ZA200108996B

ZA200108996B - 5-pyridyl-1,3-azole compounds, process for producing the same and use thereof.

Info

Publication number: ZA200108996B
Application number: ZA200108996A
Authority: ZA
Inventors: Shigenori Ohkawa; Naoyuki Kanzaki; Seiji Miwatashi
Original assignee: Takeda Chemical Industries Ltd
Priority date: 1999-04-23
Filing date: 2001-10-31
Publication date: 2003-01-31

Description

Technical Field

The present invention relates to novel 5-pyridyl-1,3-azole compounds having an excellent medical action, particularly an adenosine A; receptor antagonistic activity, a p38 MAP kinase inhibitory action, a TNF-a production-inhibitory action and the like, a process for producing the same, a pharmaceutical composition and so on.

Background Art

As a subtype of an adenosine receptor, A;, Aj, Ax and Aj are known. Adenosine exhibits tracheostenotic action to an asthma patient and, on the other hand, theophylline which is an agent for treating asthma exhibits adenosine antagonism. In addition, it has been recently shown that the activation of As; receptor in a rat causes degranulation from mast cells (Journal of Biological

Chemistry, vol.268, 16887-16890, 1993), and that A; receptor is present on eosinophils in peripheral blood and its stimulation activates phospholipase C (PLC) to increase the intracellular calcium concentration (Blood, vol.88, 3569-3574, 1996).

In addition, cytokines such as TNF-a (tumor necrosis factor-a), IL-1 (interleukin-1) and the like are biological substances which are produced by a variety of cells such as monocyte or macrophage in response to the infection and other cellular stress (Koj, A., Biochim. Biophys. Acta, 1317, 84-94 (1996)). Although these cytokines play an important role in the immune response when they are present at an appropriate amount, it is thought that the overproduction is associated with a variety of inflammatory diseases (Dinarello, C.A., Curr. Opin. Immunol., 3, 941-948 (1991)). p38 MAP kinase which was cloned as a homologue of MAP kinase is associated with the control of production of these cytokines and signal transduction system coupled with a receptor and there is a possibility that the inhibition of p38 MAP kinase becomes a drug for treating inflammatory diseases (Stein,

B., Anderson, D., Annual Report in Medicinal Chemistry, edited by

Bristol, J.A., Academic Press, vol.31l, pages 289-298, 1990).

Hitherto, as a compound exhibiting the selective antagonism for adenosine A; receptor, xanthine derivatives are reported in

GB-A-2288733 and WO 95/11681 and the following compounds are reported in Journal of Medicinal Chemistry, vol.40, 2596-2608, 1997:

NH, PD

BY CHyCH, ~ o~ CHC

STUNT

H,C N

H

®

Cl Cl 0 7s CQ)

CHyCH, ~ ~ 0 CH, 0 @

HCN (CH,) ,CHO CH,

H woo, {_) by;

N™ N-N, 4 N= =~ H.C tN

N 0 SUNY” ON

AX cl CO,CH,

In addition, in WO 97/33879, there are described an adenosine A; receptor antagonistic agent containing a compound represented by the formula:

NH,

R pag 0]

I) )=N

S wherein R represents hydrogen, chlorine, bromine, fluorine, iodine, hydroxy, Ci-¢ alkyl, Cis alkoxy or C,.4 alkylcarboxy, or a salt thereof and, more specifically, a compound

®

Me—O NH, [Sas )=N

S is described. ’

In addition, as a compound having a p38 IMAP kinase inhibitory action, imidazole derivatives are de scribed in JP-T 7- 50317 (WO 93/14081) and oxazole derivatives are described in JP-T 9-505055 (WO 95/13067), respectively.

On the other hand, as thiazole compounds , the following compounds are known: ' 1) 1,3-thiazole derivatives represented by the formula:

R: S

Jo

R™ N wherein R! represents a cycloalkyl group, a cycBic amino group, an amino group optionally having, as a substituent , 1 or 2 lower alkyl, phenyl, acetyl or lower alkoxycarbonylac-etyl, an alkyl group optionally having, as a substituent, hydreoxyl, carboxyl or lower alkoxycarbonyl, or a phenyl group optiona._lly having, as a substituent, carboxyl, 2-carboxyethenyl or 2-ca-rboxy-l-propenyl,

R? represents a pyridyl group optionally having, as a substituent, lower alkyl, R> represents a phenyl group optioraally having, as a substituent, lower alkoxy, lower alkyl, hydroxy_l, halogen or methylenedioxy, or salts thereof, which have ansalgesic, antipyretic, anti-inflammatory, anti-ulcerative , thromboxane A, (TXA;) synthesizing enzyme-inhibitory, and platelet coagulation- inhibitory activities (JP-A 60-58981}), 2) 1,3-thiazole derivatives represented by the formula:

R? S

To

RN wherein R' represents an alkyl group, an alkenyl. group, an aryl group, an aralkyl group, a cycloalkyl group, a Heterocyclic group employing carbon as an attachment point or an armino group optionally having substituents, R? represents a pyridyl group t

Eo R opticnally substituted with an alkyl group, R? represents a phenvl

Group optionally having substituents, or salts thereoZ, which have analgesic, antipyretic, anti-inflammatory, anti-ulcerative, TXE, synthesizing enzyme-inhibitory, and platelet coagulztion- inhibitory activities (Jp-A 61-10580), 3) 1,3-thiazole derivatives represented by the formula: 2

R S

1

RN wherein R! represents an alkyl group, an alkenyl group, an aryl group, an aralkyl group, a cycloalkyl group, a heterocyclic group employing carbon as an attachment point or an amino group optionally having substituents, R® represents a pyridyl group optionally substituted with an alkyl group, R? represents an aryl group optionally having substituents, or salts thereof, which have . analgesic, antipyretic, anti-inflammatory, anti-ulcerative, TXa, synthesizing enzyme-inhibitory, and platelet coagulation- inhibitory activities (USP 4,612,321), 4) imidazole derivatives represented by the formula:

NZ r” N (R )o-3 Rife) — AR—X' NR (R) o_; AR—X which have an anti-cancer activity and a cytokine inhibitory activity, more specifically, the following compounds are described (WO 97/12876) : 4

Amended Sheet 2003-01-30

=

CH, N | CH,

NT N

Oe

N

CIF,

CH NZ (Hy 0

A N

N PI

SAPO 0

N

CIF,

Since an adenosine Aj; antagonist, a p38 MAP kinase inhibiting agent and a TNEF—a production-inhibiting agent having the satisfactory activity and effect, safety, (oral) absorption, (metabolism) stability and the like have not been found, it is desired the development of the excellent adenosine A; receptor antagonist, the p38 MAP kimase-inhibiting agent and the TNF-a production-inhibiting agent as a pharmaceutical which are effective for preventing or treating adenosine RA; receptor-related diseases, cytokine-mediated diseases and the like.

Disclos ure of the Invention

The present inventor-s studied variously and, as a result, first synthesized novel compounds which may be N-oxidized and which are represented by the formula (I):

NT

PA =

R27 y X

DR

R N wherein R!' represents a hydrogen atom, a hydrocarbon group optionally having substituesnts, a heterocyclic group optionally having substituents, an amino group optionally having substituents or an acyl group,

R? represents an aromatic g-roup optionally having substituents,

®

R? represents a hydrogen atom, a pyridyl group optionally having substituents or an aromatic hydrocarbon group optionally having substituents,

X represents an oxygen atom or an optionally oxidized sulfur atom,

Y represents a bond, an oxygen atom, an optionally oxidized sulfur atom or a group represented by the formula: NR' (wherein R* represents a hydrogen atom, a hydrocarbon group optionally having substituents or an acyl group) and

Z represents a bond or a divalent acyclic hydrocarbon group optionally having substituents, or a salt thereof [hereinafter, abbreviated as Compound (I) sometimes], which has a structural characteristics that a 5-position of a ring represented by the . formula: 1 5 —X

Lye 4™N 3 wherein X represents an oxygen atom or an optionally oxidized sulfur atom, is substituted with a 4-pyridyl group, and further it has a side chain having an aromatic group at 2-position of the pyridyl group, found that the resulting Compound (I) have unexpectedly excellent pharmaceutical activities such as a selective affinity for an adenosine A; receptor and an adenosine

A; receptor antagonistic activity, a p38 MAP kinase inhibitory activity and the like based on the specific chemical structure, and that the compound has also excellent natures in the physical properties as a pharmaceutical such as stability and the like and is sufficiently satisfactory as a pharmaceutical, and completed the present invention based on these findings.

The present invention relates to (1) an optionally N-oxidized compound represented by the formula:

NT aA (n)

DR

RN wherein R' represents a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally

® having subs tituents, an amino group optionally having substituents or an acyl group,

R? representtts an aromatic group optionally having substituents,

Rr? representtts a hydrogen atom, a pyridyl group optionally having substituent s or an aromatic hydrocarbon group optionally having substituent s,

X represent s an oxygen atom or an optionally oxidized sulfur atom,

Y represent s a bond, an oxygen atom, an optionally oxidized sulfur atom or a g roup represented by the formula: NR* (wherein R* represents a hydrogen atom, a hydrocarbon group optionally having substituent s or an acyl group) and

Z represent s a bond or a divalent acyclic hydrocarbon group optionally ‘having substituents, or a salt thereof, (2) the corwpound according to (1), wherein Z is a divalent acyclic hyd rocarbon group optionally having substituents, (3) the cormpound according to (1), which is a compound represented. by the formula: ©),

NES

AL

DR

RN wherein n r epresents 0 or 1, and other symbols are as defined in (1), or a s.alt thereof, (4) the compound according to (1) or (3), wherein R! represents (i) a hydro. gen atom, (ii) a Ci-s .alkyl group, a C,-¢ alkenyl group, a C,-¢ alkynyl group, a Cs. cyclo.alkyl group, a Ce-14 aryl group or a Ci; aralkyl group [these groups may have substituents selected from the group (substituent group A) consisting of oxo, halogen atom, Ci-3 alkylenedio=y, nitro, cyano, optionally halogenated C;_¢ alkyl, optionally “halogenated C,.¢ alkenyl, carboxy C;.¢ alkenyl, optionally “halogenated C;.¢ alkynyl, optionally halogenated Ci. cycloalkyl, Ce-14 aryl, optionally halogenated C;-s alkoxy, Cig alkoxy-carbionyl-C;.¢ alkoxy, hydroxy, Ces aryloxy, Cis aralkyloxy, mercapto, orptionally halogenated C;-¢ alkylthio, Ce-14 arylthio,

Cy-16 aralkyB thio, amino, mono-C;-s alkylamino, mono-Ce-14 arylamino, di-C;-¢ alky.lamino, di-Cs-14 arylamino, formyl, carboxy, Cis alkyl-

® carbonyl, Ci cycloalkyl-carbonyl, C;_¢ alkoxy-carbonyl, Ce-14 aryl- carbonyl, C;.;6 aralkyl-carbonyl, Ce-14 aryloxy-carbonyl, Ci.i6 aralkyloxy-carbonyl, 5 or 6 membered heterocyclic carbonyl, carbamoyl, thiocarbamoyl, mono-C;-¢ alkyl-carbamoyl, di-C;¢ alkyl- carbamoyl, Ce_i4 aryl-carbamoyl, 5 or 6 membered heterocyclic carbamoyl, C;-¢ alkylsulfonyl, Ce-14 arylsulfonyl, C;-s alkylsulfinyl,

Ce-14 arylsulfinyl, formylamino, C;-¢ alkyl-carbonylamino, Ce-14 aryl-carbonylamino, C;-¢ alkoxy-carbonylamino, Ci-¢ alkylsulfonylamino, Ce-14 arylsulfonylamino, C;-¢ alkyl-carbonyloxy,

Cs-14 aryl-carbonyloxy, Ci-s alkoxy-carbonyloxy, mono-Ci-s alkyl- carbamoyloxy, di-C;-s alkyl-carbamoyloxy, Ce-14 aryl-carbamoyloxy, nicotinoyloxy, 5 to 7 membered saturated cyclic amino optionally having 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to one nitrogen atom and carbon atoms (this cyclic amino may have substituents selected from the group consisting of Cie alkyl, Ce-14 aryl, Ci-¢ alkyl-carbonyl, 5 to 10 membered aromatic heterocyclic group and oxo), 5 to 10 membered aromatic heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, sulfo, sulfamoyl, sulfinamoyl and sulfenamoyl] (iii) a 5 to 14 membered heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms optionally having substituents selected from the substituent group

N

(iv) an acyl group represented by the formula: -(C=0)-R°, -(C=0)-CR°, -(C=0)-NR°R®, -(C=S)-NHR® or -SO,~R’ (wherein R® represents (Da hydrogen atom, @a Cis alkyl group, an

CC; alkenyl group, an C,-s alkynyl group, a Cis cycloalkyl group, a

Ce-14 aryl group or a Cris aralkyl group optionally having substituents selected from the substituent group A or @a 5 to 14 membered heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms optionally having substituents selected from the substituent group A, R® represents a hydrogen atom or a Cis alkyl group, R’ represents (Da C,_¢ alkyl group, a Cz-s alkenyl group, a C;-¢ alkynyl group, a Cis cycloalkyl

® . gr-oup, a Ce-14 aryl group or a Cr.is aralkyl group optionally having suabstituents selected from the substituent group A or @a 5 to 14 membered heterocyclic group containing 1 to 4 heteroatoms of one ors two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms optionally having suibstituents selected from the substituent group A), (Ww) an amino group (this amino group may have substituents selected from the group consisting of Da Ci_¢ alkyl group, a Ci-g alLkenyl group, a Cp; alkynyl group, a Cis cycloalkyl group, a Ce-14 ar-yl group or a Cs-.16 aralkyl group optionally having substituents sexlected from the substituent group A, @a 5 to 14 membered heterocyclic group containing 1 to 4 heteroatoms of one or two kiinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms optionally having substituents selected from the substituent group A, ®an acyl group as defined im the (iv), and @a C,.¢ alkylidene group optionally having substituents selected from the substituent group A), or (wi) a 5 to 7 membered non-aromatic cyclic amino group optionally containing 1 to 4 heteroatoms of one or two kinds selected from a ni trogen atom, a sulfur atom and an oxygen atom in addition to one ni trogen atom and carbon atoms (this cyclic amino may have stabstituents selected from the group consisting of Ci-s alkyl, Ce-14 arcyl, Ci-¢ alkyl-carbonyl, 5 to 10 membered aromatic heterocyclic gr-oup and oxo);

R? represents (Da Cs.154 monocyclic or fused polycyclic ar-romatic hydrocarbon group optionally having substituents selected frrom the substituent group A or @a 5 to 14 membered aromatic heterocyclic group containing 1 to 4 heteroatoms of one or two ki_nds selected from a nitrogen atom, a sulfur atom and an oxygen atzom in addition to carbon atoms, optionally having substituents selected from the substituent group A;

R®> represents Qa hydrogen atom, @a pyridyl group optionally having substituents selected from the substituent group

A, or ®a Cg.i4 monocyclic or fused polycyclic aromatic hydrocarbon gr-oup optionally having substituents selected from the substituent gr-oup A;

X represents 0, S, SO or S0;;

Y represents a bond, O, S, SO, SO, or a group represented

® by the formula: NR' (wherein R! represents Da hydrogen atom, @a

Ci-e¢ alkyl group, a C,-¢ alkenyl group, a Cz-s alkynyl group, a Cs-e cycloalkyl group, a Ce-14 aryl group or a Ci.1s aralkyl group optionally having substituents selected from the substituent group

A or @an acyl group as defined in the (iv)),

Z represents a bond, a Ci-15 alkylene group, a C;-is alkenylene group or a C36 alkynylene group optionally having substituents selected from the substituent group A, (5) the compound according to (1), wherein R' is an amino group optionally having substituents, (6) the compound according to (1), wherein R! is (i) a Ci;-s alkyl group, (ii) a Ce¢-14 aryl group optionally substituted with substituents selected from C;_¢ alkylthio, C;-s alkylsulfonyl and halogen atom, or (iii) an amino group optionally having 1 or 2 acyl represented by the formula: -(C=0)-R°' (wherein R®' represents Da C;6 alkyl group, @a Ces.is aryl group or @a 5 to 14 membered heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms), (7) the compound according to (1), wherein R!' is an amino group optionally having 1 or 2 acyl group represented by -(C=0)-R®" (wherein R°" represents (Da Ce.;4 aryl group or @a 5 to 14 membered heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom .in addition to carbon atoms), (8) the compound according to (1), wherein R? is a Ce-14 aryl group optionally having substituents, (9) the compound according to (1), wherein R? is a Cg-14 aryl group optionally substituted with halogen atom or C;.¢ alkoxy, or a 5 to 14 membered aromatic heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, (10) the compound according to (1), wherein R? is a Ce-14 aryl group, or a 5 to 14 membered heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, (11) the compound according to (1), wherein R?® is a Cg14 aryl group optionally having substituents,

(a (12) the compound according to (1), wherein R® is a Ce-14 aryl group optionally substituted with one or two Cg alkyl or Ci alkoxy, (13) the compound according to (1), wherein X is an optionally oxidized sulfur atom, (14) the compound according to (1), wherein X is a sulfur atom, (15) the compound according to (1), wherein Y is an oxygen atom

Or a group represented by the formula: NR' (wherein R! is as defined in (1)), (16) the compound according to (1), wherein Y is an oxygen atom, an optionally oxidized sulfur atom or a group represented by the formula: NR* (wherein R* represents a C,. alkyl group), (17) the compound according to (1), wherein Y is 0, NH or s,

Co (18) the compound according to (1), wherein 27 is a lower alkylene group optionally having substituents, (18) the compound according to (1), wherein 2 is a bond or a Ci. alkylene group optionally having oxo, (20) the compound according to (1), wherein R: is (i) a Cy. alkyl group, (ii) a Ce-14 aryl group optionally substituted with Cg alkylthio, Ci alkylsulfonyl and halogen atom, or (iii) an amino group optionally having 1 or 2 acyl group represented by the formula: =-(C=0)-R*" (wherein R%’ ‘represents @ a Ci-s alkyl group, @ a

Cera aryl group or @ a S to 14 membered heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms;

R? is a Cé-14 aryl group optionally substituted with halogen atom or Ci-¢ alkoxy, or a 5 to 14 membered aromatic hetorocyclic group containing 1 to 4 hetercatoms of one or two kinds selected from nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms;

R? is a Ce-14 aryl group optionally substituted with 1 or 2

Cis alkyl or Ci.g alkoxy;

X is a sulfur atom; earth metals salts (for example, calcium salt, magnesium salt

Y 1s an oxygen atom, an optionally oxidixed sulfur atom or a group represented by the formula: NR!’ (wherein RY" represents a

Ci-s alkyl group):

Z 1s a Cig alkylene group having oxo or Cg alkyl or a bond, 11 Amended Sheet 2003-01-20

® (21) the compound according to (1), wherein R! is an amino group optionally having 1 or 2 acyl represented by -(C=0)-R>" (wherein

Re" represents Da Ce-14 aryl group or ®a 5 to 14 membered heterocyclic group containing 1 to 4 heteroatoms of one or two 9 kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms);

R? is a Cg.14 aryl group or a 5 to 14 membered aromatic heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms;

R® is a Cg-14 aryl group optionally substituted with 1 or 2

Ci-s alkyl or Ci. alkoxy;

X is a sulfur atom; Y is O, NH or S; Z is a bond or a Ci alkylene group optionally having oxo, (22) N-[5-(2-benzoylamino-4-pyridyl)-4-(3, 5- dimethylphenyl)-1,3-thiazol-2-yl]acetamide (Example Compound No.9),

N-[5- (2-benzylamino-4-pyridyl)-4-(3, 5-dimethylphenyl)-1,3~thiazol- 2-yl]acetamide (Example Compound No.10),

N-[4-[4- (4-methoxyphenyl)-2~-methyl-1, 3-thiazol-5-yl]-2- pyridyllbenzamide (Example Compound No.13),

N-[4-[2- (4-fluorophenyl)-4~ (3-methylphenyl)-1,3-thiazol-5-yl]-2~ pyridyl]lphenylacetamide (Example Compound No.14),

N-[4-[2-ethyl-4- (3-methylphenyl)-1,3-thiazol-5-yl]-2- pyridyllphenylacetamide (Example Compound No.15-2),

N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2- pyridyl]phenylacetamide (Example Compound No.15-3),

N-[4-[2-butyl~-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2- pyridyl]lphenylacetamide (Example Compound No.15-4),

N-[4-[4- (3-methylphenyl)-2~ (4-methylthiophenyl)-1,3-thiazol-5-yl]- 2-pyridyllphenylacetamide (Example Compound No.15-6),

N-[4-[2-ethyl-4- (3-methylphenyl)-1,3-thiazol-5-yl]}-2- pyridyl]lbenzamide (Example Compound No.16-1),

N-[4-[2-ethyl-4- (3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3~ phenylpropionamide (Example Compound No.16-2),

N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3~ (4-methoxyphenyl) propionamide (Example Compound No.16-3),

N-[4-[2-ethyl-4- (3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-4- phenylbutyramide (Example Compound No.16-5),

®

N-[4-[4~ (3-methylphenyl)~2-propyl-1, 3-thiazol-5-yl]-2- pyridyl]lbenzamide (Example Compound No.16-7),

N-[4-[4~(3-methylphenyl)-2-propyl-1, 3-thiazol-5-yl]-2-pyridyl]-3- phenylpropionamide (Example Compound No.16-8),

N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2- pyridyl]lbenzamide (Example Compound No.16-9),

N-[4-{2~butyl-4- (3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3- phenylpropionamide (Example Compound No.16-10),

N-(4-[2~ (4-fluorophenyl)-4- (3-methylphenyl)-1,3-thiazol-5-yl]-2-~ pyridylibenzamide (Example Compound No.16-11),

N-{4-[2~(4-fluorophenyl) ~4- (3-methylphenyl)-1,3-thiazol-5-yl]-2- pyridyl]-3-phenylpropionamide (Example Compound No.16-12),

N-[4-[4~(3-methylphenyl) -2~- (4-methylthiophenyl)-1, 3-thiazol-5-yl]- 2-pyridyl]benzamide (Example Compound No.l16-15),

N-[4-[4-(3-methylphenyl)~-2-(4-methylthiophenyl)-1,3-thiazol-5-yl}- 2-pyridyl]-3-phenylpropionamide (Example Compound No.16-16),

N-benzyl-N-[4-[2-ethyl-4~- (3-methylphenyl)-1,3-thiazol-5-yl]-2- pyridyl]amine (Example Compound No.19-2),

N-[4-[2~-ethyl-4- (3-methylphenyl)-1,3-thiazol-5~yl]-2~pyridyl]-N- (2-phenylethyl) amine (Example Compound No.19-3),

N-[4-[2~ethyl-4- (3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N- (3-phenylpropyl}amine (Example Compound No.l19-4),

N-benzyl-N-[4-[4- (3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2- pyridyl]amine (Example Compound No.139-5),

N-[4-[4~(3-methylphenyl)-2-propyl-1, 3-thiazol-5-yl]-2-pyridyl]-N- (2-phenylethyl) amine (Example Compound No.19-6),

N-[{4-[4~ (3-methylphenyl)-2-propyl-1, 3-thiazol-5-yl]-2-pyridyl]-N- (3—-phenylpropyl) amine (Example Compound No.19-7),

N-benzyl-N-[4-[2-butyl-4- (3-methylphenyl)-1, 3-thiazol-5-yl1]-2- pyridyllamine (Example Compound No.19-8),

N-[4-[2~-butyl—-4- (3-methylphenyl)~1,3-thiazol-5-yl]-2-pyridyl]-N- (2-phenylethyl) amine (Example Compound No.19-9),

N-[4-[2~butyl-4- (3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N- (3-phenylpropyl)amine (Example Compound No.19-10),

N-benzyl-N-{[4-[4-(3-methylphenyl)-2- (4-methylthiophenyl)-1, 3- thiazol-5-yl]-2-pyridyl] amine (Example Compound No.19-17),

N-[4-[4~ (3-methylphenyl) -2- (4-methylthiophenyl)-1, 3-thiazol-5-yl]- 2-pyridyl] -N-(2-phenylethyl) amine (Example Compound No.19-18),

®

N-[(4-[4- (3-methylphenyl)-2- (4-methylthiophenyl)-1, 3-thiazol-5-yl]- 2-pyridyl]-N- (3-phenylpropyl) amine (Example Compound No.19-19),

N-[4-[4- (3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5- yl]l-2-pyridyl]benzamide (Example Compound No.20),

N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5- yl]-2-pyridyl]phenylacetamide (Example Compound No.21-1),

N-[4-[4-(3-methylphenyl)-2- (4-methylsulfonylphenyl)-1,3-thiazol-5- yl]-2-pyridyl]-3-phenylpropionamide (Example Compound No.21-2),

N-benzyl-N-[4-[4- (3-methylphenyl)-2- (4-methylsulfonylphenyl)-1, 3- thiazol-5-yl]-2-pyridyl}amine (Example Compound No.21-5),

N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1, 3-thiazol-5- yl]-2-pyridyl]}-N- (3-phenylpropyl)amine (Example Compound No.21-6),

N-[4-[4-(3-methylphenyl)-2- (4-methylsulfonylphenyl)-1,3-thiazol-5- yl]-2-pyridyl]}-N- (2-phenylethyl) amine (Example Compound No.25-1),

N-(4-fluorobenzyl)-N-[4-[4- (3-methylphenyl)-2-(4- methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine (Example

Compound No.25-2), or salts thereof, (23) a prodrug of the compound according to (1), (24) a process for producing the compound according to (1), which comprises: reacting a compound represented by the formula:

ES

FUSS VID

Hal wherein Hal represents a halogen atom, and other symbols are as defined as (1), or a salt thereof with a compound represented by the formula:

R'-CSNH, (VIII) wherein R! is as defined in (1), or a salt thereof, to obtain a compound represented by the formula:

AN ry Z S

R AA (la) . /

R wherein each symbol is as defined in (1), or a salt thereof, or (ii) reacting a compound represented by the formula:

Hal 1 Xx) , ) R

R wherein Hal represents halogen atom, and other symbols are as defined as (1), or a salt thereof with a compound represented by the formula:

R?-Z-YH (XI) wherein each symbol is as defined in (1), or a salt thereof, to obtain a compound represented by the formula:

AS

REE NF » ET)

R? { wherein each symbol is as defined in (1), or a salt thereof, or (iii) reacting a compound represented by the formula:

ES

Z ) (vIn

H, 1 3 | %

R N wherein each symbol is as defined in (1), or a salt thereof with a compound represented by the formula:

R*-ZL (XVIII) wherein L represents a leaving group, and other symbols are as defined in (1), or a salt thereof, to obtain a compound represented by the formula: :

ES

= oy 8 Lo (lo) ) R

R* RS wherein each symbol is as defined in (1), or a salt thereof, or (iv) reacting a compound represented by the formula: ~

RA EN () 3 | Va

R N wherein each symbol is as defined in (1), or a salt thereof with peroxy acid, hydrogen peroxide or alkyl hydroperoxide, to obtain a

® compound represented by the formula: 0

X =

REE ~ pa (1d)

R? W wherein each symbol is as defined in (1), or a salt thereof, (25) a pharmaceutical composition which comprises the compound according to (1) or a prodrug thereof, (26) the composition according to (25), which is an adenosine Aj; receptor antagonist, (27) the composition according to (25), which is an agent for preventing or treating adenosine A; receptor-related diseases, (28) the composition according to (25), which is an agent for preventing or treating asthma or allergic diseases, (29) the composition according to (25), which is an agent for preventing or treating brain edema, cerebrovascular disease or head trauma, (30) the composition according to (25), which is an agent for inhibiting p38 MAP kinase, (31) the composition according to (25), which is a TNF-a production-inhibiting agent, (32) the composition according to (25), which is an agent for preventing or treating cytokine-mediated diseases, (33) the composition according to (25), which is an agent for preventing or treating inflammation, Addison's disease, autoimmune hemolytic anemia, Crohn's disease, psoriasis, rheumatism, spinal trauma, brain edema, multiple sclerosis, Alzheimer's disease,

Parkinson's syndrome, amyotrophic lateral sclerosis, diabetes, arthritis, toxemia, Crohn’s disease, ulcerative colitis, chronic pneumonia, silicosis, pulmonary sarcoidosis, pulmonary tuberculosis, cachexia, arteriosclerosis, Creutzfeldt-Jakob disease, virus infection, atopic dermatitis, systemic lupus erythematosus, AIDS encephalopathy, meningitis, angina, cardiac infarction, congestive heart failure, hepatitis, transplantation, dialysis hypotension or disseminated intravascular coagulation, (34) a method for antagonizing an adenosine A; receptor comprising administering an effective amount of an optionally N-

® oxidized compound represented by the formula:

NO aA | (1) )—R

RN wherein R! represents a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino group optionally having substituents or an acyl group,

R? represents an aromatic group optionally having substituents,

X represents an oxygen atom or an optionally oxidized sulfur atom,

Y represents a bond, an oxygen atom, an optionally oxidized sulfur : atom or a group represented by the formula: NR* (wherein R* represents a hydrogen atom, a hydrocarbon group optionally having substituents or an acyl group) and

Z represents a bond or a divalent acyclic hydrocarbon group optionally having substituents, or a salt thereof or a prodrug thereof to mammals, (35) a method for inhibiting p38 MAP kinase comprising administering an effective amount of an optionally N-oxidized compound represented by the formula:

NT aA (1) a

R? represents an aromatic group optionally having substituents,

R?® represents a hydrogen atom, a pyridyl group optionally having substituents or an aromatic hydrocarbon group optionally having substituents,

X represents an oxygen atom or an optionally oxidized sulfur atom,

)

Y represents a bond, an oxygen atom, an optionally oxidized sulfur atom or a group represented by the formula: NR! (wherein R* represents a hydrogen atom, a hydrocarbon group optionally having substituents or an acyl group) and 2 represents a bond or a divalent acyclic hydrocarbon group optionally having substituents, or a salt thereof or a prodrug thereof to mammals, (36) a method for inhibiting TNF-a production comprising administering an effective amount of an optionally N-oxidized compound represented by the formula:

NT

AI (n)

DR

R? represents an aromatic group optionally having substituents,

X represents an oxygen atom or an optionally oxidized sulfur atom,

Y represents a bond, an oxygen atom, an optionally oxidized sulfur atom or a group represented by the formula: NR! (wherein R* represents a hydrogen atom, a hydrocarbon group optionally having substituents or an acyl group) and

Z represents a bond or a divalent acyclic hydrocarbon group optionally having substituents, or a salt thereof or a prodrug thereof to mammals, (37) a method for preventing or treating asthma, allergic diseases, inflammation, Addison's disease, autoimmune hemolytic anemia, Crohn's disease, psoriasis, rheumatism, cerebral hemorrhage, cerebral infarction, head trauma, spinal trauma, brain edema, multiple sclerosis, Alzheimer's disease, Parkinson's syndrome, amyotrophic lateral sclerosis, diabetes, arthritis, toxemia, Crohn’s disease, ulcerative colitis, chronic pneumonia, silicosis, pulmonary sarcoidosis, pulmonary tuberculosis, cachexia,

® arteriosclerosis, Creutzfeldt-Jakob disease, virus infection, atopic dermatitis, systemic lupus erythematosus, AIDS encephalopathy, meningitis, angina, cardiac infarction, congestive heart failure, hepatitis, transplantation, dialysis hypotension or disseminated intravascular coagulation comprising administering an effective amount of an optionally N-oxidized compound represented by the formula:

NT

PAN 1 (1)

R Y

)—R

R* TN wherein R! represents a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino group optionally having substituents or an acyl group,

R? represents an aromatic group optionally having substituents,

X represents an oxygen atom or an optionally oxidized sulfur atom,

Y represents a bond, an oxygen atom, an optionally oxidized sulfur atom or a group represented by the formula: NR* (wherein R* represents a hydrogen atom, a hydrocarbon group optionally having substituents or an acyl group) and

Z represents a bond or a divalent acyclic hydrocarbon group optionally having substituents, or a salt thereof or a prodrug thereof to mammals, (38) use of an optionally N-oxidized compound represented by the formula:

NT aA (1) )—R

®

R® represents an aromatic group optionally having substituents,

R’ represents a hydrogen atom, a pyridyl group optionally having substituents or an aromatic hydrocarbon group optionally having substituents,

X represents an oxygen atom or an optionally oxidized sulfur atomm,

Y represents a bond, an oxygen atom, an optionally oxidized sulf-ur atom or a group represented by the formula: NR' (wherein R* represents a hydrogen atom, a hydrocarbon group optionally havin:qg substituents or an acyl group) and

Z represents a bond or a divalent acyclic hydrocarbon group optionally having substituents, or a salt thereof or a prodrug thereof for preparing an agent for antagonizing an adenosine Aj receptor, (39) use of an optionally N-oxidized compound represented by the formula:

NT

. (1)

Wa

RN wherein R! represents a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino group optionally having substituen ts or an acyl group,

R? represents an aromatic group optionally having substituents,

X represents an oxygen atom or an optionally oxidized sulfur atom,

Y represents a bond, an oxygen atom, an optionally oxidized sulf ur atom or a group represented by the formula: NR! (wherein R* represents a hydrogen atom, a hydrocarbon group optionally havin.g substituents or an acyl group) and

Z represents a bond or a divalent acyclic hydrocarbon group optionally having substituents, or a salt thereof or a prodrug thereof for preparing an agent for inhibiting p38 MAP kinase, (40) use of an optionally N-oxidized compound represented by the formula:

®

NO pA (1)

DR gS N wherein R' represents a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino group optionally having substituents or an acyl group,

R® represents an aromatic group optionally having substituents,

R® represents a hydrogen atom, a pyridyl group optionally having substituents or an aromatic hydrocarbon group optionally having substituents,

X represents an oxygen atom or an optionally oxidized sulfur atom,

Z represents a bond or a divalent acyclic hydrocarbon group optionally having substituents, or a salt thereof or a prodrug thereof for preparing an agent for inhibiting a TNF-a production, and (41) use of an optionally N-oxidized compound represented by the formula:

NT

AA (1)

DR

RN wherein R!' represents a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino group optionally having substituents or an acyl group,

R® represents an aromatic group optionally having substituents,

X represents an oxygen atom or an optionally oxidized sulfur atom,

Y represents a bond, an oxygen atom, an optionally oxidized sulfur

® atom or a group represented by the formula: NR' (wherein RR‘ represents a hydrogen atom, a hydrocarbon group optionall y having substituents or an acyl group) and

Z represents a bond or a divalent acyclic hydrocarbon gro—up optionally having substituents, or a salt thereof or a pr-odrug thereof for preparing an agent for preventing or treating asthma, allergic diseases, inflammation, Addison's disease, autoi-mmune hemolytic anemia, Crohn's disease, psoriasis, rheumatism, cerebral hemorrhage, cerebral infarction, head trauma, spinal trauma, brain edema, multiple sclerosis, Alzheimer's disease, Parkinson 's syndrome, amyotrophic lateral sclerosis, diabetes, arthri tis, toxemia, Crohn’s disease, ulcerative colitis, chronic pneumonia, silicosis, pulmonary sarcoidosis, pulmonary tuberculosis, cachexia, arteriosclerosis, Creutzfeldt-Jakob disease, virus infect ion, atopic dermatitis, systemic lupus erythematosus, AIDS encephalopathy, meningitis, angina, cardiac infarction, c ongestive heart failure, hepatitis, transplantation, dialysis hypot ension or disseminated intravascular coagulation.

Furthermore, the present invention relates to (42) the compound according to (1), wherein R' is an amimo group optionally having one or two acyl groups represented by t he formula: -(C=0)-R°, -(C=0)-OR°, -(C=0)-NR°R®, -(C=S)-NHR® or -SO,-R’ wherein each symbols are defined in (4), (43) the compound according to (1), wherein R' is a Cj. amlkyl group optionally having substituents, : (44) the compound according to (1), wherein R! is a Ce-14 aryl group optionally having a Ci; alkylsulfonyl group, (45) the compound according to (7), wherein R*’ is a pheryl group or a pyridyl group, (46) the compound according to (1), wherein R? is a Ce.14 -aryl group optionally having substituents or a 5 to 14 membere d aromatic heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom. and an oxygen atom in addition to carbon atoms optionally having substituents, (47) the compound according to (1), wherein R? is a phenyl group or a pyridyl group, and (48) the compound according to (1), wherein R’ is a phenyl group

® optionally substituted by one or two C;.¢ alkyl or C;.¢ alkoxy.

Best Mode to Practice the Invention

In the aforementioned formula, R' represents a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino group optionally having substituents or acyl group.

As "acyl group" represented by R!, for example, there are an acyl group represented by the formula: -(C=0)-R*®, -(C=0)-OR>, -(C=0)-NR°R®, -(C=S)-NHR® or -S0,-R’ (wherein R® represents a hydrogen atom, a hydrocarbon group optionally having substituents or a heterocyclic group optionally having substituents, R® represents a hydrogen atom or a Cis alkyl, R’ represents a hydrocarbon group optionally having substituents or a heterocyclic group optionally having substituents) and the like.

In the aforementioned formula, as "hydrocarbon group" of "hydrocarbon group optionally having substituents", for example, there are an acyclic or cyclic hydrocarbon group (for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl and the like) and the like. Among them, acyclic or cyclic hydrocarbon groups having carbon number of 1 to 16 are preferable.

As "alkyl", for example, C;.¢ alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like) is preferable and, in particular, C;_3 alkyl (for example, methyl, ethyl, propyl and isopropyl) and the like are preferable.

As "alkenyl", for example, C;.¢ alkenyl (for example, vinyl, allyl, isopropenyl, l-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2- propenyl, l-methyl-2-propenyl, 2-methyl-l-propenyl and the like) and the like are preferable.

As "alkynyl", for example, C,.¢ alkynyl (for example, ethynyl, propargyl, l-butynyl, 2-butynyl, 3-butynyl, l-hexynyl and the like) and the like are preferable.

As "cycloalkyl", for example, Cs cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like) and the like are preferable.

As "aryl", for example, Ce¢-14 aryl (for example, phenyl, 1- naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-

® anthryl and the like) and the like are preferable,

As "aralkyl", for example, Ci. aralkyl (f or example, benzyl, phenethyl, diphenylmethyl, l-naphthylmetiyl, 2- naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl., 4-phenylbutyl, 5-phenylpentyl and the like) and the like are preferable.

As "substituents" of "hydrocarbon group orpoticnally having substituents” represented by R°, for example, the:re are oxo, halogen atom (for example, fluorine, chlorine, br-omine, iodine and the like), C;-3 alkylenedioxy (for example, methyl enedioxy, ethylenedioxy and the like), nitro, cyano, optiornally halogenated

Ci-e alkyl, optionally halogenated C,.s alkenyl, camrboxy C.-s alkenyl (for example, 2-carboxyethenyl, 2-carboxy-2-methywlethenyl and the like), optionally halogenated C;-¢ alkynyl, optiomally halogenated

Cs-e cycloalkyl, Ce-14 aryl (for example, phenyl, 1 —naphthyl, 2- naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylysl, 2-anthryl and the like), optionally halogenated C;.g alkoxy, Ci-e alkoxy-carbonyl-

Ci-s alkoxy (for example, ethoxycarbonylmethyloxy and the like), hydroxy, Ce-14 aryloxy (for example, phenyloxy, l-~mmaphthyloxy, 2- naphthyloxy and the like), Cj.16 aralkyloxy (for example, benzyloxy, phenethyloxy and the like), mercapto, optionally halogenated Ci-¢ alkylthio, Ce.14 arylthio (for example, phenylthio , l-naphthylthio, 2-naphthylthio and the like), C;-i6 aralkylthio (f-or example, benzylthio, phenethylthio and the like), amino, mono-Cj-s alkylamino (for example, methylamino, ethylamino and the like), mono-Ce.14 arylamino (for example, phenylamino, l-mmaphthylamino, 2- naphthylamino and the like), di-C;._¢ alkylamino (Eor example, dimethylamino, diethylamino, ethylmethylamino and the like), di-

Ce-14 arylamino (for example, diphenylamino and th-e like), formyl, carboxy, Ci-s alkyl-carbonyl (for example, acetyl, propionyl and the like), Cis cycloalkyl-carbonyl (for example, cyclopropylcarbonyl, cyclopentylcarbonyl, cyclcheexylcarbonyl and the like), Ci-s alkoxy-carbonyl (for example, methmoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like),

Ce-14 aryl—-carbonyl (for example, benzoyl, l-naphthoyl, 2-naphthoyl and the like), Ci-16 aralkyl-carbonyl (for example , phenylacetyl, 3-phenylpropionyl and the like), Cs-14 aryloxy-caribonyl (for example, phenoxycarbonyl and the like), Cy.16 aral_kyloxy-carbonyl (for example, benzyloxycarbonyl, phenethyloxycarkoonyl and the

J like), 5 or 6 membered heterocyclic carbonyl (for example, nicotinoyl, isonicotinoyl, thenoyl, furoyl, morpholinocarbonyl, thiomorpholinocarbonyl, piperazin-l-ylcarbonyl, pyrrolidin-1- ylcarbonyl and the like), carbamoyl, thiocarbamoyl, mono-C,-s alkyl-carbamoyl (for example, methylcarbamoyl, ethylcarbamoyl and the like), di-C;.¢ alkyl-carbamoyl (for example, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl and the like), Ce-14 aryl- carbamoyl (for example, phenylcarbamoyl, l1-naphthylcarbamoyl, 2- naphthylcarbamoyl and the like), 5 or 6 membered heterocyclic carbamoyl (for example, 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4- pyridylcarbamoyl, 2-~thienylcarbamoyl, 3-thienylcarbamoyl and the like), Ci-¢ alkylsulfonyl (for example, methylsulfonyl, ethylsulfonyl and the like), Ce14 arylsulfonyl (for example, phenylsulfonyl, 1l-naphthylsulfonyl, 2-naphthylsoclfonyl and the like), Ci-¢ alkylsulfinyl (for example, methylsulfinyl, ethylsulfinyl and the like), Cg-14 arylsulfinyl (for example, phenylsulfinyl, l-naphthylsulfinyl, 2-naphthylsulfinyl and the like), formylamino, C;-¢ alkyl-carbonylamino (for example, acetylamino and the like), Ce¢-14 aryl-carbonylamino (for example,

Dbenzoylamino, naphthoylamino and the like), Ci-s alkoxy- carbonylamino (for example, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino and the like), Ci-¢ alkylsulfonylamino (for example, methylsulfonylamino, ethylsulfonylamino and the like), Cs-14 arylsulfonylamino (for example, phenylsulfonylamino, 2- naphthylsulfonylamino, 1-naphthylsul fonylamino and the like), Ci-¢ alkyl-carbonyloxy (for example, acetoxy, propionyloxy and the like), Cs-14 aryl-carbonyloxy (for example, benzoyloxy, naphthylcarbonyloxy and the like), Cis alkoxy-carbonyloxy (for example, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy and the like), mono-C,-¢ alkyl-carbamoyloxy (for example, methylcarbamoyloxy, ethylcarbamoyloxy and the like), di-

Ci-¢ alkyl-carbamoyloxy (for example, dimethylcarbamoyloxy, diethylcarbamoyloxy and the like), Cg-14 aryl-carbamoyloxy (for example, phenylcarbamoyloxy, naphthylcarbamoyloxy and the like), nicotinoyloxy, 5 to 7 membered saturated cyclic amino optionally having substituents, 5 to 10 membered aromatic heterocyclic group (for example, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-

® pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8- quinolyl, 1l-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5- isoquinolyl, l-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2- benzo [b]thienyl, 3-benzo[blthienyl, 2-besnzo[b]furanyl, 3- benzo[b]furanyl and the like), sulfo, sul famoyl, sulfinamoyl, sulfenamoyl and the like.

The "hydrocarbon group" may have 1 to 5, preferably 1 to 3 aforementioned substituents at a substitutable position and, when the number of substituents is 2 or more. respective substituents may be the same or different.

As aforementioned "optionally halogenated C;-¢ alkyl", for example, there are C;.¢4 alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, f&ert-butyl, pentyl, hexyl and the like) and the like optionally having 1 to 5, preferably 1 to 3 halogen atoms (for example, fluorire, chlorine, bromine, iodine and the like). Examples thereof are methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2- bromoethyl, 2,2,2-trifluoroethyl, penta®¥luoroethyl, propyl, 3,3,3- trifluoropropyl, isopropyl, butyl, 4,4, 4d-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyll, neopentyl, 5,5, 5- trifluoropentyl, hexyl, 6,6, 6-triflucrohexyl and the like.

As the aforementioned "optionally halogenated C,-¢ alkenyl”, for example, there are C,.¢ alkenyl (for example, vinyl, propenyl, isopropenyl, 2-buten-1-yl, 4-penten-1-yi, 5-hexen-1-yl) and the like optionally having 1 to 5, preferably 1 to 3 halogen atoms (for example, fluorine, chlorine, bromire, iodine and the like).

As the aforementioned "optionally halogenated C,-s alkynyl", there are C;.¢ alkynyl (for example, 2-buatyn-1-yl, 4-pentyn-1-yl, 5-hexyn-1-yl and the like) and the like optionally having 1 to 5, preferably 1 to 3 halogen atoms (for example, fluorine, chlorine, bromine, iodine and the like).

As the aforementioned "optionally halogenated Cie cycloalkyl", for example, there are Cs.4 cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cy/clohexyl and the like) and the like optionally having 1 to 5, preferably 1 to 3 halogen atoms (for example, fluorine, chlorine, bromirme, iodine and the like).

Examples thereof are cyclopropyl, cycloloutyl, cyclopentyl, cyclohexyl, 4,4-dichlorocyclohexyl, 2,2, 3,3-tetrafluorocyclopentyl,

J

4-chlorocyclohexyl and the like.

As the aforementioned "optionally halogenated C;_g alkoxy", for example, there are C;.s alkoxy (for example, methoxy, ethoxy, pPropoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like) and the like optionally having 1 to 5, preferably 1 to 3 halogen atoms (for example, fluorine, chlorine, bromine, iodine and the like). Examples thereof are methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like.

As the aforementioned "optionally halogenated C;.¢ alkylthio", for example, there are C;.¢ alkylthio (for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec- butylthio, tert-butylthio and the like) and the like optionally having 1 to 5, preferably 1 to 3 halogen atoms (for example, fluorine, chlorine, bromine, iodine and the like). Examples thereof are methylthio, difluoromethylthio, trifluoromethylthio, : ethylthio, propylthio, isopropylthio, butylthio, 4,4,4- trifluorobutylthio, pentylthio, hexylthio and the like.

As "5 to 7 membered saturated cyclic amino" of the aforementioned "5 to 7 membered saturated cyclic amino optionally having substituents”, there are 5 to 7 membered saturated cyclic amino optionally containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to one nitrogen atom and carbon atoms and examples thereof are pyrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, thiomorpholino, hexahydroazepin-l-yl and the like.

As "substituents" of the "5 to 7 membered saturated cyclic amino optionally having substituents", for example, there are 1 to 3 Cis alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like), Cg-14 aryl (for example, phenyl, l-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and the like), C;-¢ alkyl- carbonyl (for example, acetyl, propionyl and the like), 5 to 10 membered aromatic heterocyclic group (for example, 2-thienyl, 3- thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, l-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1l-indolyl, 2-indolyl, 3-indolyl, 2-

® benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl, 2- benzo [b] furanyl, 3-benzo[b]furanyl and the like), oxo and the like.

As "heterocyclic group" of "heterocyclic group optionally having substituents" represented b y R®>, for example, there is a monovalent group obtained by remov-ing one arbitrary hydrogen atom from a 5 to 14 membered (monocycli c, bicyclic or tricyclic) heterocycle containing 1 to 4 hete roatoms of one or two kinds selected from a nitrogen atom, a s ulfur atom and an oxygen atom in addition to carbon atoms, preferab ly (i) a 5 to 14 membered (preferably 5 to 10 membered, part icularly preferably 5 to 6 membered) aromatic heterocycle, (i i) a 5 to 10 membered (preferably 5 to 6 membered) non-a romatic heterocycle or (iii) a 7 to 10 membered bridged heterocycle .

As the aforementioned "5 to 14 membered (preferably 5 to 10 membered) aromatic heterocycle", t here are an aromatic heterocycle such as thiophene, benzo[b]thiophe ne, benzo(b] furan, benzimidazole, benzoxazole, benzothiazole, benzis othiazole, naphtho{2,3- blthiophene, furan, pyrrole, imida zole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1lH-indazole, purine, 4H-quinolizine, isoquinoli ne, quinoline, phthalazine, naphthyridine, quinoxaline, quinaz oline, cinnoline, carbazole, B- carboline, phenanthridine, acridin e, phenazine, thiazole, isothiazole, phenothiazine, isoxaz ole, furazan, phenoxazine and the like, and a ring formed by fus ing these rings (preferably monocyclic) with 1 or a plurality (preferably 1 to 2) of aromatic rings (for example, benzene ring a nd the like).

As the aforementioned "5 to 10 membered non-aromatic heterocycle", for example, there a re pyrrolidine, imidazoline, pyrazolidine, pyrazoline, piperidi ne, piperazine, morpholine, thiomorpholine, dioxazole, oxadiaz oline, thiadiazoline, triazoline, thiadiazole, dithiazole and the li ke.

As the aforementioned "7 to 10 membered bridged heterocycle", for example, there a re quinuclidine, 7- azabicyclo[2.2.1]heptane and the 1 ike.

The "heterocyclic group” is preferably a 5 to 14 membered (preferably 5 to 10 membered) (mon ocyclic or bicyclic) heterocyclic group containing pref erably 1 to 4 heteroatoms of one or two kinds selected from a nitro gen atom, a sulfur atom and an

® oxygen atom in addition to carbon atoms. More particularly, examples thereof are an aromatic heterocyclic group such as 2- thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8- quinolyl, l-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5- isoquinolyl, pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1- indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo([b] thienyl, 2-benzol[b]furanyl, 3-benzo{b]furanyl and the like, and a non-aromatic heterocyclic group such as 1l-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-imidazolinyl, 4-imidazolinyl, 2- pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2- piperidyl, 3-piperidyl, 4-piperidyl, l-piperazinyl, 2-piperazinyl, morpholino, thiomorpholino and the like.

Among them, for example, a 5 or 6 membered heterocyclic group containing 1 to 3 hetercatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms is further preferable. More particularly, examples thereof are 2- thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3- furyl, pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl, 3-pyridazinyl, 3- isothiazolyl, 3-isoxazolyl, l-pyrrolidinyl, 2-pyrrolidinyl, 3- pyrrolidinyl, 2-imidazolinyl, 4-imidazolinyl, 2-pyrazolidinyl, 3- pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidyl, 3- piperidyl, 4-piperidyl, l-piperazinyl, 2-piperazinyl, morpholino, thiomorpholino and the like.

As "substituents" of "heterocyclic group optionally having substituents”, for example, there are the same "substituents" as substituents of "hydrocarbon group optionally having substituents" represented by R®.

The "heterocyclic group" may have 1 to 5, preferably 1 to 3 aforementioned substituents at a substitutable position and, when the number of substituents is 2 or more, respective substituents may be the same or different.

As "C,-¢ alkyl" represented by R®, for example, there are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.

As "hydrocarbon group optionally having substituents" and "heterocyclic group optionally having substituents" represented by

®

R’, for example, there are the aforementioned "hydrocarbon group optionally having subst-ituents" and "heterocyclic group optionally having substituents" re=presented by R®, respectively.

As "hydrocarbon group optionally having substituents” and 8 "heterocyclic group optionally having substituents" represented by

R!, for example, there are the aforementioned "hydrocarbon group optionally having subst-ituents” and "heterocyclic group optionally having substituents" re=presented by R®, respectively.

As "amino group optionally having substituents" represented by R', for example, there are (1) an amino group optionally having 1 or 2 substituents andl (2) a cyclic amino group optionally having substituents and the li ke.

As "substituents-" of "amino group optionally having 1 or 2 substituents" of the aforementioned (1), for example, there are a hydrocarbon group optioenally having substituents, a heterocyclic group optionally having substituents, an acyl group, an alkylidene group optionally having substituents and the like. As these "hydrocarbon group opti onally having substituents" and "heterocyclic group opt.ionally having substituents", there are the same "hydrocarbon groupe optionally having substituents" and "heterocyclic group opt ionally having substituents" as those represented by R® described above, respectively. As the "acyl group", there is the same "acyl group" as that by represented by

R' as described above.

As "alkylidene group" of "alkylidene group optionally having substituents", f or example, there are a Ci-s alkylidene group (for example, met hylidene, ethylidene, propylidene and the like) and the like. As "substituents" of "alkylidene group optionally having subst ituents", there are 1 to 5, preferably 1 to 3 same substituents as "substituents" of "hydrocarbon group optionally having subst ituents" represented by R®.

When the number of the aforementioned "substituents" of "amino group optionally having 1 or 2 substituents” is 2, respective substituents may be the same or different.

As "cyclic amino group" of "cyclic amino group optionally having substituents" of the aforementioned (2), there are a 5 to 7 membered non-aromatic c yclic amino group optionally containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom,

® a sulfur atom and an oxygen atom in addition to one nitrogen atom and carbon atoms. More particularly, examples thereof are pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, thiomorpholino, hexahydroazepin-1l-yl, imidazolidin-1-yl, 2, 3- dihydro-1H-imidazol-1-yl, tetrahydro-1(2H)-pyrimidinyl, 3, 6- dihydro-1 (2H) -pyrimidinyl, 3,4-dihydro-1 (2H) - pyrimidinyl and the like. As "substituents" of "cyclic amino optionally having substituents", there are 1 to 3 same ones as "substituents" of "5 to 7 membered saturated cyclic amino group" which were described in detail as "substituents" of "hydrocarbon group optionally having substituents" represented by R®.

Examples of the 5 to 7 membered non-aromatic cyclic amino group having 1 oxo, there are 2-oxoimidazolidin-1-yl, 2-oxo-2,3- dihydro-1H-imidazol-1-yl, 2-oxotetrahydro-1(2H)-pyrimidinyl, 2- oxo-3,6-dihydro-1 (2H) -pyrimidinyl, 2-oxo-3,4-dihydro-1 (2H)- pyrimidinyl, 2-oxopyrrolidin-1-yl, 2-oxopiperidino, 2- oxopiperazin-1-yl, 3-oxopiperazin-l-yl, 2-oxo-2,3,4,5,6,7- hexahydroazepin-1-yl and the like.

As R', an amino group optionally having substituents, an aryl group optionally having substituents and an alkyl group optionally having substituents and the like are preferable.

As further preferable example of the "amino group optionally having substituents” is an amino group optionally having 1 or 2 acyl represented by the formula: -(C=0)-R>, -(C=0)-OR®, -(C=0)-NR°R®, -(C=S)-NHR®> or -S0,-R’ [wherein respective symbols represent the same meanings as described above].

Particularly preferable example is an amino group optionally having 1 or 2 acyl represented by the formula: -C(C=0)-R® or - (C=0)-NR°R® [wherein respective symbols represent the same meanings as described above].

As the "aryl group optionally having substituents", for example, there is preferably a Ce-14 aryl group (preferably a phenyl group and the like) optionally having 1 to 5 substituents selected from C;-¢ alkylthio, Cg-14 arylthio, C;-¢ alkylsulfinyl,

Cg14 arylsulfinyl, C6 alkylsulfonyl, Ce-14 arylsulfonyl and carboxy.

As the "alkyl group optionally having substituents", for example, a Cis alkyl group (for example, methyl, ethyl, propyl,

® isopropyl, butwl, isobutyl, sec-butyl, tert-butyl and the like) optionally subsstituted with 1 to 3 substituents selected from halogen atom, C,¢ alkoxy, hydroxy, carboxy and C,.s alkoxy-carbonyl and the like ar-e preferable, and particularly C;-3 alkyl group such as methyl, ethyl and the like is preferable.

Among them, as R}, (i) Cig alkyl group (for example, C4 alkyl group such as methyl, ethyl, propyl, butyl), (ii) a Ce-14 aryl group (for- example, a phenyl group) optionally substituted with substituerats selected from C;-¢ alkylthio (for example, methylthio), C; alkylsulfonyl (for example, methylsulfonyl) and halogen atom (for example, chlorine atom, fluorine atom) or (iii) an amino group optionally having 1 or 2 acyl represented by the formula: -(C=0) -R®' (wherein R®' represents Da C,_¢ alkyl group (for example, C;-3 alkyl group such as methyl), @a Ces aryl group (for example, a= phenyl group) or @a 5 to 14 membered heterocyclic group containirag 1 to 4 heteroatoms of one or two kinds selected from a nitrogern atom, a sulfur atom and an oxygen atom in addition to carbon atoms (for example, a 5 to 6 membered heterocyclic group containing 1 to 2 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms such as pyridyl group) are preferable. As R®' and R®", a phenyl group or a pyridyl group i_s suitable.

In the aforementioned formula, R? represents an aromatic group optionally having substituents.

As "aromatic group" of "aromatic group optionally having substituents" represented by R? for example, there are an aromatic hydrocarbon group, an aromatic heterocyclic group and the like.

As the "aromatic hydrocarbon group", examples thereof include a Cg-14 monocyclic or fused polycyclic (bicyclic or tricyclic) aromatic hydrocarbon group, etc. As examples, there are a Ce-14 aryl group and the like such as phenyl, l1-naphthyl, 2- naphthyl, 2-bipohenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and the like and, further preferably, a Ces-10 aryl group and the like (for example, rohenyl, l-naphthyl, 2-naphthyl and the like, preferably pherayl and the like).

As the "™aromatic heterocyclic group”, there is a monovalent group obtained by removing one arbitrary hydrogen atom from 5 to

® 14 membered (preferably 5 to 10 membered) aromatic heterocycle containing 1 to 4 heteroatoms of one or two kinds selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atoms.

As the aforementioned "5 to 14 membered (preferably 5 to 10 membered) aromatic heterocycle", for example, there are an aromatic heterocycle such as thiophene, benzo[b]thiophene, benzo [b] furan, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho{2, 3-b]thiophene, furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, 4H-quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, B-carboline, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, isoxazole, furazan, phenoxazine and the like, and a ring formed by fusing these rings (preferably monocycle) with 1 or a plurality of (preferably 1 or 2) aromatic rings (for example, benzene ring and the like).

As the "aromatic heterocyclic group", there are preferably a 5 to 14 membered (preferably 5 to 10 membered) (monocyclic or bicyclic) aromatic heterocyclic group containing preferably 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms and the like and, more particularly, there are an aromatic heterocyclic group such as 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5- quinolyl, 8-quinolyl, l-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1- indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl and the like.

As "substituents" of "aromatic group optionally having substituents”, there are 1 to 5, preferably 1 to 3 same substituents as "substituents" of "hydrocarbon group optionally having substituents" represented by R°. When the number of substituents is 2 or more, respective substituents may be the same or different.

o

As RZ, (1) 2a Cé-14 2ryl group optionally having substituents and (2) a 5 to 14 membered aromatic heterocyclic group containing l to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an Oxygen atom in addition to carbon atoms are preferable and, among them, (1) a Cg. aryl group (for example, phemyl group, naphthyl group) optionally substituted with halogen atom (for example, chlorine atom, fluorine atom) or Cg alkoxy (for- example, methoxy), (2) a 5 to 14 membered aromatic hete rocyclic group containing 1 to 4 heteroatoms of one or two kind.s selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms (for example, a 5 to 6 membered arom.atic heterocyclic group containing 1 to 2 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms such as pyridyl group, thienyl group) and the like are preferable and, in particular, a phenyl group, a pyridyl group and tzhe like are suitable.

In the aforementioned formula, R? represents a hydrogen atom,. a pyridyl group optionally having substituents or an aromatic hydrocarbon group optionally having substituents.

As "substituents" of "pyridyl group optionally having substituents” represented by R?>, there are the same substituents as "s:ubstituents" of "hydrocarbon group optionally having subst ituents” represented by RS.

The "pyridyl group" may, for example, have 1 to 5, prefe rably 1 to 3 aforementioned substituents at substitutable posit.ions and, when the number of substituents is 2 or more, respective substituents may be the same or different. In addition, an inttracyclic nitrogen atom may be N-oxidized. : As "aromatic hydrocarbon group" of "aromatic hydrocarbon group optionally having substituents" represented by R?, there is the same aromatic hydrocarbon group as "aromatic hydrocarbon group"’ of "aromatic group optionally having substituents" represented by R? and, preferably, there are a Cs, -aryl ggroup and the like such as phenyl, l-naphthyl, 2-naphthyl, 2- bipheruylvl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and the like and, furthe-r preferably, a Ceo aryl group and the like (for example, phenyl , l-naphthyl, 2-naphthyl and the like, preferably phenvl and the li ke) and the like. As "substituents" of "aromatic 34

Amended Sheet 2003-01-30

* hydrocarbon group optionally having substituents" represented by

R’, there are the same substituents as substituents of "aromatic group optionally having substituents" represented by RZ.

As R’, a Ce aryl group optionally having substituents is breferable and, among them, a Cg;4 aryl group optionally substituted with 1 or 2 Cj. alkyl (for example, methyl, ethyl and + the like) or C, alkoxy (for example, methoxy, ethoxy and the like) is preferable and, in particular, a phenyl group optionally substituted with 1 or 2 C,4 alkyl or Cig alkoxy (for example, 3- methoxyphenyl, 2-methylphenyl, 2,4-dimethylphenyl and the like) is suitable.

In the aforementioned formula, X represents an oxygen atom or an optionally oxidized sulfur atom.

As "optionally oxidized sulfur atom" represented by X, there are S, SO and SO0,.

As X, there is preferably an optionally oxidized sulfur atom. Further preferably, it is S.

In the aforementioned formula, Y represents a bond, an

OXygen atom, an optionally oxidized sulfur atom or the formula NR® (wherein R* represents a hydrogen atom, a hydrocarbon group optionally having substituents or an acyl group).

As "optionally oxidized sulfur atom" represented by Y, there are S, SO and SO,.

As "hydrocarbon group optionally having substituents" represented by RY, for example, there is the same group as "hydrocarbon group optionally having substituents" represented by

R®. Among them, a Cj-s alkyl group such as methyl, ethyl and the like and, in particular, a C;-3 alkyl group such as methyl and the like is preferable.

As "acyl group" represented by RY, there is the same group as "acyl group" represented by R'.

As Y, an oxygen atom, an optionally oxidized sulfur atom, a group represented by the formula NR' (wherein R' represents the same meaning as that described above) and the like are preferable and, among them, an oxygen atom, an optionally oxidized sulfur atom, a group represented by the formula NR" (R‘' represents a hydrogen atom or a Ci.¢ alkyl group) and the like are preferable and, further, an oxygen atom, S, SO,, NH, N(CH;) and the like are

Amended Sheet 2003-01-30

® preferable and, in particular, O or NH is suitable.

In the aforementioned formula, Z represents a bond or a divalent acyclic hydrocarbon group optionally having substituents.

As "divalent acyclic hydrocarbon group” of "divalent acyclic hydrocarbon group optionally having substituents", for example, there are a Cj-15 alkylene group (for example, methylene, ethylene, propylene, butylene, pentamethylene, hexamethylene, heptamethylene, octamethylene and the like, preferably a Ci-s alkylene group and the like), a C-16 alkenylene group (for example, vinylene, propylene, l-butenylene, 2-butenylene, l-pentenylene, 2- pentenylene, 3-pentenylene and the like), a C,-;¢ alkynylene group (ethynylene, propynylene, l-butynylene, 2-butynylene, 1- pentynylene, 2-pentynylene, 3-pentynylene and the like) and the like, preferably, a C;-;5 alkylene group, particularly preferably, a Cis alkylene group and the like. As "substituents" of "divalent acyclic hydrocarbon group optionally having substituents" represented by Z, for example, there are the same substituents as "substituents" of "hydrocarbon group optionally having substituents" represented by R°.

As Z, a lower alkylene group optionally having C:-3 alkyl (for example, methyl), oxo and the like (for example, a C;-s alkylene group such as methylene, ethylene, propylene and the like, in particular, a C;-3 alkylene group) is preferable and, among them, a Cy-¢ alkylene group optionally having oxo (for example, a Ci-3 alkylene group such as methylene, ethylene, propylene, in particular, methylene) is suitable.

More particularly, as Z, -CH,—, -{(CH;),-, -(CHy)s~, -CO-, -CH,CO-, -(CH;),CO-, -CH(CH3)- and the like are used and, in particular, -CH,-, -CO- and the like are suitable.

A nitrogen atom in Compound (I) may be N-oxidized. For example, a nitrogen atom which is a constituent atom of 4-pyridyl group as a substituent at 5-position of a ring represented by the formula:

X

CS

N wherein a symbol in the formula represents the same meaning as that described above, may be N-oxidized. As Compound (I), for

* example, a compound represented by the formula: ©), ir )

RN wherein n represents 0 or 1, and other symbols represents the same meanings as those described above, or salts thereof are preferable.

As Compound (I), compounds shown by the following (A) to (F) are preferably used. (A) Compound (I) wherein R' is an amino group optionally having substituents, R? is a Cs. aryl group optionally having substituents, R® is a Ce-14 aryl group optionally having substituents, X is a sulfur atom, Y is an oxygen atom or a group represented by the formula NR! (wherein R represents the same meaning as that described above) or (and) 2 is a lower alkylene group optionally having substituents. (B) Compound (I) wherein R! is (1) a C16 alkyl group (for example, a Ci-¢ alkyl group such as methyl, ethyl, propyl, butyl and the like), (11) a Cg-qy aryl group (for example, a phenyl group) optionally substituted with substituents selected from Cis alkylthio (for example, methylthio), Ci. alkylsulfonyl (for example, methylsulfonyl) and halogen atom (for example, chlorine atom, fluorine atom), or (iii) an amino group optionally having 1 or 2 acyl represented by the formula: -(C=0)-R®' [wherein R®' represents Da C,6 alkyl group (for example, C,.; alkyl group such as methyl and the like), @a

Ce-14 aryl group (for example, a phenyl group) or @a 5 to 14 membered heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms (for example, a 5 to ¢ membered heterocyclic group containing 1 to 2 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms such as a pyridyl group);

R® is a Ceyy aryl group (for example, a phenyl group, & naphthyl group) optionally substituted with halogen atom (for example, chlorine atom, fluorine atom) or Cj; alkoxy (for exarple, 37

Amended Sheet 2003-01.2n

Ce methoxy), or a 5 to 14 membered aromatic heterocyclic group containing 1 to 4 hetercatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms (for example, a 5 to 6 membered aromatic heterocyclic group containing 1 to 2 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms such as a pyridyl group, a thienyl group and the like};

R® is a Cg14 aryl group (particularly, a phenyl group) optionally substituted with 1 or 2 Cy alkyl (for example, methyl) or Ci¢ alkoxy (for example, methoxy);

X is a sulfur atom;

Y is an oxygen atom, an optionally oxidized sulfur atom or a group represented by the formula NR!' (R!' is a hydrogen atom or a Ci-¢ alkyl group) (in particular, an oxygen atom, S$, SO;, NH,

N(CHs;) and the like):

Z is a Cys alkylene group (in particular, a C;-3 alkylene group) optionally having oxo or C;-¢ alkyl (for example, C;_3 alkyl such as methyl) or a bond. (C) Compound (I) wherein R' is an amino group optionally having 1 or 2 acyl represented by the formula -(C=0)-R°" (wherein R®" represents (Da Cs-14 aryl group (for example, phenyl group) or @a 5 to 14 membered heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms (for example, a 5S tc 6 membered heterocyclic group containing 1 to 2 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms such as a pyridyl group):

R? is a Cg¢.14 aryl group (for example, a phenyl group) or a 5 to 14 membered aromatic heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms (for example, a 5 to 6 membered aromatic heterocyclic group containing 1 to 2 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms such as a pyridyl group);

R® is a Ces aryl group (in particular, a phenyl group) optionally substituted with 1 or 2 C;¢ alkyl (for example, methyl) or Ci. alkoxy (for example, methoxy);

®

X is a sulfur atom;

Y is O, NH or S;

Z is a bond or a C;-¢ alkylene group (in particular, a Ci-3 alkylene group optionally having oxo, such as methylene, ethylene 8 and the like) optionally having oxo. (D) Compound (I) prepared in Examples 1-79. (E) [4-(3,5-dimethylphenyl)-5-(2-phenylmethyloxy-4-pyridyl)-1, 3- thiazol-2~-yl]amine (Example Compound No. 1),

N-[4-[2-benzoylamino-4- (4-methoxyphenyl)-1, 3-thiazol-5-y1]-2- pyridyl]lbenzamide (Example Compound No. 2),

N-[4- (4-methoxyphenyl)-5-[2-[ (3-pyridylcarbonylamino) ]-4-pyridyl]- 1,3-thiazol-2-yl]nicotinamide (Example Compound No. 3),

N-[4-[2-amino-4- (4-methoxyphenyl)-1, 3-thiazol-5-yl]-2- pyridyl]lbenzamide (Example Compound No. 4),

N-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5~yl]-2- pyridyl]benzamide (Example Compound No. 5),

N-[4-[2-amino-4- (3, 5-dimethylphenyl)-1, 3-thiazol-5-yl]-2- pyridyllbenzylamine (Example Compound No. 6),

N-[4-[2-amino-4- (3, 5-dimethylphenyl)-1, 3-thiazol-5~yl]-2- pyridyllbenzamide hydrochloride (Example Compound No. 7),

N-[4-[2-amino-4- (3, 5-dimethylphenyl)-1, 3-thiazol-5-yl]-2- pyridyl]lbenzylamine dihydrochloride (Example Compound No. 8). (F) N-[5-[2-benzoylamino-4-pyridyl)-4-(3, 5-dimethylphenyl)-1, 3- thiazol-2-yl]acetamide (Example Compound No. 9),

N-[5-(2-benzylamino-4-pyridyl)-4-(3,5-dimethylphenyl)-1,3-thiazol- 2-yl)acetamide (Example Compound No. 10),

N-[4-[4- (4-methoxyphenyl)-2-methyl~-1,3-thiazol-5-yl]-2~ pyridyl]benzamide (Example Compound No. 13),

N-[4~-[2-(4-fluorophenyl)-4- (3-methylphenyl)-1, 3-thiazol-5-yl]-2- pyridyllphenylacetamide (Example Compound No. 14),

N-[4-[2~ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2~ pyridyl]lphenylacetamide (Example Compound No. 15-2),

N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2- pyridyl]phenylacetamide (Example Compound No. 15-3),

N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2- pyridyl]lphenylacetamide (Example Compound No. 15-4),

N~[4-[4- (3-methylphenyl)-2- (4-methylthiophenyl) -1, 3-thiazol-5-yl]- 2-pyridyllphenylacetamide (Example Compound No. 15-6),

®

N-[4~-[2-ethyl-4- (3-methylphenyl)-1,3-thiazol-5-yl]}-2- pyridyl]benzamide (Example Compound No. 16-1),

N-[4-[2-ethyl-4- (3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3- phenylpropionamide (Example Compound No. 16-2), 8 N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3- (4-methoxyphenyl)propionamide (Example Compound No. 16-3},

N-(4-[2-ethyl-4- (3-methylphenyl)-1,3-thiazol-5-yl]}-2-pyridyl]-4- phenylbutyramide (Example Compound No. 16-5),

N-[4-[4- (3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2- pyridyllbenzamide (Example Compound No. 16-7),

N-[4-[4- (3-methylphenyl)-2-propyl-1, 3-thiazol-5-yl]-2-pyridyl]-3- phenylpropionamide (Example Compound No. 16-8),

N-{4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2- pyridyllbenzamide (Example Compound No. 16-9),

N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5~yl]-2-pyridyl]-3- phenylpropionamide (Example Compound No. 16-10),

N-[4-[2-(4-fluorophenyl)-4- (3-methylphenyl)-1,3-thiazol-5-yl]-2- pyridyllbenzamide (Example Compound No. 16-11),

N-[4-[2- (4-fluorophenyl) -4- (3—-methylphenyl)-1,3-thiazol-5-yl]-2- pyridyl]-3-phenylpropionamide (Example Compound No. 16-12),

N-[4-[4- (3-methylphenyl)-2- (4-methylthiophenyl)~-1,3-thiazol-5-yl]- 2-pyridyl]benzamide (Example Compound No. 16-15),

N-[4-[4- (3-methylphenyl)-2- (4-methylthiophenyl)-1,3-thiazol-5-yl]- 2-pyridyl]-3-phenylpropionamide (Example Compound No. 16-16),

N-benzyl-N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2~ pyridyl]amine (Example Compound No. 19-2),

N-[4-[2-ethyl-4~(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N- (2-phenylethyl) amine (Example Compound No. 19-3),

N-[4-[2-ethyl-4- (3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N- (3-phenylpropyl)amine (Example Compound No. 19-4),

N-benzyl-N-[4-[4- (3-methylphenyl)-2-propyl-1, 3-thiazol-5-yl]-2- pyridyllamine (Example Compound No. 19-5),

N-[4-[4- (3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N- (2-phenylethyl) amine (Example Compound No. 19-6),

N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N- (3~-phenylpropyl) amine (Example Compound No. 19-7),

N-benzyl-N-[4-[2-butyl-4- (3-methylphenyl)~-1, 3-thiazol-5-yl]-2~ pyridyllamine (Example Compound No. 19-8),

N-[4-[2-butyl-4-(3-methylphenyl)-1, 3~thiazol-5-yl]-2—pyridyl]-N- (2-phenylethyl) amine (Example Compound No. 19-9),

N-[4~-[2-butyl-4- (3-methylphenyl)-1, 3~thiazol-5-yl]-2—pyridyl]-N- (3-phenylpropyl) amine (Example Compound No. 19-10),

N-benzyl-N-[4-[4~ (3-methylphenyl)-2- (4-methylthiopherayl)-1, 3- thiazol-5-yl]-2-pyridyl)amine (Example Compound No. 19-17),

N-[4-[4- (3-methylphenyl)-2- (4-methylthiophenyl) -1,3-t=hiazol-5-yl]- 2-pyridyl]-N-(2-phenylethyl)amine (Example Compound Mo. 13-18),

N-[4-[4- (3-methylphenyl)-2- (4-methylthiophenyl)-1,3-tthiazol-5-yl]- 2-pyridyl]-N- (3-phenylpropyl)amine (Example Compound No. 19-19),

N-[4-[4- (3-methylphenyl)-2- (4-methylsulfonylphenyl)-1, 3-thiazol-5- yl]-2-pyridyl]lbenzamide (Example Compound No. 20),

N-[4-[4- (3-methylphenyl)-2- (4-methylsulfonylphenyl)-1, 3-thiazol-5- yl]l-2-pyridyl]phenylacetamide (Example Compound No. 21-1},

N-[4-[4-(3-methylphenyl)-2- (4-methylsulfonylphenyl)-_11, 3-thiazol-5- yl]l-2-pyridyl]-3-phenylpropicnamide (Example Compouncd No. 21-2},

N-benzyl-N-[4-[4- (3-methylphenyl)}-2-(4-methylsulfony_lphenyl)-1, 3- thiazol-5-yl]-2-pyridyl]amine (Example Compound No. 21-5),

N-[4-[4- (3—methylphenyl)-2-(4-methylsulfonylphenyl)-11, 3-thiazol-5- yl]-2-pyridyl]-N-(3-phenylpropyl)amine (Example Compcound No. 21-6),

N-[4-[4- (3—-methylphenyl) -2- (4-methylsul fonylphenyl)-"1, 3-thiazol-5- yl]-2-pyridyl]-N- (2-phenylethyl) amine (Example Compouind No. 25-1),

N- (4-fluorobenzyl)-N-[4-[4- (3-methylphenyl)-2-(4- methylsulfonylphenyl)-1, 3-thiazol-5~-yl]-2-pyridyl]am—ne (Example

Compound No. 25-2).

As a salt of Compound (I), for example, there are a metal salt, ammonium salt, a salt with an organic base, salt with an inorganic acid, a salt with an organic acid, a salt with basic or acidic amino acid and the like. As a suitable metal salt, there are alkali metal salt such as sodium salt, potassium salt and the like; alkaline earth metal salt such as calcium salt , magnesium "salt, barium salt and the like; aluminum salt and thee like. As a suitable example of a salt with an organic base, for example, there are salts with trimethylamine, triethylamine, poyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine , triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'- dibenzylethylenediamine and the like. As a suitable example of a salt with an inorganic acid, for example, there are salts with

$ hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. As a suitable example of a salt with an organic acid, for example, there are salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. As a suitable example of a salt with a basic amino acid, for example, there are salts with arginine, lysine, ornithine and the like. As a suitable example of a salt with an acidic amino acid, for example, there are salts with aspartic acid, glutamic acid and the like.

Among them, pharmaceutically acceptable salts are preferable. For example, when a compound has an acidic functional group therein, there are inorganic salts such as alkali metal salts (for example, sodium salt, potassium salt and the like), alkaline earth metal salts (for example, calcium salt, magnesium salt, barium salt and the like), ammonium salts and the like and, when a compound has a basic functional group therein, there are salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, and salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid and the like.

A process for producing Compound (I) will be described below. Compound (Ia), (Ib), (Ic) or (1d) is a compound included in Compound (I).

Compound (I) is obtained by a method shown by the following reaction formulas 1, 2, 4 and 5 or a similar method to that.

Respective symbols in compounds in the following reaction formulas 1, 2, 4 and S have the same meanings as those described above. Compounds in the reacticn formulas include sa.ts thereof and, as the salts, for example, there are the same as those of

Compound (I). £2 Amended Sheet 2003-01-30 r (Reaction formula 1]

H

Hy R2-2-OH 3 oS (ain oS 1) Base BOY! —_— —_— 2L pz

Br Fg DR? - R~” ~~ oN

Base 2) RT CoL (ny (Iv) (W) vi)

KN

Halogenatiaon NX 0 RICSNH, (VII) EIA P S 1

I a p=

Hal R N vil) (la)

Hydrolysis PP S Halogena=tion Hal S a 1 —— Pil —_—— DR

RYN R=" N (PS) ©

R*-Z-YH x (X1) REIN NF S _— Ps Hal : Halogen

Base rR No (1b)

Compounds (II), (III), (Vv), (VIII), (XI), (XII), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXVI) and (XXVII) can be used as they are when they are commercially available or can be prepared by a method known Per se or according to the similar method to this.

Compound (IV) can be obtained koy condensing Compound (II) and Compound (III) in the presence of a base.

An amount of Compound (III) to be used is about 0.5 to about 3 moles, preferably about 0.8 to about 2 moles rela-ive to 1 mole of Compound (II).

An amount of a base to be used i.s about 1 to about 30 moles, preferably about 1 to about 10 moles re=lative to i mole of

Compound (II).

As the "base", for example, ther-e are basic salts such as sodium carbonate, potassium carbonates, cesium carbcnate, sodium 43

Amended Sheet 2003-01-30

® acetate and the like, an inorganic base such as sodium hydroxide, potassium hydroxide and the like, an aromatic amine such as pyridine, lutidine and the like, a tertiary amine such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N- dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N- methylmorpholine and the like, an alkali metal hydride such as sodium hydride, potassium hydride and the like, a metal amide such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide and the like, a metal alkoxide such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like.

It is advantageous that this reaction is conducted without a solvent or in the presence of an inert solvent. Although the solvent is not particularly limited as long as the reaction proceeds, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, amides, alcohols, water or a mixture of two or more of them are used.

A reaction temperature is usually about -5 to about 200°C, preferably about 5 to about 150°C. A reaction time is usually about 5 minutes to about 72 hours, preferably about 0.5 to about 20 hours.

Although the reaction product can be used as the reaction solution itself or as a crude product in the next step, it can be isolated from the reaction mixture according to the conventional method and can be easily purified by a separating means such as recrystallization, distillation, chromatography and the like.

Compound (VI) can be obtained by treating Compound (IV) with a base and condensing the obtained compound with Compound (V).

In Compound (V), L represents a leaving group. As "leaving group” denoted by L, for example, there are D C;-s alkoxy (for example, methoxy, ethoxy and the like), ® di-Ci alkylamino (for example, dimethylamino, diethylamino and the like), @ N-Cs.10 aryl-

N-Ci;-¢ alkylamino (for example, N-phenyl-N-methylamino and the like), @ 3 to 7 membered cyclic amino (for example, pyrrolidino, morpholino, methylaziridin-1-yl and the like) optionally substituted with Ceo aryl and (or) C,-s alkyl, ® N-C;_s alkyl-N-C_g alkoxyamino (N-methoxy-N-methylamino and the like) and the like.

Further, as "leaving group" denoted by L, for example, there are a4

® hydroxy, halogen atom (for example, fluorine, chlorine, bromine, iodine and the like), optionally halogenated C;.s alkylsulfonyloxy (for example, methanesulfonyloxy/, ethanesulfonyloxy, trichloromethanesul fonyloxy and the like),

Cs-10 arylsulfonyloxy optionally having substituents and the like.

As "Cg-10 arylsulfonyloxy optiona lly having substituents", for example, there are C¢-10 arylsulf onyloxy (for example, phenylsulfonyloxy, naphthylsulfonyloxy and the like) optionally having 1 to 3 substituents selected from C;.¢ alkyl, C,.¢ alkoxy and nitro. Examples thereof are benwzenesulfonyloxy, m- nitrobenzenesul fonyloxy, p-toluenesulfonyloxy and the like.

An amount of a base to be used is about 0.8 to about 3 moles, preferably about 1 to about 1.2 moles relative to 1 mole of

Compound (IV).

As the "base", for example, metal amides such as sodium amide, lithium diisopropylamide,~ lithium hexamethyldisilazide and the like are used.

It is advantageous that tthis reaction is conducted without a solvent or in the presence of an inert solvent for a reaction.

The solvent is not particularly limited as long as a reaction proceeds but, for example, aliphatic hydrocarbons, aromatic hydrocarbons, ethers or a mixture of two or more of them and the like are used.

A reaction temperature is usually about -78 to about 60°C, preferably about -78 to about 20°C. A reaction time is usually about 5 minutes to about 24 hour-s, preferably about 0.5 to about 3 hours.

Although a product can be used as the reaction solution itself or as a crude product in the next reaction, it can be isolated from the reaction mixtuire by the conventional method, and can be easily purified by a separating means such as recrystallization, distillation. chromatography and the like.

Compound (VII) can be obttained by treating Compound (VI) with halogens or a metal halide. This reaction is performed in the presence of a base or a basic salt if desired.

An amount of halogens or a metal halide to be used is about 1 to about 5 moles, preferably &bout 1 to about 2 moles relative bo to 1 mole of Compound (VI).

As the "halogens", there are bromine, chlorine, iodine and the like.

As the "metal halide", there are Copper halides such as copper (II) bromide, copper (II) chloride and the like.

An amount of a base to be used is about 1 to about 30 moles,

Preferably about 1 to about 10 moles relative to 1 mole of

Compound (VI).

As the "base", for example, there are inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate and the like, aromatic amines such as pyridine, lutidine and the like, tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, d-dimethylaminopyridine, N, N- dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N- methylmorpholine and the like.

It is advantageous that this reaction is performed without a solvent or in the presence of an inert solvent’ for a reaction.

The solvent is not particularly limited as long as a reaction broceeds but, for example, ethers, esters, aromatic hydrocarbons, aliphatic hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, organic acids, aromatic amines or a mixture of two or more of them and the like are used.

A reaction temperature is about -20 to about 150°C, preferably about 0 to about 100°C. A reaction time is usually about S minutes to about 24 hours, preferably about 10 minutes to about 5 hours.

Although a product can be used as the reaction solution itself or as a crude product in the next reaction, it can be isolated from the reaction mixture by the conventional method, and can be easily purified by a separating means such as recrystallization, distillation, chromatography and the like.

Compound (Ia) can be obtained by condensing Compound (VII) : with Compound (VIII). This reaction is performed in the presence of a base if desired.

In Compound (VII), Hal represents halogens.

When Compound (VIII) is Commercially available, it can be 46 Amended Sheet 2003-01-30

« used as it is, or can be obtained by the method known per se or a

Method accordingr to the known method or further a method shown in the reaction formula 3.

An amount of Compound (VIII) to be used is about 0.5 to about 3 moles, p referably about 0.8 to about 2 moles relative to 1 mole of Compound (VII).

An amount of a base to be used is about 1 to about 30 moles, preferably about 1 to about 10 moles relative to 1 mole of

Compound (VII).

As the "base", for example, there are alkali metals such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate and the like, aromatic amines such as pyridine, lutidine and the like, tertiary amines such as triethylamine, tripropylamine, tributylamine, : cyclohexyldimethy-lanmine, 4-dimethylaminopyridine, N, N- dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N- ] methylmorpholine and the like.

It is advamtageous that this reaction is performed without a solvent or in the presence of an inert solvent for a reaction.

The solvent is nortt particularly limited as long as a reaction proceeds but, for example, halogenated hydrocarbons, aliphatic hydrocarbons, arormatic hydrocarbons, ethers, amides, alcohols, nitriles or a mixture of two or more of them and the like are used.

A reaction temperature is about -5 to about 200°C, preferably about 5 to about 150°C. A reaction time is usually about 5 minutes toe about 72 hours, preferably about 0.5 to about hours.

Although a product can be used as the reaction solution itself or as a crude product in the next reaction, it can be isolated from the reaction mixture by conventional methods, and can be easily purified by a separating means such as recrystallization, distillation, chromatography and the like.

Compound (IX) can be obtained by treating Compound (Ia) with an acid.

An amount of an acid to be used is about 1 to about 100 moles, preferably about 1 to about 30 moles relative to 1 mola of

Compound (Ia). 47

Amended Sheet 2003-01-30

®

As the "acid", for example, there are mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like, organic acids such as acetic acid, propionic acid, trifluoroacetic acid and the like.

This reaction is performed in the presence of an inert solvent for a reaction. The solvent is not particularly limited as long as a reaction proceeds but, for example, water, a mixture of water and amides, a mixture of water and alcohols and the like are used.

A reaction temperature is usually about 20 to about 200°C, preferably about 60 to about 150°C. A reaction time is usually about 30 minutes to about 72 hours, preferably about 1 to about 30 hours.

Compound (X) is obtained by treating Compound (IX) with a halogenating agent.

An amount of a halogenating agent to be used is about 1 to about 10 moles, preferably about 1 to about 5 moles relative to 1 mole of Compound (IX).

As the "halogenating agent”, there are thionyl chloride, phosphorus pentachloride, phosphorus oxychloride and the like.

It is advantageous that this reaction is performed without a solvent or in the presence of an inert solvent for a reaction.

The solvent is not particularly limited as long as a reaction proceeds but, for example, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, organic acids, aromatic amines or a mixture of two or more of them and the like are used.

A reaction temperature is usually about -20 to about 150°C, preferably about 0 to about 100°C. A reaction time is usually about 5 minutes to about 24 hours, preferably about 10 minutes to about 5 hours.

Although a product can be used as the reaction solution itself or as a crude product in the next reaction, it can be isolated from the reaction mixture by the conventional method, and can be easily purified by a separating means such as recrystal lization, distillation, chromatography and the like.

Coempound (Ib) can be obtained by condensing Compound (X) with Compound (XI). This reaction is performed in the presence of a base iff desired.

Arm amount of a base to be used is about 0.8 to about 30 moles, pr-eferably about 1 to about 10 moles relative to 1 mole of

Compound (X).

Ass the "base", for example, there are basic salts such as sodium casrbonate, potassium carbonate, cesium carbonate and the like, inoorganic bases such as sodium hydroxide, potassium hydroxide= and the like, aromatic amines such as pyridine, lutidine and the l1.ike, tertiary amines such as triethylamine, tripropyl amine, tributylamine, cyclohexyldimethylamine, 4- dimethylaaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N- methylpyr-rolidine, N-methylmorpholine and the like, alkali metal hydrides such as sodium hydride, potassium hydride and the like, metal ami des such as sodium amide, lithium diisopropylamide, lithium mexamethyldisilazide and the like, metal alkoxides such as sodium me=thoxide, sodium ethoxide, potassium tert-butoxide and the like.

It= is advantageous that this reaction is performed without a solvent= or in the presence of an inert solvent for a reaction.

The solvesnt is not particularly limited as long as a reaction proceeds but, for example, aliphatic hydrocarbons, aromatic hydrocarloons, ethers or a mixture of two or more of them and the like are used.

A reaction temperature is usually about -78 to about 200°C, preferably about room temperature to about 170°C. A reaction time is usually about 5 minutes to about 72 hours, preferably about 0.5 to about 24 hours.

Al _though a product can be used as the reaction solution itself or- as a crude product in the next reaction, it can be isolated from the reaction mixture by the conventional method, and can be ea,sily purified by a separating means such as recrystal_ lization, distillation, chromatography and the like.

" CL [Reaction formula 2]

H

Hy . 3 1) Base

AN ("Bac) ,0 | x» (BuLi, etc.) NN i —_—— t ——— t AA 3

NH NH Boc , BocN R 2 2) RCOL

Xin) (X11) Vv) X1v)

I aN

Halogenat ion AS R'CSNH, (VII) . P " —_— + PP 3 —_— a BocN 1

BocN R |)

RYN

Hal (XV) (Xvi) xX R2-7L ~~

Deprotection y _ S XVID REZAN = S 3 % : 3 N

RYN R

Xvi 1) (lc)

L : leaving group ‘Boc : t-butoxycarbony

Bu : butyl

Compound (XIII) is obtained from Compound (XII) by a method described in Synthesis, p.p.877-882, 1996 or Journal of Organic

Chemistry, vol.é61l, p.p. 4810-4811, 1996.

Compound (XIV) is obtained by treating Compound (XIII) with a base and condensing the obtained compound with Compound (V).

An amount of a base to be used is about 0.8 to about 5 moles, preferably about 2 to about 2.5 moles relative to 1 mole of Compound (XIII).

As the “base”, for example, alkyllithiums such as n- butyllithium and the like and metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide and the like are used.

It is advantageous that this reaction is performed without a solvent or in the presence of an inert solvent for a reaction. The solvent is not particularly limited as long as a reaction proceeds but, for example, aliphatic hydrocarbons, arcmatic hydrocarbons, ethers or a mixture of two or more of them and the like are used. 50

Amended Sheet 2003-01-30

A Co

A reaction temperature is usually about -78 to about 60°C,

Preferably about -78 to about 20°C. A reaction time is usually &pout 5S minutes to about 24 hours, preferably about 0.5 to abou: 3

Hours.

Although a product can be used as the reaction solution ii.tself or as a crude product in the next reaction, it can be isolated from the reaction mixture by the conventional method, and

Can be easily purified by a separating means such as rCecrystallization, distillation, chromatography and the like.

Compound (XV) can be obtained by treating Compound (XIV) with halogens or a metal halide. This reaction is performed oeptionally in the presence of a base or a basic salt.

An amount of halogens or a metal halide to be used is about 1 to about S moles, preferably about 1 to about 2 moles relative to 1 mole of Compound (XIV).

As the "halogens", there are bromine, chlorine, iodine and the like.

As the "metal halide", there are copper halide such as ceopper (II) bromide, copper (II) chloride and the like. So

An amount of a base to be used is about 1 to about 10 moles, preferably about 1 to about 3 moles relative to 1 mole of Compound (XIV).

As the "base", for example, there are alkali metals such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate, sodium acetate and the like, aromatic amines such as pyridine, lutidine and the like, tertiary amines such as triethylamine, tripropylamine, tr-ibutylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine,

N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N- mesthylmorpholine and the like.

It is advantageous that this reaction is performed without & solvent or in the presence of an inert solvent for a reaction.

Th e solvent is not particularly limited as long as a reaction pr oceeds but, for example, ethers, esters, aromatic hydrocarbons, al iphatic hydrocarbons, amides, halogenated hydrocarbons, nitriles, su.lfoxides, organic acids, aromatic amines or a mixture of two or more of them and the like are used. 51

Amended Sheet 2003-01-30

®

Compound (XVI) can be obtained by condensing Compound (XV) and Compound (VIII). This reaction is performed optionally in the presence of a base.

In Compound (XV), Hal represents halogens.

When Compound (VIII) is commercially available, it can be used as it is, or is obtained by the method known per se or a method according to the known method, or further by a method shown by the following reaction formula 3. :

An amount of Compound (VIII) to be used is about 0.5 to about 3 moles, preferably about 0.8 to about 2 moles relative to 1 mole of Compound (XV).

Compound (XV).

As the "base", for example, there are basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate, sodium acetate and the like, aromatic amines such as pyridine, lutidine and the like, tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N- dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N- methylmorpholine and the like.

The solvent is not particularly limited as long as a reaction proceeds but, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, amides, alcohols, nitriles or a mixture of two or more of them and the like are used.

A reaction temperature is about -5 to about 200°C,

® preferably about 5 to about 150°C. A reaction time is usually about 5 minutes to about 72 hours, preferably about 0.5 to about 30 hours.

Although a product can be used as the reaction solution & itself or as a crude product in the next reaction, it can be isolated from the reaction mixture by the conventional method, and can be easily purified by a separating means such as recrystallization, distillation, chromatography and the like.

Compound (XVII) is obtained by deprotecting Compound (XVI) 1 using an acid or a base.

An amount of an acid or a base to be used is about 0.1 to about 50 moles, preferably about 1 to about 20 moles relative to 1 mole of Compound (XVI).

As the "acid", for example, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like,

Lewis acids such as boron trichloride, boron tribromide and the like, the use of Lewis acid together with thiols or sulfides, organic acids such as trifluoroacetic acid, p-toluenesulfonic acid and the like 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 are used.

The solvent is not particularly limited as long as a reaction proceeds but, for example, alcohols, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, halogenated hydrocarbons, sulfoxides, water or a mixture of two or more of them and the like are used.

A reaction time is usually about 10 minutes to about 50 hours, preferably about 30 minutes to about 12 hours. A reaction temperature is about 0 to about 200°C, preferably about 20 to about 120°C.

Compound (Ic) can be obtained by condensing Compound (XVII) with Compound (XVIII) optionally in the presence of a base.

An amount of Compound (XVIII) to be used is about 0.8 to

® about 5 moles, preferably about 1 to about 3 moles relative to 1 mole of Compound (XVII).

An amount of a base to be used is about 0.1 to about 3 moles, preferably about 0.3 to about 1.2 moles relative to 1 mole of Compound (XVII).

As the "base", for example, there are basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate and the like, inorganic base such as sodium hydroxide, potassium hydroxide and the like, aromatic amines such as pyridine, lutidine and the like, tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline,

N-methylpiperidine, N-methylpyrrolidine,

N-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.

A reaction temperature is usually about -78 to about 100°C, preferably about -78 to about 70°C. A reaction time is usually about 5 minutes to about 24 hours, preferably about 0.5 to about 20 hours.

Thereafter, compounds wherein R! is other than hydrogen atom can be synthesized by performing alkylation or acylation if desired.

® : [Reaction formula 3] . RH i

R CONCS —— 3» R’CONH-C—R

XIX) (XX)

R'CN

H,S (XX1) ~~

R'ICONH, — = R'CSNH, (XX11) PS VI)

Lawesson reagent

Compound (XX) is obtained by condensing Compound (XIX) and amines represented by the formula R°H.

R® represents "amino optionally having substituents" represented by the above-mentioned R'.

In Compound (XIX), R® represents an alkoxy group. As the "alkoxy group", for example, there are a Ci-¢ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like.

An amount of the "amines" to be used is about 1 to about 30 moles, preferably about 1 to about 10 moles relative to 1 mole of

Compound (XIX).

The solvent is not particularly limited as long as a reaction proceeds but, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, amides, alcohols, nitriles, ketones or a mixture of two or more of them and the like are used.

A reaction temperature is about -5 to about 200°C, preferably about 5 to about 120°C. A reaction time is usually about 5 minutes to about 72 hours, preferably about 0.5 to about 30 hours.

Compound (VIII) is obtained by hydrolysing Compound (XX) using an acid or a base.

An amount of an acid or a base to be used is about 0.1 to about 50 moles, preferably about 1 to about 20 moles relative to 1 mole of Compound (XX), respectively.

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, sodium acetate 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 are used.

Compound (VIII) can be obtained by treating Compound (XXI) with hydrogen sulfide in the presence of a base.

An amount of hydrogen sulfide is about 1 mole to about 30 moles relative to 1 mole of Compound (XXI).

Compound (XXI).

As the "base", for example, there are aromatic amines such as pyridine, lutidine and the like, tertiary amines such as

® triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N- dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N- methylmorpholine and the like, ammonia and the like.

The solvent is not particularly limited as long as a reaction proceeds but, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, aromatic amines or a mixture of two or more of them and the like are used.

This reaction is performed under atmospheric pressure or under pressurized condition. A reaction temperature is usually about -20 to about 80°C, preferably about -10 to about 30°C. A reaction time is usually about 5 minutes to about 72 hours, preferably about 0.5 to about 30 hours.

Compound (VIII) can also be obtained by treating Compound (XXII) with phosphorus pentasulfide or Lawesson’s reagent.

An amount of phosphorus pentasulfide or Lawesson’s reagent to be used is about 0.5 to about 10 moles, preferably about 0.5 to about 3 moles relative to 1 mole of Compound (XXII).

The solvent is not particularly limited as long as a reaction proceeds but, for example, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, halogenated hydrocarbons or a mixture of two or more of them and the like are used.

A reaction time is usually 10 minutes to about 50 hours, preferably about 30 minutes to about 12 hours. A reaction temperature is usually about 0 to about 150°C, preferably about 20 to about 120°C.

Although a product (VIII) can be used as the reaction solution itself or as a crude product in the next reaction, it can be isolated from the reaction mixture by the conventional method,

® and can be easily purified by a separating means such as recrystallization, distillation, chromatography and the like.

When Compound (I) (including Compound (Ia), (Ib) and (Ic)) is acylamino compound, an objective compound can be also obtained by subjecting the corresponding amine compound to an acylating reaction known per se.

For example, among Compound (I), a compound wherein R! is acylamino group optionally having substituents is obtained by reacting the corresponding 2-thiazolamine and an acylating agent optionally in the presence of a base or an acid.

An amount of an acylating agent to be used is about 1 to about 5 moles, preferably about 1 to about 2 moles relative to 1 mole of the corresponding 2-thiazolamine.

As the "acylating agent”, for example, there are carboxylic acids corresponding to an objective acyl group or a reactive derivative thereof (for example, acid halide, acid anhydride, ester and the like) and the like.

An amount of a base or an acid to be used is about 0.8 to about 5 moles, preferable about 1 to about 2 moles relative to 1 mole of the corresponding 2-thiazolamine.

As the "base", for example, there are triethylamine, pyridine, 4-dimethylaminopyridine and the like.

As the "acid", for example, there are methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid and the like.

The solvent is not particularly limited as long as a reaction proceeds but, for example, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, aromatic amines or a mixture of two or more of them and the like are used.

A reaction temperature is about -20 to about 150°C, preferably about 0 to about 100°C. A reaction time is usually 5 minutes to about 24 hours, preferably about 10 minutes to about 5 hours.

Although a product can be used as the reaction solution itself or as a crude product in the next reaction, it can be isolated from the reaction mixture by the conventional method, and

® can be easily purified by a separating means such as recrystallization, distillation, chromatography and the like.

Compound (Id) is also obtained by a method shown by the reaction formula 4 or a method according that method. [Reaction formula 4]

AN

Peroxy acid, Hydrogen peroxide or

Rey pu — > Reo pu

R: | / Alkyl hydroperoxide PS | / €)] (1d)

Compound (Id) is obtained by treating Compound (I) with an organic peroxy acid.

An amount of an organic peroxy acid to be used is about 0.8 to about 10 moles, preferable about 1 to about 3 moles relative to 1 mole of Compound (I).

As the "organic peroxy acid", for example, there are peracetic acid, trifluoroperacetic acid, m-chloroperbenzoic acid and the like.

The solvent is not particularly limited as long as a reaction proceeds but, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, organic acids, ethers, amides, sulfoxides, alcohols, nitriles, ketones or a mixture of two or more of them and the like are used.

A reaction temperature is about -20 to about 130°C, preferably about 0 to about 100°C. A reaction time is usually 5 minutes to about 72 hours, preferably about 0.5 to about 12 hours.

Alternatively, Compound (Id) is also obtained by treating

Compound (I) with hydrogen peroxide or alkyl hydroperoxide optionally in the presence of a base, an acid or a metal oxide.

An amount of hydrogen peroxide or alkyl hydroperoxide to be used is about 0.8 to about 10 moles, preferably about 1 to 3 moles to 1 mole of Compound (I).

As the "alkyl hydroperoxide", for example, there are tert- butyl hydroperoxide, cumene hydroperoxide and the like.

An amount of a base, an acid or a metal oxide to be used is

® about 0.1 to about 30 moles, preferably 0.8 to absout 5 moles relative to 1 mole of Compound (I).

As the "base", for example, there are inoreganic bases such as sodium hydroxide, potassium hydroxide and the .like, basic salts such as sodium carbonate, potassium carbonate, so«dium acetate and the like.

As the "acid", for example, there are 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.

As the "metal oxide", for example, there axe vanadium oxide (V20s) , osmium tetroxide (0s0Q,), tungsten oxide (W&D;), molybdenum: oxide (MoOs;), selenium dioxide (Se0,;), chromium ox-ide (CrO;) and the like.

It is advantageous that this reaction is peerformed without a solvent or in the presence of an inert solvent for a reaction.

The solvent is not particularly limited as long a=s a reaction proceeds but, for example, halogenated hydrocarboms, aliphatic hydrocarbons, aromatic hydrocarbons, organic acidss, ethers, amides, sulfoxides, alcohols, nitriles, ketones or a mixtwire of two or more of them and the like are used.

A reaction temperature is about -20 to abomut 130°C, preferably about 0 to about 100°C. A reaction time is usually 5 minutes to about 72 hours, preferably about 0.5 te about 12 hours.

Although a product can be used as the reaction solution itself or as a crude product in the next reaction , it can be : isolated from the reaction mixture by the convent_iocnal method, and can be easily purified by a separating means such as recrystallization, distillation, chromatography amd the like.

Alternatively, Compound (Ic) is also obtaimned by a method shown by the following reaction formula 5:

(Reaction formula 5]

R'-2L

BSH Deprotection a (XVID —_— 3 —_— “BocN ’ H,

XIV) Xxii . =

Halogenation eR: 3 ——— pe 3

H

H Hal (XXIV) (XXV) 9 1

R'CSNH, (VI11) REX — > l, DR

R RS

(lc)

Compound (XXIII) is obtained by deprotecting Compound (XIV) using an acid or a base.

An amount of an acid or a base to be used is about 0.1 to about 50 moles, preferably about 1 to about 20 moles relative to one mole of Compound (XIV), respectively.

The solvent is not particularly limited as long as a reaction

[ proceeds but, for example, alcohols, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, halogenated hydroscarbons, sulfoxides, water or a mixture of two or more of them and the like are used.

A reaction time is usually about 1 0 minutes to about 50 hours, preferably about 30 minutes to about 12 hours. A reaction temperature is about 0 to about 200°C, preferably about 20 to about 120°C.

Although a product can be used as the reaction solution itself or as a crude product in the next reaction, it can be isolated from the reaction mixture by the conventional method, and can be easily purified by a separating me ans such as recrystallization, distillation, chromato graphy and the like.

Compound (XXIV) is obtained by con densing Compound (XXIII) and Compound (XVIII) optionally in the pr esence of a base.

An amount of Compound (XVIII) to be used is about 0.8 to about 5 moles, preferably about 1 to about 3 moles relative to one mole of Compound (XXIII).

An amount of a base to be used is about 0.1 to about 3 moles, preferably about 0.3 to about 1.2 mmoles relative to 1 mole of Compound (XXIII).

As the "base", for example, basic salts such as sodium carbonate, potassium carbonate, cesium ca. rbonate, sodium acetate and the like, inorganic bases such as sodi:ium hydroxide, potassium hydroxide and the like, aromatic amines s.uch as pyridine, lutidine and the like, tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyl dimethylamine, 4- dimethylaminopyridine, N,N-dimethylanilimie, N-methylpiperidine, N- methylpyrrolidine, N-methylmorpholine andl 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.

It is advantageous that this reactzion is performed without a solvent or in the presence of an inert solvent for a reaction.

The solvent is not particularly limited ams long as a reaction proceeds but, for example, aliphatic hydr-ocarbons, aromatic hydrocarbons, ethers, water or a mixture of two or more of them and the like are usad. 2 rezction temperature is ustaily about -78 to about 100°C,

Preferably about -78 to about 70°C. A reaction time is usually about S minutes to about 24 hours, preferably about 0.5 to about hours.

Although a product can be used as the reaction solution : itself or as a crude product in the next reaction, it can be isociated from the reaction mixture by the conventional method, and

Can be easily purified by a separating means such as recrystallization, distillation, chrematography and the like.

Compound (XXV) is obtained by treating Compound (XXIV) with a halogen or a metal halide. This reaction is performed optionally in the presence of a base or a basic salt.

The amount of halogen or a metal halide to be used is about 1 to about 5 moles, preferably about 1 to about 2 moles relative to one mole of Compound (XXIV).

As the "halogens", there are bromine, chlorine, iodine and the like.

As the "metal halide", there are copper halide such as copper (II) bromide, copper (II) chloride and the like.

An amount of a base to be used is about 1 to about 10 moles, preferably about 1 to about 3 moles relative to 1 mole of Compound (XXIV).

As the "base", for example, there are alkali metals such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate, sodium acetate and the like, aromatic amines such as pyridine, lutidine and the like, tertiary amines such as triethylamine, tripropylanine, tributylamine, cyclohexyldimethylamine, ¢-dimethylaminopyridine,

N,N-dimethylaniline, N-nethylpiperidine, N-methylpyrrolidine, N- methylmorpholine and the like.

The sclvent is not particularly limited as long as a reaction proceeds but, for example, ethers, esters, aromatic hydrocarbons, aliphatic hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, organic acids, aromatic amines or & mixture of two or €3

Amended Sheet 2003-01-30

® more of them and the like are used.

A reaction temperature is usually about -20 to about 150°C, preferably about 0 to about 100°C. _A reaction time is usually about 5 minutes to about 24 hours, preferably about 10 minutes to about 5 hours.

Although a product can be used as the reaction solution itself or as a crude product in the next reaction, it can be isolated from the reaction mixture ky the conventional method, and can be easily purified by a separating means such as recrystallization, distillation, chromatography and the like.

Compound (Ic) is obtained by condensing Compound (XXV) and

Compound (VIII). This reaction is poerformed optionally in the presence of a base.

In Compound (XXV), Hal represents halogens.

An amount of Compound (VIII) to be used is about 0.5 to about 3.0 moles, preferably about 0 .8 to about 2 moles relative to 1 mole of Compound (XXV).

An amount of a base to be used is about 1 to about 30 moles, preferably about 1 to about 10 mole=s relative to 1 mole of

Compound (XXV).

As the "base", for example, there are basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate, sodium acetate amd the like, aromatic amines such as pyridine, lutidine and the _like, tertiary amines such as triethylamine, tripropylamine, trib-utylamine, cyclohexyldimethylamine, 4-dimethyl.aminopyridine, N, N- dimethylaniline, N-methylpiperidine , N-methylpyrrolidine, N- methylmorpholine and the like.

The solvent is not particularly lim ited as long as a reaction proceeds but, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons , ethers, amides, alcohols, nitriles or a mixture of two or mor e of them and the like are used.

A reaction temperature is usually about -5 to about 200°C, preferably about 5 to about 150°C. A reaction time is usually about 5 minutes to about 72 hours, preferably about 0.5 to about 30 hours.

Mn

Although a product can be used as the reaction solution itself or as a crude product in the next reaction, it can be isolated from the reaction mixture by the conventional metrod, and can be easily purified by a separating means such as recrystallization, distillation, chromatography and the like.

Thereafter, if desired, compounds other than a compound wherein R! is hydrogen atom may be synthesized by performing alkylation or acylation. (Reaction formula 6)

NX 1) Base NX 0 Halogenation » —

Hal’ CH, 2) RCOL (V) Hal’ Rr? (XXV1) (XXVI1)

XX

NX 0 R'CSNH, (VII1) —_— = S , = Hal’

Hal R’ | )—¢ 3 N

Hal R (XXVIII) x)

Hal, Hal’: Halogen + Compound (XXVII) is obtained by treating Compound (XXVTI) with a base and condensing the obtained compound with Compound (V).

In Compound (XXVI), Hal' represents a halogen atom such as fluorine, chlorine, bromine and iodine.

An amount of a base to be used is about 0.8 toc about 5 moles, preferably about 1 to about 1.2 moles relative to 1 mole of

Compound (XXVI).

As the "base", for example, alkyllithiums such as n- butyllithium and the like, metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide and the like are used.

It is advantagecus that this reaction is performed without a solvent or in the presence of an inert solvent for a reaction.

The solvent is rot particularly limited as long as a reaction proceeds but, for example, aliphatic hydrocarbons, aromatic hydrocarbons, ethers or a mixture of two or more of them and the 65

Amended Sheet 2003-01-30

- . like are used.

A reaction temperature is usually about -78 to about 60°C, preferably about -78 to about 20°C. A reaction time is usually about 5 minutes to about 24 hours, preferably about 0.5 to about 3 hours.

Although a product. can be used as the reaction soluticn itself or as a crude prodiuct in the next reaction, it can be isolated from the reactio-n mixture by the conventional method, and can be easily purified by" a separating means such as recrystailization, distil laticn, chromatography and the like.

Compound (XXVIII) is obtained by treating Compound (XXVII) with halogens or a metal halide. This reaction is performed optionally in the presenc e of a base or a basic salt.

In Compound (XXVIII ), Hal' represents a halogen atom such as fluorine, chlorine, bromi ne and iodine.

An amount of halog ens or a metal halide to be used is about 1 to about 5 moles, prefe rably about 1 to about 2 moles relative to one mole of Compound (XXVII).

As the "halogens", there are bromine, chlorine, iodine and the like.

An amount of a base to be used is about 1 to about 10 moles, preferably about 1 to about 3 moles relative to 1 mole of Compound (XXVII).

As the "base", for example, there are alkali metals such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate, sodium acetate and the like, aromatic amines such as pyridine, lutidine and the like, tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine,

N,N-dimethylaniline, N-metthylpiperidine, N-methylpyrrolidine, N- methylmorpholine and the like.

It is advantageous that this reaction is performed without a solvent or in the preserace of an inert solvent for a reaction.

The solvent is not particularly limited as long as a reaction rroceeds but, for example, ethers, esters, aromatic hydrocarbons, 66

Amended Sheet 2003-01-30

® aliphatic hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, organic acids, aromatic amines or a mixture of two or more of them and the like are used.

Compound (X) is obtained by condensing Compound (XXVIII) and Compound (VIII). This reaction is performed optionally in the presence of a base.

In Compound (XXVIII), Hal and Hal' denote halogen atoms such as fluorine, chlorine, bromine and iodine.

An amount of Compound (VIII) to be used is about 0.5 to about 3 moles, preferably about 0.8 to about 2 moles relative to 1 mole of Compound (XXVIII).

Compound (XXVIII).

A reaction temperature is usually about -5 to about 200°C,

Although a pmoduct can be used as the reaction solution itself or as a crude product in the next reaction, it can be isolated from the resaction mixture by the conventional method, and can be easily purif-ied by a separating means such as recrystallization, distillation, chromatography and the like.

In the above respective reactions, when starting compounds have amino, carboxy. hydroxy as substituents, a protecting groups which are generally used in the peptide chemistry or the like may be introduced into %these groups and, after reaction, a desired compound can be obtained by removing protecting groups if needed.

As a protectDing group for amino, for example, formyl or Cig alkyl-carbonyl (for example, acetyl, propionyl and the like), phenylcarbonyl, C;.¢ alkoxy-carbonyl (for example, methoxycarbonyl, ethoxycarbonyl and %the like), phenyloxycarbonyl, Ci-i10 aralkyloxy- carbonyl (for example, benzyloxycarbonyl and the like), trityl, phthaloyl and the l1Zke which may have substituents, respectively, are used. As these substituents, halogen atoms (for example, fluorine, chlorine, bromine, iodine and the like), Ci-¢ alkyl- carbonyl (for example, acetyl, propionyl, valeryl and the like), nitro and the like are used and the number of substituents is 1 to 3.

As a protectzing group for carboxy, for example, Cji_¢ alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like), phen=yl, trityl, silyl and the like which may have substituents, respeectively, are used. As these substituents, halogen atoms (for esxample, fluorine, chlorine, bromine, iodine and the like), form=yl, Cis alkyl-carbonyl (for example, acetyl, propionyl, butylcark®oonyl and the like), nitro, Cis alkyl (for example, methyl, ethyl, tert-butyl and the like), Cs-10 aryl (for example, phenyl, napohthyl and the like) and the like are used and the number of substituents is 1 to 3.

As a protecting group for hydroxy, for example, Ci-¢ alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like), phenwyl, Ci; aralkyl (for example, benzyl and the like), formyl, Cis aalkyl-carbonyl (for example, acetyl, propionyl and the like), phenyloxycarbonyl, C;-11 aralkyloxy-carbonyl (for example, benzyloxycarbonyl and the like), tetrahydropyranyl, tetrahydrofuranyl, silyl and the like which may have substituents, respectively, are used. As these substituents, halogen atoms (for example, fluorine, chlorine, bromine, iodine and the like), Ci-s alkyl (for example, methyl, ethyl, tert-butyl and the like), Ci-n1 aralkyl (for example, benzyl and the like), Ce-10 aryl (for example, phenyl, naphthyl and the like), nitro and the like are used and the number of substituents is 1 to 4.

In addition, as a method of removing a protecting group, the method known per se or a method according to this method is used and, for example, method by treating with an acid, a base, the ultraviolet ray, hydrazine, phenylhydrazine, sodium N- methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate and the like or a method of reduction is used.

In any cases, Compound (I) can be synthesized by further, optionally, performing the known deprotection, acylation, alkylation, hydrogenation, oxidation, reduction, carbon chain extension and substituent exchange reaction alone or in a 90 combination of two or more of them. As these reactions, the reactions described in Shinjikkenkagakukoza 14, vol.15, 1977 (Maruzen Press) are adopted.

As the above "alcohols", for example, there are methanol, ethanol, propanol, isopropanol, tert-butanol and the like.

As the above "ethers", for example, there are diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, dioxane, 1,2- dimethoxyethane and the like.

As the above "halogenated hydrocarbons", for example, there are dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride and the like.

As the above "aliphatic hydrocarbons", for example, there are hexane, pentane, cyclohexane and the like.

As the above "aromatic hydrocarbons", for example, there are benzene, toluene, xylene, chlorobenzene and the like.

As the above "aromatic amines", for example, there are pyridine, lutidine, quinoline and the like.

As the above "amides", for example, there are N,N- dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric wa : _ triamide and the like.

Ass the above "ketones", for example, there are acetone, methyl ethyl ketone and the like.

Ass the above "sulfoxides", for example, there are dimethyl sulfoxides and the like.

As the above "nitriles", for example, acetonitrile, propionit rile and the like.

As the above "organic acids", for example, there are acetic acid, pro pionic acid, trifluoroacetic acid and the like.

Wh en a desired product is obtained in a free form by the above reaction, it may be converted into a salt according to the conventiomal method or, when a desired product is obtained as a salt, it ecan be converted into a free form or another salt according to the conventional method. Compound (I) thus obtained © can be isolated and purified from the reaction solution by the known mearns, for example, trans-solvation, concentration, solvent exXtractior, fractional distillation, crystallization, recrystalM ization, chromatography and the like.

When Compound (I), (Ia), (Ib), (Ic) or (Id) is present as a configurat-ional isomer, diastereomer, conformer or the like, each can be opt-ionally isolated by the above separation and purification means. In addition, Compound (I), (Ia), (Ib), (Ic) or (Id) iss in the form of its racemate, they can be separated into

S- and R-fTorms by any conventional optical resolution.

Whe n Compound (I), (Ia), (Ib), (Ic) or (Id) exists as a

Sstereoisom.er, both the isomers alone and mixtures of each isomers are includ ed in the scope of the present invention.

In .addition, Compound (I), (Ia), (Ib), (Ic) or (Id) may be hydrated o r anhydrous.

Compoound (I) may be labeled with an isctope (for example,

H, Yc, ¥S) or the like.

A pxodrug of Compound (I) refers to a compound which is converted into Compound (I) by an enzvme, gastric acid or the like under the physiological conditions, that is, a compound which undergoes enzymatic oxidation, reduction, hvdrolysis or the like to be convesrted into Compound (I), and a compound which undergoes nydrolysis or the like by gastric acid or the like to be converted into Compound (I). As a prodrug of Compound (I), there are z 70 Amended Sheet 2003-01-30

EW compound in which an amino group of Compound (I) is acylated, alkylated or phosphorylated (for example, a compound in which an amino group of Compound (I) is elcosanoylation, alanylation, pentylaminocarbonylation, {5-methyl-2-o0xo0-1, 3-dioxolen-4- yl)methoxycarbonylation, tetrahydrofuranylation, pyrrolidinylmethylation, pivaloyloxymethylation, tert-butylation); a compound in which a hydroxy group of Compound (I) is acylated, alkylated, phosphorylated or boronylated (for example, a compound in which a hydroxy group of Compound (I) is acetylated, _palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated); a compound in which a carboxy group of Compound (I) is esterified or amidated (a compound in which a carboxy group of Compound (I) is ethylesterified, phenylesterified, carboxymethylesterified, dimethylaminomethylesterified, pivaloyloxymethylesterified, ethoxycarbonyloxyethylesterified, phthalidylesterified, (5-methyl- 2-oxo-1,3~dioxolen-4-yl)methylesterified, : cyclohexyloxycarbonylethylesterified, methylamidated); and the like. These compounds can be prepared from Compound (I) by methods known per se.

Alternatively, a prodrug of Compound (I) may be a compound which is changed into Compound (I), (Ia), (Ib), (Ic) or (Id) under the physiological conditions described in "Iyakuhin no kaihatsu", published by Hirokawashoten in 1990, vol.7, Molecular Design, pages 163-198.

Compound (I) of the present invention shows the high affinity for adenosine receptor, in particular, A; receptor and has low toxicity and minimal side effect and, therefore, is useful as a safe drug.

A pharmaceutical composition of the present invention containing Compound (I) shows an excellent adenosine A; receptor antagonistic activity to a mammal (for example, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human being and the like) and is also excellent in (oral) absorption, (metabolism) stability and the like and, therefore, can be used as an agent for preventing or treating adenosine A; receptor-related diseases, for example, asthma, allergic disease, inflammation, Addison's disease, autoimmune hemolytic anemia, Crohn's disease, psoriasis, 1 Amended Sheet 2003-01-30

® rheummatism, central nervous disease (for example, cerebrovascular disease such as cerebral hemorrhage, cerebral infarction, head trauma, spinal trauma, brain edema, multiple sclerosis and the like) , neurodegenerative disease (for example, Alzheimer's disease,

Parkiinson's syndrome, amyotrophic lateral sclerosis (ALS)), diabestes and the like. Preferably, Compound (I) is an agent for preventing or treating central nervous disease, asthma, allergic disease and the like.

Compound (I) of the present invention also shows an excellent p38 MAP kinase inhibitory activity and TNF-a inhibitory actiwity (TNF-a production inhibitory activity, TNF-a action inhibitory activity) and is also useful as a safe drug based these actiwities.

For example, a pharmaceutical composition of the present invermtion containing Compound (I) can be used as an agent for preveanting or treating p38 MAP kinase related diseases and TNF-a related disease, for example, arthritis (for example, rheumatoid arthmwritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, synowitis), toxemia (for example, sepsis, septic shock, endotoxin shock, Gram-negative sepsis, toxic shock syndrome), inflammatory bowel disease (for example, Crohn's disease, ulcerative colitis), inflammatory pulmonary disease (for example, chronic pneumonia, silicosis, pulmonary sarcoidosis, pulmonary tuberculosis), or cachexia (for example, cachexia derived from infection, carcdnocachexia, cachexia derived from acquired immunodeficiency syndrome (AIDS)), arteriosclerosis, Creutzfeldt-Jakob disease, viruss infection (for example, virus infection such as cytormegalovirus, influenzavirus, herpesvirus and the like), atopic dermatitis, systemic lupus erythematosus, AIDS encephalopathy, menimgitis, angina, cardiac infarction, congestive heart failure, hepat#titis, transplantation, dialysis hypotension, disseminated intravascular coagulation and the like to a mammal (for example, mouse=, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human being and the like). Preferably, Compound (I) is used as an agent for preventing or treating rheumatism and the like.

A preparation of the present invention containing Compound (I) has low toxicity and can be safely administered orally or paremterally (for example, locally, rectally or intravenously or

® the like) as it is or by mixing Compound (I) with a pharmacologically acceptable carrier into, for example, pharmaceutical preparations such as tablet (including dragee, film coated-tablet and the like), powders, granules, capsules (including soft capsules), solutions, injections, suppositories, sustained releasing preparations and the like according to the method known per se normally used in preparation of pharmaceutical preparations. A content of Compound (I) in a preparation of the present invention is about 0.01 to 100% by weight relative to the whole preparation. A dose is different depending upon an administration subject, route of administration, diseases and the like and the preparation may be administered, ‘as an adenosine Aj; receptor antagonistic agent, for example, as an oral agent to an asthma patient (weight about 60 kg), about 0.1 to about 30 mg active ingredient (Compound (I))/kg weight per day, preferably about 1 to 20 mg/kg weight per day, once or a few times per day.

As a pharmacologically acceptable carrier which may be used for preparing a preparation of the present invention, there are the conventional various organic or inorganic carriers as a pharmaceutical material, for example, excipient, lubricant, binder and disintegrating agent in solid preparations, or solvent, solubilizing agent, suspending agent, isotonicity, buffer and soothing agent in liquid preparations. Further, if needed, additives such as the conventional preservative, antioxidant, colorant, sweeting agent, adsorbing agent, wetting agent and the like can be appropriately used at an appropriate amount.

As an excipient, for example, there are lactose, sucrose,

D-mannitol, starch, corn starch, crystalline cellulose, light silicic acid anhydride and the like.

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

As a binder, for example, there are crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methyl cellulose, sodium carboxymethyl cellulose and the like.

As a disintegrating agent, for example, there are starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium

® carboxymethyl starch, L-hydroxypropyl cellulose and the like.

As a solvent, for example, there are water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.

As a solubilizing agent, for example, there are polyethylene glycol, propylene glycol, D~mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.

As a suspending agent, for example, there are surfactants such as stearyl triethenolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate and the like; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydoxypropyl cellulose and the like.

As an isotonicity, for example, there are glucose, D- sorbitol, sodium chloride, glycerin, D-mannitol and the like.

As a buffer, for example, there are buffering solutions such as phosphate, acetate, carbonate, citrate and the like.

As a soothing agent, for example, there are benzyl alcohol and the like.

As a preservative, for example, there are p- hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.

As an antioxidant, for example, there are sulfites, ascorbic acid, o~tocopherol and the like.

The present invention will be explained in detail by way of the following Reference Examples, Examples, Preparation Examples 30: and Test Examples but these are more examples and not limit the present invention and can be varied without departing the scope of the present invention. "Room temperature" in the following Reference Examples and

Examples indicates normally about 10°C to about 35°C. "&" 3% indicates percentage by weight unless otherwise indicated, provided that yield represents mol/mol%.

Abbreviations used elsewhere indicate the following meanings:

®

Ss: singlet d: doublet t: triplet dq: quartet dd: double doublet ddd: double double doublet dt: double triplet br: broad

J: coupling constant

Hz: Hertz

CDCl;: deuterated chloroform

H-NMR: proton nuclear magnetic resonance spectrum

Me: methyl

Examples

Reference Example 1: 2-phenylmethyloxy-4-methylpyridine

Sodium hydride (60% paraffin dispersion, 5.0g, 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 mmol) in tetrahydrofuran (50 mL) at 0°C and then, the mixture was allowed to warm up to room temperature with stirring for 15 minutes. To this solution was added a solution of 2-bromo-4-methylpyridine (19.5 mL, 110 mmol) in tetrahydrofuran (50 mL) and heated to reflux for 14 hours. To the reaction mixture was added water (200 mL) and extracted with ethyl acetate. The extract was dried and the solvent was distilled off. The crude product was distilled under reduced pressure to obtain 13 g of the title compound (67 mmol, yield 67%).

Boiling point 116-118°C (400 Pa)

H-NMR (CDCls) 6 :2.30 (3H, s), 5.37 (2H, s), 6.63 (1H, s), 6.72 (1H, 4, J=5.1Hz), 7.29-7.50 (5H, m), 8.03 (lH, d, J=5.1Hz)

Reference Example 2:

N- (3, 5-dimethylbenzoyl)propyleneimine 3, 5-Dimethylbenzoic acid (25 g, 0.17 mol) and N,N- dimethylformamide (0.1 mL) were added to thionyl chloride (50 mL) at 0°C. The mixture was heated to reflux for 2 hours. The excess thionyl chloride was distilled off under reduced pressure and toluene (50 mL) was added to the residue. Toluene was distilled

® off under reduced pressure to obtain oily 3, 5-dimethylbenzoyl chloride. A solution of propyleneimine (14 mL, 0.18 mol) in tetrahydrofuran (160 mL) was added to 1N aqueous sodium hydroxide (180 mL). To the solution was added dropwise 3, 5-dimethylbenzoyl chloride at 0°C. After complete 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 31 g of the title compound (0.16 mol, yield 99%).

Oily product

H-NMR (CDC15) 6 :1.39 (3H, d, J=5.5Hz), 2.13 (1H, d,

J=3.7Hz), 2.37(6H, s), 2.47-2.62 (2H, m), 7.19 (1H, s), 7.64 (2H, s)

Reference Example 3: 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 a solution of 1.6 M n-butyllithium in hexane (43 mL, 69 mmol) was added dropwise with stirring. After complete addition, the mixture was stirred for 10 minutes and subsequently a solution of 2-phenylmethyloxy—-4-methylpyridine (12 g, 62 mmol) in anhydrous tetrahydrofuran (12 mL) at -30°C. After additional stirring for 1h, a solution of N-(3,5-dimethylbenzoyl)propyleneimine (12 g, 62 mmol) in anhydrous tetrahydrofuran (12 mL) was added at -30°C.

After complete addition, the resulting mixture was allowed to warm up to room temperature and the mixture was stirred for 2 hours.

Water (60 mL) was added to the reaction mixture and extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane-ethyl acetate, 5:1) to obtain 89.1 g of the title compound (27 mmol, yield 443%).

Oily product

IH-NMR (CDCls3) 6 :2.37 (6H,s), 4.20 (2H, s), 5.37 (2H, s), 6.72 (1H, s), 6.81 (1H, 4, J=5.1Hz), 7.22 (1H, s), 7.30-7.49 (5H, m), 7.59 (2H, s), 8.12 (1H, d, J=5.1Hz)

Reference Example 4: 2-bromo-1-(3, 5-dimethylphenyl)-2-(2- phenylmethyloxy-4-pyridyl)ethanone hydrobromide 1-(3, 5-Dimethylphenyl)-2- (2-phenylmethyloxy-4-

® pyridyl) ethanone (3.3 g, 10 mmol) was dissolved in acetic acid (10 mL) and bromine (0.51 mL, 10 mmol) was added to the solution and stirred at room temperature for 30 minutes. The precipitated crude crystals were collected by filtration and washed with diethyl ether to obtain 4.8 g of the title compound (9.8 mmol, yield 98%). mp. 88-90°C

Reference Example 5: N-(4-methoxybenzoyl)propyleneimine

A solution of propyleneimine (25 mL, 0.36 mol) in tetrahydrofuran (200 mL) was added to 2N aqueous sodium hydroxide (180 mL). To this mixture was added dropwise a solution of 4- methoxybenzoyl chloride (51 g, 0.30 mol) in tetrahydrofuran (100 mL) at 0°C. After complete addition, the mixture was stirred further for 30 minutes. The reaction mixture was extracted with ethyl acetate. The extract was dried and the solvent was distilled off to obtain 49 g of the title compound (0.26 mol, yield 86%).

Oily product

H-NMR (CDCls) 6: 1.39 (3H, d, J=5.6Hz), 2.11 (1H, d,

J=3.0Hz), 2.51-2.57 (2H, m), 3.87 (3H, s), 6.94 (2H, d, J=8.8Hz), 8.00 (2H, d, J=8.8Hz)

Reference Example 6: 1-(4-methoxyphenyl)-2-(2-tert- butoxycarbonylamino—4-pyridyl) ethanone

A solution of 2-tert-butoxycarbonylamino-4-methylpyridine (20 g, 97 mmol) in anhydrous tetrahydrofuran (300 mL) was cooled to -78°C and a solution of 1.6 M n-butyllithium in hexane (140 mL, 0.22 mol) was added dropwise with stirring. After complete addition, the mixture was stirred at room temperature for 30 minutes. And then, the mixture was cooled to -78°C. A solution of

N-(4-methoxybenzoyl)propyleneimine in anhydrous tetrahydrofuran (50 mL) was added dropwise to the mixture. After complete addition, the mixture was stirred at room temperature for 2 hours.

Water (100 mL) and diisopropyl ether (300 mL} were added to the reaction mixture and the resulting crude crystals were collected by filtration. The crude crystals were recrystallized from tetrahydrofuran-hexane to obtain 23 g of the title compound (67 mmol, yield 69%). mp. 187-190°C

®

Reference Example 7: 4-[2-amino-4- (4-methoxyphenyl)-1,3-thiazol-5- yl}-2-pyridylamine

Bromine (0.68 mL, 13 mmol) was added to a solution of 1-(4- methoxyphenyl) -2~ (2-tert-butoxycarbonylamino-4-pyridyl) ethanone (4.5 g, 13 mmol) in acetic acid (100 mL) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated. The residue was dissolved in acetonitrile (40 mL) and to the solution was added thiourea (1.1 g, 14 mmol) and triethylamine (1.9 mL, 14 mmol) were added and the mixture was stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature and concentrated. A saturated aqueous sodium hydrogencarbonate (200 mL) was added to the residue and the resulting solid was collected by filtration and washed with water. 2N hydrochloric acid (35 mL) was added to the solids and the mixture was stirred at 100°C for 45 minutes. The reaction mixture was cooled to room temperature and, thereafter, 8N aqueous sodium hydroxide (10 mL) and a saturated aqueous solution of sodium hydrogencarbonate (100 mL) were added. The resulting crude crystals were collected by filtration, and were washed with water.

The crude crystals were recrystallized from ethanol to obtain 2.7 g of the title compound (9.1 mmol, yield 69%). mp. 251-254°C

Reference Example 8: 2-(2-amino-4-pyridyl)-1- (4-methoxyphenyl)ethanone 2N-hydrochleric acid (30 mL) was added to 1-(4- methoxyphenyl) -2- (2-tert-butoxycarbonylamino-4-pyridyl) ethanone (6.1 g, 18 mmol) and the mixture was stirred at 100°C for 2 hours.

The reaction mixture was cooled to room temperature and, thereafter, 8N-aqueous sodium hydroxide (10 mL) was added. The resulting crude crystals were filtered and washed with water. The crude crystals were recrystallized from tetrahydrofuran-hexane to obtain 4.0 g of the title compound (16 mmol, yield 92%). mp. 170-174°C

Reference Example 9: 2-(2-benzoylamino-4-pyridyl)-1-(4- methoxyphenyl)ethanone

Benzoyl chloride (4.4 g, 31 mmol) and 4- dimethylaminopyridine (0.57 g, 4.7 mmol) were added to a solution of 2-(2-amino-4-pyridyl)-1- (4-methoxyphenyl)ethanone (3.8 g, 16

® mmol) in N,N-dimethylacetamide (80 mL) and the mixture was stirred at 70°C for 12 hours. After the reaction mixture was cooled to room temperature, water (50 mL) was added. The mixture was extracted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of sodium chloride. The layer was dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in tetrahydrofuran (80 mL) and methanol (20 mL) and 1IN-aqueous solution of sodium hydroxide (50 mL) was added.

The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and water (100 mL) was added.

The mixture was extracted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of sodium chloride.

The layer was dried over magnesium sulfate, filtered and concentrated. The residue was recrystallized from ethyl acetate- hexane to obtain 3.1 g of the title compound (8.9 mmol, yield 57%). mp. 136-139°C

Reference Example 10: 1- (3, 5-dimethylphenyl)-2-(2-tert- butoxycarbonylamino-4-pyridyl) ethanone

A solution of 2-tert-butoxycarbonylamino-4-methylpyridine (17 g, 82 mmol) in anhydrous tetrahydrofuran (250 mL) was cooled to -78°C and a 1.6N solution of n-butyllithium in hexane (120 mL, 0.19 mol) was added dropwise with stirring. After complete addition, the mixture was stirred at 0°C for 30 minutes and cooled to -78°C. A solution of N-(3,5-dimethylbenzoyl)propyleneimine (21 g, 0.11 mol) in anhydrous tetrahydrofuran (50 mL) was added dropwise to the mixture. After complete addition, the mixture was stirred at room temperature for 2 hours. Water (100 mL) was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated. The residue was recrystallized from tetrahydrofuran-hexane to obtain 13 g of the title compound (37 mmol, yield 46%). mp. 133-136°C

Reference Example 11: 2- (2-amino-4-pyridyl)-1~ (3, 5~dimethylphenyl) ethanone 2N-hydrochloric acid (50 mL) was added to 1-(3,5- dimethylphenyl)-2-(2-tert-butoxycarbonylamino-4-pyridyl)ethanone

® (12 g, 36 mmol) and the mixture was stirred at 100°C for 1 hour.

After the reaction mixture was cooled to room temperature, an 8N aqueous solution of sodium hydroxide (15 mL) was added and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated. The residue was recrystallized from ethyl acetate to obtain 6.8 g of the title compound (28 mmol, yield 77%). mp. 123-126°C

Reference Example 12: 2-(2-benzoylamino-4-pyridyl)-1-(3,5- dimethylphenyl) ethanone

Benzoyl chloride (7.5 g, 53 mmol) and 4- dimethylaminopyridine (1.0 g,8.3 mmol) were added to a solution of 2-(2-amino—~4-pyridyl)-1-(3, 5-dimethylphenyl)ethanone (6.4 g, 27 mmol) in N,N-dimethylacetamide (100 mL) and the mixture was stirred at 70°C for 12 hours. After the reaction mixture was cooled to room temperature, water (50 mL) was added. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride. The layer was dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in a mixed solvent of tetrahydrofuran (150 mL) and methanol (40 mL) and 1N aqueous solution of sodium hydroxide (50 mL) was added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, water (100 mL) was added and neutralized with 2N-hydrochloric acid and a saturated aqueous solution of sodium hydrogencarbonate. The mixture was extracted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of sodium chloride. The layer was dried over magnesium sulfate, filtered and concentrated.

The residue was purified by silica gel column chromatography (hexane~ethyl acetate, 2:1) to obtain 6.4 g of the title compound (19 mmol, yield 70%).

Oily product

H-NMR (CDCl;3) 6 : 2.39 (6H, s), 4.33 (2H, s), 6.98 -7.01 (1H, m), 7.23 (1H, s), 7.45-7.58 (3H, m), 7.63 (2H, s), 7.89-7.94 (2H, m), 8.21 (1H, d, J=5.2Hz), 8.36 (lH, s), 8.71 (1H, br)

Reference Example 13

According to Reference Example 5 and using 3-methylbenzoyl

® chloride and 3-methoxybenzoyl chloride, respectively, instead of 4-methoxybenzoyl chloride, the following Reference Example compounds 13-1 and 13-2 were synthesized.

Reference Example compound 13-1:

N-(3-methylbenzoyl)propyleneimine

Oily product

H-NMR (CDCls) 6 : 1.39 (3H, d, J=5.5Hz), 2.14 (1H, d,

J=3.3Hz), 2.41 (3H, s), 2.51-2.66 (2H, m), 7.32-7.39 (2H, mm), 7.79-7.87 (2H, m).

Reference Example compound 13-2:

N- (3-methoxybenzoyl) propyleneimine

Oily product 'H-NMR (CDCl3) 6 : 1.40 (3H, d, J=5.9Hz), 2.14 (1H, d,

J=2.9Hz), 2.52-2.65 (2H, m), 3.86 (3H, s), 7.10 (1H, ddd, J=8.4, 2.6, 1.1Hz), 7.37 (1H, dd, J=8.4, 7.3Hz), 7.55 (1H, dd, J=2.6, 1.5Hz), 7.63 (1H, ddd, J=7.3, 1.5, 1.1Hz)

Reference Example 14

According to Reference Example 6 and using N-(3- methylbenzoyl)propyleneimine instead of N- (4- methoxybenzoyl)propyleneimine, the following Reference Example compound 14 was synthesized.

Reference Example compound 14: 2-(2-tert-butoxycarbonylamino-4- pyridyl) -1-(3-methylphenyl) ethanone mp. 144-146°C

Reference Example 15: 4- (methylthio)thiobenzamide 4-Methylthiobenzonitrile (12 g) was dissolved in a 4N solution of hydrogen chloride in ethyl acetate (130 mL). To this solution was added O,0-diethyl dithiophosphate (15 mL) and the mixture was stirred at room temperature for 22 hours. Water (100mL) was added to the reaction mixture and extracted with ethyl acetate. After the insoluble materials were filtered off, the filtrate was washed with a saturated aqueous solution of sodium chloride and dried and, thereafter, the sclvent was distilled off.

The residue was recrystallized from ethyl acetate to obtain 10 g of the title compound (yield 67 %). mp. 176-178°C

Reference Example 16:

According to Reference Example 15 and using 4-

® fluorobenzonitrile, 2-chlorobenzonitrile, butyronitrile and valeronitrile, respectively, instead of 4-methylthiobenzonitrile, the following Reference Example compounds 16-1 ~ 16-4 were synthesized.

Reference Example compound 16-1: 4-fluorothiobenzamide mp. 156-157°C

Reference Example compound 16-2: 2-chlorothiobenzamide mp. 58-59°C

Reference Example compound 16-3: Thiobutyramide

Oily product ‘H-NMR (CDCl3) 6: 0.99 (3H, t, J=7.6Hz), 1.72-1.93 (2H, m), 2.64 (2H, t, J=7.6Hz), 7.02 (lH, br s), 7.77 (1H, br s)

Reference Example compound 16-4: Thiovaleramide

Oily product

H-NMR (CDCl;) 6: 0.94 (3H, t, J=7.3Hz), 1.31-1.49 (2H, m), 1.68-1.83 (2H, m), 2.67 (2H, t, J=7.7Hz), 6.92 (1H, br s), 7.73 (1H, br s)

Reference Example 17: 4-[2-methyl-4-(3-methylphenyl)-1,3-thiazol- 5-yl]-2-pyridylamine

Bromine (1.0 mL, 18 mmol) was added to a solution of 2-(2- tert-butoxycarbonylamino-4-pyridyl)-1-(3- methylphenyl)ethanone (6.0 g, 18 mmol) in acetic acid (50 mL) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated. The residue was dissolved in

N,N-dimethylformamide (50 mL) and to the solution was added thicacetamide (1.4 g, 19 mmol) and the resulting mixture was stirred at room temperature for 20 hours. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate (200 mL) and extracted with ethyl acetate. The extract was dried and the solvent was distilled off. 2N-hydrochloric acid (30 mL) was added to the resulting solid and the mixture was stirred at 100°C for 1 hour. After the reaction mixture was cooled to room temperature, the mixture was basified with a 2N aqueous solution of sodium hydroxide (200 mL) and a saturated aqueous solution of sodiumhydrogen carbonate. The resulting mixture was extracted with ethyl acetate and the extract was washed with water. The extract was dried and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain 2.8 g

® of the title compound (yield 54%). mp. 152-153°C

Reference Example 18:

According to Reference Example 17 and using thiopropionamide and 4-(methylthio)thiobenzamide, respectively, instead of thioacetamide, the following Reference Example compounds 18-1 and 18-2 were synthesized.

Reference Example compound 18-1: 4-[2-ethyl-4-(3-methylphenyl)- l,3-thiazol-5-yl]-2-pyridylamine mp. 144-146°C

Reference Example compound 18-2: 4-[4-(3-methylphenyl)-2-(4~ methylthiophenyl)-1, 3-thiazol-5-yl]-2-pyridylamine mp. 181-183°C

Reference Example 19:

According to Reference Example 17 and using 1-(4- methoxyphenyl) ~2- (2-tert-butoxycarbonylamino-4-pyridyl) ethanone instead of 2-(2-tert- butoxycarbonylamino-4~-pyridyl) -1-(3- methylphenyl) ethanone, the following Reference Example compound 19 was synthesized.

Reference Example compound 19: 4-[4- (4-methoxyprhenyl)-2-methyl- 1,3-thiazol-5-yl]-2-pyridylamine np. 140-141°C

Reference Example 20:

According to Reference Example 8 and using 2-(2-tert- butoxycarbonylamino-4-pyridyl) -1- (3-methylphenyl)ethanone instead of 1-(4-methoxyphenyl)-2- (2-tert-butoxycarbonylamino-4- pyridyl) ethanone, the following Reference Example compound 20 was synthesized.

Reference Example compound 20: 2~(2-amino-4-pyridyl)-1-(3- methylphenyl) ethanone mp. 119-120°C

Reference Example 21: 2-(2-amino-4-pyridyl)-2-bromo-1-(3- methylphenyl) ethanone hydrobromide

Bromine (3.2 mL, 62 mol) was added to a solution of 2~(2- tert-butoxycarbonylamino-4-pyridyl)-~1-(3-methylphenyl)ethanone (20 g, 61 mmol) in acetic acid (60 mL) and the mixture was stirred at 80°C for 2 hours. After the reaction mixture was cooled to room

® temperature, the precipitate was filtered to obtain 19 g (yield 81%) of the title compound. mp. 182-185°C

Reference Example 22:

According to Reference Example 9 and using 2-(2-amino-4- pyridyl) -1-(3-methylphenyl)ethanone instead of 2-(2-amino-4- pyridyl) -1-(4-methoxyphenyl)ethanone, the following Reference

Example compound 22 was synthesized.

Reference Example compound 22: N-[4-(2-(3- methylphenyl)-2-oxoethyl]-2-pyridyl]benzamide mp. 67-69°C

Reference Example 23: 4-~[2-(4-fluorophenyl)-4-(3-methylphenyl)- 1,3-thiazol-5-yl]-2-pyridylamine 2-(2-Amino-4-pyridyl)-2-bromo-1- (3-methylphenyl)ethanone hydrobromide (5.0 g, 13 mmol) was dissolved in N,N- dimethylformamide (40 mL), to the solution was added 4- fluorothiobenzamide (2.1 g, 13 mmol) and the mixture was stirred at room temperature for 16 hours. A saturated aqueous solution of sodium hydrogencarbonate (200 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was dried and the solvent was distilled off. The residue was recrystallized from ethanol to obtain 3.9 g (11 mmol, yield 83%) of the title compound. mp. 160-162°C

Reference Example 24:

According to Reference Example 23 and using 2- chlorothiobenzamide, thiobutyramide and thiovaleramide, respectively, instead of 4-fluorothiobenzamide, the following

Reference Example compounds 24-1 - 24-3 were synthesized.

Reference Example compound 24-1: 4-(2-(2-chlorophenyl)-4-(3- methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine mp. 175-177°C

Reference Example compound 24-2: 4-[4-(3-methylphenyl)-2-propyl- 1,3-thiazol-5-yl]-2-pyridylamine mp. 113-115°C

Reference Example compound 24-3: 4-[2-butyl-4-(3-methylphenyl)- 1,3-thiazol-5-yl]-2-pyridylamine

Oily product

® "H-NMR (CDCl,) § : 0.98 (3H, t, J=7.3Hz), 1.39-1.59 (2H, m), 1.74-1.92 (2H, m), 2.34 (3H, s), 3.04 (2H, t, J=7.4Hz), 4.714 (2H, br s), 6.44 (1H, s), 6.56 (1H, dd, J=5.1, 1.5Hz), 7.09-7.26& (3H, m), 7.41 (1H, s), 7.96 (1H, d, J=5.4Hz)

Reference Example 25: 2-fluoro-4-methylpyridine

The title compound was obtained in the same manner &s described in Journal of Medicinal Chemistry, vol. 33, 1667—1675, 1990.

Boiling point 82-86°C (10kPa)

Reference Example 26: 2-(2-fluoro-4-pyridyl)-1-(3- methylphenyl)ethanone

A solution of diisopropylamine (44 mL, 0.31 mol) in anhydrous tetrahydrofuran (300 mL) was cooled to -78°C unde=r argon atmosphere and a 1.6M solution of n-butyllithium in hexane (190 mL, 0.31 mol) was added dropwise to the solution. After comple=te addition, the mixture was stirred for 10 minutes and subsecquently 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 at -10°C for 30 minutes. 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 completes addition, the mixture was stirred at room temperature for = hours.

Water (100 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed wzith water, dried and the solvent was distilled off. The residwme was recrystallized from isopropyl ether to obtain 35 g (yield 52%) of the title compound. mp. 66-67°C

Reference Example 27:

According to Reference Example 26 and using N-(3- methoxybenzoyl)propyleneimine instead of N-(3- methylbenzoyl)propyleneimine, the following Reference Exampole compound 27 was synthesized.

Reference Example compound 27: 2-(2-fluoro-4-pyridyl)-1-(3— methoxyphenyl) ethanone

Oily product

H-NMR (CDCl;) 6: 3.86 (3H, s), 4.31 (2H, s), 6.86 (JH, s),

® 7.03-7.19 (2H, m), 7.31-7.59 (3H, m), 8.18 (1H, d, J=5.6Hz)

Reference Example 28: [5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)- 1,3-thiazol-2-yl}amine

Bromine (1.9 mL, 37 mmol) was added to a solution of 2-(2- fluoro-4-pyridyl) -1-(3-methylphenyl)ethanone (8.5 g, 37 mmol) in acetic acid (50 mL) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated.

Triethylamine (5.2 mL, 37 mmol) was added to a mixture of this residue and thiourea (3.0 g, 40 mmol) in acetonitrile (50 mL) and the mixture was stirred at 80°C for 2 hours. A saturated aqueous solution of sodium hydrogencarbonate (50 mL) was added to the reaction mixture and the precipitated solid was collected by filtration. After the resulting solid was washed with water, it was dried. The crude crystals were recrystallized from ethanol to obtain 3.7 g (yield 35%) of the title compound. mp. 214-218°C

Reference Example 29:

According to Reference Example 28 and using 2-(2-fluoro-4- pyridyl) -1-(3-methoxyphenyl)ethanone instead of 2-(2-fluoro-4- pyridyl)-1-(3- methylphenyl) ethanone, the following Reference Example compound 29 was synthesized.

Reference Example compound 29: [5-(2-fluoro-4-pyridyl)-4-(3- methoxyphenyl)-1, 3-thiazol-2-yl] amine mp. 190-191°C

Reference Example 30: 5- (2~fluoro-4-pyridyl) -4- (3-methylphenyl) -2- (4-methylthiophenyl)-1,3-thiazole

Bromine (2.7 mL, 52 mmol) was added to a solution of 2-(2- fluoro-4-pyridyl) -1- (3-methylphenyl) ethanone (12 g, 53 mmol) in acetic acid (90 mL) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated.

This residue was dissolved in N,N-dimethylformamide (60 mL), 4- (methylthio) thiobenzamide (9.6 g, 52 mmol) was added and the mixture was stirred at room temperature for 15 hours. A saturated aqueous solution of sodium hydrogencarbonate (100 mL) was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane:ethyl acetate, 4:1) to obtain 4.7 g (yield 23%) of the title compound. mp. 97-100°C

Reference Example 31: 5-(2-fluoro-4-pyridyl)-4- (3-metlnylphenyl)-2- (4-methylsulfonylphenyl)-1, 3-thiazole

To a solution of 5-(2-fluoro-4-pyridyl)-4-(3- methylphenyl)~2- (4-methylthiophenyl)-1, 3-thiazole (2.# g, 6.9 mmol) in N,N-dimethylformamide (60 mL) was added m- chloroperbenzoic acid (3.3 g, 14 mmol) and the mixture was stirred at room temperature for 1 hour. An 8N aqueous solution of sodium hydroxide was added to the reaction mixture and the resulting solid was collected by filtration. This solid was rec:rystallized from ethanol to obtain 2.5 g (yield 85%) of the title compound. mp. 196-199°C

Example 1: [4-(3,5-dimethylphenyl)-5-(2- phenylmethyloxy-4-pyridyl)-1,3-thiazol-2-yl] amine

Triethylamine (1.4 mL, 10 mmol) was added dropwJise to a solution of 2-bromo-1- (3, 5-dimethylphenyl)-2- (2-phenyl methyloxy-4- pyridyl) ethanone hydrobromide (4.8 g, 9.8 mmol) and tlmiourea (0.77 g, 11 mmol) in acetonitrile (40 mL) and the mixture was stirred at room temperature for 3 hours. The solvent was removed. under reduced pressure, a saturated aqueous solution of sodium hydrogencarbonate was added to the residue and extract-ed with ethyl acetate. The organic layer was washed with wate r, dried and the solvent was distilled off. The resulting crude cr ystals were recrystallized from ethyl acetate to obtain 2.0 g (5.2 mmol, yield 53%) of the title compound. mp. 141-143°C

Example 2: N-[4-[2-benzoylamino-4- (4-methoxyphenyl) - 1,3-thiazol-5-yl]-2-pyridyllbenzamide

Benzoyl chloride (0.59 g, 4.2 mmol) and 4- dimethylaminopyridine (0.05 g, 0.4 mmol) were added to a solution of 4-[2-amino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]-2—pyridylamine (0.42 g, 1.4 mmol) in N,N-dimethylacetamide (10 mL) arad the mixture was stirred at 70°C for 19 hours. After the reaction mixture was cooled to room temperature, a saturated acgueous solution of sodium hydrogencarbonate (50 mL) was added. The resulting crude crystals were collected by filtration and washed with water. The crude crystals were recrystallized from ethanol to obtain 0.26 g (0.51 mmol, yield 37%) of the title compound. mp. 230-233°C

Example 3: N-[4-(4-methoxypheny)-5-[2-[(3- pyridylcarbonylamino)]-4-pyridyl]-1,3-thiazol-2-yl]lnicotinamide

Nicotinoyl chloride hydrochloride (0.72 g, 4.1 mmol) and 4- dimethylaminopyridine (0.05 g, 0.4 mmol) were added to a solution of 4-[2-amino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]-2-pyridylamine (0.41 g, 1.4 mmol) in N,N-dimethylacetamide (10 mL) and the mixture was stirred at 70°C for 19 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous solution of sodium hydrogencarbonate (50 mL) was added. The resulting crude crystals were collected by filtration and washed with water. The crude crystals were recrystallized from ethanol to obtain 0.23 g (0.44 mmol, yield 33%) of the title compound. mp. 229-232°C

Example 4: N-[4-[2-amino-4- (4-methoxyphenyl)-1, 3~- thiazol-5-yl]-2-pyridyl]lbenzamide

Bromine (0.11 mL, 2.1 mmol) was added to a solution of 2- (2-benzoylamino-4-pyridyl) -1- (4-methoxyphenyl) ethanone (0.72 gq, 2.1 mmol) in acetic acid (20 mL) at 0°C and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated. The residue was dissolved in acetonitrile (20 mL), to the solution were added thiourea (0.17 g, 2.2 mmol) and triethylamine (0.35 mL, 2.5 mmol) and the mixture was stirred at 80°C for 5 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous solution of sodium hydrogencarbonate (200 mL) was added and the resulting solid was filtered and washed with water. The resulting crude crystals were collected by filtration and washed with water. The crude crystals were recrystallized from ethanol to obtain 0.17 g (0.43 mmol, yield 21%) of the title compound. mp. 221-224°C

Example 5: N-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3~-thiazol-5- yl]-2-pyridyllbenzamide

Bromine (1.0 mL, 19 mmol) was added to a solution of 2-(2- benzoylamino-4-pyridyl)-1-(3, 5-dimethylphenyl)ethanone (6.4 g, 19 mmol) in acetic acid (80 mL) at 0°C and the mixture was stirred at

_ room temperature2 for 1 hour. The reaction mixture was concentrated. The residue was dissolved in acetonitrile (100 mL), to the solution were added thiourea (1.5 g, 19 mmol) and triethylamine (22.8 mL, 20 mmol) and the mixture was stirred at 80°C for 3 hours . After the reaction mixture was cooled to room temperature, a saturated aqueous solution of sodium hydrogencarbonat-e (200 mL) was added and the resulting solid was collected by fil tration and washed with water. The resulting crude crystals wiere collected by filtration and washed with water.

The crude crysteaals were recrystallized from ethanol to obtain 5.0 g (13 mmol, yield 68%) of the title compound. mp. 120-1.23°C

Example 6: N-[4—[2-amino-4- (3, 5-dimethylphenyl)-1,3-thiazol-5-yl]- 2-pyridyl]lbenzyl amine

Aluminum lithium hydride (0.16 g, 4.1 mmol) was added to a suspension of al uminum chloride (0.55 g, 4.1 mmol) in anhydrous tetrahydrofuran (30 mL) and the mixture was stirred at room temperature for 15 minutes. A solution of N-[4-[2-amino-4-(3,5- dimethylphenyl)—1,3-thiazol-5-yl]-2-pyridyl]benzamide (0.40 g, 1.0 mmol) in anhydrous tetrahydrofuran (10 mL) was added to the mixture and the resulting mixture was heated to reflux for 2 hours. :

After the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with a sarturated aqueous solution of sodium chloride, dried over magnesium ssulfate, filtered and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain 0.20 g (0.51 mmol, yiel.d 51%) of the title compound. mp. 99-10e2°C

Example 7: N-[4—[2-amino-4- (3, 5-dimethylphenyl)-1,3~thiazol-5-yl]- 2-pyridyl]benzamide hydrochloride

A 10% sol.ution of hydrogen chloride in methanol (10 mL) was added to a suspesnsion of N-[4~-[2-amino-4-(3,5-dimethylphenyl)-1, 3- thiazol-5-yl]-2—pyridyl]lbenzamide (0.45 g, 1.1 mmol) in methanol (30 mL) and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off and the residue was recrystallized f£from methanol to obtain 0.36 g (0.83 mmol, yield 73%) of the titl.e compound. mp. 202-2 07°C

WV

* Example 8: N-(4-{2-amino-4-(3, S-dimethylphenyl)-1,3-thiazol-5- yl]-2-pyridyl]lbenzylamine dihydrochloride oo

A 10% solution of hydrogen chloride in methanol {(10mL) was added to a suspension of N-[4-({2-amino-4- (3, 5- dimethylphenyl)-1, 3-thiazol-5-yl]-2-pyridyl]benzylamine (0.80 g, 2.1 mmol) in methanol (50 mL) and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off and the residue was recrystallized from methanol-ethyl acetate to obtain 0.73 g (1.6 mmol, yield 76%) to obtain the title compound. mp. 161-163°C

The structures of the compounds obtained in Examples 1 to 6 are shown below:

Example 1 .

XX S

H )

Me | )—NH,

Me

Example 2

NM

J

MeO

Example 3 oh. = ee

Wan — 0 \ 7

MeO 90

Amended Sheet 2003-01-30

Etxample 4 ry g

A S

)—WH,

Me

Example 5 ~y g

A S

" | HH,

Me

MExample 6

Cry

Us

Me

Example 9: N-[5-[2-benzoylamino-4-pyridyl)-4-(3,5-dimethylphenyl)- 1 ,3-thiazol-2-yl]acetamide

Acetyl chloride (0.26 mL, 3.7 mmol) and 4- dimethylaminopyridine (0.09g, 0.76 mmol) were added to a solution of N-[4-[2-amino-4- (3, 5-dimethylphenyl)-1, 3-thiazol-5-yl]-2~ pyridyllbenzamide (0.96 g, 2.4 mmol) in N,N-dimethylacetamide (20 ml) and the mixture was stirred at 70°C for 16 hours. After the rreaction mixture was cooled to room temperature, a saturated aqueous solution of sodium hydrogencarbonate (50 mL) was added.

The resulting crude crystals were collected by filtration and washed with water. The crude crystals were recrystallized from

® ethyl acetate to obtain 0.32 g (yield 30%) of the title compound. mp. 238-241°C

Example 10:

According to Example 9 and using N-[4-[2-amino-4-(3, 5- dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-benzylamine instead of N-[4-[2-amino-4-(3,5-dimethylphenyl)-1, 3-thiazol-5-yl]~2- pyridyllbenzamide, the following Example compound 10 was synthesized.

Example compound 10: N-[5-(2-benzylamino-4-pyridyl)-4-(3, 5- dimethylphenyl)-1,3-thiazol-2-yl]lacetamide mp. 217-219°C

Example 11:

According to Example 4 and using N-methylthiourea instead of thiourea, the following Example compound 11 was synthesized.

Example compound 11: N-[4-([4- (4-methoxyphenyl)-2- methylamino-1, 3-thiazol-5-yl]-2-pyridyl]benzamide mp. 237-241°C

Example 12:

According to Example 4 and using N-[4-[2-(3-methylphenyl)- 2-oxoethyl]-2-pyridyl]benzamide instead of 2-(2-benzoylamino-4- pyridyl) -1-(4-methoxyphenyl)ethanone, the following Example compound 12 was synthesized.

Example compound 12: N-[4-[2-amino-4- (3-methylphenyl)-1,3~thiazol- 5-yl]-2-pyridyl]benzamide 25 . mp. 216-217°C

Example 13: N-[4-[4- (4-methoxyphenyl) -2-methyl-1, 3-thiazol-5-yl]- 2-pyridylibenzamide

Bromine (0.18 mL, 3.5 mmol) was added to a solution of 2- (2-benzoylamino-4-pyridyl) -1- (4-methoxyphenyl)ethanone (1.2 g, 3.4 mmol) in acetic acid (10 mL) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated.

The residue was dissolved in N,N-dimethylformamide (20 mL), thicacetamide (0.30 g, 19 mmol) was added to the solution and the mixture was stirred at room temperature for 20 hours. An aqueous saturated solution of sodium hydrogencarbonate (20 mL) was added to the reaction mixture, the resulting mixture was extracted with ethyl acetate and the extract was washed with water. The extract was dried and concentrated. The residue was purified by silica

® gel column chromatography (hexane:ethyl acetate, 1:1) to obtain 0.68 g (yield 50%) of the title compound. mp. 134-135°C

Example 14: N-{4-[2-[(4-fluorophenyl)-4-(3-methylphenyl)-1,3- thiazol-5-yl]-2-pyridyl]lphenylacetamide

Phenylacetyl chloride (0.33 mL, 2.5 mmol) and triethylamine (0.31 mL, 2.2 mmol) were added to a solution of 4-[2-(4- fluorophenyl)-4-(3-methylphenyl)-1, 3-thiazol-5-yl]-2-pyridylamine (0.81 g, 2.2 mmol) in tetrahydrofuran (20 mL) and the mixture was stirred at room temperature for 13 hours. An aqueous saturated solution of sodium hydrogencarbonate (20 mL) was added to the reaction mixture, the resulting mixture was extracted with ethyl acetate and the extract was washed with water. This extract was dried and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate, 2:1) to obtain 0.86 g (yield 80%) of the title compound. mp. 187-190°C

Example 15:

According to Example 14 and using 4-{4- (4-methoxyphenyl)-2- methyl-1l,3-thiazol-5-yl]-2-pyridylamine, 4-[2-ethyl-4-(3- methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine, 4-[4-(3- methylphenyl)-2-propyl-1, 3-thiazol-5-yl}-2-pyridylamine, 4-[2- butyl-4-(3-methylphenyl)-1, 3-thiazol-5-yl]-2-pyridylamine, 4-[2- (2-chlorophenyl)-4- (3-methylphenyl)-1, 3-thiazol-5-yl]-2- pyridylamine and 4-[4- (3-methylphenyl)-2-(4-methylthiophenyl)-1, 3- thiazol-5-yl]-2-pyridylamine, respectively, instead of 4-[2-(4- fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine, the following Example compounds 15-1 - 15-6 were synthesized.

Example compound 15-1: N-[4-[4- (4-methoxyphenyl)-2-methyl-1, 3~ thiazol-5-yl]-2-pyridyl]phenylacetamide mp. 118-120°C

Example compound 15-2: N-[4-[2-ethyl-4-(3-methylphenyl)-1,3- thiazol-5-yl]-2-pyridyl]phenylacetamide mp. 107-108°C

Example compound 15-3: N-{4-[4-(3-methylphenyl)-2-propyl-1, 3- thiazol-5-yl]-2-pyridyl]phenylacetamide mp. 109-111°C

Example compound 15-4: N-[4-[2-butyl-4-(3-methylphenyl)-1,3-

® thiazol-5-yl}-2-pyridyl]phenylacetamide mp. 92-93°C

Example compound 15-5: N-[4-[2-(2-chlorophenyl)-4-(3- methylphenyl)-1, 3~thiazol-5-yl]-2-pyridyl]phenylacetamide mp. 141-142°C

Example compound 15-6: N-[4-[4-(3-methylphenyl)-2-(4- methylthiophenyl)~1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide mp. 205-206°C

Example 16:

According to Examples 14 and 15 and using benzoyl chloride, 3-phenylpropionyl chloride, 3-(4-methoxyphenyl)propionyl chloride, 3-(4-fluorophenyl)propionyl chloride, 4-phenylbutyryl chloride, 5- phenylvaleryl chloride, 2-thiophenecarbonyl chloride and 2- naphthoyl chloride, respectively, instead of phenylacetyl chloride, the following Example compounds 16-1 - 16-18 were synthesized.

Example compound 16-1: N-[4-[2-ethyl-4- (3-methylphenyl)-1,3- thiazol-5-yl]-2-pyridyllbenzamide mp. 113-114°C

Example compound 16-2: N-[4-[2-ethyl-4-(3-methylphenyl)-1,3- thiazol-5-yll-2-pyridyl]-3-phenylpropionamide mp. 126-127°C

Example compound 16-3: N-[4-[2-ethyl-4- (3-methylphenyl)-1, 3- thiazol-5-yl]-2-pyridyl]-3- (4-methoxyphenyl) propionamide mp. 137-138°C

Example compound 16-4: N-[4-[2-ethyl-4- (3-methylphenyl)-1,3-~ thiazol-5-yl1]-2-pyridyl]-3- (4-fluorophenyl)propionamide mp. 116-117°C

Example compound 16-5: N—-[4-[2-ethyl-4- (3-methylphenyl)-1,3- thiazol-5-yl]-2-pyridyl]-4-phenylbutyramide mp. 92-93°C

Example compound 16-6: N-[4-[2-ethyl-4- (3-methylphenyl)-1,3- thiazol-5-yl]-2-pyridyl]-5-phenylvaleramide mp. 86-87°C

Example compound 16-7: N-[4-[4-(3-methylphenyl)-2-propyl-1, 3- thiazol-5-yll-2-pyridyllbenzamide

Amorphous powder

H-NMR (CDCls) 6: 1.08 (3H, t, J=7.1Hz), 1.80-1.99 (2H, m), 2.34 (3H, s), 3.04 (2H, t, J=7.7Hz), 6.88 (lH, dd, J=5.2, 1.7Hz),

® 7.15-7.63 (7H, m), 7.90-7.95 (2H, m), 8.11 (1H, d, J=5.2Hz), 8.51 (1H, s), 8.61 (1H, br s)

Example compound 16-8: N-[4-[4-(3-methylphenyl)-2-propyl-1, 3- thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide mp. 103-104°C

Example compound 16-9: N-[4-([2-butyl-4-(3-methylphenyl)-1,3- thiazol-5-yl]-2-pyridyllbenzamide

Amorphous powder 'H-NMR (CDCl3) 6: 0.99 (3H, t, J=7.2Hz), 1.40-1.60 (2H, m), 1.76-1.93 (2H,m), 2.34 (3H, s), 3.06 (2H, t, J=7.7Hz), 6.88 (1H, dd, J=5.0, 1.7 Hz), 7.10-7.26 (3H, m), 7.41 (1H, s), 7.46-7.61 (3H, m), 7.94 (2H, dd, J=8.1, 1.5Hz), 8.10 (1H, d, J=5.0 Hz), 8.52 (1H, s), 8.71 (1H, br s)

Example compound 16-10: N-[4-[2-butyl-4- (3-methylphenyl)-1, 3- thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide mp. 77-78°C

Example compound 16-11: N-[4-[2-(4~fluorophenyl)-4-(3- methylphenyl)-1,3~thiazol-5~yl]-2-pyridyl]benzamide mp. 126-128°C

Example compound 16-12: N-[4-{2-(4-fluorophenyl)-4-(3- methylphenyl)-1, 3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide mp. 169-171°C

Example compound 16-13: N-{4-[2-(2-chlorophenyl)-4-(3~ methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide mp. 138-140°C

Example compound 16-14: N-[4-[2- (2-chlorophenyl) —4- (3- methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide mp. 156-158°C

Example compound 16-15: N-[4-[4~- (3-methylphenyl)-2-(4- methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyllbenzamide mp. 180-182°C

Example compound 16-16: N-[4-[4-(3-methylphenyl)-2-(4- methylthiophenyl)-1, 3-thiazol~5-yl]-2-pyridyl]-3- phenylpropionamide mp. 174-175°C

Example compound 16-17: N-[4-[4- (3-methylphenyl)-2-(4- methylthiophenyl)-1, 3-thiazol-5-yl]-2-pyridyl]-2- thiophenecarboxamide

® mp. 145-147°C

Example compound 16-18: N-[4-[4- (3-methylphenyl)-2-(4- methylthiophenyl)-1, 3-thiazol-5-yl]-2-pyridyl]-2-naphthamide mp. 184-186°C

Example 17: N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2- pyridyl] -N-methylphenylacetamide

Sodium hydride (60% paraffin dispersion, 58 mg, 1.5 mmol) was added to a solution of N-[4-[2-ethyl-4-(3-methylphenyl)-1,3- thiazol-5-yl]-2-pyridyl]phenylacetamide (0.50 g, 1.2 mmol) in dimethyl sulfoxide (5 mL) and the mixture was stirred at room temperature for 1 hour. Methyl iodide (0.09 mL, 1.5 mmol) was added to this reaction solution and the mixture was stirred at room temperature for 1 hour. A 10% aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate, 7:1—4:1) and washed with hexane to obtain 0.18 g (yield 35%) of the title compound. mp. 75-76°C

Example 18:

According to Example 17 and using N-[4-[2-ethyl-4-(3- methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide instead of N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2- pyridyl]lphenylacetamide , the following Example compound 18 was synthesized.

Example compound 18: N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol- 5-yl]-2-pyridyl]~N-methyl-3-phenylpropionamide

Oily product 'H-NMR (CDCls) 6: 1.46 (3H, t, J=7.5Hz), 2.32 (3H, s), 2.51 (2H, t, J=7.9Hz), 2.93 (2H, t, J=7.9Hz), 3.10 (2H, gq, J=7.5Hz), 3.22 (3H, s), 6.98 (1H, s), 7.03-7.29 (SH, m), 7.37(1H, s), 8.37 (1H, d, J=3.6Hz)

Example 19:

According to Example 6 and using N-[4-{4-(4-methoxyphenyl)- 2-methyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide, N-[4-[2-ethyl-4- (3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide, N-[4-[2- ethyl-4-(3-methylphenyl)-1, 3-thiazol~5-yl]-2-

pyridyl]phenylacetamide, N-[4-[2-ethyl-4-(3-methylphenyl)-1, 3- thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide, N-[4-[4-(3- methylphenyl)-2-propyl-1, 3-thiazol-5-yl]-2-pyridyl]lbenzamide, N- [4-[4- (3-methylphenyl)-2-propyl-1, 3-thiazol-5-yl]-2- pyridyllphenylacetamide, N-[4-[4-(3-methylphenyl)-2-propyl-1,3- thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide, N-[4-[2-butyl-4-(3- methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide, N-[4-[2- butyl-4- (3-methylphenyl)-1,3-thiazol-5-yl]-2- pyridyl]iphenylacetamide, N-[4-([2-butyl-4-(3-methylphenyl)-1,3- thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide, N-[4-[2-(4- fluorophenyl)-4- (3-methylphenyl)-1,3-thiazol-5-yl]-2- pyridyl]lbenzamide, N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)- 1l,3-thiazol-5-yl]-2-pyridyl]phenylacetamide, N-[4-[2-(4- fluorophenyl)-4- (3-methylphenyl)-1,3-thiazol-5~yl]-2-pyridyl]-3- phenylpropionamide, N-[4-[2-(2-chlorophenyl)-4- (3-methylphenyl)- 1,3-thiazol-5-yl]-2-pyridyl]lbenzamide, N-[4-[2-(2-chlorophenyl)-4- (3-methylphenyl)-1, 3-thiazol-5-yl]-2-pyridyl]lphenylacetamide, N- [4-[2-(2-chlorophenyl)-4- (3-methylphenyl)-1,3~thiazol-5-yl]-2- pyridyl] -3-phenylpropionamide, N-[4-[4-(3-methylphenyl)-2-(4- methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide, N-[4-[4- (3-methylphenyl)-2- (4-methylthiophenyl)-1,3-thiazol-5-yl]-2~ pyridyl]lphenylacetamide, N-[4~[4-(3-methylphenyl)-2-(4- methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]}-3- phenylpropionamide and N-[4-[4~(3-methylphenyl)-2-(4- methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-2-naphthamide, respectively, instead of N-[4- [2-amino-4- (3, S~dimethylphenyl)-1, 3- thiazol-5-yl]-2-pyridyl]benzamide, the following Example compounds 19-1 - 19-20 were synthesized.

Example compound 19-1: N-benzyl-N-[4-[4- (4-methoxyphenyl)-2- methyl-1,3-thiazol-5-yl]-2-pyridyllamine mp. 132-133°C

Example compound 19-2: N-benzyl-N-[4-[2-ethyl~4-(3-methylphenyl)~ 1,3-thiazol-5-yl]-2-pyridyl]amine mp. 106-107°C

Example compound 19-3: N-[4-[2-ethyl-4-(3-methylphenyl)-1, 3- thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl) amine mp. 87-98°C

Example compound 19-4: N-[4-[2-ethyl-4- (3-methylphenyl)-1,3-

® thiazol-5-yl]-2-pyridyl]-N- (3-phenylpropyl) amine mp. 52-53°C

Example compound 19-5: N-benzyl-N-[4-[4~ (3-methylphenyl)-2-propyl- 1,3-thiazol-5-yl]-2-pyridyl]amine

Oily product

H-NMR (CDCls) 6: 1.06(3H, t, J=7.4Hz), 1.77-1.96 (2H, m.), 2.33 (3H, s), 3.00 (2H, t, J=7.7Hz), 4.38 (2H, d, J=5.4Hz), 4. 83 (lH, br t), 6.32 (1H, s), 6.53 (1H, dd, J=5.4, 1.6Hz), 7.10-7. 40 (9H, m), 8.01 (1H, d, J=5.4Hz)

Example compound 19-6: N-[4-{4-(3-methylphenyl)-2-propyl-1, 3- thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl) amine

Oily product 'H-NMR (CDCl;) 6: 1.08 (3H, t, J=7.5Hz), 1.78-1.93 (2H, mm), 2.32 (3H, s), 2.81 (2H, t, J=7.0Hz), 3.01 (2H, t, J=7.7Hz), 3. 42 (2H, dt, J=6.2, 7.0Hz), 4.52 (1H, br t), 6.30 (1H, s), 6.51 (1H, dd, J=5.2, 1.5Hz), 7.11-7.34 (8H, m), 7.43 (1H, s), 8.00 (1H, d,

J=5.2Hz)

Example compound 18-7: N-[4-[4-(3-methylphenyl)-2-propyl-1, 3- thiazol-5-yl]}-2-pyridyl]-N-(3-phenylpropyl} amine

Oily product

H-NMR (CDCls) 6: 1.08 (3H, t, J=7.4Hz), 1.78-1.93 (4H, mm), 2.32 (3H, s), 2.66 (2H, t, J=7.2Hz), 3.01 (2H, t, J=7.7Hz), 3. 16 (2H, dt, J=6.2, 7.2Hz), 4.52 (1H, br s), 6.26 (1H, s), 6.49 (1H, dd, J=5.2, 1.5Hz), 7.07-7.32 (8H, m), 7.42 (lH, s), 7.98 (1H, 4d,

J=5.2Hz)

Example compound 19-8: N-benzyl-N-[4-[2-butyl-4-(3-methylpheny 1)~- 1,3-thiazol-5-yl]-2-pyridyl]amine

Oily product

H-NMR (CDCl;) 6: 0.97 (3H, t, J=7.3Hz), 1.38-1.59 (2H, mm), 1.73-1.90 (2H, m), 2.33 (3H, s), 3.02 (2H, t, J=7.7Hz), 4.37 ( 2H, d, J=5.7Hz), 4.83 (1H, t, J=7.3Hz), 6.31 (1H, s), 6.52 (1H, d,

J=5.5Hz), 7.09-7.43 (9H, m), 8.00 (1H, d, J=5.5Hz)

Example compound 19-9: N-[4-[2-butyl-4- (3-methylphenyl)-1,3- thiazol-5-yl]-2-pyridyl]-N- (2-phenylethyl) amine

Oily product

H-NMR (CDCls) 6: 0.98 (3H, t, J=7.3Hz), 1.39-1.59 (2H, mm), 1.74-1.92 (2H, m), 2.32 (3H, s), 2.81 (2H, t, J=7.0Hz), 3.04 ( 2H, t, J=7.7Hz), 3.41 (2H, dt, J=6.1], 7.0Hz), 4.55 (1H, t, J=6.1Hz ),

® 6.30 (1H, s), 6.51 (1H, 4d, J=5.1Hz), 7.06-7.19 (3H, m), 7.20-7.38 (5H, m), 7.43 (1H, s), 7.99 (1H, d, J=5.1Hz)

Example compound 19-10: N-[4-[2-butyl-4-(3-methylphenyl)-1,3- thiazol-5-yl]-2-pyridyl]-N- (3-phenylpropyl) amine

Oily product

H-NMR (CDCls) 6: 0.98 (3H, t, J=7.1Hz), 1.39-1.57 (2H, m), 1.75-1.98 (4H, m), 2.32 (3H, s), 2.67 (2H, t, J=7.8Hz), 3.04 (2H, t, J9=7.7Hz), 3.16 (2H, dt, J=5.9, 6.2Hz), 4.52 (1H, t, J=5.9Hz), 6.26 (1H, s), 6.49 (1H, d, J=5.1Hz), 7.06-7.38 (8H, m), 7.42 (1H, s), 7.97 (1H, d, J=5.1Hz)

Example compound 19-11: N-benzyl-N-[4-[2-(4-fluorophenyl)-4-(3- methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl] amine mp. 143-146°C

Example compound 19-12: N-[{4-[2-(4-fluorophenyl)-4-(3- methylphenyl)-1,3-thiazol=-5-yl]-2-pyridyl]-N-(2-phenylethyl) amine mp. 97-98°C

Example compound 19-13: N-{4-[2-(4-fluorophenyl)-4-(3- methylphenyl)-1,3~thiazol-5-yl]-2-pyridyl] -N- (3-phenylpropyl)amine mp. 110-112°C

Example compound 19-14: N-benzyl-N-[4-[2-(2-chlorophenyl)-4-(3- methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl] amine mp. 84-86°C

Example compound 19-15: N-[4-[2- (2-chlorophenyl)-4-(3- methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N- (2-phenylethyl) amine mp. 113-114°C

Example compound 19-16: N-[4-[2- (2-chlorophenyl) -4~- (3- methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine mp. 101-102°C

Example compound 19-17: N-benzyl-N-[4-[4-(3-methylphenyl)-2-(4- methylthiophenyl)-1,3~-thiazol-5-yl]-2-pyridyl]amine mp. 134-136°C

Example compound 19-18: N-[4-[4- (3-methylphenyl)-2-(4- methylthiophenyl)-1, 3-thiazol-5-yl]-2-pyridyl]-N-(2- phenylethyl) amine mp. 137-139°C

Example compound 19-19: N-[4-[4-(3-methylphenyl)-2-(4- methylthiophenyl)-1, 3-thiazol-5-yl]-2-pyridyl]-N-(3- phenylpropyl)amine

® mp. 106-107°C

Example compound 19-20: N-[4-[4-(3-methylphenyl)-2-(4- methylthiophenyl)-1, 3-thiazol-5-yl]-2-pyridyl]-N-(2- naphthylmethyl) amine mp. 144-145°C

Example 20: N-{4-[4-(3-methylphenyl)-2-(4-methylsulfonyl phenyl)- 1, 3-thiazol-5-yl]-2-pyridyl]benzamide

To a solution of N-[(4-{4-(3-methylphenyl)-2-(4- methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (0.50 g, 1.0 mmol) in N,N-dimethylformamide (5 mL) was added m- chloroperbenzoic acid (0.55 g, 2.2 mmol) and the mixture was stirred at room temperature for 1 hour. An 8N aqueous s olution of sodium hydroxide was added to the reaction mixture and t=he resulting solid was collected by filtration. This solid. was recrystallized from ethanol to obtain 0.29 g (yield 54%) of the title compound. mp. 212-214°C

Example 21:

According to Example 20 and using N-[4-[4- (3-metlaylphenyl) - 2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]lphenyslacetamide,

N-[{4-[4~(3-methylphenyl)-2- (4-methylthiophenyl)~-1,3-thiazol~5-yl]- 2-pyridyl]-3-phenylpropionamide, N-[4-[4-(3-methylphenyl )-2-(4- methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-2- thiophenecarboxamide, N-[4-[4-(3-methylphenyl)-2-(4- nmethylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]}-2-naphthamide, N- benzyl-N-[4-[4- (3-methylphenyl)-2- (4-methylthiophenyl)-1_,3- thiazol-5-yl]-2-pyridyl]amine, N-[4-[4-(3-methylphenyl)—2-(4- methylthiophenyl)-1, 3-thiazol-5-yl]-2-pyridyl]-N-(3- phenylpropyl) amine and N-[4-[4- (3-methylphenyl)-2-(4- methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2- naphthylmethyl) amine, respectively, instead of N-[4-[4- &X3- methylphenyl)-2-(4-methylthiophenyl)-1, 3~thiazol-5-yl]-2- pyridyl]benzamide, the following Example compounds 21-1 - 21-7 were synthesized.

Example compound 21-1: N-[4~[4-(3-methylphenyl)-2-(4- methylsulfonylphenyl)-1,3-thiazol-5-yl]~2-pyridyl]phenyl acetamide mp. 244-245°C

Example compound 21-2: N-[4-[4-(3-methylphenyl)-2-(4-

® methylsulfonylphenyl)-1, 3-thiazol-5-yl]~2-pyridyl]=-3- phenylpropionamide mp. 236-237°C

Example compound 21-3: N-[4-[4-(3-methylphenyl)-2-(4- methylsulfonylphenyl)-1,3-thiazol-5-yl]~2-pyridyl]-2- thiophenecarboxamide mp. 199-201°C

Example compound 21-4: N-[4-[4-(3-methylphenyl)-2-(4- methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]}-2-naphthamide mp. 231-233°C

Example compound 21-5: N-benzyl-N-([4-{4~ (3-methylphenyl)-2-(4- methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine mp. 148-150°C

Example compound 21-6: N-{4-([4-(3-methylphenyl)-2-(4- methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3- phenylpropyl) amine mp. 167-168°C

Example compound 21-7: N-[4-[4-(3-methylphenyl)-2-(4- methylsulfonylphenyl)-1,3-thiazol~-5-yl]-2-pyridyl]-N-(2- naphthylmethyl) amine mp. 167-168°C

Example 22: N-{4-[2-amino-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2~ pyridyl] -N-benzylamine

A mixture of [5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)- 1,3-thiazol-2-yllamine (0.29g, 1.0 mmol) and benzylamine (1.2 mL, 11 mmol) was stirred at 150°C for 3 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous solution of sodium hydrogencarbonate (20 mL) was added, the resulting mixture was extracted with ethyl acetate and extract was washed with water. This extract was dried and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate, 1:1) to obtain 0.16 g (yield 41%) of the title compound. mp. 178-179°C

Example 23:

According to Example 22 and using 4-methoxybenzylamine, 3- methoxybenzylamine, 2-methoxybenzylamine, 4-chlorobenzylamine, 3- chlorobenzylamine, (R)-1l-phenylethylamine, (S)-1l-phenylethylamine

Pe : and N-benzyl-N-methylamine instead of benzylam. ine, the following .

Example compounds 23-1 - 23-8 were synthesized .

Example compound 23-1: N-{4-[2-amino-4- (3-meth=ylphenyl)-1, 3- thiazol-5-yl]-2-pyridyl]-N- {d-methoxybenzyl) amine mp. 183-184°C

Example compound 23-2: N-[4-[2-amino-4-(3-methy/lphenyl)-1, 3- thiazol-5-yl]-2-pyridyl]-N- (3-methoxybenzyl) am#. ne mp. 152-154°C

Example compound 23-3: N-[4-[2-amino-4- (3~methyw phenyl) -1, 3- thiazol-5-yl]-2-pyridyl]-N- (2-methoxybenzyl)ami_ ne mp. 158-159°C

Example compound 23-4: N-{4-[2-amino-4- (3-methy=lphenyl)-1, 3- thiazol-5-yl]-2-pyridyl] -N- (4-chlorobenzyl) amin e mp. 182-183°C :

Example compound 23-5: N-{4-(2-amino-4~-(3-methy lphenyl) -1, 3- thiazol-5-yl]-2-pyridyl]-N-(3-chlorobenzyl) amin e mp. 180-181°C

Example compound 23-6: (R)-N-(4-[2-amino-4-(3-m ethylphenyl)-1, 3- thiazol-5-yl}-2-pyridyl]-N- (1-phenylethyl) amine - oo mp. 94-98°C

Example compound 23-7: (S)-N-[4~-[2-amino-4- (3-methylphenyl) -1, 3- thiazol-5-yl]-2-pyridyl)-N- (1-phenylethyl) amine mp. 93-96°C

Example compound 23-8: N-[4~[2-amino-4- (3-methyR phenyl) -1, 3- thiazol-~5-yl]-2-pyridyl]-N-benzyl-N-methylamine mp. 138-140°C

Example 24:

According to Example 22 and using (5-(2-£1luoro-4-pyridyl) - 4-(3-methoxyphenyl) -1, 3-thiazol-2-y1]amine inste=ad of [5-(2- : fluoro-4-pyridyl) -4-(3-methylphenyl)-1, 3-thiazol.~2-y1] amine, the following Example compound 24 was synthesized.

Example compound 24: N-[4-(2-zrino-4~ (3-methoxyp henyl)-1,3- thiazol-5-yl]-2-pyridyl]}-N-benzylamine mp. 217-218°C

Example 25:

According to Example 22 and using S-(2-fl=aoro-4-pyridyl)-4- (3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-=thiazole instead of (5-(2-fluoro-4-pyridyl)-4-(3-methvlphenvl)-1, 3-thiazol-2- 102

Ameznded Sheet 2003-01-30

Claims

® WHAT IS CLAIMED IS

1. An optionally N-oxidized compound represented by the formula: NT 2 e | (1) DR RN wherein R' represents a hydrogen. atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino gr-oup optionally having substituents or an acyl group, R® represents an aromatic group optionally having substituents, R’® represents a hydrogen atom, a pyridyl group optionally having substituents or an aromatic hydrocarbon group optionally having substituents, X represents an oxygen atom or a&n optionally oxidized sulfur atom, Y represents a bond, an oxygen &=tom, an optionally oxidized sulfur atom or a group represented by the formula: NR! (wherein R! represents a hydrogen atom, a hydrocarbon group optionally having substituents or an acyl group) and Z represents a bond or a divalermt acyclic hydrocarbon group optionally having substituents, or a salt thereof.

2. The compound according to c laim 1, wherein Z is a divalent acyclic hydrocarbon group optiorally having substituents.

3. The compound according to c¢ laim 1, which is a compound represented by the formula: 0), NE ad DR RN wherein n represents 0 or 1, and other symbols are as defined in claim 1, or a salt thereof.

4. The compound according to c laim 1 or 3, wherein R' represents (i) a hydrogen atom, (ii) a Ci-¢ alkyl group, a Cz;-¢ alkenyl group, a Cz-s alkynyl group, a Ci cycloalkyl group, a Cs-14 a ryl group or a Cr-js aralkyl group

® [these groups may have substituents selected from the group (substituent group A) consisting of oxo, halogen atom, Ci-3 alkylenedioxy, nitro, cyano, optionally halogenated C;-¢ alkyl, optionally halogenated C,s alkenyl, carboxy C,-¢ alkenyl,

optionally halogenated C;.s alkynyl, optionally halogenated Cig cycloalkyl, Ce¢-14 aryl, optionally halogenated C;-s alkoxy, Ci-g alkoxy-carbonyl-Ci.¢ alkoxy, hydroxy, Cs-14 aryloxy, Ci-1s aralkyloxy, mercapto, optionally halogenated C;-¢ alkylthio, Ce-;4 arylthio, Cs-16 aralkylthio, amino, mono-C;-¢ alkylamino, mono-Ce-;4 arylamino,

di-C;-6 alkylamino, di-Ce.14 arylamino, formyl, carboxy, Ci. alkyl- carbonyl, Css cycloalkyl-carbonyl, C;-¢ alkoxy-carbonyl, Ce-14 aryl- carbonyl, Cio; aralkyl-carbonyl, Ce-14 aryloxy-carbonyl, Cie aralkyloxy-carbonyl, 5 or 6 membered heterocyclic carbonyl, carbamoyl, thiocarbamoyl, mono-C,.s alkyl-carbamoyl, di-C;-¢ alkyl-

carbamoyl, Ce-14 aryl-carbamoyl, 5 or 6 membered heterocyclic carbamoyl, Cis alkylsulfonyl, Ce-14 arylsulfonyl, C;¢ alkylsulfinyl, Cé-14 arylsulfinyl, formylamino, C;-¢ alkyl-carbonylamino, Ce-i4 aryl-carbonylamino, C;_¢ alkoxy-carbonylamino, Ci-s alkylsulfonylamino, Ce-14 arylsulfonylamino, Cji-¢ alkyl-carbonyloxy,

Ce-14 aryl-carbonyloxy, Cis alkoxy-carbonyloxy, mono-C;-¢ alkyl- carbamoyloxy, di-C;-s alkyl-carbamoyloxy, Ce-14 aryl-carbamoyloxy, nicotinoyloxy, 5 to 7 membered saturated cyclic amino optionally having 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to one nitrogen atom and carbon atoms (this cyclic amino may have substituents selected from the group consisting of C;-s alkyl, Ce-14 aryl, Ci-¢ alkyl-carbonyl, 5 to 10 membered aromatic heterocyclic group and oxo), 5 to 10 membered aromatic heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, sulfo, sulfamoyl, sulfinamoyl and sulfenamoyl]

(iii) a 5 to 14 membered heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms optionally having substituents selected from the substituent group A,

(iv) an acyl group represented by the formula: -(C=0)-R>, -(C=0)-0R®, -(C=0)~-NR°R®, -(C=S)=-NHR® or -=SO,-R’

® (wherein R® repressents (Da hydrogen atom, @a C;s alkyl group, an Cz-¢ alkenyl group,, an Cs alkynyl group, a Cie cycloalkyl group, a Ce-14 aryl group orc a Cio16 aralkyl group optionally having substituents selescted from the substituent group A or ®a heterocyclic group optionally having substituents selected from the substituent group A, R°® represents a hydrogen atom or a Cj-s alkyl group, R’ represents Da C6 alkyl group, a Cz-s alkenyl group, a Cy. alkymyl group, a Cis cycloalkyl group, a Cg14 aryl group or a Cy.16 arralkyl group optionally having substituents selected from the substituent group A or @a heterocyclic group optionally having substituents selected from the substituent group A), (v) an amino groupe (this amino group may have substituents selected from the group consisting of Da Cis alkyl group, a Cre alkenyl group, a &;s alkynyl group, a Cis cycloalkyl group, a Céad aryl group or a C—.;¢ aralkyl group optionally having substituents selected from the substituent group A, @a heterocyclic group optionally having substituents selected from the substituent group A, @an acyl group as defined in the (iv), and @a C; alkylidene group optionally Ihaving substituents selected from the substituent group A), or (vi) a 5 to 7 memBered non-aromatic cyclic amino group optionally containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a wsulfur atom and an oxygen atom in addition to one nitrogen atom and carbon atoms (this cyclic amino may have substituents selected from the group consisting of Ci; alkyl, Ce-14 aryl, Ci.¢ alkyl~carbonyl, 5 to 10 membered aromatic heterocyclic group and oxo); R? represents Da C¢y4 monocyclic or fused polycyclic aromatic hydrocarbon group optionally having substituents selected from the substitueent group A or @a 5 to 14 membered aromatic heterocyclic groupe containing 1 to 4 heteroatoms of one or two kinds selected freom a nitrogen atom, a sulfur atom and an oxygen atom in addition —to carbon atoms, optionally having substituents selected from the substituent group A; R3 represerts Da hydrogen atom, @a pyridyl group optionally having substituents selected from the substituent group A, or @a Ce-14 monsocyclic or fused polycyclic aromatic hydrocarbon

® group optionally having substituents selected from the substituent group A; X represents 0, S, SO or S0;; Y represents a bond, O, S, SO, SO, or a group represented by the formula: NR' (wherein R! represents (Da hydrogen atom, @a Ci-s alkyl group, a C;-¢ alkenyl group, a C;-s alkynyl group, a Cs-s cycloalkyl group, a Ce-14 aryl or a Cy-16 aralkyl group optionally having substituents selected from the substituent group A or @an acyl group as defined in the (iv)), Z represents a bond, a C;.;5 alkylene group, a Ci-is alkenylene group or a C;-16 alkynylene group optionally having substituents selected from the substituent group A.

5. The compound according to claim 1, wherein R! is an amino group optionally having substituents.

6. The compound according to claim 1, wherein R! is (i) a Ci alkyl group, (ii) a Ce-14 aryl group optionally substituted with substituents selected from C;_¢ alkylthio, C;-¢ alkylsulfonyl and halogen atom, or (iii) an amino group optionally having 1 or 2 acyl represented by the formula: —- (C=0) -R®' (wherein R®' represents (Da Cis alkyl group, @a Cs.14 aryl group or @a 5 to 14 membered heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms).

7. The compound according to claim 1, wherein R! is an amino group optionally having 1 or 2 acyl group represented by -(C=0)~R®" (wherein R°" represents (Da Ces aryl group or @a 5 to 14 membered heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms).

8. The compound according to claim 1, wherein R® is a Ce-14 aryl group optionally having substituents.

9. The compound according to claim 1, wherein R® is a Ce-14 aryl group optionally substituted with halcgen atom or Cis alkoxy, or a 5 to 14 membered aromatic heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms.

10. The compound according to claim 1, wherein R? is a Ce-14 aryl group, or a 5 to 14 membered heterocyclic group containing 1 to 4

- heteroa toms of one or two kinds selected from nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms.

11. The compound according to claim 1, wherein R> is a Ce, aryl group optionally having substituents.

12. The compound according to claim 1, wherein R? is a Ce-14 aryl group opptionally substituted with one or two Cig alkyl or Cig alkoxy.

13. The compound according to claim 1, wherein X is an optionally oxidizecd sulfur atom.

14. The compound according to claim 1, wherein X is a sulfur atom.

15. The compound according to claim 1, wherein Y is an oxygen atom or a group represented by the formula: NR! (wherein R® is as defined in claim 1).

16. The= compound according to claim 1, wherein Y is an oxygen atom, ar optionally oxidized sulfur atom or a group represented by the formula: NR! (wherein RY represents a Cys alkyl group).

17. The compound according to claim 1, wherein Y is O, NH or S.

18. The compound according to claim 1, wherein Z is a lower alkylene group optionally having substituents.

18. The compound according to claim 1, wherein Z is a bond or a Ci-s alky=lene group optionally having oxo.

20. The compound according to claim 1, wherein R! is (i) a Ci-s alkyl group, (ii) a Ce-14 aryl group optionally substituted with Ci-¢ alky-lthio, Coe alkylsulfonyl and halogen atom, or (iii) an amino group o ptionally having 1 or 2 acyl group represented by the formula: -(C=0)-R*® (wherein R®’ represents @ a C,_¢ alkyl group, @ a Ce-14 arwl group or ® a 5 to 14 membered heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen. atom, a sulfur atom and an oxygen atom in addition to carbon a toms; R® is a Ce-14 aryl group optionally substituted with halogen atom or Cy. =lkoxy, or a 5 to 14 membered aromatic hetorocyclic group containing 1 to 4 hetercatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon a-toms; R® ds a Cs-14 aryl group optionally substituted with 1 or 2 Cis alkyl or Cig alkoxy: X 1s a sulfur atom; 124 Amended Sheet 2003-01-30

® Y is an oxygen atom, an optionally oxidized sulfur atom or a group represented by the formula: NR!' (wherein R*' represents a Ci-s alkyl group): Z is a Ci. alkylene group optionally having oxo or C6 alkyl or a bond.

21. The compound according to claim 1, wherein R!' is an amino group optionally having 1 or 2 acyl represented by -(C=0)-R>" (wherein R®" represents Da Ce.14 aryl group or @a 5 to 14 membered heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms); R? is a Ce-14 aryl group or a 5 to 14 membered aromatic heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms; R® is a Ce.14 aryl group optionally substituted with 1 or 2 Ci-¢ alkyl or Cis alkoxy; X is a sulfur atom; Y is O, NH or S; Z is a bond or a C;-s alkylene group optionally having oxo.

22. N-[5-(2-Benzoylamino-4-pyridyl)-4-(3,5-dimethylphenyl)-1, 3- thiazol-2-yl]acetamide, N-[5-(2-benzylamino—~-4-pyridyl)-4~ (3, 5-dimethylphenyl)~1,3-thiazol- 2-yllacetamide, N-[4-[4- (4-methoxyphenyl)-2-methyl-1,3-thiazol-5-yl]-2- pyridyllbenzamide, N-[4-[2- (4-fluorophenyl)-4- (3-methylphenyl)~-1,3-thiazol-5-yl]-2- pyridyllphenylacetamide, N-[4~-[2-ethyl-4- (3-methylphenyl)~1, 3—-thiazol-5-yl]-2- : pyridyllphenylacetamide, N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2- pyridyllphenylacetamide, N-{4-[2~butyl-4- (3~-methylphenyl)~1,3-thiazol-5-yl]-2- pyridyl]lphenylacetamide, N-[4-[4- (3-methylphenyl)~2~ (4-methylthiophenyl)-1, 3-thiazol-5-yl]- 2-pyridyl]phenylacetamide, N-[4-[2-ethyl-4- (3-methylphenyl)~1, 3-thiazol-5-yl]-2- pyridyl lbenzamide, N-[4-[2-ethyl-4- (3-methylphenyl)~1,3-thiazol-5-yl]-2~pyridyl]-3-

® ph.enylpropionamide, N-- [4-[2-ethyl-4-(3-methylphenyl) ~1,3-thiazol-5-yl]-2-pyridyl]-3- (4 -methoxyphenyl) propionamide, N—--[{4-[2-ethyl-4- (3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-4-

ph.enylbutyramide, N--[4-[4~ (3-methylphenyl)-2-propyl-1, 3-thiazol-5-yl]-2- py ridyllbenzamide, N--[4-[4- (3-methylphenyl)-2-propyl-1, 3-thiazol-5-yl]-2-pyridyl]-3- phuenylpropionamide, N-—[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2- py ridyl]lbenzamide, N— [4-[2-butyl-4-(3-methylphenyl) -1, 3-thiazol-5-yl]-2-pyridyl]-3- phienylpropionamide, N— [4-[2- (4-fluocrophenyl)-4- (3-methylphenyl)-1, 3-thiazol-5-yl]-2~ pyvridyllbenzamide, N— [4-([2- (4-fluorophenyl) -4- (3-methylphenyl)-1,3-thiazol-5-yl]-2- pyridyl] -3-phenylpropionamide, N— [4-[4- (3-methylphenyl)-2- (4-methylthiophenyl)-1, 3-thiazol~5-yl]- 2—pyridyl]benzamide, N—[4-[4-(3-methylphenyl)-2- (4~methylthiophenyl)-1,3-thiazol-5-yl]- 2—pyridyl]~3-phenylpropionamide, N—benzyl-N-[4-[2-ethyl-4- (3-methylphenyl)-1, 3-thiazol-5-yl]-2- pyvridyl]amine, N— [4-[2-ethyl-4- (3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N- (2:~phenylethyl) amine, N— [4- [2-ethyl-4-(3-methylphenyl)-1, 3-thiazol-5-yl]-2-pyridyl]-N- (33 -phenylpropyl)amine, N—benzyl-N-[4-[4- (3-methylphenyl)-2-propyl-1, 3-thiazol-5-yl]-2- pyvridyl] amine, N—[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N- (2: ~phenylethyl) amine, N— [4-[4- (3-methylphenyl) -2-propyl-1, 3-thiazol-5-yl]-2-pyridyl]-N- (33 ~phenylpropyl) amine, N—Dbenzyl~N-[4-[2-butyl-4- (3-methylphenyl)-1, 3~thiazol-5-yl]-2- pyeridyl]lamine, N— [4-[2-butyl-4- (3-methylphenyl)-1, 3-thiazol-5-yl]-2-pyridyl]-N- (2: -phenylethyl) amine, N— [4-[2-butyl-4- (3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-

(3-phenylpropyl) amine, N-benzyl-N-{[4-[4-(3-methylphenyl)-2- (4-methylthiophenyi)~1, 3- thiazol-5-yl]-2-pyridyl]amine, N-[4-[4-(3-methylphenyl) -2~ (4-methylthiophenyl)-1, 3-thiazol-5-yl]- 2-pyridyl]-N-(2-phenylethyl) amine, N-[4-(4-(3-methylphenyl) -2- (4~methylthiophenyl)-1, 3-thiazol-5-y1]~ 2-pyridyl]-N-(3-phenylpropyl) amine, N-[4-[4-(3-methylphenyl) -2- (4-methylsul fonylphenyl)-1, 3-thiazol-5— yl]l-2-pyridyl)benzamide, N-{4-[4~(3-methylphenyl) -2- (4-methylsul fonylphenyl)-1, 3-thiazol-5- y1l]-2-pyridyl]phenylacetamide, : N-14~[4-(3-methylphenyl) -2- (4-methylsulfonylphenyl) -1, 3-thiazol-5- yll-2-pyridyl]-3-phenylpropionamide, N-benzyl-N-[4-(4- (3-methylphenyl)-2- (4-methylsulfonylphenyl)-1, 3 thiazol-5-yl]-2-pyridyl] amine, N-{4-[4-(3-methylphenyl) -2- (4-methylsul fonylphenyl)-1, 3-thiazol-5- yll-2-pyridyl]-N-(3-phenylpropyl) amine, N-[4-([4- (3-methylphenyl) -2- (4-methylsul fonylphenyl)-1,3-thiazol-5- yl]-2-pyridyl]-N-(2-phenylethyl) amine, . ’ N- (4-fluorobenzyl) -N-[4-[4- (3-methylphenyl) -2— (4- methylsul fonylphenyl) 1, 3-thiazol-5-y1]-2-pyridyl] amine, or salts thereof.

23. A prodrug of the compound according to claim 1.

24. A process for producing the compound according to claim 1, which comprises: reacting a compound represented by the formula: : A er A Vi) Hal wherein Hal represents a halogen atom, and other symbols are as defined as claim 1, or a salt thereof with a compound represented : by the formula: R'-CSNH;, (VIII) wherein R! is as defined in claim 1, or a salt thereof, to obtain a compound represented by the formula: 127 Amended Sheet 2003-01-30

~~ A ¥Z R¥S 1 (la) , ) R R wherein each symbol is as defined in claim 1, or a salt thereof, or (ii) reacting a compound represented by the formula: N 2 Hal > R! xX) 3 | % R wherein Hal represents halogen atom, and other symbols are as defined as claim 1, or a salt thereof with a compound represented by the formula: R*-Z-YH (XI) wherein each symbol is as defined in claim 1, or a salt thereof, to obtain a compound represented by the formula: RS REF > . (ib) RY W wherein each symbol is as defined in claim 1, or a salt thereof, or (iii) reacting a compound represented by the formula: RS H, Z _ Xvi 3 | % R wherein each symbol is as defined in claim 1, or a salt thereof with a compound represented by the formula: R%*-ZL (XVIII)

wherein L represents a leaving group, and other symbols are as defined in claim 1, or a salt thereof, to obtain a compound represented by the formula:

eA | (lc) p R R* RS N wherein each symbol is as defined in claim 1, or a salt thereof,

® or (iv) reacting a compound represented by the formula: Rp 0) Wa RS wherein each symbol is as defined in claim 1, or a salt thereof with peroxy acid, hydrogen peroxide or alkyl hydroperoxide, to obtain a compound represented by the formula: 0 Nz REE pu (1d) R? L/ wherein each symbol is as defined in claim 1, or a salt thereof.

25. A pharmaceutical composition which comprises the compound according to claim 1 or a prodrug thereof.

26. The composition according to claim 25, which is an adenosine As; receptor antagonist.

27. The composition according to claim 25, which is an agent for preventing or treating adenosine A; receptor-related diseases.

28. The composition according to claim 25, which is an agent for preventing or treating asthma or allergic diseases.

29. The composition according to claim 25, which is an agent for preventing or treating brain edema, cerebrovascular disease or head trauma.

30. The composition according to claim 25, which is an agent for inhibiting p38 MAP kinase.

31. The composition according to claim 25, which is a TNF-a production-inhibiting agent.

32. The composition according to claim 25, which is an agent for preventing or treating cytokine-mediated diseases.

33. The composition according to claim 25, which is an agent for preventing or treating inflammation, Addison's disease, autoimmune hemolytic anemia, Crohn's disease, psoriasis, rheumatism, spinal trauma, brain edema, multiple sclerosis, Alzheimer's disease, Parkinson's syndrome, amyotrophic lateral sclerosis, diabetes,

J 4 ’ arthritis, toxemia, Crohn's disease, ulcerative colitis, chronic pneumcnia, silicosis, pulmonary sarcoidesis, pulmenary tuberculosis, cachexia, arteriosclerosis, Creutzfeldt-Jakob disease, virus infection, atopic dermatitis, systemic lupus erythematosus, AIDS encephalopathy, meningitis, angina, cardiac infarction, congestive heart failure, hepatitis, transplantation, dialysis hypotension or disseminated intravascular coagulation.

34. Use of an optionally N-oxidized compound represented by the formula: NT : AA | | (1) ) RN wherein R' represents a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino group optionally having substituents : or an acyl group, R? represents an aromatic group optionally having substituents, R3 represents a hydrogen atom, a pyridyl group optionally having substituents or an aromatic hydrocarbon group optionally having substituents, : X represents an oxygen atom or an optionally oxidized sulfur atom, Y represents a bond, an oxygen atom, an optionally oxidized sulfur atom or a group represented by the formula: NR! (wherein R® represents a hydrogen atom, a hydrocarbon group optionally having substituents or an acyl group) and Z represents a bond or a divalent acyclic hydrocarbon group optionally having substituents, or a salt thereof or a prodrug thereof for preparing an agent for antagonizing an adenosine A; receptor.

35. Use of an optionally N-oxidized compound represented by the formula: NT ON AA (1) )—F RN 130 Amended Sheet 2003-01-30

A wherein R! represents a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino group optionally having substituents Or an acyl group, R? represents an aromatic group optionally having substituents, rR’ represents a hydrogen atom, a pyridyl group optionally having substituents or an aromatic hydrocarbon group optionally having substituents, X represents an oxygen atom or an optionally oxidized sul fur atom, Y represents a bond, an oxygen atom, an optionally oxidized sulfur atom or a group represented by the formula: NR' (wherein R® represents a hydrogen atom, a hydrocarbon group optionally having substituents or an acyl group) and Z represents a bond or a divalent acyclic hydrocarbon group optionally having substituents, or a salt thereof or a prodrug thereof for preparing an agent for inhibiting p38 MAP kinase.

36. Use of an optionally N-oxidized compound represented by the formula: NTN 2 I~ e (1) R Y 1 )—R RN wherein R! represents a hydrogen atom, a hydrocarbon group optionally having Substituents, a heterocyclic group optionally having substituents, an amino group optionally having substituents or an acyl group, R? represents an aromatic group optionally having substituents, rR? represents a hydrogen atom, a pyridyl group optionally having substituents or an aromatic hydrocarbon group optionally having substituents, X represents an oxygen atom or an optionally oxidized sulfur atom, Y represents a bond, an oxygen atom, an optionally oxidized sulfur atom or a group represented by the formula: NR' (wherein R* represents a hydrogen atom, a hydrocarbon group optionally having substituents or an acyl group) and Z represents a bond or a divalent acyclic hydrocarbon group optionally having substituents, or a salt thereof or a prodrug thereof for preparing an agent for inhibiting a TNF-a production. 131 Amended Sheet 2003-01-30

A L4 / L :

37. Use of an optionally N-oxidized compound represented by the formula: NT en (1) )—R i? N wherein R! represents a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group cptionally having substituents, an amino group optionally having substituents or an acyl group, R? represents an aromatic group optionally having substituents, R’ represents a hydrogen atom, a pyridyl group optionally having substituents or an aromatic hydrocarbon group optionally having substituents, X represents an oxygen atom or an optionally oxidized sulfur atom, Y represents a bond, an oxygen atom, an optionally oxidized sulfur atom or a group represented by the formula: NR! (wherein R represents a hydrogen atom, a hydrocarbon group optionally having substituents or an acyl group) and Z represents a bond or a divalent acyclic hydrocarbon group optionally having substituents, or a salt thereof or a prodrug thereof for preparing an agent for preventing or treating asthma, allergic diseases, inflammation, Addison's disease, autoimmune hemolytic anemia, Crohn's disease, psoriasis, rheumatism, cerebral ‘hemorrhage, cerebral infarction, head trauma, spinal trauma, brain edema, multiple sclerosis, Alzheimer's disease, Parkinson's syndrome, amyotrophic lateral sclerosis, diabetes, arthritis, toxemia, Crohn’s disease, ulcerative colitis, chronic pneumonia, silicosis, pulmonary sarcoidosis, pulmonary tuberculosis, cachexia, arteriosclerosis, Creutzfeldt-Jakob disease, virus infection, atopic dermatitis, systemic lupus erythematosus, AIDS encephalopathy, meningitis, angina, cardiac infarction, congestive heart failure, hepatitis, transplantation, dialysis hypotension or disseminated intravascular coagulation. 132 Amended Sheet 2003-01-30

38. N-{é-[2-Ethyl-4-(3-methylphenyl)-1,3-thiazol-5-y1]-2- pyridyl)benzamide, N-benzyl-N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2- pyridyllamine, N-[4-{4-(3-methylphenyl)~2-(4-methylsulfonylphenyl)-1, 3- thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine, or salts thereof.

39. N-{4-[2-Ethyl-4-(3~-methylphenyl)-1,3~thiazol-5-yl]-2- pyridyl]lbenzamide, or a salt thereof.

40. N-Benzyl-N-[4~{2-ethyl-4-(3-methylphenyl)-1,3-thiazol~5-y1]-2- pyridyl]lamine, or a salt thereof.

41. N-[4-[4-(3-Methylphenyl)-2-(4-methylsulfonylphenyl)-1, 3- thiazol-5-yl]-2-pyridyl])-N-(2-phenylethyl)amine, or a salt thereof.

42. A pharmaceutical composition which comprises the compound according to claim 38 or a prodrug thereof. 133 Amended Sheet 2003-01-30