CN103539780A - Substituted pyrazolone compounds and methods and uses thereof - Google Patents

Abstract

The present invention provides some novel substituted pyrazolone compounds, pharmaceutically acceptable salts thereof, and pharmaceutical preparations thereof, which are used for regulating the activity of protein kinases and regulating intercellular or intracellular signal responses. The present invention also relates to pharmaceutical compositions comprising the compounds of the present invention, and methods for using the pharmaceutical compositions to treat mammals, especially human hyperproliferative diseases.

Description

Substituted pyrazolone compounds and methods and uses thereof

This application requires a Chinese patent application submitted to the China Patent Office on July 16, 2012, with the application number 201210244755.7, and the title of the invention is "Substituted pyrazolone compounds and their methods of use and applications", submitted on April 3, 2013 China Patent Office, the application number is 201310116831.0, the title of the invention is "Substituted pyrazolone compound and its use and application", submitted to the China Patent Office on July 27, 2012, the application number is 201210261615.0, the title of the invention A Chinese patent application for "Substituted pyrazolone compounds and their methods of use and uses" was submitted to the Chinese Patent Office on April 3, 2013, with application number 201310116710.6, and the title of the invention is "Substituted pyrazolone compounds and their use The priority of the Chinese patent application "method and use", the entire content of which is incorporated in this application by reference.

field of invention

This invention relates to novel substituted pyrazolone compounds and salts thereof for use in the treatment of hyperproliferative diseases such as cancers associated with mammals. In particular, the present invention relates to compounds for inhibiting the activity of protein tyrosine kinases, by using the compounds of the present invention to inhibit the activity of protein tyrosine kinases, thereby inhibiting intercellular or intracellular signal responses. The present invention also relates to methods of using the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention for the treatment of hyperproliferative diseases in mammals, especially humans.

Background of the invention

Protein kinases represent a large class of proteins that play an important role in maintaining control of cellular functions and in the regulation of various cellular pathologies. By regulating signal response pathways, protein kinases control cell metabolism, progression through the cell division cycle, cell proliferation and apoptosis, differentiation and survival. There are currently 500 human kinomes, of which as many as 150 are related to various human diseases, such as inflammatory diseases, cardiovascular diseases, metabolic diseases, neurodegenerative diseases and cancer.

Wherein the partial list of kinases includes 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 kinases are a subfamily of protein kinases that can also be classified as growth factor receptors (eg, Axl, VEGFR, c-Met (HGFR), Ron, EGFR, PDGFR, and FGFR) or non-receptors (eg, c-src and bcr-abl) kinases. Receptor tyrosine kinase is a transmembrane protein, which enables growth factors to cross the cell membrane and maintain the extracellular binding region. The transmembrane region and the intracellular part function as kinases, and phosphorylate a specific protein tyrosine residue, thereby affect cell proliferation. Aberrant expression or protein kinase activity is directly implicated in the pathogenesis of numerous human cancers.

Angiogenesis, the process of forming new capillaries from pre-existing blood vessels, plays a key role in the development of embryonic organs in the female/female reproductive circulatory system, as well as in the healing of inflammatory diseases and wounds role. Certain diseases are known to be associated with uncontrolled angiogenesis, such as ocular neovascularization, retinopathy (including diabetic retinopathy), age-related macular degeneration, psoriasis, hemangioblastoma, hemangioma, arteriosclerosis, inflammatory Diseases, such as rheumatoid or rheumatoid inflammatory diseases, especially arthritis (rheumatoid arthritis), or other chronic inflammatory conditions, such as chronic asthma, arterial or post-transplant atherosclerosis, endometriosis and hyperplasia Diseases such as solid tumors and liquid tumors (eg leukemia) as generally described. Solid tumors, in particular, depend on angiogenesis for their supply of nutrition, nourishment, and waste disposal. In addition, angiogenesis also promotes the growth of metastatic tumors in cells or elsewhere.

Neovascularization is a highly complex and highly orchestrated process that requires stimulation by numerous growth factors, but vascular endothelial growth factor (VEGFR) signaling response often represents a critical rate-limiting stage in both physiological and pathological angiogenesis. VEGF binds and activates receptor-type tyrosine kinases. There are three subtypes of VEGFR that have been confirmed by humans: VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1) and VEGFR-3 (Flt-4). VEGFR-2 mediates major cellular responses to VEGF, especially mitosis and angiogenesis. VEGFR-1 modulates VEGFR-2 signaling or acts as a dummy/decoy receptor sequestering VEGF from VEGFR-2. The expression of VEGFR-1 is positively regulated by hypoxia in a manner similar to that of VEGF by HIF-1; its function varies based on cell type and developmental stage. (Stuttfeld E, Ballmer-Hofer K (September 2009), "Structure and function of VEGFreceptors". IUBMB Life61(9):915-22.)

VEGFR-2 is a major mediator of mitosis and survival of vascular endothelial cells (ECs), while maintaining angiogenesis and microvascular permeability. Thus, direct inhibition of the activity of the kinase VEGFR-2 would reduce angiogenesis and tumor growth, and inhibit VEGFR-2 activity targeting genetically more stable host epithelial cells rather than mutable tumor tissue, The chances of developing drug resistance will be reduced.

Drugs that target VEGFR signaling, either alone or in combination with other chemotherapeutic agents, are effective in patients with advanced malignancies (“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, 6, 20703).

c-Met, namely hepatocyte growth factor receptor (HGFR), its main point of action is endothelial cells, and it has been confirmed that it is expressed in endothelial cells, myogenic cells, hematopoietic cells and motor neurons. The natural ligand of c-Met is hepatocyte growth factor (HGF), which is a multifunctional growth factor, namely scatter factor (SF). In both fetuses and adults, activation of c-Met promotes the formation of certain morphological, eg, invasive growths that lead to rapid cell growth, cell-to-cell division, and cell migration to their surroundings (“From Tpr-Met toMet, tumorigenesis and tubes," Oncogene, 2007, 26, 1276; and "Met Receptor Tyrosine Kinase as a Therapeutic Anticancer Target," Cancer Letter, 2009, 280, 1-14).

Persistent c-Met stimulation, overexpression or mutation exists in widespread human malignancies, including breast cancer, liver cancer, lung cancer, ovarian cancer, kidney cancer, thyroid cancer, colon cancer, malignant glioma, prostate cancer, etc. c-Met has also been implicated in atherosclerosis and pulmonary fibrosis. The aggressive growth rate of these cancer cells was radically enhanced through tumor-stroma interactions, including the HGF/c-Met pathway. Thus, substantial evidence linking c-Met signaling response to the rate of progression of some cancer diseases raises its role in the development of cancer drugs that target c-Met (“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.CancerRes.,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 Drug expediover,” Nature Disc Review , 2008, 7, 504).

Axl belongs to the subfamily of receptor tyrosine kinases (RTKs), including Tyro3 and Mer (TAM). Among them, TAM receptors are characterized by the association of two immunoglobulin analog domains and binary fibronectin type III in the extracellular domain and the cytoplasmic kinase domain. The ligands of TAM receptors are Gas6 (growth arrest-specific6) and protein S. The two vitamin K-dependent proteins have 43% amino acid sequences and have similar domain structures (“The anticoagulation factor protein S and its relative, Gas6 , are ligands for the Tyro3/Axl family of receptor tyrosine kinases,” Cell, 1995, 80, 661-670; and “Axl receptor tyrosine kinases stimulated by the vitamin K-dependent protein encoded by growth-arrest-specific gene69,” Nature, 19 373, 623-626).

Sufficient evidence shows that the Gas6/Axl system plays an important role in promoting the growth and survival of normal cells and cancer cells ("TAMreceptor tyrosine kinases: biological functions, signaling, and potential therapeutic targeting in human cancer," Adv Cancer Res, 2008, 100 ,35–83). Axl overexpression and signaling responses have been implicated in several human malignancies such as colon cancer, breast cancer, glioma, thyroid cancer, gastric cancer, melanoma, lung cancer, and renal cell carcinoma (RCC). The more specific role of Axl in biology has been confirmed in the study of glioma, that is, reducing the signaling response of Axl will reduce the growth of glioma and breast tumors, in which Axl will promote cell migration and tube formation , neovascularization and tumor growth. Axl has been shown to play multiple roles in tumorigenesis, and antibody therapy to inhibit Axl not only blocks the function of Axl in malignant tumor cells, but also blocks its function in mesenchymal tumor cells. The inhibitory effect of Axl and the additive effect of anti-VEGF suggest that blocking the function of Axl will be an effective way to improve anti-angiogenic therapy (“Axl as a potential therapeutic target in cancer: role of Axl intumor growth, metastasis and angiogenesis.” Oncogene , 2009, 28, 3442-3455; and "TAM Receptor Tyrosine Kinases: Biologic Functions, Signaling, and Potential Therapeutic Targeting in Human Cancer," Adv Cancer Res, 2008, 100, 35-83).

RON (MST1R, receptor d'origin nantais) is another member of the MET family and is a receptor casein for the ligand macrophage stimulating protein (MSP, also known as MST1 or hepatocyte growth factor-like (HGFL)) amino acid kinase, which is associated with cell differentiation, migration, and stromal invasion in vitro and in vivo—all processes that are surrogate markers of the phenotype of aggressively growing tumors with metastatic potential. RON primarily regulates tumor phenotypes in lung, thyroid, pancreas, prostate, colon and breast cancer cells and can predict poor prognosis in human breast cancer. Both the co-expression of RON and MET and the induction of RON expression through HGF-MET signaling have been described in studies of hepatocellular carcinoma. Furthermore, co-expression of RON and MET in ovarian, breast and bladder cancers predicted a worse prognosis. Considering the signal redundancy of RON and MET, the most likely way is to inhibit the signaling response of MET, which is mainly regulated by the RON signaling response (“RON(MST1R) is a novel prognostic marker and therapeutic target for gastroesophagealadenocarcinoma.” Cancer Biol Ther. 2011 July 1;12(1):9–46.).

The role of the MSP-RON signaling axis in cancer pathogenesis has been extensively studied in various disease model systems. Both in vivo and in vitro results have shown that MSP–RON signaling is important in the aggressive growth of different types of cancer. Aberrant RON activation induced by overexpression of the protein and generation of oncogenic isoforms, as well as sustained activation of multicellular signaling, is present in a variety of different types of cancer. RON signaling responses are also essential for the growth and survival of cancer cells. These properties make RON a drug target for cancer therapy (“MSP–RON signaling in cancer: pathogenesis and therapeutic potential.” Nature Reviews Cancer, 2013, 13, 466-481).

It is well known that cancer cells often employ multiple mechanisms to avoid tightly regulated cellular processes such as cell proliferation, apoptosis, and senescence. Consequently, many tumors escape inhibition of a single kinase. Systematic analysis of tumors broadly reveals that receptor tyrosine kinase (RTK) coactivation accomplishes chemoresistance in cancer cells and serves as an important biological mechanism. One approach, overcoming RTK coactivation, may involve therapeutically targeting multiple RTKs simultaneously to block oncogenic RTK signaling responses and overcome compensatory mechanisms. ("Receptor Tyrosine Kinase Coactivation Networks in Cancer," Cancer Research, 2010, 70, 3857). Anti-tumor approaches targeting VEGFR, c-Met, Ron and/or Axl signaling responses could prevent tumor cells from overcoming individual inhibition of VEGFR, c-Met(HGFR), Ron and/or Axl, thereby improving cancer therapy Effect.

Summary of the invention

The present invention relates to novel substituted pyrazolone compounds and methods of treating cell proliferative disorders. The compounds of the present invention have inhibitory effect on protein tyrosine kinase activity. What is more satisfactory is that the compounds of the present invention have multiple inhibitory functions and can inhibit signal responses like VEGFR, c-Met(HGFR), Ron and/or Axl. Correspondingly, the present invention also provides some novel inhibitors of protein tyrosine kinase receptor signaling, such as VEGF receptor signaling, HGF receptor signaling, Ron receptor signaling and/or Axl receptor signaling .

In particular, the compounds involved in the present invention, and pharmaceutically acceptable compositions thereof, can be effectively used as tyrosine kinase receptor inhibitors, such as VEGFR, c-Met, Ron and/or Axl inhibitors.

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

Or its stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or its prodrug, wherein, in formula (I) The definitions of Q, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , W, X, Y and Z are shown below.

In some embodiments, in formula (I):

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

W is CR ⁷ or N;

Each of X, Y and Z is independently H, D, C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl-C _1-4 alkylene, C _3-7 heterocycle base, C _3-7 heterocyclyl-C _1-4 alkylene, C _6-10 aryl, heteroaryl consisting of 5-10 atoms, C _6-10 aryl-C _1-4 alkylene Or (heteroaryl consisting of 5-10 atoms)-C _1-4 alkylene, wherein, the C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl-C _1-4 alkylene, C _3-7 heterocyclyl, C _3-7 heterocyclyl-C _1-4 alkylene, C _6-10 aryl, heteroaryl consisting of 5-10 atoms, C _6-10 aryl-C _1-4 alkylene and (heteroaryl consisting of 5-10 atoms)-C _1-4 alkylene can optionally be separated by 1, 2, 3, 4 or 5 independent selected from D, F, Cl, Br, CN, C _2-6 alkenyl, C _2-6 alkynyl, OR ^a , NR ^a R ^b , R ^a OC _1-4 alkylene or R ^a R ^b NC ₁ Substituents of _-4 alkylene are substituted;

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

Each of R ^a , R ^b and R ^c is independently H, C _1-6 aliphatic, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-4 alkylene Base, C _3-6 heterocyclyl, C _3-6 heterocyclyl-C _1-4 alkylene, C _6-10 aryl, heteroaryl consisting of 5-10 atoms, C _6-10 aryl -C _1-4 alkylene or (heteroaryl consisting of 5-10 atoms)-C _1-4 alkylene, when R ^a and R ^b are connected to the same nitrogen atom, R ^a , R ^b , Together with the nitrogen atoms connected to them, a substituted or unsubstituted heterocyclic ring consisting of 3-8 atoms can be optionally formed, wherein, the C _1-6 aliphatic, C _1-6 haloalkyl, C _{3 -6} cycloalkyl, C _3-6 cycloalkyl-C _1-4 alkylene, C _3-6 heterocyclyl, C _3-6 heterocyclyl-C _1-4 alkylene, C _6-10 Aryl, heteroaryl consisting of 5-10 atoms, C _6-10 aryl-C _1-4 alkylene, (heteroaryl consisting of 5-10 atoms)-C _1-4 alkylene and The heterocyclic ring composed of 3-8 atoms can be optionally composed of 1, 2, 3 or 4 independently selected from D, F, Cl, CN, N ₃ , OH, NH ₂ , C _1-6 haloalkyl, C ₁ Substituents of _-6 alkoxy or C _1-6 alkylamino; and

R ^d is H, C _1-6 alkyl, C _3-8 cycloalkyl-C _1-4 alkylene, C _3-7 heterocyclyl, C _3-7 heterocyclyl-C _1-4 alkylene or C _6-10 aryl, when R ¹ , R ² , R ³ , R ⁵ (or R ⁴ ), R ⁶ and R ⁷ are H at the same time, and R ⁴ (or R ⁵ ) is F, R ^d is not is C _3-7 heterocyclyl, wherein, the C _1-6 alkyl, C _3-8 cycloalkyl-C _1-4 alkylene, C _3-7 heterocyclyl, C _3-7 heterocycle The group-C _1-4 alkylene and C _6-10 aryl can be optionally selected from 1, 2, 3 or 4 independently selected from D, F, Cl, Br, CN, OR ^a , NR ^a R ^b , Substituents of C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, R ^a OC _1-4 alkylene or R ^a R ^b NC _1-4 alkylene.

In other embodiments, Q in formula (I) is NR ^a R ^b , -N(R ^c )C(=O)R ^d or -N(R ^c )C(=O)OR ^a .

In some other embodiments, each X, Y and Z in formula (I) are independently H, D, C _1-4 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _{1- 2} alkylene, C _3-6 heterocyclyl, C _3-6 heterocyclyl-C _1-2 alkylene, phenyl, heteroaryl consisting of 5-10 atoms, phenyl-C _1-2 Alkylene or (heteroaryl consisting of 5-10 atoms)-C _1-2 alkylene, wherein, the C _1-4 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkane Base-C _1-2 alkylene, C _3-6 heterocyclyl, C _3-6 heterocyclyl-C _1-2 alkylene, phenyl-C _1-2 alkylene, (5-10 Heteroaryl group consisting of atoms)-C _1-2 alkylene, phenyl and heteroaryl group consisting of 5-10 atoms can optionally be independently selected from D, F, Cl by 1, 2, 3 or 4 , Br, CN, C _2-4 alkenyl, C _2-4 alkynyl, OR ^a , NR ^a R ^b , ^Ra OC _1-2 alkylene or R ^a R ^b NC _1-2 alkylene base replaced.

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

In some other embodiments, each R ^a , R ^b and R ^c in formula (I) are independently H, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _{3- 6} cycloalkyl-C _1-2 alkylene, C _3-6 heterocyclyl or C _3-6 heterocyclyl-C _1-2 alkylene, when R ^a and R ^b are connected to the same nitrogen atom , R ^a , R ^b , together with the nitrogen atoms connected to them, can optionally form a substituted or unsubstituted heterocycle consisting of 3-8 atoms, wherein, the C _1-4 alkyl, C _{1 -4} haloalkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-2 alkylene, C _3-6 heterocyclyl, C _3-6 heterocyclyl-C _1-2 alkylene Alkyl and 3-8 atom heterocycles can optionally be substituted by 1, 2, 3 or 4 independently selected from D, F, Cl, CN, N ₃ , OH, NH ₂ , C _1-3 haloalkyl , C _1-3 alkoxy or C _1-3 alkylamino substituents.

In some other embodiments, in formula (I), R ^d is H, D, C _1-4 alkyl, C _3-6 cycloalkyl-C _1-2 alkylene, C _3-6 heterocyclyl or C _3-6 heterocyclyl-C _1-2 alkylene, when R ¹ , R ² , R ³ , R ⁵ (or R ⁴ ), R ⁶ and R ⁷ are H at the same time, R ⁴ (or R ⁵ ) is When F, R ^d is not C _3-6 heterocyclyl, wherein, the C _1-4 alkyl, C _3-6 cycloalkyl-C _1-2 alkylene, C _3-6 heterocyclyl or C _3-6 heterocyclyl-C _1-2 alkylene can be optionally selected from 1, 2, 3 or 4 independently selected from D, F, CN, OR ^a , NR ^a R ^b , C _1-3 alkane Substituents of C _2-4 alkenyl, C _2-4 alkynyl, R ^a OC _1-2 alkylene or R ^a R ^b NC _1-2 alkylene.

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

In other embodiments, each of X, Y and Z in formula (I) is independently H, D, CH ₃ , CH ₂ CH ₃ , phenyl or is independently selected from D by 1, 2, 3, 4 or 5 , a phenyl group substituted by a substituent of F or Cl.

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

In some other embodiments, the compound of the present invention has a structure shown in formula (II):

Wherein, the definitions of Q, X, Y and Z in formula (II) are as follows.

In some embodiments, in formula (II):

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

Each of X, Y and Z is independently H, D, C _1-6 alkyl, C _3-8 cycloalkyl, C _3-7 heterocyclyl, C _6-10 aryl, composed of 5-10 atoms Heteroaryl, C _3-8 cycloalkyl-C _1-4 alkylene, C _3-7 heterocyclyl-C _1-4 alkylene, C _6-10 aryl-C _1-4 alkylene , or (heteroaryl consisting of 5-10 atoms)-C _1-4 alkylene, wherein, the C _1-6 alkyl, C _3-8 cycloalkyl, C _3-7 heterocyclyl, C _6-10 aryl, heteroaryl consisting of 5-10 atoms, C _3-8 cycloalkyl-C _1-4 alkylene, C _3-7 heterocyclyl-C _1-4 alkylene, C _6-10 aryl-C _1-4 alkylene and (heteroaryl consisting of 5-10 atoms)-C _1-4 alkylene can be optionally replaced by 1, 2, 3, 4 or 5 independently selected from D, F, Cl, Br, CN, C _2-6 alkenyl, C _2-6 alkynyl, OR ^a , NR ^a R ^b , R ^a OC _1-4 alkylene or R ^a R ^b NC Substituted by _1-4 alkylene substituents;

Each of R ^a , R ^b and R ^c is independently H, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocyclyl, C _6-10 aryl, consisting of 5-10 atoms Heteroaryl, C _3-6 cycloalkyl-C _1-4 alkylene, C _3-6 heterocyclyl-C _1-4 alkylene, C _6-10 aryl-C _1-4 alkylene group or (heteroaryl group consisting of 5-10 atoms)-C _1-4 alkylene group, wherein, the C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 heterocyclyl group, C _6-10 aryl, heteroaryl consisting of 5-10 atoms, C _3-6 cycloalkyl-C _1-4 alkylene, C _3-6 heterocyclyl-C _1-4 alkylene, C _6-10 aryl-C _1-4 alkylene and (heteroaryl consisting of 5-10 atoms)-C _1-4 alkylene can optionally be independently selected by 1, 2, 3 or 4 Substituents from D, F, Cl, CN, N ₃ , OH, NH ₂ , C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 alkylamino; and

R ^d is a C _1-6 alkyl group, wherein the C _1-6 alkyl group can optionally be independently selected from D, F, Cl, OH, NH ₂ , C _{1- 6} alkoxy or C _1-6 alkylamino substituents.

In other embodiments, Q in formula (II) is NR ^a R ^b or -N(R ^c )C(=O)R ^d .

In some other embodiments, each X in formula (II), Y and Z are independently H, D, C _1-4 alkyl or phenyl, wherein, the C _1-4 alkyl and phenyl can be optionally is substituted by 1, 2, 3, 4 or 5 substituents independently selected from D, F or Cl.

In some other embodiments, each of R ^a , R ^b and R ^c in formula (II) is independently H, C _1-4 alkyl, C _3-6 cycloalkyl, C _3-6 heterocyclyl, C _{3 -6} cycloalkyl-C _1-2 alkylene or C _3-6 heterocyclyl-C _1-2 alkylene, wherein, the C _1-4 alkyl, C _3-6 cycloalkyl, C _3-6 heterocyclyl, C _3-6 cycloalkyl-C _1-2 alkylene and C _3-6 heterocyclyl-C _1-2 alkylene can be optionally replaced by 1, 2, 3 or 4 Substituents independently selected from D, F, Cl, CN, N ₃ , OH, NH ₂ , C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 alkylamino.

In other embodiments, ^Rd in formula (II) is Me, Et, n-Pr, i-Pr, n-Bu, i-Bu or t-Bu.

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

In other embodiments, each of X, Y and Z in formula (II) is independently H, D, Me, CH ₂ D, CHD ₂ , CD ₃ , ethyl, propyl, isopropyl, phenyl or is A phenyl group substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F or Cl.

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

In another aspect, the present invention relates to a pharmaceutical composition, which comprises (1) the compound of the present invention and (2) a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or a combination thereof.

In some embodiments, the pharmaceutical composition of the present invention further comprises additional therapeutic agents selected from chemotherapeutic drugs, antiproliferative agents, drugs for treating atherosclerosis, drugs for treating pulmonary Medications for fibrosis, or a combination of them.

In some other embodiments, the pharmaceutical composition of the present invention, wherein the additional therapeutic agent involved is Adriamycin (Adriamycin), Rapamycin (Rapamycin), Temsirolimus, Everolimus (Everolimus), Ixabepilone, Gemcitabine, cyclophosphamide, dexamethasone, etoposide, fluorouracil, afatinib, alisertib, amuvatinib, axitinib , bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib, danusertib, dovitinib, erlotinib (erlotinib), foretinib, ganetespib, gefitinib, ibrutinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib , motesanib, neratinib, niraparib, nilotinib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib , ruxolitinib, saracatinib, saridegib, sorafenib, sunitinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib , vemurafenib, vismodegib, volasertib, interferon (an interferon), carboplatin (carboplatin), topotecan (topotecan), paclitaxel (taxol), vinblastine (vinblastine), vincristine Vincristine, temozolomide, tositumomab, trabedectin, belimumab, bevacizumab, brentuximab, cetuximab, gemtuzumab, ipilimumab, ofatumumab, panitumumab, ranibizumab, rituximab, tositumomab, quercetin Trastuzumab or a combination thereof.

On the other hand, the compounds or pharmaceutical compositions of the present invention can be used to prepare medicines for preventing, treating, treating or alleviating proliferative diseases in patients.

In some embodiments, the proliferative disease of the present invention is metastatic cancer, colon cancer, gastric adenocarcinoma, bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer, skin cancer, thyroid cancer, brain tumor, neck cancer, prostate cancer , pancreatic cancer, CNS (central nervous system) cancer, malignant glioma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis.

In another aspect, the present invention relates to the use of the compound or the pharmaceutical composition of the present invention to prepare for inhibiting or regulating the activity of protein kinase in a biological sample, said use comprising using the compound of the present invention or the pharmaceutical composition and said biological sample touch.

In some of these embodiments, the protein kinase described herein is a receptor tyrosine kinase.

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

In another aspect, the present invention provides pharmaceutical compositions comprising compounds of the present invention, or stereoisomers, geometric isomers, tautomers, solvates, metabolites thereof, as inhibitors of tyrosine kinase receptors product, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or a combination thereof. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound that acts as an inhibitor of VEGF receptor signaling, HGF receptor signaling, Ron receptor signaling, and Axl receptor signaling, or a stereoisomer thereof , geometric isomers, tautomers, solvates, metabolites, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable carriers, excipients, diluents, adjuvants, vehicles, or their The combination. In other embodiments, the pharmaceutical compositions of the present invention further comprise additional therapeutic agents.

In another aspect, the present invention relates to a method of inhibiting the activity of a protein tyrosine kinase comprising contacting a compound of the present invention or a pharmaceutical composition thereof with said kinase. In some of these embodiments, the present invention relates to methods of inhibiting VEGF receptor signaling, HGF receptor signaling, Ron receptor signaling and Axl receptor signaling comprising a compound of the present invention or a pharmaceutical composition thereof in combination with the contact with the receptors. Inhibition of receptor protein kinase activity, particularly VEGF, HGF, Ron and Axl receptor signaling responses, can be performed in unicellular or multicellular organisms. If present in a multicellular organism, the methods described herein comprise administering to the organism a compound or composition of the invention. In some embodiments, the organism is a mammal and in other embodiments, the organism is a human. In some other embodiments, the method further comprises contacting the protein kinase with an additional therapeutic agent.

In another aspect, the present invention relates to a method of inhibiting cell proliferation activity, said method comprising contacting the cell with an amount of the compound of the present invention or a pharmaceutical composition thereof effective to inhibit cell proliferation. In some embodiments, the methods described herein further comprise contacting the cell with an additional therapeutic agent.

In another aspect, the present invention relates to a method of treating a cell proliferative disease in a patient, said method comprising administering to the patient a dose of a compound or composition thereof of the present invention required for effective treatment. In some embodiments, the methods described herein further comprise the administration of an additional therapeutic agent.

In another aspect, the present invention relates to a method of inhibiting tumor growth in a patient, said method comprising administering to the patient a dose of a compound of the present invention or a composition thereof required for effective treatment. In some embodiments, the methods described herein further comprise the administration of an additional therapeutic agent.

In another aspect, the present invention relates to methods for the preparation, isolation and purification of compounds encompassed by formula (I) or formula (II).

The preceding description merely outlines certain aspects of the invention, but is not intended to be limiting. These and other aspects will be described more specifically and fully below.

Detailed Description of the Invention

Definitions and General Terms

The present invention will list in detail the literature corresponding to the determined and embodied content, and the examples are all accompanied by illustrations of structural formulas and chemical formulas. The present invention is intended to cover all alternatives, modifications and equivalents which may be included within the scope of the present invention as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The invention is in no way limited to the description of the methods and materials. There are many documents and similar materials that differ from or contradict the present application, including but in no way limited to the definitions of terms, term usage, described techniques, or the scope of control like the present application.

The following definitions shall apply to the present invention unless otherwise indicated. For the purposes of the present invention, chemical elements are defined according to the Periodic Table of the Elements, CAS Edition and Handbook of Chemicals, 75, thEd, 1994. In addition, general principles of organic chemistry can be found 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, so all content Both incorporate references.

As described in the present invention, the compounds of the present invention can be optionally substituted by one or more substituents, such as the above general formula compounds, or as specific examples in the examples, subclasses, and included in the present invention A class of compounds. It should be understood that the term "optionally substituted" and the term "substituted or unsubstituted" are used interchangeably. In general, the term "optionally", whether or not preceded by the term "substituted", indicates that one or more hydrogen atoms in a given structure are replaced by a particular substituent. Unless otherwise indicated, an optional substituent may be substituted at each substitutable position of the group. It should be noted that in the present invention, when R ^a and R ^b are connected to the same nitrogen atom, R ^a , R ^b and the nitrogen atom connected to them can optionally form substituted or unsubstituted 3-8 atoms The heterocyclic ring formed, that is, R ^a , R ^b and the nitrogen atoms connected to them can form a heterocyclic ring with 3-8 atoms, and can also not form a heterocyclic ring. It is other structures well known to those skilled in the art, such as NR ^a -R ^b or R ^a -NR ^b etc. When more than one position in a given formula can be substituted by one or more substituents selected from a particular group, then the substituents can be substituted at each position the same or differently. The substituents mentioned therein can be, but not limited to, D, F, Cl, Br, N ₃ , NO ₂ , CN, OH, NH ₂ , OR ^a , CH ₂ D, CHD ₂ , CD ₃ , R ^a OC _1-4 alkylene, SR ^a , NR ^a R ^b , R ^a R ^b NC _1-4 alkylene, -C(=O)NR ^a R ^b , -N(R ^c )C(=O) NR ^a R ^b , -N(R ^c )C(=O)R ^d , -N(R ^c )S(=O)NR ^a R ^b , -N(R ^c )S(=O)R ^a ,- N(R ^c )S(=O) ₂ NR ^a R ^b , -N(R ^c )S(=O) ₂ R ^a , methyl, ethyl, n-propyl, isopropyl, methoxy, benzene Base, phenyl-C _1-2 alkylene, C _1-6 alkyl, C _1-6 aliphatic, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, _{C 3-8 cycloalkyl, C 3-7 heterocyclyl, C 3-8 cycloalkyl -} C _1-4 alkylene, C _3-7 Heterocyclyl-C _1-4 alkylene, C _6-10 aryl-C _1-4 alkylene, (heteroaryl consisting of 5-10 atoms)-C _1-4 alkylene, C _{6 -10} aryl, or a heteroaryl group consisting of 5-10 atoms, wherein, R ^a , R ^b and R ^c have the definitions as described in the present invention.

The term "aliphatic" or "aliphatic group", as used herein, means a straight (i.e. unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more degrees of unsaturation . Unless otherwise specified, aliphatic groups contain 1-20 carbon atoms, some embodiments are aliphatic groups contain 1-10 carbon atoms, other embodiments are aliphatic groups contain 1-8 Carbon atoms, in some other embodiments, the aliphatic group contains 1-6 carbon atoms, in some other embodiments, the aliphatic group contains 1-3 carbon atoms. Suitable aliphatic groups include, but are not limited to, straight or branched, substituted or unsubstituted alkyl, alkenyl or alkynyl groups, such as C _1-6 aliphatic groups, including straight or branched chain, substituted or unsubstituted C _1-6 alkyl, C _2-6 alkenyl, or C _2-6 alkynyl group. Examples of such include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, ethylene, propylene, butene, 2-butene, acetylene, propyne , butyne, 2-butyne, etc., and the aliphatic groups can be independently unsubstituted or substituted with one or more substituents described in the present invention.

The term "alkyl" or "alkyl group" used in the present invention means a saturated linear or branched monovalent hydrocarbon atomic group containing 1-20 carbon atoms. Unless otherwise specified, the alkyl group contains 1-20 carbon atoms, some embodiments are, the alkyl group contains 1-10 carbon atoms, and in other embodiments, the alkyl group contains 1-8 carbon atom, some other embodiments are that the alkyl group contains 1-6 carbon atoms, some other embodiments are that the alkyl group contains 1-4 carbon atoms, some other embodiments are that the alkyl group contains 1-3 carbon atoms.

Examples of alkyl groups include, but are not limited to, methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), n-propyl (n-Pr, -CH ₂ CH ₂ CH ₃ ), isopropyl (i-Pr, -CH(CH ₃ ) ₂ ), n-butyl (n-Bu, -CH ₂ CH ₂ CH ₂ CH ₃ ), isobutyl (i-Bu, -CH ₂ CH (CH ₃ ) ₂ ), sec-butyl (s-Bu, -CH(CH ₃ )CH ₂ CH ₃ ), tert-butyl (t-Bu, -C(CH ₃ ) ₃ ), n-pentyl (-CH _{2CH 2} CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH(CH ₂ CH ₃ ) ₂ ), 2-methyl -2-butyl (-C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1- Butyl (-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), n-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C(CH ₃ )(CH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl (-CH(CH ₂ CH ₃ ) CH(CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C(CH ₃ ) ₂ CH (CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH(CH ₃ )C(CH ₃ ) ₃ ), n-heptyl, n-octyl, etc., wherein the alkyl Groups can independently be unsubstituted or substituted with one or more substituents described herein.

As used herein, the term "alkyl" and its prefix "alk" include both straight and branched saturated carbon chains.

The term "alkylene" means a saturated divalent hydrocarbyl group obtained by removing two hydrogen atoms from a linear or branched saturated hydrocarbyl group. Unless otherwise specified, the alkylene group contains 1-10 carbon atoms, in other embodiments, the alkylene group contains 1-6 carbon atoms, and in other embodiments, the alkylene group contains 1 - 4 carbon atoms, in other embodiments the alkylene group contains 1-2 carbon atoms. Such examples include methylene (-CH ₂ -), ethylene (-CH ₂ CH ₂ -), isopropylidene (-CH(CH ₃ )CH ₂ -) and the like, wherein the alkylene Groups can independently be unsubstituted or substituted with one or more substituents described herein.

The term "alkenyl" means a linear or branched monovalent hydrocarbon group of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least One position is unsaturated, that is, one CC is a sp ² double bond, wherein the alkenyl group can be independently unsubstituted or substituted by one or more substituents described in the present invention, including groups with "Anti","Normal" or "E""Z" positioning, where specific examples include, but are not limited to, vinyl (-CH=CH ₂ ), allyl (-CH ₂ CH=CH ₂ ), etc. .

The term "alkynyl" means a linear or branched monovalent hydrocarbon group of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, in which at least one The position is unsaturated, that is, one CC is an sp triple bond, wherein the alkynyl group can be independently unsubstituted or substituted by one or more substituents described in the present invention, specific examples include, but are not limited to , ethynyl (-C≡CH), propargyl (-CH ₂ C≡CH), 1-propynyl (-C≡C-CH ₃ ) and the like.

The term "alkoxy" denotes an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning described herein. Unless specified otherwise, the alkoxy groups contain 1-20 carbon atoms, some examples are alkoxy groups contain 1-10 carbon atoms, other examples are alkoxy groups Containing 1-8 carbon atoms, some other embodiments are, the alkoxy group contains 1-6 carbon atoms, some other embodiments are, the alkoxy group contains 1-4 carbon atoms, some other embodiments Yes, alkoxy groups contain 1-3 carbon atoms.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO,-OCH ₃ ), ethoxy (EtO,-OCH ₂ CH ₃ ), 1-propoxy (n-PrO,n- Propoxy, -OCH ₂ CH ₂ CH ₃ ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH ₃ ) ₂ ), 1-butoxy (n-BuO,n- Butoxy, -OCH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH ₂ CH(CH ₃ ) ₂ ), 2-Butyl Oxygen (s-BuO, s-butoxy, -OCH(CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH ₃ ) ₃ ), 1-pentyloxy (n-pentyloxy, -OCH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyloxy (-OCH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyloxy (-OCH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butoxy (-OC(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butoxy (-OCH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-l-butoxy (-OCH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-l-butoxy (—OCH ₂ CH(CH ₃ )CH ₂ CH ₃ ), etc., wherein the alkoxy groups are independently unsubstituted or substituted with one or more substituents described herein.

The term "haloalkyl", "haloalkenyl" or "haloalkoxy" means an alkyl, alkenyl or alkoxy group substituted with one or more halogen atoms, examples of which include, but are not limited to, Trifluoromethyl, trifluoromethoxy, etc.

The term "carbocycle", "carbocyclyl" or "cycloaliphatic" refers to one or more points of attachment to the rest of the molecule, non-aromatic, saturated or partially unsaturated, including 3-12 carbon atoms, or 3-10 carbon atoms, or 3-8 carbon atoms, or monocyclic, bicyclic and tricyclic ring systems with 3-6 carbon atoms. Suitable cycloaliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl. Examples of cycloaliphatic groups further include, but are by no means limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, Cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc.

The term "cycloalkyl" refers to a saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 carbon atoms with one or more points of attachment to the rest of the molecule. Its bicyclic ring system includes spiro bicyclic and fused bicyclic rings. Some of these embodiments are ring systems containing 3-10 carbon atoms, others are ring systems containing 3-8 carbon atoms, others are ring systems containing 3-6 carbon atoms, and others Examples are ring systems containing 5-6 carbon atoms, and the cycloalkyl groups can be independently unsubstituted or substituted with one or more substituents described herein.

The term "cycloalkylalkylene" means that an alkyl group may be substituted by one or more cycloalkyl groups, wherein alkyl and cycloalkyl groups have the meanings described herein. In some of these embodiments, a cycloalkylalkylene group refers to a "lower cycloalkylalkylene" group, ie a cycloalkyl group attached to a C _1-6 alkyl group. In some other embodiments, the cycloalkyl group is attached to a C _1-4 alkyl group. In some other embodiments, the cycloalkyl group is attached to a C _1-3 alkyl group. In some other embodiments, the cycloalkyl group is attached to a C _1-2 alkyl group. Such examples include, but are not limited to, cyclopropylethyl, cyclopentylmethyl, cyclohexylmethyl, and the like. The cycloalkylalkylene groups can be independently unsubstituted or substituted with one or more substituents described herein. Such examples include, but are not limited to, cyclopropylethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.

The terms "heterocycle", "heterocyclyl" or "heterocyclic" are used interchangeably herein to refer to monocyclic, bicyclic, or tricyclic ring systems in which one or more atoms of the ring are independently optionally replaced by Replaced by heteroatoms, rings may be fully saturated or contain one or more unsaturations, but are never aromatic and have only one point of attachment to the rest of the molecule. Its bicyclic ring system includes spiro bicyclic rings and fused bicyclic rings, and one of the rings may be a monocarbocyclic or monoheterocyclic ring. One or more hydrogen atoms on the ring are independently and optionally substituted by one or more substituents described in the present invention. In some embodiments, "heterocycle", "heterocyclyl" or "heterocyclic" group is a monocyclic ring consisting of 3-7 atoms (2-6 carbon atoms and selected from N, O, P, S 1-3 heteroatoms, where S or P is optionally substituted by one or more oxygen atoms to obtain groups like SO, SO ₂ , PO, PO ₂ ), some other embodiments are, 3-6 A single ring consisting of 2 atoms (2-5 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to obtain a S=O, SO ₂ , PO, PO ₂ group, when the ring is a three-membered ring, there is only one heteroatom), or a bicyclic ring composed of 7-10 atoms (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to give groups like SO, _SO2 , PO, _PO2 ).

A heterocyclic group may be a carbon group or a heteroatom group. "Heterocyclyl" also includes radicals formed by the fusion of a heterocyclic radical with a saturated or partially unsaturated ring or heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, Morpholinyl, Thiomorpholinyl, Thioxanyl, Piperazinyl, Homopiperazinyl, Azetidinyl, Oxetanyl, Thietanyl, Homopiperidinyl, Glycidyl Base, azepanyl, oxepinyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, Indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolyl, pyrazolinyl, dithianyl, dithianyl, di Hydrogen thienyl, pyrazolidinyl imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl. Examples of the heterocyclic group also include, 1,1-dioxothiomorpholinyl, and a pyrimidinedione group in which two carbon atoms on the ring are replaced by oxygen atoms.

The term "heterocyclylalkylene" means that an alkyl group may be substituted by one or more heterocyclyl groups, wherein the alkyl and heterocyclyl groups have the meanings described herein. In some of these embodiments, a heterocyclylalkylene group refers to a "lower heterocyclylalkylene" group, ie a heterocyclyl group attached to a C _1-6 alkyl group. In some other embodiments, the heterocyclyl group is attached to a C _1-4 alkyl group. In some other embodiments, the heterocyclyl group is attached to a C _1-2 alkyl group. Such examples include, but are not limited to, 2-pyrrolidinylethyl, 3-azetidinylmethyl, and the like. The heterocyclylalkylene groups can be independently unsubstituted or substituted with one or more substituents described herein.

The term "heteroatom" refers to O, S, N, P, and Si, including forms of any oxidation state of N, S, and P; forms of primary, secondary, and tertiary amines, and quaternary ammonium salts; or The form in which hydrogen is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like in N-substituted pyrrolidinyl NR).

The term "halogen" refers to F, Cl, Br or I.

The term "H" denotes a single hydrogen atom. Such atomic groups can be linked to other groups, such as oxygen atoms, to form hydroxyl groups.

The term "D" or " ^2H " denotes a single deuterium atom. One such group is attached to a methyl group to form a mono-deuteromethyl group (-CDH ₂ ), two deuterium atoms are attached to a methyl group to form a bis-deuteromethyl group (-CD ₂ H), and three A deuterium atom is attached to a methyl group to form a tris-deuteromethyl group (-CD ₃ ).

The term " _N3 " denotes an azide structure. This group can be linked to other groups, for example, a methyl group to form azidomethane (MeN ₃ ), or a phenyl group to form azidobenzene (PhN ₃ ).

The term "aryl" may be used alone or as a part of "aralkyl", "aralkoxy" or "aryloxyalkyl" to indicate a total of 6-14 ring atoms, or 6-12 Ring atoms, or monocyclic, bicyclic, and tricyclic carbocyclic ring systems of 6-10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains rings composed of 3-7 atoms, And only one attachment point is connected to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring", eg aromatic rings may include phenyl, naphthyl and anthracene. The aryl groups can be independently unsubstituted or substituted with one or more substituents described herein.

The term "arylalkylene" means that an alkyl group may be substituted by one or more aryl groups, wherein the alkyl and aryl groups have the meanings described herein, some of which are, aryl An alkylene group refers to a "lower arylalkylene" group, ie, an aryl group attached to a C _1-6 alkyl group. In some other embodiments, an arylalkylene group refers to a "phenylene alkylene" containing a C _1-4 alkyl group. In some other embodiments, an arylalkylene group refers to an aryl group connected to a C _1-2 alkyl group. Specific examples thereof include benzyl, diphenylmethyl, phenethyl and the like. The arylalkylene groups can be independently unsubstituted or substituted with one or more substituents described herein.

The term "heteroaryl" can be used alone or as a part of "heteroarylalkyl" or "heteroarylalkoxy" to indicate a total of 5-14 ring atoms, or 5-12 ring atoms, Or monocyclic, bicyclic, and tricyclic ring systems of 5-10 ring atoms, wherein at least one ring system is aromatic, and at least one ring system contains one or more heteroatoms, wherein each ring system contains 5-7 A ring of atoms with only one point of attachment to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic".

In some other embodiments, aromatic heterocycles include, but are not limited to, the following monocycles: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5- Imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrole Base, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2 -thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3 - Thienyl, pyrazolyl (such as 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl Azolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyr Azinyl, 1,3,5-triazinyl; also includes, but is by no means limited to, the following bicyclic rings: benzimidazolyl, benzofuryl, benzothienyl, indolyl (such as 2-indole base), purinyl, quinolinyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), and isoquinolyl (such as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolinyl). The heteroaryl groups can independently be unsubstituted or substituted with one or more substituents described herein.

The term "heteroarylalkylene" means that an alkyl group may be substituted by one or more heteroaryl groups, wherein the alkyl and heteroaryl groups have the meanings described herein, some of which Yes, a heteroarylalkylene group refers to a "lower heteroarylalkylene" group, ie a heteroaryl group attached to a C _1-6 alkyl group. In some other embodiments, the heteroaryl group is attached to a C _1-4 alkyl group. In some other embodiments, the heteroaryl group is attached to a C _1-2 alkyl group. Specific examples thereof include 2-pyridylmethyl, 3-furylethyl and the like. The heteroarylalkylene groups can be independently unsubstituted or substituted with one or more substituents described herein.

The term "carboxy", whether used alone or in combination with other terms, such as "carboxyalkyl", means -CO ₂ H; the term "carbonyl", whether used alone or in combination with other terms, such as "aminocarbonyl" or ""Acyloxy" means -(C=O)-.

The term "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino", wherein the amino groups are each independently substituted with one or two alkyl groups. In some embodiments, alkylamino is a lower alkylamino group with one or two C _1-6 alkyl groups attached to a nitrogen atom. In some other embodiments, the alkylamino is a C _1-3 lower alkylamino group. Suitable alkylamino groups may be mono- or di-alkylamino, examples of which include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N- -Diethylamino and the like.

The term "arylamino" means that an amino group is substituted by one or two aryl groups, examples of which include, but are not limited to, N-phenylamino. In some embodiments, the aromatic ring on the arylamino group can be further substituted.

The term "aminoalkyl" includes C _1-10 straight or branched chain alkyl groups substituted with one or more amino groups. In some embodiments, aminoalkyl is C _1-6 "lower aminoalkyl" substituted with one or more amino groups, examples of which include, but are not limited to, aminomethyl, amino Ethyl, aminopropyl, aminobutyl and aminohexyl.

As used herein, the term "unsaturated" means that a group contains one or more degrees of unsaturation.

The term "comprising" is an open expression, that is, it includes the content specified in the present invention, but does not exclude other content.

Unless otherwise indicated, the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomerism (or conformational isomerism)): for example, those containing asymmetric centers R, S configuration, double bond (Z), (E) isomers, and (Z), (E) conformational isomers. Accordingly, individual stereochemical isomers of the compounds of the present invention or mixtures thereof as enantiomers, diastereomers, or geometric isomers (or conformational isomers) are within the scope of the present invention.

The term "tautomer" or "tautomeric form" as used in the present invention means that structural isomers with different energies can cross a low energy barrier and thus interconvert. For example, proton tautomerization (ie, prototropism) includes interconversions via migration of a proton, such as keto-enol tautomerization and imine-enamine isomerization. Valence tautomers include interconversion by recombination of some of the bonding electrons.

Unless otherwise indicated, all tautomeric forms of the compounds of the invention are included within the scope of the invention. In addition, unless otherwise indicated, the structural formulas of the compounds described herein include enriched isotopes of one or more different atoms.

The term "prodrug" used in the present invention means that a compound is transformed into a compound represented by formula (I) or formula (II) in vivo. Such conversion is effected by prodrug hydrolysis in blood or enzymatic conversion in blood or tissue to the parent structure. The prodrug compound of the present invention can be an ester. In the existing invention, the ester can be used as a prodrug including phenyl esters, aliphatic (C _1-24 ) esters, acyloxymethyl esters, carbonates , carbamates and amino acid esters. For example, a compound of the present invention that contains a hydroxyl group can be acylated to give a prodrug form of the compound. Other prodrug forms include phosphate esters, eg, phosphorylated parent hydroxyl groups. A complete discussion of prodrugs can be found in the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium 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 SJHecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

"Metabolite" refers to a product obtained through metabolism of a specific compound or its salt in vivo. Metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized using assays as described herein. Such products can be obtained by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, degreasing, enzymatic cleavage and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds, including metabolites produced by contacting a compound of the invention with a mammal for a substantial period of time.

Definitions of stereochemistry and usage of conventions in the present invention are generally referred to in the following documents: 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. The compounds of the present invention may contain an asymmetric center or a chiral center, so there are different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute the present invention part. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D, L or R, S are used to indicate the absolute configuration of the molecular chiral center. The prefixes d, l or (+), (-) are used to name the symbol of the compound's plane polarized light rotation, (-) or l means that the compound is left-handed, and the prefix (+) or d means that the compound is right-handed. The chemical structures of these stereoisomers are the same, but their three-dimensional structures are different. A particular stereoisomer may be an enantiomer, and a mixture of isomers is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is known as a racemic mixture or racemate, which can result in no stereoselectivity or stereospecificity during a chemical reaction. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers, devoid of optical activity.

The term "tautomer" or "tautomeric form" means that isomers of structures of different energies can be interconverted through a low energy barrier. For example, proton tautomers (ie, prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Atomic (valence) tautomers include interconversions of rearranged bonding electrons.

The "pharmaceutically acceptable salt" used in the present invention refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or other methods such as ion exchange methods recorded in books and literature these salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphorate Salt, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3 - Phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. The present invention also contemplates the quaternary ammonium salts of any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations formed as counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C _{1 -8} sulfonates and aromatic sulfonates.

A "solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association of solvent molecules with water.

The term "protecting group" or "Pg" refers to a substituent that reacts with another functional group, usually to block or protect specific functionality. For example, "amino-protecting group" refers to a substituent attached to the amino group to block or protect the functionality of the amino group in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxyl protecting group" refers to a substituent of a hydroxy group used to block or protect the functionality of the hydroxy group, suitable protecting groups include acetyl and silyl groups. "Carboxyl protecting group" refers to the substituent of carboxyl to block or protect the functionality of carboxyl. General carboxyl protecting groups include -CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2-(trimethylsilane base) ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenyl phosphino)ethyl, nitroethyl, etc. For a general description of protecting groups, please refer to: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

DESCRIPTION OF THE COMPOUNDS OF THE INVENTION

The present invention relates to substituted pyrazolone compounds, pharmaceutically acceptable salts thereof, and pharmaceutical preparations thereof, for treating diseases mediated by tyrosine kinase receptors, especially VEGFR, c-Met, Ron and/or Axl receptors or disease treatment has potential use. In particular, the present invention relates to a compound as shown in formula (I):

Or its stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or its prodrug, wherein, in formula (I) The definitions of Q, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , W, X, Y and Z are shown below.

In some embodiments, in formula (I):

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

W is CR ⁷ or N;

Each of X, Y and Z is independently H, D, C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl-C _1-4 alkylene, C _3-7 heterocycle base, C _3-7 heterocyclyl-C _1-4 alkylene, C _6-10 aryl, heteroaryl consisting of 5-10 atoms, C _6-10 aryl-C _1-4 alkylene Or (heteroaryl consisting of 5-10 atoms)-C _1-4 alkylene, wherein, the C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl-C _1-4 alkylene, C _3-7 heterocyclyl, C _3-7 heterocyclyl-C _1-4 alkylene, C _6-10 aryl, heteroaryl consisting of 5-10 atoms, C _6-10 aryl-C _1-4 alkylene and (heteroaryl consisting of 5-10 atoms)-C _1-4 alkylene can optionally be separated by 1, 2, 3, 4 or 5 independent selected from D, F, Cl, Br, CN, C _2-6 alkenyl, C _2-6 alkynyl, OR ^a , NR ^a R ^b , R ^a OC _1-4 alkylene or R ^a R ^b NC ₁ Substituents of _-4 alkylene are substituted;

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

Each of R ^a , R ^b and R ^c is independently H, C _1-6 aliphatic, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-4 alkylene Base, C _3-6 heterocyclyl, C _3-6 heterocyclyl-C _1-4 alkylene, C _6-10 aryl, heteroaryl consisting of 5-10 atoms, C _6-10 aryl -C _1-4 alkylene or (heteroaryl consisting of 5-10 atoms)-C _1-4 alkylene, when R ^a and R ^b are connected to the same nitrogen atom, R ^a , R ^b , Together with the nitrogen atoms connected to them, a substituted or unsubstituted heterocyclic ring consisting of 3-8 atoms can be optionally formed, wherein, the C _1-6 aliphatic, C _1-6 haloalkyl, C _{3 -6} cycloalkyl, C _3-6 cycloalkyl-C _1-4 alkylene, C _3-6 heterocyclyl, C _3-6 heterocyclyl-C _1-4 alkylene, C _6-10 Aryl, heteroaryl consisting of 5-10 atoms, C _6-10 aryl-C _1-4 alkylene, (heteroaryl consisting of 5-10 atoms)-C _1-4 alkylene and The heterocyclic ring composed of 3-8 atoms can be optionally composed of 1, 2, 3 or 4 independently selected from D, F, Cl, CN, N ₃ , OH, NH ₂ , C _1-6 haloalkyl, C ₁ Substituents of _-6 alkoxy or C _1-6 alkylamino; and

R ^d is H, C _1-6 alkyl, C _3-8 cycloalkyl-C _1-4 alkylene, C _3-7 heterocyclyl, C _3-7 heterocyclyl-C _1-4 alkylene or C _6-10 aryl, when R ¹ , R ² , R ³ , R ⁵ (or R ⁴ ), R ⁶ and R ⁷ are H at the same time, and R ⁴ (or R ⁵ ) is F, R ^d is not is C _3-7 heterocyclyl, wherein, the C _1-6 alkyl, C _3-8 cycloalkyl-C _1-4 alkylene, C _3-7 heterocyclyl, C _3-7 heterocycle The group-C _1-4 alkylene and C _6-10 aryl can be optionally selected from 1, 2, 3 or 4 independently selected from D, F, Cl, Br, CN, OR ^a , NR ^a R ^b , Substituents of C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, R ^a OC _1-4 alkylene or R ^a R ^b NC _1-4 alkylene.

In other embodiments, Q in formula (I) is NR ^a R ^b , -N(R ^c )C(=O)R ^d or -N(R ^c )C(=O)OR ^a .

In some other embodiments, each X, Y and Z in formula (I) are independently H, D, C _1-4 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _{1- 2} alkylene, C _3-6 heterocyclyl, C _3-6 heterocyclyl-C _1-2 alkylene, phenyl, heteroaryl consisting of 5-10 atoms, phenyl-C _1-2 Alkylene or (heteroaryl consisting of 5-10 atoms)-C _1-2 alkylene, wherein, the C _1-4 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkane Base-C _1-2 alkylene, C _3-6 heterocyclyl, C _3-6 heterocyclyl-C _1-2 alkylene, phenyl-C _1-2 alkylene, (5-10 Heteroaryl group consisting of atoms)-C _1-2 alkylene, phenyl and heteroaryl group consisting of 5-10 atoms can optionally be independently selected from D, F, Cl by 1, 2, 3 or 4 , Br, CN, C _2-4 alkenyl, C _2-4 alkynyl, OR ^a , NR ^a R ^b , ^Ra OC _1-2 alkylene or R ^a R ^b NC _1-2 alkylene base replaced.

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

In some other embodiments, each R ^a , R ^b and Rc in formula (I) are independently H, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 Cycloalkyl-C _1-2 alkylene, C _3-6 heterocyclyl or C _3-6 heterocyclyl-C _1-2 alkylene, when R ^a and R ^b are connected to the same nitrogen atom, R ^a , R ^b , together with the nitrogen atoms connected to them, can optionally form a substituted or unsubstituted heterocyclic ring consisting of 3-8 atoms, wherein, the C _1-4 alkyl, C _{1- 4} haloalkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-2 alkylene, C _3-6 heterocyclyl, C _3-6 heterocyclyl-C _1-2 alkylene The group and the heterocycle consisting of 3-8 atoms can optionally be 1, 2, 3 or 4 independently selected from D, F, Cl, CN, N ₃ , OH, NH ₂ , C _1-3 haloalkyl, Substituents of C _1-3 alkoxy or C _1-3 alkylamino.

In some other embodiments, in formula (I), R ^d is H, D, C _1-4 alkyl, C _3-6 cycloalkyl-C _1-2 alkylene, C _3-6 heterocyclyl or C _3-6 heterocyclyl-C _1-2 alkylene, when R ¹ , R ² , R ³ , R ⁵ (or R ⁴ ), R ⁶ and R ⁷ are H at the same time, R ⁴ (or R ⁵ ) is When F, R ^d is not C _3-6 heterocyclyl, wherein, the C _1-4 alkyl, C _3-6 cycloalkyl-C _1-2 alkylene, C _3-6 heterocyclyl or C _3-6 heterocyclyl-C _1-2 alkylene can be optionally selected from 1, 2, 3 or 4 independently selected from D, F, CN, OR ^a , NR ^a R ^b , C _1-3 alkane Substituents of C _2-4 alkenyl, C _2-4 alkynyl, R ^a OC _1-2 alkylene or R ^a R ^b NC _1-2 alkylene.

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

In other embodiments, each of X, Y and Z in formula (I) is independently H, D, CH ₃ , CH ₂ CH ₃ , phenyl or is independently selected from D by 1, 2, 3, 4 or 5 , a phenyl group substituted by a substituent of F or Cl.

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

In some other embodiments, the compound of the present invention has a structure shown in formula (II):

Wherein, the definitions of Q, X, Y and Z in formula (II) are as follows.

In some embodiments, in formula (II):

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

Each of X, Y and Z is independently H, D, C _1-6 alkyl, C _3-8 cycloalkyl, C _3-7 heterocyclyl, C _6-10 aryl, composed of 5-10 atoms Heteroaryl, C _3-8 cycloalkyl-C _1-4 alkylene, C _3-7 heterocyclyl-C _1-4 alkylene, C _6-10 aryl-C _1-4 alkylene , or (heteroaryl consisting of 5-10 atoms)-C _1-4 alkylene, wherein, the C _1-6 alkyl, C _3-8 cycloalkyl, C _3-7 heterocyclyl, C _6-10 aryl, heteroaryl consisting of 5-10 atoms, C _3-8 cycloalkyl-C _1-4 alkylene, C _3-7 heterocyclyl-C _1-4 alkylene, C _6-10 aryl-C _1-4 alkylene and (heteroaryl consisting of 5-10 atoms)-C _1-4 alkylene can be optionally replaced by 1, 2, 3, 4 or 5 independently selected from D, F, Cl, Br, CN, C _2-6 alkenyl, C _2-6 alkynyl, OR ^a , NR ^a R ^b , R ^a OC _1-4 alkylene or R ^a R ^b NC Substituted by _1-4 alkylene substituents;

Each of R ^a , R ^b and R ^c is independently H, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocyclyl, C _6-10 aryl, consisting of 5-10 atoms Heteroaryl, C _3-6 cycloalkyl-C _1-4 alkylene, C _3-6 heterocyclyl-C _1-4 alkylene, C _6-10 aryl-C _1-4 alkylene group or (heteroaryl group consisting of 5-10 atoms)-C _1-4 alkylene group, wherein, the C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 heterocyclyl group, C _6-10 aryl, heteroaryl consisting of 5-10 atoms, C _3-6 cycloalkyl-C _1-4 alkylene, C _3-6 heterocyclyl-C _1-4 alkylene, C _6-10 aryl-C _1-4 alkylene and (heteroaryl consisting of 5-10 atoms)-C _1-4 alkylene can optionally be independently selected by 1, 2, 3 or 4 Substituents from D, F, Cl, CN, N ₃ , OH, NH ₂ , C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 alkylamino; and

R ^d is a C _1-6 alkyl group, wherein the C _1-6 alkyl group can optionally be independently selected from D, F, Cl, OH, NH ₂ , C _{1- 6} alkoxy or C _1-6 alkylamino substituents.

In other embodiments, Q in formula (II) is NR ^a R ^b or -N(R ^c )C(=O)R ^d .

In some other embodiments, each X in formula (II), Y and Z are independently H, D, C _1-4 alkyl or phenyl, wherein, the C _1-4 alkyl and phenyl can be optionally is substituted by 1, 2, 3, 4 or 5 substituents independently selected from D, F or Cl.

In some other embodiments, each of R ^a , R ^b and R ^c in formula (II) is independently H, C _1-4 alkyl, C _3-6 cycloalkyl, C _3-6 heterocyclyl, C _{3 -6} cycloalkyl-C _1-2 alkylene or C _3-6 heterocyclyl-C _1-2 alkylene, wherein, the C _1-4 alkyl, C _3-6 cycloalkyl, C _3-6 heterocyclyl, C _3-6 cycloalkyl-C _1-2 alkylene and C _3-6 heterocyclyl-C _1-2 alkylene can be optionally replaced by 1, 2, 3 or 4 Substituents independently selected from D, F, Cl, CN, N ₃ , OH, NH ₂ , C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 alkylamino.

In other embodiments, ^Rd in formula (II) is Me, Et, n-Pr, i-Pr, n-Bu, i-Bu or t-Bu.

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

In other embodiments, each of X, Y and Z in formula (II) is independently H, D, Me, CH ₂ D, CHD ₂ , CD ₃ , ethyl, propyl, isopropyl, phenyl or is A phenyl group substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F or Cl.

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

In some other embodiments, the present invention relates to one of the following compounds or their stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically available Accepted salts or prodrugs thereof, but by no means limited to these compounds:

The present invention also encompasses the use of the compounds of the present invention and their pharmaceutically acceptable salts for the manufacture of medicinal products for the treatment of acute and chronic hyperproliferative diseases and/or angiogenesis-mediated diseases, including those described in the present invention. The application of the compound of the present invention in the production of anticancer drugs. The compounds of the present invention are also used in the production of a medical product to alleviate, prevent, control or treat diseases by inhibiting the activity of protein kinases. The present invention includes a pharmaceutical composition, which comprises the compound represented by formula (I) or formula (II) in combination with at least one pharmaceutically acceptable carrier, adjuvant or diluent in an effective therapeutic dose.

The present invention also includes a method of treating an angiogenesis-mediated disease in a patient, or being susceptible to it, comprising treating the patient with a therapeutically effective amount of a compound represented by formula (I) or formula (II).

Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention are Belong to the scope of the present invention.

In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes that the substance or composition must be chemically or toxicologically appropriate in relation to the other ingredients making up the formulation and the mammal being used for treatment.

The salts of the compounds of the present invention also include salts of enantiomers used to prepare or purify intermediates of compounds shown in formula (I) or formula (II) or separated enantiomers of compounds shown in formula (I) or formula (II) , but not necessarily a pharmaceutically acceptable salt.

If the compound of the present invention is basic, the desired salt may be prepared by any suitable method provided in the literature, for example, using inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids and the like. Alternatively use organic acids such as acetic, maleic, succinic, mandelic, fumaric, malonic, pyruvic, oxalic, glycolic and salicylic acids; pyranonic acids such as glucuronic and galactose Alkyd acids; α-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such as p-toluenesulfonic acid, ethanesulfonic acid, etc.

If the compound of the invention is acidic, the desired salts can be prepared by suitable methods, e.g., using inorganic or organic bases, such as ammonia (primary, secondary, tertiary), alkali metal hydroxides or alkaline earth metal hydroxides, etc. Suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia such as primary, secondary and tertiary ammonia, and cyclic ammonia such as piperidine, morpholine and piperazine etc., and inorganic salts obtained from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

Compositions, Formulations and Administration of Compounds of the Invention

According to another aspect, the characteristics of the pharmaceutical composition of the present invention include a compound of formula (I) or formula (II), specific compounds listed in the present invention, or compounds of Examples 1-31, and pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in the compositions of the invention is effective to detectably inhibit a protein kinase in a biological specimen or patient.

The compounds of the present invention exist in free form, or suitably, as pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other compounds that can be administered directly or indirectly according to the needs of patients. Adducts or derivatives, compounds described in other aspects of the present invention, their metabolites or their residues.

As described herein, the pharmaceutically acceptable composition of the present invention further comprises a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used in the present invention, includes any solvent, diluent, or other Liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders or lubricants, etc., are suitable for the specific target dosage form. As described in: 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, 1988-19 , Marcel Dekker, New York, summing up the contents of the literature herein, showing that different carriers can be used in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. Except to the extent that any conventional carrier media is incompatible with the compounds of the present invention, such as any adverse biological effects produced or interactions in a deleterious manner with any other components of the pharmaceutically acceptable composition, they The purposes of the present invention are also considered scope.

Substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphate, glycine, sorbic acid, sorbic acid, Potassium phosphate, partial glyceride mixture of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyethylene Pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl sodium cellulose, ethyl cellulose, and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, Olive, corn, and soybean oils; glycols, such as propylene glycol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; seaweed acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol, phosphate buffered solution, and other nontoxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, Coatings, sweeteners, flavors and fragrances, preservatives and antioxidants.

The compositions of the present invention may be administered orally, by injection, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implantable kit . The term "injected" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial (cavity), intrasternal, intrathecal, intraocular, intrahepatic, focal Intracranial, and intracranial injection or infusion techniques. Preferred compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of the present invention may be aqueous or oleaginous suspensions. These suspensions may be formulated according to the known art using suitable dispersing agents, wetting agents and suspending agents. Sterile injections can be sterile injection solutions or suspensions, which are non-toxic acceptable diluents or solvents for injection, such as 1,3-butanediol solution. Among the acceptable vehicles and solvents are water, Ringer's solution and isotonic sodium chloride solution. Furthermore, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

For this purpose any bland fixed oil may be a synthetic mono- or diglyceride. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially their polyoxyethylene derivatives. These oil solutions or suspensions may contain a long-chain alcohol diluent or dispersant, such as carboxymethylcellulose or similar dispersing agents, commonly used in pharmaceutical formulations of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifiers or enhancers of bioavailability, are generally used in pharmaceutically acceptable solid, liquid, or other dosage forms, and can be applied to target pharmaceutical preparations preparation.

The pharmaceutically acceptable compositions of this invention may be orally administered in any acceptable oral dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. For tablets for oral use, carriers generally include lactose and corn starch. Lubricants, such as magnesium stearate, are typically added. For oral administration in capsules, suitable diluents include lactose and dried cornstarch. When administered orally as an aqueous suspension, the active ingredient consists of emulsifying and suspending agents. Certain sweetening, flavoring or coloring agents may also be added if desired in these dosage forms.

Additionally, the pharmaceutically acceptable compositions of this invention may be administered rectally in the form of suppositories. These can be prepared by mixing the agent with a suitable non-infusing excipient which is solid at room temperature but liquid at rectal temperature, where it melts and releases the drug. Such materials include cocoa butter, beeswax, and polyethylene glycols. The pharmaceutically acceptable compositions of the present invention may be administered topically, especially when topical administration involves areas or organs where the therapeutic target is easily accessible, such as diseases of the eyes, skin or lower intestinal tract. Suitable topical formulations can be prepared and applied to these areas or organs.

Rectal suppositories (see above) or suitable enemas can be applied topically in the lower intestinal tract. Local skin spots can also be used in this way. For topical use, the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carrier compounds for topical administration of this invention include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutically acceptable compositions may be prepared in a suitable lotion or cream containing the active ingredients suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, Span-60 (sorbitan monostearate), Tween 60 (polysorbate 60), cetyl esters wax, palmityl alcohol, 2- Octyldodecanol, Benzyl Alcohol and Water.

For ophthalmic use, the pharmaceutically acceptable composition can be prepared as a formulation, such as isotonic micronized suspension, pH-adjusted sterile saline or other aqueous solution, preferably, isotonic solution and pH-adjusted sterile saline or For other aqueous solutions, disinfectant preservatives such as benzalkonium chloride can be added. In addition, for ophthalmic use, the pharmaceutically acceptable composition can be formulated into an ointment such as petrolatum. The pharmaceutically acceptable compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions may be prepared according to known techniques of formulation formulation, or may be prepared as saline solutions using benzyl alcohol or other suitable preservatives, absorption enhancers, fluorocarbons or other conventional solubilizing or dispersing agents to enhance bioavailability Spend.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Liquid dosage forms may contain, in addition to the active compound, generally known inert diluents, for example, water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzoic acid Benzyl esters, propylene glycol, 1,3-butanediol, dimethylformamide, oils and fats (especially cottonseed, groundnut, corn, microbial, olive, castor and sesame oils), glycerin, 2-tetrahydrofurfurylmethanol, polyethylene glycol , sorbitan fatty acid esters, and mixtures thereof. Besides inert diluents, the oral compositions can also contain adjuvants such as wetting agents, emulsifying or suspending agents, sweetening, flavoring, and perfuming agents.

Injections, such as sterile injections or oily suspensions, can be prepared according to known techniques using suitable dispersing agents, wetting agents and suspending agents according to formulations. Sterile injectable preparations can be sterile injectable solutions, suspensions or emulsions prepared with non-toxic injectable acceptable diluents or solvents, for example, 1,3-butanediol solution. Among the acceptable vehicles and solvents are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any bland fixed oil may be used for this purpose including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in injectables.

The injection can be sterile, such as filtered through a bacteria-defense filter, or incorporated in the form of a sterile solid composition with a sterilizing agent that can be dissolved or dispersed in sterile water or other sterile injectable media before use middle. In order to prolong the effect of the compounds of the invention, it is usually necessary to slow the absorption of the compounds by subcutaneous or intramuscular injection. In this way, the liquid suspension can be used to solve the problem of poor water solubility of crystalline or amorphous substances. The rate of absorption of a compound depends upon its rate of dissolution, which in turn depends on crystal size and crystalline shape. Additionally, delayed absorption of the compound administered by injection can be accomplished by dissolving or dispersing the compound in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers, such as polylactide-polyglycolide. The rate at which the compound is released depends on the rate at which the compound forms the polymer and the nature of the particular polymer. Other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot forms are also prepared by entrapping the compound in liposomes or microemulsions which are compatible with body tissues.

In some of these embodiments, the composition for rectal or vaginal administration is a suppository, which can be prepared by mixing the compound of the present invention with a suitable non-infusion adjuvant or carrier, such as cocoa butter, polyethylene glycol, or Suppositories are waxy substances that are solid at room temperature but liquid at body temperature and therefore melt in the vaginal or thecal cavity to release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these dosage forms, the active compound is mixed with at least one pharmaceutically acceptable inert excipient or carrier, such as sodium citrate or calcium phosphate or fillers or a) fillers such as starch, lactose, sucrose, glucose, mannitol and Silicic acid, b) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, c) humectants such as glycerin, d) disintegrants such as agar, calcium carbonate, potatoes Starch or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) blocker solutions such as paraffin, f) absorption enhancers such as quaternary ammonium compounds, g) humectants such as cetyl alcohol and glycerol monostearate Esters, h) absorbents such as kaolin and bentonite, i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. As with capsules, tablets and pills, these dosage forms may contain buffering agents.

A similar type of solid composition can be a soft or hard capsule filled with fillers, and the used excipients include lactose and macromolecular polyethylene glycol and the like. Solid dosage forms like tablets, lozenges, capsules, pills and granules can be prepared by coating, shelling such as enteric coating and other known coating methods for pharmaceutical preparations. They may optionally contain opacifying agents or, preferably, release the only active ingredient in the composition in a certain part of the intestinal tract, optionally in a delayed manner. For example implant compositions may comprise polymeric substances and waxes.

The active compounds can be in microencapsulated dosage form with one or more excipients as described herein. Solid dosage forms like tablets, lozenges, capsules, pills and granules can be coated or shelled, such as enteric coatings, release-controlling coatings and other well-known pharmaceutical formulation methods. In these solid dosage forms, the active compound may be admixed with at least one inert diluent, such as sucrose, lactose or starch. Such dosage forms may also contain, as usual, additional substances other than inert diluents, such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. As with capsules, tablets and pills, these dosage forms may contain buffering agents. They may optionally contain a sedative or, preferably, release the only active ingredient of the composition in a certain part of the intestinal tract, with any delay. Applicable implant compositions may include, but are not limited to, polymers and waxes.

Dosage forms for topical or dermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or necessary buffers. Ophthalmic pharmaceutical formulations, ear drops and eye drops are all contemplated by the present invention. In addition, the present invention also contemplates the application of transdermal patches, which have more advantages in controlling the delivery of the compound into the body. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can increase the flux of the compound across the skin, controlling the rate either by rate controlling films or by dispersing the compound in a polymer matrix or gelatin.

The compounds of the present invention are preferably formulated in dosage unit form to ease administration and uniformity of dosage. The term "dosage unit form" as used herein refers to a physically discrete unit of drug required to adequately treat a patient. It is to be understood, however, that the total daily usage of the compounds or compositions of the present invention will be determined by the attending physician based on sound medically sound judgment. The particular effective dosage level for any particular patient or organism will depend on many factors including the condition being treated and the severity of the condition, the activity of the particular compound, the particular composition employed, the age, weight, health, sex of the patient and dietary habits, timing of administration, route of administration and rate of excretion of the particular compound employed, duration of treatment, use of the drug in combination or with specific compounds, and other factors well known in the art of pharmacy.

The amount of a compound of the invention which may be combined with a carrier material to produce a single dosage composition will vary depending upon the indication and the particular mode of administration. In some embodiments, the composition can be prepared according to the preparation method into an inhibitor with a dosage of 0.01-200 mg/kg body weight/day, and the administration is carried out according to the amount of the composition accepted by the patient.

The compounds of the present invention may be administered as the sole pharmaceutical agent or in combination with one or more other additional therapeutic (pharmaceutical) agents, where the combination causes acceptable adverse effects, which is of interest in the treatment of hyperproliferative diseases such as cancer special meaning. In such cases, the compounds of the invention may be combined with known cytotoxic agents, individual transduction inhibitors or other anticancer agents, as well as mixtures and combinations thereof. As used herein, an additional therapeutic agent normally administered to treat a particular disease is known as "appropriately treating a disease". "Additional therapeutic agents" as used in the present invention include chemotherapeutic drugs or other anti-proliferative drugs that can be combined with the compounds of the present invention to treat proliferative diseases or cancer.

Chemotherapeutic or other antiproliferative agents include histone deacetylase (HDAC) inhibitors, including but not limited to, SAHA, MS-275, MGO103, and those compounds described in the following patents: WO2006/010264, WO03/ 024448, WO2004/069823, US2006/0058298, US2005/0288282, WO00/71703, WO01/38322, WO01/70675, WO03/006652, WO2004/035525, WO2005/030705, WO2005/09289 including and demethylating reagents But not limited to, 5-aza-2′-deoxycytidine (5-aza-dC), azacitidine (Vidaza), decitabine (Decitabine) and compounds described in the following documents: 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.

），阿霉素（Adriamycin），地塞米松（Dexamethasone），和环磷酰胺。抗血管生成因子（阿瓦斯丁（Avastin）及其他）。单抗类（贝利木单抗(Belimumab,

)，Brentuximab(

)，西妥昔单抗(Cetuximab,

)，吉妥单抗(Gemtuzumab,

)，伊匹单抗(Ipilimumab,)，奥法木单抗(Ofatumumab,

)，帕尼单抗(Panitumumab,)，雷珠单抗(Ranibizumab,)，利妥昔单抗(Rituximab,

)，托西莫单抗(Tositumomab,

)，曲妥珠单抗(Trastuzumab,

)）。激酶抑制剂(伊马替尼(Imatinib,

)，舒尼替尼（Sunitinib,

），索拉非尼（Sorafenib,

），西妥昔单抗（Cetuximab,

），曲妥珠单抗(Trastuzumab,)，厄洛替尼(Erlotinib,

))，达沙替尼(Dasatinib,

)，tivozanib，dovitinib，axitinib，motesanib，帕唑帕尼(pazopanib)，吉非替尼(gefitinib,

)，cediranib，brivanib，替拉替尼(telatinib)，masitinib,来那替尼(neratinib)，lenvatinib,ruxolitinib,linifanib,linsitinib,crizotinib,regorafenib,ponatinib,博舒替尼(bosutinib),塞卡替尼(saracatinib),afatinib,amuvatinib,ponatinib,quizartinib,威罗菲尼(vemurafenib,),凡德他尼(Vandetanib,

),olaparib,veliparib,iniparib,易瑞沙（Iressa）及其他)。药物抑制或激活癌症的途径如mTOR，HIF（缺氧诱导因子）途径及其他。癌症治疗较广泛的论坛见http://www.nci.nih.gov/，FDA认可的肿瘤学药物清单见http://www.fda.gov/cder/cancer/druglist-rame.htm，和默克手册，第十八版.2006，所有的内容都是结合了参考文献。In other embodiments, chemotherapeutic drugs or other anti-proliferative drugs can be combined with the compounds of the present invention to treat proliferative diseases and cancers. Known chemotherapeutic drugs include, but are not limited to, other therapies or anticancer agents that can be combined with anticancer agents of the present invention including surgery, radiation therapy (a few examples are gamma radiation, neutron beam radiation therapy, electron beam radiation therapy , proton therapy, brachytherapy and systemic radioisotope therapy), endocrine therapy, taxanes (paclitaxel, docetaxel, etc.), platinum derivatives, biological response modifiers (interferon, interleukin, tumor necrosis factor (TNF, TRAIL receptor targeting and mediators), hyperthermia and cryotherapy, dilution of any adverse reaction agents (such as antiemetics), and other approved chemotherapeutic drugs, including but not limited to, alkanes Drugs (nitrogen mustard, chlorambucil, cyclophosphamide, phenylalanine mustard, ifosfamide), antimetabolites (methotrexate, pemetrexed, etc.), purines Antagonists and pyrimidine antagonists (6-Mercaptopurine, 5-fluorouracil, Cytarabile, gemcitabine), spindle inhibitors (vinblastine, vincristine, vinorelbine, paclitaxel), podophyllum Toxins (Etoposide, Irinotecan, Topotecan), Antibiotics (Doxorubicin, Bleomycin, Mitomycin), sub Nitroureas (Carmustine, Lomustine), inorganic ions (cisplatin, carboplatin), cell division cycle inhibitors (KSP via mitotic kinesin inhibitors, CENP-E and CDK inhibitors), enzymes (asparaginase), hormones (Tamoxifen, Leuprolide, Flutamide, Megestrol), Gleevec (

), Adriamycin, Dexamethasone, and cyclophosphamide. Anti-angiogenic factors (Avastin and others). Monoclonal antibody (Belimumab, Belimumab,

), Brentuximab (

), Cetuximab (Cetuximab,

), gemtuzumab (Gemtuzumab,

), Ipilimumab (Ipilimumab, ), Ofatumumab (Ofatumumab,

), Panitumumab (Panitumumab, ), Ranibizumab (Ranibizumab, ), Rituximab (Rituximab,

), Tositumomab (Tositumomab,

), Trastuzumab (Trastuzumab,

)). Kinase inhibitors (Imatinib,

), Sunitinib (Sunitinib,

), Sorafenib (Sorafenib,

), Cetuximab (Cetuximab,

), Trastuzumab (Trastuzumab, ), Erlotinib (Erlotinib,

)), Dasatinib (Dasatinib,

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

), cediranib, brivanib, telatinib, masitinib, neratinib, lenvatinib, ruxolitinib, linifanib, linsitinib, crizotinib, regorafenib, ponatinib, bosutinib, sarcatinib (saracatinib), afatinib, amuvatinib, ponatinib, quizartinib, vemurafenib (vemurafenib, ), Vandetanib (Vandetanib,

), olaparib, veliparib, iniparib, Iressa and others). Drugs inhibit or activate cancer pathways such as mTOR, HIF (hypoxia-inducible factor) pathway and others. See http://www.nci.nih.gov/ for a broader forum on cancer treatment, http://www.fda.gov/cder/cancer/druglist-rame.htm for a list of FDA-approved oncology drugs, and Gram Handbook, Eighteenth Edition. 2006, all contents are incorporated by reference.

In other embodiments, the compounds of the present invention can be combined with cytotoxic anticancer agents. Such anticancer agents can be found in the Thirteenth Edition of The Merck Index (2001). These anticancer agents include, but are not limited to, Asparaginase, Bleomycin, Carboplatin, Carmustine, Chlorambucil, Cisplatin, L-Asparaginase (Colaspase), Cyclophosphamide, Cytarabine (Cytarabine), Dacarbazine (Dacarbazine), Actinomycin D (Dactinomycin), Daunorubicin (Daunorubicin), Adriamycin ( Doxorubicin), Epirubicin, Etoposide, 5-Fluorouracil, Hexamethylmelamine, Hydroxyurea, Ifosfamide, Irinotecan, Leucovorin, Cyclohexamethylene Nitrocarbamide, nitrogen mustard, 6-mercaptopurine, mesna (Mesna), methotrexate (Methotrexate), mitomycin C (MitomycinC), mitoxantrone (Mitoxantrone), prednisolone (Prednisolone) , Prednisone, Procarbazine, Raloxifen, Streptozocin, Tamoxifen, Thioguanine, Topotecan , Vinblastine, Vincristine, Vindesine.

Other suitable cytotoxic drugs to be administered in combination with the compounds of the present invention include, but are not limited to, those compounds that are recognized for use in the treatment of neoplastic diseases, as described in Goodman and Gilman's The Pharmacological Basis of Therapeutics ( Ninth Edition, 1996, McGraw-Hill.); These anticancer agents include, but are not limited to, aminoglutethimide (Aminoglutethimide), L-asparaginase, azathioprine, 5-azacytidine, cladrol Cladribine, Busulfan, Diethylstilbestrol, 2',2'-Difluorodeoxycytidine, Docetaxel, Erythrohydroxynonyladenine, Ethinyl Estradiol, 5-fluorouridine deoxynucleoside, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin (Idarubicin), interferon, medroxyprogesterone acetate, megestrol acetate, melphalan (Melphalan), mitotane (Mitotane), paclitaxel, pentostatin (Pentostatin), N-phosphoacetyl-L -Aspartic Acid (PALA), Plicamycin (Plicamycin), Methylcyclohexylnitrosourea (Semustine), Teniposide (Teniposide), Testosterone Propionate, Thiotepa, Trimethylcyclohexyl Melamine, uridine and vinorelbine.

)，Trabedectin(Vidal et al.,Proceedings of the American Society for Clinical Oncology,2004,23,abstract3181)，和驱动蛋白纺锤体蛋白抑制剂Eg5(Wood et al.,Curr.Opin.Pharmacol.2001,1,370-377)。Other cytotoxic anticancer agents suitable for use in combination with the compounds of the present invention include newly discovered cytotoxic substances, including, but not limited to, oxaliplatin (Oxaliplatin), gemcitabine (Gemcitabine), capecitabine (Capecitabine), a macrolide antineoplastic drug and its natural or synthetic derivatives, Temozolomide (Quinn et al., J. Clin. Oncology, 2003, 21(4), 646-651), Torto Tositumomab (tositumomab,

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

In other embodiments, the compounds of the invention may be combined with other signal transduction inhibitors. Interestingly, signal transduction inhibitors target the EGFR family, such 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) and their respective ligands. Such agents include, but are by no means limited to, antibody therapies such as Herceptin (Trastuzumab), Cetuximab (Erbitux), and Pertuzumab. Such therapies also include, but are by no means limited to, small molecule kinase inhibitors such as Iressa (Gefitinib), Erlotinib, Tykerb (Lapatinib), CANERTINIB (CI1033), AEE788 (Traxler et al., Cancer Research , 2004, 64, 4931-4941).

In other embodiments, the compounds of the present invention target receptor kinases of the split kinase domain family (VEGFR, FGFR, PDGFR, flt-3, c-kit, c-fins, etc.) in combination with other signal transduction inhibitors. ), and their respective ligands. Such agents include, but are not limited to, antibodies such as bevacizumab (Avastin). Such agents include, but are by no means limited to, small molecule inhibitors such 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/Sinitinib/SU-11248, ZD-6474 (Hennequin et al al., 92nd AACR Meeting, New Orleans, Mar.24-28, 2001, abstract 3152), KRN-951 (Taguchi et al., 95th AACR Meeting, Orlando, FIa, 2004, abstract 2575), CP-547, 632 (Beebe et al. ., Cancer Res.2003,63,7301-7309), CP-673,451 (Roberts et al., Proceedings of the American Association of Cancer Research, 2004,45, abstract 3989), CHIR-258 (Lee et al., Proceedings of the American Association of Cancer Research, 2004, 45, abstract 2130), MLN-518 (Shen et al., Blood, 2003, 102, 11, abstract 476).

)，西妥昔单抗(Cetuximab,

，伊匹单抗(Ipilimumab,)和帕妥珠单抗(Pertuzumab)。这样的疗法也包括，但绝不限于，小分子激酶抑制剂如伊马替尼(Imatinib,

)，舒尼替尼(Sunitinib,

)，索拉非尼(Sorafenib,

)，厄洛替尼(Erlotinib,)，吉非替尼(Gefitinib,

)，达沙替尼(Dasatinib,

)，尼洛替尼(Nilotinib,

)，拉帕替尼(Lapatinib,

)，克卓替尼(Crizotinib,

)，Ruxolitinib(

)，Vemurafenib(

)，Vandetanib(

)，Pazopanib)，阿法替尼(Afatinib)，alisertib,amuvatinib，阿西替尼(axitinib)，波舒替尼(bosutinib)，brivanib，canertinib，cabozantinib，西地尼布(cediranib)，dabrafenib，dacomitinib，，danusertib，dovitinib，foretinib，ganetespib，ibrutinib，iniparib，lenvatinib，linifanib，linsitinib，马赛替尼（masitinib），momelotinib，莫替沙尼(motesanib)，来那替尼(neratinib)，niraparib，oprozomib，olaparib，pictilisib，ponatinib，quizartinib，regorafenib，rigosertib，rucaparib，塞卡替尼(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，等等。In other embodiments, the compounds of the invention may be combined with other signal transduction inhibitors. Interestingly, signal transduction inhibitors target the EGFR family, such 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) and their respective ligands. Such agents include, but are by no means limited to, antibody therapies such as Trastuzumab (Trastuzumab,

), Cetuximab (Cetuximab,

, Ipilimumab (Ipilimumab, ) and Pertuzumab. Such therapies also include, but are by no means limited to, small molecule kinase inhibitors such as Imatinib (Imatinib,

), Sunitinib (Sunitinib,

), Sorafenib (Sorafenib,

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

), Dasatinib (Dasatinib,

), Nilotinib (Nilotinib,

), lapatinib (Lapatinib,

), Crizotinib,

), Ruxolitinib (

), Vemurafenib (

), Vandetanib (

), Pazopanib ), afatinib, alisertib, amuvatinib, axitinib, bosutinib, brivanib, canertinib, cabozantinib, cediranib, dabrafenib, dacomitinib, danusertib , dovitinib, foretinib, ganetespib, ibrutinib, iniparib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, niraparib, oprozomib, olaparib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, saracatinib, saridegib, tandutinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vatalanib, veliparib, vismodegib, volasertib, BMS-540215, BMS7703587, 7JNJ TKI258, GDC-0941 (Folkes, et al., J. Med. Chem., 2008, 51, 5522), BZE235, etc.

In other embodiments, the compounds of the invention can bind to histone deacetylase inhibitors. Such reagents include, but are by no means limited to, suberoylanilide hydroxamic acid (SAHA), LAQ-824 (Ottmann et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, abstract 3024), LBH-589 (Beck et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, abstract 3025), MS-275 (Ryan et al., Proceedings of the American Association of Cancer Research, 2004, 45, abstract 2452), FR-901228 (Piekarz et al. ., Proceedings of the American Society for Clinical Oncology, 2004, 23, abstract 3028) and MGCDOI03 (US6,897,220).

In other embodiments, the compounds of the invention may be combined with other anticancer agents such as proteasome inhibitors and m-TOR inhibitors. These include, but are by no means limited to, Bortezomib (Mackay et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, Abstract 3109), and CCI-779 (Wu et al., Proceedings of the American Association of Cancer Research, 2004, 45, abstract 3849). The compounds of the invention may also be combined with other anticancer agents such as topoisomerase inhibitors, including but by no means limited to camptothecin.

Those additional therapeutic agents may be administered separately from the composition comprising the compound of the invention as part of a multiple dosing regimen. Alternatively, those therapeutic agents may be part of a single dosage form, mixed together with the compounds of this invention to form a single composition. If administered as part of a multiple dosing regimen, the two active agents may be delivered to each other simultaneously, sequentially or over a period of time, such that the desired agent activity is achieved.

The amount of the compound and the additional therapeutic agent (those compositions containing an additional therapeutic agent such as those described herein) which can be combined to produce a single dosage form will vary depending on the indication and the particular mode of administration. Normally, the amount of additional therapeutic agent in the compositions of the invention will not exceed the amount normally administered for a composition comprising the therapeutic agent as the only active agent. In another aspect, the disclosed compositions additional therapeutic agent in an amount ranging from about 50% to 100% of the normal amount of prior compositions, comprising the agent as the sole active therapeutic agent. In those compositions comprising an additional therapeutic agent, the additional therapeutic agent will act synergistically with the compound of the invention.

Uses of the compounds and compositions of the invention

The pharmaceutical composition of the present invention is characterized by comprising the compound represented by formula (I) or formula (II) or the compounds listed in the present invention, and a pharmaceutically acceptable carrier, adjuvant or vehicle. The amount of compound in the compositions of the invention is effective to detectably inhibit the activity of protein kinases such as VEGFR, c-Met, Ron or Axl. The compounds of the present invention will be used as antineoplastic agents to treat patients or reduce the deleterious effects of VEGFR, c-Met, Ron and/or Axl receptor signaling responses.

The compounds of the present invention will find use in, but in no way limited to, administering to a patient an effective amount of a compound or composition of the present invention to prevent or treat a proliferative disease in a patient. Such diseases include cancer, especially metastatic cancer, atherosclerosis, and pulmonary fibrosis.

The compound of the present invention will be applied to the treatment of tumors including cancer and metastatic cancer, further including but not limited to, cancer such as bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer (including small cell lung cancer), esophageal cancer, Cancer of the gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin (including squamous cell carcinoma); hematopoietic neoplasms of the lymphatic system (including leukemia, acute lymphocytic leukemia, acute lymphoblastic Leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell leukemia and Burkitt's lymphoma); hematopoietic tumors of the bone marrow system (including acute and chronic myelogenous myelogenous leukemia, myelodysplastic syndrome, and promyelocytic leukemia); tumors of mesenchymal origin (including fibrosarcoma and rhabdomyosarcoma, and other sarcomas, such as soft tissue and cartilage); tumors of the central peripheral nervous system ( including astrocytoma, neuroblastoma, glioma, and schwannoma); and other tumors (including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid fibrosis Tumor and Kaposi's sarcoma).

The compounds of the present invention are also useful in the treatment of ophthalmic disorders such as corneal graft rejection, neovascularization of the eye, retinal neovascularization including neovascularization following injury or infection; diabetic retinopathy; retrolentic fibroplasia, and neovascularization glaucoma; retinal ischemia; vitreous hemorrhage; ulcerative disease such as gastric ulcer; pathological but nonmalignant conditions such as hemangiomas, including infantile hemangioendothelioma, nasopharyngeal and angiofibroma of avascular osteonecrosis; female reproductive Systemic disorders such as endometriosis. These compounds are also useful in the treatment of edema and vascular hyperpermeability conditions.

The compounds of the present invention are useful in the treatment of conditions associated with diabetes such as diabetic retinopathy and microangiopathy. The compounds of the invention are also useful in cases of reduced blood flow in cancer patients. The compounds of the invention also have a beneficial effect on the reduction of tumor metastasis in patients.

In addition to their therapeutic benefits in humans, the compounds of the present invention are also useful in the veterinary treatment of pets, introduced breeds and farm animals, including mammals, rodents and the like. Examples of additional animals include horses, dogs and cats. Here, the compounds of the present invention include their pharmaceutically acceptable derivatives.

Where the plural form is applied to a compound, salt, etc., it also means a single compound, salt, etc.

The method of treatment comprising the administration of the compound or composition of the present invention further comprises the administration of an additional therapeutic agent (combination therapy) to the patient, wherein the additional therapeutic agent is selected from: chemotherapy, anti-proliferative or anti-inflammatory agents, wherein the additional therapeutic The agent is appropriate for the condition being treated, and the additional therapeutic agent may be administered in combination with the compound or composition of the invention as a single dosage form, or as separate compounds or compositions as part of a multiple dosage form. Additional therapeutic agents may be administered at the same time or at different times as the compounds of the invention. In the latter case, the administration may be staggered for 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month or 2 months.

The present invention also includes a method of inhibiting the growth of cells expressing VEGFR, c-Met, Ron or Axl, the method comprising contacting the compound or composition of the present invention with the cells, thereby inhibiting the growth of the cells. Cells whose growth can be inhibited include: breast cancer cells, colorectal cancer cells, lung cancer cells, papillary cancer cells, prostate cancer cells, lymphoma cells, colon cancer cells, pancreatic cancer cells, ovarian cancer cells, cervical cancer cells, Central nervous system cancer cells, osteosarcoma cells, kidney cancer cells, hepatocellular carcinoma cells, bladder cancer cells, gastric cancer cells, head or neck squamous cell carcinoma cells, melanoma cells and leukemia cells.

The present invention provides a method for inhibiting the activity of VEGFR, c-Met, Ron or Axl kinase in a biological sample, the method comprising contacting a compound or composition of the present invention with the biological sample. The term "biological specimen" used in the present invention refers to specimens outside the living body, including but not limited to, cell culture or cell extraction; biopsy material obtained from mammals or their extracts; blood, saliva, urine, Feces, semen, tears, or other liquid substances of living tissue and their extracts. Inhibition of kinase activity in biological specimens, particularly VEGFR, c-Met, Ron and Axl kinase activity, can be used for a variety of purposes well known to those skilled in the art. Such uses include, but are by no means limited to, blood transfusions, organ transplantation, biospecimen storage, and bioassays.

An "effective amount" or "effective dose" of a compound or pharmaceutically acceptable composition of the present invention refers to an effective amount for treating or reducing the severity of one or more of the conditions mentioned in the present invention. According to the methods of the present invention, the compounds and compositions may be administered in any amount and by any route of administration effective for treating or lessening the severity of a disease. The exact amount necessary will vary from patient to patient, depending on race, age, general condition of the patient, severity of infection, particular factors, mode of administration, and the like. A compound or composition may be administered in combination with one or more other therapeutic agents, as discussed herein.

The compounds of the present invention or their pharmaceutical compositions can be applied to the coating of implantable medical devices, such as prostheses, artificial valves, artificial blood vessels, stems and urinary catheters. Vascular stems, for example, have been used to overcome restenosis (reconstriction of vessel walls after injury). However, patients using stems or other implantable devices will be at risk of clot formation or platelet activation. These adverse effects can be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a compound of the invention.

Suitable coatings and general preparation of coatings for implantable devices are described in documents US 6,099,562, US 5,886,026 and US 5,304,121, the coatings being typically biocompatible polymeric materials such as water Gel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coating may optionally be further covered with a suitable coating, such as fluorosimethicone, polysaccharase, polyethylene glycol, phospholipids, or a combination thereof, to exhibit controlled-release characteristics of the composition. Another aspect of the invention includes implantable devices coated with a compound of the invention. The compounds of the present invention may also be coated on implantable medical devices, such as beads, or mixed with polymers or other molecules to provide "drug depots", thus allowing drug Release has a longer time period.

General Synthesis Process

Generally, the compounds of the present invention can be prepared by the methods described in the present invention, and unless otherwise specified, the definitions of the substituents are as shown in formula (I) or formula (II). The following reaction schemes and examples serve to further illustrate the present invention.

Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare many other compounds of the invention and that other methods for preparing the compounds of the invention are considered to be within the scope of the invention Inside. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by using other known reagents in addition to those described in the present invention, or by incorporating Reaction conditions with some routine modifications. In addition, reactions disclosed herein or known reaction conditions are also recognized to be applicable to the preparation of other compounds of this invention.

In the examples described below, unless indicated otherwise, all temperatures are in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and used without further purification unless otherwise indicated. General reagents from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Factory, Wuhan Xinhuayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory can be purchased.

Anhydrous tetrahydrofuran, dioxane, toluene, and ether were obtained by reflux drying over sodium metal. Anhydrous dichloromethane and chloroform were obtained by refluxing and drying over calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.

The following reactions are generally carried out under positive pressure of nitrogen or argon or over anhydrous solvents with a drying tube (unless otherwise indicated), the reaction vials are all stoppered with suitable rubber stoppers, and the substrate is injected by syringe. Glassware is dried.

The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory. The NMR spectrum uses CDCl ₃ , DMSO-d ₆ , CD ₃ OD or acetone-d ₆ as the solvent (in ppm), and TMS (0 ppm) or chloroform (7.25 ppm) as the reference standard. When multiplets appear, the following abbreviations will be used: s (singlet, singlet), d (doublet, doublet), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broadened) peak), dd (doublet of doublets, double doublet), dt (doublet of triplets, double triplet). Coupling constants are expressed in Hertz (Hz).

The conditions for low-resolution mass spectrometry (MS) data are: Agilent1200Series LCMS (Zorbax SB-C18, 2.1×30mm, 4 microns, 10min, flow rate 0.6mL/min, 5%-95% (0.1% dissolved in H ₂ O Formic acid) (0.1% formic acid dissolved in CH ₃ CN)), with UV detection at 210/254 nm, using low-response electrospray mode (ESI).

Pure compounds were characterized by Agilent 1100 Series High Performance Liquid Chromatography (HPLC) with UV detection at 210 nm and 254 nm. Columns were operated at 40°C.

The following abbreviations are used throughout this disclosure:

Ac ₂ O acetic anhydride

ATP Adenosine triphosphate

BBr ₃ boron tribromide

BINAP 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl

BSA bovine serum albumin

BOC, Boc tert-butoxycarbonyl

Ca(SO ₃ CF ₃ ) ₂ calcium trifluoromethylsulfate

Cs ₂ CO ₃ cesium carbonate

CHCl ₃ Chloroform

CDCl ₃ deuterated chloroform

CH ₂ Cl ₂ , DCM dichloromethane

Cu Copper

CuI Cuprous iodide

Et ₂ O diethyl ether

EtOH ethanol

DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

D ₂ Deuterium

DIBAL Diisobutylaluminum hydride

DIAD Diisopropyl azodicarboxylate

DIEA, DIPEA, iPr ₂ Net N,N-Diisopropylethylamine

DEAD diethyl azodicarboxylate

DMF N,N-dimethylformamide, dimethylformamide

DMAP 4-Dimethylaminopyridine

DMSO Dimethyl Sulfoxide

DPPA diphenylphosphoryl azide

DTT dimercaptothreitol

EDC,EDCI 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

EDTA ethylenediaminetetraacetic acid

EtOAc, EA ethyl acetate

Et ₃ N,TEA Triethylamine

FBS Fetal Bovine Serum

g grams

h hours

HATU 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

HBr hydrobromic acid

HCl hydrochloric acid

HOAc Acetic acid

HOAT N-Hydroxy-7-azabenzotriazole

HOBt 1-Hydroxybenzotriazole Hydrate

H ₂ hydrogen

_H2O water

H ₂ O ₂ hydrogen peroxide

H ₃ PO ₄ phosphoric acid

H ₂ SO ₄ sulfuric acid

HNO ₃ nitric acid

HCOOK Potassium formate

Fe iron

LiHMDS lithium hexamethyldisilazyl

LDA lithium diisopropylamide

MBP myelin basic protein

MCPBA m-chloroperoxybenzoic acid

MeCN, CH ₃ CN Acetonitrile

MgSO ₄ magnesium sulfate

Mg ATP Magnesium Adenosine Triphosphate

MeOH, CH ₃ OH Methanol

MeI methyl iodide

MOPS 3-(N-morpholino)propanesulfonic acid

mL,ml Milliliter

N ₂ Nitrogen

NMP N-Methylpyrrolidone

NaHCO ₃ sodium bicarbonate

NaBH ₄ sodium borohydride

NaBH ₃ CN Sodium cyanoborohydride

NaOtBu Sodium tert-butoxide

NaOH Sodium Hydroxide

NaClO ₂ sodium chlorite

NaCl Sodium Chloride

NaH ₂ PO ₄ sodium dihydrogen phosphate

NaH Sodium hydride

NaI Sodium iodide

Sodium Na ₂ SO ₄ Sulfate

NBS N-Bromosuccinimide

Nonidet Nonidet lotion

NH ₃ ammonia

NH ₄ Cl Ammonium Chloride

Pd/C Palladium/carbon

Pd ₂ (dba) ₃ Tris(dibenzylideneacetone)dipalladium

Pd(OAc) ₂ palladium acetate

Pd(OH) ₂ palladium hydroxide

Pd(PPh ₃ ) _4tetrakis (triphenylphosphine)palladium

Pd(dppf)Cl ₂ 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride

P(t-Bu) ₃ tri(tert-butyl)phosphine

PE petroleum ether (60-90°C)

PBS Phosphate Buffered Saline

POCl ₃ phosphorus oxychloride

PhI(OAc) ₂ iodobenzene diacetate

_{K2CO3potassium carbonate}

KOH potassium hydroxide

RT, rt, r.t. room temperature

Rt retention time

SOCl ₂ thionyl chloride

t-BuOK Potassium tert-butoxide

TBTU O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate

THF Tetrahydrofuran

TFA trifluoroacetic acid

TBAI Tetrabutylammonium iodide

TBS tris buffered saline

TEAC bis(tetraethylammonium) carbonate

Tris Tris hydroxymethyl aminomethane

The synthetic schemes 1-4 are typical synthetic schemes for the preparation of the following example compounds. Each of X, Y, Z, W, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ has the meaning described in the present invention.

Synthetic Scheme 1

The compound of the present invention can be prepared through the above synthesis scheme 1, and the specific synthesis scheme is described in the examples. In Synthesis Scheme 1, 6-aminopyridin-3-ol ( 1 ) is first condensed with substituted pyrazolone compound ( 2 ) to generate compound ( 3 ). Under basic conditions (for example, using potassium t-tert-butoxide or sodium hydride), pyridinecarboxamide ( 4 ) reacts with compound ( 3 ) at elevated temperature and in a polar solvent (such as DMF) to give the amide compound ( 5 ). Amide compound ( 5 ) undergoes rearrangement under the action of oxidant iodobenzene diacetate or NaClO to obtain aminopyridine compound ( 6 ), and compound ( 6 ) is further acetylated to obtain the target kinase inhibitor ( 7 ).

Synthetic scheme 2

The compound of the present invention can also be prepared through the above synthesis scheme 2, and the specific synthesis scheme is described in the examples. In Synthesis Scheme 2, nitro derivatives ( 8 ) were reduced to aniline compounds ( 9 ) under catalytic hydrogenation conditions. The substituted aniline compound ( 9 ) and 4-chloropyridin-2-amine ( 10 ) were dissolved in dimethyl sulfoxide and placed under microwave conditions to react to obtain the diaryl ether compound ( 11 ). Compound ( 11 ) is condensed with substituted pyrazolone compound ( 2 ) to generate aminopyridine compound ( 12 ). Under alkaline conditions, compound ( 12 ) can be further converted into the target kinase inhibitor ( 13 ) under alkaline conditions.

Synthetic scheme 3

The compound of the present invention can also be prepared through the above synthesis scheme 3, and the specific synthesis scheme is described in the examples. In Synthesis Scheme 3, the aryl compound ( 14 ) is coupled with the substituted pyridine compound ( 15 ) at elevated temperature to obtain the diaryl ether compound ( 16 ). Compound ( 16 ) undergoes condensation reaction with substituted pyrazolone compound ( 2 ) to generate amide pyridine compound ( 17 ). Compound ( 17 ) undergoes a rearrangement reaction under the action of oxidant iodobenzene diacetate or NaClO to obtain the target kinase inhibitor ( 18 ).

Synthetic Scheme 4

Other compounds of the present invention can also be prepared by the above-mentioned synthetic scheme 4, aminopyridine compound ( 18 ) undergoes an acylation reaction with an acetylating reagent (such as acetic anhydride or acetyl chloride) under alkaline conditions to generate the target kinase inhibitor ( 19) .

Example

Example 1N-(4-((2-aminopyridin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro- 1H-pyrazole-4-carboxamide

Step 1) 4-Aminophenol

4-Nitrophenol (7g, 50.3mmol) and HCOOK (1.8g, 21.48mmol) were dissolved in THF (210mL) and water (70mL), then Pd/C (110mg, 10%Pd content, 53 %~55% water content). The reaction solution was stirred and reacted at 50° C. for 24 hours, and then concentrated in vacuo. The residual reaction solution was diluted with dichloromethane (100 mL) and filtered through celite. The filtrate was concentrated in vacuo to afford the title compound as a pale orange solid (3.28 g, 60%).

MS (ESI, pos.ion) m/z: 110.1 [M+H] ⁺ .

Step 2) 4-(4-aminophenoxy)pyridin-2-amine

4-Aminophenol (218 mg, 2 mmol) and 4-chloropyridin-2-amine (256 mg, 2 mmol) were dissolved in dimethylsulfoxide (2.5 mL), then solid sodium methoxide (216 mg, 4 mmol) was added. The reaction solution was placed under microwave, reacted at 180° C. for 40 minutes, cooled to room temperature, and quenched with water (10 mL). The reaction mixture was extracted with ethyl acetate (10 mL x 3), the combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/CH ₃ OH (v/v)=30/1) to obtain the title compound as a brown solid (103 mg, 26%).

MS(ESI,pos.ion)m/z:202.2[M+H] ⁺ ;

¹ H 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-((2-aminopyridin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro -1H-pyrazole-4-carboxamide

4-(4-aminophenoxy)pyridin-2-amine (101mg, 0.5mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H- Pyrazole-4-carboxylic acid (118 mg, 0.51 mmol) was dissolved in dichloromethane (5 mL), then EDCI (115 mg, 0.6 mmol) and HOAT (13.6 mg, 0.1 mmol) were added. After the reaction solution was stirred at 45° C. for 3 hours, the reaction was quenched with water (20 mL). The organic phase was separated and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/CH ₃ OH (v/v)=20/1) to obtain the title compound as a light gray solid (110 mg, 49.2%).

MS(ESI,pos.ion)m/z:416.4[M+H] ⁺ ;

¹ H 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).

Example 2N-(4-((2-amino-3-chloropyridin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3 -Dihydro-1H-pyrazole-4-carba Amide

Step 1) N-(4-Hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide

4-Aminophenol (1.09g, 10mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (2.37g, 10.2 mmol) was dissolved in dichloromethane (30 mL), then EDCI (2.3 g, 12 mmol) and HOAT (0.27 g, 2 mmol) were added. After the reaction mixture was stirred at 46° C. for 4 hours, it was cooled to room temperature and diluted with ethyl acetate (10 mL) and water (10 mL). After the reaction mixture was stirred at room temperature for 1 hour, it was filtered to give the title compound as a white solid (1.7 g, 52.5%).

MS(ESI,pos.ion)m/z:324.1[M+H] ⁺ ;

¹ H 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-pyridinecarboxamide

2,2,6,6-Tetramethylpiperidine (6.2mL, 37.2mmol) was dissolved in diethyl ether (50mL), and then dissolved in hexane (2.5M, 23mL) was added via syringe at 0°C over 15 minutes. , 57.5mmol) of n-butyllithium. After the reaction solution was stirred at 0°C for 0.5 hours, it was lowered to -78°C for 0.5 hours, then 3,4-dichloropyridine (5.00g, 33.8 mmol) solution. After the reaction solution was stirred at -78°C for 2 hours, trimethylsilylisocyanate (94% purity, 6.7 mL, 50.7 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 2 hours, then quenched with acetic acid (6.76 g, 112.6 mmol) and 35 mL of water. Stirring was continued overnight, and a white solid precipitated out, which was collected by filtration. The filtrate was extracted with ethyl acetate (50 mL x 3), and the combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting solids were combined and washed with 35 mL of ether to give the title compound as a pale yellow solid (2.20 g, 34.0%).

MS(ESI,pos.ion)m/z:191.1[M+H] ⁺ ;

¹ H 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=5.2 Hz, 1H).

Step 3) 3-chloro-4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)benzene Oxy)pyridinamide

N-(4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (356mg, 1.1mmol ) was dissolved in dimethyl sulfoxide (4 mL) and placed in a microwave vial, then NaH (88 mg, 2.2 mmol, 60% dispersion in mineral oil) was added at room temperature. The reaction solution was stirred at room temperature for 30 minutes, and then 3,4-dichloro-2-pyridinecarboxamide (191 mg, 1.0 mmol) was added. The reaction mixture was placed under microwave at 160°C for 2 hours, cooled to room temperature, and diluted with water (10 mL). The resulting mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to obtain the title compound as a light yellow solid (140 mg, 29%).

MS(ESI,pos.ion)m/z:478.1[M+H] ⁺ ;

¹ H 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-chloropyridin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2, 3-Dihydro-1H-pyrazole-4-carboyl amine

3-chloro-4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)phenoxy ) pyridine amide (140mg, 0.29mmol) was dissolved in a mixed solution of ethyl acetate (2.5mL), acetonitrile (2.5mL) and water (1.3mL), then added iodobenzene diacetate (113mg, 0.35mmol ). After the reaction solution was stirred at 0° C. for 30 minutes, it was raised to room temperature and stirred for 4 hours. The reaction mixture was diluted with dichloromethane (30 mL), washed with brine (20 mL x 3), and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to obtain the title compound as a pale yellow solid (37 mg, 26.8%).

MS(ESI,pos.ion)m/z:450.1[M+H] ⁺ ;

¹ H 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).

Example 3N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl -2,3-Dihydro-1H-pyrazole -4-formamide

Step 1) 4-(4-Amino-2-fluorophenoxy)-3-chloropyridinamide

4-Amino-2-fluorophenol (254 mg, 2.0 mmol) was dissolved in dimethylformamide (5 mL), and potassium tert-butoxide (359 mg, 3.2 mmol) was added. The reaction solution was stirred at room temperature for 30 minutes, and then 3,4-dichloro-2-pyridinecarboxamide (420 mg, 2.2 mmol) was added. The reaction mixture was placed under a microwave oven at 120°C for 2 hours, cooled to room temperature, and diluted with 25 mL of water. The resulting mixture was extracted with ethyl acetate (30 mL x 3), and the combined organic phases were washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=2/1) to obtain the title compound as a pale yellow solid (306 mg, 54.4%).

MS(ESI,pos.ion)m/z:282.1[M+H] ⁺ ;

¹ H 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) 3-chloro-4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)- 2-fluorophenoxy)pyridinamide

Mix 4-(4-amino-2-fluorophenoxy)-3-chloropyridinamide (306mg, 1.40mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3- Dihydro-1H-pyrazole-4-carboxylic acid (390 mg, 1.68 mmol) was suspended in dichloromethane (6 mL), then EDCI (322 mg, 1.68 mmol) and HOAT (38 mg, 0.28 mmol) were added. After stirring the reaction mixture at 45 °C for 14.5 hours, it was cooled to room temperature and quenched with 5 mL of water. The reaction mixture was extracted with ethyl acetate (10mL x3), and the combined organic phases were washed with brine (10mL x3), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/4) to obtain the title compound as a pale yellow solid (647 mg, 93.2%).

MS(ESI,pos.ion)m/z:496.1[M+H] ⁺ ;

¹ H 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=2.2 Hz,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-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-benzene Base-2,3-dihydro-1H-pyrazole-4- Formamide

3-chloro-4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2- Fluorophenoxy)pyridinamide (437mg, 0.88mmol) was suspended in a mixed solution of ethyl acetate (5mL), acetonitrile (5mL) and water (2.5mL), and then iodobenzene diacetate (341mg, 1.06 mmol). After the reaction solution was stirred at 0° C. for 30 minutes, it was warmed up to room temperature and stirred for 3 hours. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/3) to obtain the title compound as a yellow solid (290 mg, 70.6%).

MS(ESI,pos.ion)m/z:468.2[M+H] ⁺ ;

¹ H 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).

Example 4N-(4-((2-acetylamino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-benzene Group-2,3-dihydro-1H- Pyrazole-4-carboxamide

Step 1) N-(4-((2-(N-acetylacetamido)-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3 -Oxo-2-phenyl-2,3- Dihydro-1H-pyrazole-4-carboxamide

Compound N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl- 2,3-Dihydro-1H-pyrazole-4-carboxamide (0.22g, 0.47mmol), a mixture of acetic anhydride (1.3mL, 13.75mmol) and Et ₃ N (0.51g, 5.04mmol) at 60°C After stirring the reaction for 24 hours, the reaction was quenched by adding saturated Na ₂ CO ₃ aqueous solution (50 mL), the resulting mixture was extracted with EtOAc (50 mL x 3), the combined organic phases were washed with brine (50 mL x 3), washed with anhydrous Na ₂ SO ₄ was dried, then concentrated under reduced pressure, and the obtained crude product was directly used in the next reaction without further purification.

MS (ESI, pos.ion) m/z: 552.1 [M+H] ⁺ .

Step 2) N-(4-((2-Acetamido-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2- Phenyl-2,3-dihydro-1H-pyridine Azole-4-carboxamide

The compound N-(4-((2-(N-acetylacetamido)-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3- Oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (259 mg, 0.47 mmol) was dissolved in CH ₃ OH (20 mL), and Na ₂ CO ₃ was added to the reaction solution (59.8 mg, 0.56 mmol) in water (1 mL). After stirring the reaction at room temperature for 15 minutes, it was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (CH ₃ OH/EtOAc (v/v)=1/50) to obtain the title compound as a beige solid (160mg, 66.7% ).

MS(ESI,pos.ion)m/z:510.1[M+H] ⁺ ;

¹ H 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,9.0 Hz, 1H), 6.67(d, J=5.4Hz, 1H), 3.40(s, 3H), 2.71(s, 3H), 2.08(s, 3H).

Example 5N-(4-((2-aminopyridin-4-yl)oxy)-2,3-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl- 2,3-Dihydro-1H-pyrazole-4- Formamide

Step 1) 1-(Benzyloxy)-2,3-difluoro-4-nitrobenzene

Dissolve 2,4,5-trifluoronitrobenzene (5.00g, 28.2mmol) and benzyl alcohol (3.07g, 28.4mmol) in dimethylformamide (10mL), then add potassium carbonate (5.87g, 42.5 mmol). The reaction solution was stirred at room temperature for 72 hours, diluted with water (35 mL), and stirred at 4° C. overnight. After filtration, the obtained precipitate was washed with water (20 mL), and then purified by silica gel column chromatography (EtOAc/PE (v/v)=1/20) to obtain the title compound as a pale yellow solid (2.15 g, 28.7%).

¹ H 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

1-(Benzyloxy)-2,3-difluoro-4-nitrobenzene (1.93 g, 0.73 mmol) was suspended in a mixed solution of methanol (45 mL) and tetrahydrofuran (9 mL), and then Pd/C ( 333mg, 6% Pd content, 53% to 55% water content). After the reaction mixture was stirred at 32°C under H for ₁₃ hours, it was filtered through celite, and the filter cake was washed with 50 mL of ethyl acetate. The crude product obtained after the filtrate was concentrated in vacuo was washed with 30 mL of dichloromethane to afford the title compound as a dark brown solid (0.89 g, 84%).

MS(ESI,pos.ion)m/z:146.2[M+H] ⁺ ;

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

Step 3) 4-(4-Amino-2,3-difluorophenoxy)pyridineamide

4-Amino-2,3-difluorophenol (208 mg, 1.43 mmol) was dissolved in dimethylformamide (4 mL), then potassium tert-butoxide (257 mg, 2.29 mmol) was added. After the reaction solution was stirred at room temperature for 30 minutes, 4-chloropyridinecarboxamide (249 mg, 1.59 mmol) was added. The reaction mixture was placed under microwave at 120 °C for 3 h, then cooled to room temperature and diluted with 25 mL of water. The resulting mixture was extracted with ethyl acetate (30mL x3), and the combined organic phases were washed with brine (30mL x3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to obtain the title compound as an orange solid (110 mg, 41.5%).

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

¹ H 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-1H-pyrazole-4-carboxamido)-2,3- Difluorophenoxy)pyridineamide

4-(4-Amino-2,3-difluorophenoxy)pyridineamide (180mg, 0.68mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-di Hydrogen-1H-pyrazole-4-carboxylic acid (161 mg, 0.69 mmol) was suspended in dichloromethane (4 mL), then EDCI (157 mg, 0.82 mmol) and HOAT (19 mg, 0.14 mmol) were added. After the reaction mixture was stirred at 45°C for 12 hours, 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (87mg , 0.37mmol), the reaction mixture continued to stir at 45°C for 5 hours, and after cooling to room temperature, the reaction was quenched with 5mL of water and extracted with ethyl acetate (10mL x3). The combined organic phases were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (neat EtOAc) to afford the title compound as an orange solid (108 mg, 33.2%).

MS(ESI,pos.ion)m/z:480.1[M+H] ⁺ ;

¹ H 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-((2-aminopyridin-4-yl)oxy)-2,3-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl -2,3-Dihydro-1H-pyrazole-4- Formamide

4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2,3-difluoro Phenoxy)pyridine amide (108mg, 0.22mmol) was suspended in a mixed solution of ethyl acetate (2.5mL), acetonitrile (2.5mL) and water (1.5mL), then iodobenzene diacetate (96mg ,0.30mmol). After the reaction solution was stirred at 0° C. for 30 minutes, it was warmed up to room temperature and stirred for 4 hours. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (EtOAc/CH ₃ OH (v/v)=10/1) to obtain the title compound as a pale yellow solid (32 mg, 32.3%).

MS(ESI,pos.ion)m/z:452.2[M+H] ⁺ ;

¹ H 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).

Example 6N-(4-((2-acetylaminopyridin-4-yl)oxy)-2,3-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl -2,3-Dihydro-1H-pyridine Azole-4-carboxamide

The compound N-(4-((2-aminopyridin-4-yl)oxy)-2,3-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl- 2,3-dihydro-1H-pyrazole-4-carboxamide (135mg, 0.3mmol) was suspended in acetic anhydride (6mL), then triethylamine (0.4mL, 2.9mmol) was added to the reaction solution, and the After stirring the reaction at °C for 4 hours, it was filtered with suction, and the filter cake was washed successively with PE (5 mL), EtOAc (5 mL) and CH ₃ OH (2 mL) to obtain the title compound as a beige solid (102 mg, 68.9%).

MS(ESI,pos.ion)m/z:494.1[M+H] ⁺ ;

¹ H 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).

Example 7N-(4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2, 3-Difluorophenoxy)pyridine-2- base) morpholine-4-carboxamide

The compound N-(4-((2-aminopyridin-4-yl)oxy)-2,3-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl- 2,3-Dihydro-1H-pyrazole-4-carboxamide (224mg, 0.50mmol) was suspended in THF (3mL), then triethylamine (0.138mL, 0.99mmol) was added to the reaction solution, followed by Phenyl chloroformate (0.125mL, 1.00mmol) was added dropwise, the mixture was stirred and reacted at room temperature for 2 hours, then morpholine (0.4mL, 5.00mmol) was added, the mixture was stirred and reacted at room temperature for 36 hours, then saturated NH ₄ Cl aqueous solution (20mL) and CH ₂ Cl ₂ (20mL) quenched the reaction, and the resulting mixture was stirred at room temperature for 10 minutes, then extracted with CH ₂ Cl ₂ (20mL x3), and the combined organic phases were washed with brine (20mL x3), washed with anhydrous Na ₂ SO ₄ , then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=20/1) to obtain the title compound as an orange solid (148mg ,52.5%).

MS(ESI,pos.ion)m/z:565.2[M+H] ⁺ ;

¹ H 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).

Example 8 N-(4-((2-aminopyridin-4-yl)oxy)-2,5-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl- 2,3-Dihydro-1H-pyrazole-4- Formamide

Step 1) 1-(Benzyloxy)-2,5-difluoro-4-nitrobenzene

A mixed solution of 2,4,5-trifluoronitrobenzene (5.4g, 30.5mmol) and benzyl alcohol (3.2mL, 30.5mmol) was dissolved in dimethylformamide (20mL), and potassium carbonate (6.33g, 46.1 mmol). The reaction solution was stirred at room temperature for 72 hours. After adding water (60 mL) at 0°C, the resulting reaction mixture was stirred at 4°C for 24 hours. The solid was collected by filtration, washed with 30 mL of water, and dried under vacuum at 45°C to give the title compound as a light yellow solid (6.0 g, 74%).

¹ H 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

1-(Benzyloxy)-2,5-difluoro-4-nitrobenzene (1.06g, 4mmol) was suspended in a mixed solution of methanol (25mL) and tetrahydrofuran (5mL), and then Pd/C (50 %Pd content, 185mg). The reaction solution was stirred and reacted at 32° C. under H ₂ for 10 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated in vacuo. The resulting residue was washed with dichloromethane (15 mL) to give the title compound as a dark brown solid (500 mg, 86%).

MS(ESI,pos.ion)m/z:146.2[M+H] ⁺ ;

¹ H NMR (400 MHz, 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-difluorophenoxy)pyridineamide

4-Amino-2,5-difluorophenol (100mg, 0.64mmol) and 4-chloropyridinecarboxamide (110mg, 0.71mmol) were dissolved in dimethylformamide (2mL), then NaH (80mg, 1.3mmol) was added , 60% dispersed in mineral oil). The reaction solution was placed under a microwave and reacted at 120° C. for 1.5 hours. The reaction mixture was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with brine (80 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/PE (v/v)=4/1) to afford the title compound as a brown solid (52 mg, 26%).

MS (ESI, pos.ion) m/z: 266.2 [M+H] ⁺ .

Step 4) 4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2,5- Difluorophenoxy)pyridineamide

4-(4-Amino-2,5-difluorophenoxy)pyridineamide (200mg, 0.76mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-di A mixed solution of hydrogen-1H-pyrazole-4-carboxylic acid (165 mg, 0.75 mmol) was dissolved in dichloromethane (10 mL), then EDCI (175 mg, 0.93 mmol) and HOAT (26 mg, 0.15 mmol) were added. The reaction was stirred at 45° C. for 16 hours, cooled to room temperature, and diluted with ethyl acetate (20 mL). The resulting solid was filtered and dried under vacuum at 45°C overnight to give the title compound as a white solid (230 mg, 63.7%).

MS(ESI,pos.ion)m/z:480.1[M+H] ⁺ ;

¹ H 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-((2-aminopyridin-4-yl)oxy)-2,5-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl -2,3-Dihydro-1H-pyrazole-4- Formamide

4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2,5-difluoro Phenoxy)pyridineamide (80mg, 0.17mmol) was dissolved in a mixed solution of ethyl acetate (2mL), acetonitrile (2mL) and water (1mL), and then iodobenzene diacetate (70mg, 1.2mmol) was added. After the reaction solution was stirred at 0° C. for 30 minutes, it was warmed up to room temperature and stirred for 8 hours. The reaction mixture was filtered through celite, and the filter cake was washed with ethyl acetate (30 mL). The filtrate was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (DCM/CH ₃ OH (v/v)=20/1) to obtain the title compound as a white solid (51 mg, 68%).

MS(ESI,pos.ion)m/z:452.1[M+H] ⁺ ;

¹ H 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).

Example 9N-(4-((2-acetylaminopyridin-4-yl)oxy)-2,5-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl -2,3-Dihydro-1H-pyridine Azole-4-carboxamide

The compound N-(4-((2-aminopyridin-4-yl)oxy)-2,5-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl- 2,3-Dihydro-1H-pyrazole-4-carboxamide (220mg, 0.48mmol) was dissolved in acetic anhydride (8mL), then Et ₃ N (0.5mL, 1.32mmol) was added to the reaction solution, stirred at room temperature After reacting for 8 hours, it was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (DCM/CH ₃ OH (v/v)=10/1) to obtain the title compound as a white solid (175 mg, 73%).

MS(ESI,pos.ion)m/z:494.0[M+H] ⁺ ;

¹ H 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,5.7 Hz, 1H), 3.32(s, 3H), 2.70(s, 3H), 2.04(s, 3H).

Example 10N-(4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2, 5-difluorophenoxy)pyridine-2- base) morpholine-4-carboxamide

Compound N-4-((2-aminopyridin-4-yl)oxy)-2,5-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2 , 3-dihydro-1H-pyrazole-4-carboxamide (250mg, 0.56mmol) and Et ₃ N (0.25mL, 1.68mmol) were suspended in THF (10.0mL), then chloroformic acid benzene was added to the reaction solution Ester (0.25mL, 1.68mmol), stirred at room temperature for 2 hours, added morpholine (0.35mL, 3.46mmol), the mixture was stirred at room temperature for 24 hours, added NH ₄ Cl aqueous solution (40mL) and DCM (40mL), divided liquid, the aqueous phase was extracted with DCM (40mL x3), the combined organic phases were dried over anhydrous Na ₂ SO ₄ , then concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (EtOAc/PE(v/v)=4 /1) Purification afforded the title compound as a white solid (70 mg, 21%).

MS(ESI,pos.ion)m/z:565.0[M+H] ⁺ ;

¹ H 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,5.6 Hz, 1H), 3.53-3.56(m, 4H), 3.40-3.41(m, 4H), 3.35(s, 3H), 2.70(s, 3H).

Example 11N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-1,5-dimethyl-3-oxo-2 -Phenyl-2,3-dihydro-1H- Pyrazole-4-carboxamide

Step 1) 3-chloro-4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)- 2,5-Difluorophenoxy)pyridineamide

The compound N-(2,5-difluoro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4 -Formamide (395mg, 1.1mmol) was dissolved in DMF (5.0mL), then t-BuOK (202mg, 1.8mmol) was added to the reaction solution, stirred at room temperature for 30 minutes, and 3,4-dichloro-2- Pyridinecarboxamide (190mg, 1.0mmol), the mixture was stirred and reacted at 120°C under microwave conditions for 2 hours, cooled to room temperature, added water (30mL) to quench the reaction, the mixture was extracted with EtOAc (50mL x3), and the combined organic The phase was washed with brine (50mL x3), dried over anhydrous Na ₂ SO ₄ , then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/30) to obtain the title The compound was a pale yellow solid (310 mg, 60%).

MS(ESI,pos.ion)m/z:514.2[M+H] ⁺ ;

¹ H 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-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-1,5-dimethyl-3-oxo- 2-Phenyl-2,3-dihydro-1H-pyridine Azole-4-carboxamide

The compound 3-chloro-4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2 ,5-Difluorophenoxy)pyridineamide (310mg, 0.60mmol) was suspended in a mixed solvent of EtOAc (6.0mL), CH ₃ CN (6.0mL) and H ₂ O (3.0mL), cooled to 0°C , then added PhI(OAc) ₂ (234mg, 0.72mmol) to the reaction solution, stirred at 0°C for 30 minutes, raised to room temperature and stirred for 4 hours, then concentrated under reduced pressure, and the obtained residue was subjected to silica gel column layer Purification by analysis (MeOH/DCM (v/v)=1/70) gave the title compound as a light yellow solid (200mg, 69%).

MS(ESI,pos.ion)m/z:486.1[M+H] ⁺ ;

¹ H 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).

Example 12N-(4-((2-aminopyridin-4-yl)oxy)-2-chlorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3 -Dihydro-1H-pyrazole-4-carba Amide

Step 1) 4-(4-Amino-3-chlorophenoxy)pyridinamide

4-Amino-2-chlorophenol hydrochloride (446 mg, 2.4 mmol) was dissolved in dimethyl sulfoxide (4 mL), then NaH (280 mg, 7.0 mmol, 60% dispersion in mineral oil) was added. After the reaction solution was stirred at room temperature for 30 minutes, 4-chloropicolinamide (345 mg, 2.2 mmol) was added. The reaction solution was placed under microwave, reacted at 160°C for 2 hours, cooled to room temperature, and diluted with water (20 mL). The resulting mixture was extracted with ethyl acetate (20 mL x 3), and the combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/1) to obtain the title compound as an orange solid (170 mg, 29%).

MS(ESI,pos.ion)m/z:264.1[M+H] ⁺ ;

¹ H 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-(3-chloro-4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)benzene Oxy)pyridinamide

4-(4-Amino-3-chlorophenoxy)pyridineamide (191mg, 0.72mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H - Pyrazole-4-carboxylic acid (168 mg, 0.72 mmol) was suspended in dichloromethane (10 mL), then EDCI (166 mg, 0.86 mmol) and HOAT (20 mg, 0.14 mmol) were added. After the reaction solution was stirred at 46°C for 6 hours, 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (32 mg, 0.14 mmol) and EDCI (27 mg, 0.14 mmol). The reaction mixture was stirred for an additional 13 hours at 46° C., cooled to room temperature, and diluted with water (10 mL). The resulting mixture was extracted with ethyl acetate (10 mL x 3), and the combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to obtain the title compound as a pale yellow solid (160 mg, 46.5%).

MS(ESI,pos.ion)m/z:478.2[M+H] ⁺ ;

¹ H 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-((2-aminopyridin-4-yl)oxy)-2-chlorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2, 3-Dihydro-1H-pyrazole-4-carboyl amine

4-(3-chloro-4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)phenoxy ) pyridine amide (160mg, 0.33mmol) was dissolved in ethyl acetate (3mL), acetonitrile (2.5mL) and water (1.3mL) mixed solution, then added iodobenzene diacetate (130mg, 0.40mmol) at 0°C . After the reaction solution was stirred at 0° C. for 30 minutes, it was warmed up to room temperature and stirred for 3 hours. The reaction mixture was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=25/1) to obtain the title compound as a light brown solid (100 mg, 67%).

MS(ESI,pos.ion)m/z:450.2[M+H] ⁺ ;

¹ H 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).

Example 13N-(4-((2-acetylaminopyridin-4-yl)oxy)-2-chlorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2, 3-Dihydro-1H-pyrazole -4-formamide

The compound N-(4-((2-aminopyridin-4-yl)oxy)-2-chlorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3 -Dihydro-1H-pyrazole-4-carboxamide (125mg, 0.28mmol) was suspended in acetic anhydride (6.0mL), then triethylamine (0.4mL) was added to the reaction solution, and the reaction was stirred at 35°C for 13 hours After suction filtration, the filter cake was washed successively with petroleum ether (6 mL), MeOH (3 mL) and ethyl acetate (6 mL) to obtain the title compound as a light blue solid (87 mg, 63%).

MS(ESI,pos.ion)m/z:492.1[M+H] ⁺ ;

¹ H 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=5.7 Hz, 1H), 8.60(d, J=9.1Hz, 1H), 10.55(s, 1H), 11.16(s, 1H).

Example 14N-(4-(3-chloro-4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido )phenoxy)pyridin-2-yl) Morpholine-4-carboxamide

The compound N-(4-((2-aminopyridin-4-yl)oxy)-2-chlorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3 -Dihydro-1H-pyrazole-4-carboxamide (125 mg, 0.28 mmol) and Et ₃ N (0.12 mL, 0.84 mmol) were suspended in THF (4.0 mL), then phenyl chloroformate ( 0.10mL, 0.84mmol), stirred and reacted at room temperature for 22 hours, added NH ₄ Cl aqueous solution (20mL) and DCM (20mL), separated, the aqueous phase was extracted with DCM (20mL x3), and the combined organic phase was washed with anhydrous Na ₂ SO ₄ was dried, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=20/1) and washed with methanol (4 mL) to obtain the title compound as a beige solid (60 mg ,38%).

MS(ESI,pos.ion)m/z:563.2[M+H] ⁺ ;

¹ H 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).

Example 15N-(4-((2-aminopyridin-4-yl)oxy)-2-deuterophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3 -Dihydro-1H-pyrazole-4-carba Amide

The compound N-(4-((2-aminopyridin-4-yl)oxy)-2-chlorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3 -Dihydro-1H-pyrazole-4-carboxamide (200mg, 0.44mmol) and triethylamine (0.10mL, 0.66mmol) were suspended in methanol (8.0mL), then Pd/C (40mg , 20%), the mixture was stirred and reacted at 62°C for 12 hours under a deuterium atmosphere, cooled to room temperature, filtered with suction, the filtrate was concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography (MeOH/DCM (v/ v)=1/30) and purified by TLC (MeOH/DCM (v/v)=1/20) to obtain the title compound as a pale yellow solid (40 mg, 21%).

MS(ESI,pos.ion)m/z:417.3[M+H] ⁺ ;

¹ H 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).

Example 16N-(5-((2-aminopyridin-4-yl)oxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3- Dihydro-1H-pyrazole-4-carba Amide

Step 1) 4-((6-aminopyridin-3-yl)oxy)pyridineamide

6-Aminopyridin-3-ol (220 mg, 2 mmol) and t-BuOK (225 mg, 2.16 mmol) were dissolved in dimethylformamide (2.5 mL), then 4-chloropicolinamide (315 mg, 2 mmol) was added. The reaction solution was heated at 80° C. for 5 hours, cooled to room temperature, and diluted with ethyl acetate (50 mL) and water (50 mL). The organic phase was concentrated in vacuo, and the obtained residue was subjected to silica gel column chromatography (DCM/CH ₃ OH (v/v)=30/1) to obtain the title compound as a brown solid (230 mg, 50%).

MS(ESI,pos.ion)m/z:231.1[M+H] ⁺ ;

¹ H 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-1H-pyrazole-4-carboxamido)pyridine-3- base)oxy)pyridineamide

4-((6-aminopyridin-3-yl)oxy)pyridineamide (230mg, 1mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro- 1H-Pyrazole-4-carboxylic acid (237 mg, 1.02 mmol) was suspended in dichloromethane (5 mL), then EDCI (230 mg, 1.2 mmol) and HOAT (27 mg, 0.2 mmol) were added. The reaction solution was stirred at 45°C for 28 hours, cooled to room temperature, and diluted with water (10 mL) and dichloromethane (20 mL). The organic phase was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (DCM/CH ₃ OH (v/v)=40/1) to obtain the title compound as a light gray solid (111 mg, 25%).

MS(ESI,pos.ion)m/z:445.1[M+H] ⁺ ;

¹ H 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-((2-aminopyridin-4-yl)oxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3 -Dihydro-1H-pyrazole-4-carbonyl amine

4-((6-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)pyridin-3-yl) Oxy)pyridineamide (111 mg, 0.25 mmol) was dissolved in a mixed solution of ethyl acetate (2 mL), acetonitrile (2 mL) and water (1 mL), and then iodobenzene diacetate (97 mg, 0.3 mmol) was added. After the reaction solution was stirred at 0° C. for 30 minutes, it was warmed up to room temperature and stirred for 12 hours. The reaction mixture was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (DCM/CH ₃ OH (v/v)=40/1) to obtain the title compound as a light beige solid (85 mg, 81.7%).

MS(ESI,pos.ion)m/z:417.2[M+H] ⁺ ;

¹ H 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).

Example 17 N-(5-((2-acetylaminopyridin-4-yl)oxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3 -Dihydro-1H-pyrazole -4-formamide

The compound N-(5-((2-aminopyridin-4-yl)oxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3- Dihydro-1H-pyrazole-4-carboxamide (300mg, 0.72mmol) was dissolved in acetic anhydride (4mL), then Et ₃ N (400mg, 4mmol) was added to the reaction solution, and the reaction was stirred at 30°C for 12 hours , concentrated under reduced pressure, and the residue was purified by silica gel chromatography (DCM/CH ₃ OH (v/v)=40/1) to obtain the title compound as a light yellow solid (197 mg, 60.1%).

MS(ESI,pos.ion)m/z:459.0[M+H] ⁺ ;

¹ H 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).

Example 18N-(4-((6-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)pyridine- 3-yl)oxy)pyridine-2- base) morpholine-4-carboxamide

The compound N-(5-((2-aminopyridin-4-yl)oxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3- Dihydro-1H-pyrazole-4-carboxamide (171 mg, 0.41 mmol) and Et ₃ N (0.17 mL, 1.23 mmol) were suspended in THF (8.0 mL), and then phenyl chloroformate (0.15 mL, 1.23mmol), stirred at room temperature for 2 hours, added morpholine (0.21mL, 2.46mmol), stirred at room temperature for 24 hours, added NH ₄ Cl aqueous solution (40mL) and DCM (40mL), separated, and the aqueous phase was used DCM (40mL x3) was extracted, the combined organic phases were dried with anhydrous Na ₂ SO ₄ , then concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (MeOH/EtOAc(v/v)=1/50) , and purified by TLC (MeOH/EtOAc (v/v)=1/30) to give the title compound as a pale yellow solid (40 mg, 18%).

MS(ESI,pos.ion)m/z:530.2[M+H] ⁺ ;

¹ H 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).

Example 19 N-(5-((2-amino-3-chloropyridin-4-yl)oxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl- 2,3-Dihydro-1H-pyrazole -4-formamide

Step 1) N-(5-Hydroxypyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide

6-aminopyridin-3-ol (330 mg, 3 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid ( 710 mg, 306 mmol) was suspended in dimethylformamide (10 mL), then EDCI (690 mg, 3.6 mmol) and HOAT (80 mg, 0.6 mmol) were added. The reaction was stirred at 60° C. for 4 hours, cooled to room temperature, and diluted with water (100 mL) and ethyl acetate (2 mL). The reaction mixture was cooled to 0°C and stirred overnight. The solid was collected by filtration to give the title compound as a beige solid (680 mg, 70%).

MS(ESI,pos.ion)m/z:325.1[M+H] ⁺ ;

¹ H 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) 3-chloro-4-((6-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido) Pyridin-3-yl)oxy)pyridineamide

6-Aminopyridin-3-ol (324 mg, 1 mmol) and t-BuOK (135 mg, 1.2 mmol) were dissolved in dimethylformamide (2 mL), then 3,4-dichloro-2-pyridinecarboxamide ( 191 mg, 1 mmol). The reaction solution was heated at 80°C for 15 hours, cooled to room temperature, and diluted with ethyl acetate (1 mL) and water (20 mL). The reaction mixture was stirred overnight, filtered and the solid collected to give the title compound as a tan solid (290 mg, 60.5%).

MS(ESI,pos.ion)m/z:479.2[M+H] ⁺ ;

¹ H 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-chloropyridin-4-yl)oxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl -2,3-Dihydro-1H-pyrazole-4- Formamide

3-chloro-4-((6-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)pyridine- 3-yl)oxy)pyridineamide (290mg, 0.6mmol) was dissolved in a mixed solution of ethyl acetate (4mL), acetonitrile (4mL) and water (2mL), and then iodobenzene diacetate (234mg, 0.72mmol) was added. After the reaction solution was stirred at 0° C. for 30 minutes, it was warmed up to room temperature and stirred for 12 hours. The reaction mixture was filtered through celite, and the filter cake was washed with dichloromethane (30 mL). The filtrate was washed with water (20 mL) and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/CH ₃ OH (v/v)=50/1) to obtain the title compound as a light beige solid (120 mg, 44.7%).

MS(ESI,pos.ion)m/z:451.1[M+H] ⁺ ;

¹ H 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).

Example 20N-(5-((2-acetylamino-3-chloropyridin-4-yl)oxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl -2,3-Dihydro-1H- Pyrazole-4-carboxamide

N-(5-((2-amino-3-chloropyridin-4-yl)oxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2 , 3-Dihydro-1H-pyrazole-4-carboxamide (60mg, 0.13mmol) and triethylamine (26.3mg, 0.26mmol) were dissolved in a mixed solvent of methanol (1mL) and tetrahydrofuran (2mL), and then added Acetyl chloride (20.3 mg, 0.26 mmol). The reaction solution was stirred at room temperature for 3 hours, then concentrated in vacuo. The residue was treated with sodium carbonate solution, stirred at room temperature for 5 minutes, and concentrated in vacuo. The obtained residue was purified by silica gel column chromatography (DCM/CH ₃ OH (v/v)=50/1) to obtain the title compound as a light beige solid (15 mg, 22.7%).

MS(ESI,pos.ion)m/z:493.1[M+H] ⁺ ;

¹ H 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) .

Example 21N-(4-((2-acetylamino-3-chloropyridin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2, 3-Dihydro-1H-pyrazole -4-formamide

3-chloro-4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)phenoxy ) pyridine amide (124mg, 0.28mmol) was dissolved in acetic anhydride (8.0mL), then triethylamine (0.4mL) was added. After the reaction solution was stirred and reacted at 40° C. for 26 hours, the reaction mixture was washed with a saturated solution of sodium carbonate (60 mL×3), and then extracted with dichloromethane (60 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=40/1) to obtain the title compound as a pale pink solid (80 mg, 59%).

MS(ESI,pos.ion)m/z:492.2[M+H] ⁺ ;

¹ H 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).

Example 22N-(4-((2-aminopyridin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3 -Dihydro-1H-pyrazole-4-carba Amide

Step 1) N-(3-fluoro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-methanol Amide

4-Amino-2-fluorophenol (2.54g, 20mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (4.74g, 20.4mmol) was suspended in DCM (60mL), and to it were added EDCI (4.6g, 24mmol) and HOAT (0.54g, 4mmol). The reaction solution was stirred at 45° C. for 12 hours, cooled to room temperature, and quenched with water (10 mL). The mixture was stirred for an additional 4 hours, filtered and the solid was collected, washed with DCM (20 mL x 3) and dried under vacuum at 60 °C for 12 hours to give the title compound as a khaki solid (6.37 g, 93.4%).

MS(ESI,pos.ion)m/z:342.1[M+H] ⁺ ;

¹ H 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-1H-pyrazole-4-carboxamido)-2-fluorobenzene Oxy)pyridinamide

N-(3-fluoro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide ( 2.2g, 6.4mmol) and 4-chloropicolinamide (1g, 6.39mmol) were dissolved in DMSO (12mL), and NaH (615mg, 12.3mmol, 50% dispersed in mineral oil) was added thereto, and the reaction solution was After stirring at 160° C. for 20 hours, it was cooled to room temperature and quenched by adding water (70 mL). The mixture was extracted with EtOAc (100 mL x 3), the combined organic phases were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/4) to obtain the title compound as a white solid (0.85 g, 29%).

MS(ESI,pos.ion)m/z:462.1[M+H] ⁺ ;

¹ H 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-((2-aminopyridin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2, 3-Dihydro-1H-pyrazole-4-carboyl amine

4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2-fluorophenoxy ) pyridineamide (0.4g, 0.86mmol) and PhI(OAc) ₂ (419mg, 1.5mmol) were dissolved in a mixture of EtOAc (8mL), MeCN (8mL) and H ₂ O (4mL), cooled to 0°C , and stirred for 30 minutes. The reaction solution was returned to room temperature, and stirring was continued for 8 hours. The mixture was diluted with aqueous NaHCO ₃ (60 mL), and extracted with EtOAc (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=10/1) to give The title compound was a white solid (0.21 g, 56%).

MS(ESI,pos.ion)m/z:434.2[M+H] ⁺ ;

¹ H 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).

Example 23N-(4-((2-acetylaminopyridin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2, 3-Dihydro-1H-pyrazole -4-formamide

N-(4-((2-aminopyridin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3- Dihydro-1H-pyrazole-4-carboxamide (90 mg, 0.21 mmol) was dissolved in acetic anhydride (6 mL), to which Et ₃ N (0.3 mL) was added. After stirring the reaction solution at room temperature for 8 hours, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=10/1) to obtain the title compound as a white solid (53 mg, 49%).

MS(ESI,pos.ion)m/z:476.1[M+H] ⁺ ;

¹ H 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).

Example 24N-(4-((2-aminopyridin-4-yl)oxy)-2-chloro-5-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl -2,3-Dihydro-1H-pyrazole -4-formamide

Step 1) 1-chloro-4,5-difluoro-2-nitrobenzene

Add 4-chloro-1,2-difluorobenzene (8.97g, 60.4mmol) to the reaction flask, cool to 0°C, then add 98% concentrated H ₂ SO ₄ (16.1mL, 302mmol) and 65 % concentrated HNO ₃ (5.0mL, 66.4mmol), stirred at room temperature for 5 hours, poured into ice water, the resulting mixture was extracted with EtOAc (200mL x2), and the combined organic phase was sequentially washed with saturated NaHCO ₃ aqueous solution (200mL x2) and brine (200 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure to obtain the title compound as a yellow liquid (11.31 g, 96.7%).

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

Step 2) Potassium 5-chloro-2-fluoro-4-nitrophenolate

The mixture of compound 1-chloro-4,5-difluoro-2-nitrobenzene (5.12g, 26.5mmol) and 15% KOH (19.9g, 0.35mol) aqueous solution was stirred and refluxed for 3 hours, cooled to room temperature, pumped Filtration afforded the title compound as a yellow solid (5.67 g, 93.3%).

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

Step 3) 4-Amino-5-chloro-2-fluorophenol

The compound 5-chloro-2-fluoro-4-nitrophenoxide potassium (1.0g, 4.35mmol) was dissolved in a mixed solvent of EtOH (22mL, 95%) and H ₂ O (8mL), and then added to the reaction solution Iron powder (0.97g, 17.4mmol) and NH ₄ Cl (1.86g, 34.8mmol), stirred at room temperature for 10 hours, added methanol (25mL) and ethyl acetate (25mL) to dilute the reaction solution, suction filtered, and the filtrate was reduced to Concentrated under reduced pressure, the residue was diluted with ethyl acetate (40 mL), washed with brine (25 mL), dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure to give the title compound as an off-white solid (0.6 g, 85.3%).

¹ H 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-(2-chloro-5-fluoro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole -4-formamide

The compound 4-amino-5-chloro-2-fluorophenol (0.97g, 6mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole -4-carboxylic acid (1.42g, 6.12mmol) was suspended in DMF (20mL), then EDCI (0.38mg, 7.2mmol) and HOAT (0.16g, 1.2mmol) were added to the reaction solution, heated to 80°C, After stirring the reaction for 24 hours, it was cooled to 0°C, then H ₂ O (200 mL) and EtOAc (2 mL) were added to dilute the reaction solution, filtered by suction, and dried in vacuo to obtain the title compound as a light brown solid (1.2 g, 53.2%).

MS(ESI,pos.ion)m/z:376.1[M+H] ⁺ ;

¹ H 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-(5-chloro-4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)- 2-fluorophenoxy)pyridinamide

The compound N-(2-chloro-5-fluoro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole- 4-formamide (751.6mg, 2mmol) and t-BuOK (224.4mg, 2mmol) were suspended in DMF (4mL), then 4-chloropicolinamide (313.2mg, 2mmol) was added to the reaction solution, heated to 120° C and stirred for 15 hours, then cooled to room temperature, added H ₂ O (40 mL), the resulting mixture was stirred overnight at room temperature, filtered with suction, and the filter cake was subjected to silica gel column chromatography (DCM/CH ₃ OH (v/v)=50 /1) Purification gave the title compound as a pale yellow solid (290 mg, 60.5%).

MS(ESI,pos.ion)m/z:496.2[M+H] ⁺ ;

¹ H 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-((2-aminopyridin-4-yl)oxy)-2-chloro-5-fluorophenyl)-1,5-dimethyl-3-oxo-2-benzene yl-2,3-dihydro-1H-pyrazole -4-formamide

Compound 4-(5-chloro-4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2 -Fluorophenoxy)pyridinamide (297.6mg, 0.6mmol) was suspended in a mixed solvent of EtOAc (4mL), CH ₃ CN (4mL) and H ₂ O (2mL), cooled to 0°C, added PhI(OAc ) ₂ (97mg, 0.3mmol), stirred and reacted at 0°C for half an hour, raised to room temperature and stirred for 12 hours, then concentrated under reduced pressure, and the obtained residue was subjected to silica gel chromatography (DCM/CH ₃ OH(v /v)=20/1) Purification afforded the title compound as a light beige solid (220 mg, 78.3%).

MS(ESI,pos.ion)m/z:468.0[M+H] ⁺ ;

¹ H 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).

Example 25 N-(4-((2-acetylaminopyridin-4-yl)oxy)-2-chloro-5-fluorophenyl)-1,5-dimethyl-3-oxo-2-benzene Group-2,3-dihydro-1H- Pyrazole-4-carboxamide

Compound N-(4-((2-aminopyridin-4-yl)oxy)-2-chloro-5-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl -2,3-dihydro-1H-pyrazole-4-carboxamide (200mg, 0.43mmol) was dissolved in acetic anhydride (4mL), then Et ₃ N (400mg, 2.6mmol) was added to the reaction solution, and the After stirring the reaction at °C for 12 hours, it was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (DCM/CH ₃ OH (v/v)=40/1) to obtain the title compound as a light yellow solid (110mg, 50.5% ).

MS(ESI,pos.ion)m/z:510.2[M+H] ⁺ ;

¹ H 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).

Example 26N-(4-(5-chloro-4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido )-2-fluorophenoxy)pyridine -2-yl)morpholine-4-carboxamide

Compound N-(4-((2-aminopyridin-4-yl)oxy)-2-chloro-5-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl -2,3-dihydro-1H-pyrazole-4-carboxamide (234mg, 0.5mmol) and Et ₃ N (0.1mg, 1mmol) were suspended in THF (5mL), then phenyl chloroformate was added to the reaction solution (0.16mg, 1mmol), stirred at room temperature for 2 hours, added morpholine (0.44mL, 5mmol), continued stirring at room temperature for 24 hours, added NH ₄ Cl (30mL) and DCM (30mL), separated, organic phase Extracted with DCM (30mL x3), the combined organic phases were dried over anhydrous Na ₂ SO ₄ , then concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (DCM/CH ₃ OH(v/v)=50/1 ) to afford the title compound as a white solid (145 mg, 49.9%).

MS(ESI,pos.ion)m/z:581.2[M+H] ⁺ ;

¹ H 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).

Example 27 N-(4-((2-aminopyridin-4-yl)oxy)-3-chlorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3 -Dihydro-1H-pyrazole-4-carba Amide

Step 1) N-(3-chloro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-methanol Amide

The compound 4-amino-2-chlorophenol (4.0g, 28.00mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4- Carboxylic acid (7.4g, 30.11mmol) was suspended in DCM (70mL), then EDCI (6.65g, 30.11mmol) and HOAT (0.76g, 5.68mmol) were added to the reaction solution, heated to 45°C and stirred for 20 hours, then cooled to room temperature, suction filtered, the filter cake was washed with DCM (20 mL x 3), and dried overnight at 50° C. in a vacuum oven to obtain the title compound as a gray solid (7.1 g, 72.1%). MS(ESI,pos.ion)m/z:358.1[M+H] ⁺ ;

¹ H 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-(2-chloro-4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)benzene Oxy)pyridinamide

The compound N-(3-chloro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (1.074g, 3.0mmol) was suspended in DMF (12mL), then t-BuOK (539mg, 4.8mmol) was added to the reaction solution, and after stirring at room temperature for 30 minutes, 4-chloropyridinamide (517mg, 3.3mmol) was added, Warming up to 120°C and stirring for 36 hours, then cooling to room temperature, adding water (50mL) to quench the reaction, the mixture was extracted with EtOAc (50mL x3), the combined organic phase was washed with brine (50mL x3), washed with anhydrous It was dried over Na ₂ SO ₄ and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/PE(v/v)=3/1) to obtain the title compound as a white solid (580 mg, 40.4%).

MS(ESI,pos.ion)m/z:478.0[M+H] ⁺ ;

¹ H 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-((2-aminopyridin-4-yl)oxy)-3-chlorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2, 3-Dihydro-1H-pyrazole-4-carboyl amine

The compound 4-(2-chloro-4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)phenoxy Base) pyridine amide (540mg, 1.13mmol) was suspended in a mixed solvent of EtOAc (6mL), CH ₃ CN (6mL) and H ₂ O (3mL), cooled to 0°C, and then PhI(OAc ) ₂ (438mg, 1.36mmol), after stirring at 0°C for 30 minutes, it was raised to room temperature and stirred for 4.5 hours, then concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography (EtOAc/PE (v/v) =6/1) to obtain the title compound as a beige solid (265 mg, 52.2%).

MS(ESI,pos.ion)m/z:450.2[M+H] ⁺ ;

¹ H 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).

Example 28 N-(4-((2-acetylaminopyridin-4-yl)oxy)-3-chlorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2, 3-Dihydro-1H-pyrazole -4-formamide

The compound N-(4-((2-aminopyridin-4-yl)oxy)-3-chlorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3 -Dihydro-1H-pyrazole-4-carboxamide (120mg, 0.27mmol) was dissolved in acetic anhydride (5mL), then Et ₃ N (0.4mL, 1.12mmol) was added to the reaction solution, and the reaction was stirred at room temperature for 8 hours Afterwards, it was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (DCM/CH ₃ OH (v/v)=40/1) to obtain the title compound as a white solid (65 mg, 49%).

MS(ESI,pos.ion)m/z:492.0[M+H] ⁺ ;

¹ H 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).

Example 29 N-(4-(2-chloro-4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido )phenoxy)pyridin-2-yl) Morpholine-4-carboxamide

The compound N-(4-((2-aminopyridin-4-yl)oxy)-3-chlorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3 -Dihydro-1H-pyrazole-4-carboxamide (135mg, 0.3mmol) was suspended in THF (3mL), then Et ₃ N (0.080mL, 0.6mmol) was added to the reaction solution first, followed by dropwise addition Phenyl chloroformate (0.075mL, 0.6mmol), stirred at room temperature for 2 hours, then added morpholine (0.250mL, 3.0mmol), stirred at room temperature for 22 hours, added saturated NH ₄ Cl aqueous solution (20mL) and CH ₂ Cl ₂ (20mL), after stirring for 10 minutes, the mixture was extracted with CH ₂ Cl ₂ (20mLx3), the combined organic phase was washed with brine (20mLx3), dried with anhydrous Na ₂ SO ₄ , and then concentrated under reduced pressure to obtain the residue The material was purified by silica gel column chromatography (EtOAc/PE (v/v)=6/1) to obtain the title compound as a beige solid (43 mg, 25.4%).

MS(ESI,pos.ion)m/z:563.2[M+H] ⁺ ;

¹ H 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).

Example 30 N-(4-((2-aminopyridin-4-yl)oxy)-2-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2, 3-Dihydro-1H-pyrazole-4-carba Amide

Step 1) 4-amino-3-fluorophenol

Suspension of compound 3-fluoro-4-nitrophenol (2.0g, 12.73mmol), 10%Pd/C (0.4g), HCOOK (8.75g, 101.85mmol) and THF/ _H2O (70mL/20mL) After stirring the reaction at 50°C for 5 hours, it was cooled to room temperature, filtered with diatomaceous earth, the filtrate was diluted with water (30 mL), the mixture was extracted with THF (50 mL), and the obtained organic phase was dried with anhydrous Na ₂ SO ₄ , and then Concentrated under reduced pressure, the resulting residue was diluted with water (50 mL), the mixture was extracted with DCM (50 mL), the resulting organic phase was dried over anhydrous Na ₂ SO ₄ , then concentrated under reduced pressure to afford the title compound as a brown solid (1.17 g, 72.3%).

MS (ESI, pos, ion) m/z: 128.1 [M+H] ⁺ .

Step 2) N-(2-fluoro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-methanol Amide

The compound 4-amino-3-fluorophenol (1.0g, 7.87mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4- Carboxylic acid (2.19g, 9.44mmol) was suspended in CH ₂ Cl ₂ (20mL), then EDCI (3.02g, 15.7mmol) and HOAT (0.21g, 1.57mmol) were added to the reaction solution, heated to reflux and stirred for reaction After cooling to room temperature for 20 hours, water (10 mL) was added, and the resulting mixture was stirred overnight at room temperature, filtered with suction, and the filter cake was washed with water (5 mL), and then subjected to silica gel column chromatography (CH ₂ Cl ₂ /MeOH (v/v)=70/1) Purification afforded the title compound as an off-white solid (1.25 g, 46.6%).

MS (ESI, pos, ion) m/z: 342.1 [M+H] ⁺ .

Step 3) 4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-3-fluorobenzene Oxy)pyridinamide

To compound N-(2-fluoro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (300mg, 0.879mmol) and t-BuOK (118mg, 1.05mmol) were added DMF (2.5mL), stirred at room temperature for 30 minutes, added 4-chloropicolinamide (165mg, 1.05mmol), heated to 120 ° C and stirred for 5 hours, then cooled to room temperature, H ₂ O (50 mL) and EtOAc (2 mL) were added, the resulting mixture was stirred overnight at room temperature, filtered with suction, the filter cake was washed with water (5 mL), and dried in vacuo to obtain the title compound as Dark brown solid (370mg, 91.2%).

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

Step 4) N-(4-((2-aminopyridin-4-yl)oxy)-2-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2, 3-Dihydro-1H-pyrazole-4-carboyl amine

The compound 4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-3-fluorophenoxy Base) pyridine amide (370mg, 0.746mmol) was dissolved in EtOAc (4.5mL), CH ₃ CN (4.5mL) and H ₂ O (2.5mL) mixed solvent, cooled to 0 ° C, stirred for 30 minutes, added PhI (OAc) ₂ (288mg, 0.895mmol), after continuing to stir at 0°C for 30 minutes, it was raised to room temperature and continued to stir for 7 hours, suction filtered, the filter cake was washed with EtOAc (5mL), and the filtrate was concentrated under reduced pressure to obtain The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ /MeOH (v/v)=250/9), and then purified by silica gel column chromatography (CH ₂ Cl ₂ /MeOH (v/v)=50/1 ) to afford the title compound as an off-white solid (46 mg, 17.3%).

MS(ESI,pos,ion)m/z:434.2[M+H] ⁺ ;

¹ H 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=5.9 Hz, 2.1Hz, 1H), 5.96(d, J=2.0Hz, 1H), 4.58(s, 2H), 3.36(s, 3H), 2.79(s, 3H).

Example 31N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-2-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl -2,3-Dihydro-1H-pyrazole -4-formamide

Step 1) 3-chloro-4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)- 3-fluorophenoxy)pyridineamide

The compound N-(2-fluoro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (300mg, 0.879mmol), a mixture of t-BuOK (118mg, 1.05mmol) and DMF (3mL) was stirred at room temperature for 30 minutes, and 3,4-dichloro-2-pyridinecarboxamide (201mg, 1.05mmol) was added and heated The reaction was stirred at 120°C for 12 hours, then EtOAc (1 mL) and H ₂ O (20 mL) were added, and the resulting mixture was stirred at room temperature overnight and filtered with suction to obtain the title compound as a brown solid (379 mg, 87.0%). MS (ESI, pos, ion) m/z: 496.0 [M+H] ⁺ .

Step 2) N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-2-fluorophenyl)-1,5-dimethyl-3-oxo-2-benzene Base-2,3-dihydro-1H-pyrazole-4- Formamide

The compound 3-chloro-4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-3 -Fluorophenoxy)pyridinamide (379mg, 0.764mmol) was suspended in a mixed solvent of EtOAc (4.5mL), CH ₃ CN (4.5mL) and H ₂ O (2.5mL), cooled to 0°C, and stirred for 30 Minutes later, PhI(OAc) ₂ (295mg, 0.917mmol) was added, stirred and reacted at 0°C for 30 minutes, raised to room temperature and stirred for 10 hours, filtered with suction, the filter cake was washed with EtOAc (5mL), and the filtrate was reduced to Concentrate under reduced pressure, and the resulting residue was purified by silica gel column chromatography (CH ₂ Cl ₂ /MeOH (v/v)=50/1) to obtain the title compound as a yellow solid (150 mg, 47.0%).

MS(ESI,pos,ion)m/z:468.2[M+H] ⁺ ;

¹ H 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 used for analysis includes Agilent1200 series vacuum degassing furnace, binary syringe pump, orifice autosampler, column oven, and Agilent G6430 triple quadrupole mass spectrometer with electrospray ionization (ESI) source. Quantitative analysis was carried out in MRM mode, and the parameters of MRM conversion are shown in Table A:

Table A

multiple reaction detection scan 490.2 → 383.1 Fragmentation voltage 230V capillary voltage 55V Dryer temperature 350°C atomizer 40psi Dryer flow rate 10L/min

The analysis used an Agilent XDB-C18, 2.1x30mm, 3.5 μM column, injecting 5 μL of the sample. Analysis conditions: mobile phase is 0.1% formic acid aqueous solution (A) and 0.1% formic acid methanol solution (B). The flow rate was 0.4 mL/min. The mobile phase gradient is shown in Table B:

Form B

time Gradient of mobile phase B 0.5min 5% 1.0min 95% 2.2min 95% 2.3min 5% 5.0min stop

In addition, Agilent6330 series LC/MS/MS spectrometer was used for analysis, equipped with G1312A binary syringe pump, G1367A automatic sampler and G1314C UV detector; LC/MS/MS spectrometer used ESI radiation source. Optimum analysis is achieved using standards with appropriate cation model processing and MRM conversion for each analyte. A Capcell MP-C18 column, 100x4.6 mm I.D., 5 μM (Phenomenex, Torrance, California, USA) was used during the analysis. The mobile phase is 5mM ammonium acetate, 0.1% methanol in water (A): 5mM ammonium acetate, 0.1% methanol in acetonitrile (B) (70:30, v/v); the flow rate is 0.6mL/min; the column temperature is kept at room temperature; Inject 20 μL of sample.

Example A Stability in Human and Rat Liver Microsomes

Human or rat liver microsomes are incubated in polypropylene tubes and primed for replication. A typical incubation mixture consists of human or rat liver microsomes (0.5 mg protein/mL), target compound (5 μM) and NADPH (1.0 mM) potassium phosphate buffer (PBS, 100 mM, pH 7.4) in a total volume of 200 μL ), the compounds were dissolved in DMSO and diluted with PBS so that the final concentration of the DMSO solution was 0.05%. And incubate at 37°C in an air-connected water bath. After pre-incubation for 3 minutes, add protein to the mixture and start the reaction. At different time points (0, 5, 10, 15, 30 and 60 min), the same volume of ice-cold acetonitrile was added to terminate the reaction. Samples were stored at -80°C until LC/MS/MS analysis.

Compound concentrations in human or rat liver microsome incubation mixtures were determined by LC/MS/MS. The linear range of the concentration range was determined for each compound tested.

Parallel incubation experiments using denatured microsomes as a negative control were incubated at 37°C and the reactions were terminated at different time points (0, 15 and 60 min).

Dextromethorphan (70 μM) was used as a positive control, incubated at 37°C, and the reactions were terminated at different time points (0, 5, 10, 15, 30 and 60 minutes). Positive and negative control samples are included with each assay to ensure the integrity of the microsomal incubation system. In addition, the stability data of the compounds of the present invention in human or rat liver microsomes can also be obtained from the following tests. Human or rat liver microsomes are incubated in polypropylene tubes and primed for replication. A typical incubation mixture includes human or rat liver microsomes (final concentration: 0.5mg protein/mL), compound (final concentration: 1.5μM) and K-buffer solution (containing 1.0mM EDTA, 100mM, pH7 .4). Compounds were dissolved in DMSO and diluted with K-buffer solution so that the final concentration of DMSO was 0.2%. After 10 minutes of pre-incubation, 15 μL NADPH (final concentration: 2 mM) was added for enzymatic reaction, and the whole experiment was carried out in an incubation tube at 37°C. At various time points (0, 15, 30 and 60 minutes), the reaction was terminated by adding 135 μL of acetonitrile (with IS). Centrifuge at 4000rpm for 10 minutes to remove protein, collect supernatant and analyze by LC-MS/MS.

In the above experiments, ketanserin (1 μM) was selected as a positive control, incubated at 37°C, and the reaction was terminated at different time points (0, 15, 30 and 60 min). A positive control sample is included with each assay to ensure the integrity of the microsomal incubation system.

data analysis

For each reaction, the in vivo liver intrinsic clearance CL _int (ref.:Naritomi Y, Terashita S, Kimura S, Suzuki A, Kagayama A, Sugiyama Y. Prediction of human hepatic clearance from in vivo animal experiments and invitro metabolic studies with liver microsomes from animals and humans. Drug Metabolism and Disposition 2001, 29: 1316-1324. )

Table 1 Stability data of embodiments of the present invention in human and rat liver microsomes

The compounds of the present invention exhibit good half-lives (T _1/2 ) when the compounds are incubated in human and rat liver microsomes.

Pharmacokinetic evaluation after oral quantitative compound of the present invention of embodiment B mice, rats, dogs and monkeys

The present invention evaluates the pharmacokinetic studies of the compounds of the present invention in mice, rats, dogs or monkeys. The compound of the present invention is administered in the form of aqueous solution or 2% HPMC + 1% Tween-80 aqueous solution, 5% DMSO + 5% saline solution, 4% MC or capsule form. For intravenous administration, animals were dosed at 1 or 2 mg/kg. Oral doses (p.o.) were 5 or 10 mg/kg for rats and mice, and 10 mg/kg for dogs and monkeys. Blood (0.3 mL) was drawn at time points 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12 and 24 hours and centrifuged at 3,000 or 4,000 rpm for 10 minutes. Plasma solutions were collected and stored at -20°C or -70°C until LC/MS/MS analysis as described above.

Table 2 The pharmacokinetic data of the embodiments of the present invention in rats

When the compounds are administered intravenously or orally, the compounds of the present invention exhibit good pharmacokinetic properties, including ideal clearance (Cl), half-life (T _1/2 ) and good oral bioavailability.

The compounds of the present invention inhibit the activity of tyrosine kinase receptors, especially c-Met, VEGFR, Ron and Axl activities and the efficacy as antitumor drugs are evaluated by the following animal xenograft model test. The research results show that the compound of the present invention can effectively inhibit the phosphorylation of c-Met, VEGF-R2, Ron and Axl, and inhibit the proliferation of transplanted tumors in nude mice in a dose-dependent manner.

Kinase test

Kinase assays are performed by detecting myelin basic protein (MBP) incorporated into γ- ^33P -ATP. Prepare 20 μg/mL of MBP (Sigma #M-1891) tris-buffered saline (TBS; 50 mM Tris pH 8.0, 138 mM NaCl, 2.7 mM KCl) and coat high-binding white 384-well plates (Greiner) , 60 μL per well. Incubate at 4°C for 24 hours. The plate was then washed 3 times with 100 μL TBS. Kinase reactions were performed in a total volume of 34 μL in kinase buffer (5 mM Hepes pH 7.6, 15 mM NaCl, 0.01% bovine serum albumin (Sigma #I-5506), 10 mM MgCl ₂ , 1 mM DTT, 0.02% TritonX-100) . Compounds were dissolved in DMSO and added to the wells at a final concentration of 1% DMSO. Each data was determined twice, and the determination of each compound was carried out at least twice. For example, the final concentration of the enzyme is 10 nM or 20 nM. The reaction was started by adding unlabeled ATP (10 μM) and γ- ³³ P-labeled ATP (2×10 ⁶ cpm per well, 3000Ci/mmole). The reaction was carried out with shaking at room temperature for 1 hour. The 384-well plate was washed with 7x PBS, and then 50 μL of scintillation fluid was added to each well. Results were checked with a Wallac Trilux counter. For those skilled in the art, this is only one of many detection methods, and other methods are also acceptable.

IC ₅₀ of inhibition and/or inhibition constant K _i can be obtained by the above test method. _IC50 is defined as the concentration of the compound that inhibits 50% of the enzyme activity under the test conditions. Estimate _IC50 values by plotting 10 concentration points using 1/2 log dilutions (e.g., a typical curve is plotted at the following compound concentrations: 100 μM, 30 μM, 10 μM, 3 μM, 1 μM, 0.3 μM, 0.1 μM , 0.03 μM, 0.01 μM, 0 μM).

c-Met(h) Kinase Assay

Human c-Met was carried out in the presence of 8mM MOPS with a pH value of 7.0, 0.2mM EDTA, 250μM KKKSPGEYVNIEFG, 10mM magnesium acetate and [γ- ³³ P-ATP] (specific activity about 500cpm/pmol, concentration determined according to requirements) Incubation. The reaction was initiated after the addition of the MgATP mixture. After incubation at room temperature for 40 minutes, a 3% phosphoric acid solution was added thereto to stop the reaction. 10 μL of the reaction solution was spotted onto a P30 filter, washed 3 times in 5 min with 75 mM phosphoric acid, and stored in methanol solution immediately prior to drying and scintillation counting.

KDR(h) (VEGF-R2(h)) Kinase Assay

Human KDR exists in 8mM MOPS with a pH value of 7.0, 0.2mM EDTA, 0.33mg/mL myelin basic protein, 10mM magnesium acetate and [γ- ^33P -ATP] (specific activity is about 500cpm/pmol, the concentration is determined according to demand) Incubate under conditions. The reaction was initiated after the addition of the MgATP mixture. After incubation at room temperature for 40 minutes, a 3% phosphoric acid solution was added thereto to stop the reaction. 10 μL of the reaction solution was spotted onto a P30 filter, washed 3 times within 5 minutes with 75 mM phosphoric acid, and stored in methanol solution immediately prior to drying and scintillation counting.

Axl(h) Kinase Assay

Human Axl in the presence of 8mM MOPS with a pH value of 7.0, 0.2mM EDTA, 0.33mg/mL myelin basic protein, 10mM magnesium acetate and [γ- ^33P -ATP] (specific activity about 500cpm/pmol, the concentration is determined according to demand) Incubate under conditions. The reaction was initiated after the addition of the MgATP mixture. After 40 minutes of incubation at room temperature, 3% phosphoric acid solution was added to stop the reaction. 10 μL of the reaction solution was spotted onto a P30 filter, washed 3 times within 5 minutes with 75 mM phosphoric acid, and stored in methanol solution immediately prior to drying and scintillation counting.

The kinase test in the present invention is done by the British Millipore Company (Millipore UK Ltd, Dundee Technology Park, Dundee DD21SW, UK).

The kinase inhibitory activity of the compounds of the present invention can also be tested by KINOMEscan ^™ , which is mainly based on the quantitative determination of the ability of samples and immobilized, active site-directed ligands to bind to kinases competitively. The completion of this assay requires the combination of the following three elements: DNA-labeled kinase, immobilized ligand and test sample. The ability of the test sample to competitively bind the kinase with the immobilized ligand can be determined by measuring the amount of PCR in the DNA marker.

For most experiments, kinase-tagged T7 phage strains were prepared from E. coli hosts derived from the BL21 strain. That is, Escherichia coli was first cultured to the logarithmic growth phase, then infected with T7 phage, and incubated at 32°C under continuous shaking until lysed, and the lysate was centrifuged and filtered to remove cell debris. The remaining kinases produced in HEK-293 cells were then labeled with DNA for detection by qPCR. Streptavidin-coated magnetic beads react with biotinylated small-molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays. The coordinated magnetic beads are blocked by excess biotin, and the free ligands are removed by washing with blocking buffer solution (SEABLOCK ^TM (Pierce), 1% BSA, 0.05% Tween-20, 1mM DTT) to reduce non-specific binding . The binding reaction is completed in 1x binding buffer (20% SEABLOCK ^TM , 0.17x PBS, 0.05% Tween-20, 6mM DTT) through kinase, coordinated affinity magnetic beads and the sample to be tested. All reactions were performed in polystyrene 96-well plates with a final volume of 0.135 mL. The well plates tested were incubated at room temperature for 1 hour under continuous shaking, and the affinity magnetic beads were washed with washing buffer (1x PBS, 0.05% Tween-20), and then resuspended in elution buffer (1x PBS, 0.05% Tween-20, 0.5 μM non-biotinylated affinity ligand), and incubated at room temperature for 30 minutes with continuous shaking. The kinase concentration in the eluate was determined by qPCR.

The kinase test in the present invention was completed by the KINOMEscan ^TM analysis service of DiscoverRx Company (42501 Albrae St. Fremont, CA94538, USA). The test results of the examples of the present invention are listed in Table 3.

The Kds data of the embodiment of the present invention of table 3

Examples# Kd(nM)

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

Kd-Binding Constants

Cell Phosphorylation Assay

Typically, cells are preincubated with the compound to be tested to allow for sufficient target binding. The level of autophosphorylation was detected by sandwich enzyme-linked immunoassay (Sandwich-ELISA). A curve containing 8 concentration points was made using a dilution factor of 1/2log to estimate the IC ₅₀ value (measured twice for each concentration). The cell phosphorylation test in the present invention can be done by ProQinase GmbH (ProQinase GmbH, Breisacher Straβe117D-79106, Freiburg, Germany).

c-Met phosphorylation assay

It is well known that the human gastric adenocarcinoma cell line MKN45 overexpresses c-Met. c-Met overexpression leads to constitutive, ligand-independent kinase autophosphorylation. With the addition of SU11274, the level of phosphorylated Met was significantly reduced, thus confirming the inhibitory ability of the compounds of the present invention. Phosphorylated Met signal can be quantified by sandwich enzyme-linked immunoassay (Sandwich-ELISA) technique. The test set up a known Met inhibitor group to verify the reliability of the test method.

VEGF-R2 phosphorylation assay

Immortalized human umbilical vein endothelial cells (HUE) are known to overexpress VEGF-R2. Stimulation of these cells with the physiological ligand VEGF-A resulted in significant receptor autophosphorylation. Cells are pre-incubated with the compound to be tested to achieve sufficient target binding. The stimulation conditions were optimized to achieve dose-dependent inhibition of phosphorylated VEGF-R2 signal, and the phosphorylated signal was quantified by sandwich enzyme-linked immunoassay (Sandwich-ELISA) technique. The test set up a known VEGF-R2 inhibitor group to verify the reliability of the test method.

Axl phosphorylation assay

Cellular Axl phosphorylation assays are usually performed using mouse embryonic fibroblasts (MEFs). Cells were transfected to express the full-length Axl protein. A transfected cell with high Axl autophosphorylation was obtained by clonal selection. Then staurosporine was added, and the level of phosphorylated Axl was significantly reduced, so the inhibitory ability of the compound could be determined. And the level of phosphorylated Axl was quantified by sandwich enzyme-linked immunoassay (Sandwich-ELISA) technique.

Xenograft tumor model

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

(30%),16%

(30%))和化合物组。后续采用化合物对动物进行灌胃给药，从肿瘤细胞接种后的0到15天中的任何地方开始，并且通常在试验中每天进行一次。The efficacy of the compounds of the present invention was evaluated in standard murine models of xenografted tumors. Human tumor cells (U87MG glioma cells, ATCC) were cultured and collected, and subcutaneously inoculated into 6-7-week-old female nude mice (BALB/cA nu/nu, Shanghai SLAC Animal Laboratory) ( For vehicle group and each dose group: n=6-10)). When the tumor volume reached ^100-250mm , the animals were randomly divided into vehicle control group (5%DMSO+70%

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

(30%),16%

(30%)) and compound groups. Subsequent gavage dosing of the compound with the animals begins anywhere from 0 to 15 days after tumor cell inoculation, and typically occurs once daily throughout the experiment.

Tumor Growth Inhibition (TGI) Assay

Tumor evolutionary growth was assessed by tumor volume versus time. The long axis (L) and short axis (W) of subcutaneous tumors were measured twice a week by calipers, and the tumor volume (TV) was calculated by the formula (L×W ² )/2). TGI is calculated from the difference between the median tumor volume of the mice in the solvent group and the median tumor volume of the mice in the drug group, expressed as a percentage of the median tumor volume of the solvent control group, and calculated by the following formula:

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

(30%);或者7%DMSO,7%HCl(pH1),70%(30%),16%(30%)）为阴性对照。Raw statistical analysis was done by repeated measures of variance (RMANOVA). Next, multiple comparisons were performed by the Scheffe psot hoc test method. Solvent alone (5%DMSO+70%

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

(30%); or 7%DMSO, 7%HCl (pH1), 70% (30%),16% (30%)) as a negative control.

Table 4 The xenograft tumor model research data of the embodiment of the present invention

Finally, it should be noted that there are other ways to implement the invention. Accordingly, the embodiments of the present invention will be described as illustrations, but are not limited to the content described in the present invention, and may be modified within the scope of the present invention or equivalent content added in the claims. All publications or patents cited in the present invention shall be regarded as reference documents of the present invention.

Claims (26)

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;

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.

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;

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.

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.