CN1898243A

CN1898243A - Bicyclic heterocyclic p-38 kinase inhibitors

Info

Publication number: CN1898243A
Application number: CNA2004800382759A
Authority: CN
Inventors: 董庆; 王建强; J·兰; H·郎
Original assignee: Novartis AG
Current assignee: Novartis AG
Priority date: 2003-12-23
Filing date: 2004-12-23
Publication date: 2007-01-17

Abstract

Provided are bicyclic heterocycle-based p38 kinase, including p38alpha and p38beta kinase, inhibitors. Pharmaceutical compositions containing the compounds are also provided. Methods of use of the compounds and compositions are also provided, including methods of treatment, prevention, or amelioration of one or more symptoms of p38 kinase mediated diseases and disorders, including, but not limited to, inflammatory diseases and disorders.

Description

Bicyclic heterocyclic P-38 kinase inhibitor

Related application

This paper requires the right of priority of following U.S. Provisional Patent Application: the No.60/532 that on December 23rd, 2003 submitted to, the No.60/575 that on May 28th, 529 and 2004 submitted to, 113.If state's laws allow, the disclosure of above-mentioned provisional application is incorporated herein by reference in full.

The field

This paper provides the bicyclic heterocyclic compounds with cytokine inhibiting activity.Also provide bicyclic heterocyclic compounds to be used for the treatment of illness relevant with beta kinase and the purposes that is used for the treatment of the illness relevant with the p38 kinases with p38 α.

Background

A large amount of cytokines participate in inflammatory responses, comprise IL-1, IL-6, IL-8 and TNF-α.The cytokine for example overexpression of IL-1 and TNF-α is relevant with multiple disease, especially comprise inflammatory bowel, rheumatoid arthritis, psoriatic, multiple sclerosis, endotoxin shock, osteoporosis, alzheimer's disease and congestive heart failure (Henry etc., Drugs Fut., 24:1345-1354 (1999); Salituro etc., Curr.Med.Chem., 6:807-823 (1999)).Evidence in human patients shows, the protein antagonist of cytokine is effective in the treatment chronic inflammatory disease, the monoclonal antibody of TNF-α (Remicade) (Rankin etc. for example, Br.J.Rheumatol., 34:334-342 (1995)) and soluble TNF-α acceptor-Fc fusion rotein (Etanercept) (Moreland etc., 25Ann.Intern.Med., 130:478-486 (1999)).

The biosynthesizing of TNF-α takes place in response to outside stimulus in a lot of cell types, for example mitogen, infectious biological or wound.The important medium that TNF-α produces is mitogen-activated protein(MAP) (MAP) kinases, particularly p38 kinases.These kinases are activated in response to various stress stimulations, include but not limited to pro-inflammatory cytokine, intracellular toxin, UV-light and osmotic shock.The activate request upstream map kinase kinases (MKK3 and MKK6) of p38 is to the dual phosphorylation of Threonine and tyrosine in the distinctive Thr-Gly-Tyr motif of p38 isozyme.

P38 has four kinds of known isoforms, i.e. p38 α, p38 β, p38 γ and p38 δ.α and β isoform are expressed in inflammatory cell, are the crucial media that TNF-α produces.The p38 α and the β enzyme that suppress in the cell cause TNF-alpha expression level to reduce.And verified this class inhibitor of inhibitor of using p38 α and β in the inflammatory diseases animal model is effective in those diseases of treatment.Therefore, the p38 enzyme plays a significant role in the inflammatory process alpha mediated by IL-1 and TNF-.It is reported suppress p38 kinases and cytokine for example IL-1 and compound TNF-α, that be used for the treatment of inflammatory diseases be disclosed in the following document: Scios, the U.S. Patent No. 6,277,989 and 6,130,235 of Inc; The U.S. Patent No. 6,147,080 and 5,945,418 of VertexPharmaceuticals Inc; The U.S. Patent No. 6,251,914,5,977,103 and 5,658,903 of Smith-KlineBeecham Corp.; G.D.Searle ﹠amp; Co. U.S. Patent No. 5,932,576 and 6,087,496; The WO00/56738 of Astra Zeneca and WO 01/27089; Johnson ﹠amp; The WO 01/34605 of Johnson; WO00/12497 (as the quinazoline derivant of p38 kinase inhibitor); WO 00/56738 (pyridine and the pyrimidine derivatives that are used for identical purpose); WO 00/12497 (relation between the p38 kinase inhibitor has been discussed); With WO 00/12074 (piperazine and the piperidine compounds that can be used as the p38 inhibitor).

The Pyrrolotriazine compounds that can be used as tyrosine kinase inhibitor is disclosed in the U.S. Patent application No.09/573 that transfers Bristol-Myers Squibb that submitted on May 18th, 2000, in 829.In addition, Pyrrolotriazine kinase inhibitors is disclosed among the WO02/40486 that transfers Bristol-Myers Squibb.Nearest application: WO 03/032970, WO 03/033482, WO03/032971, WO 03/032986, WO 03/032980, WO 03/032987, WO 03/033483, WO 03/033457 and WO 03/032972 are introduced among the application.5-that the aminoaryl of a series of IMPH of can be used as inhibitor replaces and 6-unit ring heterocycle are disclosed among the WO 00/25780.U.S. Patent No. 6,005,109 and 6,103,900 disclose pyrazoles and the Pyrazolopyrimidines with CRF antagonistic activity.WO 03/090912 and WO 03/091229 disclose the pyrrolotriazine compounds of some useful as kinase inhibitors.Each patent application mentioned in this article, patent and publication all are introduced into this paper as a reference.

General introduction

The invention provides the composition that is used in the regulating cell factor active and the compound in the method.In one embodiment, these compounds are used in regulation and control kinase whose composition of p38 and the method, include but not limited to p38 α and p38 beta kinase activity.In some embodiments, the bicyclic heterocyclic compounds that replaced by the cycloalkyl amide moieties of these compounds.In some embodiments, the compound that this paper provided is purine, pyrrolotriazine, pyrazolopyrimidine, imidazopyrimidine and the related compound that replaces.

In one embodiment, this paper provides formula I compound:

Or its pharmaceutically acceptable derivates, wherein:

R ¹Be hydrogen, halogeno-group, alkyl, cycloalkyl, alkynyl, haloalkyl, alkoxyl group, halogenated alkoxy, plan halogeno-group ,-NR ⁴R ⁵Or-OR ⁴

R ²When occurring, be independently selected from every turn alkyl, replacement alkyl, low-grade cycloalkyl, halogeno-group, trifluoromethyl, trifluoromethoxy ,-OR ⁴,-CN ,-NR ⁴R ⁵-S (=O) alkyl ,-S (=O) aryl ,-NHSO ₂-arylidene-R ⁴,-NHSO ₂Alkyl ,-CO ₂R ⁴,-CONH ₂,-SO ₃H ,-S (O) alkyl ,-S (O) aryl ,-SO ₂NHR ⁴With-NHC (=O) NHR ⁴

N is 0,1 or 2;

R ³Be selected from hydrogen, alkyl ,-OR ⁴, replace alkyl, cycloalkyl ,-CR ⁴The heterocycle of the heteroaryl of cycloalkyl, heteroaryl, replacement, heterocycle and replacement;

Y be singly-bound ,-C (=O) NH-,-NH (C=O)-,-NH (C=O) NH-,-SO ₂NH-,-NHSO ₂-or-C (=O)-;

X ¹Be singly-bound, alkylidene group ,-O-,-S-,-S (O)-,-SO ₂-,-C (O)-,-CO (O)-or-C (O) NH-;

A is the bicyclic heterocycles ring system, has at least one heteroatoms in each ring, and wherein heteroatoms is selected from N, O and S independently of one another, and randomly by two R at the most ¹³Replace;

X ²Be singly-bound, alkylidene group ,-O-,-S-,-NH-,-N (C _1-4Alkyl)-,-NH-C _1-4Alkylidene group-,-N (C _1-4Alkyl)-C _1-4Alkylidene group-,-S (O)-,-SO ₂-,-C (O)-,-CO (O)-or-C (O) NH-;

D is monocycle or bicyclic aromatic or non-aromatics ring system, and it randomly contains four heteroatomss that are selected from N, O and S at the most, wherein with any described N, O or the adjacent CH of S heteroatoms ₂Randomly (=O) replacement, perhaps D is C by the oxo base _1-6Alkyl, wherein D is randomly by one to four (CR ⁹R ¹⁰) _wThe E group replaces;

W is the integer of 0-4;

R ¹⁰Be selected from H, C ₁-C ₄Alkyl hydroxy, C ₁-C ₄Alkylaryl and C ₁-C ₄Miscellaneous alkyl aryl, wherein said aryl or heteroaryl are unsubstituted or are independently selected from following group by 1-3 and replace: halogeno-group, NO ₂, C ₁-C ₄Alkyl, C ₃-C ₁₀Cycloalkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, haloalkyl, halogenated alkoxy, OH, C ₁-C ₄Alkoxyl group, C ₁-C ₄Alkyl-carbonyl, CN, NH ₂, NR ⁶R ⁷, SR ⁶, S (O) R ⁶, SO ₂R ⁶, SO ₃R ⁶, SO ₂NR ⁶, CO ₂H, CO ₂R ⁶And CONR ⁶R ⁷

E is selected from H, halogen, NO₂、C ₁-C ₄Alkyl, C₃-C ₁₀Cycloalkyl, C₂-C ₆Alkenyl, C₂-C ₆Alkynyl, haloalkyl, halogenated alkoxy, OH, OR⁶、CN、CHO、CO ₂R ⁶、 CONR ⁶R ⁷、OCOR ⁶、OC(＝O)OR ⁶、OC(＝O)NR ⁶R ⁷、OCH ₂CO ₂R ⁶、C(＝O)R ⁶、 NH ₂、NHR ⁶、NR ⁶R ⁷、NR ⁷C(＝O)R ⁶、NR ⁷C(＝O)OR ⁶、NR ⁷C(＝O)C(＝O)OR ⁶、 NR ⁷C(＝O)C(＝O)NR ⁶R ⁷、NR ⁷C(＝O)C(＝O)(C ₁-C ₆Alkyl), NR⁷C(＝NCN)OR ⁶、 NR ⁷C(＝O)NR ⁶R ⁷、NR ⁷C(＝NCN)NR ⁶R ⁷、NR ⁷C(＝NR ⁶)NR ⁷R ⁸、 NR ⁶SO ₂NR ⁶R ⁷、NR ⁷SO ₂R ⁶、SR ⁶、S(＝O)R ⁶、SO ₂R ⁶、SO ₃R ⁷、SO ₂NR ⁶R ⁷、 NHOH、NHOR ⁶、NR ⁶NR ⁷NR ⁸、N(COR ⁶)OH、N(CO ₂R ⁶)OH、 CONR ⁷(CR ⁹R ¹⁰) _rR ⁶、CO(CR ⁹R ¹⁰) _pO(CHR ⁹) _qCO ₂R ⁶、CO(CR ⁹CR ¹⁰) _rR ⁶、 CO(CR ⁹R ¹⁰) _pO(CR ⁹R ¹⁰) _pO(CHR ⁹) _qCO ₂R ₆、CO(CR ⁹CR ¹⁰) _rOR ⁶、 CO(CR ⁹R ¹⁰) _pO(CR ⁹R ¹⁰) _qR ⁶、CO(CR ⁶CR ¹⁰) _rNR ⁶R ⁷、 OC(O)O(CR ⁹R ¹⁰) _mNR ⁶R ⁷、O(CO) _n(CR ⁹R ¹⁰)R ⁶、O(CR ⁹R ¹⁰) _mNR ⁶R ⁷、 NR ⁷C(O)(CR ⁹R ¹⁰) _rOR ⁶、NR ⁷C(＝NC)(CR ⁹R ¹⁰) _rR ⁶、NR ⁷CO(CR ⁹R ¹⁰) _rNR ⁶R ⁷、 NR ⁷(CR ⁹R ¹⁰) _mOR ⁶、NR ⁷(CR ⁹R ¹⁰) _rCO ₂R ⁶、NR ⁷(CR ⁹R ¹⁰) _mNR ⁶R ⁷、NR ⁷、 NR ³(CR ⁹R ¹⁰) _nSO ₂(CR ⁹R ¹⁰) _rCO ₂R ⁶、NR ⁷(CR ⁹R ¹⁰) _mNR ⁶R ⁷、 NR ⁷(CR ⁹R ¹⁰) _nSO ₂(CR ⁹R ¹⁰) _qR ⁶、CONR ⁷(CR ⁹R ¹⁰) _nSO ₂(CR ⁹R ¹⁰) _qR ⁶、 SO ₂NR ⁷(CR ⁹R ¹⁰) _qR ⁶、SO ₂NR ⁶(CR ⁹R ¹⁰) _mOR ⁶、C ₂-C ₆Alkenyl, C₃-C ₁₀Cycloalkyl, C₃-C ₁₀Methyl cycloalkyl, aryl, the heterocyclic radical that randomly by one or two alkyl, is replaced, the heteroaryl and the alkylaryl that randomly by one or two alkyl, are replaced, wherein said aryl is unsubstituted or by 1 or 2, is selected from independently of one another R¹²Substituting group replace, two E groups that perhaps replace the upper adjacent atom of D form alkylene dioxo base, the inferior alkoxyl (thioalkyleneoxy) of sulfo-or alkylene two sulfo-oxygen bases (alkylenedithioxy) together;

M is the integer of 2-6;

P is the integer of 1-3;

Q is the integer of 0-3;

R is the integer of 0-6;

R ¹²When occurring, be independently selected from halogeno-group, NO at every turn ₂, C ₁-C ₄Alkyl, C ₃-C ₁₀Cycloalkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, haloalkyl, halogenated alkoxy, OH, oxo base, C ₁-C ₄Alkoxyl group, OR ⁶, O (CR ⁹R ¹⁰) CO ₂R ⁶, O (CR ⁹R ¹⁰) _mNR ⁶R ⁷, O (CR ⁹R ¹⁰) _pCN, O (CR ⁹R ¹⁰) _rC (=O) NR ⁶R ⁷, C ₁-C ₄Alkyl-carbonyl, CN, NH ₂, NHR ⁶, NR ⁶R ⁷, NR ⁷(CR ⁹R ¹⁰) CO ₂R ⁶, NR ⁷OR ⁶, NR ⁷(CR ⁹R ¹⁰) _mOR ⁶, NR ⁷CH ((CR ⁹R ¹⁰) _pOR ⁶) ₂, NR ⁷C ((CR ⁹R ¹⁰) _pOR ⁶) ₃, NR ⁷C (=O) R ⁶, NR ⁷(CR ⁹R ¹⁰) _mNR ⁶R ⁷, NR ⁷(CR ⁹R ¹⁰) _qR ⁶, SR ⁷, S (O) R ⁷, SO ₂R ⁷, SO ₂NR ⁶, SO ₃R ⁷, CO ₂H, CO ₂R ⁶And CONR ⁶R ⁷

R ⁴Be hydrogen, low alkyl group and low-grade cycloalkyl;

R ⁵Be hydrogen, low alkyl group and low-grade cycloalkyl;

R ⁶, R ⁷And R ⁸Following independently selection:

I) R ⁶, R ⁷And R ⁸Be independently selected from H, C ₁-C ₆Alkyl, C ₃-C ₁₀Cycloalkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₁-C ₆Alkyl-carbonyl, C ₃-C ₇Cycloalkyl (C ₀-C ₅Alkyl) carbonyl, C ₁-C ₆Alkoxy carbonyl, aryl (C ₀-C ₅Alkyl) carbonyl, aryl (C ₁-C ₅Alkoxyl group) carbonyl, heterocyclic radical (C ₀-C ₅Alkyl) carbonyl, heterocyclic radical (C ₁-C ₅Alkoxyl group) carbonyl, C ₁-C ₆Alkyl sulphonyl, aryl sulfonyl, heteroarylsulfonyl, C ₀-C ₄Alkylaryl, C ₀-C ₄Alkyl heterocyclic, wherein said cycloalkyl, aryl or heterocyclic radical are unsubstituted or are selected from following substituting group independently of one another by 1 or 2 and replace: C ₁-C ₄Alkyl, hydroxyl, C ₁-C ₄Alkoxyl group, F, Cl, Br, haloalkyl, NO ₂And CN; Perhaps,

Ii) when two substituting groups all are positioned on the same nitrogen-atoms (as at (NR ⁶R ⁷) or (NR ⁷R ⁸) in), R ⁶With R ⁷Perhaps R ⁶With R ⁸Perhaps R ⁷With R ⁸Can constitute with the nitrogen-atoms that they connected and be selected from following heterocycle: 1-'-aziridino, 1-azetidinyl, piperidino, 1-morpholinyl, 1-pyrrolidyl, parathiazan base, thiazolidyl, 1-piperazinyl, 1-imidazolyl, 3-azabicyclic (3,2,2) nonane-3-base and 1-tetrazyl, described heterocycle randomly are selected from following group independently of one another by 1-3 and replace: oxo base, C ₀-C ₄Alkyl OH, C ₀-C ₄Alkyl OC ₁-C ₄Alkyl, C ₀-C ₄Alkyl CONH ₂, C ₀-C ₄Alkyl CO ₂C0-C ₄Alkyl, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, C ₃-C ₇Cycloalkyl, C ₀-C ₆Alkyl-carbonyl, C ₃-C ₇Naphthene base carbonyl, C ₁-C ₆Alkoxy carbonyl, C ₃-C ₇Cyclo alkoxy carbonyl ,-NHCO alkyl, aryl, heteroaryl, aryl-alkoxy carbonyl, heteroaryl alkoxy carbonyl, C ₁-C ₆Alkyl sulphonyl, aryl sulfonyl and heteroarylsulfonyl;

R ⁹Be hydrogen or C ₁-C ₄Alkyl; And

R ¹³Be alkyl, the aryl of hydrogen, alkyl, haloalkyl, aminocarboxyl, hydroxyl, hydroxycarbonyl group, alkoxy carbonyl, cycloalkyl alkyl amino carbonyl, replacement, aryl, heteroaryl, heterocyclic radical, alkylthio, alkyl amino-carbonyl or the low-grade cycloalkyl of replacement; Wherein the substituting group on the alkyl is selected from one to four and is selected from following substituting group: halogeno-group, hydroxyl, alkoxyl group, oxo base (=O), alkyloyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aryl alkyl amino, dibasic amine, wherein 2 amino substituting groups are selected from alkyl, aryl or aralkyl; The aralkyl amido of the alkyl amido of alkyl amido, aromatic acylamino, aralkyl amido, replacement, the arylamino of replacement, replacement, sulfydryl, alkylthio, arylthio, aromatic alkylthio, alkyl sulfide carbonyl, aryl thiocarbonyl group, aralkyl thiocarbonyl group, alkyl sulphonyl, aryl sulfonyl, aralkyl alkylsulfonyl, sulfonamido be SO for example ₂NH ₂, the sulfonamido, nitro, cyano group, carboxyl, formamyl that replace CONH for example ₂, the formamyl that replaces for example CONH alkyl, CONH aryl, CONH aralkyl or wherein on the nitrogen two substituent situations that are selected from alkyl, aryl or aralkyl are arranged; Alkoxy carbonyl; aryl; the aryl that replaces; guanidine radicals and replacement or unsubstituted heterocycle; indyl for example; imidazolyl; furyl; thienyl; thiazolyl; pyrrolidyl; pyridyl; pyrimidyl etc., the substituting group on the aryl are selected from one to four and are selected from following substituting group: alkyl; the alkyl that replaces; haloalkyl; halogeno-group; trifluoromethoxy; trifluoromethyl; hydroxyl; hydroxyalkyl; aminoalkyl group; alkoxyl group; alkyloyl; alkanoyloxy; amino; arylamino; aryl alkyl amino; dialkyl amido; alkyl amido; sulfydryl; alkylthio; urea groups; nitro; cyano group; the cyano group alkyl; heterocyclic radical; carboxyl; carboxyalkyl; formamyl; alkoxy carbonyl; aminocarboxyl; the alkyl sulfide carbonyl; the aryl thiocarbonyl group; aryl sulfonic acid amides; sulfonic acid; alkyl sulphonyl; sulfonamido; aryloxy and CONR ^aR ^b, R wherein ^aAnd R ^bBe selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxycarbonyl amino alkyl and alkylamino; Perhaps R ^aAnd R ^bConstitute 3-6 unit's heterocyclic radical or heteroaryl ring with the nitrogen that they replaced.Substituting group can further be replaced by the alkyl of the aryl of hydroxyl, alkyl, alkoxyl group, aryl, replacement, replacement or aralkyl.

In one embodiment, to group A, Y, R ¹, R ², R ³, X ¹, X ²Select with D, make gained compound pair cell factor active have effect.

Arbitrarily pharmaceutically acceptable derivates also be pay close attention to, comprise salt, ester, enol ether, enol ester, solvate, hydrate and the prodrug of compound described herein.Pharmacy acceptable salt includes but not limited to amine salt, such as but not limited to N, N '-dibenzyl-ethylenediamin, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkyl amine, quadrol, N-methylglucosamine, PROCAINE HCL, PHARMA GRADE, N-benzyl-1-phenylethylamine, 1-be right-benzyl chloride base-2-tetramethyleneimine-1 '-ylmethyl benzoglyoxaline, diethylamine and other alkylamine, piperazine and three (methylol) aminomethane; An alkali metal salt is such as but not limited to lithium, potassium and sodium salt; Alkaline earth salt is such as but not limited to barium, calcium and magnesium salts; Transition metal salt is such as but not limited to zinc, aluminium salt; With other metal-salt, such as but not limited to sodium hydrogen phosphate and Di-Sodium Phosphate; Also include but not limited to the salt of mineral acid, such as but not limited to hydrochloride and vitriol; Organic acid salt is such as but not limited to acetate, lactic acid salt, malate, tartrate, Citrate trianion, ascorbate salt, succinate, butyrates, valerate and fumarate.

The present invention also provides pharmaceutical composition, it is prepared being used for and is used by suitable approach and means, the compound that one or more this paper provided or its pharmaceutically acceptable derivates that contain effective concentration, send effective treatment, prevention or improve disease or the amount of one or more symptoms of obstacle, described disease or obstacle be subjected to cytokine activity, be the regulation and control of p38 kinase activity or the influence of alternate manner in one embodiment, perhaps wherein involves cytokine activity, is the p38 kinase activity in one embodiment.Significant quantity and concentration are effective for any symptom of improving any disease or obstacle.

The invention provides treatment, prevent or improve the method for one or more symptoms of disease or obstacle, described disease or obstacle be subjected to cytokine activity, in one embodiment for the mediation of p38 kinase activity or wherein involve cytokine activity, in one embodiment for the p38 kinase activity.These class methods comprise use compound that one or more this paper provided or the treatment of its pharmaceutically acceptable derivates, prevent and improve the method for one or more symptoms of following disease: inflammatory diseases, autoimmune disorder, destructive bone disorders, proliferative disorder, vasculogenesis sexual dysfunction, infectious diseases, neurodegenerative disease and virus disease.

The present invention also provides and has used compound that this paper provides and composition regulating cell factor active, has been the method for p38 kinase activity in one embodiment.

The present invention also provides in the curee who needs is arranged compound or the composition by using one or more this paper and providing to reduce the method that induction type proinflammatory protein (inducible pro-inflammatoryprotein) is expressed, described induction type proinflammatory protein includes but not limited to prostaglandin endoperoxide synthase-2 (PGHS-2), is also referred to as cyclooxygenase-2 (COX-2).

When these methods of enforcement, his-and-hers watches now are listed as the individuality of those diseases or obstacle symptom and use the compound of significant quantity or contain treatment effective concentration compound compositions, described composition preparation is used for systemic delivery, comprise parenteral, oral or intravenously is sent, perhaps be used for part (local) or external application (topical), be used for the treatment of cytokine, be kinase mediated disease of p38 or obstacle in one embodiment, perhaps wherein involve cytokine activity, be the disease or the obstacle of p38 kinase activity in one embodiment, include but not limited to inflammatory diseases, autoimmune disorder, destructive bone disorders, proliferative disorder, the vasculogenesis sexual dysfunction, infectious diseases, neurodegenerative disease and virus disease.Amount of application is effective for improving or eliminating for one or more symptoms of these diseases or obstacle.

The invention provides a kind of goods, it contains wrapping material; Compound that this paper provided in these wrapping material or composition or its pharmaceutically acceptable derivates, its effectively the regulating cell factor, be the kinase whose activity of p38 in one embodiment, perhaps effectively treat, prevent or improve cytokine, in one embodiment for kinase mediated disease or the obstacle of p38 or wherein involve cytokine activity, be one or more symptoms of the disease of p38 kinase activity or obstacle in one embodiment; And label, its explanation with this compound or composition or its pharmaceutically acceptable derivates be used for the regulating cell factor active, in one embodiment for the p38 kinase activity or be used for the treatment of, prevent or improve cytokine, in one embodiment for kinase mediated disease or the obstacle of p38 or wherein involve cytokine activity, be one or more symptoms of the disease of p38 kinase activity or obstacle in one embodiment.

Describe in detail

A. definition

Unless otherwise defined, otherwise all technology used herein and scientific terminology all have the identical meanings of those skilled in the art's common sense.All patents, application, the application of having announced and other publication all are incorporated herein by reference in full.A term has under the situation of various definitions in this article, and the definition in this section is preferential, and other has except the regulation.

P38 α used herein represents to be disclosed in the enzyme in the following document: Han J, Richter B, Li Z, Kravchenko V, the molecular cloning .BiochimBiophys Acta.1995 of Ulevitch RJ. people p38 map kinase; 1265 (2-3): 224-7.P38 β used herein represents to be disclosed in the enzyme in the following document: Jiang Y, and Chen C, Li Z, Guo W, Gegner JA, Lin S, the 26S Proteasome Structure and Function of the mitogen-activated protein kinase that Han J. is new (p38 β) characterizes.J Biol Chem.1996 July 26; 271 (30): 17920-6.P38 γ used herein represents to be disclosed in the enzyme in the following document: Li, Z.; Jiang, Y.; Ulevitch, R.J.; Han, the basic structure .Biochem.Biophys.Res.Commun.228:334-340 of the newcomer p38 γ of J.:p38 group map kinase, 1996.P38 δ used herein represents to be disclosed in the enzyme in the following document: the molecular cloning and the sign of new p38 mitogen-activated protein kinase, Xuhong Sunny Wang, Katrina Diener, Carl L.Manthey, Shen-wu Wang, Bradley Rosenzweig, Jeffrey Bray, John Delaney, Craig N.Cole, Po-Ying Chan-Hui, Nathan Mantlo, Henri S.Lichenstein, MarkZukowski and Zhengbin Yao.

Any disease or illness that the known p38 of term used herein " illness relevant with p38 " expression plays a role therein.This comprises the known illness that is caused by IL-1, TNF, IL-6 or IL-8 overexpression.This class illness includes but not limited to inflammatory diseases, autoimmune disorder, destructive bone disorders, proliferative disorder, infectious diseases, virus disease and neurodegenerative disease.

The restraining effect of p-38 α beta kinase used herein represents that p38 α and/or p38 beta kinase are suppressed.Therefore, to suppressing the IC of p-38 α beta kinase ₅₀The mentioning of value means that compound is for suppressing at least a in p38 α and the p38 beta kinase or the two has such validity.

The pharmaceutically acceptable derivates of compound used herein comprises its salt, ester, enol ether, enol ester, acetal, ketal, ortho ester, hemiacetal, hemiketal, acid, alkali, solvate, hydrate or prodrug.The currently known methods that those skilled in the art are used for this class derivatize can easily prepare this analog derivative.Prepared compound can be applied to the animal or human, does not have great toxic action, be pharmaceutical active arranged or prodrug.Pharmacy acceptable salt includes but not limited to amine salt, such as but not limited to N, N '-dibenzyl-ethylenediamin, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkyl amine, quadrol, N-methylglucosamine, PROCAINE HCL, PHARMA GRADE, N-benzyl-1-phenylethylamine, 1-be right-benzyl chloride base-2-tetramethyleneimine-1 '-ylmethyl-benzoglyoxaline, diethylamine and other alkylamine, piperazine and three (methylol) aminomethane; An alkali metal salt is such as but not limited to lithium, potassium and sodium salt; Alkaline earth salt is such as but not limited to barium, calcium and magnesium salts; Transition metal salt is such as but not limited to zinc salt; With other metal-salt, such as but not limited to sodium hydrogen phosphate and Di-Sodium Phosphate; Also include but not limited to nitrate, borate, mesylate, benzene sulfonate, tosylate, the salt of mineral acid is such as but not limited to hydrochloride, hydrobromate, hydriodate and vitriol; With organic acid salt, such as but not limited to acetate, trifluoroacetate, maleate, oxalate, lactic acid salt, malate, tartrate, Citrate trianion, benzoate, salicylate, ascorbate salt, succinate, butyrates, valerate and fumarate.Pharmaceutically acceptable ester includes but not limited to alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl and the heterocyclic radical ester of acidic-group, and described acidic-group includes but not limited to carboxylic acid, phosphoric acid, phosphonic acids (phosphinic acid), sulfonic acid,-sulfinic acid and for boric acid (boronic acid).Pharmaceutically acceptable enol ether includes but not limited to the derivative of formula C=C (OR), and wherein R is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl or heterocyclic radical.Pharmaceutically acceptable enol ester includes but not limited to the derivative of formula C=C (OC (O) R), and wherein R is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl or heterocyclic radical.Pharmaceutically acceptable solvate and hydrate be compound and one or more solvent or water molecules, for example 1 to about 100 or 1 to about 10 or 1 mixture to about 2,3 or 4 solvents or water molecules.

Arbitrarily such mode is represented in treatment used herein, and wherein one or more symptoms of disease or obstacle are enhanced or other useful change arranged.Treatment also comprises any pharmaceutical use of composition of this paper, for example is used for the treatment of kinase mediated disease of p38 or obstacle or wherein involves the p38 kinase activity, comprises the disease or the obstacle of p38 alpha active.

Used hereinly represent and can use or relevant with it any alleviating owing to composition by using the symptom that specific compound or pharmaceutical composition improve particular obstacle, no matter be nonvolatil or provisional, continue or of short duration.

IC used herein ₅₀Represent that specific test compound realizes 50% amount, concentration or the dosage that suppresses of peak response, the regulation and control of for example p-38 kinase activity in the assay method of measuring this class response.

EC used herein ₅₀Represent that specific test compound causes that the response of dosage-dependency reaches maximum 50% dosage, concentration or the amount of expressing of the specific response of being induced, exciting or strengthened by this specific test compound.

Prodrug used herein is a kind of like this compound, and after using in the body, it is by one or more steps or process metabolism or otherwise be converted into biology, pharmacy or the therapeutics activity form of this compound.In order to prepare prodrug, pharmaceutically active compound is modified, so that can pass through metabolic process regeneration active compound.Prodrug can be designed in order to the metabolic stability that changes medicine or transport feature, shelters side effect or toxicity, improves the taste of medicine or change the further feature or the character of medicine.Based on pharmacodynamics process and the metabolic knowledge of drug disposition, in a single day those skilled in the art know pharmaceutically active compound, the prodrug that promptly can design compound is (for example referring to Nogrady (1985) Medicinal Chemistry A Biochemical Approach, OxfordUniversity Press, New York, the 388-392 page or leaf).

Should be understood that the compound that this paper provided can contain chiral centre.This class chiral centre can be (R) or (S) configuration, perhaps can be its mixture.Therefore, the compound that this paper provided can be an enantiomer-pure, or steric isomer or non-enantiomer mixture.Under the situation of amino-acid residue, this class residue can be L-or D-type.The configuration of naturally occurring amino-acid residue is generally the L type.Do not having under the specified situation, residue is the L type.Term used herein " amino acid " expression a-amino acid, they are racemic or D-or L-configuration.The amino acid whose D-isomer of title " d " (for example dAla, dSer, dVal etc.) expression before the amino acid name.Title " dl " (for example dlPip) amino acid whose L-of expression and D-isomer mixture before the amino acid name.Should be understood that the chiral centre of the compound that this paper provided the body interpolation can take place to isomerization.Therefore, those skilled in the art will recognize that for the body interpolation taking place for the isomerized compound, compound is applied with its (R) type and is equivalent to this compound and is applied with its (S) type.

The enough homogeneous of " pure substantially " used herein expression, the standard method of analysis that is used to assess this class purity by those skilled in the art does not have when measuring can easily detected impurity, described analytical procedure is tlc (TLC), gel electrophoresis, high performance liquid chromatography (HPLC) and mass spectroscopy (MS) for example, perhaps expression is enough pure, but consequently be further purified the physics and the chemical property that can on detection level, not change this material, for example enzyme and biological activity.It is well known by persons skilled in the art with the method for preparing chemical pure substantially compound that compound is carried out purifying.But chemical pure substantially compound can be the mixture of steric isomer.In this class situation, be further purified the specific activity that can increase compound.

If do not specify, alkyl used herein, alkenyl and alkynyl carbochain contain 1 to 20 carbon or 1 or 2 to 16 carbon, and are straight or brancheds.The alkenyl carbochain of 2 to 20 carbon contains 1 to 8 two key in some embodiments, and the alkenyl carbochain of 2 to 16 carbon contains 1 to 5 two key in some embodiments.The alkynyl carbochain of 2 to 20 carbon contains 1 to 8 three key in some embodiments, and the alkynyl carbochain of 2 to 16 carbon contains 1 to 5 three key in some embodiments.The alkyl of this paper illustrative, alkenyl and alkynyl include but not limited to methyl, ethyl, propyl group, sec.-propyl, isobutyl-, normal-butyl, sec-butyl, the tertiary butyl, isopentyl, neo-pentyl, tert-pentyl, isohexyl, allyl group (propenyl) and propargyl (proyl).Low alkyl group used herein, low-grade alkenyl and low-grade alkynyl represent to have from about 1 or about 2 carbon to the carbochain of about 6 carbon." alkane (alkene) (alkynes) base " used herein expression contains the alkyl of at least one two key and at least one three key.

" cycloalkyl " used herein represented saturated monocycle or encircled ring system more, be 3 to 10 carbon atoms in some embodiments, be 3 to 6 carbon atoms in other embodiments; Cycloalkenyl group and cycloalkynyl radical are represented monocycle or are encircled ring system more, comprise at least one two keys and at least one three key respectively.Cycloalkenyl group and cycloalkynyl radical can contain 3 to 10 carbon atoms in some embodiments, and cycloalkenyl group contains 4 to 7 carbon atoms in further embodiment, and cycloalkynyl radical contains 8 to 10 carbon atoms in further embodiment.The ring system of cycloalkyl, cycloalkenyl group and cycloalkynyl radical can be made up of a ring or two or more rings, they can with condense, bridging or spiral shell connect mode and link together." cycloalkanes (alkene) (alkynes) base " expression contains the cycloalkyl of at least one two key and at least one three key.

" aryl " used herein expression contains aromatic monocyclic or many cyclic groups of 6 to 19 carbon atoms.Aryl includes but not limited to the unsubstituted or fluorenyl that replaces, unsubstituted or the phenyl and the naphthyl unsubstituted or that replace that replace.

" heteroaryl " used herein expression monocycle or polycyclic aromatic ring system, be about 5 to about 15 members in some embodiments, wherein in this ring system one or more, be that 1 to 3 atom is a heteroatoms in one embodiment, just the element beyond the carbon includes but not limited to nitrogen, oxygen or sulphur.Heteroaryl can randomly condense with phenyl ring.Heteroaryl includes but not limited to furyl, imidazolyl, pyrimidyl, tetrazyl, thienyl, pyridyl, pyrryl, thiazolyl, isothiazolyl,  azoles base, different  azoles base, triazolyl, quinolyl and isoquinolyl.

" heteroaryl  " used herein group is the heteroaryl of positively charged on one or more heteroatomss.

" heterocyclic radical " used herein represented monocycle or encircled non-aromatics ring system more, be 3 to 10 members in one embodiment, be 4 to 7 members in another embodiment, in further embodiment is 5 to 6 members, wherein in this ring system one or more, be that 1 to 3 atom is a heteroatoms in some embodiments, just the element beyond the de-carbon includes but not limited to nitrogen, oxygen or sulphur.Heteroatoms is in the embodiment of nitrogen therein; this nitrogen is randomly replaced by alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocyclic radical, cycloalkylalkyl, heterocyclic radical alkyl, acyl group, guanidine radicals; perhaps this nitrogen can be by quaternized generation ammonium group, and wherein substituting group is selected as above.

One of hydrogen atom in " aralkyl " used herein expression alkyl is by the displaced alkyl of aryl.

" heteroaralkyl " used herein represents that one of hydrogen atom of alkyl wherein is by the displaced alkyl of heteroaryl.

" halo " used herein, " halogen " or " halogen ion " expression F, Cl, Br or I.

Plan halogen ion used herein or plan halogeno-group are similar to the halogen ion basically groups of behavior.This compounds can use and handles according to the mode identical with the halogen ion according to the mode identical with the halogen ion.Intend the halogen ion and include but not limited to cyanogen root, cyanate radical, thiocyanate ion, selenocyanic acid root, trifluoromethoxy and nitrine acid group.

" haloalkyl " used herein represents that wherein one or more hydrogen atoms are by the displaced alkyl of halogen.This class group include but not limited to aminomethyl just, trifluoromethyl and 1-chloro-2-fluoro ethyl.

" halogenated alkoxy " used herein expression RO-, wherein R is a haloalkyl.

" sulfinyl " used herein or " sulfinyl " expression-S (O)-." alkylsulfonyl " used herein or " sulfonyl " expression-S (O) ₂-." sulfo group " used herein expression-S (O) ₂O-.

" carboxyl " used herein expression bivalent atom group-C (O) O-.

" aminocarboxyl " used herein expression-C (O) NH ₂

" alkyl amino-carbonyl " used herein expression-C (O) NHR, wherein R is an alkyl, comprises low alkyl group." dialkyl amino carbonyl " used herein expression-C (O) NR ' R, wherein R ' and R are alkyl independently, comprise low alkyl group; " acid amides " expression-NR ' COR group, wherein R ' and R are alkyl independently, comprise low alkyl group.

" ammonia diaryl base carbonyl " expression-C used herein (O) NRR ', wherein R and R ' are independently selected from aryl, comprise lower aryl, for example phenyl.

" aryl-alkyl amino carbonyl " expression-C used herein (O) NRR ', wherein one of R and R ' they are aryl, comprise lower aryl, phenyl for example, another among R and the R ' is alkyl, comprises low alkyl group.

" aromatic yl aminocarbonyl " used herein expression-C (O) NHR, wherein R is an aryl, comprises lower aryl, for example phenyl.

" hydroxycarbonyl group " used herein expression-COOH.

" alkoxy carbonyl " used herein expression-C (O) OR, wherein R is an alkyl, comprises low alkyl group.

" aryloxycarbonyl " used herein expression-C (O) OR, wherein R is an aryl, comprises lower aryl, for example phenyl.

" alkoxyl group " used herein and " alkylthio " expression RO-and RS-, wherein R is an alkyl, comprises low alkyl group.

" aryloxy " used herein and " arylthio " expression RO-and RS-, wherein R is an aryl, comprises lower aryl, for example phenyl.

" alkylidene group " used herein expression straight chain, side chain or cyclic, be the divalent aliphatic alkyl of straight or branched in some embodiments, have 1 in one embodiment, have 1 to 12 carbon in another embodiment to about 20 carbon atoms.In further embodiment, alkylidene group comprises low-grade alkylidene.Can be randomly in alkylidene group, insert one or more oxygen, sulphur, comprise S (=O) and S (=O) ₂Group perhaps replaces or unsubstituted nitrogen-atoms, comprise-NR-and-N ⁺The RR-group, the substituting group of wherein one or more nitrogen is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl or COR, wherein R ' be alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl ,-OY or-NYY, wherein Y is hydrogen, alkyl, aryl, heteroaryl, cycloalkyl or heterocyclic radical.Alkylidene group includes but not limited to methylene radical (CH ₂-), ethylidene (CH ₂CH ₂-), propylidene ((CH ₂) ₃-), methylene-dioxy (O-CH ₂-O-) and ethylenedioxy (O-(CH ₂) ₂-O-).Term " low-grade alkylidene " expression has the alkylidene group of 1 to 6 carbon.In some embodiments, alkylidene group is a low-grade alkylidene, comprises the alkylidene group of 1 to 3 carbon atom.

" azepine alkylidene group " used herein expression-(CRR) _n-NR-(CRR) _m-, wherein n and m are 0 to 4 integer independently of one another." oxa-alkylidene group " used herein expression-(CRR) _n-O-(CRR) _m-, wherein n and m are 0 to 4 integer independently of one another." thia alkylene " used herein expression-(CRR) _n-S-(CRR) _m-,-(CRR) _n-S (=O)-(CRR) _m-and-(CRR) _n-S (=O) ₂-(CRR) _m-, wherein n and m are 0 to 4 integer independently of one another.

" alkenylene " used herein expression straight chain, side chain or cyclic, be the divalent aliphatic alkyl of straight or branched in one embodiment, having 2 in some embodiments to about 20 carbon atoms and at least one two key, is 1 to 12 carbon in other embodiments.In further embodiment, alkenylene comprises lower alkenylene.Can randomly insert one or more oxygen, sulphur or replacement or unsubstituted nitrogen-atoms in alkenylene, wherein the nitrogen substituting group is an alkyl.Alkenylene includes but not limited to-CH=CH-CH=CH-and-CH=CH-CH ₂-.Term " lower alkenylene " expression has the alkenylene of 2 to 6 carbon.In some embodiments, alkenylene is a lower alkenylene, comprises the alkenylene of 3 to 4 carbon atoms.

" alkynylene " used herein expression straight chain, side chain or cyclic, be the divalent aliphatic alkyl of straight or branched in some embodiments, having 2 in one embodiment to about 20 carbon atoms and at least one three key, is 1 to 12 carbon in another embodiment.In further embodiment, alkynylene comprises rudimentary alkynylene.Can randomly insert one or more oxygen, sulphur or replacement or unsubstituted nitrogen-atoms in alkynylene, wherein the substituting group of nitrogen is an alkyl.Alkynylene includes but not limited to-C ≡ C-C ≡ C-,-C ≡ C-and-C ≡ C-CH ₂-.Term " rudimentary alkynylene " expression has the alkynylene of 2 to 6 carbon.In some embodiments, alkynylene is rudimentary alkynylene, comprises the alkynylene of 3 to 4 carbon atoms.

" alkylene (alkene) (alkynes) base " used herein expression straight chain, side chain or cyclic, be the divalent aliphatic alkyl of straight or branched in some embodiments, have 2 in one embodiment to about 20 carbon atoms and at least one three key and at least one pair keys; Be 1 to 12 carbon in another embodiment.In further embodiment, alkylene (alkene) (alkynes) base comprises rudimentary alkylene (alkene) (alkynes) base.Can randomly insert one or more oxygen, sulphur or replacement or unsubstituted nitrogen-atoms in alkylidene group, wherein the substituting group of nitrogen is an alkyl.Alkylene (alkene) (alkynes) base includes but not limited to-C=C-(CH ₂) _n-C ≡ C-, wherein n is 1 or 2.Term " rudimentary alkylene (alkene) (alkynes) base " expression has the alkylene of 6 carbon (alkene) (alkynes) base at the most.In some embodiments, alkylene (alkene) (alkynes) base has about 4 carbon atoms.

" cycloalkylidene " used herein represented the monocycle that divalence is saturated or encircled ring system more, be 3 to 10 carbon atoms in some embodiments, be 3 to 6 carbon atoms in other embodiments; Inferior cycloalkenyl group and inferior cycloalkynyl radical are represented the divalence monocycle or are encircled ring system more, comprise at least one two keys and at least one three key respectively.Inferior in some embodiments cycloalkenyl group and inferior cycloalkynyl radical can contain 3 to 10 carbon atoms, and inferior in some embodiments cycloalkenyl group contains 4 to 7 carbon atoms, and inferior in some embodiments cycloalkynyl radical contains 8 to 10 carbon atoms.The ring system of cycloalkylidene, inferior cycloalkenyl group and inferior cycloalkynyl radical can be made up of a ring or two or more rings, they can with condense, bridging or spiral shell connect mode and link together." inferior cycloalkanes (alkene) (alkynes) base " expression contains the cycloalkylidene of at least one two key and at least one three key.

" arylidene " used herein expression monocycle or polycyclic, be monocyclic divalent aromatic radical in some embodiments, have 5 in one embodiment to about 20 carbon atoms and at least one aromatic ring, is 5 to 12 carbon in another embodiment.In further embodiment, arylidene comprises rudimentary arylidene.Arylidene includes but not limited to 1,2-, 1,3-and 1,4-phenylene.Term " rudimentary arylidene " expression has the arylidene of 6 carbon.

The monocycle or the polycyclic aromatics ring system of " inferior heteroaryl " used herein expression divalence, have about 5 to about 15 atoms in the ring in one embodiment, wherein in this ring system one or more, be that 1 to 3 atom is a heteroatoms in some embodiments, just the element beyond the carbon includes but not limited to nitrogen, oxygen or sulphur.Term " rudimentary inferior heteroaryl " is illustrated in the inferior heteroaryl that has 5 or 6 atoms in the ring.

" inferior heterocyclic radical " used herein represented divalence monocycle or encircled non-aromatics ring system more, be 3 to 10 members in some embodiments, be 4 to 7 members in one embodiment, be 5 to 6 members in another embodiment, wherein in this ring system one or more, comprise that 1 to 3 atom is a heteroatoms, just the element beyond the carbon includes but not limited to nitrogen, oxygen or sulphur.

" alkyl of replacement " used herein, " alkenyl of replacement ", " alkynyl of replacement ", " cycloalkyl of replacement ", " cycloalkenyl group of replacement ", " cycloalkynyl radical of replacement ", " aryl of replacement ", " heteroaryl of replacement ", " heterocyclic radical of replacement ", " alkylidene group of replacement ", " alkenylene of replacement ", " alkynylene of replacement ", " cycloalkylidene of replacement ", " the inferior cycloalkenyl group of replacement ", " the inferior cycloalkynyl radical of replacement ", " arylidene of replacement ", " inferior heteroaryl of replacement " and " the inferior heterocyclic radical of replacement " represents alkyl respectively, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, aryl, heteroaryl, heterocyclic radical, alkylidene group, alkenylene, alkynylene, cycloalkylidene, inferior cycloalkenyl group, inferior cycloalkynyl radical, arylidene, inferior heteroaryl and inferior heterocyclic radical, they are by one or more substituting groups, be one in some embodiments, two, three or four substituting groups replacements, wherein substituting group is selected from Q as defined herein in one embodiment ¹

" alkylidene " used herein expression divalent group, for example=CR ' R ", it is connected with an atom of another group, constitutes two keys.Alkylidene includes but not limited to methyne (=CH ₂) and ethylidine (=CHCH ₃)." inferior aralkyl " used herein represents wherein R ' or R " is the alkylidene of aryl." inferior cycloalkyl " is wherein R ' and R " connect and compose isocyclic those." inferior heterocyclic radical " be wherein at least one R ' and R " in chain, contain heteroatoms and R ' and R " and connect and compose heterocyclic those.

" amido " used herein expression divalent group-C (O) NH-." thio acylamino " expression divalent group-C (S) NH-." oxygen base amido " expression divalent group-OC (O) NH-." thia amido " expression divalent group-SC (O) NH-." dithia amido " expression divalent group-SC (S) NH-." urea groups " expression divalent group-HNC (O) NH-." thioureido " expression divalent group-HNC (S) NH-.

" Urea,amino-" used herein expression-NHC (O) NHNH-." carbazic acid base " expression divalent group-OC (O) NHNH-." different sulfo-carbazic acid base " expression divalent group-SC (O) NHNH-." sulfo-carbazic acid base " expression divalent group-OC (S) NHNH-." sulfonyl hydrazide " expression divalent group-SO ₂NHNH-." hydrazides " expression divalent group-C (O) NHNH-." azo " expression divalent group-N=N-." diazanyl " expression divalent group-NH-NH-.

If do not specify given substituent quantity (for example haloalkyl) arbitrarily, then may have one or more substituting groups.For example, " haloalkyl " can comprise one or more identical or different halogens.As another example, " C _1-3Alkoxyl phenyl " can comprise one or more identical or different contain one, the alkoxyl groups of two or three carbon.

Except as otherwise noted, otherwise the abbreviation of any protecting group used herein, amino acid and other compound all follow and their common usage, generally acknowledged abbreviation or IUPAC-IUB biochemical nomenclature commission (referring to (1972) Biochem.11:942-944).Abbreviations more used herein are listed in down:

The Ph=phenyl

The Bz=benzyl

The t-Bu=tertiary butyl

The Me=methyl

The Et=ethyl

The Pr=propyl group

Iso-P or iPr=sec.-propyl

MeOH=methyl alcohol

EtOH=ethanol

The EtOAc=ethyl acetate

The Boc=tertbutyloxycarbonyl

CBZ=carbobenzoxy or carbobenzoxy or carbobenzoxy-(Cbz)

DCM or CH ₂Cl ₂=methylene dichloride

DCE=1, the 2-ethylene dichloride

The DMF=dimethyl formamide

The DMSO=dimethyl sulfoxide (DMSO)

The TFA=trifluoroacetic acid

The THF=tetrahydrofuran (THF)

HATU=O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea  hexafluorophosphate

KOH=potassium hydroxide

K ₂CO ₃=salt of wormwood

POCl ₃=phosphoryl chloride

The KOtBu=potassium tert.-butoxide

EDC or EDCI=1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride

The DIPEA=diisopropyl ethyl amine

The HOBt=1-hydroxy benzotriazole hydrate

Between m-CPBA=-the chlorine peroxybenzoic acid

The NaH=sodium hydride

NaOH=sodium hydroxide

Na ₂SO ₄=sodium sulfate

Na ₂S ₂O ₃=Sulfothiorine

The Pd=palladium

The Pd/C=palladium carbon

Min=minute

The L=liter

The mL=milliliter

μ L=microlitre

The g=gram

The mg=milligram

The mol=mole

The mmol=mmole

The meq=milliequivalent

RT or rt=room temperature

t _r=HPLC retention time (minute)

Sat or sat ' d=are saturated

B. compound

In one embodiment, the compound that is used in composition provided herein and the method provided herein has formula I, and wherein each variable is as described below.All combinations of this class embodiment are all in the scope of present disclosure.

In one embodiment, R ¹Be hydrogen, low alkyl group, low-grade cycloalkyl, alkenyl or alkynyl.In another embodiment, R ¹Be methyl, halogeno-group, hydroxyl, low alkyl group, low-grade cycloalkyl, low-grade alkynyl, trifluoromethyl, methoxyl group, trifluoromethoxy, cyano group ,-NH ₂Or-NR ⁴R ⁵In another embodiment, R ¹Be methyl, halogeno-group, hydroxyl, low alkyl group, low-grade cycloalkyl, low-grade alkynyl, trifluoromethyl, methoxyl group, trifluoromethoxy, cyano group ,-NH ₂,-NR ⁴R ⁵Or-OR ⁴In another embodiment, R ¹Be methyl, hydroxyl, low alkyl group, low-grade cycloalkyl, low-grade alkynyl, trifluoromethyl, methoxyl group, trifluoromethoxy, cyano group ,-NH ₂,-NR ⁴R ⁵Or-OR ⁴In one embodiment, R ¹Be hydrogen or low alkyl group.In another embodiment, R ¹Be hydrogen or methyl.In another embodiment, R ¹It is methyl.

In another embodiment, R ²It is alkyl or cycloalkyl.In one embodiment, R ²It is hydrogen or alkyl.In one embodiment, R ²Be hydrogen or low alkyl group.In one embodiment, R ²Be hydrogen.

In another embodiment, R ³Be selected from alkyl, cycloalkyl, heterocyclic radical and the heteroaryl of hydrogen, alkyl, replacement.In another embodiment, R ³Be selected from alkyl ,-OR ⁴, replace alkyl, cycloalkyl ,-CR ⁴The heterocycle of the heteroaryl of cycloalkyl, heteroaryl, replacement, heterocycle and replacement.In one embodiment, R ³Be cycloalkyl, cycloalkylalkyl, alkoxyalkyl or heteroaryl.In one embodiment, R ³Be methyl, sec.-propyl, ethyl, cyclopropyl, cyclopropyl methyl, methoxymethyl,  azoles base or thiazolyl.In another embodiment, R ³It is cyclopropyl.

In another embodiment, Y be-C (=O) NH-,-NH (C=O)-,-NH (C=O) NH-,-SO ₂NH-,-NHSO ₂-or-C (=O)-.In another embodiment, Y be singly-bound ,-C (=O) NH-or-SO ₂NH-.In another embodiment, Y is-C (=O) NH-.

In another embodiment, X ¹Be singly-bound or alkylidene group.In another embodiment, X ¹Be singly-bound or-CH ₂-.In another embodiment, X ¹It is singly-bound.

In another embodiment, A is the bicyclic heterocycles ring system, and wherein each ring contains at least one N atom, and randomly by two R at the most ¹³Replace.In another embodiment, A is the bicyclic heteroaryl ring system, and wherein each ring contains at least one N atom, and it is randomly by two R at the most ¹³Replace.In another embodiment, A is the bicyclic heteroaryl ring system, and wherein each ring contains two N atoms, and randomly by two R at the most ¹³Replace.In another embodiment, A is imidazopyrimidine, pyrazolopyrimidine, imidazopyrimidine ketone or pyrazolopyrimidine ketone groups.In another embodiment, A is imidazopyrimidine or pyrazolopyrimidine group.

In another embodiment, X ²Be singly-bound, alkylidene group or-NH-.In another embodiment, X ²Be singly-bound ,-CH ₂-or-NH-.In another embodiment, X ²It is singly-bound.

In another embodiment, D is heterocyclic radical, cycloalkyl, heteroaryl or aryl, and randomly by one to four, be one or two (CR in one embodiment ⁹R ¹⁰) _wThe E group replaces.In another embodiment, D is cyclohexyl, cyclopentyl, pyridyl, pyrimidyl or phenyl, and randomly by one to four, be one or two (CR in one embodiment ⁹R ¹⁰) _wThe E group replaces.In another embodiment, D is a phenyl, and randomly by one to four, be one or two (CR in one embodiment ⁹R ¹⁰) _wThe E group replaces.

In another embodiment, A is randomly by a R ¹³Group replaces.In another embodiment, R ¹³Be alkyl, OH or NH ₂In another embodiment, R ¹³Be methyl, OH or NH ₂

In another embodiment, (CR ⁹R ¹⁰) _wE be alkyl, alkoxyl group, halogeno-group ,-CH ₂-heterocyclic radical ,-CONH-cycloalkyl, alkyl sulphonyl, alkylthio, alkyl sulfonyl amino, haloalkyl, aminocarboxyl, plan halogeno-group or heterocyclic radical, perhaps replace two (CR that D goes up adjacent atom ⁹R ¹⁰) _wThe E group constitutes alkylene dioxo base together.In another embodiment, (CR ⁹R ¹⁰) _wE is methoxyl group, methyl, 1; 2; 4-triazolyl, methyl sulphonyl, oxyethyl group, 4-methyl isophthalic acid-piperazinyl methyl, fluorine, chlorine, cyclohexyl aminocarboxyl, methanesulfonamido, methylthio group, 4-morpholinyl, trifluoromethyl, aminocarboxyl, iodine, cyano group or cyclopropyl aminocarboxyl perhaps replace two (CR that D goes up adjacent atom ⁹R ¹⁰) _wThe E group constitutes methylene-dioxy or ethylenedioxy together.

In another embodiment, R ¹Be halogeno-group, alkyl, cycloalkyl, alkynyl, haloalkyl, alkoxyl group, halogenated alkoxy, plan halogeno-group ,-NR ⁴R ⁵Or-OR ⁴Y is-C (=O) NH-,-NH (C=O)-,-NH (C=O) NH-,-SO ₂NH-,-NHSO ₂-or-C (=O)-.

In another embodiment, the compound that is used in composition provided herein and the method has formula II:

Wherein k is 0 to 4 integer; Other variable as hereinbefore defined.

In another embodiment, the compound that is used in composition provided herein and the method has formula III:

Wherein each variable as hereinbefore defined.

In another embodiment, the compound that is used in composition provided herein and the method has formula IV:

Wherein each substituting group is as above selected.

In another embodiment, the compound that is used in composition provided herein and the method has formula V:

Wherein each substituting group is as above selected.

In another embodiment, the compound that is used in composition provided herein and the method has formula VI:

Wherein each substituting group is as above selected.

In another embodiment, the compound that is used in composition provided herein and the method has formula VII:

Wherein f is 0 to 3 integer; Remaining variables is as above selected.

In another embodiment, the compound that is used in composition provided herein and the method has formula VIII:

Wherein each variable as hereinbefore defined.

In another embodiment, the compound that is used in composition provided herein and the method has formula IX:

Wherein k is 0 to 4 integer; Other variable as hereinbefore defined.

In another embodiment, the compound that is used in composition provided herein and the method has formula X:

Wherein each variable as hereinbefore defined.

In another embodiment, the compound that is used in composition provided herein and the method has formula XI:

Wherein each substituting group is as above selected.

In another embodiment, the compound that is used in composition provided herein and the method has formula XII:

Wherein each substituting group is as above selected.

In another embodiment, the compound that is used in composition provided herein and the method has formula XIII:

Wherein each substituting group is as above selected.

In another embodiment, the compound that is used in composition provided herein and the method has formula XIV:

Wherein f is 0 to 3 integer; Remaining variables is as above selected.

In another embodiment, the compound that is used in composition provided herein and the method has formula XV:

Wherein each variable as hereinbefore defined.

In another embodiment, these compounds are selected from those shown in the embodiment.

C. the preparation of compound

The compound that this paper provided generally can be prepared according to following schema and those skilled in the art's knowledge.Except the document that is incorporated herein by reference, we disclose following content.The method example that can be used for preparing the compound that this paper provides is set forth in schema 1-5.

(I) type 1H-pyrazolo [3,4-d] pyrimidine of useful herein suitable replacement can prepare by some means, and is for example shown in Figure 1 as flow process, carries out the cyclic action of acid-catalytic (5-amino-1H-pyrazoles-4-yl)-ketone and methane amide.

Schema 1

(II) type 9H-purine of useful herein suitable replacement can prepare by some means, and is for example shown in Figure 2 as flow process, carries out the cyclic action of acid-catalytic (5-amino-1H-imidazol-4 yl)-ketone and methane amide.

Schema 2

Select as an alternative, (III) the type 9H-purine that carries the 6-aryl substituent can prepare by some means, and is for example shown in Figure 3 as flow process.Solvent for example among the NMP, alkali for example DIEA in the presence of, be preferably under 60 ℃ to 250 ℃ the temperature and carrying out 4 of microwave mediation, the reaction between the amine of 6-dichloro pyrimidine-5-base amine and suitably replacement obtains mono-substituted pyrimidine.With this intermediate for example acetic acid treatment of triethyl orthoformate and catalytic acid, obtain 6-chloro-purine intermediate.Can under palladium (0) catalysis, solvent for example in DMF or the two  alkane, be preferably under 60 ℃ to 150 ℃ the temperature with thus obtained 6-chloro-purine in microwave with the organometallic reagent that suitably replaces for example tributyl tin or handling of suitably replacing for boric acid, obtain the purine of required replacement.

Schema 3

Select as an alternative, (III) the type 9H-purine that carries the 6-aryl substituent can prepare by some means, and is for example shown in Figure 4 as flow process.

Select as an alternative, (III) the type 9H-purine that carries the 6-aryl substituent can prepare by some means, and is for example shown in Figure 5 as flow process.

The suitable 5-amino-4-acyl group-pyrazoles that replaces of (IV) type that can be used as the intermediate of preparation (I) type 1H-pyrazolo [3,4-d] pyrimidine herein can prepare by some means, and is for example shown in Figure 4 as flow process.Solvent for example in toluene or the dimethylbenzene, be preferably the 3-oxo-propionitrile that will suitably replace under 60 ℃ to 150 ℃ the temperature and handling with amitraz diphenylurea.Can solvent for example in the ethanol, be preferably under 50 ℃ to 100 ℃ the temperature thus obtained intermediate handled with the hydrazine that suitably replaces, obtain 4-acyl group-5-amino-pyrazol.Can add alkali in reaction mixture, for example triethylamine or diisopropyl ethyl amine are with in the original position and the hydrazine that obtains with hydrochloride or trifluoroacetic acid salt form arbitrarily.Useful herein 3-oxo-propionitrile can be commercially available or by some means preparations, for example begin to react to prepare by lithium salts with acetonitrile from ester, as WO 99/57101 shown in the disclosed and schema 4a like that.

Schema 4

Schema 4a

(V) the type 5-amino-4-acyl group-imidazoles of suitable replacement that can be used as the intermediate of preparation (II) type 9H-purine can be by the preparation of some means, and is for example shown in Figure 5 as flow process.Can be in microwave, handle with triethyl orthoformate being preferably the amine that will suitably replace under 60 ℃ to 150 ℃ the temperature.Can solvent for example in the acetate with thus obtained intermediate with amino propane dinitrile tosylate and catalyzer for example right-toluenesulphonic acids handles, and obtains 5-amino-1H-imidazoles-4-nitrile.Make this nitrile and organometallic reagent for example Grignard reagent for example react among the THF at solvent, carry out acid hydrolysis then, obtain 4-acyl group-5-aminooimidazole.

Schema 5

D. the preparation of pharmaceutical composition

Pharmaceutical composition provided herein contains the compound that one or more this paper provided of the treatment significant quantity that is in the pharmaceutically acceptable carrier, they can be used for preventing, treating or improvement with the p38 kinases, comprise p38 kinase activity one or more symptoms relevant or that wherein involve kinase whose disease of p38 or obstacle.Include but not limited to inflammatory diseases, autoimmune disorder, destructive bone disorders, proliferative disorder, vasculogenesis sexual dysfunction, infectious diseases, neurodegenerative disease and virus disease with p38 kinases diseases associated or obstacle.The pharmaceutical carrier that is suitable for using the compound that this paper provides comprises any this class carrier that is suitable for the specific application mode well known by persons skilled in the art.

In addition, compound can be used as unique pharmacy activity component and is formulated in the composition, perhaps can make up with other activeconstituents.

Composition contains the compound that one or more this paper provides.In one embodiment, these compounds are formulated into suitable pharmaceutical preparation, and for example solution, suspensoid, tablet, dispersible tablet, pill, capsule, powder, extended release preparation or elixir supply Orally administered, perhaps sterile solution or suspension supply parenteral administration, and transdermal patch and Foradil Aerolizer formoterol fumarate.In one embodiment, use technology well known in the art and technology that above-claimed cpd is mixed with pharmaceutical composition (for example referring to Ansel Introduction to Pharmaceutical Dosage Forms, the 4th edition 1985,126).

In composition, one or more compounds of effective concentration or its pharmaceutically acceptable derivates are mixed with the pharmaceutical carrier that is fit to.Before preparation, compound can be derived as mentioned above and turn to corresponding salt, ester, enol ether or ester, acetal, ketal, ortho ester, hemiacetal, hemiketal, acid, alkali, solvate, hydrate or prodrug.Effectively delivery treatments, prevention or improvement are relevant with the p38 kinase activity or wherein involve the amount of one or more symptoms of the disease of p38 kinase activity or obstacle after using for the concentration of compound in composition.

In one embodiment, composition is used for single dose by preparation and uses.For compositions formulated, with compound dissolution, suspendible, the dispersion of certain part by weight or otherwise be blended in the selected carrier, its concentration is to make the effective concentration that illness is alleviated, prevented or one or more symptoms are enhanced of being treated.

Active compound is gone up useful effect and is not had the amount of undesirable side effect to be included in the pharmaceutically acceptable carrier to be enough to that the patient who is treated is brought into play treatment.By test compounds (for example referring to embodiment 15) in the system in external and body as herein described, can determine by rule of thumb to treat effective concentration, infer human dosage then thus.

The concentration of active compound in pharmaceutical composition will depend on absorption, inactivation and the discharge rate of active compound, physicochemical characteristics, dosage and amount of application and the other factors well known by persons skilled in the art of this compound.For example, the amount of being sent is enough to improve as herein described relevant with the p38 kinase activity or wherein involve the disease of p38 kinase activity or one or more symptoms of obstacle.

In one embodiment, the treatment effective dose should produce the serum active constituent concentration of about 0.1ng/ml to about 50-100 μ g/ml.In another embodiment, pharmaceutical composition should provide about 0.001mg dosage to about 2000mg compound/kg body weight/sky.Preparation dosage units form, with provide about 0.01mg, 0.1mg or 1mg to about 500mg, 1000mg or 2000mg, serve as extremely about 500mg activeconstituents or combination/dosage unit form that must composition of about 10mg in one embodiment.

Activeconstituents can perhaps can be divided into a plurality of smaller doses and use by the timed interval by disposable employed.Should be understood that accurate dose and treatment are the functions of the disease of treat the time length, can utilize known testing scheme by rule of thumb or in body or the extrapolation of in vitro tests data next definite.Should be noted in the discussion above that concentration and dose value also can be different because of the seriousness of the illness that will alleviate.Further should be understood that; with regard to specific arbitrarily curee; concrete dosage should be according to individual need and the professional judgement of using or monitor the personnel that composition uses regulated in time; and concentration range described herein only is an illustrative, should not limit the scope or the enforcement of composition required for protection.

In the inadequate situation of compound dissolution degree, can adopt the method that makes the compound solubilising.These class methods are well known by persons skilled in the art, include but not limited to use solubility promoter such as dimethyl sulfoxide (DMSO) (DMSO), use tensio-active agent such as TWEEN , perhaps are dissolved in the sodium bicarbonate aqueous solution.When the preparation drug composition effective, also can use the derivative of compound, for example the prodrug of compound.

After mixing or adding compound, the gained mixture can be solution, suspension, emulsion etc.The form of gained mixture depends on multiple factor, comprises predetermined method of application and the compound solubleness in selected carrier or vehicle.Effectively concentration is enough to improve the symptom of the disease for the treatment of, obstacle or illness, and can determine it by rule of thumb.

Pharmaceutical composition is provided with presented in unit dosage form to be applied to humans and animals, described presented in unit dosage form is tablet, capsule, pill, powder, granule, sterile parenteral solutions agent or suspensoid and oral solution or suspensoid and oil-aqueous emulsion for example, and it contains an amount of compound or its pharmaceutically acceptable derivates.In one embodiment, pharmacy therapeutical active compound and derivative thereof are prepared and are used with presented in unit dosage form or multiple doses form.Presented in unit dosage form used herein represents to be suitable for humans and animals curee's physics discrete unit, and packs separately as is known in the art.Each dosage unit contains the therapeutical active compound of the predetermined amount that is enough to produce required result of treatment, and required pharmaceutical carrier, vehicle or thinner.The example of presented in unit dosage form comprises ampoule and syringe, and tablet and the capsule packed separately.Presented in unit dosage form can be used by aliquot or its multiple.The multiple doses form is packed in a plurality of same unit dosage forms in the single container, uses with isolated presented in unit dosage form.The example of multiple doses form comprises bottle, tablet or capsule bottle or pint or gallon bottle.Therefore, the multiple doses form is not segregate a plurality of dosage units in packing.

Pharmaceutically the liquid composition that can use can for example prepare like this, with active compound as defined above and optional pharmaceutical auxiliary agent dissolving, disperse or otherwise be blended in the carrier, for example water, salt solution, moisture dextrose, glycerine, glycol, ethanol etc. form solution or suspension thus.If desired, the pharmaceutical composition of being used also can contain minor amounts of non-toxic auxiliary substances, for example wetting agent, emulsifying agent or solubilizing agent, pH buffer reagent etc., for example acetate, Trisodium Citrate, cyclodextrin derivative, Arlacel-20, trolamine sodium acetate, trolamine oleate and other this class material.

Prepare this class formulation really blanking method be well known by persons skilled in the art or conspicuous; For example referring to Remington ' s Pharmaceutical Sciences, Mack PublishingCompany, Easton, Pa., the 15th edition, 1975.

Can prepare and wherein contain formulation or the composition that 0.005% to 100% activeconstituents, surplus are made of non-toxic carrier.These preparation of compositions methods are well known by persons skilled in the art.Described composition can contain the 0.001%-100% activeconstituents, is 0.1-95% in one embodiment, is 75-85% in another embodiment.

1. be used for Orally administered composition

Oral Pharmaceutical dosage forms is solid, gel or liquid.Solid dosage is tablet, capsule, granule and bulk powder.The type of oral tablet comprises the masticable lozenge and the tablet of compacting, and it may be enteric coated, sugar-coat or film-coat.Capsule can be hard or soft gelatin capsule, and granule and powder can be non-effervesce or effervescive form, contain the combination of other composition well known by persons skilled in the art.

A. be used for Orally administered solids composition

In some embodiments, preparation is a solid dosage, is capsule or tablet in one embodiment.Tablet, pill, capsule, lozenge etc. can contain the compound of one or more following ingredients or like attribute: tackiness agent; Lubricant; Thinner; Glidant; Disintegrating agent; Tinting material; Sweeting agent; Correctives; Wetting agent; Emetic clothing (emetic coating); And film-coat.The example of tackiness agent comprises Microcrystalline Cellulose, tragakanta, glucose solution, gum arabic rubber cement, gelatin solution, molasses, polyvinylpyrrolidone, polyvidone, polyvinylpolypyrrolidone, sucrose and starch paste.Lubricant comprises talcum powder, starch, Magnesium Stearate or calcium stearate, spores of Wolf's claw clubmoss (lycopodium) and stearic acid.Thinner comprises for example lactose, sucrose, starch, kaolin, salt, N.F,USP MANNITOL and Lin Suanergai.Glidant includes but not limited to colloidal silica.Disintegrating agent comprises croscarmellose sodium, primojel, Lalgine, W-Gum, yam starch, wilkinite, methylcellulose gum, agar and carboxymethyl cellulose.Tinting material comprises the water-soluble FD that for example passes through License Authentication arbitrarily and C stain, its mixture; With the water-insoluble FD and the C stain that are suspended on the hydrated aluminum oxide.Sweeting agent comprises the spraying drying spices of sucrose, lactose, N.F,USP MANNITOL and artificial sweetening agent such as asccharin and any amount.Correctives comprises natural perfume that for example extracts the fruit from plant and the synthetic mixture that produces the compound of joyful sense, such as but not limited to peppermint and wintergreen oil.Wetting agent comprises propylene glycol monostearate, polyoxyethylene-sorbitan mono-oleate, Diethylene Glycol mono-laurate and polyoxyethylene laurel ether.Enteric coating comprises lipid acid, fat, wax, shellac, amination shellac and rhodia phthalic ester.Film-coat comprises Natvosol, Xylo-Mucine, Macrogol 4000 and rhodia phthalic ester.

Compound or its pharmaceutically acceptable derivates can be provided in can protecting its composition of avoiding the gastric acid environment influence.For example, composition can be formulated in the enteric coating, and it can keep integrity under one's belt, release of active compounds in intestines.Composition also can be prepared with antacid or other this constituents combination.

When dosage unit form was capsule, except the material of the above-mentioned type, it can also contain liquid vehicle, for example fatty oil.In addition, dosage unit form can contain various other modifies the material of the physical form of this dosage device, for example the dressing of sugar and other enteric agents.Compound also can be used as the component applied of elixir, suspensoid, syrup, wafer, spray agent (sprinkle), chewing gum etc.Except active compound, syrup can also contain as the sucrose of sweeting agent and some sanitas, stain and tinting material and spices.

Active substance can not damage the active substance of required effect with other yet or mixes with the material that replenishes required effect, for example antacid, H2 retarding agent and diuretic(s).Activeconstituents is compound as herein described or its pharmaceutically acceptable derivates.The activeconstituents that can comprise higher concentration is up to about 98 weight %.

In all embodiments, tablet and capsule can be as is known to persons skilled in the art like that by dressings, and purpose is to regulate the stripping of activeconstituents or make activeconstituents continue stripping.Therefore, for example, they can wrap the conventional digestible dressing of intestines, for example Whitfield's ointment phenylester, wax and rhodia phthalic ester.

B. be used for Orally administered liquid composition

Solution that liquid oral dosage form comprises aqueous solution agent, emulsion, suspensoid, obtained by non-effervescent granule reconstruct and/or suspension and the effervesce prepared product that obtains by effervescent granule reconstruct.The aqueous solution agent comprises for example elixir and syrup.Emulsion be oil-in-water-type or water-in-oil-type.

Elixir is a water alcohol prepared product clarifying, sweet taste.The pharmaceutically acceptable carrier that is used in the elixir comprises solvent.Syrup is for example concentrated aqueous solutions of sucrose of sugar, can contain sanitas.Emulsion is a kind of biphasic system, and wherein a kind of liquid is dispersed in the another kind of liquid with the bead form.The pharmaceutically acceptable carrier that is used in the emulsion is non-aqueous liquid, emulsifying agent and sanitas.Suspensoid uses pharmaceutically acceptable suspension agent and sanitas.The pharmaceutically acceptable material that is used in the non-effervescent granule of waiting to reconstitute liquid oral dosage form comprises thinner, sweeting agent and wetting agent.The pharmaceutically acceptable material that is used in the effervescent granule of waiting to reconstitute liquid oral dosage form comprises organic acid and carbon dioxide source.In above-mentioned all formulations, all use tinting material and correctives.

Solvent comprises glycerine, sorbyl alcohol, ethanol and syrup.The example of sanitas comprises glycerine, methyl p-hydroxybenzoate and propylparaben, phenylformic acid, Sodium Benzoate and alcohol.The example that is used in the non-aqueous liquid in the emulsion comprises mineral oil and oleum gossypii seminis.The example of emulsifying agent comprises gelatin, gum arabic, tragakanta, wilkinite and tensio-active agent such as polyoxyethylene sorbitan monooleate.Suspension agent comprises Xylo-Mucine, pectin, tragakanta, neusilin (Veegum) and gum arabic.Sweeting agent comprises sucrose, syrup, glycerine and artificial sweetening agent such as asccharin.Wetting agent comprises propylene glycol monostearate, polyoxyethylene-sorbitan mono-oleate, Diethylene Glycol mono-laurate and polyoxyethylene laurel ether.Organic acid comprises citric acid and tartrate.Carbon dioxide source comprises sodium bicarbonate and yellow soda ash.Tinting material comprises any water-soluble FD and C stain and its mixture through License Authentication.Correctives comprises natural perfume that for example extracts the fruit from plant and the synthetic mixture that produces the compound of pleasing mouth-feel.

For solid dosage, in one embodiment, solution or suspension in for example propylene carbonate, vegetables oil or triglyceride level are encapsulated in the gelatine capsule.This class solution and preparation thereof and seal and be disclosed in U.S. Patent No. 4,328 are in 245,4,409,239 and 4,410,545.For liquid dosage form, can be with solution, for example the solution in polyoxyethylene glycol dilutes with the pharmaceutically acceptable liquid vehicle of capacity, for example water, so that can easily measure in order to use.

Select as an alternative, liquid or semisolid oral formulations can prepare like this, with the dissolving of active compound or salt or be dispersed in vegetables oil, glycol, triglyceride level, propylene glycol ester (for example propylene carbonate) and other this class carrier, and with these solution or suspension is encapsulated in firmly or in the soft gelatin capsule shell.Other useful preparation comprises U.S. Patent No. RE28,819 and 4,358, and those described in 603.In brief, this class preparation includes but not limited to contain those of following material: the compound that this paper provided; The list of dialkyl groupization-or many-alkylene glycol, include but not limited to 1,2-Methylal(dimethoxymethane), diglyme, triglyme, tetraethylene glycol dimethyl ether, polyoxyethylene glycol-350-dimethyl ether, polyoxyethylene glycol-550-dimethyl ether, polyoxyethylene glycol-750-dimethyl ether, the wherein approximate molecular-weight average of 350,550 and 750 expression polyoxyethylene glycol; With one or more antioxidants, for example Yoshinox BHT (BHT), butylated hydroxy anisole (BHA) (BHA), Tenox PG, vitamin-E, quinhydrones, Hydroxycoumarin, thanomin, Yelkin TTS, kephalin, xitix, oxysuccinic acid, sorbyl alcohol, phosphoric acid, thio-2 acid and ester thereof and dithiocarbamate.

Other preparation includes but not limited to comprise the water-alcohol solution of pharmaceutically acceptable acetal.The alcohol that is used in these preparations is any pharmaceutically acceptable water miscible solvent with one or more hydroxyls, includes but not limited to propylene glycol and ethanol.Acetal includes but not limited to two (low alkyl group) acetal of low alkyl group aldehyde, for example acetal.

2. injection, solution and emulsion

This paper also comprises parenteral administration, is feature with subcutaneous, intramuscular or intravenous injection in one embodiment.Injection can make liquor or suspension in a usual manner, be suitable for before injection dissolving or be suspended in solid form or emulsion form in the liquid.Injection, solution or emulsion also contain one or more vehicle.The vehicle that is fit to has for example water, salt solution, dextrose, glycerine or ethanol.In addition, if desired, the pharmaceutical composition of being used also can contain minor amounts of non-toxic auxiliary substances, for example wetting agent or emulsifying agent, pH buffer reagent, stablizer, solubility enhancing agent and other this class reagent, for example sodium acetate, Arlacel-20, Emulphor FM and cyclodextrin.

This paper comprises that also implantation slowly discharges or sustained release system, so that keep constant dosage level (for example referring to U.S. Patent No. 3,710,795).In brief, the compound that this paper provided is dispersed in the solid interior skeleton, polymethylmethacrylate for example, poly-n-butyl methacrylate, plasticising or unplasticizied polyvinyl chloride, plasticising nylon, the plasticising polyethylene terephthalate, natural rubber, polyisoprene, polyisobutene, polyhutadiene, polyethylene, vinyl-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, the silicone carbonate copolymer, the hydrogel of the ester of hydrophilic polymer such as vinylformic acid and methacrylic acid, collagen, the polyvinyl acetate of the pure and mild crosslink part hydrolysis of crosslinked polyethylene, it is surrounded by the outer polymer film, polyethylene for example, polypropylene, ethylene/propene copolymer, the ethylene/ethyl acrylate multipolymer, ethylene, silicone rubber, polydimethylsiloxane, chloroprene rubber, chlorinatedpolyethylene, polyvinyl chloride, ethene chlorine and vinyl-acetic ester, Ethylene Dichloride, the multipolymer of ethene and propylene, the ionomer polyethylene terephthalate, the isoprene-isobutylene rubber epichloro hydrin rubber, the ethylene/vinyl alcohol copolymer, Ethylene/vinyl acetate/vinyl alcohol terpolymer and ethylene/vinyl ethoxy-ethanol multipolymer, it is insoluble to body fluid.In discharging ratedeterming step, compound is by the diffusion of outer polymer film.The active compound per-cent that contains in this class parenteral composition depends on the activity of its specific object and compound and curee's needs greatly.

The parenteral administration of composition comprises intravenously, subcutaneous and intramuscular administration.The parenteral administration prepared product comprise instant aseptic injectable solution, the aseptic drying products of solubility as remain face use before and the lyophilized powder of solvent, comprise subcutaneous, instant aseptic injection suspension, remain before use at once and insoluble product of the aseptic drying of carrier blended and aseptic emulsion.Solution can be water-based or nonaqueous.

If intravenously is used, the carrier that is fit to comprises the salt solution (PBS) of physiological saline or phosphate buffered and contains thickening material and the solution of solubilizing agent, for example glucose, polyoxyethylene glycol and polypropylene glycol and composition thereof.

The pharmaceutically acceptable carrier that is used in the parenteral administration comprises aqueous vehicles, non-aqueous vehicle, biocide, isotonic agent, buffer reagent, antioxidant, local anesthetic, suspension and dispersion agent, emulsifying agent, shelters or sequestrant and other pharmaceutically acceptable material.

The example of aqueous vehicles comprise sodium chloride injection, ringer's inj, etc. ooze glucose injection, sterilized water injection liquid, glucose and lactated ringer's inj.Non-aqueous parenteral vehicle comprises expressed oil, oleum gossypii seminis, Semen Maydis oil, sesame oil and the peanut oil of plant origin.The biocide that suppresses bacterium or suppress fungi concentration be must in the parenteral administration in being packaged in the multi-agent container, add, phenol or cresols, mercurial, benzylalcohol, butylene-chlorohydrin, methyl p-hydroxybenzoate and propylparaben, Thiomersalate, benzalkonium chloride and Benzethonium Chloride comprised.Isotonic agent comprises sodium-chlor and dextrose.Buffer reagent comprises phosphoric acid salt and Citrate trianion.Antioxidant comprises sodium pyrosulfate.Local anesthetic comprises vovocan.Suspension comprises Xylo-Mucine, Vltra tears and polyvinylpyrrolidone with dispersion agent.Emulsifying agent comprises polysorbate80 (TWEEN  80).Metal ion shelter or sequestrant comprises EDTA.With regard to water miscibility vehicle, pharmaceutical carrier also comprises ethanol, polyoxyethylene glycol and propylene glycol, and with regard to pH regulator, pharmaceutical carrier also comprises sodium hydroxide, hydrochloric acid, citric acid or lactic acid.

Concentration to pharmaceutically active compound is regulated, so that make injection that the significant quantity that produces required pharmacological action is provided.As known in the art, exact dosage desired depends on age, body weight and the situation of patient or animal.

The dosage unit parenteral administration is packaged in ampoule, bottle or the band needle applicator.As known in the art with put into practice like that, the preparation of the parenteral administration that is useful on all must be aseptic.

For example, intravenously or the endoarterial infusion that contains the aseptic aqueous solution of active compound is effective method of application.Another embodiment is to contain sterile aqueous or the oily solution or the suspension that must produce the active substance of required pharmacological action after the injection.

Injection is designed to part and systemic administration.In one embodiment, the treatment effective dose of being prepared contains at least about 0.1%w/w to about 90%w/w or above concentration, in some embodiments, gives the tissue the disposed active compound above 1%w/w.

The form that compound can be fit to micronization or other perhaps can be generated the better active result of solvability or generate prodrug by suspendible by derivatize.The form of gained mixture depends on multiple factor, comprises predetermined method of application and the compound solubleness in selected carrier or vehicle.Effectively concentration is enough to improve the symptom of illness, and can determine it by rule of thumb.

3. lyophilized powder

This paper also relates to lyophilized powder, and they can be reconfigured as solution, emulsion and other mixture for using.They also can and be mixed with solid or gel by reconstruct.

Aseptic freeze-dried powder is prepared as follows: compound or its pharmaceutically acceptable derivates that this paper provided are dissolved in the suitable solvent.Solvent can contain the vehicle of raising stability or other pharmacology component in powder or the reconstituted solutions.Operable vehicle includes but not limited to dextrose, sorbyl alcohol, fructose, maize treacle, Xylitol, glycerine, glucose, sucrose or other material that is fit to.Solvent also can contain buffer reagent, and for example Citrate trianion, sodium phosphate or potassiumphosphate or other this class buffer reagent well known by persons skilled in the art in one embodiment, have about neutral pH.Subsequently under standard conditions well known by persons skilled in the art with solution sterile filtration, freeze-drying then obtains required preparation.In one embodiment, gained solution will be sub-divided in and carry out freeze-drying in the bottle.Each bottle will contain the compound of single dose or multiple doses.Lyophilized powder can be stored under the felicity condition, for example about 4 ℃ to room temperature.

With this lyophilized powder of water for injection reconstruct, obtain being used for the preparation of parenteral administration.For reconstruct, lyophilized powder is added in sterilized water or other carrier that is fit to.Accurately amount depends on selected compound.This class amount can be determined by rule of thumb.

4. external application is used

The external application mixture is to prepare as described in local and the systemic administration.The gained mixture can be solution, suspension, emulsion etc., and is formulated into ointment, gelifying agent, ointment, emulsion, solution, elixir, lotion, suspensoid, tincture, paste, foaming agent, aerosol, irrigating, sprays, suppository, bandage, skin patch or other is suitable for the preparation that external application is used arbitrarily.

Compound or its pharmaceutically acceptable derivates can be formulated into external application, as by the aerosol of suck using (for example referring to U.S. Patent No. 4,044,126,4,414,209 and 4,364,923, they have described the aerosol of sending the steroide that can be used for treating inflammatory diseases, particularly asthma).These preparations that are applied to respiratory tract can be aerosol or the form that is used for the solution of spraying gun, or the micro mist form that is used to be blown into, and it is independent or makes up with inert support such as lactose.In this case, the particulate of preparation will have in one embodiment less than 50 microns, in a scheme less than 10 microns diameter.

Compound can be by preparation for part or external application, is used for skin and mucous membrane such as eye for example outward, and formulation is gelifying agent, ointment and lotion, be used for eye or be used in brain the pond in or backbone in application.External application is used and is comprised transdermal delivery, also comprises eye or mucosal administration, perhaps anapnotherapy.Also can use separately or with the nose solution of the active compound of other pharmaceutically acceptable excipient composition.

These solution, particularly be intended to the isotonic solution that those of usefulness can be mixed with the 0.01%-10% of the about 5-7 of pH with suitable salt.

5. the composition that is used for other route of administration

This paper also comprises other route of administration, for example transdermal patch (comprising iontophoresis and electrophoresis apparatus) and rectal administration.

Transdermal patch (comprising iontophoresis and electrophoresis apparatus) is well known to those skilled in the art.For example, this class patch is disclosed in U.S. Patent No. 6,267, in 983,6,261,595,6,256,533,6,167,301,6,024,975,6,010715,5,985,317,5,983,134,5,948,433 and 5,860,957.

For example, the pharmaceutical dosage form that is used for rectal administration has rectal suppository, capsule and the tablet that reaches the whole body effect.Rectal suppository used herein represents to insert the solid of rectum, and it melts under body temperature or be softening, discharges one or more pharmacology or therapeutic activity composition.The pharmaceutically acceptable material that is used in the rectal suppository is the material of matrix or vehicle and rising fusing point.The example of matrix comprise theobroma oil (theobroma oil), glycerine-gelatin, carbowax (polyoxyethylene glycol) and lipid acid list-, two-with the suitable mixture of Three-glycerol ester.Can use the combination of various matrix.The material of rising suppository fusing point comprises spermaceti and wax.Rectal suppository can be by pressing or mechanography preparation.In one embodiment, the weight of rectal suppository is about 2 to 3gm.

The tablet that is used for rectal administration and capsule are to use the pharmaceutically acceptable material identical with Orally administered preparation and by identical with it method preparation.

6. targeting preparation

The compound that this paper provided or its pharmaceutically acceptable derivates also can be formulated into particular organization, acceptor or other zone of target in curee's body.A lot of these class targeted approach are well known to those skilled in the art.This paper comprises that all these class targeted approach are used for composition of the present invention.About the limiting examples of targeted approach, for example referring to U.S. Patent No. 6,316,652,6,274,552,6,271,359,6,253,872,6,139,865,6,131,570,6,120,751,6,071,495,6,060,082,6,048,736,6,039,975,6,004,534,5,985,307,5,972,366,5,900,252,5,840,674,5,759,542 and 5,709,874.

In one embodiment, liposome turbid liquor (comprising tissue-target liposomes, for example tumour-target liposomes) also can be suitable as pharmaceutically acceptable carrier.These can be prepared according to method known to those skilled in the art.For example, Liposomal formulation can be as U.S. Patent No. 4,522, the such preparation described in 811.In brief, by generating liposome at dry Yelkin TTS phatidylcholine of flask interior and kephalin acyl Serine (mol ratio 7: 3), for example multilamelar vesicles (multilamellar vesicle, MLV).Add the solution of compound in the phosphate buffered saline (PBS) that does not contain divalent cation (PBS) that this paper provided, shaking flasks is disperseed until lipid film.Washing gained vesicle is to remove non-encapsulated compound, and centrifugation is resuspended among the PBS then.

7. goods

Compound or pharmaceutically acceptable derivates can be packaged into a kind of goods, and it contains wrapping material; The compound that this paper provided in these wrapping material or its pharmaceutically acceptable derivates, it can be used to regulate and control the p38 kinase activity effectively, perhaps is used for the treatment of, prevents or improve kinase mediated disease of p38 or obstacle or wherein involve the disease of p38 kinase activity or one or more symptoms of obstacle; And label, its explanation is used to regulate and control the p38 kinase activity with this compound or composition or its pharmaceutically acceptable derivates or is used for the treatment of, prevents or improve kinase mediated disease of p38 or obstacle or wherein involve the disease of p38 kinase activity or one or more symptoms of obstacle.

The goods that this paper provided contain wrapping material.The wrapping material that are used for the packaged pharmaceuticals product are well known to those skilled in the art.For example referring to U.S. Patent No. 5,323,907,5,052,558 and 5,033,252.The example of drug packages material includes but not limited to Blister Package, bottle, pipe, sucker, pump, bag, bottle, container, syringe, bottle and is suitable for choice of formulation arbitrarily and the predetermined method of application and the wrapping material of treatment.The several formulations of expection compound that this paper provided and composition can be used as and wherein involves mediators or the disease of influencing factor or the various treatments of obstacle of p38 kinase activity as the symptom or the cause of disease arbitrarily.

E. the evaluation of compound activity

Standard physiology, pharmacology and biochemical method can be used for test compounds, with discriminating possess the regulating cell factor active, comprise the p38 kinase activity bioactive those.

In the radioactivity enzyme assay, measure the inhibition activity of compound.Buffer reagent is formed (Biochemistry, 1998, the 37 volumes, 16573-16581 pages or leaves) such as employing Lisnock.Peptide substrates be selected from Chen etc. (Biochemistry, 2000, the 39 volumes, 2079-2087).P38 α, [γ- ³³P-ATP] and the concentration of peptide equal 1nM, 85 μ M and 250 μ M respectively.Utilize the absorption on the filter bed, use 100mM phosphoric acid subsequently,, measure and mix in the peptide succeeded by washing with alcohol ³³P.

Other condition that is used for p38 α enzyme assay has also been described in the document.They be different from described assay method part be buffer reagent form (Biochemistry, 2000, the 39 volumes, 2079-2087) or substrate (Biochemistry, 1998, the 37 volumes, the 16573-16581 page or leaf) or the two (Protein Sci., 1998, the 7 volumes, the 2249-2255 page or leaf).

F. the using method of compound and composition

In some embodiments, the compound that this paper provided is the selective depressant of p38 kinase activity, and in one embodiment, these compounds are inhibitor of p38 kinases isoform, includes but not limited to p38 α and p38 beta kinase.Therefore, formula (I) compound has effect in the treatment illness relevant with the p38 kinase activity.This class illness comprises wherein as the disease of carrying out the consequence regulating cell factor level of signal conduction in the cell via p38, particularly with cytokine IL-1, IL-4, IL-8 and TNF-α overexpression diseases associated.

In view of they activity as p38 α/beta kinase inhibitor, formula (I) compound can be used for treating the illness relevant with p38, includes but not limited to inflammatory diseases, autoimmune disorder, destructive bone disorders, proliferative disorder, vasculogenesis sexual dysfunction, infectious diseases, neurodegenerative disease and virus disease.

The related inflammatory diseases of the illness relevant with p38 includes but not limited to acute pancreatitis, chronic pancreatitis, asthma, transformation reactions and adult respiratory distress syndrome.

The related autoimmune disorder of the illness relevant with p38 includes but not limited to glomerulonephritis, rheumatoid arthritis, systemic lupus erythematous, scleroderma, chronic thyroiditis, Graves disease, autoimmunity gastritis, insulin-dependent diabetes mellitus (type i diabetes), autoimmune hemolytic anemia, the autoimmunity neutrophilic leukocyte reduces, thrombopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel, ulcerative colitis, crohn, psoriatic or graft versus host disease (GVH disease).

The related destructive bone disorders of the illness relevant with p38 includes but not limited to osteoporosis, osteoarthritis and the relevant bone disorders with multiple myeloma.

The related proliferative disease of the illness relevant with p38 includes but not limited to acute myeloid leukaemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi sarcoma and multiple myeloma.

The related infectious diseases of the illness relevant with p38 includes but not limited to sepsis, septic shock and shigellosis.

The related virus disease of the illness relevant with p38 includes but not limited to that acute hepatitis infects (comprising hepatitis A, hepatitis B and hepatitis C), HIV infects and the CMV retinitis.

The related degenerative disease of the illness relevant with p38 includes but not limited to alzheimer's disease, Parkinson's disease, cerebral ischemia and other neurodegenerative disease.

" illness relevant with p38 " also comprises the platelet aggregation of ischemia/reperfusion, heart attack, myocardial ischemia, organ anoxic, blood vessel hyperplasia, cardiac hypertrophy and thrombin induction in the apoplexy.

In addition, the p38 inhibitor that this paper provided also can suppress the expression of induction type proinflammatory protein, and for example prostaglandin endoperoxide synthase-2 (PGHS-2) is also referred to as cyclooxygenase-2 (COX-2).Therefore, other " illness of p38-mediation " has oedema, analgesia, heating and pain, for example neuromuscular pain, headache, cancer pain, toothache and arthritis ache.

Can also can be responsible for cytokine (IL-1, TNF, IL-6, the IL-8) grouping of this disease by the disease of p38 inhibitor for treating that this paper provided or prevention easily according to the tool letter.

Therefore, the disease of IL-1-mediation or the illness Inflammatory response, inflammatory bowel, tuberculosis, atherosclerosis, myodegeneration, emaciation, psoriatic arthritis, reiter syndrome, gout, traumatic arthritis, rubella arthritis (rubella arthritis), acute synovitis, diabetes, pancreas beta cell disease and the alzheimer's disease that comprise rheumatoid arthritis, osteoarthritis, apoplexy, endotoxemia and/or toxic shock syndrome, endotaxin induction.

The disease or the illness of TNF-mediation comprise rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, urarthritis and other disorder of joint, sepsis, septic shock, endotoxin shock, the Gram-negative sepsis, toxic shock syndrome, the adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, sarcoidosis of lung (pulmonary sarcoisosis), bone resorption disease, reperfusion injury, graft-vs-host reaction, allograft rejection, heating that infection causes and myalgia, be secondary to the emaciation of infection, AIDS, ARC or malignant tumour, keloid forms, scar tissue forms, crohn, ulcerative colitis or pyresis.The disease of TNF-mediation also comprises virus infection, for example HIV, CMV, influenza and bleb; Infect with the animal disease poison, for example slow virus infection includes but not limited to equine infectious anemia virus, goat arthritis virus, visna virus (visna virus) or chronic progress pneumonia virus of sheep (maede virus); Perhaps retroviral infection comprises feline immunodeficiency virus, bovine immunodeficiency virus or dog immunodeficiency virus.

The disease of IL-8-mediation or illness comprise that soaking into a large amount of neutrophils is the disease of feature, for example psoriatic, inflammatory bowel, asthma, heart and renal reperfusion injury, adult respiratory distress syndrome, thrombosis and glomerulonephritis.

In addition, the compound that this paper provided can external application be used for the treatment of or prevents by IL-1 or TNF is caused or the illness that worsens.This class illness comprises that joint inflammation, eczema, psoriatic, inflammatory dermatosis disease are for example tanned severely, the inflammatory eye disease disease illness of conjunctivitis, pyresis, pain and other and inflammation-related for example.

In one embodiment, can include but not limited to pancreatitis (acute or chronic) with the concrete illness or the disease of compounds for treating provided herein, asthma, transformation reactions, the adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematous, scleroderma, chronic thyroiditis, Graves disease, autoimmunity gastritis, diabetes, autoimmune hemolytic anemia, the autoimmunity neutrophilic leukocyte reduces, thrombopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel, ulcerative colitis, crohn, psoriatic, graft versus host disease (GVH disease), the Inflammatory response of endotaxin induction, tuberculosis, atherosclerosis, myodegeneration, emaciation, psoriatic arthritis, reiter syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, pancreas beta cell disease; Soaking into a large amount of neutrophils is the disease of feature; Rheumatoid spondylitis, urarthritis and other disorder of joint, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, sarcoidosis of lung, bone resorption disease, allograft rejection, heating that infection causes and myalgia, be secondary to the emaciation of infection, keloid forms, scar tissue forms, ulcerative colitis, pyresis, influenza, osteoporosis, osteoarthritis and the bone disorders relevant with multiple myeloma, acute myeloid leukaemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi sarcoma, multiple myeloma, sepsis, septic shock and shigellosis; Alzheimer's disease, Parkinson's disease, cerebral ischemia or the neurodegenerative disease that causes by traumatic damage; The vasculogenesis sexual dysfunction comprises solid tumor, eye neovascularization and infant's vascular tumor (infantilehaemangiomas); Virus disease comprises that acute hepatitis infects (comprising hepatitis A, hepatitis B and hepatitis C), HIV infects and the CMV retinitis, AIDS, SARS, ARC or malignant tumour and bleb; Platelet aggregation, endotoxemia and/or the toxic shock syndrome of the ischemic in apoplexy, myocardial ischemia, the apoplexy heart attack, organ anoxic, blood vessel hyperplasia, heart and renal reperfusion injury, thrombosis, cardiac hypertrophy, thrombin induction and with the relevant illness of prostaglandin endoperoxides enzyme synthase-2.

In addition, the p38 inhibitor that this paper provided suppresses the expression of induction type proinflammatory protein, and for example prostaglandin endoperoxide synthase-2 (PGHS-2) is also referred to as cyclooxygenase-2 (COX-2).Therefore, other illness relevant with p38 comprises oedema, analgesia, heating and pain, for example the pain, toothache and the arthritis ache that cause of neuromuscular pain, headache, cancer.The compound that this paper provided also can be used for the treatment of the animal disease poison to be infected, and for example slow virus infection includes but not limited to equine infectious anemia virus; Perhaps retroviral infection comprises feline immunodeficiency virus, bovine immunodeficiency virus and dog immunodeficiency virus.

G. combination treatment

This paper also provides the method for the treatment illness relevant with the p38 kinases, and this method is used the independent of significant quantity or is suitable for treating formula (I) compound that this class treatment of conditions agent is made up each other and/or with other the curee who needs is arranged.The example of this other therapeutical agent of class comprises the imidazo (1 that reflunomide, rolipram, calphostin, CSAID, 4-replace, 2-A) quinoxaline, it is disclosed in U.S. Patent No. 4,200,750 and S.Ceccarelli etc. " imidazo (1,2-a) quinoxaline-4-amine: the non-xanthine A that a class is new _IAdenosine receptor antagonists ", European Journal of Medicinal Chemistry the 33rd volume, (1998) are in the 943-955 page or leaf; Interleukin-10, glucocorticosteroid, salicylate, nitrogen oxide and other immunosuppressor; Nuclear translocation inhibitor, for example Gusperimus (DSG); Nonsteroidal anti-inflammatory (NSAID), for example Ibuprofen BP/EP, celecoxib and rofecoxib; Steroide, for example prednisone or dexamethasone; Antiviral agent, for example Abacavir; Antiproliferative, for example methotrexate, leflunomide, FK506 (tacrolimus, Prograf); Cytotoxicity medicine, for example azathioprine and endoxan; The TNF-alpha inhibitor, for example tenidap, anti-TNF antibody or soluble TNF acceptor, and rapamycin (sirolimus or Rapamune) or derivatives thereof.

When the compound that is provided with this paper was used in combination, above-mentioned other therapeutical agent can for example use according to amount given among the Physicians ' Desk Reference (PDR), perhaps determine consumption by those of ordinary skills.In the method that this paper provided, other therapeutical agent of this class can be before the compound administration that this paper provided, simultaneously or use afterwards.

The following example is only presented for purposes of illustration, is not to be intended to limit the scope of the invention.With in an embodiment abbreviation as defined herein.Compound among the embodiment (is for example determined by this embodiment and their step of preparation, the title compound of " 1A " expression embodiment 1 steps A), be that the embodiment of embodiment title compound determines (for example, the title compound of " 2 " expression embodiment 2) only perhaps by this compound wherein.

Universal method. mass-spectrometric data obtains on Thermo Finnigan LCQ Duo Ion Trap mass spectrograph.The HPLC data are at C ₁₈The Betasol post (2.1 * 50mm) last acquisitions, use gradient elution 10-90% (solvent orange 2 A: acetonitrile+0.025%v TFA; Solvent B: water+0.025%v TFA), go through 4 minutes (flow velocity 0.50mL/min).The purification condition of preparation HPLC: ThermoHypersi-Keystone Betasil C18 post 250 * 21.2mm, particle diameter 5 μ m, mobile phase: A, water+0.025%TFA; B, acetonitrile+0.025%TFA; Gradient from 40 to 70%B; Flow velocity 15mL/min.

Embodiment 1

The preparation of N-cyclopropyl-4-methyl-3-(the 4-phenyl-pyrazole is [3,4-d] pyrimidine-1-yl also)-benzamide

A.3-amino-N-cyclopropyl-4-methyl-benzamide

Under RT, (10.2g, 67.5mmol) ((15.5g, 81mmol 1.2eq), add DMAP (cat.) then 2eq) to add EDCI in the mixture in DMF (150mL) for 9.33mL, 135.0mmol with cyclopropylamine to 3-amino-4-methyl-phenylformic acid.To be reflected to stir under the RT and spend the night, concentrate then.Resistates is water-soluble again, extract with EtOAc.With organic layer NaCl solution washing, use Na ₂SO ₄Drying concentrates.By flash chromatography on silica gel method purifying crude product (gradient elution: 1: 1EtOAc/ hexane, 100%EtOAc then), obtain 1A, be solid (9.5g, 72%).

B.N-cyclopropyl-3-diazanyl-4-methyl-benzamide

To under 0 ℃, 3-amino-N-cyclopropyl-4-methyl-benzamide of stirring (52mg 0.27mmol) adds dense HCl (3mL) in the solution in water (3mL), add then Sodium Nitrite (20mg, 0.30mmol).Reaction mixture is stirred 40min down at 0 ℃, and (114mg, the 0.61mmol) solution in dense HCl (1mL) stir mixture 1 hour, place 20 hours down at-20 ℃ then, are warming up to RT then to add tin chloride (II) then.Use Na ₂CO ₃CH is used in the solution neutralization ₂Cl ₂Extract six times.Combining extraction liquid is used Na ₂SO ₄Drying concentrates, and the gained solid need not to be further purified and can use.HPLC?t _R?1.06min；MS?m/z?205.9[M+H] ⁺。

C.3-(5-amino-4-benzoyl-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide

In the EtOH solution (10mL) of the hydrazine 1B that is stirring, add 2-benzoyl-3-phenyl amino vinyl cyanide (676mg; 0.27mmol, preparation: Grothaus, J.Am.Chem.Soc.58; 1334 (1936)), mixture heating up (bathing temperature=65-70 ℃) is reached 16 hours.Mixture is cooled to RT, concentrates,, remove impurity, use 8 then with 1: 1 EtOAc/ hexane wash-out by purified by flash chromatography: 2EtOAc/ hexane wash-out, obtain title compound, be pale solid (18mg, 0.05mmol, 19%).HPLC?t _R?2.11min；MS?m/z?361.1[M+H] ⁺； ¹H?NMR(CD ₃OD，300MHz)δ7.92(d，J＝7.6，1H)，7.81(m，4H)，7.54(m，4H)，2.85(m，1H)，2.22(s，3H)，0.80(d，J＝5.7，2H)，0.63(s，2H)ppm； ¹³C?NMR(CD ₃OD，75MHz)δ191.2，170.1，153.8，143.3，142.0，141.1，136.9，134.8，132.9，132.7，130.1，129.7，129.2，128.1，104.8，24.1，17.7，6.6ppm。

D.N-cyclopropyl-4-methyl-3-(the 4-phenyl-pyrazole is [3,4-d] pyrimidine-1-yl also)-benzamide

With 3-(5-amino-4-benzoyl-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide (72mg, 0.20mmol), the mixture of methane amide (1.0mL, excessive) and acetate (0.2mL) is at 160 ℃ of following microwave heating 20min.After the cooling, with mixture CH ₂Cl ₂With water dilution, separation of C H ₂Cl ₂Layer is used Na ₂SO ₄Drying is filtered, and concentrates.By preparation HPLC purifying crude product, obtain title compound (46mg, 62%), be white solid.HPLC?t _R＝2.3min；MS?m/z?370.3[M+H] ⁺。

In a comparable manner by the feedstock production of suitable replacement following compounds:

Table 1.

Embodiment 2

The preparation of N-cyclopropyl-4-methyl-3-(6-phenyl-purine-9-yl)-benzamide

A.3-(5-amino-4-cyano group-imidazoles-1-yl)-N-cyclopropyl-4-methyl-benzamide

The mixture of 3-amino-N-cyclopropyl-4-methyl-benzamide (380mg, 2.0mmol see embodiment 1A) in the 2.0mL triethyl orthoformate stirred 20 minutes under 120 ℃, in microwave.Under reduced pressure remove and desolvate.Resistates is dissolved in 5mL acetate again, add then amino propane dinitrile right-tosylate (506mg, 2.0mmol) and sodium acetate (164mg, 2.0mmol).Reaction mixture at room temperature stirred spend the night.Mixture with the dilution of 20mL water, is regulated pH to 8.0 with the NaOH aqueous solution.The gained mixture extracts (3 * 50mL) with EtOAc.Merge organic layer, MgSO is used in water (10mL) and salt solution (10mL) washing ₄Drying is filtered, and concentrates in a vacuum.By silica gel column chromatography purifying resistates (10/1, methylene chloride), obtain 2A, be colorless solid (170mg, 30%).HPLC?t _R＝1.39min；MS?m/z?282[M+H] ⁺。

B.3-(5-amino-4-benzoyl-imidazoles-1-yl)-N-cyclopropyl-4-methyl-benzamide

At room temperature, to the 3-under nitrogen (5-amino-4-cyano group-imidazoles-1-yl)-N-cyclopropyl-4-methyl-benzamide (56.4mg, 0.2mmol) the THF solution (1mL, excessive) of adding 1M phenyl-magnesium-bromide in the solution in dry THF (10mL).After 1 hour, add 3N HCl solution (10mL), mixture is stirred spend the night.Solution is neutralized with rare NaOH aqueous solution.With mixture with ethyl acetate extraction (2 * 100mL), wash with water, use Na ₂SO ₄Drying concentrates.By HPLC purifying crude product, obtain 3B, be white solid (56mg, 78%).HPLC?t _R＝2.07min；MS?m/z361.17[M+H] ⁺。

C.N-cyclopropyl-4-methyl-3-(6-phenyl-purine-9-yl)-benzamide

With 3-(5-amino-4-benzoyl-imidazoles-1-yl)-N-cyclopropyl-4-methyl-benzamide (33mg, 0.09mmol), the mixture of methane amide (0.5mL, excessive) and acetate (0.1mL) heats 20min under 200 ℃, in microwave.After the cooling, with mixture CH ₂Cl ₂With water dilution, separation of C H ₂Cl ₂Layer is used Na ₂SO ₄Drying is filtered, and concentrates.By preparation HPLC purifying crude product, obtain title compound (20mg, 59%), be white solid: HPLC t _R=2.20min; MS m/z 370.3[M+H] ⁺

Table 2.

Embodiment 3

N-cyclopropyl-4-methyl-3-[6-(4-sulfydryl phenyl)-purine-9-yl]-preparation of benzamide

A.3-(5-amino-4-cyano group-imidazoles-1-yl)-N-cyclopropyl-4-methyl-benzamide

(380mg, 2.0mmol) mixture in the 2.0mL triethyl orthoformate stirred 20 minutes under 120 ℃, in microwave with 3-amino-N-cyclopropyl-4-methyl-benzamide.Under reduced pressure remove and desolvate.Resistates is dissolved in 5mL acetate, add then amino propane dinitrile right-tosylate (506mg, 2.0mmol) and sodium acetate (164mg, 2.0mmol).Reaction mixture at room temperature stirred spend the night.Mixture with the dilution of 20mL water, is filtered the gained precipitation, obtain 3-(5-amino-4-cyano group-imidazoles-1-yl)-N-cyclopropyl-4-methyl-benzamide 3A, be colorless solid (170mg, 30%).HPLC?t _R＝1.39min；MS?m/z?282[M+H] ⁺。

B.3-(5-amino-4-benzoyl-imidazoles-1-yl)-N-cyclopropyl-4-methyl-benzamide

At room temperature, to the 3-under nitrogen (5-amino-4-cyano group-imidazoles-1-yl)-N-cyclopropyl-4-methyl-benzamide (100mg, 0.36mmol) add the THF solution (5mL, excessive) of 0.5M4-sulfydryl phenyl-magnesium-bromide in the solution in dry THF (15mL).After 1 hour, add 3N HCl (10mL), mixture is stirred spend the night.Solution is neutralized with rare NaOH aqueous solution.With mixture with ethyl acetate extraction (2 * 100mL), wash with water, use Na ₂SO ₄Drying concentrates.By HPLC purifying crude product, obtain 3B, be white solid.

C.N-cyclopropyl-4-methyl-3-[6-(4-sulfydryl phenyl)-purine-9-yl]-benzamide

With 3-[5-amino-4-(4-sulfydryl-benzoyl)-imidazoles-1-yl]-N-cyclopropyl-4-methyl-benzamide (33mg; 0.09mmol), the mixture of methane amide (0.5mL, excessive) and right-toluenesulphonic acids (10mg) heats 30min under 180 ℃, in microwave.After the cooling, mixture with EtOAc and water dilution, is separated the EtOAc layer, use Na ₂SO ₄Drying is filtered, and concentrates.By preparation HPLC purifying crude product, obtain title compound (20mg, 59%), be white solid: HPLC t _R=2.47min; MSm/z 416.27[M+H] ⁺

Table 3.

Embodiment 4

N-cyclopropyl-3-[6-(3-methanesulfonamido-phenyl)-purine-9-yl]-preparation of 4-methyl-benzamide

A.3-(5-amino-6-chloro-pyrimidine-4-base amino)-N-cyclopropyl-4-methyl-benzamide

To 4,6-two chloro-pyrimidine-5-base amine (328mg, 2.0mmol) with 3-amino-N-cyclopropyl-4-methyl-benzamide (760mg 4.0mmol) adds N in the mixture in NMP (1.5mL), the N-diisopropyl ethyl amine (348 μ l, 2.0mmol).Reaction mixture is used microwave heating 30 minutes down at 220 ℃.Be cooled to RT then,,, obtain compound 4A, be pale solid (267mg, 0.84mmol, 42%) with 3: 1 EtOAc/ hexane wash-outs by purified by flash chromatography.HPLC?t _R＝1.59min；MSm/z?318[M+H] ⁺； ¹H?NMR(300MHz，CD ₃OD)δ0.64-0.68(m，2H)，0.80-0.84(m，2H)，2.23(s，3H)，2.83-2.87(m，1H)，7.40(d，J＝7.9，1H)，7.66(d，J＝7.9，1H)，7.80(m，2H)ppm。

B.3-(6-chloro-purine-9-yl)-N-cyclopropyl-4-methyl-benzamide

(420mg 1.32mmol) uses microwave heating 15 minutes at triethyl orthoformate (1mL) and the mixture in the acetate (3) down at 120 ℃ with 3-(5-amino-6-chloro-pyrimidine-4-base is amino)-N-cyclopropyl-4-methyl-benzamide.Be cooled to room temperature,,, obtain compound 4B, be white solid (350mg, 1.07mmol, 81%) with 1: 1 EtOAc/ hexane wash-out by the column chromatography purifying.HPLC?t _R＝2.07min；MS?m/z?328[M+H] ⁺； ¹H?NMR(300MHz，CD ₃OD)δ0.58-0.59(m，2H)，0.72-0.77(m，2H)，2.13(s，3H)，2.77-2.82(m，1H)，7.55(d，J＝7.9Hz，1H)，7.82(s，1H)，7.91(d，J＝7.9Hz，1H)，8.65(s，1H)，8.69(s，1H)ppm。

C.N-cyclopropyl-3-[6-(3-methanesulfonamido-phenyl)-purine-9-yl]-4-methyl-benzamide

To compound 4B (16mg, 0.046mmol), 3-methanesulfonamido-Dai boric acid and Pd (Ph ₃P) ₄(5.5mg adds 1 in mixture 0.0048mmol), 4-two  alkane (0.2mL) and sat. K ₂CO ₃(0.1ml).Then the gained suspension is used microwave heating 10 minutes down at 120 ℃.Be cooled to RT then,, obtain title compound, be white solid (7.6mg, 0.016mmol, 33%) by the HPLC purifying.HPLC?t _R＝1.96min；MS?m/z?463[M+H] ⁺； ¹H?NMR(300MHz，CD ₃OD)δ0.64(m，2H)，0.79-0.82(m，2H)，2.21(s，3H)，2.84-2.88(m，1H)，3.08(s，3H)，7.47-7.62(m，3H)，7.89-7.98(m，2H)，8.57-8.68(m，3H)，8.95(s，1H)ppm。

Prepared following compounds by suitable replacement for boric acid in a comparable manner:

Table 4.

Embodiment 5

The preparation of N-cyclopropyl-4-methyl-3-(6-pyridine-2-base-purine-9-yl)-benzamide

With 3-(6-chloro-purine-9-yl)-N-cyclopropyl-4-methyl-benzamide (16mg, 0.049mmol), Pd (PPh ₃) ₄(5.7mg, 0.0049mmol) (36mg, mixture 0.098mmol) are suspended among the DMF (0.25mL) with 2-tributyl tin alkyl-pyridine.Mixture is used microwave heating 10 minutes down at 160 ℃.By the HPLC purified mixture, obtain required product, be white solid (16mg, 0.043mmol, 88%).HPLC?t _R＝1.59min；MS?m/z?371[M+H] ⁺。

Organic stannane by suitable replacement has prepared following compounds in a comparable manner:

Embodiment 5-2, N-cyclopropyl-4-methyl-3-(6-pyrimidine-2-base-purine-9-yl)-benzamide, HPLC t _R=1.40min; MS m/z 371.4[M+H] ⁺

Embodiment 5-3, N-cyclopropyl-4-methyl-3-(6-pyrimidine-2-base-purine-9-yl)-benzamide, HPLC t _R=1.40min; MS m/z 372[M+H] ⁺

Embodiment 5-4, N-cyclopropyl-4-methyl-3-(6-thiazol-2-yl-purine-9-yl)-benzamide, HPLC t _R=1.85min; MS m/z 377[M+H] ⁺

Embodiment 6

The preparation of N-cyclopropyl-3-(2-hydroxyl-6-phenyl-purine-9-yl)-4-methyl-benzamide

(9.2mg 0.026mmol) adds urea (20mg) in the solution in 0.3mL acetate, mixture is heated 20min under 180 ℃, in microwave to the 3-that is stirring (5-amino-4-benzoyl-imidazoles-1-yl)-N-cyclopropyl-4-methyl-benzamide.By HPLC purifying crude product, obtain colorless solid (2.4mg, 24%).HPLC?t _R＝1.63min；MS?m/z?386[M+H] ⁺。

Embodiment 7

The preparation of N-cyclopropyl-4-methyl-3-(6-phenyl amino-purine-9-yl)-benzamide

(10mg, 0.029mmol) (14mg, 0.15mmol) mixture in 0.2mL two  alkane is used microwave heating 20 minutes down at 140 ℃ with aniline with 3-(6-chloro-purine-9-yl)-N-cyclopropyl-4-methyl-benzamide.Be cooled to RT then,, obtain title compound, be pale solid (5.2mg, 46%) by the HPLC purifying.HPLC?t _R＝2.09min；MS?m/z?385[M+H] ⁺。

Amine by suitable replacement has prepared following compounds in a comparable manner:

Table 5.

Embodiment 8

The preparation of N-cyclopropyl-4-methyl-3-(6-phenyl-purine-9-ylmethyl)-benzamide

A.3-[(5-amino-6-chloro-pyrimidine-4-base is amino)-methyl]-N-cyclopropyl-4-methyl-benzamide

To benzyl amine (41mg, 0.2mmol) with 4,6-two chloro-pyrimidine-5-base amine (99mg, 0.6mmol) add in the mixture in 0.5mL 1-butanols triethylamine (28 μ l, 0.2mmol).Reaction mixture was stirred 6 hours down at 80 ℃.Be cooled to RT then.Under reduced pressure remove and desolvate.By the purified by flash chromatography crude product, with 3: 1 EtOAc/ hexane wash-outs, obtain muriate, be pale solid (32mg, 48%).HPLC?t _R＝1.97min；MS?m/z?332[M+H] ⁺。

B.N-cyclopropyl-4-methyl-3-(6-phenyl-purine-9-ylmethyl)-benzamide

Utilize the method described in the embodiment 4C to prepare title compound.HPLC?t _R＝1.86min；MS?m/z?342[M+H] ⁺。

Embodiment 9

The preparation of 3-(6-cyclopentyl-purine-9-yl)-N-cyclopropyl-4-methyl-benzamide

To under room temperature, nitrogen, 3-(5-amino-4-cyano group-imidazoles-1-yl)-N-cyclopropyl-4-methyl-benzamide (140mg) of stirring adds cyclopentyl bromination magnesium (2.5mL, 2M diethyl ether solution) in the solution among the THF (25mL, exsiccant).Mixture was at room temperature stirred 3 hours, remove then and desolvate.Resistates is dissolved in EtOAc again, and Na is used in water, salt water washing ₂SO ₄Drying concentrates.Resistates is dissolved in MeOH (2.0mL) again, adds HC (OMe) ₃(2.0mL) and TsOH (catalytic amount).Mixture is used microwave irradiation 20min down with 120 ℃.Remove and desolvate,, use the EtOAc wash-out, further by the preparation HPLC purifying, obtain title compound then, be white solid (41.2mg, 23%) by silica gel column chromatography purifying crude product.HPLC?t _R＝2.07min；MS?m/z362.31[M+H] ⁺。

Grignard reagent by suitable replacement has prepared following compounds in a comparable manner:

Embodiment 9-2, N-cyclopropyl-3-(6-cyclopropyl-purine-9-yl)-4-methyl-benzamide, HPLCt _R=1.78min; MS m/z 334.28[M+H] ⁺

Embodiment 9-3, N-cyclopropyl-4-methyl-3-[6-(tetrahydrochysene-pyrans-4-yl)-purine-9-yl]-benzamide, HPLC t _R=1.78min; MS m/z 378.23[M+H] ⁺

Embodiment 10

The preparation of N-cyclopropyl-4-methyl-3-(6-phenoxy group-purine-9-yl)-benzamide

To 3-(6-chloro-purine-9-yl)-N-cyclopropyl-4-methyl-benzamide (embodiment 4B) (21mg, 0.064mmol) add in the solution in DMF (0.2mL) pentamethylene alcohol (59 μ l, 0.64mmol).Mixture is used microwave heating 30 minutes down at 150 ℃.Be cooled to RT, by PTLC or HPLC purifying, obtain required product then, be white solid (10mg, 0.027mmol, 41%).HPLCt _R＝2.09min；MS?m/z?386[M+H] ⁺。

Embodiment 11

N-cyclopropyl-4-methyl-3-[6-(4-morpholine-4-ylmethyl-phenyl)-purine-9-yl]-preparation of benzamide

A.3-[6-(4-brooethyl-phenyl)-purine-9-yl]-preparation of N-cyclopropyl-4-methyl-benzamide

To N-cyclopropyl-3-[6-(4-hydroxymethyl-phenyl)-purine-9-yl]-4-methyl-benzamide (58mg, 0.145mmol, see embodiment 4C-31) add carbon tetrabromide (58mg in the mixture in methylene dichloride (0.5mL), 0.175mmol), add then triphenyl phosphine (47mg, 0.179mmol).Mixture was stirred 1 hour under RT,,, obtain required product, be crude product (88mg, 0.19mmol, 63%) with EtOAc/ hexane (1: 1) wash-out then by column purification.

B.N-cyclopropyl-4-methyl-3-[6-(4-morpholine-4-ylmethyl-phenyl)-purine-9-yl]-preparation of benzamide

To compound 11A (10mg, 0.022mmol) add in the mixture in methylene dichloride (0.2mL) morpholine (19 μ l, 0.21mmol).Mixture was stirred 10 minutes under RT, by preparation type TLC purifying, use 10%MeOH/CH then ₂Cl ₂Wash-out obtains required compound, is white solid (4.8mg, 0.01mmol, 47%).HPLC?t _R＝1.65min；MS?m/z?469[M+H] ⁺。

Embodiment 11B-2, N-cyclopropyl-4-methyl-3-[6-(4-morpholine-4-ylmethyl-phenyl)-purine-9-yl]-benzamide, HPLC t _R=1.65min; MS m/z 469[M+H] ⁺

Embodiment 11B-3, N-cyclopropyl-3-[6-(4-dimethylamino methyl-phenyl)-purine-9-yl]-4-methyl-benzamide, HPLC t _R=1.66min; MS m/z 427[M+H] ⁺

Embodiment 12

N-cyclopropyl-4-methyl-3-[6-(4-methylamino formyl radical-phenyl)-purine-9-yl]-preparation of benzamide

A.4-[9-(5-cyclopropyl formamyl-2-methyl-phenyl)-9H-purine-6-yl]-phenylformic acid

Under 20 ℃; to 4-[9-(5-cyclopropyl formamyl-2-methyl-phenyl)-9H-purine-6-yl]-methyl benzoate (65mg; 0.87mmol) add in the solution in 2mL tetrahydrofuran (THF), 2mL methyl alcohol and 1mL water sodium hydroxide (2M, 0.15mL, 0.3mmol).Reaction mixture was stirred 5 hours under this temperature, drip in the 2N aqueous hydrochloric acid then and clear soln, obtain solid.Filter and collect product, obtain colorless solid (50mg, 80%).HPLC?t _R＝2.01min；MS?m/z?414[M+H] ⁺。

B.N-cyclopropyl-4-methyl-3-[6-(4-methylamino formyl radical-phenyl)-purine-9-yl]-benzamide

Under 20 ℃; to 4-[9-(5-cyclopropyl formamyl-2-methyl-phenyl)-9H-purine-6-yl]-phenylformic acid (10mg; 0.024mmol) and methylamine (3.0mg; 0.097mmol) add I-hydroxybenzotriazole (7.4mg in the solution in the dry DMF of 0.5mL; 0.048mmol) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (9.2mg, 0.048mmol).Reaction mixture was stirred 4 hours down at 20 ℃.Add 2mL water then.Filter and collect product, obtain colorless solid (8.2mg, 80%).HPLC?t _R＝1.99min；MS?m/z?427[M+H] ⁺。

Ortho-formiate by suitable replacement has prepared following compounds in a comparable manner:

Embodiment 12B-2, N-cyclopropyl-3-[6-(4-cyclopropyl formamyl-phenyl)-purine-9-yl]-4-methyl-benzamide, HPLC t _R=2.12min; MS m/z 453[M+H] ⁺

Embodiment 13

N-cyclopropyl-4-methyl-3-[6-(4-[1,3,4]  diazole-2-base-phenyl)-purine-9-yl]-preparation of benzamide

A.N-cyclopropyl-3-[6-(4-diazanyl carbonyl-phenyl)-purine-9-yl]-4-methyl-benzamide

To 4-[9-(5-cyclopropyl formamyl-2-methyl-phenyl)-9H-purine-6-yl]-(65mg adds 1mL one hydrazine hydrate to methyl benzoate in the solution of 0.15mmoD in 1mL methyl alcohol.Reaction mixture was at room temperature stirred 4 hours.Remove methyl alcohol, add 2mL water then.Filter and collect product, obtain colorless solid (47mg, 72%).HPLC?t _R＝1.62min；MS?m/z?428[M+H] ⁺。

B.N-cyclopropyl-4-methyl-3-[6-(4-[1,3,4]  diazole-2-base-phenyl)-purine-9-yl]-benzamide

To N-cyclopropyl-3-[6-(4-diazanyl carbonyl-phenyl)-purine-9-yl]-(8.0mg 0.019mmol) adds three acetate to 4-methyl-benzamide in the solution in the 0.5mL trimethyl orthoformate.Reaction mixture was stirred 10 minutes under 120 ℃, in microwave.Add 0.5mL methylene dichloride and 3mL hexane then.Filter and collect product, obtain colorless solid (6.0mg, 73%).HPLC?t _R＝2.12min；MS?m/z?438[M+H] ⁺。

Embodiment 13B-2, N-cyclopropyl-4-methyl-3-{6-[4-(5-methyl-[1,3,4]  diazole-2-yl)-phenyl]-purine-9-yl }-benzamide, HPLC t _R=2.14min; MS m/z 452[M+H] ⁺

Embodiment 13B-3, N-cyclopropyl-3-{6-[4-(5-ethyl-[1,3,4]  diazole-2-yl)-phenyl]-purine-9-yl }-4-methyl-benzamide, HPLC t _R=2.24min; MS m/z 466[M+H] ⁺

Ortho-formiate by 12A and suitably replacement has prepared following compounds in a comparable manner:

Embodiment 13B-4, N-cyclopropyl-4-methyl-3-[6-(3-[1,3,4]  diazole-2-base-phenyl)-purine-9-yl]-benzamide, HPLC t _R=2.12min; MS m/z 438[M+H] ⁺

Embodiment 13B-5, N-cyclopropyl-4-methyl-3-{6-[3-(5-methyl-[1,3,4]  diazole-2-yl)-phenyl]-purine-9-yl }-benzamide, HPLC t _R=2.14min; MS m/z 452[M+H] ⁺

Embodiment 13B-6N-cyclopropyl-3-{6-[3-(5-ethyl-[1,3,4]  diazole-2-yl)-phenyl]-purine-9-yl }-4-methyl-benzamide, HPLC t _R=2.26min; MS m/z 466[M+H] ⁺

Embodiment 14

The preparation of 3-(6-cyclohexyl-2-hydroxyl-purine-9-yl)-N-cyclopropyl-4-methyl-benzamide

At room temperature, THF solution (the 2M that in the 3-under nitrogen (5-amino-4-cyano group-imidazoles-1-the yl)-solution of N-cyclopropyl-4-methyl-benzamide (28mg, 0.1mmol see embodiment 2A) in dry THF (5mL), adds 1M cyclohexyl bromination magnesium, 0.25mL, 0.5mmol).Reaction mixture after stirring 4 hours under this temperature, is added 5mL water.With mixture with ethyl acetate extraction (3 * 20mL), wash with water, use MgSO ₄Drying concentrates.Crude product is dissolved in the 2mL methylene dichloride.Add 1 then, and the 1-carbonyl dimidazoles (32mg, 0.2mmol).After at room temperature stirring 1 hour, mixture is diluted with 50mL ethyl acetate and water, the separating ethyl acetate layer, MgSO is used in water, salt water washing then ₄Dry.After filtering and concentrating,, obtain solid (22mg, 57%) by preparation HPLC purifying crude product.HPLC?t _R＝1.94min；MS?m/z?392[M+H] ⁺。

Embodiment 15

The compound that utilizes following external test method can prove that this paper provides suppresses the synthetic or active ability of cytokine.

The kinase whose generation of p38

CDNA by PCR human cloning p38 α and β.With α and β cDNA subclone to the DEST2 plasmid (Gateway, InVitrogen) in.At expression in escherichia coli His ₆-p38 fusion rotein uses Ni ^{+ 2}-NTA-agarose is by affinity chromatography purifying from Bacterial Lysates.Activate His by hatching with constitutive activity MKK6 ₆-p38 albumen.By affinity chromatography isolating active p38 from MKK6.Constitutive activity MKK6 with Raingeaud etc. (Mol.Cell.Biol., 1247-1255 (1996)) similar mode generates.

The PBMC that LPS-stimulates generates TNF-α

Obtain heparinization people whole blood from the healthy volunteer.By Accu-paque density gradient centrifugation purifying peripheral blood lymphocytes (PBMC) from people's whole blood, with 5 * 10 ⁶The concentration of/ml is resuspended in to be measured in the substratum (the RPMI substratum that contains 10% foetal calf serum).Under RT, 175 μ L cell suspensions and 10 μ L test compounds (in 4%DMSO) were hatched 30 minutes in 96 hole tissue culturing plates.Add 15 μ L LPS (13.33 μ g/ml storing solution) to cell suspension then, under 37 ℃, plate is being contained 5%CO ₂Moistening atmosphere in hatched 18 hours.After hatching, collect substratum, be stored under-20 ℃.

Washing THP-1 cell (TIB-202, ATCC), with 1 * 10 ⁵The concentration of/ml is resuspended in to be measured in the substratum (the RPMI substratum that contains 3% foetal calf serum).Under RT, 175 μ L cell suspensions and 10 μ L test compounds (in 4%DMSO) were hatched 30 minutes in 96 hole tissue culturing plates.Add 15 μ L LPS (13.33 μ g/ml storing solution) to cell suspension then, under 37 ℃, plate is being contained 5%CO ₂Moistening atmosphere in hatched 18 hours.After hatching, collect substratum, be stored under-20 ℃.

(BioSource International, Camarillo CA) carry out quantitatively the TNF-α concentration in the substratum to utilize the standard ELISA test kit.(SigmaPlot, SPSS Inc.) calculate the concentration of TNF-α and the IC of test compound by four parameter logistic curves ₅₀Value (the TNF-α generation that compound suppresses LPS-and stimulates reaches 50% concentration).

P38 α assay method

Used p38 α assay method based on measure with pyruvate kinase coupling gained NADH oxidizing reaction and lactic dehydrogenase enzyme reaction in the ADP that discharges.Mensuration is carried out in 384 hole UV-plates.Final volume is 25 μ L, and 2.5 μ L are dissolved in compound solution among the 10%DMSO, 17.5 μ L measure damping fluid and 5 μ L ATP prepare by adding.Measure damping fluid and contain following reagent: 25mM HEPES, 20mM 2-Phosphoric acid glycerol esters pH 7.6,10mM MgCl to obtain the final concentration in mensuration ₂, 0.1mM sodium orthovanadate, 0.5mM phosphoenolpyruvic acid, 0.12mM NADH, 3.1mg/mlLDH, 6.67mg/ml pyruvate kinase, 0.25mM peptide substrates, 2mM DTT, 0.005% tween 80 and 20nM be from the p38 alpha kinase of Upstate.With test compound and p38 alpha kinase preincubate 60 minutes, add ATP to 0.15mM final concentration to begin reaction.Under 37 ℃, utilize SpectraMax to read the plate spectrophotometer and under 340nm, measured speed of reaction 10 minutes.Utilize SigmaPlot to suppress data by the analysis of the non-linear least square Return Law.

The mouse that LPS-stimulates produces TNF-α

(Balb/c is female, age in 6-8 week, Taconic Labs to mouse; N=8/ treatment group) peritoneal injection be suspended in lipopolysaccharides (LPS) in the Sterile Saline (50 μ g/kg coli strain 0111:B4, Sigma).After 90 minutes, pass through CO ₂: O ₂Suction makes the mouse calmness, obtains blood sample.Separation of serum is according to manufacturer's the ELISA determination and analysis TNF-α concentration of specification sheets (BioSource International) by being purchased.Before lps injection at the Orally administered test compound of different time.Compound is with suspension in different carriers or solubilizing agent or solution form administration.

Because various variations will be apparent to those skilled in the art, so the present invention only is subjected to the restriction of claims scope.

Claims

1. the compound that has formula I:

Or its pharmaceutically acceptable derivates, wherein:

R ¹Be halogeno-group, alkyl, cycloalkyl, alkynyl, haloalkyl, alkoxyl group, halogenated alkoxy, plan halogeno-group ,-NR ⁴R ⁵Or-OR ⁴

N is 0,1 or 2;

Y is-C (=O) NH-,-NH (C=O)-,-NH (C=O) NH-,-SO ₂NH-,-NHSO ₂-or-C (=O)-;

W is the integer of 0-4;

E is selected from H, halogen, NO₂、C ₁-C ₄Alkyl, C₃-C ₁₀Cycloalkyl, C₂-C ₆Alkenyl, C₂-C ₆Alkynyl, haloalkyl, halogenated alkoxy, OH, OR⁶、CN、CHO、CO ₂R ⁶、 CONR ⁶R ⁷、OCOR ₆、OC(＝O)OR ⁶、OC(＝O)NR ⁶R ⁷、OCH ₂CO ₂R ⁶、C(＝O)R ⁶、 NH ₂、NHR ⁶、NR ⁶R ⁷、NR ⁷C(＝O)R ⁶、NR ⁷C(＝O)OR ⁶、NR ⁷C(＝O)C(＝O)OR ⁶、 NR ⁷C(＝O)C(＝O)NR ⁶R ⁷、NR ⁷C(＝O)C(＝O)(C ₁-C ₆Alkyl), NR⁷C(＝NCN)OR ⁶、 NR ⁷C(＝O)NR ⁶R ⁷、NR ⁷C(＝NCN)NR ⁶R ⁷、NR ⁷C(＝NR ⁶)NR ⁷R ⁸、 NR ⁶SO ₂NR ⁶R ⁷、NR ⁷SO ₂R ⁶、SR ⁶、S(＝O)R ⁶、SO ₂R ⁶、SO ₃R ⁷、SO ₂NR ⁶R ⁷、 NHOH、NHOR ⁶、N(COR ⁶)OH、N(CO ₂R ⁶)OH、CONR ⁷(CR ⁹R ¹⁰) _rR ⁶、 CO(CR ⁹R ¹⁰) _pO(CHR ⁹) _qCO ₂R ⁶、CO(CR ⁹CR ¹⁰) _rR ⁶、 CO(CR ⁹R ¹⁰) _pO(CR ⁹R ¹⁰) _pO(CHR ⁹) _qCO ₂R ⁶、CO(CR ⁹CR ¹⁰) _rOR ⁶、 CO(CR ⁹R ¹⁰) _pO(CR ⁹R ¹⁰) _qR ⁶、CO(CR ⁶CR ¹⁰) _rNR ⁶R ⁷、 OC(O)O(CR ⁹R ¹⁰) _mNR ⁶R ⁷、O(CO) _n(CR ⁹R ¹⁰)R ⁶、O(CR ⁹R ¹⁰) _mNR ⁶R ⁷、 NR ⁷C(O)(CR ⁹R ¹⁰) _rOR ⁶、NR ⁷C(＝NC)(CR ⁹R ¹⁰) _rR ⁶、NR ⁷CO(CR ⁹R ¹⁰) _rNR ⁶R ⁷、 NR ⁷(CR ⁹R ¹⁰) _mOR ⁶、NR ⁷(CR ⁹R ¹⁰) _rCO ₂R ⁶、NR ⁷(CR ⁹R ¹⁰) _mNR ⁶R ⁷、 NR ³(CR ⁹R ¹⁰) _nSO ₂(CR ⁹R ¹⁰) _rCO ₂R ⁶、NR ⁷(CR ⁹R ¹⁰) _mNR ⁶R ⁷、 NR ⁷(CR ⁹R ¹⁰) _nSO ₂(CR ⁹R ¹⁰) _qR ⁶、CONR ⁷(CR ⁹R ¹⁰) _nSO ₂(CR ⁹R ¹⁰) _qR ⁶、 SO ₂NR ⁷(CR ⁹R ¹⁰) _qR ⁶、SO ₂NR ⁶(CR ⁹R ¹⁰) _mOR ⁶, aryl, the heterocyclic radical that randomly by one or two alkyl, is replaced, the heteroaryl and the alkylaryl that randomly by one or two alkyl, are replaced, wherein said aryl is unsubstituted or by 1 or 2, is selected from independently of one another R¹²Substituting group replace, two E groups that perhaps replace the upper adjacent atom of D form alkylene dioxo base, the inferior alkoxyl of sulfo-or alkylene two sulfo-oxygen bases together;

M is the integer of 2-6;

P is the integer of 1-3;

Q is the integer of 0-3;

R is the integer of 0-6;

R ⁴Be hydrogen, low alkyl group and low-grade cycloalkyl;

R ⁵Be hydrogen, low alkyl group and low-grade cycloalkyl;

R ⁶, R ⁷And R ⁸Following independently selection:

Ii) when two substituting groups all are positioned on the same nitrogen-atoms (as at (NR ⁶R ⁷) or (NR ⁷R ⁸) in), R ⁶With R ⁷Perhaps R ⁶With R ⁸Perhaps R ⁷With R ⁸Can constitute with the nitrogen-atoms that they connected and be selected from following heterocycle: 1-'-aziridino, 1-azetidinyl, piperidino, 1-morpholinyl, 1-pyrrolidyl, parathiazan base, thiazolidyl, 1-piperazinyl, 1-imidazolyl, 3-azabicyclic (3,2,2) nonane-3-base and 1-tetrazyl, described heterocycle randomly are selected from following group independently of one another by 1-3 and replace: oxo base, C ₀-C ₄Alkyl OH, C ₀-C ₄Alkyl OC ₁-C ₄Alkyl, C ₀-C ₄Alkyl CONH ₂, C ₀-C ₄Alkyl CO ₂C ₀-C ₄Alkyl, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, C ₃-C ₇Cycloalkyl, C ₀-C ₆Alkyl-carbonyl, C ₃-C ₇Naphthene base carbonyl, C ₁-C ₆Alkoxy carbonyl, C ₃-C ₇Cyclo alkoxy carbonyl ,-NHCO alkyl, aryl, heteroaryl, aryl-alkoxy carbonyl, heteroaryl alkoxy carbonyl, C ₁-C ₆Alkyl sulphonyl, aryl sulfonyl and heteroarylsulfonyl;

R ⁹Be hydrogen or C ₁-C ₄Alkyl; And

R ¹³Be alkyl, the aryl of hydrogen, alkyl, haloalkyl, aminocarboxyl, hydroxyl, hydroxycarbonyl group, alkoxy carbonyl, cycloalkyl alkyl amino carbonyl, replacement, aryl, heteroaryl, heterocyclic radical, alkylthio, alkyl amino-carbonyl or the low-grade cycloalkyl of replacement; Wherein the substituting group on the alkyl is selected from one to four and is selected from following substituting group: halogeno-group, hydroxyl, alkoxyl group, oxo base (=O), alkyloyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aryl alkyl amino, dibasic amine, wherein 2 amino substituting groups are selected from alkyl, aryl or aralkyl; The aralkyl amido of the alkyl amido of alkyl amido, aromatic acylamino, aralkyl amido, replacement, the arylamino of replacement, replacement, sulfydryl, alkylthio, arylthio, aromatic alkylthio, alkyl sulfide carbonyl, aryl thiocarbonyl group, aralkyl thiocarbonyl group, alkyl sulphonyl, aryl sulfonyl, aralkyl alkylsulfonyl, sulfonamido be SO for example ₂NH ₂, the sulfonamido, nitro, cyano group, carboxyl, formamyl that replace CONH for example ₂, the formamyl that replaces for example CONH alkyl, CONH aryl, CONH aralkyl or wherein on the nitrogen two substituent situations that are selected from alkyl, aryl or aralkyl are arranged; Alkoxy carbonyl; aryl; the aryl that replaces; heterocycle guanidine radicals and replacement or unsubstituted; indyl for example; imidazolyl; furyl; thienyl; thiazolyl; pyrrolidyl; pyridyl; pyrimidyl etc., the substituting group on the aryl are selected from one to four and are selected from following substituting group: alkyl; the alkyl that replaces; haloalkyl; halogeno-group; trifluoromethoxy; trifluoromethyl; hydroxyl; hydroxyalkyl; aminoalkyl group; alkoxyl group; alkyloyl; alkanoyloxy; amino; arylamino; aryl alkyl amino; dialkyl amido; alkyl amido; sulfydryl; alkylthio; urea groups; nitro; cyano group; the cyano group alkyl; heterocyclic radical; carboxyl; carboxyalkyl; formamyl; alkoxy carbonyl; aminocarboxyl; the alkyl sulfide carbonyl; the aryl thiocarbonyl group; aryl sulfonic acid amides; sulfonic acid; alkyl sulphonyl; sulfonamido; aryloxy and CONR ^aR ^b, R wherein ^aAnd R ^bBe selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxycarbonyl amino alkyl and alkylamino; Perhaps R ^aAnd R ^bConstitute 3-6 unit's heterocyclic radical or heteroaryl ring with the nitrogen that they replaced; Substituting group can further be replaced by the alkyl of the aryl of hydroxyl, alkyl, alkoxyl group, aryl, replacement, replacement or aralkyl.

2. the compound of claim 1, wherein R ¹Be low alkyl group, low-grade cycloalkyl, alkenyl or alkynyl.

3. the compound of claim 1 or claim 2, wherein R ¹Be methyl, halogeno-group, hydroxyl, low alkyl group, low-grade cycloalkyl, low-grade alkynyl, trifluoromethyl, methoxyl group, trifluoromethoxy, cyano group ,-NH ₂Or-NR ⁴R ⁵

4. the compound of claim 1-3, wherein R ¹Be methyl, halogeno-group, hydroxyl, low alkyl group, low-grade cycloalkyl, low-grade alkynyl, trifluoromethyl, methoxyl group, trifluoromethoxy, cyano group ,-NH ₂,-NR ⁴R ⁵Or-OR ⁴

5. the compound of claim 1-4, wherein R ¹Be methyl, hydroxyl, low alkyl group, low-grade cycloalkyl, low-grade alkynyl, trifluoromethyl, methoxyl group, trifluoromethoxy, cyano group ,-NH ₂,-NR ⁴R ⁵Or-OR ⁴

6. the compound of claim 1-5, wherein R ¹It is low alkyl group.

7. the compound of claim 1-6, wherein R ¹It is methyl.

8. the compound of claim 1-7, wherein R ²It is alkyl or cycloalkyl.

9. the compound of claim 1-8, wherein R ²It is alkyl.

10. the compound of claim 1-9, wherein R ²Be hydrogen.

11. the compound of claim 1-10, wherein R ³Be selected from alkyl, cycloalkyl, heterocyclic radical and the heteroaryl of hydrogen, alkyl, replacement.

12. the compound of claim 1-10, wherein R ³Be selected from alkyl ,-OR ⁴, replace alkyl, cycloalkyl ,-CR ⁴The heterocycle of the heteroaryl of cycloalkyl, heteroaryl, replacement, heterocycle and replacement.

13. the compound of claim 1-12, wherein R ³Be cycloalkyl, cycloalkylalkyl, alkoxyalkyl or heteroaryl.

14. the compound of claim 1-13, wherein R ³Be methyl, sec.-propyl, ethyl, cyclopropyl, cyclopropyl methyl, methoxymethyl,  azoles base or thiazolyl.

15. the compound of claim 1-14, wherein R ³It is cyclopropyl.

16. the compound of claim 1-15, wherein Y be-C (=O) NH-or-SO ₂NH-.

17. the compound of claim 1-16, wherein Y is-C (=O) NH-.

18. the compound of claim 1-17, wherein X ¹Be singly-bound or alkylidene group.

19. the compound of claim 1-18, wherein X ¹Be singly-bound or-CH ₂-.

20. the compound of claim 1-19, wherein X ¹It is singly-bound.

21. the compound of claim 1-20, wherein A is the bicyclic heterocycles ring system, and wherein each ring contains at least one N atom, and randomly by two R at the most ¹³Replace.

22. the compound of claim 1-21, wherein A is the bicyclic heteroaryl ring system, and wherein each ring contains at least one N atom, and randomly by two R at the most ¹³Replace.

23. the compound of claim 1-22, wherein A is the bicyclic heteroaryl ring system, and wherein each ring contains two N atoms, and randomly by two R at the most ¹³Replace.

24. the compound of claim 1-23, wherein A is imidazopyrimidine, pyrazolopyrimidine, imidazopyrimidine ketone or pyrazolopyrimidine ketone groups.

25. the compound of claim 1-24, wherein A is imidazopyrimidine or pyrazolopyrimidine group.

26. the compound of claim 1-25, wherein X ²Be singly-bound, alkylidene group or-NH-.

27. the compound of claim 1-26, wherein X ²Be singly-bound ,-CH ₂-or-NH-.

28. the compound of claim 1-27, wherein X ²It is singly-bound.

29. the compound of claim 1-28, wherein D is heterocyclic radical, cycloalkyl, heteroaryl or aryl, and randomly by one to four, be one or two (CR in one embodiment ⁹R ¹⁰) _wThe E group replaces.

30. the compound of claim 1-29, wherein D is cyclohexyl, cyclopentyl, pyridyl, pyrimidyl, pyrrolidyl, piperidyl or phenyl, and randomly by one to four, be one or two (CR in one embodiment ⁹R ¹⁰) _wThe E group replaces.

31. the compound of claim 1-30, wherein D is a phenyl, and randomly by one to four, be one or two (CR in one embodiment ⁹R ¹⁰) _wThe E group replaces.

32. the compound of claim 1-31, wherein R ¹³Be alkyl, OH or NH ₂

33. the compound of claim 1-32, wherein R ¹³Be methyl, OH or NH ₂

34. the compound of claim 1-33, wherein (CR ⁹R ¹⁰) _wE be alkyl, alkoxyl group, halogeno-group ,-the CH2-heterocyclic radical ,-CONH-cycloalkyl, alkyl sulphonyl, alkylthio, alkyl sulfonyl amino, haloalkyl, aminocarboxyl, plan halogeno-group or heterocyclic radical, perhaps replace two (CR that D goes up adjacent atom ⁹R ¹⁰) _wThe E group constitutes alkylene dioxo base together.

35. the compound of claim 1-34, wherein (CR ⁹R ¹⁰) _wE is methoxyl group, methyl, 1; 2; 4-triazolyl, methyl sulphonyl, oxyethyl group, 4-methyl isophthalic acid-piperazinyl methyl, fluorine, chlorine, cyclohexyl aminocarboxyl, methanesulfonamido, methylthio group, 4-morpholinyl, trifluoromethyl, aminocarboxyl, iodine, cyano group or cyclopropyl aminocarboxyl perhaps replace two (CR that D goes up adjacent atom ⁹R ¹⁰) _wThe E group constitutes methylene-dioxy or ethylenedioxy together.

36. the compound of claim 1-35, wherein this compound has formula II:

Wherein k is 0 to 4 integer.

37. any one compound among the claim 1-35, wherein this compound has formula III:

Wherein k is 0 to 4 integer.

38. the compound of claim 1-35, wherein this compound has formula IV:

Wherein k is 0 to 4 integer.

39. the compound of claim 1-35, wherein this compound has formula V:

Wherein k is 0 to 4 integer.

40. the compound of claim 1-35, wherein this compound has formula VI:

Wherein k is 0 to 4 integer.

41. the compound of claim 1-35, wherein this compound has formula VII:

Wherein f is 0 to 3 integer.

42. the compound of claim 1-35, wherein this compound has formula VIII:

Wherein f is 0 to 3 integer.

43. the compound of claim 1-35, wherein this compound has formula IX:

Wherein k is 0 to 4 integer.

44. the compound of claim 1-35, wherein this compound has formula X:

Wherein k is 0 to 4 integer.

45. the compound of claim 1-35, wherein this compound has formula XI:

Wherein k is 0 to 4 integer.

46. the compound of claim 1-35, wherein this compound has formula XII:

Wherein k is 0 to 4 integer.

47. the compound of claim 1-35, wherein this compound has formula XIII:

Wherein k is 0 to 4 integer.

48. the compound of claim 1-35, wherein this compound has formula XIV:

Wherein f is 0 to 3 integer.

49. the compound of claim 1-35, wherein this compound has formula XV:

Wherein f is 0 to 3 integer.

50. the compound of claim 1-49, wherein this compound is selected from those shown in the embodiment.

51. pharmaceutical composition, it comprises compound any among claim 1-50 and the 95-103 and pharmaceutically acceptable carrier.

52. the pharmaceutical composition of claim 51, it is formulated into for single dose and uses.

53. be used for the treatment of the claim 1-50 of the kinase mediated disease of p38 and the compound of 95-103.

54. the purposes of the compound of claim 1-50 and 95-103 in the preparation medicine, described medicine is used for the treatment of the kinase mediated disease of p38.

55. treat, prevent or improve the method for one or more symptoms of disease or obstacle, described disease or obstacle are subjected to the influence of the regulation and control of cytokine activity or alternate manner or wherein involve cytokine activity, and this method comprises the formula I compound of the patient that needs are arranged being used significant quantity:

Or its pharmaceutically acceptable derivates, wherein:

N is 0,1 or 2;

W is the integer of 0-4;

R ¹⁰Be selected from H, C ₁-C ₄Alkyl hydroxy, C ₁-C ₄Alkylaryl and C ₁-C ₄Miscellaneous alkyl aryl, wherein said aryl or heteroaryl are unsubstituted or are independently selected from following group by 1-3 and replace: halogeno-group, NO ₂, C ₁-C ₄Alkyl, C ₃-C ₁₀Cycloalkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, haloalkyl, halogenated alkoxy, OH, C ₁-C ₄Alkoxyl group, C ₁-C ₄Alkyl-carbonyl, CN, NH ², NR ⁶R ⁷, SR ⁶, S (O) R ⁶, SO ₂R ⁶, SO ₃R ⁶, SO ₂NR ⁶, CO ₂H, CO ₂R ⁶And CONR ⁶R ⁷

E is selected from H, halogen, NO₂、C ₁-C ₄Alkyl, C₃-C ₁₀Cycloalkyl, C₂-C ₆Alkenyl, C₂-C ₆Alkynyl, haloalkyl, halogenated alkoxy, OH, OR⁶、CN、CHO、CO ₂R ⁶、 CONR ⁶R ⁷、OCOR ₆、OC(＝O)OR ⁶、OC(＝O)NR ⁶R ⁷、OCH ₂CO ₂R ⁶、C(＝O)R ⁶、 NH ₂、NHR ⁶、NR ⁶R ⁷、NR ⁷C(＝O)R ⁶、NR ⁷C(＝O)OR ⁶、NR ⁷C(＝O)C(＝O)OR ⁶、 NR ⁷C(＝O)C(＝O)NR ⁶R ⁷、NR ⁷C(＝O)C(＝O)(C ₁-C ₆Alkyl), NR⁷C(＝NCN)OR ⁶、 NR ⁷C(＝O)NR ⁶R ⁷、NR ⁷C(＝NCN)NR ⁶R ⁷、NR ⁷C(＝NR ⁶)NR ⁷R ⁸、 NR ⁶SO ₂NR ⁶R ⁷、NR ⁷SO ₂R ⁶、SR ⁶、S(＝O)R ⁶、SO ₂R ⁶、SO ₃R ⁷、SO ₂NR ⁶R ⁷、 NHOH、NHOR ⁶、NR ⁶NR ⁷NR ⁸、N(COR ⁶)OH、N(CO ₂R ⁶)OH、 CONR ⁷(CR ⁹R ¹⁰) _rR ⁶、CO(CR ⁹R ¹⁰) _pO(CHR ⁹) _qCO ₂R ⁶、CO(CR ⁹CR ¹⁰) _rR ⁶、 CO(CR ⁹R ¹⁰) _pO(CR ⁹R ¹⁰) _pO(CHR ⁹) _qCO ₂R ⁶、CO(CR ⁹CR ¹⁰) _rOR ⁶、 CO(CR ⁹R ¹⁰) _pO(CR ⁹R ¹⁰) _qR ⁶、CO(CR ⁶CR ¹⁰) _rNR ⁶R ⁷、 OC(O)O(CR ⁹R ¹⁰) _mNR ⁶R ⁷、O(CO) _n(CR ⁹R ¹⁰)R ⁶、O(CR ⁹R ¹⁰) _mNR ⁶R ⁷、 NR ⁷C(O)(CR ⁹R ¹⁰) _rOR ⁶、NR ⁷C(＝NC)(CR ⁹R ¹⁰) _rR ⁶、NR ⁷CO(CR ⁹R ¹⁰) _rNR ⁶R ⁷、 NR ⁷(CR ⁹R ¹⁰) _mOR ⁶、NR ⁷(CR ⁹R ¹⁰) _rCO ₂R ⁶、NR ⁷(CR ⁹R ¹⁰) _mNR ⁶R ⁷、NR ⁷、 NR ³(CR ⁹R ¹⁰) _nSO ₂(CR ⁹R ¹⁰) _rCO ₂R ⁶、NR ⁷(CR ⁹R ¹⁰) _mNR ⁶R ⁷、 NR ⁷(CR ⁹R ¹⁰) _nSO ₂(CR ⁹R ¹⁰) _qR ⁶、CONR ⁷(CR ⁹R ¹⁰) _nSO ₂(CR ⁹R ¹⁰) _qR ⁶、 SO ₂NR ⁷(CR ⁹R ¹⁰) _qR ⁶、SO ₂NR ⁶(CR ⁹R ¹⁰) _mOR ⁶、C ₂-C ₆Alkenyl, C₃-C ₁₀Cycloalkyl, C₃-C ₁₀Methyl cycloalkyl, aryl, the heterocyclic radical that randomly by one or two alkyl, is replaced, the heteroaryl and the alkylaryl that randomly by one or two alkyl, are replaced, wherein said aryl is unsubstituted or by 1 or 2, is selected from independently of one another R¹²Substituting group replace, two E groups that perhaps replace the upper adjacent atom of D form alkylene dioxo base, the inferior alkoxyl of sulfo-or alkylene two sulfo-oxygen bases together;

M is the integer of 2-6;

P is the integer of 1-3;

Q is the integer of 0-3;

R is the integer of 0-6;

R ⁴Be hydrogen, low alkyl group and low-grade cycloalkyl;

R ⁵Be hydrogen, low alkyl group and low-grade cycloalkyl;

R ⁶, R ⁷And R ⁸Following independently selection:

R ⁹Be hydrogen or C ₁-C ₄Alkyl; And

56. the method for claim 55, wherein cytokine activity is subjected to the p38 kinase regulatory.

57. the method for claim 55 or 56, wherein the p38 kinases is p38 α, p38 β, p38 γ or p38 δ.

58. any one method among the claim 55-57, wherein said disease or obstacle are selected from inflammatory diseases, autoimmune disorder, destructive bone disorders, proliferative disorder, vasculogenesis sexual dysfunction, infectious diseases, neurodegenerative disease and virus disease.

59. the method for claim 58, wherein said inflammatory diseases is selected from acute pancreatitis, chronic pancreatitis, asthma, transformation reactions and adult respiratory distress syndrome.

60. the method for claim 58, wherein said autoimmune disorder are selected from glomerulonephritis, rheumatoid arthritis, systemic lupus erythematous, scleroderma, chronic thyroiditis, Graves disease, autoimmunity gastritis, insulin-dependent diabetes mellitus (type i diabetes), autoimmune hemolytic anemia, the minimizing of autoimmunity neutrophilic leukocyte, thrombopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel, ulcerative colitis, crohn, psoriatic and graft versus host disease (GVH disease).

61. the method for claim 58, wherein said destructive bone disorders is selected from osteoporosis, osteoarthritis and the bone disorders relevant with multiple myeloma.

62. the method for claim 58, wherein said proliferative disorder is selected from acute myeloid leukaemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi sarcoma and multiple myeloma.

63. the method for claim 58, wherein said infectious diseases is selected from sepsis, septic shock and shigellosis.

64. the method for claim 58, wherein said virus disease are selected from, and acute hepatitis infects (comprising hepatitis A, hepatitis B and hepatitis C), HIV infects and the CMV retinitis.

65. the method for claim 58, wherein said degenerative disease are selected from acute alzheimer's disease, Parkinson's disease, cerebral ischemia and other neurodegenerative disease.

66. the method for claim 55, wherein said disease or obstacle are subjected to the influence of active regulation and control of cytokine IL-1, TNF, IL-6 or IL-8 or alternate manner.

67. the method for claim 66, wherein said disease or obstacle are subjected to the influence of active regulation and control of cytokine IL-1 or alternate manner.

68. the method for claim 65 or 66, the wherein disease of cytokine IL-1 regulation and control or the obstacle Inflammatory response, inflammatory bowel, tuberculosis, atherosclerosis, myodegeneration, emaciation, psoriatic arthritis, reiter syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, diabetes, pancreas beta cell disease and the alzheimer's disease that are selected from rheumatoid arthritis, osteoarthritis, apoplexy, endotoxemia and/or toxic shock syndrome, endotaxin induction.

69. the method for claim 66 or 67, wherein the disease or the obstacle of cytokine TNF regulation and control are selected from rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, urarthritis and other disorder of joint, sepsis, septic shock, endotoxin shock, the Gram-negative sepsis, toxic shock syndrome, the adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, sarcoidosis of lung, bone resorption disease, reperfusion injury, graft-vs-host reaction, allograft rejection, heating that infection causes and myalgia, be secondary to the emaciation of infection, AIDS, malignant tumour, keloid forms, scar tissue forms, crohn, ulcerative colitis or pyresis.

70. the method for claim 66 or 67, wherein the disease or the obstacle of cytokine TNF regulation and control are relevant with virus infection.

71. the method for claim 70, wherein said virus infection is selected from HIV, CMV, influenza and bleb.

72. the method for claim 70, wherein said virus infection are to be infected by the animal disease poison that equine infectious anemia virus, goat arthritis virus, visna virus, chronic progress pneumonia virus of sheep, retroviral infection are caused.

73. the method for claim 66 or 67, wherein the disease or the obstacle of cytokine IL-8 regulation and control are selected from psoriatic, inflammatory bowel, asthma, heart reperfusion injury, renal reperfusion injury, adult respiratory distress syndrome, thrombosis and glomerulonephritis.

74. reduce the method that the induction type proinflammatory protein is expressed, it comprises the formula I compound of the patient that needs are arranged being used significant quantity:

Or its pharmaceutically acceptable derivates, wherein:

N is 0,1 or 2;

W is the integer of 0-4;

M is the integer of 2-6;

P is the integer of 1-3;

Q is the integer of 0-3;

R is the integer of 0-6;

R ⁴Be hydrogen, low alkyl group and low-grade cycloalkyl;

R ⁵Be hydrogen, low alkyl group and low-grade cycloalkyl;

R ⁶, R ⁷And R ⁸Following independently selection:

R ⁹Be hydrogen or C ₁-C ₄Alkyl; And

R ¹³Be alkyl, the aryl of hydrogen, alkyl, haloalkyl, aminocarboxyl, hydroxyl, hydroxycarbonyl group, alkoxy carbonyl, cycloalkyl alkyl amino carbonyl, replacement, aryl, heteroaryl, heterocyclic radical, alkylthio, alkyl amino-carbonyl or the low-grade cycloalkyl of replacement; Wherein the substituting group on the alkyl is selected from one to four and is selected from following substituting group: halogeno-group, hydroxyl, alkoxyl group, oxo base (=O), alkyloyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aryl alkyl amino, dibasic amine, wherein 2 amino substituting groups are selected from alkyl, aryl or aralkyl; The aralkyl amido of the alkyl amido of alkyl amido, aromatic acylamino, aralkyl amido, replacement, the arylamino of replacement, replacement, sulfydryl, alkylthio, arylthio, aromatic alkylthio, alkyl sulfide carbonyl, aryl thiocarbonyl group, aralkyl thiocarbonyl group, alkyl sulphonyl, aryl sulfonyl, aralkyl alkylsulfonyl, sulfonamido be SO for example ₂NH ₂, the sulfonamido, nitro, cyano group, carboxyl, formamyl that replace CONH for example ₂, the formamyl that replaces for example CONH alkyl, CONH aryl, CONH aralkyl or wherein on the nitrogen two substituent situations that are selected from alkyl, aryl or aralkyl are arranged; Alkoxy carbonyl; aryl; the aryl that replaces; heterocycle guanidine radicals and replacement or unsubstituted; indyl for example; imidazolyl; furyl; thienyl; thiazolyl; pyrrolidyl; pyridyl; pyrimidyl etc., the substituting group on the aryl are selected from one to four and are selected from following substituting group: alkyl; the alkyl that replaces; haloalkyl; halogeno-group; trifluoromethoxy; trifluoromethyl; hydroxyl; hydroxyalkyl; aminoalkyl group; alkoxyl group; alkyloyl; alkanoyloxy; amino; arylamino; aryl alkyl amino; dialkyl amido; alkyl amido; sulfydryl; alkylthio; urea groups; nitro; cyano group; the cyano group alkyl; heterocyclic radical; carboxyl; carboxyalkyl; formamyl; alkoxy carbonyl; aminocarboxyl; the alkyl sulfide carbonyl; the aryl thiocarbonyl group; aryl sulfonic acid amides; sulfonic acid; alkyl sulphonyl; sulfonamido; aryloxy and CONR ^aR ^b, R wherein ^aAnd R ^bBe selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxycarbonyl amino alkyl and alkylamino; Perhaps R ^aAnd R ^bConstitute 3-6 unit's heterocyclic radical or heteroaryl ring with the nitrogen that they replaced.Substituting group can further be replaced by the alkyl of the aryl of hydroxyl, alkyl, alkoxyl group, aryl, replacement, replacement or aralkyl.

75. the method for claim 74, wherein said proinflammatory protein are prostaglandin endoperoxide synthase-2 (PGHS-2).

76. the method for one or more symptoms of treatment, prevention or improvement and induction type proinflammatory protein diseases associated or obstacle, it comprises uses formula I compound to the curee that needs are arranged:

Or its pharmaceutically acceptable derivates, wherein:

N is 0,1 or 2;

W is the integer of 0-4;

M is the integer of 2-6;

P is the integer of 1-3;

Q is the integer of 0-3;

R is the integer of 0-6;

R ¹²When occurring, be independently selected from halogeno-group, NO at every turn ₂, C ₁-C ₄Alkyl, C ₃-C ₁₀Cycloalkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, haloalkyl, halogenated alkoxy, OH, oxo base, C ₁-C ₄Alkoxyl group, OR ⁶, O (CR ⁹R ¹⁰) CO ₂R ⁶, O (CR ⁹R ¹⁰) _mNR ⁶R ⁷, O (CR ⁹R ¹⁰) _pCN, O (CR ⁹R ¹⁰) _rC (=O) NR ⁶R ⁷, C ₁-C ₄Alkyl-carbonyl, CN, NH ₂, NHR ⁶, NR ⁶R ⁷, NR ⁷(CR ⁹R ¹⁰) CO ₂R ⁶, NR ⁷OR ⁶, NR ⁷(CR ⁹R ¹⁰) _mOR ⁶, NR ⁷CH ((CR ⁹R ¹⁰) _pOR ⁶) ₂, NR ⁷C ((CR ⁹R ¹⁰) _pOR ⁶) ₃, NR ⁷C (=O) R ⁶, NR ⁷(CR ⁹R ¹⁰) _mNR ⁶R ⁷, NR ⁷(CR ⁹R ¹⁰) _qR ⁶, SR ⁷, S (O) R ⁷, SO ₂R ⁷, SO ₂NR ⁶, SO ³R ₇, CO ₂H, CO ₂R ⁶And CONR ⁶R ⁷

R ⁴Be hydrogen, low alkyl group and low-grade cycloalkyl;

R ⁵Be hydrogen, low alkyl group and low-grade cycloalkyl;

R ⁶, R ⁷And R ⁸Following independently selection:

R ⁹Be hydrogen or C ₁-C ₄Alkyl; And

77. the method for claim 76, wherein said disease or obstacle are selected from pain, toothache and arthritis ache that oedema, analgesia, heating, pain, neuromuscular pain, headache, cancer cause.

78. suppress the method for p38 kinase activity, it comprises the formula I compound of the patient that needs are arranged being used significant quantity:

Or its pharmaceutically acceptable derivates, wherein:

N is 0,1 or 2;

W is the integer of 0-4;

E is selected from H, halogen, NO₂、C ₁-C ₄Alkyl, C₃-C ₁₀Cycloalkyl, C₂-C ₆Alkenyl, C₂-C ₆Alkynyl, haloalkyl, halogenated alkoxy, OH, OR⁶、CN、CHO、CO ₂R ⁶、 CONR ⁶R ⁷、OCOR ₆、OC(＝O)OR ⁶、OC(＝O)NR ⁶R ⁷、OCH ₂CO ₂R ⁶、C(＝O)R ⁶、 NH ₂、NHR ⁶、NR ⁶R ⁷、NR ⁷C(＝O)R ⁶、NR ⁷C(＝O)OR ⁶、NR ⁷C(＝O)C(＝O)OR ⁶、 NR ⁷C(＝O)C(＝O)NR ⁶R ⁷、NR ⁷C(＝O)C(＝O)(C ₁-C ₆Alkyl), NR⁷C(＝NCN)OR ⁶、 NR ⁷C(＝O)NR ⁶R ⁷、NR ⁷C(＝NCN)NR ⁶R ⁷、NR ⁷C(＝NR ⁶)NR ⁷R ⁸、 NR ⁶SO ₂NR ⁶R ⁷、NR ⁷SO ₂R ⁶、SR ⁶、S(＝O)R ⁶、SO ₂R ⁶、SO ₃R ⁷、SO ₂NR ⁶R ⁷、 NHOH、NHOR ⁶、NR ⁶NR ⁷NR ⁸、N(COR ⁶)OH、N(CO ₂R ⁶)OH、 CONR ⁷(CR ⁹R ¹⁰) _rR ⁶、CO(CR ⁹R ¹⁰) _pO(CHR ⁹) _qCO ₂R ⁶、CO(CR ⁹CR ¹⁰) _rR ⁶、 CO(CR ⁹R ¹⁰) _pO(CR ⁹R ¹⁰) _pO(CHR ⁹) _qCO ₂R ⁶、CO(CR ⁹CR ¹⁰) _rOR ⁶、 CO(CR ⁹R ¹⁰) _pO(CR ⁹R ¹⁰) _qR ⁶、CO(CR ⁶CR ¹⁰) _rNR ⁶R ⁷、 OC(O)O(CR ⁹R ¹⁰) _mNR ⁶R ⁷、O(CO) _n(CR ⁹R ¹⁰)R ⁶、O(CR ⁹R ¹⁰) _mNR ⁶R ⁷、 NR ⁷C(O)(CR ⁹R ¹⁰) _rOR ⁶、NR ⁷C(＝NC)(CR ⁹R ¹⁰) _rR ⁶、NR ⁷CO(CR ⁹R ¹⁰) _rNR ⁶R ⁷、 NR ⁷(CR ⁹R ¹⁰) _mOR ⁶、NR ⁷(CR ⁹R ¹⁰) _rCO ₂R ⁶、NR ⁷(CR ⁹R ¹⁰) _mNR ⁶R ⁷、NR ⁷、 NR ³(CR ⁹R ¹⁰) _nSO ₂(CR ⁹R ¹⁰) _rCO ₂R ⁶、NR ⁷(CR ⁹R ¹⁰) _mNR ⁶R ⁷、 NR ⁷(CR ⁹R ¹⁰) _nSO ₂(CR ⁹R ¹⁰) _qR ⁶、CONR ⁷(CR ⁹R ¹⁰) _nSO ₂(CR ⁹R ¹⁰) _qR ⁶、 SO ₂NR ₇(CR ⁹R ¹⁰) _qR ⁶、SO ₂NR ⁶(CR ⁹R ¹⁰) _mOR ⁶、C ₂-C ₆Alkenyl, C₃-C ₁₀Cycloalkyl, C₃-C ₁₀Methyl cycloalkyl, aryl, the heterocyclic radical that randomly by one or two alkyl, is replaced, the heteroaryl and the alkylaryl that randomly by one or two alkyl, are replaced, wherein said aryl is unsubstituted or by 1 or 2, is selected from independently of one another R¹²Substituting group replace, two E groups that perhaps replace the upper adjacent atom of D form alkylene dioxo base, the inferior alkoxyl of sulfo-or alkylene two sulfo-oxygen bases together;

M is the integer of 2-6;

P is the integer of 1-3;

Q is the integer of 0-3;

R is the integer of 0-6;

R ⁴Be hydrogen, low alkyl group and low-grade cycloalkyl;

R ⁵Be hydrogen, low alkyl group and low-grade cycloalkyl;

R ⁶, R ⁷And R ⁸Following independently selection:

I) R ⁶, R ⁷And R ⁸Be independently selected from H, C ₁-C ₆Alkyl, C ₃-C ₁₀Cycloalkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₁-C ₆Alkyl-carbonyl, C ₃-C ₇Cycloalkyl (C ₀-C ₅Alkyl) carbonyl, C ₁-C ₆Alkoxy carbonyl, aryl (C ₀-C ₅Alkyl) carbonyl, aryl (C ₁-C ₅Alkoxyl group) carbonyl, heterocyclic radical (C ₀-C ₅Alkyl) carbonyl, heterocyclic radical (C ₁-C ₅Alkoxyl group) carbonyl, C ₁-C ₆Alkyl sulphonyl, aryl sulfonyl, heteroarylsulfonyl, C ₀-C ₄Alkylaryl, C ₀-C ₄Alkyl heterocyclic, wherein said cycloalkyl, aryl or heterocyclic radical are unsubstituted or are selected from following substituting group independently of one another by 1 or 2 and replace: C ₁-C ₄Alkyl, hydroxyl, C ₁-C ₄Alkoxyl group, F, Cl, Br, haloalkyl, NO ₂CN; Perhaps,

R ⁹Be hydrogen or C ₁-C ₄Alkyl; And

79. the method for claim 78, wherein the p38 kinases is selected from p38 alpha kinase, p38 beta kinase, p38 γ kinases and p38 δ kinases.

80. the method for claim 78 or 79, wherein the p38 kinases is selected from p38 alpha kinase and p38 beta kinase.

81. the method for claim 55, wherein said disease or obstacle are selected from pancreatitis, asthma, transformation reactions, the adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematous, scleroderma, chronic thyroiditis, Graves disease, autoimmunity gastritis, diabetes, autoimmune hemolytic anemia, the autoimmunity neutrophilic leukocyte reduces, thrombopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel, ulcerative colitis, crohn, psoriatic, graft versus host disease (GVH disease), the Inflammatory response of endotaxin induction, tuberculosis, atherosclerosis, myodegeneration, emaciation, psoriatic arthritis, reiter syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, pancreas beta cell disease; Soaking into a large amount of neutrophils is the disease of feature; Rheumatoid spondylitis, urarthritis and other disorder of joint, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, sarcoidosis of lung, bone resorption disease, allograft rejection, heating that infection causes and myalgia, be secondary to the emaciation of infection, keloid forms, scar tissue forms, ulcerative colitis, pyresis, influenza, osteoporosis, osteoarthritis and the bone disorders relevant with multiple myeloma, acute myeloid leukaemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi sarcoma, multiple myeloma, sepsis, septic shock and shigellosis; Alzheimer's disease, Parkinson's disease, cerebral ischemia or the neurodegenerative disease that causes by traumatic damage; Vasculogenesis sexual dysfunction, solid tumor, eye neovascularization, infant's vascular tumor; Virus disease, acute hepatitis infection, hepatitis A, hepatitis B, hepatitis C, HIV infection, the CMV retinitis, AIDS, SARS, ARC, malignant tumour, bleb; Platelet aggregation, endotoxemia and/or the toxic shock syndrome of the ischemic in apoplexy, myocardial ischemia, the apoplexy heart attack, organ anoxic, blood vessel hyperplasia, heart and renal reperfusion injury, thrombosis, cardiac hypertrophy, thrombin induction and with the relevant illness of prostaglandin endoperoxides enzyme synthase-2.

82. suppress the active method of kinase protein, it comprises makes described albumen contact with formula I compound or its pharmaceutically acceptable derivates:

Wherein:

N is 0,1 or 2;

W is the integer of 0-4;

E is selected from H, halogen, NO₂、C ₁-C ₄Alkyl, C₃-C ₁₀Cycloalkyl, C₂-C ₆Alkenyl, C₂-C ₆Alkynyl, haloalkyl, halogenated alkoxy, OH, OR⁶、CN、CHO、CO ₂R ⁶、 CONR ⁶R ⁷、OCOR ₆、OC(＝O)OR ⁶、OC(＝O)NR ⁶R ⁷、OCH ₂CO ₂R ⁶、C(＝O)R ⁶、 NH ₂、NHR ⁶、NR ⁶R ⁷、NR ⁷C(＝O)R ⁶、NR ⁷C(＝O)OR ⁶、NR ⁷C(＝O)C(＝O)OR ⁶、 NR ⁷C(＝O)C(＝O)NR ⁶R ⁷、NR ⁷C(＝O)C(＝O)(C ₁-C ₆Alkyl), NR⁷C(＝NCN)OR ⁶、 NR ⁷C(＝O)NR ⁶R ⁷、NR ⁷C(＝NCN)NR ⁶R ⁷、NR ⁷C(＝NR ⁶)NR ⁷R ⁸、 NR ⁶SO ₂NR ⁶R ⁷、NR ⁷SO ₂R ⁶、SR ⁶、S(＝O)R ⁶、SO ₂R ⁶、SO ₃R ⁷、SO ₂NR ⁶R ⁷、 NHOH、NHOR ⁶、NR ⁶NR ⁷NR ⁸、N(COR ⁶)OH、N(CO ₂R ⁶)OH、 CONR ⁷(CR ⁹R ¹⁰) _rR ⁶、CO(CR ⁹R ¹⁰) _pO(CHR ⁹) _qCO ₂R ⁶、CO(CR ⁹CR ¹⁰) _rR ⁶、 CO(CR ⁹R ¹⁰) _pO(CR ⁹R ¹⁰) _pO(CHR ⁹) _qCO ₂R ⁶、CO(CR ⁹CR ¹⁰) _rOR ⁶、 CO(CR ⁹R ¹⁰) _pO(CR ⁹R ¹⁰) _qR ⁶、CO(CR ⁶CR ¹⁰) _rNR ⁶R ⁷、 OC(O)O(CR ⁹R ¹⁰) _mNR ⁶R ⁷、O(CO) _n(CR ⁹R ¹⁰)R ⁶、O(CR ⁹R ¹⁰) _mNR ⁶R ⁷、 NR ⁷C(O)(CR ⁹R ¹⁰) _rOR ⁶、NR ⁷C(＝NC)(CR ⁹R ¹⁰) _rR ⁶、NR ⁷CO(CR ⁹R ¹⁰) _rNR ⁶R ⁷、 NR ⁷(CR ⁹R ¹⁰) _mOR ⁶、NR ⁷(CR ⁹R ¹⁰) _rCO ₂R ⁶、NR ⁷(CR ⁹R ¹⁰) _mNR ⁶R ⁷、NR ⁷、 NR ³(C ^R9R ¹⁰) _nSO ₂(CR ⁹R ¹⁰) _rCO ₂R ⁶、NR ⁷(CR ⁹R ¹⁰) _mNR ⁶R ⁷、 NR ⁷(CR ⁹R ¹⁰) _nSO ₂(CR ⁹R ¹⁰) _qR ⁶、CONR ⁷(CR ⁹R ¹⁰) _nSO ₂(CR ⁹R ¹⁰) _qR ⁶、 SO ₂NR ⁷(CR ⁹R ¹⁰) _qR ⁶、SO ₂NR ⁶(CR ⁹R ¹⁰) _mOR ⁶、C ₂-C ₆Alkenyl, C₃-C ₁₀Cycloalkyl, C₃-C ₁₀Methyl cycloalkyl, aryl, the heterocyclic radical that randomly by one or two alkyl, is replaced, the heteroaryl and the alkylaryl that randomly by one or two alkyl, are replaced, wherein said aryl is unsubstituted or by 1 or 2, is selected from independently of one another R¹²Substituting group replace, two E groups that perhaps replace the upper adjacent atom of D form alkylene dioxo base, the inferior alkoxyl of sulfo-or alkylene two sulfo-oxygen bases together;

M is the integer of 2-6;

P is the integer of 1-3;

Q is the integer of 0-3;

R is the integer of 0-6;

R ⁴Be hydrogen, low alkyl group and low-grade cycloalkyl;

R ⁵Be hydrogen, low alkyl group and low-grade cycloalkyl;

R ⁶, R ⁷And R ⁸Following independently selection:

R ⁹Be hydrogen or C ₁-C ₄Alkyl; And

83. the method for one or more symptoms of treatment, prevention or the disease that to improve with the active imbalance of kinase protein be feature, it comprises uses formula I compound:

Or its pharmaceutically acceptable derivates, wherein:

R2When occurring, be independently selected from every turn alkyl, replacement alkyl, low-grade cycloalkyl, halogeno-group, trifluoromethyl, trifluoromethoxy ,-OR4,-CN ,-NR4R5-S (=O) alkyl ,-S (=O) aryl ,-NHSO2-arylidene-R4,-NHSO<pre TranNum="4604" listing-type="program-listing"><![CDATA[2]] 〉</pre>Alkyl ,-CO2R4,-CONH2,-SO3H ,-S (O) alkyl ,-S (O) aryl ,-SO2NHR4With-NHC (=O) NHR4

N is 0,1 or 2;

W is the integer of 0-4;

R ¹⁰Be selected from H, C ₁-C ₄Alkyl hydroxy, C ₁-C ₄Alkylaryl and C ₁-C ₄Miscellaneous alkyl aryl, wherein said aryl or heteroaryl are unsubstituted or are independently selected from following group by 1-3 and replace: halogeno-group, NO ₂, C ₁-C ₄Alkyl, C ₃-C ₁₀Cycloalkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, haloalkyl, halogenated alkoxy, OH, C ₁-C ₄Alkoxyl group, C ₁-C ₄Alkyl-carbonyl, CN, NH ₂, NR ⁶R ⁷, SR ⁶, S (O) ₂R ⁶, SO ₂R ⁶, SO ₃R ⁶, SO ₂NR ⁶, CO ₂H, CO ₂R ⁶And CONR ⁶R ⁷

M is the integer of 2-6;

P is the integer of 1-3;

Q is the integer of 0-3;

R is the integer of 0-6;

R ⁴Be hydrogen, low alkyl group and low-grade cycloalkyl;

R ⁵Be hydrogen, low alkyl group and low-grade cycloalkyl;

R ⁶, R ⁷And R ⁸Following independently selection:

R ⁹Be hydrogen or C ₁-C ₄Alkyl; And

84. the method for claim 82, wherein said kinase protein are the tyrosine-kinase zymoproteins.

85. the method for claim 82, wherein said kinase protein are FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, flt-1, IGF-1R, KDR, PDGFR, tie2 or VEGFR.

86. treat, prevent or improve the method for one or more symptoms of vascular proliferation obstacle, fibrosis obstacle, " mesangium " cell proliferation obstacle, metabolic obstacle, transformation reactions, asthma, thrombosis, nervous system disorders, retinopathy, psoriatic, rheumatoid arthritis, diabetes, myodegeneration or cancer, it comprises uses formula I compound:

Or its pharmaceutically acceptable derivates, wherein:

N is 0,1 or 2;

W is the integer of 0-4;

E is selected from H, halogen, NO₂、C ₁-C ₄Alkyl, C₃-C ₁₀Cycloalkyl, C₂-C ₆Alkenyl, C₂-C ₆Alkynyl, haloalkyl, halogenated alkoxy, OH, OR⁶、CN、CHO、CO ₂R ⁶、 CONR ⁶R ⁷、OCOR ₆、OC(＝O)OR ⁶、OC(＝O)NR ⁶R ⁷、OCH ₂CO ₂R ⁶、C(＝O)R ⁶、 NH ₂、NHR ⁶、NR ⁶R ⁷、NR ⁷C(＝O)R ⁶、NR ⁷C(＝O)OR ⁶、NR ⁷C(＝O)C(＝O)OR ⁶、 NR ⁷C(＝O)C(＝O)NR ⁶R ⁷、NR ⁷C(＝O)C(＝O)(C ₁-C ₆Alkyl), NR⁷C(＝NCN)OR ⁶、 NR ⁷C(＝O)NR ⁶R ⁷、NR ⁷C(＝NCN)NR ⁶R ⁷、NR ⁷C(＝NR ⁶)NR ⁷R ⁸、 NR ⁶SO ₂NR ⁶R ⁷、NR ⁷SO ₂R ⁶、SR ⁶、S(＝O)R ⁶、SO ₂R ⁶、SO ₃R ⁷、SO ₂NR ⁶R ⁷、 NHOH、NHOR ⁶、NR ⁶NR ⁷NR ⁸、N(COR ⁶)OH、N(CO ₂R ⁶)OH、 CONR ⁷(CR ⁹R ¹⁰) _rR ⁶、CO(CR ⁹R ¹⁰) _pO(CHR ⁹) _qCO ₂R ⁶、CO(CR ⁹CR ¹⁰) _rR ⁶、 CO(CR ⁹R ¹⁰) _pO(CR ⁹R ¹⁰) _pO(CHR ⁹) _qCO ₂R ⁶、CO(CR ⁹CR ¹⁰) _rOR ⁶、 CO(CR ⁹R ¹⁰) _pO(CR ⁹R ¹⁰) _qR ⁶、CO(CR ⁶CR ¹⁰) _rNR ⁶R ⁷、 OC(O)O(CR ₉R ¹⁰) _mNR ⁶R ⁷、O(CO) _n(CR ⁹R ¹⁰)R ⁶、O(CR ⁹R ¹⁰) _mNR ⁶R ⁷、 NR ⁷C(O)(CR ₉R ¹⁰) _rOR ⁶、NR ⁷C(＝NC)(CR ⁹R ¹⁰) _rR ⁶、NR ⁷CO(CR ⁹R ¹⁰) _rNR ⁶R ⁷、 NR ⁷(CR ⁹R ¹⁰) _mOR ⁶、NR ⁷(CR ⁹R ¹⁰) _rCO ₂R ⁶、NR ⁷(CR ⁹R ¹⁰) _mNR ⁶R ⁷、NR ⁷、 NR ³(CR ⁹R ¹⁰) _nSO ₂(CR ⁹R ¹⁰) _rCO ₂R ⁶、NR ⁷(CR ⁹R ¹⁰) _mNR ⁶R ⁷、 NR ⁷(CR ⁹R ¹⁰) _nSO ₂(CR ⁹R ¹⁰) _qR ⁶、CONR ⁷(CR ⁹R ¹⁰) _nSO ₂(CR ⁹R ¹⁰) _qR ⁶、 SO ₂NR ⁷(CR ⁹R ¹⁰) _qR ⁶、SO ₂NR ⁶(CR ⁹R ¹⁰) _mOR ⁶、C ₂-C ₆Alkenyl, C₃-C ₁₀Cycloalkyl, C₃-C ₁₀Methyl cycloalkyl, aryl, the heterocyclic radical that randomly by one or two alkyl, is replaced, the heteroaryl and the alkylaryl that randomly by one or two alkyl, are replaced, wherein said aryl is unsubstituted or by 1 or 2, is selected from independently of one another R¹²Substituting group replace, two E groups that perhaps replace the upper adjacent atom of D form alkylene dioxo base, the inferior alkoxyl of sulfo-or alkylene two sulfo-oxygen bases together;

M is the integer of 2-6;

P is the integer of 1-3;

Q is the integer of 0-3;

R is the integer of 0-6;

R ⁴Be hydrogen, low alkyl group and low-grade cycloalkyl;

R ⁵Be hydrogen, low alkyl group and low-grade cycloalkyl;

R ⁶, R ⁷And R ⁸Following independently selection:

R ⁹Be hydrogen or C ₁-C ₄Alkyl; And

87. the method for one or more symptoms of the disease of treatment, prevention or improvement and associated angiogenesis out of control, it comprises uses formula I compound:

Or its pharmaceutically acceptable derivates, wherein:

N is 0,1 or 2;

W is the integer of 0-4;

M is the integer of 2-6;

P is the integer of 1-3;

Q is the integer of 0-3;

R is the integer of 0-6;

R ⁴Be hydrogen, low alkyl group and low-grade cycloalkyl;

R ⁵Be hydrogen, low alkyl group and low-grade cycloalkyl;

R ⁶, R ⁷And R ⁸Following independently selection:

R ⁹Be hydrogen or C ₁-C ₄Alkyl; And

88. treat, prevent or improve the method for one or more symptoms of tumor disease, it comprises uses formula I compound:

Or its pharmaceutically acceptable derivates, wherein:

N is 0,1 or 2;

W is the integer of 0-4;

E is selected from H, halogen, NO₂、C ₁-C ₄Alkyl, C₃-C ₁₀Cycloalkyl, C₂-C ₆Alkenyl, C₂-C ₆Alkynyl, haloalkyl, halogenated alkoxy, OH, OR⁶、CN、CHO、CO ₂R ⁶、 CONR ⁶R ⁷、OCOR ₆、OC(＝O)OR ⁶、OC(＝O)NR ⁶R ⁷、OCH ₂CO ₂R ⁶、C(＝O)R ⁶、 NH ₂、NHR ⁶、NR ⁶R ⁷、NR ⁷C(＝O)R ⁶、NR ⁷C(＝O)OR ⁶、NR ⁷C(＝O)C(＝O)OR ⁶、 NR ⁷C(＝O)C(＝O)NR ⁶R ⁷、NR ⁷C(＝O)C(＝O)(C ₁-C ₆Alkyl), NR⁷C(＝NCN)OR ⁶、 NR ⁷C(＝O)NR ⁶R ⁷、NR ⁷C(＝NCN)NR ⁶R ⁷、NR ⁷C(＝NR ⁶)NR ⁷R ⁸、 NR ⁶SO ₂NR ⁶R ⁷、NR ⁷SO ₂R ⁶、SR ⁶、S(＝O)R ⁶、SO ₂R ⁶、SO ₃R ⁷、SO ₂NR ⁶R ⁷、 NHOH、NHOR ⁶、NR ⁶NR ⁷NR ⁸、N(COR ⁶)OH、N(CO ₂R ⁶)OH、 CONR ⁷(CR ⁹R ¹⁰) _rR ⁶、CO(CR ⁹R ¹⁰) _pO(CHR ⁹) _qCO ₂R ⁶、CO(CR ⁹CR ¹⁰) _rR ⁶、 CO(CR ⁹R ¹⁰) _pO(CR ⁹R ¹⁰) _pO(CHR ⁹) _qCO ₂R ⁶、CO(CR ⁹CR ¹⁰) _rOR ⁶、 CO(CR ⁹R ¹⁰) _pO(CR ⁹R ¹⁰) _qR ⁶、CO(CR ⁶CR ¹⁰) _rNR ⁶R ⁷、 OC(O)O(CR ⁹R ¹⁰) _mNR ⁶R ⁷、O(CO) _n(CR ⁹R ¹⁰)R ⁶、O(CR ⁹R ¹⁰) _mNR ⁶R ⁷、 NR ⁷C(O)(CR ⁹R ¹⁰) _rOR ⁶、NR ⁷C(＝NC)(CR ⁹R ¹⁰) _rR ⁶、NR ⁷CO(CR ⁹R ¹⁰) _rNR ⁶R ⁷、 NR ⁷(CR ⁹R ¹⁰) _mOR ⁶、NR ⁷(CR ⁹R ¹⁰) _rCO ₂R ⁶、NR ⁷(CR ⁹R ¹⁰) _mNR ⁶R ⁷、NR ⁷、 NR ³(CR ⁹R ¹⁰) _nSO ₂(CR ⁹R ¹⁰) _rCO ₂R ⁶、NR ⁷(CR ⁹R ¹⁰) _mNR ⁶R ⁷、 NR ⁷(CR ⁹R ¹⁰) _nSO ₂(CR ⁹R ¹⁰) _qR ⁶、CONR ₇(CR ⁹R ¹⁰) _nSO ₂(CR ⁹R ¹⁰) _qR ⁶、 SO ₂NR ⁷(CR ⁹R ¹⁰) _qR ⁶、SO ₂NR ⁶(CR ⁹R ¹⁰) _mOR ⁶、C ₂-C ₆Alkenyl, C₃-C ₁₀Cycloalkyl, C₃-C ₁₀Methyl cycloalkyl, aryl, the heterocyclic radical that randomly by one or two alkyl, is replaced, the heteroaryl and the alkylaryl that randomly by one or two alkyl, are replaced, wherein said aryl is unsubstituted or by 1 or 2, is selected from independently of one another R¹²Substituting group replace, two E groups that perhaps replace the upper adjacent atom of D form alkylene dioxo base, the inferior alkoxyl of sulfo-or alkylene two sulfo-oxygen bases together;

M is the integer of 2-6;

P is the integer of 1-3;

Q is the integer of 0-3;

R is the integer of 0-6;

R ⁴Be hydrogen, low alkyl group and low-grade cycloalkyl;

R ⁵Be hydrogen, low alkyl group and low-grade cycloalkyl;

R ⁶, R ⁷And R ⁸Following independently selection:

R ⁹Be hydrogen or C ₁-C ₄Alkyl; And

89. treat, prevent or improve the method for one or more symptoms of cancer, it comprises uses formula I compound:

Or its pharmaceutically acceptable derivates, wherein:

N is 0,1 or 2;

W is the integer of 0-4;

M is the integer of 2-6;

P is the integer of 1-3;

Q is the integer of 0-3;

R is the integer of 0-6;

R ⁴Be hydrogen, low alkyl group and low-grade cycloalkyl;

R ⁵Be hydrogen, low alkyl group and low-grade cycloalkyl;

R ⁶, R ⁷And R ⁸Following independently selection:

R ⁹Be hydrogen or C ₁-C ₄Alkyl; And

90. the method for claim 89, wherein said disease is a solid tumor.

91. the method for claim 89 or 90, wherein said cancer pair cell toxicity medicine has resistance.

92. the method for claim 89 or 90, wherein said cancer are mammary cancer, cancer of the stomach, ovarian cancer, colorectal carcinoma, lung cancer, the cancer of the brain, laryngocarcinoma, lymphsystem cancer, the cancer that comprises the genitourinary tract of bladder and prostate gland, osteocarcinoma and carcinoma of the pancreas.

93. the method for cancer chemotherapy, it comprises uses formula I compound:

Or its pharmaceutically acceptable derivates, wherein:

N is 0,1 or 2;

W is the integer of 0-4;

M is the integer of 2-6;

P is the integer of 1-3;

Q is the integer of 0-3;

R is the integer of 0-6;

R ⁴Be hydrogen, low alkyl group and low-grade cycloalkyl;

R ⁵Be hydrogen, low alkyl group and low-grade cycloalkyl;

R ⁶, R ⁷And R ⁸Following independently selection:

R ⁹Be hydrogen or C ₁-C ₄Alkyl; And

94. any one method among the claim 55-93, wherein R ¹Be methyl, halogeno-group, hydroxyl, low alkyl group, low-grade cycloalkyl, low-grade alkynyl, trifluoromethyl, methoxyl group, trifluoromethoxy, cyano group ,-NH ₂,-NR ⁴R ⁵Or-OR ⁴Y is-C (=O) NH-,-NH (C=O)-,-NH (C=O) NH-,-SO ₂NH-,-NHSO ₂-or-C (=O)-.

95. any one compound among the claim 1-50 is if wherein D is C _1-6Alkyl, then X ²Not singly-bound or alkylidene group.

96. any one compound among the claim 1-50, wherein D is monocycle or bicyclic aromatic or non-aromatics ring system, and it randomly contains four heteroatomss that are selected from N, O and S at the most, wherein with any described N, O or the adjacent CH of S heteroatoms ₂Randomly (=O) replacement, wherein D is randomly by one to four (CR by the oxo base ⁹R ¹⁰) _wThe E group replaces.

97. any one compound among the claim 1-50, wherein D is C _1-6Alkyl, X at this moment ²Be-NH-,-N (C _1-4Alkyl)-,-NH-C _1-4Alkylidene group-,-N (C _1-4Alkyl)-C _1-4Alkylidene group-.

98. the compound of claim 1-50 and 95-97, wherein X ²Be singly-bound, alkylidene group ,-N (C _1-4Alkyl)-or-NH-.

99. the compound of claim 1-50 and 95-98, wherein X ²Be singly-bound ,-CH ₂-,-NH-,-N (Me)-,-N (Et)-,-N (n-Pr)-,-N (i-Pr)-,-NNCH ₂-or-N (n-Pr) CH ₂-.

100. the compound of claim 1-50 and 95-99; wherein D is azacinyl; diaza  base; azepine  base; thiazolyl; suberyl; two ring [2.2.1] heptyl; cyclopropyl; cyclobutyl; morpholinyl; piperazinyl; neo-pentyl; 1-methyl isopentyl; the 3-amyl group; 1; 4-oxygen azepine  base; methyl; n-propyl; ethyl; the 2-butyl; the tertiary butyl; tetrahydrofuran base; THP trtrahydropyranyl; 7-azabicyclic [2.2.1] heptyl; cyclohexyl; cyclopentyl; pyridyl; pyrimidyl; pyrrolidyl; piperidyl or phenyl, and randomly by one to four; be one or two (CR in one embodiment ⁹R ¹⁰) _wThe E group replaces.

101. the compound of claim 1-50 and 95-100; wherein D is azacinyl, diaza  base, azepine  base, thiazolyl, suberyl, two ring [2.2.1] heptyl, cyclopropyl, cyclobutyl, morpholinyl, piperazinyl, 1; 4-oxygen azepine  base, tetrahydrofuran base, THP trtrahydropyranyl, 7-azabicyclic [2.2.1] heptyl, cyclohexyl, cyclopentyl, pyridyl, pyrimidyl, pyrrolidyl, piperidyl or phenyl, and randomly by one to four, be one or two (CR in one embodiment ⁹R ¹⁰) _wThe E group replaces.

102. the compound of claim 1-50 and 95-101, wherein (CR ⁹R ¹⁰) _wE be alkyl, alkoxyl group, halogeno-group ,-CH ₂-heterocyclic radical ,-CONH-cycloalkyl, alkyl sulphonyl, alkylthio, alkyl sulfonyl amino, haloalkyl, aminocarboxyl, alkyl-carbonyl, dialkyl amino carbonyl, alkyl-carbonyl-amino, alkoxy carbonyl, hydroxyalkyl, alkoxyalkyl, heterocyclic radical alkyl, alkyl-carbonyl-N (alkyl)-, cycloalkyl amino carbonyl, alkyl amino-carbonyl, heteroaryl, dialkyl aminoalkyl, plan halogeno-group or heterocyclic radical, perhaps replace two (CR that D goes up adjacent atom ⁹R ¹⁰) _wThe E group constitutes alkylene dioxo base together.

103. the compound of claim 1-50 and 95-102, wherein (CR ⁹R ¹⁰) _wE is a methoxyl group; methyl; 1; 2; the 4-triazolyl; methyl sulphonyl; oxyethyl group; 4-methyl isophthalic acid-piperazinyl methyl; fluorine; chlorine; the cyclohexyl aminocarboxyl; methanesulfonamido; methylthio group; the 4-morpholinyl; trifluoromethyl; aminocarboxyl; methoxycarbonyl; hydroxymethyl; ethoxy carbonyl; ethyl; methoxymethyl; the methyl carbonylamino; the dimethylamino carbonyl; the methyl carbonyl; dimethylamino methyl; methyl carbonyl-N (Me)-; the diethylin methyl; the morpholinyl methyl; the methylamino carbonyl; 1; 3; 4- di azoly; the cyclopropyl aminocarboxyl; the 5-methyl isophthalic acid; 3; 4- di azoly; 5-ethyl-1; 3; 4- di azoly; iodine; cyano group or cyclopropyl aminocarboxyl perhaps replace two (CR that D goes up adjacent atom ⁹R ¹⁰) _wThe E group constitutes methylene-dioxy or ethylenedioxy together.

104. any one method among the claim 55-94, wherein said compound is selected from compound any among claim 1-50 and the 95-103.