CN1934107A

CN1934107A - 2-(3-substituted-aryl)amino-4-aryl-thiazoles as tyrosine kinase inhibitors

Info

Publication number: CN1934107A
Application number: CNA2005800081898A
Authority: CN
Inventors: A·穆西; M·丘福利尼; C·韦穆特; B·吉茨莱
Original assignee: AB Science SA
Current assignee: AB Science SA
Priority date: 2004-01-30
Filing date: 2005-01-28
Publication date: 2007-03-21
Also published as: JP2007519711A; WO2005073225A1; NO20063861L; AU2005209485A1; BRPI0507271A; EP1711497A1; NZ548884A; KR20060129413A; IL177007A0; ZA200606152B; CA2554925A1

Abstract

The present invention relates to novel compounds selected from 2-(3substitutedaryl)amino-4-aryl-thiazoles that selectively modulate, regulate, and/or inhibit signal transduction mediated by certain native and/or mutant tyrosine kinases implicated in a variety of human and animal diseases such as cell proliferative, metabolic, allergic, and degenerative disorders. More particularly, these compounds are potent and selective c-kit inhibitors.

Description

2-(3-substituted aryl) amino-4-aryl-thiazole as tyrosine kinase inhibitor

The present invention relates to be selected from the compounds of 2-(3-substituted aryl) amino-4-aryl-thiazole, this compound selective modulation, adjusting and/or the signal conduction that inhibition is natural by some and/or mutant is tyrosine kinase mediated, this kinases relates to various human and animal's diseases such as hyperplasia, metabolism, allergy and sex change illness.Especially, these compounds are c-test kit inhibitor effectively and optionally.

Tyrosylprotein kinase is acceptor type or non-acceptor type protein, and it transfers to proteinic tyrosine residues with the terminal phosphate salt of ATP, therefore activation or deactivation of signal pathway.Known these protein relate to many celelular mechanisms, and it causes illness such as abnormal cell proliferation and migration and inflammation under the disruptive situation.

To today, there are about 58 kinds of known receptor tyrosine kinases.Other Tyrosylprotein kinase is known vegf receptor (people such as Kim, Nature 362, pp.841-844,1993), pdgf receptor, c-test kit and FLK family.These acceptors can be transmitted to signal other Tyrosylprotein kinase, comprise Src, Raf, Frk, Btk, Csk, Abl, Fes/Fps, Fak, Jak, Ack etc.

In tyrosine kinase receptor, the c-test kit causes particular interest.In fact, the c-test kit is the key receptor of activation mastocyte, prove that it directly or indirectly relates to many pathology, WO 03/004007, WO 03/004006, WO03/003006, WO03/003004, WO 03/002114, WO 03/002109 have been submitted to about this respect applicant, WO03/002108, WO03/002107, WO03/002106, WO 03/002105, WO03/039550, WO 03/035050, WO03/035049, US60/359,652 and US60/359651.

Find that the mastocyte that exists in the patient tissue involves or cause the generation of disease, as autoimmune disease (rheumatoid arthritis, inflammatory bowel disease (IBD)) allergic disease, tumor vessel generation, inflammatory diseases and interstitial cystitis.In these diseases, show that mastocyte participates in disorganization by the mixture that discharges different proteolytic enzyme and medium such as histamine, neutral protease, lipid deutero-medium (prostaglandin(PG), thromboxan and leukotrienes) and various cytokine (IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, TNF-α, GM-CSF, MIP-la, MIP-lb, MIP-2 and IFN-γ).

C-test kit acceptor also can be by sudden change constitutively activate, cause manifesting of abnormal cell proliferation and disease such as mastocytosis and various cancers.

Therefore, target c-test kit causes these illnesss with minimizing mastocyte is proposed.

Therefore main purpose of the present invention is to find to suppress effectively and the optionally compound of wild-type and/or sudden change c-test kit.

Many different compounds have been described as tyrosine kinase inhibitor, for example two monocycles, dicyclo or heterocyclic aryl compound (WO 92/20642), (US 5 for vinylidene-7-azaindole derivatives (WO94/14808) and 1-cyclopropyl-4-pyridyl-quinolone, 330,992), (US 5 for compound of styryl, 217,999), (US 5 for the pyridinyl compounds of styryl replacement, 302,606), seleno indoles and selenide (WO 94/03427), three ring poly-hydroxy compounds (WO 92/21660) and benzylphosphonic acid compounds (WO 91/15495), pyrimidine derivatives (US 5,521,184 and WO99/03854), (US 5 for the dihydroindole ketone that dihydroindole ketone derivate and pyrroles replace, 792,783, EP934 931, US 5,834,504, US 5,883,116, US 5,883,113, US 5,886, and 020, WO96/40116 and WO 00/38519), and two monocycles, bicyclic aryl and heteroaryl compound (EP584222, US 5,656,643 and WO 92/20642), (EP 602851, and EP520 722, and US 3 for quinazoline derivant, 772,295 and US 4,343,940) and aryl and heteroaryl quinazoline (US5,721,237, US 5,714,493, US 5,710,158 and WO 95/15758).

Yet these compounds do not have effectively and the optionally inhibitor of a kind of c-of being described as test kit or c-test kit approach.

Compare with our the previous invention of describing in W02004014903, we find that the compound corresponding to 2-(3-aminoaryl) amino-4-aryl-thiazole is effectively and the optionally inhibitor of c-test kit or c-test kit approach.These compounds are good candidate of treatment disease such as autoimmune disorder, inflammatory diseases, cancer and mastocytosis.

We determine that now other 2-(3-substituted aryl) amino-4-aryl-thiazole derivative shows that the very intensive to several form c-test kits suppresses active.

Detailed Description Of The Invention

Therefore, the present invention relates to belong to the 2-(compound of 3-ketone group arylamino-4-aryl-thiazole.These compounds can selectivity suppress to relate to the signal conduction of tyrosine kinase phosphorylation c-test kit and its mutant forms.In the first embodiment, the object of the invention is the compound of general formula I, and it can represent free alkali form or its pharmaceutical salts of material:

General formula I

Wherein

R ⁶And R ⁷Be independently from each other following a kind of:

I) hydrogen, halogen (being selected from F, Cl, Br or I),

Ii) alkyl ¹Group, this group definition is to comprise 1-10 carbon atom or 2 or linearity, branching or the cycloalkyl of 3-10 carbon atom, (for example methyl, ethyl, propyl group, butyl, amyl group, hexyl ...) and randomly by one or more heteroatomss such as halogen (being selected from F, Cl, Br or I), oxygen and nitrogen (latter optional be the form of side basic nitrogen functional group); And trifluoromethyl, carboxyl, cyano group, nitro, formyl radical replace;

(iii) aryl ¹Group, phenyl or its replacement variant of this group definition for have one or more substituent arbitrary combination at any one ring position, this substituting group is

-halogen (being selected from I, F, Cl or Br);

-alkyl ¹Group;

-the cycloalkyl, aryl or the heteroaryl that randomly replace by side basic nitrogen functional group;

-trifluoromethyl, O-alkyl ¹, carboxyl, cyano group, nitro, formyl radical, hydroxyl, NH-alkyl ¹, N (alkyl ¹) (alkyl ¹) and amino, latter's nitrogen substituting group randomly is the form of basic nitrogen functional group;

(iv) heteroaryl ¹Group, this group definition is pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, pyrryl, furyl, oxazolyl, isoxazolyl, triazolyl, tetrazyl, indyl, benzoglyoxaline, quinolyl, they can have one or more substituent arbitrary combination in addition at any one ring position, and this substituting group is

-halogen (being selected from F, Cl, Br or I);

-alkyl ¹Group;

(v) trifluoromethyl, carboxyl, cyano group, nitro, formyl radical, hydroxyl, N (alkyl ¹) (alkyl ¹) and amino, latter's nitrogen substituting group randomly is the form of basic nitrogen functional group.

R ⁸Be one of following:

(i) hydrogen, or

The linearity or the branched-alkyl that (ii) comprise 1-10 carbon atom and randomly replace by one or more heteroatomss such as halogen (being selected from F, Cl, Br or I), oxygen and nitrogen, the latter randomly is the form of side basic nitrogen functional group, or

(iii) CO-R8 or COOR8 or CONHR8 or SO2R8, wherein R8 can be

-the linearity or the branched-alkyl that comprise 1-10 carbon atom and randomly replace by one or more heteroatomss such as halogen (being selected from F, Cl, Br or I), oxygen and nitrogen, the latter randomly is the form of side basic nitrogen functional group, or

-aryl replaces variant, comprises 1-10 carbon atom and randomly by the alkyl of one or more heteroatomss such as halogen (being selected from F, Cl, Br or I), oxygen and nitrogen replacement, the latter randomly is the form of side basic nitrogen functional group as the phenyl of the arbitrary combination that has one or more substituting groups such as halogen (being selected from F, Cl, Br or I) at any one ring position or its; And trifluoromethyl, C _1-6Alkoxyl group, carboxyl, cyano group, nitro, formyl radical, hydroxyl, C _1-6Alkylamino, two (C _1-6Alkyl) amino and amino, latter's nitrogen substituting group randomly is the form of side basic nitrogen functional group; And CO-R, COO-R, CONH-R, SO2-R and SO2NH-R, wherein R is linearity or the branched-alkyl that comprises 1-10 carbon atom and randomly replaced by at least one heteroatoms, particularly halogen (being selected from F, Cl, Br or I), oxygen and nitrogen, the latter randomly is the form of side basic nitrogen functional group, or

-heteroaryl such as pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, pyrryl, furyl oxazolyl isoxazolyl, triazolyl, tetrazyl, indyl, benzoglyoxaline, quinolyl, it can be in addition has one or more substituting groups such as halogen (is selected from F at any one ring position, Cl, Br or I) arbitrary combination, comprise 1-10 carbon atom and randomly (be selected from F by one or more heteroatomss such as halogen, Cl, Br or I), oxygen, with the alkyl that nitrogen replaces, the latter randomly is the form of side basic nitrogen functional group; And trifluoromethyl, C _1-6Alkoxyl group, carboxyl, cyano group, nitro, formyl radical, hydroxyl, C _1-6Alkylamino, two (C _1-6Alkyl) amino and amino, latter's nitrogen substituting group randomly is the form of side basic nitrogen functional group; And CO-R, COO-R, CONH-R, SO2-R and SO2NH-R, wherein R is linearity or the branched-alkyl that comprises 1-10 carbon atom and randomly replaced by at least one heteroatoms, particularly halogen (being selected from F, Cl, Br or I), oxygen and nitrogen, and the latter randomly is the form of side basic nitrogen functional group.

Each linearity or branched-alkyl that is independently selected from hydrogen, halogen (being selected from F, Cl, Br or I), comprises 1-10 carbon atom and randomly replace of R2, R3, R4 and R5 by one or more heteroatomss such as halogen (being selected from F, Cl, Br or I), oxygen and nitrogen, latter's formula randomly is the shape of side basic nitrogen functional group; And trifluoromethyl, C _1-6Alkoxyl group, amino, C _1-6Alkylamino, two (C _1-6Alkyl) amino, carboxyl, cyano group, nitro, formyl radical, hydroxyl; with CO-R, COO-R, CONH-R, SO2-R and SO2NH-R; wherein R is linearity or the branched-alkyl that comprises 1-10 carbon atom and randomly replaced by at least one heteroatoms, particularly halogen (being selected from F, Cl, Br or I), oxygen and nitrogen, and the latter randomly is the form of side basic nitrogen functional group.

A is: CH2, O, S, SO2, CO or COO,

B is key or NH, NCH3, NR ^*, (CH2) n (n is 0,1 or 2), O, S, SO2, CO or COO,

B ' is key or NH, NCH3, NR ^*, (CH2) n (n is 0,1 or 2), O, S, SO2, CO or COO,

R ^*It is alkyl ¹, aryl ¹Or heteroaryl ¹

W is key or is selected from following connector: NH, NHCO, NHCOO, NHCONH, NHSO2, NHSO2NH, CO, CONH, COO, COCH2, (CH2) n (n is 0,1 or 2), CH2-CO, CH2COO, CH2-NH, O, OCH2, S, SO2 or SO2NH.

R ¹Be:

A) halogen that comprises 1-10 carbon atom and randomly by at least one heteroatoms, particularly be selected from I, Cl, Br or F replaces and/or has the linearity or the branched-alkyl of side basic nitrogen functional group;

B) aryl that is randomly replaced by alkyl or heteroaryl or the halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replace or have the aryl of side basic nitrogen functional group

C) alkyl ¹, aryl ¹Or heteroaryl ¹

Be understandable that the C1-C10 alkyl comprises methyl, ethyl, propyl group and C2-C4 alkyl or C2-C10 alkyl.

For example, the subgroup of compound can corresponding to

Wherein R1, R4 and R6 have the meaning of above definition.

Be understandable that A-B-B ' includes but not limited to:

CH2, CH2-CO, CH2-CO-CH2, CH2COO, CH2-CH2-CO, CH2-CH2-COO, CH2-NH, CH2-CH2-NH, CH2-NH-CH2 or CH2-NH-CO or CH2-CO-NH

Be understandable that A-B-B ' also includes but not limited to:

CO-CH2, COO-CH2, CO-CH2-CH2, CO-NH or CO-NH-CH2 and O-CH2

Be understandable that also the NH among B or the B ' also can be NCH3.

In above general formula I, when W is not singly-bound, be understandable that A also can be NH or NCH3.

In above general formula, imagine following combination:

-R6 is (iv), and R4 is H or CH3, A-B-B ' be CO-NH and R1 as defined above.

-R6 is (iv), and R4 is H or CH3, A-B-B ' be CH2-CO-NH and R1 as defined above.

-R6 is (iv), and R4 is H or CH3, A-B-B ' be CH2-CO and R1 as defined above.

-R6 is (iv), and R4 is H or CH3, A-B-B ' be CH2-NH-CO and R1 as defined above.

-R6 is (iv), and R4 is H or CH3, A-B-B ' be CH2-NH and R1 as defined above.

-R6 is (iv), and R4 is H or CH3, A-B-B ' be CH2 and R1 as defined above.

-R6is W-(iv), R4 is the C1-C2 alkyl, A-B-B ' be CO-NH and R1 as defined above.

-R6 is (iv), and R4 is the C1-C2 alkyl, A-B-B ' be CH2-CO-NH and R1 as defined above.

-R6 is (iv), and R4 is the C1-C2 alkyl, A-B-B ' be CH2-CO and R1 as defined above.

-R6 is the pyridyl according to (iv), and R4 is the C1-C2 alkyl, A-B-B ' be CO-NH, CH2-CO-NH, CH2-CO, CH2-NH, CH2-NH-CO and R1 as defined above.

In above combination, R1 can be an alkyl ¹

In above combination, R1 can be an aryl ¹

In above combination, R1 can be a heteroaryl ¹

In a preferred embodiment, when ABB ' is CONH, the present invention relates to the compound of following general formula I-1:

Wherein R is H or organic group, and this organic group can for example be selected from and comprise 1-10 carbon atom randomly replaced or had side basic nitrogen functional group by at least one heteroatoms linearity or branched-alkyl; Cycloalkyl, aryl or the heteroaryl that is replaced by alkyl, cycloalkyl, aryl or heteroaryl randomly, wherein alkyl, cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has side basic nitrogen functional group.

In other embodiment preferred, the present invention relates to the acid amides-aniline compound of following general formula I-2:

Wherein R is H or organic group, and this organic group can for example be selected from and comprise 1-10 carbon atom randomly replaced or had side basic nitrogen functional group by at least one heteroatoms linearity or branched-alkyl; Randomly the halogen that by heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Or the cycloalkyl, aryl or the heteroaryl that randomly replace by cycloalkyl, aryl or heteroaryl, wherein substituting group cycloalkyl, aryl or heteroaryl randomly by:

-heteroatoms, the halogen that particularly is selected from I, Cl, Br or F replace and/or have the heteroaryl of side basic nitrogen functional group;

-SO2-R group, wherein R is alkyl, cycloalkyl, aryl or heteroaryl, its halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has side basic nitrogen functional group;

-CO-R or CO-NRR ' group, wherein R and R ' are independently selected from H, alkyl, cycloalkyl, aryl or heteroaryl, and its heteroatoms that randomly by at least one heteroatoms, particularly is selected from I, Cl, Br or F replaces, and/or has side basic nitrogen functional group.

R1 has in the specific compound of above-mentioned meaning therein, the present invention relates to acid amides-benzylamine compound of following general formula 1-3:

Wherein R is H or organic group, and this organic group can for example be selected from and comprise linearity or the branched-alkyl that halogen that 1-10 carbon atom randomly by at least one heteroatoms, particularly be selected from I, Cl, Br or F replaces and/or have side basic nitrogen functional group; Randomly the halogen that by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Or the alkyl, cycloalkyl, aryl or the heteroaryl that replace by alkyl, cycloalkyl, aryl or heteroaryl, wherein substituting group alkyl, cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has side basic nitrogen functional group;

-SO2-R group, wherein R is alkyl, cycloalkyl, aryl or the heteroaryl that the halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces or have side basic nitrogen functional group; Or-CO-R or-CO-NRR ' group, wherein R and R ' are independently selected from H or aryl, heteroaryl, alkyl or cycloalkyl, it randomly replaces and/or has side basic nitrogen functional group by at least one heteroatoms.

R1 has in the specific compound of above-mentioned meaning therein, the present invention relates to the acid amides-phenolic compound of following general formula I-4:

Wherein R is H or organic group, and this organic group can for example be selected from and comprise linearity or the branched-alkyl that halogen that 1-10 carbon atom randomly by at least one heteroatoms, particularly be selected from I, Cl, Br or F replaces and/or have side basic nitrogen functional group;

Randomly the halogen that by heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Or the alkyl, cycloalkyl, aryl or the heteroaryl that replace by alkyl, cycloalkyl, aryl or heteroaryl, wherein substituting group alkyl, cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has side basic nitrogen functional group;

-SO2-R group, wherein R is alkyl, cycloalkyl, aryl or the heteroaryl that the halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or have side basic nitrogen functional group; Or-CO-R or-CO-NRR ' group, wherein R and R ' are independently selected from H or are randomly replaced and/or had aryl, heteroaryl, the alkyl or cycloalkyl of side basic nitrogen functional group by at least one heteroatoms.

In the compound of general formula I, The present invention be more particularly directed to 3-(thiazol-2-yl the amino)-benzamide compounds of following general formula I-5:

Wherein Y is singly-bound, comprises linearity or branched-alkyl, particularly CH2 or the CH2-CH2 of 1-10 carbon atom; Or NH

Wherein Z represents randomly at aryl or the heteroaryl of one or more ring positions by the arbitrary combination replacement of following group:

-halogen such as F, Cl, Br, I;

-comprise 1-10 carbon atom randomly by at least one heteroatoms (for example halogen) and/or have the linearity or the branched-alkyl of side basic nitrogen functional group; Randomly the halogen that by at least one heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Or the cycloalkyl, aryl or the heteroaryl that replace by alkyl, cycloalkyl, aryl or heteroaryl, wherein substituting group alkyl, cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has side basic nitrogen functional group;

-O-R, wherein R comprises 1-10 carbon atom randomly replaced and/or had side basic nitrogen functional group by at least one heteroatoms (for example halogen) linearity or branched-alkyl; Randomly the halogen that by at least one heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Or the cycloalkyl, aryl or the heteroaryl that replace by alkyl, cycloalkyl, aryl or heteroaryl, wherein substituting group alkyl, cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has side basic nitrogen functional group;

-NRaRb, wherein Ra and Rb represent hydrogen or comprise 1-10 carbon atom randomly replaced and/or had side basic nitrogen functional group or ring by at least one heteroatoms (for example halogen) linearity or branched-alkyl; Randomly the halogen that by at least one heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Or or the cycloalkyl, aryl or the heteroaryl that replace by alkyl, cycloalkyl, aryl or heteroaryl, wherein substituting group alkyl, cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has side basic nitrogen functional group;

R ²Be hydrogen, halogen or the linearity that comprises 1-10 carbon atom or branched-alkyl, trifluoromethyl, cyano group or alkoxyl group;

R ³Be hydrogen, halogen or the linearity that comprises 1-10 carbon atom or branched-alkyl, trifluoromethyl, cyano group or alkoxyl group;

R ⁴Be hydrogen, halogen or the linearity that comprises 1-10 carbon atom or branched-alkyl, trifluoromethyl, cyano group or alkoxyl group;

R ⁵Be hydrogen, halogen or the linearity that comprises 1-10 carbon atom or branched-alkyl, trifluoromethyl, cyano group or alkoxyl group;

R ⁶Be one of following:

(i) have the aryl of arbitrary combination of one or more substituting groups such as halogen, the alkyl that comprises 1-10 carbon atom, trifluoromethyl and alkoxyl group such as phenyl or its at any one ring position and replace variant;

(ii) heteroaryl is as 2,3, or the 4-pyridyl, and it can have the arbitrary combination of one or more substituting groups such as halogen, the alkyl that comprises 1-10 carbon atom, trifluoromethyl and alkoxyl group in addition;

(iii) for example 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl of five-ring aromatic heterocyclic group, it can have the arbitrary combination of one or more substituting groups such as halogen, the alkyl that comprises 1-10 carbon atom, trifluoromethyl and alkoxyl group in addition;

Iv) H, be selected from the halogen of I, F, Cl or Br; NH2, NO2 or SO2-R, wherein R is linearity or the branched-alkyl that the halogen that comprises one or more groups such as 1-10 carbon atom and randomly by at least one heteroatoms, particularly be selected from I, Cl, Br or F replaces and/or have side basic nitrogen functional group;

And R ⁷Be one of following:

Iv) H, be selected from the halogen of I, F, Cl or Br; NH2, NO2 or SO2-R, wherein R is linearity or the branched-alkyl that the halogen that comprises one or more groups such as 1-10 carbon atom and randomly by at least one heteroatoms, particularly be selected from I, Cl, Br or F replaces and/or have side basic nitrogen functional group.

The example of the preferred compound of above general formula below is described:

001:4-[4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzoyl-amido]-phenylformic acid 2-diethylamino-ethyl ester

In the compound of general formula I, the present invention is implemented by the compound of following general formula I I especially:

General formula I I

Wherein X be R or NRR ' and wherein R and R ' is independently selected from H, randomly by at least one heteroatoms, for example be selected from F, I, the halogen of Cl and Br replaces and randomly has aryl, heteroaryl, alkyl or the cycloalkyl of side basic nitrogen functional group; Or the aryl, heteroaryl, the alkyl or cycloalkyl that replace by aryl, heteroaryl, alkyl or cycloalkyl, wherein substituting group aryl, heteroaryl, the alkyl or cycloalkyl halogen that randomly by at least one heteroatoms, for example is selected from F, I, Cl or Br replaces and randomly has side basic nitrogen functional group

R ²Be hydrogen, halogen or the linearity that comprises 1-10 carbon atom or branched-alkyl, trifluoromethyl or alkoxyl group;

R ³Be hydrogen, halogen or the linearity that comprises 1-10 carbon atom or branched-alkyl, trifluoromethyl or alkoxyl group;

R ⁴Be hydrogen, halogen or the linearity that comprises 1-10 carbon atom or branched-alkyl, trifluoromethyl or alkoxyl group;

R ⁵Be hydrogen, halogen or the linearity that comprises 1-10 carbon atom or branched-alkyl, trifluoromethyl or alkoxyl group;

R ⁶Be one of following:

In another kind changes, substituent R 6, it is connected to the position 4 of thiazole ring in general formula I I, can occupy the position 5 of thiazole ring on the contrary.

In the preferred compound of corresponding general formula I and II, R1 and X are respectively substituted alkyl, aryl or the heteroaryls that has side basic nitrogen functional group in the compound that the present invention relates to, for example represent to m that wherein wavy line and arrow line correspond to the tie point of the nuclear structure of general formula I or II by structure a shown below.

Group a to f and g in m, the X of the R1 of general formula I and general formula I I is group d preferably.Arrive m for g equally, arrow comprises by the tie point of phenyl to nuclear structure.

In addition, in the preferred compound of general formula I or II, R in the compound that the present invention relates to ²And R ³Be hydrogen.Preferably, R ⁴Be methyl and R ⁵Be H.In addition, R ⁶Preferably 3-pyridyl (with reference to following structure g), or 4-pyridyl (with reference to following structure h).Wavy line among structure g and the h corresponds to the tie point of the nuclear structure of general formula I or II.

Therefore, the present invention's imagination:

The compound of general formula I I shown in 1-is above, wherein X is group d and R ⁶It is the 3-pyridyl.

The compound of general formula I I shown in 2-is above, wherein X is group d and R ⁴It is methyl.

General formula I or the compound of II, wherein R shown in 3-is above ¹Be group d and R ²Be H.

General formula I or the compound of II, wherein R shown in 4-is above ¹Be group d and R ³Be H.

General formula I or the compound of II, wherein R shown in 5-is above ¹Be group d and R ²And/or R ³And/or R ⁵Be H.

General formula I or the compound of II, wherein R shown in 6-is above ⁶Be 3-pyridyl and R ³It is methyl.

General formula I or the compound of II, wherein R shown in 7-is above ⁶Be 3-pyridyl and R ²Be H.

General formula I or the compound of II, wherein R shown in 8-is above ²And/or R ³And/or R ⁵Be H and R ⁴It is methyl.

General formula I or the compound of II, wherein R shown in 9-is above ²And/or R ³And/or R ⁵Be H, R ⁴Be methyl and R ⁶It is the 3-pyridyl.

In the compound of general formula I I, the present invention is that the compound of hydrogen is implemented by wherein R2, R3, R5 especially,, corresponding to following general formula I I-1:

General formula I I-1

Wherein X be R or NRR ' and wherein R and R ' be independently selected from H or organic group, this organic group can for example be selected from and comprise 1-10 carbon atom randomly by at least one heteroatoms replacement or have the linearity or the branched-alkyl of side basic nitrogen functional group; Randomly the halogen that by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Or the cycloalkyl, aryl or the heteroaryl that randomly replace by cycloalkyl, aryl or heteroaryl, wherein substituting group cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has side basic nitrogen functional group;

R ⁶Be one of following:

(ii) heteroaryl is as 2,3, or the 4-pyridyl, and it can have the arbitrary combination of one or more substituting groups, the alkyl that comprises 1-10 carbon atom, trifluoromethyl and alkoxyl group such as halogen in addition;

Embodiment:

002:N-(3,5-couple-trifluoromethyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide

¹H NMR(DMSO-d ⁶)δ＝2.36(s，3H，ArCH ₃)；7.43(d，1H，J＝7.5Hz，Ar-H)；7.68(dd，1H，J＝7.5，1.5Hz，Ar-H)；7.73(s，1H，thiazol-H)；7.82(m，3H，pyridyl-H+Ar-H)；8.54(m，4H，pyridyl-H+2xAr-H)；8.85(br s，1H，Ar-H)；9.67(s，1H，NH)，10.84(s，1H，NH)。

003:N-(3,5-couple-trifluoromethyl-phenyl)-4-methyl-3-(4-pyridin-3-yl-thiazol-2-yl amino)-benzamide

092:N-cyclohexyl-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide

¹H NMR(DMSO-d ⁶)δ＝1.00-1.40(m，5H，eyclo-H)；1.50-1.85(m，5H，eyelo-H)；2.34(s，3H，ArCH ₃)；7.28(d，1H，J＝7.9Hz，Ar-H)；7.48(dd，1H，J＝7.9，1.5Hz，Ar-H)；7.67(s，1H，thiazol-H)；7.82(d，2H，J＝6.0Hz，pyridyl-H)；8.57(d，2H，J＝6.0Hz，pyridyl-H)；8.63(d，1H，J＝1.5Hz，Ar-H)；9.55(s，1H，NH)。

093:4-methyl-N-(1-Methyl-1H-indole-6-yl)-3-(4-pyridin-3-yl-thiazol-2-yl amino)-benzamide

094:N-(2-methoxyl group-ethyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide

096:N-(2-cyano group-ethyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide

In the compound of general formula I I, the present invention is that the compound of substituted aryl is implemented by X wherein especially, corresponding to N-[3-(thiazol-2-yl amino)-phenyl]-amide group and following general formula I I-3:

General formula I I-3

Wherein Ra, Rb, Rc, Rd, Re are independently selected from H or organic group, and this organic group for example is selected from and comprises 1-10 carbon atom randomly replaced and/or had side basic nitrogen functional group by at least one heteroatoms linearity or branched-alkyl; Randomly by heteroatoms, particularly be selected from the halogen of I, Cl, Br or F or have cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Cycloalkyl, aryl or the heteroaryl that replaces by cycloalkyl, aryl or heteroaryl randomly, wherein substituting group cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has side basic nitrogen functional group;

-SO2-R group, wherein R is alkyl, cycloalkyl, aryl or the heteroaryl that the halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces or have side basic nitrogen functional group; Or-CO-R or-CO-NRR ' group, wherein R and R ' are independently selected from H, the heteroatoms that randomly by at least one heteroatoms, particularly is selected from I, Cl, Br or F replaces and or have alkyl, cycloalkyl, aryl or a heteroaryl of side basic nitrogen functional group;

Ra, Rb, Rc, Rd, Re also can be

-halogen such as I, Cl, Br and F

-NRR ' group, wherein R and R ' they are H or comprise 1-10 carbon atom randomly replaced and/or had side basic nitrogen functional group by at least one heteroatoms linearity or branched-alkyl; Randomly the halogen that by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Or the cycloalkyl, aryl or the heteroaryl that randomly replace by cycloalkyl, aryl or heteroaryl, wherein substituting group cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has side basic nitrogen functional group;

-OR group, wherein R is H or comprises 1-10 carbon atom randomly replaced and/or had side basic nitrogen functional group by at least one heteroatoms linearity or branched-alkyl; Randomly the halogen that by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Or the cycloalkyl, aryl or the heteroaryl that randomly replace by cycloalkyl, aryl or heteroaryl, wherein substituting group cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has side basic nitrogen functional group;-SO2-R ' group, wherein R ' is alkyl, cycloalkyl, aryl or the heteroaryl that the halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces or have side basic nitrogen functional group;

-NRaCORb group, wherein Ra and Rb are H or comprise 1-10 carbon atom randomly replaced and/or had side basic nitrogen functional group by at least one heteroatoms linearity or branched-alkyl; Randomly the halogen that by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Or the cycloalkyl, aryl or the heteroaryl that randomly replace by cycloalkyl, aryl or heteroaryl, wherein substituting group cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has side basic nitrogen functional group;

-NRaCONRbRc group, wherein Ra and Rb are H or comprise 1-10 carbon atom and randomly replace and/or have side basic nitrogen functional group's linearity or branched-alkyl by at least one heteroatoms; Randomly the halogen that by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Or the cycloalkyl, aryl or the heteroaryl that randomly replace by cycloalkyl, aryl or heteroaryl, wherein substituting group cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has side basic nitrogen functional group;

-COOR, wherein R comprises 1-10 carbon atom randomly by at least one heteroatoms (for example halogen) and/or have the linearity or the branched-alkyl of side basic nitrogen functional group; Randomly the halogen that by at least one heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Or the cycloalkyl, aryl or the heteroaryl that replace by alkyl, cycloalkyl, aryl or heteroaryl, wherein substituting group alkyl, cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces, and/or has side basic nitrogen functional group;

-CONRaRb, wherein Ra and Rb are hydrogen or comprise 1-10 carbon atom randomly replaced and/or had side basic nitrogen functional group by at least one heteroatoms (for example halogen) linearity or branched-alkyl; Randomly the halogen that by at least one heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Or the cycloalkyl, aryl or the heteroaryl that replace by alkyl, cycloalkyl, aryl or heteroaryl, wherein substituting group alkyl, cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces, and/or has side basic nitrogen functional group;

-NHCOOR, wherein R comprises 1-10 carbon atom randomly replaced and/or had side basic nitrogen functional group by at least one heteroatoms (for example halogen) linearity or branched-alkyl; Randomly the halogen that by at least one heteroatoms, particularly is selected from I, Cl, Br or F replaces, and/or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Or the cycloalkyl, aryl or the heteroaryl that replace by alkyl, cycloalkyl, aryl or heteroaryl, wherein substituting group alkyl, cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has side basic nitrogen functional group;

-OSO ₂R, wherein R comprises 1-10 carbon atom randomly replaced and/or had side basic nitrogen functional group by at least one heteroatoms (for example halogen) linearity or branched-alkyl; Randomly the halogen that by at least one heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Or the cycloalkyl, aryl or the heteroaryl that replace by alkyl, cycloalkyl, aryl or heteroaryl, wherein substituting group alkyl, cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has side basic nitrogen functional group;

-NRaOSO ₂Rb, wherein Ra and Rb comprise 1-10 carbon atom randomly by at least one heteroatoms (for example halogen) and/or have the linearity or the branched-alkyl of side basic nitrogen functional group; Ra also can be a hydrogen; Randomly the halogen that by at least one heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Or the cycloalkyl, aryl or the heteroaryl that replace by alkyl, cycloalkyl, aryl or heteroaryl, wherein substituting group alkyl, cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has side basic nitrogen functional group;

-CN group

-trifluoromethyl

R ⁴Be hydrogen, halogen or comprise 1-10 carbon atom linearity or branched-alkyl, trifluoromethyl or alkoxyl group;

R ⁶Be one of following:

Iv) H, be selected from I, F, Cl or Br halogen; NH2, NO2 or SO2-R, wherein R is linearity or the branched-alkyl that the halogen that comprises one or more groups such as 1-10 carbon atom and randomly by at least one heteroatoms, particularly be selected from I, Cl, Br or F replaces and/or have side basic nitrogen functional group.

Embodiment

028:N-(2-fluoro-3-trifluoromethyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide

029:N-(3-fluoro-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide

030:4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-N-(3-trifluoromethyl-phenyl)-benzamide

031:4-methyl-N-(4-methyl-3-trifluoromethyl-phenyl)-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide

032:N-(2-fluoro-5-trifluoromethyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide

¹H NMR(DMSO-d ⁶)δ＝2.39(s，3H，ArCH ₃)；7.41(d，1H，J＝7.9Hz，Ar-H)；7.54-7.70(m，3H，Ar-H)；7.72(s，1H，thiazol-H)；7.82(d，2H，J＝6.0Hz，pyridyl-H)；8.10(dd，1H，J＝6.8，2.2Hz，Ar-H)；8.55(d，2H，J＝6.0Hz，pyridyl-H)；8.84(d，1H，J＝1.8Hz，Ar-H)；9.65(s，1H，NH)；10.31(s，1H，NH)。

033:N-(4-cyano group-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide

034:N-(4-fluoro-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide

035:N-(3-fluoro-4-methyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide

036:N-(the 4-tertiary butyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide

038:N-(3-cyano group-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide

039:N-(3-cyano group-4-methyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide

¹H NMR(DMSO-d ⁶)δ＝2.37(s，3H，ArCH ₃)；2.46(s，3H，ArCH ₃)；7.43(m，2H，Ar-H)；7.63(dd，1H，J＝7.9，1.8Hz，Ar-H)；7.72(s，1H，thiazol-H)；7.83(d，2H，J＝6.0Hz，pyridyl-H)；7.96(dd，1H，J＝8.3，1.8Hz，Ar-H)；8.19(d，1H，J＝2.3Hz，Ar-H)；8.55(d，2H，J＝6.0Hz，pyridyl-H)；8.81(d，1H，J＝1.5Hz，Ar-H)；9.65(s，1H，NH)；10.46(s，1H，NH)。

040:N-(3-bromo-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide

041:N-(3-bromo-4-methyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide

042:N-(3,5-two bromo-4-methyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide

043:N-(3-chloro-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide

044:N-(3-chloro-4-methyl-phenyl) 4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide

045:N-(3-methoxyl group-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide

Tolyl-benzamide between 046:4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-N-

047:N-(4-fluoro-3-methyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide

048:N-(3-iodo-4-methyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide

049:4-methyl-N-(3-nitro-phenyl)-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide

050:4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-N-p-methylphenyl-benzamide

051:4-methyl-N-phenyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide

052:N-(3,4-dimethyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide

053:4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-N-(3-trifluoromethoxy-phenyl) benzamide

054:N-(3,4-dicyano-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide

055:N-(2-fluoro-5-methyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino) benzamide

056:N-(2,4-two fluoro-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide

057:N-(4-cyano group-2-fluoro-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide

058:N-(2-fluoro-4-methyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide

059:N-(2,4-two fluoro-phenyl)-4-methyl-3-(4-pyridin-3-yl-thiazol-2-yl amino)-benzamide

060:N-(4-cyano group-2-fluoro-phenyl)-4-methyl-3-(4-pyridin-3-yl-thiazol-2-yl amino)-benzamide

061:N-(2-fluoro-4-methyl-phenyl)-4-methyl-3-(4-pyridin-3-yl-thiazol-2-yl amino)-benzamide

062:N-(4-cyano group-phenyl)-4-methyl-3-(4-pyridin-3-yl-thiazol-2-yl amino)-benzamide

065:N-(4-fluoro-phenyl)-4-methyl-3-(4-pyridin-3-yl-thiazol-2-yl amino)-benzamide

Tolyl-benzamide between 099:4-methyl-3-(4-pyridin-3-yl-thiazol-2-yl amino)-N-

100:4-methyl-3-(4-pyridin-3-yl-thiazol-2-yl amino)-N-(3-trifluoromethyl-phenyl)-benzamide

101:4-methyl-N-(4-methyl-3-trifluoromethyl-phenyl)-3-(4-pyridin-3-yl-thiazol-2-yl amino)-benzamide

102:N-(2-fluoro-3-trifluoromethyl-phenyl)-4-methyl-3-(4-pyridin-3-yl-thiazol-2-yl amino)-benzamide

105:N-(4-cyano group-3-trifluoromethyl-phenyl)-4-methyl-3-(4-pyridin-3-yl-thiazol-2-yl amino)-benzamide

106:N-(4-cyano group-3-methyl-phenyl)-4-methyl-3-(4-pyridin-3-yl-thiazol-2-yl amino)-benzamide

In the compound of general formula I I, the present invention is that the compound of aryl substituent group is implemented by X wherein especially, corresponding to 4-(4-replacement-1-ylmethyl)-N-[3-(thiazol-2-yl amino)-phenyl]-benzamide family and following general formula I I-4:

General formula I I-4

Wherein X is a heteroatoms, as O or N

Wherein Ra, Rb, Rd, Re, Rf, Rg, Rh are independently selected from H or organic group, and this organic group can for example be selected from and comprise 1-10 carbon atom randomly by at least one heteroatoms and/or have the linearity or the branched-alkyl of side basic nitrogen functional group; Randomly the halogen that by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Or the cycloalkyl, aryl or the heteroaryl that randomly replace by cycloalkyl, aryl or heteroaryl, wherein substituting group cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has side basic nitrogen functional group;

-or NRR ' group, wherein R and R ' they are H or comprise 1-10 carbon atom randomly replaced and/or had side basic nitrogen functional group by at least one heteroatoms linearity or branched-alkyl; Randomly the halogen that by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Or the cycloalkyl, aryl or the heteroaryl that randomly replace by cycloalkyl, aryl or heteroaryl, wherein substituting group cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has side basic nitrogen functional group;

-or the OR group, wherein R is H or comprises 1-10 carbon atom randomly replaced and/or had side basic nitrogen functional group by at least one heteroatoms linearity or branched-alkyl; Randomly the halogen that by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has cycloalkyl, the aryl heteroaryl of side basic nitrogen functional group; Or the cycloalkyl, aryl or the heteroaryl that randomly replace by cycloalkyl, aryl or heteroaryl, wherein substituting group cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has side basic nitrogen functional group;-SO2-R ' group, wherein R ' is alkyl, cycloalkyl, aryl or the heteroaryl that the halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces or have side basic nitrogen functional group;

-or the NRaCORb group, wherein Ra and Rb are H or comprise 1-10 carbon atom randomly replaced and/or had side basic nitrogen functional group by at least one heteroatoms linearity or branched-alkyl; Randomly the halogen that by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Or the cycloalkyl, aryl or the heteroaryl that randomly replace by cycloalkyl, aryl or heteroaryl, wherein substituting group cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has side basic nitrogen functional group;

-or NRaCONRbRc group, wherein Ra and Rb are H or comprise 1-10 carbon atom and randomly replace and/or have side basic nitrogen functional group's linearity or branched-alkyl by at least one heteroatoms; Randomly the halogen that by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Or the cycloalkyl, aryl or the heteroaryl that randomly replace by cycloalkyl, aryl or heteroaryl, wherein substituting group cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has side basic nitrogen functional group;

-or COOR, wherein R comprises 1-10 carbon atom randomly by at least one heteroatoms (for example halogen) and/or have the linearity or the branched-alkyl of side basic nitrogen functional group; Randomly the halogen that by at least one heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Or the cycloalkyl, aryl or the heteroaryl that replace by alkyl, cycloalkyl, aryl or heteroaryl, wherein substituting group alkyl, cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has side basic nitrogen functional group;

-or CONRaRb, wherein Ra and Rb are hydrogen or comprise 1-10 carbon atom randomly replaced and/or had side basic nitrogen functional group by at least one heteroatoms (for example halogen) linearity or branched-alkyl; Randomly the halogen that by at least one heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Or the cycloalkyl, aryl or the heteroaryl that replace by alkyl, cycloalkyl, aryl or heteroaryl, wherein substituting group alkyl, cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has side basic nitrogen functional group;

-or NHCOOR, wherein R comprises 1-10 carbon atom randomly replaced and/or had side basic nitrogen functional group by at least one heteroatoms (for example halogen) linearity or branched-alkyl; Randomly the halogen that by at least one heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Or the cycloalkyl, aryl or the heteroaryl that replace by alkyl, cycloalkyl, aryl or heteroaryl, wherein substituting group alkyl, cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has side basic nitrogen functional group;

-or OSO ₂R, wherein R comprises 1-10 carbon atom randomly replaced and/or had side basic nitrogen functional group by at least one heteroatoms (for example halogen) linearity or branched-alkyl; Randomly the halogen that by at least one heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Or the cycloalkyl, aryl or the heteroaryl that replace by alkyl, cycloalkyl, aryl or heteroaryl, wherein substituting group alkyl, cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has side basic nitrogen functional group;

-or NRaOSO ₂Rb, wherein Ra and Rb comprise 1-10 carbon atom randomly by at least one heteroatoms (for example halogen) and/or have the linearity or the branched-alkyl of side basic nitrogen functional group; Ra also can be a hydrogen; Randomly the halogen that by at least one heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Or the cycloalkyl, aryl or the heteroaryl that replace by alkyl, cycloalkyl, aryl or heteroaryl, wherein substituting group alkyl, cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has side basic nitrogen functional group;

-or-the SO2-R group, wherein R is alkyl, cycloalkyl, aryl or the heteroaryl that the halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces or have side basic nitrogen functional group; Or-CO-R or-CO-NRR ' group, alkyl, cycloalkyl, aryl or heteroaryl that wherein R and R ' are independently selected from H, the heteroatoms that randomly by at least one heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or have side basic nitrogen functional group.

Ra, Rb, Rd, Re also can be halogen such as Cl, F, Br, I or trifluoromethyl;

R ⁶Be one of following:

Embodiment

004:4-methyl-N-[4-(4-methyl-piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide

¹H NMR(MeOH-d ₄)δ＝2.41(s，6H，NCH ₃+ArCH ₃)；2.50-2.70(m，4H，pyperazine-H)；2.90(m，4H，pyperazine-H)；3.68(br s，2H，CH2-piperazine)；7.38(d，1H，J＝7.9Hz，Ar-H)；7.50(m，1H，thiazol-H)；7.60(m，1H，Ar-H)；7.76(d，1H，J＝8.3Hz，Ar-H)；7.90(m，2H，pyridyl-H)；8.00(m，1H，Ar-H)；8.12(m，1H，Ar-H)；8.46(m，2H，pyridyl-H)；8.90(m，1H，Ar-H)。

005:4-methyl-N-{4-[1-(4-methyl-piperazine-1-yl)-ethyl]-phenyl }-3-(4-pyridin-3-yl-thiazol-2-yl amino)-benzamide

In the compound of general formula I I, the present invention is that the compound of aryl substituent group is implemented by X wherein especially, corresponding to 3-dibasic-amino N-[3-(thiazol-2-yl amino)-phenyl]-benzamide family and following general formula I I-5:

General formula I I-5

Wherein Ra, Rb, Rc, Re, Rf, Rg are independently selected from H or organic group, and this organic group can for example be selected from and comprise 1-10 carbon atom randomly replaced and/or had side basic nitrogen functional group by at least one heteroatoms linearity or branched-alkyl; Randomly the halogen that by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Or the cycloalkyl, aryl or the heteroaryl that randomly replace by cycloalkyl, aryl or heteroaryl, wherein substituting group cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has side basic nitrogen functional group;

-or the OR group, wherein R is H or comprises 1-10 carbon atom randomly replaced and/or had side basic nitrogen functional group by at least one heteroatoms linearity or branched-alkyl; Randomly the halogen that by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Or the cycloalkyl, aryl or the heteroaryl that randomly replace by cycloalkyl, aryl or heteroaryl, wherein substituting group cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has side basic nitrogen functional group;-SO2-R ' group, wherein R ' is alkyl, cycloalkyl, aryl or the heteroaryl that the halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces or have side basic nitrogen functional group;

-or COOR, wherein R comprises 1-10 carbon atom randomly by at least one heteroatoms (for example halogen) and/or have the linearity or the branched-alkyl of side basic nitrogen functional group; Randomly the halogen that by at least one heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Or the cycloalkyl, aryl or the heteroaryl that replace by alkyl, cycloalkyl, aryl or heteroaryl, wherein substituting group alkyl, cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has the heteroaryl of side basic nitrogen functional group;

-or CONRaRb, wherein Ra and Rb are hydrogen or comprise 1-10 carbon atom randomly replaced and/or had side basic nitrogen functional group by at least one heteroatoms (for example halogen) linearity or branched-alkyl; Randomly the halogen that by at least one heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Or the cycloalkyl, aryl or the heteroaryl that replace by alkyl, cycloalkyl, aryl or heteroaryl, wherein substituting group alkyl, cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has the heteroaryl of side basic nitrogen functional group;

-or NHCOOR, wherein R comprises 1-10 carbon atom randomly replaced and/or had side basic nitrogen functional group by at least one heteroatoms (for example halogen) linearity or branched-alkyl; Randomly the halogen that by at least one heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Or the cycloalkyl, aryl or the heteroaryl that replace by alkyl, cycloalkyl, aryl or heteroaryl, wherein substituting group alkyl, cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has the heteroaryl of side basic nitrogen functional group;

-or OSO ₂R, wherein R comprises 1-10 carbon atom randomly replaced and/or had side basic nitrogen functional group by at least one heteroatoms (for example halogen) linearity or branched-alkyl; Randomly the halogen that by at least one heteroatoms, particularly is selected from I, Cl, Br or F replaces, and/or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Or the cycloalkyl, aryl or the heteroaryl that replace by alkyl, cycloalkyl, aryl or heteroaryl, wherein substituting group alkyl, cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has the heteroaryl of side basic nitrogen functional group;

-or NRaOSO ₂Rb, wherein Ra and Rb comprise 1-10 carbon atom randomly by at least one heteroatoms (for example halogen) and/or have the linearity or the branched-alkyl of side basic nitrogen functional group; Ra also can be a hydrogen; Randomly the halogen that by at least one heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Or the cycloalkyl, aryl or the heteroaryl that replace by alkyl, cycloalkyl, aryl or heteroaryl, wherein substituting group alkyl, cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has the heteroaryl of side basic nitrogen functional group;

Ra, Rb, Rc, Re also can be halogen such as Cl, F, Br, I or trifluoromethyl;

R ⁶Be one of following:

Embodiment

089:N-(3-dimethylamino-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide

¹H NMR(DMSO-d ⁶)δ＝2.36(s，3H，ArCH ₃)；2.88(s，6H，2xCH ₃)；6.50(d，1H，J＝7.9Hz，Ar-H)；7.10-7.30(m，3H，Ar-H)；7.38(d，1H，J＝7.9Hz，Ar-H)；7.62(dd，1H，J＝7.9，1.5Hz，Ar-H)；7.70(s，1H，thiazol-H)；7.85(d，2H，J＝6.4Hz，pyridyl-H)；8.54(d，1H，J＝6.4Hz，pyridyl-H)；8.78(br s，1H，Ar-H)；9.63(s，1H，NH)，10.04(s，1H，NH)。

090:N-(3-dimethylamino-phenyl)-4-methyl-3-(4-pyridin-3-yl-thiazol-2-yl amino)-benzamide

In second embodiment, the present invention relates to make the method for the compound of above-mentioned general formula I.This requires the condensation of the thiocarbamide of the substrate of general formula 10 and Class1 1.

Substituting group in the general formula 10 " L " is the freestone leavings group (for example, L can be selected from chlorine, bromine, iodine, tosyloxy, methylsulfonyl oxygen, trifluoro-methanesulfonyl oxy etc., reaches preferably bromine of L) in the nucleophilic substitution reaction.

Radicals R 1 among the general formula 11a is corresponding to alkoxyl group.

10 produce the thiazole type product of general formula 12a-d with the reaction of 1a-d.

General formula 12a is identical with general formula I.Therefore, the R1 among the 12a is corresponding to the R1 in the general formula I.

Compound synthesizes embodiment

General: all chemical of use are commercial reagents level products.Dimethyl formamide (DMF), methyl alcohol (MeOH) are anhydrous class of trade and further not refining and use.Methylene dichloride and tetrachloro furans (THF) be distillation newly under argon gas stream before using.Use the silica gel 60F 254 of precoating by thin-layer chromatography, the process of Fluka TLC plate monitoring reaction, it under UV light as seen. ¹Multiplicity in the HNMR spectrum is designated as unimodal (s), wide unimodal (br s), bimodal (d), three peaks (t), four peaks (q) and multimodal (m) and NMR spectrum carries out on 300MHz Bruker spectrometer.

4-acetyl bromide-pyridine, HBr salt

(17.2g, (12g is 99mmol) in cold (0 ℃) solution in acetate 108mmol) to be added drop-wise to the 4-ethanoyl-pyridine that comprises 33%HBr (165mL) with dibromo under vigorous stirring.The mixture of vigorous stirring is warmed up to 40 ℃ of following 2h and then to 75 ℃.After 75 ℃ of following 2h, with mixture cooling with adopt ether (400mL) dilution with precipitated product, with this product by filtered and recycled with adopt ether and washing with acetone to obtain white crystal (100%).Can be with this material from methyl alcohol and ether recrystallize.

¹H NMR (DMSO-d ⁶) δ=5.09 (s, 2H, CH ₂Br); 8.62 (m, 2H, pyridyl-H); 9.07 (m, 2H, pyridyl-H).

4-methyl-3-sulfo-urea groups-benzoic acid methyl ester

(5.64g, (3.54g is 88mmol) in the well-beaten solution in acetone (50mL) 80mmol) to be added drop-wise to ammonium thiocyanate with Benzoyl chloride.With the mixture 15min that refluxes, then portions slowly add 3-amino-4-methyl-benzoic acid methyl ester (13.2g, 80mmol).After 1 hour, filtering separation glassy yellow throw out is passed through in reaction mixture impouring water (350mL) neutralization.This thick solid was at room temperature stirred 2 hours in 200mL methyl alcohol with excessive Anhydrous potassium carbonate.Then, solvent is under reduced pressure removed and crude product wax is adopted ethyl acetate extraction and adopts water washing.Organic layer is passed through Na ₂SO ₄Dry and concentrated to obtain white solid.Solid is stirred 15min and filters to obtain in ether be the final product of white solid.

¹H NMR(DMSO-d ⁶)δ＝2.22(s，3H，ArCH ₃)；3.81(s，3H，CO ₂CH ₃)；7.38(d，1H，J＝7.9Hz，Ar-H)；7.70(dd，1H，J＝7.9，1.5Hz，Ar-H)；7.82(d，1H，J＝1.8Hz，Ar-H)。

4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzoic acid methyl ester

With 4-acetyl bromide-pyridine HBr salt (0.40g, 1.43mmol), 4-methyl-3-sulfo-urea groups-benzoic acid methyl ester (0.32g, 1.43mmol) and KHCO ₃The mixture of (～0.4g) in ethanol (10mL) stirred 20 hours down at 75 ℃.With the mixture cooling, filter and (remove KHCO ₃) and vapourisation under reduced pressure.Resistates is dissolved in CHCl ₃(40mL) with employing saturated sodium bicarbonate aqueous solution and employing water washing.Organic layer is passed through Na ₂SO ₄Dry and concentrated.Grinding and filter crude product to obtain in amount of ethyl acetate is the final product of orange solids.

¹H NMR(DMSO-d ⁶)δ＝2.38(s，3H，ArCH ₃)；3.88(s，3H，CO ₂CH ₃)；7.58(dd，1H，J＝7.9，1.8Hz，Ar-H)；7.75(s，1H，thiazol-H)；7.85(d，2H，J＝6.0Hz，pyridyl-H)；8.62(d，1H，J＝6.0Hz，pyridyl-H)；9.12(d，1H，J＝1.8Hz，Ar-H)；9.63(s，1H，NH)。

N-(4-cyano group-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide

4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzoic acid methyl ester

Under argon gas atmosphere, the 2M drips of solution of trimethyl aluminium in hexane (1.9mL) is added to 4-amino-cyanobenzene (0.29g, 2.46mmol) cold (0 ℃) solution in anhydrous methylene chloride (30mL).Mixture is warmed up to room temperature and at room temperature stirred 30 minutes.Slowly add 4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzoic acid methyl ester (0.80g, 2.46mmol) solution in anhydrous methylene chloride (30mL) and with the heating 5 hours under refluxing of the mixture that obtains.Mixture is cooled to 0 ℃ and the quenching of dropping 4N aqueous sodium hydroxide solution (3mL).Mixture is adopted methylene dichloride (3 * 20mL) extractions.The organic layer that merges is adopted salt solution (3 * 20mL) washings and by anhydrous MgSO ₄Dry.After the grinding of crude product in methyl alcohol, obtain N-(4-cyano group-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide with 98%.

¹H NMR(CDCl ₃)δ＝2.40(s，3H，ArCH ₃)；7.40(d，1H，J＝7.9Hz，Ar-H)；7.63(dd，1H，J＝7.9，1.5Hz，Ar-H)；7.72(s，1H，thiazole-H)；7.80-7.88(m，4H，Ar-H)；8.10(d，2H，J＝8.6Hz，Ar-H)；8.56(m，2H，Ar-H)；8.86(d，1H，J＝1.8Hz，Ar-H)；9.66(br s，1H，NH).

Embodiment:

In the 3rd embodiment, the present invention relates to comprise the pharmaceutical composition of above-claimed cpd.

Such medicine can adopt the form that is suitable for pharmaceutical composition for oral administration, and it can use pharmaceutical carrier well known in the art to adopt the proper dosage preparation.Such carrier can make pharmaceutical composition be formulated as tablet, pill, lozenge, capsule, liquid agent, gel, syrup, paste, suspension etc. to allow the patient ingest.Except that activeconstituents, these pharmaceutical compositions can comprise suitable pharmaceutical carrier, and this carrier comprises vehicle and promote active compound to be processed into the auxiliary agent of preparation that said preparation can use in pharmacy.The further details of preparation and medicine-feeding technology can be found in Remington ' s Pharmaceutical Sciences (Maack PublishingCo., Easton, latest edition Pa.).

Composition of the present invention also can adopt the medicine that is used for topical or the form of make-up composition.

Such composition can adopt following form to present: the dispersion of gel, paste, ointment, emulsion, lotion, liquid, aqueous suspension, moisture-alcohols or oily solution or lotion or whey type or the liquid of anhydrous or lipotropy gel or newborn type or the emulsion of semi-solid denseness, they are by disperseing fat to obtain mutually at aqueous phase or vice versa, or the suspension of soft, the semi-solid denseness of emulsion or gel type or emulsion or microemulsion, micropartical or cryptomere dispersion are to ion and/or nonionic type.These compositions prepare according to standard method.

Composition according to the present invention comprises any composition that is generally used for dermatology and makeup.It can comprise and is selected from following at least a composition: wetting ability or lipotropy jelling agent, wetting ability or lipotropy promoting agent, sanitas, lubricant, viscosity strengthen polymkeric substance, wetting agent, tensio-active agent, sanitas, oxidation inhibitor, solvent and filler, oxidation inhibitor, solvent, spices, filler, screening agent, sterilant, odour absorbents or coloured material.

As can be used for oil of the present invention, can mention mineral oil (whiteruss), vegetables oil (liquid distillate of shea butter, sunflower oil), animal oil, synthetic oil, silicone oil (cyclomethicone) and fluorinated oil.Fatty Alcohol(C12-C14 and C12-C18), lipid acid (stearic acid) and wax (paraffin, carnauba wax, beeswax) also can be used as fatty substance.

As can be used for emulsifying agent of the present invention, imagination stearin, Polysorbate 60 and PEG-6/PEG-32/ stearic acid diol ester mixture.

As wetting ability gelling agent, can mention that carboxyvinyl polymer (carbomer), acrylic acid or the like copolymerization put as acrylate/alkyl acrylate copolymer, polyacrylamide, polysaccharide such as hydroxypropylcellulose, clay and natural resin, as the lipotropy jelling agent, can mention modified clay such as wilkinite, fatty acid metal soap such as aluminum stearate and hydrophobic silica or ethyl cellulose and polyethylene.

As the hydrophilic active agent, can use protein or protein hydrolystate, amino acid, polyvalent alcohol, urea, wallantoin, sugar and sugar derivatives, VITAMIN, starch and plant milk extract, particularly aloetic those.

As the lipotropy promoting agent, can use Vogan-Neu (vitamin A) and its derivative, tocopherol (vitamin-E) and its derivative, basic lipid acid, ceramide and essential oil.These reagent increase extra preserving moisture or the dermalaxia feature when adopting.

In addition, tensio-active agent can be included in the composition so that the darker infiltration of compound to be provided, and this compound can reduce mastocyte, as tyrosine kinase inhibitor, and preferred c-test kit inhibitor.

In the composition of imagination, the present invention includes the penetration enhancers that for example is selected from mineral oil, water, ethanol, triactin, glycerine or propylene glycol; For example be selected from the interior poly-agent of polyisobutene, polyvinyl acetate (PVA) and polyvinyl alcohol, and thickening material.

The chemical process that strengthens the local absorption of medicine is well known in the art.For example, have the infiltration compound of strengthening the property and comprise sodium lauryl sulphate (Dugard, P.H. and Sheuplein, R.J., " Effects of Ionic Surfactants on the Permeability of Human Epidermis:An Electrometric Study, " J.Ivest.Dermatol., V.60, pp.263-69,1973), lauryl amine oxide compound (Johnson etc., US 4,411, and 893), ozone (Rajadhyaksha, US4,405,616 and 3,989,816) and decyl methyl sulfoxide (Sekura, D.L and Scala, J., " ThePercutaneous Absorption of Alkylmethyl sulfide; " Pharmacology of Skin, Advances In Biolocy of Skin, (Appleton-Century Craft) are V.12, pp.257-69,1972).The infiltration of having observed the polarity that increases a group in the amphipathic molecule and can increase them is strengthened the property but cost is the skin irritation (Cooper that increases them, E.R. and Berner, B., " Interaction of Surfactants with Epidermal Tissues:PhysiochemicalAspects, " Surfactant Science Series, V.16, Reiger, M.M.ed. (MarcelDekker, Inc.) pp.195-210,1987).

The second class chemical intensifier is commonly referred to solubility promoter.These materials are relatively easily by local absorption with based on various mechanism, and the infiltration that reaches for some medicines strengthens.Ethanol (Gale etc., U.S.Pat.No.4,615,699 and Campbell etc., U.S.Pat.Nos.4,460,372 and 4,379,454), (US 3,740 for methyl-sulphoxide, 420 and 3,743,727, with US 4,575,515), and glycerol derivative (US 4,322,433) is the example that shows the compound of the ability that strengthens all cpds absorption.

Pharmaceutical composition of the present invention also can wish to adopt the atomizing preparaton to be administered into the target area in patient respiratory road.

Carry the equipment and the method for the atomizing transmission of pharmaceutical formulation to be disclosed in US 5,906,202.Preparaton is solution preferably, as the aqueous solution, ethanolic soln, moisture/ethanolic soln, salts solution, soliquid and crystallite suspension.For example atomization particle comprises above-mentioned activeconstituents and carrier, (as medical active respiratory medications and carrier), they form when forcing preparaton by nozzle, and the form of this nozzle is preferably flexible porous-film.Particle has enough little size makes that their hang time enough in air when particle forms, and makes the patient particle can be sucked patient's lung.

Present invention resides in US 5,556, the system of describing in 611:

-in pressurized vessel the liquefied gas system (liquefied gas is as propellant gas (as lower boiling FCHC or propane, butane),

-suspension aerosol (active material particle suspends in mutually at liquid propellant with solid form),

-gas under pressure system (is used pressurized gas such as nitrogen, carbonic acid gas, nitrous oxide, air.

Therefore, pharmaceutical preparation produced according to the present invention is active substance dissolved in suitable non-toxicity medium or disperses and this solution or dispersion are atomized into aerosol, promptly is distributed in the carrier gas especially carefully.For example with aerosol propellants gas bag, pump aerosol or for liquid haze or the form of the known miscellaneous equipment of solid atomizing self this be possible technically, it allows accurate single dosage especially.

Therefore, the present invention also relates to comprise the compound of above definition and this preparaton, preferably have an aerosol apparatus of the dosage valve of metering.

Pharmaceutical composition of the present invention also can wish to be used for intranasal administration.

In this regard, those skilled in the art recognize easily with the pharmaceutical carrier of compound administration to the nasal mucosa surface.These carriers are described in Remington ' s Pharmaceutical Sciences " 16 editions, 1980, Ed.Arthur Osol, the disclosure of the document is hereby incorporated by.

Suitably the specific administration type of imagination is depended in the selection of carrier.For the administration by the upper respiratory tract, composition can be mixed with solution, for example water or etc. infiltration salt solution, buffering or buffered not, or be formulated as suspension are formulated as drops or sprays is used for intranasal administration.Preferably, such solution or suspension with respect to nasal discharge be isoosmotic with have about identical pH, about pH 7.4 of pH 4.0-or pH 6.0-pH 7.0 according to appointment.Buffer reagent should be that physiology is compatible and comprise phosphate buffered saline buffer simply by way of example.For example, representative nasal decongestant is described as being buffered to about 6.2 pH (Remington ' s, Id. is at 1445 pages).Certainly, those skilled in the art can determine easily that suitable brine content and pH are used in the nose and/or the harmless aqueous carrier of upper respiratory tract administration.

Carrier comprises that nasal gel, emulsion, paste or viscosity are the about 3000cps of about 10-or about 2500-6500cps or bigger ointment in the common nose, and it also can be used for providing with the more lasting of nasal mucosa surface and contacts.Such carrier viscosity preparaton simply by way of example, can based on alkylcellulose and/or full-bodied other biological compatibility carrier well known in the art (referring to as., Remington ' s quotes as above.Preferred alkylcellulose is, as the methylcellulose gum of concentration for about 5-about 1000 or the every 100ml carrier of more mg.Simply by way of example, the more preferably concentration of methylcellulose gum is the every 100ml carrier of the about mg of about 25-.

Other composition, can comprise also that as glycerine extra viscosity, moisture to be provided for preparing keep or pleasant quality and smell at sanitas as known in the art, tinting material, lubricated or viscous mineral matter or vegetables oil, spices, natural or synthetic plant milk extract such as perfume oil and wetting agent and viscosity intensifier.For the intranasal administration of solution according to the present invention or suspension, various device can be used for producing drops, droplet and sprays in this area.

The premeasuring unitary dose divider that preparation comprises dropper or spraying equipment comprises one or more drug doses to be administered and is another object of the present invention, and wherein this dropper or spraying equipment comprise as drops or solution or the suspension carried as sprays.The present invention also comprises test kit, and this test kit comprises the compound of one or more units dehydration dosage, and the salt of any requirement and/or buffer reagent, sanitas, tinting material etc., and it prepares solution or suspension by the water that adds suitable quantity.

Another aspect of the present invention relates to the purposes that this compound is used to prepare medicine.In other words, the present invention includes treatment and relate to the method for being regulated the transduction of c-test kit, this method comprises the Mammals that the compound administration of the above definition of significant quantity is treated like this to needs.

More particularly, target of the present invention is to treat the method that is selected from following disease: autoimmune disease, allergic disease, bone loss, cancer such as aleukemic leukemia and GIST, tumor vessel generation, inflammatory diseases, inflammatory bowel disease (IBD), interstitial cystitis, mastocytosis, transmissible disease, metabolic disease, fibrosis, diabetes or CNS illness, this method comprise the Mammals that the compound administration of the above explanation of significant quantity is treated like this to needs.

Above-claimed cpd is used to prepare the medicine that treatment relates to the disease of being regulated the transduction of c-test kit, and this disease includes but not limited to:

-neoplastic disease such as mastocytosis, canine tooth mastocytoma, people's gastrointestinal stromal tumors (GISTs) (" GIST "), small cell lung cancer, nonsmall-cell lung cancer, acute myelocytic leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, chronic granulocytic leukemia, colorectal carcinoma, cancer of the stomach, gastrointestinal stromal tumors (GISTs), carcinoma of testis, glioblastoma, solid tumor and astrocytoma.

-tumor vessel takes place.

-disease of metabolism such as diabetes and its chronic complicating diseases; Obesity; Type ii diabetes; Hyperlipidaemia and dyslipidemia; Atherosclerosis; Hypertension; And cardiovascular disorder.

-allergic disease such as asthma, rhinallergosis, allergic sinusitis, anaphylaxis syndrome, urticaria, angioedema, atopic dermatitis, allergic contact dermatitis, erythema nodosum, erythema multiforme, the venulitis that causes the epidermis necrosis and insect bite skin inflammation and blood-sucking parasites are invaded and harassed.

-interstitial cystitis.

-bone loss (osteoporosis).

-inflammatory diseases such as rheumatoid arthritis, conjunctivitis, rheumatoid spondylitis, osteoarthritis, urarthritis and other arthritic conditions.

-autoimmune disease such as multiple sclerosis, psoriatic, enteritis disease, ulcerative colitis, crohn, rheumatoid arthritis and polyarthritis, part and systemic scleroderma, systemic lupus erythematosus, discoid lupus erythematosus, epidermis lupus, dermatomyositis, polymyositis, sacroiliitis syndrome, nodular panniculitis, auto immune enteropathy and proliferative glomerulonephritis.

-graft versus host disease (GVH disease) or transplant rejection in any organ transplantation that comprises kidney, pancreas, liver, heart, lung and marrow.

-by other autoimmune disease that the present invention includes such as chronic active hepatitis and chronic tired syndrome.

-epidermis issues blister illness such as pemphigus.

-vasculitis.

-with the melanophore dysfunction of disease-related as from the hypermelanosis of melanophore dysfunction and comprise mole, the sun and aging color spot, Dubreuilh melanoderma, mole with and the Evil malaria.In this regard, the compound that the present invention includes above definition is used to make the medicine that brightens human skin or the purposes of makeup.

-CNS illness such as mental illness, migraine, pain, the loss of memory and neurocyte are degenerated.More particularly, the method according to this invention is used for the treatment of following illness: dysthymia disorders, it comprises Qing Xu Evil pessimum obstacle, cyclothymic disorder, the two poles of the earth dysthymia disorders, serious or " melancholia " depression, the atypia dysthymia disorders, refractory depression disease, seasonal depression disease, apositia, Bulimia nerovsa, premenstrual syndrome, PMS, slow and the loss of concentration of other syndrome such as nerve, pessimistic worried, exciting, the oneself opposes, sexual desire reduces, pain, it comprises acute pain, postoperative pain, chronic pain, nociceptive pain, cancer pain, neuropathic pain, psychogenic pain syndrome, anxiety disorder, it comprises the anxiety relevant with forced respiration and irregular pulse, phobia, obsessive compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, psychosis emergency case such as panic attack, comprise psychosis, delusional disorder, conversion disorder, phobia, mania, vain hope, the separation property outbreak, it comprises dissociative amnesia, dissociative fugue and dissociative identity disorder, depersonalization, catatonia, epileptic seizures, the cacopathia emergency case, it comprises suicide, the oneself ignores, strong or aggressive behaviour, wound, borderline personality, and acute mental disorder, schizophrenia, it comprises paranoid schizophrenia, disorganized schizophrenia, catatonic schizophrenia, and undifferentiated schizophrenia.

-neurodegenerative disease, it comprises alzheimer's disease, Parkinson's disease, Heng Yandun disease, prion disease, motor neurone disease (MND) and amyotrophic lateral sclerosis (ALS).

-psychoactive substance use disorders includes but not limited to dopy, Drug abuse, drug addiction, drug dependence, withdrawal symptom and overdose referred in this.

-cerebral ischemia

-fibrosis

-Duchenne muscular dystrophy

About mastocytosis, the compound that the present invention imagines above definition is used for the treatment of dissimilar purposes, and they can followingly be classified:

Classification I is made up of two subclass other (IA and IB).Classification IA is formed by the disease that mast cells infiltration strictness wherein is confined to skin.This classification is represented the most common disease form and is comprised: i) urticaria pigmentosa, it is the most common form of epidermis mastocytosis, particularly in children, run into, ii) dispersivity epidermis mastocytosis, iii) single mastocytoma and iv) some rare hypotype class blebs, erythroderma and whole vasodilation mastocytosis of giving birth to.Very painless process among the excellent prognosis (prognosis) that is characterized as in children them of these forms and spontaneous remission and the adult.The long-term surviving of this form disease usually can with normal population quite, and seldom be transformed into the mastocytosis of another kind of form.Classification IB is by having or do not have painless general disease (SM) expression that epidermis relates to.These forms in the adult than in children more generally.The course of disease is normally painless, but can occur the sign of aggressive Huo Evil mastocytosis sometimes, causes impaired gradually organ dysfunction.

Classification II comprises mastocytosis and relevant hematology illness, as myelosis or myelodysplastic syndrome, or acute leukemia.These a little Evil mastocytosises are not usually directed to skin.Progression of disease depends on the type of the relevant hematology illness of regulating prediction usually.

Classification III is expressed by aggressive whole body mastocytosis, and wherein a plurality of organs are common by a large amount of infiltrations of unusual mastocyte.In the patient who tangled by this type of aggressive clinical course, the peripheral blood feature of sign myeloproliferative disease is more outstanding.Progression of disease may be very quick, and similar in appearance to acute leukemia, or some patients can show the longer survival time.

At last, classification IV mastocytosis comprises mast cell leukemia, it is characterized by to account for the circulation mastocyte of white corpuscle more than 10% and the existence of mastocyte primary particle.This essence express possibility among the mankind infrequent types aleukemic leukemia and have the prognosis of non-constant, mutually like in the rapid progress variant of Evil mastocytosis.The mastocyte aleukemic leukemia can be newborn or as occurring in latter stage of urticaria pigmentosa or whole body mastocytosis.

The present invention also imagine as being used for the treatment of send out cell infection again, the method as bacterial cystitis is infected in recurrence after asymptomatic period.More particularly, the present invention can implement to be used for the treatment of infectation of bacteria such as the Gram-negative intestinal cell that FimH expresses, and comprises colibacillus, pneumobacillus, serratia marcesens, Citrobactor freudii and Salmonella typhimurium.In this method of treatment infectation of bacteria, antibiotic administration is interested separately, in order or together at least a, and this microbiotic is selected from bacitracin, cephalosporins, penicillins, aminoglycoside, tetracyclines, Streptomycin sulphate or macrolide antibiotics such as erythromycin; Fluoroquinolones, actinomycin, sulfamido or trimethoprim.

In a preferred embodiment, the present invention relates to treat the method for following neoplastic disease: as mastocytosis, the canine tooth mastocytoma, human gastrointestinal mesenchymoma (" GIST "), small cell lung cancer, nonsmall-cell lung cancer, acute myelocytic leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, chronic granulocytic leukemia, colorectal carcinoma, stomach and intestine, gastrointestinal stromal tumors (GISTs), carcinoma of testis, glioblastoma, and astrocytoma, this method comprises the mankind or the Mammals for the treatment of like this to needs, particularly dog or cat administration are at the compound of this definition.

In other embodiment preferred, the present invention relates to treat the method for following allergic disease: invade and harass as asthma, rhinallergosis, allergic sinusitis, anaphylaxis syndrome, urticaria, angioedema, atopic dermatitis, allergic contact dermatitis, erythema nodosum, erythema multiforme, the venulitis that causes the epidermis necrosis and insect bite skin inflammation and blood-sucking parasites, this method comprise to needs like this mankind of treatment or Mammals, particularly dog or cat administration at the compound of this definition.

In another embodiment preferred still, the present invention relates to treat the method for following inflammatory diseases: as rheumatoid arthritis, conjunctivitis, rheumatoid spondylitis, osteoarthritis, urarthritis and other arthritic conditions, this method comprises to the compound of the so human administration for the treatment of of needs in this definition.

In another embodiment preferred still, the present invention relates to treat the method for following autoimmune disease: as multiple sclerosis, psoriatic, enteritis disease, ulcerative colitis, crohn, rheumatoid arthritis and polyarthritis, part and systemic scleroderma, systemic lupus erythematosus, discoid lupus erythematosus, epidermis lupus, dermatomyositis, polymyositis, sacroiliitis syndrome, nodular panniculitis, auto immune enteropathy and proliferative glomerulonephritis, this method comprises to the compound of the so human administration for the treatment of of needs in this definition.

In another embodiment preferred still, the present invention relates to treat the graft versus host disease (GVH disease) in any organ transplantation that comprises kidney, pancreas, liver, heart, lung and marrow or the method for transplant rejection, this method comprise to needs so the human administration of treatment at the compound of this definition.

Embodiment 1: external TK suppresses coordination and measures

Process

The purifying cells internal area of the c-test kit that use is expressed in baculovirus is tested.The prediction of kinase activity is by the phosphorylation evaluation of tyrosine, and this cruel propylhomoserin comprises the target peptide of being measured prediction by known ELISA.

The test-results of test compounds

Result in the table 1 shows effective restraining effect of catalytic activity of the c-test kit of IC50＜10 μ M.Further the test (not shown) is indicated the perfect competitive inhibitor of at least a compound as ATP.

Embodiment 2: external TK suppresses coordination and measures

Process

C-test kit WT and sudden change C-test kit (JM) are measured

Proliferation assay

With cell 5 * 10 ⁴Before the 96-orifice plate in the every hole of individual cell is cultivated three times in PBS washed twice and adopt green blood somatomedin (HGF) to stimulate or do not adopt such stimulation.After cultivating 2 days, (Amersham Life Science UK) added 6 hours with [3H] thymidine of 37Bq (1.78Tbq/mmol).Filter and in scintillometer, measure [3H] thymidine introducing amount with cell collection with by glass fibre filter.For proliferation assay, all medicines are prepared as 20mM stoste and preservation under-80 ℃ at thing in DMSO.Before each test, make the fresh diluent among the PBS.When cultivating beginning, add the DMSO dissolved drug.Adopt corresponding DMSO diluent to carry out contrast culture.By getting the propagation that does not have to suppress is 100% with the percentage expression result.

Cell

Ba/F3 mouse test kit and people's test kit, Ba/F3 m test kit D27 (nearly film disappearance) is derived from mouse IL-3 dependency Ba/F3 proB lymphoidocyte.FMA3 and P815 clone are the mastocyte oncocytes of expressing the endogenous mutant form of test kit, i.e. the disappearance of framework in the nearly film coding region of the mouse of acceptor-codon 573-579.Human leukemia basin blood MC is that HMC-1 expresses sudden change JM-V560G;

Immune precipitation determination and western blot analysis

For each mensuration, the rmKL stimulation that is cell is adopted 250ng/ml is distinguished in dissolving and immunoprecipitation 5.106Ba/F3 cell and Ba/F3-derived cell and the sudden change of various c-test kit as described people such as (, 1996) Beslu.Cell lysates is adopted the anti-mouse KIT of rabbit immune serum immunoprecipitation, anti-KIT tenuigenin territory guiding people such as (, 1991) Rottapel.Western blot is adopted the anti-phosphatide tyrosine of 4G10 antibody (UBI) or adopt the anti-mouse KIT of rabbit immune serum or employing different antibodies hybridization (describing) in the antibody paragraph.The goat anti-rabbit igg antibody (Immunotech) that then film is adopted the mountain sheep anti-mouse igg antibody of HRP-joint or adopt HRP to engage is hatched, then by adopting hatching of ECL reagent (Amersham) to manifest protein of interest matter.

Test-results

Provide the test-results of use such scheme at table 2 according to all cpds of the present invention:

Table 2:

Target	IC50(mM)	Compound
Target	IC50(mM)	Compound	C-test kit WT	IC50＜10mM	001；002；003；004；005；028；029；030； 031；032；033；034；35；036；038；039； 040；041；042；043；044；045；046；047； 048；049；050；051；052；053；054；055； 056；057；058；059；060；061；062；0.65； 089；090；092；093；094；096；099；100； 101；102；105；106
C-test kit JM D27	IC50＜1mM		C-test kit WT	IC50＜10mM

Claims

1. the compound of general formula I:

General formula I

Wherein

R ⁶And R ⁷Be independently from each other following a kind of:

I) hydrogen, halogen (being selected from F, Cl, Br or I),

Ii) alkyl ¹Group, this group definition is to comprise 1 to 10 carbon atom or from linearity, branching or the cycloalkyl of 2 or 3 to 10 carbon atoms, (for example methyl, ethyl, propyl group, butyl, amyl group, hexyl ...) and randomly by one or more heteroatomss such as halogen (being selected from F, Cl, Br or I), oxygen or nitrogen (latter randomly is the form of side basic nitrogen functional group); And trifluoromethyl, carboxyl, cyano group, nitro, formyl radical replace;

-halogen (being selected from I, F, Cl or Br);

-alkyl ¹Group;

-halogen (being selected from F, Cl, Br or I);

-alkyl ¹Group;

-the cycloalkyl, aryl or the heteroaryl that randomly replace by side basic nitrogen functional group,

(v) trifluoromethyl, carboxyl, cyano group, nitro, formyl radical, hydroxyl, N (alkyl ¹) (alkyl ¹) and amino, latter's nitrogen substituting group randomly is the form of basic nitrogen functional group,

R ⁸Be one of following:

(i) hydrogen, or

(iii) CO-R8 or COOR8 or CONHR8 or SO2R8, wherein R8 can be

Phenyl or its replacement variant of-aryl as have one or more substituent arbitrary combination at any one ring position, wherein substituting group such as halogen (being selected from F, Cl, Br or I), the linearity or the branched-alkyl that comprise 1-10 carbon atom and randomly replace by one or more heteroatomss such as halogen (being selected from F, Cl, Br or I), oxygen and nitrogen, the latter randomly is the form of side basic nitrogen functional group; And trifluoromethyl, C _1-6Alkoxyl group, carboxyl, cyano group, nitro, formyl radical, hydroxyl, C _1-6Alkylamino, two (C _1-6Alkyl) amino and amino, latter's nitrogen substituting group randomly is the form of side basic nitrogen functional group; And CO-R, COO-R, CONH-R, SO2-R and SO2NH-R, wherein R is linearity or the branched-alkyl that comprises 1-10 carbon atom and randomly replaced by at least one heteroatoms, particularly halogen (being selected from F, Cl, Br or I), oxygen and nitrogen, the latter randomly is the form of side basic nitrogen functional group, or

-heteroaryl such as pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, pyrryl, furyl oxazolyl isoxazolyl, triazolyl, tetrazyl, indyl, benzoglyoxaline, quinolyl, it can have one or more substituent arbitrary combination at any one ring position in addition, wherein substituting group such as halogen (are selected from F, Cl, Br or I), comprise 1-10 carbon atom and randomly (be selected from F by one or more heteroatomss such as halogen, Cl, Br or I), oxygen, with the alkyl that nitrogen replaces, the latter randomly is the form of side basic nitrogen functional group; And trifluoromethyl, C _1-6Alkoxyl group, carboxyl, cyano group, nitro, formyl radical, hydroxyl, C _1-6Alkylamino, two (C _1-6Alkyl) amino and amino, latter's nitrogen substituting group randomly is the form of side basic nitrogen functional group; And CO-R, COO-R, CONH-R, SO2-R and SO2NH-R, wherein R is linearity or the branched-alkyl that comprises 1-10 carbon atom and randomly replaced by at least one heteroatoms, particularly halogen (being selected from F, Cl, Br or I), oxygen and nitrogen, the latter randomly is the form of side basic nitrogen functional group

Each linearity or branched-alkyl that is independently selected from hydrogen, halogen (being selected from F, Cl, Br or I), comprises 1-10 carbon atom and randomly replace of R2, R3, R4 and R5 by one or more heteroatomss such as halogen (being selected from F, Cl, Br or I), oxygen and nitrogen, the latter randomly is the form of side basic nitrogen functional group; And trifluoromethyl, C _1-6Alkoxyl group, amino, C _1-6Alkylamino, two (C _1-6Alkyl) amino, carboxyl, cyano group, nitro, formyl radical, hydroxyl; with CO-R, COO-R, CONH-R, SO2-R and SO2NH-R; wherein R is linearity or the branched-alkyl that comprises 1-10 carbon atom and randomly replaced by at least one heteroatoms, particularly halogen (being selected from F, Cl, Br or I), oxygen and nitrogen; the latter randomly is the form of side basic nitrogen functional group

A is: CH2, O, S, SO2, CO or COO,

B is key or NH, NCH3, NR ^*, (CH2) n (n is 0,1 or 2), O, S, SO2, CO or COO,

B ' is key or NH, NCH3, NR ^*, (CH2) n (n is 0,1 or 2), O, S, SO2, CO or COO;

R ^*It is alkyl ¹, aryl ¹Or heteroaryl ¹

W is key or is selected from following connector: NH, NHCO, NHCOO, NHCONH, NHSO2, NHSO2NH, CO, CONH, COO, COCH2, (CH2) n (n is 0,1 or 2), CH2-CO, CH2COO, CH2-NH, O, OCH2, S, SO2 or SO2NH

R ¹Be:

B) aryl or the heteroaryl that is randomly replaced by alkyl or aryl, wherein the substituting group alkyl or aryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has side basic nitrogen functional group

C) alkyl ¹, aryl ¹Or heteroaryl ¹

2. compound according to claim 1, wherein R6 is (iv), and R4 is H or CH3, and A-B-B ' is CO-NH.

3. according to claim 1 have general formula I I compound:

General formula I I

Wherein X be R or NRR ' and wherein R and R ' be independently selected from H, aryl, heteroaryl, alkyl or cycloalkyl, its halogen that randomly by at least one heteroatoms, for example is selected from F, I, Cl or Br replaces and randomly has side basic nitrogen functional group; Or the aryl, heteroaryl, the alkyl or cycloalkyl that replace by aryl, heteroaryl, alkyl or cycloalkyl, wherein substituting group aryl, heteroaryl, the alkyl or cycloalkyl halogen that randomly by at least one heteroatoms, for example is selected from F, I, Cl or Br replaces and randomly has side basic nitrogen functional group

R ⁶Be one of following:

(i) have the aryl of one or more substituent arbitrary combination such as phenyl or its at any one ring position and replace variant, wherein substituting group such as halogen, the alkyl that comprises 1-10 carbon atom, trifluoromethyl and alkoxyl group;

4. according to claim 1 or 3 described compounds, wherein R1 and X are respectively substituted alkyl, aryl or the heteroaryls that has side basic nitrogen functional group, this functional group is represented to m that by structure a shown below wherein wavy line and arrow line correspond to the tie point of the nuclear structure of general formula I or II

5. compound according to claim 4, wherein arrow is by the tie point of phenyl to nuclear structure.

6. according to claim 1 or 3 described compound, wherein R ⁶Be 3-pyridyl (with reference to following structure g) or 4-pyridyl (with reference to following structure h), the wavy line among structure g and the h corresponds to the tie point of the nuclear structure of general formula I or II

7. according to claim 3 have general formula I I-3 compound:

General formula I I-3

Wherein Ra, Rb, Rc, Rd, Re are independently selected from H or organic group, and this organic group for example is selected from and comprises 1-10 carbon atom randomly replaced and/or had side basic nitrogen functional group by at least one heteroatoms linearity or branched-alkyl; Randomly the halogen that by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Cycloalkyl, aryl or the heteroaryl that replaces by cycloalkyl, aryl or heteroaryl randomly, wherein substituting group cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has side basic nitrogen functional group;

-SO2-R group, wherein R is alkyl, cycloalkyl, aryl or the heteroaryl that the halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces or have side basic nitrogen functional group; Or-CO-R or-CO-NRR ' group, wherein R and the R ' heteroatoms that is independently selected from H or randomly by at least one heteroatoms, particularly is selected from I, Cl, Br or F replace and or have alkyl, cycloalkyl, an aryl heteroaryl of side basic nitrogen functional group;

Ra, Rb, Rc, Rd, Re also can be

-halogen such as I, Cl, Br and F

-NRR ' group, wherein R and R ' they are H or comprise 1-10 carbon atom randomly replaced and/or had side basic nitrogen functional group by at least one heteroatoms linearity or branched-alkyl; Randomly by heteroatoms, particularly be selected from the halogen of I, Cl, Br or F or have cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Cycloalkyl, aryl or the heteroaryl that replaces by cycloalkyl, aryl or heteroaryl randomly, wherein substituting group cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has side basic nitrogen functional group;

-OR group, wherein R is H or comprises 1-10 carbon atom randomly replaced and/or had side basic nitrogen functional group by at least one heteroatoms linearity or branched-alkyl; Randomly the halogen that by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Cycloalkyl, aryl or the heteroaryl that replaces by cycloalkyl, aryl or heteroaryl randomly, wherein substituting group cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has side basic nitrogen functional group;-SO2-R ' group, wherein R ' is alkyl, cycloalkyl, aryl or the heteroaryl that the halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces or have side basic nitrogen functional group;

-NRaCORb group, wherein Ra and Rb are H or comprise 1-10 carbon atom randomly replaced and/or had side basic nitrogen functional group by at least one heteroatoms linearity or branched-alkyl; Randomly the halogen that by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Cycloalkyl, aryl or the heteroaryl that replaces by cycloalkyl, aryl or heteroaryl randomly, wherein substituting group cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has side basic nitrogen functional group;

-NRaCONRbRc group, wherein Ra and Rb are H or comprise 1-10 carbon atom randomly replaced and/or had side basic nitrogen functional group by at least one heteroatoms linearity or branched-alkyl; Randomly the halogen that by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Cycloalkyl, aryl or the heteroaryl that replaces by cycloalkyl, aryl or heteroaryl randomly, wherein substituting group cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces or has side basic nitrogen functional group;

-COOR, wherein R comprises 1-10 carbon atom randomly by at least one heteroatoms (for example halogen) and/or have the linearity or the branched-alkyl of side basic nitrogen functional group; Randomly the halogen that by at least one heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Or the cycloalkyl, aryl or the heteroaryl that replace by alkyl, cycloalkyl, aryl or heteroaryl, wherein substituting group alkyl, cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has side basic nitrogen functional group;

-CONRaRb, wherein Ra and Rb are hydrogen or comprise 1-10 carbon atom randomly replaced and/or had side basic nitrogen functional group by at least one heteroatoms (for example halogen) linearity or branched-alkyl; Randomly the halogen that by at least one heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Or the cycloalkyl, aryl or the heteroaryl that replace by alkyl, cycloalkyl, aryl or heteroaryl, wherein substituting group alkyl, cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has side basic nitrogen functional group;

-NHCOOR, wherein R comprises 1-10 carbon atom randomly replaced and/or had side basic nitrogen functional group by at least one heteroatoms (for example halogen) linearity or branched-alkyl; Randomly the halogen that by at least one heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has cycloalkyl, aryl or the heteroaryl of side basic nitrogen functional group; Or the cycloalkyl, aryl or the heteroaryl that replace by alkyl, cycloalkyl, aryl or heteroaryl, wherein substituting group alkyl, cycloalkyl, aryl or the heteroaryl halogen that randomly by heteroatoms, particularly is selected from I, Cl, Br or F replaces and/or has side basic nitrogen functional group;

-CN group

-trifluoromethyl

R ⁶Be one of following:

8. compound according to claim 7, it is selected from N-(2-fluoro-3-trifluoromethyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide, N-(3-fluoro-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide, 4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-N-(3-trifluoromethyl-phenyl)-benzamide, 4-methyl-N-(4-methyl-3-trifluoromethyl-phenyl)-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide, N-(2-fluoro-5-trifluoromethyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide, N-(4-cyano group-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide, N-(4-fluoro-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide, N-(3-fluoro-4-methyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide, N-(the 4-tertiary butyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide, N-(3-cyano group-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide, N-(3-cyano group-4-methyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide, N-(3-bromo-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide, N-(3-bromo-4-methyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide, N-(3,5-two bromo-4-methyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide, N-(3-chloro-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide, N-(3-chloro-4-methyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide, N-(3-methoxyl group-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide, tolyl-benzamide between 4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-N-, N-(4-fluoro-3-methyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide, N-(3-iodo-4-methyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide, 4-methyl-N-(3-nitro-phenyl)-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide, 4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-N-p-methylphenyl-benzamide, 4-methyl-N-phenyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide, N-(3,4-dimethyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide, 4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-N-(3-trifluoromethoxy-phenyl)-benzamide, N-(3,4-dicyano-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide, N-(2-fluoro-5-methyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide, N-(2,4-two fluoro-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide, N-(4-cyano group-2-fluoro-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide, N-(2-fluoro-4-methyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide, N-(2,4-two fluoro-phenyl)-4-methyl-3-(4-pyridin-3-yl-thiazol-2-yl amino)-benzamide, N-(4-cyano group-2-fluoro-phenyl)-4-methyl-3-(4-pyridin-3-yl-thiazol-2-yl amino)-benzamide, N-(2-fluoro-4-methyl-phenyl)-4-methyl-3-(4-pyridin-3-yl-thiazol-2-yl amino)-benzamide, N-(4-cyano group-phenyl)-4-methyl-3-(4-pyridin-3-yl-thiazol-2-yl amino)-benzamide, N-(4-fluoro-phenyl)-4-methyl-3-(4-pyridin-3-yl-thiazol-2-yl amino)-benzamide, tolyl-benzamide between 4-methyl-3-(4-pyridin-3-yl-thiazol-2-yl amino)-N-, 4-methyl-3-(4-pyridin-3-yl-thiazol-2-yl amino)-N-(3-trifluoromethyl-phenyl)-benzamide, 4-methyl-N-(4-methyl-3-trifluoromethyl-phenyl)-3-(4-pyridin-3-yl-thiazol-2-yl amino)-benzamide, N-(2-fluoro-3-trifluoromethyl-phenyl)-4-methyl-3-(4-pyridin-3-yl-thiazol-2-yl amino)-benzamide, N-(4-cyano group-3-trifluoromethyl-phenyl)-4-methyl-3-(4-pyridin-3-yl-thiazol-2-yl amino)-benzamide, N-(4-cyano group-3-methyl-phenyl)-4-methyl-3-(4-pyridin-3-yl-thiazol-2-yl amino)-benzamide, 4-methyl-N-[4-(4-methyl-piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide, 4-methyl-N-{4-[1-(4-methyl-piperazine-1-yl)-ethyl]-phenyl }-3-(4-pyridin-3-yl-thiazol-2-yl amino)-benzamide, N-(3-dimethylamino-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-yl amino)-benzamide, N-(3-dimethylamino-phenyl)-4-methyl-3-(4-pyridin-3-yl-thiazol-2-yl amino)-benzamide.

9. pharmaceutical composition comprises arbitrary described compound according to claim 1-8.

10. pharmaceutical composition according to claim 9, it is suitable for oral administration.

11. the arbitrary described compound of claim 1-8 is used for the dermal drug composition or the make-up composition of topical.

12. veterinary composition comprises arbitrary described compound according to claim 1-8.

13. according to the application of the arbitrary described compound of claim 1-8 in the preparation medicine.

14. application according to claim 13, its preparation be used for the treatment of the medicine that is selected from following disease in application: autoimmune disease, allergic disease, bone loss, cancer such as aleukemic leukemia and GIST, tumor vessel take place, inflammatory diseases, as sacroiliitis, inflammatory bowel disease (IBD), interstitial cystitis, mastocytosis, transmissible disease, metabolic disease, fibrosis, diabetes or CNS illness.