WO2001074811A2

WO2001074811A2 - Substituted 1,3-thiazole compounds, their production and use

Info

Publication number: WO2001074811A2
Application number: PCT/JP2001/002629
Authority: WO
Inventors: Shigenori Ohkawa; Ken-Ichi Naruo; Seiji Miwatashi; Hiroyuki Kimura
Original assignee: Takeda Chemical Industries Ltd
Current assignee: Takeda Pharmaceutical Co Ltd
Priority date: 2000-03-30
Filing date: 2001-03-29
Publication date: 2001-10-11
Anticipated expiration: 2002-09-30
Also published as: EP1268474A2; WO2001074811A3; US7495018B2; AU2001244618A1; CA2404384A1; US20040053973A1

Abstract

(1) A 1,3-thiazole compound of which the 5-position is substituted with a 4-pyridyl group having a substituent including no aromatic group or (2) a 1,3-thiazole compound of which the 5-position is substituted with a pyridyl group having at the position adjacent to a nitrogen atom of the pyridyl group a substituent including no aromatic group has an excellent p38 MAP kinase inhibitory activity.

Description

DESCRIPTION Substituted 1 , 3-thiazole Compounds , Their Production and Use

Technical Field

The present invention relates to an excellent p38 MAP kinase inhibitor, a TNF-α production inhibitor, an adenosine receptor antagonist, and a selective phosphodiesterase IV (PDE IV) inhibitor and the like. More specifically, the present invention relates to a pharmaceutical composition comprising a 1,3-thiazole- based compound having an activity to prevent and/or treat cytokine-mediated diseases based on a p38 MAP kinase inhibiting activity, a TNF-α production inhibiting activity, a phosphodiesterase (PDE) inhibiting activity and the like, and to prevent and/or treat adenosine receptor mediated diseases based on an adenosine receptor antagonising activity.

Background

Cytokines such as TNF-α (tumor necrosis factor- α) , IL-1 (interleukin-1) and the like are biological substances produced by various cells such as monoσytes, macrophages and the like in response to cellular stress such as infection and the like (Koj, A. , Biochim. Biophys. Acta, 1317, 84-94 (1996)). These cytokines play an important role in immune reactions when they are present in an appropriate amount, while it is believed that excess production thereof is related to a lot of inflammatory diseases (Dinarello, C.A., Curr. Opin. Immunol., 3, 941-948 (1991)). A p38 MAP kinase cloned as a homologue of a MAP kinase is concerned with control of the production of these cytokines, and with a signal transfer system coupled with a receptor, so inhibition of a p38 MAP kinase provides a possibility of a remedy for inflammatory diseases (Stein, B., Anderson, D., Annual Report in Medicinal Chemistry, Bristol, J. A. (ed.). Academic Press , 31, pp. 289 to 298, (1996)).

As examples having such a p38 MAP kinase inhibiting activity, imidazole derivatives are described in JP-A 7-50317 (WO 93/14081) and oxazole derivatives are described in JP-A 9-505055 (WO 95/13067), respectively.

On the other hand, as a thiazole-based compound, the following compounds, etc. are known.

1) 1,3-thiazole derivatives of the formula:

wherein R¹ represents a cycloalkyl group, a cyclic amino group, an amino group optionally having one or two lower alkyls, phenyls, acetyls or lower alkoxycarbonylacetyls as a substituent, an alkyl group optionally having hydroxyl, σarboxyl or lower alkoxycarbonyl as a substituent , or a phenyl group optionally having carboxyl , 2-carboxyethenyl or 2-carboxy-l-propenyl as a substituent, R² represents a pyridyl group optionally having a lower alkyl as a substituent, and R³ represents a phenyl group optionally having a lower alkoxy, lower alkyl, hydroxyl, halogen or methylenedioxy as a substituent, or a salt thereof, having analgesic, antipyretic, anti-inflammatory, antiulσer, thromboxane A₂ (TXA₂) synthase inhibitory, and antithrombotic activities (JP-A No. 60-58981).

2) 1,3-thiazole derivatives of the formula:

wherein R¹ represents an alkyl group, alkenyl group, aryl group, aralkyl group, cycloalkyl group, heterocyclic group having carbon as a connecting moiety, or amino group , R represents a pyridyl group optionally substituted with an alkyl group, and R³ represents a phenyl group optionally having a substituent , or a salt thereof , having analgesic , antipyretic, anti-inflammatory, antiulcer, TXA₂ synthase inhibitory, and antithrombotic activities (JP-A No. 61-10580) .

3) 1,3-thiazole derivatives of the formula:

wherein R¹ represents an alkyl group, alkenyl group, aryl group, aralkyl group, cycloalkyl group, heterocyclic group having carbon as a connecting moiety, or amino group, R² represents a pyridyl group optionally substituted with an alkyl group, and R³ represents an aryl group optionally having a substituent , or a salt thereof , having analgesic , antipyretic, anti-inflammatory, antiulcer, TXA₂ synthase inhibitory, and antithrombotic activities (USP 4,612,321) .

4) Compounds of the formula:

wherein R¹ represents phenyl optionally having a substituent, R² represents a C_x_₆ alkyl or (CH₂)_nAr (n is

0 to 2, and Ar is phenyl optionally having a substituent) ,

R³ represents hydrogen or C_x_₄ alkyl, R⁴ represents hydrogen,

Ci.₄ alkyl or the like, R⁵ represents hydrogen or C₁.₄ alkyl, and R⁶ represents hydrogen, C_1-4 alkyl or the like, or a salt thereof, having a gastric acid secretion inhibitory activity (JP-A No. 7-503023, WO 93/15071).

5) Compounds of the formula:

wherein R¹ represents pyridyl or the like, R² represents phenyl or the like, R³ and R⁴ represent hydrogen or methyl, R^s represents methyl or the like, and R⁶ represents hydrogen, methyl or the like, or a salt thereof, which are an anti-inflammatory agent and antiallergic agent (DE-A-3601411) .

6) Compounds of the formula:

wherein R¹ represents a lower alkyl substituted with a halogen, R² represents pyridyl or the like, and R³ represents phenyl or the like, or a salt thereof, having anti-inflammatory, antipyretic, analgesic and antiallergic activities (JP-A No. 5-70446). 7) Thiazole compounds of the formula:

wherein R represents a lower alkyl group; lower haloalkyl group; lower hydroxyalkyl group; lower alkoxy lower alkyl group; aralkyloxy lower alkyl group or the like, R¹ represents a cycloalkyl group optionally substituted with a lower alkyl group and the like, and R² represents an aryl group optionally having a substituent , or the like , or a pharmaceutically acceptable salt thereof, having a TNF-α selective production inhibitory activity and/or IFN-γ production inhibitory activity (JP-A No.11-49762). There is a strong need to develop compounds having an excellent p38 MAP kinase inhibitory activity, TNF- α production inhibitory activity, adenosine receptor antagonizing activity and PDE IV inhibitory activity.

Disclosure of Invention

The present inventors have studied various compounds, and have found for the first time that 1,3-thiazole compounds having such specificity in chemical structure that the 5-position of a 1,3-thiazole skeleton is substituted with a 4-pyridyl group having a substituent including no aromatic group (hereinafter, sometimes abbreviated as compound (la)), 1,3-thiazole compounds having such specificity in chemical structure that the 5-position of a 1,3-thiazole skeleton is substituted with a pyridyl group having at the position adjacent to a nitrogen atom of the pyridyl group a substituent including no aromatic group (hereinafter, sometimes abbreviated as compound (lb)) or 1,3-thiazole compounds having such specificity in chemical structure that the 5-position of a 1,3-thiazole skeleton is substituted with a 4-pyridyl group having at the position adjacent to a nitrogen atom of the 4-pyridyl group a substituent including no aromatic group (hereinafter, sometimes abbreviated as compound (Ic)) has an unexpectedly excellent p38 MAP kinase inhibitory activity, TNF-α production inhibitory activity, adenosine receptor antagonizing activity and PDE IV inhibitory activity based on their specific chemical structure, and is excellent also in pharmaceutical properties such as stability, leading to completion of the present invention based on this knowledges. Namely, the present invention provides: [1] A 1,3-thiazole compound of which 5-position is substituted with a 4-pyridyl group having a substituent including no aromatic group, provided that the 1,3- thiazole compound is not N- [4- (3, 5-dimethylphenyl) -5- (2-hydroxy-4-pyridyl) -1, 3-thiazol-2-yl]acetamide or 4- [2- (acetylamino) -4- (3, 5-dimethylphenyl) -1 , 3-thiazol-5- yl]-2-pyridyl acetate, or a salt thereof;

[ 2 ] A compound as defined in [ 1 ] which is a compound represented by the formula:

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 of which 5-position is substituted with a pyridyl group having a substituent including no aromatic group, at a position adjacent to a nitrogen atom of the pyridyl group, provided that the 1,3-thiazole compound is not N-[4-(3,5- dimethylphenyl) -5- ( 2-hydroxy-4-pyridyl) -1 , 3-thiazol-2- yl]acetamide or 4- [2- (acetylamino) -4- (3,5- dimethylphenyl) -1, 3-thiazol-5-yl] -2-pyridyl acetate, or a salt thereof;

[ 4 ] A compound as defined in [ 3 ] which is a compound represented by the formula:

wherein R^la 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, R^2a represents a pyridyl group having a substituent including no aromatic group, at a position adjacent to a nitrogen atom of the pyridyl group, and R^3a represents an aromatic group optionally having a substituent, or a salt thereof; [5] A 1,3-thiazole compound of which 5-position is substituted with a 4-pyridyl group having a substituent including no aromatic group, at a position adjacent to a nitrogen atom of the 4-pyridyl group, provided that the 1,3-thiazole compound is not N-[4-(3,5- dimethylphenyl) -5- (2-hydroxy-4-pyridyl) -1,3-thiazol-2- yljacetamide or 4- [2- (acetylamino) -4- (3, 5- dimethylphenyl) -l,3-thiazol-5-yl] -2-pyridyl acetate, 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, C^ alkylenedioxy, nitro, cyano, C_x.₆ alkyl which may be halogenated, C₂_₆ alkenyl which may be halogenated, carboxy C₂.₆ alkenyl, C₂.₆ alkynyl which may be halogenated, C₃_.₈ cycloalkyl which may be halogenated, C₃.₈ cycloalkyl-Ci.g alkyl,

alkoxy which may be halogenated, C₁.₆ alkoxy-carbonyl-C-_L.g alkoxy, hydroxy, mercapto, C_x._β alkylthio which may be halogenated, amino, ir.ono-C._L_₆ alkylamino,

alkylamino, C₃.₈ cycloalkylamino, C₃.₈ cycloalkyl-C-_L.g alkylamino, N-C₃.₈ σycloalkyl-N-Ci.g alkylamino, formyl, carboxy, carboxy-C₂.₆ alkenyl, carboxy-Ci.₆ alkyl, C₁_₆ alkyl- carbonyl which may be halogenated, C₃.₈ cycloalkyl- carbonyl optionally substituted by C_x_₆ alkyl, C_x.₆ alkoxy-carbonyl, carbamoyl, thiocarbamoyl, mono-C^ alkyl-carbamoyl,

alkyl-carbamoyl, C_x_₆ alkylsulfonyl, C__₆ alkylsulfinyl, formylamino, C_x_₆ alkyl-carbonylamino, C₃.₈ cycloalkyl-carbonylamino which maybe substituted by C_x_₆ alkyl, C _₆ alkoxy-carbonylamino, C_λ_₆ alkylsulfonylamino, C_±_₆ alkyl-carbonyloxy, C₁_₆ alkoxy-carbonyloxy,

alkyl-σarbamoyloxy, di-Ci.g 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 selected from C₁.₆ alkyl, C_x_₆ alkyl-carbonyl andoxo), sulfo, sulfamoyl, sulfinamoyl, sulfenamoyl or a group obtained by connecting 2 to 3 of these substituents (e.g., (i) C _₆ alkyl, (ii) amino, (iii) .₆ alkylamino, (iv) C₃_₈ cycloalkylamino , (v) 5- to 7-membered aliphatic heterocyclic amino containing 1 to 4 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 containing 1 to 4 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, C_x.₆ alkoxy, C₁_₆ alkylthio, C₁.₆ alkylsulfinyl, C_x_₆ alkylsulfonyl, C₃_₈ cycloalkyl, 5- to 7-membered aliphatic heterocyclic group containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, C_x_₆ alkyl-carbonyl, C₃.₈ cycloalkyl-carbonyl, 5- to 7- membered aliphatic heterocyclic-carbonyl containing 1 to 4 hetero atoms 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 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, C_x.₆ alkylamino, C₁_₆ alkoxy-carbonyl, C₃.₈ σycloalkoxy-carbonyl, 5- to 7-membered aliphatic heterocyclic-oxycarbonyl containing 1 to 4 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 substituent is a C^ alkyl group, a C₂_₆ alkenyl group, a C₂.₆ alkynyl group, a C₃._a cycloalkyl group, a C₆.₁₄ aryl group or a C₇.₁₆ aralkyl group, optionally having a substituent selected from Group A of substituents consisting of oxo, a halogen atom, C^ alkylenedioxy, nitro, cyano, C₁_₆ alkyl which may be halogenated, C₂.₆ alkenyl which may be halogenated, carboxy C₂.₆ alkenyl, C₂_₆ alkynyl which may be halogenated, C₃.₈ cycloalkyl which may be halogenated, C₃.₈ cyσloalkyl-C_!^ alkyl, C₆.₁₄ aryl, C₁_₈ alkoxy which may be halogenated, C^g alkoxy- carbonyl-Ci.g alkoxy, hydroxy, C₆.₁₄ aryloxy, C₇.₁₆ aralkyloxy, mercapto, C__₆ alkylthio which may be halogenated, C₆_₁₄ arylthio, C₇.₁₆ aralkylthio, amino, mono-Ci.g alkylamino, mono-C₆.₁₄ arylamino,

alkylamino, C₃.₈ cycloalkylamino , di-C₆.₁₄ arylamino, C₃.₈ cycloalkyl-Ci.j alkylamino, N-C₃.₈ cycloalkyl-N-C-_L.g alkylamino, formyl, carboxy, C_x.₆ alkyl-carbonyl which may be halogenated, C₃.₈ cycloalkyl-carbonyl optionally substituted by C₁_₆ alkyl, C_x__& alkoxy-carbonyl, C₆.₁₄ aryl-carbonyl, C₇.₁₆ aralkyl-carbonyl, C₆.₁₄ aryloxy- carbonyl, C₇.₁₆ 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 ,

alkyl-carbamoyl, alkyl-carbamoyl, mono-C₆.₁₄ aryl-carbamoyl, di-C₆.₁₄ 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, C_x.₆ alkylsulfonyl, C₆.₁₄ arylsulfonyl, Q.₁_₆ alkylsulfinyl, C₆._X4 arylsulfinyl, formylamino, C__₆ alkyl-carbonylamino, C₃_₈ cycloalkyl- carbonylamino optionally substituted by C_x_₆ alkyl, C₆_ ₁₄ aryl-carbonylamino, C_x_₆ alkoxy-carbonylamino, C _.₆ alkylsulfonylamino, C₆_₁₄ arylsulfonylamino, C_x.₆ alkyl- carbonyloxy, C₆_₁₄ aryl-carbonyloxy, C_x_₆ alkoxy- carbonyloxy,

alkyl-carbamoyloxy,

alkyl-σarbamoyloxy, mono-C₆.₁₄ 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 an oxygen atom in addition to carbon atoms (this heterocyclic group optionally has a substituent selected from C-^g alkyl, C₆_₁₄ aryl, C-^g alkyl-carbonyl which may be halogenated, 5- to 10- 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 and oxo), sulfo, sulfamoyl, sulfinamoyl, sulfenamoyl and a group formed by connecting 2 to 3 of these substituents (e.g., (i)

alkyl, (ii) C₆.₁₄ aryl, (iii) amino, (iv)

alkylamino, (v) C₃.₈ σycloalkylamino, (vi) C₆.₁₄ arylamino, (vii) 5- to 7-membered heterocyclic amino containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, (viii)

alkyl-carbonyl amino, (ix) C₃-₈ cycloalkyl-carbonylamino, (x) C₆._α4 aryl- carbonylamino or (xi) 5- to 7-membered heterocyclic- carbonyl amino containing 1 to 4 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, C₁.₆ alkoxy, C₆.₁₄ aryloxy,

alkylthio, C₆.₁₄ arylthio,

alkylsulfinyl, C₆.₁₄ arylsulfinyl,

alkylsulfonyl, C₆.₁₄ arylsulfonyl, C₃_₈ cycloalkyl, 5- to 7-membered heterocyclic group containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, C₆.₁₄ aryl, C__₆ alkyl-carbonyl, C₃-₈ cycloalkyl-carbonyl, 5- to 7-membered heterocyclic-carbonyl containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, C₆.₁₄ aryl-carbonyl, C₃.₈ cycloalkoxy, 5- to 7-membered heterocyclic-oxy containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms,

alkylamino, C₆.₁₄ arylamino,

alkoxy-carbonyl, C₃_₈ cycloalkoxy-carbonyl, 5- to 7- membered heterocyclic-oxycarbonyl containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, C₆.₁₄ aryloxycarbonyl , etc.)

(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=0)-R^5a, -(C=0)-OR^5a, -(C=0)-NR^5aR^6a, - (C=S) -NHR^5a, - (C=0)-N(OR^5a)R^6a, -(C=S)-NHOR^5a or -S0₂-R^7a (wherexn R^5a represents φ a hydrogen atom, (2) a C__₆ alkyl group, a C₂.₆ alkenyl group , a C₂.₆ alkynyl group , a C₃_₈ cycloalkyl group , a C₆_₁₄ aryl group or a C₇_₁₆ aralkyl group, optionally having a substituent selected from Group A of substituents, or (3) 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, R^6a represents a hydrogen atom or a

alkyl group, and R^7a represents ® a alkyl group, a C₂.₆ alkenyl group, a C₂_₆ alkynyl group, a C₃.₈ cycloalkyl group, a C₆.₁₄ aryl group or a C₇_₁₆ aralkyl group, optionally having a substituent selected from Grou A of substituents, or © 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) ,

( 4 ) the amino group optionally having a substituent is

(i) an amino group optionally having 1 or 2 substituents selected from the group consisting of φ a alkyl group, a C₂.₆ alkenyl group, a C₂.₆ alkynyl group, a C₃.₈ cycloalkyl group, a C₆.₁₄ aryl group.and a C₇.₁₆ aralkyl group, optionally having a substituent selected from Group A of 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, ® an acyl group of the formula: -(C=0)-R^Sa, -(C=0)-OR^5a, -(C=0)-NR^5aR⁶ , -(C=S)-NHR^5a, -(C=0)- N(OR^5a)R^6a, -(C=S)-NHOR^5a or -S0₂-R^7a (wherein each symbol is as defined above), and ® a

alkylidene group optionally having a substxtuent selected from Group A of substituents, or

(ii) a 5- to 7-membered aliphatic 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 atom in addition to one nitrogen atom and carbon atoms, which optionally has a substituent selected from the group consisting of

alkyl, C₆.₁₄ aryl,

alkyl-carbonyl which may be halogenated,

alkoxy- carbonyl, 5- to 10-membered aromatic heterocyclic group containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nxtrogen 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,

alkyl which may be halogenated, C₂_₆ alkenyl which may be halogenated, carboxy C₂._s alkenyl, C₂.₆ alkynyl which may be halogenated, C₃_₈ cycloalkyl which may be halogenated, C₃-₈ cycloalkyl-C-_L.g alkyl, C_±_₈ alkoxy which may be halogenated, C_x_₆ alkoxy-carbonyl-C__₆ alkoxy, hydroxy, mercapto,

alkylthio which may be halogenated, amino, ir.ono-C._L_₆ alkylamino,

alkylamino, C₃_₈ cycloalkylamino, C₃_₈

alkylamino, N-C₃_₈ cycloalkyl-N-C-_L.g alkylamino, formyl, carboxy, carboxy-C₂_g alkenyl,

alkyl, C₁.₆ alkyl- carbonyl which may be halogenated, C₃_₈ cycloalkyl- carbonyl optionally substituted by

alkyl,

alkoxy-carbonyl, carbamoyl, thiocarbamoyl, mo o-C-_L.g alkyl-carbamoyl, alkyl-carbamoyl,

alkylsulfonyl, C₁_₆ alkylsulfinyl, formylamino,

alkyl-carbonylamino, C₃_₈ cycloalkyl-carbonylamino which may be substituted by C _₆ alkyl ,

alkoxy-carbonylamino , C₁_₆ alkylsulfonylamino , C₁_₆ alkyl-carbonyloxy,

alkoxy-carbonyloxy, raono- .j alkylcarbamoyloxy, di-C^ ₆ 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 selected from C_x_₆ alkyl,

alkyl-carbonyl andoxo), sulfo, sulfamoyl, sulfinamoyl, sulfenamoyl or a group obtained by connecting 2 to 3 of these substituents (e.g., (i) C_x_₆ alkyl, (ii) amino, (iii)

alkylamino, (iv) C₃_₈ σycloalkylamino, (v) 5- to 7-membered aliphatic heterocyclic amino containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms , (vi) C^g alkyl-carbonyl amino, (vii) C₃_₈ cycloalkyl-carbonylamino or (viii) 5- to 7- membered aliphatic heterocyclic-carbonyl amino containing 1 to 4 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,

alkoxy,

alkylthio, C_J._J alkylsulfinyl, C₁_₆ alkylsulfonyl, C₃_₈ cycloalkyl, 5- to 7-membered aliphatic heterocyclic group containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms,

alkyl-carbonyl, C₃.₈ cycloalkyl-carbonyl, 5- to 7- membered aliphatic heterocyclic-carbonyl containing 1 to 4 hetero atoms 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 heteroσyσlic- oxy containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms,

alkoxy-carbonyl, C₃_₈ cycloalkoxy-carbonyl, 5- to 7-membered aliphatic heterocyclic-oxycarbonyl containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, etc.),

(6) the aromatic group optxonally having a substituent is φ a C₆_₁₄ mono-cyclic or fused poly-cyclic aromatic hydrocarbon group optionally having a substituent selected from Group A of substituents, or © 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;

[8] A compound as defined in [2] or [4] wherein R¹ represents (i) a hydrogen atom, (ii) a C__₆ alkyl group optionally substituted by a substituent selected from the group consisting of a halogen atom,

alkoxy-carbonyl, carboxy, cyano, C ______ alkylthio,

alkylsulfinyl,

alkylsulfonyl, hydroxy,

alkoxy and

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(0)_n-R^lbb (wherein R^lbb represents a C₁_₆ alkyl group, and n represents an integer of 0 to 2), (iv) a C₇.₁₅ aralkyl group-, (v) an amino group optionally having one or two substituents selected from ® C;_L_₆ alkyl, C _₆ 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, C^ ₅ alkyl or

alkoxy, ® C₆_₁₄ aryl-carbamoyl, ©

alkyl-carbamoyl which may be halogenated, © C^g alkoxy-carbonyl which may be halogenated, CD C._L_₆ alkoxy-carbamoyl and (D C₆_₁₄ aryloxy-carbamoyl, (vi) a 5- to 10-membered heterocyclic group containxng 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,

alkyl, C₆_₁₄ aryl or C-_L.g alkoxy-carbonyl, (vii) an acyl group represented by the formula:- (C=0) -R⁵ (wherein R^sb represents a hydrogen atom, a C-_L_₆-alkyl group which may be halogenated or a C₆_₁₄ aryl group which may be halogenated) , or (viii) an acyl group represened by the formula: - (C=0) -OR^5c (wherein R^5c represents a hydrogen atom or a

alkyl grou ) ;

[9] A compound as defined in [2] or [4] wherein the substituent having no aromatic group is

(1) a C-_L.g alkyl group (this C^ alkyl may be substituted by a halogen atom, cyano, hydroxy, C₃_₈ cycloalkyl or 5- to 7-membered aliphatic heterocyclic group containing hetero atoms selected from a nxtrogen 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 ® to®; φ a

alkyl group (this C-_L_₆ alkyl group may be substituted by a halogen atom, cyano, hydroxy, C₃_₈ cycloalkyl or 5- to 7-membered aliphatic heterocyclic grou having 1 to 4 hetero atoms selected f om a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms) ,

alkyl- carbonyl group may be substxtuted by a halogen atom, cyano , hydroxy, C₃_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),

® a C-_L.g alkoxy-carbonyl group,

© a C₃_₈ cycloalkyl-carbonyl group optionally substituted by C___₆ alkyl, (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 C___₆ alkyl or

alkyl-carbonyl) ,

© 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 C-_L_₆ alkyl or C₁.₆ alkyl-carbonyl)

(4) a 5- to 7-membered aliphatic cyclic amino group optionally further containing hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms and one nitrogen atom (this aliphatic cyclic amino group may be substituted by C _ ₆ alkyl or C-_L_₆ alkyl-carbonyl) ,

(5) a hydroxy group, or

(6) a

alkyl-carbonyloxy group.

[10] A compound as defined in [2] or [4] wherein R³ is ® a C₆_₁₄ aryl group or © a 5- to 14-membered aromatic heterocyclic group preferably containing 1 to 4 of 1 or 2 kinds of hatero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, which optionally has substituents selected from the group consisting of C-_L_₆ alkyl which may be halogenated, C__₆ alkoxy, a halogen atom, carboxyl, C_x_ _s alkoxy-carbonyl, cyano, C___₆ alkylthio and C___s alkylsulfonyl;

[ 11 ] A compound as defined in [ 3 ] which is a compound of the formula:

wherein Rilb represents (i) a hydrogen atom, (ii) a C^g alkyl group optionally substituted by a substituent selected from the group consisting of a halogen atom, Ci.g alkoxy-carbonyl, carboxy, cyano, C₁_₆ alkylthio, C_ι_₆ alkylsulfinyl, Ci.g alkylsulfonyl, hydroxy, Ci_₆ alkoxy and C_ι_g 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(0)_n- _R ^ib (_R ^ib _rep_resents a Ci._g alkyl group, and n represents an integer of 0 to 2), (iv) a C₇.₁₅ aralkyl group, (v) an amino group optionally having one or two substituents selected from ® Ci_₆ alkyl, © Ci_₆ alkyl-carbonyl, ® Ci_₆ alkoxy-carbonyl, ® 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 C_ι.₆ alkoxy, © C₆__ι4 aryl-carbamoyl, © Ci_₆ alkyl-carbamoyl which may be halogenated, ® Ci.g alkoxy-carbonyl which may be halogenated, © Ci_₆ alkoxy-carbamoyl and® C₆.₁₄ 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, Ci.g alkyl, C₆.₁₄ aryl, Ci_₆ alkyl-carbonyl or Ci_ ₆ alkoxy-carbonyl, (vii) an acyl group represented by the formula: - (C=0) -R⁵ (wherein R^s represents a hydrogen atom, a Ci_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) -OR^Sc (wherein R⁵° represents a hydrogen atom or

alkyl group),

R^2b represents a pyridyl group having at the position adjacent to a nitrogen atom of the pyridyl group a substituent selected from the group consisting of

(1) a Ci.g alkyl group (this Ci_₆ alkyl group may be substituted by a halogen atom, cyano, hydroxy, C₃.₈ 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 ® to ®;

® a Ci_₆ alkyl group (this C_ι_₆ alkyl group may be substituted by a halogen atom, cyano, hydroxy, C₃_₈ 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) ,

® a Ci_₆ alkyl-carbonyl group (this Ci_₆ alkyl- carbonyl group may be substituted by a halogen atom, cyano , hydroxy, C₃_₈ 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),

® a Ci_₆ alkoxy-carbonyl group,

© 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 Ci_₆ alkyl or C_ι_₆ alkyl-carbonyl) ,

© 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 Ci_₆ alkyl or Ci_₆ alkyl-carbonyl) , (4) a 5- to 7-membered aliphatic 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 Ci_ ₆ alkyl or C₁_₆ alkyl-carbonyl) ,

( 5 ) a hydroxy group, and

(6) a Ci_₆ alkyl-carbonyloxy group, and

R^3b represents ® a C₆_₁₄ aryl group or © a 5- to 14-membered aromatic heterocyclic group containing 1 to 4 of 1 or 2 kinds of hatero 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_₆ alkyl which may be halogenated, C_ι_₆ alkoxy, a halogen atom, carboxyl, Ci_ ₆ alkoxy-carbonyl, cyano, Ci_₆ alkylthio and Ci_₆ alkylsulfonyl, or a salt thereof;

[12] A compound as defined in [11] wherein the pyridyl group is a 4-pyridyl group;

[13] A compound as defined in [11] wherein R^lb is a C-_L.g alkyl group optionally having a substituent selected from the group consisting of a halogen atom, hydroxy, Ci_₆ alkoxy, Ci_₆ alkylthio, Ci.g alkylsulfinyl and C-_L_₆ alkylsulfonyl, R^2b is a 4-pyridyl group having a C_x.₆ alkyl-carbonyl-amino group or a C₃_₈ cycloalkylamino group at the position adjacent to a nitrogen atom of the 4- pyridyl group, R^3b is a C₆.₁₄ aryl group which optionally has a substituent selected from the group consisting of Ci.g alkyl and a halogen atom;

[14] A compound as defined in [11] wherein R^lb is a C_ι_₃ alkyl group optionally having a substituent selected from the group consisting of a halogen atom, hydroxy, C___₆ alkoxy, Ci_₆ alkylthio, Ci_₆ alkylsulfinyl and Ci_₆ alkylsulfonyl, R^2b is a 4-pyridyl group having a Ci_₃ alkyl-carbonyl-amino group or a C₃.₈ cycloalkylamino group at the position adjacent to a nitrogen atom of the 4- pyridyl group, R^3b is a phenyl group which optionally has a substituent selected from the group consisting of methyl and 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 (Example 3),

[4- ( S-^methylphenyl) -5- ( 2-methyl-4-pyridyl) -1,3- thiazol-2-yl]amine (Example 7-4),

2-ethyl-5-(2-fluoro-4-pyridyl) -4- (3- methylphenyl) -1, 3-thiazole (Example 11),

5- ( 2-fluoro-4-pyridyl) -4- ( 3-methylphenyl) -2- [ 4- (methylthio)phenyl] -1,3-thiazole (Example 15),

4- (3-methylphenyl) -5- (2-methyl-4-pyridyl) -2- [4- (methylthio)phenyl] -1,3-thiazole (Example 16-1),

4- [ 2-ethyl-4- ( 3-methylphenyl) -1 , 3-thiazol-5- yl] -2-pyridylamine (Example 22),

N- [ 4- [ 2-ethyl-4- ( 3-methylphenyl) -1 , 3-thiazol-5- yl] -2-pyridyl]acetamide (Example 29-2),

N- [4- [2-ethyl-4- (3-methylphenyl) -1,3-thiazol-5- yl] -2-pyridyl]propionamide (Example 29-4),

N-[4-[4-(3-chlorophenyl) -2-methyl-1,3-thiazol- 5-yl] -2-pyridyl] acetamide (Example 30-1),

N- [ 4- [ 4- ( 3-chlorophenyl) -2-ethyl-1,3-thiazol-5- yl] -2-pyridyl]acetamide (Example 30-2),

N- [4- [4-(3-chlorophenyl)-2-propyl-l,3-thiazol- 5-yl] -2-pyridyl]acetamide (Example 30-3),

N-[4-[4-(3-chlorophenyl) -2-methyl-1,3-thiazol- 5-yl] -2-pyridyl]propionamide (Example 30-7),

N-[4-[4-(3-chlorophenyl) -2-ethyl-1,3-thiazol-5- yl] -2-pyridyl]propionamide (Example 30-8),

N- [ 4- [ 4- ( 3-chlorophenyl) -2-propyl-l , 3-thiazol- 5-yl] -2-pyridyl]propionamide (Example 30-9),

N-cyclohexyl-4- [2-ethyl-4- (3-methylphenyl) -1,3- thiazol-5-yl] -2-pyridylamine (Example 36-4), N-cyclohexyl-4- [4- (3-methylphenyl) -2- (4- methylsulfonylphenyl) -1 , 3-thiazol-5-yl] -2- pyridylamine (Example 36-5),

N-cyclopentyl-4- [2-ethyl-4- (3-methylphenyl) - l,3-thiazol-5-yl] -2-pyridylamine (Example 36-6),

N-σyclopentyl-4- [4- (3-methylphenyl) -2- (4- methylsulfonylphenyl) -1 , 3-thiazol-5-yl] -2- pyridylamine (Example 36-7),

4- [ 4- ( 3-chlorophenyl) -2-ethyl-l , 3-thiazol-5- yl] -N-cyclohexyl-2-pyridylamine (Example 36-10),

4- [4- (3-chlorophenyl) -2-ethyl-l , 3-thiazol-5- yl] -N-cyclopentyl-2-pyridylamine (Example 36-11),

N- [4- (3-methylphenyl) -5- ( 2-methyl-4-pyridyl) - l,3-thiazol-2-yl]acetamide (Example 39),

N- [4- (3,5-dimethylphenyl) -5- ( 2-methyl-4- pyridyl) -1 , 3-thxazol-2-yl]nicotinamide (Example 42-1),

6-chloro-N- [4- (3,5-dimethylphenyl) -5- (2-methyl- 4-pyridyl) -1,3-thiazol-2-yl]nicotinamide (Example 44- 3),

N- [ 4- ( 3 , 5-dimethylphenyl) -5- ( 2-methyl-4- pyridyl) -1 , 3-thiazol-2-yl] -6-methylnicotinamide (Example 46-3) ,

N- [ 4- ( 3 , 5-dimethylphenyl) -5- ( 2-methyl-4- pyridyl) -1 , 3-thiazol-2-yl] -6-methoxynicotinamide (Example 48-3) ,

4- (3-methylphenyl) -5- ( 2-methyl-4-pyridyl) -2- ( 4- methylsulf nylphenyl) -1 , 3-thiazole (Example 54),

4- ( 3-methylphenyl) -5- ( 2-methyl-4-pyridyl) -2- ( 4- methylsulfonylphenyl) -1,3-thiazole (Example 57),

5- (2-fluoro-4-pyridyl) -4- ( 3-methylphenyl) - 2 - (4- methylsulfonylphenyl) -1 , 3-thiazole (Example 58-4),

N-[4-[4-(3-chlorophenyl) -2- ( 4- methylsulfonylphenyl) -1 , 3-thiazol-5-yl] -2- pyridyl]aσetamide (Example 58-6),

N-[4-[4-(3-chlorophenyl)-2-(4- methylsul onylphenyl) -1 ,3-thiazol-5-yl] -2- pyridyl] ropionamide (Example 58-7),

N- [ 4- [ 4- ( 3-chlorophenyl) -2- ( 4- methylsulfonylphenyl) -1, 3-thiazol-5-yl] -2- pyridyl]pivalamide (Example 58-8), or a salt thereof;

[16] A pro-drug of a compound as claimed in any one as defined in [1] to [5];

[17] A method for producing a compound as defined in [1] or [3] comprising

(1) reacting a compound represented by the formula: H

9 ' ₃

R-C-COR

I

Hal wherein Hal represents a halogen atom, R² and R³ are as defined in Claim 2, or a salt thereof with a compound of the formula: S ι II

R-C-NH₂ wherein R¹ is as defined in Claim 2 , or a salt thereof, or

(2) reacting a compound represented by the formula:

H

R^2a-C-COR^3a

I

Ha l wherein Hal represents a halogen atom, R^2a and R^3a are as defined in Claim 4 , or a salt thereof with a compound represented by the formula:

wherein R^la is as defined in Claim 4 , or a salt thereof;

[18] A pharmaceutical composition containing the compound as claimed in any one of [1] to [5] or a prodrug thereof ;

[19] The composition as defined in [18] which is a p38 MAP kinase inhibitor;

[20] The composition as defined in [18] which is a TNF-α production inhibitor;

[21] The composition as defined in [18] which is a composition for preventing or treating a cytokine- madiated disease;

[22] The composition as defined in [18] which is an adenosine receptor antagonist;

[23] The composition as defined in [18] which is a composition for preventing or treating adenosine receptor-mediated diseases;

[24] The composition as defined in [18] which is a composition for preventing or treating asthma or allergic diseases;

[25] The composition as defined in [18] which is a composition for preventing or treating inflammation, Addison's disease, autoimmune hemolytic anemia, Crohn's disease, psoriasis, rheumatism, spinal cord injury, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, diabetes, arthritis, toxaemias, ulcerative colitis, chronic pneumonia, pulmonary silicosis, pulmonary sarcoidosis, lung tuberculosis, cachexia, arterial sclerosis, Creutzfeldt-Jakob disease, virus infection, atopic dermatitis, systemic lupus erythematosus , AIDS encephalopathy, meningitis, angina pectoris, myocardial infarction, congestive heart failure, hepatitis, transplant, dialysis hypotension or diffuse intravascular coagulation symdrome;

[26] The composition as defined in [18] which is a composition for preventing or treating chronic rheumatoid arthritis or osteoarthritis;

[27] The composition as defined in [18] which is a composition for preventing or treating cerebral edema, cerebrovascular disorder, head trauma, cerebral infarction or apoplectic stroke;

[28] A method for inhibiting p38 MAP kinase which comprises administering an effective amount of the compound as defined in any one of [1] to [5] or a pro-drug thereof to mammals;

[ 29 ] A method for inhibiting TNF-α production which comprises administering an effective amount of the compound as defined in any one of [1] to [5] or a pro-drug thereof to mammals ;

[30] A method for antagonizing an adenosine receptor which comprises administering an effective amount of the compound as defined in any one of [ 1 ] to [5] or a pro-drug thereof to mammals;

[31] A method for preventing or treating asthma or allergic diseases which comprises administering an effective amount of the compound as defined in any one of [1] to [5] or a pro-drug thereof to mammals;

[32] A method for preventing or treating inflammation, Addison's disease, autoimmune hemolytic anemia, Crohn's disease, psoriasis, rheumatism, spinal cord injury, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, diabetes, arthritis, toxaemias, ulcerative colitis, chronic pneumonia, pulmonary silicosis, pulmonary sarcoidosis, lung tuberculosis, caσhexia, arterial sclerosis, Creutzfeldt-Jakob disease, virus infection, atopic dermatitis, systemic lupus erythematosus , AIDS encephalopathy, meningitis, angina pectoris , myocardial infarction, congestive heart failure, hepatitis, transplant, dialysis hypotension or diffuse intravascular coagulation symdrome which comprises administering an effective amount of the compound as defined in [1] to [5] or a pro-drug thereof to mammals; [33] A method for preventing or treating chronic rheumatoid arthritis or osteoarthritis which comprises administering an effective amount of the compound as defined in [1] to [5] or a pro-drug thereof to mammals;

[34] A method for preventing or treating cerebral edema, cerebrovascular disorder, head trauma, cerebral infarction or apoplectic stroke which comprises administering an effective amount of the compound as defined in any one of [1] to [5] or a pro-drug thereof to mammals ;

[35] Use of the compound as defined in any one of [1] to [5] or a pro-drug thereof for producing a p38 MAP kinase inhibitor:

[36] Use of the compound as defined in any one of [1] to [5] or pro-drug thereof for producing a TNF-α production inhibitor;

[37] Use of the compound as defined in any one of [ 1 ] to [ 5 ] or a pro-drug thereof for producing an adnosine receptor antoganist;

[38] Use of the compound as defined in any one of [1] to [5] or a pro-drug thereof for producing a composition for preventing or treating asthma and allergic diseases;

[39] Use of the compound as defined in any one of [1] to [5] or a pro-drug thereof for producing a composition for preventing or treating inflammation, Addison ' s disease, autoimmune hemolytic anemia, Crohn's disease, psoriasis, rheumatism, spinal cord injury, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, diabetes, arthritis, toxaemias, ulcerative colitis, chronic pneumonia, pulmonary silicosis, pulmonary sarcoidosis, lung tuberculosis, cachexia, arterial sclerosis, Creutzfeldt-Jakob disease, virus infection, atopic dermatitis, systemic lupus erythematosus, AIDS encephalopathy, meningitis, angina pectoris, myocardial infarction, congestive heart failure, hepatitis, transplant, dialysis hypotension or diffuse intravascular coagulation symdrome;

[40] Use of the compound as defined in any one of [1] to [5] or a pro-drug thereof for producing a composition for preventing or treating chronic rheumatoid arthritis or osteoarthritis; and

[41] Use of the compound as defined in any one of [1] to [5] or a pro-drug thereof for producing a composition for preventing or treating cerebral edema, cerebrovascular disorder, head trauma, cerebral infarction or apoplectic stroke.

In this specification, as the "acyl group", for example, a acyl group represented by the formula: - (C=0)-R^s, -(C=0)-OR⁵, -(C=0)-NR⁵R⁶, -(C=S)-NHR⁵ , - (C=0)-N(OR⁵)R⁶, -(C=S)-NHOR⁵ or -S0₂-R⁷ wherein R⁵ 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 Ci_₆ alkyl group, and R⁷ 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 substituent" represented by R⁵, for example, an acyclic or cyclic hydrocarbon group (e.g. , alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl and the like), etc. are exemplified. Of them, an acyclic or cyclic hydrocarbon group having 1 to 16 carbon atoms, etc. are preferable.

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_₈ cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyσlohexyl and the like), etc. are preferable.

As the "aryl", for 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 C₇_₁₆ aralkyl group

(e.g., benzyl, phenethyl, diphenylmethyl, 1- naphthylmethyl , 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, for example, oxo, a halogen atom (e.g., fluorine, chlorine, bromine, iodine and the like), Ci_₃ alkylenedioxy (e.g., methylenedioxy, ethylenedioxy and the like), nitro, cyano, Ci_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_g alkynyl which may be halogenated, C₃.₈ cycloalkyl which may be halogenated, C₃_₈ cycloalkyl-C_ι_₆ alkyl, C₆_₁₄ aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and the, like), Ci_₈ alkoxy which may be halogenated, Ci_₆ alkoxy-carbonyl-Ci_₆ alkoxy (e.g., ethoxycarbonylmethyloxy and the like), hydroxy, C₆.₁₄ aryloxy (e.g., phenyloxy, 1-naphthyloxy, 2-naphthyloxy and the like), C₇.₁₆ aralkyloxy (e.g., benzyloxy. phenethyloxy and the like) , merσapto, C_ι_₆ alkylthio which may be halogenated, C₆.₁₄ arylthio (e.g., phenylthio, 1-naphthylthio, 2-naphthylthio and the like), C₇_₁₆ aralkylthio (e.g., benzylthio, phenethylthio and the like), amino, mono-Ci_₆ alkylamino (e.g., methylamino, ethylamino and the like), raono-C₆.₁₄ arylamino (e.g., phenylamino, 1-naphthylamino, 2-naphthylamino and the like), di-Ci.g alkylamino (e.g., dimethylamino, diethylamino, ethylmethylamino and the like), C₃.₈ cycloalkylamino (e.g. , cyclopentylamino , σyclohexylamino and the like), dx-Cg_₁₄ arylamino (e.g., diphenylamino and the like), C₃.₈ cycloalkyl-C_ι_₆ alkylamino (e.g., cyclopentylmethylamino, cyclohexylmethylamino , cyσlopentylethylamino, cyclohexylethylamino and the like) , N-C₃_₈ cycloalkyl- N-Ci.₆ alkylamino (N-cyclopentyl-N-methylamino, N- cyclohexyl-N-methylamino, N-cyclopentyl-N-ethylamino, N-cyσlohexyl-N-ethylamino and the like) , formyl, carboxy, carboxy-C₂.g alkenyl, carboxy-C_ι_₆ alkyl, C___.₆ alkyl- carbonyl which may be halogenated (e.g., aσetyl, propionyl, pivaloyl and the like), C₃.₈ cycloalkyl- carbonyl optionally substituted by C_ι_₆ alkyl such as methyl, ethyl, etc. (e.g., cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, 1-methyl- cyclohexyl-carbonyl and the like), Ci.g alkoxy-carbonyl (e.g. , methoxycarbonyl , ethoxycarbonyl, propoxycarbonyl , tert-butoxycarbonyl and the like), C₆.₁₄ aryl-carbonyl (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl and the like), C₇.₁₆ aralkyl-carbonyl (e.g., phenylacetyl, 3- phenylpropionyl and the like), C₆.₁₄ aryloxy-carbonyl (e.g., phenoxyσarbonyl and the like), C₇.₁₆ aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, 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, isoniσotinoyl, thenoyl, furoyl, morpholinocarbonyl, thiomorpholinocarbonyl, piperazin-1-ylcarbonyl , pyrrolidin-1-ylcarbonyl and the like), carbamoyl, thiocarbamoyl , mono-C_ι_₆ alkyl- carbamoyl (e.g. , methylcarbamoyl, ethylcarbamoyl, and the like), di-Ci.₆ alkyl-carbamoyl (e.g., dimethylcarbamoyl , diethylcarbamoyl, ethylmethylσarbamoyl and the like), mono- or di-C₆__ι4 aryl-carbamoyl (e.g., phenylcarbamoyl, 1- naphthylcarbamoyl, 2-naphthylcarbamoyl and the like), mono- or di- 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 (e.g., 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2- thienylcarbamoyl , 3-thienylcarbamoyl and the like), Ci_₆ alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl and the like), Ci_₆ alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl and the like), C₆.₁₄ arylsulfonyl (e.g., phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl and the like), C₆__ι4 arylsulfinyl (e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl and the like), formylamino, Ci_₆ alkyl-carbonylamino (e.g. , acetylamino, propionylamino , pivaloylamino and the like), C₃.₈ cycloalkyl-carbonylamino optionally substituted by C _ ₅ alkyl (e.g. , cyclopropylcarbonylamino , σyclopentylcarbonylamino, cyclohexylcarbonylamino and the like), C₆.₁₄ aryl-carbonylamino (e.g., benzoylamino, naphthoylamino and the like), Ci.g alkoxy-carbonylamino (e.g. , methoxycarbonylamino , ethoxycarbonylamino , propoxycarbonylamino , butoxycarbonylamino and the like) , Ci.g alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino and the like) , C₆__ι4 arylsulfonylamino (e.g., phenylsulfonylamino, 2-naphthylsulfonylamino, 1-naphthylsulfonylamino and the like), C-_L_₆ alkyl- carbonyloxy (e.g. , acetoxy, propionyloxy and the like) , C₆__ι4 aryl-carbonyloxy (e.g., benzoyloxy, naphthylcarbonyloxy and the like), C_ι_₆ alkoxy- carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy and the like), mono-C_ι_₆ alkyl- σarbamoyloxy (e.g. , methylcarbamoyloxy, ethylcarbamoyloxy and the like), di-Ci.g alkyl- carbamoyloxy (e.g., dimethylcarbamoyloxy, diethylcarbamoyloxy and the like), mono- or di-C₆.₁₄ aryl-carbamoyloxy (e.g., phenylcarbamoyloxy, naphthylcarba oyloxy and the like) , 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 an oxygen atom in addition to carbon atoms (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, sulfo, sulfamoyl, sulfinamoyl, sulfenamoyl, a group obtained by connecting two or more (e.g., 2 to 3) of these substituents (e.g., (i) C___₆ alkyl, (ii) C₆_₁₄ aryl, (iii) amino, (iv) Ci_₆ alkylamino, (v) C₃.₈ cycloalkylamino, (vi) Cg_₁₄ arylamino, (vii) 5- to 7- membered heterocyclic amino containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, (viii) C___₆ alkyl- carbonyl amino, (ix) C₃.₈ cycloalkyl-carbonylamino, (x) C₆.₁₄ aryl-carbonylamino or (xi) 5- to 7-membered heterocyclic-carbonyl amino containing 1 to 4 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, Ci_₆ alkoxy, C₆.₁₄ aryloxy, Ci_₆ alkylthio, C₆__ι4 arylthio, C_ι_₆ alkylsulfinyl, Cg.₁₄ arylsulfinyl,

alkylsulfonyl, C₆.₁₄ arylsulfonyl, C₃.₈ cycloalkyl, 5- to 7-membered heterocyclic group containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, C₆_₁₄ aryl, Ci.g alkyl-carbonyl, C₃.₈ cycloalkyl-carbonyl, 5- to 7- membered heterocyclic-carbonyl containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, C₆_₁₄ aryl-carbonyl, C₃.₈ cycloalkoxy, 5- to 7-membered heterocyclic-oxy containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, C_ι_₆ alkylamino, C₆.₁₄ arylamino, Ci_₆ alkoxy-carbonyl, C₃.₈ cycloalkoxy-carbonyl, 5- to 7-membered heterocyclic-oxycarbonyl containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, C₆.₁₄ aryloxycarbonyl, etc.) (sometimes referred to as Group A of substituents).

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 different .

As the above-mentioned "C_ι_₆ alkyl which may be halogenated", for example, C__₆ 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 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 exemplified.

As the above-mentioned "C^:₆ alkenyl which may be halogenated", for example, C₂.₆ alkenyl (e.g., vinyl, propenyl, isopropenyl, 2-buten-l-yl, 4-penten-l-yl, 5-hexen-l-yl 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 the above-mentioned "C₂.₆ alkynyl which may be halogenated", for example, C₂.₆ alkynyl (e.g., 2- butyn-1-yl, 4-pentyn-l-yl, 5-hexyn-l-yl 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 the above-mentioned "C₃.₈ cycloalkyl which may be halogenated", for example, C₃.₈ cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyσlohexyl 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, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4 , 4-dichlorocyclohexyl, 2,2,3,3- tetrafluorocyclopentyl, 4-chlorocyclohexyl, etc. are exemplified.

As the above-mentioned "C_ι_₈ alkoxy which may be halogenated", for example, C_ι_₈ 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 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 "Ci_₆ alkylthio which may be halogenated", for example, Ci_₆ alkylthio (e.g., methylthio, ethylthio, propylthip, 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, 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 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 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- 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 C_ι_₆ alkyl (e.g. , methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like), C₆.₁₄ aryl (e.g. , phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and the like), C__₆ alkyl-carbonyl (e.g., acetyl, propionyl and the like) which may be halogenated, Ci_₆ 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.

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 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 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 aliphatic 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, lH-indazole, purine, 4H-quinolidine, isoquinoline, quinoline, phthalazine, naphthylidine , quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, isooxazole, 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 aliphatic heterocyclic ring", for example, pyrrolidine, imidazoline, pyrazolidine, pyrazoline, piperidine,

1 piperazine, morpholine, thiomorpholine, dioxazole, oxadiazoline, thiadiazoline, triazoline, thiadiazole. dithiazole, etc. are exemplified.

As the above-mentioned "7- to 10-membered bridged 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 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, 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- benzo[b] thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl and the like, and aliphatic heterocylic groups such as, for example, 1-pyrrolidinyl, 2-pyrrolidinyl, 3- pyrrolidinyl, 3-oxazolxdinyl, 1-imidazolidinyl, 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, 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-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 above-mentioned "hydrocarbon group optionally having a substituent" represented by R⁵, 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 of the substituent is 2 or more, they may be the same or different .

As the "Ci_₆ alkyl group" represented by R⁵, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. are exemplified.

As the "hydrocarbon group optionally having a substituent" and "heterocyclic group optionally having a substituent" represented by R⁷, for example, the above-mentioned "hydrocarbon group optionally having a substituent" and "heterocyclic group optionally having a substituent" represented by R⁵ are exemplified, respectively.

As the "hydrocarbon group optionally having a substituent" represented by R¹ and R^l , for example, the "hydrocarbon group optionally having a substituent" represented by R⁵ is exemplified.

As the "heterocyclic group optionally having a substituent" represented by R¹ and R^la, for example, the "heterocyclic group optionally having a substituent" represented by R⁵ is exemplified. As the "amino group optionally having a substituent" represented by R¹ and R^la, for example, (1) an amino group optionally having 1 or 2 substituents and (2) a cyclic amino group optionally having a substituent are exemplified.

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, 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 substituent" represented by R⁵ are exemplified, respectively.

As the "alkylidene group" of the above-mentioned "alkylidene group optionally having a substituent", for example, C _₆ alkylidene (e.g., methylidene, ethylidene, propylidene and the like), etc. are exemplified. As the "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 R⁵ are 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" , for example, a 5- to 7-membered aliphatic 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, 1-imidazolidinyl, 2, 3- ihydro-(1H) -imidazolyl, tetrahydro-l( 2H) - pyrimidinyl, 3, 6-dihydro-1(2H) -pyrimidinyl, 3,4- dihydro-l(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 R⁵.

As specific examples of the 5- to 7-membered aliphatic cyclic amino group having one oxo, for example, 2-oxoimidazolidin-l-yl, 2-oxo-2 , 3-dihydro-lH- imidazol-1-yl, 2-oxoteterahydro-l(2H) -pyrimidinyl, 2 - oxo-3, 6-dihydro-l(2H) -pyrimidinyl, 2-oxo-3 , 4-dihydro- 1 (2H) -pyrimidinyl, 2-oxopyrrolidin-l-yl, 2- oxopiperidino, 2-oxopiperazin-l-yl, 3-oxopiperazin-l- yl, 2-OXO-2 , 3, 4, 5, 6 , 7-hexahydroazepin-l-yl, etc. are exemplified.

R¹ or R^la is preferably an alkyl group optionally having a substituent, an aryl group optionally having a substituent, an amino group optionally having a substituent, a heterocyclic group optionally having a substituent, an acyl group represented by the formula: -(C=0)-R⁵ (wherein R⁵ is as defined above), an acyl group represented by the formula: -(C=0)-OR^s (wherein R⁵ is as defined above), or the like.

As the "alkyl group optionally having a substituent" , for example, a C_ι.₆ alkyl group (preferably. methyl, ethyl, propyl, butyl and the like) optionally having 1 to 5 substituents selected from a halogen atom, carboxy, hydroxy, Ci.g alkoxy, C_x_₆ alkoxy-carbonyl, Ci_₆ alkylthio, Ci_₆ alkylsulfinyl, C₁_₆ alkylsulfonyl, and the like, etc. are preferably exemplified.

As the above-mentioned "aryl group optionally having a substituent", for example, a C₆__ι4 aryl group (preferably, phenyl and the like) optionally having 1 to 5 substituents selected from a halogen atom, Ci_₆ alkylthio, C₆__ι4 arylthio, Ci_₆ alkylsulfinyl, C₆.₁₄ arylsulfinyl, C_ι_₆ alkylsulfonyl, C₆__ι4 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)-R⁵, - (C=0)-OR⁵, -(C=0)-NR⁵R⁶, -(C=S)-NHR⁵, - (C=0) -N(OR⁵)R⁶, -(C=S)-NHOR⁵ or -S0₂-R⁷ (wherein each symbol is as defined above), etc. are preferably exemplified.

Further preferably, R¹ is an amino group optionally having 1 or 2 acyls represented by the formula: -(C=0)-R⁵ or - (C=0) -NR⁵R⁶ (wherein each symbol is as defined above) , etc. are exemplified.

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 atom in addition to carbon atoms are used, and of them, a 5- to 10-membered aliphatic heterocyclic group, a 5- to 7-membered aromatic heterocyclic group, etc. are preferable.

As the "substituent" of the "heterocyclic group optionally having a substituent", for example, an oxo group, a Ci_₆ alkyl group (e.g., methyl, ethyl, etc.), a ^C ₆-i₄ aryl group (e.g. , phenyl, etc. ) , a Ci_₆ alkyl-carbonyl group (e.g., acetyl, etc.), a Ci_₆ alkoxy-carbonyl group (e.g., methoxycarbonyl , ethoxycarbonyl , etc.) and the like are used, and the number of substituents is 1 to 3.

As R⁵ of the "acyl group represented by the formula: - (C=O -R⁵" , a hydrogen atom, a hydrocarbon group optionally having a substitutent and an aromatic heterocyclic group optionally having a substituent are preferable, and particularly, ® a hydrogen atom, ® a Ci_₆ alkyl group which may be halogenated (e.g., methyl, ethyl, propyl, trifluoromethyl, etc.), © a C₆__ι4 aryl group which may be halogenated (e.g. , phenyl, naphthyl, fluorophenyl, chlorophenyl, etc.), ©a 5- to 7-membered aromatic heterocyclic group (e.g., pyridyl, thienyl, pyrrolyl, furyl, pyridazinyl, pyrimidinyl, etc.) which may be substituted by a halogen atom (e.g., fluorine, chlorine, bromine, etc.), optionally halogenated Ci_₆ alkyl (e.g., methyl, ethyl, propyl, trifluoromethyl, etc.), Ci_g alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy, etc.), and the like are preferable.

As R⁵ of the "acyl group represented by the formula: - (C=0) -OR^s , a hydrogen atom and a hydrocarbon group optionally substituted are preferable, and particularly, a hydrogen atom and a Ci_₆ alkyl group (e.g. , methyl , ethyl , propyl , etc . ) , and the like are preferable .

As R¹ or R^la, (i) a hydrogen atom, (ii) a Ci_₆ alkyl group optionally substituted by a substituent selected from the group consisting of a halogen atom, Ci_₆ alkoxy-carbonyl, carboxy, cyano, Ci_₆ alkylthio, Ci_₆ alkylsulfinyl, C_ι.₆ alkylsulfonyl, hydroxy, Ci_₆ alkoxy and Ci_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(0)_n- _R ^ibb (_R ^ibb repr s nts _a c_ι_, al_kyl group, and n represents an integer of 0 to 2), (iv) a C₇.₁₅ aralkyl group, (v) an amino group optionally having one or two substituents selected from ® Ci_₆ alkyl, © Ci_₆ alkyl-carbonyl, ® 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, C_ι_₆ alkyl or C _₆ alkoxy, ® C₆__li aryl-carbamoyl, © Ci_₆ alkyl-carbamoyl which may be halogenated, © Ci_₆ alkoxy-carbonyl which may be halogenated, ® C_ι_₆ alkoxy-carbamoyl and ® C₆.₁₄ 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, Ci_₆ alkyl, C₆.₁₄aryl, Ci.g alkoxy-carbonyl or Ci_₆ alkyl-carbonyl, (vii) an acyl group represented by the formula:- (C=0) -R^5b (wherein R^5b represents a hydrogen atom, a Ci_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) -OR^s° (wherein R^5c represents a hydrogen atom or a Ci_₆ alkyl group), and the like are suitable.

As the Ci.g alkyl group represented by R¹ or R^la, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. are used, and particularly, Ci_₄ alkyl groups such as methyl, ethyl, propyl, butyl and the like are preferable.

As the halogen atom which is a substituent of the Ci.g alkyl group represented by R¹ or R^la, for example, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom are preferable.

As the Ci.g alkoxy-carbonyl which is a substituent of the Ci.g alkyl group represented by R¹ or R^la, for example, methoxycarbonyl, ethoxycarbonyl and the like are preferable.

As the Ci.g alkylthio which is a substituent of the Ci.g alkyl group represented by R¹ or R^la, for example. methylthio, ethylthio and the like are preferable.

As the Ci.g alkylsulfinyl which is a substituent of the Ci_₆ alkyl group represented by R¹ or R^la, for example, methylsulfinyl, ethylsulfinyl and the like are preferable.

As the Ci_₆ alkylsulfonyl which is a substituent of the Ci.g alkyl group represented by R¹ or R^la, for example, methylsulfonyl, ethylsulfonyl and the like are preferable.

As the C__₆ alkoxy which is a substituent of the C__₆ alkyl group represented by R¹ or R^la, for example, methoxy, ethoxy, propoxy and the like are preferable.

As the Ci.g alkyl-carbonyl which is a substituent of the Ci.g alkyl group represented by R¹ or R^la, for example, acetyl, propionyl and the like are preferable.

As the Ci.g alkyl group represented by R^lb, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. are used, and of them, Ci_₄ alkyl groups such as methyl, ethyl, propyl, butyl and the like are preferable, and methyl is particularly preferable.

As the C₆_i₄ aryl group represented by R¹ or R^la, for example, phenyl, naphthyl, etc. are preferable, and of them, phenyl is particularly preferable.

As the halogen atom which is a substituent of the C₆__ι4 aryl group represented by R¹ or R^la, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom are used.

As the C₇.₁₅ aralkyl group represented by R¹ or R^la, for example, phenyl-Ci_₃ alkyl groups such as benzyl, phenylethyl, phenylpropyl and the like are preferable.

As the Ci.g alkyl group which is a substituent of an amino group represented by R¹ or R^la, for example, methyl , ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. are used, and of them. C_ι_₃ alkyl groups such as methyl, ethyl, propyl and the like are preferable, particularly, methyl is preferable.

As the Ci.g alkyl-carbonyl which is a substituent of an amino group represented by R¹ or R^la, for example, a Ci_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 R¹ or R^la, for example, a 5- to 7-membered heterocyclic (e.g., furyl, thienyl, pyrrolyl, 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 halogen atom such as a chlorine atom and the like, Ci_₆ alkyl group such as methyl, ethyl and the like, and C_ι_₆ alkoxy such as methoxy, ethoxy and the like are preferable .

As the Cg.₁₄ aryl-carbamoyl which is a substituent of an amino group represented by R¹ or R^la, for example, phenyl-carbamoyl, etc. are preferable.

As the Ci_₆ alkyl-carbamoyl which may be halogenated which is a substituent of an amino group represented by R¹ or R^la, for example, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl optionally substituted by a halogen atom (e.g., chlorine atom) and the like are preferable.

As the Ci_g alkoxy-carbonyl which may be halogenated which is a substituent of an amino group represented by R¹ or R^la, for example, methoxycarbonyl, ethoxycarbonyl , propoxycarbonyl optionally substituted by halogen atoms (e.g., a chlorine atom) and the like are preferable.

As the Ci.g alkoxy-carbamoyl which is a substituent of an amino group represented by R¹ or R^la, for example, methoxycarbamoyl, ethoxycarbamoyl , propoxycarbamoyl and the like are preferable.

As the Cg_₁₄ aryloxy-carbamoyl which is a substituent of an amino group represented by R¹ or R^la, for example, phenyloxy-carbamoyl and the like are preferable.

As the 5- to 10-membered aliphatic heterocyclic group represented by R¹ or R^la, 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 used, and of them, 4-piperidyl, 1- piperazinyl, 3-oxazolidinyl, 1-imidazolidinyl and the like are preferable.

As the 5- to 10-membered aliphatic heterocyclic group optionally substituted by oxo, C_ι_₆ alkyl (preferably, methyl, ethyl), C₆.₁₄ aryl (preferably, phenyl) , Ci_₆ alkyl-carbonyl (preferably, acetyl) or Ci_₆ alkoxy-carbonyl (preferably, methoxycarbonyl, ethoxycarbonyl) represented by R¹ or R^la, 1-methyl-4- piperidyl, 4-methyl-1-piperazinyl, 2-oxo-3- oxazolidinyl, 2-oxo-l-imidazolidinyl, 2-oxo-3-phenyl- 1-imidazolidinyl and the like are preferable.

As R^sb of the formula: -(C=0)-R^5D represented by R¹ or R^la, a hydrogen atom, a Ci_₆ alkyl group which may be halogenated by a fluorine atom, a chlorine atom and the like (e.g., methyl, ethyl, trifluoromethyl, etc.), a C₆.₁₄ 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 R^5C of the formula: -(C=0)-OR^So, a hydrogen atom and a Ci_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 (la), 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 (lb) the "substituent containing no aromatic group" 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 R², and "the substituent containing no 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 R^2a, for example, a halogen atom (e.g., fluorine, chlorine, bromine, iodine and the like), Ci_₃ alkylenedioxy (e.g., methylenedioxy, ethylenedioxy and the like), nitro, cyano, Ci_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 cycloalkyl which may be halogenated, C₃.₈ σycloalkyl-C_ι_₆ alkyl, C__₈ alkoxy which may be halogenated, C_x_₆ alkoxy-carbonyl-Ci_₆ alkoxy (e.g. , ethoxycarbonylmethyloxy and the like) , hydroxy, mercapto, Ci.g alkylthio which may be halogenated, amino, mono-Ci_₆ alkylamino (e.g. , methylamino, ethylamino and the like) , di-Ci.₆ alkylamino (e.g., dimethylamino , diethylamino , ethylmethylamino and the like) , C₃.₈ cycloalkylamino (e.g. , cyclopentylamino, cyclohexylamino and the like), C₃_₈ cycloalkyl-Ci.g alkylamino (e.g., cyσlopentylmethylamino , cyclohexylmethylamino , cyclopentylethylamino , cyclohexylethylamino and the like), N-C₃_₈ cycloalkyl- N-Ci_g 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-Ci_₆ alkyl, Ci.g alkyl-carbonyl which may be halogenated (e.g., acetyl, propionyl, 2 , 2, 2-trifluoroacetyl, 3,3,3- trifluoropropionyl,2,2-difluoropropionyl and the like) , C₃-₈ cycloalkyl-carbonyl optionally substituted by C_ι_₆ alkyl (e.g., cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, 1-methyl-cyclohexyl-carbonyl and the like), C_ι_₆ alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl , tert-butoxycarbonyl and the like), carbamoyl, thiocarbamoyl, mono-C_ι_₆ alkyl-carbamoyl (e.g. , methylcarbamoyl, ethylcarbamoyl, and the like), di-Ci_₆ alkyl-carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl , ethylmethylcarbamoyl and the like) , Ci_₆ alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl and the like), Ci_₆ alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl and the like), formylamino, C_ι_₆ alkyl-carbonylamino (e.g., acetylamino , propionylamino , pivaloylamino and the like ) , ^C ₃-₈ cycloalkyl-carbonylamino optionally substituted by Ci.g alkyl (e.g., cyclopropylcarbonylamino , cyclopentylcarbonylamino, cyclohexylcarbonylamino, 1- methyl-cyclohexylcarbonylamino and the like), Ci_₆ alkoxy-carbonylamino (e.g., methoxycarbonylamino, ethoxycarbonylamino , propoxycarbonylamino , butoxycarbonylamino and the like), C₁_₆ alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino and the like), C_ι_₆ alkyl-carbonyloxy (e.g., acetoxy, propionyloxy and the like), Ci_₆ alkoxy-carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonylox , butoxycarbonyloxy and the like),

alkylcarbamoyloxy (e.g. , methylcarbamoyloxy, ethylcarbamoyloxy and the like), di-C^ alkylcarbamoyloxy (e.g., dimethylcarbamoyloxy, diethylcarbamoyloxy and the like), 5- to 7-membered aliphatic heterocyclic group having a substituent , sulfo , sulfamoyl, sulfinamoyl, sulfenamoyl, a group formed by connecting 2 to 3 of these substituents (e.g., (i) C_ι_ ₆ alkyl, (ii) amino, (iii) Ci_₆ alkylamino, (iv) C₃_₈ cycloalkylamino, (v) 5- to 7-membered aliphatic heterocyclic amino containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, (vi) C_ι_₆ alkyl-carbonyl amino, (vii) C₃.₈ cycloalkyl-carbonylamino or (viii) 5- to 7- membered aliphatic heterocyclic-carbonyl amino containing 1 to 4 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, C-_L_₆ alkoxy, Ci_₆ alkylthio, Ci_₆ alkylsulfinyl, Ci_₆ alkylsulfonyl, C₃.₈ cycloalkyl, 5- to 7-membered aliphatic heterocyclic group containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, C__₆ alkyl-carbonyl, C₃.₈ cycloalkyl-carbonyl, 5- to 7- membered aliphatic heterocyclic-carbonyl containing 1 to 4 hetero atoms 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 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, Ci.g alkylamino, Ci_₆ alkoxy-carbonyl, C₃_₈ cycloalkoxy-carbonyl, 5- to 7-membered aliphatic heterocyclic-oxycarbonyl containing 1 to 4 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 "Cii₆ alkyl which may be halogenated", for example, Ci_₆ 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 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 exemplified.

As the above-mentioned "C₂.₆ alkenyl which may be halogenated", for example, C₂.₆ alkenyl (e.g., vinyl, propenyl, isopropenyl, 2-buten-l-yl, 4-penten-l-yl, 5-hexen-l-yl 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 the above-mentioned "C₂_₆ alkynyl which may be halogenated", for example, C₂.₆ alkynyl (e.g., 2- butyn-1-yl, 4-pentyn-l-yl, 5-hexyn-l-yl 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 the above-mentioned "C₃.₈ cycloalkyl which may be halogenated", for example, C₃_₈ 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, 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-chloroσyclohexyl, etc. are exemplified.

As the above-mentioned "Ci_₈ alkoxy which may be halogenated", for example, Ci_₈ alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, see- butoxy, pentyloxy, 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 "C_ι_₆ alkylthio which may be halogenated", for example, C_ι_₆ 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, 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 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 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- 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 Ci_₆ alkyl (e.g. , methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like), Ci_₆ alkyl-carbonyl (e.g., acetyl, propionyl and the like), oxo, etc. are exemplified.

Provided that , when

(i) R¹ or R^l is an acetylamino group, and R³ or R^3a is a 3,5-dimethylphenyl group. (ii) R¹ or R^la is a Ci_₆ alkyl-carbonylamino group, and R³ or R^3a is a C₆.₁₄ aryl group substituted by a Ci.g alkyl group, or

(iii) R¹ or R^la is an amino group optionally having a substituent, and R³ or R^3a 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), C_x_ ₃ alkylenedioxy (e.g., methylenedioxy, ethylenedioxy and the like), nitro, cyano, Ci_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 cycloalkyl which may be halogenated, C₃.₈ cycloalkyl -C _₆ alkyl, Ci_₈ alkoxy which may be halogenated, Ci_₆ alkoxy-carbonyl-C_ι_₆ alkoxy (e.g. , ethoxycarbonylmethyloxy and the like), mercapto, C_x_₆ alkylthio which may be halogenated, amino, mono-Ci_₆ alkylamino (e.g. , methylamino, ethylamino and the like) , i-C-_L.g alkylamino (e.g., dimethylamino, diethylamino , ethylmethylamino and the like) , C₃.₈ cycloalkylamino (e.g. , cyclopentylamino, cyclohexylamino and the like), C₃.₈ cycloalkyl-Ci.g alkylamino (e.g., cyclopentylmethylamino, cyclohexylmethylamino and the like) , N-C₃.₈ cycloalkyl-N-Ci.g alkylamino (e.g., N-cyclopentyl-N- methylamino, N-σyclohexyl-N-methylamino, N- cyclopentyl-N-ethylamino, N-cyclohexyl-N-ethylamino and the like), formyl, carboxy, carboxy-C₂.₆ alkenyl, carboxy-Ci.g alkyl, C___₆ alkyl-carbonyl (e.g., acetyl, propionyl and the like), C₃.₈ cycloalkyl-carbonyl optionally substituted by C_ι_₆ alkyl (e.g., cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, 1-methyl-cyclohexyl-carbonyl and the like), Ci_₆ alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxyσarbonyl, tert-butoxycarbonyl and the like), carbamoyl, thiocarbamoyl , mono-C_ι_₆ alkyl-carbamoyl (e.g. , methylcarbamoyl, ethylcarbamoyl. and the like), di-Ci_₆ alkyl-carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl and the like) , C_ι_₆ alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl and the like), Ci_₆ alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl and the like), formylamino, Ci_₆ alkyl-carbonylamino (e.g., acetylamino, propionylamino , pivaloylamino and the like) , C₃-₈ cycloalkyl-carbonylamino optionally substituted by Ci.g alkyl (e.g., cyclopropylcarbonylamino, cyclopentylcarbonylamino , cyclohexylcarbonylamino and the like), Ci_₆ alkoxy-carbonylamino (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino , butoxycarbonylamino and the like) , Ci.g alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino and the like) , C_ι_₆ alkoxy-carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy and the like) , mono-Ci_₆ alkyl-carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy and the like) , di-C_ι_₆ 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 exemplified. Further, a group obtained by connecting two or more (e.g. , (i) Ci_g alkyl, (ii) amino, (iii) Ci_₆ alkylamino, (iv) C₃.₈ cycloalkylamino, (v) 5- to 7-membered aliphatic heterocyclic amino containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, (vi) Ci_₆ alkyl-carbonyl amino, (vii) C₃.₈ cycloalkyl-carbonylamino or (viii) 5- to 7- membered aliphatic heterocyclic-carbonyl amino containing 1 to 4 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, Ci_₆ alkoxy, Ci_₆ alkylthio, Ci.g alkylsulfinyl, C__₆ alkylsulfonyl, C₃.₈ cycloalkyl, 5- to 7-membered aliphatic heterocyclic group containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, Ci_₆ alkyl-carbonyl, C₃.₈ cycloalkyl-carbonyl, 5- to 7- membered aliphatic heterocyclic-carbonyl containing 1 to 4 hetero atoms 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 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, Ci_₆ alkylamino, C_ι_₆ alkoxy-carbonyl, C₃.₈ cycloalkoxy-carbonyl, 5- to 7-membered aliphatic heterocyclic-oxycarbonyl containing 1 to 4 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 Ci_₆ alkyl group (e.g. , methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like, preferably a Ci_₄ alkyl group such as methyl, ethyl, propyl, butyl and the like) : this Ci.g alkyl group may be substituted by a halogen atom, cyano , hydroxy, C₃.₈ 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 (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 halogen atom (e.g., fluorine atom, chlorine atom, bromine atom, iodine atom) , (3) an amino group optionally having a substituent selected from the group consisting of the following ® to®:

® a Ci.g alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like, preferably C_ι_₃ alkyl groups such as methyl, ethyl, propyl and the like) , this Ci_₆ alkyl group may be substituted by a halogen atom, cyano, hydroxy, ^C ₃-₈ 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 (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),

© a Ci.g alkyl-carbonyl group (e.g., acetyl, propionyl, butyryl, valeryl, isovaleryl, 2- methylpropionyl, pivaloyl and the like), this Ci_₆ alkyl-carbonyl group may be substituted by a halogen atom, cyano, hydroxy, C₃.₈ cycloalkyl or 5- to 7-membered aliphatic heterocyclic group optionally 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-piperazinyl, 3-pxperazinyl, 4- piperazinyl, morpholino, 2-morpholinyl, 3-morpholinyl, thiomorpholino, 2-thiomorpholinyl, 3-thiomorpholinyl, hexahydroazepin-1-yl and the like),

® a Ci.g alkoxy-carbonyl group (e.g., methoxycarbonyl , ethoxycarbonyl , propoxycarbonyl , butoxycarbonyl, isobutoxycarbonyl, seσ-butoxycarbonyl, tert-butoxycarbonyl and the like),

© a C₃.₈ cycloalkyl-carbonyl group optionally substituted by Ci_₆ alkyl such as methyl, ethyl (e.g., cyclopropylσarbonyl, cyclobutylcarbonyl , cyclopentylσarbonyl, cyclohexylcarbonyl , 1-methyl- cyclohexylcarbonyl and the like),

© a 5- to 7-membered aliphatic heterocyclic group optionally 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, (e.g, 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 Ci_

₅ alkyl (e.g., methyl, ethyl), C_ι_₆ alkyl-carbonyl (e.g., acetyl, propionyl) and the like.

® 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 optionally 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 Ci_₆ alkyl (e.g., methyl, ethyl), Ci_

₆ alkyl-carbonyl (e.g., acetyl, propionyl) and the like.

(4) a 5- to 7-membered aliphatic cyclic amino group which may contain further 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 aliphatic cyclic amino group may be substituted with C_ι_₆ alkyl (e.g., methyl, ethyl), Ci_₆ alkyl-carbonyl (e.g., acetyl, propionyl) and the like.

( 5 ) a hydroxyl group , (6) a Ci.g alkyl-carbonyloxy group (e.g., acetyloxy, propionyloxy, butyryloxy and the like) .

The "pyridyl group" represented by R² and R^2a 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, 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 the position adjacent to a nitrogen atom of the pyridyl group a substituent including no aromatic group" represented by R^2a, 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 R³ , an aromatic hydrocarbon group, an aromatic heterocyclic group, etc. are exemplified.

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-biphenylyl, 4-biphenylyl, 2-anthryl and the like, etc. are exemplified.

As the "aromatic heterocyclic group", for example, a 5- or 14-membered (preferably, 5- or 10-membered) monocyclic or bicyclic aromatic heterocyclic groups 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 , are exemplified. Specifically, an aromatic heterocylic group such as , for example, 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, 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-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 for the "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 aliphatic carbon ring. Preferable is a 5- or 6-membered aliphatic carbon ring.

R³ and R^3a preferably represent a C₆_₁₄ aryl group, or 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. More preferably, they represent a phenyl group optionally having a substituent or a thienyl group optionally having a substituent, and a phenyl group optionally having a substituent is particularly preferable.

As the substituent on the Cg.₁₀ aryl group, a phenyl group, a 5- to 14-membered aromatic heterocyclic group and a thienyl group, preferable are 1 to 3 substituents selected from a halogen atom, Ci_₃ alkylenedioxy, Ci_₆ alkyl which may be halogenated, carboxy C₂.₆ alkenyl, C₃_₈ cycloalkyl, Ci_₈ alkoxy which may be halogenated, hydroxy, C₇_₁₆ aralkyloxy, Ci_₆ alkyl-carbonyloxy, carboxy, Ci_₅ alkoxy-carbonyl, cyano, C__₆ alkylthio, Ci_₆ alkylsulfonyl and particularly, a halogen atom, Ci_₆ alkyl which may be halogenated (e.g. , Ci_₃ alkyl such as methyl , ethyl, propyl and the like) , Ci_₈ alkoxy which may be halogenated (e.g. , C_ι_₃ alkoxy such as methoxy, ethoxy and the like) , carboxy, Ci_₆ alkoxy-carbonyl, cyano, Ci_₆ alkylthio (e.g., methylthio, ethylthio), C₁.₆ alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl) , etc. are preferable. Further, two alkyl groups adjacent as substituents may form a 5-membered aliphatic carbocyclic ring.

As the compound (Ibb), specifically, compounds represented by the following formula are preferably used:

wherein R^lb represents (i) a hydrogen atom, (ii) a Ci_₆ alkyl group optionally substituted by a substituent selected from the group consisting of a halogen atom, C_ι_₆ alkoxy-carbonyl, carboxy, cyano, Ci_₆ alkylthio, Ci_₆ alkylsulfinyl, Ci_₆ alkylsulfonyl, hydroxy, Ci_₆ alkoxy and Ci_₆ alkyl-carbonyl, (iii) a C₆__ι4 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-R^lbb (R^{l D} represents a Ci_₆ alkyl group, and n represents an integer of 0 to 2 ) , (iv) a C₇.₁₅ aralkyl group, (v) an amino group optionally having one or two substituents selected from ® Ci_₆ alkyl, ® Ci_₆ alkyl- carbonyl, ® C-_L_₆ alkoxy-carbonyl, ® 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 group or Ci_₆ alkoxy, © C₆.₁₄ aryl-carbamoyl, © Ci_₆ alkyl-carbamoyl which may be halogenated, ® Ci_₆ alkoxy-carbonyl which may be halogenated, ® Ci_₆ alkoxy-carbamoyl and® C₆__ι4 aryloxy-carbamoyl, (vi) a 5- to 10-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 , optionally substituted by oxo , C₁_₆ alkyl , ^C ₆-i₄ aryl, Ci_₆ alkyl-carbonyl or Ci_₆ alkoxy-carbonyl, (vii) an acyl group represented by the formula: - (C=0) -R^5b (wherein R^5b represents a hydrogen atom, a Ci_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)-OR^5c (wherein R^5c represents a hydrogen atom or a Ci_₆ alkyl group) ,

R^2D 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 Ci.g alkyl group (this Ci_₆ alkyl group may be substituted by a halogen atom, cyano, hydroxy, C₃.₈ 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,

® a Ci_₆ alkyl group (this Ci_₆ alkyl group may be substituted by halogen atoms, cyano, hydroxy, C₃.₈ 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 ) ,

® a C₃_₈ cycloalkyl group,

® a Ci._g alkyl-carbonyl group (this Ci_₆ alkyl- carbonyl group may be substituted by halogen atoms , cyano , hydroxy, C₃.₈ 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),

® a Ci.g alkoxy-carbonyl group,

® a C₃.₈ cycloalkyl-carbonyl group optionally substituted by C__₆ alkyl,

© 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 C_ι_₆ alkyl or C__₆ alkyl-carbonyl) ,

® 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 Ci_₆ alkyl or Ci_₆ alkyl-carbonyl) ,

(4) a 5- to 7-membered aliphatic cyclic amino group optionally further containing hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms and one nitrogen atom (this aliphatic cyclic amino group may be substituted by Ci_ ₆ alkyl or Ci_₆ alkyl-carbonyl) ,

( 5 ) a hydroxy group, and

(6) a Ci.g alkyl-carbonyloxy group, and

R^3b represents ® a C₆.₁₄ aryl group or © 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 Ci_₆ alkyl which may be halogenated, Ci_₆ alkoxy, a halogen atom, carboxyl, Ci_₆ alkoxy-carbonyl, cyano, Ci_₆ alkylthio and Ci_g alkylsulfonyl. As the Ci.g alkyl group represented by R^lb, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. are used, and particularly, a Ci_₄ alkyl group such as methyl, ethyl, propyl, butyl and the like are preferable, and a C__₃ alkyl group such as methyl, ethyl, propyl, etc. are particularly preferable.

As the halogen atom which is a substituent of the Ci.g alkyl group represented by R^lb, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom and the like are used.

As the Ci_g alkoxy-carbonyl which is a substituent of the C__₆ alkyl group represented by R^lD, for example, methoxycarbonyl, ethoxycarbony and the like are preferable.

As the Ci.g alkylthio which is a substituent of the Ci.g alkyl group represented by R^lb, for example, methylthio, ethylthio and the like are preferable.

As the Ci.g alkylsulfinyl which is a substituent of the Ci.g alkyl group represented by R^l , for example, methylsulfinyl, ethylsulfinyl and the like are preferable.

As the Ci_₆ alkylsulfonyl which is a substituent of the Ci.g alkyl group represented by R^lb, for example, methylsulfonyl, ethylsulfonyl and the like are preferable.

As the Ci.g alkoxy which is a substituent of the Ci_₆ alkyl group represented by R^lb, for example, methoxy, ethoxy, propoxy and the like are preferable.

As the Ci_g alkyl-carbonyl which is a substituent of the Ci.g alkyl group represented by R^lb, for example, acetyl, propionyl and the like are preferable.

As the Ci.g alkyl group represented by R^lb, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. are used, and particularly, a Ci_₃ alkyl group such as methyl, ethyl, propyl and the like are preferable, particularly, methyl is preferable.

As the C₆__ι4 aryl group represented by R^lb, for example , phenyl, naphthyl, etc. are preferable, and of them, phenyl is particularly preferable.

As the halogen atom which is a substituent of the Cg_₁₄ aryl group represented by R^lb, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom are used.

As the C₇_₁₅ aralkyl group represented by R^lb, for example, a phenyl-Ci_₃ alkyl group such as benzyl, phenylethyl, phenylpropyl and the like are preferable.

As the Ci.g alkyl group which is a substituent of an amino group represented by R^lb, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. are used, and particularly, a Ci_₃ alkyl group such as methyl, ethyl, propyl and the like are preferable, particularly, methyl is preferable.

As the Ci_₆ alkyl-carbonyl which is a substituent of an amino group represented by R^lb, for example, a Ci_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 R^l , 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 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 halogen atom such as a chlorine atom, a Ci._g alkyl group such as methyl, ethyl and the like, and a Ci_₆ alkoxy group 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 R^lD, for example, phenyl-carbamoyl, etc. are preferable.

As the Ci.g alkyl-carbamoyl which may be halogenated which is a substituent of an amino group represented by R^lb, for example, methylcarbamoyl , ethylcarbamoyl , propylcarbamoyl optionally substituted by a halogen atom (e.g., chlorine atom) and the like are preferable.

As the Ci.g alkoxy-carbonyl which may be halogenated which is a substituent of an amino group represented by R^lb, for example, methoxycarbamoyl, ethoxycarbamoyl, propoxycarbamoyl optionally substituted by halogen atoms (e.g., chlorine atom) and the like are preferable.

As the Ci.g alkoxy-carbamoyl which is a substituent of an amino group represented by R^lD, for example, methoxycarbamoyl , ethoxycarbamoyl , propoxycarbamoyl and the like are preferable.

As the C₆.₁₄ aryloxy-carbamoyl which is a substituent of an amino group represented by R^lb, for example, phenyloxycarbamoyl and the like are preferable.

As the 5- to 10-membered aliphatic heterocyclic group represented by R^lb, 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 used, and of them, 4-piperidyl, 1- piperazinyl, 3-oxazolidinyl, 1-imidazolidinyl and the like are preferable.

As the 5- to 10-membered aliphatic heterocyclic group optionally substituted by oxo, Ci_₆ alkyl (preferably, methyl, ethyl), C₆.₁₄ aryl (preferably. phenyl), C_ι_₆ alkyl-carbonyl (preferably, acetyl, propionyl) or Ci_₆ alkoxy-carbonyl (preferably, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl) represented by R^lb, 1-methyl-4-piperidyl, 4-methyl-1- piperazinyl, 2-oxo-3-oxazolidinyl, '2-oxo-l- imidazolidinyl, 2-oxo-3-phenyl-1-imidazolidinyl and the like are preferable .

As R^5b of the formula: -(C=0)-R^5b represented by R^lb, a hydrogen atom, a Ci_₆ alkyl group which may be halogenated (methyl, ethyl, trifluoromethyl and the like), a C₆__ι4 alkyl group which may be halogenated (phenyl, naphthyl, fluorophenyl, chlorophenyl and the like), etc. are preferable.

As R^5c of the formula - (C=0) -0R^5c represented by R^lb, , a hydrogen atom, a C_ι_₃ alkyl group (methyl, ethyl, etc. ) , etc. are preferable.

As R^lb, a Ci.g alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, pentyl, hexyl, etc.) is preferable, particularly, a C_ι_₃ alkyl group such as methyl, ethyl, propyl, etc. is preferable.

As specific examples of a substituent of the pyridyl group represented by R^2b, 1 to 3, preferably 1 or 2 substituents selected from the following (1) to (6), particularly (1) to (4) are used.

(1) a Ci_₆ alkyl group (e.g. , methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like, preferably a C_x_₄ alkyl group such as methyl, ethyl, propyl, butyl and the like) : this Ci.g alkyl group may be substituted by a halogen atom, cyano , hydroxy, C₃.₈ cycloalkyl or 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 (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 halogen atom (e.g., fluorine atom, chlorine atom, bromine atom, iodine atom),

(3) an amino group optionally having a substituent selected from the group consisting of the following φ to®:

® a Ci.g alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like, preferably a Ci_₃ alkyl group such as methyl, ethyl, propyl and the like) : this C_ι_₆ alkyl group may be substituted by a halogen atom, cyano , hydroxy , ^C ₃-₈ cycloalkyl or 5- to 7-membered aliphatic heterocyclic group optionally containing 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-piperazinyl, morpholino, 2-morpholinyl, 3-morpholinyl, thiomorpholino, 2-thiomorpholinyl, 3- thiomorpholinyl, hexahydroazepin-1-yl and the like),

® a Ci.g alkyl-carbonyl group (e.g., acetyl, propionyl, butylyl, valeryl, isovaleryl, 2- methylbutyryl , pivaloyl and the like): this Ci_₆ alkyl-carbonyl group may be substituted by a halogen atom, cyano, hydroxy , C₃_₈ cycloalkyl or 5- to 7-membered aliphatic heterocyclic group optionally containing 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- piperazinyl, morpholino, 2-morpholinyl, 3-morpholinyl, thiomorpholino, 2-thiomorpholinyl, 3-thiomorpholinyl, hexahydroazepin-1-yl and the like),

® a Ci.g alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl and the like),

© a C₃.₈ cycloalkyl-carbonyl group optionally substituted by Ci_₆ alkyl such as methyl, ethyl (e.g., cyclopropylcarbonyl , cyclobutylcarbonyl , cyclopentylcarbonyl, cyclohexylcarbonyl, 1-methyl- cyclohexylcarbonyl and the like),

© a 5- to 7-membered aliphatic heterocyclic group optionally 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-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 Ci.g alkyl (e.g., methyl, ethyl) or C___₆ alkyl-carbonyl (e.g., acety, propionyl),

® 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 and the like) -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 heterocyclic-carbonyl group may be substituted by Ci.g alkyl (e.g., methyl, ethyl) or Ci.g alkyl-carbonyl (e.g., acety, propionyl),

(4) a 5- or 7-membered aliphatic cyclic amino group which may contain 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 aliphatic cyclic amino group may be substituted with Ci.g alkyl (e.g. , methyl, ethyl) , C_ι_₆ alkyl-carbonyl (e.g. , acety, propionyl) and the like.

( 5 ) a hydroxyl group ,

(6) a Ci.g alkyl-carbonyloxy group (e.g. , acetyloxy, propionyloxy, butyryloxy and the like) .

Of them, as a substituent of the pyridyl group represented by R^2b, for example, a Ci_₆ alkyl-carbonylamino group (e.g. , acetylamino , propionylamino , butylylamino , valerylamino , isovalerylamino, 2-methylbutyrylamino, pivaloylamino and the like) is preferable, and particularly, a C_ι_₃ alkyl-carbonylamino group such as acetyl, propionylamino, etc. is preferable.

As the C₆.₁₄ aryl group represented by R^3b, 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 R^3b, 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.

As the Ci.g alkyl group which may be halogenated, which is a substituent of the C₆__ι4 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., fluorine, chlorine and the like) are used, and particularly, a Ci_₃ alkyl group which may be halogenated such as methyl, ethyl, propyl, trifluoromethyl and the like are preferable.

As the Ci_₆ alkoxy which is a substxtuent of the C₆.₁₄ aryl group or the aromatic heterocyclic group, for example, methoxy, ethoxy, propoxy, etc. are used, and of them, methoxy is particularly preferable.

As the halogen atom which is a substituent of the Cg.₁₄ aryl group or the aromatic heterocyclic group, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom are used, and of them, a fluorine atom and a chlorine atom, etc. are preferable.

As the Ci.g 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 preferable.

As the Ci_₆ alkylthio which is a substituent of the C₆.₁₄ aryl group or the aromatic heterocyclic group, for example, methylthio, ethylthio and the like are preferable.

As the Ci_₆ alkylsulfonyl which is a substituent of the C₆.₁₄ aryl group or the aromatic heterocyclic group, for example, methylsulfonyi, ethylsulfonyl and the like are preferable.

As R^3b, a C₆.₁₄ aryl group optionally having a substituent selected from the group consisting of Ci_₆ 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 (Ibbb), for example, (1) the compound (Ibbb) wherein R^lb is a Ci_₆ alkyl group optionally having a substituent selected from the group consisting of a halogen atom, hydroxy, Ci_₆ alkoxy, Ci_ ₆ alkylthio, Ci_₆ alkylsulfinyl and C_ι_₆ alkylsulfonyl, R^2b is a Ci.g alkyl-carbonylamino group or a C₃_₈ cycloalkylamino group, R^3b is a C₆.₁₄ aryl group optionally having a substituent selected from the group consisting of Ci.g alkyl and a halogen atom,

(2) the compound (Ibbb) wherein R^lb is a C_ι_₃ alkyl group optionally having a substituent selected from the group consisting of a halogen atom, hydroxy, Ci_₆ alkoxy, Ci_ ₆ alkylthio, C_ι_₆ alkylsulfinyl and Ci_₆ alkylsulfonyl, R^2b is a Ci_₃ alkyl-carbonylamino group or a C₃.₈ cycloalkylamino group, R^3b is a phenyl group optionally having a substituent selected from the group consisting of methyl or a chlorine atom, and the like are preferable. As preferable specific examples of the compound (Ibbb) , compounds produced in Examples 1 to 113 described later are exemplified, and of them, 5-[2-(tert- butoxycarbonylamino) -4-pyridyl] -2-ethyl-4- ( 3- methylphenyl) -1,3-thiazol (Example 3), [4- (3- methylphenyl) -5- (2-methyl-4-pyridyl) -1, 3-thiazol-2- yl] amine (Example 7-4), 2-ethyl-5- ( 2-fluoro-4- pyridyl) -4- ( 3-methylphenyl) -1 , 3-thiazole (Example 11), 5- (2-fluoro-4-pyridyl) -4- (3-methylphenyl) -2- [4- (methylthio) henyl] -1, 3-thiazole (Example 15), 4- (3- methylphenyl) -5- ( 2-methyl-4-pyridyl) -2- [4- (methylthio)phenyl] -1, 3-thiazole (Example 16-1), 4- [ 2-ethyl-4- (3-methylphenyl) -1 , 3-thiazol-5-yl] -2- pyridylamine (Example 22), N- [ 4- [ 2-ethyl-4- ( 3- methylphenyl) -1 , 3-thiazol-5-yl] -2-pyridyl]acetamide (Example 29-2), N- [4- [ 2-ethyl-4- ( 3-methylphenyl) -1 , 3- thiazol-5-yl] -2-pyridyl]propionamide (Example 29-4), N- [4- [4- (3-chlorophenyl) -2-methyl-1 , 3-thiazol-5-yl] - 2-pyridyl]acetamide (Example 30-1), N-[4-[4-(3- chlorophenyl) -2-ethyl-l, 3-thiazol-5-yl] -2- pyridyl]aσetamide (Example 30-2), N-[4-[4-(3- chlorophenyl) -2-propyl-1 , 3-thiazol-5-yl] -2- pyridyl]acetamide (Example 30-3), N-[4-[4-(3- chlorophenyl) -2-methyl-1,3-thiazol-5-yl] -2- pyridyl]propionamide (Example 30-7), N-[4-[4-(3- chlorophenyl) -2-ethyl-l, 3-thiazol-5-yl] -2- pyridyl]propionamide (Example 30-8), N-[4-[4-(3- chlorophenyl) -2-propyl- 1, 3-thiazol-5-yl] -2- pyridyl]propionamide (Example 30-9), N-cyclohexyl-4- [ 2-ethyl-4- ( 3-methylphenyl) -1 , 3-thiazol-5-yl] -2- pyridylamine (Example 36-4), N-cyclohexyl-4- [ 4- ( 3- methylphenyl) -2- ( 4-methylsulfonylphenyl) -1 , 3-thiazol- 5-yl] -2-pyridylamine (Example 36-5), N-cyclopentyl-4- [2-ethyl-4-( 3-methylphenyl) -1 , 3-thiazol-5-yl] -2- pyridylamine (Example 36-6), N-cyclopentyl-4- [4- (3- methylphenyl) -2- ( 4-methylsulfonylphenyl) -1 , 3-thiazol- 5-yl] -2-pyridylamine (Example 36-7), 4- [4- (3- σhlorophenyl) -2-ethyl-l , 3-thiazol-5-yl] -N-cyclohexyl- 2-pyridylamine (Example 36-10), 4- [4- (3- chlorophenyl) -2-ethyl-l , 3-thiazol-5-yl] -N- cyclopentyl-2-pyridylamine (Example 36-11), N-[4-(3- methylphenyl) -5- ( 2-methyl-4-pyridyl) -1 , 3-thiazol-2- yl]acetamide (Example 39), N- [4- (3 , 5-dimethylphenyl) - 5- ( 2-methyl-4-pyridyl) -1 , 3-thiazol-2-yl]nicotinamide (Example 42-1), 6-chloro-N- [ 4- ( 3 , 5-dimethylphenyl) -5- ( 2-methyl-4-pyridyl) -1 , 3-thiazol-2-yl]nicotinamide (Example 44-3), N- [4- (3 , 5-dimethylphenyl) -5- (2- methyl-4-pyridyl) -1 , 3-thiazol-2-yl] -6- methylήicotinamide (Example 46-3), N-[4-(3,5- dimethylphenyl) -5- ( 2-methyl-4-pyridyl) -1 , 3-thiazol-2- yl] -6-methoxynicotinamide (Example 48-3), 4-(3- methylphenyl) -5- ( 2-methyl-4-pyridyl) -2- ( 4- methylsulfinylphenyl) -1,3-thiazole (Example 54), 4- (3-methylphenyl) -5- ( 2-methyl-4-pyridyl) -2- (4- methylsulfonylphenyl) -1,3-thiazole (Example 57), 5- (2-fluoro-4-pyridyl) -4- ( 3-methylphenyl) -2- (4- methylsulfonylphenyl) -1,3-thiazole (Example 58-4), N- [ 4- [ 4- ( 3-chlorophenyl) -2- ( 4-methylsulfonylphenyl) - 1 ,3-thiazol-5-yl] -2-pyridyl]acetamide (Example 58-6), N- [4- [4- (3-chlorophenyl) -2- ( 4-methylsulfonylphenyl) - 1 , 3-thiazol-5-yl] -2-pyridyl]propionamide (Example 58- 7) , N-[4-[4-(3-chlorophenyl)-2-(4- methylsulfonylphenyl) -1 , 3-thiazol-5-yl] -2- pyridyl]pivalamide (Example 58-8) and the like are preferable.

As a salt of the compound (la), (lb) or (Ic), for example, metal salts, ammonium salts, 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, triethanolamin, cyclohexylamine, dicyclohexyamine, N,N' -dibenzylethylenediamine, etc. are exemplified. As suitable examples of salts with inorganic acids, for example, salts with hydrochloric acid, hydrobromiσ 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, maleic 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 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 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 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, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, etc. are preferable.

A pro-drug of the compound (la), compound (lb), compound (Iσ), compound (Iaa), compound (Ibb) or a salt thereof of the present invention (hereinafter, sometimes referred to as compound (I) of the present invention) means a compound which is converted into the compound ( I ) of the present invention by reactions of enzymes, gastric acid and the like under physiological conditions in organisms, namely, a compound which causes enzymatic oxidation, reduction, hydrolysis and the like to be converted into the compound (I) of the present invention, and a compound which causes hydrolysis and the like by gastric acid, etc. to be converted into a compound (I) of the present invention.

As the pro-drug of the compound (I) of the present invention, compounds obtained by acylation, alkylation and phosphorylation of an amino group of the compound (I) of the present invention (e.g., compounds obtained by eicosanoylation, alanylation, pentylaminocarbonylation, ( 5-methyl-2-oxo-l,3-dioxolen-4- yl)methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert- butylation of an amino group of the compound (I) of the present invention, etc.); compounds obtained by acylation, alkylation, phosphorylation and boration of a hydroxyl group of the compound (I) of the present invention (e.g., compounds obtained by acetylation, palmitoylation, propanoylation, pivaloylation, succinylation, fumarylation, alanylation, dimethylaminomethylcarbonylation of a hydroxyl group of the compound (I) of the present invention, etc.); compounds obtained by esterification and amidation of a carboxyl group of the compound ( I ) of the present invention (e.g., compounds obtained by ethylesterification, phenylesterification , carboxymethylesterification, dimethylaminomethylesterification, pivaloyloxymethylesterification, ethoxycarbonyloxyethylesterification, phthalidylesterification, ( 5-methyl-2-oxo-l , 3- dioxolene-4-yl)methylesterification, cyclohexyloxycarbonylethylesterification, methylamidation of a carboxyl group of the compound ( I ) of the present invention, etc.), etc. are exemplified. These compounds can be produced from the compound ( I ) of the present invention according to methods known per se.

Further, a prodrug of the compound (I) of the present invention may also be one which is converted into the compound (I) of the present invention under physiological conditions as described in "Iyakuhin no Kaihatsu", vol.7, Bunshi Sekkei, pp.163 to 198, Hirokawa Shoten, 1990.

A method for producing the compound ( la) , (lb), (Iσ) or a salt thereof of the present invention will be illustrated below. Hereinafter, the compound (I) means a compound including compounds (la), (lb), (Ic), (Ibb) and (Ibbb) .

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-ANo.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 formulae also include salts, and as this salt, for example, the same salts as for the compound (la) are exemplified.

Reaction Formula 1 R³C0R⁸

2 ^H 3

R -C-COR

]

Ha l

(1 X)

R'-C- (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 (III), R⁸ represents, for example, ® a Ci_₆ alkoxy (e.g., methoxy, ethoxy and the like), © a di-Ci_g alkylamino (e.g., dimethylamino , diethylamino and the like), ® an N-C₆.₁₀ aryl-N-Ci_₆ alkylamino (e.g., N-phenyl-N-methylamino and the like), © a 3- to 7- membered cyclic amino optionally substituted with a C₆.₁₀ 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 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) .

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, 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 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 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 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.

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, 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 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 R⁸ are exemplified.

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 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 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 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 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 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, 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 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.

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 .

A compound (I) can be obtained by condensing a 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, 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).

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 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.

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.

Reaction formula 2: ι S

^{R H} II

R¹⁰CONCS ^ R^{1 0}CONH-C-R '

(X I ) (X I I )

yd ro l ys i s

(XIV) P₄S₁₀ (X)

Lawesson' s reagent

A compound (XII) can be obtained by condensing a compound (XI) with amines represented by R¹H.

In the compound (XI), R¹⁰ 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, Ci_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).

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 , 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, preferably from about 0.5 to about 30 hours.

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 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.

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 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 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 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 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 (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, 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 minutes to about 72 hours, preferably from about 0.5 to about 30 hours.

A compound (X) can also be obtained by treating a compound (XIII) with dithiophosphoric acid 0,0-diethyl ester 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, 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 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 .

A compound (X) can also be obtained by treating a 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) .

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 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 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 acyamino optionally having a substituent is obtained by reacting the 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.

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 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-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 .

Further, of compounds (I), that in which a substituent at the 5-position of a thiazole ring is acylaminopyridyl optionaly 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 .

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 mol of the corresponding 5- (2- aminopyridyl) thiazole .

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.

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 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 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 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 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 .

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 .

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 "cfmines", 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 .

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 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, 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 reaction can progress, and for example, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, amides, halogenated hydrocarbons, nitriles, water or mixtures of two or more of them, etc. are used.

The reaction temperature is from about 0°C to about 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 .

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 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 "organic peracid", for example, peracetic acid, pertrifluoroacetic acid, m- chloroperbenzoiσ 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, halogenated 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 time is usually from about 5 minutes to about 72 hours, 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. 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 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 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, organic acids such as formic acid, acetic acid and the like, etc. are exemplified.

As the above-mentioned "metal oxide", for example, vanadium oxide (V₂0₅), osmium tetraoxide (Os0₄), tungsten oxide (W0₃), molybdenum oxide (Mo0₃), selenium dioxide (Se0₂), 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 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 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 purifie^~d by separation means such as recrystallization, distillation, chromatography and the like.

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.

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 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 about 5 mol per mol of the corresponding sulfide.

As the above-mentioned "metal oxide", for example, vanadium oxide (V₂0₅) , osmium tetraoxide (Os0₄) , tungsten oxide (W0₃) , molybdenum oxide (Mo0₃), selenium dioxide (Se0₂), chromium oxide (Cr0₃), etc. are exemplified.

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.

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.

As the protective group for amino, for example, formyl or, C___₆ alkyl-carbonyls (e.g., acetyl, propionyl and the like) , phenylcarbonyl , C__₆ alkoxy-carbonyls (e.g. , methoxycarbony, ethoxycarbonyl and the like), phenyloxycarbonyl , C₇.₁₀ aralkyloxy-carbonyls (e.g., 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_₆ alkyl-carbonyls (e.g. , acetyl, propionyl, valeryl and the like) , nitro, etc. are used, and the number of the substituent is 1 to 3.

As the protective group for carboxy, for example, Ci.g 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, halogen atoms (e.g., fluorine, chlorine, bromine, iodine and the like), formyl, Ci_₆ alkyl- carbonyls (e.g., acetyl, propionyl, butylcarbonyl and the like), nitro, C__.₆ alkyls (e.g., methyl, ethyl, tert-butyl and the like), C₆__ι0 aryls (e.g., phenyl, naphthyl and the like), etc. are used, and the number of the substituent is 1 to 3. As the protective group for hydroxy, for example, Ci.g alkyls (e.g. , methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like), phenyl, C₇__ϋ aralkyls (e.g., benzyl and the like) , formyl, C_ι_₆ alkyl-carbonyls (e.g. , acetyl, propionyl and the like) , phenyloxycarbonyl, C ._lλ aralkyloxy-carbonyls (e.g., benzyloxycarbonyl and the like), tetrahydropyranyl, tetrahydrofuranyl, andsilyl, each optionally having a substituent, and so on are used. As these substituents, halogen atoms (e.g., fluorine, chlorine , bromine, iodine and the like) , C_ι_₆ alkyls (e.g. , methyl, ethyl, tert-butyl and the like), C₇._ϋ aralkyls (e.g., benzyl and the like), C₆.₁₀ 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, 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 Shin Jikken Kagaku Koza 14, 15, 1977 (Maruzen) , etc. are adopted.

As the above-mentioned "alcohols", for example, methanol, ethanol, propanol, isopropanol, tert-butanol, etc. are exemplified.

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.

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.

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, 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.

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. Thus obtained compound (I) can be isolated and purified from a reaction solution by known means, for example, rolling, concentration, solvent extraction, fractionation, crystallization, 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.

Further, the compound (I) may be a hydrate or non-hydrate.

The compound (I) may be labeled with an isotope (e.g., ³H, ¹⁴C, ³⁵S), etc.

The compound (I) of the present invention or a pro-drug thereof (hereinafter also referred to as the compound of the present invention) has an excellent p38 MAP kinase inhibitory activity, TNF-α inhibitory activity (TNF-α production inhibitory activity, TNF-α action inhibitory activity), phosphodiesterase IV (PDE IV) inhibitory activity, adenosine receptor (e.g., adenosine A_1# A_2a, A_2b, A₃ receptors) antagonizing activity and the like , further has low toxicity and few side effects . Therefore, the compound of the present invention is useful as a safe medicine such as a p38 MAP kinase inhibitor, a TNF-α production inhibitor, a PDE IV inhibitor, an adenosine receptor (e.g., adenosine A_x, A_2a, A_2b or A₃ receptor) antagonist, etc.

A pharmaceutical composition comprising the compound of the present invention shows an excellent p38 MAP kinase inhibitory activity and TNF-α inhibitory activity on mammals (e.g., mouse, rat, hamster, rabbit, felis, canis, bovine, ovis, monkey, human and the like) and has also an excellent (oral) .absorbing property, (metabolic) stability and the like. Therefore, this composition can be used as a pharmaceutical composition for preventing and/or treating p38 MAP kinase-mediated diseases and TNF-α production-mediated diseases, for example, asthma, allergic diseases, atopic dermatitis, inflammation, inflammatory eye diseases, Addison's disease, autoimmune hemolytic anemia, systemic lupus erythematosus , psoriasis, rheumatism, central nerve disorders (e.g., cerebrovascular disorders such as encephalorrhagy, cerebral infarction and the like, head trauma, spinal cord injury, cerebral edema, multiple sclerosis and the like), neuro-degenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), aquired immune deficiency syndrome (AIDS) encephalopathy), meningitis, diabetes, arthritis (e.g., chronic rheumatoid arthritis , osteoarthritis, rheumatoid spondylitis , gouty arthritis , synovitis), toxaemias (e.g., sepsis, septic shock, endotoxic shock. Gram-negative sepsis, toxic shock syndrome), inflammatory bowel diseases (e.g., Crohn's disease, ulcerative colitis) , inflammatory lung diseases (e.g., chronic pneumonia, pulmonary silicosis , pulmonary sarcoidosis, lung tuberculosis), or cachexias (e.g., cachexy due to infection, cancerous cachexia, cachexy due to acquired immume deficiency syndrome (AIDS) ) , arterial sclerosis, Creutzfeldt-Jakob disease, virus infection (e.g., virus infection by cytomegalovirus , influenza virus, herpes virus and the like), angina pectoris, myocardial infarction, congestive heart failure, hepatitis, transplant, dialysis hypotension, diffuse intravascular coagulation symdrome, etc. A pharmaceutical composition comprising the compound of the present invention shows an excellent adenosine receptor antagonizing activity on mammals (e.g., mouse, rat, hamster, rabbit, felis, canis, bovine, ovis, monkey, human and the like) and has also an excellent (oral) absorbing property, (metabolic) stability and the like. Therefore, this composition can be used as a pharmaceutical composition for preventing and/or treating adenosine receptor-mediated diseases (particulaly, adenosine A₃ receptor-mediated diseases) , for example, asthma, allergic diseases, inflammation, Addison's disease, autoimmune he olytic anemia, Crohn's disease, psoriasis, rheumatism, central nerve disorders (e.g. , cerebrovascular disorders such as encephalorrhagy, cerebral infarction, apoplectic stroke and the like, head trauma, spinal cord injury, cerebral edema, multiple sclerosis and the like), neuro-degenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), diabetes and the like, preferably, central nerve disorders, asthma, allergic disorders and the like) .

Further, a pharmaceutical composition comprising the compound of the present invention shows an excellent PDE IV inhibitory activity, and can be used as a pharmaceutical composition for preventing and/or treating diseases caused by inflammation, for example, bronchial asthma, chronic obstructive pulmonary disease (COPD), chronic rheumatoid arthritis, autoimmune diseases, diabetes mellitus, graft versus host disease, multiple sclerosis, sepsis, psoriasis, osteoporosis, depression, central function degradation after cerebrovascular obturation, cerebrovascular dementia, Alzheimer's dementia, obesity, cardiac insufficiency, etc.

A pharmaceutical composition comprising the compound of the present invention has a low toxicity, and can be formulated, according to means known per se generally used in production of medicinal preparations, as it is or in admixture with a pharmacologically acceptable carrier, into for example tablets (including sugar-coated tablet and film-coated tablet), powders, granules, capsules (including soft capsule), liquid, injections, suppository, sustained release preparations and the like, and safely administered orally or parenterally (e.g., topical, rectal, intravenous administrations, etc.). The content of the compound of the present invention in the preparation of the present invention is from about 0.01 to about 100 wt% based on the whole preparation. This dose varies depending on the subject to be dosed, dose route, disease, symptom and the like, and it may advantageously be administered orally, as a p38 MAP kinase-mediated disease preventive and therapeutic agent, for example to an arthritis patient (body weight: about 60 kg) , in a dosage of about 0.01 to about 30 mg/kg-body weight/day, preferably about 0.1 to about 20 mg/kg-body weight/day, further preferably about 1 to about 20 mg/kg-body weight/day in terms of the effective component [the compound of the present invention], in one time or divided into several times a day.

As a pharmacologically acceptable carrier which may be used in production of a preparation of the present invention, various conventional organic or inorganic carrier substances are exemplified as preparation raw materials, and for example, an excipient, brightener, binder and disintegrating agent in a solid preparation, and a solvent, solubilizer, suspending agent, isotonization agent, buffer, soothing agent and the like in a liquid preparation, etc. are exemplified. Further, if necessary, usual additives such as a preservative. antioxidant, coloring agent, sweetener, adsorbent, wetting agent and the like can be appropriately used in suitable amount .

As the exipient, for example, lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silic acid, etc. are exemplified.

As the brightener, for example, magnesium stearate, calcium stearate, talc, colloidal silica, etc. are exemplified.

As the binder, for example, crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, starch, saccharose, gelatin, methyl cellulose, carboxymethyl cellulose sodium, etc. are exemplified.

As the disintegrating agent, for example, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, etc. are exemplified.

As the solvent, for example, injection water, alcohol, propylene glycol, Macrogol, sesame oil, corn oil, olive oil, etc. are exemplified.

As the dissociation aid, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, etc. are exemplified.

As the suspending agent, for example, surfactants such as stearyltriethanolamine, sodium laurylsulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerine monostearate and the like; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethyl cellulose sodium, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and the like, etc. are exemplified.

As the isotonization agent, for example, glucose. D-sorbitol, sodium chloride, glycerine, D-mannitol, etc. are exemplified.

As the buffer, for example, buffering solutions of a phosphate, acetate, carbonate, citrate, etc. are exemplified.

As the soothing agent, for example, benzyl alcohol, etc. are exemplified.

As the preservative, for example, p- hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc. are exemplified.

As the antioxidant, for example, a sulfite, ascorbic acid, α-tocopherol, etc. are exemplified.

Further, the compound of the present invention can be used in combination with other drugs than the compound of the present invention.

Examples of the drug which can be combined with the compound of the present invention (hereinafter, sometimes referred to as combination drug) include the following compounds .

(1) Non-steroidal anti-inflammatory drugs (NSAIDs) ® Classical NSAIDs

Alcofenac, acechrofenac, sulindac, tolmetin, etodolac, fenoprofen, tiaprofenic acid, meclofenamic acid, meroxicam, theoxicam, lolnoxicam, nabtomen; acetaminophen, phenacetin, ethenzamide, sulpyrine, antipyrine, migrenin, aspirin, mefenamic acid, flufenamic acid, dichlorophenac sodium, loxoprofen sodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen, pxaprozin, flurbiprofen, fenbufen, pranoprofen, frotacfenin, piroxicam, epirizole, tiaramide hydrochloride, sartoprofen, gabexate mesilate, camostat mesilate, urinastatin, colchicines, probenezide, sulfinpyrazon, benzbromarone, allopurinol, sodium aurothiomalate, sodium hyaluronate, sodium salicylate, morphine hydrochloride , salicylic acid, atropine, scopolamine, morphine, pethidine, levorphanol, oxymorphone, or a salt thereof, and the like.

Salicylic acid derivatives (e.g., cerecoxiv, lofecoxiv, aspirin), MK-663, baldecoxiv, SC-57666, thylacoxiv, S-2474, dichlofenac, indomethacin, loxoprofen, and the like.

ML-300, p54 (COX inhibition & 5-lipoxygenase inhibition) and the like.

® Nitric oxide free type NSAIDs

(2) Disease modifying anti-rheumatic drugs (DMARDs)

® Gold preparation

Auranofin and the like .

D-penicillamine

® Anti-malarial agent

Chloroquine and the like.

Refulnomide and the like.

(3) Anti-cytokine agents

(I) Protein preparations

(i) TNF inhibitors

Ethanarcept, infliximav, D2E7, CDP-571, PASSTNF-α, soluble TNF receptor, TNF-α binding protein, anti-TNF-α antibody and the like.

(ii) Interleukin-1 inhibitors

Anaquinra (interleukin-1 receptor antagonist), soluble interleukin-1 receptor and the like.

(iii) Interleukin-6 inhibitors MRA (anti-interleukin-6 receptor antibody), anti-interleukin-6 antibody, Sant-7 (interleukin-6 receptor antagonist) and the like.

(iv) Interleukin-10 drugs

Interleukin-10 and the like.

(v) Interleukin-12 inhibitors

Anti-interleukin-12 antibody and the like.

(v) Drugs having interferon-α and -γ inhibition and TNF-α inhibition simultaneously

AGT-1.

(II) Nonprotein preparations

(i) MAP kinase inhibitors

PD-98059 and the like.

(ii) Gene regulators

Inhibitors of a molecule related to signal transfer such as SP-100030, NF- K , NF- K B, IKK-1, IKK-2, AP-1 etc., and the like.

(iii) Cytokine production suppressors

T-614, SR-31747, sonatimod and the like.

(iv) TNF-α converting enzyme inhibitors

(v) Interleukin-lβ converting enzyme inhibitors

HMR3480/VX-740 and the like.

(vi) Interleukin-6 antagonists

SANT-7 and the like.

(vii) Interleukin-8 inhibitors

IL-8 antagonist, CXCRl & CXCR2 antagonist and the like.

(viii) Chemokine antagonists

MCP-1 antagonist and the like.

(ix) Interleukin-2 receptor antagonists

Denileukin, diftitox and the like.

(x) Therapeutic vaccines

TNF-α vaccine and the like.

(xi) Gene therapeutic agents

Gene therapeutic agents intended to accentuate expression of a gene having an anti-inflammatory action such as interleukin-4, interleukin-10, soluble interleukin-1 receptor, soluble TNF-α receptor, HSV-tk and the like .

(xii) Anti-sense compounds

ISIS-104838 and the like.

(4) Immunomodulators (immunosuppressant )

(i) T-cell differentiation modifiers

Ethyl 6,7-dimethoxy-4- ( 3 , 4-dimethoxyphenyl ) -2- (1,2, 4-triazol-l-ylmethyl)quinoline-3-carboxylate (JP-A No. 7-118266)

(ii) Others

Methotrexate, cyclophosphamide, MX- 68, atiprimode dihydrochloride, BMS- 188667, CKD-461, limexolone, cyclosporin, tacrolimus, gusperimus , azathiopurine, anti-lymphocyte serum, dry sulfonated immunoglobulin, erythropoietin, colony stimulation factor, interleukin, interferon and the like.

(5) Steroid drugs

Dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone, triamcinolone acetonide, fluocinonide, fluocinolone acetonide, prednisolone, methylprednisolone, cortisone acetate, hydrocortisone, fluorometholone, beclomethasone propionate, erythritol and the like.

(6) c-JUN N-terminal kinase (JNK) inhibitor

Compounds described in WO00/35906, WO00/35909, WO00/35921, WO00/64872 or WO00/75118.

(7) Others

(i) T-cell inhibitors

IR-501 (T-cell receptor peptide) and the like, (ii) Inosine monophosphate dehydrogenase (IMPDH) inhibitors

Micophenolate mophetyl, VX-497 and the like, (iii) Adhesive molecule inhibitors ISIS-2302, selectin inhibitor, ELAM-1, VCAM-1, ICAM-1 and the like.

( iv) Thalido ide

(v) Monocyte therapeutic agents

Leukobax and the like .

(vi) Cathapsin inhibitors

(vii) Matrix MMPs inhibitors

BB-3644, CGS-27023A, Bay-12-9566, KB-R7785, L- 758354, POL-641 and the like.

(viii) Glucose- 6-phosphate dehydrogenase inhibitors

CBF-BS2 and the like.

(ix) Hydroortate dehydrogenase (DHODH) inhibitors

(x) Phosphodiesterase IV (PDE IV) inhibitors

CG-1088 and the like.

(xi) Phospholipase A₂ inhibitors

(xii) iNOS inhibitors

NOX-200 and the like.

(xiii) Microtuble stimulants

Pacritaxel and the like.

(xiv) Microtuble inhibitors

Leumacon and the like.

(xv) MHC class II antagonists

ZD-2315 and the like.

(xvi) Prostacyclin agonists

Iloprost and the like.

(xvii) CD4 antagonists

4162W94, kelliximav and the like.

(xviii) CD23 antagonists

(xix) LTB4 receptor antagonists

CGS-25019C and the like.

(xx) 5-lipoxygenase inhibitors

Dileuton and the like.

(xxi) Cholinesterase inhibitors

Galanthamine and the like . (xxii) Thyrosinkinase inhibitors

YT-146 and the like.

(xxiii) Carepsin B inhibitors

(xxiv) Adenosine deaminase inhibitors

Pentostatin and the like.

(xxv) Osteogenesis stimulants

(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 No. 8-231659) and the like .

(xxvi) Dipeptidyl peptitase inhibitors

TMC-2A and the like.

(xxvii) TRK-530, TOK-8801

(xxviii) Collagen agonists

AI-200 and the like.

(xxix) Capsaicin cream

(xxx) Hyaluronic acid derivatives

Sinvisc δhylan G-F 20), othovisσ and the like.

(xxxi) Glucosamine sulfate

(xxxii) Amyprilose

(6) Used after synovia excision.

(7) Used after therapy using Prosorba column.

Examples of the combination drug other than the above-mentioned compounds include antibacterial agents, antifύngal agents, antiprotozoan agents, antibiotics, antitussive and expectorants, sedatives, narcotics, antiulcer agents, antiarrhythmic agents, hypotensive diuretics, anticoagulants, tranquilizers , antipsychotics, antitumor agents, anti-hyperlipidemia agents, muscle relaxants, anticonvulsants , antidepressants, antiallergic agents, cardiac restoratives, arrhythmia therapeutic agents, vasodilators, vasoconstrictors, hypotensive diuretics, diabetes therapeutic agents, antinarcotics , vitamin agents, vitamin derivatives, antiasthmatic agents, thamuria and acrasia therapeutic agents, atopic dermatitis therapeutic agents, allergic gastritis therapeutic agents, vasopressor agents, endotoxin antagonists or antibories, signal transfer inhibitors, inflammatory mediator action suppressants, inflammatory mediator action suppressing antibodies, anti- inflammatory mediator action suppressants, anti- inflammatory mediator action suppressing antibodies, and the like. Specific examples thereof are listed below. (1) Antibacterial agents φ Sulfa drugs

Sulfamethizole, sulfisoxazole, sulfamonomethoxin, sulfamethyzole, salazosulfapyridine, sulfadiazine silver and the like.

Nalidixic acid, pipemidic acid trihydrate, enoxacin, norfloxacin, ofloxacin, tosfloxacin tosilate, cyprofloxacin hydrochloride , lomefloxacin hydrochloride , sparfloxacin, fleloxacin and the like.

® Anti-tuberculous agents

Isoniazid, ethambutol (ethambutol hydrochloride) , p-aminosalicylic acid (calcium p-aminosalicylate) , pyradinamide , ethionamide, prothionamide, rifampicin, streptomycin sulfate, kanamyσin sulfate, cycloserine and the like.

® Anti-acid fast bacteria drugs

Diaphenylsulfone, rifampicin and the like.

® Anti-viral drugs

Idoxuridine, aciclovir, vitalavin, ganciclovir and the like.

Didopsin, didanosin, sarcitavin, indinavir sulfate ethanol adduct, litonavir and the like.

® Anti-spiroσhaeta drugs ® Antibiotics

Tetraσyclin hydrochloride, ampicillin, piperacillin, gentamycin, dibekaσin, kanendomyci , lipidmycin, tobramycin, amikacin, fradiomycin, sisomycin, tetracycline, oxytetracycline, rolitetracycline, doxycycline, ampicillin, piperacillin, ticarcillin, cephalothin, cefapirin, cefaloridine, cefaclor, cefalexin, cefuroxadine , cefadroxil, defamandole, cefatoam, cefuroxime, cefathiam, cefathiamhexetyl, cefuroxime akycetyl, cefdinyl, σefditorenepivoxyl, ceftazidime, cefpiramide, σefsulodin, σefmenoxime, cef odoxime proxetyl , cefpirom, cefazopurane, cefepim, cefsulodin, σefmenoxime, cefmethazole, cefminox, cefaxytin, σefbuperazone, latamoquinacef , flomoquinacef , cefazolin, cefataxime, ce operazone,ceftizoxime, moxalactam, thienamycin, sulfazesin, azthreonam, or a salt thereof , griseofulvin, lancasidines [Journal of Antibiotics, 38, 877-885 (9185)], azole-based compounds [2-[(2R, 2R)-2-(2,4- difluorophenyl)-2-hydroxy-l-methyl-3-(lH-l,2,4- triazol-1-yl)propyl]-4-[4-(2,2,3,3- tetrafluoropropoxy)phenyl-3- (2H, 4H) -1, 2 , 4-triazolone, fulconazole, itraconazole, etc.] and the like. (2) Antifungal agents

® Polyethylene-based antibiotics (e.g., amphotericin, B, nystatin, trichomycin)

® Cytosine metabolism antagonists (e.g., flucytosine)

® Imidazole derivatives (e.g., econazole, clotrimazole, miconazole nitrate, bihonazole, cloconazole)

' © Thiocarbamic acid derivatives (e.g.. trinaphthol and the like)

(3) Anti-protozoan agents

Metronidazole, tinidazole, diethyl citrate carbamycin, quinine hydrochloride, quinine sulfate and the like .

(4) Antitussive and expectorants

Ephedrine hydrochloride , noscapine hydrochloride, dihydrocodeine phosphate, isoproterenol hydrochloride, ephedrine hydrochloride , methylephedrine hydrochloride , noscapine hydrochloride, allocramide, chlorophedianole, picoperidamine, chloperastine, protokylol, isoproterenol, salbutamol, terebuthaline, oxypetebanol , morphine hydrochloride, dextropetolfan hydrobromide , oxycodone hydrochloride , dimorfan phosphate, tipepidine hibenzate, pentoxyverine citrate, clofedanole hydrochloride, benzonatate, guaifenesin, bromhexine hydrochloride, ambroxol hydrochloride, acetylcysteine, ethylcycteine hydrochloride, carbocysteine and the like.

(5) Sedatives

Chlorpromazine hydrochloride, atropine hydrochloride, phenobarbitol, barbitol, amobarbitol, pentobarbitol, thiopentanol sodium, thiamylal sodium, nitrazepam, estazolam, flurazepam, haloxazolam, triazolam, flunitrazepam, bromovalerylurea, chloral hydrate, triclofos sodium and the like.

(6) Narcotics

(6-1) Local anesthetics

Cocaine hydrochloride, procaine hydrochloride, lidocaine, dibucaine hydrochloride, tetracaine hydrochloride, mepivacaine hydrochloride, bupivacaine hydrohcloride , oxybuprocaine hydrochloride, ethyl aminobenzoate, oxethazeine, and the like.

(6-2) General anesthetics

® Inhalation anesthetics (e.g. , ether, halothane, nitrous oxide, influrane, enflurane) © Vein anesthetics (e.g. , ketamine hydrochloride, droperidol, thiopental sodium, thiamylal sodium, pentobarbitol) , and the like.

(7) Anti-ulcer agents

Methacropromide , histidin hydrochloride, lansoprazole, methocropramide, pirenzepine, cimetidine, ranitidine, famotidine, urogastrin, oxathezeine, proglumide, omeprazole, sucralfate, sulpiride, cetraxate, gefalnate, aldioxa, teprenone, prostaglandin and the like .

(8) Arrhythmia therapeutic agents

® Calcium channel blockers (e.g., verapamil, diltiazem) , and the like.

(9) Hypotensive diuretics

Hexamethonium bromide, clonidine hydrochloride, hydrochlorothiazide, trichlormetiazide, furosemide, ethacrynic acid, bumetanide, mefruside, azosemide, spironolactone, potassium canrenoate, triamterene, amiloride, acetazolamide, D-mannitol, isosorubide, aminoferine and the like.

(10) Anticoagulants

Heparin sodium, sodium citrate, activated protein C, tissue factor route inhibitor, antithrombin III, dalteparin sodium, warfarin potassium, algatrovane, gabexate, sodium citrate, ozaσrel sodium, ethyl icosapentaenoate, varaprosto sodium, alprostadil, ticlopidine hydrochloride, pentoxyfylline, dipyridamole, thiokinase, urokinase, streptokinase, and the like. (11) Tranquilizers

Diazepam, lorazepam, oxazepam, chlordiazepoxide, medazepam, oxazolam, σloxazolam, clotiazepam, bromazepam, etizolam, fludiazepamm, hydroxydine, and the like.

(12) Antiphychotics

Chlorpromazine hydrochloride, prochlorperazine, trifluoroperazine, thiolidazine hydrochloride, perphenazine malate, fluphenazine enantate, prochlorperazine maleate, levomepromazine maleate, promethazine hydrochloride, haloperidol, bromperidol, spiperone, reserpine, clocapramine hydrochloride, sulpiride, zotepine and the like.

(13) Anti-tumor agents

6-0- (N-chloroacetylcarbamoyl)fumagylol, bleomycin, methotrexate, actinomycin D, mitomycin C, daunorubicin, adriamycin, neocarzinostatin, cytosine arabinoside, fluorouracil, tetrahydrofuryl-5- fluorouracil,. picibanil, lenthinan, levamisole, bestatin, ajmexone, glycyrrhizin, doxorubicin hydrochloride, aclarubicin hydrochloride, bleomycin hydrochloride, peplomycin sulfate, vincristine sulfate, illinotecane hydrochloride, cyclophosphamide, melphalan, disulfane, thiotepa, procarbazine hydrochloride, cisplatin, azathiopurine, mercaptopurine, tegafur, carmofur, cytarabine, methyltestosterone, testosterone propioante, testosterone enantate, mepitiostane,phosphestolol, chlormazinone acetate, eupurine acetate, bucelerin acetate and the like.

(14) Anti-hyperlipidemia agents

Clofibrate, etheyl 2-chloro-3- [4- (2-methyl-2- pheylpropoxy)phenyl]propioante (Chemical and Pharmaceutical Bulletin, 38, 2792 to 2796 (1990)), pravastatine, sinvastatine, probucol, bezafibrate, clinofibrate, nicomol, cholestyramine, dextran sulfate sodium and the like .

(15) Muscle relaxants

Pridinol, tubocurarine, pancuronium, tolperisone hydrochloride, chlorphenesin carbamate, baclofen, chlormezanone, mephenesin, clozoxazone, epirizone, thizanidine and the like.

(16) Anti-convulsants

Phenytoin, ethosuximide, acetazolamide, chloridiazepoxide, tripetadione, carbamazepine, phenobarbitol, primidone, sulthiam, sodium palpuroate, clonazepam, nitrazepam and the like.

(17) Anti-depressants

Imipramine, clomipramine , noxiptiline, phenelzine, amytriptiline hydrochloride, nortriptiline hydrochloride, amoxapine, mianserin hydrochloride, maprotiline hydrochloride, sulpiride, fluboxamine maleate, trazodone hydrochloride and the like.

(18) Anti-allergic agents

Diphenhydramine , chlorpheniramine, tripelenamine, methoziramine, clemizole, diphenylpyraline , methoxyphenamine, sodium cromoglycate, tranilast, lepirinast, anlexanone, ibudilast, ketotifen, terphenazine, mequitazine, azelastin, epinastin, ozagrel hydrochloride, planlucast-hydrate, ceratrodust and the like.

(19) Cardiac Restorative

Transbiooxocamphor, telefinol, aminophylin, etilefrine, dopamine, dobutamine, denopamine, aminophylin, paecinaline, amlinone, pimobendane, ubidecarenone, digitoxin, digoxin, methyldigoxin, lanatoside C, G-strophanthin, and the like.

(20) Vasodilators

Oxyfedrine, diltiazem, tolazoline, hexobendine, bamethane, clonidine, methyldopa, guanabenz and the like. (21) Vasoconstrictors

Dopamine, dobutamine, denopamine and the like.

(22) Hypotensive diuretics

Hexamethonium bromide , pentolinium, mecamylamine, ecarazine, clonidine, diltiazem, nifedipine and the like.

(23) Diabetes therapeutic agents

Tolbutamide, chlorpropamide , acetohexamide, glibenclamide, tolazamide, acalbose, epalrestat, troglytazone, glucagon, glymidine, glypzide, phenformin, puformin, metformin and the like.

(24) Antinarcotiσs

Levallolphan, nalorphine, naloxone, or salt thereof, and the like.

(25) Fat soluble vitamins φ Vitamins A: vitamin A_x , vitamin A₂ and retinol palmitate

© Vitamins D: vitamins D_x, D₂, D₃, D₄ and D_s © Vitamins E: α-toσopherol, β-tocopherol, γ- tocopherol, δ -tocopherol, dl-α-tocopherol nicotinate ® Vitamins K: vitamins K_1# K₂, K₃ and K₄ © Foliσ acid (vitamin M) , and the like.

(26) Vitamin derivatives

Various derivatives of vitamins, for example, vitamin D₃ derivatives such as 5 , 6-trans-cholecalciferol, 2 , 5-hydroxycholecalciferol, 1-α- hydroxycholecalciferol and the like, vitamin D₂ derivatives such as 5.6-trans-ergocalciferol, and the like.

(27) Anti-asthmatic agents

Isoprenaline hydrochloride, salbutamol sulfate, procatechol hydrochloride, terbutaline sulfate, trimetoquinol hydrochloride , tulobuterol hydrochloride , orciprenaline sulfate, fenoterol hydrobromide, ephedrine hydrochloride, iprotropium bromide, oxytropium bromide, fultropium bromide, theophyline, aminophyline, sodium cromoglycate, tranilast, lepirinast, anlexanone, ibudilast, ketotifen, terphenazine, mequitazine, azelastin, epinastin, ozagrel hydrochloride, planluσast-hydrate, ceratrodust, dexamethasone, prednisolone, hydrocortiaone, vecropetazone propionate, and the like.

(28) Thamuria and acrasia therapeutic agents flavoxate hydrochloride and the like .

(29) Atopic dermatitis therapeutic agents

Sodium cromoglycate and the like .

(30) Allergic rhinitis therapeutic agents

Sodium cromoglycate, chlorpheniramine maleate, alimemazine tartarate, clemastine fumarate, homochlorcyclizine hydrochloride, terfenazine, mequitazine and the like.

(31) Vasopressors

Dopamine, dobutamine, denopamine, digitoxin, digoxin, methyldigoxin, lanatoside C, G-strophanthin, and the like.

(32) Others

Hydroxicam, diaserine, megestrol acetate, nicerogoline, prostaglandin and the like.

Combination of compounds of the present invention with combination drugs provide the following excellent effects :

(1) The dose can be reduced in comparison with a case in which the compound of the present invention or a combination drug is administered alone.

(2) A drug to be combined with the compound of the present invention can be selected depending on symptoms (mild, serious and the like) of patients.

(3) The therapeutic period can be lengthened by selecting a combination drug having a different action mechanism than that of the compound of the present invention.

(4) The therapeutic effect can be sustained by selecting a combination drug having a different action mechanism than that of the compound of the present invention.

(5) By combining the compound of the present invention with a combination drug, synergic effect can be obtained.

Hereinafter, combined use of the compound (I) of the present invention with a combination drug is referred to as "combination agent of the present invention".

In use of a combination agent of the present invention, the administration time of the compound of the present invention and a combination drug is not restricted, and the compound of the present invention or a pharmaceutical composition thereof and a combination drug or a pharmaceutical composition thereof can be administered to an administration subject simultaneously, or may be administered at different times. The dosage of a combination drug may be determined according to the administration amount clinically used, and can be appropriately selected depending on an administration subject, administration route, disease, combination and the like .

The administration mode of a combination agent of the present invention is not particularly restricted, and it is sufficient that the compound of the present invention and a combination drug are combined in administration. Examples of such administration mode include the following methods :

(1) The compound of the present invention and a combination drug are simultaneously produced to give a single preparation which is administered. (2) The compound of the present invention and a combination drug are separately produced to give two kinds of preparations which are administered simultaneously by the same administration route. (3) The compound of the present invention and a combination 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 compound of the present invention and a combination 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 a combination drug are separately produced to 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 a combination drug are administered in this order, or in the reverse order) .

The combination agent of the present invention has low toxicity, and for example, the compound of the present invention or (and) the above-mentioned combination drug can be mixed, according to a method known per se, with a pharmacologically allowable 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, 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.

As the pharmacologically allowable carrier which may be used in production of a combination agent of the present invention, various organic or inorganic carrier substances conventionally used as a preparation raw material are exemplified, and for example, an excipient, lubricant, binder and disintegrating agent in a solid preparation, or a solvent, dissolution aid, suspending agent, isotonizing agent, buffer, soothing agent and the like in a liquid preparation, are listed. Further, if desirable, usual additives such as a preservative, antioxidant, coloring agent , sweetening agent , adsorbent, wetting agent and the like can also be appropriately used in suitable amount .

As the excipient, for example, lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like are listed.

As the lubricant, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like are listed.

As the binder, for example, crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcllulose , polyvinylpyrrolidone , starch, sucrose, gelatin, methylcellulose, carboxymethylcellulose sodium and the like are listed.

Examples of the disintegrating agent include starch, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylstarch sodium, L- hydroxypropylcellulose and the like .

Examples of the solvent include injection water, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.

Disclosed as examples of the dissolution aid are polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.

Disclosed as examples of the suspending agent are surfactants such as stearyl triethanolamine, sodium laurylsulfate, laurylaminopropionic acid, lecithine, benzalkonium chloride, benzetonium chloride, glycerin monostearate and the like; hydrophilic polymers such as polyvinyl alcohol, polyvinyl pyrrolidone, carboxymethylcellulose sodium, methylcellulose, hydroxymethylcellulose , hydroxyethylcelluose , hydroxypropylcellulose and the like .

As the isotonizing agent, for example, glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like are listed.

As the buffer, for example, buffer solutions of a phosphate, acetate, carbonate, citrate and the like, etc. , are listed.

As the soothing agent, benzyl alcohol and the like are listed.

Examples of the preservative include p- oxybenzoates, chlorobutanol, benzyl alcohol, phenetyl alcohol, dehydroacetic acid, sorbic acid and the like.

Example of the antioxidant include sulfites, ascorbic acid, α-tocopherol and the like.

The compounding ratio of the compound of the present invention to a combination drug in a combination agent in the present invention can be appropriately selected depending on an administration subject, administration route, diseases and the like.

For example, the content of the compound of the present invention in a 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 to 50% by weight, further preferably from about 0-5 to 20% by weight, based on the preparation.

The content of a combination drug in a 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 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 a combination agent of the present invention differs depending 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 a combination drug are separately prepared respectively, 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 a combination drug can be made into an aqueous injection 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 pyrosύlfite, 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, 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-oxybenzoate, benzole acid, methylparaben, propylparaben , benzyl alcohol and the like) , a dissolving agent (e.g., cone, 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 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 disintegrating agent (e.g., starch, calcium carbonate and the like) , a binder (e.g. , starch, gum Arabic, 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 the compound of the present invention or a combination drug, according to a method known per se, and the mixture can be compression-molded, then if desirable the molder product can be coated by a method known per se for the purpose of masking of taste, enteric property or durability, to obtain a 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 stearate succinate, Eudoragit (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 a combination drug can be made 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, Witebsols (manufactured by Dynamite Novel, DE), etc.], intermediate grade fatty acids [e.g., Myglyols (manufactured by Dynamite Novel, DE), etc.], or vegetable oils (e.g., sesame oil, soybean 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 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.

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 .

The compound of the present invention is preferably molded into an oral administration preparation such as a solid preparation (e.g., powder, granule, tablet, capsule) and the like, or molded into a rectum administration preparation such as a suppository. Particularly, an oral administration preparation is preferable.

A combination 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 a combination drug, and preparation thereof, [2] a sustained release preparation or quick release preparation of the compound of the present invention or a combination drug, and preparation thereof, [3] a sublingual, buccal or intraoral quick disintegrating agent of the compound of the present invention or a combination drug, and preparation thereof, will be specifically described below. [1] Injection and preparation thereof

An injection prepared by dissolving the compound of the present invention or a combination drug into water is 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 a combination drug, and if desirable, a benzoate and/or salicylate, into water.

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 the like, etc. are listed.

The concentration of the compound of the present invention or a combination 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 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-oxybenzoate, benzoic acid and the like) , a dissolving agent (cone, glycerin, meglumine and the 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 a combination drug and if desirable, 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 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 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 a combination drug with a film agent such as a water- insoluble substance, swellable polymer and the like. For example, a sustained release preparation for oral administration of once 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 and the like. cellulose esters such as cellulose stearate, cellulose propionate and the like, polyvinyl esters such as polyvinyl acetate, polyvinyl butyrate and the like, acrylic aσid/methacrylic acid copolymers , methyl methacrylate copolymers , ethoxyethyl methacrylate/cinnamoethyl methacryalte/aminoalkyl methacrylate copolymers, polyacrylic acid, polymethacrylic acid, methacrylic acid alkylamide copolymers, poly(methyl methacrylate) , polymethacrylate, polymethacrylamide , aminoalkyl methacryalte copolymers , poly(methacrylic anhydride) , glycidyl methacrylate copolymer, particularly, acrylic acid-based polymers such as Eudoragits (Rhom Farma) such as Eudoragit RS- 100, RL-100, RS-30D, RL-30D, RL-PO, RS-PO (ethyl acryalte ^• methyl methacryalte * trimethyl chloride methacryalte * ammoniumethyl copolymer) , Eudoragit NE- 30D (methyl methacryalte ^• ethyl acrylate copolymer) , and the like, hardened oils such as hardened castor oil (e.g. , Lovery wax (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 swell are preferable, and polymers manifesting small swelling in acidic regions such as in stomach and large swelling in neutral regions such as in small intestine and large intestine are preferable.

As such a polymer having an acidic dissociating group and showing pH dependent swell, cross-linkable polyacrylic acid copolymers such as, for example, Carbomer 934P, 940, 941, 974P, 980, 1342 and the like, polycarbophil, calcium polycarbophil (last two are manufactured by BF Goodrich), Hibiswako 103, 104, 105, 304 (all are manufactured by Wako Purechemical Co. , Ltd.), and the like, are listed. The film agent used in a sustained release preparation may further contain a hydrophilic substance.

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, hydroxypropylmethylcellulose , carboxymethylcellulose sodium and the like, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol and the like are listed.

The content of a water-insoluble substance in the film agent of a sustained release preparation is from about 30 to.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 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, then, coating the resulting nucleus with a film agent solution prepared by heat-solvating a water-insoluble substance , swellable polymer and the like or by dissolving or dispersing it in a solvent. I . Preparation of nucleus containing drug

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.

When the nucleus is composed of granules or fine particles , the average particle size thereof is preferably from about 150 to 2000 μm, further preferably, from about 500 to 1400 μm.

Preparation of the nucleus can be effected by a usual 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.

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 the like, starch, crystalline cellulose, calcium phosphate, corn starch and the like are used. Among them, crystalline cellulose, corn starch are preferable .

As the binder, 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, carboxymethylcelulose calcium (ECG505), crosscarmelose sodium (Ac-Di-Sol) , crosslinked polyvinylpyrrolidone (Crosspovidone) , lower substitution hydroxypropylcellulose (L-HPC) and the like are used. Among them, hydroxypropylcellulose, polyvinylpyrrolidone, lower substitution hydroxypropylcellulose are preferable. As the lubricant and coagulation inhibitor, 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, maleic acid and the like, are used.

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 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, crystalline cellulose, waxes can be used, and the average particle size thereof is preferably from about 100 μm to 1500 μm.

For separating a drug and a film agent contained in a nucleus , the surface of the nucleus may be coated with a 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 hydroxypropyplcellulose are used. The protective agent may contain, as a stabilizer, acids such as tartaric acid, citric acid, succinic acid, fumaric acid, maleic 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 .

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

A nucleus obtained in the above-mentioned step I is coated with a film agent solution obtained by heat-solvating 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 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, 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% (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, 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 acid such as tartaric acid, citric acid, succinic acid, fumaric acid, maleic 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 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 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.

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 exipient 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.

When the quick release preparation is an oral solid preparation, it usually contains, in addition to the above-mentioned components , also a disintegrating agent . As this disintegrating agent , there are used, for example , carboxymethylcellulose calcium (ECG-505, manufactured by 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 α-nized 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 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 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 example, a binder (e.g., sucrose, gelatin, gum Arabic powder, methylcellulose, hydroxypropylcellulose , hydroxypropylmethylcellulose, carboxylmethylcellulose, polybinylpyrrolidone, pluran, dextrin and the like), a lubricant (e.g., polyethylene glycol, magnesium stearate, talc, light anhydrous silicic acid (for example, aerosil (Nippon Aerosil)), a surfactant (e.g., anionic surfactants such as sodium alkylsulfate and the like, nonioniσ surfactants such as polyoxyethylene fatty acid ester and polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivatives and 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 reparation can be prepared by, based on a usual technology of producing preparations. mixing the above-mentioned components, and if necessary, further kneading 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-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 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 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 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] Sublinguial, buσcal or intraoral quick disintegrating agent and preparation thereof

Sublinguial, 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 sublinguial, buccal or intraoral quick disintegrating agent, a preparation containing the compound of the present invention or a combination 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, β-cyclodextrin or β-cyclodextrin derivatives (e.g., hydroxypropyl-β- 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 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, dicalσium phosphate, calcium carbonate and the like are listed, and particularly, crystalline cellulose (e.g. , fine crystalline 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) , polymethacylic acid, polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolicone, 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, 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 sublinguial, buccal or intraoral quick disintegrating agent can be produced by mixing the compound of the present invention or a combination 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 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 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 (film) , the compound of the present invention or a combination 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 plasticizer, stabilizer. antioxidant, preservative, coloring agent, buffer, sweetening agent and the like may also 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 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 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 a combination drug, and a water- soluble or 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 from a solution prepared by dissolving the compound of the present invention or a combination 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 a combination drug.

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, xathane gum and the like; polysaccharides; alginic acids; carboxymethylcelluloses; carageenans; dextrans; pectines; 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-alanine, L-asparatic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine, L- leucine, L-phenylalanine and the like, are losted.

One or more of the matrix forming agents can be introduced in a solution or suspension before solidification. Such a matrix forming agent may be present in addition to a surfactant, or may be present while a surfactant is being excluded. The matrix forming agent aids to maintain the compound of the present invention or a combination drug in the solution or suspension in diffused condition, in addition 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 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, vanilla, cherry, grape flavor and combinations thereof. Examples of the suitable pH controlling agent include citric acid, tartaric acid, phosphoric acid, hydrochloric acid and maleic 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 compounds .

The preparation contains the compound of the present invention or a combination 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 a combination 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 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 being placed in an oral cavity.

The content of the above-mentioned exipient in the whole preparation is from about 10 to 99% by weight, preferably from about 30 to 90% by weight. The content of β-cyclodextrin or β-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 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, 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.

The dosage of a combination agent of the present invention differs depending on the kind of 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 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 invention or a combination drug, respectively, once or apportioned to 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 to be administered.

The amount of a combination drug can be set at any value unless side effects are problematic. The daily dosage in terms of a combination drug differs depending on the severity, age, sex, body weight, sensitivity difference of the subject, administration period, interval, and nature, pharmacy, kind of the pharmaceutical preparation, kind of effective ingredient , and the like, and is 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 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 or divided into 4-times a day .

In the administration of a medicine of the present invention, the compound of the present invention may be administered after administration of a combination drug or a combination drug may be administered after administration of the compound of the present invention, though they may be 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 a combination drug is administered first, a method in which the compound of the present invention is administered within a 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 combination drug is exemplified. When the compound of the present invention is administered first, a method in which a combination drug is administered within a 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 , a combination 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 daily dose of about 0.005 to 100 mg/kg.

Best Mode for Carrying out the Invention

The following reference examples, examples, preparation examples and experiments will illustrate the present invention further in detail below, but these are only examples and do not limit the scope of the present invention, and further, may be varied within a range which is not outside the range of the present invention.

In the following reference examples and example, room temperature" means usually temperatures from about 10°C to about 35°C. "%" is by weight unless otherwise stated. Yield is represented by mol/mol%.

Abbreviations used in this text have the following meanings . s; singlet d: doublet t: triplet q: quartet dd: double doublet ddd: double double doublet dt : double triplet br : broad

J: coupling constant

Hz: Hertz

CDCI₃ : deuterium chloroform

DMSO-d₆: dimethylsulfoxide-dg

^XH-NMR: proton nuclear magnetic resonance spectrum

Me : methyl

Sequence numbers in the sequence table of the present specification mean the following sequences. [SEQ ID No. 1]

It indicates a nucleotide sequence of a primer p38-U used in Example 1. [SEQ ID No. 2]

It indicates a nucleotide sequence of a primer PAG-L used in Example 1. [SEQ ID No. 3]

It indicates a nucleotide sequence of a primer MKK-U used in Example 1. [SEQ ID No. 4] It indicates a nucleotide sequence of a primer MKK-L used in Example 1. [SEQ ID No. 5]

It indicates a nucleotide sequence of a primer SER-U used in Example 1. [SEQ ID No. 6]

It indicates a nucleotide sequence of a primer SER-L used in Example 1.

Working Example Reference Example 1 l-bromo-3-ethylbenzene

To a solution of 3-ethylaniline (10.0 g, 82.5 mmol) in 50% sulfanic acid (43.6g) was added dropwise an aqueous solution (16.5 mL) of sodium nitrite (6.83 g, 99.0 mmol) over 30 minutes at 0°C. The resulting reaction mixture was stirred for 45 minutes at 0°C. This diazonium salt solution was added dropwise to a solution of copper (I) bromide (12.4g, 86.6mmol)in a 48% hydrobromic acid (82.5 mL) while heating gently under reflux. After the addition, the reaction mixture was heated to reflux for 30 minutes. The reaction mixture was cooled to room temperature, and extracted with ether . The extracts were sequentially washed with a IN-aqueous sodium hydroxide solution and brine, and filtrated, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=20 : 1) to obtain a title compound (6.13g, yield 40%).

Oil

'H-NMR (CDC1₃) δ : 1.23 (3H, t, J= 7.5 Hz ) , 2.63 (2H, q, J= 7.5 Hz), 7.11-7.20 (2H, m) , 7.28-7.38 (2H, m) .

Reference Example 2

The following reference example compound 2 was synthesized according to Reference Example 1, using 3- (1-methylethyl) aniline instead of 3-ethylaniline. Reference Example compound 2 : l-bromo-3- ( 1-methylethyl) benzene

Oil

'H-NMR (CDC1₃) δ : 1.24 (6H, d, J=7.0Hz), 2.77-2.99 (1H, m) , 7.03-7.16 (2H, m) , 7.27-7.34 (1H, m) , 7.37 (1H, s).

Reference Example 3

3-ethylbenzoic acid

Under an argon atmosphere, a solution of 1- bromo-3-ethylbenzene (5.1 g, 28 mmol) in tetrahydrofuran (45 mL) was added dropwise to a mixture of magnesium turnings (0.74 g, 31 mmol) in tetrahydrofuran (5.0 mL), and the mixture was stirred for 30 minutes under the same condition. The reaction mixture was added to crashed dry ice, and the mixture was stirred for 1 hour. To the reaction mixture was added lN-hydrochloric acid, and extracted with ethyl acetate. The extracts were dried, filtrated and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl aσetate=5:l) to obtain a title compound (3.87g, yield 93%) .

Oil

^XH-NMR (CDC1₃) δ : 1.28 (3H, t, J= 7.5 Hz) , 2.73 (2H, q, J= 7.5 Hz), 7.34-7.50 (2H, m) , 7.92-7.98 (2H, m) .

Reference Example 4

The following reference example compounds 4-1 and 4-2 were synthesized according to Reference Example 3, using l-bromo-3- ( 1-methylethyl)benzene, l-bromo-4- fluoro-3-methylbenzene instead of l-bromo-3- ethylbenzene . Reference Example compound 4-1:

3- ( 1-methylethyl) benzoic acid Oil

^XH-NMR (CDC1₃) δ : 1.29 (6H, d, J=7.0Hz), 2.98-3.06 (1H, m) , 7.38-7.54 (2H, m) , 7.90-8.02 (2H, m) . Reference Example compound 4-2:

4-fluoro-3-methylbenzoic acid m.p. 165 - 167°C.

Reference Example 5

3-ethylbenzoyl chloride

3-ethylbenzoic acid (9.40 g, 62.6 mmol) was added slowly to thionyl chloride (45 mL), and N,N- dimethylformamide (3 drops) was added dropwise. The resulting reaction mixture was heated under reflux for 2 hours under the same condition. The reaction mixture was concentrated, and used in the subsequent reaction without further purification.

Reference Example 6

The following reference example compounds 6-1 to 6-4 were synthesized according to Reference Example 5, using 3- ( 1-methylethyl) benzoic acid, 4-fluoro-3- methylbenzoic acid, 4-cyclohexylbenzoic acid and 3,5- dimethylbenzoic acid instead of 3-ethylbenzoic acid. Reference Example compound 6-1:

3 - ( 1-methylethyl ) benzoyl chloride

This was used in the subsequent reaction without purification. Reference Example compound 6-2:

4-fluoro-3 -methylbenzoyl chloride

This was used in the subsequent reaction without purification . Reference Example compound 6-3:

4-cyclohexylbenzoyl chloride

This was used in the subsequent reaction without purification . Reference Example compound 6-4:

3, 5-dimethylbenzoyl chloride b.p. 82 - 85°C (933 Pa) .

Reference Example 7 :

N- (4-chlorobenzoyl)propyleneimine,

A solution of propyleneimine (12 mL, 0.15 mol) in tetrahydrofuran (160 mL) was added to an 1 N-aqueous sodium hydroxide solution. To this mixture was added dropwise 4-chlorobenzoyl chloride (25 g, 0.14 mol) atO°C. After completion of the addition, the mixture was further stirred for 30 minutes. The reaction mixture was extracted with ethyl acetate. The extract was dried, and the solvent was distilled off to obtain a title compound (25 g, yield 89%) .

Oil

"H-NMR (CDC1₃) δ : 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 8

The following reference example compounds 8-1 to 8-16 were synthesized according to Reference Example 7, using 3 -chlorobenzoyl chloride, 3-methylbenzoyl chloride, 3 , 5-dimethylbenzoyl chloride, 4-fluorobenzoyl chloride, benzoyl chloride, 3-bromobenzoyl chloride, 4- (methylthio Jbenzoyl chloride, 2-thiophenecarbonyl chloride, 3-propylbenzoyl chloride, 3- trifluoromethylbenzoyl chloride, 3-ethylbenzoyl chloride, 3- ( 1-methylethyl) benzoyl chloride, 4- fluoro- 3-methylbenzoyl chloride, 3 -fluorobenzoyl chloride, 3-methoxybenzoyl chloride and 4- methoxybenzoyl chloride, respectively, instead of 4- chlorobenzoyl chloride. Reference Example Compound 8-1: N- ( 3-chlorobenzoyl )propyleneimine ,

Oil

^XH-NMR (CDC1₃) δ : 1.40 (3H, d, J= 5.1 Hz) , 2.17 (IH, d, J= 3.3 Hz), 2.53-2.68 (2H, m) , 7.40 (IH, dd, J= 7.7, 8.1 Hz), 7.53 (IH, ddd, J= 1.5, 2.2, 8.1 Hz), 7.90 (IH, dt, J= 7.7, 1.5 Hz), 8.00 (IH, dd, J= 1.5, 2.2 Hz). Reference Example Compound 8-2:

N- ( 3-methylbenzoyl ) propyleneimine ,

Oil

^-NMR (CDC1₃) δ : 1.39 (3H, d, J= 5.5 Hz) , 2.14 (IH, d, J= 3.3 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 Compound 8-3:

N- ( 3 , 5-dimethylbenzoyl)propyleneimine ,

Oil

^XH-NMR (CDC1₃) δ : 1.39 (3H, d, J= 5.5 Hz) , 2.13 (IH, d, J= 3.7 Hz), 2.37 (6H, s), 2.47-2.62 (2H, m) , 7.19 (IH, s), 7.64 (2H, s). Reference Example Compound 8-4:

N- (4-fluorobenzoyl) ropyleneimine.

Oil

^XH-NMR (CDC1₃) δ :, 1.39 (3H, d, J= 5.2 Hz) , 2.14-2.15 (IH, m) , 2.52-2.63 (2H, m) , 7.08-7.19 (2H, m) , 8.00-8.10 (2H, m) . Reference Example Compound 8-5:

N-benzoylpropyleneimine ,

Oil

^XH-NMR (CDC1₃) δ : 1.40 (3H, d, J= 6.0 Hz) , 2.15 (IH, d, J=3.2 Hz), 2.52-2.67 (2H, m) , 7.40-7.61 (3H, m) , 7.98-8.07 (2H, m) . Reference Example Compound 8-6:

N- ( 3 -bromobenzoyl) propyleneimine ,

Oil

^XH-NMR (CDC1₃) δ : 1.40 (3H, d, J= 5.2 Hz) , 2.16-2.18 (IH, m), 2.53-2.65 (2H, m) , 7.34 (IH, t, J=7.9 Hz), 7.65-7.71 (IH, m) , 7.95 (IH, d, J=7.9 Hz), 8.16 (IH, t,

J=1.8 Hz) .

Reference Example Compound 8-7:

N- [4- (methylthio)benzoyl)propyleneimine.

Oil

^XH-NMR (CDC1₃) δ : 1.49 (,'3H, d, J= 6.0 Hz ) , 2.13 (IH, d, J=3.2 Hz), 2.49-2.60 (5H, m) , 7.24-7.30 (2H, m) , 7.90-7.96 (2H, m) . Reference Example Compound 8-8:

N- ( 2-thiophenecarbonyl) propyleneimine ,

Oil

^XH-NMR (CDC1₃) δ : 1.43 (3H, d, J= 5.2 Hz) , 2.14 (IH, d, J=3.6 Hz), 2.56-2.72 (2H, m) , 7.08-7.16 (IH, m) , 7.53-7.60 (IH, m) , 7.75-7.81 (IH, m) . Reference Example Compound 8-9:

N- ( 3-propylbenzoyl )propyleneimine ,

Oil

^XH-NMR (CDC1₃) δ : 0.95 (3H, t, J= 7.3 Hz) , 1.40 (3H, d, J=4.8 Hz), 1.59-1.78 (2H, m) , 2.14 (IH, d, J=2.8 Hz), 2.52-2.74 (4H, m) , 7.34-7.43 (2H, m) , 7.81-7.89 (2H, m) . Reference Example Compound 8-10:

N- ( 3-trifluoromethylbenzoyl) propyleneimine.

Oil

^XH-NMR (CDC1₃) δ : 1.42 (3H, d, J= 5.5 Hz) , 2.20 (IH, d, J=3.3 Hz), 2.56-2.67 (2H, m) , 7.61 (IH, t, J=7.7 Hz), 7.81 (IH, d, J=7.7 Hz) , 8.21 (IH, d, J=7.7 Hz) , 8.30 (IH, s). Reference Example Compound 8-11:

N- ( 3 -ethylbenzoyl) propyleneimine.

Oil

^-NMR (CDC1₃) δ : 1.27 (3H, t, J= 7.5 Hz) , 1.40 (3H, d, J=5.5 Hz), 2.14 (IH, d, J=2.9 Hz), 2.52-2.61 (2H, m) , 2.71 (2H, q, J=7.5Hz), 7.32-7.41 (2H, m) , 7.81-7.89 (2H, m) . Reference Example Compound 8-12: N- [ 3- ( 1-methylethyl ) benzoyl ] propyleneimine ,

Oil

^-NMR (CDC1₃) δ : 1.29 (6H, t, J= 7.0 Hz) , 1.40 (3H, d, J=5.9 Hz), 2.14 (IH, d, J=3.7 Hz), 2.51-2.64 (2H, m) , 2.87-3.10 (IH, m) , 7.33-7.46 (2H, m) , 7.84 (IH, dt , J=7.0, 1.8 Hz) . 7.91 (IH, s) . Reference Example Compound 8-13:

N- ( 4-fluoro-3 -methylbenzoyl)propyleneimine ,

Oil

"H-NMR (CDC1₃) δ : 1.39 (3H, d, J= 5.4 Hz) , 2.14 (IH, d, J=3.4 Hz), 2.33 (3H, s), 2.51-2.61 (2H, m) , 7.06 (IH, t, J=8.8 Hz), 7.81-7.90 (2H, m) . Reference Example Compound 8-14:

N- ( 3-fluorobenzoyl)propyleneimine ,

Oil

^XH-NMR (CDC1₃) δ : 1.40 (3H, d, J= 5.5 Hz) , 2.16 (IH, d, J=3.3 Hz), 2.52-2.68 (2H, m) , 7.25 (IH, ddd, J=l.l, 2.6, 8.4 Hz), 7.43 (IH, ddd, J=5.5, 7.7, 8.1 Hz), 7.69 (IH, ddd, J=1.5, 2.6, 8.1Hz), 7.81 (IH, ddd, J=l.l, 1.5, 7.7 Hz) . Reference Example Compound 8-15:

N- ( 3-methoxybenzoyl )propyleneimine ,

Oil

^XH-NMR (CDCI₃) δ : 1.40 (3H, d, J= 5.9 Hz) , 2.14 (IH, d, J=2.9 Hz), 2.52-2.65 (2H, m) , 3.86 (3H, s), 7.10 (IH, ddd, J=l.l, 2.6, 8.4 Hz), 7.37 (IH, dd, J=8.4, 7.3 Hz), 7.55 (IH, dd, J=1.5, 2.6 Hz ) , 7.63 (IH, ddd, J=l.l, 1.5, 7.3 Hz) . Reference Example Compound 8-16:

N- ( 4 -methoxyphenyl )propyleneimine ,

Oil

'H-NMR (CDC1₃) δ : 1.39 (3H, d, J= 5.9 Hz) , 2.11 (IH, d, J=3.3 Hz), 2.50-2.63 (2H, m) , 3.87 (3H, s), 6.94 (2H, d, J=9.2 Hz),- 8.00 (IH, d, J=9.2 Hz). Reference Example 9

2 -fluoro-4 -methylpyridine

This was synthesized according to a method described in Journal of Medicinal Chemistry, 33, 1667-1675, 1990. m.p. 82 - 86°C (10 kPa) .

Reference Example 10

2-phenylmethyloxy-4-methylpyridine

Sodium hydride ( 60% paraffin dispersion, 5.0 g, 120 mmol) was washed with hexane (5 mL) twice, and suspended in tetrahydrofuran (200 mL) . To this suspension was added dropwise a solution of benzyl alcohol (14 g, 120 mol) in tetrahydrofuran (50 mL) at 0°C, and the mixture was allowed to warm to room temperature and stirred for 15 minutes. To this solution was added a solution of 2-bromo- 4-methylpyridine (20 mL, 110 mol) in tetrahydrofuran (50 mL), and the mixture was heated to reflux for 14 hours. Water (200 mL) was added to the reaction mixture, and extracted with ethyl acetate. The extracted solution was dried, and the solvent was distilled off. The crude product was distilled under reduced pressure to obtain a title compound (13 g, yield 67%) . b.p. 116 - 118°C (400 Pa). - MR (CDC1₃) δ : 2.30 (3H, s), 5.37 (2H, s), 6.63 (IH, s), 6.72 (IH, d, J= 5.1Hz), 7.29-7.50 (5H, m) , 8.03 (IH, d, J= 5.1 Hz) .

Reference Example 11

2 -tert-butoxycarbonylamino-4-methylpyridine

It was synthesized according to a method described in Synthesis, pp. 877 to 882, 1996 or Journal of Organic

Chemistry, 61, pp. 4810 to 4811, 1996. Reference Example 12

2- ( 2-fluoro-4-pyridyl ) - 1- ( 3- methylphenyl ) ethanone

Under an argon atmosphere, a solution of diisopropylamine (44mL, 0.31mol) in anhydrous tetrahydrofuran (300 mL) was cooled to -78°C, and to this was added dropwise a 1.6 M n-butyllithium hexane solution (190 mL, 0.31 mol) with stirring. After completion of the addition, the solution was stirred for 10 minutes, subsequently, a solution of 2-fluoro-4-methylpyridine (34.5 g, 0.31 mol) in anhydrous tetrahydrofuran (30 mL) was added. The reaction mixture was stirred for 30 minutes at -10°C. The reaction solution was cooled to -78°C, and a solution of N-(3- methylbenzoyl) propyleneimine (52 g, 0.30 mol) in anhydrous tetrahydrofuran (30 mL) was added dropwise. After completion of the addition, the mixture was stirred for 2 hours at room temperature. To the reaction mixture was added water ( 100 mL ) , and extracted with ethyl acetate, . The extracted solution was washed with water, dried, then, the solvent was distilled off. The residue was re- crystallized from isopropyl ether to obtain a title compound (35 g, yield 52%). m.p. 66 - 67°C.

Reference Example 13

The following reference example compounds 13-1 to 13-3 were synthesized according to Reference Example 12, using N- (3-methoxybenzoyl) propyleneimine, N-(4- fluorobenzoyl)propyleneimine and N-(3- chlorobenzoyl) propyleneimine instead of N-(3- methylbenzoyl )propyleneimine . Reference Example compound 13-1:

2- ( 2-fluoro-4-pyridyl ) - 1- ( 3- methoxyphenyl ) ethanone Oil

^XH-NMR (CDC1₃) δ : 3.86 (3H, s), 4.31 (2H, s), 6.86 (IH, s), 7.03-7.19 (2H, m) , 7.31-7.59 (3H, m) , 8.18 (IH, d, J= 5.6 Hz) . Reference Example compound 13-2:

1- (4-fluorophenyl) -2- ( 2-fluoro-4- pyridyl ) ethanone m. p. 100 - 101°C. Reference Example compound 13-3:

1- (3-chlorophenyl) -2- ( 2-fluoro-4- pyridyl ) ethanone m. p. 84 - 86°C.

Reference Example 14

1- ( 3-methylphenyl ) -2- ( 2-methyl- 4 - pyridyl ) ethanone

A solution of diisopropylamine (112 mL) in anhydrous tetrahydrofuran (760 mL) was cooled to -50°C, and to this was added dropwise a 1.6 M n-butyllithium hexane solution ( 500 mL ) with stirring . After completion of the addition, the solution was stirred for 10 minutes, subsequently, a solution of 2,4-lutidine (87.9 mL) in anhydrous tetrahydrofuran (76 mL) was added dropwise at -30°C . The reaction mixture was stirred for 1 hour , then , a solution of N- ( 3-methylbenzoyl) propyleneimine (134 g) in anhydrous tetrahydrofuran (76 mL) was added dropwise at -78°C. After completion of the addition, the mixture was stirred for 2 hours at -78°C. The reaction mixture was allowed to warm to room temperature, to this was added water (800 mL), and extracted with ethyl acetate. The extracts were washed with water, dried, then, the solvent was distilled off . The resulted residue was crystallized from isopropyl ether-hexane to obtain a title compound (156 g, yield 91%) . m.p. 56 - 57°C. Reference Example 15

The following reference example compounds 15-1 and 15-2 were synthesized according to Reference Example 14, using N- (3, 5-dimethylbenzoyl)propyleneimine and N-(4- fluorobenzoyl)propyleneimine instead of N-(3- methylbenzoyl )propyleneimine . Reference Example compound 15-1:

1- ( 3 , 5-dimethylphenyl ) -2- ( 2 -methyl-4- pyridyl ) ethanone

Oil

^XH-NMR (CDC1₃) δ : 2.38 (6H, s), 2.54 (3H, s), 4.21 (2H, s), 6.98-7.10 (IH, m) , 7.01 (IH, m) , 7.06 (IH, s), 7.23 (IH, s), 7.60 (2H, s), 8.42-8.45 (IH, m) . Reference Example compound 15-2:

2- ( 2 -methyl-4- yridyl ) - 1- ( 4 - fluorophenyl ) ethanone m. p. 79 - 81°C.

Reference Example 16

The following reference example compounds 16-1 and 16-2 were synthesized according to Reference Examples 14 and 15, using 7 -choline instead of 2 , 4-lutidine. Reference Example compound 16-1:

2- ( 2 , 6-dimethyl-4-pyridyl ) - 1- ( 3- methylphenyl ) ethanone m.p. 46 - 48°C Reference Example compound 16-2:

1- (3, 5-dimethylphenyl) -2- (2, 6-dimethyl-4- pyridyl ) ethanone m. p. 135 - 136°C.

Reference Example 17

2- (2-tert-butoxycarbonylamino-4-pyridyl) -1- (4- methoxyphenyl ) ethanone A solution of 2-tert-butoxycarbonylamino-4- methylpyridine (20 g, 97 mmol) in anhydrous tetrahydrofuran (300 mL) was cooled to -78°C, and to this was added dropwise a 1.6 M n-butyllithium hexane solution (140 mL, 0.23 mol) with stirring. After completion of the addition, the solution was stirred for 30 minutes at 0°C, then, the solution was cooled to -78°C. A solution of N-( 4-methoxybenzoyl)propyleneimine (25 g, 0.13 mol) in anhydrous tetrahydrofuran (50 mL) was added dropwise. After completion of the addition, the reaction mixture was stirred for 2 hours at room temperature. To the reaction mixture was added water (100 mL) and isopropyl ether (300 mL), and the resulted crude crystal was filtrated. This crude crystal was recrystallized from tetrahydrofuran-hexane to obtain a title compound (23 g, yield: 69%). m.p. 187 - 190°C.

Reference Example 18

The following reference example compounds 18-1 to 18-15 were synthesized according to Reference Example 17, using N- (3-methylbenzoyl)propyleneimine, N-(3,5- dimethylbenzoyl)propyleneimine , N- ( 3- chlorobenzoyl)propyleneimine , N-benzoylpropyleneimine , N- (4-fluorobenzoyl)propyleneimine, N- [3- ( tri luoromethyl)benzoyl ]propyleneimine , N- ( 3- bromobenzoyl)propyleneimine , N- [ 4- (methylthio)benzoyl]propyleneimine, N- (2- thiophenecarbonyl)propyleneimine, N- ( 3- propylbenzoyl)propyleneimine , N- [ 3- ( 1- methylethyl)benzoyl]propyleneimine , N- ( 4-fluoro-3- methylbenzoyl)propyleneimine, N- ( 3- fluorobenzoyl)propyleneimine , N- ( 4- chlorobenzoyl)propyleneimine and N-(3- ethylbenzoyl)propyleneimine instead of N-(4- methoxybenzoyl ) propyleneimine . Reference Example compound 18-1:

2- (2-tert-butoxycarbonylamino-4-pyridyl) -1- (3- methylphenyl ) ethanone m. p. 144 - 146°C. Reference Example compound 18-2:

2- ( 2-tert-butoxycarbonylamino-4-pyridyl) -1- (3,5-dimethylphenyl ) ethanone m. p. 133 - 136°C. Reference Example compound 18-3:

2- ( 2-tert-butoxycarbonylamino-4-pyridyl) -1- ( 3- chlorophenyl ) ethanone m. p. 152 - 153°C. Reference Example compound 18-4:

2- ( 2-tert-butoxycarbonylamino-4-pyridyl) -1- phenylethanone m. p. 162 - 163°C. Reference Example compound 18-5:

2- ( 2-tert-butoxycarbonylamino-4-pyridyl) -1- ( 4- fluorophenyl ) ethanone m. p. 139 - 141°C. Reference Example compound 18-6:

2- ( 2-tert-butoxycarbonylamino-4-pyridyl) -1- [3- ( trifluoromethyl ) phenyl ] ethanone m. p. 149 - 150°C. Reference Example compound 18-7:

1- (3-bromophenyl) -2- (2-tert- butoxycarbonylamino-4-pyridyl) ethanone m. p. 132 - 133°C. Reference Example compound 18-8:

2- ( 2-tert-butoxycarbonylamino-4-pyridyl) -1- [ 4- (methylthio ) phenyl ] ethanone m. p. 177 - 178°C. Reference Example compound 18-9:

2- ( 2-tert-butoxycarbonylamino-4-pyridyl) -1- (2- thienyl) ethanone m. p. 161 - 162°C. Reference Example compound 18-10:

2- ( 2-tert-butoxycarbonylamino-4-pyridyl) -1- ( 3- propylphenyl ) ethanone m. p. 110 - 111°C. Reference Example compound 18-11:

2- ( 2-tert-butoxycarbonylamino-4-pyridyl) -1- [ ( 1- methylethyl ) phenyl] ethanone m. p. 176 - 177°C. Reference Example compound 18-12:

2- ( 2-tert-butoxycarbonylamino-4-pyridyl) -1- ( 4- fluoro-3-methylphenyl ) ethanone m. p. 143 - 144°C. Reference Example compound 18-13:

2- ( 2-tert-butoxycarbonylamino-4 -pyridyl) -1- ( 3- fluorophenyl) ethanone m. p. 164 - 165°C. Reference Example compound 18-14:

2- ( 2-tert-butoxycarbonylamino-4-pyridyl) -1- ( 4- chlorophenyl ) ethanone m. p. 155 - 156°C. Reference Example compound 18-15:

2- (2-tert-butoxycarbonylamino-4-pyridyl) -1- (3- ethylphenyl ) ethanone m. p. 122 - 123°C.

Reference Example 19

1- ( 3, 5-dimethylphenyl) -2- ( 2-phenylmethyloxy-4- pyridyl ) ethanone

A solution of diisopropylamine (9.6 mL, 69 mmol) in anhydrous tetrahydrofuran (60 mL) was cooled to -50°C, and to this was added dropwise a 1.6 M n-butyllithium hexane solution (43 mL, 69 mmol) with stirring. After completion of the addition, the solution was stirred for 10 minutes, subsequently, a solution of 2- phenylmethyloxy-4-methylpyridine (12 g, 62 mmol) iii anhydrous tetrahydrofuran (12 mL) was dropped at -30°C. After stirring for 1 hour, a solution of N-(3,5- dimethylbenzoyl)propyleneimine (12 g, 62 mmol) in anhydrous tetrahydrofuran (12 mL) was added dropwise at -30°C. After completion of the addition, the mixture was allowed to warm to room temperature gradually, and stirred for 2 hours. Water (60 L) was added to the reaction mixture, and extracted with ethyl acetate . The extracted solution was washed with water, dried, then, the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=5:l) to obtain a title compound (9.1 g, yield 44%).

Oil

^XH-NMR (CDC1₃) δ : 2.37 (6H, s), 4.20 (2H, s), 5.37 (2H, s), 6.72 (IH, s), 6.81 (IH, d, J= 5.1 Hz), 7.22 (IH, s), 7.30-7.49 (5H, m) , 7.59 (2H, s), 8.12 (IH, d, J= 5.1 Hz) .

Reference Example 20

2-bromo-2- ( 2-tert-butoxycarbonylamino-4- pyridyl) -1- ( 4-methoxyphenyl) ethanone hydrobromide

To a solution of 2- ( 2-tert-butoxycarbonylamino- 4-pyridyl) -1- (4-methoxyphenyl) ethanone (0.36 g, 1.1 mmol) in acetic acid (5 mL) was added bromine (0.058 mL, 1.1 mmol) , and the mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated, and the residue was washed with isopropyl ether to obtain a title compound (0.44 g, yield 82%).

Amorphous .

^XH-NMR (CDC1₃) δ : 1.55 (6H, s), 3.92 (3H, s), 6.35 (IH, s) , 6.99-7.03 (2H, m) , 7.66 (IH, dd, J= 6.6 , 1.8 Hz ) , 8.02-8.07 (2H, m) , 8.20 (IH, d, J= 6.6 Hz), 8.70 (2H, d, J= 1.8 Hz), 11.02 (IH, br s). Reference Example 21

The following reference example compounds 21-1 to 21-4 were synthesized according to Reference Example 20, using 2- (2-tert-butoxycarbonylamino-4-pyridyl) -1- (3- methylphenyl)ethanone , 2- ( 2-1ert-butoxycarbonylamino- 4-pyridyl) -l-(3, 5-dimethylphenyl) ethanone, l-(3, 5- dimethylphenyl) -2- ( 2-phenylmethyloxy-4- pyridyl ) ethanone and 1- (3-bromophenyl) -2- (2-tert- butoxycarbonylamino-4-pyridyl) ethanone, respectively, instead of 2- ( 2-tert-butoxycarbonylamino-4-pyridyl) - 1- ( 4-methoxyphenyl)ethanone . Reference Example compound 21-1:

2-bromo-2- ( 2-tert-butoxycarbonylamino-4- pyridyl) -1- ( 3-methylphenyl) ethanone hydrobromide

This was used in the subsequent reaction without purification. Reference Example compound 21-2:

2-bromo-2- ( 2-tert-butoxycarbonylamino-4- pyridyl) -1- ( 3 , 5-dimethylphenyl) ethanone hydrobromide

This was used in the subsequent reaction without purification. Reference Example compound 21-3:

2-bromo-1- ( 3 , 5-dimethylphenyl) -2- ( 2- phenylmethyloxy-4-pyridyl)ethanone hydrobromide m.p. 88 to 90°C. Reference Example compound 21-4:

2-bromo-l- (3-bromophenyl) -2- ( 2-tert- butoxycarbonylamino-4-pyridyl) ethanone hydrobromide

This was used in the subsequent reaction without purification.

Reference Example 22

2-bromo-l- (3-methylphenyl) -2- ( 2-methyl-4- pyridyl) ethanone hydrobromide 1- ( 3-methylphenyl) -2- ( 2-methyl-4- pyridyl) ethanone (150 g) was dissolved in acetic acid (450 mL) , bromine (34.3 mL) was added to this, and the mixture was stirred for 3 hours at 70°C. The reaction solution was cooled by ice water, and the deposited crystal was filtrated off . The crystal was washed with ethyl acetate to obtain a title compound (168 g, yield 66%). m.p. 144 - 146°C.

Reference Example 23

The following reference example compounds 23-1 to 23-22 were synthesized according to Reference Example 22, using 2- ( 2-fluoro-4-pyridyl) -l-(3- methylphenyl) ethanone, 2- (2-fluoro-4-pyridyl) -1- (3- methoxyphenyl) ethanone, 2- (2-fluoro-4-pyridyl) -l-(4- fluorophenyl)ethanone, 2- (2-fluoro-4-pyridyl) -1- (3- chlorophenyl) ethanone, 1- ( 3, 5-dimethylphenyl) -2- (2- methyl-4-pyridyl) ethanone, 2- ( 2-methyl-4-pyridyl) -1- (4-fluorophenyl) ethanone, 2- ( 2 , 6-dimethyl-4-pyridyl) - l-( 3-methylphenyl) ethanone, 1- (3, 5-dimethylphenyl) -2- (2, 6-dimethyl-4-pyridyl) ethanone, 2- (2-tert- butoxycarbonylamino-4-pyridyl) -1- (3- methylphenyl) ethanone , 2- ( 2-1ert-butoxycarbonylamino- 4-pyridyl) -1- (3-chlorophenyl) ethanone, 2- (2-tert- butoxycarbonylamino-4-pyridyl) -1-phenylethanone, 2- ( 2-tert-butoxycarbonylamino-4-pyridyl) -1- ( 4- fluorophenyl)ethanone, 2- ( 2-tert-butoxycarbonylamino- 4-pyridyl) -1- [ 3- ( trifluoromethyl)phenyl] ethanone , 2- ( 2-tert-butoxycarbonylamino-4-pyridyl) -1- ( 3- bromophenyl) ethanone, 2- ( 2-tert-butoxycarbonylamino- 4-pyridyl) -1- [4- (methylthio)phenyl] ethanone, 2- (2- tert-butoxycarbonylamino-4-pyridyl) -1- (2- thienyl ) ethanone , 2- ( 2-1ert-butoxycarbonylamino-4- pyridyl) -1- ( 3-propylphenyl) ethanone, 2- (2-tert- butoxycarbonylamino-4-pyridyl) -1- [ ( 1- methylethyl)phenyl ] ethanone , 2- ( 2-tert- butoxycarbonylamino-4-pyridyl) -1- (3- fluorophenyl) ethanone , 2 - ( 2-1ert-butoxycarbonylamino- 4-pyridyl) -1- ( 4-chlorophenyl) ethanone, 2- (2-tert- butoxycarbonylamino-4-pyridyl) -1- (3- ethylphenyl) ethanone and 2- (2-tert- butoxycarbonylamino-4-pyridyl) -1- (4-fluoro-3- methylphenyl) ethanone, respectively, instead of l-(3- methylphenyl ) -2- (2 -methyl-4-pyridyl) ethanone. Reference Example compound 23-1:

2-bromo-2- (2-fluoro-4-pyridyl) -1- (3- ' methylphenyl ) ethanone hydrobromide

This was used in the subsequent reaction without purification . Reference Example compound 23-2:

2-bromo-2- ( 2-fluoro-4-pyridyl ) - 1- ( 3- methoxyphenyl) ethanone hydrobromide

This was used in the subsequent reaction without purification . Reference Example compound 23-3:

2 -bromo-2- (2-fluoro-4-pyridyl) -1- (4- fluorophenyl ) ethanone hydrobromide

Amorphous

^XH-NMR (DMSO-dg) δ : 7.16 (IH, s), 7.37-7.54 (4H, m), 8.11-8.24 (2H, m) , 8.30 (IH, d, J= 5.0 Hz). Reference Example compound 23-4:

2-bromo-l- ( 3-chlorophenyl) -2- (2-fluoro-4- pyridyl) ethanone hydrobromide

Amorphous

^-NM (DMSO-dg) δ : 7.19 (IH, s), 7.38 (IH, s), 7.52-7.56 (IH, m) , 7.64 (IH, t, J=8.0 Hz ) , 7.77-7.82 (IH, m), 8.05-8.09 (IH, m) , 8.16 (IH, t, J=1.8 Hz), 8.32 (IH, d, J=5.2 Hz), 10.23 (IH, br s). Reference Example compound 23-5:

2-bromo-l- (3, 5 -dimethylphenyl) -2- (2-methyl-4- pyridyl ) ethanone hydrobromide

This was used in the subsequent reaction without purification. Reference Example compound 23-6:

2 -bromo- 1 - ( 4-fluorophenyl) -2- ( 2-methyl-4- pyridyl ) ethanone hydrobromide

Amorphous

^XH-NMR (DMSO-dg) δ : 3.02 (3H, s), 6.68 (IH, s), 7.23 (2H, t, J=8.4 Hz), 8.05 (IH, s), 8.10-8.22 (3H, m) , 8.65 (IH, br s) . Reference Example compound 23-7:

2-bromo-2- ( 2 , 6-dimethyl-4-pyridyl) -1- ( 3- methylphenyl) ethanone hydrobromide

This was used in the subsequent reaction without purification. Reference Example compound- 23-8 :

2-bromo-1- ( 3 , 5-dimethylphenyl) -2- ( 2 , 6 -dimethyl- 4-pyridyl) ethanone hydrobromide m.p. 208 - 212°C Reference Example compound 23-9:

2- (2 -amino-4-pyridyl) -2-bromo-l- (3- methylphenyl ) ethanone hydrobromide m.p. 182 - 185°C Reference Example compound 23-10:

2- (2-amino-4-pyridyl) -2-bromo-l- ( 3- chlorophenyl ) ethanone hydrobromide m.p. 199 - 200°C Reference Example compound 23-11:

2- ( 2-amino-4-pyridyl) -2-bromo-l-phenylethanone hydrobromide m.p. 155 - 156°C Reference Example compound 23-12:

2- (2-amino-4-pyridyl) -2-bromo-l- (4- fluorophenyl ) ethanone hydrobromide m.p. 171 - 172°C Reference Example compound 23-13:

2- (2-amino-4-pyridyl) -2-bromo-l- [3- ( trifluoromethyl)phenyl] ethanone hydrobromide m.p. 174 - 175°C Reference Example compound 23-14:

2 - ( 2 -amino-4-pyridyl ) -2 -bromo- 1- ( 3 - bromophenyl) ethanone hydrobromide

This was used in the subsequent reaction without purification . Reference Example compound 23-15:

2- (2 -amino- 4-pyridyl) -2-bromo-l- [4- (methylthio ) phenyl ] ethanone hydrobromide

Amorphous

^XH-NMR (DMSO-dg) δ : 6.96-7.09 (2H, m) , 7.24 (IH, s), 7.32-7.43 (IH, m) , 7.98 (IH, d, J=6.6 Hz), 8.12-8.36 (2H, m). Reference Example compound 23-16:

2- (2 -amino-4-pyridyl) -2-bromo-l- (2- thienyl) ethanone hydrobromide

Amorphous

^XH-NMR (DMSO-dg) δ : 2.57 (3H, s), 6.94-7.01 (IH, m), 7.14 (IH, s), 7.21 (IH, s), 7.38-7.46 (2H, m) , 7.83-8.06 (3H, m) , 8.21 (2H, br) . Reference Example compound 23-17:

2- (2 -amino-4-pyridyl) -2-bromo-l- (3- propylphenyl ) ethanone hydrobromide

Amorphous

^XH-NMR (DMSO-dg) δ : 0.90 (3H, t, J=7.3 Hz), 1.53-1.73 (2H, m) , 2.65 (2H, t, J=7.5 Hz), 3.40 (2H, br s), 6.97 (IH, dd, J=1.8, 6.6 Hz ) , 7.13 (IH, s), 7.19 (IH, s), 7.46-7.59 (2H, m) , 7.89-7.99 (3H, m) , 8.14 (IH, br d, J=6.6 Hz) . Reference Example compound 23-18:

2- (2 -amino-4-pyridyl) -2-bromo-l- [3- (1- methylethyl ) phenyl ] ethanone hydrobromide Amorphous

^-NMR (DMSO-dg) δ : 1.24 (6H, d, J=6.6 Hz), 3.00 (IH, septet, J=6.6 Hz), 7.15 (IH, s), 7.17 (IH, s), 7.46-7.65 (2H, m) , 7.88-7.98 (4H, m) , 8.09 (IH, br s). Reference Example compound 23-19:

2- (2 -amino- 4-pyridyl) -2-bromo-l- (3- fluorophenyl )ethanone hydrobromide m.p. 206 - 207°C Reference Example compound 23-20:

2- (2-amino- 4-pyridyl) -2-bromo-l- (4- chlorophenyl ) ethanone hydrobromide m.p. 202 - 203°C Reference Example compound 23-21:

2- (2-amino-4 -pyridyl) -2-bromo-l- (3- ethylphenyl ) ethanone hydrobromide m.p. 46 - 47°C Reference Example compound 23-22:

2- (2-amino-4 -pyridyl) -2-bromo-l- ( 4-fluoro-3- methylphenyl ) ethanone hydrobromide m.p. 225 - 226°C

Reference Example 24

4- (methylthio) thiobenzamide

4- (methylthio)benzonitrile (12 g, 80 mmol) was dissolved in a solution of 4 N hydrogen chloride in ethyl acetate (130 mL). To this solution was added dithiophosphoric acid 0,0-diethyl ester(15 mL, 88 mmol) , and the mixture was stirred for 22 hours at room temperature. Water (100 mL) was added to the reaction mixture, and extracted with ethyl acetate. The insoluble material was filtrated off, then, the filtrate was washed with brine, dried, then, the solvent was distilled off. The residue was recrystallized from ethyl acetate to obtain a title compound (10 g, yield 67%). m.p. 176 - 178°C. Reference Example 25

The following reference example compounds 25-1 to 25-10 were synthesized according to Reference Example 24, using 2-chlorobenzonitrile, 4-chlorobenzonitrile , 2- fluorobenzonitrile, 4-fluorobenzonitrile, 2,4- difluorobenzonitrile, butyronitrile, valerbnitrile, 3-phenylpropionitrile, 4-phenylbutyronitrile, 1- methylpiperidine-4-carbonitrile, respectively, instead of 4- (methylthio Jbenzonitrile. Reference Example compound 25-1:

2-chlorothiobenzamide m.p. 58 - 59°C Reference Example compound 25-2:

4-chlorothiobenzamide m.p. 130 - 131°C Reference Example compound 25-3:

2-fluorothiobenzamide m.p. 113 - 114°C Reference Example compound 25-4:

4-fluorothiobenzamide m.p. 156 - 157°C Reference Example compound 25-5: 2 , 4 -difluorothiobenzamide m.p. 127 - 128°C Reference Example compound 25-6: thiobutyramide Oil

'H-NMR (CDC1₃) δ : 0.99 (3H, t, J= 7.6 Hz), 1.72-1.93 (2H, m) , 2.64 (2H, t, J= 7.6 Hz), 7.02 (IH, br s), 7.77 ( IH, br s) . Reference Example compound 25-7: thiovaleramide

Oil

1 H-NMR (CDC1₃) δ : 0.94 (3H, t, J= 7.3 Hz), 1.31-1.49 (2H, m) , 1.68-1.83 (2H, m) , 2.67 (2H, t, J= 7.7 Hz), 6.92 (IH, br s) , 7.73 (IH, br s) . Reference Example compound 25-8:

3-phenyl ( thiopropionamide ) m.p. 83 - 84°C Reference Example compound 25-9:

4-phenyl ( thiobutyramide ) m.p. 60 - 61°C Reference Example compound 25-10: l-methylpiperidine-4-carbothioamide m.p. 216 - 220°C

Reference Example 26 ethyl ( 4-phenyl- 1- piperazinyl ) carbothioylcarbamate

To a solution of ethyl isothiocyanatoformate (8.1 g, 62 mmol) in acetone (30 mL) was added 1- phenylpiperazine (10 g, 62 mmol), and the mixture was heated to reflux for 1 hour. The reaction mixture was concentrated, and the crude crystal was recrystallized from ethyl acetate to obtain a title compound (13 g, yield 73%). m.p. 134 - 135°C.

Reference Example 27

The following reference example compound 27 was synthesized according to Reference Example 26 using 1-methylpiperazine instead of 1-phenylpiperazine. Reference example compound 27: ethyl (4-methyl- 1- piperazinyl ) carbothioylcarbamate m.p. 155 - 157°C

Reference Example 28

4-phenyl- 1-piperazinecarbothioamide Ethyl ( 4-phenyl-1- piperazinyl) carbothioylcarbamate (13 g, 44 mmol) was added to cone, hydrochloric acid (44 mL) , and the mixture was stirred for 2 hours at 80°C. The reaction mixture was made basic with an 8N-aqueous sodium hydroxide solution, and the crystal was collected by filtration. The crystal was washed with water, and dried to obtain a title compound (6.1 g, yield 63%). m.p. 178 - 179°C

Reference Example 29

The following reference example compound 29 was synthesized according to Reference Example 28 using ethyl ( 4-methyl-1-piperazinyl) carbothioylcarbamate instead of ethyl ( 4-phenyl-1-piperazinyl) carbothioylcarbamate . Reference example compound 29:

4-methyl-1-piperazinecarbothioamide m.p. 173 - 175°C

Reference Example 30

3,3,3-trifluorothiopropionamide

To a solution of 3,3, 3-trifluoropropionamide (2.00 g, 15.7 mmol) in anhydrous tetrahydrofuran (100 mL) was added a Lawesson's reagent (3.79 g, 9.37 mmol), and the mixture was heated under reflux for 2 hours . The mixture was cooled to room temperature, then, an aqueous saturated sodium hydrogen carbonate solution was added to the reaction mixture, and extracted with ethyl acetate. The extracts were dried, to distill off the solvent. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=10:l to 4:1) to give a title compound (1.85 g, yield: 82%).

Oil

^XH-NMR (CDC1₃) δ : 3.61 (2H, q, J= 10.4 Hz), 6.70 - 8.00 (2H, m) . Reference Example 31

The following reference example compounds 31-1 and 31-2 were synthesized according to Reference Example 30, using ethyl 3-amino-3-oxopropanate and ethyl 2-amino- 2-oxoacetate instead of 3, 3 , 3-trifluoropropionamide. Reference Example compound 31-1: ethyl 3-amino-3-thioxopropanate

Oil

^XH-NMR (CDC1₃) δ : 1.31 (3H, t, J=7.1 Hz), 3.85 (2H, s), 4.22 (2H, q, J=7.1 Hz), 7.74 (IH, br s), 8.92 (IH, br s) . Reference Example compound 31-2: ethyl 2-amino-2-thioxoacetate

^-NMR (CDC1₃) δ : 1.41 (3H, t, J=7.2 Hz), 4.38 (2H, q, J=7.2 Hz), 7.68 (IH, br s), 8.24 (IH, br s).

Reference Example 32

The following reference example compound 32 was synthesized according to Example 33 described later, using 4- (3-methylphenyl) -2- [4- (methylthio)phenyl] -5- (4-pyridyl) -1 , 3-thiazole instead of 4-(3,5- dimethylphenyl) -5- (2-methyl-4-pyridyl) -2- [4- (methylthio)phenyl] -1 , 3-thiazole. Reference Example compound 32:

4- [ 4- ( 3-methylphenyl) -2- ( 4- methylsulfonylphenyl) -1 , 3-thiazol-5-yl]pyridine N- oxide m.p. 196 - 197°C

Reference Example 33

1-tert-butoxycarbonylpiperidine-4-carboxamide To a solution of piperidine-4-carboxamide (5.0 g, 39 mmol) in water (30 mL) was added di-tert-butyl dicarbonate (9.2 mL, 40 mmol) slowly, and then the reaction mixture was stirred at room temperature for 24 hours. The resulting mixture was extracted with ethyl acetate, and the extracts were washed with brine, dried, and concentrated in vacuo. The residue was crystallized from ethyl acetate to give a title compound (6.9 g, yield 78%). m.p. 163-165 C

Reference Example 34

The following reference example compound 34 was synthesized according to Reference example 30, using 1- tert-butoxycarbonylpiperidine-4-carboxamide instead of 3,3,3-trifluoropropionamide . Reference Example compound 34:

1-tert-butoxycarbonylpiperidine-4-carbothioamide m.p. 129-131 ΩC Reference Example 35

The following reference example compound 35 was synthesized according to Reference example 12, using N- ( 3-ethylbenzoyl)propyleneimine instead of N-(3- methylbenzoyl)propyleneimine Reference Example compound 35:

1- ( 3-ethylphenyl) -2- ( 2-fluoro-4-pyridyl)ethanone m.p. 59-60 ΩC

Reference Example 36

The following reference example compound 36 was synthesized according to Reference example 22, using 1- ( 3-ethylphenyl) -2- ( 2-fluoro-4-pyridyl) ethanone instead of 1- (3-methylphenyl) -2- (2-methyl-4-pyridyl) ethanone Reference Example compound 36:

2-bromo-1- ( 3-ethylphenyl) -2- ( 2-fluoro-4- pyridyl) ethanone hydrobromide amorphous

'H-NMRfDMSO-dg) d: 1.22 (3H, t, J= 7.6Hz), 2.70 (2H, q, J= 7.6Hz), 7.19 (IH, s), 7.39 (IH, s), 7.45-7.58 (3H, m) , 7 . 77 ( IH , br s ) , 7 . 92 - 7 . 97 ( 2H , m) , 8 . 30 ( IH , d , J= 5 . 6Hz ) .

Reference Example 37 ethyl 2,2-difluoropropionate

To ethyl pyruvate ( 3.0 g, 26 mmol) was added dropwise dimethylaminosulfur trifluoride (3.4 L, 26 mmol) over 1 hour and the reaction mixture was stirred at 60 ΩC for 4 hours. The resulting mixture was poured into ice-water and extracted with ethyl acetate . The extracts were washed with brine, dried, and concentrated under reduced pressure to give a title compound (1.2 g, yield 78%).

Oil

¹H-NMR(CDC1₃) d: 1.36 (3H, t, J= 7.2Hz ) , 1.81 (3H, t, J= 19.0Hz), 4.33 (2H, q, J= 7.2Hz ) . Reference Example 38

2,2-difluoropropionic acid

A solution of ethyl 2,2-difluoropropionate (1.2 g, 8.8 mmol) in ethanol (26 mL) was added to 2N aqueous sodium hydroxide (26 mL) and the resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was acidified with 2N hydrochloric acid and extracted with ether. The extracts were dried, and concentrated under reduced pressure to give a title compound (0.90 g, yield 92%).

Oil d: 1.85 (3H, t, J= 19.0Hz), 6.21 (IH,

Reference Example 39

2 , 2-difluoropropionamide

To a solution of 2,2-difluoropropionic acid (7.8 g, 71 mmol) in tetrahydrofuran (80 mL) was added oxalyl chloride (6.6 mL, 78 mmol) at room temperature and then N,N-dimethylformamide (2drops) was added to the solution. The reaction mixture was stirred at room temperature for 2 hours. The resulting solution was added dropwise to 25% aqueous ammonia at OΩC over 15 minutes, and stirred for 1 hour. The reaction mixture was extractedwith ethyl acetate. The extracts were dried, and concentrated under reduced pressure. The obtained crude mixture was crystallized from hexane to give a title compound (3.7 g, yield 49%). m.p. 70-71ΩC Reference Example 40

The following reference example compound 40 was synthesized according to Reference example 24, using (methylthio)acetonitrile instead of 4- (methylthio)benzonitrile. Reference Example compound 40:

(methylthio)thioacetamide m.p. 66-67ΩC Reference Example 41

The following reference example compound 41-1 and 41-2 were synthesized according to Reference example 30, using 3- (methylthio)propionamide and 2,2-difluoropropionamide instead of 3, 3, 3-trifluoropropionamide. Reference Example compound 41-1:

3- (methylthio)thiopropionamide

Oil

'H-NMRfCDCl d: 2.17 (3H, s), 2.93 (4H, s), 7.52 (2H, br s) . Reference Example compound 41-2:

2 , 2-difluorothiopropionamide

Oil

"H-NMRfCDCl d: 1.98 (3H, t, J= 18.5 HZ), 7.56 (IH, br s) , 7.72 (IH, br s) . Reference Example 42

2-amino-1-methyl-2-oxoethyl benzoate

To a solution of 2-hydroxypropionamide (10.8 g, 121 mmol) in pyridine (40 mL) was added benzoyl chloride (14.2 mL, 122 mmol) at O C and the reaction mixture was allowed to warm up to room temperature. The resulting mixture was stirred at room temperature for 3 hours and the solvent was removed under reduced pressure to give a residue. To the residue an aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The extracts were washed with an IN hydrochloric acid twice and brine. The organic solution was dried, and concentrated under reduced pressure. The obtained crude crystal was recrystallized from ethyl acetate-hexane to give a title compound (17.9 g, yield 77%). m.p. 116-117ΩC Reference Example 43

2-amino-1-methyl-2-thioxoethyl benzoate

To a solution of 2-amino-1-methyl-2-oxoethyl benzoate (10.0 g, 52.0 mmol) in 1 , 2-dimethoxyethane (90 mL) was added Lawesson's reagent (11.2 g, 27.7 mmol) at OΩC and the reaction mixture was allowed to warm up to room temperature. The resulting mixture was stirred at room temperature for 24 hours and the precipitate was removed by filtration. The resulting solution was concentrated under reduced pressure to give a residue. The residue was dissolved in ethyl acetate and the solution was washed with brine. The organic solution was dried, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=2:l) to obtain a crude crystal. The crude crystal was recrystallized from ethyl acetate-hexane to give a title compound (8.60 g, yield 79%). m.p. 100-101ΩC

Example 1

[5- (2-amino-4-pyridyl) -4- ( 4-methoxyphenyl) -1,3- thiazol-2-yl] amine

To a solution of 2-bromo-2- (2-tert- butoxycarbonylamino-4-pyridyl) -1- (4- methoxyphenyl) ethanone hydrobromide (synthesized from 2- ( 2-tert-butoxycarbonylamino-4-pyridyl) -1- ( 4- methoxyphenyl) ethanone (4.5 g, 13 mmol) according to the method descrxbed in Reference Example 20) in acetonitrile (40 mL) were added thiourea (1.1 g, 14 mmol) and triethylamine (1.9 mL, 14 mmol), and the mixture was stirred for 2 hours at 80°C. The reaction mixture was cooled to room temperature, then, concentrated. To the residue was added a saturated aqueous sodium hydrogen carbonate solution (200 mL) , and the resulting solid was filtrated, and washed with water. To this solid was added 2N-hydrochloric acid (35 mL) , and the mixture was stirred for 45 minutes at 100°C. The reaction mixture was cooled to room temperature, then, 8N-sodium hydroxide aqueous solution (10 mL) and aqueous sodium hydrogen carbonate solution (100 mL) were added. The resulted crude crystal was filtrated, and washed with water. This crude crystal was recrystallized from ethanol to obtain a title compound (2.7 g, yield 69%) . m.p. 251 to 254°C

Example 2

[5- ( 2-tert-butoxyσarbonylamino-4-pyridyl) -3- ( 4- methoxyphenyl) - 1 , 3-thiazol-2-yl ] amine

To a solution of 2- ( 2-tert-butoxycarbonylamino- 4-pyridyl) -1- ( 4-methoxyphenyl) ethanone (6.1 g, 18 mmol) in acetic acid (100 mL) was added bromine (1.0 mL), and the mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated. The residue was dissolved in acetonitrile (100 mL) , and to this solution were added thiourea (1.1 g, 14 mmol) and triethylamine (3.0 mL, 22 mmol), and the mixture was stirred at room temperature for 2 hours, then, concentrated. To the residue was added a saturated aqueous sodium hydrogen carbonate solution (50 mL), and the resulted solid was filtrated, washed with water, and recrystallized from ethanol to give a title compound (1.7 g, yield: 24%). m.p. 270°C or more (dec.)

Example 3

[5- (2-tert-butoxycarbonylamino) -4-pyridyl] -2- ethyl-4- (3-methylphenyl) -1, 3-thiazole A solution of 2-bromo-2- ( 2-tert- butoxycarbonylamino-4-pyridyl) -1- (3- methylphenyl) ethanone hydrobromide (synthesized from 2- (2-tert-butoxycarbonylamino-4-pyridyl) -1- (3- methylphenyl) ethanone (5.0 g, 24 mmol) according to the method described in Reference Example 21) and thiopropionamide (1.4 g, 16 mmol) in N,N- dimethylformamide (50 mL) was stirred for 14 hours at room temperature. To the reaction mixture was poured an aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extracts were washed with water, then, dried and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=4:l) to obtain a crystal. This crystal was washed with hexane to obtain a title compound (2.43 g, yield 39%) . m.p. 162 - 163°C

Example 4

The following example compounds 4-1 and 4-2 were synthesized according to Example 3, using thioacetamide and 4- (methylthio) thiobenzamide instead of thiopropionamide . Example compound 4-1:

5- [2- (tert-butoxycarbonylamino) -4-pyridyl] -2- methyl-4- (3-methylphenyl) -1,3-thiazole

This was used in the subsequent reaction without purification. Example compound 4-2:

[ 5- [2- (tert-butoxycarbonylamino) -4-pyridyl] -4- (3-methylphenyl) -2- [4- (methylthio)phenyl] -1,3- thiazole

This was used in the subsequent reaction without purification .

Example 5

The following example compound 5 was synthesized according to Example 4, using 2-bromo-2- (2-tert- butoxycarbonylamino-4-pyridyl) -1- ( 4- methoxyphenyl) ethanone hydrobromide instead of 2- bromo-2- (2-tert-butoxycarbonylamino-4-pyridyl) -1- (3- methylphenyl) ethanone hydrobromide .

Example compound 5: 5- [ 2- ( tert-butoxycarbonylamino) - 4-pyridyl] -4- ( 4-methoxyphenyl) -2-methyl-1, 3-thiazole.

This was used in the subsequent reaction without purification .

Example 6

[ 5- ( 2-fluoro-4-pyridyl) -4- ( 3-methylphenyl) -1 , 3- thiazol-2-yl] amine

To a mixture of 2-bromo-2- (2-fluoro-4-pyridyl) - 1- (3-methylphenyl)ethanone hydrobromide and thiourea (3.03 g, 39.8 mmol) in acetonitrile (50 mL) was added triethylamine (5.2 mL, 37.3 mmol), and the mixture was stirred for 2 hours at 80°C. Aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the deposited solid was collected by filtration. The resulted solid was washed with water, then, dried. The crude crystal was recrystallized from ethanol to obtain a title compound (3.67 g, yield 35%). m.p. 214 - 218°C.

Example 7 The following example compounds 7-1 to 7-8 were synthesized according to Example 6, using 2-bromo-2- ( 2-fluoro-4 -pyridyl ) -1- ( 3-methoxyphenyl ) ethanone hydrobromide, 2-bromo-l- (3-chlorophenyl) -2- (2-fluoro- 4 -pyridyl) ethanone hydrobromide, 2-bromo-l- (4- fluorophenyl ) -2- ( 2-fluoro-4-pyridyl ) ethanone hydrobromide , 2-bromo- 1- ( 3-methylphenyl ) -2 - ( 2-methyl- 4 -pyridyl) ethanone hydrobromide, 2-bromo-l- (3, 5- dimethylphenyl ) -2- (2-methyl-4-pyridyl) ethanone hydrobromide , 2 -bromo- 1- ( 3 , 5-dimethylphenyl ) -2- ( 2 , 6 - dimethyl- 4 -pyridyl) ethanone hydrobromide and 2-bromo- 1- ( 3 , 5-dimethylphenyl ) -2- ( 2 , 6 -dimethyl- 4- pyridyl) ethanone hydrobromide, 2-bromo-l- (4- fluorophenyl ) -2- ( 2-methyl-4-pyridyl ) ethanone hydrobromide, respectively, instead of 2 -bromo-2- (2- fluoro- 4 -pyridyl) -1- (3-methylphenyl) ethanone hydrobromide . Example compound 7 - 1 :

[5- ( 2-fluoro-4 -pyridyl) -4- ( 3-methoxyphenyl) -1,3- thiazol- 2-yl ] amine m.p. 190 - 191°C. Example compound 7-2:

4- ( 3 -chlorophenyl ) - 5- ( 2-fluoro-4-pyridyl ) - 1 , 3 - thiazol-2-yl ] amine m.p. 227 - 228°C. Example compound 7-3:

[4- (4-fluorophenyl) -5- ( 2-fluoro-4-pyridyl) -1,3- thiazol- 2-yl] amine m.p. 243 - 245°C. Example compound 7-4:

[4- (3-methylphenyl) -5- ( 2-methyl-4-pyridyl) -1 , 3- thiazol- 2-yl ] amine m.p. 205 - 206°C. Example compound 7-5:

[4- (3, 5-dimethylphenyl) -5- ( 2-methyl-4 -pyridyl) - 1, 3-thiazol-2-yl]amine m.p. 219 - 220°C. Example compound 7-6:

[5- (2, 6-dimethyl-4-pyridyl) -3- (3-methylphenyl) - 1 , 3-thiazol-2-yl]amine m.p. 214 - 216°C. Example compound 7-7:

[4- (3, 5-dimethylphenyl) -5- (2, 6 -dimethyl-4- pyridyl) -1, 3-thiazol-2-yl] amine m.p. 256 - 258°C. Example compound 7-8:

[4- (4-fluorophenyl) -5- ( 2-methyl-4-pyridyl) -1,3- thiazol-2 -yl ] amine m.p. 233 - 234°C.

Example 8

The following example compound 8 was synthesized according to Example 6, using N-methylthiourea instead of thiourea. Example compound 8 :

N-methyl- [ 5- ( 2-fluoro-4-pyridyl) -4- ( 3- methylphenyl) -1 , 3-thiazol-2-yl]amine m.p. 186 - 187°C

Example 9

The following example compound 9 was synthesized according to Example 8, using 2-bromo-2- ( 2 -methyl-4- pyridyl ) - 1- ( 3-methylphenyl ) ethanone hydrobromide instead of 2-bromo-2- (2-fluoro-4-pyridyl) -1- ( 3- methylphenyl ) ethanone hydrobromide . Example compound 9 :

N-methyl- [4- (3-methylphenyl) -5- ( 2-methyl-4- pyridyl) -1 , 3-thiazol-2-yl]amine m.p. 164 - 165°C Example 10

The following example compound 10 was synthesized according to Example 9, using N,N-dimethylthiourea instead of N-methylthiourea. Example compound 10:

N,N-dimethyl- [4- (3-methylphenyl) -5- ( 2 -methyl-4- pyridyl) -1 , 3-thiazol-2-yl]amine m.p. 77 - 79°C

Example 11

2-ethyl-5-(2-fluoro-4-pyridyl)-4-(3- methylphenyl) -1, 3-thiazole

A solution of 2-bromo-2- ( 2-fluoro-4-pyridyl) -1- (3-methylphenyl) ethanone hydrobromide (11 g, 29 mmol) and thiopropionamide (2.7 g, 30 mmol) in N,N- dimethylformamide (30 mL) was stirred for 14 hours at room temperature. Aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and extracted with ethyl acetate . The extracts were washed with water, dried, then, the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane-ethyl acetate= 4:1) to obtain a title compound (3.3 g, yield 38%) .

Oil

^XH-NMR (CDC1₃) δ : 1.64 (3H, t, J= 7.6 Hz ) , 2.34 (3H, s), 3.10 (2H, q, J= 7.6 Hz), 6.84-6.86 (IH, m) , 7.05- 7.09 (IH, m) , 7.13-7.25 (3H, m) , 7.37 (IH, s), 8.10 (IH, d, J= 5.6 Hz) .

Example 12

The following example compound 12 was synthesized according to Example 11, using 2-bromo-l- (3- chlorophenyl ) -2- (2-fluoro-4-pyridyl) ethanone hydrobromide instead of 2-bromo-2- (2-fluoro-4- pyridyl) - 1- ( 3-methylphenyl ) ethanone hydrobromide . Example compound 12:

2-ethyl-4- (3-chlorophenyl) -5- (2-fluoro-4- pyridyl) -1 , 3-thiazole m.p. 102 - 103°C

Example 13

The following example compound 13 was synthesized according to Example 11, using 2-bromo-l- (3- methylphenyl) -2- (2-methyl-4-pyridyl) ethanone hydrobromide instead of 2-bromo-2- (2-fluoro-4- pyridyl) -1- ( 3-methylphenyl) ethanone hydrobromide . Example compound 13:

2-ethyl-4- ( 3-methylphenyl) -5- ( 2-methyl-4- pyridyl) -1 , 3-thiazole

Oil

^-NMR (CDC1₃) δ : 1.45 (3H, t, J= 7.6 Hz) , 2.33 (3H, s), 2.51 (3H, s), 3.09 (2H, q, J= 7.6 Hz), 6.99 (IH, dd, J=1.2, 5.2 Hz), 7.13-7,30 (4H, m) , 7.39 (IH, s) , 8.38 (IH, d, J=5.2 Hz) .

Example 14

The following example compounds 14-1 to 14-14 were synthesized according to Example 13, using 2- chlorothiobenzamide, 4-chlorothiobenzamide, 2- fluorothiobenzamide, 4-fluorothiobenzamide, 2,4- difluorothiobenzamide, thiobenzamide , phenyl( thioacetamide) , 3-phenyl( thiopropionamide) , 4- phenyl( thiobutyramide) , thiovaleramide, thiobutyramide, ethyl 2-amino-2-thioxoacetate, 4-methyl-l- piperazinecarbothioamide and l-methylpiperidine-4- carbothioamide, respectively, instead of thiopropionamide . Example compound 14-1:

2- ( 2-chlorophenyl) -4- ( 3-methylphenyl) -5- ( 2- methyl-4-pyridyl) -1 , 3-thiazole m.p. 83 - 84°C Example compound 14-2:

2 - ( 4-chlorophenyl ) -4 - ( 3-methylphenyl ) -5- ( 2 - methyl-4 -pyridyl) -1 , 3-thiazole m.p. 104 - 105°C Example compound 14-3:

2- ( 2-fluorophenyl ) -4- ( 3-methylphenyl) - 5- ( 2- methyl-4 -pyridyl) -1 , 3-thiazole m.p. 73 - 74°C Example compound 14-4:

2- ( 4-fluorophenyl ) -4- ( 3-methylphenyl ) -5- ( 2- methyl-4 -pyridyl) -1,3-thiazole m.p. 89 - 91°C Example compound 14-5:

2- ( 2 , 4-difluorophenyl ) - 4- ( 3 -methylphenyl ) - 5- ( 2- methyl-4 -pyridyl) -1 , 3-thiazole m.p. 90 - 91°C Example compound 14-6:

4- (3-methylphenyl) -5- ( 2-methyl-4-pyridyl) -2- phenyl-1 , 3-thiazole m.p. 79 - 80°C Example compound 14-7:

4- (3-methylphenyl) -5- ( 2 -methyl-4-pyridyl) -2- (phenylmethyl) -1, 3-thiazole m.p. 82 - 84°C Example compound 14-8:

4- ( 3-methylphenyl ) - 5- ( 2 -methyl-4-pyridyl) -2 - ( 2- phenylethyl ) - 1 , 3-thiazole m.p. 64 - 65°C Example compound 14-9:

4- ( 3-methylphenyl ) -5- ( 2-methyl-4-pyridyl) -2- ( 3- phenylpropyl) -1 , 3-thiazole

Oil

^XH-NMR (CDC1₃) δ : 2.12-2.27 (2H, m) , 2.33 (3H, s), 2.50 (3H, s), 2.79 (2H, t, J=7.7 Hz), 3.08 (2H, t, J=7.9 Hz) , 6.98 (IH, dd, J=1.4, 5.6 Hz) , 7.10-7.35 (9H, m) , 7.38 (IH, s), 8.38 (IH, d, J=5.6 Hz). Example compound 14-10:

2-butyl-4- ( 3-methylphenyl ) - 5- ( 2-methyl-4- pyridyl) - 1 , 3-thiazole

Oil

^XH-NMR (CDC1₃) δ : 0.99 (3H, t, J=7.1 Hz), 1.43- 1.56 (2H, m) , 1.76-1.91 (2H, m) , 2.33 (3H, s), 2.50 (3H, s), 3.05 (2H, t, J=7.9 Hz), 6.99 (IH, d, J=5.4 Hz), 7.10-7.20 (4H, m) , 7.38 (IH, s), 8.37 (IH, d, J=5.4 Hz). Example compound 14-11:

4- (3-methylphenyl) -5- ( 2-methyl-4-pyridyl) -2- propyl-1 , 3-thiazole

Oil

^-NMR (CDC1₃) δ : 1.08 (3H, t, J=7.4 Hz), 1.79- 2.00 (2H, m) , 2.33 (3H, s), 2.50 (3H, s), 3.03 (2H, t, J=7.4 Hz) , 6.99 (IH, d, J=5.3 Hz ) , 7.10-7.20 (4H, m) , 7.39 (IH, s), 8.37 (IH, d, J=5.3 Hz). Example compound 14-12:

Ethyl [ 4- ( 3-methylphenyl ) - 5- ( 2 -methyl-4- pyridyl) -1 , 3-thiazol-2-yl]carboxylate m.p. 97 - 98°C Example compound 14-13:

4- (3-methylphenyl) -2- ( 4-methylpiperazin-l-yl) - 5- (2 -methyl-4-pyridyl) -1 , 3-thiazole m.p. 115 - 116°C Example compound 14-14:

4- ( 3-methylphenyl) -2- ( l-methylpiperazin-4-yl) - 5- ( 2 -methyl-4-pyridyl) -1 , 3-thiazole m.p. 127 - 130°C

Example 15

The following example compound 15 was synthesized according to Example 11, using 4- (methylthio) thiobenzamide, instead of thiopropionamide. Example compound 15:

5- (2-fluoro-4-pyridyl) -4- (3-methylphenyl) -2- [4- (methylthio )phenyl ] - 1 , 3-thiazole m.p. 97 - 100°C

Example 16

The following example compounds 16-1 to 16-6 were synthesized according to Example 15, using 2-bromo-l- (3-methylphenyl) -2- (2-methyl-4-pyridyl) ethanone hydrobromide, 2-bromo-l- (3, 5-dimethylphenyl) -2- ( 2- methyl-4-pyridyl) ethanone hydrobromide, 2-bromo- 1- (3,5-dimethylphenyl ) -2- ( 2 , 6 -dimethyl-4- pyridyl) ethanone hydrobromide, 2-bromo-l- (3 , 5- dimethylphenyl) -2- (2 , 6-dimethyl-4-pyridyl) ethanone hydrobromide, 2-bromo-l- (4-fluorophenyl) -2- (2-methyl- 4-pyridyl) ethanone hydrobromide and 2- ( 2-amino- 4- pyridyl) -2-bromo-l- (3-chlorophenyl) ethanone hydrobromide, respectively, instead of 2 -bromo-2- (2- fluoro-4-pyridyl) -1- (3-methylphenyl) ethanone hydrobromide . Example compound 16-1:

4- (3 -methylphenyl) -5- ( 2-methyl-4-pyridyl) -2- [4- (methylthio) phenyl] - 1 , 3-thiazole m.p. 119 - 122°C Example compound 16-2:

4- ( 3 , 5-dimethylphenyl) -5- ( 2 -methyl-4-pyridyl) - 2- [4- (methylthio)phenyl] -1,3-thiazole m.p. 123 - 125°C Example compound 16-3:

5- ( 2 , 6 -dimethyl-4-pyridyl ) -4 - ( 3-methylphenyl ) - 2- [4- (methylthio) phenyl] -1 , 3-thiazole m.p. 112 - 114°C Example compound 16-4:

4- ( 3 , 5-dimethylphenyl) - 5- ( 2 , 6 -dimethyl-4- pyridyl) -2- [4- (methylthio)phenyl] -1, 3-thiazole m.p. 134 - 136°C Example compound 16-5:

4- ( 4-fluorophenyl) -5- ( 2-methyl-4-pyridyl) -2- [ 4- (methylthio)phenyl] -1 , 3-thiazole m.p. 99 - 100°C Example compound 16-6:

4- [ 4- ( 3-chlorophenyl) -2- [ 4- (methylthio)phenyl- 1 , 3-thiazol-5-yl] -2-pyridylamine m.p. 183 - 184°C

Example 17

4- [ 2- ( 2-chlorophenyl) -4- ( 3-methylphenyl) -1 , 3- thiazol- 5-yl] -2-pyridylamine

A solution of 2- ( 2-amino-4-pyridyl) -2-bromo-l- (3-methylphenyl) ethanone hydrobromide (5.00 g, 12.3 mmol) and 2-chlorothiobenzamide (1.06 g, 11.9 mmol) in N,N-dimethylformamide (40 mL) was stirred for 14 hours at room temperature. Aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and extracted with ethyl acetate. The extracts were washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane- ethyl acetate= 4:1 to 2:1) to obtain a crystal. This crystal was washed with isopropyl ether, to obtain a title compound (3.15 g, yield 81%). m.p. 175 - 177°C

Example 18

The following example compounds 18-1 to 18-6 were synthesized according to Example 17, using 4- fluorothiobenzamide, thiovaleramide, 3,3,3- trifluorothiopropionamide, thiobutyramide, ethyl 3- amino-3-thioxopropanate, ethyl 2-amino-2-thioxoacetate, respectively, instead of 2-chlorothiobenzamide. Example compound 18-1: 4- [ 2- ( 4 -fluorophenyl ) -4 - ( 3-methylphenyl ) -1 , 3- thiazol-5-yl] -2-pyridylamine m.p. 160 - 162°C Example compound 18-2:

4- [ 2-butyl-4- ( 3-methylphenyl ) - 1 , 3-thiazol- 5- yl ] -2-pyridylamine

Oil

'H-NMR (CDC1₃) δ : 0.98 (3H, t, J=7.3 Hz), 1.39- 1.59 (2H, m) , 1.76-1.92 (2H, m) , 2.34 (3H, s), 3.04 (2H, t, J=7.4 Hz), 4.14 (2H, br s), 6.44 (IH, s), 6.56 (IH, dd, J=1.5, 5.4 Hz) , 7.09-7.26 (3H, m) , 7.41 (IH, s) , 7.96 (IH, d, J=5.4 Hz) . Example compound 18-3:

4- [ 4- ( 3-methylphenyl ) -2- ( 2 , 2 , 2 -trifluoroethyl ) - 1 , 3-thiazol-5-yl] -2-pyridylamine m.p. 131 - 132°C Example compound 18-4:

4- [ 4- ( 3-methylphenyl) -2 -propyl- 1 , 3-thiazol- 5- y1 ] -2 -pyridylamine m.p. 113 - 115°C Example compound 18-5:

Ethyl [ 5- ( 2-amino-4-pyridyl ) -4- ( 3- methylphenyl ) - 1 , 3-thiazol-2-yl ] acetate m.p. 128 - 129°C Example compound 18-6:

Ethyl [ 5- ( 2 -amino-4-pyridyl) -4 - ( 3- methylphenyl) -1, 3-thiazol-2-yl]carboxylate m.p. 147 - 148°C

Example 19

The following example compound 22 was synthesized according to Example 17, using thiopropionamide instead of 2-chlorothiobenzamide.

Example 20 The following example compounds 20-1 to 20-12 were synthesized according to Example 19, using 2- (2- amino-4-pyridyl) -2-bromo-l- ( 3-chlorophenyl)ethanone hydrobromide, 2- ( 2-amino-4-pyridyl) -2-bromo- 1- phenylethanone hydrobromide, 2- (2-amino-4-pyridyl) -2- bromo-1- (4-fluorophenyl) ethanone hydrobromide, 2- (2- amino-4-pyridyl) -2-bromo-l- [ 3-

( trifluoromethyl)phenyl] ethanone hydrobromide, 2- (2- amino-4-pyridyl) -2-bromo-l- [ 4-

(methylthio)phenyl] ethanone hydrobromide, 2-(2-amino- 4-pyridyl) -2-bromo-l- (3-fluorophenyl)ethanone hydrobromide, 2- (2-amino-4-pyridyl) -2-bromo-l- ( 4- chlorophenyl) ethanone hydrobromide, 2- ( 2-amino-4- pyridyl) -2-bromo-l- ( 3-ethylphenyl) ethanone hydrobromide, 2- ( 2-amino-4-pyridyl) -2-bromo-l- ( 4- fluoro-3-methylphenyl)ethanone hydrobromide, 2- (2- amino-4-pyridyl) -2-bromo-l- [3- (1- methylethyl)phenyl]ethanone hydrobromide, 2-(2-amino- 4-pyridyl) -2-bromo-l- ( 3-propylphenyl)ethanone hydrobromide, 2- ( 2-amino-4-pyridyl) -2-bromo-1- ( 2- thienyl) ethanone hydrobromide, respectively, instead of 2- (2-amino-4-pyridyl) -2-bromo-l- (3- methylphenyl) ethanone hydrobromide . Example compound 20-1:

4- [2-ethyl-4-(3-chlorophenyl) -1 , 3-thiazol-5- yl]-2-pyridylamine m.p. 132 - 133°C Example compound 20-2:

4- ( 2-ethyl-4-phenyl-1,3-thiazol-5-yl) -2- pyridylamine m.p. 158 - 159°C Example compound 20-3:

4- [ 2-ethyl-4- ( 4-fluorophenyl) -1 , 3-thiazol-5- yl] -2-pyridylamine m.p. 140 - 141°C Example compound 20-4:

4- [ 2 -ethyl-4- [ 3- ( trifluoromethyl ) phenyl ] - 1 , 3- thiazol- 5-yl] -2-pyridylamine m.p. 117 - 118°C Example compound 20-5:

4- [ 2-ethyl-4- [ 4- (methylthio )phenyl ] - 1 , 3- thiazol- 5-yl] -2-pyridylamine m.p. 119 - 120°C Example compound 20-6:

4 - [ 2-ethyl-4- ( 3-fluorophenyl ) - 1 , 3-thiazol- 5 - yl ] -2-pyridylamine m.p. 153 - 154°C Example compound 20-7:

4- [ 4 - ( 4 -chlorophenyl ) -2 -ethyl-1,3-thiazol-5 - yl ] - 2-pyridylamine m.p. 136 - 137°C Example compound 20-8:

4- [ 2-ethyl-4- ( 3-ethylphenyl) - 1 , 3-thiazol- 5-yl ] 2-pyridylamine m.p. 128 - 129°C Example compound 20-9:

4- [2-ethyl-4- ( 4-fluoro-3-methylphenyl) -1,3- thiazol-5-yl] -2-pyridylamine m.p. 134 - 135°C Example compound 20-10:

4-[2-ethyl-4-[3-(l-methylethyl)phenyl]-l,3- thiazol-5-yl] -2-pyridylamine m.p. 80 - 81°C Example compound 20-11:

4- [2-ethyl-4- (3-propylphenyl) -1, 3-thiazol-5- yl ] -2-pyridylamine m.p. 72 - 74°C Example compound 20-12:

4 - [ 2-ethyl-4 - ( 2-thienyl ) - 1 , 3-thiazol- 5-yl] -2- pyridylamine m.p. 159 - 160°C

Example 21

The following example compounds 21-1 and 21-2 were synthesized according to Example 18, using 2- (2- amino- 4 -pyridyl ) - 2 -bromo- 1 - ( 3 -chlorophenyl ) ethanone hydrobromide instead of 2- (2 -amino- 4 -pyridyl) -2- bromo- 1 - ( 3 -methylphenyl ) ethanone hydrobromide . Example compound 21-1:

4- [ 4- (3 -chlorophenyl) -2 -propyl- 1 , 3 -thiazol- 5- yl] -2-pyridylamine m.p. 99 - 100°C Example compound 21-2:

Ethyl [ 5- ( 2 -amino-4 -pyridyl) -4- (3- chlorophenyl) -1 , 3-thiazol-2-yl]acetate m.p. 154 - 155°C

Example 22

4- [2-ethyl-4-( 3-methylphenyl) -1 , 3 -thiazol- 5- yl ] - 2-pyridylamine

To 5 - [ 2 - ( tert -butoxycarbonylamino ) - 4-pyridyl ] - 2 -ethyl- 4- (3-methylphenyl) -1 , 3-thiazole (synthesized from 2- ( 2 -tert -butoxycarbonylamino -4 -pyridyl) -1- (3- methylphenyl) ethanone (35 g, 170 mmol) according to the method described in Example 3) was added 2N-hydrochloric acid (200 mL) , and the mixture was stirred for 1 hour at 100°C. The reaction mixture was cooled to room temperature, then, made alkaline with a 2N aqueous sodium hydrogen carbonate solution (200 mL) and aqueous sodium hydrogen carbonate solution. The resulted mixture was extracted by ethyl acetate, and the extracts were washed with water. This extracts were dried and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate= 1:1) to obtain a crystal. This crystal was washed with isopropyl ether. to obtain a title compound (17 g, yield 55%). m.p. 144 - 146°C

Example 23

The following example compounds 23-1 to 23-3 were synthesized according to Example 22, using 5- [2- ( tert-butoxycarbonylamino) -4-pyridyl] -2-methyl-4- (3- methylphenyl) -1 , 3-thiazole, 5- [ 2- ( tert- butoxycarbonylamino) -4-pyridyl] -4- (3-methylphenyl) -2- [ 4- (methylthio)phenyl] -1,3-thiazole and 5-[2-(tert- butoxycarbonylamino) -4-pyridyl ] -4- ( 4-methoxyphenyl) - 2-methyl-1, 3-thiazole, respectively, instead of 5-[2- ( tert-butoxycarbonylamino) -4-pyridyl] -2-ethyl-4- (3- methylphenyl) -1 , 3-thiazole . Example compound 23-1:

4- [2-methyl-4- (3-methylphenyl) -1, 3-thiazol-5- yl] -2-pyridylamine m.p. 152 - 153°C Example compound 23-2:

4- [ 4- ( 3-methylphenyl) -2- [ 4- (methylthio)phenyl] - 1 , 3-thiazol-5-yl] -2-pyridylamine m.p. 181 - 183°C Example compound 23-3:

4- [4- (4-methoxyphenyl) -2-methyl-1, 3-thiazol-5- yl] -2-pyridylamine m.p. 140 - 141°C

Example 24

[5- (2-amino-4-pyridyl) -4- (3-methylphenyl) -1,3- thiazol-2-yl]acetic acid

To a suspension of ethyl [5- (2-amino-4- pyridyl) -4- (3-methylphenyl) -1, 3-thiazol-2-yl]acetate (7.00 g, 19.8 mmol) in ethanol (40 mL) was added a IN aqueous sodium hydroxide solution ( 40 mL) , and the mixture was stirred for 2 hours at the room temperature under the same condition. The reaction mixture was neutralized with 2N hydrochloric acid (20 mL), then, the produced, solid was collected by filtration. The crude product was washed with water, and dried to obtain a title compound (6.10 g, yield: 95%) . m.p. 132 - 133°C

Example 25

The following example compounds 25-1 to 25-3 were synthesized according to Example 24, using ethyl [5- ( 2-amino-4-pyridyl) -4- (3-methylphenyl) -1 , 3-thiazol-2- yl]carboxylate, ethyl [ 5- (2-methyl-4-pyridyl) -4- ( 3- methylphenyl) -1, 3-thiazol-2-yl]carboxylate and ethyl [5- (2-amino-4-pyridyl) -4- (3-chlorophenyl) -1,3- thiazol-2-yl]acetate, respectively, instead of ethyl [5- (2-amino-4-pyridyl) -4- (3-methylphenyl) -1,3- thiazol-2-yl] acetate. Example compound 25-1:

5- ( 2-amino-4-pyridyl) -4- (3-methylphenyl) -1,3- thiazole-2-carboxylic acid m.p. 156 - 157°C Example compound 25-2:

5-(2-methyl-4-pyridyl) -4- (3-methylphenyl) -1,3- thiazole-2-carboxylic acid m.p. 135 - 136°C Example compound 25-3:

[5- (2-methyl-4-pyridyl) -4- (3-chlorophenyl) -1, 3- thiazol-2-yl]acetic acid

This was used in the subsequent reaction without puri ication.

Example 26

4- ( 3-methylphenyl) -5- ( 2-methyl-4-pyridyl) -1 , 3- thiazole

4- ( 3-methylphenyl) -5- ( 2-methyl-4-pyridyl) -1 , 3- thiazole-2-carboxylic acid (0.20 g, 0.64 mmol) was stirred for 15 minutes at 150°C. It was cooled to room temperature, then, the crude product was purified by silica gel column chromatography (ethyl acetate) to obtain a title compound (0.17 g, yield 98%).

Oil

^XU-NMR (CDC1₃) δ : 2.34 (3H, s), 2.53 (3H, s), 7.04 (IH, d, J=5.1 Hz), 7.16-7.24 (4H, m) , 7.43 (IH, s), 8.42 (IH, d, J=5.1 Hz), 8.88 (IH, s).

Example 27

The following example compounds 27-1 and 27-2 were synthesized according to Example 26, using 5- (2- amino- 4-pyridyl ) -4- ( 3-methylphenyl) - 1 , 3-thiazole-2- carboxylic acid and [ 5- (2-amino-4-pyridyl) -4- (3- chlorophenyl) -1 ,3-thiazol-2-yl] acetic acid. Example compound 27-1:

4- [4- (3-methylphenyl) -1 , 3-thiazol-5-yl] -2- pyridylamine m.p. 91 - 92°C Example compound 27-2:

4- [4- (3-chlorophenyl) -2-methyl-1 , 3-thiazol- 5- yl ]-2 -pyridylamine m.p. 142 - 143°C

Example 28

N- [4- [2-ethyl-4-( 3-methylphenyl) -1 , 3-thiazol-5- yl ] -2 -pyridyl ] cyclohexanecarboxamide

To a solution of 4- [2 -ethyl-4- (3-methylphenyl) - 1,3-thiazol-5-yl] -2-pyridylamine (0.80 g, 2.7 mmol) in tetrahydrofuran (10 mL) were added cyclohexanecarbonyl chloride (0.40 mL, 3.0 mmol) and triethylamine (0.39 mL, 2.8 mmol) sequentially, and the mixture was stirred for 1 hour at room temperature. To the reaction mixture was added an aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extracts were washed with an aqueous sodium hydrogen carbonate solution, then, dried and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=20:l to 4:1) to obtain a crystal. This crystal was washed with hexane to obtain a title compound (0.83 g, yield 75%) . m.p. 98 - 100°C

Example 29

The following example compounds 29-1 to 29-5 were synthesized according to Example 28, using cyclopentanecarbonyl chloride, acetyl chloride, 1- methylcyclohexanecarbonyl chloride, propionyl chloride and pivaloyl chloride instead of cyclohexanecarbonyl chloride . Example compound 29-1:

N- [ 4- [ 2-ethyl- 4 - ( 3-methylphenyl) - 1 , 3-thiazol- 5- yl ] -2-pyridyl ] cyclopentanecarboxamide m.p. 123 - 125°C. Example compound 29-2:

N- [ 4- [ 2-ethyl-4 - ( 3-methylphenyl) - 1 , 3-thiazol-5- yl ] -2-pyridyl ] acetamide m.p. 119 - 120°C. Example compound 29-3:

N- [ 4 - [ 2-ethyl-4- ( 3 -methylphenyl ) - 1 , 3 -thiazol- 5- yl] -2-pyridyl] -1-methylcyclohexanecarboxamide

Oil

"H-NMR (CDC1₃) δ : 1.28 (3H, s), 1,30-1.75 (11H, m) , 1.98-2.12 (2H, ) , 2,33 (3H, s), 3.08 (2H, q, J=7.6 Hz), 6.79-6.85 (IH, m) , 7.10-7.25 (3H, m) , 7.38-7.42 (IH, m) , 8.04-8.07 (2H, m) , 8.40-8.43 (IH, m) . Example compound 29-4:

N- [ 4- [ 2 -ethyl-4- ( 3-methylphenyl ) - 1 , 3 -thiazol-5- yl ] -2 -pyridyl ] propionamide m.p. 103 - 104°C Example compound 29-5:

N- [4- [2 -ethyl- 4- (3-methylphenyl ) -1,3-thiazol-5- yl] - 2-pyridyl ] pivalamide

Oil

^XH-NMR (CDC1₃) δ : 1.34 (9H, s), 1.44 (3H, t, J=7.6 Hz) , 2.33 (3H, s) , 3.08 (2H, q, J=7.6 Hz ) , 6.79-6.84 (IH, m), 7.09-7.27 (3H, m) , 7.36-7.39 (IH, m) , 8.03-8.10 (2H, m) , 8.38-8.42 (IH, m) .

Example 30

The following example compounds 30-1 to 30-12 were synthesized according to Example 29, using 4- [4- (3- chlorophenyl) -2-methyl- 1, 3-thiazol-5-yl] -2- pyridylamine , 4- [4- (3-chlorophenyl) -2-ethyl-l ,3- thiazol-5-yl] -2-pyridylamine, 4- [4- (3-chlorophenyl) - 2 -propyl- 1, 3-thiazol-5-yl] -2-pyridylamine, 4- [2- ethyl-4- ( 2-thienyl) -1 , 3-thiazol-5-yl] -2-pyridylamine and 4- [ 4- ( 3-chlorophenyl ) -2 - [ 4- (methylthio)phenyl ] - 1 , 3-thiazol-5-yl] -2-pyridylamine, respectively, instead of 4- [2-ethyl-4- ( 3-methylphenyl) -1 , 3-thiazol- 5 -yl]-2-pyridylamine . Example compound 30-1:

N- [4- [4-(3-chlorόphenyl)-2-methyl-l,3-thiazol- 5-yl] -2 -pyridyl ]acetamide m.p. 112 - 115°C. Example compound 30-2:

N- [4- [4- (3-chlorophenyl) -2-ethyl-l, 3-thiazol-5- yl ]-2 -pyridyl ] acetamide m.p. 149 - 150°C. Example compound 30-3:

N- [ 4- [4- (3-chlorophenyl) -2 -propyl- 1 , 3-thiazol- 5-yl ] -2-pyridyl] acetamide m.p. 144 - 145°C. Example compound 30-4: N- [4- [2-ethyl-4-( 2-thienyl) -1,3-thiazol- 5-yl] - 2 -pyridyl ] acetamide m.p. 154 - 155°C. Example compound 30-5:

N-[4-[4-(3-chlorophenyl) -2- [ 4- (methylthio)phenyl] -1, 3-thiazol-5-yl] -2- pyridyl ] acetamide m.p. 207 - 208°C. Example compound 30-6:

N- [4- [4-(3-chlorophenyl) -2-ethyl-l , 3-thiazol-5- yl ] -2-pyridyl ] - 1 -methylcyclohexanecarboxamide

Oil

^XH-NMR (CDC1₃) δ : 1.28 (3H, s), 1.35-1.82 (11H, m) , 1.95-2.13 (2H, m) , 3.08 (2H, q, J=7.8 Hz ) , 6.80-6.84 (IH, m), 7.19-7,37 (3H, m) , 7.53-7.62 (IH, m) , 8.07-8.12 (IH, m) , 8.25-8.35 (IH, m) , 8.40-8.43 (IH, m) . Example compound 30-7:

N- [4- [4-(3-chlorophenyl) -2-methyl-l , 3-thiazol- 5-yl ] -2-pyridyl ] propionamide m.p. 134 - 135°C. Example compound 30-8:

N-[4-[4-(3-chlorophenyl ) -2-ethyl-1,3-thiazol-5- yl ] -2 -pyridyl ]propionamide m.p. 132 - 133°C. Example compound 30-9:

N- [ 4- [ 4- ( 3-chlorophenyl) -2-propyl-l , 3-thiazol- 5-yl] -2-pyridyl]propionamide m.p. 103 - 104°C. Example compound 30-10:

N- [4- [2-ethyl-4-( 2-thienyl) -1,3-thiazol-5-yl ] - 2-pyridyl ]propionamide m.p. 187 - 188°C. Example compound 30-11:

N-[4-[4-(3-chlorophenyl) -2 - [ 4- (methylthio)phenyl] -1, 3-thiazol-5-yl] -2- pyridyl ] propionamide m.p. 187 - 188°C. Example compound 30-12:

N-[4-[4-(3-chlorophenyl)-2-[4- (methylthio ) phenyl ] - 1 , 3-thiazol-5-yl ] -2- pyridyl ] ivalamide m.p. 119 - 120°C.

Example 31

N- (cyclohexylmethyl) -4- [2-ethyl-4- (3- methylphenyl ) -1 , 3-thiazol-5-yl] -2-pyridylamine

To a solution of aluminum chloride (0.40 g, 3.0 mmol) in tetrahydrofuran (40 mL) was added lithium aluminum hydride (0.12 g, 3.0 mmol) at 0°C. To this solution was added dropwise a solution of N-[4-[2- ethyl-4- (3-methylphenyl) -1 , 3-thiazol-5-yl] -2- pyridyl]cyclohexanecarboxamine (0.40 g, 0.99 mmol) in tetrahydrofuran (10 mL) , and the mixture was heated under reflux for 1 hour. The reaction mixture was cooled to room temprature, to this was added ice water, and extracted with ethyl acetate. The extracts were washed with an aqueous sodium hydrogen carbonate solution, then, dried and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=20:l to 4:1) to obtain a crystal. This crystal was washed with hexane to obtain a title compound (0.27 g, yield 70%) . m.p. 74 - 75°C

Example 32

The following example compound 32 was synthesized according to Example 31, using N- [4- [2 -ethyl- 4- (3- methylphenyl ) -1 , 3-thiazol-5-yl] -2- pyridyl]cyclopentanecarboxamine instead of N-[4-[2- ethyl-4- ( 3-methylphenyl) -1 , 3-thiazol-5-yl] -2- pyridyl ] cyclohexanecarboxamine . Example compound 32:

N- (cyclopentylmethyl) -4- [2-ethyl-4- (3- methylphenyl) -1 , 3-thiazol-5-yl] -2-pyridylamine m.p. 67 - 69°C.

Example 33

[4- (3-methylphenyl) -5- ( 2-pyperidino-4-pyridyl) - 1 , 3-thiazol-2-yl]amine

5- ( 2 -fluoro-4-pyridyl ) -4- ( 3-methylphenyl) - 1 , 3- thiazol-2 -yl] amine (0.70 g, 2.5 mmol) and piperidine (2.0 mL, 20 mmol) were stirred at 150°C for 3 hours. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate=l:l) to obtain a title compound (0.62 g, yield 72%). m.p. 181 - 182°C

Example 34

The following example compounds 34-1 to 34-3 were synthesized according to Example 33, using morpholine, cyclohexylamine and cyclopentylamine instead of piperidine. Example compound 34-1:

[4- (3-methylphenyl) -5- ( 2-morpholino-4-pyridyl) - 1 , 3-thiazol-2-yl]amine m.p. 188 - 189°C. Example compound 34-2:

[5- (2-cyclohexylamino-4 -pyridyl) -4- (3- methylphenyl) -1, 3-thiazol-2-yl] amine m.p. 168 - 169°C. Example compound 34-3:

[ 5- ( 2-cyclopentylamino-4-pyridyl) - 4- ( 3- methylphenyl) -1 , 3-thiazol-2-yl]amine m.p. 169 - 170°C. Example 35

The following example compounds 35-1 and 35-2 were synthesized according to Example 34, using 4- (3- chlorophenyl ) - 5 - ( 2-fluoro-4-pyridyl ) -1 , 3-thiazol-2- yl] amine and 5- (2-fluoro-4-pyridyl ) -4- (3- methylphenyl) -2- (4 -methylsulfonylphenyl) -1, 3-thiazole instead of 5- (2-fluoro-4-pyridyl) -4- (3-methylphenyl) - 1,3-thiazol-2-yl ] amine Example compound 35-1:

[4- (3-chlorophenyl) -5- ( 2-piperidino-4 -pyridyl) - 1,3-thiazol-2-yl ] amine m.p. 206 - 208°C. Example compound 35-2:

4- ( 3-methylphenyl ) - 2- ( 4 -methylsulfonylphenyl ) - 5- (2 -piperidino-1-pyridyl) -1 , 3-thiazole m.p. 155 - 157°C.

Example 36

The following example compounds 36-1 to 36-11 were synthesized according to Example 34, using 5- (2- fluoro-4-pyridyl) -4- ( 4-fluorophenyl) -1 , 3-thiazol-2- yl] amine, N-methyl- [5- (2-fluoro-4-pyridyl) -4- (3- methylphenyl) -1 , 3-thiazol- 2 -yl] amine, 2 -ethyl-5- (2- fluoro-4-pyridyl) -4- (3-methylphenyl) -1,3-thiazole, 5- ( 2-fluoro-4-pyridyl) -4- (3-methylphenyl) -2- ( 4- methylsulfonylphenyl) -1 , 3-thiazole and 4- (3- chlorophenyl) -2-ethyl-5- ( 2-fluoro- 4 -pyridyl) -1,3- thiazole, respectively, instead of 5- (2-fluoro-4- pyridyl) -4- (3-methylphenyl) -1 , 3-thiazol-2-yl] amine . Example compound 36-1:

[5- (2-cyclohexylamino-4-pyridyl) -4- (4- fluorophenyl ) - 1 , 3-thiazol-2 -yl ] amine m.p. 194 - 195°C. Example compound 36-2:

N-methyl- [5- ( 2-cyclohexylamino-4-pyridyl) -4- ( 3- methylphenyl ) - 1 , 3-thiazol-2 -yl ] amine m.p. 211 - 212°C. Example compound 36-3:

N-methyl- [5- (2-cyclopentylamino-4-pyridyl) -4- ( 3-methylphenyl) -1 , 3-thiazol-2-yl]amine m.p. 170 - 172°C. Example compound 36-4:

N-cyclohexyl-4- [2-ethyl-4- (3-methylphenyl) -1,3- thiazol- 5-yl] -2-pyridylamine m.p. 110 - 112°C. Example compound 36-5:

N-cyclohexyl-4- [4- (3-methylphenyl) -2- (4- methylsulfonylphenyl) -1 , 3-thiazol-5-yl] - 2 - pyridylamine m.p. 197 - 199°C. Example compound 36-6:

N-cyclopentyl-4- [ 2 -ethyl-4- ( 3-methylphenyl) - 1 , 3-thiazol-5-yl] -2-pyridylamine m.p. 117 - 118°C. Example compound 36-7:

N-cyclopentyl-4- [4- (3-methylphenyl) -2- (4- methylsulfonylphenyl) -1 , 3-thiazol-5-yl] -2- pyridylamine m.p. 154 - 156°C. Example compound 36-8:

4 - ( 3-methylphenyl) -2 - ( 4-methylsulfonylphenyl ) - 5- (2-morpholino-4 -pyridyl) -1 , 3-thiazole m.p. 200 - 202°C. Example compound 36-9:

2 -ethyl-4- (3-methylphenyl) -5- ( 2-morpholino-4- pyridyl ) - 1 , 3 -thiazole m.p. 69 - 71°C. Example compound 36-10:

4- [ 4 - ( 3-chlorophenyl ) -2-ethyl-1,3-thiazol- 5- yl] -N-cyclohexyl-2-pyridylamine m.p. 106 - 107°C. Example compound 36-11:

4- [4- (3-chlorophenyl) -2-ethyl-l , 3-thiazol- 5- yl] -N-cyclopentyl-2-pyridylamine m.p. 110 - 111°C.

Example 37

The following example compounds 37-1 to 37-5 were synthesized according to Example 36, using pyrrolidine, N-methylcyclohexylamine, (cyclohexylmethyl) amine and 1-methylpiperazine, respectively, instead of cyclohexylamine . Example compound 37-1:

2-ethyl-4- ( 3-methylphenyl) -5- [ 2- ( 1- pyrrolidinyl ) -4-pyridyl] -1 , 3-thiazole m.p. 108 - 109°C. Example compound 37-2:

N-cyclohexyl-N-methyl-4- [4- (3-methylphenyl) -2- ( 4-methylsulfonylphenyl) -1 , 3-thiazol-5-yl] -2- pyridylamine m.p. 173 - 174°C. Example compound 37-3:

N-cyclohexylmethyl-4- [ 4- ( 3-methylphenyl) -2- ( 4- methylsulfonylphenyl) -1 , 3-thiazol-5-yl] -2- pyridyla ine m.p. 157 - 159°C. Example compound 37-4:

4- ( 3-methylphenyl) -2- ( 4-methylsulfonylphenyl) - 5- [ 2- (1-pyrrolidinyl) -4-pyridyl] -1 , 3-thiazole m.p. 199 - 201°C. Example compound 37-5:

4 - ( 3-methylphenyl) -5- [ 2- ( 4-methyl- 1- piperazinyl ) -4-pyridyl ] -2- ( 4-methylsulfonylphenyl ) - 1 , 3-thiazole m.p. 153 - 154°C. Example 38

N- [ 5- ( 2-acetylamino-4-pyridyl) -4- ( 4- methoxyphenyl) -1 , 3-thiazol-2-yl]acetamide

To a solution of 4- [2-amino-4- ( 4- methoxyphenyl) -1 , 3-thiazol-5-yl] -2-pyridylamine (0.40 g, 1.4 mmol) and 4-dimethylaminopyridine (0.055 g, 0.45 mmol) in N,N-dimethylacetamide (10 mL) was added acetyl chloride (0.3 mL, 4.2 mmol), and the mixture was stirred for 14 hours at 70°C. An aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and extracted with ethyl acetate. The extracts were washed with brine, then, dried and concentrated. The crude crystal was recrystallized from ethanol to obtain a title compound (0.30 g, yield 58%). m.p. 262 - 264°C

Example 39

N- [4- (3-methylphenyl) -5- ( 2-methyl-4-pyridyl) - 1, 3-thiazol-2-yl] acetamide

To a solution of [ 4- ( 3-methylphenyl) -5- ( 2- methyl-4-pyridyl) -1 , 3-thiazol-2-yl]amine (0.50 g, 1.8 mmol) and 4-dimethylaminopyridine (0.061 g, 0.50 mmol) in N,N-dimethylacetamide (15 mL) was added acetyl chloride (0.19 mL, 2.7 mmol), and the mixture was stirred for 14 hours at 80°C. An aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the deposited solid was filtrated. The resulted solid was washed with water, then, dried. The crude crystal was recrystallized from ethanol , to obtain a title compound (0.39 g, yield 67%). m.p. 230 - 231°C

Example 40

The following example compounds 40-1 to 40-3 were synthesized according to Example 39, using [4-(3,5- dimethylphenyl ) -5- ( 2-methyl-4-pyridyl) -1 , 3-thiazol-2 - yl] amine, [5- (2, 6-dimethyl-4-pyridyl) -4- (3- methylphenyl) -1, 3-thiazol-2-yl]amine and [4-(3,5- dimethylphenyl) -5- (2 , 6 -dimethyl-4-pyridyl) -1,3- thiazol-2-yl]amine, respectively, instead of [4- (3- methylphenyl) -5- (2-methyl-4 -pyridyl) -1 , 3-thiazol-2- yl ] amine . Example compound 40-1:

N- [4- (3,5-dimethylphenyl) -5- ( 2 -methyl-4- pyridyl) -1, 3-thiazol-2-yl] acetamide m.p. 236 - 237°C. Example compound 40-2:

N- [ 5- ( 2 , 6-dimethyl-4-pyridyl ) -4- ( 3- methylphenyl) - 1 , 3-thiazol- 2 -yl] acetamide m.p. 185 - 187°C. Example compound 40-3: - [ 4- ( 3 , 5-dimethylphenyl ) - 5- ( 2 , 6 -dimethyl-4- pyridyl) -1, 3-thiazol-2-yl] acetamide m.p. 266 - 267°C.

Example 41

The following example compound 41 was synthesized according to Example 39, using nicotinoyl chloride hydrochloride instead of acetyl chloride. Example compound 41:

N- [4- (3-methylphenyl) -5- ( 2 -methyl- 4 -pyridyl) - 1 , 3-thiazol-2-yl]nicotinamide m.p. 175 - 178°C.

Example 42

The following example compounds 42-1 to 42-10 were synthesized according to Example 41, using [4- (3,5- dimethylphenyl) -5- (2-methyl-4-pyridyl) -1, 3-thiazol- 2- y1] amine , [ 4- ( 3 , 5-dimethylphenyl ) -5- ( 2 , 6-dimethyl-4 - pyridyl) -1 , 3-thiazol-2-yl] amine, [5- (2- cyclohexylamino-4-pyridyl) -4- (3-methylphenyl) -1,3- thiazol- 2 -yl ] amine , [ 5- ( 2-cyclopentylamino-4- pyridyl) -4- (3-methylphenyl) -1, 3-thiazol-2-yl]amine, [5- (2-cyclohexylamino-4-pyridyl) -4- ( 4-fluorophenyl) - 1, 3-thiazol-2-yl] amine, [5- (2-fluoro-4-pyridyl) -4- (3- methylphenyl) -1 , 3-thiazol-2 -yl] amine, [4- (4- fluorophenyl) -5- ( 2-methyl-4-pyridyl ) -1 , 3-thiazol-2- yl] amine, N- [5- (2-cyclohexylamino-4-pyridyl) -4- (3- methylphenyl) -1, 3-thiazol-2-yl] -N-methylamine, N- [ 5- (2-cyclopentylamino-4-pyridyl) -4- (3-methylphenyl) - 1 , 3-thiazol-2-yl] -N-methylamine and N-methyl-N- [ 5- ( 2- methyl- 4 -pyridyl) -4- (3-methylphenyl) -1 , 3-thiazol-2- yl]amine, respectively, instead of [4- (3- methylphenyl ) -5- (2 -methyl-4 -pyridyl) -1, 3-thiazol-2- yl] amine. Example compound 42-1:

N- [ 4 - ( 3 , 5-dimethylphenyl) -5- ( 2 -methyl-4- pyridyl ) - 1 , 3-thiazol-2-yl ] nicotinamide m.p. 203 - 206°C Example compound 42-2:

N- [4- (3, 5-dimethylphenyl) -5- ( 2 , 6-dimethyl-4- pyridyl ) - 1 , 3-thiazol-2 -yl ] nicotinamide m.p. 267 - 268°C Example compound 42-3:

N- [5- (2-cyclohexylamino-4-pyridyl) -4- (3- methylphenyl ) - 1 , 3-thiazol-2 -yl ] nicotinamide m.p. 201 - 203°C Example compound 42-4:

N- [ 5- ( 2-cyclopentylamino-4 -pyridyl) -4- ( 3- methylphenyl) -1 , 3-thiazol-2-yl]nicotinamide m.p. 215 - 216°C Example compound 42-5:

N- [5- (2-cyclohexylamino-4-pyridyl) -4- (4- fluorophenyl) -1 , 3-thiazol-2-yl]nicotinamide m.p. 136 - 138°C Example compound 42-6:

N- [ 5- ( 2-fluoro-4-pyridyl) -4- (3-methylphenyl) - 1 , 3-thiazol-2-yl]nicotinamide m.p. 229 - 231°C Example compound 42-7:

N- [ 4- ( 4-fluorophenyl) -5- ( 2 -methyl-4-pyridyl) - 1 , 3-thiazol-2-yl]nicotinamide m.p. 261 - 262°C Example compound 42-8:

N- [ 5- (2-cyclohexylamino-4-pyridyl) -4- (3- methylphenyl ) -1 , 3-thiazol-2-yl] -N-methylnicotinamide m.p. 147 - 148°C Example compound 42-9:

N- [5- ( 2 -cyclopentylamino-4-pyridyl) -4- (3- methylphenyl) -1 , 3-thiazol-2-yl]N-methylnicotinamide m.p. 148 - 148°C Example compound 42-10:

N-methyl-N- [ 5- ( 2-methyl-4-pyridyl) -4- (3- methylphenyl ) -1 , 3-thiazol-2-yl]nicotinamide

Oil

^Η-NMR (CDC1₃) δ : 2.35 (3H, s), 2.53 (3H, s), 3,78 (3H, s), 7.05 (IH, d, J=5.2 Hz), 7.06-7.30 (4H, m) , 7.41 (IH, s), 7.49 (IH, dd, J=5.2, 7.0Hz), 7.95 (IH, d, J=7,0 Hz), 8,40 (IH, d, J=5.2Hz), 8.80 (IH, d, J=5.2Hz), 8.88 (IH, s).

Example 43

The following example compound 43 was synthesized according to Example 39 using 6-chloro-3-pyridylcarbonyl chloride hydrochloride instead of acetyl chloride. Example compound 43:

6-chloro-N- [4- (3-methylphenyl) -5- (2-methyl-4- pyridyl ) -1 , 3-thiazol-2-yl] nicotinamide m.p. 228 - 230°C Example 44

The following example compounds 44-1 to 44-4 were synthesized according to Example 43, using [5- (2- cyclohexylamino-4-pyridyl) -4- ( 3-methylphenyl) -1 , 3- thiazol-2-yl]amine, [5- (2-cyclopentylamino-4- pyridyl) -4- (3-methylphenyl) -1, 3-thiazol-2-yl] amine, [ 4- ( 3 , 5-dimethylphenyl) -5- ( 2-methyl-4-pyridyl) -1 , 3- thiazol-2-yl]amine and N-methyl- [5- ( 2- cyclopentylamino-4-pyridyl) -4- (3-methylphenyl) -1,3- thiazol-2-yl]amine, respectively, instead of [4- (3- methylphenyl) -5- (2-methyl-4-pyridyl) -1, 3-thiazol-2- yl] amine . Example compound 44-1:

6-chloro-N- [5- ( 2-cyclohexylamino-4-pyridyl) -4- ( 3-methylphenyl) -1 , 3-thiazol-2-yl] nicotinamide m.p. 255 - 256°C Example compound 44-2:

6-σhloro-N- [5- ( 2-cyclopentylamino-4-pyridyl) -4- ( 3-methylphenyl) -1 , 3-thiazol-2-yl] nicotinamide m.p. 211 - 212°C Example compound 44-3:

6-chloro-N- [ 4- ( 3 , 5-dimethylphenyl) -5- ( 2-methyl- 4-pyridyl) - 1 , 3-thiazol-2-yl]nicotinamide m.p. 271 - 273°C Example compound 44-4:

6-chloro-N- [5- ( 2-cyclohexylamino-4-pyridyl) -4- ( 3-methylphenyl) -1 , 3-thiazol-2-yl] -N- methylnicotinamide m.p. 171 - 172°C

Example 45

The following example compound 45 was synthesized according to Example 39, using 6-methyl-3- pyridylcarbonyl chloride hydrochloride instead of acetyl chloride .

Example compound 45:

6 -methyl-N- [ 4- ( 3-methylphenyl ) -5- ( 2-methyl-4- pyridyl) -1, 3-thiazol-2-yl] nicotinamide m.p. 233 - 234°C

Example 46

The following example compounds 46-1 to 46-4 were synthesized according to Example 45, using [5- (2- cyclohexylamino- 4-pyridyl) -4- (3-methylphenyl) -1,3- thiazol-2-yl]amine, [5- ( 2-cyclopentylamino-4- pyridyl) -4- (3-methylphenyl) -1 , 3-thiazol-2 -yl] amine, [ 4- ( 3 , 5 -dimethylphenyl ) - 5- ( 2-methyl-4-pyridyl) - 1 , 3- thiazol-2-yl] amine and N-methyl- [5- (2- cyclopentylamino- 4-pyridyl) -4- (3-methylphenyl) -1,3- thiazol-2-yl]amine, respectively, instead of [4- (3- methylphenyl ) -5- ( 2 -methyl- 4 -pyridyl) -1, 3-thiazol-2- yl ] amine . Example compound 46-1:

N- [ 5- ( 2-cyclohexylamino-4-pyridyl) -4- ( 3- methylphenyl) -1 , 3-thiazol-2-yl] -6-methylnicotinamide m.p. 242 - 243°C Example compound 46-2:

N- [ 5- ( 2 -cyclopentylamino- 4 -pyridyl) -4- ( 3- methylphenyl ) -1 , 3-thiazol-2-yl] -6-methylnicotinamide m.p. 213 - 214°C Example compound 46-3:

N- [ 4- ( 3 , 5-dimethylphenyl ) - 5- ( 2 -methyl-4- pyridyl ) - 1 , 3-thiazol-2-yl ] - 6 -methylnicotinamide m.p. 252 - 253°C Example compound 46-4:

N- [5- (2 -cyclopentylamino-4-pyridyl) -4- (3- methylphenyl ) - 1 , 3-thiazol-2-yl ] -N, 6 - dimethylnicotinamide m.p. 117 - 118°C Example 47

The following example compound 47 was synthesized according to Example 39, using 6-methoxy-3- pyridylcarbonyl chloride hydrochloride instead of acetyl chloride. Example compound 47:

6-methoxy-N- [4- (3-methylphenyl) -5- ( 2-methyl-4- pyridyl) -1 , 3-thiazol-2-yl]nicotinamide m.p. 224 - 226°C

Example 48

The following example compounds 48-1 and 48-3 were synthesized according to Example 47, using [5- (2- cyclohexylamino-4-pyridyl) -4- (3-methylphenyl) -1,3- thiazol-2-yl]amine, [5- ( 2-cyclopentylamino- 4- pyridyl) -4- (3-methylphenyl) -1 , 3-thiazol-2-yl] amine and [ 4- ( 3 , 5 -dimethylphenyl) -5- ( 2 -methyl-4-pyridyl) - 1 , 3-thiazol-2-yl]amine, respectively, instead of [4- ( 3-methylphenyl) - 5- ( 2-methyl-4-pyridyl) - 1 , 3-thiazol- 2 -yl] amine. Example compound 48-1:

N- [ 5- ( 2-cyclohexylamino-4-pyridyl) -4- ( 3- methylphenyl) -1 , 3-thiazol-2-yl] -6-methoxynicotinamide m.p. 191 - 192°C Example compound 48-2:

N- [ 5- ( 2-cyσlopentylamino-4-pyridyl) -4- ( 3- methylphenyl ) -1 , 3-thiazol-2 -yl] -6-methoxynicotinamide m.p. 219 - 221°C Example compound 48-3:

N- [ 4 - ( 3 , 5-dimethylphenyl ) - 5- ( 2-methyl-4- pyridyl ) - 1 , 3-thiazol-2-yl ] - 6 -methoxynicotinamide m.p. 242 - 244°C

Example 49 The following example compound 49 was synthesized according to Example 39, using 2-methoxy-3- pyridylcarbonyl chloride hydrochloride instead of acetyl chloride. Example compound 49:

2-methoxy-N- [ 4- ( 3-methylphenyl) -5- ( 2-methyl-4- pyridyl) -1, 3-thiazol-2-yl]nicotinamide m.p. 169 - 170°C

Example 50

The following example compound 50 was synthesized according to Example 39, using [5- (2-tert- butoxycarbonylamino-4-pyridyl) -3- (4-methoxyphenyl) - 1, 3-thiazol-2-yl] amine instead of [4-(3- methylphenyl) -5- ( 2-methyl-1-pyridyl) -1 , 3-thiazol-2- yl] amine . Example compound 50:

N- [5- (2-amino-4-pyridyl) -4- ( 4-methoxyphenyl) - 1 , 3-thiazol-2-yl]acetamide m.p. 247 - 250°C

Example 51

The following example compound 51 was synthesized according to Example 50, using benzoyl chloride instead of acetyl chloride. Example compound 51:

N- [5- (2-amino-4-pyridyl) -4- (4-methoxyphenyl) - 1,3-thiazol-2-yl]benzamide m.p. 219 - 222°C

Example 52

N- [ 4- ( 2 , 6-dimethyl-4-pyridyl) -5- ( 3- methylphenyl) -1 , 3-thiazol-2-yl] -N' -phenylurea

To a solution of [4- (2, 6-dimethyl-4-pyridyl) -5- (3-methylphenyl) -1, 3-thiazol-2-yl]amine (0.50 g, 1.7 mmol) in N,N-dimethylacetamide (20 mL) was added phenyl isoσyanate (0.28 mL, 2.6 mmol), and the mixture was stirred for 14 hours at 80°C. Aqueous sodium hydrogen carbonate was poured into the reaction mixture, and extracted with ethyl acetate. The extracts were washed with brine, then, dried to be concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate= 1:1) . The resulted crude crystal was recrystallized from ethyl acetate-hexane to obtain a title compound (0.34 g, yield 48%). m.p. 173 - 174°C.

Example 53

The following example compounds 53-1 to 53-4 were synthesized according to Example 52, using [ 4- ( 3,5- dimethylphenyl ) -5- (2, 6 -dimethyl-4-pyridyl) -1,3- thiazol-2-yl]amine, [5- ( 2-cyclohexylamino-4-pyridyl) - 4- ( 3-methylphenyl ) - 1 , 3-thiazol-2-yl ] amine , [ 5- ( 2 - cyclopentylamino-4-pyridyl) -4- (3-methylphenyl) -1,3- thiazol-2-yl]amine and [4- (3-methylphenyl) -5- ( 2- methyl-4-pyridyl) -1, 3-thiazol-2-yl]amine, respectively, instead of [4- ( 2 , 6-dimethyl-4-pyridyl) - 5- ( 3-methylphenyl) -1, 3-thiazol-2-yl] amine . Example compound 53-1:

N- [ 4- ( 3 , 5- imethylphenyl ) -5 - ( 2 , 6 -dimethyl-4 - pyridyl) -1 , 3-thiazol-2-yl] -N' -phenylurea m.p. 219 - 222°C. Example compound 53-2:

N- [ 5- ( 2-cyclohexylamino-4-pyridyl) -4- ( 3- methylphenyl) -1 , 3-thiazol-2-yl] -N' -phenylurea m.p. 198 - 199°C. Example compound 53-3:

N- [ 5- ( 2-cyclopentylamino-4-pyridyl) -4- ( 3- methylphenyl) -1 , 3-thiazol-2-yl] -N' -phenylurea m.p. 188 - 190°C. Example compound 53-4:

N- [4- (3-methylphenyl) -5- ( 2-methyl-4-pyridyl) - 1 , 3-thiazol-2-yl] -N' -phenylurea m.p. 168 - 169°C.

Example 54

4- ( 3-methylphenyl) -5- ( 2-methyl-4-pyridyl) -2- ( 4- methylsulfinylphenyl) -1 , 3-thiazole

To a solution of 4- (3-methylphenyl) -5- ( 2- methyl-4-pyridyl) -2- [4- (methylthio)phenyl] -1,3- thiazole (0.55 g, 1.4 mmol) in acetic acid (15 mL) was added a solution of potassium persulfate (0.43 g, 1.6 mmol) in water (8 mL), and the mixture was stirred for 14 hours at room temperature. An aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and extracted with ethyl acetate. The extracts were washed with water, dried, then, the solvent was distilled off. The residue was purified by column chromatography (filler: Chromatorex NH DM1020 (trade name, manufactured by Fuji Silysia Chemical Ltd.), hexane-ethyl acetate= 1:4), and recrystallized from ethyl acetate-hexane to obtain a title compound (0.15 g, yield 26%). m.p. 128 - 130°C.

Example 55

5- (2 , 6-dimethyl-4-pyridyl) -4- (3-methylphenyl) - 2- (4-methylsulfinylphenyl) -1, 3-thiazole

To a solution of 5- (2 , 6-dimethyl.-4-pyridyl) -4- ( 3-methylphenyl) -2- [4- (methylthio)phenyl] -1,3- thiazole (0.41 g, 1.0 mmol) in N,N-dimethylformamide (15 mL) was added m-chloroperbenzoiσ acid (0.25 g, 1.0 mmol) , and the mixture was stirred for 1 hour at room temperature . A 8N aqueous sodium hydroxide solution was poured into the reaction mixture, and extracted with ethyl acetate. The extracted solution was washed with brine, dried, then. the solvent was distilled off. The residue was purified by column chromatography (filler: Chromatorex NH DM1020 (trade name, manufactured by Fuji Silysia Chemical Lte. ) , hexane-ethyl acetate= 1:2), to obtain a title compound (0.41 g, yield 97%) . m.p. 133 - 134°C.

Example 56

The following example compounds 56-1 and 56-2 were synthesized according to Example 55, using 4- ( 3,5- dimethylphenyl ) -5- (2-methyl- 4 -pyridyl) -2- [4- (methylthio)phenyl] -1, 3-thiazole and 4- ( 3,5- dimethylphenyl) -5- (2, 6-dimethyl-4 -pyridyl) -2- [4- (methylthio)phenyl] -1 , 3-thiazole instead of instead of 5- (2, 6-dimethyl-4-pyridyl) -4- (3-methylphenyl) -2- [4- (methylthio)phenyl] -1 , 3-thiazole Example compound 56-1:

4- (3, 5-dimethylphenyl) -5- ( 2-methyl-4-pyridyl) - 2- ( 4-methylsulfinylphenyl) -1 , 3-thiazole m.p. 151 - 153°C. Example compound 56-2:

4 - ( 3 , 5-dimethylphenyl ) -5- ( 2 , 6 -dimethyl-4- pyridyl ) -2- ( 4-methylsulfinylphenyl ) - 1 , 3-thiazole m.p. 151 - 154°C.

Example 57

4- ( 3-methylphenyl ) - 5- ( 2 -methyl-4-pyridyl) -2- ( 4 - methylsulfonylphenyl) -1 , 3-thiazole

To a solution of 4-( 3-methylphenyl)-5-( 2- methyl-4-pyridyl) -2- [4- (methylthio) phenyl] -1,3- thiazole (0.61 g, 1.6 mmol) in N,N-dimethylformamide (15 mL) was added m-chloroperbenzoic acid (0.87 g, 3.6 mmol) , and the mixture was stirred for 30 minutes at room temperature. An aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and extracted with ethyl acetate. The extracts were washed with water, dried, then, the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane-ethyl acetate= 1:1), and recrystallized from ethanol to obtain a title compound (0.39 g, yield 59%) . m.p. 134 - 138°C.

Example 58

The following example compounds 58-1 to 58-8 were synthesized according to Example 57, using 4- (3,5- dimethylphenyl) -5- (2-methyl-4-pyridyl) -2- [4- (methylthio)phenyl] -1 , 3-thiazole, 5- (2 , 6-dimethyl-4- pyridyl) -4- (3-methylphenyl) -2- [ 4- (methylthio)phenyl] - 1,3-thiazole , 4- ( 3 , 5-dimethylphenyl) -5- ( 2 , 6-dimethyl- 4-pyridyl) -2- [4- (methylthio)phenyl] -1,3-thiazole, 5- (2-fluoro-4-pyridyl) -4- (3-methylphenyl) -2- [4- (methylthio)phenyl] -1,3-thiazole, 4- (4- luoropheyl) - 5- (2-methyl-4-pyridyl) -2- [4- (methylthio)phenyl] -1,3- thiazole, N- [4- [ 4- ( 3-chlorophenyl) -2- [4- (methylthio)phenyl] -1 , 3-thiazol-5-yl] -2- pyridyl] acetamide, N- [4- [4- (3-chlorophenyl) -2- [4- (methylthio)phenyl] -1, 3-thiazol-5-yl] -2- pyridyl] propionamide and N- [4- [4- (3-chlorophenyl) -2- [4- (methylthio)phenyl] -1 , 3-thiazol-5-yl] -2- pyridyl]pivalamide . Example compound 58-1:

4- ( 3 , 5-dimethylphenyl) -5- ( 2-methyl-4-pyridyl) - 2- ( 4-methylsulfonylphenyl) - 1 , 3-thiazole , m.p. 196 - 197°C. Example compound 58-2:

5- ( 2 , 6-dimethyl-4-pyridyl) -4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) -1, 3-thiazole, m.p. 182 - 184°C. Example compound 58-3: 4- ( 3 , 5-dimethylphenyl ) - 5- ( 2 , 6-dimethyl-4- pyridyl ) -2- ( 4-methylsulfonylphenyl ) - 1 , 3-thiazole , m.p. 217 - 220°C. Example compound 58-4:

5- (2-fluoro-4-pyridyl) -4- (3-methylphenyl) -2- (4- methylsulfonylphenyl) -1,3-thiazole, m.p. 195 - 199°C. Example compound 58-5:

4- (4-fluorophenyl) -5- ( 2-methyl- 4-pyridyl) -2- (4- methylsulfonylphenyl) -1, 3-thiazole, m.p. 190 - 192°C. Example compound 58-6:

N-[4-[4-(3-chlorophenyl)-2-(4- methylsulfonylphenyl) -1, 3-thiazol-5-yl] -2- pyridyl ] acetamide , m.p. 216 - 217°C. Example compound 58-7:

N-[4-[4-(3-chlorophenyl)-2-(4- methylsulfonylphenyl) -1 , 3-thiazol-5-yl] -2- pyridyl ] propionamide , m.p. 224 - 225°C. Example compound 58-8:

N-[4-[4-(3-chlorophenyl ) -2 - ( 4 - methylsulfonylphenyl) -1 , 3-thiazol-5-yl] -2- pyridyl ] pivalamide , m.p. 122 - 123°C.

Example 59

4- [ 4- ( 3,5-dimethylphenyl) -2- (4- methylsulfonylphenyl) -1 , 3-thiazol-5-yl] -2- methylpyridine N-oxide

To a solution of 4- [4- (3, 5-dimethylphenyl) -5- ( 2-methyl-4 -pyridyl) -2- [ 4- (methylthio )phenyl] - 1 , 3- thiazole (0.60 g, 1.5 mmol) in N,N-dimethylformamide (20 mL) was added m-chloroperbenzoic acid (0.80 g, 3.2 mmol) , and the mixture was stirred for 30 minutes at room temperature. m-Chloroperbenzoic acid (0.11 g, 0.45 mmol) was added to the reaction mixture, and the mixture was further stirred for 20 minutes at room temperature. m-Chloroperbenzoic acid (0.38 g, 1.5 mmol) was added to the reaction mixture, and the mixture was further stirred for 20 minutes at room temperature. An aqueous sodium hydrogen carbonate solution was poured, and extracted with ethyl acetate . The extracts were washed with water, dried, then, the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane-ethyl acetate= 1:4), and recrystallized from ethanol to obtain a title compound (0.30 g, yield 44%). m.p. 255 - 256°C.

Example 60

N-[4-[4-(3-chlorophenyl) -2- ( 1-methylpiperidin-4- yl) -l,3-thiazol-5-yl] -2-pyridyl]propionamide dihydrochloride .

To a solution of N- [4- [4- ( 3-chlorophenyl) -2- (4- piperidyl) -1 , 3-thiazol-5-yl] -2-pyridyl]propionamide (0.31 g, 0.72 mmol) in N,N-dimethylformamide (8 mL)were added potassium carbonate (0.11 g, 0.82 mmol)and methyl iodide (0.045 mL, 0.72 mmol) were added sequentially, and stirred at room temperature for 20 hours. Aqueous sodium hydrogen carbonate was added to the reaction mixture and extracted with ethyl acetate . The extracts were washed with brine, dried, and concentrated. The residue was purified by column chromatography (filler: Chromatorex NH DM1020 (trade name, manufactured by Fuji Silysia Chemical Ltd. ) , hexane-ethyl acetate = 1 : 1) and treated with 10% solution of hydrogen chloride in methanol to obtain hydrochloride. The crude crystalline was washed with ethyl acetate to give a title compound (0.12 g, yield 32%). m.p. 248-253 C Example 61

The following example compound 61 was synthesized according to Example 53, using 2-chloroethyl isocyanate instead of phenyl isocyanate. Example compound 61:

N- ( 2-chloroethyl) -N' - [ 5- ( 2-methyl-4-pyridyl ) -4- ( 3-methylphenyl) -1 , 3-thiazol-2-yl]urea m.p. 149 - 151°C.

Example 62

The following example compound 62 was synthesized according to Example 39, using 2-chloroethyl σhloroformate instead of acetyl chloride Example compound 62:

2-chloroethyl [ 4- ( 3-methylphenyl) -5- ( 2-methyl- 4-pyridyl) -1 , 3-thiazol-2-yl]carbamate m.p. 156 - 158°C.

Example 63

N-methoxy-N' - [4- (3-methylphenyl) -5- ( 2-methyl-4- pyridyl) -1 , 3-thiazol-2-yl]urea

To a solution of [4- (2-methyl-4-pyridyl) -3- (3- methylphenyl) -1, 3-thiazol-2-yl]amine (0.50 g, 1.8 mmol) in N,N-dimethylacetamide (20 mL) was added 1,1- carbonyldiimidazole (0.43 g, 2.7 mmol), and the mixture was stirred for 3 hours at room temperature. A 0- methylhydroxylamine hydrochloride (0.22 g, 2,7 mmol) was added to the reaction mixture, and the mixture was stirred for 24 hours at room temperature. An aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the produced solid was filtrated. This solid was washed with water, and dried. The crude product was purified by column chromatography (filler: Chromatorex NH DM1020 (trade name, manufactured by Fuji Silysia Chemical Ltd.), ethyl acetate). The resulted crystal was recrystallized from ethyl acetate to obtain a title compound (0.16 g, yield 25%). m.p. 194 - 195°C.

Example 64

The following example compound 64 was synthesized according to Example 63, using O-phenylhydroxylamine hydrochloride instead of O-methylhydroxylamine hydrochloride . Example compound 64:

N- [ 4- (3-methylphenyl) -5- ( 2-methyl-4-pyridyl) - 1 , 3-thiazol-2-yl] -N' -phenyloxyurea m.p. 154 - 155°C

Example 65

3- [4- (3-methylphenyl) -5- ( 2-methyl-4-pyridyl) - 1 , 3-thiazol-5-yl] -oxazolidin-2-one

To a solution of 2-chloroethyl [4- (3- methylphenyl) -5- (2-methyl-4-pyridyl) -1, 3-thiazol-2- yl]carbamate (0.30 g, 0.80 mmol) in N,N- dimethylformamide (3 mL) was added potassium tert- butoxide (0.12 g, 1.1 mmol), and the mixture was stirred at room temperature for 1 hour. An aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and extracted with ethyl acetate. The extracts were washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate= 4:1) to obtain a crystal. This crystal was recrystallized from hexane-ethyl acetate, to obtain a title compound (0.20 g, yield 72%). m.p. 80 - 82°C

Example 66

The following example compound 66 was synthesized according to Example 65, using N- (2-chloroethyl) -N' - [ 5- ( 2-methyl-4-pyridyl) -4- ( 3-methylphenyl) -1 , 3- thiazol-2-yl]urea instead of 2-chloroethyl [4- (3- methylphenyl) -5- ( 2-methyl-4-pyridyl) -1 , 3-thiazol-2- yl ] carbamate . Example compound 66:

1- [4- (3-methylphenyl) -5- (2-methyl-4-pyridyl) - 1 , 3-thiazol-2-yl]imidazolidin-2-one m.p. 200 - 201°C

Example 67

1- [4- (3-methylphenyl) -5- (2-methyl-4-pyridyl) - 1, 3-thiazol-2-yl] -3-phenylimidazolidin-2-one

To a suspension of 1- [4- (3-methylphenyl) -5- ( 2- methyl-4-pyridyl) -1, 3-thiazol-2-yl] -3-imidazolidin-2- one (0.42 g, 1.2 mmol) , copper powder (0.23 g, 3.6 mmol) , copper chloride (0.01 g, 0.12 mmol) and potassium acetate (0.23 g, 2.4 mmol) in N,N-dimethylacetamide (10 mL) was added bromobenzene (0.56 g, 3.6 mmol), and the mixture was stirred at 150°C for 4 hours. After filtration, water was added, and extracted with ethyl acetate. The extracts were washed with water, then, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate= 4:1) to obtain crude crystal. This crude crystal was recrystallized from ethyl acetate, to obtain a title compound (0.18 g, yield 35%). m.p. 180 - 182°C

Example 68

The following example compounds 68-1 and 68-2 were synthesized according to Example 59, using 4- (3- methylphenyl) -5- ( 2-methyl-4-pyridyl) -2 - [ 4- (methylthio)phenyl] -1 , 3-thiazole and 2-ethyl-4- (3- methylphenyl) -5- ( 2-methyl-4-pyridyl) -1 , 3-thiazole instead of 4- (3 , 5-dimethylphenyl) -5- (2-methyl-4- pyridyl) -2- [4- (methylthio)phenyl] -1, 3-thiazole. Example compound 68-1:

4- [ 4- ( 3-methylphenyl ) -2 - ( 4- methylsulfonylphenyl) -1 , 3-thiazol-5-yl] -2- methylpyridine N-oxide m.p. 197 - 198°C Example compound 68-2:

[ 2-ethyl-4- ( 3-methylphenyl ) - 1 , 3-thiazol-5-yl] - 2-methylpyridine N-oxide

Oil

^-NMR (CDC1₃) δ : 1.41 (3H, t, J=7.6 Hz), 2.34 (3H, s), 2.46 (3H, s), 3.09 (2H, q, J=7.6 Hz), 7.01 (IH, dd, J=2.2, 7.0 Hz) , 7.12-7.24 (4H, m) , 8.10 (IH, d, J=2.0 Hz) .

Example 69

5- (2-chloro-4-pyridyl) -2-ethyl-4- (3- methylphenyl ) - 1 , 3-thiazole

A solution of 4- [2-ethyl-4- ( 3-methylphenyl) - 1 , 3-thiazol-5-yl]pyridine N-oxide (1.00 g, 3.37 mmol) in phosphorus oxychloride (6.5 mL) was stirred at 100°C for 2 hours. The reaction solution was cooled, and poured into a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extracts were washed with brine, then, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate= 2:1) to obtain a title compound (0.90 g, yield 81%).

Oil -NMR (CDCI₃) δ : 1.42 (3H, t, J=7.8Hz), 2.35 (3H, s), 3.10 (2H, q, J=7.8 Hz), 7.09 (IH, dd, J=1.4, 5.2 Hz), 7.12-7.30 (4H, m) , 7.37 (IH, s), 8.22-8.27 (IH, m) .

Example 70

A solution of 4- [ 2 -ethyl-4- ( 3-methylphenyl) - l,3-thiazol-5-yl]pyridine N-oxide (1.0 g, 3.2 mmol) in phosphorus oxychloride (8 mL) was stirred at 100°C for 1 hour. The reaction solution was cooled, and poured into a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extracts were washed with brine, then, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate= 10:1 to 2:1) to 5- ( 2-chloro-6- methyl- 4-pyridyl) -2-ethyl-4- (3-methylphenyl) -1,3- thiazole (0.60 g, yield 57%) and 5- ( 2-chloromethyl-4- pyridyl) -2-ethyl-4- (3-methylphenyl) -1 , 3-thiazole (0.20 g, yield 19%) . Example compound 70-1:

5- ( 2-chloro-6 -methyl-4-pyridyl) -2-ethyl-4- ( 3- methylphenyl )- 1 , 3-thiazole

Oil

"H-NMR (CDC1₃) δ : 1.45 (3H, t, J=7.8 Hz), 2.35 (3H, s), 2.45 (3H, s), 3.09 (2H, q, J=7.8 Hz), 6.98 (IH, s), 7.06 (IH, s), 7.12-7.24 (3H, m) , 7.38 (IH, s). Example compound 70-2:

5- ( 2-chloromethyl-4-pyridyl) -2 -ethyl-4- (3- methylphenyl) -1 , 3-thiazole

Oil

"H-NMR (CDCI₃) δ : 1.46 (3H, t, J=7.6 Hz), 2.33 (3H, s), 3.10 (2H, q, J=7.6 Hz), 4.59 (2H, s), 7.10-7.23 (4H, m), 7.35-7.40 (2H, m) , 8.42-8.47 (IH, m) .

Example 71

5- ( 2-cyanomethyl-4-pyridyl) -2-ethyl-4- ( 3- methylphenyl) -1,3-thiazole

A suspension of 5- (2-chloromethyl-4-pyridyl) -2- ethyl-4-( 3-methylphenyl) -1,3-thiazole (0.40 g, 1.2 mmol), potassium cyanide (0.095 g, 1.5 mmol), 18-crown-6 (0.14 g, 0.51 mmol) in acetonitrile ( 5 mL) was heated under reflux for 6 hours. After cooling, an aqueous potassium carbonate solution was added, and extracted with ethyl acetate. The extracts were washed with brine, then, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate= 2:1). The resulting crystal was washed with hexane- isopropyl ether to obtain a title compound (0.19 g, 48%) . m.p. 68 - 69°C

Example 72

4- [ 4- ( 3-methylphenyl) -2- ( 4- methylsulfonylphenyl) -1 , 3-thiazol-5-yl] -2- pyridylmethanol

To a solution of 4- [4- (3-methylphenyl) -2- ( 4- methylsulfonylphenyl) -1 , 3-thiazol-5-yl]pyridine N- oxide (0.43 g, 1.0 mmol) in methylene chloride (10 mL) was added trimethyloxonium tetrafluoroborate (0.17 g, 1.2 mmol), and the mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and methanol (15 mL) was added to the residue. To the mixture was added a solution of ammonium persulfate (0.05 g, 0.22 mmol) in water (lmL) under reflux, and the mixture was heated to reflux for 30 minutes. A solution of ammonium persulfate (0.03 g, 0.11 mmol) in water (1 mL) was added to the reaction mixture, and the mixture was further heated to reflux for 13 hours. The reaction mixture was cooled to room temperature, then, concentrated under reduced pressure. To the residue was added an aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulfate, and filtrated and concentrated under reduced pressure. The residued was purified by column chromatography (filler: Chromatorex NH DM1020 (trade name, manufactured by Fuji Silysia Chemical Ltd. ) , ethyl acetate) to obtain a title compound (0.26 g, yield 61%)'. m.p. 172 - 173°C

Example 73

2 - ( 4 -methylsulfonylphenyl ) - 4 - ( 3-methylphenyl ) - 5- [2- ( 1-pyrrolidinylmethyl) -4-pyridyl] -1 , 3-thiazole dihydrochloride

To a solution of 4- [4- (3-methylphenyl) -2- (4- methylsulfonylphenyl) -1 , 3-thiazol-5-yl] -2- pyridylmethanol (0.43 g, 1.0 mmol) in tetrahydrofuran (20 mL) was added thionyl chloride (0.08 mL, 1.0 mmol), and the mixture was stirred for 20 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was added to a suspension of pyrrolidine (0.09 mL, 1.1 mmol) and potassium carbonate (0.36 g, 2.6 mmol) in N,N-dimethylformamide (10 mL), and the mixture was stirred for 27 hours at room temperature. To the mixture was added an aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulfate, and filtrated and concentrated under reduced pressure. The residue was purified by column chromatography (filler: Chromatorex NH DM1020 (trade name, manufactured by Fuji Silysia Chemical Ltd. ) , hexane-ethyl acetate=l:2) . The resulted oil was dissolved in methanol (10 mL), and to this was added a 10% hydrogen chloride-methanol solution (5 mL), and the mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure , and the resulting solid was washed with ethanol, to obtain a title compound (yield 17%).

Amorphous

^XH-NMR (CDC1₃) δ : 1.90-2.10 (4H, m) , 2.33 (3H, s), 3.31 (3H, s), 4.10-4.40 (4H, m) , 4.53 (2H, s), 7.28 (3H, s), 7.43-7.47 (2H, m) , 7.67 (IH, s), 8.12 (2H, d, J=8.0 Hz), 8.30 (2H, d, J=8.0 Hz), 8.68 (IH, d, J=5.2 Hz). Example 74

2-ethyl-4- ( 3-methylphenyl) -5- [ 2- ( 1- pyrrolidinylmethyl) -4-pyridyl] -1,3-thiazole dihydrochloride

To a solution of 5- (2-chloromethyl-4-pyridyl) - 2-ethyl-4-( 3-methylphenyl) -1,3-thiazole (0.20 g, 0.61 mmol) in pyrrolidine (0.5 mL) was stirred for 1 hour at 80°C. After cooling, to this was added an aqueous potassium carbonate solution, and extracted with ethyl acetate. The extracts were washed with brine, then, dried and concentrated. The residue was purified by alumina column chromatography (hexane-ethyl acetate=2 : 1) . The resulting oil was made into a hydrochloride by using a solution of 4N-hydrogen chloride in ethyl acetate, and recrystallized from ethanol- isopropyl ether, to obtain a title compound (0.23 g, 85%). m.p. 146 - 151°C

Example 75

To a solution of 2-bromo-l- ( 3-bromophenyl) -2- [ 2- (tert-butoxycarbonylamino) -4-pyridyl] ethanone hydrobromide (22 g, 51 mmol) in N,N, -dimethylformamide (100 mL) was added thiopropionamide (4.3 g, 49 mmol) , and the mixture was stirred for 2 hours at room temperature. Into the reaction mixture was poured an aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extracts were washed with water, then, dried and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=4 : 1) , then, recrystallized from hexane-ethyl acetate to obtain 4- (3-bromophenyl) -5- [2- (tert- butoxycarbonylamino) -4-pyridyl] -2-ethyl-l , 3-thiazole (6.0 g, yield 27%) and 5- ( 2-amino-4-pyridyl) -4- ( 3- bromophenyl) -2-ethyl-l, 3-thiazole (1.4 g, yield 8%). Example compound 75-1: 4- ( 3-bromophenyl) -5- [ 2- (tert- butoxycarbonylamino) -4-pyridyl] -2-ethyl-l , 3-thiazole m.p. 172 - 174°C Example compound 75-2:

4- [ 4- ( 3-bromophenyl) -2-ethyl-1,3-thiazol-5-yl] - 2-pyridylamine m.p. 132 - 134°C

Example 76

4- [4- (3-cyanophenyl) -2-ethyl-l, 3-thiazol-5-yl] - 2-pyridylamine

To a solution of 4- (3-bromophenyl) -5- [2- (tert- butoxycarbonylamino) -4-pyridyl] -2-ethyl-l , 3-thiazole (0.5 g, 1.1 mmol) in N,N-dimethylformanide (10 mL) was added copper cyanide (0.25 g, 1.6 mmol) , and the mixture was stirred for 20 hours at 150°C under argon atmosphere. Into the reaction mixture was poured ammonia water, and the deposit was removed, then, extracted with ethyl acetate. The extracts were washed with water, then, dried and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=4:l) to obtain a crystal. This crystal was washed with hexane-ethyl acetate to obtain a title compound (0.19 g, yield 57%). m.p. 178 - 179°C

Example 77

3- [5- (2-amino-4-pyridyl) -2-ethyl-l, 3-thiazol-4- yl]benzoic acid

To a solution of 5- (2-amino-4-pyridyl) -4- (3- cyanophenyl) -2-ethyl-l, 3-thiazole (0,50 g, 1.6 mmol) in acetic acid (5 mL) was added 50% sulfuric acid (2.0 mL), and the mixture was stirred for 6 hours at 110°C. The reaction mixture was basified with aqueous sodium hydroxide solution and washed with ethylacetate. The aqueous phase was neutralized with hydrochloric acid, and the deposited crystal was washed with water and ethyl ether to obtain a title compound (0.45 g, yield 84%). m.p. 273 - 274°C

Example 78

Methyl 3- [ 5- (2-amino-4-pyridyl) -2-ethyl-l , 3- thiazol-4-yl]benzoate

To a solution of 3- [5- ( 2-amino-4-pyridyl) -4- (3- cyanophenyl) -2-ethyl-l , 3-thiazol-4-yl]benzoic acid (0.3 g, 1.0 mmol) in methanol (10 mL) was added concentrated sulfuric acid (0.1 mL) and the mixture was stirred for 5 hours at 70°C. The reaction mixture was basified with sodium hydroxide solution and extracted with ethyl acetate . The extracts were washed with water, then, dried and concentrated. The residue was washed with hexane-ethyl acetate to obtain a title compound (0.29 g, yield 85%) . m.p. 173 - 174°C

Example 79

To a solution of 4- (3-bromophenyl) -5- [2- (tert- butoxycarbonylamino) -4-pyridyl] -2-ethyl-l , 3-thiazole (1.0 g, 2.2 mmol) in tetrahydrofuran (20 mL) was added dropwise a 1.5 M n-butyllithium hexane solution (2.9 mL, 4.3 mmol), and the mixture was stirred for 15 minutes. The reaction mixture was poured onto dry ice, and extracted with ethyl acetate-tetrahydrofuran. The extracts were washed with an aqueous sodium hydroxide solution, then, dried and concentrated. The residue was recrystallized from hexane-ethyl acetate to obtain 5- [2- (tert-butoxyσarboylamino) -4-pyridyl] -2-ethyl-4- phenyl-1 , 3-thiazole (0.29 g, yield 35%). The aqueous layer was made acidic with hydrochloric acid, then, extracted with ethyl acetate-tetrahydrofuran. The extracts were washed with water, then, dried and concentrated. The residue was washed with ethyl acetate to obtain [5- [2- (tert-butoxycarboylamino) -4-pyridyl] -

2-ethyl-l , 3-thiazol-4-yl]benzoiσ acid (0.21 g, yield

23%).

Example compound 79-1:

5- [ 2- ( tert-butoxycarbonylamino) -4-pyridyl ] -2- ethyl-4-phenyl-1 , 3-thiazole m.p. 154 - 155°C Example compound 79-2:

3- [ 5 - [ 2- ( tert-butoxycarbonylamino) -4 -pyridyl] - 2-ethyl-l , 3-thiazol-4-yl]benzoic acid

'H-NMR (CDC1₃) δ : 1.37 (3H, t, J=7.5Hz), 1.45 (9H, s) , 3.08 (2H, q, J=7.5 Hz) , 6.83 (IH, dd, J=1.4, 5.0 Hz ) , 7,34-7.37 (2H, m) , 7.42-7.49 (2H, m) , 7.86 (IH, s), 8.16 (IH, d, J=5.0 Hz), 9.91 (IH, s).

Example 80

4- [ 2- ( 1-tert-butoxycarbonylpiperidin-4-yl)-4-(3- chlorophenyl) -1,3-thiazol-5-yl] -2-pyridylamine

A solution of 2- (2-amino-4-pyridyl)-2-bromo-l- (3-chlorophenyl)ethanone hydrobromide (2.74 g, 8.36 mmol) and l-tert-butoxycarbonylpiperidine-4-carbothioamide in N,N-dimethylformamide (50 mL) was stirred at room temperature for 3 hours . Aqueous sodium hydrogen carbonate was added to the reaction mixture and extracted with ethyl acetate. The extracts were washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) and then purified by column chromatography (filler: Chromatorex NH DM1020 (trade name, manufactured by Fuji Silysia Chemical Ltd. ), ethyl acetate) . The obtained crude crystalline was recrystallized from ethyl acetate-hexane to give a title compound (1.94 g, yield 50%). m.p. 143-145 ΩC Example 81

N- [ 4- [ 2- ( 1-tert-butoxycarbonylpiperidin-4-yl) -4- ( 3-chlorophenyl) -1 , 3-thiazol-5-yl] -2-pyridyl ] acetamide

To a solution of [4- [2- (1-tert- butoxycarbonylpiperidin-4-yl) -4- (3-chlorophenyl) -1,3- thiazol-5-yl] -2-pyridylamine (1.60 g, 3.40 mmol) in tetrahydrofuran (20 mL) were added acetyl chloride (0.25 mL, 3.52 mmol) and triethylamine (0.50 mL, 3.58 mmol) at O C sequentially, and the resulting mixture was stirred at room temperature for 3 hours . Aqueous sodium hydrogen carbonate was added to the reaction mixture and extracted with ethyl acetate. The extracts were washed with brine, dried, and concentrated. The residue was purified by column chromatography (filler: Chromatorex NH DM1020 (trade name, manufactured by Fuji Silysia Chemical Ltd. ) , hexane - ethyl acetate = 1 : 1) to give a title compound (1.79 g, yield 98%) . amorphous solid

d: 1.49 (9H, s), 1.68-1.88 (2H, m) , 2.13-2.21 (5H, m) , 2.91 (2H, br t, J= 12.0 Hz), 3.12-3.25 (IH, m). 4.20-4.27 (2H, m) , 6.87 (IH, dd, J= 1.8, 5.4Hz), 7.18-7.35 (3H, m) , 7.56 (IH, t, J= 1.8 Hz), 8.15 (IH, d, J= 5.4 Hz), 8.27-8.33 (2H, m) .

Example 82

The following reference example compounds 82-1 to 82-12 were synthesized according to Example 81, using 4- ( 2-ethyl-4-phenyl-1,3-thiazol-5-yl) -2-pyridylamine , 4- [ 2-ethyl-4- ( 4-fluorophenyl) -1 , 3-thiazol-5-yl] -2- pyridylamine , 4- [ 2-ethyl-4- ( 3-trifluoromethylphenyl) - 1,3-thiazol-5-yl] -2-pyridylamine, 4- [2-ethyl-4- (4- fluoro-3-methylphenyl) -1 , 3-thiazol-5-yl] -2-pyridylamine, 4- [ 2-et yl-4- ( 3-fluorophenyl) -1 , 3-thiazol-5-yl] -2- pyridylamine , 4- [ 2-ethyl-4- ( 4-chlorophenyl) -1 , 3- thiazol-5-yl] -2-pyridylamine, 4- [2-ethyl-4- (3- ethylphenyl) -1, 3-thiazol-5-yl] -2-pyridylamine, 4- [2- ethyl-4-[3-(l-methylethyl)phenyl]-l,3-thiazol-5-yl]-2- pyridylamine, 4- [2-ethyl-4- (3-propylphenyl) -1,3- thiazol-5-yl] -2-pyridylamine, 4- [2-methyl-4- (3- methylphenyl) -1, 3-thiazol-5-yl] -2-pyridylamine, 4- [4- (3-methylphenyl) -l,3-thiazol-5-yl] -2-pyridylamine and 4- [ 4- ( 3-methylphenyl) -2- [ 4- (methylthio)phenyl] -1 , 3- thiazol-5-yl] -2-pyridylamine, respectively, instead of 4- [ 2- ( 1-tert-butoxycarbonylpiperidin-4-yl) -4- ( 3- chlorophenyl) -1,3-thiazol-5-yl] -2-pyridylamine. Example compound 82-1:

N-[4-(2-ethyl-4-phenyl-l,3-thiazol-5-yl)-2- pyridyl]acetamide m.p. 175-176 ΩC Example compound 82-2:

N- [ 4- [ 2-ethyl-4- ( 4-fluorophenyl) -1 , 3-thiazol-5- yl] -2-pyridyl]acetamide m.p. 190-191 ΩC Example compound 82-3:

N- [ 4- [ 2-ethyl-4- ( 3-trifluoromethylphenyl) -1 , 3- thiazol-5-yl] -2-pyridyl]acetamide m.p. 146-147 ΩC Example compound 82-4:

N- [ 4- [ 2-ethyl-4- ( 4-fluoro-3-methylphenyl) -1 , 3- thiazol-5-yl] -2-pyridyl] acetamide m.p. 142-143 ΩC Example compound 82-5:

N- [4- [2-ethyl-4-( 3-fluorophenyl) -1,3-thiazol-5- yl] -2-pyridyl]acetamide m.p. 141-142 ΩC Example compound 82-6:

N-[ 4- [4- (4-chlorophenyl) -2-ethyl-l, 3-thiazol-5- yl] -2-pyridyl]acetamide m.p. 190-191 ΩC Example compound 82-7:

N-[4-[2-ethyl-4-(3-ethylphenyl)-l,3-thiazol-5- yl] -2-pyridyl] acetamide m.p. 112-113 ΩC Example compound 82-8:

N-[4-[2-ethyl-4-[3-(l-methylethyl)phenyl]-l,3- thiazol-5-yl] -2-pyridyl] acetamide m.p. 116-117 C Example compound 82-9:

N- [ 4- [ 2-ethyl-4- ( 3-propylphenyl) -1 , 3-thiazol-5- yl] -2-pyridyl] acetamide m.p. 121-122 C Example compound 82-10:

N- [ 4- [ 2-methyl-4- ( 3-methylphenyl) -1 , 3-thiazol-5- yl] -2-pyridyl] acetamide m.p. 162-163 ΩC Example compound 82-11:

N- [4- [4- (3-methylphenyl)-1,3-thiazol-5-yl] -2- pyridyl] acetamide m.p. 149-150 C Example compound 82-12:

N- [4- [4- (3-methylphenyl) -2- [4- (methylthio)phenyl] -1 , 3-thiazol-5-yl] -2- pyridyl]acetamide m.p. 181-182 ΩC Example 83

The following example compound 83 was synthesized according to Example 81, using propionyl chloride instead of acetyl chloride. Example compound 83:

N- [ 4- [ 2- ( l-tert-butoxycarbonylpiperidin-4-yl) -4- ( 3-chlorophenyl) -1 , 3-thiazol-5-yl] -2- pyridyl]propionamide amorphous solid

'H-NMR CDCI d: 1.25 (3H, t, J= 7.5 Hz ) , 1.49 (9H, s), 1.66-1.89 (2H, m) , 2.08-2.22 (2H, m) , 2.44 (2H, q, J= 7.5 Hz), 2.82-3.00 (2H, m) , 3.11-3.24 (IH, m) . 4.18-4.30 (2H, m), 6.84 (IH, dd, J= 1.8, 5.0 Hz), 7.19-7.36. (3H, m) , 7.56 (IH, t, J= 3.2 Hz), 8.13 (IH, d, J= 5.0 Hz), 8.18 (IH, br s), 8.33 (IH, s) . Example 84

The following reference example compounds 84-1 to 84-9 were synthesized according to Example 83, using 4- ( 2-ethyl-4-phenyl-1,3-thiazol-5-yl) -2-pyridylamine, 4- [ 2-ethyl-4- ( 4-fluorophenyl) -1 , 3-thiazol-5-yl] -2- pyridylamine , 4- [ 2-ethyl-4- ( 3-trifluoromethylphenyl) - l,3-thiazol-5-yl] -2-pyridylamine, 4- [2-ethyl-4-(4- fluoro-3-methylphenyl) -1 , 3-thiazol-5-yl] -2-pyridylamine, 4- [2-ethyl-4-(3-fluorophenyl) -l,3-thiazol-5-yl] -2- pyridylamine , 4- [ 2-ethyl-4- ( 4-chlorophenyl) -1 , 3- thiazol-5-yl] -2-pyridylamine, 4- [2-ethyl-4- [ 3- timethylethyl)phenyl] -1 , 3-thiazol-5-yl] -2-pyridylamine, 4-[2-ethyl-4-(3-propylphenyl)-l,3-thiazol-5-yl]-2- pyridylamine and 4- [4- (3-methylphenyl) -2- [4- (methylthio )phenyl] -1 , 3-thiazol-5-yl] -2-pyridylamine, respectively, instead of 4- [2-(l-tert- butoxycarbonylpiperidin-4-yl) -4- (3-chlorophenyl) -1,3- thiazol-5-yl] -2-pyridylamine. Example compound 84-1:

N-[4-(2-ethyl-4-phenyl-l,3-thiazol-5-yl)-2- pyridyl ]propionamide m.p. 139-140 ΩC Example compound 84-2:

N-[ 4- [2-ethyl-4-( 4-fluorophenyl) -1 , 3-thiazol-5- yl ] -2-pyridyl ]propionamide m.p. 156-157 C Example compound 84-3:

N- [ 4- [ 2-ethyl-4-( 3-trifluoromethylphenyl) -1,3- thiazol-5-yl] -2-pyridyl]propionamide m.p. 126-127 ΩC Example compound 84-4:

N- [ 4- [ 2-ethyl-4- ( 4-fluoro-3-methylphenyl) -1 , 3- thiazol-5-yl] -2-pyridyl]propionamide m.p. 105-107 ec Example compound 84-5:

N- [4- [2-ethyl-4-(3-fluorophenyl) -1, 3-thiazol-5- yl] -2-pyridyl]propionamide m.p. 121-122 C Example compound 84-6:

N- [4- [4- (4-chlorophenyl) -2-ethyl-l, 3-thiazol-5- yl] -2-pyridyl]propionamide m.p. 152-153 ΩC Example compound 84-7:

N- [ 4- [ 2-ethyl-4- [3- ( 1-methylethyl)phenyl] -1 , 3- thiazol-5-yl] -2-pyridyl]propionamide m.p. 93-94 ΩC Example compound 84-8:

N- [ 4- [ 2-ethyl-4- ( 3-propylphenyl) -1 , 3-thiazol-5- yl] -2-pyridyl]propionamide m.p. 124-125 C Example compound 84-9:

N-[4- [4- (3-methylphenyl) -2- [4- (methylthio)phenyl] -1 , 3-thiazol-5-yl] -2- pyridyl]propionamide m.p. 171-172 C

Example 85

The following example compound 85 was synthesized according to Example 28, using butyryl chloride instead of cyclohexanecarbonyl chloride . Example compound 85:

N- [ 4- [ 2-ethyl-4- ( 3-methylphenyl) -1 , 3-thiazol-5- yl] -2-pyridyl]butyramide m.p. 88-89 ΩC Example 86

The following example compound 86 was synthesized according to Example 85, using 4- [4- ( 3-chlorophenyl) -2- ethyl-l,3-thiazol-5-yl] -2-pyridylamine instead of 4-[2- ethyl-4-(3-methylphenyl)-l,3-thiazol-5-yl]-2- pyridylamine . Example compound 86:

N- [4- [4- (3-chlorophenyl) -2-ethyl-l, 3-thiazol-5- yl] -2-pyridyl]butyramide m.p. 119-120 ΩC

Example 87

The following example compounds 87-1 and 87-2 were synthesized according to Example 85 , using valeryl chloride and hexanoyl chloride, respectively, instead of butyryl chloride . Example compound 87-1:

N- [ 4- [ 2-ethyl-4- ( 3-methylphenyl) -1 , 3-thiazol-5- yl] -2-pyridyl]valer mide m.p. 81-82 ΩC Example compound 87-2:

N- [ 4- [ 2-ethyl-4- ( 3-methylphenyl) -1 , 3-thiazol-5- yl] -2-pyridyl]hexanamide m.p. 84-85 ΩC

Example 88

The following example compounds 88-1 and 88-2 were synthesized according to Example 86 , using valeryl chloride and hexanoyl chloride, respectively, instead of butyryl chloride . Example compound 88-1:

N-[4-[4-(3-chlorophenyl) -2-ethyl-1,3-thiazol-5- yl] -2-pyridyl]valeramide m.p. 109-110 C Example compound 88-2: N- [4- [4- (3-chlorophenyl) -2-ethyl-l, 3-thiazol-5- yl] -2-pyridyl]hexanamide m.p. 114-115 C

Example 89

The following example compound 89 was synthesized according to Example 28, using butyryl chloride instead of cyclopentylacetyl chloride. Example compound 89:

N-[4-[2-ethyl-4-(3-methylphenyl)-l,3-thiazol-5- yl] -2-pyridyl]cyclopentylacetamide m.p. 85-86 C

Example 90

The following example compounds 90-1 and 90-2 were synthesized according to Example 89, using 4- [4- (3- chlorophenyl) -2-ethyl-1,3-thiazol-5-yl] -2-pyridylamine and 4- [4- (4-chlorophenyl) -2-ethyl-1,3-thiazol-5-yl] -2- pyridylamine, respectively, instead of 4- [2-ethyl-4- (3- methylphenyl) -1 , 3-thiazol-5-yl] -2-pyridylamine . Example compound 90-1:

N-[4-[4-(3-chlorophenyl) -2-ethyl-1,3-thiazol-5- yl] -2-pyridyl]cyclopentylacetamide m.p. 121-122 ΩC Example compound 90-2:

N- [4- [4- (4-chlorophenyl) -2-ethyl-l , 3-thiazol-5- yl] -2-pyridyl]cyclopentylacetamide m.p. 149-150 ΩC

Example 91

N- [4- [4- (3-chlorophenyl) -2- (4-piperxdyl) -1 , 3- thiazol-5-yl] -2-pyridyl] acetamide dihydrochloride

To a solution of N- [4- [2- (1-tert- butoxycarbonylpiperidin-4-yl) -4- (3-chlorophenyl) -1,3- thiazol-5-yl] -2-pyridylacetamide (1.44 g, 2.81 mmol) in methanol (10 mL) was added 2N-hydrochloric acid (4 mL) and stirred at 80ΩC for an hour. The solvent was removed under reduced pressure and the residue was recrystallized from methanol to give a title compound (0.87 g, yield 64%). m.p. 193-195 ΩC

Example 92

The following example compound 92 was synthesized according to Example 91, using N- [4- [2-(l-tert- butoxycarbonylpiperidin-4-yl) -4- ( 3-chlorophenyl) -1 , 3- thiazol-5-yl] -2-pyridylpropionamide instead of N-[4-[2- ( 1-tert-butoxycarbonylpiperidin-4-yl) -4- ( 3- chlorophenyl) -1 , 3-thiazol-5-yl] -2-pyridylacetamide . Example compound 92:

N- [ 4- [ 4- (3-chlorophenyl) -2- (4-piperidyl) -1,3- thiazol-5-yl] -2-pyridyl]propionamide dihydrochloride m.p. 202-203 ΩC

Example 93

N- [ 4- [ 2- ( l-acetylpiperidin-4-yl) -4- ( 3- σhlorophenyl) -1 , 3-thiazol-5-yl] -2-pyridyl]acetamide

To a suspension of N- [4- [4- ( 3-chlorophenyl) -2- ( 4-piperidyl) -1 , 3-thiazol-5-yl] -2-pyridyl]acetamide dihydrochloride (0.41 g, 0.84 mmol) in tetrahydrofuran (20 mL) were added acetyl chloride (0.13 mL, 1.8 mmol) and triethylamine (0.50 mL, 3.6 mmol) sequentially, and the resulting mixture was stirred at room temperature for 30 minutes . Aqueous sodium hydrogen carbonate was added to the reaction mixture and extracted with ethyl acetate. The extracts were washed with water, dried, and concentrated. The residue was recrystallized from ethyl acetate-hexane to give a title compound (0.24 g, yield 62%). m.p. 143-145 ΩC

Example 94 The following example compound 94 was synthesized according to Example 93, using N-[4-[4-(3- chlorophenyl) -2- ( 4-piperidyl) -1 , 3-thiazol-5-yl] -2- pyridyl]propionamide dihydrochloride instead of N-[4- [ 4- ( 3-chlorophenyl) -2- ( 4-piperidyl) -1 , 3-thiazol-5-yl] - 2-pyridyl]acetamide dihydrochloride . Example compound 94:

N- [4- [ 2- ( l-acetylpiperidin-4-yl) -4- (3- chlorophenyl) -1 , 3-thiazol-5-yl] -2-pyridyl]propionamide m.p. 174-175 ΩC Example 95

The following example compound 95 was synthesized according to Example 11, using 2-bromo-l- (3- ethylphenyl) -2- (2-fluoro-4-pyridyl)ethanone hydrobromide instead of 2-bromo-2- (2-fluoro-4-pyridyl) - 1- ( 3-methylphenyl)ethanone hydrobromide. Example compound 95:

2-ethyl-4- ( 3-ethylphenyl) -5- ( 2-fluoro-4-pyridyl) - 1,3-thiazole

Oil Η-NMR CDCl d: 1.18 (3H, t, J= 7.6 Hz ) , 1.46 (3H, t, J= 7.6 Hz), 2.62 (2H, q, J= 7.6 Hz), 3.10 (2H, q, J= 7.6 Hz), 6.86 (IH, t, J= 1.4 Hz), 7.07 (IH, dt, J = 1.4, 5.2 Hz), 7.16-7.30 (3H, m) , 7.33 (IH, s), 8.10 (IH, d, J= 5.2 Hz) . Example 96

N-cyclopentyl-4- [2-ethyl-4- ( 3-ethylphenyl) -1 , 3- thiazol-5-yl] -2-pyridyl]amine

2-ethyl-4- ( 3-ethylphenyl) -5- ( 2-fluoro-4- pyridyl) -1,3-thiazole (0.51 g, 1.6 mmol) and cyclopentylamine (1.6 mL, 16 mmol) were stirred at 140ΩC for 12 hours. Aqueous sodium hydrogen carbonate was added to the reaction mixture and extracted with ethyl acetate. The extracts were washed with aqueous sodium hydrogen • carbonate and brine, in order, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate = 4 : 1). The obtained crude crystalline was recrystallized from isopropyl ether to give a title compound (0.40 g, yield 66%). m.p. 77-79 ΩC Example 97

The following example compound 97 was synthesized according to Example 96, using cyclohexylamine instead of cyclopentylamine . Example compound 97:

N-cyσlohexyl-4-[2-ethyl-4-(3-ethylphenyl)-l,3-_ thiazol-5-yl] -2-pyridyl] amine m.p. 115-116 C

Example 98

The following example compounds 98-1 and 98-2 were synthesized according to Example 57, using N-[4-[4-(3- methylphenyl) -2- [ 4- (methylthio )phenyl] -1 , 3-thiazol-5- yl]-2-pyridyl] acetamide and N- [4- [4- (3-methylphenyl) -2- [ 4- (methylthio)phenyl] -1 , 3-thiazol-5-yl] -2- pyridyl ]propionamide , respectively, instead of 4- (3- methylphenyl) -5- ( 2-methyl-4-pyridyl) -2- [ 4- (methylthio)phenyl] -1 , 3-thiazole . Example compound 98-1:

N- [4- [4- (3-methylphenyl) -2- ( 4- methylsulfonylphenyl) -1 , 3-thiazol-5-yl] -2- pyridyl] acetamide m.p. 222-223 ΩC Example compound 98-2:

N- [4- [4- (3-methylphenyl) -2- (4- methylsulfonylphenyl) -1 , 3-thiazol-5-yl] -2- pyridyl ]propionamide m.p. 238-239 C

Example 99 The following example compounds 99-1 and 99-2 were synthesized according to Example 17, using 3- (methylthio) thiopropionamide and 2-amino-1-methyl-2- thioxoethyl benzoate instead of 2-chlorothiobenzamide. Example compound 99-1:

4- [ 4- ( 3-methylphenyl) -2- [ 2- (methylthio)ethyl] - l,3-thiazol-5-yl] -2-pyridylamine m.p. 98-99 C Example compound 99-2:

1- [ 5- ( 2-amino-4-pyridyl) -4- ( 3-methylphenyl) -1 , 3- thiazol-2-yl]ethyl benzoate m.p. 89-91 ΩC

Example 100

The following example compounds 100-1 and 100-2 were synthesized according to Example 99, using 2-(2-amino- 4-pyridyl) -2-bromo-1- ( 3-chlorophenyl)ethanone hydrobromide instead of 2- (2-amino-4-pyridyl) -2-bromo- 1- (3-methylphenyl)ethanone hydrobromide. Example compound 100-1:

4- [ 4- ( 3-chlorophenyl) -2- [2- (methylthio)ethyl] - 1 ,3-thiazol-5-yl] -2-pyridylamine m.p. 96-97 ΩC Example compound 100-2:

1- [5- ( 2-amino-4-pyridyl) -4-(3-chlorophenyl) -1,3- thiazol-2-yl]ethyl benzoate

Amorphous -NMR CDCl d: 1.89 (3H, d, J= 6.4Hz), 4.50 (2H, br s), 6.38-6.47 (2H, m) , 6.56 (IH, dd, J= 1.4, 5.6 Hz), 7.23-7.38 (3H, m) , 7.45-7.53 (2H, m) , 7.58-7.66 (2H, m) , 8.01 (IH, d, J= 5.6Hz), 8.11-8.16 (2H, m) .

Example 101

The following example compounds 101-1 and 101-2 were synthesized according to Example 100, using (methylthio)thioacetamide and 2,2- difluorothiopropionamide instead of 3- (methylthio)thiopropionamide . Example compound 101-1:

4- [4- ( 3-chlorophenyl) -2- (methylthio)methyl-1,3- thiazol-5-yl] -2-pyridylamine m.p. 111-112 ΩC Example compound 101-2:

4- [ 4- ( 3-chlorophenyl) -2- ( 1 , 1-difluoroethyl) -1 , 3- thiazol-5-yl] -2-pyridylamine m.p. 131-132 ΩC

Example 102

The following example compounds 102-1 to 102-6 were synthesized according to Example 83, using, 4- [4- (3- methylphenyl) -2- [2- (methylthio)ethyl] -l,3-thiazol-5- yl] -2-pyridylamine, 4- [4- (3-chlorophenyl) -2- [2- (methylthio)ethyl] -1 , 3-thiazol-5-yl] -2-pyridylamine, 4- [4- (3-chlorophenyl) -2- (methylthioJmethyl-1 , 3-thiazol-5- yl] -2-pyridylamine, 4- [4- (3-chlorophenyl) -2- (1,1- difluoroethyl) -1,3-thiazol-5-yl] -2-pyridylamine, 1- [5- (2-amino-4-pyridyl) -4- ( 3-methylphenyl) -1 , 3-thiazol-2- yl] ethyl benzoate and 1- [5- (2-amino-4-pyridyl) -4- (3- chlorophenyl) -1, 3-thiazol-2-yl]ethyl benzoate respectively, instead of 4- [2- ( 1-tert- butoxycarbonylpiperidin-4-yl) -4- ( 3-chlorophenyl) -1 , 3- thiazol-5-yl] -2-pyridylamine. Example compound 102-1:

N-[ 4- [4- (3-methylphenyl) -2- [2- (methylthio)ethyl] - 1, 3-thiazol-5-yl] -2-pyridyl]propionamide m.p. 85-86 ΩC Example compound 102-2:

N- [4- [4- ( 3-chlorophenyl) -2- [2- (methylthio)ethyl] - 1,3-thiazol-5-yl] -2-pyridyl]propionamide m.p. 91-92 ΩC Example compound 102-3:

N- [ 4- [ 4- (3-chlorophenyl) -2- (methylthio)methyl- 1,3-thiazol-5-yl] -2-pyridyl]propionamide m.p. 118-119 ΩC Example compound 102-4:

N- [ 4- [ 4- ( 3-chlorophenyl) -2- ( 1 , 1-difluoroethyl) - 1,3-thiazol-5-yl] -2-pyridyl]propionamide m.p. 141-142 C Example compound 102-5:

1- [4- (3-methylphenyl) -5- (2-propionylamino-4- pyridyl) -1 , 3-thiazol-2-yl] ethyl benzoate m.p. 102-103 C Example compound 102-6:

1- [4- (3-chlorophenyl) -5- ( 2-propionylamino-4- pyridyl) -l,3-thiazol-2-yl]ethyl benzoate m.p. 124-127 C

Example 103

The following example compounds 103-1 and 103-2 were synthesized according to Example 81, using l-[5-(2- amino-4-pyridyl) -4- ( 3-chlorophenyl) - 1 , 3-thiazol-2- yl] ethyl benzoate and ethyl [5- (2-amino-4-pyridyl) -4- (3-chlorophenyl)-l,3-thiazol-2-yl]acetate instead of [4-[2-(l-tert-butoxycarbonylpiperidin-4-yl) -4- ( 3- chlorophenyl) -l,3-thiazol-5-yl] -2-pyridylamine. Example compound 103-1:

1- [ 5- (2-acetylamino-4-pyridyl) -4- (3- chlorophenyl) -1, 3-thiazol-2-yl] ethyl benzoate m.p. 152-154 ΩC Example compound 103-2: ethyl [5-(2-acetylamino-4-pyridyl) -4- (3- chlorophenyl) -1 , 3-thiazol-2-yl ] acetate m.p. 99-100 ΩC

Example 104 N- [ 4- [ 2- ( 1-hydroxyethyl) -4- ( 3-methylphenyl) -1 , 3- thiazol-5-yl] -2-pyridyl]propionamide

An IN aqueous sodium hydroxide solution was added dropwise to a solution of 1- [4- (3-methylphenyl) -5- (2- propionylamino-4-pyridyl) -1 , 3-thiazol-2-yl]ethyl benzoate (1.63 g, 3.46 mmol) in methanol (5 mL) and tetrahydrofuran (20 mL) at OΩC and the reaction mixture was allowed to warm up to room temperature. The resulting mixture was stirred at room temperature for 30 minutes and the solvent was removed under reduced pressure. The residue was treated with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extracts were washed with aqueous sodium hydrogen carbonate solution and brine. The resulting solution was dried, and concentrated under reduced pressure. The obtained crude crystal was recrystallized from ethyl acetate-hexane to give a title compound (1.12 g, yield 89%). m.p. 115-116ΩC

Example 105

The following example compound 105 was synthesized according to Example 104, using 1- [4- (3-chlorophenyl) - 5- (2-propionylamino-4-pyridyl) -1 , 3-thiazol-2-yl]ethyl benzoate instead of 1- [4- (3-methylphenyl) -5- (2- propionylamino-4-pyridyl) -1 , 3-thiazol-2-yl]ethyl benzoate. Example compound 105:

N- [ 4- [ 4- ( 3-chlorophenyl) -2- ( 1-hydroxyethyl) -1 , 3- thiazol-5-yl] -2-pyridyl]propionamide m.p. 131-132 C

Example 106

N- [4- [ 2-acetyl-4- ( 3-methylphenyl) -1 , 3-thiazol-5- yl] -2-pyridyl]propionamide

A solution of dimethylsulfoxide (0.30 mL, 4.2 mmol) in dichloromethane (1.0 mL) was added to a solution of oxalyl chloride (0.11 mL, 1.26 mmol) at -78ΩC and the resulting mixture was stirred for 15 minutes. A solution of N-[4-[2-(l-hydroxyethyl) -4- ( 3-methylphenyl) -1 , 3- thiazol-5-yl] -2-pyridyl]propionamide (0.38 g, 1.0 mmol) in dichloromethane (1.5 mL) was added to the mixture and the resulting mixture was stirred for 45 minutes. The reaction mixture was allowed to warm up to -50ΩC and triethylamine (0.72 mL, 5.17 mmol) was added dropwise to the mixture. The resultxng mixture was stirred for 30 minutes and poured into aqueous sodium hydrogen carbonate . The mixture was extracted with ethyl acetate and the extracts were washedwith aqueous sodium hydrogen carbonate solution and brine. The resulting solution was dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=2:l) to obtain a crude crystal. The obtained crude crystal was recrystallized from isopropyl ether to give a title compound (0.22 g, yield 58%). m.p. 121-123ΩC

Example 107

The following example compound 107 was synthesized according to Example 106, using N-[4-[4-(3- chlorophenyl) -2- (1-hydroxyethyl) -1,3-thiazol-5-yl] -2- pyridyl]propionamide instead of N-[4-[2-(l- hydroxyethyl) -4- ( 3-methylphenyl) -1 , 3-thiazol-5-yl] -2- pyridyl]propionamide . Example compound 107:

N- [ 4- [ 2-acetyl-4- ( 3-chlorophenyl) -1 , 3-thiazol-5- yl] -2-pyridyl]propionamide m.p. 115-117 ec

Example 108

N-ethyl-N'-[4- [2-ethyl-4-( 3-methylphenyl) -1,3- thiazol-5-yl] -2-pyridyl]urea

To A solution of 4- [2-ethyl-4- ( 3-methylphenyl) - 1, 3-thiazol-5-yl] -2-pyridylamine (0.50 g, 1.7 mmol) in N,N-dimethylacetamide (10 mL) was added ethyl isocyanate (0.20 mL, 2.5 mmol) and the reaction mixture was stirred at 80ΩC for 20 hours. The reaction mixture was poured into aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extracts were washed with aqueous sodium hydrogen carbonate solution and brine. The resulting solution was dried, and concentrated under reduced pressure . The obtained crude crystal was recrystallized from ethyl acetate-hexane to give a title compound (0.29 g, yield 47%) . m.p. 160-162ΩC

Example 109

The following example compound 109 was synthesized according to Example 108, using 4- [4- (3-chlorophenyl) - 2-ethyl-l, 3-thiazol-5-yl] -2-pyridylamine instead of 4- [ 2-ethyl-4- ( 3-methylphenyl) -1 , 3-thiazol-5-yl] -2- pyridylamine . Example compound 109:

N-[4-[4-(3-chlorophenyl) -2-ethyl-1,3-thiazol-5- yl] -2-pyridyl]-N" -ethyl-urea m.p. 177-180 ΩC

Example 110

The following example compound 110 was synthesized according to Example 81, using 1- [5- (2-amino-4- pyridyl) -4- ( 3-methylphenyl) -1 , 3-thiazol-2-yl]ethyl benzoate instead of [4- [2- (1-tert- butoxycarbonylpiperidin-4-yl) -4- (3-chlorophenyl) -1,3- thiazol-5-yl] -2-pyridylamine. Example compound 110: 1- [5- (2-acetylamino-4-pyridyl) -4- (3- methylphenyl) -1,3-thiazol-2-yl]ethyl benzoate m.p. 110-113 ΩC Example 111

The following example compounds 111-1 and 111-2 were synthesized according to Example 104, using l-[5-(2- acetylamino-4-pyridyl) -4- ( 3-methylphenyl) -1 , 3-thiazol- 2-yl]ethyl benzoate and 1- [5- (2-acetylamino-4- pyridyl) -4- ( 3-chlorophenyl) -1 , 3-thiazol-2-yl]ethyl benzoate instead of 1- [4- (3-methylphenyl) -5- ( 2- propionylamino-4-pyridyl) -1 , 3-thiazol-2-yl]ethyl benzoate. Example compound 111-1:

N- [4- [2- ( 1-hydroxyethyl) -4- (3-methylphenyl) - 1,3-thiazol-5-yl] -2-pyridyl]acetamide m.p. 99-102 ΩC Example compound 111-2:

N- [4- [4- (3-chlorophenyl) -2- (1-hydroxyethyl) -1, 3- thiazol-5-yl] -2-pyridyl] acetamide m.p. 142-145 ec Example 112

The following example compound 112 was synthesized according to Example 106, using N-[4-[4-(3- chlorophenyl) -2- ( 1-hydroxyethyl) -1 , 3-thiazol-5-yl] -2- pyridyl]acetamide instead of N- [4- [2- (1-hydroxyethyl) - 4- (3-methylphenyl) -1 , 3-thiazol-5-yl] -2- pyridyl]propionamide. Example compound 112:

N- [4- [2-aσetyl-4-(3-chlorophenyl) -1,3-thiazol-5- yl] -2-pyridyl]acetamide m.p. 180-183 ΩC Example 113

The following example compounds 113-1 and 113-2 were synthesized according to Example 101, using 2-(2-amino- 4-pyridyl) -2-bromo-l- ( 3-methylphenyl)ethanone hydrobromide instead of 2- (2-amino-4-pyridyl) -2-bromo- 1- (3-chlorophenyl)ethanone hydrobromide Example compound 113-1:

4- [4- (3-methylphenyl) -2- (methylthio)methyl-1 , 3- thiazol-5-yl] -2-pyridylamine m.p. 113-114 ΩC

Example compound 113-2 :

4- [ 2- ( 1 , 1- dif luoroethyl ) -4- ( 3-methylphenyl) - 1 , 3- thiazol-5-yl] -2-pyridylamine m. p . 140- 141 ΩC

The compounds produced in Examples 1 to 113 are shown in Tables 1 to 20.

Table 1

Example

Compound Rb Rr. mp/°C

No.

NH₂

-NH, MeO 51-254 N -i y- 2

Me₃COCONh

-NH, MeO

N -o- > 270 (dec)

Me₃COCONH Me

-CH₂Me <ό- 162-163

_ Me

-NH, ■o- o- 214-218

F\ MeO

7-1 -NH, - - 190-191

F\ Cl

7-2 -NH, ^■o- \^~V- 227-228

7-3 -NH, b- - - 243-245

^Mev_ Me

7-4 -NH, .Q- 205-206 y^~

Me

7-8 -NH,

N^>- ^F-χ=/^~ 233-234

Table 2

s.

M X-\

Example

Compound Rb mp/°C

No.

Me

11 -CH₂Me - oil

Table 3

Rb S

X x- R_*

Example

Compound Rb _c mp/°C

No.

14-12 -C0₂CH₂Me 97-98

Me Mε

14-13 e 115-116

^•^ NM

N.

Table 4

Example

Compound Ra Rb Re mp/°C

No.

H₂ Me

18-2 -(CH₂)₃Me

H₂N Me o- oil

18-3 -CH₂CF₃ to-

H₂N Me - 131-132

18-4 -(CH₂)₂Me

H₂N Me o- 113-115

18-5 -CH₂C0₂CH₂Me - 128-129

H₂N

20-2 -CH₂Me 0^~ 158-159

20-3 -CH₂Me ^H2V ? X- 140-141

H₂N

20-4 -CH₂Me tQx- 117-118

H₂N

20-5 -CH₂Me 19-120

N^ - ^{Mes- >—} 1

H₂

20-6 -CH₂Me b- 153-154

H₂

20-7 -CH₂Me α-Q- 136-137

Table 5

Example

Compound Rb mp/°C

No.

21-2 -CH₂C0₂CH₂Me 154-155

H,N Me

24 -CH₂C0₂H 132-133

H,N Me o-

25-1 -C0₂H 156-157

M e

25-2 -C0₂H - 135-136

Table 6

Example

Compound Rb mp/°C

No.

H₂N Cl,

27-2 -Me 142-143

MeCONH Me

29-2 -CH₂Me - 119-120

MeCH₂CONH, M

29-4 -CH₂Me 103-104 N

Me₃CCONH Me

29-5 -CH₂Me oil MeCONH C ol -

30-1 -Me 112-115

MeCONH Cl,

30-3 -(CH^Me 144-145 MeCONH

30-4 -CH₂Me

N (X- 154-155

Table 7

Rb

X i-H.

Example

Compound Rb mp / °C

No.

MeCH,CONH Cl

30-7 -Me 134-135

N \ b~

MeCH₂CONH Cl

30-8 -CH₂Me κ^~ - 132-133

MeCH₂CONH Cl

30-9 -(CH₂)₂Me 03-104 N

MeCH₂CONH

30-10 -CH₂Me 187-188 N 0-

Table 8

Example

Compound R_ R_b R_C mp/°C

No.

36-1 -NH₂ °1>- <o- 194-195

Me

36-4 -CH₂Me °? - 110-112

Me

36-8 — MS0₂Me M 200-202

CM Table 9

Example

Compound . ' R_b R_c mp/°C

No.

37-2 11733--11;74

37-5 153-154

MeCONH

38 -NHCOMe ^~V_ ,___ _^M _ 262-264

N y — MeO-^ ' —

39 -NHCOMe 230-231

40-1 -NHCOMe

Table 10

40-2 -NHCOMe 185-187

40-3 -NHCOMe 266-267

Table 11

Rb -_V-Sb

Example - Compound Rb mp/°C No.

42-9 -NMeCO-Λx > NH

42-10 -NMeC

46-3 -NHCO 252-253

Table 12

^RbY^Sv_ Af^~R»

Example

Compound Ra Rb Re mp/°C

No.

NH₂

50 -NHCOMe N2>- MeOXζl — 247-250

52 -NHCONH- > 173-174

53-1 - HCONH- >

-.198-199

Me Me

53-4 -NHCONH- > -169 N^ CM 168 Table 13

Example

Compound Rb R_c mp/°C

No.

58-4 λ /-S0₂Me 195-199

58-6 216-217

58-7 224-225

Table 14

^Rb>-S Re ^N

Example

Compound Ra Rb Re ^• additives mp/°C No. _

Me₃CCONH

58-8 — i -SOsM XX 122-123

59 — -SQ₂Me °-θ- 255-256

Me> Me

61 -NHCONH(CH2)₂CI 149-151

Me . Me -

62 -NHC0₂(CH₂)₂CI €x CM 156-158

. Me Me

63 -NHCONHOMe - 194-195

O Me Me

65 -N O \ / - CM 80-82

0 Me e

66 X

-N NH \ / • - \ ~ 200-201

cι. e

69 -CH₂Me

^N^^~ CM oil Table 15

Example

Compound Rb additives mp/°C

No.

le

72 λ /r-S0₂Me ' r- 172-173

73 ~S0₂Me 2HCI amorphous

74 -CH₂Me 2HCI 146-151

H₂N NC

76 -CH₂Me - - O" 178-179

H₂N H0₂C

77 -CH₂Me ^ - - Cx 273-274

Me₃COCONH

79-1 -CH₂Me CM f ~ 154-155

Me₃COCONH ■ Ho₂ς

79-2 -CH₂Me / \\ amorphous Table 16

Example

Compound R_a Rb Re mp/°C

No

H₂N Cl

80 —^NCOOCMe₃ 143-145

K 7^~ MeCONH ^C'\

81 — < NCOOCMe₃ T - amorphous

Q-

MeCONH

82-2 -CH₂Me ^~ 190-191

Me - - ^F~x₌ CONH F₃C

82-3 -CH₂Me 146-147

MeCONH M bes -

82-4 -CH₂Me

N^~ <M 142-143

MeCONH

82-6 -CH₂Me c^ 190-191

MeCONH MeCH₂

82-7 -CH₂Me 3

MeCONH Me₂ ^ 112-11 CH

82-8 -CH₂Me CM 116-117

MeCONH Me(CH₂)₂

82-9 -CH₂Me CM 121-122

MeCONH Me

82-10 -Me

MeCONH Me^ 162-163

82-11 -H ^ Q- 149-150

MeCONH M

82-12 — ^~SMe *0^~ 181-182 — Table 17

Rb

X R,

Example

Compound Rb mp/°C

No.

MeCH₂CONF Cl,

83 amorphous NCOOCMe₃ . N" ^

MeCH₂CONH

84-5 -CH₂Me 121-122 N

MeCH₂CONhl b-

84-6 -CH₂Me N Λ ci- '/ \ 152-153

MeCH₂CONH Me₂CH

84-7 -CH₂Me 93-94 N

MeCH₂CONH Me(CH₂)₂

84-8 -CH₂Me 25 N > C 124-1

Me(CH₂)₂CONH Cl,

86 -CH₂Me 119-120 N

Me(CH₂)₃CONH Me

87-1 -CH₂Me K Or 81-82 Table 18

^Rb S

R ^N^^Ra

Example

Compound Rb additives mp/°C

No.

Me(CH₂)₃CONH Cl

88-1 -CH₂Me // \ 109-110

Me(CH₂)₄CONhl Cl.

88-2 -CH₂Me N %— < ^ 114-115

MeCONH Cl.

91 -o NH MΛ_ ^2HCI 193-195

93 NCOMe 160-161

94 NCOMe 174-175

Table 19 b :

X, 'Xn»

Example- Compound Rb mp / °C No.

MeCONH Me.

98-1 — c /MS0₂Me 222-223 N

H₂N ^ev_

99-1 -CH₂CH₂SMe 98-99 N

100-2 amorphous

MeCH₂CONH Me;

102-1 -CH₂CH₂SMe A Or 85-86

MeCH₂CONH Cl,

102-2 -CH₂CH₂SMe

N Or 91-92

MeCH₂CONH Cl.

102-3 -CH₂SMe 1 18-119 N

Table 20

Example

Compound Ra Rb o mp/°C

No.

MeCOHN Cl

103-1 -CH(Me)OCO-<Q> =}- fi^~ — 152-154

MeCOH

103-2 -CH₂C0₂CH₂Me 99-100

105 -CH(OH)Me 131-132

MeCH₂COHN Cl

107 -COMe fi~ — 115-117

MeCH₂NHCOHN Cl

109 -CH₂Me ^- fi~ — 160-162

MeCOHN Me

110 -CH(Me)OCC >- N^- CM 110-113

MeCOHN Me

111-1 -CH(OH)Me 99-102 ^-

MeCOH

111-2 -CH(OH)Me 142-145

Preparation Example 1

(1) Example compound 29-2 10.0 mg

(2) Lactose 60.0 mg

(3) Corn starch 35.0 mg

(4) Gelatin 3.0 mg

(5) Magnesium stearate 2.0 mg

10.0 mg of Example compound 29-2, 60.0 mg of lactose and 35.0 mg of Corn starch are granulated through a 1mm mesh sieve using 0.03 ml of a 10% gelatin aqueous solution (3.0 g in terms of gelatin) , then, dried at 40°C and sieved again. Thus obtained granules are mixed with 2.0 mg of magnesium stearate and compressed. The resulted core tablets are coated with sugar coating made from a water suspension of sucrose, titanium dioxide, talc and Arabic gum. The coated tables are endowed with gloss by bees wax to give coated tablets.

Preparation Example 2

(1) Example compound 29-2 10.0 mg

(2) Lactose 70.0 mg

(3) Corn starch 50.0 mg

(4) Soluble starch 7.0 mg

(5) Magnesium stearate 3.0 mg

10.0 mg of Example compound 29-2 and 3.0 mg of magnesium stearate are granulated with 0.07 ml of an aqueous solution of soluble starch (7.0 mg in terms of soluble starch), then, dried, and mixed with 70.0 mg of lactose and 50.0 mg of corn starch. The mixture is compressed to obtain tablets.

Preparation Example 3

(1) Example compound 29-2 5.0 mg

(2) Sodium Chloride 20.0 mg

(3) Distilled water amount to give total amount of 2 ml 5.0 mg of Example compound 29-2 and 20.0 mg of sodium chloride are dissolved in distilled water, and to this was added water to give a total amount of 2.0 ml. The solution is filtrated, and a 2 ml ampule is filled with the filtrate under sterile condition. The ampule is disinfected, then, sealed to give an injection solution.

Reference preparation example 1

(1) Lofecoxiv 5.0 mg

(2) Sodium chloride 20.0 mg

(3) Distilled water amount to give a total amount of 2 ml

5.0 mg of lofecoxiv and 20.0 mg of sodium chloride are dissolved in distilled water, and to this is added water to give a total amount of 2.0 ml. The solution is filtrated, and a 2 ml ampule is filled with the filtrate under sterile condition. The ampule is disinfected, then, sealed to give an injection solution.

Reference preparation example 2

(1) Lofecoxiv 50 mg

(2) Lactose 34 mg

(3) Corn starch 10.6 mg

(4) Corn starch (paste) 5 mg

(5) Magnesium stearate 0.4 mg

(6) Calcium carboxymethylcellulose 20 mg Total 120 mg

The above-described components (1) to (6) are mixed according to a normal method, and tabletted by a tabletting machine to obtain tablets.

< Preparation Example 4

Any of preparations of Preparation Examples 1 to

3 and any of preparations of Reference Preparation

Examples 1 and 2 are combined. Experiment 1

Genetic manipulation methods described below are based on methods described in Maniatis et al. , Molecular Cloning, ColdSpring Harbor Laboratory, 1989, and the appended reagent protocol.

(1) Cloning of human p38 MAP kinase gene and preparation of recombinant Baculovirus

Cloning of human p38 MAP kinase gene was conducted by a PCR method using primer set p38-U: 5'- ACCACTCGAGATGGACTACAAGGACGACGATGACAAGTCTCAGGAGAGGCCCA CGTTeTACC-3" [SEQ ID No. 1] and PAG-L: 5'- ACCCGGTACCACCAGGTGCTCAGGACTCCATCTCT-3' [SEQ ID No . 2] synthesized referring to the nucleotide sequence of p38 MAP kinase gene of Han et al. , Science 265 (5173) , 808-811 (1994), utilizing kidney cDNA (QUICK-Clone cDNA, manufactured by Toyobo Co., Ltd.) as a template.

A PCR reaction was performed according to Hot Start method using AmpliWax PCR Gem 100 (Takara Shuzo Co . , Ltd.). For preparing lower layer mixed liquid, 2 μL of lOxLA PCR Buffer, 3 μL of 2.5 mM dNTP solution, each 2.5 μL of 12.5 μM primer solution, and 10 μL of sterile distilled water were mixed. For preparing upper layer mixed liquid, 1 μL of human heart cDNA (1 ng/mL) as a template, 3 μL of lOxLA PCR Buffer, 1 μL of 2.5 M dNTP solution, 0.5 μL of TaKaRa LA Taq DNA polymerase (Takara Shuzo Co. , Ltd. ) and 24.5 μL of sterile distilled water were mixed. To the prepared lower mixed liquid was added one AmpliWax PCR Gem 100 (Takara Shuzo Co . , Ltd.), treated for 5 minutes at 70°C and 5 minutes in ice, then, the upper mixed liquid was added, to prepare a reaction solution for PCR. A tube filled with the reaction solution was set on Thermal Cycler (Perkin Elmer) , then, treated for 2 minutes at 95°C. Further, a cycle including 15 seconds at 95°C and 2 minutes at 68°C was repeated 35 times, then, treated for 8 minutes at 72°C. The resulted PCR product was subjected to agarose gel (1%) electrophoresis, a 1.1 kb DNA fragment containing a p38 MAP kinase gene was recovered from the gel, then, pT7Blue-T vector (Takara Shuzo Co. , Ltd. ) was inserted to prepare a plasmid pHP38.

4.8 kb Xhol-Kpnl fragment of plasmid pFASTBACl (CIBCOBRL) and 1.1 kb Xhol-Kpn fragment of the above- mentioned plasmid pHP38 were ligated to construct plasmid PFBHP38.

Plasmid pFBHP38 and BAC-TO-BAC Baculovirus Expression System (GIBCOBRL) were used to prepare virus stock BAC-HP38 of recombinant baculovirus.

(2) Cloning of human MKK3 gene and preparation of recombinant baculovirus

Cloning of human MKK3 gene was conducted by a PCR method using primer set MKK-U: 5'-

ACAAGAATTCATAACATATGGCTCATCATCATCATCATCATTCCAAGCCACCC GCACCCAA-3' [SEQ ID No. 3] and MKK-L: 5'- TCCCGTCTAGACTATGAGTCTTCTCCCAGGAT-3* [SEQ ID No . 4] synthesized referring to the nucleotide sequence of MKK3 gene of Derijard, B. et al.. Science 267 (5198), 682- 685 (1995), utilizing kidney cDNA (QUICK-Clone cDNA, manufactured by Toyobo Co., Ltd.) as a template.

A PCR reaction was performed according to Hot Start method using AmpliWax PCR Gem 100 (Takara Shuzo Co. , Ltd.). For preparing lower layer mixed liquid, 2 μL of lOxLA PCR Buffer, 3 μL of 2.5 mM dNTP solution, each 2.5 μL of 12.5 μM primer solution, and 10 μL of sterile distilled water were mixed. For preparing upper layer mixed liquid, 1 μL of human kidney cDNA (1 ng/mL) as a template, 3 μL of lOxLA PCR Buffer, 1 μL of 2.5 mM dNTP solution, 0.5 μL of TaKaRa LA Taq DNA polymerase (Takara Shuzo Co. , Ltd. ) and 24.5 μL of sterile distilled water were mixed. To the prepared lower mixed liquid was added one AmpliWax PCR Gem 100 (Takara Shuzo Co. , Ltd. ) , treated for 5 minutes at 70°C and 5 minutes in ice, then, the upper mixed liquid was added, to prepare a reaction solution for PCR. A tube filled with the reaction solution was set on Thermal Cycler ( Perkin Elmer) , then, treated for 2 minutes at 95°C . Further, a cycle including 15 seconds at 95°C and 2 minutes at 68°C was repeated 35 times, then, treated for 8 minutes at 72°C. The resulted PCR product was subjected to agarose gel (1%) electrophoresis, a 1.0 kb DNA fragment containing a MKK3 gene was recovered from the gel, then, pT7Blue-T vector (Takara Shuzo Co., Ltd.) was inserted to prepare a plasmid pHMKK3.

For converting MKK3 into constitutively active type (Ser at 189 is converted into Glu, and. Thr at 193 is converted into Glu), mutation was introduced by QuikChange Site-Directed Mutagenesis Kit (Stratagene) using primer set SER-U: 5 ' -

GGCTACTTGGTGGACGAGGTGGCCAAGGAGATGGATGCCGGCTGC-3 ' [ SEQ ID No. 5] and SER-L: 5'-

GCAGCCGGCATCCATCTCCTTGGCCACCTCGTCCACCAAGTAGCC-3 ' [ SEQ ID No. 6], to obtain pcaMKK3.

4.8 kb EcoRI-Xbal fragment of plasmid pFASTBACl (CIBCOBRL) and 1.0 kb EcoRI-Xbal fragment of the above-mentioned plasmid pcaMKK3 were ligated to construct plasmid pFBcaMKK3.

Plasmid pFBcaMKK3 and BAC-TO-BAC Baculovirus Expression System (GIBCOBRL) were used to prepare virus stock BAC-caMKK3 of recombinant baculovirus.

(3) Preparation of active type p38 MAP kinase

Sf-21 cells were inoculated on 100 mL Sf-900II SF medium (GIBCOBRL) to give lxl0⁶cells/mL, then, cultured for 24 hours at 27°C. Each 0.2 mL of virus stocks BAC-HP38 and BAC-caMKK3 of the recombinant baculovirus were added, then, cultured for further 48 hours. Cells were separated from the culture solution by centrifugal separation (3000 rpm, 10 min.), then, washed with PBS twice. The cells were suspended in 10 mL of Lysis buffer (25mM HEPES (pH7.5), 1% TritonX, 130mM NaCl, ImM EDTA, ImM DTT, 25mM β-glycerophosphate, 20mM leupeptin, ImM APMSF, ImM Sodium orthovanadate) , then, treatment by Homogenizer (POLYTRON) for 2 minutes at 20000 rpm was performed twice to lyse the cells. Active type p38 MAP kinase was purified from the supernatant obtained by centrifugal separation (40000 rpm, 45 minutes) , by using Anti-FLAG M2 Affinity Gel (Eastman Chemical).

(4) To 37.5 μL of a reaction solution (25mM HEPES (pH 7.5), 10 mM Magnesium Acetate) containing 260 ng of active type p38 MAP kinase and 1 μg of Myelin Basic Protein was added 2.5 μL of a sample compound dissolved in DMSO, then, the mixture was kept at 30°C for 5 minutes. The reaction was initiated by adding 10 μL of an ATP solution (2.5 μMATP, 0.1 μCi[T-³²P] ATP). After reaction for 60 minutes at 30°C, the reaction was terminated by adding 50 μL of a 20% TCA solution. The reaction solution was left for 20 minutes at 0°C, then, acid insoluble fraction was transferred to GF/C filter (Packard Japan) using Cell Harvester (Packard Japan) , and washed with 250 mM H₃P0₄. After drying for 60 minutes at 45°C, 40 μL of Microscint 0 (Packard Japan) was added, and radiation activity was measured by Top Counter (Packard Japan) . The concentration (IC₅₀ value) of a sample compound necessary for inhibiting 50% of incorporation into the acid insoluble fraction of ³²P was calculated by PRISM 2.01 (GraphPad Software).

The results are shown below. Table 21

Experiment 2

Measurement of inhibitory activity of TNF-α production

THP-1 cells cultured in a PRMI 1640 medium (Life Technologies, Inc., USA) containing 1% inactivated fetal bovine serum (Life Technologies, Inc. ) and lOmM HEPES (pH 7.5) were inoculated on a 96 well plate to give 1x10^s cells/well, then, 1 μL of a sample compound dissolved in DMSO was added. After incubation for 1 hour at 37°C in a C0₂ incubator, LPS (Wako Pure Chemical Industries Ltd. ) was added to give a final concentration of 5 μg/mL. After incubation for 4 hours at 37°C in a C0₂ incubator, the supernatant was obtained by centrifugal separation. The TNF-α concentration in the supernatant was measured by ELISA (R&D Systems, Quantikine Kit). The concentration (IC_S0 value) of a sample compound necessary for inhibiting 50% of TNF-α production was calculated by PRISM 2.01 (GraphPad Software) .

The results are shown below. Table 22

From the above-described results, it is known that compounds of the present invention have excellent inhibitory activity of ,p38 MAP kinase and TNF-α production.

INDUSTRIAL APPLICABILITY The compound (la), (lb) or (Ic) of the present invention or a salt thereof or a pro-drug thereof has an excellent p38 MAP kinase inhibitory activity, TNF-α inhibitory activity and the like, and can be used as a pharmaceutical composition for preventing or treating cytokine-mediated diseases such as p38 MAP kinase- mediated diseases, TNF-α-mediated diseases and the like, and as a pharmaceutical composition for preventing or treating adenosine receptor-mediated diseases.

Claims

1. A 1,3-thiazole compound of which 5-position is substituted with a 4-pyridyl group having a substituent including no aromatic group, provided that the 1,3- thiazole compound is not N- [4- (3, 5-dimethylphenyl) -5- (2-hydroxy-4-pyridyl)-i,3-thiazol-2-yl]acetamide or 4-

[2- (acetylamino) -4- (3, 5-dimethylphenyl) -1 , 3-thiazol-5- yl] -2-pyridyl acetate, or a salt thereof.

2. A compound as claimed in Claim 1 which is a compound represented by the formula:

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 of which 5-position is substituted with a pyridyl group having a substituent including no aromatic group, at a position adjacent to a nitrogen atom of the pyridyl group, provided that the 1,3-thiazole compound is not N- [4- ( 3,5- dimethylphenyl) -5- (2-hydroxy-4-pyridyl) -l,3-thiazol-2- yl]acetamide or 4- [2- (acetylamino) -4- (3, 5- dimethylphenyl) -l,3-thiazol-5-yl] -2-pyridyl acetate, or a salt thereof.

4. A compound of Claim 3 which is a compound he formula:

wherein R^la 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, at a position adjacent to a nitrogen atom of the pyridyl group, and R^3a represents an aromatic group optionally having a substituent, or a salt thereof.

5. A 1,3-thiazole compound of which 5-position is substituted with a 4-pyridyl group having a substituent including no aromatic group, at a position adjacent to a nitrogen atom of the 4-pyridyl group, provided that the 1,3-thiazole compound is not N- [4- ( 3,5- dimethylphenyl) -5- (2-hydroxy-4-pyridyl) -1,3-thiazol-2- yl]acetamide or 4- [2- (acetylamino) -4- (3, 5- dimethylphenyl) -1,3-thiazol-5-yl]-2-pyridyl acetate, or a salt thereof.

6. A compound as claimed in any one of Claims 1 to 5 wherein the substituent including no aromatic group is a halogen atom, C_x_₃ alkylenedioxy, nitro, cyano, C₁.₆ alkyl which may be halogenated, C₂_₆ alkenyl which may be halogenated, carboxy C₂_₆ alkenyl, C₂.₆ alkynyl which may be halogenated, C₃.₈ cycloalkyl which may be halogenated, C₃.₈ cycloalkyl-Ci.g alkyl, C_x_₈ alkoxy which may be halogenated, C_x_₆ alkoxy-carbonyl -C_x_₆ alkoxy, hydroxy, mercapto, C_x_₆ alkylthio which may be halogenated, amino, mono-Ci.g alkylamino, di-C_x.₆ alkylamino, di-C₆.₁₄ arylamino, ₃-₈ cycloalkylamino, C₃_₈ cycloalkyl -C_x_₆ alkylamino, N-C₃.₈ cycloalkyl-N-Cj_L.g alkylamino, formyl, carboxy, carboxy-C₂_₆ alkenyl, carboxy-C-_L.g alkyl, C_x_₆ alkyl- carbonyl which may be halogenated, C₃_₃ cycloalkyl- carbonyl optionally substituted by C_x_₆ alkyl, C_x_₆ alkoxy-carbonyl, carbamoyl, thiocarbamoyl , raono-C ₆ alkyl-carbamoyl, di-C^_g alkyl-carbamoyl, C_x_₆ alkylsulfonyl, C_x_₆ alkylsulfinyl, formylamino, C_x_₆ alkyl-carbonylamino, C₃.₈ cycloalkyl-carbonylamino which maybe substituted by Ci.g alkyl, C_x_₆ alkoxy-carbonylamino, Ci.g alkylsulfonylamino, C_ι_₆ alkyl-carbonyloxy, Ci_₆ alkoxy-carbonyloxy, mono-Ci_₆ alkyl-carbamoyloxy, di-Ci_₆ alkyl-carbamoyloxy, 5- to 7-membered aliphatic heterocyclic 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 atom in addition to one nitrogen atom and carbon atoms (this aliphatic heterocyclic group optionally has a substituent selected from Ci.g alkyl, C_ι_₆ alkyl-carbonyl and oxo), sulfo, sulfamoyl, sulfinamoyl, sulfenamoyl or a group obtained by connecting 2 to 3 of these substituents.

7. A compound as claimed in Claim 2 or 4 wherein (1) the hydrocarbon group optionally having a substituent is a Ci_₆ alkyl group, a C₂.₆ alkenyl group, a C₂_₆ alkynyl group, a C₃.₈ cycloalkyl group, a C₆.₁₄ aryl group or a C₇.₁₆ aralkyl group, optionally having a substituent selected from Group A of substituents consisting of oxo, a halogen atom, C^ alkylenedioxy, nitro, cyano, C_x_₆ alkyl which may be halogenated, C₂.₆ alkenyl which may be halogenated, carboxy C₂.₆ alkenyl, C₂_g alkynyl which may be halogenated, C₃.₈ cycloalkyl which may be halogenated, C₃.₈ cycloalkyl-C_x.g alkyl, C₆.₁₄ aryl, C_x__s alkoxy which' may be halogenated,

alkoxy- carbonyl-Ci.g alkoxy, hydroxy, C₆_₁₄ aryloxy, C₇.₁₆ aralkyloxy, mercapto, C_x_₆ alkylthio which may be halogenated, C₆.₁₄ arylthio, C₇.₁₆ aralkylthio, amino, mono-C-_L.g alkylamino, mono-C₆.₁₄ arylamino,

alkylamino, di-C₆.₁₄ arylamino, C₃.₈ cycloalkylamino, di-C₆.₁₄ arylamino, C₃.₈ cycloalkyl-Ci.g alkylamino, N-C₃. ₈ cycloalkyl-N-Ci.g alkylamino, formyl, carboxy, C^g alkyl-carbonyl which may be halogenated, C₃.₈ cycloalkyl-carbonyl optionally substituted by

alkyl. C_x_₆ alkoxy-carbonyl, C₆.₁₄ aryl-carbonyl, C₇.₁₆ aralkyl- carbonyl, C₆.₁₄ aryloxy-carbonyl, C₇.₁₆ 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,

alkyl-carbamoyl,

alkyl-carbamoyl, mono-C₆.₁₄ aryl-carbamoyl, di-C₆_₁₄ 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, C_x_₆ alkylsulfonyl, C₆.₁₄ arylsulfonyl, C_x_₆ alkylsulfinyl, C₆.₁₄ arylsulfinyl, formylamino,

alkyl-carbonylamino, C₃.₈ cycloalkyl-carbonylamino optionally substituted by

alkyl, C₆.₁₄ aryl- carbonylamino,

alkoxy-carbonylamino,

alkylsulfonylamino, C₆_₁₄ arylsulfonylamino, C_x_₆ alkyl- carbonyloxy, C₆.₁₄ aryl-carbonyloxy, C-^g alkoxy- carbonyloxy,

alkyl-carbamoyloxy,

alkyl-carbamoyloxy, mono-C₆_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 an oxygen atom in addition to carbon atoms (this heterocyclic group optionally has a substituent selected from C_x_₆ alkyl, C₆.₁₄ aryl,

alkyl-carbonyl which may be halogenated, 5- to 10- 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 and oxo), sulfo, sulfamoyl, sulfina oyl, sulfenamoyl and a group formed by connecting 2 to 3 of these substituents,

(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=0)-R^5a, -(C=0)-OR^5a, -(C=0)-NR^5aR^6a, - ( C=S) -NHR^5a, - (C=0)-N(OR^5a)R^6a, -(C=S)-NHOR^5a or -S0₂-R^7a (wherein R^5a represents ® a hydrogen atom, d⁾ a C_x.g alkyl group, a C₂.₆ alkenyl group, a C₂.₆ alkynyl group, a C₃.₈ cycloalkyl group, a C₆.₁₄ aryl group or a C₇_₁₆ aralkyl group, optionally having a substituent selected from Group A of substituents, or (3) 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, R^6a represents a hydrogen atom or a C _₆ alkyl group, and R^7a represents ® a <Z_X_₆ alkyl group, a C₂.₆ alkenyl group, a C₂.₆ alkynyl group, ^a C₃.₈ cycloalkyl group, a C₆_₁₄ aryl group or a C₇.₁₆ 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 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

(i) an amino group optionally having 1 or 2 substituents selected from the group consisting of ® a _x_₆ alkyl group, a C₂.₆ alkenyl group, a C₂.₆ alkynyl group, a C₃.₈ cycloalkyl group, a C₆.₁₄ aryl group and a C₇.₁₆ aralkyl group, optionally having a substituent selected from Group A of 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, ® an acyl group of the formula: -(C=0)-R⁵ , -(C=0)-OR^5a, -(C=0)-NR^5aR^6a, -(C=S)-NHR^5a , -(C=0)- N(OR^5a)R^6a, -(C=S)-NH0R^5a or -S0₂-R^7a (wherein each symbol is as defined above), and ©a C_x_₆ alkylidene group optionally having a substituent selected frpm Group A of substituents, or

(ii) a 5- to 7-membered aliphatic 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 atom in addition to one nitrogen atom and carbon atoms, which optionally has a substituent selected from the group consisting of C__₆ alkyl, C₆.₁₄ aryl, C^g alkyl-carbonyl which may be halogenated, C_x_₆ alkoxy- carbonyl, 5- to 10-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, and oxo,

(5) the substituent containing no aromatic group is a halogen atom, Ci_₃ alkylenedioxy, nitro, cyano, Ci_₆ alkyl which may be halogenated, C₂.₆ alkenyl which may be halogenated, carboxy C₂_₆ alkenyl, C₂.₆ alkynyl which may be halogenated, C₃.₈ cycloalkyl which may be halogenated, C₃-₈ cycloalkyl-Ci.g alkyl, C_ι_₈ alkoxy which may be halogenated, C-^g alkoxy-carbonyl-Ci.g alkoxy, hydroxy, mercapto, Ci.g alkylthio which may be halogenated, amino, mono-Ci.g alkylamino, di-C_ι_₆ alkylamino, C₃.₈ cycloalkylamino, C₃.₈ cycloalkyl-C_ι_₆ alkylamino, N-C₃.₈ cycloalkyl-N-Ci.g alkylamino, formyl, carboxy, carboxy-C₂_g alkenyl, σarboxy-Ci_₆ alkyl, Ci_₆ alkyl- σarbonyl which may be halogenated, C₃.₈ cycloalkyl- carbonyl optionally substituted by Ci_₆ alkyl, Ci_₆ alkoxy-carbonyl, carbamoyl, thiocarbamoyl,

alkyl-carbamoyl, di-C_ι_₆ alkyl-carbamoyl, Ci.g alkylsulfonyl, C_₆ alkylsulfinyl, formylamino, Ci_₆ alkyl-carbonylamino, C₃.₈ cycloalkyl-carbonylamino which may be substituted by Ci_₆ alkyl, Ci_₆ alkoxy-carbonylamino , Ci.g alkylsulfonylamino, Ci_₆ alkyl-carbonyloxy, Ci_₆ alkoxy-carbonyloxy, mono-Ci.₆ alkylcarbamoyloxy, i-Ci_ ₆ alkyl-carbamoyloxy, 5- to 7-membered aliphatic heterocyclic 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 atom in addition to carbon atoms (this aliphatic heterocyclic group optionally has a substituent selected from Ci_₆ alkyl, C_ι_₆ alkyl-carbonyl and oxo), sulfo, sulfamoyl, sulfinamoyl, sulfenamoyl or a group obtained by connecting 2 to 3 of these substituents,

(6) the aromatic group optionally having a substituent is ® 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 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 claimed in Claim 2 or 4 wherein R¹ represents (i) a hydrogen atom, (ii) a Ci.g alkyl group optionally substituted by a substituent selected from the group consisting of a halogen atom, C^₆ alkoxy-carbonyl, carboxy, cyano, Ci_₆ alkylthio, C _₆ alkylsulfinyl, Ci_₆ alkylsulfonyl, hydroxy, Ci_₅ alkoxy and Ci_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(0)_n-R^lbb (wherein R^lbb represents a Ci.g alkyl group, and n represents an integer of 0 to 2), (iv) a C₇.₁₅ aralkyl group, (v) an amino group optionally having one or two substituents selected from ® Ci.g alkyl, ® C_x_₆ alkyl-carbonyl, (1)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 Ci_₆ alkoxy, ® C₆.₁₄ aryl-carbamoyl, (D C_x_₆ alkyl-carbamoyl which may be halogenated, © Ci.g alkoxy-carbonyl which may be halogenated, © Ci_₆ alkoxy-carbamoyl and (D C₆__ι4 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, Ci_₆ alkyl, C₆.₁₄ aryl or C_ι_₆ alkoxy-carbonyl, (vii) an acyl group represented by the formula: - (C=0) -R^5b (wherein R^5D represents a hydrogen atom, a C_ι_₆ alkyl group which may be halogenated or a C₆_₁₄ aryl group which may be halogenated) , or (viii) an acyl group represened by the formula: - (C=0) -0R^c (wherein R^5c represents a hydrogen atom or a Ci.g alkyl group) .

9. A compound as claimed in Claim 2 or 4 wherein the substituent having no aromatic group is

(1) a Ci.g alkyl group (this Ci_₆ alkyl may be substituted by a halogen atom, cyano, hydroxy, or 5- to 6-membered aliphatic heterocyclic group optionally containing hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms) ,

(2) a halogen atom,

® a Ci_₆ alkyl group (this Ci_₆ alkyl group may be substituted by a halogen atom, cyano, hydroxy, C₃.₈ cycloalkyl or 5- to 7-membered aliphatic heterocyclic group optionally having 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms), φ a C₃.₈ cycloalkyl group, a C__₆ alkyl-carbonyl group (this C_ι_₆ alkyl- carbonyl group may be substituted by a halogen atom, cyano , hydroxy, C₃.₈ cycloalkyl or 5- to 7-membered aliphatic heterocyclic group optionally having 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms),

® a Ci_₆ alkoxy-carbonyl group,

⁽5) a C₃.₈ cycloalkyl-carbonyl group optionally substituted by C_lr.₆ alkyl,

(6) a 5- to 6-membered aliphatic heterocyclic group optionally 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 Ci_₆ alkyl or C_x_₆ alkyl-carbonyl) ,

© a 5- to 6-membered aliphatic heterocyclic- carbonyl group optionally 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 Ci_₆ alkyl or C_x_₆ alkyl-carbonyl) ,

(4) a 5- to 7-membered aliphatic cyclic amino group optionally further containing hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms and one nitrogen atom (this aliphatic cyclic amino group may be substituted by C_x_ ₆ alkyl or Ci_₆ alkyl-carbonyl) ,

( 5 ) a hydroxy group , or

(6) a Ci.g alkyl-carbonyloxy group.

10. A compound as claimed in Claim 2 or 4 wherein R³ is φ a C₆__ι4 aryl group or © a 5- to 14-membered aromatic heterocyclic group preferably containing 1 to 4 of 1 or 2 kinds of hatero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, which optionally has substituents selected from the group consisting of Ci_₆ alkyl which may be halogenated, Ci.g alkoxy, a halogen atom, carboxyl, Ci_ ₆ alkoxy-carbonyl, cyano, Ci_₆ alkylthio and Ci_₆ alkylsulfonyl .

11. A compound as claimed in Claim 3 which is a compound of the formula:

wherein R^lb represents (i) a hydrogen atom, (ii) a C_x_.₆ alkyl group optionally substituted by a substituent selected from the group consisting of a halogen atom, Ci_₆ alkoxy-carbonyl, carboxy, cyano, Ci_₆ alkylthio, C__₆ alkylsulfinyl, Ci_₆ alkylsulfonyl, hydroxy, Ci_₆ alkoxy and Ci.g 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(0)_n- _R ^ib (_R ^it>b re r s nts a C_x_₆ alkyl group, and n represents an integer of 0 to 2), (iv) a C₇.₁₅ aralkyl group, (v) an amino group optionally having one or two substituents selected from ® Ci.g alkyl, (2) C^g alkyl-carbonyl, φ C_x_₆ alkyl-carbonyl, ® 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 Ci_₆ alkoxy, ® C₆.₁₄ aryl-carbamoyl, © Ci_₆ alkyl-carbamoyl which may be halogenated, © Ci_₆ alkoxy-carbonyl which may be halogenated, © Ci_₆ alkoxy-carbamoyl and ® C₆_₁₄ 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, Ci_₆ alkyl, Cg_₁₄ aryl, Ci_₆ alkyl-carbonyl or C__ ₆ alkoxy-carbonyl, (vii) an acyl group represented by the formula: - (C=0) -R^5b (wherein R^5b represents a hydrogen atom, a Ci_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) -OR^5c (wherein R^5c represents a hydrogen atom or C_x_.₆ alkyl group),

( 1 ) a Ci.g alkyl group ( this C_x_₆ alkyl group may be substituted by a halogen atom, cyano, hydroxy, or a 5- to 7-membered aliphatic heterocyclic group optionally containing hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms) ,

(2) a halogen atom,

® a Ci.g alkyl group (this Ci_₆ alkyl group may be substituted by a halogen atom, cyano, hydroxy, C₃.₈ cycloalkyl or a 5- to 7-membered aliphatic heterocyclic group optionally having 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms), φ a C₃.₈ cycloalkyl group, φ a Ci.g alkyl-carbonyl group (this Ci_₆ alkyl- carbonyl group may be substituted by a halogen atom, cyano , hydroxy, C₃.₈ cycloalkyl or a 5- to 7-membered aliphatic heterocyclic group optionally having 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms). (s) a Ci.g alkoxy-carbonyl group,

© a 5- to 7-membered aliphatic heterocyclic group optionally 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 Ci_₆ alkyl or Ci_₆ alkyl-carbonyl) ,

© a 5- to 7-membered aliphatic heterocyclic- carbonyl group optionally 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 C_ι_₆ alkyl or Ci_₆ alkyl-carbonyl) ,

(4) a 5- to 7-membered aliphatic cyclic amino group optionally further containing 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 C _ ₆ alkyl or Ci_₆ alkyl-carbonyl) ,

( 5 ) a hydroxy group, and

(6) a Ci_₆ alkyl-carbonyloxy group, and

R^3b represents ® a C₆.₁₄ aryl group or © a 5- to 14-membered aromatic heterocyclic group containing 1 to 4 of 1 or 2 kinds of hatero 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 Ci_₆ alkyl which may be halogenated, Ci_₆ alkoxy, a halogen atom, carboxyl, Ci_ ₆ alkoxy-carbonyl, cyano, C_x_₆ alkylthio and C_x_₆ alkylsulfonyl, or a salt thereof.

12. A compound as defined in [11] wherein the pyridyl group is a 4-pyridyl group.

13. A compound as defined in [11] wherein R^lb is a Ci.g alkyl group optionally having a substituent selected from the group consisting of a halogen atom, hydroxy, C_ι_₆ alkoxy, C_ι_₆ alkylthio, Ci_₆ alkylsulfinyl and C_ι_₆ alkylsulfonyl, R^2b is a 4-pyridyl group having a Ci_₆ alkyl-carbonyl-amino group or a C₃.₈ cycloalkylamino group at the position adjacent to a nitrogen atom of the 4- pyridyl group, R^3b is a C₆__ι4 aryl group which optionally has a substituent selected from the group consisting of Ci.g alkyl and a halogen atom.

14. A compound as defined in [11] wherein R^lb is a Ci_₃ alkyl group optionally having a substituent selected from the group consisting of a halogen atom, hydroxy, C_ι_₆ alkoxy, C_ι_₆ alkylthio, Ci_₆ alkylsulfinyl and Ci_₆ alkylsulfonyl, R^2b is a 4-pyridyl group having a Ci_₃ alkyl-carbonyl-amino group or a C₃.₈ cycloalkylamino group at the position adjacent to a nitrogen atom of the 4-pyridyl group, R^3b is a phenyl group which optionally has a substituent selected from the group consisting of methyl and a chlorine atom.

15. A compound as claimed in Claim 5 which is 5- [2-(tert-butoxycarbonylamino) -4-pyridyl] -2-ethyl-4- (3-methylphenyl) -1,3-thiazole,

[4- (3-methylphenyl) -5- (2-methyl-4-pyridyl) -1,3- thiazol-2-yl] amine ,

2-ethyl-5-(2-fluoro-4-pyridyl)-4-(3- methylphenyl) -1,3-thiazole,

5- (2-fluoro-4-pyridyl) -4- (3-methylphenyl) -2- [4- (methylthio )phenyl] -1 , 3-thiazole ,

4- ( 3-methylphenyl) -5- ( 2-methyl-4-pyridyl) -2- [ 4- (methylthio )phenylJ -1 , 3-thiazole ,

4- [2-ethyl-4-( 3-methylphenyl) -1 , 3-thiazol-5- yl ] -2-pyridylamine ,

N- [4- [2-ethyl-4-( 3-methylphenyl) -1,3-thiazol-5- yl] -2-pyridyl] acetamide,

N- [ 4- [ 2-ethyl-4- ( 3-methylphenyl) - 1 , 3-thiazol-5- yl] -2-pyridyl] ropionamide, N- [4- [4- (3-chlorophenyl) -2-methyl-1 , 3-thiazol- 5-yl] -2-pyridyl] acetamide,

N_ [4- [4- (3-chlorophenyl) -2-ethyl-1,3-thiazol-5- yl] -2-pyridyl] acetamide ,

N- [4- [4- (3-chlorophenyl) -2-propyl-1, 3-thiazol- 5-yl] -2-pyridyl]acetamide ,

N- [4- [4- (3-chlorophenyl) -2-methyl-1, 3-thiazol- 5-yl] -2-pyridyl]propionamide ,

N-[4-[4-(3-chlorophenyl) -2-ethyl-1,3-thiazol-5■ yl] -2-pyridyl]propionamide,

N- [ 4- [ 4- (3-chlorophenyl) -2-propyl-l , 3-thiazol- 5-yl] -2 -pyridyl]propionamide,

N-cyclohexyl-4- [2-ethyl-4- (3-methylphenyl) -1,3- thiazol-5-yl] -2-pyridylamine,

N-cyclohexyl-4- [4- (3-methylphenyl) -2- ( 4- methylsulfonylphenyl) -1 , 3-thiazol-5-yl] -2- pyridylamine ,

N-cyclopentyl-4- [ 2-ethyl-4- (3-methylphenyl) - 1 , 3-thiazol-5-yl] -2-pyridylamine,

N-cyclopentyl-4- [4- (3-methylphenyl) -2- (4- methylsulfonylphenyl) -1 , 3-thiazol-5-yl] -2- pyridylamine ,

4- [4- (3-chlorophenyl) -2-ethyl-l , 3-thiazol-5- yl] -N-cyclohexyl-2-pyridylamine,

4- [4- (3-chlorophenyl) -2-ethyl-l , 3-thiazol-5- yl] -N-cyclopentyl-2-pyridylamine,

N- [ 4- ( 3-methylphenyl) -5- ( 2-methyl-4-pyridyl) - 1 , 3-thiazol-2-yl]acetamide,

N- [4- (3, 5-dimethylphenyl) -5- ( 2-methyl-4- pyridyl) -1 , 3-thiazol-2-yl]nicotinamide,

6-chloro-N- [4- (3, 5-dimethylphenyl) -5- ( 2-methyl- 4-pyridyl) -1 , 3-thiazol-2-yl]nicotinamide ,

N-[ 4- (3,5-dimethylphenyl) -5- ( 2-methyl-4- pyridyl) -1 , 3-thiazol-2-yl] -6-methylnicotinamide,

N- [ 4- ( 3 , 5-dimethylphenyl) -5- ( 2-methyl-4- pyridyl) -1 , 3-thiazol-2-yl] -6-methoxynicotinamide,

4- (3-methylphenyl) -5- (2-methyl-4-pyridyl) -2- (4- methylsulfinylphenyl) -1 , 3-thiazole,

4- ( 3-methylphenyl) -5- ( 2-methyl-4-pyridyl) -2- ( 4- methylsulfonylphenyl) -1 , 3-thiazole ,

5- (2-fluoro-4-pyridyl) -4- (3-methylphenyl) -2- (4- methylsulfonylphenyl) -1 , 3-thiazole ,

N-[4-[4-(3-chlorophenyl) -2- ( 4- methylsulfonylphenyl) -1 , 3-thiazol-5-yl] -2- pyridyl]acetamide ,

N- [ 4- [ 4- ( 3-chlorophenyl) -2- ( 4- methylsulfonylphenyl) -1 , 3-thiazol-5-yl] -2- pyridyl] ropionamide ,

N-[4-[4-(3-chlorophenyl) -2- ( 4- methylsulfonylphenyl) -1 , 3-thiazol-5-yl] -2- pyridyl]pivalamide , or a salt thereof.

16. A pro-drug of a compound as claimed in any one of Claims 1 to -5.

17. A method for producing a compound as claimed in Claim 2 or 4 comprising

(1) reacting a compound represented by the formula:

H

R²-C-C0R³

I

Hal wherein Hal represents a halogen atom, R² and R³ are as defined in Claim 2, or a salt thereof with a compound of the formula: S

R'-C-NH₂ wherein R¹ is as defined in Claim 2 , or a salt thereof, or

(2) reacting a compound represented by the formula: 3a

R^2a-C-C0R

Ha l wherein Hal represents a halogen atom, R^2a and R^3a are as defined in Claim 4 , or a salt thereof with a compound represented by the formula: S

R^1a-!-NH₂ wherein R^la is as defined in Claim 4 , or a salt thereof.

18. A pharmaceutical composition containing the compound as claimed in any one of Claims 1 to 5 or a prodrug thereof .

19. The composition as claimed in Claim 18 which is a p38 MAP kinase inhibitor.

20. The composition as claimed in Claim 18 which is a TNF-α production inhibitor.

21. The composition as claimed in Claim 18 which is a composition for preventing or treating a cytokine-madiated disease.

22. The composition as claimed in Claim 18 which is an adenosine receptor antagonist.

23. The composition as claimed in Claim 18 which is a composition for preventing or treating adenosine receptor-mediated diseases.

24. The composition as claimed in Claim 18 which is a composition for preventing or treating asthma or allergic diseases.

25. The composition as claimed in Claim 18 which is a composition for preventing or treating inflammation, Addison's disease, autoimmune hemolytic anemia, Crohn's disease, psoriasis, rheumatism, spinal cord injury, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, diabetes, arthritis, toxaemias, ulcerative colitis, chronic pneumonia, pulmonary silicosis, pulmonary sarcoidosis, lung tuberculosis, cachexia, arterial sclerosis, Creutzfeldt-Jakob disease, virus infection, atopic dermatitis, systemic lupus erythematosus , AIDS encephalopathy, meningitis, angina pectoris, myocardial infarσtion, congestive heart failure, hepatitis, transplant, dialysis hypotension or diffuse intravascular coagulation symdrome.

26. The composition as claimed in Claim 18 which is a composition for preventing or treating chronic rheumatoid arthritis or osteoarthritis .

27. The composition as claimed in Claim 18 which is a composition for preventing or treating cerebral edema, cerebrovascular disorder, head trauma, cerebral infarction or apoplectic stroke.

28. A method for inhibiting p38 MAP kinase which comprises administering an effective amount of the compound as claimed in any one of Claims 1 to 5 or a pro-drug thereof to mammals.

29. A method for inhibiting TNF-α production which comprises administering an effective amount of the compound as claimed in any one of Claims 1 to 5 or a pro-drug thereof to mammals.

30. A method for antagonizing an adenosine receptor which comprises administering an effective amount of the compound as claimed in any one of Claims 1 to 5 or a pro-drug thereof to mammals.

31. A method for preventing or treating asthma or allergic diseases which comprises administering an effective amount of the compound as claimed in any one of Claims 1 to 5 or a pro-drug thereof to mammals.

32. A method for preventing or treating inflammation, Addison's disease, autoimmune hemolytic anemia, Crohn's disease, psoriasis, rheumatism, spinal cord injury, multiple sclerosis, Alzheimer's disease. Parkinson's disease, amyotrophic lateral sclerosis, diabetes, arthritis, toxaemias, ulcerative colitis, chronic pneumonia, pulmonary silicosis, pulmonary sarcoidosis, lung tuberculosis, cachexia, arterial sclerosis, Creutzfeldt-Jakob disease, virus infection, atopic dermatitis, systemic lupus erythematosus, AIDS encephalopathy, meningitis, angina pectoris, myocardial infarction, congestive heart failure, hepatitis, transplant, dialysis hypotension or diffuse intravascular coagulation symdrome which comprises administering an effective amount of the compound as claimed in any one of Claims 1 to 5 or a pro-drug thereof to mammals .

33. A method for preventing or treating chronic rheumatoid arthritis or osteoarthritis which comprises administering an effective amount of the compound as claimed in any one of Claims 1 to 5 or a pro-drug thereof to mammals .

34. A method for preventing or treating cerebral edema, cerebrovascular disorder, head trauma, cerebral infarction or apoplectic stroke which comprises administering an effective amount of the compound as claimed in any one of Claims 1 to 5 or a pro-drug thereof to mammals .

35. Use of the compound as claimed in any one of Claims 1 to 5 or a pro-drug thereof for producing a p38 MAP kinase inhibitor.

36. Use of the compound as claimed in any one of Claims 1 to 5 or pro-drug thereof for producing a TNF-α production inhibitor.

37. Use of the compound as claimed in any one of Claims 1 to 5 or a pro-drug thereof for producing an adnosine receptor antoganist.

38. Use of the compound as claimed in any one of Claims 1 to 5 or a pro-drug thereof for producing a composition for preventing or treating asthma and allergic diseases .

39. Use of the compound as claimed in any one of Claims 1 to 5 or a pro-drug thereof for producing a composition for preventing or treating inflammation, Addison's disease, autoimmune hemolytic anemia, Crohn's disease, psoriasis, rheumatism, spinal cord injury, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, diabetes, arthritis, toxaemias, ulcerative colitis, chronic pneumonia, pulmonary silicosis, pulmonary sarcoidosis, lung tuberculosis, cachexia, arterial sclerosis, Creutzfeldt-Jakob disease, virus infection, atopic dermatitis, systemic lupus erythematosus, AIDS encephalopathy, meningitis, angina pectoris, myocardial infarction, congestive heart failure, hepatitis, transplant, dialysis hypotension or diffuse intravascular coagulation symdrome.

40. Use of the compound as claimed in any one of Claims 1 to 5 or a pro-drug thereof for producing a composition for preventing or treating chronic rheumatoid arthritis or osteoarthritis.

41. Use of the compound as claimed in any one of Claims 1 to 5 or a pro-drug thereof for producing a composition for preventing or treating cerebral edema, cerebrovascular disorder, head trauma, cerebral infarction or apoplectic stroke.