkyl groups such as benzyl, phenylethyl, phenylpropyl and the like are preferable.
As the C1_s alkyl group which is a substituent of an amino group represented by R1' or Rld, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. are used, and of them, C1_3 alkyl groups such as methyl, ethyl, propyl and the like are preferable, particularly, methyl is preferable.
As the C1_6 alkyl-carbonyl which is a substituent of an amino group represented by Rl~ or Rld, for example, a C1_3 alkyl-carbonyl group such as acetyl, propionyl and the like are preferable.
As the "5- to 7-membered heterocyclic-carbonyl io containing 1 to 4 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms" which is a substituent of an amino group represented by R1° or Rld, for example, a 5- to 7-membered heterocyclic (e. g., furyl, thienyl, pyrrolyl, is pyridyl, pyrimidinyl, pyridazinyl and the like)-carbonyl group containing 1 or 2 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, etc. are preferable. As the substituent of the heterocyclic group of this heterocyclic-carbonyl group, a Zo halogen atom such as a chlorine atom and the like, C1_6 alkyl group such as methyl, ethyl and the like, and C1_6 alkoxy such as methoxy, ethoxy and the like are preferable.
As the C6_14 aryl-carbamoyl which is a substituent of an amino group represented by R1° or Rld, for example, phenyl-25 carbamoyl, etc. are preferable.
As the C,__6 alkyl-carbamoyl which may be halogenated which is a substituent of an amino group represented by R1°
or Rld, for example, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl optionally substituted by a halogen atom so (e, g,, chlorine atom) and the like are preferable.
As the C1_6 alkoxy-carbonyl which may be halogenated which is a substituent of an amino group represented by R1~
or Rld, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl optionally substituted by halogen atoms (e. g., a chlorine atom) and the like are preferable.
As the C1_6 alkoxy-carbamoyl which is a substituent of an amino group represented by R1° or Rld, for example, methoxycarbamoyl, ethoxycarbamoyl, propoxycarbamoyl and the like are preferable.
As the C6_19 aryloxy-carbamoyl which is a substituent of an amino group represented by R1~ or Rld, phenyloxy-carbamoyl and the like are preferable.
2o As the 5- to 10-membered non-aromatic heterocyclic group represented by R1~ or Rld, for example, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 3-oxazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 2-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 15 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl, morpholino, thiomorpholino and the like, are used, and of them, 4-piperidyl, 1-piperazinyl, 3-oxazolidinyl, 1-imidazolidinyl and the like are preferable.
As the 5- to 10-membered non-aromatic heterocyclic 2o group optionally substituted by oxo, Cl-6 alkyl (preferably, methyl, ethyl) , C6_14 aryl (preferably, phenyl) , C1_6 alkyl-carbonyl (preferably, acetyl) or C1-6 alkoxy-carbonyl (preferably, methoxycarbonyl, ethoxycarbonyl) represented by R1° or Rld, 1-methyl-4-piperidyl, 4-methyl-1-piperazinyl, 2-25 oxo-3-oxazolidinyl, 2-oxo-1-imidazolidinyl, 2-oxo-3-phenyl-1-imidazolidinyl and the like are preferable.
As Rsd of the formula: - (C=O) -R5d represented by Rl~ or Rld, a hydrogen atom, a C1_6 alkyl group which may be halogenated by a fluorine atom, a chlorine atom and the like 30 (e.g., methyl, ethyl, trifluoromethyl, etc.), a G6-19 aryl group which may be halogenated by a fluorine atom, a chlorine atom and the like (e. g., phenyl, naphthyl, fluorophenyl, chlorophenyl, etc.) are preferable.

As Rsd of the formula: - (C=O) -ORSd represented by R1° or Rld, a hydrogen atom and a C1_3 alkyl group (methyl, ethyl, etc.) are preferable.
As the "substituent containing no aromatic group"
carried by a 4-pyridyl group substituted at the 5-position of a compound (Ia), the ~substituent containing no aromatic group" substituted at the position adjacent to a nitrogen atom of a pyridyl group substituted at the 5-position of a compound (Ib) the ~substituent containing no aromatic group"
io substituted at the position adjacent to a nitrogen atom of a 4-pyridyl group substituted at the 5-position of a compound (Ic), the ~substituent containing no aromatic group" of the ~4-pyridyl group having a substituent containing no aromatic group" represented by RZ°, and ~the substituent containing no IS aromatic group" of the ~pyridyl group having at the position adjacent to a nitrogen atom of the pyridyl group a substituent containing no aromatic group" represented by R2d, for example, a halogen atom (e. g., fluorine, chlorine, bromine, iodine and the like), C1_3 alkylenedioxy (e. g., 2o methylenedioxy, ethylenedioxy and the like), vitro, cyano, C1_6 alkyl which may be halogenated, C2_6 alkenyl which may be halogenated, carboxy CZ_6 alkenyl (e.g., 2-carboxyethenyl, 2-carboxy-2-methylethenyl and the like), C2_6 alkynyl which may be halogenated, C3_$ cycloalkyl which may be halogenated, C3-B
25 cycloalkyl-C,__6 alkyl, C,_$ alkoxy which may be halogenated, C1_6 alkoxy-carbonyl-C1_6 alkoxy (e. g., ethoxycarbonylmethyloxy and the like), hydroxy, mercapto, C1_6 alkylthio which may be halogenated, amino, mono-C1-6 alkylamino (e. g., methylamino, ethylamino and the like), di-C1_6 alkylamino (e. g., 3o dimethylamino, diethylamino, ethylmethylamino and the like), C3_8 cycloalkylamino (e. g., cyclopentylamino, cyclohexylamino and the like) , C3-$ cycloalkyl-Cl_6 alkylamino (e. g. , cyclopentylmethylamino, cyclohexylmethylamino, cyclopentylethylamino, cyclohexylethylamino and the like), N-C3_e cycloalkyl-N-C1_6 alkylamino (e.g. , N-cyclopentyl-N-methylamino, N-cyclohexyl-N-methylamino, N-cyclopentyl-N-ethylamino, N-cyclohexyl-N-ethylamino and the like), formyl, carboxy, carboxy-C2_6 alkenyl, carboxy-C1_6 alkyl, C1_6 alkyl-carbonyl which may be halogenated (e. g., acetyl, propionyl, 2,2,2-trifluoroacetyl, 3,3,3-trifluoropropionyl, 2,2-difluoropropionyl and the like), C3_B cycloalkyl-carbonyl optionally substituted by C1_6 alkyl (e. g., to cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, 1-methyl-cyclohexyl-carbonyl and the like), C1_6 alkoxy-carbonyl (e. g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like), carbamoyl, thiocarbamoyl, mono-C1-6 alkyl-carbamoyl (e. g., is methylcarbamoyl, ethylcarbamoyl, and the like), di-C1_6 alkyl-carbamoyl (e. g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl and the like), C1_6 alkylsulfonyl (e. g., methylsulfonyl, ethylsulfonyl and the like), C1_s alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl and the 20 like) , formylamino, C1_6 alkyl-carbonylamino (e.g. , acetylamino, propionylamino, pivaloylamino and the like), C3_B
cycloalkyl-carbonylamino optionally substituted by C1_6 alkyl (e. g., cyclopropylcarbonylamino, cyclopentylcarbonylamino, cyclohexylcarbonylamino, 1-methyl-cyclohexylcarbonylamino and 25 the like) , C,_6 alkoxy-carbonylamino (e. g. , methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino and the like), C1_s alkylsulfonylamino (e. g., methylsulfonylamino, ethylsulfonylamino and the like), C1_6 alkyl-carbonyloxy (e. g., so acetoxy, propionyloxy and the like), C1_6 alkoxy-carbonyloxy (e. g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy and the like), mono-C1_s alkylcarbamoyloxy (e. g., methylcarbamoyloxy, ethylcarbamoyloxy and the like), di-C1_s alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy, diethylcarbamoyloxy and the like), 5- to 7-membered aliphatic heterocyclic group optionally having a substituent, sulfo, sulfamoyl, sulfinamoyl, sulfenamoyl, a group formed by connecting 2 or more (e.g. , 2 to 3) of these substituents (e.g. , (i) C1_s alkyl, (ii) amino, (iii) Cl_s alkylamino, (iv) C3_g cycloalkylamino, (v) 5- to 7-membered aliphatic heterocyclic amino containing 1 to 4 of 1 or 2 kinds of hetero atoms io selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, (vi) C1_s alkyl-carbonyl amino, (vii) C3_B cycloalkyl-carbonylamino or (viii) 5- to 7-membered aliphatic heterocyclic-carbonyl amino containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen 15 atom, a sulfur atom and an oxygen atom in addition to carbon atoms, which is optionally substituted, respectively, by a substituent selected from the group consisting of a halogen atom, cyano, hydroxy, C1_s alkoxy, C1-s alkylthio, C1_s alkylsulfinyl, Cl-s alkylsulfonyl, C3_B cycloalkyl, 5- to 7-2a membered aliphatic heterocyclic group containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, C1_s alkyl-carbonyl, 5- to 7-membered aliphatic heterocyclic-carbonyl containing 1 to 4 of 1 or 2 kinds of hetero atoms 25 selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, C3_8 cycloalkoxy, 5- to 7-membered aliphatic heterocyclic-oxy containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, 3o Ci-s alkylamino , C1_s alkoxy-carbonyl , C3_$ cycloalkoxy-carbonyl , 5- to 7-membered aliphatic heterocyclic-oxycarbonyl containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, etc.) and the like are exemplified.
As the above-mentioned "C1-s alkyl which may be halogenated", for example, C1_s alkyl (e. g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tent-butyl, pentyl, hexyl and the like) which may have 1 to 5, preferably 1 to 3 halogen atoms (e. g., fluorine, chlorine, bromine, iodine and the like), etc. are exemplified. As specific examples thereof, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-1° trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl, etc. are exemplified.
I5 As the above-mentioned "C2-s alkenyl which maybe halogenated", far example, C2_s alkenyl (e. g., vinyl, propenyl, isopropenyl, 2-buten-1-yl, 4-penten-1-yl, 5-hexen-1-yl and the like) which may have 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine and the zo like), etc. are exemplified.
As the above-mentioned "CZ_s alkynyl which may be halogenated", for example, C2_s alkynyl (e.g., 2-butyn-1-yl, 4-pentyn-1-yl, 5-hexyn-1-yl and the like) which may have 1 to 5, preferably 1 to 3 halogen atoms (e. g., fluorine, chlorine, 2s bromine, iodine and the like), etc. are exemplified.
As the above-mentioned "C3_$ cycloalkyl which may be halogenated", for example, C3_g cycloalkyl (e. g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like) which may have 1 to 5, preferably 1 to 3 halogen atoms (e. g., fluorine, 3o chlorine, bromine, iodine and the like), etc. are exemplified.
As specific examples thereof, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dichlorocyclohexyl, 2,2,3,3-tetrafluorocyclopentyl, 4-chlorocyclohexyl, etc. are exemplified.
As the above-mentioned "C1_$ alkoxy which may be halogenated", for example, C1_B alkoxy (e. g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, s hexyloxy and the like) which may have 1 to 5, preferably 1 to 3 halogen atoms (e. g., fluorine, chlorine, bromine, iodine and the like), etc. are exemplified. As specific examples thereof, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc. are exemplified.
As the above-mentioned "C1_6 alkylthio which may be halogenated", for example, C1_6 alkylthio (e. g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-ts butylthio, tert-butylthio and the like) which may have 1 to 5, preferably 1 to 3 halogen atoms (e. g., fluorine, chlorine, bromine, iodine and the like), etc. are exemplified. As specific examples thereof, methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, 2o butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio, etc. are exemplified.
As the "5- to 7-membered aliphatic heterocyclic group"
of the above-mentioned "5- to 7-membered aliphatic heterocyclic group optionally having a substituent", for 2s example, 5- to 7-membered aliphatic heterocyclic group containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms are exemplified, and as specific examples thereof, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-30 pyrrolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl, 3-piperazinyl, 4-piperazinyl, morpholino, 2-morpholinyl, 3-morpholinyl, thiomorpholino, 2-thiomorpholinyl, 3-thiomorpholinyl, hexahydroazepin-1-yl, etc. are exemplified.
As the ~substituent" of the above-mentioned ~5- to 7-membered aliphatic heterocyclic group optionally having a substituent", for example, 1 to 3 of C1_6 alkyl (e. g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like), C1_6 alkyl-carbonyl (e. g., acetyl, propionyl and the like), oxo, etc. are exemplified.
Provided that, when (i) R1° or Rld is an acetylamino group, and R3° or R3d is io a 3,5-dimethylphenyl group, (ii) R1° or Rld is a C1_6 alkyl-carbonylamino group, and R3° or R3d is a C6_19 aryl group substituted by a Ci_6 alkyl group, or (iii) Rl~ or Rld is an amino group optionally having a T5 substituent, and R3° or R3d is an aromatic hydrocarbon group optionally having a substituent, there are exemplified, as the "substituent containing no aromatic group", a halogen atom (e. g., fluorine, chlorine, bromine, iodine and the like), C1_3 alkylenedioxy (e. g., 2o methylenedioxy, ethylenedioxy and the like), nitro, cyano, C1_6 alkyl which may be halogenated, C2_6 alkenyl which may be halogenated, carboxy C2_6 alkenyl (e.g., 2-carboxyethenyl, 2-carboxy-2-methylethenyl and the like), C2_6 alkynyl which may be halogenated, C3_8 cycloahkyl which may be halogenated, C3_$
2s cycloalkyl-C,_6 alkyl, C,__8 alkoxy which may be halogenated, C1_6 alkoxy-carbonyl-C1_6 alkoxy (e. g., ethoxycarbonylmethyloxy and the like), mercapto, C1_6 alkylthio which may be halogenated, amino, mono-C1_6 alkylamino (e. g., methylamino, ethylamino and the like), di-C1_6 alkylamino (e. g., 3o dimethylamino, diethylamino, ethylmethylamino and the like), C3_$ cycloalkylamino (e. g., cyclopentylamino, cyclohexylamino and the like) , C3_B cycloalkyl-C1_6 alkylamino (e. g. , cyclopentylmethylamino, cyclohexylmethylamino, cyclopentylethylamino, cyclohexylethylamino and the like), N-C3_g cycloalkyl-N-C~_s alkylamino (e.g. , N-cyclopentyl-N-methylamino, N-cyclohexyl-N-methylamino, N-cyclopentyl-N-ethylamino, N-cyclohexyl-N-ethylamino and the like), formyl, s carboxy, carboxy-C2_s alkenyl, carboxy-C1_s alkyl, C1_s alkyl-carbonyl (e. g., acetyl, propionyl and the like), C3_8 cycloalkyl-carbonyl optionally substituted by C1_s alkyl (e. g., cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, 1-methyl-cyclohexyl-carbonyl and the like), C1_s alkoxy-io carbonyl (e. g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like), carbamoyl, thiocarbamoyl, mono-C1_s alkyl-carbamoyl (e. g., methylcarbamoyl, ethylcarbamoyl, and the like), di-C1_s alkyl-.
carbamoyl (e. g., dimethylcarbamoyl, diethylcarbamoyl, 3s ethylmethylcarbamoyl and the like) , C1_s alkylsulfonyl (e. g. , methylsulfonyl, ethylsulfonyl and the like), C1-s alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl and the like), formylamino, C1_s alkyl-carbonylamino (e. g., acetylamino, propionylamino, pivaloylamino and the like), C3_B
2o cycloalkyl-carbonylamino optionally substituted by C1-s alkyl (e. g., cyclopropylcarbonylamino, cyclopentylcarbonylamino, cyclohexylcarbonylamino and the like), C1_s alkoxy-carbonylamino (e. g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, 2s butoxycarbonylamino and the like), C,_6 alkylsulfonylamino (e. g., methylsulfonylamino, ethylsulfonylamino and the like), C1_s alkoxy-carbonyloxy (e. g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy and the like) , mono-C1_s alkyl-carbamoyloxy (e.g. , 3o methylcarbamoyloxy, ethylcarbamoyloxy and the like), di-C1-s alkyl-carbamoyloxy (e. g., dimethylcarbamoyloxy, diethylcarbamoyloxy and the like), 5- to 7-membered aliphatic heterocyclic group optionally having a substituent (preferably, 5- to 7-membered aliphatic heterocyclic group having 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms), sulfo, sulfamoyl, sulfinamoyl, sulfenamoyl and the like are s exemplified. Further, a group obtained by connecting two or more (e.g. , 2 or 3) (e.g. , (i) Cl_6 alkyl, (ii) amino, (iii) C1_6 alkylamino, (iv) C3_e cycloalkylamino, (v) 5- to 7-membered aliphatic heterocyclic amino containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a to sulfur atom and an oxygen atom in addition to carbon atoms, (vi) C1_6 alkyl-carbonyl amino, (vii) C3_8 cycloalkyl-carbonylamino or (viii) 5- to 7-membered aliphatic heterocyclic-carbonyl amino containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom is and an oxygen atom in addition to carbon atoms, which is substituted, respectively, by a substituent selected from the group consisting of a halogen atom, cyano, hydroxy, C1-s alkoxy, C1_6 alkylthio, C1_6 alkylsulfinyl, Cl_6 alkylsulfonyl, C3-g cycloalkyl, 5- to 7-membered aliphatic heterocyclic group Zo containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, C1-6 alkyl-carbonyl, 5- to 7-membered aliphatic heterocyclic-carbonyl containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a 2s sulfur atom and an oxygen atom in addition to carbon atoms, C3_a cycloalkoxy, 5- to 7-membered aliphatic heterocyclic-oxy containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, C1_6 alkylamino, C1_6 alkoxy-carbonyl, 3o C3~8 cycloalkoxy-carbonyl, 5- to 7-membered aliphatic heterocyclic-oxycarbonyl containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, etc.), etc. can also be used as a substituent.
Among these substituents, specifically, 1 to 3, preferably 1 or 2 substituents selected from the following (1) to (6) , particularly (1) to (4) are preferably used.
(1) a C1_6 alkyl group (e. g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like, preferably a Cl_4 alkyl group such as methyl, ethyl, propyl, butyl and the like): this C1_6 alkyl group may be substituted by a halogen atom, cyano, hydroxy, io C3_8 cycloalkyl or a 5- to 7-membered aliphatic heterocyclic group containing 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms (e. g., 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-15 piperazinyl, 2-piperazinyl, 3-piperazinyl, 4-piperazinyl, morpholino, 2-morpholinyl, 3-morpholinyl, thiomorpholino, 2-thiomorpholinyl, 3-thiomorpholinyl, hexahydroazepin-1-yl and the like), (2) a halogen atom (e. g., fluorine atom, chlorine atom, 2o bromine atom, iodine atom), (3) an amino group optionally having a substituent selected from the group consisting of the following 1) to 7):
1) a C1_6 alkyl group (e. g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 25 hexyl and the like, preferably C,_3 alkyl groups such as methyl, ethyl, propyl and the like), this C1_6 alkyl group may be substituted by a halogen atom, cyano, hydroxy, C3_e cycloalkyl or 5- to 7-membered aliphatic heterocyclic group containing 1 to 4 hetero atoms selected from a nitrogen atom, so an oxygen atom and a sulfur atom in addition to carbon atoms (e. g., 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl, 3-piperazinyl, 4-piperazinyl, morpholino, 2-morpholinyl, 3-morpholinyl, thiomorpholino, 2-thiomorpholinyl, 3-thiomorpholinyl, hexahydroazepin-1-yl and the like), 2) a C3-8 cycloalkyl group (e. g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like), 3) a C1_6 alkyl-carbonyl group (e. g., acetyl, propionyl, butyryl, valeryl, isovaleryl, 2-methylpropionyl, pivaloyl and the like), this C1_6 alkyl-carbonyl group may be substituted by a halogen atom, cyano, hydroxy, C3_B cycloalkyl or 5- to io 7-membered aliphatic heterocyclic group containing 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-15 piperazinyl, 3-piperazinyl, 4-piperazinyl, morpholino, 2-morpholinyl, 3-morpholinyl, thiomorpholino, 2-thiomorpholinyl, 3-thiomorpholinyl, hexahydroazepin-1-yl and the like), 4) a C1_6 alkoxy-carbonyl group (e.g. , methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, 2o isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl and the like) , 5) a C3_$ cycloalkyl-carbonyl group optionally substituted by C1_6 alkyl such as methyl, ethyl (e. g., cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, 2s cyclohexylcarbonyl, 1-methyl-cyclohexylcarbonyl and the like), 5) a 5- to 7-membered aliphatic heterocyclic group having 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms (e. g., 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 3o piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl, 3-piperazinyl, 4-piperazinyl, morpholino, 2-morpholinyl, 3-morpholinyl, thiomorpholino, 2-thiomorpholinyl, 3-thiomorpholinyl, hexahydroazepin-1-yl, etc.). This aliphatic heterocyclic group may be substituted by C1_6 alkyl (e.g. , methyl, ethyl) and the like.
7) a 5- to 7-membered aliphatic heterocyclic (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl, 3-piperazinyl, 4-piperazinyl, morpholino, 2-morpholinyl, 3-morpholinyl, thiomorpholino, 2-thiomorpholinyl, 3-thiomorpholinyl, hexahydroazepin-1-yl, etc.)-carbonyl group having 1 to 4 hetero atoms selected from a nitrogen atom, an io oxygen atom and a sulfur atom in addition to carbon atoms.
This aliphatic heterocyclic-carbonyl group may be substituted by C1_6 alkyl (e. g. , methyl, ethyl) and the like.
(4) a 5- to 7-membered saturated cyclic amino group which may contain further 1 to 4 hetero atoms selected from a is nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms and one nitrogen atom (e. g., 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl and the like). This saturated cyclic amino group may be substituted with C1_s alkyl (e. g., methyl, ethyl) and the like.
20 ( 5 ) a hydroxyl group , (6) a C1_6 alkyl-carbonyloxy group (e. g., acetyloxy, propionyloxy, butyryloxy and the like).
The "pyridyl group" represented by R2° and RZd may have, for example, 1 to 5, preferably 1 to 3 of the above-mentioned 25 substituents at substitutable positions, and when the number of substituents is 2 or more, they may be the same or different. Further, an endocyclic nitrogen atom of the ~pyridyl group" may be N-oxidized.
As the ~pyridyl group" of the "pyridyl group having at 3o the position adjacent to a nitrogen atom of the pyridyl group a substituent including no aromatic group" represented by R2a, 1-, 2-, 3- and 4-pyridyl group are exemplified, and 4-pyridyl group is particularly preferable.

As the "aromatic group" of the "aromatic group optionally having a substituent," represented by R3~ and R3a, an aromatic hydrocarbon group, an aromatic heterocyclic group, etc. are exemplified.
s As the "aromatic hydrocarbon group", for example, a monocyclic or fused polycyclic (bicyclic or tricyclic) aromatic hydrocarbon group having 6 to 14 carbon atoms are exemplified. As specific examples thereof, for example, C6_14 aryl such as phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-io biphenylyl, 4-biphenylyl, 2-anthryl and the like, etc. are exemplified.
As the "aromatic heterocyclic group", for example, a 5-to 14-membered (preferably, 5- to 10-membered) (monocyclic or bicyclic) aromatic heterocyclic groups preferably containing is 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, are exemplified. Specifically, an aromatic heterocyclic group such as, for example, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, Zo 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, pirazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3-2s benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl and the like, are exemplified.
As the "substituent" of the above-mentioned "aromatic group optionally having a substituent", for example, 1 to 5, preferably 1 to 3 of the same moieties as fox the 30 "substituent" of the above-mentioned "hydrocarbon group optionally having a substituent" represented by R5~ are exemplified. When the number of the substituents is two or more, these substituents may be the same or different.

Further, adjacent two substituents may form a 4- to 7-membered non-aromatic carbon ring. Preferable is a 5- or 6-membered non-aromatic carbon ring.
R3° and R3d preferably represent a Cs_1q aryl group, or a s 5- to 14-membered aromatic heterocyclic group preferably containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms. More preferably, they represent a phenyl group optionally having a substituent or a thienyl zo group optionally having a substituent, and a phenyl group optionally having a substituent is particularly preferable.
As the substituent on the Cs_lo aryl group, a phenyl group, a 5- to 14-membered aromatic heterocyclic group and a thienyl group, preferable are 1 to 3 substituents selected Is from a halogen atom, C1_3 alkylenedioxy, C1_s alkyl which may be halogenated, carboxy C2_s alkenyl, C3_B cycloalkyl, C1_8 alkoxy which may be halogenated, hydroxy, C~_16 aralkyloxy, C1_ s alkyl-carbonyloxy, carboxy, C1_s alkoxy-carbonyl, cyano, C1_s alkylthio, C1_s alkylsulfonyl and particularly, a halogen atom, 2o Ci-s alkyl which may be halogenated (e. g. , C1_3 alkyl such as methyl, ethyl, propyl and the like), C1_$ alkoxy which may be halogenated (e.g., C1_3 alkoxy such as methoxy, ethoxy and the like), carboxy, C1-s alkoxy-carbonyl, cyano, C1_s alkylthio (e. g., methylthio, ethylthio), C1_s alkylsulfonyl (e. g., 2s methylsulfonyl, ethylsulfonyl), etc. are preferable. Further, two alkyl groups adjacent as substituents may form a 5-membered non-aromatic carbocyclic ring.
As the compound (Va), specifically, compounds represented by the following formula are preferably used:
,y2e S
so I ~~R~e (vza) N
wherein Rle represents (i) a hydrogen atom, (ii) a C1_s alkyl group optionally substituted by a substituent selected from the group consisting of a halogen atom, C1_s alkoxy-carbonyl, carboxy, cyano, C1_s alkylthio, C1_s alkylsulfinyl, C1_s alkylsulfonyl, hydroxy, C1_s alkoxy and C1_s alkyl-carbonyl, (iii) a Cs_14 aryl group optionally having a substituent selected from the group consisting of a halogen atom and a group represented by the formula: -S(0)n-Rlf (Rif represents a C1_s alkyl group, and n represents an integer of 0 to 2), (iv) a C~-15 aralkyl group, (v) an amino group optionally having io one or two substituents selected from 1) C1_s alkyl, 2) C1-s alkyl-carbonyl, 3) C1_s alkoxy-carbonyl, 4) 5- to 7-membered heterocyclic-carbonyl containing 1 to 4 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, in addition to carbon atoms, optionally IS substituted with a halogen atom, C1-s alkyl group or C1_s alkoxy, 5) Cs_14 aryl-carbamoyl, 6) C1-s alkyl-carbamoyl which may be halogenated, 7) C1_s alkoxy-carbonyl which may be halogenated, 8) C1_s alkoxy-carbamoyl and 9) Cs_19 aryloxy-carbamoyl, (vi) a 5- to 10-membered heterocyclic group 2o containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, optionally substituted by oxo, C1_s alkyl, Cs_~4 aryl, C1_s alkyl-carbonyl or C1-s alkoxy-carbonyl, (vii) an acyl group represented by the formula: - (C=O) -Rid 2s (wherein R5d represents a hydrogen atom, a C,_-s alkyl group which may be halogenated or a Cs-i9 aryl group which may be halogenated), or (viii) an acyl group represented by the formula : - (C=0) -ORsd (wherein R5d represents a hydrogen atom or a C1_s alkyl group) , 3o Rae represents a pyridyl group (preferably, 4-pyridyl group and this pyridyl group may be N-oxidized.) having at the position adjacent to a nitrogen atom of the pyridyl group a substituent selected from the group (particularly, consisting of (1) to (4)) consisting of (1) a C1_6 alkyl group (this C1_6 alkyl group may be substituted by a halogen atom, cyano, hydroxy, C3_e cycloalkyl or a 5- to 7-membered aliphatic heterocyclic group containing 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms), (2) a halogen atom, (3) an amino group optionally having a substituent selected from the group consisting of the following 1) to 7);
io 1 ) a C1_6 alkyl group (this Cl_6 alkyl group may be substituted by halogen atoms, cyano, hydroxy, G3_8 cycloalkyl or 5- to 7-membered aliphatic heterocyclic group having 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms), i5 2) a C3-a cycloalkyl group, 3 ) a C1_6 alkyl-carbonyl group (this C1_6 alkyl-carbonyl group may be substituted by halogen atoms, cyano, hydroxy, C3_$ cycloalkyl or 5- to 7-membered aliphatic heterocyclic group having 1 to 4 hetero atoms selected from a nitrogen Zo atom, an oxygen atom and a sulfur_atom in addition to carbon atoms ) , 4) a C1-6 alkoxy-carbonyl group, 5) a C3-$ cycloalkyl-carbonyl group optionally substituted by C1_6 alkyl, 25 6) a 5- to 7-membered aliphatic heterocyclic group having 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms (this aliphatic heterocyclic group may be substituted by C1_s alkyl or C1_6 alkyl-carbonyl) , 30 7) a 5- to 7-membered aliphatic heterocyclic-carbonyl group having 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms (this aliphatic heterocyclic-carbonyl group may be substituted by C1_s alkyl or C1_s alkyl-carbonyl) , (4) a 5- to 7-membered saturated cyclic amino group optionally further containing 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms and one nitrogen atom (this saturated cyclic amino group may be substituted by C1_s alkyl or Cl_s alkyl-carbonyl) , (5) a hydroxy group, and (6) a C1-s alkyl-carbonyloxy group, and R3e represents ( 1 ) a Cs-lg aryl group or ( 2 ) a 5- to 14-membered aromatic heterocyclic group preferably containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, which optionally has a substituent selected from the group consisting of C1-s alkyl which may be halogenated, Cl_s alkoxy, a halogen atom, carboxyl, C1_s alkoxy-carbonyl, cyano, C1-s alkylthio and C1_s alkylsulfonyl.
As the C1_s alkyl group represented by Rle, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, 2~ tert-butyl, pentyl, hexyl, etc. are used, and particularly, a C1-9 alkyl group such as methyl, ethyl, propyl, butyl and the like are preferable, and a C1_3 alkyl group such as methyl, ethyl, propyl, etc. are particularly preferable.
As the halogen atom which is a substituent of the C1_s alkyl group represented by Rle, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom and the like are used.
As the C1_s alkoxy-carbonyl which is a substituent of the C1_s alkyl group represented by Rle, for example, methoxycarbonyl, ethoxycarbonyl and the like are preferable.
so As the C1_s alkylthio which is a substituent of the C1_s alkyl group represented by Rle, for example, methylthio;
ethylthio and the like are preferable.
As the C1-s alkylsulfinyl which is a substituent of the C1_s alkyl group represented by Rle, for example, methylsulfinyl, ethylsulfinyl and the like are preferable.
As the C1_6 alkylsulfonyl which is a substituent of the C1-s alkyl group represented by Rle, for example, methylsulfonyl, ethylsulfonyl and the like axe preferable.
As the G1_s alkoxy which is a substituent of the Cl_s alkyl group represented by Rle, for example, methoxy, ethoxy, propoxy and the like are preferable.
As the C1_s alkyl-carbonyl which is a substituent of the io C1_s alkyl group represented by Rle, for example, acetyl, propionyl and the like are preferable.
As the C1_s alkyl group represented by Rlf, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. are used, and particularly, a 15 Ci-3 alkyl group such as methyl, ethyl, propyl and the like are preferable, particularly, methyl is preferable.
As the Cs-i4 aryl group represented by Rle, for example, phenyl, naphthyl, etc. are preferable, and of them, phenyl is particularly preferable.
2o As the halogen atom which is a substituent of the Cs-i4 aryl group represented by Rle, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom are used.
As the C~_15 aralkyl group represented by Rle, for example, a phenyl-C1_3 alkyl group such as benzyl, phenylethyl, 25 phenylpropyl and the like are preferable.
As the C1-s alkyl group which is a substituent of an amino group represented by Rle, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tent-butyl, pentyl; hexyl, etc. are used, and particularly, a C1_3 alkyl 3o group such as methyl, ethyl, propyl and the like are preferable, particularly, methyl is preferable.
As the C1_s alkyl-carbonyl which is a substituent of an amino group represented by Rle, for example, a C1-3 alkyl-carbonyl group such as acetyl, propionyl and the like are preferable.
As the "5- to 7-membered heterocyclic-carbonyl containing 1 to 4 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, in addition to carbon atoms" which is a substituent of an amino group represented by Rle, for example, a 5- to 7-membered heterocyclic (e. g., pyridyl and the like)-carbonyl group containing 1 or 2 hetero atoms selected from the group Io consisting of a nitrogen atom, an oxygen atom and a sulfur atom, etc. axe preferable. As the substituent of the heterocyclic group of this heterocyclic-carbonyl group, a halogen atom such as a chlorine atom, a C1_6 alkyl group such as methyl, ethyl and the like, and a C1_6 alkoxy group such as s5 methoxy, ethoxy and the like are preferable.
As the C6_14 aryl-carbamoyl which is a substituent of an amino group represented by Rle, for example, phenyl-carbamoyl, etc. are preferable.
As the C1-6 alkyl-carbamoyl which may be halogenated 2o which is a substituent of an amino group represented by Rle, for example, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl optionally substituted by a halogen atom (e. g., chlorine atom) and the like are preferable.
As the C1_6 alkoxy-carbonyl which may be halogenated 25 which is a substituent of an amino group represented by Rle, for example, methoxycarbamoyl, ethoxycarbamoyl, propoxycarbamoyl optionally substituted by halogen atoms (e. g., chlorine atom) and the like are preferable.
As the C1_6 alkoxy-carbamoyl which is a substituent of 3o an amino group represented by Rle, for example, methoxycarbamoyl, ethoxycarbamoyl, propoxycarbamoyl and the like are preferable.
As the C6-is aryloxy-carbamoyl which is a substituent of an amino group represented by Rle, for example, phenyloxycarbamoyl and the like are preferable.
As the 5- to 10-membered non-aromatic heterocyclic group represented by Rle, for example, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 3-oxazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 2-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl, morpholino, thiomorpholino and the like, are io used, and of them, 4-piperidyl, 1-piperazinyl, 3-oxazolidinyl, 1-imidazolidinyl and the like are preferable.
As the 5- to 10-membered non-aromatic heterocyclic group optionally substituted by oxo, C1_6 alkyl (preferably, methyl, ethyl) , C6-1q aryl (preferably, phenyl) , G1_6 alkyl-is carbonyl (preferably, acetyl, propionyl) or C1_6 alkoxy-carbonyl (preferably, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl) represented by Rle, 1-methyl-4-piperidyl, 4-methyl-1-piperazinyl, 2-oxo-3-oxazolidinyl, 2-oxo-1-imidazolidinyl, 2-oxo-3-phenyl-1-imidazolidinyl and the like 2o are preferable.
As R5d of the formula: - (C=0) -Rsd represented by Rle, a hydrogen atom, a C1_6 alkyl group which may be halogenated (methyl, ethyl, trifluoromethyl and the like), a C6_19 alkyl group which may be halogenated (phenyl, naphthyl, 2s fluorophenyl, chlorophenyl and the like), etc. are preferable.
As RSd of the formula - (C=O) -ORSd represented by Rle, , a hydrogen atom, a C1_3 alkyl group (methyl, ethyl, etc.), etc.
are preferable.
As Rle, a C1_6 alkyl group (e . g. , methyl , ethyl , propyl , 3o isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) is preferable, particularly, a C1_3 alkyl group such as methyl, ethyl, propyl, etc. is preferable.
As specific examples of a substituent of the pyridyl group represented by RZe, 1 to 3, preferably 1 or 2 substituents selected from the following (1) to (6), particularly (1) to (4) are used.
( 1 ) a C1-6 alkyl group ( a . g . , methyl , ethyl , propyl , s isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like, preferably a Cl_4 alkyl group such as methyl, ethyl, propyl, butyl and the like): this C1_6 alkyl group may be substituted by a halogen atom, cyano, hydroxy, C3_8 cycloalkyl or 5- to 7-membered aliphatic heterocyclic io group containing hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms (e. g., 1-pyrralidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl, 3-piperazinyl, 4-piperazinyl, is morpholino, 2-morpholinyl, 3-morpholinyl, thiomorpholino, 2-thiomorpholinyl, 3-thiomorpholinyl, hexahydroazepin-1-yl and the like) , (2) a halogen atom (e. g., fluorine atom, chlorine atom, bromine atom, iodine atom), 2° (3) an amino group optionally having a substituent selected from the group consisting of the following 1) to 6):
1) a C1-6 alkyl group (e. g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like, preferably a C1_3 alkyl group such as Zs methyl, ethyl, propyl and the like): this C,_6 alkyl group may be substituted by a halogen atom, cyano, hydroxy, C3-$
cycloalkyl or 5- to 7-membered aliphatic heterocyclic group containing 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms 30 (e. g., 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl, 3-piperazinyl, 4-piperazinyl, morpholino, 2-morpholinyl, 3-morpholinyl, thiomorpholino, 2-thiomorpholinyl, 3-thiomorpholinyl, hexahydroazepin-1-yl and the like) , 2) a C3_$ cycloalkyl group (e. g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like), s 3) a C1_6 alkyl-carbonyl group (e. g., acetyl, propionyl, butyryl, valeryl, isovaleryl, 2-methylbutyryl, pivaloyl and the like): this C1_6 alkyl-carbonyl group may be substituted by a halogen atom, cyano, hydroxy, C3_8 cycloalkyl or 5- to 7-membered aliphatic heterocyclic group containing 1 to 4 io hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl, 3-piperazinyl, 4-piperszinyl, morpholino, 2-Is morpholinyl, 3-morpholinyl, thiomorpholino, 2-thiomorpholinyl, 3-thiomorpholinyl, hexahydroazepin-1-yl and the like), 4) a C1_6 alkoxy-carbonyl group (e. g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl 2o and the like) , 5) a C3_$ cycloalkyl-carbonyl group optionally substituted by C1_6 alkyl such as methyl, ethyl (e. g., cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, 1-methyl-cyclohexylcarbonyl and the like), 2s 6) a 5- to 7-membered aliphatic heterocyclic group having 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms (e. g., 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-so piperazinyl, 2-piperazinyl, 3-piperazinyl, 4-piperazinyl, morpholino, 2-morpholinyl, 3-morpholinyl, thiomorpholino, 2-thiomorpholinyl, 3-thiomorpholinyl, hexahydroazepin-1-yl and the like). This aliphatic heterocyclic group may be substituted by C1_6 alkyl (e.g. , methyl, ethyl) or C1_6 alkyl-carbonyl (e. g., acetyl, propionyl), 7) a 5- to 7-membered aliphatic heterocyclic (e.g., 1 pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, piperidino, 2 s piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2 piperazinyl, 3-piperazinyl, 4-piperazinyl, morpholino, 2-morpholinyl, 3-morpholinyl, thiomorpholino, 2-thiomorpholinyl, 3-thiomorpholinyl, hexahydroazepin-1-yl and the like)-carbonyl group having 1 to 4 hetero atoms selected from a to nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms. This aliphatic heterocyclic-carbonyl group may be substituted by Ci_6 alkyl (e. g. , methyl, ethyl) or C1_s alkyl-carbonyl (e. g., acetyl, propionyl), (4) a 5- or 7-membered saturated cyclic amino group is which may further contain 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms and one nitrogen atom (e. g., 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl and the like). This saturated cyclic amino group may be substituted with C1-s 2o alkyl (e. g., methyl, ethyl), and the like.
(5) a hydroxyl group, (6) a C1_6 alkyl-carbonyloxy group (e. g., acetyloxy, propionyloxy, butyryloxy and the like).
Of them, as a substituent of the pyridyl group 2s represented by R2b, for example, a C,_6 alkyl-carbonylamino group (e. g., acetylamino, propionylamino, butyrylamino, valerylamino, isovalerylamino, 2-methylbutyrylamino, pivaloylamino and the like) is preferable, and particularly, a C1_3 alkyl-carbonylamino group such as acetylamino, so propionylamino, etc. is preferable.
As the C6_14 aryl group represented by R3e, for example, phenyl, naphthyl, etc. are preferable, and of them, phenyl is particularly preferable.

As the 5- to 14-membered aromatic heterocyclic group preferably containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, represented by R3e, for example, a 5- or 6-membered aromatic heterocyclic group preferably containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, such as thienyl and the like, are preferable.
io As the C1_6 alkyl group which may be halogenated, which is a substituent of the C6_14 aryl group or the aromatic heterocyclic group, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. which may be substituted by a halogen atom (e. g., is fluorine, chlorine and the like) are used, and particularly, a C1-3 alkyl group which may be halogenated such as methyl, ethyl, propyl, trifluoromethyl and the like are preferable.
As the C1_6 alkoxy which is a substituent of the C6-i4 aryl group or the aromatic heterocyclic group, for example, 2o methoxy, ethoxy, propoxy, etc. are used, and of them, methoxy is particularly preferable.
As the halogen atom which is a substituent of the C6_14 aryl group or the aromatic heterocyclic group, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom are 2s used, and of them, a fluorine atom and a chlorine atom, etc.
are preferable.
As the C1_6 alkoxy-carbonyl which is a substituent of the C6_14 aryl group or the aromatic heterocyclic group, for example, methoxycarbonyl, ethoxycarbonyl and the like are 3o preferable.
As the C1_6 alkylthio which is a substituent of the C6_19 aryl group for example, methylthio, ethylthio and the like are preferable.

As the C1_s alkylsulfonyl which is a substituent of the Cs-i4 aryl group, for example, methylsulfonyl, ethylsulfonyl and the like are preferable.
As R3e, a Cs_1q aryl group optionally having a substituent selected from the group consisting of C1_s alkyl and a halogen atom is preferable, and a phenyl group optionally substituted by methyl or a chlorine atom is more preferable.
As the compound (VIa), for example, io (1) the compound (VIa) wherein Rl~ is a C1_s alkyl group optionally having a substituent selected from the group consisting of a halogen atom, hydroxy, C1_s alkoxy, C1-s alkylthio, C1_s alkylsulfinyl and C1_s alkylsulfonyl, R2e is a C1_s alkyl-carbonylamino group or a C3_e cycloalkylamino group, 3s Rse is a Cs_14 aryl group optionally having a substituent selected from the group consisting of C1_s alkyl and a halogen atom, (2) the compound (VIa) wherein Rle is a C1_3 alkyl group optionally having a substituent selected from the group 2o consisting of a halogen atom, hydroxy, C1_s alkoxy, C1-s alkylthio, Cl_s alkylsulfinyl and C1_s alkylsulfonyl, RZe is a C1_3 alkyl-carbonylamino group or a C3_8 cycloalkylamino group, R3e is a phenyl group optionally having a substituent selected from the group consisting of methyl or a chlorine 25 atom, and the like are preferable.
As preferable specific examples of the compound (VIa), compounds produced in Reference Examples H 1 to 113 described later are exemplified, and of them, 5-[2-(tert-butoxycarbonylamino)-4-pyridyl]-2-ethyl-4-(3-methylphenyl)-30 1,3-thiazol (Reference Example H 3), [4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]amine (Reference Example H 7-4), 2-ethyl-5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazole (Reference Example H 11), 5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-2-[4-(methylthio)phenyl]-1,3-thiazole (Reference Example H 15), 4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-2-[4-(methylthio)phenyl]-1,3-thiazole (Reference Example H 16-1), 4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine (Reference Example H 22), N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]acetamide (Reference Example H 29-2), N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]propionamide (Reference Example H
io 29-4), N-[4-[4-(3-chlorophenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl]acetamide (Reference Example H 30-1), N-[4-[4-(3-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-2-pyridyl]acetamide (Reference Example H 30-2), N-[4-[4-(3-chlorophenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]acetamide (Reference is Example H 30-3) , N- [4- [4- (3-chlorophenyl) -2-methyl-1, 3-thiazol-5-yl]-2-pyridyl]propionamide (Reference Example H 30-7), N-[4-[4-(3-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-2-pyridyl]propionamide (Reference Example H 30-8) , N-[4-[4-(3-chlorophenyl)-2-propyl-1,3-thiazol-5-yl]-2-2o pyridyl]propionamide (Reference Example H 30-9), N-cyclohexyl-4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine (Reference Example H 36-4), N-cyclohexyl-4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine (Reference Example H 36-5), N-cyclopentyl-2s 4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine (Reference Example H 36-6), N-cyclopentyl-4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine (Reference Example H 36-7), 4-[4-(3-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-N-cyclohexyl-2-so pyridylamine (Reference Example H 36-10), 4-[4-(3-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-N-cyclopentyl-2-pyridylamine (Reference Example H 36-11), N-[4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]acetamide (Reference Example H 39), N-[4-(3,5-dimethylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]nicotinamide (Reference Example H 42-1), 6-chloro-N-[4-(3,5-dimethylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]nicotinamide (Reference Example H 44-3), N-[4-(3,5-dimethylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]-6-methylnicotinamide (Reference Example H 46-3), N-[4-(3,5-dimethylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]-6-methoxynicotinamide (Reference Example H 48-3), 4-(3-io methylphenyl ) -5- ( 2-methyl-4-pyridyl ) -2- ( 4-methylsulfinylphenyl)-1,3-thiazole (Reference Example H 54), 4- (3-methylphenyl) -5- (2-methyl-4-pyridyl) -2.- (4-methylsulfonylphenyl)-1,3-thiazole (Reference Example H 57), 5- ( 2-f luoro-4-pyridyl ) -4- ( 3-methylphenyl ) -2- ( 4-zs methylsulfonylphenyl)-1,3-thiazole (Reference Example H 58-4), N-[4-[4-(3-chlorophenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]acetamide (Reference Example H 58-6), N-[4-[4-(3-chlorophenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]propionamide (Reference Example H 58-20 7) , N- [4- [4- (3-chlorophenyl) -2- (4-methylsulfonylphenyl) -1, 3-thiazol-5-yl]-2-pyridyl]pivalamide (Reference Example H 58-8) and the like are preferable.
The compounds (IV) , (V) and (VI) of the present invention do not include N-[4-(3,5-dimethylphenyl)-5-(2-2s hydroxy-4-pyridyl)-1,3-thiazol-2-yl]acetamide and 4-[2-(acetylamino)-4-(3,5-dimethylphenyl)-1,3-thiazol-2-yl]-2-pyridyl acetate.
As a salt of the compound (IV) , (V) or (VI) of the present invention, for example, metal salts, ammonium salts, so salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. are exemplified. As suitable examples of metal salts, for example, alkali metal salts such as sodium salts, potassium salts and the like; alkaline earth metal salts such as potassium salts, magnesium salts, barium salts and the like; aluminum salts; etc. are exemplified. As suitable examples of salts with organic bases, for example, salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, etc. are exemplified. As suitable examples of salts with inorganic acids, for example, salts io with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. are exemplified. As suitable examples of salts with organic acids, for example, salts with formic acid, acetic acid, trifluoroacetic acid, phthalic.acid, fumaric acid, oxalic acid, tartaric acid, malefic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. are exemplified. As suitable examples of salts with basic amino acids, for example, salts with arginine, lysine, ornithine, etc. are exemplified, and as suitable 2o examples of salts with acidic amino acids, for example, salts with aspartic acid, glutamic acid, etc. are exemplified.
Of them, pharmaceutically acceptable salts are preferable. When an acidic functional group is contained in a compound, for example, inorganic salts such as alkali metal 2s salts (e. g., sodium salts, potassium salts and the like), alkaline earth metal salts (e. g., calcium salts, magnesium salts, barium salts and the like), and ammonium salts, etc.
are exemplified, and when a basic functional group is contained in a compound, for example, salts with inorganic 3o acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. or salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, malefic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, etc. are preferable.
A method for producing the compound (IV), (V), (VI) or a salt thereof of the present invention will be illustrated below. Hereinafter, the compound (I') means a compound including compounds (IV) , (V) , (VI) , (Va) and (VIa) .
The compound (I) of the present invention is obtained by a method represented by the following reaction formula 1 or methods according to this method, and additionally, obtained, for example, by methods described in JP-A No. 60-58981, JP-A No. 61-10580, JP-T No. 7-503023, WO 93/15071, DE-A-3601411, JP-A No. 5-70446 and methods according to them.
Symbols of compounds in the following reaction formulae 1 to 2 are as defined above. Compounds in the reaction I5 formulae also include salts, and as this salt, for example, the same salts as for the compound (IV) are exemplified.
Reaction Formula 1 R3~COR~
R CH CN ( I I I ' ) R2~CH-CORD H+
2c-(I I' > cN (IV' ) R2~-CH2COR~
(VIII') e~
R2°-CHg 2c- R3~COR9~

(V' ) (VI' ) (VI I' ) H
R2~-C-COR3 I
Hal (IX') S
R~~-C-NH2 (X' ) (I' ) When compounds (II' ) , (III' ) , (V' ) , (VII' ) , (XI' ) , (XIII' ) and (XIV' ) are commercially available, they may be used without any treatment, and also can be produced by methods known per se or methods according to them.
The compound (IV') is obtained by condensing a compound (II') with a compound (III') in the presence of a base.
In the compound ( I I I ' ) , R8° represents , for example , ( 1 ) a Cl_6 alkoxy (e. g. , methoxy, ethoxy and the like) , (2) a di-C1_6 alkylamino (e.g., dimethylamino, diethylamino and the like) , (3) an N-C6_lo aryl-N-C1_6 alkylamino (e.g. , N-phenyl-N-zo methylamino and the like), (4) a 3- to 7-membered saturated cyclic amino optionally substituted with a C6_lo aryl and (or) C1_6 alkyl (e. g., pyrrolidin-1-yl, morpholino, methylaziridin-1-yl, and the like), etc.
The amount of the compound (III') used is about 0.5 to Is about 3.0 mol, preferably about 0.8 to about 2.0 mol per mol of the compound (II').
The amount of a base used is about 1.0 to about 30 mol, preferably about 1.0 to about 10 mol per mol of the compound (II' ) .
2o As the ~base", for example, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and the like, inorganic bases such as sodium hydroxide, potassium hydroxide and the like, aromatic amines such as pyridine, lutidine and the like, tertiary amines such triethylamine, tripropylamine, 25 tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like, alkali metal hydrides such as sodium hydride, potassium hydride and the like, metal amides such as sodium 3o amide, lithium diisopropylamide, lithium hexamethyldisilazide and the like, metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like, etc.
are exemplified.

The present reaction is advantageously conducted in the absence or presence of a solvent inactive to the reaction.
This solvent is not particularly restricted providing the reaction can progress, and for example, halogenated hydrocarbons,' aliphatic hydrocarbons, aromatic hydrocarbons, ethers, amides, alcohols, water or mixtures of two or more of them, etc. are used.
The reaction temperature is usually from about -5°C to about 200°C, preferably from about 5°C to about 150°C.
The io reaction time is usually from about 5 minutes to about 72 hours, preferably from about 0.5 to about 30 hours.
The product can be used in the following reaction as the reaction solution itself or as a crude product, and can also be isolated from the reaction mixture according to an 15 ordinary method, and can be easily purified by separation means such as recrystallization, distillation, chromatography and the like.
A compound (VIII') is obtained by treating a compound (IV') with an acid.
2o The amount of an acid used is about 1.0 to about 100 mol, preferably about 1.0 to about 30 mol per mol of the compound ( IV' ) .
As the "acid", for example, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, etc. are used.
The present reaction is conducted in the presence of a solvent inactive to the reaction. The solvent is not particularly restricted providing the reaction can progress, and for example, water, mixtures of water with amides, so mixtures of water with alcohols, etc. are used.
The reaction temperature is usually from about 20°C to about 200°C, preferably from about 60°C to about 150°C.
The reaction time is usually from about 30 minutes to about 72 hours, preferably from about 1 hour to about 30 hours.
The product can be used in the following reaction as the reaction solution itself or as a crude product, and can also be isolated from the reaction mixture according to an ordinary method, and can be easily purified by separation means such as recrystallization, distillation, chromatography and the like.
A compound (VIII') can also be obtained by condensing a compound (VII') with a compound (VI') obtained by treating a io compound (V' ) with a base .
In the compound (VI'), M represents, for example, an alkali metal such as lithium, sodium, potassium and the like.
In the compound (VII'), as R9, for example, the same moieties as for RB are exemplified.
is The amount of a base used is about 1.0 to about 30 mol, preferably about 1.0 to about 10 mol per mol of the compound (V' ) .
As the "base", for example, metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide 2o and the like, and alkyl metal compounds such as alkyllithium and the like are used.
The present reaction is advantageously conducted in the absence or presence of a solvent inactive to the reaction.
This solvent is not particularly restricted providing the 25 reaction can progress, and for example, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, or mixtures of two or more of them, etc. are used.
The reaction temperature is usually from about -78°C to about 60°C, preferably from about -78°C to about 20°C.
The so reaction time is usually from about 5 minutes to about 24 hours, preferably from about 0.5 to about 3 hours.
The product can be used in the following reaction as the reaction solution itself or as a crude product, and can also be isolated from the reaction mixture according to an ordinary method, and can be easily purified by separation means such as recrystallization, distillation, chromatography and the like.
A compound (IX') is obtained by treating a compound (VIII') with halogens. This reaction is conducted in the presence of a base or basic salt, if necessary.
In the compound (IX'), Hal represents halogens.
The amount of halogens used is about 1.0 to about 5.0 io mol, preferably about 1.0 to about 2.0 mol per mol of the compound (VIII').
As the "halogens", bromine, chlorine, iodine, etc. are exemplified.
The amount of a base used is about 1.0 to about 10.0 Is mol, preferably about 1.0 to about 3.0 mol per mol of the compound (VIII').
As the "base", for example, aromatic amines such as pyridine, lutidine and the like, tertiary amines such triethylamine, tripropylamine, tributylamine, 2o cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like, etc. are exemplified.
The amount of a basic salt used is about 1.0 to about 10.0 mol, preferably about 1.0 to about 3.0 mol per mol of 2s the compound (VIII').
As the "basic salt", for example, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium acetate, potassium acetate, etc. are exemplified.
3o The present reaction is advantageously conducted in the absence or presence of a solvent inactive to the reaction.
This solvent is not particularly restricted providing the reaction can progress, and for example, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, organic acids, aromatic amines, or mixtures of two or more of them, etc. are used.
The reaction temperature is usually from about -20°C to about 150°C, preferably from about 0°C to about 100°C.
The reaction time is usually from about 5 minutes to about 24 hours, preferably from about 10 minutes to about 5 hours.
The product can be used in the following reaction as the reaction solution itself or as a crude product, and can Io also be isolated from the reaction mixture according to an ordinary method, and can be easily purified by separation means such as recrystallization, distillation, chromatography and the like.
A compound (I') can be obtained by condensing a is compound (IX') with a compound (X'). The present reaction is conducted in the presence of a base, if necessary.
When the compound (X') is commercially available, it may be used without any treatment, and also can be obtained by methods known per se or methods according to them, further, 2o can be obtained by a method of the following reaction formula 2, etc.
The amount of the compound (X') used is about 0.5 to about 3.0 mol, preferably about 0.8 to about 2.0 mol per mol of the compound (IX').
25 The amount of a base used is about 1.0 to about 30 mol, preferably about 1.0 to about 10 mol per mol of the compound (IX') .
As the "base", for example, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium 3o hydrogen carbonate and the like, aromatic amines such as pyridine, lutidine and the like, tertiary amines such triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like, etc. are exemplified.
The present reaction is advantageously conducted in the absence or presence of a solvent inactive to the reaction.
This solvent is not particularly restricted providing the reaction can progress, and for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, amides, alcohols, nitriles, or mixtures of two or more of them, etc. are used.
to The reaction temperature is from about -5°C to about 200°C, preferably from about 5°C to about 150°C. The reaction time is usually from about 5 minutes to about 72 hours, preferably from about 0.5 to about 30 hours.
The product can be used in the following reaction as IS the reaction solution itself or as a crude product, and can also be isolated from the reaction mixture according to an ordinary method, and can be easily purified by separation means such as recrystallization, distillation, chromatography and the like.
2o Reaction Formula 2 R'°H
R ~ o~ CONCS R~ o° CONH-C-R ~
(XI' ) (XI I' R~°-CN H2S or (Et0) 2PSSH Hydro I ys i s (X111') R~°-CONH2 R~~-C-NHZ
(X I V' ) PaS' o (X' ) Lawesson's reagent A compound (XII') can be obtained by condensing a compound (XI' ) with amines represented by R1~H.

In the compound (XI' ) , R1°° represents an aromatic hydrocarbon group or alkoxy. As the "aromatic hydrocarbon group", a phenyl group optionally having a substituent, etc.
are listed. As the "alkoxy", for example, C1_6 alkoxys such as methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like, etc. are exemplified.
The amount of the "amines" used is about 1.0 to about 30 mol, preferably about 1.0 to about 10 mol per mol of the compound (XI' ) .
io The present reaction is advantageously conducted in the absence or presence of a solvent inactive to the reaction.
This solvent is not particularly restricted providing the reaction can progress, and for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, 15 ethers, amides, alcohols, nitriles, ketones, or mixtures of two or more of them, etc. are used.
The reaction temperature is from about -5°C to about 200°C, preferably from about 5°C to about 120°C. The reaction time is usually from about 5 minutes to about 72 hours, 2o preferably from about 0.5 to about 30 hours.
The product can be used in the following reaction as the reaction solution itself or as a crude product, and can also be isolated from the reaction mixture according to an ordinary method, and can be easily purified by separation 2s means such as recrystallization, distillation, chromatography and the like.
A compound (X') can be obtained by hydrolyzing the compound (XII') with an acid or base.
The amount of the acid or base used is about 0.1 to so about 50 mol, preferably about 1 to about 20 mol, respectively, per mole of the compound (XII').
As the "acid", for example, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like, Lewis acids such as boron trichloride, boron tribromide and the like, co-use of Lewis acids with thiols or sulfides, and organic acids such as trifluoroacetic acid, p-toluenesulfonic acid and the like, etc. are used.
s As the "base", for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide and the like, basic salts such as sodium carbonate, potassium carbonate and the like, metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the io like, organic bases such as triethylamine, imidazole, formamidine and the like, etc. are used.
The present reaction is advantageously conducted in the absence or presence of a solvent inactive to the reaction.
This solvent is not particularly restricted providing the ~s reaction can progress, and for example, alcohols, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, halogenated hydrocarbons, sulfoxides, water or mixtures of two or more of them, etc. are used.
The reaction time is usually from about 10 minutes to 2o about 50 hours, preferably from about 30 minutes to about 12 hours. The reaction temperature is usually from about 0°C to about 200°C, preferably from about 20°C to about 120°C.
A compound (X') can also be obtained by treating a compound (XIII') with hydrogen sulfide in the presence of a 2s base.
The amount of hydrogen sulfide used is about 1 to about 30 mol per mol of the compound (XIII').
The amount of a base used is about 1.0 to about 30 mol, preferably about 1,0 to about 10 mol per mol of the compound 30 (XIII' ) .
As the "base", for example-, aromatic amines such as pyridine, lutidine and the like, tertiary amines such triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like, etc. are used.
The present reaction is advantageously conducted in the absence or presence of a solvent inactive to the reaction.
This solvent is not particularly restricted providing the reaction can progress, and for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, aromatic amines, or mixtures of two or more of them, to etc. are used.
The present reaction is effected under normal pressure or positive pressure. The reaction temperature is usually from about -20°C to about 80°C, preferably from about -10°C to about 30°C. The reaction time is usually from about 5 j5 minutes to about 72 hours, preferably from about 0.5 to about 30 hours.
The product can be used in the following reaction as the reaction solution itself or as a crude product, and can also be isolated from the reaction mixture according to an 20 ordinary method, and can be easily purified by separation means such as recrystallization, distillation, chromatography and the like.
A compound (X') can also be obtained by treating a compound (XIII') with dithiophosphoric acid 0,0-diethyl ester 25 in the presence of an acid.
The amount of dithiophosphoric acid 0,0-diethyl ester used is about 0.9 to about 2 mol per mole of the compound (XIII' ) .
The amount of an acid used is about 3.0 to about 30 mol, so preferably about 3.0 to about 10 mol per mol of the compound (XIII' ) .
As the "acid", for example, hydrogen halides such as hydrogen chloride, hydrogen bromide and the like, and mineral acids such as hydrochloric acid, hydrobromic acid and the like, etc. are exemplified.
The present reaction is advantageously conducted in the absence or presence of a solvent inactive to the reaction.
This solvent is not particularly restricted providing the reaction can progress, and for example, halogenated hydrocarbons, alcohols, amides, ethers, esters, water, or mixtures of two or more of them, etc. are used.
The reaction temperature is usually from about 0°C to io about 80°C, preferably from about 0°C to about 30°C.
The reaction time is usually from about 5 minutes to about 72 hours, preferably from about 0.5 hours to about 30 hours.
The product can be used in the following reaction as the reaction solution itself or as a crude product, and can 15 also be isolated from the reaction mixture according to an ordinary method, and can be easily purified by separation means such as recrystallization, distillation, chromatography and the like.
A compound (X') can also be obtained by treating a 2o compound (XIV') with phosphorus pentasulfide or a Lawesson's reagent.
The amount of the phosphorus pentasulfide or Lawesson's reagent used is about 0.5 to about 10 mol, preferably about 0.5 to about 3 mol per mole of the compound (XIV').
25 The present reaction is advantageously conducted in the absence or presence of a solvent inactive to the reaction.
This solvent is not particularly restricted providing the reaction can progress, and for example, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, halogenated so hydrocarbons, or mixtures of two or more of them, etc. are used.
The reaction time is usually from about 10 minutes to about 50 hours, preferably from about 30 minutes to about 12 hours. The reaction temperature is usually from about 0°C to about 150°C, preferably from about 20°C to about 120°C.
The product (X') can be used in the following reaction as the reaction solution itself or as a crude product, and can also be isolated from the reaction mixture according to an ordinary method, and can be easily purified by separation means such as recrystallization, distillation, chromatography and the like.
When the compound (I') is an acylamino compound, the to corresponding amine can be subjected to an acylation reaction known per se to obtain the intended substance.
For example, of compounds (I'), that in which a substituent at the 2-position of a thiazole ring is acylamino optionally having a substituent is obtained by reacting the IS corresponding 2-thiazolamine and acylating agent, if necessary, in the presence of a base or acid.
The amount of the acylating agent used is about 1.0 to about 5.0 mol, preferably about 1.0 to about 2.0 mol per mol of the corresponding 2-thiazolamine.
2o As the ~acylating agent", for example, carboxylic acids corresponding to the acyl group of the intended substance, or reactive derivatives thereof (e. g., acid halide, acid anhydride, ester and the like), etc. are exemplified.
The amount of a base or acid used is about 0.8 to about 25 5.0 mol, preferably about 1.0 to about 2.0 mol per mol of the corresponding 2-thiazolamine.
As the "base", for example, triethylamine, pyridine, 4-dimethylaminopyridine, etc. are exemplified.
As the "acid", for example, methanesulfonic acid, p-3o toluenesulfonic acid, camphor-sulfonic acid, etc. are exemplified.
The present reaction is advantageously conducted in the absence or presence of a solvent inactive to the reaction.

This solvent is not particularly restricted providing the reaction can progress, and for example, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, aromatic amines, or mixtures of two or more of them, etc. are used.
The reaction temperature is from about -20°C to about 150°C, preferably from about 0°C to about 100°C. The reaction time is usually from about 5 minutes to about 24 hours, preferably from about 10 minutes to about 5 hours.
io The product can be used in the following reaction as the reaction solution itself or as a crude product, and can also be isolated from the reaction mixture according to an ordinary method, and can be easily purified by separation means such as recrystallization, distillation, chromatography 15 and the like.
Further, of compounds (I'), that in which a substituent at the 5-position of a thiazole ring is acylaminopyridyl optionally having a substituent is obtained by reacting the corresponding 5-(2-aminopyridyl)thiazole and acylating agent, if necessary in the presence of a base or acid.
The amount of the acylation agent used is from about 1.0 to about 5.0 mol, preferably from about 1.0 to about 2.0 mol per mol of the corresponding 5-(2-aminopyridyl)thiazole.
As the "acylating agent", for example, carboxylic acids 25 corresponding to the acyl group of the intended substance, or reactive derivatives thereof (e. g., acid halide, acid anhydride, ester and the like), etc. are exemplified.
The amount of a base or acid used is from about 0.8 to about 5.0 mol, preferably from about 1.0 to about 2.0 mol per 3o mol of the corresponding 5-(2-aminopyridyl)thiazole.
As the "base", for example, triethylamine, pyridine, 4-dimethylaminopyridine, etc. are exemplified.
As the "acid", for example, methanesulfonic acid, p-toluenesulfonic acid, camphor-sulfonic acid, etc. are exemplified.
The present reaction is advantageously conducted in the absence or presence of a solvent inactive to the reaction.
This solvent is not particularly restricted providing the reaction can progress, and for example, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, aromatic amines, or mixtures of two or more of .them, etc. are used.
1o The reaction temperature is from about -20°C to about 150°C, preferably from about 0°C to about 100°G. The reaction time is usually from about 5 minutes to about 24 hours, preferably from about 10 minutes to about 5 hours.
The product can be used in the following reaction as IS the reaction solution itself or as a crude product, and can also be isolated from the reaction mixture according to an ordinary method, and can be easily purified by separation means such as recrystallization, distillation, chromatography and the like.
2o Of compounds (I'), that in which a substituent at the 5-position of a thiazole ring is alkylaminopyridyl optionally having a substituent is obtained by reducing the corresponding acylaminopyridine with a reducing agent.
The amount of the reducing agent used is from about 1.0 25 to about 5.0 mol, preferably from about 1.0 to about 3.0 mol per mol of the corresponding acylaminopyridine.
As the "reducing agent", for example, metal hydrides such as aluminum hydride, diisobutylaluminum hydride and the like, metal hydrogen complex compounds such as lithium so aluminum hydride, sodium boron hydride and the like, borane complexes such as borane tetrahydrofuran complex, borane dimethylsulfide complex and the like, alkyl boranes such as thexyl borane, dicyamyl borane and the like, etc. are exemplified.
In the present reaction, an acid is also added together with a reducing agent, if necessary.
The amount of an acid used is from about 0.8 to about s 5.0 mol, preferably from about 1.0 to about 3.0 mol per mol of the corresponding acylaminopyridine.
As the "acid", for example, Lewis acids such as aluminum chloride and the like, are exemplified.
The present reaction is advantageously conducted in the io absence or presence of a solvent inactive to the reaction.
This solvent is not particularly restricted providing the reaction can progress, and for example, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, halogenated hydrocarbons, or mixtures of two or more of them, etc. are Is used.
The reaction temperature is from about -78°C to about 150°C, preferably from about 0°C to about 100°C. The reaction time is usually from about 5 minutes to about 24 hours, preferably from about 10 minutes to about 5 hours.
20 The product can be used in the following reaction as the reaction solution itself or as a crude product, and can also be isolated from the reaction mixture according to an ordinary method, and can be easily purified by separation means such as recrystallization, distillation, chromatography 2s and the like.
Of compounds (I'), that in which a substituent at the 5-position of a thiazole ring is alkylaminopyridyl optionally having a substituent is obtained by condensing the corresponding 5-(2-halogenopyridyl)thiazole with amines.
3o The amount of the amine used is from about 1.0 to about 100.0 mol, preferably from about 1.0 to about 20.0 mol per mol of the corresponding 5-(2-halogenopyridyl)thiazole.
As the halogen of the "5-(2-halogenopyridyl)thiazole", fluorine, chlorine, bromine, iodine, etc. are exemplified.
As the "amines", for example, aliphatic amines and cyclic amines corresponding to the intended alkylamine, etc.
are exemplified.
The present reaction is conducted, if necessary in the presence of a base or basic salt.
The amount of the base used is from about 1.0 to about 10.0 mol, preferably from about 1.0 to about 3.0 mol per mol of the corresponding 5-(2-halogenopyridyl)thiazole.
to As the "base", for example, aromatic amines such as pyridine, lutidine and the like, tertiary amines such triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-15 methylmorpholine and the like, etc. are used.
The amount of the basic salt used is from about 1.0 to about 10.0 mol, preferably from about 1.0 to about 3.0 mol per mol of the corresponding 5-(2-halogenopyridyl)thiazole.
As the "basic salt", for example, sodium carbonate, 2o potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium acetate, potassium acetate, etc. are used.
The present reaction is advantageously conducted in the absence or presence of a solvent inactive to the reaction.
This solvent is not particularly restricted providing the 25 reaction can progress, and for example, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, amides, halogenated hydrocarbons, nitrites, water or mixtures of two or more of them, etc. are used.
The reaction temperature is from about 0°C to about 30 300°C, preferably from about 20°C to about 200°C. The reaction time is usually from about 5 minutes to about 48 hours, preferably from about 10 minutes to about 15 hours.
The product can be used in the following reaction as the reaction solution itself or as a crude product, and can also be isolated from the reaction mixture according to an ordinary method, and can be easily purified by separation means such as recrystallization, distillation, chromatography and the like.
When the compound (I') is an N-oxide, it is obtained by treating the corresponding pyridyl compound with an organic peracid.
The amount of the organic peracid used is from about io p,g to about 10 mol, preferably from about 1.0 to about 3.0 mol per mol of the corresponding pyridyl compound.
As the above-mentioned "organic peracid", for example, peracetic acid, pertrifluoroacetic acid, m-chloroperbenzoic acid, etc. are exemplified.
Zs The present reaction is advantageously conducted in the absence or presence of a solvent inactive to the reaction.
This solvent is not particularly restricted providing the reaction can progress, and for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, 20 organic acids, ethers, amides, sulfoxides, alcohols, nitriles, ketones or mixtures of two or more of them, etc. are used.
The reaction temperature is from about -20°C to about 130°C, preferably from about 0°C to about 100°C. The reaction time is usually from about 5 minutes to about 72 hours, 2s preferably from about 0.5 to about 12 hours.
Further, an N-oxide can also be obtained by treating the corresponding pyridyl compound with hydrogen peroxide or alkyl hydroperoxide, if necessary in the presence of a base, acid or metal oxide.
so The amount of the hydrogen peroxide or alkyl hydroperoxide used is from about 0.8 to about 10 mol, preferably from about 1.0 to about 3.0 mol per mol of the corresponding pyridyl compound.

As the above-mentioned ~alkyl hydroperoxide", for example, tert-butyl hydroperoxide, cumene hydroperoxide, etc.
are exemplified.
The amount of the base, acid or metal oxide used is s from about 0.1 to about 30 mol, preferably from about 0.8 to about 5 mol per mol of the corresponding pyridyl compound.
As the above-mentioned ~base", for example, inorganic bases such as sodium hydroxide, potassium hydroxide and the like, basic salts such as sodium carbonate, potassium zo carbonate and the like, etc. are exemplified.
As the above-mentioned ~acid", for example, mineral acids such as hydrochloric acid, sulfuric acid, perchloric acid and the like, Lewis acids such as boron trifluoride, aluminum chloride, titanium tetrachloride and the like, ~s organic acids such as formic acid, acetic acid and the like, etc. are exemplified.
As the above-mentioned ~metal oxide", for example, vanadium oxide (VZ05) , osmium tetraoxide (0s04) , tungsten oxide (W03) , molybdenum oxide (Mo03) , selenium dioxide (Se02) , 2o chromium oxide (Cr03), etc. are exemplified.
The present reaction is advantageously conducted in the absence or presence of a solvent inactive to the reaction.
This solvent is not particularly restricted providing the reaction can progress, and for example, halogenated 2s hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, organic acids, ethers, amides, sulfoxides, alcohols, nitriles, ketones or mixtures of two or more of them, etc. are used.
The reaction temperature is from about -20°C to about 130°C, preferably from about 0°C to about 100°C. The reaction so time is usually from about 5 minutes to about 72 hours, preferably from about 0.5 to about 12 hours.
The product can be used in the following reaction as the reaction solution itself or as a crude product, and can also be isolated from the reaction mixture according to an ordinary method, and can be easily purified by separation means such as recrystallization, distillation, chromatography and the like.
s When the compound (I') is an S-oxide, it is obtained by treating the corresponding sulfide with a peroxide.
The amount of the peroxide used is from about 0.8 to about 10 mol, preferably from about 1.0 to about 3.0 mol per mol of the corresponding sulfide.
As the above-mentioned "peracid", for example, peracetic acid, pertrifluoroacetic acid, m-chloroperbenzoic acid, potassium persulfate, meta-periodic acid, etc. are exemplified.
The present reaction is advantageously conducted in the Is absence or presence of a solvent inactive to the reaction.
This solvent is not particularly restricted providing the reaction can progress, and for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, organic acids, ethers, amides, sulfoxides, alcohols, nitriles, 2o ketones or mixtures of two or more of them, etc. are used.
The reaction temperature is from about -20°C to about 130°C, preferably from about 0°C to about 100°C. The reaction time is usually from about 5 minutes to about 72 hours, preferably from about 0.5 to about 12 hours.
2s Further, an S-oxide can also be obtained by treating the corresponding sulfide with hydrogen peroxide or alkyl hydroperoxide, if necessary in the presence of a base,. acid or metal oxide.
The amount of the hydrogen peroxide or alkyl 3o hydroperoxide used is from about 0.8 to about 10 mol, preferably from about 1.0 to about 3.0 mol per mol of the corresponding sulfide.
As the above-mentioned "alkyl hydroperoxide", for example, tert-butyl hydroperoxide, cumene hydroperoxide, etc.
are exemplified.
The amount of the "base, acid or metal oxide" used is from about 0.1 to about 30 mol, preferably from about 0.8 to s about 5 mol per mol of the corresponding sulfide.
As the above-mentioned "base", for example, inorganic bases such as sodium hydroxide, potassium hydroxide and the like, basic salts such as sodium carbonate, potassium carbonate and the like, etc. are exemplified.
1o As the above-mentioned ~acid", for example, mineral acids such as hydrochloric acid, sulfuric acid, perchloric acid and the like, Lewis acids such as boron trifluoride, aluminum chloride, titanium tetrachloride and the like, organic acids such as formic acid, acetic acid and the like, is etc. are exemplified.
As the above-mentioned "metal oxide", for example, vanadium oxide (V205) , osmium tetraoxide (0s04) , tungsten oxide (W03) , molybdenum oxide (Mo03) , selenium dioxide (Se02) , chromium oxide (Cr03), etc. are exemplified.
2o The present reaction is advantageously conducted in the absence or presence of a solvent inactive to the reaction.
This solvent is not particularly restricted providing the reaction can progress, and for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, 2s organic acids, ethers, amides, sulfoxides, alcohols, nitriles, ketones or mixtures of two or more of them, etc. are used.
The reaction temperature is from about -20°C to about 130°C, preferably from about 0°C to about 100°C. The reaction time is usually from about 5 minutes to about 72 hours, so preferably from about 0.5 to about 12 hours.
The product can be used in the following reaction as the reaction solution itself or as a crude product, and can also be isolated from the reaction mixture according to an ordinary method, and can be easily purified by separation means such as recrystallization, distillation, chromatography and the like.
In the above-mentioned reactions, when a starting material has amino, carboxy, hydroxy as a substituent, a protective group as generally used may be introduced into these groups by peptide chemistry and the like, and the intended compound can be obtained by removing the protective group after the reaction, if necessary.
to As the protective group for amino, for example, formyl or, C1_s alkyl-carbonyls (e.g., acetyl, propionyl and the like), phenylcarbonyl, C1_s alkoxy-carbonyls (e. g., methoxycarbony, ethoxycarbonyl and the like), phenyloxycarbonyl, C~-to aralkyloxy-carbonyls (e. g., 15 benzyloxycarbonyl and the like), trityl, phthaloyl, each optionally having a substituent, etc. are used. As these substituents, halogen atoms (e. g., fluorine, chlorine, bromine, iodine and the like), C1_s alkyl-carbonyls (e. g., acetyl, propionyl, valeryl and the like), nitro, etc. are 2o used, and the number of the substituent is 1 to 3.
As the protective group for carboxy, for example, C1-s alkyls (e. g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like), phenyl, trityl, silyl, each optionally having a substituent, etc. are used. As these substituents, 25 halogen atoms (e.g., fluorine, chlorine, bromine, iodine and the like) , formyl, C1_s alkyl-carbonyls (e. g. , acetyl, propionyl, butylcarbonyl and the like), nitro, C1_s alkyls (e. g., methyl, ethyl, tert-butyl and the like), Cs-to aryls (e.g., phenyl, naphthyl and the like), etc. are used, and the 3o number of the substituent is 1 to 3.
As the protective group for hydroxy, for example, C1-s alkyls (e. g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like), phenyl, C~_11 aralkyls (e.g., benzyl and the like) , formyl, C1_6 alkyl-carbonyls (e.g. , acetyl, propionyl and the like), phenyloxycarbonyl, C~_11 aralkyloxy-carbonyls (e. g., benzyloxycarbonyl and the like), tetrahydropyranyl, tetrahydrofuranyl, and silyl, each optionally having a substituent, and so on are used. As these substituents, halogen atoms (e. g., fluorine, chlorine, bromine, iodine and the like), C1_6 alkyls (e. g., methyl, ethyl, tert-butyl and the like), C~_11 aralkyls (e. g., benzyl and the like) , C6-to aryls (e. g. , phenyl, naphthyl and the like), nitro, etc. are used, and the number of the substituent is 1 to 4.
For removing a protective group, method known per se or methods according to them are used, and for example, methods for treating with an acid, a base, ultraviolet ray, hydrazine, 15 phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate and the like, or reducing methods are used.
In any case, further if necessary, the compound (I) can be synthesized by using known de-protection reactions, acylation reactions, alkylation reactions, hydrogenation reactions, oxidation reactions, reduction reactions, carbon chain extension reactions, substituent interchange reactions, each alone or in combination of two or more of them. As these reactions, for example, methods described in 25 Shinjikkenkagakukoza 14, vol. 15, 1977 (Maruzen Press), etc.
are adopted.
As the above-mentioned ~alcohols", for example, methanol, ethanol, propanol, isopropanol, tert-butanol, etc.
are exemplified.
so As the above-mentioned "ethers", for example, diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc. are exemplified.
As the above-mentioned ~halogenated hydrocarbons", for example, dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, etc. are exemplified.
As the above-mentioned "aliphatic hydrocarbons", for example, hexane, pentane, cyclohexane, etc. are exemplified.
As the above-mentioned "aromatic hydrocarbons", for example, benzene, toluene, xylene, chlorobenzene, etc. are exemplified.
As the above-mentioned "aromatic amines", for example, pyridine, lutidine, quinoline, etc. are exemplified.
io As the above-mentioned "amides", for example, N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, etc. are exemplified.
As the above-mentioned "ketones", for example, acetone, methyl ethyl ketone, etc. are exemplified.
IS As the above-mentioned "sulfoxides", for example, dimethylsulfoxide, etc. are exemplified.
As the above-mentioned "nitriles", for example, acetonitrile, propionitrile, etc. are exemplified.
As the above-mentioned "organic acids", for example, 2o acetic acid, propionic acid, trifluoroacetic acid, etc. are exemplified.
As the above-mentioned "esters", for example, methyl acetate, ethyl acetate, amyl acetate, ethyl propionate, etc.
are exemplified.
2s When the intended substance is obtained in the free form by the above-mentioned reaction, it may be converted into a salt according to an ordinary method, while when obtained in the form of a salt, it can also be converted into a free form or other salt according to an ordinary method.
so Thus obtained compound (I') can be isolated and purified from a reaction solution by known means, for example, rolling, concentration, solvent extraction, fractionation, crystal-lization, recrystallization, chromatography and the like.

When the compound (I') is present as a configuration isomer, diastereomer, conformer or the like, if necessary, each can be isolated by the above-mentioned separation and purification means. When the compound (I') is a racemate, it can be separated into an S form and R form by a usual optical resolution.
When a stereoisomer is present in the compound (I'), this isomer alone and mixtures thereof are also included in the present invention.
io Further, the compound (I') may be a hydrate or non-hydrate.
The compound (I') may be labeled with an isotope (e. g., 3H, 19C, 35S) , etc.
is [compound (VII)]
[1] An optionally N-oxidized compound represented by the formula:
N ~ N
S
~>--R1 m RZm N ( Im) wherein ring C is a 4-pyrimidinyl group optionally having substituents, Rlm is a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having 2s substituents, an amino group optionally having substituents or an acyl group, and RZm is an aromatic group optionally having substituents, or a salt thereof.
[2] The compound of the above-mentioned [1], wherein the 3o compound (Im) is an optionally N-oxidized compound represented by the formula:
R3n.W~Zn N~N
S
I ~~R, R2n N
wherein n ( In) Zn is a bond, -NR4n- (Ran is a hydrogen atom or a hydrocarbon group optionally having substituents), an oxygen atom or an optionally oxidized sulfur atom, Wn is a bond or a divalent hydrocarbon group optionally having io substituents, Rln is a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino group optionally having substituents or an acyl group, 15 Rzn is an aromatic group optionally having substituents, and R3" is a hydrogen atom, a hydrocarbon group optionally having substituents or a heterocyclic group optionally having substituents.
[3] The compound of the above-mentioned [2], wherein both W°
2o and Zn are each a bond.
[4] The compound of the above-mentioned [1], wherein the compound (Im) is an optionally N-oxidized compound represented by the formula:
R3f/wfN~R4f 2s N~N
S
~~-R,f ~f N (If' ) wherein Wf is a bond or a divalent hydrocarbon group optionally having substituents, Rif is a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino group optionally having substituents or an acyl group, R2f is an aromatic group optionally having substituents, io R3f is a hydrocarbon group optionally having substituents or a heterocyclic group optionally having substituents, and R4f is a hydrogen atom or a hydrocarbon group optionally having substituents.
[5] The compound of the above-mentioned [4], wherein the 15 compound (If') is an optionally N-oxidized compound represented by the formula:
O
R~~N'R4s NI \N
S\
i~R~e R29 N ( I g . ) 2o wherein Rlq is a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino group optionally having substituents or an acyl group, -2s R2q is an aromatic group optionally having substituents, R3g is a hydrocarbon group optionally having substituents or a heterocyclic group optionally having substituents, and R4g is a hydrogen atom or a hydrocarbon group optionally having substituents.

[6] The compound of the above-mentioned [4], wherein th4compound (If') is an optionally N-oxidized compound represented by the formula:
R3wN.R4n N ~N
S
1h RZh ~ N~R ( Ih' ) wherein R1'' is a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having io substituents, an amino group optionally having substituents or an acyl group, RZ'' is an aromatic group optionally having substituents, R3h is a hydrocarbon group optionally having substituents or a heterocyclic group optionally having substituents, and is Rah is a hydrogen atom or a hydrocarbon group optionally having substituents.
[7] A prodrug of the compound of (1].
As the "hydrocarbon group" of the "hydrocarbon group optionally having substituents" in the compounds represented Zo by the formulae (Im) , (In) , (If' ) , (Ig' ) and (Ih' ) , for example, an acyclic or cyclic hydrocarbon group (e. g., alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl etc.) and the like can be mentioned. Of these, an acyclic or cyclic hydrocarbon group having 1 to 16 carbon atoms and the like are preferable.
25 As the "alkyl", for example, C1_6 alkyl (e. g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) and the like are preferable.
As the "alkenyl", for example, Cz_6 alkenyl (e. g., vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl etc.) and the like are preferable.
As the "alkynyl", for example, CZ_6 alkynyl (e. g., ethynyl, propargyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-hexynyl etc.) and the like are preferable.
As the "cycloalkyl", for example, C3_$ cycloalkyl (e. g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl etc.) and the like are preferable.
As the "aryl", for example, C6_14 aryl (e.g., phenyl, 1-to naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl etc.) and the like are preferable.
As the "aralkyl", for example, C~_16 aralkyl (e. g., benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-15 phenylpentyl etc.) and the like are preferable.
As the "substituent" of the ~hydrocarbon group optionally having substituents", for example, oxo, halogen atom (e. g., fluorine, chlorine, bromine, iodine etc.), C1_3 alkylenedioxy (e. g., methylenedioxy, ethylenedioxy etc.), vitro, cyano, 20 optionally halogenated C1_6 alkyl, optionally halogenated C2_s alkenyl, carboxy CZ_6 alkenyl (e.g., 2-carboxyethenyl, 2-carboxy-2-methylethenyl etc.), optionally halogenated CZ_s alkynyl, optionally halogenated C3_8 cycloalkyl, C6_14 aryl (e. g., phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-25 biphenylyl, 2-anthryl etc.), optionally halogenated C,_B alkoxy, C1_6 alkoxy-carbonyl-C1_6 alkoxy (e. g., ethoxycarbonylmethyloxy etc.), hydroxy, C6_14 aryloxy (e. g., phenyloxy, 1-naphthyloxy, 2-naphthyloxy etc. ) , C~_16 aralkyloxy (e. g. , benzyloxy, phenethyloxy etc.), mercapto, optionally halogenated C1_s 3o alkylthio, C6_14 arylthio (e.g., phenylthio, 1-naphthylthio, 2-naphthylthio etc.), C~_16 aralkylthio (e. g., benzylthio, phenethylthio etc.), amino, mono-C1_6 alkylamino (e. g., methylamino, ethylamino etc.), mono-C6_14 arylamino (e. g., phenylamino, 1-naphthylamino, 2-naphthylamino etc.), di-C1_s alkylamino (e. g., dimethylamino, diethylamino, ethylmethylamino etc.), C3_$ cycloalkylamino (e. g., cyclopentylamino, cyclohexylamino etc.), di-Cs_14 arylamino (e. g., diphenylamino etc.), formyl, carboxy, carboxy-C1_s alkyl (e. g., carboxymethyl, carboxyethyl etc.), C1_s alkyl-carbonyl (e. g., acetyl, propionyl, pivaloyl etc.), C3_$ cycloalkyl-carbonyl (e. g:, cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl etc.), C1_s alkoxy-carbonyl (e. g., io methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl etc.), Cs_14 aryl-carbonyl (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl etc.), C~_ls aralkyl-carbonyl (e. g., phenylacetyl, 3-phenylpropionyl etc.), Cs_14 aryloxy-carbonyl (e. g., phenoxycarbonyl etc.), C~-is aralkyloxy-carbonyl (e. g., 15 benzyloxycarbonyl, phenethyloxycarbonyl etc.), 5- or 6-membered heterocyclic carbonyl (e. g., nicotinoyl, isonicotinoyl, thenoyl, furoyl, morpholinocarbonyl, thiomorpholinocarbonyl, piperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl etc.), carbamoyl, thiocarbamoyl, mono-C1_s alkyl-2o carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl etc.), di-C1-s alkyl-carbamoyl (e. g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl etc.), mono- or di-Cs-i4 aryl-carbamoyl (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl etc.), mono- or di-5- or 6-membered 2s heterocyclic carbamoyl (e.g., 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl etc.), C1_s alkylsulfonyl (e. g., methylsulfonyl, ethylsulfonyl etc.), C1_s alkylsulfinyl (e. g., methylsulfinyl, ethylsulfinyl etc.), Cs_14 arylsulfonyl (e. g., phenylsulfonyl, 30 1-naphthylsulfonyl, 2-naphthylsulfonyl etc.), Cs-14 arylsulfinyl (e. g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl etc.), formylamino, C1_s alkyl-carbonylamino (e. g., acetylamino, propionylamino, pivaloylamino etc.), C3-8 cycloalkyl-carbonylamino (e. g., cyclopentylcarbonylamino, cyclohexylcarbonylamino etc.), Cs_14 aryl-carbonylamino (e. g., benzoylamino, naphthoylamino etc.), C1_s alkoxy-carbonylamino (e. g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino etc.), C1_s alkylsulfonylamino (e. g., methylsulfonylamino, ethylsulfonylamino etc.), Cs-i4 arylsulfonylamino (e. g., phenylsulfonylamino, 2-naphthylsulfonylamino, 1-naphthylsulfonylamino etc.), C1_s alkyl-carbonyloxy (e. g., 1o acetoxy, propionyloxy etc. ) , Cs_14 aryl-carbonyloxy (e.g. , benzoyloxy, naphthylcarbonyloxy etc.), C1_s alkoxy-carbonyloxy (e. g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy etc.), mono-C1_s alkyl-carbamoyloxy (e. g., methylcarbamoyloxy, ethylcarbamoyloxy is etc.), di-C1_s alkyl-carbamoyloxy (e. g., dimethylcarbamoyloxy, diethylcarbamoyloxy etc.), mono- or di-Cs-19 aryl-carbamoyloxy (e. g., phenylcarbamoyloxy, naphthylcarbamoyloxy etc.), nicotinoyloxy, isonicotinoyloxy, 5- to 7-membered saturated cyclic amino optionally having substituents, 5- to 10-membered 2o aromatic heterocyclic group (e.g., 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo(b]thienyl, 3-benzo[b]thienyl, 2-25 benzo[b]furanyl, 3-benzo[b]furanyl etc.), sulfo, sulfamoyl, sulfinamoyl, sulfenamoyl, a group wherein 2 or more (e.g., 2-3) of these substituents are bonded and the like can be mentioned.
The "hydrocarbon group" may have, for example, 1 to 5, so preferably 1 to 3, of the above-mentioned substituents at substitutable positions, and when the number of substituents is 2 or more, the respective substituents may be the same or different.

As the aforementioned "optionally halogenated C1_6 alkyl", for example, C1_6 alkyl (e. g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally having 1 to 5, preferably 1 to 3, halogen atoms (e. g., fluorine, chlorine, bromine, iodine etc.) and the like can be mentioned. As specific examples, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl;, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, io isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl and the like can be mentioned.
As the aforementioned "optionally halogenated C2_s alkenyl", for example, C2_6 alkenyl (e. g., vinyl, propenyl, i5 isopropenyl, 2-buten-1-yl, 4-penten-1-yl, 5-hexen-1-yl etc.) optionally having 1 to 5, preferably 1 to 3, halogen atoms (e. g., fluorine, chlorine, bromine, iodine etc.) and the like can be mentioned. As specific examples, vinyl, propenyl, 3,3,3-trifluoropropenyl, 2-buten-1-yl, 4,4,4-trifluoro-2-2o buten-1-yl, 4-penten-1-yl, 5-hexen-1-yl and the like can be mentioned.
As the aforementioned "optionally halogenated C2_6 alkynyl", for example, C2_6 alkynyl (e.g., 2-butyn-1-yl, 4-pentyn-1-yl, 5-hexyn-1-yl etc.) optionally having 1 to 5, 2s preferably 1 to 3, halogen atoms (e. g., fluorine, chlorine, bromine, iodine etc.) and the like can be mentioned. As specific examples, propargyl, 2-butyn-1-yl, 4,4,4-trifluoro-2-butyn-1-yl, 4-pentyn-1-yl, 5,5,5-trifluoro-4-pentyn-1-yl, 5-hexyn-1-yl and the like can be mentioned.
so As the aforementioned "optionally halogenated C3_B
cycloalkyl", for example, C3-$ cycloalkyl (e. g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl etc.) optionally having 1 to 5, preferably 1 to 3, halogen atoms (e.g., fluorine, chlorine, bromine, iodine etc.) and the like can be mentioned. As specific examples, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 4,4-dichlorocyclohexyl, 2,2,3,3-tetrafluorocyclopentyl, 4-chlorocyclohexyl and the like can be mentioned.
As the aforementioned "optionally halogenated C1-8 alkoxy", for example, C1_e alkoxy (e. g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally having 1 to 5, preferably 1 to 3, halogen io atoms (e.g., fluorine, chlorine, bromine, iodine etc.) and the like can be mentioned. As specific examples, for example, methoxy, difluoromethoxy; trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy 15 and the like can be mentioned.
As the aforementioned "optionally halogenated C1_s alkylthio", for example, C1_6 alkylthio (e. g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio etc.) optionally having 1 to 5, preferably 1 to 20 3, halogen atoms (e. g., fluorine, chlorine, bromine, iodine etc.) and the like can be mentioned. As specific examples, methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio and the like can be mentioned.
2s As the "5- to 7-membered saturated cyclic amino" of the aforementioned "5- to 7-membered saturated cyclic amino optionally having substituents", for example, a 5- to 7-membered saturated cyclic amino optionally containing, besides one nitrogen atom and carbon atom(s), 1 or 2 kinds of 1 to 4 3o hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom can be mentioned. As specific examples, pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, thiomorpholino, hexahydroazepin-1-yl and the like can be mentioned.
As the ~substituent" of the ~5- to 7-membered saturated cyclic amino optionally having substituents", for example, 1 to 3 substituents from C1_s alkyl (e. g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.), Cs_14 aryl (e. g., phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl etc.), C1_s alkyl-carbonyl (e.g., acetyl, propionyl, pivaloyl etc.), 5- to 10-membered aromatic heterocyclic group (e.g., 2-thienyl, 3-io thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl etc.), Zs oxo and the like can be mentioned.
The ~divalent hydrocarbon group" of the ~divalent hydrocarbon group optionally having substituents" in the compounds represented by the formulae (In) and (If') refers to a divalent group derived from the "hydrocarbon group" of the 2o aforementioned ~hydrocarbon group optionally having substituents", and, for example, a divalent group derived from alkylene, alkenylene, alkynylene or cycloalkane, a divalent group derived from cycloalkene, a divalent group derived from aromatic hydrocarbon ring and the like can be mentioned.
2s As the "alkylene", for example, C,__,5 alkylene group (e. g., methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene and the like, preferably C1_s alkylene etc.) and the like can be mentioned.
3o As the "alkenylene", for example, CZ_ls alkenylene group (e.g., vinylene, propenylene, 1-butenylene, 2-butenylene, 1-pentenylene, 2-pentenylene, 3-pentenylene etc.) and the like can be mentioned.

As the ~alkynylene", for example, C2_ls alkynylene group (ethynylene, propynylene, 1-butynylene, 2-butynylene, 1-pentynylene, 2-pentynylene, 3-pentynylene etc.) can be mentioned.
As the ~cycloalkane", for example, C3-~ cycloalkane such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptene, cyclooctane and the like, and the like can be mentioned.
As the ~cycloalkene", for example, C3_e cycloalkene such to as cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene and the like, and the like can be mentioned.
As the ~aromatic hydrocarbon ring", a hydrocarbon ring having 6 to 14 carbon atoms such as benzene ring, naphthalene 15 ring and the like, and the like can be mentioned.
The divalent group derived from "cycloalkane", "cycloalkene" or "aromatic hydrocarbon.ring" refers to a divalent group obtained by removing two hydrogen atoms from one carbon atom of, or removing one hydrogen atom from each of 2o two different carbon atoms of "cycloalkane", ~cycloalkene" or ~aromatic hydrocarbon ring", and the like. Specifically, for example, , . , , , l , , , , , -, , I i , \ l ~ \ l and the like are used, preferably, r s r r r ~ , . ~ / . ~
and the like are used, and more preferably, Q Q.Q
and the like are widely used.
As the "substituent" of the "divalent hydrocarbon group", to those similar to the "substituent" of the aforementioned ~hydrocarbon group optionally having substituents" can be mentioned.
The ~divalent hydrocarbon group" may have, for example, 1 to 4, preferably 1 to 3, of the above-mentioned substituents is at substitutable positions, and when the number of substituents is 2 or more, the respective substituents may be the same or different.
As the divalent hydrocarbon group optionally having substituents, C,__,5 alkylene group optionally substituted by oxo 2o group, and the like are preferable. Particularly, C1-6 alkylene optionally substituted by oxo group, and the like are preferable.
As the ~heterocyclic group" of the ~heterocyclic group optionally having substituents" in the compounds represented 2s by the formulae (Im) , (In) , (If') , (Ig') and (Ih') , for example, a monovalent group obtained by removing optional one hydrogen atom from a 5- to 14-membered (monocyclic, bicyclic or tricyclic) heterocycle containing,~besides carbon atom(s), 1 or 2 kinds of 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, preferably (i) a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle, (ii) a 5- to 10-membered non-aromatic heterocycle or (iii) a 7- to 10-membered bridged heterocycle, and the like can be mentioned.
As the above-mentioned "5 to 14-membered (preferably 5-to 10-membered) aromatic heterocycle", for example, an io aromatic heterocycle such as thiophene, benzo[b]thiophene, benzo[b]furan, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, 4H-is quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, ~-carboline, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, isoxazole, furazan, phenoxazine and the like, a ring formed by condensation of these rings 2° (preferably monocycle) with one or plural (preferably 1 or 2) aromatic rings (e.g., benzene ring etc.) and the like can be mentioned.
As the above-mentioned "5- to 10-membered non-aromatic heterocycle", for example, pyrrolidine, imidazoline, 25 pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, thiomorpholine, dioxazole, oxadiazoline, thiadiazoline, triazoline, thiadiazole, dithiazole and the like can be mentioned.
As the above-mentioned ~7 to 10-membered crosslinked so heterocycle", for example, quinuclidine, 7-azabicyclo(2.2.1]heptane and the like can be mentioned.
The preferable ~heterocyclic group" is a 5 to 14-membered (preferably 5- to 10-membered) (monocyclic or bicyclic) heterocyclic group preferably containing, besides carbon atom(s), 1 or 2 kinds of 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom. Specific examples include aromatic heterocyclic groups such as 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1-io indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl and the like, non-aromatic heterocyclic groups such as 1-pyrrolizinyl, 2-pyrrolizinyl, 3-pyrrolizinyl, 2-imidazolinyl, 4-imidazolinyl, 2-pyrazolidinyl, 3-pyrazolidinyl, 15 4-pyrazolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl, morpholino, thiomorpholino and the like, and the like.
Of these, for example, a 5- or 6-membered heterocyclic group containing, besides carbon atom(s), 1 to 3 hetero atoms 2o selected from nitrogen atom, sulfur atom and oxygen atom, and the like are more preferable. Specifically, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1-pyrrolizinyl, 2-pyrrolizinyl, 3-25 pyrrolizinyl, 2-imidazolinyl, 4-imidazolinyl, 2-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl, morpholino, thiomorpholino and the like can be mentioned.
As the "substituent" of the "heterocyclic group 30 optionally having substituents", those similar to the "substituent" of the aforementioned "hydrocarbon group optionally having substituents" can be mentioned.
The "heterocyclic group" may have, for example, 1 to 5, preferably 1 to 3, of the above-mentioned substituents at substitutable positions, and when the number of substituents is 2 or more, the respective substituents may be the same or different.
s As the ~acyl group" in the compounds represented by the formulae (Im) , (In) , (If' ) , (Ig' ) , and (Ih' ) , for example, an acyl group represented by the formula: -(C=0)-R', - (C=O) -OR', - (C=O) -NR~Re, - (C=S) -NHR~ or -S02-R9 wherein R' is a hydrogen atom, a hydrocarbon group optionally having io substituents or a heterocyclic group optionally having substituents, R8 is a hydrogen atom or C1_6 alkyl group, and R9 is a hydrocarbon group optionally having substituents or a heterocyclic group optionally having substituents, and the like can be mentioned.
is As the ~hydrocarbon group optionally having substituents"
and ~heterocyclic group optionally having substituents", those similar to the aforementioned can be used.
As the ~C1_6 alkyl group", methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2° hexyl and the like can be mentioned.
As the ~amino group optionally having substituents" in the compounds represented by the formulae (Im) , (In) , (If' ) , (Ig'), and (Ih'), (1) an amino group optionally having 1 or 2 substituents and (2) a cyclic amino group optionally having Zs substituents can be mentioned.
As the ~substituent" of the ~amino group optionally having 1 or 2 substituents" of the above-mentioned (1), for example, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an acyl 3o group, an alkylidene group optionally having substituents and the like can be mentioned. As these "hydrocarbon group optionally having substituents", ~heterocyclic group optionally having substituents" and "acyl group", those similar to the aforementioned can be respectively used.
As the "alkylidene group" of the "alkylidene group optionally having substituents", for example, C1_6 alkylidene (e. g., methylidene, ethylidene, propylidene etc.) and the like can be mentioned. As the ~substituent" of the "alkylidene group optionally having substituents", those similar to the ~substituent" of the aforementioned ~hydrocarbon group optionally having substituents" can be mentioned. The ~alkylidene group" can be substituted by 1 to 5, preferably 1 io to 3, of these substituents.
When the number of ~substituents" of the above-mentioned ~amino group optionally having 1 or 2 substituents" is 2, the respective substituents may be the same or different.
As the ~cyclic amino group" of the "cyclic amino group i5 optionally having substituents" of the above-mentioned (2), a 5- to 7-membered non-aromatic cyclic amino group optionally containing, besides one nitrogen atom and carbon atom(s), 1 or 2 kinds of 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom can be mentioned. As specific 2o examples, pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, thiomorpholino, hexahydroazepin-1-yl, imidazolidin-1-yl, 2,3-dihydro-1H-imidazol-1-yl, tetrahydro-1(2H)-pyrimidinyl, 3,6-dihydro-1(2H)-pyrimidinyl, 3,4-dihydro-1(2H)-pyrimidinyl and the like can be mentioned.
25 As the ~substituent" of the ~cyclic amino group optionally having substituents", for example, those similar to the ~substituent" of the "5- to 7-membered saturated cyclic amino optionally having substituents" explained in detail as the ~substituent" of the aforementioned ~hydrocarbon group 30 optionally having substituents", and the like can be mentioned, wherein the "cyclic amino group" is preferably substituted by 1 to 3 of these substituents.
As specific examples of a 5- to 7-membered non-aromatic cyclic amino group having one oxo, 2-oxoimidazolidin-1-yl, 2-oxo-2,3-dihydro-1H-imidazol-1-yl, 2-oxotetrahydro-1(2H)-pyrimidinyl, 2-oxo-3,6-dihydro-1(2H)-pyrimidinyl, 2-oxo-3,4-dihydro-1(2H)-pyrimidinyl, 2-oxopyrrolidin-1-yl, 2-oxopiperidino, 2-oxopiperazin-1-yl, 3-oxopiperazin-1-yl, 2-oxo-2,3,4,5,6,7-hexahydroazepin-1-yl and the like can be mentioned.
In the present invention, as the "aromatic group" of the "aromatic group optionally having substituents in the io compounds represented by the formulae (Im) , (In) , (If' ) , (Ig' ) , and (Ih')", for example, aromatic hydrocarbon group, aromatic heterocyclic group and the like can be mentioned.
As the "aromatic hydrocarbon group", for example, a monocyclic or fused polycyclic (di- or tri-cyclic) aromatic I5 hydrocarbon group having 6 to 14 carbon atoms and the like can be mentioned. As specific examples, Cs_1q aryl such as phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and the like, and the like, preferably Cs-to aryl (e. g., phenyl, 1-naphthyl, 2-naphthyl and the like, 2o preferably phenyl etc.), and the like can be mentioned.
As the "aromatic heterocyclic group", a monovalent group obtained by removing one optional hydrogen atom from a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle containing, besides carbon atom(s), 1 or 2 kinds 25 of 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, and the like can be mentioned.
As the "5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle", for example, aromatic heterocycle such as thiophene, benzo[b]thiophene, benzo[b]furan, benzimidazole, 3o benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3 b]thiophene, furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, 4H-quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, (~-carboline, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, isoxazole, furazan, phenoxazine and the like, a ring formed by condensation of these rings (preferably monocycle) with one or plural (preferably 1 or 2) aromatic rings (e. g., benzene ring etc.), and the like can be mentioned.
As the preferable ~aromatic heterocyclic group", a 5- to 14-membered (preferably 5- to 10-membered) (monocyclic or to bicyclic) aromatic heterocyclic group preferably containing, besides carbon atom(s), 1 or 2 kinds of 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, and the like, specifically, an aromatic heterocyclic group such as 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, is 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 20 2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl and the like can be mentioned.
As the ~substituent" of the ~aromatic group optionally having substituents", 1 to 5, preferably 1 to 3, of those similar to the "substituent" of the aforementioned 25 ~hydrocarbon group optionally having substituents" can be mentioned. When the number of the substituents is 2 or more, the respective substituents may be the same or different.
As the ~substituent" of the ~4-pyrimidinyl group optionally having substituents" for ring C, for example, a so group represented by the formula: -Zn-W"-R3° wherein the symbols in the formula are as defined above as well as halogen atom (e.g., fluorine, chlorine, bromine, iodine etc.), C1-3 alkylenedioxy (e. g., methylenedioxy, ethylenedioxy etc.), nitro, cyano, optionally halogenated C1_s alkyl, optionally halogenated Cz-s alkenyl, carboxy C2_s alkenyl (e. g. , 2-carboxyethenyl, 2-carboxy-2-methylethenyl etc.), optionally halogenated CZ_s alkynyl, optionally halogenated C3_$ cycloalkyl, s Cs-i4 aryl (e. g., phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl etc.), optionally halogenated Cl_e alkoxy, C1_s alkoxy-carbonyl-C1_s alkoxy (e. g. , ethoxycarbonylmethyloxy etc.), hydroxy, Cs_14 aryloxy (e. g., phenyloxy, 1-naphthyloxy, 2-naphthyloxy etc.), C~_ls aralkyloxy io (e. g:, benzyloxy, phenethyloxy etc.), mercapto, optionally halogenated Cl_s alkylthio, Cs_14 arylthio (e.g. , phenylthio, 1-naphthylthio, 2-naphthylthio etc.), C~_ls aralkylthio (e. g., benzylthio, phenethylthio etc.), amino, mono-C1_s alkylamino (e. g., methylamino, ethylamino etc.), mono-Cs_19 arylamino (e. g., is phenylamino, 1-naphthylamino, 2-naphthylamino etc.), di-C1_s alkylamino (e. g., dimethylamino, diethylamino, ethylmethylamino etc.), C3_$ cycloalkylamino (e. g., cyclopentylamino, cyclohexylamino etc.), di-Cs_14 arylamino (e. g., diphenylamino etc.), formyl, carboxy, carboxy-C1-s alkyl (e. g., carboxymethyl, carboxyethyl etc.), C1_s alkyl-carbonyl (e. g., acetyl, propionyl, pivaloyl etc.), C3_e cycloalkyl-carbonyl (e. g., cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl etc. ) , Cl_s alkoxy-carbonyl (e. g. , methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-2s butoxycarbonyl etc.), Cs-,_4 aryl-carbonyl (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl etc.), C~-is aralkyl-carbonyl (e. g., phenylacetyl, 3-phenylpropionyl etc.), Cs_14 aryloxy-carbonyl (e. g., phenoxycarbonyl etc.), C~-is aralkyloxy-carbonyl (e. g., benzyloxycarbonyl, phenethyloxycarbonyl etc.), 5 or 6-membered 3o heterocyclic-carbonyl (e. g., nicotinoyl, isonicotinoyl, thenoyl, furoyl, morpholinocarbonyl, thiomorpholinocarbonyl, piperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl etc.), carbamoyl, thiocarbamoyl, mono-C1_s alkyl-carbamoyl (e. g., methylcarbamoyl, ethylcarbamoyl etc.), di-C1_6 alkyl-carbamoyl (e. g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl etc.), mono- or di-C6_l4aryl-carbamoyl (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl, 2-s naphthylcarbamoyl etc.), mono- or di-5 or 6-membered heterocyclic carbamoyl (e.g., 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl etc.), C1_6 alkylsulfonyl (e. g., methylsulfonyl, ethylsulfonyl etc.), C1_6 alkylsulfinyl (e. g., methylsulfinyl, to ethylsulfinyl etc.), C6_14 arylsulfonyl (e. g., phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl etc.), C6_14 arylsulfinyl (e. g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl etc.), formylamino, C1_6 alkyl-carbonylamino (e. g., acetylamino, propionylamino, pivaloylamino etc.), C3_e cycloalkyl-is carbonylamino (e. g., cyclopentylcarbonylamino, cyclohexylcarbonylamino etc.), C6_19 aryl-carbonylamino (e. g., benzoylamino, naphthoylamino etc.), C1_6 alkoxy-carbonylamino (e. g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino etc.), C1-20 6alkylsulfonylamino (e. g., methylsulfonylamino, ethylsulfonylamino etc.), C6_14 arylsulfonylamino (e. g., phenylsulfonylamino, 2-naphthylsulfonylamino, 1-naphthylsulfonylamino etc.), C1_6 alkyl-carbonyloxy (e. g., acetoxy, propionyloxy etc.), C6_1q aryl-carbonyloxy (e. g., Zs benzoyloxy, naphthylcarbonyloxy etc.), C,__6 alkoxy-carbonyloxy (e. g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy etc.), mono-C1_6 alkyl-carbamoyloxy (e. g., methylcarbamoyloxy, ethylcarbamoyloxy etc.), di-C1-6 alkyl-carbamoyloxy (e. g., dimethylcarbamoyloxy, 3o diethylcarbamoyloxy etc.), mono- or di-C6_14 aryl-carbamoyloxy (e. g., phenylcarbamoyloxy, naphthylcarbamoyloxy etc.), nicotinoyloxy, isonicotinoyloxy, optionally having substituents 5- to 7-membered saturated cyclic amino, 5- to 10-membered aromatic heterocyclic group (e.g., 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-s indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl etc.), sulfo, sulfamoyl, sulfinamoyl, sulfenamoyl and a group linked with or 2 or more of these substituents (e.g., 2-3) can be mentioned, with particular preference given to a group 1o represented by the formula: -Zn-W°-R3n.
As the salt of Compound (Im) , (In) , (If' ) , (Ig' ) and (Ih'), for example, a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid is and the like can be mentioned. As examples of suitable metal salt, alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt, barium salt and the like; aluminum salt and the like can be mentioned. As a suitable example of a salt 2o with an organic base, for.example, salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine etc., and the like can be mentioned. As a suitable example of the salt with Zs an inorganic acid, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid etc., and the like can be mentioned. As a suitable example of the salt with an organic acid, for example, salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, 3o fumaric acid, oxalic acid, tartaric acid, malefic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid etc., and the like can be mentioned. As a suitable example of the salt with a basic amino acid, for example, salts with arginine, lysine, ornithine etc., and the like can be mentioned. As a suitable example of the salt with an acidic amino acid, for example, salts with aspartic acid, glutamic acid etc., and the like can be mentioned.
Of these, pharmaceutically acceptable salts are preferable. For example, when a compound has an acidic functional group therein, inorganic salts such as alkali metal salts (e. g., sodium salt, potassium salt and the like), to alkaline earth metal salts (e. g., calcium salt, magnesium salt, barium salt and the like), and the like, ammonium salts and the like can be mentioned, and when a compound has a basic functional group therein, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric Zs acid, phosphoric acid and the like, and salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, malefic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid and the like, and the like can be mentioned.
2o The production methods of Compound (Im) (including (In), ( I f ' ) , ( Ig' ) , ( Ih' ) ) , or a salt thereof of the present invention are explained in the following.
Compound (Im) can be obtained by the methods described in JP-A-60-58981, 61-10580, 5-70446, 7-503023, DE-A-3601411, WO
25 93/15071, WO 00/64894 and the like or a method analogous thereto and the like, as well as a method shown in the following Reaction Schemes 1, 2 and 3 or a method analogous thereto and the like. Here, the production method of Compound (Im) is briefly described.
so Compound (Im) or a salt thereof can be produced by a method characterized by reacting a compound represented by the formula:

N ~N O
R~"
Hal wherein ring C is a 4-pyrimidinyl group optionally having substituents, Hal is a halogen, and R2m is an aromatic group optionally having substituents, or a salt thereof with a compound represented by the formula:
R1"'CSNHz wherein Rlm is a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino group optionally having substituents or an acyl group [as regards compound RImCSNH2, refer to compound (VII) appearing below in the present specification] or a salt thereof (see Reaction Schemes 1, 2, 3 and 4 below for the detail).
15 Respective symbols in the compounds in Reaction Schemes 1, 2, 3 and 4 are as defined above. The compounds in Reaction Schemes may form a salt, and as the salt, for example, those similar to the salt of Compound (I), and the like can be mentioned. For Compound (II) , (III) , (IV) , (X) , (XI) , (XV) , (XVI) , (XVIII) and (XIX) , commercially available compounds can be used, or can be produced according to a method known per se or a method analogous thereto.
Reaction Scheme 1 H3 H~
(tBoc)20 I w 1) base w (BuLi etc.) t ~
BocNH"N
' ~H2 'NH Boc 2) R2COL' (II) (III) (IV) (V) halogenation ~ R'CSNH2 (VII) t _ BocNH I S
tBocN ~ 2 ~ /
Hal R2 (VI) (VIII) w R3-INL2 W
deprotection ~~ ,,i~ S (X) R3/w ~ ~ S
---~. H2 n 2 I / ~ --~- R4 2~/
R R
(IX) (lo) tBoc: t-butoxycarbonyl Bu: butyl L~,L2: leaving group Hal: halogen In the following, L1, L2 and L3 (Reaction Scheme 2) each denote a leaving group. The ~leaving group" denoted by L1, L2 and L3 is, for example (1) Cl_6 alkoxy (e.g. , methoxy, ethoxy etc. ) , (2) di-C1-6 alkylamino (e.g. , dimethylamino, diethylamino etc . ) , ( 3 ) N-C6-to aryl-N-C1-6 alkylamino ( a . g. , N-phenyl-N-methylamino etc.), (4) 3 to 7-membered cyclic amino (e. g., pyrrolidino, morpholino, methylaziridin-1-yl etc.) optionally substituted by C6_lo aryl and/or Cl_6 alkyl, (5) N-Cl_6 alkyl-N-Cl_ alkoxyamino (N-methoxy-N-methylamino etc.) and the like, (6) hydroxy, (7) halogen atom (e. g., fluorine, chlorine, bromine, iodine etc.), (8) optionally halogenated C1-s alkylsulfonyloxy (e. g., methanesulfonyloxy, ethanesulfonyloxy, is trifluoromethanesulfonyloxy etc. ) , (9) C6_lo arylsulfonyloxy optionally having substituents, (10) optionally halogenated Cl-s alkylsulfonyl (e. g., methanesulfonyl, ethanesulfonyl, trifluoromethanesulfonyl etc. ) , (11) C6_lo arylsulfonyl optionally having substituents and the like can be mentioned.
As the "C6_lo arylsulfonyloxy optionally having substituents", for example, C6_lo arylsulfonyloxy (e. g., phenylsulfonyloxy, naphthylsulfonyloxy etc.) optionally having 1 to 3 substituents selected from C1_6 alkyl, Cl_6 alkoxy and nitro, and the like can be mentioned. As specific examples, benzenesulfonyloxy, m-nitrobenzenesulfonyloxy, p-toluenesulfonyloxy and the like can be mentioned.
io As the "C6-to arylsulfonyl optionally having substituents", for example, C6_lo arylsulfonyl (e. g., phenylsulfonyl, naphthylsulfonyl etc.) optionally having 1 to 3 substituents selected from Cl_6 alkyl, C1_6 alkoxy and nitro, and the like can be mentioned. As specific examples, benzenesulfonyl, m-z5 nitrobenzenesulfonyl, p-toluenesulfonyl and the like can be mentioned.
Compound (III) is obtained by protecting Compound (II) with di-t-butyl dicarbonate.
The amount of di-t-butyl dicarbonate to be used is about 20 0.8 to about 5 moles, preferably about 1 to about 1.5 moles, per 1 mole of Compound (II).
It is advantageous to carry out this reaction without a solvent or in the presence of an inert solvent for the reaction. The solvent is not particularly limited as long as 25 the reaction proceeds, but, for example, aromatic hydrocarbons, ethers, alcohols, esters or a mixture of two or more of them and the like are used.
The reaction temperature is usually about 0 to about 100°C, preferably about 0 to about 60°C. The reaction time is 3o usually about 5 minutes to about 48 hours, preferably about 1 hour to about 24 hours.
Although the product can be used as a reaction solution itself or as a crude product in the next reaction, it can be isolated from the reaction mixture by a conventional method, and can be easily purified by a separating methods such as recrystallization, distillation, chromatography and the like.
To obtain Compound (V), Compound (III) is treated with a base, followed by condensing with Compound (IV).
The amount of base to be used is about 0.8 to about 5 moles, preferably about 2 to about 2.5 moles, per 1 mole of Compound (III).
As the ~base", for example, alkyl lithiums such as n-io butyl lithium and the like, and metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide and the like are used.
It is advantageous to carry out this reaction without a solvent or in the presence of an inert solvent for the 15 reaction. The solvent is not particularly limited as long as the reaction proceeds, but, for example, aliphatic hydrocarbons, aromatic hydrocarbons, ethers or a mixture of two or more of them and the like are used.
The reaction temperature is usually about -78 to about 2° 60°C, preferably about -78 to about 20°C. The reaction time is usually about 5 minutes to about 24 hours, preferably about 0.5 hour to about 3 hours.
Although the product can be used as a reaction solution itself or as a crude product in the next reaction, it can be 25 isolated from the reaction mixture by a conventional method, and can be easily purified by a separating methods such as recrystallization, distillation, chromatography and the like.
Compound (VI) can be obtained by treating Compound (V) with a halogen or metal halide. Where desired, this reaction so is carried out in the presence of a base or a basic salt.
As the "halogen", chlorine, bromine, iodine and the like can be mentioned.
As the "metal halide", copper halides such as copper(II) bromide, copper(II) chloride and the like can be mentioned.
Accordingly, in Compound (VI), Hal is halogen such as chlorine, bromine, iodine and the like.
The amount of halogen or metal halide to be used is about 1 to about 5 moles, preferably about 1 to about 2 moles, per 1 mole of compound (V) .
The amount of a base to be used is about 1 to about 10 moles, preferably about 1 to about 3 moles, per 1 mole of Compound (V) .
to As the "base", for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium acetate and the like, aromatic amines such as pyridine, Is lutidine and the like, tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like, and the like can be mentioned.
2o It is advantageous to carry out this reaction without a solvent or in the presence of an inert solvent for the reaction. The solvent is not particularly limited as long as the reaction proceeds, but, for example, ethers, esters, aromatic hydrocarbons, aliphatic hydrocarbons, amides, 25 halogenated hydrocarbons, nitriles, sulfoxides, organic acids, aromatic amines or a mixture of two or more of them and the like are used.
The reaction temperature is about -20 to about 150°C, preferably about 0 to about 100°C. The reaction time is so usually about 5 minutes to about 24 hours, preferably about 10 minutes to about 5 hours.
Although the product can be used as a reaction solution itself or as a crude product in the next reaction, it can be isolated from the reaction mixture by a conventional method, and can be easily purified by a separating methods such as recrystallization, distillation, chromatography and the like.
Compound (VIII) can be obtained by condensing Compound (VI) with Compound (VII). This reaction is performed optionally in the presence of a base.
When Compound (VII) is commercially available, it can be used as it is, or is obtained by a method known per se or a method according to a known method, or further by a method so shown by the following Reaction Scheme 4.
The amount of Compound (VII) to be used is about 0.5 to about 3 moles, preferably about 0.8 to about 2 moles, per 1 mole of Compound (VI).
The amount of a base to be used is about 1 to about 30 15 moles, preferably about 1 to about 10 moles, per 1 mole of Compound (VI).
As the "base", for example, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium acetate and the like, aromatic 2o amines such as pyridine, lutidine and the like, tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like, and the like can be mentioned.
2s It is advantageous to carry out this reaction without a solvent or in the presence of an inert solvent for the reaction. The solvent is not particularly limited as long as the reaction proceeds, but, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, 3o ethers, amides, alcohols, nitriles or a mixture of two or more of them and the like are .used.
The reaction temperature is about -5 to about 200°C, preferably about 5 to about 150°C. The reaction time is usually about 5 minutes to about 72 hours, preferably about 0.5 to about 30 hours.
Although the product can be used as a reaction solution itself or as a crude product in the next reaction, it can be isolated from the reaction mixture by a conventional method, and can be easily purified by a separating methods such as recrystallization, distillation, chromatography and the like.
Compound (IX) is obtained by deprotecting Compound (VIII) using an acid or a base.
io The amount of an acid or a base to be used is about 0.1 to about 50 moles, preferably about 1 to about 20 moles, per 1 mole of Compound (VIII).
As the "acid", for example, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and the 15 like, Lewis acids such as boron trichloride, boron tribromide and the like, the use of Lewis acid together with thiols or sulfides, organic acids such as trifluoroacetic acid, p-toluenesulfonic acid and the like, and the like are used.
As the "base", for example, metal hydroxides such as 2o sodium hydroxide, potassium hydroxide, barium hydroxide and the like, basic salts such as sodium carbonate, potassium carbonate and the like, metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like, organic bases such as triethylamine, imidazole, 25 formamidine and the like, and the like are used.
It is advantageous to carry out this reaction without a solvent or in the presence of an inert solvent for the reaction. The solvent is not particularly limited as long as the reaction proceeds, but, for.example, alcohols, ethers, so aromatic hydrocarbons, aliphatic hydrocarbons, halogenated hydrocarbons, sulfoxides, water or a mixture of two or more of them and the like are used.
The reaction time is usually about 10 minutes to about 50 hours, preferably about 30 minutes to about 12 hours. The reaction temperature is usually about 0 to about 200°C, preferably about 20 to about 120°C.
Compound (Io) can be obtained by condensing Compound (IX) s with Compound (X) optionally in the presence of a base.
The amount of Compound (XVIII) to be used is about 0.8 to about 5 moles, preferably about 1 to about 3 moles, per 1 mole of Compound (XVI I ) .
The amount of the.base to be used is about 0.1 to about 5 io moles, preferably about 0.8 to about 2.5 moles, per 1 mole of Compound (XVI I ) .
As the "base", for example, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate and the like, metal hydroxides such as sodium Is hydroxide, potassium hydroxide and the like, aromatic amines such as pyridine, lutidine and the like, tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-2o methylmorpholine and the like, alkali metal hydrides such as sodium hydride, potassium hydride and the like, metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide and the like, metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and 2s the like, and the like can be mentioned.
It is advantageous to carry out this reaction without a solvent or in the presence of an inert solvent for the reaction. The solvent is not particularly limited as long as the reaction proceeds, but, for example, aliphatic so hydrocarbons, aromatic hydrocarbons, ethers, amides or a mixture of two or more of them and the like are used.
The reaction temperature is usually about -78 to about 100°C, preferably about -78 to about 70°C. The reaction time is usually about 5 minutes to about 24 hours, preferably about 0.5 to about 20 hours.
Although the product can be used as a reaction solution itself or as a crude product in the next reaction, it can be isolated from the reaction mixture by a conventional method, and can be easily purified by a separating methods such as recrystallization, distillation, chromatography and the like.
Thereafter, compounds wherein R4 is other than hydrogen atom can be synthesized by performing alkylation or acylation and 1o the like, if desired.
Reaction Scheme 2 L 3~~~~~ 2 1 ) base N' I 0 ha I ogenat i on N CH3 2) R2COL~(IV) L N R
(XI) (XI I) N ~ 0 R~ CSNH2 (V I I ) N' Ls~N ~ R2 Ls~N ~ S~Ri Ha I R2 N
(X111) (XIV) ( R3~\Z ~ S Ha I : ha I ogen L~,L3: leaving group (1p) Compound (XII) can be obtained by treating Compound (XI) with a base and condensing Compound (IV).
The amount of the base to be used is about 0.8 to about 3 moles, preferably about 1 to about 1.2 moles, per 1 mole of compound (XI).
As the ~base", for example, metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide and the like are used.
It is advantageous to carry out this reaction without a solvent or in the presence of an inert solvent for the reaction. The solvent is not particularly limited as long as the reaction proceeds, but, for example, aliphatic hydrocarbons, aromatic hydrocarbons, ethers or a mixture of to two or more of them and the like are used.
The reaction temperature is usually about -78 to about 60°C, preferably about -78 to about 20°C. The reaction time is usually about 5 minutes to about 24 hours, preferably about 0.5 to about 3 hours is Although the product can be used as a reaction solution itself or as a crude product in the next reaction, it can be isolated from the reaction mixture by a conventional method, and can be easily purified by a separating methods such as recrystallization, distillation, chromatography and the like.
2o Compound (XIII) can be obtained by treating Compound (XII) with a halogen or metal halides. Where desired, this reaction is carried out in the presence of a base or a basic salt.
As the "halogen", chlorine, bromine, iodine and the like 25 can be mentioned.
As the ~metal halide", copper halides such as copper(II) bromide, copper(II) chloride and the like can be mentioned.
Accordingly, in compound (XIII), Hal methods halogen such as chlorine, bromine, iodine and the like.
3o The amount of halogen or metal halide to be used is about 1 to about 5 moles, preferably about 1 to about 2 moles, per 1 mole of compound (XIII) .
The amount of the base to be used is about 1 to about 10 moles, preferably about 1 to about 3 moles, per 1 mole of Compound (XII) .
As the "base", for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide and the like, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium acetate and the like, aromatic amines such as pyridine, lutidine and the like, tertiary amines such as a triethylamine, tripropylamine, tributylamine, io cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like, and the like can be mentioned.
It is advantageous to carry out this reaction without a solvent or in the presence of an inert solvent for the 15 reaction. The solvent is not particularly limited as long as the reaction proceeds, but, for example, ethers, esters, aromatic hydrocarbons, aliphatic hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, organic acids, aromatic amines or a mixture of two or more of them and the 20 like are used.
The reaction temperature is about -20 to about 150°C, preferably about 0 to about 100°C. The reaction time is usually about 5 minutes to about 24 hours, preferably about 10 minutes to about 5 hours.
25 Although the product can be used as a reaction solution itself or as a crude product in the next reaction, it can be isolated from the reaction mixture by a conventional method, and can be easily purified by a separating methods such as recrystallization, distillation, chromatography and the like.
3o Compound (XIV) can be obtained by condensing Compound (XIII) with Compound (VII). Where desired, this reaction is carried out in the presence of a base.
The amount of Compound (VII) to be used is about 0.5 to about 3 moles, preferably about 0.8 to about 2 moles, per 1 mole of Compound (XIII).
The amount of the base to be used is about 1 to about 30 moles, preferably about 1 to about 10 moles, per 1 mole of s compound (XIII).
As the "base", for example, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium acetate and the like, aromatic amines such as pyridine, lutidine and the like, tertiary to amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like, and the like can be mentioned.
It is advantageous to carry out this reaction without a is solvent or in the presence of an inert solvent for the reaction. The solvent is not particularly limited as long as the reaction proceeds, but, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, amides, alcohols, nitriles or a mixture of two or more 20 of them and the like are used.
The reaction temperature is about -5 to about 200°C, preferably about 5 to about 150°C. The reaction time is usually about 5 minutes to about 72 hours, preferably about 0.5 hour to about 30 hours.
Zs Although the product can be used as a reaction solution itself or as a crude product in the next reaction, it can be isolated from the reaction mixture by a conventional method, and can be easily purified by a separating methods such as recrystallization, distillation, chromatography and the like.
so Compound (Ip) can be obtained by condensing Compound (XIV) with Compound (XV).
Where desired, this reaction is carried out in the presence of a base.

The amount of Compound (XV) to be used is about 1 to about 100 moles, preferably about 1 to about 30 moles, per 1 mole of Compound (XIV).
As the "base", for example, basic salts such as sodium s carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium acetate and the like, aromatic amines such as pyridine, lutidine and the like, tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-io dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like, alkali metal hydrides such as sodium hydride, potassium hydride and the like, metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide and the like, metal alkoxides such as is sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like, and the like can be mentioned.
It is advantageous to carry out this reaction without a solvent or in the presence of an inert solvent for the reaction. The solvent is not particularly limited as long as 2o the reaction proceeds, but, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, sulfoxides, alcohols, nitriles, ketones or a mixture of two or more of them and the like are used.
The reaction temperature is about -5 to about 200°C, 2s preferably about 5 to about 120°C. The reaction time is usually about 5 minutes to about 72 hours, preferably about 0.5 hour to about 30 hours.
Although the product can be used as a reaction solution itself or as a crude product in the next reaction, it can be 3o isolated from the reaction mixture by a conventional method, and can be easily purified by a separating methods such as recrystallization, distillation, chromatography and the like.

Reaction Scheme 3 N ~ 1 ) base N' I 0 ha I ogenat i on 3iw~ 3iW ~ 2 R Z N CH3 2) RZCOL~ ( I V) R Z N R
(XX) (XX I ) N' 0 R~ CSNH2 (V I I ) N I
3iWw R3~w~Z~N R R Z N I ~~Ri Hal R2 N
(XX I I ) (1q) Hal: halogen L1: leaving group Compound (XXI) can be obtained by treating Compound (XX) with a base and condensing Compound (IV).
The amount of the base to be used is about 0.8 to about 3 moles, preferably about 1 to about 1.2 moles, per 1 mole of Compound (XX) .
io As the "base", for example, metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide and the like are used.
It is advantageous to carry out this reaction without a solvent or in the presence of an inert solvent for the 15 reaction. The solvent is not particularly limited as long as the reaction proceeds, but, for example, aliphatic hydrocarbons, aromatic hydrocarbons, ethers or a mixture of two or more of them and the like are used.
The reaction temperature is usually about -78 to about 20 60°C, preferably about -78 to about 20°C. The reaction time is usually about 5 minutes to about 24 hours, preferably about 0.5 to about 3 hours.
Although the product can be used as a reaction solution itself or as a crude product in the next reaction, it can be isolated from the reaction mixture by a conventional method, and can be easily purified by a separating methods such as recrystallization, distillation, chromatography and the like.
Compound (XXII) can be obtained by treating Compound (XXI) with halogen or metal halide. Where desired, this reaction is carried out in the presence of a base or a basic salt.
As the ~halogen", chlorine, bromine, iodine and the like io can be mentioned.
As the "metal halide", copper halide such as copper(II) bromide, copper(II) chloride and the like can be mentioned.
Accordingly, Hal in Compound (XXII) methods halogen such as chlorine, bromine, iodine and the like.
is The amount of the halogen or metal halide to be used is about 1 to about 5 moles, preferably about 1 to about 2 moles, per 1 mole of Compound (XXI).
The amount of the base to be used is about 1 to about 10 moles, preferably about 1 to about 3 moles, per 1 mole of 2o Compound (XXI ) .
As the "base", for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide and the like, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium 25 hydrogen carbonate, sodium acetate and the like, aromatic amines such as pyridine, lutidine and the like, tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-3o methylmorpholine and the like, and the like can be mentioned.
It is advantageous to carry out this reaction without a solvent or in the presence of an inert solvent for the reaction. The solvent is not particularly limited as long as the reaction proceeds, but, for example, ethers, esters, aromatic hydrocarbons, aliphatic hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, organic acids, aromatic amines or a mixture of two or more of them and the like are used.
The reaction temperature is about -20 to about 150°C, preferably about 0 to about 100°C. The reaction time is usually about 5 minutes to about 24 hours, preferably about 10 minutes to about 5 hours.
so Although the product can be used as a reaction solution itself or as a crude product in the next reaction, it can be isolated from the reaction mixture by a conventional method, and can be easily purified by a separating methods such as recrystallization, distillation, chromatography and the like.
i5 Compound (Iq) can be obtained by condensing Compound (XXII) with Compound (VII). Where desired, this reaction is carried out in the presence of a base.
The amount of Compound (VII) to be used is about 0.5 to about 3 moles, preferably about 0.8 to about 2 moles, per 1 2o mole of Compound (XXI I ) .
The amount of the base to be used is about 1 to about 30 moles, preferably about 1 to about 10 moles, per 1 mole of Compound (XXII).
As the "base", for example, basic salts such as sodium 25 carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium acetate and the like, aromatic amines such as pyridine, lutidine and the like, tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-so dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N
methylmorpholine and the like, and the like can be mentioned.
It is advantageous to carry out this reaction without a solvent or in the presence of an inert solvent for the reaction. The solvent is not particularly limited as long as the reaction proceeds, but, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, amides, alcohols, nitriles or a mixture of two or more of them and the like are used.
The reaction temperature is about -5 to about 200°C, preferably about 5 to about 150°C. The reaction time is usually about 5 minutes to about 72 hours, preferably about 0.5 hour to about 30 hours.
1~ Although the product can be used as a reaction solution itself or as a crude product in the next reaction, it can be isolated from the reaction mixture by a conventional method, and can be easily purified by a separating methods such as recrystallization, distillation, chromatography and the like.
Reaction Scheme 4 R'H
R9CONCS R9CONH-C-R~°
(XVI) (XVII) H2S or R'-CN (Et0)zPSSH
(XVI I I) R'-CONH2 R'CSNHz (X I X) PaS, o °r (V I I ) Lawess°n's reagent wherein R1° is an amino group optionally having substituents, and other symbols are as defined above.
Compound (XVII) can be obtained by condensing Compound (XVI) with amines represented by the formula: R1°H (e.g., 1-propylamine, 1-butylamine, pyrrolidine, piperidine, piperazine, 4-methylpiperazine, 4-phenylpiperidine and the like, preferably, pyrrolidine, piperidine, piperazine, 4-methylpiperazine etc.).
In Compound (XVII), R9 is an aromatic hydrocarbon group or alkoxy. As the "aromatic hydrocarbon group", phenyl group optionally having substituents and the like can be mentioned.
As the "alkoxy", for example, C1_6 alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like, and the like can be mentioned.
io The amount of the "amines" to be used is about 1.0 to about 30 moles, preferably about 1.0 to about 10 moles, per 1 mole of Compound (XVI).
It is advantageous to carry out this reaction without a solvent or in the presence of an inert solvent for the 15 reaction. The solvent is not particularly limited as long as the reaction proceeds, but, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, amides, alcohols, nitriles, ketones or a mixture of two or more of them and the like are used.
2o The reaction temperature is about -5 to about 200°C, preferably about 5 to about 120°C. The reaction time is usually about 5 minutes to about 72 hours, preferably about 0.5 to about 30 hours.
Although the product can be used as a reaction solution 25 itself or as a crude product in the next reaction, it can be isolated from the reaction mixture by a conventional methods, and can be easily purified by a separating methods such as recrystallization, distillation, chromatography and the like..
Compound (VII) is obtained by hydrolyzing Compound (XVII) 3o using an acid or a base.
The amount of acid or base to be used is about 0.1 to about 50 moles, preferably about 1 to about 20 moles, per 1 mole of Compound (XVII), respectively.

As the "acid", for example, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like, Lewis acids such as boron trichloride, boron tribromide and the like, the use of Lewis acid together with thiols or sulfides, organic acids such as trifluoroacetic acid, p-toluenesulfonic acid and the like, and the like are used.
As the "base", for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide and the like, basic salts such as sodium carbonate, potassium to carbonate and the like, metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like, organic bases such as triethylamine, imidazole, formamidine and the like, and the like are used.
It is advantageous to carry out this reaction without a 15 solvent or in the presence of an inert solvent for the reaction. The solvent is not particularly limited as long as the reaction proceeds, but, for example, alcohols, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, halogenated hydrocarbons, sulfoxides, water or a mixture of two or more of 20 them and the like are used.
The reaction time is usually about 10 minutes to about 50 hours, preferably about 30 minutes to about 12 hours. The reaction temperature is usually about 0 to about 200°C, preferably about 20 to about 120°C.
25 Compound (VII) can be also obtained by treating Compound (XVIII) with hydrogen sulfide in the presence of a base.
The amount of hydrogen sulfide to be used is about 1 to about 30 moles, per 1 mole of Compound (XVIII).
The amount of base to be used is about 1.0 to about 30 3o moles, preferably about 1.0 to about 10 moles, per 1 mole of Compound (XVIII).
As the "base", for example, aromatic amines such as pyridine, lutidine and the like, tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like, and the like can be mentioned.
It is advantageous to carry out this reaction without a solvent or in the presence of an inert solvent for the reaction. The solvent is not particularly limited as long as the reaction proceeds, but, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, Io ethers, aromatic amines or a mixture of two or more of them and the like are used.
This reaction is performed under atmospheric pressure or under a pressurized condition. The reaction temperature is usually about -20 to about 80°C, preferably about -10 to about is 30°C. The reaction time is usually about 5 minutes to about 72 hours, preferably about 0.5 hour to about 30 hours.
Although the product can be used as a reaction solution itself or as a crude product in the next reaction, it can be isolated from the reaction mixture by a conventional methods, 2o and can be easily purified by a separating methods such as recrystallization, distillation, chromatography and the like.
Compound (VII) can be also obtained by treating compound (XVIII) with O,O-diethyl dithiophosphate in the presence of an acid.
2s The amount of O,0-diethyl dithiophosphate to be used is about 0.9 to about 2 moles, relative to 1 mole of Compound (XVIII) .
The amount of acid to be used is about 3.0 to about 30 moles, preferably about 3.0 to about 10 moles, per 1 mole of 3o Compound (XVIII) .
As the acid, for example, hydrogen halides such as hydrogen chloride, hydrogen bromide and the like, mineral acids such as hydrochloric acid, hydrobromic acid and the like, and the like are used.
It is advantageous to carry out this reaction without a solvent or in the presence of an inert solvent for the reaction. The solvent is not particularly limited as long as the reaction proceeds, but, for example, halogenated hydrocarbons, alcohols, amides, ethers, esters, water or a mixture of two or more of them and the like are used.
The reaction temperature is generally about 0 to about 80°C, preferably about 0 to about 30°C. The reaction time is to generally about 5 minutes to about 72 hours, preferably about 0.5 hour to about 30 hours.
Although the product can be used as a reaction solution itself or as a crude product in the next reaction, it can be isolated from the reaction mixture by a conventional methods, 15 and can be easily purified by a separating methods such as recrystallization, distillation, chromatography and the like.
Compound (VII) can also be obtained by treating Compound (XIX) with phosphorus pentasulfide or Lawesson's reagent.
The amount of the phosphorus pentasulfide or Lawesson's 2o reagent to be used is about 0.5 to about 10 moles, preferably about 0.5 to about 3 moles, per 1 mole of Compound (XIX).
It is advantageous to carry out this reaction without a solvent or in the presence of an inert solvent for the reaction. The solvent is not particularly limited as long as 25 the reaction proceeds, but, for example, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, halogenated hydrocarbons or a mixture of two or more of them and the like are used.
The reaction time is usually 10 minutes to about 50 hours, preferably about 30 minutes to about 12 hours. The reaction 3o temperature is usually about 0 to about 150°C, preferably about 20 to about 120°C.
Although the product (VII) can be used as a reaction solution itself or as a crude product in the next reaction, it can be isolated from the reaction mixture by a conventional methods, and can be easily purified by a separating methods such as recrystallization, distillation, chromatography and the like.
When Compound (Im) is an acylamino compound, the objective compound can be also obtained by subjecting the corresponding amine compound to an acylating reaction known per se.
Of Compound (Im), for example, a compound wherein R1 is 3o acylamino group optionally having substituents is obtained by reacting the corresponding 2-thiazolamine and an acylating agent optionally in the presence of a base or an acid.
The amount of the acylating agent to be used is about 1 to about 5 moles, preferably about 1 to about 2 moles, per 1 15 mole of the corresponding 2-thiazolamine.
As the "acylating agent", for example, carboxylic acids corresponding to an objective acyl group or a reactive derivative thereof (e. g., acid halide, acid anhydride, ester and the like) and the like can be mentioned.
2o The amount of the base or acid to be used is about 0.8 to about 5 moles, preferable about 1 to about 2 moles, per 1 mole of the corresponding 2-thiazolamine.
As the "base", for example, triethylamine, pyridine, 4-dimethylaminopyridine and the like can be mentioned.
25 As the "acid", for example, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid and the like can be mentioned.
It is advantageous to carry out this reaction without a solvent or in the presence of an inert solvent for the 3o reaction. The solvent is not particularly limited as long as the reaction proceeds, but, for example, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, aromatic amines or a mixture of two or more of them and the like are used.
The reaction temperature is about -20 to about 150°C, preferably about 0 to about 100°C. The reaction time is usually 5 minutes to about 24 hours, preferably about 10 s minutes to about 5 hours.
Although the product can be used as a reaction solution itself or as a crude product in the next reaction, it can be isolated from the reaction mixture by a conventional methods, and can be easily purified by a separating methods such as io recrystallization, distillation, chromatography and the like.
When Compound (Im) is an N-oxide compound, it is obtained by treating the corresponding pyrimidine compound with an organic peroxy acid.
The amount of the organic peroxy acid to be used is about is 0.8 to about 10 moles, preferable about 1.0 to about 3.0 moles, per 1 mole of the corresponding pyrimidine compound.
As the "organic peroxy acid", for example, peracetic acid, trifluoroperacetic acid, m-chloroperbenzoic acid and the like can be mentioned.
zo It is advantageous to carry out this reaction without a solvent or in the presence of an inert solvent for the reaction. The solvent is not particularly limited as long as the reaction proceeds, but, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, zs organic acids, ethers, amides, sulfoxides, alcohols, nitrites, ketones or a mixture of two or more of them and the like are used.
The reaction temperature is about -20°C to about 130°C, preferably about 0 to about 100°C. The reaction time is 3o usually 5 minutes to about 72 hours, preferably about 0.5 hour to about 12 hours.
Alternatively, the N-oxide compound is also obtained by treating the corresponding pyrimidine compound with hydrogen peroxide or alkyl hydroperoxide in the presence of a base, an acid or a metal oxide, if desired.
The amount of the hydrogen peroxide or alkyl hydroperoxide to be used is about 0.8 to about 10 moles, preferably about 1.0 to about 3.0 moles, per 1 mole of the corresponding pyrimidine compound.
As the "alkyl hydroperoxide", for example, tert-butyl hydroperoxide, cumene hydroperoxide and the like can be mentioned.
io The amount of the base, acid or metal oxide to be used is about 0.1 to about 30 moles, preferably 0.8 to about 5 moles, per 1 mole of the corresponding pyrimidine compound.
As the "base", for example, inorganic bases such as sodium hydroxide, potassium hydroxide and the like, basic is salts such as sodium carbonate, potassium carbonate and the like, and the like can be mentioned.
As the "acid", for example, mineral acids such as hydrochloric acid, sulfuric acid, perchloric acid and the like, Lewis acids such as boron trifluoride, aluminum chloride, 2° titanium tetrachloride and the like, organic acids such as formic acid, acetic acid and the like, and the like can be mentioned.
As the "metal oxide", for example, vanadium oxide (e. g., V205 etc. ) , osmium tetroxide (0s04) , tungsten oxide (e. g. , W03 2s etc.), molybdenum oxide (e. g., Mo03 etc.), selenium dioxide (Se02) , chromium oxide (e. g. , Cr03 etc. ) and the like can be mentioned.
It is advantageous to carry out this reaction without a solvent or in the presence of an inert solvent for the 3o reaction. The solvent is not particularly limited as long as the reaction proceeds, but, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, organic acids, ethers, amides, sulfoxides, alcohols, nitriles, ketones or a mixture of two or more of them and the like are used.
The reaction temperature is about -20°C to about 130°C, preferably about 0°C to about 100°C. The reaction time is usually 5 minutes to about 72 hours, preferably about 0.5 hour to about 12 hours.
Although the product can be used as a reaction solution itself or as a crude product in the next reaction, it can be a mixture isolated by a conventional method, and can be easily io purified by a separating methods such as recrystallization, distillation, chromatography and the like.
When compound (Im) is an S-oxide compound, it can be obtained by treating the corresponding sulfide compound with peroxide.
I5 The amount of peroxide to be used is about 0.8 to about males, preferably about 1.0 to about 3.0 moles, relative to 1 mole of the corresponding sulfide compound.
As the "peroxide", for example, peracetic acid, trifluoroperacetic acid, m-chloroperbenzoic acid, potassium 2o persulfate, metaperiodic acid and the like can be mentioned.
It is advantageous to carry out this reaction without a solvent or in the presence of an inert solvent for the reaction. The solvent is not particularly limited as long as the reaction proceeds, but, for example, halogenated 2s hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, organic acids, ethers, amides, sulfoxides, alcohols, nitriles, ketones or a mixture of two or more of them and the like are used.
The reaction temperature is about -20°C to about 130°C, 3o preferably about 0°C to about 100°C. The reaction time is usually about 5 minutes to about 72 hours, preferably about 0.5 hour to about l2 hours.
In addition, an S-oxide compound can be obtained by treating the corresponding sulfide compound with hydrogen peroxide or alkyl hydroperoxide in the presence of a base, acid and/or metal oxide, if desired.
The amount of the hydrogen peroxide or alkyl hydroperoxide to be used is about 0.8 to about 10 moles, preferably about 1.0 to about 3.0 moles, per 1 mole of the corresponding sulfide compound.
As the "alkyl hydroperoxide", for example, tert-butyl hydroperoxide, cumene hydroperoxide and the like can be io mentioned.
The amount of the "base, acid or metal oxide" to be used is about 0.1 to about 30 moles, preferably about 0.8 to about moles, per 1 mole of the corresponding sulfide compound.
As the "base", for example, inorganic bases such as I5 sodium hydroxide, potassium hydroxide and the like, basic salts such as sodium carbonate, potassium carbonate and the like, and the like can be mentioned.
As the "acid", for example, mineral acids such as hydrochloric acid, sulfuric acid, perchloric acid and the like, 2° Lewis acids such as boron trifluoride, aluminum chloride, titanium tetrachloride and the like, organic acids such as formic acid, acetic acid and the like, and the like can be mentioned.
As the "metal oxide", for example, vanadium oxide (e. g., 2s VzOs etc. ) , osmium tetroxide (0s04) , tungsten oxide (e.g. , W03 etc.), molybdenum oxide (e. g., Mo03 etc.), selenium dioxide (Se02), chromium oxide (e.g., Cr03 etc.) and the like can be mentioned.
It is advantageous to carry out this reaction without a 3o solvent or in the presence of an inert solvent for the reaction. The solvent is not particularly limited as long as the reaction proceeds, but, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, organic acids, ethers, amides, sulfoxides, alcohols, nitriles, ketones or a mixture of two or more of them and the like are used.
The reaction temperature is about -20°C to about 130°C, preferably about 0°C to about 100°C. The reaction time is usually about 5 minutes to about 72 hours, preferably about 0.5 to about 12 hours.
Although the product can be used as a reaction solution itself or as a crude product in the next reaction, it can be a to mixture isolated by a conventional methods, and can be easily purified by a separating methods such as recrystallization, distillation, chromatography and the like.
In the respective reactions mentioned above, when starting compounds have amino, carboxy, hydroxy as 15 substituents, a protecting groups which are generally used in the peptide chemistry or the like may be introduced into these groups and, after reaction, a desired compound can be obtained by removing protecting groups if needed.
As a protecting group for amino, for example, formyl or 2o Ci-s alkyl-carbonyl (e.g. , acetyl, propionyl and the like) , phenylcarbonyl, C1_6 alkoxy-carbonyl (e. g., methoxycarbonyl, ethoxycarbonyl and the like), phenyloxycarbonyl, C~_lo aralkyloxy-carbonyl (e. g., benzyloxycarbonyl and the like), trityl, phthaloyl and the like, which may have substituents 25 are used. As these substituents, halogen atoms) (e. g., fluorine, chlorine, bromine, iodine and the like), C1-s alkyl-carbonyl (e. g., acetyl, propionyl, valeryl and the like), nitro and the like are used and the number of substituents is 1 to 3.
3o As a protecting group for carboxy, for example, C1_s alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like), phenyl, trityl, silyl and the like, which may have substituents, are used. As these substituents, halogen atoms) treating the corresponding sulfide (e. g., fluorine, chlorine, bromine, iodine and the like), formyl, C1_s alkyl-carbonyl (e. g., acetyl, propionyl, butylcarbonyl and the like), nitro, C1_s alkyl (e. g., methyl, ethyl, tert-butyl and the like) , Cs_lo aryl (e. g. , phenyl, s naphthyl and the like) and the like are used and the number of substituents is 1 to 3.
As a protecting group for hydroxy, for example, C1_s alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tent-butyl and the like) , phenyl, C~_11 aralkyl (e. g. , benzyl and the like) , to formyl, C1_s alkyl-carbonyl (e.g., acetyl, propionyl and the like), phenyloxycarbonyl, C~_11 aralkyloxy-carbonyl (e. g., benzyloxycarbonyl and the like), tetrahydropyranyl, tetrahydrofuranyl, silyl and the like, which may have substituents, are used. As these substituents, halogen atoms) is (e. g., fluorine, chlorine, bromine, iodine and the like), C1_s alkyl (e.g., methyl, ethyl, tert-butyl and the like), C~_11 aralkyl (e. g. , benzyl and the like) , Cs_lo aryl (e. g. , phenyl, naphthyl and the like), nitro and the like are used, wherein the number of substituents is 1 to 4.
2o In addition, as a method of removing a protecting group, a method known per se or a method according to such method is used, and, for example, method by treating with an acid, a base, ultraviolet rays, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium 2s acetate and the like or a method of reduction is used.
In any case, Compound (I) can be synthesized by optionally applying further known deprotection, acylation, alkylation, hydrogenation, oxidation, reduction, carbon chain extension and substituent exchange reactions alone or a 3o combination of two or more of them. As these reactions, those described in, for example, Shinjikkenkagakukoza 14, vo1.15, 1977 (Maruzen Press) and the like are adopted.
As the above "alcohols", for example, methanol, ethanol, propanol, isopropanol, tert-butanol and the like can be mentioned.
As the above ~ethers", for example, diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and the like can be mentioned.
As the above ~halogenated hydrocarbons", for example, dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride and the like can be mentioned.
As the above "aliphatic hydrocarbons", for example, 1o hexane, pentane, cyclohexane and the like can be mentioned.
As the above ~aromatic hydrocarbons", for example, benzene, toluene, xylene, chlorobenzene and the like can be mentioned.
As the above "aromatic amines", for example, pyridine, 15 lutidine, quinaline and the like can be mentioned.
As the above ~amides", for example, N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide and the like can be mentioned.
As the above "ketones", far example, acetone, methyl 2o ethyl ketone and the like can be mentioned.
As the above "sulfoxides", for example, dimethyl sulfoxide and the like can be mentioned.
As the above "nitrites", for example, acetonitrile, propionitrile and the like can be mentioned.
2s As the above "organic acids", for example, acetic acid, propionic acid, trifluoroacetic acid and the like can be mentioned.
As the above ~esters", for example, methyl acetate, ethyl acetate, amyl acetate, methyl propionate and the like so can be mentioned.
When a desired product is obtained in a free form by the above reaction, it may be converted into a salt according to conventional methods or, when a desired product is obtained as a salt, it can be converted into a free form or another salt according to conventional methods. Compound (Im) thus obtained can be isolated and purified from the reaction solution by the known methods, for example, trans-solvation, concentration, s solvent extraction, fractional distillation, crystallization, recrystallization, chromatography and the like.
When Compound (Im) is present as a configurational isomer (stereoisomer), diastereomer, conformer or the like, each can be optionally isolated by the above separation and io purification methods. In addition, when Compound (Im) is in the form of its racemate, they can be separated into S- and R-forms by any conventional optical resolution.
When Compound (Im) includes stereoisomers, both the isomers alone and mixtures of each isomers are included in the is scope of the present invention.
In addition, Compound (I) may be a hydrate or non-hydrate.
Compound (I) may be labeled with an isotope (e. g., 3H, 19C, ssS and the like) or the like.
A prodrug of Compounds (Ia) , (II) , (III) , (Iva) , (Va) , Zo (VIa) , (Im) , (In) , (If' ) , (Ig' ) or (Ih' ) above (hereinafter abbreviated as Compound (A) refers to a compound which is converted to Compound (A) as a result of a reaction with an enzyme, gastric acid etc. under physiological conditions in vivo, thus a compound that undergoes enzymatic oxidation, Zs reduction, hydrolysis etc. to convert into Compound (A) and a compound that undergoes hydrolysis and the like by gastric acid etc. to convert into Compound (A). As a prodrug for Compound (A), a compound obtained by subjecting an amino group in Compound (A) to an acylation, alkylation or phosphorylation 30 (e.g., a compound obtained by subjecting an amino group in Compound (A) to an eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylation, etc.); a compound obtained by subjecting a hydroxy group in Compound (A) to an acylation, alkylation, phosphorylation and boration (e. g., a compound obtained by subjecting a hydroxy group in Compound (A) to an acetylation, palmitoylation, propanoylation, pivaloylation, succinylation, fumarylation, alanylation, dimethylaminomethylcarbonylation, etc.); a compound obtained by subjecting a carboxyl group in Compound (A) to an esterification or amidation (e. g., a compound so obtained by subjecting a carboxyl group in Compound (A) to an ethylesterification, phenylesterification, carboxymethylesterification, dimethylaminomethylesterification, pivaloyloxymethylesterification, ethoxycarbonyloxyethylesterification, phthalidylesterification, z5 (5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterification, cyclohexyloxycarbonylethylesterification and methylamidation, etc.) and the like can be mentioned. Any of these compounds can be produced from Compound (A) by a method known per se.
A prodrug for Compound (A) may also be one which is 2o converted to Compound (A) under physiological conditions as described in "IYAKUHIN no KAIHATSU (Development of Pharmaceuticals ) , Vol. 7, Design of Molecules, p. 163-198, Published by HIROKAWA SHOTEN (1990).
In addition, as the p38 MAP kinase inhibitor and/or the 25 TNF-a production inhibitor to be used in the present invention, the compounds described in W098/57966, W098/56377, W098/25619, W098/07425, W098106715, US5739143, W097/35855, W097/33883, wo97/32583, wo97/25048, wo97/25046, w096/10143, w096/21654, w095/07922, wo2000/09525 " wo99/17776, wo99/01131, wo98/28292, so wp97/25047, W097/25045, US5658903, W096/21452, W099/18942, US5756499, US5864036, US6046208, US5716955, US5811549, US5670527, US5969184, W02000/31072, W02000/31063, W02000/20402, W02000/18738, W02000/17175, W02000/12497, W02000/12074, W02000/07991, W02000/07980, W02000/02561, US6096711, W099/64400, W099/61440, W099/59959, W099/58523, W099/58502, W099/57101, W099/32111, W099/32110, W099/26657, W099/20624, W099/18942, W099/15164, W099/00357, W098/52940, W098/52937, s W098/52558, W098/06715, W097/22256, W096/21452, W02000/43366, W02000/42003, W02000/42002, W02000/41698, W02000/41505, W02000/40243, W02000/34303, W02000/25791, W02000/17204, W02000/10563, US6080546, W099/61426, W099/32463, W099/32121, W099/17776, W098/28292, W098/27098, W098/25619, W098/20868, io W097/35855, W097/32583, W097/25048, W097/25047, W097/25046, W097/25045, US5658903, W096/40143, W096/21654, W02000/55153, W02000/55120, W02000/26209, US6046208, US5756499, US5864036, JP-A-2000-86657, W099/59960, W099/21859, W099/03837, W099/01449, W099/01136, WO/, W099/01130, US5905089, W098/57966, is WOgg/52941, W098/47899, W098/07425, W097/33883, W02000/42213, W099/58128, W02000/04025, W02000/40235, W02000/31106, W097/46228, W02000/59904, W02000/42003, W02000/42002, W02000/41698, W02000/10563, W099/61426, W099/32463, US6002008, W098/43960, W098/27098, W097/35856, W097/35855, W096/22985, 2o Jp-A-61-145167 and the like, and the like can be used.
Of the p38 MAP kinase inhibitor and/or the TNF-a production inhibitor to be used in the present invention, a compound containing a pyridyl group or a salt thereof, wherein 2s a substituent has been introduced into a position of nitrogen atom of the pyridyl group, or a compound containing a pyridyl group and an aromatic hydrocarbon group, or a salt thereof, wherein a polar group has been introduced into the aromatic hydrocarbon group can be preferably used, because P450 (e. g., 3o Cyp3A4) inhibitory action and the like is reduced, which in turn reduces side effects such as liver toxicity and the like, thereby enabling combined use with other drugs.
As the pyridyl group of the "compound containing a pyridyl group" "compound containing a pyridyl group and an aromatic hydrocarbon group", any of 1-pyridyl group, 2-pyridyl group, 3-pyridyl group and 4-pyridyl group can be used. Of these, 4-pyridyl group is preferable. As the aromatic hydrocarbon group of the "compound containing a pyridyl group and an aromatic hydrocarbon group", for example, a monocyclic or fused polycyclic (di- or tricyclic) aromatic hydrocarbon group having 6 to 14 carbon atoms and the like can be mentioned. Concrete examples thereof include Cs_14 aryl such as To phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and the like, with preference given to phenyl.
As the "compound containing a pyridyl group" or "compound containing a pyridyl group and an aromatic is hydrocarbon group", the above-mentioned compounds (I)-(VI) and the like are used.
As the substituent that can be introduced into the a-position of the pyridyl group, for example, those similar to the "substituent" of the above-mentioned "pyridyl group zo optionally having substituents" represented by RZ and the like can be mentioned. Concretely, 1 to 3 of the following substituents can be introduced.
(i) halogen atom, (ii) C~_s alkyl group, C2-s alkenyl group, CZ-s alkynyl group, C3-s zs cycloalkyl group, Cs_,_9 aryl group and C~_,s aralkyl group [these groups may have 1 to 5 substituents selected from a group consisting of oxo, halogen atom, C1_3 alkylenedioxy, vitro, cyano, optionally halogenated C1_s alkyl, optionally halogenated C2-s alkenyl, carboxy CZ_s alkenyl, optionally halogenated CZ_s so alkynyl, optionally halogenated C3_s cycloalkyl, Cs_14 aryl, optionally halogenated Cl_a alkoxy, Cl_s alkoxy-carbonyl-Cl-s alkoxy, hydroxy, Cs_la aryloxy, C~_ls aralkyloxy, mercapto, optionally halogenated C1-s alkylthio, Cs-i4 arylthio, C7-is aralkylthio, amino, mono-C1_6 alkylamino, mono-Cs_14 arylamino, di-Cl_s alkylamino, di-Cs_14 arylamino, formyl, carboxy, Cl_s alkyl-carbonyl, C3_s cycloalkyl-carbonyl, C1_s alkoxy-carbonyl, Cs_1q aryl-carbonyl, C~_ls aralkyl-carbonyl, Cs_14 aryloxy-carbonyl, s C~-is aralkyloxy-carbonyl, 5 or 6-membered heterocyclic carbonyl, carbamoyl, thiocarbamoyl, mono-C1_s alkyl-carbamoyl, di-C1_s alkyl-carbamoyl, Cs_14 aryl-carbamoyl, 5- or 6-membered heterocyclic carbamoyl, C1_s alkylsulfonyl, Cs_14 arylsulfonyl, C1_s alkylsulfinyl, Cs_1q arylsulfinyl, formylamino, Cl_s alkyl-io carbonyl amino, Cs_14 aryl-carbonylamino, Cl_s alkoxy-carbonylamino, C1_s alkylsulfonylamino, Cs_14 arylsulfonylamino, Cl_s alkyl-carbonyloxy, Cs_19 aryl-carbonyloxy, Cl_s alkoxy-carbonyloxy, mono-C1_s alkyl-carbamoyloxy, di-C1_s alkyl-carbamoyloxy, Cs_14 aryl-carbamoyloxy, nicotinoyloxy, 5- to 7-15 membered saturated cyclic amino containing, besides one nitrogen atom and carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom (this cyclic amino may have substituents selected from the group consisting of Cl_s alkyl, Cs_14 aryl, Cl_s alkyl-carbonyl, 20 5- to 10-membered aromatic heterocyclic group and oxo), and 5-to 10-rnembered aromatic heterocyclic group, containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, sulfo, sulfamoyl, sulfinamoyl and sulfenamoyl (substituent 2s group A) ]
(iii) 5- to 14-membered heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, which may have 1 to 3 substituents selected from substituent group A, 30 (iv) acyl group represented by the formula: - (C=O) -R5, - (C=O) -ORS , - ( C=O ) -NRSRs , - ( C=S ) -NHRS or -SOz-R' wherein RS is (1) hydrogen atom, (2) Cl_s alkyl group, C2_s alkenyl group, C2_s alkynyl group, C3_s cycloalkyl group, Cs_14 aryl group or C~_16 aralkyl group, each of which may have 1 to 3 substituents selected from substituent group A, or (3) 5- to 14-membered heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, which may have 1 to 3 substituents selected from substituent group A, R6 is hydrogen atom or Cl_6 alkyl group, and R' is (1) Cl_6 alkyl group which may have 1 to 3 substituents selected from substituent group A, C2_6 alkenyl group, CZ_6 alkynyl group, C3_6 cycloalkyl group, Cs_ 14 aryl group or C~_16 aralkyl group, or (3) 5- to 14-membered heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, which may have 1 to 3 substituents selected from substituent group A, is (v) amino group (this amino group may have 1 or 2 substituents selected from (1) C1_6 alkyl group which may have 1 to 3 substituents selected from substituent group A, CZ_6 alkenyl group, C2_6 alkynyl group, C3_6 cycloalkyl group, C6_14 aryl group and C~_16 aralkyl group, (2) 5- to 14-membered heterocyclic 2o group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, which may have 1 to 3 substituents selected from substituent group A, and (3) acyl group shown by the above-mentioned (iv) ) , 2s (vi) 5- to 7-membered non-aromatic cyclic amino group containing, besides one nitrogen atom and carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom (this cyclic amino group may have 1 to 3 substituents selected from Cl_6 alkyl, C6_14 aryl, Cl_s so alkyl-carbonyl, 5- to10-membered aromatic heterocyclic group and oxo), and (vii) Cl_6 alkoxy group, C6_14 aryloxy group and C~_16 aralkyloxy group, which may have 1 to 3 substituents selected from substituent group A.
Of these, the following substituents are preferable.
(i) halogen atom, (ii) Cl_6 alkyl group, (iii) amino group (this amino group may have 1 or 2 substituents selected from (1) C1_s alkyl group, CZ_6 alkenyl group, C2_6 alkynyl group, C3_s cycloalkyl group, C6_1q aryl group and C~_16 aralkyl group, which may have 1 to 3 substituents selected from substituent group A, (2) 5- to 14-membered heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from io nitrogen atom, sulfur atom and oxygen atom, which may have 1 to 3 substituents selected from substituent group A, and (3) acyl group shown by the formula: - (C=0) -RS, - (C=0) -ORS, - (C=O) -NRSR6 wherein RS is (1) hydrogen atom, (2) Cl_6 alkyl group, C2_s alkenyl group, C2_6 alkynyl group, C3_6 cycloalkyl group, C6_19 aryl group or C~_16 aralkyl group, each of which may have 1 to 3 substituents selected from substituent group A, or (3) 5- to 14-membered heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, which may have 1 to 3 2o substituents selected from substituent group A, and R6 is hydrogen atom or C1_6 alkyl group) and (iv) 5- to 7-membered non-aromatic cyclic amino group containing, besides one nitrogen atom and carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom 25 (this cyclic amino group may have 1 to 3 substituents selected from Cl_6 alkyl , C6_14 aryl , Cl_6 alkyl-carbonyl , 5- to 10-membered aromatic heterocyclic group and oxo).
As the polar group that can be introduced into the aromatic hydrocarbon group of the ~compound containing a 3o pyridyl group and an aromatic hydrocarbon group or a salt thereof", for example, 1 to 3 selected from (1) halogen atom, (2) hydroxy, (3) amino optionally having 1 or 2 substituents selected from substituents selected from substituent group A

and acyl shown by the above-mentioned (iv), (4)nitro, (5) carboxy, (6) formyl, (7) Cl_6 alkoxy optionally having 1 to 3 substituents selected from substituent group A, (8) C1_6 alkoxy-carbonyl optionally having 1 to 3 substituents selected from substituent group A, (9) cyano and (10) C1_6 alkyl and C6_14 aryl optionally having 1 to 3 selected from these polar groups (groups shown in the above-mentioned (1)-(9)) as substituents are mentioned. Of these, Cl_6 alkyl and C6_14 aryl optionally having 1 to 3 substituents selected from (1) carboxy, (2) io hydroxy, (3) carboxy and hydroxy, and the like are preferable.
As P450, CYP1A1, CYP1A2, CYP2A1, CYP2A2, CYP2A4, CYP2A5, CYP2A6, CYP2B1, CYP2B2, CYP2B4, CYP2B5, CYP2B6, CYP2B9, CYP2C2, CYP2C3, CYP2C4, CYP2C5, CYP2C6, CYP2C7, CYP2C8, CYP2C9, CYP2C11, CYP2C12, CYP2C14, CYP2C19, CYP2C29, CYP2D1, CYP2D2, 15 Cyp2D6, CYP2D9, CYP2E1, CYP2F1, CYP2F2, CYP2G1, CYP3A1, CYP3A2, CYP3A3, CYP3A4, CYP3A6, CYP3A7, CYP4A1, CYP4B1 and the like can be mentioned, with preference given to CYP2C9, CYP2D6 and CYP3A4.
2o In the present specification, the above-mentioned p38 MAP kinase inhibitor and/or the TNF-a, production inhibitor are sometimes collectively abbreviated as the compound of the present invention.
The compound of the present invention has superior 2s pggMAp kinase inhibitory action, TNF-a inhibitory action (TNF-o, production inhibitory action, TNF-a activity inhibitory action), phosphodiesterase IV (PDE IV) inhibitory action and the like, is superior in (oral) absorbability, (metabolism) stability and the like, and shows low toxicity and fewer side 3o effects. Therefore, the compound can be used as a safe pharmaceutical product.
A pharmaceutical composition containing the compound of the present invention can be used for a mammal (e. g., mouse, rat, hamster, rabbit, cat, dog, bovine, sheep, monkey, human etc.) as a prophylactic or therapeutic agent of various pains shown in the following.
cancer pain, acute pain due to inflammation, pain associated with chronic inflammation, postoperative pain (pain of incision, deep pain, visceral pain, postoperative chronic pain and the like), muscular pain (muscular pain associated with chronic pain disease, stiff neck and the like), arthritic pain, tooth pain, temporomandibular joint pain, headache (migrain, io tension-type headache, headache due to fever, headache caused by hypertension), visceral pain (cardiac pain, anginal pain, abdominal pain, kidney pain, ureteral pain, bladder pain, pain in the field of obstetrics and gynecology (intermenstrual pain, menstrual cramps, labor pain)), nerve pain (ruptured disc, 15 radicular pain, postherpetic neuralgia, trigeminal neuralgia), reflex sympathetic dystrophy, complex regional pain syndrome and the like.
A pharmaceutical composition containing the compound of the present invention can be also used for a mammal (e. g., 2o mouse, rat, hamster, rabbit, cat, dog, bovine, sheep, monkey, human etc.) as an agent for the suppression of osteoclast activation and inhibitor of osteoclast formation.
Osteoclast is a cell multinucleated by differentiation and fusion of hematopoietic cells, which has bone matrix 2s decomposability and plays a role of resorbing bone from osteoclast that newly forms bone in the bone metabolism. The maintenance of bone mass and form depends on the balance of the formation and resorption by the both cells. When osteoclast is activated to promote resorption of the bone, so this balance is broken, and a decrease in the bone mass and morphological destruction and deformation occur. In addition, since osteoclast is involved in the adjustment of blood calcium concentration via resorption of bone, which is a calcium storage organ, extreme activation of osteoclast results in an increase in the blood calcium concentration.
The compound of the present invention suppresses the activation of osteoclast and can inhibit the formation of osteoclast. Thus, the compound can be used as an agent for the prophylaxis or treatment of, for example, (1) postmonopausal or senile primary osteoporosis, (2) secondary osteoporosis caused by inflammation (rheumatism and the like), blood system malignant disease (malignant lymphoma, leukemia and the like), 1o endocrine disorder (thyroid hyperfunction, diabetes and the like) or administration of pharmaceutical agent such as adrenal cortex hormone and the like, (3) bone or joint tissue destruction or deformation associated with bone metastasis of tumor or rheumatism, (4) Paget's disease or (5) hypercalcemia ZS and the like.
Of the compounds of the present invention, a compound having both effects of the prophylaxis or treatment of pain and the suppression of activation and/or inhibition of formation of osteoclast is useful because it alleviates pain 2o such as arthritic pain and the like, and simultaneously prevents or treats diseases related to osteoclast, such as destruction and deformation of bone or joint tissue and the like.
25 The pharmaceutical composition of the present invention containing the compound of the present invention shows low toxicity, and can be safely administered orally or parenterally (e. g., topical, rectal, intravenous administration etc.) as a pharmaceutical preparation of the 3o compound of the present invention as it is or after admixing with a pharmacologically acceptable carrier to give, for example, tablet (including sugar-coated tablet and film-coated tablet), powder, granule, capsules (including soft capsules), liquid, injection, suppository, sustained-release preparation and the like, according to a methods known per se used for the general production method for pharmaceutical preparations.
The content of the Compound of the present invention in a s pharmaceutical composition of the present invention is about 0.01 to about 100% by weight relative to the whole preparation.
As the pharmacologically acceptable carrier which may be used for preparing a pharmaceutical composition of the present invention, the conventional various organic or inorganic io carriers as a pharmaceutical material, for example, excipient, lubricant, binder and disintegrating agent in solid preparations, or solvent, solubilizing agent, suspending agent, isotonizing agent, buffer and soothing agent in liquid preparations, and the like can be mentioned. Further, if is needed, additives such as the conventional preservative, antioxidant, colorant, sweetening agent, adsorbing agent, wetting agent and the like can be appropriately used at an appropriate amount.
As the excipient, for example, lactose, saccharose, D-2o mannitol, starch, corn starch, crystalline cellulose, light silicic acid anhydride and the like can be mentioned.
As the lubricant, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like can be mentioned.
2s As the binder, for example, crystalline cellulose, saccharose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like can be mentioned.
so As the disintegrating agent, for example, starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, L-hydroxypropylcellulose and the like can be mentioned.

As the solvent, for example, water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like can be mentioned.
As the solubilizing agent, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, tris-aminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like can be mentioned.
As the suspending agent, for example, surfactants such as stearyl triethenolamine, sodium lauryl sulfate, lauryl io aminopropionate, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate and the like; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, i5 hydroxypropylcellulose and the like, and the like can be mentioned.
As the isotonizing agent, for example, glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like can be mentioned.
2o As the buffer, for example, buffering solutions such as phosphate, acetate, carbonate, citrate and the like, and the like can be mentioned.
As the soothing agent, for example, benzyl alcohol and the like can be mentioned.
25 As the preservative, for example, p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like can be mentioned.
As the antioxidant, for example, sulfites, ascorbic acid, a-tocopherol and the like can be mentioned.
so While the content of additive such as carrier and the like in the pharmaceutical composition of the present invention varies depending on the form of the preparation, it is generally about 1 to 99.99 wt~, preferably about 10 to 90 wt~, relative to the entire preparation.
While the dose of the pharmaceutical composition of the present invention varies depending on the administration subject, administration route, disease, symptoms and the like, s it is, for example, about 0.01 to about 30 mg/kg body weight, preferably about 0.1 to about 20 mg/kg body weight, more preferably about 1 to about 20 mg/kg body weight, in the amount of an active ingredient [the compound of the present invention] per one day, which is orally administered to io patients with pain (body weight about 60 kg) once a day or several times a day in divided doses. For example, moreover, it is orally administered to patients with primary osteoporosis (body weight about 60 kg) in a daily dose of about 0.01 to about 30 mg/kg body weight, preferably about 0.1 Zs to about 20 mg/kg body weight, more preferably about 1 to about 20 mg/kg body weight, in the amount of an active ingredient [the compound of the present invention], once a day or several times a day in divided doses.
2o As the drugs that can be used in combination with the compound of the present invention (hereinafter the drug is sometimes abbreviated as a concomitant drug) includes, for example, the following.
(1) non-steroidal antiinflammatory drugs (NSAIDs) 2s (i) classical NSAIDs alcofenac, aceclofenac, sulindac, tolmetin, etodolac, fenoprofen, thiaprofenic acid, meclofenamic acid, meloxicam, tenoxicam, lornoxicam, nabumeton, acetaminophen, phenacetin, ethenzamide, sulpyrine, antipyrine, migrenin, aspirin, 3o mefenamic acid, flufenamic acid, diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen, fenbufen, pranoprofen, floctafenine, piroxicam, epirizole, tiaramide hydrochloride, zaltoprofen, gabexate mesylate, camostat mesylate, ulinastatin, colchicine, probenecid, sulfinpyrazone, benzbromarone, allopurinol, sodium aurothiomalate, hyaluronate sodium, sodium salicylate, morphine hydrochloride, salicylic acid, atropine, scopolamine, morphine, pethidine, levorphanol, oxymorphone or a salt thereof and the like.
(ii) cyclooxygenase inhibitor (COX-1 selective inhibitor, COX-2 selective inhibitor and the like) salicylic acid derivatives (e. g., celecoxib, Rofecoxib, 1o aspirin), MK-663, valdecoxib, SC-57666, tiracoxib, S-2474, diclofenac, indomethacin, loxoprofen and the like.
(iii) drug concurrently having COX inhibitory activity and 5-lipoxygenase inhibitory activity ML-3000, p54 (COX inhibitor & 5-lipoxygenase inhibitor) and 15 the like.
(iv) nitric oxide-releasing NSAIDs (2) disease-modifying anti-rheumatic drugs (DMARDs) (i) gold preparation Auranofin and the like.
20 (ii) penicillamine D-penicillamine (iii) sulfasalazine (iv) antimalarial drug chloroquine and the like.
25 (v) pyrimidine synthesis inhibitor leflunomide and the like.
(vi) prograf (3) anti-cytokine drug (I) protein drug 30 (i) TNF inhibitor etanercept, infliximab, D2E7, CDP-571, PASSTNF-a, soluble TNF-a, receptor, TNF-a, binding protein, anti-TNF-a, antibody and the like.

(ii) interleukin-1 inhibitor anakinra (interleukin-1 receptor antagonist), soluble interleukin-1 receptor and the like.
(iii) interleukin-6 inhibitor s MRA (anti-interleukin-6 receptor antibody), anti-interleukin-6 antibody and the like.
(iv) interleukin-10 drug interleukin-10 and the like.
(v) interleukin-12 inhibitor to anti-interleukin-12 antibody and the like.
(vi) drug concurrently having interferon-a, and -Y inhibitory activity and TNF-a inhibitory activity (polyclonal antibody) (II) non-protein drug is (i) MAP kinase inhibitor PD-98059 and the like.
(ii) gene modulator SP-100030, inhibitor of molecule involved in signal transduction, such as NF-K, NF-KB, IKK-1, IKK-2, AP-1 and the 20 like (iii) cytokine production inhibitor T-614, SR-31747, sonatimod and the like.
(iv) TNF-~, converting enzyme inhibitor (v) interleukin-1(3 converting enzyme inhibitor Zs HMR3480/VX-740 and the like.
(vi) interleukin-6 antagonist SANT-7 and the like.
(vii) interleukin-8 inhibitor IL-8 antagonist, CXCR1 & CXCR2 antagonist and the like.
30 (viii) chemokine antagonist MCP-1 antagonist and the like.
(ix) interleukin-2 receptor antagonist denileukin diftitox and the like.

(x) therapeutic vaccines TNF-a vaccine and the like.
(xi) gene therapy drug gene therapy drugs aiming at promoting the expression of gene s having an anti-inflammatory action such as interleukin-4, interleukin-10, soluble interleukin-1 receptor, soluble TNF-a receptor and the like.
(xii) antisense compound ISIS-104838 and the like.
zo (4) immunomodulator (immunosuppressant) (i) T cell differentiation modulator ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylate (JP-A-7-118266) (ii) others is methotrexate, cyclophosphamide, MX-68, atiprimod dihydrochloride, BMS-188667, CKD-461, rimexolone, cyclosporine, tacrolimus, gusperimus, azathiopurine, antilymphocyte serum, freeze-dried sulfonated normal immunoglobulin, erythropoietin, colony stimulating factor, interleukin, interferon and the 2° like.
( 5 ) steroid dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone, triamcinolone acetonide, fluocinonide, fluocinolone acetonide, prednisolone, methylprednisolone, 2s cortisone acetate, hydrocortisone, fluorometholone, beclomethasone dipropionate, estriol and the like.
( 6 ) c-Jun N terminal kinase (JNK) inhibitor compounds described in WO00/35906, WO00/35909, W000/35921, W000/64872 or W000/75118 and the like.
30 (7) angiotensin converting enzyme inhibitor enalapril, captopril, ramipril, lisinopril, cilazapril, perindopril and the like.
(8) angiotensin II receptor antagonist candesartan cilexetil (TCV-116), valsartan, irbesartan, olmesartan, eprosartan and the like.
(9) diuretic drug hydrochlorothiazide, spironolactone, furosemide, indapamide, bendrofluazide, cyclopenthiazide and the like.
(10) cardiotonic drug digoxin, dobutamine and the like.
(11) ~3 receptor antagonist carvedilol, metoprolol, atenolol and the like.
to (12) Ca sensitizer MCC-135 and the like.
(13) Ca channel antagonist nifedipine, diltiazem, verapamil and the like.
(14) anti-platelet drug, anticoagulator 15 heparin, aspirin, warfarin and the like.
(15) HMG-CoA reductase inhibitor atorvastatin, simvastatin and the like.
(16) contraceptive (i) sex hormone or derivatives thereof 2o gestagen or a derivative thereof (progesterone, 17a,-hydroxy progesterone, medroxyprogesterone, medroxyprogesterone acetate, norethisterone, norethisterone enanthate, norethindrone, norethindrone acetate, norethynodrel, levonorgestrel, norgestrel, ethynodiol diacetate, desogestrel, norgestimate, 25 gestodene, progestin, etonogestrel, drospirenone, dienogest, trimegestone, nestorone, chlormadinone acetate, mifepristone, nomegestrol acetate, Org-30659, TX-525, EMM-310525) or a combination of a gestagen or a derivative thereof and an estrogen or a derivative thereof (estradiol, estradiol 3o benzoate, estradiol cypionate, estradiol dipropionate, estradiol enanthate, estradiol hexahydrobenzoate, estradiol phenylpropionate, estradiol undecylate, estradiol valerate, estrone, ethinylestradiol, mestranol) and the like.

(ii) antiestrogen ormeloxifene, mifepristone, Org-33628 and the like.
(iii) spermatocide ucarcide and the like.
(17) others (i) T cell inhibitors IR-501 (T cell receptor peptide) and the like.
(ii) inosine monophosphate dehydrogenase (IMPDH) inhibitor mycophenolate mofetil, VX-497 and the like.
io (iii) adhesion molecule inhibitor ISIS-2302, selectin inhibitor, ELAM-1, VCAM-1, ICAM-1 and the like.
(iv) thalidomide (v) cathepsin inhibitor 1$ (vi) matrix metalloprotease (MMPs) inhibitor BB-3644, CGS-27023A, Bay-12-9566, KB-87785, L-758354, POL-641 and the like.
(vii) glucose-6-phosphate dehydrogenase inhibitor CBF-BS2 and the like.
2o (viii) hydroorotate dehydrogenase (DHODH) inhibitor (ix) phosphodiesterase IV (PDE IV) inhibitor CG-1088 and the like.
(x) phospholipase AZ inhibitor (xi) iNOS inhibitor 25 NOX-200 and the like.
(xii) microtubule stimulating drug paclitaxel and the like.
(xiii) microtubule inhibitor reumacon and the like.
30 (xiv) MHC class II antagonist ZD-2315 and the like.
(xv) prostacyclin agonist iloprost and the like.

(xvi) CD4 antagonist 4162W94, keliximab and the like.
(xvii) CD23 antagonist (xviii) LTB4 receptor antagonist CGS-25019C and the like.
(xix) 5-lipoxygenase inhibitor zileuton and the like.
(xx) cholinesterase inhibitor galanthamine and the like.
io (xxi) tyrosine kinase inhibitor YT-146 and the like.
(xxii) cathepsin B inhibitor (xxiii) adenosine deaminase inhibitor pentostatin and the like.
is (xxiv) osteogenesis stimulator (2R,4S)-(-)-N-[4-(diethoxyphosphorylmethyl)phenyl]-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxamide or a salt thereof (JP-A-8-231659) and the like.
(xxv) dipeptidylpeptidase inhibitor TMC-2A and the like.
(xxvi) TRK-530, TOK-8801 (xxvii) collagen agonist AI-200 and the like.
(xxviii) capsaicin cream 2s (xxix) hyaluronic acid derivative synvisc (hylan G-F 20), orthovisc and the like.
(xxx) glucosamine sulfate (xxxi) amiprilose Other concomitant drugs besides the above-mentioned so include, for example, antibacterial agent, antifungal agent, antiprotozoal agent, antibiotic, antitussive and expectorant drug, sedative, anesthetic, antiulcer drug, antiarrhythmic agent, hypotensive diuretic drug, anticoagulant, tranquilizer, antipsychotic, antitumor drug, hypolipidemic drug, muscle relaxant, anticonvulsant, antidepressant, antiallergic drug, cardiac, antiarrhythmic agent, vasodilator, vasoconstrictor, hypotensive diuretic drug, antidiabetic drug, antinarcotic, vitamin, vitamin derivative, antiasthmatic, therapeutic agent for pollakisuria/anischuria, therapeutic agent for atopic dermatitis, therapeutic agent for allergic rhinitis, hypertensor, endotoxin-antagonist or -antibody, signal transduction inhibitor, inhibitor of inflammatory mediator io activity, antibody to inhibit inflammatory mediator activity, inhibitor of anti-inflammatory mediator activity, antibody to inhibit anti-inflammatory mediator activity and the like.
Specific examples thereof include the following.
(1) antibacterial agent 15 1 ) sulfa drug sulfamethizole, sulfisoxazole, sulfamonomethoxine, sulfamethizole, salazosulfapyridine, silver sulfadiazine and the like.
2) quinoline antibacterial agent 2o nalidixic acid, pipemidic acid trihydrate, enoxacin, norfloxacin, ofloxacin, tosufloxacin tosilate, ciprofloxacin hydrochloride, lomefloxacin hydrochloride, sparfloxacin, fleroxacin and the like.
3) antiphthisic 25 isoniazid, ethambutol (ethambutol hydrochloride), p-aminosalicylic acid (calcium p-aminosalicylate), pyrazinamide, ethionamide, protionamide, rifampicin, streptomycin sulfate, kanamycin sulfate, cycloserine and the like.
4) antiacidfast bacterium drug 30 diaphenylsulfone, rifampicin and the like.
5) antiviral drug idoxuridine, acyclovir, vidarabine, gancyclovir and the like.
6) anti-HIV agent zidovudine, didanosine, zalcitabine, indinavir sulfate ethanolate, ritonavir and the like.
7) antispirochetele 8) antibiotic tetracycline hydrochloride, ampicillin, piperacillin, gentamicin, dibekacin, kanendomycin, lividomycin, tobramycin, amikacin, fradiomycin, sisomicin, tetracycline, oxytetracycline, rolitetracycline, doxycycline, ampicillin, piperacillin, ticarcillin, cephalothin, cephapirin, Zo cephaloridine, cefaclor, cephalexin, cefroxadine, cefadroxil, cefamandole, cefotoam, cefuroxime; cefotiam, cefotiam hexetil, cefuroxime axetil, cefdinir, cefditoren pivoxil, ceftazidime, cefpiramide, cefsulodin, cefmenoxime, cefpodoxime proxetil, cefpirome, cefozopran, cefepime, cefsulodin, cefmenoxime, cefmetazole, cefminox, cefoxitin, cefbuperazone, latamoxef, flomoxef, cefazolin, cefotaxime, cefoperazone, ceftizoxime, moxalactam, thienamycin, sulfazecin, aztreonam or a salt thereof, griseofulvin, lankacidin-group [Journal of Antibiotics (J. Antibiotics), 38, 877-885(1985)], azole 2o compound [2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone, fluconazole, itraconazole] and the like.
(2) antifungal agent 2s 1) polyethylene antibiotic (e. g., amphotericin B, nystatin, trichomycin) 2) griseofulvin, pyrrolnitrin and the like.
3) cytosine metabolism antagonist (e. g., flucytosine) 4) imidazole derivative (e. g., econazole, clotrimazole, 3o miconazole nitrate, bifonazole, croconazole) 5) triazole derivative (e. g. fluconazole, itraconazole) 6) thiocarbamic acid derivative (e. g. trinaphthol) ( 3 ) antiprotozoal agent metronidazole, tinidazole, diethylcarbamazine citrate, quinine hydrochloride, quinine sulfate and the like.
(4) antitussive and expectorant drug ephedrine hydrochloride, noscapine hydrochloride, codeine phosphate, dihydrocodeine phosphate, isoproterenol hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, noscapine hydrochloride, alloclamide, chlophedianol, picoperidamine, cloperastine, protokylol, isoproterenol, salbutamol, terbutaline, oxymetebanol, morphine io hydrochloride, dextromethorfan hydrobromide, oxycodone hydrochloride, dimemorphan phosphate, tipepidine hibenzate, pentoxyverine citrate, clofedanol hydrochloride, benzonatate, guaifenesin, bromhexine hydrochloride, ambroxol hydrochloride, acetylcysteine, ethyl cysteine hydrochloride, carbocysteine 15 and the like.
( 5 ) sedative chlorpromazine hydrochloride, atropine sulfate, phenobarbital, barbital, amobarbital, pentobarbital, thiopental sodium, thiamylal sodium, nitrazepam, estazolam, flurazepam, 2o haloxazolam, triazolam, flunitrazepam, bromovalerylurea, chloral hydrate, triclofos sodium and the like.
(6) anesthetic ( 6-1 ) local anesthetic cocaine hydrochloride, procaine hydrochloride, lidocaine, 25 dibucaine hydrochloride, tetracaine hydrochloride, mepivacaine hydrochloride, bupivacaine hydrochloride, oxybuprocaine hydrochloride, ethyl aminobenzoate, oxethazaine) and the like.
(6-2) general anesthetic 1) inhalation anesthetic (e. g., ether, halothane, nitrous so oxide, isoflurane, enflurane), 2) intravenous anesthetic (e. g., ketamine hydrochloride, droperidol, thiopental sodium, thiamylal sodium, pentobarbital) and the like.

(7) antiulcer drug histidine hydrochloride, lansoprazole, metoclopramide, pirenzepine, cimetidine, ranitidine, famotidine, urogastrone, oxethazaine, proglumide, omeprazole, sucralfate, sulpiride, cetraxate, gefarnate, aldioxa, teprenone, prostaglandin and the like.
(8) antiarrhythmic agent 1) Na channel blocker (e. g., quinidine, procainamide, disopyramide, ajmaline, lidocaine, mexiletine, phenytoin), so 2) ~-blocker (e. g., propranolol, alprenolol, bufetolol hydrochloride, oxprenolol, atenolol, acebutolol, metoprolol, bisoprolol, pindolol, carteolol, arotinolol, 3) K channel blocker (e. g., amiodarone), 4) Ca channel blocker (e.g., verapamil, diltiazem) and the I5 like.
(9) hypotensive diuretic drug hexamethonium bromide, clonidine hydrochloride, hydrochlorothiazide, trichlormethiazide, furosemide, ethacrynic acid, bumetanide, mefruside, azosemide, 2o spironolactone, potassium canrenoate, triamterene, amiloride, acetazolamide, D-mannitol, isosorbide, aminophylline and the like.
(10) anticoagulant heparin sodium, sodium citrate, activated protein C, tissue 25 factor pathway inhibitor, antithrombin III, dalteparin sodium, warfarin potassium, argatroban, gabexate, sodium citrate, ozagrel sodium, ethyl icosapentate, beraprost sodium, alprostadil, ticlopidine hydrochloride, pentoxifylline, dipyridamole, tisokinase, urokinase, streptokinase and the 30 like .
(11) tranquilizer diazepam, lorazepam, oxazepam, chlordiazepoxide, medazepam, oxazolam, cloxazolam, clotiazepam, bromazepam, etizolam, fludiazepam, hydroxyzine and the like.
(12) antipsychotic chlorpromazine hydrochloride, prochlorperazine, trifluoperazine, thioridazine hydrochloride, perphenazine maleate, fluphenazine enanthate, prochlorperazine maleate, levomepromazine maleate, promethazine hydrochloride, haloperidol, bromperidol, spiperone, reserpine, clocapramine hydrochloride, sulpiride, zotepine and the like.
(13) antitumor drug 6-O-(N-chloroacetylcarbamoyl)fumagillol, bleomycin, methotrexate, actinomycin D, mitomycin C, daunorubicin, adriamycin, neocarzinostatin, cytosine arabinoside, fluorouracil, tetrahydrofuryl-5-fluorouracil, picibanil, lentinan, levamisole, bestatin, azimexon, glycyrrhizin, i5 doxorubicin hydrochloride, aclarubicin hydrochloride, bleomycin hydrochloride, peplomycin sulfate, vincristine sulfate, vinblastine sulfate, irinotecan hydrochloride, cyclophosphamide, melphalan, busulfan, thiotepa, procarbazine hydrochloride, cisplatin, azathioprine, mercaptopurine, 2o tegafur, carmofur, cytarabine, methyltestosterone, testosterone propionate, testosterone enanthate, mepitiostane, fosfestrol, chlormadinone acetate, leuprorelin acetate, buserelin acetate and the like.
(14) antihypolipidemic drug 2s clofibrate, ethyl 2-chloro-3-[4-(2-methyl-2-phenylpropoxy)-phenyl]propionate [Chemical and Pharmaceutical Bulletin CChem.
Pharm. Bull), 38, 2792-2796 (1990)], pravastatin, simvastatin, probucol, bezafibrate, clinofibrate, nicomol, cholestyramine, dextran sulfate sodium and the like.
30 (15) muscle relaxant pridinol, tubocurarine, pancuronium, tolperisone hydrochloride, chlorphenesin carbamate, baclofen, chlormezanone, mephenesin, chlorzoxazone, eperisone, tizanidine and the like.

(16) anticonvulsant phenytoin, ethosuximide, acetazolamide, chlordiazepoxide, trimethadione, carbamazepine, phenobarbital, primidone, sulthiame, sodium valproate, clonazepam, diazepam, nitrazepam s and the like.
(17) antidepressant imipramine, clomipramine, noxiptiline, phenelzine, amitriptyline hydrochloride, nortriptyline hydrochloride, amoxapine, mianserin hydrochloride, maprotiline hydrochloride, io sulpiride, fluvoxamine maleate, trazodone hydrochloride and the like.
( 18 ) antiallergic drug diphenhydramine, chlorpheniramine, tripelennamine, metodilamine, clemizole, diphenylpyraline, methoxyphenamine, is sodium cromoglicate, tranilast, repirinast, amlexanox, ibudilast, ketotifen, terfenadine, mequitazine, azelastine hydrochloride, epinastine, ozagrel hydrochloride, pranlukast hydrate, seratrodast and the like.
(19) cardiac 2o traps-~-oxocamphor, terephyllol, aminophylline, etilefrine, dopamine, dobutamine, denopamine, aminophylline, bencirin, amrinone, pimobendan, ubidecarenone, digitoxin, digoxin, methyldigoxin, lanatoside C, G-strophanthin and the like.
(20) vasodilator 2s oxyfedrine, diltiazem, tolazoline, hexobendine, bamethan, clonidine, methyldopa, guanabenz and the like.
(21) vasoconstrictor dopamine, dobutamine denopamine and the like.
(22) hypotensive diuretic drug 3o hexamethonium bromide, pentolinium, mecamylamine, ecarazine, clonidine, diltiazem, nifedipine and the like.
(23) antidiabetic drug tolbutamide, chlorpropamide, acetohexamide, glibenclamide, tolazamide, acarbose, epalrestat, troglitazone, glucagon, glymidine, glipizide, phenformin, buformin, metformin and the like.
(24) antinarcotic s levallorphan, nalorphine, naloxone or a salt thereof and the like.
(25) fat-soluble vitamin 1) vitamin A: vitamin A1, vitamin A2 and retinol palmitate 2) vitamin D: vitamin Dl, D2, D3, D4 and DS
3) vitamin E: a-tocopherol, ~-tocopherol, Y-tocopherol, g-tocopherol, dl-a,-tocopherol nicotinate 4) vitamin K: vitamin K1, K2, K3 and K4 5) folic acid (vitamin M) and the like.
(26) vitamin derivative is various derivatives of vitamins, for example, vitamin D3 derivatives such as 5,6-trans-cholecalciferol, 2,5-hydroxycholecalciferol, 1-a,-hydroxycholecalciferol and the like, vitamin D2 derivatives such as 5,6-trans-ergocalciferol and the like.
2o (27) antiasthmatic isoprenaline hydrochloride, salbutamol sulfate, procaterol hydrochloride, terbutaline sulfate, trimetoquinol hydrochloride, tulobuterol hydrochloride, orciprenaline sulfate, fenoterol hydrobromide, ephedrine hydrochloride, Zs ipratropium bromide, oxitropium bromide, flutropium bromide, theophylline, aminophylline, sodium cromoglicate, tranilast, repirinast, amlexanox, ibudilast, ketotifen, terfenadine, mequitazine, azelastine, epinastine, ozagrel hydrochloride, pranlkast hydrate, seratrodast, dexamethasone, prednisolone, so hydrocortisone, hydrocortisone sodium succinate, beclometasone dipropionate and the like.
(28) therapeutic agent for pollakisuria/anischuria flavoxate hydrochloride and the like.

(29) therapeutic agent for atopic dermatitis sodium cromoglicate and the like.
(30) therapeutic agent for allergic rhinitis sodium cromoglicate, chlorpheniramine maleate, alimemazine s tartrate, clemastine fumarate, homochlorcyclizine hydrochloride, terfenadine, mequitazine and the like.
(31) hypertensive drug dopamine, dobutamine, denopamine, digitoxin, digoxin, methyldigoxin, lanatoside C, G-strophanthin and the like.
to (32) Others hydroycam, diacerein, megestrol acetate, nicergoline, prostaglandins and the like.
By combining the compound of the present invention and a concomitant drug, a superior effect such as is (1) the dose can be reduces as compared to single administration of the compound of the present invention or a combination drug, (2) the drug to be combined with the compound of the present invention can be selected according to the condition of 2o patients (mild case, severe case and the like), (3) the period of treatment can be set longer by selecting a combination drug having different action and mechanism from the compound of the present invention, (4) a sustained treatment effect can be designed by selecting 2s a combination drug having different action and mechanism from the compound of the present invention, (5) a synergistic effect can be afforded by a combined use of the compound of the present invention and a combination drug, and the like, can be achieved.
3o As regards the use of the combination agent of the present invention, the administration time of the compound of the present invention and the concomitant drug is not restricted, and the compound of the present invention or the concomitant drug can be administered to an administration subject simultaneously, or may be administered at different times. In addition, the combination agent can be used after synovectomy, after treatment with Prosorba column, after s mononuclear cell therapy, and the like. The dosage of the concomitant drug may be determined according to the dose clinically used, and can be appropriately selected depending on an administration subject, administration route, disease, combination and the like.
to The administration mode of the compound of the present invention and the concomitant drug of the present invention is not particularly restricted, and it is sufficient that the compound of the present invention and the concomitant drug are combined in administration. Examples of such administration is mode include the following methods: (1) The compound of the present invention and the concomitant drug are simultaneously produced to give a single preparation which is administered.
(2) The compound of the present invention and the concomitant drug are separately produced to give two kinds of preparations 2o which are administered simultaneously by the same administration route. (3) The compound of the present invention and the concomitant drug are separately produced to give two kinds of preparations which are administered by the same administration route only at the different times. (4) The 2s compound of the present invention and the concomitant drug are separately produced to give two kinds of preparations which are administered simultaneously by the different administration routes. (5) The compound of the present invention and the concomitant drug are separately produced to 3o give two kinds of preparations which are administered by the different administration routes only at different times (for example, the compound of the present invention and the concomitant drug are administered in this order, or in the reverse order) .
A combination agent of the present invention has low toxicity, and for example, the compound of the present invention or (and) the above-mentioned concomitant drug can be s mixed, according to a method known per se, with a pharmacologically acceptable carrier to give pharmaceutical compositions, for example, tablets (including a sugar-coated tablet, film-coated tablet), powders, granules, capsules (including a soft capsule), solutions, injections, io suppositories, sustained release agents and the like which can be safely administered orally or parenterally (e. g., local, rectum, vein, and the like). An injection can be administered by intravenous, intramuscular, subcutaneous or intraorgan route, or directly to the lesion.
is As the pharmacologically acceptable carrier which may be used for preparing a preparation of a combination agent of the present invention, there are the various conventional organic or inorganic carriers as pharmaceutical materials, for example, excipient, lubricant, binder and disintegrating agent in solid 2o preparations, or solvent, solubilizing agent, suspending agent, isotonizing agent, buffer and soothing agent in liquid preparations. Further, if needed, additives such as the conventional preservative, antioxidant, colorant, sweetening agent, adsorbing agent, wetting agent and the like can be 2s appropriately used in an appropriate amount.
As the excipient, for example, there are lactose, sucrose, D-mannitol, starch, corn starch, microcrystalline cellulose, light anhydrous silicic acid and the like.
As the lubricant, for example, there are magnesium 3o stearate, calcium stearate, talc, colloidal silica and the like.
As the binder, for example, there are microcrystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, saccharose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like.
As the disintegrating agent, for example, there are starch, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylstarch, L-hydroxypropylcellulose and the like.
As the solvent, for example, there are water for injection, alcohol, propylene glycol, macrogol., sesame oil, I° corn oil, olive oil and the like.
As the solubilizing agent, for example, there are polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, tris-aminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
is As the suspending agent, for example, there are surfactants such as stearyl triethenolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate and the like; hydrophilic polymers such as polyvinyl alcohol, 2° polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like.
As the isotonizing agent, for example, there are glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
25 As the buffer, for example, there are buffering solutions such as phosphate, acetate, carbonate, citrate and the like.
As the soothing agent, for example, there are benzyl alcohol and the like.
As the preservative, for example, there are p-so hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
As the antioxidant, for example, there are sulfites, ascorbic acid, a-tocopherol and the like.

The compounding ratio of the compound of the present invention to the concomitant drug in the combination agent of the present invention can be appropriately selected depending on an administration subject, administration route, diseases and s the like.
For example, the content of the compound of the present invention in the combination agent of the present invention differs depending on the form of a preparation, and usually from about 0.01 to 100 by weight, preferably from about 0.1 io to 50~ by weight, further preferably from about 0.5 to 20~ by weight, based on the preparation.
The content of the concomitant drug in the combination agent of the present invention differs depending on the form of a preparation, and usually from about 0.01 to 100 by Zs weight, preferably from about 0.1 to 50~ by weight, further preferably from about 0.5 to 20~ by weight, based on the preparation.
The content of additives such as a carrier and the like in the combination agent of the present invention differs depending 20 on the form of a preparation, and usually from about 1 to 99.99 by weight, preferably from about 10 to 90~ by weight, based on the preparation.
In the case when the compound of the present invention and the combination drug are separately prepared respectively, 2s the same contents may be adopted.
These preparations can be produced by a method known per se usually used in a preparation process.
For example, the compound of the present invention and the concomitant drug can be made into an aqueous injection so together with a dispersing agent (e. g., Tween 80 (manufactured by Atlas Powder, US), HCO 60 (manufactured by Nikko Chemicals), polyethylene glycol, carboxymethylcellulose, sodium alginate, hydroxypropylmethylcellulose, dextrin and the like), a stabilizer (e.g., ascorbic acid, sodium pyrosulfite, and the like), a surfactant (e.g., Polysorbate 80, macrogol and the like), a solubilizer (e.g., glycerin, ethanol and the like), a buffer (e. g., phosphoric acid and alkali metal salt thereof, s citric acid and alkali metal salt thereof, and the like), an isotonizing agent (e. g., sodium chloride, potassium chloride, mannitol, sorbitol, glucose and the like), a pH regulator (e.g., hydrochloric acid, sodium hydroxide and the like), a preservative (e. g., ethyl p-hydroxybenzoate, benzoic acid, Io methylparaben, propylparaben, benzyl alcohol and the like), a dissolving agent (e.g., conc. glycerin, meglumine and the like), a dissolution aid (e.g., propylene glycol, sucrose and the like), a soothing agent (e.g., glucose, benzyl alcohol and the like), and the like, or can be dissolved, suspended or Zs emulsified in a vegetable oil such as olive oil, sesame oil, cotton seed oil, corn oil and the like or a dissolution aid such as propylene glycol and molded into an oily injection.
In the case of a preparation for oral administration, an excipient (e.g., lactose, sucrose, starch and the like), a 2o disintegrating agent (e.g., starch, calcium carbonate and the like), a binder (e. g., starch, acacia, carboxymethylcellulose, polyvinylpyrrolidone, hydroxpropylcellulose and the like), a lubricant (e. g., talc, magnesium stearate, polyethylene glycol 6000 and the like) and the like, for example, can be added to Zs the compound of the present invention or the combination drug, according to a method known per se, and the mixture can be compression-molded, then if desirable, the molded product can be coated by a method known per se for the purpose of masking of taste, enteric property or durability, to obtain a so preparation for oral administration. As this coating agent, for example, hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (methacrylic acid~acrylic acid copolymer, manufactured by Rohm, DE), pigment (e.g., iron oxide red, titanium dioxide, et.) and the like can be used. The preparation for oral administration may be any of a quick release preparation and a sustained release preparation.
For example, in the case of a suppository, the compound of the present invention and the combination drug can be made io into an oily or aqueous solid, semisolid or liquid suppository according to a method known per se. As the oily substrate used in the above-mentioned composition, for example, glycerides of higher fatty acids [e. g., cacao butter, Witepsols (manufactured by Dynamite Novel, DE), etc.], intermediate is grade fatty acids [e. g., Miglyols (manufactured by Dynamite Nobel, DE), etc.], or vegetable oils (e.g., sesame oil, soy bean oil, cotton seed oil and the like), and the like are listed. Further, as the aqueous substrate, for example, polyethylene glycols, propylene glycol are listed, and as the z° aqueous gel substrate, for example, natural gums, cellulose derivatives, vinyl polymers, acrylic acid polymers and the like are listed.
As the above-mentioned sustained release agent, sustained release microcapsules and the like are listed.
z5 For obtaining a sustained release microcapsule, a method known per se can be adopted, and for example, it is preferably molded into a sustained release preparation shown in the following [2] before administration.
A compound of the present invention is preferably molded so into an oral administration preparation such as a solid preparation (e.g., powder, granule, tablet, capsule) and the like, or molded into a rectal administration preparation such as a suppository. Particularly, an oral administration preparation is preferable.
The concomitant drug can be made into the above-mentioned drug form depending on the kind of the drug.
[1] An injection of the compound of the present invention or the concomitant drug, and preparation thereof, [2] a sustained release preparation or quick release preparation of the compound of the present invention or the concomitant drug, and preparation thereof, [3] a sublingual, buccal or intraoral quick integrating agent of the compound of the present ~ invention or the concomitant drug, and preparation thereof, will be described below specifically.
[1] Injection and preparation thereof An injection prepared by dissolving the compound of the present invention or the concomitant drug into water is I5 preferable. This injection may be allowed to contain a benzoate and/or salicylate.
The injection is obtained by dissolving the compound of the present invention or the concomitant drug, and if desirable, a benzoate and/or salicylate, into water.
2o As the above-mentioned salts of benzoic acid and salicylic acid, for example, salts of alkali metals such as sodium, potassium and the like, salts of alkaline earth metals such as calcium, magnesium and the like, ammonium salts, meglumine salts, organic acid salts such as tromethamol and 25 the like, etc. are listed.
The concentration of the compound of the present invention or the concomitant drug in an injection is from 0.5 to 50 w/v~, preferably from about 3 to 20 w/v~. The concentration of a benzoate salt or/and salicylate salt is o from 0.5 to 50 w/v~, preferably from 3 to 20 w/v~.
Into a preparation of the present invention, additives usually used in an injection, for example, a stabilizer (ascorbic acid, sodium pyrosulfite, and the like), a surfactant (Polysorbate 80, macrogol and the like), a solubilizer (glycerin, ethanol and the like), a buffer (phosphoric acid and alkali metal salt thereof, citric acid and alkali metal salt thereof, and the like), an isotonizing agent (sodium chloride, potassium chloride, and the like), a dispersing agent (hydroxypropylmethylcellulose, dextrin), a pH
regulator (hydrochloric acid, sodium hydroxide and the like), a preservative (ethyl p-hydroxybenzoate, benzoic acid and the like), a dissolving agent (conc. glycerin, meglumine and the zo like), a dissolution aid (propylene glycol, sucrose and the like), a soothing agent (glucose, benzyl alcohol and the like), and the like, can be appropriately compounded. These additives are generally compounded in a proportion usually used in an injection.
It is advantageous that pH of an injection is controlled from 2 to 12, preferably from 2.5 to 8.0 by addition of a pH
regulator.
An injection is obtained by dissolving the compound of the present invention or the concomitant drug and if desirable, 2o a benzoate and/or a salicylate, and if necessary, the above-mentioned additives into water. These may be dissolved in any order, and can be appropriately dissolved in the same manner as in a conventional method of producing an injection.
An aqueous solution for injection may be advantageously 2s be heated, alternatively, for example, filter sterilization, high pressure heat sterilization and the like can be conducted in the same manner as for a usual injection, to provide an injection.
It may be advantageous that an aqueous solution for so injection is subjected to high pressure heat sterilization at 100 to 121°C for 5 to 30 minutes.
Further, a preparation endowed with an antibacterial property of a solution may also be produced so that it can be used as a preparation which is divided and administered multiple times.
[2] Sustained release preparation or quick release preparation, and preparation thereof A sustained release preparation is preferable which is obtained, if desirable, by coating a nucleus containing the compound of the present invention or the concomitant drug with a film agent such as a water-insoluble substance, swellable polymer and the like. For example, a sustained release io preparation for oral administration for a single administration per day type is preferable.
As the water-insoluble substance used in a film agent, there are listed, for example, cellulose ethers such as ethylcellulose, butylcellulose ad the like, cellulose esters 15 such as cellulose stearate, cellulose propionate and the like, polyvinyl esters such as polyvinyl acetate, polyvinyl butyrate and the like, acrylic acid/methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylate/cinnamoethyl methacrylate/aminoalkyl methacrylate copolymers, polyacrylic 2o acid, polymethacrylic acid, methacrylic acid alkylamide copolymers, poly(methyl methacrylate), polymethacrylate, polymethacrylamide, aminoalkyl methacrylate copolymers, poly(methacrylic anhydride), glycidyl methacrylate copolymer, particularly, acrylic acid-based polymers such as Eudragits 2s (Rohm Pharma) such as Eudragit RS-100, RL-100, RS-30D, RL-30D, RL-PO, RS-PO (ethyl acrylate~methyl methacrylate~trimethyl chloride methacrylate~ammoniumethyl copolymer), Eudragit NE-30D
(methyl methacrylate~ethyl acrylate copolymer), and the like, hardened oils such as hardened castor oil (e.g., Lovery wax 30 (Freunt) and the like), waxes such as carnauba wax, fatty acid glycerin ester, paraffin and the like, polyglycerin fatty esters, and the like.
As the swellable polymer, polymers having an acidic dissociating group and showing pH dependent swelling are preferable, and polymers manifesting slight swelling in acidic regions such as in the stomach and greater swelling in neutral regions such as in the small intestine and the large intestine are preferable.
As such a polymer having an acidic dissociating group and showing pH dependent swelling, cross-linkable polyacrylic acid copolymers such as, for example, Carbomer 934P, 940, 941, 974P, 980, 1342 and the like, polycarbophil, calcium polycarbophil to (last two are manufactured by BF Goodrich), Hibiswako 103, 104, 105, 304 (all are manufactured by Wako Pure Chemical Co., Ltd.), and the like, are listed.
The film agent used in a sustained release preparation may further contain a hydrophilic substance.
Is As the hydrophilic substance, for example, polysaccharides which may contain a sulfate group such as pullulan, dextrin, alkali metal alginate and the like, polysaccharides having a hydroxyalkyl group or carboxyalkyl group such as hydroxypropylcellulose, 2o hydroxypropylmethylcellulose, carboxymethylcellulose sodium and the like, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol and the like.
The content of a water-insoluble substance in the film agent of a sustained release preparation is from about 30 to 25 90% (w/w) , preferably from about 35 to 80% (w/w) , further preferably from about 40 to 75% (w/w), the content of a swellable polymer is from about 3 to 30% (w/w), preferably from about 3 to 15% (w/w). The film agent may further contain a hydrophilic substance, and in which case, the content of a 3o hydrophilic substance in the film agent is about 50% (w/w) or less, preferably about 5 to 40% (w/w), further preferably from about 5 to 35% (w/w). This % (w/w) indicates % by weight based on a film agent composition which is obtained by removing a solvent (e. g., water, lower alcohols such as methanol, ethanol and the like) from a film agent solution.
The sustained release preparation is produced by preparing a nucleus containing a drug as exemplified below, s then, coating the resulting nucleus with a film agent solution prepared by heat-solving a water-insoluble substance, swellable polymer and the like or by dissolving or dispersing it in a solvent.
I. Preparation of nucleus containing drug io The form of nucleus containing a drug to be coated with a film agent (hereinafter, sometimes simply referred to as nucleus) is not particularly restricted, and preferably, the nucleus is formed into particles such as a granule or fine particle.
is When the nucleus is composed of granules or fine particles, the average particle size thereof is preferably from about 150 to 2000 Vin, further preferably, from about 500 to 1400 Vin.
Preparation of the nucleus can be effected by a usual 2o production method. For example, a suitable excipient, binding agent, integrating agent, lubricant, stabilizer and the like are mixed into a drug, and the mixture is subjected to a wet extrusion granulating method, fluidized bed granulating method or the like, to prepare a nucleus.
2s The content of drugs in a nucleus is from about 0.5 to 95% (w/w), preferably from about 5.0 to 80% (w/w), further preferably from about 30 to 70% (w/w).
As the excipient contained in the nucleus, for example, saccharides such as sucrose, lactose, mannitol, glucose and so the like, starch, crystalline cellulose, calcium phosphate, corn starch and the like are used. Among them, crystalline cellulose and corn starch are preferable.
As the bonder, for example, polyvinyl alcohol, hydroxypropyl cellulose, polyethylene glycol, polyvinyl pyrrolidone, Pluronic F68, gum Arabic, gelatin, starch and the like are used. As the disintegrating agent, for example, carboxymethylcellulose calcium (ECG505), crosscarmelose sodium s (Ac-Di-Sol), crosslinked polyvinylpyrrolidone (Crospovidone), lower substituted hydroxypropylcellulose (L-HPC) and the like are used. Among them, hydroxypropylcellulose, polyvinylpyrrolidone, lower substituted hydroxypropylcellulose are preferable. As the lubricant and coagulation inhibitor, to for example, talc, magnesium stearate and inorganic salts thereof are used, and as the lubricant, polyethylene glycol and the like are used. As the stabilizer, acids such as tartaric acid, citric acid, succinic acid, fumaric acid, malefic acid and the like, are used.
is A nucleus can also be prepared by, in addition to the above-mentioned, for example, a rolling granulation method in which a drug or a mixture of a drug with an excipient, lubricant and the like is added portionwise onto an inert carrier particle which is the core of the nucleus while 2o spraying a binder dissolved in a suitable solvent such as water, lower alcohol (e. g., methanol, ethanol and the like) and the like, a pan coating method, a fluidized bed coating method or a melt granulating method. As the inert carrier particle, for example, those made of sucrose, lactose, starch, 2s crystalline cellulose, waxes can be used, and the average particle size thereof is preferably from about 100 ~m to 1500 Vim.
For separating a drug and a film agent contained in a nucleus, the surface of the nucleus may be coated with a so protective agent. As the protective agent, for example, the above-mentioned hydrophilic substances, water-insoluble substances and the like are used. As the protective agent, preferably polyethylene glycol, and polysaccharides having a hydroxyalkyl group or carboxyalkyl group are used, more preferably, hydroxypropylmethylcellulose and hydroxypropylcellulose are use. The protective agent may contain, as a stabilizer, acids such as tartaric acid, citric acid, succinic acid, fumaric acid, malefic acid and the like, and lubricants such as talc and the like. When the protective agent is used, the coating amount is from about 1 to 15~ (w/w), preferably from about 1 to 10~ (w/w), further preferably from about 2 to 8~ (w/w), based on the nucleus.
io The protective agent can be coated by a usual coating method, and specifically, the protective agent can be coated, for example, by a fluidized bed coating method, pan coating method and the like.
II. Coating of nucleus with film agent 15 A nucleus obtained in the above-mentioned step I is coated with a film agent solution obtained by heat-solving the above-mentioned water-insoluble substance and pH-dependent swellable polymer, and a hydrophilic substance, or by dissolving or dispersing them in a solvent, to give a 2o sustained release preparation.
As the method for coating a nucleus with a film agent solution, for example, a spray coating method and the like are listed.
The composition ratio of a water-insoluble substance, 2s swellable polymer and hydrophilic substance in a film agent solution is appropriately selected so that the contents of these components in a coated film are the above-mentioned contents, respectively.
The coating amount of a film agent is from about 1 to 90~
30 (w/w), preferably from about 5 to 50~ (w/w), further preferably from about 5 to 35~ (w/w), based on a nucleus (not including coating amount of protective agent).
As the solvent in a film agent solution, water or an organic solvent can be used alone or in admixture thereof. In the case of use in admixture, the mixing ratio of water to an organic solvent (water/organic solvent: by weight) can be varied in the range from 1 to 100$, and preferably from 1 to about 30~. The organic solvent is not particularly restricted providing it dissolves a water-insoluble substance, and for example, lower alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol and the like, lower alkanone such as acetone and the like, acetonitrile, io chloroform, methylene chloride and the like are used. Among them, lower alcohols are preferable, and ethyl alcohol and isopropyl alcohol are particularly preferable. Water, and a mixture of water with an organic solvent are preferably used as a solvent for a film agent. In this case, if necessary, an 15 acid such as tartaric acid, citric acid, succinic acid, fumaric acid, malefic acid and the like may also be added into a film agent solution for stabilizing the film agent solution.
An operation of coating by spray coating can be effected by a usual coating method, and specifically, it can be effected by 2o spray-coating a film agent solution onto a nucleus by a fluidized bed coating method, pan coating method and the like.
In this case, if necessary, talc, titanium oxide, magnesium stearate, calcium stearate, light anhydrous silicic acid and the like may also be added as a lubricant, and glycerin fatty 25 ester, hardened castor oil, triethyl citrate, cetyl alcohol, stearyl alcohol and the like may also be added as a plasticizer.
After coating with a film agent, if necessary, an antistatic agent such as talc and the like may be mixed.
so The quick release preparation may be liquid (solution, suspension, emulsion and the like) or solid (particle, pill, tablet and the like). Oral agents and parenteral agents such as an injection and the like are used, and oral agents are preferable.
The quick release preparation, usually, may contain, in addition to an active component drug, also carriers, additives and excipients conventionally used in the production field (hereinafter, sometimes abbreviated as excipient). The preparation excipient used is not particularly restricted providing it is an excipient ordinarily used as a preparation excipient. For example, as the excipient for an oral solid preparation, lactose, starch, corn starch, crystalline cellulose (Acevil PH101, manufactured by Asahi Chemical Industry Co., Ltd., and the like), powder sugar, granulated sugar, mannitol, light anhydrous silicic acid, magnesium carbonate, calcium carbonate, L-cysteine and the like are listed, and preferably, corn starch and mannitol and the like are listed. These excipients can be used alone or in combination of two or more. The content of the excipient is, for example, from about 4.5 to 99.4 w/w%, preferably from about 20 to 98.5 w/w%, further preferably from about 30 to 97 w/w%, based on the total amount of the quick release preparation.
The content of a drug in the quick release preparation can be appropriately selected in the range from about 0.5 to 95%, preferably from about 1 to 60% based on the total amount of the quick release preparation.
2s When the quick release preparation is an oral solid preparation, it usually contains, in addition to the above-mentioned components, also an integrating agent. As this integrating agent, there are used, for example, carboxymethylcellulose calcium (ECG-505, manufactured by 3o Gotoku Yakuhin), crosscarmelose sodium (for example, Actisol, manufactured by Asahi Chemical Industry Co., Ltd.), crosspovidone (for example, Colicone CL, manufactured by BASF), lower substitution hydroxypropylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd.), carboxymethylstarch (manufactured by Matsutani Kagaku K.K.), carboxymethylstarch sodium (Exprotab, manufactured by Kimura Sangyo), partially pregelatinized starch (PCS, manufactured by Asahi Chemical Industry Co., Ltd.), and the like are used, and for example, those which disintegrate a granule by adsorbing water in contact with water, causing swelling, or making a channel between an effective ingredient constituting the nucleus and an excipient, can be used. These disintegrating agents can be io used alone or in combination of two or more. The amount of the disintegrating agent used is appropriately selected depending on the kind and compounding amount of a drug used, design of releasing property, and the like, and for example, from about 0.05 to 30 w/w~, preferably from about 0.5 to 15 w/w~, based 15 on the total amount of the quick releasing agent.
When the quick release preparation is an oral solid preparation, it may further contain, in addition to the above-mentioned composition, if desired, additives conventional in solid preparations. As such an additive, there are used, for 2o example, a binder (e. g., sucrose, gelatin, gum Arabic powder, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxylmethylcellulose, polyvinylpyrrolidone, pullulan, dextrin and the like), a lubricant (e. g., polyethylene glycol, magnesium stearate, talc, 2s light anhydrous silicic acid (e. g., aerosil (Nippon Aerosil)), a surfactant (e. g., anionic surfactants such as sodium alkylsulfate and the like, nonionic surfactants such as polyoxyethylene fatty acid ester and polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivatives and 3o the like), a coloring agent (e. g., tar coloring matter, caramel, iron oxide red, titanium oxide, riboflavins), if necessary, an appetizing agent (e. g., sweetening agent, aroma and the like), an adsorbent, preservative, wetting agent, antistatic agent, and the like. Further, as the stabilizer, an organic acid such as tartaric acid, citric acid, succinic acid, fumaric acid and the like may also be added.
As the above-mentioned binder, hydroxypropylcellulose, polyethylene glycol and polyvinylpyrrolidone and the like are preferably used.
The quick releasing preparation can be prepared by, based on a usual technology of producing preparations, mixing the above-mentioned components, and if necessary, further kneading to the mixture, and molding it. The above-mentioned mixing is conducted by generally used methods, for example, mixing, kneading and the like. Specifically, when a quick release preparation is formed, for example, into a particle, it can be prepared, according to the same means as in the above-I5 mentioned method for preparing a nucleus of a sustained release preparation, by mixing the components using a vertical granulator, universal kneader (manufactured by Hata Tekkosho), fluidized bed granulator FD-5S (manufactured by Pulek), and the like, then, subjecting the mixture to a wet extrusion 2o granulation method, fluidized bed granulation method and the like.
Thus obtained quick releasing preparation and sustained releasing preparation may be themselves made into products or made into products appropriately together with preparation 25 excipients and the like, separately, by an ordinary method, then, may be administered simultaneously or may be administered in combination at any administration interval, or they may be themselves made into one oral preparation (e. g., granule, fine particle, tablet, capsule and the like) or made so into one oral preparation together with preparation excipients and the like. It may also be permissible that they are made into granules or fine particles, and filled in the same capsule to be used as a preparation for oral administration.

[3] Sublingual, buccal or intraoral quick disintegrating agent and preparation thereof Sublingual, buccal or intraoral quick disintegrating agents may be a solid preparation such as tablet and the like, or may be an oral mucosa membrane patch (film).
As the sublingual, buccal or intraoral quick disintegrating agent, a preparation containing the compound of the present invention or the concomitant drug and an excipient is preferable. It may contain also auxiliary agents such as a lubricant, isotonizing agent, hydrophilic carrier, water-dispersible polymer, stabilizer and the like. Further, for easy absorption and increase in in vivo use efficiency, cyclodextrin or ~-cyclodextrin derivatives (e. g., hydroxypropyl-~-cyclodextrin and the like) and the like may also be contained.
As the above-mentioned excipient, lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid and the like are listed. As the lubricant, magnesium stearate, calcium stearate, talc, colloidal silica 2o and the like are listed, and particularly, magnesium stearate and colloidal silica are preferable. As the isotonizing agent, sodium chloride, glucose, fructose, mannitol, sorbitol, lactose, saccharose, glycerin, urea and the like are listed, and particularly, mannitol is preferable. As the hydrophilic carrier, swellable hydrophilic carriers such as crystalline cellulose, ethylcellulose, crosslinkable polyvinylpyrrolidone, light anhydrous silicic acid, silicic acid, dicalcium phosphate, calcium carbonate and the like are listed, and particularly, crystalline cellulose (e. g., fine crystalline 3o cellulose and the like) is preferable. As the water-dispersible polymer, gums (e. g., gum tragacanth, acacia gum, cyamoposis gum), alginates (e. g., sodium alginate), cellulose derivatives (e. g., methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose), gelatin, water-soluble starch, polyacrylic acids (e. g., Carbomer), polymethacrylic acid, polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone, polycarbofil, ascorbate palmitates and the like are listed, and hydroxypropylmethylcellulose, polyacrylic acid, alginate, gelatin, carboxymethylcellulose, polyvinylpyrrolidone, polyethylene glycol and the like are preferable. Particularly, hydroxypropylmethylcellulose is preferable. As the stabilizer, to cysteine, thiosorbitol, tartaric acid, citric acid, sodium carbonate, ascorbic acid, glycine, sodium sulfite and the like are listed, and particularly, citric acid and ascorbic acid are preferable.
The sublingual, buccal or intraoral quick disintegrating 15 agent can be produced by mixing the compound of the present invention or the concomitant drug and an excipient by a method known per se. Further, is desirable, auxiliary agents such as a lubricant, isotonizing agent, hydrophilic carrier, water-dispersible polymer, stabilizer, coloring agent, sweetening 2o agent, preservative and the like may be mixed. The sublingual, buccal or intraoral quick disintegrating agent is obtained by mixing the above-mentioned components simultaneously or at a time interval, then subjecting the mixture to tablet-making molding under pressure. For obtaining suitable hardness, it 25 may also be permissible that the materials are moistened by using a solvent such as water, alcohol and the like if desired before and after the tablet making process, and after the molding, the materials are dried, to obtain a product.
In the case of molding into a mucosa membrane patch 30 (film), the compound of the present invention or the concomitant drug and the above-mentioned water-dispersible polymer (preferably, hydroxypropylcellulose, hydroxypropylmethylcellulose), excipient and the like are dissolved in a solvent such as water and the like, and the resulted solution is cast, to give a film. Further, additives such as a plasticizes, stabilizer, antioxidant, preservative, coloring agent, buffer, sweetening agent and the like may also s be added. For imparting suitable elasticity to the film, glycols such as polyethylene glycol, propylene glycol and the like may be contained, or for enhancing adhesion of the film to an intraoral mucosa membrane lining, a bio-adhesive polymer (e.g., polycarbofil, carbopol) may also be contained. In the io casting, a solution is poured on the non-adhesive surface, spread to uniform thickness (preferably, about 10 to 1000 micron) by an application tool such as a doctor blade and the like, then, the solution is dried to form a film. It may be advantageous that thus formed film is dried at room, is temperature or under heat, and cut into given area.
As the preferable intraoral quick disintegrating agent, there are listed solid quick scattering dose agents composed of a network body comprising the compound of the present invention or the concomitant drug, and a water-soluble or 2o water-diffusible carrier which is inert to the compound of the present invention or combination drug, are listed. This network body is obtained by sublimating a solvent from the solid composition constituted of a solution prepared by dissolving the compound of the present invention or the Zs concomitant drug in a suitable solvent.
It is preferable that the composition of an intraoral quick disintegrating agent contains a matrix forming agent and a secondary component, in addition to~the compound of the present invention or the concomitant drug.
so Examples of the matrix forming agent include animal proteins or vegetable proteins such as gelatins, dextrins and, soybean, wheat and psyllium seed protein and the like; rubber substances such as gum Arabic, guar gum, agar, xarithan gum and the like; polysaccharides; alginic acids;
carboxymethylcelluloses; carageenans; dextrans; pectins;
synthetic polymers such as polyvinylpyrrolidone and the like;
substances derived from a gelatin-gum Arabic complex, and the like. Further, saccharides such as mannitol, dextrose, lactose, galactose, trehalose and the like; cyclic saccharides such as cyclodextrin and the like; inorganic salts such as sodium phosphate, sodium chloride and aluminum silicate and the like;
amino acids having 2 to 12 carbon atoms such as glycine, L-io alanine, L-aspartic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine, L-phenylalanine and the like, are contained.
One or more of the matrix forming agents can be introduced in a solution or suspension before solidification.
15 Such as matrix forming agent may be present in addition to a surfactant, or may be present while a surfactant being excluded. The matrix forming agent aids to maintain the compound of the present invention or the concomitant drug in the solution or suspension in diffused condition, in addition 2o to formation of the matrix.
The composition may contain secondary components such as a preservative, antioxidant, surfactant, thickening agent, coloring agent, pH controlling agent, flavoring agent, sweetening agent, food taste masking agent and the like. As 25 the suitable coloring agent, there are listed red, black and yellow iron oxides, and FD & C dyes such as FD & C Blue 2, FD
& C Red 40 and the like manufactured by Elis and Eberald.
Examples of the suitable flavoring agent include mint, raspberry, licorice, orange, lemon, grape fruit, caramel, 3o vanilla, cherry, grape flavor and combinations thereof.
Examples of the suitable pH controlling agent include citric acid, tartaric acid, phosphoric acid, hydrochloric acid and malefic acid. Examples of the suitable sweetening agent include aspartame, acesulfame K and thaumatin and the like. Examples of the suitable food taste masking agent include sodium bicarbonate, ion exchange resin, cyclodextrin-containing compounds, adsorbent substances and microcapsulated s apomorphine.
The preparation contains the compound of the present invention or the concomitant. drug in an amount usually from about 0.1 to 50% by weight, preferably from about 0.1 to 30%
by weight, and preferable are preparations (such as the above-mentioned sublingual agent, buccal and the like) which can dissolve 90% or more the compound of the present invention or the concomitant drug (into water) within the time range of about 1 to 60 minutes, preferably of about 1 to 16 minutes, more preferably of about 2 to 5 minutes, and intraoral quick is disintegrating preparations which are disintegrated within the range of 1 to 60 seconds, preferably of 1 to 30 seconds, further preferably of 1 to 10 seconds after place in an oral cavity.
The content of the above-mentioned excipient in the whole preparation is from about 10 to 99% by weight, preferably from about 30 to 90% by weight. The content of ~-cyclodextrin or cyclodextrin derivative in the whole preparation is from 0 to about 30% by weight. The content of the lubricant in the whole preparation is from about 0.01 to 10% by weight, preferably 2s from about 1 to 5% by weight. The content of the isotonizing agent in the whole preparation is from about 0.1 to 90% by weight, preferably, from about 10 to 70% by weight. The content of the hydrophilic carrier agent in the whole preparation is from about 0.1 to 50% by weight, preferably, so from about 10 to 30% by weight. The content of the water-dispersible polymer in the whole preparation is from about 0.1 to 30% by weight, preferably, from about 10 to 25% by weight.
The content of the stabilizer in the whole preparation is from about 0.1 to 10~ by weight, preferably, from about 1 to 5~ by weight. The above-mentioned preparation may further contain additives such as a coloring agent, sweetening agent, preservative and the like, if necessary.
s The dosage of a combination agent of the present invention differs depending on the kind of a compound (I), age, body weight, condition, drug form, administration method, administration period and the like, and for example, for one sepsis patient (adult, body weight: about 60 kg), the Io combination agent is administered intravenously, at a dose of about 0.01 to 1000 mg/kg/day, preferably about 0.01 to 100 mg/kg/day, more preferably about 0.1 to 100 mg/kg/day, particularly about 0.1 to 50 mg/kg/day, especially about 1.5 to 30 mg/kg/day, in terms of the compound of the present zs invention or the concomitant drug, respectively, once or divided several times in a day. Of course, since the dose as described above varies depending on various conditions, amounts smaller than the above-mentioned dosage may sometimes be sufficient, further, amounts over that range sometimes have 2o to be administered.
The amount of the concomitant drug can be set at any value unless side effects are problematical. The daily dosage in terms of the combination drug differs depending on the severity, age, sex, body weight, sensitivity difference of the 2s Subject, administration period, interval, and nature, pharmacology, kind of the pharmaceutical preparation, kind of effective ingredient, and the like, and not particularly restricted, and the amount of a drug is, in the case of oral administration for example, usually from about 0.001 to 2000 3o mg, preferably from about 0.01 to 500 mg, further preferably from about 0.1 to 100 mg, per 1 kg of a mammal and this is usually administered once to 4-times divided in a day.
In administration of a medicine of the present invention, the compound of the present invention may be administered after administration of the concomitant drug or the concomitant drug may be administered after administration of the compound of the present invention, though they may be s administered simultaneously. When administered at a time interval, the interval differs depending on the effective ingredient, drug form and administration method, and for example, when the concomitant drug is administered first, a method in which the compound of the present invention is io administered within time range of from 1 minute to 3 days, preferably from 10 minutes to 1 day, more preferably from 15 minutes to 1 hour after administration of the concomitant drug is exemplified. When the compound of the present invention is administered first, a method in which the concomitant drug is zs administered within time range of from 1 minute to 1 day, preferably from 10 minutes to 6 hours, more preferably from 15 minutes to 1 hour after administration of the compound of the present invention is exemplified.
In a preferable administration method, for example, the 2o concomitant drug which has been formed into an oral administration preparation is administered orally at a daily dose of about 0.001 to 200 mg/kg, and 15 minutes after, the compound of the present invention which has been formed into an oral administration preparation is administered orally at a 2s daily dose of about 0.005 to 100 mg/kg.
Best mode of the invention The present invention is explained in detail by way of the following Reference Example, Examples, Preparation 3o Examples and Test Examples but these are mere examples and do not limit the present invention and can be varied without departing the scope of the present invention.
"Room temperature" in the following Reference Example and Examples indicates normally about 10°C to about 35°C. "~"
indicates percentage by weight unless otherwise indicated, provided that yield represents mol/mol~.
Abbreviations used elsewhere indicate the following meanings:
s: singlet d: doublet t: triplet q: quartet Io dd: double doublet ddd: double double doublet dt: double triplet br: broad J: coupling constant 15 Hz: Hertz CDC13: deuterated chloroform 1H-NMR: proton nuclear magnetic resonance Me: methyl 2o Reference Example A 1 1-(4-methoxyphenyl)-2-(3-pyridyl)ethanone A solution of diisopropylamine (33.2 mL) in anhydrous tetrahydrofuran (300 mL) was cooled to -78°C and a 1.6 M n-butyllithium/hexane solution (148 mL) was added dropwise with 2s stirring. After completion of dropwise addition, the mixture was stirred for 10 min at the same temperature, and then (3-picoline (20 g) was added dropwise. The temperature was raised to -10-0°C, and after stirring for 20 min, a solution of ethyl p-anisate (19.4 g) in anhydrous tetrahydrofuran (40 mL) was 3o added dropwise. After completion of dropwise addition, the mixture was stirred at room temperature for 1 h, and water (100 mL) was added. The organic solvent was evaporated under reduced pressure and an oily product was extracted with ethyl acetate. The extract was washed with water, and after drying, the solvent was evaporated. The remaining crude crystals were recrystallized from ethyl acetate-isopropyl ether to give the title compound (20.8 g, yield 85$).
m.p. . 71-72°C.
Reference Examg~le A 2:
In accordance with the above-mentioned Reference Example A 1 and respectively using, instead of ethyl p-anisate, ethyl benzoate, ethyl 3,4-dimethoxybenzoate, ethyl 3,4,5-io trimethoxybenzoate, ethyl 4-(methoxymethoxy)benzoate, ethyl 4-fluorobenzoate, ethyl 4-ethylbenzoate, ethyl 3,4-methylenedioxybenzoate, methyl 5-indanylcarboxylate, methyl 5,6,7,8-tetrahydro-2-naphthoate, methyl 1,4-benzodioxane-6-carboxylate and methyl 2-naphthoate, the following Reference 15 Example A compounds 2-1 to 2-11 were synthesized.
Reference Example compound A 2-1: 1-phenyl-2-(3-pyridyl)ethanone m.p.. 44.5-45.5°C.
Reference Example A compound 2-2: 1-(3,4-dimethoxyphenyl)-2-20 (3-pyridyl) ethanone m.p. . 114-115°C.
Reference Example A compound 2-3:
2-(3-pyridyl)-1-(3,4,5-trimethoxyphenyl)ethanone m.p.. 104-105°C.
Reference Example A compound 2-4: 1-(4-methoxymethoxyphenyl)-25 2- (3-pyridyl) ethanone m. p. . 43-44°C.
Reference Example A compound 2-5: 1-(4-fluorophenyl)-2-(3-pyridyl)ethanone oil.
Reference Example A compound 2-6: 1-(4-ethylphenyl)-2-(3-pyridyl) ethanone m.p. . 80-81°C.
so Reference Example A compound 2-7: 1-(3,4-methylenedioxyphenyl)-2-(3-pyridyl)ethanone m.p.. 98-99°C.
Reference Example A compound 2-8: 1-(5-indanyl)-2-(3-pyridyl)ethanone m.p.. 55-56°C.

Reference Example A compound 2-9: 2-(3-pyridyl)-1-(5,6,7,8-tetrahydro-2-naphthyl)ethanone m.p.. 65-66°C.
Reference Example A compound 2-10: 1-(1,4-benzodioxan-6-yl)-2-(3-pyridyl)ethanone m.p.. 89-90°C.
Reference Example A compound 2-11: 1-(2-naphthyl)-2-(3-pyridyl)ethanone m.p.. 69-70°C.
Reference Example A 3 In accordance with the above-mentioned Reference Example io A 2 and respectively using a-picoline, Y-picoline and 3,5-lutidine instead of ~=picoline, the following Reference Example A compounds 3-1 to 3-3 were synthesized.
Reference Example A compound 3-1: 1-phenyl-2-(2-i5 pyridyl)ethanone m.p.. 59-60°C.
Reference Example A compound 3-2: 1-(4-methoxyphenyl)-2-(2-pyridyl) ethanone m.p. . 77-78°C.
Reference Example A compound 3-3: 1-phenyl-2-(4-pyridyl)ethanone m.p.. 109-110°C.
zo Reference Example A 4 1-(4-methoxyphenyl)-2-(4-pyridyl)ethanone A solution of diisopropylamine (33.2 mL) in anhydrous tetrahydrofuran (300 mL) was cooled to -78°C and 1.6 M n-butyllithium-hexane solution (148 mL) was added dropwise with 25 stirring. After completion of dropwise addition, the mixture was stirred for 10 min at the same temperature, then Y-picoline (20 g) was added dropwise. The temperature was raised to -10-0°C, and after stirring for 20 min, a solution of ethyl p-anisate (19.4 g) in anhydrous tetrahydrofuran (40 mL) was 3o added dropwise. After completion of dropwise addition, the mixture was stirred at room temperature for 1 h, and water (100 mL) was added. The organic solvent was evaporated under reduced pressure and an oily product was extracted with ethyl acetate. The extract was washed with water, and after drying, the solvent was evaporated. The remaining crude crystals were recrystallized from ethyl acetate-isopropyl ether to give the title compound (16.2 g, yield 66 %).
s m.p.: 103-104°C.
Reference Example A 5 2-(5-methyl-3-pyridyl)-1-phenylethanone A solution of diisopropylamine (20.2 mL) in anhydrous tetrahydrofuran (180 mL) was cooled to -78°C, and a 1.6 M n 1o butyllithium-hexane solution (90 mL) was added dropwise with stirring. After completion of dropwise addition, the mixture was stirred for 10 min at the same temperature, and then 3,5-lutidine (14 g) was added dropwise. The temperature was raised to -10-0°C, and after stirring for 20 min, a solution of ethyl is benzoate (9.8 g) in anhydrous tetrahydrofuran (20 mL) was added dropwise. After completion of dropwise addition, the mixture was stirred at room temperature for 1 h, and water (100 mL) was added. The organic solvent was evaporated under reduced pressure and an oily product was extracted with ethyl 2o acetate. The extract was washed with water, and after drying, the solvent was evaporated. The remaining crude crystals were recrystallized from ethyl acetate-isopropyl ether to give the title compound (10 g, yield 70%).
m.p. : 53-54°C.
zs Reference Example A 6 2-bromo-1-(4-methoxyphenyl)-2-(3-pyridyl)ethanone hydrobromide 1- ( 4-Methoxyphenyl ) -2- ( 3-pyridyl ) ethanone ( 6 . 9 g) was dissolved in acetic acid (36 mL), bromine (1.7 mL) was added, and the mixture was stirred at 80°C for 3 h. The reaction 3o mixture was cooled with iced water and the precipitated crude crystals were collected by filtration. The crude crystals were recrystallized from ethanol-ethyl ether to give the title compound (10 g, yield 89%).

m.p. : 188-195°C.
Reference Example A 7 In accordance with the above-mentioned Reference Example A 6, 1-phenyl-2-(3-pyridyl)ethanone, 1-(3,4-dimethoxyphenyl)-2- ( 3-pyridyl ) ethanone , 2- ( 3-pyridyl ) -1- ( 3 , 4 , 5-trimethoxyphenyl) ethanone, 1-(4-methoxymethoxyphenyl)-2-(3-pyridyl)ethanone, 1-(4-fluorophenyl)-2-(3-pyridyl)ethanone, 1-phenyl-2-(2-pyridyl)ethanone, 1-(4-methoxyphenyl)-2-(2-pyridyl)ethanone, 1-phenyl-2-(4-pyridyl)ethanone, 1-(4-Io methoxyphenyl)-2-(4-pyridyl)ethanone, 2-(5-methyl-3-pyridyl)-1-phenylethanone, 1-(4-ethylphenyl)-2-(3-pyridyl)ethanone, 1-(3,4-methylenedioxyphenyl)-2-(3-pyridyl)ethanone, 1-(5-indanyl ) -2- ( 3-pyridyl ) ethanone , 2- ( 3-pyridyl ) -1- ( 5 , 6 , 7 , 8-tetrahydro-2-naphthyl)ethanone, 1-(1,4-benzodioxan-6-yl)-2-(3-i5 pyridyl) ethanone, 1- (2-naphthyl) -2- (3-pyridyl) ethanone and 1-(4-methoxyphenyl)-2-(2-pyridyl)ethanone were respectively used instead of 1-(4-methoxyphenyl)-2-(3-pyridyl)ethanone, the following Reference Example A compounds 7-1 to 7-17 were synthesized.
2o Reference Example A compound 7-1: 2-bromo-1-phenyl-2-(3-pyridyl)ethanonehydrobromide m.p.. 208-215°C.
Reference Example A compound 7-2:
2-bromo-1-(3,4-dimethoxyphenyl)-2-(3-pyridyl)ethanonehydrobromide m.p.. 191-193°C.
2s Reference Example A compound 7-3: 2-bromo-2-(3-pyridyl)-1-(3,4,5-trimethoxyphenyl)ethanone hydrobromide m.p.. 184-186°C.
Reference Example A compound 7-4: 2-bromo-1-(4-hydroxyphenyl)-2-(3-pyridyl)ethanone hydrobromide Used in the next reaction without purification.
3o Reference Example A compound 7-5: 2-bromo-1-(4-fluorophenyl)-2-(3-pyridyl)ethanone hydrobromide m.p.. 189-191°C.
Reference Example A compound 7-6: 2-bromo-1-phenyl-2-(2-pyridyl)ethanone hydrobromide m.p.. 180-181°C.

Reference Example A compound 7-7: 2-bromo-1-(4-methoxyphenyl)-2-(2-pyridyl)ethanone hydrobromide m.p.. 170-171°C.
Reference Example A compound 7-8: 2-bromo-1-phenyl-2-(4-pyridyl)ethanone hydrobromide m.p.. 230-232°C.
s Reference Example A compound 7-9: 2-bromo-1-(4-methoxyphenyl)-2-(4-pyridyl)ethanone hydrobromide m.p.. 207-209°C.
Reference Example A compound 7-10: 2-bromo-2-(5-methyl-3-pyridyl)-1-phenylethanone hydrobromide m.p.. 189-193°C.
Reference Example A compound 7-11: 2-bromo-1-(4-ethylphenyl)-io 2-(3-pyridyl)ethanone hydrobromide m.p.. 145-146°C.
Reference Example A compound 7-12: 2-bromo-1-(3,4-methylenedioxyphenyl)-2-(3-pyridyl)ethanone hydrobromide m.p..
174-175°C.
Reference Example A compound 7-13: 2-bromo-1-(5-indanyl)-2-(3-is pyridyl)ethanone hydrobromide m.p.. 177-178°C.
Reference Example A compound 7-14: 2-bromo-2-(3-pyridyl)-1-(5,6,7,8-tetrahydro-2-naphthyl)ethanone hydrobromide m.p..
160-162°C .
Reference Example A compound 7-15: 1-(1,4-benzodioxan-6-yl)-2-Zo bromo-2-(3-pyridyl)ethanone hydrobromide oil.
Reference Example A compound 7-16: 2-bromo-1-(2-naphthyl)-2-(3-pyridyl)ethanone hydrobromide m.p.. 197-199°C.
Reference Example A compound 7-17: 2-bromo-1-(4-methoxyphenyl)-2-(2-pyridyl)ethanone hydrobromide m.p.. 170-2s 171°C.
Reference Example A 8 [4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazol-2-yl]amine To a suspension of thiourea (0.52 g) in acetonitrile (40 mL) was added 2-bromo-1-(4-methoxyphenyl)-2-(3-so pyridyl)ethanone hydrobromide (2.5 g) and triethylamine (0.95 mL) was slowly added dropwise with stirring. After completion of dropwise addition, the mixture was stirred at a refluxing temperature for 3 h, and after allowing to cool, the precipitated crystals were collected by filtration. The crystals were washed successively with saturated sodium hydrogencarbonate solution, water, ethanol and ethyl-ether and dried. The obtained crude crystals were recrystallized from tetrahydrofuran to give the title compound (1.5 g, yield 90%).
m.p.. 265-266°C.
Reference Example A 9 N-methyl [4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazol-2-yl]amine to To a suspension of N-methylthiourea (0.24 g) in acetonitrile (18 mL) was added 2-bromo-1-(4-methoxyphenyl)-2-(3-pyridyl)ethanone hydrobromide (1.0 g) and triethylamine (0.4 mL) was slowly added dropwise with stirring. After completion of dropwise addition, the mixture was stirred at a 15 refluxing temperature for 3 h, and the solvent was evaporated.
To the residue was added saturated aqueous sodium hydrogencarbonate and the mixture was extracted with ethyl acetate, and the extract was washed with water and dried, and the solvent was evaporated. The remaining crude crystals were 2o recrystallized from ethyl acetate-isopropyl ether to give the title compound (0.65 g, yield 85%).
m.p.: 158-159°C.
Reference Example A 10 N-[4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazol-2-25 yl]acetamide Using [(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazol-2-yl]amine as a starting compound and according to a method similar to Reference Example A 23-128 to be mentioned below, the title compound was obtained (yield 82%).
3o m.p.. 208-210°C.
Reference Example A 11 2-(4-acetylpiperazin-1-yl)-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazole In a solution of 1-piperazinecarbothioamide (0.39 g) in acetonitrile (15 mL) was suspended 2-bromo-1-(4-methoxyphenyl)-2-(3-pyridyl)ethanone hydrobromide (1.0 g) and triethylamine (0.4 mL) was slowly added dropwise with stirring.
After completion of dropwise addition, the mixture was stirred at a refluxing temperature for 3 h, and the solvent was evaporated. To the residue was added saturated aqueous sodium hydrogencarbonate and the mixture was extracted with ethyl acetate, and the extract was washed with water and dried, and io the solvent was evaporated. The residue was dissolved 'in pyridine (2 mL) and cooled with ice. Acetyl chloride (0.3 mL) was added, and the mixture was left standing at room temperature for 1 h. The reaction mixture was poured into iced water, and the resulting product was extracted with ethyl is acetate. The extract was washed with water, and after drying, the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate-methanol=9:1) to give the title compound (0.30 g, yield 28~).
oil 2o Reference Example A 12 [4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazol-2-yl]amine hydrochloride [4-(4-Methoxyphenyl)-5-(3-pyridyl)-1,3-thiazol-2-yl]amine (200 mg) was dissolved in 1°s hydrochloric acid-Zs methanol (3.2 mL) and the solvent was evaporated. The obtained crude crystals were recrystallized from methanol-ethyl acetate to give the title compound (180 mg, yield 80~).
m.p.: 145-150°C.
The chemical structural formulas of the compounds 30 obtained in Reference Example s A8 to 12 are shown in the following Table 1.

Table 1 Rb S
Rc Reference Example A Ra Rb Rc additives Compound 8 -NH2 N ~ Me0 ~

9 -NHMe ~ Me0 ~

-NHCOMe ~ Me0 ~

11 -NV -COMB N ~ Me0 ~

12 ~ -NH2 N ~ Me0 ~ ~ HCI

Reference Example A 13 Reference Example A compounds 13-1 to 13-102 shown in the following Tables 2-7 were synthesized in accordance with the methods described in Reference Example A 8-12, JP-A-61-10580 and USP 4,612,321.

Table 2 Rb~N -Ra Rc Reference Example Rb Rc m.p.
A / ~
Compound Re 13-1 -NHMe N ~ / \ 168-i 13-2 -NH2 N ~ / \ 253-254 13-3 -NN2 N \ Me0 ~ \ 240-241 MeO

Me0 13-4 -NH2 N ~ Me0 ~ \ 168-169 Me0 13-5 -NHMe N ~ F-~- 157-158 Me i 3-6 -NHMe / \ ~ \ 205-206 N

13-7 -NH2 N ~ HO ~ \ 266-268 13-8 -NHCOCH2COOCH2Me N ~ Me0 ~ \ 201-202 13-9 -NHCOCH2COOMe N ~ ~ \ 185-186 13-10 -NH2 / N / \ 236-237 13-11 -NHMe ~ N ~ \ 215-216 i 3-12 -NHMe ~ N Me0 ~ \ 214-215 13-13 -NH2 ~ N Me0 ~ \ 217-218 13-14 -NH2 N~ \ Me0 ~ \ 282-284 i 3-15 -NH2 N _~ / ~ 248250 13-i -NHMe N _\ Me0 ~ \ i 77-7 i 3-17 -N~ N ~ Me0 ~ \ 130-131 13-18 -NNV N ~ Me0 ~ \ 134-135 Table 3 R~ S
,,~ ~?-~, R~
Reference Example A R: ~~ R~ m.p, ~ ~
M~~..~
13-1S -Gf~gMe ~ MeI7~ 8d-84.5 M ~~?

13-2Q -CN~Me ~~- ~rle0 '~ ~9-60 ~

~ ~-2~-G~~M s ~-- Ho ~-- 3 ~~-~
x~

~~-2a -~e Me~ i~3-~~~

~s-x~ -~~zr~~ nr' ss-e~~
~

~3~-24---~ ~ ~3S-136 13-25 --~~ ~ M~+C3 104-iti5 13-~6 ~~ MeO ggw86 ?~' M
' ~

13-2?'-~N- ~ I~et7~- 1~5-i9~5 Matt 13M2B -~ ~ MeO 211y213 M e~

13-~8 "'~"'~ ~~~ HC? 2~tD-282 19-3t3---~ - t #~tf-i 13-31 -- ~"" M e1~ ~~--8~-93 Metl 13-32 --~ MeO 7't'#-1i2 ~A t~U

LV-f-!re VF

~~-~~

M et~

M~

13-36 --~~--CC3f~f~ ~rlan~ 24~~#8 W AeO

Table 4 Rb S
~N Ra Rc Reference Rb Rc m.p. /
Example ~
A Ra Compound 13-36 -Me N ~ HOOC-CH=CH / 208-209 \

f 3-37 ~ \ CH=CHCOOH ~ \ 255-256 N~\

Me /
13-38 / \ H=G N \ MeO~ 225-226 Y

COOH Me 13-39 -(CH~3COOH N ~ / \ 143-i44 13-40 -(CH2)3COOH N ~ Me0 ~ \ 163-164 Me 13-41 -(CHz)3COOH / ~ ~ \ 134-135 N

13-42 -(CHz)eCOOH N \ / \ 112-113 13-43 -(CH~40H N ~ ~ \ 5i-52 13-44 -NHCH2Me N ~ Me0 ~ \ 154-155 O
13-45 -NHMe Q / ~ 87-i 88 13-46 -NHMe N ~ MeCHz ~ \ 124-125 13-47 -NHMe N~ ~ ~ \ 191-192 f 3-48 -N(CH2Me)z N ~ Me0 ~ \ of 1 13-49 -NMez ~ Me0 ~ \ o i 1 13-50 -CH2Me N \ Me0 ~ \ oil Me0 13-51 -CH2Me N ~ ~ \ oil i3-52 -(CHz)sMe N ~ ~ \ oil 13-53 -CH2Me N~ ~ Me0 ~ \ oil Table 5 Rbl'N Ra Rc Reference Rb Rc m.p. / 'C
Example A R$
Compound 13-54 ~ \ N ~ Me0 ~ \ 704-705 13-55 -CH2COOH N \ / \ oil t 3-56 -(CH2)3COOMe ~ ~ \ o i 1 13-57 -(CH2)SCOOH N ~ ~ \ o i 1 13-58 -(CH2)SCOOH N \ Me0 ~ \ oii Me0 13-59 -(CH2)40H N ~ Me0 / ~ o i 1 13-60 -(CH2)sOH N ~ Me0 ~ \ oil 13-61 -(CH~ZMe N ~ Me0 ~ \ o i 1 13-62 -CHMe2 ~ Me0 ~ \ oil O
13-63 -NMe2 / \ ~ / \ 76-77 N

O
13-64 -N(CH2Me)2 N ~ p / \ 97-98 O
13-65 -NHMe N '\ Or / \ 234-235 O
t 3-66 -NMe2 N _\ p / \ t 44-145 / \
13-67 -NHMe N ~ ~ 146-147 Me0 OMe t 3-68 -NHMe N ~ / \ ' 153-154 13-69 -NHMe N _\ F ~ \ 205-206 t 3-70 -NHMe N _\ CI ~ \ 224-225 t3-7t -NHMe N~ \ Br ~ \ 206-207 Table 6 Rb~N>-Ra Rc Re erenceample A Ra Rb - _Rc additives ~:p. / 'C
Compound 13-72 -NHMe N~ \ ~ \ 191-192 13-73 -NHMe N ~ ~ ~ 16B-169 13-74 -NHMe N ~ / \ 172-173 13-75 -NHCH2CH2 \ ~ MeO ~ \ 126-127 /

13-76 "H \ N ~ Me0 ~ \ 222-223 13-77 S N ~ Me0 ~ \ 132-133 I

13-78 ~ N ~ Me0-~- 90-91 I

13-79 \ N ~ Me0 ~ \ 148-149 /
CI

CMe3 13-80 --(\ N ~ Me0 ~ \ 180-i 81 /j-OCOMe -' tCMe3 13-81 --O-COOH N ~ F ~ \ 240-241 O
i3-82 \ N ~ p / \ 258-259 ~
COOH

i 3-83 -NMe2 N ~ / \ 85-86 .

13-84 -N(CH2Me)2 N ~ / \ 56-57 13-85 -CH2NH2 ~ Me0 / ~ of 1 i 3-86 -CH2NHMe N ~ Me0 ~ \ o i 1 13-87 -NHCOMe N ~ MeO ~ \ HCI 214-217 13-88 -NHCOMe ~ N Me0 ~ \ 228-231 13-89 -NHCOMe N~ \ Me0 ~ \ HCI 275-278 13-90 -NHCOCH2Me ~ ~ ~ \ HC! 248-251 Table 7 Iab~N Ra Reference Rtr H~
Example A R~
Compound 18-8'I -NMGOCH2Me tul~~ 1~~-1~9~

13-92 -NHC(3CHN9ex ~ ~ MeO~ 213-216 13-93 WH2 ~ I4~e~CH~}~O~ 212-215 13-94 -NHCOI'Ae~ ~~"' A~e~GH~~t7 / 23Q233 ~' 13-85 -NH2 ~ ~C"D'~ 18&18~

13-~ -NHC~M8 ~~ f~le~JCt~-~- 23t?-234 13-9T -NHG ~ Mea J-,-,~' 275-278 13-98 -I~HCf3Me Ht~ 28?-292 13-~9 -WM et~~8 ~t ,-",~~Me ~ ~ 1 S9-1 '"" ?~

13-lOtt -PdHC~3Nle 2~-v24 13-101 -NHGDMe ~- 176-1?8 13-102 -N~CNNMez ~ ~ 118-12~?

Reference Example A 14 N-(4-chlorobenzoyl)propyleneimine A solution of propyleneimine (12.3 mL) in tetrahydrofuran (160 mL) was added to 1N aqueous sodium s hydroxide solution. To this mixture was added dropwise 4-chlorobenzoyl chlaride (25 g) at 0°C. After completion of dropwise addition, the mixture was stirred for further 30 min.
The reaction mixture was extracted with ethyl acetate. The extract was dried, and the solvent was evaporated to give the io title compound (24.9 g, yield 89%).
oil 1H-NMR (CDC13) $: 1.39 (3H, d, J= 5.5 Hz), 2.15 (1H, d, J= 2.9 Hz), 2.51-2.66 (2H, m), 7.39-7.47 (2H, m), 7.93-8.01 (2H, m).
Reference Example A 15 15 In accordance with Reference Example A 14, 3-chlorobenzoyl chloride, 2-chlorobenzoyl chloride, 2-methylbenzoyl chloride, 3-methylbenzoyl chloride, 4-methylbenzoyl chloride, 2-methoxybenzoyl chloride, 3-methoxybenzoyl chloride, 4-ethylbenzoyl chloride, 4-(1-2o methylethyl)benzoyl chloride, 4-(1,1-dimethylethyl)benzoyl chloride, 4-propylbenzoyl chloride, 4-butylbenzoyl chloride, 4-hexylbenzoyl chloride, 4-trifluoromethoxybenzoyl chloride, 4-trifluoromethylbenzoyl chloride, 3,4-dimethoxybenzoyl chloride, 3,4-dimethylbenzoyl chloride, 3,5-dimethylbenzoyl 2s chloride, 3,4-methylenedioxybenzoyl chloride, 2-naphthoyl chloride, 4-fluorobenzoyl chloride and 3-cyclopentyloxy-4-methoxybenzoyl chloride were respectively used instead of 4-chlorobenzoyl chloride, the following Reference Example A
compounds 15-1 to 15-22 were synthesized.
so Reference Example A compound 15-1: N-(3-chlorobenzoyl)-propyleneimine oil 1H-NMR (CDC13) $: 1.40 (3H, d, J= 5. 1 Hz) , 2. 17 (1H, d, J= 3.3 Hz), 2.53-2.68 (2H, m), 7.40 (1H, dd, J= 8.1, 7.7 Hz), 7.53 (1H, ddd, J= 8.1, 2.2, 1.5 Hz), 7.90 (1H, dt, J= 7.7, 1.5 Hz), 8.00 (1H, dd, J= 2.2, 1.5 Hz).
Reference Example A compound 15-2: N-(2-chlorobenzoyl)-propyleneimine oil 1H-NMR (CDC13) g: 1.30 (3H, d, J= 5. 1 Hz) , 2. 12 (1H, d, J= 3.3 Hz), 2.53 (1H, d, J= 5.5 Hz), 2.56-2.68 (1H, m), 7.28-7.48 (3H, m) , 7.75-7.81 (1H, m) .
1o Reference Example A compound 15-3: N-(2-methylbenzoyl)-propyleneimine 1H-NMR (CDC13) $: 1.30 (3H, d, J= 5. 5 Hz) , 2.08 (1H, d, J= 3.3 Hz), 2.43-2.57 (5H, m), 7,20-7.31 (2H, m), 7.33-7.43 (1H, m), 15 7.g9 (1H, d, J= 7.7 Hz).
Reference Example A compound 15-4: N-(3-methylben.zoyl)-propyleneimine oil 1H-NMR (CDC13) $: 1.39 (3H, d, J= 5.5 Hz) , 2.14 (1H, d, J= 3.3 2o Hz) , 2.41 (3H, s) , 2.51-2.66 (2H, m) , 7.32-7.39 (2H, m) , 7.79-7.87 (2H, m).
Reference Example A compound 15-5: N-(4-methylbenzoyl)-propyleneimine oil 2s 1H-NMR (CDC13) $: 1.39 (3H, d, J= 5. 5 Hz) , 2. 12 (1H, d, J= 2.9 Hz) , 2.42 (3H, s) , 2.50-2.62 (2H, m) , 7.25 (2H, d, J= 8.1 Hz) , 7.92 (2H, d, J= 8.1 Hz).
Reference Example A compound 15-6: N-(2-methoxybenzoyl)-propyleneimine 30 pil 1H-NMR (CDC13) $: 1.30 (3H, d, J= 5.5 Hz) , 2.10 (1H, d, J= 3.3 Hz), 2.50 (1H, d, J= 5.9Hz), 2.53-2.65 (1H, m), 3.90 (3H, s), 6.95-7.05 (2H, m), 7.41-7.52 (1H, m), 7.81-7.88 (1H, m).

Reference Example A compound 15-7: N-(3-methoxybenzoyl)-propyleneimine oil 1H-NMR (CDC13) $: 1.40 (3H, d, J= 5.9 Hz) , 2. 14 (1H, d, J= 2.9 Hz) , 2. 52-2.65 (2H, m) , 3.86 (3H, s) , 7. 10 (1H, ddd, J= 8.4, 2.6, 1.1 Hz), 7.37 (1H, dd, J= 8.4, 7.3 Hz), 7.55 (1H, dd, J=
2.6, 1.5 Hz), 7.63 (1H, ddd, J= 7.3, 1.5, 1.1 Hz).
Reference Example A compound 15-8: N-(4-ethylbenzoyl)-propyleneimine io oil 1H-NMR (CDC13) $: 1.27 (3H, t, J= 7.6 Hz) , 1. 39 (3H, d, J= 5.5 Hz) , 2. 13 (1H, d, J= 3.3 Hz) , 2.50-2.61 (2H, m) , 2.71 (2H, q, J= 7.6 Hz), 7.28 (2H, d, J= 7.7 Hz), 7.95 (2H, d, J= 7.7 Hz).
Reference Example A compound 15-9: N-[4-(1-methylethyl)-i5 benzoyl]propyleneimine oil 1H-NMR (CDC13) $: 1.28 (6H, d, J= 7.0 Hz), 1.40 (3H, d, J= 5.5 Hz), 2.13 (1H, d, J= 3.3 Hz), 2.50-2.64 (2H, m), 2.90-3.05 (1H, m), 7.31 (2H, d, J= 8.2 Hz), 7.96 (2H, d, J= 8.2 Hz).
2o Reference Example A compound 15-10: N-[4-(1,1-dimethylethyl)-benzoyl]propyleneimine A solution of propyleneimine (11 mL, 0.14 mol) in tetrahydrofuran (160 mL) was added to 2N aqueous sodium hydroxide solution (70 mL). To this mixture was added dropwise 2s 4-(1,1-dimethylethyl)benzoyl chloride (25 g, 0.13 mol) at 0°C.
After completion of dropwise addition, the mixture was stirred further for 30 min. The reaction mixture was extracted with ethyl acetate. The extract was dried, and the solvent was evaporated to give the title compound (27 g, 0.13 mol, yield 3o gg%) .
oil 1H-NMR (CDC13) $: 1. 35 (9H, s) , 1. 41 (3H, d, J= 5. 5 Hz) , 2. 12 (1H, d, J= 2.9 Hz), 2.51-2.64 (2H, m), 7.47 (2H, d, J= 8.8 Hz), 7.96 (2H, d, J= 8.8 Hz).
Reference Example A compound 15-11: N-(4-propylbenzoyl)-propyleneimine oil s 1H-NMR (CDC13) $: 0.96 (3H, t, J= 7.3 Hz), 1.39 (3H, d, J= 5.5 Hz), 1.57-1.75 (2H, m), 2.12 (1H, d, J= 3.3 Hz), 2.50-2.59 (2H, m) , 2.65 (2H, t, J= 7.7 Hz) , 7.26 (2H, d, J= 8.1 Hz) , 7.94 (2H, d, J= 8.1 Hz).
Reference Example A compound 15-12: N-(4-butylbenzoyl)-to propyleneimine oil 1H-NMR (CDC13) $: 0.94 (3H, t, J= 7.1 Hz), 1.26-1.47 (5H, m), 1.54-1.73 (2H, m), 2.12 (1H, d, J= 2.9 Hz), 2.51-2.62 (2H; m), 2.67 (2H, t, J= 7.7 Hz) , 7.26 (2H, d, J= 8.1 Hz) , 7.94 (2H, d, 15 J= g_1 Hz), Reference Example A compound 15-13: N-(4-hexylbenzoyl)-propyleneimine oil 1H-NMR (CDC13) $: 0.89 (3H, t, J= 6.6 Hz), 1.24-1.38 (6H, m), 1.39 (3H, d, J= 5.5 Hz), 1.56-1.68 (2H, m), 2.12 (1H, d, J=
3.3 Hz), 2.51-2.61 (2H, m), 2.66 (2H, t, J= 7.7 Hz), 7.26 (2H, d, J= 8.1 Hz), 7.94 (2H, d, J= 8,1 Hz).
Reference Example A compound 15-14: N-(4-trifluoromethoxybenzoyl)propyleneimine 2s oil 1H-NMR (CDC13) g: 1.40 (3H, d, J= 5.5 Hz), 2.16 (1H, d, J= 3.3 Hz), 2.53-2.68 (2H, m), 7.29 (2H, d, J= 9.0 Hz), 8.08 (2H, d, J= 9.0 Hz).
Reference Example A compound 15-15: N-(4-so trifluoromethylbenzoyl)propyleneimine oil 1H-NMR (CDC13) $:1.40 (3H, d, J= 5.5 Hz), 2.19 (1H, d, J= 3.7 Hz), 2.54-2.70 (2H, m), 7.73 (2H, d, J= 8.0 Hz), 8.13 (2H, d, J= 8.0 Hz).
Reference Example A compound 15-16: N-(3,4-dimethoxybenzoyl)-propyleneimine oil 1H-NMR (CDC13) $: 1.41 (3H, d, J= 5.5 Hz) , 2. 12 (1H, d, J= 3.3 Hz) , 2. 51-2. 63 (2H, m) , 3.94 (3H, s) , 3.95 (3H, s) , 6.92 (1H, d, J= 8.5 Hz), 7.56 (1H, d, J= 2.2 Hz), 7.69 (1H, dd, J= 8.5, 2.2 Hz) .
Reference Example A compound 15-17: N-(3,4-dimethylbenzoyl)-propyleneimine oil 1H-NMR (CDC13) $: 1.39 (3H, d, J= 5.5 Hz) , 2. 12 (1H, d, J= 3.3 Hz) , 2.32 (6H, s) , 2.49-2.61 (2H, m) , 7.21 (1H, d, J= 7.7 Hz) , 7.77 (1H, dd, J= 7.7, 1.8 Hz), 7.80 (1H, d, J= 1.8 Hz).
15 Reference Example A compound 15-18: N-(3,5-dimethylbenzoyl)-propyleneimine 3,5-Dimethylbenzoic acid (25 g, 0.17 mol) and dimethylformamide (0.1 mL) were added to thionyl chloride (50 mL) at 0°C successively. The mixture was refluxed under 2o heating for 2 h. The excess thionyl chloride was evaporated under reduced pressure and to the residue was added toluene (50 mL). Toluene was evaporated under reduced pressure to give oily 3,5-dimethylbenzoyl chloride. A solution of propyleneimine (14 mL, 0.18 mol) in tetrahydrofuran (160 mL) 25 was added to 1N aqueous sodium hydroxide solution (180 mL).
3,5-Dimethylbenzoyl chloride was added dropwise to this mixture at 0°C. After completion of dropwise addition, the mixture was stirred further for 30 min. The reaction mixture was extracted with ethyl acetate. The extract was dried, and 3o the solvent was evaporated to give the title compound (31 g, 0.16 mol, yield 99$).
oil 1H-NMR (CDC13)$: 1.39 (3H, d, J= 5.5 Hz), 2.13 (1H, d, J= 3.7 Hz) , 2.37 (6H, s) , 2.47-2.62 (2H, m) , 7. 19 (1H, s) , 7.64 (2H, s) .
Reference Example A compound 15-19: N-(3,4-methylenedioxybenzoyl)propyleneimine oil 1H-NMR (CDC13) g: 1.38 (3H, d, J= 4.9 Hz) , 2.11 (1H, d, J= 3. 1 Hz) , 2.48-2. 64 (2H, m) , 6.05 (2H, s) , 6. 86 (1H, d, J= 8.2 Hz) , 7.48 (1H, d, J= 1.7 Hz), 7.65 (1H, dd, J= 8.2, 1.7 Hz).
Reference Example A compound 15-20: N-(2-naphthoyl)-io propyleneimine oil 1H-NMR (CDC13) g: 1.44 (3H, d, J= 5.5 Hz), 2.22 (1H, d, J= 3.3 Hz), 2.57-2.84 (2H, m), 7.50-7.65 (2H, m), 7.85-8.00 (3H, m), 8.06 (1H, dd, J= 8.6, 1.5 Hz) , 8.59 (1H, s) .
is Reference Example A compound 15-21: N-(4-fluorobenzoyl)-propyleneimine oil 1H-NMR (CDC13) g: 1.39 (3H, d, J= 5.2 Hz) , 2.14-2. 15 (1H, m) , 2.52-2.63 (2H, m), 7.08-7.19 (2H, m), 8.00-8.10 (2H, m).
2o Reference Example compound A 15-22: N-(3-cyclopentyloxy-4-methoxybenzoyl)propyleneimine oil 1H-NMR (CDC13) g: 1.40 (3H, d, J= 5.1 Hz) , 1.54-1.68 (2H, m) , 1.73-2.06 (6H, m), 2.11 (1H, d, J= 3.3 Hz), 2.51-2.63 (2H, m), 2s 3.91 (3H, s), 4.79-4.90 (1H, m), 6.90 (1H, d, J= 8.4 Hz), 7.55 (1H, d, J= 1.8 Hz), 7.65 (1H, dd, J= 8.4, 1.8 Hz).
Reference Example A 16 1-(2-chlorophenyl)-2-(4-pyridyl)ethanone A solution of diisopropylamine (15 mL) in anhydrous so tetrahydrofuran (100 mL) was cooled at -50°C and 1.6 M n-butyllithium/hexane solution (69 mL) was added dropwise with stirring. After completion of dropwise addition, the mixture was stirred for 10 min and a solution of Y-picoline (20 g) in anhydrous tetrahydrofuran (10 mL) was added dropwise at -30°C.
The mixture was stirred for 1 h and a solution of N-(2-chlorobenzoyl)propyleneimine (20 g) in anhydrous tetrahydrofuran (10 mL) was added dropwise at -10°C. After completion of dropwise addition, the mixture was stirred for at room temperature for 2 h. To the reaction mixture was added water (100 mL) and the mixture was extracted with ethyl acetate. The extract was washed with water, and after drying, the solvent was evaporated. The residue was purified by silica to gel column chromatography (hexane-ethyl acetate=1:1) to give the title compound (16 g, yield 71~).
oil 1H-NMR (CDC13) g: 4.28 (2H, s) , 7.20 (2H, d, J= 6.2 Hz) , 7.28-7.39 (1H, m) , 7.41-7.48 (3H, m) , 8. 56 (2H, d, J= 6.2 Hz) .
15 Reference Example A 17 In accordance with Reference Example A 16, N-(3-chlorobenzoyl)propyleneimine, N-(4-chlorobenzoyl)-propyleneimine, N-(2-methylbenzoyl)propyleneimine, N-(3-methylbenzoyl)propyleneimine, N-(4-methylbenzoyl)-2o propyleneimine, N-(2-methoxybenzoyl)propyleneimine, N-(3-methoxybenzoyl)propyleneimine, N-(4-ethylbenzoyl)-propyleneimine, N-[4-(1-methylethyl)benzoyl]propyleneimine, N-[4-(1,1-dimethylethyl)benzoyl]propyleneimine, N-(4-propylbenzoyl)propyleneimine, N-(4-butylbenzoyl)propyleneimine, 2s N-(4-hexylbenzoyl)propyleneimine, N-(4-trifluoromethoxybenzoyl)propyleneimine, N-(4-trifluoromethylbenzoyl)propyleneimine, N-(3,4-dimethoxybenzoyl)propyleneimine, N-(3,4-dimethylbenzoyl)-propyleneimine, N-(3,5-dimethylbenzoyl)propyleneimine, N-(3,4-3o methylenedioxybenzoyl)propyleneimine, N-(2-naphthoyl)-propyleneimine and N-(3-cyclopentyloxy-4-methoxybenzoyl)-propyleneimine, instead of N-(2-chlorobenzoyl)propyleneimine, the following Reference Example A compounds 17-1 to 17-21 were synthesized.
Reference Example A compound 17-1: 1-(3-chlorophenyl)-2-(4-pyridyl)ethanone m. p . : 79-80°C .
Reference Example A compound 17-2: 1-(4-chlorophenyl)-2-(4-pyridyl)ethanone m.p.: 93-94°C.
Reference Example A compound 17-3: 1-(2-methylphenyl)-2-(4-pyridyl)ethanone io oil 1H-NMR (CDC13) $: 2.48 (3H, s) , 4.23 (2H, s) , 7.19 (2H, d, J=
6.2 Hz) , 7.24-7.47 (3H, m) , 7.73 (1H, d, J= 7.7 Hz) , 8.56 (2H, d, J= 6.2 Hz) .
Reference Example A compound 17-4: 1-(3-methylphenyl)-2-(4-is pyridyl) ethanone m.p. : 115-116°C.
Reference Example A compound 17-5: 1-(4-methylphenyl)-2-(4-pyridyl)ethanone m.p.. 110-111°C.
2o Reference Example A compound 17-6: 1-(2-methoxyphenyl)-2-(4-pyridyl)ethanone oil 1H-NMR (CDC13) g: 3.92 (3H, s) , 4.30 (2H, s) , 6.95-7.07 (2H, m) , 7.17 (2H, d, J= 5.9 Hz), 7.50 (1H, ddd, J= 8.4, 7.3, 1.8 Hz), 2s 7.73 (1H, dd, J= 7.7, 1.8 Hz), 8.53 (2H, d, J= 5.9 Hz).
Reference Example A compound 17-7: 1-(3-methoxyphenyl)-2-(4-pyridyl)ethanone oil 1H-NMR (CDC13) g: 3. 86 (3H, s) , 4.28 (2H, s) , 7. 14 (1H, ddd, J=
3o g.1, 2.6, 1.1 Hz), 7.20 (2H, d, J= 6.2 Hz), 7.36 (1H, dd, J=
8.1, 7.7 Hz), 7.51 (1H, dd, J= 2.6, 1.5 Hz), 7.58 (1H, ddd, J=
7.7, 1.5, 1.1 Hz), 8.57 (2H, d, J= 6.2 Hz).
Reference Example A compound 17-8: 1-(4-ethylphenyl)-2-(4-pyridyl)ethanone m.p.. 87-89°C.
Reference Example A compound 17-9: 1-[4-(1-methylethyl)phenyl]-2-(4-pyridyl)ethanone m.p. : 86-88°C.
Reference Example A compound 17-10: 1-[4-(1,1-dimethylethyl)-phenyl]-2-(4-pyridyl)ethanone A solution of diisopropylamine (15 mL, 0.11 mol) in anhydrous tetrahydrofuran (100 mL) was cooled to -50°C, 1.6 M
io n-butyllithium-hexane solution (69 mL, 0.11 mol) was added dropwise with stirring. After completion of dropwise addition, the mixture was stirred for 10 min, and then a solution of Y-picoline (9.3 g, 0.10 mol) in anhydrous tetrahydrofuran (10 mL) was added dropwise at -30°C. The mixture was stirred for 1 I5 h, a solution of N-[4-(1,1-dimethylethyl)benzoyl]-propyleneimine (22 g, 0.10 mol) in anhydrous tetrahydrofuran (10 mL) was added dropwise at -30°C. After completion of dropwise addition, the temperature of the mixture was increased gradually to room temperature and the mixture was 2o stirred for 2 h. To the reaction mixture was added water (100 mL), the mixture was extracted with ethyl acetate. The extract was washed with water, and after drying, the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate, 1:1) and recrystallized 25 from diisopropyl ether-hexane to give the title compound (11 g, yield 43%).
m.p.: 75-76°C.
Reference Example A compound 17-11: 1-(4-propylphenyl)-2-(4-pyridyl)ethanone 3o m,p.: 71-72°C.
Reference Example A compound 17-12: 1-(4-butylphenyl)-2-(4-pyridyl)ethanone m.p.: 41-43°C.

Reference Example A compound 17-13: 1-(4-hexylphenyl)-2-(4-pyridyl)ethanone m.p.. 57-58°C.
Reference Example A compound 17-14: 2-(4-pyridyl)-1-(4-s trifluoromethoxyphenyl)ethanone m.p.. 65-66°C.
Reference Example A compound 17-15: 2-(4-pyridyl)-1-(4-trifluoromethylphenyl)ethanone m.p.: 94-95°C.
io Reference Example A compound 17-16: 1-(3,4-dimethoxyphenyl)-2-(4-pyridyl)ethanone m.p.: 110-111°C.
Reference Example A compound 17-17: 1-(3,4-dimethylphenyl)-2-(4-pyridyl) ethanone is m.p.: 81-83°C.
Reference Example A compound 17-18 1-(3,5-dimethylphenyl)-2-(4-pyridyl)ethanone A solution of diisopropylarnine (15 mL, 0.11 mol) in anhydrous tetrahydrofuran (100 mL) was cooled to -50°C, 1.6 M
2o n-butyllithium-hexane solution (69 mL, 0.11 mol) was added dropwise with stirring. After completion of dropwise addition, the mixture was stirred for 10 min, and a solution of y-picoline (9.3 g, 0.10 mol) in anhydrous tetrahydrofuran (10 mL) was added dropwise at -30°C. The mixture was stirred for 1 2s h~ a solution of N-(3,5-dimethylbenzoyl)propyleneimine (19 g, 0.10 mol) in anhydrous tetrahydrofuran (10 mL) was added dropwise at -30°C. After completion of dropwise addition, the temperature of the mixture was gradually raised to room temperature and the mixture was stirred for 2 h. To the so reaction mixture was added water (100 mL) and the mixture was extracted with ethyl acetate. The extract was washed with water, and after drying, the solvent was evaporated. The residue was crystallized from diisopropyl ether-hexane to give the title compound (13 g, yield 58~).
m. p. . 90-91°C.
Reference Example A compound 17-19: 1-(3,4-methylenedioxyphenyl)-2-(4-pyridyl)ethanone m.p.: 126-127°C.
Reference Example A compound 17-20: 1-(2-naphthyl)-2-(4-pyridyl)ethanone m.p. . 114-115°C.
Reference Example A compound 17-21: 1-(3-cyclopentyloxy-4-i o methoxyphenyl ) -2- ( 4-pyridyl ) ethanone m.p.: 87-89°C.
Reference Example A 18 In accordance with Reference Example A 17, the following Reference Example A compound 18-1-18-9 were synthesized using Y-picoline instead of ~3-picoline.
Reference Example A compound 18-1: 1-(2-chlorophenyl)-2-(3-pyridyl)ethanone oil 1H-NMR (CDC13) g: 4.28 (2H, s), 7.18-7.49 (5H, m), 7.59-7.67 20 (1H, m), 8.47-8.56 (2H, m).
Reference Example A compound 18-2: 1-(3-chlorophenyl)-2-(3-pyridyl)ethanone oil 1H-NMR (CDC13) $: 4.29 (2H, s), 7.25-7.34 (1H, m), 7.44 (1H, t, 25 J= 7.7 Hz), 7.54-7.63 (2H, m), 7.90 (1H, dt, J= 7.7, 1.5 Hz), 8.00 (1H, dd, J= 1.8, 1.5 Hz), 8.49-8.57 (2H, m).
Reference Example A compound 18-3: 1-(4-chlorophenyl)-2-(3-pyridyl)ethanone 1H-NMR (CDC13) g: 4.27 (2H, s), 7.24-7.31 (1H, m), 7.47 (2H, d, so J= g.8 Hz), 7.55-7.63 (1H, m), 7.96 (2H, d, J= 8.8 Hz), 8.46-8.53 (2H, m) .
Reference Example A compound 18-4: 1-(2-methylphenyl)-2-(3-pyridyl)ethanone 01.1 1H-NMR (CDC13) g: 2.47 (3H, s) , 4.23 (2H, s) , 7. 18-7.47 (5H, m) , 7.73 (1H, d, J= 7.7 Hz), 8.47-8.56 (2H, m).
Reference Example A compound 18-5: 1-(3-methylphenyl)-2-(3-pyridyl)ethanone oil 1H-NMR (CDC13) g: 2.43 (3H, s) , 4.29 (2H, s) , 7. 17-7.36 (1H, m) , 7.36-7.46 (2H, m), 7.58-7.65 (1H, m), 7.78-7.86 (2H, m), 8.50-8.56 (2H, m).
Reference Example A compound 18-6: 1-(4-methylphenyl)-2-(3-pyridyl)ethanone m. p. . 72-74°C.
Reference Example A compound 18-7: 1-(3-methoxyphenyl)-2-(3-pyridyl)ethanone 15 oil 1H-NMR (CDC13) $: 3.86 (3H, s) , 4.29 (2H, s) , 7. 14 (1H, ddd, J=
8.1, 2.6, 1.8 Hz), 7.28 (1H, dd, J= 7.3, 4.8 Hz), 7.40 (1H, dd, J= 8.1, 7.7 Hz), 7.53 (1H, dd, J= 2.6, 1.8 Hz), 7.58-7.65 (2H, m) , 8. 50-8. 55 (2H, m) .
2o Reference Example A compound 18-8: 1-[4-(1,1 dimethylethyl)phenyl]-2-(3-pyridyl)ethanone oil 1H-NMR (CDC13) $: 1.34 (9H, s) , 4.28 (2H, s) , 7.22-7.31 (1H, m) , 7.50 (2H, d, J= 8.4 Hz), 7.56-7.65 (1H, m), 7.96 (2H, d, J=
2s 8.4 Hz), 8.48-8.55 (2H, m).
Reference Example A compound 18-9: 1-(3,5-dimethylphenyl)-2-(3-pyridyl)ethanone oil 1H-NMR (CDC13) $: 2.38 (6H, s) , 4.27 (2H, s) , 7.24-7. 30 (2H, m) , 30 7. 58-7. 63 (3H, m) , 8. 50-8. 52 (2H, m) .
Reference Example A 19 In accordance with Reference Example A 1, the following Reference Example A compound 19 was synthesized using ethyl 4-dimethylaminobenzoate instead of ethyl p-anisate.
Reference Example A compound 19: 1-(4-dimethylaminophenyl)-2-(4-pyridyl) ethanone m.p.: 189-192°C.
Reference Example A 20 1- (4-fluorophenyl) -2- (4-pyridyl) ethanone A solution of diisopropylamine (29 mL) in anhydrous tetrahydrofuran (300 mL) was cooled to -78°C, and 1.6 M n-butyllithium/hexane solution (140 mL) was added dropwise with stirring. After completion of dropwise addition, the mixture was stirred for 10 min, and then a solution of Y-picoline (21 g) in anhydrous tetrahydrofuran (50 mL) was added. The reaction mixture was stirred at -10°C for 30 min. The reaction solution was cooled to -78°C and a solution of N-(4-i5 fluorobenzoyl)propyleneimine (36 g) in anhydrous tetrahydrofuran (50 mL) was added dropwise. After completion of dropwise addition, the mixture was stirred at room , temperature for 3 h. To the reaction mixture was added water (100 mL) and extracted with ethyl acetate. The extract was 2° washed with water, and after drying, the solvent was evaporated. The residue was crystallized from diisopropyl ether to give the title compound (28 g, yield 66~).
m.p.: 90-91°C.
Reference Example A 21 zs 4- (methylthio) thiobenzamide 4-Methylthiobenzonitrile (12 g) was dissolved in a solution (130 mL) of 4N hydrogen chloride in ethyl acetate. To this solution was added 0,0-diethyl dithiophosphate (15 mL) and the mixture was stirred at room temperature for 22 h. To 3o the reaction mixture was added water (100 mL), and the mixture was extracted with ethyl acetate. The insoluble material was filtered off and the filtrate was washed with saturated brine, dried and the solvent was evaporated. The residue was recrystallized from ethyl acetate to give the title compound (10 g, yield 67~) .
m.p. . 176-178°C.
Reference Example A 22 s In accordance with Reference Example A 6 and respectively using 1-(2-chlorophenyl)-2-(3-pyridyl)ethanone, 1-(3-chlorophenyl)-2-(3-pyridyl)ethanone, 1-(4-chlorophenyl)-2- ( 3-pyridyl ) ethanone , 1- ( 2-methylphenyl ) -2- ( 3-pyridyl)ethanone, 1-(3-methylphenyl)-2-(3-pyridyl)ethanone, 1-1° (4-methylphenyl)-2-(3-pyridyl)ethanone, 1-(3-methoxyphenyl)-2-( 3-pyridyl ) ethanone , 1- [ 4- ( 1,1-dimethylethyl ) phenyl ] -2- ( 3-pyridyl)ethanone, 1-(3,5-dimethylphenyl)-2 -(3-pyridyl)ethanone, 1-(2-chlorophenyl)-2-(4-pyridyl)ethanone, 1-(3-chlorophenyl)-2-(4-pyridyl)ethanone, 1-(4-chlorophenyl)-2-(4-zs pyridyl)ethanone, 1-(2-methylphenyl)-2-(4-pyridyl)ethanone, 1-(3-methylphenyl)-2-(4-pyridyl)ethanone, 1-(4-methylphenyl)-2-(4-pyridyl)ethanone, 1-(2-methoxyphenyl)-2-(4-pyridyl)ethanone, 1-(3-methoxyphenyl)-2-(4-pyridyl)ethanone, 1-(4-ethylphenyl)-2- ( 4-pyridyl ) ethanone , 1- [ 4- ( 1-methylethyl ) phenyl ] -2- ( 4-2o pyridyl)ethanone, 1-[4-(1,1-dimethylethyl)phenyl]-2-(4-pyridyl)ethanone, 1-(4-propylphenyl)-2-(4-pyridyl)ethanone, 1-(4-butylphenyl) -2- (4-pyridyl) ethanone, 1- (4-hexylphenyl) -2- (4-pyridyl) ethanone, 2- (4-pyridyl) -1- (4-trifluoromethoxyphenyl)ethanone, 2-(4-pyridyl)-1-(4-2s trifluoromethylphenyl)ethanone, 1-(4-dimethylaminophenyl)-2-(4-pyridyl)ethanone hydrobromide, 1-(3,4-dimethoxyphenyl)-2-(4-pyridyl) ethanone, 1- (3, 4-dimethylphenyl) -2- (4-pyridyl)ethanone, 1-(3,5-dimethylphenyl)-2-(4-pyridyl)ethanone, 1- (3, 4-methylenedioxyphenyl) -2- (4-pyridyl) ethanone, 1- (2-3o naphthyl ) -2- ( 4-pyridyl ) ethanone , 1- ( 4-f luorophenyl ) -2- ( 4-pyridyl)ethanone and 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethanone instead of 1-(4-methoxyphenyl)-2-(3-pyridyl)ethanone, the following Reference Example A compounds 22-1 to 22-33 were synthesized.
Reference Example A compound 22-1: 2-bromo-1-(2-chlorophenyl)-2-(3-pyridyl)ethanone hydrobromide m.p.: 88-90°C.
Reference Example A compound 22-2: 2-bromo-1-(3-chlorophenyl)-2-(3-pyridyl)ethanone hydrobromide m.p.. 164-166°C
Reference Example A compound 22-3: 2-bromo-1-(4-chlorophenyl)-2-(3-pyridyl)ethanone hydrobromide to Used in the next reaction without purification.
Reference Example A compound 22-4: 2-bromo-1-(2-methylphenyl)-2-(3-pyridyl)ethanone hydrobromide Used in the next reaction without purification.
Reference Example A compound 22-5: 2-bromo-1-(3-methylphenyl)-15 2-(3-pyridyl)ethanone hydrobromide Used in the next reaction without purification.
Reference Example A compound 22-6: 2-bromo-1-(4-methylphenyl)-2-(3-pyridyl)ethanone hydrobromide m.p.: 96-98°C.
2o Reference Example A compound 22-7: 2-bromo-1-(3-methoxyphenyl)-2-(3-pyridyl)ethanone hydrobromide Used in the next reaction without purification.
Reference Example A compound 22-8: 2-bromo-1-[4-(1,1-dimethylethyl)phenyl]-2-(3-pyridyl)ethanone hydrobromide 25 m.p.. 190-194°C.
Reference Example A compound 22-9: 2-bromo-1-(3,5-dimethylphenyl)-2-(3-pyridyl)ethanone hydrobromide m.p.: 195-197°C.
Reference Example A compound 22-10: 2-bromo-1-(2-so chlorophenyl)-2-(4-pyridyl)ethanone hydrobromide m.p. : 157-159°C.
Reference Example A compound 22-11: 2-bromo-1-(3-chlorophenyl)-2-(4-pyridyl)ethanone hydrobromide m.p. : 178-181°C.
Reference Example A compound 22-12: 2-bromo-1-(4-chlorophenyl)-2-(4-pyridyl)ethanone hydrobromide m.p.: 189-193°C.
s Reference Example A compound 22-13: 2-bromo-1-(2-methylphenyl)-2-(4-pyridyl)ethanone hydrobromide m.p. : 183-186°C.
Reference Example A compound 22-14: 2-bromo-1-(3-methylphenyl)-2-(4-pyridyl)ethanone hydrobromide to Used in the next reaction without purification.
Reference Example A compound 22-15: 2-bromo-1-(4-methylphenyl)-2-(4-pyridyl)ethanone hydrobromide m.p.. 111-113°C.
Reference Example A compound 22-16: 2-bromo-1-(2 is methoxyphenyl)-2-(4-pyridyl)ethanone hydrobromide m. p. . 168-171°C.
Reference Example A compound 22-17: 2-bromo-1-(3-methoxyphenyl)-2-(4-pyridyl)ethanone hydrobromide Used in the next reaction without purification.
2o Reference Example A compound 22-18: 2-bromo-1-(4-ethylphenyl)-2-(4-pyridyl)ethanone hydrobromide m.p.. 170-173°C.
Reference Example A compound 22-19: 2-bromo-1-[4-(1-methylethyl)phenyl]-2-(4-pyridyl)ethanone hydrobromide 2s m,p.: 185-188°C.
Reference Example A compound 22-20: 2-bromo-1-[4-(l,l-dimethylethyl)phenyl]-2-(4-pyridyl)ethanone hydrobromide 1-[4-(1,1-Dimethylethyl)phenyl]-2-(4-pyridyl)ethanone (10 g, 39 mmol) was dissolved in acetic acid (40 mL) and so bromine (2.0 mL, 39 mmol) was added. The mixture was stirred at 80°C for 3 h. The reaction mixture was cooled with iced water and the precipitated crude crystals were collected by filtration. The crude crystals were washed with ethyl acetate to give the title compound (9.6 g, yield 81~).
m. p. : 209-212°C.
Reference Example A compound 22-21: 2-bromo-1-(4-propylphenyl)-2-(4-pyridyl)ethanone hydrobromide m. p. . 167-170°C.
Reference Example A compound 22-22: 2-bromo-1-(4-butylphenyl)-2-(4-pyridyl)ethanone hydrobromide m. p. . 158-161°C.
Reference Example A compound 22-23: 2-bromo-1-(4-hexylphenyl)-io 2-(4-pyridyl)ethanone hydrobromide m.p. : 153-155°C.
Reference Example A compound 22-24: 2-bromo-2-(4-pyridyl)-1-(4-trifluoromethoxyphenyl)ethanone hydrobromide Used in the next reaction without purification.
15 Reference Example A compound 22-25: 2-bromo-2-(4-pyridyl)-1-(4-trifluoromethylphenyl)ethanone hydrobromide m.p.. 190-194°C.
Reference Example A compound 22-26: 2-bromo-1-(4-dimethylaminophenyl)-2-(4-pyridyl)ethanone dihydrobromide 2o m.p.. 163-167°C.
Reference Example A compound 22-27: 2-bromo-1-(3,4-dimethoxyphenyl)-2-(4-pyridyl)ethanone hydrobromide m.p.: 174-175°C.
Reference Example A compound 22-28: 2-bromo-1-(3,4-2s dimethylphenyl)-2-(4-pyridyl)ethanone hydrobromide m.p.: 196-199°C.
Reference Example A compound 22-29: 2-bromo-1-(3,5-dimethylphenyl)-2-(4-pyridyl)ethanone hydrobromide 1-(3,5-Dimethylphenyl)-2-(4-pyridyl)ethanone (7.0 g, 31 3o mmol) was dissolved in acetic acid (35 mL) and bromine (1.6 mL, 31 mmol) was added. The mixture was stirred at 80°C for 3 h.
Ethyl acetate was added to the residue and the precipitated crude crystals were collected by filtration. The crude crystals were washed with ethyl acetate to give the title compound (16 g, yield 96~).
m.p.. 216-219°C.
Reference Example A compound 22-30: 2-bromo-1-(3,4-methylenedioxyphenyl)-2-(4-pyridyl)ethanone hydrobromide m.p.: 211-214°C.
Reference Example A compound 22-31: 2-bromo-1-(2-naphthyl)-2-(4-pyridyl)ethanone hydrobromide m.p.: 149-152°C.
io Reference Example A compound 22-32: 2-bromo-1-(4-fluorophenyl)-2-(4-pyridyl)ethanone hydrobromide m.p.: 185-189°C.
Reference Example A compound 22-33: 2-bromo-1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethanone 15 hydrobromide m.p.: 168-170°C.
Reference Example A 23 In accordance with the method described in Reference Example s A 8-12, JP-A-61-10580 and USP 4,612,321, Reference 2o Example A compounds 23-1 to 23-294 and 23-295 to 23-349 shown in the following Tables 8 to 31 were synthesized.

Table 8 Rn~~~-R~
R~
Reference Rb Rr additives t'n.P.
Example ~.' A q~
Compound 23-t -NHCO - ~ HGt 2f>i~

~8-2 -SINGE? ~. ~ Z HGt 244-2A6 23-3 -NMGO ~ ~- HCI 25a-256 ~g..,~ -tdHGf7 -t~ ! 1 NCB ~T5 ~3-6 -t~tHGO '"" ~""~-' 23~

2.3-a -NEiGOMe ~~ ~,~'G'~'~'"' 2't8-22~f -htHGO~Ie ~ ~ ~t8-~2I~

~3-8 -NM~"'~ f ~ 2NGt i48-148 23-9 -N~tGO ~~~ N ~ ~~8 23-1 f# -NHCOCH ~--~ ~ -- 22&-29fl 2~-1 t -NHCQ~ ~GHx~~'~~
~ t 6-2.t ~~-1 ~ -NMGC~ (G~i ~~~" ~ 198-2Q~
a~~Me Z3-13 -~1WCCJ ~~.'~-l~~~Me ! ~' 206-c06 2~-14 -NHCO {CH 2~~M~~ ~ 'i 78-'f 23-1~ -NHCOe~ N ~ I ~. ~t9-~2t3 -i s -Nr~eo ~ , -- ~a~o--~-- Ma ass-~~~

~s-1~ -r~HCO- ~ ~~o-~--- ~cr ~d~.~as Table 9 Rb~N~Ra Rc Reference R R m. . .
Example b ~ additives / C
A R p Compound a 23-18 -NHCO S I N ~ Me0 ~ \ HCI 237-289 23-19 -NHCO-O N ~ Me0 ~ \ HCI ,220-223 23-20 -NHCOCH2 ~ / N ~ Me0 ~ \ i 84-185 23-21 -NHCO(CH~2 ~ N ~ Me0 ~ \ 214-216 /

2~~ -NHCO(CH~2Me N ~ Me0-~-- 197-198 23-23 -NHCO(CH2)3Me N ~ Me0 ~ \ 188-190 23-24 -NHCO(CH2)4Me N ~ Me0 ~ \ 167-169 23-25 -NHCOCMe3 N ~ Me0 ~ \ 245-246 23-26 -NHCO ~ / N~ \ ~ \ 237-238 23-27 -NHCO O I N _\ / \ 240 23-28 . -NHCO S ( N _\ ~ \ 240 23-29 -NHCOCH2 \ / N~ \ ~ \ 233-234 23-30 -NHCO(CH2)2 N _~ ~ \ 214-216 \ /

23-31 -NHCOCMe3 N _\ ~ \ 206-208 23-32 -NHCO ~ N N _\ / \ 247 23-33 -NHCO(CH~J2Me N~ \ ~ \ 212-214 23-34 -NHCO(CH~3Me N~ \ ~ \ 232-234 23-35 -NHCO(CH~4Me N _\ ~ \ 245-246 Table 10 Rb~N~R$
Rc Reference Rb Rc m.p. /'C
Example A Ra Compound 23-36 -NHCO-O N _~ ~ \ 219-220 23-37 -NHCOCHzINe N-\ Me0 ~ ~ 254-256 23-38 -NHCO \ ~ N _\ Me0 ~ \ 255-257 23-39 -NH2 N ~ CI ~ \ 278-280 23-40 -NHCOMe N ~ Cl ~ \ 266-268 23-41 -NHCOCH2Me N ~ CI ~ \ 241-242 23-42 -NH2 N ~ Me ~ ~ 286-288 23-43 -NHCOMe N ~ Me ~ \ . 260-281 23-~ -NHCOCH2Me N ~ Me ~ \ 226-227 CI
23-45 -NHCOMe N ~ / \ 217-219 / \ CI
23-46 -NHCOCH2Me ~ \ ~ 228-229 N

23-47 -NHCOMe / \ M8 N ~ \ 235-236 Me 23-48 -NHCOCH2Me / \ ~ \ 239-241 N

CI
23-49 -NHCOMe N~ \ ~ \ 290-293 23-50 -NHCOCH2Me N _\ / ~ 289-290 Me 23-51 -NHCOMe N~ \ / \ 287-289 Table 11 RbhN Re Rc tteter~ence Rb Rc m.p. / '<r Example A Re Compound Me 23-52 -NHCOCH2Me N _~ / ~ ~ 258-260 23-53 -NHCOMe N _~ CI ~ ~ 317-320 23-54 -NHCOCH2Me N _~ CJ / ~ 257-259 23-55 -NHCOMe N _~ Me ~ ~ 308-309 23-56 -NHCOCH2Me N _~ Me ~ ~ 249-250 23-57 -NH2 N ~ / ~ 228-230 23-58 -NH2 ~ ~ Me N / ~ 231-232 CI
23-59 -NH2 N~ ~ / 1 256-258 Me 23-60 -NH2 N _~ / ~ 255-258 23-61 -NH2 N~ ~ C) ~ ~ >300 23-62 -NHy N~ ~ Me ~ ~ 296-298 23-63 -N=C(Me)NMe2 N ~ ~ ~ 129-131 23-64 -NHCOMe N _~ Me0 ~ ~ 282-284 Me0 23-fi5 -NHCOMe N ~ / ~ 23fi-239 Me0 23-66 -NHCOCH2Me N / ~ 222-224 _ Me0 23-67 -NHCO ~ / N ~ / ~ 236-239 Table 12 Rb~N Ra Rc Reference ExampleRe Rb R~ m,p, / 'C
A

Compound Me0 23-68 -NHCOMe N~ ~ / \ 234-236 Me0 23-69 -NHCOCH2Me N~ \ / \ 237-239 _ Me0 23-70 -NHCO \ / N~-' / \ 220-222 23-71 -NHCOMe N~ ~ \ 294-297 23-72 -NHCOCH2Me N _~ ~ ~ 267-269 23-73 -N(CH2Me)COMeN~ ~ Me0 ~ \ 143-144 23-74 -N((CH2)4Me)COMeN~ \ Me0 ~ ~ 111-113 23-75 e \ / N~ \ Me0 ~ ~ 162-164 ~p M

Me0 23-76 -NH2 N ~ / ~ 206-209 Me0 23-77 -NH2 N~ ~ / ~ 232-234 Ct 23-78 -NHy N ~ / ~ 236-239 CI
23-79 -NH2 N _~ / ~ 232-235 23-80 -NH~ N~ MeO ~ \ 287-289 CI
23-81 N~ \ Me0 ~ \ 330-333 -NHCO ~ /

23-82 N! \ Me0 ~ \ 292-294 -NHCO \ /

Table 13 Rb~N?-Ra Rc Reference ExampleRe Rb Rc m.p. / 'C
A
Compound 23-83 -NHCO \ / CI N~ Me0 ~ \ 346-348 \

23-84 -NHCO \ / OMe N~ Me0 ~ \ 308-310 \

23-85 -NH2 N~ HO ~ \ 323-326 \

CI
23-86 -NHCOMe N ~ ~ \ 259-261 \ CI
23-87 -NHCOMe N~- / \ 292-293 23-88 'N \ ~ N _\ Me0 ~ \ 161-7 63 COMB

Me 23-89 -NH2 N ~ / \ 235-237 23-90 -NHCOMe N _\ MeC00 ~ \ 254-257 23-91 -NHCOCH2- fl N~ Me0 ~ \ 274-277 \

23-92 -NHCOMe / \ Me N / \ 237-239 23-93 -NHCOMe N _\ HO ~ \ 285-287 Me 23-94 -NH2 N _\ ~ \ 235-238 Me 23-95 -NHCOMe N~ / \ 272-274 \

OMe 23-96 -NH2 N~ / \ 213-215 OMe 23-97 -NHCOMe N _\ / \ 259-261 23-98 -NHCO(CH2)4CI N~ Me0 ~ \ 228-229 \

Table 14 Rb~N Ra R~
Reference Rb R~ m - P .
Example / C
A Ra Compound 23-99 -NHCOMe _~ ~ ~ 2 ~ ~ 254-257 23-100 ~ _~ Me ~ ~ 159-160 O

23-101 -NHC ~ N N~ ~ Me ~ ~ 278-281 23-102 -NHC ~ ,N ~ ~ Me ~ ~ 295-297 23-103 -NHCO S I _~ Me ~ ~ 262-264 23_104 -NHCO OI _~ Me ~ ~ 266-269 23-105 -NHCOCHMe2 N_~ Me ~ ~ 227-230 23-106 -NHCOCMe3 ~ ~ Me ~ ~ ~ 254-256 23-107 -NHCOCH2CHMe2 ~ ~ Me ~ ~ 261-262 23-108 -NHCONH(CH~2Me _~ Me ~ ~ 215-219 23-109 -NH2 _~ MeCH2 ~ ~ 285-288 23-110 -NHCOMe N~ ~ MeCH2 ~ ~ 294-295 23-111 -NHCOMe ~ ~ MeCH2 ~ ~ 206-209 23-112 -NHCOMe N~ ~ Me(CH~3 ~ ~ 201-203 23-113 -NHCOMe ~ ~ Me(CH2)g ~ ~ 210-212 23-114 -NHCO(CH~j~CI N ~ Me ~ ~ 191-194 Table 15 Rb~N~-Ra Rc Reference Rb Rc m . p Example . /
A Ra ~

Compound 23-1i5 N~ N~ ~ Me0 ~ ~ 133-135 O

23-116 -NHCO{CH~SCI N~ ~ Me0 ~ ~ 223-225 Me 23-117 -NHCO ~ / N _~ Me0 ~ ~ 351-352 Me Me0 23-118 -NHCOMe N _~ M~ / ~ 265-267 Me 23-119 -NHCOMe N _~ Me ~ ~ 248-250 23-120 -NHCOMe N~ ~ MezCH ~ ~ 295-297 23-121 -NHCO{CH2)2COOCH2MeN _~ Me0 / ~ 261-264 23-122 -NHCO{CH2)2COOH N ~~ Me0 ~ ~ 334-336 23-123 -NHp N~ ~ Me2CH ~ ~ 267-269 Me0 23-124 -NH2 N~ ~ ~ ~ 218-219 Me0 Me 23-125 -NH2 N _~ / ~ 248-250 Me O
23-126 -NH2 N~ ~ 0 / ~ 273-275 23-127 -NHCOMe N ~~ O
p / ~ 295-296 Me 23-128 -NHCOMe N '~ / ~ 284-286 Me 23-129 -NHCOMe N _~ Me2N ~ ~ 289-291 Table 16 Rb~N Ra Rc Reference Rb Rc additives m' p' ~
Example ~
A R$
Compound 23-130 -NHCOCHMe2 N~ \ Me2CH ~ \ 284-285 23-131 -NHCOCMe3 N~ \ Me2CH ~ \ 293-295 23-132 -NHCONH(CH~2Me N~ ~ Me2CH ~ ~ 287-28g Me 23-133 -NH2 N i\ / \ 242-244 Me 23-t 34 -NHz N _~ Me2N ~ \ 309-311 23-135 -CH2COOCH2Me N~ \ Me0 ~ \ HCl 150-152 23-136 -CH2NHC0 ~ ~ N~ \ Me0 ~ \ 150-151 23-137 -NHCOMe N _\ Me3C ~ \ 280-281 23-138 -NHCOCHMe2 N _\ Me3C ~ \ 303-304 23-139 -NHCOCMe3 N ~\ Me3C ~ \ 317-319 23-140 -NHCOMe N~ ~ 1 / \ 342-345 23-141 -NHCOCHMe2 N~ \ \ / ~ 297-298 23-142 -NHCOCMe3 N~ \ \ / \ 3i3-315 23-143 -NH2 N _\ Me3C ~ \ 254-257 23-144 -NH2 N ~\ ~ / \ 261-264 23-145 -CH2COOH N~ \ MeO ~ \ 135-137 23-146 -CH2CONHMe N~ \ Me0 ~ \ i29-i30 Table 17 RbJ'N Ra Rc Reference Rb Rc m. p . /
Example ~
A Ra Compound 23-147 -Me N _~ Me0 ~ ~ 132-133 23-148 -NHCOMe N~ ~ Me(CH2)2 ~ 256-258 ~

23-149 -NHCOCHMe2 N~ ~ Me(CH2)2 ~ 269-272 ~

23-150 -NHCO ~ ~ . N~ Me(CH2)2 ~ 240-242 ~ ~

23-151 -NHCOMe N~ ~ Me(CH2)3 ~ 259-261 ~

23-152 -NHCOMe N~ ~ Me(CH2)5 ~ 237-239 ~

23-153 -NHCOMe N~ ~ CFgO ~ ~ 296-298 23-154 -NHCOCHMe2 N~ ~ CF30 ~ ~ 285-286 23-155 -NHCOCF3 N~ ~ Me0 ~_~ 260-262 23-156 -NHCONHCH2Me N~ ~ Me0 ~ ~ 224-226 23-157 -NHCONHCH2Me N~ ~ Me2CH ~ ~ 181-i83 23-158 -NH2 N~ ~ Me(CH2)2 ~ 240-242 ~

23-159 -NH2 N _~ Me(CH~3 ~ ~ 204-206 2&160 -NH2 N~ ~ Me(CH2)5 ~ 178-179 ~

23-161 -NH2 N~ ~ CF30 ~ ~ 262-264 23-i62 -COOH N~ ~ Me0 ~ ~ 141-143 23-163 -NHCOCH2Me N~ ~ Me3C ~ ~ 295-297 23-164 -NHCO ~ ~ N~ ~ Me3C ~ ~ 292-294 N N~ ~ Me3C ~ ~ 326-328 23-165 -NHCO ~ /

Table 18 Rb~N Ra Rc Refen:nce Example A Rb Rc m - p - ~
Ra 'C
Compound 23-166 -NHCO \ ~N N~ \ Me3C ~ \ 326-329 23-167 -NHCOCH2 ~ ~ N _\ Me3C ~ \ 277-279 23-168 -NHCO-~ N ,\ Me3C ~ ~ 309-311 23-169 -NHCONHCH2Me N,\ Me3C ~ \ 289-292 23-170 -NHCONH(GH2)2Me N~ ~ Me3C ~ ~ 212-214 23-i 71 -NHCOCH20Me N~ ~ Me3C ~ \ 248-249 23-172 -NHCOMe N ~ Me3C ~ \ 228-230 23-173 -NHCOCH2Me N ~ Me3C ~ ~ 244-246 23-174 -NHCOCHMe2 N ~ Me3C / ~ 228-229 23-175 -NHCOCH2 \ / N ~ Me3C ~ \ 204-208 23-i 76 -NHCO ~ / N ~ Me3C ~ \ 216-218 23-177 -NHGO-Q N ~ Me3C ~ \ 218-220 23-178 -NHCO \ N ~ ~ Me3C / \ 251-253 23-179 -NHCO \ ,N ~ Me3C / \ 271-273 23-180 -NHCONHCH2Me N ~ Me3C ~ \ 302-305 .

23-181 -NHCONH(CH2)2MeN ~ Me3C ~ \ 190-192 23-182 -NH2 N ~ Me3C / \ 239-241 23-183 -NH2 N' ~ CF3 / \ 304-306 Table 19 Rb~N Ra R~
Reference Example A Rb R~ m. p . /
Ra ~
Com,~ound 23-i84 -NHCOMs N_~ CF3 ~ ~ 328-330 23-185 -NHCOCH2Me N~ ~ CF3 ~ ~ 284-286 23-186 -NHCOCHMe2 N~ ~ . CF3 ~ ~ 274 275 23-187 -NHCOCHZ ~ ~ N' ~ CF3 ~ ~ 295-296 23-188 -NHCO-O . N _~ CF3 ~ ~ 254-255 23-189 -NHCO-Q N~ ~ CF3 ~ ~ 272-273 23-190 -NHCO ~ N N _~ CF3 ~ ~ 262-264 23-191 -NHCO ~ ,N N~ ~ CF3 ~ ~ 263-264 23-i 92 -NHCONHCH2Me N~ ~ CF3 ~ ~ 206-207 23-193 -NHCONH(CH~2Me N~ ~ CF3 ~ ~ 208-2i0 Me 23-194 -NHCOCH2Me N_~ ~ ~ 281-293 Me Me 23-195 -NHCOCHMe2 N _~ ~ ~ 270-272 Me Me 23-186 -NHCOCHp ~ N~ ~ . ~ ~ 226-229 ~

Me Me 23-187 -NHCO ~ ~ N~ ~ ~ ~ 285-286 Me Me 23-198 -NHCO-~ N -~ ~ ~ 275-278 Me Table 20 Rb~NS-Ra Rc Reference Rb Rc m. p . / 'C
Example A Ra Compound Me N N _~ ~ ~ . 267-270 23-199 -NHCO ~ /
.

Me Me 23200 -NHCO ~ ,N N~ ~ / ~ 302-304 Me Me 23201 -NHCONHCH2Me N~ ~ / ~ 202-203 Me Me 23202 -NHCONH(CH2)2Me N~ ~ ~ ~ 128-130 Me Me 23-203 -NHCOCH20Me N _~ ~ ~ 220-222 Me Me 23-204 -NH2 N ~ / ~ 237-240 Me Me 23205 -NHCOMe N ~ ~ ~ 288-289 Me Me 23-206 -NHCOCH2Me N ~ / ~ 292-293 Me Me 23207 -NHCOCHMe2 N ~ ~ ~ 253-254 Me Me 23-208 -NHCOCHp ~ / N ~ ~ ~ 235-238 Me Table 21 Rb~N Ra Rc Reference Example A Re Rb Rc additives ~' p'/ '~
C0mp0und Me 23-209 -NHCO ~ / N ~ ' ~ ~ 300-301 Me Me 23-210 -NHCO ~ ~ N ~ / \ 277-278 Me Me 23-211 -NHCO ~ ~N N ~ ~ \ ~ 278-280 Me Me 23-212 -NHCONHCH2Me ~ ~ / \ 220-224 N Me Me 23-213 -NHCONH(CHz}2Me / ~ / \

Me 23-214 -COOCH2Me N _~ MeO / \ 149-150 23-215 -NHCOCH2NMe2 N ;~ Me3C ~ ~ 230-231 23-216 -NHZ N ~ MeCH20COCH20 ~ \ 167-169 23-217 -NHCOMe N Z MeCH2OCOCH2O ~ \ 195-197 23-218 -NHCOMe N ~ HOCOCH20 ~ ~ 266-270 23-219 -NH2 N~ \ MeCH20COCH20 ~ ~ 181-185 23-220 -NHCOMe N '\ MeCH20COCH20 ~ \ 239-244 23-221 -NHCOMe N~ \ HOCOCH20 /'\ HC~ 237-242 23-222 ~ H N~ \ Me0 ~ \ 248-250 O

Table 22 Rb~N>-Ra Rc Reference Example Rb R~ additives m~p A
Compound Ra Me 23-223 -NHCOCHzOH N~ \ ~ \ 243-245 Me Me 3-224 NHCOMe N -\ ~ \ 71-373 HO
Me \ Me 23-225 -NHCOMe N~ / \ 350-351 MeCO
Me Me 23-226 -~~e \ / N~ \ ~ \ t56-157 Me Me 23-227 -NHOCH2 \ N _\ ~ \ 171-172 / M

e 23-228 -NHCO \ ~ N~ ~ Me ~ ~ 278-278 23-229 -NHCO \ ~ N~ \ MeCH2 / \ 276-277 23-230 -NHCO ~ ~ N~ \ Me(CH2)2 ~ \ 25Q-251 23-231. -NHCO ~ ~ N_\ Me(CH2)3 ~ \ 241-242 23-232 -NMeCOMe N_\ Me0 ~ \ HCI 219-222 Me 23-233 -NHMe N~ \ ~ \ 226-227 Me Table 23 RbJ' N Ra Rc Reference Example A Ra Rc Rc additives m-p-~ 'O
Compound Me 23-234 -NMeCOMe N~ ~ / ~ 171-174 Me Me 23-235 -NMeCOMe N~ \ ~ \ HCI 189-193 M

e Me 23-236 -NMeCO ~ N~ \ / \ 2i0-214 ~

Me Me 23-237 -NMeCO ~ N~ ~ ~ \ HCI 210-2i4 ~

Me Me 23-238 -NMeCO ~ N'_\ / \ 212-214 ~

Me Me 23-239 -NMeCO ~ N _\ ~ \ 2HC1 206-210 ~

Me Me 23-240 -NHCO ~ ~ N~ \ ~ ~ HCI 285-287 Me Me 23-241 -NHCO ~ N N~ ~ ~ \ 2HC1 264-269 Me Me 23-242 -NHCH2Me N _\ ~ \ 179-182 M

e 23-243 -NHCO ~ N N _\ Me3C ~ ~ 2HC1 327-329 23-244 -NHCO ~ N N _\ Me ~ ~ . 293-295 Me Table 24 Rb~N Ra Rc Reference Example A R8 Rb Rc additives m' ~'' ~ ~
Compound 23-245 -NHCO N~ N _~ Me3C ~ ~ 245-247 Me 23-246 -NHCO N~ N ~~ / ~ 269-270 Me 23-247 -NHCO N / N_~ Me3C ~ ~ 171-173 23-248 -NMeCO ~ / N~-- Me0 ~ ~ 141-142 23-249 -NMeCO ~ / N ~~ Me0 ~ ~ HCt 194-196 23-250 -NMeCO ~ ~ N ~ Me0 / ~ 144-145 23 251 -NMeCO ~ N N_~ Me0 ~ ~ 2HCl 775-178 23-252 ~ ZMe N ~ Me0 ~ ~ HCI 184-187 23-253 '~ M ~ / N _~ Me0 ~ ~ 128-130 23-254 '~ 2M ~ / N~ ~ Me0 / ~ HCI 749-'!51 N
23-255 -~H ~ ~ / N ~~ Me0 ~ ~ 144-145 N
23-256 -~H M ~ / N,~ Me0 ~ ~ 2HCI 151-154 23-257 -NMeCOMe N _~ Me3C ~ ~ 186-188 Table 25 Rb~N Ra Rc Reference R R m. P C
Example b c additives A R
Compound a 23-258 -NMeCOMe N~ ~ Me3C ~ ~ HCI 189-191 23-259 -NMeCO ~ ~ N~ ~ Me3C ~ ~ 204-206 23-260 -NMeCO ~ ~ N~ ~ Me3C ~ ~ HCI 202-203 23-261 -NMeCO ~ ~ N~ ~ Me3C ~ ~ 136-138 23-262 -NMeCO ~ N N~ ~ Me3C ~ ~ 2HCI 169-17i 23-263 ~ 2Me N~ ~ Me3C ~ ~ 182-183 23-264 -NCOMe N' ~ Me3C ~ ~ HCI 184-185 ~H2Me 23-265 C N~ ~ Me3C ~ ~ 222-224 e ~

H M

23-266 C N~ ~ Me3C ~ ~ HCI 219-222 e ~

H M

N
23-267 -NCO ~ ~ N~ ~ Me3C ~ ~ 159-160 ~

G
H2Me N
23-268 -NCO ~ ~ N~ ~ MegC ~ ~ 2HCI 159-191 ~H2Me 23-269 -NHCH2Me N~ ~ Me0 ~ ~ 175-176 23-270 -NHMe N~ ~ Me3C ~ ~ 286-289 23-271 -NHCH2Me N~ ~ Me3C ~ ~ 223-225 Table 26 Rb~N~Ra Rc Reference Rb Rc additives m'p~
Example / 'C
A Ra Compound Me 23-272 CH~M a N _\ / \ 159-161 Me Me 23-273 CH2Me N' -\ / \ HCt 179-184 Me _ Me 23-274 -NCO \ / N' / \ 178-182 \

CH2Me _ '' Me !N Me 23-275 -NCO N~ \ ~ 174-778 CH2Me Me Me 23-276 -NH{CH~2Me N _\ / \ 177-180 Me Me -NCOMe 23-277 ~CH2)2Me N ,_\ / \ 130-132 M e _ Me 23-278 -NCO \ / N'r\ / \ 138-140 (CH~2Me Me .

_N Me 23-279 -NCO \ / N' / t 130-131 \

_ (CH~2Me Me Me 23-280 -NH(CH2)3MeN _\ / \ 165-168 Me Me 23-281 -NHCH2 \ N _\ ~ \ i 86-188 /

Me Me 23-282 _ N~ \ / \ 793-195 -NCHy \
/

COMB
Me Me 23-283 -NH \ N N '\ / \ 230-234 Me Table 27 ~N Ra Rc Reference Rb Rc m - P - /
Example 'C
A Re Compound _ Me 23-284 ' N' \ / \ 183-187 -N \

N
COM Me 23-285 (CHM Me N ~ \ Me0 ~ \ 137-i 38 23-28fi -NCO \ / N' -\ Me0 ~ \ 144-146 (CH~2Me N
23-287 -NCO \ ~ N' \ Me0 ~ \ 131-132 (CH~2Me 23-288 CHMe2 N~-' Me0 ~ \ i22-i24 23-289 ~CHM Me N~ \ Me3C ~ \ 142-144 23-290 -NH(CH2)2Me N~ ~ Me0 ~ \ 141-142 23-291 -NHCHMe2 N~ \ Me0 ~ \ 161-163 23-292 -NH(CH2)2Me N~ \ Me3C ~ ~ 188-191 ~23-293 -NHCO \ ~ N' ~ Me0 ~ \ 131-132 Me 23-294 ~ -NHCOMe O-N _\ ~ \ 332-334 ~ Me Table 28 R
x ~ Ra Rc Reference Rb R~ m-P- / 'C
Example A Ra Compound 23-295 -NCOCH=CH2 N ~ Me ~ \ 236-238 23-296 -NHCON \ / ~ \ Me / ~ 217-219 23-297 -NHCON \ / ~ ~ Me9 ~ \ 296-298 23-298 -NHC \ / COZMe N \ Me / ~ 304-306 23-299 -NHC \ / C02H N~ ~ Me / ~ 33235 2300 \ / SMe ~ \ Me / ~ 127-128 23-30t \ / SMe ~ ~ Meg / ~ 125-126 M

23-302 . \ / SMe N~ \ / \ 142-144 M

e 23-303 \ / SOMe ~ \ Me / ~ 169-170 2304 \ / SOMe N ~ Me9 / ~ 184-185 .

M

23-305 \ / SOMe ' \ / \ 199-201 Me 23-306 \ / S02Me ~ \ Me / ~ 211-212 23-307 \ / S02Me ~ ~ Me3 / ~ 215-217 M
23-308 \ / S02Me ' \ / \ 205-207 Me 23-309 \ / SMe N ~ / ~, 115-118 23-3i0 \ / SMe _\ C / \ 147-149 23-311 \ / SOMe ' \ / \ 186-188 23-312 \ / SOMe ' ~ C / ~ 187-189 Table 29 F~b~N~-R~
R~
Reference ~ R~ , additives m.p. j Example A R~
Compound ~-313 ~ SC32Ms N~' ~"~~~"- '~ 91 i 23314 l l ~G2Me N~--- Ci-.~-.. 202-2tt~

N1e 23-3i5 -NHC)NH-~ N' 1~T-16~

~e ~3-3't& f~RGt'~CH~CI !~'~~ Me~,C-HG! X67-~

Met?

~$-3i7 -tst~~ N~--- 2~7 2'~~

Me ~3-31 B -Nli~Ae 1~ 185-187 Me~

2331~ ~~lHCti~Rs N' p 2~7250 ~

M

2.3~32#x -I~IHGH2-~ I~ fl 179-1$3 ~' 23-32t -NHCO~H-N~ ~ ! ~ HCI 23Z»236 Cf 2~-3~ -t~HCDC1-f~ N~~, N~ ~' " Me~C"'~' 23~-X35 -3~3 .-NhiCt3CH-~ N'~~ ~~ ! ~ ~33"~34 l~~Ae~

-N~1COCH~
N M~O~ 1 ~'S-1 ~6 ~
~--~
-.

~'3 325 -NHC~1~NH N' '~ M~~~1-22~
a Table 30 Rb~ N Ra Rc Reference Rb R~ m, p . ~
Example ~
A Ra Compound M
2326 \ / SMe ~ M / \ 159-161 _ , M
23-327 \ / SOMe N~ M / \ 161-164 _ M
2328 \ / SOzAAe _\ M / \ 194-196 23-329 -NHCOCH20H N ~ Me ~ \ 228-230 23-330 -NHCOCH20H N \ Mes / ~ 261-263 23-331 -NHC \ / C02Na ~ \ Me / \ 386-389 M

23-332 -NHC \ / COzMe N \ / \ 300-303 M

e M

23-333 -NHC \ / C02Na ~ \ / \ 393-395 M

e _ M
-NC \ / \ / 23-125 \

23-334 . _ (CH~2C02CH~II M a a M
' \ 161-163 -NC~ / \

Me Me (CH~2C02 H2 M

23-336 -NH(CH~2C02CH2MeN~ ~ / \ 161-162 Me M

23-337 -NHC \ / C02H ~ ~ / \ 347-349 Me _ M
338 NC \ / ~ \ / \ 166-167 - CH2C02CH2Me Me Table 31 Rb Ra Rc Reference Rb Rc m - P - /
Example C
A Ra Compound M
339 NC ~ N ~ ~ / \ 146-147 CHZC02CH2Me Me M

23-340 -NHCH2C02CH2Me ~ ~ / \ 142-143 Me C02Me , M
N~ / \ 53-256 _NHC \ /
Me C02H , M
I~- / \ 350-353 -NH \ /
Me C02Na . , M
/ \ 257-261 _NHC \ /

Me M

23-344 -NHC \ / CI ~ ~ / \ 276-279 Me M
H _ ~ \ / \

23-345 _NHC \ /
Me M
23-346 -NH(CH~2C02CH2 \ / ~ \ / \ 149-150 Me _ M
\ / \ 175-177 23-347 -NHCON \
_ ~ M
23-348 -NHCO \ / C02Me ~ / \ 272-274 _ ~\ M
23-349 -NHC , \ / CO2H / \ 341-343 Reference Example A 23-128 N-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]acetamide To a solution of [4- (3, 5-dimethylphenyl) -5- (4-pyridyl) -1,3-thiazol-2-yl]amine (0.50 g, 1.78 mmol) and 4-dimethylaminopyridine (0.06 g, 0.51 mmol) in N,N-dimethylacetamide (5 mL) was added acetyl chloride (0.21 g, 2.67 mmol) and the mixture was stirred at 80°C for 14 h. To the reaction mixture was poured aqueous sodium io hydrogencarbonate. The precipitated solid was collected by filtration. The obtained solid was washed with water and dried.
The crude crystals were recrystallized from ethanol to give the title compound (0.17 g, yield 29%).
m. p. : 284-286°C.
Reference Example A 23-133 [4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine To a solution of 2-bromo-1-(3,5-dimethylphenyl)-2-(4-pyridyl)ethanone hydrobromide (5.0 g, 13 mmol) and thiourea (1.0 g, 14 mmol) in acetonitrile (60 mL) was added dropwise 2o triethylamine (1.9 ml, 14 mmol) and the mixture was stirred at room temperature for 3 h. The solvent was concentrated under reduced pressure and a saturated aqueous sodium hydrogencarbonate solution was added to the residue. The mixture was extracted with ethyl acetate. The organic layer 2s was washed with water and the solvent was evaporated. The obtained crude crystals were recrystallized from ethyl acetate to give the title compound (2.0 g, 7.2 mmol, yield 55%).
m.p.: 242-244°C.
Reference Example A 23-137 so N- [4- [4- (1,1-dimethylethyl) phenyl] -5- (4-pyridyl) -1, 3-thiazol-2-yl]acetamide To a solution of [4-[4-(1,1-dimethylethyl)phenyl]-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (0.40 g, 1.29 mmol) and 4-DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

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Claims (26)

1. An agent for the prophylaxis or treatment of pain and/or suppression of activation and/or inhibition of formation of osteoclast, which contains a p38 MAP kinase inhibitor and/or a TNF-.alpha., production inhibitor.
2. The agent of claim 1 for the prophylaxis or treatment of pain, which contains a p38 MAP kinase inhibitor and/or a TNF-.alpha., production inhibitor.
3. The agent of claim 1 for the suppression of activation and/or inhibition of formation of osteoclast, which contains a p38 MAP kinase inhibitor and/or a TNF-.alpha. production inhibitor.
4. The agent of claim 1, wherein the p38 MAP kinase inhibitor and/or the TNF-.alpha. production inhibitor are/is a 1,3-thiazole compound substituted at the 5-position by a pyridyl group optionally having substituents, or a salt thereof or a prodrug thereof.
5. The agent of claim 1, wherein the p38 MAP kinase inhibitor and/or the TNF-.alpha. production inhibitor are/is a compound represented by the formula:

wherein R1 represents a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino group optionally having substituents or an acyl group;
R2 represents a pyridyl group optionally having substituents; and R3 represents an aromatic group optionally having substituents, a salt thereof or a prodrug thereof.
6. The agent of claim 1, wherein the p38 MAP kinase inhibitor and/or the TNF-.alpha. production inhibitor are/is an optionally N-oxidized compound represented by the formula:

wherein R1a represents a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino group optionally having substituents or an acyl group;
R2a represents an aromatic group optionally having substituents;
R3a represents a hydrogen atom, a pyridyl group optionally having substituents or an aromatic hydrocarbon group optionally having substituents;
X a represents an oxygen atom or an optionally oxidized sulfur atom;
Y a represents a bond, an oxygen atom, an optionally oxidized sulfur atom or a group represented by the formula: NR4a (wherein R4a represents a hydrogen atom, a hydrocarbon group optionally having substituents or an acyl group); and Z a represents a bond or a divalent acyclic hydrocarbon group optionally having substituents, or a salt thereof, or a prodrug thereof.
7. The agent of claim 1, wherein the p38 MAP kinase inhibitor and/or the TNF-.alpha. production inhibitor are/is a compound represented by the formula:

wherein a is N or C;
b is CH when a is N, or O when a is C;
~ denotes a single or a double bond dependent upon whether the azole ring is an imidazole ring or an oxazole ring;
Z b is N or CH;
W b is -NR6b-Y b- , -O- or -S- , where R6b is a hydrogen atom, C1-4 alkyl group, C3-8 cycloalkyl group, C3-8 cycloalkyl-C1-3 alkyl group, C6-18 aryl group, C3-18 heteroaryl group, C7-19 aralkyl group or C4-19 heteroaralkyl group, and -Y b- is C1-4 alkylene group or a bond;
R2b is phenyl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, trifluoromethyl, cyano, amido, thioamido, carboxylate, thiocarboxylate, C1- alkoxy, C1-4 alkyl, amino, and mono- or di-C1-4 alkylamino;
R3b is a hydrogen atom, a halogen atom, C1-10 alkyl group, C2-4 alkenyl group, C3-10 cycloalkyl group, C3-18 heterocycloalkyl group, C6-18 aryl group, C3-18 heteroaryl group or -CH=N-NH-C(NH)NH2 (wherein C1-10 alkyl group, C2-4 alkenyl group, C3-10 cycloalkyl group, C3-18 heterocycloalkyl group, C6-18 aryl group, C3-18 heteroaryl group and -CH=N-NH-C(NH)NH2 are each optionally substituted by 1 to 4 substituents selected from the group consisting of C1-4 alkyl optionally substituted by hydroxy, halogen atom, halo-substituted-C1-4 alkyl, hydroxy, C1-4 alkoxy, C1-4 alkylthio, carboxy, carbonyl optionally substituted by C1-6 alkyl or C1-6 alkoxy, amino, mono- or di-C1-4 alkylamino and 5- to 7- membered N-heterocyclic group optionally further containing heteroatom(s)); and R5b is C6-18 aryl group, C3-18 heteroaryl group or C3-12 cycloalkyl group each of which is optionally substituted by 1 to 4 substituents selected from the group consisting of C1-4 alkyl, halogen, halo-substitued-C1-4 alkyl, hydroxy, C1-4 alkoxy, C1-4 alkylthio, amino, mono-or di-C1-4 alkylamino and 5- to 7-membered N-heterocyclic group optionally further containing heteroatom(s), or a salt thereof or a prodrug thereof.
8. The agent of claim 1, wherein the p38 MAP kinase inhibitor and/or the TNF-.alpha. production inhibitor is a 1,3-thiazole compound substituted at the 5-position by a 4-pyridyl group having substituents free of aromatic group, or a salt thereof or a prodrug thereof.
9. The agent of [8], wherein the 1,3-thiazole compound is a compound represented by the formula:

wherein R1c is a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino group optionally having substituents or an acyl group;

R2c is a 4-pyridyl group having substituents free of aromatic group; and R3c is an aromatic group optionally having substituents, or a salt thereof.
10. The agent of claim 1, wherein the p38 MAP kinase inhibitor and/or the TNF-.alpha., production inhibitor is a 1,3-thiazole compound substituted at the 5-position by a pyridyl group having substituents free of aromatic group at a position next to a nitrogen atom of the pyridyl group, or a salt thereof, or a prodrug thereof.
11. The agent of claim 10, wherein the 1,3-thiazole compound is a compound represented by the formula:
wherein R1d is a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino group optionally having substituents or an aryl group;
R2d is a pyridyl group having substituents free of aromatic group at a position next to a nitrogen atom of the pyridyl group; and R3d is an aromatic group optionally having substituents;
or a salt thereof.
12. The agent of claim 1, wherein the p38 MAP kinase inhibitor and/or the TNF-.alpha., production inhibitor are/is a 1,3-thiazole compound substituted at the 5-position by a 4-pyridyl group having substituents free of aromatic group at a position next to a nitrogen atom of the 4-pyridyl group, or a salt thereof or a prodrug thereof.
13. The agent of claim 1, wherein the p38 MAP kinase inhibitor and/or the TNF-.alpha., production inhibitor are/is N-[5-(2-benzoylamino-4-pyridyl)-4-(3,5-dimethylphenyl)-1,3-thiazol-2-yl]acetamide, N-[5-(2-benzylamino-4-pyridyl)-4-(3,5-dimethylphenyl)-1,3-thiazol-2-yl]acetamide, N-[4-[4-(4-methoxyphenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide, N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide, N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide, N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide, N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide, N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide, N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide, N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide, N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-(4-methoxyphenyl)propionamide, N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-4-phenylbutyramide, N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide, N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide, N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl)benzamide, N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide, N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl)benzamide, N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl)-3-phenylpropionamide, N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide, N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide, N-benzyl-N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine, N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine, N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine, N-benzyl-N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]amine, N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine, N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine, N-benzyl-N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine, N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine, N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine, N-benzyl-N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl)amine, N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine, N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine, N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide, N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide, N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide, N-benzyl-N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine, N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine, N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine, N-(4-fluorobenzyl)-N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine, (S)-N-[4-(3-methylphenyl)-5-(2-(1-phenylethylamino)-4-pyridyl)-1,3-thiazol-2-yl]nicotinamide, (R)-N-[4-(3-methylphenyl)-5-(2-(1-phenylethylamino)-4-pyridyl)-1,3-thiazol-2-yl]nicotinamide, (S)-N-[4-(3-methylphenyl)-5-(2-(1-phenylethylamino)-4-pyridyl)-1,3-thiazol-2-yl]-2-methylnicotinamide, (R)-N-[4-(3-methylphenyl)-5-(2-(1-phenylethylamino)-4-pyridyl)-1,3-thiazol-2-yl]-2-methylnicotinamide, (S)-N-[4-(3-methylphenyl)-5-(2-(1-phenylethylamino)-4-pyridyl)-1,3-thiazol-2-yl]-2-chloronicotinamide, (R)-N-[4-(3-methylphenyl)-5-(2-(1-phenylethylamino)-4-pyridyl)-1,3-thiazol-2-yl]-2-chloronicotinamide, (S)-N-[4-(3-methylphenyl)-5-(2-(1-phenylethylamino)-4-pyridyl)-1,3-thiazol-2-yl]-2-methoxynicotinamide, (R)-N-[4-(3-methylphenyl)-5-(2-(1-phenylethylamino)-4-pyridyl)-1,3-thiazol-2-yl]-2-methoxynicotinamide, N-[5-(2-benzylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]nicotinamide, N-[5-(2-benzylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]-2-methoxynicotinamide, N-[5-(2-benzylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]-2-chloronicotinamide, N-[5-(2-benzylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]-2-methylnicotinamide, N-[5-(2-benzoylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]nicotinamide, N-[5-(2-benzoylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]-2-methylnicotinamide, N-[5-(2-benzoylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]-2-chloronicotinamide, N-[5-(2-benzoylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]-2-methoxynicotinamide, (S)-N-(1-phenylethyl)-4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine, (R)-N-(1-phenylethyl)-4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine, (S)-N-(1-phenylethyl)-4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridylamine, (R)-N-(1-phenylethyl)-4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridylamine, (S)-N-(1-phenylethyl)-4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine, (R)-N-(1-phenylethyl)-4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine, (S)-N-(1-phenylethyl)-4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridylamine, (R)-N-(1-phenylethyl)-4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridylamine, (S)-N-(1-phenylethyl)-4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine, (R)-N-(1-phenylethyl)-4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine, (S)-N-(1-phenylethyl)-4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine, (R)-N-(1-phenylethyl)-4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine, or a salt thereof.
14. The agent of claim 3, which is an agent for the prophylaxis or treatment of (1) postmonopausal or senile primary osteoporosis, (2) secondary osteoporosis caused by inflammation, blood system malignant disease, endocrine disorder or administration of pharmaceutical agent, (3) bone or joint tissue destruction or deforming associated with bone metastasis of tumor or rheumatism,(4) Paget's disease or(5) hypercalcemia.
15. A method for the prophylaxis or treatment of pain, which comprises administering an effective amount of p38 MAP kinase inhibitor and/or the TNF-.alpha. production inhibitor to a mammal.
16. A method for the suppression of activation and/or inhibition of formation of osteoclast, which comprises administering an effective amount of p38 MAP kinase inhibitor and/or the TNF-.alpha., production inhibitor to a mammal.
17. A method for the prophylaxis or treatment of(1) postmonopausal or senile primary osteoporosis,(2) secondary osteoporosis caused by inflammation, blood system malignant disease, endocrine disorder or administration of pharmaceutical agent,(3) bone or joint tissue destruction or deforming associated with bone metastasis of tumor or rheumatism,(4) Paget's disease or(5) hypercalcemia, which comprises administering an effective amount of p38 MAP kinase inhibitor and/or the TNF-.alpha. production inhibitor to a mammal.
18. Use of a p38 MAP kinase inhibitor and/or a TNF-.alpha.
production inhibitor for the production of an agent for the prophylaxis or treatment of pain.
19. Use of a p38 MAP kinase inhibitor and/or a TNF-.alpha.
production inhibitor for the production of an agent for the suppression of activation and/or inhibition of formation of osteoclast.
20. Use of a p38 MAP kinase inhibitor and/or a TNF-.alpha.
production inhibitor for the production of an agent for the prophylaxis or treatment of (1) postmonopausal or senile primary osteoporosis, (2) secondary osteoporosis caused by inflammation, blood system malignant disease, endocrine disorder or administration of pharmaceutical agent, (3) bone or joint tissue destruction or deforming associated with bone metastasis of tumor or rheumatism, (4) Paget's disease or (5) hypercalcemia.
21. A method for reducing a P450 inhibitory action of a compound containing a pyridyl group or a salt thereof, which comprises introducing a substituent into the .alpha.-position of a nitrogen atom of the pyridyl group of the compound or a salt thereof.
22. A method far reducing a P450 inhibitory action of a compound containing a pyridyl group and an aromatic hydrocarbon group, or a salt thereof, which comprises introducing a polar group into the aromatic hydrocarbon group of the compound or a salt thereof.
23. The method of claim 22, further comprising introducing a substituent into the .alpha.-position of a nitrogen atom of the pyridyl group.
24. The method of claim 21 or 22, wherein the P450 is CYP2C9, CYP2D6 or CYP3A4.
25. The method of claim 21 or 23, wherein the substituent is 1 to 3 selected from (i) halogen atom, (ii) C1-6 alkyl group, C2-6 alkenyl group, C2-6 alkynyl group, C3-6 cycloalkyl group, C6-14 aryl group and C7-16 aralkyl group [these groups may have 1 to 5 substituents selected from a group consisting of oxo, halogen atom, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C2-6 alkenyl, carboxy C2-6 alkenyl, optionally halogenated C2-6 alkynyl, optionally halogenated C3-6 cycloalkyl, C6-14 aryl, optionally halogenated C1-8 alkoxy, C1-6 alkoxy-carbonyl-C1-6 alkoxy, hydroxy, C6-14 aryloxy, C7-16 aralkyloxy, mercapto, optionally halogenated C1-6 alkylthio, C6-14 arylthio, C7-16 aralkylthio, amino, mono-C1-6 alkylamino, mono-C6-14 arylamino, di-C1-6 alkylamino, di-C6-14 arylamino, formyl, carboxy, C1-6 alkyl-carbonyl, C3-6 cycloalkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, C6-14 aryloxy-carbonyl, C7-14 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, carbamoyl, thiocarbamoyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-14 aryl-carbamoyl, 5- or 6-membered heterocyclic carbamoyl, C1-14 alkylsulfonyl, C6-14 arylsulfonyl, C1-6 alkylsulfinyl, C6-14 arylsulfinyl, formylamino, C1-6 alkyl-carbonylamino, C6-14 aryl-carbonylamino, C1-6 alkoxy-carbonylamino, C1-6 alkylsulfonylamino, C6-14 arylsulfonylamino, C1-6 alkyl-carbonyloxy, C6-14 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-14 aryl-carbamoyloxy, nicotinoyloxy, 5- to 7-membered saturated cyclic amino containing1 to 4 of 1 or 2 kinds of hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, besides one nitrogen atom and carbon atom (this cyclic amino may have substituents selected from the group consisting of C1-6 alkyl, C6-14 aryl, C1-6 alkyl-carbonyl, 5- to 10-membered aromatic heterocyclic group and oxo), and 5-to 10-membered aromatic heterocyclic group, containing1 to 4 of 1 or 2 kinds of hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, besides carbon atom, sulfo, sulfamoyl, sulfinamoyl and sulfenamoyl (substituent group A)], (iii) 5- to 14-membered heterocyclic group containing1 to 4 of 1 or 2 kinds of hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, besides carbon atom, which may have 1 to 3 substituents selected from substituent group A, (iv) acyl group represented by the formula: -(C=O)-R5, -(C=O)-OR5, -(C=O)-NR5R6, -(C=S)-NHR5 or -SO2-R7 wherein R5 is (1) hydrogen atom, (2) C1-6 alkyl group, C2-6 alkenyl group, C2-6 alkynyl group, C3-6 cycloalkyl group, C6-14 aryl group or C7-16 aralkyl group, which may have 1 to 3 substituents selected from substituent group A or (3) 5- to 14-membered heterocyclic group containing1 to 4 of 1 or 2 kinds of hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, besides carbon atom, which may have 1 to 3 substituents selected from substituent group A, R6 is hydrogen atom or C1-6 alkyl group, and R7 is (1) C1-6 alkyl group, C2-6 alkenyl group, C2-6 alkynyl group, C3-6 cycloalkyl group, C6-14 aryl group or C7-16 aralkyl group, which may have 1 to 3 substituents selected from substituent group A or (3) 5- to 14-membered heterocyclic group containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, besides carbon atom, which may have 1 to 3 substituents selected from substituent group A, (v) amino group (this amino group may have 1 or 2 substituents selected from (1) C1-6 alkyl group, C2-6 alkenyl group, C2-6 alkynyl group, C3-6 cycloalkyl group, C6-14 aryl group or C7-16 aralkyl group, which may have 1 to 3 substituents selected from substituent group A, (2) 5- to 14-membered heterocyclic group containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, besides carbon atom, which may have 1 to 3 substituents selected from substituent group A, and (3) acyl group shown by the above-mentioned (iv)), (vi) 5- to 7-membered non-aromatic cyclic amino group containing1 to 4 of 1 or 2 kinds of hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, besides one nitrogen atom and carbon atom, (this cyclic amino group may have 1 to 3 substituents selected from C1-6 alkyl, C6-14 aryl, C1-6 alkyl-carbonyl, 5- to 10-membered aromatic heterocyclic group and oxo), and (vii) C1-6 alkoxy group, C6-14 aryloxy group and C7-16 aralkyloxy group, which may have 1 to 3 substituents selected from substituent group A.
26. The method of claim 22, wherein the polar group is 1 to 3 selected from (1) halogen atom, (2) hydroxy, (3) amino optionally having 1 or 2 substituents selected from a substituent selected from substituent group A and acyl shown by the above-mentioned (iv), (4) nitro, (5) carboxy, (6) formyl, (7) C1-6 alkoxy optionally having 1 to 3 substituents selected from substituent group A, (8) C1-6 alkoxy-carbonyl optionally having 1 to 3 substituents selected from substituent group A, (9) cyano and (10) C1-6 alkyl or C6-14 aryl having 1 to 3 groups from the above-mentioned (1)-(9) as substituents.
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