CN103539780A

CN103539780A - Substituted pyrazolone compounds as well as use method and application of substituted pyrazolone compounds

Info

Publication number: CN103539780A
Application number: CN201310298827.0A
Authority: CN
Inventors: 习宁; 吴彦君; 廖敏; 冯彦铭
Original assignee: Add And Open Up Scientific Co; Guangdong HEC Pharmaceutical
Current assignee: Add And Open Up Scientific Co; Guangdong HEC Pharmaceutical
Priority date: 2012-07-16
Filing date: 2013-07-16
Publication date: 2014-01-29
Also published as: CN103565653B; CN103565653A

Abstract

The invention provides novel substituted pyrazolone compounds, pharmaceutically accepted slats of the substituted pyrazolone compounds and pharmaceutical preparations of the substituted pyrazolone compounds, wherein the substituted pyrazolone compounds are used for regulating the activity of protein kinase and intercellular or intracellular signal response. The invention also relates to a pharmaceutical composition containing the compounds and a method for treating high-proliferative diseases of mammals and particularly human beings by using the pharmaceutical composition.

Description

The pyrazolone compounds and using method and the purposes that replace

The application requires to submit on 07 16th, 2012 Patent Office of the People's Republic of China, application number is 201210244755.7, denomination of invention is the Chinese patent application of " pyrazolone compounds of replacement and using method thereof and purposes ", in on 04 03rd, 2013, submit Patent Office of the People's Republic of China to, application number is 201310116831.0, denomination of invention is the Chinese patent application of " pyrazolone compounds of replacement and using method thereof and purposes ", in on 07 27th, 2012, submit Patent Office of the People's Republic of China to, application number is 201210261615.0, denomination of invention is the Chinese patent application of " pyrazolone compounds of replacement and using method thereof and purposes " and on 04 03rd, 2013, submits Patent Office of the People's Republic of China to, application number is 201310116710.6, denomination of invention is the right of priority of the Chinese patent application of " pyrazolone compounds of replacement and using method thereof and purposes ", its full content is by reference in conjunction with in this application.

Invention field

The invention relates to pyrazolone compounds and the salt thereof of new replacement, be used for the treatment of the disease of higher proliferation, for example the cancer relevant with Mammals.The present invention is especially about the compound of arrestin tyrosine kinase activity, the activity of the application of the invention compound arrestin Tyrosylprotein kinase, thus suppress iuntercellular or intracellular signal response.The present invention is about treating Mammals with compound of the present invention or the composition that pharmaceutically comprises the compounds of this invention equally, especially the method for mankind's hyperproliferative disease.

Background of invention

Protein kinase has represented the protein that a large class plays an important role in cellular function retentive control and various cytopathic regulation and control.By conditioning signal, respond approach, protein kinase is being controlled the metabolism of cell, the carrying out of cell division cycle, cell proliferation and apoptosis, differentiation and survival.Current existing 500 kinds of human kinase groups, wherein reach 150 kinds more than relevant to mankind's various diseases, as inflammatory diseases, cardiovascular disorder, metabolism class disease, nerve degenerative diseases and cancer.

The list of wherein said kinases part comprises abl, AATK, ALK, Akt, axl, bmx, bcr-abl, Blk, Brk, Btk, csk, c-kit, c-Met, c-src, c-fins, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRaf1, CSF1R, CSK, DDR1, DDR2, EPHA, EPHB, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FER, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, GSG2, GSK, Hck, ILK, INSRR, IRAK4, ITK, IGF-1R, INS-R, Jak, KSR1, KDR, LMTK2, LMTK3, LTK, Lck, Lyn, MATK, MERTK, MLTK, MST1R, MUSK, NPR1, NTRK, MEK, PLK4, PTK, p38, PDGFR, PIK, PKC, PYK2, RET, ROR1, ROR2, RYK, ros, Ron, SGK493, SRC, SRMS, STYK1, SYK, TEC, TEK, TEX14, TNK1, TNK2, TNNI3K, TXK, TYK2, TYRO3, tie, tie2, TRK, Yes and Zap70.

Protein tyrosine kinase is the subfamily of protein kinase, can also range growth factor receptors (as: Axl, VEGFR, c-Met (HGFR), Ron, EGFR, PDGFR and FGFR) or non-acceptor (as: c-src and bcr-abl) kinases.Receptor tyrosine kinase is transmembrane protein, can make somatomedin cross over cytolemma and keep extracellular calmodulin binding domain CaM, and cross-film district and intracellular portion be as having kinase whose function, and phosphorylation is in a concrete protein-tyrosine residue, thereby affects cell proliferation.Abnormal expression or protein kinase activity can directly involve the pathogeny of numerous human cancers.

Vasculogenesis is from the blood vessels that prestore, to form the process of new capillary vessel, and this allelotaxis for embryo in women/jenny reproduction recycle system plays critical effect, also the healing of inflammatory diseases and wound is also played a part very important simultaneously.As everyone knows, some disease and associated angiogenesis out of control, for example eye neovascularization, retinopathy (comprising diabetic retinopathy), the macular degeneration relevant with the age, psoriasis, hemangioblastoma, vascular tumor, arteriosclerosis, inflammatory diseases, for example rheumatoid or rheumatic inflammatory disease, sacroiliitis (rheumatoid arthritis) particularly, or other chronic inflammatory diseases, chronic asthma for example, artery or transplanting artery are atherosis, endometriosis and proliferative disease, common described noumenal tumour and liquid tumors (for example leukemia) for example.Noumenal tumour, depends on especially vasculogenesis and supplies with nutrition, nutrient and refuse processing to it.In addition, vasculogenesis can promote the growth of cell or other position transfer tumours equally.

New vasculogenesis is the process of a high complexity and hight coordinate, and its requirement has a large amount of factors stimulated growth, but vascular endothelial growth factor (VEGFR) signal response represents critical rate-limiting step conventionally in physiology and pathology vasculogenesis.VEGF combination activated receptor type tyrosine kinase.The VEGFR hypotype of having been confirmed by the mankind has three kinds: VEGFR-1(Flt-1), VEGFR-2(KDR/Flk-1) and VEGFR-3(Flt-4).The main cell of VEGFR-2 mediation VEGF is replied, especially mitotic division and vasculogenesis.VEGFR-1 regulates the conduction of VEGFR-2 signal or isolates VEGF and VEGFR-2 as virtual/decoy receptor.The expression of VEGFR-1 is regulated by anoxic forward, and it is similar that its mechanism and VEGF are regulated by HIF-1; The type of its function based on cell and developmental stage and change.（Stuttfeld?E,Ballmer-Hofer?K(September2009),"Structure?and?function?of?VEGF?receptors".IUBMB?Life61(9):915-22.）

VEGFR-2 is mitotic division and the survival that mainly mediates vascular endothelial cell (EC), keeps vasculogenesis and microvascular perviousness simultaneously.Therefore, the activity that directly suppresses kinases VEGFR-2 will reduce the growth of vasculogenesis and tumour, and suppress VEGFR-2 targeting more stable epithelial activity of host on genetics, but not suppress variable tumor tissues, will reduce the probability of resistance development.

Some drug targetings act on VEGFR signal response; no matter be individually dosed; or with other chemotherapeutic agent coupling; all to patients with advanced malignant tumor effectively (" VEGF-targeted therapy:mechanisms of anti-tumor activity; " Nature Reviews Cancer; 2008,8,579; " Molecular basis for sunitinib efficacy and future clinical development, " Nature Reviews Drug Discovery, 2007,6,734; And " Angiogenesis:an organizing principle for drug discovery " Nature Reviews Drug Discovery, 2007,6,273).

C-Met, i.e. hepatocyte growth factor receptor (HGFR), its main point of application is at endotheliocyte, and has confirmed that it is at endotheliocyte, myogenous cells, all has expression in hematopoietic cell and motor neuron.The natural part of c-Met is pHGF (HGF), and it is a multi-functional somatomedin, i.e. dispersion factor (SF).In fetus and adult; activate the formation that c-Met can promote some form; for example, invasive growth will cause the Fast Growth of cell, intercellular division; to it, move (" From Tpr-Met to Met; tumorigenesis and tubes, " Oncogene, 2007 with cell around; 26,1276; And " Met Receptor Tyrosine Kinase as a Therapeutic Anticancer Target, " Cancer Letter, 2009,280,1-14).

The human malignancies extensively existing exists lasting c-Met to stimulate, cross and express or variation, comprises mammary cancer, liver cancer, lung cancer, ovarian cancer, kidney, thyroid carcinoma, colorectal carcinoma, glioblastoma, prostate cancer etc.C-Met involves atherosclerosis and pulmonary fibrosis equally.By the interaction of mesenchyma stroma of tumors, comprise HGF/c-Met approach, the invasive growth speed of these cancer cells has thoroughly been improved.Therefore, a large amount of evidences show that c-Met signal response is relevant with certain cancers advancing of disease speed, and improved its with take role status in the cancer drug exploitation that c-Met is main target spot (" Molecular cancer therapy:can our expectation be MET, " Euro.J.Cancer, 2008, 44,641-651, and " Targeting the c-Met Signaling Pathway in Cancer, " Clin.Cancer Res., 2006, 12, 3657) .Agents targeting c-Met signaling pathway are now under clinical investigation. (" Novel Therapeutic Inhibitors of the c-Met Signaling Pathway in Cancer, " Clinical Cancer Research, 2009, 15, 2207), and " Drug development of MET inhibitors:targeting oncogene addiction and expedience, " Nature Review Drug Discovery, 2008, 7, 504).

Axl belongs to the subfamily of tyrosine kinase receptor (RTKs), comprises Tyro3 and Mer (TAM).Wherein TAM acceptor is by characterizing in 2 similar object areas of immunoglobulin (Ig) of extracellular region and tenuigenin kinases district associating and binary fibronectin III type.The part of TAM acceptor is Gas6 (growth arrest-specific6) and Protein S; there is 43% aminoacid sequence in two kinds of vitamin k-dependent proteins; and there are similar domain structure (" The anticoagulation factor protein S and its relative; Gas6; are ligands for the Tyro 3/Axl family of receptor tyrosine kinases, " Cell, 1995; 80,661-670; And " Axl receptor tyrosine kinase stimulated by the vitamin K-dependent protein encoded by growth-arrest-specific gene6, " Nature, 1995,373,623-626).

Ample evidence show Gas6/Axl system in advancing normal cell and growth of cancer cells and survival, playing the part of important role (" TAM receptor tyrosine kinases:biologic functions; signaling; and potential therapeutic targeting in human cancer; " Adv Cancer Res, 2008,100,35 – 83).Axl crosses expression and signal response involves several human malignancies, as colorectal carcinoma, mammary cancer, neurospongioma, thyroid carcinoma, cancer of the stomach, melanoma, lung cancer and renal cell carcinoma (RCC).Axl effect more specifically in biology is confirmed in gliomatous research, the signal response that reduces Axl will reduce the growth of neurospongioma and breast tumor, and wherein Axl will promote that cell migration, pipeline form, new vessel forms and tumor growth.Axl has been proved in tumour generates and has played the part of multiple player, and antibody therapy suppresses Axl and not only can block the function of Axl in malignant cell, also can block its function in mesenchymal neoplasm cell simultaneously.The function that the restraining effect of Axl and the additive effect of anti-VEGF show to block Axl will be to improve effective way (" Axl as a potential therapeutic target in cancer:role of Axl in tumor growth; metastasis and angiogenesis. " Oncogene of angiogenesis inhibitor treatment; 2009; 28,3442-3455; And " TAM Receptor Tyrosine Kinases:Biologic Functions, Signaling, and Potential Therapeutic Targeting in Human Cancer, " Adv Cancer Res, and 2008,100,35-83).

RON (MST1R, recepteur d'origine nantais) another member of ShiMET family, part macrophage stimulating protein (MSP, be also referred to as MST1 or quasi-liver cell somatomedin (HGFL)) a kind of receptor tyrosine kinase, it is all the surrogate markers thing with the invasive growth tumor phenotypes of metastatic potential to the cytodifferentiation of in vitro and in vivo, migration and relevant-all these processes of matrix invasion and attack.RON is mainly adjusted in tumor phenotypes in lung, Tiroidina, pancreas, prostate cancer, colon and breast cancer cell and poor prognosis that can predict human mammary cancer.The coexpression of RON and MET and the RON by HGF-MET signal induction express and in the research of hepatocellular carcinoma, described.In addition, RON and the MET coexpression in ovarian cancer, mammary cancer and bladder cancer is indicating a kind of worse prognosis.The signal of considering RON and MET is tediously long; most probable mode is to suppress the signal response of MET, and mainly by RON signal response, regulates (" RON (MST1R) is a novel prognostic marker and therapeutic target for gastroesophageal adenocarcinoma. " Cancer Biol Ther.2011July1; 12 (1): 9 – 46.).

MSP-RON signal shaft role in carcinogenesis was widely studied in various diseases model system.In body, all show that with external result of study MSP – RON signal response is all very important in the invasive growth of dissimilar cancer.In that induced by the overexpression of protein and the generation of carcinogenic hypotype and many cells, the indicated abnormal RON activation of sustained activation of signal transduction is present in various dissimilar cancers.RON signal response is also necessary for growth and the existence of cancer cell.These characteristics make RON become cancer therapy a drug target (" MSP – RON signalling in cancer:pathogenesis and therapeutic potential. " Nature Reviews Cancer, 2013,13,466-481).

As everyone knows, cancer cells tends to adopt number of mechanisms to avoid the tight regulate process of cell, as cell proliferation, apoptosis and aging.Therefore, a lot of tumours can flee from out from single kinase inhibitory activity.By to tumour, wide systems analysis shows, tyrosine kinase receptor (RTK) coactivation completes chemoresistance by cancer cells, and as important biomechanism.One of them method is, overcomes RTK coactivation, may be involved in the upper targeting for the treatment of in multiple RTKs simultaneously, thereby block carcinogenic RTK signal response, and overcome compensatory mechanism.(“Receptor?Tyrosine?Kinase?Coactivation?Networks?in?Cancer,”Cancer?Research,2010,70,3857)。Targeting is in VEGFR, c-Met, and the anti-tumor method of Ron and/or Axl signal response can prevent that tumour cell from overcoming VEGFR, c-Met (HGFR), the independent restraining effect of Ron and/or Axl, thus improve the result for the treatment of of cancer.

Abstract of invention

The present invention relates to the method for pyrazolone compounds and the treatment cell proliferation disorders of new replacement.Compound of the present invention has restraining effect to protein tyrosine kinase activity.More satisfactory, compound of the present invention has multiple inhibitor function, can suppress as VEGFR c-Met (HGFR), Ron and/or Axl signal response.Correspondingly, the present invention also provides the inhibitor of some new protein tyrosine kinase receptor signal responses, as vegf receptor signal response, and the response of HGF receptor signal, the response of Ron receptor signal and/or the response of Axl receptor signal.

Especially, compound involved in the present invention, and pharmaceutically acceptable composition, can be effective as tyrosine kinase receptor inhibitor, as VEGFR, and c-Met, the inhibitor of Ron and/or Axl.

On the one hand, the present invention relates to a kind of suc as formula the compound shown in (I):

Or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or its prodrug, wherein, Q in formula (I), R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, W, X, shown in Y and Z are defined as follows.

In some embodiments, in formula (I):

Q is H, NR ^ar ^b, OR ^a,-N (R ^c) C (=O) R ^dor-N (R ^c) C (=O) OR ^a;

W is CR ⁷or N;

Each X, Y and Z are H independently, D, C _1-6alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-4alkylidene group, C _3-7heterocyclic radical, C _3-7heterocyclic radical-C _1-4alkylidene group, C _6-10aryl, 5-10 former molecular heteroaryl, C _6-10aryl-C _1-4alkylidene group or (5-10 former molecular heteroaryl)-C _1-4alkylidene group, wherein, described C _1-6alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-4alkylidene group, C _3-7heterocyclic radical, C _3-7heterocyclic radical-C _1-4alkylidene group, C _6-10aryl, 5-10 former molecular heteroaryl, C _6-10aryl-C _1-4alkylidene group and (5-10 former molecular heteroaryl)-C _1-4alkylidene group can be optionally by 1,2, and 3,4 or 5 are independently selected from D, F, Cl, Br, CN, C _2-6thiazolinyl, C _2-6alkynyl, OR ^a, NR ^ar ^b, R ^ao-C _1-4alkylidene group or R ^ar ^bn-C _1-4the substituting group of alkylidene group replaces;

Each R ¹, R ², R ³, R ⁴, R ⁵, R ⁶and R ⁷be H independently, D, F, Cl, Br, CN, N ₃, OR ^a, C _1-6alkyl, C _1-6haloalkyl, C _2-6thiazolinyl or C _2-6alkynyl;

Each R ^a, R ^band R ^cbe H independently, C _1-6aliphatics, C _1-6haloalkyl, C _3-6cycloalkyl, C _3-6cycloalkyl-C _1-4alkylidene group, C _3-6heterocyclic radical, C _3-6heterocyclic radical-C _1-4alkylidene group, C _6-10aryl, 5-10 former molecular heteroaryl, C _6-10aryl-C _1-4alkylidene group or (5-10 former molecular heteroaryl)-C _1-4alkylidene group, works as R ^aand R ^bwhile being connected with same nitrogen-atoms, R ^a, R ^b, together with the nitrogen-atoms being connected with them, can optionally form 3-8 replacement or non-substituted former molecular heterocycle, wherein, described C _1-6aliphatics, C _1-6haloalkyl, C _3-6cycloalkyl, C _3-6cycloalkyl-C _1-4alkylidene group, C _3-6heterocyclic radical, C _3-6heterocyclic radical-C _1-4alkylidene group, C _6-10aryl, 5-10 former molecular heteroaryl, C _6-10aryl-C _1-4alkylidene group, (5-10 former molecular heteroaryl)-C _1-4alkylidene group and 3-8 former molecular heterocycle can be optionally by 1,2, and 3 or 4 are independently selected from D, F, Cl, CN, N ₃, OH, NH ₂, C _1-6haloalkyl, C _1-6alkoxyl group or C _1-6the substituting group of alkylamino replaces; With

R ^dfor H, C _1-6alkyl, C _3-8cycloalkyl-C _1-4alkylidene group, C _3-7heterocyclic radical, C _3-7heterocyclic radical-C _1-4alkylidene group or C _6-10aryl, works as R ¹, R ², R ³, R ⁵(or R ⁴), R ⁶and R ⁷be H simultaneously, R ⁴(or R ⁵) while being F, R ^dbe not C _3-7heterocyclic radical, wherein, described C _1-6alkyl, C _3-8cycloalkyl-C _1-4alkylidene group, C _3-7heterocyclic radical, C _3-7heterocyclic radical-C _1-4alkylidene group and C _6-10aryl can be optionally by 1,2, and 3 or 4 are independently selected from D, F, Cl, Br, CN, OR ^a, NR ^ar ^b, C _1-6alkyl, C _2-6thiazolinyl, C _2-6alkynyl, R ^ao-C _1-4alkylidene group or R ^ar ^bn-C _1-4the substituting group of alkylidene group replaces.

In other embodiment, in formula (I), Q is NR ^ar ^b,-N (R ^c) C (=O) R ^dor-N (R ^c) C (=O) OR ^a.

In other embodiment, each X in formula (I), Y and Z are H independently, D, C _1-4alkyl, C _3-6cycloalkyl, C _3-6cycloalkyl-C _1-2alkylidene group, C _3-6heterocyclic radical, C _3-6heterocyclic radical-C _1-2alkylidene group, phenyl, 5-10 former molecular heteroaryl, phenyl-C _1-2alkylidene group or (5-10 former molecular heteroaryl)-C _1-2alkylidene group, wherein, described C _1-4alkyl, C _3-6cycloalkyl, C _3-6cycloalkyl-C _1-2alkylidene group, C _3-6heterocyclic radical, C _3-6heterocyclic radical-C _1-2alkylidene group, phenyl-C _1-2alkylidene group, (5-10 former molecular heteroaryl)-C _1-2alkylidene group, phenyl and 5-10 former molecular heteroaryl can be optionally by 1,2, and 3 or 4 are independently selected from D, F, Cl, Br, CN, C _2-4thiazolinyl, C _2-4alkynyl, OR ^a, NR ^ar ^b, R ^ao-C _1-2alkylidene group or R ^ar ^bn-C _1-2the substituting group of alkylidene group replaces.

In other embodiment, each R in formula (I) ¹, R ², R ³, R ⁴, R ⁵, R ⁶and R ⁷be H, D, F or Cl independently.

In other embodiment, each R in formula (I) ^a, R ^band R ^cbe H independently, C _1-4alkyl, C _1-4haloalkyl, C _3-6cycloalkyl, C _3-6cycloalkyl-C _1-2alkylidene group, C _3-6heterocyclic radical or C _3-6heterocyclic radical-C _1-2alkylidene group, works as R ^aand R ^bwhile being connected with same nitrogen-atoms, R ^a, R ^b, together with the nitrogen-atoms being connected with them, can optionally form 3-8 replacement or non-substituted former molecular heterocycle, wherein, described C _1-4alkyl, C _1-4haloalkyl, C _3-6cycloalkyl, C _3-6cycloalkyl-C _1-2alkylidene group, C _3-6heterocyclic radical, C _3-6heterocyclic radical-C _1-2alkylidene group and 3-8 former molecular heterocycle can be optionally by 1,2, and 3 or 4 are independently selected from D, F, Cl, CN, N ₃, OH, NH ₂, C _1-3haloalkyl, C _1-3alkoxyl group or C _1-3the substituting group of alkylamino replaces.

In other embodiment, R in formula (I) ^dfor H, D, C _1-4alkyl, C _3-6cycloalkyl-C _1-2alkylidene group, C _3-6heterocyclic radical or C _3-6heterocyclic radical-C _1-2alkylidene group, works as R ¹, R ², R ³, R ⁵(or R ⁴), R ⁶and R ⁷be H simultaneously, R ⁴(or R ⁵) while being F, R ^dbe not C _3-6heterocyclic radical, wherein, described C _1-4alkyl, C _3-6cycloalkyl-C _1-2alkylidene group, C _3-6heterocyclic radical or C _3-6heterocyclic radical-C _1-2alkylidene group can be optionally by 1,2, and 3 or 4 are independently selected from D, F, CN, OR ^a, NR ^ar ^b, C _1-3alkyl, C _2-4thiazolinyl, C _2-4alkynyl, R ^ao-C _1-2alkylidene group or R ^ar ^bn-C _1-2the substituting group of alkylidene group replaces.

In other embodiment, in formula (I), Q is NH ₂or-N (R ^c) C (=O) R ^d.

In other embodiment, each X in formula (I), Y and Z are H independently, D, CH ₃, CH ₂cH ₃, phenyl or by 1,2,3,4 or 5 are independently selected from D, the phenyl group that the substituting group of F or Cl replaces.

In other embodiment, in formula (I), Q is:

In other embodiment, the compounds of this invention has structure shown in formula (II):

Wherein, Q in formula (II), X, shown in Y and Z are defined as follows.

In some embodiments, in formula (II):

Q is NR ^ar ^b,-N (R ^c) C (=O) R ^dor-N (R ^c) C (=O) OR ^a;

Each X, Y and Z are H independently, D, C _1-6alkyl, C _3-8cycloalkyl, C _3-7heterocyclic radical, C _6-10aryl, 5-10 former molecular heteroaryl, C _3-8cycloalkyl-C _1-4alkylidene group, C _3-7heterocyclic radical-C _1-4alkylidene group, C _6-10aryl-C _1-4alkylidene group, or (5-10 former molecular heteroaryl)-C _1-4alkylidene group, wherein, described C _1-6alkyl, C _3-8cycloalkyl, C _3-7heterocyclic radical, C _6-10aryl, 5-10 former molecular heteroaryl, C _3-8cycloalkyl-C _1-4alkylidene group, C _3-7heterocyclic radical-C _1-4alkylidene group, C _6-10aryl-C _1-4alkylidene group and (5-10 former molecular heteroaryl)-C _1-4alkylidene group can be optionally by 1,2, and 3,4 or 5 are independently selected from D, F, Cl, Br, CN, C _2-6thiazolinyl, C _2-6alkynyl, OR ^a, NR ^ar ^b, R ^ao-C _1-4alkylidene group or R ^ar ^bn-C _1-4the substituting group of alkylidene group replaces;

Each R ^a, R ^band R ^cbe H independently, C _1-6alkyl, C _3-6cycloalkyl, C _3-6heterocyclic radical, C _6-10aryl, 5-10 former molecular heteroaryl, C _3-6cycloalkyl-C _1-4alkylidene group, C _3-6heterocyclic radical-C _1-4alkylidene group, C _6-10aryl-C _1-4alkylidene group or (5-10 former molecular heteroaryl)-C _1-4alkylidene group, wherein, described C _1-6alkyl, C _3-6cycloalkyl, C _3-6heterocyclic radical, C _6-10aryl, 5-10 former molecular heteroaryl, C _3-6cycloalkyl-C _1-4alkylidene group, C _3-6heterocyclic radical-C _1-4alkylidene group, C _6-10aryl-C _1-4alkylidene group and (5-10 former molecular heteroaryl)-C _1-4alkylidene group can be optionally by 1,2, and 3 or 4 are independently selected from D, F, Cl, CN, N ₃, OH, NH ₂, C _1-6haloalkyl, C _1-6alkoxyl group or C _1-6the substituting group of alkylamino replaces; With

R ^dfor C _1-6alkyl, wherein, described C _1-6alkyl can be optionally by 1,2, and 3 or 4 are independently selected from D, F, Cl, OH, NH ₂, C _1-6alkoxyl group or C _1-6the substituting group of alkylamino replaces.

In other embodiment, in formula (II), Q is NR ^ar ^bor-N (R ^c) C (=O) R ^d.

In other embodiment, each X in formula (II), Y and Z are H independently, D, C _1-4alkyl or phenyl, wherein, described C _1-4alkyl and phenyl can be optionally by 1,2, and 3,4 or 5 are independently selected from D, and the substituting group of F or Cl replaces.

In other embodiment, each R in formula (II) ^a, R ^band R ^cbe H independently, C _1-4alkyl, C _3-6cycloalkyl, C _3-6heterocyclic radical, C _3-6cycloalkyl-C _1-2alkylidene group or C _3-6heterocyclic radical-C _1-2alkylidene group, wherein, described C _1-4alkyl, C _3-6cycloalkyl, C _3-6heterocyclic radical, C _3-6cycloalkyl-C _1-2alkylidene group and C _3-6heterocyclic radical-C _1-2alkylidene group can be optionally by 1,2, and 3 or 4 are independently selected from D, F, Cl, CN, N ₃, OH, NH ₂, C _1-6haloalkyl, C _1-6alkoxyl group or C _1-6the substituting group of alkylamino replaces.

In other embodiment, R in formula (II) ^dfor Me, Et, n-Pr, i-Pr, n-Bu, i-Bu or t-Bu.

In other embodiment, in formula (II), Q is NH ₂or-N (R ^c) C (=O) R ^d.

In other embodiment, each X in formula (II), Y and Z are H independently, D, Me, CH ₂d, CHD ₂, CD ₃, ethyl, propyl group, sec.-propyl, phenyl or by 1,2,3,4 or 5 are independently selected from D, the phenyl group that the substituting group of F or Cl replaces.

In other embodiment, in formula (II), Q is:

On the other hand, the present invention relates to a kind of pharmaceutical composition, it comprises (1) the compounds of this invention and (2) pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle, or their combination.

In some embodiments, pharmaceutical composition of the present invention, further comprises additional treatment agent, these additional treatment agent are selected from chemotherapeutic agent, and antiproliferative is used for the treatment of atherosclerotic medicine, the medicine that is used for the treatment of pulmonary fibrosis, or their combination.

In other embodiment, pharmaceutical composition of the present invention, wherein related additional treatment agent is Zorubicin (Adriamycin), Wyeth-Ayerst Laboratories (Rapamycin), Temsirolimus, everolimus (Everolimus), Ixabepilone, gemcitabine (Gemcitabin), endoxan (cyclophosphamide), dexamethasone (dexamethasone), Etoposide (etoposide), Fluracil (fluorouracil), Ah method is for Buddhist nun (afatinib), alisertib, amuvatinib, Axitinib (axitinib), SKI-606 (bosutinib), brivanib, cabozantinib, AZD2171 (cediranib), crenolanib, Ke Zhuo is for Buddhist nun (crizotinib), dabrafenib, dacomitinib, Dasatinib (dasatinib), danusertib, dovitinib, Tarceva (erlotinib), foretinib, ganetespib, Gefitinib (gefitinib), ibrutinib, imatinib (imatinib), iniparib, lapatinibditosylate (lapatinib), lenvatinib, linifanib, linsitinib, Masitinib (masitinib), momelotinib, not for husky Buddhist nun (motesanib), HKI-272 (neratinib), niraparib, AMN107 (nilotinib), oprozomib, olaparib, pazopanib (pazopanib), pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, fork clip is for Buddhist nun (saracatinib), saridegib, Xarelto (sorafenib), Sutent (sunitinib), tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, ZD6474 (vandetanib), veliparib, vemurafenib, vismodegib, volasertib, Interferon, rabbit (an interferon), carboplatin (carboplatin), Hycamtin (topotecan), taxol (taxol), vinealeucoblastine(VLB) (vinblastine), vincristine(VCR) (vincristine), Temozolomide (temozolomide), tositumomab (tositumomab), trabedectin, belimumab, rhuMAb-VEGF (bevacizumab), brentuximab, cetuximab, gemtuzumab, ipilimumab, ofatumumab, panitumumab, ranibizumab, rituximab, tositumomab, trastuzumab (trastuzumab) or their combination.

On the other hand, can be with the compounds of this invention or pharmaceutical composition for the preparation of the purposes of protecting, process, treat or alleviate the medicine of patient's proliferative disease.

In some embodiments, proliferative disease of the present invention is metastatic carcinoma, colorectal carcinoma, adenocarcinoma of stomach, bladder cancer, mammary cancer, kidney, liver cancer, lung cancer, skin carcinoma, thyroid carcinoma, brain tumor, neck cancer, prostate cancer, carcinoma of the pancreas, CNS(central nervous system) cancer, glioblastoma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis.

On the other hand, the present invention relates to use the compounds of this invention or pharmaceutical composition to contact with described biological sample for the preparation of suppressing or regulate the purposes of protein kinase activity, described purposes to comprise in biological sample with the compounds of this invention or pharmaceutical composition.

Some embodiments therein, protein kinase of the present invention is receptor tyrosine kinase.

In other embodiment, receptor tyrosine kinase of the present invention is VEGFR, c-Met, Ron, Axl or their combination.

On the other hand, the invention provides some pharmaceutical compositions, it comprises the present invention as the compound of tyrosine kinase receptor inhibitor, or its steric isomer, geometrical isomer, tautomer, solvate, meta-bolites, or its pharmacy acceptable salt, pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle, or their combination.In some embodiments, pharmaceutical composition provided by the present invention comprises and can be used as vegf receptor signal response, the response of HGF receptor signal, the compound of the response of Ron receptor signal and the agent of Axl receptor signal response suppression, or its steric isomer, geometrical isomer, tautomer, solvate, meta-bolites, or its pharmacy acceptable salt, or pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle, or their combination.In other embodiment, pharmaceutical composition of the present invention further comprises additional treatment agent.

On the other hand, the present invention relates to a kind of method of arrestin tyrosine kinase activity, the method comprises the compounds of this invention or its pharmaceutical composition contacts with described kinases.In some embodiments, the present invention relates to suppress vegf receptor signal response therein, the response of HGF receptor signal, the method for the response of Ron receptor signal and the response of Axl receptor signal, the method comprises the compounds of this invention or its pharmaceutical composition contacts with described acceptor.Suppress receptor protein kinase activity, particularly VEGF, HGF, Ron and the response of Axl receptor signal can be carried out in unicellular or multi-cell organism.If be present in multi-cell organism, method described in the invention comprises uses compound of the present invention or composition to carry out administration to organism.Some of them embodiment is, described organism is Mammals, and other embodiment is that described organism is the mankind.Other embodiment is, described method further comprises contacting of protein kinase and additional treatment agent.

On the other hand, the present invention relates to a kind of method that suppresses cell-proliferation activity, described method comprises the compounds of this invention or its pharmaceutical composition effectively dosage and the cells contacting of inhibition of cell proliferation.In some embodiments, the method for the invention further comprises contacting of additional treatment agent and cell.

On the other hand, the present invention relates to a kind of method of the patient's for the treatment of cell proliferation disorders, described method comprises needs of patients and effectively treats the dosage of required compound of the present invention or its composition administration.In some embodiments, the method for the invention further comprises the administration of additional treatment agent.

On the other hand, the present invention relates to a kind of method that suppresses patient tumors growth, described method comprises needs of patients and effectively treats the dosage of required compound of the present invention or its composition administration.In some embodiments, the method for the invention further comprises the administration of additional treatment agent.

On the other hand, the present invention relates to the method for preparation, separation and the purifying of the compound that formula (I) or formula (II) comprise.

Content noted earlier has only been summarized some aspect of the present invention, but is not limited to these aspects.The content of these aspects and other aspect will be done more concrete complete description below.

Circumstantial letter of the present invention

Definition and general terms

The present invention will list the corresponding document of specific content of determining in detail, and embodiment is attended by the diagram of structural formula and chemical formula.The present invention has expectedly contains all choices, variant and coordinator, and these may be included in existing invention field as claim is defined.Those skilled in the art is many similar or be equal to method described herein and material by identification, and these can be applied to go in practice of the present invention.The present invention is limited to absolutely not the description of method and material.Have a lot of documents distinguish or conflict with similar material and the present patent application, comprising but be never limited to the definition of term, the usage of term, the technology of description, or the scope of controlling as the present patent application.

Unless the present invention shows other aspects of the following definition of application.According to object of the present invention, chemical element is according to the periodic table of elements, CAS version and pharmaceutical chemicals handbook, and 75, thEd, 1994 define.In addition, organic chemistry General Principle is shown in " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999, and " March's Advanced Organic Chemistry; " by Michael B.Smith and Jerry March, John Wiley & Sons, New York:2007, therefore all contents have all merged reference.

Picture is described in the invention, and compound of the present invention can optionally be replaced by one or more substituting group, as general formula compound above, or the special example in picture embodiment the inside, and subclass, and the compounds that comprises of the present invention.Should be appreciated that " optional replacement " this term can exchange use with " substituted or non-substituted " this term.Generally speaking, term " optionally ", no matter whether be positioned at term " replacement " before, all represents that the one or more hydrogen atoms in given structure are replaced by concrete substituting group.Unless other aspects show, an optional substituted radical can replace in each commutable position of group.Should note in the present invention R ^aand R ^bwhile being connected with same nitrogen-atoms, R ^a, R ^btogether with the nitrogen-atoms being connected with them, can optionally form 3-8 replacement or non-substituted former molecular heterocycle, i.e. R ^a, R ^btogether with the nitrogen-atoms being connected with them, can form the heterocycle of 3-8 atom, also can not form heterocycle, for other structures well known to those skilled in the art, as N-R ^a-R ^bor R ^a-N-R ^bdeng.Not only one or more substituting group that position can be selected from concrete group in given structural formula replaces, and substituting group can replace in each position identical or differently so.Wherein said substituting group can be, but be not limited to D, F, Cl, Br, N ₃, NO ₂, CN, OH, NH ₂, OR ^a, CH ₂d, CHD ₂, CD ₃, R ^ao-C _1-4alkylidene group, SR ^a, NR ^ar ^b, R ^ar ^bn-C _1-4alkylidene group ,-C (=O) NR ^ar ^b,-N (R ^c) C (=O) NR ^ar ^b,-N (R ^c) C (=O) R ^d,-N (R ^c) S (=O) NR ^ar ^b,-N (R ^c) S (=O) R ^a,-N (R ^c) S (=O) ₂nR ^ar ^b,-N (R ^c) S (=O) ₂r ^a, methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, phenyl, phenyl-C _1-2alkylidene group, C _1-6alkyl, C _1-6aliphatics, C _1-6haloalkyl, C _1-6alkoxyl group, C _1-6alkylamino, C _2-6thiazolinyl, C _2-6alkynyl, C _3-8cycloalkyl, C _3-7heterocyclic radical, C _3-8cycloalkyl-C _1-4alkylidene group, C _3-7heterocyclic radical-C _1-4alkylidene group, C _6-10aryl-C _1-4alkylidene group, (5-10 former molecular heteroaryl)-C _1-4alkylidene group, C _6-10aryl, or 5-10 former molecular heteroaryl, wherein, R ^a, R ^band R ^cthere is definition as described herein.

Term " aliphatic " or " aliphatic group " that the present invention uses, represent straight chain (being non-side chain) or side chain, the substituted or non-substituted complete saturated or hydrocarbon chain that contains one or more degrees of unsaturation.Unless otherwise detailed instructions, aliphatic group contains 1-20 carbon atom, some of them embodiment is, aliphatic group contains 1-10 carbon atom, and other embodiment is that aliphatic group contains 1-8 carbon atom, other embodiment is, aliphatic group contains 1-6 carbon atom, and other embodiment is that aliphatic group contains 1-3 carbon atom.Suitable aliphatic group comprises, but is not limited to, straight or branched, and substituted or non-substituted alkyl, alkenyl or alkynyl group, as C _1-6aliphatic group, comprises straight or branched, substituted or non-substituted C _1-6alkyl, C _2-6thiazolinyl, or C _2-6alkynyl group.Such example comprises, but is not limited to methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, ethene, propylene, butylene, 2-butylene, acetylene, propine, butine, 2-butyne, etc., and described aliphatic group can not be substituted independently or be replaced by one or more substituting groups described in the invention.

Term " alkyl " or " alkyl group " that the present invention uses, represent containing the saturated straight chain of 1-20 carbon atom or the monovalence hydrocarbon polymer atomic group of side chain.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom, and some of them embodiment is that alkyl group contains 1-10 carbon atom, other embodiment is, alkyl group contains 1-8 carbon atom, and other embodiment is that alkyl group contains 1-6 carbon atom, other embodiment is, alkyl group contains 1-4 carbon atom, and other embodiment is that alkyl group contains 1-3 carbon atom.

The example of alkyl group comprises, but is not limited to, methyl (Me ,-CH ₃), ethyl (Et ,-CH ₂cH ₃), n-propyl (n-Pr ,-CH ₂cH ₂cH ₃), sec.-propyl (i-Pr ,-CH (CH ₃) ₂), normal-butyl (n-Bu ,-CH ₂cH ₂cH ₂cH ₃), isobutyl-(i-Bu ,-CH ₂cH (CH ₃) ₂), sec-butyl (s-Bu ,-CH (CH ₃) CH ₂cH ₃), the tertiary butyl (t-Bu ,-C (CH ₃) ₃), n-pentyl (CH ₂cH ₂cH ₂cH ₂cH ₃), 2-amyl group (CH (CH ₃) CH ₂cH ₂cH ₃), 3-amyl group (CH (CH ₂cH ₃) ₂), 2-methyl-2-butyl (C (CH ₃) ₂cH ₂cH ₃), 3-methyl-2-butyl (CH (CH ₃) CH (CH ₃) ₂), 3-methyl isophthalic acid-butyl (CH ₂cH ₂cH (CH ₃) ₂), 2-methyl-1-butene base (CH ₂cH (CH ₃) CH ₂cH ₃), n-hexyl (CH ₂cH ₂cH ₂cH ₂cH ₂cH ₃), 2-hexyl (CH (CH ₃) CH ₂cH ₂cH ₂cH ₃), 3-hexyl (CH (CH ₂cH ₃) (CH ₂cH ₂cH ₃)), 2-methyl-2-amyl group (C (CH ₃) ₂cH ₂cH ₂cH ₃), 3-methyl-2-amyl group (CH (CH ₃) CH (CH ₃) CH ₂cH ₃), 4-methyl-2-amyl group (CH (CH ₃) CH ₂cH (CH ₃) ₂), 3-methyl-3-amyl group (C (CH ₃) (CH ₂cH ₃) ₂), 2-methyl-3-amyl group (CH (CH ₂cH ₃) CH (CH ₃) ₂), 2,3-dimethyl-2-butyl (C (CH ₃) ₂cH (CH ₃) ₂), 3,3-dimethyl-2-butyl (CH (CH ₃) C (CH ₃) ₃), n-heptyl, n-octyl, etc., wherein said alkyl group can not be substituted independently or replaced by one or more substituting groups described in the invention.

Term used in the present invention " alkyl " and its prefix " alkane ", all comprise the saturated carbon chains of straight chain and side chain.

Term " alkylidene group " represents to remove two resulting saturated bivalent hydrocarbon radical groups of hydrogen atom from the saturated hydrocarbyl of straight or branched.Unless otherwise detailed instructions, alkylidene group contains 1-10 carbon atom, and other embodiment is, alkylidene group contains 1-6 carbon atom, and other embodiment is that alkylidene group contains 1-4 carbon atom, other embodiment is that alkylidene group contains 1-2 carbon atom.Such example comprises methylene radical (CH ₂-), ethylidene (CH ₂cH ₂-), isopropylidene (CH (CH ₃) CH ₂-) etc., wherein said alkylidene group can not be substituted independently or replaced by one or more substituting groups described in the invention.

Term " alkenyl " represents 2-12 carbon atom, or 2-8 carbon atom, or 2-6 carbon atom, or the monovalence alkyl of the straight or branched of 2-4 carbon atom, and wherein at least one position is undersaturated condition, and a C-C is sp ²two keys, wherein the group of alkenyl can not be substituted independently or replaced by one or more substituting groups described in the invention, comprises that group has the location of negation " just " or " E " " Z ", and wherein concrete example comprises, but be not limited to vinyl (CH=CH ₂), allyl group (CH ₂cH=CH ₂) etc.

Term " alkynyl " represents 2-12 carbon atom, or 2-8 carbon atom, or 2-6 carbon atom, or the monovalence alkyl of the straight or branched of 2-4 carbon atom, wherein at least one position is undersaturated condition, a C-C is sp triple bond, wherein alkynyl group can not be substituted independently or replaced by one or more substituting groups described in the invention, and concrete example comprises, but is not limited to, ethynyl (C ≡ CH), propargyl (CH ₂c ≡ CH), 1-proyl (C ≡ C-CH ₃) etc.

Term " alkoxyl group " represents that alkyl group is connected with molecule rest part by Sauerstoffatom, and wherein alkyl group has implication as described in the present invention.Unless otherwise detailed instructions, described alkoxy base contains 1-20 carbon atom, and some of them embodiment is that alkoxy base contains 1-10 carbon atom, other embodiment is, alkoxy base contains 1-8 carbon atom, and other embodiment is that alkoxy base contains 1-6 carbon atom, other embodiment is, alkoxy base contains 1-4 carbon atom, and other embodiment is that alkoxy base contains 1-3 carbon atom.

The example of alkoxy base comprises, but is not limited to, methoxyl group (MeO ,-OCH ₃), oxyethyl group (EtO ,-OCH ₂cH ₃), 1-propoxy-(n-PrO, n-propoxy-,-OCH ₂cH ₂cH ₃), 2-propoxy-(i-PrO, i-propoxy-,-OCH (CH ₃) ₂), 1-butoxy (n-BuO, n-butoxy ,-OCH ₂cH ₂cH ₂cH ₃), 2-methyl-l-propoxy-(i-BuO, i-butoxy ,-OCH ₂cH (CH ₃) ₂), 2-butoxy (s-BuO, s-butoxy ,-OCH (CH ₃) CH ₂cH ₃), 2-methyl-2-propoxy-(t-BuO, t-butoxy ,-OC (CH ₃) ₃), 1-pentyloxy (n-pentyloxy ,-OCH ₂cH ₂cH ₂cH ₂cH ₃), 2-pentyloxy (OCH (CH ₃) CH ₂cH ₂cH ₃), 3-pentyloxy (OCH (CH ₂cH ₃) ₂), 2-methyl-2-butoxy (OC (CH ₃) ₂cH ₂cH ₃), 3-methyl-2-butoxy (OCH (CH ₃) CH (CH ₃) ₂), 3-methyl-l-butoxy (OCH ₂cH ₂cH (CH ₃) ₂), 2-methyl-l-butoxy (OCH ₂cH (CH ₃) CH ₂cH ₃), etc., wherein said alkoxy base can not be substituted independently or replaced by one or more substituting groups described in the invention.

Term " haloalkyl ", " haloalkenyl group " or " halogenated alkoxy " represents alkyl, and thiazolinyl or alkoxy base are replaced by one or more halogen atom, and such example comprises, but is not limited to, trifluoromethyl, trifluoromethoxy etc.

Term " carbocyclic ring ", " carbocylic radical " or " annular aliphatic " refer to that one or more tie points are connected to the rest part of molecule, non-aromatic, saturated or part is undersaturated, comprise 3-12 carbon atom, or 3-10 carbon atom, or 3-8 carbon atom, or the monocycle of 3-6 carbon atom, dicyclo and three-ring system.Suitable cyclic aliphatic group comprises, but is not limited to cycloalkyl, cycloalkenyl group and cycloalkynyl radical.The example of cyclic aliphatic group further comprises, but is never limited to cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-thiazolinyl, 1-cyclopentyl-2-thiazolinyl, 1-cyclopentyl-3-thiazolinyl, cyclohexyl, 1-cyclohexyl-1-thiazolinyl, 1-cyclohexyl-2-thiazolinyl, 1-cyclohexyl-3-thiazolinyl, cyclohexadienyl, suberyl, ring octyl group, ring nonyl, ring decyl, ring undecyl, cyclo-dodecyl, etc.

Term " cycloalkyl " refers to that one or more tie points are connected to the rest part of molecule, saturated, containing monocycle, dicyclo or the three-ring system of 3-12 carbon atom.Its bicyclic system comprises spiral shell dicyclo and condensed-bicyclic.Some of them embodiment is the member ring systems containing 3-10 carbon atom, other embodiment is the member ring systems containing 3-8 carbon atom, other embodiment is the member ring systems containing 3-6 carbon atom, other embodiment is the member ring systems containing 5-6 carbon atom, and described group of naphthene base can not be substituted independently or be replaced by one or more substituting groups described in the invention.

Term " cycloalkyl alkylidene group " represents that alkyl group can be replaced by one or more group of naphthene base, and wherein alkyl and group of naphthene base have implication as described in the present invention.Some of them embodiment is, cycloalkyl alkylidene group refers to " more rudimentary cycloalkyl alkylidene group " group, and group of naphthene base is connected to C _1-6alkyl group on.Other embodiment is that group of naphthene base is connected to C _1-4alkyl group on.Other embodiment is that group of naphthene base is connected to C _1-3alkyl group on.Other embodiment is that group of naphthene base is connected to C _1-2alkyl group on.Such example comprises, but is not limited to cyclopropyl ethyl, cyclopentyl-methyl, cyclohexyl methyl etc.Described cycloalkyl alkylidene group can not be substituted independently or replaced by one or more substituting groups described in the invention.Such example comprises, but is not limited to cyclopropyl ethyl, cyclopentyl-methyl, cyclohexyl methyl etc.

Term " heterocycle ", " heterocyclic radical " or " heterocycle " commutative use herein, all refer to monocycle, dicyclo, or three-ring system, wherein the upper one or more atoms of ring are independent is optionally replaced by heteroatoms, ring can be completely saturated or comprise one or more degrees of unsaturation, but is never the fragrant same clan, only has a tie point to be connected to the rest part of molecule.Its bicyclic system comprises spiral shell dicyclo and condensed-bicyclic, and one of them ring can be monocyclic carbocyclic ring or single heterocycle.Wherein one or more ring hydrogen atoms are independent optionally to be replaced by one or more substituting groups described in the invention.Some of them embodiment is, " heterocycle " " heterocyclic radical " or " heterocycle " group be 3-7 former molecular monocycle (2-6 carbon atom be selected from N, O, P, the 1-3 of a S heteroatoms, is optionally replaced and obtains picture SO, SO by one or more Sauerstoffatom at this S or P ₂, PO, PO ₂group), other embodiment is, 3-6 former molecular monocycle (2-5 carbon atom and be selected from N, O, P, the 1-3 of a S heteroatoms, is optionally replaced and obtains looking like S=O, SO by one or more Sauerstoffatom at this S or P ₂, PO, PO ₂group, when described ring is triatomic ring, wherein only have a heteroatoms), or 7-10 former molecular dicyclo (4-9 carbon atom be selected from N, O, P, the 1-3 of a S heteroatoms, is optionally replaced and obtains picture SO, SO by one or more Sauerstoffatom at this S or P ₂, PO, PO ₂group).

Heterocyclic radical can be carbon back or heteroatoms base." heterocyclic radical " equally also comprises heterocyclic group and saturated or the unsaturated ring of part or heterocyclic fused formed group.The example of heterocycle comprises, but be not limited to, pyrrolidyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, thioxane base, piperazinyl, homopiperazine base, azelidinyl, oxa-cyclobutyl, thia cyclobutyl, homopiperidinyl, epoxypropyl, nitrogen heterocyclic heptyl, oxepane base, thia suberyl, oxygen azatropylidene base, diazepine base, sulphur azatropylidene base, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1, 3-dioxy amyl group, pyrazolinyl, dithiane base, dithiode alkyl, dihydro-thiophene base, pyrazolidyl imidazolinyl, imidazolidyl, 1, 2, 3, 4-tetrahydro isoquinolyl.The example of heterocyclic group also comprises, 1,1-dioxy thio-morpholinyl, and wherein encircle two carbon atoms by Sauerstoffatom replacement as pyrimidine dione base.

Term " heterocyclic radical alkylidene group " represents that alkyl group can be replaced by one or more heterocyclic radical groups, and wherein alkyl and heterocyclic radical group have implication as described in the present invention.Some of them embodiment is, heterocyclic radical alkylidene group refers to " more rudimentary heterocyclic radical alkylidene group " group, and heterocyclic radical group is connected to C _1-6alkyl group on.Other embodiment is that heterocyclic radical group is connected to C _1-4alkyl group on.Other embodiment is that heterocyclic radical group is connected to C _1-2alkyl group on.Such example comprises, but is not limited to 2-tetramethyleneimine ethyl, 3-azetidine methyl etc.Described heterocyclic radical alkylidene group can not be substituted independently or replaced by one or more substituting groups described in the invention.

Term " heteroatoms " refers to O, S, and N, P and Si, comprise N, the form of S and any oxidation state of P; The form of primary, secondary, tertiary amine and quaternary ammonium salt; Or the substituted form of the hydrogen in heterocycle on nitrogen-atoms, for example, N(is as the N in 3,4-dihydro-2 h-pyrrole base), NH(is as the NH in pyrrolidyl) or the pyrrolidyl that replaces as N-of NR(in NR).

Term " halogen " refers to F, Cl, Br or I.

Term " H " represents single hydrogen atom.Such atomic group can be connected with other groups, is for example connected with Sauerstoffatom, forms oh group.

Term " D " or " ²h " represent single D atom.Such atomic group is connected with a methyl, forms list-deuterated methyl (CDH ₂), two D atoms are connected with a methyl, form two-deuterated methyl (CD ₂h), and three D atoms are connected with a methyl, form three-deuterated methyl (CD ₃).

Term " N ₃" represent a nitrine structure.This group can be connected with other groups, for example, can be connected to form triazonmethane (MeN with a methyl ₃), or be connected to form phenylazide (PhN with a phenyl ₃).

Term " aryl " can be used separately or as most of " aralkyl ", " aralkoxy " or " aryloxy alkyl ", represent to contain altogether 6-14 annular atoms, or 6-12 annular atoms, or the monocycle of 6-10 annular atoms, dicyclo, and the carbocyclic ring system of three rings, wherein, at least one member ring systems is aromatic, and wherein each member ring systems comprises 3-7 former molecular ring, and only has an attachment point to be connected with the rest part of molecule.Term " aryl " can and term " aromatic nucleus " exchange use, as aromatic nucleus can comprise phenyl, naphthyl and anthracene.Described aromatic yl group can not be substituted independently or replaced by one or more substituting groups described in the invention.

Term " aryl alkylene " represents that alkyl group can be replaced by one or more aromatic yl group, wherein alkyl and aromatic yl group have implication as described in the present invention, some of them embodiment is, aryl alkylene group refers to " more rudimentary aryl alkylene " group, and aromatic yl group is connected to C _1-6alkyl group on.Other embodiment is that aryl alkylene group refers to containing C _1-4" the benzene alkylene " of alkyl.Other embodiment is that aryl alkylene group refers to that aromatic yl group is connected to C _1-2alkyl group on.Wherein specific examples comprises benzyl, diphenyl methyl, styroyl etc.Described aryl alkylene group can not be substituted independently or replaced by one or more substituting groups described in the invention.

Term " heteroaryl " can be used separately or as most of " heteroarylalkyl " or " heteroaryl alkoxyl group ", represent to contain altogether 5-14 annular atoms, or 5-12 annular atoms, or the monocycle of 5-10 annular atoms, dicyclo, and three-ring system, wherein at least one member ring systems is aromatic, and at least one member ring systems comprises one or more heteroatomss, wherein each member ring systems comprises 5-7 former molecular ring, and only has an attachment point to be connected with molecule rest part.Term " heteroaryl " can be used with term " fragrant heterocycle " or " heteroaromatics " exchange.

Other embodiment is, virtue heterocycle comprises following monocycle, but be not limited to these monocycles: 2-furyl, 3-furyl, TMSIM N imidazole base, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrryl, 2-pyrryl, 3-pyrryl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, pyridazinyl (as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazyl (as 5-tetrazyl), triazolyl (as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (as 2-pyrazolyl), isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 3-thio biphosphole base, 1, 3, 4-thio biphosphole base, 1, 2, 5-thio biphosphole base, pyrazinyl, 1, 3, 5-triazinyl, also comprise following dicyclo, but be never limited to these dicyclos: benzimidazolyl-, benzofuryl, benzothienyl, indyl (as 2-indyl), purine radicals, quinolyl (as 2-quinolyl, 3-quinolyl, 4-quinolyl), and isoquinolyl (as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl).Described heteroaryl groups can not be substituted independently or replaced by one or more substituting groups described in the invention.

Term " heteroaryl alkylidene group " represents that alkyl group can be replaced by one or more heteroaryl groups, wherein alkyl and heteroaryl groups have implication as described in the present invention, some of them embodiment is, heteroaryl alkylidene group refers to " more rudimentary heteroaryl alkylidene group " group, and heteroaryl groups is connected to C _1-6alkyl group on.Other embodiment is that heteroaryl groups is connected to C _1-4alkyl group on.Other embodiment is that heteroaryl groups is connected to C _1-2alkyl group on.Wherein specific examples comprises 2-picolyl, 3-furans ethyl etc.Described heteroaryl alkylidene group can not be substituted independently or replaced by one or more substituting groups described in the invention.

No matter term " carboxyl " is to use separately or be used in conjunction with other terms, as " carboxyalkyl ", expression-CO ₂h; No matter term " carbonyl ", be to use separately or be used in conjunction with other terms,, as " aminocarboxyl " or " acyloxy ", represent-(C=O)-.

Term " alkylamino " comprises " N-alkylamino " and " N, N-dialkyl amido ", and wherein amino group is replaced by one or two alkyl group respectively independently.Some of them embodiment is that alkylamino is one or two C _1-6alkyl is connected to the more rudimentary alkylamino group on nitrogen-atoms.Other embodiment is that alkylamino is C _1-3more rudimentary alkylamino group.Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example comprises, but is not limited to N-methylamino-, N-ethylamino, N, N-dimethylamino, N, N-diethylin etc.

Term " virtue is amino " represents that amino group is replaced by one or two aromatic yl group, and such example comprises, but is not limited to N-phenylamino.Some of them embodiment is that the aromatic ring on fragrant amino can further be substituted.

Term " aminoalkyl group " comprises the C being replaced by one or more amino _1-10straight or branched alkyl group.Some of them embodiment is, aminoalkyl group is by C that one or more amino group replaced _1-6" more rudimentary aminoalkyl group ", such example comprises, but is not limited to aminomethyl, aminoethyl, aminopropyl, ammonia butyl and ammonia hexyl.

The term that used in the present invention " undersaturated " represents to contain one or more degrees of unsaturation in group.

Term " comprises " for open language, comprises the content that the present invention is specified, but does not get rid of otherwise content.

Unless other aspects show, structural formula described in the invention comprises that all isomeric forms are (as enantiomerism, diastereo-isomerism, and rotamerism (or conformational isomerism)): the R, the S configuration that for example contain asymmetric center, (Z) of two keys, (E) isomer, and (Z), the conformer of (E).Therefore, the single three-dimensional chemical isomer of compound of the present invention or its enantiomer, diastereomer, or the mixture of geometrical isomer (or conformer) all belongs to scope of the present invention.

Term used in the present invention " tautomer " or " tautomeric form " expression have the structure isomeride of different-energy can cross low energy barrier, thereby transforms mutually.For example, proton tautomerism body (being prototropy) comprises by proton shifting and carries out change, as the change of keto-enol formula and imines-enamine isomerization.Valence tautomers comprises by some bonding electronss recombinates and carries out change.

Unless other aspects show, within all tautomeric forms of compound of the present invention are included in scope of the present invention.In addition, unless other aspects show, the structural formula of compound described in the invention comprises the enriched isotope of one or more different atoms.

Term used in the present invention " prodrug ", represents that a compound is converted into the compound shown in formula (I) or formula (II) in vivo.Such conversion is hydrolyzed by prodrug or the impact that is precursor structure through enzymatic conversion in blood or tissue in blood.Prodrug compounds of the present invention can be ester, and what in existing invention, ester can be used as prodrug has phenyl ester class, an aliphatics (C _1-24) ester class, acyloxy methyl ester class, carbonic ether, amino formate and amino acid esters.For example a compound in the present invention comprises hydroxyl, its acidylate can be obtained to the compound of prodrug form.Other prodrug form comprises phosphoric acid ester, if these phosphate compounds are that hydroxyl phosphorylation on parent obtains.Can be with reference to Publication about Document about the complete discussion of prodrug: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14of the A.C.S.Symposium Series, Edward B.Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J.Rautio et al., Prodrugs:Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and S.J.Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

" meta-bolites " refers to that concrete compound or its salt is in vivo by the resulting product of metabolism.The meta-bolites of a compound can identify by the known technology in affiliated field, and its activity can be by adopting the method for test to characterize as described in the invention.Such product can be by the oxidation of drug compound process, reduces, and hydrolysis, amidated, desamido-effect, esterification, fat abstraction, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes the meta-bolites of compound, comprise compound of the present invention is fully contacted to the meta-bolites that for some time produces with Mammals.

The definition of neutral body chemistry of the present invention and the use of convention be conventionally with reference to Publication about Document: S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; And Eliel, E.and Wilen, S., " Stereochemistry of Organic Compounds ", John Wiley & Sons, Inc., New York, 1994. compounds of the present invention can comprise asymmetric center or chiral centre, therefore have different steric isomers.The stereoisomeric forms in any ratio that compound of the present invention is all, include, but not limited to, diastereomer, and enantiomer, atropisomer, and their mixture, as racemic mixture, formed a part of the present invention.A lot of organic compound all exist with optical activity form, i.e. the plane of their capable Plane of rotation polarized light.When describing optically active compound, prefix D, L or R, S are used for representing the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) are used for naming the symbol of compound plane polarized light rotation, and (-) or l refer to that compound is left-handed, and prefix (+) or d refer to that compound is dextrorotation.The chemical structure of these steric isomers is identical, but their three-dimensional arrangement is different.Specific steric isomer can be enantiomorph, and the mixture of isomer is commonly referred to enantiomeric mixture.The mixture of enantiomers of 50:50 is called as racemic mixture or racemic modification, and this may cause in chemical reaction process, there is no stereoselectivity or stereospecificity.Term " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomers, lack optical activity.

Term " tautomer " or " tautomeric form " refer to that the isomers of the structure of different-energy can transform mutually by low energy barrier.For example proton tautomerism body (being prototropic tautomer) comprises the change by proton shifting, as the isomerization of keto-acid-enol form and imines-enamine.Valence (valency) tautomer comprises the change that reassembles into bonding electron.

" pharmacy acceptable salt " used in the present invention refers to organic salt and the inorganic salt of compound of the present invention.Pharmacy acceptable salt is for we are known in affiliated field, as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:1-19. records.The salt that pharmaceutically acceptable nontoxic acid forms comprises, but is not limited to, and the inorganic acid salt that react formation with amino group has hydrochloride, hydrobromate, phosphoric acid salt, vitriol, perchlorate, and organic acid salt is as acetate, oxalate, maleate, tartrate, Citrate trianion, succinate, malonate, or obtain these salt by the additive method recorded on books document as ion exchange method.Other pharmacy acceptable salts comprise adipate, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, bisulfate, borate, butyrates, camphorate, camsilate, cyclopentyl propionate, digluconate, dodecyl sulfate, esilate, formate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodate, 2-hydroxy-ethanesulfonate salt, lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, pivalate, propionic salt, stearate, thiocyanate-, tosilate, undecylate, valerate, etc..The salt obtaining by suitable alkali comprises basic metal, alkaline-earth metal, ammonium and N ⁺(C _1-4alkyl) ₄salt.The present invention also intends having conceived the formed quaternary ammonium salt of compound of the group of any comprised N.Water-soluble or oil soluble or disperse product to obtain by quaternization.Basic metal or alkaline earth salt comprise sodium, lithium, and potassium, calcium, magnesium, etc.Pharmacy acceptable salt further comprises suitable, nontoxic ammonium, the amine positively charged ion that quaternary ammonium salt and gegenions form, and as halogenide, oxyhydroxide, carboxylate, hydrosulfate, phosphoric acid compound, nitric acid compound, C _1-8azochlorosulfonate acid compound and aromatic sulphonic acid compound.

" solvate " of the present invention refers to one or more solvent molecules and the formed associated complex of compound of the present invention.The solvent that forms solvate comprises, but is not limited to water, Virahol, ethanol, methyl alcohol, methyl-sulphoxide, ethyl acetate, acetic acid, monoethanolamine.Term " hydrate " refers to that solvent molecule is the formed associated complex of water.

When term " blocking group " or " Pg " refer to a substituting group and other reacted with functional groups, be commonly used to blocking-up or protect special functional.For example; " amino blocking group " refers to that a substituting group is connected to block or protect in compound amino functional with amino group; suitable amido protecting group comprises ethanoyl; trifluoroacetyl group; tertbutyloxycarbonyl (BOC), the sub-methoxycarbonyl (Fmoc) of carbobenzoxy-(Cbz) (CBZ) and 9-fluorenes.Similarly, " hydroxy-protective group " refers to that the substituting group of hydroxyl is used for blocking or protecting the functional of hydroxyl, and suitable blocking group comprises ethanoyl and silyl." carboxy protective group " refer to the substituting group of carboxyl be used for blocking-up or protection carboxyl functional, comprise-CH of general carboxyl-protecting group ₂cH ₂sO ₂ph, cyano ethyl, 2-(TMS) ethyl; 2-(TMS) ethoxyl methyl, 2-(p-toluenesulfonyl) ethyl, 2-(p-nitrophenyl alkylsulfonyl) ethyl; 2-(diphenylphosphino) ethyl, nitro-ethyl, etc.Can reference for the general description of blocking group: T W.Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; And P.J.Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

The description of compound of the present invention

The present invention relates to the pyrazolone compounds replacing, its pharmacy acceptable salt, and pharmaceutical preparation, to tyrosine kinase receptor, VEGFR especially, c-Met, the treatment of the receptor-mediated disease of Ron and/or Axl or illness has potential purposes.Particularly, the present invention relates to a kind of suc as formula the compound shown in (I):

In some embodiments, in formula (I):

Q is H, NR ^ar ^b, OR ^a,-N (R ^c) C (=O) R ^dor-N (R ^c) C (=O) OR ^a;

W is CR ⁷or N;

In other embodiment, each R in formula (I) ^a, R ^bwith Rc be H independently, C _1-4alkyl, C _1-4haloalkyl, C _3-6cycloalkyl, C _3-6cycloalkyl-C _1-2alkylidene group, C _3-6heterocyclic radical or C _3-6heterocyclic radical-C _1-2alkylidene group, works as R ^aand R ^bwhile being connected with same nitrogen-atoms, R ^a, R ^b, together with the nitrogen-atoms being connected with them, can optionally form 3-8 replacement or non-substituted former molecular heterocycle, wherein, described C _1-4alkyl, C _1-4haloalkyl, C _3-6cycloalkyl, C _3-6cycloalkyl-C _1-2alkylidene group, C _3-6heterocyclic radical, C _3-6heterocyclic radical-C _1-2alkylidene group and 3-8 former molecular heterocycle can be optionally by 1,2, and 3 or 4 are independently selected from D, F, Cl, CN, N ₃, OH, NH ₂, C _1-3haloalkyl, C _1-3alkoxyl group or C _1-3the substituting group of alkylamino replaces.

In other embodiment, in formula (I), Q is NH ₂or-N (R ^c) C (=O) R ^d.

In other embodiment, in formula (I), Q is:

Wherein, Q in formula (II), X, shown in Y and Z are defined as follows.

In some embodiments, in formula (II):

Q is NR ^ar ^b,-N (R ^c) C (=O) R ^dor-N (R ^c) C (=O) OR ^a;

In other embodiment, in formula (II), Q is NR ^ar ^bor-N (R ^c) C (=O) R ^d.

In other embodiment, in formula (II), Q is NH ₂or-N (R ^c) C (=O) R ^d.

In other embodiment, in formula (II), Q is:

In other embodiment, the present invention relates to following one of them compound or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or its prodrug, but be never limited to these compounds:

The present invention also comprises the application of compound of the present invention and pharmacy acceptable salt thereof, for the production of pharmaceutical prod treatment acute and chronic hyperproliferative disease and/or blood vessel, the disease mediating occurs, and comprises that those are described in the invention.The application of compound of the present invention in producing cancer therapy drug.Compound of the present invention alleviates by arrestin kinase activity for the production of a kind of medical supplies equally, stops, and controls or treatment disease.The present invention comprises pharmaceutical composition, and this pharmaceutical composition comprises compound and at least one pharmaceutically acceptable carrier of formula (I) or formula (II) representative, the required effective treatment consumption of combination of assistant agent or thinner.

The present invention comprises the disease that mediation occurs treatment patient vessel equally, or the method to this illness sensitivity, and the treatment significant quantity that the method comprises use formula (I) or formula (II) representative compound is treated patient.

Unless other aspects show, the steric isomer that compound of the present invention is all, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, salt and pharmaceutically acceptable prodrug all belong to scope of the present invention.

Specifically, salt is pharmacy acceptable salt.Term " pharmaceutically acceptable " comprises that material or composition must be to be applicable to chemistry or toxicologically, relevant with the Mammals that forms other components of preparation and be used for the treatment of.

The salt of compound of the present invention also comprise for the preparation of or purifying formula (I) or formula (II) shown in the salt of enantiomer of compound separation shown in the intermediate of compound or formula (I) or formula (II), but pharmacy acceptable salt not necessarily.

If compound of the present invention is alkaline, conceivable salt can prepare by any suitable method providing on document, for example, uses mineral acid, example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid etc.Or use organic acid, as acetic acid, toxilic acid, succsinic acid, amygdalic acid, fumaric acid, propanedioic acid, pyruvic acid, oxalic acid, hydroxyethanoic acid and Whitfield's ointment; Pyrans saccharic acid, as glucuronic acid and galacturonic acid; Alpha-hydroxy acid, as citric acid and tartrate; Amino acid, as aspartic acid and L-glutamic acid; Aromatic acid, as phenylformic acid and styracin; Sulfonic acid, as tosic acid, ethyl sulfonic acid, etc.

If compound of the present invention is acid, conceivable salt can prepare by suitable method, as, use mineral alkali or organic bases, as ammonia (uncle's ammonia, parahelium, tertiary ammonia), alkali metal hydroxide or alkaline earth metal hydroxides, etc.Suitable salt comprises, but is not limited to, the organic salt obtaining from amino acid, and as glycine and arginine, ammonia, as uncle's ammonia, parahelium and tertiary ammonia, and ring-type ammonia, as piperidines, morpholine and piperazine etc., and from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium obtain inorganic salt.

The composition of compound of the present invention, preparation and administration

According on the other hand, the feature of pharmaceutical composition of the present invention comprises the compound of formula (I) or formula (II), the particular compound that the present invention is listed, or the compound of embodiment 1-31, and pharmaceutically acceptable carrier, assistant agent, or vehicle.In composition of the present invention, the amount of compound can suppress the protein kinase in biological sample or patient body effectively detectablely.

There is free form in compound of the present invention, or suitable, as pharmaceutically acceptable derivates.According to the present invention, pharmaceutically acceptable derivates comprises, but be not limited to, pharmaceutically acceptable prodrug, salt, ester, the salt of ester class, or can be directly or indirectly according to other any adducts or derivatives of needing administration of patient, the described compound in other aspects of the present invention, its meta-bolites or his residue.

Picture is described in the invention, and the pharmaceutically acceptable composition of the present invention further comprises pharmaceutically acceptable carrier, assistant agent, or vehicle, these are applied as the present invention, comprise any solvent, thinner, or other liquid excipients, dispersion agent or suspension agent, tensio-active agent, isotonic agent, thickening material, emulsifying agent, sanitas, solid binder or lubricant, etc., be suitable for distinctive target formulation.As described with Publication about Document: In Remington:The Science and Practice of Pharmacy, 21st edition, 2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988-1999, Marcel Dekker, New York, the comprehensive content of document herein, show that different carriers can be applicable to preparation and their known preparation methods of pharmaceutically acceptable composition.Carrier medium and the inconsistent scope of compound of the present invention except any routine, the any bad biological effect that for example produced or the interaction producing in the mode being harmful to any other component of pharmaceutically acceptable composition, their purposes is also the scope that the present invention considers.

The material that can be used as pharmaceutically acceptable carrier comprises, but be not limited to, ion-exchanger, aluminium, aluminum stearate, Yelkin TTS, serum protein, as human serum protein, buffer substance is as phosphoric acid salt, glycine, Sorbic Acid, potassium sorbate, the partial glycerol ester mixture of saturated vegetable fatty acid, water, salt or ionogen, as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, colloid silicon, Magnesium Trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-blocking-up polymer, lanolin, sugar, as lactose, dextrose plus saccharose, starch is as W-Gum and potato starch, the derivative of Mierocrystalline cellulose and it is as Xylo-Mucine, ethyl cellulose and rhodia, natural gum powder, Fructus Hordei Germinatus, gelatin, talcum powder, auxiliary material is as cocoa butter and suppository wax, oily as peanut oil, oleum gossypii seminis, Thistle oil, sesame oil, sweet oil, Semen Maydis oil and soya-bean oil, glycols compound, as propylene glycol and polyoxyethylene glycol, ester class is as ethyl oleic acid ester and ethyl laurate, agar, buffer reagent is as magnesium hydroxide and aluminium hydroxide, Lalgine, pyrogen-free water, Deng oozing salt, Lin Ge (family name) solution, ethanol, phosphate buffer solution, and other nontoxic proper lubrication agent are as Sulfuric acid,monododecyl ester, sodium salt and Magnesium Stearate, tinting material, releasing agent, dressing dress material, sweeting agent, seasonings and spices, sanitas and antioxidant.

Composition of the present invention can be oral administration, drug administration by injection, and spraying inhalation, topical, per rectum administration, nose administration, containing taking administration, vagina administration or by the administration of the property implanted medicine box.Term as used herein " through what inject " comprises subcutaneous, vein, intramuscular, IA, in synovial membrane (chamber), intrasternal, in film, intraocular, in liver, intralesional, and the injection of encephalic or infusion techniques.Preferred composition is oral administration, to intraperitoneal administration or intravenous injection.The injection system of composition sterile of the present invention can be suspension water or oleaginous.These suspension can adopt suitable dispersion agent, wetting agent and suspension agent to manufacture by formula according to known technology.Aseptic injection can be aseptic parenteral solution or suspension, is nontoxic acceptable thinner or solvent of injection, as 1,3 butylene glycol solution.These acceptable vehicle and solvent can be water, Ringer's solution and isotonic sodium chlorrde solution.Further, aseptic nonvolatile oil can be used as solvent or suspension medium by convention.

With this end in view, the nonvolatile oil of any gentleness can be list or the DG synthesizing.Lipid acid, as the glyceride derivative of oleic acid and it can be used for the preparation of injectable, as natural pharmaceutically acceptable grease, as sweet oil or Viscotrol C, their polyoxyethylene deriv particularly.These oil solutions or suspension can comprise long-chain alcohol thinner or dispersion agent, and as carboxymethyl cellulose or similar dispersion agent, the pharmaceutical preparation that is generally used for pharmaceutically acceptable formulation comprises emulsion and suspension.The tensio-active agent that other are conventional, as Tweens, the reinforcer of spans and other emulsifying agents or bioavailability, is generally used for pharmaceutically acceptable solid, liquid, or other formulations, and can be applied to the preparation of drug target preparation.

The pharmaceutically acceptable composition of the present invention can be to carry out oral administration with any acceptable oral dosage form, comprising, but be not limited to capsule, tablet, water suspension processed or solution.About tablet, orally use, carrier generally comprises lactose and W-Gum.Lubricant, as Magnesium Stearate, is all typically added.For capsule oral administration, suitable thinner comprises lactose and dry W-Gum.When oral administration is water suspension processed, its effective constituent is comprised of emulsifying agent and suspension agent.If expect these formulations, some sweeting agent, seasonings or tinting material also can be added.

In addition, the pharmaceutically acceptable composition of the present invention can be with the form rectal administration of suppository.These can be by reagent and suitable non-perfusion adjuvant are mixed with and are formed, this adjuvant be at room temperature solid but next in the temperature of rectum be liquid, thereby in rectum, melt and discharge medicine.Such material comprises cocoa butter, beeswax, and polyethylene glycols.The pharmaceutically acceptable composition of the present invention can be topical, and particularly during local application, the therapeutic goal that relates to region or organ easily reaches, as the disease of eye, skin or lower intestinal tract.Suitable local application's preparation can prepare and be applied to these fields or organ.

Rectal suppository (seeing above content) or suitable enema can be applied to the local application of lower intestine.Local skin spot is medication so also.For local application, pharmaceutically acceptable composition can be prepared into suitable ointment by formulation method, and this ointment packets is suspended in or is dissolved in one or more carriers containing activeconstituents.The carrier compound of topical of the present invention comprises, but is not limited to mineral oil, whiteruss, white vaseline, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.In addition, pharmaceutically acceptable composition can be prepared into suitable lotion or emulsion, and this lotion or emulsion comprise activeconstituents and is suspended in or is dissolved in one or more pharmaceutically acceptable carriers.Suitable carrier comprises, but is not limited to mineral oil, Arlacel-60 (Arlacel-60), polysorbate60 (Polysorbate 60), cetyl esters wax, palmityl alcohol, 2-Standamul G, phenylcarbinol and water.

For composition eye use, pharmaceutically acceptable, can be prepared into preparation; as waited micronize suspension oozing, the Sterile Saline of pH regulator or other aqueous solution, preferably; the Sterile Saline of isotonic solution and pH regulator or other aqueous solution, can add disinfection preservative as benzalkonium chloride.In addition, for eye use, pharmaceutically acceptable composition can be prepared into ointment as vaseline oil by pharmaceutical formulation.The pharmaceutically acceptable composition of the present invention can carry out administration by gaseous solvents or the inhalation of nose.Such composition can prepare according to the known technology of pharmaceutical formulation, maybe can be prepared into salts solution, with phenylcarbinol or other suitable sanitass, absorption enhancer, fluorocarbon or other conventional solubilizing agent or dispersion agent, improve bioavailability.

The liquid dosage form of oral administration comprises, but is not limited to pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir.Except active ingredient beyond the region of objective existence, liquid dosage form can comprise known general inert diluent, for example, and water or other solvents, solubilizing agent and emulsifying agent, as ethanol, Virahol, ethyl-carbonate, ethyl acetate, phenylcarbinol, peruscabin, propylene glycol, 1,3 butylene glycol, dimethyl formamide, grease (cottonseed particularly, Semen arachidis hypogaeae, corn, microorganism, olive, castor-oil plant and sesame oil), glycerine, Tetrahydrofurfuryl Alcohol, polyoxyethylene glycol, sorbitan alcohol fatty acid ester, and their mixture.Except the thinner of inertia, oral compositions also can comprise assistant agent as wetting agent, emulsifying agent or suspension agent, sweeting agent, seasonings and perfume compound.

Injection, as aseptic parenteral solution or oleaginous suspension can adopt suitable dispersion agent, wetting agent and suspension agent to prepare by pharmaceutical formulation according to known technology.Aseptic injection can be nontoxic through acceptable thinner or solvent are made parenterally aseptic parenteral solution, suspension or emulsion, for example, and 1,3 butylene glycol solution.Acceptable vehicle and solvent can be water, Lin Ge (family name) solution, U.S.P. and isotonic sodium chlorrde solution.In addition, aseptic nonvolatile oil is by convention as solvent or suspension medium.With this end in view the nonvolatile oil of any gentleness can comprise synthetic list or DG.In addition, lipid acid can be applied to injection as oleic acid.

Injection can be aseptic, filters, or mix disinfectant with the form of aseptic solid composite as defended strainer by bacterium, and disinfectant can be dissolved in or be scattered in sterilized water or other aseptic injection media before use.In order to extend the effect of compound of the present invention, conventionally need to slow down by subcutaneous injection or intramuscularly the absorption of compound.Can realize like this problem of utilizing liquid suspension to solve crystal or amorphous material poorly water-soluble.The specific absorption of compound depends on its dissolution rate, depends on successively grain size and crystal shape.In addition, can by compound, in oils vehicle, dissolve or disperse the delay of compound injection administration to absorb.

Injection storage form is by biodegradable polymkeric substance, and as many lactic acid-polyglycolide forms, the microcapsule matrix of compound completes.The controlled release ratio of compound depends on the ratio of compound formation polymkeric substance and the character of particular polymer.Other biodegradable polymers comprise poly-(positive ester class) and gather (acid anhydrides).Injection storage form also can embed liposome or the microemulsion compatible with bodily tissue by compound and prepare.

Some of them embodiment is, the composition of rectum or vagina administration is suppository, suppository can be by mixing compound of the present invention to prepare with auxiliary material or the carrier of suitable non-perfusion, as cocoa butter, polyoxyethylene glycol, or suppository wax, they are solid but next for liquid at body temperature in room temperature, therefore in vagina or cavity of tunica vaginalis, just melt release of active compounds.

The solid dosage of oral administration comprises capsule, tablet, pill, pulvis and granula.In these formulations, active compound mixes with at least one pharmaceutically acceptable inert excipient or carrier, as Trisodium Citrate or calcium phosphate or filling agent or a) weighting agent as starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid, b) tackiness agent is as carboxymethyl cellulose, alginate, gelatin, Povidone, sucrose and gum arabic, c) wetting Agent for Printing Inks is as glycerine, d) disintegrating agent is as agar, calcium carbonate, potato starch or tapioca (flour), Lalgine, some silicate and sodium carbonate, e) retarding agent solution is as paraffin, f) absorption enhancer is as quaternary ammonium compounds, g) wetting agent is as hexadecanol and glyceryl monostearate, h) absorption agent is as white bole and bentonite, i) lubricant is as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, Sulfuric acid,monododecyl ester, sodium salt, and their mixture.As for capsule, tablet and pill, these formulations can comprise buffer reagent.

The solids composition of similar type can be that weighting agent riddles soft or hard capsule, and the auxiliary material using has lactose and high molecular polyoxyethylene glycol etc.The agent of solid dosage photo, lozenge, capsule, pill and granula can be by dressings, add shell prepares as known coating method on enteric coating and other drug preparation.They can optionally comprise opalizer, or preferably, in certain part of enteron aisle, at random, with the unique activeconstituents in the method release composition postponing.As implant compositions can comprise polymer material and wax.

Active compound can form microcapsule formulations with together with one or more vehicle described in the invention.The agent of solid dosage photo, lozenge, capsule, pill and granula can or add shell by dressing, as enteric coating, controlled release coat and other known drug formulation process.In these solid dosages, active compound can mix with at least one inert diluent, as sucrose, and lactose or starch.Such formulation also can comprise the substance except inert diluent as general application, if compressing tablet lubricant and other compression aids are as Magnesium Stearate and Microcrystalline Cellulose.As for capsule, tablet and pill, these formulations can comprise buffer reagent.They can optionally comprise tranquilizer, or preferably, in certain part of enteron aisle, with the unique activeconstituents in the method release composition postponing arbitrarily.Applicable implant compositions can comprise, but be not limited to polymer and wax.

Compound of the present invention by part or through the formulation of percutaneous drug delivery, comprise ointment, paste, emulsion, lotion, gelifying agent, pulvis, solution, sprays, inhalation, paster.Activeconstituents mixes mutually with pharmaceutically acceptable carrier and any essential sanitas or essential buffer reagent under aseptic condition.The pharmaceutical preparation of ophthalmology, ear drop and eye drops are all the scopes that the present invention considers.In addition, the present invention also considers the application of transdermal patch, and it has more advantage aspect control compound is delivered in body, and such formulation can prepare by dissolving or decentralized compound in suitable medium.Absorption enhancer can increase compound through the flow of skin, and through-rate is controlled film or compound is scattered in to polymer matrix or gelatin is controlled its speed.

Compound of the present invention is preferably prepared into dose unit type to alleviate the homogeneity of dosage and dosage by pharmaceutical formulation.Term " dosage " unit's type " refer to that herein patient obtains suitably treating the physical dispersion unit of required medicine.Yet, should be appreciated that compound of the present invention or composition total usage every day will be judged and determine according to reliable medical science scope by doctor in charge.Concrete effective dose level will depend on that many factors comprise the illness that is treated and the seriousness of illness for any one special patient or organism, the activity of particular compound, concrete composition used, patient's age, body weight, healthy state, sex and food habits, administration time, the discharge rate of route of administration and particular compound used, the time length for the treatment of, medicinal application in drug combination or with specific compound coupling, and the known factor of some other pharmaceutical field.

The change of consumption that can produce the compound of the present invention of single dosage form composition in conjunction with carrier substance is depended on and is cured mainly and special mode of administration.Some of them embodiment is that composition can be prepared into dosage at the inhibitor of 0.01-200mg/kg body weight/day by formulation method, accepts the amount of composition carry out administration by patient.

Compound of the present invention can carry out administration with only pharmaceutical agents or in conjunction with one or more other additional treatment (pharmacy) agent, wherein drug combination causes acceptable untoward reaction, and this has special meaning for high proliferative disease as the treatment of cancer.In this case, compound of the present invention can be in conjunction with known cytotoxic agent, single transduction inhibitor or other antitumor and anticancer agents, and their mixture and combination.Picture is used in the present invention, the disease that the normal drug treatment of additional treatment agent is special, known exactly " treating suitably disease "." additional treatment agent " used in the present invention comprises that chemotherapeutic agent or other antiproliferative medicines can be in conjunction with compounds for treating proliferative disease of the present invention or cancers.

Chemotherapeutic agent or other anti-proliferative drugs comprise histon deacetylase (HDAC) (HDAC) inhibitor, include, but are not limited to, SAHA, MS-275, MGO103, and the described compound of those following patents: WO2006/010264, WO03/024448, WO2004/069823, US2006/0058298, US2005/0288282, WO00/71703, WO01/38322, WO01/70675, WO03/006652, WO2004/035525, WO2005/030705, WO2005/092899, comprise with demethylation reagent, but be not limited to, 5-nitrogen-2 '-the Deoxyribose cytidine (5-aza-dC) of mixing, azacitidine (Vidaza), Decitabine (Decitabine) and with the described compound of Publication about Document: US6, 268137, US5, 578, 716, US5, 919, 772, US6, 054, 439, US6, 184, 211, US6, 020, 318, US6, 066, 625, US6, 506, 735, US6, 221, 849, US6, 953, 783, US11/393, 380.

Other embodiment is that chemotherapeutic agent or other anti-proliferative drugs can be in conjunction with compounds for treating proliferative disease of the present invention and cancers.Known chemotherapeutic agent comprises, but be not limited to, other therapies or carcinostatic agent can be combined carcinostatic agent of the present invention and be comprised surgery, (a little example is as gamma-radiation for radiotherapy, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy and system isotope therapy), endocrinotherapy, taxanes (taxol, Docetaxel etc.), the derivative of platinum, biological response modifier (Interferon, rabbit, interleukin, tumour necrosis factor (TNF), the effect of TRAIL receptor target and vehicle), overheated and psychrotherapy, dilute the reagent (as antiemetic) of any untoward reaction, chemotherapeutic agent with other approvals, include, but are not limited to, alkanisation medicine (mustargen, Chlorambucil, endoxan, melphalan, ifosfamide), metabolic antagonist (methotrexate, pemetrexed (Pemetrexed) etc.), purine antagonist and pyrimidine antagonist (6-MP (6-Mercaptopurine), 5 FU 5 fluorouracil, Cytarabile, gemcitabine (Gemcitabine)), spindle poison (vinealeucoblastine(VLB), vincristine(VCR), vinorelbine, taxol), podophyllotoxin (Etoposide, irinotecan (Irinotecan), Hycamtin (Topotecan)), microbiotic (Dx (Doxorubicin), bleomycin (Bleomycin), mitomycin (Mitomycin)), nitrosourea (carmustine (Carmustine), lomustine (Lomustine)), mineral ion (cis-platinum, carboplatin), (KSP passes through mitotic kinesin inhibitors to cell division cycle inhibitor, CENP-E and CDK inhibitor), ferment (asparaginase), hormone (tamoxifen (Tamoxifen), Leuprolide (Leuprolide), flutamide (Flutamide), megestrol (Megestrol)), imatinib mesylate (

), Zorubicin (Adriamycin), dexamethasone (Dexamethasone), and endoxan.Anti-angiogenesis (Avastin (Avastin) and other).Monoclonal antibody class (Baily wood monoclonal antibody (Belimumab,

), Brentuximab (

), Cetuximab (Cetuximab,

), WAY-CMA 676 (Gemtuzumab,

), her monoclonal antibody (Ipilimumab, ), method wood monoclonal antibody difficult to understand (Ofatumumab,

), Victibix (Panitumumab, ), Lucentis (Ranibizumab, ), Rituximab (Rituximab,

), tositumomab (Tositumomab,

), Herceptin (Trastuzumab,

)).Kinase inhibitor (imatinib (Imatinib,

), Sutent (Sunitinib,

), Xarelto (Sorafenib,

), Cetuximab (Cetuximab,

), Herceptin (Trastuzumab, ), Tarceva (Erlotinib,

)), Dasatinib (Dasatinib,

), tivozanib, dovitinib, axitinib, motesanib, pazopanib (pazopanib), Gefitinib (gefitinib,

), cediranib, brivanib, Telatinib (telatinib), masitinib, HKI-272 (neratinib), lenvatinib, ruxolitinib, linifanib, linsitinib, crizotinib, regorafenib, ponatinib, bosutinib (bosutinib), fork clip is for Buddhist nun (saracatinib), afatinib, amuvatinib, ponatinib, quizartinib, Wei Luofeini (vemurafenib ), ZD6474 (Vandetanib,

), olaparib, veliparib, iniparib, Iressa (Iressa) and other).Medicine suppress or the approach that activates cancer as mTOR, HIF(hypoxia inducible factor) approach and other.Cancer therapy more widely forum is shown in http:// www.nci.nih.gov/, the oncology list of medications of FDA approval is shown in http:// www.fda.gov/cder/cancer/druglist-rame.htm, and Merck handbook, the 18 edition .2006, all contents are all to combine reference.

Other embodiment is that compound of the present invention can be in conjunction with cytotoxin carcinostatic agent.Such carcinostatic agent can be inner the finding of the 13 edition the Merck index (2001).These carcinostatic agents comprise, but be never limited to, Asparaginase (Asparaginase), bleomycin (Bleomycin), carboplatin, carmustine (Carmustine), Chlorambucil (Chlorambucil), cis-platinum, L-ASP (Colaspase), endoxan, cytosine arabinoside (Cytarabine), Dacarbazine (Dacarbazine), dactinomycin (Dactinomycin), daunorubicin (Daunorubicin), Zorubicin (Dx), epirubicin (Epirubicin), Etoposide (Etoposide), 5-fluor-uracil, hexamethyl trimeric cyanamide, hydroxyurea, ifosfamide, irinotecan, folinic acid, lomustine, mustargen, Ismipur, mesna (Mesna), methotrexate (Methotrexate), ametycin (MitomycinC), mitoxantrone (Mitoxantrone), prednisolone (Prednisolone), prednisone (Prednisone), Procarbazine (Procarbazine), raloxifene (Raloxifen), streptozocin (Streptozocin), tamoxifen (Tamoxifen), Tioguanine (Thioguanine), Hycamtin, vinealeucoblastine(VLB), vincristine(VCR), vindesine.

Comprise with other suitable cytotoxic drugs of compound drug combination of the present invention, but be not limited to, these are applied to the compound of neoplastic disease treatment admittedly, as with described in Publication about Document: Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition, 1996, McGraw-Hill.), these carcinostatic agents comprise, but be never limited to, aminoglutethimide (Aminoglutethimide), ASP, azathioprine, 5-azacytidine, CldAdo (Cladribine), busulfan (Busulfan), stilboestrol, 2', 2'-difluoro dCDP choline, Docetaxel, red hydroxyl nonyl VITAMIN B4 (Erythrohydroxynonyladenine), Ethinylestradiol, 5 FU 5 fluorouracil deoxynucleoside, floxuridine monophosphate, fludarabine phosphate (Fludarabine phosphate), Fluoxymesterone (Fluoxymesterone), flutamide (Flutamide), Hydroxyprogesterone caproate bp 98, idarubicin (Idarubicin), Interferon, rabbit, medroxyprogesterone acetate, Magace, melphalan (Melphalan), mitotane (Mitotane), taxol, pentostatin (Pentostatin), N-phosphoric acid ethanoyl-L-Aspartic acid (PALA), Plicamycin (Plicamycin), Me-CCNU (Semustine), teniposide (Teniposide), Uniteston, phosphinothioylidynetrisaziridine (Thiotepa), trimethylammonium trimeric cyanamide, urine nucleosides and vinorelbine.

Other cytotoxin class carcinostatic agents suitable and compound combined utilization of the present invention comprise newfound cytotoxic substance, comprising, but be not limited to, oxaliplatin (Oxaliplatin), gemcitabine (Gemcitabine), capecitabine (Capecitabine), Macrolide antitumour drug and natural or synthetic derivative thereof, Temozolomide (Temozolomide) (Quinn et al., J. Clin.Oncology, 2003,21 (4), 646-651), tositumomab (tositumomab

), Trabedectin (Vidal et al., Proceedings of the American Society for Clinical Oncology, 2004,23, abstract3181), with kinesin spindle body protein inhibitor Eg5 (Wood et al., Curr.Opin.Pharmacol.2001,1,370-377).

Other embodiment is that compound of the present invention can be in conjunction with other signal transduction inhibitors.What is interesting is that signal transduction inhibitor is using EGFR family as target, as EGFR, HER-2 and HER-4 (Raymond et al., Drugs, 2000,60 (Suppl.l), 15-23; Harari et al., Oncogene, 2000,19 (53), 6102-6114) with their parts separately.Such reagent comprises, but is never limited to, and antibody therapy is as Trastuzumab (trastuzumab), Cetuximab (Erbitux), and handkerchief trastuzumab (Pertuzumab).Such therapy also comprises, but be never limited to, small molecules kinase inhibitor is as Iressa (Gefitinib), Tarceva (Erlotinib), Tykerb (Lapatinib), CANERTINIB (CI1033), AEE788 (Traxler et al., Cancer Research, 2004,64,4931-4941).

Other embodiment is, compound of the present invention in conjunction with other signal transduction inhibitor targetings in the receptor kinase of division kinases field family (VEGFR, FGFR, PDGFR, flt-3, c-kit, c-fins, etc.), and their parts separately.Such reagent comprises, but is not limited to, and antibody is as rhuMAb-VEGF (Avastin).Such reagent comprises, but be never limited to, micromolecular inhibitor is as Gleevec/Imanitib, Sprycel (Dasatinib), Tasigna/Nilotinib, Nexavar (Vandetanib), Vatalanib (PTK787/ZK222584) (Wood et al., Cancer Res.2000, 60 (8), 2178-2189), Telatinib/BAY-57-9352, BMS-690514, BMS-540215, Axitinib/AG-013736, Motesanib/AMG706, Sutent/Sunitinib/SU-11248, ZD-6474 (Hennequin et al., 92nd AACR Meeting, New Orleans, Mar.24-28, 2001, abstract 3152), KRN-951 (Taguchi et al., 95th AACR Meeting, Orlando, FIa, 2004, abstract2575), CP-547, 632 (Beebe etal., Cancer Res.2003, 63, 7301-7309), CP-673, 451 (Roberts et al., Proceedings of the American Association of Cancer Research, 2004, 45, abstract3989), CHIR-258 (Lee et al., Proceedings of the American Association of Cancer Research, 2004, 45, abstract2130), MLN-518 (Shen et al., Blood, 2003, 102, 11, abstract 476).

Other embodiment is that compound of the present invention can be in conjunction with other signal transduction inhibitors.What is interesting is that signal transduction inhibitor is using EGFR family as target, as EGFR, HER-2 and HER-4 (Raymond et al., Drugs, 2000,60 (Suppl.l), 15-23; Harari et al., Oncogene, 2000,19 (53), 6102-6114) with their parts separately.Such reagent comprises, but is never limited to, antibody therapy as Herceptin (Trastuzumab,

), Cetuximab (Cetuximab,

, her monoclonal antibody (Ipilimumab, ) and handkerchief trastuzumab (Pertuzumab).Such therapy also comprises, but is never limited to, small molecules kinase inhibitor as imatinib (Imatinib,

), Sutent (Sunitinib,

), Xarelto (Sorafenib,

), Tarceva (Erlotinib, ), Gefitinib (Gefitinib,

), Dasatinib (Dasatinib,

), AMN107 (Nilotinib,

), lapatinibditosylate (Lapatinib,

), gram Zhuo for Buddhist nun (Crizotinib,

), Ruxolitinib (

), Vemurafenib (

), Vandetanib (

), Pazopanib ), Ah method is for Buddhist nun (Afatinib), alisertib, amuvatinib, Axitinib (axitinib), SKI-606 (bosutinib), brivanib, canertinib, cabozantinib, AZD2171 (cediranib), dabrafenib, dacomitinib, , danusertib, dovitinib, foretinib, ganetespib, ibrutinib, iniparib, lenvatinib, linifanib, linsitinib, Masitinib (masitinib), momelotinib, not for husky Buddhist nun (motesanib), HKI-272 (neratinib), niraparib, oprozomib, olaparib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, fork clip is for Buddhist nun (saracatinib), saridegib, tandutinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vatalanib, veliparib, vismodegib, volasertib, BMS-540215, BMS777607, JNJ38877605, TKI258, GDC-0941(Folkes, et al., J.Med.Chem., 2008, 51, 5522), BZE235, etc..

Other embodiment is that compound of the present invention can bonding histone deacetylase inhibitors.Such reagent comprises, but be never limited to, suberoylanilide hydroxamic acid (SAHA), LAQ-824 (Ottmann et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, abstract3024), LBH-589 (Beck et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, abstract3025), MS-275 (Ryan et al., Proceedings of the American Association of Cancer Research, 2004, 45, abstract2452), FR-901228 (Piekarz et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, abstract3028) and MGCDOI03 (US6, 897, 220).

Other embodiment is that compound of the present invention can be in conjunction with other carcinostatic agents as proteasome inhibitor and m-TOR inhibitor.These comprise, but be never limited to Velcade (Bortezomib) (Mackay et al., Proceedings of the American Society for Clinical Oncology, 2004,23, Abstract3109), and CCI-779 (Wu et al., Proceedings of the American Association of Cancer Research, 2004,45, abstract3849).Compound of the present invention can also, in conjunction with other carcinostatic agents as topoisomerase enzyme inhibitor, include, but not limited to camptothecine.

Those additional treatment agent can separate administration with the composition that comprises compound of the present invention, as a part for many dosage regimens.Or those therapeutical agents can be parts for one-pack type, form single composition together with compound of the present invention.If administration is as a part for many dosage regimens, two promoting agents can transmit mutually simultaneously continuously or within for some time, thereby obtain destination agent activity.

The change that can produce the compound of one-pack type and the consumption of additional treatment agent (those compositions that comprise an additional treatment agent are as described in the invention) in conjunction with carrier substance is depended on and is cured mainly and special mode of administration.Normally, the amount of composition additional treatment of the present invention agent comprises therapeutical agent as the amount of the normal administration of unique promoting agent using being no more than composition.On the other hand, the scope of the amount of existing disclosed composition additional treatment agent is approximately the 50%-100% of existing composition normal amount, and the reagent comprising is as unique active therapeutic agent.In the composition that comprises additional treatment agent at those, additional treatment agent will play synergy with compound of the present invention.

The purposes of compound of the present invention and composition

The feature of pharmaceutical composition of the present invention comprises the compound shown in formula (I) or formula (II) or the listed compound of the present invention, and pharmaceutically acceptable carrier, assistant agent or vehicle.In composition of the present invention the amount of compound effectively detectablely arrestin kinases as VEGFR, c-Met, the activity of Ron or Axl.The compounds of this invention will be treated patient as antitumor drug or reduce VEGFR, c-Met, the deleterious effect of Ron and/or the response of Axl receptor signal.

Compound of the present invention will be applied to, but never be limited to, and by the significant quantity of compound of the present invention or composition, patient's administration be prevented or treated patient's proliferative disease.Such disease comprises cancer, metastatic carcinoma especially, atherosclerosis, and pulmonary fibrosis.

Compound of the present invention comprises cancer and metastatic carcinoma by the treatment that is applied to knurl, further includes, but are not limited to, and cancer is as bladder cancer, mammary cancer, colorectal carcinoma, kidney, liver cancer, lung cancer (comprising small cell lung cancer), esophagus cancer, carcinoma of gallbladder, ovarian cancer, carcinoma of the pancreas, cancer of the stomach, cervical cancer, thyroid carcinoma, prostate cancer, and skin carcinoma (comprising squamous cell carcinoma); Lymphsystem hematopoiesis tumour (comprises leukemia, acute lymphoblastic tumour leukemia, acute lymphoblastic leukemia, B cell lymphoma, t cell lymphoma, He Jiejin (family name) lymphoma, non-hodgkin's (family name) lymphoma, hairy cell leukemia and Burkitt lymphoma); Marrow system hematopoiesis tumour (comprising acute and chronic myelocytic leukemia, myelodysplastic syndrome, and promyelocyte leukemia); The tumour of mesenchymal cell origin (comprise fibrosarcoma and rhabdosarcoma, and other sarcomas, as soft tissue and cartilage); Maincenter peripheral nervous system knurl (comprising astrocytoma, neuroblastoma, neurospongioma, and schwannoma); With other tumours (comprising melanoma, spermocytoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicle knurl and Ka Bo Ji (family name) sarcoma).

Compound of the present invention also can be used for treating for example corneal graft rejection of eye disease, and the new vessel of eye forms, and retinal neovascularization forms and comprises that damage or metainfective new vessel form; Diabetic retinopathy; Terry's sign disease, and neovascular glaucoma; Retinal ischemia; Vitreous hemorrhage; Ulcer disease is as stomach ulcer; Pathological but non-malignant situation, as vascular tumor, comprises baby's hemangioendothelioma, the hemangiofibroma of nasopharynx and ANB; Female repro ductive system is disorderly as endometriosis.These compounds are equally also used for the treatment of oedema and the too high situation of vascular permeability.

Compound of the present invention can be for the treatment of the situation relevant to diabetes as diabetic retinopathy and microangiopathy.The situation that compound of the present invention reduces for cancer patients's volume of blood flow equally.Compound of the present invention shifts to reduce to patient tumors also beneficial effect.

Compound of the present invention, except useful to human treatment, also can be applicable to the animal of veterinary treatment pet, introduced variety and the animal on farm, comprises Mammals, rodent etc.The example of other animal comprises horse, dog and cat.At this, compound of the present invention comprises its pharmaceutically acceptable derivates.

Plural form is being applied to compound, and in the situation of salt etc., it also means single compound, salt etc.

The methods for the treatment of that comprises compound of the present invention or composition administration, further comprise the administration to patient's additional treatment agent (combination therapy), wherein additional treatment agent is selected from: chemotherapy, antiproliferative or anti-inflammatory agent, wherein additional treatment agent is applicable to treated disease, and additional treatment agent can with compound of the present invention or composition Combined Preparation, compound of the present invention or composition be as single formulation, or the compound separating or composition are as a part for multi-form.Additional treatment agent can from compound of the present invention administration simultaneously or administration when different.The latter's situation, administration can be staggered and be carried out as 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, within 1 month or 2 months, carries out.

The present invention comprises equally to expressing VEGFR, c-Met, and the cytostatic method of Ron or Axl, this method comprises compound of the present invention or composition and cells contacting, thus cell growth inhibiting.The cell of the suppressed growth of energy comprises: breast cancer cell, colorectal cancer cell, lung carcinoma cell, papillary carcinoma cell, prostate cancer cell, lymphoma cell, colon cancer cell, pancreatic cancer cell, ovarian cancer cell, cervical cancer cell, central nervous system cancer cells, human osteosarcoma cell, kidney cancer cell, hepatocellular carcinoma cells, transitional cell bladder carcinoma cell line, stomach cancer cell, head or carcinoma of neck cell, melanoma cell and leukemia cell.

The invention provides and in biological sample, suppress VEGFR, c-Met, the method for Ron or Axl kinase activity, this method comprises compound of the present invention or composition is contacted with biological sample.Term used in the present invention " biological sample " refers to the sample of live body outside, include, but not limited to cell cultures or cell extraction; The examination of living tissue material obtaining from Mammals or its extract; Blood, saliva, urine, ight soil, seminal fluid, tears, or other living tissue liquid substance and extracts thereof.Suppress kinase activity, particularly VEGFR in biological sample, c-Met, Ron and Axl kinase activity, can be used for the known multiple use of one of ordinary skill in the art.Such purposes comprises, but is never limited to hematometachysis, organ transplantation, biological sample storage and biological assay.

" significant quantity " of compound of the present invention or pharmaceutically acceptable composition or " effective dose " refer to the significant quantity of processing or alleviating the severity of illness that one or more the present invention mentions.The method according to this invention, compound and composition can be the severity that any dosage and any route of administration are come effectively for the treatment of or palliated a disease.Essential measuring accurately changes the situation according to patient, and this depends on race, the age, and patient's general condition, the severity of infection, special factor, administering mode, etc.Compound or composition can with one or more other treatment agent Combined Preparation, as discussed in the present invention.

Compound of the present invention or its pharmaceutical composition can be applied to the dressing of implantable medical device, as prosthese, and artificial valve, artificial blood vessel, stem and catheter.For example, vascular stem, has been used to overcome restenosis (after damage, vessel wall shrinks again).Yet patient uses stem or other implantable devices, and by having, clot forms or the risk of platelet activation.The pharmaceutically acceptable composition precoating device that these disadvantageous effects can comprise compound of the present invention by use stops or alleviates.

The general preparation method of suitable dressing and the dressing of implantable device is in document US6,099,562, US5,886,026 and US5, in 304,121, describe to some extent, dressing be typically biocompatible polymer material as hydrogel polymer, poly-methyl two silicon ethers, polycaprolactone, polyoxyethylene glycol, poly(lactic acid), ethane-acetic acid ethyenyl ester, and composition thereof.Dressing can optionally further be covered by suitable dressing, as fluoro Simethicone, and polysaccharidase, polyoxyethylene glycol, phospholipid, or their combination, come performance group compound to control the feature discharging.Another aspect of the present invention comprises the implantable device that uses compound coating of the present invention.Compound of the present invention also can be coated on the medical instruments in implantable, as pearl, or " medicine storage institute " is provided with polymkeric substance or other molecular mixing, therefore with the comparison of pharmaceutical aqueous solution administering mode, allow drug release to have longer time limit.

General building-up process

Usually, compound of the present invention can prepare by method described in the invention, unless there is further instruction, wherein substituent definition is suc as formula shown in (I) or formula (II).Reaction scheme below and embodiment are for further illustrating content of the present invention.

The professional in affiliated field will recognize: chemical reaction described in the invention can be used for preparing suitably many other compounds of the present invention, and is all contemplated within the scope of the present invention for the preparation of other method of compound of the present invention.For example; according to the present invention, the synthetic of the compound of those non-illustrations can successfully be completed by modifying method by those skilled in the art; as suitable protection, disturb group, by utilizing other known reagent except described in the invention, or reaction conditions is made to the modification of some routines.In addition, reaction disclosed in this invention or known reaction conditions are also applicable to the preparation of other compounds of the present invention admittedly.

The embodiments described below, are decided to be degree Celsius unless other aspects show all temperature.Reagent is bought in goods providers as Aldrich Chemical Company, and Arco Chemical Company and Alfa Chemical Company does not have during use through being further purified, unless other aspects show.General reagent is from Xi Long chemical plant, Shantou, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu chemical company limited, Tianjin good fortune chemical reagent factory in morning, Wuhan Xin Huayuan development in science and technology company limited, Qingdao ，He Haiyang Chemical Plant, Qingdao of Teng Long chemical reagent company limited buys and obtains.

Anhydrous tetrahydro furan, dioxane, toluene, ether is through sodium Metal 99.5, to reflux to be dried to obtain.Anhydrous methylene chloride and chloroform are through hydrolith, to reflux to be dried to obtain.Ethyl acetate, sherwood oil, normal hexane, N,N-dimethylacetamide and DMF are through the prior Dryly use of anhydrous sodium sulphate.

Below reaction is generally at nitrogen or argon gas direct draught or on anhydrous solvent, overlaps a drying tube (unless showing aspect other), and reaction flask is suitable soft rubber ball beyond the Great Wall all, and substrate is squeezed into by syringe.Glassware was all dried.

Chromatographic column is to use silicagel column.Silica gel (300-400 order) is purchased from Haiyang Chemical Plant, Qingdao.NMR (Nuclear Magnetic Resonance) spectrum is with CDCl ₃, DMSO-d ₆, CD ₃oD or acetone-d ₆for solvent (YippmWei unit), use TMS (0ppm) or chloroform (7.25ppm) as reference standard.When there is multiplet, by the abbreviation of using below: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, double doublet), dt (doublet of triplets, two triplets).Coupling constant, represents with hertz (Hz).

The condition of Algorithm (MS) data is: and Agilent1200Series LCMS (Zorbax SB-C18,2.1 * 30mm, 4 microns, 10min, flow velocity is 0.6mL/min, (0.1% is dissolved in H to 5%-95% ₂the formic acid of O) in (0.1% is dissolved in CH ₃the formic acid of CN)), at 210/254nm, with UV, detect, by low-response EFI pattern (ESI).

The characteristic manner of pure compound is: Agilent1100Series high speed liquid chromatography (HPLC), detects with UV at 210nm and 254nm.Post operates under 40 ° of C.

The use of brief word below runs through the present invention:

Ac ₂o diacetyl oxide

ATP adenosine triphosphate

BBr ₃boron tribromide

BINAP 2, and 2'-pair-(diphenyl phosphine)-1,1'-dinaphthalene

BSA bovine serum albumin

BOC, Boc tert-butoxycarbonyl

Ca (SO ₃cF ₃) ₂trifluoromethyl calcium sulfate

Cs ₂cO ₃cesium carbonate

CHCl ₃chloroform

CDCl ₃deuterochloroform

CH ₂cl ₂, DCM methylene dichloride

Cu copper

CuI cuprous iodide

Et ₂o ether

EtOH ethanol

DBU 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene

D ₂deuterium gas

DIBAL diisobutyl aluminium hydride

DIAD diisopropyl azodiformate

DIEA, DIPEA, iPr ₂net DIPEA

DEAD diethyl azodiformate

DMF DMF, dimethyl formamide

DMAP DMAP

DMSO dimethyl sulfoxide (DMSO)

DPPA diphenyl phosphate azide

DTT DTT

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

EDTA ethylenediamine tetraacetic acid (EDTA)

EtOAc, EA ethyl acetate

Et ₃n, TEA triethylamine

FBS foetal calf serum

G gram

H hour

HATU 2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester

HBr Hydrogen bromide

HCl hydrochloric acid

HOAc acetic acid

HOAT N-hydroxyl-7-azepine benzotriazole

HOBt I-hydroxybenzotriazole hydrate

H ₂hydrogen

H ₂o water

H ₂o ₂hydrogen peroxide

H ₃pO ₄phosphoric acid

H ₂sO ₄sulfuric acid

HNO ₃nitric acid

HCOOK potassium formiate

Fe iron

The silica-based base lithium of LiHMDS hexamethyl two

LDA lithium diisopropyl amido

MBP myelin basic protein

MCPBA metachloroperbenzoic acid

MeCN, CH ₃cN acetonitrile

MgSO ₄sal epsom

Mg ATP adenosine triphosphate magnesium

MeOH, CH ₃oH methyl alcohol

MeI methyl iodide

MOPS 3-(N-morpholino) propanesulfonic acid

ML, ml milliliter

N ₂nitrogen

NMP N-Methyl pyrrolidone

NaHCO ₃sodium bicarbonate

NaBH ₄sodium borohydride

NaBH ₃cN sodium cyanoborohydride

NaOtBu sodium tert-butoxide

NaOH sodium hydroxide

NaClO ₂textone

NaCl sodium-chlor

NaH ₂pO ₄sODIUM PHOSPHATE, MONOBASIC

NaH sodium hydride

NaI sodium iodide

Na ₂sO ₄sodium sulfate

NBS N-bromo-succinimide

Nonidet promise is lotion

NH ₃ammonia

NH ₄cl ammonia chloride

Pd/C drapes over one's shoulders palladium/carbon

Pd ₂(dba) ₃three (dibenzalacetone) two palladiums

Pd (OAc) ₂palladium

Pd (OH) ₂palladium hydroxide

Pd (PPh ₃) ₄tetrakis triphenylphosphine palladium

Pd (dppf) Cl ₂1,1 '-bis-(diphenylphosphino) ferrocene palladium chloride

P (t-Bu) ₃three (tertiary butyl) phosphine

PE sherwood oil (60-90 ° of C)

PBS phosphate buffered saline (PBS)

POCl ₃phosphorus oxychloride

PhI (OAc) ₂iodobenzene diacetate

K ₂cO ₃salt of wormwood

KOH potassium hydroxide

RT, rt, r.t. room temperature

Rt retention time

SOCl ₂sulfur oxychloride

T-BuOK potassium tert.-butoxide

TBTU O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid ester

THF tetrahydrofuran (THF)

TFA trifluoroacetic acid

TBAI tetrabutylammonium iodide

TBS TBS

TEAC bis-(tetraethyl ammonium) carbonate

Tris Tutofusin tris

Described synthetic schemes 1-4 is the typical synthetic schemes of the following embodiment compound of preparation.Each X, Y, Z, W, R ¹, R ², R ³, R ⁴, R ⁵and R ⁶there is implication of the present invention.

Synthetic schemes 1

Compound of the present invention can prepare by above-mentioned synthetic schemes 1, and concrete synthetic schemes is shown in that embodiment describes.6-aminopyridine-3-alcohol in synthetic schemes 1 ( 1) first with the pyrazolone compounds replacing ( 2) condensation reaction generation compound ( 3).Under alkaline condition, (for example, use t-potassium tert.-butoxide or sodium hydride), pyridine carboxamide ( 4) and compound ( 3) under the condition of rising temperature and polar solvent (as DMF) reaction obtain amide compound ( 5).Amide compound under oxygenant iodobenzene diacetate or NaClO effect ( 5) occur rearrangement reaction obtain aminopyridine compounds ( 6), compound ( 6) further acetylize obtain target kinase inhibitor ( 7).

Synthetic schemes 2

Compound of the present invention also can prepare by above-mentioned synthetic schemes 2, and concrete synthetic schemes is shown in that embodiment describes.In synthetic schemes 2, nitro-derivative ( 8) under shortening condition, be reduced to aniline compound ( 9).The aniline compound replacing ( 9) and 4-chloropyridine-2-amine ( 10) be dissolved in methyl-sulphoxide, and be placed under microwave condition, reaction obtain diaryl ether compound ( 11).Compound ( 11) and the pyrazolone compounds that replaces ( 2) condensation reaction generation aminopyridine compounds ( 12).Under alkaline condition, compound ( 12) can further under alkaline condition, be converted into target kinase inhibitor ( 13).

Synthetic schemes 3

Compound of the present invention also can prepare by above-mentioned synthetic schemes 3, and concrete synthetic schemes is shown in that embodiment describes.In synthetic schemes 3, aryl compound ( 14) first with the pyridine compounds replacing ( 15) under the condition of rising temperature, there is coupling reaction, obtain diaryl ether compound ( 16).Compound ( 16) and the pyrazolone compounds that replaces ( 2) generation condensation reaction generation acid amides pyridine compounds ( 17).Compound ( 17) under oxygenant iodobenzene diacetate or NaClO effect, occur rearrangement reaction obtain target kinase inhibitor ( 18).

Synthetic schemes 4

Other compounds of the present invention also can prepare by above-mentioned synthetic schemes 4, aminopyridine compounds ( 18) with acetylation reagent (as, diacetyl oxide or Acetyl Chloride 98Min.) under alkaline condition, occur acylation reaction generate target kinase inhibitor ( 19).

Embodiment

embodiment 1N-(4-((PA-4-yl) oxygen base) phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-methane amide

step 1) PAP

4-nitrophenol (7g, 50.3mmol) and HCOOK (1.8g, 21.48mmol) are dissolved in THF (210mL) and water (70mL), then add wherein Pd/C (110mg, 10%Pd content, 53%～55% water-content).Reaction solution is at 50 ° of C stirring reactions after 24 hours, vacuum concentration.Residual reaction passes through diatomite filtration after methylene dichloride (100mL) dilution for liquid.It is light orange solids (3.28g, 60%) that filtrate obtains title compound by vacuum concentration.

MS(ESI,pos.ion)m/z:110.1[M+H] ⁺。

step 2) 4-(4-amino-benzene oxygen) pyridine-2-amine

PAP (218mg, 2mmol) and 4-chloropyridine-2-amine (256mg, 2mmol) are dissolved in methyl-sulphoxide (2.5mL), then add solid sodium methylate (216mg, 4mmol).Reaction solution is placed under microwave, and 180 ° of C reactions, after 40 minutes, are cooled to room temperature, water (10mL) cancellation.Ethyl acetate for reaction mixture (10mL x3) extraction, anhydrous sodium sulfate drying vacuum concentration for the organic phase of merging.Residue is by silica gel column chromatography (DCM/CH ₃oH (v/v)=30/1) to obtain title compound be brown solid (103mg, 26%) to purifying.

MS(ESI,pos.ion)m/z:202.2[M+H] ⁺；

¹H?NMR(400MHz,CDCl ₃):δ(ppm)3.65(s,2H),4.37(s,1H),5.89-5.90(d,J=2.04Hz,1H),6.25-6.27(dd,J=2.08Hz,5.88Hz,1H),6.68-6.71(m,2H),6.86-6.89(m,2H),7.88-7.89(d,J=5.88Hz,1H)。

step 3) N-(4-((PA-4-yl) oxygen base) phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-methane amide

By 4-(4-amino-benzene oxygen) pyridine-2-amine (101mg, 0.5mmol) He 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid (118mg, 0.51mmol) be dissolved in methylene dichloride (5mL), then add EDCI (115mg, 0.6mmol) and HOAT (13.6mg, 0.1mmol).Reaction solution is at 45 ° of C stirring reactions after 3 hours, and water (20mL) cancellation is reacted.The separated final vacuum of organic phase is concentrated.Residue is by silica gel column chromatography (DCM/CH ₃oH (v/v)=20/1) to obtain title compound be light gray solid (110mg, 49.2%) to purifying.

MS(ESI,pos.ion)m/z:416.4[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)2.71(s,3H),3.36(s,3H),5.80-5.81(d,J=2.16Hz,1H),5.92(s,2H),6.12-6.14(dd,J=2.24Hz,5.8Hz,1H),7.08-7.10(m,2H),7.42-7.45(m,2H),7.51-7.53(m,1H),7.57-7.61(m,2H),7.65-7.67(m,2H),7.77-7.79(d,J=5.8Hz,1H)。

embodiment 2N-(4-((2-amino-3-chloropyridine-4-yl) oxygen base) phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-first acid amides

step 1) N-(4-hydroxy phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-methane amide

By PAP (1.09g, 10mmol) He 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid (2.37g, 10.2mmol) be dissolved in methylene dichloride (30mL), then add EDCI (2.3g, 12mmol) and HOAT (0.27g, 2mmol).Reaction mixture after 4 hours, is cooled to room temperature at 46 ° of C stirring reactions, and dilutes with ethyl acetate (10mL) and water (10mL).After reaction mixture stirring at room 1 hour, filter, obtaining title compound is white solid (1.7g, 52.5%).

MS(ESI,pos.ion)m/z:324.1[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)2.68(s,3H),3.32(s,3H),6.72(d,J=8.8Hz,2H),7.36-7.42(m,4H),7.49(t,J=7.4Hz,1H),7.57(t,J=7.6Hz,2H),9.21(s,1H),10.46(s,1H)。

step 2) 3,4-dichloro-2-pyridyl methane amide

2,2,6,6-tetramethyl piperidine (6.2mL, 37.2mmol) is dissolved in to diethyl ether (50mL), then at 0 ° of C, by syringe, in 15 minutes, adds the n-Butyl Lithium that is dissolved in hexane (2.5M, 23mL, 57.5mmol).Reaction solution stirs after 0.5 hour at 0 ° of C, is down to-78 ° of C and keeps 0.5 hour, then by syringe, in 15 minutes, to adding in reaction solution, is dissolved in 3 of ether (20mL), 4-dichloropyridine (5.00g, 33.8mmol) solution.Reaction solution stirs after 2 hours at-78 ° of C, adds isocyanic acid trimethyl silane (94% purity, 6.7mL, 50.7mmol).Reaction mixture rises to room temperature and stirs 2 hours, then uses acetic acid (6.76g, 112.6mmol) and 35mL shrend to go out.Continue to stir and spend the night, separate out white solid, filter and collect.Filtrate extracts by ethyl acetate (50mL x3), salt solution for organic phase (50mL) washing of merging, and concentrated with anhydrous sodium sulfate drying final vacuum.Gained solid is merged, and with 35mL ether, wash that to obtain title compound be faint yellow solid (2.20g, 34.0%).

MS(ESI,pos.ion)m/z:191.1[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)8.48(d,J=5.2Hz,1H),8.09(br?s,1H),7.82(s,1H),7.81(d,J=5.2Hz,1H)。

step 3) the chloro-4-of 3-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formamido-) phenoxy group) picolinamide

By N-(4-hydroxy phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-methane amide (356mg, 1.1mmol) be dissolved in methyl-sulphoxide (4mL), and be placed in a microwave bottle, then room temperature adds NaH (60% is scattered in mineral oil for 88mg, 2.2mmol).Reaction solution stirring at room adds 3,4-dichloro-2-pyridyl methane amide (191mg, 1.0mmol) after 30 minutes.Reaction mixture is placed under microwave, and 160 ° of C reactions, after 2 hours, are cooled to room temperature, dilute with water (10mL).Gained is ethyl acetate (30mL x3) extraction for mixture.Salt solution for organic phase (30mL x3) washing merging, after anhydrous sodium sulfate drying, vacuum concentration.It is faint yellow solid (140mg, 29%) that residue obtains title compound by silica gel column chromatography (DCM/MeOH (v/v)=50/1) purifying.

MS(ESI,pos.ion)m/z:478.1[M+H] ⁺;

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)2.71(s,3H),3.35(s,3H),6.82(d,J=5.4Hz,1H),7.19(d,J=9.0Hz,2H),7.44(d,J=7.5Hz,2H),7.53(m,1H),7.59(m,2H),7.74(m,3H),8.02(s,1H),8.33(d,J=5.4Hz,1H),10.84(s,1H)。

step 4) N-(4-((2-amino-3-chloropyridine-4-yl) oxygen base) phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formyl amine

By the chloro-4-of 3-, (4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formamido-) phenoxy group) picolinamide (140mg, 0.29mmol) be dissolved in the mixing solutions of ethyl acetate (2.5mL), acetonitrile (2.5mL) and water (1.3mL), then at 0 ° of C, add iodobenzene diacetate (113mg, 0.35mmol).Reaction solution stirs after 30 minutes at 0 ° of C, rises to room temperature and continues to stir 4 hours.After methylene dichloride for reaction mixture (30mL) dilution, with salt solution (20mL x3) washing, and vacuum concentration.It is faint yellow solid (37mg, 26.8%) that residue obtains title compound by silica gel column chromatography (DCM/MeOH (v/v)=50/1) purifying.

MS(ESI,pos.ion)m/z:450.1[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)2.70(s,3H),3.37(s,3H),5.95(d,J=5.6Hz,1H),6.36(s,2H),7.10(d,J=8.5Hz,2H),7.44(d,J=7.6Hz,2H),7.51(m,1H),7.59(m,2H),7.66(d,J=8.5Hz,2H),7.75(d,J=5.6Hz,1H),10.79(s,1H)。

embodiment 3N-(4-((2-amino-3-chloropyridine-4-yl) oxygen base)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole -4-methane amide

step 1) 4-(4-amino-2-fluorophenoxy)-3-chloropyridine acid amides

4-amino-2-fluorophenol (254mg, 2.0mmol) is dissolved in dimethyl formamide (5mL), adds potassium tert.-butoxide (359mg, 3.2mmol).Reaction solution, stirring at room 30 minutes, then adds 3,4-dichloro-2-pyridyl methane amide (420mg, 2.2mmol).Reaction mixture is placed under microwave, and 120 ° of C react 2 hours, are cooled to after room temperature, with the dilution of 25mL water.Gained is ethyl acetate (30mL x3) extraction for mixture, the salt solution for organic phase of merging (30mL x3) washing, and after anhydrous sodium sulfate drying, vacuum concentration.It is faint yellow solid (306mg, 54.4%) that residue obtains title compound by silica gel column chromatography (EtOAc/PE (v/v)=2/1) purifying.

MS(ESI,pos.ion)m/z:282.1[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)8.30(d,J=5.6Hz,1H),8.03(s,1H),7.73(s,1H),7.03(t,J=9.0Hz,1H),6.72(dd,J=0.8Hz,5.6Hz,1H),6.53(dd,J=2.4Hz,13.2Hz,1H),6.44(dd,J=1.8Hz,8.7Hz,1H),5.55(s,2H)。

step 2) the chloro-4-of 3-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formamido-)-2-fluorophenoxy) picolinamide

By 4-(4-amino-2-fluorophenoxy)-3-chloropyridine acid amides (306mg, 1.40mmol) He 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid (390mg, 1.68mmol) be suspended in methylene dichloride (6mL), then add EDCI (322mg, 1.68mmol) and HOAT (38mg, 0.28mmol).Reaction mixture stirs after 14.5 hours at 45 ° of C, is cooled to room temperature, and goes out with 5mL shrend.Ethyl acetate for reaction mixture (10mL x3) extraction, the salt solution for organic phase of merging (10mL x3) washing, after anhydrous sodium sulfate drying, vacuum concentration.It is faint yellow solid (647mg, 93.2%) that residue obtains title compound by silica gel column chromatography (EtOAc/PE (v/v)=1/4) purifying.

MS(ESI,pos.ion)m/z:496.1[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)10.98(s,1H),8.33(d,J=5.6Hz,1H),8.06(br?s,1H),7.99(dd,J=2.2Hz,13.2Hz,1H),7.75(br?s,1H),7.60(t,J=7.2Hz,2H),7.52(m,1H),7.45(d,J=5.6Hz,2H),7.35(m,2H),6.84(d,J=5.5Hz,1H),3.37(s,3H),2.71(s,3H)。

step 3) N-(4-((2-amino-3-chloropyridine-4-yl) oxygen base)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4- methane amide

By the chloro-4-of 3-, (4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formamido-)-2-fluorophenoxy) picolinamide (437mg, 0.88mmol) be suspended in the mixing solutions of ethyl acetate (5mL), acetonitrile (5mL) and water (2.5mL), then at 0 ° of C, add iodobenzene diacetate (341mg, 1.06mmol).Reaction solution stirs after 30 minutes at 0 ° of C, rises to room temperature, continues to stir 3 hours.Reaction mixture carries out vacuum concentration, and it is yellow solid (290mg, 70.6%) that residue obtains title compound by silica gel column chromatography (PE/EtOAc (v/v)=1/3) purifying.

MS(ESI,pos.ion)m/z:468.2[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)10.93(s,1H),7.92(d,J=12.6Hz,1H),7.74(d,J=5.7Hz,1H),7.59(t,J=7.4Hz,2H),7.52(m,1H),7.43(d,J=7.6Hz,2H),7.28(d,J=4.3Hz,2H),6.40(s,2H),5.92(d,J=5.6Hz,1H),5.86(d,J=1.9Hz,1H),3.36(s,3H),2.70(s,3H)。

embodiment 4N-(4-((2-acetylaminohydroxyphenylarsonic acid 3-chloropyridine-4-yl) oxygen base)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H- pyrazole-4-carboxamide

step 1) N-(4-((2-(N-ethanoyl kharophen)-3-chloropyridine-4-yl) oxygen base)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3- dihydro-1 h-pyrazole-4-methane amide

Compound N-(4-((2-amino-3-chloropyridine-4-yl) oxygen base)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-methane amide (0.22g, 0.47mmol), diacetyl oxide (1.3mL, 13.75mmol) and Et ₃the mixture of N (0.51g, 5.04mmol) after 24 hours, adds saturated Na at 60 ° of C stirring reactions ₂cO ₃the aqueous solution (50mL) cancellation reaction, the EtOAc for mixture obtaining (50mL x3) extraction, the salt solution for organic phase of merging (50mL x3) is washed, and uses anhydrous Na ₂sO ₄dry, concentrating under reduced pressure then, the crude product obtaining is directly used in next step reaction without being further purified.

MS(ESI,pos.ion)m/z:552.1[M+H] ⁺。

step 2) N-(4-((2-acetylaminohydroxyphenylarsonic acid 3-chloropyridine-4-yl) oxygen base)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrrole azoles-4-methane amide

By compound N-(4-((2-(N-ethanoyl kharophen)-3-chloropyridine-4-yl) oxygen base)-3-fluorophenyl)-1; 5-dimethyl-3-oxo-2-phenyl-2; 3-dihydro-1 h-pyrazole-4-methane amide (259mg, 0.47mmol) is dissolved in CH ₃in OH (20mL), then in reaction solution, add Na ₂cO ₃the water of (59.8mg, 0.56mmol) (1mL) solution.Stirring at room was reacted after 15 minutes, concentrating under reduced pressure, and the residue obtaining is through silica gel column chromatography (CH ₃oH/EtOAc (v/v)=1/50) purifying, obtaining title compound is beige solid (160mg, 66.7%).

MS(ESI,pos.ion)m/z:510.1[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)10.97(s,1H),10.27(s,1H),8.20(d,J=5.6Hz,1H),7.98(dd,J=2.3Hz,13.2Hz,1H),7.60(m,2H),7.54(m,1H),7.44(d,J=7.3Hz,2H),7.38(m,1H),7.33(dd,J=2.0Hz,9.0Hz,1H),6.67(d,J=5.4Hz,1H),3.40(s,3H),2.71(s,3H),2.08(s,3H)。

embodiment 5N-(4-((PA-4-yl) oxygen base)-2,3-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4- methane amide

step 1) 1-(benzyloxy)-2, the fluoro-4-oil of mirbane of 3-bis-

2,4,5-trifluoronitrobenzene (5.00g, 28.2mmol) and phenylcarbinol (3.07g, 28.4mmol) are dissolved in dimethyl formamide (10mL), then add salt of wormwood (5.87g, 42.5mmol).Reaction solution is in stirring at room after 72 hours, and water (35mL) dilutes, and 4 ° of C continue stirring and spend the night.Filter, the precipitation water (20mL) obtaining is washed, and then by silica gel column chromatography (EtOAc/PE (v/v)=1/20) purifying, to obtain title compound be faint yellow solid (2.15g, 28.7%).

¹H?NMR(400MHz,CDCl ₃):δ(ppm)7.90(m,1H),7.43(s,2H),7.42(s,2H),7.39(m,1H),6.86(m,1H),5.27(s,2H)。

step 2) 4-amino-2,3-difluorophenol

By 1-(benzyloxy)-2, the fluoro-4-oil of mirbane of 3-bis-(1.93g, 0.73mmol) is suspended in the mixing solutions of methyl alcohol (45mL) and tetrahydrofuran (THF) (9mL), then adds Pd/C (333mg, 6%Pd content, 53%～55% water-content).Reaction mixture is at H ₂under condition, in 32 ° of C, stir after 13 hours, by diatomite filtration, 50mL ethyl acetate washing for filter cake.The crude product obtaining after filtrate vacuum concentration is with after 30mL washed with dichloromethane, and obtaining title compound is Vandyke brown solid (0.89g, 84%).

MS(ESI,pos.ion)m/z:146.2[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)6.49(m,1H),6.38(m,1H),4.71(s,2H)。

step 3) 4-(4-amino-2,3-difluoro phenoxy group) picolinamide

By 4-amino-2,3-difluorophenol (208mg, 1.43mmol) is dissolved in dimethyl formamide (4mL), then adds potassium tert.-butoxide (257mg, 2.29mmol).Reaction solution after 30 minutes, adds 4-chloropyridine methane amide (249mg, 1.59mmol) in stirring at room.Reaction mixture is placed under microwave, and 120 ° of C reactions, after 3 hours, are cooled to room temperature, and dilute with 25mL water.Resulting ethyl acetate (30mL x3) extraction for mixture, the salt solution for organic phase of merging (30mL x3) washing, anhydrous sodium sulfate drying final vacuum is concentrated.It is orange solids (110mg, 41.5%) that residue obtains title compound by silica gel column chromatography (PE/EtOAc (v/v)=1/2) purifying.

MS(ESI,pos.ion)m/z:266.0[M+H] ⁺,283.2[M+NH ₄] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)8.42(d,J=5.6Hz,1H),7.84(br?s,1H),7.65(d,J=2.5Hz,1H),7.03(m,1H),6.77(m,1H),6.56(m,1H),5.56(br?s,1H),3.08(s,2H)。

step 4) 4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formamido-)-2,3-difluoro phenoxy group) picolinamide

By 4-, (4-amino-2,3-difluoro phenoxy group) picolinamide (180mg, 0.68mmol) He 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid (161mg, 0.69mmol) is suspended in methylene dichloride (4mL), then adds EDCI (157mg, 0.82mmol) and HOAT (19mg, 0.14mmol).Reaction mixture is at 45 ° of C stirring reactions after 12 hours, add again 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid (87mg, 0.37mmol), reaction mixture continues, after 5 hours, to be cooled to after room temperature at 45 ° of C stirring reactions, with the 5mL shrend reaction of going out, with ethyl acetate (10mL x3) extraction.Salt solution for organic phase (10mL x3) washing merging, with anhydrous sodium sulfate drying vacuum concentration.It is orange solids (108mg, 33.2%) that residue obtains title compound by silica gel column chromatography (pure EtOAc) purifying.

MS(ESI,pos.ion)m/z:480.1[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)11.2(s,1H),8.55(d,J=5.7Hz,1H),8.34(m,1H),8.16(br?s,1H),7.76(br?s,1H),7.64(m,3H),7.59(d,J=7.8Hz,1H),7.46(m,3H),7.28(m,1H),3.38(s,3H),2.71(s,3H)。

step 5) N-(4-((PA-4-yl) oxygen base)-2,3-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4- methane amide

By 4-, (4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formamido-)-2,3-difluoro phenoxy group) picolinamide (108mg, 0.22mmol) be suspended in ethyl acetate (2.5mL), acetonitrile (2.5mL) and water (1.5mL) mixing solutions, then under 0 ° of C, add iodobenzene diacetate (96mg, 0.30mmol).Reaction solution stirs after 30 minutes under 0 ° of C, rises to room temperature, continues to stir 4 hours.Reaction mixture vacuum concentration, residue is by silica gel column chromatography (EtOAc/CH ₃oH (v/v)=10/1) to obtain title compound be faint yellow solid (32mg, 32.3%) to purifying.

MS(ESI,pos.ion)m/z:452.2[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)11.12(s,1H),8.27(m,1H),7.81(d,J=5.8Hz,1H),7.60(m,2H),7.54(m,1H),7.44(d,J=7.4Hz,2H),7.16(m,1H),6.19(m,1H),5.98(s,2H),5.86(d,J=1.9Hz,1H),3.34(s,3H),2.70(s,3H)。

embodiment 6N-(4-((2-kharophen pyridin-4-yl) oxygen base)-2,3-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrrole azoles-4-methane amide

By compound N-(4-((PA-4-yl) oxygen base)-2,3-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-methane amide (135mg, 0.3mmol) is suspended in diacetyl oxide (6mL), then in reaction solution, add triethylamine (0.4mL, 2.9mmol), at 35 ° of C stirring reactions after 4 hours, suction filtration, filter cake is used PE (5mL) successively, EtOAc (5mL) and CH ₃oH (2mL) washes, and obtaining title compound is beige solid (102mg, 68.9%).

MS(ESI,pos.ion)m/z:494.1[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)11.16(s,1H),10.60(s,1H),8.31(m,1H),8.20(d,J=5.8Hz,1H),7.70(d,J=2.0Hz,1H),7.61(m,2H),7.52(m,1H),7.45(m,2H),7.22(m,1H),6.73(dd,J=2.4Hz,5.7Hz,1H),3.38(s,3H),2.71(s,3H),2.04(s,3H)。

embodiment 7N-(4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formamido-)-2,3-difluoro phenoxy group) pyridine-2- base) morpholine-4-methane amide

By compound N-(4-((PA-4-yl) oxygen base)-2,3-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-methane amide (224mg, 0.50mmol) be suspended in THF (3mL), then in reaction solution, add triethylamine (0.138mL, 0.99mmol), next dropwise add phenyl chloroformate (0.125mL, 1.00mmol), mixture is at room temperature condition stirring reaction after 2 hours again, add again morpholine (0.4mL, 5.00mmol), mixture after 36 hours, adds saturated NH at room temperature condition stirring reaction ₄the Cl aqueous solution (20mL) and CH ₂cl ₂(20mL) cancellation reaction, the mixture obtaining stirs after 10 minutes at room temperature condition, uses CH ₂cl ₂(20mL x3) extraction, the salt solution for organic phase of merging (20mL x3) is washed, and uses anhydrous Na ₂sO ₄dry, concentrating under reduced pressure then, it is orange solids (148mg, 52.5%) that the residue obtaining obtains title compound through silica gel column chromatography (EtOAc/PE (v/v)=20/1) purifying.

MS(ESI,pos.ion)m/z:565.2[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)11.16(s,1H),9.32(s,1H),8.30(m,1H),8.14(d,J=5.8Hz,1H),7.60(m,2H),7.53(m,1H),7.44(m,3H),7.20(m,1H),6.66(dd,J=2.4Hz,5.7Hz,1H),3.55(dd,J=4.4Hz,5.1Hz,4H),3.41(dd,J=4.1Hz,4.8Hz,4H),3.38(s,3H),2.71(s,3H)。

embodiment 8N-(4-((PA-4-yl) oxygen base)-2,5-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4- methane amide

step 1) 1-(benzyloxy)-2, the fluoro-4-oil of mirbane of 5-bis-

2,4,5-trifluoronitrobenzene (5.4g, 30.5mmol) and phenylcarbinol (3.2mL, 30.5mmol) mixing solutions are dissolved in to dimethyl formamide (20mL), then add salt of wormwood (6.33g, 46.1mmol).Reaction solution was stirring at room reaction 72 hours.Under 0 ° of C, add after water (60mL), gained reaction mixture continues to stir 24 hours at 4 ° of C.Solid collected by filtration, and use 30mL water washing, it is faint yellow solid (6.0g, 74%) that 45 ° of C vacuum-dryings obtain title compound.

¹H?NMR(400MHz,CDCl ₃):δ(ppm)5.22(s,2H),6.85-6.89(m,1H),7.40-7.43(m,5H),7.89-7.94(m,1H)。

step 2) 4-amino-2,5-difluorophenol

By 1-(benzyloxy)-2, the fluoro-4-oil of mirbane of 5-bis-(1.06g, 4mmol) is suspended in the mixing solutions of methyl alcohol (25mL) and tetrahydrofuran (THF) (5mL), then add Pd/C (50%Pd content, 185mg).Reaction solution is at H ₂under condition in 32 ° of C stirring reactions 10 hours.Reaction mixture is by diatomite filtration, and filtrate is carried out vacuum concentration.Gained is methylene dichloride (15mL) washing for residue, and obtaining title compound is Vandyke brown solid (500mg, 86%).

MS(ESI,pos.ion)m/z:146.2[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)4.68(s,2H),6.53-6.65(m,2H),9.06(br,1H)。

step 3) 4-(4-amino-2,5-difluoro phenoxy group) picolinamide

By 4-amino-2,5-difluorophenol (100mg, 0.64mmol) and 4-chloropyridine methane amide (110mg, 0.71mmol) are dissolved in dimethyl formamide (2mL), then add NaH (60% is scattered in mineral oil for 80mg, 1.3mmol).Reaction solution is placed under microwave, and 120 ° of C react 1.5 hours.Reaction mixture is cooled to room temperature, and water (20mL) dilution, with ethyl acetate (30mL x3) extraction.Salt solution for organic phase (80mL) washing merging, with anhydrous sodium sulfate drying, and vacuum concentration.It is brown solid (52mg, 26%) that residue obtains title compound by rapid column chromatography (EtOAc/PE (v/v)=4/1) purifying.

MS(ESI,pos.ion)m/z:266.2[M+H] ⁺。

step 4) 4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formamido-)-2,5-difluoro phenoxy group) picolinamide

By 4-, (4-amino-2,5-difluoro phenoxy group) picolinamide (200mg, 0.76mmol) He 1,5-dimethyl-3-oxo-2-phenyl-2, the mixing solutions of 3-dihydro-1 h-pyrazole-4-carboxylic acid (165mg, 0.75mmol) is dissolved in methylene dichloride (10mL), then adds EDCI (175mg, 0.93mmol) and HOAT (26mg, 0.15mmol).Reaction solution stirs 16 hours at 45 ° of C, is cooled to room temperature, and dilutes by ethyl acetate (20mL).Filter, gained solid, spends the night in 45 ° of C vacuum-dryings, and obtaining title compound is white solid (230mg, 63.7%).

MS(ESI,pos.ion)m/z:480.1[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)11.24(s,1H),8.53-8.57(m,2H),8.15(s,1H),7.75(s,1H),7.53-7.59(m,4H),7.44-7.45(m,3H),7.24-7.25(d,J=5.2Hz,1H),3.43(s,3H),2.70(s,3H)。

step 5) N-(4-((PA-4-yl) oxygen base)-2,5-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4- methane amide

By 4-, (4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formamido-)-2,5-difluoro phenoxy group) picolinamide (80mg, 0.17mmol) be dissolved in the mixing solutions of ethyl acetate (2mL), acetonitrile (2mL) and water (1mL), then add iodobenzene diacetate (70mg, 1.2mmol).Reaction solution stirs after 30 minutes under 0 ° of C, rises to room temperature, continues to stir 8 hours.Reaction mixture passes through diatomite filtration, ethyl acetate washing (30mL) for filter cake.Filtrate is carried out vacuum concentration, and gained residue is by silica gel column chromatography (DCM/CH ₃oH (v/v)=20/1) to obtain title compound be white solid (51mg, 68%) to purifying.

MS(ESI,pos.ion)m/z:452.1[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)11.18(s,1H),8.45-8.50(dd,J=7.4Hz,12.8Hz,1H),7.79-7.81(d,J=5.76Hz,1H),7.57-7.61(m,2H),7.43-7.54(m,4H),6.16-6.18(m,1H),5.96(s,2H),5.83-5.83(d,J=2.16Hz,1H),3.37(s,3H),2.70(s,3H)。

embodiment 9N-(4-((2-kharophen pyridin-4-yl) oxygen base)-2,5-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrrole azoles-4-methane amide

By compound N-(4-((PA-4-yl) oxygen base)-2,5-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-methane amide (220mg, 0.48mmol) be dissolved in diacetyl oxide (8mL), then in reaction solution, add Et ₃n (0.5mL, 1.32mmol), stirring at room was reacted after 8 hours, concentrating under reduced pressure, the residue obtaining is through silica gel column chromatography (DCM/CH ₃oH (v/v)=10/1) to obtain title compound be white solid (175mg, 73%) to purifying.

MS(ESI,pos.ion)m/z:494.0[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)11.21(s,1H),10.58(s,1H),8.49-8.54(dd,J=7.3Hz,12.8Hz,1H),8.18-8.20(d,J=5.7Hz,1H),7.67-7.68(m,1H),7.51-7.61(m,4H),7.43-7.45(m,2H),6.70-6.72(dd,J=2.4Hz,5.7Hz,1H),3.32(s,3H),2.70(s,3H),2.04(s,3H)。

embodiment 10N-(4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formamido-)-2,5-difluoro phenoxy group) pyridine-2- base) morpholine-4-methane amide

By compound N-4-((PA-4-yl) oxygen base)-2,5-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-methane amide (250mg, 0.56mmol) and Et ₃n (0.25mL, 1.68mmol) be suspended in THF (10.0mL), then in reaction solution, add phenyl chloroformate (0.25mL, 1.68mmol), after stirring at room 2 hours, add morpholine (0.35mL, 3.46mmol), mixture after 24 hours, adds NH in stirring at room reaction ₄the Cl aqueous solution (40mL) and DCM (40mL), separatory, DCM for water (40mL x3) extraction, the organic phase anhydrous Na of merging ₂sO ₄dry, concentrating under reduced pressure then, it is white solid (70mg, 21%) that the residue obtaining obtains title compound through silica gel column chromatography (EtOAc/PE (v/v)=4/1) purifying.

MS(ESI,pos.ion)m/z:565.0[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)11.20(s,1H),9.28(s,1H),8.47-8.52(dd,J=7.3Hz,12.8Hz,1H),8.12-8.14(d,J=5.7Hz,1H),7.57-7.61(m,2H),7.50-7.54(m,2H),7.39-7.45(m,3H),6.63-6.65(dd,J=2.5Hz,5.6Hz,1H),3.53-3.56(m,4H),3.40-3.41(m,4H),3.35(s,3H),2.70(s,3H)。

embodiment 11N-(4-((2-amino-3-chloropyridine-4-yl) oxygen base)-2,5-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H- pyrazole-4-carboxamide

step 1) the chloro-4-of 3-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formamido-)-2,5-difluoro phenoxy group) picolinamide

By compound N-(2, the fluoro-4-hydroxy phenyl of 5-bis-)-1, 5-dimethyl-3-oxo-2-phenyl-2, 3-dihydro-1 h-pyrazole-4-methane amide (395mg, 1.1mmol) be dissolved in DMF (5.0mL), then in reaction solution, add t-BuOK (202mg, 1.8mmol), after stirring at room 30 minutes, add 3, 4-dichloro-2-pyridyl methane amide (190mg, 1.0mmol), mixture under microwave condition at 120 ° of C stirring reactions after 2 hours, be cooled to room temperature, add water (30mL) cancellation reaction, EtOAc for mixture (50mL x3) extraction, the salt solution for organic phase (50mL x3) merging is washed, use anhydrous Na ₂sO ₄dry, concentrating under reduced pressure then, it is faint yellow solid (310mg, 60%) that the residue obtaining obtains title compound through silica gel column chromatography (MeOH/DCM (v/v)=1/30) purifying.

MS(ESI,pos.ion)m/z:514.2[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)2.70(s,3H),3.38(s,3H),6.96(d,J=5.5Hz,1H),7.45(d,J=7.0Hz,2H),7.51-7.55(m,1H),7.58-7.66(m,3H),7.75(s,1H),8.05(s,1H),8.34(d,J=5.5Hz,1H),8.53-8.58(m,1H),11.25(s,1H)。

step 2) N-(4-((2-amino-3-chloropyridine-4-yl) oxygen base)-2,5-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrrole azoles-4-methane amide

Compound 3-chlorin-4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formamido-)-2,5-difluoro phenoxy group) picolinamide (310mg, 0.60mmol) is suspended in to EtOAc (6.0mL), CH ₃cN (6.0mL) and H ₂in the mixed solvent of O (3.0mL), be cooled to 0 ° of C, then in reaction solution, add PhI (OAc) ₂(234mg, 0.72mmol), stirs after 30 minutes at 0 ° of C, rise to room temperature stirring reaction 4 hours, then concentrating under reduced pressure, it is faint yellow solid (200mg, 69%) that the residue obtaining obtains title compound through silica gel column chromatography (MeOH/DCM (v/v)=1/70) purifying.

MS(ESI,pos.ion)m/z:486.1[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)2.70(s,3H),3.38(s,3H),6.01(d,J=5.6Hz,1H),6.42(s,2H),7.43(d,J=7.2Hz,2H),7.50-7.55(m,2H),7.60(t,J=7.4Hz,2H),7.75(d,J=5.6Hz,1H),8.48-8.53(m,1H),11.19(s,1H)。

embodiment 12N-(4-((PA-4-yl) oxygen base)-2-chloro-phenyl-)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-first acid amides

step 1) 4-(4-amino-3-chlorophenoxy) picolinamide

4-amino-2-chlorophenate hydrochlorate (446mg, 2.4mmol) is dissolved in to methyl-sulphoxide (4mL), then adds NaH (60% is scattered in mineral oil for 280mg, 7.0mmol).Reaction solution after 30 minutes, adds 4-chloropyridine methane amide (345mg, 2.2mmol) in stirring at room.Reaction solution is placed under microwave, and 160 ° of C reactions, after 2 hours, are cooled to room temperature, water (20mL) dilution.Gained is ethyl acetate (20mL x3) extraction for mixture, salt solution for organic phase (20mL) washing of merging, anhydrous sodium sulfate drying, and vacuum concentration.It is orange solids (170mg, 29%) that residue obtains title compound by silica gel column chromatography (EtOAc/PE (v/v)=1/1) purifying.

MS(ESI,pos.ion)m/z:264.1[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)5.45(s,2H),6.89(d,J=8.7Hz,1H),6.92(m,1H),7.11(m,1H),7.16(d,J=2.6Hz,1H),7.34(d,J=2.6Hz,1H),7.68(s,1H),8.10(s,1H),8.47(d,J=5.6Hz,1H)。

step 2) 4-(the chloro-4-of 3-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formamido-) phenoxy group) picolinamide

By 4-(4-amino-3-chlorophenoxy) picolinamide (191mg, 0.72mmol) He 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid (168mg, 0.72mmol) be suspended in methylene dichloride (10mL), then add EDCI (166mg, 0.86mmol) and HOAT (20mg, 0.14mmol).Reaction solution stirs after 6 hours at 46 ° of C, adds 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid (32mg, 0.14mmol) and EDCI (27mg, 0.14mmol).Reaction mixture continues to stir 13 hours at 46 ° of C, is cooled to room temperature, and water (10mL) dilution.Gained is ethyl acetate (10mL x3) extraction for mixture, salt solution for organic phase (10mL) washing of merging, anhydrous sodium sulfate drying, and vacuum concentration.It is faint yellow solid (160mg, 46.5%) that residue obtains title compound by silica gel column chromatography (DCM/MeOH (v/v)=50/1) purifying.

MS(ESI,pos.ion)m/z:478.2[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)2.71(s,3H),3.37(s,3H),7.19(m,1H),7.23(m,1H),7.43(m,3H),7.50(m,2H),7.60(m,2H),7.72(s,1H),8.13(s,1H),8.52(d,J=5.6Hz,1H),8.63(d,J=9.1Hz,1H),11.19(s,1H)。

step 3) N-(4-((PA-4-yl) oxygen base)-2-chloro-phenyl-)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formyl amine

By 4-(the chloro-4-(1 of 3-, 5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formamido-) phenoxy group) picolinamide (160mg, 0.33mmol) be dissolved in ethyl acetate (3mL), acetonitrile (2.5mL) and water (1.3mL) mixing solutions, then under 0 ° of C, add iodobenzene diacetate (130mg, 0.40mmol).Reaction solution stirs after 30 minutes under 0 ° of C, rises to room temperature, continues to stir 3 hours.Reaction mixture carries out vacuum concentration, and it is light brown solid (100mg, 67%) that gained residue obtains title compound by silica gel column chromatography (DCM/MeOH (v/v)=25/1) purifying.

MS(ESI,pos.ion)m/z:450.2[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)2.71(s,3H),3.43(s,3H),5.83(d,J=2.1Hz,1H),5.95(s,2H),6.16(m,1H),7.14(m,1H),7.45(d,J=7.3Hz,2H),7.52(t,J=7.3Hz,1H),7.60(t,J=7.3Hz,2H),7.80(d,J=5.8Hz,2H),8.56(d,J=9.1Hz,1H),11.12(s,1H)。

embodiment 13N-(4-((2-kharophen pyridin-4-yl) oxygen base)-2-chloro-phenyl-)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole -4-methane amide

By compound N-(4-((PA-4-yl) oxygen base)-2-chloro-phenyl-)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-methane amide (125mg, 0.28mmol) be suspended in diacetyl oxide (6.0mL), then in reaction solution, add triethylamine (0.4mL), 35 ° of C stirring reactions are after 13 hours, suction filtration, filter cake is used sherwood oil (6mL) successively, MeOH (3mL) and ethyl acetate (6mL) are washed, obtaining title compound is light blue solid (87mg, 63%).

MS(ESI,pos.ion)m/z:492.1[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)2.04(s,3H),2.72(s,3H),3.37(s,3H),6.68(m,1H),7.18(m,1H),7.44(m,3H),7.52(t,J=7.4Hz，1H)7.60(t,J=7.5Hz,2H)，7.67(d,J=2.0Hz,1H),8.18(d,J=5.7Hz,1H),8.60(d,J=9.1Hz,1H),10.55(s,1H),11.16(s,1H)。

embodiment 14N-(4-(the chloro-4-of 3-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formamido-) phenoxy group) pyridine-2-yl) morpholine-4-methane amide

By compound N-(4-((PA-4-yl) oxygen base)-2-chloro-phenyl-)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-methane amide (125mg, 0.28mmol) and Et ₃n (0.12mL, 0.84mmol) is suspended in THF (4.0mL), then in reaction solution, adds phenyl chloroformate (0.10mL, 0.84mmol), and stirring at room reaction, after 22 hours, adds NH ₄the aqueous solution of Cl (20mL) and DCM (20mL), separatory, DCM for water (20mL x3) extraction, the organic phase anhydrous Na of merging ₂sO ₄dry, concentrating under reduced pressure, residue, after silica gel column chromatography (EtOAc/PE (v/v)=20/1) purifying, then uses methyl alcohol (4mL) to wash, and obtaining title compound is beige solid (60mg, 38%).

MS(ESI,pos.ion)m/z:563.2[M+H] ⁺；

¹H?NMR(400MHz,CDCl ₃):δ(ppm)2.80(s,3H),3.35(s,3H),3.50(t,J=4.8Hz,4H),3.73(t,J=4.8Hz,4H),6.50(m,1H),7.02(m,1H),7.14(d,J=2.7Hz,1H),7.29(s,1H),7.39(d,J=7.2Hz,2H),7.46(m,1H),7.55(m,2H),7.65(s,1H),8.02(d,J=5.9Hz,1H),8.60(d,J=9.0Hz,1H),11.03(s,1H)。

embodiment 15N-(4-((PA-4-yl) oxygen base)-2-deuterium phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-first acid amides

By compound N-(4-((PA-4-yl) oxygen base)-2-chloro-phenyl-)-1, 5-dimethyl-3-oxo-2-phenyl-2, 3-dihydro-1 h-pyrazole-4-methane amide (200mg, 0.44mmol) and triethylamine (0.10mL, 0.66mmol) be suspended in methyl alcohol (8.0mL), then in reaction solution, add Pd/C (40mg, 20%), mixture under deuterium compression ring border in 62 ° of C stirring reactions after 12 hours, be cooled to room temperature, suction filtration, filtrate decompression is concentrated, the residue obtaining is after silica gel column chromatography (MeOH/DCM (v/v)=1/30) purifying, through TLC (MeOH/DCM (v/v)=1/20) purifying, obtaining title compound is again faint yellow solid (40mg, 21%).

MS(ESI,pos.ion)m/z:417.3[M+H] ⁺；

¹H?NMR(400MHz,CDCl ₃):δ(ppm)2.80(s,3H),3.36(s,3H),4.75(s,2H),5.93(d,J=1.8Hz,1H),6.31(m,1H),7.04(d,J=8.8Hz,2H),7.37(d,J=7.4Hz,2H),7.47(m,1H),7.56(m,2H),7.68(d,J=8.8Hz,2H),10.73(s,1H)。

embodiment 16N-(5-((PA-4-yl) oxygen base) pyridine-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-first acid amides

step 1) 4-((6-aminopyridine-3-yl) oxygen base) picolinamide

6-aminopyridine-3-alcohol (220mg, 2mmol) and t-BuOK (225mg, 2.16mmol) are dissolved in to dimethyl formamide (2.5mL), then add 4-chloropyridine methane amide (315mg, 2mmol).Reaction solution heats after 5 hours under 80 ° of C, is cooled to room temperature, with ethyl acetate (50mL) and water (50mL) dilution.Organic phase vacuum concentration, gained residue is by silica gel column chromatography (DCM/CH ₃oH (v/v)=30/1) obtaining title compound is brown solid (230mg, 50%).

MS(ESI,pos.ion)m/z:231.1[M+H] ⁺；

¹H?NMR(400MHz,CDCl ₃):δ(ppm)6.09(s,2H),6.53-6.56(d,J=8.88Hz,1H),7.12-7.14(dd,J=2.64Hz,5.6Hz,1H),7.31-7.34(dd,J=2.92Hz,8.88Hz,1H),7.35-7.36(d,J=2.48Hz,1H),7.70(s,1H),7.83-7.84(d,J=2.8Hz,1H),8.11(s,1H),8.46-8.49(d,J=5.6Hz,1H)。

step 2) 4-((6-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formamido-) pyridin-3-yl) oxygen base) picolinamide

By 4-((6-aminopyridine-3-yl) oxygen base) picolinamide (230mg, 1mmol) He 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid (237mg, 1.02mmol) be suspended in methylene dichloride (5mL), then add EDCI (230mg, 1.2mmol) and HOAT (27mg, 0.2mmol).Reaction solution stirs 28 hours at 45 ° of C, is cooled to after room temperature water (10mL) and methylene dichloride (20mL) dilution.Organic phase vacuum concentration, gained residue is by purification by silica gel column chromatography (DCM/CH ₃oH (v/v)=40/1) obtaining title compound is light gray solid (111mg, 25%).

MS(ESI,pos.ion)m/z:445.1[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)2.72(s,3H),3.33(s,3H),7.20-7.22(dd,J=2.64Hz,5.64Hz,1H),7.43-7.46(m,3H),7.52-7.54(m,1H),7.58-7.62(m,2H),7.72(s,3H),7.75-7.78(dd,J=2.88Hz,8.96Hz,1H),8.13(s,1H),8.27-8.28(d,J=2.68Hz,1H),8.34-8.36(d,J=9.08Hz,1H),8.52-8.54(d,J=5.6Hz,1H)。

step 3) N-(5-((PA-4-yl) oxygen base) pyridine-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formyl amine

By 4-, ((6-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formamido-) pyridin-3-yl) oxygen base) picolinamide (111mg, 0.25mmol) be dissolved in the mixing solutions of ethyl acetate (2mL), acetonitrile (2mL) and water (1mL), then add iodobenzene diacetate (97mg, 0.3mmol).Reaction solution stirs after 30 minutes at 0 ° of C, rises to room temperature, continues to stir 12 hours.Reaction mixture vacuum concentration, gained residue is by silica gel column chromatography (DCM/CH ₃oH (v/v)=40/1) to obtain title compound be oldlace solid (85mg, 81.7%) to purifying.

MS(ESI,pos.ion)m/z:417.2[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)2.71(s,3H),3.38(s,3H),5.83(s,1H),5.98(s,2H),6.17(s,1H),7.08-7.10(m,2H),7.42-7.81(m,6H),7.80-7.81(d,J=5.8Hz,1H),8.17(s,1H),8.29-8.31(d,J=8.56Hz,1H),11.19(s,1H)。

embodiment 17N-(5-((2-kharophen pyridin-4-yl) oxygen base) pyridine-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole -4-methane amide

By compound N-(5-((PA-4-yl) oxygen base) pyridine-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-methane amide (300mg, 0.72mmol) is dissolved in diacetyl oxide (4mL), then in reaction solution, adds Et ₃n (400mg, 4mmol), 30 ° of C stirring reactions are after 12 hours, concentrating under reduced pressure, residue is successively analysed (DCM/CH through silica gel ₃oH (v/v)=40/1) to obtain title compound be light yellow solid (197mg, 60.1%) to purifying.

MS(ESI,pos.ion)m/z:459.0[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)11.23(s,1H),10.57(s,1H),8.34-8.31(d,J=9.1Hz,1H),8.22-8.21(d,J=2.8Hz,1H),8.20-8.19(d,J=5.7Hz,1H),7.72-7.69(dd,J=9.0Hz,2.8Hz,1H),7.67-7.67(d,J=1.6Hz,1H),7.62-7.59(m,2H),7.54-7.51(m,1H),7.46(s,1H),7.44(s,1H),3.37(s,3H),2.72(s,3H),2.05(s,3H)。

embodiment 18N-(4-((6-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formamido-) pyridin-3-yl) oxygen base) pyridine-2- base) morpholine-4-methane amide

By compound N-(5-((PA-4-yl) oxygen base) pyridine-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-methane amide (171mg, 0.41mmol) and Et ₃n (0.17mL, 1.23mmol) is suspended in THF (8.0mL), then in reaction solution, adds phenyl chloroformate (0.15mL, 1.23mmol), stirring at room, after 2 hours, adds morpholine (0.21mL, 2.46mmol), stirring at room reaction, after 24 hours, adds NH ₄the Cl aqueous solution (40mL) and DCM (40mL), separatory, DCM for water (40mL x3) extraction, the organic phase anhydrous Na of merging ₂sO ₄dry, then concentrating under reduced pressure, the residue obtaining is after silica gel column chromatography (MeOH/EtOAc (v/v)=1/50) purifying, then to use TLC (MeOH/EtOAc (v/v)=1/30) purifying to obtain title compound be faint yellow solid (40mg, 18%).

MS(ESI,pos.ion)m/z:530.2[M+H] ⁺；

¹H?NMR(400MHz,CDCl ₃):δ(ppm)2.79(s,3H),3.36(s,3H),3.50(t,J=4.8Hz,4H),3.72(t,J=4.8Hz,4H),6.49-6.51(m,1H),7.36-7.38(m,3H),7.42-7.46(m,2H),7.52-7.56(m,2H),7.66(s,1H),8.03(d,J=5.6Hz,1H),8.14(d,J=2.7Hz,1H),8.34(d,J=9.0Hz,1H),11.19(s,1H)。

embodiment 19N-(5-((2-amino-3-chloropyridine-4-yl) oxygen base) pyridine-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole -4-methane amide

step 1) N-(5-pyridone-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-methane amide

By 6-aminopyridine-3-alcohol (330mg, 3mmol) He 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid (710mg, 306mmol) be suspended in dimethyl formamide (10mL), then add EDCI (690mg, 3.6mmol) and HOAT (80mg, 0.6mmol).Reaction solution stirs 4 hours at 60 ° of C, is cooled to room temperature, and water (100mL) and ethyl acetate (2mL) dilution.Reaction mixture is cooled to 0 ° of C and stirs and spend the night.Filter, collect solid, obtaining title compound is light brown solid (680mg, 70%).

MS(ESI,pos.ion)m/z:325.1[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)2.50(s,3H),3.33(s,3H),7.18-7.20(dd,J=2.3Hz,8.8Hz,1H),7.40-7.42(d,J=7.5Hz,2H),7.48-7.52(m,1H),7.56-7.60(m,2H),7.81-7.82(d,J=2.2Hz,1H),7.95(s,1H),8.04-8.06(d,J=8.8Hz,1H),9.61(s,1H),10.85(s,1H)。

step 2) the chloro-4-of 3-((6-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formamido-) pyridin-3-yl) oxygen base) picolinamide

6-aminopyridine-3-alcohol (324mg, 1mmol) and t-BuOK (135mg, 1.2mmol) are dissolved in to dimethyl formamide (2mL), then add 3,4-dichloro-2-pyridyl methane amide (191mg, 1mmol).Reaction solution, 80 ° of C heating 15 hours, is cooled to after room temperature, with ethyl acetate (1mL) and water (20mL) dilution.Reaction mixture stirs and spends the night, and filters, and collects solid, and obtaining title compound is brown solid (290mg, 60.5%).

MS(ESI,pos.ion)m/z:479.2[M+H] ⁺；

¹H?NMR(400MHz,CDCl ₃):δ(ppm)2.72(s,3H),3.35(s,3H),6.91-6.92(d,J=5.5Hz,1H),6.09(s,2H),7.43-7.45(m,2H),7.50-7.54(m,1H),7.58-7.62(m,2H),7.73-7.76(m,2H),8.03(s,1H),8.26-8.27(d,J=2.7Hz,1H),8.33-8.36(m,2H),11.26(s,1H)。

step 3) N-(5-((2-amino-3-chloropyridine-4-yl) oxygen base) pyridine-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4- methane amide

By the chloro-4-of 3-, ((6-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formamido-) pyridin-3-yl) oxygen base) picolinamide (290mg, 0.6mmol) be dissolved in ethyl acetate (4mL), acetonitrile (4mL) and water (2mL) mixing solutions, then add iodobenzene diacetate (234mg, 0.72mmol).Reaction solution stirs after 30 minutes under 0 ° of C, rises to room temperature, continues to stir 12 hours.Reaction mixture is by diatomite filtration, and methylene dichloride for filter cake (30mL) washs.After filtrate water (20mL) washing, vacuum concentration.Residue is by silica gel column chromatography (DCM/CH ₃oH (v/v)=50/1) to obtain title compound be oldlace solid (120mg, 44.7%) to purifying.

MS(ESI,pos.ion)m/z:451.1[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)2.71(s,3H),3.36(s,3H),5.99-6.01(d,J=5.6Hz,1H),6.42(s,2H),7.42-7.44(m,2H),7.51-7.53(m,1H),7.57-7.61(m,2H),7.63-7.66(dd,J=2.9Hz,9.0Hz,1H),7.76-7.77(d,J=5.6Hz,1H),8.18-8.19(d,J=2.8Hz,1H),8.28-8.30(d,J=9.1Hz,1H),11.21(s,1H)。

embodiment 20N-(5-((2-acetylaminohydroxyphenylarsonic acid 3-chloropyridine-4-yl) oxygen base) pyridine-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H- pyrazole-4-carboxamide

By N-(5-((2-amino-3-chloropyridine-4-yl) oxygen base) pyridine-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-methane amide (60mg, 0.13mmol) and triethylamine (26.3mg, 0.26mmol) be dissolved in the mixed solvent of methyl alcohol (1mL) and tetrahydrofuran (THF) (2mL), then add Acetyl Chloride 98Min. (20.3mg, 0.26mmol).Reaction solution at room temperature stirred after 3 hours, vacuum concentration.After residue is processed with sodium carbonate solution, stirring at room 5 minutes, and vacuum concentration.Gained residue is by silica gel column chromatography (DCM/CH ₃oH (v/v)=50/1) to obtain title compound be oldlace solid (15mg, 22.7%) to purifying.

MS(ESI,pos.ion)m/z:493.1[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)2.08(s,3H),2.71(s,3H),3.35(s,3H),6.72-6.74(d,J=5.6Hz,1H),7.43-7.45(m,2H),7.50-7.54(m,1H),7.58-7.62(m,2H),7.63-7.66(dd,J=2.9Hz,9.0Hz,1H),8.19-8.20(d,J=5.6Hz,1H),8.26-8.27(d,J=2.8Hz,1H),8.33-8.35(d,J=9.1Hz,1H),10.24(s,1H),11.25(s,1H)。

embodiment 21N-(4-((2-acetylaminohydroxyphenylarsonic acid 3-chloropyridine-4-yl) oxygen base) phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole -4-methane amide

By the chloro-4-of 3-, (4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formamido-) phenoxy group) picolinamide (124mg, 0.28mmol) is dissolved in diacetyl oxide (8.0mL), then adds triethylamine (0.4mL).Stirring reaction is after 26 hours under 40 ° of C for reaction solution, and saturated solution (60mL x3) washing by reaction mixture with sodium carbonate, uses methylene dichloride (60mL x3) extraction afterwards.The organic phase anhydrous sodium sulfate drying merging, vacuum concentration.It is lightpink solid (80mg, 59%) that residue obtains title compound by silica gel column chromatography (DCM/MeOH (v/v)=40/1) purifying.

MS(ESI,pos.ion)m/z:492.2[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)2.07(s,3H),2.70(s,3H),3.37(s,3H),6.64(d,J=5.6Hz,1H),7.20(d,J=9.0Hz,2H),7.44(d,J=7.2Hz,2H),7.51(m,1H),7.59(m,2H),7.72(d,J=9.0Hz,2H),8.18(d,J=5.6Hz,1H),10.21(s,1H),10.83(s,1H)。

embodiment 22N-(4-((PA-4-yl) oxygen base)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-first acid amides

step 1) N-(the fluoro-4-hydroxy phenyl of 3-)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-methane amide

By 4-amino-2-fluorophenol (2.54g, 20mmol) He 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid (4.74g, 20.4mmol) be suspended in DCM (60mL), and add wherein EDCI (4.6g, 24mmol) and HOAT (0.54g, 4mmol).Reaction solution stirs after 12 hours at 45 ° of C, is cooled to room temperature, and adds water (10mL) cancellation.Mixture continue to stir 4 hours, filters, and collects solid, gained for solid DCM (20mL x3) wash, and in 60 ° of C vacuum-dryings 12 hours, obtaining title compound was khaki color solid (6.37g, 93.4%).

MS(ESI,pos.ion)m/z:342.1[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)10.59(s,1H),9.58(s,1H),7.64(dd,J=2.4Hz,13.5Hz,1H),7.60(m,2H),7.50(m,1H),7.42(m,2H),6.97(m,1H),6.88(dd,J=9.6Hz,8.8Hz,1H),3.34(s,3H),2.70(s,3H)。

step 2) 4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formamido-)-2-fluorophenoxy) picolinamide

By N-(the fluoro-4-hydroxy phenyl of 3-)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-methane amide (2.2g, 6.4mmol) and 4-chloropyridine methane amide (1g, 6.39mmol) are dissolved in DMSO (12mL), and add wherein NaH (615mg, 12.3mmol, 50% is scattered in mineral oil), reaction solution stirs after 20 hours at 160 ° of C, be cooled to room temperature, add water (70mL) cancellation.By EtOAc for mixture (100mL x3) extraction, the salt solution for organic phase (100mL) of merging is washed, anhydrous Na ₂sO ₄dry, and concentrating under reduced pressure.Gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=1/4) purifying, and obtaining title compound is white solid (0.85g, 29%).

MS(ESI,pos.ion)m/z:462.1[M+H] ⁺；

¹H?NMR(400MHz,CDCl ₃):δ(ppm)10.87(s,1H),8.40-8.41(d,J=5.6Hz,1H),7.88-7.92(dd,J=2.4Hz,12.6Hz,1H),7.82-7.83(d,J=3.9Hz,1H),7.71-7.71(d,J=2.5Hz,1H),7.54-7.58(m,2H),7.46-7.49(m,1H),7.35-7.37(d,J=8.6Hz,2H),7.07-7.11(m,1H),6.96-6.98(dd,J=2.5Hz,5.6Hz,1H),5.56(s,1H),3.37(s,3H),2.79(s,3H)。

step 3) N-(4-((PA-4-yl) oxygen base)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formyl amine

By 4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formamido-)-2-fluorophenoxy) picolinamide (0.4g, 0.86mmol) and PhI (OAc) ₂(419mg, 1.5mmol) is dissolved in EtOAc (8mL), MeCN (8mL) and H ₂in the mixed solution of O (4mL), be cooled to 0 ° of C, stir 30 minutes.Reaction solution is returned to room temperature, continue to stir 8 hours.Mixture NaHCO ₃the aqueous solution (60mL) dilution, and extract with EtOAc (100mL x3).The salt solution for organic phase (100mL) merging is washed, anhydrous Na ₂sO ₄dry, and concentrating under reduced pressure, gained residue is through silica gel column chromatography (DCM/MeOH (v/v)=10/1) purifying, and obtaining title compound is white solid (0.21g, 56%).

MS(ESI,pos.ion)m/z:434.2[M+H] ⁺；

¹H?NMR(400MHz,CDCl ₃):δ(ppm)10.83(s,1H),7.91-7.92(d,J=5.9Hz,1H),7.83-7.86(dd,J=2.4Hz,10.1Hz,1H),7.56-7.58(m,2H),7.46-7.52(d,J=5.9Hz,2H),7.35-7.37(d,J=8.6Hz,2H),7.04-7.09(m,1H),6.29-6.31(m,1H),5.92-5.93(d,J=2.1Hz,1H),4.45(s,2H),3.37(s,3H),2.79(s,3H)。

embodiment 23N-(4-((2-kharophen pyridin-4-yl) oxygen base)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole -4-methane amide

By N-(4-((PA-4-yl) oxygen base)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-methane amide (90mg, 0.21mmol) is dissolved in diacetyl oxide (6mL), adds wherein Et ₃n (0.3mL).After reaction solution stirring at room 8 hours, concentrating under reduced pressure.Gained residue is through silica gel column chromatography (DCM/MeOH (v/v)=10/1) purifying, and obtaining title compound is white solid (53mg, 49%).

MS(ESI,pos.ion)m/z:476.1[M+H] ⁺；

¹H?NMR(400MHz,CDCl ₃):δ(ppm)10.83(s,1H),8.15(s,1H),8.05-8.07(d,J=5.8Hz,1H),7.84-7.89(m,2H),7.54-7.58(m,2H),7.47-7.49(d,J=7.3Hz,1H),7.35-7.37(d,J=7.4Hz,2H),7.25(s,1H),7.06-7.11(m,1H),6.53-6.54(dd,J=2.2Hz,5.7Hz,1H),3.36(s,3H),2.79(s,3H),2.16(s,3H)。

embodiment 24N-(4-((PA-4-yl) oxygen base) the chloro-5-fluorophenyl of-2-)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole -4-methane amide

step 1) 1-is chloro-4, the fluoro-2-oil of mirbane of 5-bis-

To adding in reaction flask 4-chloro-1,2-difluorobenzene (8.97g, 60.4mmol), is cooled to 0 ° of C, and then adds successively 98% dense H ₂sO ₄(16.1mL, 302mmol) and 65% dense HNO ₃(5.0mL, 66.4mmol),, pours in frozen water after 5 hours in stirring at room reaction, the EtOAc for mixture obtaining (200mL x2) extraction, and the organic phase of merging is used saturated NaHCO successively ₃the aqueous solution (200mL x2) and salt solution (200mL) are washed, and use anhydrous Na ₂sO ₄dry, it is yellow liquid (11.31g, 96.7%) that concentrating under reduced pressure obtains title compound.

¹H?NMR(400MHz,CDCl ₃):δ(ppm)7.41-7.45(m,1H),7.86-7.90(m,1H)。

step 2) the chloro-2-fluoro-4-nitrophenol of 5-potassium

Compound 1-is chloro-4, the fluoro-2-oil of mirbane of 5-bis-(5.12g, 26.5mmol) and 15% KOH (19.9g, 0.35mol) the mixture stirring and refluxing of the aqueous solution, after 3 hours, is cooled to room temperature, suction filtration, obtaining title compound is yellow solid (5.67g, 93.3%).

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)6.20(d,J=13.2Hz,1H),7.70(d,J=8.6Hz,1H)。

step 3) the chloro-2-fluorophenol of 4-amino-5-

Compound 5-chloro-2-fluoro-4-nitrophenol potassium (1.0g, 4.35mmol) is dissolved in to EtOH (22mL, 95%) and H ₂in the mixed solvent of O (8mL), then in reaction solution, add iron powder (0.97g, 17.4mmol) and NH ₄cl (1.86g, 34.8mmol), stirring at room reaction is after 10 hours, add methyl alcohol (25mL) and ethyl acetate (25mL) dilute reaction solution, suction filtration, filtrate decompression is concentrated, ethyl acetate for residue (40mL) dilution, washes with salt solution (25mL), uses anhydrous Na ₂sO ₄dry, it is pale solid (0.6g, 85.3%) that concentrating under reduced pressure obtains title compound.

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)4.90(s,2H),6.60(d,J=12.9Hz,1H),6.79(d,J=8.8Hz,1H),9.11(s,1H)。

step 4) N-(the fluoro-4-hydroxy phenyl of the chloro-5-of 2-)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-methane amide

By the chloro-2-fluorophenol of compound 4-amino-5-(0.97g, 6mmol) with 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid (1.42g, 6.12mmol) be suspended in DMF (20mL), then in reaction solution, add EDCI (0.38mg, 7.2mmol) and HOAT (0.16g, 1.2mmol), be heated to 80 ° of C, after stirring reaction 24 hours, be cooled to 0 ° of C, then add H ₂o (200mL) and EtOAc (2mL) dilute reaction solution, suction filtration, vacuum-drying, obtaining title compound is light brown solid (1.2g, 53.2%).

MS(ESI,pos.ion)m/z:376.1[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)2.68(s,3H),3.34(s,3H),7.03(d,J=8.8Hz,1H),7.41-7.43(m,2H),7.48-7.52(m,1H),7.56-7.60(m,2H),8.31(d,J=13.8Hz,1H),10.08(s,1H),10.95(s,1H)。

step 5) 4-(the chloro-4-of 5-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formamido-)-2-fluorophenoxy) picolinamide

By compound N-(fluoro-4-hydroxy phenyl of the chloro-5-of 2-)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-methane amide (751.6mg, 2mmol) and t-BuOK (224.4mg, 2mmol) be suspended in DMF (4mL), then to 4-chloropyridine methane amide (313.2mg in reaction solution, 2mmol), be heated to 120 ° of C stirring reaction 15 hours, be then cooled to room temperature, add H ₂o (40mL), the mixture stirred overnight at room temperature obtaining, suction filtration, filter cake is through silica gel column chromatography (DCM/CH ₃oH (v/v)=50/1) to obtain title compound be light yellow solid (290mg, 60.5%) to purifying.

MS(ESI,pos.ion)m/z:496.2[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)11.37(s,1H),8.69-8.66(d,J=13.4Hz,1H),8.55-8.54(d,J=5.6Hz,1H),8.15(s,1H),7.78-7.75(m,2H),7.62-7.58(m,2H),7.55-7.51(m,1H),7.46-7.43(m,3H),7.26-7.24(dd,J=5.6Hz,2.6Hz,1H),3.38(s,3H),2.72(s,3H)。

step 6) N-(4-((PA-4-yl) oxygen base) the chloro-5-fluorophenyl of-2-)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole -4-methane amide

Compound 4-(the chloro-4-of 5-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formamido-)-2-fluorophenoxy) picolinamide (297.6mg, 0.6mmol) is suspended in to EtOAc (4mL), CH ₃cN (4mL) and H ₂in the mixed solvent of O (2mL), be cooled to 0 ° of C, add PhI (OAc) ₂(97mg, 0.3mmol), after half an hour, rises to room temperature stirring reaction 12 hours in 0 ° of C stirring reaction, concentrating under reduced pressure then, and the residue obtaining is successively analysed (DCM/CH through silica gel ₃oH (v/v)=20/1) purifying obtains title compound oldlace solid (220mg, 78.3%).

MS(ESI,pos.ion)m/z:468.0[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)11.32(s,1H),8.63-8.60(d,J=13.4Hz,1H),7.82-7.81(d,J=5.9Hz,1H),7.64-7.62(m,3H),7.55-7.54(m,1H),7.46-7.44(m,2H),6.22-6.20(dd,J=5.8Hz,2.2Hz,1H),6.05(s,2H),5.85-5.84(d,J=2.0Hz,1H),3.33(s,3H),2.71(s,3H)。

embodiment 25N-(4-((2-kharophen pyridin-4-yl) oxygen base) the chloro-5-fluorophenyl of-2-)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H- pyrazole-4-carboxamide

By compound N-(4-((PA-4-yl) oxygen base) chloro-5-fluorophenyl of-2-)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-methane amide (200mg, 0.43mmol) be dissolved in diacetyl oxide (4mL), then in reaction solution, add Et ₃n (400mg, 2.6mmol), at 30 ° of C stirring reactions after 12 hours, concentrating under reduced pressure, the residue obtaining is through silica gel column chromatography (DCM/CH ₃oH (v/v)=40/1) to obtain title compound be light yellow solid (110mg, 50.5%) to purifying.

MS(ESI,pos.ion)m/z:510.2[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)12.15(s,1H),11.38(s,1H),9.45-9.42(d,J=13.4Hz,1H),9.00-8.98(d,J=5.7Hz,1H),8.50-8.48(m,2H),8.42-8.38(m,2H),8.34-8.31(m,1H),8.26-8.24(m,2H),7.52-7.50(dd,J=5.7Hz,1.3Hz,1H),4.14(s,3H),3.51(s,3H),2.84(s,3H)。

embodiment 26N-(4-(the chloro-4-of 5-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formamido-)-2-fluorophenoxy) pyridine -2-yl) morpholine-4-methane amide

By compound N-(4-((PA-4-yl) oxygen base) chloro-5-fluorophenyl of-2-)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-methane amide (234mg, 0.5mmol) and Et ₃n (0.1mg, 1mmol) is suspended in THF (5mL), then in reaction solution, adds phenyl chloroformate (0.16mg, 1mmol), stirring at room reaction, after 2 hours, adds morpholine (0.44mL, 5mmol), room temperature continued stirring reaction after 24 hours, added NH ₄cl (30mL) and DCM (30mL), separatory, DCM for organic phase (30mL x3) extraction, the organic phase anhydrous Na of merging ₂sO ₄dry, concentrating under reduced pressure then, the residue obtaining is through silica gel column chromatography (DCM/CH ₃oH (v/v)=50/1) to obtain title compound be white solid (145mg, 49.9%) to purifying.

MS(ESI,pos.ion)m/z:581.2[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)11.35(s,1H),9.30(s,1H),8.65-8.61(d,J=13.4Hz,1H),8.14-8.13(d,J=5.7Hz,1H),7.69-7.67(d,J=8.1Hz,1H),7.62-7.58(m,2H),7.54-7.51(m,1H),7.45-7.40(m,3H),6.65-6.63(dd,J=5.7Hz,2.2Hz,1H),3.55-3.53(m,4H),3.43-3.36(m,7H),2.71(s,3H)。

embodiment 27N-(4-((PA-4-yl) oxygen base)-3-chloro-phenyl-)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-first acid amides

step 1) N-(3-chloro-4-hydroxyl phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-methane amide

By compound 4-amino-2-chlorophenol (4.0g, 28.00mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid (7.4g, 30.11mmol) be suspended in DCM (70mL), then in reaction solution, add EDCI (6.65g, 30.11mmol) and HOAT (0.76g, 5.68mmol), be heated to 45 ° of C stirring reaction 20 hours, then be cooled to room temperature, suction filtration, DCM for filter cake (20mL x3) washes, at vacuum drying oven in 50 ° of C dried overnight, obtaining title compound is gray solid (7.1g, 72.1%).MS(ESI,pos.ion)m/z:358.1[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)10.56(s,1H),9.92(s,1H),7.59(m,2H),7.50(m,1H),7.42(m,2H),7.83(dd,J=2.6Hz,8.7Hz,1H),6.90(d,J=8.7Hz,1H),6.88(dd,J=9.6Hz,8.8Hz,1H),3.33(s,3H),2.68(s,3H)。

step 2) 4-(the chloro-4-of 2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formamido-) phenoxy group) picolinamide

By compound N-(3-chloro-4-hydroxyl phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-methane amide (1.074g, 3.0mmol) be suspended in DMF (12mL), then in reaction solution, add t-BuOK (539mg, 4.8mmol), after stirring at room 30 minutes, add 4-chloropyridine acid amides (517mg, 3.3mmol), be warming up to 120 ° of C stirring reaction 36 hours, then be cooled to room temperature, add water (50mL) cancellation reaction, EtOAc for mixture (50mL x3) extraction, the salt solution for organic phase (50mL x3) merging is washed, and uses anhydrous Na ₂sO ₄dry, concentrating under reduced pressure then, it is white solid (580mg, 40.4%) that the residue obtaining obtains title compound through silica gel column chromatography (EtOAc/PE (v/v)=3/1) purifying.

MS(ESI,pos.ion)m/z:478.0[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)10.95(s,1H),8.53(d,J=5.6Hz,1H),8.16(d,J=2.4Hz,1H),8.13(br?s,1H),7.72(br?s,1H),7.60(m,2H),7.51(m,2H),7.44(d,J=7.3Hz,2H),7.38(d,J=8.8Hz,1H),7.32(d,J=2.6Hz,1H),7.17(dd,J=2.6Hz,5.6Hz,1H),3.16(d,J=5.2Hz,3H),2.70(s,3H)。

step 3) N-(4-((PA-4-yl) oxygen base)-3-chloro-phenyl-)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formyl amine

Compound 4-(the chloro-4-of 2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formamido-) phenoxy group) picolinamide (540mg, 1.13mmol) is suspended in to EtOAc (6mL), CH ₃cN (6mL) and H ₂in the mixed solvent of O (3mL), be cooled to 0 ° of C, then in reaction solution, add PhI (OAc) ₂(438mg, 1.36mmol), at 0 ° of C, stir after 30 minutes, rise to room temperature stirring reaction 4.5 hours, then concentrating under reduced pressure, it is beige solid (265mg, 52.2%) that the residue obtaining obtains title compound through silica gel column chromatography (EtOAc/PE (v/v)=6/1) purifying.

MS(ESI,pos.ion)m/z:450.2[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)10.89(s,1H),8.10(d,J=2.4Hz,1H),7.79(d,J=5.8Hz,1H),7.59(m,2H),7.52(m,1H),7.43(d,J=5.7Hz,3H),7.25(d,J=8.8Hz,1H),6.13(dd,J=2.3Hz,5.8Hz,1H),5.93(s,2H),5.72(d,J=2.2Hz,1H),3.36(s,3H),2.70(s,3H)。

embodiment 28N-(4-((2-kharophen pyridin-4-yl) oxygen base)-3-chloro-phenyl-)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole -4-methane amide

By compound N-(4-((PA-4-yl) oxygen base)-3-chloro-phenyl-)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-methane amide (120mg, 0.27mmol) is dissolved in diacetyl oxide (5mL), then in reaction solution, adds Et ₃n (0.4mL, 1.12mmol), stirring at room was reacted after 8 hours, concentrating under reduced pressure, the residue obtaining is through silica gel column chromatography (DCM/CH ₃oH (v/v)=40/1) to obtain title compound be white solid (65mg, 49%) to purifying.

MS(ESI,pos.ion)m/z:492.0[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)10.92(s,1H),10.53(s,1H),8.16-8.17(d,J=5.7Hz,1H),8.12-8.13(d,J=2.4Hz,1H),7.49-7.61(m,4H),7.42-7.47(m,3H),7.29-7.32(d,J=8.7Hz,1H),6.60-6.62(dd,J=2.4Hz,5.7Hz,1H),3.36(s,3H),2.70(s,3H),2.03(s,3H)。

embodiment 29N-(4-(the chloro-4-of 2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formamido-) phenoxy group) pyridine-2-yl) morpholine-4-methane amide

By compound N-(4-((PA-4-yl) oxygen base)-3-chloro-phenyl-)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-methane amide (135mg, 0.3mmol) is suspended in THF (3mL), then in reaction solution, first adds Et ₃n (0.080mL, 0.6mmol), next dropwise adds phenyl chloroformate (0.075mL, 0.6mmol), and stirring at room is after 2 hours, then adds morpholine (0.250mL, 3.0mmol), and stirring at room reaction, after 22 hours, adds saturated NH ₄the Cl aqueous solution (20mL) and CH ₂cl ₂(20mL), stir after 10 minutes mixture CH ₂cl ₂(20mLx3) extraction, the salt solution for organic phase (20mLx3) of merging is washed, and uses anhydrous Na ₂sO ₄dry, concentrating under reduced pressure then, it is beige solid (43mg, 25.4%) that the residue obtaining obtains title compound through silica gel column chromatography (EtOAc/PE (v/v)=6/1) purifying.

MS(ESI,pos.ion)m/z:563.2[M+H] ⁺；

¹H?NMR(400MHz,DMSO-d ₆):δ(ppm)10.92(s,1H),9.25(s,1H),8.12(s,1H),8.11(d,J=3.9Hz,1H),7.59(m,2H),7.52(m,1H),7.44(m,3H),7.31(m,2H),6.56(dd,J=2.3Hz,5.7Hz,1H),3.54(t,J=4.4Hz,5.0Hz,4H),3.37(brs,7H),2.70(s,3H)。

embodiment 30 N-(4-((PA-4-yl) oxygen base)-2-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-first acid amides

step 1) 4-amino-3-fluorophenol

Compound 3-fluoro-4-nitrophenol (2.0g, 12.73mmol), 10%Pd/C (0.4g), HCOOK (8.75g, 101.85mmol) and THF/H ₂the suspension of O (70mL/20mL) after 5 hours, is cooled to room temperature at 50 ° of C stirring reactions, uses diatomite suction filtration, filtrate water (30mL) dilution, THF for mixture (50mL) extraction, the organic phase anhydrous Na obtaining ₂sO ₄dry, concentrating under reduced pressure then, the residue water (50mL) obtaining dilution, DCM mixture for (50mL) extracts, the organic phase anhydrous Na obtaining ₂sO ₄dry, concentrating under reduced pressure then, obtaining title compound is brown solid (1.17g, 72.3%).

MS(ESI,pos,ion)m/z:128.1[M+H] ⁺。

step 2) N-(the fluoro-4-hydroxy phenyl of 2-)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-methane amide

By compound 4-amino-3-fluorophenol (1.0g, 7.87mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid (2.19g, 9.44mmol) is suspended in CH ₂cl ₂(20mL) in, then in reaction solution, add EDCI (3.02g, 15.7mmol) and HOAT (0.21g, 1.57mmol), be heated to reflux and stirring reaction 20 hours, then be cooled to room temperature, add water (10mL), and the mixture obtaining is stirred and spent the night at room temperature condition, suction filtration, filter cake water (5mL) is washed, and then through silica gel column chromatography (CH ₂cl ₂/ MeOH (v/v)=70/1) to obtain title compound be rice white solid (1.25g, 46.6%) to purifying.

MS(ESI,pos,ion)m/z:342.1[M+H] ⁺。

step 3) 4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formamido-)-3-fluorophenoxy) picolinamide

To compound N-(fluoro-4-hydroxy phenyl of 2-)-1,5-dimethyl-3-oxo-2-phenyl-2, in the mixture of 3-dihydro-1 h-pyrazole-4-methane amide (300mg, 0.879mmol) and t-BuOK (118mg, 1.05mmol), add DMF (2.5mL), after stirring at room 30 minutes, add 4-chloropyridine methane amide (165mg, 1.05mmol), be heated to 120 ° of C stirring reaction 5 hours, then be cooled to room temperature, add H ₂o (50mL) and EtOAc (2mL), the mixture stirred overnight at room temperature obtaining, suction filtration, filter cake water (5mL) is washed, vacuum-drying, obtaining title compound is dark brown solid (370mg, 91.2%).

MS(ESI,pos,ion)m/z:462.2[M+H] ⁺,Rt=3.012min。

step 4) N-(4-((PA-4-yl) oxygen base)-2-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formyl amine

Compound 4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formamido-)-3-fluorophenoxy) picolinamide (370mg, 0.746mmol) is dissolved in to EtOAc (4.5mL), CH ₃cN (4.5mL) and H ₂in O (2.5mL) mixed solvent, be cooled to 0 ° of C, stir after 30 minutes, add PhI (OAc) ₂(288mg, 0.895mmol), continues to stir after 30 minutes at 0 ° of C, and rise to room temperature and continue stirring reaction 7 hours, suction filtration, EtOAc for filter cake (5mL) washes, and filtrate decompression is concentrated, and the residue obtaining is through silica gel column chromatography (CH ₂cl ₂/ MeOH (v/v)=250/9) after purifying, again use silica gel column chromatography (CH ₂cl ₂/ MeOH (v/v)=50/1) to obtain title compound be rice white solid (46mg, 17.3%) to purifying.

MS(ESI,pos,ion)m/z:434.2[M+H] ⁺；

¹H?NMR(400MHz,CDCl ₃):δ(ppm)10.90(s,1H),8.46(t,J=8.7Hz,1H),7.91(d,J=5.9Hz,1H),7.54(t,J=7.6Hz,2H),7.45(t,J=7.4Hz,1H),7.36(d,J=7.3Hz,2H),6.86(d,J=9.0Hz,2H),6.30(dd,J=5.9Hz,2.1Hz,1H),5.96(d,J=2.0Hz,1H),4.58(s,2H),3.36(s,3H),2.79(s,3H)。

embodiment 31N-(4-((2-amino-3-chloropyridine-4-yl) oxygen base)-2-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole -4-methane amide

step 1) the chloro-4-of 3-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formamido-)-3-fluorophenoxy) picolinamide

By compound N-(fluoro-4-hydroxy phenyl of 2-)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-methane amide (300mg, 0.879mmol), t-BuOK (118mg, 1.05mmol) and the mixture stirring at room of DMF (3mL) after 30 minutes, add 3,4-dichloro-2-pyridyl methane amide (201mg, 1.05mmol), be heated to 120 ° of C stirring reaction 12 hours, then add EtOAc (1mL) and H ₂o (20mL), the mixture stirred overnight at room temperature obtaining, suction filtration, obtaining title compound is brown solid (379mg, 87.0%).MS(ESI,pos,ion)m/z:496.0[M+H] ⁺。

step 2) N-(4-((2-amino-3-chloropyridine-4-yl) oxygen base)-2-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4- methane amide

Compound 3-chlorin-4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formamido-)-3-fluorophenoxy) picolinamide (379mg, 0.764mmol) is suspended in to EtOAc (4.5mL), CH ₃cN (4.5mL) and H ₂in the mixed solvent of O (2.5mL), be cooled to 0 ° of C, stir after 30 minutes, add PhI (OAc) ₂(295mg, 0.917mmol), after 30 minutes, rises to room temperature stirring reaction 10 hours at 0 ° of C stirring reaction, suction filtration, and EtOAc for filter cake (5mL) washes, and filtrate decompression is concentrated, and the residue obtaining is through silica gel column chromatography (CH ₂cl ₂/ MeOH (v/v)=50/1) to obtain title compound be yellow solid (150mg, 47.0%) to purifying.

MS(ESI,pos,ion)m/z:468.2[M+H] ⁺；

¹H?NMR(400MHz,CDCl ₃):δ(ppm)10.97(s,1H),8.53(t,J=9.0Hz,1H),7.81(d,J=5.9Hz,1H),7.56(t,J=7.6Hz,2H),7.48(t,J=7.4Hz,1H),7.39(d,J=7.4Hz,2H),6.95-6.90(m,1H),6.90-6.86(m,1H),6.17(d,J=5.9Hz,1H),5.21(s,2H),3.38(s,3H),2.81(s,3H)。

Biological test

bioanalytical method

The LC/MS/MS system of analyzing use comprises Agilent1200 series vacuum degassing furnace, binary syringe pump, orifice plate automatic sampler, post thermostat container, tri-grades of level Four bar mass spectrographs of Agilent G6430 in charged spray ionization (ESI) source.Quantitative analysis is carried out under MRM pattern, and the parameter of MRM conversion is as shown in Table A:

Table A

Many reaction detection scanning	490.2→383.1
		Cracked voltage	230V
Capillary voltage	55V
		Dryer temperature	350°C
Spraying gun	40psi
		Moisture eliminator flow velocity	10L/min

Analyze and use Agilent XDB-C18,2.1x30mm, 3.5 μ M posts, inject 5 μ L samples.Analysis condition: the aqueous formic acid that moving phase is 0.1% (A) and 0.1% formic acid methanol solution (B).Flow velocity is 0.4mL/min.Eluent gradient is as shown in table B:

Table B

Time	The gradient of Mobile phase B
		0.5min	5%
1.0min	95%
		2.2min	95%
2.3min	5%
		5.0min	stop

In addition, the series of the Agilent6330 in addition LC/MS/MS spectrograph for analyzing, is equipped with G1312A binary syringe pump, G1367A automatic sampler and G1314C UV detector; LC/MS/MS spectrograph adopts ESI radioactive source.Each analyte is carried out to suitable positively charged ion models treated to use reference liquid and best analysis is carried out in MRM conversion.During analyzing, use Capcell MP-C18 post, specification is: 100x4.6mm I.D., 5 μ M (Phenomenex, Torrance, California, USA).Moving phase is 5mM ammonium acetate, 0.1% methanol aqueous solution (A): 5mM ammonium acetate, 0.1% methanol acetonitrile solution (B) (70:30, v/v); Flow velocity is 0.6mL/min; Column temperature remains on room temperature; Inject 20 μ L samples.

stability in embodiment A people and rat liver microsomes

People or rat liver microsomes are placed in to polypropylene test tube and hatch, and guide it to copy.Typically hatch mixed solution and comprise people or rat liver microsomes (0.5mg protein/mL), target compound (5 μ M) and cumulative volume are NADPH (1.0mM) potassium phosphate buffer (PBS of 200 μ L, 100mM, pH value is 7.4), by compound dissolution in DMSO, and use PBS to be diluted, the concentration that makes its final DMSO solution is 0.05%.And hatch in the water-bath communicating with air under 37 ° of C, preincubate adds albumen in backward mixed solution in 3 minutes and starts reaction.In different time points (0,5,10,15,30 and 60min), add the ice-cold acetonitrile termination reaction of same volume.Sample is preserved until carry out LC/MS/MS analysis under-80 ° of C.

The concentration of compound in people or rat liver microsomes mixtures incubated is to measure by the method for LC/MS/MS.The linearity range of concentration range is determined by each test-compound.

Parallel microsome of hatching test use sex change, as negative control, is hatched under 37 ° of C, and reaction stops at different time point (0,15 and 60 minute).

Dextromethorphane Hbr (70 μ Μ), as positive control, is hatched under 37 ° of C, and reaction stops at different time point (0,5,10,15,30 and 60 minutes).In each measuring method, all comprise positive and negative control sample, to guarantee the integrity of microsome hatching system.In addition, the stability data of compound of the present invention in people or rat liver microsomes also can be obtained by following test.People or rat liver microsomes are placed in to polypropylene test tube and hatch, and guide it to copy.Typical mixtures incubated comprise people or rat liver microsomes (ultimate density: 0.5mg albumen/mL), compound (ultimate density: 1.5 μ M) and cumulative volume be the K-buffered soln (containing 1.0mM EDTA, 100mM, pH7.4) of 30 μ L.By compound dissolution, in DMSO, and with K-buffered soln dilution, the ultimate density that makes DMSO is 0.2%.After preincubate 10 minutes, add 15 μ L NADPH (ultimate density: 2mM) carry out enzymatic reaction, whole test is carried out in the incubation tube of 37 ° of C.In different time points (0,15,30 and 60 minutes), add 135 μ L acetonitriles (containing IS) termination reaction.With 4000rpm centrifugal 10 minutes, except Deproteinization, collect supernatant liquid, with LC-MS/MS, analyze.

In above-mentioned test, ketanserin (1 μ M) is selected as positive control, under 37 ° of C, hatches, and reaction stops at different time point (0,15,30 and 60 minutes).In each measuring method, all comprise positive control sample, to guarantee the integrity of microsome hatching system.

data analysis

For each reaction, the concentration (representing with per-cent) by compound in people or rat liver microsomes are hatched, by the per-cent mapping of Relative Zero time point, is inferred CLint CL in body with this _int(ref.:Naritomi Y, Terashita S, Kimura S, Suzuki A, Kagayama A, Sugiyama Y.Prediction of human hepatic clearance from vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans.Drug Metabolism and Disposition 2001,29:1316-1324.)

The stability data of table 1 embodiment of the present invention in people and rat liver microsomes

When compound is incubated in people and rat liver microsomes, compound of the present invention shows good transformation period (T _1/2).

pharmacokinetic Evaluation after the oral quantitative the compounds of this invention of Embodiment B mouse, rat, dog and monkey

The present invention to the compounds of this invention the pharmacokinetic in mouse, rat, dog or monkey body assess.The compounds of this invention is with the aqueous solution of the aqueous solution or 2%HPMC+1% tween-80, the salt brine solution of 5%DMSO+5%, and 4%MC or capsule form are carried out administration.For intravenous administration, animal gives 1 or the dosage of 2mg/kg.For oral dosage (p.o.), rat and mouse are 5 or 10mg/kg, and dog and monkey are 10mg/kg.At time point, be 0.25,0.5,1.0,2.0,3.0,4.0,6.0,8.0, within 12 and 24 hours, get blood (0.3mL), and 3,000 or 4,000rpm under centrifugal 10 minutes.Collect plasma solutions, and under-20 ° of C or-70 ° of C, preserve until carry out above-mentioned LC/MS/MS analysis.

The pharmacokinetic data of table 2 embodiment of the present invention in rat body

During by the quiet notes of compound or oral administration, compound of the present invention shows good pharmacokinetic property, comprises desirable clearance rate (Cl), transformation period (T _1/2) oral administration biaavailability of becoming reconciled.

It is active that the compounds of this invention suppresses tyrosine kinase receptor, particularly suppresses c-Met, VEGFR, and Ron and Axl are active and test to evaluate by following animal heteroplastic transplantation model as the effect of antitumor drug.Result of study shows that the compounds of this invention can suppress c-Met effectively, VEGF-R2, the phosphorylation of Ron and Axl, and the propagation of the inhibition transplanted tumor in nude mice of dose-dependently.

Kinase assay

Kinase assay by detection mix γ- ³³the myelin basic protein of P-ATP (MBP) completes.MBP (Sigma#M-1891) Tutofusin tris buffer salt solution (TBS for preparing 20 μ g/mL; 50mM Tris pH8.0,138mM NaCl, 2.7mMKCl), white 384 orifice plates (Greiner) of coated high associativity, every hole 60 μ L.4 ° of C, hatch 24 hours.With 100 μ L TBS, wash plate 3 times afterwards.Kinase reaction is kinase buffer liquid (5mM Hepes pH7.6,15mM NaCl, 0.01% bovine serum albumin (Sigma#I-5506), the 10mM MgCl of 34 μ L at cumulative volume ₂, 1mM DTT, 0.02%TritonX-100) in carry out.Compound dissolution, in DMSO, is added in each hole, and the ultimate density of DMSO is 1%.Each data determination twice, the mensuration of each compound is at least carried out twice test.Such as, the ultimate density of enzyme is 10nM or 20nM.Add and do not have markd ATP(10 μ M) and γ- ³³the every hole 2 * 10 of ATP(of P mark ⁶cpm, 3000Ci/mmole) start to react.Reflection at room temperature concussion is carried out 1 hour.384 orifice plates clean with the PBS of 7x, then add the scintillation solution of every hole 50 μ L.By Wallac Trilux counter detected result.To those of ordinary skill in the art, this is only a kind of in numerous detection methods, and other method also can.

The IC that above-mentioned test method can be inhibited ₅₀and/or inhibition constant K _i.IC ₅₀be defined as under test conditions the compound concentration while suppressing 50% enzymic activity.Utilize the extension rate of 1/2log to make the curve that comprises 10 concentration point, estimation IC ₅₀value (for example, making a typical curve by following compound concentration: 100 μ M, 30 μ M, 10 μ M, 3 μ M, 1 μ M, 0.3 μ M, 0.1 μ M, 0.03 μ M, 0.01 μ M, 0 μ M).

c-Met (h) kinase assays

The MOPS that people c-Met is 7.0 in 8mM pH value, 0.2mM EDTA, 250 μ M KKKSPGEYVNIEFG, 10mM magnesium acetate and [γ- ³³p-ATP] hatch under (the about 500cpm/pmol of specific activity, concentration according to demand determine) condition of existing.After adding MgATP mixture, start reaction.After hatching 40 minutes under room temperature, add wherein 3% phosphoric acid solution to carry out termination reaction.The reaction solution of 10 μ L is on the mottled P30 of being distributed in strainer, and in 5 minutes, cleans 3 times with 75mM phosphoric acid, and before dry and scintillation counting, put at once methanol solution and preserve.

kDR (h) (VEGF-R2 (h)) kinase assays

The MOPS that people KDR is 7.0 in 8mM pH value, 0.2mM EDTA, 0.33mg/mL myelin basic protein, 10mM magnesium acetate and [γ- ³³p-ATP] hatch under (the about 500cpm/pmol of specific activity, concentration according to demand determine) condition of existing.After adding MgATP mixture, start reaction.After hatching 40 minutes under room temperature, add wherein 3% phosphoric acid solution termination reaction.10 μ L reaction solutions are on the mottled P30 of being distributed in strainer, and in 5 minutes, clean 3 times with 75mM phosphoric acid, and before dry and scintillation counting, put at once methanol solution and preserve.

axl (h) kinase assays

The MOPS that people Axl is 7.0 in 8mM pH value, 0.2mM EDTA, 0.33mg/mL myelin basic protein, 10mM magnesium acetate and [γ- ³³p-ATP] hatch under (the about 500cpm/pmol of specific activity, concentration according to demand determine) condition of existing.After adding MgATP mixture, start reaction.After hatching 40 minutes under room temperature, add 3% phosphoric acid solution to carry out termination reaction.10 μ L reaction solutions are on the mottled P30 of being distributed in strainer, and in 5 minutes, clean 3 times with 75mM phosphoric acid, and before dry and scintillation counting, put at once methanol solution and preserve.

(Millipore UK Ltd, Dundee Technology Park, Dundee DD21SW, the UK) that kinase assay Shi You Britain Millipore company in the present invention completes.

The kinase inhibiting activity of the compounds of this invention also can pass through KINOMEscan ^tMtest, it mainly based on quantitative assay sample and fixing, have the part of active-site directed and a test of kinases competitive binding ability.Completing of this test needs in conjunction with following three elements: the kinases of DNA-mark, fixing part and testing sample.The kinase whose ability of competitive binding of testing sample and fixed ligands can be determined by measuring the amount of the PCR in DNA marker.

For great majority tests, the T7 phage strains of kinases-mark is that the escherichia coli host that origin comes from BL21 bacterial strain prepares.First intestinal bacteria are cultivated to logarithmic phase, then with T7 phage, are infected, and by its under continuous concussion in 32 ° of C hatchings until cracking, lysate is centrifugal, suction filtration, remove cell debris.And then the remaining kinases producing in HEK-293 cell carrys out mark with DNA, for the detection of qPCR.The magnetic bead that is coated with Streptavidin at room temperature reacts after 30 minutes with biotinylated small molecules part, generates the affine resin for kinase assay.The magnetic bead that coordination is good is stopped up by excessive vitamin H, with sealing buffered soln (SEABLOCK ^tM(Pierce), 1%BSA, 0.05% tween 20,1mM DTT) wash and remove free part, to reduce non-specific binding.Association reaction is all at 1x binding buffer liquid (20%SEABLOCK by the magnetic bead of kinases, affinity that coordination is good and testing sample ^tM, 0.17x PBS, 0.05% tween 20,6mM DTT) in complete.Carry out in 96 orifice plates of the polystyrene that is all 0.135mL in final volume of responding.The orifice plate of test is all being hatched 1 hour in room temperature condition under concussion continuously, the magnetic bead of affinity is all used lavation buffer solution (1x PBS, 0.05% tween 20) washing, then be resuspended to elution buffer (1x PBS, 0.05% tween 20, the abiotic elementization affinity ligands of 0.5 μ M) in, and under concussion, in room temperature condition, hatching 30 minutes continuously.Kinases concentration in elutriant is measured by qPCR.

The KINOMEscan of the kinase assay Shi You DiscoveRx company in the present invention ^tM(42501Albrae St.Fremont, CA94538, the USA) that Analysis Service completes, the test result of the embodiment of the present invention is listed in table 3.

The Kds data of table 3 embodiment of the present invention

Embodiment #

Kd(nM)

?	KDR(h)	c-Met(h)
			Embodiment 1	>3000(IC ₅₀)	611(IC ₅₀)
Embodiment 2	43	13
			Embodiment 3	23	4.4
Embodiment 4	540	24
			Embodiment 5	3300	37
Embodiment 8	1500	4.8
			Embodiment 9	160	1.8
Embodiment 11	340	1.4
			Embodiment 12	19000	56
Embodiment 13	570	18
			Embodiment 15	3800	180
Embodiment 16	1800	200
			Embodiment 17	25	20
Embodiment 18	39	2.9
			Embodiment 19	26	16
Embodiment 20	1600	620
			Embodiment 21	1100	120
Embodiment 22	>3000(IC ₅₀)	84(IC ₅₀)
			Embodiment 23	13	5.1

Kd-binding constant (Binding Constants)

Cells phosphorylation test

Conventionally, cell and testing compound preincubate, make it reach sufficient target combination.Utilize sandwich ELISA (Sandwich-ELISA) technology for detection autophosphorylation level.Utilize the extension rate of 1/2log to make the curve that comprises 8 concentration point, estimation IC ₅₀value (each concentration determination 2 times).In the present invention, cells phosphorylation test can pass through that ProQinase GmbH company (ProQinase GmbH, Breisacher Stra β e117D-79106, Freiburg, Germany) completes.

the test of c-Met phosphorylation

As everyone knows, people's gastric adenocarcinoma cells strain MKN45 crosses expression c-Met.C-Met crosses to express and causes composing type, the kinases autophosphorylation of the non-dependence of part.Add SU11274, phosphorylation Met level significantly reduces, and therefore can determine the inhibition ability of the compounds of this invention.By sandwich ELISA (Sandwich-ELISA) technology, can carry out quantitatively phosphorylation Met signal.Known Met inhibitor group is established in test, with the reliability of checking test method.

the test of VEGF-R2 phosphorylation

Known immortal human huve cell (HUE) is crossed VEGF expression-R2.With physiological part VEGF-A, stimulate these cells, can cause obvious acceptor autophosphorylation.Cell and testing compound preincubate, reach sufficient target combination.Optimize incentive condition, reach the inhibition phosphorylation VEGF-R2 signal of dose-dependently, and by sandwich ELISA (Sandwich-ELISA) technology, phosphorylation signal is carried out quantitatively.Known VEGF-R2 inhibitor group is established in test, with the reliability of checking test method.

the test of Axl phosphorylation

Conventionally utilize mouse embryo fibroblasts (MEF) to carry out the test of cell Axl phosphorylation.Cell is by the Axl albumen of transfection expression total length.By clonal selection, obtain afterwards the transfectional cell of a height A xl autophosphorylation.Then add star shaped spore native, phosphorylation Axl level significantly reduces, inhibition ability that therefore can deterministic compound.And by sandwich ELISA (Sandwich-ELISA) technology, phosphorylation Axl level is carried out quantitatively.

Xenotransplantation tumor model

The drug effect of the compounds of this invention is to evaluate by the standard muroid model of transplantation tumor.Human tumor cells (U87MG glioma cell, ATCC) after cultivating, collecting, (BALB/cA nu/nu, Shanghai SLAC Animal Lab.) in the female nude mouse body in age in week (for group of solvents and each dosage group: n=6-10)) in rear veutro subcutaneous vaccination in 6-7.When gross tumor volume reaches 100-250mm ³time, animal is divided into solvent control group (5%DMSO+70% randomly

(30%), 7%HCl (pH1), 18% (30%); Or 7%DMSO, 7%HCl (pH1), 70%

(30%), 16%

) and compound group (30%).Following adopted compound carries out gastric infusion to animal, starting Anywhere in 0 to 15 day from tumor cell inoculation, and conventionally carry out once every day in test.

tumor growth suppresses (TGI) and analyzes

The crystallization growth of tumour is to evaluate by the relation of gross tumor volume and time.The major axis of Subcutaneous tumor (L) and minor axis (W) measure weekly twice by calipers, and the volume of tumour (TV) is by formula (L * W ²)/2) calculate.TGI is calculated by the intermediate value of group of solvents mouse tumor volume and the difference of medicine group mouse tumor volume intermediate value, with the percentage of solvent control group gross tumor volume intermediate value, recently represents, by following formula, calculates:

Primary statistics is analyzed by repeating variance determination and analysis (RMANOVA) and is completed.Next by Scheffe psot hoc test method, carry out multiple comparisons.Separate solvent (5%DMSO+70%

(30%), 7%HCl (pH1), 18%

(30%); Or 7%DMSO, 7%HCl (pH1), 70% (30%), 16% (30%)) negative contrast.

The xenotransplantation tumor model data of table 4 embodiment of the present invention

Finally it should be noted that alternate manner can be implemented the present invention in addition.Correspondingly, embodiments of the invention are to describe as illustration, but are not limited to content described in the invention, may be also the modification done within the scope of the present invention or the equivalents added in the claims.All publications that the present invention quotes or patent all will be as reference of the present invention.

Claims

1. one kind suc as formula the compound shown in (I):

Or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or its prodrug, wherein:

Q is H, NR ^ar ^b, OR ^a,-N (R ^c) C (=O) R ^dor-N (R ^c) C (=O) OR ^a;

W is CR ⁷or N;

2. compound according to claim 1, wherein, Q is NR ^ar ^b,-N (R ^c) C (=O) R ^dor-N (R ^c) C (=O) OR ^a.

3. compound according to claim 1, wherein, each X, Y and Z are H independently, D, C _1-4alkyl, C _3-6cycloalkyl, C _3-6cycloalkyl-C _1-2alkylidene group, C _3-6heterocyclic radical, C _3-6heterocyclic radical-C _1-2alkylidene group, phenyl, 5-10 former molecular heteroaryl, phenyl-C _1-2alkylidene group or (5-10 former molecular heteroaryl)-C _1-2alkylidene group, wherein, described C _1-4alkyl, C _3-6cycloalkyl, C _3-6cycloalkyl-C _1-2alkylidene group, C _3-6heterocyclic radical, C _3-6heterocyclic radical-C _1-2alkylidene group, phenyl-C _1-2alkylidene group, (5-10 former molecular heteroaryl)-C _1-2alkylidene group, phenyl and 5-10 former molecular heteroaryl can be optionally by 1,2, and 3 or 4 are independently selected from D, F, Cl, Br, CN, C _2-4thiazolinyl, C _2-4alkynyl, OR ^a, NR ^ar ^b, R ^ao-C _1-2alkylidene group or R ^ar ^bn-C _1-2the substituting group of alkylidene group replaces.

4. compound according to claim 1, wherein, each R ¹, R ², R ³, R ⁴, R ⁵, R ⁶and R ⁷be H, D, F or Cl independently.

5. compound according to claim 1, wherein, each R ^a, R ^band R ^cbe H independently, C _1-4alkyl, C _1-4haloalkyl, C _3-6cycloalkyl, C _3-6cycloalkyl-C _1-2alkylidene group, C _3-6heterocyclic radical or C _3-6heterocyclic radical-C _1-2alkylidene group, works as R ^aand R ^bwhile being connected with same nitrogen-atoms, R ^a, R ^b, together with the nitrogen-atoms being connected with them, can optionally form 3-8 replacement or non-substituted former molecular heterocycle, wherein, described C _1-4alkyl, C _1-4haloalkyl, C _3-6cycloalkyl, C _3-6cycloalkyl-C _1-2alkylidene group, C _3-6heterocyclic radical, C _3-6heterocyclic radical-C _1-2alkylidene group and 3-8 former molecular heterocycle can be optionally by 1,2, and 3 or 4 are independently selected from D, F, Cl, CN, N ₃, OH, NH ₂, C _1-3haloalkyl, C _1-3alkoxyl group or C _1-3the substituting group of alkylamino replaces.

6. compound according to claim 1, wherein, R ^dfor H, D, C _1-4alkyl, C _3-6cycloalkyl-C _1-2alkylidene group, C _3-6heterocyclic radical or C _3-6heterocyclic radical-C _1-2alkylidene group, works as R ¹, R ², R ³, R ⁵(or R ⁴), R ⁶and R ⁷be H simultaneously, R ⁴(or R ⁵) while being F, R ^dbe not C _3-6heterocyclic radical, wherein, described C _1-4alkyl, C _3-6cycloalkyl-C _1-2alkylidene group, C _3-6heterocyclic radical or C _3-6heterocyclic radical-C _1-2alkylidene group can be optionally by 1,2, and 3 or 4 are independently selected from D, F, CN, OR ^a, NR ^ar ^b, C _1-3alkyl, C _2-4thiazolinyl, C _2-4alkynyl, R ^ao-C _1-2alkylidene group or R ^ar ^bn-C _1-2the substituting group of alkylidene group replaces.

7. compound according to claim 1, wherein, Q is NH ₂or-N (R ^c) C (=O) R ^d.

8. compound according to claim 1, wherein, each X, Y and Z are H independently, D, CH ₃, CH ₂cH ₃, phenyl or by 1,2,3,4 or 5 are independently selected from D, the phenyl group that the substituting group of F or Cl replaces.

9. compound according to claim 1, wherein Q is:

10. compound according to claim 1, has structure shown in formula (II):

Wherein:

Q is NR ^ar ^b,-N (R ^c) C (=O) R ^dor-N (R ^c) C (=O) OR ^a;

11. compounds according to claim 10, wherein, Q is NR ^ar ^bor-N (R ^c) C (=O) R ^d.

12. compounds according to claim 10, wherein, each X, Y and Z are H independently, D, C _1-4alkyl or phenyl, wherein, described C _1-4alkyl and phenyl can be optionally by 1,2, and 3,4 or 5 are independently selected from D, and the substituting group of F or Cl replaces.

13. compounds according to claim 10, wherein, each R ^a, R ^band R ^cbe H independently, C _1-4alkyl, C _3-6cycloalkyl, C _3-6heterocyclic radical, C _3-6cycloalkyl-C _1-2alkylidene group or C _3-6heterocyclic radical-C _1-2alkylidene group, wherein, described C _1-4alkyl, C _3-6cycloalkyl, C _3-6heterocyclic radical, C _3-6cycloalkyl-C _1-2alkylidene group and C _3-6heterocyclic radical-C _1-2alkylidene group can be optionally by 1,2, and 3 or 4 are independently selected from D, F, Cl, CN, N ₃, OH, NH ₂, C _1-6haloalkyl, C _1-6alkoxyl group or C _1-6the substituting group of alkylamino replaces.

14. compounds according to claim 1, wherein, R ^dfor Me, Et, n-Pr, i-Pr, n-Bu, i-Bu or t-Bu.

15. compounds according to claim 1, wherein, Q is NH ₂or-N (R ^c) C (=O) R ^d.

16. compounds according to claim 1, wherein, each X, Y and Z are H independently, D, Me, CH ₂d, CHD ₂, CD ₃, ethyl, propyl group, sec.-propyl, phenyl or by 1,2,3,4 or 5 are independently selected from D, the phenyl group that the substituting group of F or Cl replaces.

17. compounds according to claim 1, wherein Q is:

18. compounds according to claim 1, have following one of them structure:

19. 1 kinds of pharmaceutical compositions comprise compound or the pharmaceutically acceptable carrier described in claim 1-18 any one, vehicle, thinner, assistant agent, vehicle, or their combination.

20. pharmaceutical compositions according to claim 19, wherein further comprise additional treatment agent, and these additional treatment agent are selected from chemotherapeutic agent, antiproliferative, be used for the treatment of atherosclerotic medicine, be used for the treatment of the medicine of pulmonary fibrosis, or their combination.

21. pharmaceutical compositions according to claim 20, wherein said additional treatment agent is Zorubicin (Adriamycin), Wyeth-Ayerst Laboratories (Rapamycin), Temsirolimus, everolimus (Everolimus), Ixabepilone, gemcitabine (Gemcitabin), endoxan (cyclophosphamide), dexamethasone (dexamethasone), Etoposide (etoposide), Fluracil (fluorouracil), Ah method is for Buddhist nun (afatinib), alisertib, amuvatinib, Axitinib (axitinib), SKI-606 (bosutinib), brivanib, cabozantinib, AZD2171 (cediranib), crenolanib, Ke Zhuo is for Buddhist nun (crizotinib), dabrafenib, dacomitinib, Dasatinib (dasatinib), danusertib, dovitinib, Tarceva (erlotinib), foretinib, ganetespib, Gefitinib (gefitinib), ibrutinib, imatinib (imatinib), iniparib, lapatinibditosylate (lapatinib), lenvatinib, linifanib, linsitinib, Masitinib (masitinib), momelotinib, not for husky Buddhist nun (motesanib), HKI-272 (neratinib), niraparib, AMN107 (nilotinib), oprozomib, olaparib, pazopanib (pazopanib), pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, fork clip is for Buddhist nun (saracatinib), saridegib, Xarelto (sorafenib), Sutent (sunitinib), tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, ZD6474 (vandetanib), veliparib, vemurafenib, vismodegib, volasertib, Interferon, rabbit (an interferon), carboplatin (carboplatin), Hycamtin (topotecan), taxol (taxol), vinealeucoblastine(VLB) (vinblastine), vincristine(VCR) (vincristine), Temozolomide (temozolomide), tositumomab (tositumomab), trabedectin, belimumab, rhuMAb-VEGF (bevacizumab), brentuximab, cetuximab, gemtuzumab, ipilimumab, ofatumumab, panitumumab, ranibizumab, rituximab, tositumomab, trastuzumab (trastuzumab) or their combination.

Pharmaceutical composition described in 22. 1 kinds of rights to use requirement 1-18 any one described in compound or claim 19-21 any one is for the preparation of the purposes of protecting, process, treat or alleviate the medicine of patient's proliferative disease.

23. according to the purposes of compound described in claim 22 or pharmaceutical composition, and wherein said proliferative disease is metastatic carcinoma, colorectal carcinoma, adenocarcinoma of stomach, bladder cancer, mammary cancer, kidney, liver cancer, lung cancer, skin carcinoma, thyroid carcinoma, brain tumor, neck cancer, prostate cancer, carcinoma of the pancreas, CNS(central nervous system) cancer, glioblastoma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis.

24. 1 kinds of rights to use require compound described in 1-18 any one or the pharmaceutical composition described in claim 19-21 any one to come to require compound described in 1-18 any one or right to use to require the pharmaceutical composition described in 19-21 any one to contact with described biological sample for the preparation of suppressing or regulate the purposes of the medicine of protein kinase activity, described purposes to comprise right to use in biological sample.

25. purposes according to claim 24, wherein said protein kinase is receptor tyrosine kinase.

26. purposes according to claim 25, wherein receptor tyrosine kinase is VEGFR, c-Met, Ron, Axl or their combination.