CN103864764A

CN103864764A - Indazole-substituted pyrimidinamine derivative, and preparation method and use thereof

Info

Publication number: CN103864764A
Application number: CN201210532927.0A
Authority: CN
Inventors: 张龙; 范传文; 杨莹莹; 邢昭彬; 刘小军; 黄文淑; 周豪杰; 郑庆梅
Original assignee: Qilu Pharmaceutical Co Ltd
Current assignee: Qilu Pharmaceutical Co Ltd
Priority date: 2012-12-11
Filing date: 2012-12-11
Publication date: 2014-06-18

Abstract

The invention belongs to the field of pharmaceutical chemicals, and relates to an indazole-substituted pyrimidine derivative represented by formula I, and its pharmaceutically acceptable salt, a solvate of the derivative, or a solvate of the salt. The above compounds are effective tyrosine kinase inhibitors. The invention also relates to a preparation method of the indazole-substituted pyrimidine derivative, a medicinal composition containing the indazole-substituted pyrimidine derivative, its pharmaceutically acceptable salt, the solvate of the derivative or the solvate of the salt, and a use of the indazole-substituted pyrimidine derivative, its pharmaceutically acceptable salt, the solvate of the derivative or the solvate of the salt in the preparation of medicines for treating or adjunctively treating the proliferation and migration of tyrosine kinase mediated tumors or tyrosine kinase driven tumor cells in mammals (comprising human).

Description

Pyrimidinamine derivatives, Preparation Method And The Use that indazole replaces

Technical field

The invention belongs to field of medicine and chemical technology, relate to pyrimidinamine derivatives, the solvate of its pharmacy acceptable salt, described derivative or the solvate of described salt that a kind of indazole replaces.The invention still further relates to preparation method, its pharmaceutical composition and the purposes of the pyrimidinamine derivatives of described indazole replacement.

Background technology

Tumour is one of principal disease of serious threat human life and quality of life, and according to the World Health Organization (WHO) statistics, the patient approximately 6,900,000 of tumour is died from the whole world every year.Due to the change of living environment and life habit, under the effect of poor environment and some unfavorable factors, the M & M of tumour is progressively ascendant trend in recent years.

The treatment of tumour was realized by finding tumour destruction in the past, now along with deepening continuously to cell signaling Study of way, it is more and more deep that the effect of the oncogene of people to tumour cell inside and antioncogene is understood, the antitumor drug new for the specific molecular shot design of tumour more and more receives publicity, and becomes the hot fields of research.And that anti-tumor drugs targeting has also been applied to as a kind of new methods for the treatment of is clinical, and obtain in recent years significant progress.Now known, propagation, differentiation, migration and the apoptosis of protein tyrosine kinase (Protein tyrosine kinases, PTK) signal path and tumour cell have substantial connection (Li Sun, et al., Drug Discov Today, 2000,5,344-353), utilizing protein tyrosine kinase inhibitor interference or block Tyrosylprotein kinase path can be for oncotherapy (Fabbro D., et al., CurrOpin Pharmacol, 2002,2,374-381).

The peptide chain-ordering that most cells growth factor receptors contains Tyrosylprotein kinase, in many tumours, crossing of visible different tyrosine kinase receptors expressed or activated, cross and express as common EGF-R ELISA (EGFR) in epithelial cell tumour, in glioma, common platelet derived growth factor receptor (PDGFR) is crossed expression etc.According to the similarity of peptide chain-ordering and structural feature thereof, these acceptors are divided into again some families: 1) Epidermal Growth Factor Receptor Family, comprise EGFR, HER-2, HER-3, HER-4 etc., and the high expression level of this receptoroid is common in epithelial cell tumour; 2) Insulin Receptor Family, comprises insulin receptor, IGF-1 (IGF-R) and Regular Insulin associated receptor (IRR) etc., the high expression level of common this receptoroid in leukemia; 3) Platelet Derived Growth Factor Receptor Family (PDGFR), comprises PDGFR-α, PDGFR-β, CSF-1R, c-Kit etc., this receptoroid common high expression level in cerebral tumor, leukemia; 4) fibroblast growth factor acceptor (FGFR), comprises FGFR-1, FGFR-2, FGFR-3, FGFR-4 etc., and this receptoroid plays an important role aspect vasculogenesis; 5) vascular endothelial growth factor receptor (VEGFR), comprises VEGFR-1, VEGFR-2, VEGFR-3, is the important positivity regulatory factor of vasculogenesis.Tyrosine kinase receptor overexpression in dissimilar tumour, cause abnormal signal in its cell to activate, cause cell transformation, constantly breed, promote generation, the development of tumour, inhibited apoptosis, therefore, target tyrosine kinase signal approach is the research direction of good antitumor drug.

Vascular endothelial growth factor (VEGF) be Main Function in the somatomedin of vascular endothelial cell, there is the endothelial cell proliferation of promotion, increase the several functions such as microvascular permeability, induction of vascular generation.At present, VEGF family mainly comprises 6 member: VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E and PDF.Wherein, VEGF-C is a newcomer of VEGF family, is obtained by the separation and purification from PC-3 PC3 of the use Flt4 affinity chromatographies such as Joukov.VEGF-C can activate the Flt4 on lymphatic endothelial specifically, therefore, and the VEGF-C B cell growth factor that is otherwise known as.VEGF-C has the dual function that stimulates blood vessel and lymphatic vessel to generate, and its acceptor VEGFR-2 is mainly distributed in vascular endothelial cell, promotes vascular endothelial cell proliferation, migration and angiogenic growth by being combined with VEGFR-2.The formation of tumour and development substantially can be divided into two stages, i.e. clone's property multiplicative stage of tumour cell and the vascularization that comes next promotes tumour to continue the stage of growth.VEGF acts on self existing vasoganglion endotheliocyte, makes its differentiation and forms new blood vessel.Neovascularity not only provides basis for the exchange of substance of tumour cell, also can paracrine some cytokines promote the propagation of tumour cells; Simultaneously because the structural pipe wall of new vessel lacks integrity, between endotheliocyte, connect loose, basilar membrane thickness differ, rupture or lack as, oncocyte is easy to intravasation chamber and blood invasion and attack and transfer occurs.Thereby the growth of VEGF and tumour and transfer relationship close.VEGF can detect in the majority tissue of healthy human body, but expression amount is very micro-, in many tumours, especially in noumenal tumour, occurs high expression level, as: in liver cancer, cerebral tumor, mammary cancer, lung cancer and renal carcinoma tissue.Due to growth and the dependency of transfer to new vessel of solid tumor, therefore VEGF is the more satisfactory target site of blocking-up solid tumor vascularization.There are two viewpoints to promote the research of tumour angiogenesis inhibitor, first: the general new vessel of health adult is less, therefore it has been generally acknowledged that angiogenesis inhibitor side effect is less; Second: in angiogenesis, related endotheliocyte is normal cell, there is not genomic instability, this just means that angiogenesis inhibitor treatment not too can produce resistance.VEGFR is a kind of diffusible blood vessel endothelium specificity mitogen and Angiogenesis factor receptors, in physiological and pathologic vessels forming process, plays a crucial role, and can suppress endothelial cell apoptosis.This family has 3 members, i.e. VEGFR1, VEGFR2, VEGFR3.Generally believe that at present it is to be mediated in conjunction with institute with the vegf receptor 2 (VEGFR-2) that is positioned at Surface of Vascular Endothelial Cells by VEGF that VEGF induction of vascular generates, VEGF causes after being combined with VEGFR-2 that VEGFR-2 forms dimer and lures tyrosine kinase mediated phosphorylation into, the one-step activation of going forward side by side downstream signal Signal Transduction Pathways (the Ferrara N that is correlated with, Gerber HP, Lecouter J.The biologyof VEGF and its receptors.Nat Med, 2003,3:669-676; Kim KJ, Li B, Winer J, et al.Inhibition of vascular endothelial growthfactor induced angiogenesis suppresses tumour growth invivo.Nature, 1993,362:841-844).

Thr6 PDGF BB (PDGF) is mainly expressed in inoblast, smooth muscle cell and kidney, testis, brain, with the close relationship that has of tumour.In most of glioblastoma multiformes, exist the autocrine loop that PDGF and acceptor thereof form, comprise overexpression or the overactivity of the autocrine stimulation of PDGF in tumour, pdgf receptor or by stimulating intratumoral vasculature to generate, these processes all can promote tumor growth.

In recent years, people are devoted to suppress cellular signal transduction pathways with development of new target spot antitumor drug.Signal transduction inhibitor is lowered existence and the proliferation signal of tumour, promotes apoptosis, rather than by cytotoxicity, therefore selectivity is higher, toxic side effect is less.Existing ten multi-signal transduction inhibitor are applied to clinical treatment tumour at present, are mainly tyrosine kinase inhibitor series antineoplastic medicament.The comparatively maturation of wherein developing as main multiple receptor tyrosine kinases inhibitor antitumor drug take VEGFR, PDGFR target spot, has had 5 medicines listings: Sutent, BAY 43-9006, pazopanib etc. at present.

Small molecule tyrosine kinase inhibitors is as new anti-tumor drugs targeting, and for a fan new window has been opened in treatment and the prevention of tumour, and its side effect is slight, has good tolerance.Although existing more than 10 small molecule tyrosine kinase inhibitors is that clinical cancer therapy has been made very large contribution at present, but still need to find that some have the other compound of the pharmacological characteristics of better activity in vivo and/or improvement than existing tyrosine kinase inhibitor.Therefore develop new improved or more efficient tyrosine kinase inhibitor, more in depth understand relation between such medicine and known target protein with and the mechanism of performance antitumor action clinical therapy of tumor is had great importance.

Summary of the invention

One aspect of the present invention relates to pyrimidinamine derivatives, its pharmacy acceptable salt, the solvate of described derivative or the solvate of described salt that the indazole shown in formula I replaces,

Formula I

Wherein,

R ₀be selected from hydrogen atom, C _1-4alkyl, cycloalkyl;

R is selected from

R ₁～R ₆respectively independently selected from hydrogen atom, halogen, C _1-4the C that alkyl, one or more halogen replace _1-4alkyl, C _1-4the C that alkoxyl group, one or more halogen replace _1-4alkoxyl group, cycloalkyl, thiazolinyl, alkynyl, hydroxyl ,-NR ₁₀r ₁₁,-SOR ₁₀,-SO ₂r ₁₀,-NR ₁₀sO ₂r ₁₁,-SO ₂nR ₁₁r ₁₀,-COR ₁₀,-NR ₁₁cOR ₁₀,-CONR ₁₁r ₁₀,-OCOR ₁₀,-CN ,-NO ₂; Or the R of above-mentioned arbitrary neighborhood ₁～R ₅can with together with carbon atom on phenyl ring, form 4-8 unit heterocycle, described heteroatoms is at random selected from S or N or O;

R ₇be selected from C _1-4alkyl, C _3～8cycloalkyl; Hydrogen on described alkyl or cycloalkyl can be replaced by one or more halogens arbitrarily;

R ₈respectively independently selected from hydrogen atom, halogen, C _1-4the C that alkyl, one or more halogen replace _1-4alkyl, C _1-4alkoxyl group, cycloalkyl, amino ,-CN ,-NO that alkoxyl group, one or more halogen replace ₂;

Work as R ₁～R ₅while independently not forming heterocycle structure respectively, R ₉be selected from halogen, C _1-4the C that alkyl, one or more halogen replace _1-4alkyl, C _1-4alkoxyl group, cycloalkyl, amino ,-CN ,-NO that alkoxyl group, one or more halogen replace ₂; Work as R ₁～R ₅in carbon atom on any two adjacent substituting group and phenyl ring while forming 4-8 unit heterocycle, R ₉be selected from hydrogen, halogen, C _1-4the C that alkyl, one or more halogen replace _1-4alkyl, C _1-4alkoxyl group, cycloalkyl, amino ,-CN ,-NO that alkoxyl group, one or more halogen replace ₂;

R ₁₀and R ₁₁respectively independently selected from hydrogen atom, C _1-4the C that alkyl, one or more halogen replace _1-4alkyl, cycloalkyl;

N is selected from 0～3 integer.

In one embodiment of the invention, pyrimidinamine derivatives, its pharmacy acceptable salt, the solvate of described derivative or the solvate of described salt that the indazole shown in formula I replaces,

Wherein,

R ₀be selected from hydrogen atom, C _1-4alkyl, C _3～8cycloalkyl;

R is selected from

R ₁～R ₅respectively independently selected from hydrogen atom, halogen, C _1-4the C that alkyl, one or more halogen replace _1-4alkyl, C _1-4the C that alkoxyl group, one or more halogen replace _1-4alkoxyl group, alkynyl, hydroxyl ,-SO ₂nR ₁₁r ₁₀,-CONR ₁₁r ₁₀,-CN ,-NO ₂; Or the R of above-mentioned arbitrary neighborhood ₁～R ₅can with together with carbon atom on phenyl ring, form 4-8 unit heterocycle and (for example ought be selected from R ₁～R ₅arbitrary substituting group be C _1-4alkoxyl group ,-SO ₂nR ₁₁r ₁₀,-CONR ₁₁r ₁₀time, this substituting group can form with adjacent substituting group 4-8 unit heterocycle together with carbon atom on phenyl ring, and wherein said 4-8 unit heterocycle contains 1～2 heteroatoms, described heteroatoms is at random selected from S or N or O);

R ₆, R ₇, R ₈, R ₉respectively independently selected from hydrogen atom, halogen, C _1-4the C that alkyl, one or more halogen replace _1-4alkyl, C _1-4the C that alkoxyl group, one or more halogen replace _1-4alkoxyl group, C _3～8cycloalkyl, amino ,-CN ,-NO ₂;

R ₁₀and R ₁₁respectively independently selected from hydrogen atom, C _1-4the C that alkyl, one or more halogen replace _1-4alkyl, C _3～8cycloalkyl;

N is selected from 0～3 integer.

In a preferred embodiment of the present invention, pyrimidinamine derivatives, its pharmacy acceptable salt, the solvate of described derivative or the solvate of described salt that the indazole shown in formula I replaces, wherein, R ₀be selected from hydrogen atom, C _1-4alkyl, is preferably hydrogen atom, methyl.

In a preferred embodiment of the present invention, pyrimidinamine derivatives, its pharmacy acceptable salt, the solvate of described derivative or the solvate of described salt that the indazole shown in formula I replaces, wherein, R ₁～R ₅respectively independently selected from hydrogen atom, halogen, C _1-4the C that alkyl, one or more halogen replace _1-4alkyl, C _1-4alkoxyl group, alkynyl ,-SO ₂nR ₁₁r ₁₀,-CONR ₁₁r ₁₀, or the R of above-mentioned arbitrary neighborhood ₁～R ₅can with together with carbon atom on phenyl ring, form 4-8 unit heterocycle, described heteroatoms is at random selected from S or N or O;

Preferably, R ₁～R ₅respectively independently selected from hydrogen atom, halogen, ethynyl, methyl, ethyl, propyl group, sec.-propyl, methoxyl group, oxyethyl group, propoxy-,-SO ₂nR ₁₁r ₁₀,-CONR ₁₁r ₁₀, or the R of above-mentioned arbitrary neighborhood ₁～R ₅can jointly be constructed as follows structure with phenyl ring:

or 2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae]-dioxane.

In a preferred embodiment of the present invention, pyrimidinamine derivatives, its pharmacy acceptable salt, the solvate of described derivative or the solvate of described salt that the indazole shown in formula I replaces, wherein, R ₆, R ₇, R ₈, R ₉respectively independently selected from hydrogen atom, halogen, C _1-4the C that alkyl, one or more halogen replace _1-4alkyl; Preferably, R ₆, R ₇, R ₈, R ₉respectively independently selected from hydrogen atom, Cl, F, Br, methyl; Further preferably, R ₆, R ₇, R ₈, R ₉respectively independently selected from hydrogen atom, F, methyl; More preferably, R ₆for F, R ₇for methyl, R ₈for hydrogen atom or methyl, R ₉for hydrogen atom or F.

In a preferred embodiment of the present invention, pyrimidinamine derivatives, its pharmacy acceptable salt, the solvate of described derivative or the solvate of described salt that the indazole shown in formula I replaces, wherein, R ₁₀and R ₁₁respectively independently selected from hydrogen atom, C _1-4the C that alkyl, one or more halogen replace _1-4alkyl; Preferably, R ₁₀and R ₁₁respectively independently selected from hydrogen atom, methyl.

In a preferred embodiment of the present invention, pyrimidinamine derivatives, its pharmacy acceptable salt, the solvate of described derivative or the solvate of described salt that the indazole shown in formula I replaces, wherein, n is 0 or 1.

In one embodiment of the invention, pyrimidinamine derivatives, its pharmacy acceptable salt, the solvate of described derivative or the solvate of described salt that the indazole shown in formula I replaces, wherein:

R ₀be selected from hydrogen atom, C _1-4alkyl, C _3～6cycloalkyl;

R is selected from

R ₂for hydrogen atom ,-SO ₂nR ₁₁r ₁₀or CONH ₂;

R ₃for hydrogen atom, F, Cl, Br, methyl, methoxyl group or sec.-propyl; Or R ₂and R ₃jointly form following structure with phenyl ring: optionally by C ₁～C ₄alkyl replace 1,1-dioxy benzisothiazole ring, optionally by C ₁～C ₄the 1-oxygen isoindoline that alkyl replaces;

R ₄for hydrogen atom, halogen, C _1-4the C that alkyl, one or more halogen replace _1-4alkyl, C _1-4the C that alkoxyl group, one or more halogen replace _1-4alkoxyl group, cycloalkyl, thiazolinyl, alkynyl or-SO ₂nH ₂; Or R ₃and R ₄form following structure with phenyl ring is common: 2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae]-dioxane, optionally by C ₁～C ₄alkyl replace 1,1-dioxy benzisothiazole ring, optionally by C ₁～C ₄the 1-oxygen isoindoline that alkyl replaces;

R ₁, R ₅, R ₆respectively independently selected from hydrogen atom, halogen, C _1-4the C that alkyl, one or more halogen replace _1-4alkyl, C _1-4the C that alkoxyl group, one or more halogen replace _1-4alkoxyl group, cycloalkyl, thiazolinyl, alkynyl;

R ₈respectively independently selected from hydrogen atom, halogen, C _1-4the C that alkyl, one or more halogen replace _1-4alkyl;

R ₉be selected from halogen, C _1-4the C that alkyl, one or more halogen replace _1-4alkyl, C _1-4alkoxyl group, cycloalkyl that alkoxyl group, one or more halogen replace, or jointly form optionally by C as R2 and R3 ₁～C ₄1 of alkyl replacement, when 1-dioxy isothiazole ring, R ₉be selected from hydrogen atom, halogen, C _1-4the C that alkyl, one or more halogen replace _1-4alkyl, C _1-4alkoxyl group, cycloalkyl that alkoxyl group, one or more halogen replace;

N is 0 or 1.

In a preferred embodiment of the present invention, pyrimidinamine derivatives, its pharmacy acceptable salt, the solvate of described derivative or the solvate of described salt that the indazole shown in formula I replaces, wherein,

R ₀be selected from hydrogen atom, methyl;

R is selected from

R ₁for hydrogen atom or F;

R ₂for hydrogen atom ,-SO ₂nH ₂or CONH ₂;

R ₃for hydrogen atom, F, Cl, Br, methyl, methoxyl group or sec.-propyl; Or R ₂and R ₃jointly form following structure with phenyl ring:

R ₄for hydrogen atom, ethynyl, methyl, trifluoromethyl, methoxyl group, Cl, Br or-SO ₂nH ₂; Or R ₃and R ₄with common 2,3-dihydrobenzo [b] [the Isosorbide-5-Nitrae]-dioxane that forms of phenyl ring;

R ₅for hydrogen atom;

R ₆for F; R ₇for methyl; R ₈for hydrogen atom or methyl; R ₉for hydrogen atom or F;

N is 0 or 1.

R ₀be selected from methyl;

R is selected from

R ₁for hydrogen atom;

R ₂for hydrogen atom or-SO ₂nH ₂, and R ₃for methyl, or R2 and R3 and common 1,1-dioxy benzo [d] the isothiazole ring that forms of phenyl ring;

R ₄for hydrogen atom, ethynyl or-SO ₂nH ₂;

R ₅for hydrogen atom;

R ₆for hydrogen atom or F; R ₇for methyl; R ₈for hydrogen atom or methyl; R ₉for hydrogen atom or F;

N is 0 or 1.

R ₀be selected from methyl;

R is selected from

R ₁for hydrogen atom;

R ₂for hydrogen atom or-SO ₂nH ₂, and R ₃for methyl, or R ₂and R ₃with common 1,1-dioxy benzo [d] the isothiazole ring that forms of phenyl ring;

R ₄for hydrogen atom or-SO ₂nH ₂;

R ₅for hydrogen atom;

N is 0 or 1.

R ₀be selected from methyl;

R is selected from

R ₁for hydrogen atom;

R ₂for-SO ₂nH ₂and R ₃for methyl, or R2 and R3 and common 1,1-dioxy benzo [d] the isothiazole ring that forms of phenyl ring;

R ₄for hydrogen atom; R ₅for hydrogen atom; R ₇for methyl; R ₈for hydrogen atom or methyl;

In the time that R2 and R3 do not form heterocycle structure, R ₉for F, in the time of R2 and R3 and the common formation of phenyl ring 1,1-dioxy benzo [d] isothiazole ring, R ₉for hydrogen atom; N is 0.

In a preferred embodiment of the present invention, the pyrimidinamine derivatives that the indazole shown in formula I replaces is selected from following compound:

2-methyl-5-(4-(1-methyl isophthalic acid H-indazole-5 base amino) pyrimidine-2--amino) benzsulfamide (compound 1);

2-methyl-5-(4-((1-methyl isophthalic acid H-indazole-5 base) methylamino) pyrimidine-2--amino) benzsulfamide (compound 2);

2-methyl-5-(4-((2-methyl-2H-indazole-5 base) methylamino) pyrimidine-2--amino) benzsulfamide (compound 3);

5-(4-((1,3-dimethyl-1H-indazole-5-yl) methylamino) pyrimidine-2--amino)-2-methyl benzenesulfonamide (compound 4);

5-(4-((2,3-dimethyl-2H-indazole-5-yl) methylamino) pyrimidine-2--amino)-2-methyl benzenesulfonamide (compound 5);

N ⁴-(2,3-dimethyl-2H-indazole-5-yl)-N ²-(3-ethynyl phenyl)-N ⁴-methylpyrimidine-2,4-diamines (compound 6);

N ⁴-(1,3-dimethyl-1H-indazole-5-yl)-N ²-(3-ethynyl phenyl)-N ⁴-methylpyrimidine-2,4-diamines (compound 7);

N ²-(2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae]-dioxane-6-yl)-N ⁴-(2,3-dimethyl-2H-indazole-5-yl)-N ⁴-methylpyrimidine-2,4-diamines (compound 8);

N ²-(2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae]-dioxane-6-yl)-N ⁴-(1,3-dimethyl-1H-indazole-5-yl)-N ⁴-methylpyrimidine-2,4-diamines (compound 9);

N ⁴-(2,3-dimethyl-2H-indazole-5-yl)-N ²-(3,4-xylyl)-N ⁴-methylpyrimidine-2,4-diamines (compound 10);

N ⁴-(1,3-dimethyl-1H-indazole-5-yl)-N ²-(3,4-xylyl)-N ⁴-methylpyrimidine-2,4-diamines (compound 11);

N ²-(the chloro-3-of 4-(trifluoromethyl) phenyl)-N ⁴-(2,3-dimethyl-2H-indazole-5-yl)-N ⁴-methylpyrimidine-2,4-diamines (compound 12);

N ²-(the chloro-3-of 4-(trifluoromethyl) phenyl)-N ⁴-(1,3-dimethyl-1H-indazole-5-yl)-N ⁴-methylpyrimidine-2,4-diamines (compound 13);

N ²-(the chloro-4-fluorophenyl of 3-)-N ⁴-(2,3-dimethyl-2H-indazole-5-yl)-N ⁴-methylpyrimidine-2,4-diamines (compound 14);

N ²-(the chloro-4-fluorophenyl of 3-)-N ⁴-(1,3-dimethyl-1H-indazole-5-yl)-N ⁴-methylpyrimidine-2,4-diamines (compound 15);

N ²-(the bromo-2-fluorophenyl of 4-)-N ⁴-(2,3-dimethyl-2H-indazole-5-yl)-N ⁴-methylpyrimidine-2,4-diamines (compound 16);

N ²-(the bromo-2-fluorophenyl of 4-)-N ⁴-(1,3-dimethyl-1H-indazole-5-yl)-N ⁴-methylpyrimidine-2,4-diamines (compound 17);

N ⁴-(2,3-dimethyl-2H-indazole-5-yl)-N ²-(the fluoro-5-aminomethyl phenyl of 2-)-N ⁴-methylpyrimidine-2,4-diamines (compound 18);

N ⁴-(1,3-dimethyl-1H-indazole-5-yl)-N ²-(the fluoro-5-aminomethyl phenyl of 2-)-N ⁴-methylpyrimidine-2,4-diamines (compound 19);

N ²-(the chloro-3-aminomethyl phenyl of 4-)-N ⁴-(2,3-dimethyl-2H-indazole-5-yl)-N ⁴-methylpyrimidine-2,4-diamines (compound 20);

N ²-(the bromo-4-aminomethyl phenyl of 3-)-N ⁴-(2,3-dimethyl-2H-indazole-5-yl)-N ⁴-methylpyrimidine-2,4-diamines (compound 21);

5-(4-((the fluoro-1-methyl isophthalic acid of 4-H-indazole-5-yl) (methylamino) pyrimidine-2-base-amino)-2-methyl benzenesulfonamide (compound 22);

5-(4-((the fluoro-2-methyl-2H-of 4-indazole-5-yl) (methylamino) pyrimidine-2-base-amino)-2-methyl benzenesulfonamide (compound 23);

5-(4-((the fluoro-1-methyl isophthalic acid of 7-H-indazole-6-yl) (methylamino) pyrimidine-2-base-amino)-2-methyl benzenesulfonamide (compound 24);

5-(4-((the fluoro-2-methyl-2H-of 7-indazole-6-yl) (methylamino) pyrimidine-2-base-amino)-2-methyl benzenesulfonamide (compound 25);

5-(4-((the fluoro-2-methyl-2H-of 7-indazole-5-yl) (methylamino) pyrimidine-2-base-amino)-2-methyl benzenesulfonamide (compound 26);

5-(4-((the fluoro-1-methyl isophthalic acid of 7-H-indazole-5-yl) (methylamino) pyrimidine-2-base-amino)-2-methyl benzenesulfonamide (compound 27);

5-(4-((4-fluoro-1,3-methyl isophthalic acid H-indazole-6-yl) (methylamino) pyrimidine-2-base-amino)-2-methyl benzenesulfonamide (compound 28);

5-(4-((4-fluoro-2,3-dimethyl-2H-indazole-6-yl) (methylamino) pyrimidine-2-base-amino)-2-methyl benzenesulfonamide (compound 29);

6-(4-((the fluoro-2-methyl-2H-of 7-indazole-6-yl) (methylamino) pyrimidine-2-base-amino)-3,3-dimethyl 1-isoindolinone (compound 30);

6-(4-((the fluoro-1-methyl isophthalic acid of 7-H-indazole-5-yl) (methylamino) pyrimidine-2-base-amino)-3,3-dimethyl 1-isoindolinone (compound 31);

6-(4-((the fluoro-1-methyl isophthalic acid of 7-H-indazole-6-yl) (methylamino) pyrimidine-2-base-amino)-3,3-dimethyl-2-hydrogen-benzo [d] isothiazole-1,1-dioxy (compound 32);

6-(4-((the fluoro-2-methyl-2H-of 7-indazole-6-yl) (methylamino) pyrimidine-2-base-amino)-3,3-dimethyl-2-hydrogen-benzo [d] isothiazole-1,1-dioxy (compound 33);

6-(4-((the fluoro-1-methyl isophthalic acid of 7-H-indazole-5-yl) (methylamino) pyrimidine-2-base-amino)-3,3-dimethyl-2-hydrogen-benzo [d] isothiazole-1,1-dioxy (compound 34);

6-(4-((the fluoro-2-methyl-2H-of 7-indazole-5-yl) (methylamino) pyrimidine-2-base-amino)-3,3-dimethyl-2-hydrogen-benzo [d] isothiazole-1,1-dioxy (compound 35);

6-(4-((4-fluoro-2,3-methyl-2H-indazole-6-yl) (methylamino) pyrimidine-2-base-amino)-2,3-dihydro-benzo [d] isothiazole-1,1-dioxy (compound 36);

6-(4-((2,3-methyl-2H-indazole-6-yl) (methylamino) pyrimidine-2-base-amino)-2,3-dihydro-benzo [d] isothiazole-1,1-dioxy (compound 37);

6-(4-((the fluoro-2-methyl-2H-of 4-indazole-5-yl) (methylamino) pyrimidine-2-base-amino)-2,3-dihydro-benzo [d] isothiazole-1,1-dioxy (compound 38);

Preferably, the pyrimidinamine derivatives that the indazole shown in formula I of the present invention replaces is selected from following compound:

6-(4-((the fluoro-2-methyl-2H-of 4-indazole-5-yl) (methylamino) pyrimidine-2-base-amino)-2,3-dihydro-benzo [d] isothiazole-1,1-dioxy (compound 38).

Further preferably, the pyrimidinamine derivatives that the indazole shown in formula I of the present invention replaces is selected from following compound:

Still more preferably, the pyrimidinamine derivatives that the indazole shown in formula I of the present invention replaces is selected from following compound:

Again further preferably, the pyrimidinamine derivatives that the indazole shown in formula I of the present invention replaces is selected from following compound:

Particularly preferably, the pyrimidinamine derivatives that the indazole shown in formula I of the present invention replaces is selected from following compound:

6-(4-((2,3-methyl-2H-indazole-6-yl) (methylamino) pyrimidine-2-base-amino)-2,3-dihydro-benzo [d] isothiazole-1,1-dioxy (compound 37).

Term used herein " alkyl " refers to saturated straight or branched monovalence alkyl, and having 1-8 carbon atom (is C _1-8alkyl), preferably 1-6 carbon atom (is C _1-6alkyl), or 1-4 carbon atom (is C _1-4alkyl) or 1-3 carbon atom (be C _1-3alkyl).The example of " alkyl " includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, neo-pentyl, n-hexyl, 2-methyl amyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl etc.

Term used herein " thiazolinyl " refers to have 2-8 carbon atom, the preferably monovalence ethylenically unsaturated hydrocarbons base of 2-6 carbon atom, they can be straight or branched and there is at least 1 carbon-carbon double bond.Concrete thiazolinyl includes but not limited to vinyl (CH=CH ₂), n-propenyl (CH ₂cH=CH ₂), pseudoallyl (C (CH ₃)=CH ₂), butenyl etc.

Term used herein " alkynyl " refers to have 2-8 carbon atom, the preferably monovalence acetylene series unsaturated alkyl of 2-6 carbon atom, they can be straight or branched and there is at least 1 carbon carbon triple bond.Concrete alkynyl includes but not limited to ethynyl (C ≡ CH), propargyl (CH ₂c ≡ CH) etc.

Term used herein " halogen " refers to fluorine, chlorine, bromine or iodine.Preferred halogen group is fluorine, chlorine or bromine.

Term used herein " alkoxyl group " refers to group-OR ^a, wherein R ^afor alkyl as herein defined.The example of " alkoxyl group " includes but not limited to methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy, n-pentyloxy, positive hexyloxy, 1,2-dimethyl butoxy etc.

Term used herein " one or more halogen-substituted alkyl " refers to by halogen list defined herein or polysubstituted alkyl as herein defined.Include but not limited to-the CF of example of " one or more halogen-substituted alkyl " ₃,-CHF ₂,-CH ₂cCl ₃deng.

Term used herein " one or more halogen substituted alkoxy " refers to by halogen list defined herein or polysubstituted alkoxyl group as herein defined.Include but not limited to-the OCF of example of " one or more halogen substituted alkoxy " ₃,-OCHF ₂,-OCH ₂cCl ₃deng.

Term used herein " cycloalkyl " refers to have 3-12 carbon atom, preferably 3-8 carbon atom, more preferably 5-6 carbon atom and have monocycle or the cyclic hydrocarbon group of multiple fused rings or bridging ring system.As an example, this class cycloalkyl can comprise: single ring architecture, and such as cyclopropyl, cyclobutyl, cyclopentyl, ring octyl group, 1-methyl cyclopropyl, 2-methylcyclopentyl, 2-methyl ring octyl group etc.; And polynuclear plane, such as adamantyl etc.

Above-mentioned pharmacy acceptable salt is selected from: hydrochloride, vitriol, mesylate, tosilate, benzene sulfonate, fumarate, maleate, malate, or such as hydrate of the solvate of these salt.

Another aspect of the present invention relates to a kind of pharmaceutical composition, it comprises pyrimidinamine derivatives, its pharmacy acceptable salt, the solvate of described derivative or the solvate of described salt that the indazole shown in above-mentioned formula I replaces, and optional one or more pharmaceutically acceptable carrier and/or auxiliary materials.

The preparation method who also has an aspect to relate to the pyrimidinamine derivatives of the indazole replacement shown in above-mentioned formula I of the present invention, comprises the steps:

1) by 2 shown in formula i, 4-dichloro pyrimidine and corresponding containing amino indazole compound R-NH ₂(shown in formula ii) pyrimidine derivatives that the 4-position shown in synthesis type iii-1 replaces under suitable alkali exists;

Suitable alkali comprises organic bases, mineral alkali; Wherein organic bases is preferably tertiary amine (as triethylamine, diisopropyl ethyl amine etc.), and mineral alkali is preferably sodium carbonate, salt of wormwood, cesium carbonate etc.Preferred organic bases is diisopropyl ethyl amine, and preferred mineral alkali is sodium carbonate.What in part embodiment, use is that organic bases is as diisopropyl ethyl amine; What in other a part of embodiment, use is that mineral alkali is as sodium carbonate;

2) work as R ₀when hydrogen atom, by step 1) the 4-position shown in the formula iii-1 that the obtains pyrimidine derivatives and the target compound shown in corresponding ammonia (shown in formula iv) synthesis type I that replace:

Or work as R ₀for C _1-4when alkyl, cycloalkyl, by step 1) first the aminopyridine derivative that replaces of the 4-position shown in the formula iii-1 that obtains carry out alkylation, obtain compound shown in formula iii-2, then with the synthesising target compound shown in corresponding ammonia (shown in formula iv) synthesis type I:

Wherein, R, R ₀-R ₅definition described in above-mentioned formula I.

Also aspect of the present invention relates to pyrimidinamine derivatives, its pharmacy acceptable salt, the solvate of described derivative or the solvate of described salt that the indazole shown in above-mentioned formula I replaces in the purposes of preparing in tyrosine kinase inhibitor.

Also aspect of the present invention relate to pyrimidinamine derivatives, its pharmacy acceptable salt, the solvate of described derivative or the solvate of described salt that the indazole shown in above-mentioned formula I replaces for the preparation of in treating and/or preventing Mammals with the medicine of receptor tyrosine kinase relative disease in purposes.Particularly, described Mammals is the mankind.Described comprises with receptor tyrosine kinase relative disease: the tumour being mediated by receptor tyrosine kinase or the tumor cell proliferation being driven by receptor tyrosine kinase and migration.

Also aspect of the present invention relates to pyrimidinamine derivatives, its pharmacy acceptable salt, the solvate of described derivative or the solvate of described salt that the indazole shown in above-mentioned formula I the replaces purposes in the medicine of the tumour being mediated by receptor tyrosine kinase for the preparation for the treatment of or assisting therapy and/or prevention Mammals or cancer or the tumor cell proliferation being driven by receptor tyrosine kinase and migration.Particularly, described Mammals is the mankind.Described tumour or cancer comprise VEGFR or the responsive cancer of PDGFR Tyrosylprotein kinase, as the tumour of VEGFR, PDGFR high expression level and VEGF driving, comprise that noumenal tumour is as the cancer of bile duct, bone, bladder, brain/central nervous system, breast, knot rectum, uterine endometrium, stomach, head and neck, liver, lung (especially nonsmall-cell lung cancer), neurone, esophagus, ovary, pancreas, prostate gland, kidney, skin, testis, Tiroidina, uterus and vulva etc., and non-noumenal tumour is as leukemia, multiple myeloma or lymphoma etc.

According to the present invention, can expect that the compounds of this invention can be used for treating the responsive cancer of the Tyrosylprotein kinase such as VEGFR or PDGFR completely, as VEGFR, the tumour that PDGFR high expression level and VEGF drive, comprise that noumenal tumour is as bile duct, bone, bladder, brain/central nervous system, breast, knot rectum, uterine endometrium, stomach, head and neck, liver, lung (especially nonsmall-cell lung cancer), neurone, esophagus, ovary, pancreas, prostate gland, kidney, skin, testis, Tiroidina, the cancer of uterus and vulva etc., with non-noumenal tumour as leukemia, multiple myeloma or lymphoma etc.

Derivative of the present invention can regulate the activity of protein kinase, can be for prevention and the treatment of protein kinase dependency cell dysfunction, thus compound of the present invention can also be used for preventing and treating the dysfunction that relates to paraprotein kinase activity.Therefore, also aspect of the present invention relates to pyrimidinamine derivatives, its pharmacy acceptable salt, the solvate of described derivative or the solvate of described salt that the indazole shown in above-mentioned formula I replaces or pharmaceutical composition of the present invention for the preparation of preventing and/or treating purposes in the medicine of protein kinase dependency cell dysfunction disease or in the purposes for the preparation of preventing and/or treating in the medicine of the dysfunction disease that relates to paraprotein kinase activity.

An also aspect of the present invention relates to a kind of method that treats and/or prevents disease relevant to Tyrosylprotein kinase in Mammals, described method comprises pyrimidinamine derivatives, its pharmacy acceptable salt, the solvate of described derivative or the solvate of described salt of the indazole replacement of the present invention of using significant quantity, or pharmaceutical composition of the present invention.

Also aspect of the present invention relates in a kind for the treatment of or assisting therapy and/or prevention Mammals (comprising people) Mammals the method by tyrosine kinase mediated tumour or the tumor cell proliferation being driven by Tyrosylprotein kinase and migration, the method comprises pyrimidinamine derivatives, its pharmacy acceptable salt, the solvate of described derivative or the solvate of described salt of the indazole replacement of the present invention of using significant quantity, or pharmaceutical composition of the present invention.

An also aspect of the present invention relates to one and treats and/or prevents the tumour of Mammals (comprising people) or the method for cancer, described method comprises to the pyrimidinamine derivatives, its pharmacy acceptable salt, the solvate of described derivative or the solvate of described salt that have the indazole of the present invention of administration significant quantity of needs to replace, or pharmaceutical composition of the present invention.Described tumour or cancer comprise VEGFR or the responsive cancer of PDGFR Tyrosylprotein kinase, as the tumour of VEGFR, PDGFR high expression level and VEGF driving, comprise that noumenal tumour is as the cancer of bile duct, bone, bladder, brain/central nervous system, breast, knot rectum, uterine endometrium, stomach, head and neck, liver, lung (especially nonsmall-cell lung cancer), neurone, esophagus, ovary, pancreas, prostate gland, kidney, skin, testis, Tiroidina, uterus and vulva etc., and non-noumenal tumour is as leukemia, multiple myeloma or lymphoma etc.

The invention will be further described below.

All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if when the expressed implication of these documents and the present invention are inconsistent, be as the criterion with statement of the present invention.In addition, various terms and phrase that the present invention uses have the general sense of well known to a person skilled in the art, nonetheless, the present invention still wishes at this, these terms and phrase to be described in more detail and to be explained, the term of mentioning and phrase, if any inconsistent with known implication, are as the criterion with the implication that the present invention was explained.

In the method for synthetic compound of formula i of the present invention, the various starting material that react used are that those skilled in the art can prepare according to existing knowledge, or can make by the known method of document, or can buy by business.In above reaction scheme, intermediate used, starting material, reagent, reaction conditions etc. all can be made appropriate change according to those skilled in the art existing knowledge.Or, other formula I compound that those skilled in the art also can specifically not enumerate according to the synthetic the present invention of second aspect present invention method.

Formula I compound of the present invention can be used in combination with other activeconstituents, for example, as long as it does not produce other detrimental actions, anaphylaxis.

Active compound shown in formula I of the present invention can be used as unique cancer therapy drug and uses, or can combine use with one or more other antitumor drugs.Combination therapy realizes by each being treated to component while, order or separating administration.

Term used herein " composition " means to comprise the product of the each appointment composition that comprises specified amount, and any product of the combination results of direct or indirect each appointment composition from specified amount.

Compound of the present invention can use with the form derived from mineral acid or organic acid pharmacy acceptable salt.Word " pharmacy acceptable salt " refers to, within the scope of reliable medical judgment, be suitable for contacting with zootic tissue with the mankind and not occurring excessive toxicity, stimulation, anaphylaxis etc., and with rational effect/risk than the salt matching.Pharmacy acceptable salt is well known in the art.For example, S.M.Berge, et al., J.Pharmaceutical Sciences, have been described in detail pharmacy acceptable salt in 1977,66:1.Described salt can be by making the free alkali functionality of the compounds of this invention and suitable organic acid reaction, in final separation and the preparation of purge process situ or the preparation separately of the compounds of this invention.Representational acid salt includes but not limited to acetate, adipate, alginates, Citrate trianion, aspartate, benzoate, benzene sulfonate, hydrosulfate, vitriol, butyrates, camphorate, camsilate, digluconate, glycerophosphate, Hemisulphate, enanthate, hexanoate, fumarate, hydrochloride, hydrobromate, hydriodate, 2-isethionate (different thiosulphate, isothionate), lactic acid salt, maleate, mesylate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, Pivalate, propionic salt, succinate, tartrate, thiocyanate-, phosphoric acid salt, malate, glutaminate, supercarbonate, tosilate and undecane hydrochlorate.Equally, alkaline nitrogen-containing group can be quaternized with following material: elementary alkyl halide is as the muriate of methyl, ethyl, propyl group and butyl, bromide and iodide; Sulfuric acid dialkyl is as methyl-sulfate, diethyl ester, dibutylester and diamyl ester; Long-chain halogenide is as the muriate of decyl, dodecyl, tetradecyl and octadecyl, bromide and iodide; Arylalkyl halogenide is as bromotoluene and phenethyl bromide and other.

Formula I compound of the present invention also comprises its isomer, raceme, enantiomorph, diastereomer, enantiomorph enriched substance, solvate and ester, formula I compound of the present invention and its isomer, raceme, enantiomorph, diastereomer, enantiomorph enriched substance, solvate and ester can also form solvate, such as hydrate, alcohol adduct etc.Above-claimed cpd can also be prodrug or the form that discharges in vivo described activeconstituents after metabotic change.Selecting and preparing suitable prodrug derivant is technology as well known to those skilled in the art.In general, for object of the present invention, as suitable with non-solvent compound form in the solvate form thereof of water, ethanol etc. with the acceptable solvent of pharmacy.

The active compound amount of gained can change the actual dose level of each activeconstituents in pharmaceutical composition of the present invention, so that can effectively obtain required therapeutic response for concrete patient, composition and administering mode.Dosage level must according to the activity of particular compound, route of administration, the severity of the patient's condition for the treatment of and the patient's to be treated patient's condition and medical history select.But the way of this area is, the dosage of compound is from lower than level that required result for the treatment of requires, increasing gradually dosage, until obtain required effect for obtaining.

When treating and/or preventing or other treatment and/or when prevention for above-mentioned, a kind of the compounds of this invention that treats and/or prevents significant quantity can be applied with pure form, or with the acceptable ester of pharmacy or prodrug forms (in the situation that there are these forms) application.Or described compound can be accepted to contain this object compound and one or more medicines the pharmaceutical composition administration of vehicle.The compounds of this invention that word " treats and/or prevents significant quantity " refers to be applicable to the reasonable effect/risk of any therapeutic treatment and/or prevention than the compound of the q.s for the treatment of obstacle.But the total daily dosage portion that it should be understood that the compounds of this invention and composition must maked decision within the scope of medical judgment reliably by attending physician.For any concrete patient, concrete treatment effective dose level must be determined according to many factors, and described factor comprises the severity of treated obstacle He this obstacle; The activity of the particular compound adopting; The concrete composition adopting; Patient's age, body weight, general health situation, sex and diet; Administration time, route of administration and the excretion rate of the particular compound adopting; The treatment time length; The medicine that is used in combination with adopted particular compound or uses simultaneously; And the known similar factor of medical field.For example, the way of this area is, the dosage of compound is from lower than level that required result for the treatment of requires, increasing gradually dosage, until obtain required effect for obtaining.In general, particularly people's dosage can be between 0.001～1000mg/kg body weight/day, for example, between 0.01～100mg/kg body weight/day, for example, between 0.01～10mg/kg body weight/day for Mammals for formula I compound of the present invention.

Use the familiar pharmaceutical carrier of those skilled in the art can be prepared into the pharmaceutical composition containing the compounds of this invention of effective dose.Therefore the present invention also provides the pharmaceutical composition that comprises the compounds of this invention formulated together with one or more nontoxic drug acceptable carriers.That described pharmaceutical composition can be mixed with especially is specially for oral administration with solid or liquid form, for parenteral injection or for rectal administration.

Described pharmaceutical composition can be mixed with many formulations, is convenient to administration, for example, and oral preparations (as tablet, capsule, solution or suspension); Injectable preparation (as injectable solution or suspension, or injectable dried powder, before injection, add injection water to use immediately).In described pharmaceutical composition, carrier comprises: the tackiness agent that oral preparations uses is (as starch, normally corn, wheat or rice starch, gelatin, methylcellulose gum, Xylo-Mucine and/or polyvinylpyrrolidone), thinner is (as lactose, dextrose, sucrose, N.F,USP MANNITOL, sorbyl alcohol, Mierocrystalline cellulose, and/or glycerine), lubricant is (as silicon-dioxide, talcum, stearic acid or its salt, normally Magnesium Stearate or calcium stearate, and/or polyoxyethylene glycol), if and needed, also contain disintegrating agent, as starch, agar, Lalgine or its salt, normally sodiun alginate, and/or effervescent mixture, solubility promoter, stablizer, suspension agent, non-pigment, correctives etc., the sanitas that injectable preparation uses, solubilizing agent, stablizer etc., matrix that topical formulations is used, thinner, lubricant, sanitas etc.Pharmaceutical preparation can oral administration or parenteral mode (for example intravenously, subcutaneous, intraperitoneal or part) administration, if some drugs is unsettled under stomach condition, can be mixed with enteric coated tablets.

More particularly, pharmaceutical composition of the present invention can by oral, rectum, parenteral, pond, intravaginal, intraperitoneal, part (as by powder, ointment or drops), a mouthful cheek give the mankind and other Mammalss, or give as oral spray or nasal mist.Term used herein " parenteral " refers to comprise the administering mode of intravenously, intramuscular, intraperitoneal, breastbone interior, subcutaneous and intra-articular injection and transfusion.

The composition that is suitable for parenteral injection can comprise physiologically acceptable aseptic moisture or non-aqueous solution agent, dispersion agent, suspensoid or emulsion, and for the aseptic powder that reconstitutes sterile injectable solution agent or dispersion agent.Suitable moisture or nonaqueous carrier, thinner, solvent or vectorial example comprises that water, ethanol, polyvalent alcohol (propylene glycol, polyoxyethylene glycol, glycerine etc.), vegetables oil (as sweet oil), injectable organic ester are as ethyl oleate and their suitable mixture.

These compositions also can contain auxiliary material, as sanitas, wetting agent, emulsifying agent and dispersion agent.By various antibacterial agents and anti-mycotic agent, such as parabens, trichloro-butyl alcohol, phenol, Sorbic Acid etc., can guarantee to prevent the effect of microorganism.Also expect to comprise isotonic agent, such as carbohydrate, sodium-chlor etc.By using the material that can postpone absorption, for example aluminum monostearate and gelatin, the prolongation that can reach injectable drug form absorbs.

In suspensoid, remove active ingredient beyond the region of objective existence and also can contain suspension agent, the mixture of such as ethoxylation i-octadecanol, polyoxyethylene sorbitol and polyoxyethylene sorbitan esters, Microcrystalline Cellulose, inclined to one side aluminium hydroxide, wilkinite, agar and tragacanth gum or these materials etc.

In some cases, be the effect of prolong drug, expect to slow down absorption subcutaneous or intramuscularly medicine.This can realize by the liquid suspension of the crystal with poorly water-soluble or amorphous substance.Like this, the absorption rate of medicine depends on its dissolution rate, and dissolution rate can be depending on crystallographic dimension and crystal formation.Or, the delay of the medicament forms of parenteral admin absorb by by this medicine dissolution in or be suspended in oily vehicle and realize.

Injectable depot formulations form can be prepared by forming the microcapsule matrix of medicine at biodegradable polymer in as polylactide-PGA (polylactide-polyglycolide).Can, according to the character of the ratio of medicine and polymkeric substance and the concrete polymkeric substance adopting, drug releasing rate be controlled.The example of other biological degradable polymer comprises poe class (poly (0rthoesters)) and polyanhydrides (poly (anhydrides)).Injectable depot formulations also can by pharmaceutical pack is embedded in can be compatible with bodily tissue liposome or micro emulsion in prepare.

Injectable formulation can be for example by filtering or carry out sterilizing by the disinfectant that mixes aseptic solid composite form with bacterial filter, and described solids composition can be dissolved or dispersed in sterilized water or other sterile injectable medium before use.

The compounds of this invention or its composition can be by oral method or parenteral administration modes.Oral administration can be tablet, capsule, Drug coating, and enteron aisle external application preparation has injection and suppository etc.These preparations are prepared according to method appreciated by those skilled in the art.The auxiliary material of conventional use in order to manufacture tablet, capsule, Drug coating auxiliary material used, for example starch, gelatin, gum arabic, silica, polyoxyethylene glycol, liquid dosage form solvent used is as water, ethanol, propylene glycol, vegetables oil (as Semen Maydis oil, peanut oil, olive wet goods).In the preparation that contains the compounds of this invention, also have other auxiliary material, for example tensio-active agent, lubricant, disintegrating agent, sanitas, correctives and pigment etc.The dosage that contains formula I compound of the present invention in tablet, capsule, Drug coating, injection and suppository is that the compound amount existing in unit dosage form is calculated.In unit dosage form, the general content of formula I compound of the present invention is 1-5000mg, and preferred unit dosage form contains 10-500mg, and preferred unit dosage form contains 20-300mg.Specifically, the solid dosage for oral administration that the present invention can provide comprises capsule, tablet, pill, powder and granule.In this type of solid dosage, active compound can be accepted vehicle or carrier with the medicine of at least one inertia and mix as Trisodium Citrate or Si Liaodengji dicalcium phosphate feed grade and/or following material: a) weighting agent or extender are as starch, lactose, sucrose, glucose, mannitol and silicic acid; B) tackiness agent is as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Sudan Gum-arabic; C) wetting Agent for Printing Inks is as glycerine; D) disintegrating agent is as agar, calcium carbonate, potato or tapioca (flour), Lalgine, some silicate and sodium carbonate; E) solution retarding agent is as paraffin; F) absorb accelerator as quaternary ammonium compound; G) wetting agent is as hexadecanol and Zerol; H) sorbent material as kaolin and wilkinite and i) lubricant as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate and their mixture.The in the situation that of capsule, tablet and pill, in described formulation, also can comprise buffer reagent.

The solids composition of similar type uses vehicle such as lactose and high molecular weight polyethylene glycol etc., also can be used as the weighting material in soft capsule and hard capsule.

The solid dosage of tablet, dragee (dragees), capsule, pill and granule can be prepared together with dressing and shell material other clothing materials as known in enteric coating material and field of medicine preparations.These solid dosages can optionally contain opalizer, and its composition also can make it just or preferentially at certain position of enteron aisle optionally with delayed mode release of active ingredients.The example of operable embedding composition comprises polymer substance and wax class.If be applicable to, active compound also can be made into micro-capsule form with one or more above-mentioned vehicle.

Liquid dosage form for oral administration comprises the acceptable emulsion of pharmacy, solution, suspensoid, syrup and elixir.Liquid dosage form also can contain the conventional inert diluent in this area except containing active ingredient beyond the region of objective existence, for example water or other solvents, solubilizing agent and emulsifying agent be ethanol, Virahol, ethyl-carbonate, ethyl acetate, benzylalcohol, peruscabin, propylene glycol, 1,3 butylene glycol, dimethyl formamide, oils (particularly Oleum Gossypii semen, peanut oil, Semen Maydis oil, germ oil, sweet oil, Viscotrol C and sesame oil), glycerine, tetrahydrofurfuryl alcohol (tetrahydrofurfuryl alcohol), polyoxyethylene glycol and the fatty acid ester of sorbitan and their mixture for example.Oral compositions also can comprise auxiliary material, for example wetting agent, emulsifying agent and suspension agent, sweeting agent, correctives and flavouring agent except comprising inert diluent.

For the preferably suppository of composition of rectum or vagina administration.Suppository can be by mixing the compounds of this invention to prepare with suitable non-irritating excipient or carrier for example theobroma oil, polyoxyethylene glycol or suppository wax, they are at room temperature solid, but next at body temperature is liquid, therefore can in rectal cavity or vaginal canal, melts and discharge active compound.

Compound of the present invention and composition thereof are also considered for topical.Comprise powder, sprays, ointment and inhalation for the local dosage form that gives the compounds of this invention.Under aseptic condition by active compound and pharmaceutically acceptable carrier and any required sanitas, buffer reagent or propellant mixing.Ophthalmic preparation, eye ointment, powder and solution are also considered within the scope of the present invention.

The compounds of this invention also can liposome form administration.As known in the art, liposome makes with phosphatide or other lipid materials conventionally.Liposome is formed by the single or multiple lift aquation liquid crystal being scattered in water-bearing media.On any nontoxic, physiology that can form liposome, can accept and metabolizable lipid all can use.The present composition of liposome form, except containing the compounds of this invention, also can contain stablizer, sanitas, vehicle etc.Preferred lipid is natural and synthetic phosphatide and phosphatidylcholine (Yelkin TTS), and they can use separately or together.The method that forms liposome is well known in the art.Referring to for example Prescott, Ed., Methods inCell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p.33.

The inventor is surprised to find, and the pyrimidinamine derivatives that indazole shown in partial structural formula I replaces confirms to have the effect of good inhibition vasculogenesis and lower cytotoxicity in the test of rat artery ring and cell toxicity test.From transplanted tumor in nude mice test, also find that these compounds have good activity in vivo, and the restraining effect of part of compounds to tumour and positive control Sunitinib are quite or be better than positive control.In addition, from the mortality ratio of animal, analyze, the active compound preferably of part demonstrates the toxicity less than positive control Sunitinib.Specifically, compound of the present invention can be used for the responsive cancer of the Tyrosylprotein kinase such as prevention or treatment VEGFR or PDGFR, as VEGFR, the tumour that PDGFR high expression level and VEGF drive, comprise that noumenal tumour is as bile duct, bone, bladder, brain/central nervous system, breast, knot rectum, uterine endometrium, stomach, head and neck, liver, lung (especially nonsmall-cell lung cancer), neurone, esophagus, ovary, pancreas, prostate gland, kidney, skin, testis, Tiroidina, the cancer of uterus and vulva etc., with non-noumenal tumour as leukemia, multiple myeloma or lymphoma etc.

Embodiment

Below in conjunction with embodiment, embodiment of the present invention are described in detail, but it will be understood to those of skill in the art that the following example is only for the present invention is described, and should not be considered as limiting scope of the present invention.Unreceipted actual conditions person in embodiment, carries out according to the condition of normal condition or manufacturers's suggestion.The unreceipted person of production firm of agents useful for same or instrument, being can be by the conventional products of commercial acquisition.

Further illustrate the present invention below by concrete Preparation Example and biological test example, still, should be understood to, these embodiment and test example are only used for the use specifically describing more in detail, and should not be construed as for limiting in any form the present invention.

The present invention carries out generality and/or concrete description to the material and the test method that use in test.Although be well known in the art for realizing many materials and the working method that the object of the invention uses, the present invention still does to describe in detail as far as possible at this.It will be apparent to those skilled in the art that hereinafter, if not specified, material therefor of the present invention and working method are well known in the art.

In basis, unless otherwise indicated, wherein: (i) temperature with degree Celsius (℃) represent, operate under room temperature or temperature environment and carry out; (ii) organic solvent anhydrous sodium sulfate drying, the evaporation of solvent Rotary Evaporators reduction vaporization, bathes temperature not higher than 60 ℃; (iii) for reaction process, thin-layer chromatography (TLC) is followed the tracks of; (iv) end product has satisfied proton magnetic resonance (PMR) spectrum (1H-NMR) and mass spectrum (MS) data.

embodiment 1:2-methyl-5-(4-(1-methyl isophthalic acid H-indazole-5-base amino) pyrimidine-2-base ammonia base) benzsulfamide (compound 1) synthetic:

synthesizing of a.N-(2-chloropyrimide-4-yl)-1-methyl isophthalic acid H indazole-5-ammonia:

By raw material 2, 4-dichloro pyrimidine (4.689g, 31.47m mol) and 5-amino-1-methyl isophthalic acid H-indazole (1.54g, 10.49mmol) be dissolved in the mixing solutions of 10ml THF and 40ml ethanol, after stirring, obtain red tan solution, add wherein again sodium bicarbonate (2.644g), 30 ℃ of reaction 14h, it is complete that TLC detects indazole raw material reaction, decompression steams solvent, add 300ml water suspendible, ethyl acetate equivalent extraction 2 times, anhydrous sodium sulfate drying, after concentrating under reduced pressure, rapid column chromatography target product N-(2-chloropyrimide-4-yl)-1-methyl isophthalic acid H indazole-5-ammonia 2.7g (productive rate 98%).

b.2-methyl-5-(4-(1-methyl isophthalic acid H-indazole-5 base amino) pyrimidine-2--amino) benzene sulphur synthesizing of acid amides:

Compound 1

By N-(2-chloropyrimide-4-yl)-1-methyl isophthalic acid H indazole-5-ammonia (0.26g, 1m mol) and 5-amino-2-methyl benzsulfamide (0.19g, 1m mol) join in 8ml Virahol, add wherein again 1 concentrated hydrochloric acid, be warming up to 80 ℃ of reaction 6h, LC-MS detects, raw material transforms completely, after concentrating under reduced pressure, add wherein 300ml methylene dichloride, with saturated sodium bicarbonate solution back extraction several, organic layer anhydrous sodium sulfate drying, concentrating under reduced pressure column chromatography obtains target product compound 1 (0.27g, productive rate 66%).

Compound 1 (0.2g) is dissolved in the Virahol of 80 ℃ of 6ml, adds 2 concentrated hydrochloric acids, backflow 2h, has a large amount of solids to separate out, suction filtration, and dry cake obtains the hydrochloride of compound 1.

¹H-NMR(600MHz，DMSO-d ₆，δ _ppm)：8.04(Broad s，1H)，7.98(s，1H)，7.97(s，1H)，7.79(m，3H)，7.66(d，1H J＝7.8)，7.47(m，3H)，7.37(d，1H J＝7.8)，6.52(Broad s，1H)，4.05(s，3H)，2.60(s，3H).ESI-MS：[M+H] ⁺410.2、[2M+H] ⁺819.6。

embodiment 2:2-methyl-5-(4-((1-methyl isophthalic acid H-indazole-5 base) methylamino) pyrimidine-2- base amino) benzsulfamide (compound 2) synthetic:

Compound 2

N-(2-chloropyrimide-4-yl)-1-methyl isophthalic acid H indazole-5-ammonia (synthetic method is shown in embodiment 1) 1g is dissolved in 50ml THF, be cooled to 10 ℃, add wherein NaH (0.278g, 3 equivalents), then naturally rise to room temperature, continue reaction 1h.Be cooled to-5 ℃, then add wherein the THF solution (5ml) of methyl iodide (1.64g), slowly rise to room temperature, continue reaction 4h, it is complete that TLC detects raw material reaction.Add 0.5ml shrend to go out, concentrating under reduced pressure removes after solvent, adds 150ml water, has a large amount of solids to separate out, suction filtration, and filter cake washing 3 times, obtains the methylated N-of target product (2-chloropyrimide-4-yl)-1-methyl isophthalic acid H indazole-5-ammonia 1.1g after vacuum-drying.By methylated gained N-(2-chloropyrimide-4-yl)-1-methyl isophthalic acid H indazole-5-ammonia (0.27g, 1m mol) and 5-amino-2-methyl benzsulfamide (0.19g, 1m mol) join in 8ml Virahol, add wherein again 1 concentrated hydrochloric acid, be warming up to 80 ℃ of reaction 7h, LC-MS detects, raw material transforms completely, after concentrating under reduced pressure, add wherein 300ml methylene dichloride, with saturated sodium bicarbonate solution back extraction several, organic layer anhydrous sodium sulfate drying, concentrating under reduced pressure column chromatography obtains target product compound 2 (0.35g, productive rate 83%).

Can obtain the hydrochloride of compound 2 with the similar salifying method of compound 1.

¹H-NMR(600MHz，DMSO-d ₆，δ _ppm)：8.43(Broad s，1H)，8.32(s，1H)，8.16(s，1H)，7.86(s，1H)，7.84(d，2H)，7.66(Broad s，1H)，7.42(m，2H)，5.82(Broad s，1H)，4.11(s，3H)，3.58(s，3H)，2.60(s，3H).ESI-MS：[M+H] ⁺424.4、[2M+H] ⁺847.8。

embodiment 3:2-methyl-5-(4-((2-methyl-2H-indazole-5 base) methylamino) pyrimidine-2- base amino) benzsulfamide (compound 3) synthetic:

Compound 3

Repeat and the similar reactions steps of the embodiment of the present invention 2, take 5-amino-2-methyl-2H-indazole as raw material, can obtain compound 3.

ESI-MS：[M+H] ⁺424.4、[2M+H] ⁺847.8。

embodiment 4:5-(4-((1,3-dimethyl-1H-indazole-5-yl) methylamino) pyrimidine-2- base amino)-2-methyl benzenesulfonamide (compound 4) synthetic:

Compound 4

Repeat and the similar reactions steps of the embodiment of the present invention 2, with 5-amino-1,3-dimethyl-1H-indazole is raw material, can obtain compound 4.

Can obtain the hydrochloride of compound 4 with the similar salifying method of compound 1.

¹H-NMR(600MHz，DMSO-d ₆，δ _ppm)：12.4(Broad s，1H)，11.2(Broad s，1H)，8.46(s，1H)，7.85(s，2H)，7.76(d，1H)，7.67(d，1H)，7.45(m，2H)，7.39(d，1H)，5.80(Broad s，1H)，4.02(s，3H)，3.59(s，3H)，2.59(s，3H)，2.48(s，3H)；

ESI-MS：[M+H] ⁺438.2。

embodiment 5:5-(4-((2,3-dimethyl-2H-indazole-5-yl) methylamino) pyrimidine-2- base amino)-2-methyl benzenesulfonamide (compound 5) synthetic:

Compound 5

Repeat and the similar reactions steps of the embodiment of the present invention 2, with 5-amino-2,3-dimethyl-2H-indazole is raw material, can obtain compound 5.

Can obtain the hydrochloride of compound 5 with the similar salifying method of compound 1.

¹H-NMR(600MHz，DMSO-d ₆，δ _ppm)：12.4(Broad s，1H)，10.9(Broad s，1H)，8.43(s，1H)，7.85(Broad s，2H)，7.80(s，1H)，7.67(m，2H)，7.42(s，1H)，7.16(dd，1H)，5.80(Broad s，1H)，4.09(s，3H)，3.56(s，3H)，2.61(s，3H)，2.56(s，3H)；

ESI-MS：[M+H] ⁺438.3。

embodiment 6:N ⁴ -(2,3-dimethyl-2H-indazole-5-yl)-N ² -(3-ethynyl phenyl)-N ⁴ - methylpyrimidine-2,4-diamines (compound 6) synthetic:

Compound 6

Repeat and the similar reactions steps of the embodiment of the present invention 2, with 5-amino-2,3-dimethyl-2H-indazole and an alkynyl aniline are raw material, can obtain compound 6.

Can obtain the hydrochloride of compound 6 with the similar salifying method of compound 1.

¹H-NMR(600MHz，DMSO-d ₆，δ _ppm)：12.4(Broad s，1H)，10.9(Broad s，1H)，7.86(m，2H)，7.68(m，2H)，7.42(s，1H)，7.26(s，1H)，7.16(dd，1H)，5.86(Broad s，1H)，4.09(s，3H)，3.56(s，3H)，2.61(s，3H)；

ESI-MS：[M+H] ⁺369.4。

embodiment 7:N ⁴ -(1,3-dimethyl-1H-indazole-5-yl)-N ² -(3-ethynyl phenyl)-N ⁴ - methylpyrimidine-2,4-diamines (compound 7) synthetic:

Compound 7

Repeat and the similar reactions steps of the embodiment of the present invention 2, with 5-amino-1,3-dimethyl-1H-indazole and an alkynyl aniline are raw material, can obtain compound 7.

Can obtain the hydrochloride of compound 7 with the similar salifying method of compound 1.

¹H-NMR(600MHz，DMSO-d ₆，δ _ppm)：12.4(Broad s，1H)，11.1(s，1H)，7.83(m，2H)，7.75(m，2H)，7.67(s，1H)，7.48(s，1H)，7.39(d，2H)，7.26(Broad s，2H)，5.81(Broad s，1H)，4.02(s，3H)，3.56(s，3H)，2.47(s，3H)；

ESI-MS：[M+H] ⁺369.4。

embodiment 8:N ² -(2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae]-dioxane-6-yl)-N ⁴ -(2,3-bis- methyl-2H-indazole-5-yl)-N ⁴ -methylpyrimidine-2,4-diamines (compound 8) synthetic:

Compound 8

Repeat and the similar reactions steps of the embodiment of the present invention 2, with 5-amino-2,3-dimethyl-2H-indazole and 2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae]-dioxane-6-ammonia are raw material, can obtain compound 8.

Can obtain the hydrochloride of compound 8 with the similar salifying method of compound 1.

¹H-NMR(600MHz，DMSO-d ₆，δ _ppm)：12.15(Broad s，1H)，10.59(s，1H)，7.78(Broad s，1H)，7.67(d，1H)，7.15(dd，2H)，6.96(Broad d，2H)，5.78(s，1H)，4.24(s，4H)，4.09(s，3H)，3.52(s，3H)，2.61(s，3H)；ESI-MS：[M+H] ⁺403.4。

embodiment 9:N ² -(2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae]-dioxane-6-yl)-N ⁴ -(1,3-bis- methyl isophthalic acid H-indazole-5-yl)-N ⁴ -methylpyrimidine-2,4-diamines (compound 9) synthetic:

Compound 9

Repeat and the similar reactions steps of the embodiment of the present invention 2, with 5-amino-1,3-dimethyl-1H-indazole and 2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae]-dioxane-6-ammonia are raw material, can obtain compound 9.

Can obtain the hydrochloride of compound 9 with the similar salifying method of compound 1.

¹H-NMR(600MHz，DMSO-d ₆，δ _ppm)：10.46(Broad s，1H)，10.30(s，1H)，7.82(Broad s，2H)，7.78(d，1H)，7.71(d，1H)，7.34(dd，2H)，7.21(d，1H)，6.96(Broad d，1H)，5.85(s，1H)，4.23(s，4H)，4.01(s，3H)，3.52(s，3H)，2.47(s，3H)；

ESI-MS：[M+H] ⁺403.5。

embodiment 10:N ⁴ -(2,3-dimethyl-2H-indazole-5-yl)-N ² -(3,4-xylyl) -N ⁴ -methylpyrimidine-2,4-diamines (compound 10) synthetic:

Compound 10

Repeat and the similar reactions steps of the embodiment of the present invention 2, with 5-amino-2,3-dimethyl-2H-indazole and 3,4-methyl phenylamino are raw material, can obtain compound 10.

Can obtain the hydrochloride of compound 10 with the similar salifying method of compound 1.

¹H-NMR(600MHz，DMSO-d ₆，δ _ppm)：12.18(Broad s，1H)，10.61(s，1H)，7.79(Broad s，2H)，7.66(d，1H)，7.34(d，2H)，7.16(dd，2H)，4.08(s，3H)，3.54(s，3H)，2.21(Broad s，6H)，2.61(s，3H)；

ESI-MS：[M+H] ⁺373.5。

embodiment 11:N ⁴ -(1,3-dimethyl-1H-indazole-5-yl)-N ² -(3,4-xylyl) -N ⁴ -methylpyrimidine-2,4-diamines (compound 11) synthetic:

Compound 11

Repeat and the similar reactions steps of the embodiment of the present invention 2, with 5-amino-1,3-dimethyl-1H-indazole and 3,4-methyl phenylamino are raw material, can obtain compound 11.

Can obtain the hydrochloride of compound 11 with the similar salifying method of compound 1.

¹H-NMR(600MHz，DMSO-d ₆，δ _ppm)：12.32(Broad s，1H)，10.68(s，1H)，7.82(Broad s，2H)，7.73(d，1H)，7.38(d，3H)，7.19(broad s，2H)，5.73(s，3H)，4.02(s，3H)，3.55(s，3H)，2.21(Broad s，6H)，2.47(s，3H)；

ESI-MS：[M+H] ⁺373.5。

embodiment 12:N ² -(the chloro-3-of 4-(trifluoromethyl) phenyl)-N ⁴ -(2,3-dimethyl-2H- indazole-5-yl)-N ⁴ -methylpyrimidine-2,4-diamines (compound 12) synthetic:

Compound 12

Repeat and the similar reactions steps of the embodiment of the present invention 2, with 5-amino-2,3-dimethyl-2H-indazole and the chloro-3-trifluoromethyl of 4-phenylamino are raw material, can obtain compound 12.

Can obtain the hydrochloride of compound 12 with the similar salifying method of compound 1.

¹H-NMR(600MHz，DMSO-d ₆，δ _ppm)：11.07(Broad s，1H)，8.41(Broad s，2H)，7.89(d，1H)，7.78(d，2H)，7.67(d，2H)，7.16(dd，2H)，5.94(s，1H)，4.09(s，3H)，3.54(s，3H)，2.61(s，3H)；

ESI-MS：[M+H] ⁺447.5。

embodiment 13:N ² -(the chloro-3-of 4-(trifluoromethyl) phenyl)-N ⁴ -(1,3-dimethyl-1H- indazole-5-yl)-N ⁴ -methylpyrimidine-2,4-diamines (compound 13) synthetic:

Compound 13

Repeat and the similar reactions steps of the embodiment of the present invention 2, with 5-amino-1,3-dimethyl-1H-indazole and the chloro-3-trifluoromethyl of 4-phenylamino are raw material, can obtain compound 13.

Can obtain the hydrochloride of compound 13 with the similar salifying method of compound 1.

¹H-NMR(600MHz，DMSO-d ₆，δ _ppm)：10.98(Broad s，1H)，8.42(Broad s，2H)，7.89(d，1H)，7.81(d，2H)，7.74(d，2H)，7.36(dd，2H)，5.90(s，1H)，4.02(s，3H)，3.54(s，3H)，2.47(s，3H)；

ESI-MS：[M+H] ⁺447.5。

embodiment 14:N ² -(the chloro-4-fluorophenyl of 3-)-N ⁴ -(2,3-dimethyl-2H-indazole-5-yl) -N ⁴ -methylpyrimidine-2,4-diamines (compound 14) synthetic:

Compound 14

Repeat and the similar reactions steps of the embodiment of the present invention 2, with 5-amino-2,3-dimethyl-2H-indazole and the fluoro-3-chlorobenzene of 4-ammonia are raw material, can obtain compound 14.

Can obtain the hydrochloride of compound 14 with the similar salifying method of compound 1.

¹H-NMR(600MHz，DMSO-d ₆，δ _ppm)：10.63(Broad s，1H)，8.41(Broad s，2H)，7.87(d，1H)，7.76(d，2H)，7.67(d，2H)，7.52(s，1H)，7.16(dd，2H)，5.90(s，1H)，4.08(s，3H)，3.52(s，3H)，2.61(s，3H)；

ESI-MS：[M+H] ⁺397.5。

embodiment 15:N ² -(the chloro-4-fluorophenyl of 3-)-N ⁴ -(1,3-dimethyl-1H-indazole-5-yl) -N ⁴ -methylpyrimidine-2,4-diamines (compound 15) synthetic:

Compound 15

Repeat and the similar reactions steps of the embodiment of the present invention 2, with 5-amino-1,3-dimethyl-1H-indazole and the fluoro-3-chlorobenzene of 4-ammonia are raw material, can obtain compound 15.

Can obtain the hydrochloride of compound 15 with the similar salifying method of compound 1.

ESI-MS：[M+H] ⁺397.5。

embodiment 16:N ² -(the bromo-2-fluorophenyl of 4-)-N ⁴ -(2,3-dimethyl-2H-indazole-5-yl) -N ⁴ -methylpyrimidine-2,4-diamines (compound 16) synthetic:

Compound 16

Repeat and the similar reactions steps of the embodiment of the present invention 2, with 5-amino-2, the bromo-2-Fluoroaniline of 3-dimethyl-2H-indazole and 4-is raw material, can obtain compound 16.

Can obtain the hydrochloride of compound 16 with the similar salifying method of compound 1.

¹H-NMR(600MHz，DMSO-d ₆，δ _ppm)：12.65(Broad s，1H)，10.37(Broad s，1H)，7.87(Broad s，2H)，7.77(d，1H)，7.72(m，1H)，7.67(d，2H)，7.53(s，1H)，7.14(dd，2H)，5.90(s，1H)，4.09(s，3H)，3.47(s，3H)，2.60(s，3H)；

ESI-MS：[M+H] ⁺441.6。

embodiment 17:N ² -(the bromo-2-fluorophenyl of 4-)-N ⁴ -(1,3-dimethyl-1H-indazole-5-yl) -N ⁴ -methylpyrimidine-2,4-diamines (compound 17) synthetic

Compound 17

Repeat and the similar reactions steps of the embodiment of the present invention 2, with 5-amino-1, the bromo-2-Fluoroaniline of 3-dimethyl-1H-indazole and 4-is raw material, can obtain compound 17.

Can obtain the hydrochloride of compound 17 with the similar salifying method of compound 1.

¹H-NMR(600MHz，DMSO-d ₆，δ _ppm)：10.30(Broad s，1H)，7.82(Broad s，2H)，7.74(d，2H)，7.35(m，2H)，7.70(Broad s，1H)，5.90(s，1H)，4.02(s，3H)，3.48(s，3H)，2.47(s，3H)；

ESI-MS：[M+H] ⁺441.6。

embodiment 18:N ⁴ -(2,3-dimethyl-2H-indazole-5-yl)-N ² -(the fluoro-5-aminomethyl phenyl of 2-) -N ⁴ -methylpyrimidine-2,4-diamines (compound 18) synthetic:

Compound 18

Repeat and the similar reactions steps of the embodiment of the present invention 2, with 5-amino-2,3-dimethyl-2H-indazole and the fluoro-5-methyl of 2-phenylamino are raw material, can obtain compound 18.

Can obtain the hydrochloride of compound 18 with the similar salifying method of compound 1.

¹H-NMR(600MHz，DMSO-d ₆，δ _ppm)：10.10(Broad s，1H)，7.85(Broad s，1H)，7.78(s，1H)，7.66(d，1H)，7.22(s，1H)，7.16(dd，1H)，7.07(s，1H)，6.83(dd，1H)，6.57(dd，1H)，6.31(m，1H)，5.90(s，1H)，4.08(s，3H)，3.47(s，3H)，2.60(s，3H)，2.14(s，3H)；

ESI-MS：[M+H] ⁺377.5。

embodiment 19:N ⁴ -(1,3-dimethyl-1H-indazole-5-yl)-N ² -(the fluoro-5-aminomethyl phenyl of 2-) -N ⁴ -methylpyrimidine-2,4-diamines (compound 19) synthetic:

Compound 19

Repeat and the similar reactions steps of the embodiment of the present invention 2, with 5-amino-1,3-dimethyl-1H-indazole and the fluoro-5-methyl of 2-phenylamino are raw material, can obtain compound 19.

Can obtain the hydrochloride of compound 19 with the similar salifying method of compound 1.

ESI-MS：[M+H] ⁺377.5。

embodiment 20:N ² -(the chloro-3-aminomethyl phenyl of 4-)-N ⁴ -(2,3-dimethyl-2H-indazole-5-yl) -N ⁴ -methylpyrimidine-2,4-diamines (compound 20) synthetic:

Compound 20

Repeat and the similar reactions steps of the embodiment of the present invention 2, with 5-amino-2,3-dimethyl-2H-indazole and the chloro-3-methyl of 4-phenylamino are raw material, can obtain compound 20.

Can obtain the hydrochloride of compound 20 with the similar salifying method of compound 1.

¹H-NMR(600MHz，DMSO-d ₆，δ _ppm)：10.80(Broad s，1H)，7.85(Broad s，1H)，7.78(s，1H)，7.67(d，1H)，7.48(Broad s，1H)，7.16(dd，1H)，5.90(s，1H)，4.09(s，3H)，3.54(s，3H)，2.61(s，3H)，2.14(broad s，3H)；

ESI-MS：[M+H] ⁺393.5。

embodiment 21:N ² -(the bromo-4-aminomethyl phenyl of 3-)-N ⁴ -(2,3-dimethyl-2H-indazole-5-yl) -N ⁴ -methylpyrimidine-2,4-diamines (compound 21) synthetic:

Compound 21

Repeat and the similar reactions steps of the embodiment of the present invention 2, with 5-amino-2,3-dimethyl-2H-indazole and the bromo-4-methyl of 3-phenylamino are raw material, can obtain compound 21.

Can obtain the hydrochloride of compound 21 with the similar salifying method of compound 1.

¹H-NMR(600MHz，DMSO-d ₆，δ _ppm)：12.02(Broad s，1H)，10.54(s，1H)，7.81(s，1H)，7.75(d，1H)，7.68(d，1H)，7.49(d，1H)，7.27(d，1H)，7.17(dd，1H)，5.79(s，1H)，4.06(s，3H)，3.53(s，3H)，2.62(s，3H)，2.33(s，3H)；

ESI-MS：[M+H] ⁺437.6。

embodiment 22:5-(4-((the fluoro-1-methyl isophthalic acid of 4-H-indazole-5-yl) (methylamino) pyrimidine -2-base-amino)-2-methyl benzenesulfonamide (compound 22) synthetic:

Compound 22

synthesizing of a.N-(2-chloropyrimide-4-yl) the fluoro-1-methyl isophthalic acid of-4-H indazole-5-ammonia:

By raw material 2, 4-dichloro pyrimidine (14.8g, 100m mol) and the fluoro-5-amino-1-of 4-methyl isophthalic acid H-indazole (1.65g, 10.0mmol) be suspended in 100ml butanols, add wherein again diisopropyl ethyl amine (DIEPA) 3ml, after stirring, be warming up to 50 ℃, reaction, 20h, it is complete that TLC detects indazole raw material reaction, decompression steams solvent, add 300ml water suspendible, ethyl acetate equivalent extraction 2 times, anhydrous sodium sulfate drying, after concentrating under reduced pressure, rapid column chromatography target product N-(2-chloropyrimide-4-yl) the fluoro-1-methyl isophthalic acid of-4-H indazole-5-ammonia (productive rate 91%).

b.5-(4-((the fluoro-1-methyl isophthalic acid of 4-H-indazole-5-yl) (methylamino) pyrimidine-2-base-amino) synthesizing of-2-methyl benzenesulfonamide:

Compound 22

By N-(2-chloropyrimide-4-yl) the fluoro-1-methyl isophthalic acid of-4-H indazole-5-ammonia (0.55g, 2m mol) be dissolved in 50ml THF, be cooled to 10 ℃, add wherein NaH (0.15g), then naturally rise to room temperature, continue reaction 1h.Be cooled to-5 ℃, then add wherein the THF solution (0.8g is dissolved in 5mlTHF) of methyl iodide, slowly rise to room temperature, continue reaction 4h, it is complete that TLC detects raw material reaction.Add 0.5ml shrend to go out, concentrating under reduced pressure removes after solvent, adds 150ml water, there are a large amount of solids to separate out, suction filtration, filter cake washing 3 times, obtains the methylated N-of target product (2-chloropyrimide-4-yl) the fluoro-1-methyl isophthalic acid of-4-H indazole-5-ammonia (0.56g) after vacuum-drying.

¹H-NMR(600MHz，DMSO-d ₆，δ _ppm)：8.27(1H)，7.98(1H)，7.67(1H)，7.48(1H)，6.12(s，1H)，4.12(s，3H)，3.41(s，3H)；ESI-MS：[M+H] ⁺292.4

By methylated gained N-(2-chloropyrimide-4-yl) the fluoro-1-methyl isophthalic acid of-4-H indazole-5-ammonia (0.29g, 1m mol) and 5-amino-2-methyl benzsulfamide (0.19g, 1m mol) join in 8ml Virahol, add wherein again 1 concentrated hydrochloric acid, be warming up to 80 ℃ of reaction 20h, LC-MS detects, and raw material transforms completely.After concentrating under reduced pressure, add wherein 300ml methylene dichloride, with saturated sodium bicarbonate solution back extraction several, organic layer anhydrous sodium sulfate drying, concentrating under reduced pressure column chromatography obtains target product 0.41g (productive rate 92%).

Can obtain the hydrochloride of compound 22 with the similar salifying method of compound 1

¹H-NMR(600MHz，DMSO-d ₆，δ _ppm)：12.6(Broad s，1H)，11.21(s，1H)，8.49(s，1H)，8.33(s，1H)，7.93(d，1H)，7.72(d，1H)，7.67(d，1H)，7.54(t，1H)，7.43(m，2H)，5.86(s，1H)，4.12(s，3H)，3.56(s，3H)，2.59(s，3H)；ESI-MS：[M+H] ⁺442.3。

embodiment 23:5-(4-((the fluoro-2-methyl-2H-of 4-indazole-5-yl) (methylamino) pyrimidine -2-base-amino)-2-methyl benzenesulfonamide (compound 23) synthetic:

Compound 23

Repeat and the similar reactions steps of the embodiment of the present invention 22, take the fluoro-5-amino-2-methyl-2H-of 4-indazole as raw material, can obtain compound 23.

Can obtain the hydrochloride of compound 23 with the similar salifying method of compound 1.

¹H-NMR(600MHz，DMSO-d ₆，δ _ppm)：12.6(Broad s，1H)，10.99(s，1H)，8.46(s，1H)，8.74(s，1H)，7.90(d，1H)，7.67(d，1H)，7.63(d，1H)，7.43(m，3H)，7.30(t，1H)，5.88(d，1H)，4.24(s，3H)，3.55(s，3H)，2.59(s，3H)；ESI-MS：[M+H] ⁺442.3。

embodiment 24:5-(4-((the fluoro-1-methyl isophthalic acid of 7-H-indazole-6-yl) (methylamino) pyrimidine -2-base-amino)-2-methyl benzenesulfonamide (compound 24) synthetic:

Compound 24

Repeat and the similar reactions steps of the embodiment of the present invention 22, take the fluoro-6-amino-1-of 7-methyl isophthalic acid H-indazole as raw material, can obtain compound 24.

Can obtain the hydrochloride of compound 24 with the similar salifying method of compound 1.

¹H-NMR (600MHz，DMSO-d ₆，δ _ppm)：11.07(Broad s，1H)，8.42(Broad s，1H)，8.24(d，1H)，7.91(Broad s，1H)，7.73(s，1H)，7.63(Broads，1H)，7.44-7.40(m，4H)，7.43(m，2H)，5.86(s，1H)，4.23(s，3H)，3.56(s，3H)，2.56(s，3H)；ESI-MS：[M+H] ⁺442.3。

embodiment 25:5-(4-((the fluoro-2-methyl-2H-of 7-indazole-6-yl) (methylamino) pyrimidine -2-base-amino)-2-methyl benzenesulfonamide (compound 25) synthetic:

Compound 25

Repeat and the similar reactions steps of the embodiment of the present invention 22, take the fluoro-6-amino-2-methyl-2H-of 7-indazole as raw material, can obtain compound 25.

Can obtain the hydrochloride of compound 25 with the similar salifying method of compound 1.

¹H-NMR (600MHz，DMSO-d ₆，δ _ppm)：10.87(Broad s，1H)，8.39(Broad s，1H)，8.61(d，1H)，7.88(Broad s，1H)，7.68(s，1H)，7.63(Broad s，1H)，7.43(s，2H)，7.18(m，1H)，5.86(s，1H)，4.25(s，3H)，3.55(s，3H)，2.56(s，3H)；ESI-MS：[M+H] ⁺442.3。

embodiment 26:5-(4-((the fluoro-2-methyl-2H-of 7-indazole-5-yl) (methylamino) pyrimidine -2-base-amino)-2-methyl benzenesulfonamide (compound 26) synthetic:

Compound 26

Repeat and the similar reactions steps of the embodiment of the present invention 22, take the fluoro-5-amino-2-methyl-2H-of 7-indazole as raw material, can obtain compound 26.

Can obtain the hydrochloride of compound 26 with the similar salifying method of compound 1.

¹H-NMR (600MHz，DMSO-d ₆，δ _ppm)：11.04(Broad s，1H)，8.40(Broad s，1H)，8.13(d，1H)，7.90(Broad s，1H)，7.67(Broads，1H)，7.44(s，1H)，7.38(m，2H)，7.21(m，1H)，5.86(s，1H)，4.23(s，3H)，3.61(s，3H)，2.57(s，3H)；ESI-MS：[M+H] ⁺442.3。

embodiment 27:5-(4-((the fluoro-1-methyl isophthalic acid of 7-H-indazole-5-yl) (methylamino) pyrimidine -2-base-amino)-2-methyl benzenesulfonamide (compound 27) synthetic:

Compound 27

Repeat and the similar reactions steps of the embodiment of the present invention 22, take the fluoro-5-amino-1-of 7-methyl isophthalic acid H-indazole as raw material, can obtain compound 27.

Can obtain the hydrochloride of compound 27 with the similar salifying method of compound 1.

¹H-NMR(600MHz，DMSO-d ₆，δ _ppm)：11.04(Broad s，1H)，8.57(s，1H)，8.44(Broad s，1H)，7.88(Broad s，1H)，7.69(Broad s，1H)，7.44(s，3H)，7.19(m，1H)，7.13(m，1H)，5.86(s，1H)，4.17(s，3H)，3.59(s，3H)，2.57(s，3H)；ESI-MS：[M+H] ⁺442.3。

embodiment 28:5-(4-((4-fluoro-1,3-dimethyl-1H-indazole-6-yl) (methylamino) pyrimidine-2-base-amino)-2-methyl benzenesulfonamide (compound 28) synthetic:

Compound 28

Repeat and the similar reactions steps of the embodiment of the present invention 22, with the fluoro-6-of 4-amino-1,3-dimethyl-1H-indazole is raw material, can obtain compound 28.

Can obtain the hydrochloride of compound 28 with the similar salifying method of compound 1.

¹H-NMR (600MHz，DMSO-d ₆，δ _ppm)：11.21(Broad s，1H)，8.38(Broad s，1H)，7.96(d，1H)，7.65(s，1H)，7.61(Broad s，1H)，7.44(s，2H)，7.32(Broad s，1H)，7.02(d，1H)，6.11(s，1H)，3.97(s，3H)，3.59(s，3H)，2.59(s，3H)，2.57(s，3H)；ESI-MS：[M+H] ⁺456.2。

embodiment 29:5-(4-((4-fluoro-2,3-dimethyl-2H-indazole-6-yl) (methylamino) pyrimidine-2-base-amino)-2-methyl benzenesulfonamide (compound 29) synthetic:

Compound 29

Repeat and the similar reactions steps of the embodiment of the present invention 22, with the fluoro-6-of 4-amino-2,3-dimethyl-2H-indazole is raw material, can obtain compound 29.

¹H-NMR(600MHz，DMSO-d ₆，δ _ppm)：9.42(s，1H)，8.57(s，1H)，7.87(d，1H，J＝6.0)，7.72(d，1H，J＝7.8)，7.32(d，1H，J＝1.2)，7.24(s，2H)，7.14(d，1H，J＝7.8)，6.72(d，1H，J＝12.0)，5.83(d，1H，J＝6.0)，4.06(s，3H)，3.48(s，3H)，2.71(s，3H)，2.57(s，3H)；ESI-MS：[M+H] ⁺456.1。

embodiment 30:6-(4-((the fluoro-2-methyl-2H-of 7-indazole-6-yl) (methylamino) pyrimidine -2-base-amino)-3,3-dimethyl 1-isoindolinone (compound 30) synthetic:

Compound 30

Repeat and the similar reactions steps of the embodiment of the present invention 22, with the fluoro-6-amino-2-methyl-2H-indazole of 7-and 6-amino-3,3-dimethyl 1-isoindolinone is raw material, can obtain compound 30.

Can obtain the hydrochloride of compound 30 with the similar salifying method of compound 1.

¹H-NMR(600MHz，DMSO-d ₆，δ _ppm)：9.38(s，1H)，8.52(d，2H)，8.12(s，1H)，7.87(m，2H)，7.55(s，1H)，7.34(d，1H)，7.08(d，1H)，5.80(d，1H)，4.23(s，3H)，3.47(s，3H)，1.41(s，6H)；ESI-MS：[M+H] ⁺432.3。

embodiment 31:6-(4-((the fluoro-1-methyl isophthalic acid of 7-H-indazole-5-yl) (methylamino) pyrimidine -2-base-amino)-3,3-dimethyl 1-isoindolinone (compound 31) synthetic:

Compound 31

Repeat and the similar reactions steps of the embodiment of the present invention 22, with the fluoro-5-amino-1-of 7-methyl isophthalic acid H-indazole and 6-amino-3,3-dimethyl 1-isoindolinone is raw material, can obtain compound 31.

Can obtain the hydrochloride of compound 31 with the similar salifying method of compound 1.

¹H-NMR(600MHz，DMSO-d ₆，δ _ppm)：9.42(s，1H)，8.54、8.43(d，2H)，8.14(s，1H)，7.85(s，2H)，7.41(s，1H)，7.12(s，1H)，7.01(s，1H)，5.65(s，1H)，4.16(s，3H)，3.51(s，3H)，1.42(s，6H)；ESI-MS：[M+H] ⁺432.3。

embodiment 32:6-(4-((the fluoro-1-methyl isophthalic acid of 7-H-indazole-6-yl) (methylamino) pyrimidine -2-base-amino)-3,3-dimethyl-2-hydrogen-benzo [d] isothiazole-1, the closing of 1-dioxy (compound 32) become:

Compound 32

Repeat and the similar reactions steps of the embodiment of the present invention 22, with the fluoro-6-amino-1-of 7-methyl isophthalic acid H-indazole and 3,3-dimethyl-6-amino-2-hydrogen-benzo [d] isothiazole-c1,1-dioxy is raw material, can obtain compound 32.

Can obtain the hydrochloride of compound 32 with the similar salifying method of compound 1.

¹H-NMR(600MHz，DMSO-d ₆，δ _ppm)：11.01(Broad s，1H)，8.21(s，1H)，8.24(d，1H)，7.95(Broad s，2H)，7.69(m，2H)，7.60(Broad s，1H)，7.39(d，1H)，6.10(s，1H)，4.21(s，3H)，3.52(s，3H)，1.50(s，6H)；ESI-MS：[M+H] ⁺468.2。

embodiment 33:6-(4-((the fluoro-2-methyl-2H-of 7-indazole-6-yl) (methylamino) pyrimidine -2-base-amino)-3,3-dimethyl-2-hydrogen-benzo [d] isothiazole-1, the closing of 1-dioxy (compound 33) become:

Compound 33

Repeat and the similar reactions steps of the embodiment of the present invention 22, with the fluoro-6-amino-2-methyl-2H-indazole of 7-and 3,3-dimethyl-6-amino-2-hydrogen-benzo [d] isothiazole-1,1-dioxy is raw material, can obtain compound 33.

Can obtain the hydrochloride of compound 33 with the similar salifying method of compound 1.

¹H-NMR(600MHz，DMSO-d ₆，δ _ppm)：11.09(Broad s，1H)，8.61(d，1H)，8.13(Broad s，1H)，8.00(s，1H)，7.91(d，1H)，7.78(d，1H)，7.68(m，2H)，7.17(d，1H)，6.04(d，1H)，4.24(s，3H)，3.53(s，3H)，1.52(s，6H)；ESI-MS：[M+H] ⁺468.2。

embodiment 34:6-(4-((the fluoro-1-methyl isophthalic acid of 7-H-indazole-5-yl) (methylamino) pyrimidine -2-base-amino)-3,3-dimethyl-2-hydrogen-benzo [d] isothiazole-1, the closing of 1-dioxy (compound 34) become:

Compound 34

Repeat and the similar reactions steps of the embodiment of the present invention 22, with the fluoro-5-amino-1-of 7-methyl isophthalic acid H-indazole and 3,3-dimethyl-6-amino-2-hydrogen-benzo [d] isothiazole-1,1-dioxy is raw material, can obtain compound 34.

Can obtain the hydrochloride of compound 34 with the similar salifying method of compound 1.

¹H-NMR(600MHz，DMSO-d ⁶，δ _ppm)：10.94(Broad s，1H)，8.55(s，1H)，8.20(Broad s，1H)，7.98-7.66(m，4H)，7.18(m，1H)，7.12(m，1H)，5.85(s，1H)，4.17(s，3H)，3.56(s，3H)，1.53(s，6H)；ESI-MS：[M+H] ⁺468.3。

embodiment 35:6-(4-((the fluoro-2-methyl-2H-of 7-indazole-5-yl) (methylamino) pyrimidine -2-base-amino)-3,3-dimethyl-2-hydrogen-benzo [d] isothiazole-1, the closing of 1-dioxy (compound 35) become:

Compound 35

Repeat and the similar reactions steps of the embodiment of the present invention 22, with the fluoro-5-amino-2-methyl-2H-indazole of 7-and 3,3-dimethyl-6-amino-2-hydrogen-benzo [d] isothiazole-1,1-dioxy is raw material, can obtain compound 35.

Can obtain the hydrochloride of compound 35 with the similar salifying method of compound 1.

¹H-NMR(600MHz，DMSO-d ₆，δ _ppm)：11.17(Broad s，1H)，8.13(s，1H)，7.96(Broad s，1H)，7.70(m，3H)，7.34(m，1H)，7.19(m，1H)，5.85(s，1H)，4.22(s，3H)，3.58(s，3H)，1.52(s，6H)；ESI-MS：[M+H] ⁺468.2。

(((4-fluoro-2,3-methyl-2H-indazole-6-yl) (methylamino) is phonetic for 4-for embodiment 36:6- pyridine-2-base-amino)-2,3-dihydro-benzo [d] isothiazole-1,1-dioxy (compound 36) synthetic:

Compound 36

Repeat and the similar reactions steps of the embodiment of the present invention 22, with the fluoro-6-of 4-amino-2,3-dimethyl-2H-indazole and 6-amino-2,3-dihydro-benzo [d] isothiazole-1,1-dioxy is raw material, can obtain compound 36.

¹H-NMR(600MHz，DMSO-d ₆，δ _ppm)：9.65(s，1H)，8.40(s，1H)，7.94(d，1H)，7.86(dd，1H)，7.72(d，1H)，7.34(m，2H)，6.74(d，1H)，5.90(d，1H)，4.30(d，2H)，4.06(s，3H)，3.47(s，3H)，2.71(s，3H)；ESI-MS：[M+H] ⁺454.2。

embodiment 37:6-(4-((2,3-methyl-2H-indazole-6-yl) (methylamino) pyrimidine-2- base-amino)-2,3-dihydro-benzo [d] isothiazole-1,1-dioxy (compound 37) synthetic:

Compound 37

Repeat and the similar reactions steps of the embodiment of the present invention 1, with 6-amino-2,3-dimethyl-2H-indazole and 6-amino-2,3-dihydro-benzo [d] isothiazole-1,1-dioxy is raw material, can obtain compound 37.

¹H-NMR(600MHz，DMSO-d ₆，δ _ppm)：9.65(s，1H)，8.43(s，1H)，7.89(d，J＝6，1H)，7.87(dd，1H)，7.77(d，J＝8.4，1H)，7.73(t，1H)，7.47(s，1H)，7.37(d，J＝8.0，1H)，6.90(dd，1H)，5.82(s，1H)，4.30(d，J＝4.8，2H)，4.06(s，3H)，3.49(s，3H)，2.63(s，3H)。

ESI-MS：[M+H] ⁺436.4。

embodiment 38:6-(4-((the fluoro-2-methyl-2H-of 4-indazole-5-yl) (methylamino) pyrimidine -2-base-amino)-2,3-dihydro-benzo [d] isothiazole-1,1-dioxy (compound 38) synthetic:

Compound 38

Repeat and the similar reactions steps of the embodiment of the present invention 1, with the fluoro-2-methyl-2H-indazole of 5-amino-4-and 6-amino-2,3-dihydro-benzo [d] isothiazole-1,1-dioxy is raw material, can obtain compound 38.

¹H-NMR(600MHz，DMSO-d ₆，δ _ppm)：10.99(s，1H)，8.73(s，1H)，7.92(d，1H)，8.27(s，1H)，7.83(s，1H)，7.62(m，2H)，7.29(m，1H)，5.90(s，1H)，4.40(d，2H)，4.23(s，3H)，3.50(s，3H)；ESI-MS：[M+H] ⁺440.4。

biological experiment

Can measure the restraining effect that compound of the present invention generates new vessel in vitro with following experiment, to the restraining effect of transplanted tumor in nude mice in body.

a) restraining effect to rat artery ring angiogenesis

This test is carried out (Nicosia, R.F., et al.Am J Pathol., 1997,151,1379-1386) with reference to the method for the descriptions such as R.F.Nicosia.

The de-cervical vertebra of rat (purchased from Beijing Vital River Experimental Animals Technology Co., Ltd.) is put to death, careful separation thoracic aorta, put into the vessel that fill physiological saline, carefully cut unnecessary tissue, blood vessel is cut into the vascular circle thin slice that 1mm is thick with eye scissors, in 96 porocyte culture plates of precooling, every hole central authorities add the vascular circle of 1 separator well, carefully add Matrigel glue (purchased from BD company) the 70 μ l that melt in advance that vascular circle is covered, hatch 1h for 37 ℃, it is solidified.Trial-product (is comprised to compound 1-38 prepared by embodiment, positive control drug Pazopanib (can be synthetic with reference to the method for embodiment in WO020591101 69) dilutes 2 times for final concentration with the RPMI1640 substratum (purchased from GIBCO) containing 10% (v/v) foetal calf serum (FBS), every hole adds 70 μ l, put into incubator cellar culture, at least two multiple holes of each compound, each test repeats twice.The final concentration gradient of positive control drug and test-compound (compound 1-38 prepared by embodiment) is set as 10,1,0.1 μ g/ml, and establish the negative control hole that does not add the compounds of this invention, negative control hole is changed fresh medium on the 3rd day, and medicine is changed in positive control hole and test-compound hole on the 3rd day.At 37 ℃, 5% (v/v) CO ₂under environment, cultivate after 7 days, the survival condition of micro-Microscopic observation vascular circle, take pictures simultaneously, the area that uses Image Pro Plus computed in software capillary blood vessel to cover, pass through formula: inhibiting rate (%)=(area (negative control hole)-area (dosing holes))/area (negative control hole) × 100%, calculate average inhibiting rate, the results are shown in Table 1.

Table 1: the restraining effect of the compounds of this invention to rat artery ring angiogenesis

b) transplanted tumor in nude mice test

Transplanted tumor in nude mice experimental animal is selected female Balb/cA nude mouse (purchased from Fukang biotech inc of China, Beijing), and knurl strain adopts human colon carcinoma HT 29 knurl strains (purchased from hospital of tumour tumor center of Shandong hospital).

Under aseptic condition, the tumor tissue of getting growth animated period cuts into 1.5mm ³left and right fritter, is inoculated under the armpit of nude mouse right side.With vernier caliper measurement transplanted tumor diameter, treat that tumor growth is to about 120mm ³after by animal random packet, positive controls (Pazopanib group) and test-compound (compound prepared by embodiment 2,4,5,22-23,29,36-38) animal groups gastric infusion every day 80mg/kg, treatment 20 days continuously, negative control group gives the water for injection of equivalent containing 0.1% (v/v) Tween 80 (purchased from Shanghai Shen Yu medication chemistry company limited).Measure diameter of tumor 2-3 time weekly, weigh Mouse Weight simultaneously.In test, observation index has the xicity related indexs such as relative tumor proliferation rate, body weight and general state.The calculation formula of gross tumor volume (tumor volume, TV) is: TV=1/2 × a × b ², wherein a, b represent respectively tumour major diameter and minor axis.Calculate relative tumour volume (relative tumor volume, RTV) according to the result of measuring, calculation formula is: RTV=V _t/ V ₀.Wherein V ₀for the gross tumor volume of administration pre-test, V _tfor the gross tumor volume of measuring after each administration.

The evaluation index of anti-tumor activity is relative tumor proliferation rate T/C (%), and calculation formula is as follows: T/C (%)=(T _rTV/ C _rTV) × 100%, wherein T _rTVfor treatment group RTV; C _rTVnegative control group RTV.

Inhibition rate of tumor growth=(1-T/C) × 100% relatively

Judgement criteria is: T/C (%) > 40% is for invalid; T/C (%)≤40%, and processing P < 0.05 is effective by statistics.Test-results is in table 2.(Wave is Mouse Weight, compared with negative control, and d ₂₁the absolute value of Wave more the bright compound of novel is larger on the animation impact of animal, can indirectly reflect the toxicity of compound.In " antitumor drug pharmacodynamics governing principle " judgement criteria about Nude Mouse Model, stipulate T/C (%))≤40% explanation compound effective, therefore (1-T/C) × 100% >=60% is effective.)

The therapeutic action analysis of table 2. the compounds of this invention (using the administration in continuous 21 days of 200mg/kg oral dose) to human colon carcinoma HT 29 Nude Mice

Note: (1) RTV: relative tumour volume; V _ave: mean tumour volume; W _ave: nude mice mean body weight;

(2) #: compared with positive controls, P < 0.05

From transplanted tumor in nude mice test, can find, the compounds of this invention has transplanted tumor activity in good inhibition HT-29 body, and wherein restraining effect and the positive control of compound 2 to tumour is suitable; Compound 29 and compound 37 are better than positive control medicine to the restraining effect of tumour.And after positive controls medication, wherein have 1 mice with tumor body weight to have obvious decline, and mouse state is poor, and occurs yellowing of the skin, and the just middle phenomenons such as blood of being with, in administration death in 20 days.In experiment, nude mice body weight slightly declines after the compounds of this invention 38 medications, after other the compounds of this invention 2,4,5,22-23,29,36-37 medication, there is no weight loss, state is better, have no obvious toxicity, show that the compounds of this invention toxicity is low compared with positive control compound.

In sum, the compounds of this invention all shows good biological activity in vitro with in body, anti-tumor in vivo test show compound curative effect and positive control medicine more excellent, and show the toxicity low compared with positive control medicine.Results suggest, compound of the present invention can be developed the antitumor drug that becomes more promising efficient, low toxicity.

Although the specific embodiment of the present invention has obtained detailed description, it will be understood to those of skill in the art that.According to disclosed all instructions, can carry out various modifications and replacement to those details, these change all within protection scope of the present invention.Four corner of the present invention is provided by claims and any equivalent thereof.

Claims

1. the indazole shown in formula I replaces pyrimidinamine derivatives, its pharmacy acceptable salt, the solvate of described derivative or the solvate of described salt,

Formula I

Wherein,

R ₀be selected from hydrogen atom, C _1-4alkyl, cycloalkyl;

R is selected from

R ₁～R ₆respectively independently selected from hydrogen atom, halogen, C _1-4the C that alkyl, one or more halogen replace _1-4alkyl, C _1-4the C that alkoxyl group, one or more halogen replace _1-4alkoxyl group, cycloalkyl, thiazolinyl, alkynyl, hydroxyl ,-NR ₁₀r ₁₁,-SOR ₁₀,-SO ₂r ₁₀,-NR ₁₀sO ₂r ₁₁,-SO ₂nR ₁₁r ₁₀,-COR ₁₀,-CONR ₁₁r ₁₀,-NR ₁₁cOR ₁₀,-OCOR ₁₀,-CN ,-NO ₂; Or the R of above-mentioned arbitrary neighborhood ₁～R ₅can with together with carbon atom on phenyl ring, form 4-8 unit heterocycle, described heteroatoms is at random selected from S or N or O;

Work as R ₁～R ₅while independently not forming assorted ring structure respectively, R ₉be selected from halogen, C _1-4the C that alkyl, one or more halogen replace _1-4alkyl, C _1-4alkoxyl group, cycloalkyl, amino ,-CN ,-NO that alkoxyl group, one or more halogen replace ₂; Work as R ₁～R ₅in carbon atom on any two adjacent substituting group and phenyl ring while forming 4-8 unit heterocycle, R ₉be selected from hydrogen, halogen, C _1-4the C that alkyl, one or more halogen replace _1-4alkyl, C _1-4alkoxyl group, cycloalkyl, amino ,-CN ,-NO that alkoxyl group, one or more halogen replace ₂;

N is selected from 0～3 integer.

2. pyrimidinamine derivatives claimed in claim 1, its pharmacy acceptable salt, the solvate of described derivative or the solvate of described salt,

Wherein,

R ₀be selected from hydrogen atom, C _1-4alkyl, C _3～8cycloalkyl;

R is selected from

R ₁～R ₅respectively independently selected from hydrogen atom, halogen, C _1-4the C that alkyl, one or more halogen replace _1-4alkyl, C _1-4the C that alkoxyl group, one or more halogen replace _1-4alkoxyl group, alkynyl, hydroxyl ,-SO ₂nR ₁₁r ₁₀,-CONR ₁₁r ₁₀,-CN ,-NO ₂; Or the R of above-mentioned arbitrary neighborhood ₁～R ₅can with together with carbon atom on phenyl ring, form 4-8 unit heterocycle and (for example ought be selected from R ₁～R ₅arbitrary substituting group be C _1-4alkoxyl group ,-SO ₂nR ₁₁r ₁₀or-CONR ₁₁r ₁₀time, this substituting group can form with adjacent substituting group 4-8 unit heterocycle together with carbon atom on phenyl ring, and wherein said 4-8 unit heterocycle contains 1～2 heteroatoms, described heteroatoms is at random selected from S or N or O);

N is selected from 0～3 integer;

Preferably, R ₀be selected from hydrogen atom, C _1-4alkyl, more preferably R ₀for hydrogen atom, methyl;

Preferably, R ₁～R ₅respectively independently selected from hydrogen atom, halogen, C _1-4the C that alkyl, one or more halogen replace _1-4alkyl, C _1-4alkoxyl group, alkynyl ,-SO ₂nR ₁₁r ₁₀,-CONR ₁₁r ₁₀, or the R of above-mentioned arbitrary neighborhood ₁～R ₅can with together with carbon atom on phenyl ring, form 4-8 unit heterocycle, described heteroatoms is at random selected from S or N or O; Further preferably, R ₁～R ₅respectively independently selected from hydrogen atom, halogen, ethynyl, methyl, ethyl, propyl group, sec.-propyl, methoxyl group, oxyethyl group, propoxy-,-SO ₂nR ₁₁r ₁₀,-CONR ₁₁r ₁₀, or the R of above-mentioned arbitrary neighborhood ₁～R ₅can jointly be constructed as follows structure with phenyl ring:

or 2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae]-dioxane;

Preferably, R ₆, R ₇, R ₈, R ₉respectively independently selected from hydrogen atom, halogen, C _1-4the C that alkyl, one or more halogen replace _1-4alkyl; Further preferably, R ₆, R ₇, R ₈, R ₉respectively independently selected from hydrogen atom, Cl, F, Br, methyl; Again further preferably, R ₆, R ₇, R ₈, R ₉respectively independently selected from hydrogen atom, F, methyl; More preferably, R ₆for F, R ₇for methyl, R ₈for hydrogen atom or methyl, R ₉for hydrogen atom or F;

Preferably, R ₁₀and R ₁₁respectively independently selected from hydrogen atom, C _1-4the C that alkyl, one or more halogen replace _1-4alkyl; More preferably, R ₁₀and R ₁₁respectively independently selected from hydrogen atom, methyl;

Preferably, n is 0 or 1.

3. pyrimidinamine derivatives claimed in claim 1, its pharmacy acceptable salt, the solvate of described derivative or the solvate of described salt, wherein:

R ₀be selected from hydrogen atom, C _1-4alkyl, C _3～6cycloalkyl;

R is selected from

R ₂for hydrogen atom ,-SO ₂nR ₁₁r ₁₀or CONH ₂;

N is 0 or 1;

Preferably, described pyrimidinamine derivatives, its pharmacy acceptable salt, the solvate of described derivative or the solvate of described salt, wherein,

R ₀be selected from hydrogen atom, methyl;

R is selected from

R ₁for hydrogen atom or F;

R ₂for hydrogen atom ,-SO ₂nH ₂or CONH ₂;

R ₅for hydrogen atom;

N is 0 or 1;

Further preferably, described pyrimidinamine derivatives, its pharmacy acceptable salt, the solvate of described derivative or the solvate of described salt, wherein,

R ₀be selected from methyl;

R is selected from

R ₁for hydrogen atom;

R ₄for hydrogen atom, ethynyl or-SO ₂nH ₂;

R ₅for hydrogen atom;

N is 0 or 1;

Still more preferably, described pyrimidinamine derivatives, its pharmacy acceptable salt, the solvate of described derivative or the solvate of described salt, wherein,

R ₀be selected from methyl;

R is selected from

R ₁for hydrogen atom;

R ₄for hydrogen atom or-SO ₂nH ₂;

R ₅for hydrogen atom;

N is 0 or 1;

Particularly preferably, described pyrimidinamine derivatives, its pharmacy acceptable salt, the solvate of described derivative or the solvate of described salt, wherein,

R ₀be selected from methyl;

R is selected from

R ₁for hydrogen atom;

4. pyrimidinamine derivatives claimed in claim 1, its pharmacy acceptable salt, the solvate of described derivative or the solvate of described salt, wherein, is selected from following compound:

N ⁴-(1,3 dimethyl-1H-indazole-5-yl)-N ²-(3,4-xylyl)-N ⁴-methylpyrimidine-2,4-diamines (compound 11);

5. a pharmaceutical composition, it comprises pyrimidinamine derivatives, its pharmacy acceptable salt, the solvate of described derivative or the solvate of described salt that in claim 1 to 4, the indazole described in any one replaces, and pharmaceutically acceptable carrier and/or auxiliary material.

6. the preparation method of pyrimidinamine derivatives claimed in claim 1, comprises the steps:

Comprise the steps:

1) by 2 shown in formula i, 4-dichloro pyrimidine and the corresponding pyrimidine derivatives containing amino indazole compound R-NH2 (shown in formula ii) 4-position replacement shown in synthesis type iii-1 under suitable alkali exists:

Suitable alkali comprises organic bases, mineral alkali; Preferred organic bases is tertiary amine (as triethylamine, diisopropyl ethyl amine etc.), and preferred mineral alkali is sodium carbonate, salt of wormwood, cesium carbonate etc.; Preferred organic bases is diisopropyl ethyl amine, and preferred mineral alkali is sodium carbonate;

2) in the time of R0 hydrogen atom, by step 1) the 4-position shown in the formula iii-1 that the obtains pyrimidine derivatives and the target compound shown in corresponding ammonia (shown in formula iv) synthesis type I that replace:

Wherein, R, R ₀-R ₅definition described in above-mentioned formula I.

7. in claim 1 to 4, the indazole described in any one replaces pyrimidinamine derivatives, its pharmacy acceptable salt, the solvate of described derivative or the solvate of described salt, or pharmaceutical composition claimed in claim 5 is in the purposes of preparing in tyrosine kinase inhibitor.

8. in claim 1 to 4, the indazole described in any one replaces pyrimidinamine derivatives, its pharmacy acceptable salt, the solvate of described derivative or the solvate of described salt, or pharmaceutical composition claimed in claim 5 in for the preparation for the treatment of or assisting therapy and/or prevention Mammals with the medicine of receptor tyrosine kinase relative disease in purposes;

Preferably, described Mammals is the mankind;

Preferably, describedly comprise with receptor tyrosine kinase relative disease: the tumour being mediated by receptor tyrosine kinase or cancer or the tumor cell proliferation being driven by receptor tyrosine kinase and migration.

9. purposes claimed in claim 8, wherein said tumour or cancer comprise VEGFR or the responsive cancer of PDGFR Tyrosylprotein kinase, as VEGFR, the tumour that PDGFR high expression level and VEGF drive (comprises that noumenal tumour is as bile duct, bone, bladder, brain/central nervous system, breast, knot rectum, uterine endometrium, stomach, head and neck, liver, lung (especially nonsmall-cell lung cancer), neurone, esophagus, ovary, pancreas, prostate gland, kidney, skin, testis, Tiroidina, the cancer of uterus and vulva etc., with non-noumenal tumour as leukemia, multiple myeloma or lymphoma etc.).

10. in claim 1 to 4, the indazole described in any one replaces pyrimidinamine derivatives, its pharmacy acceptable salt, the solvate of described derivative or the solvate of described salt, or pharmaceutical composition claimed in claim 5 is for the preparation of preventing and/or treating purposes in the medicine of protein kinase dependency cell dysfunction disease or in the purposes for the preparation of preventing and/or treating in the medicine of the dysfunction disease that relates to paraprotein kinase activity.