TWI220900B - 5-pyridyl-1,3-azole compounds, their production and use - Google Patents

Abstract

An optionally N-oxidized compound represented by the formula, wherein R1 represents hydrogen, hydrocarbon, heterocycle, amino, acyl, R2 represents an aromatic group, R3 represents hydrogen, pyridyl, aromatic hydrocarbon, X represents oxygen, or optionally oxidized sulfur. Y represents a bond, oxygen, optionally oxidized sulfur, a group represented by the formula NR4 (R4 represents hydrogen, hydrocarbon or acyl) and Z represents a bond or a divalent straight chain hydrocarbon, or a salt thereof has an excellent adenosine A3 receptor antagonistic activity and is used as an agent for preventing or treating diseases related to an adenosine A3 receptor. Furthermore, the compound (I) or a salt thereof has p38 MAP kinase inhibitory activity and TNF-alpha inhibitory activity and is used as an agent for preventing or treating diseases related to p38 MAP kinase and TNF-alpha.

Description

Ϊ220900 A7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs ------ ^ B7 V. Description of the invention (1) [Field of the invention] The present invention relates to an excellent medicinal effect (especially adenosine A3 receptor antagonistic activity , P38 MAP kinase inhibitory effect, TNF_α production inhibitory effect, etc.), a novel 5.pyridyl-1,3-azole compound, a method for preparing these compounds, and a pharmaceutical composition. [Background Art] It is generally known that Ai, ASa, An and A3 are subtypes of adenosine receptors. Glandular spine shows a narrowing effect on the trachea in asthmatic patients, and tea test, which is an asthma therapeutic agent, shows an adenosine antagonistic effect. In addition, it has recently been demonstrated that activation of A3 receptors in mice causes mast cells to precipitate particles (jOUrnal OB Biological Chemistry, vol. 268, 16887-16890, 1993), and that A3 receptors are present in the end-termed jk fluid eosinophils. In the white blood cells of red blood cells, stimulating it will activate phospholipase C (PLC) and increase the intracellular calcium concentration (Blood, vol. 88, 3569-3574, 1996). In addition, cytokines such as TNF-α (tumor necrosis factor-α), il-1 (interleukin-1), etc. are produced by various cells (such as monocytes or macrophages) in response to infection and other cellular stresses. Biomass (Koj, A., Biochem. Biophys. Acta, 1317, 84-94 (1996)). When these cytokines are present in appropriate amounts, they play an important role in the immune response, but it is generally believed that a variety of inflammatory diseases are associated with their overproduction (Dinarell〇, CA, Cun ·. 〇pin · Immunol, 3, 941_948 (1991) ). P38 MAP kinase, which is transformed into a MAP kinase homologue, is related to the production control of these cytokines and the signal transduction system linked to the receptor. Therefore, the inhibition of p38 MAP kinase may become a therapeutic agent for inflammatory diseases (Stein , B., Anderson (Please read the notes on the back before filling out this page) · »1 -------- ίί # · This paper size applies to China National Standard (CNS) A4 specifications ⑵〇χ 297 公^) 1 311859 i 1220900 Α7 Β7 V. Description of the Invention (2) D.? Annual Report in Medical Chemistry, edited by Bristol, JA. Academic Press, vol. 31, pages 289-298, 1996) So far, compounds that have selective antagonistic effects on adenosine A3 receptors are the xanthine derivatives described in GB-A-22 8873 3 and WO 95/11681 And the following compounds described in Journal of Medicinal Chemistry, vol.40, 2596-2608, 1997:

c〇2ch3 In addition, 'WO 97/33879' contains adenosine A3 receptor antagonists of the following compounds or their salts: This paper is in accordance with the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 2 311859 (please first Read the notes on the back and fill in this page) _f installed ________Order _________ ιζ ^ υ ^ υο Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy Γ 5. Description of the invention (

0 S in which R represents hydrogen, gas, bromoalkoxy or (^ _4 alkylcarboxy fluoro, iodine, hydroxyl, Cy alkyl, c) In detail, the compound of the following formula is mentioned:

0 S In addition, the imid derivatives described in JP_A 7_5〇317 (w〇93 / 14〇81) and the oxazole derivatives described in JP_A 9-5〇5〇55 (w〇95 / 13〇67) are respectively It is a compound with p38 MAP kinase inhibitory activity. On the other hand, the following compounds are known as thiazole compounds: U does not have analgesics, antipyretics, anti-inflammatory, anti-ulcer, protoplastin 8 (TXA2) synthetic enzyme inhibitory properties, and platelet coagulation inhibitory properties 7 (JP -A60_58981) 1,3-thiazole derivative or its salt:

In the formula, R1 represents a cycloalkyl group, a cyclic amino group, an amine group having 1 or 2 alkylphenyl groups, an ethyl fluorenyl group, or a lower alkoxycarbonyl ethyl fluorenyl substituent as necessary, and optionally 1 or 2 hydroxyl groups , A carboxyl group or a lower alkoxycarbonyl substituent, or a phenyl group having a retarder group, a 2-Weiylethenyl group, or a 2-Weiyl-1-propenyl group as necessary, and R2 represents a lower alkyl group as necessary Substituted pyridyl Thai paper size is applicable to China National Standard (CNS) A4 (210 x 297 mm) 311859 (Please read the precautions on the back before filling this page) ------- With 220900 V. Description of the invention (4) means a phenyl group having a lower alkoxy group, a lower alkynyl group, a carbonyl group, a halogen or a methylenediyl substituent as needed, 2) shown by the following formula 1,3-pyrazole derivatives or salts thereof having analgesic, antipyretic, anti-inflammatory, anti-ulcer, inhibitor of TXA2 synthetic enzymes, and inhibitor of platelet coagulation (JP-A 61-10580):

In the formula, R1 represents an alkyl group, an alkenyl group, an aryl group, an aralkyl group, a cycloalkyl group, a carbon-bonded heterocyclic group, or an amine group having a substituent if necessary, and R2 represents a pyridyl group substituted with an alkyl group as necessary , R3 represents a phenyl group having a substituent as necessary, 3) the formula shown below has analgesic, antipyretic, anti-inflammatory, anti-ulcer, TXA2 synthase inhibitory property, and platelet coagulation inhibitory property (usp 4,612,321) -Thiosal derivatives or salts thereof:

(Please read the notes on the back before filling this page)-丨 丨 丨 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic AffairsR1 stands for alkyl, alkenyl, aryl, aralkyl, cycloalkyl, A carbon-bonded heterocyclic group or an amine group having a substituent as necessary, R2 represents a pyridyl group substituted with an alkyl group as necessary, R3 represents an aryl group having a substituent as needed, 4) has anticancer activity shown by the following formula And cytokine-inhibitory activity of saliva derivatives:

# · L22〇9〇〇 Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs Γ A7 B7 V. Description of the Invention (5) In detail, the compound of the following formula (WO 97/12876)

Adenosine As receptor antagonists, p38 MAP kinase inhibitors and TNF-α production inhibitors have not been found due to their satisfactory activity and potency, safety, (oral) absorption, (metabolic) stability, etc. Therefore, the industry has become a pharmaceutical agent for adenosine As receptor antagonists, ρ3 8 MAP kinase inhibitors and TNF-α production inhibitors that can effectively prevent or treat adenosine As receptor-related diseases and cytokine-mediated diseases. There is a need for development. [Disclosure of the Invention] The inventors conducted various studies. As a result, first, a novel compound represented by the following formula (1), which may be N-oxidized [hereinafter sometimes abbreviated to compound (I)], or its salt: was synthesized:

^ The paper size is in accordance with China National Standard (CNS) A4 (210 X 297 mm) Γ% Read the > I on the back before filling in this page} «I 骏 -------- Order --- ------ # · 1220900 A7 B7 V. Description of the invention (6) Heterocyclic group of 2-generation group, amine group having substituents as needed, or slit group, R represents aryl group having substituents as needed, Tables represent hydrogen atoms, batches with substituents as needed or aromatic hydrocarbon groups with substituents as required, X represents oxygen atoms or sulfur atoms that are oxidized as needed, Y represents chemical bonds, oxygen atoms, and oxidized as needed A sulfur atom or a group other than the formula nr4 (R4 represents a fluorene atom, a hydrocarbon group or a fluorenyl group having a substituent if necessary) and Z represents a chemical bond or a divalent straight-chain hydrocarbon group having a substituent if necessary. Its structural characteristics are: A ring represented by the following formula: (where X represents an oxygen atom or an optionally oxidized sulfur atom) at the fifth position. It is substituted with a 4 It 疋 group, and further has a base side at the second position of the bulk group. Chain, and found that the resulting compound ⑴ is based on this specific chemical structure; unexpectedly excellent pharmaceutical activity, such as for adenosine Selective affinity of the 3 receptors and adenosine 8 3 receptor antagonistic activity, p3 8 MAP kinase inhibitory activity, etc., and these compounds have excellent physical properties (such as stability, etc.) as pharmaceutical agents and are very attractive A satisfactory pharmaceutical agent, the inventor completed the present invention based on these findings6. The present invention is related to (1) the optionally oxidized compound or its salt as shown in the formula below: This paper has been used in accordance with Chinese National Standard (CNS) A4 (21 × 297 mm) 311859 (Please read the back first (Notes on this page, please fill out this page) --------

Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs

(1 in the formula, R1 represents a hydrogen atom, a hydrocarbon group having a substituent if necessary, a heterocyclic group having a substituent if necessary, an amino group having a substituent if necessary, or a fluorenyl group, and R2 represents an aryl group having a substituent if necessary , R3 represents a hydrogen atom, a pyridyl group having a substituent as needed or an aromatic hydrocarbon group having a substituent as necessary, X represents an oxygen atom or a sulfur atom that is oxidized if necessary, and Y represents a chemical bond, an oxygen atom, and an oxidation A sulfur atom or a group represented by the formula nr4 (where r4 represents a hydrogen atom, a hydrocarbon group optionally having a substituent, or an alcohol group) and z represents a chemical bond or a divalent straight-chain hydrocarbon group having a substituent as required, (2) such as The compound of (1), wherein z is a divalent straight-chain hydrocarbon group having a substituent as necessary, (3) The compound of (1) is a compound represented by the following formula or a salt thereof:

: 4) Compounds such as (1) or (3), where R1 represents i) hydrogen atom, this paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 7 311859 (Please read the note on the back first Please fill in this page for matters)

• ϋ ϋ ϋ 一 I ϋ I n ϋ Βϋ I # · 1220900 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (8) (ii) Cu alkyl, alkenyl, c2 6 alkynyl, u Alkyl, c "4aryl, or C ^ 6aralkyl [These groups may have a group selected from the group consisting of oxo, halogen atom, CV3 alkylene monooxy, nitro, cyano, and halogenated Cw Alkyl, halogenated C2_0 alkenyl, carboxyl c2 6 alkenyl, halogenated alkynyl, halogenated q 6 cycloalkyl, Q 14 aryl, halogenated alkoxy if necessary , Ci-0 alkoxy_carbonyl_Ci 6 alkoxy, hydroxyl, C ^ 4 aryloxy, C7] 6 aralkyloxy, mercapto, halogenated Cu alkylthio, C6 "4 arylthio Group, C7_10 aralkylthio group, amine group, mono-Cw alkylamino group, mono-C6_14 arylamino group, di_C16 alkylamino group, di_c6_H arylamino group, formamyl group, carboxyl group, Cw alkyl-carbonyl group , C36 cycloalkyl_carbonyl, Ci · 6alkoxy-carbonyl, C6 "4aryl-carbonyl, c7_i6arylalkyl_carbonyl, C614 aryloxy-carbonyl, C ^ 6aralkyloxy-carbonyl, 5 Or 6-membered heterocyclic carbonyl, carbamoyl, thiocarbamoyl, mono- Cl_6 alkyl_carbamoyl, di_Ci-6 alkyl-carbamoyl, C6 ^ 4 aryl-carbamoyl, 5 or 6-membered heterocyclic carbamoyl, Cw alkyl, fluorenyl, C6_h square sulfenyl, c16 alkylidene fluorenyl 'arylsulfinyl fluorenyl, methylamidoamine, ci6 alkyl_weiamino, C ^ 4 aryl-carbonylamino'Cw alkoxy-carbonylamine Methyl, C16 alkylsulfonylamino, Cn4arylmethylamino, Cualkenyl-Weioxy, c614aryl-quinoxy, alkoxy-carbonyloxy, mono-Cw alkyl-amine formamidine Oxy, di-Ci 6 alkyl-carbamoyloxy, C0_M aryl-carbamoyloxy, nicotinylfluorenyloxy, with the exception of one nitrogen and carbon atoms having 1 to 4 as required 5- to 7-membered saturated amine groups selected from one or two heteroatoms of nitrogen, sulfur, and oxygen atoms (this cyclic amine group may have a group selected from the group consisting of Ci 6 alkyl, C 6 14 aryl, Cw alkyl-carbonyl, 5 to 10-membered aromatic heterocyclic group and oxo group C, please read the back; I want to fill in this page before the matter} Pack ----- 111 Order · 11! 11 #- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 8 311859 1220900 A7 -__ B7_______ V. Specify the substituents of the group (9), 5 to 10 membered aromatic heterocyclic groups, sulfones containing 1 to 4 carbon atoms selected from one or two kinds of nitrogen atoms, sulfur atoms, and oxygen atoms in addition to carbon atoms Acid group, amine sulfonyl group, amine fluorenyl group and amine group (substituent group of substituent group A)], (Hi) optionally having a substituent selected from substituent group A except carbon Extraatom 'contains 1 to 4 5 to 14 membered heterocyclic groups selected from one or two heteroatoms selected from nitrogen, sulfur and oxygen atoms, (iv) a fluorenyl group represented by the following formula:-(C = 0 ) -R5, 雠 (OO) -OR5,-(〇0) -NR5R6,-(C = S) -NHR5 or _S02-R7 (where R5 represents ① 氲 atom, ② optionally has a member selected from the substituent group A <6 alkyl, C2_6 alkenyl, C2.6 alkynyl, C3_6 cycloalkyl, C6_14 aryl or C7_16 aralkyl, or ③ optionally has a substituent selected from the substituent group a In addition to carbon atoms, it contains 5 to 14 membered heterocyclic groups selected from one to two nitrogen atoms, sulfur atoms, and oxygen atoms, or two heteroatoms, R6 represents a hydrogen atom or a Cw alkyl group, and R7 represents ① Cu alkane having a substituent selected from the substituent group a is required Group, C2_6 alkenyl group, C2_6 alkynyl group, C3_6 cycloalkyl group, C6-14 square group or C7_16 aryl group, or ② optionally having a substituent selected from the substituent group A in addition to a carbon atom, containing 1 to 4 A 5- to 14-membered heterocyclic group selected from one or two heteroatoms of nitrogen, sulfur and oxygen atoms, (v) an amino group (this amine group may have a group selected Ci-6 alkyl, C2 6 alkenyl, alkynyl, 6 ring of substituents of group A

Order IIIIII Printed alkyl, aryl, or c? Ιβ aralkyl groups by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. ② If necessary, it has a substituent selected from the substituent group A in addition to the carbon atom. Selected from nitrogen atoms,

311859 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 1220900 A7 __— B7 V. Description of the invention (10) 5 to 14-membered heterocyclic group of one of the sparse and oxygen atoms or two heteroatoms, as in (~) A defined fluorenyl group, and ④ a substituent having a group selected from the group consisting of &lt; 6 alkylene as a substituent of the substituent group a as required), or (vi) containing in addition to a nitrogen atom and a carbon atom, 1 to 4 5 to 7 membered non-aromatic cyclic amine groups selected from one or two heteroatoms of nitrogen, sulfur and oxygen atoms (this cyclic amine group may have a group selected from the group consisting of Cl 6 alkyl, c 6_14 Aryl, ci · 6 alkyl-carbonyl, 5 to 10-membered aromatic heterocyclic groups and substituents of the group consisting of oxo groups); R2 represents ① c6_14 having a substituent selected from the substituent A as necessary Monocyclic or fused polycyclic aromatic hydrocarbon group or ② optionally having a substituent in addition to carbon atoms, containing 1 to 4 5 to 14 members selected from one or two heteroatoms of nitrogen, sulfur and oxygen atoms Aromatic heterocyclic group; R3 represents ① hydrogen atom, ② an amidinyl group having a substituent selected from the substituent A as necessary, or ③ optionally having an optional group C6_14 monocyclic or fused polycyclic aromatic hydrocarbon group which is a substituent of the substituent A; X represents 0, S 'so or so2; Y represents a chemical bond, 0, S, SO, S02 or a group represented by the formula NR4 ( Wherein R4 represents ① a hydrogen atom, ② a cv6 alkyl group, a c2_6 alkenyl group, a c2_6 alkynyl group, a c3_6 cycloalkyl group, a c6 14 square group, or a C ^ 6 square alkyl group or ③ as a fluorenyl group as defined in (iv)); Z represents a chemical bond, optionally a chrysene group, a c2-16 alkenyl group, or a c2-16 alkynyl group having a substituent selected from the substituent group A, (5) such as (1) A compound, where ... is an amine group having a substituent as necessary, (6) A compound such as (1), wherein R1 is 1 or 2 selected from (if necessary, please read the notes on the back before filling (This page)-Scale Pack ----- ϋ n ϋ ^ _ mMKm 11 Βϋ ϋ ϋ 1 ^ — · When this paper is sized _ Home Fresh (CNS) A4 Regulation ―, χguan public love 1 10 311859 1220900 A7 Economy Printed by the Intellectual Property Cooperative of the Ministry of Intellectual Property Bureau. 5. Description of the Invention (Π) (OCw alkyl, (π) is optionally substituted with a substituent selected from Ci 6 alkylthio, Cl-6 alkylsulfonyl and i element atom. c6_14 An aryl group, or (iii) a fluorenyl group represented by the formula-(C = 〇) -R5 '(where R5' represents ① Ci 6 alkyl group, ② C614 aryl group, or ③ contains from 1 to 4 selected from carbon atoms Amine group which is a substituent of one of nitrogen atom, sulfur atom and oxygen atom or 5 to 14 member heterocyclic group of two heteroatoms), (7) the compound of (1), wherein R1 is 1 or 2 if necessary Each fluorene group represented by the formula-(c = o) -r5 "(where R5" represents ①C6 i4 aryl group or ② in addition to carbon atoms, contains 1 to 4 selected from one or two of nitrogen, sulfur and oxygen atoms A heteroatom of 5 to 14 membered heterocyclyl), (8) as the compound of (1), where r2 is a dagger with a substituent if necessary ... aryl, (9) as the compound of (1), Where r2 is a C6_M aryl group substituted with a prime atom or an alkoxy group, or 5 to Η containing one to two or two heteroatoms selected from nitrogen, sulfur, and oxygen atoms in addition to carbon atoms Member aromatic heterocyclic group, (10) a compound such as fluorene, which has rn C614 aryl group, or contains 1 to 4 one or two heteroatoms selected from nitrogen, sulfur, and oxygen atoms in addition to carbon atoms To 14 members Cyclic groups, (11) compounds such as ⑴, where c aryl groups have substituents as needed, (12) compounds such as (1), where r3 is rhyme γ γ K is regarded as one or two groups Or C! · 6 alkoxy-substituted c6 l4 aryl, (13) Such as the compound of ⑴, X in t is the sulfur atom that is oxidized as needed. This paper size applies the Chinese National Standard (CNS) A4 specification (_210 x 297 public love) 6-14 (Please read the notes on the back before filling out this page) 1 -------- Order --------- 11 311859 1220900 (18) As in (1) Compound alkylene, (19) Compound alkylene such as (1), (20) Compound A7 such as (1) V. Description of the invention (12) (14) Compound such as (1), where χ is Sulfur atom, (15) A compound as described in (1), its group (defined in ...), a milk atom or represented by the formula · 4-= as a compound of ⑴ 'where ¥ is an oxygen atom and optionally oxidized Among them, the atom or the group represented by the formula NR4 ′ (where R4 ′ represents a k-alkyl group), (17) A compound such as (1), wherein γ is 0, Nh, or S, and z is a group having a substituent as necessary Low level where z is a chemical bond or optionally oxygen ^ R in eight is (i) a Cl-6 alkyl group, (ii) a Cw alkylthio group, an alkylsulfonyl group, and an aryl group substituted with a halogen atom, or (ii) i or 2 if necessary c = 〇) _R5, shown as 醢 1 group (where R5 represents ①Cm alkyl group, ②C6_m aryl group or ③ in addition to carbon atom, contains 1 to 4 selected from one or two of nitrogen atom, sulfur atom and oxygen atom 5 to 14-membered heterocyclic group of heterogen J) amine group of substituents; R2 is a C6_H aryl group substituted by a halogen atom or a Ci_6 alkoxy group if necessary or contains carbon atoms in addition! 4 to 5 to 14 membered aromatic heterocyclic groups selected from one or two heteroatoms of nitrogen atom, sulfur atom, and oxygen atom; R is to be selected by 1 or 2 Cw alkyl or Cu alkyl groups Substitute; C6-14 aryl; X is a sulfur atom; Υ is an oxygen atom, a sulfur atom that is oxidized if necessary, or a group _ (where R4 'represents a CV6 alkyl group); 311859 --- ----- ^ -------- (Please read the notes on the back before filling out this page) t Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 1220900 A7 Printed by the Employee Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs V. Description of the invention (l3) z is a C &quot; alkylene or chemical bond having an oxo group or a c "alkyl group as required, (21) A compound such as (1), wherein R1 is 1 or 2 formulas as required -(C = 〇) -R5 ”(where R5” 砉 ^^ ^ ^ ^ C614 square group or ② In addition to carbon atoms, contains 丨 4 selected from nitrogen, sulfur and oxygen atoms One or two heteroatoms (5 to 14 membered heterocyclyl) amine groups; R is a C6_M aryl group or contains one or two selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms Heteroatom 5 to M-membered aromatic heterocyclic groups; 'R is a C6- 1 4 square group substituted with 1 or 2 C6 alkyl groups or c "alkoxy groups as necessary; X is a sulfur atom; Y is 0, NH or s; z is a chemical bond (^ _6 alkylene group, (22) N- [5- (2-benzylideneamino_4_pyridinyl) -4_ (3, 5-Dimethylphenyl) _1,3-thiazole_2.yl] acetamidinium (the compound of Example 9), ^ • [5- (2-benzylamino-4-methylpyridyl) -4 -(3,5-dimethylphenyl) _1,3-thien-2-yl] acetamidine (the compound of Example 10), Ν- [4_ [4 · (4-methoxyphenyl) -2 -Methyl-1,3-thiazol-5-yl] _2_pyridyl] benzidine (the compound of Example 13), N- [4- [2- (4-fluorophenyl) -4- (3- (Methylphenyl) -1,3_thiazole_5_yl] _2_pyridyl] phenylacetamide (the compound of Example 14), N- [4- [2-ethyl_4_ (3_methylbenzene Group) -1,3-thiazol-5-yl] _2_pyridyl] phenylacetamide (Example 1 5-2 compound), N- [4 · [4- (3-methylphenyl) -2 -Propyl-1,3-thiazole-5_yl] _2_pyridyl] benzene paper size applicable to China National Standard (CNS) A4 (210 X 297 mm) Read the notes on the back and fill in this page I I I I I Order

311859 1220900 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the Invention (14) Acetylamine (Compound of Example 15-3), N- [4- [2-butyl-4- (3-methyl Phenyl) -1,3-thiazol-5-yl] -2-pyridyl] phenylacetamide (the compound of Example 15-4), N- [4- [4- (3-methylphenyl) -2- (4-methylthiophenyl) -1,3-thiazole · 5 · yl] -2-pyridyl] phenylacetamide (the compound of Example 15-6), Ν- [4- [2- Ethyl-4- (3-methylphenyl) -1,3-ammon-5-yl] -2-amidine ratio σ amidyl] benzidine (the compound of Example 16-1), Ν- [4 · [2-Ethyl-4- (3-methylphenyl) -1,3-thiazol-5-yl] -2-pyridyl] -3-phenylpropanamide (Compound of Example 16-2), N -[4- [2-ethyl-4- (3-methylphenyl) -1,3-thiazol-5-yl] -2-pyridyl] -3- (4-methoxyphenyl) propaneamidine Amine (Compound of Example 16-3), N · [4- [2-ethyl-4- (3-methylphenyl) -1,3-thiazol · 5 · yl] -2-pyridyl] -4- Phenylbutyramine (the compound of Example 16-5), N- [4- [4- (3-methylphenyl) -2-propyl-1,3-thiazol-5-yl] -2-pyridyl ] Benzamidine (the compound of Example 16-7), N- [4- [4- (3-methylbenzene ) -2-propyl-1,3_ 1¾ fluoren-5-yl] -2-〇 than σ amidyl] -3_ phenylpropanamine (the compound of Example 16-8), Ν_ [4- [2-butyl- 4- (3-methylphenyl) -1,3-thiazol-5-yl] -2 · Πpyridyl] benzidine (the compound of Example 16-9), Ν- [4- [2 · but 4- (3-methylphenyl) -1,3-thiazol-5-yl] -2-¾pyridyl] -3-phenylpropanamide (the compound of Example 16-10), N- [4 -[2- (4-fluorophenyl) -4- (3-methylphenyl) -1,3-thiazol-5-yl] -2-pyridyl] benzidine (the compound of Example 16-11) , N- [4- [2- (4- ^ phenyl) -4- (3-methylphenyl) -1,3-sialo-5-yl] -2-〇 (Please first Read the notes on the back and fill in this page) t Staple ---------

This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 14 311859 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 1220900 A7 B7 V. Description of the invention (15) Base] -3-phenylpropane Amine (Compound of Example 16-12), N_ [4 · [4- (3-methylphenyl) -2- (4-methylthiophenyl) -1,3-thiazol-5-yl] -2- Pyridyl] benzidine (the compound of Example 16-15), N- [4- [4- (3-methylphenyl) -2- (4-methylthiophenyl) -1,3_thiazole_ 5-yl] -2-pyridyl] -3-phenylpropanamide (the compound of Example 16-16), N-benzyl-N- [4- [2-ethyl-4- (3-methyl Phenyl) -1,3-thiazol-5-yl] -2-pyridyl] amine (the compound of Example 19-2), Ν_ [4 · [2-ethyl_4- (3-methylphenyl)- 1,3-D based on 5-yl] -2-o than σ-based] -N- (2-phenylethyl) amine (the compound of Example 19-3), Ν_ [4- [2-ethyl- 4- (3-methylphenyl) -1,3-thiazol-5-yl] -2-pyridyl] -N- (3-phenylpropyl) amine (the compound of Example 19-4), N-benzene Methyl-N- [4- [4 · (3-methylphenyl) -2-propyl-1,3-thiazole-5 · yl] -2-pyridyl] amine (the compound of Example 19-5), Ν- [4 · [4 · (3-methylphenyl)- 2-propyl-1,3-thiazol-5-yl] -2-pyridyl] -N- (2-phenylethyl) amine (the compound of Example 19-6), N- [4- [4- ( 3-methylphenyl) -2-propyl-1,3-thiazol-5-yl] -2-pyridyl] -N- (3-phenylpropyl) amine (compound of Example 19-7), N -Benzyl-N- [4- [2-butyl-4- (3-methylphenyl) -1,3-thiazol-5-yl] _2_pyridyl] amine (the compound of Example 19-8), Ν · [4- [2-butyl-4- (3-methylphenyl) _ 1,3-_yl sigma-5-yl] -2-only stilbyl] _ Ν- (2-phenyl Ethyl) amine (compound of Example 19-9), N- [4- [2-butyl-4- (3-methylphenyl) -1,3-thiazol-5-yl] -2-pyridyl] -N- (3-phenylpropyl) amine (the compound of Example 19-10), N-benzyl-N- [4- [4- (3-methylphenyl) _2- (4-methylthio Phenyl) -1,3-thia (Please read the precautions on the back before filling this page)

This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 15 311859 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 1220900 A7 B7 V. Description of the invention (16) azole-5-yl] -2- Pyridyl] amine (the compound of Examples 19-17),] ^-[4- [4- (3-methylphenyl) -2- (4-methylthiophenyl) -1,3-thiazole-5- Group] -2_% pyridyl] -N- (2-phenylethyl) amine (the compound of Example 19-18),] ^-[4- [4- (3-methylphenyl) -2- (4-methyl Thiophenyl) -1,3-thiazol-5-yl] -2-pyridyl] -N- (3-phenylpropyl) amine (the compound of Example 19-19), Ν- [4- [ 4- (3-methylphenyl) -2- (4-methylsulfonamidophenyl) -1,3-thiazole · 5-yl ^ 2-pyridyl] benzidine (the compound of Example 20), Ν_ [4- [4- (3 · methylphenyl) -2- (4-methylsulfonylphenyl) -1,3-thiazol-5-yl] -2-pyridyl] phenylacetamidine Amine (compound of Example 21-1), Ν · [4- [4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) -1,3-thiazol-5-yl] -2-pyridyl] -3-phenylpropanamide (the compound of Example 21-2), N-benzyl-N- [4- [4- (3-methylphenyl) -2- (4- Methanesulfonylphenyl) -1,3-thiazol-5-yl] -2 -Pyridyl] amine (the compound of Example 21-5), N- [4- [4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) _1,3-thiazole-5 -Yl] -2-pyridyl] _N- (3-phenylpropyl) amine (the compound of Example 21-6), N- [4- [4- (3-methylphenyl) -2- (4- Methanesulfonylphenyl) -1,3-thiazol-5-yl] -2-pyridyl] -N- (2-phenylethyl) amine (the compound of Example 25-1), N- (4- Fluorobenzyl) -N- [4- [4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) -1,3-thiazol-5-yl] -2- Pyridyl] amine (the compound of Example 25_2), (S) -N- [4- (3-methylphenyl) -5- (2- (1 • phenylethylamino) -4-pyridyl) -1 , 3-thiazol-2-yl] nicotinamide, (R) -N- [4- (3-methylphenyl)-: 5- (2- (1-phenylethylamino) -4- Pyridyl) -1,3-thiazol-2-yl] nicotinamide, (S) -N- [4- (3-methylphenyl) -5- (2-Phenylethylamino) -4-pyridyl)-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) Z 311859 (Please read the precautions on the back before filling this page)

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 1220900 A7 B7 V. Description of the invention (17) 1,3-thiazol-2-yl] -2-methylnicotinamide, (R) -N- [4- ( 3 -methylphenyl) -5- (2- (1-phenylethylamino) -4 -pyridine) -1,3-sialyl-2-yl] -2-methyl Amine '(S) -N- [4- (3-methylphenyl) _5- (2- (1-phenylethylamino) · 4-D specific octyl group) _ 1,3_thiazole_2_yl] -2-Chlornicotinamine, (R) -N- [4- (3-methylphenyl) -5- (2- (1-phenylethylamino) -4 -D to fluorenyl) _ 1,3-fluorene_2_yl] -2-gas in the test amine '(S) -N- [4- (3-methylphenyl) -5- (2- (1-phenylethylamine Group) -4 -D than dianyl) _ 1,3_thiazol-2-yl] -2-methoxynicotinamide, (R) -N- [4- (3-methylphenyl) -5 -(2- (1-phenylethylamino) -4-pyridyl) -1,3-thiazol-2-yl] -2-methoxynicotinamide, N- [5 · (2-benzyl Amineamino 4-4-sigma stilbene) -4- (3-methylphenyl) -1,3-pentavale 2-yl] nicotinamide, N- [5- (2-benzylamine) 4--4-pyridinyl) _4- (3-methylphenyl) -1,3-thiazol-2-yl] -2-methoxynicotinamide, N- [5- (2-benzyl Amino-4-carbamoyl) -4- (3-methylphenyl) _1,3_thiazole-2- ] -2-Gas amine 'N- [5- (2-benzylamino-4-o to σ amidyl) -4- (3-methylphenyl) -1,3- 嚷 嗤 _ 2 -yl] -2 -methylamine ^ N- [5- (2. Benzamidoamino-4-saldinyl) -4- (3-methylphenyl) -1,3 -Thiazol-2-yl] in stilbamine, N_ [5_ (2-benzylideneamino-4-ohidinyl) -4_ (3-methylphenyl) -1,3-thizone- 2-yl] -2 -methyl amine 'N- [5- (2-benzylideneamino-4-carbamoyl) -4- (3-methylphenyl) -1,3 -Thi (Please read the notes on the back before filling this page) Order --------- · This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 17 311859 Ministry of Economy Wisdom Printed by the Consumer Cooperative of the Property Bureau 1220900 Α7 Β7 V. Description of the invention (18) 嗤 -2-yl] -2 -Chlorochloramine, N- [5- (2-benzylamidoamine-4-yl) (Pyridyl) -4- (3-methylphenyl) -1,3-thienyl-2-yl] -2 -methoxyamine, (S) _N- (1-phenylethyl)- 4- [2-Ethyl-4- (3-methylphenyl) -1,3-thiazole-5_yl] -2-¾11 Aminylamine '(R) -N- (l-phenylethyl)- 4- [2-ethyl-4- (3-methylphenyl) -1,3-thiazole-5 -yl] -2 -radhenylamine (S) -N- (l-phenylethyl) -4- [4- (3-methylphenyl) -2-propyl-1,3-thiazol-5-yl] -2. Nylamine '(R) -N- (l-phenylethyl) -4- [4- (3-methylphenyl) -2-propyl-1,3-fluorene **-yl]- 2-Smallylamine '(S) -N_ (l-phenylethyl) -4- [2-butyl-4- (3-methylphenyl) -1,3-penta-5-yl] -2 -Lyridylamine '(R) -N- (l · phenylethyl) -4- [2-butyl-4- (3-methylphenyl) -1,3-thiazole-5- Phenyl] -2 _D than nicotylamine '(S) -N- (l-phenylethyl) -4_ [4 · (3-methylphenyl) -2- (4-methylthiophenyl) -1,3 -D-based fluorenyl-5 -yl] -2 -D ratio to 1 ^ Amine amine '(R) -N- (l-phenylethyl) -4- [4- (3-methylphenyl ) -2- (4-methylthiophenyl) -1,3-thiazol-5-yl] -2-pyridylamine, (S) -N- (l-phenylethyl) -4- [4_ (3-methylphenyl) -2- (4-methylsulfonamidophenyl) · 1,3 -exo-5 -yl] -2 -pyridylamine '(R) -N- ( l-phenylethyl) -4- [4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) -1,3 -fluoren-5-yl] -2- Hexylamine ('S-N- (1-phenylethyl) -4- [2- (4-fluorophenyl) · 4- (3-methylphenyl) -1,3- (please first Read the notes on the reverse side and fill out this page) _Binding—Bookbinding — This paper size applies to China National Standard (CNS) A4 specifications ( 210 X 297 mm) 18 311859 ^ 20900 A7 V. Description of the invention (19) sialyl_5_yl] _2_pyridylamine, (R) _N_ (1-benzylethyl) _4_ [2_ (4_fluoro Phenyl) imidazol-5-ylb 2-pyridylamine, or a salt thereof, phenylphenyl) -M_ (23)-a compound such as (1) which is a predrug, (24)-a compound such as ( 1) A method of a compound comprising: (0) making a compound represented by the following formula or a salt thereof:

(VII) In the formula, Hal represents a peptidyl atom, and other symbols are defined by-,) τ. Incidentally, a compound or a salt thereof reacts: R1 &quot; CSNH2 (VIII) where R1 is defined as in (1), and the following化 4 物 shown by the formula and the following formula or its salt:

(la) Printed by the Intellectual Property Office of the Ministry of Economic Affairs and Consumer Affairs Co., Ltd. The symbols in the formula are as defined in (1), or (ii) the compound represented by the formula below or its salt ...

(X) where Hal represents a halogen atom, and other symbols are as shown in the compound shown in (1) or a salt thereof: as defined by R2-Z-YH (XI), and with the following formula -------- ^- -------- (Please read the precautions on the back before filling this page) This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) 311859 19 V. Description of the invention (2〇) Each symbol in the formula is defined by the salt in (j): to obtain the compound represented by the following formula or its R &gt; Z,

(lb) each symbol in the formula is as defined in ⑴, or (⑴) the compound represented by the following formula or its salt

(XVII) Each symbol in the formula is as defined in ⑴, which is inverse of the compound or its salt shown in the following formula (please read the precautions on the back before filling this page).

In the formula R2-ZL (XVIII), L represents a leaving group, and other symbols are as defined in ⑴, which shows the compound or its fermentation: The following formula is obtained: — — — — — — — — — Consumers' Cooperatives, Intellectual Property Bureau, Ministry of Economic Affairs Print

(Ic)

Each symbol in the formula is as defined in (1), or (lv) makes the compound represented by the following formula or its salt ...

This paper size applies to China National Standard (CNS) A4 specifications (21Q x 297) 20 311859 1220900 V. Description of the invention (21 A7 B7, the symbols in it are as defined in (1), and peroxy acid, argon peroxide Or, the reaction is based on an emulsified rat, and a compound or a salt thereof shown in the following formula is obtained:

(Id) Each symbol in the formula is as defined in (1), (25) — a pharmaceutical composition, including a compound containing (丨) or a prodrug thereof, (26) a composition such as (25), Adenosine, receptor antagonists, (27) Compositions such as (25) are preventive or therapeutic agents for adenosine 8-3 receptor related diseases, preventive or treatment for asthma or allergic diseases (please read the Please fill out this page again) Ｍ 装 ----- Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs (28) Composition agents such as (25), (29) Composition prevention agents such as (25) (30) Compositions such as (25) (31) Compositions such as (25) (32) Compositions such as (25), (33) Compositions such as (25) are inflammation, Addison Addison's disease, autoimmune hemolytic anemia, Crohn's disease, psoriasis, rheumatic 'spine trauma, cerebral edema, multiple sclerosis, Alzheimer's Moore's disease, Parkinson's syndrome, amyotrophic lateral sclerosis cerebral edema, cerebrovascular disease or head trauma inhibitor of p38 MAP kinase, inhibitor of TNF-α production The prevention and treatment of cytokine intervening diseases This paper scale applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 21 311859 • Li · 1220900 A7 B7 Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs Description of the invention (22) chemical disease, diabetes mellitus, arthritis, toxemia, ulcerative colitis, chronic pneumonia, lithiasis, pulmonary sarcoma, tuberculosis, cachexia, arteriosclerosis, spastic pseudosclerosis, viral infection , Preventive or therapeutic agents for atopic dermatitis, systemic lupus erythematosus, myelitis, angina, myocardial infarction, congestive heart failure, hepatitis, transplantation, dialysis hypotension, or disseminated intravascular coagulation, (34 ) —A method for raising an anti-adenosine receptor, which comprises administering to a mammal an effective compound or a salt thereof, as required by the formula shown below: N ^ | (丨) I R3 into N where R1 represents A hydrogen atom, a hydrocarbon group having a substituent as necessary, a heterocyclic group having a substituent as needed, an amine group having a substituent as needed, or a fluorenyl group, R2 represents an aryl group having a substituent as necessary, and R3 represents a nitrogen atom , Pyridyl with substituents or aromatic nicotine with substituents as required, X represents oxygen atom or sulfur atom that is oxidized if necessary, Y represents chemical bond, oxygen atom, sulfur that is oxidized as needed An atom or a group represented by the formula NR4 (where R4 represents a hydrogen atom, a hydrocarbon group optionally having a substituent, or a fluorenyl group) and Z represents a chemical bond or a divalent straight chain hydrocarbon group having a substituent, if necessary, (3 5) A method for inhibiting p38 MAP kinase, comprising administering to a mammal an effective amount of an optionally oxidized compound or a salt thereof as shown in the following formula: This paper is in accordance with Chinese National Standard (CNS) A4 (21G χ 297) ) 22 311859 (Please read the precautions on the back before filling in this page)-·· Installation -----

I I: aJ at n I ϋ ϋ ϋ I # ·-1220900 A7 V. Description of the invention (23

(I) wherein R1 represents a hydrogen atom, a hydrocarbon group having a substituent if necessary, a heterocyclic group having a substituent if necessary, an amine group having a substituent, or an alcohol group, and R2 represents an aromatic group having a substituent if necessary R represents a hydrogen atom, a pyridyl group having a substituent as required or an aromatic hydrocarbon group having a substituent as necessary, X represents an oxygen atom or a sulfur atom that has been oxidized if necessary, and Y represents a chemical bond, an oxygen atom, An oxidized sulfur atom or a group represented by the formula nr4 (where R4 represents a hydrogen atom, a hydrocarbon group having a substituent as required, or a fluorenyl group) and Z represents a chemical bond or a divalent straight chain hydrocarbon group having a substituent, if necessary, (36 ) —A method for inhibiting the production of TNF_ α, which includes administering an effective amount of an optionally oxidized compound or a salt thereof to the mammal as shown in the following formula: (Please read the precautions on the back before filling this page) --- ---- Order --- Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs (I) ^ r1 where R1 represents a hydrogen atom, a hydrocarbon group having a substituent as required, a heterocyclic group having a substituent as required, and Requires an amine group with a substituent, or fluorene Group, R2 represents an aryl group with a substituent as needed, R3 represents a hydrogen atom, a pyridyl group with a substituent if needed, or a Chinese standard (CNS) A4 specification (210 X 297 mm) applicable to this paper standard 23 311859 1220900 A7

This paper size applies to Chinese National Standard (CNS) A4 (210 χ 297 mm) 24 311859 1220900 A7

V. Description of the invention (25) Aromatic hydrocarbon group of substituent, X represents oxygen atom or sulfur atom which is oxidized if necessary, Y represents chemical bond, oxygen atom, sulfur atom which is oxidized as required or π by formula NR4 (Where R represents a fluorene atom, a hydrocarbon group having a substituent as required, or a fluorenyl group) and r2 / Z, ζ represents a fluorene or a divalent straight-chain hydrocarbon group having a substituent as required, (38) — Use of an optionally oxidized compound or a salt thereof as shown in the formula to prepare an adenosine 8-3 receptor antagonist:

In the formula, R1 represents a hydrogen atom, a hydrocarbon group having a substituent if necessary, a heterocyclic group having a substituent if necessary, an amino group having a substituent if necessary, or a fluorenyl group, and R2 represents an aryl group having a substituent if necessary, ( (Please read the notes on the back before filling out this page) • ^ ί ----- Order ---- I ---- Printed by R3 of the Intellectual Property Bureau of the Ministry of Economy's Consumer Cooperatives to indicate a hydrogen atom, with substituents as needed Pyridine group or an aromatic hydrocarbon group having a substituent as necessary, X represents an oxygen atom or an optionally oxidized sulfur atom, γ represents a chemical bond, an oxygen atom, an optionally oxidized sulfur atom, or a group represented by the formula NR4 ( Where R4 represents a hydrogen atom, a hydrocarbyl group having a substituent as required, or a fluorenyl group;) and Z represents a chemical bond or a divalent straight-chain hydrocarbon group having a substituent as necessary, (39) — a kind of Use of oxidized compounds or their salts to prepare p38 MAP kinase inhibitors: This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 25 311859 I22〇90〇A7 ___B7 V. Description of the invention (26)

In the formula, R1 represents a fluorene atom, a hydrocarbon group having a substituent if necessary, a heterocyclic group having a substituent if necessary, an amino group having a substituent if necessary, or a fluorenyl group, R2 represents an aryl group having a substituent if necessary, R3 Represents a fluorene atom, a pyridyl group having a substituent if necessary, or an aromatic hydrocarbon group having a substituent if necessary, X represents an oxygen atom or a sulfur atom that is oxidized if necessary, and Y represents a chemical bond, an oxygen atom, and a sulfur atom that is oxidized if necessary Or a group represented by the formula NR4 (where R4 represents a hydrogen atom, a hydrocarbon group optionally having a substituent, or a fluorenyl group) and z represents a chemical bond or a divalent straight-chain hydrocarbon group having a substituent if necessary, (40)-a kind of use Use of the oxidized compound or its salt to prepare TNF-α production inhibitor as shown in the following formula: (Please read the precautions on the back before filling this page) Printed by the Intellectual Property Bureau Staff Consumer Cooperative

In the formula, R1 represents a hydrogen atom, a hydrocarbon group having a substituent as needed, a heterocyclic group having a substituent as needed, an amino group having a substituent as needed, or a fluorenyl group, R2 represents an aryl group having a substituent as needed, R3 Represents a hydrogen atom, a pyridyl group with a substituent as needed, or a Chinese paper standard (CNS) A4 specification (210 X 297 public love) applicable to this paper size (210 X 297 public love) 26 311859 1220900

Aromatic hydrocarbon groups of substituents, X represents oxygen atom hiu See sulfur atoms that need to be oxidized, Y represents chemical bonds, oxygen atoms, optionally sulfur atoms that are oxidized, or a group dipped by formula NR4 (where R4 represents a hydrogen atom, Hydrocarbyl group having substituents, or fluorenyl group as needed) and Z represents a chemical bond or a divalent straight-chain hydrocarbon group having substituents as necessary, (41) A device using an optionally oxidized compound represented by the following formula or a salt thereof to equip inflammation 'Addison's disease, autoimmune hemolytic anemia, Crohn's disease, psoriasis, rheumatism, spinal trauma, cerebral edema, multiple sclerosis, Alzheimer's disease, Parkinson's syndrome, muscular atrophy Lateral sclerosis, diabetes, arthritis, toxemia, ulcerative colitis, chronic pneumonia, silica & pediatric, pulmonary sarcoma, tuberculosis, cachexia, arteriosclerosis, spastic pseudosclerosis, viral infection, Atopic dermatitis, systemic lupus erythematosus', meningitis, angina, myocardial infarction, congestive heart failure, hepatitis, transplantation, dialysis hypotension or disseminated intravascular coagulation :

In the formula, R1 represents a hydrogen atom, a hydrocarbon group having a substituent as needed, a heterocyclic group having a substituent as needed, an amino group having a substituent as needed, or a fluorenyl group, R2 represents an aryl group having a substituent as needed, R3 Represents a hydrogen atom, a pyridyl group with a substituent as required, or a Chinese standard (CNS) A4 specification (210 X 297 mm) as required for this paper size 27 311859 &quot; (Please read the precautions on the back before filling in this Page) -------- Order printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy 1220900 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy A7 B7 V. Description of the invention (28) Substituent aromatic hydrocarbon groups, Table X A non-oxygen atom or an optionally oxidized sulfur atom, γ represents a chemical bond, an oxygen atom, an optionally oxidized sulfur atom, or a group not represented by the formula NR4 (where R4 represents a hydrogen atom, a hydrocarbon group having a substituent as needed, or Fluorenyl) and Z represent a divalent linear hydrocarbon group having a chemical bond or optionally having a substituent. Furthermore, the present invention relates to compounds of (42) such as (1), in which R1 is 1 or 2 formulas as required:-(C = 0) -R5, gas c = 〇y〇R5, &lt; c = 〇) _nr5r6, _ (c = s) _nhr5 or S〇2 R (each symbol in the formula is as defined in (4)) amine group of fluorenyl group, (43) the compound as in (1), where Ci6 alkyl having substituents as required, (44) compounds such as (1), where R1 is a C6_14 aryl group having Ci6 alkylsulfonyl groups as required, (45) compounds such as (7), where R5, , Is phenyl or pyridyl, (46) A compound such as (1), in which R2 is a c6i4 aryl group having a substituent as required or a substituent having a substituent in addition to a carbon atom, and contains from 4 to 4 selected from nitrogen A 5- to 14-membered aromatic heterocyclic group of one or two heteroatoms of one atom, sulfur atom, and oxygen atom, (47) A compound such as (1) in which R 2 is phenyl or pyridyl, and (48) such as ( 1) A compound in which R3 is a phenyl group substituted with one or two Ci6 alkyl groups or C! · 6 alkyloxy groups as necessary. [Detailed description of the invention] In the foregoing formulas, R1 represents a hydrogen atom, and optionally has a substituent (please read the precautions on the back before filling this page). ----- ^^^^ 1 This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 28 311859 1220900 A7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (29) ^ See the heterocyclic group for which a substituent is required '. An amine group or a fluorenyl group for which a substituent is required. The "fluorenyl group" shown is, for example, represented by the formula: _ (匸 = 〇) _ &amp; 5,-(〇) OR, (OCO-NW,-(〇S) -NHR ^ _S〇2-R7 A fluorenyl group (where R5 represents a hydrogen atom, a hydrocarbon group optionally having a substituent or a heterocyclic group optionally having a substituent, R6 represents a gas atom or a C &quot; alkyl group, and R7 represents a hydrocarbon group having a substituent as needed A heterocyclic group having a substituent is required), etc. In the foregoing formulae, the Γ hydrocarbon group in the "hydrocarbon group having a substituent as necessary" is, for example, a straight or cyclic hydrocarbon group (for example, an alkyl group, an alkenyl group, Alkynyl, cycloalkyl, aryl, aralkyl, etc.). Among them, a straight or cyclic hydrocarbon group having 1 to 16 carbons is preferred. "Alkyl" is, for example, Ci-6 alkyl (for example Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second butyl, third butyl, pentyl'hexyl, etc.) are preferred, especially Cl_3 alkyl (for example, methyl , Ethyl, propyl, and isopropyl) are particularly preferred. "Alkenyl" refers to, for example, alkenyl (eg, vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3_butene , Methyl-2-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl, etc.) and the like are preferred. The "alkynyl" is, for example, a Cw alkynyl (for example, ethynyl , Propargyl, 1-butynyl, 2-butynyl, 3-butynyl 'κhexynyl, etc.) are preferred. "Cycloalkyl" is, for example, Cs-6 cycloalkyl (eg, cyclo Propyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) are preferred. "Aryl" refers to, for example, C6 · &quot; aryl (for example, phenyl, h-naphthyl, and paper). Chinese national standards apply. (CNS) A4 specification (210 X 297 mm)-&quot; ----- 29 311859 (Please read the note on the back first? Matters before filling out this page) Installation ------ --- Order- -Qin · 1220900 A7 V. Description of the invention (30) 2-naphthyl and 2-biphenyl are preferred. • Bibenzyl, 4-biphenyl, 2-anthryl, etc.) are better than "aralkyl". Ethyl, diphenylmethylethyl, 3-phenylpropyl Intellectual Property Bureau of the Ministry of Economic Affairs Employee Cooperative Co-operative printed for example 'C ^ 6aralkyl (eg, benzyl, benzyl-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenyl 4-phenylbutyl, 5-phenylpentyl, etc.) are preferred. The "substituent" in the "nicotinyl group which has a substituent as needed" is, for example, an oxo group, a prime atom (for example, fluorine, gas, bromine, iodine, etc.), a diphenylene dioxy group (for example, 'methylene Dioxin, ethoxyl, etc. ^ Continued, cyano, optionally substituted Ci6 alkyl, optionally substituted C2-6 alkenyl, carboxy C2 · 6 alkenyl (for example, 2-carboxyethylene Group, 2_hydroxymethyl methyl vinyl, etc.), if necessary, _chemical &quot; _ Guohua C2 · 6 alkynyl, optionally halogenated C3 · 6% alkyl, cVh aryl (for example, phenyl , Naphthyl, 2-naphthyl, 2-biphenyl, 3.biphenyl, 4, phenyl, 2-anthryl, etc.), Cw alkoxy, Ci_6alkoxy_carbonylalkane, if necessary Oxy (for example, ethoxycarbonyl + methylmethyloxy, etc.), hydroxy, C "4aryloxy (for example, phenyloxy, 1-naphthyloxy, 2-naphthyloxy, etc.), aralkyl Oxy (for example, benzyloxy, phenethyloxy, etc.), fluorenyl, alkylthio, halogenated if necessary, c0_M arylthio (for example, phenylthio, phenathio, 2_ Naphthylthio, etc.), C ^ 6aralkylthio (for example, benzylthio, Ethylthio, etc.), amine, early alkylamino (eg, methylamino, ethylamino, etc.), arylamino (eg, aniline, 1 · naphthylamine, 2-naphthylamine, etc.), Di Ci66 &quot; Burned amine group (such as' dimethylamine, diethylamine, ethylmethylamino, etc.), di_C6: arylamino group (such as diphenylamino, etc.), formamyl, carboxyl, Cw Alkane (such as ethyl alcohol, propionyl, etc.), C3_6 cycloalkyl-carbonyl (such as 13¾¾ (CNS) A4 in this paper) (^ 297 public love) ------- (Please read the back first Please fill in this page before filling out) Install -------- ^ --------- ^^ 1 1220900 A7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs V. Invention Description (31) t 'Cyclopropylcyclo, cyclopentyl, cyclohexyl, etc., alkoxy, such as methoxy, ethoxy, ethoxy, trioxolyl, etc., c6 .14 aryl groups (for example, benzoate, bucarboxyl, 2-methylformyl, etc.), c7_16 aryl groups (for example, phenylethylfluorenyl,% terminal fluorenyl, etc.) , C6_ &quot; aryloxy_ several groups (for example, phenoxy several groups, etc.), C, 16 aralkyl Oxy-carbonyl (for example, 'benzyloxycarbonyl, $ ethyloxycarbonyl, etc.), 5 or 6-membered heterocyclic groups (for example, final test group, isoamyl group, thienylmethyl group, methylformyl group) Group, pure morpholine group, thiomorpholinyl group, fluorinated small group group,% slightly bityl group, etc.), aminomethyl group, thiomethylamino group, monosexyl-6 alkyl group -Aminomethyl (for example, methylaminomethyl, ethylaminomethyl, etc.), Di_Cl_6alkyl_aminomethyl (for example, 'dimethylaminomethyl, diethylaminomethyl) Ethyl alcohol, ethyl methylamine methylamine, etc.), C6.14 aryl-aminomethyl ethyl alcohol (eg, phenylaminomethyl ethyl, i • naphthylamino methyl ethyl, 2 · zekiamine methyl ethyl Base, etc.), 5 or 6-membered heterocyclic amine formamidine (fluorene, 2-carboamidomethyl carbamoyl group, 3-methylpyridylamine carbamoyl group, 4-methylpyridylamine carbamoyl group, 2_2 Phenylaminomethylmethyl, 3-thienylaminomethyl, etc.), Ci 6 amino groups (for example, methyl and ethyl fluorenyl groups, etc.) &quot; Aryl groups (for example, Phenyl sulfenyl, naphthyl galanyl, 2, phenyl galanyl, etc.), U-based sulfinyl (for example, methyl sulfinyl) , Ethylidene fluorenyl, etc.), c "4 aryl fluorinated phenylene (for example, phenylene fluorinated phenylene, q-based fluorinated phenylene, 2_Czechyl fluorinated phenylene, etc.), methyl alcohol Amine group, Cm alkyl group, fluorenyl group (for example, ethylamino group, etc.), C6-14 aryl-quinamine group (eg, benzamidine group, naphthylamino group, etc.), cv6 oxygen group- Qianji (for example, methoxychiamine, ethoxychimine, propoxychiamine, butoxychiamine, etc.), c &quot; continuous amines. This paper applies Chinese national standard (CNS) A4. Specifications (210 X 297 male (please read the precautions on the back before filling out this page) Pack ----- --- Order -----Qin · 311859 κ Β7 V. Description of the invention (32) Such as' methyl Sulfonylamino, ethylsulfonylamino, etc.), c (for example, phenylglymanyl, sulfonium 7aryl, and sulfoniumamine, etc.), 6-alkynyl, and carbonyloxy (for example, ethylamino) · Nylenyl amidyl aryl-carbonyloxymeta α, ί ', # m donkey oxy, etc.), c614 oxy-chioxy (for example, methoxychioxy, ethoxy ▲, etc.), Cw Oxycarbonyloxy, etc.), monoambugan I, propoxyquinoxy, ethylamino, ethylamine Alkoxy, etc.), dialkyl (for example, methylamine methoxy (for example, 'dimethylamine formamyloxy, 6-alkylaminoformamyl, etc.), c6- &quot; aryl-carbamoyl Alkyloxy (e.g. phenyl: methylamyloxyamine methyloxy, etc.), final alkynyloxy, alkynyloxy, naphthalene 5 to 7-membered saturated cyclic amine, 5 In this case, aromatic 2 has a substituent m X ^, a heterocyclic group (for example, 2-earthyl, 3-thienyl, 2-pyridyl, 3-pyridinylquinolinyl, 3-quinolinyl, 4- Quinolinyl, 5-quinolinyl :, 4-pyridyl, 2-n mm ^ earth, quinolinyl, 1-isoquinolinyl, 3-isoquinolinyl, 4-isoquinolinyl, 5-iso Λ-ir, pyrenyl, 1-II-methoxyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl ', glycine, benzo [b] thienyl, 3-benzene Acene [b] thienyl, 2-benzo [b] furanyl, 3 Chu, # ▲ L Benkai [b] furanyl, etc.), fluorenyl, sulfamoyl, aminesulfinyl, and amine sulfur nice. The "smoke-based" may have in a replaceable position! To 5 preferred ^ 3 When the substituent is 2 or more, each substituent may be the same or different. The aforementioned "halogenated Cl_6 alkyl group as needed" is, for example, a Cw alkyl group having 1 to 5, preferably 1 to 3 halogen atoms (for example, fluorine, gas, bromine, Angstrom, etc.) as needed (for example, Methyl, ethyl, propyl, isopropyl, butyl isobutyl, first butyl, second butyl, pentyl, hexyl, etc.), detailed 311859 (please read the precautions on the back before filling in this Page) Chang -------- Order 1 # Printed on the paper by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. The paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 32 1220900 B7 V. Description of the invention (33) 'is methyl, methyl, fluoromethylethyl, 2-bromoethyl, 2,22_fmethyl, trifluorof,, ethyl, penta® 7 * Longsan Propyl, isopropyl, butyl earth, propyl, 3,3,3-butyl, tertiary butyl, pentyl, isopentyl, neofluorene, butadiene,;, 5 isobutyl, Dihexyl, 6,6,6-trifluorohexyl, etc. The aforementioned "diluted group, if necessary," is a C2_6 alkenyl group (for example, vinyl, propenyl, "1" having 1 to 5 and preferably 1 to 3 halogen atoms (for example, fluorine: iodine, etc.) 'Butene-1-yl, 4-pentene + yl, 5-hexanyl, etc., propynyl, 2_ The aforementioned "halogenated c2 6 alkynyl as necessary" has 1 to 5, preferably u C2 · 6 alkynyl (for example, 2-butynyl + fluorinated gas / alkyne-yl, etc.) of 3 halogen atoms (for example, iodine, etc. as required). "C3 6 cycloalkyl" is, c, 3-6 cycloalkyl (for example, cyclopropyl, cyclopropyl, etc.), which has 1 to 5, preferably 1 to 3 halogen atoms (for example, ^ dibromo, iodine, etc.). Cyclobutylfluorocyclohexyl, etc.), examples of which are cyclopropyl, cyclobutyl 'cyclopentyl, pentamyl, cyclohexyl, 4,4-dichlorocyclohexyl, 2,2,3,3-tetracycline Fluorocyclopentyl, 4, and cyclocyclohexyl ^ The aforementioned "Cy-alkoxy group halogenated as necessary" is earth, etc. For example, if necessary, it has 1 to 5, preferably 1 to 3, halogen atoms (-4 Such as' fluorine, gas, bromine, aunt, etc.) Cu alkoxy (for example, methoxy, ethyl 4 ^ I, propoxy, isopropoxy, butoxy, isobutoxy, second butanyl, oxy, joxy, etc.) 'Examples are methoxy, dimethoxy, Trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, I --------- J gas group, 4,4,4 · This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm). Flupentyl, please read the note on the back before filling in this page. Preparation 1220900 A7 __ B7 V. Description of the invention (34) Trifluorobutoxy, isobutoxy, second butoxy, pentyloxy, hexyloxy, etc. The aforementioned "halogenated Ci4 alkylthio group" For example, a Cw alkylthio group (for example, methylthio, ethylthio, propylthio) having 1 to 5, preferably 1 to 3 halogen atoms (for example, fluorine, chlorine, molybdenum, iodine, etc.) as needed Group, isopropylthio, butylthio, second butylthio, third butylthio, etc.), examples of which are methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio Base, isopropylthio, butylthio Group, 4,4,4-trifluorobutylthio group, pentylthio group, hexylthio group, etc. The "5 to 7-membered saturated cyclic amino group having 5 to 7-membered saturated cyclic amino groups having substituents as necessary" "Amino groups" are, in addition to a nitrogen atom and a carbon atom, optionally a 5 to 7 membered saturated cyclic amine group having 1 to 4 heteroatoms selected from one or two of nitrogen, sulfur and oxygen atoms, Examples thereof are pyrrolidin-1-yl, piperidinyl, piperidin-1-yl, morpholinyl, thiomorpholinyl, hexamethylazepine-1-yl, and the like. As for "with a substituent as necessary, The "substituent" in the "5- to 7-membered saturated cyclic amino group" is, for example, a Cw alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second butyl , Tertiary butyl, pentyl, hexyl, etc.), C6 &quot; aryl (for example, phenyl, naphthyl, 2-naphthyl, 2-biphenyl, 3-biphenyl, 4-biphenyl, 2-anthracene, etc.), c ^ alkyl-carbonyl (e.g., ethylfluorenyl, propionyl, etc.), 5- to 10-membered aromatic heterocyclic groups (e.g., 2-thienyl, 3-thienyl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolinyl, 3-quinolinyl, 4_lin Base, 5-pentolinyl, 8-quinolinyl, isoquinolinyl, 3-isoquinolinyl, 4-isoquinolinyl, 5-isoquinolinyl, indolyl, 2-indole , 3-indolyl, 2-benzothiazolyl, 2-benzo [b] thienyl, 3-benzo [b] thienyl, 2-benzo [b] furanyl, 3-benzo [ b] Furan basic paper size applies Chinese National Standard (CNS) A4 specification (21G X 297 Public Love 1-34 311859 C, please read the precautions on the back before filling this page). -------- 1220900 A7 5. Description of the invention (35), etc.), oxo, etc. The "heterocyclic group" in the "heterocyclic group having a substituent as necessary" is, for example, from i to 4 containing one to two heteroatoms selected from nitrogen, sulfur, and fluorene atoms in addition to carbon atoms. 5 to 14 member (monocyclic, bicyclic or three%) heterocyclic monovalent radical obtained by removing an arbitrary hydrogen atom, preferably (丨) 5 to W members (preferably 5 to 10 members, particularly preferably 5 to 6 members) ) Aromatic heterocycles, (ii) 5 to 10 members ^ Jiaojia 5 to 6 members) Non-aromatic heterocycles or (iii) 7 to i 0 member heterocyclic bridge ring description "5 to 14 members (preferably 5 To 10 members) aromatic heterocycles "are, for example, hexene, benzo [b] thiophene, benzo [b] furan, benzimidazole, oh sal, oh bite, π ratio coax, spurt bite, tower coax, Exhale noise, alien attack, CD, salivary, pharyngeal, 4Η · quin coax, isoquinoline, quinoline, benign tower coax, naphthalene bite, sialoline '㈣, yesterday saliva, 舞, π, Bite, ㈣, 嚷 sniff, 唾 、, 徘 耕, 异, 异, 呋, 呋, 咕, 噚 噚, etc. to form a ring. Square group fluorene (for example, benzene ring and other descriptions of "5- to 10-membered non-aromatic heterocyclic rings" are: oxazoline, pyrazolidine, pyrazoline, piperidine, piperidine, 'A-pyridine,' di-siala , Dioxoline, thiadisialoline, trisialline, Shaanxi: morpholine, etc. Panidazole, dithia, the aforementioned "7 to 10-membered heterocyclic bridge ring" is, for example, ring [2,2 , 1] heptane, etc. Kun 11 疋, 7-nitrobis "heterocyclic group" is preferably, in addition to carbon atoms, preferably atomic-or two kinds of hetero: to 4 paper size is suitable for ¥ t specifications ⑵〇 χ297 ϋ_ ^ Heteroatoms 5 to 35 31185 ____________ «» 1 -------- (Please read the notes on the back before filling this page) il- Α7

V. Description of the Invention (36) The Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs prints a "member (preferably 5 to 10 members) (monocyclic or bicyclic) heterocyclic group. In particular, ^ is, for example, 2-thienyl , 3-thienyl, 2-furanyl, 3-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5-quinyl Phenyl, 8-quinolinyl, ^ isoquinolinyl, 3-isoquinolinyl, private isoquinolinyl '5-isoquinolinyl, pharminyl, 2-pyrimidinyl, apyrimidinyl, each group 2_pyranyl, 3_takienyl, 3_isothiazolyl, 3_isoisopyridyl, sylvestris, 2-indolyl, 3_indolyl, 2 • benzothiazole Aromatic heterocyclic groups such as phenyl, 2-benzo [b] ^ phenyl, fluorenyl [b] thienyl, 2-benzo [b] furanyl, 3-benzo [b] furanyl, and for example丨 _pyrrolidinyl, 2-pyrrolidinyl, bipyridyl, 2-imidolinyl, 4 · imidolinyl, 2-bipyridyl, 3-pyrazolidyl, 4-pyrazolyl Non-aromatic heterocyclic groups such as pyridyl, piperidinyl, 2-piperidinyl, 3-piperidinyl, renipesyl, 1-piperazinyl, 2-piperidinyl, morphinyl, thiomorpholinyl, etc. Cyclo base. Where ' In addition to carbon atoms, 5- to 6-membered heterocyclic groups containing i to 3 heteroatoms selected from nitrogen, sulfur and oxygen atoms are more preferred. Examples are 2-thienyl, thiothienyl, 2-pyridine Base, 3-pyridyl, enpyridyl, 2-pyranyl, 3-furanyl, pyrimidinyl, 2-pyrimidinyl, 3-pyrrolyl, 3-pyridyl, 3-isothiazolyl, Hongyi Oxazolyl, pyrrolidinyl, 2-pyrrolidinyl, 3-pyridyl, 2-imidazolinyl, 4-misoquinolinyl, 2-pyridinyl, 3-pyridinyl ' Renpyrazolyl, piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-piperidinyl, 2-piperidinyl, morpholinyl, thiomorpholinyl, etc. The "substituent" in the "heterocyclic group having a substituent as necessary" is, for example, "the same as the" substituent "in the" hydrocarbon group having a substituent as required "shown by R5. This paper size applies to China National Standard (CNS) A4 specification (21 × 297 mm) 36 311859 (Please read the precautions on the back before filling this page) Loading -------- Order- 丨 # 蝥 20900 A7 B7____ 5. Description of the invention (37) The "heterocyclic group" may have 1 to 5, preferably 1 to 3, of the aforementioned substituents at the substitutable position. When the substituent is 2 or more, each substituent is Can be the same or different. The "Cu alkyl group" represented by R6 is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second butyl, third butyl, pentyl, hexyl and the like. The "hydrocarbyl group having a substituent as needed" and "heterocyclic group having a substituent as necessary" shown by R7, for example, the "hydrocarbon group having a substituent as necessary" and "optionally having a substituent as shown in the aforementioned R5" Heterocyclyl ". The "amine group having a substituent as needed" shown by R1 is, for example, (1) an amine group having 1 or 2 substituents as needed and (2) a cyclic amine group having a substituent as needed. The "substituent" in the above (1) "amine group having 1 or 2 substituents as needed" is, for example, a hydrocarbon group having a substituent as needed, a heterocyclic group having a substituent as needed, a fluorenyl group, An alkylene group having a substituent is required. The "hydrocarbyl group having a substituent as needed" and the "heterocyclic group having a substituent as necessary" are respectively different from the "nicotinyl group having a substituent as necessary" and "the heterocyclic group having a substituent as necessary" as shown in the aforementioned R5. "Cyclobase" is the same. The "醯 基" is the same as the "醯 基" shown in R1 above. The "alkylene group" in the "alkylene group optionally having a substituent" is, for example, a "q · 6 alkylene group (for example, methylene, ethylene, propylene, etc.). The "substituent" in the "alkylene group optionally having a substituent" is 1 to 5 'preferably 1 to 3, which is the same as the "substituent group" in the "hydrocarbyl group having a substituent optionally represented by R5" Substituents. (Please read the precautions on the back before filling out this page) Packing -------- Order 丨 #-Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs This paper applies CNG x7iK21 () x 297 ^ 37 311859 1220900 A7: ~~ -BI__ Fifth, the description of the invention (38) I Tian Zhe described the "substituent" in the "amino group having 1 or 2 substituents as necessary" 4 2 when each The substituents may be the same or different. As for (2) the "cyclic | amine | amine group" in the "cyclic amine group which has a substituent as needed" is 'except for one nitrogen atom and carbon atom, it needs to have i selected from the nitrogen atom' sulfur atom and oxygen A 5 to 7 member non-square cyclic amine group of one or two heteroatoms. Specifically, examples thereof are pyrrolidin-1-yl, piperidinyl \ piperin-1 · yl, morpholinyl, thiomorpholinyl, hexahydroazepine-1-yl, imidazolidine-1- Base, 2, Hongdihydro_1H imidazole small group, tetrahydro_ι (2Η) _ fluorenyl, 3,6_dihydro_1 (211 &gt; pendiyl, 34_dihydromoridinyl, etc. As for " "Substituent-in a cyclic amine group having a substituent as necessary" is 1 to 3 "substituents" as in "5- to 7-membered saturated cyclic amine group", and these substituents are shown as "R5" "Substituent" in "Hydrocarbyl Group Having Substituent Group As Needed" is detailed. An example of a 5 to 7-membered non-aromatic cyclic amine group having 1 oxo group is 2-oxoimidazolidine ::! _ Group, 2-oxo group_2,3_dihydro_1H_imidazolyl group, 2 · oxotetrahydrobinder group, 2-oxo-3,6_dihydro_1 (2Η) _cancer Fluorenyl, 2-oxo_3,4_dihydro-1 (2-)-continyl, 2-oxo, holox-1-yl, 2-oxopiperidinyl, 2-oxo Oxopiperazin-1-yl, 3-oxopiperazine-1-yl, 2-oxo-2,3,4,5,6,7-hexahydroazepine-1-yl and the like. R1 is preferably an amine group having a substituent as needed, an aryl group having a substituent as needed, and Alkyl groups of substituents, etc. A further preferred example of "amine group having a substituent as needed" is to have 1 or 2 if necessary by the formula-(C = 0) -R5,-(C = 〇) -〇r5, _ (c == 0) _ NR5R6,-(OShNHR5 or -S02-R7 [Each symbol in the formula indicates the above (please read the precautions on the back before filling this page). --- Stupid-Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economics This paper is printed to the Chinese National Standard (CNS) A4 (210 X 297 mm) 38 311859 1220900 Description of the invention (39) Same meaning] amine group which is not brewed. Particularly good, and is represented by the formula-(OOW or-(C = 0) _NR5R6 "^ has the same meaning as 1 or 2 as needed] 醯The amino group of X. The table of each X number is not as good as the above "Aryl with substituents as needed-^ square group" It is preferably to have from 5 to 5 selected from Cw alkylthio, c6-14 arylthio, as required Arylene group, c aryl arylene group, c1-6 alkynyl group, 6'14 6'14 square group continuation group and heterogeneous C0] 4 aryl group (preferably benzene Base, etc.). Need to have substituents and positions ", for example, the heart needs to be 3 CV6 radicals selected from the group consisting of halogen atoms, C", alkoxy, aryl, phenyl, and c, oxygen-generating groups (for example, A (Ethyl, ethylpropyl, butyl, isobutyl, second butyl, third butyl, etc.) are preferred, and special Cl_3 groups such as methyl and ethyl are preferred. Among them, Ri is represented by ⑴C &quot; alkyl (for example, Ci 4 alkyl such as methyl, ethyl, propyl, butyl, etc.). It is necessary to have a group selected from C &quot; Aryl (for example, phenyl) or (out) substituents of alkylsulfonyl (for example, methylsulfonyl) and halogen atoms (for example, L, for example, gas, fluorine, etc.) 2 fluorenyl groups represented by the formula-(0 = 0) inferior to 5, (R5 in 2 represents ①Cu alkyl (for example, Ci · 3 alkyl such as methyl), ② &amp; &quot; Fangmei (for example, benzyl) Or ③ In addition to carbon atoms, 5 to 14 membered heterocyclic groups containing j to 4 selected from one or two heteroatoms of nitrogen, sulfur, and oxygen atoms (for example, in addition to carbon atoms, 1 to 2 members selected from 5- to 6-membered heterocyclic groups such as heteroatoms of nitrogen, sulfur and oxygen atoms such as pyridyl)). As for R5 'and R5 ", phenyl or pyridyl is suitable. , R2 represents an aryl group with a substituent as needed. This paper size applies to China National Standard (CNS) A4 specifications ⑽ x 297

(Please read the phonetic on the back? Matters before filling out this page) •• 翔

I n I Βϋ n ^ F a ϋ n · n ϋ I n I iST_ &quot; ^ Description of the description (4〇) is :: Shows the "aryl group" in the "aryl group with substituents as required" No hydrocarbyl group, aromatic heterocyclic group, etc. or tricyclic) aromatic examples include C-monocyclic or polycyclic (bicyclic extraction) etc. 'Examples thereof 胄 C- &quot; aryl groups such as phenyl, naphthyl 3, biphenyl, 4-biphenyl, 2-M, etc., etc.). 6, aryl (for example, phenyl, naphthyl, naphthyl, etc., preferably phenylene from nitrogen :: group :: groups "and" from containing in addition to atom breakage ... It is preferably 5 to 10 members ; ^ One or two heteroatoms of 5 to "monovalent radicals. Heart) square group heterocyclic ring to remove an arbitrary hydrogen atom to obtain the aforementioned" 5 to 14 member (preferably 5 to 10 member ring) aromatic "Heterocycles" are: Mito :: Heterocyclic groups such as thiophene, benzophenone, benzo [b] pyran, benzo :, benzimidazole, benzothiazole, benzoiso: benzopyran ,,,, .Oh &quot; coax, thiabenzone: 0ϋ1Ηold saliva, sores, 4η · quin cocoon, isoxoline, cylindine, acridine: phlenoxanil, quinsialine, phosphine, carbazine 1 · carb Lin, brown bite, brown bite, thia saliva, isothio saliva, phenothalline, iso-salary, furobenzo, etc., and fused these rings (preferably monocyclic) and 1 or more (preferably a ) A ring formed by an aromatic ring (eg, a benzene ring, etc.). Or "aromatic heterocyclic group" is preferred, except for 5 to 4 members selected from one or two or more members (preferably 5 to 1 (members)) of nitrogen, sulfur and oxygen atoms (monocyclic or bicyclic) Heterocyclyl, etc., thienyl, 3.thienyl, 2-pyridyl, 3_ late to two 'National Standard (CNS_) 14 specifications of this paper (210 X 297 male Eding 1220900 A7 V. Description of the invention (<) Pyridyl, 3-methylamino, 4-nltyl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl 5-quinolinyl, 8-quinolinyl, r isofluorinyl ,% Isoquinolinyl, 'isoisolinolinyl, 5.isoquinolinyl, _yl, 2 • pyridyl, 4-pyridyl, 3-pyridyl, 2-misoyl, 3-taggeryl, 3_ Isothiazolyl,% isoxazolyl, dolyl L-dolyl, 3-benzyl, 2-benzothiazyl, 2-benzobenzothienyl, thienyl, 3-benzo [b] thienyl, 2-benzo Aromatic heterocyclic groups such as benzo [b] pyridyl, 3 benzo [b] furanyl, etc. The "substituent" in "aryl groups having substituents as needed" is] to 5 ', preferably 1 to 3 Are the same substituents as the "substituent" in the "hydrocarbyl group having a substituent as required" shown by R5. When there are 2 or more substituents, each The substituents may be the same or different. R2 contains (1) a Ce i4 aryl group having a substituent as needed and (2) in addition to a carbon atom, containing 1 to 4 selected from one of a nitrogen atom, a sulfur atom, and an oxygen atom, or 5 to 14-membered aromatic heterocyclic groups of two kinds of heteroatoms are preferred, and among them, preferred are halogen atoms (for example, gas atoms, fluorine atoms) or c &quot; methoxy (for example, methoxy) 5) to 14-membered aromatic heterocycles containing one or two heteroatoms selected from nitrogen, sulfur, and oxygen atoms, in addition to carbon atoms, substituted aryl groups (eg, phenyl, naphthyl), (For example, 5 to 6-membered aromatic heterocyclic groups containing 1 to 2 heteroatoms selected from nitrogen, sulfur, and oxygen atoms other than carbon atoms such as pyridyl, thienyl), etc., especially phenyl In the foregoing formulas, R3 represents a hydrogen atom, and optionally has a substituent ratio. A aryl group or an aromatic hydrocarbon group having a substituent as required. R3 shows "pyridine having a substituent as necessary "Substituent" in "base" This standard applies to the Zhongguanjia Standard (CNS) A4 specification (210 X 297 public love) &quot; --- 41 311859 (Please read the precautions on the back before filling out this page) • Install -------- ^ --------- ^^^ 1 Staff of Intellectual Property Bureau, Ministry of Economic Affairs Printed by the Consumer Cooperative 1220900 A7 ___B7 V. Description of the invention (Sulfurized sulfur atom or a group represented by formula NR4 (R4 represents a gas atom, a hydrocarbon group or a fluorenyl group with a substituent as needed). The "sulfur atom that needs to be oxidized" is S, S0, so. The "hydrocarbon group having a substituent as necessary" shown by R4 is, for example, the same group as the "hydrocarbon group having a substituent as necessary" shown by ~. In the secondary compound, a C "_6 alkyl group such as a methyl group, an ethyl group, etc., particularly a q3 alkyl group such as a methyl group, etc. is preferred. The "fluorenyl" represented by R4 is the same group as the "fluorenyl" represented by R !. Y is preferably an oxygen atom, an optionally oxidized sulfur atom, a group represented by formula 4 (R4 represents the same meaning as above), and the like, among them, an oxygen atom, an optionally oxidized sulfur atom, or formula NR4, The shown group (R4, which represents a fluorene atom or a Cu alkyl group) or the like is more preferable. Further, an oxygen atom 's, s02, NH, N (CH3), or the like is preferable, and ο or nh is particularly suitable.

In the foregoing formulas, 'Z represents a chemical bond or a divalent linear hydrocarbon group having a substituent as necessary. The "r-valent divalent linear hydrocarbon group" in the "divalent linear hydrocarbon group having substituents as necessary" is, for example, CU15 alkylene (for example, methylene, ethylene, propyl, butyl, butyl) Base, hexyl, heptyl, octyl, etc., preferably alkylene, etc.), c2_16 alkenyl (eg, vinylene, propenyl, 1-butenyl, 2-butene , 1-pentenyl, 2-pentenyl, 3-pentenyl, etc.), c2_16 alkynyl (ethynyl, propynyl, 1-butynyl, 2-butene Alkynyl, 1-pentylynyl, pentynyl, 3 · pentynyl, etc.) are preferably alkylene, particularly preferably Cw alkylene and the like. As for the size of the paper in the "divalent linear hydrocarbon group having a substituent as required" shown by Z, the Chinese National Standard (CNS) A4 specification (210 X 297 mm 43 311859 1220900 A7) is applied. 5. Description of the invention (44) The "substituent" is, for example, the same as the "substituent" of the "hydrocarbon group having a substituent as necessary" shown by R5. Z preferably has a Ci 3 alkyl group (for example, methyl group), an oxo group, etc. as necessary. Lower alkylene (for example, c16 alkylene such as methyl, ethyl, propyl, etc., especially M · 3 alkyl), of which alkylene having an oxo group as needed (eg , Ci 3 alkylene such as methylene, ethylene, especially methylene, etc. is appropriate. Soil 'In detail, the z used is -CH2_, _ (CH2) 2, CO-, _CH2C 〇 ~ (CH2) 2C〇_, _CH (CH3) _, etc. 2 3_, -CO-, etc. are suitable. The nitrogen atom in the compound ⑴ may be N_ oxidized. For example, the ring is shown as: The symbol in the same meaning as above) The nitrogen atom at the 5th position of the pyridyl group constituting the atom, which can be N_ oxidized. Humanized soil / pyridine is, for example, the chemical formula shown below Or a salt thereof: .⑴ preferred (Read precautions to fill out the back of the page) Atsushi -------- i 4- prescribed portion wise economic property Office employee consumer cooperatives PRINTED ⑼

In the formula, η represents 0 or i, and other symbols represent the same meanings as described above. For the compound, use the compound (A) shown in the following (A) to (F) ^ R1 is the slope with substituents if necessary. ° 2 Paper size_ai_gy ^) A4 size (⑽297)) soil, R2 is A7 printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 311859 1220900 5. Description of the Invention (45) A 4-aryl group with a substituent is required, R2 is a C ^ 4 aryl group with a substituent as required, and X is a sulfur atom Γ is an oxygen atom or a group represented by formula NR4 (where R4 has the same meaning as above) or (and) z is a lower alkylene group having a substituent as necessary. (B) in compound (I), Ri is ⑴Cw alkyl (for example, q * alkyl such as methyl, ethyl, propyl, butyl, etc.), (ii) is optionally selected from c ^ 6 alkylthio ( For example, methylthio), Ci 6 alkylsulfonyl (for example, methylsulfonyl), and a C6_14 aryl substituted with a substituent of a # atom (eg, gas atom, fluorine atom), or (iii) Need to have 1 or 2 formula-(〇〇) -R5, shown fluorenyl [where R5, represents ① alkyl (for example, Cl · 3 alkyl such as methyl, etc.), ② C6_ &quot; aryl (for example, phenyl ) Or ③ 5 to 14 membered heterocyclic groups containing 1 to 4 heteroatoms selected from one or two of nitrogen, sulfur, and oxygen atoms in addition to carbon atoms (for example, containing 1 to 2 in addition to carbon atoms 5 to 6 membered heterocyclic group selected from heteroatoms of nitrogen, sulfur and oxygen atoms such as pyridyl)]; R2 is a halogen atom (for example, a gas atom 'fluorine atom) or Ci as required 6 Alkoxy (for example, methoxy) substituted CO aryl (for example, phenyl, naphthyl), or in addition to carbon atoms, containing 1 to 4 selected from nitrogen? 5 to 14-membered aromatic heterocyclic groups of one or two heteroatoms of sulfur, oxygen, and oxygen (for example, in addition to carbon atoms, containing 1 to 2 heteroatoms selected from nitrogen, sulfur, and oxygen atoms 5 to 6-membered aromatic heterocyclic groups such as pyridyl, thienyl, etc.); R3 is q which is optionally substituted with 1 or 2 Ci-6 alkyl (for example, methyl) or alkoxy (for example, methoxy) μ aryl (especially phenyl) X is a sulfur atom; (please read the precautions on the back before filling this page).% pack -------- 4-

311859 1220900 A7 B7 V. Description of the invention (46) The dioxy atom depends on the sulfur atom to be oxidized or the group represented by the formula NR4, (where R4 represents a hydrogen atom or a calcined group) (especially, an oxygen atom, s, S〇2, NH, N (CH3), etc.); Z is a Cw alkyl group (in particular, c &quot; alkylene group) having an oxo group or a Ci 6 alkyl group (for example, alkyl group, methane, etc.) as required ) Or chemical bond. (c) R1 in the chemical compound (I) has 1 or 2 formulas _ (c = 〇) _R5, if necessary, so that the fluorenyl group (where R represents ①c6 "aryl" such as phenyl), ② In addition to carbon atoms, it contains 1 to 4 5 to 14 membered heterocyclic groups selected from one or two heteroatoms selected from nitrogen, sulfur and oxygen atoms (for example, in addition to carbon atoms From a heteroatom of a nitrogen atom, a sulfur atom, and an oxygen atom to a member of a heterocyclic group such as pyridyl)); R2 is a c0_M aryl group (for example, phenyl group) or contains i to 4 in addition to carbon atoms Election: 5 to 14-membered aromatic heterocyclic groups of one or two heteroatoms of nitrogen, sulfur, and oxygen (for example, in addition to carbon atoms, containing 1 to 2 atoms selected from nitrogen, sulfur, and oxygen atoms 5 to 6-membered aromatic heterocyclic group such as pyridyl) of hetero atom; R is optionally 1 or 2 C &quot; alkyl (for example, methyl) or C1 6 alkoxy (for example, methoxy) Substituted c6_14 aryl (especially phenyl); 6 X is a sulfur atom; Y is 0, or §; k

z is a chemical bond or an alkylene group having an oxo group (especially 疋 'C1-3 alkylene group such as methyl group, ethyl group, etc.) or a chemical bond. (D) Compound VII prepared in Example 1-79. (E) [4- (3,5-Diy ^ yl) _5_ (2.Phenylmethyloxypyridyl) _ This paper is a standard standard 家 χ 2 ------- ^ 46 311859 Economy Printed by the Consumer Cooperatives of the Ministry of Intellectual Property Bureau 1220900 A7 B7 V. Description of the invention (47) 1,3-thiazol-2-yl] amine (the compound of Example 1), 1 ^-[4- [2-benzylamine Methyl-4- (4-methoxyphenyl) -1,3-hydran-5-yl] -2 · pyridyl] benzidine (the compound of Example 2), N- [4- (4-methoxy Phenyl) -5- [2-[(3- Ohpyridylcarbonylamino)]-4-laridinyl] · 1,3-thiazol-2-yl] nicotinamide (the compound of Example 3), Ν -[4 · [2 -Amino-4- (4-methoxyphenyl) -1,3 · II-ylfluorene · 5-yl] -2-D specific sulfanyl] benzidine (Compound of Example 4) , Ν · [4- [2-aminoamino · 4- (3,5-dimethylphenyl) -1,3-D fluorenyl-5 · yl] -2-fluorenylmethyl] benzidine (Compound of Example 5), N- [4- [2-Amino-4- (3,5-dimethylphenyl) -1,3-salyl-5-yl] -2-D than aryl] Benzylamine (the compound of Example 6), the ratio of Ν_ [4- [2-amino-4- (3,5-dimethylphenyl) -1,3-D-methyl-5-yl] -2-D Fluorenyl] benzamidine hydrochloride (compound of Example 7), Ν- [4- [2- -4- (3,5-dimethylphenyl) - 1,3-thiazol-5-yl] -2-pyridyl] benzylamine dihydrochloride (Example Compound 8). (F) Ν- [5- (2-benzylaminoamino-4-ohsylamino) -4- (3,5-dimethylphenyl) -1,3-thiazol-2-yl] ethyl Hydrazine (compound of Example 9), ^^-[5- (2-benzylamino-4-yl-11-yl) -4- (3,5-dimethylphenyl) -1,3-fluorene Azol-2-yl] acetamide (the compound of Example 10), N- [4- [4- (4-methoxyphenyl) -2-methyl-1,3-thiazol-5-yl] -2- Pyridyl] benzidine (Compound of Example 13), N_ [4- [2- (4-fluorophenyl) -4- (3-methylphenyl) -1,3-thiazol-5-yl]- 2-pyridinyl] phenylacetamide (the compound of Example 14), N- [4- [2-ethyl-4- (3-methylphenyl) -1,3-thiazole-5-yl]- 2-Methylpyridyl] benzene (please read the precautions on the back before filling out this page) Loading -------- Qin-This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) ) 47 311859 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 1220900 A7 B7 V. Description of the invention (48) Acetylamine (compound of Example 15-2), N- [4- [4- (3-methylphenyl) ) -2 · propyl-1,3-penta-5-yl] -2-B specific phenyl] phenylacetamide (the compound of Example 15-3), N- [4- [2-butyl- 4- (3 · methylphenyl) -1 3-thiazol-5-yl] -2-pyridyl] phenylacetamide (the compound of Example 15-4), N- [4- [4- (3-methylphenyl) -2- (4-methyl Thiophenyl) -1,3-thiazol-5-yl] -2-pyridyl] phenylacetamide (the compound of Example 15-6), N- [4- [2-ethyl-4_ (3- (Methylphenyl) -1,3-thiazol-5-yl] -2-pyridinyl] benzidine (the compound of Example 16-1), N- [4- [2-ethyl_4- ( 3 -methylphenyl) _1,3 -D group Jun-5-yl] -2 -D ratio σ amidyl] -3 _ phenylpropanamine (the compound of Example 16-2), Ν- [4- [2 -Ethyl-4- (3-methylphenyl) -1,3-thiazol-5-yl] -2-pyridyl] -3- (4-methoxyphenyl) propanamide (Example 16-3 Compound), N- [4_ [2-ethyl-4- (3-methylphenyl) -1,3_fluoren-5-yl] -2 -D specific octyl] -4_phenylbutane Amine (Compound of Example 16-5), N- [4- [4- (3-methylphenyl) -2-propyl-1,3-thiazol-5-yl] -2-pyridyl] benzidine Amine (Compound of Example 16-7), N- [4- [4- (3-methylphenyl) -2-propyl-1,3-thiazole-5 · yl] -2-pyridyl] -3- Phenylpropanamine (the compound of Example 16-8), N- [4- [2-butyl-4- (3-methylphenyl) -1,3-thiazole-5-yl] -2-pyridyl Benzamidine (Example 16-9 compound), N- [4- [2-butyl-4- (3.methylphenyl) -1,3-thiazol-5-yl] -2-pyridyl] -3-benzene Propylamidine (the compound of Example 16-10), N- [4- [2- (4-fluorophenyl) -4- (3-methylphenyl) -1,3-thiazol-5-yl]- 2-Pyridine (please read the precautions on the back before filling this page) • Loading -------- *-This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 48 311859 Economy Printed by the Consumer Cooperatives of the Ministry of Intellectual Property Bureau 1220900 Α7 Β7 V. Description of the Invention (49) yl] benzamide (Compound of Example 16-11), Ν- [4- [2 · (4-Gaphenyl) -4_ (3-Methylphenyl) _ 1,3- 嚷 σs-5-yl] -2-pyridyl] -3-phenylpropanamide (the compound of Example 16-12), Ν- [4- [4- (3-methylphenyl) -2- (4-methylthiophenyl) -1,3-ammonium-5-yl] -2-pyridyl] benzidine (Example 16-15 Compound ), Ν- [4 · [4- (3-methylphenyl) -2- (4-methylthiophenyl) -1,3-fluoren-5-yl] -2-pyridylbenzene 3-benzene Propylamine (the compound of Examples 16-16), N-benzyl-N_ [4- [2-ethyl-4- (3 · methylphenyl) -1,3-thiazol-5-yl]- 2-pyridine ] Amine (Compound of Example 19-2), N- [4- [2-ethyl-4_ (3-methylphenyl) -1,3-thiazol-5-yl] -2-pyridyl] -N- (2-phenylethyl) amine (compound of Example 19-3), N- [4- [2-ethyl-4- (3-fluorenylphenyl) -1,3-fluoren-5-yl] -2-Πbifluorenyl] _N_ (3-phenylpropyl) amine (the compound of Example 19-4), N-benzyl-N_ [4- [4- (3-methylphenyl) -2 -Propyl-1,3-thiazol-5-yl] -2-pyridyl] amine (the compound of Example 19-5), N- [4- [4- (3-methylphenyl) -2-propyl -1,3-thiazol-5-yl] -2-pyridyl] -N- (2-phenylethyl) amine (the compound of Example 19-6), N- [4- [4- (3- -methyl Phenyl) -2-propyl-1,3-thiazol-5-yl] -2-pyridyl] -N- (3-phenylpropyl) amine (compound of Example 19-7), N-benzyl -N- [4- [2-butyl-4- (3-methylphenyl) -1,3 · thiazol-5-yl] -2-pyridyl] amine (the compound of Example 19-8), Ν · [4- [2-Butyl-4- (3-methylphenyl) -1,3-thiazol-5-yl] -2-pyridyl] -N- (2 · phenylethyl) amine (Example 19-9 compound), N- [4- [2-butyl-4 · (3-methylphenyl) -1,3_fluoren-5-yl] -2 -fluorenyl] _ (please Read the notes on the back before filling (This page) «§Shang -------- Order --- Qin-This paper size applies to the Chinese National Standard (CNS) A4 (210 X 297 mm) 49 311859 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Preparation 1220900 A7 ___B7___ V. Description of the invention (50) N- (3-phenylpropyl) amine (the compound of Example 19-10), N-benzyl-N- [4- [4- (3-methylbenzene Group) -2- (4-methylthiophenyl) -1,3-thiazol-5-ylb 2-pyridyl] amine (compound of Example 19-17), N- [4- [4- (3- Methylphenyl) -2- (4-methylthiophenyl) -1,3-thiazole-5 · yl] -2-Πpyridyl] -N- (2-phenylethyl) amine (Example 19-18 compound), Ν- [4- [4- (3-methylphenyl) -2- (4-methylthiophenyl) -1,3-fluorene-1 ^ -5-yl] -2_ Pyridyl] -N- (3-phenylpropyl) amine (the compound of Examples 19-19), Ν- [4- [4- (3- (methylphenyl) -2- (4-methylcontinuous group) Phenyl) -1,3-pyridyl-5-yl; 1- 2-pyridyl] benzidine (Example 20 compound), N- [4- [4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) -1,3-thiazol-5-yl] -2-pyridyl] phenylacetamide (the compound of Example 21-1), N- [4- [4- ( 3-methylphenyl) -2- (4-methylcontinued Phenyl) -1,3-fluoren-5-yl] -2-pyridyl] -3-phenylpropanamine (the compound of Example 21-2), N-benzyl-N- [4- [4 -(3-methylphenyl) -2- (4-methylsulfonylphenyl) -1,3-thiazol-5-yl] -2-pyridyl] amine (the compound of Example 21-5), N -[4- [4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) · 1,3-thiazol-5-yl] -2-pyridyl] -N- ( 3-phenylpropyl) amine (the compound of Example 21-6), N- [4- [4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) -1,3 -Thiazol-5-yl] -2-pyridyl] -N- (2-phenylethyl) amine (the compound of Example 25-1), N- (4-fluorobenzyl) -N- [4- [ 4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) -1,3 · thiazol-5-yl] -2-pyridyl] amine (the compound of Example 25-2), (S) -N- [4- (3-methylphenyl) -5- (2- (1-phenylethylamino) -4-pyridyl) -1,3-thiazol-2-yl] smoke Alkylamine, (R) -N_ [4- (3-methylphenyl) -5- (2- (1-phenylethylamino) -4-pyridyl)-(Please read the precautions on the back first (Fill in this page again) • «i equipment -------- order II- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 50 311859 Printed by the Consumer Cooperatives of the Ministry of Intellectual Property Bureau 1220900 A7 B7___ V. Description of the invention (51) 1,3-thiazol-2-yl] nicotinamide, (S) -N- [4- (3-methylphenyl) ) -5- (2- (1-phenylethylamino) -4 -D specific octyl) _ 1,3-thiazol-2-yl] -2-methylnicotinamide, (R) _N- [4- (3-methylphenyl) -5- (2- (1-phenylethylamino) -4-methyl stilbyl) _ 1.3- Thiazol-2-ylbutan-2-methylnicotinamide , (S) -N- [4- (3-methylphenyl) -5- (2- (1-phenylethylamino) -4-pyridyl) -1.3-thiazol-2-yl] -2 -Chlornicotinamide, (R) -N- [4- (3-methylphenyl) _5- (2- (1-phenylethylamino) -4-pyridyl) -1,3-thiazole 2-yl] -2-chloronicotinamide, (S) -N- [4- (3-methylphenyl) -5- (2- (1-phenylethylamino) -4-〇 Specific σdenyl) _ 1,3-thiazol-2-yl] -2-methoxynicotinamide, (R) -N- [4_ (3-methylphenyl) -5- (2- (1- Phenylethylamino) -4-methylamino) -1,3-thiazol-2-yl] -2-methoxynicotinamide, N- [5- (2-benzylamino-4- Sigma stilbene) -4- (3-methylphenyl) -1,3-ammonium 2-yl] terminal base hydrazine, N- [5- (2-benzylamino-4-hydroxypyridine) ) -4- (3-methylphenyl) -1,3-thiazole -2-yl] -2-methoxynicotinamide, N- [5- (2-benzylamino-4-laridinyl) -4- (3-methylphenyl) -1,3 -Thiazol-2-yl] -2-ylamine, 1 ^ _ [5- (2-benzylamino-4-methylpyridyl) -4- (3-methylphenyl)- 1,3-Sialyl-2-yl] -2-methylnicotinamide, N- [5- (2- (benzylideneamino) -4-pyridyl) -4- (3-methyl Phenyl) -1,3-thiazol-2-yl] nicotinylamine, N- [5- (2- (benzylamino) -4-aminomethyl) -4- (3-methyl Phenyl) -1,3-嚷 (Please read the precautions on the back before filling out this page) «i pack -------- This paper size applies to China National Standard (CNS) A4 (210 X 297 (Mm) 51 311859 W0900 A7 -----_ B7 _________ V. Description of the invention (52) Health _2_yl] -2-methyl terminal test amine, grave _ [5_ (2- (benzylideneamino) ) _4_pyridyl) -4_ (3_methylphenyl) -1,3-thiasialyl] -2-neicotinamine, N_ [5- (2- (benzylideneamino)- 4-pyridyl) -4- (3-methylphenyl) -1,3-thienyl] -2-methoxy final fluorenylamine, (S) -N- (i-phenylethyl) _4 -[2_ethyl_4 (3methylphenyl) 13thiazole-5_ylb 2-pyridylamine, (R) -N- (l-phenylethyl Group) -4- [2_ethyl_4_ (3methylphenyl) 13thiazol-yl] _2-pyridylamine, (S) -N_ (l-phenylethyl) _4_ [4- (3- (Methylphenyl) _2_propyl_13_thiazolyl_ylb_pyridylamine, (R) -N- (l-phenylethyl) _4_ [4_ (3_methylphenyl) _2_ Propyl · 13-thiazole-5-yl-2-pyridylamine, (8)-&gt; 1- (1-phenylethyl) _4- [2-butyl_4- (3-methylphenyl ) -1,3-thiazol-5-yl] -2-¾alkylamine, (R) -N- (l-phenylethyl) -4- [2-butyl-4_ (3-methylbenzene ) -I, 3-thiow-5-yl] -2-pyridylamine, (8)-&gt; 1_ (1-phenylethyl) -4- [4- (3-methylphenyl) -2- (4-methylthiophenyl) -1,3-thiazol-5-yl] -2-pyridylamine, &gt; ^ (1_phenylethyl) -4- [4- ( 3-methylphenyl) _2- (4-methylthiophenyl) -1,3-thiazol-5-yl] -2-pyridylamine, (S) -N- (l-phenylethyl) -4- [4- (3-methylphenyl) -2- (4-methylcontinylphenyl) -1,3_fluoren-5-yl] -2-¾benzylamine '(R ) -N- (l-phenylethyl) -4- [4- (3 · methylphenyl) -2- (4-methylsulfonylbenzene (Please read the precautions on the back before filling this page ) .Equipment -------- II- Staff Consumption Cooperation The paper size printed by the company applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 52 311859 3 · 5 A7 B7 Printed invention description (53 γ-based) printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs-1, 3 -Thiazole-5 its-phenylethyl), amine, (: diyl +); 2 wide base di '' phenyl) · 4 · (3 ^ phenylbenzyl wow ..., two: 'Gabenzene "You methylbenzyl)] Salts of compound (I) 'Inorganic acid salts, organic acids such as' metal salts, ammonium salts, suitable metal salts are J, and experimental or acidic amino acids, etc., salts such as Turn salt, :: metal salt such as sodium salt, _zun, etc .: Chengzhizun kM, barium salt, etc .; and aluminum, etc. Examples of alkaline earth metals are, for example, plate = m salt, etc. Appropriate: Methylamine, triethylamine, π ratio test salt: methyl hydrazone, ethanolamine, diethanolamine, three: methyl methyl beer, 2, hexylamine, Ν, Ν_ diphenyl% amine ' Examples of cyclohexylamine are as follows. Suitable for the salt formed with hydrochloric acid, hydrobromic acid, ^ a, Tian inorganic and so on. Examples of Shikikuchi M ’s acid, thiosulfate-Zhoutian organic acid salts are t L acid, phosphorus "di I acetic acid, phthalic acid, fumaric acid, oxalic acid", and formic acid, "phosphonic acid, amber" Acids' salts formed by malic acid, methanesulfonic acid, benzene and acids, maleic acid, etc. Examples of suitable basic amine acid salts: acids, Salts are, for example, and examples are, for example, 'aspartic acid, glutamic acid, and the like: 70% of the amino acid salt of glycine. Eight' is preferably a pharmaceutically acceptable salt. Its 当 'compounds, etc.), soil testing: / Inorganic salts such as metal testing salts (such as sodium salts), soil metal salts (such as dance salts, town salts, barium salts, etc.) and ammonium salts are in Jiatiankou When it has a functional group, it is compatible with inorganic materials such as hydrochloric acid, sulfuric acid, phosphoric acid, etc. and organic acids such as acetic acid, phthalic acid. The paper size is suitable for Chinese painting. _ 3, — II · III! (Please read the notes on the back before filling this page)

I ϋ ϋ ^ «I n eemm II ϋ I Φ 53 311 859 122 009,900 5. Description of the invention (54) Fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, The salts formed by toluenesulfonic acid and the like are preferred. The production method of the compound (I) is described below. The compound (Ia), (Ib), (Ic) or (Id) is included in the compound (i). Compound (I) is prepared by the method shown in the following reaction formulas i, 2, 4, and 5 or a method analogous thereto. Each symbol of the compounds in the following reaction formulas has the same meaning as described above. The compounds in the reaction formula include their salts, and their salts are the same as those of the compound VII. [Reaction formula 1] (Please read the precautions on the back before filling in this page) • 丨 丨 丨!

(II)

1) Alkali-) 2) R3COL (V)

(VI)

il! Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economics Hydrolysis

(IX) halogenation reaction

(X)

This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 54 311859 1220900 A7 B7 V. Description of the invention (55) Chemical substances (II), (Ιπ), (ν), (νιπ), (Χι), (χιι), (χνιι), (Park Π) (ΧΙχ), (ΧΧ), (XXI), (XXII), (XXVI), and (XXVII) can be used if they are known in the city, or It can be prepared by known methods or similar methods. The chelating substance (1 乂) can be obtained by examining the existence of τ and condensing the compound ⑼ with the compound (ie, by condensation. The amount of the compound (111) used is about 0.05 to about 3 moles relative to 1 mole of the compound (11). Ears, preferably about 0.8 to about 2 moles. * The amount used is about 1 to about moles, preferably about 1 to about 10 moles, relative to 1 mole of the compound ("). The" base "used is, For example, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, etc., 'inorganic test salts such as sodium hydroxide, potassium hydroxide, etc., aromatic amines such as pyridine, dimethylpyridine, etc., tertiary amines such as triethyl Amine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, μ j methylaniline, N-methyl piperazine, sense methyl ... N_f morpholine, etc., metal hydrides For example, sodium hydride, hydrogen hydride, etc., metal amine compounds such as sodium amine, lithium diisopropylamide, hexamethyldistone azide, etc., metal alkoxides such as sodium methoxide, sodium ethoxide, third butanol Potassium, etc. ^ It is advantageous to perform the reaction without a solvent or in the presence of an inert solvent, as long as the reaction can proceed, the solvent is not particularly limited, For example, the calcining furnace ^ hydrocarbons, aromatic hydrocarbons, ethers, amines, alcohols, water, or two or more of them: can be used. The reaction temperature is usually about -5 ° C to about 200 ° C, more than The best time is about 5 1 5 0 C. The reaction time is usually 5 minutes to about 7 2 hours: Du I ----------- Mach 1 The best is about 0.5 This paper size applies Chinese national standards ( CNS) A4 specification (210 X 297 mm_) ----- 55 311857 -------- ^ — (Please read the notes on the back before filling out this page) #-Staff of the Intellectual Property Bureau of the Ministry of Economic Affairs Printed by the Consumer Cooperative 1220900 A7 B7 __ 5. Description of the invention (56) to about 20 hours. Although the reaction product can be used directly or as a crude product in the next step, it can also be separated from the reaction mixture and borrowed according to conventional methods. For example, purification is performed by recrystallization, distillation, and chromatography. Compound (vi) is prepared by subjecting compound (IV) to condensation treatment with compound (V). In compound (V), L means leaving. The "leaving group" shown by L is, for example, ①q · 6alkoxy (for example, methoxy, ethoxy, etc.), ②dialkylamino (for example, dimethylamino Diethylamino, etc.), ③N_C6io aryl-N-CV, alkylamino (for example, N_phenyl_N_methylamino, etc.), ④ if necessary, 〇6 · 1 () aryl and (or ) Cw alkyl substituted 3 to 7-membered cyclic amine groups (eg, pyrrolidinyl, morpholinyl, methylaziridine, etc.), (g) N_Cw alkyl_N-Cw alkoxyamines (For example, N_methoxy_N_methylamino, etc.) Further, the "leaving group" that L does not have is, for example, a hydroxyl group, a pixel atom (for example, fluorine, gas, mo, iodine, etc.), Toothed Cm alkylsulfonyloxy (for example, methanesulfonyloxy, ethanesulfonyloxy, trigasmethanesulfonyloxy, etc.), arylsulfonyloxy with substituents as required Base etc. As for the "C0_1G arylsulfonyloxy group having a substituent as necessary" is a dagger having 1 to 3 optional Cw alkyl, Ci 6 alkoxy, and nitro substituents, an arylsulfonyloxy group (Eg, phenylsulfonyloxy, naphthylsulfonyloxy, etc.), examples of which are benzylsulfonyloxy, m-nitrobenzenesulfonyloxy, p-toluenesulfonyloxy, etc. γ is relative to 1 The mole compound (IV) is used in an amount of about 0. 8 to about 3 moles, preferably about 1 to about 12 moles. "Examination" used is' for example, metal amines such as sodium amine, diisobenzyl, and sizing standards (CN_S) A4 size ⑵〇x 297 mm) ---- ^ &quot; 311859 (please read the back first Please note this page before filling in this page) • equipment -------- ^ 1. 1220900 A7 B7

V. Description of the invention (57) Lithium propylamide, lithium hexamethyldisilazide and the like. Hydrocarbon ° c This reaction is carried out in the absence of a solvent or in the presence of a reaction-inert solvent. The solvent is not particularly limited as long as the reaction can proceed. For example, an aliphatic aromatic hydrocarbon, an ether, or a mixture of two or more thereof. Etc. can be used. The reaction temperature is usually about -78 to about 60 (rc, preferably about -78 to about 20). The reaction time is usually about 5 minutes to about 24 hours, preferably about 0.05 to about hour. Although the reaction product may be directly or roughly The product is used in the next reaction, but it can also be separated from the reaction mixture by conventional methods and can be purified by separation methods such as recrystallization, distillation, chromatography, etc. Compound (VII) The compound can be treated by halogen or metal halide (VI). If necessary, this reaction can be carried out in the presence of a test or test salt. The amount of halogen or metal halide used is about 1 to about 5 mols relative to 1 mol of compound (VI), It is preferably about 1 to about 2 moles. "Halogen" is bromine, chlorine, iodine, etc. "Metal halide" is a steel halide such as copper bromide (π), copper chloride (H), etc. Relative to 1 mole The ear compound (VI) is used in an amount of about 1 to about 30 moles, preferably about 1 to about 10 moles. The "base" used is, for example, an inorganic salt such as sodium hydroxide, potassium hydroxide, hydrogen Lithium oxide, etc., alkaline salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, etc., aromatic Amines such as pyridine, dimethylpyridine, etc., tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N_methylpiperidine, N-methylpyrrolidine, N- (Please read the precautions on the back before filling out this page). Scale Pack -------- Order — Consumer Consumption Cooperative of Intellectual Property Bureau, Ministry of Economic Affairs The paper size for printing is applicable to the Chinese National Standard (CNS) A4 (210 X 297 mm) 57 311859 1220900 A7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (58) Methylmorpholine, etc. This reaction It is solvent-free or in the presence of a reaction-inert solvent. However, as long as the reaction can proceed, the solvent is not particularly different. For example, bonds, bonds, square hydrocarbons, aliphatic hydrocarbons, and dentified hydrocarbons. The sulfoxide, the organic amine, or a mixture of two or more thereof can be used. The reaction temperature is about -20 to about 15 (rc, preferably about 0 to about 100). The reaction time is usually 5 minutes to About 24 hours, preferably: about 5 hours. Although the reaction product can be used directly or as a crude product in the next reaction, it can also be used. Isolate it from the reaction mixture by conventional methods and purify it by separation methods such as recrystallization, distillation, chromatography, etc. Compound (h) can be prepared by condensing compound (VII) with compound (VIII). If necessary, this The reaction can be carried out in the presence of a base. In the compound (VII), Hal represents halogen. If the compound (VIII) is commercially available, it can be used as it is, or it can be further known by a method or according to the reaction formula 3 Prepared by the method. The amount of the compound (νπι) used is about 0.5 to about 3 moles, preferably about 08 to about 2 moles, relative to 1 mole of the compound (νπ). VII), the amount of base used is from about 1 to about 30 moles, preferably from about 1 to about 10 moles. The "bases" used are, for example, inorganic bases such as sodium hydroxide, potassium hydroxide, rat lithium oxide, etc., test salts such as sodium carbonate, carbonate, sodium carbonate, sodium bicarbonate, etc., aromatic amines such as pyridine, dimethyl Pyridine, etc. Examples of tertiary amines # Di ^ &amp; amine 'Tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylamine Basic paper standards are based on Chinese Standards (CNS) A4 ^ 1 () χTear public love) ^ 3ΐΐ859 (Please read the precautions on the back before filling in this page} _ «· Installation ---- Order --- Qin | 1220900 A7 V. Description of the invention (59) π ratio, N, N _ Dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N_fluorenylmorpholine, etc. It is advantageous to perform the reaction without a solvent or in the presence of a reaction-inert solvent, but as long as the reaction can proceed, the solvent There is no particular limitation, for example, a hydrogenated hydrocarbon, an aliphatic hydrocarbon, an aromatic hydrocarbon, an ether, amidine, an alcohol, a nitrile, or a mixture of two or more thereof may be used. The reaction temperature is usually about -5 to about 200 ° C. , Preferably about 5 to about 15 ° C. The reaction time is usually 5 minutes to about 72 hours, preferably about 05 to about 30 hours. Although the reaction product may be directly It can be used as the crude product in the next reaction, but it can also be separated from the reaction mixture by conventional methods and purified by separation methods such as recrystallization, distillation, and chromatography. The compound (la) can be prepared by acid treatment. The compound (Ix) is obtained. The amount of the acid used is about 1 to about 100 moles, preferably about 1 to about 30 moles, relative to 1 mole of the compound (la). The "acid" used is, for example, Inorganic acids such as hydrochloric acid, osmium bromide, sulfuric acid and other organic acids such as acetic acid, propionic acid, trifluoroacetic acid, etc. This reaction is advantageously performed without a solvent or in the presence of a reaction-inert solvent, but as long as the reaction can proceed, the solvent Special restrictions, for example, use of water, a mixture of water and amidine, a mixture of water and alcohol, etc. The reaction temperature is usually about 20 to about 200. (:, preferably about 60 to about 150 ° C. The reaction time is usually It is 30 minutes to about 72 hours, preferably about i to about 30 hours. Although the reaction product can be used directly or as a crude product for the next reaction, this paper size applies the Chinese National Standard (CNS) A4 specification (21 °). X 297 male f)-1 --- 59 311859 ( Read the Zhuyin on the back? Matters and then fill out this page) Install -------- ^-I ------ ^^^ 1 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs! 22〇9〇 〇Α7 Β7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 5. Description of the Invention (60) The conventional method can also be used. Jiang: Gwaf eight self-reaction, separation of this compound and borrowing, such as renewing, steaming, Purification by chromatography and other separation methods. Then, the compound (⑻) can be prepared by treating the compound (ιχ) with a chemical agent. Relative to 1 mole, the human t, τν, ^ are compounded. (IX), the amount of halogenating agent used is about 10 moles, preferably about! To about 5 moles. The "chemical agents used in β" are sulfite gas, pentagas, and acid gas. This reaction is advantageous in that the reaction is carried out in the presence of a solvent, but as long as the reaction can proceed, the solvent is not particularly limited, such as, &quot;, use, aromatic hydrocarbons, aliphatic hydrocarbons, amines, and dendritic hydrocarbons. , Nitrile, maple, aromatic acid, aromatic amine, or a mixture of two or more thereof can be used. The reaction temperature is usually about -20 to about 15 ° C, preferably about 0 to about 100 ° C. The reaction time is usually 5 minutes to about 24 hours, preferably about 10 minutes to about 5 hours. Although The reaction product can be used directly or as a crude product in the next reaction, but it can also be separated from the reaction mixture by conventional methods and purified by separation methods such as recrystallization, distillation, and chromatography. Compound (X) Compound (Ib) can be prepared by condensing with compound (XI). If necessary, the reaction can be carried out in the presence of a test. The amount of the base to be used is about 08 to about 30 moles relative to 1 mole of compound (X). It is preferably about 1 to about 10 moles. The "base" used is, for example, a basic salt such as sodium carbonate, potassium carbonate, carbonic acid, etc., an inorganic salt such as sodium nitrate, potassium nitrate, etc., and an aromatic amine such as pyridine , Dimethylpyridine, etc., tertiary amines such as triethylamine, tripropylamine, triamine, hexamethylene monomethylamine, 4-monomethylamino group,] Sf, N -dimethylaniline, paper Standards apply to China National Standard (CNS) A4 (210 x 297 mm) 311859 Please read back Si Please re-fill this note I _ binding

A7 V. Description of the invention (M, N-f-piperidine bite, N-methylpyrrolide bite, N-methyl compounds such as sodium hydride, hydrogenated M "" test metal weathering potassium, etc., metal amidates such as amination Sodium, monopropyllithium amide, sodium hexamethyldi-pentanoate, sodium ethoxide, tertiary butyl alkoxides such as sub-alcohols This reaction is carried out without solvent or in the presence of a reaction-inert solvent, as long as the reaction is acceptable; There is no particular limitation on the solvent to be reacted. For example, a solvent, a formulae, or a mixture of two or more thereof may be used. That is, the reaction temperature is usually about 200 to about 200 t, preferably t 17〇 ° C. The reaction time is usually from 58 to about 24 hours. For the knife clock to about 72 hours, preferably about .5 although the reaction product itself can be used as a reaction solution or a crude product. ^ It should be used, but it can also be separated from the reaction mixture by known methods: for example, recrystallization, distillation, chromatography and other purification methods. [Reaction formula 2] Φ Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

This paper size applies Chinese National Standard (CNS) A4 specifications (210 311859 1220900 Α7 Β7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, printed by i, invention description (63)), but the solvent is not particularly limited as long as the reaction can proceed, such as The use of aliphatic hydrocarbons, aromatic hydrocarbons, ethers or a mixture of two or more thereof can be used. The reaction temperature is usually about -78 to about 60 ° C, preferably about -78 to about 20 C. The reaction time is usually About 5 minutes to about 24 hours, preferably about 0 5 to about 3 hours. Although the reaction product can be used directly or as a crude product in the next reaction, it can also be separated from the reaction mixture by conventional methods and borrowed from, for example, It is purified by separation methods such as recrystallization, distillation, chromatography, etc. Compound (XV) can be prepared by treating compound (XIV) with halogen or metal halide. If necessary, this reaction can be carried out in the presence of a base. Relative to 1 Mo Ear compound (XIV), the amount of halogen or metal halide used is about 1 to about 5 moles, preferably about 1 to about 2 moles. "Halogen" is bromine, gas, iodine, etc. "Metal Aide" is Steel compounds such as brominated steel ( π), vaporized copper (π), etc. The amount of base used is about 1 to about 10 mols, preferably about 1 to about 3 mols, relative to 1 mol compound (XIV). The "test" used is For example, test metal salts such as sodium hydroxide, bell hydroxide, bell hydroxide, etc., test salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, etc., aromatic amines such as Π,唆 and the like, tertiary amines such as diethylamine, dipropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylamino group I1 to 唆, Ν, Ν-monomethylaniline, Ν-methylpiperidine, Ν-methyl P bilo bite, Ν-methyl morpholine, etc. This reaction is carried out without solvent or in the presence of a reaction-inert solvent. This paper is in accordance with the Chinese National Standard (CNS) A4 specification (21〇χ 297 mm). ) 63 311859 (Please read the precautions on the back before filling out this page) Pack ----- ϋ · 1 1 Hitomi ^ 1. 1220900 A7 V. Description of the invention (64) Profits, but as long as the reaction can proceed, the solvent and Without particular limitation,:, square hydrocarbons, aliphatic hydrocarbons, ammonium amines, anhydrolized hydrocarbons, nitriles, and maple's are :, aromatic amines, or mixtures of two or more thereof. 2. The reaction temperature is about -20 to about 150 t, preferably about 0 to about 150. The reaction time is usually 5 minutes to about 24 hours, preferably about 10 minutes. Although printed by a cooperative, the reaction product can be directly or in the form of a crude product. The reaction can also be separated from the reaction mixture by conventional methods and purified by separation methods such as recrystallization, distillation, chromatography, etc. ° To make compounds (XV ) And compound (VIII) are condensed to prepare compound (X VI). If necessary, the reaction can be carried out in the presence of a base. In compound (XV), Hal represents halogen. If the compound (VIII) is commercially available, it can be used as it is, or it can be prepared by a known method or a further method shown in Reaction Formula 3. The amount of the compound (νπι) used is about 0.5 to about 3 moles, preferably about 0.8 to about 2 moles, relative to 1 mole of the compound (XV). The amount of the base used is about 1 to about 30 moles, preferably about 1 to about 10 moles, relative to 1 mole of the compound (XV). The "examination" used is, for example, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium acetate, etc., aromatic amines such as D-bite, dimethylamine, etc., 'tertiary amines such as triethyl Amine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, ν, N-dimethylaniline, N-methylpiperazine, N-methylpyrrolidine, N_methyl Morin and so on. This reaction is carried out without solvent or in the presence of a reaction-inert solvent. The paper size applies Chinese National Standard (CNS) A4 (210 X 297 mm) 311859. Please read the precautions on the back before filling in this page} 1 ^ Packing -------- Order --------- 1220900 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 65 Β7 V. Invention Description (65) ~-Profits, but as long as the reaction can proceed, The solvent is not particularly limited, and for example, a dentified hydrocarbon, an aliphatic hydrocarbon, an aromatic warp, a sulfonamide, an alcohol, a nitrile, or a mixture of two or more thereof may be used. The temperature is usually about _5 to about 5%, preferably about 5 to about &quot; c. The reaction time is usually 5 minutes to about 72 hours, and more preferably about 30 hours. Although the reaction product itself can be used as a reaction solution or a crude product for the next reaction, it can also be separated from the reaction mixture by using $ and purified by separation methods such as recrystallization, crystallization, distillation, and chromatography. Compound (XVI) can be prepared by treating acid (XVI) with acid or base. The amount of acid or base used is about 01 to about 50 moles, preferably about 1 to about 20 moles, relative to 1 mole of human μ / VWT. ear. The "acid" used is, for example, an inorganic acid such as hydrochloric acid, hydrogen acid, sulfuric acid, and the like, a Lewis acid such as boron trichloride, boron trioxide, and the like, and a Lewis acid or sulfide, and an organic acid such as three Fluoroacetic acid, p-toluene acid, etc. The "alkali" is, for example, metal hydroxides such as sodium hydroxide, potassium oxide, barium hydroxide, etc., and test salts such as sodium carbonate, carbonic acid, sodium methoxide, sodium ethoxide, and third butanol. Potassium and other organic tests such as diethylamine, imidazole, formamidine, etc. This reaction is advantageous in the absence of a solvent or in the presence of a reaction-inert solvent, but the solvent is not particularly limited as long as the reaction can proceed. Examples include alcohols, ethers: aromatic hydrocarbons, aliphatic hydrocarbons, fumes, sulfoxide, Water or a mixture of two or more thereof. Xiongxi this paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 male shame) 311859 (Please read the precautions on the back before filling this page). Outfit -------- Order --- ------ 1220900 A7

1220900 A7, Description of invention (67) The reaction is used, but it can also be separated from the reaction mixture by I method and purified by separation methods such as recrystallization, grave distillation, crane, chromatography, etc. After the bean, if necessary ' Then you can carry out trivalent reaction or tritiary reaction to synthesize compounds where R4 is other than hydrogen atom. [Reaction formula 3] R CONCS (XIX) r6h R CONH-C-R (XX)

(Please read the precautions on the back before filling out this page) R CSNH, (VIII) Compound (XX) is produced by the condensed compound (XIX) and printed by the consumer property cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Intellectual Property Bureau of formula R6H . R6 represents the "amine group which may have a substituent as needed" shown by said R1. In formula (XIX), R5 represents an alkoxy group, for example, a Cw alkoxy group such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, and the like. The amount of "amine" to be used is about i to about 30 moles, preferably about 1 to about 10 moles, relative to 1 mole of the compound (XIX). This reaction is carried out without solvent or in the presence of a reaction-inert solvent. The paper size is applicable to the Chinese National Standard (CNS) A4 (210 X 297 mm) 67 311859 1220900 A7 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Description of the invention (68) However, as long as the reaction can proceed, nourishing: sword *-^, there are no particular restrictions on the stimulants, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, sulfonium amines , Alcohols, nitriles, amidines, or a mixture of two or more of them may be used. 'The reaction temperature is usually about -50c to about 7ηη〇Γ # 社 去. The king is about 20 ° C, preferably about 5 to about 120 ° C. The reaction time is usually about 5 minutes to about 72 hours, preferably about 0.5 to about 30 hours. Although the reaction product can be used directly or cut to the crude product for use in the next step, it can also be separated from the compound by conventional methods, such as recrystallization, distillation, chromatography, etc. It was purified. Compound (viii) is prepared by hydrolyzing compound αx) using an acid or a base. Relative to 1 mole compound (χχ), the amount of acid or test used is about 01 to about 50 moles, preferably about 1 to about 20 moles. The "acid" used is, for example, an inorganic acid such as hydrochloric acid, etc., a Lewis acid such as boron trichloride, boron tribromide, or the like, or an sulfide, and an organic acid such as trifluoroacetic acid. The "base" used is, for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide, etc., basic salts such as sodium carbonate, potassium carbonate, sodium acetate, etc., and metal alkoxides such as sodium methoxide, sodium ethoxide, Potassium tert-butoxide, etc. Organic tests such as triethylamine, imidazole, formamidine, etc. It is advantageous to perform the reaction without a solvent or in the presence of a reaction-inert solvent. However, as long as the reaction can proceed, the solvent is not particularly limited. For example, by-product alcohol, ether, aromatic hydrocarbon, aliphatic hydrocarbon, halogenated hydrocarbon, submill, Water or two or more of its paper sizes are subject to Chinese National Standard (CNS) A4 specifications (210 X 297 mm hydrobromic acid, sulfo-louis, and thio-p-toluenesulfonic acid (please read the precautions on the back before filling this page) «褒 -----« — III — — — 4 ^-· 68 311859 1220900 V. Description of the invention (69) Mixture, etc. The reaction time is usually about 10 minutes to about 50 hours, preferably about 30. Minutes to about 12 hours. The reaction temperature is about 0 to about 200 ° C, preferably about 20 to about 120 ° C. The compound (VIn) can be prepared by treating the compound (XXJ) with hydrogen sulfide in the presence of a base. The amount of hydrogen sulfide used is about 1 to about 30 moles relative to 1 mole of the compound (XXI). The amount of base used is preferably about 1 to about 30 moles relative to 1 mole of the compound (χχι), preferably About 1 to about 10 moles. The "base" used is, for example, an aromatic amine such as pyridine, dimethylpyridine Etc., secondary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N_methyl 11 pyridine, N-methylmorpholine, etc., ammonia water, etc. This reaction is advantageously carried out without a solvent or in the presence of a reaction-inert solvent, but the solvent is not particularly limited as long as the reaction can proceed, for example, halogenated hydrocarbons, lipids All of the hydrocarbons, aromatic hydrocarbons, ethers, aromatic amines, or mixtures of two or more thereof can be used. This reaction is carried out under atmospheric pressure or reduced pressure. The reaction temperature is about -20 to about 80. :, Preferably about -10 to about 3 (Γ (:. The reaction time is usually about 5 minutes to about 72 hours, preferably about 0.05 to about 30 hours. Although the reaction product itself can be used as a reaction solution or The crude product is used in the next step, but it can also be separated from the reaction mixture according to conventional methods and purified by methods such as recrystallization, distillation, chromatography, etc. This paper size applies the Chinese National Standard (CNS) A4 specification ( 210 X 297 mm) 311859 ί Please read the notes on the back before filling in this ) _________ Order _________ Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 69 1220900 A7 V. Description of the invention (70) The compound (vm) can also be processed by phosphorus pentasulfide or Lawesson reagent The compound (χχΙΙ) is prepared. The amount of the phosphorus pentasulfide or Laverson reagent used is about 0.5 to about 10 moles, preferably about 0.05 to about 3 moles, relative to 1 mole of the compound (XXII). The reaction is preferably carried out without a solvent or in the presence of a reaction-inert solvent, but the solvent is not particularly limited as long as the reaction can be performed, for example, ether, aromatic hydrocarbon, aliphatic hydrocarbon, i-hydrocarbon, or a mixture of two or more thereof be usable. The reaction time is usually about 10 minutes to about 50 hours, preferably about 30 minutes to about 12 hours. The reaction temperature is usually about 0 to about 15 (rc, preferably about 20 to about 120 ° C.) Although the product (VIII) can be used as a reaction solution or as a crude product in the next reaction, conventional methods can also be used. It can be separated from the reaction mixture and purified by separation methods such as recrystallization, distillation, and chromatography. When compound (1) (comprising compounds (Ia), (Ib), and (Ic)) is an amido compound The target compound is obtained by subjecting the corresponding amine compound to a known amination reaction. For example, 'in the compound R, R1 is a 醯 amino group having a substituent if necessary'. In the presence of a base or an acid, the corresponding 2 • It is prepared by reacting thiazolamide with a halogenating agent. The amount of halogenating agent used is about 1 to about 5 moles, preferably about i to about 2 moles, relative to 2-thiazolamide corresponding to 1 mole. "Brewing agent" is, for example, a carboxylic acid corresponding to the target fluorenyl group or a reactive derivative thereof (fluorenyl halide, anhydride, ester, etc.), etc. The base used or the 2-thiazolamide corresponding to 1 mole corresponds to The amount of acid is about &amp; Zhang scale applicable home standard (CNS) A4 ^^ depending on public love)-C Please read first Please fill in this page again if necessary. F Pack -------- ^ __________ Printed by the Employees ’Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 311859 1220900 Printed by the Employees’ Cooperatives of the Intellectual Property Bureau of the Ministry of Economy ___B7 V. Description of the invention ( 71 0.8 to about 5 moles, preferably about 1 to about 2 moles. The "test" used is, for example, triethylamine n 4-pyridine, etc.-The "acid" used for the T amino group is, for example, formazan Burning acid, p-methylbenzylsulfonic acid, etc. ', It is considered to be advantageous to perform the reaction without a solvent or in the presence of a reaction-inert solvent', but as long as the reaction can proceed, the solvent is not particularly limited. Hydrocarbons, aliphatic fumes, ammonium amines, hydrocarbons, nitriles, sulfonates, aromatic amines, or mixtures of one or more thereof may be used. The reaction temperature is usually from about 20 to about 15 rc, preferably about 0 To about 100 t. The reaction time is usually 5 minutes to about 24 hours, preferably about 10 minutes to about 5 hours. Although the reaction product itself can be used as a reaction solution or as a crude product for the next reaction, it can also be used Isolate it from the reaction mixture using conventional methods and recalculate it for example , Be distillation, chromatography and other separation means was purified compound may also use the method shown ⑽ reaction formula 4 or prepared according to the method is a method [Chemical Formula 4]

Peroxyacid, hydrogen peroxide or chloroperoxide

(Id) (Please read the notes on the back before filling this page) Loading ----- --- Order --------- This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 71 311859 1220900 A7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (72) The compound (id) is prepared by treating compound VII with organic peroxyacid. Relative to! Amount of organic peroxyacid used for Mohr compound ⑴ ': approx. 8 to about 10 moles' is preferably about i to about 3 moles. "Organic peroxyacid" is, for example, peracetic acid, peracetic acid, perbenzoic acid, and the like. This reaction is advantageously carried out without a solvent or in the presence of a reaction-inert solvent, but the solvent is not particularly limited as long as the reaction can proceed, for example, hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, organic acids, bonds, amines, amines, Maple, alcohol, diet, ketone or a mixture of one or more thereof may be used. . The reaction temperature is usually about -20 to about 13 (rc, preferably about 0 to about _. (:. The reaction time is usually from 5 minutes to about 72 hours, preferably from about to about 12 hours.) Or compound (Id ) Can also be prepared by treating the compound ⑴ with hydrogen peroxide or alkyl hydroperoxide in the presence of acid, or metal oxide. = For 1 mole compound ⑴, the hydrogen peroxide or hydroperoxy group used The amount is from about 0.8 to about 10 moles, preferably from about i to about 3 moles. Alkyl hydrogen peroxide "is, for example, 'third butyl nitrogen peroxide, cumene hydrogen peroxide, and the like. 1 mole compound ⑴, the amount of test, acid or metal oxide used is about G.1 to about 3 G mole, preferably about G 8 to about 5 mole. "Base" is, for example, an inorganic base such as hydrogen Sodium oxide ', potassium hydroxide, etc., basic salts such as sodium carbonate, potassium carbonate, sodium acetate, etc. "Acids" are, for example, inorganic acids such as hydrochloric acid, sulfuric acid, and Lewis acids such as diguiporium. ^ ^ _ Boronization , Aluminum oxide, titanium tetrachloride, etc., organic acid examples t specifications ⑽χ tear public love) 72 311859 (Please read the precautions on the back before filling this page ) Equipment -------- Summer — — — — — — — — 1220900 A7

5. Description of the invention (73) Formic acid, acetic acid, etc. "Metal oxides" are, for example, 'Vanadium oxide (V205), H4O4), tungsten oxide (WO3), oxide (MgO3), chromium dioxide (Cr03), and the like. 2 'It is advantageous to carry out the reaction without a solvent or in the presence of a reaction-inert solvent', but the solvent is not particularly limited as long as the reaction can be performed, for example, a dentified hydrocarbon, an aliphatic hydrocarbon, an aromatic hydrocarbon, an organic acid, an ether, a halogen Amine, maple, alcohol, nitrile, ketone, or a mixture of one or more thereof can be used. The reaction temperature is usually about 20 to about 130 t, preferably about 0 to about ° C. The reaction time is usually 5 minutes to about 72 hours, and preferably about 0.00 to about 12 hours. Although the reaction product itself can be used as a reaction solution or as a crude product for the next reaction ', it can also be separated from the reaction mixture by conventional methods and purified by separation methods such as recrystallization, distillation, and chromatography. Alternatively, compound (Ic) can also be prepared by the method shown in the following reaction formula 5: [反应 式 5] ------------ «» 装 -------- ^- -------- (Please read the notes on the back before filling out this page) Printed by the Employees' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs This paper is sized for the Chinese National Standard (CNS) A4 (210 X 297 mm) 73 311859 1220900 A7 B7 V. Description of the invention (74)

R -ZL (XVIII)

R] csmz (vim)

(1C) Compound (XXIII) can be produced by deprotecting compound (XIV) using an acid or a base. Relative to compound (XIV), the amount of acid or test used is about ft 1 21 to about 50 moles, preferably about 1 to about 20 moles. · The "acid" used is (Please read the notes on the back before filling this page) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, for example, inorganic acids such as hydrochloric acid, h acid, etc., and Lewis acids such as boron trichloride , Boron tribromide, etc., lice /, acid, sulfur, fermentation or sulphide are used together, organic acids such as two-Lewis and Hong-qi acid, materials, etc. The "test" used for the mepensulfur test is, for example, metal oxides such as osmium potassium oxide, barium hydroxide, etc., test salts such as sodium oxycarbonate, -sodium, potassium carbonate, etc. Salts such as sodium methoxide, sodium ethoxide, diethylamine, triethylamine, miso, methyl vein, etc. ^ Paper size applies Zhongguanjia standard x 297 mm)

31185Q Pack -------- ^ --------- Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 1220900 V. Description of the invention (75 This reaction is in the absence of a refrigerant or in the presence of an inert solvent It is advantageous to proceed as long as the reaction can be performed 'the solvent is not particularly limited, for example, the use of alcohols, ethers, aromatic hydrocarbons, cooking, detection μ. _ Yue Yue no enthalpy' halogenated hydrocarbons, Asian maple, water or two or Various kinds of mixtures, etc. The coin horse is about 10 minutes to about 50 hours, preferably about 30 minutes to about 12 hours. The reaction temperature is about G to about fine. C, preferably about 20 to about 120 ° C. Although the reaction product itself can be used as a reaction solution or as a crude product for the next reaction, it can also be separated from the reaction mixture by conventional methods and purified by separation methods such as recrystallization, distillation, and chromatography. XXIV) It can be prepared by condensing a compound with compound (XVIII) in the presence of a base, if necessary. The amount of compound (xvm) used is about 0-8 to about 5 moles, relative to 1 mole of compound (XXII). About mol to about 3 moles, relative to i mole compounds (XXIII), The amount is about 0 "to about 3 moles, preferably about 03 to about 12 moles. The" test "used is, for example, a test salt such as sodium carbonate, potassium carbonate, sodium acetate, etc., and an inorganic test such as hydrogen Sodium oxide, aerobic oxidation, etc., aromatic amines such as gadolinium, dimethyl, etc., tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylamine Howl, N, N-dimethylaniline, N-methylpiperidine, N_methylpyrrolidine, N_methylmorpholine, etc., alkali metal hydrides such as sodium hydride, trioxine, etc., metal amines For example, sodium amination, diisopropyl amination, hexamethyldibuminyl a.m T Φ lithium silicon azide, etc., metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, and the like. Zhang scale is applicable to Zhongguanjia Standard (CNS) A4 specification (2iq χ 29) 311859 (Please read the precautions on the back before filling this page) Installation 丨 丨 丨 ---- ^ --------- 75 1220900 A7 —__________ B7__ V. Description of the invention (76) A ---- This reaction is advantageously performed in the absence of a solvent or in the presence of a reaction inert solvent ', but as long as the reaction can proceed, the solvent is not particularly limited, For example, the fat brigade ----------- i. Mu Guang, please read S3 first and then fill in the tribute), Fang Lagar, ether, water or a mixture of two or more of them Can be used. . The reaction temperature is usually about -78 to about 100. (:, Preferably about -78 to about 70 ° C. The reaction time is usually about 5 minutes to about 24 hours, preferably about 0.5 to about 20 hours. Although the reaction product itself can be used as a reaction solution or a The crude product should be used below, but it can also be separated from the reaction mixture by conventional methods and purified by separation methods such as recrystallization, distillation, chromatography, etc. Compound (XXV) can be treated with halogen or metal halide Compound (XXIV). This reaction can be carried out in the presence of a base or a basic salt if necessary. The amount of halogen or metal halide used is about 1 to about 5 moles relative to 1 mole of compound (XXIV). It is preferably about 1 to about 2 moles. "Self-priming" is bromine, gas, exchange, etc. "Metal halide" is a steel precursor such as copper bromide (11), gasified copper (11), etc. Intellectual property of the Ministry of Economic Affairs The bureau ’s consumer cooperative prints about 1 to about 10 moles, preferably about 1 to about 3 moles, relative to 1 mole of compound (XXIV). The base used is, for example, a metal test salt such as Sodium hydroxide, potassium hydroxide, lithium hydroxide, etc., alkaline salts such as sodium carbonate, carbon Potassium acid, carbonate, sodium bicarbonate, sodium acetate, etc., aromatic amines such as pyridine, dimethylpyridine, etc., secondary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-diamine Methylamine π specific bite, N, N_dimethylaniline, N_methylpiperidine, N_methylpyridine Paper size national standard (CNS) A4 specifications (210 X 297 public love) 76 311859 1220900 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (77) Pyridine 'N-methylmorpholine, etc. This: It should be carried out without solvent or in the presence of a reaction inert solvent, as long as the reaction can proceed The solvent is not particularly: = Hydrocarbons, nitriles, fluorenes, acid diamines, and one or more of them can be used. The reaction temperature is about -20 to about 15.0, preferably about 0 to about == Usually 5 minutes to about 24 hours, preferably about i. Minutes to minutes Although the reaction product itself can be a reaction solution or used as a crude product in the next reaction, it can also be separated from the reaction mixture by conventional methods And purified by separation methods such as recrystallization, distillation, and chromatography. Ic) can be prepared by condensing compound (χχν) with compound (Vi〗). This reaction can be carried out in the presence of a base if necessary. In compound (XXV), Hal represents halogen. Relative to 1 mole compound (χχν) The amount of the compound (vm) used is about 0.5 to about 3 moles, preferably about 08 to about 2 moles. Compared to 1 mole of the compound (χχν), the amount used is about 1 to about 3 Mol, preferably from about 1 to about 10 mol. The test used is, for example, a test salt such as sodium carbonate, potassium carbonate, carbonate carbonate, sodium bicarbonate, sodium acetate, etc., aromatic amines such as pyridine, diamine Methylpyridine and the like, tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N_dimethylaniline, N_methylpiperidine, N-methylpyrrolidine, methylmorpholine and the like. &amp; The reaction is carried out without solvent or in the presence of a reaction inert solvent. The paper size applies Chinese National Standard (CNS) A4 specifications (210 X 297 Public Love 77 311859 (Please read the precautions on the back before filling this page). -------- ^ --------- ^^^ 1 · 1220900 A7 V. Description of the Invention (⑽) The "base" used is, for example, alkali metal salts such as sodium hydroxide, hydroxide Potassium, lithium hydroxide, etc., basic salts such as sodium carbonate, potassium carbonate, carbonic acid, sodium carbonate sodium hydrogen acetate, etc., aromatic amines such as D specific bite, dimethyl H specific bite, etc., primary amines such as diethylamine , Tripropylamine, tributylamine, cyclohexyldimethylamine, anorthodimethylamine, Nn-based aniline, N-methylamine, ~ methylrotidine, N-methylmorpholine, etc. This reaction It is advantageous to perform the reaction without a solvent or in the presence of a reaction-inert solvent, but the solvent is not particularly limited as long as the reaction can proceed, for example, a bond, an ester, an aromatic hydrocarbon, an aliphatic hydrocarbon, amidine, a drawing hydrocarbon, a nitrile, a Maple, organic acid, aromatic amine or a mixture of two or more thereof can be used. The reaction temperature is about -20 to about 150. (:, preferably about 0 to about The reaction time is usually from 5 minutes to about 24 hours, preferably from about 10 minutes to about 5 hours. Although the reaction product itself can be a reaction solution or used as a crude product in the next reaction, it can also be used. The known method is to separate it from the reaction mixture and purify it by separation methods such as recrystallization, distillation, and chromatography. Compound (X) can be prepared by condensing compound (XXVIII) and compound (vm). This reaction can be used as needed It is performed in the presence of a base. In the compound (XXVIII), Hal and Hal represent functional element atoms such as fluorine, gas, bromine, and moth. The amount of the compound (VIII) used is about 0.5 to 1 mole of the compound (XXVIII). About 3 moles, preferably about 0.8 to about 2 moles. The amount of base used is about 1 to 1 moles compound (XXVIII)] to (please read the precautions on the back before filling this page) ----- — — — — — — — — — — Employees of the Intellectual Property Bureau of the Ministry of Economic Affairs of the Consumer Cooperative Restriction 30 Moore, go hot 1 sign hot 1 η Miao and

1220900 A7 B7 V. "Inspection" used in the description of the invention is, for example, basic salts such as sodium carbonate, potassium carbonate, carbonate, sodium bicarbonate, sodium acetate, etc., aromatic amines such as pyridine, dimethylpyridine, etc. Hydrazone, etc., secondary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, methyl Pyrrolidine, N-methylmorpholine and the like. This reaction is advantageously performed without a solvent or in the presence of a reaction-inert solvent, but the solvent is not particularly limited as long as the reaction can be performed, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, amidines, alcohols, nitriles, or A mixture of two or more of them may be used. The reaction temperature is usually about -5 to about 2000c, preferably about 5 to about 150c. The reaction time is usually 5 minutes to about 72 hours, preferably about 05 to about 30 hours. Although the reaction product itself can be used as a reaction solution or as a crude product for the next reaction, it can also be separated from the reaction mixture by conventional methods and purified by separation methods such as recrystallization, distillation, and chromatography. Thereafter, if necessary, compounds in which R4 is other than a hydrogen atom can be synthesized. In each of the above reactions, when the starting compound has a substituent amine group, a retarder group, and a warp group, a protective group commonly used in peptide chemistry can be introduced into these groups. After the reaction, the protective group can be removed if necessary, The desired compound is obtained. The protecting group for an amine group is, for example, a methylamino group or an alkyl-carbonyl group (for example, ethylfluorenyl, propionyl, etc.), a phenylcarbonyl group, a Ci 6 alkoxy-carbonyl group (for example, methoxycarbonyl, ethyl Oxycarbonyl group, etc.), phenyloxycarbonyl group, 0710 aralkyloxyalkyl group (for example, benzyloxycarbonyl group, etc.), trityl group, phthalofluorenyl group, etc., which may each have a substituent, examples of substituents For the southern atom (for example, fluorine, 'paper size applies Chinese National Standard (CNS) A4 specifications (210 X 297 mm)) 311859 (Please read the precautions on the back before filling this page) -------- Order --------- Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 1220900 A7 V. Description of the Invention (82) Lice, bromine, iodine, etc., Ci 6 alkyl-carbonyl (for example, ethenylpentyl Fluorenyl, etc.), nitro, etc., the number of substituents is ^ 3. The protective group for the retardation group is, for example, a U axis such as a propyl group, a propyl group, an isopropyl group, a butyl group, a third butyl group, etc.), a benzyl group, a tertiary group, a silyl group, etc. Have taken

Examples of prime substituents are halo, (for example, chaos, gas, bromine, iodine, etc.), formamyl, and C carbonyl (for example, 7 酼, ^, ^, ^) Carbonyl, etc.), nitrime, alkyl (for example, fluorenyl, ethyl, tertiary: hydrazone, etc.), C6-H &gt; square group (for example, benzyl, naphthyl, etc.), etc., number of substituents From 丨 to 3. The protecting group for a radical is, for example, Ci 6 alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, third butyl, etc.), phenyl, / aryl (for example , Benzyl, etc.), formamyl, ^ 6 alkynyl (eg, 7), such as &quot;, Yixian, Cingji, etc.), phenyloxyalkyl, C7 &quot; 'The present methyloxycarbonyl group, etc.), tetrahydropyranyl group, tetrahydrofuranyl group, silane group may have a substituent, and examples of the substituent are pixel atoms (such as rustic gas, odor, moth, etc.)' Cl- 6 alkyl groups (for example, methyl, ethyl, I group, etc.), c? N aralkyl (for example, benzyl, etc.), c6 10 aryl (for example, benzyl, naphthyl, etc.), nitro, etc. The number of substituents is from 1 to 3. In addition, the removal of the protecting group can be performed by a method known per se or according to the method, for example, acid, alkali, ultraviolet, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutyl fluoride Method of reduction or reduction of ammonium, palladium acetate and the like. In any case, the compound (I) can be further, if necessary, individually A or more of known deprotection, alkylation, alkylation, hydrogenation, E paper rule (applicable standard (CNS) A4 size (X 297 mm)) ------- 82 311859 (Please read the notes on the back before filling out this page) -------- Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, etc. as described in the first paragraph. The above-mentioned "alcohol third butanol, etc." The above-mentioned "furan and dioxane are hexane, pentane, cyclohexane, etc." benzene, toluene, xylene, benzene such as pyridine, dimethylpyridine quinoline, Description of the Invention (83 Oxidation, reduction, chain extension and reaction can be synthesized by reactions of the new experimental department, wind-based group exchange, etc., etc., Yu Lecture 14, νο1 · 15, 1977 (Jiushan Publishing House) For example, 'methanol, ethanol, propanol, isopropanol :, such as ethyl acetate, isopropyl bond, phenyl bond, tetrazine, "two two is = burning, etc.: ... gas burning, carbon tetracarbonation, etc. I : 'One milk tiger, gas imitation, I2 · II The above "aliphatic hydrocarbons" are the above "aromatic hydrocarbons", etc. The above "aromatic amines" are the above, etc. A. Its "fermented amines" is' for example, N , N-dimethylfamidamine, N, N ·. Methylacetamide, trimethylamine hexamethylphosphate, etc. The above-mentioned "left" is, for example,-, methyl ethyl I㈣. For example, di-f-fluorene, etc. The aforementioned "nitrile" is, for example, acetonitrile, propionate, etc. The aforementioned "organic acid" is, for example, acetic acid, propionic acid, or tridenamic acid Etc. When the desired product in the free form is obtained by the above reaction, it can be converted into a salt according to conventional methods, or when the desired product is a salt, it can also be converted according to conventional methods. Converted into free form or another salt. This system is used for example, dissolving, concentrating, 311859 ------------ • equipment -------- order ------- ------- (Please read the notes on the back before filling this page) This paper size applies to Chinese National Standard (CNS) A4 specifications (2) ^ 297 mm 1220900 A7 B7 V. Description of the invention (solvent extraction, Fractional distillation, crystallization, chromatography, etc., are separated and purified from the reaction solution. When compound (I), (la), (lb), (Ic), or (Id) presents configurational isomers, non-image isomers , Conformational isomers, etc., they can be separated as required by the above separation and purification methods. In addition, the compounds (I), (la), (lb), (IC), or (Id) are in racemic form, It can be resolved into S- and R-types by any conventional optical analysis method. When compound (I), (la), (lb), (Ic), or (id) appears as a stereoisomeric%, its single Isomer or Mixtures of each isomer are included within the scope of the present invention. In addition, compound (I), (la), (Ib), (Ic), or (Id) may be hydrated or anhydrous. Compound (I) may be used Isotopes (for example, 3H, &quot; c, 35s) are marked. Please read the note above. Note: The pre-drug drive before printing compound (I) by employees of the Intellectual Property Bureau of the Ministry of Economic Affairs refers to the use of enzymes under physiological conditions. , Gastric acid, etc., which are compounds converted into compound VII, that is, compounds converted into compound (1) through enzymatic oxidation, reduction, hydrolysis, and the like, and compounds that are converted into compound ⑴ through hydrolysis of gastric acid, etc. Compounds were pre-drug-prevented as compounds in which the amine group of the compound ⑴ was tritiated, alkylated, or petrified (for example, the amine group of the compound 被 was fermented by peanut, aromatic, aniline carbonylation, (5- Fluorenyl-2-oxo-1,3-dicyclopentene-4-yl) methoxycarboxylation, tetrahydrofurylation, pyrrolidinylmethyl sulfonation, difluorenyl ethoxylation , Third butylated compounds, etc.); compounds where the hydroxyl group of ϋ σ⑴ is tritiated, fluorinated, phosphorylated, or boronated (for example, the hydroxyl group of compound (1) is acetyl blue blue , Hexadecanoic acid, acrylic acid, cyanide, cyanide, cyanide, quasi (CNS heart size ⑵0 X amber 84 、, rich 84

311R5Q

1220900 Consumption Cooperation of Employees of Intellectual Property Bureau, Ministry of Economic Affairs, 85 A7 Printed by the V. Description of the Invention (%, compounds such as methylated, diamidomethylcarbonylated, etc.); the enemies of compounds ⑴ are esterified or amidoamine Compounds (e.g., the Wei group of compound (I) is esterified, phenyl esterified, carboxymethylated, dimethylaminomethylated, trimethylacetoxymethylated, ethoxycarbonyloxy Ethylation, phthalic esterification, (5-methyloxo "1,3-disocyclopentan-4-yl) methylation, cyclohexyl ethyl esterification, or methylation amination, etc. Compounds). Their compounds can be prepared from compound (I) using a method known per se. Alternatively, the pre-exposure of compound (I) can be a development of medicameiits published by Guangchuan Bookstore in 990 ' ', Compounds converted to compound (I), (Ia), (Ib), (Ic), or (Id) under physiological conditions described in Volume 7 "Molecular Design" on pages 163 to 198 . The compound ⑴ of the present invention has a moderate affinity for adenosine receptors (especially, a3 receptors), has low toxicity, and has the lowest side effects. Therefore, it can be used as a safe drug. The pharmaceutical composition of the present invention containing the compound (I) has excellent adenosine and receptor antagonistic effects on mammals (for example, mice, rats, hamsters, rabbits, dogs, cattle, sheep, wolves, humans, etc.) Active and has excellent (oral) absorption, (metabolic) stability, etc., therefore, it can be used as adenosine 8 3 receptor-related disorders [for example, asthma, allergic diseases, inflammation, Addison's disease, Autoimmune hemolytic anemia, Crohn's disease, psoriasis, rheumatism, central nervous system diseases (eg, cerebrovascular diseases such as cerebral hemorrhage, cerebral infarction, head trauma, spinal trauma, cerebral edema, multiple sclerosis, etc.), neurodegeneration Disease (Example 2 Alzheimer's Disease, Parkinson's Syndrome, Amyotrophic Lateral Sclerosis 311859 --------------------- Order ------ --- (Please read the precautions on the back before filling out this page) 1220900 A7 __ B7 V. Description of the invention (86) 系 Compounds are preventive or therapeutic agents for central nervous disease, asthma, allergic diseases, etc. Formula of the present invention⑴ The compound also has excellent P38 MAP kinase inhibitory activity and TNF-α inhibitory activity (TNF_α production inhibitory activity, __action inhibitory activity), and can be used in safe agents based on these activities. For example, the pharmaceutical composition of the present invention containing compound ⑴ can be used as ρ38 kinase-related disorders and ™ F- «Related conditions [for example, arthritis (eg rheumatoid arthritis, osteoarthritis, rheumatic spondylitis, gouty inflammation: synovitis), toxemia (eg, septicemia, septic shock, Endotoxin shock, gram-negative septicemia, toxin shock syndrome], inflammatory bowel disease (such as' Clone's disease, ulcerative colitis), inflammatory lung disease (such as chronic pneumonia, dream soil, Pulmonary sarcoma, tuberculosis), or cachexia (e.g., an infectious malignant disease, a carcininia cancerous cachexia derived from an acquired immune deficiency syndrome (AIDS)), arteriosclerosis Spastic pseudosclerosis, viral infections (eg, cytomegalovirus, influenza virus, herpesvirus, etc.), atopic dermatitis, systemic lupus erythematosus, AIDS encephalopathy, osteomyelitis, asthma, myocardial infarction , Congestive heart failure, hepatitis, transplantation, dialysis, hypotension, or disseminated intravascular coagulation, etc.] and administered to mammals (for example, 'mouse, rat, hamster, rabbit, tracing, dog, Cattle, sheep, monkeys, humans, etc.), preferably, the compound of formula 系 is a preventive or therapeutic agent for rheumatic diseases, etc. The preparation of the present invention containing compound ⑴ has low toxicity, which can be based on this or based on the nature of pharmaceutical preparations commonly used in nature Known methods allow compound IX to be mixed with a drug and a physiologically acceptable carrier to form 'for example, pharmaceutical preparations such as lozenges (including the paper size applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 public love) 86 311859 122. 900A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs V. Invention Description (87) Sugar-coated tablets, film-coated tablets, etc.), powders, granules, capsules (including soft capsules), solutions, injections, suppositories, Sustained-release agents and the like are safely administered orally or parenterally (for example, topically, rectally and intravenously, etc.). The content of the compound (I) in the preparation of the present invention is about 0.001 to 100% by weight based on the entire preparation. The dosage varies depending on the subject's administration route, condition, and the like. Preparations that are adenosine α3 receptor antagonists can be, for example, oral dosages of about 0.1 to about 30 milligrams of active ingredient per kilogram. (Compound (I)), preferably about 1 to 20 milligrams per kilogram per day, administered to a patient with asthma (body weight about 60 kilograms) once or in divided portions. The pharmacologically acceptable carriers that can be used to prepare the preparations of the present invention are various organic or inorganic carriers that are conventionally used as pharmaceutical materials. For example, excipients, lubricants, isotonic agents and disintegrations of solid preparations can be appropriately used in an appropriate amount. Agents, or solvents, solubilizers, suspending agents, isotonic agents, buffers and soothing agents for liquid preparations. Also, if necessary, additives such as conventional preservatives, antioxidants, colorants, sweeteners, adsorbents, humectants and the like can be used. Excipients are, for example, lactose, sucrose, mannitol, starch, corn starch, crystalline cellulose, light silicic anhydride, and the like. The lubricant is, for example, magnesium stearate, calcium stearate, talc, colloidal macadam, and the like. Binders are 'for example, crystalline cellulose, sucrose, D-mannitol, dextrin, propyl cellulose, hydroxypropyl methyl cellulose, poly (vinyl pyrrolidone), starch, sucrose, gelatin, formazan Cellulose, sodium carboxymethyl cellulose, and the like. The disintegrant is, for example, starch, carboxymethyl cellulose, carboxymethyl cellulose, potassium potassium, carboxymethyl cellulose sodium, L-hydroxypropyl cellulose, and the like. 1 This paper size applies to China National First "------ (Please read the notes on the back before filling this page) -------- ^ ---------. Yy ZX 1U ΓΜ (\ will regulate 0 * y-*-87 311859 izzuyuu Digestion 5. Description of the invention (88) The solvent is, for example, alcohol 'sesame oil, corn, and the solubilizer is, for example, benzyl benzoate, sodium carbonate, Suspensions such as sodium citrate are, for example, B7 distilled water for injection, olive oil, etc. I Glycol, propylene glycol, D-mannitol amino methyl alcohol, cholesterol, triethanolamine alcohol, propylene glycol, polyethyl lauryl sulfate, Moon / Surfactants such as stearyl triethanolamine, ammonium, vaporized armor "* Amino propionate, lecithin, vaporized benzyl methane such as poly-a-pore pore ammonium, glyceryl monostearate, etc .; hydrophilic Polymers such as t (ethylene glycol), flat vinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, f-based wheels, etc. Earth cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose Isotonic agents are, for example, oils, D.mannitol, etc. Buffering agents are, for example, buffer solutions such as salts. Analgesics are, for example, preservatives , Such as ethanol, dehydroacetic acid, sorbic acid, etc. Antioxidants are, for example, sulfites, etc. [The best mode for implementing the present invention] A recording will borrow the following reference examples, examples, preparation examples, and test examples in more detail Illustrate the present invention, but they are just more examples and do not limit the present invention 'and can be changed within the scope of not departing from the present invention. &Quot; The paper size is applicable to the sunny standard (⑽Α4⑽) 茂 ~ 1 88

Meaning I

Glucose, D-sorbitol, sodium gasification, glycine, acetate, carbonate, citric acid | I benzyl alcohol, etc. Parabens Gas butanol, benzyl alcohol, benzene ascorbic acid, α-tocopherol 311859 1220900

In the following reference examples and examples, "room temperature" usually means about 100 ° C to about 35 ° C. Unless otherwise indicated, "%" means% by weight, but the yield represents mole / mole%. The abbreviations used in this specification indicate the following meanings: s: singlet d: doublet t: triplet q: fourfold dd: doubletwin ddd: doubletwint dt: doublet triplet br: widetlet J: coupling constant

HzHertz CDC13Nitride gas e-NMR: proton nuclear magnetic resonance spectrum

Me: Methyl [Example] Reference Example 1: 2-phenylmethyloxy-4-methyl p-bit ratio Washing sodium hydride (60% paraffin dispersion, $ 0 g, 120 mmol) with hexane (5 ml) Mol) twice and suspended in tetrahydrofuran (200 ml). At 0 ° C, add a solution of benzyl alcohol (14 g, 120 mmol) in tetrahydrofuran (50 ml) dropwise to this suspension, and then stir for 15 minutes to mix (please read the precautions on the back before filling (This page) -------- ^ --------- · Printed by the Consumers' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, the paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) ) 89 311859 1220900 A7 V. Description of the invention (9) The product is warmed to room temperature. To this solution, a solution of TO_M ^, containing 2 · bromo-4-methylpyridine (19 ml, 110 mmol) was added to the mixture and refluxed. Add 埶 hours. Water (200 ml) was added to the reaction mixture, and ethyl acetate was used to: dehydrate the extract and evaporate the solvent, evaporate the crude product under reduced pressure, 13 g of the title compound (67 mmol, 67% yield). Again at the boiling point: 116-118t (400 Pa) lH-NMRiCDCl3) (5: 2.30 (3H s) 5 37f2H A s), 6.72 (1H, d, J = 5 1Η2 &quot; (=, :), 5.37 ( 2Η, Magic, 6.63 (1H. J.5.1HZ) ^ 5 · 1Η2) ^. 29 &gt; 7.50 (5Η, m), 8.03 (1H, item elimination reference example 2: N- (3,5-dimethylbenzene Formamidine) propylimine at 0 ° C, 3,5-dimethylbenzoic acid (25 g, 017 mol) and n, n-methylformamidine (0 "ml) were added to the Sulfur gas (50 ml), and the mixture was heated under reflux for 2 hours. The excess sulfurous gas was distilled off under reduced pressure, and benzene (50 ml) was added to the residue. Toluene was distilled off under reduced pressure to obtain a 5-5-dichloromethane. Methyl benzamidine gas. A solution of n-propylimine (14 ml, 0.018 mol) in tetrahydrofuran (160 ml) was added to a 1N aqueous solution of sodium hydroxide (180 ml). At 0 ° C., it was added dropwise. 3,5-Dimethyl benzamidine gas was added to the solution, and after the addition was complete, the mixture was further stirred for 30 minutes. The reaction mixture was extracted with ethyl acetate, the extract was dehydrated, and the solvent was distilled off to obtain 31 g of the title compound ( (〇16mol, 99% yield). Oily product iH-NMR (CDC13) &lt; 5: 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 (lH, s) # 7.64 (2H, s) Reference Example 3: This paper size is in accordance with China National Standard (CNS) A4 (210 x 297 mm) &quot; ------ 9〇311859 page order »1220900 A7 V. Description of the invention (91) W3,5- Dimethylphenyl) -2- (2-phenylfluorenyloxy group such as sulfanyl) acetamidine makes anhydrous tetraisopropylamine (9.6ml, 69 units of glycerol, .t pen) The furfuran (60 ml) solution was cooled to -50 ° C, and with stirring, ^ ^ Ye Ye Bu 'dropwise added a solution containing 1.6 M n-butyl Jingzhixian (49 ml, 60 mmol) After the addition was completed, the mixture was stirred for a minute), and then, at -3 (TC ', anhydrous tetrahydromethane containing 2-benzylmethyloxy_4_methyl was added dropwise (12 g' 62 mmol). (12 ml) solution. After the addition was complete, the resulting mixture was warmed 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 and dehydrated, and steamed. The solvent was removed. The residue was purified by dream gel column chromatography (hexane-ethyl acetate, 5: 1). To obtain 91 g of the title compound (27 mmol, 44% yield). 〇 Oily product W-NMR (CDC13) 6: 2.37 (6H, s), 4.20 (2H, s), 5 37 (2Η S), 6.72 (1Η, s), 6.81 (1Η , d, J = 5.1Hz), 7 22 (1Η s) 7-30-7.49 (5H, m), 7.59 (2H, s), 8.12 Uh, d, Reference Example 4: 2-Bromo-l- (3 , 5-Dimethylphenyl) -2- (2-Phenylmethyloxy_4_Amidinyl) ethoxy hydrobromide makes 1- (3,5-dimethylphenyl) -2 -(2-phenylmethyloxy_4_ohidinyl) Ethyl 1 (3.3 g, 10 mmol) was dissolved in acetic acid (10 ml), and bromine (0.51 ml, 10 millimoles) in the solution and stirred for 30 minutes. The precipitated crude crystals were collected by filtration, and washed with diethyl ether to obtain 48 g of the titled human (9,8 mmol, 98% yield).

Melting point: 88-90 ° C This paper is sized for China National Standard (CNS) A4 (210 X 297 mm) m — 91 311859 (Please read the precautions on the back before filling this page) ------- -1 Ding 丨 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 1220900 A7 V. Description of the Invention (92 Reference Example 5: N- (4-methoxybenzyl) propyleneimine with propyleneimine (25 ml, 0.36 mol) of tetrahydrofuran (200 ml) solution into an aqueous sodium hydroxide solution (100 ml), at 0. (:, 4-methoxybenzidine containing Gas (51 g, 0.30 mol) in a four-gas blow (100 ml) solution. After the addition was complete, the mixture was stirred for another 30 minutes. The reaction mixture was extracted with ethyl acetate, the extract was dehydrated, and the valley was evaporated. All 49 g of the title compound were obtained (Q J6 mole, yield μ%). Oily product &quot; H-NMR (CDC13) 6: 1.39 (3H, d, J = 5.6Hz) # 2.11 (1Η, 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: ^ (拉Methoxyphenyl) -2- (2-Third-butoxycarbonylaminospurinyl) _ Cool an anhydrous tetrahydrofuran (300 ml) solution containing 2-third-butoxycarbonylaminomethylpyridine (20 g, 97 mmol) to _78 ° C, and dropwise add h6M n-butyllithium to it. Hexane solution (140 ml, G.22 moles). After the addition was complete 'stir the mixture at room temperature for 30 minutes. Then, cool it to -78 C' and dropwise add N- (4- Anhydrous tetrahydrofuran solution of methoxybenzyl) propaneimine (50 ml). After the addition was complete, the mixture was stirred at room temperature for 2 hours. 'Water (100 ml) and isopropyl ether (300 ml) were added. Ml), and the resulting crude crystals were collected by filtration. The crude crystals were recrystallized with tetrahydrofuran-hexane to obtain 23 g of the title compound (67 mmol, yield 69%). Melting point: 187-190. Reference Example 7 : This paper is suitable for iii ^ 76NS) A4 size ⑽χ 297 public hair) 92 3π (Please read the precautions on the back before filling this page) --------- ^ -------- -· Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economy 1220900 A7 B7 V. Description of the Invention (93) 4- [2-Amino-4- (4-methoxyphenyl) -1,3 · thiazol-5-yl ] -2-Pyridylamine with bromine (0.68 mmol Liters, 13 millimoles) to 1- (4-methoxyphenyl) _2_ (2-tertiary butoxychimine group_4-0 than bite) ethyl ketone (4.5 g, 13 millimoles) The solution was stirred in acetic acid (100 ml) at room temperature for 30 minutes. The reaction mixture was concentrated and the residue was dissolved in acetonitrile (40 ml). To this was added thiourea (11 g, 14 mmol) and triethylamine (1.9 ml, 14 mmol). (The mixture was stirred for 2 hours. Then, it was cooled to room temperature and concentrated. A saturated aqueous solution of sodium bicarbonate (200 ml) was added to the residue, and the resulting solid was washed with water. 2N hydrochloric acid (3 5 ml) of the solid. After stirring the mixture at 100 ° C. for 45 minutes, it was allowed to cool to room temperature, and then 8 N aqueous sodium hydroxide solution (10 ml) and a saturated aqueous solution of sodium bicarbonate (100 ml) were added. Ml). The resulting crude crystals were collected by filtration, washed with water, and recrystallized with ethanol to obtain 2.7 g of the title compound (9.1 mmol, yield 69%). Melting point: 251-254 ° C Reference Example 8: 2 -(2-amino-4-D than pyridylmethoxyphenyl) ethanone with 2N hydrochloric acid (10 ml) in 1- (4-fluorenyloxyphenyl) _2- (2. Tert-butoxycarbonylamine Phenyl-4-D than nicotinyl) ethyl ketone (61 g, 18 mmol), the mixture was stirred at 1000 for 2 hours, cooled to room temperature, and then 8 n hydrogen was added Aqueous sodium hydroxide solution (10 ml). The resulting crude crystals were collected by filtration, washed with water, and recrystallized with tetrahydrofuran-hexane to obtain 4.0 g of the title compound (16 mmol, 92% yield). Melting point: 170-174 ° C Reference example 9: (Please read the precautions on the back before filling out this page) • -------- tTi Printed by the Intellectual Property Bureau Staff Consumer Cooperatives of the Ministry of Economic Affairs This paper is applicable to China Standard (CNS) A4 specification (21〇X 297 public love) 93 311859 1220900 A7 B7 V. Description of the invention (94) 2- (2-benzylaminoaminopyridinylmethoxyphenyl) ethyl ketone added benzamidine Gas (4.4 g, 31 mmol) and 4-dimethylaminopyridine (0.51 g, 4.7 mmol) with 2- (2-amino_4_π than pyridylmethoxyphenyl) ethyl Ketone (3.8 g, 16 mmol): In a solution of dimethylacetamide (80 ml), the mixture was stirred at 70 ° C for 12 hours. After cooling to room temperature, water (50 Ml). The mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in tetrahydrofuran (80 mmol). L) and methanol (20 mL), 1N aqueous sodium hydroxide solution (50 mL) was added. After stirring the mixture at room temperature for 3 hours, it was concentrated and water (200 mL) was added. This was extracted with ethyl acetate. The organic layer of the mixture was washed with a saturated aqueous solution of sodium vaporization, dehydrated with magnesium sulfate, filtered, and concentrated. The residue was recrystallized with ethyl acetate-hexane to obtain 31 g of the title compound (8.9 mmol, 57% yield). ).

Melting point: 136_139 ° C Reference example 10: 1- (3,5-dimethylphenyl) _2_ (2_third butoxycarbonylamino group_4_π than pyridyl) ethyl ketone cooling with 2-third butoxycarbonyl Amino_4_methylpyridine (17 g, 82 mmol) in anhydrous tetrahydrofuran (250 ml) solution to -8 ° C, while stirring, 20 ml of hexane solution of N-butyllithium was added dropwise. After the addition of mol was completed, the mixture was stirred at 0 ° C for 30 minutes and then cooled to -78 ° C. To this was added dropwise a solution of N- (3,5-dimethylbenzyl) propaneimine (21 g, 0.11 mol) in anhydrous tetrahydrofuran (50 ml). After the addition was completed, the mixture was stirred at room temperature for 2 hours, water (100 ml) was added thereto, and extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dehydrated with magnesium sulfate. This paper is sized according to the Chinese National Standard (CNS) A4 (210 X 297 mm) 94 311 »59 (Please read the note on the back? Matters before filling out this page ) -in ---- ^ --------- · Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 1220900 A7 B7 V. Description of the invention (95) Filtration and concentration. The residue was recrystallized from tetrahydrofuran · hexane to obtain n g of the title compound (37 mmol, 46% yield). Melting point: 13 3 -13 6 ° C Reference example 11: 2- (2-Amino-4-Π specific bite) -1- (3,5-dimethylphenyl) ethanone with 2 N hydrochloric acid (50 Ml) in 1- (3,: 5-dimethylphenyl) · 2- (2-Secondylbutadienylamino-4-D than octyl) aceta (12 g, 36 mmol), The mixture was stirred at 100 ° C for 1 hour, and it was cooled to room temperature, and then 8 ν 氲 aqueous sodium oxide solution (15 ml) was added and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydroxide solution, dehydrated with magnesium sulfate, filtered and concentrated. The residue was recrystallized from ethyl acetate to obtain 6.8 g of the title compound (28 mmol, 77% yield). Melting point: 123-126 ° C Reference example 12: 2- (2-Benzamidine-4-4-IIpyridinyl) -1_ (3,5-dimethylphenyl) ethanone

Add benzamidine gas (7.5 g, 55 mmol) and 4-dimethylaminopyridine (1.0 g, 8.3 mmol) to 2- (2-amino_4-D than pyridyl) -1_ (3,5_dimethylphenyl) ethanone (6.4 g, 27 mmol) in N, N-dimethylacetamide (1 () 0 ml) solution at 70 ° C This mixture was stirred for 12 hours. After cooling 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 vaporization, dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in a mixed solvent of tetrahydrofuran (150 ml) and methanol (40 ml), and a 1 N aqueous sodium hydroxide solution (50 ml) was added. After disturbing the mixture for 3 hours at room temperature, concentrate it, add water (100 ml) and apply Chinese National Standard (CNS) A4 specification (210 X 297 mm) at 2 N paper size ----- — 95 311859 (Please read the notes on the back before filling out this page) --1 ------ ^ --------- Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy 1220900 A7 B7 V. Description of the invention (96) Hydrochloric acid and a saturated aqueous solution of sodium bicarbonate are neutralized. The mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium vaporization, dehydrated with tritium 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, 70% yield). Oily product W-NMR (CDC13) (5: 2.39 (6Η, S), 4.33 (2Η, s), 6.9β-7 · 〇1 (1Η, m), 7.23 (1Η · s), 7.45-7 · 58 (3Η, m), 7.63 (2Η, s), 7.89-7.94 (2Η, m) # 8.21 (lHf d # J-5.2Hz) # 8.36 (1H # S) # 8.71 (1H, br) Reference Example 13 According to the method of Reference Example 5, the following reference example 13 was synthesized by using 3-methylbenzidine chloride and 3-methoxybenzidine chloride instead of 4-methoxybenzidine gas. Compounds -1 and 13-2. Reference Example 13_1 · N- (3-methylbenzylidene) propylideneimine oil product 'H-NMR (CDC13) 6: 1.39 (3H, d, J = 5.5Hz) r 2.14 (1H, d, J = 3.3Hz), 2.41 (3H, s), 2.51-2.66 (2H, m), 7.32-7 · 39 (2H, m), 7.79-7.87 (2H, m) · Reference Example 13-2: N- (3-methoxybenzylidene) propylideneimine oily product ^ -NMR (CDC13) 5: 1.40 (3H, ά§ J = 5- 9Hz) # 2.14 (1H # d, J = 2.9Hz) # 2.52-2.65 (2H, m) # 3.88 (3H, s), 7.10 (1H, ddd, J = 8.4Hz, 2 · 6, 1 · 1Ηζ) , 7.37 (1H, dd, J = 8.4 # 7.3Ηζ), 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 the method of Reference Example 6, using N- (3-methylbenzylidene) propene (please first Read the notes on the reverse side and fill out this page) A4 specification (210 X 297 mm) 96 311859 1220900 A7 B7 V. Description of the invention (97) The imine instead of N- (4-methoxybenzyl) propaneimine was used to synthesize the following Reference Example 14 compounds. Reference Example 14: 2- (2-Third-butoxycarbonylamino_4-11 than pyridyl) -1- (3-methylphenyl) ethane_ Melting Point: 144-146 ° C Reference Example 15: 4- (Methylthio) thiobenzylamine Dissolve 4-methylthiobenzonitrile (12 g) in 4 N hydrochloric acid in ethyl acetate (130 ml), and add dithiophosphoric acid to it. 〇_ diethyl ester (15 ml), the mixture was stirred at room temperature for 22 hours. Water was added and extraction was performed with ethyl acetate. After the insoluble matter was filtered off, the filtrate was washed with a saturated aqueous solution of sodium chloride and dehydrated, and then the solvent was distilled off. The residue was recrystallized from ethyl acetate to obtain 10 g of the title compound (yield 67%). Melting point: 176-178 ° C Reference Example 16 According to the method of Reference Example 15, using 4-fluorobenzonitrile, 2-gas benzonitrile, butyronitrile, and valeronitrile instead of 4-methylthiobenzonitrile The following Reference Example 16-1 to 16-4 compounds were synthesized. Reference example 16_1: 4-fluorothiobenzamide

Melting point: 156-157 ° C Reference Example 16-2: 2-chlorothiobenzamide

Melting point: 58-59 ° C Reference Example 16-3: Thiobutyramide oily product (Please read the precautions on the back before filling this page} -Ψ -------- 1 ----- ---- Refer. Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs, Consumer Cooperatives. This paper is printed in accordance with the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 97 311859! 220,000 Printed by the cooperative A7 __Β7 V. Description of the invention (98) &quot; H-NMR (CDC13) (5: 0.99 (3H, t, J = 7.6Hz) # 1.72-1.93 (2H # in), 2.64 (2H, t # Js7.6Hz) # 7.02 (1H, bir s), 7.77 (1H br s) Reference Example 16-4: Thiopentylamine oil product ^ -NMR (CDCI3) 5: 0.94 (3H, t # J-7.3 Hz) # 1.31-1,49 (2H # m), 1.68-1.83 (2H # m) # 2.67 (2H # t, J = 7 * 7Hz), 6.92 (1H br s), 7.73 (1H, br s) # Reference Example 17 · 4- [2-Methyl-4- (3-methylphenyl) -l, 3-thizone_5_jib 2_ [] Added bromine (1 0 ml, 18 mmoles) to 2- (2-third-butoxycarbonylamino_4-D specific bite) -1- (3-methylphenyl) ethanone (60 g, 18 MM) in acetic acid (50 ml) and stirred at room temperature for 30 minutes. The reaction was concentrated and mixed The residue was dissolved in N, N-dimethylformamide (30 ml), thioacetamide (1.4 g, 19 mmol) was added thereto, and the resulting mixture was stirred at room temperature for 20 minutes. Hour. To the reaction mixture was added a saturated aqueous solution of sodium bicarbonate (200 ml), and the mixture was extracted with ethyl acetate. The extract was dehydrated, and the solvent was distilled off. 2 N hydrochloric acid (30 ml) was added to the resulting solid. The mixture was stirred for 1 hour. After it was allowed to cool to room temperature, the mixture was tested with a 2 n aqueous sodium hydroxide solution (200 ml) and a vaporized sodium saturated aqueous solution (100 ml). The resulting mixture was extracted with ethyl acetate. The mixture, extract was washed with water, dehydrated, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain 28 g of the title compound (54% yield). Melting point: 152-153 ° C Reference Example 1 8 According to the method of Reference Example 17, use thiopropylammonium and 4- (CNS) A4 specification for the former (X 297 public love) — 98 311859 (Please read the precautions on the back before (Fill in this page) --------- ^ --------- 1220900 Member of Intellectual Property Bureau, Ministry of Economic Affairs Printed by the Industrial and Consumer Cooperatives A7 B7 V. Description of the Invention (99) Thio) thiobenzamide replaces thioacetamide and the following reference examples are synthesized! 8-1 and 18-2 compounds. Reference Example 18-1: 4- [2-ethyl-4 · (3-methylphenyl) -1,3-thiazol-5-yl] _2_

Pyridylamine melting point: 144_146 ° C Reference Example 18-2: 4- [4- (3-methylphenyl) _2_ (4_methylthiophenyl) _1,3_ 嚷 σ--5-yl]- Melting point of 2- 卩 t-methylfluorenylamine: 181-383 ° C Reference Example 19 According to the method of Reference Example 17, 1 彳 4-methoxyphenyl) -2- (2-tert-butoxycarbonylamino-4- The following compound of Reference Example 19 was synthesized by using ¾pyridyl) ethanyl instead of 2- (2-third-butoxycarbonylamino-4-4-methylidene) -1- (3-methylphenyl) ethanone. Reference Example 19: 4- [4- (4 • methoxyphenyl) _2-methyl-1,3_thiazole_5_yl] · 2_arimidinylamine Melting point: 140-141 ° C Reference Example 20 According to The method of Reference Example 8 uses 2- (2-tertiary-butoxyquinamino_4-pyridyl) -1- (3-methylphenyl) ethanone instead of 1_ (4_methoxyphenyl) _2_ ( 2_Second-butoxyeminamino-4-ohyl) ethyl ketone to synthesize the compound of Reference Example 20 below. Reference Example 20: 2- (2-Amino-4-B specific octyl) -1- (3-methylbenzyl) ethanone Melting point: 119-120 ° C Reference Example 21: (Please read the note on the back first Please fill in this page for matters) • -----------------. This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 99 311859 1220900 A7 V. Description of the invention (iw) 2- (2-Amino-4-D than bityl) m- (3i-phenyl) ethanone hydrobromide Add bromine (3.2 ml, 62 mmol) to 2_ (2 _Third-butoxychitamino-4-II-ratio)-: 1- (34-phenylphenyl) ethanone (20 g, 6 mM) in a solution of acetic acid (ml); 'Stir in 2 hour. After the reaction mixture was cooled to room temperature, the precipitate was collected by filtration to obtain 19 g of the title compound (yield: 81%). Melting point: 182-185. (: Reference Example 22 In accordance with the method of Reference Example 9, 2- (2-amino_4_amylidylmethylphenyl) ethanone was used instead of 2- (2-aminopyridyl) 1- (4-methoxy). Phenyl) ethanone to synthesize the compound of Reference Example 22 below. Reference example 22: N- [4- [2- (3-methylphenyl) -2_oxoethyl] _2 • pyridyl] benzamidine Melting point: 67-69 ° C Reference example 23: 4- [2- (4-fluorophenyl) -4- (3-methylphenyl) · ι, 3-thiazole · 5-ylb 2-pyridylamine ) -2-bromo "-(3-methylbenzyl) ethanone hydrobromide (5.0 g, 13 mmol) was dissolved in N, N-dimethylformamide (40 ml) at To this was added 4-fluorothiobenzamide (2.1 g, 13 mmol), and the mixture was stirred at room temperature for 16 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution (200 ml), and Ethyl acetate was extracted. The extract was dehydrated and the solvent was distilled off. The residue was recrystallized from ethanol to obtain 39 g of the title compound (11 mmol, yield 83%). (Please read the precautions on the back first (Fill in this page) --------- ^ --------- This paper is printed by the Consumers' Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs, and the paper size is applicable to China National Standard (CNS) A4 (21〇X 297 (Public Love) 100 311859 1220900 59 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Description of Invention ( 101) Melting point: 160-162 ° c Reference Example 24 According to the method of Reference Example 23, 2-gas thiobenzoate, thiobutyramine and thiopentamidine are used instead of 4-fluorothiobenzidine and The following Reference Examples 24-1 to 24-3 were synthesized.

Reference Example 24-1: 4- [2 · (2-Gaphenyl) -4_ (3-methylphenyl) _153_thiazole_5_yl] _2-pyridylamine Melting point: 175-177 ° C Reference Example 24 -2: 4- [4- (3 • methylphenyl) -2-propyl-1,3-thiazole-5_ylb 2-pyridylamine

Melting point: 113_115 ° C Reference Example 24-3: 4- [2-Butyl-4- (3-methylphenyl) _153_thiazole-5 • yl] _2_ Pyridylamine oily product &quot; H-NMR ( CDC13) (5: 0.98 (3H, t, J = 7.3Hz) # 1.39-1. (2H, m), 1.74-1 · 92 (2H, m), 2.34 (3H, s), 3 04 (2H, t J = 7.4Hz), 4.14 (2H # brs) f 6.44 (1H # s), 6.56 (1H # dd # J = 5. 1 · 5Ηζ), 7.09-7 · 26 (3H M), 7.41 (1H, s), 7.96 (1H, d / J = 5.4Hz) Reference Example 2 5: 2-Fluoro-4-methylamidine ratio 唆 Journal of Medicinal Chemistry, ν〇 1.33, 1667 · 1675 1990 The title compound was prepared by the method described in 1990. Melting point 82-86 ° C (lOkPa) Reference Example 26: (Please read the precautions on the back before filling this page). ------ -^ --------- · This paper size applies to China National Standard (CNS) A4 (210 X 297 public love) 101 311859 丄 220900 A7

V. Description of the invention (102) Printing of 2- (2_fluoro-4-11pyridinyl) -1- (3-methylphenyl) ethyl _ in the argon atmosphere Then, an anhydrous tetrahydrofuran (300 ml) solution containing diisopropylamine (44 ml, 0.31 mol) was cooled to ⑽, and a hexane solution (1.6 M containing n-butyllithium) was added dropwise to the solution. Ml, 031 mol). After the addition was complete, the mixture was stirred for 10 minutes, and then a solution of 2-gas_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. It was then cooled to -78 c, and anhydrous tetrahydrofuran (30 ml) containing ν_ (3-methylbenzylhydrazine) propylimine (52 g, 0.30 mol) was added dropwise thereto. After the addition was complete, the mixture was stirred at room temperature for 2 hours, then water (30 ml) was added and extracted with ethyl acetate. The extract was washed with water, dehydrated, and the solvent was distilled off. The residue was recrystallized from isopropyl ether to obtain 35 g of the title compound (52% yield). Melting point 66-67 ° C Reference Example 27 According to the method of Reference Example 26, N- (3-methylbenzylidene) propylideneimine was used instead of N- (3-methylbenzylidene) propylideneimine The following Reference Example 27 compounds were synthesized. Reference example 27: 2- (2-fluoro-4-carynyl) 4- (3-methoxyphenyl) ethanone oily product iH-NMR (CDC13) 0: 3.86 (3H, s), 4 · 31 (2H, S), 6.86 (1Η, s), 7.03-7 · 19 (2Η · m), 7.31-7 · 59 (3Η, m). 8.18 (1Η, d , J = 5.6Hz) Reference Example 28: [5- (2-fluoro-4-pyridinyl) -4_ (3_methylphenyl) _i, 3_thiazole_2-yl] amine with bromine (1.9 ml , 37 mmol) to 2- (2-fluoro-4-pyridinyl)-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 102 311859 (Please read the note on the back first Please fill in this page again for matters) —---- II i I Order · -------- 1220900 Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Description of Invention (103)

A solution of 1- (3 • methylphenyl) ethanone (8.5 g, 37 mol) in acetic acid (50 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated. Add triethylamine (5.2 ml, 37 mmol) to an acetonitrile (50 ml) solution containing the residue and thiourea (30 g, 40 mmol), and stir the mixture at 80 ° C for 2 hours . A saturated aqueous sodium bicarbonate solution (50 ml) was added to the reaction mixture 'and the precipitated solid was filtered. The obtained solid was washed with water and then dried. This crude crystal was recrystallized from ethanol to obtain 3.7 g of the title compound (yield 35%). Melting point: 214-218 ° C Reference Example 29 According to the method of Reference Example 28, 2- (2-fluoro-4-cronoyl) -1- (3-methoxyphenyl) ethanone was used instead of 2- (2- Fluoro-4-fl is higher than that of fluorene) · fluorene- (3-methylphenyl) ethanone to synthesize the compound of Reference Example 29 below. Reference Example 29: [5 · (2-fluoro-4-Πpyridinyl) -4- (3-methoxyphenyl) -13 · thiazol-2-yl] amine Melting point: 190-191 ° C Reference Example 30 : 5- (2-fluoro-4-1¾pyridyl) -4 · (3-methylphenyl) -2- (4-methylthiophenylthiazole) with bromine (2.7 ml, 52 mmol) to 2_ (2-fluoro_4_arimidinyl) _ 1- (3-methylphenyl) ethanone (12 g, 53 mmol) in acetic acid (90 ml) solution 'Stir at room temperature for 2 hours The reaction mixture was concentrated, and the residue was dissolved in N, N-dimethylformamide (60 ml), and 4- (methylthio) thiobenzamide (9.6 g, 52 mmol) was added thereto. (Ear), stir the mixture for 15 hours at room temperature. Pour sodium bicarbonate saturated water into the reaction mixture (please read the precautions on the back before filling this page) -------- Order ---- ----- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 103 311859 1220900 A7 V. Description of the invention (104) (100 ml), extracted with ethyl acetate. The extract was washed with water, dehydrated, and the solvent was removed. The residue was subjected to "column chromatography (Kein: Ethyl acetate '4: 1) ,," Tuning to obtain 4.7 g of the title compound (yield 23%). Melting point: 97-1. 00. Reference Example 31: 5- (2i4mM_ (3-methylphenyl) _2 methyl ceryl phenyl group 1,3-嚷 w sitting-in containing 5_ (2 • fluoropyridyl) -4- (3-methylphenyl) _2_ (4-methylsulfuric acid) 1,3_thiazole (2.7 g, 6.9 mmol) To a solution of N, N-dimethylformamidine (60 ml) was added m-aperoxybenzoic acid (33 g, 14 mmol), and the mixture was stirred at room temperature for 1 hour. Add 8 N aqueous sodium hydroxide solution was used to react the compound, and the resulting solid was filtered. This solid was recrystallized from ethanol to obtain 2.5 g of the title compound (yield 85%). Melting point: 196-199. (: Example 1: [4- (3,5-monomethylphenyl) -5- (2-phenylmethyloxy_4_pyridyl) _1,3_thiazole-2_yl] amine was added dropwise with triethylamine ( (1.4 ml, 10 mmol) to 2 · bromo "-p,% dimethylphenyl) -2- (2-phenylmethyloxy-4-pyridyl) acetamidohydroxide ( This mixture was stirred at room temperature for 3 hours in a solution of 4.8 g, 9.8 mmol) and thiourea (0.0 g, u mmol) in acetonitrile (40 mL). The solvent was removed, and a saturated aqueous solution of sodium bicarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dehydrated, and the solvent was distilled off. The obtained crude crystals were obtained with ethyl acetate, ... 5.2 millimolars, yield 53%) The title of this paper is in accordance with Chinese National Standard (CNS) A4 size ⑵G x 297 public hair) -------------- 104 311859 (Please read first Note on the back, please fill in this page) --------- ^ --------- · Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 1220900 A7 --------- — B7__ _ 5. Description of the invention (105) Compound. Melting point: 14 1 -14 3 Example 2: N_ [4_ [2-benzylideneamino_4_ (4_methoxyphenyl) ”. -Thiazolyl 2-pyridyl] benzamidine ^ Add benzamidine gas (0.59 mg, 4.2 mmol) and 4-dimethylaminopyridine (0.05 g, 0.4 MM) to ν, ν_dimethylformamidine containing '[octaamino_4 (4methoxythiazole-5_yl) · 2-pyridylamine (42 g, 4 mmol) In an amine (ίοmL) solution, the mixture was stirred at 7rc for 19 hours. 俟 After cooling to room temperature, a saturated aqueous solution of sodium bicarbonate (50 liters) was added. The resulting crude crystals were filtered and washed with water. This crude The crystals were recrystallized from ethanol to obtain 0.26 g (0.51 mmol, yield 37 &lt;) / ❶) of the title compound. Melting point: 230-233 ° C Example 3: N_ [4- (4 • methoxyphenyl) -5_ [2-[(3-D than pyridylcarbonylamino)]-4-11 than pyridyl group 1, 3-thiazol-2-yl] nicotinylamine added nicotinic hydrazone hydrochloride (0.72 g, 4.1 mmol) and 4-dimethylaminocarbamidine (0.05 g, 0.4 mmol) to N, N- containing 4_ [2-amino-4- (4-methoxyphenyl) -1,3-thiazol-5-yl] _2_pyridylamine (0.41 g, 1.4 mol) In a solution of dimethylacetamide (10 ml), the mixture was stirred at 7 (rc for 19 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous sodium hydrogen carbonate solution (50 ml) was added. The resulting crude crystals were filtered and treated with Wash with water. This crude crystals were recrystallized from ethanol to obtain 0.23 g (0.44 mmol, 33% yield) of the title compound 0 (please read the precautions on the back before filling this page) ------- -Can be printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. The paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 105 311859 1220900 A7

V. Description of the invention (106) Melting point: 229-232 ° C Example 4: N- [4- [2-Amino-4- (4-methoxyphenyl) -1,3-thiazole-5-ylbub 2 _ Oh bityl] benzamidine at 0 ° C, add bromine (0.11 ml, 2.1 mmol) to 2 (2-benzylamino-4-methylamino) -1- (4- In a solution of methoxyphenyl) ethyl ketone (ο?) G, 2 1 is mol) in acetic acid (20 ml), the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was dissolved in acetonitrile (20 ml), and thiourea (0.17 g, 2.2 mmol) and triethylamine (0 35 ml, 25 mmol) were added thereto at 80 The mixture was stirred at ° C for 5 hours. Next, it was cooled to a temperature 'and a saturated aqueous solution of carbonic acid sodium (200 liters) was added, and the solid formed by overfishing was washed with water. The resulting coarse crystals were separated by filtration, washed with water, and recrystallized with ethanol to obtain 0.17 g of the title compound (0.43 mmol, 21% yield). Melting point: 221-224 ° C Example 5: N- [ 4- [2-Amino · 4- (3,5-dimethylphenyl) _1,3-thiazole-5 · yl] -2-pyridyl] benzamide at 0 ° C, bromine (1 0 ml, 19 mmoles) to 2- (2-benzylaminoamino-4-IIpyridinyl) -1- (3,5-dimethylphenyl) ethanone (6.4 g, 19 mmol) of acetic acid (80 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was dissolved in acetonitrile (100 ml), and thiourea (1.5 g, 19 mmol) and triethylamine (2.8 ml, 20 mmol) were added thereto. The mixture was stirred at 80 ° C for 3 hours. Cool the reaction mixture (Please read the notes on the back before filling this page)

-------- Order-I Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs, Consumer Cooperatives This paper is printed in accordance with the Chinese National Standard (CNS) A4 (210 x 297 mm) 106 311859 1220900 Cooperative printed A7 V. Description of invention (107) After reaching room temperature, a saturated aqueous solution of sodium bicarbonate (200 ml) was added, and the resulting solid was filtered and washed with water. The resulting coarse crystals were filtered, washed with water, and recrystallized with ethanol to obtain 5.0 g of the title compound (13 mmol, yield 68%).

Melting point: 120-123 ° C Example 6: N- [4- [2-Amino-4- (3,5-dimethylphenyl) -l53_thiazole_5_yl] _2_pyridyl] benzyl Add ammonium lithium halide (0.16 g, 4. mmol) to a suspension of anhydrous tetrahydrofuran (30 ml) containing aluminum vaporized (0.55 g, 4.1 mmol) and stir in the chamber. This mixture was for 15 minutes. To this was added ν_ [4_ [2-amino (3,5-dimethylphenyl) _13_thiazole_5_ylb 2-pyridyl] benzylamine ^ g, 1.0 mmol) A solution of anhydrous tetrahydrofuran (10 ml) was heated at reflux for 2 hours. After the reaction mixture was cooled to room temperature, water was added and extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous solution of vaporized sodium, dehydrated with magnesium sulfate, filtered and concentrated. The residue was recrystallized from ethyl acetate · hexane to obtain 0.20 g (0.51 mmol, 51% yield) of the title compound. Melting point: 99-1〇2 ° c Example 7: N [4 [2Amine ice (3,5_dimethylphenylsulfonyl) | carolinyl] benzamidine hydrochloride ', 〇 / 〇 solution of hydrochloric acid in methanol (10 ml) to N- [4- [2-amino-4 (3,5-monomethylphenyl)],% thiazole and 2-pyridyl] benzene A suspension of formamidine (0.45 g ^^ millimoles) in methanol (30 ml) was stirred at room temperature. The paper size was measured by financial standards. Χ ----- 107 311859 -------- Order --- (Please read the precautions on the back before filling out this page} 1220900 V. Description of the invention (108 This mixture is 30 minutes. The solvent is distilled off, and the residue is recrystallized with methanol to obtain 0.36 g (〇 · 83 mmol, 73% yield) of the title compound. Melting point: 202-207 ° C Example 8: N- [4- [2 • Amino-4- (3,5-dimethylphenyl) _l53_thiazole _5_yl] _2_pyridyl] benzylamine dihydrochloride Add ο %% hydrochloric acid in methanol (10 ml) to N_ [4 [2_amino-4- (3,5-dimethyl) Phenyl) _53_thiazole_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. Distilled off Solvents, The residue was recrystallized with methanol-ethyl acetate to obtain 0.73 g (1.6 mmol, yield 7 6%) of the title compound. Melting point: 161-163 ° C The structures of the compounds obtained in Examples 1 to 6 are shown below: Example 1 (Please read the notes on the back before filling out this page) Example 2 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 2

This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 311859 --------- ^ --------- · 1220900 A7 B7 V. Description of the invention (109)

Example

(Please read the notes on the back before filling out this page) Example Example Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs Example Example

Me This paper size is applicable to China National Standard (CNS) A4 (210 x 297 mm) 109 311859 -------- ^ --------- 1220900 A7 B7 V. Description of the invention (⑽) Example 6

Example 9: Ν · [5- [2-benzylamidoamino-4_pyridyl] _4_ (3,5-dimethylphenylfluoren-2-yl] acetamidamine

Add acetam (0.26 ml, 3.7 mmol) and 4-dimethylaminopyridine (0.09 g, 0.76 mmol) to N- [4_ [2amino 4 (35-dimethyl) Benzyl) -1,3-thiazol-5-yl] -2-pyridyl] benzidine (0 96 g, 2.4 mmol) N, N-dimethylacetamide (20 ml) In the solution, the mixture was stirred at 700 m for 16 hours.俟 After cooling to room temperature, a saturated aqueous solution of sodium bicarbonate (50 liters) was added. The resulting coarse crystals were separated by filtration and washed with water. This crude crystal was recrystallized from ethyl acetate to obtain 0 32 g (yield 30%) of the title compound. Melting point: 238_241 ° C Example 10 According to the method of Example 9, n- [4- [2-amino-4_ (3,5 · dimethylphenyl) -1,3-thiazole_5-yl] -2 was used. -Pyridyl] -N · phenylamine instead of N_ [4- [2_amino-4- (3,5 -monomethylphenyl) -1,3 -sulfan-5-yl] -2- Π Bieryl] benzylamine to synthesize the compound of Example 10 below. Example 10: N_ [5- (2-benzylamino-4-Πpyridinyl) -4- (3,5 · dimethylbenzene (Please read the precautions on the back before filling this page})- ---------------- This paper is printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. The paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 110 311859 1220900 A7 1 --------- --B7 V. Description of the invention (ill) group) -1,3-thiazol-2-yl] acetamidine Refining point: 217-219 ° C Example 11 The method according to Example 4 The following compound of Example 11 was synthesized by using small methylurea instead of thiourea. Example 11: N- [4 · [4- (4-methoxyphenyl) _2_amido_13_thiazolyl]-2-pyridyl ] Benzamidine Melting point: 237-241 ° C Example 12 According to the method of Example 4, ν- [4- [2- (3-methylphenyl) _2_oxoethyl] -2-pyridyl] The following compound of Example 2 was synthesized by replacing benzamidine with 2- (2-benzylaminoamino_4-pyridinyl) -1- (4-methoxyphenyl) ethanone. Example 12: N- [ 4- [2-Amino-4- (3-methylphenyl) -1,3-thiazole · 5-ylb-pyridyl] benzidine. Melting point: 216-217. (: Example 13: Ν -[4- [4- (4-methoxyphenyl) -2-methyl-1,3-thia Azole-5-ylb 2-pyridyl] benzylamine Add bromine (0.18 ml, 3.5 mol) to a solution containing 2- (2-benzylamino-4-methylpyridyl) This mixture was stirred at room temperature for 30 minutes in a solution of methyl) ethyl ketone (12 g, 34 mmol) in acetic acid (10 ml). The reaction mixture was concentrated and the residue was dissolved in N, N-dimethylformamidine Amine (20 ml) was added with thioacetamide (0.30 g, 19 mmol), and the resulting mixture was stirred at room temperature for 20 hours. Nitrogen carbonate was added to the reaction mixture (please read the back first) Note to note? Please fill out this page again.) -------- t- 丨 Printed by the Consumers' Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs, the paper size is applicable to China National Standard (CNS) A4 (21〇X 297 mm) 111 311859 1220900 Printed A7 by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the Invention (ll2) Sodium saturated aqueous solution (20 ml) was extracted with ethyl acetate, and the extract was washed with water. The extract was dehydrated and concentrated The residue was purified by silica gel column chromatography (hexane: ethyl acetate, 1: 1) to obtain 68 g of the title compound (yield 50%). Melting point: 134-135 ° C Example 14: N- [4- [2-[(4-fluorophenyl) -4- (3-methylphenyl) -i, 3 -Thiazol-5-yl] -2-pyridyl] phenylacetamidamine with phenylacetamidine (0.33 ml, 2.5 mmol) and triethylamine (0.31 strokes, 2.2 mmol) ) To 4- [2- (4-fluorophenyl) -4- (3-methylphenyl) -1,3-thiazole-5-yl] -2-pyridylamine (0.81 g, 2 2 mmol) of tetrahydrofuran (20 ml), and the mixture was stirred at room temperature for 13 hours. A saturated aqueous sodium hydrogen carbonate solution (20 ml) was added thereto, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water. The extract was dehydrated and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate, 2: 1) to obtain 0.86 g of the title compound (yield 80%). Melting point: 187-190 ° C Example 15 According to the method of Example 14, 4_ [4_ (enmethoxymethoxyphenyl) · 2_methyl_1,3_thiazol-5-ylb 2-pyridylamine, 4_ [ 2_ethyl_4_ (3_methyl &quot; 'ylphenyl) -1,3-thiazol-5-yl] -2-pyridylamine, 4- [4- (3-methylphenyl) _2_ Propyl_1,3-thiazolyl-yl] _2-pyridylamine, 4- [2-butyl-4- (3-methylphenyl) _1,3-thiazol-5-yl] -2- Pyridylamine, 4_ [2- (2 · Phenylphenyl) _4_ (3_methyl1phenyl) _1,3-Poseal · 5 · yl] -2-ti-methylamine and 4-f4 gas3 _Methylphenyl) -2- (4- (Please read the note on the back? Matters before filling out this page) -------- ^ --------- Employees of the Intellectual Property Bureau of the Ministry of Economic Affairs Printed by the Consumer Cooperative 1220900 A7 B7 V. Description of the invention (113) Methylthiophenyl) -1,3-hydrasal-5-yl] -2_11 than 4- [2-methylphenyl] ) -4- (3-methylphenyl) -1,3-D-sialyl-5-yl] -2 -II than nicotylamine to synthesize the compounds of Examples 15.1 to 15-6 below.

Example 15-1: Ν- [4- [4- (4-methoxyphenyl) -2-methyl-1,3-thiazol-5-yl] -2-pyridyl] phenylacetamide. Melting point: 118-120 ° C

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

Example 15-3 · N- [4- [4- (3-methylphenyl) -2 -propyl-1,3- sigma--5-yl] -2-pyridyl] phenylacetamide Melting point: 109-111 ° C

Example 15-4: N- [4- [2-Butyl_4- (3-methylphenyl) -l, 3-thiazol-5-yl] -2-D-pyridyl] phenylacetamide Melting point: 92_93 ° C

Example 15.5: Ν- [4- [2- (2 · Gaphenyl) -4- (3-methylphenyl) -1,3-thiazol-5-yl] -2-pyridyl] phenyl Ethylamine melting point: 141-142 ° C Example 15-6: N- [4- [4- (3-methylphenyl) -2- (4-methylthiophenyl) -1,3-thizone 5--5-yl] -2 -D than fluorenyl] phenylethylamine Melting point: 205-206 ° C Example 16 According to the method of Examples 14 and 15, using benzamidine chloride and 3-phenylpropylammonium gas, respectively , 3- (4-methoxyphenyl) propanine, 3- (4-fluorophenyl) propanyl chloride, (Please read the precautions on the back before filling this page) -------- tr --------- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 113 311859 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy 1220900 A7 B7 V. Description of the invention (114) Instead of phenylacetamidine, 4-phenylbutaneamidine, 5-phenylpentamidine chloride, 2-thienylcarbonyl chloride, and 2-naphthylammonium chloride were used to synthesize the following Example-16.18 compounds. Example 16-1: Ν- [4- [2 · ethyl- -methylphenyl) -1,3-thienyl-5 · yl]-

2-pyridyl] benzamidine Melting point: 113-114 ° C

Example 16-2: N- [4- [2-ethyl-4- (3-methylphenyl) -i, 3_thiazole_5_yl] -2-pyridyl] phenylpropanilamine 126-127 ° C

Example 16-3: N- [4- [2-ethyl-4- (3-methylphenyl) -i, 3-thiazole-5_yl] -2-pyridyl] _3- (4-methoxy Phenyl) propanilamine Melting point: 137-138 ° C

Example 16-4: N- [4- [2-Ethyl-4- (3-methylphenyl) _1,3-thiazol-5-yl] -2-pyridyl] -3- (4-fluorobenzene Based) Propylamine Melting point: 116-117 ° C

Example 16_5: N- [4- [2-Ethyl-4- (3-methylphenyl) -l, 3-thiazole-5_ylb 2-pyridyl] -4-phenylbutyramide 92-93 ° C

Example 16-6: Ν- [4 · [2-ethyl_4- (3-methylphenyl) -1,3-thiazol-5-yl] -2 -0 specific octyl] -5-phenyl Melamine melting point: 86-87 ° C Example 16-7: Ν · [4 · [4- (3 · methylphenyl) _2 · propyl-1,3-thiazol-5-yl] _ 2 -1¾ Bityl] benzamidine amorphous powder ---------------- (Please read the precautions on the back before filling this page) Ordering parameters · This paper size applies to Chinese national standards ( CNS) A4 specification (210 X 297 mm) 114 311859 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy 1220900 A7 B7___ V. Description of the invention (l15) &quot; H-NMR (CDC13) δ: 1.08 (3Η, t, J = 7.1Hz) # 1.80-1 · 99 (2Η, m), 2.34 (3Η, s), 3.04 (2Η, t, J = 7.7Hz), 6.88 (1Η, 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) f 8.61 (1H, br s)

Example 16-8: N- [4- [4- (3-methylphenyl) -2-propyl-1,3-thiazol-5-yl] -2-pyridyl] -3-phenylpropionamidine Amine melting point: 103-104 ° C Example 16-9: N- [4- [2-butyl-4- (3 · methylphenyl) -1,3 · thiazol-5-yl] -2-pyridyl] benzene Formamidine amorphous powder &quot; H-NMR (CDC13) 5: 0 · 99 (3Η, t, J = 7.2Hz), 1.40-1.60 (2H, π〇, 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 · 5Ηζ), 8 · 10 (1H, d, J = 5.0 Hz) , 8.52 (1H, s), 8.71 (1H, br s) Example 16-10: N- [4- [2-butyl-4- (3-methylphenyl) -1,3- Thiazol-5-yl] -2-sigma stilbyl] -3 -phenylpropanamine Melting point: 77-781

Examples 16-11: Ν- [4- [2- (4-fluorophenyl) -4- (3-methylphenyl) -1,3-thiazole-5-yl] -2-pyridyl] benzyl Melamine melting point: 126-128 ° C

Example 16-12: N- [4- [2- (4-fluorophenyl) -4- (3-methylphenyl) -1,3-thiasal-5-yl] -2 -D ] -3 -Phenylpropanamine Melting point: 169-171 ° C Example 16-13: N- [4- [2- (2-chlorophenyl) -4_ (3-methylphenyl) -1,3 -Thiazole-5 -based] -2 -D than fluorenyl] benzylamine (Please read the notes on the back before filling this page) -------- tr- 丨 This paper size is applicable to China Standard (CNS) A4 specification (210 X 297 mm) 115 311859 1220900 A7 V. Description of the invention (116)

Your point ·· 13 8-140 ° C Example 16-14: N- [4- [2- (2-Gasphenyl) -4- (3-methylphenyl) · ι, 3-thiazole 5-yl ] -2 -D Specific phenyl] phenylpropanamine

Hyun point: 156-158 ° C

Example 16-15 ·· Ν- [4_ [4 · (3-methylphenyl) _2_ (4 · methylthiophenyl) 13-thienyl] _2_pyridyl] benzamidine Melting point: 180 -182 ° C Example 16-16: N- [4- [4- (3-methylphenyl) _2- (4-methylthiophenyl) _13_thiazol-5-yl] -2-pyridyl]- 3-Benzylpropanamide melting point: 174-175. (: Examples 16-17: N_ [4- [4- (3-methylphenyl) -2_ (4-methylthiophenyl) _13_

Glusal-5-yl] -2_fl specific octyl] -2-methylphenanthramine Melting point: 145-147 ° C Example 16-18: N_ [4- [4- (3-methylphenyl)- 2_ (Heartylmethylthiophenyl) 13_11fluorenyl] · 2_π to πdenyl] -2-naphthoic acid amine Melting point: 184-186 ° C Example 17: N- [4- [2-ethyl-4- (3-methylphenyl) -L3-thiazole_5_yl] _2_pyridyl] -N-methylphenylacetamidine with sodium hydride (60% paraffin dispersion, 58 mg, 15 mmol) To N- [4- [2 · ethyl-4- (3-methylphenyl) -1,3-thiazole-5_yl] -2-pyridyl] phenylacetamide (0.50 g, 1.2% Mol) in a solution of dimethylimine (5 ml) and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added methyllin (09 mL '1.5 mg), and the mixture was stirred at room temperature for 1 hour. The paper size is applicable to China National Standard (CNS) A4 specification ⑵G X 297 public love) ------ 116 311859 (Please read the precautions on the back before filling this page) -------- Order · — Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, printed 1220900 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, printed A7 B7 V. Description of the invention (117) Add 10% ammonium chloride aqueous solution and extract it with ethyl acetate. The extract was washed with a gasified sodium saturated aqueous solution, dehydrated 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. Melting point: 75-76 ° C Example 18 According to the method of Example 17, using N- [4- [2-ethyl-4- (3-methylphenyl) -1,3-thiazol-5-yl] -2 -Pyridyl] -3-phenylpropanamide in place of N- [4- [2-ethyl-4- (3-methylphenyl) -1,3-thiazol-5-yl] -2-pyridyl ] Phenylacetamide to synthesize the compound of Example 18 below. Example 18 ·· N- [4- [2-Ethyl-4- (3-methylphenyl) -1,3 · thiazol-5-yl] -2-naphthyl] -N-methyl-3 -Phenylpropylamine ^ -NMR (CDC13) 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, q, J = 7.5Hz) f 3.22 (3Hf s), 6.98 (1H, s) # 7.03-7.29 (9H, m) 0 7 · 37 (1Η · s), 8.37 (1H, d, J = 3.6Hz), Example 19 According to the method of Example 6, N- [4 · [4- (4 · methoxyphenyl) _2-methyl -1,3 · thiazol-5-yl] -2-pyridyl] benzidine, N- [4- [2-ethyl-4- (3-methylphenyl) -1,3 · thiazole -5-yl] -2-pyridyl] benzamidine, N_ [4_ [2_. 4- (3-methylphenyl) -l, 3-thiazol-5-yl] -2-pyridyl] phenylacetamide, N- [4- [2_ethyl-4- (3 -Methylphenyl) · 1,3-thiazol-5-yl] -2-pyridyl] -3-phenylpropanamine, N- [4- [4- (3-methylphenyl) -2 -Propyl-1,3-thienyl-5-yl] -2-o-pyridyl] benzidine, N- [4- [4- (3-methylphenyl) -2-propyl- (Please read the notes on the back before filling this page)-ϋ ϋ

ϋ ϋ ϋ · ϋ ^ ^ I n ϋ «1 n ϋ 1.— i_i I This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 117 311859 1220900 A7 V. Description of invention (⑽) 1 , 3-thiazol-5-yl] -2-pyridyl] phenylacetamide, N_ [4_ [4_ (3_methylphenyl) -2 · propyl · 1,3-thiasal · 54]- 2- [alpha] -pyridyl 3-phenylpropanilamine, [4 [2-butyl-4- (3-methylphenyl) pyridyl] 2-pyridyl] benzylamine, N_ [4- [2 · butyl 1 (3-methylphenylW, 3-thiasal-5-yl] yl] -3-phenylpropanamide, N_ [4_ [2_ (4_fluorophenyl) _4_ (3_methylphenyl1,3-D-sialyl-5-yl) -2-n-ratio] benzidine, N_ [4_ [2_ (4_Phenylphenyl) &gt; 4- (3 -Methylphenyl) -1,3-thiazole ·% kib 2-pyridyl] phenylacetamide, ... [仁 [2- (4-fluorophenyl) -4- (3-methylphenyl ) _L53_thiazole_5 • yl] _2_pyridyl] -3-phenylpropylamidamine, N_ [4- | &gt; (2 · Phenyl) _4- (3_methylphenyl) _1, 3-thienyl-5-yl] -2-o-bityl] benzidine,] ^-[4_ [2- (2-chlorophenyl) -4- (3.methylphenylthiazole-5 _Jib 2_pyridyl] phenylacetamidamine, n_ [4- [2- (2- (Lactylphenyl) -4- (3-methylphenyl -13-thiasal-5-yl] -2-fluorenpyridyl] -3-phenylpropanilamine, N- [4- [4- (3-methylphenyl) _2_ (4_methylsulfide Phenyl) -1,3-thiazol-5-yl] -2-¾pyridyl] benzamide, n- [4- [4- (3-methylbenzyl) -2 · (4-methyl Thiophenyl) -1,3-thiazol-5-yl] -2-pyridyl] phenylacetamide, N- [4- [4- (3-methylphenyl) -2- (4-methyl Thiophenyl) -l, 3-thiow-5-ylb 2-pyridyl] -3-phenylpropanamide and N- [4- [4- (3-methylphenyl) -2- (4-methylthiophenyl) -1,3-thiazol-5-yl] -2-Πpyridinyl] _2-naphthylamidine instead of N · [4- [2-amino-4- (3 -Methylphenyl) -1,3-thiazol-5-yl] -2-pyridyl] benzamide to synthesize the compounds of Examples 19-1 to 19-20 below.

Example 19-1: N-benzyl-N- [4- [4- (4-methoxyphenyl) -2-methyl-1,3-thiazol-5-yl] -2-pyridyl] amine Melting point: 132-133 ° C Example 19-2: N-benzyl · N- [4- [2-ethyl · 4- (3-methylphenyl) _1,3- 嚷 (Please read the Please note this page and fill in this page again. B7 V. Description of Invention (119)

嗤-&quot; 5-based] -2-ohylidene] amine Melting point: 106-107 ° C

Example 19-3 ·· N- [4- [2-ethyl-4- (3-methylphenyl) -1,3 · thiazol-5 · yl] -2-pyridylbenzene N- (2-benzene Ethyl) amine Melting point: 97-98 ° C

Example 19-4: N- [4- [2-Ethyl 4- (3-methylphenyl) -1,3-thiazol-5-yl] -2-pyridyl] -N- (3-benzene Propyl) amine Melting point: 52-53 ° C Example 19-5: N-benzyl-N- [4- [4- (3-methylphenyl) -2 · propyl-1,3-thiazole -5-yl] -2-pyridyl] amine oily product &quot; H-NMR (CDC13) δ: 1.06 (3H # tg J = 7.4Hz), 1.77-1-96 (2H, m), 2.33 (3Η · s) · 00 (2H, t, J = 7.7Hz), 4.38 (2H, d, J = 5.4Hz), 4.83 (1H, l &gt; rt), 6.32 (1H , s), 6.53 (1H, dd, J = 5.4, 1.6Ηζ), 7.10-7 · 40 (9H, m), 8.01 (1H, d, J «5-4Hz) Example 19 -6: N- [4- [4- (3-methylphenyl) · 2 · propyl-1,3-thiazol-5-yl] -2-pyridyl] -N · (2-phenylethyl Base) amine oily product ^ -NMR (CDCI3) δ: 1.08 (3Η, t§ J = 7.5Hz), 1.78-1.93 (2H, m), 2.32 (3H, s), 2.81 (2H, t, J = 7.〇Hz), 3.01 (2H, t, J * 7.7Hz) # 3.42 (2H.dt, J = 6.2 # 7.0Hz) # 4.52 (1H # brt) # 6.30 (1H # s ), 6.51 (1H # dd # J = 5.2 # 1.5Hz), 7.11-7.34 (8H, m) # 7-43 (lHf s), 8.00 (1H, dr J = 5.2Hz) Example 19-7: N- [4- [4- (3-methylphenyl) _2-propyl-1,3-thiazol-5-yl] -2-pyridylb N- (3-phenylpropyl) amine oily product ( Please read the precautions on the back before filling out this page) --------- Order ---------. The paper size printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs applies the Chinese national standard ( CNS) A4 specification (210 X 297 mm) 119 311859 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 1220900 A7 ___B7____ V. Invention Description (™) XH-NMR (CDC13) &lt; 5: 1.08 (3H, t, J = 7.4Hz) # 1.78-1.93 (4H, m), 2.32 (3H, s), 2.66 (2H, t, J = 7.2Hz), 3.01 (2H, t, J = 7.7Hz &gt; , 3.16 (2H, dt, J = 6.2, 7.2Ηζ), 4.52 (1H, brs), 6.26 (1H, s), 6.49 (1H, dd, J = 5.2 # 1.5Hz), 7.07-7-32 (8H, m), 7.42 (1H, s), 7.98 (1H, d # J = 5.2Hz) Example 19-8: N-benzyl-N- [4- [2-butyl- 4- (3-methylphenyl) -1,3-thiazol-5-yl] -2-pyridyl] amine oily product &quot; H-NMR (CDCI3) &lt; 5: 0.97 (3H, t, J = 7.3Hz), 1.38-1.59 (2Hr m), 1.73 · 1 · 90 (2Η, m), 2.33 (3Η, s), 3.02 (2Η, 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 19-9: N- [4- [2-butyl 4- (3-methylphenyl) -1,3-thiazol-5-yl] -2-D than pyridyl] -N- (2-phenylethyl) amine oily product ^ -NMR (CDCI3 ) δ: 0.98 (3H # t, J = 7.3Hz), 1.39-1.59 (2Hr m), 1.74-1 · 92 (2H, m), 2.32 (3H, s), 2.81 (2H , t, J = 7.0Hz), 3.04 (2H, t # J »7-7Hz) r 3.41 (2H # dt # J = 6.1, 7-0Hz), 4.55 (1H # t, J = 6.1Hz) # 6.30 (1H # s), 6.51 (1H # d # 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 19_10: N- [4- [2-butyl_4_ (3-methylphenyl) _1,3-thiazole_5-yl] -2 -Pyridyl] -N- (3-phenylpropyl) amine oily product (please read the precautions on the back before filling this page) -------- The size of the paper is applicable to the Chinese National Standard (CNS ) A4 specification (210 X 297 mm) 120 311859 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 1220900 A7 B7___ V. Description of the invention (121) ^ -NMR (CDCI3) δ: 0.98 (3Η, 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 (2Η , t, J = 7.7Hz), 3.16 (2Η, dt, J = 5.9, 6 · 2Ηζ), 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 19-11: N-benzyl-N- [4- [2- (4-fluorophenyl) -4- (3-methylphenyl) -1,3 -fluoren-5-yl]- 2-Hydroyl] amine melting point: 143-146 ° C Example 19-12: N- [4- [2- (4-fluorophenyl) -4- (3-fluorenylphenyl) -1,3_ Thiazal-5-yl] -2 -〇 than σ amidyl] -N- (2-phenylethyl) amine Melting point: 97-98 ° C

Example 19-13: N- [4- [2- (4-fluorophenyl) -4- (3-methylphenyl) -l, 3-thienyl-5-yl] -2 _ ] -N-(3-phenylpropyl) amine Melting point: 110_112 ° C

Example 19-14: N-benzyl-N- [4- [2- (2-Gaphenyl) -4- (3-methylphenyl) -1,3-sialo-5-yl] -2-¾ Amine] Amine melting point: 84-86 ° C

Example 19-15: N- [4- [2- (2-chlorophenyl) -4- (3-methylphenyl) -l, 3-thiazole-5-yl] -2-Π specific group] -N- (2-phenylethyl) amine Melting point: 113-114 ° C

Example 19-16: N_ [4- [2_ (2-chlorophenyl) -4- (3-methylphenyl) · 1,3-thiazole-5-yl] -2-0-σ specific group] · N- (3-phenylpropyl) amine Melting point: 101-102 ° C Example 19-17: N-benzylidene_N · [4- [4- (3-methylphenyl) -2_ (4 -Methylthiophenyl) -1,3_ 嚷 σ-sit-5-yl] -2-¾bentyl] amine (Please read the precautions on the back before filling this page) 丨 丨! This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 121 311859 1220900 A7 i. Description of the invention (122)

Melting point: 134-136 ° C Example 19-18: N- [4- [4ac3Tiangan # I —methylbenzyl) -2- (4-methylthiophenyl) -1,3- sialo- 5-yl] -2-methylamino

Melting point: 137-139 ° C Example 19_19: N- [4_ [4_n Tiangan — methylbenzyl) _2- (4-methylthiophenyl) -1,3-thiazol-5-yl] -2 · pyridyl · Ία 〇 # J Ν- (3-Benzylpropyl) amine

Melting point: 106-107 ° C Example 19-20: N- [4- [4_ (3_f-based benzyl) 2 (4 • methylthiophenyl_

嚷 嗤 _5_yl] _2_pyridyl] -naphthylmethyl) amine melting point · 144_145 ° C Example 20: N_ [4_ [4- (3methylphenyl) _2 (4_methyl, fluorenyl) Phenyl) -1,3_thiazol-5-yl than fluorenyl] benzyl with amine in N- [4- [4- (3_methyl and its aberrant base) _2 · (4_methylthiobenzene Group) _1,3_thiasal-5-yl] -2-carbinyl] benzidine amine (0.50 g, 10 mol) Νν · dimethylformamide (5 ml) ,) Add m-aerated perbenzoic acid (0555 g, 2.2 mol) to the stock solution, add 1 to the room and stir the mixture for 1 hour. To the reaction mixture was added 8 N hydrogenated aqueous solution of sodium hydroxide, and the resulting solid was filtered. This solid was recrystallized from ethanol to obtain 0.29 g (54% yield) of the title compound. Melting point: 212_214 ° C Example 21 According to the method of Example 20, n [4 [4 (3methylphenyl) -2- (4-methylthiophenyl) _ι, 3-thiazolyl] _2_pyridyl ] Phenylacetamide, N_ [4- [4- (3-methylphenyl) · 2- (4-methylthiophenyl) -13 • thiazole-5_ (Please read the notes on the back before filling (This page) -------- 1 · Printed by the Consumers' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs This paper is printed in accordance with the Chinese National Standard (CNS) A4 (210 X 297 public love) 122 311859 1220900 A7 B7 printed by the Employees ’Cooperative Association 5. Description of the invention (I23) group] -2 · Π than bityl] -3 -phenylpropanamide, N- [4- [4- (3-methylphenyl) -2- (4-methylthiophenyl) · 1,3-thiazol-5-yl] -2-pyridyl] -2-thiophenemethylamine, N- [4- [4- (3- -methyl Phenyl) -2- (4-methylthiophenyl) -1,3-thiazol-5-yl] -2-methylpyridinyl] _2-naphthylamidine, 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 instead of N- [4- [4- (3-methylphenyl) -2- (4-methylthiophenyl) -1,3-sialyl-5 · yl]- 2·

Pyridyl] benzamidine to synthesize the compounds of Examples 21-1 to 21-7 below. Example 21-1: N- [4- [4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) -1,3-thiazol-5-yl] -2-pyridine Methyl] phenylacetamide Melting point: 244-245 ° C

Example 21-2: N- [4- [4- (3-methylphenyl) -2_ (4-methylsulfonylphenyl) -1,3-thiazol-5-yl] -2-pyridyl] -3-Phenylpropanamine melting point: 236-237 ° C

Example 21.3: N- [4- [4- (3-methylphenyl) -2_ (4-methylsulfonamidophenyl) -1,3-thiazol-5-yl] -2-pyridyl ] -2-Thienolamide Melting point: 199_201 ° C

Example 21_4: Ν- [4- [4- (3-Methylphenyl) -2- (4-methylsulfonylphenyl) -1,3-thiazol-5-yl] 2-pyridyl] -2_Naphthylmethoxamine Melting point: 231-233 ° C Example 21_5: N-benzyl-N- [4- [4- (3 · methylphenyl) _2_ (4_methylcontinuylphenyl) ) -1,3-thiazol-5-yl] -2-pyridyl] Amine &amp; Zhang scale is applicable to China National Standard (CNS) A4 (210 X 297 mm) 311859 (Please read the precautions on the back first (Fill in this page) -------- 1220900

V. Description of the invention (124) Melting point: 148-150 ° C

Example 21-6 · N- [4- [4- (3-methylphenyl) _2_ (4-methylsulfonylbenzyl) _ 1,3-thiazol-5-yl] -2-pyridyl] fluorene _ (3_phenylpropyl) amine Melting point: 167-168 ° C Example 21-7: N_ [4- [4_ (3_methylphenyl) _2_ (4-methylsulfonylphenyl)> 1 , 3-Thiazole_5_yl-2-pyridyl] with _ (2-naphthylmethyl) amine Melting point: 167-168 ° C Example 22: Ν- [4 · [2-amino-4- (3 _Methylphenyl) _ΐ53 · thiazole_5_yl2-pyridyl] · N-benzylamine at 150C, stirred with [5- (2-fluoro-4-pyridyl) -4- ( 3-Methylphenyl) -1,3-thiazol-2-yl] amine (0.29 g, ΐ0 mmol) and benzylamine (2 ml, 11 mmol) for 3 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous sodium hydrogen carbonate solution (20 ml) was added, and the resulting mixture was extracted with ethyl acetate and the extract was washed with water. The extract was dehydrated and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate, i · 丨) to obtain 0.16 g (yield 41%) of the title compound. Melting point: 178-179 ° C Example 23 According to the method of Example 22, 4-methoxybenzylamine, 3-methoxybenzylamine, 2-methoxybenzylamine, 4-oxybenzylamine, 3_gas The benzylamine, (R) -1-phenylethylamine, (S) -1-phenylethylamine, and N-benzylmethylamine were used in place of benzylamine to synthesize the compounds of Examples 23-1 to 23-8 below. Example 23-1: N- [4- [2-Amino-4- (3-methylphenyl) -1,3-thiazol-5-yl] _ Standards are applicable to China National Standard (CNS) A4 specifications (210 X 297 Public Meal 1 124 ^ 1859 (Please read the notes on the back before filling in this page) -------- ^ --------- Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 1220900 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (I25)

2-D than pyridyl] -N_ (4-methoxybenzyl) amine Melting point: 183-184 ° C Example 23.2: Ν- [4- [2 · amino-4- (3-methylphenyl) _ι, 3-thien-5-yl] ·

2-Arylamidyl] -N- (3-methoxybenzyl) amine Melting point: 152-154 ° C Example 23-3: N- [4- [2-Amino-4- (3-methylbenzene) ) -I, 3-thiazole_5 · yl] _

2-α than pyridyl] -N- (2-methoxybenzyl) amine Melting point: 158-159 ° C Example 23-4: N_ [4_ [2-Amino-4- (3 • methylphenyl) ) _Ι, 3_thiazole_5_yl] _

2-Amididinyl] -N · (4-Gabenzyl) amine Melting point: 182-183 ° C Example 23-5: Ν- [4- [2 · Amino_4- (3 • methylphenyl) ) _Ι, 3 · thiazole-5_yl] _

Melting point of 2-pyridyl] -N- (3-gasbenzyl) amine 180-181 ° C Example 23_6: (R) -N_ [4_ [2-Amino-4_ (3-methylphenyl) _1, 3_thien-5-

Benzyl 2-pyridyl] -N- (l-phenylethyl) amine Melting point: 94-98 ° C Example 23-7: (S) _N- [4- [2-Amino-4 · (3- Methylphenyl) _ι, 3-thizone-5

Methyl] -2-pyridyl] -N- (l-phenylethyl) amine Melting point: 93-96 ° C Example 23-8 ·· N- [4- [2-Amino-4- (3-methyl Phenylphenyl: ^ Thiazole ^ -yl] -2-pyridyl] -N-benzyl-N-methylamine Melting point: 138-140 ° C Example 24 (Please read the precautions on the back before filling this page ) -------- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 125 311859 1220900 A7 B7 V. Description of the invention (126) According to the method of Example 22, use [5- (2-Fluoro-4-pyridinyl) -4- (3-methoxyphenyl) -1,3-thiasialyl] amine instead of [5- (2-fluoro-4-methylpyridinyl) -4 -(3 -A

Phenyl) -1,3-thiazol-2-yl] amine to synthesize the compound of Example 24 below. Example 24: N_ [4- [2_Amino- 4- (3-methoxyphenyl) -1,3-thienyl-5-yl] -2-pyridyl] -N-benzylamine Melting point: 217 -218 ° C

Example 25 According to the method of Example 22, [5_ (2_fluoro_4 _ [[[pyridinyl) _4_ (3-methylphenyl) -2- (4-methylsulfonylphenyl)) Thiazole in place of [5- (2-fluoro-4-1¾fluorenyl) -4- (3-methylphenyl) _ι, 3-thiafluoren-2-yl] amine, and 2-phenylethylamine, 4-fluoro The following examples 25-1 to 25-5 were synthesized by benzylamine, N_benzyl_N-methylamine, N_methyl_2_benzylethylamine and 2-thienylmethylamine in place of benzylamine. Example 25-1: Ν · [4- [4- (3-methylphenyl)> 2- (4-methylsulfonylphenyl) -1,3-thien-5-yl] -2-Π Specific octyl] (2-phenylethyl) amine Melting point: 174-176 ° C Please read the precautions on the back before filling in% This page fi

I I ▲ Member of the Intellectual Property Office of the Ministry of Economic Affairs Example 25-2: N_ (4-fluorophenylfluorenyl) -N- [4- [4 · (3_methylphenyl) · 2 · (4-methyl

Benzene fluorenylphenyl) _1,3_thiazol-5-yl] -2-11 than pyridyl] amine Melting point: 155-158 ° C

Example 25-3: N-benzyl-N · methyl-N_ [ren [4- (3-methylphenyl) _2_ (4-monomethylsulfonylphenyl) -1,3-thiazole-5 -Kib 2-pyridyl] amine Melting point: 165-166 ° C Printed by Cooperative Society Example 25-4: N-methyl-N- [4_ [4- (3 · methylphenyl) _2_ (4_methyl Sulfonylphenyl) -1,3-thienyl-5 · yl] -2-¾Bentyl] -N- (2 · phenylethyl) amine

126 311859 1220900 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs Α7 Β7 V. Description of Invention (127)

Melting point: 116-117QC Example 25 ··· N- [4- [4- (3 · methylphenyl) _244-methylsulfonylphenyl) _ 1,3 · thiazol-5-yl] -2_ Pyridyl] -ν_ (2-thienylmethyl) amine Melting point: 107-109 ° C Example 26: 4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) _5_ ( 2_phenylthio_4_ohidinyl) -1,3-thiazole containing 5- (2-fluoro-4-pyridyl) _4_ (3-methylphenyl) _2_ (4_methylsulfonylbenzene Base) -1,3-thiazole (0.40 g, 0.94 mmol) and thiophenol (100 ml, 9.7 mmol) were stirred at 150 t for 10 hours. After the reaction mixture was cooled, a saturated aqueous sodium hydrogen carbonate solution was added, and the resulting mixture was extracted with ethyl acetate and washed with water. The extract was dehydrated and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate, 1: 1) and recrystallized from ethanol to obtain 0.34 g (yield 70%) of the title compound. Melting point: 116-118 ° C Example 27: 5- (2-Bentylmethylthio-4-D specific sulfanyl group) _4- (3--fluorenylphenyl) _2_ (4_methylcontinyl) -1 , Sodium hydride (60% stone mound dispersion, 013 g, 3.2 mmol) was washed twice with thiazal, and suspended in N, N-dimethylformamide (15 ml) in. Phenylmethanethiol (0.35 ml, 3.0 mmol) was added to this suspension and stirred for 10 minutes. To this mixture was added 5- (2-fluoro-4_11 specific octyl) -4- (3-methylphenyl) -2- (4-methylphenylmethyl) -i, 3-thiidine ( 0.49 g, 1.2 mol) of Ν, Ν-dimethylformamide (5 ml) solution, and stir for 1 hour (please read the precautions on the back before filling this page) Order this paper size Applicable to China National Standard (CNS) A4 specification (21 × 297 mm) 127 311859 1220900 A7 ----------- B7 ____ 5. When the invention is described (like). An 8 N aqueous sodium hydroxide solution was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate, and the extract was washed with water. The extract was dehydrated and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate, 2: 1) to obtain 0.48 g (yield 79%) of the title compound. Boiling point: 182-185 ° C Example 2 8: 4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) _5_ (2_benzylsulfonyl-4-pyridyl) -1,3-thiazole containing 4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) _5_ (2 • phenylthio_4_arimidinyl) -1,3 -To a solution of thiazole (0.48 g, 0.93 mmol) in N, N-dimethylformamide (L); The mixture was stirred at room temperature for 1 hour. An 8 N aqueous sodium hydroxide solution was added to the reaction mixture, and the resulting solid was separated by filtration. This solid was recrystallized from ethanol to obtain 0.42 g (82% yield) of the title compound.

Melting point: 126-128 ° C The compounds prepared in the above Examples 9-28 are shown in Tables 丨 to 6 (Please read the precautions on the back before filling this page) -------- Order ---- ----- Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

311859 1220900 A7B7 V. Description of the invention (129) Table 1

R2 * Z'Y

Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economics Compound No. R2 2 Y 9 'ca -NH- 10 〇 • 〇V -NH- 11 〇 • c〇 · -NH · 12 ~ ιΌ) • CO- -NH- 13 &lt;} -CO · -NH · 14 • ch2co · • NH- 15-1 〇-ch2co- -NH- 15-2 ο • ch2co · -NH- 15-3 -〇-ch2c〇 * -Nhl · 15- 4 -ch2c〇- -NH- 15-5 ~~ 〇 * ch2c〇- -NH- 15-6 -ch2co -NH · 16-1 -〇-CO- -NH- 16-2 〇 (ch2) 2c〇 --NH- -NHCOMe -NHCOMe -Me MeO ~ ^ — -Me MeO ~ ^ ~ R1 R3

mp / ° C

Me Me

238-241

217-219 -NHMe MeO Me -o- 237 · 241 (Please read the precautions on the back before filling this page)

-NH 2 216-217 134-135 187-190 118-120 -------- Order ---------

107 · 108 109-111 92-93 141-142 205-206 126-127 This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 129 311859 1220900 A7 B7 V. Description of the invention (⑽) Table 2 Winning Cases

R 2 · Z · '• hr

R3- ^ R1

Y R1 R3

mp / CC (Please read the notes on the back before filling this page) -------- tr ---------. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 16-3 16- 4 16-5 16-6 16-7 16-8 16-9 16 · 10 16-11 16 * 12 16-13 16-14 * 16-15 16-16 OMe-(0Η2) 2 ^ Ο- -NH- -CH2Me -ooo ooo -〇 ~ oo-(CH2) 3C〇- -NH- ΌΗ2ΜΘ-(CHghCQ- ~ NH * -ΟΗρΜβ -CO- -NH--(CH2) 2Me * (CH2) 2CO- -NH- ^ (CH2) 2Me -CO-.. -NH--(CH2) 3Me-(CH2) 2CO- -NH--(CH2) 3Me * CO- -NH ·-(CH2) 2C〇- -NH- -CO- · ΝΗ · • (〇 闩 2) 2〇〇_ · ΝΗ-

-CO- -NH 137-138 92-93 86 ^ 87 amorphous 103 * 104 amorphous 77-78 ~ 0 ~ f 126028 169-171

Cl

Cl ， SMe-(CH2) 2CO- -NH- — ^ SMe

17Φ175 138-140 156-158 180 * 182 This paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) 130 311859 1220900 A7 B7 V. Description of the invention (131) Table 3

R2.Z.Y

A winning example combined! r2 z Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 16-17 • CO · -NH- 16-18 &lt; P -CO · * NH · 17 -o -ch2co · -NMe- 18 —Q _ (ch2) 2co '19 · 1 hQ -CH2 · · ΝΗ · 19-2 o • ch2 * · ΝΗ · 19-3 〇 · 《CH2) 2 · * ΝΗ · 19-4 〇- (CHJa- · ΝΗ · 19-5 〇 • CHg · -ΝΗ · 19-6 • (CH2) 2- • ΝΗ- 19-7 • (CH2) 3. -ΝΗ- 19-8 -o • ch2 · -ΝΗ- 19 * 9-(CH2) 2- · ΝΗ · * CH2Me * CH2Me • CH2Mq-(CH2) 2Me-(CH ^ Me • (CHgJgMe-(CHgJaMe Υ R1 R3 mp / * C Me o- 145 * 147 ~ 〇 * Sh / le Me 184-186 • CH2Me Me 〇- 75-76 • CH2Me &quot; b- oil -Me 132 * 133 106-107

Me 〇-VV Me (Please read the notes on the back before filling in this page) 97 * 98 52 * 53

oH oil oil • oil oil -------- tr ---------. This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 131 311859 1220900 A7 B7 5 、 Explanation of invention (l32) Table 4

R 2 · Z, Ν '

V R1 Spiritual Combination i y

Y R1, R3

mp / ° C 19-10 A * (CH2) 3- -NH-, (CH2) 3Me 19-11 Seven · Call · 19-12 ~ 1ζ} ·-(CH2) r -NH- -NH- _ Me Let 5-

Me 19-13 19-14 19-15 —- (ch2) 3 -—- ch2 '-(CH2) 2 * -NH · -NH · • NH- 19-16 a- (CH2) 3- 19-17 _Q Price 19-18 --- (CH2) 2--NH · -NH-

On b-b-

Me SMe Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 19-19 19-20 20 —- (CHgJa * cHz- 0 (Please read the precautions on the back before filling this page) -------- 143- 146. 97-98 110-112 84-86 * 113-114 * 101.102 134-136 137-139 106-107 144- 145 212-214 — — — — — — — — — —NH- ~ • ~ 〇 ^ SMe — ^^-SG2Me -NH-

-NH CO · · ΝΗ · This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) • SMe

Me

Me 132 311859 1220900 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the Invention (I33) Table 5 R2 * Z'Y

Y

r3. mp / ° C 21-1 21-2 21-3 21-4 21-5 Ο —- (CH2) 2C〇- ~ ύ ~ (3 GH2OO * * NH. (0 · • co- • CHg-' ~ ^ 3 ~ SQ2Me • NH- — ^^-S02Me, NH · — ^ ~ ^ ~ S02Me -NH- — ^^-SOgMe -NH- — ^^-S02Me

Vv V 244-245 236-237 199-201 231-233 148-150

Me 167-168 (Please read the notes on the back before filling this page) -------- Order 21-6 —- (CHjJs--ΝΉ · SOgMe 21-7 &lt; P -CH2 * * NH- —S02Mi 22 0 -CHg * • NH · -NH2 23-1 -CH2 · -NH- -NH2 23-2 OMe • CH ^ · -NH * -NH2 23-3 Me ^ _ ^ -pH2--NH · · · ΝΗ2 23-4 ~ 0 ^ C, -ch2- · ΝΗ · ~ ΝΗ2 23-5 • ch2 · -NH-, NH2 23-6 ~ o CHMe · (R) • NH- -NH2

Me b-, ev 167-168 178-179 183-184 152-154 158-159 182-183

180-18T 94 * 98 This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 133 311859 1220900 A7 B7 V. Description of the invention (134) Table 6 R2Z ·, 1ST, (Please read the Note for this page, please fill out this page) -------- tr_ — Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

Winning Example I

R2 Z

Y R1 R3

mp / eC 23-7 23 · 8 24 25-1 25-2 25-3 25-4 25-5 26 27 28 —-CHMe_ (S) 〇 · 〇Η2 '—- (CH2) 2 —-CH2-〇 -CH2- -NMe · -o-〇-o -ΝΗ · • CH2. -NMe ·-(CH2) 2 · • CH2 · -ΝΗ · NH- · ΝΗ ·

Meb- MeO Plant 'Me · ~ ^ _3 ^ S02Me 93-96 -nh2 -NHo ~ ^ 3 ^ S〇2Me • NMe- — • NH- — ^^ S02Me Me each ~ ^ J-S02Me, —— .Me ~ ^ _ ^-S02Me / = \ Me -S02-— "^ -S02Me ^ \ — This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 134 138-140 217-218 174-176. 155-158 165-166 116-117 107-109 116-118 182-1B5 126 * 128 311859 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy 1220900 A7 ____B7__ V. Description of the invention (135) Preparation example 1: (1) Example 1 compound 50 g (2) lactose 34 mg (3) corn starch 10.6 mg (4) corn starch (paste) 5 mg (5) magnesium stearate 0.4 mg (6) carboxymethyl cellulose 20 mg A total of 120 mg was mixed according to the conventional method (1) to (6) and made into tablets by a compression tablet machine. Formulation Example 2: (1) Example 16-1 Compound 10.0 mg (2) Lactose 60.0 g (3) Corn starch 35.0 mg (4) Gelatin 3.0 mg (5) Magnesium stearate 2.0 g g 0.03 ml 10% gelatin An aqueous solution (3.0 g of gelatin) was used to granulate 10.0 g of the compound of Example 16-1 and a mixture of 60.0 mg of lactose and 35.0 mg of corn starch through a 1 mm mesh sieve, then dried at 40 ° C and sieved again . The granules thus obtained were mixed with 2.0 mg of magnesium stearate and compressed to spin. The resulting core was coated with a sugar coating containing sucrose, titanium dioxide, talc and acacia gum suspension. The coated tablet was polished with beeswax to obtain a coated keying agent. Preparation Example 3: (Please read the precautions on the back before filling in this page) -------- 1T --------- · This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 135 311859

1. Description of the invention (l36) (1) Example 16_1 Compound 10.0 mg (2) Lactose 70.0 mg (3) Corn starch 50.0 mg (4) Soluble starch 7.0 mg (5) Magnesium stearate 3.0 mg in 0.07 ml Soluble starch aqueous solution (7.0 mg of soluble starch) After granulating 10.0 mg of the compound of Example 16-1 and 3.0 mg of magnesium stearate, the teaching agent and 700 mg of lactose and 500 mg of corn flour mixing. This dry compound is compressed into an ingot. Formulation Example 4: (1) 5.0 mg of the compound of Example 18 (2) 20.0 mg of the salt (3) Distilled water to a total amount of 2 ml 5.0 mg of the compound of Example 18 and 20.0 g of sodium gaseous solution were dissolved in distilled water, and water was added to the total amount For 2.0 ml. The solution was filtered, and aseptically filled into a 2 ml ampoule. After sterilization, the ampoule was sealed to prepare a solution for injection. Test Example 1: The genetic process was performed according to the method described in Molecular Cloning (Molecular Transplantation) published by Cold Spring Harbor Laboratory in 1989 or the experimental procedure accompanying the reagent. 1) Transplantation of human adenosine A3 receptor The human brain cDNA was used to perform adenosine a3 receptor gene transfer by PCR method. Take 1 Naike brain cDNA (QUICK-Clone eDNA, TOYOBO, (Please read the precautions on the back before filling out this page) -------- Order --------- Ministry of Economic Affairs Printed by the Intellectual Property Bureau Staff Consumer Cooperatives This paper is printed in accordance with the Chinese National Standard (CNS) A4 (21 × 297 mm) 136 311859 Printed by the Intellectual Property Bureau Staff Consumer Cooperatives 1220900 A7 B7 V. Invention Description (137)

Osaka) was used as a template, and 5'- CGCCTCTAGACAAGATGCCCAACAACAGCACTGG-3 was added with reference to the base sequence of the adenosine A3 receptor gene described in Salvatere et al. (Proc. Natl. Acad. Sci. USA, 90: 10365-10369, 1993). Sequence number: 1) and 5'- CGGGGTCGACACTACTCAGAATTCTTCAAGG-3, (sequence number: 2) 50 picomoles of each primer set and using TakaraLAPCR kit Ver. 2 (Takara shuzo) (Reaction conditions: from 95 ° C for 1 minute '66 (35 cycles consisting of 1 minute at 75 ° C and 2 minutes at 75 ° C). PCR reactions were performed using a DNA thermal cycler (Parkin Elmer). The obtained PCR product was subjected to agarose gel electrophoresis, and a 1.0 kb DNA fragment was recovered. Then, the original TA Cloning Kit (Funacon) was used to transduce the ^ A3 receptor gene. Next, the generated plastids were decomposed with the restriction enzyme Xbal (Takarashuzo), treated with T4 DNA polymerase (Takarashuzo) to form blunt-end fragments, and further decomposed with Sall (Takarashuzo) to prepare adenosine A3 receptor fragments. 2) Preparation of plastids expressing human adenosine A3 receptor. Bglll (Takarashuzo) was used to dissociate the SR α promoter derived from PTB1411 described in JP-A 5_076385, and it was linked to EcoRI via DNA ligation kit (Takarashuzo). (Takarashuzo) decomposes the pCI vector to make pCI-SR α. Then, this pCI_SRa was decomposed with Clal (Takarashuzo) and treated with T4 DNA polymerase (Takarashuzo) to make it blunt. On the other hand, pGFP-Cl (Toyobo) is decomposed by Bsu36I (Daiichikagakuyakuhin), and T4 DNA polymerase (please read the precautions on the back before filling this page) -------- 11_ 丨 This paper size Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 137 311859 1220900 A7 V. Description of the invention (i30 (Takarashuzo) is processed into a blunt end to obtain a 1.63 kb DNA fragment, followed by a DNA ligation kit (Takarashuzo) The two were ligated and transformed into competent E. coli JM109 cells to obtain plastid pMSRa neo. Next, pMSRaneo was decomposed with EcoRI (Takarashuzo), treated with T4 DNA polymerase (Takarashuzo) into blunt ends, and further mixed with Sall (Takarashuzo) decomposed 5.4 kb DNA fragment and the above 1] The gland ridge As receptor gene was ligated with a DNA ligation kit (Takarashuzo), and transformed into E. coli JM109 competent cells (Takarashuzo) to obtain plastid pA3SRa 3) Introduce plastids expressing human adenosine a3 receptor into CHO (dhfr-) cells and express them. Will be cultured in 750 ml tissue culture flasks (Vecton Dickinson) containing 10% fetal bovine serum (L if etic Oriental). Of CHO (dhfr_) cells obtained on Ham F12 medium (Nihonseiyaku) were detached at 0.5 g / L trypsin-0.2 g / L EDTA (Lifetic Oriental), and then the cells were washed with 1 PB S (Lifetic Oriental), Centrifuge (1,000 rpm, 5 minutes) and resuspend in PBS.

| Next, use the DNA Pulser (Biorad)

Part I I was introduced into the cell. That is, 8 × 10 6 cells and 10 μg of pA3SRa representing human Ϊ gland ridge 8 receptor were added to a 0.4 cm photometer, and electroporation was performed with a volume of 0.8 1 ml at a voltage of 0.25 kV and a capacitance of 960 // F. Then, after the cells were removed, the cells were transferred to Ham F12 containing 10% fetal bovine serum and cultured for 24 hours. After that, the cells were detached, centrifuged, and suspended in the added gene voxel f I (geneticin &gt; Lifetic Oriental). ) jL 500 micrograms / ml contains! The paper size of 0% tire paper is suitable for Ningguo National Standard (CNS) A4 specification (21 × 297 male) --- 138 311859 (Please read the precautions on the back before filling this page) -------- tr --------- 1220900 A7 B7 V. Description of the invention (wo) Lake. 5) Adenosine A3 receptor binding test Add [3H] -NECA (Amershan) as a ligand to the analysis buffer II containing 100 μg / ml of the membrane obtained above 4) and various test compound concentrations The concentration of the ligand was adjusted to 10 nM, and the reaction was performed at room temperature for 1 hour. Then, 'Selfervester (Packard) was filtered, and the reaction solution was used to transfer the membrane to a unit filter GF / C (Packard), and washed three times with cooled 50 mM Tris buffer (pH 7.5).俟 After the filter is dried, add Microscint 0 (Packard) to the filter, measure the radioactivity with an advanced counter (Packard), and calculate with PRIM 2.01 software (Graphpad Software) what is needed to reduce the amount of [3h] _NECA combined with membrane differentiation Test compound concentration (IC5.). As a result, IC5 of the compound of Example 1. The value was 11.6 nM, and it was found that the compound (I) had excellent affinity for the adenosine A3 receptor. Test Example 2: Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs (please read the note 3 on the back before filling out this page) According to the Molecular Cloning book published by Cold Spring Harbor Laboratory in 1989 (Maniatis et al. ) Gene manipulation as described in the method or in the experimental procedure accompanying the reagents. 1) Transfection of human p 3 8 MAP kinase gene and preparation of recombinant Baculovirus Using PCR method, use the P38 MAP kinase gene described in Han et al. (Science 285 (5173), 808-811 (1994)) P38_U: 5, _

ACCACTCCAGATGGACTACAAGGACGACGATGACAAGT This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 140 311859 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 1220900 A7 B7 V. Description of the invention (called CTCAGGAGAGGGGCACACGTTCTACC-3, (serial number: 3 ) And PAG-L: 5,-ACCCGGTACCACCAGGTGCTCAGGACTCCATCTCT-3, (sequence number: 4) primer set, using kidney cDNA (Toyobo, QUICK-Clone cDNA) as a template, the human p38 MAP kinase gene was transfected. AmpliWax PCR Gem 100 (Takara shuzo), PCR was performed using the Hot Start method. Mix 2 μl of 10 times LA PCR buffer, 3 μl of 2.5 mM dNTP solution, 12 · 5 // 2.5 μM primer solution each Liters and 10 microliters of sterile distilled water as a low-mix solution; using 1 microliter of human heart cDNA (1 nanogram / ml) as a template, mix 3 microliters of 10-fold LA PCR buffer, 1 microliter of 2.5 mM dNTP solution, 〇5 microliters of TaKaRa LA Taq DNA polymerase (Takara shuzo), and 24 5 microliters of sterile distilled water as a high-mix solution. To the prepared low-mix solution was added an AmpliWax PCR Gem 10 0 (Takara shuzo), treated for 5 minutes at 7qoc and 5 minutes in ice, and then added a highly mixed solution to prepare a PCR reaction solution. The tube containing the reaction solution was placed in a thermal cycler (Parkin Elmei ·) , And treated at 95 ° C for 2 minutes. Further, a cycle consisting of 95 ° C for 15 seconds and 68 ° C for 2 minutes was repeated 35 times, and then treated at 72 ° C for 8 minutes. The obtained PCR product was subjected to agarose gel ( 1%) electrophoresis analysis, recovering a 1.1 kb DNA fragment containing the p38 MAP kinase gene, and then inserting it into the pT7Blue-T vector (Takara shuzo) to produce a plastid pHP38. Linked plastid pFASTBACl (CIBCOBRL) 4.8 kb Xh〇i_ ΚρηΙ fragment and 1.1 kb Xhol-Kpn fragment of the above-mentioned plastid pHP38, (Please read the note on the back? Matters before filling out this page) — — — — — — — — This paper size applies Chinese national standards ( CNS) A4 specification (210 X 297 mm) 141 311859 1220900 A7 B7 V. Description of invention (manufacturing plastid PFBHP38. (Please read the precautions on the back before filling out this page.) Use plastid PFBHP38 and BAC-TO-BAC baculovirus expression system to make recombinant baculovirus stock BAC-HP38. 2) The transfection of human MKK3 gene and the preparation of recombinant baculovirus The PCR method was used to make the MKK3 gene base sequence described with reference to Derijard, B. et al. (Science 267 (5198), 682-685 (1995)) MKK-U: 5, ACAAGAATTCATAACATATGGCTCATCATCATCATCAT TTCCAAGCCACCCGCACCCAA-3, (sequence number: 5) &amp; MKK-L: 5, -TCCCCTCTAGACTATGAGTCTTCTCCCAGGAT-3, (sequence number: 6) primer set, and use kidney cDNA (Toyobo, QUICK-Clone cDNA) for the human MKK3 gene. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. AmpliWax PCR Gem 100 (Takara shuzo) was used to perform a PCR reaction using a hot start method. Mix 2 microliters of 10x LA PCR buffer, 3 microliters of 2.5 mM dNTP solution, 2.5 microliters each of 12.5 // M primer solution, and 10 microliters of sterile distilled water as a low-mix solution; mix 1 microliter of human kidney cDNA (l nanograms / ml), 3 µl of 10-fold LAPCR buffer, 1 µl of 2.5 mM dNTP solution, 0.5 µl of TaKaRa LA Taq DNA polymerase (Takara shuzo), and 24.5 µl of sterile distilled water as a highly mixed solution . An AmpliWax PCR Gem 100 (Takara shuzo) was added to the prepared low-mix solution, and treated at 70 ° C for 5 minutes and in ice for 5 minutes, and then a high-mix solution was added to prepare a PCR reaction solution. The tube containing the reaction solution was placed in a thermal cycler (Parkin Elmer) and treated at 95 ° C for 2 minutes. Further, the paper size is 35 times repeated at 95 ° C for 15 seconds and 68 ° C for 2 minutes. The paper size applies the Chinese National Standard (CNS) A4 (210 X 297 mm) 142 311859 1220900 A7 B7 V. Description of the invention (1 岣After the completion of the cycle, the treatment was performed at 72 ° C for 8 minutes. The obtained PCR product was subjected to agarose gel (1%) electrophoresis analysis, and a 1.0 kb DNA fragment containing the MKK3 gene was recovered, and then inserted into the pT7Blue-T vector ( Takara shuzo) to produce the plastid PHMKK3. To make the MKK3 mutation into a constitutively active form (position 1 89 from Ser to Glu, position 193 from The to Glu), use the QuickChange Site-Directed Mutagenesis kit, using SER-U The primer set of: 5'-GGCTACTTGGTGGACGAGGTGGCCAAGGAGATGGATGC CGGCTGG-3 '(sequence number: 7) &amp; SER-L: 5, -GCAGCCGGCATCCATCTCCTTGGCCACCTGGTCCACCAA GTAGCC-3' (sequence number: 8) caused mutations, and plastid pcaMKK3 was obtained pFASTBACl (CIBCOBRL) 4.8 kb EcoRI-Xbal fragment and the above-mentioned plastid pcaMKK3 1.0 kb EcoRI-Xbal fragment to produce plastid pFBcaMKK3. Use plastid pFBcaMKK3 and BAC-TO-BAC baculovirus expression system Recombinant baculovirus reservoir BAC_caMKK3 was produced. 3) Preparation of active p38 MAP kinase Sf-21 cells were seeded in 100 ml Sf-900II SFM medium (GIBCOBRL) to 1 x 106 cells / ml at 27 ° C for 24 hours. After adding 0.2 ml each of recombinant baculovirus reservoirs BAC-HP38 and BAC_caMKK3, the cells were further cultured for 48 hours. After centrifugation (3000 rpm, 10 minutes) to separate the cells from the cell fluid, wash the cells twice with PBS. Suspension of cells in 10 ml of lysis buffer (25 mMHEPES (pH 7.5), 1% (please read the precautions on the back before filling out this page) Order --------- Consumption by the Intellectual Property Bureau of the Ministry of Economic Affairs The paper size printed by the cooperative is applicable to China National Standard (CNS) A4 (210 X 297 mm) 143 311859 1220900 A7 B7 V. Description of the invention (144)

TritonX, 130 mM NaCl, 1 mM EDTA, 1 mM DTT, 25 mM Dot-Glycerol Esterase, 20 mM Leupeptin, 1 mM APMSF, 1 mM Sodium Orthosulfate) in a homogenizer (POLYTRON) in 2000 Process twice at rpm for 2 minutes to grind cells. The resulting supernatant was centrifuged at 40,000 rpm for 45 minutes. The active p38 MAP kinase was purified using Anti-FLAG M2 affinity chromatography colloid (Eastman Chemical). 4) Measurement of p38 MAP kinase inhibitory activity 2.5 microliters of the test compound dissolved in DMSO was added to a 37.5 microliter reaction solution (25mM HEPES (pH 7.5) containing 260 nanograms of active p38 MAP kinase and 1 microgram of Myelin basic protein). ), 10 mM magnesium acetate), and maintained at 30 ° C for 5 minutes. Add 10 μl of ATP solution (2.5 // M ATP, 0.1 / i Ci [g-32P] ATP) to start the reaction. After the reaction was allowed to proceed at 30 ° C for 60 minutes, 50 e L of a 20% TCA solution was added to stop the reaction. After allowing the reaction solution to stand at 0 ° C for 20 minutes, the acidic insolubility was transferred to a GF / C filter (Packard Japan) using Selfervester (Packard Japan), and washed with 250 mM Η3PO4. After drying at 45 ° C for 60 minutes, 40 // M Microscint 0 (Japanese Packard) was added, and the radiation activity was measured with an advanced counter (Packard in Japan). PRIM 2.01 software (Graphpad Software) was used to calculate the concentration (IC5. Value) required to inhibit 50% 32P absorption into acidic insolubility. The results are shown in Table 7. [Table 7] (Please read the notes on the back before filling this page)

11 an —ϋ ϋ n sip, · a ^ in · ϋ ϋ n I Printed case number IC50UM by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs) 1 0.43 2 0.063 3 0.023 4 0.020 5 0.029 6 0.023 This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 144 311859 1220900 A7 ------— B7 ________— ____ V. Description of the invention (The results show that compound ⑴ has p38 MAP kinase inhibitory activity. Test Example 3 : (Please read the precautions on the back before filling this page) Measurement of TNF-a production inhibitory activity

THP cells cultured on pRI 1640 medium containing 1% non-action fetal calf serum (manufactured by Life Technologies, Inc., USA) and 10 mM HEpES (pH 7 5) were seeded at 96 cells / slot at 96 cells / well. After the petri dish was added, 1 microliter of the test compound dissolved in dmSO was added thereto. After incubating in a carbon dioxide gas incubator at 37 ° C for 1 hour, LPS (Yakojunyaku) was added to a final concentration of 5 µg / liter. After culturing in a 37 ° C carbonic acid gas incubator for 4 hours, the supernatant was obtained by centrifugation. ELISA (R &amp; D system, Quantikine kit) was used to determine the concentration of TNF α in the supernatant. The concentration (IC50 value) required to inhibit 50% TNF-α production was calculated using PRIM 2.0 software (Graphpad Software). The results are shown in Table 8. [Table 8] Example No. IC50 (/ zM) 3 0.026 4 0.014 5 0.020 6 0.140 This result shows that the compound VII has excellent TNF-α production inhibitory activity. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs [Industry availability] Compound (I) or its salt has excellent adenosine receptor antagonistic activity, which can be used for this paper rule + 0 @ 家 标准 （CNS) A4 Specification （ (210 x 297 mm) 145 311859 1220900 A7 -_____ B7__ V. Description of the invention (I46) It is used for the prevention or treatment of adenoid As receptor-related diseases. In addition, the compound ⑴ or its salt has excellent p38 MAP kinase inhibitory effect-the best-in-class activity and TNF-α production inhibitory activity, and can be used as prevention or treatment of diseases related to P38 MAP kinase inhibitory activity and TNF-α inhibitory activity.剂 的 用。 The use of the agent. (Please read the precautions on the back before filling out this page) The paper printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 146 311859 Employees of the Intellectual Property Bureau of the Ministry of Economic Affairs Printed by the Consumer Cooperative 1220900 A7 B7_ V. Description of the invention (14 is the Sequence Listing &lt; 110 &gt; Takeda Chemical Industry Co., Ltd. &lt; 12〇 &gt; 5-pyridyl-1,3-azole compound, its preparation method and use, and Use &lt; 130> 2605 case &lt; 150 &gt; JP2000-126289 &lt; 151 &gt; 2000-04-21 &lt; 160 &gt; 8 &lt; 210 &gt; 1 &lt; 211 &gt; 34 &lt; 212 &gt; DNA &lt; 213> artificial sequence &lt; 400 &gt; 1

CGCCTCTAGA CAAGATGCCC AACAACAGCA CTGC 34 &lt; 210 &gt; 2 &lt; 211 &gt; 34 &lt; 212 &gt; DNA &lt; 213 &gt; Artificial sequence &lt; 400 &gt; 2 CGGGGTCGAC ACTACTCAGA ATTCTTCTCA ATGC 34 &lt; 210 &gt; 3 &lt; 211 &gt; 62 &gt; 62 DNA &lt; 213> Artificial sequence &lt; 400 &gt; 3 ACCACTCGAG ATGGACTACA AGGACGACGA TGACAAGTCT CAGGAGAGGC CCACGTTCTA 60 CC 62 &lt; 210 &gt; 4 &lt; 211 &gt; 35 &lt; 212 &gt; DNA &lt; 213> Artificial sequence (please read the notes on the back first) (Fill in this page again.) This paper size is in accordance with China National Standard (CNS) A4 (210 X 297 mm) 147 311859 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 1220900 A7 _____B7___ 5. Description of the Invention (⑽) &lt; 400 &gt; 4 ACCCGGTACC ACCAGGTGCT CAGGACTCCA TCTCT 35 &lt; 210 &gt; 5 &lt; 211 &gt; 61 &lt; 212 &gt; DNA &lt; 213> artificial sequence &lt; 400 &gt; 5 ACAAGAATTC ATAACATATG GCTCATCATC ATCATCATCA TTCCAAGCCA CCCGCACCCA 60 A &lt; 6 &lt;210; 32 &lt; 212 &gt; DNA &lt; 213 &gt; artificial sequence &lt; 400 &gt; 6 TCCCGTCTAG ACTATGAGTC TTCTCCCAGG AT 32 &lt; 210 &gt; 7 &lt; 211 &gt; 45 &lt; 212 &gt; DNA &lt; 213> Sequence &lt; 400 &gt; 7 GGCTACTTGG TGGACGAGGT GGCCAAGGAG ATGGATGCCG GCTGC 45 &lt; 210 &gt; 8 &lt; 211 &gt; 45 &lt; 212 &gt; DNA &lt; 213> artificial sequence &lt; 400 &gt; 8 GCAGCCGGCA TCCATCTCCT TGGCCACCTC GTCCACCA The note? Please fill in this page for more information) ^^ · 1111111 This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 148 311859

Claims (1)

3 90 20 12) a6 Amended Patent Application No. 89122035 (June 1, 1993) 1. An optionally oxidized compound represented by the following formula, (I) wherein R1 is (i) Ci-6 alkyl, (ii) phenyl substituted with c ^ 6 alkylthio, cN6 alkylthioxanthate or halogen atom if necessary, or (iii) 1 or 1 if necessary 2 Cw alkyl groups or 1 or 2 amine groups of the formula-(C = 0) -R5, wherein the fluorenyl group (where R5 'represents ①alkyl or ②pyridyl) substituents; R2 is optionally halogen Atomic or cN6 alkoxy substituted phenyl or naphthyl, or pyridyl or thienyl; r3 is a phenyl substituted with 1 or 2 C! _6 alkyl or Cw alkoxy if necessary; Central Standards Bureau of the Ministry of Economic Affairs Printed by the Employee Welfare Committee. X is a sulfur atom; Y is an oxygen atom, an oxidized sulfur atom if necessary, or a group represented by the formula NR4, (where R4 'represents hydrogen or a Cw alkyl group); z is an oxo group if necessary C or C6 radical :): complete radical or chemical bond; or its salt. For example, the compound of item 1 in the scope of Shen Qing's patent, in which R1 is 1 or 2 formulas-(〇〇) -R5, as shown in the formula (where R5 "represents pyr A4 · (Gu earnΪT 311859 (revised Edition) 胺 220900 ° amidyl) amine group; R2 is phenyl, naphthyl, pyridyl or thienyl; R3 is phenyl substituted with 1 or 2 Cw alkyl or cl 6 alkoxy if necessary; i X Is a sulfur atom; γ is 0, NH or S; and the chemical bond with Z is a Cl_4 alkylene group having an oxo group as required. 3. The compound according to item 丨 in the scope of the patent application, which is selected from the group consisting of the following compounds : N- [5- (2-benzylideneamino-4-pyridyl) -4_α% dimethylphenyl) -1,3-thiazol-2-yl] acetamidine, Ν- [5- ( 2 · benzylamino_4-pyridyl) -4_ (3,5_dimethylphenyl) _ 1,3-thiazol-2-yl] acetamidamine, Ν- [4- [4_ ( 4-methoxyphenyl) _2 • methyl-1,3-thienyl-5-yl] -2-methyl. Phenyl] phenylmethylamine, Ν- [4- [2 · (4-fluorobenzyl) -4- (3-methylphenyl) -1,3-thiasal-5-yl; μ 2-pyridyl] phenylacetamide, N- [4- [2-ethyl-4- (3 -Methylphenyl) -1,3-thiazol-5-yl] -2-pyridyl] phenylethyl Amine, printed by N- [4- [4- (4- (3-fluorenylphenyl) -2-propyl-1,3-thiazol-5-yl] -2-pyridyl] Phenylacetamidine, N_ [4- [2-butyl-4- (3-methylphenyl) -1,3-thiazol-5-yl] -2-pyridyl] benzylethylamine, Ν · [4- [4- (3-methylphenyl) -2- (4-methylthiophenyl) -1,3-thiazol-5-yl] · 2-pyridyl] phenylacetamide, N- [4- [2-Ethyl-4- (3-fluorenylphenyl) -1,3-thiazol-5-yl] -2-pyridine The paper size is applicable to China National Standard (CNS) A4 (210X297 Mm) 311859 (revised version) 1220900 _H3_yl] benzamide, N- [4- [2-ethyl-4- (3-fluorenylphenyl) -1,3-thiazol-5-yl]- 2-pyridyl] -3 -phenylpropanylamine, N- [4- [2-ethyl-4- (3-methylphenyl) -1,3-thiazol-5-yl] -2-port Bipyridyl] _3- (4-methoxyphenyl) propanamidin, N- [4- [2-ethyl- 4- (3-methylphenyl) -1,3 -D roll ϋ-5 -Yl] -2-Methylpyridinyl] -4-phenylbutamidamine, N- [4- [4- (3-methylphenyl) -2-propyl-1,3-thiazole-5- Yl] -2-pyridyl] benzidine, N- [4- [4- (3-methylphenyl) -2-propyl-1,3-thiazol-5-yl] -2-pyridine Pyridyl] -3-phenylpropanamide, N · [4- [2-butyl-4- (3-methylphenyl) -1,3-thiazol-5-yl] -2-pyridyl] Benzamidine, N- [4- [2-butyl-4- (3-methylphenyl) -1,3-thiazol-5-yl] -2-pyridyl] -3 -phenylpropanol Amine, N- [4- [2- (4-fluorophenyl) -4- (3-methylphenyl) -1,3-thiazol-5-yl] -2-pyridyl] benzamide, Printed by N- [4- [2- (4-fluorophenyl) -4- (3-methylphenyl) -1,3-thiazol-5-yl] -2- Sigma stilbene] -3 -phenylalaninamine 'N- [4- [4- (3- (fluorenylphenyl))-2- (4- (fluorenylthiophenyl) -1,3-sialyl-5_ Phenyl] -2-pyridyl] phenylhydrazine, N- [4- [4- (3-fluorenylphenyl) -2- (4-fluorenylthiophenyl) -1,3-sialyl. Ci-5 -yl] -2-(] pyridinyl] -3 -phenylpropionic acid amine, N-benzyl-N- [4- [2-ethyl-4- (3-methylphenyl ) -1,3-thiazole-5- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 3 311859 (revised edition) 1220900 H3-based] -2-pyridyl] amine, Ν- [4- [2-Ethyl-4- (3-fluorenylphenyl) -1,3-thiazol-5-yl] -2-pyridyl] -N- (2-phenylethyl) amine 'N- [4 -[2-ethyl-4- (3-methylphenyl) -1,3-thiazol-5-yl] -2-pyridyl] -N- (3-phenylpropyl) amine 'N-benzene Methyl-N- [4- [4- (3-methylphenyl) -2-propyl-1,3-siazol-5-yl] -2-pyridyl] amine, N- [4- [ 4- (3-methylphenyl) -2-propyl-1,3-thiazol-5-yl] -2-pyridyl] -N- (2-phenylethyl) amine 'N- [4- [4- (3-methylphenyl) -2-propyl-1,3-thiazol-5-yl] -2-pyridyl] -N- (3-phenylpropyl) amine, N-benzyl -N- [4- [2-butyl-4- (3-methylphenyl) -1,3-thiazol-5-yl] -2 -ohidine group] amine 'N- [4- [2 -Butyl- 4- (3-methylphenyl) -1,3- D-stem 1 ^ S- 5-yl] -2-mouth ratio. Amine] -N- (2-phenylethyl) amine ' N- [4- [2-butyl-4- (3-methylphenyl) -1,3-thiazole -5-yl] -2-pyridyl] -N- (3-phenylpropyl) amine 'printed by N-benzyl-N- [4- [4- (3 (3) -Methylphenyl) -2- (4-fluorenylthiophenyl) -1,3-thiazol-5-yl] -2-pyridyl] amine, N- [4 · [4- (3-methyl Benzyl) · 2- (4 · fluorenylthiophenyl) -1,3-thiazol-5-yl] -2-pyridyl] -N_ (2-phenylethyl) amine, N- [4- [ 4- (3-methylphenyl) -2- (4-fluorenylthiophenyl) -1,3-thiazol-5-yl] -2 · Π ratio sigmayl] -N- (3-benzylpropane ) Amine 'N- [4- [4- (3-methylphenyl) -2- (4-fluorenylsulfonylphenyl) -1,3-thiazole This paper is sized to the Chinese National Standard (CNS) A4 specification (210X297 mm) 4 31 1859 (revised version) 1220900 H3 azole-5-yl] -2-pyridyl] benzamidine, N- [4- [4- (3-methylphenyl)- 2- (4-methylsulfonylphenyl) -1,3-thienyl-5-yl] -2-〇 than σ amidyl] phenylacetamide, Ν- [4- [4- (3- (Methylphenyl) -2- (4-methylsulfonylphenyl) -1,3-thia ° -5 -yl] -2-sigmayl] -3 -benzyl propionate, N- Phenylfluorenyl-N- [4- [4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) -1,3 -sialo-5 -yl] -2- D ratio Amine] amine 'Ν- [4- [4- (3-fluorenylphenyl) -2- (4-methylsulfonylphenyl) -1,3-thiaσ-5-yl] -2- D ratio σ amidyl] -N- (3-phenylpropyl) amine 'N- [4- [4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) -1 , 3-thiazol-5-yl] -2-pyridyl] -N- (2-phenylethyl) amine, N- (4-fluorophenylfluorenyl) -N- [4 · [4- (3- (Methylphenyl) -2- (4-methylsulfonylphenyl) -1,3-sialyl-5-yl] -2-methylamino] amine '(S) -N- [4- ( 3-methylphenyl) -5- (2- (1-phenylethylamino) -4-methylpyridyl) -1,3-thiazol-2-yl] nicotinamide, (R)- N- [4- (3-methylphenyl) -5- (2- (1-phenylethylamino) -4-ratio. (Fixed base) -1,3-thiazol-2-yl] nicotinamide, printed by (S) -N- [4- (3 -fluorene base) -5- (2- (1-benzylethylamino) -4-orthopyridyl) -1,3-thiazol-2-yl] -2-methylnicotinamide, (R) -N- [4- (3- Fluorenylphenyl) -5- (2- (1-phenylethylamino) -4-methylpyridyl) -1,3-sialyl-2-yl] -2-methylamine (S) -lSi- [4- (3-methylphenyl) -5- (2- (1-phenylethylamino) -4-port ratio ° denature) -1,3 -fluorenylfluorene-2 -Base] -2 -Gas test amine '(R) -N- [4- (3-methylbenzyl) -5- (2- (1-benzylethylamino) -4-mouth to mouth The paper size specified in this paper applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 5 311859 (revised version) 1220900 _H3_ base) -1, 3-卩 17 17 sitting-2-base]-2-gas test amine, (S) -N- [4- (3-methylphenyl) -5- (2- (1-phenylethylamino) -4-D than fluorenyl) -1,3-thiazol-2-yl ] -2-methoxynicotinamide, (r) -N- [4- (3-methylphenyl) -5- (2- (1-phenylethylamino) -4-carbamyl) -1,3-thiazol-2-yl] -2-methoxynicotinamide, N- [5- (2-benzylamino-4-carbamyl) -4- (3-fluorene Phenyl) -1,3-thia. Sit-2 -yl] in the following amines, N- [5- (2-phenylfluorenylamino-4-carbamoyl) -4- (3-fluorenylphenyl) -1,3-thiazole-2 -Yl] -2-methoxynicotinamide, N- [5- (2-phenylfluorenylamino-4-methylpyridinyl) -4- (3-methylphenyl) -1,3_thiazole -2-yl] -2-chloronicotinamide, N- [5- (2-phenylfluorenylamino-4-methylpyridinyl) -4- (3-methylphenyl) -1,3_ Thiazol-2-yl] -2-methylnicotinamide, N- [5- (2-benzylideneamino-4-carolinyl) -4- (3-methylphenyl) -1 , 3-thiazol-2-yl] nicotinamide, N- [5- (2-benzylamino-4 -sigma stilbyl) -4- (3-methylphenyl) _ 1,3 -Thiazol-2-yl] -2-methylnicotinamide, printed by N- [5- (2-benzylideneamino-4-17-based only) -4 by the Employee Welfare Committee of the Central Standards Bureau of the Ministry of Economic Affairs -(3-methylphenyl) -1,3-¾ 嗤 -2-yl] -2-chloroamine amine 'N- [5- (2-phenylhydrazone amine-4-〇 than σ (Amino group) -4- (3-methylphenyl) * ~ 1,3-thiazol-2-yl] -2-methoxynicotinamide, (S) -N- (l-phenylethyl)- 4- [2-ethyl-4- (3-fluorenylphenyl) -1,3-tetrazol-5-yl] -2-pyridylamine, (R) -N- (l-phenylethyl ) -4- [2-ethyl-4- (3-methylphenyl ) -1,3- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 6 311859 (revised edition) 1220900 ________ H3_thiazol-5-yl] -2-pyridylamine, S) -N- ( l-phenylethyl) -4- [4- (3-methylphenyl) _2_propyl-13-thiazol-5-yl] -2-pyridylamine, (R) -NU · phenylethyl ) -4- [4- (3-methylphenyl) _2_propyl4,3-thiazol-5-yl] -2-pyridylamine, (S) -N_ (l-phenylethyl) -4- [2-butyl-4- (3-fluorenylphenyl) -1,3-thiazol-5-yl] -2-pyridylamine, (11) -fluorene (1-phenylethyl) -4- [2-butyl-4- (3-methylphenyl) -1,3-thiazol-5-yl] -2-pyridylamine, (S) -N- (1-phenylethyl ) -4- [4- (3 -fluorenylphenyl) _2- (4-methylsulfanyl) -1,3-fluorene ° -5-yl] -2-methylamino, (R. ) -N- (l-phenylethyl) -4- [4- (3-methylphenyl) -2_ (4-methylthio basic group) -1,3-sialo-5-yl]- 2 -Syrylamine, (8)-: ^ (1-phenylethyl) -4- [4- (3-methylphenyl) _2- (4-methylsaflavinylphenyl) -1, 3-thiazol-5-yl] -2-pyridylamine, (R) -N_ (l-phenylethyl) -4- [4- (3-methylphenyl) _2_ (4-methyl luteinyl benzene ) -1,3-thiazol-5-yl] -2-pyridylamine, printed by (S) -N- (l-phenylethyl) -4- [2- ( 4-fluorophenyl) -4- (3-methylphenyl) -1,3-thiazol-5-yl] -2-pyridylamine, (R) -N- (l-benzylethyl [2 -(4-fluorophenyl) -4- (3-fluorenylphenyl) -1,3-thiasal-5-yl] -2-pyridylamine, or a salt thereof. 4. A method for manufacturing a compound as claimed in item 1 of the patent application scope, comprising: (i) using a compound represented by the following formula or a salt thereof: H3 H3 Hal (VII) The other symbols in the boundary of item 1 are the compounds shown in the scope of application for patents or their salts: R -CSNH2 (VIII): In R, as defined in the scope of application for applications, the following compounds are obtained: Or its salt: ^ 1 (la) Each symbol in the formula is as defined in item 帛 丨 of the scope of patent application, or u) the compound or its salt represented by the formula: Hal (X) Half is a prime atom in the printed form of the Staff Welfare Committee of the Central Standards Bureau of the Ministry of Economic Affairs, and other symbols are as defined in item 1 of the patent scope, and react with the compound or its salt represented by the following formula: R2-Z- The symbols in the formula YH (XI) are as defined in the scope of the patent application No. 1 to obtain the compound or its salt as shown in the following formula: (lb) t paper standard phase Zhong Guanzhun (CNS) A4 specification (210X297) (Centi) 3 Π 859 (revised edition) 1220900 compounds or their salts ·············· His symbols such as straightening μ ~ m τ are called the compounds or salts thereof shown in Patent Drywell No. 1 ·· The symbols in the printed form of the Staff Welfare Committee of the Central Standards Bureau of the Ministry of Economic Affairs are as defined in the application for the application of fecal brake r_ r ·, # patent target siege, and force (Sichuan) to use the following formula: "· ^ 丨 疋, or (XVII) The symbols in the formula are reacted with the compounds or their salts as shown in the scope of the patent application: Jinjieyi 'and R2 &quot; ZL (XVIII) where L represents a leaving group, as defined by its term, and obtained by (lc) Each symbol in the formula is as defined in item 1 of the scope of patent application, or (iv) the compound represented by the following formula or its salt ... 3 (I) Each symbol in the formula is as defined in the scope of application patent No. 1JM, and reacts with peroxyacid, hydrogen peroxide or hospital hydrogen peroxide to obtain the compound or its salt represented by the following formula: 311859 (revised edition) Standards are applicable to China National Standard (CNS) A4 (210X297). 1220900 Printed by the Staff Welfare Committee of the Central Standards Bureau of the Ministry of Economic Affairs (Id) X and Chinese symbols are as defined in item 1 of the scope of patent application. 5. A pharmaceutical composition for antagonizing the glandular astrocytes 3 receptor, which includes a compound containing item 1 of the patent application. 6. A pharmaceutical composition for inhibiting p38MAp kinase, which includes a compound containing the first item of the patent application. 7. A human race pharmaceutical composition for inhibiting the production of TNF-a, which includes a compound containing, for example, the first item of the patent application scope. 8. The pharmaceutical composition for the prevention or treatment of diseases related to the item 5 in the scope of the patent application. 9. The pharmaceutical composition for the prevention or treatment of diseases such as the scope of application for item 5. 10. The pharmaceutical composition according to item 5 of the patent application for the prevention or treatment of vascular diseases or head trauma. 1 L The pharmaceutical composition according to item 5 of the scope of patent application is a preventive or therapeutic agent for cytokine-mediated diseases. 12 ·: Any one of the pharmaceutical composition in the scope of application patents 帛 5 to 帛 7, which is human disease, Addison's disease, autoimmune lytic negative blood, Crohn's disease , Psoriasis, rheumatism, spinal trauma, cerebral edema, multiple sclerosis, Alzheimer's disease, Parkinson's syndrome, amyotrophic lateral sclerosis, diabetes, acute inflammation, toxemia, ulcerative Colitis, chronic pneumonia, silencing adenosine A3, asthma or allergic brain edema, 311859 (revised version) _ 1220900 Soil = Inflammation, pulmonary sarcoma, tuberculosis, cachexia, arteriosclerosis, spastic pseudosclerosis, viral infection, atopic dermatitis, systemic lupus erythematosus, myelitis, narrow heart Preventive or therapeutic agent for myocardial infarction, myocardial infarction, congestive heart failure, hepatitis, transplantation, dialysis hypotension or disseminated intravascular coagulation. It is used for the preparation of antagonists. It is used for the preparation of inhibitors. It is used for the preparation of inhibitors. 14. A pharmaceutical agent of the compound P38MAP kinase as described in claim 1 of the scope of patent application. 1 5 · Drug produced by the compound TNF- as claimed in item 1 of the patent scope. Printed by the Staff Welfare Committee of the Central Bureau of Standards of the Ministry of Economic Affairs 16. If the scope of the patent application is 1 item, it is used to prepare inflammation, Addison's disease, autoimmune hemolytic anemia, Crohn's disease, psoriasis, rheumatism, Spinal trauma, cerebral edema, multiple sclerosis, Alzheimer's disease, Parkinson's syndrome, amyotrophic lateral sclerosis, diabetes, arthritis, toxemia, ulcerative colitis, chronic pneumonia, Silicosis, pulmonary sarcoma, tuberculosis, malignant disease, arteriosclerosis, spastic pseudosclerosis, viral infection, atopic dermatitis, systemic lupus erythematosus, myelitis, angina, myocardial infarction Recording: Use as a preventive or therapeutic agent for visceral failure, hepatitis, transplantation, dialysis, hypotension, or disseminated intravascular solids. 311859 (revised edition) This paper size is applicable to China National Standard (CNS) A4 (21〇297mm)