CN1658834A - Method of treating mucus hypersecretion - Google Patents

Method of treating mucus hypersecretion Download PDF

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CN1658834A
CN1658834A CN038129884A CN03812988A CN1658834A CN 1658834 A CN1658834 A CN 1658834A CN 038129884 A CN038129884 A CN 038129884A CN 03812988 A CN03812988 A CN 03812988A CN 1658834 A CN1658834 A CN 1658834A
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伯吉特·琼
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Boehringer Ingelheim Pharma GmbH and Co KG
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Abstract

The invention relates to the use of p38 kinase inhibitors for the preparation of a pharmaceutical composition suitable for inhalation for the treatment of mucus hypersecretion. Furthermore the invention is directed to pharmaceutical compositions suitable for inhalation comprising p38 kinase inhibitors and to methods for the preparation thereof.

Description

The method of treatment Polyblennia
The present invention relates to the p38 inhibitors of kinases and be used for the treatment of purposes in the pharmaceutical composition that is suitable for sucking of Polyblennia in preparation.In addition, the present invention relates to the pharmaceutical composition that comprises the p38 inhibitors of kinases that is suitable for sucking, with and preparation method thereof.
Background of invention
Protein kinase participates in the cell response of various kinds of cell external signal.Recently, found mitogen-activated protein kinase (MAPK) family.The member of this family is for activating the Ser/Thr kinases [B.Stein etc., Ann.Rep.Med.Chem., 31, pp.289-98 (1996)] of its substrate by phosphorylation.MAPKs self comprises that by multiple signal somatomedin, cytokine, UV irradiation and pressure inducement agent are activated.
A kind of MAPK that should special concern is p38.P38, known also is cell factor inhibiting anti-inflammation drugs conjugated protein (CSBP) and RK, also obtains with separating the inductive Mus pre-B cell of LPS from transfection lipopolysaccharide (LPS) receptor CD14.P38 separates and checks order, and has obtained its this proteic cDNA of coding in volume behaviour and mice.At Pressure stimulation,, or observe the activation of p38 in the cell that infiltration stimulates and cytokine such as IL-1 and TNF handle as lipopolysaccharide (LPS), UV, anisomycin.
Find based on this, it is believed that p38 and other MAPKs play a role in the cellular response of mediation to inflammatory stimulus, as leukocyte recruitment, monocytes/macrophages activate, organize again gulp down, heating, acute phase response and neutrocytophilia.In addition, MAPKs as p38, has participated in platelet aggregation, immunodeficiency imbalance, autoimmune disease, cell death, anaphylaxis, osteoporosis and the neurodegenerative diseases of cancer, thrombin induction.By suppressing inducing of prostaglandin endoperoxide synthase-2, the p38 inhibitor has been used for pain control field.
In the conduction of the air flue of respiratory system, mucociliary system serves as primary defense mechanism and shifts out air flue in the lung with the microgranule that will suck or infectious substance.In addition, the toxicity of the material in air flue fluid restriction microgranule and stop the activity of infectious substance.The physical mechanism of cough with mucus discharge airway path (referring to, " Foundation of Respiratory Care, " Pierson and Kacmarek for example, eds. (1992) Churchill Livingstone Inc.New York, New York; " Harrison ' s Principlesof Internal Medicine ", Fauci etc., eds. (1997) 14th Edition, McGraw Hill, NewYork, New York).
Mucociliary system is by ciliated epithelial cell, epithelium goblet cell, and the serous cell and the myxocyte composition that are arranged in submucosal gland.Cilium is secreted in the airway passage inner chamber by the passive exercise of the active transport of the chloride ion by epithelium and water around, described aqueous layer by aqueous layer (cilium surrounding fluid) and forms.Cilium contacts with mucus in swimming in aqueous layer, and makes mucus to glottis motion (referring to Pierson and Kacmarek) by the ahead running of single direction.Mucus is produced and is secreted into after threshing in the inner chamber of air flue by epithelium goblet cell and submucosal gland cell.
Although mucus promotes to suck the removing of microgranule or infectious substance usually, the air flue Polyblennia may cause carrying out property airway obstruction.In peripheral airways, cough is invalid to removing secretion.And because its little space, the situation of mucus plugging air flue easily takes place in the little air flue that comprises many goblet cells.The air flue supersecretion influences considerable individuality.
Supersecretion has for example participated in cystic fibrosis, and the latter is one of modal, fatal in the world hereditary.Cystic fibrosis is the autosomal recessive disease, and this disease causes ring-AMP-deopendent protein kinase activation reactionless reply (Pierson and Kacmarek) of air flue mucomembranous cell to the film chloride channel.Concurrent electrolyte imbalance reduces the mucous hydration level of air flue, thereby produces the mucus of high viscosity in the lung of the individuality of suffering from cystic fibrosis.Supersecretion blocks the air flue of cystic fibrosis individuality, and then the infringement pulmonary function.
Suffer from that high-level mucous result is in the excessive secretion lung disease patient lung, mucosa go out to descend clearly.Pathogenic agent such as antibacterial, for example Pseudomonas aeruginosa (Pseudomonas aeruginosa) produces bacterium colony usually in mucus, causes regular pulmonary infection.
The typical method of the individuality that treatment air flue supersecretion involves comprise antibiotic therapy, bronchodilator (as, methylxantines, sympathomimetic, anticholinergic with strong β 2 adrenergic stimulation character), utilize corticosteroid, the oral administration of general or the suction liquefaction mucus of eliminating the phlegm, and aerosol delivery " dissolving mucus " agent, as water, macroion saline solution (hyperonic saline solution) (, the same) referring to Harrison ' s.(Shak waits (1990) Proc.Natl.Acad. (USA) 87:9188-9192 to the newer therapy of cystic fibrosis in order to use DNAse at the mucus that is rich in DANN or saliva; Hubbard, R.C. etc. (1991) N.Engl.J.Med.326:812).In addition, also can be used to promote the mucous removing of viscosity by beaing, vibrate and getting rid of the physiotherapy of chest of forming.Lung transplantation is serious blennosis people's final selection.Particularly, existence can reduce the demand of the specific drug that mucus forms in the air flue.
Disclosure of the Invention
Be surprised to find through the p38 of inhalation inhibitors of kinases and be suitable for use in the minimizing Polyblennia.
Therefore, the present invention relates to the p38 inhibitors of kinases and be used for the treatment of the particularly purposes in the inhalable drug compositions of cystic fibrosis of Polyblennia in preparation.
The p38 inhibitors of kinases that can be used for the scope of the invention is being known in the art.Suitable compound is disclosed in for example US5,716,972, US 5,686,455, US 5,656,644, US5,593,992, US 5,593,991, US5,663,334, US 5,670,527, US 5,559,137,5,658,903, US 5,739,143, US 5,756,499, US 6,277,989, US 6,340,685 and US 5,716,955 and PCT application WO 92/12154, WO 94/19350, WO 95/09853, WO 95/09851, WO 95/09847, WO 95/09852, WO 97/25048, WO 97/25047, WO 97/33883, WO 97/35856, WO 97/35855, WO 97/36587, WO 97/47618, WO 97/16442, WO 97/16441, WO 97/12876, WO 98/25619, WO 98/06715, WO 98/07425, WO 98/28292, WO 98/56377, WO 98/07966, WO 98/56377, WO 98/22109, WO 98/24782, WO 98/24780, WO 98/22457, WO 98/52558, WO 98/52559, WO 98/52941, WO 98/52937, WO 98/52940, WO 98/56788, WO 98/27098, WO 98/47892, WO 98/47899, WO 98/50356, WO 98/32733, WO 99/58523, WO 99/01452, WO 99/01131, WO 99/01130, WO 99/01136, WO 99/17776, WO 99/32121, WO 99/58502, WO 99/58523, WO 99/57101, WO 99/61426, WO 99/59960, WO 99/59959, WO 99/00357, WO 99/03837, WO 99/01441, WO 99/01449, WO 99/03484, WO 99/15164, WO 99/32110, WO 99/32111, WO 99/32463, WO 99/64400, WO 99/43680, WO 99/17204, WO 99/25717, WO 99/50238, WO 99/61437, WO 99/61440, WO 00/26209, WO 00/18738, WO 00/17175, WO 00/20402, WO 00/01688, WO 00/07980, WO 00/07991, WO 00/06563, WO 00/12074, WO 00/12497, WO 00/31072, WO 00/31063, WO 00/23072, WO 00/31065, WO 00/35911, WO 00/39116, WO 00/43384, WO 00/41698, WO 00/69848, WO 00/26209, WO 00/63204, WO 00/07985, WO 00/59904, WO 00/71535, WO 00/10563, WO 00/25791, WO 00/55152, WO 00/55139, WO 00/17204, WO 00/36096, WO 00/55120, WO 00/55153, WO 00/56738, WO 01/21591, WO 01/29041, WO 01/29042, WO 01/62731, WO 01/05744, WO 01/05745, WO 01/05746, WO 01/05749, WO 01/05751, WO 01/27315, WO 01/42189, WO 01/00208, WO 01/42241, WO 01/34605, WO 01/47897, WO 01/64676, WO 01/37837, WO 01/38312, WO 01/38313, WO 01/36403, WO 01/38314, WO 01/47921, WO 01/27089, among DE 19842833 and the JP 2,000 86657, it openly is incorporated herein by reference with its integral body here.
The chemical compound that should note especially in the purposes of the present invention discloses following p38 inhibitor of the prior art for those: US 6,277,989, US 6,340,685, WO 00/12074, WO 00/12497, WO00/59904, WO 00/71535, WO 01/64676, WO 99/61426, WO 00/10563, WO00/25791, WO 01/37837, WO 01/38312, WO 01/38313, WO 01/38314, WO01/47921, WO 99/61437, WO 99/61440, WO 00/17175, WO 00/17204, WO00/36096, WO 98/27098, WO 99/00357, WO 99/58502, WO 99/64400, WO99/01131, WO 00/43384, WO 00/55152, WO 00/55139 and WO 01/36403.
In preferred embodiments, the present invention relates to the p38 inhibitors of kinases and be used for the treatment of purposes in the inhalable drug compositions of Polyblennia in preparation, wherein the p38 inhibitors of kinases is selected from as disclosed formula among the WO99/01131 1Chemical compound:
Figure A0381298800391
Wherein
R 1Be 4-pyridine radicals, pyrimidine radicals, 4-pyridazinyl, 1,2,4-triazine-5-base, quinolyl, isoquinolyl, or quinazoline-4-basic ring, described ring is by Y-R aReplacement is also optional by the replacement of other independent substituent, and described substituent group is selected from C 1-4Alkyl, halogen, hydroxyl, C 1-4Alkoxyl, C 1-4Alkylthio group, C 1-4Alkyl sulphinyl, CH 2OR 12, amino, single and two-C 1-6The amino that alkyl replaces, have 5～7 annular atomses and randomly comprise and be selected from oxygen, sulfur or NR 15Other heteroatomic N-heterocyclic rings, N (R 10) C (O) R bOr NHR a
Y is oxygen or sulfur;
R 4Be phenyl, naphthalene-1-base or naphthalene-Ji or heteroaryl, described group optional by 1 or a plurality of substituent group replace, each substituent group is selected independently, and to 4-phenyl, 4 naphthalenes-1-base, 5-naphthalene-2-base or 6-naphthalene-2-base substituent group, is halogen, cyano group, nitro, C (Z) NR 7R 17, C (Z) OR 16, (CR 10R 20) vCOR 12, SR 5, SOR 5, OR 12, halogenated-C 1-4Alkyl, C 1-4Alkyl, ZC (Z) R 12, NR 10C (Z) R 16Or (CR 10R 20) vNR 10R 20, and, be halogen, cyano group, C (Z) NR to the replacement of other positions 13R 14, C (Z) OR 3, (CR 10R 20) M "COR 3, S (O) mR 3, OR 3, halogenated-C 1-4Alkyl, C 1-4Alkyl, (CR 10R 20) M "R 10C (Z) R 3, NR 10S (O) M 'R 8, NR 10S (O) M 'NR 7R 17, ZC (Z) R 3Or (CR 10R 20) M "NR 13R 14
Z is oxygen or sulfur;
N is 1～10 integer;
M is 0, or 1 or 2 integer;
M ' is 1 or 2 integer;
M " be 0, or 1～5 integer;
V is 0, or 1～2 integer;
R 2Be (A) (R of-C (H) 22);
A is optional aryl, heterocyclic radical or the heteroaryl ring that replaces, or the C of A for replacing 1-10Alkyl;
R 22Be the optional C that replaces 1-10Alkyl;
R aBe aryl, aryl C 1-6Alkyl, heterocyclic radical, heterocyclic radical C 1-6Alkyl, heteroaryl, heteroaryl C 1-6Alkyl, wherein each several part can be chosen wantonly and be substituted;
R bBe hydrogen, C 1-6Alkyl, C 3-7Cycloalkyl, aryl, aryl C 1-4Alkyl, heteroaryl, heteroaryl C 1-4Alkyl, heterocyclic radical or heterocyclic radical C 1-4Alkyl, wherein each several part can be chosen wantonly and be substituted;
R 3Be heterocyclic radical, heterocyclic radical C 1-10Alkyl or R 8
R 5Be hydrogen, C 1-4Alkyl, C 2-4Alkenyl, C 2-4Alkynyl or NR 7R 17, get rid of composition SR 5Be SNR 7R 17And SOR 5Situation for SOH;
R 6Be hydrogen, medicinal cation, C 1-10Alkyl, C 3-7Cycloalkyl, aryl, aryl C 1-4Alkyl, heteroaryl, heteroaryl C 1-4Alkyl, heterocyclic radical, aryl or C 1-10Alkanoyl;
R 7And R 17Be selected from hydrogen or C independently of one another 1-4Alkyl or R 7And R 17Coupled nitrogen forms 5～7 Yuans heterocycle together, and described heterocycle is selected from oxygen, sulfur or NR optional comprising 15Other hetero atoms;
R 8Be C 1-10Alkyl, halogenated C 1-10Alkyl, C 2-10Alkenyl, C 2-10Alkynyl, C 3-7Cycloalkyl, C 5-7Cycloalkenyl group, aryl, aryl C 1-10Alkyl, heteroaryl, heteroaryl C 1-10Alkyl, (CR 10R 20) nOR 11, (CR 10R 20) nS (O) mR 18, (CR 10R 20) nNHS (O) 2R 18, (CR 10R 20) nNR 13R 14Wherein said aryl, aryl alkyl, heteroaryl, heteroaryl alkyl can be chosen wantonly and be substituted;
R 9Be hydrogen, C (Z) R 11Or the optional C that replaces 1-10Alkyl, S (O) 2R 18, the optional aryl that replaces or the optional aryl C that replaces 1-4Alkyl;
R 10And R 20Be selected from hydrogen or C independently of one another 1-4Alkyl;
R 11Be hydrogen, C 1-10Alkyl, C 3-7Cycloalkyl, heterocyclic radical, heterocyclic radical C 1-10Alkyl, aryl, aryl C 1-10Alkyl, heteroaryl or heteroaryl C 1-10Alkyl, wherein these parts can be chosen wantonly and be substituted;
R 12Be hydrogen or R 16
R 13And R 14Be selected from hydrogen or the optional C that replaces independently of one another 1-4Alkyl, the optional aryl that replaces or the optional aryl C that replaces 1-4Alkyl, or connected nitrogen-atoms forms 5～7 element heterocycles together, and described heterocycle is selected from oxygen, sulfur or NR optional comprising 9Other hetero atoms;
R 15Be R 10Or C (Z)-C 1-4Alkyl;
R 16Be C 1-4Alkyl, halogenated-C 1-4Alkyl or C 3-7Cycloalkyl;
R 18Be C 1-10Alkyl, C 3-7Cycloalkyl, heterocyclic radical, aryl, aryl 1-10Alkyl, heterocyclic radical, heterocyclic radical-C 1-10Alkyl, heteroaryl or heteroaryl 1-10Alkyl;
Or its officinal salt.
In above-mentioned formula 1In the chemical compound, R 2Be the alkyl derivative that replaces.Be to be appreciated that first mesomethylene carbon on this chain is a tertiary carbon, and it comprises a hydrogen partial.This ethylidene has two other substituent groups, R 22Part and A part ,-C (H) is (R (A) 22).A and R 22Both can not be unsubstituted C 1-10Moieties.
In preferred embodiments, R 2For-C (AA 1) (A) part, wherein AA 1Be R 22Part, but be in particular amino acid whose side chain (R), will further describe here.
Compatibly, A is the optional C that replaces 13-7Cycloalkyl, aryl, heteroaryl or heterocyclic ring, or the C of A for replacing 1-10Moieties.
When A was aryl, heteroaryl and heterocyclic ring, this ring can be substituted one or repeatedly independently, preferably, and by C 1-10Alkyl; Halogen; Halogenated C 1-10Alkyl such as CF 3(CR 10R 20) tOR 11(CR 10R 20) tNR 12R 14, amino or single-or two-C particularly 1-4Alkyl amino; (CR 10R 20) tS (O) mR 18, wherein m is 0,1 or 2; SH; NR 10C (Z) R 3(as NHCO (C 1-10Alkyl)); Or NR 10S (O) mR 8(as NHSO 2(C 1-10Alkyl)) replace 1～3 time.
Compatibly, t is 0, or 1～4 integer.
When A was the cycloalkyl of optional replacement, it was for having R 22Replace as the group of giving a definition.
When A is that this ring is preferably morpholino, pyrrolidinyl, piperazinyl or piperidines basic ring when choosing replace heterocyclic wantonly.
When the aryl moiety of A, be preferably benzyl ring for optional replacement.
When the heteroaryl ring of A for optional replacement, it is as defining in the following definitional part.
As the C of A for replacing 1-10In the time of moieties, alkyl chain can be straight or branched.This chain is substituted 11 or repeatedly independently, is preferably replaced 1～3 time by following groups: halogen, as fluorine, chlorine, bromine or iodine; Halogenated C 1-10Alkyl is as CF 3C 3-7Cycloalkyl, C 1-10Alkoxyl is as methoxy or ethoxy; The C that hydroxyl replaces 1-10Alkoxyl; Halogenated C 1-10Alkoxyl is as OCF 2CF 2H; OR 11S (O) mR 18(wherein m is 0,1 or 2); NR 13R 14C (Z) NR 13R 14S (O) M 'NR 13R 14NR 23C (Z) R 11NHS (O) 2R 18C (Z) R 11OC (Z) R 11C (Z) OR 11C (Z) NR 11OR 9N (OR 6) C (Z) NR 13R 14N (OR 6) C (Z) R 11C (=NOR 6) R 11NR 23C (=NR 19) NR 13R 14OC (Z) NR 13R 14NR 23C (Z) NR 13R 14Or NR 23C (Z) OR 10
Preferably A is C 3-7Cycloalkyl, or C 1-6Alkyl more preferably is C 1-2Alkyl, that is, methylene or ethylidene part are more preferably by the monobasic methylene moiety of the above-mentioned group of mentioning.
Preferably, when A be C 1-10In the time of alkyl, it is by OR 11, R wherein 11Be preferably hydrogen, aryl or aryl alkyl; NR 13R 14OC (Z) R 11C (Z) OR 11Replace.
More preferably, A is by OR 11Replace, wherein R 11Be hydrogen.
Compatibly, R 22Be C 1-10Alkyl chain, this chain can be straight or branched and can choose wantonly independently by following groups and replace one or repeatedly, preferably replace 1～3 time: halogen, as fluorine, chlorine or iodine; Halogenated C 1-10Alkyl; C 1-10Alkoxyl is as methoxy or ethoxy; The C that hydroxyl replaces 1-10Alkoxyl; Halogenated C 1-10Alkoxyl is as OCF 2CF 2H; OR 11; S (O) mR 18NR 13R 14C (Z) NR 13R 14S (O) M 'NR 13R 14NR 23C (Z) R 11NHS (O) 2R 18C (Z) R 11OC (Z) OR 11C (Z) OR 11C (Z) NR 11OR 9N (OR 6) C (Z) NR 13R 14N (OR 6) C (Z) R 11C (=NOR 6) R 11NR 23C (=NR 19) NR 13R 14OC (Z) NR 13R 14NR 23C (Z) NR 13R 14NR 23C (Z) OR 10The optional C that replaces 3-7Cycloalkyl; The optional aryl that replaces is as phenyl; The optional heteroaryl that replaces; Or the optional heterocyclic radical that replaces.Optional substituent group on these cycloalkyl, aryl, heteroaryl and heterocyclic moiety is as hereinafter definition.
It should be noted that those comprise the R as the carbon of the first connection base 22Substituent group, i.e. C (Z) OR 11C (Z) NR 11OR 9, C (Z) R 11, C (Z) NR 13R 14And C (=NOR 6) R 11, can be the sole carbon atom in the alkyl chain.Therefore, R 22Group can be, for example, and carboxyl, aldehyde or amide, and be the substituent group of MU (methylene unit), as the carbamyl ylmethyl, or acetamidomethyl.
R preferably 22Be C 1-6Unsubstituted or replace alkyl is as C 1-3Alkylidene (alkylene) is as methyl, ethyl or isopropyl, or by above-mentioned monobasic methylene or the ethylidene part of mentioning part, or be substituted those substituent groups of first methylene unit of the above-mentioned alkyl chain of mentioning, as carboxyl, C (O) OR 11C (O) NR 13R 14Or R 22For the optional aryl that replaces, as benzyl or phenethyl.In other words, R 22Can be the optional alkyl that replaces, or R 22Can be C (Z) OR 11C (Z) NR 11OR 9, C (Z) R 11, C (Z) NR 13R 14Or C (=NOR 6) R 11
R preferably 22Be C unsubstituted or that replace 1-6Alkyl more preferably is C 1-2Alkylidene chain is as methylene or ethylidene part, more preferably methylene.
Preferably alkyl chain is by OR 11Replace, wherein R 11Be preferably hydrogen, aryl or aryl alkyl; S (O) mR 18, wherein m is 0 and R 18Be C 1-6Alkyl; Or the optional aryl that replaces, i.e. benzyl or phenethyl part.
More preferably, R 22Be phenyl, benzyl, CH 2OH or CH 2-O-aryl.
Preferably, A and R 22In one of or both comprise hydroxylic moiety, as at C 1-6Alkyl OR 11In, R wherein 11Be hydrogen, i.e. CH 2CH 2OH.
Compatibly, work as AA 1In the time of for amino acid whose side chain residue (R), it is the C of straight or branched 1-6Alkyl.This means (COOH) (NH of structure R-C (H) 2) in the amino acid whose R group of core.This R residue term is, for example, and the CH of alanine 3, (the CH of valine 3) 2CH-, leucic (CH 3) 2CH-CH 2-, the phenyl-CH of phenylalanine 2-, the CH of methionine 3-S-CH 2-CH 2-, etc.All main aminoacid of generally acknowledging usually all are included in wherein, as but be not limited to, alanine, arginine, agedoite acid, my god (door) winter propylhomoserin, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, oxylysine, methylhistidin and other naturally occurring aminoacid that does not see in the albumen, as Beta-alanine, γ-An Jidingsuan, homocysteine, homoserine, citrulline, ornithine, canavanine, djenkolic acid and beta-cyano alanine, or other naturally occurring nonmammalian aminoacid.
AA preferably 1Residue for phenylalanine or alanine.
Preferably A is the C that hydroxyl replaces 1-10Alkyl and R 22Be C 1-10The C that alkyl or hydroxyl replace 1-10Alkyl.
In other embodiment preferred, the present invention relates to the purposes that the p38 inhibitors of kinases is used for preparing the inhalable drug compositions for the treatment of Polyblennia, wherein the p38 inhibitors of kinases is selected from disclosed following chemical compound among the WO99/01131:
1-(1,3-dihydroxy third-2-yl)-(4-fluorophenyl)-5-(2-phenoxy pyrimidine-4-yl) imidazoles;
Instead-and 1-(4-hydroxy-cyclohexyl)-4-(4-fluorophenyl) 5-[(2-methoxyl group) pyrimidine-4-yl] imidazoles;
1-(4-piperidyl)-4-(4-fluorophenyl)-5-(2-methoxyl group-4-pyrimidine radicals) imidazoles;
(4-fluorophenyl)-2-(4-methylsulfinyl phenyl)-5-(4-pyridine radicals)-imidazoles;
In another embodiment, the present invention relates to the p38 inhibitors of kinases and be used for the treatment of purposes in the inhalable drug compositions of Polyblennia in preparation, wherein the p38 inhibitors of kinases is selected from as at US 6,277, disclosed formula in 989 2Chemical compound
Figure A0381298800441
With and officinal salt,
Wherein
R 1Be H, alkyl (1-6C) or aryl alkyl, optional by individual alkyl (1-6C), halogen, OR, the NR of being independently selected from of 1-3 on aryl 2, SR ,-OOCR ,-NROCR, RCO ,-COOR ,-CONR 2,-SO 2NR 2, CN, CF 3And NO 2In substituent group replace, wherein each R is H or low alkyl group (1-4C) independently;
Each R 2Be alkyl (1-6C), halogen, OR, SR, OOCR, NROCR, COOR, RCO, CONR independently 2, SO 2NR 2, CN, CF 3Or NO 2, wherein each R is H or low alkyl group (1-4C) independently;
Each l, m and n are 0,1 or 2 independently; And
Ar is phenyl, 2-, 3-or 4-pyridine radicals, indyl, 2-or 4-pyrimidine radicals, or benzimidazolyl, each optional alkyl, alkenyl, alkynyl, aryl, N-aryl, NH-aroyl, halogen, OR, NR that is optionally substituted 2, SR ,-OOCR ,-NROCR, RCO ,-COOR ,-CONR 2, SO 2NR 2, CN, CF 3Or NO 2Replace, wherein each R is H or alkyl (1-4C) independently;
Preferably the present invention relates to the p38 inhibitors of kinases and be used for the treatment of purposes in the inhalable drug compositions of Polyblennia in preparation, wherein the p38 inhibitors of kinases is selected from as at US6, disclosed formula in 277,989 2Chemical compound, wherein
R 1Be H;
R 2Be halogen, m is 0,1, or 2, and l is 1 or 2;
Ar is the 4-pyridine radicals.
In concrete embodiment preferred, the present invention relates to the p38 inhibitors of kinases and be used for the treatment of purposes in the inhalable drug compositions of Polyblennia in preparation, wherein the p38 inhibitors of kinases is selected from US 6,277,989 disclosed following chemical compounds:
2-phenyl-4-(4-pyridinylamino)-quinazoline;
2-(2-bromophenyl)-4-(4-pyridinylamino)-quinazoline;
2-(2-chlorphenyl)-4-(4-pyridinylamino)-quinazoline;
2-(2-fluorophenyl)-4-(4-pyridinylamino)-quinazoline;
2-(2-aminomethyl phenyl)-4-(4-pyridinylamino)-quinazoline;
2-(4-fluorophenyl)-4-(4-pyridinylamino)-quinazoline;
2-(3-methoxybenzene amido (anilyl))-4-(4-pyridinylamino)-quinazoline;
2-(2, the 6-Dichlorobenzene base)-4-(4-pyridinylamino)-quinazoline;
2-(2, the 6-dibromo phenyl)-4-(4-pyridinylamino)-quinazoline;
2-(2, the 6-difluorophenyl)-4-(4-pyridinylamino)-quinazoline;
2-(2-fluorophenyl)-4-(4-pyridinylamino)-6, the 7-dimethoxyquinazoline;
2-(4-fluorophenyl)-4-(4-pyridinylamino)-6, the 7-dimethoxyquinazoline;
2-(2-fluorophenyl)-4-(4-pyridinylamino)-6-nitro-quinazoline;
2-(2-fluorophenyl)-4-(4-pyridinylamino-6-amido quinazoline;
2-(2-fluorophenyl)-4-(4-pyridinylamino)-7-amido quinazoline;
2-(2-fluorophenyl)-4-(4-pyridinylamino)-6-(3-methoxy-benzyl amino)-quinazoline;
2-(2-fluorophenyl)-4-(4-pyridinylamino)-6-(4-methoxy-benzyl amino)-quinazoline;
2-(2-fluorophenyl)-4-(4-pyridinylamino)-6-(2-isobutylamino)-quinazoline; And
2-(2-fluorophenyl)-4-(4-pyridinylamino)-6-(4-methyl mercapto (mercapto) benzylamino)-quinazoline;
With and officinal salt.
In another embodiment preferred, the present invention relates to the p38 inhibitors of kinases and be used for the treatment of purposes in the inhalable drug compositions of Polyblennia in preparation, wherein the p38 inhibitors of kinases is selected from as at US 6,340, disclosed formula in 685 3a, 3b, 3cOr 3dChemical compound
Figure A0381298800461
Figure A0381298800462
Or
With and officinal salt,
Each Z wherein 1And Z 2Be CR independently 4Or N;
Each R wherein 4Independently for being selected from H and alkyl (1-6C);
Wherein said alkyl comprises that randomly one or more is selected from the hetero atom of O, S and N, and wherein said alkyl is optional by one or more following substituent group replacement, and described substituent group is selected from halogen, OR, SR, NR 2, RCO, COOR, CONR 2, OOCR, NROCR, CN ,=O, 5 or 6 Yuans saturated carbocyclic rings or comprise the heterocyclic ring of 1-2 N, and randomly comprise 1-2 the heteroatomic 6-person's aromatic rings of N, the R in the wherein aforementioned optional substituent group is H or alkyl (1-6C);
R 1For
Wherein
X 1Be CO, SO, CHOH or SO 2
M is 1;
Y is the optional alkyl that replaces, the optional aryl that replaces, or the optional aryl alkyl that replaces;
N is 0,1 or 2;
Z 3Be N;
X 2Be CH or CH 2And
Ar is by directly being coupled to X 21 or 2 phenyl moiety form, described 1 or 2 phenyl moiety is optional to be replaced by following substituent group, described substituent group is selected from halogen, nitro, alkyl (1-6C), alkenyl (1-6C), CN, CF 3, RCO, COOR, CONR 2, NR 2, OR, SR, OOCR, NROCR (R in the wherein aforementioned group is H or 1-6C alkyl) and phenyl, himself is optional to be replaced by aforementioned substituent group;
R 2For being selected from H and alkyl (1-6C);
Wherein said alkyl comprises that randomly one or more is selected from the hetero atom of O, S and N, and wherein said alkyl is optional by one or more following substituent group replacement, and described substituent group is selected from halogen, OR, SR, NR 2, RCO, COOR, CONR 2, OOCR, NROCR (R in the wherein aforementioned group is H or 1-6C alkyl) CN ,=O, 5 or 6 Yuans saturated carbocyclic rings or comprise the heterocyclic ring of 1-2 N and randomly comprise 1-2 the heteroatomic 6-person's aromatic rings of N;
R 3Be H, halogen, NO 2, alkyl (1-6C), alkenyl (1-6C), CN, OR, SR, NR 2, RCO, COOR, CONR 2, OOCR or NROCR, wherein R is H or alkyl (1-6C).
In concrete embodiment preferred, the present invention relates to the p38 inhibitors of kinases in the purposes that is used for preparing the inhalable drug compositions for the treatment of Polyblennia, wherein the p38 inhibitors of kinases is selected from US 6,340, disclosed following chemical compound in 685:
4-(2, the 6-difluorobenzyl)-piperazinyl-benzimidazole-5-carboxylic acid amides;
4-(2, the 3-difluorobenzyl)-piperazinyl-benzimidazole-5-carboxylic acid amides;
4-(3, the 5-difluorobenzyl)-piperazinyl-benzimidazole-5-carboxylic acid amides;
4-(3-benzyl chloride base)-piperazinyl-benzimidazole-5-carboxylic acid amides;
4-(4-carboxyl methyl-benzyl)-piperazinyl-benzimidazole-5-carboxylic acid amides;
4-(4-methoxy-benzyl)-piperazinyl-benzimidazole-5-carboxylic acid amides;
4-(4-trifluoro-methoxybenzyl)-piperazinyl-benzimidazole-5-carboxylic acid amides;
4-(4-methyl-benzyl)-piperazinyl-benzimidazole-5-carboxylic acid amides;
4-(2,4-dichloro-benzoyl base)-piperazinyl-benzimidazole-5-carboxylic acid amides;
4-(3,4-dichloro-benzoyl base) piperazinyl-benzo indazole-5-carboxylic acid amides;
4-[is anti--3-(trifluoromethyl)-cinnamoyl]-piperazinyl-benzimidazole-5-carboxylic acid amides;
4-(4-chlorobenzene formacyl)-piperazinyl-benzimidazole-5-carboxylic acid amides;
4-methyl (benzomethyl) benzoyl-piperazine base (piperazyl)-benzimidazole-5-carboxylic acid amides;
4-(2-trifluoromethyl benzoyl)-piperazinyl-benzimidazole-5-carboxylic acid amides;
4-(4-methoxyl group (methxy) benzoyl)-piperazinyl-benzimidazole-5-carboxylic acid amides;
4-(3, the 4-Dichlorobenzene base)-piperazinyl-benzimidazole (benzimnidazole)-5-carboxylic acid amides;
4-(4-chlorobenzhydryl)-piperazinyl-benzimidazole-5-carboxylic acid amides;
4-is anti--1-cinnamyl piperazine base-benzimidazole-5-carboxylic acid amides;
4-(4-chlorphenyl)-piperazinyl-benzimidazole-5-carboxylic acid amides;
Two (4-the fluorophenyl)-methyl of 4-[]-piperazinyl-benzimidazole-5-carboxylic acid amides;
4-(4-benzyl chloride base)-piperazinyl-benzimidazole-5-carboxylic acid amides;
4-(2-benzyl chloride base)-piperazinyl-benzimidazole-5-carboxylic acid amides;
4-benzyl diethylenediamine base-benzimidazole (benzinudazole)-5-carboxylic acid amides (carboxamnide);
4-(4-methyl mercapto benzyl)-piperazinyl-benzimidazole-5-carboxylic acid amides;
4-(3,4,5-trimethoxy benzyl)-piperazinyl-benzimidazole-5-carboxylic acid amides;
4-(2-naphthyl methyl)-piperazinyl-benzimidazole-5-carboxylic acid amides;
4-(4-diethylamino benzyl)-piperazinyl-benzimidazole-5-carboxylic acid amides;
4-(xenyl methyl)-piperazinyl-benzimidazole-5-carboxylic acid amides;
4-(4-phenoxy benzyl)-piperazinyl-benzimidazole-5-carboxylic acid amides;
4-(4-quinolyl methyl)-piperazinyl-benzimidazole-5-carboxylic acid amides;
4-(4-benzyl chloride base)-piperazinyl-1-(2-propyl group)-indole-5-carboxylic acid amides;
4-(3-benzyl chloride base)-piperazinyl-benzimidazole-5-carboxylic acid amides;
4-(3-benzyl chloride base)-piperazinyl-N-(2-propyl group)-benzimidazole-5-carboxylic acid amides;
4-(3-benzyl chloride base)-piperazinyl-N-(2-propyl group)-benzimidazole-6-carboxylic acid amides;
4-(3-benzyl chloride base)-piperazinyl-N-methyl-benzimidazole-5-carboxylic acid amides;
4-(3-benzyl chloride base)-piperazinyl-N-methyl-benzimidazole-6-carboxylic acid amides;
4-(3-benzyl chloride base)-piperazinyl-N-ethyl-benzimidazole-5-carboxylic acid amides; And
4-(3-benzyl chloride base)-piperazinyl-N-ethyl-benzimidazole-6-carboxylic acid amides.
In another embodiment preferred, the present invention relates to the p38 inhibitors of kinases and be used for the treatment of purposes in the inhalable drug compositions of Polyblennia in preparation, wherein the p38 inhibitors of kinases is selected from as disclosed formula in WO 00/43384 4Chemical compound
Wherein
Ar 1For being selected from the heterocyclic radical of pyrroles, pyrrolidine, pyrazoles, imidazoles, oxazole, thiazole, furan and thiophene; And Ar wherein 1Can be by 1 or a plurality of R 1, R 2Or R 3Replace;
Ar 2Be phenyl, naphthyl, quinoline, isoquinolin, tetralyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl or indole, each group is optional by 1～3 R 2Group replaces;
L connects base, for
C 1-10Saturated or unsaturated side chain or straight chain carbochain;
Wherein one or more methylene is randomly substituted by O, N or S independently; And
Wherein said connection base is optional by 0-2 oxo group and one or more C 1-4Branched-chain or straight-chain alkyl replaces, described alkyl can by 1 or a plurality of halogen atom replace;
Q is selected from:
A) phenyl, naphthyl, pyridine, pyrimidine, pyridazine, imidazoles, benzimidazole, furan, thiophene, pyrans, benzodiazine, oxazole also [4,5-b] pyridine and imidazo [4,5-b] pyridine, each group is optional to be replaced by 1～3 group, and described group is selected from halogen, C 1-6Alkyl, C 1-6Alkoxyl, hydroxyl, list-or two-(C 1-3Alkyl) amino, C 1-6Alkyl-S (O) mAnd phenyl amino, wherein said benzyl ring is optional to be selected from halogen, C by 1～2 1-6Alkyl and C 1-6The substituent group of alkoxyl replaces;
B) Pentamethylene oxide., oxolane, 1,3-dioxane pentanone, 1,3-dioxanone, 1,4-dioxane, morpholine, tetrahydro-1,4-thiazine, tetrahydro-1,4-thiazine sulfoxide, tetrahydro-1,4-thiazine sulfone, piperidines, piperidones, tetrahydro pyrimidine ketone, Ketohexamethylene, Hexalin, pentamethylene thioether, pentamethylene sulfoxide, pentamethylene sulfone, tetramethylene thioether, tetramethylene sulfoxide and tetramethylene sulfone, each group is optional to be replaced by 1～3 following radicals, and described group is selected from C 1-6Alkyl, C 1-6Alkoxyl, hydroxyl, list-or two-(C 1-3Alkyl) amino-C 1-3Alkyl, phenyl amino-C 1-3Alkyl and C 1-3Alkoxy-C 1-3Alkyl;
C) C 1-6Alkoxyl, the second month in a season or tertiary amine, wherein amino nitrogen is covalently bond to and is selected from C 1-3Alkyl and C 1-5On alkoxyalkyl and the phenyl groups, wherein benzyl ring is optional is selected from following substituent group replacement by 1～2: halogen, C 1-6Alkoxyl, hydroxyl or list-or two-(C 1-3Alkyl) amino, C 1-6Alkyl-S (O) r, phenyl-S (O) t, wherein said benzyl ring is optional to be selected from halogen, C by 1～2 1-6Alkoxyl, hydroxyl or list-or two-(C 1-3Alkyl) amino substituent group replaces;
R 1Be selected from:
A) randomly be partially or completely halogenated C 3-10Branched-chain or straight-chain alkyl, and optional by 1～3 phenyl, naphthyl or be selected from pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl heterocyclic radical and replace; Each phenyl, naphthyl or the heterocycle that is selected from above-mentioned group are selected from halogen, optional part or complete halogenated C by 0～5 1-6Branched-chain or straight-chain alkyl, C 3-8Cycloalkyl, C 5-8Cycloalkenyl group, hydroxyl, cyano group, optional part or complete halogenated C 1-3Alkoxyl, NH 2C (O) and two (C 1-3) group of alkyl amino-carbonyl replaces;
B) C 3-7Cycloalkyl is selected from cyclopropyl, cyclobutyl, Pentamethylene. base, cyclohexyl, cycloheptane base, bicyclo-pentyl, bicyclohexane base and bicycloheptane base, and described group is randomly for partially or completely halogenated and randomly by 1～3 C 1-3Alkyl replaces, or wherein 1～3 ring methylene be independently selected from O, S, CHOH,＞C=O,＞the similar group of C=S and the alternate described cycloalkyl of NH;
C) randomly be partially or completely halogenated C 3-10Branched alkenyl, and optional by 1～3 C 1-5Branched-chain or straight-chain alkyl, phenyl, naphthyl or heterocyclic radical replace, each heterocyclic radical is independently selected from pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, and each phenyl, naphthyl or heterocyclic radical are selected from following group replacement by 0～5: halogen, optional part or complete halogenated C 1-6Branched-chain or straight-chain alkyl, cyclopropyl, cyclobutyl, Pentamethylene. base, cyclohexyl, cycloheptane base, bicyclo-pentyl, bicyclohexane base and bicycloheptane base, hydroxyl, cyano group, optional part or complete halogenated C 1-3Alkoxyl, NH 2C (O), single-or two (C 1-3) alkyl amino-carbonyl;
D) be selected from the C of cyclopentenyl, cyclohexenyl group, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyl groups and bicycloheptene base 5-7Cycloalkenyl group, wherein said cycloalkenyl group are randomly by 1～3 C 1-3Alkyl replaces;
E) cyano group; And,
F) methoxycarbonyl, ethoxy carbonyl and propoxycarbonyl;
R 2Be selected from: randomly be partially or completely halogenated C 1-6Branched-chain or straight-chain alkyl, acetyl group, aroyl, randomly be partially or completely halogenated C 1-4Side chain or straight chain alkoxyl, halogen, methoxycarbonyl and phenyl sulfonyl;
R 3Be selected from:
A) phenyl, naphthyl or heterocyclic radical, described heterocyclic radical are selected from pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, tetrahydrofuran base, isoxazolyl, isothiazolyl, quinolyl, isoquinolyl, indyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzoisoxazole base, benzopyrazoles base, benzo thiapyran base, cinnolinyl, pteridyl (pterindinyl), phthalazinyl, naphthyl pyridine radicals, quinoxalinyl, quinazolyl, purine radicals and indazolyl; Wherein said phenyl, naphthyl or heterocyclic radical are optional to be replaced by 1～5 substituent group, and described substituent group is selected from C 1-6Branched-chain or straight-chain alkyl, be selected from phenyl, naphthyl, heterocycle, optional part or complete halogenated C as described above 1-6Branched-chain or straight-chain alkyl, cyclopropyl, cyclobutyl, Pentamethylene. base, cyclohexyl, cycloheptane base, bicyclo-pentyl, bicyclohexane base, bicycloheptane base, phenyl C 1-5Alkyl, naphthyl C 1-5Alkyl, halogen, hydroxyl, cyano group, randomly be partially or completely halogenated C 1-3Alkoxyl, phenoxy group, naphthoxy, the wherein said heterocyclic moiety of heteroaryloxy are selected from as described above group, nitro, amino, list-or two-(C 1-3) the amino wherein said heterocyclic radical of alkyl amino, phenyl amino, naphthyl amino, heterocyclic radical partly is selected from group, NH as described above 2C (O), single-or two-(C 1-3) alkyl amino-carbonyl, C 1-5Alkyl-C (O)-C 1-4Alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3) alkyl amino-C 1-5Alkyl, amino-S (O) 2, two-(C 1-3) alkyl amino-S (O) 2, R 4-C 1-5Alkyl, R 5-C 1-5Alkoxyl, R 6-C (O)-C 1-5Alkyl and R 7-C 1-5Alkyl (R 8) N;
B) condensed aryl is selected from benzocyclobutane alkyl, indanyl, indenyl, dihydro naphthyl, tetralyl, benzocyclohepta alkyl and benzocyclohepta thiazolinyl; Or the condensed heterocycle base, be selected from cyclopenta (penteno) pyridine, hexamethylene and pyridine, cyclopentano pyrimidine, hexamethylene and pyrimidine, cyclopentano pyrazine, hexamethylene and pyrazine, cyclopentano pyridazine, hexamethylene and pyridazine, cyclopentano quinoline, hexamethylene and quinoline, cyclopentano isoquinolin, hexamethylene and isoquinolin, cyclopentano indole, hexamethylene diindyl, cyclopentano benzimidazole, hexamethylene and benzimidazole, cyclopentano benzoxazole, hexamethylene and benzoxazole, cyclopentano imidazoles, hexamethylene and imidazoles, cyclopentano thiophene and hexamethylene bithiophene; Wherein said fused-aryl or annelated heterocycles basic ring are selected from following substituent group by 0～3 and replace, and described substituent group is independently selected from phenyl, naphthyl and is selected from the heterocyclic radical of pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, optional part or complete halogenated C 1-6Branched-chain or straight-chain alkyl, halogen, cyano group, optional part or complete halogenated C 1-3Alkoxyl, phenoxy group, naphthoxy, the wherein said heterocyclic radical of heterocyclic oxy group partly are selected from as described above group, nitro, amino, list-or two-(C 1-3) the amino wherein said heterocyclic radical of alkyl amino, phenyl amino, naphthyl amino, heterocyclic radical partly is selected from group, NH as described above 2C (O), single-or two-(C 1-3) alkyl amino-carbonyl, C 1-4Alkyl-OC (O), C 1-5Alkyl-C (O)-C 1-4Branched-chain or straight-chain alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3) alkyl amino-C 1-5Alkyl, R 9-C 1-5Alkyl, R 10-C 1-5Alkoxyl, R 11-C (O)-C 1-5Alkyl and R 12-C 1-5Alkyl (R 13) N;
C) cycloalkyl is selected from Pentamethylene. base, cyclohexyl, cycloheptane base, bicyclo-pentyl, bicyclohexane base and bicycloheptane base, wherein said cycloalkyl can be randomly for partially or completely halogenated and can be randomly by 1～3 C 1-3Alkyl replaces;
D) C 5-7Cycloalkenyl group is selected from cyclopentenyl, cyclohexenyl group, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyl groups and bicycloheptene base, and wherein said cycloalkenyl group can be randomly by 1～3 C 1-3Alkyl replaces; And
E) acetyl group, aroyl, alkoxy carbonyl alkyl or phenyl sulfonyl;
F) randomly be partially or completely halogenated C 1-6Branched-chain or straight-chain alkyl;
Or R 1And R 2Randomly form condensed phenyl or pyridyl ring together,
And each R wherein 8, R 13Independently for being selected from: hydrogen and randomly be partially or completely halogenated C 1-4Branched-chain or straight-chain alkyl;
Each R 4, R 5, R 6, R 7, R 9, R 10, R 11And R 12Independently for being selected from: morpholine, piperidines, piperazine, imidazoles and tetrazolium;
m＝0、1、2；
r＝0、1、2；
t＝0、1、2；
X=O or S with and physilogically acceptable acid or salt.
In preferred embodiments, the present invention relates to the p38 inhibitors of kinases and be used for the treatment of purposes in the inhalable drug compositions of Polyblennia in preparation, wherein the p38 inhibitors of kinases is selected from as disclosed formula in WO 00/43384 4Chemical compound, Ar wherein 2Be naphthyl, tetralyl, indanyl or indenyl.
The preferred inferior aspect of the present invention comprises formula 4The purposes of chemical compound, wherein Ar 2Be naphthyl.
The preferred inferior aspect of the present invention comprises formula as in the previous paragraph 4The purposes of chemical compound, wherein:
Ar 1Be thiophene or pyrazoles;
Ar 2Be the 1-naphthyl;
L is C 1-6Saturated or unsaturated side chain or straight chain carbochain, wherein one or more methylene is optional is substituted by O, N or S independently; And
Wherein said connection base is optional by 0-2 oxo group and one or more C 1-4Branched-chain or straight-chain alkyl replaces, wherein said alkyl can by 1 or a plurality of halogen atom replace;
R 1Be selected from the C of side chain or straight chain 1-4Alkyl, randomly be partially or completely halogenated cyclopropyl and cyclohexyl, and described group can be randomly by 1～3 C 1-3Alkyl replaces;
R 3Be selected from side chain or straight chain C 1-4Alkyl, cyclopropyl, phenyl, pyridine radicals, each group is optional as above to replace alkoxy carbonyl alkyl; Side chain or straight chain C 1-6Alkyl; The cyclopropyl of aforesaid optional replacement or cyclopenta.
The preferred inferior aspect of the present invention comprises formula as in the previous paragraph 4The purposes of chemical compound, wherein Ar 1Be pyrazoles.
The preferred inferior aspect of the present invention comprises formula as in the previous paragraph 4The purposes of chemical compound, wherein L is C 1-5Saturated carbochain, wherein one or more methylene is optional is substituted by O, N or S independently; And wherein said connection base is optional by 0-2 oxo group and one or more C 1-4Branched-chain or straight-chain alkyl replaces, described alkyl can by 1 or a plurality of halogen atom replace;
The embodiment of concrete preferred L is propoxyl group, ethyoxyl, methoxyl group, methyl, propyl group, C 3-5Acetylene (acetylene) or methylamino, each group is optional as above to be replaced.
The embodiment of preferred L is the optional ethyoxyl that replaces.
Following chemical compound is representational formula 4Chemical compound and should specifically merit attention according to the present invention:
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(suitable-2,6-thebaine-4-yl) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(anti--2,6-thebaine-4-yl) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(2-(methoxy) morpholine-4-yl) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(morpholine-4-yl)-2-oxo ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(morpholine-4-yl)-2-methyl ethoxy) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(morpholine-4-yl)-1-methyl ethoxy) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-tetrahydro-1,4-thiazine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(1-oxo tetrahydro-1,4-thiazine-4-yl) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl)-3-methyl naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-piperidin-4-yl-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(1-acetyl group piperidin-4-yl) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-Thiazolidine-3-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(morpholine-4-base-ketonic oxygen generation) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(tetrahydropyran-4-base) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(N-methyl-2-methoxy ethyl amino) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(1-oxo-Tetramethylene sulfide-3-yl) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-morpholine-4-base-propyl group) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(morpholine-4-base-methyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-Thiazolidine-3-base-propyl group) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-(Pentamethylene oxide .-2-base-oxygen) propyl group) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-pyridin-4-yl-ethyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-pyridin-4-yl-vinyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-(morpholine-4-yl) propine-1-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-(Pentamethylene oxide .-2-base-oxygen base) propine-1-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-(methoxymethoxy) propine-1-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-(morpholine-4-yl)-3-methyl propine-1-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-(morpholine-4-yl)-3,3-dimethyl propine-1-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-(Pentamethylene oxide .-2-base-oxygen base) butine-1-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-(furan-2-base carbonyl oxygen base) propine-1-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-(piperidines-1-yl) propine-1-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-(2-methoxy morpholine-4-yl) propine-1-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(pyridin-4-yl-methoxyl group) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-pyridin-4-yl-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-pyridin-4-yl-propoxyl group) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-imidazoles-1-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-benzimidazole-1-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(3, the 4-Dimethoxyphenyl)-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(pyridin-4-yl-methylamino) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(pyridin-4-yl-carbonylamino) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(morpholine-4-base-acetamido) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(pyridin-3-yl-methylamino) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(pyridin-3-yl-carbonylamino) naphthalene-1-yl]-urea;
1-[5-is different-propyl group-2-phenyl-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
1-[5-(tetrahydropyran-3-base)-2-phenyl-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
1-[5-cyclohexyl-2-phenyl-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
1-[5-(2,2, the 2-trifluoroethyl)-2-phenyl-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
1-[5-(1-methyl ring third-1-yl)-2-phenyl-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
1-[5-ethoxy carbonyl-2-phenyl-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
1-[5-(1-methyl cyclohexane-1-yl)-2-phenyl-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-methyl-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-benzyl-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(4-chlorphenyl)-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-butyl-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(ethoxy carbonyl methyl)-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(4-methyl-3-carbamoyl phenyl)-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(4-methyl-3-(2-ethoxy carbonyl vinyl) phenyl)-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(4-methyl-3-(morpholine-4-yl) aminomethyl phenyl)-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(4-methyl-3-dimethylaminomethyl phenyl)-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(3-(2-morpholine-4-base-ethyl) phenyl)-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(3-(tetrahydropyran-4-base amino) phenyl)-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(3-dimethylaminomethyl phenyl)-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(4-(tetrahydropyran-4-base amino) phenyl)-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(4-(3-benzyl urea groups) phenyl)-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-chloropyridine-5-yl)-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-picoline-5-yl)-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-methoxypyridine-5-yl)-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-picoline-5-yl)-2H-pyrazole-3-yl]-3-[4-(2-pyridin-4-yl-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-picoline-5-yl)-2H-pyrazole-3-yl]-3-[4-(2-(anti--2,6-thebaine-4-yl) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-picoline-5-yl)-2H-pyrazole-3-yl]-3-[4-(3-morpholine-4-base-propine-1-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(2-dimethylaminomethyl morpholine-4-yl) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-is different-propyl group-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-cyclopropyl-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(thiene-3-yl-)-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-cyclopenta-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-is different-propyl group-2H-pyrazole-3-yl]-3-[4-(tetrahydropyran-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-cyclopropyl-2H-pyrazole-3-yl]-3-[4-(1-oxo-Tetramethylene sulfide-3-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(thiene-3-yl-)-2H-pyrazole-3-yl]-3-[4-(2-pyridine radicals-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-cyclopenta-2H-pyrazole-3-yl]-3-[4-(pyridin-4-yl-methoxyl group) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-(pyridin-4-yl) propine-1-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-(2-methylamino pyridin-4-yl) propine-1-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-(1-oxo-Tetramethylene sulfide-3-yl) propine-1-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-(Thiazolidine-3-yl) propine-1-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-(tetrahydropyran-4-base) propine-1-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-methylamino pyrimidine-4-base-methoxyl group) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(2-methylamino pyrimidine-4-yl) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(4-methoxyl group benzo imidazoles-1-yl) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(4-methylamino benzo imidazoles-1-yl) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(2-imidazo [4,5-b] pyridine-1-yl) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-[1,8] benzodiazine-4-yl) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(3,4-dihydro-2H-pyrans is [2,3-b] pyridine-5-yl also) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-pyridin-3-yl-2H-pyrazole-3-yl]-3-[4-(2-methylamino pyrimidine-4-base-methoxyl group) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-picoline-5-yl)-2H-pyrazole-3-yl]-3-[4-(2-(2-methylamino pyrimidine-4-yl) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-picoline-5-yl)-2H-pyrazole-3-yl]-3-[4-(2-(4-methoxyl group benzo imidazoles-1-yl) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-picoline-5-yl)-2H-pyrazole-3-yl]-3-[4-(2-(4-methylamino benzo imidazoles-1-yl) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-picoline-5-yl)-2H-pyrazole-3-yl]-3-[4-(2-(2-imidazo [4,5-b] pyridine-1-yl) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-picoline-5-yl)-2H-pyrazole-3-yl]-3-[4-(2-[1,8] benzodiazine-4-yl) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-picoline-5-yl)-2H-pyrazole-3-yl]-3-[4-(2-(3,4-dihydro-2H-pyrans is [2,3-b] pyridine-5-yl also) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-cyclopropyl-2H-pyrazole-3-yl]-3-[4-(2-methylamino pyrimidine-4-base-methoxyl group) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-cyclopropyl-2H-pyrazole-3-yl]-3-[4-(2-(2-methylamino pyrimidine-4-yl) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-cyclopropyl-2H-pyrazole-3-yl]-3-[4-(2-(4-methoxyl group benzo imidazoles-1-yl) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-cyclopropyl-2H-pyrazole-3-yl]-3-[4-(2-(4-methylamino benzo imidazoles-1-yl) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-methyl-2H-pyrazole-3-yl]-3-[4-(2-(2-imidazo [4,5-b] pyridine-1-yl) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-methyl-2H-pyrazole-3-yl]-3-[4-(2-[1,8] benzodiazine-4-yl) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-methyl-2H-pyrazole-3-yl]-3-[4-(2-(3,4-dihydro-2H-pyrans is [2,3-b] pyridine-5-yl also) ethyoxyl) naphthalene-1-yl]-urea
With and physilogically acceptable acid or salt.
In concrete embodiment preferred, the purposes p38 inhibitors of kinases that the present invention relates to is used for the treatment of purposes in the inhalable drug compositions of Polyblennia in preparation, and wherein the p38 inhibitors of kinases is selected from as disclosed following formula in WO 00/43384 4Chemical compound:
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(suitable-2,6-thebaine-4-yl) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(anti--2,6-thebaine-4-yl) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(2-(methoxy) morpholine-4-yl) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(morpholine-4-yl)-2-oxo ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(morpholine-4-yl)-2-methyl ethoxy) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(morpholine-4-yl)-1-methyl ethoxy) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-tetrahydro-1,4-thiazine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(1-oxo tetrahydro-1,4-thiazine-4-yl) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl)-3-methyl naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(morpholine-4-base-ketonic oxygen) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(tetrahydropyran-4-base) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(1-oxo-Tetramethylene sulfide-3-yl) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-morpholine-4-base-propyl group) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(morpholine-4-base-methyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-pyridin-4-yl-ethyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-(morpholine-4-yl) propine-1-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-(Pentamethylene oxide .-2-base-oxygen base) propine-1-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-(Pentamethylene oxide .-2-base-oxygen base) butine-1-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-(piperidines-1-yl) propine-1-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-(2-methoxy morpholine-4-yl) propine-1-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(pyridin-4-yl-methoxyl group) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-pyridin-4-yl-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-pyridin-4-yl-propoxyl group) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-imidazoles-1-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(3, the 4-Dimethoxyphenyl)-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(pyridin-4-yl-methylamino) naphthalene-1-yl]-urea;
1-[5-is different-propyl group-2-phenyl-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
1-[5-cyclohexyl-2-phenyl-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
1-[5-(2,2, the 2-trifluoroethyl)-2-phenyl-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
1-[5-(1-methyl ring third-1-yl)-2-phenyl-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
1-[5-(1-methyl cyclohexane-1-yl)-2-phenyl-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-methyl-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(4-chlorphenyl)-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-butyl-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(4-methyl-3-carbamoyl phenyl)-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(4-methyl-3-(morpholine-4-yl) aminomethyl phenyl)-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(4-methyl-3-dimethylaminomethyl phenyl)-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(3-dimethylaminomethyl phenyl)-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-chloropyridine-5-yl)-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-picoline-5-yl)-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-methoxypyridine-5-yl)-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-picoline-5-yl)-2H-pyrazole-3-yl]-3-[4-(2-pyridin-4-yl-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-picoline-5-yl)-2H-pyrazole-3-yl]-3-[4-(2-(anti--2,6-thebaine-4-yl) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-picoline-5-yl)-2H-pyrazole-3-yl]-3-[4-(3-morpholine-4-base-propine-1-yl) naphthalene-1-yl]-urea.
Concrete preferred formula 4Chemical compound is:
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(1-oxo tetrahydro-1,4-thiazine-4-yl) ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-picoline-5-yl)-2H-pyrazole-3-yl]-3-[4-(2-pyridin-4-yl-ethyoxyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-methoxypyridine-5-yl)-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-base-ethyoxyl) naphthalene-1-yl]-urea or
The 1-[5-tert-butyl group-2-methyl-2H-pyrazole-3-yl]-3-[4-(2-morpholine-Ji-ethyoxyl) naphthalene-1-yl]-urea.
In another embodiment preferred, the present invention relates to the p38 inhibitors of kinases and be used for the treatment of purposes in the inhalable drug compositions of Polyblennia in preparation, wherein the p38 inhibitors of kinases is selected from as disclosed formula in WO 00/55139 5Chemical compound.
Figure A0381298800631
Wherein:
Ar 1Be selected from: pyrroles, pyrrolidine, pyrazoles, imidazoles, oxazole, thiazole, furan and thiophene; Ar wherein 1Can be by 1 or a plurality of R 1, R 2Or R 3Replace;
Ar 2For: phenyl, naphthyl, quinoline, isoquinolin, tetralyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl or indole, each group is optional by 0～3 R 2Group replaces;
X is:
A) C 5-8Cycloalkyl or cycloalkenyl group, optional by 0-2 oxo group or 0-3C 1-4Branched-chain or straight-chain alkyl, C 1-4Alkoxyl or C 1-4The alkyl amino chain replaces;
B) phenyl, furan, thiophene, pyrroles, imidazole radicals, pyridine, pyrimidine, pyridone, dihydropyridine ketone, maleimide, dihydro maleimide, piperidines, piperazine or pyrazine, each group is optional independently by 0-3C 1-4Branched-chain or straight-chain alkyl, C 1-4Alkoxyl, hydroxyl, nitrile, list-or two-(C 1-3Alkyl) amino, C 1-6Alkyl-S (O) mOr halogen replaces;
Y is: chemical bond or optional part or complete halogenated saturated or unsaturated C 1-4Side chain or straight chain carbochain, wherein one or more methylene is optional by O, NH, S (O), S (O) 2Or S replaces and wherein Y is optional independently by 0-2 oxo group and one or more C 1-4Branched-chain or straight-chain alkyl replaces, described alkyl can by 1 or a plurality of halogen atom replace;
Z is:
A) phenyl, pyridine, pyrimidine, pyridazine, imidazoles, furan, thiophene, pyrans, each group is optional to be selected from halogen, C by 1～3 1-6Alkyl, C 1-6Alkoxyl, hydroxyl, list-or two-(C 1-3Alkyl) amino, C 1-6Alkyl-S (O) m, COOH and phenyl amino replace, wherein said benzyl ring is optional to be selected from halogen, C by 1～2 1-6Alkyl and C 1-6The group of alkoxyl replaces;
B) Pentamethylene oxide., oxolane, 1,3-dioxane pentanone, 1,3-dioxanone, 1,4-dioxane, morpholine, tetrahydro-1,4-thiazine, tetrahydro-1,4-thiazine sulfoxide, piperidines, piperidones, piperazine, tetrahydro pyrimidine ketone, Ketohexamethylene, Hexalin, pentamethylene thioether, pentamethylene sulfoxide, pentamethylene sulfone, tetramethylene thioether, tetramethylene sulfoxide or tetramethylene sulfone, each group is optional to be selected from nitrile, C by 1～3 1-6Alkyl, C 1-6Alkoxyl, hydroxyl, list-or two-(C 1-3Alkyl) amino-C 1-3Alkyl, phenyl amino-C 1-3Alkyl and C 1-3Alkoxy-C 1-3Alkyl replaces;
C) C 1-6Alkoxyl, the second month in a season or tertiary amine, wherein amino nitrogen is covalently bond to and is selected from C 1-3Alkyl, C 1-5Alkoxyalkyl, pyridine radicals-C 1-3Alkyl, imidazole radicals-C 1-3Alkyl, tetrahydrofuran base-C 1-3The group of alkyl, phenyl amino, wherein said benzyl ring is optional to be selected from halogen, C by 1～2 1-6Alkoxyl, hydroxyl or list-or two-(C 1-3Alkyl) amino, C 1-6Alkyl-S (O) mAnd phenyl-S (O) mGroup replace, wherein said benzyl ring is optional to be selected from halogen, C by 1～2 1-6Alkoxyl, hydroxyl or list-or two-(C 1-3Alkyl) the amino replacement;
R 1For:
A) optional part or complete halogenated C 3-10Branched-chain or straight-chain alkyl, described group is optional to be replaced by 1～3 phenyl, naphthyl or the heterocyclic radical that is selected from pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl; Each phenyl, naphthyl or the heterocycle that is selected from this section the above-mentioned group of record are selected from halogen, optional part or complete halogenated C by 0～5 1-6Branched-chain or straight-chain alkyl, C 3-8Cycloalkyl, C 5-8Cycloalkenyl group, hydroxyl, nitrile, optional part or complete halogenated C 1-3Alkoxyl, NH 2C (O) and two (C 1-3) group of alkyl amino-carbonyl replaces;
B) be selected from the C of cyclopropyl, cyclobutyl, Pentamethylene. base, cyclohexyl, cycloheptane base, bicyclo-pentyl, bicyclohexane base and bicycloheptane base 3-7Cycloalkyl, each group are randomly for partially or completely halogenated and randomly by 1～3 C 1-3Alkyl replaces, or wherein 1～3 ring methylene be independently selected from O, S, CHOH,＞C=O,＞analog of the alternate described cycloalkyl of group of C=S and NH;
C) optional part or complete halogenated C 3-10Branched alkenyl, described group is optional to be selected from C by 1～3 1-5The group of branched-chain or straight-chain alkyl, phenyl, naphthyl or heterocyclic radical replaces, each heterocyclic radical is independently selected from pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, and each described phenyl, naphthyl or heterocyclic radical are selected from halogen, optional part or complete halogenated C by 0～5 1-6Branched-chain or straight-chain alkyl, cyclopropyl, cyclobutyl, Pentamethylene. base, cyclohexyl, cycloheptane base, bicyclo-pentyl, bicyclohexane base, bicycloheptane base, hydroxyl, nitrile, optional part or complete halogenated C 1-3Alkoxyl, NH 2C (O) and list-or two (C 1-3) group of alkyl amino-carbonyl replaces;
D) C 5-7Cycloalkenyl group is selected from cyclopentenyl, cyclohexenyl group, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyl groups and bicycloheptene base, and wherein said cycloalkenyl group is optional by 1～3 C 1-3Alkyl replaces;
E) nitrile; Or
F) C 1-6Side chain or straight chain alkoxy carbonyl, C 1-6Branched-chain or straight-chain alkyl amino carbonyl, C 1-6Branched-chain or straight-chain alkyl carbonylamino-C 1-3-alkyl;
R 2For: optional part or complete halogenated C 1-6Branched-chain or straight-chain alkyl, acetyl group, aroyl, optional part or complete halogenated C 1-4Side chain or straight chain alkoxyl, halogen, methoxycarbonyl or phenyl sulfonyl;
R 3For:
A) phenyl, naphthyl or be selected from pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, tetrahydrofuran base isoxazolyl, isothiazolyl, quinolyl, isoquinolyl, indyl, benzimidazolyl, benzofuranyl benzoxazolyl, the benzoisoxazole base, the benzopyrazoles base, the benzo thiapyran base, cinnolinyl, pteridyl, phthalazinyl, the naphthyl pyridine radicals, quinoxalinyl, quinazolyl, the heterocyclic radical of purine radicals and indazolyl, wherein said phenyl, naphthyl or heterocyclic radical are optional to be replaced by 1～5 substituent group that is selected from the following radicals: phenyl, naphthyl, be selected from the heterocycle of the above-mentioned group of record in this section, optional part or complete halogenated C 1-6Branched-chain or straight-chain alkyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, two cyclopenta, dicyclohexyl, two suberyl, phenyl C 1-5Alkyl, naphthyl C 1-5Alkyl, halogen, hydroxyl, nitrile, randomly be partially or completely halogenated C 1-3Alkoxyl, phenoxy group, naphthoxy, the wherein said heterocyclic moiety of heteroaryloxy are selected from this section the above-mentioned group, nitro, amino, list of record-or two-(C 1-3) the amino wherein said heterocyclic radical of alkyl amino, phenyl amino, naphthyl amino, heterocyclic radical partly is selected from above-mentioned group, the NH of record in this section 2C (O), single-or two-(C 1-3) alkyl amino-carbonyl, C 1-5Alkyl-C (O)-C 1-4Alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3) alkyl amino-C 1-5Alkyl, amino-S (O) 2, two-(C 1-3) alkyl amino-S (O) 2, R 4-C 1-5Alkyl, R 5-C 1-5Alkoxyl, R 6-C (O)-C 1-5Alkyl and R 7-C 1-5Alkyl (R 8) N, carboxyl-list-or two-(C 1-5)-alkyl-amino;
B) condensed aryl is selected from benzocyclobutane alkyl, indanyl, indenyl, dihydro naphthyl, tetralyl, benzocyclohepta alkyl and benzocyclohepta thiazolinyl; Or the condensed heterocycle base, be selected from cyclopenta pyridine, hexamethylene and pyridine, cyclopentano pyrimidine, hexamethylene and pyrimidine, cyclopentano pyrazine, hexamethylene and pyrazine, cyclopentano pyridazine, hexamethylene and pyridazine, cyclopentano quinoline, hexamethylene and quinoline, cyclopentano isoquinolin, hexamethylene and isoquinolin, cyclopentano indole, hexamethylene diindyl, cyclopentano benzimidazole, hexamethylene and benzimidazole, cyclopentano benzoxazole, hexamethylene and benzoxazole, cyclopentano imidazoles, hexamethylene and imidazoles, cyclopentano thiophene and hexamethylene bithiophene; Wherein said fused-aryl or annelated heterocycles basic ring are replaced by 0～3 substituent group that is selected from following radicals, described substituent group is independently selected from phenyl, naphthyl and heterocyclic radical, described heterocyclic radical is selected from pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, optional part or complete halogenated C 1-6Branched-chain or straight-chain alkyl, halogen, nitrile, optional part or complete halogenated C 1-3Alkoxyl, phenoxy group, naphthoxy, the wherein said heterocyclic radical of heterocyclic oxy group partly are selected from this section the above-mentioned group, nitro, amino, list of record-or two-(C 1-3) the amino wherein said heterocyclic radical of alkyl amino, phenyl amino, naphthyl amino, heterocyclic radical partly is selected from above-mentioned group, the NH of record in this section 2C (O), single-or two-(C 1-3) alkyl amino-carbonyl, C 1-4Alkyl-OC (O), C 1-5Alkyl-C (O)-C 1-4Branched-chain or straight-chain alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3) alkyl amino-C 1-5Alkyl, R 9-C 1-5Alkyl, R 10-C 1-5Alkoxyl, R 11-C (O)-C 1-5Alkyl and R 12-C 1-5Alkyl (R 13) N;
C) cycloalkyl is selected from cyclopenta, cyclohexyl, suberyl, two cyclopenta, dicyclohexyl and two suberyl, and wherein said cycloalkyl is optional part or complete halo and is chosen wantonly 1～3 C 1-3Alkyl replaces;
D) C 5-7Cycloalkenyl group is selected from cyclopentenyl, cyclohexenyl group, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyl groups and bicycloheptene base, and wherein said cycloalkenyl group is optional by 1～3 C 1-3Alkyl replaces;
E) acetyl group, aroyl, alkoxy carbonyl alkyl or phenyl sulfonyl; Or
F) optional part or complete halogenated C 1-6Branched-chain or straight-chain alkyl;
Or R 1And R 2Can randomly form condensed phenyl or pyridyl ring together;
Each R 8And R 13Independently for being selected from: hydrogen and randomly be partially or completely halogenated C 1-4Branched-chain or straight-chain alkyl;
Each R 4, R 5, R 6, R 7, R 9, R 10, R 11And R 12Independently for being selected from morpholine, piperidines, piperazine, imidazoles and tetrazolium;
M is 0,1 or 2;
W is O or S
With and pharmaceutically acceptable derivant.
In another embodiment preferred, the present invention relates to the p38 inhibitors of kinases in the purposes that is used for preparing the inhalable drug compositions for the treatment of Polyblennia, wherein the p38 inhibitors of kinases is selected from as disclosed formula in WO 00/55139 5Chemical compound
Wherein:
Ar 2For naphthyl, tetralyl, indanyl or indenyl and
W is O.
In another embodiment preferred, the present invention relates to the p38 inhibitors of kinases in the purposes that is used for preparing the inhalable drug compositions for the treatment of Polyblennia, wherein the p38 inhibitors of kinases be selected from as WO 00/55139 in disclosed formula 5Chemical compound
Wherein:
Ar 1Be selected from thiophene and pyrazoles;
X is C 5-7Cycloalkyl or C 5-7Cycloalkenyl group, optional by 0-2 oxo group or 0-3 C 1-4Branched-chain or straight-chain alkyl, C 1-4Alkoxyl or C 1-4Alkyl amino replaces; Or X is phenyl, pyridine, tetrahydropyridine, pyrimidine, furan or thiophene, and each group is optional independently by 0-3 C 1-4Branched-chain or straight-chain alkyl, C 1-4Alkoxyl, hydroxyl, nitrile, list-or two-(C 1-3Alkyl) amino, C 1-6Alkyl-S (O) mOr halogen replaces;
R 1Be side chain or straight chain C 1-4Alkyl, cyclopropyl or cyclohexyl, optional part or complete halo are also optional by 1～3 C 1-3Alkyl replaces;
R 3Be side chain or straight chain C 1-4Alkyl, phenyl, pyrimidine radicals, pyrazolyl or pyridine radicals, each group is optional as above-mentionedly is substituted aspect the wideest, as above-mentioned alkoxy carbonyl alkyl or cyclopropyl or the cyclopenta that is optionally substituted in aspect the wideest.
In another embodiment preferred, the present invention relates to the p38 inhibitors of kinases in the purposes that is used for preparing the inhalable drug compositions for the treatment of Polyblennia, wherein the p38 inhibitors of kinases be selected from as WO 00/55139 in disclosed formula 5Chemical compound
Wherein:
Ar 1Be pyrazoles;
X is cyclopentenyl, cyclohexenyl group or cycloheptenyl, and is optional by oxo group or 0-3 C 1-4Branched-chain or straight-chain alkyl, C 1-4Alkoxyl or C 1-4Alkyl amino replaces; Or X is phenyl, pyridine, furan or thiophene, and each group is optional independently by 0-3 C 1-4Branched-chain or straight-chain alkyl, C 1-4Alkoxyl, hydroxyl, nitrile, list-or two-(C 1-3Alkyl) amino, C 1-6Alkyl-S (O) mOr halogen replaces.
In another preferred embodiment, the present invention relates to the p38 inhibitors of kinases in the purposes that is used for preparing the inhalable drug compositions for the treatment of Polyblennia, wherein the p38 inhibitors of kinases be selected from as WO 00/55139 in disclosed formula 5Chemical compound
Wherein:
Y is-CH 2-,-CH 2CH 2-,-CH 2NH-,-CH 2CH 2NH-or chemical bond;
And
Z is phenyl, imidazoles, furan, piperazine, Pentamethylene oxide., morpholine, tetrahydro-1,4-thiazine, tetrahydro-1,4-thiazine sulfoxide, piperidines, pyridine, the second month in a season or tertiary amine, and wherein amino nitrogen is covalently bond to and is selected from C 1-3Alkyl and C 1-5The group of alkoxyalkyl, phenyl amino, wherein said benzyl ring is optional to be selected from halogen, C by 1～2 1-6Alkoxyl, hydroxyl or list-or two-(C 1-3Alkyl) amino, C 1-6Alkyl-S (O) mAnd phenyl-S (O) mReplace, wherein said benzyl ring is optional by 1～2 halogen, C 1-6Alkoxyl, hydroxyl or list-or two-(C 1-3Alkyl) the amino replacement.
In another embodiment, the present invention relates to the p38 inhibitors of kinases in the purposes that is used for preparing the inhalable drug compositions for the treatment of Polyblennia, wherein the p38 inhibitors of kinases is selected from as disclosed formula in WO 00/55139 5Chemical compound, wherein:
Ar 1Be the 5-tert-butyl group-pyrazole-3-yl; Wherein the pyrazoles ring can be by R 3Replace;
R 3Be side chain or straight chain C 1-4Alkyl, phenyl, pyrimidine radicals, pyrazolyl, pyridine radicals, each group optional as above-mentioned the wideest aspect in the mode described replace, as above-mentioned the wideest aspect in the mode the described alkoxy carbonyl alkyl or cyclopropyl or the cyclopenta that replace.
In another embodiment preferred, the present invention relates to the p38 inhibitors of kinases in the purposes that is used for preparing the inhalable drug compositions for the treatment of Polyblennia, wherein the p38 inhibitors of kinases be selected from as WO 00/55139 in disclosed formula 5Chemical compound, wherein X is a pyridine radicals.
In another embodiment preferred, the present invention relates to the p38 inhibitors of kinases in the purposes that is used for preparing the inhalable drug compositions for the treatment of Polyblennia, wherein the p38 inhibitors of kinases is selected from as formula disclosed in WO 00/55139 5Chemical compound, wherein pyridine radicals is connected to Ar by 3-pyridine radicals position 1
In another embodiment preferred, the present invention relates to the p38 inhibitors of kinases and be used for the treatment of purposes in the inhalable drug compositions of Polyblennia in preparation, wherein the p38 inhibitors of kinases be selected from mention below as disclosed formula in WO00/55139 5Chemical compound:
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(4-(morpholine-4-yl) phenyl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(4-(morpholine-4-base-methyl) phenyl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(4-(2-(morpholine-4-yl) ethyl) phenyl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(4-dimethylaminophenyl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-(morpholine-4-yl) phenyl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-(morpholine-4-base-methyl) phenyl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(5-morpholine-4-ylmethyl-pyridine-2-yl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(5-morpholine-4-ylmethyl-furan-2-yl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-methyl-2H-pyrazole-3-yl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-phenyl-2H-pyrazole-3-yl]-3-[4-(4-piperidines-1-ylmethyl-phenyl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-phenyl-2H-pyrazole-3-yl]-3-[4-(4-(4-methyl piperazine-1-yl) aminomethyl phenyl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3,4-two (morpholine-4-base-methyl) phenyl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-pyridin-4-yl methyl-pyridin-3-yl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-(1-oxo-tetrahydro-1,4-thiazine-4-ylmethyl) pyridin-3-yl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(6-(1-oxo-tetrahydro-1,4-thiazine-4-ylmethyl) pyridin-3-yl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-tetrahydropyran-4-base methyl-pyridin-3-yl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-(1-oxo-Tetramethylene sulfide-3-ylmethyl) pyridin-3-yl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-(imidazoles-1-ylmethyl) pyridin-3-yl) naphthalene-1-yl] urea;
1-[2-(3-dimethylaminomethyl phenyl)-5-(1-methyl-cyclohexyl base)-2H-pyrazole-3-yl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl) naphthalene-1-yl] urea;
1-[2-(5-(1-methyl-cyclohexyl base)-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-ylmethyl-pyrimidine-5-yl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(3-methoxyl group-5-(2-morpholine-4-base-ethyoxyl) phenyl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(3-(2-morpholine-4-base-ethyoxyl) phenyl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-3-(dimethylamino) phenyl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-3-(methyl sulphonyl) phenyl) naphthalene-1-yl] urea;
The 5-tert-butyl group-3-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl) naphthalene-1-yl] urea groups } the thiophene-2-carboxylic acid methyl ester;
The 5-tert-butyl group-3-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl) naphthalene-1-yl] urea groups } the thiophene-2-carboxylic acid methyl nitrosourea;
The 5-tert-butyl group-1-methyl-3-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl) naphthalene-1-yl] urea groups }-1H-pyrroles-2-carboxylic acid methyl ester;
The 5-tert-butyl group-1-methyl-3-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl) naphthalene-1-yl] urea groups }-1H-pyrroles-2-carboxylic acid methyl amide;
2-acetyl-amino N-(the 5-tert-butyl group-3-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl) naphthalene-1-yl] urea groups } thiophene-2-ylmethyl) acetamide;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-morpholine-4-base-hexamethylene-1-thiazolinyl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-morpholine-4-base-ring heptan-1-thiazolinyl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-(2-morpholine-4-base-ethylamino) hexamethylene-1-thiazolinyl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-morpholine-4-base-ring heptan-1-thiazolinyl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(3-(pyridin-4-yl-methylamino) hexamethylene-1-thiazolinyl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(3-(dimethyl aminoethyl amino) hexamethylene-1-thiazolinyl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(3-(pyridin-3-yl-methylamino) hexamethylene-1-thiazolinyl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(3-(phenyl-methylamino) hexamethylene-1-thiazolinyl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(3-(2-phenylethyl amino) hexamethylene-1-thiazolinyl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(3-(furan-2-base-methylamino) hexamethylene-1-thiazolinyl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(3-(2-pyridine-2-base-ethylamino) hexamethylene-1-thiazolinyl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(3-(2-piperidines-1-base-ethylamino) hexamethylene-1-thiazolinyl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(3-(2-imidazol-4 yl-ethylamino) hexamethylene-1-thiazolinyl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(3-(pyridine-2-base-methylamino) hexamethylene-1-thiazolinyl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(3-(2-(4-methoxyphenyl) ethylamino) hexamethylene-1-thiazolinyl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(4-morpholine-4-ylmethyl-3-oxo-hexamethylene-1-thiazolinyl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(4-(1-oxo-Tetramethylene sulfide-3-ylmethyl)-3-oxo-hexamethylene-1-thiazolinyl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(4-(1-oxo-tetrahydro-1,4-thiazine-4-ylmethyl)-3-oxo-hexamethylene-1-thiazolinyl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(4-methyl piperazine-1-ylmethyl)-3-oxo-hexamethylene-1-thiazolinyl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-{6-oxo-1-(tetrahydrochysene-pyrans-4-ylmethyl)-1,2,3,6-tetrahydrochysene-pyridin-4-yl } naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(2-oxo-1-pyridin-4-yl methyl-piperidin-4-yl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(6-oxo-1-pyridin-4-yl-1,2,3,6-tetrahydrochysene-pyridin-4-yl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-oxo-1-pyridin-4-yl-1,2,3,6-tetrahydrochysene-pyridin-4-yl) naphthalene-1-yl] urea;
The 5-tert-butyl group-3-{3-[4-(6-oxo-1-pyridin-4-yl-1,2,3,6-tetrahydrochysene-pyridin-4-yl) naphthalene-1-yl] urea groups } the thiophene-2-carboxylic acid methyl ester;
The 5-tert-butyl group-1-methyl-3-{3-[4-(6-oxo-1-pyridin-4-yl-1,2,3,6-tetrahydrochysene-pyridin-4-yl) naphthalene-1-yl] urea groups } pyrroles-2-carboxylic acid methyl ester;
The 5-tert-butyl group-1-methyl-3-{3-[4-(6-oxo-1-pyridin-4-yl-1,2,3,6-tetrahydrochysene-pyridin-4-yl) naphthalene-1-yl] urea groups } pyrroles-2-carboxylic acid methyl amide;
The 5-tert-butyl group-3-{3-[4-(3-morpholine-4-base-hexamethylene-1-thiazolinyl) naphthalene-1-yl] urea groups } the thiophene-2-carboxylic acid methyl ester;
The 5-tert-butyl group-1-methyl-3-(3-[4-(3-morpholine-4-base-hexamethylene-1-thiazolinyl) naphthalene-1-yl] urea groups } pyrroles-2-carboxylic acid methyl ester; And
The 5-tert-butyl group-1-methyl-3-{3-[4-(3-morpholine-4-base-hexamethylene-1-thiazolinyl) naphthalene-1-yl] urea groups pyrroles-2-carboxylic acid methyl amide with and pharmaceutically acceptable derivant.
Preferably the present invention relates to the p38 inhibitors of kinases and be used for the treatment of purposes in the inhalable drug compositions of Polyblennia in preparation, wherein the p38 inhibitors of kinases is selected from formula 5Chemical compound:
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(4-(morpholine-4-base-methyl) phenyl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(4-(2-(morpholine-4-yl) ethyl) phenyl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-(morpholine-4-base-methyl) phenyl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(5-morpholine-4-ylmethyl-pyridine-2-yl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(5-morpholine-4-ylmethyl-furan-2-yl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl) naphthalene-1-yl] urea;
The 1-[5-tert-butyl group-2-methyl-2H-pyrazole-3-yl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl) naphthalene-1-yl] urea and
Its pharmaceutically acceptable derivant.
In another embodiment, the present invention relates to the p38 inhibitors of kinases and be used for the treatment of purposes in the inhalable drug compositions of Polyblennia in preparation, wherein the p38 inhibitors of kinases is selected from as disclosed formula in WO00/55139 5aChemical compound
Figure A0381298800741
Wherein:
Ar 1For: pyrroles, pyrrolidine, pyrazoles, imidazoles, oxazole, thiazole, furan and thiophene; Ar wherein 1Optional by one or more R 1, R 2Or R 3Replace;
Ar 2For: phenyl, naphthyl, quinoline, isoquinolin, tetralyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl and indole, each group is optional by 0～3 R 2Group replaces;
X is:
C 5-8Cycloalkyl or cycloalkenyl group, optional by 1 or 2 oxo group or 1～3 C 1-4Alkyl,
C 1-4Alkoxyl or C 1-4The alkyl amino chain replaces, and wherein said each group is side chain or straight chain;
Phenyl, furyl, thienyl, pyrrole radicals, pyrazolyl, imidazole radicals, pyridine radicals, tetrahydro pyridyl, pyrimidine radicals, pyriconyl, dihydropyridine ketone group, dimaleoyl imino, dihydro dimaleoyl imino, piperidyl, benzimidazole, 3H-imidazo [4,5-b] pyridine, piperazinyl, pyridazinyl or pyrazinyl; Each group is optional to be selected from C by 1～3 independently 1-4Alkyl, C 1-4Alkoxyl, hydroxyl, nitrile, amino, list-or two-(C 1-3Alkyl) amino, single-or two-(C 1-3Alkyl amino) carbonyl, NH 2C (O), C 1-6Alkyl-S (O) mOr the group of halogen replaces;
Y is: chemical bond or optional part or complete halogenated C 1-4Saturated or unsaturated side chain or straight chain carbochain, wherein one or more C atom is optional by O, N or S (O) mReplace and wherein Y is optional independently by 1 or 2 oxo group, nitrile, phenyl, hydroxyl or 1 or a plurality of optional C that is substituted one or more halogen atom 1-4Alkyl replaces;
Z is: aryl; indanyl; heteroaryl; described heteroaryl is selected from benzimidazolyl; pyridine radicals; pyrimidine radicals; pyridazinyl; pyrazinyl; imidazole radicals; pyrazolyl; triazolyl; tetrazole radical; furyl; thienyl and pyranose; heterocycle is selected from piperazinyl; the tetrahydropyrimidine ketone group; hexamethylene ketone group (cyclohexanonyl); hexamethylene acyl group (cyclohexanolyl); the 2-oxa--or 2-thia-5-aza-bicyclo [2.2.1] heptane base; the pentamethylene sulfenyl; the pentamethylene sulfoxide group; the pentamethylene sulfonyl; the tetramethylene sulfenyl; tetramethylene sulfoxide base or tetramethylene sulfonyl; THP trtrahydropyranyl; tetrahydrofuran base; 1; 3-dioxo Ketocyclopentane base; 1; 3-dioxanone base; 1; 4-dioxane base; morpholino; tetrahydro-1,4-thiazine generation; tetrahydro-1,4-thiazine is for sulfoxide group; tetrahydro-1,4-thiazine is for sulfonyl; piperidyl; piperidone base; pyrrolidinyl and dioxo Pentamethylene. base, each aforementioned Z group are chosen substituted 11～3 following radicals wantonly and are replaced: halogen; C 1-6Alkyl, C 1-6Alkoxyl, C 1-3Alkoxy-C 1-3Alkyl, C 1-6Alkoxy carbonyl, aroyl, 4-hetaroylpyrazol, heterocycle C 1-3Above-mentioned definition in the wherein said heteroaryl of acyl group and heterocycle such as this section, C 1-3Acyl group, oxo, hydroxyl, pyridine radicals-C 1-3Alkyl, imidazole radicals-C 1-3Alkyl, tetrahydrofuran base-C 1-3Alkyl, nitrile-C 1-3Alkyl, nitrile, carboxyl, phenyl, wherein said benzyl ring is optional to be replaced by 1～2 following radicals: halogen, C 1-6Alkoxyl, hydroxyl or list-or two-(C 1-3Alkyl) amino, amino-S (O) m, C 1-6Alkyl-S (O) mOr phenyl-S (O) m, wherein said benzyl ring is optional by 1～2 halogen, C 1-6Alkoxyl, hydroxyl, halogen or list-or two-(C 1-3Alkyl) the amino replacement;
Or Z is optional by 1～3 amino, amino carbonyl or amino-C 1-3Alkyl replaces, and wherein the N atom is optional independently by amino C 1-6Alkyl, C 1-3Alkyl, aryl C 0-3Alkyl, C 1-5Alkoxy C 1-3Alkyl, C 1-5Alkoxyl, aroyl, C 1-3Acyl group, C 1-3Alkyl-S (O) m-or aryl C 0-3Alkyl-S (O) m-single-or two-replacing, aforementioned each alkyl and the aryl that is connected to amino chosen wantonly by 1～2 halogen, C 1-6Alkyl, C 1-6Alkoxyl, hydroxyl or list-or two-(C 1-3Alkyl) the amino replacement;
Or Z is optional by 1～3 as aryl noted earlier, heterocycle or heteroaryl replacement in this section, and each group is chosen wantonly conversely by halogen, C 1-6Alkyl or C 1-6Alkoxyl replaces;
Or Z is hydroxyl, hydroxyl C 1-3Alkyl, halogen, nitrile, amino wherein N atom are optional independently by C 1-6Alkyl, amino C 1-6Alkyl, aryl C 0-3Alkyl, C 1-5Alkoxy C 1-3Alkyl, C 1-5Alkoxyl, aroyl, C 1-3Acyl group, C 1-3Alkyl-S (O) m-, aryl C 0-3Alkyl-S (O) m-, nitrile C 1-4Alkyl or C 1-3Alkoxy C 1-3Alkyl is singly-or two-replace, it is optional by 1～2 halogen, C to be connected to each amino aforesaid alkyl and aryl 1-6Alkyl, C 1-6Alkoxyl, hydroxyl or list-or two-(C 1-3Alkyl) amino, C 1-6Alkoxyl heteroaryl C 0-3Alkyl, heteroaryl C 0-3Alkyl or heterocycle C 0-3Alkyl replaces, and is noted earlier in wherein said heteroaryl and heterocycle such as this section,
Or Z is side chain or straight chain C 1-6Alkyl, C 1-6Alkoxyl, C 1-3Acyl amino, nitrile C 1-4Alkyl, C 1-6Alkyl-S (O) m, and phenyl-S (O) m,, wherein benzyl ring is optional by 1～2 halogen, C 1-6Alkoxyl, hydroxyl or list-or two-(C 1-3Alkyl) the amino replacement;
R 1For:
A) randomly partially or completely halogenated C 1-10Branched-chain or straight-chain alkyl, each group is optional to be selected from following group replacement by 1～3: phenyl, naphthyl or heterocyclic radical are selected from pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl; Each phenyl, naphthyl or the heterocycle that is selected from above-mentioned group can be selected from following group by 0～5 and replace: halogen, optional part or complete halogenated C 1-6Branched-chain or straight-chain alkyl, C 3-8Cycloalkyl, C 5-8Cycloalkenyl group, hydroxyl, nitrile, optional part or complete halogenated C 1-3Alkoxyl, NH 2C (O) and two (C 1-3) alkyl amino-carbonyl;
B) C 3-7Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, two cyclopenta, dicyclohexyl and two suberyl, and each group optional part or complete halo are also optional by 1～3 C 1-3Alkyl replaces, or wherein 1～3 ring methylene be independently selected from O, S, CHOH,＞C=O,＞analog of C=S and the alternate described cycloalkyl of NH;
C) optional part or complete halogenated C 3-10Branched alkenyl, each group is optional by 1～3 C 1-5Branched-chain or straight-chain alkyl, phenyl, naphthyl or heterocyclic radical replace, each heterocyclic radical is independently selected from pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, and each phenyl, naphthyl or heterocyclic radical can be selected from following group replacement by 0～5: halogen, optional part or complete halogenated C 1-6Branched-chain or straight-chain alkyl, cyclopropyl, cyclobutyl, Pentamethylene. base, cyclohexyl, cycloheptane base, bicyclo-pentyl, bicyclohexane base, bicycloheptane base, hydroxyl, nitrile, optional part or complete halogenated C 1-3Alkoxyl, NH 2C (O) and list-or two (C 1-3) alkyl amino-carbonyl;
D) C 5-7Cycloalkenyl group is selected from cyclopentenyl, cyclohexenyl group, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyl groups and bicycloheptene base, and wherein said cycloalkenyl group is optional by 1～3 C 1-3Alkyl replaces;
E) nitrile; Or
F) C 1-6Side chain or straight chain alkoxy carbonyl, C 1-6Branched-chain or straight-chain alkyl amino carbonyl, C 1-6Branched-chain or straight-chain alkyl carbonylamino-C 1-3-alkyl;
R 2For: C 1-6Branched-chain or straight-chain alkyl, optional part or complete halo are also optional to be replaced by nitrile, or R 2Be acetyl group, aroyl, partially or completely halogenated C randomly 1-4Side chain or straight chain alkoxyl, halogen, methoxycarbonyl or phenyl sulfonyl;
R 3For:
A) phenyl, naphthyl or heterocyclic radical, described heterocyclic radical is selected from pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, tetrahydrofuran base isoxazolyl, isothiazolyl, quinolyl, isoquinolyl, indyl, benzimidazolyl, benzofuranyl benzoxazolyl, the benzoisoxazole base, the benzopyrazoles base, the benzo thiapyran base, cinnolinyl, pteridyl, phthalazinyl, the naphthyl pyridine radicals, quinoxalinyl, quinazolyl, purine radicals and indazolyl, wherein said phenyl, naphthyl or heterocyclic radical are optional to be selected from following group replacement by 1～5: phenyl, naphthyl, be selected from the heterocycle of the above-mentioned group of record in this section, optional part or complete halogenated C 1-6Branched-chain or straight-chain alkyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, two cyclopenta, dicyclohexyl, two suberyl, phenyl C 1-5Alkyl, naphthyl C 1-5Alkyl, halogen, hydroxyl, oxo, nitrile, optional part or complete halogenated C 1-3Alkoxyl, C 1-3Alkoxy C 1-5Alkyl, C 1-3Alkylthio, C 1-3Alkylthio C 1-5Alkyl, phenoxy group, naphthoxy, the wherein said heterocyclic moiety of heteroaryloxy are selected from this section the above-mentioned group, nitro, amino, list of record-or two-(C 1-3) the amino wherein said heterocyclic radical of alkyl amino, phenyl amino, naphthyl amino, heterocyclic radical partly is selected from above-mentioned group, the NH of record in this section 2C (O), single-or two-(C 1-3) alkyl amino-carbonyl, C 1-5Alkyl-C (O)-C 1-4Alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3) alkyl amino-C 1-5Alkyl, amino-S (O) 2, two-(C 1-3) alkyl amino-S (O) 2, R 4-C 1-5Alkyl, R 5-C 1-5Alkoxyl, R 6-C (O)-C 1-5Alkyl and R 7-C 1-5Alkyl (R 8) N, carboxyl-list-or two-(C 1-5)-alkyl-amino;
B) condensed aryl is selected from benzocyclobutane alkyl, indanyl, indenyl, dihydro naphthyl, tetralyl, benzocyclohepta alkyl and benzocyclohepta thiazolinyl; Or the condensed heterocycle base, be selected from cyclopenta pyridine, hexamethylene and pyridine, cyclopentano pyrimidine, hexamethylene and pyrimidine, cyclopentano pyrazine, hexamethylene and pyrazine, cyclopentano pyridazine, hexamethylene and pyridazine, cyclopentano quinoline, hexamethylene and quinoline, cyclopentano isoquinolin, hexamethylene and isoquinolin, cyclopentano indole, hexamethylene diindyl, cyclopentano benzimidazole, hexamethylene and benzimidazole, cyclopentano benzoxazole, hexamethylene and benzoxazole, cyclopentano imidazoles, hexamethylene and imidazoles, cyclopentano thiophene and hexamethylene bithiophene; Wherein said fused-aryl or annelated heterocycles basic ring are replaced by the substituent group that 0～3 group is independently selected from the following groups: phenyl, naphthyl and heterocyclic radical, described heterocyclic radical is selected from pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, optional part or complete halogenated C 1-6Branched-chain or straight-chain alkyl, halogen, nitrile, optional part or complete halogenated C 1-3Alkoxyl, phenoxy group, naphthoxy, the wherein said heterocyclic radical of heterocyclic oxy group partly are selected from above-mentioned group, nitro, amino, list-or two-(C 1-3) the amino wherein said heterocyclic radical of alkyl amino, phenyl amino, naphthyl amino, heterocyclic radical partly is selected from above-mentioned group, NH 2C (O), single-or two-(C 1-3) alkyl amino-carbonyl, C 1-4Alkyl-OC (O), C 1-5Alkyl-C (O)-C 1-4Branched-chain or straight-chain alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3) alkyl amino-C 1-5Alkyl, R 9-C 1-5Alkyl, R 10-C 1-5Alkoxyl, R 11-C (O)-C 1-5Alkyl and R 12-C 1-5Alkyl (R 13) N;
C) cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, two cyclopenta, dicyclohexyl and two suberyl, and wherein cycloalkyl optional part or complete halo are also randomly by 1～3 C 1-3Alkyl replaces;
D) C 5-7Cycloalkenyl group is selected from cyclopentenyl, cyclohexenyl group, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyl groups and bicycloheptene base, and wherein cycloalkenyl group is optional by 1～3 C 1-3Alkyl replaces;
E) acetyl group, aroyl, C 1-6Alkoxy carbonyl C 1-6The alkyl or phenyl sulfonyl; Or
F) optional part or complete halogenated C 1-6Branched-chain or straight-chain alkyl;
Or R 1And R 2Randomly form fused phenyl or pyridyl ring together;
Each R 8And R 13Independently for being selected from: hydrogen and optional part or complete halogenated C 1-4Branched-chain or straight-chain alkyl;
Each R 4, R 5, R 6, R 7, R 9, R 10, R 11And R 12Independently for being selected from morpholine, piperidines, piperazine, imidazoles and tetrazolium;
M is 0,1 or 2;
W is O or S;
Wherein X directly connects 1 or 2-Y-Z, and
Its pharmaceutically acceptable derivant.
In another embodiment, the present invention relates to the p38 inhibitors of kinases in the purposes that is used for preparing treatment Polyblennia ground inhalable drug compositions, wherein the p38 inhibitors of kinases is selected from formula 5aChemical compound, wherein:
Ar 2For naphthyl, tetralyl, indanyl or indenyl and
W is O.
In another embodiment, the present invention relates to the p38 inhibitors of kinases in the purposes that is used for preparing treatment Polyblennia ground inhalable drug compositions, wherein the p38 inhibitors of kinases is selected from formula 5aChemical compound, wherein:
Ar 1Thiophene or pyrazoles are independently of one another by 1～3 R 1, R 2Or R 3Replace;
X is:
C 5-7Cycloalkyl or cycloalkenyl group, optional by 1 or 2 oxo group or 1～3 C 1-4Alkyl, C 1-4Alkoxyl or C 1-4The alkyl amino chain replaces, and each group can be side chain or straight chain;
Phenyl, indanyl, furyl, thienyl, imidazole radicals, pyridine radicals, pyrazinyl, tetrahydro pyridyl, pyrimidine radicals, pyriconyl, piperidyl, benzimidazole or piperazinyl; Each group is optional independently by 1～3 C 1-4Alkyl, C 1-4Alkoxyl, hydroxyl, nitrile, amino, list-or two-(C 1-3Alkyl) amino, single-or two-(C 1-3Alkyl amino) carbonyl, NH 2C (O), C 1-6Alkyl-S (O) mOr halogen replaces;
Y is: chemical bond or optional part or complete halogenated C 1-4Saturated or unsaturated side chain or straight chain carbochain, wherein one or more C atom is optional is replaced by O or N, and wherein Y is optional independently by 1 or 2 oxo group, nitrile, phenyl, hydroxyl or 1 or a plurality of optional by one or more halogen atom replacement ground C 1-4Alkyl replaces;
Z is: phenyl; heteroaryl is selected from pyridine radicals, imidazole radicals, furyl and thienyl; heterocycle is selected from piperazinyl, 2-oxa--5-aza-bicyclo [2.2.1] heptane base, pentamethylene sulfenyl, pentamethylene sulfoxide group, pentamethylene sulfonyl, tetrahydrofuran base, morpholino, tetrahydro-1,4-thiazine generation and piperidyl, and aforementioned each Z group is optional to be selected from following group by 1～3 and to replace: halogen, C 1-6Alkyl, C 1-6Alkoxyl, C 1-3Alkoxy-C 1-3Alkyl, C 1-6Alkoxy carbonyl, aroyl, morpholino carbonyl, C 1-3Acyl group, oxo, hydroxyl, pyridine radicals-C 1-3Alkyl, imidazole radicals-C 1-3Alkyl, tetrahydrofuran base-C 1-3Alkyl, nitrile-C 1-3Alkyl, nitrile, carboxyl, phenyl, wherein benzyl ring is optional is replaced by 1～2 following radicals: halogen, C 1-6Alkoxyl, hydroxyl or list-or two-(C 1-3Alkyl) amino, amino-S (O) m, C 1-6Alkyl-S (O) mOr phenyl-S (O) mWherein said benzyl ring is optional by 1～2 halogen, C 1-6Alkoxyl, hydroxyl, halogen or list-or two-(C 1-3Alkyl) the amino replacement;
Or Z is optional by 1～3 amino, amino carbonyl or amino-C 1-3Alkyl replaces, and wherein the N atom is optional independently by amino C 1-6Alkyl, C 1-3Alkyl, aryl C 0-3Alkyl, C 1-5Alkoxy C 1-3Alkyl, C 1-5Alkoxyl, aroyl, C 1-3Acyl group, C 1-3Alkyl-S (O) m-or aryl C 0-3Alkyl-S (O) m-be singly-or two-replace, it is optional by 1～2 halogen, C to be connected to amino aforementioned each alkyl and aryl 1-6Alkyl or C 1-6Alkoxyl replaces;
Or Z is optional by 1～3 as foregoing aryl, heterocycle or heteroaryl replacement in this section, and each group is chosen wantonly conversely by halogen, C 1-6Alkyl or C 1-6Alkoxyl replaces;
Or Z is hydroxyl, hydroxyl C 1-3Alkyl, halogen, nitrile, amino wherein N atom are optional independently by aroyl, C 1-3Acyl group, C 1-6Alkyl, C 1-5Alkoxy C 1-3Alkyl, pyridine radicals C 1-3Alkyl, tetrahydrofuran base C 1-3Alkyl, nitrile C 1-4Alkyl or phenyl is singly-or two-replacing, wherein said benzyl ring is optional by 1～2 halogen, C 1-6Alkoxyl, hydroxyl or list-or two-(C 1-3Alkyl) the amino replacement, or Z is side chain or straight chain C 1-6Alkyl, C 1-6Alkoxyl or nitrile C 1-4Alkyl;
R 1For:
Optional part or complete halogenated C 1-4Branched-chain or straight-chain alkyl;
Optional part or complete halogenated cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl and suberyl, each group is optional by 1～3 C 1-3Alkyl replaces, or wherein 1～3 ring methylene is selected from the analog of the alternate described cycloalkyl of group of O, S and NH independently;
Optional part or complete halogenated C 3-10Branched alkenyl, each group is optional by 1～3 C 1-5Branched-chain or straight-chain alkyl replaces;
Cyclopentenyl and cyclohexenyl group, optional by 1～3 C 1-3Alkyl replaces;
R 2For: C 1-6Branched-chain or straight-chain alkyl, optional part or complete halo are also optional to be replaced by nitrile;
R 3For:
Phenyl or heterocyclic radical, described heterocyclic radical is selected from pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl and pyrazolyl, wherein said phenyl or heterocyclic radical are optional to be replaced by 1～5 substituent group that is selected from following groups: phenyl, be selected from the heterocycle of the above-mentioned group of record in this section, optional part or complete halogenated C 1-6Branched-chain or straight-chain alkyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, two cyclopenta, dicyclohexyl, two suberyl, phenyl C 1-5Alkyl, naphthyl C 1-5Alkyl, halogen, hydroxyl, oxo, nitrile, randomly be partially or completely halogenated C 1-3Alkoxyl, C 1-3Alkoxy C 1-5Alkyl, C 1-3Alkylthio, C 1-3Alkylthio C 1-5Alkyl, phenoxy group, naphthoxy, the wherein said heterocyclic moiety of heteroaryloxy are selected from this section the above-mentioned group, nitro, amino, list of record-or two-(C 1-3) the amino wherein said heterocyclic radical of alkyl amino, phenyl amino, naphthyl amino, heterocyclic radical partly is selected from above-mentioned group, the NH of record in this section 2C (O), single-or two-(C 1-3) alkyl amino-carbonyl, C 1-5Alkyl-C (O)-C 1-4Alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3) alkyl amino-C 1-5Alkyl, amino-S (O) 2, two-(C 1-3) alkyl amino-S (O) 2, R 4-C 1-5Alkyl, R 5-C 1-5Alkoxyl, R 6-C (O)-C 1-5Alkyl and R 7-C 1-5Alkyl (R 8) N, carboxyl-list-or two-(C 1-5)-alkyl-amino;
Condensed aryl is selected from benzocyclobutane alkyl, indanyl, indenyl; Wherein said fused-aryl is replaced by the substituent group that 0～3 group is independently selected from following radicals: phenyl, naphthyl and heterocyclic radical, described heterocyclic radical is selected from pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, optional part or complete halogenated C 1-6Branched-chain or straight-chain alkyl, halogen, nitrile, optional part or complete halogenated C 1-3Alkoxyl, phenoxy group, naphthoxy, the wherein said heterocyclic radical of heterocyclic oxy group partly are selected from this section the above-mentioned group, nitro, amino, list of record-or two-(C 1-3) the amino wherein said heterocyclic radical of alkyl amino, phenyl amino, naphthyl amino, heterocyclic radical partly is selected from above-mentioned group, the NH of record in this section 2C (O), single-or two-(C 1-3) alkyl amino-carbonyl, C 1-4Alkyl-OC (O), C 1-5Alkyl-C (O)-C 1-4Branched-chain or straight-chain alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3) alkyl amino-C 1-5Alkyl, R 9-C 1-5Alkyl, R 10-C 1-5Alkoxyl, R 11-C (O)-C 1-5Alkyl and R 12-C 1-5Alkyl (R 13) N;
Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, wherein cycloalkyl optional part or halo and optional by 1～3 C fully 1-3Alkyl replaces;
C 1-6Alkoxy carbonyl C 1-6Alkyl;
Or R 1And R 2Randomly form fused phenyl or pyridyl ring together;
Each R 8And R 13Independently for being selected from: hydrogen and C 1-4Branched-chain or straight-chain alkyl optional part or complete halo;
And
Each R 4, R 5, R 6, R 7, R 9, R 10, R 11And R 12Independently for being selected from morpholine, piperidines, piperazine, imidazoles and tetrazolium;
Wherein X directly is connected to one-Y-Z.
In another embodiment, the present invention relates to the p38 inhibitors of kinases in the purposes that is used for preparing treatment Polyblennia ground inhalable drug compositions, wherein the p38 inhibitors of kinases is selected from formula 5aChemical compound, wherein:
Ar 1Be pyrazoles;
X is:
Cyclopentenyl, cyclohexenyl group, cycloheptenyl, optional by oxo group or 1～3 C 1-4Alkyl, C 1-4Alkoxyl or C 1-4The alkyl amino chain replaces, and each group can be side chain or straight chain; Phenyl, furyl, thienyl, pyridine radicals, pyrazinyl piperidyl or pyrimidine radicals, each group is optional independently by 1～3 C 1-2Alkyl, C 1-2Alkoxyl, hydroxyl or halogen replace;
Z is:
Phenyl, heteroaryl are selected from pyridine radicals, imidazole radicals and furyl; Heterocycle is selected from 2-oxa--5-aza-bicyclo [2.2.1] heptane base, pentamethylene sulfenyl, pentamethylene sulfoxide group, pentamethylene sulfonyl, tetrahydrofuran base, THP trtrahydropyranyl, piperazinyl, morpholino, tetrahydro-1,4-thiazine generation, tetrahydro-1,4-thiazine for sulfoxide and piperidyl, and aforementioned each Z group is optional to be replaced by 1～3 substituent group that is selected from the following radicals: halogen, C 1-6Alkyl, C 1-6Alkoxyl, C 1-3Alkoxy-C 1-3Alkyl, C 1-6Alkoxy carbonyl, aroyl, morpholino carbonyl, C 1-3Acyl group, oxo, hydroxyl, pyridine radicals-C 1-3Alkyl, imidazole radicals-C 1-3Alkyl, tetrahydrofuran base-C 1-3Alkyl, nitrile-C 1-3Alkyl, nitrile, carboxyl, phenyl, wherein benzyl ring is optional by 1～2 halogen, C 1-6Alkoxyl, hydroxyl or list-or two-(C 1-3Alkyl) amino, amino-S (O) m, C 1-6Alkyl-S (O) mOr phenyl-S (O) mReplace, wherein said benzyl ring is optional by 1～2 halogen, C 1-6Alkoxyl, hydroxyl, halogen or list-or two-(C 1-3Alkyl) the amino replacement;
Or Z is optional by 1～3 amino, amino carbonyl or amino-C 1-3Alkyl replaces, and wherein the N atom is optional is by amino C independently 1-6Alkyl, C 1-3Alkyl, aryl C 0-3Alkyl, C 1-5Alkoxy C 1-3Alkyl, C 1-5Alkoxyl, aroyl, C 1-3Acyl group, C 1-3Alkyl-S (O) m-, pyridine radicals C 0-3Alkyl, tetrahydrofuran base C 0-3Alkyl or aryl C 0-3Alkyl-S (O) m-aforementioned list-or two-replace, it is optional by 1～2 halogen, C to be connected to each amino alkyl and aryl 1-6Alkyl or C 1-6Alkoxyl replaces;
Or Z is hydroxyl, hydroxyl C 1-3Alkyl, halogen, nitrile, amino, wherein the N atom is optional independently by C 1-6Alkyl, pyridine radicals C 0-3Alkyl, tetrahydrofuran base C 0-3Alkyl, C 1-5Alkoxy C 1-3Alkyl, C 1-3Acyl group, nitrile C 1-4The alkyl or phenyl list-or two-replace, wherein benzyl ring is optional by 1～2 halogen, C 1-6Alkoxyl, hydroxyl or list-or two-(C 1-3Alkyl) the amino replacement, or Z is side chain or straight chain C 1-6Alkyl, C 1-6Alkoxyl or nitrile C 1-4Alkyl;
R 1For:
Optional part or complete halogenated C 1-4Branched-chain or straight-chain alkyl;
Cyclopropyl, cyclobutyl, Pentamethylene. base, cyclohexyl and cycloheptane base, each group optional part or complete halo are also optional by 1～3 C 1-3Alkyl replaces, or wherein 1～3 ring methylene is independently selected from the similar group of the alternate described cycloalkyl of group of O, S and NH;
C 3-10Branched alkenyl, optional part or complete halo are also optional by 1～3 C 1-3Branched-chain or straight-chain alkyl replaces;
Cyclopentenyl and cyclohexenyl group, optional by 1～3 C 1-3Alkyl replaces;
R 2For: C 1-6Branched-chain or straight-chain alkyl, optional part or complete halo are also optional to be replaced by nitrile;
R 3For: phenyl or heterocyclic radical, described heterocyclic radical is selected from pyridine radicals, pyrimidine radicals, pyridazinyl and pyrazolyl, and wherein said phenyl or heterocyclic radical are optional to be replaced by 1～5 substituent group that is selected from the following group: phenyl, be selected from heterocycle, optional part or the complete halogenated C of the above-mentioned group of record in this section 1-6Branched-chain or straight-chain alkyl, phenyl C 1-5Alkyl, halogen, hydroxyl, oxo, nitrile, optional part or complete halogenated C 1-3Alkoxyl, C 1-3Alkylthio, C 1-3Alkylthio C 1-5Alkyl, amino, list-or two-(C 1-3) alkyl amino, NH 2C (O) or list-or two-(C 1-3) alkyl amino-carbonyl, C 1-6Alkoxy carbonyl C 1-6Alkyl;
Or R 3Be cyclopropyl or cyclopenta, each group optional part or complete halo are also optional by 1～3 C 1-3Alkyl replaces,
Or R 1And R 2Randomly form fused phenyl or pyridyl ring together.
In another embodiment, the present invention relates to the p38 inhibitors of kinases in the purposes that is used for preparing the inhalable drug compositions for the treatment of Polyblennia, wherein the p38 inhibitors of kinases is selected from formula 5aChemical compound, wherein:
Y is-CH 2-,-O-(CH 2) 0-3-,-CH 2CH 2-,-CH 2NH-,-CH 2CH 2-NH-, NH-CH 2CH 2-,-CH 2-NH-CH 2-,-NH-,-NH-C (O)-,-C (O)-,-CH (OH)-,-CH 2(CH 2CH 3)-or chemical bond;
X is:
Cyclohexenyl group, optional by oxo group or 1～3 C 1-4Alkyl, C 1-4Alkoxyl or C 1-4Alkyl amino chain, each group can be side chain or straight chain replaces; Phenyl, pyridine radicals, pyrazinyl, piperidyl or pyrimidine radicals, each group is optional independently by 1～3 C 1-2Alkyl, C 1-2Alkoxyl, hydroxyl or halogen replace;
Z is: phenyl; heteroaryl is selected from pyridine radicals, imidazole radicals and furyl; heterocycle is selected from 2-oxa--5-aza-bicyclo [2.2.1] heptane base, pentamethylene sulfenyl, pentamethylene sulfoxide group, pentamethylene sulfonyl, tetrahydrofuran base, THP trtrahydropyranyl, piperazinyl, morpholino, tetrahydro-1,4-thiazine generation, tetrahydro-1,4-thiazine for sulfoxide and piperidyl, and each group of aforementioned Z is optional to be replaced by 1～3 substituent group that is selected from the group in following: halogen, C 1-6Alkyl, C 1-6Alkoxyl, C 1-3Alkoxy-C 1-3Alkyl, C 1-6Alkoxy carbonyl, aroyl, morpholino carbonyl, C 1-3Acyl group, oxo, hydroxyl, pyridine radicals-C 1-3Alkyl, imidazole radicals-C 1-3Alkyl, tetrahydrofuran base-C 1-3Alkyl, nitrile-C 1-3Alkyl, nitrile, carboxyl, phenyl, wherein benzyl ring is optional by 1～2 halogen, C 1-6Alkoxyl, hydroxyl or list-or two-(C 1-3Alkyl) amino, amino-S (O) m, C 1-6Alkyl-S (O) mOr phenyl-S (O) mReplace, wherein benzyl ring is optional by 1～2 halogen, C 1-6Alkoxyl, hydroxyl, halogen or list-or two-(C 1-3Alkyl) the amino replacement;
Or Z is optional by 1～3 amino or amino carbonyl replacement, and wherein the N atom is optional independently by amino C 1-6Alkyl, C 1-3Alkyl, aryl C 0-3Alkyl, C 1-5Alkoxy C 1-3Alkyl, C 1-5Alkoxyl, aroyl, C 1-3Acyl group, C 1-3Alkyl-S (O) m-or aryl C 0-3Alkyl-S (O) m-single-or two-replace, it is optional by 1～2 halogen, C to be connected to amino aforementioned each alkyl and aryl 1-6Alkyl or C 1-6Alkoxyl replaces;
Or Z is hydroxyl, hydroxyl C 1-3Alkyl, halogen, nitrile, amino, wherein the N atom is optional independently by C 1-3Alkyl, pyridine radicals C 1-2Alkyl, tetrahydrofuran base C 1-2Alkyl, C 1-3Alkoxy C 1-3Alkyl, C 1-3Acyl group, nitrile C 1-4Alkyl, phenyl are singly-or two-replace, wherein benzyl ring is optional by 1～2 halogen, C 1-6Alkoxyl, hydroxyl or list-or two-(C 1-3Alkyl) the amino replacement,
Or Z is side chain or straight chain C 1-6Alkyl, C 1-6Alkoxyl or nitrile C 1-4Alkyl;
R 1For: optional part or complete halogenated C 1-4Branched-chain or straight-chain alkyl;
R 2For: C 1-3Branched-chain or straight-chain alkyl, optional part or complete halo are also optional to be replaced by nitrile;
R 3For:
Phenyl or heterocyclic radical, described heterocyclic radical is selected from pyridine radicals, pyrimidine radicals and pyrazolyl, and wherein said phenyl or heterocyclic radical are optional to be selected from optional part or complete halogenated C by 1～5 1-3Branched-chain or straight-chain alkyl, optional part or complete halogenated C 1-3Alkoxyl, C 1-3Alkylthio, C 1-3Alkylthio C 1-5Alkyl, amino or NH 2C (O) replaces; C 1-3Alkoxy carbonyl;
Or R 3Be cyclopropyl or cyclopenta, each group optional part or complete halo are also optional by 1～3 C 1-3Alkyl replaces.
In another embodiment, the present invention relates to the p38 inhibitors of kinases in the purposes that is used for preparing the inhalable drug compositions for the treatment of Polyblennia, wherein the p38 inhibitors of kinases is selected from formula 5aChemical compound, wherein:
Ar 1Be the 5-tert-butyl group-pyrazole-3-yl; Wherein the pyrazoles ring is independently by 1～2 R 2Or R 3Replace;
X is:
Cyclohexenyl group;
Phenyl, pyridine radicals, pyrazinyl, piperidyl or pyrimidine radicals, each group is optional independently by C 1-2Alkoxyl or hydroxyl replace;
Z is:
Phenyl, heteroaryl is selected from pyridine radicals and furyl, heterocycle is selected from 2-oxa--5-aza-bicyclo [2.2.1] heptane base, pentamethylene sulfenyl, pentamethylene sulfoxide group, tetrahydrofuran base, piperazinyl, morpholino, tetrahydro-1,4-thiazine generation and piperidyl, and aforementioned each Z group is optional by 1～3 C 1-3Alkyl, C 1-3Alkoxyl, oxo, hydroxyl or NH 2C (O)-replacement;
Or Z is hydroxyl C 1-3Alkyl, amino, wherein optional pyridyl methyl, oxolane ylmethyl, C independently of N atom 1-3Alkoxy C 1-3Alkyl, C 1-3Acyl group or nitrile C 1-4The alkyl list-or two-replace,
Or Z is nitrile C 1-4Alkyl;
R 3For:
Phenyl or heterocyclic radical, described heterocyclic radical is selected from pyridine radicals, pyrimidine radicals and pyrazolyl, and wherein said phenyl or heterocyclic radical are optional to be selected from optional part or complete halogenated C by 1～2 1-2Alkyl, optional part or complete halogenated C 1-2Alkoxyl, C 1-2Alkylthio, C 1-2Alkylthio C 1-3Alkyl, amino or NH 2C (O) replaces;
C 1-3Alkoxy carbonyl;
Or R 3Be cyclopropyl or cyclopenta, each group optional part or complete halo are also optional by 1～3 C 1-3Alkyl replaces.
In another embodiment, the present invention relates to the p38 inhibitors of kinases in the purposes that is used for preparing the inhalable drug compositions for the treatment of Polyblennia, wherein the p38 inhibitors of kinases is selected from formula 5aChemical compound, wherein X is a pyridine radicals.
In another embodiment, the present invention relates to the p38 inhibitors of kinases in the purposes that is used for preparing the inhalable drug compositions for the treatment of Polyblennia, wherein the p38 inhibitors of kinases is selected from formula 5aChemical compound, wherein pyridine radicals is connected to Ar by 3-pyridine radicals position 1
Preferably, the present invention relates to the p38 inhibitors of kinases in the purposes that is used for preparing the inhalable drug compositions for the treatment of Polyblennia, wherein the p38 inhibitors of kinases is selected from formula 5aChemical compound:
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(4-morpholine-4-base-aminomethyl phenyl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[3-(4-morpholine-4-base-aminomethyl phenyl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(5-morpholine-4-base-methylfuran-2-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-(morpholine-4-base-methyl) cyclohexenyl group)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(4-morpholine-4-yl) ethylphenyl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(4-dimethylaminomethyl phenyl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(5-(morpholine-4-base-methyl) pyridine-2-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(6-(morpholine-4-base-methyl) pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-(morpholine-4-base-methyl) pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-methyl-2H-pyrazole-3-yl]-3-[4-(6-(morpholine-4-base-methyl) pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(3-(2-(morpholine-4-yl) ethylamino) cyclohexenyl group)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3,4-(morpholine-4-base-methyl) phenyl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(4-methyl piperazine (piperzin)-1-base-methyl) phenyl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(piperidines-1-base-methyl) phenyl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(3-(2-(pyridine-2-yl) ethylamino) cyclohexenyl group)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(4-(2-(pyridin-4-yl) ethylamino methyl) phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(4-(pyridin-3-yl-methylamino methyl) phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(4-(3,4-dimethoxy benzene ylmethyl)-3-hydroxy phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(6-oxo-1,6-dihydro-pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(4-(morpholine-4-base-methyl) phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(4-(morpholine-4-base-methyl) imidazoles-1-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(4-(morpholine-4-base-methyl) imidazoles-1-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(4-(furan-3-base-methyl)-3-hydroxy phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-(4-hydroxybutyl amino) pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(4-(pyridin-3-yl-methyl)-3-hydroxy phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(4-methyl-3-carbamoyl phenyl)-2H-pyrazole-3-yl]-3-[4-(6-(morpholine-4-base-methyl) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(4-(imidazoles-2-base-methyl)-3-hydroxy phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(4-(3-hydroxymorpholine-4-base-methyl) phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(4-(N-2-methoxy ethyl-N-methylamino methyl) phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(4-(4-hydroxymorpholine-4-base-methyl) phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(3-(morpholine-4-base-methyl) cyclohexenyl group)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(4-(oxolane-3-base-methyl)-3-hydroxy phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(4-(N, N-two-(2-methoxy ethyl) amino methyl) phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-(3-cyano group propoxyl group) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(4-morpholine-4-base-methyl-piperidyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(4-(N, N-two-(2-cyano ethyl) amino methyl) phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(1-morpholine-4-base-indane-5-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(4-(furan-2-base-methyl)-3-hydroxy phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(4-(tetrahydro-1,4-thiazine-4-base-methyl) phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(4-(3-carboxamide groups morpholine-4-base-methyl) phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(4-(2-methyl-3-oxo-piperazine-1-base-methyl) phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-methylpyrimidine-5-yl)-2H-pyrazole-3-yl]-3-[4-(6-(morpholine-4-base-methyl) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-(4-hydroxyl butoxy) pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[3-tert-butyl group-1 ' H-[1,4 '] connection pyrazoles-5-yl]-3-[4-(6-(morpholine-4-base-methyl) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(4-(furan-2-base-methyl)-3-methoxyphenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(5-(morpholine-4 carbonyl) pyrazine-2-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-(tetrahydric thiapyran-4-group-amino) pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-cyano ethyl)-2H-pyrazole-3-yl]-3-[4-(6-(morpholine-4-base-methyl) pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-(2,6-thebaine-4-base-methyl) pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-methoxypyridine-5-yl)-2H-pyrazole-3-yl]-3-[4-(6-(morpholine-4-base-methyl) pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(the amino y pyridine of 2--5-yl)-2H-pyrazole-3-yl]-3-[4-(6-(morpholine-4-base-methyl) pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-oxo-1,6-dihydropyridine-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-(morpholine-4-base-methyl) pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-(morpholine-4-base-4-carbonyl) pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-(2-oxa--5-aza-bicyclo [2.2.1] heptan-5-base-methyl) pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(4-(3-carbamoyl phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(4-(N-(2-cyano ethyl)-N-(pyridin-3-yl-methyl) amino methyl) phenyl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(4-(N-(2-cyano ethyl)-N-(pyridine-2-base-methyl) amino methyl) phenyl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(4-(N-(2-cyano ethyl)-N-(oxolane-2-base-methyl) amino methyl) phenyl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-(morpholine-4-base-methyl)-4-methoxypyridine-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-(1-morpholine-4-base-propyl group) pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-(N-(3-methoxy-propyl) amino) pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-(N-(3-methoxy-propyl)-N-methylamino) pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[3-tert-butyl group-1 '-methyl isophthalic acid ' H-[1,4 '] connection pyrazoles-5-yl]-3-[4-(6-(morpholine-4-base-methyl) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-benzyl-2H-pyrazole-3-yl]-3-[4-(6-(morpholine-4-base-methyl) pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(4-(N-N-two-(2-cyano ethyl) amino methyl) phenyl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(4-(4-carbamoyl phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-(1-oxo-tetrahydric thiapyran-4 bases-amino) pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-(Pentamethylene oxide .-4 bases-amino) pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[3-tert-butyl group-1 '-(3-cyano group propyl group)-1 ' H-[1,4 '] connection pyrazoles-5-yl]-3-[4-(6-(morpholine-4-base-methyl) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-methanesulfinyl phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-mesyl phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-sulfoamido phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-(morpholine-4-yl) carbonyl phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(5-(tetrahydric thiapyran-4 bases-amino) pyrazine-2-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-(methyl carbonylamino) pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(6-(morpholine-4-base-4-carbonyl) phenyl)-naphthalene-1-yl]-urea;
The 1-[3-tert-butyl group-1 '-(3-methyl mercapto propyl group)-1 ' H-[1,4 '] connection pyrazoles-5-yl]-3-[4-(6-(morpholine-4-base-methyl) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(5-(morpholine-4-base-carbonyl) pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(5-(morpholine-4-base-methyl) pyrazine-2-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-aminopyridine-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-(1-methyl piperidine-4-base-amino) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-methylpyrimidine-5-yl)-2H-pyrazole-3-yl]-3-[4-(6-(2-methyl-3-oxo-piperazine-1-base-methyl) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-methylpyrimidine-5-yl)-2H-pyrazole-3-yl]-3-[4-(6-(morpholine-4-base-carbonyl) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-methylpyrimidine-5-yl)-2H-pyrazole-3-yl]-3-[4-(6-(N, N-two-(2-methoxy ethyl) amino methyl) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-methylpyrimidine-5-yl)-2H-pyrazole-3-yl]-3-[4-(6-(1-oxo-tetrahydro-1,4-thiazine-4-base-methyl) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-methylpyrimidine-5-yl)-2H-pyrazole-3-yl]-3-[4-(6-(tetrahydropyran-4-base-amino) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-methylpyrimidine-5-yl)-2H-pyrazole-3-yl]-3-[4-(5-(morpholine-4-base-methyl) pyrazine-2-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-methylthiopyrimidine-5-yl)-2H-pyrazole-3-yl]-3-[4-(6-(morpholine-4-base-methyl) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(6-(2-methyl-3-oxo-piperazine-1-base-methyl) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(6-(pyridin-3-yl-oxygen base) pyridin-3-yl) naphthalene-1-yl]-urea
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(6-(pyridin-3-yl-amino) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-methoxy pyrimidine-5-yl)-2H-pyrazole-3-yl]-3-[4-(6-(morpholine-4-base-methyl) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(5-carbamoyl pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-aminopyrimidine-5-yl)-2H-pyrazole-3-yl]-3-[4-(6-(morpholine-4-base-methyl) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-methylpyrimidine-5-yl)-2H-pyrazole-3-yl]-3-[4-(4-(morpholine-4-base-methyl) phenyl) naphthalene-1-yl]-urea;
The 1-[3-tert-butyl group-1 '-methyl isophthalic acid ' H-[1,4 '] connection pyrazoles-5-yl]-3-[4-(6-(morpholine-4-base-methyl) phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-cyclopropyl pyrimidine-5-yl)-2H-pyrazole-3-yl]-3-[4-(6-(morpholine-4-base-methyl) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(pyridin-3-yl-amino) pyrimidine-5-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(6-(1-oxo-tetrahydric thiapyran-4-group-amino) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(6-(tetrahydro-1,4-thiazine-4-base-methyl) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-benzyl-3H-imidazo [4,5-b] pyridine-6-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-(pyridin-3-yl-methyl) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(morpholine-4-base-carbonyl) pyrimidine-5-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(morpholine-4-base-methyl) pyrimidine-5-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(3-amino-4-carbamoyl phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(6-(1-oxo-tetrahydro-1,4-thiazine-4-base-methyl) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(6-(pyridin-3-yl-methyl) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(6-(hydroxyl-pyridin-3-yl-methyl) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-methylpyrimidine-5-yl)-2H-pyrazole-3-yl]-3-[4-(2-(morpholine-4-base-methyl) pyrimidine-5-yl) naphthalene-1-yl]-urea;
With and pharmaceutically acceptable derivant.
In another embodiment, the present invention relates to the p38 inhibitors of kinases and be used for the treatment of purposes in the inhalable drug compositions of Polyblennia in preparation, wherein the p38 inhibitors of kinases is selected from following formula 5aChemical compound:
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(5-(morpholine-4-base-methyl) pyridine-2-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(6-(morpholine-4-base-methyl) pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(3-(2-(pyridine-2-yl) ethylamino) cyclohexenyl group)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(4-(pyridin-3-yl-methylamino methyl) phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(4-(morpholine-4-base-methyl) phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-(4-hydroxybutyl amino) pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(4-methyl-3-carbamoyl phenyl)-2H-pyrazole-3-yl]-3-[4-(6-(morpholine-4-base-methyl) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(4-(3-hydroxy piperidine-1-base-methyl) phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(4-(4-hydroxymorpholine-4-base-methyl) phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(3-(morpholine-4-base-methyl) cyclohexenyl group)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(4-(oxolane-3-base-methyl)-3-hydroxy phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(4-(N, N-two-(2-methoxy ethyl) amino methyl) phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-(3-cyano group propoxyl group) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(4-morpholine-4-base-methyl-piperidyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(4-(N, N-two-(2-cyano ethyl) amino methyl) phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(4-(furan-2-base-methyl)-3-hydroxy phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(4-(tetrahydro-1,4-thiazine-4-base-methyl) phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(4-(3-carboxamide groups piperidines-1-base-methyl) phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(4-(2-methyl-3-oxo-piperazine-1-base-methyl) phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-methylpyrimidine-5-yl)-2H-pyrazole-3-yl]-3-[4-(6-(morpholine-4-base-methyl) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-(4-hydroxyl butoxy) pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[3-tert-butyl group-1 ' H-[1,4 '] connection pyrazoles-5-yl]-3-[4-(6-(morpholine-4-base-methyl) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-(tetrahydric thiapyran-4-group-amino) pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-cyano ethyl)-2H-pyrazole-3-yl]-3-[4-(6-(morpholine-4-base-methyl) pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-(2,6-thebaine-4-base-methyl) pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-methoxypyridine-5-yl)-2H-pyrazole-3-yl]-3-[4-(6-(morpholine-4-base-methyl) pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-aminopyridine-5-yl)-2H-pyrazole-3-yl]-3-[4-(6-(morpholine-4-base-methyl) pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-(morpholine-4-base-4-carbonyl) pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-(2-oxa--5-aza-bicyclo [2.2.1] heptan-5-base-methyl) pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(4-(N-(2-cyano ethyl)-N-(pyridin-3-yl-methyl) amino methyl) phenyl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(4-(N-(2-cyano ethyl)-N-(oxolane-2-base-methyl) amino methyl) phenyl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-(morpholine-4-base-methyl)-4-methoxypyridine-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-(1-morpholine-4-base-propyl group) pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[3-tert-butyl group-1 '-methyl isophthalic acid ' H-[1,4 '] connection pyrazoles-5-yl]-3-[4-(6-(morpholine-4-base-methyl) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-(1-oxo-tetrahydric thiapyran-4 bases-amino) pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-(Pentamethylene oxide .-4 bases-amino) pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(5-(tetrahydric thiapyran-4 bases-amino) pyrazine-2-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(6-(methyl carbonylamino) pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[3-tert-butyl group-1 '-(3-methyl mercapto propyl group)-1 ' H-[1,4 '] connection pyrazoles-5-yl]-3-[4-(6-(morpholine-4-base-methyl) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-methylpyrimidine-5-yl)-2H-pyrazole-3-yl]-3-[4-(6-(1-oxo-tetrahydro-1,4-thiazine-4-base-methyl) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-methylpyrimidine-5-yl)-2H-pyrazole-3-yl]-3-[4-(6-(tetrahydropyran-4-base-amino) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-methylthiopyrimidine-5-yl)-2H-pyrazole-3-yl]-3-[4-(6-(morpholine-4-base-methyl) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-aminopyrimidine-5-yl)-2H-pyrazole-3-yl]-3-[4-(6-(morpholine-4-base-methyl) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[3-tert-butyl group-1 '-methyl isophthalic acid ' H-[1,4 '] connection pyrazoles-5-yl]-3-[4-(6-(morpholine-4-base-methyl) phenyl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(6-(1-oxo-tetrahydric thiapyran-4-group-amino) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(6-(tetrahydro-1,4-thiazine-4-base-methyl) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(morpholine-4-base-carbonyl) pyrimidine-5-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(2-(morpholine-4-base-methyl) pyrimidine-5-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-p-methylphenyl-2H-pyrazole-3-yl]-3-[4-(6-(1-oxo-tetrahydro-1,4-thiazine-4-base-methyl) pyridin-3-yl) naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-methylpyrimidine-5-yl)-2H-pyrazole-3-yl]-3-[4-(2-(morpholine-4-base-methyl) pyrimidine-5-yl) naphthalene-1-yl]-urea and
Its pharmaceutically acceptable derivant.
In another embodiment preferred, the present invention relates to the p38 inhibitors of kinases and be used for the treatment of purposes in the inhalable drug compositions of Polyblennia in preparation, wherein the p38 inhibitors of kinases is selected from as disclosed formula in WO 00/55139 6Chemical compound,
Figure A0381298800951
Wherein:
G is:
The C of fragrance 6-10The C of carbocyclic ring or saturated or unsaturated non-fragrance 3-10Carbocyclic ring;
Comprise 1 or a plurality of O of being selected from, N and the heteroatomic 6-10 person's heteroaryl of S;
Comprise one or more and be selected from O, N and the heteroatomic 5-8 person's monocyclic heterocycles of S;
Or
8-11 person's bicyclic heterocycles comprises the hetero atom that one or more is selected from O, N and S;
Wherein G is by 1 or a plurality of R 1, R 2Or R 3Replace;
Ar is: phenyl, naphthyl, quinolyl, isoquinolyl, tetralyl, tetrahydric quinoline group, tetrahydro isoquinolyl, benzimidazolyl, benzofuranyl, dihydro benzo furyl, indolinyl, benzothienyl, dihydrobenzo thienyl, indanyl, indenyl or indyl, each group is optional by one or more R 4Or R 5Replace;
X is:
C 5-8Cycloalkyl or cycloalkenyl group, optional by 1 or 2 oxo group or 1～3 C 1-4Alkyl,
C 1-4Alkoxyl or C 1-4The alkyl amino chain replaces;
Phenyl, furyl, thienyl, pyrrole radicals, pyrazolyl, imidazole radicals, pyridine radicals, pyrimidine radicals, pyriconyl, dihydropyridine ketone group, dimaleoyl imino, dihydro dimaleoyl imino, piperidyl, benzimidazole, 3H-imidazo [4,5-b] pyridine, piperazinyl, pyridazinyl or pyrazinyl;
Y is: chemical bond or optional part or complete halogenated saturated or unsaturated C 1-4Side chain or straight chain carbochain, wherein one or more methylene is optional by O, N or S (O) mReplace, and wherein Y is optional independently by 1 or 2 oxo group, phenyl or 1 or a plurality of optional C that is replaced by one or more halogen atom 1-4Alkyl replaces;
Z is:
Phenyl, pyridine radicals, pyrimidine radicals, pyridazinyl, pyrazinyl, imidazole radicals, pyrazolyl, triazolyl, tetrazole radical, furyl, thienyl, pyranose, each group is optional by 1～3 halogen, C 1-6Alkyl, C 1-6Alkoxyl, hydroxyl, amino, list-or two-(C 1-3Alkyl) amino, C 1-6Alkyl-S (O) m, CN, CONH 2, COOH or phenyl amino replace, wherein benzyl ring is optional by 1～2 halogen, C 1-6Alkyl or C 1-6Alkoxyl replaces; THP trtrahydropyranyl, tetrahydrofuran base, 1; 3-dioxo Ketocyclopentane base, 1; 3-dioxanone base, 1; for sulfonyl, piperidyl, piperidone base, piperazinyl, tetrahydropyrimidine ketone group, hexamethylene ketone group, hexamethylene acyl group, pentamethylene sulfenyl, pentamethylene sulfoxide group, pentamethylene sulfonyl, tetramethylene thioether, tetramethylene sulfoxide base or tetramethylene sulfonyl, each group is optional by 1～3 nitrile, C for sulfoxide group, tetrahydro-1,4-thiazine for 4-dioxacyclohexyl, morpholinyl, tetrahydro-1,4-thiazine base, tetrahydro-1,4-thiazine 1-6Alkyl, C 1-6Alkoxyl, hydroxyl, amino, list-or two-(C 1-3Alkyl) amino-C 1-3Alkyl, CONH 2, phenyl amino-C 1-3Alkyl or C 1-3Alkoxy-C 1-3Alkyl replaces;
Halogen, C 1-4Alkyl, nitrile, amino, hydroxyl, C 1-6Alkoxyl, NH 2C (O), single-or two (C 1-3Alkyl) amino carbonyl, list-or two (C 1-6Alkyl) amino, the second month in a season or tertiary amine, wherein amino nitrogen is covalently bond to C 1-3Alkyl or C 1-5Alkoxyalkyl, pyridine radicals-C 1-3Alkyl, imidazole radicals-C 1-3Alkyl, tetrahydrofuran base-C 1-3Alkyl, nitrile-C 1-3Alkyl, carboxylic acid amides-C 1-3Alkyl, phenyl, wherein benzyl ring is optional by 1～2 halogen, C 1-6Alkoxyl, hydroxyl or list-or two-(C 1-3Alkyl) amino, C 1-6Alkyl-S (O) mOr phenyl-S (O) mReplace, wherein benzyl ring is optional by 1～2 halogen, C 1-6Alkoxyl, hydroxyl, halogen or list-or two-(C 1-3Alkyl) the amino replacement;
C 1-6Alkyl-S (O) mAnd phenyl-S (O) m, wherein benzyl ring is optional by 1～2 halogen, C 1-6Alkoxyl, hydroxyl or list-or two-(C 1-3Alkyl) the amino replacement;
Each R 1Be independently:
C 1-10Alkyl is randomly replaced by 1～3 substituent group that is selected from the following groups by partially or completely halo is also optional: C 3-10Cycloalkyl, hydroxyl, phenyl, naphthyl, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl; Aforementioned each group is optional to be replaced by 1～5 substituent group that is selected from following groups: halogen, optional part or complete halogenated C 1-6Alkyl, C 3-8Cycloalkyl, C 5-8Cycloalkenyl group, hydroxyl, nitrile, optional part or complete halogenated C 1-3Alkoxyl or NH 2C (O), single-or two (C 1-3Alkyl) amino and single-or two (C 1-3Alkyl) amino carbonyl;
Ring propoxyl group, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy or suberyl oxygen base, each group optional part or complete halo are also optional by 1～3 optional part or complete halogenated C 1-3Alkyl, CN, hydroxyl C 1-3Alkyl or aryl replaces; Or wherein 1～3 the ring methylene independently by O, S (O) m, CHOH,＞C=O,＞the similar group of C=S or the alternate described cycloalkyl of NH;
Phenoxy group or benzyloxy, each group optional part or complete halo are also optional by 1～3 optional part or complete halogenated C 1-3Alkyl, CN, hydroxyl C 1-3Alkyl or aryl replaces; Or wherein 1～2 ring methine is substituted the similar group of described cyclophane base independently by N;
Cyclopropane base, Tetramethylene. base, Pentamethylene. base, cyclohexyl, cycloheptane base, bicyclo-pentyl, bicyclohexane base or bicycloheptane base, each group optional part or complete halo are also optional by 1～3 randomly partially or completely halogenated C 1-3Alkyl, CN, hydroxyl C 1-3Alkyl or aryl replaces; Or wherein 1～3 the ring methylene independently by O, S (O) m, CHOH,＞C=O,＞the similar group of C=S or the alternate described cycloalkyl of NH;
C 3-10Side chain or straight alkenyl, each group optional part or complete halo are also randomly replaced by 1～3 substituent group that is selected from the following groups: C 1-5Branched-chain or straight-chain alkyl, phenyl, naphthyl, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl, aforementioned each group can be replaced by 0～5 substituent group that is selected from the following groups: halogen, optional part or complete halogenated C 1-6Alkyl, cyclopropane base, Tetramethylene. base, Pentamethylene. base, cyclohexyl, cycloheptane base, bicyclo-pentyl, bicyclohexane base and bicycloheptane base, hydroxyl, nitrile, optional part or complete halogenated C 1-3Alkoxyl, NH 2C (O), single-or two (C 1-3Alkyl) amino carbonyl; C 3-10Side chain or straight alkenyl randomly are selected from O, N and S (O) by one or more mHetero atom interrupt;
Cyclopentenyl, cyclohexenyl group, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyl groups or bicycloheptene base, wherein said cycloalkenyl group randomly is selected from C by 1～3 1-3The group of alkyl replaces;
Nitrile, halogen;
Methoxycarbonyl, ethoxy carbonyl and propoxycarbonyl;
Silicyl comprises 3 optional parts or complete halogenated C 1-4Alkyl;
C 3-6Alkynyl side chain or straight chain carbochain, optional part or halogenated fully, wherein one or more methylene is optional by O, NH or S (O) mReplacement and wherein said alkynyl are optional independently by 1 or 2 oxo group, pyrrolidinyl, pyrrole radicals, one or more C 1-4Alkyl replaces, and described alkyl is optional by one or more halogen atom, nitrile, morpholino, piperidyl, piperazinyl, imidazole radicals, phenyl, pyridine radicals, tetrazole radical, or the optional list that is replaced by one or more halogen atom-or two (C 1-3Alkyl) the amino replacement;
Each R 2, R 4And R 5For
Optional part or complete halogenated C 1-6Branched-chain or straight-chain alkyl, acetyl group, aroyl, C 1-4Side chain or straight chain alkoxyl, each group optional part or halogenated fully, halogen, nitrile, methoxycarbonyl, optional part or complete halogenated C 1-3Alkyl-S (O) mOr phenyl sulfonyl; C 1-6Alkoxyl, hydroxyl, amino or list-or two-(C 1-4Alkyl) amino, nitrile, halogen; OR 6
Nitro; Or
Optional part or complete halogenated list-or two-(C 1-4Alkyl) amino-S (O) 2, or H 2NSO 2Each R 3Be independently:
Phenyl, naphthyl, morpholinyl, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, pyrrolidinyl, imidazole radicals, pyrazolyl, thiazolyl oxazolyl, triazolyl, tetrazole radical, thienyl, furyl, tetrahydrofuran base isoxazolyl, isothiazolyl, quinolyl, isoquinolyl, indyl, benzimidazolyl, benzofuranyl benzoxazolyl, the benzoisoxazole base, the benzopyrazoles base, the benzo thiapyran base, cinnolinyl, pteridyl, phthalazinyl, the naphthyl pyridine radicals, quinoxalinyl, quinazolyl, purine radicals or indazolyl, aforementioned each group is optional to be replaced by 1～3 substituent group that is selected from the following groups: phenyl, naphthyl, as foregoing heterocycle or heteroaryl in this section, optional part or complete halogenated C 1-6Branched-chain or straight-chain alkyl, cyclopropane base, Tetramethylene. base, Pentamethylene. base, cyclohexyl, cycloheptane base, bicyclo-pentyl, bicyclohexane base, bicycloheptane base, phenyl C 1-5Alkyl, naphthyl C 1-5Alkyl, halogen, hydroxyl, oxo, nitrile, optional part or complete halogenated C 1-3Noted earlier in the wherein said heterocyclic radical of alkoxyl, phenoxy group, naphthoxy, heteroaryloxy or heterocyclic oxy group or heteroaryl moieties such as this section, nitro, amino, list-or two-(C 1-3Alkyl) noted earlier, NH in amino, phenyl amino, naphthyl amino, heteroaryl or the wherein said heteroaryl heterocyclic moiety of heterocyclic amino group such as this section 2C (O), single-or two-(C 1-3Alkyl) amino carbonyl, C 1-5Alkyl-C (O)-C 1-4Alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3Alkyl) amino-C 1-5Alkyl, amino-S (O) 2, two-(C 1-3Alkyl) amino-S (O) 2, R 7-C 1-5Alkyl, R 8-C 1-5Alkoxyl, R 9-C (O)-C 1-5Alkyl, R 10-C 1-5Alkyl (R 11) N, carboxyl-list-or two-(C 1-5Alkyl)-amino;
Condensed aryl is selected from benzocyclobutane alkyl, indanyl, indenyl, dihydro naphthyl, tetralyl, benzocyclohepta alkyl and benzocyclohepta thiazolinyl; Or condensed heteroaryl, be selected from the cyclopenta pyridine base, hexamethylene and pyridine radicals, the cyclopentano pyrimidine radicals, hexamethylene and pyrimidine radicals, the cyclopentano pyrazinyl, hexamethylene and pyrazinyl, the cyclopentano pyridazinyl, hexamethylene and pyridazinyl, the cyclopentano quinolyl, hexamethylene and quinolyl, the cyclopentano isoquinolyl, hexamethylene and isoquinolyl, the cyclopentano indyl, hexamethylene diindyl base, the cyclopentano benzimidazolyl, hexamethylene and benzimidazolyl, the cyclopentano benzoxazolyl, hexamethylene and benzoxazolyl, the cyclopentano imidazole radicals, hexamethylene and imidazole radicals, cyclopentano thienyl and hexamethylene bithiophene base; Wherein said fused-aryl or condensed heteroaryl ring are replaced by the substituent group that is selected from the following groups by 0～3 independently: phenyl, naphthyl, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, optional part or complete halogenated C 1-6Alkyl, halogen, nitrile, optional part or complete halogenated C 1-3Noted earlier in the wherein said heteroaryl of alkoxyl, phenoxy group, naphthoxy, heteroaryloxy or heterocyclic oxy group or heterocyclic moiety such as this section, nitro, amino, list-or two-(C 1-3Alkyl) noted earlier, NH in amino, phenyl amino, naphthyl amino, heteroaryl or the wherein said heteroaryl of heterocyclic amino group or heterocyclic moiety such as this section 2C (O), single-or two-(C 1-3Alkyl) amino carbonyl, C 1-4Alkyl-OC (O), C 1-5Alkyl-C (O)-C 1-4Alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3) alkyl amino-C 1-5Alkyl, R 12-C 1-5Alkyl, R 13-C 1-5Alkoxyl, R 14-C (O)-C 1-5Alkyl or R 15-C 1-5Alkyl (R 16) N;
Cyclopropane base, Tetramethylene. base, Pentamethylene. base, cyclohexyl, cycloheptane base, bicyclo-pentyl, bicyclohexane base or bicycloheptane base, each group optional part or complete halo are also optional by 1～3 C 1-3Alkyl replaces, or wherein 1～3 ring methylene independently by O, S, CHOH,＞C=O,＞the similar group of C=S or the alternate described cycloalkyl of NH;
Cyclopentenyl, cyclohexenyl group, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyl groups or bicycloheptene base, each is optional by 1～3 C 1-3Alkyl replaces;
C 1-4Alkyl-phenyl-C (O)-C 1-4Alkyl-, C 1-4Alkyl-C (O)-C 1-4Alkyl-or C 1-4Alkyl-phenyl-S (O) m-C 1-4Alkyl-;
C 1-6Alkyl or C 1-6Side chain or straight chain alkoxyl, each group optional part or fully halogenated or optional by R 17Replace;
OR 18Or it is optional by OR 18The C that replaces 1-6Alkyl;
Optional by R 19Amino or the list that replaces-or two-(C 1-5Alkyl) amino;
R 20C (O) N (R 21)-, R 22O-or R 23R 24NC (O)-; R 26(CH 2) mC (O) N (R 21)-or R 26C (O) (CH 2) mN (R 21)-;
By R 23R 24The C of NC (O)-replacement 2-6Alkenyl;
C 2-6Alkynyl side chain or straight chain carbochain, optional part or halogenated fully, wherein one or more methylene is optional by O, NH, S (O) mReplacement and wherein said alkynyl are optional to be replaced by 1 or 2 substituent group that is selected from the following groups independently: oxo group, pyrrolidinyl, pyrrole radicals, morpholinyl, piperidyl, piperazinyl, imidazole radicals, phenyl, pyridine radicals, one or more optional C that is replaced by one or more halogen atom of tetrazole radical 1-4Alkyl, nitrile, morpholino, piperidyl, piperazinyl, imidazole radicals, phenyl, pyridine radicals, tetrazole radical, or the optional list that is replaced by one or more halogen atom-or two (C 1-4Alkyl) amino; Or aroyl;
R 6For: C 1-4Alkyl, optional part or complete halo are also optional by R 26Replace;
Each R 7, R 8, R 9, R 10, R 12, R 13, R 14, R 15, R 17, R 19, R 25And R 26Be independently: nitrile, phenyl, morpholino, piperidyl, piperazinyl, imidazole radicals, pyridine radicals, tetrazole radical, amino or optional part or complete halogenated list-or two-(C 1-4Alkyl) amino;
Each R 11And R 16Be independently: optional part or complete halogenated hydrogen or C 1-4Alkyl;
R 18Be independently: hydrogen or optional independently by oxo or R 25The C that replaces 1-4Alkyl;
R 20Be independently: optional part or complete halogenated C 1-10Alkyl, phenyl, or pyridine radicals;
R 21Be independently: hydrogen or optional part or complete halogenated C 1-3Alkyl;
Each R 22, R 23And R 24Be independently: hydrogen, optional part or complete halogenated C 1-6Alkyl, described C 1-6Alkyl is randomly interrupted by one or more O, N or S, described C 1-6The also optional independently coverlet of alkyl-or two-(C 1-3Alkyl) amino carbonyl, phenyl, pyridine radicals, amino or single-or two-(C 1-4Alkyl) the amino replacement, each group optional part or complete halo and optional coverlet-or two-(C 1-3Alkyl) the amino replacement;
Or R 23And R 24Randomly form heterocycle or heteroaryl ring together;
M=0,1 or 2;
W be O or S and
Its pharmaceutically acceptable derivant.
In another embodiment preferred, the present invention relates to the p38 inhibitors of kinases in the purposes that is used for preparing the inhalable drug compositions for the treatment of Polyblennia, wherein the p38 inhibitors of kinases is selected from formula 6Chemical compound, wherein
G is:
Phenyl, naphthyl, benzocyclobutane alkyl, dihydro naphthyl, tetralyl, benzocyclohepta alkyl, benzocyclohepta thiazolinyl, indanyl, indenyl;
Pyridine radicals, pyriconyl, quinolyl, the dihydroquinoline base, tetrahydric quinoline group (quinoyl), isoquinolyl, tetrahydro isoquinolyl (isoquinoyl), pyridazinyl, pyrimidine radicals, pyrazinyl, benzimidazolyl, benzothiazolyl benzoxazolyl, benzofuranyl, benzothienyl, the benzopyrazoles base, dihydro benzo furyl, the dihydrobenzo thienyl, benzo oxazolone base (oxazolonyl), benzo [1,4] oxazine-3-ketone group, benzo dioxo cyclopentenyl, benzo [1,3] dioxole-2-ketone group, benzofuran-3-ketone group, the tetrahydro benzo pyranose, indyl, indolinyl, the indole ketone group, the indoline ketone group, phthalimidyl;
The oxa-cyclobutyl, pyrrolidinyl, tetrahydrofuran base, tetrahydro-thienyl, piperidyl, piperazinyl, morpholinyl, THP trtrahydropyranyl, the dioxane base, the tetramethylene sulfonyl, tetramethylene sulfoxide base oxazolinyl, thiazolinyl, imidazolinyl, tetrahydro pyridyl, homopiperidinyl, pyrrolinyl, tetrahydro-pyrimidine base, decahydroquinolyl, the Decahydroisoquinolinpreparation base, the tetrahydro-1,4-thiazine base, thiazolidinyl Er Qing oxazinyl, dihydro pyranyl, oxocanyl, heptacanyl, sulfur oxinane base or dithian base; Wherein G is by 1 or a plurality of R 1, R 2Or R 3Replace;
In another embodiment preferred, the present invention relates to the p38 inhibitors of kinases in the purposes that is used for preparing the inhalable drug compositions for the treatment of Polyblennia, wherein the p38 inhibitors of kinases is selected from formula 6Chemical compound, wherein
G is phenyl, pyridine radicals, pyriconyl, naphthyl, quinolyl, isoquinolyl, pyrazinyl, benzimidazolyl, benzoxazolyl, benzofuranyl, benzothienyl, benzopyrazoles base, dihydro benzo furyl, dihydrobenzo thienyl, indanyl, indenyl, indyl, indolinyl, indole ketone group or indoline ketone group, and wherein G is by 1 or a plurality of R 1, R 2Or R 3Replace;
Ar is: naphthyl, quinolyl, isoquinolyl, tetralyl, tetrahydric quinoline group, tetrahydro isoquinolyl, indanyl, indenyl or indyl, each group is optional by one or more R 4Or R 5Group replaces;
X is: phenyl, furyl, thienyl, pyrrole radicals, pyrazolyl, imidazole radicals, pyridine radicals, pyrimidine radicals, pyriconyl, dihydropyridine ketone group, dimaleoyl imino, dihydro dimaleoyl imino, piperidyl, piperazinyl, pyridazinyl or pyrazinyl,
Y is:
Chemical bond or
C 1-4Saturated or unsaturated carbochain, wherein one of carbon atom is randomly by O, N or S (O) mSubstitute and wherein Y is optional independently by 1 or 2 oxo group, phenyl or 1 or a plurality of optional C that is replaced by one or more halogen atom 1-4Alkyl replaces;
Z is:
Phenyl, pyridine radicals, pyrimidine radicals, pyridazinyl, pyrazinyl, imidazole radicals, furyl, thienyl, dihydro-thiazolyl, dihydro-thiazolyl sulfoxide group, pyranose, pyrrolidinyl, each group is optional by 1～3 nitrile, C 1-3Alkyl, C 1-3Alkoxyl, amino, list-or two-(C 1-3Alkyl) amino, CONH 2Or OH replaces;
THP trtrahydropyranyl, tetrahydrofuran base, 1; 3-dioxo Ketocyclopentane base, 1; 3-dioxanone base, 1; 4-dioxacyclohexyl, morpholinyl, tetrahydro-1,4-thiazine base, tetrahydro-1,4-thiazine are for sulfoxide group, piperidyl, piperidone base, piperazinyl, tetrahydropyrimidine ketone group, pentamethylene sulfenyl, pentamethylene sulfoxide group, pentamethylene sulfonyl, tetramethylene sulfenyl, tetramethylene sulfoxide base or tetramethylene sulfonyl, and wherein each group is optional by 1～3 nitrile, C 1-3Alkyl, C 1-3Alkoxyl, amino, list-or two-(C 1-3Alkyl) amino, CONH 2Or OH replaces;
Nitrile, C 1-6Alkyl-S (O) m, halogen, hydroxyl, C 1-4Alkoxyl, amino, list-or two-(C 1-6Alkyl) amino, single-or two-(C 1-3Alkyl) amino carbonyl or NH 2C (O);
Each R 1Be independently:
C 3-6Alkyl, optional part or complete halo are also optional by 1～3 C 3-6Cycloalkyl, phenyl, thienyl, furyl, isoxazolyl or isothiazolyl replace; Aforementioned each group is optional to be replaced by 1～3 substituent group that is selected from the following radicals: halogen, optional part or complete halogenated C 1-3Alkyl, hydroxyl, nitrile or optional part or complete halogenated C 1-3Alkoxyl;
Cyclopropyl, cyclobutyl, Pentamethylene. base, cyclohexyl, bicyclo-pentyl or bicyclohexane base, each group optional part or complete halo are also randomly by 1～3 randomly partially or completely halogenated C 1-3Alkyl, CN, hydroxyl C 1-3Alkyl or phenyl replaces; Or wherein 1～3 ring methylene independently by O, S, CHOH,＞C=O,＞the similar group of C=S or the alternate described cycloalkyl of NH; Or silicyl, comprise 3 optional parts or complete halogenated C 1-4Alkyl;
R 2Be independently: halogen, C 1-3Alkoxyl, optional part or complete halogenated C 1-3Alkyl-S (O) m, phenyl sulfonyl or nitrile;
R 3Be independently:
Phenyl, morpholino, pyridine radicals, pyrimidine radicals, pyrazinyl, pyrrole radicals, pyrrolidinyl, imidazole radicals, pyrazolyl, each group is optional to be replaced by 1～3 substituent group that is selected from the following radicals: phenyl, naphthyl, as foregoing heterocycle or heteroaryl, optional part or complete halogenated C in this section 1-6Alkyl, cyclopropane base, Tetramethylene. base, Pentamethylene. base, cyclohexyl, cycloheptane base, bicyclo-pentyl, bicyclohexane base, bicycloheptane base, phenyl C 1-5Alkyl, naphthyl C 1-5Alkyl, halogen, oxo, hydroxyl, nitrile, optional part or complete halogenated C 1-3Noted earlier in the wherein said heteroaryl of alkoxyl, phenoxy group, naphthoxy, heteroaryloxy or heterocyclic oxy group or heterocyclic moiety such as this section, nitro, amino, list-or two-(C 1-3Alkyl) noted earlier, NH in amino, phenyl amino, naphthyl amino, heteroaryl or the wherein said heteroaryl of heterocyclic amino group or heterocyclic moiety such as this section 2C (O), single-or two-(C 1-3Alkyl) amino carbonyl, C 1-5Alkyl-C (O)-C 1-4Alkyl, list-or two-(C 1-3Alkyl) amino, single-or two-(C 1-3) alkyl amino-C 1-5Alkyl, list-or two-(C 1-3Alkyl) amino-S (O) 2, R 7-C 1-5Alkyl, R 8-C 1-5Alkoxyl, R 9-C (O)-C 1-5Alkyl, R 10-C 1-5Alkyl (R 11) N, carboxyl-list-or two-(C 1-5)-alkyl-amino;
C 1-3Alkyl or C 1-4Alkoxyl, each group optional part or fully halogenated or optional by R 17Replace;
OR 18Or it is optional by OR 18The C that replaces 1-6Alkyl;
Amino or single-or two-(C 1-5Alkyl) amino, optional by R 19Replace;
R 20C (O) N (R 21)-, R 22O-; R 23R 24NC (O)-; R 26CH 2C (O) N (R 21)-or R 26C (O) CH 2N (R 21)-;
By R 23R 24The C of NC (O)-replacement 2-4Alkenyl; Or C 2-4Alkynyl side chain or straight chain carbochain, optional part or complete halo and optional independently by 1 or 2 oxo group, pyrrolidinyl, pyrrole radicals, morpholinyl, piperidyl, piperazinyl, imidazole radicals, phenyl, pyridine radicals, tetrazole radical or 1 or a plurality of optional C that is replaced by one or more halogen atom 1-4Alkyl replaces; And
R 23And R 24Randomly form imidazole radicals, piperidyl, morpholinyl, piperazinyl or pyridyl ring together.
In another preferred embodiment, the present invention relates to the p38 inhibitors of kinases in the purposes that is used for preparing the inhalable drug compositions for the treatment of Polyblennia, wherein the p38 inhibitors of kinases is selected from formula 6Chemical compound, wherein:
G is phenyl, pyridine radicals, pyriconyl, naphthyl, quinolyl, isoquinolyl, pyrazinyl, benzothienyl, dihydro benzo furyl, dihydrobenzo thienyl, indanyl, indyl, indolinyl, indole ketone group or indoline ketone group, and wherein G is by 1 or a plurality of R 1, R 2Or R 3Replace;
Ar is a naphthyl;
X is phenyl, imidazole radicals, pyridine radicals, pyrimidine radicals, piperidyl, piperazinyl, pyridazinyl or pyrazinyl, and each group is optional independently by 1～3 C 1-4Alkyl, C 1-4Alkoxyl, hydroxyl, nitrile, amino, list-or two-(C 1-3Alkyl) amino, single-or two-(C 1-3Alkyl amino) carbonyl, NH 2C (O), C 1-6Alkyl-S (O) mOr halogen replaces;
Y is:
Chemical bond or
C 1-4Saturated carbochain, wherein one of carbon atom is randomly substituted by O, N or S and wherein Y is optional is replaced by oxo group independently;
Z is:
Phenyl, pyridine radicals, pyrimidine radicals, pyridazinyl, pyrazinyl, imidazole radicals, dihydro-thiazolyl, dihydro-thiazolyl sulfoxide, pyranose or pyrrolidinyl, each group is optional by 1～2 C 1-2Alkyl or C 1-2Alkoxyl replaces;
THP trtrahydropyranyl, morpholinyl, tetrahydro-1,4-thiazine base, tetrahydro-1,4-thiazine are for sulfoxide group, piperidyl, piperidone base, piperazinyl or tetrahydropyrimidine ketone group, and each group is optional by 1～2 C 1-2Alkyl or C 1-2Alkoxyl replaces; Or C 1-3Alkoxyl;
Each R 1Be independently:
C 3-5Alkyl, optional part or complete halo are also optional by the phenyl, optional part or the complete halogenated C that are replaced by 0～3 halogen 1-3Alkyl, hydroxyl, nitrile or optional part or complete halogenated C 1-3Alkoxyl replaces;
Cyclopropyl, cyclobutyl, Pentamethylene. base, cyclohexyl, bicyclo-pentyl or bicyclohexane base, each group optional part or complete halo are also optional by 1～3 optional part or complete halogenated C 1-3Alkyl, CN, hydroxyl C 1-3Alkyl or phenyl replaces; And one of them ring methylene is by the similar group of the alternate cyclopropyl of O, cyclobutyl, Pentamethylene. base, cyclohexyl, bicyclo-pentyl or bicyclohexane base; And silicyl, comprise 3 optional part or complete halogenated C independently 1-2Alkyl;
Each R 2Be independently: bromine, chlorine, fluorine, methoxyl group, methyl sulphonyl or nitrile;
Each R 3Be independently:
Phenyl, morpholino, pyridine radicals, pyrimidine radicals, pyrrolidinyl, 2,5-pyrrolidine-2,4-diketo base, imidazole radicals, pyrazolyl, aforementioned each group is optional to be selected from optional part or complete halogenated C by 1～3 1-3Alkyl, halogen, oxo, hydroxyl, nitrile and optional part or complete halogenated C 1-3The substituent group of alkoxyl replaces;
C 1-3Alkyl or C 1-3Alkoxyl, each group optional part or fully halogenated or optional by R 17Replace;
OR 18Or C 1-3Alkyl, optional by OR 18Replace;
Amino or single-or two-(C 1-3Alkyl) amino, optional by R 19Replace;
R 20C (O) N (R 21)-, R 22O-; R 23R 24NC (O)-; R 26CH 2C (O) N (R 21)-or R 26C (O) CH 2N (R 21)-;
By R 23R 24The C of NC (O)-replacement 2-4Alkenyl; Or by the C of pyrrolidinyl or pyrrole radicals replacement 2-4Alkynyl;
And
R 23And R 24Randomly form morpholino together.
In another preferred embodiment, the present invention relates to the p38 inhibitors of kinases in the purposes that is used for preparing the inhalable drug compositions for the treatment of Polyblennia, wherein the p38 inhibitors of kinases is selected from formula 6Chemical compound wherein
G is phenyl, pyridine radicals, pyriconyl, naphthyl, quinolyl, isoquinolyl, dihydro benzo furyl, indanyl, indolinyl, indole ketone group or indoline ketone group, and wherein G is by 1 or a plurality of R 1, R 2Or R 3Replace;
Ar is the 1-naphthyl;
X is: phenyl, imidazole radicals, pyridine radicals, pyrimidine radicals, piperidyl, piperazinyl, pyridazinyl or pyrazinyl;
Y is:
Chemical bond or
-CH 2-,-CH 2CH 2-,-C (O)-,-O-,-S-,-NH-CH 2CH 2CH 2-,-N (CH 3)-or-NH-;
Each R 1Be independently:
C 3-5Alkyl, optional part or complete halo are also optional to be replaced by phenyl;
Cyclopropyl, Pentamethylene. base, cyclohexyl and bicyclo-pentyl, optional by 1～3 optional part or complete halogenated methyl, CN, hydroxymethyl or phenyl replacement; Or by methyl substituted 2-tetrahydrofuran base; Or
Trimethyl silyl;
Each R 3Be independently:
Phenyl, morpholinyl, pyridine radicals, pyrimidine radicals, pyrrolidinyl, 2,5-pyrrolidine-2,4-diketo base, imidazole radicals or pyrazolyl, wherein aforementioned arbitrary group is optional by optional part or complete halogenated C 1-2Alkyl replaces;
C 1-3Alkyl or C 1-3Alkoxyl, each group optional part or fully halogenated or optionally replaced by diethylamino;
OR 18Or it is optional by OR 18The C that replaces 1-3Alkyl;
Amino or single-or two-(C 1-3Alkyl) amino, optional by R 19Replace;
CH 3C (O) NH-, R 22O-; R 23R 24NC (O)-; R 26CH 2C (O) N (R 21)-or R 26C (O) CH 2N (R 21)-;
By R 23R 24The C of NC (O)-replacement 2-4Alkenyl; Or by the C of pyrrolidinyl or pyrrole radicals replacement 2-4Alkynyl;
R 23And R 24Be H or R 23And R 24Randomly form morpholino together; And R 26Be morpholino.
In another preferred embodiment, the present invention relates to the p38 inhibitors of kinases in the purposes that is used for preparing the inhalable drug compositions for the treatment of Polyblennia, wherein the p38 inhibitors of kinases is selected from formula 6Chemical compound
G is phenyl, pyridine radicals or naphthyl, and wherein G is by 1 or a plurality of R 1, R 2Or R 3Replace;
X is: imidazole radicals or pyridine radicals;
Y is :-CH 2-,-NH-CH 2CH 2CH 2-or-NH-;
Z is a morpholino;
Each R 1Be independently: the tert-butyl group, sec-butyl, tertiary pentyl or phenyl;
R 2Be chlorine;
R 3Be independently: methyl, methoxyl group, methoxy, hydroxypropyl, acetamide, morpholino or morpholino carbonyl.
In another preferred embodiment, the present invention relates to the p38 inhibitors of kinases in the purposes that is used for preparing the inhalable drug compositions for the treatment of Polyblennia, wherein the p38 inhibitors of kinases is selected from formula 6Chemical compound, wherein X is a pyridine radicals.
In another preferred embodiment, the present invention relates to the p38 inhibitors of kinases and be used for the treatment of purposes in the inhalable drug compositions of Polyblennia in preparation, wherein the p38 inhibitors of kinases is selected from formula 6Chemical compound, wherein pyridine radicals links to each other with Ar by 3-pyridine radicals position.
Preferably the present invention relates to the p38 inhibitors of kinases and be used for the treatment of purposes in the inhalable drug compositions of Polyblennia in preparation, wherein the p38 inhibitors of kinases is selected from following formula 6Chemical compound:
1-(3-cyano group-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(3-fluoro-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(4-chloro-2-trifluoromethyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(2-chloro-5-trifluoromethyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(3,4-dimethyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(3-iodo-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-3-between tolyl-urea
1-(4-methyl mercapto-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(3-chloro-4-methyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(4-chloro-3-nitro-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(2,5-two chloro-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-3-naphthalene-2-base-urea
1-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-3-phenyl-urea
1-(3-chloro-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(4-chloro-3-trifluoromethyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-3-(2,4,6-three chloro-phenyl)-urea
1-(2-methyl-3-nitro-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(4-methyl-2-nitro-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(2,3-two chloro-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(2-methoxyl group-5-methyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(2-chloro-6-methyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(2,4-two chloro-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(4-methyl-3-nitro-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(2,4-dimethyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(2,3-dimethyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(4-cyano group-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-3-(3,4,5-trimethoxy-phenyl)-urea
1-xenyl-4-base-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(2,5-two fluoro-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(3-chloro-2-methoxyl group-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(2-fluoro-3-trifluoromethyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(4-benzyloxy-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(2-methyl mercapto-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(2-fluoro-6-trifluoromethyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(4-fluoro-3-trifluoromethyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-3-(2,4,5-trimethyl-phenyl)-urea
1-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-3-(4-trifluoromethyl-phenyl)-urea
1-(3-methyl mercapto-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(2-methoxyl group-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(2-fluoro-5-trifluoromethyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(4-methoxyl group-2-methyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(2-fluoro-5-nitro-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(4-ethyoxyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(2,5-dimethoxy-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(4,5-dimethyl-2-nitro-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(5-chloro-2-methyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(2-isopropyl-6-methyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(2-difluoro-methoxy-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(4-isopropyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(4-methoxyl group-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(3-ethyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(2-ethyoxyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(4-butoxy-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
4-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups }-the benzoic acid ethyl ester
1-(4-butyl-2-methyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(2,6-two bromo-4-isopropyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(3-methoxyl group-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-3-(4-trifluoromethylthio-phenyl)-urea
5-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups }-different phthalic acid dimethyl esters
1-(3-cyclopentyloxy-4-methoxyl group-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
3-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups }-the benzoic acid ethyl ester
1-(the 5-tert-butyl group-2-hydroxyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(2-hydroxymethyl-4-phenyl-cyclohexyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(2-methyl mercapto-5-trifluoromethyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-3-(4-amoxy-xenyl-3-yl)-urea
4-methoxyl group-3-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups }-benzoic acid methyl ester
1-(2,5-diethoxy-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-benzothiazole-6-base-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
N-(2,5-diethoxy-4-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups }-phenyl)-Benzoylamide
1-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-3-(3-phenoxy group-phenyl)-urea
1-(5-ethylsulfonyl-2-methoxyl group-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
4-methoxyl group-3-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups }-N-phenyl-Benzoylamide
1-(2-methyl isophthalic acid, 3-dioxo-2, the different diindyl-5-yl that draws of 3-dihydro-1H-)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(2,3-dimethyl-1H-indole-5-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
N-butyl-4-methoxyl group-3-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups }-benzsulfamide
1-[3-(2-methyl-[1,3] dioxy ring penta-2-yl)-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(3-methoxyl group-5-trifluoromethyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(2,4-dimethoxy-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(2-methyl-4-nitro-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(2-methoxyl group-4-nitro-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(4-chloro-2-nitro-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(5-chloro-2-methoxyl group-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(3,5-dimethoxy-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-3-(4-trifluoromethoxy-phenyl)-urea
1-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-3-(3-trifluoromethylthio-phenyl)-urea
1-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-3-(2-phenoxy group-phenyl)-urea
1-(2-methoxyl group-5-nitro-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(5-chloro-2,4-dimethoxy-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(3,5-couple-trifluoromethyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(the 2-tert-butyl group-5-methyl-pyridin-4-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(3-methyl-naphthalene-2-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(the 3-tert-butyl group-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(4-methyl-xenyl-3-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(the 4-tert-butyl group-xenyl-2-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(5-chloro-2,4-dimethoxy-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(5-isopropyl-2-methyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(5-sec-butyl-2-methoxyl group-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(the 5-tert-butyl group-2-methoxyl group-3-propyl group-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(the 5-tert-butyl group-2-methoxy-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(the 5-tert-butyl group-2-methyl-phenyl)-3-(4-{6-[(3-methoxyl group-propyl group)-methyl-amino]-pyridin-3-yl }-naphthalene-1-yl)-urea
1-(the 5-tert-butyl group-2-methyl-phenyl)-3-[4-(4-morpholine-4-ylmethyl-imidazoles-1-yl)-naphthalene-1-yl]-urea
1-(the 5-tert-butyl group-2-methyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(the 5-tert-butyl group-2-methyl-phenyl)-3-{4-[6-(3-methoxyl group-propyl group amino)-pyridin-3-yl]-naphthalene-1-yl }-urea
1-(the 5-tert-butyl group-2-methyl-pyridin-3-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(the 5-tert-butyl group-2-morpholine-4-base-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-(the 6-tert-butyl group-2-chloro-3-methyl-pyridin-4-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
1-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-3-(3-trifluoromethyl-phenyl)-urea
1-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-3-(4-trifluoromethoxy-phenyl)-urea
1-[5-(1,1-dimethyl-propyl group)-2-methoxyl group-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
The 1-[5-tert-butyl group-2-(1H-pyrazoles-4-yl)-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
The 1-[5-tert-butyl group-2-(2-methyl-pyrimidine-5-yl)-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
The 1-[5-tert-butyl group-2-(3-hydroxyl-propyl group)-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
The 1-[5-tert-butyl group-2-(3-morpholine-4-base-3-oxo-propyl group)-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
The 1-[5-tert-butyl group-2-(morpholine-4-carbonyl)-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea
N-(the 5-tert-butyl group-2-methoxyl group-3-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups }-phenyl)-acetamide
With and pharmaceutically acceptable derivant.
1-(the 2-tert-butyl group-5-methyl-pyridin-4-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(3-methyl-naphthalene-2-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 3-tert-butyl group-phenyl)-3-[4-(4-morpholine-4-ylmethyl-phenyl)-naphthalene-1-yl]-urea;
1-(the 3-tert-butyl group-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(4-methyl-xenyl-3-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 4-tert-butyl group-xenyl-2-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(5-chloro-2,4-dimethoxy-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(5-isopropyl-2-methyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(5-sec-butyl-2-methoxyl group-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methoxyl group-3-propyl group-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methoxy-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-[4-(2-morpholine-4-ylmethyl-pyrimidine-5-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-[4-(4-tetrahydro-1,4-thiazine-4-ylmethyl-phenyl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-[4-(6-morpholine-4-ylmethyl-phenyl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-{4-[4-(tetrahydrochysene-pyrans-4-base is amino)-phenyl]-naphthalene-1-yl }-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-{4-[6-(4-methyl-piperazine-1-ylmethyl)-pyridin-3-yl]-naphthalene-1-yl }-urea;
1-(the 5-tert-butyl group-2-methyl-phenyl)-3-(4-{6-[(3-methoxyl group-propyl group)-methyl-amino]-pyridin-3-yl }-naphthalene-1-yl)-urea;
1-(the 5-tert-butyl group-2-methyl-phenyl)-3-[4-(4-morpholine-4-ylmethyl-imidazoles-1-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methyl-phenyl)-3-[4-(4-morpholine-4-ylmethyl-phenyl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methyl-phenyl)-3-{4-[6-(3-methoxyl group-propyl group amino)-pyridin-3-yl]-naphthalene-1-yl }-urea;
1-(the 5-tert-butyl group-2-methyl-pyridin-3-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-morpholine-4-base-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 6-tert-butyl group-2-chloro-3-methyl-pyridin-4-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 6-tert-butyl group-2-chloro-3-methyl-pyridin-4-yl)-3-[4-(6-tetrahydro-1,4-thiazine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-[2-methoxyl group-5-(1-methyl-cyclopropyl)-phenyl]-3-[4-(2-morpholine-4-ylmethyl-pyrimidine-5-yl)-naphthalene-1-yl]-urea;
1-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-3-(3-trifluoromethyl-phenyl)-urea;
1-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-3-(4-trifluoromethoxy-phenyl)-urea;
1-[5-(1,1-dimethyl-propyl group)-2-methoxyl group-phenyl]-3-[4-(4-tetrahydro-1,4-thiazine-4-ylmethyl-phenyl)-naphthalene-1-yl]-urea;
1-[5-(1,1-dimethyl-propyl group)-2-methoxyl group-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-[5-(1-cyano group-cyclopropyl)-2-methoxyl group-phenyl]-3-[4-(2-morpholine-4-ylmethyl-pyrimidine-5-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(1H-pyrazoles-4-yl)-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-methyl-pyrimidine-5-yl)-phenyl]-3-[4-(5-pyridin-4-yl methyl-pyridine-2-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-methyl-pyrimidine-5-yl)-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(3-hydroxyl-propyl group)-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(3-morpholine-4-base-3-oxo-propyl group)-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(morpholine-4-carbonyl)-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
The 2-[4-tert-butyl group-2-(3-{4-[6-(2,6-dimethyl-morpholine-4-ylmethyl)-pyridin-3-yl]-naphthalene-1-yl }-urea groups)-phenoxy group]-acetamide;
3-{4-[3-(the 5-tert-butyl group-2-methoxyl group-phenyl)-urea groups]-naphthalene-1-yl }-Benzoylamide;
The 4-tert-butyl group-2-{3-[4-(2-chloro-4-morpholine-4-ylmethyl-phenyl)-naphthalene-1-yl]-urea groups }-Benzoylamide;
With and pharmaceutically acceptable derivant.
More preferably the present invention relates to the p38 inhibitors of kinases and be used for the treatment of purposes in the inhalable drug compositions of Polyblennia in preparation, wherein the p38 inhibitors of kinases is selected from following formula 6Chemical compound:
1-(the 2-tert-butyl group-5-methyl-pyridin-4-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 3-tert-butyl group-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(4-methyl-xenyl-3-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 4-tert-butyl group-xenyl-2-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(5-isopropyl-2-methyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(5-sec-butyl-2-methoxyl group-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methoxy-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methyl-phenyl)-3-(4-{6-[(3-methoxyl group-propyl group)-methyl-amino]-pyridin-3-yl }-naphthalene-1-yl)-urea;
1-(the 5-tert-butyl group-2-methyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methyl-pyridin-3-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-[5-(1,1-dimethyl-propyl group)-2-methoxyl group-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(1H-pyrazoles-4-yl)-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-methyl-pyrimidine-5-yl)-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(3-hydroxyl-propyl group)-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(morpholine-4-carbonyl)-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
N-(the 5-tert-butyl group-2-methoxyl group-3-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups }-phenyl)-acetamide
With and pharmaceutically acceptable derivant.
In another embodiment preferred, the present invention relates to the p38 inhibitors of kinases and be used for the treatment of purposes in the inhalable drug compositions of Polyblennia in preparation, wherein the p38 inhibitors of kinases is selected from as disclosed formula in WO 00/55139 7Chemical compound:
Figure A0381298801171
Wherein:
E is a carbon or be selected from-O-,-NH-and-hetero atom of S-;
G is:
The C of fragrance 6-10The saturated or unsaturated C of carbocyclic ring or non-fragrance 3-10Carbocyclic ring;
The monocyclic, bicyclic or tricyclic heteroaryl of 6-14 person comprises 1 or the hetero atom of more a plurality of O of being selected from, N and S;
6-8 person's monocyclic heterocycles comprises the hetero atom that one or more is selected from O, N and S; Or
8-11 person's bicyclic heterocycles comprises the hetero atom that one or more is selected from O, N and S;
Wherein G is optional by one or more R 1, R 2Or R 3Replace;
Ar is: phenyl, naphthyl, quinolyl, isoquinolyl, tetralyl, tetrahydric quinoline group, tetrahydro isoquinolyl, benzimidazolyl, benzofuranyl, dihydro benzo furyl, indolinyl, benzothienyl, dihydrobenzo thienyl, indanyl, indenyl or indyl, each group is optional by one or more R 4Or R 5Replace;
X is:
C 5-8Cycloalkyl or cycloalkenyl group, optional by 1 or 2 oxo group or 1～3 C 1-4Alkyl,
C 1-4Alkoxyl or C 1-4The alkyl amino chain replaces, and each group can be side chain or straight chain;
Aryl, furyl, thienyl, pyrrole radicals, pyrazolyl, imidazole radicals, pyridine radicals, pyrimidine radicals, pyriconyl, dihydropyridine ketone group, dimaleoyl imino, dihydro dimaleoyl imino, piperidyl, benzimidazole, 3H-imidazo [4,5-b] pyridine, piperazinyl, pyridazinyl or pyrazinyl; Each group is optional independently by 1～3 C 1-4Alkyl, C 1-4Alkoxyl, hydroxyl, nitrile, amino, list-or two-(C 1-3Alkyl) amino, single-or two-(C 1-3Alkyl amino) carbonyl, NH 2C (O), C 1-6Alkyl-S (O) mOr halogen replaces;
Y is: chemical bond or optional part or complete halogenated C 1-4Saturated or unsaturated side chain or straight chain carbochain, wherein one or more C atom is optional by O, N or S (O) mReplace and wherein Y is optional independently by 1 or 2 oxo group, nitrile, phenyl or 1 or a plurality of optional C that is replaced by one or more halogen atom 1-4Alkyl replaces;
Z is: aryl; heteroaryl is selected from pyridine radicals; piperazinyl; pyrimidine radicals; pyridazinyl; pyrazinyl; imidazole radicals; pyrazolyl; triazolyl; tetrazole radical; furyl; thienyl and pyranose; heterocycle is selected from the tetrahydropyrimidine ketone group; the hexamethylene ketone group; the hexamethylene acyl group; the 2-oxa--or 2-thia-5-aza-bicyclo [2.2.1] heptane base; the pentamethylene sulfenyl; the pentamethylene sulfoxide group; the pentamethylene sulfonyl; the tetramethylene sulfenyl; tetramethylene sulfoxide base or tetramethylene sulfonyl; THP trtrahydropyranyl; tetrahydrofuran base; 1; 3-dioxo Ketocyclopentane base; 1; 3-dioxanone base; 1; the 4-dioxacyclohexyl; morpholino; tetrahydro-1,4-thiazine generation; tetrahydro-1,4-thiazine is for sulfoxide group; tetrahydro-1,4-thiazine is for sulfonyl; piperidyl; piperidone base; pyrrolidinyl and dioxo cyclopenta, aforementioned each Z group is optional to be replaced by 1～3 substituent group that is selected from the following group: halogen; C 1-6Alkyl, C 1-6Alkoxyl, C 1-3Alkoxy-C 1-3Alkyl, C 1-6Alkoxy carbonyl, aroyl, C 1-3Acyl group, oxo, hydroxyl, pyridine radicals-C 1-3Alkyl, imidazole radicals-C 1-3Alkyl, tetrahydrofuran base-C 1-3Alkyl, nitrile-C 1-3Alkyl, nitrile, carboxyl, phenyl, wherein benzyl ring is optional is replaced by 1～2 substituent group that is selected from the following groups: halogen, C 1-6Alkoxyl, hydroxyl or list-or two-(C 1-3Alkyl) amino, C 1-6Alkyl-S (O) mOr phenyl-S (O) m, wherein benzyl ring is optional by 1～2 halogen, C 1-6Alkoxyl, hydroxyl, halogen or list-or two-(C 1-3Alkyl) the amino replacement;
Or Z is optional by 1～3 amino or amino-C 1-3Alkyl replaces, and wherein the N atom is optional independently by amino C 1-6Alkyl, C 1-3Alkyl, aryl C 0-3Alkyl, C 1-5Alkoxy C 1-3Alkyl, C 1-5Alkoxyl, aroyl, C 1-3Acyl group, C 1-3Alkyl-S (O) m-or aryl C 0-3Alkyl-S (O) m-single-or two-replace, it is optional by 1～2 halogen, C to be connected to amino aforementioned each alkyl and aryl 1-6Alkyl or C 1-6Alkoxyl replaces;
Or Z is optional by 1～3 as foregoing aryl, heterocycle or heteroaryl replacement in this section, and each group is chosen wantonly conversely by halogen, C 1-6Alkyl or C 1-6Alkoxyl replaces;
Or Z is hydroxyl, halogen, nitrile, amino, and wherein the N atom is optional independently by C 1-3Acyl group, C 1-6Alkyl or C 1-3Alkoxy C 1-3Alkyl, side chain or straight chain C 1-6Alkyl, C 1-6Alkoxyl, C 1-3Acyl amino, nitrile C 1-4Alkyl, C 1-6Alkyl-S (O) mAnd phenyl-S (O) mSingle-or two-replace, wherein benzyl ring is optional by 1～2 halogen, C 1-6Alkoxyl, hydroxyl or list-or two-(C 1-3Alkyl) the amino replacement;
Each R 1Be independently: side chain or straight chain C 1-10Alkyl, optional part or complete halo, wherein one or more C atom is randomly independently by O, N or S (O) mSubstitute and wherein said C 1-10Alkyl is optional to be replaced by 1～3 substituent group that is selected from the group in following: C 3-10Cycloalkyl, hydroxyl, oxo, phenyl, naphthyl, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, pyrrolidinyl, imidazole radicals, pyrazolyl, thienyl, furyl, dioxo cyclopenta, isoxazolyl or isothiazolyl; Aforementioned each group is optional to be replaced by 1～5 substituent group that is selected from the following groups: halogen, optional part or complete halogenated C 1-6Alkyl, C 3-8Cycloalkyl, C 5-8Cycloalkenyl group, hydroxyl, nitrile, optional part or complete halogenated C 1-3Alkoxyl or NH 2C (O), single-or two (C 1-3Alkyl) amino and single-or two (C 1-3Alkyl) amino carbonyl;
Or R 1For
Ring propoxyl group, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy or suberyl oxygen base, each group optional part or complete halo are also optional by 1～3 optional part or complete halogenated C 1-3Alkyl, nitrile, hydroxyl C 1-3Alkyl or aryl replaces; Or wherein 1～3 the ring methylene independently by O, S (O) m, CHOH,＞C=O,＞the similar group of C=S or the alternate described cycloalkyl of NH;
Phenoxy group or benzyloxy, each group optional part or complete halo and optional by 1～3 optional part or complete halogenated C 1-3Alkyl, nitrile, hydroxyl C 1-3Alkyl or aryl replaces; Or wherein 1～2 the ring methine independently by the similar group of the alternate described cyclophane base of N;
Cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, bicyclo-pentyl, bicyclohexane base or bicycloheptane base, each group optional part or complete halo are also optional by 1～3 optional part or complete halogenated C 1-3Alkyl, nitrile, hydroxyl C 1-3Alkyl or aryl replaces; Or wherein 1～3 the ring methylene independently by O, S (O) m, CHOH,＞C=O,＞the similar group of C=S or the alternate described cycloalkyl of NH;
C 3-10Side chain or straight alkenyl, each group optional part or complete halo and optional by 1～3 the substituent group replacement that is selected from the following radicals: C 1-5Branched-chain or straight-chain alkyl, phenyl, naphthyl, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl, aforementioned each group is replaced by 1～5 substituent group that is selected from the following groups: halogen, optional part or complete halogenated C 1-6Alkyl, cyclopropane base, Tetramethylene. base, Pentamethylene. base, cyclohexyl, cycloheptane base, bicyclo-pentyl, bicyclohexane base and bicycloheptane base, hydroxyl, nitrile, optional part or complete halogenated C 1-3Alkoxyl, NH 2C (O), single-or two (C 1-3Alkyl) amino carbonyl; Randomly be selected from O, N and S (O) by one or more mThe C that interrupts of hetero atom 3-10Side chain or straight alkenyl;
Cyclopentenyl, cyclohexenyl group, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyl groups or bicycloheptene base, wherein said cycloalkenyl group are randomly by 1～3 C 1-3Alkyl replaces;
Oxo, nitrile, halogen;
Silicyl comprises 3 optional parts or complete halogenated C 1-4Alkyl; Or C 3-6Alkynyl side chain or straight chain carbochain, optional part or complete halo and wherein one or more methylene is optional by O, NH or S (O) mReplace and wherein said alkynyl is optional is replaced by following radicals independently: 1 or 2 oxo group, hydroxyl, pyrrolidinyl, pyrrole radicals, THP trtrahydropyranyl, one or more optional C that is substituted one or more halogen atom 1-4Alkyl, nitrile, morpholino, piperidyl, piperazinyl, imidazole radicals, phenyl, pyridine radicals, tetrazole radical or the optional list that is replaced by one or more halogen atom-or two (C 1-3Alkyl) amino;
Each R 2, R 4And R 5For
Optional part or complete halogenated C 1-6Branched-chain or straight-chain alkyl, C 1-6Acyl group, aroyl, C 1-4Side chain or straight chain alkoxyl, each group optional part or halogenated fully, halogen, methoxycarbonyl, optional part or complete halogenated C 1-3Alkyl-S (O) mOr phenyl-S (O) m
OR 6, C 1-6Alkoxyl, hydroxyl, nitrile, nitro, halogen;
Or amino-S (O) m-, wherein the N atom is optional independently by C 1-6Alkyl or aryl C 0-3Alkyl list-or two-replace, or amino wherein the N atom is optional independently by C 1-3Alkyl, aryl C 0-3Alkyl, C 1-6Acyl group, C 1-6Alkyl-S (O) m-or aryl C 0-3Alkyl-S (O) m-single-or two-replacing, aforementioned each group alkyl in this section and aryl optional part or complete halo are also optional by 1～2 C 1-6Alkyl or C 1-6Alkoxyl replaces;
Each R 3Be independently:
Phenyl, naphthyl, morpholino, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, pyrrolidinyl, imidazole radicals, pyrazolyl, thiazolyl oxazolyl, [1,3,4] oxadiazoles, triazolyl, tetrazole radical, thienyl, furyl, tetrahydrofuran base isoxazolyl, isothiazolyl, quinolyl, isoquinolyl, indyl, benzimidazolyl, benzofuranyl benzoxazolyl, the benzoisoxazole base, the benzopyrazoles base, the benzo thiapyran base, cinnolinyl, pteridyl, phthalazinyl, the naphthyl pyridine radicals, quinoxalinyl, quinazolyl, purine radicals or indazolyl, aforementioned each group is optional to be replaced by 1～3 substituent group that is selected from the following groups: phenyl, naphthyl, as foregoing heterocycle or heteroaryl in this section, optional part or complete halogenated C 1-6Branched-chain or straight-chain alkyl, cyclopropane base, Tetramethylene. base, Pentamethylene. base, cyclohexyl, cycloheptane base, bicyclo-pentyl, bicyclohexane base, bicycloheptane base, phenyl C 1-5Alkyl, naphthyl C 1-5Alkyl, halogen, hydroxyl, oxo, nitrile, optional part or complete halogenated C 1-3Noted earlier in the wherein said heterocyclic radical of alkoxyl, phenoxy group, naphthoxy, heteroaryloxy or heterocyclic oxy group or heteroaryl moieties such as this section, nitro, amino, list-or two-(C 1-3Alkyl) noted earlier, NH in amino, phenyl amino, naphthyl amino, heteroaryl or the wherein said heteroaryl heterocyclic moiety of heterocyclic amino group such as this section 2C (O), single-or two-(C 1-3Alkyl) amino carbonyl, C 1-5Alkyl-C (O)-C 1-4Alkyl, amino-C 1-5Alkyl, list-or two-(C 1-5Alkyl) amino, single-or two-(C 1-3Alkyl) amino-C 1-5Alkyl, amino-S (O) 2, two-(C 1-3Alkyl) amino-S (O) 2, R 7-C 1-5Alkyl, R 8-C 1-5Alkoxyl, R 9-C (O)-C 1-5Alkyl, R 10-C 1-5Alkyl (R 11) N, carboxyl-list-or two-(C 1-5Alkyl)-amino;
Condensed aryl is selected from benzocyclobutane alkyl, indanyl, indenyl, dihydro naphthyl, tetralyl, benzocyclohepta alkyl and benzocyclohepta thiazolinyl; Or condensed heteroaryl, be selected from the cyclopenta pyridine base, hexamethylene and pyridine radicals, the cyclopentano pyrimidine radicals, hexamethylene and pyrimidine radicals, the cyclopentano pyrazinyl, hexamethylene and pyrazinyl, the cyclopentano pyridazinyl, hexamethylene and pyridazinyl, the cyclopentano quinolyl, hexamethylene and quinolyl, the cyclopentano isoquinolyl, hexamethylene and isoquinolyl, the cyclopentano indyl, hexamethylene diindyl base, the cyclopentano benzimidazolyl, hexamethylene and benzimidazolyl, the cyclopentano benzoxazolyl, hexamethylene and benzoxazolyl, the cyclopentano imidazole radicals, hexamethylene and imidazole radicals, cyclopentano thienyl and hexamethylene bithiophene base; Wherein said fused-aryl or condensed heteroaryl ring are replaced by 0～3 substituent group that is selected from the following groups independently: phenyl, naphthyl, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, optional part or complete halogenated C 1-6Alkyl, halogen, nitrile, optional part or complete halogenated C 1-3Noted earlier in the wherein said heteroaryl of alkoxyl, phenoxy group, naphthoxy, heteroaryloxy or heterocyclic oxy group or heterocyclic moiety such as this section, nitro, amino, list-or two-(C 1-3Alkyl) noted earlier, NH in amino, phenyl amino, naphthyl amino, heteroaryl or the wherein said heteroaryl of heterocyclic amino group or heterocyclic moiety such as this section 2C (O), single-or two-(C 1-3Alkyl) amino carbonyl, C 1-4Alkyl-OC (O), C 1-5Alkyl-C (O)-C 1-4Alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3) alkyl amino-C 1-5Alkyl, R 12-C 1-5Alkyl, R 13-C 1-5Alkoxyl, R 14-C (O)-C 1-5Alkyl or R 15-C 1-5Alkyl (R 16) N;
Cyclopropane base, Tetramethylene. base, Pentamethylene. base, cyclohexyl, cycloheptane base, bicyclo-pentyl, bicyclohexane base or bicycloheptane base, each group are randomly for partially or completely halo is also optional by 1～3 C 1-3Alkyl replaces, or wherein 1～3 ring methylene independently by O, S, CHOH,＞C=O,＞C=S or the similar group of the alternate described cycloalkyl of NH;
Cyclopentenyl, cyclohexenyl group, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyl groups or bicycloheptene base, each is optional by 1～3 C 1-3Alkyl replaces;
C 1-4Alkyl-phenyl-C (O)-C 1-4Alkyl-, C 1-4Alkyl-C (O)-C 1-4Alkyl-or C 1-4Alkyl-phenyl-S (O) m-C 1-4Alkyl-;
C 1-6Alkyl or C 1-6Side chain or straight chain alkoxyl, each group optional part or fully halogenated or optional by R 17Replace;
OR 18Or it is optional by OR 18The C that replaces 1-6Alkyl;
Optional by R 19Amino or the list that replaces-or two-(C 1-5Alkyl) amino;
R 20C (O) N (R 21)-, R 22O-or R 23R 24NC (O)-; R 26(CH 2) mC (O) N (R 21)-,
R 23R 24NC (O)-C 1-3Alkoxyl or R 26C (O) (CH 2) mN (R 21)-;
By R 23R 24The C of NC (O)-replacement 2-6Alkenyl;
C 2-6Alkynyl side chain or straight chain carbochain, optional part or halogenated fully, wherein one or more methylene is optional by O, NH, S (O) mReplace and the optional substituent group that is selected from independently in the following groups of wherein said alkynyl replaces: 1 or 2 oxo group, pyrrolidinyl, pyrrole radicals, morpholino, piperidyl, piperazinyl, imidazole radicals, phenyl, pyridine radicals, tetrazole radical, one or more optional C that is replaced by one or more halogen atom 1-4Alkyl, nitrile, morpholino, piperidyl, piperazinyl, imidazole radicals, phenyl, pyridine radicals, tetrazole radical, or the optional list that is replaced by one or more halogen atom-or two (C 1-4Alkyl) amino;
C 1-6Acyl group or aroyl;
R 6For: C 1-4Alkyl, optional part or complete halo are also optional by R 26Replace;
Each R 7, R 8, R 9, R 10, R 12, R 13, R 14, R 15, R 17, R 19, R 25And R 26Be independently: nitrile, phenyl, morpholino, piperidyl, piperazinyl, imidazole radicals, pyridine radicals, tetrazole radical, amino or optional part or complete halogenated list-or two-(C 1-4Alkyl) amino;
Each R 11And R 16Be independently: hydrogen or optional part or complete halogenated C 1-4Alkyl;
R 18Be independently: hydrogen or optional independently by oxo or R 25The C that replaces 1-4Alkyl;
R 20Be independently: optional part or complete halogenated C 1-10Alkyl, phenyl or pyridine radicals;
R 21Be independently: hydrogen or optional part or complete halogenated C 1-3Alkyl;
Each R 22, R 23And R 24Be independently: hydrogen, optional part or complete halogenated C 1-6Alkyl, described C 1-6Alkyl is randomly interrupted described C by one or more O, N or S 1-6The also optional independently coverlet of alkyl-or two-(C 1-3Alkyl) amino carbonyl, phenyl, pyridine radicals, amino or single-or two-(C 1-4Alkyl) the amino replacement, each group optional part or complete halo and optional coverlet-or two-(C 1-3Alkyl) the amino replacement;
Or R 23And R 24Randomly form heterocyclic radical or heteroaryl ring together;
M=0,1 or 2;
W be O or S and
Its pharmaceutically acceptable derivant.
In preferred embodiments, the present invention relates to the p38 inhibitors of kinases in the purposes that is used for preparing the inhalable drug compositions for the treatment of Polyblennia, wherein the p38 inhibitors of kinases is selected from formula 7Chemical compound wherein:
E is-CH 2-,-NH-or-O-;
W is O;
And
G is:
Phenyl, naphthyl, benzocyclobutane alkyl, dihydro naphthyl, tetralyl, benzocyclohepta alkyl, benzocyclohepta thiazolinyl, indanyl, indenyl;
Pyridine radicals, pyriconyl, quinolyl, the dihydroquinoline base, tetrahydric quinoline group, isoquinolyl, tetrahydro isoquinolyl, pyridazinyl, pyrimidine radicals, pyrazinyl, benzimidazolyl, benzothiazolyl benzoxazolyl, benzofuranyl, benzothienyl, the benzopyrazoles base, dihydro benzo furyl, dibenzofuran group, dihydrobenzo thienyl; benzoxazole ketone group, benzo [1,4] oxazine-3-ketone group, the benzodioxole base, benzo [1,3] dioxole-2-ketone group, benzofuran-3-ketone group, the tetrahydro benzo pyranose, indyl, 2,3-dihydro-1H-indyl, indolinyl, the indole ketone group, the indoline ketone group, phthalimidyl, chromoyl; The oxa-cyclobutyl, pyrrolidinyl, tetrahydrofuran base, tetrahydro-thienyl, piperidyl, piperazinyl, morpholino, THP trtrahydropyranyl, dioxacyclohexyl, the tetramethylene sulfonyl, tetramethylene sulfoxide base oxazolinyl, 3,4-dihydro-2H-benzo [1,4] oxazinyl, thiazolinyl, imidazolinyl, tetrahydro pyridyl, homopiperidinyl, pyrrolinyl, tetrahydro-pyrimidine base, decahydroquinolyl, the Decahydroisoquinolinpreparation base, tetrahydro-1,4-thiazine generation, thiazolidinyl Er Qing oxazinyl, dihydro pyranyl, oxocanyl, heptacanyl, sulfur oxa-cyclohexyl or dithia cyclohexyl;
Wherein G is optional is replaced by one or more R1, R2 or R3.
In another embodiment, the present invention relates to the p38 inhibitors of kinases in the purposes that is used for preparing the inhalable drug compositions for the treatment of Polyblennia, wherein the p38 inhibitors of kinases is selected from formula 7Chemical compound wherein:
E is-NH-;
G is phenyl, pyridine radicals, pyriconyl, naphthyl, quinolyl, isoquinolyl, pyrazinyl, benzimidazolyl, benzoxazolyl, benzoxazole ketone group, benzofuranyl, benzothienyl, benzopyrazoles base, dihydro benzo furyl, dihydrobenzo thienyl, 3,4-dihydro-2H-benzo [1,4] oxazinyl, indanyl, indenyl, indyl, indolinyl, indole ketone group, 2,3-dihydro-1H-indyl or indoline ketone group, wherein G is optional by one or more R 1, R 2Or R 3Replace;
Ar is: naphthyl, quinolyl, isoquinolyl, tetralyl, tetrahydric quinoline group, tetrahydro isoquinolyl, indanyl, indenyl or indyl, each group is optional by one or more R 4Or R 5Group replaces;
X is: phenyl, furyl, thienyl, pyrrole radicals, pyrazolyl, imidazole radicals, pyridine radicals, pyrimidine radicals, pyriconyl, dihydropyridine ketone group, dimaleoyl imino, dihydro dimaleoyl imino, piperidyl, piperazinyl, pyridazinyl or pyrazinyl; Each group is optional independently by 1～3 C 1-4Alkyl, C 1-4Alkoxyl, hydroxyl, nitrile, amino, list-or two-(C 1-3Alkyl) amino, single-or two-(C 1-3Alkyl amino) carbonyl, NH 2C (O), C 1-6Alkyl-S (O) mOr halogen replaces;
Y is:
Chemical bond or
C 1-4Saturated or unsaturated carbochain, wherein one or more C atom is randomly by O, N or S (O) mSubstitute, and wherein the optional substituent group that is selected from independently in the following radicals of Y replaces: 1 or 2 oxo group, nitrile, phenyl or 1 or a plurality of optional C that is replaced by one or more halogen atom 1-4Alkyl;
Z is: phenyl; heteroaryl is selected from pyridine radicals; piperazinyl; pyrimidine radicals; pyridazinyl; pyrazinyl; imidazole radicals; furyl; thienyl and pyranose; heterocycle is selected from 2-oxa--5-aza-bicyclo [2.2.1] heptane base; the tetrahydropyrimidine ketone group; the pentamethylene sulfenyl; the pentamethylene sulfoxide group; the pentamethylene sulfonyl; the tetramethylene sulfenyl; tetramethylene sulfoxide base tetramethylene sulfonyl; THP trtrahydropyranyl; tetrahydrofuran base; 1; 3-dioxo Ketocyclopentane base; 1; 3-dioxanone base; 1; the 4-dioxacyclohexyl; morpholino; tetrahydro-1,4-thiazine generation; tetrahydro-1,4-thiazine is for sulfoxide group; piperidyl; piperidone base; dihydro-thiazolyl; the dihydro-thiazolyl sulfoxide group; pyrrolidinyl and dioxo cyclopenta, each group is optional by 1～3 nitrile; C 1-3Alkyl, C 1-3Alkoxyl, amino, list-or two-(C 1-3Alkyl) amino, CONH 2Or OH replaces;
Or Z optional by as foregoing phenyl, heterocycle or heteroaryl replacement in this section, each substituent group is chosen wantonly conversely by halogen, C 1-3Alkyl or C 1-3Alkoxyl replaces;
Or Z is nitrile, nitrile C 1-3Alkyl, C 1-6Alkyl-S (O) m, halogen, hydroxyl, C 1-3Alkyl, C 1-3Acyl amino, C 1-4Alkoxyl, amino, list-or two-(C 1-3Alkyl) amino carbonyl, or amino list or two-replace by amino C 1-6Alkyl or C 1-3Alkoxy C 1-3Alkyl;
Each R 1Be independently:
Side chain or straight chain C 1-6Alkyl, optional part or halogenated fully, wherein one or more C atom is randomly independently by O, N or S (O) mSubstitute and wherein said C 1-6Alkyl is optional by 1～3 C 3-6Cycloalkyl, oxo, phenyl, dioxo cyclopenta, pyrrolidinyl, furyl, isoxazolyl or isothiazolyl replace; Aforementioned each group is optional to be selected from halogen, optional part or complete halogenated C by 1～3 1-3Alkyl, hydroxyl, nitrile and optional part or complete halogenated C 1-3The group of alkoxyl replaces;
Cyclopropyl, cyclobutyl, Pentamethylene. base, cyclohexyl, bicyclo-pentyl or bicyclohexane base, each group optional part or complete halo are also optional by 1～3 randomly partially or completely halogenated C 1-3Alkyl, nitrile, hydroxyl C 1-3The group of alkyl or phenyl replaces; Or wherein 1～3 ring methylene independently by O, S, CHOH,＞C=O,＞the similar group of C=S or the alternate described cycloalkyl of NH; Oxo;
C 3-6Alkynyl side chain or straight chain carbochain, optional part or halogenated fully, wherein one or more methylene is optional by O, NH or S (O) mReplace and the optional substituent group that is selected from independently in the following groups of wherein said alkynyl replaces: 1 or 2 oxo group, hydroxyl, pyrrolidinyl, pyrrole radicals, THP trtrahydropyranyl, the optional C that is replaced by one or more halogen atom 1-4Alkyl, nitrile, morpholino, piperidyl, piperazinyl, imidazole radicals, phenyl, pyridine radicals, tetrazole radical or the optional list that is replaced by one or more halogen atom-or two (C 1-3Alkyl) amino;
Or
Silicyl comprises 3 optional parts or complete halogenated C 1-4Alkyl; R 2Be independently:
Optional part or complete halogenated C 1-5Branched-chain or straight-chain alkyl, acetyl group, aroyl, C 1-4Side chain or straight chain alkoxyl, each group optional part or halogenated fully, halogen, methoxycarbonyl, optional part or complete halogenated C 1-2Alkyl-S (O) mOr phenyl-S (O) m
C 1-3Alkoxyl, hydroxyl, nitrile, nitro, halogen;
Or amino-S (O) m-wherein the N atom is optional independently by C 1-3Alkyl or aryl C 0-3Alkyl list-or two-replace, or amino wherein the N atom is optional independently by C 1-3Alkyl, aryl C 0-3Alkyl, C 1-3Acyl group, C 1-4Alkyl-S (O) m-or aryl C 0-3Alkyl-S (O) m-single-or two-replacing, aforementioned each group alkyl in this section and aryl optional part or complete halo are also optional by 1～2 C 1-3Alkyl or C 1-3Alkoxyl replaces;
R 3Be independently:
Phenyl, morpholino, pyridine radicals, pyrimidine radicals, pyrazinyl, pyrrole radicals, pyrrolidinyl, imidazole radicals, [1,3,4] oxadiazoles, pyrazolyl, each group is optional to be replaced by 1～3 substituent group that is selected from the following groups: phenyl, naphthyl, as foregoing heterocycle or heteroaryl, optional part or complete halogenated C in this section 1-6Alkyl, cyclopropane base, Tetramethylene. base, Pentamethylene. base, cyclohexyl, cycloheptane base, bicyclo-pentyl, bicyclohexane base, bicycloheptane base, phenyl C 1-5Alkyl, naphthyl C 1-5Alkyl, halogen, oxo, hydroxyl, nitrile, optional part or complete halogenated C 1-3Noted earlier in the wherein said heteroaryl of alkoxyl, phenoxy group, naphthoxy, heteroaryloxy or heterocyclic oxy group or heterocyclic moiety such as this section, nitro, amino, list-or two-(C 1-3Alkyl) noted earlier, NH in amino, phenyl amino, naphthyl amino, heteroaryl or the wherein said heteroaryl of heterocyclic amino group or heterocyclic moiety such as this section 2C (O), single-or two-(C 1-3Alkyl) amino carbonyl, C 1-5Alkyl-C (O)-C 1-4Alkyl, list-or two-(C 1-3Alkyl) amino, single-or two-(C 1-3) alkyl amino-C 1-5Alkyl, list-or two-(C 1-3Alkyl) amino-S (O) 2, R 7-C 1-5Alkyl, R 8-C 1-5Alkoxyl, R 9-C (O)-C 1-5Alkyl, R 10-C 1-5Alkyl (R 11) N, carboxyl-list-or two-(C 1-5)-alkyl-amino;
C 1-3Alkyl or C 1-4Alkoxyl, each group optional part or fully halogenated or optional by R 17Replace;
OR 18Or it is optional by OR 18The C that replaces 1-6Alkyl;
Optional by R 19Amino or the list that replaces-or two-(C 1-5Alkyl) amino;
R 20C (O) N (R 21)-, R 22O-; R 23R 24NC (O)-; R 26CH 2C (O) N (R 21)-, R 23R 24NC (O)-C 1-2Alkoxyl or R 26C (O) CH 2N (R 21)-;
By R 23R 24The C of NC (O)-replacement 2-4Alkenyl; Or
Optional part or complete halogenated C 2-4Alkynyl side chain or straight chain carbochain, wherein one of methylene is randomly substituted by O and the optional substituent group that is selected from independently in the following groups replaces: 1 or 2 oxo group, pyrrolidinyl, pyrrole radicals, morpholino, piperidyl, piperazinyl, imidazole radicals, phenyl, pyridine radicals, tetrazole radical or 1 or a plurality of optional C that is replaced by one or more halogen atom 1-4Alkyl;
C 1-3Acyl group; And
R 23And R 24Randomly form imidazole radicals, piperidyl, morpholino, piperazinyl or pyridyl ring together.
In another preferred embodiment, the present invention relates to the p38 inhibitors of kinases in the purposes that is used for preparing the inhalable drug compositions for the treatment of Polyblennia, wherein the p38 inhibitors of kinases is selected from formula 7Chemical compound wherein:
G is phenyl, pyridine radicals, pyriconyl, naphthyl, quinolyl, isoquinolyl, pyrazinyl, 3,4-dihydro-2H-benzo [1,4] oxazinyl, benzothienyl, dihydro benzo furyl, dihydrobenzo thienyl, benzoxazolyl, indanyl, indyl, indolinyl, indole ketone group or indoline ketone group, wherein G is optional by one or more R 1, R 2Or R 3Replace;
Ar is a naphthyl;
X is phenyl, imidazole radicals, pyridine radicals, pyrimidine radicals, piperidyl, piperazinyl, pyridazinyl or pyrazinyl, and each group is optional independently by 1～3 C 1-4Alkyl, C 1-4Alkoxyl, hydroxyl, nitrile, amino, list-or two-(C 1-3Alkyl) amino, single-or two-(C 1-3Alkyl amino) carbonyl, NH 2C (O), C 1-6Alkyl-S (O) mOr halogen replaces;
Y is:
Chemical bond or
C 1-4Saturated carbochain, wherein one or more C atom is randomly substituted by O, N or S and wherein Y is optional is replaced by nitrile or oxo independently;
Z is: phenyl, pyridine radicals, pyrimidine radicals, pyridazinyl, pyrazinyl, imidazole radicals, dihydro-thiazolyl, dihydro-thiazolyl sulfoxide, pyranose, pyrrolidinyl, Phenylpiperazinyl, THP trtrahydropyranyl, tetrahydrofuran base, dioxo cyclopenta, 2-oxa--5-aza-bicyclo [2.2.1] heptane base, morpholino, tetrahydro-1,4-thiazine generation, tetrahydro-1,4-thiazine are for sulfoxide group, piperidyl, piperidone base, piperazinyl or tetrahydropyrimidine ketone group, and each substituent group is optional by 1～2 C 1-2Alkyl or C 1-2Alkoxyl replaces;
Or Z is hydroxyl, C 1-3Alkyl, C 1-3Alkoxyl, C 1-3Acyl amino, C 1-3Alkyl sulphonyl, nitrile C 1-3Alkyl or by C 1-3Alkoxy C 1-3The amino of alkyl list or two-replacement;
Each R 1Be independently:
Optional part or complete halogenated side chain or straight chain C 1-5Alkyl, wherein one or more C atom is randomly independently by O, N or S (O) mSubstitute and wherein said C 1-5Alkyl is optional to be replaced by oxo, dioxo cyclopenta, pyrrolidinyl, furyl or phenyl, and each group is optional by 1～3 halogen, optional part or complete halogenated C 1-3Alkyl, hydroxyl, nitrile and optional part or complete halogenated C 1-3The group of alkoxyl replaces;
Cyclopropyl, cyclobutyl, Pentamethylene. base, cyclohexyl, bicyclo-pentyl or bicyclohexane base, each group optional part or complete halo are also optional by 1～3 optional part or complete halogenated C 1-3Alkyl, nitrile, hydroxyl C 1-3Alkyl or phenyl replaces; And one of them ring methylene is by the similar group of the alternate cyclopropyl of O, cyclobutyl, Pentamethylene. base, cyclohexyl, bicyclo-pentyl or bicyclohexane base;
Oxo;
Optional part or complete halogenated C 2-4Alkynyl, wherein one or more methylene is optional is replaced by O and the optional substituent group that is selected from independently in the following groups replaces: 1 or 2 oxo group, hydroxyl, pyrrolidinyl, pyrrole radicals, THP trtrahydropyranyl, the optional C that is replaced by one or more halogen atom 1-4Alkyl, nitrile, morpholino, piperidyl, piperazinyl, imidazole radicals, phenyl, pyridine radicals, tetrazole radical, or the optional list that is replaced by one or more halogen atom-or two (C 1-3Alkyl) amino;
Or
Silicyl comprises 3 optional parts or complete halogenated C 1-2Alkyl;
Each R 2Be independently:
Optional part or complete halogenated C 1-4Alkyl, optional part or complete halogenated C 1-4Alkoxyl, bromine, chlorine, fluorine, methoxycarbonyl, methyl-S (O) m, ethyl-S (O) m, each group optional part or complete halogenated or phenyl-S (O) m
Or R 2Be single-or two-C 1-3Acyl amino, amino-S (O) mOr S (O) mAmino, wherein the N atom is by C 1-3Alkyl or phenyl, nitrile, nitro or amino list-or two-replace;
Each R 3Be independently:
Phenyl, morpholino, pyridine radicals, pyrimidine radicals, pyrrolidinyl, 2,5-pyrrolidine-2,4-diketo base, imidazole radicals, [1,3,4] oxadiazoles, pyrazolyl, aforementioned each group is optional by 1～3 optional part or complete halogenated C 1-3Alkyl, halogen, oxo, hydroxyl, nitrile and optional part or complete halogenated C 1-3Alkoxyl replaces;
C 1-3Alkyl or C 1-3Alkoxyl, optional part or fully halogenated or optional by R 17Replace;
OR 18Or it is optional by OR 18The C that replaces 1-3Alkyl;
Optional by R 19Amino or the list that replaces-or two-(C 1-3Alkyl) amino;
R 20C (O) N (R 21)-, R 22O-; R 23R 24NC (O)-; R 26CH 2C (O) N (R 21)-, NH 2C (O) methoxyl group or R 26C (O) CH 2N (R 21)-;
By R 23R 24The C of NC (O)-replacement 2-4Alkenyl; Or
By the C of pyrrolidinyl or pyrrole radicals replacement 2-4Alkynyl;
C 1-3Acyl group and
R 23And R 24Randomly form morpholino together.
In another embodiment preferred, the present invention relates to the p38 inhibitors of kinases and be used for the treatment of purposes in the inhalable drug compositions of Polyblennia in preparation, wherein the p38 inhibitors of kinases is selected from formula 7Chemical compound, wherein:
G is phenyl, pyridine radicals, pyriconyl, 2-naphthyl, quinolyl, isoquinolyl, dihydro benzo furyl, indanyl, 5-indyl, 3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-8-base, benzoxazolyl, 2,3-Er hydrogen benzoxazole-7-base, 2-oxo-2,3-dihydro-1H-indole-5-base, indolinyl, indole ketone group or indoline ketone group, wherein G is optional by one or more R 1, R 2Or R 3Replace;
Ar is the 1-naphthyl;
X is: phenyl, imidazole radicals, pyridine radicals, pyrimidine radicals, piperidyl, piperazinyl, pyridazinyl or pyrazinyl;
Y is: chemical bond or-CH 2-,-CH 2CH 2-,-C (O)-,-O-,-S-,-NH-CH 2CH 2CH 2-,-N (CH 3)-, CH 2(CN) CH 2-NH-CH 2Or-NH-;
Z is morpholino, dioxo cyclopenta, tetrahydrofuran base, pyridine radicals, 2-oxa--5-aza-bicyclo [2.2.1] heptane base, C 1-3Alkoxyl phenyl piperazinyl, hydroxyl, C 1-3Alkyl, N, N-two C 1-3Alkoxy C 1-3Alkyl amino, C 1-3Acyl amino, C 1-3Alkyl sulphonyl or nitrile C 1-3Alkyl;
Each R 1Be independently:
Optional part or complete halogenated C 1-5Alkyl, wherein one or more C atom is randomly substituted and wherein said C by O or N independently 1-5Alkyl is optional by oxo, dioxo cyclopenta, pyrrolidinyl, furyl or optional by C 1-3The phenyl that alkoxyl replaces replaces; Cyclopropyl, Pentamethylene. base, cyclohexyl and bicyclo-pentyl, optional by 1～3 optional part or complete halogenated methyl, nitrile, hydroxymethyl or phenyl replacement; Or by methyl substituted 2-tetrahydrofuran base; Or trimethyl silyl;
Hydroxyl or Pentamethylene oxide .-2-oxygen base that propinyl replaces;
R 2Be single-or two-C 1-3Acyl amino, amino-S (O) mOr S (O) mAmino, wherein the N atom is by C 1-3The alkyl or phenyl list-or two-bromine, chlorine, fluorine, nitrile, nitro, amino, optional part or complete halogenated methyl sulphonyl or phenyl sulfonyl replaced;
Each R 3Be independently:
Phenyl, morpholino, pyridine radicals, pyrimidine radicals, pyrrolidinyl, 2,5-pyrrolidine-2,4-diketo base, imidazole radicals, [1,3,4] oxadiazole or pyrazolyls, each group is optional by optional part or complete halogenated C 1-2Alkyl replaces;
C 1-3Alkyl or C 1-3Alkoxyl, each group optional part or fully halogenated or optionally replaced by diethylamino;
OR 18Or it is optional by OR 18The C that replaces 1-3Alkyl;
Optional by R 19Amino or the list that replaces-or two-(C 1-3Alkyl) amino;
CH 3C (O) NH-, R 22O-; R 23R 24NC (O)-; R 26CH 2C (O) N (R 21)-, NH 2C (O) methoxyl group or R 26C (O) CH 2N (R 21)-;
By R 23R 24The C of NC (O)-replacement 2-4Alkenyl; Or by the C of pyrrolidinyl or pyrrole radicals replacement 2-4Alkynyl;
C 1-2Acyl group; And
R 23And R 24Be H or R 23And R 24Randomly form morpholino together; And R 26Be morpholino.
In another embodiment preferred, the present invention relates to the p38 inhibitors of kinases in the purposes that is used for preparing the inhalable drug compositions for the treatment of Polyblennia, wherein the p38 inhibitors of kinases is selected from formula 7Chemical compound wherein:
G is phenyl, pyridine radicals, 5-indyl, 3-oxo-3, and 4-dihydro-2H-benzo [1,4] oxazine-8-base, benzoxazolyl, 2,3-Er hydrogen benzoxazole-7-base, 2-oxo-2,3-dihydro-1H-indole-5-base or 2-naphthyl, wherein G is optional by one or more R 1, R 2Or R 3Replace;
X is: imidazole radicals, pyridine radicals, pyrimidine radicals or pyrazinyl;
Y is: chemical bond, CH 2(CN) CH 2-NH-CH 2,-CH 2-,-NH-CH 2CH 2CH 2-or-NH-;
Z is morpholine-4 base, dioxy ring penta-2 base, tetrahydrofuran base, pyridine radicals, 2-oxa--5-aza-bicyclo [2.2.1] heptan-5 base, methoxyphenylpiperazderivatives base, hydroxyl, methyl, N, N-dimethoxy-ethyl amino, acetyl-amino, methyl sulphonyl or cyano ethyl;
Each R 1Be independently: the tert-butyl group, sec-butyl, tertiary pentyl, phenyl, Pentamethylene oxide .-2-oxygen base propinyl, hydroxypropyn base, trihalomethyl, 2,2-diethyl propiono or cyclohexyl;
R 2Be chlorine, nitro, amino, nitrile, methyl sulphonyl amino, diacetyl amino, phenyl sulfonyl amino, N, N-two (methyl sulphonyl) amino, methyl sulphonyl or trihalomethyl sulfonyl;
R 3Be independently: methyl, C 1-3Alkoxyl, methoxy, hydroxypropyl, dimethylamino, C 1-4Alkyl amino, NH 2C (O) methoxyl group, acetyl group, pyrrolidinyl, imidazole radicals, pyrazolyl, morpholino or morpholino carbonyl.
In another embodiment preferred, the present invention relates to the p38 inhibitors of kinases and be used for the treatment of purposes in the inhalable drug compositions of Polyblennia in preparation, wherein the p38 inhibitors of kinases is selected from wherein that X is the formula of pyridine radicals 7Chemical compound.
In another embodiment preferred, the present invention relates to the p38 inhibitors of kinases and be used for the treatment of purposes in the inhalable drug compositions of Polyblennia in preparation, wherein the p38 inhibitors of kinases is selected from formula 7Chemical compound, wherein pyridine radicals is connected to Ar by 3-pyridine radicals position.
Preferably in another embodiment preferred, the present invention relates to the p38 inhibitors of kinases and be used for the treatment of purposes in the inhalable drug compositions of Polyblennia in preparation, wherein the p38 inhibitors of kinases is selected from following formula 7Chemical compound:
1-(the 4-tert-butyl group-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methyl-phenyl)-3-[4-(4-morpholine-4-ylmethyl-piperidines-1-yl)-naphthalene-1-yl]-urea;
1-(6-chloro-4-trifluoromethyl-pyridine-2-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(4-difluoro-methoxy-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(3-methyl-naphthalene-2-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-[2-methoxyl group-5-(1-methyl isophthalic acid-phenyl-ethyl)-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
(the 5-tert-butyl group-2-methyl-phenyl)-carbamic acid 3-(5-{4-[3-(the 5-tert-butyl group-2-methyl-phenyl)-urea groups]-naphthalene-1-yl }-pyridine-2-base is amino)-propyl diester;
1-(the 6-tert-butyl group-benzo [1,3] dioxole-5-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
N-(the 5-tert-butyl group-2-methoxyl group-3-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups }-phenyl)-acetamide;
1,3-pair-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-3-(2,2-dimethyl-[1,3] dioxy ring penta-4-ylmethyl)-2-hydroxyl-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(2-pyrrolidine-1-base-ethyoxyl)-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-3-(2,3-dihydroxy-propyl group)-2-hydroxyl-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(2,3-dimethyl-1H-indole-5-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-3-(2-is to toloxyl-5-trifluoromethyl-phenyl)-urea;
1-[2-(2-methoxyl group-phenoxy group)-5-trifluoromethyl-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-3-naphthalene-1-base-urea;
The 1-{5-tert-butyl group-2-methyl-3-[3-(tetrahydrochysene-pyrans-2-oxygen base)-third-1-alkynyl]-phenyl }-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-{5-tert-butyl group-2-[3-(tetrahydrochysene-pyrans-2-oxygen base)-third-1-alkynyl]-phenyl }-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(5-hydroxymethyl-2-methyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(2-methoxyl group-dibenzofurans-3-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(2,5-two-tert-butyl group-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-[3-(4-bromo-1-methyl isophthalic acid H-pyrazole-3-yl)-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(3-hydroxyl-5,6,7,8-tetrahydrochysene-naphthalene-2-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(1-acetyl group-2,3-dihydro-1H-indole-5-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-3-(3-oxazole-5-base-phenyl)-urea;
1-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-3-(3-[1,3,4] oxadiazole-2-base-phenyl)-urea;
1-(2-methoxyl group-5-trifluoromethyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
Furan-2-carboxylic acid (the 4-tert-butyl group-2-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups }-phenyl)-amide;
1-(2-methoxyl group-4-phenyl amino-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(5-methoxyl group-2-methyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(3-hydroxyl-naphthalene-2-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
N, N-diethyl-4-methoxyl group-3-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups }-benzsulfamide;
1-(2,2-two fluoro-benzo [1,3] dioxole-5-yls)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-[5-(1,1-dimethyl-propyl group)-2-phenoxy group-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-[5-(2,2-dimethyl-propiono)-2-methyl-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
2-chloro-5-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups }-the benzoic acid isopropyl esters;
1-(4-amino-3,5-two bromo-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-3-(3-hydroxyl-third-1-alkynyl)-2-methyl-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(3-hydroxyl-third-1-alkynyl)-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-3-(2,2-dimethyl-[1,3] dioxy ring penta-4-ylmethyl)-2-methoxyl group-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-3-(2,3-dihydroxy-propyl group)-2-methoxyl group-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(5-tert-butoxy-2-methoxyl group-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-[5-(1-cyano group-cyclopropyl)-2-methoxyl group-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-3-(2-diethylamino-ethyl)-2-methoxyl group-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-[4-(6-[1,3] dioxy ring penta-2-base-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-pyrrolidine-1-base-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-dimethylamino-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-propoxyl group-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-[4-(6-hydroxymethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-{4-[6-(2,6-dimethyl-morpholine-4-ylmethyl)-pyridin-3-yl]-naphthalene-1-yl }-urea;
2-(the 5-tert-butyl group-2-methoxyl group-phenyl)-N-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-acetamide;
1-(2-methoxyl group-5-phenoxy group-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indole-7-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-cyclopentyloxy-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-{4-[6-(3-pyridin-3-yl-pyrrolidine-1-ylmethyl)-pyridin-3-yl]-naphthalene-1-yl }-urea;
1-(5-cyclohexyl-2-methoxyl group-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(2,4-dimethoxy-5-trifluoromethyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 6-tert-butyl group-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-7-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methoxyl group-3-nitro-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 3-amino-5-tert-butyl group-2-methoxyl group-phenyl)-3-[4-(6-methyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
N-acetyl group-N-(the 5-tert-butyl group-2-methoxyl group-3-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups }-phenyl)-acetamide;
1-(the 6-tert-butyl group-4-methyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-8-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[6-tert-butyl group-4-(2-morpholine-4-base-ethyl)-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-8-yl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-ethyoxyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-isopropoxy-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-imidazoles-1-base-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
N-(the 5-tert-butyl group-2-methoxyl group-4-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups }-phenyl)-Methanesulfomide;
1-(the 5-tert-butyl group-3-ethylamino-2-methoxyl group-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
N-(the 5-tert-butyl group-2-methoxyl group-3-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups }-phenyl)-two (first sulphur) amide;
The 1-[5-tert-butyl group-2-(1-methyl isophthalic acid H-pyrazoles-4-yl)-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(2-methanesulfinyl-5-trifluoromethyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(2-ethylsulfonyl-5-trifluoromethyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-[4-(6-{[pair-(2-methoxyl group-ethyl)-amino]-methyl }-pyridin-3-yl)-naphthalene-1-yl]-3-(the 5-tert-butyl group-2-methoxyl group-phenyl)-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-{4-[6-(3-dimethylamino-pyrrolidine-1-ylmethyl)-pyridin-3-yl]-naphthalene-1-yl }-urea;
N-[1-(5-{4-[3-(the 5-tert-butyl group-2-methoxyl group-phenyl)-urea groups]-naphthalene-1-yl }-pyridine-2-ylmethyl)-pyrrolidine-3-yl]-acetamide;
1-(1-acetyl group-3,3-dimethyl-2,3-dihydro-1H-indole-5-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
N-(the 5-tert-butyl group-2-methoxyl group-3-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups }-phenyl)-propionic acid amide.;
1-(the 5-tert-butyl group-2-methyl-benzoxazoles-7-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-3-(3-fluoroform sulphur y1-phenyl)-urea;
N-(the 5-tert-butyl group-2-methoxyl group-3-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups }-phenyl)-isobutyramide;
2-(the 4-tert-butyl group-2-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups }-phenoxy group)-acetamide;
1-(the 5-tert-butyl group-2-oxo-2,3-dihydro-benzoxazoles-7-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 6-tert-butyl group-3-cyano group-2-methoxymethoxy-pyridin-4-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 6-tert-butyl group-3-cyano-2-hydroxy--pyridin-4-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-3-cyano group-2-methoxyl group-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-3-(1,3,3-trimethyl-2,3-dihydro-1H-indole-5-yl)-urea;
1-(the 5-tert-butyl group-benzoxazoles-7-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
N-(the 5-tert-butyl group-2-methoxyl group-3-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups }-phenyl)-benzsulfamide;
Ethyl sulfonic acid (the 5-tert-butyl group-2-methoxyl group-3-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups }-phenyl)-amide;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-[4-(4-morpholine-4-ylmethyl-piperidines-1-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(1-methyl isophthalic acid H-pyrazoles-4-yl)-phenyl]-3-[4-(4-morpholine-4-ylmethyl-piperidines-1-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-[4-(2-morpholine-4-ylmethyl-pyrimidine-5-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methyl mercapto-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methoxyl group-pyridin-3-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
2,2,2-three fluoro-ethyl sulfonic acids (the 5-tert-butyl group-2-methoxyl group-3-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups }-phenyl)-amide;
N-(5-{4-[3-(the 5-tert-butyl group-2-methyl-phenyl)-urea groups]-naphthalene-1-yl }-pyrazine-2-yl)-Methanesulfomide;
1-[4-(6-{[pair-(2-cyano group-ethyl)-amino]-methyl }-pyridin-3-yl)-naphthalene-1-yl]-3-(the 5-tert-butyl group-2-methoxyl group-phenyl)-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-{4-[6-(4-methyl-piperazine-1-ylmethyl)-pyridin-3-yl]-naphthalene-1-yl }-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-[4-(6-tetrahydro-1,4-thiazine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-{4-[6-(2,6-dimethyl-piperidines-1-ylmethyl)-pyridin-3-yl]-naphthalene-1-yl }-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-{4-[6-(1-oxo-tetrahydrochysene-thiapyran-4-base is amino)-pyridin-3-yl]-naphthalene-1-yl }-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-{4-[6-(tetrahydrochysene-pyrans-4-base is amino)-pyridin-3-yl]-naphthalene-1-yl }-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-[4-(6-{[(2-cyano group-ethyl)-(tetrahydrochysene-furan-2-ylmethyl)-amino]-methyl }-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-{4-[6-(2-methoxy-morpholine-4-ylmethyl)-pyridin-3-yl]-naphthalene-1-yl }-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-(4-{6-[(2-morpholine-4-base-ethylamino)-methyl]-pyridin-3-yl }-naphthalene-1-yl)-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-{4-[6-(2-methyl-3-oxo-piperazine-1-ylmethyl)-pyridin-3-yl]-naphthalene-1-yl }-urea;
1-(5-{4-[3-(the 5-tert-butyl group-2-methoxyl group-phenyl)-urea groups]-naphthalene-1-yl }-pyridine-2-ylmethyl)-piperidines-3-carboxylic acid amide;
1-(5-{4-[3-(the 5-tert-butyl group-2-methoxyl group-phenyl)-urea groups]-naphthalene-1-yl }-pyridine-2-ylmethyl)-piperidines-4-carboxylic acid amide;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-{4-[6-(1-oxo-114-tetrahydro-1,4-thiazine-4-ylmethyl)-pyridin-3-yl]-naphthalene-1-yl }-urea;
1-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indole-5-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-{4-[6-(3-oxo-piperazine-1-ylmethyl)-pyridin-3-yl]-naphthalene-1-yl }-urea;
1-{4-[6-(4-acetyl group-piperazine-1-ylmethyl)-pyridin-3-yl]-naphthalene-1-yl }-3-(the 5-tert-butyl group-2-methoxyl group-phenyl)-urea;
4-(5-{4-[3-(the 5-tert-butyl group-2-methoxyl group-phenyl)-urea groups]-naphthalene-1-yl }-pyridine-2-ylmethyl)-piperazine-1-carboxylic acid ethyl ester;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-(4-{6-[(2-pyridin-3-yl-ethylamino)-methyl]-pyridin-3-yl }-naphthalene-1-yl)-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-(4-{6-[(tetrahydrochysene-furan-3-base is amino)-methyl]-pyridin-3-yl }-naphthalene-1-yl)-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-[4-(6-{[(2-cyano group-ethyl)-pyridin-3-yl methyl-amino]-methyl }-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-(4-{6-[(2-methyl mercapto-ethylamino)-methyl]-pyridin-3-yl }-naphthalene-1-yl)-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-{4-[6-(2-oxa--5-aza-bicyclo [2.2.1] heptan-5-ylmethyl)-pyridin-3-yl]-naphthalene-1-yl }-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-{4-[6-(2,6-dimethyl-morpholine-4-ylmethyl)-pyridin-3-yl]-naphthalene-1-yl }-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-(4-{6-[(2-piperazine-1-base-ethylamino)-methyl]-pyridin-3-yl }-naphthalene-1-yl)-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-{4-[6-(4-pyrimidine-2-base-piperazine-1-ylmethyl)-pyridin-3-yl]-naphthalene-1-yl }-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-{4-[6-(4-pyridine-2-base-piperazine-1-ylmethyl)-pyridin-3-yl]-naphthalene-1-yl }-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-(4-{6-[4-(3-methoxyl group-phenyl)-piperazine-1-ylmethyl]-pyridin-3-yl }-naphthalene-1-yl)-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-{4-[6-(morpholine-4-carbonyl)-pyridin-3-yl]-naphthalene-1-yl }-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-{4-[6-(2-thia-5-aza-bicyclo [2.2.1] heptan-5-ylmethyl)-pyridin-3-yl]-naphthalene-1-yl }-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-[4-(5-morpholine-4-ylmethyl-pyrazine-2-yl)-naphthalene-1-yl]-urea;
1-(the 6-tert-butyl group-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-8-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 3-amino-5-tert-butyl group-2-methoxyl group-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
N-(5-{4-[3-(the 5-tert-butyl group-2-methoxyl group-phenyl)-urea groups]-naphthalene-1-yl }-pyridine-2-yl)-acetamide;
N-(the 5-tert-butyl group-2-methoxyl group-3-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups }-phenyl)-N-methyl-acetamide;
N-(the 5-tert-butyl group-2-methoxyl group-3-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups }-phenyl)-2,2,2-three fluoro-acetamides;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-{4-[6-(pyridine-3-oxygen base)-pyridin-3-yl]-naphthalene-1-yl }-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-{4-[6-(pyridin-3-yl amino)-pyridin-3-yl]-naphthalene-1-yl }-urea;
[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-carbamic acid 3-tert-butyl group-phenylester;
N-(the 5-tert-butyl group-2-methoxyl group-3-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups-phenyl)-Methanesulfomide and
Its pharmaceutically acceptable derivant.
In another embodiment preferred, the present invention relates to the p38 inhibitors of kinases and be used for the treatment of purposes in the inhalable drug compositions of Polyblennia in preparation, wherein the p38 inhibitors of kinases is selected from following formula 7Chemical compound:
1-(3-methyl-naphthalene-2-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
N-(the 5-tert-butyl group-2-methoxyl group-3-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups }-phenyl)-acetamide;
The 1-[5-tert-butyl group-3-(2,3-dihydroxy-propyl group)-2-hydroxyl-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(2,3-dimethyl-1H-indole-5-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-{5-tert-butyl group-2-methyl-3-[3-(tetrahydrochysene-pyrans-2-oxygen base)-third-1-alkynyl]-phenyl }-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(2-methoxyl group-5-trifluoromethyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-[5-(2,2-dimethyl-propiono)-2-methyl-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-3-(3-hydroxyl-third-1-alkynyl)-2-methyl-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-2-(3-hydroxyl-third-1-alkynyl)-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-3-(2,2-dimethyl-[1,3] dioxy ring penta-4-ylmethyl)-2-methoxyl group-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-3-(2,3-dihydroxy-propyl group)-2-methoxyl group-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(5-tert-butoxy-2-methoxyl group-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-[5-(1-cyano group-cyclopropyl)-2-methoxyl group-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
The 1-[5-tert-butyl group-3-(2-diethylamino-ethyl)-2-methoxyl group-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-[4-(6-[1,3] dioxy ring penta-2-base-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-pyrrolidine-1-base-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-dimethylamino-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-propoxyl group-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-[4-(6-hydroxymethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-{4-[6-(2,6-dimethyl-morpholine-4-ylmethyl)-pyridin-3-yl]-naphthalene-1-yl }-urea;
1-(5-cyclohexyl-2-methoxyl group-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(2,4-dimethoxy-5-trifluoromethyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methoxyl group-3-nitro-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 3-amino-5-tert-butyl group-2-methoxyl group-phenyl)-3-[4-(6-methyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
N-acetyl group-N-(the 5-tert-butyl group-2-methoxyl group-3-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups }-phenyl)-acetamide;
1-(the 6-tert-butyl group-4-methyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-8-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-ethyoxyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-isopropoxy-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-imidazoles-1-base-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-3-ethylamino-2-methoxyl group-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
N-(the 5-tert-butyl group-2-methoxyl group-3-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups }-phenyl)-two (first sulphur) amide;
The 1-[5-tert-butyl group-2-(1-methyl isophthalic acid H-pyrazoles-4-yl)-phenyl]-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(2-methanesulfinyl-5-trifluoromethyl-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-[4-(6-{[pair-(2-methoxyl group-ethyl)-amino]-methyl }-pyridin-3-yl)-naphthalene-1-yl]-3-(the 5-tert-butyl group-2-methoxyl group-phenyl)-urea;
N-[1-(5-{4-[3-(the 5-tert-butyl group-2-methoxyl group-phenyl)-urea groups]-naphthalene-1-yl }-pyridine-2-ylmethyl)-pyrrolidine-3-yl]-acetamide;
1-(1-acetyl group-3,3-dimethyl-2,3-dihydro-1H-indole-5-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
N-(the 5-tert-butyl group-2-methoxyl group-3-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups }-phenyl)-propionic acid amide.;
1-(the 5-tert-butyl group-2-methyl-benzoxazoles-7-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-3-(3-fluoroform sulphur y1-phenyl)-urea;
N-(the 5-tert-butyl group-2-methoxyl group-3-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups }-phenyl)-isobutyramide;
2-(the 4-tert-butyl group-2-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups }-phenoxy group)-acetamide;
1-(the 5-tert-butyl group-2-oxo-2,3-dihydro-benzoxazoles-7-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-3-cyano group-2-methoxyl group-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-benzoxazoles-7-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
N-(the 5-tert-butyl group-2-methoxyl group-3-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups }-phenyl)-benzsulfamide;
Ethyl sulfonic acid (the 5-tert-butyl group-2-methoxyl group-3-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups }-phenyl)-amide;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-[4-(2-morpholine-4-ylmethyl-pyrimidine-5-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methyl mercapto-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methoxyl group-pyridin-3-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
2,2,2-three fluoro-ethyl sulfonic acids (the 5-tert-butyl group-2-methoxyl group-3-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups }-phenyl)-amide;
N-(5-{4-[3-(the 5-tert-butyl group-2-methyl-phenyl)-urea groups]-naphthalene-1-yl }-pyrazine-2-yl)-Methanesulfomide;
1-[4-(6-{[pair-(2-cyano group-ethyl)-amino]-methyl }-pyridin-3-yl)-naphthalene-1-yl]-3-(the 5-tert-butyl group-2-methoxyl group-phenyl)-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-{4-[6-(4-methyl-piperazine-1-ylmethyl)-pyridin-3-yl]-naphthalene-1-yl }-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-[4-(6-tetrahydro-1,4-thiazine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-{4-[6-(2,6-dimethyl-piperidines-1-ylmethyl)-pyridin-3-yl]-naphthalene-1-yl }-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-{4-[6-(1-oxo-tetrahydrochysene-thiapyran-4-base is amino)-pyridin-3-yl]-naphthalene-1-yl }-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-{4-[6-(tetrahydrochysene-pyrans-4-base is amino)-pyridin-3-yl]-naphthalene-1-yl }-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-[4-(6-{[(2-cyano group-ethyl)-(tetrahydrochysene-furan-2-ylmethyl)-amino]-methyl }-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-{4-[6-(2-methoxy-morpholine-4-ylmethyl)-pyridin-3-yl]-naphthalene-1-yl }-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-{4-[6-(2-methyl-3-oxo-piperazine-1-ylmethyl)-pyridin-3-yl]-naphthalene-1-yl }-urea;
1-(5-{4-[3-(the 5-tert-butyl group-2-methoxyl group-phenyl)-urea groups]-naphthalene-1-yl }-pyridine-2-ylmethyl)-piperidines-3-carboxylic acid amide;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-{4-[6-(1-oxo-114-tetrahydro-1,4-thiazine-4-ylmethyl)-pyridin-3-yl]-naphthalene-1-yl }-urea;
1-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indole-5-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-{4-[6-(3-oxo-piperazine-1-ylmethyl)-pyridin-3-yl]-naphthalene-1-yl }-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-(4-{6-[(tetrahydrochysene-furan-3-base is amino)-methyl]-pyridin-3-yl }-naphthalene-1-yl)-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-[4-(6-{[(2-cyano group-ethyl)-pyridin-3-yl methyl-amino]-methyl }-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-{4-[6-(2-oxa--5-aza-bicyclo [2.2.1] heptan-5-ylmethyl)-pyridin-3-yl]-naphthalene-1-yl }-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-{4-[6-(2,6-dimethyl-morpholine-4-ylmethyl)-pyridin-3-yl]-naphthalene-1-yl }-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-(4-{6-[4-(3-methoxyl group-phenyl)-piperazine-1-ylmethyl]-pyridin-3-yl }-naphthalene-1-yl)-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-{4-[6-(morpholine-4-carbonyl)-pyridin-3-yl]-naphthalene-1-yl }-urea;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-[4-(5-morpholine-4-ylmethyl-pyrazine-2-yl)-naphthalene-1-yl]-urea;
1-(the 6-tert-butyl group-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-8-yl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
1-(the 3-amino-5-tert-butyl group-2-methoxyl group-phenyl)-3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea;
N-(5-{4-[3-(the 5-tert-butyl group-2-methoxyl group-phenyl)-urea groups]-naphthalene-1-yl }-pyridine-2-yl)-acetamide;
N-(the 5-tert-butyl group-2-methoxyl group-3-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups }-phenyl)-N-methyl-acetamide;
N-(the 5-tert-butyl group-2-methoxyl group-3-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups }-phenyl)-2,2,2-three fluoro-acetamides;
1-(the 5-tert-butyl group-2-methoxyl group-phenyl)-3-{4-[6-(pyridine-3-oxygen base)-pyridin-3-yl]-naphthalene-1-yl }-urea;
[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-carbamic acid 3-tert-butyl group-phenylester;
N-(the 5-tert-butyl group-2-methoxyl group-3-{3-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea groups-phenyl)-Methanesulfomide and
Its pharmaceutically acceptable derivant.
The concrete preferably p38 inhibitors of kinases of the present invention is used for the treatment of purposes in the inhalable drug compositions of Polyblennia in preparation, and wherein the p38 inhibitors of kinases is selected from following chemical compound:
Example 1:
Figure A0381298801451
Example 2:
Example 3:
Example 4:
Example 5:
Example 6:
Example 7:
Figure A0381298801463
With and pharmaceutically acceptable derivant.
The present invention includes the purposes of the pharmaceutically acceptable derivant of formula 1,2,3a, 3b, 3c, 3d, 4,5,5a, 6 and 7 chemical compounds." pharmaceutically acceptable derivant " refers to any officinal salt or the ester of The compounds of this invention, or any other chemical compound, described chemical compound can (directly or indirectly) provide chemical compound of the present invention, pharmacologically active metabolite or pharmacologically active residue after to patient's administration.The pharmacologically active metabolite is construed as finger can be through enzyme process or the metabolic any The compounds of this invention of chemical method.It comprises, for example, and the metabolic compounds of the hydroxylated or oxidation of formula 1,2,3a, 3b, 3c, 3d, 4,5,5a, 6 and 7 chemical compounds.
The officinal salt of aforesaid compound comprises those salt derived from pharmaceutically acceptable inorganic and organic acid and alkali.The example of appropriate acid comprises hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic, lactic acid, salicylic acid, succinic acid, p-methyl benzenesulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid and benzenesulfonic acid.Other acid, as oxalic acid, although itself is not pharmaceutically acceptable, can be used for preparing as obtain The compounds of this invention with and the salt of the intermediate of pharmaceutically acceptable acid addition salts.Salt derived from appropriate base comprises alkali metal (as sodium), alkaline-earth metal (as magnesium), ammonium and N-(C 1-C 4Alkyl) 4 +Salt.
Term physiological acceptable salt and term officinal salt synonym within the scope of the present invention.
On the other hand, the present invention relates to pharmaceutical formulation and be suitable for sucking the Polyblennia that is used for the treatment of that comprises at least a p38 kinase inhibitor for treating effective dose.
Inhalable formulations according to the present invention comprises can suck powder, comprise the metered aerosol of propellant or do not contain the sucked solution of propellant.The powder that sucks according to the present invention comprises the p38 inhibitors of kinases, randomly can accept mixed with excipients with physiology.Within the scope of the present invention, term the sucked solution that do not contain propellant comprises that also stand-by concentrate or sterilization can suck solution.The preparation that can be used in the scope of the invention will be described in more detail in the next part of description.
In the inhalable drug compositions, the p38 inhibitors of kinases can be used about 100～10000 μ g in single dose, 1000～9000 μ g preferably, more preferably 1500～8000 μ g the p38 inhibitors of kinases.About 2000～about 7000 μ g, more preferably administration of p38 inhibitors of kinases/single dose of 2500～6000 μ g that preferred pharmaceutical compositions in the scope of the invention provides.Preferably to the patient of needs with once a day or the p38 inhibitors of kinases of the about 3000～about 5500 μ g of administered twice.
A) imbedibility powder:
Imbedibility powder of the present invention can comprise the mixture of p38 inhibitors of kinases itself or itself and suitable physiologically acceptable excipient.
If when p38 inhibitors of kinases and physiologically acceptable excipient form mixture, can use following physiologically acceptable excipient to prepare these imbedibility powder of the present invention: the mutual mixture of monosaccharide (for example glucose or arabinose), disaccharide (for example lactose, sucrose, maltose), oligosaccharide and polysaccharide (for example glucosan), polyhydric alcohol (for example Sorbitol, mannitol, xylitol), salt (for example sodium chloride, calcium carbonate) or these excipient.Preferred monosaccharide or the disaccharidase of using, and to use lactose or glucose preferred, particularly (but being not limited to) uses its hydrate type.With purpose of the present invention, lactose is particularly preferred excipient, and the most preferred with lactose monohydrate.
In the scope of imbedibility powder of the present invention, the mean diameter maximum of excipient is up to 250 microns, with 10 to 150 microns preferred, with 15 to 80 microns the bests.As if the more particulate excipient that sometimes with mean diameter is the 1-9 micron be added in the above-mentioned excipient also suitable.These more the particulate excipient also be selected from top listed excipient.At last, in order to prepare imbedibility powder of the present invention, add micronization active substance p38 inhibitors of kinases in excipient mixture, preferred mean diameter is the 0.5-10 micron, more preferably the 1-5 micron.Adopt polishing and micronization, reach the mode that last blending constituent is known in the art with the method for making imbedibility powder of the present invention.
Imbedibility powder of the present invention can comprise the single mixture of powders of p38 inhibitors of kinases or simultaneously only to comprise the imbedibility powder type administration that separates of p38 inhibitors of kinases.
The imbedibility powder of the present invention that comprises physiologically acceptable excipient and p38 inhibitors of kinases can adopt the inhaler administration that illustrates among the US 4570630A for example, it is to utilize volumetric bottle to transmit single dose, or utilizes other mode administrations that illustrate among the DE 3625685A.The imbedibility powder that contains p38 inhibitors of kinases and optional and physiologically acceptable excipient composition according to the present invention can adopt for example known name to be called Turbuhaler The inhaler administration, for example use the disclosed inhaler administration of EP 237507A.Preferably, the imbedibility powder packaging of the present invention that comprises p38 inhibitors of kinases and physiologically acceptable excipient (is made so-called suction medicine bag) in medicine bag, is used for the illustrated inhaler of WO for example 94/28958.
A kind ofly use the preferred especially inhaler of drug regimen of the present invention and be shown among Fig. 1 to inhale medicine bag.
This inhaler (Handyhaler), be characterised in that the base 1 that comprises two windows 2, a dividing plate 3, air feeding mouth is wherein arranged and a screen cloth 5 is housed, use screen cloth lid 4 fixing, one connects the medicine bag bottle 6 of dividing plate 3, on the bottle button 9 is arranged, two Tip-headed needles 7 are housed on the button, can promote spring 8, one connects the interface unit 12 of base 1, dividing plate 3 and loam cake 11, utilizes a rotating shaft 10 to flick or close cap, around medicine bag bottle 6 and be positioned at screen cloth lid 4 and 3 diameters arranged at the aperture below 1 millimeter 13 with center below the screen cloth 5.
Primary air enters between dividing plate 3 and the base 1 near transit point.The reduced width of this regional internal partition forms a narrow and small air intake.Therefore air-flow drives in the wrong direction and enters in the medicine bag bottle 6 through inlet.Air-flow further by filter screen and filter screen holder, enters in the interface unit.There is the sub-fraction air-flow to enter device between interface unit and the dividing plate, flows through then between filter screen holder and the dividing plate, enter in the primary air.Because foozle, so this section air-flow can some uncertainties occur with developed width between filter screen holder and the dividing plate.If when using new tool or reusable instrument, therefore the air-flow resistance of inhaler may have some gaps with desired value.In order to proofread and correct this error, around medicine bag bottle 6 and be positioned at screen cloth lid 4 and 3 diameters arranged at the aperture below 1 millimeter 13 with center below the screen cloth 5.Air-flow sees through these apertures 13, is flowed in the primary air by base, to reduce the resistance of air-flow slightly of inhaler.The actual diameter of these apertures 13 can be selected by the suitable plug-in unit in the instrument, makes the mean air flow resistance equal desired value.
If imbedibility powder of the present invention is packed in the medicine bag (inhaler) when using for above-mentioned its preferred usage, the dose in each medicine bag of packing into should be every medicine bag and contains 1 to 50 milligram of imbedibility powder, with 3 to 45 milligrams preferably, better with 5 to 40 milligrams.In each single dose of the present invention, these medicine bags contain the common or separate doses of above-mentioned p38 inhibitors of kinases.
B) inhalational aerosol that driven of propellant gas:
The inhalational aerosol that contains propellant gas according to the present invention can comprise the p38 inhibitors of kinases that is dissolved in the propellant gas or is the even type that looses.The propellant gas that can be used for preparing inhalational aerosol of the present invention is known in the art.Suitable propellant gas is selected from hydro carbons, as n-propane, normal butane or iso-butane and halogenated hydrocarbon, as the fluoro derivatives of methane, ethane, propane, butane, cyclopropane or Tetramethylene..Above-mentioned propellant gas can use separately or use with its mixture.Particularly preferred propellant gas is selected from: TG 134a (1,1,1, the 2-tetrafluoroethane) and the alkyl halide derivant of TG 227 (1,1,1,2,3,3, the 3-heptafluoro-propane) with its mixture.
The inhalational aerosol that propellant drives according to the present invention also can comprise other compositions, as cosolvent, stabilizing agent, surfactant, antioxidant, lubricant and pH regulator agent.All these compositions are known in the art.
The inhalational aerosol that contains propellant gas according to the present invention can comprise the p38 inhibitors of kinases up to 5 weight %.Aerosol comprises for example p38 inhibitors of kinases of 0.002 to 5 weight %, 0.01 to 3 weight %, 0.015 to 2 weight % according to the present invention.
Loose during type if the p38 inhibitors of kinases is even, the mean diameter of active substance is preferably up to 10 microns, with 0.1 to 5 micron preferred, better with 1 to 5 micron.
The above-mentioned inhalational aerosol that propellant drives according to the present invention can use inhaler known in the art (MDIs=decides the inhaler of dosage) administration.Therefore, the present invention relates to the pharmaceutical composition that the p38 inhibitors of kinases is used to prepare the inhalational aerosol form that above-mentioned propellant drives on the other hand, and the inhaler that described compositions and one or more are fit to use these aerosols makes up.
In addition, the present invention relates to the purposes that the p38 inhibitors of kinases is used for preparation card pipe (cartridge), when loading onto suitable switch, can be used in the suitable inhaler, wherein comprise a kind of according to the present invention the above-mentioned inhalational aerosol that contains propellant gas.Suitable card pipe reaches and load the method that contains the inhalational aerosol of propellant gas according to the present invention in these card pipes is known in the art.
C) do not contain the imbedibility solution of propellant:
Preferred especially the utilization according to p38 inhibitors of kinases according to the present invention prepares imbedibility solution and the suspension that does not contain propellant.Employed solvent can be aqueous or alcohol, and is preferred with alcoholic solution.Solvent can be water itself, or makes water and alcoholic acid mixture.The relative scale of ethanol and water is restriction not, but high volume percentage is 70%, and more especially high volume percentage is 60%, and optimal volume percentage ratio is 30%.All the other volumes are then supplied with water.The solution or the suspension that contain the p38 inhibitors of kinases use appropriate acid to transfer to pH 2 to 7, and be preferred with 2 to 5.Can use and be selected from mineral acid or organic acid acid adjustment pH.Suitable inorganic acid example comprises hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and/or phosphoric acid.Specially suitable organic acid example comprises ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propanoic acid, or the like.Preferred mineral acid is hydrochloric acid and sulphuric acid.Also can use the acid that forms acid-addition salts with above-mentioned a kind of active substance.In the organic acid, preferred with ascorbic acid, fumaric acid and citric acid.If when needing, can use the mixture of above-mentioned acid, especially when these acid still have other character except its acidify character, during for example as flavoring agent, antioxidant or complexant, as, for example citric acid or ascorbic acid.According to the present invention, be particularly suitable for using hydrochloric acid to adjust pH.
According to the present invention, needn't add ethylenediaminetetraacetic acid (EDTA) or its a kind of known salts edetate in this preparation as stabilizing agent or complexant.Other embodiments can comprise this chemical compound or these chemical compounds.In preferred embodiments, the content of sodium ethylene diamine tetracetate is lower than 100 milligrams/100 milliliters, and is preferred to be lower than 50 milligrams/100 milliliters, better to be lower than 20 milligrams/100 milliliters.The content of common sodium ethylene diamine tetracetate is that 0 to 10 milligram/100 milliliters imbedibility solution is preferred.
Can add cosolvent and other excipient to not containing in the imbedibility solution of propellant according to the present invention.Preferred co-solvents is to comprise those of hydroxyl or other polar groups, for example alcohols: isopropyl alcohol particularly, and glycols, particularly: propylene glycol, Polyethylene Glycol, polypropylene glycol, polyethers, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid ester class.Herein, any pharmaceutically acceptable material represented in excipient and additive term, and it is for active substance but can prepare in the suitable solvent on medicine with active substance or various active material, to improve the character of active substance preparation.Preferably, these materials do not have pharmacological action or in the pharmacological action that does not have significantly or do not expect at least aspect the required curative effect.Excipient and additive comprise for example surfactant, as soybean lecithin, oleic acid, sorbitan ester, as polysorbate, polyvinylpyrrolidone, other can guarantee or prolong stabilizing agent, complexant, antioxidant and/or the antiseptic of final pharmaceutical preparation pot-life, and flavoring agent, vitamin and/or other additives known in the art.Additive also comprises pharmaceutically acceptable salt, as sodium chloride, as the isotonia agent.
Preferred excipient comprises antioxidant, as, for example ascorbic acid (but its restrictive condition is not for being used for adjusting pH), vitamin A, vitamin E, tocopherol and intravital similar vitamin of the natural people of being present in and provitamin.Antiseptic can be used for preventing that preparation is by pathogen contamination.Suitable preservatives is that those are known in the art, particularly cetylpyridinium chloride salt, Benasept or benzoic acid or benzoate, and as sodium benzoate, its concentration is known in the art.The content concn of foregoing preservatives preferably up to 50 milligrams/100 milliliters, better with 5 to 20 milligrams/100 milliliters.
Except aqueous solvent and p38 inhibitors of kinases, only comprise Benasept and ethanedioic acid tetraacethyl sodium in the preferred formulation.In another preferred embodiment, do not contain ethanedioic acid tetraacethyl sodium.
The special use of imbedibility solution that does not contain propellant according to the present invention can make the inhaler administration of the small amount of liquid preparation i.e. atomizing in seconds formation aerosol that is fit to the therapeutic suction of therapeutic dose.Within the scope of the present invention, preferred inhaler preferably can be when each spraying be moved, make the active matter quality that is lower than 100 microlitres (preferred to be lower than 50 microlitres, better with 10 to 30 microlitres) atomizing forms the aerosol of mean diameter less than 20 microns (preferably less than 10 microns), so the part that can suck in the aerosol is equivalent to treat effective dose.
Thisly do not use composition of liquid medicine that propellant transmits dosing for example to be recorded in the International Patent Application WO 91/14468 and WO 97/12687 (especially referring to Fig. 6 a and 6b) for inhalant device.The title of wherein illustrated nebulizer (device) is known as Respimat
This nebulizer (Respimat ) conveniently be used to produce the inhalational aerosol of the present invention that contains the p38 inhibitors of kinases.Because less than the length of 9-15 centimetre and 2 to 4 centimeters width, therefore, this device can be carried at any time by the patient with cylindric and hand-held size for it.Nebulizer uses high pressure, sees through the pharmaceutical preparation of small nozzle ejection certain volume amount, therefore produces the aerosol that can suck.
Preferred aerosol apparatus is made up of last body part (upper housing part), pump box (pumphousing), nozzle, the office of locking (locking mechanism), spring box (spring housing), spring (spring) and accumulator tank (storage container) basically, it is characterized in that
-pump box is fixed in the body, and wherein an end comprises the nozzle body that has nozzle or nozzle arrangement,
-with the hollow thromboembolism of valve,
-can fix this hollow thromboembolism and be arranged in the power switch flange (power takeoffflange) of body,
-be arranged in the office of locking of body,
-including the spring box of spring, it can utilize rotary stand rotation on last body part,
-be contained in the following body part of spring box on axially.
Hollow thromboembolism with valve is equivalent to WO 97/12687 disclosed device.Its part is outstanding to be stretched in the cylinder of pump box, can move vertically in cylinder.Can be especially referring to Fig. 1 to 4, especially Fig. 3, and relevant explanation.When starting spring that time, can be under its maximum pressure liquid (promptly deciding the active substance solution of dosage) be produced 5 to 60Mpa pressure (about 50 to 600 crust) with the hollow thromboembolism of valve, be preferably 10 to 60Mpa (about 100 to 600 cling to).The preferred volume of each ejection is 10 to 50 microlitres, and particularly preferred volume is 10 to 20 microlitres, and the most particularly preferred volume is 15 microlitres.
Valve preferably is contained in hollow pin beyond the Great Wall, is the surface with the valve.
The preferred microstructureization of nozzle in the nozzle body also promptly adopts microtechnique to make.The valve of microstructureization for example is disclosed among the WO-94/07607; Its disclosure is incorporated herein by reference, particularly Fig. 1 wherein and related description thereof.
Valve is to be combined closely by for example two sheet glass and silicon chip to form, and wherein the passage of a slice with one or more microstructureizations at least can connect the upstream side of the injector to nozzle exit end.On nozzle exit end, has a dark 2-10 micron at least, the circle of wide 5-15 micron or non-circular openings.Preferred depth is the 4.5-6.5 micron, and preferable width is the 7-9 micron.
If when many (preferred two) nozzle opening was arranged, the nozzle emission direction in the nozzle body can parallel to each otherly extend out or can tilt mutually along the nozzle opening direction.Have in the nozzle body of at least two nozzle openings at the outlet end, the mutual angle of emission direction is 20 to 160 °, preferred 60 to 150 °, and with 80 to 100 ° of the bests.Nozzle opening be arranged as 10 to 200 microns at interval, 10 to 100 microns of preferred interval are with 30 to 70 microns the bests at interval.Again with the 50 microns the bests in interval.Therefore emission direction will be near nozzle opening.
The pressure that enters that strikes the liquid drug preparation of nozzle body is up to 600 crust, and therefore preferred 200 to 300 crust can form the aerosol that can suck by the nozzle opening aerosolization.The preferred size droplet diameter of aerosol is up to 20 microns, preferred 3 to 10 microns.
The office of locking comprises a spring, and the pref. cylindrical spiral compression spring is as the source of mechanical energy.When the action of the determining positions start assembly of last lock set, this spring promptly acts on the power switch flange.By making progress and downward closing motion, accurately the flange of restricted power switch moves.Preferably utilize the power gear device, the pusher gear of arachnoid for example, when the spring box in last body and following body rotated in the opposite direction, the external torque that is produced promptly made the spring deflection.The last body of this device and the flange of power switch have single or multiple V-type gear.
With the last lock set annular array of the surface engaged of locking in the power switch flanged periphery.Its by for example have can radial strain a circle plastic cement or becket form.This ring is arranged in the axial vertical plane of aerosolizer.After the spring deflection, the last latching surface of last lock set moves in the power switch flange path, stops spring relaxation.Last lock set utilizes pushbutton enable.The button that starts connects or is coupled to lock set.In order to start the office of locking, the parallel planar annular that moves to of start button preferably enters in the aerosolizer; This measure causes deformable ring plate to be out of shape in planar annular.The relevant detailed structure that this locks office is illustrated in WO 97/20590.
Following body is along the spring box axial advance and cover the storage capsule of body frame structure, bearing and liquid.
When aerosolizer started, last body was the rotation of corresponding body down, the related rotating spring case of following body.Therefore spring compresses, and via the pusher gear deflection of helical form, the i.e. engagement automatically of office of locking.The anglec of rotation is preferably the aliquot part of 360 degree, for example 180 degree.In the time of the spring deflection, the power switch part in the last body moves along distance to a declared goal, and the hollow thromboembolism is sucked in the cylinder of pump box, and the result makes some liquid be sucked out outside the accumulator tank, enters in the altitude chamber of position before nozzle.
If when needing, many commutative accumulator tanks that contain the liquid of wanting aerosolization successively can be advanced in the aerosolizer, use in order.Accumulator tank contains waterborne aerosol preparation of the present invention.
The aerosolization process is to be begun by light pressure start button.Therefore, the office of locking opens towards the strong approach of power switch group.The spring of deflection promotes thromboembolism and enters in the cylinder of pump box.Liquid is promptly with aerosolization form jetting nozzle.
Be disclosed in PCT application case WO 97/12683 and WO97/20590 about this structure has further detailed content, its disclosure is incorporated herein by reference.
The element of aerosolizer (nebulizer) is made by the material that is fit to this purpose.Other parts that may allow in the body of aerosolizer and its operation to use are preferably made by plastic cement, for example the material of injection moulding formation.The treatment time spent, then use safe material on the physiology.
Fig. 2 a/b that present patent application is enclosed is identical with employed Fig. 6 a/b among the WO 97/12687, and it shows the nebulizer (Respimat that conveniently is used to suck the water-borne aerosol according to the present invention ).
Aerosolizer longitudinal section figure when Fig. 2 a shows the spring deflection, and the aerosolizer longitudinal section figure of Fig. 2 b when showing spring relaxation.
Last body (51) contains pump box (52), and the one end is fixed on the holder (53) of aerosolizer nozzle.In the holder nozzle body (54) and filter screen (55).Hollow thromboembolism (57) is fixed in the power switch flange (56) of the office of locking, and part is outstanding to be stretched in the cylinder of pump box.The end of hollow thromboembolism has valve (58).The hollow thromboembolism utilizes capping (59) sealing.When spring relaxation, the power switch flange promptly presses close to go up the shutdown switch (60) in the body.When the spring deflection, the power switch flange is promptly pressed close to the shutdown switch (61) on the power switch flange.After the spring deflection, last lock set (62) in last body shutdown switch (61) and support (63) between move.Lock set in start button (64) connection.Last body end is interface unit (65), and utilization can add superjacent over cap (66) sealing.
Contain the spring box (67) of compression spring (68) but be to utilize handgrip (69) that a brief period of time covers and rotating shaft bolster on one's body upper casing, can rotate.Following body (70) is pushed spring box to.It in the spring box the commutative accumulator tank (71) that contains the liquid (72) of aerosolizable.Accumulator tank utilizes seal cover (73) sealing, and the hollow thromboembolism can stretch in the accumulator tank through the sealing lid, and the one end is immersed in the liquid (supply active substance solution).
The rotating shaft of mechanical counter (74) is fixed in the shell of spring box.Rotating shaft end towards last body part is driving pinion (75).Sliding panel (76) is positioned in the rotating shaft.
Above-mentioned aerosolizer is fit to make the suitable aerosol that sucks of aerosol atomizing formation according to the present invention.
(Respimat when if preparation uses the said method atomizing according to the present invention ), in all number of times of operation inhaler (starting spraying), the conveying capacity of at least 97% (being preferably at least 98%) should be equivalent to prescribed dose, and its error is no more than 25%, and is preferred to be no more than 20%.During each the startup, the specified amount that is transmitted is that 5 to 30 milligrams of preparations are preferred, with 5 to 20 milligrams of preparation the bests.
Yet preparation also can utilize and be different from above-mentioned inhaler atomizing, for example injection stream inhaler or other fixed inhalers according to the present invention.
Therefore, the present invention relates to the purposes that the p38 inhibitors of kinases is used to prepare a kind of pharmaceutical preparation on the other hand, and described preparation is as above-mentioned imbedibility solution or the suspension that does not contain propellant to make up with the device that is fit to throw with these preparations, preferably with Respimat Combination.Preferably, the present invention relates to the p38 inhibitors of kinases and be used for preparing the imbedibility solution that do not contain propellant or the purposes of suspension, be characterised in that to comprise that the known name of p38 inhibitors of kinases combination is called Respimat according to the present invention Device.In addition, the present invention relates to the preferred Respimat of the inhalant device of above-mentioned confession Purposes, be characterised in that wherein to comprise above-mentioned imbedibility solution or the suspension that does not contain propellant according to the present invention.
The imbedibility solution or the suspension that do not contain propellant according to the present invention can be concentrated solution or ready-made available solution of aseptic imbedibility or suspension, and the above-mentioned Respimat that is designed for Solution and suspension.Ready-made available preparation can for example be added isotonia normal saline solution solution and be made by concentrated solution.But the fixed or portable type nebulizer administration of ready-made available sterile preparation working power operation, it can utilize principle in the mound, Fen (Venturi principle) or other principles, produces the aerosol that can suck via ultrasound wave or compressed air.
Therefore, the present invention is related to the purposes as the p38 inhibitors of kinases of above-mentioned imbedibility solution that does not contain propellant or form of suspension on the other hand, it is to be concentrated solution or ready-made available sterile preparation, make up with the device that is fit to throw with these solution, it is characterized in that this device adopts power operated movable type or portable type nebulizer, it can utilize principle in the mound, Fen (Venturi principle) or other principles, produces the aerosol that can suck via ultrasound wave or compressed air.
Following example is to be described in more detail the present invention, but with example the scope of the invention is not limited in the following embodiment.
Example of formulations
Can suck powder (being filled in the capsule):
1)
Composition μ g/ capsule
Example 1 ????3500
Lactose ????3500
Gross weight ????7000
2)
Composition μ g/ capsule
Example 1 ????3000
Lactose ????4000
Gross weight ????7000
3)
Composition μ g/ capsule
Example 1 ????5000
Lactose ????5000
Gross weight ????10000
4)
Composition μ g/ capsule
Example 1 ????5000
Lactose ????2000
Gross weight ????7000
5)
Composition μ g/ capsule
Example 1 ????5000
Gross weight ????5000
6)
Composition μ g/ capsule
Example 2 ????3500
Lactose ????3500
Gross weight ????7000
7)
Composition μ g/ capsule
Example 2 ????3000
Lactose ????4000
Gross weight ????7000
8)
Composition μ g/ capsule
Example 2 ????5000
Gross weight ????5000
9)
Composition μ g/ capsule
Example 3 ????5000
Lactose ????5000
Gross weight ????10000
10)
Composition μ g/ capsule
Example 3 ????5000
Lactose ????2000
Gross weight ????7000

Claims (30)

1.p38 inhibitors of kinases is used for the treatment of purposes in the inhalable drug compositions of Polyblennia in preparation.
2. according to the purposes of claim 1, wherein Polyblennia is associated with cystic fibrosis.
3. according to the purposes of claim 1 or 2, wherein the p38 inhibitors of kinases is selected from US patent 5,716,972, US 5,686,455, US 5,656,644, US 5,593,992, US 5,593,991, US5,663,334, US 5,670,527, US 5,559,137,5,658,903, US 5,739,143, US5,756,499, US 6,277,989, US 6,340,685 and US 5,716,955 and PCT application WO 92/12154, WO 94/19350, WO 95/09853, WO 95/09851, WO 95/09847, WO 95/09852, WO 97/25048, WO 97/25047, WO 97/33883, WO 97/35856, WO 97/35855, WO 97/36587, WO 97/47618, WO 97/16442, WO 97/16441, WO 97/12876, WO 98/25619, WO 98/06715, WO 98/07425, WO 98/28292, WO 98/56377, WO 98/07966, WO 98/56377, WO 98/22109, WO 98/24782, WO 98/24780, WO 98/22457, WO 98/52558, WO 98/52559, WO 98/52941, WO 98/52937, WO 98/52940, WO 98/56788, WO 98/27098, WO 98/47892, WO 98/47899, WO 98/50356, WO 98/32733, WO 99/58523, WO 99/01452, WO 99/01131, WO 99/01130, WO 99/01136, WO 99/17776, WO 99/32121, WO 99/58502, WO 99/58523, WO 99/57101, WO 99/61426, WO 99/59960, WO 99/59959, WO 99/00357, WO 99/03837, WO 99/01441, WO 99/01449, WO 99/03484, WO 99/15164, WO 99/32110, WO 99/32111, WO 99/32463, WO 99/64400, WO 99/43680, WO 99/17204, WO 99/25717, WO 99/50238, WO 99/61437, WO 99/61440, WO 00/26209, WO 00/18738, WO 00/17175, WO 00/20402, WO 00/01688, WO 00/07980, WO 00/07991, WO 00/06563, WO 00/12074, WO 00/12497, WO 00/31072, WO 00/31063, WO 00/23072, WO 00/31065, WO 00/35911, WO 00/39116, WO 00/43384, WO 00/41698, WO 00/69848, WO 00/26209, WO 00/63204, WO 00/07985, WO 00/59904, WO 00/71535, WO 00/10563, WO 00/25791, WO 00/55152, WO 00/55139, WO 00/17204, WO 00/36096, WO 00/55120, WO 00/55153, WO 00/56738, WO 01/21591, WO 01/29041, WO 01/29042, WO 01/62731, WO 01/05744, WO 01/05745, WO 01/05746, WO 01/05749, WO 01/05751, WO 01/27315, WO 01/42189, WO 01/00208, WO 01/42241, WO 01/34605, WO 01/47897, WO 01/64676, WO 01/37837, WO 01/38312, WO 01/38313, WO 01/36403, WO 01/38314, WO 01/47921, WO 01/27089, disclosed chemical compound among DE 19842833 and the JP 2,000 86657.
4. according to the purposes of claim 3, wherein the p38 inhibitors of kinases is selected from US 6,277,989, US 6,340,685, WO 00/12074, WO 00/12497, WO 00/59904, WO 00/71535, WO 01/64676, WO 99/61426, WO 00/10563, WO 00/25791, WO 01/37837, WO 01/38312, WO 01/38313, WO 01/38314, WO 01/47921, WO 99/61437, WO 99/61440, WO 00/17175, WO 00/17204, WO 00/36096, WO 98/27098, WO 99/00357, WO 99/58502, WO 99/64400, WO 99/01131, WO 00/43384, WO 00/55152, disclosed chemical compound among WO 00/55139 and the WO 01/36403.
5. according to the purposes of claim 4, wherein the p38 inhibitors of kinases is a formula 1Chemical compound
Figure A038129880003C1
Wherein
R 1Be 4-pyridine radicals, pyrimidine radicals, 4-pyridazinyl, 1,2,4-triazine-5-base, quinolyl, isoquinolyl or quinazoline-4-basic ring, described ring is by Y-R aReplace and randomly replaced by other independent substituent, described substituent group is selected from C 1-4Alkyl, halogen, hydroxyl, C 1-4Alkoxyl, C 1-4Alkylthio group, C 1-4Alkyl sulphinyl, CH 2OR 12, amino, single and two-C 1-6Amino, N-heterocyclic ring that alkyl replaces, this ring have 5～7 annular atomses and randomly comprise and be selected from oxygen, sulfur or NR 15, N (R 10) C (O) R bOr NHR aOther hetero atoms;
Y is oxygen or sulfur;
R 4Be phenyl, naphthalene-1-base or naphthalene-Ji, or heteroaryl, its optional by 1 or a plurality of substituent group replace, each substituent group is selected independently, and to 4-phenyl, 4 naphthalenes-1-base, 5-naphthalene-2-base or 6-naphthalene-2-base substituent group, is halogen, cyano group, nitro, C (Z) NR 7R 17, C (Z) OR 16, (CR 10R 20) vCOR 12, SR 5, SOR 5, OR 12, halogenated-C 1-4Alkyl, C 1-4Alkyl, ZC (Z) R 12, NR 10C (Z) R 16Or (CR 10R 20) vNR 10R 20, and, be halogen, cyano group, C (Z) NR to the replacement of other positions 13R 14, C (Z) OR 3, (CR 10R 20) M "COR 3, S (O) mR 3, OR 3, halogenated-C 1-4Alkyl, C 1-4Alkyl, (CR 10R 20) M "R 10C (Z) R 3, NR 10S (O) M 'R 8, NR 10S (O) M 'NR 7R 17, ZC (Z) R 3Or (CR 10R 20) M "NR 13R 14
Z is oxygen or sulfur;
N is 1～10 integer;
M is 0, or 1 or 2 integer;
M ' is 1 or 2 integer;
M " be 0, or 1～5 integer;
V is 0, or 1～2 integer;
R 2Be (A) (R of-C (H) 22);
A is optional aryl, heterocyclic radical or the heteroaryl ring that replaces, or the C of A for replacing 1-10Alkyl;
R 22Be the optional C that replaces 1-10Alkyl;
R aBe aryl, aryl C 1-6Alkyl, heterocyclic radical, heterocyclic radical C 1-6Alkyl, heteroaryl, heteroaryl C 1-6Alkyl, wherein each several part can be chosen wantonly and be substituted;
R bBe hydrogen, C 1-6Alkyl, C 3-7Cycloalkyl, aryl, aryl C 1-4Alkyl, heteroaryl, heteroaryl C 1-4Alkyl, heterocyclic radical or heterocyclic radical C 1-4Alkyl, wherein each several part can be chosen wantonly and be substituted;
R 3Be heterocyclic radical, heterocyclic radical C 1-10Alkyl or R 8
R 5Be hydrogen, C 1-4Alkyl, C 2-4Alkenyl, C 2-4Alkynyl or NR 7R 17, exclusive segment SR 5Be SNR 7R 17And SOR 5Situation for SOH;
R 6Be hydrogen, medicinal cation, C 1-10Alkyl, C 3-7Cycloalkyl, aryl, aryl C 1-4Alkyl, heteroaryl, heteroaryl C 1-4Alkyl, heterocyclic radical, aryl or C 1-10Alkanoyl;
R 7And R 17Be selected from hydrogen or C independently of one another 1-4Alkyl or R 7And R 17Coupled nitrogen forms 5～7 element heterocycle basic rings together, and this ring is selected from oxygen, sulfur or NR optional comprising 15Other hetero atoms;
R 8Be C 1-10Alkyl, halogenated C 1-10Alkyl, C 2-10Alkenyl, C 2-10Alkynyl, C 3-7Cycloalkyl, C 5-7Cycloalkenyl group, aryl, aryl C 1-10Alkyl, heteroaryl, heteroaryl C 1-10Alkyl, (CR 10R 20) nOR 11, (CR 10R 20) nS (O) mR 18, (CR 10R 20) nNHS (O) 2R 18, (CR 10R 20) nNR 13R 14Wherein said aryl, aryl alkyl, heteroaryl, heteroaryl alkyl can be chosen wantonly and be substituted;
R 9Be hydrogen, C (Z) R 11Or the optional C that replaces 1-10Alkyl, S (O) 2R 18, the optional aryl that replaces or the optional aryl C that replaces 1-4Alkyl;
R 10And R 20Be selected from hydrogen or C independently of one another 1-4Alkyl;
R 11Be hydrogen, C 1-10Alkyl, C 3-7Cycloalkyl, heterocyclic radical, heterocyclic radical C 1-10Alkyl, aryl, aryl C 1-10Alkyl, heteroaryl or heteroaryl C 1-10Alkyl, wherein these parts can be chosen wantonly and be substituted;
R 12Be hydrogen or R 16
R 13And R 14Be selected from hydrogen or the optional C that replaces independently of one another 1-4Alkyl, the optional aryl that replaces or the optional aryl C that replaces 1-4Alkyl, or connected nitrogen-atoms forms 5～7 element heterocycles together, and this ring is selected from oxygen, sulfur or NR optional comprising 9Other hetero atoms;
R 15Be R 10Or C (Z)-C 1-4Alkyl;
R 16Be C 1-4Alkyl, halogenated-C 1-4Alkyl, or C 3-7Cycloalkyl;
R 18Be C 1-10Alkyl, C 3-7Cycloalkyl, heterocyclic radical, aryl, aryl 1-10Alkyl, heterocyclic radical, heterocyclic radical-C 1-10Alkyl, heteroaryl or heteroaryl 1-10Alkyl;
Or its officinal salt.
6. according to the purposes of claim 4, wherein the p38 inhibitors of kinases is a formula 2Chemical compound:
Figure A038129880005C1
Wherein
R 1Be H, alkyl (1-6C) or aryl alkyl, choose wantonly on aryl and replaced that described substituent group is independently selected from alkyl (1-6C), halogen, OR, NR by the 1-3 substituent group 2, SR ,-OOCR ,-NROCR, RCO ,-COOR ,-CONR 2,-SO 2NR 2, CN, CF 3And NO 2, wherein each R is H or low alkyl group (1-4C) independently;
Each R 2Be alkyl (1-6C), halogen, OR, SR, OOCR, NROCR, COOR, RCO, CONR independently 2, SO 2NR 2, CN, CF 3Or NO 2, wherein each R is H or low alkyl group (1-4C) independently;
Each l, m and n are 0,1 or 2 independently; And
Ar is phenyl, 2-, 3-or 4-pyridine radicals, indyl, 2-or 4-pyrimidine radicals or benzimidazolyl, the optional substituted alkyl of each group, alkenyl, alkynyl, aryl, N-aryl, NH-aroyl, halogen, OR, NR 2, SR ,-OOCR ,-NROCR, RCO ,-COOR ,-CONR 2, SO 2NR 2, CN, CF 3Or NO 2Replace, wherein each R is H or alkyl (1-4C) independently, or its officinal salt.
7. according to the purposes of claim 4, wherein the p38 inhibitors of kinases is a formula 3a, 3b, 3cOr 3dChemical compound
Figure A038129880006C1
Figure A038129880006C2
Or
With and officinal salt,
Each Z wherein 1And Z 2Be CR independently 4Or N;
Each R wherein 4Independently for being selected from H and alkyl (1-6C);
Wherein said alkyl randomly comprises hetero atom that one or more is selected from O, S and N and wherein said alkyl is optional is replaced by one or more substituent group, and described substituent group is selected from halogen, OR, SR, NR 2, RCO, COOR, CONR 2, OOCR, NROCR, CN ,=O, 5 or 6 Yuans saturated carbocyclic rings or comprise the heterocyclic ring of 1-2 N and randomly comprise 1-2 the heteroatomic 6-person's aromatic rings of N, the R in the wherein aforementioned optional substituent group is H or alkyl (1-6C);
R 1For
Wherein
X 1Be CO, SO, CHOH or SO 2
M is 1;
Y is the optional alkyl that replaces, the optional aryl that replaces or the optional aryl alkyl that replaces;
N is 0,1 or 2;
Z 3Be N;
X 2Be CH or CH 2And
Ar is made up of 1 or 2 phenyl moiety that directly is coupled to X2, and the optional base that is substituted of described 1 or 2 phenyl moiety replaces, and described substituent group is selected from halogen, nitro, alkyl (1-6C), alkenyl (1-6C), CN, CF 3, RCO, COOR, CONR 2, NR 2, OR, SR, OOCR, NROCR, (R in the wherein aforementioned group is H or 1-6C alkyl) and phenyl, self is optional to be replaced by aforementioned substituent group;
R 2Be selected from H and alkyl (1-6C);
Wherein said alkyl comprises that randomly one or more is selected from the hetero atom of O, S and N, and wherein said alkyl is optional is replaced by one or more substituent group, and described substituent group is selected from halogen, OR, SR, NR 2, RCO, COOR, CONR 2, OOCR, NROCR, (R in the wherein aforementioned group is H or 1-6C alkyl) CN ,=O, 5 or 6 Yuans saturated carbocyclic rings or comprise the heterocyclic ring of 1-2 N and randomly comprise 1-2 the heteroatomic 6-person's aromatic rings of N;
R 3Be H, halogen, NO 2, alkyl (1-6C), alkenyl (1-6C), CN, OR, SR, NR 2, RCO, COOR, CONR 2, OOCR or NROCR, wherein R is H or alkyl (1-6C).
8. according to the purposes of claim 4, wherein the p38 inhibitors of kinases is a formula 4Chemical compound
Wherein
Ar 1For being selected from the heterocyclic radical of pyrroles, pyrrolidine, pyrazoles, imidazoles, oxazole, thiazole, furan and thiophene; And Ar wherein 1Can be by 1 or a plurality of R 1, R 2Or R 3Replace;
Ar 2Be phenyl, naphthyl, quinoline, isoquinolin, tetralyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl or indole, each group is optional by 1～3 R 2Group replaces;
L connects base, for
C 1-10Saturated or unsaturated side chain or straight chain carbochain;
Wherein one or more methylene is optional is substituted by O, N or S independently; And
Wherein said connection base is optional by 0-2 oxo group and one or more C 1-4Branched-chain or straight-chain alkyl replaces, described alkyl can by 1 or a plurality of halogen atom replace;
Q is selected from:
A) phenyl, naphthyl, pyridine, pyrimidine, pyridazine, imidazoles, benzimidazole, furan, thiophene, pyrans, benzodiazine, oxazole also [4,5-b] pyridine and imidazo [4,5-b] pyridine, described group is optional to be replaced by 1～3 group, and described group is selected from halogen, C 1-6Alkyl, C 1-6Alkoxyl, hydroxyl, list-or two-(C 1-3Alkyl) amino, C 1-6Alkyl-S (O) mAnd phenyl amino, wherein said benzyl ring is optional to be selected from halogen, C by 1～2 1-6Alkyl and C 1-6The group of alkoxyl replaces;
B) Pentamethylene oxide., oxolane, 1,3-dioxo Ketocyclopentane, 1,3-dioxanone, 1,4-dioxane, morpholine, tetrahydro-1,4-thiazine, tetrahydro-1,4-thiazine sulfoxide, tetrahydro-1,4-thiazine sulfone, piperidines, piperidones, tetrahydro pyrimidine ketone, Ketohexamethylene, Hexalin, pentamethylene thioether, pentamethylene sulfoxide, pentamethylene sulfone, tetramethylene thioether, tetramethylene sulfoxide and tetramethylene sulfone, it is optional by 1～3 group replacement, and described group is selected from C 1-6Alkyl, C 1-6Alkoxyl, hydroxyl, list-or two-(C 1-3Alkyl) amino-C 1-3Alkyl, phenyl amino-C 1-3Alkyl and C 1-3Alkoxy-C 1-3Alkyl;
C) C 1-6Alkoxyl, the second month in a season or tertiary amine, wherein said amino nitrogen are covalently bond to and are selected from C 1-3Alkyl and C 1-5Alkoxyalkyl and phenyl groups, wherein this benzyl ring is optional is replaced by 1～2 group, and described group is selected from halogen, C 1-6Alkoxyl, hydroxyl or list-or two-(C 1-3Alkyl) amino, C 1-6Alkyl-S (O) r, phenyl-S (O) t, wherein said benzyl ring is optional to be selected from halogen, C by 1～2 1-6Alkoxyl, hydroxyl or list-or two-(C 1-3Alkyl) amino group replaces;
R 1Be selected from:
(a) C 3-10Branched-chain or straight-chain alkyl, it can be randomly for partially or completely halogenated and optional by 1～3 phenyl, naphthyl or heterocyclic radical replacement, and described heterocyclic radical is selected from pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl; Each phenyl, naphthyl or the heterocycle that is selected from above-mentioned group are replaced by 0～5 following radicals, and described group is selected from halogen, optional part or complete halogenated C 1-6Branched-chain or straight-chain alkyl, C 3-8Cycloalkyl, C 5-8Cycloalkenyl group, hydroxyl, cyano group, optional part or complete halogenated C 1-3Alkoxyl, NH 2C (O) and two (C 1-3) alkyl amino-carbonyl;
(b) C 3-7Cycloalkyl is selected from cyclopropyl, cyclobutyl, Pentamethylene. base, cyclohexyl, cycloheptane base, bicyclo-pentyl, bicyclohexane base and bicycloheptane base, and each group is randomly for partially or completely halogenated and can be randomly by 1～3 C 1-3Alkyl replaces, or wherein 1～3 ring methylene be independently selected from O, S, CHOH,＞C=O,＞the similar group of the alternate described cycloalkyl of group of C=S and NH;
(c) C 3-10Branched alkenyl, it is randomly for partially or completely halogenated and optional by 1～3 C 1-5Branched-chain or straight-chain alkyl, phenyl, naphthyl or heterocyclic radical replace, each heterocyclic radical is independently selected from pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, and each phenyl, naphthyl or heterocyclic radical are replaced by 0～5 substituent group that is selected from the following group: halogen, optional part or complete halogenated C 1-6Branched-chain or straight-chain alkyl, cyclopropyl, cyclobutyl, Pentamethylene. base, cyclohexyl, cycloheptane base, bicyclo-pentyl, bicyclohexane base and bicycloheptane base, hydroxyl, cyano group, optional part or complete halogenated C 1-3Alkoxyl, NH 2C (O), single-or two (C 1-3) alkyl amino-carbonyl;
(d) C 5-7Cycloalkenyl group is selected from cyclopentenyl, cyclohexenyl group, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyl groups and bicycloheptene base, and wherein said cycloalkenyl group can be randomly by 1～3 C 1-3Alkyl replaces;
(e) cyano group; And,
(f) methoxycarbonyl, ethoxy carbonyl and propoxycarbonyl;
R 2Be selected from: randomly be partially or completely halogenated C 1-6Branched-chain or straight-chain alkyl, acetyl group, aroyl, randomly be partially or completely halogenated C 1-4Side chain or straight chain alkoxyl, halogen, methoxycarbonyl and phenyl sulfonyl;
R 3Be selected from:
A) phenyl, naphthyl or heterocyclic radical, described heterocyclic radical are selected from pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, tetrahydrofuran base, isoxazolyl, isothiazolyl, quinolyl, isoquinolyl, indyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzoisoxazole base, benzopyrazoles base, benzo thiapyran base, cinnolinyl, pteridyl, phthalazinyl, naphthyl pyridine radicals, quinoxalinyl, quinazolyl, purine radicals and indazolyl; Wherein said phenyl, naphthyl or heterocyclic radical are optional to be replaced by 1～5 substituent group that is selected from the following radicals: C 1-6Branched-chain or straight-chain alkyl, phenyl, naphthyl, the heterocycle that is selected from aforesaid group, optional part or complete halogenated C 1-6Branched-chain or straight-chain alkyl, cyclopropyl, cyclobutyl, Pentamethylene. base, cyclohexyl, cycloheptane base, bicyclo-pentyl, bicyclohexane base, bicycloheptane base, phenyl C 1-5Alkyl, naphthyl C 1-5Alkyl, halogen, hydroxyl, cyano group, randomly be partially or completely halogenated C 1-3Alkoxyl, phenoxy group, naphthoxy, the wherein said heterocyclic moiety of heteroaryloxy are selected from aforesaid group, nitro, amino, list-or two-(C 1-3) the amino wherein said heterocyclic radical of alkyl amino, phenyl amino, naphthyl amino, heterocyclic radical partly is selected from aforesaid group, NH 2C (O), single-or two-(C 1-3) alkyl amino-carbonyl, C 1-5Alkyl-C (O)-C 1-4Alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3) alkyl amino-C 1-5Alkyl, amino-S (O) 2, two-(C 1-3) alkyl amino-S (O) 2, R 4-C 1-5Alkyl, R 5-C 1-5Alkoxyl, R 6-C (O)-C 1-5Alkyl and R 7-C 1-5Alkyl (R 8) N;
B) condensed aryl is selected from benzocyclobutane alkyl, indanyl, indenyl, dihydro naphthyl, tetralyl, benzocyclohepta alkyl and benzocyclohepta thiazolinyl; Or the condensed heterocycle base, be selected from cyclopenta pyridine, hexamethylene and pyridine, cyclopentano pyrimidine, hexamethylene and pyrimidine, cyclopentano pyrazine, hexamethylene and pyrazine, cyclopentano pyridazine, hexamethylene and pyridazine, cyclopentano quinoline, hexamethylene and quinoline, cyclopentano isoquinolin, hexamethylene and isoquinolin, cyclopentano indole, hexamethylene diindyl, cyclopentano benzimidazole, hexamethylene and benzimidazole, cyclopentano benzoxazole, hexamethylene and benzoxazole, cyclopentano imidazoles, hexamethylene and imidazoles, cyclopentano thiophene and hexamethylene bithiophene; Wherein said fused-aryl or annelated heterocycles basic ring are replaced by 0～3 substituent group that is independently selected from the following radicals: phenyl, naphthyl and heterocyclic radical, described heterocyclic radical are selected from pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, optional part or complete halogenated C 1-6Branched-chain or straight-chain alkyl, halogen, cyano group, optional part or complete halogenated C 1-3Alkoxyl, phenoxy group, naphthoxy, the wherein said heterocyclic radical of heterocyclic oxy group partly are selected from as defined above group, nitro, amino, list-or two-(C 1-3) the amino wherein said heterocyclic radical of alkyl amino, phenyl amino, naphthyl amino, heterocyclic radical partly is selected from group, NH as defined above 2C (O), single-or two-(C 1-3) alkyl amino-carbonyl, C 1-4Alkyl-OC (O), C 1-5Alkyl-C (O)-C 1-4Branched-chain or straight-chain alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3) alkyl amino-C 1-5Alkyl, R 9-C 1-5Alkyl, R 10-C 1-5Alkoxyl, R 11-C (O)-C 1-5Alkyl and R 12-C 1-5Alkyl (R 13) N;
C) cycloalkyl is selected from Pentamethylene. base, cyclohexyl, cycloheptane base, bicyclo-pentyl, bicyclohexane base and bicycloheptane base, wherein cycloalkyl can be randomly for partially or completely halogenated and can be randomly by 1～3 C 1-3Alkyl replaces;
D) C 5-7Cycloalkenyl group is selected from cyclopentenyl, cyclohexenyl group, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyl groups and bicycloheptene base, and wherein said cycloalkenyl group can be randomly by 1～3 C 1-3Alkyl replaces; And
E) acetyl group, aroyl, alkoxy carbonyl alkyl or phenyl sulfonyl;
F) randomly be partially or completely halogenated C 1-6Branched-chain or straight-chain alkyl;
Or R 1And R 2Can randomly form condensed phenyl or pyridyl ring together,
And each R wherein 8, R 13Independently for being selected from: hydrogen and randomly be partially or completely halogenated C 1-4Branched-chain or straight-chain alkyl;
Each R 4, R 5, R 6, R 7, R 9, R 10, R 11And R 12Independently for being selected from: morpholine, piperidines, piperazine, imidazoles and tetrazolium;
m＝0、1、2；
r＝0、1、2；
t＝0、1、2；
X=O or S with and physilogically acceptable acid or salt.
9. according to the purposes of claim 4, wherein the p38 inhibitors of kinases is a formula 5Chemical compound
Figure A038129880011C1
Wherein:
Ar 1Be selected from: pyrroles, pyrrolidine, pyrazoles, imidazoles, oxazole, thiazole, furan and thiophene; Ar wherein 1Can be by 1 or a plurality of R 1, R 2Or R 3Replace;
Ar 2For: phenyl, naphthyl, quinoline, isoquinolin, tetralyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl or indole, each group is optional by 0～3 R 2Group replaces;
X is:
A) C 5-8Cycloalkyl or cycloalkenyl group, optional by 0-2 oxo group or 0-3 C 1-4Branched-chain or straight-chain alkyl, C 1-4Alkoxyl or C 1-4The alkyl amino chain replaces;
B) phenyl, furan, thiophene, pyrroles, imidazole radicals, pyridine, pyrimidine, pyridone, dihydropyridine ketone, maleimide, dihydro maleimide, piperidines, piperazine or pyrazine, each group is optional independently by 0-3 C 1-4Branched-chain or straight-chain alkyl, C 1-4Alkoxyl, hydroxyl, nitrile, list-or two-(C 1-3Alkyl) amino, C 1-6Alkyl-S (O) mOr halogen replaces;
Y is:
Chemical bond or optional part or complete halogenated C 1-4Saturated or unsaturated side chain or straight chain carbochain, wherein one or more methylene is optional by O, NH, S (O), S (O) 2Or S replaces and wherein Y is optional independently can be by 1 or the C of a plurality of halogen atom replacement by 0-2 oxo group and one or more 1-4Branched-chain or straight-chain alkyl replaces;
Z is:
A) phenyl, pyridine, pyrimidine, pyridazine, imidazoles, furan, thiophene, pyrans, described group is optional to be replaced by 1～3 substituent group that is selected from the following groups: halogen, C 1-6Alkyl, C 1-6Alkoxyl, hydroxyl, list-or two-(C 1-3Alkyl) amino, C 1-6Alkyl-S (O) m, COOH and phenyl amino, wherein benzyl ring is optional is selected from halogen, C by 1～2 1-6Alkyl and C 1-6Substituent group in the alkoxyl replaces;
B) Pentamethylene oxide., oxolane, 1,3-dioxane pentanone, 1,3-dioxanone, 1,4-dioxane, morpholine, tetrahydro-1,4-thiazine, tetrahydro-1,4-thiazine sulfoxide, piperidines, piperidones, piperazine, tetrahydro pyrimidine ketone, Ketohexamethylene, Hexalin, pentamethylene thioether, pentamethylene sulfoxide, pentamethylene sulfone, tetramethylene thioether, tetramethylene sulfoxide or tetramethylene sulfone, each group is optional to be replaced by 1～3 substituent group that is selected from the following radicals: nitrile, C 1-6Alkyl, C 1-6Alkoxyl, hydroxyl, list-or two-(C 1-3Alkyl) amino-C 1-3Alkyl, phenyl amino-C 1-3Alkyl and C 1-3Alkoxy-C 1-3Alkyl;
C) C 1-6Alkoxyl, the second month in a season or tertiary amine, wherein amino nitrogen is covalently bond to and is selected from C 1-3Alkyl, C 1-5Alkoxyalkyl, pyridine radicals-C 1-3Alkyl, imidazole radicals-C 1-3Alkyl, tetrahydrofuran base-C 1-3Group in alkyl, the phenyl amino, wherein benzyl ring is optional by 1～2 halogen, C 1-6Alkoxyl, hydroxyl or list-or two-(C 1-3Alkyl) amino, C 1-6Alkyl-S (O) mAnd phenyl-S (O) mReplace, wherein said benzyl ring is optional by 1～2 halogen, C 1-6Alkoxyl, hydroxyl or list-or two-(C 1-3Alkyl) the amino replacement;
R 1For:
A) C 3-10Branched-chain or straight-chain alkyl, optional part or complete halo and optionally replaced by 1～3 substituent group that is selected from the following groups: phenyl, naphthyl or heterocyclic radical, described heterocyclic radical are selected from pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl; Each phenyl, naphthyl or the heterocycle that is selected from this section the above-mentioned group of record are replaced by 0～5 substituent group that is selected from the following groups: halogen, optional part or complete halogenated C 1-6Branched-chain or straight-chain alkyl, C 3-8Cycloalkyl, C 5-8Cycloalkenyl group, hydroxyl, nitrile, optional part or complete halogenated C 1-3Alkoxyl, NH 2C (O) and two (C 1-3) alkyl amino-carbonyl;
B) C 3-7Cycloalkyl is selected from cyclopropyl, cyclobutyl, Pentamethylene. base, cyclohexyl, cycloheptane base, bicyclo-pentyl, bicyclohexane base and bicycloheptane base, and each group is randomly for halo partially or completely and randomly by 1～3 C 1-3Alkyl replaces, or wherein 1～3 ring methylene be independently selected from O, S, CHOH,＞C=O,＞the similar group of the alternate described cycloalkyl of group among C=S and the NH;
C) C 3-10Branched alkenyl, optional part or complete halo are also optional by 1～3 C 1-5Branched-chain or straight-chain alkyl, phenyl, naphthyl or heterocyclic radical replace, each heterocyclic radical is independently selected from pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, and each phenyl, naphthyl or heterocyclic radical are replaced by 0～5 substituent group that is selected from the following groups: halogen, optional part or complete halogenated C 1-6Branched-chain or straight-chain alkyl, cyclopropyl, cyclobutyl, Pentamethylene. base, cyclohexyl, cycloheptane base, bicyclo-pentyl, bicyclohexane base, bicycloheptane base, hydroxyl, nitrile, optional part or complete halogenated C 1-3Alkoxyl, NH 2C (O) and list-or two (C 1-3) alkyl amino-carbonyl;
D) C 5-7Cycloalkenyl group is selected from cyclopentenyl, cyclohexenyl group, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyl groups and bicycloheptene base, and wherein said cycloalkenyl group is optional by 1～3 C 1-3Alkyl replaces;
E) nitrile; Or
F) C 1-6Side chain or straight chain alkoxy carbonyl, C 1-6Branched-chain or straight-chain alkyl amino carbonyl, C 1-6Branched-chain or straight-chain alkyl carbonylamino-C 1-3-alkyl;
R 2For: optional part or complete halogenated C 1-6Branched-chain or straight-chain alkyl, acetyl group, aroyl, optional part or complete halogenated C 1-4Side chain or straight chain alkoxyl, halogen, methoxycarbonyl or phenyl sulfonyl;
R 3For:
A) phenyl, naphthyl or heterocyclic radical, described heterocyclic radical is selected from pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, tetrahydrofuran base isoxazolyl, isothiazolyl, quinolyl, isoquinolyl, indyl, benzimidazolyl, benzofuranyl benzoxazolyl, the benzoisoxazole base, the benzopyrazoles base, the benzo thiapyran base, cinnolinyl, pteridyl, phthalazinyl, the naphthyl pyridine radicals, quinoxalinyl, quinazolyl, purine radicals and indazolyl, wherein said phenyl, naphthyl or heterocyclic radical are optional to be replaced by 1～5 substituent group that is selected from the following radicals: phenyl, naphthyl, be selected from the heterocycle of the above-mentioned group of record in this section, optional part or complete halogenated C 1-6Branched-chain or straight-chain alkyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, two cyclopenta, dicyclohexyl, two suberyl, phenyl C 1-5Alkyl, naphthyl C 1-5Alkyl, halogen, hydroxyl, nitrile, randomly be partially or completely halogenated C 1-3Alkoxyl, phenoxy group, naphthoxy, the wherein said heterocyclic moiety of heteroaryloxy are selected from this section the above-mentioned group, nitro, amino, list of record-or two-(C 1-3) the amino wherein said heterocyclic radical of alkyl amino, phenyl amino, naphthyl amino, heterocyclic radical partly is selected from above-mentioned group, the NH of record in this section 2C (O), single-or two-(C 1-3) alkyl amino-carbonyl, C 1-5Alkyl-C (O)-C 1-4Alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3) alkyl amino-C 1-5Alkyl, amino-S (O) 2, two-(C 1-3) alkyl amino-S (O) 2, R 4-C 1-5Alkyl, R 5-C 1-5Alkoxyl, R 6-C (O)-C 1-5Alkyl and R 7-C 1-5Alkyl (R 8) N, carboxyl-list-or two-(C 1-5)-alkyl-amino;
B) condensed aryl is selected from benzocyclobutane alkyl, indanyl, indenyl, dihydro naphthyl, tetralyl, benzocyclohepta alkyl and benzocyclohepta thiazolinyl; Or the condensed heterocycle base, be selected from cyclopenta pyridine, hexamethylene and pyridine, cyclopentano pyrimidine, hexamethylene and pyrimidine, cyclopentano pyrazine, hexamethylene and pyrazine, cyclopentano pyridazine, hexamethylene and pyridazine, cyclopentano quinoline, hexamethylene and quinoline, cyclopentano isoquinolin, hexamethylene and isoquinolin, cyclopentano indole, hexamethylene diindyl, cyclopentano benzimidazole, hexamethylene and benzimidazole, cyclopentano benzoxazole, hexamethylene and benzoxazole, cyclopentano imidazoles, hexamethylene and imidazoles, cyclopentano thiophene and hexamethylene bithiophene; Wherein said fused-aryl or annelated heterocycles basic ring are replaced by 0～3 substituent group that is independently selected from the following radicals: phenyl, naphthyl and heterocyclic radical, described heterocyclic radical is selected from pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, optional part or complete halogenated C 1-6Branched-chain or straight-chain alkyl, halogen, nitrile, optional part or complete halogenated C 1-3Alkoxyl, phenoxy group, naphthoxy, the wherein said heterocyclic radical of heterocyclic oxy group partly are selected from this section the above-mentioned group, nitro, amino, list of record-or two-(C 1-3) the amino wherein said heterocyclic radical of alkyl amino, phenyl amino, naphthyl amino, heterocyclic radical partly is selected from above-mentioned group, the NH of record in this section 2C (O), single-or two-(C 1-3) alkyl amino-carbonyl, C 1-4Alkyl-OC (O), C 1-5Alkyl-C (O)-C 1-4Branched-chain or straight-chain alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3) alkyl amino-C 1-5Alkyl, R 9-C 1-5Alkyl, R 10-C 1-5Alkoxyl, R 11-C (O)-C 1-5Alkyl and R 12-C 1-5Alkyl (R 13) N;
C) cycloalkyl is selected from cyclopenta, cyclohexyl, suberyl, two cyclopenta, dicyclohexyl and two suberyl, wherein cycloalkyl optional part or halo and optional by 1～3 C fully 1-3Alkyl replaces;
D) C 5-7Cycloalkenyl group is selected from cyclopentenyl, cyclohexenyl group, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyl groups and bicycloheptene base, and wherein said cycloalkenyl group is optional by 1～3 C 1-3Alkyl replaces;
E) acetyl group, aroyl, alkoxy carbonyl alkyl or phenyl sulfonyl; Or
F) optional part or complete halogenated C 1-6Branched-chain or straight-chain alkyl;
Or R 1And R 2Can randomly form condensed phenyl or pyridyl ring together;
Each R 8And R 13Independently for being selected from: hydrogen and randomly be partially or completely halogenated C 1-4Branched-chain or straight-chain alkyl;
Each R 4, R 5, R 6, R 7, R 9, R 10, R 11And R 12Independently for being selected from morpholine, piperidines, piperazine, imidazoles and tetrazolium;
M is 0,1 or 2;
W be O or S and
Its pharmaceutically acceptable derivant.
10. according to the purposes of claim 4, wherein the p38 inhibitors of kinases is a formula 5aChemical compound
Wherein:
Ar 1For: pyrroles, pyrrolidine, pyrazoles, imidazoles, oxazole, thiazole, furan and thiophene; Ar wherein 1Optional by one or more R 1, R 2Or R 3Replace;
Ar 2For: phenyl, naphthyl, quinoline, isoquinolin, tetralyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl and indole, each group is optional by 0～3 R 2Group replaces;
X is:
C 5-8Cycloalkyl or cycloalkenyl group, optional by 1 or 2 oxo group or 1～3 C 1-4Alkyl,
C 1-4Alkoxyl or C 1-4The alkyl amino chain replaces, and each group can be side chain or straight chain;
Phenyl, furyl, thienyl, pyrrole radicals, pyrazolyl, imidazole radicals, pyridine radicals, tetrahydro pyridyl, pyrimidine radicals, pyriconyl, dihydropyridine ketone group, dimaleoyl imino, dihydro dimaleoyl imino, piperidyl, benzimidazole, 3H-imidazo [4,5-b] pyridine, piperazinyl, pyridazinyl or pyrazinyl; Each group is optional independently by 1～3 C 1-4Alkyl, C 1-4Alkoxyl, hydroxyl, nitrile, amino, list-or two-(C 1-3Alkyl) amino, single-or two-(C 1-3Alkyl amino) carbonyl, NH 2C (O), C 1-6Alkyl-S (O) mOr halogen replaces;
Y is:
Chemical bond or optional part or complete halogenated C 1-4Saturated or unsaturated side chain or straight chain carbochain, wherein one or more C atom is optional by O, N or S (O) mReplace and wherein Y is optional independently by 1 or 2 oxo group, nitrile, phenyl, hydroxyl or 1 or a plurality of C 1-4Alkyl replaces, and described alkyl is optional to be replaced by one or more halogen atom;
Z is:
Aryl; indanyl; heteroaryl; described heteroaryl is selected from benzimidazolyl; pyridine radicals; pyrimidine radicals; pyridazinyl; pyrazinyl; imidazole radicals; pyrazolyl; triazolyl; tetrazole radical; furyl; thienyl and pyranose; heterocycle is selected from piperazinyl; the tetrahydropyrimidine ketone group; the hexamethylene ketone group; the hexamethylene acyl group; the 2-oxa--or 2-thia-5-aza-bicyclo [2.2.1] heptane base; the pentamethylene sulfenyl; the pentamethylene sulfoxide group; the pentamethylene sulfonyl; the tetramethylene sulfenyl; tetramethylene sulfoxide base or tetramethylene sulfonyl; THP trtrahydropyranyl; tetrahydrofuran base; 1; 3-dioxo Ketocyclopentane base; 1; 3-dioxanone base; 1; the 4-dioxacyclohexyl; morpholino; tetrahydro-1,4-thiazine generation; tetrahydro-1,4-thiazine is for sulfoxide group; tetrahydro-1,4-thiazine is for sulfonyl; piperidyl; piperidone base; pyrrolidinyl and dioxo cyclopenta, aforementioned each Z group is optional to be replaced by 1～3 substituent group that is selected from the following radicals: halogen; C 1-6Alkyl, C 1-6Alkoxyl, C 1-3Alkoxy-C 1-3Alkyl, C 1-6Alkoxy carbonyl, aroyl, 4-hetaroylpyrazol, heterocycle C 1-3Front definition, C in the wherein said heteroaryl of acyl group and heterocycle such as this section 1-3Acyl group, oxo, hydroxyl, pyridine radicals-C 1-3Alkyl, imidazole radicals-C 1-3Alkyl, tetrahydrofuran base-C 1-3Alkyl, nitrile-C 1-3Alkyl, nitrile, carboxyl, phenyl, wherein benzyl ring is optional by 1～2 halogen, C 1-6Alkoxyl, hydroxyl or list-or two-(C 1-3Alkyl) amino, amino-S (O) m, C 1-6Alkyl-S (O) mOr phenyl-S (O) mReplace, wherein said benzyl ring is optional by 1～2 halogen, C 1-6Alkoxyl, hydroxyl, halogen or list-or two-(C 1-3Alkyl) the amino replacement;
Or Z is optional by 1～3 amino, amino carbonyl or amino-C 1-3Alkyl replaces, and wherein the N atom is optional independently by amino C 1-6Alkyl, C 1-3Alkyl, aryl C 0-3Alkyl, C 1-5Alkoxy C 1-3Alkyl, C 1-5Alkoxyl, aroyl, C 1-3Acyl group, C 1-3Alkyl-S (O) m-or aryl C 0-3Alkyl-S (O) m-be singly-or two-replace, it is optional by 1～2 halogen, C to be connected to amino aforementioned each alkyl and aryl 1-6Alkyl, C 1-6Alkoxyl, hydroxyl or list-or two-(C 1-3Alkyl) the amino replacement;
Or Z is optional by 1～3 as foregoing aryl, heterocycle or heteroaryl replacement in this section, and each substituent group is chosen wantonly conversely by halogen, C 1-6Alkyl or C 1-6Alkoxyl replaces;
Or Z is hydroxyl, hydroxyl C 1-3Alkyl, halogen, nitrile, amino, wherein the N atom is optional independently by C 1-6Alkyl, amino C 1-6Alkyl, aryl C 0-3Alkyl, C 1-5Alkoxy C 1-3Alkyl, C 1-5Alkoxyl, aroyl, C 1-3Acyl group, C 1-3Alkyl-S (O) m-, aryl C 0-3Alkyl-S (O) m-, nitrile C 1-4Alkyl or C 1-3Alkoxy C 1-3The alkyl list-or two-replace, it is optional by 1～2 halogen, C to be connected to amino aforementioned each alkyl and aryl 1-6Alkyl, C 1-6Alkoxyl, hydroxyl or list-or two-(C 1-3Alkyl) amino, C 1-6Alkoxyl heteroaryl C 0-3Alkyl, heteroaryl C 0-3Alkyl or heterocycle C 0-3Alkyl replaces, and wherein said heteroaryl and heterocycle such as this section front define,
Or Z is side chain or straight chain C 1-6Alkyl, C 1-6Alkoxyl, C 1-3Acyl amino, nitrile C 1-4Alkyl, C 1-6Alkyl-S (O) mAnd phenyl-S (O) m, wherein benzyl ring is optional by 1～2 halogen, C 1-6Alkoxyl, hydroxyl or list-or two-(C 1-3Alkyl) the amino replacement;
R 1For:
A) C 1-10Branched-chain or straight-chain alkyl randomly partially or completely halogenated and is optionally replaced by 1～3 phenyl, naphthyl or the heterocyclic radical that is selected from pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl; Each phenyl, naphthyl or the heterocycle that is selected from above-mentioned group are replaced by 0～5 substituent group that is selected from the following groups: halogen, optional part or complete halogenated C 1-6Branched-chain or straight-chain alkyl, C 3-8Cycloalkyl, C 5-8Cycloalkenyl group, hydroxyl, nitrile, optional part or complete halogenated C 1-3Alkoxyl, NH 2C (O) and two (C 1-3) alkyl amino-carbonyl;
B) C 3-7Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, two cyclopenta, dicyclohexyl and two suberyl, and each group optional part or complete halo are also optional by 1～3 C 1-3Alkyl replaces, or wherein 1～3 ring methylene be independently selected from O, S, CHOH,＞C=O,＞group of C=S and NH the similar group of alternate described cycloalkyl;
C) C 3-10Branched alkenyl, optional part or complete halo are also optional by 1～3 C 1-5Branched-chain or straight-chain alkyl, phenyl, naphthyl or heterocyclic radical replace, each heterocyclic radical is independently selected from pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, and each phenyl, naphthyl or heterocyclic radical are replaced by 0～5 substituent group that is selected from the following groups: halogen, optional part or complete halogenated C 1-6Branched-chain or straight-chain alkyl, cyclopropyl, cyclobutyl, Pentamethylene. base, cyclohexyl, cycloheptane base, bicyclo-pentyl, bicyclohexane base, bicycloheptane base, hydroxyl, nitrile, optional part or complete halogenated C 1-3Alkoxyl, NH 2C (O) and list-or two (C 1-3) alkyl amino-carbonyl;
D) C 5-7Cycloalkenyl group is selected from cyclopentenyl, cyclohexenyl group, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyl groups and bicycloheptene base, and wherein said cycloalkenyl group is optional by 1～3 C 1-3Alkyl replaces;
E) nitrile; Or
F) C 1-6Side chain or straight chain alkoxy carbonyl, C 1-6Branched-chain or straight-chain alkyl amino carbonyl, C 1-6Branched-chain or straight-chain alkyl carbonylamino-C 1-3-alkyl;
R 2For: C 1-6Branched-chain or straight-chain alkyl, optional part or complete halo are also optional to be replaced by nitrile,
Or R 2Be acetyl group, aroyl, partially or completely halogenated C randomly 1-4Side chain or straight chain alkoxyl, halogen, methoxycarbonyl or phenyl sulfonyl;
R 3For:
A) phenyl, naphthyl or heterocyclic radical, described heterocyclic radical is selected from pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, tetrahydrofuran base isoxazolyl, isothiazolyl, quinolyl, isoquinolyl, indyl, benzimidazolyl, benzofuranyl benzoxazolyl, the benzoisoxazole base, the benzopyrazoles base, the benzo thiapyran base, cinnolinyl, pteridyl, phthalazinyl, the naphthyl pyridine radicals, quinoxalinyl, quinazolyl, purine radicals and indazolyl, wherein said phenyl, naphthyl or heterocyclic radical are chosen substituted 11～5 substituent group that is selected from the following groups wantonly and are replaced: phenyl, naphthyl, be selected from the heterocycle of the above-mentioned group of record in this section, optional part or complete halogenated C 1-6Branched-chain or straight-chain alkyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, two cyclopenta, dicyclohexyl, two suberyl, phenyl C 1-5Alkyl, naphthyl C 1-5Alkyl, halogen, hydroxyl, oxo, nitrile, optional part or complete halogenated C 1-3Alkoxyl, C 1-3Alkoxy C 1-5Alkyl, C 1-3Alkylthio, C 1-3Alkylthio C 1-5Alkyl, phenoxy group, naphthoxy, the wherein said heterocyclic moiety of heteroaryloxy are selected from this section the above-mentioned group, nitro, amino, list of record-or two-(C 1-3) the amino wherein said heterocyclic radical of alkyl amino, phenyl amino, naphthyl amino, heterocyclic radical partly is selected from above-mentioned group, the NH of record in this section 2C (O), single-or two-(C 1-3) alkyl amino-carbonyl, C 1-5Alkyl-C (O)-C 1-4Alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3) alkyl amino-C 1-5Alkyl, amino-S (O) 2, two-(C 1-3) alkyl amino-S (O) 2, R 4-C 1-5Alkyl, R 5-C 1-5Alkoxyl, R 6-C (O)-C 1-5Alkyl and R 7-C 1-5Alkyl (R 8) N, carboxyl-list-or two-(C 1-5)-alkyl-amino;
B) condensed aryl, be selected from the benzocyclobutane alkyl, indanyl, indenyl, the dihydro naphthyl, tetralyl, benzocyclohepta alkyl and benzocyclohepta thiazolinyl, or the condensed heterocycle base, be selected from cyclopenta pyridine, hexamethylene and pyridine, the cyclopentano pyrimidine, hexamethylene and pyrimidine, the cyclopentano pyrazine, hexamethylene and pyrazine, the cyclopentano pyridazine, hexamethylene and pyridazine, the cyclopentano quinoline, hexamethylene and quinoline, cyclopentano isoquinolin, hexamethylene and isoquinolin, the cyclopentano indole, the hexamethylene diindyl, the cyclopentano benzimidazole, hexamethylene and benzimidazole, the cyclopentano benzoxazole, hexamethylene and benzoxazole, the cyclopentano imidazoles, hexamethylene and imidazoles, cyclopentano thiophene and hexamethylene bithiophene; Wherein said fused-aryl or annelated heterocycles basic ring are replaced by 0～3 substituent group that is independently selected from the following groups: phenyl, naphthyl and heterocyclic radical, described heterocyclic radical is selected from pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, optional part or complete halogenated C 1-6Branched-chain or straight-chain alkyl, halogen, nitrile, optional part or complete halogenated C 1-3Alkoxyl, phenoxy group, naphthoxy, the wherein said heterocyclic radical of heterocyclic oxy group partly are selected from the group, nitro, amino, list of above-mentioned definition-or two-(C 1-3) the amino wherein said heterocyclic radical of alkyl amino, phenyl amino, naphthyl amino, heterocyclic radical partly is selected from group, the NH of above-mentioned definition 2C (O), single-or two-(C 1-3) alkyl amino-carbonyl, C 1-4Alkyl-OC (O), C 1-5Alkyl-C (O)-C 1-4Branched-chain or straight-chain alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3) alkyl amino-C 1-5Alkyl, R 9-C 1-5Alkyl, R 10-C 1-5Alkoxyl, R 11-C (O)-C 1-5Alkyl and R 12-C 1-5Alkyl (R 13) N;
C) cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, two cyclopenta, dicyclohexyl and two suberyl, and wherein cycloalkyl is optional part or complete halo and randomly by 1～3 C 1-3Alkyl replaces;
D) C 5-7Cycloalkenyl group is selected from cyclopentenyl, cyclohexenyl group, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyl groups and bicycloheptene base, and wherein said cycloalkenyl group is optional by 1～3 C 1-3Alkyl replaces;
E) acetyl group, aroyl, C 1-6Alkoxy carbonyl C 1-6The alkyl or phenyl sulfonyl; Or
F) optional part or complete halogenated C 1-6Branched-chain or straight-chain alkyl;
Or R 1And R 2Randomly form fused phenyl or pyridyl ring together;
Each R 8And R 13Independently for being selected from: hydrogen and optional part or complete halogenated C 1-4Branched-chain or straight-chain alkyl;
Each R 4, R 5, R 6, R 7, R 9, R 10, R 11And R 12Independently for being selected from morpholine, piperidines, piperazine, imidazoles and tetrazolium;
M is 0,1 or 2;
W is O or S;
Wherein X is connected directly to 1 or 2-Y-Z, and
Its pharmaceutically acceptable derivant.
11. according to the purposes of claim 4, wherein the p38 inhibitors of kinases is a formula 6Chemical compound
Figure A038129880019C1
Wherein:
G is:
The C of fragrance 6-10The saturated or unsaturated C of carbocyclic ring or non-fragrance 3-10Carbocyclic ring;
6-10 person's heteroaryl comprises 1 or the hetero atom of more a plurality of O of being selected from, N and S;
5-8 person's monocyclic heterocycles comprises the hetero atom that one or more is selected from O, N and S;
Or
8-11 person's bicyclic heterocycles comprises the hetero atom that one or more is selected from O, N and S;
Wherein G is by 1 or a plurality of R 1, R 2Or R 3Replace;
Ar is:
Phenyl, naphthyl, quinolyl, isoquinolyl, tetralyl, tetrahydric quinoline group, tetrahydro isoquinolyl, benzimidazolyl, benzofuranyl, dihydro benzo furyl, indolinyl, benzothienyl, dihydrobenzo thienyl, indanyl, indenyl or indyl, each group is optional by one or more R 4Or R 5Replace;
X is:
C 5-8Cycloalkyl or cycloalkenyl group, optional by 1 or 2 oxo group or 1～3 C 1-4Alkyl, C 1-4Alkoxyl or C 1-4The alkyl amino chain replaces;
Phenyl, furyl, thienyl, pyrrole radicals, pyrazolyl, imidazole radicals, pyridine radicals, pyrimidine radicals, pyriconyl, dihydropyridine ketone group, dimaleoyl imino, dihydro dimaleoyl imino, piperidyl, benzimidazole, 3H-imidazo [4,5-b] pyridine, piperazinyl, pyridazinyl or pyrazinyl;
Y is:
Chemical bond or optional part or complete halogenated C 1-4Saturated or unsaturated side chain or straight chain carbochain, wherein one or more methylene is optional by O, N or S (O) mReplace and wherein Y is optional independently by 1 or 2 oxo group, phenyl or 1 or a plurality of optional C that is replaced by one or more halogen atom 1-4Alkyl replaces;
Z is:
Phenyl, pyridine radicals, pyrimidine radicals, pyridazinyl, pyrazinyl, imidazole radicals, pyrazolyl, triazolyl, tetrazole radical, furyl, thienyl, pyranose, each group is optional by 1～3 halogen, C 1-6Alkyl, C 1-6Alkoxyl, hydroxyl, amino, list-or two-(C 1-3Alkyl) amino, C 1-6Alkyl-S (O) m, CN, CONH 2, COOH or phenyl amino replace, wherein benzyl ring is optional by 1～2 halogen, C 1-6Alkyl or C 1-6Alkoxyl replaces;
THP trtrahydropyranyl, tetrahydrofuran base, 1; 3-dioxo Ketocyclopentane base, 1; 3-dioxanone base, 1; for sulfonyl, piperidyl, piperidone base, piperazinyl, tetrahydropyrimidine ketone group, hexamethylene ketone group, hexamethylene acyl group, pentamethylene sulfenyl, pentamethylene sulfoxide group, pentamethylene sulfonyl, tetramethylene thioether, tetramethylene sulfoxide base or tetramethylene sulfonyl, each group is optional by 1～3 nitrile, C for sulfoxide group, tetrahydro-1,4-thiazine for 4-dioxacyclohexyl, morpholinyl, tetrahydro-1,4-thiazine base, tetrahydro-1,4-thiazine 1-6Alkyl, C 1-6Alkoxyl, hydroxyl, amino, list-or two-(C 1-3Alkyl) amino-C 1-3Alkyl, CONH 2, phenyl amino-C 1-3Alkyl or C 1-3Alkoxy-C 1-3Alkyl replaces;
Halogen, C 1-4Alkyl, nitrile, amino, hydroxyl, C 1-6Alkoxyl, NH 2C (O), single-or two (C 1-3Alkyl) amino carbonyl, list-or two (C 1-6Alkyl) amino, the second month in a season or tertiary amine, wherein amino nitrogen is covalently bond to C 1-3Alkyl or C 1-5Alkoxyalkyl, pyridine radicals-C 1-3Alkyl, imidazole radicals-C 1-3Alkyl, tetrahydrofuran base-C 1-3Alkyl, nitrile-C 1-3Alkyl, carboxylic acid amides-C 1-3Alkyl, phenyl, wherein benzyl ring is optional by 1～2 halogen, C 1-6Alkoxyl, hydroxyl or list-or two-(C 1-3Alkyl) amino, C 1-6Alkyl-S (O) mOr phenyl-S (O) mReplace, wherein benzyl ring is optional by 1～2 halogen, C 1-6Alkoxyl, hydroxyl, halogen or list-or two-(C 1-3Alkyl) the amino replacement;
C 1-6Alkyl-S (O) mAnd phenyl-S (O) m, wherein benzyl ring is optional by 1～2 halogen, C 1-6Alkoxyl, hydroxyl or list-or two-(C 1-3Alkyl) the amino replacement;
Each R 1Be independently:
C 1-10Alkyl is randomly for partially or completely halogenated and optional by 1～3 C 3-10Cycloalkyl, hydroxyl, phenyl, naphthyl, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl replace;
Aforementioned each group is optional to be replaced by 1～5 substituent group that is selected from the following groups: halogen, optional part or complete halogenated C 1-6Alkyl, C 3-8Cycloalkyl, C 5-8Cycloalkenyl group, hydroxyl, nitrile, optional part or complete halogenated C 1-3Alkoxyl or NH 2C (O), single-or two (C 1-3Alkyl) amino and singly-or two (C 1-3Alkyl) amino carbonyl;
Ring propoxyl group, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy or suberyl oxygen base, each group optional part or complete halo are also optional by 1～3 optional part or complete halogenated C 1-3Alkyl, CN, hydroxyl C 1-3Alkyl or aryl replaces; Or wherein 1～3 the ring methylene independently by O, S (O) m, CHOH,＞C=O,＞the similar group of C=S or the alternate described cycloalkyl of NH;
Phenoxy group or benzyloxy, each group optional part or complete halo are also optional by 1～3 optional part or complete halogenated C 1-3Alkyl, CN, hydroxyl C 1-3Alkyl or aryl replaces; Or wherein 1～2 the ring methine independently by the similar group of the alternate described cyclophane base of N; Cyclopropane base, Tetramethylene. base, Pentamethylene. base, cyclohexyl, cycloheptane base, bicyclo-pentyl, bicyclohexane base or bicycloheptane base, each group optional part or complete halo are also optional by 1～3 randomly partially or completely halogenated C 1-3Alkyl, CN, hydroxyl C 1-3Alkyl or aryl replaces; Or wherein 1～3 the ring methylene independently by O, S (O) m, CHOH,＞C=O,＞the similar group of C=S or the alternate described cycloalkyl of NH;
C 3-10Side chain or straight alkenyl, each group optional part or complete halo are also randomly replaced by 1～3 substituent group that is selected from the following radicals: C 1-5Branched-chain or straight-chain alkyl, phenyl, naphthyl, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl, aforementioned each group is replaced by 0～5 substituent group that is selected from the following groups: halogen, optional part or complete halogenated C 1-6Alkyl, cyclopropane base, Tetramethylene. base, Pentamethylene. base, cyclohexyl, cycloheptane base, bicyclo-pentyl, bicyclohexane base and bicycloheptane base, hydroxyl, nitrile, optional part or complete halogenated C 1-3Alkoxyl, NH 2C (O), single-or two (C 1-3Alkyl) amino carbonyl; Randomly be selected from O, N and S (O) by one or more mThe C that interrupts of hetero atom 3-10Side chain or straight alkenyl;
Cyclopentenyl, cyclohexenyl group, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyl groups or bicycloheptene base, wherein said cycloalkenyl group are randomly by 1～3 C 1-3Alkyl replaces;
Nitrile, halogen;
Methoxycarbonyl, ethoxy carbonyl and propoxycarbonyl;
Silicyl comprises 3 optional parts or complete halogenated C 1-4Alkyl;
C 3-6Alkynyl side chain or straight chain carbochain, optional part or complete halo, wherein one or more methylene is optional by O, NH or S (O) mReplacement and wherein said alkynyl are optional independently by 1 or 2 oxo group, pyrrolidinyl, pyrrole radicals, one or more optional C that is replaced by one or more halogen atom 1-4Alkyl, nitrile, morpholino, piperidyl, piperazinyl, imidazole radicals, phenyl, pyridine radicals, tetrazole radical, or the optional list that is replaced by one or more halogen atom-or two (C 1-3Alkyl) the amino replacement;
Each R 2, R 4And R 5For
Optional part or complete halogenated C 1-6Branched-chain or straight-chain alkyl, acetyl group, aroyl, C 1-4Side chain or straight chain alkoxyl, each group optional part or halogenated fully, halogen, nitrile, methoxycarbonyl, optional part or complete halogenated C 1-3Alkyl-S (O) m, or phenyl sulfonyl; C 1-6Alkoxyl, hydroxyl, amino, or single-or two-(C 1-4Alkyl) amino, nitrile, halogen; OR 6
Nitro; Or
Optional part or complete halogenated list-or two-(C 1-4Alkyl) amino-S (O) 2, or H 2NSO 2Each R 3Be independently:
Phenyl, naphthyl, morpholinyl, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, pyrrolidinyl, imidazole radicals, pyrazolyl, thiazolyl oxazolyl, triazolyl, tetrazole radical, thienyl, furyl, tetrahydrofuran base isoxazolyl, isothiazolyl, quinolyl, isoquinolyl, indyl, benzimidazolyl, benzofuranyl benzoxazolyl, the benzoisoxazole base, the benzopyrazoles base, the benzo thiapyran base, cinnolinyl, pteridyl, phthalazinyl, the naphthyl pyridine radicals, quinoxalinyl, quinazolyl, purine radicals or indazolyl, aforementioned each group is optional to be replaced by 1～3 substituent group that is selected from the following groups: phenyl, naphthyl, as foregoing heterocycle or heteroaryl in this section, optional part or complete halogenated C 1-6Branched-chain or straight-chain alkyl, cyclopropane base, Tetramethylene. base, Pentamethylene. base, cyclohexyl, cycloheptane base, bicyclo-pentyl, bicyclohexane base, bicycloheptane base, phenyl C 1-5Alkyl, naphthyl C 1-5Alkyl, halogen, hydroxyl, oxo, nitrile, optional part or complete halogenated C 1-3Noted earlier in the wherein said heterocyclic radical of alkoxyl, phenoxy group, naphthoxy, heteroaryloxy or heterocyclic oxy group or heteroaryl moieties such as this section, nitro, amino, list-or two-(C 1-3Alkyl) noted earlier, NH in amino, phenyl amino, naphthyl amino, heteroaryl or the wherein said heteroaryl heterocyclic moiety of heterocyclic amino group such as this section 2C (O), single-or two-(C 1-3Alkyl) amino carbonyl, C 1-5Alkyl-C (O)-C 1-4Alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3Alkyl) amino-C 1-5Alkyl, amino-S (O) 2, two-(C 1-3Alkyl) amino-S (O) 2, R 7-C 1-5Alkyl, R 8-C 1-5Alkoxyl, R 9-C (O)-C 1-5Alkyl, R 10-C 1-5Alkyl (R 11) N, carboxyl-list-or two-(C 1-5Alkyl)-amino; Condensed aryl is selected from benzocyclobutane alkyl, indanyl, indenyl, dihydro naphthyl, tetralyl, benzocyclohepta alkyl and benzocyclohepta thiazolinyl; Or condensed heteroaryl, be selected from the cyclopenta pyridine base, hexamethylene and pyridine radicals, the cyclopentano pyrimidine radicals, hexamethylene and pyrimidine radicals, the cyclopentano pyrazinyl, hexamethylene and pyrazinyl, the cyclopentano pyridazinyl, hexamethylene and pyridazinyl, the cyclopentano quinolyl, hexamethylene and quinolyl, the cyclopentano isoquinolyl, hexamethylene and isoquinolyl, the cyclopentano indyl, hexamethylene diindyl base, the cyclopentano benzimidazolyl, hexamethylene and benzimidazolyl, the cyclopentano benzoxazolyl, hexamethylene and benzoxazolyl, the cyclopentano imidazole radicals, hexamethylene and imidazole radicals, cyclopentano thienyl and hexamethylene bithiophene base; Wherein said fused-aryl or condensed heteroaryl ring replace for the substituent group that is selected from the following groups by 0～3 independently: phenyl, naphthyl, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, optional part or complete halogenated C 1-6Alkyl, halogen, nitrile, optional part or complete halogenated C 1-3Noted earlier in the wherein said heteroaryl of alkoxyl, phenoxy group, naphthoxy, heteroaryloxy or heterocyclic oxy group or heterocyclic moiety such as this section, nitro, amino, list-or two-(C 1-3Alkyl) noted earlier, NH in amino, phenyl amino, naphthyl amino, heteroaryl or the wherein said heteroaryl of heterocyclic amino group or heterocyclic moiety such as this section 2C (O), single-or two-(C 1-3Alkyl) amino carbonyl, C 1-4Alkyl-OC (O), C 1-5Alkyl-C (O)-C 1-4Alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3) alkyl amino-C 1-5Alkyl, R 12-C 1-5Alkyl, R 13-C 1-5Alkoxyl, R 14-C (O)-C 1-5Alkyl or R 15-C 1-5Alkyl (R 16) N;
Cyclopropane base, Tetramethylene. base, Pentamethylene. base, cyclohexyl, cycloheptane base, bicyclo-pentyl, bicyclohexane base or bicycloheptane base, each group optional part or complete halo are also optional by 1～3 C 1-3Alkyl replaces, or wherein 1～3 ring methylene independently by O, S, CHOH,＞C=O,＞C=S or the similar group of the alternate described cycloalkyl of NH;
Cyclopentenyl, cyclohexenyl group, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyl groups or bicycloheptene base, each group is optional by 1～3 C 1-3Alkyl replaces;
C 1-4Alkyl-phenyl-C (O)-C 1-4Alkyl-, C 1-4Alkyl-C (O)-C 1-4Alkyl-or C 1-4Alkyl-phenyl-S (O) m-C 1-4Alkyl-;
C 1-6Alkyl or C 1-6Side chain or straight chain alkoxyl, each group optional part or fully halogenated or optional by R 17Replace;
OR 18Or it is optional by OR 18The C that replaces 1-6Alkyl;
Optional by R 19Amino or the list that replaces-or two-(C 1-5Alkyl) amino;
R 20C (O) N (R 21)-, R 22O-or R 23R 24NC (O)-; R 26(CH 2) mC (O) N (R 21)-or R 26C (O) (CH 2) mN (R 21)-;
By R 23R 24The C of NC (O)-replacement 2-6Alkenyl;
C 2-6Alkynyl side chain or straight chain carbochain, optional part or halogenated fully, wherein one or more methylene is optional by O, NH, S (O) mReplacement and wherein said alkynyl are optional independently by 1 or 2 oxo group, pyrrolidinyl, pyrrole radicals, morpholinyl, piperidyl, piperazinyl, imidazole radicals, phenyl, pyridine radicals, tetrazole radical, one or more optional C that is replaced by one or more halogen atom 1-4Alkyl, nitrile, morpholino, piperidyl, piperazinyl, imidazole radicals, phenyl, pyridine radicals, tetrazole radical, or the optional list that is replaced by one or more halogen atom-or two (C 1-4Alkyl) the amino replacement; Or
Aroyl;
R 6For: optional part or complete halogenated C 1-4Alkyl and optional by R 26Replace;
Each R 7, R 8, R 9, R 10, R 12, R 13, R 14, R 15, R 17, R 19, R 25And R 26Be independently: nitrile, phenyl, morpholino, piperidyl, piperazinyl, imidazole radicals, pyridine radicals, tetrazole radical, amino or optional part or complete halogenated list-or two-(C 1-4Alkyl) amino;
Each R 11And R 16Be independently: hydrogen or optional part or complete halogenated C 1-4Alkyl;
R 18Be independently: hydrogen or optional independently by oxo or R 25The C that replaces 1-4Alkyl;
R 20Be independently: optional part or complete halogenated C 1-10Alkyl, phenyl or pyridine radicals;
R 21Be independently: hydrogen or optional part or complete halogenated C 1-3Alkyl;
Each R 22, R 23And R 24Be independently:
Hydrogen, optional part or complete halogenated C 1-6Alkyl, described C 1-6Alkyl is randomly interrupted described C by one or more O, N or S 1-6The also optional independently coverlet of alkyl-or two-(C 1-3Alkyl) amino carbonyl, phenyl, pyridine radicals, amino or single-or two-(C 1-4Alkyl) the amino replacement, each group optional part or complete halo and optional coverlet-or two-(C 1-3Alkyl) the amino replacement;
Or R 23And R 24Randomly form heterocyclic radical or heteroaryl ring together;
M=0,1 or 2;
W be O or S and
Its pharmaceutically acceptable derivant.
12. according to the purposes of claim 4, wherein the p38 inhibitors of kinases is a formula 7Chemical compound
Wherein:
E is a carbon or be selected from-O-,-NH-and-hetero atom of S-;
G is:
The C of fragrance 6-10The saturated or unsaturated C of carbocyclic ring or non-fragrance 3-10Carbocyclic ring;
The monocyclic, bicyclic or tricyclic heteroaryl of 6-14 person comprises 1 or the hetero atom of more a plurality of O of being selected from, N and S;
6-8 person's monocyclic heterocycles comprises the hetero atom that one or more is selected from O, N and S;
Or
8-11 person's bicyclic heterocycles comprises the hetero atom that one or more is selected from O, N and S;
Wherein G is optional by one or more R 1, R 2Or R 3Replace;
Ar is: phenyl, naphthyl, quinolyl, isoquinolyl, tetralyl, tetrahydric quinoline group, tetrahydro isoquinolyl, benzimidazolyl, benzofuranyl, dihydro benzo furyl, indolinyl, benzothienyl, dihydrobenzo thienyl, indanyl, indenyl or indyl, each group is optional by one or more R 4Or R 5Replace;
X is:
C 5-8Cycloalkyl or cycloalkenyl group, optional by 1 or 2 oxo group or 1～3 C 1-4Alkyl, C 1-4Alkoxyl or C 1-4The alkyl amino chain replaces, and each group is side chain or straight chain;
Aryl, furyl, thienyl, pyrrole radicals, pyrazolyl, imidazole radicals, pyridine radicals, pyrimidine radicals, pyriconyl, dihydropyridine ketone group, dimaleoyl imino, dihydro dimaleoyl imino, piperidyl, benzimidazole, 3H-imidazo [4,5-b] pyridine, piperazinyl, pyridazinyl or pyrazinyl; Each group is optional independently by 1～3 C 1-4Alkyl, C 1-4Alkoxyl, hydroxyl, nitrile, amino, list-or two-(C 1-3Alkyl) amino, single-or two-(C 1-3Alkyl amino) carbonyl, NH 2C (O), C 1-6Alkyl-S (O) mOr halogen replaces;
Y is:
Chemical bond or optional part or complete halogenated C 1-4Saturated or unsaturated side chain or straight chain carbochain, wherein one or more C atom is optional by O, N or S (O) mReplace and wherein Y is optional independently by 1 or 2 oxo group, nitrile, phenyl or 1 or a plurality of optional C that is replaced by one or more halogen atom 1-4Alkyl replaces;
Z is:
Aryl; heteroaryl; be selected from pyridine radicals; piperazinyl; pyrimidine radicals; pyridazinyl; pyrazinyl; imidazole radicals; pyrazolyl; triazolyl; tetrazole radical; furyl; thienyl and pyranose; heterocycle; be selected from the tetrahydropyrimidine ketone group; the hexamethylene ketone group; the hexamethylene acyl group; the 2-oxa--or 2-thia-5-aza-bicyclo [2.2.1] heptane base; the pentamethylene sulfenyl; the pentamethylene sulfoxide group; the pentamethylene sulfonyl; the tetramethylene sulfenyl; tetramethylene sulfoxide base or tetramethylene sulfonyl; THP trtrahydropyranyl; tetrahydrofuran base; 1; 3-dioxo Ketocyclopentane base; 1; 3-dioxanone base; 1; the 4-dioxacyclohexyl; morpholino; tetrahydro-1,4-thiazine generation; tetrahydro-1,4-thiazine is for sulfoxide group; tetrahydro-1,4-thiazine is for sulfonyl; piperidyl; piperidone base; pyrrolidinyl and dioxo cyclopenta, aforementioned each Z group is optional to be replaced by 1～3 substituent group that is selected from the following radicals: halogen; C 1-6Alkyl, C 1-6Alkoxyl, C 1-3Alkoxy-C 1-3Alkyl, C 1-6Alkoxy carbonyl, aroyl, C 1-3Acyl group, oxo, hydroxyl, pyridine radicals-C 1-3Alkyl, imidazole radicals-C 1-3Alkyl, tetrahydrofuran base-C 1-3Alkyl, nitrile-C 1-3Alkyl, nitrile, carboxyl, phenyl, wherein benzyl ring is optional by 1～2 halogen, C 1-6Alkoxyl, hydroxyl or list-or two-(C 1-3Alkyl) amino, C 1-6Alkyl-S (O) mOr phenyl-S (O) mReplace, wherein benzyl ring is optional by 1～2 halogen, C 1-6Alkoxyl, hydroxyl, halogen or list-or two-(C 1-3Alkyl) the amino replacement;
Or Z is optional by 1～3 amino or amino-C 1-3Alkyl replaces, and wherein the N atom is optional independently by amino C 1-6Alkyl, C 1-3Alkyl, aryl C 0-3Alkyl, C 1-5Alkoxy C 1-3Alkyl, C 1-5Alkoxyl, aroyl, C 1-3Acyl group, C 1-3Alkyl-S (O) m-or aryl C 0-3Alkyl-S (O) m-single-or two-replace, it is optional by 1～2 halogen, C to be connected to amino aforementioned each alkyl and aryl 1-6Alkyl or C 1-6Alkoxyl replaces;
Or Z is optional by 1～3 as foregoing aryl, heterocycle or heteroaryl replacement in this section, and each group is chosen wantonly conversely by halogen, C 1-6Alkyl or C 1-6Alkoxyl replaces;
Or Z is hydroxyl, halogen, nitrile, amino, and wherein the N atom is optional independently by C 1-3Acyl group, C 1-6Alkyl or C 1-3Alkoxy C 1-3Alkyl, side chain or straight chain C 1-6Alkyl, C 1-6Alkoxyl, C 1-3Acyl amino, nitrile C 1-4Alkyl, C 1-6Alkyl-S (O) mAnd phenyl-S (O) mSingle-or two-replace, wherein benzyl ring is optional by 1～2 halogen, C 1-6Alkoxyl, hydroxyl or list-or two-(C 1-3Alkyl) the amino replacement;
Each R 1Be independently:
Optional part or complete halogenated side chain or straight chain C 1-10Alkyl, wherein one or more C atom is randomly independently by O, N or S (O) mSubstitute, and wherein said C 1-10Alkyl is optional by 1～3 C 3-10Cycloalkyl, hydroxyl, oxo, phenyl, naphthyl, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, pyrrolidinyl, imidazole radicals, pyrazolyl, thienyl, furyl, dioxo Pentamethylene. base, isoxazolyl or isothiazolyl replace; Aforementioned each group is optional to be replaced by 1～5 substituent group that is selected from the following groups: halogen, optional part or complete halogenated C 1-6Alkyl, C 3-8Cycloalkyl, C 5-8Cycloalkenyl group, hydroxyl, nitrile, optional part or complete halogenated C 1-3Alkoxyl or NH 2C (O), single-or two (C 1-3Alkyl) amino and singly-or two (C 1-3Alkyl) amino carbonyl;
Or R 1For
Ring propoxyl group, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy or suberyl oxygen base, each group optional part or complete halo are also optional by 1～3 optional part or complete halogenated C 1-3Alkyl, nitrile, hydroxyl C 1-3Alkyl or aryl replaces; Or wherein 1～3 the ring methylene independently by O, S (O) m, CHOH,＞C=O,＞the similar group of C=S or the alternate described cycloalkyl of NH;
Phenoxy group or benzyloxy, each group optional part or complete halo are also optional by 1～3 optional part or complete halogenated C 1-3Alkyl, nitrile, hydroxyl C 1-3Alkyl or aryl replaces; Or wherein 1～2 the ring methine independently by the similar group of the alternate described cyclophane base of N; Cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, bicyclo-pentyl, bicyclohexane base or bicycloheptane base, each group optional part or complete halo are also optional by 1～3 optional part or complete halogenated C 1-3Alkyl, nitrile, hydroxyl C 1-3Alkyl or aryl replaces; Or wherein 1～3 the ring methylene independently by O, S (O) m, CHOH,＞C=O,＞the similar group of C=S or the alternate described cycloalkyl of NH;
C 3-10Side chain or straight alkenyl, each group optional part or complete halo are also optional to be replaced by 1～3 substituent group that is selected from the following groups: C 1-5Branched-chain or straight-chain alkyl, phenyl, naphthyl, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl, aforementioned each group is replaced by 1～5 substituent group that is selected from the following groups: halogen, optional part or complete halogenated C 1-6Alkyl, cyclopropane base, Tetramethylene. base, Pentamethylene. base, cyclohexyl, cycloheptane base, bicyclo-pentyl, bicyclohexane base and bicycloheptane base, hydroxyl, nitrile, optional part or complete halogenated C 1-3Alkoxyl, NH 2C (O), single-or two (C 1-3Alkyl) amino carbonyl; Randomly be selected from O, N and S (O) by one or more mThe C that interrupts of hetero atom 3-10Side chain or straight alkenyl; Cyclopentenyl, cyclohexenyl group, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyl groups or bicycloheptene base, wherein said cycloalkenyl group are randomly by 1～3 C 1-3Alkyl replaces;
Oxo, nitrile, halogen;
Silicyl comprises 3 optional parts or complete halogenated C 1-4Alkyl; Or optional part or complete halogenated C 3-6Alkynyl side chain or straight chain carbochain, wherein one or more methylene is optional by O, NH or S (O) mReplace and the optional substituent group that is selected from independently in the following groups of wherein said alkynyl replaces: 1 or 2 oxo group, hydroxyl, pyrrolidinyl, pyrrole radicals, THP trtrahydropyranyl, one or more optional C that is replaced by one or more halogen atom 1-4Alkyl, nitrile, morpholino, piperidyl, piperazinyl, imidazole radicals, phenyl, pyridine radicals, tetrazole radical or the optional list that is replaced by one or more halogen atom-or two (C 1-3Alkyl) amino;
Each R 2, R 4And R 5For
Optional part or complete halogenated C 1-6Branched-chain or straight-chain alkyl, C 1-6Acyl group, aroyl, C 1-4Side chain or straight chain alkoxyl, each group optional part or halogenated fully, halogen, methoxycarbonyl, optional part or complete halogenated C 1-3Alkyl-S (O) mOr phenyl-S (O) mOR 6, C 1-6Alkoxyl, hydroxyl, nitrile, nitro, halogen;
Or amino-S (O) m-, wherein the N atom is optional independently by C 1-6Alkyl or aryl C 0-3Alkyl list-or two-replace, or amino wherein the N atom is optional independently by C 1-3Alkyl, aryl C 0-3Alkyl, C 1-6Acyl group, C 1-6Alkyl-S (O) m-or aryl C 0-3Alkyl-S (O) m-be single-or two-replace aforementioned each alkyl and aryl optional part or halo and choosing wantonly fully in this section by 1～2 C 1-6Alkyl or C 1-6Alkoxyl replaces;
Each R 3Be independently:
Phenyl, naphthyl, morpholino, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, pyrrolidinyl, imidazole radicals, pyrazolyl, thiazolyl oxazolyl, [1,3,4] oxadiazoles, triazolyl, tetrazole radical, thienyl, furyl, tetrahydrofuran base isoxazolyl, isothiazolyl, quinolyl, isoquinolyl, indyl, benzimidazolyl, benzofuranyl benzoxazolyl, the benzoisoxazole base, the benzopyrazoles base, the benzo thiapyran base, cinnolinyl, pteridyl, phthalazinyl, the naphthyl pyridine radicals, quinoxalinyl, quinazolyl, purine radicals or indazolyl, aforementioned each group is optional to be replaced by 1～3 substituent group that is selected from the following groups: phenyl, naphthyl, as foregoing heterocycle or heteroaryl in this section, optional part or complete halogenated C 1-6Branched-chain or straight-chain alkyl, cyclopropane base, Tetramethylene. base, Pentamethylene. base, cyclohexyl, cycloheptane base, bicyclo-pentyl, bicyclohexane base, bicycloheptane base, phenyl C 1-5Alkyl, naphthyl C 1-5Alkyl, halogen, hydroxyl, oxo, nitrile, optional part or complete halogenated C 1-3Noted earlier in the wherein said heterocyclic radical of alkoxyl, phenoxy group, naphthoxy, heteroaryloxy or heterocyclic oxy group or heteroaryl moieties such as this section, nitro, amino, list-or two-(C 1-3Alkyl) noted earlier, NH in amino, phenyl amino, naphthyl amino, heteroaryl or the wherein said heteroaryl heterocyclic moiety of heterocyclic amino group such as this section 2C (O), single-or two-(C 1-3Alkyl) amino carbonyl, C 1-5Alkyl-C (O)-C 1-4Alkyl, amino-C 1-5Alkyl, list-or two-(C 1-5Alkyl) amino, single-or two-(C 1-3Alkyl) amino-C 1-5Alkyl, amino-S (O) 2, two-(C 1-3Alkyl) amino-S (O) 2, R 7-C 1-5Alkyl, R 8-C 1-5Alkoxyl, R 9-C (O)-C 1-5Alkyl, R 10-C 1-5Alkyl (R 11) N, carboxyl-list-or two-(C 1-5Alkyl)-amino;
Condensed aryl, be selected from the benzocyclobutane alkyl, indanyl, indenyl, the dihydro naphthyl, tetralyl, benzocyclohepta alkyl and benzocyclohepta thiazolinyl, or condensed heteroaryl is selected from the cyclopenta pyridine base, hexamethylene and pyridine radicals, the cyclopentano pyrimidine radicals, hexamethylene and pyrimidine radicals, the cyclopentano pyrazinyl, hexamethylene and pyrazinyl, the cyclopentano pyridazinyl, hexamethylene and pyridazinyl, the cyclopentano quinolyl, hexamethylene and quinolyl, the cyclopentano isoquinolyl, hexamethylene and isoquinolyl, the cyclopentano indyl, hexamethylene diindyl base, the cyclopentano benzimidazolyl, hexamethylene and benzimidazolyl, the cyclopentano benzoxazolyl, hexamethylene and benzoxazolyl, the cyclopentano imidazole radicals, hexamethylene and imidazole radicals, cyclopentano thienyl and hexamethylene bithiophene base; Wherein said fused-aryl or condensed heteroaryl ring replace for the substituent group that is selected from the following groups by 0～3 independently: phenyl, naphthyl, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, optional part or complete halogenated C 1-6Alkyl, halogen, nitrile, optional part or complete halogenated C 1-3Noted earlier in the wherein said heteroaryl of alkoxyl, phenoxy group, naphthoxy, heteroaryloxy or heterocyclic oxy group or heterocyclic moiety such as this section, nitro, amino, list-or two-(C 1-3Alkyl) noted earlier, NH in amino, phenyl amino, naphthyl amino, heteroaryl or the wherein said heteroaryl of heterocyclic amino group or heterocyclic moiety such as this section 2C (O), single-or two-(C 1-3Alkyl) amino carbonyl, C 1-4Alkyl-OC (O), C 1-5Alkyl-C (O)-C 1-4Alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3) alkyl amino-C 1-5Alkyl, R 12-C 1-5Alkyl, R 13-C 1-5Alkoxyl, R 14-C (O)-C 1-5Alkyl or R 15-C 1-5Alkyl (R 16) N;
Cyclopropane base, Tetramethylene. base, Pentamethylene. base, cyclohexyl, cycloheptane base, bicyclo-pentyl, bicyclohexane base or bicycloheptane base, each group are randomly for partially or completely halogenated and optional by 1～3 C 1-3Alkyl replaces, or wherein 1～3 ring methylene independently by O, S, CHOH,＞C=O,＞the similar group of C=S or the alternate described cycloalkyl of NH; Cyclopentenyl, cyclohexenyl group, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyl groups or bicycloheptene base, each is optional by 1～3 C 1-3Alkyl replaces;
C 1-4Alkyl-phenyl-C (O)-C 1-4Alkyl-, C 1-4Alkyl-C (O)-C 1-4Alkyl-or C 1-4Alkyl-phenyl-S (O) m-C 1-4Alkyl-;
C 1-6Alkyl or C 1-6Side chain or straight chain alkoxyl, each group optional part or fully halogenated or optional by R 17Replace;
OR 18Or it is optional by OR 18The C that replaces 1-6Alkyl;
Optional by R 19Amino or the list that replaces-or two-(C 1-5Alkyl) amino;
R 20C (O) N (R 21)-, R 22O-or R 23R 24NC (O)-; R 26(CH 2) mC (O) N (R 21)-, R 23R 24NC (O)-C 1-3Alkoxyl or R 26C (O) (CH 2) mN (R 21)-;
By R 23R 24The C of NC (O)-replacement 2-6Alkenyl;
C 2-6Alkynyl side chain or straight chain carbochain, optional part or halogenated fully, wherein one or more methylene is optional by O, NH, S (O) mReplacement and wherein said alkynyl are optional independently by 1 or 2 oxo group, pyrrolidinyl, pyrrole radicals, morpholino, piperidyl, piperazinyl, imidazole radicals, phenyl, pyridine radicals, tetrazole radical, one or more optional C that is replaced by one or more halogen atom 1-4Alkyl, nitrile, morpholino, piperidyl, piperazinyl, imidazole radicals, phenyl, pyridine radicals, tetrazole radical, or the optional list that is replaced by one or more halogen atom-or two (C 1-4Alkyl) the amino replacement;
C 1-6Acyl group or aroyl;
R 6For: optional part or complete halogenated C 1-4Alkyl is also optional by R 26Replace;
Each R 7, R 8, R 9, R 10, R 12, R 13, R 14, R 15, R 17, R 19, R 25And R 26Be independently: nitrile, phenyl, morpholino, piperidyl, piperazinyl, imidazole radicals, pyridine radicals, tetrazole radical, amino or optional part or complete halogenated list-or two-(C 1-4Alkyl) amino;
Each R 11And R 16Be independently: hydrogen or optional part or complete halogenated C 1-4Alkyl;
R 18Be independently: hydrogen or optional independently by oxo or R 25The C that replaces 1-4Alkyl;
R 20Be independently: optional part or complete halogenated C 1-10Alkyl, phenyl or pyridine radicals;
R 21Be independently: hydrogen or optional part or complete halogenated C 1-3Alkyl;
Each R 22, R 23And R 24Be independently: hydrogen, optional part or complete halogenated C 1-6Alkyl, described C 1-6Alkyl is randomly interrupted described C by one or more O, N or S 1-6The also optional independently coverlet of alkyl-or two-(C 1-3Alkyl) amino carbonyl, phenyl, pyridine radicals, amino or single-or two-(C 1-4Alkyl) the amino replacement, each group optional part or complete halo and optional coverlet-or two-(C 1-3Alkyl) the amino replacement;
Or R 23And R 24Randomly form heterocyclic radical or heteroaryl ring together;
M=0,1 or 2;
W be O or S and
Its pharmaceutically acceptable derivant.
13. the pharmaceutical preparation that is suitable for sucking comprises at least a p38 inhibitors of kinases that is used for the treatment of Polyblennia treatment effective dose.
14. according to the pharmaceutical composition of claim 13, wherein single-dose is equivalent to the p38 kinase inhibition agent dose of 100～10000 μ g.
15. according to the pharmaceutical composition of claim 13 or 14, wherein it is to be selected from can suck powder, comprise the metered aerosol of propellant and not have the sucked solution of propellant or the preparation of suspension.
16. according to claim 13,14 or 15 pharmaceutical composition, wherein it is for can suck powder, described powder comprises the p38 inhibitors of kinases and suitable physiology can be accepted excipient, described excipient is selected from monosaccharide, disaccharide, widow-and polysaccharide, polyhydric alcohol, salt, or these excipient and the mixture of another.
17. according to the sucked powder of claim 16, the maximum mean diameter of excipient 250 μ m at the most wherein are preferably between 10 and 150 μ m.
18. comprise capsule according to the sucked powder of claim 16 or 17.
19. according to the pharmaceutical composition of claim 15, wherein it is for only comprising the sucked powder of p38 inhibitors of kinases as its composition.
20. according to the pharmaceutical composition of claim 15, wherein it is the sucked solution of no propellant or suspension, comprises water, ethanol or water and alcoholic acid mixture as solvent.
21. according to each pharmaceutical composition in the claim 13～20, wherein the p38 inhibitors of kinases is selected from US patent 5,716,972, US 5,686,455, US 5,656,644, US 5,593,992, US 5,593,991, US 5,663,334, US 5,670,527, US 5,559,137,5,658,903, US5,739,143, US 5,756,499, US 6,277,989, US 6,340,685 and US 5,716,955 and PCT application WO 92/12154, WO 94/19350, WO 95/09853, WO 95/09851, WO95/09847, WO 95/09852, WO 97/25048, WO 97/25047, WO 97/33883, WO97/35856, WO 97/35855, WO 97/36587, WO 97/47618, WO 97/16442, WO97/16441, WO 97/12876, WO 98/25619, WO 98/06715, WO 98/07425, WO98/28292, WO 98/56377, WO 98/07966, WO 98/56377, WO 98/22109, WO98/24782, WO 98/24780, WO 98/22457, WO 98/52558, WO 98/52559, WO98/52941, WO 98/52937, WO 98/52940, WO 98/56788, WO 98/27098, WO98/47892, WO 98/47899, WO 98/50356, WO 98/32733, WO 99/58523, WO99/01452, WO 99/01131, WO 99/01130, WO 99/01136, WO 99/17776, WO99/32121, WO 99/58502, WO 99/58523, WO 99/57101, WO 99/61426, WO99/59960, WO 99/59959, WO 99/00357, WO 99/03837, WO 99/01441, WO99/01449, WO 99/03484, WO 99/15164, WO 99/32110, WO 99/32111, WO99/32463, WO 99/64400, WO 99/43680, WO 99/17204, WO 99/25717, WO99/50238, WO 99/61437, WO 99/61440, WO 00/26209, WO 00/18738, WO00/17175, WO 00/20402, WO 00/01688, WO 00/07980, WO 00/07991, WO00/06563, WO 00/12074, WO 00/12497, WO 00/31072, WO 00/31063, WO00/23072, WO 00/31065, WO 00/35911, WO 00/39116, WO 00/43384, WO00/41698, WO 00/69848, WO 00/26209, WO 00/63204, WO 00/07985, WO00/59904, WO 00/71535, WO 00/10563, WO 00/25791, WO 00/55152, WO00/55139, WO 00/17204, WO 00/36096, WO 00/55120, WO 00/55153, WO00/56738, WO 01/21591, WO 01/29041, WO 01/29042, WO 01/62731, WO01/05744, WO 01/05745, WO 01/05746, WO 01/05749, WO 01/05751, WO01/27315, WO 01/42189, WO 01/00208, WO 01/42241, WO 01/34605, WO01/47897, WO 01/64676, WO 01/37837, WO 01/38312, WO 01/38313, WO01/36403, WO 01/38314, WO 01/47921, WO 01/27089, disclosed chemical compound among DE 19842833 and the JP2000 86657.
22. pharmaceutical composition according to claim 21, wherein the p38 inhibitors of kinases is selected from US6,277,989, US 6,340,685, WO 00/12074, WO 00/12497, WO 00/59904, WO00/71535, WO 01/64676, WO 99/61426, WO 00/10563, WO 00/25791, WO01/37837, WO 01/38312, WO 01/38313, WO 01/38314, WO 01/47921, WO99/61437, WO 99/61440, WO 00/17175, WO 00/17204, WO 00/36096, WO98/27098, WO 99/00357, WO 99/58502, WO 99/64400, WO 99/01131, WO00/43384, WO 00/55152, disclosed chemical compound among WO 00/55139 and the WO 01/36403.
23. according to the pharmaceutical composition of claim 22, wherein the p38 inhibitors of kinases is a formula 1Chemical compound
Figure A038129880033C1
R wherein 1, R 2And R 4Has implication given in the claim 5.
24. according to the pharmaceutical composition of claim 22, wherein the p38 inhibitors of kinases is a formula 2Chemical compound
Figure A038129880033C2
R wherein 1, R 2, Ar, m, n and l have implication given in the claim 6.
25. according to the pharmaceutical composition of claim 22, wherein the p38 inhibitors of kinases is a formula 3a, 3b, 3cOr 3dChemical compound
Figure A038129880034C1
Or
Figure A038129880034C3
R wherein 1, R 2, R 3, Z 1And Z 2Has implication given in the claim 7.
26. according to the pharmaceutical composition of claim 22, wherein the p38 inhibitors of kinases is a formula 4Chemical compound
Ar wherein 1, Ar 2, X, L and Q have implication given in the claim 8.
27. according to the pharmaceutical composition of claim 22, wherein the p38 inhibitors of kinases is a formula 5Chemical compound
Figure A038129880034C5
Ar wherein 1, Ar 2, W, X, Y and Z have implication given in the claim 9.
28. according to the pharmaceutical composition of claim 22, wherein the p38 inhibitors of kinases is a formula 5aChemical compound
Figure A038129880034C6
Ar wherein 1, Ar 2, W, X, Y and Z have implication given in the claim 10.
29. according to the pharmaceutical composition of claim 22, wherein the p38 inhibitors of kinases is a formula 6Chemical compound
Wherein Ar, W, G, X, Y and Z have implication given in the claim 11.
30. according to the pharmaceutical composition of claim 22, wherein the p38 inhibitors of kinases is a formula 7Chemical compound
Wherein Ar, W, G, E, X, Y and Z have implication given in the claim 12.
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