CN103130791B - A kind of new benzamides compounds - Google Patents

Abstract

The present invention relates to pharmaceutical chemistry field, be specifically related to a kind of new benzamides compounds or its pharmaceutically acceptable salt, its preparation method, and the pharmaceutical composition that contains this compounds and in the application of preparing in antineoplastic.

Description

A kind of new benzamides compounds

Technical field

The present invention relates to pharmaceutical chemistry field, be specifically related to benzamide compound or its pharmacy of a class brand newUpper acceptable salt, and the pharmaceutical composition that contains this compounds and in the application of preparing in medicine.

Background technology

Malignant tumour is the No.1 killer of current human health, and its incidence of disease is only second to cardiovascular disease. Sending out of tumourRaw relevant with the overexpression of cell signal with development, protein kinase is subject to extensive concern as the important medium of signal conduction,Wherein EGFR-TK is the most extensive and important kinases family in human body, becomes target spot important in tumor research. CloselyNian Lai, though there is the exploitation listing of some novel tyrosine protein kinase inhibitors, but still cannot meet growing cancer far awayDisease patient's needs. Antineoplastic is still the important directions of research and development.

Protein kinase is that the phosphoric acid of atriphos (ATP) is transferred to specific serine, the threonine on proteinOr enzyme on tyrosine residue. The phenol of protein tyrosine kinase (PTKs) on can the multiple key protein tyrosine residue of catalysisHydroxyl generation phosphorylation, and then the function of mobilizing function albumen. In human body, in 520 multiple protein kinases, nearly half is junket ammoniaAcid kinase (PTKs). They have occupied very consequence in intracellular signal transduction pathway, regulate in cell body rawA series of physiology courses such as length, differentiation, death. Protein tyrosine kinase functional disturbance can cause a series of diseases in organismDisease, the known and a lot of disease associations of the abnormal signal that caused by it, comprise cancer, inflammation, autoimmune disease, metabolic diseaseDisease, infection, central nervous system disease and angiocardiopathy etc. Research shows, proto-oncogene more than half and oncogeneActivate all relevant to protein tyrosine kinase. The unconventionality expression of protein tyrosine kinase can cause cell proliferation to regulate generation disorderlyRandom, and then cause tumour to occur. In addition, the unconventionality expression of EGFR-TK also with invasion and attack and the transfer of tumour, the new blood vessel of tumourGeneration, the chemotherapy resistance to the action of a drug of tumour is closely related. Carry out antineoplastic research and development taking EGFR-TK as target spot and become the worldOn a focus, drug development mechanism of Ye Shi various countries study drop into emphasis.

The protein (p210Bcr-Abl) of Bcr-Abl gene expression 210kD. The Abl part of Bcr-Abl protein containsThe EGFR-TK of Abl, Abl is a kind of non-acceptor EGFR-TK, primary structure has the sarcoma homology 2 of N end(srchomology, SH2), SH1, SH2 is in conjunction with the tyrosine residue of phosphorylation, and SH1 has tyrosine kinase activity. It is formerIn the c-Abl of type, be subject to tight adjusting, but activated continuously in Bcr-Abl fused protein, thereby cause Growth of CellsOut of control. Bcr-Abl is present in the patient of 95% chronic myelogenous leukemia (CML), and 10-25% acute lymphoblastic is whiteIn the patient of blood disease (ALL). Gleevec is a kind of inhibitor of Bcr-Abl EGFR-TK, and controls through the clinical one that provesTreat effective inhibitor of chronic granulocytic leukemia. But lasting treatment with imatinib very easily produces drug resistance, some CMLPatient late or blast the phase of crisis can recur. Up to the present, existing 22 kinds of above mutant reported, as M244V,G250E、Q252H、Y253F、Y253H、E255K、F311L、T315I、F317L、M351T、F359V、V379I、L387M、H396PDeng, wherein modal is T315I.

Stem cell factor c-Kit (CD117) is a kind of growth factor receptors with tyrosine kinase activity, by former cancer baseBecause c-kit produces. C-kit sudden change causes the continuous activation of c-Kit EGFR-TK function, causes the tyrosine that is independent of partKinase activity, c-Kit autophosphorylation, and uncontrolled cellular proliferation. C-Kit has excessive table at most of gastrointestinal stromal tumorsReach and suddenly change. Gastrointestinal stromal tumor is mainly to occur in it the elderly, and approximately 70% tumour occurs under one's belt, 20-30%Occur in small intestine, be less than 10% and occur in esophagus, coton and rectal. Classical cancer chemotherapy means are to gastrointestinal stromal tumorInoperative, and Imatinib can reach effective treatment by suppressing c-Kit, shows the morbidity machine of c-Kit in these diseasesIn system, play a crucial role. C-Kit also has overexpression and sudden change in other various human cancers, comprises general mast cellIncrease disease, neuroblastoma, germinoma, ED-SCLC, breast cancer, melanoma, oophoroma, stem cell knurl,Acute myeloid leukaemia, nasal sinus lymthoma etc.

Vascular endothelial growth factor (VEGF) be embryo occur and wound healing process in start angiopoieticThe mitogen of a high special is also a kind of effectively vascularization and vasopermeability inducible factor. VEGF is so farTill the present, induction of vascular generates the strongest material, directly induction of vascular endothelial cell proliferation, migration and formation blood vessel. VEGF is GuangA member of propylhomoserin growth factor superfamily, belongs to a newcomer in EGFR-TK subfamily, its architectural feature and biologyLearning characteristic makes it rebuild side Zhi Xunhuan, tumor prognosis, metastases and implement targeted therapy and gene therapy in ischemic tissueBecome important research object in field.

Vascular endothelial growth factor receptor (VEGFR) is only present in Surface of Vascular Endothelial Cells, has tyrosine-kinaseEnzymatic activity. The VEGFR having confirmed at present has two kinds, i.e. fms sample EGFR-TK-1 (flt-1, VEGFR1) and tire liver kinases-1 (flk-1/KDR, VEGFR2). VEGFR2 has strong tyrosine kinase activity, is angiopoietic main signal transmissionBody, it has obvious chemotaxis and mitogenic activity, after activation, can cause vascular endothelial cell division, propagation andMigration. It is mainly expressed in tumor vascular endothelial cell, and in tumour epithelial cell, does not express or low expression. VEGFR-2 energyMediation forms the required all inner skin cell functions of tumor neogenetic blood vessels, comprises propagation, survival, migration, the blood vessel of endothelial cellForm and maintenance vasopermeability. It is targeted therapy taking new vessels as target that antineoplastic vascular forms, with respect to tumourCell is that the targeted therapy of target has certain superiority, and antitumor spectra is wide, and targeting is stable, after antibody enters in body, and canDirectly be combined with the VEGF/VEGFR of Surface of Vascular Endothelial Cells, do not need to penetrate blood vessel, easily enter people tumor area, generally,The vascularization that VEGF regulates is rare under the non-pathological state becoming in human body, so for the targeted therapy of VEGF and VEGFRConventionally seldom affect other normal physiology courses.

Platelet derived growth factor (PDGFs) must with cell membrane on corresponding receptors bind after its biology of competence exertion effectShould, pdgf receptor (PDGFR), if PDGFR-α and PDGFR-β are a kind of transmembrane glycoproteins, has protein tyrosine kinase activity.Its part forms (PDGF-A) by two A chains, or two B chains formation (PDGF-B), or the abnormity two of an A chain and a B chainPolymers forms. Once and ligand binding, platelet derived growth factor receptor forms dimer, and its EGFR-TK is activated,District sends signal downstream. Platelet derived growth factor signal and a series of disease association, growth factor signal path fromSecretion activates with some glioma, myeloproliferative disease, tumour, Huppert's disease and comprises knuckle skin fiber meatKnurls etc. are relevant. Platelet derived growth factor drives the organic disease reaction of vascular diseases, as narrow in atherosclerotic, arteryNarrow, pulmonary hypertension and retinal disease, and liver fibrosis disease, comprise pulmonary interstitial fibrosis, cirrhosis, chorionitis, kidneyBead sclerosis and myocardial fibrosis. Except above-mentioned disease, suppress PDGFR and can also treat various autoimmune diseases and inflammationProperty disease comprises diabetes, especially type i diabetes, rheumatoid arthritis, psoriasis and Crohn disease etc.

Summary of the invention

The invention provides structural formula suc as formula I compound or pharmaceutically acceptable salt,

Formula I

Wherein:

Ring C is 5 yuan of monocycles, can further contain 1 O atom, or contain 1 or 2 hetero atom that is independently selected from N, S; OrIt is 6 yuan～12 yuan monocycles that person encircles C, can further contain 1～4 hetero atom that is independently selected from O, N, S; Ring C is preferably five yuan of carbonThe hexatomic ring that ring, ring carbon atom are replaced by a nitrogen-atoms, 12 rings that ring carbon atom is replaced by four oxygen atoms; More preferably, the phenyl ring that ring C condenses with it forms following group,

R₁Hydrogen, tertbutyloxycarbonyl, NR₄R₅、NR₄(CH₂)nR₆，

Wherein R₄、R₅Independently be selected from hydrogen, C_1-6Alkyl, C_1-6Hydroxyalkyl, C_1-6Haloalkyl, C_1-6Cyanogen substituted alkyl, C_2-6Thiazolinyl,C_2-6Alkynyl, aryl, heteroaryl, cycloalkyl, Heterocyclylalkyl, or R₄、R₅Form heteroaryl or contain 1 with the N atom that is connected them～2 are independently selected from saturated 5 or 6 rings of N or the replacement of O atom, and described heteroaryl, saturated 5 or 6 rings also can be by C_1-6AlkaneBase, C_1-6Alkoxyl, C_1-6Hydroxyalkyl, C_1-6Haloalkyl, C_1-6Cyanogen substituted alkyl, halogen, cyano group, C_2-6Thiazolinyl, C_2-6Alkynyl, virtueThe group of base, heteroaryl, cycloalkyl or Heterocyclylalkyl replaces; Preferably, R₄、R₅Independently be selected from hydrogen, C_1-6Alkyl, or R₄、R₅Form and be selected from saturated 5 or 6 rings that N or O atom replace containing 1～2 with the N atom that is connected them, and described 5 or 6 yuanRing also can be further by C_1-6Alkyl replaces; More preferably, R₄、R₅Independently be selected from hydrogen, C_1-6Alkyl, or R₄、R₅CoupledN atom form and be selected from saturated 6 rings that N, O atom replace containing 1～2, and 6 described rings also can be further by C_1-6Alkyl replaces; Most preferred, R₄、R₅Independently be selected from hydrogen, methyl, ethyl, or R₄、R₅Coupled N atom forms morpholineRing, piperazine ring, piperidine ring, and described morpholine ring, piperazine ring, piperidine ring can be further by C_1-4Alkyl replace (for example methyl,Ethyl).

N is 1～6 integer, is preferably 1 or 2.

R₆Be selected from heteroaryl, NR₉R₁₀Or CHR₁₁R₁₂；

Wherein heteroaryl is preferably bicyclic heteroaryl, and more preferably 5 yuan of bicyclic heteroaryls, most preferably are imidazole radicals;

R₉And R₁₀Independently be selected from separately hydrogen, C_1-6Alkyl, C_1-6Hydroxyalkyl, C_1-6Haloalkyl, C_1-6Cyanogen substituted alkyl, C_2-6Thiazolinyl or C_2-6Alkynyl, or R₉And R₁₀The saturated heterocyclic alkyl that forms 5 or 6 rings together with connecting their nitrogen-atoms, this is fullReplaced by 1～2 hetero atom that is independently selected from N or O further with the available ring carbon atom of Heterocyclylalkyl, and described saturated heterocyclicAlkyl can be independently selected from tertbutyloxycarbonyl, halogen, cyano group, C by 1,2 or 3_1-6Alkyl, C_1-6Hydroxyalkyl, C_1-6Haloalkyl,C_1-6Cyanogen substituted alkyl, C_2-6Thiazolinyl, C_2-6The group of alkynyl replaces; Preferably, R₉And R₁₀Independently be selected from hydrogen or C_1-6Alkyl, orPerson R₉And R₁₀Form the saturated heterocyclic alkyl of 5 or 6 rings together with connecting their nitrogen-atoms, the ring carbon of this saturated heterocyclic alkylAtom can be replaced by 1～2 hetero atom that is independently selected from N or O further, and described saturated heterocyclic alkyl can be by 1,2 or 3Independently be selected from tertbutyloxycarbonyl, halogen, cyano group, C_1-6The group of alkyl replaces; More preferably, R₉And R₁₀Independently be selected fromHydrogen, C_1-4Alkyl, or R₉And R₁₀Form the saturated heterocyclic alkyl of 6 rings together with connecting their nitrogen-atoms, this saturated heterocyclicThe available ring carbon atom of alkyl is replaced by 1～2 hetero atom that is independently selected from N or O further, and described Heterocyclylalkyl alternativelyIndependently be selected from tertbutyloxycarbonyl or C by 1,2 or 3_1-4The group of alkyl replaces; Most preferred, R₉And R₁₀Independently be selected fromHydrogen, methyl or ethyl, or R₉And R₁₀Form and can be independently selected from tertiary fourth oxygen by 1 or 2 together with connecting their nitrogen-atomsMorpholine ring, piperazine ring, piperidine ring that carbonyl, methyl or ethyl replace.

R₁₁And R₁₂Form 5 yuan or 6 ring saturated cyclic alkyls together with connecting their carbon atom, this saturated cyclic alkylsAvailable ring carbon atom is replaced by 1～2 hetero atom that is independently selected from N or O further, and described saturated cyclic alkyls can be by 1 or 2Independently be selected from tertbutyloxycarbonyl, halogen, cyano group, C_1-6Alkyl, C_1-6Hydroxyalkyl, C_1-6Haloalkyl, C_1-6Cyanogen substituted alkyl, C_2-6Thiazolinyl or C_2-6The group of alkynyl replaces; Preferably, R₁₁And R₁₂Form 5 or 6 rings together with connecting their carbon atomSaturated cyclic alkyls, the available ring carbon atom of this saturated cyclic alkyls is replaced by 1～2 hetero atom that is independently selected from N or O further,And described saturated cyclic alkyls can be independently selected from tertbutyloxycarbonyl, halogen, cyano group, C by 1 or 2_1-6The group of alkyl replaces;More preferably, R₁₁And R₁₂Form 6 yuan of saturated cyclic alkyls together with connecting their carbon atom, the ring carbon of this saturated cyclic alkyls is formerSon can be replaced by 1～2 hetero atom that is independently selected from N or O further, and described cycloalkyl is alternatively by 1 or 2 independent choosingFrom in tertbutyloxycarbonyl or C_1-4The group of alkyl replaces; Most preferred, R₁₁And R₁₂Shape together with connecting their carbon and nitrogen atomsOne-tenth can be independently selected from the piperidine ring that tertbutyloxycarbonyl, methyl or ethyl replace by 1 or 2.

R₂Hydrogen, halogen, cyano group, nitro, C_1-6Alkyl, C_1-6Hydroxyalkyl, C_1-6Haloalkyl, C_1-6Cyanogen substituted alkyl or C_1-6Alkoxyl; R₂Preferably C_1-6Alkyl or halogen; R₂Most preferable.

Z is heteroaryl, selectively by 1,2 or 3 R₃Institute replaces; Z is preferably 5 yuan of bicyclic heteroaryls, 6 yuan of assorted virtues of monocycleThe bicyclic heteroaryl condensing between base, bicyclic heteroaryl, contains 1,2 or 3 ring hetero atom that is independently selected from N, O or S, and described is assortedAryl can be replaced by oxygen, and in heteroaryl, partial double bond can be replaced by hydrogen; Z is more preferably pyridine radicals, Imidazopyrazines base, imidazoPyridazinyl, thiazolyl, imidazole radicals, pyrazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazinyl, pyridazinyl, oxazinyl, 1,2,4-thiadiazolyl group, triazolyl, tetrazole radical, triazine radical, oxadiazolyl, 2-oxo-1,2-dihydropyridine base, 4-oxo-Isosorbide-5-Nitrae-Dihydropyridine base, purine radicals, pyrrolopyridinyl, pyrrolo-pyrimidine radicals, Pyrrolopyrazine base, Pyrazolopyridine base, pyrazoloPyrimidine radicals, Triazolopyridazines base, Triazolopyridine base, Bi Ding Bing oxazinyl, imidazopyridyl, 3-oxo-3,4-dihydro-pyrroleDing Bing oxazine, imidazolidine pyridine radicals, pyrrolin pyridine radicals; Z is pyridine radicals, Imidazopyrazines base, imidazoles more preferablyAnd pyridazinyl, thiazolyl; Z most preferably is pyridin-3-yl, imidazoles (1,2-b) pyridazine-3-base, thiazol-2-yl.

R₃Independently be selected from hydrogen, halogen, cyano group, OR_a、SR_a、NR_bR_c、C(O)NR_bR_c、C_1-6Alkyl, C_1-6Hydroxyalkyl, C_1-6Haloalkyl, C_1-6Cyanogen substituted alkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, NR_bC(O)R_d、NR_bS(O)₂R_d、S(O)₂NR_bR_c、C(O)R_d、C(O)OR_a、S(O)₂R_d, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl; R₃Be preferably hydrogen, halogen, cyano group, C_1-6Alkyl, NR_bR_c、C(O)NR_bR_c、NR_bC(O)R_d、C(O)R_d、C(O)OR_a, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl; R₃Be more preferably hydrogen, halogenElement, cyano group, C_1-6Alkyl, C (O) NR_bR_c、NR_bC(O)R_d、C(O)R_d、C(O)OR_a；R₃More preferably hydrogen, halogen, cyano group, C_1-4AlkaneBase, C (O) NR_bR_c、NR_bC(O)R_d；R₃Most preferably be hydrogen, chlorine, fluorine, methyl, ethyl, carbamoyl group (C (O) NHCH₃), acetyl ammoniaBase (NHC (O) CH₃)。

R_a、R_b、R_cAnd R_dIndependently be selected from hydrogen, C_1-6Alkyl, C_1-6Hydroxyalkyl, C_1-6Haloalkyl, C_1-6Cyanogen substituted alkyl, C_2-6AlkeneBase, C_2-6Alkynyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl, or R_bAnd R_cThe nitrogen-atoms shape together connecting with themBecome the Heterocyclylalkyl of 4,5,6 or 7 rings, and be independently selected from halogen, cyano group, C by 1,2 or 3 alternatively_1-6Alkyl, C_1-6HydroxylAlkyl, C_1-6Haloalkyl, C_1-6Cyanogen substituted alkyl, C_2-6Thiazolinyl, C_2-6The base of alkynyl, aryl, heteroaryl, cycloalkyl and HeterocyclylalkylGroup replaces. Preferably, R_a、R_b、R_cAnd R_dIndependently be selected from hydrogen, C_1-6Alkyl, C_1-6Hydroxyalkyl, C_1-6Haloalkyl, C_1-6Cyanogen generationAlkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl; More preferably, R_a、R_b、R_cAnd R_dIndependent choosingFrom in hydrogen, C_1-6Alkyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl; Preferred, R_a、R_b、R_cAnd R_dIndependently be selected from hydrogen,C_1-6Alkyl; Most preferred, R_a、R_b、R_cAnd R_dIndependently be selected from hydrogen, methyl, ethyl, n-pro-pyl, isopropyl.

In the compound or its salt of formula I of the present invention, being formula Ia compound or pharmaceutically can of a class preferred embodimentThe salt of accepting,

Formula Ia

Wherein:

Z and R₂Definition identical with formula I;

R₇Be selected from hydrogen, C_1-6Alkyl, C_1-6Alkoxyl, C_1-6Hydroxyalkyl, C_1-6Haloalkyl, C_1-6Cyanogen substituted alkyl, halogen, cyanogenBase, C_2-6Thiazolinyl, C_2-6Alkynyl, aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl; R₇Be preferably hydrogen or C_1-6Alkyl; R₇Most preferably beHydrogen or C_1-4Alkyl.

R₈Be selected from hydrogen, C_1-6Alkyl, C_1-6Alkoxyl, C_1-6Hydroxyalkyl, C_1-6Haloalkyl, C_1-6Cyanogen substituted alkyl, C_2-6Thiazolinyl,C_2-6Alkynyl, aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl; R₈Be preferably hydrogen or C_1-6Alkyl; R₈More preferably hydrogen or C_1-4AlkaneBase; R₈Most preferably be hydrogen or methyl.

In the compound or its salt of formula I of the present invention, another kind of is preferred embodiment formula Ib compound or pharmaceuticallyAcceptable salt,

Formula Ib

Wherein:

R₂、R₉, Rx and Z definition identical with formula I;

R₄Be selected from hydrogen, C_1-6Alkyl, C_1-6Hydroxyalkyl, C_1-6Haloalkyl, C_1-6Cyanogen substituted alkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, virtueBase, heteroaryl, cycloalkyl or Heterocyclylalkyl; Preferably, R₄Be selected from hydrogen, C_1-6Alkyl; Most preferred, R₄Be selected from hydrogen, methyl or secondBase.

Preferred compound of the present invention comprises:

1-(dimethylamino)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-2,3-dihydro-1H-Indenes-5-formamide

1-[N-methyl-N-[2-(dimethylamino) ethyl] amino]-N-{4-methyl-3-[4-(pyridine radicals-3-yl)] thiopheneAzoles-2-amino } phenyl-2,3-dihydro-1H-indenes-5-formamide

N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-[2-(4-morpholinyl) ethylamino]-2,3-dihydro-1H-indenes-5-formamide

(1S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-[2-(4-morpholinyl) ethylAmino]-2,3-dihydro-1H-indenes-5-formamide

(1R)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-[2-(4-morpholinyl) ethylAmino]-2,3-dihydro-1H-indenes-5-formamide

(S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-[2-(4-methyl piperazine-1-Base)-ethylamino]-2,3-dihydroindene-5-formamide

(S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-[N-methyl-N-[2-(4-firstBase piperazine-1-yl) ethyl] amino]-2,3-dihydroindene-5-formamide

(S)-N-{[4-methyl-3-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-methylamino-2,3-dihydroindene-5-formamide

(S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-[2-(dimethylamino) ethyl ammoniaBase]-2,3-dihydroindene-5-formamide

(S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-[N-methyl-N-(2-diformazan ammoniaBase ethyl) amino]-2,3-dihydroindene-5-formamide

(S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-dimethylamino-2,3-dihydroIndenes-5-formamide

(S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-[N-methyl-N-[2-(4-Quinoline base) ethyl] amino]-2,3-dihydroindene-5-formamide

N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-(4-methyl piperazine base)-2,3-dihydroChange indenes-5-formamide

N-{4-methyl-3-[4-(imidazoles [1,2-b] pyrazine-3-yl) thiazole-2-amino] phenyl }-1-[N-methyl-N-(2-dimethylaminoethyl) amino]-2,3-dihydroindene-5-formamide

(S)-N-{4-methyl-3-[4-(imidazoles [1,2-b] pyridazine-3-yl) thiazole-2-amino] phenyl }-1-(4-methylPiperazinyl)-2,3-dihydroindene-5-formamide

N-[4-methyl-3-(2 '-acetylaminohydroxyphenylarsonic acid 4,5 '-dithiazole-2-amino) phenyl]-1-[N-methyl-N-(2-diformazanAmino-ethyl) amino]-2,3-dihydroindene-5-formamide

N-[4-methyl-3-(2 '-acetylaminohydroxyphenylarsonic acid 4,5 '-dithiazole-2-amino) phenyl]-1-(4-methyl piperazine base)-2,3-dihydroindene-5-formamide

(S)-N-[4-methyl-3-(2 '-methyl-4,5 '-dithiazole-2-amino) phenyl]-1-(4-methyl piperazine base)-2,3-dihydroindene-5-formamide N-[4-methyl-3-(2 '-methyl-4,5 '-dithiazole-2-amino) phenyl]-1-(4-methyl piperazinePiperazine base)-2,3-dihydroindene-5-formamide

(S)-N-methyl-5-{2-[2-methyl-5-[1-(4-methyl piperazine base)-2,3-dihydroindene-5-formamido group]Phenyl amino] thiazole-4-yl } pyridine-2-carboxamide

(S)-N-{3-[4-(6-chlorine imidazoles [1,2-b] pyridazine-3-yl) thiazole-2-amino] phenyl }-1-(4-methyl piperazineBase)-2,3-dihydroindene-5-formamide

(S)-N-{3-[4-(6-flumizole [1,2-b] pyridazine-3-yl) thiazole-2-amino] phenyl }-1-(4-methyl piperazineBase)-2,3-dihydroindene-5-formamide

(1S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-tertiary the fourth of 1-{N-methyl-N-[(1-Oxygen carbonyl-piperidin-4-yl) methyl] amino }-2,3-dihydro-1H-indenes-5-formamide

(1S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-{N-methyl-N-[(piperidines-4-yl) methyl] amino }-2,3-dihydro-1H-indenes-5-formamide

(1S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-{N-methyl-N-[(1H-miaowAzoles-4-yl) methyl] amino }-2,3-dihydro-1H-indenes-5-formamide

6-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl amino formoxyl }-3,4-dihydro-isoquinoline-2 (1H)-carboxylic acid tert-butyl esters

N-{[4-methyl-3-(pyridin-3-yl) thiazole-2-amino] phenyl }-1,2,3,4-tetrahydroisoquinoline-6-formamide

7-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl amino formoxyl }-3,4-dihydro-isoquinoline-2 (1H)-carboxylic acid tert-butyl esters

N-{[4-methyl-3-(pyridin-3-yl) thiazole-2-amino] phenyl }-1,2,3,4-tetrahydroisoquinoline-7-formamide

N-{[4-methyl-3-(4-pyridin-3-yl) thiazole-2-amino] phenyl-2,3,5,6,8,9-hexahydrobenzene also [Isosorbide-5-Nitrae,7,10] four oxo cyclododecane-12-formamides

The present invention also provides a kind of method of preparing above-mentioned formula I compound, comprises following synthetic schemes:

Synthetic schemes 1

Compound formula 1-4 can use synthetic schemes 1 synthetic. 5-is bromo-2, and 3-dihydro 1-Indanone is through sodium borohydride reductionAfter obtain intermediate 1-1. Intermediate 1-1, with after thionyl chloride reaction, generates chloro intermediate 1-2, reacts with amine, uses potashFor alkali, can obtain intermediate 1-4. As the mixture 1-4 of enantiomter can be by chiral hplc orWith chiral acid, as camphorsulfonic acid, split and obtain single enantiomter pure compounds.

Synthetic schemes 2

Chiral intermediate 2-7 can be synthetic by synthetic schemes 2. 5-bromindion reacts the hand that obtains protection with chiral reagentProperty intermediate 2-1. Intermediate 2-1 obtains intermediate 2-2 with the de-sulfinyl of sour example hydrochloric acid. To after intermediate 2-2 protection, use carbonAcid potassium is made the synthetic intermediate 2-4 that obtains of alkali. Sodium hydrogen is made alkali, and intermediate 2-4 and iodomethane reaction obtain intermediate 2-5. By centreAfter body 2-5 deprotection, with ketone or aldehyde reaction, reduce and obtain chiral intermediate 2-7 with sodium cyanoborohydride.

When the t-butyl sulfonamide reaction of 5-bromindion configuration contrary to the above, and successively according to above-mentioned steps reaction,Can obtain the midbody compound contrary with 2-7 configuration.

Synthetic schemes 3

Chiral intermediate 3-5 can be synthetic by synthetic schemes 3. 5-bromindion reacts the hand that obtains protection with chiral reagentProperty intermediate 3-1. Intermediate 3-1 obtains intermediate 3-2 with the de-sulfinyl of sour example hydrochloric acid. Make alkali with sodium hydrogen or potash, inMesosome 3-2 and halogenated amine reaction obtain intermediate 3-3. To after intermediate 3-3 protection, make the synthetic intermediate that obtains of alkali with potash3-4. With formaldehyde, as methylating reagent, as reducing agent, reaction obtains intermediate 3-5 to sodium cyanoborohydride.

Synthetic schemes 4

Compound 4-4 can obtain by scheme 4 is synthetic. During 2-methyl-5-nitro aniline and ammonium thiocyanate reaction obtainMesosome 4-1. Intermediate 4-1 and bromine ethanone derivatives 4-2 reaction obtain nitro intermediate 4-3. A kind of reducing agent of intermediate 4-3As palladium/carbon, stannous chloride or Raney's nickel reduction obtain amino intermediate 4-4.

Synthetic schemes 5

Final compound general formula 5-3 can be according to synthetic shown in synthetic schemes 5. Carboxylate intermediate 5-1 can with alkali asNaOH or lithium hydroxide are hydrolyzed to carboxylic acid 5-2, and carboxylic acid 5-2 and anil obtain general formula 5-3 with coupling reagent condensationFinal compound. The final compound of general formula 5-3 can also try as coupling with LiHMDS by ester 5-1 and anilAgent reaction obtains.

Synthetic schemes 6

Final compound 6-3 can be synthetic by synthetic schemes 6. Intermediate 6-1 can be by it by R₁The chemical combination replacingThing and electrophilic reagent are as aldehyde, and ketone or anhydride reaction obtain. Intermediate 6-1 reacts with CO at a kind of alcohol, makes catalyst with palladium, therebyProvide intermediate general formula 6-2. The final compound of general formula 6-3 can use LiHMDS as coupling by ester 6-2 and anilAgent reaction obtains.

In above-mentioned synthetic schemes, substituent definition is identical with definition above, comprise definition that scope is the widest andAll preferred definition. R is C_1-6Alkyl, be preferably methyl, ethyl.

In many cases, due to amino and/or carboxylic group or the existence of group similarly, compound of the present inventionCan form acid and/or basic salt.

" compound " of the present invention comprises all stereoisomers, geometric isomer, dynamic isomer and isotope.

The compounds of this invention can be asymmetric, for example, has one or more stereoisomers. Unless separately hadBright, comprise all stereoisomers, as enantiomter and diastereoisomer. The Asymmetrical substitute carbon atom that contains of the present inventionCompound can be separated with the pure form of optical activity or racemic form. The pure form of optical activity can from outsideRacemic mixture splits, or uses chiral raw material or chiral reagent to synthesize.

The compounds of this invention also comprises tautomeric forms. Tautomeric forms derives from a singly-bound and adjacentThe migration of a proton is also followed in two key exchanges together.

The present invention also comprises all isotopic atoms, no matter is at intermediate or last compound. Isotopic formerAttached bag is drawn together has identical atomicity, but different quality number. For example, the isotope of hydrogen comprises tritium and deuterium.

The compounds of this invention also comprises pharmaceutically acceptable salt. Pharmaceutically acceptable salt refers in a parent compoundThe form of base group conversion salify. Pharmaceutically acceptable salt include but not limited to, for example amine (ammonia) base inorganic orOrganic acid salt. Pharmaceutically acceptable salt of the present invention can be synthesized by parent compound, i.e. basic group in parent compoundGroup reacts in a solvent system with the acid of 1-4 equivalent. Suitable salt is set forth in Remingtong ' sPharmaceuticalScicences, 17thed., MackPublishingCompany, Easton, Pa., 1985, p.1418 and JournalofPharmaceuticalScience, in 66,2 (1977).

Pharmaceutically acceptable acid-addition salts can be prepared by inorganic and organic acid. The inorganic acid of derived acids addition salts comprisesHydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc. The organic acid of derived acids addition salts comprise acetic acid, propionic acid, glycolic, pyruvic acid,Oxalic acid, malic acid, malonic acid, butanedioic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, firstSulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid, salicylic acid etc.

The compounds of this invention and pharmaceutically acceptable salt also comprise solvate or hydrate forms. In general, moltenThe form of agent compound or hydrate and the form of non-solvent compound are equal to, and contain within the scope of the invention. In the present inventionLikely there is polycrystal or unbodied form in some compound. Generally speaking, all physical form have equal useOn the way, and contain within the scope of the invention.

Except as otherwise noted, the term adopting herein has following implication:

" halogen " comprises fluorine, chlorine, bromine and iodine.

“C_1-6Alkyl " refer to the saturated hydrocarbons group of straight or branched, for example methyl, ethyl, propyl group (for example n-pro-pyl and differentPropyl group), butyl (for example normal-butyl, isobutyl group, the tert-butyl group), amyl group (for example n-pentyl, isopentyl, neopentyl), n-hexyl.

" hydroxyalkyl " refers to the alkyl that hydroxyl replaces.

" haloalkyl " refers to the alkyl that one or more halogens replace, for example CH₂F、CHF₂、CF₃、C₂F₅、CCl₃Deng.

" cyanoalkyl " or " cyanogen substituted alkyl " refers to the alkyl that cyano group replaces.

" thiazolinyl " refers to the alkyl with one or more carbon-carbon double bonds, for example vinyl, acrylic, 1,3-butadiene,Maleic base, anti-cyclobutenyl etc.

" alkynyl " refers to the alkyl with one or more carbon carbon triple bonds, such as acetenyl, propinyl etc.

" cycloalkyl " comprises cycloalkyl group and Heterocyclylalkyl, refers to that the group that contains one or more saturated carbon rings (comprisesVolution), cycloalkyl can have 3 to 20 carbon atoms. The example of cycloalkyl comprise cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl,Suberyl etc.

" Heterocyclylalkyl " refers to that the atom of one or more Cheng Huan in " cycloalkyl " is hetero atom, as former in oxygen, nitrogen or sulphurSon. The example of preferred Heterocyclylalkyl includes but not limited to oxolane, thiophane, pyrrolidines, oxazolidine, thiazolidine, miaowAzoles alkane, isoxazole alkyl, isothiazolidine, pyrazolidine, morpholine, thiomorpholine, piperazine, piperidyl etc.

" aryl " refers to full carbon monocycle or the fused polycycle group of 14 carbon atoms at the most, has the pi-electron body of total conjugatedSystem; The limiting examples of aryl is phenyl, naphthyl and anthryl, can be replacement or unsubstituted.

" heteroaryl " comprise bicyclic heteroaryl that bicyclic heteroaryl, phenyl ring and bicyclic heteroaryl condense, bicyclic heteroaryl itBetween the bicyclic heteroaryl that condenses, containing 1,2 or 3 ring hetero atom that is independently selected from N, O or S, remaining annular atoms is C, can haveThe pi-electron system of total conjugated. Described heteroaryl can be replaced by oxygen, and for example the one-tenth theheterocyclic nitrogen atom in heteroaryl can be by oxygenChange and form nitrogen oxygen composition, in heteroaryl, partial double bond can be replaced by hydrogen. Preferred heteroaryl is containing 5-12 annular atoms, more preferablyContaining 5-10 annular atoms. The bicyclic heteroaryl that can enumerate includes but not limited to pyrrole radicals, furyl, thienyl, pyridine radicals, pyrroleMutter base, imidazole radicals, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrimidine radicals, pyrazinyl, pyridazinyl, oxazineBase, 1,2,4-thiadiazolyl group, triazolyl, tetrazole radical, triazine radical, oxadiazolyl, 2-oxo-1,2-dihydropyridine, 4-oxo-1,4-dihydropyridine. The bicyclic heteroaryl condensing between bicyclic heteroaryl includes but not limited to purine radicals, pyrrolopyridinyl, pyrrolesAnd pyrimidine radicals, Pyrrolopyrazine base, Pyrrolopyridazine base, Pyrazolopyridine base, pyrazolopyrimidine base, pyrazolo pyridazine base, pyrroleAzoles pyrazinyl, Triazolopyridazines base, Triazolopyridine base, Bi Ding Bing oxazine, Bi Ding Bing oxazine, imidazopyridyl, imidazolesAnd pyridazinyl, 3-oxo-3,4-dihydro-Bi Ding Bing oxazine, imidazolidine pyridine radicals, pyrrolin pyridine radicals. Phenyl ring withThe bicyclic heteroaryl that bicyclic heteroaryl condenses includes but not limited to benzofuranyl, benzothienyl, benzothiazolyl, indolesBase, indazolyl, quinolyl, isoquinolyl, carbazyl, benzimidazolyl. Preferred five yuan or six membered heteroaryl non-limitingExample be thienyl, furyl, pyranose, pyrrole radicals, imidazole radicals, pyrazolyl, pyridine radicals, pyrazinyl, pyrimidine radicals, pyridazinyl,Thiazolyl, oxazolyl, isoxazolyl, isothiazolyl.

On the other hand, the invention provides a kind of method that regulates albumen kinase activity, comprising described albumen is swashedEnzyme contacts with above-claimed cpd or its pharmaceutically acceptable salt.

Preferably, described protein kinase is selected from Abl, VEGFR2, c-Kit and PDGFR β. In addition, described protein kinase comprisesThe kinases of sudden change, its mutant kinase is selected from the Abl kinases of sudden change.

Moreover, the present invention provide above-claimed cpd or its pharmaceutically acceptable salt for the preparation for the treatment of disease simultaneously orApplication in the medicine of imbalance, wherein said disease or imbalance be relevant to protein kinase activity or with the abnormal phase of cell proliferationClose.

In addition, the present invention also provides a kind of method for the treatment of patient disease or imbalance, wherein said disease or imbalance be withKinase activity is correlated with, and comprises the above-claimed cpd from effective dose to patient or its pharmaceutically acceptable salt that give.

" treatment effective dose " refers in the time needing the mammal of such treatment, is enough to the effectively general formula for the treatment ofThe amount of compound. Treatment effective dose by depend on healing potion used given activity, patient age, physiological situation, itsThe existence of his morbid state and nutrition condition and change. In addition the treatment of other medicines that, patient may just accept will be to by impactDetermining of the treatment effective dose of the healing potion giving.

" treatment " means any treatment to disease in mammalian body, comprising:

I) prevent disease, cause the clinical symptoms of disease not develop;

Ii) suppress disease, stop the development of clinical symptoms; And/or

Iii) palliate a disease, cause disappearing of clinical symptoms.

It is individually dosed that compound or its salt of the present invention can be used as active material, preferably with the form of its pharmaceutical compositionAdministration.

Another aspect of the present invention, provides a kind of pharmaceutical composition, and it contains formula I compound defined herein or itsSalt and pharmaceutically acceptable carrier.

Said composition can be the form that is applicable to oral administration (for example tablet, hard or soft capsule, water or oil suspension, breastAgent, dispersible powder or granule etc.), be suitable for form (for example finely divided powder or the liquid aerosol of inhalationAgent), the form that is suitable for the outer injection of stomach and intestine is (for example, in intravenous, subcutaneous, muscle, in blood vessel or infusion administration asepticSolution, powder-injection, supensoid agent or emulsion), be suitable for form (for example ointment, gel, water or the oil solution or mixed of topicalSuspension), be suitable for the form (for example suppository) of rectally.

Above-mentioned composition can make with conventional method with acceptable carrier in conventional pharmaceutical. For example, oral administrationComposition can be first by this compound with conventional pharmaceutically acceptable carrier as excipient, disintegrant, adhesive, lubricatedThe mixing such as agent, coating agent, colouring agent, are made into required formulation, as granule, capsule, tablet etc.

The amount of application of the compounds of this invention can according to the type of route of administration, patient's age, body weight, the disease for the treatment of,The variations such as the order of severity, its daily dose can be 0.01～50mg/Kg. In general, by the form administration of the outer injection of stomach and intestineTime dosage lower, preferred oral administration.

The compounds of this invention and salt thereof can give separately or combine use with other therapeutic agent of the above-mentioned disease for the treatment of. EspeciallyIt is, in antineoplaston, should consider and other chemotherapeutics, hormone or antibody drug drug combination. Therefore, of the present inventionClose therapy and comprise other activating agent of at least one formula I compound or its salt and at least one. Formula I compound or its salt and otherActivating agent can give together or separately give, and in the time separately giving, can successively give simultaneously or with any order.

Detailed description of the invention

With specific embodiment, the present invention is described in further detail below, but content of the present invention is not limited to these enforcementExample.

Embodiment 1:1-(dimethylamino)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-2,3-The preparation of dihydro-1H-indenes-5-formamide

Steps A: 5-is bromo-2,3-dihydroindene-1-alcohol

5-is bromo-2, and 3-dihydro 1-Indanone (5 grams, 23.8 mMs) is suspended in the methyl alcohol of 100 milliliters. Under agitationSlowly add sodium borohydride (1 gram, 26.4 mMs), within approximately 10 minutes, add. Stir after 1 hour, solvent decompression is removed again. Add100 milliliters of ethyl acetate, then add 100 milliliters of saturated sodium bicarbonate solutions. Through the stirring of 30 minutes, water separatory funnelRemove, organic phase saturated aqueous common salt washed twice, with anhydrous sodium sulfate drying, obtains 4.8 grams of title compounds after concentrating.¹H-NMR(CDCl₃)δ7.40(1H，d，J＝8Hz)，7.36(1H，d，J＝4Hz)，7.29(1H，t，J＝8.8Hz)，5.22(1H，dd，J＝4Hz)，3.05-3.00(1H，m)，2.85-2.80(1H，m)，2.54-2.49(1H，m)，2.00-1.93(1H，m)，1.72(1H，d，J＝8Hz).

The bromo-1-of step B:5-is chloro-2,3-dihydroindene

By bromo-5-2,3-dihydroindene-1-alcohol (4.8 grams, 22.6 mMs) is dissolved in the carrene of 30 milliliters,Carrene (20 milliliters) solution of the cooling lower slow dropping thionyl chloride of ice bath (6.7 milliliters), adds for approximately 20 minutes. In room temperatureLower stirring is after 2 hours, and reduced pressure concentration is except desolventizing. Residue is dissolved in 100 milliliters of ethyl acetate. This frozen water for solution (3 ×50 milliliters) and saturated aqueous common salt (3 × 50 milliliters) washing, dried over sodium sulfate, obtains 5 grams of title compounds after concentrating.¹H-NMR(CDCl₃)δ7.40(1H，d，J＝8Hz)，7.36(1H，d，J＝4Hz)，7.29(1H，t，J＝8.8Hz)，5.37(1H，dd，J＝4Hz)，3.21-3.14(1H，m)，2.92-2.85(1H，m)，2.65-2.56(1H，m)，2.41-2.35(1H，m).

Step C:N, N-dimethyl-5-is bromo-2, the preparation of 3-dihydro-1H-indenes-1-amine

By chloro-bromo-5-1-2,3-dihydroindene (100 milligrams, 0.43 mM) is dissolved in 15 milliliters of acetonitriles. Add carbonAcid potassium (70 milligrams, 0.51 mM) and dimethylamine (120 milligrams, 0.88 mM, 33% aqueous solution). Mixture is at 60 DEG CUnder condition, stir and spend the night. Insoluble matter is filtered to be removed, concentrated 100 milligrams of the title compounds (96%) that obtain of filtrate.¹H-NMR(CDCl₃)δ7.35(1H，d，J＝8Hz)，7.32(1H，d，J＝4Hz)，7.22(1H，d，J＝8Hz)，4.27(1H，t，J＝6Hz)，2.91-2.88(1H，m)，2.84-2.78(1H，m)，2.21(6H，s)，2.08-2.01(2H，m).

Step D:1-(dimethylamino)-2,3-dihydro-1H-indenes-5-carboxylic acid, ethyl ester

By N, N-dimethyl-5-is bromo-2, and 3-dihydro-1H-indenes-1-amine (100 milligrams, 0.42 mM) solvent is in ethanol(20 milliliters). Successively by methyl-sulfoxide (0.08 milliliter), triethylamine (0.08 milliliter), palladium (30 milligrams, 0.13 mM)Join in reaction system with 1,3-bis-(diphenylphosphine) propane (50 milligrams, 0.12 mM). After being vacuumized, system passes intoCarbon monoxide stirs 24 hours at 100 DEG C. Insoluble matter is removed by filter, after filtrate is concentrated, separate acetic acid second with silicagel columnEster/benzinum (V/V=3/2) obtains 40 milligrams of title compounds (41%) as eluant, eluent.¹H-NMR(CDCl₃)δ7.92(1H，d，J＝8Hz)，7.80(1H，d，J＝8Hz)，7.44(1H，d，J＝8Hz)，4.39-4.34(2H，m)，2.98-2.94(1H，m)，2.88-2.86(1H，m)，2.41-2.40(1H，m)，2.60(6H，s)，2.24-2.08(2H，m)，1.41(3H，t，J＝16Hz).

Step e: 1-(dimethylamino)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-2,3-bis-The preparation of hydrogen-1H-indenes-5-formamide

By 1-(dimethylamino)-2,3-dihydro-1H-indenes-5-carboxylic acid, ethyl ester (100 milligrams, 0.43 mM) and 6-methyl-N¹-(4-(pyridin-3-yl) thiazol-2-yl) phenyl-1,3-diamines (145 milligrams, 0.51 mM) is dissolved in the tetrahydrochysene of new steamingIn furans (20 milliliters). Under ice bath is cooling, LiHMDS (1.7 milliliters, 1M) is added drop-wise in reaction system. This system is in room temperatureLower stirring is spent the night, and the water of about 10 milliliters adds in reactant liquor, and extracts with carrene (3 × 20 milliliters). Organic phase nothingAqueous sodium persulfate is dry, and the thick product silica gel that reduced pressure concentration obtains is prepared plate separating-purifying (methylene chloride/methanol=10/1) and obtainedTo 50 milligrams of title compounds (25%).¹H-NMR(CDCl₃)δ9.06(1H，s)，8.48(1H，d，J＝4Hz)，8.29(1H，d，J＝4Hz)，8.12(1H，d，J＝8Hz)，7.75(1H，s)，7.73(1H，d，J＝8Hz)，7.54(2H，d，J＝8Hz)，7.31-7.27(2H，m)，7.18(1H，d，J＝8Hz)，6.83(1H，s)，4.52(1H，t，J＝4Hz)，2.99-2.79(2H，m)，2.33(9H，s)，2.19-2.10(2H，m).MS：m/z，470.2(M+H).

Wherein 6-methyl-N¹-(4-(pyridin-3-yl) thiazol-2-yl) phenyl-1, the preparation method of 3-diamines is as follows,

The preparation of the bromo-thiazole-2-of step (1): N-(2-methyl-5-nitrophenyl)-4-amine

By 2,4-, bis-bromo thiazoles (20.6 mMs), 2-methyl-5-nitro aniline (22.6 mMs), potash (61.8MM), two (diphenylphosphine)-9 of three (dibenzalacetone) two palladiums (0.618 mM) and 4,5-, 9-dimethyl oxa-anthracene(1.9 mMs) are mixed in toluene (100 milliliters). With nitrogen replacement 3 times, at 100 DEG C, stir and spend the night. Be cooled to room temperature,Add 50 ml waters, use dichloromethane extraction 3 times. Extract anhydrous sodium sulfate drying, column chromatography (benzinum: ethyl acetate=1: 1) separate and obtain 2.2 grams of title compounds.¹H-NMR(CDCl₃)δ7.55(1H，dd，J＝2.4Hz&J＝2.4Hz)，7.50(1H，d，J＝2Hz)，7.17(1H，d，J＝8Hz)，3.89(2H，brs)，2.24(3H，s).

The preparation of step (2): N-(2-methyl-5-nitrophenyl)-4-(3-pyridine radicals)-thiazole-2-amine

3-pyridine boric acid (5 mMs), step (1) compound (5 mMs) are dissolved in dioxane-water (1: Isosorbide-5-Nitrae 0ml)In, add potash (15 mMs), with argon replaces gas 3 times, then add two (triphenyl phosphorus) palladium chlorides (1 mM),Heating reflux reaction 10h. Cooling, remove solvent under reduced pressure, residue dissolves with carrene, anhydrous sodium sulfate drying, column chromatographyObtain N-(2-methyl-5-nitrophenyl)-4-(3-pyridine radicals)-0.9 gram of thiazole-2-amine. MS:m/z, 313.0 (M+H)

Step (3): N¹-[4-(3-pyridine radicals)-thiazol-2-yl]-6-methyl isophthalic acid, the preparation of 3-phenylenediamine

Stannous chloride (6.6 mMs) is dissolved in 4 milliliters of concentrated hydrochloric acids. Under ice-water bath is cooling, by the change of step (2)Compound (0.5 gram, 1.6 mMs) slowly adds in reaction system, and at room temperature stirs 6 hours. System is poured in trash ice,, be extracted with ethyl acetate 3 times to 10 left and right with solid sodium hydroxide adjusting pH. Extract anhydrous sodium sulfate drying, decompression is steamedAfter heating up in a steamer the thick product carrene recrystallization obtaining except desolventizing, obtain 6-methyl-N¹-(4-(pyridin-3-yl) thiazole-2-Base) phenyl-1,0.375 gram of 3-diamines.

Embodiment 2:1-[N-methyl-N-[2-(dimethylamino) ethyl] amino]-N-{4-methyl-3-[4-(pyridine radicals-3-Base)] thiazole-2-amino } phenyl-2, the preparation of 3-dihydro-1H-indenes-5-formamide

Steps A: N¹-(5-bromo-2,3-dihydroindene-1-yl)-N¹，N²，N²-trimethyl ethylenediamine

Obtain 250 milligrams of title compounds according to the synthetic method of step C in embodiment 1 and trimethyl reacting ethylenediamine.¹H-NMR(CDCl₃)δ7.35-7.30(2H，m)，7.23(1H，d，J＝8Hz)，4.38(1H，t，J＝8Hz)，3.00-2.96(6H，m)，3.79(3H，s)，2.33(3H，s)，2.23(3H，s)，2.15-2.01(2H，m).

Step B:1-[N-methyl-N-[2-(dimethylamino) ethyl] amino]-2, the system of 3-dihydroindene-5-carboxylic acid, ethyl esterStandby

Obtain 50 milligrams of title compounds according to the synthetic method of step D in embodiment 1 and ethanol synthesis.¹H-NMR(CDCl₃)δ7.91-7.90(2H，m)，7.44(1H，d，J＝8Hz)，4.55(1H，t，J＝6Hz)，4.39(2H，q，J＝8Hz)，3.11-3.07(3H，m)，2.99-2.96(1H，m)，2.92-2.84(2H，m)，2.81(6H，s)，2.23(3H，s)，2.19-2.10(2H，m)，1.28(3H，t，J＝8Hz).

Step C:1-[N-methyl-N-[2-(dimethylamino) ethyl] amino]-N-{4-methyl-3-[4-(pyridine radicals-3-Base)] thiazole-2-amino } phenyl-2, the preparation of 3-dihydro-1H-indenes-5-formamide

According to the synthetic method of step e in embodiment 1 and 6-methyl-N¹-(4-(pyridin-3-yl) thiazol-2-yl) phenyl-1,3-diamine reactant obtains 30 milligrams of title compounds.¹H-NMR(CDCl₃)δ9.06(1H，s)，8.50(1H，d，J＝4Hz)，8.40(1H，s)，8.29(1H，d，J＝4Hz)，8.12(1H，d，J＝8Hz)，7.77(1H，s)，7.73(1H，d，J＝8Hz)，7.57(1H，d，J＝8Hz)，7.49(1H，brs)，7.31(1H，dd，J＝8Hz)，7.20(1H，d，J＝8Hz)，6.85(1H，s)，4.52(1H，t，J＝4Hz)，2.99-2.79(6H，m)，2.81(6H，s)，2.33(3H，s)，2.26(3H，s)，2.19-2.10(2H，m).MS：m/z，527.3(M+H).

Embodiment 3:N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-[2-(4-morpholinyl) secondBase amino]-2, the preparation of 3-dihydro-1H-indenes-5-formamide

Steps A: N-[2-(4-morpholinyl) ethyl]-5-is bromo-2,3-dihydroindene-1-amine

Obtain 130 milligrams of title compounds according to the synthetic method of step C in embodiment 1 and 2-(4-morpholinyl) ethamine.¹H-NMR(CDCl₃)δ7.35-7.30(2H，m)，7.23(1H，d，J＝8Hz)，4.22(1H，t，J＝8Hz)，3.71-3.67(4H，m)，2.99-2.95(1H，m)，2.84-2.75(3H，m)，2.57-2.51(2H，m)，2.49-2.45(4H，m)，1.88-1.80(2H，m).

Step B:1-[2-(4-morpholinyl) ethylamino]-2, the preparation of 3-dihydroindene-5-carboxylic acid, ethyl ester

Obtain 100 milligrams of title compounds according to the synthetic method of step D in embodiment 1.¹H-NMR(CDCl₃)δ7.91-7.90(2H，m)，7.44(1H，d，J＝8Hz)，4.55(1H，t，J＝6Hz)，4.39(2H，q，J＝8Hz)，3.66(4H，brs)，3.06(1H，brs)，2.87-2.81(3H，m)，2.66-2.62(2H，m)，2.43(5H，brs)，2.12(2H，brs)，1.40-1.37(3H，t，J＝6Hz).

Step C:N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-[2-(4-morpholinyl) ethylAmino]-2, the preparation of 3-dihydro-1H-indenes-5-formamide

According to the synthetic method of step e in embodiment 1 and 6-methyl-N¹-(4-(pyridin-3-yl) thiazol-2-yl) phenyl-1,3-diamine reactant obtains 50 milligrams of title compounds.¹H-NMR(CDCl₃)δ9.06(1H，s)，8.50(1H，d，J＝4Hz)，8.40(1H，s)，8.29(1H，d，J＝4Hz)，8.12(1H，d，J＝8Hz)，7.77(1H，s)，7.73(1H，d，J＝8Hz)，7.57(1H，d，J＝8Hz)，7.49(1H，brs)，7.31(1H，dd，J＝8Hz)，7.20(1H，d，J＝8Hz)，6.85(1H，s)，4.52(1H，t，J＝4Hz)，3.66(4H，brs)，3.06(1H，brs)，2.87-2.81(3H，m)，2.66-2.62(2H，m)，2.43(5H，brs)，2.26(3H，s)，2.13(2H，brs).MS：m/z，555.2(M+H).

Embodiment 4:(1S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-[2-(4-morpholineBase) ethylamino]-2, the preparation of 3-dihydro-1H-indenes-5-formamide

Steps A: (S)-N-[(1S)-5-is bromo-2,3-dihydroindene-1-yl] preparation of-t-butyl sulfonamide

By bromo-5-2,3-dihydro-1H-1-Indanone (20 grams, 948 mMs) and (S)-t-butyl sulfonamide (11.6Gram, 95.7 mMs) be dissolved in anhydrous tetrahydro furan (200 milliliters), add purity titanium tetraethoxide (50 milliliters). At 70 DEG C, addReact 20 hours, be cooled to after-50 DEG C, slowly add sodium borohydride solids (14.8 grams). Under room temperature condition, react 5 hours. ?Under ice bath is cooling, add 100 ml waters, be extracted with ethyl acetate, concentrated rear column chromatography for separation obtains 8.2 grams of title compounds.¹H-NMR：(CDCl₃)：δ7.46(1H，d，J＝8.0Hz)，7.38(1H，d，J＝3.2Hz)，7.35(1H，d，J＝1.6Hz)，4.84(1H，q，J＝14.0Hz)，3.42(1H，d，J＝6.8Hz)，3.03-2.96(1H，m)，2.87-2.79(1H，m)，2.54-2.46(1H，m)，2.06-1.97(1H，m)，1.24(9H，s).

Step B:(S)-5-is bromo-2, the preparation of 3-dihydroindene-1-amine hydrochlorate

By (S)-N-[(1S)-5-is bromo-2,3-dihydroindene-1-yl]-t-butyl sulfonamide (8.2 grams, 26 mMs)Be mixed in carrene (100 milliliters), pass into hydrogen chloride gas, react concentrated 5 grams of the title compounds that obtain after 4 hours.¹H-NMR(CDCl₃)：δ7.34(1H，s)，7.29(1H，d，J＝25.6Hz)，7.19(1H，J＝7.6Hz)，4.28(1H，t，J＝7.6Hz)，2.96-2.89(1H，m)，2.82-2.74(1H，m)，2.53-2.45(1H，m)，1.74-1.64(1H，m)，1.55(2H，s).

Step C:(S) the bromo-N-[2-of-5-(4-morpholinyl) ethyl]-2, the preparation of 3-dihydroindene-1-amine

React and obtain title compound with the bromo-2-of 1-(4-morpholinyl) ethane according to the synthetic method of step C in embodiment 1250 milligrams.¹H-NMR(CDCl₃)δ7.35-7.30(2H，m)，7.23(1H，d，J＝8Hz)，4.22(1H，t，J＝8Hz)，3.71-3.67(4H，m)，2.99-2.95(1H，m)，2.84-2.75(3H，m)，2.57-2.51(2H，m)，2.49-2.45(4H，m)，1.88-1.80(2H，m).

Step D:(S)-1-[2-(4-morpholinyl) ethylamino]-2, the preparation of 3-dihydroindene-5-carboxylic acid, ethyl ester

Obtain 60 milligrams of title compounds according to the synthetic method of embodiment 1 step D.¹H-NMR(CDCl₃)δ7.91-7.90(2H，m)，7.44(1H，d，J＝8Hz)，4.55(1H，t，J＝6Hz)，4.39(2H，q，J＝8Hz)，3.66(4H，brs)，3.06(1H，brs)，2.87-2.81(3H，m)，2.66-2.62(2H，m)，2.43(5H，brs)，2.12(2H，brs)，1.40(3H，t，J＝6Hz).

Step e: (1S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-[2-(4-morpholineBase) ethylamino]-2, the preparation of 3-dihydro-1H-indenes-5-formamide

According to the synthetic method of step e in embodiment 1 and 6-methyl-N¹-(4-(pyridin-3-yl) thiazol-2-yl) phenyl-1,3-diamine reactant obtains 35 milligrams of title compounds.¹H-NMR(CDCl₃)δ9.06(1H，s)，8.50(1H，d，J＝4Hz)，8.40(1H，s)，8.29(1H，d，J＝4Hz)，8.12(1H，d，J＝8Hz)，7.77(1H，s)，7.73(1H，d，J＝8Hz)，7.57(1H，d，J＝8Hz)，7.49(1H，brs)，7.31(1H，dd，J＝8Hz)，7.20(1H，d，J＝8Hz)，6.85(1H，s)，4.52(1H，t，J＝4Hz)，3.66(4H，brs)，3.06(1H，brs)，2.87-2.81(3H，m)，2.66-2.62(2H，m)，2.43(5H，brs)，2.26(3H，s)，2.13(2H，brs).MS：m/z，555.2(M+H).

Embodiment 5:(1R)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-[2-(4-morpholineBase) ethylamino]-2, the preparation of 3-dihydro-1H-indenes-5-formamide

Steps A: (R)-N-[(1R)-5-is bromo-2,3-dihydroindene-1-yl] preparation of-t-butyl sulfonamide

Method with reference to embodiment 4 steps A obtains 8.2 grams of title compounds with (R)-t-butyl sulfonamide.¹H-NMR：(CDCl₃)：δ7.46(1H，d，J＝8.0Hz)，7.38(1H，d，J＝3.2Hz)，7.35(1H，d，J＝1.6Hz)，4.84(1H，q，J＝14.0Hz)，3.42(1H，d，J＝6.8Hz)，3.03-2.96(1H，m)，2.87-2.79(1H，m)，2.54-2.46(1H，m)，2.06-1.97(1H，m)，1.24(9H，s).

Step B:(R)-5-is bromo-2, the preparation of 3-dihydroindene-1-amine hydrochlorate

Obtain 5 grams of title compounds according to the method for embodiment 4 step B.¹H-NMR：(CDCl₃)：δ7.34(1H，s)，7.29(1H，d，J＝25.6Hz)，7.19(1H，J＝7.6Hz)，4.28(1H，t，J＝7.6Hz)，2.96-2.89(1H，m)，2.82-2.74(1H，m)，2.53-2.45(1H，m)，1.74-1.64(1H，m)，1.55(2H，s).

Step C:(R) the bromo-N-[2-of-5-(4-morpholinyl) ethyl]-2, the preparation of 3-dihydroindene-1-amine

React with 2-chloroethyl-4-morpholine according to the synthetic method of step C in embodiment 4 and obtain title compound 130 millisGram.¹H-NMR(CDCl₃)δ7.35-7.30(2H，m)，7.23(1H，d，J＝8Hz)，4.22(1H，t，J＝8Hz)，3.71-3.67(4H，m)，2.99-2.95(1H，m)，2.84-2.75(3H，m)，2.57-2.51(2H，m)，2.49-2.45(4H，m)，1.88-1.80(2H，m).

Step D:(R)-1-[2-(4-morpholinyl) ethylamino]-2, the preparation of 3-dihydroindene-5-carboxylic acid, ethyl ester

Obtain 60 milligrams of title compounds according to the synthetic method of step D in embodiment 4.¹H-NMR(CDCl₃)δ7.91-7.90(2H，m)，7.44(1H，d，J＝8Hz)，4.55(1H，t，J＝6Hz)，4.39(2H，q，J＝8Hz)，3.66(4H，brs)，3.06(1H，brs)，2.87-2.81(3H，m)，2.66-2.62(2H，m)，2.43(5H，brs)，2.12(2H，brs)，1.40(3H，t，J＝6Hz).

Step e: (R)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-[2-(4-morpholinyl)Ethylamino]-2, the preparation of 3-dihydro-1H-indenes-5-formamide

According to the synthetic method of step e in embodiment 4 and 6-methyl-N¹-(4-(pyridin-3-yl) thiazol-2-yl) phenyl-1,3-diamine reactant obtains 35 milligrams of title compounds.¹H-NMR(CDCl₃)δ9.06(1H，s)，8.50(1H，d，J＝4Hz)，8.40(1H，s)，8.29(1H，d，J＝4Hz)，8.12(1H，d，J＝8Hz)，7.77(1H，s)，7.73(1H，d，J＝8Hz)，7.57(1H，d，J＝8Hz)，7.49(1H，brs)，7.31(1H，dd，J＝8Hz)，7.20(1H，d，J＝8Hz)，6.85(1H，s)，4.52(1H，t，J＝4Hz)，3.66(4H，brs)，3.06(1H，brs)，2.87-2.81(3H，m)，2.66-2.62(2H，m)，2.43(5H，brs)，2.26(3H，s)，2.13(2H，brs).MS：m/z，555.2(M+H).

Embodiment 6:(S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-[2-(4-methylPiperazine-1-yl)-ethylamino]-2, the preparation of 3-dihydroindene-5-formamide

Steps A: the bromo-N-[2-of (S)-5-(4-methylpiperazine-1-yl) ethyl]-2, the preparation of 3-dihydroindene-1-amine

Being mixed with under cooling to ice bath (S)-N-((S)-5-bromo-2,3-dihydroindene-1-yl)-t-butyl sulfonamideIn dry DMF (20 milliliters) solution of (embodiment 4 steps A compounds) (420 milligrams, 1.3 mMs), add sodium hydrogen (520 millisGram, 21.7 mMs), stir and after 30 minutes, add 1-(2-chloroethyl)-4-methyl piperazine hydrochloride (365 milligrams, 2.25 millis rubYou) continue to stir and spend the night. The cancellation that adds water after system is cooling, is extracted with ethyl acetate, in the middle of column chromatography for separation obtains after dry515 milligrams of bodies.

Add 10 milliliters of concentrated hydrochloric acids to being mixed with in the methanol solution of above-claimed cpd (515 milligrams, 1.52 mMs). Room temperatureLower stirring, after 2 hours, with 2N sodium hydrate aqueous solution adjusting pH to 10, is extracted with ethyl acetate. After extract is dried and concentratesTo 400 milligrams of title compounds.¹H-NMR(CDCl3)：δ7.32(1H，s)，7.31(1H，d，J＝8.0Hz)，7.20(1H，d，J＝7.6Hz)，4.35(1H，t，J＝7.6Hz)，2.88-2.82(1H，m)，2.80-2.76(1H，m)，2.55-2.46(10H，m)，2.27-2.24(2H，m)，2.24(3H，s)，2.09-1.98(2H，m).

Step B:(S)-1-[2-(4-methylpiperazine-1-yl) ethylamino]-2, the system of 3-dihydroindene-5-carboxylic acid, ethyl esterStandby

Obtain 10 milligrams of title compounds according to the synthetic method of step D in embodiment 1.¹H-NMR(CDCl₃)：δ7.91(1H，s)，7.89(1H，d，6.8Hz)，7.30(1H，d，J＝6.0Hz)，4.39-4.31(3H，m)，3.47-3.00(2H，m)，2.91(5H，m)，2.65-2.39(8H，m)，2.35(3H，s)，1.98-1.92(2H，m)，1.39(3H，t，J＝7.2Hz).

Step C:(S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-[2-(4-methyl piperazinePiperazine-1-yl)-ethylamino]-2, the preparation of 3-dihydroindene-5-formamide

According to the synthetic method of step e in embodiment 1 and 6-methyl-N¹-(4-(pyridin-3-yl) thiazol-2-yl) phenyl-1,3-diamine reactant obtains 3 milligrams of title compounds.¹H-NMR(CDCl₃)δ9.06(1H，s)，8.50(1H，d，J＝4Hz)，8.40(1H，s)，8.29(1H，d，J＝4Hz)，8.12(1H，d，J＝8Hz)，7.77(1H，s)，7.73(1H，d，J＝8Hz)，7.57(1H，d，J＝8Hz)，7.49(1H，brs)，7.31(1H，dd，J＝8Hz)，7.20(1H，d，J＝8Hz)，6.93(1H，s)，4.33(1H，t，J＝6Hz)，3.10-3.05(1H，m)，2.90-2.83(1H，m)，2.28-2.78(4H，m)，2.47(8H，brs)，2.33(3H，s)，2.21(3H，s)，2.10-2.03(1H，m)，1.95-1.90(1H，m).MS：m/z，568.3(M+H).

Embodiment 7:(S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-[N-methyl-N-[2-(4-methylpiperazine-1-yl) ethyl] amino]-2, the preparation of 3-dihydroindene-5-formamide

Steps A: (S)-1-{N-methyl-N-[2-(4-methylpiperazine-1-yl) ethyl] amino }-2,3-dihydroindene-5-The preparation of carboxylic acid, ethyl ester

To being mixed with (S)-1-[2-(4-methylpiperazine-1-yl) ethylamino]-2,3-dihydroindene-5-carboxylic acid, ethyl ester (130Milligram, 0.39 mM) ethanolic solution in add formaldehyde (58 milligrams, 0.77 mM) and formic acid (45 milligrams, 0.96 rub in the leastYou). Stir after 5 minutes, add sodium cyanoborohydride (37 milligrams, 0.58 mM). Under room temperature, stir 4 hours, use 1N hydrogen-oxygenChange sodium water solution and regulate pH to 10 dichloromethane extraction. Dry concentrated 140 milligrams of the title compounds that obtain of extract(100％)。MS：m/z，346.24(M+H).

Step B:(S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-[N-methyl-N-[2-(4-methylpiperazine-1-yl) ethyl] amino]-2, the preparation of 3-dihydroindene-5-formamide

According to the synthetic method of step e in embodiment 1 and 6-methyl-N¹-(4-(pyridin-3-yl) thiazol-2-yl) phenyl-1,3-diamine reactant obtains 3 milligrams of title compounds.¹H-NMR(CDCl₃)δ9.06(1H，s)，8.50(1H，d，J＝4Hz)，8.40(1H，s)，8.29(1H，d，J＝4Hz)，8.12(1H，d，J＝8Hz)，7.77(1H，s)，7.73(1H，d，J＝8Hz)，7.57(1H，d，J＝8Hz)，7.49(1H，brs)，7.31(1H，dd，J＝8Hz)，7.20(1H，d，J＝8Hz)，6.93(1H，s)，4.33(1H，t，J＝6Hz)，3.10-3.05(1H，m)，2.90-2.83(1H，m)，2.28-2.78(4H，m)，2.47(8H，brs)，2.36(3H，s)，2.33(3H，s)，2.21(3H，s)，2.10-2.03(1H，m)，1.95-1.90(1H，m).MS：m/z，582.3(M+H).

Embodiment 8:(S)-N-{[4-methyl-3-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-methylamino-2,3-bis-The preparation of hydrogenation indenes-5-formamide

Steps A: (S)-N-methyl-5-is bromo-2, the preparation of 3-dihydroindene-1-amine

According to the synthetic method of steps A in embodiment 7, the compound of embodiment 4 step B, through reaction, obtains title chemical combination250 milligrams of things.¹H-NMR(CDCl₃)δ7.35(1H，d，J＝8Hz)，7.32(1H，d，J＝4Hz)，7.22(1H，d，J＝8Hz)，4.29(1H，t，J＝6Hz)，3.08-3.05(1H，m)，2.91-2.88(1H，m)，2.56(3H，s)，2.08-2.01(2H，m).

Step B:(S)-1-methylamino-2, the preparation of 3-dihydroindene-5-carboxylic acid, ethyl ester

Obtain 60 milligrams of title compounds according to the synthetic method of step D in embodiment 1.¹H-NMR(CDCl₃)δ7.92(1H，d，J＝8Hz)，7.80(1H，d，J＝8Hz)，7.44(1H，d，J＝8Hz)，4.39-4.34(3H，m)，3.08-3.05(1H，m)，2.91-2.88(1H，m)，2.60(3H，s)，2.41-2.40(1H，m)，2.08-1.98(1H，m)，1.41(3H，t，J＝16Hz).

Step C:(S)-N-{[4-methyl-3-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-methylamino-2,3-dihydroChange the preparation of indenes-5-formamide

According to the synthetic method of step e in embodiment 1 and 6-methyl-N¹-(4-(pyridin-3-yl) thiazol-2-yl) phenyl-1,3-diamine reactant obtains 35 milligrams of title compounds.¹H-NMR(CDCl₃)δ9.07(1H，s)，8.53(1H，d，J＝8Hz)，8.31(1H，s)，8.15(2H，d，J＝8Hz)，7.74(1H，s)，7.71(2H，d，J＝8Hz)，7.33-7.30(1H，m)，7.22(2H，d，J＝4Hz)，7.15(1H，brs)，6.89(1H，s)，4.29(1H，t，J＝6Hz)，3.08-3.05(1H，m)，2.91-2.88(1H，m)，2.56(3H，s)，2.08-2.01(2H，m).MS：m/z，456.2(M+H).

Embodiment 9:(S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-[2-(diformazan ammoniaBase) ethylamino]-2, the preparation of 3-dihydroindene-5-formamide

Steps A: (S)-N¹-(5-bromo-2,3-dihydroindene-1-yl)-N²，N²The preparation of-dimethyl-ethylenediamine

According to the chloro-N of method 2-of embodiment 6 steps A, the reaction of N-dimethyl amine obtains 250 milligrams of title compounds.¹H-NMR(CDCl₃)δ7.35-7.30(2H，m)，7.23(1H，d，J＝8Hz)，4.38(1H，t，J＝8Hz)，3.00-2.96(6H，m)，2.33(3H，s)，2.23(3H，s)，2.15-2.01(2H，m).

Step B:(S)-1-[2-(dimethylamino) ethylamino]-2, the preparation of 3-dihydroindene-5-carboxylic acid, ethyl ester

Obtain 60 milligrams of title compounds according to the synthetic method of step D in embodiment 1. MS:m/z, 277.37 (M+H).

Step C:(S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-[2-(dimethylamino)Ethylamino]-2, the preparation of 3-dihydroindene-5-formamide

According to the synthetic method of step e in embodiment 1 and 6-methyl-N¹-(4-(pyridin-3-yl) thiazol-2-yl) phenyl-1,3-diamine reactant obtains 8 milligrams of title compounds.¹H-NMR(CDCl₃)δ9.06(1H，s)，8.50(1H，d，J＝4Hz)，8.29(1H，d，J＝4Hz)，8.25(1H，s)，8.12(1H，d，J＝8Hz)，7.73(2H，d，J＝8Hz)，7.46(1H，d，J＝8Hz)，7.31-7.27(2H，m)，7.20(1H，d，J＝8Hz)，6.88(1H，s)，4.52(1H，t，J＝4Hz)，2.99-2.79(2H，m)，2.46(6H，s)，2.33(3H，s)，2.19-2.10(2H，m).MS：m/z，513.2(M+H).

Embodiment 10:(S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-[N-methyl-N-(2-dimethylaminoethyl) amino]-2, the preparation of 3-dihydroindene-5-formamide

Steps A: (S)-1-[N-methyl-N-(2-dimethylaminoethyl) amino]-2,3-dihydroindene-5-carboxylic acid, ethyl esterPreparation

(S)-1-[2-(dimethylamino) ethylamino of embodiment 9 step B]-2,3-dihydroindene-5-carboxylic acid, ethyl esterObtain 250 milligrams of title compounds with reference to the synthetic method of steps A in embodiment 7, MS:m/z, 291.2 (M+H).

Step B:(S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-[N-methyl-N-(2-Dimethylaminoethyl) amino]-2, the preparation of 3-dihydroindene-5-formamide

Obtain 35 milligrams of title compounds according to the synthetic method of step e in embodiment 1.¹H-NMR(CDCl₃)δ9.06(1H，s)，8.50(1H，d，J＝4Hz)，8.29(1H，d，J＝4Hz)，8.25(1H，s)，8.12(1H，d，J＝8Hz)，7.73(2H，d，J＝8Hz)，7.46(1H，d，J＝8Hz)，7.31-7.27(2H，m)，7.20(1H，d，J＝8Hz)，6.88(1H，s)，4.52(1H，t，J＝4Hz)，2.99-2.79(2H，m)，2.46(6H，s)，2.33(3H，s)，2.26(3H，s)，2.19-2.10(2H，m).MS：m/z，527.3(M+H).

Embodiment 11:(S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-dimethylamino-The preparation of 2,3-dihydroindene-5-formamide

Steps A: (S)-1-dimethylamino-2, the preparation of 3-dihydroindene-5-carboxylic acid, ethyl ester

(S)-1-methylamino-2 of embodiment 8 step B, 3-dihydroindene-5-carboxylic acid, ethyl ester is with reference to embodiment 7 steps AMethod obtains 60 milligrams of title compounds.¹H-NMR(CDCl₃)δ7.92(1H，d，J＝8Hz)，7.80(1H，d，J＝8Hz)，7.44(1H，d，J＝8Hz)，4.39-4.34(3H，m)，3.08-3.05(1H，m)，2.91-2.88(1H，m)，2.60(6H，s)，2.41-2.40 (1H, m), 2.08-1.98 (1H, m), 1.41 (3H, t, J=16Hz). step B:(S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-dimethylamino-2, the preparation of 3-dihydroindene-5-formamide

According to the synthetic method of step e in embodiment 1 and 6-methyl-N¹-(4-(pyridin-3-yl) thiazol-2-yl) phenyl-1,3-diamine reactant obtains 37 milligrams of title compounds.¹H-NMR(CDCl₃)δ9.06(1H，s)，8.48(1H，d，J＝4Hz)，8.29(1H，d，J＝4Hz)，8.12(1H，d，J＝8Hz)，7.75(1H，s)，7.73(1H，d，J＝8Hz)，7.54(2H，d，J＝8Hz)，7.31-7.27(2H，m)，7.18(1H，d，J＝8Hz)，6.83(1H，s)，4.52(1H，t，J＝4Hz)，2.99-2.79(2H，m)，2.33(9H，s)，2.19-2.10(2H，m).MS：m/z，470.2(M+H).

Embodiment 12:(S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-[N-methyl-N-[2-(4-morpholinyl) ethyl] amino]-2, the preparation of 3-dihydroindene-5-formamide

Steps A: (S)-1-[N-methyl-N-[2-(4-morpholinyl) ethyl] amino]-2,3-dihydroindene-5-carboxylic acid, ethyl esterPreparation

(S)-1-[2-(4-morpholinyl) ethylamino of embodiment 4 step D]-2,3-dihydroindene-5-carboxylic acid, ethyl ester rootObtain 230 milligrams of title compounds according to the method for embodiment 7 steps A.¹H-NMR(CDCl₃)：δ7.28(1H，s)，7.26(1H，d，J＝8.0Hz)，7.19(1H，d，J＝8.0Hz)，4.37(1H，t，J＝7.2Hz)，3.64(4H，t，J＝4.4Hz)，2.84-2.76(4H，m)，2.54-2.44(4H，m)，2.39-2.27(4H，m)，2.27(3H，s)，2.09-2.06(2H，m)，1.98-1.95(1H，m).

Step B:(S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-[N-methyl-N-[2-(4-morpholinyl) ethyl] amino]-2, the preparation of 3-dihydroindene-5-formamide

According to the synthetic method of step e in embodiment 1 and 6-methyl-N¹-(4-(pyridin-3-yl) thiazol-2-yl) phenyl-1,3-diamine reactant obtains 35 milligrams of title compounds.¹H-NMR(CDCl₃)δ9.06(1H，s)，8.50(1H，d，J＝4Hz)，8.40(1H，s)，8.29(1H，d，J＝4Hz)，8.12(1H，d，J＝8Hz)，7.77(1H，s)，7.73(1H，d，J＝8Hz)，7.57(1H，d，J＝8Hz)，7.49(1H，brs)，7.31(1H，dd，J＝8Hz)，7.20(1H，d，J＝8Hz)，6.85(1H，s)，4.52(1H，t，J＝4Hz)，3.70(4H，brs)，2.95-2.83(2H，m)，2.60-2.56(4H，m)，2.47(4H，brs)，2.30(6H，s)，2.19-2.03(2H，m).MS：m/z，569.3(M+H).

Embodiment 13:N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-(4-methyl piperazineBase)-2, the preparation of 3-dihydroindene-5-formamide

The preparation of steps A: 1-(5-bromo-2,3-dihydroindene-1-yl)-4-methyl piperazine

React and marked with N methyl piperazine according to the compound of the synthetic method embodiment 1 step B of embodiment 1 step C0.8 gram of compound of topic (62%).¹H-NMR(CDCl₃)δ7.34(1H，s)，7.30(1H，d，J＝8.0Hz)，7.20(1H，d，J＝8.0Hz)，4.28(1H，t，J＝7.2Hz)，2.90-2.86(1H，m)，2.83-2.79(1H，m)，2.70-2.32(8H，m)，2.28(3H，s)，2.13-2.04(2H，m).

Step B:1-(4-methyl piperazine base)-2, the preparation of 3-dihydroindene-5-carboxylic acid, ethyl ester

Obtain 210 milligrams of title compounds according to the synthetic method of embodiment 1 step D.¹H-NMR(CDCl₃)7.89(1H，d，J＝8.8Hz)，7.88(1H，s)，7.40(1H，d，J＝8.8Hz)，4.39-4.33(3H，m)，2.95-2.92(1H，m)，2.88-2.82(1H，m)，2.80-2.30(8H，m)，2.29(3H，s)，2.16-2.11(2H，m)，1.38(3H，t，J＝7.2Hz).

Step C:N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-(4-methyl piperazine base)-2,The preparation of 3-dihydroindene-5-formamide

According to the synthetic method of embodiment 1 step e and 6-methyl-N¹-(4-(pyridin-3-yl) thiazol-2-yl) phenyl-1,3-diamine reactant obtains 250 milligrams of title compounds.¹H-NMR(CDCl₃)δ9.06(1H，s)，8.50(1H，d，J＝4Hz)，8.40(1H，s)，8.29(1H，d，J＝4Hz)，8.12(1H，d，J＝8Hz)，7.77(1H，s)，7.73(1H，d，J＝8Hz)，7.57(1H，d，J＝8Hz)，7.49(1H，brs)，7.31(1H，dd，J＝8Hz)，7.20(1H，d，J＝8Hz)，6.93(1H，s)，4.33(1H，t，J＝6Hz)，3.10-3.05(1H，m)，2.90-2.83(1H，m)，2.68(8H，brs)，2.40(3H，s)，2.33(3H，s)，2.17-2.14(2H，m).MS：m/z，525.2(M+H).

Embodiment 14:N-{4-methyl-3-[4-(imidazoles [1,2-b] pyridazine-3-yl) thiazole-2-amino] phenyl }-1-[N-Methyl-N-(2-dimethylaminoethyl) amino]-2, the preparation of 3-dihydroindene-5-formamide

Steps A: the preparation of 3-bromine imidazoles [1,2-b] pyridazine

Imidazoles [1,2-b] pyridazine (6.0 grams, 50 mMs) is dissolved in chloroform (50 milliliters) to N-bromo fourth twoAcid imide (NBS) (9.8 grams, 55 mMs) slowly adds wherein. System return stirring 30 minutes. After cool to room temperature, by pHValue is adjusted to 8-9 with saturated aqueous sodium carbonate, is extracted with ethyl acetate. Extract washes with water, saturated common salt washing, anhydrous sulphurAcid sodium is dry, after concentrating, obtains 9.9 grams of title compounds.¹H-NMR(CDCl₃)：δ8.47(1H，dd，J＝1.6Hz，J＝4.4Hz)，7.96(1H，dd，J＝1.6Hz，J＝9.2Hz)，7.80(1H，s)，7.09-7.12(1H，dd，J＝4.4Hz，J＝9.2Hz).

The preparation of step B:1-(imidazoles [1,2-b] pyridazine-3-yl) ethyl ketone

3-bromine imidazoles [1,2-b] pyridazine (6.8 grams, 34.3 mMs) is dissolved in to anhydrous tetrahydro furan (50 millis that heavily steamRise) in. Under nitrogen protection, the tetrahydrofuran solution of ethylmagnesium bromide (1M, 51.5 milliliters) is slowly added drop-wise to body at 0 DEG CIn system and stir after 30 minutes, by the tetrahydrofuran solution (30 of N-methoxyl group-N-methylacetamide (7.1 grams, 68.7 mMs)Milliliter) be slowly added drop-wise in system. Temperature of reaction system stirs 10 hours after being returned to room temperature. Water (50 milliliters) adds reaction bodyAfter system, be extracted with ethyl acetate. Extract anhydrous sodium sulfate drying, concentrated rear column chromatography (benzinum: ethyl acetate=10: 1By 1: 1) separate and obtain 3.4 grams of title compounds.¹H-NMR(CDCl₃)：δ8.61(1H，dd，J＝1.2Hz，J＝4.0Hz)，8.45(1H，s)，8.10(1H，dd，J＝1.6Hz，J＝9.2Hz)，7.27-7.30(1H，dd，J＝4.4Hz&J＝9.2Hz)，2.75(3H，s).

The preparation of the bromo-1-of step C:2-(imidazoles [1,2-b] pyridazine-3-yl) ethyl ketone hydrobromate

Under ice-water bath is cooling, to the glacial acetic acid that is mixed with 1-(imidazoles [1,2-b] pyridazine-3-yl) ethyl ketone (20.5 mMs)In the solution of (50 milliliters), slowly drip bromine (16.6 mMs). At 100 DEG C, add reaction 1 hour, cooling after, filter receiveThe precipitation that collection produces, washes with ether, is dried and obtains thick product. This product is dissolved in carrene, uses saturated sodium carbonate waterSolution is washed, and after organic phase is dry, concentrated, obtains 3.2 grams of title compounds.¹H-NMR(CDCl₃)：δ8.68(1H，s)，8.62(1H，dd，J＝1.2Hz，J＝4.4Hz)，8.35(1H，dd，J＝1.2Hz&J＝9.2Hz)，7.54-7.57(1H，dd，J＝4.4Hz&J＝9.2Hz)，4.86(2H，s).

The preparation of step D:N-(2-methyl-5-nitro benzene) thiazole-4-(imidazoles [1,2-b] pyridazine-3-yl)-2-amine

1-(2-methyl-5-nitro benzene) thiocarbamide (5.68 mMs) potash (8.4 grams, 60.9 mMs) is miscible in to 50In ml methanol. Under high degree of agitation, by bromo-2-1-(imidazoles [1,2-b] pyridazine-3-yl) ethyl ketone hydrobromate (1.3 grams,4.05 mMs) add stirring reaction 3 hours. Add 50 milliliters, water, after gained sedimentation and filtration, wash 3 times, ether is washed 3 times,Dry 1.4 grams of the title compounds that obtain.¹H-NMR(CDCl₃)：δ9.87(1H，s)，9.59(1H，d，J＝2.0Hz)，8.90(1H，d，J＝3.6Hz)，8.81(1H，s)，8.61(1H，dd，J＝1.2Hz&J＝8.0Hz)，7.90(1H，s)，7.81(1H，dd，J＝2.0Hz&J＝8.0Hz)，7.61(1H，q，J＝4.4Hz)，7.48(1H，d，J＝8.0Hz)，2.48(3H，t，J＝1.6Hz).

Step e: N¹-[4-(imidazoles [1,2-b] pyridazine-3-yl) thiazol-2-yl]-6-methyl-phenyl-1, the system of 3-diaminesStandby

Stannous chloride (1.32 grams, 6.96 mMs) is dissolved in 30 milliliters of concentrated hydrochloric acids. In the cooling elder generation of ice-water bath, by 4-(imidazoles [1,2-b] pyridazine-3-yl)-N-(2-methyl-5-nitro benzene) thiazole-2-amine (2.0 grams, 5.7 mMs) slowly addsIn reaction system, and at room temperature stir 6 hours. System is poured in trash ice, with solid sodium hydroxide regulate pH to 10 left and right,Be extracted with ethyl acetate 3 times. Extract anhydrous sodium sulfate drying, decompression distillation goes out the thick product dichloromethane that desolventizing obtainsAfter alkane recrystallization, obtain 1.68 grams of title compounds.¹H-NMR(CDCl₃)：δ9.19(1H，s)，8.70(1H，dd，J＝1.6Hz&J＝3.6Hz)，8.22(1H，dd，J＝1.6Hz&J＝9.2Hz)，7.65(1H，s)，7.30(1H，q，J＝4.4Hz)，7.16(1H，d，J＝2.4Hz)，6.85(1H，d，J＝8.0Hz)，6.27(1H，dd，J＝2.4Hz，J＝8.0Hz)，4.95(2H，s)，2.10(3H，s).

Step F: N-{4-methyl-3-[4-(imidazoles [1,2-b] pyridazine-3-yl) thiazole-2-amino] phenyl }-1-[N-firstBase-N-(2-dimethylaminoethyl) amino]-2, the preparation of 3-dihydroindene-5-formamide

According to the synthetic method of embodiment 1 step e, with 1-[N-methyl-N-[2-(dimethylamino) of embodiment 2 step BEthyl] amino]-2, the reaction of 3-dihydroindene-5-carboxylic acid, ethyl ester obtains 15 milligrams of title compounds.¹H-NMR(CDCl₃)：δ8.62-8.63(2H，m)，8.39(1H，s)，8.06(2H，dd，J＝1.6Hz&J＝7.6Hz)，7.79(1H，s)，7.54(1H，d，J＝8.4Hz)，7.27-7.30(2H，m)，7.21(1H，d，J＝8.4Hz)，4.54(1H，t，J＝7.2Hz)，3.00-3.13(3H，m)，2.89-2.97(1H，m)，2.76-2.83(2H，m)，2.68(6H，s)，2.34(3H，s)，2.27(3H，s)，2.15-2.22(2H，m).MS：m/z，567.3(M+H).

Embodiment 15:(S)-N-{4-methyl-3-[4-(imidazoles [1,2-b] pyridazine-3-yl) thiazole-2-amino] phenyl }-1-(4-methyl piperazine base)-2, the preparation of 3-dihydroindene-5-formamide

Steps A: the preparation of (S)-1-(5-bromo-2,3-dihydroindene-1-yl)-4-methyl piperazine

4-methyl isophthalic acid-(5-bromo-2,3-dihydroindene-1-yl) piperazine (10 grams, 33.9 mMs) and L (-)-camphorsulfonic acid(15.7 grams, 67.6 mMs) are dissolved in methyl alcohol, add isopropyl alcohol (200 milliliters), and then mixture refluxes 10 minutes. ReactionAfter mixture cool to room temperature, stirring is spent the night. After must filtering, to a large amount of solids, be dissolved in methyl alcohol (30 milliliters) and isopropyl alcohol(75 milliliters). After vlil 15 minutes, and then under room temperature, stir 24 hours. After filtration, obtain a large amount of mixtures, willIt is dissolved in 1M sodium hydrate aqueous solution (30 milliliters), under room temperature, stirs after 30 minutes, adds ethyl acetate (50 milliliters). MixedCompound is extracted with ethyl acetate, organic phase saturated common salt water washing, and anhydrous sodium sulfate drying, after Vacuum Concentration, obtains title1.2 grams of compounds (12% productive rate). The chiral purity detecting through chiral hplc is e.e.=98.38%.¹H-NMR(CDCl₃)δ7.34(1H，s)，7.30(1H，d，J＝8.0Hz)，7.20(1H，d，J＝8.0Hz)，4.27(1H，t，J＝7.2Hz)，2.94-2.86(1H，m)，2.83-2.75(1H，m)，2.55-2.43(8H，br，s)，2.28(3H，s)，2.16-2.01(2H，m)。

Step B:(S)-1-(4-methyl piperazine base)-2, the preparation of 3-dihydroindene-5-Ethyl formate

Obtain 0.9 gram of title compound according to the synthetic method of embodiment 1 step D.¹H-NMR(CDCl₃)7.89(1H，d，J＝8.8Hz)，7.88(1H，s)，7.40(1H，d，J＝8.8Hz)，4.39-4.33(3H，m)，2.95-2.92(1H，m)，2.88-2.82(1H，m)，2.80-2.30(8H，m)，2.29(3H，s)，2.16-2.11(2H，m)，1.38(3H，t，J＝7.2Hz).

Step C:(S)-N-{4-methyl-3-[4-(imidazoles [1,2-b] pyridazine-3-yl) thiazole-2-amino] phenyl }-1-(4-methyl piperazine base)-2, the preparation of 3-dihydroindene-5-formamide

According to the synthetic method of embodiment 1 step e, with the N of embodiment 14 step e¹-[4-(imidazoles [1,2-b] pyridazine-3-Base) thiazol-2-yl]-6-methyl-phenyl-1,3-diamine reactant obtains 49 milligrams of title compounds.¹H-NMR(CDCl₃)：δ8.63-8.66(2H，m)，8.41(1H，s)，8.09(2H，dd，J＝1.2Hz&J＝8.0Hz)，7.81-7.84(3H，m)，7.54(1H，d，J＝8.4Hz)，7.28-7.33(2H，m)，7.22(1H，d，J＝8.4Hz)，4.46(1H，t，J＝7.2Hz)，3.00-3.13(3H，m)，2.68(6H，s)，2.62-2.66(2H，m)，2.51(3H，s)，2.34(3H，s)，2.14-2.24(2H，m).MS：m/z，565.2(M+H).

Embodiment 16:N-[4-methyl-3-(2 '-acetylaminohydroxyphenylarsonic acid 4,5 '-dithiazole-2-amino) phenyl]-1-[N-methyl-N-(2-dimethylaminoethyl) amino]-2, the preparation of 3-dihydroindene-5-formamide

Steps A: the preparation of 2-acetyl bromide acetaldehyde

Under nitrogen protection, acetone (751 mMs) and acetaldehyde (631 mMs) are added slowly and are mixed with methyl alcohol respectivelyIn ether (200 milliliters) solution of sodium (750 mMs). In dropping process, maintain reaction temperature at 25-30 DEG C. Dropwise,System stirs after 15 minutes produced solid filtering is collected, and washes with ether, after being dried, obtains 46.5 grams, intermediate.

Above-mentioned gained compound is dissolved in carrene (500 milliliters), is cooled to-70 DEG C. By bromine, (430 millis rubYou) carrene (50 milliliters) solution be slowly added drop-wise in reaction system, and at this temperature, stir after 8 hours reaction temperatureDegree returns to room temperature. After sedimentation and filtration in system is collected, wash with carbon tetrachloride, after being dried, obtain 26.8 grams of title compounds。¹H-NMR(CDCl₃)：δ8.34(1H，s)，2.32(3H，s).

The preparation of step B:2-amino--5-acetyl thiazole hydrobromide salt

2-acetyl bromide acetaldehyde (67 mMs) is dissolved in acetone (300 milliliters). Under ice-water bath is cooling, by thiocarbamide(67 mMs) slowly add and stir 10 minutes. Reaction temperature stirs 20 hours and adds hot reflux 1 hour after returning to room temperature.System temperature after returning to room temperature is collected produced sedimentation and filtration, after being dried, obtains 9.41 grams of title compounds.¹H-NMR(CDCl₃)：δ8.32(1H，s)，2.51(3H，s).

The preparation of step C:N-(5-acetylthiazole-2-yl) acetamide hydrobromate

2-amino--5-acetyl thiazole hydrobromide salt (42.2 mMs) is dissolved in 150 milliliters of glacial acetic acid. By hydrogen bromineAqueous acid (211 mMs) slowly adds, and heating reflux reaction 12 hours. After cool to room temperature, by the precipitation producingFilter is collected, and ether is washed, and after being dried, obtains 9.15 grams of title compounds.¹H-NMR(CDCl₃)：δ12.58-12.45(1H，brs)，8.34(1H，s)，2.51(3H，s)，2.19(3H，s).

Step D:N-[5-(2-acetyl bromide) thiazol-2-yl] preparation of acetamide

Obtain 4.12 grams of title compounds according to the method for embodiment 14 step C.¹H-NMR(CDCl₃)：δ12.85-12.68(1H，brs)，8.50(1H，s)，7.50(3H，s)，4.78(2H，s)，2.35(3H，s).

Step e: N-[2-(2-methyl-5-nitrophenyl amino)-4,5 '-dithiazole-2 '-yl] preparation of acetamide

Obtain 618 milligrams of title compounds according to the method for embodiment 14 step D.¹H-NMR(CDCl₃)：δ12.25-12.08(1H，brs)，9.86-9.68(1H，brs)，9.43(1H，s)，7.81(1H，d，J＝6.4Hz)，7.47(2H，d，J＝8.4Hz)，7.22(1H，s)，4.78(2H，s)，2.43(3H，s)，2.17(3H，s).

The preparation of step F: N-(2-(5-amino-2-methyl phenyl amino)-4,5 '-dithiazole-2 '-yl) acetamide

Obtain 402 milligrams of title compounds according to the method for embodiment 14 step e.¹H-NMR(CDCl₃)：δ12.15-12.08(1H，brs)，9.22(1H，s)，7.77(1H，s)，6.95(1H，s)，6.92(1H，d，J＝2.4Hz)，6.87(2H，d，J＝8.0Hz)，6.33(1H，dd，J＝2.4Hz&，J＝2.0Hz)，2.16(3H，s)，2.07(3H，s).

Step G:N-[4-methyl-3-(2 '-acetylaminohydroxyphenylarsonic acid 4,5 '-dithiazole-2-amino) phenyl]-1-[N-methyl-N-(2-dimethylaminoethyl) amino]-2, the preparation of 3-dihydroindene-5-formamide

According to the synthetic method of embodiment 1 step e, with 1-[N-methyl-N-[2-(dimethylamino) of embodiment 2 step BEthyl] amino]-2, the reaction of 3-dihydroindene-5-carboxylic acid, ethyl ester obtains 20.6 milligrams of title compounds.¹H-NMR(CDCl₃)：δ12.11(1H，brs)，10.21(1H，s)，9.48(1H，s)，8.35(1H，d，J＝2.0Hz)，7.93(2H，d，J＝8.0Hz)，7.85(1H，s)，7.46-7.44(3H，m)，7.19(1H，d，J＝6.4Hz)，7.01(1H，s)，4.54(1H，t，J＝7.2Hz)，3.00-3.13(3H，m)，2.89-2.97(1H，m)，2.76-2.83(2H，m)，2.68(6H，s)，2.34(3H，s)，2.27(3H，s)，2.15-2.22(2H，m).MS：m/z，590.2(M+H).

Embodiment 17:N-[4-methyl-3-(2 '-acetylaminohydroxyphenylarsonic acid 4,5 '-dithiazole-2-amino) phenyl]-1-(4-methylPiperazinyl)-2, the preparation of 3-dihydroindene-5-formamide

N-(2-(5-amino-2-methyl phenyl amino)-4, the 5 '-dithiazole-2 '-yl) acetamide of embodiment 16 step FWith the 1-(4-methyl piperazine base)-2 of embodiment 13 step B, 3-dihydroindene-5-carboxylic acid, ethyl ester closing according to embodiment 1 step eOne-tenth method obtains 5.7 milligrams of title compounds.¹H-NMR(CDCl₃)：δ12.11(1H，brs)，10.21(1H，s)，9.48(1H，s)，8.35(1H，d，J＝2.0Hz)，7.93(2H，d，J＝8.0Hz)，7.85(1H，s)，7.46-7.44(3H，m)，7.19(1H，d，J＝6.4Hz)，7.01(1H，s)，4.46(1H，t，J＝7.2Hz)，3.00-3.13(3H，m)，2.89-2.97(1H，m)，2.68(6H，s)，2.62-2.66(2H，m)，2.51(3H，s)，2.34(3H，s)，2.14-2.24(2H，m).MS：m/z，588.2(M+H).

Embodiment 18:(S)-N-[4-methyl-3-(2 '-methyl-4,5 '-dithiazole-2-amino) phenyl]-1-(4-methylPiperazinyl)-2, the preparation of 3-dihydroindene-5-formamide

The preparation of steps A: 1-(2-methylthiazol-5-yl) ethyl ketone

2-acetyl bromide acetaldehyde (7 grams, 42 mMs) is dissolved in acetone (150 milliliters). Under ice-water bath is cooling, willThioacetamide (3.19 grams, 42 mMs) slowly adds and stirs 10 minutes. Reaction temperature return to stir after room temperature 20 littleTime and add hot reflux 1 hour. System temperature after returning to room temperature is collected produced sedimentation and filtration, after being dried, obtains titleCompound obtains 3.73 grams of title compounds.¹H-NMR(CDCl₃)：δ8.50(1H，s)，2.73(3H，s)，2.55(3H，s).

The preparation of the bromo-1-of step B:2-(2-methylthiazol-5-yl) ethyl ketone

Obtain 1.5 grams of title compounds according to the method for embodiment 14 step C.¹H-NMR(CDCl₃)：δ6.70(1H，d，J＝3.6Hz)，4.12(2H，s)，3.92(3H，s).

Step C:2 '-methyl-N-(2-methyl-5-nitro benzene)-4, the preparation of 5 '-dithiazole-2-amine

Obtain 63 milligrams of title compounds according to the method for embodiment 14 step D.¹H-NMR(CDCl₃)：δ9.89(1H，brs)，9.44(1H，s)，8.01(1H，s)，7.80(1H，d，J＝7.8Hz)，7.47(1H，d，J＝7.8Hz)，7.31(1H，s)，2.67(3H，s)，2.43(3H，s).

Step D:6-methyl-N¹-(2 '-methyl-4,5 '-dithiazole-2-yl) benzene-1, the preparation of 3-diamines

Obtain 47 milligrams of title compounds according to the method for embodiment 14 step e.¹H-NMR(CDCl₃)：δ9.21(1H，brs)，7.92(1H，s)，7.00(1H，s)，6.89(1H，d，J＝2.4Hz)，6.84(1H，d，J＝8.0Hz)，6.29(1H，dd，J＝2.4Hz&J＝2.4Hz)，4.90(2H，brs)，2.62(3H，s)，2.07(3H，s).

Step e: (S)-N-[4-methyl-3-(2 '-methyl-4,5 '-dithiazole-2-amino) phenyl]-1-(4-methyl piperazineBase)-2, the preparation of 3-dihydroindene-5-formamide

According to (S)-1-(4-methyl piperazine base)-2 of the synthetic method of embodiment 1 step e and embodiment 15 step B, 3-The reaction of dihydroindene-5-Ethyl formate obtains 17.3 milligrams of title compounds.¹H-NMR(CDCl₃)：δ10.21(1H，s)，9.53(1H，s)，8.31(1H，s)，7.93(2H，d，J＝2.0Hz)，7.79(1H，d，J＝7.2Hz)，7.46(1H，d，J＝8.0Hz)，7.33(1H，s)，7.21(1H，d，J＝8.0Hz)，6.89(1H，s)，4.46(1H，t，J＝7.2Hz)，3.00-3.13(2H，m)，2.79(3H，s)，2.68(6H，s)，2.62-2.66(2H，m)，2.51(3H，s)，2.34(3H，s)，2.14-2.24(2H，m).MS：m/z，545.2(M+H).

Embodiment 19:N-[4-methyl-3-(2 '-methyl-4,5 '-dithiazole-2-amino) phenyl]-1-(4-methyl piperazineBase)-2, the preparation of 3-dihydroindene-5-formamide

6-methyl-N of embodiment 18 step D¹-(2 '-methyl-4,5 '-dithiazole-2-yl) benzene-1,3-diamines and enforcementThe 1-(4-methyl piperazine base)-2 of example 13 step B, 3-dihydroindene-5-carboxylic acid, ethyl ester is according to the synthetic method of embodiment 1 step eObtain 9.5 milligrams of title compounds.¹H-NMR(CDCl₃)：δ10.21(1H，s)，9.53(1H，s)，8.31(1H，s)，7.93(2H，d，J＝2.0Hz)，7.79(1H，d，J＝7.2Hz)，7.46(1H，d，J＝8.0Hz)，7.33(1H，s)，7.21(1H，d，J＝8.0Hz)，6.89(1H，s)，4.46(1H，t，J＝7.2Hz)，3.00-3.13(2H，m)，2.79(3H，s)，2.68(6H，s)，2.62-2.66(2H，m)，2.51(3H，s)，2.34(3H，s)，2.14-2.24(2H，m).MS：m/z，545.2(M+H).

Embodiment 20:(S)-N-methyl-5-{2-[2-methyl-5-[1-(4-methyl piperazine base)-2,3-dihydroindene-5-Formamido group] phenyl amino] thiazole-4-yl } preparation of pyridine-2-carboxamide

Steps A: the preparation of 5-acetyl thiazole-2-carboxylic acid, ethyl ester

React with sulfo-oxamethane and obtain 750 milligrams of title compounds according to the method for embodiment 16 step B. MS:m/z，200.0(M+H).

The preparation of step B:N-methyl-5-acetylthiazole-2-formamide

5-acetyl thiazole-2-carboxylic acid, ethyl ester (750 milligrams) is dissolved in the saturated methanol solution of methylamine (20 milliliters) to chamberTemperature is lower to be stirred 20 hours. Concentrated obtain 690 milligrams of title compounds except desolventizing. MS:m/z, 185.0 (M+H).

The preparation of step C:N-methyl-5-(2-acetyl bromide)-thiazole-2-formamide

Obtain 800 milligrams of title compounds according to the method for embodiment 14 step C. MS:m/z, 262.9 (M+H).

Step D:N-methyl-2-(2-methyl-5-nitro-phenyl amino)-4, the preparation of 5 '-dithiazole-2 '-formamide

Obtain 742 milligrams of title compounds according to the method for embodiment 14 step D. MS:m/z, 376.0 (M+H).

Step e: N-methyl-2-(5-amino-2-methyl-phenyl amino)-4, the preparation of 5 '-dithiazole-2 '-formamide

Obtain 340 milligrams of title compounds according to the method for embodiment 14 step e. MS:m/z, 346.1 (M+H).

Step F: (S)-N-methyl-5-{2-[2-methyl-5-[1-(4-methyl piperazine base)-2,3-dihydroindene-5-formylAmino] phenyl amino] thiazole-4-yl } preparation of pyridine-2-carboxamide

According to (S)-1-(4-methyl piperazine base)-2 of the synthetic method of embodiment 1 step e and embodiment 15 step B, 3-The reaction of dihydroindene-5-Ethyl formate obtains 15 milligrams of title compounds.¹H-NMR(DMSO)δ10.23(1H，s)，9.54(1H，s)，9.17(1H，d，J＝1.2Hz)，8.71(1H，d，J＝8.0Hz)，8.64(1H，d，J＝7.6Hz)，8.50(1H，dd，J＝2.0Hz&J＝2.0Hz)，8.03(1H，d，J＝8.0Hz)，7.87-7.83(2H，m)，7.64(1H，s)，7.43-7.38(2H，m)，7.20(1H，d，J＝8.0Hz)，4.44(1H，brs)，3.02-2.95(5H，m)，2.87(7H，brs)，2.82(4H，brs)，2.28(3H，s)，2.13(2H，m).MS：m/z，582.3(M+H).

Embodiment 21:(S)-N-{3-[4-(6-chlorine imidazoles [1,2-b] pyridazine-3-yl) thiazole-2-amino] phenyl }-1-(4-methyl piperazine base)-2, the preparation of 3-dihydroindene-5-formamide

Steps A: (Z)-N '-(6-chlorine pyridazine-3-yl)-N, the preparation of N-methyl carbonamidine

3-amino-6-chlorine pyridazine (22.9 mMs) is dissolved in 10 milliliters of DMF dimethylacetals,Add hot reflux 1 hour at 110 DEG C. Concentrated obtain 1.5 grams of title compounds except desolventizing.

The preparation of step B:1-(6-chlorine imidazoles [1,2-b] pyridazine-3-yl) ethyl ketone

By above-claimed cpd (1 gram, 4.6 mMs), sodium iodide (4.4 mMs) and bromacetone (8.28 mMs) are miscibleIn dry DMF (5 milliliters), at 100 DEG C, stir 4 hours. Be cooled to room temperature, concentrated except desolventizingAnd add 20 ml waters, use dichloromethane extraction 3 times. Extract anhydrous sodium sulfate drying, column chromatography (ethyl acetate/oilEther=2/5) separate and obtain 0.7 gram of title compound. MS:m/z, 196.0 (M+H).

The preparation of the bromo-1-of step C:2-(6-chlorine imidazoles [1,2-b] pyridazine-3-yl) ethyl ketone

Obtain 685 milligrams of title compounds according to the method for embodiment 14 step C. MS:m/z, 273.9 (M+H).

The system of step D:N-(2-methyl-5-nitro benzene)-4-(6-chlorine imidazoles [1,2-b] pyridazine-3-yl)-thiazole-2-amineStandby

Obtain 300 milligrams of title compounds according to the method for embodiment 14 step D.

Step e: N¹-[4-(6-chlorine imidazoles [1,2-b] pyridazine-3-yl) thiazol-2-yl]-6-methyl isophthalic acid, 3-phenylenediaminePreparation

Obtain 200 milligrams of title compounds according to the method for embodiment 14 step e. MS:m/z, 357.1 (M+H).

Step F: (S)-N-{3-[4-(6-chlorine imidazoles [1,2-b] pyridazine-3-yl) thiazole-2-amino] phenyl }-1-(4-firstBase piperazinyl)-2, the preparation of 3-dihydroindene-5-formamide

According to (S)-1-(4-methyl piperazine base)-2 of the synthetic method of embodiment 1 step e and embodiment 15 step B, 3-The reaction of dihydroindene-5-Ethyl formate obtains 22 milligrams of title compounds.¹H-NMR(DMSO)：δ8.41(1H，d，J＝4.0Hz)，8.36(1H，s)，7.98(1H，d，J＝9.6Hz)，7.84(1H，s)，7.80(1H，d，J＝4.0Hz)，7.72(1H，d，J＝8.0Hz)，7.13(1H，d，J＝4.0Hz)，7.11(1H，d，J＝4.0Hz)，4.38(1H，t，J＝6.8Hz)，3.04-2.93(1H，m)，2.91-2.83(1H，m)，2.64-2.44(8H，brs)，2.33(3H，s)，2.30(3H，s)，2.22-2.11(2H，m).MS：m/z，601.2(M+H).

Embodiment 22:(S)-N-{3-[4-(6-flumizole [1,2-b] pyridazine-3-yl) thiazole-2-amino] phenyl }-1-(4-methyl piperazine base)-2, the preparation of 3-dihydroindene-5-formamide

Steps A: the preparation of 6-fluorine pyridazine-3-amine

3,6-difluoro pyridazine (60.3 mMs) and 25 milliliters of ammoniacal liquor are mixed in tube sealing, add at 70 DEG C reaction 2 littleTime. Cooled and filtered is collected the precipitation producing, and washes with water, dry 4.28 grams of the title compounds that obtain. MS:m/z, 114.0 (M+H).

Step B:(Z)-N '-(6-fluorine pyridazine-3-yl)-N, the preparation of N-dimethyl carbonamidine

Obtain 1.44 grams of title compounds according to the method for embodiment 21 steps A by the reaction of 6-fluorine pyridazine-3-amine. MS:m/z，169.1(M+H).

The preparation of step C:1-(6-flumizole [1,2-b] pyridazine-3-yl) ethyl ketone

Obtain 1.44 grams of title compounds according to the method for embodiment 21 step B.¹H-NMR(CDCl₃)δ8.44(1H，s)，8.19(1H，dd，J＝9.6Hz，8.8Hz)，7.14(1H，d，J＝9.6Hz)，2.76(3H，s).

Bromo-1-(the 6-of step D:2-FluorineImidazoles [1,2-b] pyridazine-3-yl) preparation of ethyl ketone

Obtain 746 milligrams of title compounds according to the method for embodiment 14 step C. MS:m/z, 258.0 (M+H).

The system of step e: N-(2-methyl-5-nitro benzene)-4-(6-flumizole [1,2-b] pyridazine-3-yl)-thiazole-2-amineStandby

Obtain 300 milligrams of title compounds according to the method for embodiment 14 step D. MS:m/z, 371.1 (M+H).

Step F: N¹-[4-(6-flumizole [1,2-b] pyridazine-3-yl) thiazol-2-yl]-6-methyl isophthalic acid, 3-phenylenediaminePreparation

Obtain 86 milligrams of title compounds according to the method for embodiment 14 step e. MS:m/z, 341.1 (M+H).

Step G:(S)-N-{3-[4-(6-flumizole [1,2-b] pyridazine-3-yl) thiazole-2-amino] phenyl }-1-(4-firstBase piperazinyl)-2, the preparation of 3-dihydroindene-5-formamide

According to (S)-1-(4-methyl piperazine base)-2 of the synthetic method of embodiment 1 step e and embodiment 15 step B, 3-The reaction of dihydroindene-5-Ethyl formate obtains 21 milligrams of title compounds.¹H-NMR(DMSO)：δ10.22(1H，s)，10.00(1H，s)，8.84(1H，s)，8.47(1H，d，J＝6.0Hz)，8.44(1H，d，J＝2.0Hz)，7.88(1H，d，J＝6.8Hz)，7.86(1H，d，8.0Hz)，7.66(1H，s)，7.45(1H，d，J＝8.0Hz)，7.37(1H，d，J＝10.0Hz)，7.34(1H，d，J＝9.6Hz)，7.19(1H，d，J＝8.4Hz)，4.52(1H，t，J＝6.8Hz)，3.51-3.42(4H，brs)，3.19-2.92(5H，brs)，2.92-2.85(1H，m)，2.79(3H，s)，2.50(3H，s)，2.49-2.54(1H，m)，2.18-1.99(1H，m).

Embodiment 23:(1S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-{N-methyl-N-[(1-tertbutyloxycarbonyl-piperidin-4-yl) methyl] amino }-2, the preparation of 3-dihydro-1H-indenes-5-formamide

Steps A: (S)-5-bromine 2, the preparation of 3-dihydroindene-1-amine carboxylic acid tert-butyl ester

By bromo-(S)-5-2,3-dihydroindene-1-amine (12 mMs) is dissolved in oxolane (50 milliliters), adds threeEthamine (1.3 grams, 17 mMs) and di-tert-butyl dicarbonic acid ester (14 mMs). Under room temperature, stir and spend the night, add 200 milliliters of secondAcetoacetic ester, filters insoluble matter. Filtrate water is washed, dry concentrated 3.2 grams of the title compounds that obtain.¹H-NMR(CDCl₃)δ7.37(1H，s)，7.34(1H，d，J＝8.0Hz)，7.20(1H，d，J＝8.0Hz)，5.17-5.11(1H，m)，4.76-4.66(1H，m)，2.98-2.11(1H，m)，2.87-2.79(1H，m)，2.62-2.54(1H，m)，1.85-1.75(1H，m)，1.50(9H，s).

Step B:(S)-1-(t-butoxycarbonyl amino)-2, the preparation of 3-dihydroindene-5-carboxylic acid, ethyl ester

Obtain 294 milligrams of title compounds according to the synthetic method of step D in embodiment 1.¹H-NMR(CDCl₃)：δ7.89(1H，d，J＝8.8Hz)，7.88(1H，s)，7.36(1H，d，J＝8.0Hz)，5.20(1H，d，J＝8.0Hz)，4.77(1H，d，J＝7.6Hz)，4.36(2H，q，J＝14.4Hz)，3.96-3.91(1H，m)，3.01-2.94(1H，m)，2.89-2.81(1H，m)，2.68-2.57(1H，m)，1.48(9H，s)，1.38(3H，t，J＝7.2Hz).

Step C:(S)-1-(N-methyl-N-tertbutyloxycarbonyl-amino)-2, the preparation of 3-dihydroindene-5-carboxylic acid, ethyl ester

Under ice bath is cooling, sodium hydrogen (20 mMs) is added to and is mixed with (S)-1-(t-butoxycarbonyl amino)-2,3-dihydroChange in dry DMF (20 milliliters) solution of indenes-5-carboxylic acid, ethyl ester (3.9 mMs), and stir 30 minutes. By iodomethane (19.7MM) be slowly added drop-wise in above-mentioned system, under room temperature, stir 4 hours. Add ethyl acetate, wash with water, saturated common salt washing,Dry concentrated rear column chromatography for separation obtains 1.2 grams of title compounds. MS:m/z, 320.2 (M+H).

Step D:(S)-1-methylamino-2, the preparation of 3-dihydroindene-5-carboxylic acid, ethyl ester

To being mixed with (S)-1-(N-methyl-N-tertbutyloxycarbonyl-amino)-2,3-dihydroindene-5-carboxylic acid, ethyl ester (1.0 grams,3.1 mMs) ethanolic solution in add concentrated hydrochloric acid (12N, 5 milliliters). Under room temperature, stir 3 hours, decompression distillation removes desolventizing,And regulate pH to 10-11 with the sodium hydrate aqueous solution of (6N). Be extracted with ethyl acetate this solution, extract saturated aqueous common saltWash, after dry concentrating, obtain 600 milligrams of title compounds.¹H-NMR(CDCl₃)：δ7.94(1H，d，J＝6.4Hz)，7.94(1H，s)，7.58(1H，d，J＝8.0Hz)，4.62-4,58(1H，m)，4.36(2H，q，J＝14.0Hz)，3.903(1H，s)，3.23-3.12(1H，m)，3.01-2.94(1H，m)，2.60(3H，s)，2.58-2.5(1H，m)，2.26-2.17(1H，m)，1.38(3H，t，J＝7.2Hz).

Step e: 1-{N-methyl-N-[(1-tertbutyloxycarbonyl-piperidin-4-yl) methyl] amino }-2,3-dihydro-1H-indenes-The preparation of 5-carboxylic acid, ethyl ester

Under room temperature, 4-formaldehyde piperidines-1-carboxylic acid tert-butyl ester (0.69 mM) is added to and is mixed with (S)-1-methylamino-2,3-The ethanolic solution of dihydroindene-5-carboxylic acid, ethyl ester (0.46 mM), and stir 5 minutes. By formic acid (1.2 mMs) and cyano groupSodium borohydride (0.7 mM) is added to respectively in system, continues to stir 4 hours. With ethyl acetate dilution, wash saturated food with waterSalt washing, dry concentrated, paper chromatography separates and obtains 158 milligrams of title compounds. MS:m/z, 417.3 (M+H).

Step F: (1S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-{N-methyl-N-[(1-tertbutyloxycarbonyl-piperidin-4-yl) methyl] amino }-2, the preparation of 3-dihydro-1H-indenes-5-formamide

Obtain 25 milligrams of title compounds according to the method for embodiment 1 step e.¹H-NMR(CDCl₃)：δ9.08(1H，d，J＝1.6Hz)，8.54(1H，dd，J＝4.8Hz，1.6Hz)，8.29(1H，d，J＝1.6Hz)，8.18-8.14(1H，m)，7.85(1H，s)，7.73(1H，s)，7.70(1H，d，J＝2.0Hz)，7.42(1H，d，J＝7.6Hz)，7.33(1H，dd，J＝8.0Hz，5.2Hz)，7.24-7.19(2H，m)，7.14(1H，brs)，6.92(1H，s)，4.42(1H，t，J＝7.6Hz)，4.13-4.04(1H，m)，3.01-2.94(1H，m)，2.89-2.82(1H，m)，2.73-2.67(2H，m)，2.34(3H，s)，2.29-2.04(6H，m)，2.23(3H，s)，1.72-1.67(2H，m)，1.46(9H，s)，1.05-0.94(2H，m).MS：m/z，653.3(M+H).

Embodiment 24:(1S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-{N-methyl-N-[(piperidin-4-yl) methyl] amino }-2, the preparation of 3-dihydro-1H-indenes-5-formamide

Hydrogen chloride gas is passed into and is mixed with (1S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-N-methyl-N-[(1-tertbutyloxycarbonyl-piperidin-4-yl) and methyl] amino }-2,3-dihydro-1H-indenes-5-formamide (20 milligrams)Carrene (20 milliliters) in, under room temperature, stir 4 hours. To 10-11, use acetic acid by 6N sodium hydrate aqueous solution adjusting pH valueEthyl ester extraction. Extract washes with water, dry concentrated 2.02 milligrams of the title compounds that obtain.¹H-NMR(CD₃OD)：δ9.41(1H，s)，9.05(1H，d，J＝4.4Hz)，8.77(1H，d，J＝6.4Hz)，8.64(1H，s)，8.02(1H，s)，7.90-7.87(3H，m)，7.64(1H，s)，7.56-7.36(2H，m)，5.23(1H，t，J＝4.8Hz)，3.37(2H，d，J＝4.8Hz)，3.07-2.87(4H，brs)，2.87-2.78(2H，m)，2.77-2.40(7H，brs)，2.21(3H，s)，2.20-2.14(2H，m)，1.93-1.92(1H，m).MS：m/z，553.3(M+H).

Embodiment 25:(1S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-{N-methyl-N-[(1H-imidazol-4 yl) methyl] amino }-2, the preparation of 3-dihydro-1H-indenes-5-formamide

Steps A: (S)-1-{N-methyl-N-[(1H-imidazol-4 yl) methyl] amino }-2,3-dihydro-1H-indenes-5-carboxylic acidThe preparation of ethyl ester

Obtain according to the compound of the embodiment of the method 23 step D of embodiment 23 step e and 1H-imidazoles-4-formolite reaction110 milligrams of title compounds.¹H-NMR(CDCl₃)：δ7.90(1H，s)，8.99(1H，brs)7.89(1H，d，J＝6.8Hz)，7.77(1H，s)，7.59(1H，d，J＝6.8Hz)，7.11(1H，s)，4.69-4.64(3H，m)，4.35(2H，q，J＝14.4Hz)，3.89(3H，s)，3.84(1H，t，J＝3.8Hz)，3.1-2.0(1H，m)，2.95-2.87(1H，m)，2.31-2.29(1H，m)，1.38(3H，t，J＝7.2Hz).

Step B:(1S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-{N-methyl-N-[(1H-imidazol-4 yl) methyl] amino }-2, the preparation of 3-dihydro-1H-indenes-5-formamide

Obtain 30 milligrams of title compounds according to the method for embodiment 1 step e.¹H-NMR(DMSO)：δ10.21(1H，s)，9.46(1H，s)，9.16(1H，d，J＝2.0Hz)，8.61(1H，d，J＝2.0Hz)，8.49(1H，dd，J＝8.0Hz，3.6Hz)，8.34-8.31(1H，m)，7.86(1H，s)，7.81(1H，d，J＝18.4Hz)，7.58(1H，d，J＝7.6Hz)，7.47(1H，s)，7.45-7.42(1H，m)，7.38(1H，dd，J＝8.0Hz，8.0Hz)，7.20(1H，d，J＝8.4Hz)，7.10(1H，s)，4.65-4.59(1H，m)，3.7-3.68(2H，m)，3.11-2.99(2H，m)，2.93-2.87(1H，m)，2.23(3H，s)，2.21-2.16(2H，m)，2.05-1.97(1H，m).MS：m/z，536.2(M+H).

Embodiment 26:6-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl amino formoxyl }-3,4-bis-The preparation of hydrogen isoquinoline-2 (1H)-carboxylic acid tert-butyl ester

Steps A: the 2-tert-butyl group-6-ethyl-3,4-dihydro-isoquinoline-2, the preparation of 7 (1H)-dicarboxylic esters

According to the method for embodiment 1 step D, 6-is bromo-3, and 4-dihydro-isoquinoline-2 (1H)-carboxylic acid tert-butyl ester obtains through reaction74 milligrams of title compounds.¹H-NMR(CDCl₃)δ7.83(1H，d，J＝7.6Hz)，7.79(1H，br，s)，7.20(1H，J＝8.0Hz)，4.61(2H，s)，4.37(2H，q，J＝7.6Hz)，3.66(2H，s)，2.88(2H，t，J＝5.6Hz)，1.49(9H，s)，1.37(3H，t，J＝7.6Hz).

Step B:6-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl amino formoxyl }-3,4-dihydroThe preparation of isoquinolin-2 (1H)-carboxylic acid tert-butyl ester

Obtain 5 milligrams of title compounds according to the synthetic method of embodiment 1 step e.¹H-NMR(CDCl₃)δ9.09(1H，s)，8.55(1H，d，J＝3.2Hz)，8.32(1H，s)，8.16(1H，m)，7.82(1H，s)，7.70(2H，m)，7.34(1H，m)，7.26(4H，m)，6.93(1H，s)，4.64(2H，s)，3.68(2H，s)，2.91(2H，s)，2.34(3H，s)，1.52(9H，m).MS：m/z，542.2(M+H).

Embodiment 27:N-{[4-methyl-3-(pyridin-3-yl) thiazole-2-amino] phenyl }-1,2,3,4-Tetrahydroisoquinoli-The preparation of quinoline-6-formamide

The compound of embodiment 26 prepares 2 milligrams of title compounds according to the method for embodiment 24.¹H-NMR(CDCl₃)δ10.28(1H，s)，9.61(1H，s)，9.50(2H，s)，9.37(1H，s)，8.91(1H，d，J＝5.6Hz)，8.83(1H，d，J＝2Hz)，8.73(1H，d，J＝5.2Hz)，7.92(3H，m)，7.79(1H，d，J＝4.8Hz)，7.20(1H，d，J＝8Hz)，4.34(2H，s)，3.56(2H，m)，3.26(2H，m)，2.28(3H，m).MS：m/z，442.2(M+H).

Embodiment 28:7-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl amino formoxyl }-3,4-bis-The preparation of hydrogen isoquinoline-2 (1H)-carboxylic acid tert-butyl ester

According to the method for embodiment 1 step e, 7-is bromo-3, and 4-dihydro-isoquinoline-2 (1H)-carboxylic acid tert-butyl ester obtains through reaction5 milligrams of title compounds.¹H-NMR(CDCl₃)δ9.09(1H，s)，8.54(1H，d，J＝4Hz)，8.32(1H，s)，8.19(1H，d，J＝8Hz)，7.96(1H，s)，7.67(2H，d，J＝4Hz)，7.37(1H，dd，J＝4.2Hz&J＝4.8Hz)，7.23(1H，s)，7.21(2H，d，J＝4Hz)，6.92(1H，s)，4.63(2H，s)，3.67(2H，brs)，2.89(2H，brs)，2.33(3H，s)，1.52(9H，s).MS：m/z，542.2(M+H).

Embodiment 29:N-{[4-methyl-3-(pyridin-3-yl) thiazole-2-amino] phenyl }-1,2,3,4-Tetrahydroisoquinoli-The preparation of quinoline-7-formamide

The compound of embodiment 28 prepares 2.13 milligrams of title compounds according to the method for embodiment 24.¹H-NMR(CDCl₃)δ9.49(1H，s)，9.15(1H，d，J＝8Hz)，8.82(1H，s)，8.75(1H，d，J＝5.2Hz)，8.12(1H，s)，7.92(2H，t，J＝8Hz)，7.66(1H，s)，7.43(1H，d，J＝8Hz)，7.23(2H，s)，4.48(2H，s)，3.57(2H，t，J＝6.4Hz)，3.31(2H，dd，J＝1.6Hz&J＝1.6Hz)，2.33(3H，s).MS：m/z，442.2(M+H).

Embodiment 30:N-{[4-methyl-3-(4-pyridin-3-yl) thiazole-2-amino] phenyl }-2,3,5,6,8,9-six hydrogenThe preparation of benzo [Isosorbide-5-Nitrae, 7,10] four oxo cyclododecane-12-formamides

The preparation of steps A: 4-(benzyloxy)-3-methyl hydroxybenzoate

To be mixed with acetonitrile (250 millis of MDB (208 mMs) and potash (208 mMs)Rise) at 85 DEG C, stir 4 hours. Add bromobenzyl (208 mMs), at 65 DEG C, stir 12 hours. Cool to room temperature, crosses filteringGo produced precipitation, filtrate concentrating removed desolventizing and obtained thick liquid. Add water, be extracted with ethyl acetate. Extract is concentratedColumn chromatography for separation obtains 8 grams of title compounds.¹H-NMR(CDCl₃)：δ7.611(1H，t，J＝1.6Hz)，7.58(1H，d，J＝2.4Hz)，7.43-7.39(5H，m)，6.95(1H，d，J＝8.0Hz)，5.68(1H，s)，5.17(2H，s)，3.88(3H，s).

Step B:4-(benzyloxy)-3-{2-[2-(2-chloroethoxy) ethyoxyl] ethyoxyl } preparation of methyl benzoate

To be mixed with 4-(benzyloxy)-3-methyl hydroxybenzoate (11.6 mMs), potash (34.8 mMs) and 1,The acetonitrile solution return stirring of two (2-chloroethoxy) ethane (29 mMs) of 2-3 days. After cooling, filter precipitation, filtrate is concentrated,Column chromatography for separation (5: 1=n-hexane: ethyl acetate) obtains 7.0 grams of title compounds.¹H-NMR(CDCl₃)：δ7.63(1H，d，J＝2.0Hz)，7.56(1H，d，J＝2.0Hz)，7.43-7.26(5H，m)，6.90(1H，d，J＝8.4Hz)，5.15(2H，s)，4.19(2H，t，J＝4.8Hz)，3.87(11H，brs)，3.52(2H，t，J＝6.0Hz).

Step C:4-hydroxyl-3-{2-[2-(2-chloroethoxy) ethyoxyl] ethyoxyl } preparation of methyl benzoate

By 4-(benzyloxy)-3-{2-[2-(2-chloroethoxy) ethyoxyl] ethyoxyl } methyl benzoate (7.35 mMs)Be mixed in methyl alcohol (50 milliliters) with palladium carbon (300 milligrams), pass into hydrogen (10MPa). Under room temperature, stir and spend the night, elimination precipitation,Concentrated filtrate obtains 1.7 grams of title compounds.¹H-NMR(CDCl₃)：δ7.67(1H，d，J＝8.4Hz，)，7.62(1H，d，J＝2.0Hz)，7.01(1H，s)，6.94(1H，8.4Hz)，4.22(2H，t，J＝8.4Hz)，3.86-3.83(5H，m)，3.79-3.72(6H，m)，3.65(2H，t，J＝6.0Hz).

Step D:2,3,5,6,8,9-hexahydrobenzene is the preparation of [Isosorbide-5-Nitrae, 7,10] four oxo cyclododecane-12-carboxylate methyl esters also

To be mixed with 4-hydroxyl-3-{2-[2-(2-chloroethoxy) ethyoxyl] ethyoxyl } methyl benzoate (2.5 mMs),The acetonitrile solution return stirring of potash (12.5 mMs) and hexafluoro phosphatization potassium (1.25 mMs) 3 days. After cooling, elimination is heavyForm sediment. Filtrate is concentrated, and column chromatography for separation obtains 118 milligrams of title compounds.¹H-NMR(CDCl₃)：δ7.65(1H，d，J＝2.0Hz)，7.61(1H，t，J＝6.0Hz)，6.90(1H，d，J＝8.4Hz)，4.16(4H，dd，J＝6.4Hz，4.0Hz)，3.83-3.81(5H，m)，3.76(2H，t，J＝6.4Hz)，3.71(4H，s).

Step e: N-{[4-methyl-3-(4-pyridin-3-yl) thiazole-2-amino] phenyl }-2,3,5,6,8,9-hexahydrobenzeneAnd the preparation of [Isosorbide-5-Nitrae, 7,10] four oxo cyclododecane-12-formamides

By 2,3,5,6,8,9-hexahydrobenzene also [Isosorbide-5-Nitrae, 7,10] four oxo cyclododecane-12-carboxylate methyl esters (0.42 milli rubYou) and 6-methyl-N¹-[4-(pyridin-3-yl) thiazol-2-yl] phenyl-1,3-diamines (0.51 mM) is dissolved in new steamingIn oxolane (20 milliliters). Under ice bath is cooling, LiHMDS (1.7 milliliters, 1M) is added drop-wise in reaction system. This system existsUnder room temperature, stir and spend the night. The water of about 10 milliliters adds in reactant liquor, and extracts with carrene (3x20 milliliter). Organic phase is usedAnhydrous sodium sulfate drying, the thick product silica gel that reduced pressure concentration obtains is prepared plate separating-purifying (methylene chloride/methanol=10/1)Obtain 100 milligrams of title compounds.¹H-NMR(CDCl₃)：δ9.04(1H，s)，8.77(1H，brs)，8.43(1H，d，J＝3.6Hz)，8.18(1H，d，J＝1.2Hz)，8.05(1H，d，J＝8.0Hz)，7.85(1H，brs)，7.60(1H，d，J＝1.6Hz)，7.53(1H，dd，J＝1.6Hz&J＝1.6Hz)，7.32-7.23(2H，m)，7.12(1H，d，J＝8.4Hz)，6.91(1H，d，J＝8.4Hz)，6.80(1H，s)，4.14(4H，brs)，3.81(2H，brs)，3.71(6H，brs)，3.45(3H，s).MS：m/z，533.2(M+H).

Embodiment 31

A: kinase activity test

Material and principle: take even phase time-resolved fluorescence (HTRF) method set up and optimized c-Kit kinase activity and examinedLining platform, carries out the mensuration of compound activity. In this test, kinase whose activity is with substrate (the little peptide of N end mark biotin)Phosphorylation level be index. After substrate is phosphorylated, its phosphorylation enough by the specific antibody of Eu (europium) mark (buy inCisbio) identify, add the allophycocyanin (XL-665 buys in Cisbio) of marked by streptavidin, with substrate end simultaneouslyThe biotin label combination of end, the distance of Eu and XL-665 enough approaches like this, excites energy between the two under 320nm wavelengthEnough there is energy and shift, under 665nm, specific fluorescence can be detected, the activity of the direct reaction enzymes of this glimmering light intensity.

Experimental technique: the determination of activity (IC of compound₅₀PH-value determination pH)

Compound is started to carry out with 100% methyl-sulfoxide (DMSO) gradient dilution of 3 times from 1mM, each concentration is got 4 μ lJoin (50mM4-HEPES (HEPES) pH7.0,0.1mMNa in the reaction buffer of 96 μ l₃VO4、0.01% bovine serum albumin(BSA) (BAS), 5mMMgCl₂With 1mM dithiothreitol (DTT) (DTT)), get 2.5 μ l and join 384 orifice plates(OptiPlate-384, PerkinElmer), then adds the kinases of 5 μ l, centrifugal mixing, then add the ATP of 2.5 μ l (dense eventuallyDegree is Km value) start and react. 384 orifice plates are put in to 23 degree reaction 120 (c-Kit) minute in incubator, then add 5 μ l'sEu-antibody, the XL-665 of the marked by streptavidin of 5 μ l stops reaction. In incubator, hatch after 1 hour, at Envision(PerkinElmer) on, read fluorescent value. The IC of compound₅₀Value is used GraFit6.0 software to calculate.

Experimental data shows, in the present invention, compound is all very high to suppressing the inhibition activity of c-Kit, wherein, embodiment 9,10, needed concentration (IC when 15,20,21 and 22 compounds reach 50% to c-Kit kinase activity inhibiting rate₅₀, nM) between20～100nM. Similarly, the IC of embodiment 1,2,3,4,8,11,12,13,14,19,24,25,26 and 27 compounds₅₀Value between100～500nM; The IC of embodiment 5,6,7,16,17,18,23,28,29 and 30 compounds₅₀Value is between 500～800nM.

B: cell proliferation test

Human leukemia cell line K562 is at incubator (37 degree, 5%CO₂) middle with RPMI1640 culture medium and 10% hyclone(FBS) suspend and cultivate. In the detection of compound, K562 cell (1000, every hole) is laid in 96 orifice plates (Corning). SecondIt prepares compound, carries out 3 times of gradient dilutions from 10mM with 100%DMSO, and each concentration is got 4 μ l and join the serum-free of 96 μ lCulture medium be diluted to 40 times of compounds, then get that in the cell culture fluid that 5 μ l join 195 μ l, (DMSO final concentration is0.1%, v/v), to process after 72 hours (3 days), every hole adds 35 μ l's(Invitrogen) reagent, 37Degree is hatched 4 hours, then measures chemiluminescence signal, uses GraphPadPrism5.0 to calculate compound on cell proliferation and presses downThe IC of system₅₀Value.

According to aforesaid operations, obtain the compounds of this invention and will reach 50% inhibiting rate institute to the growth that suppresses K562 cellConcentration (the IC needing₅₀, nM). Can be found out by experimental result, embodiment's 2,3,10,12,13,15,17,18,19,20 and 21Compound has very high inhibition activity: embodiment 2,10,13,18,19,20 and 21 for chronic myelogenous leukemia cell K562Compound will reach the needed concentration (IC of 50% inhibiting rate to the growth that suppresses K562 cell₅₀, nM) and be 10nM-200nM, realExecute example 3,12,15 and 17 compounds and will reach the needed concentration (IC of 50% inhibiting rate to the growth that suppresses K562 cell₅₀，nM)For 200nM-800nM, the IC of other embodiment compounds₅₀Value is all less than 1000nM. These results show, the compounds of this invention canEffectively to treat chronic myelogenous leukemia.

Claims (19)

1. structural formula is suc as formula I compound or a pharmaceutically acceptable salt,

Wherein:

The phenyl ring that ring C condenses with it forms following group,

R₁Hydrogen, tertbutyloxycarbonyl, NR₄R₅Or NR₄(CH₂)nR₆；

Wherein R₄、R₅Independently be selected from hydrogen, C_1-6Alkyl, or R₄、R₅Form containing 1～2 and be selected from N or O with the N atom that is connected themSaturated 5 or 6 rings that atom replaces, and 5 or 6 described rings also can be further by C_1-6Alkyl replaces;

N is 1～6 integer;

R₆Be selected from 5 yuan of bicyclic heteroaryls, NR₉R₁₀Or CHR₁₁R₁₂；

Wherein R₉And R₁₀Independently be selected from hydrogen, C_1-4Alkyl, or R₉And R₁₀Form 6 rings together with connecting their nitrogen-atomsSaturated heterocyclic alkyl, the available ring carbon atom of this saturated heterocyclic alkyl is got by 1 hetero atom that is independently selected from N or O furtherGeneration, and described Heterocyclylalkyl is alternatively by 1 C_1-4Alkyl replaces;

R₁₁And R₁₂Form 6 yuan of saturated cyclic alkyls together with connecting their carbon atom, the available ring carbon atom of this saturated cyclic alkyls entersOne step ground is replaced by 1 N hetero atom, and described cycloalkyl is replaced by 1 tertbutyloxycarbonyl alternatively;

R₂Hydrogen, halogen, cyano group, nitro, C_1-6Alkyl, C_1-6Hydroxyalkyl, C_1-6Haloalkyl, C_1-6Cyanogen substituted alkyl or C_1-6AlcoxylBase;

Z is pyridine radicals, Imidazopyridazine base or thiazolyl, selectively by 1,2 or 3 R₃Institute replaces;

R₃For halogen, cyano group, C_1-6Alkyl, C (O) NR_bR_cOr NR_bC(O)R_d；

R_b、R_cAnd R_dIndependently be selected from hydrogen or C_1-6Alkyl.

2. the compound of claim 1 or pharmaceutically acceptable salt, wherein R₄、R₅Independently be selected from hydrogen, methyl, ethyl, orR₄、R₅Coupled N atom forms morpholine ring, piperazine ring, piperidine ring, and described morpholine ring, piperazine ring, piperidine ring canFurther by C_1-4Alkyl replaces.

3. compound claimed in claim 1 or pharmaceutically acceptable salt, wherein n is 1 or 2.

4. compound claimed in claim 1 or pharmaceutically acceptable salt, wherein R₉And R₁₀Independently be selected from hydrogen, methyl or secondBase, or R₉And R₁₀Form together with connecting their nitrogen-atoms the morpholine ring that can be replaced by 1 methyl or ethyl, piperazine ring orPiperidine ring.

5. compound claimed in claim 1 or pharmaceutically acceptable salt, wherein, R₁₁And R₁₂Be connected their carbon and nitrogen atoms oneRise and form the piperidine ring that can be replaced by 1 tertbutyloxycarbonyl.

6. compound claimed in claim 1 or pharmaceutically acceptable salt, wherein R₂For methyl.

7. compound claimed in claim 1 or pharmaceutically acceptable salt, wherein, Z is that pyridin-3-yl, imidazoles (1,2-b) are rattled awayPiperazine-3-base or thiazol-2-yl.

8. compound claimed in claim 1 or pharmaceutically acceptable salt, wherein, R₃For halogen, cyano group, C_1-4Alkyl, C (O)NR_bR_cOr NR_bC(O)R_d。

9. compound claimed in claim 8 or pharmaceutically acceptable salt, wherein, R₃For chlorine, fluorine, methyl, ethyl, carbamylBase or acetylamino.

10. compound claimed in claim 1 or pharmaceutically acceptable salt, wherein, R_b、R_cAnd R_dIndependently be selected from hydrogen, firstBase, ethyl, n-pro-pyl or isopropyl.

11. formula I a compound or pharmaceutically acceptable salts,

Wherein:

R₂Hydrogen, halogen, cyano group, nitro, C_1-6Alkyl, C_1-6Hydroxyalkyl, C_1-6Haloalkyl, C_1-6Cyanogen substituted alkyl or C_1-6AlcoxylBase;

Z is pyridine radicals, Imidazopyridazine base or thiazolyl, selectively by 1,2 or 3 R₃Institute replaces;

R₃For halogen, cyano group, C_1-6Alkyl, C (O) NR_bR_cOr NR_bC(O)R_d；

R_b、R_cAnd R_dIndependently be selected from hydrogen or C_1-6Alkyl;

R₇Be selected from hydrogen, C_1-6Alkyl, C_1-6Alkoxyl, C_1-6Hydroxyalkyl, C_1-6Haloalkyl or C_1-6Cyanogen substituted alkyl;

R₈Be selected from hydrogen, C_1-6Alkyl, C_1-6Alkoxyl, C_1-6Hydroxyalkyl, C_1-6Haloalkyl or C_1-6Cyanogen substituted alkyl.

The compound of 12. claims 11 or pharmaceutically acceptable salt, wherein R₈For hydrogen or C_1-4Alkyl.

The compound of 13. claims 12 or pharmaceutically acceptable salt, wherein R₈For hydrogen or methyl.

14. formula I b compound or pharmaceutically acceptable salts,

Wherein:

Wherein R₉And R₁₀Independently be selected from hydrogen, C_1-4Alkyl, or R₉And R₁₀Form 6 rings together with connecting their nitrogen-atomsSaturated heterocyclic alkyl, the available ring carbon atom of this saturated heterocyclic alkyl is got by 1 hetero atom that is independently selected from N or O furtherGeneration, and described Heterocyclylalkyl is alternatively by 1 C_1-4Alkyl replaces;

R₂Hydrogen, halogen, cyano group, nitro, C_1-6Alkyl, C_1-6Hydroxyalkyl, C_1-6Haloalkyl, C_1-6Cyanogen substituted alkyl or C_1-6AlcoxylBase;

Z is pyridine radicals, Imidazopyridazine base or thiazolyl, selectively by 1,2 or 3 R₃Institute replaces;

R₃For hydrogen, halogen, cyano group, C_1-6Alkyl, C (O) NR_bR_cOr NR_bC(O)R_d；

R_b、R_cAnd R_dIndependently be selected from hydrogen or C_1-6Alkyl;

R₄Be selected from hydrogen, C_1-6Alkyl, C_1-6Hydroxyalkyl, C_1-6Haloalkyl or C_1-6Cyanogen substituted alkyl.

The compound of 15. claims 14 or pharmaceutically acceptable salt, wherein R₄Be selected from hydrogen, C_1-6Alkyl.

The compound of 16. claims 15 or pharmaceutically acceptable salt, wherein R₄Be selected from hydrogen, methyl or ethyl.

The compound of 17. claims 1 or pharmaceutically acceptable salt, it comprises:

1-(dimethylamino)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-2,3-dihydro-1H-indenes-5-formamide

1-[N-methyl-N-[2-(dimethylamino) ethyl] amino]-N-{4-methyl-3-[4-(pyridine radicals-3-yl)] thiazole-2-Amino } phenyl-2,3-dihydro-1H-indenes-5-formamide

N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-[2-(4-morpholinyl) ethylamino]-2,3-Dihydro-1H-indenes-5-formamide

(1S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-[2-(4-morpholinyl) ethyl ammoniaBase]-2,3-dihydro-1H-indenes-5-formamide

(1R)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-[2-(4-morpholinyl) ethyl ammoniaBase]-2,3-dihydro-1H-indenes-5-formamide

(S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-[2-(4-methylpiperazine-1-yl)-secondBase amino]-2,3-dihydroindene-5-formamide

(S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-[N-methyl-N-[2-(4-methyl piperazinePiperazine-1-yl) ethyl] amino]-2,3-dihydroindene-5-formamide

(S)-N-{[4-methyl-3-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-methylamino-2,3-dihydroindene-5-firstAcid amides

(S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-[2-(dimethylamino) ethylamino]-2,3-dihydroindene-5-formamide

(S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-[N-methyl-N-(2-dimethylamino secondBase) amino]-2,3-dihydroindene-5-formamide

(S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-dimethylamino-2,3-dihydroindene-5-formamide

(S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-[N-methyl-N-[2-(4-morpholinyl)Ethyl] amino]-2,3-dihydroindene-5-formamide

N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-(4-methyl piperazine base)-2,3-dihydroIndenes-5-formamide

N-{4-methyl-3-[4-(imidazoles [1,2-b] pyridazine-3-yl) thiazole-2-amino] phenyl }-1-[N-methyl-N-(2-bis-Methylamino ethyl) amino]-2,3-dihydroindene-5-formamide

(S)-N-{4-methyl-3-[4-(imidazoles [1,2-b] pyridazine-3-yl) thiazole-2-amino] phenyl }-1-(4-methyl piperazineBase)-2,3-dihydroindene-5-formamide

N-[4-methyl-3-(2 '-acetylaminohydroxyphenylarsonic acid 4,5 '-dithiazole-2-amino) phenyl]-1-[N-methyl-N-(2-dimethylaminoEthyl) amino]-2,3-dihydroindene-5-formamide

N-[4-methyl-3-(2 '-acetylaminohydroxyphenylarsonic acid 4,5 '-dithiazole-2-amino) phenyl]-1-(4-methyl piperazine base)-2,3-bis-Hydrogenation indenes-5-formamide

(S)-N-[4-methyl-3-(2 '-methyl-4,5 '-dithiazole-2-amino) phenyl]-1-(4-methyl piperazine base)-2,3-bis-Hydrogenation indenes-5-formamide

N-[4-methyl-3-(2 '-methyl-4,5 '-dithiazole-2-amino) phenyl]-1-(4-methyl piperazine base)-2,3-dihydroIndenes-5-formamide

(S)-N-methyl-5-{2-[2-methyl-5-[1-(4-methyl piperazine base)-2,3-dihydroindene-5-formamido group] phenylAmino] thiazole-4-yl } pyridine-2-carboxamide

(S)-N-{3-[4-(6-chlorine imidazoles [1,2-b] pyridazine-3-yl) thiazole-2-amino] phenyl }-1-(4-methyl piperazine base)-2,3-dihydroindene-5-formamide

(S)-N-{3-[4-(6-flumizole [1,2-b] pyridazine-3-yl) thiazole-2-amino] phenyl }-1-(4-methyl piperazine base)-2,3-dihydroindene-5-formamide

(1S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-{N-methyl-N-[(1-tertiary butyloxycarbonylBase-piperidin-4-yl) methyl] amino }-2,3-dihydro-1H-indenes-5-formamide

(1S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-{N-methyl-N-[(piperidin-4-yl)Methyl] amino }-2,3-dihydro-1H-indenes-5-formamide

(1S)-N-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl }-1-{N-methyl-N-[(1H-imidazoles-4-Base) methyl] amino }-2,3-dihydro-1H-indenes-5-formamide

6-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl amino formoxyl }-3,4-dihydro-isoquinoline-2(1H)-carboxylic acid tert-butyl ester

N-{[4-methyl-3-(pyridin-3-yl) thiazole-2-amino] phenyl }-1,2,3,4-tetrahydroisoquinoline-6-formamide

7-{4-methyl-3-[4-(pyridin-3-yl) thiazole-2-amino] phenyl amino formoxyl }-3,4-dihydro-isoquinoline-2(1H)-carboxylic acid tert-butyl ester

N-{[4-methyl-3-(pyridin-3-yl) thiazole-2-amino] phenyl }-1,2,3,4-tetrahydroisoquinoline-7-formamide

N-{[4-methyl-3-(4-pyridin-3-yl) thiazole-2-amino] phenyl-2,3,5,6,8,9-hexahydrobenzene also [Isosorbide-5-Nitrae, 7,10] four oxo cyclododecane-12-formamides.

The compound of 18. claim 1-17 any one or pharmaceutically acceptable salt are for the preparation for the treatment of disease or imbalanceApplication in medicine, wherein said disease or imbalance are relevant to protein kinase activity or abnormal relevant with cell proliferation.

19. 1 kinds of pharmaceutical compositions, the compound that it contains any one in claim 1-17 or pharmaceutically acceptable salt andPharmaceutically acceptable carrier.