WO2021057782A1 - 杂环衍生物及其用途 - Google Patents

杂环衍生物及其用途 Download PDF

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WO2021057782A1
WO2021057782A1 PCT/CN2020/117074 CN2020117074W WO2021057782A1 WO 2021057782 A1 WO2021057782 A1 WO 2021057782A1 CN 2020117074 W CN2020117074 W CN 2020117074W WO 2021057782 A1 WO2021057782 A1 WO 2021057782A1
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group
membered
alkyl
optionally substituted
alkoxy
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PCT/CN2020/117074
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French (fr)
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吴永谦
万中晖
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南京药捷安康生物科技有限公司
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Priority to US17/754,131 priority Critical patent/US20220298146A1/en
Priority to EP20868130.4A priority patent/EP4036086A1/en
Priority to JP2022519122A priority patent/JP2022549678A/ja
Publication of WO2021057782A1 publication Critical patent/WO2021057782A1/zh

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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention belongs to the field of medicine, and specifically relates to TAM family kinase/ and Ron kinase inhibitor compounds represented by general formula (I), and pharmaceutically acceptable salts, esters, stereoisomers, tautomers and containing them
  • the pharmaceutical composition, pharmaceutical preparations and uses of the drug can selectively inhibit the tyrosine kinase TAM family/and Ron kinase, and can be used for the treatment and/or prevention of diseases mediated by the abnormal expression of the receptor of the TAM family kinase/and Ron kinase and/or its ligand.
  • the TAM family includes three members: Axl, Mer, and Tyro-3.
  • the family includes an extracellular domain, a transmembrane domain, and a conserved intracellular kinase domain.
  • the extracellular domain consists of two immunoglobulin-like domains connected with two type III fibronectin repeat units.
  • the conserved amino acid sequence KW(I/L)A(I/L)ES of its intracellular kinase domain is a unique structural feature of the TAM family.
  • This family has a common ligand-growth inhibition specific protein 6 (Gas6), which can bind to all TAM receptors, but the binding strength is different.
  • Axl alias UFO, Ark, Tyro-7, JTK1
  • Mer alias c-Mer, Mertk, Eyk, Nyk, Tyro-12
  • Tyro-3 alias Sky, Byk, Rse, Dtk, etc.
  • Gas6 and ProS are abnormally expressed in various solid tumors such as lung cancer, gastric cancer, liver cancer and various hematomas such as AML, ALL, CML, and are related to the poor prognosis of the disease, disease progression, tumor metastasis, and tumor drug resistance, etc. There is a strong correlation (Douglas K, Nature reviews, 2014).
  • Axl as a tyrosine kinase, has been proven to be one of the reasons for the resistance of EGFR inhibitors in NSCLC, and is closely related to the metastasis of many solid tumors.
  • the drugs developed with this target also confirmed that inhibiting Axl can delay the resistance of EGFR inhibitors and the effect of tumor metastasis (T. Jimbo, Annals of Oncology, 2017; Sacha J. Holland, American Association for Cancer Research, 2010 ).
  • Axl, Mer, Tryo-3 and TAM family ligands also play a major role in the direction of immune tumors.
  • Inhibition of the TAM family and its ligands can reverse the immunosuppressive environment of tumors and enhance the immune system by promoting the polarization of macrophages to M1 macrophages, increasing the activation and function of effector T cells, and enhancing the anti-tumor activity of NK cells.
  • Ability to kill tumor cells Yamamoto, IL-12, IL-12, IL-12, IL-12, IL-12, IL-12, IL-12, etc.
  • the development of such inhibitors can have a strong inhibitory and therapeutic effect on a variety of solid and hematological tumors induced by the family, such as lung cancer, liver cancer, breast cancer, glioma, melanoma, AML, ALL, CML, etc. .
  • TAM family receptors and ligands can regulate vascular smooth muscle homeostasis, platelet aggregation, thrombus stabilization, erythropoiesis, oligodendrocyte survival, osteoclast function, phagocytosis of apoptotic cells, inflammation , Innate immunity and many other physiological functions. Therefore, TAM family inhibitors can also be used for endometriosis, vascular disease/injury, psoriasis, visual defects/pathology (caused by macular degeneration, diabetes, premature birth, etc.), kidney disease, Related diseases such as rheumatoid arthritis and osteoporosis.
  • Ron Human cell transmembrane receptor protein Ron (macrophage stimulating 1 receptor, MST1R), also known as macrophage stimulating protein receptor (MSP-receptor), hepatocyte growth factor like, HGFL ) Receptor.
  • MST1R macrophage stimulating 1 receptor
  • MSP-receptor macrophage stimulating protein receptor
  • HGFL hepatocyte growth factor like, HGFL
  • Ron gene is expressed in human epithelial tissues, granulocytes, monocytes, megakaryocytes, and tonsil germinal layer, small intestine, colon, kidney, lung, bone marrow, and osteoclasts.
  • Ron's role in the occurrence and development of a variety of common epithelial tumors in the human body has been widely confirmed.
  • Ron can be detected in 33%-96% of clinical specimens of pancreatic cancer, and the expression of Ron is positively correlated with tumor pathology (Thomas RM, et al. CancerRes, 2007, 67(13): 6075-6082.).
  • About 50% of breast cancer patients overexpress Ron.
  • the expression level of Ron in breast cancer of postmenopausal women is significantly higher than that of normal breast tissue and premenopausal breast cancer.
  • Studies on transgenic mice have shown that Ron’s overexpression is sufficient to induce breast transformation and has high metastasis. More than 86% of transgenic mice have metastases in the liver and lungs (Glendon M. Zinser, American Association for Cancer Research, 2006).
  • Ron is also abnormally expressed in non-small cell lung cancer, head and neck squamous cell carcinoma and other malignant tumors, and is related to tumor invasion and prognosis
  • the present invention provides a novel heterocyclic derivative inhibitor compound and pharmaceutically acceptable salts, esters, stereoisomers, and tautomers thereof (hereinafter, sometimes referred to as the compound of the present invention).
  • the compound of the present invention has an inhibitory effect on TAM family kinases, and can be used to treat and/or prevent diseases mediated by the abnormal expression of TAM family kinase receptors and/or their ligands.
  • the compounds of the present invention can also target Ron kinase and have an inhibitory effect on Ron kinase.
  • the compounds of the present invention can be used to treat and/or prevent diseases mediated by abnormal expression of TAM family kinases/and Ron kinase receptors and/or their ligands.
  • the compound of the present invention reverses the immunosuppressive environment in the tumor microenvironment, inhibits tumor growth, migration, and/or drug resistance, and exerts tumor immune effects and anti-tumor efficacy.
  • W is selected from a hydrogen atom or a C 1-6 alkyl group optionally substituted by a substituent
  • R represents a group represented by the following general formula (b):
  • X 4 and X 5 are each independently selected from C;
  • M 3 is selected from hydrogen atom, cyano group, hydroxyl group, halogen atom, carboxyl group, nitro group, -NR b R c , -C(O)R d , -C(O)NR b R c , -OC(O)NR b R c , -NR b C(O)OR d , -NR b C(O)R d , -SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d ; or optional substituted by a C 1-6 alkyl, C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, -C 1-6 alkyl -R ', - C 1-6 Alkoxy -R', -O-R', -C(O)-R', -SO 2 -R', -NR b C(O)-R', 3-12 membere
  • Cy 2 is selected from optionally substituted by one to the plurality of R 2 substituted 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl
  • R 2 are each independently selected from hydrogen atom, cyano group, hydroxyl group, halogen atom, carboxyl group, nitro group, -NR b R c , -C(O)R d , -C(O)NR b R c , -OC(O)NR b R c , -NR b C(O)OR d , -NR b C(O)R d , -SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d ; or C 1-6 alkyl, C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl,
  • Cy 3 is selected from 5-10 membered heteroaryl groups optionally substituted by one or more R 3 , R 3 is each independently selected from hydrogen atom, cyano group, hydroxyl group, halogen atom, carboxyl group, nitro group, -NR b R c , -C(O)R d , -C(O)NR b R c , -OC(O)NR b R c , -NR b C(O)OR d , -NR b C(O)R d ,- SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d ; or C 1-6 alkyl, C 1-6 alkoxy, C 2-8 alkene optionally substituted by substituents Group, C 2-8 alkynyl, -C 1-6 alkyl-R', -C 1-6 alkoxy-R', -O-R', -C(O)-R',
  • Cy 4 is selected from 5-9 membered heterocyclic groups and 5-9 membered heteroaryl groups optionally substituted with one or more R 4 ,
  • R 4 is each independently selected from hydrogen atom, cyano group, hydroxyl group, halogen atom, carboxyl group, Nitro, -NR b R c , -C(O)R d , -C(O)NR b R c , -OC(O)NR b R c , -NR b C(O)OR d , -NR b C(O)R d , -SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d ; or C 1-6 alkyl, C 1-6 alkane optionally substituted by substituents Oxy, C 2-8 alkenyl, C 2-8 alkynyl, -C 1-6 alkyl-R', -C 1-6 alkoxy-R', -O-
  • L is selected from -NR b -, -O-, -S-, -(CR a R a ) m -, and m is selected from an integer of 1-3;
  • R a does not exist, or at each occurrence, each is independently selected from a hydrogen atom, a cyano group, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, -NR e R f , -C(O)R g , -C( O)NR e R f , -OC(O)NR e R f , -NR e C(O)OR g , -NR e C(O)R g , -SO 2 -NR e R f , -SO 2 R g , -NR e SO 2 R g , or C 1-6 alkyl, C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, -C 1 optionally substituted by substituents -6 alkyl-R', -C 1-6 alkoxy-R', -O-R', -C(O)-R',
  • R b and R c are not present, or each time they appear, they are independently selected from hydrogen atom, hydroxyl group, -C(O)R g , -C(O)NR e R f , -SO 2 -NR e R f , -SO 2 R g ; or C 1-6 alkyl, -C 1-6 alkyl-R', -C(O)-R', -SO 2 -R', optionally substituted by substituents 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclic group, 6-14 membered aryl, 5-10 membered heteroaryl;
  • R d does not exist, or at each occurrence, each is independently selected from hydrogen atom, -NR e R f , -NR e C(O)OR g , -NR e C(O)R g , -NR e SO 2 R g; or optionally substituted C 1-6 alkyl, C 1-6 alkoxy, -C 1-6 alkyl -R ', - C 1-6 alkoxy -R', -O-R', -NR e C(O)-R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclic group, 6-14 membered aryl, 5- 10-membered heteroaryl;
  • R e and R f are not present, or each time they appear, they are independently selected from hydrogen atom, hydroxyl group, carboxyl group, cyano group, nitro group, halogen atom; or C 1-6 alkyl group optionally substituted by substituents , -C 1-6 alkyl-R', -C(O)-R', -SO 2 -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocycle Group, 6-14 membered aryl group, 5-10 membered heteroaryl group;
  • R g does not exist, or at each occurrence, each is independently selected from hydrogen atoms; or C 1-6 alkyl, C 1-6 alkoxy, -C 1-6 alkyl optionally substituted by substituents -R', -C(O)-R', -SO 2 -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclic group, 6-14 membered aryl group , 5-10 membered heteroaryl group;
  • R' is a 3-12 membered cycloalkyl group, a 3-12 membered cycloalkenyl group, a 3-14 membered heterocyclic group, a 6-14 membered aryl group, a 5-10 membered heteroaryl group;
  • n is an integer from 0-4;
  • substituents in the "optionally substituted by substituents" are each independently selected from: hydroxyl, mercapto, amino, carboxy, cyano, nitro, halogen atom, C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl group, C 1-6 alkoxy, C 1-6 alkyl C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, C 1-6 alkyl Alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonyl Oxy, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 1-6 alkylsulfonyl, C 1-6 alkylthio, 3-12 membered cycloalky
  • a compound represented by general formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof is provided:
  • W is selected from a hydrogen atom or a C 1-6 alkyl group optionally substituted by a substituent
  • R represents a group represented by the following general formula (b):
  • X 4 and X 5 are respectively selected from C;
  • M 3 is selected from hydrogen atom, cyano group, hydroxyl group, halogen atom, carboxyl group, nitro group, -NR b R c , -C(O)R d , -C(O)NR b R c , -OC(O)NR b R c , -NR b C(O)OR d , -NR b C(O)R d , -SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d ; or optional C 1-6 alkyl, C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclic group substituted by substituents;
  • Cy 2 is selected from 6-14 membered aryl groups and 5-10 membered heteroaryl groups optionally substituted by one or more R 2 ,
  • R 2 is each independently selected from hydrogen atom, cyano group, hydroxyl group, halogen atom, carboxyl group, nitro group ⁇ , -NR b R c , -C(O)R d , -C(O)NR b R c , -OC(O)NR b R c , -NR b C(O)OR d , -NR b C (O) R d , -SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d ; or C 1-6 alkyl, C 1-6 alkoxy optionally substituted by substituents Group, C 2-8 alkenyl, C 2-8 alkynyl, -C 1-6 alkyl-R', -C 1-6 alkoxy-R', -
  • Cy 3 is selected from 5-10 membered heteroaryl groups optionally substituted with one or more R 3 , and R 3 is each independently selected from hydrogen atom, cyano group, hydroxyl group, halogen atom, carboxyl group, nitro group, -NR b R c , -C(O)R d , -C(O)NR b R c , -OC(O)NR b R c , -NR b C(O)OR d , -NR b C(O)R d ,- SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d ; or C 1-6 alkyl, C 1-6 alkoxy, C 2-8 alkene optionally substituted by substituents Group, C 2-8 alkynyl, -C 1-6 alkyl-R', -C 1-6 alkoxy-R', -O-R', -C(O)-R'
  • Cy 4 is selected from 5-9 membered heteroaryl groups optionally substituted with one or more R 4 , R 4 is each independently selected from hydrogen atom, cyano group, hydroxyl group, halogen atom, carboxyl group, nitro group, -NR b R c , -C(O)R d , -C(O)NR b R c , -OC(O)NR b R c , -NR b C(O)OR d , -NR b C(O)R d ,- SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d ; or C 1-6 alkyl, C 1-6 alkoxy, C 2-8 alkene optionally substituted by substituents Group, C 2-8 alkynyl, -C 1-6 alkyl-R', -C 1-6 alkoxy-R', -O-R', -C(O)-R',
  • L is selected from -NR b -, -O-, -S-;
  • R a does not exist, or at each occurrence, each is independently selected from a hydrogen atom, a cyano group, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, -NR e R f , -C(O)R g , -C( O)NR e R f , -OC(O)NR e R f , -NR e C(O)OR g , -NR e C(O)R g , -SO 2 -NR e R f , -SO 2 R g , -NR e SO 2 R g ; or C 1-6 alkyl, C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, -C 1 optionally substituted by substituents -6 alkyl-R', -C 1-6 alkoxy-R', -O-R', -C(O)-R',
  • R b and R e are not present, or each time they appear, they are independently selected from hydrogen atom, hydroxyl group, -C(O)R g , -C(O)NR e R f , -SO 2 -NR e R f , -SO 2 R g ; or C 1-6 alkyl, -C 1-6 alkyl-R', -C(O)-R', -SO 2 -R', optionally substituted by substituents 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-14 membered heterocyclic group, 6-14 membered aryl, 5-10 membered heteroaryl;
  • R d does not exist, or at each occurrence, each is independently selected from hydrogen atom, -NR e R f , -NR e C(O)OR g , -NR e C(O)R g , -NR e SO 2 R g; or optionally substituted C 1-6 alkyl, C 1-6 alkoxy, -C 1-6 alkyl -R ', - C 1-6 alkoxy -R', -O-R', -NR e C(O)-R', 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-14 membered heterocyclic group, 6-14 membered aryl, 5- 10-membered heteroaryl;
  • R e and R f are not present, or each time they appear, they are independently selected from hydrogen atom, hydroxyl group, carboxyl group, cyano group, nitro group, halogen atom; or C 1-6 alkyl group optionally substituted by substituents, -C 1-6 alkyl-R', -C(O)-R', -SO 2 -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclic group , 6-14 membered aryl, 5-10 membered heteroaryl;
  • R g does not exist, or at each occurrence, is independently selected from hydrogen atoms; or C 1-6 alkyl, C 1-6 alkoxy, -C 1-6 alkyl optionally substituted by substituents- R', -C(O)-R', -SO 2 -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
  • R' is a 3-8 membered cycloalkyl group, a 3-8 membered cycloalkenyl group, a 3-14 membered heterocyclic group, a 6-14 membered aryl group, a 5-10 membered heteroaryl group;
  • n is an integer of 0-3;
  • substituents in the "optionally substituted by substituents" are each independently selected from: hydroxyl, mercapto, amino, carboxy, cyano, nitro, halogen atom, C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl group, C 1-6 alkoxy, C 1-6 alkyl C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, C 1-6 alkyl Alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonyl Oxy, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 1-6 alkylsulfonyl, C 1-6 alkylthio, 3-8 membered cycloalky
  • X 1 is N
  • X 2 is CR a
  • X 1 is CR a
  • X 2 is N
  • X 1 is CR a
  • X 2 is CR a
  • a compound represented by general formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof is provided:
  • X 4 is selected from C
  • X 5 is selected from C
  • M 3 is selected from hydrogen atom, hydroxyl group, halogen atom, carboxyl group, nitro group, -NR b R c , -C(O)R d , -C(O)NR b R c , -NR b C(O)R d ; Or C 1-6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic group optionally substituted by substituents;
  • Cy 2 is selected from phenyl optionally substituted with one or more R 2 , 5-6 membered heteroaryl, R 2 is each independently selected from hydrogen atom, hydroxyl group, halogen atom, carboxyl group, nitro group, -NR b R c , -C(O)R d , -C(O)NR b R c , -NR b C(O)R d ; or C 1-6 alkyl, C 1-6 alkoxy optionally substituted by substituents base;
  • Cy 3 is selected from 5-6 membered heteroaryl groups optionally substituted with one or more R 3 , R 3 is each independently selected from hydrogen atom, hydroxyl group, halogen atom, carboxyl group, nitro group, -NR b R c , -C (O)R d , -C(O)NR b R c , -NR b C(O)R d ; or C 1-6 alkyl, C 1-6 alkoxy optionally substituted by substituents;
  • Cy 4 is selected from 5-6 membered heteroaryl groups or 9-membered heteroaryl groups optionally substituted with one or more R 4 ,
  • R 4 is each independently selected from hydrogen atom, hydroxyl group, halogen atom, nitro group, -NR b R c , -C(O)R d , -C(O)NR b R c , -NR b C(O)R d ; or C 1-6 alkyl, C 1-6 optionally substituted by substituents Alkoxy, or, two R 4 can form a 5-6 membered oxygen-containing cyclic group with the atom to which they are attached;
  • L is selected from -O-;
  • R a does not exist, or at each occurrence, each is independently selected from a hydrogen atom, or a C 1-6 alkyl group optionally substituted by a substituent;
  • R b and R c are not present, or at each occurrence, each is independently selected from a hydrogen atom, or a C 1-6 alkyl group optionally substituted by a substituent;
  • R d does not exist, or at each occurrence, each is independently selected from a hydrogen atom, or a C 1-6 alkyl group optionally substituted by a substituent;
  • n is an integer of 0-2;
  • substituents in the "optionally substituted by substituents" are each independently selected from: a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, a C 1-6 alkyl group, and a C 1-6 alkoxy group;
  • X 1 is N
  • X 2 is CR a
  • X 1 is CR a
  • X 2 is N
  • X 1 is CR a
  • X 2 is CR a
  • Cy 3 is Y 2 , Y 3 , Y 6 , and Y 7 are each independently selected from CH or N, and at least one of them is N.
  • a compound represented by general formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof is provided:
  • X 4 is selected from C
  • X 5 is selected from C
  • M 3 is selected from a hydrogen atom; or a C 1-6 alkyl group, a C 2-8 alkenyl group, a C 2-8 alkynyl group, a 3-8 membered cycloalkyl group, a 5-6 membered heterocyclic ring optionally substituted by a substituent base;
  • Cy 2 is selected from phenyl and 5-6 membered heteroaryl optionally substituted with one or more R 2;
  • Cy 3 represents optionally substituted by one or more R 3
  • Y 2 , Y 3 , Y 6 and Y 7 are each independently selected from CH or N, and at least one is N;
  • Cy 4 is selected from 6-membered heteroaryl or 9-membered heteroaryl optionally substituted with one to more R 4;
  • R 2 is each independently selected from hydrogen atom, hydroxyl group, halogen atom, carboxyl group, nitro group, -NR b R c , -C(O)R d , -C(O)NR b R c , -NR b C(O ) R d ; or C 1-6 alkyl, C 1-6 alkoxy optionally substituted by substituents;
  • R 3 is each independently selected from hydrogen atom, hydroxyl group, halogen atom, carboxyl group, nitro group, -NR b R c , -C(O)R d , -C(O)NR b R c , -NR b C(O ) R d ; or C 1-6 alkyl, C 1-6 alkoxy optionally substituted by substituents;
  • R 4 is each independently selected from a hydrogen atom, a hydroxyl group, a halogen atom, a nitro group, -NR b R c , -C(O)R d , -C(O)NR b R c , -NR b C(O)R d , 5-10 membered heteroaryl; or C 1-6 alkyl, C 1-6 alkoxy optionally substituted by substituents;
  • L is selected from -O-;
  • R a does not exist, or at each occurrence, each is independently selected from a hydrogen atom, a C 1-6 alkyl group, and a halogenated C 1-6 alkyl group;
  • R b and R c are not present, or each time they appear, they are each independently selected from a hydrogen atom and a C 1-6 alkyl group;
  • R d does not exist, or at each occurrence, each is independently selected from a hydrogen atom and a C 1-6 alkyl group;
  • n is an integer of 0-2;
  • substituents in the "optionally substituted by substituents" are each independently selected from: hydroxyl, mercapto, amino, carboxy, cyano, nitro, halogen atom, C 1-6 alkyl, C 1-6 alkoxy base;
  • X 1 is N
  • X 2 is CR a
  • X 1 is CR a
  • X 2 is N
  • X 1 is CR a
  • X 2 is CR a
  • Cy 4 is selected from a 6-membered N-containing heteroaryl group or a 9-membered N-containing heteroaryl group optionally substituted with one to more R 4.
  • a compound represented by general formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof is provided:
  • M 3 is selected from a hydrogen atom, a C 1-6 alkyl group, a C 2-8 alkenyl group, a C 2-8 alkynyl group, a 3-6 membered cycloalkyl group, and a 5-6 membered heterocyclic group;
  • Cy 2 is selected from phenyl optionally substituted with one to more R 2;
  • Cy 3 represents optionally substituted by one or more R 3
  • Y 2 , Y 3 , Y 6 and Y 7 are independently selected from CH or N, and at least one is N;
  • Cy 4 is selected from those optionally substituted with one or more R 4
  • R 2 is each independently selected from hydrogen atom, hydroxyl group, halogen atom, carboxyl group, nitro group, -NR b R c , -C(O)R d , -C(O)NR b R c , -NR b C(O ) R d ; or C 1-6 alkyl, C 1-6 alkoxy optionally substituted by substituents;
  • R 3 is each independently selected from hydrogen atom, hydroxyl group, halogen atom, carboxyl group, nitro group, -NR b R c , -C(O)R d , -C(O)NR b R c , -NR b C(O ) R d ; or C 1-6 alkyl, C 1-6 alkoxy optionally substituted by substituents;
  • R 4 is each independently selected from a hydrogen atom, a hydroxyl group, a halogen atom, a nitro group, -NR b R c , -C(O)R d , -C(O)NR b R c , -NR b C(O)R d ; or C 1-6 alkyl, C 1-6 alkoxy optionally substituted by substituents;
  • L is selected from -O-;
  • R a does not exist, or at each occurrence, each is independently selected from a hydrogen atom, a C 1-6 alkyl group, and a halogenated C 1-6 alkyl group;
  • R b and R c are not present, or each time they appear, they are each independently selected from a hydrogen atom and a C 1-6 alkyl group;
  • R d does not exist, or at each occurrence, each is independently selected from a hydrogen atom and a C 1-6 alkyl group;
  • n is an integer of 0-1;
  • substituents in the "optionally substituted by substituents" are each independently selected from: a hydroxyl group, a mercapto group, an amino group, a carboxyl group, a cyano group, a nitro group, and a halogen atom.
  • a compound represented by general formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof is provided:
  • W is selected from hydrogen atoms
  • R represents a group represented by the following general formula (b):
  • X 4 is selected from C;
  • X 5 is selected from C;
  • M 3 is selected from: hydrogen atom, hydroxyl group, halogen atom, nitro group, C 1-4 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, 3-6 membered cycloalkyl group, 5-6 membered hetero Ring base
  • Cy 2 is selected from optionally substituted with one or more R 2 R 2 is each independently selected from hydrogen atom, hydroxyl, fluorine, chlorine, bromine, C 1-4 alkyl;
  • Cy 3 is selected from those optionally substituted with one or more R 3 R 3 is each independently selected from hydrogen atom, hydroxyl, fluorine, chlorine, bromine, C 1-4 alkyl;
  • Cy 4 is selected from those optionally substituted with one or more R 4
  • R 4 is each independently selected from a hydrogen atom, a hydroxyl group, a halogen atom, an amino group, (C 1-4 alkyl) 1-2 amino-, C 1-4 alkyl, halogenated C 1-4 alkyl, C 1- 4 alkoxy, halogenated C 1-4 alkoxy, 3-14 membered heterocyclic group;
  • L is -O-
  • R a does not exist, or at each occurrence, each is independently selected from a hydrogen atom, a C 1-6 alkyl group, and a halogenated C 1-6 alkyl group;
  • R b does not exist, or at each occurrence, each is independently selected from a hydrogen atom and a C 1-6 alkyl group;
  • n is an integer of 0-1;
  • X 1 is N
  • X 2 is CR a
  • X 1 is CR a
  • X 2 is N
  • X 1 is CR a
  • X 2 is CR a
  • the present invention provides the following technical solutions.
  • W is selected from a hydrogen atom or a C 1-6 alkyl group optionally substituted by a substituent
  • R represents a group represented by the following general formula (b′):
  • X 4 and X 5 are each independently selected from CR a or N;
  • M 3 is selected from hydrogen atom, cyano group, hydroxyl group, halogen atom, carboxyl group, nitro group, -NR b R c , -C(O)R d , -C(O)NR b R c , -OC(O)NR b R c , -NR b C(O)OR d , -NR b C(O)R d , -SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d ; or optional C 1-6 alkyl substituted by substituents, C 1-6 alkoxy optionally substituted by substituents, C 2-8 alkenyl optionally substituted by substituents, C 2 optionally substituted by substituents -8alkynyl , -C 1-6 alkyl optionally substituted by substituents -R', -C 1-6 alkoxy optionally substituted by substituents -R',
  • CY 2 is selected from optionally substituted with one or more R 2 substituted 3-12 membered cycloalkyl, optionally substituted by one or more R 2 3-12 membered cycloalkenyl, optionally substituted with one or more R 2 3-14 membered heterocyclyl, optionally substituted by 2 are each independently selected from a hydrogen atom is substituted with more than one R 2 group, and a 6-14 membered aryl being optionally substituted with one or more 2 R 5-10 membered heteroaryl group, R, a cyano group , Hydroxyl group, mercapto group, halogen atom, carboxyl group, nitro group, -NR b R c , -C(O)R d , -C(O)NR b R c , -OC(O)NR b R c , -NR b C(O)R d , -NR b C(O)OR d , -SO 2 -NR b
  • Cy 3 is selected from 5-10 membered heteroaryl groups optionally substituted by more than one R 3 , R 3 is each independently selected from hydrogen atom, cyano group, hydroxyl group, mercapto group, halogen atom, carboxyl group, nitro group, -NR b R c , -C(O)R d , -C(O)NR b R c , -OC(O)NR b R c , -NR b C(O)R d , -NR b C(O)OR d , -SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d , C 1-6 alkyl optionally substituted by substituents, C 1-6 alkane optionally substituted by substituents Oxy, C 2-8 alkenyl optionally substituted by substituents, C 2-8 alkynyl optionally substituted by substituents, -C 1-6 alkyl optional
  • CY 4 is selected from optionally substituted with one or more R 4 substituted 3-12 membered cycloalkyl, optionally substituted by one or more R 4 3-14 membered heterocyclyl, optionally substituted with one or more of R 4 5-14 Membered heteroaryl group and 6-14 membered aryl group optionally substituted by more than one R 4 ,
  • R 4 is each independently selected from hydrogen atom, cyano group, hydroxyl group, mercapto group, halogen atom, carboxyl group, nitro group, -NR b R c , -C(O)R d , -C(O)NR b R c , -OC(O)NR b R c , -NR b C(O)R d , -NR b C(O)OR d , -SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d , C 1-6 alkyl
  • L is selected from -NR b -, -O-, -S-, -(CR a R a ) m -, and m is selected from an integer of 1-3;
  • R a does not exist, or at each occurrence, each is independently selected from a hydrogen atom, a cyano group, a hydroxyl group, a mercapto group, a halogen atom, a carboxyl group, a nitro group, -NR b R c , -C(O)R d ,- C(O)NR b R c , -OC(O)NR b R c , -NR b C(O)R d , -NR b C(O)OR d , -SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d , C 1-6 alkyl optionally substituted by substituents, C 1-6 alkoxy optionally substituted by substituents, C 2 optionally substituted by substituents -8 alkenyl, C 2-8 alkynyl optionally substituted by a substituent,-C 1-6 alkyl optionally substituted
  • R b and R c each does not exist, or at each occurrence, each is independently selected from a hydrogen atom, a hydroxyl group, a C 1-6 alkyl group optionally substituted by a substituent, and a C 1 optionally substituted by a substituent -6 alkyl-R', -C(O)-R', -SO 2 -R', 3-12-membered cycloalkyl optionally substituted by substituents, 3-12-membered optionally substituted by substituents Cycloalkenyl, 3-14 membered heterocyclic group optionally substituted by substituents, 6-14 membered aryl optionally substituted by substituents, 5-10 membered heteroaryl optionally substituted by substituents;
  • R d does not exist, or at each occurrence, each is independently selected from hydroxyl, halogen atom, amino, -amino (C 1-6 alkyl optionally substituted by substituent ) 1-2, optionally substituted Substituted C 1-6 alkyl, C 1-6 alkoxy optionally substituted by substituents, -C 1-6 alkyl optionally substituted by substituents -R', -optionally substituted by substituents C 1-6 alkoxy-R', -O-R', 3-12 membered cycloalkyl optionally substituted by substituents, 3-12 membered cycloalkenyl optionally substituted by substituents, optionally substituted by Substituent substituted 3-14 membered heterocyclic group, optionally substituted 6-14 membered aryl group, optionally substituted 5-10 membered heteroaryl group;
  • R' is each independently selected from 3-12 membered cycloalkyl optionally substituted by substituents, 3-12 membered cycloalkenyl optionally substituted by substituents, 3-14 membered heterocyclic ring optionally substituted by substituents Group, a 6-14 membered aryl group optionally substituted by a substituent and a 5-10 membered heteroaryl group optionally substituted by a substituent;
  • q is an integer from 0-4;
  • n is an integer from 0-4;
  • substituents in the "optionally substituted by substituents" are each independently selected from: hydroxyl, mercapto, amino, carboxy, cyano, nitro, halogen atom, C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl group, C 1-6 alkoxy, C 1-6 alkyl C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, C 1-6 alkyl Alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonyl Oxy, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 1-6 alkylsulfonyl, C 1-6 alkylthio, 3-12 membered cycloalky
  • Cy 2 does not represent a heterocyclic group
  • X 4 represents CR a ;
  • X 4 represents CR a ;
  • X 4 represents CR a ;
  • X 1 represents when CR a R a, R a group on the 1 X does not have a carbonyl group;
  • M 3 is selected from hydrogen atom, cyano group, hydroxyl group, halogen atom, carboxyl group, nitro group, -NR b R c , -C(O)R d , -C(O)NR b R c , -OC(O)NR b R c , -NR b C(O)R d , -NR b C(O)OR d , -SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d ; or optional C 1-6 alkyl substituted by substituents, C 1-6 alkoxy optionally substituted by substituents, C 2-8 alkenyl optionally substituted by substituents, C 2 optionally substituted by substituents -8 alkynyl, 3-8 membered cycloalkyl optionally substituted by substituents, 3-14 membered heterocyclic group optionally substituted by substituents;
  • R 2 is independently selected from hydrogen atoms, hydroxy, halogen Atom, carboxyl group, nitro group, -NR b R c , -C(O)R d , -C(O)NR b R c , -NR b C(O)OR d , C 1 optionally substituted by substituents -6 alkyl group, C 1-6 alkoxy group optionally substituted by substituents; preferably, R 2 is each independently selected from a hydrogen atom, a hydroxyl group, a halogen atom, a C 1-6 alkyl group, and a hydroxyl group C 1- 6 alkyl, amino C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy; preferably, R 2 is each independently selected from Hydro
  • Cy 3 is selected from 5-10 membered heteroaryl groups optionally substituted by more than one R 3 , R 3 is each independently selected from hydrogen atom, hydroxyl group, halogen atom, carboxyl group, nitro group, -NR b R c , -C (O)R d , -C(O)NR b R c , -NR b C(O)R d , C 1-6 alkyl optionally substituted by substituents, C 1- optionally substituted by substituents 6 Alkoxy; preferably, R 3 is each independently selected from a hydrogen atom, a hydroxyl group, a halogen atom, a C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, an amino C 1-6 alkyl group, a halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy; preferably, R 3 is each independently selected from hydrogen atom, hydroxyl, fluorine, chlorine,
  • CY 4 is selected from optionally substituted with one or more R 4 is 5-10 membered heterocyclyl, optionally substituted with one or more R 4 is aryl, and 5-10 membered heteroaryl optionally substituted with one or more R 4 6-10 Yuan aryl group;
  • R 4 is each independently selected from hydrogen atom, hydroxyl group, halogen atom, carboxyl group, nitro group, -NR b R c , -C(O)R d , -C(O)NR b R c , -NR b C(O)R d , C 1-6 alkyl optionally substituted by substituents, C 1-6 alkoxy optionally substituted by substituents, 5-10 membered heteroaryl optionally substituted by substituents
  • R 4 is each independently selected from hydrogen atom, hydroxyl group, halogen atom, amino group, (C 1-6 alkyl) 1-2 amino-, C 1-6 alkyl, hydroxy C 1-6 alkane Group
  • L is selected from -NR b -, -O- and -S-;
  • R a does not exist, or at each occurrence, each is independently selected from a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, a nitro group, -NR b R c , -C(O)R d , -C(O)NR b R c , -NR b C(O)R d , C 1-6 alkyl optionally substituted by substituents, C 1-6 alkoxy optionally substituted by substituents; preferably, R a is not Exist, or in each occurrence, each independently selected from hydrogen atom, hydroxyl group, halogen atom, carboxyl group, nitro group, C 1-6 alkyl group, C 1-6 alkoxy group, halogenated C 1-6 alkyl group Preferably, R a does not exist, or each time it occurs, each is independently selected from a hydrogen atom, a C 1-6 alkyl group, and a C 1-6 alkoxy group;
  • R b and R c does not exist, or each time they occur, each is independently selected from a hydrogen atom and a C 1-6 alkyl group optionally substituted with a substituent; preferably, R b and R c each does not exist , Or at each occurrence, each is independently selected from hydrogen atom, C 1-6 alkyl, halo C 1-6 alkyl; preferably, R b and R c each does not exist, or in each occurrence When, each is independently selected from a hydrogen atom, a C 1-6 alkyl group;
  • R d does not exist, or at each occurrence, each is independently selected from hydroxyl group, halogen atom, amino group, -amino group (C 1-6 alkyl group optionally substituted by substituent ) 1-2, optionally substituted group substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy group; it is preferable that, R d does not exist, or at each occurrence, is independently selected from hydroxy, amino, - Amino (C 1-6 alkyl) 1-2 , C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy; preferably , R d does not exist, or at each occurrence, each is independently selected from hydroxyl, amino, C 1-4 alkyl, halo C 1-4 alkyl, C 1-4 alkoxy, halo C 1 -4 alkoxy;
  • R' is selected from 3-8 membered cycloalkyl optionally substituted by substituents, 3-8 membered cycloalkenyl optionally substituted by substituents, 3-10 membered heterocyclyl optionally substituted by substituents, any A 6-10 membered aryl group substituted by a substituent and a 5-6 membered heteroaryl group optionally substituted by a substituent; preferably, R'is selected from a 3-6 membered cycloalkyl group optionally substituted by a substituent , 4-7 membered heterocyclic groups optionally substituted by substituents, 6-10 membered aryl groups optionally substituted by substituents and 5-6 membered heteroaryl groups optionally substituted by substituents; preferably, R 'Choose from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, oxetanyl, ox
  • substituents in "optionally substituted by substituents” are each independently selected from: hydroxy, mercapto, amino, carboxy, cyano, nitro, halogen atom, C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, C 1-6 alkylamino , (C 1-6 alkyl) 2 amino, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonyloxy , C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 1-6 alkylsulfonyl, C 1 -6 alkylthio, 3-8 membered cycloalkyl, 6-10
  • n 0, 1, 2, 3 or 4,
  • q 0, 1, 2, 3, or 4.
  • X 1 is NR b
  • X 2 is CR a R a
  • X 1 is CR a R a
  • X 2 is NR b
  • X 2 is CR a R a
  • X 1 is CR a R a
  • X 1 is CR a R a
  • X 2 is CR a R a
  • X 2 is CR a R a
  • X 3 is CR a R a ;
  • X 1 is CR a R a
  • X 3 is CR a R a.
  • X 4 is selected from N, X 5 is selected from CR a ; or
  • X 4 is selected from CR a
  • X 5 is selected from CR a ;
  • X 4 is selected from N
  • X 5 is selected from N
  • X 4 is selected from CR a
  • X 5 is selected from N.
  • M 3 is selected from hydrogen atom, hydroxyl group, halogen atom, carboxyl group, nitro group, -NR b R c , -C(O)R d , -C(O)NR b R c , -NR b C(O)R d ; Or C 1-6 alkyl optionally substituted by substituents, C 2-8 alkenyl optionally substituted by substituents, C 2-8 alkynyl optionally substituted by substituents, optionally substituted by substituents 3-8 membered cycloalkyl group, 3-8 membered heterocyclic group optionally substituted by substituents;
  • R 2 is independently selected from a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, Nitro, -NR b R c , -C(O)R d , -C(O)NR b R c , -NR b C(O)R d ; or C 1-6 alkane optionally substituted by substituents Group, C 1-6 alkoxy optionally substituted by substituents;
  • Cy 3 is selected from 5-6 membered heteroaryl groups optionally substituted with one or more R 3 , and R 3 is each independently selected from hydrogen atom, hydroxyl group, halogen atom, carboxyl group, nitro group, -NR b R c , -C( O) R d , -C(O)NR b R c , -NR b C(O)R d ; or C 1-6 alkyl optionally substituted by substituents, C 1- optionally substituted by substituents 6 alkoxy;
  • Cy 4 is selected from 5-9 membered heteroaryl groups optionally substituted by more than one R 4 , R 4 is each independently selected from hydrogen atom, hydroxyl group, halogen atom, nitro group, -NR b R c , -C(O) R d , -C(O)NR b R c , -NR b C(O)R d ; or C 1-6 alkyl optionally substituted by substituents, C 1-6 alkane optionally substituted by substituents Oxy, 5-6 membered heteroaryl optionally substituted by substituents;
  • L is selected from -O-;
  • R a does not exist, or at each occurrence, each is independently selected from a hydrogen atom, or a C 1-6 alkyl group optionally substituted by a substituent;
  • R b and R c are not present, or at each occurrence, each is independently selected from a hydrogen atom, or a C 1-6 alkyl group optionally substituted by a substituent;
  • R d does not exist, or at each occurrence, each is independently selected from a hydrogen atom, or a C 1-6 alkyl group optionally substituted by a substituent;
  • n is an integer of 0-2;
  • substituents in the "optionally substituted with substituents" are each independently selected from: a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, a C 1-6 alkyl group, and a C 1-6 alkoxy group.
  • Cy 3 represents optionally substituted by more than one R 3
  • Y 2 , Y 3 , Y 6 and Y 7 are each independently selected from CR a R a or NR b , and at least one of them is NR b .
  • Cy 3 represents optionally one Replaced by R 3 above
  • the groups shown, Y 2 , Y 3 , Y 6 , and Y 7 are each independently selected from CH or N, and at least one of them is N;
  • R 3 is each independently selected from hydrogen atom, hydroxyl group, halogen atom, carboxyl group, nitro group, -NR b R c , -C(O)R d , -C(O)NR b R c , -NR b C(O ) R d , a C 1-6 alkyl group optionally substituted by a substituent, a C 1-6 alkoxy group optionally substituted by a substituent; preferably, R 3 is each independently selected from a hydrogen atom, a hydroxyl group, and a halogen Atom, C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy Group; Preferably, each of R 3 is independently selected from a hydrogen atom, a hydroxyl group, a fluorine, a chlorine, a bromine, and a C 1-4 alkyl group
  • Cy 4 represents optionally substituted by more than one R 4
  • Y 4 and Y 5 are each independently selected from CR a R a or NR b
  • ring B forms a five-membered ring.
  • Y 4 and Y 5 are CR a R a
  • ring B contains NR
  • the five-membered heteroaromatic ring of b preferably, Cy 4 represents optionally substituted by more than one R 4
  • Y 4 and Y 5 are each independently CH
  • ring B is a five-membered heteroaromatic ring containing 1-2 NR b;
  • R 4 is each independently selected from hydrogen atom, hydroxyl group, halogen atom, carboxyl group, nitro group, -NR b R c , -C(O)R d , -C(O)NR b R c , -NR b C(O ) R d , C 1-6 alkyl optionally substituted by substituents, C 1-6 alkoxy optionally substituted by substituents, 5-6 membered heteroaryl; preferably, R 4 is each independently Selected from hydrogen atom, hydroxyl group, halogen atom, amino group, (C 1-6 alkyl) 1-2 amino-, C 1-6 alkyl group, hydroxy C 1-6 alkyl group, amino C 1-6 alkyl group, halogen Substituted C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkyl C 1-6 Alkoxy, C 1-6 alkoxy
  • M 3 is selected from: hydrogen atom, hydroxyl group, halogen atom, nitro group, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, 3-6 membered cycloalkyl group, 5-6 membered hetero Ring base
  • Cy 2 is selected from optionally substituted by more than one R 2 R 2 is each independently selected from hydroxyl, fluorine, chlorine, bromine, C 1-4 alkyl;
  • Cy 3 is selected from those optionally substituted with more than one R 3 Preferred are the following groups optionally substituted by more than one R 3:
  • the * terminal is connected to N, the ⁇ terminal is connected to L, and R 3 is each independently selected from hydroxyl, fluorine, chlorine, bromine, and C 1-4 alkyl groups;
  • Cy 4 is selected from those optionally substituted with more than one R 4 R 4 is each independently selected from hydroxyl, halogen atom, amino, (C 1-4 alkyl) 1-2 amino-, C 1-4 alkyl, halogenated C 1-4 alkyl, C 1-4 alkoxy Group, halogenated C 1-4 alkoxy, pyrrolyl, furyl, thienyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl.
  • a compound represented by formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof is provided, and the compound is selected from:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one of the compound represented by any one of the above formula (I), its pharmaceutically acceptable salt, ester, stereoisomer, and tautomer .
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by any one of the above formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer, which may optionally contain one Or a variety of pharmaceutical carriers.
  • the present invention also provides a pharmaceutically acceptable dosage form comprising a compound represented by any one of the above formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer, which optionally contains One or more pharmaceutical carriers.
  • a pharmaceutical composition or dosage form comprising a compound represented by any one of the above formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer is provided , which may optionally contain at least one second therapeutically active agent.
  • the second therapeutically active agent is at least one selected from the group consisting of antimetabolites, growth factor inhibitors, silk classification inhibitors, antitumor hormones, alkylating agents , Metallic platinums, topoisomerase inhibitors, hormone drugs, immunomodulators, tumor suppressor genes, cancer vaccines, immune checkpoint inhibitors or antibodies related to tumor immunotherapy, small molecule drugs and cell therapy agents.
  • the pharmaceutical composition or dosage form can be administered in any suitable manner known in the art, such as oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, Intradermal, intrathecal and epidural), transdermal, rectal, nasal, transpulmonary, topical (including oral and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal administration methods, etc., when applied to the need for treatment And/or preventive patients or subjects.
  • parenteral including subcutaneous, intramuscular, intravenous, intraarterial, Intradermal, intrathecal and epidural
  • transdermal rectal
  • nasal, transpulmonary topical (including oral and sublingual)
  • vaginal intraperitoneal, intrapulmonary and intranasal administration methods, etc.
  • the pharmaceutical composition or dosage form can be made into conventional solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be made into oral liquid preparations, such as oral solutions, Oral suspension, syrup, etc.
  • oral preparations suitable fillers, binders, disintegrants, lubricants, etc. can be added.
  • the pharmaceutical composition can be made into injections, sterile powders for injections and concentrated solutions for injections.
  • injections When preparing an injection, it can be produced by a conventional method in the existing pharmaceutical field.
  • the pharmaceutical composition When used for rectal administration, the pharmaceutical composition can be made into suppositories and the like.
  • the pharmaceutical composition can be made into an inhalant or a spray.
  • a compound represented by any one of the above formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, the above-mentioned pharmaceutical composition, and the above-mentioned dosage form are provided for the preparation of drugs for the treatment and/or prevention of diseases mediated by abnormal expression of TAM family kinase receptors and/or their ligands.
  • the abnormal expression of TAM family kinase receptors and/or their ligands include at least one of the following diseases: tumors, tumor immunity, endometriosis, vascular diseases/injuries, psoriasis, visual defects/lesions (including macular degeneration, diabetes, and premature birth), kidneys Diseases, rheumatoid arthritis, osteoporosis and other related diseases.
  • a compound represented by any one of the above formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, the above-mentioned pharmaceutical composition, and the above-mentioned dosage form are provided.
  • Method for treating and/or preventing diseases mediated by abnormal expression of TAM family kinase receptor and/or its ligand, and diseases mediated by abnormal expression of TAM family kinase receptor and/or its ligand Including at least one of the following diseases: tumor, tumor immunity, endometriosis, vascular disease/injury, psoriasis, visual defect/pathology (including macular degeneration, diabetes and premature birth), kidney disease, rheumatoid Related diseases such as arthritis and osteoporosis.
  • a compound represented by any one of the above formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, the above-mentioned pharmaceutical composition, and the above-mentioned dosage form are provided
  • the TAM family kinases/and Ron kinase receptors and/or their ligands include at least one of the following diseases: tumors, tumor immunity, endometriosis, vascular diseases/injuries, psoriasis, visual defects/pathologies (including macular degeneration, diabetes, and Causes such as premature birth), kidney disease, rheumatoid arthritis, osteoporosis and other related diseases.
  • a compound represented by any one of the above formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, the above-mentioned pharmaceutical composition, and the above-mentioned dosage form are provided.
  • Diseases mediated by abnormal expression of the body include at least one of the following diseases: tumors, tumor immunity, endometriosis, vascular diseases/injuries, psoriasis, visual defects/lesions (including macular degeneration, diabetes, and premature birth). Caused by), kidney disease, rheumatoid arthritis, osteoporosis and other related diseases.
  • the tumors include sarcomas, lymphomas and cancers, specifically respiratory system cancers, mesothelioma, nervous system tumors, skin malignancies, bone cancers, squamous cell carcinomas, breast cancers , Head and neck cancer, urinary and reproductive system cancer, biliary system cancer, sarcoma, digestive system cancer, leukemia, lymphoma, myelodysplastic syndrome, carcinoma in situ, cell tumor.
  • the tumors include sarcomas, lymphomas and cancers, specifically lung cancer, thyroid cancer, oral cancer, pharyngeal cancer, peritoneal cancer, glioma, neurofibromatosis, skin cancer, melanoma Tumor, multiple myeloma, lung squamous cell carcinoma, esophageal squamous cell carcinoma, ductal breast cancer, brain cancer, ovarian cancer, uterine body cancer, endometrial cancer, prostate cancer, testicular cancer, bladder cancer, kidney cancer, renal pelvis cancer, bile duct Cancer, gallbladder cancer, osteosarcoma, liposarcoma, Ewing's sarcoma, liver cancer, gastric cancer, esophageal cancer, colorectal cancer, pancreatic cancer, cardia cancer, gastrointestinal stromal tumor, colorectal villous adenoma, acute leukemia, chronic leukemia, non-Honey Chikin malignant
  • the compound of the present invention has an inhibitory effect on TAM family kinases, and can be used to treat and/or prevent diseases mediated by the abnormal expression of TAM family kinase receptors and/or their ligands.
  • the compounds of the present invention can also target Ron kinase and have an inhibitory effect on Ron kinase.
  • the compounds of the present invention can be used to treat and/or prevent diseases mediated by abnormal expression of TAM family kinases/and Ron kinase receptors and/or their ligands.
  • the compound of the present invention can reverse the immunosuppressive environment in the tumor microenvironment by targeting inhibition of TAM family kinases and/or Ron kinases, inhibit tumor growth, migration, and/or drug resistance, and exert tumor immune effects and anti-tumor efficacy.
  • the compound of the present invention can selectively act on TAM family kinases and Ron kinases, and avoid unnecessary inhibitory effects on other kinases.
  • the compound of the present invention has a long half-life in the body, has excellent metabolic stability in the body, and has excellent druggability. Therefore, the compound of the present invention can improve the efficacy of the drug, reduce the burden of medication on the patient, and improve the patient's compliance.
  • hydrocarbons or hydrocarbon-derived groups such as propyl, propoxy, butyl
  • butane, butene, butenyl, hexane, etc. have the same meaning when the prefix "positive" is not prefixed.
  • propyl is generally understood as n-propyl
  • butyl is generally understood as n-butyl, unless otherwise specified.
  • C ab group (a and b represent an integer of 1 or more, a ⁇ b) means that the "group” has ab carbon atoms, for example, a C 1-4 alkyl group means a carbon atom Alkyl group with number of 1-4, C 1-4 alkoxy group, which means alkoxy group with carbon number of 1-4, C 3-10 cycloalkyl group, which means ring with carbon number of 3-10 Alkyl group, C 1-4 alkoxy C 1-4 alkyl group, means a group formed by bonding an alkoxy group having 1 to 4 carbon atoms and an alkyl group having 1 to 4 carbon atoms.
  • group and “group” mean a monovalent group or a group with a valence of more than divalent as required.
  • cycloalkyl also expressed as cycloalkyl group
  • a monovalent group obtained by one hydrogen atom also includes a group with a divalent or higher valence obtained by removing two or more hydrogen atoms from the same carbon atom or two or more different carbon atoms.
  • a group with a valence of one or more valence usually refers to a monovalent group or a divalent group, but the group may have a higher valence (e.g., trivalent, tetravalent, pentavalent, Six valence, etc.).
  • base e.g., trivalent, tetravalent, pentavalent, Six valence, etc.
  • the group "derived by removing more than one hydrogen atom” as used herein refers to a monovalent group obtained by removing one hydrogen atom, a divalent group obtained by removing two hydrogen atoms, and a group obtained by removing three hydrogen atoms.
  • the trivalent group obtained, the tetravalent group obtained by removing four hydrogen atoms, etc. can be determined according to the valence of the group (for example, monovalent, divalent, trivalent, tetravalent, etc.) to determine the number of hydrogen atoms to be removed .
  • halogen atom in the present invention means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • it is a fluorine atom, a chlorine atom, and a bromine atom.
  • halo in the present invention means that the hydrogen atom on any carbon atom in the substituent is replaced by one or more halogen atoms which are the same or different.
  • Halogen atom is as defined above.
  • C 1-6 alkyl group in the present invention refers to a linear or branched alkyl group derived from an alkane portion containing 1-6 carbon atoms by removing more than one hydrogen atom, including linear C 1 -6 alkyl and branched C 1-6 alkyl.
  • a C 1-6 alkyl group has a branch (branched C 1-6 alkyl group), it has at least 3 carbon atoms.
  • C 1-6 alkyl for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, Isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1 -Methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3- Dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1-methyl-2-methylpropyl, etc.
  • the "C 1-6 alkyl group” preferably includes a "C 1-4 alkyl group", and the "C 1-6 al
  • Haldroxy C 1-6 alkyl of the present invention, "cyano C 1-6 alkyl”, “amino C 1-6 alkyl”, “C 1-6 alkylamino C 1-6 alkyl “, “halogenated C 1-6 alkyl”, “C 1-6 alkoxy C 1-6 alkyl” means more than one hydroxy, cyano, amino, C 1-6 alkylamino, halogen, C Each of the 1-6 alkoxy groups independently replaces the group formed by the hydrogen atom on the C 1-6 alkyl group.
  • C 1-6 alkylamino "(C 1-6 alkyl) 2 amino", “C 1-6 alkylaminocarbonyl”, “C 1-6 alkylcarbonyl”, “C 1-6 alkane "C 1-6 alkylsulfonylamino group”, “C 1-6 alkylsulfonyl group”, “C 1-6 alkylthio group” and the like containing “C 1-6 alkyl”
  • the group refers to the C 1-6 alkyl group and the corresponding groups such as -NH-, -CO-O-, -NH-CO-, -CO-, -SO 2 NH-, -SO 2 -, -S-, etc. The group formed by connecting the group.
  • C 1-6 alkyl can be combined with -NH-, -CO-O-, -NH-CO-, -CO-, -SO 2 NH-, -SO 2.
  • -, -S- and other corresponding groups are connected to form groups.
  • the "C 2-8 alkenyl group” in the present invention refers to a linear or branched alkenyl group derived by removing more than one hydrogen atom from an alkene moiety of 2-8 carbon atoms containing at least one carbon-carbon double bond
  • vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadien-1-yl, 1-penten-3-yl can be cited , 2-penten-1-yl, 3-penten-1-yl, 3-penten-2-yl, 1,3-pentadien-1-yl, 1,4-pentadiene-3- Group, 1-hexen-3-yl, 1,4-hexadien-1-yl.
  • the "C 2-8 alkenyl group” contains a carbon-carbon double bond.
  • the "C 2-8 alkynyl group” in the present invention refers to a linear or branched alkyne derived by removing more than one hydrogen atom from an alkyne moiety of 2-8 carbon atoms containing at least one carbon-carbon triple bond.
  • the hydrocarbon group includes, for example, ethynyl, propynyl, 2-butyn-1-yl, 2-pentyn-1-yl, 3-pentyn-1-yl, 4-methyl-2-pentyne- 1-yl, 2-hexyn-1-yl, 2-hexyn-2-yl, 3-hexyn-1-yl, 3-hexyn-2-yl and the like.
  • the "C 2-8 alkynyl group” contains a carbon-carbon triple bond.
  • C 1-6 alkoxy refers to the present invention as hereinbefore defined “C 1-6 alkyl” through an oxygen atom to the parent moiety is connected, i.e., "C 1-6 alkyl -O- "Group, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy, neopentyloxy, n-hexoxy, etc. .
  • the "C 1-4 alkoxy group” refers to the above-mentioned example containing 1-4 carbon atoms, that is, the "C 1-4 alkyl-O-" group.
  • halogenated C 1-6 alkoxy group refers to one or more halogen atoms, C 1-6 alkoxy, C 1-6 alkyl and other corresponding groups each independently replacing C 1-6 alkoxy A group formed by more than one hydrogen atom on the group.
  • the "(group) 1-2 amino-" or “-amino (group) 1-2 " in the present invention means that one hydrogen or two hydrogens in the amino group (-NH 2 ) may be substituted by a group.
  • “-amino (C 1-6 alkyl optionally substituted by substituents) 1-2” means -NH (C 1-6 alkyl optionally substituted by substituents), -N (optionally substituted by substituents) Substituted C 1-6 alkyl) 2
  • “(C 1-4 alkyl optionally substituted by substituent) 1-2 amino-” means (C 1-4 alkyl optionally substituted by substituent) NH -, (C 1-4 alkyl optionally substituted by a substituent ) 2 N-.
  • the "fused ring" in the present invention refers to a multi-ring system structure formed by two or more ring structures connected in a union, spiro, or bridge connection.
  • the fused ring refers to a condensed ring structure formed by two or more ring structures sharing two adjacent ring atoms (that is, sharing a bond).
  • the bridged ring refers to a condensed ring structure formed by two or more ring structures sharing two non-adjacent ring atoms with each other.
  • the spiro ring refers to a condensed ring structure formed by two or more ring structures sharing one ring atom with each other.
  • cycloalkyl group or “cycloalkyl group” (hereinafter referred to as “cycloalkyl group”) in the present invention refers to a monovalent group derived from a cycloalkane or (as required) a group having a valence of more than two Groups, the cycloalkanes include monocyclic cycloalkanes or fused-ring cycloalkanes. It is, for example, a "3-12 membered cycloalkyl", that is, it may have 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring-forming carbon atoms.
  • a certain membered cycloalkyl includes all possible monocyclic and fused rings (including fused in the form of union, spiro, and bridge).
  • the cycloalkyl group can be a 3-12-membered monovalent group or (as required) a divalent or higher group, and can be a 3-10 membered monovalent group or (as required) a divalent or higher group.
  • It can be a 3-8 membered monovalent group or (as required) a bivalent or higher group, a 3-6 membered monovalent group or (as required) a bivalent or higher group, 4-6 A monovalent group or (as required) a group with a valence of two or more, a monovalent group with a valence of 5 to 7 or (as required) a group with a valence of two or more.
  • (monovalent or more than divalent) monocyclic cycloalkyl groups may include 3-12 membered cycloalkyl groups, 3-10 membered cycloalkyl groups, 3-8 membered cycloalkyl groups, and 3-6 membered cycloalkanes. Group, 4-6 membered cycloalkyl, 5-6 membered cycloalkyl, 5-7 membered cycloalkyl.
  • Examples include but are not limited to: cyclopropanyl, cyclobutanyl, cyclopentyl, cyclohexane, cycloheptyl, cyclooctyl, cyclopentane-1,3-diyl, cyclohexane -1,4-diyl, cycloheptane-1,4-diyl, etc.
  • the (monovalent or divalent or more) fused-ring cycloalkyl group includes a pentacyclic cycloalkyl group, a bridged cycloalkyl group, and a spirocycloalkyl group.
  • the (monovalent or divalent or more) pentacyclic cycloalkyl group can be a 6-11 membered hexacyclic cycloalkyl group, a 7-10 membered hexacyclic cycloalkyl group, and representative examples thereof include, but are not limited to, a bicyclic ring [3.1. 1]Heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane and bicyclo[4.2.1]nonane derivatives The obtained monovalent group or a group more than divalent.
  • the (monovalent or more than divalent) bridged cycloalkyl group can also be a monovalent group obtained by removing a hydrogen atom from a 6-12-membered bridged ring, a 7-11-membered bridged ring, or from the same carbon as required.
  • bridge ring examples include but are not limited to:
  • the (monovalent or more than divalent) spirocyclic cycloalkyl group may be a monovalent group obtained by removing a hydrogen atom from a 7-12-membered spiro ring or a 7-11-membered spiro ring, or from the same carbon atom as required A group with more than two valences obtained by removing two or more hydrogen atoms from different carbon atoms.
  • spiro rings include, but are not limited to:
  • cycloalkenyl group in the present invention refers to a group having at least one double bond in the above-mentioned cycloalkyl group. It may be, for example, a "3-12 membered cycloalkenyl group", that is, it may have 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring-forming carbon atoms. Unless otherwise specified, a certain membered cycloalkenyl group includes all possible monocyclic and condensed rings (including condensed in the form of union, spiro, and bridge).
  • 3-12 membered cycloalkenyl group may include 3-12 membered cycloalkenyl group, 3-8 membered cycloalkenyl group, 4-6 membered cycloalkenyl group, 7-11 membered spirocycloalkenyl group, 7-11 membered cycloalkenyl group Alkenyl, 6-11 membered bridged cycloalkenyl, etc.
  • cycloalkenyl groups include cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, 1,4-cyclohexadien-1-yl, cycloheptenyl, 1,4- Cycloheptadien-1-yl, cyclooctenyl, 1,5-cyclooctadien-1-yl, etc., but not limited thereto.
  • the "heterocyclic ring” in the present invention includes at least one selected from O, S, and N in the ring (may be 1-5, 1-4, 1-3, 1-2 or 1 )
  • the heterocyclic ring of the present invention may be a monocyclic ring system or a condensed ring system (condensed in the form of a union, spiro, or bridge).
  • heterocyclic rings examples include pyrroline, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, tetrahydropyran, dihydropyridine, dihydropyridazine, dioxane, and oxathipol.
  • At least one ring carbon atom in the above 7-12-membered spiro ring, 7-11-membered spiro ring, 6-12-membered bridged ring, and 7-11-membered bridged ring can be replaced with one selected from O, S, and N.
  • the heteroatoms in the resulting heterocycles are preferably replaced by 1-4 heteroatoms.
  • 6-12 membered cyclic group 7-10 membered cyclic group, 6-10 membered cyclic group, 6-12 membered saturated cyclic group, 6-12 membered spiro heterocyclic group, 6-12 membered cyclic group, 6-12 membered cyclic group , 7-11 membered spiro heterocyclic ring, 6-12 membered saturated spiro heterocyclic ring, 7-11 membered saturated spiro heterocyclic ring, 6-12 membered bridged heterocyclic ring, 7-11 membered bridged heterocyclic ring, 6-12 membered saturated bridged heterocyclic ring Ring, 7-8 membered saturated bridged heterocyclic ring.
  • heterocyclic group refers to a monovalent or divalent or higher group derived from the aforementioned "heterocyclic ring".
  • the "heterocyclic group” in the present invention may also be a non-aromatic one in which at least one ring carbon atom of the above-mentioned cycloalkyl or cycloalkenyl is replaced by at least one heteroatom selected from O, S, and N.
  • a cyclic group having a valence or more than divalent is preferably replaced by 1 to 4 heteroatoms.
  • the "heterocyclic group” may be a heterocyclic group having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14 ring-forming atoms. It may include 3-14 membered heterocyclic group, 3-10 membered heterocyclic group, 4-10 membered heterocyclic group, 3-8 membered heterocyclic group, 4-8 membered heterocyclic group, 4-6 membered heterocyclic group , 3-12 membered heterocyclic group, 4-12 membered heterocyclic group, 5-9 membered heterocyclic group, including single heterocyclic group or condensed heterocyclic group.
  • heterocyclic group refers to a monovalent or (as required) divalent or higher monocyclic heterocyclic group, a monovalent or (as required) divalent or higher bicyclic heterocyclic group system, or a monovalent or (as required) bicyclic heterocyclic group )
  • a polycyclic heterocyclic group system with more than two valences also called a fused ring system
  • saturated and partially saturated heterocyclic groups but excluding aromatic rings.
  • it includes all possible monocyclic, condensed rings (including condensed in the form of union, spiro, and bridge), saturated, and partially saturated conditions. It may be, for example, a "3-14 membered heterocyclic group”.
  • the monovalent or (as required) divalent or more single heterocyclic group may include 3-14 membered heterocyclic group, 3-12 membered heterocyclic group, 3-10 membered heterocyclic group, 4-10 membered heterocyclic group, 3-8 membered heterocyclic group, 3-8 membered saturated heterocyclic group, 4-8 membered heterocyclic group, 3-6 membered heterocyclic group, 4-6 membered heterocyclic group, 4-7 membered heterocyclic group, 5 -7 membered heterocyclic group, 5-6 membered heterocyclic group, 5-6 membered oxygen-containing heterocyclic group, 3-8 membered nitrogen-containing heterocyclic group, 5-6 membered nitrogen-containing heterocyclic group, 5-6 membered saturated Heterocyclic group and so on.
  • it may also include 3-14 membered oxygen-containing heterocyclic group, 3-14 membered nitrogen-containing heterocyclic group, 3-12 membered oxygen-containing heterocyclic group, 3-12 membered sulfur-containing heterocyclic group, 3-12 membered Sulfone group (S(O) 2 ) heterocyclic group, 3-12 membered sulfoxide group (S(O)) heterocyclic group, etc.
  • heterocyclyl examples include, but are not limited to, aziridinyl, oxetanyl, thietanyl, azetidinyl, oxetanyl, thietanyl, Tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothienyl, imidazolidinyl, pyrazolidinyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, 1,2-thiazolidinyl, 1, 3-thiazolidinyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, piperidinyl, piperazinyl, morpholinyl, 1,4-dioxanyl, 1, 4-oxathiolanyl; 4,5-dihydroisoxazolyl, 4,5-dihydrooxazolyl, 2,5-dihydrooxazolyl,
  • the monovalent or (as required) divalent or more fused heterocyclic ring includes a heterocyclic group, a spiro heterocyclic group, a bridge heterocyclic group, which can be saturated, partially saturated or unsaturated, but not aromatic .
  • the fused heterocyclic group may include the above heterocyclic group fused to a 6-14 membered aryl group (such as a benzene ring), a 3-12 membered cycloalkyl group, a 3-12 membered cycloalkenyl group, a 3-14 membered heterocyclic group or a 3 Derived from -14 membered heteroaryl, 5-6 membered monocyclic cycloalkyl, 5-6 membered monocyclic cycloalkenyl, 5-6 membered monocyclic heterocyclic group or 5-6 membered monocyclic heteroaryl group Heterocyclic group.
  • a 6-14 membered aryl group such as a benzene ring
  • a 3-12 membered cycloalkyl group such as a benzene ring
  • 3-12 membered cycloalkenyl group such as a benzene ring
  • 3-14 membered heterocyclic group such as a benz
  • the heterocyclic group may include 6-12 membered cyclic group, 7-10 membered cyclic group, 6-10 membered cyclic group, 6-12 membered saturated cyclic group, and representative examples include but are not limited to: 3-azabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.2.0]heptyl, 3,8-diazabicyclo[4.2.0]octyl, 3, 7-Diazabicyclo[4.2.0]octyl, octahydropyrrolo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3, 4-b][1,4]oxazinyl, octahydro-1H-pyrrolo[3,4-c]pyridyl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydro Benzofuran-3-yl, in
  • the spiro heterocyclic group can be a monovalent one obtained by removing a hydrogen atom from a 6-12 membered spiro heterocyclic ring, a 7-11 membered spiro heterocyclic ring, a 6-12 membered saturated spiro heterocyclic ring, and a 7-membered saturated spiro heterocyclic ring.
  • the bridged heterocyclic group can be obtained by removing one hydrogen atom from 6-12 membered heterocyclic ring, 7-11 membered bridged heterocyclic ring, 6-12 membered saturated bridged heterocyclic ring, and 7-8 membered saturated bridged heterocyclic ring.
  • Examples of bridged heterocycles include but are not limited to:
  • the "aromatic ring” in the present invention refers to a carbocyclic hydrocarbon having aromaticity. Monovalent groups derived from aromatic carbocyclic hydrocarbons or groups with more than two valences as required.
  • the aromatic carbocyclic hydrocarbons include 6-14 membered aromatic rings, 6-10 membered aromatic rings, 6 -8 membered monocyclic aromatic hydrocarbons and 8-14 membered condensed ring aromatic hydrocarbons.
  • the 6-8 membered monocyclic aryl group is, for example, phenyl.
  • the 8-14 membered fused ring aryl group is, for example, naphthyl, phenanthryl, anthracenyl and the like. When it is a divalent group, a phenylene group, a naphthylene group, etc. can be mentioned.
  • aryl group or "aromatic group” (hereinafter referred to as "aryl group”) in the present invention refers to a monovalent group derived from aromatic carbocyclic hydrocarbons or divalent or higher groups as required Group. It includes 6-14 membered aryl groups and 6-10 membered aryl groups.
  • the 6-14 membered aryl group is, for example, phenyl, naphthyl, phenanthryl, and anthracenyl.
  • 6-10 membered aryl groups include phenyl and naphthyl. When it is a divalent group, a phenylene group, a naphthylene group, etc. can be mentioned.
  • heteromatic ring in the present invention refers to having at least one (may be 1-5, 1-4, 1-3, 1-2 or 1) heteroatom selected from O, S, N A cyclic hydrocarbon with aromaticity of ring-forming atoms. It can be a 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14-membered aromatic cyclic group, and preferably has 1 to 3 heteroatoms.
  • the heteroaromatic ring of the present invention may be a monocyclic ring system or a condensed ring system (condensed in the form of a union, spiro, or bridge).
  • heteroaryl group refers to a group with more than one valence derived from the above-mentioned "heteroaryl ring".
  • heteroaryl group in the present invention may also be one containing at least one heteroatom selected from O, S, and N, and the number of ring-forming atoms is 5, 6, 7, 8, 9, 10, 11. 12, 13, or 14 aromatic cyclic hydrocarbon group.
  • heteroaryl group may have 1, 2, 3, 4, or 5 heteroatoms as ring-forming atoms.
  • Heteroaryl groups include mono-heteroaryl groups and condensed heteroaryl groups. Unless otherwise specified, a certain-membered heteroaryl group includes all monocyclic, condensed rings, all aromatics, and partial aromatics that may be formed.
  • Mono-heteroaryl groups may include 5-7 membered heteroaryl groups, 5-6 membered heteroaryl groups, 6-membered heteroaryl groups, 6-membered nitrogen-containing heteroaryl groups, examples of which include, but are not limited to, furyl, imidazolyl, isoxa Azolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiophene Group, triazolyl and triazinyl.
  • a fused heteroaryl group refers to a group formed by fusing a single ring heteroaromatic ring to a phenyl group, cycloalkenyl group, heteroaryl group, cycloalkyl group, and heterocyclic group.
  • the fused heteroaryl group can be 8-12-membered heteroaryl, 9-10-membered heteroaryl, 9-membered heteroaryl, 9-membered nitrogen-containing heteroaryl (9-membered nitrogen-containing heteroaryl), examples include but are not limited to benzo Imidazolyl, benzofuranyl, benzothienyl, benzoxadiazolyl, benzothiadiazolyl, benzothiazolyl, cinolinyl, 5,6-dihydroquinolin-2-yl, 5 , 6-Dihydroisoquinolin-1-yl, furopyridyl, indazolyl, indolyl, isoindolyl, isoquinolinyl, naphthyridinyl, purinyl, quinolinyl, 5, 6 , 7,8-tetrahydroquinolin-2-yl, 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetra
  • the "5- to 14-membered cyclic group" in the present invention refers to a group having 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14 ring-forming atoms, which may be the present invention
  • the above-mentioned cycloalkyl group, cycloalkenyl group, heterocyclic group, aromatic ring group, and heteroaryl group have 5-14 ring-forming atoms. It may specifically include 5-10 membered cyclic groups and 5-6 membered cyclic groups.
  • Examples include, but are not limited to, pyrroline, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, tetrahydropyran, dihydropyridine, dihydropyridazine, dioxane, oxathipol, Cyclopentane sulfide, tetrahydrofuran, tetrahydropyran, tetrahydrothiazole, tetrahydroisothiazole, pyrrole, pyrazine, pyrazole, indole, tetrazole, furan, thiophene, pyridine, imidazole, triazole, tetrazole, three Groups derived from azine, pyridazine, pyrimidine, pyrazine, isoxazole, thiazole, isothiazole, thiadiazole, oxazole, oxadiazole, benz
  • one to more and “more than one” mean that the number of substituents can be all positions in the substituted group that can be chemically substituted, preferably 1-6, more preferably 1-5 , More preferably 1-3, more preferably 1-2, and more preferably one.
  • the number of substituents can be 0 (that is, unsubstituted), or from 1 to all chemically substituted positions in the group to be substituted.
  • the number is preferably 1-6, more preferably 1-5, more preferably 1-4, more preferably 1-3, more preferably 1-2 or 1.
  • the present invention provides a compound represented by general formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof:
  • W is selected from a hydrogen atom or a C 1-6 alkyl group optionally substituted by a substituent
  • R represents a group represented by the following general formula (b) or (b′):
  • X 4 and X 5 are each independently selected from CR a or N;
  • M 3 is selected from hydrogen atom, cyano group, hydroxyl group, halogen atom, carboxyl group, nitro group, -NR b R c , -C(O)R d , -C(O)NR b R c , -OC(O)NR b R c , -NR b C(O)OR d , -NR b C(O)R d , -SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d ; or optional C 1-6 alkyl substituted by substituents, C 1-6 alkoxy optionally substituted by substituents, C 2-8 alkenyl optionally substituted by substituents, C 2 optionally substituted by substituents -8alkynyl , -C 1-6 alkyl optionally substituted by substituents -R', -C 1-6 alkoxy optionally substituted by substituents -R',
  • CY 2 is selected from optionally substituted with one or more R 2 substituted 3-12 membered cycloalkyl, optionally substituted by one or more R 2 3-12 membered cycloalkenyl, optionally substituted with one or more R 2 3-14 membered heterocyclyl, optionally substituted by 2 are each independently selected from a hydrogen atom is substituted with more than one R 2 group, and a 6-14 membered aryl being optionally substituted with one or more 2 R 5-10 membered heteroaryl group, R, a cyano group , Hydroxyl group, mercapto group, halogen atom, carboxyl group, nitro group, -NR b R c , -C(O)R d , -C(O)NR b R c , -OC(O)NR b R c , -NR b C(O)R d , -NR b C(O)OR d , -SO 2 -NR b
  • Cy 3 is selected from 5-10 membered heteroaryl groups optionally substituted by more than one R 3 , R 3 is each independently selected from hydrogen atom, cyano group, hydroxyl group, mercapto group, halogen atom, carboxyl group, nitro group, -NR b R c , -C(O)R d , -C(O)NR b R c , -OC(O)NR b R c , -NR b C(O)R d , -NR b C(O)OR d , -SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d , C 1-6 alkyl optionally substituted by substituents, C 1-6 alkane optionally substituted by substituents Oxy, C 2-8 alkenyl optionally substituted by substituents, C 2-8 alkynyl optionally substituted by substituents, -C 1-6 alkyl optional
  • CY 4 is selected from optionally substituted with one or more R 4 substituted 3-12 membered cycloalkyl, optionally substituted by one or more R 4 3-14 membered heterocyclyl, optionally substituted with one or more of R 4 5-14 Membered heteroaryl group and 6-14 membered aryl group optionally substituted by more than one R 4 ,
  • R 4 is each independently selected from hydrogen atom, cyano group, hydroxyl group, mercapto group, halogen atom, carboxyl group, nitro group, -NR b R c , -C(O)R d , -C(O)NR b R c , -OC(O)NR b R c , -NR b C(O)R d , -NR b C(O)OR d , -SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d , C 1-6 alkyl
  • L is selected from -NR b -, -O-, -S-, -(CR a R a ) m -, and m is selected from an integer of 1-3;
  • R a does not exist, or at each occurrence, each is independently selected from a hydrogen atom, a cyano group, a hydroxyl group, a mercapto group, a halogen atom, a carboxyl group, a nitro group, -NR b R c , -C(O)R d ,- C(O)NR b R c , -OC(O)NR b R c , -NR b C(O)R d , -NR b C(O)OR d , -SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d , C 1-6 alkyl optionally substituted by substituents, C 1-6 alkoxy optionally substituted by substituents, C 2 optionally substituted by substituents -8 alkenyl, C 2-8 alkynyl optionally substituted by a substituent,-C 1-6 alkyl optionally substituted
  • R b and R c each does not exist, or at each occurrence, each is independently selected from a hydrogen atom, a hydroxyl group, a C 1-6 alkyl group optionally substituted by a substituent, and a C 1 optionally substituted by a substituent -6 alkyl-R', -C(O)-R', -SO 2 -R', 3-12-membered cycloalkyl optionally substituted by substituents, 3-12-membered optionally substituted by substituents Cycloalkenyl, 3-14 membered heterocyclic group optionally substituted by substituents, 6-14 membered aryl optionally substituted by substituents, 5-10 membered heteroaryl optionally substituted by substituents;
  • R d does not exist, or at each occurrence, each is independently selected from hydroxyl, halogen atom, amino, -amino (C 1-6 alkyl optionally substituted by substituent ) 1-2, optionally substituted Substituted C 1-6 alkyl, C 1-6 alkoxy optionally substituted by substituents, -C 1-6 alkyl optionally substituted by substituents -R', -optionally substituted by substituents C 1-6 alkoxy-R', -O-R', 3-12 membered cycloalkyl optionally substituted by substituents, 3-12 membered cycloalkenyl optionally substituted by substituents, optionally substituted by Substituent substituted 3-14 membered heterocyclic group, optionally substituted 6-14 membered aryl group, optionally substituted 5-10 membered heteroaryl group;
  • R' is each independently selected from 3-12 membered cycloalkyl optionally substituted by substituents, 3-12 membered cycloalkenyl optionally substituted by substituents, 3-14 membered heterocyclic ring optionally substituted by substituents Group, a 6-14 membered aryl group optionally substituted by a substituent and a 5-10 membered heteroaryl group optionally substituted by a substituent;
  • q is an integer from 0-4;
  • n is an integer from 0-4;
  • substituents in the "optionally substituted by substituents" are each independently selected from: hydroxyl, mercapto, amino, carboxy, cyano, nitro, halogen atom, C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl group, C 1-6 alkoxy, C 1-6 alkyl C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, C 1-6 alkyl Alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonyl Oxy, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 1-6 alkylsulfonyl, C 1-6 alkylthio, 3-12 membered cycloalky
  • Cy 2 when the group represented by M 3 carries an aryl group, Cy 2 does not represent a heterocyclic group.
  • Cy 2 does not represent a heterocyclic group.
  • Cy 2 when the group represented by M 3 carries an aryl group, Cy 2 does not represent a heteroaryl group.
  • Cy 2 does not represent a heteroaryl group.
  • X 4 represents CR a .
  • X 4 represents CR a .
  • X 4 represents CR a .
  • X 1 represents CR a R a
  • R a group on the 1 X does not have a carbonyl group.
  • M 3 is selected from a branched C 1-6 alkyl group optionally substituted by a substituent, and a 3-8 membered cycloalkyl group optionally substituted by a substituent.
  • X 4 is selected from N, X 5 is selected from CR a ; or X 4 is selected from CR a , X 5 is selected from CR a ; or X 4 is selected from N, X 5 is selected from N; Or X 4 is selected from CR a , and X 5 is selected from N.
  • X 1 is NR b .
  • X 2 is NR b .
  • formula (b) and formula (b') only carry one carbonyl group.
  • At most two of X 1 , X 2 , X 3 , X 4 , and X 5 are NR b .
  • X 4 represents CR a .
  • X 5 represents CR a .
  • M 3 represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl Base, vinyl, allyl or propenyl
  • 2 Cy 2 is selected from optionally substituted with one or more R 6-14 membered aryl, optionally substituted with one or more 2 R 5-10 membered heteroaryl.
  • Cy 2 is selected from optionally substituted by one or more R 2 phenyl, optionally substituted with one or more R 2 5-6 membered heteroaryl.
  • Cy 2 is selected from those optionally substituted with more than one R 2
  • the group represented by Cy 2 does not have a heterocyclic group. In one embodiment of the present invention, when M 3 is a group carrying an aryl group, the group represented by Cy 2 does not have a carbonyl group.
  • Cy 3 is selected from 5-10 membered heteroaryl groups optionally substituted with more than one R 3.
  • Cy 3 is selected from 5-6 membered heteroaryl groups optionally substituted with more than one R 3.
  • Cy 3 represents optionally substituted by more than one R 3
  • Y 2 , Y 3 , Y 6 and Y 7 are each independently selected from CR a R a or NR b , and at least one of them is NR b .
  • Cy 3 represents optionally one Replaced by R 3 above
  • the shown groups, Y 2 , Y 3 , Y 6 , and Y 7 are each independently selected from CH or N, and at least one of them is N.
  • Cy 3 is selected from those optionally substituted with more than one R 3
  • Cy 3 is selected from the following groups optionally substituted with more than one R 3:
  • the * terminal is connected to N, and the ⁇ terminal is connected to L.
  • Cy 4 is selected from 5-9 membered heteroaryl groups optionally substituted with more than one R 4.
  • Cy 4 is selected from 5-9 membered heterocyclic groups optionally substituted with more than one R 4.
  • Cy 4 4 is selected from optionally substituted by one or more R 5-10 membered heterocyclyl, optionally substituted with one or more 4 R 5-10 membered heteroaryl, and optionally One or more R 4 substituted 6-10 membered aryl groups.
  • Cy 4 represents optionally substituted by more than one R 4
  • the group shown, in the formula, Represents a single bond or a double bond
  • Y 4 and Y 5 are each independently selected from CR a R a or NR b
  • ring B forms a five-membered ring.
  • Y 4 and Y 5 are CR a R a
  • ring B contains NR
  • the five-membered heteroaromatic ring of b preferably, Cy 4 represents optionally substituted by more than one R 4
  • Y 4 and Y 5 are each independently CH
  • ring B is a five-membered heteroaromatic ring containing 1-2 NR b.
  • Cy 4 is selected from those optionally substituted with more than one R 4
  • R 2 is each independently selected from a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, -NR b R c , -C(O)R d , -C(O)NR b R c , -NR b C(O)OR d , C 1-6 alkyl optionally substituted with a substituent, and C 1-6 alkoxy optionally substituted with a substituent.
  • R 2 is each independently selected from a hydrogen atom, a hydroxyl group, a halogen atom, a C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, an amino C 1-6 alkyl group, a halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy; preferably, R 2 is each independently selected from hydrogen atom, hydroxyl, fluorine, chlorine, bromine, C 1-4 alkyl.
  • R 3 is each independently selected from a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, -NR b R c , -C(O)R d , -C(O)NR b R c , -NR b C(O)R d , C 1-6 alkyl optionally substituted with a substituent, and C 1-6 alkoxy optionally substituted with a substituent.
  • R 3 is each independently selected from a hydrogen atom, a hydroxyl group, a halogen atom, a C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, an amino C 1-6 alkyl group, a halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy; preferably, R 3 is each independently selected from hydrogen atom, hydroxyl, fluorine, chlorine, bromine, C 1-4 alkyl.
  • R 4 is each independently selected from a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, -NR b R c , -C(O)R d , -C(O)NR b R c , -NR b C(O)R d , C 1-6 alkyl optionally substituted by substituents, C 1-6 alkoxy optionally substituted by substituents, 5 optionally substituted by substituents -10 membered heteroaryl.
  • R 4 is each independently selected from a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, -NR b R c , -C(O)R d , -C(O)NR b R c , -NR b C(O)R d , C 1-6 alkyl optionally substituted by substituents, C 1-6 alkoxy optionally substituted by substituents, 5 optionally substituted by substituents -6 membered heteroaryl.
  • R 4 are each independently selected from a hydrogen atom, a hydroxyl group, a halogen atom, an amino group, (C 1-6 alkyl) 1-2 amino-, C 1-6 alkyl , Hydroxy C 1-6 alkyl, amino C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 alkoxy Group C 1-6 alkyl, C 1-6 alkyl C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, pyrrolyl, furyl, thienyl, oxazolyl, Isoxazolyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, pyridazinyl.
  • R 4 is selected from hydrogen atom, hydroxyl group, mercapto group, halogen atom, amino group, (C 1-4 alkyl) 1-2 amino-, C 1-4 alkyl, halogenated C 1 -4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy C 1-4 alkyl, C 1-4 alkyl C 1-4 alkoxy, C 1-4 alkoxy C 1 -4 Alkoxy, halogenated C 1-4 alkoxy, pyrrolyl, furyl, thienyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl.
  • R a is not present, or each time it occurs, each is independently selected from a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, a nitro group, -NR b R c , -C(O) R d , -C(O)NR b R c , -NR b C(O)R d , C 1-6 alkyl optionally substituted by substituents, C 1-6 alkoxy optionally substituted by substituents base.
  • R a is absent, or at each occurrence, is independently selected from a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, C 1-6 alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkyl.
  • R a is not present, or at each occurrence, each is independently selected from a hydrogen atom, a C 1-6 alkyl group, and a C 1-6 alkoxy group.
  • each of R b and R c does not exist, or each occurrence is independently selected from a hydrogen atom and a C 1-6 alkyl group optionally substituted with a substituent.
  • each of R b and R c does not exist, or each occurrence is independently selected from a hydrogen atom, a C 1-6 alkyl group, and a halogenated C 1-6 alkyl group.
  • each of R b and R c does not exist, or each occurrence is independently selected from a hydrogen atom and a C 1-6 alkyl group.
  • R d does not exist, or at each occurrence, each is independently selected from hydroxyl group, halogen atom, amino group, -amino group (C 1-6 alkyl group optionally substituted by substituent) 1-2 , C 1-6 alkyl optionally substituted by substituents, C 1-6 alkoxy optionally substituted by substituents.
  • R d is absent, or at each occurrence, each is independently selected from hydroxyl, amino, -amino (C 1-6 alkyl) 1-2 , C 1-6 alkyl , Halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy.
  • R d is not present, or at each occurrence, each is independently selected from hydroxyl, amino, C 1-4 alkyl, halo C 1-4 alkyl, C 1-4 Alkoxy, halogenated C 1-4 alkoxy.
  • R' is selected from 3-8 membered cycloalkyl optionally substituted by substituents, 3-8 membered cycloalkenyl optionally substituted by substituents, optionally substituted by substituents 3-10 membered heterocyclic group, 6-10 membered aryl group optionally substituted by substituents and 5-6 membered heteroaryl group optionally substituted by substituents.
  • R' is selected from 3-6 membered cycloalkyl optionally substituted by substituents, 4-7 membered heterocyclyl optionally substituted by substituents, and optionally substituted 6-10 membered aryl group and 5-6 membered heteroaryl group optionally substituted by substituents.
  • R' is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, oxetanyl, oxetanyl, oxolol Group, oxanyl, oxepanyl, pyrrolyl, furyl, thienyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, pyridazinyl.
  • the substituents in "optionally substituted by substituents” are each independently selected from: hydroxyl, mercapto, amino, carboxy, cyano, nitro, halogen atom, C 1-6 alkyl , C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy Group, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonyloxy, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 1 -6 alkylsulfonyl, C 1-6 alkylthio, 3-8 membered
  • the substituents in "optionally substituted by substituents” are each independently selected from: hydroxyl, mercapto, amino, carboxy, cyano, nitro, halogen atom, C 1-4 alkyl , C 1-4 alkoxy C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl C 1-4 alkoxy, C 1-4 alkoxy C 1-4 alkoxy Group, C 1-4 alkylamino, (C 1-4 alkyl) 2 amino, C 1-4 alkylaminocarbonyl, (C 1-4 alkyl) 2 aminocarbonyl, C 1-4 alkylcarbonyl, C 1-4 alkylcarbonyloxy, C 1-4 alkylcarbonylamino, C 1-4 alkylsulfonylamino, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, C 1 -4 Alkylsulfonyl, C 1-4 Alkylthio, cyclopropy
  • n is 0, 1, 2, 3, or 4.
  • n is 0, it means that M 3 is directly bonded to the N atom of formula (b) or formula (b').
  • q is 0, 1, 2, 3, or 4.
  • q is 0, it means that Cy 2 is directly bonded to X 4 .
  • L is selected from -NR b -, -O- and -S-, preferably -O-.
  • M 3 when When a part of N is connected to a double bond in formula (b) or formula (b′), M 3 does not exist. That is, at this time, Part of the N atoms in the formula (b) or (b'), due to the double bond (or the formation of a large ⁇ bond when forming a heteroaromatic ring), so the N atom except for the adjacent ring-forming atoms, no There will be other atoms bonded.
  • the "ester” in the present invention refers to a pharmaceutically acceptable ester formed by the compound of the present invention, more specifically, the formate, acetate, propionate, butyrate, and acrylic acid esters of the compound of the present invention. Ester, ethyl succinate, etc., but not limited to these.
  • the "pharmaceutically acceptable salt” in the present invention refers to pharmaceutically acceptable acid and base addition salts or solvates thereof.
  • Such pharmaceutically acceptable salts include salts of acids such as hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfurous acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid , Hydroiodic acid, alkanoic acid (such as acetic acid, CH 3 -(CH 2 ) n -COOH (where n is 0 to 4)), etc.
  • Salts of bases sodium salt, potassium salt, calcium salt, ammonium salt, etc. Those skilled in the art know a variety of non-toxic pharmaceutically acceptable addition salts.
  • the hydrogen atom, fluorine atom, carbon atom, nitrogen atom, oxygen atom, sulfur atom, etc. in the present invention also include their respective radioactive isotopes or stable isotopes.
  • the tumors of the present invention include sarcomas, lymphomas and cancers, and can be respiratory system cancer, mesothelioma, nervous system tumor, skin malignant tumor, bone cancer, squamous cell carcinoma, breast cancer, head and neck cancer, urinary and reproductive Systemic cancer, biliary system cancer, sarcoma, digestive system cancer, leukemia, lymphoma, myelodysplastic syndrome, carcinoma in situ, cell tumor.
  • the tumor of the present invention may specifically be lung cancer, thyroid cancer, oral cancer, pharyngeal cancer, peritoneal cancer, glioma, neurofibromatosis, skin cancer, melanoma, multiple myeloma, lung squamous cell carcinoma, esophageal squamous cell carcinoma , Breast duct cancer, brain cancer, ovarian cancer, uterine body cancer, endometrial cancer, prostate cancer, testicular cancer, bladder cancer, kidney cancer, renal pelvis cancer, cholangiocarcinoma, gallbladder cancer, osteosarcoma, liposarcoma, Ewing's sarcoma, Liver cancer, stomach cancer, esophageal cancer, colorectal cancer, pancreatic cancer, gastric cardia cancer, gastrointestinal stromal tumor, colorectal villous adenoma, acute leukemia, chronic leukemia, non-Hodgkin's malignant lymphoma (NHL), T/NK cell lymph
  • A/and B means A alone, or both A and B.
  • TAM family kinase/and Ron kinase refers to "TAM family kinase” alone or both "TAM family kinase” and “Ron kinase”.
  • the "stereoisomer" of the compound of formula (I) of the present invention means that when the compound of formula (I) has an asymmetric atom, it will produce enantiomers; when the compound has a carbon-carbon double bond or a cyclic structure, it will Produce cis-trans isomers, all enantiomers, diastereomers, racemates, cis-trans isomers, geometric isomers, epimers and Their mixtures are all included in the scope of the present invention.
  • the definition of the compounds of the present invention includes all possible stereoisomers and their mixtures. In particular, it includes racemic forms and isolated optical isomers with specified activities.
  • the racemic form can be resolved by physical methods, such as fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography.
  • a single optical isomer can be obtained from the racemate by a conventional method (for example, salt formation with an optically active acid, followed by crystallization).
  • tautomer of the compound of formula (I) of the present invention refers to the isomer of the functional group produced when a certain atom in the compound of formula (I) moves rapidly in two positions is called tautomer;
  • tautomer When the hydrogen at the alpha position of the carbonyl functional group is on the alpha carbon, a keto tautomer is produced; when the hydrogen at the alpha position of the carbonyl functional group is on the oxygen of the carbonyl group, an alcohol tautomer is produced.
  • the pharmaceutical composition of the present invention comprises at least one of the compound represented by formula (I), its pharmaceutically acceptable salts, esters, stereoisomers, and tautomers.
  • the pharmaceutical composition of the present invention comprises a compound represented by formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer and optionally one or more pharmaceutical carriers.
  • composition of the present invention can be administered in any suitable manner known in the art, such as oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), Transdermal, rectal, nasal, transpulmonary, topical (including oral and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal administration methods, etc., are administered to patients or subjects in need of treatment and/or prevention.
  • parenteral including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural
  • Transdermal rectal
  • nasal, transpulmonary topical (including oral and sublingual)
  • vaginal intraperitoneal, intrapulmonary and intranasal administration methods, etc.
  • the pharmaceutical composition of the present invention can be made into conventional solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be made into oral liquid preparations, such as oral solutions, oral suspensions, syrups, and the like.
  • oral preparations suitable excipients, diluents, sweeteners, solubilizers, lubricants, binders, tablet disintegrating agents, stabilizers, preservatives or encapsulating materials can be added. Many substances.
  • the pharmaceutical composition can be made into injections, sterile powders for injections and concentrated solutions for injections. When preparing an injection, it can be produced by a conventional method in the existing pharmaceutical field.
  • the pharmaceutical composition When preparing an injection, it is not necessary to add an additive, or an appropriate additive can be added according to the nature of the drug.
  • the pharmaceutical composition When used for rectal administration, the pharmaceutical composition can be made into suppositories and the like.
  • the pharmaceutical composition When used for pulmonary administration, can be made into an inhalant or a spray.
  • suitable solid carriers include, but are not limited to, for example, cellulose, glucose, lactose, mannitol, magnesium stearate, magnesium carbonate, sodium carbonate, sodium saccharin, sucrose, dextrin, talc, starch, pectin, gelatin , Tragacanth, gum arabic, sodium alginate, paraben, methyl cellulose, sodium carboxymethyl cellulose, low melting wax, cocoa butter, etc.
  • Suitable liquid carriers include, but are not limited to, water, ethanol, polyols (for example, glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, glycerides, and mixtures thereof.
  • the method of preparing the pharmaceutical composition of the present invention is generally known.
  • the preparation of the pharmaceutical composition of the present invention by known methods includes conventional mixing, granulating, tableting, coating, dissolving or lyophilizing methods.
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate amounts of active ingredients.
  • the unit dosage form can be packaged as a package containing discrete quantities of preparation, such as packaged tablets, capsules, or powders in vials or ampoules.
  • the dosage of the drug depends on various factors, including the age, weight and condition of the patient, and the route of administration. The precise dose administered is determined based on the judgment of the treating physician.
  • the usual dosage for administering the active compound may be, for example, about 0.01 mg to about 100 mg per day, about 0.05 mg to about 75 mg per day, about 0.1 mg to about 50 mg per day, or about 5 mg to about 10 mg per day.
  • the desired dose also depends on the specific compound used, the severity of the disease, the route of administration, the weight and health of the patient, and the judgment of the treating physician.
  • the compounds of the present invention can be prepared by various methods including standard chemical methods. Unless otherwise indicated, any previously defined variables will continue to have the previously defined meaning. Exemplary general synthetic methods are illustrated in the following schemes, and can be easily modified to prepare other compounds of the present invention. Those skilled in the art can implement the following reactions according to the conventional methods taught in the art (for example, Organic Synthesis 2nd, Michael B. Smith etc.). The specific compounds of the present invention are specifically prepared in the example section.
  • the preparation method of the compound represented by the general formula (I) can be prepared by, for example, the following method, but is not limited thereto.
  • formula (I-a) is added to the solvent, peptide coupling reagent, base, and formula (I-b) are added, and the stirring reaction is complete, and the formula (I-j) is isolated; or,
  • M 3 , W, R, n, Cy 3 , L and Cy 4 are as defined above;
  • Cy 5 is derived from the group defined by Cy 4;
  • k is an integer of 0-2;
  • PG is a protecting group, and a protecting group known in the art can be used, for example, it can be selected from tert-butoxycarbonyl, benzyloxycarbonyl, acetyl, and p-methoxybenzyl;
  • LG is a leaving group or a boronic acid or a boronic acid ester, and a leaving group known in the art can be used, for example, it can be selected from leaving groups such as chlorine, bromine, iodine, methanesulfonate or benzenesulfonate;
  • R 1 is a C 1-6 alkyl group.
  • k represents the number of PG groups connected to a N atom, and a hydrogen atom is optionally connected to the N atom so that the valence of the N atom meets the trivalence.
  • the solvent is selected from: N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, toluene, benzene, xylene, trimethylbenzene, cyclohexane, hexane, Dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, methyl acetate, ethyl acetate, acetone, methyl ethyl ketone, One of acetonitrile, methanol, ethanol, isopropanol, tert-butanol, water, and mixtures thereof;
  • the base is selected from: methylamine, ethylamine, propylamine, N,N-diisopropylethylamine, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, One of diethanolamine, ethylenediamine, pyridine, picoline, quinoline, and mixtures thereof;
  • the acid is selected from: formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid Dicarboxylic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethylsulfonic acid; hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid;
  • the peptide coupling reagent is selected from: 2-(7-azobenzotriazole)-tetramethylurea hexafluorophosphate (HATU), benzotriazole-N, N, N', N '-Tetramethylurea hexafluorophosphate (HBTU), 2-(1H-benzo[d][1,2,3]triazo-1-yl)-1,1,3,3-tetramethyl One of TBTU and its mixture;
  • the coupling reagent is selected from: phosphorus oxychloride, dicyclohexylcarbodiimide (DCC), N,N'-carbonyldiimidazole, isobutyl chloroformate, 1-n-propyl phosphoric anhydride, etc. Species and their mixtures.
  • a person skilled in the art can prepare a compound of formula (I) from a compound of formula (Ij) according to conventional methods in the art.
  • the following schematically provides a method for preparing a compound of formula (I) from a compound of formula (Ij) method:
  • the compound of formula (Ij) is added to a suitable solvent (such as methanol, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, etc., preferably N,N-dimethylformamide).
  • a suitable solvent such as methanol, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, etc., preferably N,N-dimethylformamide.
  • the compound of formula (I-j) can be prepared by reacting the compound of formula (I-a) with the compound of formula (I-b),
  • M 3 , R, n, W, Cy 3 , L, PG, k, and Cy 5 are as defined above.
  • a person skilled in the art can prepare a compound of formula (Ij) from a compound of formula (Ia) and a compound of formula (Ib) according to conventional methods in the art.
  • the following schematically provides a compound of formula (Ia) and formula (Ia) The method for preparing the compound of formula (Ij) by reacting the compound of (Ib):
  • a suitable solvent such as tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, etc., preferably N,N-dimethylformamide
  • a suitable peptide coupling reagent preferably 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • a suitable base such as three Ethylamine, pyridine, N,N-diisopropylethylamine, etc., preferably N,N-diisopropylethylamine
  • the compound of formula (Ia) and the compound of formula (Ib) are added to a suitable base (such as pyridine), the temperature is reduced to a suitable temperature (such as 0°C), and the coupling reagent (such as phosphorus oxychloride) is added dropwise After adding and stirring for a suitable time (such as 0.5 to 3 hours) until the reaction is complete, the reaction solution is concentrated under reduced pressure, an appropriate amount of water is added, and the extract is extracted with a suitable extractant (such as ethyl acetate). The extract is concentrated, and the crude product is subjected to conventional
  • the compound of formula (Ij) can be isolated by purification method (such as silica gel column chromatography).
  • the compound of formula (I-a) can be prepared by the compound of formula (I-c),
  • R 1 is a C 1-6 alkyl group
  • M 3 , R and n are as defined above.
  • a person skilled in the art can prepare a compound of formula (Ia) from a compound of formula (Ic) according to conventional methods in the art. The following schematically provides a method for preparing a compound of formula (Ia) from a compound of formula (Ic):
  • the compound of formula (Ic) is dissolved in a suitable solvent (such as methanol, ethanol, tetrahydrofuran, dioxane, etc., preferably methanol), and a suitable base (such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.) is added , Preferably lithium hydroxide), stir at a suitable temperature (such as room temperature) for a suitable time (such as 0.5 to 3 hours), after the reaction is completed, concentrate under reduced pressure, and adjust with an aqueous solution of a suitable acid (such as hydrochloric acid, citric acid)
  • a suitable acid such as hydrochloric acid, citric acid
  • the pH value is in a suitable range (such as 2-5), and the compound of formula (Ia) is obtained by filtration.
  • the compound of formula (I-c) can be prepared by reacting the compound of formula (I-d) with the compound of formula (I-e),
  • R and R 1 are as defined above, and LG, M 3 and n are as defined above.
  • a person skilled in the art can prepare a compound of formula (Ic) from a compound of formula (Id) and a compound of formula (Ie) according to conventional methods in the art. The following schematically provides a compound of formula (Id) and formula ( Method for preparing compound of formula (Ic) by reaction of compound of Ie):
  • the compound of formula (Id) and the compound of formula (Ie) (LG is a leaving group) are dissolved in a suitable solvent (such as acetonitrile, tetrahydrofuran, N, N-dimethylformamide, etc.), preferably N, N -Dimethylformamide), add an appropriate base (such as sodium carbonate, potassium carbonate, cesium carbonate, etc., preferably potassium carbonate), stir and react at a suitable temperature (such as 50°C) for a suitable time (such as 10-16 hours) ), after the reaction is completed, water and a suitable extractant are added, and the crude product is separated by conventional purification means (such as silica gel column chromatography) to obtain the compound of formula (Ic);
  • a suitable solvent such as acetonitrile, tetrahydrofuran, N, N-dimethylformamide, etc.
  • an appropriate base such as sodium carbonate, potassium carbonate, cesium carbonate, etc., preferably potassium carbonate
  • the compound of formula (Id) and the compound of formula (Ie) are dissolved in a suitable solvent (such as acetonitrile, dichloromethane, chloroform, pyridine, N,N-dimethyl Formamide, etc., preferably N,N-dimethylformamide), add a suitable base (such as triethylamine, pyridine, etc.) and a suitable catalyst (such as copper acetate, copper chloride, etc.), under air or oxygen conditions , At an appropriate temperature (such as room temperature to 50 °C), the reaction time (such as 14 hours). After the reaction, the crude product is obtained through conventional post-treatments (such as extraction and concentration), and then the product is obtained through conventional purification means (such as silica gel column chromatography).
  • a suitable solvent such as acetonitrile, dichloromethane, chloroform, pyridine, N,N-dimethyl Formamide, etc., preferably N,N-dimethylformamide
  • a suitable base such as tri
  • the compound of formula (I-b) can be prepared by reacting the compound of formula (I-k),
  • Cy 3 , L, k, PG and Cy 5 are as defined above.
  • a person skilled in the art can prepare a compound of formula (Ib) from a compound of formula (Ik) according to conventional methods in the art. The following schematically provides a method for preparing a compound of formula (Ib) from a compound of formula (Ik):
  • the compound of formula (Ik) and a suitable reducing agent such as iron powder, zinc powder, stannous chloride, sodium dithionite, etc., preferably iron powder, ammonium sulfide, ferrous sulfate heptahydrate, etc.
  • a suitable reducing agent such as iron powder, zinc powder, stannous chloride, sodium dithionite, etc., preferably iron powder, ammonium sulfide, ferrous sulfate heptahydrate, etc.
  • the solvent such as ethanol, ammonium chloride aqueous solution, acetic acid, ammonia water, mixed ethanol and ammonium chloride aqueous solution, etc.
  • a suitable temperature such as 80°C
  • a suitable time such as 2 hours.
  • the compound of formula (I-k) can be prepared by reacting the compound of formula (I-f),
  • the compound of formula (If) is added to an appropriate solvent (such as 1,4-dioxane, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, etc.), preferably N,N-dimethylformamide), add appropriate catalysts such as palladium acetate, palladium chloride, etc., add appropriate ligands (BINAP, XPhos, SPhos, Ruphos, etc.), add appropriate bases (such as potassium carbonate, carbonic acid, etc.) Sodium, triethylamine, N,N-diisopropylethylamine, etc., preferably potassium carbonate), add NH(PG) k (such as benzophenone imine, p-methoxybenzylamine, tert-butylamine), where appropriate Stir for an appropriate time (such as 14 hours) at a temperature (such as room temperature to 110°C). After the reaction, the crude product is obtained
  • the compound of formula (I-f) can be prepared by reacting the compound of formula (I-g) with the compound of formula (I-h).
  • L, Cy 5 , Cy 3 and LG are as defined above;
  • a person skilled in the art can prepare a compound of formula (If) from a compound of formula (Ig) and a compound of formula (Ih) according to conventional methods in the art.
  • the following schematically provides a compound of formula (Ig) and formula ( The compound of Ih) The method for preparing the compound of formula (If):
  • the compound of formula (Ig) and the compound of formula (Ih) are added to an appropriate solvent (such as tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, etc.), preferably N, N-dimethylformamide), add a suitable base (such as potassium carbonate, sodium carbonate, triethylamine, N,N-diisopropylethylamine, etc., preferably potassium carbonate), at a suitable temperature (such as room temperature to 80°C) Stir for an appropriate time (e.g. 14 hours).
  • the crude product is obtained by conventional post-treatment methods (such as filtration, extraction, etc.), and then separated by conventional purification means (such as silica gel column chromatography) to obtain the product.
  • the compound of formula (I-c) can be prepared by the following reaction:
  • X 1, X 2, X 5, X 4 is independently selected from C, CH or CH 2
  • R '2 is C 1-6 alkoxy or di-substituted amino group
  • Cy 2 R 1 , M 3 and n are as defined above.
  • the compound of formula (Im) is added to an appropriate solvent (such as toluene, xylene, trimethylbenzene, N,N-dimethylformamide, N,N-dimethylacetamide, etc., preferably toluene), and appropriate Reagents (such as N,N-dimethylformamide dimethyl acetal, trimethyl orthoformate, triethyl orthoformate, etc., preferably N,N-dimethylformamide dimethyl acetal), heating Stir for an appropriate time (e.g. 15 hours) to an appropriate temperature (e.g. 100°C).
  • an appropriate temperature e.g. 100°C
  • the compound of formula (I-n) can be obtained by conventional post-treatment methods (such as filtration, extraction, concentration, etc.).
  • the compound of formula (In) and the compound of formula (Io) to a suitable solvent (such as ethanol, isopropanol, toluene, etc.), heat to a suitable temperature (such as 100°C), and react for a suitable time (such as 3h) .
  • a suitable solvent such as ethanol, isopropanol, toluene, etc.
  • a suitable temperature such as 100°C
  • a suitable time such as 3h
  • the compound of formula (I-c) can be obtained by conventional purification method (such as silica gel column chromatography).
  • the compound of formula (I-c) can be prepared by the following reaction:
  • a person skilled in the art can prepare a compound of formula (Ic) from a compound of formula (Ip) according to conventional methods in the art. The following schematically provides a method for preparing a compound of formula (Ic) from a compound of formula (Ip):
  • the compound of formula (Ip) and the compound of formula (Iq) are added to an appropriate solvent (such as dichloromethane, chloroform, 1,2-dichloroethane, etc., preferably dichloromethane), and the temperature is lowered to an appropriate temperature (such as 0°C), add an appropriate base (such as potassium carbonate, sodium carbonate, sodium hydroxide, etc., preferably potassium carbonate), slowly increase to room temperature and react for an appropriate time (such as 3-15 hours). After the reaction is completed, pass the conventional Purification methods (such as silica gel column chromatography) obtain the compound of formula (Ir).
  • an appropriate solvent such as dichloromethane, chloroform, 1,2-dichloroethane, etc., preferably dichloromethane
  • an appropriate base such as potassium carbonate, sodium carbonate, sodium hydroxide, etc., preferably potassium carbonate
  • the compound of formula (Ir) to a suitable solvent (such as toluene, xylene, trimethylbenzene, N,N-dimethylformamide, N,N-dimethylacetamide, etc., preferably toluene), and add a suitable reagent (Such as N,N-dimethylformamide dimethyl acetal, trimethyl orthoformate, triethyl orthoformate, etc., preferably N,N-dimethylformamide dimethyl acetal), heat to appropriate Stir for an appropriate time (e.g. 15 hours) at a temperature (e.g. 110 °C).
  • the compound of formula (I-c) can be obtained by conventional post-treatment methods (such as filtration, extraction, concentration, etc.) and purification methods (such as silica gel column chromatography).
  • the compound of formula (I-c) can be prepared by the following reaction formula:
  • a person skilled in the art can prepare a compound of formula (Ic) from a compound of formula (Is) according to conventional methods in the art. The following schematically provides a method for preparing a compound of formula (Ic) from a compound of formula (Is):
  • the compound of formula (Is) and the compound of formula (It) are added to a suitable solvent (such as methanol, ethanol, isopropanol, etc., preferably ethanol), and reacted at a suitable temperature (such as 80°C) for a suitable time (such as 15 hours).
  • a suitable solvent such as methanol, ethanol, isopropanol, etc., preferably ethanol
  • a suitable temperature such as 80°C
  • a suitable time such as 15 hours.
  • the compound of formula (I-u) can be obtained by conventional purification methods (such as silica gel column chromatography).
  • reaction solution is adjusted to an appropriate pH value (such as 5-6), and the formula (Iv) is obtained by conventional post-treatment methods (such as filtration, extraction, concentration, etc.) and purification methods (such as silica gel column chromatography) compound of.
  • an appropriate pH value such as 5-6
  • purification methods such as silica gel column chromatography
  • the compound of formula (I-v) to a suitable solvent (such as acetonitrile), add a suitable oxidizing agent (such as copper chloride), and raise it to a suitable temperature (such as 80°C) and react for a suitable time (such as 2 to 4 hours).
  • a suitable solvent such as acetonitrile
  • a suitable oxidizing agent such as copper chloride
  • a suitable temperature such as 80°C
  • the compound of formula (I-c) can be obtained by conventional post-treatment methods (such as filtration, extraction, concentration, etc.) and purification methods (such as silica gel column chromatography).
  • the compound of formula (I-t) can be prepared by the following reaction formula:
  • X 2 and X 5 are independently selected from CH or CH 2
  • PG is a well-known protecting group in the art (such as tert-butoxycarbonyl, benzyloxycarbonyl, acetyl, p-methoxybenzyl, etc.)
  • R 1 , M 3 and n are as defined above, and n ⁇ 1.
  • a person skilled in the art can prepare a compound of formula (It) from a compound of formula (Iw) according to conventional methods in the art. The following schematically provides a method for preparing a compound of formula (It) from a compound of formula (Iw):
  • the compound of formula (Iw) and the compound of formula (Ix) are added to a suitable solvent (such as dichloromethane, methanol, ethanol, etc., preferably dichloromethane), and a suitable acid (such as acetic acid) and a dehydrating agent (such as magnesium sulfate), then add a suitable reducing agent (such as sodium triacetoxyborohydride, sodium cyanoborohydride, etc.), and react at a suitable temperature (such as room temperature) for a suitable time (such as 15 hours). After the reaction, the compound of formula (I-y) is obtained through conventional post-treatment methods (such as filtration, extraction, concentration, etc.);
  • a suitable solvent such as dichloromethane, methanol, ethanol, etc., preferably dichloromethane
  • a suitable acid such as acetic acid
  • a dehydrating agent such as magnesium sulfate
  • a suitable reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydr
  • the compound of formula (I-y) and the compound of formula (I-z) are added to a suitable solvent (such as ethanol) and reacted at a suitable temperature (such as 80° C.) for a suitable time (such as 15 hours).
  • a suitable solvent such as ethanol
  • a suitable temperature such as 80° C.
  • a suitable time such as 15 hours.
  • the compound of formula (I-a1) is obtained by conventional post-treatment methods (such as filtration, extraction, concentration, etc.) and purification methods (such as silica gel column chromatography);
  • the compound of formula (I-a1) is treated with an appropriate deprotection method (such as acid, base, hydrogenation, oxidation, etc.), through conventional post-treatment methods (such as filtration, extraction, concentration, etc.) and purification methods (such as Recrystallization, silica gel column chromatography, etc.) to obtain the compound of formula (It).
  • an appropriate deprotection method such as acid, base, hydrogenation, oxidation, etc.
  • conventional post-treatment methods such as filtration, extraction, concentration, etc.
  • purification methods such as Recrystallization, silica gel column chromatography, etc.
  • the compound of formula (I-a1) can be prepared by the following reaction formula:
  • X 2 and X 5 are independently selected from CH or CH 2
  • PG is a well-known protecting group in the art (such as tert-butoxycarbonyl, benzyloxycarbonyl, acetyl, p-methoxybenzyl, etc.)
  • LG is a known leaving group in the art (such as benzenesulfonate, mesylate, etc.)
  • R 1 , M 3 and n are as defined above.
  • the compound of formula (I-o) is dissolved in a suitable solvent (such as ethanol), and the compound of formula (I-z) is added at a suitable temperature (such as 0° C. to room temperature), and reacted for a suitable time (2-15 hours).
  • a suitable solvent such as ethanol
  • the compound of formula (I-z) is added at a suitable temperature (such as 0° C. to room temperature), and reacted for a suitable time (2-15 hours).
  • the compound of formula (I-a2) can be obtained by conventional post-treatment methods (such as filtration, extraction, concentration, etc.) and purification methods (such as recrystallization, silica gel column chromatography, etc.).
  • the compound of formula (I-a2) to a suitable solvent (such as dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, etc.), and add a suitable base (such as triethylamine, N,N-diisopropylethylamine, etc.) N-methylmorpholine, etc.), reduce to an appropriate temperature (such as -5°C), add the compound of formula (I-a3), and warm to room temperature for a suitable time (such as 14 hours).
  • the compound of formula (I-a1) can be obtained by conventional post-treatment methods (such as filtration, extraction, concentration, etc.) and purification methods (such as recrystallization, silica gel column chromatography, etc.).
  • R represents a group represented by general formula (b)
  • the compound of formula (Id) can be prepared by the following reaction formula:
  • LG is a leaving group known in the art (such as chlorine)
  • PG is a protecting group known in the art (preferably tert-butoxycarbonyl)
  • R 1 is as defined above.
  • a person skilled in the art can prepare a compound of formula (Id) from a compound of formula (I-d3) according to conventional methods in the art. The following schematically provides the preparation of a compound of formula (Id) from a compound of formula (I-d3) Compound method:
  • the compound of formula (I-d3) is dissolved in a suitable solvent (such as ethyl acetate), the temperature is lowered to a suitable temperature (such as 0°C), the compound of formula (I-d4) is added, and the reaction is appropriately raised to room temperature. Time (e.g. 15 hours). After the reaction is over, add an appropriate base (such as potassium carbonate) to quench, and through conventional post-treatment methods (such as filtration, extraction, concentration, etc.) and purification methods (such as recrystallization, silica gel column chromatography, etc.) to obtain the formula (I- d5) compound.
  • a suitable solvent such as ethyl acetate
  • a suitable temperature such as 0°C
  • the compound of formula (I-d4) is added, and the reaction is appropriately raised to room temperature. Time (e.g. 15 hours).
  • an appropriate base such as potassium carbonate
  • purification methods such as recrystallization, silica gel column chromatography, etc.
  • the compound of formula (I-d5) is dissolved in a suitable solvent (such as methyl tert-butyl ether), cooled to a suitable temperature (such as 0°C), and a suitable reducing agent (such as triphenylphosphine, tri-n-butyl) is added. Phosphine, etc., preferably tri-n-butyl phosphine), warm up to room temperature and react for an appropriate time (such as 15 hours).
  • the compound of formula (I-d6) can be obtained by conventional post-treatment methods (such as filtration, extraction, concentration, etc.) and purification methods (such as recrystallization, silica gel column chromatography, etc.).
  • the compound of formula (I-d6) is dissolved in a suitable solvent (such as dichloromethane, tetrahydrofuran, etc.), cooled to a suitable temperature (such as 0°C), and a suitable base (such as triethylamine, N, N- Diisopropylethylamine, potassium carbonate, sodium carbonate, etc., preferably triethylamine) and a suitable protecting group reagent (such as di-tert-butyl dicarbonate) are raised to room temperature and reacted for a suitable time (such as 15 hours).
  • the compound of formula (I-d7) can be obtained by conventional post-treatment methods (such as filtration, extraction, concentration, etc.) and purification methods (such as recrystallization, silica gel column chromatography, etc.).
  • the compound of formula (I-d7) to an appropriate solvent (such as toluene, xylene, trimethylbenzene, N,N-dimethylformamide, N,N-dimethylacetamide, etc., preferably toluene), and add appropriate Reagents (such as N,N-dimethylformamide dimethyl acetal, trimethyl orthoformate, triethyl orthoformate, etc., preferably N,N-dimethylformamide dimethyl acetal), heating To an appropriate temperature (e.g. 60°C) and stir for an appropriate time (e.g. 15 hours).
  • the compound of formula (I-d) can be obtained by conventional post-treatment methods (such as filtration, extraction, concentration, etc.) and purification methods (such as recrystallization, silica gel column chromatography, etc.).
  • the compound represented by general formula (I) can be prepared by the method shown below,
  • M 3 , R, n, Cy 3 , Cy 4 , L, LG, PG, k, and Cy 5 are as defined above.
  • the solvent is selected from: N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, toluene, benzene, xylene, trimethylbenzene, cyclohexane, hexane, Dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, methyl acetate, ethyl acetate, acetone, methyl ethyl ketone, One of acetonitrile, methanol, ethanol, isopropanol, tert-butanol, water, and mixtures thereof;
  • the catalyst is selected from: palladium chloride, palladium acetate, tris(dibenzylidene indeneacetone) dipalladium and mixtures thereof;
  • the ligand is selected from: 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, triphenylphosphine, and mixtures thereof;
  • the base is selected from: methylamine, ethylamine, propylamine, N,N-diisopropylethylamine, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, One of diethanolamine, ethylenediamine, pyridine, picoline, quinoline, and mixtures thereof;
  • the acid is selected from: formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid Dicarboxylic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethylsulfonic acid; hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid;
  • the peptide coupling reagent is selected from: 2-(7-azobenzotriazole)-tetramethylurea hexafluorophosphate (HATU), benzotriazole-N, N, N', N '-Tetramethylurea hexafluorophosphate (HBTU), 2-(1H-benzo[d][1,2,3]triazo-1-yl)-1,1,3,3-tetramethyl One of TBTU and its mixture;
  • the coupling reagent is selected from: phosphorus oxychloride, dicyclohexylcarbodiimide (DCC), N,N'-carbonyldiimidazole, isobutyl chloroformate, 1-n-propyl phosphoric anhydride, etc. Species and their mixtures.
  • the compound represented by general formula (I) can be prepared by the method shown below.
  • the compound of formula (I) can be prepared by deprotecting the compound of formula (I-j).
  • M 3 , R, n, W, Cy 3 , L, PG, k, R 1 and Cy 5 are as defined above.
  • a person skilled in the art can prepare a compound of formula (I) from a compound of formula (Ij) according to conventional methods in the art.
  • the following schematically provides a method for preparing a compound of formula (I) from a compound of formula (Ij) method:
  • the compound of formula (Ij) is added to a suitable solvent (such as methanol, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, etc., preferably N,N-dimethylformamide).
  • a suitable solvent such as methanol, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, etc., preferably N,N-dimethylformamide.
  • the compound of formula (I-j) can be prepared by reacting the compound of formula (I-j).
  • M 3 , R, n, Cy 3 , L and Cy 5 are as defined above.
  • the compound of formula (I-j') is added to an appropriate solvent (such as 1,4-dioxane, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide) Etc., preferably N,N-dimethylformamide), add an appropriate catalyst such as palladium acetate, palladium chloride, etc., add an appropriate ligand (BINAP, XPhos, SPhos, Ruphos, etc.), add an appropriate base (such as carbonic acid) Potassium, sodium carbonate, triethylamine, N,N-diisopropylethylamine, etc., preferably potassium carbonate), add NPG (such as benzophenone imine, p-methoxybenzylamine, tert-butylamine), where appropriate Stir at a temperature (e.g.
  • an appropriate solvent such as 1,4-dioxane, tetrahydrofuran, ace
  • the crude product is obtained by conventional post-treatment methods (such as filtration, extraction, etc.), and then separated by conventional purification means (such as silica gel column chromatography) to obtain the compound of formula (I-j).
  • the compound of formula (I-j') can be prepared by reacting the compound of formula (I-a) with the compound of formula (I-f').
  • M 3 , R, n, Cy 3 , L and Cy 5 are as defined above.
  • a person skilled in the art can prepare a compound of formula (I-j') from a compound of formula (Ia) and a compound of formula (I-f') according to conventional methods in the art.
  • the following schematically provides the formula (I-j') Method for preparing a compound of formula (I-j') by reacting a compound of Ia) with a compound of formula (I-f'):
  • a suitable solvent such as tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, etc., preferably N,N-dimethylformamide
  • a suitable peptide coupling reagent preferably 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • a suitable base such as three Ethylamine, pyridine, N,N-diisopropylethylamine, etc., preferably N,N-diisopropylethylamine
  • an appropriate temperature such as 0°C
  • stir for an appropriate time such as 10-30 Minutes
  • add the compound of formula (I-f') and stir at a suitable temperature (such as 0°C to ambient temperature) for a suitable time (such as 1 to 16 hours).
  • the compound of formula (Ia) and the compound of formula (I-f') are added to a suitable base (such as pyridine), cooled to a suitable temperature (such as 0°C), and a coupling reagent (such as trichloro) is added dropwise. Phosphorus oxide), after stirring for a suitable time (such as 0.5 to 3 hours) until the reaction is complete, the reaction solution is concentrated under reduced pressure, an appropriate amount of water is added, extracted with a suitable extractant (such as ethyl acetate), and the extract is concentrated. The crude product is separated by conventional purification methods (such as silica gel column chromatography) to obtain the compound of formula (I-j').
  • a suitable base such as pyridine
  • a suitable temperature such as 0°C
  • a coupling reagent such as trichloro
  • the compound of formula (I-a) can be prepared by the compound of formula (I-c).
  • R 1 is a C 1-6 alkyl group
  • M 3 , R and n are as defined above.
  • a person skilled in the art can prepare a compound of formula (Ia) from a compound of formula (Ic) according to conventional methods in the art. The following schematically provides a method for preparing a compound of formula (Ia) from a compound of formula (Ic):
  • the compound of formula (Ic) is dissolved in a suitable solvent (such as methanol, ethanol, tetrahydrofuran, dioxane, etc., preferably methanol), and a suitable base (such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.) is added , Preferably lithium hydroxide), stir at a suitable temperature (such as room temperature) for a suitable time (such as 0.5 to 3 hours), after the reaction is completed, concentrate under reduced pressure, and adjust with an aqueous solution of a suitable acid (such as hydrochloric acid, citric acid)
  • a suitable acid such as hydrochloric acid, citric acid
  • the pH value is in a suitable range (such as 2-5), and the compound of formula (Ia) is obtained by filtration.
  • the compound of formula (I-c) can be prepared by reacting the compound of formula (I-d) with the compound of formula (I-e).
  • LG is a leaving group (for example, chlorine, bromine, iodine, methanesulfonate or benzenesulfonate, etc.) or boric acid, boric acid ester, M 3 and n are as defined above.
  • a person skilled in the art can prepare a compound of formula (Ic) from a compound of formula (Id) and a compound of formula (Ie) according to conventional methods in the art. The following schematically provides a compound of formula (Id) and formula ( Method for preparing compound of formula (Ic) by reaction of compound of Ie):
  • the compound of formula (Id) and the compound of formula (Ie) (LG is a leaving group) are dissolved in a suitable solvent (such as acetonitrile, tetrahydrofuran, N, N-dimethylformamide, etc.), preferably N, N -Dimethylformamide), add an appropriate base (such as sodium carbonate, potassium carbonate, cesium carbonate, etc., preferably potassium carbonate), stir and react at a suitable temperature (such as 50°C) for a suitable time (such as 10-16 hours) ), water and a suitable extractant are added after the reaction, and the crude product is separated by conventional purification means (such as silica gel column chromatography) to obtain the compound of formula (Ic).
  • a suitable solvent such as acetonitrile, tetrahydrofuran, N, N-dimethylformamide, etc.
  • an appropriate base such as sodium carbonate, potassium carbonate, cesium carbonate, etc., preferably potassium carbonate
  • a suitable temperature such as
  • the compound of formula (Id) and the compound of formula (Ie) are dissolved in a suitable solvent (such as acetonitrile, dichloromethane, chloroform, pyridine, N,N-dimethyl Formamide, etc., preferably N,N-dimethylformamide), add a suitable base (such as triethylamine, pyridine, etc.) and a suitable catalyst (such as copper acetate, copper chloride, etc.), under air or oxygen conditions , At an appropriate temperature (such as room temperature to 50 °C), the reaction time (such as 14 hours). After the reaction, the crude product is obtained through conventional post-treatments (such as extraction and concentration), and then the product is obtained through conventional purification means (such as silica gel column chromatography).
  • a suitable solvent such as acetonitrile, dichloromethane, chloroform, pyridine, N,N-dimethyl Formamide, etc., preferably N,N-dimethylformamide
  • a suitable base such as tri
  • the compound of formula (I-f') can be prepared by reacting the compound of formula (I-h') with the compound of formula (I-g).
  • an appropriate solvent such as tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, etc., Preferably N,N-dimethylformamide
  • an appropriate base such as potassium carbonate, sodium carbonate, triethylamine, N,N-diisopropylethylamine, etc., preferably potassium carbonate
  • an appropriate temperature such as room temperature to 80°C
  • stir for an appropriate time e.g. 14 hours.
  • the crude product is obtained by conventional post-treatment methods (such as filtration, extraction, etc.), and then separated by conventional purification means (such as silica gel column chromatography) to obtain the product.
  • the reaction solvent can use solvents commonly used in the art, including but not limited to ethers, alkanes, halogenated alkanes, aromatic hydrocarbons, alcohols, etc.
  • solvents commonly used in the art, including but not limited to ethers, alkanes, halogenated alkanes, aromatic hydrocarbons, alcohols, etc.
  • N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, aromatic hydrocarbons (such as toluene, benzene, xylene, trimethylbenzene, etc.) can be cited, Saturated hydrocarbons (such as cyclohexane, hexane, etc.), halogenated hydrocarbons (such as dichloromethane, chloroform, 1,2-dichloroethane, etc.), ethers (such as tetrahydrofuran, diethyl ether, dioxane, 1 , 2-Dimethoxyethane
  • the bases used may be bases commonly used in the art, including organic bases and inorganic bases.
  • organic bases include methylamine, ethylamine, propylamine, N,N-diisopropylethylamine, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, two Ethanolamine, ethylenediamine, pyridine, picoline, quinoline, etc.
  • inorganic bases hydroxides, carbonates, and bicarbonates of alkali metals (for example, lithium, sodium, potassium, cesium); alkaline earth metals ( Magnesium, calcium, strontium, barium) hydroxides, carbonates, bicarbonates; sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, etc.
  • the acid used may be the acids commonly used in the art, including organic acids and inorganic acids.
  • organic acids include formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, and phthalic acid.
  • Formic acid ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, and ethylsulfonic acid
  • examples of inorganic acids include hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, and hydroiodic acid.
  • the reducing agent used may be a reducing agent commonly used in the art, including but not limited to, triphenylphosphine, tri-n-butylphosphine, sodium triacetoxyborohydride, sodium cyanoborohydride , Sodium borohydride, iron powder, zinc powder, stannous chloride, sodium dithionite, hydrogen, etc.
  • the oxidant used may be the oxidant commonly used in the art, including but not limited to copper chloride, manganese dioxide, permanganate, dichromate, peroxyacetic acid, peroxybenzoic acid Wait.
  • the catalyst used may be a catalyst commonly used in the art, including but not limited to such as copper acetate, copper chloride, palladium carbon, ferric chloride, palladium acetate, [1,1'-bis(two Phenylphosphino)ferrocene]palladium dichloride and the like.
  • a catalyst commonly used in the art including but not limited to such as copper acetate, copper chloride, palladium carbon, ferric chloride, palladium acetate, [1,1'-bis(two Phenylphosphino)ferrocene]palladium dichloride and the like.
  • reaction conditions are not indicated in the examples, it shall be carried out in accordance with the conventional conditions or the conditions recommended by the manufacturer.
  • the reagents or instruments used without the manufacturer's indication are all conventional products that can be obtained on the market.
  • PE Petroleum ether
  • HATU 2-(7-Azobenzotriazole)-tetramethylurea hexafluorophosphate
  • Ruphos 2-Dicyclohexylphosphorus-2',6'-diisopropoxy-1,1'-biphenyl
  • Step 6 N-(5-((6-Bromo-1-methyl-1H-indazol-5-yl)oxy)pyridin-2-yl)-5-(4-fluorophenyl)-1- Synthesis of isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide
  • Step 7 4-(5-((6-(5-(4-Fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamido)pyridine -3-yl)oxy)-1-methyl-1H-indazol-6-yl)-1H-pyrazole-1-carboxylic acid tert-butyl ester
  • Step 8 5-(4-Fluorophenyl)-1-isopropyl-N-(5-((1-methyl-6-(1H-pyrazol-4-yl)-1H-indazole-5 -Yl)oxy)pyridin-2-yl)-4-oxo-1,4-dihydropyridazine-3-carboxamide
  • TLC monitors the completion of the reaction, adds DCM (20mL) and water (10mL), adds sodium bicarbonate to the reaction system to adjust the pH to 7-8, separates the layers, the organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure.
  • TLC monitors that the reaction is complete add water (150mL) to the reaction solution, add sodium percarbonate (35.7g) twice, stir for 1 hour at 25°C, adjust the pH to 2 ⁇ 3 with citric acid aqueous solution, and add hydrogen sulfite Sodium (12.75g), the reaction solution was extracted with toluene (100mL), the organic phases were combined, washed with water (2 ⁇ 10mL), concentrated under reduced pressure, a solid precipitated out, filtered under reduced pressure, the filter cake was the product (10.0g, yield: 60.5%).
  • Step 3 Synthesis of N-(3-chloro-4-((6-nitro-pyridin-3-yl)oxy)pyridin-2-yl)-1,1-diphenylanimine
  • Step 4 Synthesis of 5-((3-chloro-2-((diphenylmethylene)amino)pyridin-4-yl)oxy)pyridin-2amine
  • N-(3-Chloro-4-((6-nitro-pyridin-3-yl)oxy)pyridin-2-yl)-1,1-diphenylanimine (2.0g, 4.64mmol, 1.0 eq) was added to a 20% (NH 4 ) 2 S aqueous solution (15 mL, 10.0 eq), isopropanol (100 mL) was added, the reaction was carried out at room temperature for 1 hour, and heated to 70° C. for 2 hours. After the reaction was completed, it was cooled to room temperature, water (50 mL) was added, and ethyl acetate extraction (3 ⁇ 50 mL) was added.
  • Step 5 N-(5-((3-chloro-2-((diphenylmethylene)amino)pyridin-4-yl)oxy)pyridin-2-yl)-5-(4-fluorobenzene Yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide
  • Step 6 N-(5-((2-amino-3-chloropyridin-4-yl)oxy)pyridin-2-yl)-5-(4-fluorophenyl)-1-isopropyl-4 Synthesis of -oxo-1,4-dihydropyridazine-3-carboxamide
  • N-(5-((3-chloro-2-((diphenylmethylene)amino)pyridin-4-yl)oxy)pyridin-2-yl)-5-(4-fluorophenyl) -1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (400.0mg, 0.607mmol, 1.0eq) was added to isomethanol (4mL), water (0.7mL) and Concentrated hydrochloric acid (0.2 mL), stirred at room temperature for 30 minutes, TLC monitored the reaction to be complete, cooled to room temperature, added saturated aqueous NaHCO 3 solution, adjusted the pH to 7-8, extracted with DCM (20 mL ⁇ 3), combined the organic phases.
  • Step 1 N-(5-((2,3-Dichloropyridin-4-yl)oxy)pyrimidin-2-yl)-5-(4-fluorophenyl)-1-isopropyl-4- Synthesis of oxo-1,4-dihydropyridazine-3-carboxamide
  • TLC monitors the completion of the reaction, adds ethyl acetate (200mL) and water (150mL), separates the layers, and extracts the aqueous phase with ethyl acetate (100mL).
  • Step 2 N-(5-((3-chloro-2-((diphenylmethylene)amino)pyridin-4-yl)oxy)pyrimidin-2-yl)-5-(4-fluorobenzene Yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide
  • N-(5-((2,3-dichloropyridin-4-yl)oxy)pyrimidin-2-yl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo -1,4-Dihydropyridazine-3-carboxamide (1.54g, 2.98mmol, 1.0eq) was added to 1,4-dioxane (16mL), benzophenone imine (812.4mg, 4.48 mmol, 1.5eq), cesium carbonate (1.94g, 5.97mmol, 2.0eq), Pd 2 (dba) 3 (273.6mg, 0.29mmol, 0.1eq), 1,1'-binaphthyl-2,2'-bis Diphenylphosphine (278.9mg, 0.44mmol, 0.15eq) was refluxed at 110°C for 12 hours.
  • Step 3 N-(5-((2-amino-3-chloropyridin-4-yl)oxy)pyrimidin-2-yl)-5-(4-fluorophenyl)-1-isopropyl-4 Synthesis of -oxo-1,4-dihydropyridazine-3-carboxamide
  • N-(5-((3-chloro-2-((diphenylmethylene)amino)pyridin-4-yl)oxy)pyrimidin-2-yl)-5-(4-fluorophenyl) -1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (565.0mg, 0.85mmol, 1.0eq) was dissolved in methanol (10mL), concentrated hydrochloric acid (0.2mL) was added, React at room temperature for 1 hour. TLC detects that the reaction is complete.
  • Step 1 N-(5-((3-chloro-2-((diphenylmethylene)amino)pyridin-4-yl)oxy)pyridin-2-yl)-1-cyclopropyl-5 Synthesis of -(4-Fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide
  • Step 2 N-(5-((2-amino-3-chloropyridin-4-yl)oxy)pyridin-2-yl)-1-cyclopropyl-5-(4-fluorophenyl)-4 Synthesis of -oxo-1,4-dihydropyridazine-3-carboxamide
  • Step 1 N-(5-((2,3-Dichloropyridin-4-yl)oxy)pyrimidin-2-yl)-5-(4-fluorophenyl)-1-cyclopropyl-4- Synthesis of oxo-1,4-dihydropyridazine-3-carboxamide
  • Step 2 N-(5-((3-chloro-2-((diphenylmethylene)amino)pyridin-4-yl)oxy)pyrimidin-2-yl)-5-(4-fluorobenzene Base)-1-cyclopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide
  • N-(5-((2,3-dichloropyridin-4-yl)oxy)pyrimidin-2-yl)-5-(4-fluorophenyl)-1-cyclopropyl-4-oxo -1,4-Dihydropyridazine-3-carboxamide (960.0mg, 1.87mmol, 1.0eq) was added to 1,4-dioxane (10mL), benzophenone imine (508.4mg, 2.80 mmol, 1.5eq), cesium carbonate (1.22g, 3.74mmol, 2.0eq), Pd 2 (dba) 3 (171.2mg, 0.18mmol, 0.1eq) and 1,1'-binaphthyl-2,2'-bis Diphenylphosphine (174.5mg, 0.28mmol, 0.15eq) was stirred at 110°C under reflux for 12 hours.
  • TLC monitors that the reaction is complete, cools to room temperature, and concentrates.
  • Step 3 N-(5-((2-amino-3-chloropyridin-4-yl)oxy)pyrimidin-2-yl)-5-(4-fluorophenyl)-1-cyclopropyl-4 Synthesis of -oxo-1,4-dihydropyridazine-3-carboxamide
  • N-(5-((3-chloro-2-((diphenylmethylene)amino)pyridin-4-yl)oxy)pyrimidin-2-yl)-5-(4-fluorophenyl) -1-Cyclopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (360.0mg, 0.54mmol, 1.0eq) was dissolved in methanol (6mL), concentrated hydrochloric acid (0.15mL) was added, React at room temperature for 1 hour. TLC detects that the reaction is complete.
  • Step 2 Synthesis of N-(3-chloro-4-((5-nitropyridin-2-yl)oxy)pyridin-2-yl)-1,1-diphenylmethylamine
  • N-(3-chloro-4-((5-nitropyridin-2-yl)oxy)pyridin-2-yl)-1,1-diphenylformimine (7.00g, 16.25mmol, 1.0 eq) was dissolved in isopropanol (70 mL), 20% ammonium sulfide aqueous solution (55.37g, 162.52mmol, 10.0eq) was added, and the reaction was stirred at 20°C for 1.0h under nitrogen protection, and the temperature was raised to 70°C and the reaction was stirred for 2.5h.
  • Step 4 N-(6-((3-chloro-2-((diphenylmethylene)amino)pyridin-4-yl)oxy)pyridin-3-yl)-1-cyclopropyl-5 Synthesis of -(4-Fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide
  • Step 5 N-(6-((2-amino-3-chloropyridin-4-yl)oxy)pyridin-3-yl)-1-cyclopropyl-5-(4-fluorophenyl)-4 Synthesis of -oxo-1,4-dihydropyridazine-3-carboxamide
  • N-(6-((3-chloro-2-((diphenylmethylene)amino)pyridin-4-yl)oxy)pyridin-3-yl)-1-cyclopropyl-5-( 4-Fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide (152.0mg, 0.23mmol, 1.0eq) was dissolved in methanol (5mL), and concentrated hydrochloric acid ( 0.1mL), react at room temperature for 0.5h. TLC monitors the completion of the reaction.
  • Step 1 N-(5-((3-chloro-2-((diphenylmethylene)amino)pyridin-4-yl)oxy)pyridin-2-yl)-5-(4-fluorobenzene Yl)-1-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide
  • Step 2 N-(5-((2-amino-3-chloropyridin-4-yl)oxy)pyridin-2-yl)-5-(4-fluorophenyl)-1-methyl-4- Synthesis of oxo-1,4-dihydropyridazine-3-carboxamide
  • N-(5-((3-chloro-2-((diphenylmethylene)amino)pyridin-4-yl)oxy)pyridin-2-yl)-5-(4-fluorophenyl) -1-Methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (210.0mg, 0.33mmol, 1.0eq) was added to methanol (2mL), and hydrochloric acid (1mol/L, 1mL) was added , Stir at room temperature for 5 hours.
  • N-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)-1,1-diphenylformimine (470mg, 1.19mmol, 1.0eq)
  • FeSO 4 ⁇ 7H 2 O (6.59 g, 23.7 mmol, 20.0 eq)
  • NH 3 ⁇ H 2 O (2.49 g, 71.1 mmol, 60.0 eq)
  • Step 4 N-(5-((2-((Diphenylmethylene)amino)pyridin-4-yl)oxy)pyridin-2-yl)-5-(4-fluorophenyl)-1 Synthesis of -isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide
  • Step 5 N-(5-((2-Aminopyridin-4-yl)oxy)pyridin-2-yl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo- Synthesis of 1,4-Dihydropyridazine-3-carboxamide
  • Step 1 Synthesis of ethyl 1-allyl-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxylate
  • Ethyl 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxylate (475.0mg, 1.81mmol, 1.0eq), bromopropene (442.0mg, 3.65mmol, 2.0eq) and potassium carbonate (1.38g, 9.96mmol, 5.5eq) were added to DMF (15mL), and the reaction was stirred at 50°C for 3h. TLC monitored the completion of the reaction.
  • Step 2 Synthesis of 1-allyl-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxylic acid
  • the aqueous phase was dropped with concentrated hydrochloric acid to adjust the pH to 3, and a large amount of precipitate was precipitated.
  • Suction filtration dissolve the filter cake with dichloromethane (30 mL), dry with anhydrous sodium sulfate, filter with suction, and concentrate the filtrate under reduced pressure to obtain the product (418.0 mg, yield: 99.5%).
  • Step 3 1-allyl-N-(5-((3-chloro-2-((diphenylmethylene)amino)pyridin-4-yl)oxy)pyridin-2-yl)-5 Synthesis of -(4-Fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide
  • Step 4 1-allyl-N-(5-((2-amino-3-chloropyridin-4-yl)oxy)pyridin-2-yl)-5-(4-fluorophenyl)-4 Synthesis of -oxo-1,4-dihydropyridazine-3-carboxamide
  • Step 1 N-(5-((3-chloro-2-((diphenylmethylene)amino)pyridin-4-yl)oxy)pyridin-2-yl)-2-cyclopropyl-6 Synthesis of -(4-Fluorophenyl)-5-oxo-2,5-dihydropyridazine-4-carboxamide
  • Step 2 N-(5-((2-amino-3-chloropyridin-4-yl)oxy)pyridin-2-yl)-2-cyclopropyl-6-(4-fluorophenyl)-5 Synthesis of -oxo-2,5-dihydropyridazine-4-carboxamide hydrochloride
  • Step 1 Synthesis of 1-allyl-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxylic acid ethyl ester
  • Step 2 Synthesis of 1-allyl-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxylic acid
  • Ethyl 1-allyl-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxylate (343.0mg, 1.13mmol, 1.0eq) was added to methanol ( 6mL), add an aqueous solution (3mL) of lithium hydroxide monohydrate (142.7mg, 3.40mmol, 3.0eq), react at room temperature for 1 hour, TLC monitors that the reaction is complete, concentrate, adjust the pH of the system to 3-4 with 6mol/L hydrochloric acid , A solid precipitated, stirred for 1 hour, filtered with suction, and dried the filter cake to obtain the product (310.0 mg, yield: 100%).
  • Step 3 Synthesis of 5-((3-chloro-2-((4-methoxybenzyl)amino)pyridin-4-yl)oxy)pyrimidin-2-amine
  • Step 4 1-allyl-N-(5-((3-chloro-2-((4-methoxybenzyl)amino)pyridin-4-yl)oxy)pyrimidin-2-yl)- Synthesis of 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide
  • Step 5 1-allyl-N-(5-(((2-amino-3-chloropyridinyl-4-yl)oxy)pyrimidin-2-yl)-5-(4-fluorophenyl) Synthesis of -4-oxo-1,4-dihydropyridazine-3-carboxamide
  • Step 1 N-(6-((3-chloro-2-((diphenylmethylene)amino)pyridin-4-yl)oxy)pyridin-3-yl)-5-(4-fluorobenzene Yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide
  • Step 2 N-(6-((2-amino-3-chloropyridin-4-yl)oxy)pyridin-3-yl)-5-(4-fluorophenyl)-1-isopropyl-4 Synthesis of -oxo-1,4-dihydropyridazine-3-carboxamide
  • N-(6-((3-chloro-2-((diphenylmethylene)amino)pyridin-4-yl)oxy)pyridin-3-yl)-5-(4-fluorophenyl) -1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (230mg, 0.349mmol, 1.0eq) was added to methanol (4mL) and water (0.8mL), and then concentrated Hydrochloric acid (0.2 mL), stirred at room temperature for 30 minutes, TLC monitored the reaction to be complete.
  • Step 1 N-(2-((3-chloro-2-((4-methoxybenzyl)amino)pyridin-4-yl)oxy)pyrimidin-5-yl)-5-(4-fluoro (Phenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide
  • Step 2 N-(2-((2-amino-3-chloropyridin-4-yl)oxy)pyrimidin-5-yl)-5-(4-fluorophenyl)-1-isopropyl-4 Synthesis of -oxo-1,4-dihydropyridazine-3-carboxamide
  • N-(2-((3-chloro-2-((4-methoxybenzyl)amino)pyridin-4-yl)oxy)pyrimidin-5-yl)-5-(4-fluorophenyl )-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (155.0mg, 0.25mmol, 1.0eq) dissolved in trifluoroacetic acid (4mL) and dichloromethane (1mL In the mixed solution of ), the reaction was stirred at 60°C for 4 hours, and the reaction was completed as monitored by TLC.
  • Step 3 Synthesis of 2-((3-chloro-2-((4-methoxybenzyl)amino)pyridin-4-yl)oxy)pyrimidin-5-amine
  • Step 4 N-(2-((3-chloro-2-((4-methoxybenzyl)amino)pyridin-4-yl)oxy)pyrimidin-5-yl)-1-cyclopropyl- Synthesis of 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide
  • Step 5 N-(2-((2-Amino-3-chloropyridin-4-yl)oxy)pyrimidin-5-yl)-1-cyclopropyl-5-(4-fluorophenyl)-4 Synthesis of -oxo-1,4-dihydropyridazine-3-carboxamide
  • Step 1 N-(6-((3-chloro-2-((diphenylmethylene)amino)pyridin-4-yl)oxy)pyridin-3-yl-6-(4-fluorophenyl ) Synthesis of 2-isopropyl-5-oxo-2,5-dihydropyridazine-4-carboxamide
  • Step 2 N-(6-((2-amino-3-chloropyridin-4-yl)oxy)pyridin-3-yl)-6-(4-fluorophenyl)-2-isopropyl-5 -Synthesis of oxo-2,5-dihydropyridazine-4-carboxamide
  • Step 1 N-(6-((3-chloro-2-((diphenylmethylene)amino)pyridin-4-yl)oxy)pyridin-3-yl)-2-cyclopropyl-6 Synthesis of -(4-Fluorophenyl)-5-oxo-2,5-dihydropyridazine-4-carboxamide
  • Step 2 N-(6-((2-amino-3-chloropyridin-4-yl)oxy)pyridin-3-yl)-2-cyclopropyl-6-(4-fluorophenyl)-5 -Synthesis of oxo-2,5-dihydropyridazine-4-carboxamide
  • Step 1 1-Allyl-N-(6-((2-amino-3-chloropyridin-4-yl)oxy)pyridin-3-yl)-5-(4-fluorophenyl)-4 Synthesis of -oxo-1,4-dihydropyridazine-3-carboxamide
  • Step 1 1-allyl-N-(2-((3-chloro-2-((4-methoxybenzyl)amino)pyridin-4-yl)oxy)pyrimidin-5-yl)- Synthesis of 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide
  • Step 2 1-allyl-N-(2-((2-amino-3-chloropyridin-4-yl)oxy)pyrimidin-5-yl)-5-(4-fluorophenyl)-4 Synthesis of -oxo-1,4-dihydropyridazine-3-carboxamide
  • Step 1 N-(2-((3-chloro-2-((4-methoxybenzyl)amino)pyridin-4-yl)oxy)pyrimidin-5-yl)-2-cyclopropyl- Synthesis of 6-(4-fluorophenyl)-5-oxo-2,5-dihydropyridazine-4-carboxamide
  • Step 2 N-(2-((2-amino-3-chloropyridin-4-yl)oxy)pyrimidin-5-yl)-2-cyclopropyl-6-(4-fluorophenyl)-5 -Synthesis of oxo-2,5-dihydropyridazine-3-carboxamide
  • H1299 is a non-small cell lung cancer cell.
  • Test object the compound of the present invention, the structure of which is shown in the foregoing.
  • Test equipment protein electrophoresis apparatus (manufactured by Bio Rad), membrane transfer apparatus (manufactured by Bio Rad), exposure apparatus (manufactured by Tanon), CO 2 cell incubator (manufactured by Thermo).
  • H1299 cells in a 6-well plate (containing 10% FBS 1640 medium, 5 ⁇ 10 5 cells per well), and culture them for 18 hours at 37°C and 5% CO 2 , then starve the cells overnight and add different concentrations of compounds.
  • the final concentration of the compound is 1.1nM, 3.3nM, 10nM, 30nM, and the final content of DMSO is 1 ⁇ .
  • the negative control well is a medium containing 1 ⁇ DMSO.
  • hGAS6 R&D, final concentration 200ng/mL
  • Use GraphPad 5.0 software to calculate IC 50 value to detect the inhibitory activity of the compound on cell pAxl.
  • H1299 is a non-small cell lung cancer cell.
  • Test object the compound of the present invention, the structure of which is shown in the foregoing.
  • Test equipment protein electrophoresis apparatus (manufactured by Bio Rad), membrane transfer apparatus (manufactured by Bio Rad), exposure apparatus (manufactured by Tanon), CO 2 cell incubator (manufactured by Thermo).
  • H1299 cells in a 6-well plate (containing 10% FBS 1640 medium, 5 ⁇ 10 5 cells per well), and culture them for 18 hours at 37°C and 5% CO 2 , then starve the cells overnight and add different concentrations of compounds.
  • the final concentration of the compound was 0.37nM, 1.1nM, 3.3nM, 10nM, and the final content of DMSO was 1 ⁇ .
  • the negative control well is a medium containing 1 ⁇ DMSO.
  • Test substance the compound of the present invention, its structure and preparation are shown in the foregoing.
  • the compound was dissolved in 100% DMSO to prepare a stock solution with a maximum concentration of 500 ⁇ M.
  • Ron(h) enzyme was dissolved in 8mM MOPS (pH 7.0), 0.2mM EDTA, 250 ⁇ M GGMEDIYFEFMGGKKK to prepare an enzyme solution with a final concentration of 40.4nM.
  • Test object Ron(h) Compound 11 2
  • Compound 12 19
  • Compound 13 16
  • Compound 18 14
  • Compound 19 64
  • Compound 23 92
  • Compound 33 17
  • Compound 35 5
  • Compound 37 12
  • Test substance the compound of the present invention, its structure and preparation are shown in the foregoing.
  • the compound was dissolved in 100% DMSO to prepare a stock solution with a maximum concentration of 500 ⁇ M.
  • the Axl(h) enzyme was dissolved in 8mM MOPS (pH 7.0), 0.2mM EDTA, 250 ⁇ M KKSRGDYMTMQIG to prepare an enzyme solution with a final concentration of 1.7nM.
  • Mer(h) enzyme was dissolved in 8mM MOPS (pH 7.0), 0.2mM EDTA, 30mM NaCl, 250 ⁇ M GGMEDIYFEFMGGKKK to prepare an enzyme solution with a final concentration of 3.1nM.
  • 8mM MOPS pH 7.0
  • 0.2mM EDTA 0.1% EDTA
  • 30mM NaCl 0.1% EDTA
  • 250 ⁇ M GGMEDIYFEFMGGKKK a final concentration of 3.1nM.
  • 10mM magnesium acetate, 10 ⁇ M [ ⁇ - 33 P]-ATP to form a Mg/ATP mixture to activate the enzymatic reaction.
  • Tyro3 the enzyme is dissolved in 8mM MOPS (pH 7.0), 0.2mM EDTA, 1mM MnCl 2, 250 ⁇ M KVEKIGEGTYGVVYK prepare to become a final concentration of 38nM enzyme solution.
  • the compound of the present invention has good inhibitory activity against Axl(h), Mer(h) and Tyro3(h). Therefore, the compound of the present invention can be used for prevention and/or treatment by Axl(h), Mer(h) and Tyro-3(h) mediated diseases.
  • Test substance the compound of the present invention, its structure and preparation are shown in the foregoing.
  • the compound was dissolved in 100% DMSO to prepare a stock solution with a maximum concentration of 500 ⁇ M.
  • the LCK(h) enzyme was dissolved in 50mM Tris pH 7.5, 0.1mM EGTA, 0.1mM Na 3 VO 4 , 250 ⁇ M KVEKIGEGTYGVVYK to prepare an enzyme solution with a final concentration of 45 nM.
  • Test substance the compound of the present invention, prepared according to the method of the example
  • Experimental compounds 11, 12, 35 prepared by dissolving 5% DMSO + 20% (30% solutol) + 75% saline to prepare a solution.
  • the compound solutions were administered to beagle dogs by intragastric administration at a dose of 1.0 mg/kg.
  • the blood sampling time points are: 0min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 10h, 24h.
  • Experimental compounds 11, 12, 35 Prepare a solution by dissolving 5% DMSO + 20% (30% solutol) + 75% saline with a prescription. The compound solution is given to beagle dogs by intravenous bolus at a dose of 1.0 mg/kg.
  • the blood sampling time points are: 0min, 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 10h, 24h.
  • Experimental compound 17 and compound 37 a solution was prepared by dissolving prescription 5% DMSO + 20% PEG400 + 75% (20% Captisol in Saline), and the compound solution was administered to beagle dogs by intragastric administration at a dose of 5.0 mg/kg.
  • the blood sampling time points are: 0min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 10h, 24h.
  • Experimental compound 17 and compound 37 Dissolve and prepare a solution with a prescription of 5% DMSO + 20% PEG400 + 75% (20% Captisol in Water). The compound solution is given to beagle dogs by intravenous bolus at a dose of 1.0 mg/kg , The blood sampling time points are: 0min, 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 10h, 24h.
  • Experimental compound 18 Dissolve and prepare a solution with prescription 5%DMA+30%PEG400+65%(20%captisol in saline). The compound solution is administered to beagle dogs by gavage at a dose of 5.0mg/kg, and blood is collected at the time point It is: 0min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 10h, 24h.
  • Experimental compound 18 Dissolve and prepare a solution with prescription 5%DMA+30%PEG400+65%(20%captisol in saline). The compound solution is given to beagle dogs by intravenous bolus at a dose of 1.0mg/kg, blood sampling time The points are: 0min, 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 10h, 24h.
  • the concentration of the test substance used the output result of Analyst 1.6.3 of AB.
  • Microsoft Excel calculates the mean, standard deviation, coefficient of variation and other parameters (analyst 1.6.3 directly output does not need to be calculated), and the PK parameters are calculated using Pharsight Phoenix 6.1 software NCA (T max is the median).
  • the present invention provides a novel TAM family kinase inhibitor compound, which has good kinase inhibitory activity and can be used to treat and/or prevent diseases mediated by abnormal expression of TAM family kinase receptors and/or ligands.
  • the compounds of the present invention can also target Ron kinases, and can be used to treat and/or prevent diseases mediated by abnormal expression of TAM family kinases and Ron kinase receptors and/or their ligands.
  • the compounds of the present invention can inhibit the growth, migration, and/or drug resistance of tumors caused by TAM family kinases/and Ron kinases.

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Abstract

一种通式(I)所表示的TAM家族激酶/和Ron激酶抑制剂化合物、其药学上可接受的盐、酯、立体异构体、互变异构体及包含它们的药物组合物、药物制剂及用途。所述化合物可选择性抑制酪氨酸激酶TAM家族/和Ron激酶，可用于TAM家族激酶/和Ron激酶的受体和/或其配体异常表达所介导的疾病治疗和/或预防。其通过靶向抑制TAM家族激酶/和Ron激酶，逆转肿瘤微环境中的免疫抑制环境，抑制肿瘤的生长、迁移、和/或耐药表现，发挥肿瘤免疫效应和抗肿瘤疗效。

Description

杂环衍生物及其用途 技术领域
本发明属于医药领域，具体涉及通式(I)所表示的TAM家族激酶/和Ron激酶抑制剂化合物、其药学上可接受的盐、酯、立体异构体、互变异构体及包含它们的药物组合物、药物制剂及用途。本发明化合物可选择性抑制酪氨酸激酶TAM家族/和Ron激酶，可用于TAM家族激酶/和Ron激酶的受体和/或其配体异常表达所介导的疾病治疗和/或预防。
背景技术
TAM家族包括Axl、Mer、Tyro-3这3个成员，该家族包含胞外域、跨膜域和保守的胞内激酶域。其中胞外域由两个免疫球蛋白样的结构域连接两个III型纤维连接蛋白重复单元组成。其胞内激酶域的保守氨基酸序列KW(I/L)A(I/L)ES是TAM家族所独有的结构特征。该家族有1个共同的配体-生长抑制特异性蛋白6(Gas6)，该配体能够与所有TAM受体结合，但结合强弱有所差异。除此外TAM家族还有维生素K依赖蛋白S(vitamin K dependent protein S，ProS)、短粗样蛋白Tubby、重组人短粗样蛋白1(Tulp1)、半乳糖凝集素-3(galectin-3)等相关受体(吴彦君，中国新药杂志，2016；卢萍，中华实用诊断与治疗杂志，2016)。
其中Axl(别称UFO、Ark、Tyro-7、JTK1)、Mer(别称c-Mer、Mertk、Eyk、Nyk、Tyro-12)、Tyro-3(别称Sky、Byk、Rse、Dtk等)、galectin-3、Gas6、ProS在肺癌、胃癌、肝癌等多种实体瘤及AML、ALL、CML等多种血液瘤中均存在异常表达，并与疾病的不良预后、疾病进展、肿瘤转移及肿瘤耐药等有着较强的相关性(Douglas K，Nature reviews，2014)。尤其是Axl作为一种酪氨酸激酶，已被证实是造成NSCLC中EGFR抑制剂耐药的原因之一，并与多种实体瘤的转移关系密切。而以此为靶点开发的药物也证实了抑制Axl可延缓EGFR抑制剂的耐药及肿瘤转移的效果(T.Jimbo，Annals of Oncology，2017；Sacha J.Holland，American Association for Cancer Research，2010)。与此同时，Axl、Mer、Tryo-3及TAM家族配体在免疫肿瘤方向也有着重大的作用。抑制TAM家族及其配体可通过促进巨噬细胞向M1型巨噬细胞的极化、增加效应 T细胞的激活及功能、增强NK细胞抗肿瘤活性等手段逆转肿瘤的免疫抑制环境、增强免疫系统杀伤肿瘤细胞能力(Yemsratch T.Akalu，Immunological Reviews，2017；Greg Lemke，Nature Reviews Immunology，2008)。因此开发此类抑制剂可对该家族所诱导的多种实体及血液肿瘤有着较强的抑制及治疗作用，如肺癌、肝癌、乳腺癌、脑胶质瘤、黑色素瘤、AML、ALL、CML等。
除了上述肿瘤疾病领域外，TAM家族受体及配体可调节血管平滑肌稳态、血小板聚集、血栓稳定化、红细胞生成、少突胶质细胞存活、破骨细胞功能、凋亡细胞的吞噬、炎症、先天免疫等多项生理功能。因此TAM家族抑制剂也可用于因TAM家族信号通路紊乱所引发的子宫内膜异位、血管疾病/损伤、牛皮癣、视觉缺陷/病变(黄斑变性、糖尿病及早产等原因所致)、肾脏疾病、类风湿性关节炎、骨质疏松症等相关疾病。
人类细胞跨膜受体蛋白Ron(macrophage stimulating 1 receptor，MST1R)，又称为巨噬细胞刺激蛋白受体(macrophage stimulating protein receptor，MSP-receptor)、类肝细胞生长因子(hepatocyte growth factor like，HGFL)受体。Ron基因在人体上皮组织、粒细胞、单核细胞、巨核细胞以及扁桃体生发层、小肠、结肠、肾脏、肺、骨髓、破骨细胞中有表达。
Ron在人体多种常见上皮性肿瘤的发生发展中所起的作用已被广泛地证实。在33％-96％胰腺癌临床标本中可检测到Ron，而Ron的表达与肿瘤病理进程成正相关(Thomas RM，et al.CancerRes，2007，67(13)：6075-6082.)。约50％的乳腺癌患者过度表达Ron，绝经后妇女乳腺癌Ron表达水平较之正常乳腺组织和绝经前乳腺癌显著提高。通过转基因小鼠的研究表明，Ron的过度表达足以诱发乳腺转型并具有较高的转移性，大于86％的转基因小鼠肝和肺中有转移灶(Glendon M.Zinser，American Association for Cancer Research，2006)。此外Ron还在非小细胞肺癌、头颈部鳞癌等多种恶性肿瘤中异常表达且与肿瘤浸润进展和预后的相关。
发明内容
本发明提供一种新型杂环衍生物抑制剂化合物及其药学上可接受 的盐、酯、立体异构体、互变异构体(以下，有时也称为本发明化合物)。本发明的化合物对于TAM家族激酶具有抑制作用，可用于治疗和/或预防由TAM家族激酶受体和/或其配体异常表达所介导的疾病。另外，本发明的化合物还可以靶向Ron激酶，对于Ron激酶具有抑制作用。通过本发明的化合物，可用于治疗和/或预防由TAM家族激酶/和Ron激酶受体和/或其配体异常表达所介导的疾病。本发明化合物通过抑制TAM家族激酶/和Ron激酶，逆转肿瘤微环境中的免疫抑制环境，抑制肿瘤的生长、迁移、和/或耐药表现，发挥肿瘤免疫效应和抗肿瘤疗效。
具体而言，本发明采用的技术方案如下：
通式(I)表示的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体：
Figure PCTCN2020117074-appb-000001
其中，W选自氢原子或任选被取代基取代的C 1-6烷基；
R表示如下通式(b)所示的基团：
Figure PCTCN2020117074-appb-000002
Figure PCTCN2020117074-appb-000003
表示在环结构中任选存在的双键部分，
Figure PCTCN2020117074-appb-000004
部分通过连接基团与M 3基团连接；
X 1、X 2、X 3分别独立选自CR a、C＝O、NR b、O，且其中至少一个为C＝O；
X 4、X 5分别独立选自C；
M 3选自氢原子、氰基、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-OC(O)NR bR c、-NR bC(O)OR d、-NR bC(O)R d、-SO 2-NR bR c、-SO 2R d、-NR bSO 2R d；或任选被取代基取代的C 1-6烷基、 C 1-6烷氧基、C 2-8烯基、C 2-8炔基、-C 1-6烷基-R’、-C 1-6烷氧基-R’、-O-R’、-C(O)-R’、-SO 2-R’、-NR bC(O)-R’、3-12元环烷基、3-12元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基；
Cy 2选自任选被一至多个R 2取代的3-12元环烷基、3-12元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基，R 2各自独立的选自氢原子、氰基、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-OC(O)NR bR c、-NR bC(O)OR d、-NR bC(O)R d、-SO 2-NR bR c、-SO 2R d、-NR bSO 2R d；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-8烯基、C 2-8炔基、-C 1-6烷基-R’、-C 1-6烷氧基-R’、-O-R’、-C(O)-R’、-SO 2-R’、-NR bC(O)-R’、3-12元环烷基、3-12元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基；
Cy 3选自任选被一至多个R 3取代的5-10元杂芳基，R 3各自独立的选自氢原子、氰基、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-OC(O)NR bR c、-NR bC(O)OR d、-NR bC(O)R d、-SO 2-NR bR c、-SO 2R d、-NR bSO 2R d；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-8烯基、C 2-8炔基、-C 1-6烷基-R’、-C 1-6烷氧基-R’、-O-R’、-C(O)-R’、-SO 2-R’、-NR bC(O)-R’、3-12元环烷基、3-12元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基；
Cy 4选自任选被一至多个R 4取代的5-9元杂环基、5-9元杂芳基，R 4各自独立的选自氢原子、氰基、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-OC(O)NR bR c、-NR bC(O)OR d、-NR bC(O)R d、-SO 2-NR bR c、-SO 2R d、-NR bSO 2R d；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-8烯基、C 2-8炔基、-C 1-6烷基-R’、-C 1-6烷氧基-R’、-O-R’、-C(O)-R’、-SO 2-R’、-NR bC(O)-R’、3-12元环烷基、3-12元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基，或者，两个R 4可以与所连接的原子形成5-6元环状基团；
L选自-NR b-、-O-、-S-、-(CR aR a) m-，m选自1-3的整数；
R a不存在，或者在每次出现时，各自独立地选自氢原子、氰基、羟基、卤素原子、羧基、硝基、-NR eR f、-C(O)R g、-C(O)NR eR f、-OC(O)NR eR f、-NR eC(O)OR g、-NR eC(O)R g、-SO 2-NR eR f、-SO 2R g、-NR eSO 2R g，或任选被取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-8烯基、C 2-8炔基、-C 1-6烷基-R’、-C 1-6烷氧基-R’、-O-R’、-C(O)-R’、-SO 2-R’、-NR eC(O)-R’、 3-12元环烷基、3-12元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基；
R b、R c不存在，或者在每次出现时，各自独立地选自氢原子、羟基、-C(O)R g、-C(O)NR eR f、-SO 2-NR eR f、-SO 2R g；或任选被取代基取代的C 1-6烷基、-C 1-6烷基-R’、-C(O)-R’、-SO 2-R’、3-12元环烷基、3-12元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基；
R d不存在，或者在每次出现时，各自独立地选自氢原子、-NR eR f、-NR eC(O)OR g、-NR eC(O)R g、-NR eSO 2R g；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基、-C 1-6烷基-R’、-C 1-6烷氧基-R’、-O-R’、-NR eC(O)-R’、3-12元环烷基、3-12元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基；
R e、R f不存在，或者在每次出现时，各自独立的选自氢原子、羟基、羧基、氰基、硝基、卤素原子；或任选被取代基取代的C 1-6烷基、-C 1-6烷基-R’、-C(O)-R’、-SO 2-R’、3-12元环烷基、3-12元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基；
R g不存在，或者在每次出现时，各自独立的选自氢原子；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基、-C 1-6烷基-R’、-C(O)-R’、-SO 2-R’、3-12元环烷基、3-12元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基；
R’为3-12元环烷基、3-12元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基；
n为0-4的整数；
所述“任选被取代基取代”中的取代基各自独立地选自：羟基、巯基、氨基、羧基、氰基、硝基、卤素原子、C 1-6烷基、C 1-6烷氧基C 1-6烷基、C 1-6烷氧基、C 1-6烷基C 1-6烷氧基、C 1-6烷氧基C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷基氨基羰基、(C 1-6烷基) 2氨基羰基、C 1-6烷基羰基、C 1-6烷基羰基氧基、C 1-6烷基羰基氨基、C 1-6烷基磺酰氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 1-6烷基磺酰基、C 1-6烷基硫基、3-12元环烷基、6-14元芳基、3-12元杂环基、5-10元杂芳基和氧代基。
在本发明的一个实施方式中，提供通式(I)表示的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体：
其中，W选自氢原子或任选被取代基取代的C 1-6烷基；
R表示如下通式(b)所示的基团：
Figure PCTCN2020117074-appb-000005
Figure PCTCN2020117074-appb-000006
部分通过连接基团与M 3基团连接；
X 1、X 2、X 3分别独立地选自CR a、C＝O、NR b，且其中至少一个为C＝O；
X 4、X 5分别选自C；
M 3选自氢原子、氰基、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-OC(O)NR bR c、-NR bC(O)OR d、-NR bC(O)R d、-SO 2-NR bR c、-SO 2R d、-NR bSO 2R d；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-8烯基、C 2-8炔基、3-8元环烷基、3-14元杂环基；
Cy 2选自任选被一至多个R 2取代的6-14元芳基、5-10元杂芳基，R 2各自独立地选自氢原子、氰基、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-OC(O)NR bR c、-NR bC(O)OR d、-NR bC(O)R d、-SO 2-NR bR c、-SO 2R d、-NR bSO 2R d；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-8烯基、C 2-8炔基、-C 1-6烷基-R’、-C 1-6烷氧基-R’、-O-R’、-C(O)-R’、-SO 2-R’、-NR bC(O)-R’、3-8元环烷基、3-8元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基；
Cy 3选自任选被一至多个R 3取代的5-10元杂芳基，R 3各自独立地选自氢原子、氰基、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-OC(O)NR bR c、-NR bC(O)OR d、-NR bC(O)R d、-SO 2-NR bR c、-SO 2R d、-NR bSO 2R d；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-8烯基、C 2-8炔基、-C 1-6烷基-R’、-C 1-6烷氧基-R’、-O-R’、-C(O)-R’、-SO 2-R’、-NR bC(O)-R’、3-8元环烷基、3-8元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基；
Cy 4选自任选被一至多个R 4取代的5-9元杂芳基，R 4各自独立地选自氢原子、氰基、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-OC(O)NR bR c、-NR bC(O)OR d、-NR bC(O)R d、-SO 2-NR bR c、 -SO 2R d、-NR bSO 2R d；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-8烯基、C 2-8炔基、-C 1-6烷基-R’、-C 1-6烷氧基-R’、-O-R’、-C(O)-R’、-SO 2-R’、-NR bC(O)-R’、3-8元环烷基、3-8元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基，或者，两个R 4可以与所连接的原子形成5-6元环状基团；
L选自-NR b-、-O-、-S-；
R a不存在，或者在每次出现时，各自独立地选自氢原子、氰基、羟基、卤素原子、羧基、硝基、-NR eR f、-C(O)R g、-C(O)NR eR f、-OC(O)NR eR f、-NR eC(O)OR g、-NR eC(O)R g、-SO 2-NR eR f、-SO 2R g、-NR eSO 2R g；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-8烯基、C 2-8炔基、-C 1-6烷基-R’、-C 1-6烷氧基-R’、-O-R’、-C(O)-R’、-SO 2-R’、-NR eC(O)-R’、3-8元环烷基、3-8元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基；
R b、R e不存在，或者在每次出现时，各自独立地选自氢原子、羟基、-C(O)R g、-C(O)NR eR f、-SO 2-NR eR f、-SO 2R g；或任选被取代基取代的C 1-6烷基、-C 1-6烷基-R’、-C(O)-R’、-SO 2-R’、3-8元环烷基、3-8元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基；
R d不存在，或者在每次出现时，各自独立地选自氢原子、-NR eR f、-NR eC(O)OR g、-NR eC(O)R g、-NR eSO 2R g；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基、-C 1-6烷基-R’、-C 1-6烷氧基-R’、-O-R’、-NR eC(O)-R’、3-8元环烷基、3-8元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基；
R e、R f不存在，或者在每次出现时，独立的选自氢原子、羟基、羧基、氰基、硝基、卤素原子；或任选被取代基取代的C 1-6烷基、-C 1-6烷基-R’、-C(O)-R’、-SO 2-R’、3-12元环烷基、3-12元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基；
R g不存在，或者在每次出现时，独立的选自氢原子；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基、-C 1-6烷基-R’、-C(O)-R’、-SO 2-R’、3-12元环烷基、3-12元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基；
R’为3-8元环烷基、3-8元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基；
n为0-3的整数；
所述“任选被取代基取代”中的取代基各自独立地选自：羟基、巯基、氨基、羧基、氰基、硝基、卤素原子、C 1-6烷基、C 1-6烷氧基C 1-6烷基、C 1-6烷氧基、C 1-6烷基C 1-6烷氧基、C 1-6烷氧基C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷基氨基羰基、(C 1-6烷基) 2氨基羰基、C 1-6烷基羰基、C 1-6烷基羰基氧基、C 1-6烷基羰基氨基、C 1-6烷基磺酰氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 1-6烷基磺酰基、C 1-6烷基硫基、3-8元环烷基、6-14元芳基、3-8元杂环基、5-10元杂芳基和氧代基；
优选地，X 1为N，X 2为CR a，X 3为C＝O；
优选地，X 1为CR a，X 2为N，X 3为C＝O；
优选地，X 1为CR a，X 2为CR a，X 3为C＝O。
在本发明的一个实施方式中，提供通式(I)表示的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体：
其中，X 1、X 2、X 3分别独立地选自CR a、C＝O、NR b，且其中至少一个为C＝O；
X 4选自C，X 5选自C；
M 3选自氢原子、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-NR bC(O)R d；或任选被取代基取代的C 1-6烷基、C 2-8烯基、C 2-8炔基、3-8元环烷基、3-8元杂环基；
Cy 2选自任选被一至多个R 2取代的苯基、5-6元杂芳基，R 2各自独立地选自氢原子、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-NR bC(O)R d；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基；
Cy 3选自任选被一至多个R 3取代的5-6元杂芳基，R 3各自独立地选自氢原子、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-NR bC(O)R d；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基；
Cy 4选自任选被一至多个R 4取代的5-6元杂芳基或9元并杂芳基，R 4各自独立地选自氢原子、羟基、卤素原子、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-NR bC(O)R d；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基，或者，两个R 4可以与所连接的原子形成5-6元含氧环状基团；
L选自-O-；
R a不存在，或者在每次出现时，各自独立地选自氢原子，或任选 被取代基取代的C 1-6烷基；
R b、R c不存在，或者在每次出现时，各自独立地选自氢原子，或任选被取代基取代的C 1-6烷基；
R d不存在，或者在每次出现时，各自独立地选自氢原子，或任选被取代基取代的C 1-6烷基；
n为0-2的整数；
所述“任选被取代基取代”中的取代基各自独立地选自：羟基、氨基、羧基、氰基、硝基、卤素原子、C 1-6烷基、C 1-6烷氧基；
优选地，X 1为N，X 2为CR a，X 3为C＝O；
优选地，X 1为CR a，X 2为N，X 3为C＝O；
优选地，X 1为CR a，X 2为CR a，X 3为C＝O；
优选地，Cy 3为
Figure PCTCN2020117074-appb-000007
Y 2、Y 3、Y 6、Y 7分别独立的选自CH或N，并且至少有一个为N。
在本发明的一个实施方式中，提供通式(I)表示的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体：
其中，X 1、X 2、X 3分别独立地选自CR a、C＝O、NR b，且其中至少一个为C＝O；
X 4选自C，X 5选自C；
M 3选自氢原子；或任选被取代基取代的C 1-6烷基、C 2-8烯基、C 2-8炔基、3-8元环烷基、5-6元杂环基；
Cy 2选自任选被一至多个R 2取代的苯基、5-6元杂芳基；
Cy 3表示任选被一至多个R 3取代的
Figure PCTCN2020117074-appb-000008
Y 2、Y 3、Y 6和Y 7各自独立地选自CH或N，且至少一个为N；
Cy 4选自任选被一至多个R 4取代的6元杂芳基或9元并杂芳基；
R 2各自独立地选自氢原子、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-NR bC(O)R d；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基；
R 3各自独立地选自氢原子、羟基、卤素原子、羧基、硝基、-NR bR c、 -C(O)R d、-C(O)NR bR c、-NR bC(O)R d；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基；
R 4各自独立地选自氢原子、羟基、卤素原子、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-NR bC(O)R d、5-10元杂芳基；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基；
L选自-O-；
R a不存在，或者在每次出现时，各自独立地选自氢原子、C 1-6烷基、卤代C 1-6烷基；
R b、R c不存在，或者在每次出现时，各自独立地选自氢原子、C 1-6烷基；
R d不存在，或者在每次出现时，各自独立地选自氢原子、C 1-6烷基；
n为0-2的整数；
所述“任选被取代基取代”中的取代基各自独立地选自：羟基、巯基、氨基、羧基、氰基、硝基、卤素原子、C 1-6烷基、C 1-6烷氧基；
优选地，X 1为N，X 2为CR a，X 3为C＝O；
优选地，X 1为CR a，X 2为N，X 3为C＝O；
优选地，X 1为CR a，X 2为CR a，X 3为C＝O；
优选地，Cy 4选自任选被一至多个R 4取代的6元含N杂芳基或9元含N并杂芳基。
在本发明的一个实施方式中，提供通式(I)表示的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体：
其中，X 1、X 2分别独立地选自CR a或NR b，X 3为C＝O；
M 3选自氢原子、C 1-6烷基、C 2-8烯基、C 2-8炔基、3-6元环烷基、5-6元杂环基；
Cy 2选自任选被一至多个R 2取代的苯基；
Cy 3表示任选被一至多个R 3取代的
Figure PCTCN2020117074-appb-000009
Y 2、Y 3、Y 6和Y 7独立地选自CH或N，且至少一个为N；
Cy 4选自任选被一至多个R 4取代的
Figure PCTCN2020117074-appb-000010
Figure PCTCN2020117074-appb-000011
R 2各自独立地选自氢原子、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-NR bC(O)R d；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基；
R 3各自独立地选自氢原子、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-NR bC(O)R d；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基；
R 4各自独立地选自氢原子、羟基、卤素原子、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-NR bC(O)R d；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基；
L选自-O-；
R a不存在，或者在每次出现时，各自独立地选自氢原子、C 1-6烷基、卤代C 1-6烷基；
R b、R c不存在，或者在每次出现时，各自独立地选自氢原子、C 1-6烷基；
R d不存在，或者在每次出现时，各自独立地选自氢原子、C 1-6烷基；
n为0-1的整数；
所述“任选被取代基取代”中的取代基各自独立地选自：羟基、巯基、氨基、羧基、氰基、硝基、卤素原子。
在本发明的一个实施方式中，提供通式(I)表示的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体：
其中，W选自氢原子；
R表示如下通式(b)所示的基团：
Figure PCTCN2020117074-appb-000012
Figure PCTCN2020117074-appb-000013
部分通过连接基团与M 3基团连接；
X 1、X 2分别独立地选自CR a或NR b，X 3为C＝O；
X 4选自C；X 5选自C；
M 3选自：氢原子、羟基、卤素原子、硝基、C 1-4烷基、C 2-6烯基、C 2-6炔基、3-6元环烷基、5-6元杂环基；
Cy 2选自任选被一至多个R 2取代的
Figure PCTCN2020117074-appb-000014
R 2各自独立地选自氢原子、羟基、氟、氯、溴、C 1-4烷基；
Cy 3选自任选被一至多个R 3取代的
Figure PCTCN2020117074-appb-000015
Figure PCTCN2020117074-appb-000016
R 3各自独立地选自氢原子、羟基、氟、氯、溴、C 1-4烷基；
Cy 4选自任选被一至多个R 4取代的
Figure PCTCN2020117074-appb-000017
Figure PCTCN2020117074-appb-000018
R 4各自独立地选自氢原子、羟基、卤素原子、氨基、(C 1-4烷基) 1-2氨基-、C 1-4烷基、卤代C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷氧基、3-14元杂环基；
L为-O-；
R a不存在，或者在每次出现时，各自独立地选自氢原子、C 1-6烷基、卤代C 1-6烷基；
R b不存在，或者在每次出现时，各自独立地选自氢原子、C 1-6烷基；
n为0-1的整数；
优选地，X 1为N，X 2为CR a，X 3为C＝O；
优选地，X 1为CR a，X 2为N，X 3为C＝O；
优选地，X 1为CR a，X 2为CR a，X 3为C＝O。
更进一步具体地，本发明提供以下技术方案。
方案1.通式(I)表示的化合物或其药学上可接受的盐、酯、立体异 构体、互变异构体：
Figure PCTCN2020117074-appb-000019
其中，W选自氢原子或任选被取代基取代的C 1-6烷基；
R表示如下通式(b′)所示的基团：
Figure PCTCN2020117074-appb-000020
Figure PCTCN2020117074-appb-000021
部分通过连接基团与M 3基团连接；
X 1、X 2、X 3各自独立选自CR aR a、C＝O和NR b，且其中至少一个为C＝O；
X 4、X 5各自独立选自CR a或N；
M 3选自氢原子、氰基、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-OC(O)NR bR c、-NR bC(O)OR d、-NR bC(O)R d、-SO 2-NR bR c、-SO 2R d、-NR bSO 2R d；或任选被取代基取代的C 1-6烷基、任选被取代基取代的C 1-6烷氧基、任选被取代基取代的C 2-8烯基、任选被取代基取代的C 2-8炔基、-任选被取代基取代的C 1-6烷基-R’、-任选被取代基取代的C 1-6烷氧基-R’、-O-R’、-C(O)-R’、-SO 2-R’、-NR bC(O)-R’、任选被取代基取代的3-12元环烷基、任选被取代基取代的3-12元环烯基、任选被取代基取代的3-14元杂环基、任选被取代基取代的6-14元芳基、任选被取代基取代的5-10元杂芳基；当
Figure PCTCN2020117074-appb-000022
部分的N在式(b′)中连接有双键时，M 3不存在；
Cy 2选自任选被一个以上R 2取代的3-12元环烷基、任选被一个以 上R 2取代的3-12元环烯基、任选被一个以上R 2取代的3-14元杂环基、任选被一个以上R 2取代的6-14元芳基和任选被一个以上R 2取代的5-10元杂芳基，R 2各自独立的选自氢原子、氰基、羟基、巯基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-OC(O)NR bR c、-NR bC(O)R d、-NR bC(O)OR d、-SO 2-NR bR c、-SO 2R d、-NR bSO 2R d、任选被取代基取代的C 1-6烷基、任选被取代基取代的C 1-6烷氧基、任选被取代基取代的C 2-8烯基、任选被取代基取代的C 2-8炔基、-任选被取代基取代的C 1-6烷基-R’、-任选被取代基取代的C 1-6烷氧基-R’、-O-R’、-C(O)-R’、-SO 2-R’、-NR bC(O)-R’、任选被取代基取代的3-12元环烷基、任选被取代基取代的3-12元环烯基、任选被取代基取代的3-14元杂环基、任选被取代基取代的6-14元芳基、任选被取代基取代的5-10元杂芳基；
Cy 3选自任选被一个以上R 3取代的5-10元杂芳基团，R 3各自独立的选自氢原子、氰基、羟基、巯基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-OC(O)NR bR c、-NR bC(O)R d、-NR bC(O)OR d、-SO 2-NR bR c、-SO 2R d、-NR bSO 2R d、任选被取代基取代的C 1-6烷基、任选被取代基取代的C 1-6烷氧基、任选被取代基取代的C 2-8烯基、任选被取代基取代的C 2-8炔基、-任选被取代基取代的C 1-6烷基-R’、-任选被取代基取代的C 1-6烷氧基-R’、-O-R’、-C(O)-R’、-SO 2-R’、-NR bC(O)-R’、任选被取代基取代的3-12元环烷基、任选被取代基取代的3-12元环烯基、任选被取代基取代的3-14元杂环基、任选被取代基取代的6-14元芳基、任选被取代基取代的5-10元杂芳基；
Cy 4选自任选被一个以上R 4取代的3-12元环烷基、任选被一个以上R 4取代的3-14元杂环基、任选被一个以上R 4取代的5-14元杂芳基和任选被一个以上R 4取代的6-14元芳基，R 4各自独立的选自氢原子、氰基、羟基、巯基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-OC(O)NR bR c、-NR bC(O)R d、-NR bC(O)OR d、-SO 2-NR bR c、-SO 2R d、-NR bSO 2R d、任选被取代基取代的C 1-6烷基、任选被取代基取代的C 1-6烷氧基、任选被取代基取代的C 2-8烯基、任选被取代基取代的C 2-8炔基、-任选被取代基取代的C 1-6烷基-R’、-任选被取代基取代的C 1-6烷氧基-R’、-O-R’、-C(O)-R’、-SO 2-R’、-NR bC(O)-R’、任选被取代基取代的3-12元环烷基、任选被取代基取代的3-12元环烯基、任选被取代 基取代的3-14元杂环基、任选被取代基取代的6-14元芳基、任选被取代基取代的5-10元杂芳基，或者，两个R 4可以与所连接的原子形成5-14元环状基团；
L选自-NR b-、-O-、-S-、-(CR aR a) m-，m选自1-3的整数；
R a不存在，或者在每次出现时，各自独立地选自氢原子、氰基、羟基、巯基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-OC(O)NR bR c、-NR bC(O)R d、-NR bC(O)OR d、-SO 2-NR bR c、-SO 2R d、-NR bSO 2R d、任选被取代基取代的C 1-6烷基、任选被取代基取代的C 1-6烷氧基、任选被取代基取代的C 2-8烯基、任选被取代基取代的C 2-8炔基、-任选被取代基取代的C 1-6烷基-R’、-任选被取代基取代的C 1-6烷氧基-R’、-O-R’、-C(O)-R’、-SO 2-R’、-NR bC(O)-R’、任选被取代基取代的3-12元环烷基、任选被取代基取代的3-12元环烯基、任选被取代基取代的3-14元杂环基、任选被取代基取代的6-14元芳基、任选被取代基取代的5-10元杂芳基；
R b、R c各自不存在，或者在每次出现时，各自独立地选自氢原子、羟基、任选被取代基取代的C 1-6烷基、-任选被取代基取代的C 1-6烷基-R’、-C(O)-R’、-SO 2-R’、任选被取代基取代的3-12元环烷基、任选被取代基取代的3-12元环烯基、任选被取代基取代的3-14元杂环基、任选被取代基取代的6-14元芳基、任选被取代基取代的5-10元杂芳基；
R d不存在，或者在每次出现时，各自独立地选自羟基、卤素原子、氨基、-氨基(任选被取代基取代的C 1-6烷基) 1-2、任选被取代基取代的C 1-6烷基、任选被取代基取代的C 1-6烷氧基、-任选被取代基取代的C 1-6烷基-R’、-任选被取代基取代的C 1-6烷氧基-R’、-O-R’、任选被取代基取代的3-12元环烷基、任选被取代基取代的3-12元环烯基、任选被取代基取代的3-14元杂环基、任选被取代基取代的6-14元芳基、任选被取代基取代的5-10元杂芳基；
R’各自独立地选自任选被取代基取代的3-12元环烷基、任选被取代基取代的3-12元环烯基、任选被取代基取代的3-14元杂环基、任选被取代基取代的6-14元芳基和任选被取代基取代的5-10元杂芳基；
q为0-4的整数；
n为0-4的整数；
所述“任选被取代基取代”中的取代基各自独立地选自：羟基、巯基、 氨基、羧基、氰基、硝基、卤素原子、C 1-6烷基、C 1-6烷氧基C 1-6烷基、C 1-6烷氧基、C 1-6烷基C 1-6烷氧基、C 1-6烷氧基C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷基氨基羰基、(C 1-6烷基) 2氨基羰基、C 1-6烷基羰基、C 1-6烷基羰基氧基、C 1-6烷基羰基氨基、C 1-6烷基磺酰氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 1-6烷基磺酰基、C 1-6烷基硫基、3-12元环烷基、6-14元芳基、3-12元杂环基、5-10元杂芳基和氧代基。
方案2.根据方案1所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体，其中，
当M 3表示的基团中携带芳基时，Cy 2不表示杂环基；
当M 3表示任选被取代基取代的C 1-6烷基时，X 4表示CR a；
当M 3表示的基团中携带芳基时，X 4表示CR a；
当M 3表示的基团中携带环烷基时，X 4表示CR a；
当M 3表示任选被取代基取代的C 1-6烷基、X 1表示CR aR a时，X 1上的R a基团中不具有羰基；
当M 3表示的基团中携带芳基时，X 2不表示C＝O。
方案3.根据前述任一方案所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体，
M 3选自氢原子、氰基、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-OC(O)NR bR c、-NR bC(O)R d、-NR bC(O)OR d、-SO 2-NR bR c、-SO 2R d、-NR bSO 2R d；或任选被取代基取代的C 1-6烷基、任选被取代基取代的C 1-6烷氧基、任选被取代基取代的C 2-8烯基、任选被取代基取代的C 2-8炔基、任选被取代基取代的3-8元环烷基、任选被取代基取代的3-14元杂环基；
Cy 2选自任选被一个以上R 2取代的6-14元芳基、任选被一个以上R 2取代的5-10元杂芳基，R 2各自独立地选自氢原子、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-NR bC(O)OR d、任选被取代基取代的C 1-6烷基、任选被取代基取代的C 1-6烷氧基；优选的是，R 2各自独立地选自氢原子、羟基、卤素原子、C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基；优选的是，R 2各自独立地选自氢原子、羟基、氟、氯、溴、C 1-4烷基；
Cy 3选自任选被一个以上R 3取代的5-10元杂芳基团，R 3各自独立地选自氢原子、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、 -C(O)NR bR c、-NR bC(O)R d、任选被取代基取代的C 1-6烷基、任选被取代基取代的C 1-6烷氧基；优选的是，R 3各自独立地选自氢原子、羟基、卤素原子、C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基；优选的是，R 3各自独立地选自氢原子、羟基、氟、氯、溴、C 1-4烷基；
Cy 4选自任选被一个以上R 4取代的5-10元杂环基、任选被一个以上R 4取代的5-10元杂芳基和任选被一个以上R 4取代的6-10元芳基；R 4各自独立地选自氢原子、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-NR bC(O)R d、任选被取代基取代的C 1-6烷基、任选被取代基取代的C 1-6烷氧基、任选被取代基取代的5-10元杂芳基；优选的是，R 4各自独立地选自氢原子、羟基、卤素原子、氨基、(C 1-6烷基) 1-2氨基-、C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6烷氧基C 1-6烷基、C 1-6烷基C 1-6烷氧基、C 1-6烷氧基C 1-6烷氧基、5-6元杂芳基；优选的是，R 4选自氢原子、羟基、巯基、卤素原子、氨基、(C 1-4烷基) 1-2氨基-、C 1-4烷基、卤代C 1-4烷基、C 1-4烷氧基、C 1-4烷氧基C 1-4烷基、C 1-4烷基C 1-4烷氧基、C 1-4烷氧基C 1-4烷氧基、卤代C 1-4烷氧基、吡咯基、呋喃基、噻吩基、噁唑基、异噁唑基、吡唑基、咪唑基、吡啶基、嘧啶基、哒嗪基；
L选自-NR b-、-O-和-S-；
R a不存在，或者在每次出现时，各自独立地选自氢原子、卤素原子、羟基、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-NR bC(O)R d、任选被取代基取代的C 1-6烷基、任选被取代基取代的C 1-6烷氧基；优选的是，R a不存在，或者在每次出现时，各自独立地选自氢原子、羟基、卤素原子、羧基、硝基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基，优选的是，R a不存在，或者在每次出现时，各自独立地选自氢原子、C 1-6烷基、C 1-6烷氧基；
R b、R c各自不存在，或者在每次出现时，各自独立地选自氢原子、任选被取代基取代的C 1-6烷基；优选的是，R b、R c各自不存在，或者在每次出现时，各自独立地选自氢原子、C 1-6烷基、卤代C 1-6烷基；优选的是，R b、R c各自不存在，或者在每次出现时，各自独立地选自氢原子、C 1-6烷基；
R d不存在，或者在每次出现时，各自独立地选自羟基、卤素原子、 氨基、-氨基(任选被取代基取代的C 1-6烷基) 1-2、任选被取代基取代的C 1-6烷基、任选被取代基取代的C 1-6烷氧基；优选的是，R d不存在，或者在每次出现时，各自独立地选自羟基、氨基、-氨基(C 1-6烷基) 1-2、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基；优选的是，R d不存在，或者在每次出现时，各自独立地选自羟基、氨基、C 1-4烷基、卤代C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷氧基；
R’选自任选被取代基取代的3-8元环烷基、任选被取代基取代的3-8元环烯基、任选被取代基取代的3-10元杂环基、任选被取代基取代的6-10元芳基和任选被取代基取代的5-6元杂芳基；优选的是，R’选自任选被取代基取代的3-6元环烷基、任选被取代基取代的4-7元杂环基、任选被取代基取代的6-10元芳基和任选被取代基取代的5-6元杂芳基；优选的是，R’选自环丙基、环丁基、环戊基、环己基、苯基、萘基、氧杂环丙基、氧杂环丁基、氧杂环戊基、氧杂环己基、氧杂环庚基、吡咯基、呋喃基、噻吩基、噁唑基、异噁唑基、吡唑基、噻唑基、吡啶基、嘧啶基、哒嗪基；
“任选被取代基取代”中的取代基各自独立地选自：羟基、巯基、氨基、羧基、氰基、硝基、卤素原子、C 1-6烷基、C 1-6烷氧基C 1-6烷基、C 1-6烷氧基、C 1-6烷基C 1-6烷氧基、C 1-6烷氧基C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷基氨基羰基、(C 1-6烷基) 2氨基羰基、C 1-6烷基羰基、C 1-6烷基羰基氧基、C 1-6烷基羰基氨基、C 1-6烷基磺酰氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 1-6烷基磺酰基、C 1-6烷基硫基、3-8元环烷基、6-10元芳基、3-8元杂环基、5-6元杂芳基和氧代基；优选的是，“任选被取代基取代”中的取代基各自独立地选自：羟基、巯基、氨基、羧基、氰基、硝基、卤素原子、C 1-4烷基、C 1-4烷氧基C 1-4烷基、C 1-4烷氧基、C 1-4烷基C 1-4烷氧基、C 1-4烷氧基C 1-4烷氧基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、C 1-4烷基氨基羰基、(C 1-4烷基) 2氨基羰基、C 1-4烷基羰基、C 1-4烷基羰基氧基、C 1-4烷基羰基氨基、C 1-4烷基磺酰氨基、卤代C 1-4烷基、卤代C 1-4烷氧基、C 1-4烷基磺酰基、C 1-4烷基硫基、环丙基、环丁基、环戊基、环己基、环庚基、苯基、萘基、氧杂环丙基、氧杂环丁基、氧杂环戊基、氧杂环己基、氧杂环庚基、吡咯基、呋喃基、噻吩基、噁唑基、异噁唑基、吡唑基、噻唑基、吡啶基、嘧啶基、哒嗪基和氧代基，
n为0、1、2、3或4，
q为0、1、2、3或4。
方案4.根据前述任一方案所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体，其中，
X 1为NR b，X 2为CR aR a，X 3为C＝O；或者
X 1为CR aR a，X 2为NR b，X 3为C＝O；或者
X 1为C＝O，X 2为CR aR a，X 3为C＝O；或者
X 1为CR aR a，X 2为C＝O，X 3为C＝O；或者
X 1为CR aR a，X 2为CR aR a，X 3为C＝O；或者
X 1为C＝O，X 2为CR aR a，X 3为CR aR a；或者
X 1为CR aR a，X 2为C＝O，X 3为CR aR a。
方案5.根据前述任一方案所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体，其中，
X 4选自N，X 5选自CR a；或者
X 4选自CR a，X 5选自CR a；或者
X 4选自N，X 5选自N；或者
X 4选自CR a，X 5选自N。
方案6.根据前述任一方案所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体，其中，
M 3选自氢原子、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-NR bC(O)R d；或任选被取代基取代的C 1-6烷基、任选被取代基取代的C 2-8烯基、任选被取代基取代的C 2-8炔基、任选被取代基取代的3-8元环烷基、任选被取代基取代的3-8元杂环基；
Cy 2选自任选被一个以上R 2取代的苯基、任选被一个以上R 2取代的5-6元杂芳基，R 2各自独立地选自氢原子、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-NR bC(O)R d；或任选被取代基取代的C 1-6烷基、任选被取代基取代的C 1-6烷氧基；
Cy 3选自任选被一个以上R 3取代的5-6元杂芳基，R 3各自独立地选自氢原子、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-NR bC(O)R d；或任选被取代基取代的C 1-6烷基、任选被取代基取代的C 1-6烷氧基；
Cy 4选自任选被一个以上R 4取代的5-9元杂芳基，R 4各自独立地 选自氢原子、羟基、卤素原子、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-NR bC(O)R d；或任选被取代基取代的C 1-6烷基、任选被取代基取代的C 1-6烷氧基、任选被取代基取代的5-6元杂芳基；
L选自-O-；
R a不存在，或者在每次出现时，各自独立地选自氢原子，或任选被取代基取代的C 1-6烷基；
R b、R c不存在，或者在每次出现时，各自独立地选自氢原子，或任选被取代基取代的C 1-6烷基；
R d不存在，或者在每次出现时，各自独立地选自氢原子，或任选被取代基取代的C 1-6烷基；
n为0-2的整数；
所述“任选被取代基取代”中的取代基各自独立地选自：羟基、氨基、羧基、氰基、硝基、卤素原子、C 1-6烷基、C 1-6烷氧基。
方案7.根据前述任一方案所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体，其中，
Cy 3表示任选被一个以上R 3取代的
Figure PCTCN2020117074-appb-000023
所示的基团，式中，
Figure PCTCN2020117074-appb-000024
表示单键或双键，Y 2、Y 3、Y 6和Y 7各自独立地选自CR aR a或NR b，且其中至少一个为NR b，优选的是，Cy 3表示任选被一个以上R 3取代的
Figure PCTCN2020117074-appb-000025
所示的基团，Y 2、Y 3、Y 6、Y 7各自独立的选自CH或N，并且至少有一个为N；
R 3各自独立地选自氢原子、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-NR bC(O)R d、任选被取代基取代的C 1-6烷基、任选被取代基取代的C 1-6烷氧基；优选的是，R 3各自独立地选自氢原子、羟基、卤素原子、C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基；优选的是，R 3各自独立地选自氢原子、羟基、氟、氯、溴、C 1-4烷基。
方案8.根据前述任一方案所述的化合物或其药学上可接受的盐、 酯、立体异构体、互变异构体，其中，
Cy 4表示任选被一个以上R 4取代的
Figure PCTCN2020117074-appb-000026
所示的基团，式中，
Figure PCTCN2020117074-appb-000027
表示单键或双键，Y 4、Y 5各自独立地选自CR aR a或NR b，环B形成五元环，当Y 4、Y 5为CR aR a时，环B形成含有NR b的五元杂芳环，优选的是，Cy 4表示任选被一个以上R 4取代的
Figure PCTCN2020117074-appb-000028
式中，Y 4和Y 5各自独立地为CH，环B为含有1-2个NR b的五元杂芳环；
R 4各自独立地选自氢原子、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-NR bC(O)R d、任选被取代基取代的C 1-6烷基、任选被取代基取代的C 1-6烷氧基、5-6元杂芳基；优选的是，R 4各自独立地选自氢原子、羟基、卤素原子、氨基、(C 1-6烷基) 1-2氨基-、C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6烷氧基C 1-6烷基、C 1-6烷基C 1-6烷氧基、C 1-6烷氧基C 1-6烷氧基、吡咯基、呋喃基、噻吩基、噁唑基、异噁唑基、吡唑基、咪唑基、噻唑基、吡啶基、嘧啶基、哒嗪基；优选的是，R 4选自氢原子、羟基、巯基、卤素原子、氨基、(C 1-4烷基) 1-2氨基-、C 1-4烷基、卤代C 1-4烷基、C 1-4烷氧基、C 1-4烷氧基C 1-4烷基、C 1-4烷基C 1-4烷氧基、C 1-4烷氧基C 1-4烷氧基、卤代C 1-4烷氧基、吡咯基、呋喃基、噻吩基、噁唑基、异噁唑基、吡唑基、咪唑基。
方案9.根据前述任一方案所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体，其中，
M 3选自：氢原子、羟基、卤素原子、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、3-6元环烷基、5-6元杂环基；
Cy 2选自任选被一个以上R 2取代的
Figure PCTCN2020117074-appb-000029
R 2各自独立地选自羟基、氟、氯、溴、C 1-4烷基；
Cy 3选自任选被一个以上R 3取代的
Figure PCTCN2020117074-appb-000030
Figure PCTCN2020117074-appb-000031
优选为任选被一个以上R 3取代的以下基团：
Figure PCTCN2020117074-appb-000032
*端与N相连，·端与L相连，R 3各自独立地选自羟基、氟、氯、溴、C 1-4烷基；
Cy 4选自任选被一个以上R 4取代的
Figure PCTCN2020117074-appb-000033
Figure PCTCN2020117074-appb-000034
R 4各自独立地选自羟基、卤素原子、氨基、(C 1-4烷基) 1-2氨基-、C 1-4烷基、卤代C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷氧基、吡咯基、呋喃基、噻吩基、噁唑基、异噁唑基、吡唑基、咪唑基。
方案10.根据前述任一方案所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体，其中，Cy 4选自任选被一个以上R 4取代的5-9元杂环基、任选被一个以上R 4取代的5-9元杂芳基。
方案11.根据前述任一方案所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体，其中，M 3表示甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、乙烯基、烯丙基或丙烯基。
在本发明的一个实施方式中，提供式(I)所示的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体，所述化合物选自：
Figure PCTCN2020117074-appb-000035
Figure PCTCN2020117074-appb-000036
Figure PCTCN2020117074-appb-000037
Figure PCTCN2020117074-appb-000038
本发明还提供一种药物组合物，其包含上述式(I)任一项所示的化合物、其药学上可接受的盐、酯、立体异构体、互变异构体中的至少一种。
本发明还提供包含上述式(I)任一项所示的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体的药物组合物，其可以任选含有一种或多种药用载体。
本发明还提供包含上述式(I)任一项所示的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体的药学上可接受的剂型，其任选含有一种或多种药用载体。
在本发明的一个实施方式中，提供包含上述式(I)任一项所示的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体的药物组合物或剂型，其可以任选地含有至少一种第二治疗活性剂。
在本发明的一个实施方式中，所述的第二治疗活性剂为选自以下的至少一种：抗代谢物、生长因子抑制剂、有丝分类抑制剂、抗肿瘤激素类、烷化剂类、金属铂类、拓扑异构酶抑制剂、激素药、免疫调节剂、肿瘤抑制基因、癌疫苗、免疫检查点抑制剂或肿瘤免疫治疗相关的抗体、小分子药物和细胞疗法药剂。
在本发明的一个实施方式中，所述的药物组合物或剂型可以以本领域公知的任何合适的给药方式，例如可以通过口服，肠胃外(包括皮下、肌内、静脉内、动脉内、皮内、鞘内和硬膜外)，透皮，直肠，鼻，经肺，局部(包括口腔和舌下)，阴道，腹膜内，肺内和鼻内等给药等方式，施用于需要治疗和/或预防的患者或受试者。
在本发明的一个实施方式中，所述药物组合物或剂型可制成常规的固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；也可制成口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。制成口服制剂时，可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。用于肠胃外给药时，所述药物组合物可制成注射剂、注射用无菌粉末与注射用浓溶液。制成注射剂时，可采用现有制药领域中的常规方法生产，配置注射剂时，可以不加入附加剂，也可以根据药物的性质加入适宜的附加剂。用于直肠给药时，所述药物组合物可制成栓剂等。用于经肺给药时，所述药物组合物可制成吸入剂或喷雾剂等。
本发明的一个实施方式中，提供上述式(I)任一项所示的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、上述药物组合物、上述剂型用于制备治疗和/或预防由TAM家族激酶受体和/或其配体异常表达所介导的疾病的药物中的用途，所述的TAM家族激酶受体和/或其配体异常表达所介导的疾病包括以下疾病中的至少一种：肿瘤、肿瘤免疫、子宫内膜异位、血管疾病/损伤、牛皮癣、视觉缺陷/病变(包括黄斑变性、糖尿病及早产等原因所致)、肾脏疾病、类风湿性关节炎、骨质疏松症等相关疾病。
本发明的一个实施方式中，提供上述式(I)任一项所示的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、上述药物组合 物、上述剂型用于治疗和/或预防由TAM家族激酶受体和/或其配体异常表达所介导的疾病的方法，所述的TAM家族激酶受体和/或其配体异常表达所介导的疾病包括以下疾病中的至少一种：肿瘤、肿瘤免疫、子宫内膜异位、血管疾病/损伤、牛皮癣、视觉缺陷/病变(包括黄斑变性、糖尿病及早产等原因所致)、肾脏疾病、类风湿性关节炎、骨质疏松症等相关疾病。
本发明的一个实施方式中，提供上述式(I)任一项所示的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、上述药物组合物、上述剂型用于制备治疗和/或预防由TAM家族激酶/和Ron激酶受体和/或其配体异常表达所介导的疾病的药物中的用途，所述的TAM家族激酶/和Ron激酶受体和/或其配体异常表达所介导的疾病包括以下疾病中的至少一种：肿瘤、肿瘤免疫、子宫内膜异位、血管疾病/损伤、牛皮癣、视觉缺陷/病变(包括黄斑变性、糖尿病及早产等原因所致)、肾脏疾病、类风湿性关节炎、骨质疏松症等相关疾病。
本发明的一个实施方式中，提供上述式(I)任一项所示的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、上述药物组合物、上述剂型用于治疗和/或预防由TAM家族激酶/和Ron激酶受体和/或其配体异常表达所介导的疾病的方法，所述的TAM家族激酶/和Ron激酶受体和/或其配体异常表达所介导的疾病包括以下疾病中的至少一种：肿瘤、肿瘤免疫、子宫内膜异位、血管疾病/损伤、牛皮癣、视觉缺陷/病变(包括黄斑变性、糖尿病及早产等原因所致)、肾脏疾病、类风湿性关节炎、骨质疏松症等相关疾病。
本发明的一个实施方式中，所述的肿瘤包括肉瘤、淋巴瘤和癌症，具体可以为呼吸系统癌症、间皮瘤、神经系统肿瘤、皮肤恶性肿瘤、骨癌、鳞状上皮细胞癌、乳腺癌、头颈癌、泌尿及生殖系统癌症、胆道系统癌症、肉瘤、消化系统癌症、白血病、淋巴瘤、骨髓增生异常综合征、原位癌、细胞瘤。
本发明的一个实施方式中，所述的肿瘤包括肉瘤、淋巴瘤和癌症，具体可以为肺癌、甲状腺癌、口腔癌、咽癌、腹膜癌、胶质瘤、神经纤维瘤病、皮肤癌、黑色素瘤、多发性骨髓瘤、肺鳞癌、食管鳞癌、乳腺导管癌、脑癌、卵巢癌、宫体癌、子宫内膜癌、前列腺癌、睾丸癌、膀胱癌、肾癌、肾盂癌、胆管癌、胆囊癌、骨肉瘤、脂肪肉瘤、 尤文肉瘤、肝癌、胃癌、食管癌、大肠癌、胰腺癌、贲门癌、胃肠道间质瘤、大肠绒毛腺瘤、急性白血病、慢性白血病、非霍奇金恶性淋巴瘤(NHL)、T/NK细胞淋巴瘤、霍奇金淋巴瘤(HL)、骨髓增生异常综合征、原位癌、细胞瘤。
发明效果
本发明的化合物对于TAM家族激酶具有抑制作用，可用于治疗和/或预防由TAM家族激酶受体和/或其配体异常表达所介导的疾病。另外，本发明的化合物还可以靶向Ron激酶，对于Ron激酶具有抑制作用。通过本发明的化合物，可用于治疗和/或预防由TAM家族激酶/和Ron激酶受体和/或其配体异常表达所介导的疾病。本发明化合物通过靶向抑制TAM家族激酶/和Ron激酶，逆转肿瘤微环境中的免疫抑制环境，抑制肿瘤的生长、迁移、和/或耐药表现，发挥肿瘤免疫效应和抗肿瘤疗效。并且，本发明的化合物可以选择性地作用于TAM家族激酶/和Ron激酶，而避免对于其他激酶的不必要的抑制作用。
进而，本发明的化合物在体内的半衰期长，具有优异的体内代谢稳定性，成药性优异，因此本发明化合物可以提高药物疗效，减轻患者的服药负担，提高患者的顺从性。
具体实施方式
下面将结合具体实施方式对本发明的实施方案进行更为详细的说明，但是本领域的技术人员将会理解，下列描述的具体实施方式仅用于说明本发明，而不应视为对本发明的保护范围的限定。相反，本发明意图涵盖可被包括在由权利要求所限定的本发明范围之内的所有替代、修改和等同的方式。在没有特别说明的情况下，本发明的各实施方案可以以任意地方式进行组合，由此而得的技术方案的转换、变形、改变也包括在本发明的范围之中，并且并未超出本发明的范围。
在本发明的上下文中，除非另有明确定义，或者该含义超出了本领域技术人员的理解范围，3个碳原子以上的烃或烃衍生的基团(比如丙基、丙氧基、丁基、丁烷、丁烯、丁烯基、己烷等)在未冠以词头“正”时均具有与冠以词头“正”时相同的含义。比如，丙基一般理解为正丙基，而丁基一般理解为正丁基，除非另有明确。
本说明书提到的所有出版物、专利申请、专利和其它参考文献全都引于此供参考。除非另有定义，本说明书所用的所有技术和科学术语都具有本领域技术人员常规理解的含义。在有冲突的情况下，以本说明书的定义为准。
在本说明书的上下文中，除了明确说明的内容之外，未提到的任何事宜或事项均直接适用本领域已知的那些而无需进行任何改变。而且，本文描述的任何实施方式均可以与本文描述的一种或多种其他实施方式自由结合，由此而形成的技术方案或技术思想均视为本发明原始公开或原始记载的一部分，而不应被视为是本文未曾披露或预期过的新内容，除非本领域技术人员认为该结合是明显不合理的。
本发明中，“C a-b基团”(a和b表示1以上的整数，a＜b)的表述表示“基团”存在a-b个碳原子，例如，C 1-4烷基，即表示碳原子数为1-4的烷基，C 1-4烷氧基，即表示碳原子数为1-4的烷氧基，C 3-10环烷基，即表示碳原子数为3-10的环烷基，C 1-4烷氧基C 1-4烷基，即表示碳原子数为1-4的烷氧基与碳原子数为1-4的烷基键合而成的基团。
本发明中，“基”和“基团”表示一价基团或者根据需要的符合化合价的二价以上的基团，例如“环烷基(也表述为环烷基团)”包括从其中去除一个氢原子而得到的一价基团，也包括从其中的相同的碳原子或不同的两个以上碳原子上去除两个以上氢原子而得到的二价以上的基团。当“环烷基”作为末端基团时，其自然为一价基团，当环烷基在结构中作为连接基团时，其为二价以上的基团。本发明中，一价或二价以上的基团通常是指一价基团或二价基团，但是根据需要，该基团可以为更高的化合价(例如三价、四价、五价、六价等)。本领域技术人员可以毫无疑义地的确定“基”和“基团”所表示价态数。在本文所述的“去除一个以上氢原子而衍生得到”基团是指，去除一个氢原子而得到的一价基团、去除两个氢原子而得到的二价基团、去除三个氢原子而得到的三价基团、去除四个氢原子而得到的四价基团等，可以根据基团的化合价(例如1价、2价、3价、4价等)确定所要去除的氢原子数目。
本发明所述的“卤素原子”是指氟原子、氯原子、溴原子、碘原子。优选为氟原子、氯原子、溴原子。
本发明所述的“卤代”是指取代基中的任意碳原子上的氢原子被一个或多个相同或不同的卤素原子取代。“卤素原子”如前文所定义。
本发明所述的“C 1-6烷基”是指从含有1-6个碳原子的烷烃部分去除一个以上氢原子而衍生得到的直链或支链的烷基，其包括直链C 1-6烷基和支链C 1-6烷基。事实上，本领域技术人员公知的是，C 1-6烷基具有支链(支链C 1-6烷基)的情况下，其至少具有3个碳原子。作为“C 1-6烷基”的例子，例如，可以列举甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3，3-二甲基丁基、2，2-二甲基丁基、1，1-二甲基丁基、1，2-二甲基丁基、1，3-二甲基丁基、2，3-二甲基丁基、2-乙基丁基和1-甲基-2-甲基丙基等。“C 1-6烷基”优选地包括“C 1-4烷基”，所述“C 1-4烷基”是指含有1-4个碳原子的上述实例。
本发明所述的“羟基C 1-6烷基”、“氰基C 1-6烷基”、“氨基C 1-6烷基”、“C 1-6烷基氨基C 1-6烷基”、“卤代C 1-6烷基”、“C 1-6烷氧基C 1-6烷基”是指一个以上羟基、氰基、氨基、C 1-6烷基氨基、卤素、C 1-6烷氧基各自独立地替代C 1-6烷基上的氢原子所形成的基团。
“C 1-6烷基氨基”、“(C 1-6烷基) 2氨基”、“C 1-6烷基氨基羰基”、“C 1-6烷基羰基”、“C 1-6烷基羰基氧基”、“C 1-6烷基磺酰氨基”、“C 1-6烷基磺酰基”、“C 1-6烷基硫基”等包含“C 1-6烷基”的基团是指C 1-6烷基各自与-NH-、-CO-O-、-NH-CO-、-CO-、-SO 2NH-、-SO 2-、-S-等相应的基团连接形成的基团。例如，可以列举上述“C 1-6烷基”中所列举的基团各自与-NH-、-CO-O-、-NH-CO-、-CO-、-SO 2NH-、-SO 2-、-S-等相应的基团连接形成的基团。
本发明所述的“C 2-8烯基”是指从含有至少一个碳碳双键的2～8个碳原子的烯烃部分去除一个以上氢原子而衍生得到的直链或支链的烯烃基，例如，可以列举乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、1，3-丁二烯-1-基、1-戊烯-3-基、2-戊烯-1-基、3-戊烯-1-基、3-戊烯-2-基、1，3-戊二烯-1-基、1，4-戊二烯-3-基、1-己烯-3-基、1，4-己二烯-1-基。优选的是，“C 2-8烯基”中含有一个碳碳双键。
本发明所述的“C 2-8炔基”是指从含有至少一个碳碳叁键的2～8个碳原子的炔烃部分去除一个以上氢原子而衍生得到的直链或支链的炔烃基，例如，可以列举乙炔基、丙炔基、2-丁炔-1-基、2-戊炔-1-基、3-戊炔-1-基、4-甲基-2-戊炔-1-基、2-己炔-1-基、2-己炔-2-基、3-己炔-1- 基、3-己炔-2-基等。优选的是，“C 2-8炔基”中含有一个碳碳叁键。
本发明所述的“C 1-6烷氧基”是指前文所定义的“C 1-6烷基”通过氧原子与母体部分连接的基团，即“C 1-6烷基-O-”基团，例如，可以列举甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、正戊氧基、新戊氧基和正己氧基等。所述的“C 1-4烷氧基”指含有1-4个碳原子的上述实例，即“C 1-4烷基-O-”基团。
本发明所述的“卤代C 1-6烷氧基”、“C 1-6烷氧基C 1-6烷氧基”、“C 1-6烷基C 1-6烷氧基”等包含“C 1-6烷氧基”的基团是指一个以上卤素原子、C 1-6烷氧基、C 1-6烷基等相应的基团各自分别独立地替代C 1-6烷氧基上的一个以上氢原子所形成的基团。
本发明所述的“(基团) 1-2氨基-”或者“-氨基(基团) 1-2”表示氨基(-NH 2)中的一个氢或者两个氢可以被基团取代。例如“-氨基(任选被取代基取代的C 1-6烷基) 1-2”表示-NH(任选被取代基取代的C 1-6烷基)、-N(任选被取代基取代的C 1-6烷基) 2，“(任选被取代基取代的C 1-4烷基) 1-2氨基-”表示(任选被取代基取代的C 1-4烷基)NH-、(任选被取代基取代的C 1-4烷基) 2N-。
本发明所述的“稠环”是指由两个或两个以上环状结构以并、螺、桥的连接方式所形成的多环系结构。所述的并环是指由两个或两个以上环状结构彼此公用两个相邻的环原子(即共用一个键)所形成的稠环结构。所述的桥环是指有两个或两个以上环状结构彼此共用两个非相邻的环原子所形成的稠环结构。所述的螺环是指由两个或两个以上环状结构彼此共用一个环原子所形成的稠环结构。
本发明所述的“环烷基”或“环烷基团”(以下通称为“环烷基”)是指从环烷烃衍生得到的一价基团或(根据需要的)二价以上的基团，所述环烷烃包括单环环烷烃或者稠环环烷烃。其例如为“3-12元环烷基”，即可以具有3、4、5、6、7、8、9、10、11或12个成环碳原子。在不特别指明的情况下，某元环烷基，包括可能形成的所有单环、稠环(包括以并、螺、桥的形式稠合)的情形。环烷基可以是3-12元的一价基团或(根据需要的)二价以上的基团，可以是3-10元的一价基团或(根据需要的)二价以上的基团、可以是3-8元的一价基团或(根据需要的)二价以上的基团、3-6元的一价基团或(根据需要的)二价以上的基团、4-6元的一价基团或(根据需要的)二价以上的基团、5-7元的一价基团或(根据需要的) 二价以上的基团。
具体而言，(一价或二价以上的)单环环烷基可以包括3-12元环烷基、3-10元环烷基、3-8元环烷基、3-6元环烷基、4-6元环烷基、5-6元环烷基、5-7元环烷基。其实例包括但不限于：环丙烷基、环丁烷基、环戊烷基、环己烷基、环庚烷基、环辛烷基、环戊烷-1，3-二基、环己烷-1，4-二基、环庚烷-1，4-二基等。
(一价或二价以上的)稠环环烷基包括并环环烷基、桥环烷基、螺环烷基。
(一价或二价以上的)并环环烷基可以为6-11元并环环烷基、7-10元并环环烷基，其的表示性例子包括但不限于由双环[3.1.1]庚烷、双环[2.2.1]庚烷、双环[2.2.2]辛烷、双环[3.2.2]壬烷、双环[3.3.1]壬烷和双环[4.2.1]壬烷衍生得到的一价基团或二价以上的基团。
(一价或二价以上的)桥环环烷基还可以是从6-12元桥环、7-11元桥环去掉一个氢原子而得的一价基团，或者根据需要从相同的碳原子上或不同的碳原子上去掉两个以上氢原子而得的二价以上的基团。
所述的桥环的实例包括但不限于：
Figure PCTCN2020117074-appb-000039
Figure PCTCN2020117074-appb-000040
(一价或二价以上的)螺环环烷基可以是从7-12元螺环、7-11元螺环去掉一个氢原子而得的一价基团，或者根据需要从相同的碳原子上或不同的碳原子上去掉两个以上氢原子而得的二价以上的基团。螺环实例包括但不限于：
Figure PCTCN2020117074-appb-000041
Figure PCTCN2020117074-appb-000042
本发明所述的“环烯基”是指在上述环烷基的基团中具有至少一个双键而得的基团。其例如可以是“3-12元环烯基”，即可以具有3、4、5、6、7、8、9、10、11或12个成环碳原子。在不特别指明的情况下，某元环烯基，包括可能形成的所有单环、稠环(包括以并、螺、桥的形式稠合)的情形。“3-12元环烯基”可以包括3-12元环烯基、3-8元环烯基、 4-6元环烯基、7-11元螺环烯基、7-11元并环烯基、6-11元桥环烯基等。环烯基的实例可以列举环丁烯基、环戊烯基、环戊二烯基、环己烯基、1，4-环己二烯-1-基、环庚烯基、1，4-环庚二烯-1-基、环辛烯基、1，5-环辛二烯-1-基等，但不限于此。
本发明所述的“杂环”包括在环内含有选自O、S、N中的至少一个(可以为1-5个、1-4个、1-3个、1-2个或者1个)杂原子作为成环原子的非芳香性的环状烃。其可以是具有3、4、5、6、7、8、9、10、11、12、13、14个成环原子的杂环。在环中可以任选地具有至少一个双键。本发明的杂环可以是单环系统，也可以是稠环系统(以并、螺、桥的形式稠合)。作为杂环的实例，可以列举吡咯啉、吡咯烷、哌啶、哌嗪、吗啉、硫代吗啉、四氢吡喃、二氢吡啶、二氢哒嗪、二噁烷、噁噻戊环、硫化环戊烷、四氢呋喃、四氢吡喃、四氢噻唑、四氢异噻唑等的单环杂环；二氢吲哚、异二氢吲哚、苯并吡喃、苯并二噁烷、四氢喹啉、苯并[d]噁唑-2(3H)-酮、四氢苯并噻吩等的稠合杂环。进而，可以列举将上述7-12元螺环、7-11元螺环、6-12元桥环、7-11元桥环中的至少一个环碳原子替换为选自O、S、N中的杂原子而得到的杂环，优选被1-4个杂原子替换。进而，还可以列举本发明下述的6-12元并环基、7-10元并环基、6-10元并环基、6-12元饱和并环基、6-12元螺杂环、7-11元螺杂环、6-12元饱和螺杂环、7-11元饱和螺杂环、6-12元桥杂环、7-11元桥杂环、6-12元饱和桥杂环，7-8元饱和桥杂环。
本发明所述的“杂环基”或“杂环基团”(以下通称为“杂环基”)是指从上述“杂环”衍生得到的一价或二价以上的基团。另外，本发明所述的“杂环基”还可以是上述环烷基或环烯基的至少一个环碳原子被选自O、S、N中的至少一个杂原子替代的非芳香性的一价或二价以上的环状基团，优选被1-4个杂原子替代。另外，杂环基同时还包括碳原子、硫原子被氧代、氮代的情况，例如碳原子、硫原子被C(＝O)、S(＝O)、S(＝O) 2、S(＝O)(＝N)替代。
具体而言，“杂环基”，可以为具有3、4、5、6、7、8、9、10、11、12、13、14个成环原子的杂环基团。其可以包括3-14元杂环基、3-10元杂环基、4-10元杂环基、3-8元杂环基、4-8元杂环基、4-6元杂环基、3-12元杂环基、4-12元杂环基、5-9元杂环基，包括单杂环基或者稠杂环基。
另外，“杂环基”是指一价或(根据需要的)二价以上单环杂环基、一价或(根据需要的)二价以上双环杂环基系统或一价或(根据需要的)二价以上的多环杂环基系统(也称为稠环系统)，包括饱和、部分饱和的杂环基，但不包括芳环。在不特别指明的情况下，包括可能形成的所有单环、稠环(包括以并、螺、桥的形式稠合)、饱和、部分饱和的情形。其可以是例如“3-14元杂环基”。
一价或(根据需要的)二价以上的单杂环基可以包括3-14元杂环基、3-12元杂环基、3-10元杂环基、4-10元杂环基、3-8元杂环基、3-8元饱和杂环基、4-8元杂环基、3-6元杂环基、4-6元杂环基、4-7元杂环基、5-7元杂环基、5-6元杂环基、5-6元含氧杂环基、3-8元含氮杂环基、5-6元含氮杂环基、5-6元饱和杂环基等。进而，还可以包括3-14元含氧杂环基、3-14元含氮杂环基、3-12元含氧杂环基、3-12元含硫杂环基、3-12元含砜基(S(O) 2)杂环基、3-12元含亚砜基(S(O))杂环基等。“杂环基”的实例包括但不限于氮杂环丙烷基、氧杂环丙烷基、硫杂环丙烷基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、四氢呋喃基、四氢吡咯基、四氢噻吩基、咪唑烷基、吡唑烷基、1，2-噁唑烷基、1，3-噁唑烷基、1，2-噻唑烷基、1，3-噻唑烷基、四氢-2H-吡喃基、四氢-2H-噻喃基、哌啶基、哌嗪基、吗啉基、1，4-二氧杂环己烷基、1，4-氧硫杂环己烷基；4，5-二氢异噁唑基、4，5-二氢噁唑基、2，5-二氢噁唑基、2，3-二氢噁唑基、3，4-二氢-2H-吡咯基、2，3-二氢-1H-吡咯基、2，5-二氢-1H-咪唑基、4，5-二氢-1H-咪唑基、4，5-二氢-1H-吡唑基、4，5-二氢-3H-吡唑基、4，5-二氢噻唑基、2，5-二氢噻唑基、2H-吡喃基、4H-吡喃基、2H-噻喃基、4H-噻喃基、2，3，4，5-四氢吡啶基、1，2-异噁嗪基、1，4-异噁嗪基或6H-1，3-噁嗪基等。
一价或(根据需要的)二价以上的稠杂环包括并杂环基、螺杂环基、桥杂环基，其可以是饱和的、部分饱和的或不饱和的，但不是芳香性的。稠杂环基可以包括上述杂环基稠合到6-14元芳基(例如苯环)、3-12元环烷基、3-12元环烯基、3-14元杂环基或3-14元杂芳基、5-6元的单环环烷基、5-6元单环环烯基、5-6元单环杂环基或5-6元单环杂芳基而得的杂环基。
所述的并杂环基可以包括6-12元并环基、7-10元并环基、6-10元并环基、6-12元饱和并环基，表示性实例包括但不限于：3-氮杂双环 [3.1.0]己烷基、3，6-二氮杂双环[3.2.0]庚烷基、3，8-二氮杂双环[4.2.0]辛烷基、3，7-二氮杂双环[4.2.0]辛烷基、八氢吡咯并[3，4-c]吡咯基、八氢吡咯并[3，4-b]吡咯基、八氢吡咯并[3，4-b][1，4]噁嗪基、八氢-1H-吡咯并[3，4-c]吡啶基、2，3-二氢苯并呋喃-2-基、2，3-二氢苯并呋喃-3-基、二氢吲哚-1-基、二氢吲哚-2-基、二氢吲哚3-基、2，3-二氢苯并噻吩-2基、八氢-1H-吲哚基、八氢苯并呋喃基、八氢环戊二烯并[c]吡咯、六氢环戊二烯并[c]呋喃、2，2-二氧代六氢环戊二烯并[c]噻吩、2-亚氨基-2氧代-八氢环戊烯并[c]噻吩。
所述的螺杂环基可以为从6-12元螺杂环、7-11元螺杂环、6-12元饱和螺杂环、7元饱和螺杂环去掉一个氢原子而得的一价基团，或者根据需要从相同碳原子上或不同的碳原子上分别去掉一个氢原子而得的二价以上的基团，螺杂环的实例包括但不限于：
Figure PCTCN2020117074-appb-000043
Figure PCTCN2020117074-appb-000044
所述的桥杂环基可以为从6-12元桥杂环、7-11元桥杂环、6-12元饱和桥杂环，7-8元饱和桥杂环去掉一个氢原子而得的一价基团，或者根据需要从相同的碳原子上或不同的碳原子上分别去掉一个氢原子而得的二价以上的基团，桥杂环的实例包括但不限于：
Figure PCTCN2020117074-appb-000045
Figure PCTCN2020117074-appb-000046
本发明所述“芳环”是指具有芳香性的碳环烃。从芳香性的碳环烃衍生得到的一价基团或根据需要得到的二价以上的基团，所述芳香性的碳环烃包括6-14元芳环、6-10元芳环、6-8元单环芳烃和8-14元稠环芳烃。6-8元单环芳基例如为苯基。8-14元稠环芳基例如为萘基、菲基、蒽基等。当为二价基团时，可以列举亚苯基、亚萘基等。
本发明所述的“芳基”或“芳族基团”(以下通称为“芳基”)是指含有从芳香性的碳环烃衍生得到的一价基团或根据需要的二价以上的基团。其包括6-14元芳基、6-10元芳基。6-14元芳基例如为苯基、萘基、菲基、蒽基。6-10元芳基例如苯基、萘基。当为二价基团时，可以列举亚苯基、亚萘基等。
本发明所述“杂芳环”是指具有至少一个(可以为1-5个、1-4个、1-3个、1-2个或1个)选自O、S、N的杂原子的成环原子的具有芳香性的环状烃。其可以为5、6、7、8、9、10、11、12、13或14元的芳香性的环状基团，优选具有1-3个杂原子。另外，本发明的杂芳环可以是单环系统，也可以是稠环系统(以并、螺、桥的形式稠合)。具体而言，可以列举吡咯、吡嗪、吡唑、吲哚、四唑、呋喃、噻吩、吡啶、咪唑、三唑、四唑、三嗪、哒嗪、嘧啶、吡嗪、异噁唑、噻唑、异噻唑、噻二唑、噁唑、噁二唑等的单环杂芳环；还可以列举异吲哚、吲唑、中氮茚、异二氢吲哚、喹啉、异喹啉、噌啉、2，3-二氮杂萘、喹唑啉、萘啶、喹喔啉、嘌呤、蝶啶、苯并咪唑、苯并异噁唑、苯并噁唑、苯并噁二唑、苯并异噻唑、苯并噻唑、苯并噻二唑、苯并呋喃、异苯并呋喃、苯并噻吩、苯并三唑、咪唑并吡啶、三唑并吡啶、咪唑并噻唑、吡嗪并哒嗪、苯并咪唑啉等的稠合杂芳环。
本发明所述的“杂芳基”或“杂芳基团”(以下通称为“杂芳基”)是指从上述“杂芳环”衍生的一价以上的基团。另外，本发明所述的“杂芳基”还可以是，含有选自O、S、N中的至少一个杂原子的成环原子数为5、6、7、8、9、10、11、12、13或14的芳香性的环状烃基。即，可以是5-14元杂芳基、5-10元杂芳基、5-9元杂芳基、5-6元杂芳基、6元杂芳基、6元含氮杂芳基。杂芳基中可以具有1、2、3、4或5个杂原子作为成环原子。另外，杂芳基还包括碳原子、硫原子被氧代、氮代的情况，例如碳原子、硫原子被C(＝O)、S(＝O)、S(＝O) 2、S(＝O)(＝N)替代。杂芳基包括单杂芳基和稠杂芳基，在不特别指明的情况下，某元杂芳基，包括可能形成的所有单环、稠环、全部芳香、部分芳香的情形。单杂芳基可以包括5-7元杂芳基、5-6元杂芳基、6元杂芳基、6元含氮杂芳基，其实例包括但不仅限于呋喃基、咪唑基、异噁唑基、噻唑基、异噻唑基、噁二唑基、噁唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、吡唑基、吡咯基、四唑基、噻二唑基、噻吩基、三唑基和三嗪基。 在某些实例中，稠杂芳基是指单环杂芳环稠合到苯基、环烯基、杂芳基、环烷基、杂环基所形成的基团，稠杂芳基可以为8-12元并杂芳基、9-10元并杂芳基、9元并杂芳基、9元含氮杂芳基(9元含氮并杂芳基)，例子包括但不限于苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并噁二唑基、苯并噻二唑基、苯并噻唑基、噌啉基、5，6-二氢喹啉-2-基、5，6-二氢异喹啉-1-基、呋喃并吡啶基、吲唑基、吲哚基、异吲哚基、异喹啉基、萘啶基、嘌呤基、喹啉基、5，6，7，8-四氢喹啉-2-基、5，6，7，8-四氢喹啉基、5，6，7，8-四氢喹啉-4-基、5，6，7，8-四氢异喹啉-1-基、噻吩并吡啶基、4，5，6，7-四氢苯并[c][1，2，5]噁二唑基和6，7-二氢苯并[c][1，2，5]噁二唑-4(5H)酮基。所述杂芳基也可以是从上述基团衍生的二价基团。
本发明所述的“5-14元环状基团”是指具有5、6、7、8、9、10、11、12、13、14个成环原子的基团，其可以是本发明上述的环烷基团、环烯基团、杂环基团、芳环基团、杂芳基团具有5-14个成环原子的情况。其具体可以包括5-10元环状基团、5-6元环状基团。另外，本发明所述的“5-6元环状基团”是指化学结构上可行的5-6个环原子的环状结构，环原子可以任选地选自C、N、O、S、C(＝O)、S(＝O)、S(＝O) 2、S(＝O)(＝N)，所形成的环状结构可以是单环，也可以是稠合的多环，可以是饱和的，也可以是部分饱和的，还可以是芳香的。其实例包括但不限于由吡咯啉、吡咯烷、哌啶、哌嗪、吗啉、硫代吗啉、四氢吡喃、二氢吡啶、二氢哒嗪、二噁烷、噁噻戊环、硫化环戊烷、四氢呋喃、四氢吡喃、四氢噻唑、四氢异噻唑、吡咯、吡嗪、吡唑、吲哚、四唑、呋喃、噻吩、吡啶、咪唑、三唑、四唑、三嗪、哒嗪、嘧啶、吡嗪、异噁唑、噻唑、异噻唑、噻二唑、噁唑、噁二唑、苯等衍生得到的基团。优选的是，其是5-6元含氧环状基团，即是具有至少一个O的成环原子数为5或6的环状基团。
本发明所述的“一至多个”、“一个以上”是指取代基的数量可以为所取代基团中所有化学上可以被取代的位置，优选1-6个，更有选1-5个，更优选1-3个，更优选1-2个，更优选为1个。
本发明所述的“任选被取代基取代”中，取代基的数量可以为0个(即，未被取代)，或者为1至待取代基团中的所有化学上可以被取代的位置的数量，优选1-6个，更优选1-5个，更优选1-4个，更优选1-3个，更优选1-2个或1个。
本发明提供一种通式(I)表示的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体：
Figure PCTCN2020117074-appb-000047
其中，W选自氢原子或任选被取代基取代的C 1-6烷基；
R表示如下通式(b)或(b′)所示的基团：
Figure PCTCN2020117074-appb-000048
Figure PCTCN2020117074-appb-000049
部分通过连接基团与M 3基团连接；
X 1、X 2、X 3各自独立选自CR aR a、C＝O和NR b，且其中至少一个为C＝O；
X 4、X 5各自独立选自CR a或N；
M 3选自氢原子、氰基、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-OC(O)NR bR c、-NR bC(O)OR d、-NR bC(O)R d、-SO 2-NR bR c、-SO 2R d、-NR bSO 2R d；或任选被取代基取代的C 1-6烷基、任选被取代基取代的C 1-6烷氧基、任选被取代基取代的C 2-8烯基、任选被取代基取代的C 2-8炔基、-任选被取代基取代的C 1-6烷基-R’、-任选被取代基取代的C 1-6烷氧基-R’、-O-R’、-C(O)-R’、-SO 2-R’、-NR bC(O)-R’、任选被取代基取代的3-12元环烷基、任选被取代基取代的3-12元环烯基、任选被取代基取代的3-14元杂环基、任选被取代基取代的6-14元芳基、任选被取代基取代的5-10元杂芳基；当
Figure PCTCN2020117074-appb-000050
部分的N在式(b′)中连接有双键时，M 3不存在；
Cy 2选自任选被一个以上R 2取代的3-12元环烷基、任选被一个以上R 2取代的3-12元环烯基、任选被一个以上R 2取代的3-14元杂环基、任选被一个以上R 2取代的6-14元芳基和任选被一个以上R 2取代的5-10元杂芳基，R 2各自独立的选自氢原子、氰基、羟基、巯基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-OC(O)NR bR c、-NR bC(O)R d、-NR bC(O)OR d、-SO 2-NR bR c、-SO 2R d、-NR bSO 2R d、任选被取代基取代的C 1-6烷基、任选被取代基取代的C 1-6烷氧基、任选被取代基取代的C 2-8烯基、任选被取代基取代的C 2-8炔基、-任选被取代基取代的C 1-6烷基-R’、-任选被取代基取代的C 1-6烷氧基-R’、-O-R’、-C(O)-R’、-SO 2-R’、-NR bC(O)-R’、任选被取代基取代的3-12元环烷基、任选被取代基取代的3-12元环烯基、任选被取代基取代的3-14元杂环基、任选被取代基取代的6-14元芳基、任选被取代基取代的5-10元杂芳基；
Cy 3选自任选被一个以上R 3取代的5-10元杂芳基团，R 3各自独立的选自氢原子、氰基、羟基、巯基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-OC(O)NR bR c、-NR bC(O)R d、-NR bC(O)OR d、-SO 2-NR bR c、-SO 2R d、-NR bSO 2R d、任选被取代基取代的C 1-6烷基、任选被取代基取代的C 1-6烷氧基、任选被取代基取代的C 2-8烯基、任选被取代基取代的C 2-8炔基、-任选被取代基取代的C 1-6烷基-R’、-任选被取代基取代的C 1-6烷氧基-R’、-O-R’、-C(O)-R’、-SO 2-R’、-NR bC(O)-R’、任选被取代基取代的3-12元环烷基、任选被取代基取代的3-12元环烯基、任选被取代基取代的3-14元杂环基、任选被取代基取代的6-14元芳基、任选被取代基取代的5-10元杂芳基；
Cy 4选自任选被一个以上R 4取代的3-12元环烷基、任选被一个以上R 4取代的3-14元杂环基、任选被一个以上R 4取代的5-14元杂芳基和任选被一个以上R 4取代的6-14元芳基，R 4各自独立的选自氢原子、氰基、羟基、巯基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-OC(O)NR bR c、-NR bC(O)R d、-NR bC(O)OR d、-SO 2-NR bR c、-SO 2R d、-NR bSO 2R d、任选被取代基取代的C 1-6烷基、任选被取代基取代的C 1-6烷氧基、任选被取代基取代的C 2-8烯基、任选被取代基取代的C 2-8炔基、-任选被取代基取代的C 1-6烷基-R’、-任选被取代基取代的C 1-6烷氧基-R’、-O-R’、-C(O)-R’、-SO 2-R’、-NR bC(O)-R’、任选被取代基取 代的3-12元环烷基、任选被取代基取代的3-12元环烯基、任选被取代基取代的3-14元杂环基、任选被取代基取代的6-14元芳基、任选被取代基取代的5-10元杂芳基，或者，两个R 4可以与所连接的原子形成5-14元环状基团；
L选自-NR b-、-O-、-S-、-(CR aR a) m-，m选自1-3的整数；
R a不存在，或者在每次出现时，各自独立地选自氢原子、氰基、羟基、巯基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-OC(O)NR bR c、-NR bC(O)R d、-NR bC(O)OR d、-SO 2-NR bR c、-SO 2R d、-NR bSO 2R d、任选被取代基取代的C 1-6烷基、任选被取代基取代的C 1-6烷氧基、任选被取代基取代的C 2-8烯基、任选被取代基取代的C 2-8炔基、-任选被取代基取代的C 1-6烷基-R’、-任选被取代基取代的C 1-6烷氧基-R’、-O-R’、-C(O)-R’、-SO 2-R’、-NR bC(O)-R’、任选被取代基取代的3-12元环烷基、任选被取代基取代的3-12元环烯基、任选被取代基取代的3-14元杂环基、任选被取代基取代的6-14元芳基、任选被取代基取代的5-10元杂芳基；
R b、R c各自不存在，或者在每次出现时，各自独立地选自氢原子、羟基、任选被取代基取代的C 1-6烷基、-任选被取代基取代的C 1-6烷基-R’、-C(O)-R’、-SO 2-R’、任选被取代基取代的3-12元环烷基、任选被取代基取代的3-12元环烯基、任选被取代基取代的3-14元杂环基、任选被取代基取代的6-14元芳基、任选被取代基取代的5-10元杂芳基；
R d不存在，或者在每次出现时，各自独立地选自羟基、卤素原子、氨基、-氨基(任选被取代基取代的C 1-6烷基) 1-2、任选被取代基取代的C 1-6烷基、任选被取代基取代的C 1-6烷氧基、-任选被取代基取代的C 1-6烷基-R’、-任选被取代基取代的C 1-6烷氧基-R’、-O-R’、任选被取代基取代的3-12元环烷基、任选被取代基取代的3-12元环烯基、任选被取代基取代的3-14元杂环基、任选被取代基取代的6-14元芳基、任选被取代基取代的5-10元杂芳基；
R’各自独立地选自任选被取代基取代的3-12元环烷基、任选被取代基取代的3-12元环烯基、任选被取代基取代的3-14元杂环基、任选被取代基取代的6-14元芳基和任选被取代基取代的5-10元杂芳基；
q为0-4的整数；
n为0-4的整数；
所述“任选被取代基取代”中的取代基各自独立地选自：羟基、巯基、氨基、羧基、氰基、硝基、卤素原子、C 1-6烷基、C 1-6烷氧基C 1-6烷基、C 1-6烷氧基、C 1-6烷基C 1-6烷氧基、C 1-6烷氧基C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷基氨基羰基、(C 1-6烷基) 2氨基羰基、C 1-6烷基羰基、C 1-6烷基羰基氧基、C 1-6烷基羰基氨基、C 1-6烷基磺酰氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 1-6烷基磺酰基、C 1-6烷基硫基、3-12元环烷基、6-14元芳基、3-12元杂环基、5-10元杂芳基和氧代基。
在本发明的一个实施方式中，当M 3表示的基团中携带芳基时，Cy 2不表示杂环基。
在本发明的一个实施方式中，Cy 2不表示杂环基。
在本发明的一个实施方式中，当M 3表示的基团中携带芳基时，Cy 2不表示杂芳基。
在本发明的一个实施方式中，Cy 2不表示杂芳基。
在本发明的一个实施方式中，当M 3表示任选被取代基取代的C 1-6烷基时，X 4表示CR a。
在本发明的一个实施方式中，当M 3表示的基团中携带芳基时，X 4表示CR a。
在本发明的一个实施方式中，当M 3表示的基团中携带环烷基时，X 4表示CR a。
在本发明的一个实施方式中，当M 3表示任选被取代基取代的C 1-6烷基、X 1表示CR aR a时，X 1上的R a基团中不具有羰基。
在本发明的一个实施方式中，当M 3表示的基团中携带芳基时，X 2不表示C＝O。
在本发明的一个实施方式中，M 3选自任选被取代基取代的支链C 1-6烷基、任选被取代基取代的3-8元环烷基。
在本发明的一个实施方式中，X 1为NR b，X 2为CR aR a，X 3为C＝O；或者X 1为CR aR a，X 2为NR b，X 3为C＝O；或者X 1为C＝O，X 2为CR aR a，X 3为C＝O；或者X 1为CR aR a，X 2为C＝O，X 3为C＝O；或者X 1为CR aR a，X 2为CR aR a，X 3为C＝O；或者X 1为C＝O，X 2为CR aR a，X 3为CR aR a；或者X 1为CR aR a，X 2为C＝O，X 3为CR aR a。
在本发明的一个实施方式中，X 4选自N，X 5选自CR a；或者X 4选自CR a，X 5选自CR a；或者X 4选自N，X 5选自N；或者X 4选自CR a， X 5选自N。
在本发明的一个实施方式中，X 1不表示C＝O。
在本发明的一个实施方式中，X 2不表示C＝O。
在本发明的一个实施方式中，X 1为NR b。
在本发明的一个实施方式中，X 2为NR b。
在本发明的一个实施方式中，X 3为C＝O。
在本发明的一个实施方式中，式(b)、式(b′)只携带1个羰基。
在本发明的一个实施方式中，X 1，X 2，X 3，X 4，X 5中最多有两个为NR b。
在本发明的一个实施方式中，X 4表示CR a。
在本发明的一个实施方式中，X 5表示CR a。
在本发明的一个实施方式中，M 3表示甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、乙烯基、烯丙基或丙烯基
在本发明的一个实施方式中，Cy 2选自任选被一个以上R 2取代的6-14元芳基、任选被一个以上R 2取代的5-10元杂芳基。
在本发明的一个实施方式中，Cy 2选自任选被一个以上R 2取代的苯基、任选被一个以上R 2取代的5-6元杂芳基。
在本发明的一个实施方式中，Cy 2选自任选被一个以上R 2取代的
Figure PCTCN2020117074-appb-000051
在本发明的一个实施方式中，Cy 2表示的基团中，不带有杂环基。在本发明的一个实施方式中，当M 3为携带芳基的基团时，Cy 2表示的基团中，不具有羰基。
在本发明的一个实施方式中，Cy 3选自任选被一个以上R 3取代的5-10元杂芳基团。
在本发明的一个实施方式中，Cy 3选自任选被一个以上R 3取代的5-6元杂芳基。
在本发明的一个实施方式中，Cy 3表示任选被一个以上R 3取代的
Figure PCTCN2020117074-appb-000052
所示的基团，式中，
Figure PCTCN2020117074-appb-000053
表示单键或双键，Y 2、Y 3、Y 6和Y 7各自独立地选自CR aR a或NR b，且其中至少一个为NR b，优选的是，Cy 3表示任选被一个以上R 3取代的
Figure PCTCN2020117074-appb-000054
所示的基团，Y 2、Y 3、Y 6、Y 7各自独立的选自CH或N，并且至少有一个为N。
在本发明的一个实施方式中，Cy 3选自任选被一个以上R 3取代的
Figure PCTCN2020117074-appb-000055
在本发明的一个实施方式中，Cy 3选自任选被一个以上R 3取代的以下基团：
Figure PCTCN2020117074-appb-000056
*端与N相连，·端与L相连。
在本发明的一个实施方式中，Cy 4选自任选被一个以上R 4取代的5-9元杂芳基。
在本发明的一个实施方式中，Cy 4选自任选被一个以上R 4取代的5-9元杂环基。
在本发明的一个实施方式中，Cy 4选自任选被一个以上R 4取代的5-10元杂环基、任选被一个以上R 4取代的5-10元杂芳基和任选被一个以上R 4取代的6-10元芳基。
在本发明的一个实施方式中，Cy 4表示任选被一个以上R 4取代的
Figure PCTCN2020117074-appb-000057
所示的基团，式中，
Figure PCTCN2020117074-appb-000058
表示单键或双键，Y 4、Y 5各自独立地选自CR aR a或NR b，环B形成五元环，当Y 4、Y 5为CR aR a时，环B形成含有NR b的五元杂芳环，优选的是，Cy 4表示任选被一 个以上R 4取代的
Figure PCTCN2020117074-appb-000059
式中，Y 4和Y 5各自独立地为CH，环B为含有1-2个NR b的五元杂芳环。
在本发明的一个实施方式中，Cy 4选自任选被一个以上R 4取代的
Figure PCTCN2020117074-appb-000060
在本发明的一个实施方式中，R 2各自独立地选自氢原子、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-NR bC(O)OR d、任选被取代基取代的C 1-6烷基、任选被取代基取代的C 1-6烷氧基。
在本发明的一个实施方式中，R 2各自独立地选自氢原子、羟基、卤素原子、C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基；优选的是，R 2各自独立地选自氢原子、羟基、氟、氯、溴、C 1-4烷基。
在本发明的一个实施方式中，R 3各自独立地选自氢原子、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-NR bC(O)R d、任选被取代基取代的C 1-6烷基、任选被取代基取代的C 1-6烷氧基。
在本发明的一个实施方式中，R 3各自独立地选自氢原子、羟基、卤素原子、C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基；优选的是，R 3各自独立地选自氢原子、羟基、氟、氯、溴、C 1-4烷基。
在本发明的一个实施方式中，R 4各自独立地选自氢原子、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-NR bC(O)R d、任选被取代基取代的C 1-6烷基、任选被取代基取代的C 1-6烷氧基、任选被取代基取代的5-10元杂芳基。
在本发明的一个实施方式中，R 4各自独立地选自氢原子、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-NR bC(O)R d、任选被取代基取代的C 1-6烷基、任选被取代基取代的C 1-6烷氧基、任 选被取代基取代的5-6元杂芳基。
在本发明的一个实施方式中，优选的是，R 4各自独立地选自氢原子、羟基、卤素原子、氨基、(C 1-6烷基) 1-2氨基-、C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6烷氧基C 1-6烷基、C 1-6烷基C 1-6烷氧基、C 1-6烷氧基C 1-6烷氧基、吡咯基、呋喃基、噻吩基、噁唑基、异噁唑基、吡唑基、咪唑基、噻唑基、吡啶基、嘧啶基、哒嗪基。
在本发明的一个实施方式中，R 4选自氢原子、羟基、巯基、卤素原子、氨基、(C 1-4烷基) 1-2氨基-、C 1-4烷基、卤代C 1-4烷基、C 1-4烷氧基、C 1-4烷氧基C 1-4烷基、C 1-4烷基C 1-4烷氧基、C 1-4烷氧基C 1-4烷氧基、卤代C 1-4烷氧基、吡咯基、呋喃基、噻吩基、噁唑基、异噁唑基、吡唑基、咪唑基。
在本发明的一个实施方式中，R a不存在，或者在每次出现时，各自独立地选自氢原子、卤素原子、羟基、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-NR bC(O)R d、任选被取代基取代的C 1-6烷基、任选被取代基取代的C 1-6烷氧基。
在本发明的一个实施方式中，R a不存在，或者在每次出现时，各自独立地选自氢原子、羟基、卤素原子、羧基、硝基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基。
在本发明的一个实施方式中，R a不存在，或者在每次出现时，各自独立地选自氢原子、C 1-6烷基、C 1-6烷氧基。
在本发明的一个实施方式中，R b、R c各自不存在，或者在每次出现时，各自独立地选自氢原子、任选被取代基取代的C 1-6烷基。
在本发明的一个实施方式中，R b、R c各自不存在，或者在每次出现时，各自独立地选自氢原子、C 1-6烷基、卤代C 1-6烷基。
在本发明的一个实施方式中，R b、R c各自不存在，或者在每次出现时，各自独立地选自氢原子、C 1-6烷基。
在本发明的一个实施方式中，R d不存在，或者在每次出现时，各自独立地选自羟基、卤素原子、氨基、-氨基(任选被取代基取代的C 1-6烷基) 1-2、任选被取代基取代的C 1-6烷基、任选被取代基取代的C 1-6烷氧基。
在本发明的一个实施方式中，R d不存在，或者在每次出现时，各 自独立地选自羟基、氨基、-氨基(C 1-6烷基) 1-2、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基。
在本发明的一个实施方式中，R d不存在，或者在每次出现时，各自独立地选自羟基、氨基、C 1-4烷基、卤代C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷氧基。
在本发明的一个实施方式中，R’选自任选被取代基取代的3-8元环烷基、任选被取代基取代的3-8元环烯基、任选被取代基取代的3-10元杂环基、任选被取代基取代的6-10元芳基和任选被取代基取代的5-6元杂芳基。
在本发明的一个实施方式中，R’选自任选被取代基取代的3-6元环烷基、任选被取代基取代的4-7元杂环基、任选被取代基取代的6-10元芳基和任选被取代基取代的5-6元杂芳基。
在本发明的一个实施方式中，R’选自环丙基、环丁基、环戊基、环己基、苯基、萘基、氧杂环丙基、氧杂环丁基、氧杂环戊基、氧杂环己基、氧杂环庚基、吡咯基、呋喃基、噻吩基、噁唑基、异噁唑基、吡唑基、噻唑基、吡啶基、嘧啶基、哒嗪基。
在本发明的一个实施方式中，“任选被取代基取代”中的取代基各自独立地选自：羟基、巯基、氨基、羧基、氰基、硝基、卤素原子、C 1-6烷基、C 1-6烷氧基C 1-6烷基、C 1-6烷氧基、C 1-6烷基C 1-6烷氧基、C 1-6烷氧基C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷基氨基羰基、(C 1-6烷基) 2氨基羰基、C 1-6烷基羰基、C 1-6烷基羰基氧基、C 1-6烷基羰基氨基、C 1-6烷基磺酰氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 1-6烷基磺酰基、C 1-6烷基硫基、3-8元环烷基、6-10元芳基、3-8元杂环基、5-6元杂芳基和氧代基。
在本发明的一个实施方式中，“任选被取代基取代”中的取代基各自独立地选自：羟基、巯基、氨基、羧基、氰基、硝基、卤素原子、C 1-4烷基、C 1-4烷氧基C 1-4烷基、C 1-4烷氧基、C 1-4烷基C 1-4烷氧基、C 1-4烷氧基C 1-4烷氧基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、C 1-4烷基氨基羰基、(C 1-4烷基) 2氨基羰基、C 1-4烷基羰基、C 1-4烷基羰基氧基、C 1-4烷基羰基氨基、C 1-4烷基磺酰氨基、卤代C 1-4烷基、卤代C 1-4烷氧基、C 1-4烷基磺酰基、C 1-4烷基硫基、环丙基、环丁基、环戊基、环己基、环庚基、苯基、萘基、氧杂环丙基、氧杂环丁基、氧杂环戊基、氧杂环己 基、氧杂环庚基、吡咯基、呋喃基、噻吩基、噁唑基、异噁唑基、吡唑基、噻唑基、吡啶基、嘧啶基、哒嗪基和氧代基。
在本发明的一个实施方式中，n为0、1、2、3或4。当n为0时，表示M 3直接键合于式(b)或式(b′)的N原子上。
在本发明的一个实施方式中，q为0、1、2、3或4。当q为0时，表示Cy 2直接键合于X 4。
在本发明的一个实施方式中，L选自-NR b-、-O-和-S-，优选为-O-。
在本发明中，当
Figure PCTCN2020117074-appb-000061
部分的N在式(b)或式(b′)中连接有双键时，M 3不存在。即，此时，
Figure PCTCN2020117074-appb-000062
部分的N原子在式(b)或式(b′)中，由于键合有双键(或形成杂芳环时形成大π键)，因此N原子除了相邻的成环原子之外，不会键合有其他原子。本发明所述的“酯”是指，本发明的化合物形成的药学上可接受的酯，更具体而言是本发明化合物的甲酸酯、乙酸酯、丙酸酯、丁酸酯、丙烯酸酯和乙基琥珀酸酯等的酯，但不限于此。
本发明所述的“药学上可接受的盐”是指可药用的酸和碱的加成盐或其溶剂化物。这样的可药用盐包括诸如以下的酸的盐：盐酸、磷酸、氢溴酸、硫酸、亚硫酸、甲酸、甲苯磺酸、甲磺酸、硝酸、苯甲酸、柠檬酸、酒石酸、马来酸、氢碘酸、链烷酸(诸如乙酸、CH 3-(CH 2) n-COOH(其中n是0～4))等。碱的盐：钠盐、钾盐、钙盐、铵盐等。本领域技术人员知晓多种无毒的可药用加成盐。
本发明中的氢原子、氟原子、碳原子、氮原子、氧原子、硫原子等还包括其各自的放射性同位素或稳定同位素。
本发明所述的肿瘤包括肉瘤、淋巴瘤和癌症，可以为呼吸系统癌症、间皮瘤、神经系统肿瘤、皮肤恶性肿瘤、骨癌、鳞状上皮细胞癌、乳腺癌、头颈癌、泌尿及生殖系统癌症、胆道系统癌症、肉瘤、消化系统癌症、白血病、淋巴瘤、骨髓增生异常综合征、原位癌、细胞瘤。
本发明所述的肿瘤具体可以为肺癌、甲状腺癌、口腔癌、咽癌、腹膜癌、胶质瘤、神经纤维瘤病、皮肤癌、黑色素瘤、多发性骨髓瘤、肺鳞癌、食管鳞癌、乳腺导管癌、脑癌、卵巢癌、宫体癌、子宫内膜 癌、前列腺癌、睾丸癌、膀胱癌、肾癌、肾盂癌、胆管癌、胆囊癌、骨肉瘤、脂肪肉瘤、尤文肉瘤、肝癌、胃癌、食管癌、大肠癌、胰腺癌、贲门癌、胃肠道间质瘤、大肠绒毛腺瘤、急性白血病、慢性白血病、非霍奇金恶性淋巴瘤(NHL)、T/NK细胞淋巴瘤、霍奇金淋巴瘤(HL)、骨髓增生异常综合征、原位癌、细胞瘤。
本发明中，“A/和B”的表述是指A单独，或者A和B两者。例如“TAM家族激酶/和Ron激酶”是指“TAM家族激酶”单独或者“TAM家族激酶”和“Ron激酶”两者。
本发明式(I)化合物的“立体异构体”是指当式(I)化合物存在不对称原子时，会产生对映异构体；当化合物存在碳碳双键或环状结构时，会产生顺反异构体，所有式(I)化合物的对映异构体、非对映异构体、消旋异构体、顺反异构体、几何异构体、差向异构体及其混合物，均包括在本发明范围中。本发明的化合物的定义包括所有可能的立体异构体和它们的混合物。特别是包括外消旋形式和具有指定活性的分离的旋光异构体。外消旋形式可通过物理方法拆分，例如分级结晶、非对映体衍生物的分离或结晶或通过手性柱色谱法分离。可以由外消旋物通过常规方法(例如与光学活性酸成盐、接着结晶)获得单个的旋光异构体。
本发明式(I)化合物的“互变异构体”是指当式(I)化合物中某一原子在两个位置迅速移动而产生的官能团异构体称为互变异构体；当含有羰基的官能团α位上的氢在α碳上时，产生酮式互变异构体；当含有羰基的官能团α位上的氢在羰基的氧上时，产生醇式互变异构体。
本发明的药物组合物包含式(I)所示化合物、其药学上可接受的盐、酯、立体异构体、互变异构体中的至少一种。
本发明的药物组合物包含式(I)所示化合物，或其药学上可接受的盐、酯、立体异构体、互变异构体和任选的一种或多种药用载体。
本发明的药物组合物可以以本领域公知的任何合适的给药方式，例如可以通过口服，肠胃外(包括皮下、肌内、静脉内、动脉内、皮内、鞘内和硬膜外)，透皮，直肠，鼻，经肺，局部(包括口腔和舌下)，阴道，腹膜内，肺内和鼻内等给药等方式，施用于需要治疗和/或预防的患者或受试者。
本发明的药物组合物可制成常规的固体制剂，如片剂、胶囊剂、 丸剂、颗粒剂等；也可制成口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。制成口服制剂时，可以加入适宜的赋形剂、稀释剂、甜味剂、增溶剂、润滑剂、粘合剂、片剂崩解剂、稳定剂、防腐剂或包封材料的一种或多种物质。用于肠胃外给药时，所述药物组合物可制成注射剂、注射用无菌粉末与注射用浓溶液。制成注射剂时，可采用现有制药领域中的常规方法生产，配置注射剂时，可以不加入附加剂，也可以根据药物的性质加入适宜的附加剂。用于直肠给药时，所述药物组合物可制成栓剂等。用于经肺给药时，所述药物组合物可制成吸入剂或喷雾剂等。本发明中，合适的固体载体包括但不限于例如纤维素、葡萄糖、乳糖、甘露醇、硬脂酸镁、碳酸镁、碳酸钠、糖精钠、蔗糖、糊精、滑石、淀粉、果胶、明胶、黄芪胶、阿拉伯胶、藻酸钠、对羟基苯甲酸酯、甲基纤维素、羧甲基纤维素钠、低熔点蜡、可可脂等。合适的液体载体包括但不限于水、乙醇、多元醇(例如甘油、丙二醇、液体聚乙二醇等)、植物油、甘油酯及其混合物。
制备本发明的药物组合物的方法一般是已知的。以已知的方法制备本发明的药物组合物包括常规的混合、制粒、压片、包衣、溶解或冻干方法。
药物制剂优选为单位剂量形式。在该形式中，制剂被细分成含有适当量的活性组分的单位剂量。可以将单位剂量形式包装成含有离散量的制剂的包装，诸如包装的片剂、胶囊剂或在小瓶或安瓿中的粉剂。
药物的施用剂量取决于各种因素，包括患者的年龄、体重和状态以及给药途径。施用的精确剂量基于治疗医生的判断确定。用于施用活性化合物的通常剂量可以是例如每天约0.01mg至大约100mg，每天大约0.05mg至大约75mg，每天大约0.1mg至大约50mg/天，或者每天大约5mg至大约10mg。期望的剂量还取决于采用的具体化合物、疾病的严重程度、施用途径、患者的体重和健康状况以及治疗医生的判断。
本发明通式(I)化合物的制备方法
通过标准化学方法在内的多种方法，可以制备本发明的化合物。除非另外指出，否则任何前面定义的变量将继续具有前面定义的含义。示例性的一般合成方法阐述在下述方案中，并且可以很容易的改进以制备本发明的其他化合物。本领域技术人员可以根据本领域教导的常 规方法(例如Organic Synthesis 2nd，Michael B.Smith etc.)实施以下的反应。在实施例部分中具体地制备本发明的具体化合物。
通式(I)所示化合物的制备方法例如可以通过以下的方法进行制备，但不限于此。
反应式
Figure PCTCN2020117074-appb-000063
其中，如上所示，由式(I-a)和式(I-b)制备得到的式(I-j)化合物，进一步进行脱保护后，得到式(I)所示化合物。
Figure PCTCN2020117074-appb-000064
其中，将式(I-a)加入到溶剂中，加入肽偶联试剂、碱、和式(I-b)，搅拌反应完全，分离得式(I-j)；或者，
将式(I-a)和式(I-b)，加入到碱中，滴加偶联试剂，搅拌反应完全，分离得到式(I-j)，
将式(I-j)加入到溶剂中，加入酸，搅拌反应完全，分离得式(I)；
其中，M 3、W、R、n、Cy 3、L和Cy 4如上文所定义；
Cy 5衍生自Cy 4所定义的基团；
k为0-2的整数；
PG为保护基团，可以使用本领域公知的保护基团，例如可以选自 叔丁氧基羰基，苄基氧基羰基，乙酰基，对甲氧基苄基；
LG为离去基团或硼酸、硼酸酯，可以使用本领域公知的离去基团，例如可以选自氯、溴、碘、甲磺酸酯或苯磺酸酯等离去基团；
R 1为C 1-6烷基。
如上所示，k表示连接于N原子的PG基团数目，该N原子上任选地连接有氢原子，以使该N原子的化合价满足3价。
所述的溶剂选自：N，N-二甲基甲酰胺、N，N-二甲基乙酰胺、二甲基亚砜、甲苯、苯、二甲苯、三甲苯、环己烷、己烷、二氯甲烷、氯仿、1，2-二氯乙烷、四氢呋喃、乙醚、二噁烷、1，2-二甲氧基乙烷、乙酸甲酯、乙酸乙酯、丙酮、甲基乙基酮、乙腈、甲醇、乙醇、异丙醇、叔丁醇、水中的一种和其混合物；
所述的碱选自：甲胺、乙胺、丙胺、N，N-二异丙基乙胺、三甲胺、三乙胺、二环己基胺、乙醇胺、二乙醇胺、三乙醇胺、葡甲胺、二乙醇胺、乙二胺、吡啶、甲基吡啶、喹啉中的一种和其混合物；
所述的酸选自：甲酸、乙酸、丙酸、三氟乙酸、柠檬酸、乳酸、酒石酸、草酸、马来酸、富马酸、扁桃酸、戊二酸、苹果酸、安息香酸、邻苯二甲酸、抗坏血酸、苯磺酸、对甲苯磺酸、甲基磺酸、乙基磺酸；盐酸、硫酸、硝酸、碳酸、氢溴酸、磷酸、氢碘酸；
所述的肽偶联试剂选自：2-(7-偶氮苯并三氮唑)-四甲基脲六氟磷酸酯(HATU)、苯并三氮唑-N，N，N′，N′-四甲基脲六氟磷酸酯(HBTU)、2-(1H-苯并[d][1，2，3]三偶氮-1-基)-1，1，3，3-四甲基脲四氟硼酸酯(TBTU)的一种和其混合物；
所述的偶联试剂选自：三氯氧磷、二环己基碳二亚胺(DCC)、N，N′-羰基二咪唑、氯甲酸异丁酯、1-正丙基磷酸酐等的一种和其混合物。
本领域技术人员可以根据本领域技术常规方法由式(I-j)的化合物来制备式(I)的化合物，下述示意性地提供了由式(I-j)的化合物来制备式(I)的化合物的方法：
例如，将式(I-j)的化合物加入合适的溶剂中(如甲醇、四氢呋喃、N，N-二甲基甲酰胺、N，N-二甲基乙酰胺等，优选N，N-二甲基甲酰胺)，加入水，再加入合适的酸(甲酸、乙酸、丙酸、三氟乙酸、柠檬酸、乳酸、酒石酸、草酸、马来酸、富马酸、扁桃酸、戊二酸、苹果酸、安息香酸、邻苯二甲酸、抗坏血酸、苯磺酸、对甲苯磺酸、甲 基磺酸、乙基磺酸；盐酸、硫酸、硝酸、碳酸、氢溴酸、磷酸、氢碘酸)，室温搅拌适当的时间(如10～30分钟)，监测反应完全后，加入适量的水，调节PH，用合适的萃取剂(如乙酸乙酯)萃取，萃取液浓缩，粗品经常规的纯化方法(如硅胶柱层析)分离得到式(I)的化合物。
如上所示，式(I-j)的化合物可以通过式(I-a)的化合物与式(I-b)的化合物反应制备，
Figure PCTCN2020117074-appb-000065
其中，M 3、R、n、W、Cy 3、L、PG、k和Cy 5如上文所定义。
本领域技术人员可以根据本领域技术常规方法由式(I-a)的化合物和式(I-b)的化合物来制备式(I-j)的化合物，下述示意性地提供了由式(I-a)的化合物和式(I-b)的化合物反应来制备式(I-j)的化合物的方法：
例如，将式(I-a)的化合物加入合适的溶剂中(如四氢呋喃、N，N-二甲基甲酰胺、N，N-二甲基乙酰胺等，优选N，N-二甲基甲酰胺)，加入合适肽偶联试剂(优选2-(7-氧化苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯)，再加入合适的碱(如三乙胺、吡啶、N，N-二异丙基乙胺等，优选N，N-二异丙基乙胺)，降至适当的温度(如0℃)，搅拌适当的时间(如10～30分钟)，加入式(I-b)的化合物，在适当的温度(如0℃至环境温度)搅拌合适的时间(如1～16小时)。将反应液减压浓缩，加入适量的水，用合适的萃取剂(如乙酸乙酯)萃取，萃取液浓缩，粗品经常规的纯化方法(如硅胶柱层析)分离得到式(I-j)的化合物；
又例如，将式(I-a)的化合物和式(I-b)的化合物加入合适的碱中(如吡啶)，降至适当的温度(如0℃)，滴加偶联试剂(如三氯氧磷)，加完搅拌合适的时间(如0.5～3小时)至反应完全，将反应液减压浓缩，加入适量的水，用合适的萃取剂(如乙酸乙酯)萃取，萃取液浓缩，粗品经常规的纯化方法(如硅胶柱层析)分离得到式(I-j)的化合物。
如上所示，式(I-a)的化合物可通过式(I-c)的化合物制备，
Figure PCTCN2020117074-appb-000066
其中，R 1为C 1-6烷基，M 3、R和n如上文中所定义。本领域技术人员可以根据本领域技术常规方法由式(I-c)的化合物制备式(I-a)的化合物，下述示意性地提供了由式(I-c)的化合物制备式(I-a)的化合物的方法：
例如，将式(I-c)的化合物溶解于合适的溶剂(如甲醇，乙醇，四氢呋喃，二氧六环等，优选甲醇)，加入合适的碱(如氢氧化锂，氢氧化钠，氢氧化钾等，优选氢氧化锂)，在适当的温度(如室温)，搅拌适当的时间(如0.5～3小时)，反应结束后，减压浓缩，用适当的酸(如盐酸、柠檬酸)的水溶液调节pH值至合适范围(如2～5)，过滤得到式(I-a)的化合物。
式(I-c)的化合物可以通过式(I-d)的化合物与式(I-e)的化合物反应制备，
Figure PCTCN2020117074-appb-000067
其中，R和R 1如上文中所定义，LG、M 3和n如上文中所定义。本领域技术人员可以根据本领域技术常规方法由式(I-d)的化合物和式(I-e)的化合物制备式(I-c)的化合物，下述示意性地提供了由式(I-d)的化合物和式(I-e)的化合物反应制备式(I-c)的化合物的方法：
例如，将式(I-d)的化合物和式(I-e)的化合物(LG为离去基团)溶解于合适的溶剂(如乙腈、四氢呋喃、N，N-二甲基甲酰胺等，优选N，N-二甲基甲酰胺)中，加入适当的碱(如碳酸钠、碳酸钾、碳酸铯等，优选碳酸钾)，在适当的温度(如50℃)搅拌反应适当的时间(如10～16小时)，反应结束后加入水和适当的萃取剂，粗产品通过常规的纯化手段分离(如硅胶柱层析)得到式(I-c)的化合物；
又例如，将式(I-d)的化合物和式(I-e)的化合物(LG为硼酸或硼酸酯)溶解于合适的溶剂(如乙腈，二氯甲烷，氯仿，吡啶，N，N-二甲基甲酰胺等，优选N，N-二甲基甲酰胺)，加入适当的碱(如三乙 胺，吡啶等)和适当的催化剂(如醋酸铜，氯化铜等)，在空气或氧气条件下，在适当的温度(如室温至50℃)，反应适当的时间(如14小时)。反应结束后，通过常规后处理(如萃取，浓缩)得到粗品，再通过常规的纯化手段(如硅胶柱层析)得到产品。
如上所示，式(I-b)的化合物可通过式(I-k)的化合物反应制备，
Figure PCTCN2020117074-appb-000068
其中，Cy 3、L、k、PG和Cy 5如上文所定义。本领域技术人员可以根据本领域技术常规方法由式(I-k)的化合物制备式(I-b)的化合物，下述示意性地提供了由式(I-k)的化合物制备式(I-b)的化合物的方法：
例如，将式(I-k)的化合物和合适的还原剂(如铁粉、锌粉、氯化亚锡、连亚二硫酸钠等，优选铁粉，硫化铵，七水合硫酸亚铁等)加入适当的溶剂(如乙醇，氯化铵水溶液，醋酸，氨水，乙醇和氯化铵水溶液混合等)，在适当的温度(如80℃)反应适当的时间(如2小时)。反应完全后，过滤，减压浓缩，用合适的萃取剂(如二氯甲烷)萃取，减压浓缩得到产品。
如上所示，式(I-k)的化合物可通过式(I-f)的化合物反应制备，
Figure PCTCN2020117074-appb-000069
其中，L、Cy 3、Cy 5、LG如上文所定义；本领域技术人员可以根据本领域技术常规方法由式(I-f)的化合物制备式(I-k)的化合物，下述示意性地提供了由式(I-f)的化合物制备式(I-k)的化合物的方法：
例如，将式(I-f)的化合物加入适当的溶剂(如1，4-二氧六环，四氢呋喃，乙腈，N，N-二甲基甲酰胺、N，N-二甲基乙酰胺等，优选N，N-二甲基甲酰胺)，加入适当的催化剂如醋酸钯，氯化钯等，加入适当的配体(BINAP，XPhos，SPhos，Ruphos等)，加入适当的碱(如碳酸钾，碳酸钠，三乙胺，N，N-二异丙基乙胺等，优选碳酸钾)，加入NH(PG) k(如二苯甲酮亚胺，对甲氧基苄胺，叔丁胺)，在适当的温度(如室温至110℃)搅拌适当的时间(如14小时)。反应结束后，通过常规的后处理方法(如过滤，萃取等)得到粗品，再通过常规的纯化手段分离(如硅胶柱层析)得到产品。
如上所示，式(I-f)的化合物可通过式(I-g)的化合物与式(I-h)的化合物反应制备。
Figure PCTCN2020117074-appb-000070
其中，L、Cy 5、Cy 3和LG如上文所定义；
本领域技术人员可以根据本领域技术常规方法由式(I-g)的化合物和式(I-h)的化合物制备式(I-f)的化合物，下述示意性地提供了由式(I-g)的化合物和式(I-h)的化合物制备式(I-f)的化合物的方法：
例如，将式(I-g)的化合物和式(I-h)的化合物加入适当的溶剂(如四氢呋喃，乙腈，N，N-二甲基甲酰胺、N，N-二甲基乙酰胺等，优选N，N-二甲基甲酰胺)，加入适当的碱(如碳酸钾，碳酸钠，三乙胺，N，N-二异丙基乙胺等，优选碳酸钾)，在适当的温度(如室温至80℃)搅拌适当的时间(如14小时)。反应结束后，通过常规的后处理方法(如过滤，萃取等)得到粗品，再通过常规的纯化手段分离(如硅胶柱层析)得到产品。
在本发明的某些实施方式中，R表示通式(b)所示的基团时，式(I-c)的化合物可由如下反应制备：
Figure PCTCN2020117074-appb-000071
在某些实施方式中，式(I-c)的化合物可由如下反应制备：
Figure PCTCN2020117074-appb-000072
其中，X 1，X 2，X 5，X 4分别独立选自C、CH或CH 2，X 3为C＝O，R′ 2为C 1-6烷氧基或双取代氨基，Cy 2，R 1，M 3和n如上文中所定义。本领域技术人员可以根据本领域技术常规方法由式(I-m)的化合物制备式(I-c)的化合物，下述示意性地提供了由式(I-m)的化合物制备式(I-c) 的化合物的方法：
例如，将式(I-m)的化合物加入适当的溶剂(如甲苯，二甲苯，三甲苯，N，N-二甲基甲酰胺，N，N-二甲基乙酰胺等，优选甲苯)，加入合适的试剂(如N，N-二甲基甲酰胺二甲基缩醛，原甲酸三甲酯，原甲酸三乙酯等，优选N，N-二甲基甲酰胺二甲基缩醛)，加热至适当的温度(如100℃)搅拌适当的时间(如15小时)。反应结束后，通过常规的后处理方法(如过滤，萃取，浓缩等)得到式(I-n)的化合物。
将式(I-n)的化合物和式(I-o)的化合物加入合适的溶剂(如乙醇，异丙醇，甲苯等)中，加热到合适的温度(如100℃)，反应适当的时间(如3h)。反应结束后，通过常规的纯化方法(如硅胶柱层析)得到式(I-c)的化合物。
在另外一些实施方式中，式(I-c)的化合物可由如下反应制备：
Figure PCTCN2020117074-appb-000073
其中，X 1，X 5，X 4分别独立选自C、CH或CH 2，X 3为C＝O，Cy 2，R 1，M 3和n如上文中所定义。本领域技术人员可以根据本领域技术常规方法由式(I-p)的化合物制备式(I-c)的化合物，下述示意性地提供了由式(I-p)的化合物制备式(I-c)的化合物的方法：
例如，将式(I-p)的化合物和式(I-q)的化合物加入适当的溶剂(如二氯甲烷，氯仿，1，2-二氯乙烷等，优选二氯甲烷)，降温至适当的温度(如0℃)，加入适当的碱(如碳酸钾，碳酸钠，氢氧化钠等，优选碳酸钾)，缓慢升至室温反应适当的时间(如3～15小时)，反应结束后，通过常规的纯化方法(如硅胶柱层析)得到式(I-r)的化合物。
将式(I-r)的化合物加入适当的溶剂(如甲苯，二甲苯，三甲苯，N，N-二甲基甲酰胺，N，N-二甲基乙酰胺等，优选甲苯)，加入合适的试剂(如N，N-二甲基甲酰胺二甲基缩醛，原甲酸三甲酯，原甲酸三乙酯等，优选N，N-二甲基甲酰胺二甲基缩醛)，加热至适当的温度(如110 ℃)搅拌适当的时间(如15小时)。反应结束后，通过常规的后处理方法(如过滤，萃取，浓缩等)及纯化方法(如硅胶柱层析)得到式(I-c)的化合物。
在另外一些实施方式中，式(I-c)的化合物可由如下反应式制备：
Figure PCTCN2020117074-appb-000074
其中，X 2，X 5，X 4分别独立选自C、CH或CH 2，X 3为C＝O，Cy 2，R 1，M 3和n如上文中所定义。本领域技术人员可以根据本领域技术常规方法由式(I-s)的化合物制备式(I-c)的化合物，下述示意性地提供了由式(I-s)的化合物制备式(I-c)的化合物的方法：
例如，将式(I-s)的化合物和式(I-t)的化合物加入适当的溶剂(如甲醇，乙醇，异丙醇等，优选乙醇)，在适当的温度(如80℃)反应适当的时间(如15小时)。反应结束后，通过常规的纯化方法(如硅胶柱层析)得到式(I-u)的化合物。
将式(I-u)的化合物加入适当的溶剂(如四氢呋喃，2-甲基四氢呋喃，N，N-二甲基甲酰胺，N，N-二甲基乙酰胺，乙醇等，优选2-甲基四氢呋喃)，降至适当的温度(如0℃)，加入适当的碱(如氢化钠，叔丁醇钠，叔丁醇钾，乙醇钠等，优选叔丁醇钾)，加完升至适当的温度(如室温)搅拌适当的时间(如15小时)。反应结束后，将反应液调至适当的pH值(如5～6)，通过常规的后处理方法(如过滤，萃取，浓缩等)及纯化方法(如硅胶柱层析)得到式(I-v)的化合物。
将式(I-v)的化合物加入适当的溶剂(如乙腈)中，加入适当的氧化剂(如氯化铜)，升至适当的温度(如80℃)反应适当的时间(如2～4小时)。反应结束后，通过常规的后处理方法(如过滤，萃取，浓缩等)及纯化方法(如硅胶柱层析)得到式(I-c)的化合物。
其中式(I-t)的化合物可由如下反应式制备：
Figure PCTCN2020117074-appb-000075
其中，X 2，X 5分别独立选自CH或CH 2，PG为本领域公知的保护基团(如叔丁氧基羰基，苄基氧基羰基，乙酰基，对甲氧基苄基等)，R 1，M 3和n如上文中所定义，n≥1。本领域技术人员可以根据本领域技术常规方法由式(I-w)的化合物制备式(I-t)的化合物，下述示意性地提供了由式(I-w)的化合物制备式(I-t)的化合物的方法：
例如，将式(I-w)的化合物和式(I-x)的化合物加入合适的溶剂(如二氯甲烷，甲醇，乙醇等，优选二氯甲烷)中，加入适当的酸(如乙酸)和脱水剂(如硫酸镁)，再加入适当的还原剂(如三乙酰氧基硼氢化钠，氰基硼氢化钠等)，在适当的温度(如室温)反应适当的时间(如15小时)。反应结束后，通过常规的后处理方法(如过滤，萃取，浓缩等)得到式(I-y)的化合物；
将式(I-y)的化合物和式(I-z)的化合物加入适当的溶剂(如乙醇)中，在适当的温度(如80℃)反应适当的时间(如15小时)。反应结束后，通过常规的后处理方法(如过滤，萃取，浓缩等)及纯化方法(如硅胶柱层析)得到式(I-a1)的化合物；
将式(I-a1)的化合物采用适当的脱保护的方法(如酸，碱，氢化，氧化等)进行处理，通过常规的后处理方法(如过滤，萃取，浓缩等)及纯化方法(如重结晶，硅胶柱层析等)得到式(I-t)的化合物。
在另外一些实施方式中，式(I-a1)的化合物可由如下反应式制备：
Figure PCTCN2020117074-appb-000076
其中，X 2，X 5分别独立选自CH或CH 2，PG为本领域公知的保护基团(如叔丁氧基羰基，苄基氧基羰基，乙酰基，对甲氧基苄基等)，LG为本领域公知的离去基团(如苯磺酸酯，甲磺酸酯等)，R 1，M 3和n如上文中所定义。本领域技术人员可以根据本领域技术常规方法由式 (I-o)的化合物制备式(I-a1)的化合物，下述示意性地提供了由式(I-o)的化合物制备式(I-a1)的化合物的方法：
例如，将式(I-o)的化合物溶解于适当的溶剂(如乙醇)中，在适当的温度(如0℃至室温)加入式(I-z)的化合物，反应适当的时间(2～15小时)。反应结束后，通过常规的后处理方法(如过滤，萃取，浓缩等)及纯化方法(如重结晶，硅胶柱层析等)得到式(I-a2)的化合物。
将式(I-a2)的化合物加入适当的溶剂(如二氯甲烷，四氢呋喃，2-甲基四氢呋喃等)，加入适当的碱(如三乙胺，N，N-二异丙基乙胺，N-甲基吗啉等)，降至适当的温度(如-5℃)，加入式(I-a3)的化合物，升至室温反应适当的时间(如14小时)。反应结束后，通过常规的后处理方法(如过滤，萃取，浓缩等)及纯化方法(如重结晶，硅胶柱层析等)得到式(I-a1)的化合物。
在本发明的某些实施方式中，R表示通式(b)所示的基团时，
Figure PCTCN2020117074-appb-000077
其中，X 1，X 4，X 5分别独立选自C、CH或CH 2，X 2为N，X 3为C＝O，Cy 2如上文中所定义。式(I-d)的化合物可由如下反应式制备：
Figure PCTCN2020117074-appb-000078
其中，LG为本领域公知的离去基团(如氯)，PG为本领域公知的保护基团(优选叔丁氧羰基)，R 1如上文所定义。本领域技术人员可以 根据本领域技术常规方法由式(I-d3)的化合物制备式(I-d)的化合物，下述示意性地提供了由式(I-d3)的化合物制备式(I-d)的化合物的方法：
例如，将式(I-d3)的化合物溶解于适当的溶剂(如乙酸乙酯)中，降温至适当的温度(如0℃)，加入式(I-d4)的化合物，升至室温反应适当的时间(如15小时)。反应结束后，加入适当的碱(如碳酸钾)淬灭，通过常规的后处理方法(如过滤，萃取，浓缩等)及纯化方法(如重结晶，硅胶柱层析等)得到式(I-d5)的化合物。
将式(I-d5)的化合物溶解于适当的溶剂(如甲基叔丁基醚)，降温至适当的温度(如0℃)，加入适当的还原剂(如三苯基膦，三正丁基膦等，优选三正丁基膦)，升至室温反应适当的时间(如15小时)。反应结束后，通过常规的后处理方法(如过滤，萃取，浓缩等)及纯化方法(如重结晶，硅胶柱层析等)得到式(I-d6)的化合物。
将式(I-d6)的化合物溶解于适当的溶剂中(如二氯甲烷，四氢呋喃等)，降温至适当的温度(如0℃)，加入适当的碱(如三乙胺，N，N-二异丙基乙胺，碳酸钾，碳酸钠等，优选三乙胺)和适当的保护基试剂(如二碳酸二叔丁酯)，升至室温反应适当的时间(如15小时)。反应结束后，通过常规的后处理方法(如过滤，萃取，浓缩等)及纯化方法(如重结晶，硅胶柱层析等)得到式(I-d7)的化合物。
将式(I-d7)的化合物加入适当的溶剂(如甲苯，二甲苯，三甲苯，N，N-二甲基甲酰胺，N，N-二甲基乙酰胺等，优选甲苯)，加入合适的试剂(如N，N-二甲基甲酰胺二甲基缩醛，原甲酸三甲酯，原甲酸三乙酯等，优选N，N-二甲基甲酰胺二甲基缩醛)，加热至适当的温度(如60℃)搅拌适当的时间(如15小时)。反应结束后，通过常规的后处理方法(如过滤，萃取，浓缩等)及纯化方法(如重结晶，硅胶柱层析等)得到式(I-d)的化合物。
在本发明的某些实施方式中，通式(I)所示化合物可由如下所示的方法制备，
反应式
Figure PCTCN2020117074-appb-000079
将式(I-a)加入到溶剂中，加入肽偶联试剂、碱、和式(I-f′)，搅拌反应完全，分离得式(I-j′)；或者，
将式(I-a)和式(I-f′)，加入到碱中，滴加偶联试剂，搅拌反应完全，分离得到式(I-j′)，
将式(I-j′)，加入到溶剂中，加入碱、钯催化剂、配体、碱、NPG，搅拌反应完全，分离得式(I-j)；
将式(I-j)，加入到溶剂中，加入酸，搅拌反应完全，分离得式(I)；
其中，M 3、R、n、Cy 3、Cy 4、L、LG、PG、k和Cy 5如上文所定义。
所述的溶剂选自：N，N-二甲基甲酰胺、N，N-二甲基乙酰胺、二甲基亚砜、甲苯、苯、二甲苯、三甲苯、环己烷、己烷、二氯甲烷、氯仿、1，2-二氯乙烷、四氢呋喃、乙醚、二噁烷、1，2-二甲氧基乙烷、乙酸甲酯、乙酸乙酯、丙酮、甲基乙基酮、乙腈、甲醇、乙醇、异丙醇、叔丁醇、水中的一种和其混合物；
所述的催化剂选自：氯化钯、醋酸钯、三(二亚苄基茚丙酮)二钯和其混合物；
所述的配体选自：1，1′-联萘-2，2′-双二苯膦、三苯基膦、和其混合物；
所述的碱选自：甲胺、乙胺、丙胺、N，N-二异丙基乙胺、三甲胺、三乙胺、二环己基胺、乙醇胺、二乙醇胺、三乙醇胺、葡甲胺、二乙 醇胺、乙二胺、吡啶、甲基吡啶、喹啉中的一种和其混合物；
所述的酸选自：甲酸、乙酸、丙酸、三氟乙酸、柠檬酸、乳酸、酒石酸、草酸、马来酸、富马酸、扁桃酸、戊二酸、苹果酸、安息香酸、邻苯二甲酸、抗坏血酸、苯磺酸、对甲苯磺酸、甲基磺酸、乙基磺酸；盐酸、硫酸、硝酸、碳酸、氢溴酸、磷酸、氢碘酸；
所述的肽偶联试剂选自：2-(7-偶氮苯并三氮唑)-四甲基脲六氟磷酸酯(HATU)、苯并三氮唑-N，N，N′，N′-四甲基脲六氟磷酸酯(HBTU)、2-(1H-苯并[d][1，2，3]三偶氮-1-基)-1，1，3，3-四甲基脲四氟硼酸酯(TBTU)的一种和其混合物；
所述的偶联试剂选自：三氯氧磷、二环己基碳二亚胺(DCC)、N，N′-羰基二咪唑、氯甲酸异丁酯、1-正丙基磷酸酐等的一种和其混合物。
在本发明的某些实施方式中，通式(I)所示化合物的可由如下所示的方法制备。
反应式
Figure PCTCN2020117074-appb-000080
如上所示，式(I)的化合物可以通过式(I-j)的化合物进行脱保护反应制备。
其中，M 3、R、n、W、Cy 3、L、PG、k、R 1和Cy 5如上文所定义。
本领域技术人员可以根据本领域技术常规方法由式(I-j)的化合物来制备式(I)的化合物，下述示意性地提供了由式(I-j)的化合物来制备式(I)的化合物的方法：
例如，将式(I-j)的化合物加入合适的溶剂中(如甲醇、四氢呋喃、N，N-二甲基甲酰胺、N，N-二甲基乙酰胺等，优选N，N-二甲基甲酰胺)，加入水，再加入合适的酸(甲酸、乙酸、丙酸、三氟乙酸、柠檬酸、乳酸、酒石酸、草酸、马来酸、富马酸、扁桃酸、戊二酸、苹果酸、安息香酸、邻苯二甲酸、抗坏血酸、苯磺酸、对甲苯磺酸、甲基磺酸、乙基磺酸；盐酸、硫酸、硝酸、碳酸、氢溴酸、磷酸、氢碘酸)，室温搅拌适当的时间(如10～30分钟)，监测反应完全后，加入适量的水，调节PH，用合适的萃取剂(如乙酸乙酯)萃取，萃取液浓缩，粗品经常规的纯化方法(如硅胶柱层析)分离得到式(I-j)的化合物。
如上所示，式(I-j)的化合物可以通过式(I-j)的化合物反应制备。
Figure PCTCN2020117074-appb-000081
其中，M 3、R、n、Cy 3、L和Cy 5如上文所定义。
本领域技术人员可以根据本领域技术常规方法由式(I-j’)的化合物来制备式(I-j)的化合物，下述示意性地提供了由式(I-j’)的化合物来制备式(I-j)的化合物的方法：
例如，将式(I-j’)的化合物加入适当的溶剂(如1，4-二氧六环，四氢呋喃，乙腈，N，N-二甲基甲酰胺、N，N-二甲基乙酰胺等，优选N，N-二甲基甲酰胺)，加入适当的催化剂如醋酸钯，氯化钯等，加入适当的配体(BINAP，XPhos，SPhos，Ruphos等)，加入适当的碱(如碳酸钾，碳酸钠，三乙胺，N，N-二异丙基乙胺等，优选碳酸钾)，加入NPG(如二苯甲酮亚胺，对甲氧基苄胺，叔丁胺)，在适当的温度(如室温至110℃)搅拌适当的时间(如14小时)。反应结束后，通过常规的后处理方法(如过滤，萃取等)得到粗品，再通过常规的纯化手段分离(如硅胶柱层析)得到式(I-j)的化合物。
如上所示，式(I-j’)的化合物可以通过式(I-a)的化合物与式(I-f’)的化合物反应制备。
Figure PCTCN2020117074-appb-000082
其中，M 3、R、n、Cy 3、L和Cy 5如上文所定义。
本领域技术人员可以根据本领域技术常规方法由式(I-a)的化合物和式(I-f’)的化合物来制备式(I-j’)的化合物，下述示意性地提供了由式(I-a)的化合物和式(I-f’)的化合物反应来制备式(I-j’)的化合物的方法：
例如，将式(I-a)的化合物加入合适的溶剂中(如四氢呋喃、N，N-二甲基甲酰胺、N，N-二甲基乙酰胺等，优选N，N-二甲基甲酰胺)，加入合适肽偶联试剂(优选2-(7-氧化苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯)，再加入合适的碱(如三乙胺、吡啶、N，N-二异丙基乙胺等，优选N，N-二异丙基乙胺)，降至适当的温度(如0℃)，搅拌适当的时间(如10～30分钟)，加入式(I-f’)的化合物，在适当的温度(如0℃至环境温度)搅拌合适的时间(如1～16小时)。将反应液减压浓缩，加入适量的水，用合适的萃取剂(如乙酸乙酯)萃取，萃取液浓缩，粗品经常规的纯化方法(如硅胶柱层析)分离得到式(I-j’)的化合物。
又例如，将式(I-a)的化合物和式(I-f’)的化合物加入合适的碱中(如吡啶)，降至适当的温度(如0℃)，滴加偶联试剂(如三氯氧磷)，加完搅拌合适的时间(如0.5～3小时)至反应完全，将反应液减压浓缩，加入适量的水，用合适的萃取剂(如乙酸乙酯)萃取，萃取液浓缩，粗品经常规的纯化方法(如硅胶柱层析)分离得到式(I-j’)的化合物。
如上所示，式(I-a)的化合物可通过式(I-c)的化合物制备。
Figure PCTCN2020117074-appb-000083
其中，R 1为C 1-6烷基，M 3、R和n如上文中所定义。本领域技术人员可以根据本领域技术常规方法由式(I-c)的化合物制备式(I-a)的化合物，下述示意性地提供了由式(I-c)的化合物制备式(I-a)的化合 物的方法：
例如，将式(I-c)的化合物溶解于合适的溶剂(如甲醇，乙醇，四氢呋喃，二氧六环等，优选甲醇)，加入合适的碱(如氢氧化锂，氢氧化钠，氢氧化钾等，优选氢氧化锂)，在适当的温度(如室温)，搅拌适当的时间(如0.5～3小时)，反应结束后，减压浓缩，用适当的酸(如盐酸、柠檬酸)的水溶液调节pH值至合适范围(如2～5)，过滤得到式(I-a)的化合物。
如上所示，式(I-c)的化合物可以通过式(I-d)的化合物与式(I-e)的化合物反应制备。
Figure PCTCN2020117074-appb-000084
其中，R、R 1、M 3和n如上文中所定义，LG为离去基团(例如为氯、溴、碘、甲磺酸酯或苯磺酸酯等)或硼酸、硼酸酯，M 3和n如上文中所定义。本领域技术人员可以根据本领域技术常规方法由式(I-d)的化合物和式(I-e)的化合物制备式(I-c)的化合物，下述示意性地提供了由式(I-d)的化合物和式(I-e)的化合物反应制备式(I-c)的化合物的方法：
例如，将式(I-d)的化合物和式(I-e)的化合物(LG为离去基团)溶解于合适的溶剂(如乙腈、四氢呋喃、N，N-二甲基甲酰胺等，优选N，N-二甲基甲酰胺)中，加入适当的碱(如碳酸钠、碳酸钾、碳酸铯等，优选碳酸钾)，在适当的温度(如50℃)搅拌反应适当的时间(如10～16小时)，反应结束后加入水和适当的萃取剂，粗产品通过常规的纯化手段分离(如硅胶柱层析)得到式(I-c)的化合物。
又例如，将式(I-d)的化合物和式(I-e)的化合物(LG为硼酸或硼酸酯)溶解于合适的溶剂(如乙腈，二氯甲烷，氯仿，吡啶，N，N-二甲基甲酰胺等，优选N，N-二甲基甲酰胺)，加入适当的碱(如三乙胺，吡啶等)和适当的催化剂(如醋酸铜，氯化铜等)，在空气或氧气条件下，在适当的温度(如室温至50℃)，反应适当的时间(如14小时)。反应结束后，通过常规后处理(如萃取，浓缩)得到粗品，再通过常规的纯化手段(如硅胶柱层析)得到产品。
如上所示，式(I-f’)的化合物可通过式(I-h’)的化合物和式(I-g) 的化合物反应制备。
Figure PCTCN2020117074-appb-000085
其中，Cy 3、L、LG、W和Cy 5如上文所定义。本领域技术人员可以根据本领域技术常规方法由式(I-h’)的化合物和式(I-g)的化合物制备式(I-f’)的化合物，下述示意性地提供了由式(I-h’)的化合物和式(I-g)的化合物制备式(I-f’)的化合物的方法：
例如，将式(I-g)的化合物和式(I-h’)的化合物加入适当的溶剂(如四氢呋喃，乙腈，N，N-二甲基甲酰胺、N，N-二甲基乙酰胺等，优选N，N-二甲基甲酰胺)，加入适当的碱(如碳酸钾，碳酸钠，三乙胺，N，N-二异丙基乙胺等，优选碳酸钾)，在适当的温度(如室温至80℃)搅拌适当的时间(如14小时)。反应结束后，通过常规的后处理方法(如过滤，萃取等)得到粗品，再通过常规的纯化手段分离(如硅胶柱层析)得到产品。
本发明化合物的合成中，反应溶剂可以使用本领域中常用的溶剂，包括但不限于醚类，烷烃类，卤代烷烃类，芳烃类，醇类等。具体而言，可以列举N，N-二甲基甲酰胺、N，N-二甲基乙酰胺、二甲基亚砜、芳族烃类(例如甲苯、苯、二甲苯、三甲苯等)、饱和烃类(例如环己烷、己烷等)、卤代烃类(例如二氯甲烷、氯仿、1，2-二氯乙烷等)、醚类(例如四氢呋喃、乙醚、二噁烷、1，2-二甲氧基乙烷等)、酯类(例如乙酸甲酯、乙酸乙酯等)、酮类(例如丙酮、甲基乙基酮等)、腈类(例如乙腈等)、醇类(例如甲醇、乙醇、异丙醇、叔丁醇等)、水和它们的混合溶剂等。
本发明化合物的合成中，使用的碱可以是本领域常用的碱类，包括有机碱和无机碱。作为有机碱，可以列举甲胺、乙胺、丙胺、N，N-二异丙基乙胺、三甲胺、三乙胺、二环己基胺、乙醇胺、二乙醇胺、三乙醇胺、葡甲胺、二乙醇胺、乙二胺、吡啶、甲基吡啶、喹啉等；作为无机碱，可以列举碱金属(例如锂、钠、钾、铯)的氢氧化物、碳酸盐、碳酸氢盐；碱土金属(镁、钙、锶、钡)的氢氧化物、碳酸盐、碳酸氢盐；叔丁醇钠，叔丁醇钾，乙醇钠等。
本发明化合物的合成中，使用的酸可以是本领域常用的酸类，包 括有机酸和无机酸。作为有机酸，可以列举甲酸、乙酸、丙酸、三氟乙酸、柠檬酸、乳酸、酒石酸、草酸、马来酸、富马酸、扁桃酸、戊二酸、苹果酸、安息香酸、邻苯二甲酸、抗坏血酸、苯磺酸、对甲苯磺酸、甲基磺酸、乙基磺酸；作为无机酸，可以列举盐酸、硫酸、硝酸、碳酸、氢溴酸、磷酸、氢碘酸等。
本发明化合物的合成中，使用的还原剂，可以是本领域常用的还原剂，包括但不限于，三苯基膦、三正丁基膦、三乙酰氧基硼氢化钠、氰基硼氢化钠、硼氢化钠、铁粉、锌粉、氯化亚锡、连亚二硫酸钠、氢气等。
本发明化合物的合成中，使用的氧化剂，可以是本领域常用的氧化剂，包括但不限于，氯化铜、二氧化锰、高锰酸盐、重铬酸盐、过氧乙酸、过氧苯甲酸等。
本发明化合物的合成中，所用的催化剂，可以是本领域常用的催化剂，包括但不限于如醋酸铜，氯化铜、钯炭、氯化铁、醋酸钯、[1，1′-双(二苯基膦基)二茂铁]二氯化钯等。实施例
根据下述实施例和实验例，可以更好地理解本发明。并且本领域的技术人员容易理解，实施例所描述的内容仅用于说明本发明，不应当也不会限制权利要求书中所详细描述的本发明。
实施例中未注明具体反应条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售获得的常规产品。
在本发明中，除非另外说明，其中：(i)温度以摄氏度(℃)表示，除非另外说明，操作在室温环境下进行；(ii)反应进程用薄层色谱(TLC)或LC-MS跟踪；(iii)终产物具有清晰的质子核磁共振光谱( 1H-NMR)数据和质谱(MS)数据。
在本发明中所使用的缩写和英文表述具有以下含义。
DCM：二氯甲烷
DMF：N，N-二甲基甲酰胺
EA：乙酸乙酯
MeOH：甲醇
PE：石油醚
BINAP：(±)-2，2′-双-(二苯膦基)-1，1′-联萘
(NH 4) 2S：硫化铵
Boc-：叔丁氧羰基
DMSO：二甲基亚砜
Pd 2(dba) 3：三(二亚苄基丙酮)二钯
Pd(OAc) 2：醋酸钯
EtOH：乙醇
-PMB：(4-甲氧基苄基)-
HATU：2-(7-偶氮苯并三氮唑)-四甲基脲六氟磷酸酯
XPhos：2-二环己基磷-2′，4′，6′-三异丙基联苯
SPhos：2-双环己基膦-2′，6′-二甲氧基联苯
Ruphos：2-二环己基磷-2′，6′-二异丙氧基-1，1′-联苯
实施例1 5-(4-氟苯基)-1-异丙基-N-(5-((1-甲基-6-(1H-吡唑-4-基)-1H-吲唑-5-基)氧基)吡啶-2-基)-4-氧代-1，4-二氢哒嗪-3-甲酰胺(化合物1)的合成
Figure PCTCN2020117074-appb-000086
步骤1：2，4-二溴-5-羟基苯甲醛的合成
Figure PCTCN2020117074-appb-000087
将间羟基苯甲醛(10.0g，0.0819mol，1.0eq)加入DCM(100mL)中，缓慢滴加溴(27.5g，0.172mol，2.1eq)，室温搅拌4小时。TLC监测反应完全后，滴加硫代硫酸钠水溶液(质量分数10％)直到反应液红色褪去，有灰色固体析出，减压抽滤，滤饼为产物(8.0g，收率：35.1％)。
步骤2：2，4-二溴-5-((6-硝基-吡啶-3-基)氧基)苯甲醛的合成
Figure PCTCN2020117074-appb-000088
将2，4-二溴-5-羟基苯甲醛(5.6g，20mmol，1.0eq)、5-氟-2-硝基吡啶(2.84g，20mmol，1.0eq)和碳酸钾(4.14g，30mmol)加入到烧瓶中，再加入乙腈(15mL)和N，N-二甲基乙酰胺(15mL)，60℃加热反应16小时，TLC监测反应完全，减压浓缩，加入乙酸乙酯(100mL)，有机相水洗(4×20mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，粗品经硅胶柱层析(PE∶EA＝30∶1～10∶1)纯化得产品(3.5g，收率：43.7％)。
步骤3：5-(2，4-二溴-5-((2-甲基亚肼基)甲基)苯氧基)-2-硝基吡啶的合成
Figure PCTCN2020117074-appb-000089
将2，4-二溴-5-((6-硝基-吡啶-3-基)氧基)苯甲醛(3.12g，7.8mmol，1.0eq)、甲基肼硫酸盐(2.25g，15.6mmol)加入到烧瓶中，加入四氢呋喃(30mL)和三乙胺(3.16g，31.2mmol)，加热至80℃反应16小时，TLC监测反应完全。加入乙酸乙酯(100mL)，有机相水洗(4×20mL)，无水硫酸钠干燥，过滤，滤液减压浓缩得产品(2g，收率：59.6％)。
步骤4：6-溴-1-甲基-5-((6-硝基-吡啶-3-基)氧基)-1H-吲唑的合成
Figure PCTCN2020117074-appb-000090
将5-(2，4-二溴-5-((2-甲基亚肼基)甲基)苯氧基)-2-硝基吡啶(2.0g，4.67mmol，1.0eq)、碳酸钾(968.8mg，7.02mL)、氯化亚铜(46.28mg，0.468mmol)和DMF(20mL)加热至110℃反应16小时，TLC监测反应完全，减压浓缩，加入乙酸乙酯(50mL)，有机相水洗(4×10mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，粗品经硅胶柱层析纯化(PE∶EA＝20∶1～5∶1)得产品(500mg，收率：30.6％)。
步骤5：5-((6-溴-1-甲基-1H-吲唑-5-基)氧基)吡啶-2-胺的合成
Figure PCTCN2020117074-appb-000091
将6-溴-1-甲基-5-((6-硝基-吡啶-3-基)氧基)-1H-吲唑(500.0mg，1.43mmol，1.0eq)、铁粉(802mg，14.3mmol)和饱和氯化铵溶液(2.5mL)加入 乙醇(5mL)中，加热至80℃反应8小时，TLC监测反应完全，减压浓缩，加入乙酸乙酯(50mL)和水(10mL)，分液，有机相无水硫酸钠干燥，过滤，滤液减压浓缩得产品(348.0mg，收率：76.2％)。
步骤6：N-(5-((6-溴-1-甲基-1H-吲唑-5-基)氧基)吡啶-2-基)-5-(4-氟苯基)-1-异丙基-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成
Figure PCTCN2020117074-appb-000092
将5-((6-溴-1-甲基-1H-吲唑-5-基)氧基)吡啶-2-胺(348.0mg，1.086mmol，1.0eq)、5-(4-氟苯基)-1-异丙基-4-氧代-1，4-二氢哒嗪-3-羧酸(300mg，1.086mmol)加入吡啶(5mL)中，滴加三氯氧磷(188.0mg，1.41mmol)。室温反应30分钟，TLC监测反应完全，加入水(30mL)，有固体析出，减压抽滤，滤饼为产物(400.0mg，收率：63.9％)。
步骤7：4-(5-((6-(5-(4-氟苯基)-1-异丙基-4-氧代-1，4-二氢哒嗪-3-甲酰胺基)吡啶-3-基)氧基)-1-甲基-1H-吲唑-6-基)-1H-吡唑-1-羧酸叔丁酯的合成
Figure PCTCN2020117074-appb-000093
将N-(5-((6-溴-1-甲基-1H-吲唑-5-基)氧基)吡啶-2-基)-5-(4-氟苯基)-1-异丙基-4-氧代-1，4-二氢哒嗪-3-甲酰胺(350.0mg，0.608mmol)、4-(4，4，5，5-四甲基-1，3，2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-羧酸叔丁酯(286.2mg，0.973mmol)、[1，1′-双(二叔丁基膦)二茂铁]二氯化钯(II)(19.8mg，0.0304mmol)、磷酸钾(516.2mg，2.432mmol)、二碳酸二叔丁酯(106.3mg，0.486mmol)加入水(0.5mL)和1，4-二氧六环(5mL)中，100℃反应11小时，TLC监测反应完全，加入水(20mL)，有固体析出，减压抽滤，滤饼加入二氯甲烷溶解，无水硫酸钠干燥，过滤，滤液减压浓缩，粗品经硅胶柱层析纯化(DCM∶MeOH＝60∶1～10∶1)得产品(350 mg，收率：86.7％)。
步骤8：5-(4-氟苯基)-1-异丙基-N-(5-((1-甲基-6-(1H-吡唑-4-基)-1H-吲唑-5-基)氧基)吡啶-2-基)-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成
Figure PCTCN2020117074-appb-000094
将4-(5-((6-(5-(4-氟苯基)-1-异丙基-4-氧代-1，4-二氢哒嗪-3-甲酰胺基)吡啶-3-基)氧基)-1-甲基-1H-吲唑-6-基)-1H-吡唑-1-羧酸叔丁酯(350.0mg，0.527mmol)加入DCM(5mL)中，加入三氟乙酸(2.5mL)，室温搅拌反应4小时。TLC监测反应完全，加入DCM(20mL)和水(10mL)，向反应体系中加入碳酸氢钠调节pH值至7～8，分液，有机相无水硫酸钠干燥，过滤，滤液减压浓缩，粗品经硅胶柱层析纯化(DCM∶MeOH＝40∶1～10∶1)得产品(218.0mg，收率：73.3％)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：13.03(s，1H)，8.39-8.36(d，1H)，8.15-8.14(d，1H)，8.10(s，1H)，8.04(s，1H)，7.91(s，1H)，7.80-7.75(m，2H)，7.62(s，1H)，7.35(s，1H)，7.26(s，1H)，7.25(s，1H)，7.22-7.16(t，2H)，4.74-4.69(t，1H)，4.15(s，3H)，1.67-1.65(d，6H).
分子式：C 30H 25FN 8O 3；分子量：564.58；LC-MS(Pos，m/z)＝565.23[M+H] +.
实施例2 N-(5-((2-氨基-3-氯吡啶-4-基)氧基)吡啶-2-基)-5-(4-氟苯基)-1-异丙基-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成(化合物11)
Figure PCTCN2020117074-appb-000095
步骤1：2，3-二氯吡啶-4-醇的合成
Figure PCTCN2020117074-appb-000096
将二异丙胺(16.1g，0.16mol)加入四氢呋喃(80mL)中，冰盐浴冷却至-10℃，缓慢滴加正丁基锂(62.6mL，0.157mmol)，反应半小时，将上述反应液缓慢滴加到2，3-二氯吡啶(15.0g，0.101mol，1.0eq)和三异丙基硼酸酯(38.18g，0.203mol)的四氢呋喃(150mL)溶液中，25℃下反应3小时。TLC监测反应完全，向反应液中加入水(150mL)，分两次加入过碳酸钠(35.7g)，25℃搅拌1小时，用柠檬酸水溶液调节pH值至2～3，再加入亚硫酸氢钠(12.75g)，反应液用甲苯(100mL)萃取，合并有机相，水洗(2×10mL)，减压浓缩，有固体析出，减压抽滤，滤饼为产物(10.0g，收率：60.5％)。
步骤2：2，3-二氯-4-((6-硝基-吡啶-3-基)氧基)吡啶的合成
Figure PCTCN2020117074-appb-000097
将2，3-二氯吡啶-4-醇(4.68g，0.0285mol，1.0eq)、5-氟-2-硝基吡啶(4.06g，0.0285mol，1.0eq)和碳酸锂(3.17g，0.0428mol)加入DMSO(40mL)中，120℃加热反应16小时，TLC监测反应完全，加入乙酸乙酯(200mL)，有机相水洗(4×20mL)，无水硫酸钠干燥，过滤，减压浓缩，粗品用乙酸乙酯(20mL)打浆得产品(7g，产率：86.2％)。
步骤3：N-(3-氯-4-((6-硝基-吡啶-3-基)氧基)吡啶-2-基)-1，1-二苯基甲亚胺的合成
Figure PCTCN2020117074-appb-000098
将2，3-二氯-4-((6-硝基-吡啶-3-基)氧基)吡啶(7.0g，0.0246mol，1.0eq)、二苯基甲亚胺(4.46g，0.0246mol)、醋酸钯(139.2mg，0.62mmol)、BINAP(582.0mg，0.93mmol)和碳酸铯(16.0g，0.0492mol)加入1，4-二氧六环(50mL)中，加热至100℃反应16小时，TLC监测反应完全。加入乙酸乙酯(200mL)，有机相水洗(4×15mL)，无水硫酸钠干燥，过滤， 滤液减压浓缩，粗品经硅胶柱层析(DCM∶MeOH＝100∶1～10∶1)纯化得产品(9g，收率：84.9％)。
步骤4：5-((3-氯-2-((二苯基亚甲基)氨基)吡啶-4-基)氧基)吡啶-2胺的合成
Figure PCTCN2020117074-appb-000099
将N-(3-氯-4-((6-硝基-吡啶-3-基)氧基)吡啶-2-基)-1，1-二苯基甲亚胺(2.0g，4.64mmol，1.0eq)加入20％的(NH 4) 2S水溶液(15mL，10.0eq)中，加入异丙醇(100mL)，室温反应1小时，加热至70℃反应2小时。反应结束，降至室温，加水(50mL)，乙酸乙酯萃取(3×50mL)，有机相合并，无水硫酸钠干燥，过滤，滤液减压浓缩，粗品经硅胶柱层析(DCM∶MeOH＝50∶1～20∶1)纯化得到产品(300.0mg，收率：16.1％)。
步骤5：N-(5-((3-氯-2-((二苯基亚甲基)氨基)吡啶-4-基)氧基)吡啶-2-基)-5-(4-氟苯基)-1-异丙基-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成
Figure PCTCN2020117074-appb-000100
将5-((3-氯-2-((二苯基亚甲基)氨基)吡啶-4-基)氧基)吡啶-2胺(275.0mg，0.686mmol，1.0eq)、5-(4-氟苯基)-1-异丙基-4-氧代-1，4-二氢哒嗪-3-羧酸(189.5mg，0.686mmol，1.0eq)溶解于吡啶(5mL)中，滴加三氯氧磷(157.8mg，1.029mmol，1.5eq)，室温搅拌30分钟。TLC监测反应完全，加入水(20mL)淬灭，用乙酸乙酯(50mL)萃取，有机相无水硫酸钠干燥，过滤，滤液减压浓缩得产品(400mg，收率：88.5％)。
步骤6：N-(5-((2-氨基-3-氯吡啶-4-基)氧基)吡啶-2-基)-5-(4-氟苯基)-1-异丙基-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成
Figure PCTCN2020117074-appb-000101
将N-(5-((3-氯-2-((二苯基亚甲基)氨基)吡啶-4-基)氧基)吡啶-2-基)-5-(4-氟苯基)-1-异丙基-4-氧代-1，4-二氢哒嗪-3-甲酰胺(400.0mg，0.607mmol，1.0eq)加入异甲醇(4mL)中，加入水(0.7mL)和浓盐酸(0.2mL)，室温搅拌30分钟，TLC监测反应完全，冷却至室温，加入饱和NaHCO 3水溶液，将pH值调至7～8，用DCM萃取(20mL×3)，有机相合并，无水硫酸钠干燥，过滤，滤液减压浓缩，粗品经硅胶柱层析(DCM∶MeOH＝30∶1～10∶1)纯化得到产品(201.0mg，收率：59.2％)。
1H-NMR(300MHz，CDCl 3)δ(ppm)：13.19(s，1H)，8.52(d，1H)，8.24(s，1H)，8.23(s，1H)，8.49(d，1H)，7.83-7.75(m，2H)，7.51(t，1H)，7.18(t，2H)，6.12(d，1H)，5.09(s，2H)，4.79-4.66(m，1H)，1.68(s，3H)，1.66(s，3H).
分子式：C 24H 20ClFN 6O 3；分子量：494.91；LC-MS(Pos，m/z)＝494.05[M+H] +.
实施例3 N-(5-((2-氨基-3-氯吡啶-4-基)氧基)嘧啶-2-基)-5-(4-氟苯基)-1-异丙基-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成(化合物12)
Figure PCTCN2020117074-appb-000102
步骤1：N-(5-((2，3-二氯吡啶-4-基)氧基)嘧啶-2-基)-5-(4-氟苯基)-1-异丙基-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成
Figure PCTCN2020117074-appb-000103
将5-(4-氟苯基)-1-异丙基-4-氧代-1，4-二氢哒嗪-3-羧酸(1.0g，3.61mmol，1.0eq)加入吡啶(10mL)中，加入5-((2，3-二氯吡啶-4-基)氧基)嘧啶-2-胺(930.5mg，3.61mmol，1.0eq)和三氯氧磷(0.5mL)，室温搅拌15分钟。TLC监测反应完全，加入乙酸乙酯(200mL)和水(150mL)，分液，水相再用乙酸乙酯(100mL)萃取，有机相合并，无水硫酸钠干燥，抽滤，滤液经硅胶柱层析(100-200目硅胶，二氯甲烷∶甲醇＝100∶1～50∶1)纯化得产品(1.56g，收率：83.8％)。
步骤2：N-(5-((3-氯-2-((二苯基亚甲基)氨基)吡啶-4-基)氧基)嘧啶-2-基)-5-(4-氟苯基)-1-异丙基-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成
Figure PCTCN2020117074-appb-000104
将N-(5-((2，3-二氯吡啶-4-基)氧基)嘧啶-2-基)-5-(4-氟苯基)-1-异丙基-4-氧代-1，4-二氢哒嗪-3-甲酰胺(1.54g，2.98mmol，1.0eq)加入1，4-二氧六环(16mL)中，加入二苯甲酮亚胺(812.4mg，4.48mmol，1.5eq)、碳酸铯(1.94g，5.97mmol，2.0eq)、Pd 2(dba) 3(273.6mg，0.29mmol，0.1eq)、1，1′-联萘-2，2′-双二苯膦(278.9mg，0.44mmol，0.15eq)，110℃回流12小时。TLC监测反应完全后，冷却至室温，浓缩，粗品经硅胶柱层析纯化(100-200目硅胶，二氯甲烷∶甲醇＝100∶1～50∶1)得产物(565.0mg，收率：28.6％)。
步骤3：N-(5-((2-氨基-3-氯吡啶-4-基)氧基)嘧啶-2-基)-5-(4-氟苯 基)-1-异丙基-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成
Figure PCTCN2020117074-appb-000105
将N-(5-((3-氯-2-((二苯基亚甲基)氨基)吡啶-4-基)氧基)嘧啶-2-基)-5-(4-氟苯基)-1-异丙基-4-氧代-1，4-二氢哒嗪-3-甲酰胺(565.0mg，0.85mmol，1.0eq)溶于甲醇(10mL)，加入浓盐酸(0.2mL)，室温反应1小时，TLC检测反应完全，用饱和碳酸钠水溶液调节pH值至8，加入乙酸乙酯(100mL)，分液，水相再用二氯甲烷(100mL)萃取，有机相合并，无水硫酸钠干燥，过滤，滤液浓缩，粗品经硅胶柱层析纯化(100-200目硅胶，二氯甲烷∶甲醇＝80∶1～40∶1)得产物(257.0mg，收率：60.6％)。
1HNMR(300MHz，DMSO-d 6)δ(ppm)：12.85(s，1H)，8.87(s，1H)，8.66(s，2H)，8.19(s，2H)，7.90-7.94(m，2H)，7.77-7.78(d，J＝5.7Hz，1H)，7.28-7.34(t，J＝9Hz，2H)，6.48(s，2H)，6.11-6.13(d，J＝5.7Hz，1H)，4.69-4.73(t，J＝13.2Hz，1H)，1.47-1.49(d，J＝6.6Hz，6H).
分子式：C 23H 19 ClFN 7O 3；分子量：495.90；LC-MS(Pos，m/z)＝496.02[M+H] +.
实施例4 N-(5-((2-氨基-3-氯吡啶-4-基)氧基)吡啶-2-基)-1-环丙基-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成(化合物17)
Figure PCTCN2020117074-appb-000106
步骤1：N-(5-((3-氯-2-((二苯基亚甲基)氨基)吡啶-4-基)氧基)吡啶-2-基)-1-环丙基-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成
Figure PCTCN2020117074-appb-000107
将1-环丙基-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-羧酸(62.9mg，0.22mmol，1.0eq)加入吡啶(3mL)中，加入5-((3-氯-2-(((二苯基亚甲基)氨基)吡啶-4-基)氧基)吡啶-2-胺(92.0mg，0.22mmol，1.0eq)和三氯氧磷(0.2mL)，室温搅拌0.5小时。TLC监测反应完全，加入乙酸乙酯(50mL)和水(100mL)，分液，有机相无水硫酸钠干燥，抽滤，滤液浓缩得粗品(201.3mg)，直接用于下一步。
步骤2：N-(5-((2-氨基-3-氯吡啶-4-基)氧基)吡啶-2-基)-1-环丙基-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成
Figure PCTCN2020117074-appb-000108
将N-(5-((3-氯-2-((二苯基亚甲基)氨基)吡啶-4-基)氧基)吡啶-2-基)-1-环丙基-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-甲酰胺(201.3mg粗品，0.22mmol，1.0eq)加入甲醇(15mL)中，加入水(5.0mL)和浓盐酸(0.5mL)，室温搅拌1小时，TLC监测反应完全，减压浓缩，加入EA(50mL)和水(50mL)，分液，有机相无水硫酸钠干燥，过滤，滤液减压浓缩，粗品经制备薄层色谱纯化(DCM∶MeOH＝20∶1)得到产品(50.0mg，两步收率：44.2％)。
1HNMR(400MHz，DMSO-d 6)δ(ppm)：12.94(s，1H)，8.93(s，1H)， 8.33-8.35(d，J＝9Hz，1H)，8.28-8.29(d，J＝2.8Hz，1H)，7.92-7.96(m，2H)，7.79-7.80(d，J＝5.64Hz，1H)，7.73-7.76(dd，J＝2.92，2.96Hz，1H)，7.31-7.36(t，J＝8.92Hz，2H)，6.44(s，2H)，6.05-6.06(d，J＝5.64Hz，1H)，4.11-4.14(q，J＝3.72Hz，1H)，1.31-1.33(t，J＝3.04Hz，2H)，1.11-1.13(q，J＝1.84Hz，2H).
分子式：C 24H 18ClFN 6O 3；分子量：492.90；LC-MS(Pos，m/z)＝493.07[M+H] +.
实施例5 N-(5-((2-氨基-3-氯吡啶-4-基)氧基)嘧啶-2-基)-5-(4-氟苯基)-1-环丙基-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成(化合物18)
Figure PCTCN2020117074-appb-000109
步骤1：N-(5-((2，3-二氯吡啶-4-基)氧基)嘧啶-2-基)-5-(4-氟苯基)-1-环丙基-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成
Figure PCTCN2020117074-appb-000110
将5-(4-氟苯基)-1-环丙基-4-氧代-1，4-二氢哒嗪-3-羧酸(1.5g，5.46mmol，1.0eq)加入吡啶(15mL)中，加入5-((2，3-二氯吡啶-4-基)氧基)嘧啶-2-胺(1.4g，5.46mmol，1.0eq)和三氯氧磷(0.5mL)，室温搅拌15分钟。TLC监测反应完全，加入乙酸乙酯(200mL)和水(150mL)，分液，水相用乙酸乙酯(150mL)萃取，有机相合并，无水硫酸钠干燥，抽滤，滤液浓缩，粗品经硅胶柱层析纯化(100-200目硅胶，二氯甲烷∶甲醇＝100∶1～50∶1)得产品(2.38g，收率：85.0％)。
步骤2：N-(5-((3-氯-2-((二苯基亚甲基)氨基)吡啶-4-基)氧基)嘧啶-2- 基)-5-(4-氟苯基)-1-环丙基-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成
Figure PCTCN2020117074-appb-000111
将N-(5-((2，3-二氯吡啶-4-基)氧基)嘧啶-2-基)-5-(4-氟苯基)-1-环丙基-4-氧代-1，4-二氢哒嗪-3-甲酰胺(960.0mg，1.87mmol，1.0eq)加入1，4-二氧六环(10mL)中，加入二苯甲酮亚胺(508.4mg，2.80mmol，1.5eq)、碳酸铯(1.22g，3.74mmol，2.0eq)、Pd 2(dba) 3(171.2mg，0.18mmol，0.1eq)和1，1′-联萘-2，2′-双二苯膦(174.5mg，0.28mmol，0.15eq)，110℃回流搅拌12小时。TLC监测反应完全，冷却至室温，浓缩，粗品经硅胶柱层析纯化(100-200目硅胶，二氯甲烷∶甲醇＝100∶1～40∶1)得产品(365.0mg，收率：29.7％)。
步骤3：N-(5-((2-氨基-3-氯吡啶-4-基)氧基)嘧啶-2-基)-5-(4-氟苯基)-1-环丙基-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成
Figure PCTCN2020117074-appb-000112
将N-(5-((3-氯-2-((二苯基亚甲基)氨基)吡啶-4-基)氧基)嘧啶-2-基)-5-(4-氟苯基)-1-环丙基-4-氧代-1，4-二氢哒嗪-3-甲酰胺(360.0mg，0.54mmol，1.0eq)溶于甲醇(6mL)，加入浓盐酸(0.15mL)，室温反应1小时，TLC检测反应完全，用饱和碳酸钠水溶液调节pH值至8，加入乙酸乙酯(100mL)，分液，水相再用二氯甲烷(100mL)萃取，有机相合 并，无水硫酸钠干燥，过滤，滤液经制备薄层色谱纯化(二氯甲烷∶甲醇＝20∶1)得产物(158.0mg，收率：58.5％)。
1HNMR(300MHz，DMSO-d 6)δ(ppm)：12.79(s，1H)，8.88(s，1H)，8.66(s，2H)，7.88-8.19(m，2H)，7.72-7.78(m，1H)，7.28-7.34(t，J＝9Hz，2H)，6.49(s，2H)，6.10-6.12(d，J＝2Hz，1H)，4.04-4.11(m，1H)，1.22-1.29(m，2H)，1.10-1.12(m，2H).
分子式：C 23H 17 ClFN 7O 3；分子量：493.88；LC-MS(Pos，m/z)＝494.17[M+H] +.
实施例6 N-(6-((2-氨基-3-氯吡啶-4-基)氧基)吡啶-3-基)-1-环丙基-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成(化合物19)
Figure PCTCN2020117074-appb-000113
步骤1：2，3-二氯-4-((5-硝基吡啶-2-基)氧基)吡啶的合成
Figure PCTCN2020117074-appb-000114
将2-氟-5-硝基吡啶(11.0g，77.38mmol，1.0eq)、2，3-二氯-4-羟基吡啶(12.69g，77.38mmol，1.0eq)和碳酸锂(8.58g，116.07mmol，1.5eq)加入DMSO(110mL)中，120℃搅拌反应16h。TLC监测反应完全，加入乙酸乙酯(300mL)，用饱和食盐水(50mL×4)洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩，粗品用乙酸乙酯(50mL)打浆，抽滤，得产品(20.55g，收率：92.8％)。
步骤2：N-(3-氯-4-((5-硝基吡啶-2-基)氧基)吡啶-2-基)-1，1-二苯基甲胺的合成
Figure PCTCN2020117074-appb-000115
将2，3-二氯-4-((5-硝基吡啶-2-基)氧基)吡啶(20.80g，72.71mmol，1.0eq)、二苯甲酮亚胺(13.174g，72.69mmol，1.0eq)、醋酸钯(0.408g，1.82mmol，0.025eq)、BINAP(1.721g，2.76mmol，0.038eq)和碳酸铯(47.38g，145.42mmol，2.0eq)加入1，4-二氧六环(160mL)中，氮气保护下100℃搅拌反应过夜。TLC监测反应完全，减压浓缩，加入乙酸乙酯(200mL)，依次用水(50mL×3)和饱和食盐水(50mL)洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩，粗品经硅胶柱层析纯化(DCM∶MeOH＝60∶1)得产品(11.3g，收率：36.1％)。
步骤3：6-((3-氯-2-((二苯基亚甲基)氨基)吡啶-4-基)氧基)吡啶-3-胺的合成
Figure PCTCN2020117074-appb-000116
将N-(3-氯-4-((5-硝基吡啶-2-基)氧基)吡啶-2-基)-1，1-二苯基甲亚胺(7.00g，16.25mmol，1.0eq)溶于异丙醇(70mL)中，加入20％硫化铵水溶液(55.37g，162.52mmol，10.0eq)，氮气保护下20℃搅拌反应1.0h，升温至70℃继续搅拌反应2.5h。TLC监测反应完全，减压浓缩，加入乙酸乙酯(80mL)，用饱和食盐水(40mL×2)洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩，粗品经硅胶柱层析纯化(DCM∶MeOH＝50∶1)得产品(2.73g，收率：41.9％)。
步骤4：N-(6-((3-氯-2-((二苯基亚甲基)氨基)吡啶-4-基)氧基)吡啶-3-基)-1-环丙基-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成
Figure PCTCN2020117074-appb-000117
将6-((3-氯-2-((二苯基亚甲基)氨基)吡啶-4-基)氧基)吡啶-3-胺(200.0mg，0.50mmol，1.0eq)和1-环丙基-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-甲酸(137.0mg，0.50mmol，1.0eq)溶于吡啶(5mL)中，加入POCl 3(115.0mg，0.75mmol，1.5eq)，室温搅拌反应0.5h。TLC监测反应完全，将反应液倒入水(15mL)中，用乙酸乙酯(15mL×2)萃取，有机相合并，饱和食盐水(15mL)洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩，粗品经制备薄层色谱纯化(DCM∶MeOH＝20∶1)得产品(152.0mg，收率：46.4％)。
步骤5：N-(6-((2-氨基-3-氯吡啶-4-基)氧基)吡啶-3-基)-1-环丙基-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成
Figure PCTCN2020117074-appb-000118
将N-(6-((3-氯-2-((二苯基亚甲基)氨基)吡啶-4-基)氧基)吡啶-3-基)-1-环丙基-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-甲酰胺(152.0mg，0.23mmol，1.0eq)溶于甲醇(5mL)中，搅拌下滴加浓盐酸(0.1mL)，室温反应0.5h。TLC监测反应完全，将反应液倒入饱和NaHCO 3水溶液(10mL)中，用二氯甲烷(15mL×2)萃取，有机相合并，饱和食盐水(15mL)洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩，粗品经制备薄层色谱纯化(DCM∶MeOH＝15∶1)得产品(91.0mg，收率：79.8％)。
1H NMR(400MHz，DMSO-d 6)δ(ppm)：12.21(s，1H)，8.91(s，1H)，8.51-8.50(d，J＝2.6Hz，1H)，8.31-8.28(dd，J＝2.7，6.1Hz，1H)， 7.95-7.91(m，2H)，7.87-7.85(d，J＝5.5Hz，1H)，7.35-7.31(m，2H)，7.22-7.19(d，J＝8.8Hz，1H)，6.42(s，2H)，6.36-6.35(d，J＝5.5Hz，1H)，4.13-4.07(m，1H)，1.31-1.30(m，2H)，1.12-1.10(m，2H).
分子式：C 24H 18ClFN 6O 3；分子量：492.90；LC-MS(Pos，m/z)＝493.10[M+H] +.
实施例7 N-(5-((2-氨基-3-氯吡啶-4-基)氧基)吡啶-2-基)-5-(4-氟苯基)-1-甲基-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成(化合物33)
Figure PCTCN2020117074-appb-000119
步骤1：N-(5-((3-氯-2-((二苯基亚甲基)氨基)吡啶-4-基)氧基)吡啶-2-基)-5-(4-氟苯基)-1-甲基-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成
Figure PCTCN2020117074-appb-000120
将5-(4-氟苯基)-1-甲基-4-氧代-1，4-二氢哒嗪-3-羧酸(124.03mg，0.5mmol，1.0eq)和5-((3-氯-2-(((二苯基亚甲基)氨基)吡啶-4-基)氧基)吡啶-2-胺(200.0mg，0.5mmol，1.0eq)溶解于吡啶(5mL)，滴加三氯氧磷(329.0mg，2.15mmol，4.3eq)，室温搅拌一小时。TLC监测反应完全，加入水(20mL)淬灭，用DCM(3×50mL)萃取，有机相合并，水洗，饱和食盐水洗，无水硫酸钠干燥，过滤，减压浓缩得产品(210.0mg，收率：66.6％)。
步骤2：N-(5-((2-氨基-3-氯吡啶-4-基)氧基)吡啶-2-基)-5-(4-氟苯基)-1-甲基-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成
Figure PCTCN2020117074-appb-000121
将N-(5-((3-氯-2-((二苯基亚甲基)氨基)吡啶-4-基)氧基)吡啶-2-基)-5-(4-氟苯基)-1-甲基-4-氧代-1，4-二氢哒嗪-3-甲酰胺(210.0mg，0.33mmol，1.0eq)加入甲醇(2mL)中，加入盐酸(1mol/L，1mL)，室温搅拌5小时。TLC监测反应完全，加入饱和NaHCO 3水溶液，将pH值调至7～8，用EA萃取，有机相合并，水洗，饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，粗品经制备薄层色谱(DCM∶MeOH＝10∶1)分离得到产物(53.0mg，收率：34.14％)。
1HNMR(300MHz，CDCl 3)δ(ppm)：13.10(s，1H)，8.91(s，1H)，8.37-8.34(d，1H)，8.30-8.29(d，1H)，7.97-7.91(m，2H)，7.80-7.79(d，1H)，7.78-7.74(m，1H)，7.38-7.32(t，2H)，6.46(s，2H)，6.07-6.05(d，1H)，4.14(s，3H).
分子式：C 22H 16ClFN 6O 3；分子量：466.86；LC-MS(Pos，m/z)＝467.04[M+H] +.
实施例8 N-(5-((2-氨基吡啶-4-基)氧基)吡啶-2-基)-5-(4-氟苯基)-1-异丙基-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成(化合物34)
Figure PCTCN2020117074-appb-000122
步骤1：2-氯-4-((6-硝基吡啶-3-基)氧基)吡啶的合成
Figure PCTCN2020117074-appb-000123
将2-氯-4-羟基吡啶(500mg，3.86mmol，1.0eq)、5-氟-2-硝基吡啶(550mg，3.86mmol，1.0eq)和K 2CO 3(1.07g，7.72mmol，2.0eq)加入DMF(5mL)中，升温至88℃反应16h。TLC监测反应完全，加入H 2O(30mL)淬灭，EA萃取(20mL×2)，有机相浓缩，粗品经硅胶柱层析(DCM∶MeOH＝20∶1)分离得产物(800mg，收率：82.4％)。
步骤2：N-(4-((6-硝基吡啶-3-基)氧基)吡啶-2-基)-1，1-二苯基甲亚胺的合成
Figure PCTCN2020117074-appb-000124
将2-氯-4-((6-硝基吡啶-3-基)氧基)吡啶(720mg，2.86mmol，1.0eq)、二苯甲酮亚胺(519mg，2.86mmol，1.0eq)、Pd(OAc) 2(16.1mg，0.072mmol，0.025eq)、BINAP(67.7mg，0.11mmol)和Cs 2CO 3(1.86g，5.72mmol)加入1，4-二氧六环(8mL)，氮气保护下，加热至100℃反应24h。加入H 2O(30mL)淬灭，EA萃取(20mL×2)，有机相浓缩，粗品经硅胶柱层析(PE∶EA＝5∶1～2∶1)分离得产品(476mg，收率：42.0％)。
步骤3：5((2-((二苯基亚甲基)氨基)吡啶-4-基)氧基)吡啶-2-胺的合成
Figure PCTCN2020117074-appb-000125
将N-(4-((6-硝基吡啶-3-基)氧基)吡啶-2-基)-1，1-二苯基甲亚胺(470mg，1.19mmol，1.0eq)、FeSO 4·7H 2O(6.59g，23.7mmol，20.0eq)和NH 3·H 2O(2.49g，71.1mmol，60.0eq)溶解于EtOH(10mL)中，加热至80℃反应2h。TLC监测原料反应完全，抽滤，滤液加入H 2O(20mL)，加入NH 3·H 2O(1mL)，EA萃取(2×20mL)，有机相浓缩，粗品经硅胶柱层析(DCM∶MeOH＝50∶1～30∶1)分离得到产物(290mg，收率：66.8％)。
步骤4：N-(5-((2-((二苯基亚甲基)氨基)吡啶-4-基)氧基)吡啶-2-基)-5-(4-氟苯基)-1-异丙基-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成
Figure PCTCN2020117074-appb-000126
将5((2-((二苯基亚甲基)氨基)吡啶-4-基)氧基)吡啶-2-胺(290mg，0.79mmol，1.0eq)和5-(4-氟苯基)-1-异丙基-4-氧代-1，4-二氢哒嗪-3-羧酸(219mg，0.79mmol，1.0eq)溶解于吡啶(5mL)，滴加三氯氧磷(182mg，1.19mmol，1.5eq)，室温搅拌20分钟。TLC监测反应完全，加入水(30mL)淬灭，用EA(50mL)萃取，有机相无水硫酸钠干燥，过滤，滤液减压浓缩，粗品经硅胶柱层析(DCM∶MeOH＝100∶1～50∶1)分离得产物(350mg，收率：70.8％)。
步骤5：N-(5-((2-氨基吡啶-4-基)氧基)吡啶-2-基)-5-(4-氟苯基)-1-异丙基-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成
Figure PCTCN2020117074-appb-000127
将N-(5-((2-((二苯基亚甲基)氨基)吡啶-4-基)氧基)吡啶-2-基)-5-(4- 氟苯基)-1-异丙基-4-氧代-1，4-二氢哒嗪-3-甲酰胺(350mg，0.560mmol，1.0eq)加入甲醇(4mL)中，加入水(0.7mL)和浓盐酸(0.2mL)，室温搅拌30分钟，TLC监测反应完全。加入饱和NaHCO 3水溶液，将pH值调至7～8，用EA(20mL)萃取，有机相无水硫酸钠干燥，过滤，滤液减压浓缩，粗品经硅胶柱层析(DCM∶MeOH＝60∶1～30∶1)分离得到产物(170mg，收率：65.9％)。
1HNMR(300MHz，DMSO)δ(ppm)：13.03(s，1H)，8.93(s，1H)，8.39-8.36(d，J＝9.0Hz，1H)，8.28-8.27(d，J＝3.0Hz，1H)，7.98-7.93(m，2H)，7.85-7.83(d，J＝5.7Hz，1H)，7.78-7.74(dd，J＝9.0，3.0Hz，1H)，7.37-7.31(t，J＝8.9Hz，2H)，6.24-6.21(dd，J＝6.0，2.4Hz，1H)，6.06(s，2H)，5.88-5.87(d，J＝2.1Hz，1H)，4.81-4.72(m，1H)，1.54(s，3H)，1.52(s，3H).
分子式：C 24H 21FN 6O 3；分子量：460.47；LC-MS(Pos，m/z)＝461.18[M+H] +.
实施例9 1-烯丙基-N-(5-((2-氨基-3-氯吡啶-4-基)氧基)吡啶-2-基)-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成(化合物35)
Figure PCTCN2020117074-appb-000128
步骤1：1-烯丙基-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-甲酸乙酯的合成
Figure PCTCN2020117074-appb-000129
将5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-甲酸乙酯(475.0mg，1.81mmol，1.0eq)、溴丙烯(442.0mg，3.65mmol，2.0eq)和碳酸钾(1.38g， 9.96mmol，5.5eq)加入DMF(15mL)中，50℃搅拌反应3h。TLC监测反应完全，将反应液倒入水(15mL)中，用乙酸乙酯(2×15mL)萃取，有机相合并，饱和食盐水(15mL)洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩，粗品经硅胶柱层析纯化(DCM∶MeOH＝20∶1)得产品(463.0mg，收率：84.6％)。
步骤2：1-烯丙基-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-甲酸的合成
Figure PCTCN2020117074-appb-000130
将1-烯丙基-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-甲酸乙酯(463.0mg，1.53mmol，1.0eq)和一水合氢氧化锂(531.0mg，12.67mmol，8.25eq)加入甲醇(30mL)和水(10mL)的混合液中，室温搅拌反应2h。TLC监测反应完全，减压浓缩，加入水(20mL)，用乙酸乙酯(10mL)萃取，水相滴加浓盐酸调节pH值至3，析出大量沉淀。抽滤，将滤饼用二氯甲烷(30mL)溶解，无水硫酸钠干燥，抽滤，滤液减压浓缩得产品(418.0mg，收率：99.5％)。
步骤3：1-烯丙基-N-(5-((3-氯-2-((二苯基亚甲基)氨基)吡啶-4-基)氧基)吡啶-2-基)-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成
Figure PCTCN2020117074-appb-000131
将1-烯丙基-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-甲酸(274.0mg，1.00mmol，1.0eq)和5-((3-氯-2-((二苯基亚甲基)氨基)吡啶-4-基)氧基)吡啶-2-胺(400.0mg，1.00mmol，1.0eq)溶于吡啶(5mL)中，加入POCl 3(230.0mg，1.50mmol，1.5eq)，室温搅拌反应0.5h。TLC监测反应完全， 将反应液倒入水(15mL)中，用乙酸乙酯(2×15mL)萃取，有机相合并，饱和食盐水(15mL)洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩，粗品经制备薄层色谱纯化(DCM∶MeOH＝20∶1)得产品(417.0mg，收率：63.5％)。
步骤4：1-烯丙基-N-(5-((2-氨基-3-氯吡啶-4-基)氧基)吡啶-2-基)-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成
Figure PCTCN2020117074-appb-000132
将1-烯丙基-N-(5-((3-氯-2-((二苯基亚甲基)氨基)吡啶-4-基)氧基)吡啶-2-基)-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-甲酰胺(417.0mg，0.63mmol，1.0eq)溶于甲醇(5mL)中，搅拌下滴加浓盐酸(0.1mL)，室温反应0.5h。TLC监测反应完全，将反应液倒入NaHCO 3饱和水溶液(10mL)中，用二氯甲烷(2×15mL)萃取，有机相合并，饱和食盐水(15mL)洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩，粗品经制备薄层色谱纯化(DCM∶MeOH＝15∶1)得产品(230.0mg，收率：73.5％)。
1H NMR(400MHz，DMSO-d 6)δ(ppm)：12.96(s，1H)，8.91(s，1H)，8.36-8.34(d，J＝9.0Hz，1H)，8.29-8.28(d，J＝2.8Hz，1H)，7.95-7.91(dd，J＝5.7，3.0Hz，2H)，7.80-7.74(m，2H)，7.37-7.33(t，J＝8.9Hz，2H)，6.45(s，2H)，6.20-6.11(m，1H)，6.06-6.05(d，J＝5.6Hz，1H)，5.39-5.35(m，2H)，5.00-4.98(d，J＝5.7Hz，2H).
分子式：C 24H 18ClFN 6O 3；分子量：492.90；LC-MS(Pos，m/z)＝493.12[M+H] +.
实施例10 N-(5-((2-氨基-3-氯吡啶-4-基)氧基)吡啶-2-基)-2-环丙基-6-(4-氟苯基)-5-氧代-2，5-二氢哒嗪-4-甲酰胺(化合物36)盐酸盐的合成
Figure PCTCN2020117074-appb-000133
步骤1：N-(5-((3-氯-2-((二苯基亚甲基)氨基)吡啶-4-基)氧基)吡啶-2-基)-2-环丙基-6-(4-氟苯基)-5-氧代-2，5-二氢哒嗪-4-甲酰胺的合成
Figure PCTCN2020117074-appb-000134
将2-环丙基-6-(4-氟苯基)-5-氧代-2，5-二氢哒嗪-4-羧酸(109.1mg，0.39mmol，1.05eq)加入吡啶(5mL)中，加入5-((3-氯-2-((二苯基亚甲基)氨基)吡啶-4-基)氧基)吡啶-2-胺(152.0mg，0.37mmol，1.0eq)和三氯氧磷(0.1mL)，室温搅拌10分钟。TLC监测反应完全后，加入乙酸乙酯(50mL)和水(50mL)分液，有机相无水硫酸钠干燥后过滤，滤液减压浓缩经薄层制备色谱分离纯化得N-(5-((3-氯-2-((二苯基亚甲基)氨基)吡啶-4-基)氧基)吡啶-2-基)-2-环丙基-6-(4-氟苯基)-5-氧代-2，5-二氢哒嗪-4-甲酰胺(175.0mg，收率：66.8％)。
步骤2：N-(5-((2-氨基-3-氯吡啶-4-基)氧基)吡啶-2-基)-2-环丙基-6-(4-氟苯基)-5-氧代-2，5-二氢哒嗪-4-甲酰胺盐酸盐的合成
Figure PCTCN2020117074-appb-000135
将N-(5-((3-氯-2-((二苯甲基)氨基)吡啶-4-基)氧基)吡啶-2-基)-2-环丙基-6-(4-氟苯基)-5-氧代-2，5-二氢哒嗪-4-甲酰胺(175.0mg，0.26mmol，1.0eq)加入甲醇(6mL)，加入浓盐酸(0.5mL)，室温搅拌0.5小时，TLC监测反应完全后，体系过滤，滤饼干燥得到产物N-(5-((2-氨基-3-氯吡啶-4-基)氧基)吡啶-2-基)-2-环丙基-6-(4-氟苯基)-5-氧代-2，5-二氢哒嗪-4-甲酰胺盐酸盐(100.0mg，收率：70.9％)。
1HNMR(400MHz，DMSO-d 6)δ(ppm)：12.66(s，1H)，9.24(s，1H)，8.36-8.41(m，2H)，8.12-8.15(m，2H)，7.90-7.92(m，1H)，7.83-7.86(m，1H)，7.73-7.75(m，1H)，7.32-7.36(t，J＝6.84Hz，2H)，6.34-6.36(m，1H)，4.25-4.27(m，1H)，1.30-1.33(m，2H)，1.09-1.11(m，2H).
分子式：C 24H 19 Cl 2FN 6O 3；分子量：529.35；LC-MS(Pos，m/z)＝493.00[M+H] +.
实施例11 1-烯丙基-N-(5-(((2-氨基-3-氯吡啶-4-基)氧基)嘧啶-2-基)-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成(化合物37)
Figure PCTCN2020117074-appb-000136
步骤1：1-烯丙基-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-羧酸乙酯的合成
Figure PCTCN2020117074-appb-000137
将5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-羧酸乙酯(320.0mg，1.22mmol，1.0eq)溶于DMF(10mL)，加入碳酸钾(506.0mg，3.66mmol，3.0eq)和烯丙基溴(162.0mg，1.34mmol，1.1eq)，50℃反应2小时，TLC监测反应完全，冷却至室温，加入乙酸乙酯(30mL)稀释，用饱和食盐水洗(30mL×4)，无水硫酸钠干燥，抽滤，滤液浓缩，粗品经制备薄层色谱纯化(二氯甲烷∶甲醇＝20∶1)得产品(343.0mg，收率：93.2％)。
步骤2：1-烯丙基-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-羧酸的合成
Figure PCTCN2020117074-appb-000138
将1-烯丙基-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-羧酸乙酯(343.0mg，1.13mmol，1.0eq)加入甲醇(6mL)，加入一水合氢氧化锂(142.7mg，3.40mmol，3.0eq)的水溶液(3mL)，室温反应1小时，TLC监测反应完全，浓缩，用6mol/L盐酸调节体系pH值至3-4，有固体析出，搅拌1小时，抽滤，滤饼干燥得到产品(310.0mg，收率：100％)。
步骤3：5-((3-氯-2-((4-甲氧基苄基)氨基)吡啶-4-基)氧基)嘧啶-2-胺的合成
Figure PCTCN2020117074-appb-000139
将5-((2，3-二氯吡啶-4-基)氧基)嘧啶-2-胺(1.0g，3.88mmol，1.0eq)加入(4-甲氧基苯基)甲胺(4.8g，34.92mmol，9.0eq)，微波150℃反应2小时，TLC监测反应完全，加入乙酸乙酯(200mL)和水(150mL)，分液，水相再用DCM(200mL)萃取，有机相合并，无水硫酸钠干燥，抽滤，滤液浓缩，粗品经硅胶柱层析(100-200目硅胶，二氯甲烷∶甲醇＝100∶1～80∶1)纯化得产品(480.0mg，收率：34.5％)。
步骤4：1-烯丙基-N-(5-((3-氯-2-((4-甲氧基苄基)氨基)吡啶-4-基)氧基)嘧啶-2-基)-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成
Figure PCTCN2020117074-appb-000140
将1-烯丙基-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-羧酸(276.4mg，1.00mmol，1.0eq)加入吡啶(6mL)中，加入5-((3-氯-2-((4-甲氧基苄基) 氨基)吡啶-4-基)氧基)嘧啶-2-胺(360.6mg，1.00mmol，1.0eq)和三氯氧磷(0.1mL)，室温搅拌15分钟。TLC监测反应完全，加入乙酸乙酯(200mL)和水(150mL)，分液，水相再用乙酸乙酯(100mL)萃取，饱和氯化铵水溶液洗，有机相合并，无水硫酸钠干燥，抽滤，滤液浓缩，粗品经硅胶柱层析(100-200目硅胶，二氯甲烷∶甲醇＝100∶1～60∶1)纯化得产品(300.0mg，收率：48.4％)。
步骤5：1-烯丙基-N-(5-(((2-氨基-3-氯吡啶基-4-基)氧基)嘧啶-2-基)-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成
Figure PCTCN2020117074-appb-000141
将1-烯丙基-N-(5-((3-氯-2-((4-甲氧基苄基)氨基)吡啶-4-基)氧基)嘧啶-2-基)-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-甲酰胺(263.0mg，0.42mmol，1.0eq)加入DCM(2mL)中，加入三氟乙酸(4mL)，60℃反应3小时，TLC监测反应完全，冷却至室温，体系用饱和碳酸钠水溶液调节pH值至8，加入DCM(200mL)，分液，有机相无水硫酸钠干燥，过滤，滤液浓缩，粗品经制备薄层色谱纯化(二氯甲烷∶甲醇＝20∶1)得产物(187.0mg，收率：88.6％)。
1HNMR(300MHz，DMSO-d 6)δ(ppm)：12.79-12.81(s，1H)，8.87(s，1H)，8.67(s，2H)，7.88-7.92(t，J＝12Hz，2H)，7.77-7.79(d，J＝6Hz，1H)，7.30-7.36(t，J＝9Hz，2H)，6.50(s，2H)，6.08-6.13(t，J＝6Hz，2H)，5.30-5.35(t，J＝9Hz，2H)，4.94-4.95(d，J＝3Hz，2H).
分子式：C 23H 17 ClFN 7O 3；分子量：493.88；LC-MS(Pos，m/z)＝494.11M+H] +.
实施例12 N-(6-((2-氨基-3-氯吡啶-4-基)氧基)吡啶-3-基)-5-(4-氟苯基)-1-异丙基-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成(化合物13)
Figure PCTCN2020117074-appb-000142
步骤1：N-(6-((3-氯-2-((二苯基亚甲基)氨基)吡啶-4-基)氧基)吡啶-3-基)-5-(4-氟苯基)-1-异丙基-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成
Figure PCTCN2020117074-appb-000143
将6-((3-氯-2-(二苯基亚甲基)氨基吡啶-4-基)氧基)吡啶-3-胺(435mg，1.09mmol，1.0eq)和5-(4-氟苯基)-1-异丙基-4-氧代-1，4-二氢哒嗪-3-羧酸(300mg，1.09mmol，1.0eq)加入吡啶(5mL)，搅拌溶解，然后滴加三氯氧磷(251mg，1.64mmol，1.5eq)，室温搅拌30分钟。TLC监测反应完全，加入水(20mL)淬灭，用EA(50mL)萃取，有机相减压浓缩，粗品经硅胶柱层析纯化(DCM∶MeOH＝100∶1～50∶1)得产物(230mg，收率32.0％)。
步骤2：N-(6-((2-氨基-3-氯吡啶-4-基)氧基)吡啶-3-基)-5-(4-氟苯基)-1-异丙基-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成
Figure PCTCN2020117074-appb-000144
将N-(6-((3-氯-2-((二苯基亚甲基)氨基)吡啶-4-基)氧基)吡啶-3-基)-5-(4-氟苯基)-1-异丙基-4-氧代-1，4-二氢哒嗪-3-甲酰胺(230mg， 0.349mmol，1.0eq)加入甲醇(4mL)和水(0.8mL)中，然后加入浓盐酸(0.2mL)，室温搅拌30分钟，TLC监测反应完全。体系冷却至室温，加入饱和NaHCO 3水溶液，将pH值调至7～8，用EA(20mL×2)萃取，有机相减压浓缩，粗品经硅胶柱层析纯化(DCM∶MeOH＝60∶1～30∶1)得产物(92mg，收率：53.3％)。
1H NMR(300MHz，CDCl 3)δ(ppm)：12.87(s，1H)，8.56-8.55(d，J＝2.4Hz，1H)，8.43-8.39(m，1H)，8.11(s，1H)，7.93-7.91(d，J＝5.7Hz，1H)，7.71-7.67(m，2H)，7.23-7.17(t，J＝9.0Hz，2H)，7.08-7.05(d，J＝8.7Hz，1H)，6.45-6.43(d，J＝5.7Hz，1H)，5.01(s，2H)，4.75-4.68(m，1H)，1.67(s，3H)，1.65(s，3H).
分子式：C 24H 20ClFN 6O 3；分子量：494.91；LC-MS(Pos，m/z)＝495.15[M+H] +.
实施例13 N-(2-((2-氨基-3-氯吡啶-4-基)氧基)嘧啶-5-基)-5-(4-氟苯基)-1-异丙基-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成(化合物16)
Figure PCTCN2020117074-appb-000145
步骤1：N-(2-((3-氯-2-((4-甲氧基苄基)氨基)吡啶-4-基)氧基)嘧啶-5-基)-5-(4-氟苯基)-1-异丙基-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成
Figure PCTCN2020117074-appb-000146
将5-(4-氟苯基)-1-异丙基-4-氧代-1，4-二氢哒嗪-3-羧酸(309.5mg，1.12mmol，1.0eq)和2-((3-氯-2-((4-甲氧基苄基)氨基)吡啶-4-基)氧基)嘧啶-5-胺(380.7mg，1.06mmol，0.95eq)加入吡啶(6mL)中，搅拌溶解，然后滴加5滴三氯氧磷，室温搅拌30分钟。TLC监测反应完全，加入水 (10mL)淬灭，用EA(20mL)萃取，有机相饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，粗品经硅胶柱层析(DCM∶MeOH＝100∶1～90∶1)纯化得产物(155.0mg，收率22.4％)。
步骤2：N-(2-((2-氨基-3-氯吡啶-4-基)氧基)嘧啶-5-基)-5-(4-氟苯基)-1-异丙基-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成
Figure PCTCN2020117074-appb-000147
将N-(2-((3-氯-2-((4-甲氧基苄基)氨基)吡啶-4-基)氧基)嘧啶-5-基)-5-(4-氟苯基)-1-异丙基-4-氧代-1，4-二氢哒嗪-3-甲酰胺(155.0mg，0.25mmol，1.0eq)溶于三氟乙酸(4mL)和二氯甲烷(1mL)的混合液中，60℃搅拌反应4h，TLC监测反应完全。体系冷却至室温，加入饱和Na 2CO 3水溶液，将pH值调至7～8，用DCM(10mL)萃取，有机相无水硫酸钠干燥，过滤，浓缩，粗品经制备薄层色谱纯化(DCM∶MeOH＝15∶1)得到产物(100.0mg，收率：80.1％)。
1H NMR(300MHz，DMSO-d 6)δ(ppm)：12.48(s，1H)，9.04(s，2H)，8.93(s，1H)，7.98-7.92(m，3H)，7.37-7.31(t，J＝9.0Hz，2H)，6.59-6.57(d，J＝5.4Hz，1H)，6.50(s，2H)，4.79-4.70(m，1H)，1.52-1.50(s，6H).
分子式：C 23H 19ClFN 7O 3；分子量：495.90；LC-MS(Pos，m/z)＝496.15[M+H] +.
实施例14 N-(2-((2-氨基-3-氯吡啶-4-基)氧基)嘧啶-5-基)-1-环丙基-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成(化合物20)
Figure PCTCN2020117074-appb-000148
步骤1：2-((2，3-二氯吡啶-4-基)氧基)-5-硝基嘧啶的合成
Figure PCTCN2020117074-appb-000149
将2-氯-5-硝基嘧啶(11.000g，67.08mmol，1.0eq)、2，3-二氯-4-羟基吡啶(10.703g，67.09mmol，1.0eq)和三乙胺(8.140g，80.44mmol，1.2eq)冰浴下加入DMSO(60mL)中，自然升至室温搅拌反应过夜。TLC监测反应完全，加入乙酸乙酯(300mL)，用饱和食盐水洗涤(50mL×4)，有机相无水硫酸钠干燥，抽滤，滤液减压浓缩，粗品用乙酸乙酯(50mL)打浆，抽滤得产品(17.85g，收率：92.7％)。
步骤2：2-((2，3-二氯吡啶-4-基)氧基)嘧啶-5-胺的合成
Figure PCTCN2020117074-appb-000150
将2-((2，3-二氯吡啶-4-基)氧基)-5-硝基嘧啶(11.050g，38.49mmol，1.0eq)、还原铁粉(12.930g，230.96mmol，6.0eq)和氯化铵(24.750g，461.92mmol，12.0eq)加入乙醇(100mL)和水(50mL)的混合液中，80℃搅拌反应2h。TLC监测反应完全，经硅藻土抽滤，滤液减压浓缩，向浓缩液中加入饱和NaHCO 3水溶液至不再产生气泡为止。加入乙酸乙酯(80mL)，有机相用饱和食盐水(40mL)洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩，粗品经硅胶柱层析纯化(DCM∶MeOH＝50∶1)得产品(5.068g，收率：51.2％)。
步骤3：2-((3-氯-2-((4-甲氧基苄基)氨基)吡啶-4-基)氧基)嘧啶-5-胺的合成
Figure PCTCN2020117074-appb-000151
将2-((2，3-二氯吡啶-4-基)氧基)嘧啶-5-胺(2.800g，10.89mmol，1.0eq)溶于对甲氧基苄胺(15mL)中，微波150℃反应1.5h。TLC监测反应完全，加入乙酸乙酯(50mL)，依次用0.1mol/L稀盐酸(50mL×4)和饱和食盐水(50mL×2)洗涤，有机相无水硫酸钠干燥，抽滤，滤液减压浓缩，粗品经硅胶柱层析纯化(PE∶EA＝1∶4)得产品(1.8g，收率：46.2％)。
步骤4：N-(2-((3-氯-2-((4-甲氧基苄基)氨基)吡啶-4-基)氧基)嘧啶-5-基)-1-环丙基-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成
Figure PCTCN2020117074-appb-000152
将2-((3-氯-2-((4-甲氧基苄基)氨基)吡啶-4-基)氧基)嘧啶-5-胺(357.8mg，1.00mmol，1.0eq)和1-环丙基-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-甲酸(274.3mg，1.00mmol，1.0eq)溶于吡啶(10mL)中，加入POCl 3(230.0mg，1.50mmol，1.5eq)，室温搅拌反应0.5h。TLC监测反应完全，将反应液倒入水(30mL)中，用乙酸乙酯萃取(30mL×2)，有机相合并，饱和食盐水洗涤(15mL)，无水硫酸钠干燥，抽滤，滤液减压浓缩，粗品经制备薄层色谱纯化(DCM∶MeOH＝20∶1)得产品(223.0mg，收率：36.3％)。
步骤5：N-(2-((2-氨基-3-氯吡啶-4-基)氧基)嘧啶-5-基)-1-环丙基-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成
Figure PCTCN2020117074-appb-000153
将N-(2-((3-氯-2-((4-甲氧基苄基)氨基)吡啶-4-基)氧基)嘧啶-5- 基)-1-环丙基-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-甲酰胺(223.0mg，0.36mmol，1.0eq)溶于三氟乙酸(20mL)和二氯甲烷(5mL)的混合液中，60℃搅拌反应4.5h。TLC监测反应完全，将反应液倒入饱和NaHCO 3水溶液(30mL)中，用二氯甲烷(30mL×2)萃取，有机相合并，饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩，粗品经制备薄层色谱纯化(DCM∶MeOH＝15∶1)得产品(94.0mg，收率：52.4％)。
1H NMR(400MHz，DMSO-d 6)δ(ppm)：12.36(s，1H)，9.03(s，2H)，8.94(s，1H)，7.96-7.92(m，3H)，7.36-7.31(t，J＝8.9Hz，2H)，6.58-6.57(d，J＝5.5Hz，1H)，6.50(s，2H)，4.14-4.09(m，1H)，1.33-1.29(m，2H)，1.14-1.10(m，2H).
分子式：C 23H 17ClFN 7O 3；分子量：493.88；LC-MS(Pos，m/z)＝494.13[M+H] +.
实施例15 N-(6-((2-氨基-3-氯吡啶-4-基)氧基)吡啶-3-基)-6-(4-氟苯基)-2-异丙基-5-氧代-2，5-二氢哒嗪-4-甲酰胺的合成(化合物23)
Figure PCTCN2020117074-appb-000154
步骤1：N-(6-((3-氯-2-((二苯基亚甲基)氨基)吡啶-4-基)氧基)吡啶-3-基-6-(4-氟苯基)-2-异丙基-5-氧代-2，5-二氢哒嗪-4-甲酰胺的合成
Figure PCTCN2020117074-appb-000155
将6-((3-氯-2-((二苯基亚甲基)氨基)吡啶-4-基)氧基)吡啶-3-胺(200.0mg，0.50mmol，1.0eq)和6-(4-氟苯基)-2-异丙基-5-氧代-2，5-二氢哒嗪-4-甲酸(138.0mg，0.50mmol，1.0eq)溶于吡啶(5mL)中，加入 POCl 3(115.0mg，0.75mmol，1.5eq)，室温搅拌反应0.5h。TLC监测反应完全，将反应液倒入水(15mL)中，用乙酸乙酯(15mL×2)萃取，有机相合并，饱和食盐水(15mL)洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩，粗品经制备薄层色谱纯化(DCM∶MeOH＝20∶1)得产品(148.0mg，收率：45.0％)。
步骤2：N-(6-((2-氨基-3-氯吡啶-4-基)氧基)吡啶-3-基)-6-(4-氟苯基)-2-异丙基-5-氧代-2，5-二氢哒嗪-4-甲酰胺的合成
Figure PCTCN2020117074-appb-000156
将N-(6-((3-氯-2-((二苯基亚甲基)氨基)吡啶-4-基)氧基)吡啶-3-基)-6-(4-氟苯基)-2-异丙基-5-氧代-2，5-二氢哒嗪-4-甲酰胺(148.0mg，0.22mmol，1.0eq)溶于甲醇(5mL)中，搅拌下滴加浓盐酸(0.1mL)，室温搅拌反应0.5h。TLC监测反应完全，将反应液倒入饱和NaHCO 3水溶液(10mL)中，用二氯甲烷(15mL×2)萃取，有机相合并，饱和食盐水(15mL)洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩，粗品经制备薄层色谱纯化(DCM∶MeOH＝10∶1)得产品(89.0mg，收率：80.0％)。
1H NMR(400MHz，DMSO-d 6)δ(ppm)：12.26(s，1H)，9.21(s，1H)，8.55-8.54(d，J＝2.6Hz，1H)，8.33-8.30(m，1H)，8.21-8.17(m，2H)，7.87-7.86(d，J＝5.5Hz，1H)，7.38-7.33(m，2H)，7.22-7.20(d，J＝8.8Hz，1H)，6.42(s，2H)，6.37-6.35(d，J＝5.5Hz，1H)，4.90-4.83(m，1H)，1.51-1.50(d，J＝6.5Hz，6H).
分子式：C 24H 20ClFN 6O 3；分子量：494.91；LC-MS(Pos，m/z)＝495.15[M+H] +.
实施例16 N-(6-((2-氨基-3-氯吡啶-4-基)氧基)吡啶-3-基)-2-环丙基-6-(4-氟苯基)-5-氧代-2，5-二氢哒嗪-4-甲酰胺的合成(化合物38)
Figure PCTCN2020117074-appb-000157
步骤1：N-(6-((3-氯-2-((二苯基亚甲基)氨基)吡啶-4-基)氧基)吡啶-3-基)-2-环丙基-6-(4-氟苯基)-5-氧代-2，5-二氢哒嗪-4-甲酰胺的合成
Figure PCTCN2020117074-appb-000158
将6-((3-氯-2-((二苯基亚甲基)氨基)吡啶-4-基)氧基)吡啶-3-胺(200.0mg，0.50mmol，1.0eq)和2-环丙基-6-(4-氟苯基)-5-氧代-2，5-二氢哒嗪-4-甲酸(137.0mg，0.50mmol，1.0eq)溶于吡啶(5mL)中，加入POCl 3(115.0mg，0.75mmol，1.5eq)，室温搅拌反应0.5h。TLC监测反应完全，将反应液倒入水(15mL)中，用乙酸乙酯(15mL×2)萃取，有机相合并，饱和食盐水(15mL)洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩，粗品经制备薄层色谱纯化(DCM∶MeOH＝20∶1)得产品(80.0mg，收率：24.4％)。
步骤2：N-(6-((2-氨基-3-氯吡啶-4-基)氧基)吡啶-3-基)-2-环丙基-6-(4-氟苯基)-5-氧代-2，5-二氢哒嗪-4-甲酰胺的合成
Figure PCTCN2020117074-appb-000159
将N-(6-((3-氯-2-((二苯基亚甲基)氨基)吡啶-4-基)氧基)吡啶-3- 基)-2-环丙基-6-(4-氟苯基)-5-氧代-2，5-二氢哒嗪-4-甲酰胺(80.0mg，0.12mmol，1.0eq)溶于甲醇(5mL)中，搅拌下滴加浓盐酸(0.1mL)，室温搅拌反应0.5h。TLC监测反应完全，将反应液倒入饱和NaHCO 3水溶液(10mL)中，用二氯甲烷(15mL×2)萃取，有机相合并，饱和食盐水(15mL)洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩，粗品经制备薄层色谱纯化(DCM∶MeOH＝10∶1)得产品(48.0mg，收率：80.0％)。
1H NMR(400MHz，DMSO-d 6)δ(ppm)：12.18(s，1H)，9.21(s，1H)，8.54-8.53(d，J＝2.6Hz，1H)，8.33-8.30(m，1H)，8.15-8.11(m，2H)，7.87-7.86(d，J＝5.5Hz，1H)，7.37-7.32(m，2H)，7.22-7.20(d，J＝8.8Hz，1H)，6.42(s，2H)，6.37-6.35(d，J＝5.5Hz，1H)，4.27-4.21(m，1H)，1.32-1.30(m，2H)，1.11-1.08(m，2H).
分子式：C 24H 18ClFN 6O 3；分子量：492.90；LC-MS(Pos，m/z)＝493.15[M+H] +.
实施例17 1-烯丙基-N-(6-((2-氨基-3-氯吡啶-4-基)氧基)吡啶-3-基)-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成(化合物39)
Figure PCTCN2020117074-appb-000160
步骤1：1-烯丙基-N-(6-((2-氨基-3-氯吡啶-4-基)氧基)吡啶-3-基)-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成
Figure PCTCN2020117074-appb-000161
将6-((3-氯-2-((二苯基亚甲基)氨基)吡啶-4-基)氧基)吡啶-3-胺(400.8mg，1.00mmol，1.0eq)和1-烯丙基-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-甲酸(274.3mg，1.00mmol，1.0eq)溶于吡啶(10mL)中，加入POCl 3(230.0mg，1.50mmol，1.5eq)，室温搅拌反应0.5h。TLC监测反应完全，将反应液倒入0.1mol/L稀盐酸(30mL)中，用乙酸乙酯(30mL×2)萃取，有机相合并，饱和食盐水(15mL)洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩，粗品经制备薄层色谱纯化(DCM∶MeOH＝15∶1)得产品(132.0mg，收率：26.8％)。
1H NMR(400MHz，DMSO-d 6)δ(ppm)：12.21(s，1H)，8.90(s，1H)，8.52-8.51(d，J＝2.6Hz，1H)，8.31-8.28(dd，J＝2.7，6.1Hz，1H)，7.94-7.91(dd，J＝5.6，3.3Hz，2H)，7.87-7.86(d，J＝5.5Hz，1H)，7.36-7.32(t，J＝8.9Hz，2H)，7.22-7.20(d，J＝8.8Hz，1H)，6.44(s，2H)，6.37-6.36(d，J＝5.5Hz，1H)，6.18-6.11(m，1H)，5.38-5.37(m，1H)，5.34-5.33(t，1H)，4.97-4.95(d，J＝5.9Hz，2H).
分子式：C 24H 18ClFN 6O 3；分子量：492.90；LC-MS(Pos，m/z)＝493.32[M+H] +.
实施例18 1-烯丙基-N-(2-((2-氨基-3-氯吡啶-4-基)氧基)嘧啶-5-基)-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成(化合物40)
Figure PCTCN2020117074-appb-000162
步骤1：1-烯丙基-N-(2-((3-氯-2-((4-甲氧基苄基)氨基)吡啶-4-基)氧基)嘧啶-5-基)-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成
Figure PCTCN2020117074-appb-000163
将2-((3-氯-2-((4-甲氧基苄基)氨基)吡啶-4-基)氧基)嘧啶-5-胺(357.8mg，1.00mmol，1.0eq)和1-烯丙基-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-甲酸(274.3mg，1.00mmol，1.0eq)溶于吡啶(10mL)中，加入POCl 3(230.0mg，1.50mmol，1.5eq)，室温搅拌反应0.5h。TLC监测反应完全，将反应液倒入水(30mL)中，用乙酸乙酯(30mL×2)萃取，有机相合并，饱和食盐水(15mL)洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩，粗品经制备薄层色谱纯化(DCM∶MeOH＝20∶1)得产品(208.0mg，收率：33.9％)。
步骤2：1-烯丙基-N-(2-((2-氨基-3-氯吡啶-4-基)氧基)嘧啶-5-基)-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-甲酰胺的合成
Figure PCTCN2020117074-appb-000164
将1-烯丙基-N-(2-((3-氯-2-((4-甲氧基苄基)氨基)吡啶-4-基)氧基)嘧啶-5-基)-5-(4-氟苯基)-4-氧代-1，4-二氢哒嗪-3-甲酰胺(208.0mg，0.34mmol，1.0eq)溶于三氟乙酸(20mL)和二氯甲烷(5mL)的混合液中，60℃搅拌反应4.5h。TLC监测反应完全，将反应液倒入饱和NaHCO 3水溶液(30mL)中，并滴加饱和NaHCO 3水溶液至不产生气泡为止，用二氯甲烷(30mL×2)萃取，合并有机相，饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩，粗品经制备薄层色谱纯化(DCM∶MeOH＝15∶1)得产品(110.0mg，收率：65.8％)。
1H NMR(400MHz，DMSO-d 6)δ(ppm)：12.35(s，1H)，9.03(s，2H)，8.92(s，1H)，7.95-7.91(m，3H)，7.37-7.32(t，J＝8.9Hz，2H)，6.59-6.57(d，J＝5.5Hz，1H)，6.50(s，2H)，6.19-6.10(m，1H)，5.39-5.37(m，1H)，5.35-5.34(t，J＝1.4Hz，1H)，4.98-4.96(d，J＝5.9Hz，2H).
分子式：C 23H 17ClFN 7O 3；分子量：493.88；LC-MS(Pos，m/z)＝494.28[M+H] +.
实施例19 N-(2-((2-氨基-3-氯吡啶-4-基)氧基)嘧啶-5-基)-2-环丙基-6-(4-氟苯基)-5-氧代-2，5-二氢哒嗪-4-甲酰胺的合成(化合物57)
Figure PCTCN2020117074-appb-000165
步骤1：N-(2-((3-氯-2-((4-甲氧基苄基)氨基)吡啶-4-基)氧基)嘧啶-5-基)-2-环丙基-6-(4-氟苯基)-5-氧代-2，5-二氢哒嗪-4-甲酰胺的合成
Figure PCTCN2020117074-appb-000166
将2-((3-氯-2-((4-甲氧基苄基)氨基)吡啶-4-基)氧基)嘧啶-5-胺(267.5mg，0.75mmol，1.0eq)和2-环丙基-6-(4-氟苯基)-5-氧代-2，5-二氢哒嗪-4-甲酸(205.0mg，0.75mmol，1.0eq)溶于吡啶(10mL)中，加入POCl 3(171.9mg，1.12mmol，1.5eq)，室温搅拌反应0.5h。TLC监测反应完全，将反应液倒入水(30mL)中，用乙酸乙酯(30mL×2)萃取，有机相合并，饱和食盐水(15mL)洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩，粗品经制备薄层色谱纯化(DCM∶MeOH＝20∶1)得产品(119.0mg，收率：25.9％)。
步骤2：N-(2-((2-氨基-3-氯吡啶-4-基)氧基)嘧啶-5-基)-2-环丙基-6-(4-氟苯基)-5-氧代-2，5-二氢哒嗪-3-甲酰胺的合成
Figure PCTCN2020117074-appb-000167
将N-(2-((3-氯-2-((4-甲氧基苄基)氨基)吡啶-4-基)氧基)嘧啶-5-基)-2-环丙基-6-(4-氟苯基)-5-氧代-2，5-二氢哒嗪-4-甲酰胺(119.0mg，0.19mmol，1.0eq)溶于三氟乙酸(20mL)和二氯甲烷(5mL)的混合液中，60℃搅拌反应4.5h。TLC监测反应完全，将反应液倒入饱和NaHCO 3水溶液(30mL)中，并滴加饱和NaHCO 3水溶液至不产生气泡为止，用二氯甲烷(30mL×2)萃取，有机相合并，饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩，粗品经制备薄层色谱纯化(DCM∶MeOH＝10∶1)得产品(63.0mg，收率：65.8％)。
1H NMR(400MHz，DMSO-d 6)δ(ppm)：12.16(s，1H)，9.22(s，1H)，9.05(s，2H)，8.15-8.12(dd，J＝5.7，3.2Hz，2H)，7.94-7.92(d，J＝5.4Hz，1H)，7.37-7.32(t，J＝8.9Hz，2H)，6.58-6.56(d，J＝5.4Hz，1H)，6.49(s，2H)，4.27-4.21(m，1H)，1.34-1.30(m，2H)，1.12-1.09(m，2H).
分子式：C 23H 17ClFN 7O 3；分子量：493.88；LC-MS(Pos，m/z)＝494.24[M+H] +.
实验例1本发明化合物的pAx1细胞抑制活性测试
H1299为非小细胞肺癌细胞。
测试物：本发明中的化合物，其结构见前文所示。
测试仪器：蛋白电泳仪(Bio Rad制)，转膜仪(Bio Rad制)，曝光仪(Tanon制)，CO 2细胞培养箱(Thermo制)。
试验方法：
将H1299细胞接种于6孔板中(含10％FBS 1640培养基，每孔5×10 5细胞)，37℃，5％CO 2贴壁培养18h后，饥饿细胞过夜，加入不同浓度的化合物，化合物终浓度为1.1nM，3.3nM，10nM，30nM，其中DMSO 终含量均为1‰。阴性对照孔为含有1‰ DMSO的培养基。37℃，5％CO 2孵育60min后，每孔加入hGAS6(R&D，终浓度200ng/mL)，继续孵育60min后，提取细胞总蛋白进行蛋白免疫印迹(Western Blot)实验，使用GraphPad 5.0软件计算IC 50值，检测化合物对细胞pAxl的抑制活性。
测试结果如下表1所示：
表1本发明化合物对细胞pAxl的抑制活性-IC 50(nM)
化合物 IC 50(nM)
化合物1 1.1
化合物11 ＜1.1
化合物12 3.3
化合物13 1.1-3.3
化合物16 10
化合物17 ＜1.1
化合物18 3.3
化合物19 3.3-10
化合物20 10-30
化合物33 3.3-10
化合物34 10
化合物35 ＜1.1
化合物36的盐酸盐 10
化合物37 1.1
化合物39 1.1-3.3
化合物40 10
由表1实验结果可见，本发明的化合物对H1299细胞pAxl具有显著的抑制作用，说明本发明化合物可以在细胞水平有效抑制Axl活性，是良好的Axl抑制剂。
实验例2本发明化合物的pMer细胞抑制活性测试
H1299为非小细胞肺癌细胞。
测试物：本发明中的化合物，其结构见前文所示。
测试仪器：蛋白电泳仪(Bio Rad制)，转膜仪(Bio Rad制)，曝光仪 (Tanon制)，CO 2细胞培养箱(Thermo制)。
试验方法：
将H1299细胞接种于6孔板中(含10％FBS 1640培养基，每孔5×10 5细胞)，37℃，5％CO 2贴壁培养18h后，饥饿细胞过夜，加入不同浓度的化合物，化合物终浓度为0.37nM，1.1nM，3.3nM，10nM，其中DMSO终含量均为1‰。阴性对照孔为含有1‰ DMSO的培养基。37℃，5％CO 2孵育60min后，每孔加入Human MerMab(R&D，终浓度200ng/mL)，继续孵育60min后，提取细胞总蛋白进行蛋白免疫印迹(Western Blot)实验，使用Image J软件对结果进行灰度分析，并使用GraphPad 5.0软件计算IC 50值，检测化合物对细胞pMer的抑制活性。
测试结果如下表2所示：
表2本发明化合物对细胞pMer的抑制活性-IC 50(nM)
化合物 IC 50(nM)
化合物11 1.1
化合物12 1.1
化合物13 3.3-10
化合物17 ＜1.1
化合物18 1.1
化合物19 10
化合物33 3.3
化合物35 0.37
化合物37 3.3
化合物39 3.3-10
由表2实验结果可见，本发明的化合物对H1299细胞pMer具有显著的抑制作用，说明本发明化合物可以在细胞水平有效抑制Mer活性，是良好的Mer抑制剂。
实验例3本发明化合物的酶学活性测试
测试物：本发明中的化合物，其结构及制备见前文所示。
试验方法：
(1)制备化合物储备液
将化合物溶解于100％DMSO制备成最高浓度为500μM的储备液。
(2)制备化合物工作液
稀释化合物储备液至化合物终浓度为500μM，150μM，50μM，15μM，5μM，1.5μM，0.5μM，0.15μM，0.05μM，作为化合物工作液(50×)。
(3)制备不同酶反应液
Ron(h)
Ron(h)酶溶解于8mM MOPS(pH 7.0)，0.2mM EDTA，250μM GGMEDIYFEFMGGKKK中，制备成为终浓度为40.4nM的酶液。使用10mM醋酸镁，10μM[γ- 33P]-ATP组成Mg/ATP混合液，激活酶学反应。
(4)酶促反应
在384孔板中，加入化合物工作液，使终浓度分别为10000nM，3000nM，1000nM，300nM，100nM，30nM，10nM，3nM，1nM，再加入按照上述条件制备的不同酶反应液，室温孵育40min后，加入0.5％磷酸溶液终止试验。取10μL反应液滴至P30滤纸，以0.425％磷酸溶液清洗4次后，甲醇清洗一次，置于闪烁计数仪检测。使用Image J软件对结果进行灰度分析，并使用GraphPad 5.0软件计算IC 50值。
测试结果如下表3所示：
表3本发明的化合物对Ron(h)激酶的抑制活性-IC 50(nM)
测试物 Ron(h)
化合物11 2
化合物12 19
化合物13 16
化合物17 7
化合物18 14
化合物19 64
化合物23 92
化合物33 17
化合物35 5
化合物37 12
化合物39 12
由表3实验结果可见，本发明的化合物对Ron(h)具有良好的抑制活性，因此本发明化合物可用于治疗和/或预防由Ron(h)介导的疾病。
实验例4本发明化合物的酶学活性测试
测试物：本发明中的化合物，其结构及制备见前文所示。
试验方法：
(1)制备化合物储备液
将化合物溶解于100％DMSO制备成最高浓度为500μM的储备液。
(2)制备化合物工作液
稀释化合物储备液至化合物终浓度为500μM，150μM，50μM，15μM，5μM，1.5μM，0.5μM，0.15μM，0.05μM，作为化合物工作液(50×)。
(3)制备不同酶反应液
a)Axl(h)
Axl(h)酶溶解于8mM MOPS(pH 7.0)，0.2mM EDTA，250μM KKSRGDYMTMQIG中，制备成为终浓度为1.7nM的酶液。使用10mM醋酸镁，10μM[γ- 33P]-ATP组成Mg/ATP混合液，激活酶学反应。
b)Mer(h)
Mer(h)酶溶解于8mM MOPS(pH 7.0)，0.2mM EDTA，30mM NaCl，250μM GGMEDIYFEFMGGKKK中，制备成为终浓度为3.1nM的酶液。使用10mM醋酸镁，10μM[γ- 33P]-ATP组成Mg/ATP混合液，激活酶学反应。
c)Tyro-3(h)
Tyro3(h)酶溶解于8mM MOPS(pH 7.0)，0.2mM EDTA，1mM MnCl 2，250μM KVEKIGEGTYGVVYK中，制备成为终浓度为38nM的酶液。使用10mM醋酸镁，10μM[γ- 33P]-ATP组成Mg/ATP混合液，激活酶学反应。
(4)酶促反应
在384孔板中，加入化合物工作液，使终浓度分别为10000nM，3000nM，1000nM，300nM，100nM，30nM，10nM，3nM，1nM，再加入按照上述条件制备的不同酶反应液，室温孵育40min后，加入0.5％磷酸溶液终止试验。取10μL反应液滴至P30滤纸，以0.425％磷酸溶液清洗4次后，甲醇清洗一次，置于闪烁计数仪检测。使用Image J软件对结果进行灰度分析，并使用GraphPad 5.0软件计算IC 50值。
测试结果如下表4所示：
表4本发明的化合物对不同激酶的抑制活性-IC 50(nM)
Figure PCTCN2020117074-appb-000168
-表示未测定
由表4实验结果可见，本发明的化合物对Axl(h)，Mer(h)及Tyro3(h)具有良好的抑制活性，因此本发明化合物在可用于预防和/或治疗由Axl(h)，Mer(h)及Tyro-3(h)介导的疾病。
实验例5本发明化合物的酶学活性测试
测试物：本发明中的化合物，其结构及制备见前文所示。
试验方法：
制备化合物储备液：
将化合物溶解于100％DMSO制备成最高浓度为500μM的储备液。
制备化合物工作液：
稀释化合物储备液至化合物终浓度为500μM，150μM，50μM，15μM，5μM，1.5μM，0.5μM，0.15μM，0.05μM，成为化合物工作液(50×)。
制备不同酶反应液：
LCK(h)
LCK(h)酶溶解于50mM Tris pH 7.5，0.1mM EGTA，0.1mM Na 3VO 4，250μM KVEKIGEGTYGVVYK中，制备成为终浓度为45nM的酶液。使用10mM醋酸镁，10μM[γ- 33P]-ATP组成Mg/ATP混合液，激活酶学反应。
酶促反应：
在384孔板中，加入化合物工作液，使终浓度分别为10000nM，3000nM，1000nM，300nM，100nM，30nM，10nM，3nM，1nM，再加入按照上述条件制备的不同酶反应液，室温孵育40min后，加入0.5％磷酸溶液终止试验。取10μL反应液滴至P30滤纸，以0.425％磷酸溶液清洗4次后，甲醇清洗一次，置于闪烁计数仪检测。使用Image J软件对结果进行灰度分析，并使用GraphPad 5.0软件计算IC 50值。
测试结果如下表5所示：
表5本发明的化合物对LCK(h)激酶的抑制活性-IC 50(nM)
Figure PCTCN2020117074-appb-000169
由表5实验结果可见，本发明的化合物对LCK(h)的抑制活性低，可以表明本发明化合物对LCK(h)产生免疫抑制的风险低。
实验例6本发明化合物的比格犬PK评价实验
测试物：本发明化合物，按照实施例方法制备
动物给药及样品采集：
实验用化合物11、12、35：用处方5％DMSO+20％(30％solutol)+75％saline溶解制备溶液剂，化合物的溶液剂分别以1.0mg/kg的剂量灌胃给予比格犬，采血时间点为：0min，15min，30min，1h，2h，4h，6h，8h，10h，24h。
实验用化合物11、12、35：用处方5％DMSO+20％(30％solutol)+75％saline溶解制备溶液剂，化合物的溶液剂以1.0mg/kg的剂量静脉推注给予比格犬，采血时间点为：0min，5min，15min，30min，1h，2h，4h，6h，8h，10h，24h。
实验用化合物17、化合物37：用处方5％DMSO+20％PEG400+75％(20％Captisol in Saline)溶解制备溶液剂，化合物的溶液剂以5.0mg/kg的剂量灌胃给予比格犬，采血时间点为：0min，15min，30min，1h，2h，4h，6h，8h，10h，24h。
实验用化合物17、化合物37：用处方5％DMSO+20％PEG400+75％(20％Captisol in Water)溶解制备溶液剂，化合物的溶液剂以1.0mg/kg的剂量静脉推注给予比格犬，采血时间点为：0min，5min，15min，30min，1h，2h，4h，6h，8h，10h，24h。
实验用化合物18：用处方5％DMA+30％PEG400+65％(20％captisol in saline)溶解制备溶液剂，化合物的溶液剂以5.0mg/kg的剂量灌胃给予比格犬，采血时间点为：0min，15min，30min，1h，2h，4h，6h，8h，10h，24h。
实验用化合物18：用处方5％DMA+30％PEG400+65％(20％captisol in saline)溶解制备溶液剂，化合物的溶液剂以1.0mg/kg的剂量静脉推注给予比格犬，采血时间点为：0min，5min，15min，30min，1h，2h，4h，6h，8h，10h，24h。
经上肢静脉取血约1mL左右的血液，血液采集后放置到含有EDTA-K2抗凝管中。血液样品在4℃条件下1800g离心5min得到血浆样品，血浆在血液采集后的30min内制备。血浆测试前存放在-80℃冰箱内。
样品分析方法：
从-80℃冰箱中取出待测样品，室温自然融化后涡旋5min；精密吸取20μL血浆样品至1.5mL离心管中；加入200μL浓度为100ng/mL的内标工作溶液(甲苯磺丁脲的甲醇溶液)，混匀；涡旋5min后，12000 rpm离心5min；精密吸取50μL上清液至预先加有150μL/每孔水的96-孔板中；涡旋混匀5min，进行LC-MS/MS测定分析。
数据处理方法：
测试物浓度使用AB公司的Analyst 1.6.3输出结果。Microsoft Excel计算均值、标准差、变异系数等参数(Analyst 1.6.3直接输出的不用计算)，PK参数采用Pharsight Phoenix 6.1软件NCA计算(T max为中位数)。
实验结果如表6所示：
表6中化合物在比格犬体内的PK参数(IV：1mg/kg，PO：1mg/kg，n＝3)
表6本发明化合物的PK实验结果
Figure PCTCN2020117074-appb-000170
注：iv：静脉推注，po：灌胃给予；t z1/2：末端消除半衰期，Cl _obs：清除率，V z_obs：表观分布容积，T max：血药浓度达峰时间，AUC last：药-时曲线下面积0～24h，F％：绝对生物利用度
由表6实验结果可以看出，本发明化合物具有良好的药代动力学特征，成药性好。
产业实用性
本发明提供一种新型的TAM家族激酶抑制剂化合物，该化合物具有良好的激酶抑制活性，可用于治疗和/或预防由TAM家族激酶受体和/或其配体异常表达所介导的疾病。并且，本发明的化合物还可以靶向Ron激酶，可用于治疗和/或预防由TAM家族激酶/和Ron激酶的受 体和/或其配体异常表达所介导的疾病。进而，本发明的化合物可抑制由TAM家族激酶/和Ron激酶引起的肿瘤的生长、迁移、和/或耐药表现。

Claims (11)

  1. 通式(I)表示的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体：
    Figure PCTCN2020117074-appb-100001
    其中，W选自氢原子或任选被取代基取代的C 1-6烷基；
    R表示如下通式(b)所示的基团：
    Figure PCTCN2020117074-appb-100002
    Figure PCTCN2020117074-appb-100003
    表示在环结构中任选存在的双键部分，
    Figure PCTCN2020117074-appb-100004
    部分通过连接基团与M 3基团连接；
    X 1、X 2、X 3分别独立选自CR a、C＝O、NR b、O，且其中至少一个为C＝O；
    X 4、X 5分别独立选自C；
    M 3选自氢原子、氰基、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-OC(O)NR bR c、-NR bC(O)OR d、-NR bC(O)R d、-SO 2-NR bR c、-SO 2R d、-NR bSO 2R d；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-8烯基、C 2-8炔基、-C 1-6烷基-R’、-C 1-6烷氧基-R’、-O-R’、-C(O)-R’、-SO 2-R’、-NR bC(O)-R’、3-12元环烷基、3-12元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基；
    Cy 2选自任选被一至多个R 2取代的3-12元环烷基、3-12元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基，R 2各自独立的选自氢原子、氰基、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-OC(O)NR bR c、-NR bC(O)OR d、-NR bC(O)R d、-SO 2-NR bR c、-SO 2R d、 -NR bSO 2R d；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-8烯基、C 2-8炔基、-C 1-6烷基-R’、-C 1-6烷氧基-R’、-O-R’、-C(O)-R’、-SO 2-R’、-NR bC(O)-R’、3-12元环烷基、3-12元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基；
    Cy 3选自任选被一至多个R 3取代的5-10元杂芳基，R 3各自独立的选自氢原子、氰基、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-OC(O)NR bR c、-NR bC(O)OR d、-NR bC(O)R d、-SO 2-NR bR c、-SO 2R d、-NR bSO 2R d；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-8烯基、C 2-8炔基、-C 1-6烷基-R’、-C 1-6烷氧基-R’、-O-R’、-C(O)-R’、-SO 2-R’、-NR bC(O)-R’、3-12元环烷基、3-12元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基；
    Cy 4选自任选被一至多个R 4取代的5-9元杂环基、5-9元杂芳基，R 4各自独立的选自氢原子、氰基、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-OC(O)NR bR c、-NR bC(O)OR d、-NR bC(O)R d、-SO 2-NR bR c、-SO 2R d、-NR bSO 2R d；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-8烯基、C 2-8炔基、-C 1-6烷基-R’、-C 1-6烷氧基-R’、-O-R’、-C(O)-R’、-SO 2-R’、-NR bC(O)-R’、3-12元环烷基、3-12元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基，或者，两个R 4可以与所连接的原子形成5-6元环状基团；
    L选自-NR b-、-O-、-S-、-(CR aR a) m-，m选自1-3的整数；
    R a不存在，或者在每次出现时，各自独立地选自氢原子、氰基、羟基、卤素原子、羧基、硝基、-NR eR f、-C(O)R g、-C(O)NR eR f、-OC(O)NR eR f、-NR eC(O)OR g、-NR eC(O)R g、-SO 2-NR eR f、-SO 2R g、-NR eSO 2R g，或任选被取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-8烯基、C 2-8炔基、-C 1-6烷基-R’、-C 1-6烷氧基-R’、-O-R’、-C(O)-R’、-SO 2-R’、-NR eC(O)-R’、3-12元环烷基、3-12元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基；
    R b、R c不存在，或者在每次出现时，各自独立地选自氢原子、羟基、-C(O)R g、-C(O)NR eR f、-SO 2-NR eR f、-SO 2R g；或任选被取代基取代的C 1-6烷基、-C 1-6烷基-R’、-C(O)-R’、-SO 2-R’、3-12元环烷基、3-12元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基；
    R d不存在，或者在每次出现时，各自独立地选自氢原子、-NR eR f、 -NR eC(O)OR g、-NR eC(O)R g、-NR eSO 2R g；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基、-C 1-6烷基-R’、-C 1-6烷氧基-R’、-O-R’、-NR eC(O)-R’、3-12元环烷基、3-12元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基；
    R e、R f不存在，或者在每次出现时，各自独立的选自氢原子、羟基、羧基、氰基、硝基、卤素原子；或任选被取代基取代的C 1-6烷基、-C 1-6烷基-R’、-C(O)-R’、-SO 2-R’、3-12元环烷基、3-12元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基；
    R g不存在，或者在每次出现时，各自独立的选自氢原子；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基、-C 1-6烷基-R’、-C(O)-R’、-SO 2-R’、3-12元环烷基、3-12元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基；
    R’为3-12元环烷基、3-12元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基；
    n为0-4的整数；
    所述“任选被取代基取代”中的取代基各自独立地选自：羟基、巯基、氨基、羧基、氰基、硝基、卤素原子、C 1-6烷基、C 1-6烷氧基C 1-6烷基、C 1-6烷氧基、C 1-6烷基C 1-6烷氧基、C 1-6烷氧基C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷基氨基羰基、(C 1-6烷基) 2氨基羰基、C 1-6烷基羰基、C 1-6烷基羰基氧基、C 1-6烷基羰基氨基、C 1-6烷基磺酰氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 1-6烷基磺酰基、C 1-6烷基硫基、3-12元环烷基、6-14元芳基、3-12元杂环基、5-10元杂芳基和氧代基；
  2. 如权利要求1所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体，
    其中，W选自氢原子或任选被取代基取代的C 1-6烷基；
    R表示如下通式(b)所示的基团：
    Figure PCTCN2020117074-appb-100005
    Figure PCTCN2020117074-appb-100006
    部分通过连接基团与M 3基团连接；
    X 1、X 2、X 3分别独立地选自CR a、C＝O、NR b，且其中至少一个为C＝O；
    X 4、X 5分别选自C；
    M 3选自氢原子、氰基、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-OC(O)NR bR c、-NR bC(O)OR d、-NR bC(O)R d、-SO 2-NR bR c、-SO 2R d、-NR bSO 2R d；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-8烯基、C 2-8炔基、3-8元环烷基、3-14元杂环基；
    Cy 2选自任选被一至多个R 2取代的6-14元芳基、5-10元杂芳基，R 2各自独立地选自氢原子、氰基、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-OC(O)NR bR c、-NR bC(O)OR d、-NR bC(O)R d、-SO 2-NR bR c、-SO 2R d、-NR bSO 2R d；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-8烯基、C 2-8炔基、-C 1-6烷基-R’、-C 1-6烷氧基-R’、-O-R’、-C(O)-R’、-SO 2-R’、-NR bC(O)-R’、3-8元环烷基、3-8元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基；
    Cy 3选自任选被一至多个R 3取代的5-10元杂芳基，R 3各自独立地选自氢原子、氰基、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-OC(O)NR bR c、-NR bC(O)OR d、-NR bC(O)R d、-SO 2-NR bR c、-SO 2R d、-NR bSO 2R d；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-8烯基、C 2-8炔基、-C 1-6烷基-R’、-C 1-6烷氧基-R’、-O-R’、-C(O)-R’、-SO 2-R’、-NR bC(O)-R’、3-8元环烷基、3-8元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基；
    Cy 4选自任选被一至多个R 4取代的5-9元杂芳基，R 4各自独立地选自氢原子、氰基、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-OC(O)NR bR c、-NR bC(O)OR d、-NR bC(O)R d、-SO 2-NR bR c、-SO 2R d、-NR bSO 2R d；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-8烯基、C 2-8炔基、-C 1-6烷基-R’、-C 1-6烷氧基-R’、-O-R’、-C(O)-R’、-SO 2-R’、-NR bC(O)-R’、3-8元环烷基、3-8元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基，或者，两个R 4可以与所连接的原子形成5-6元环状基团；
    L选自-NR b-、-O-、-S-；
    R a不存在，或者在每次出现时，各自独立地选自氢原子、氰基、羟基、卤素原子、羧基、硝基、-NR eR f、-C(O)R g、-C(O)NR eR f、-OC(O)NR eR f、-NR eC(O)OR g、-NR eC(O)R g、-SO 2-NR eR f、-SO 2R g、-NR eSO 2R g；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-8烯基、C 2-8炔基、-C 1-6烷基-R’、-C 1-6烷氧基-R’、-O-R’、-C(O)-R’、-SO 2-R’、-NR eC(O)-R’、3-8元环烷基、3-8元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基；
    R b、R c不存在，或者在每次出现时，各自独立地选自氢原子、羟基、-C(O)R g、-C(O)NR eR f、-SO 2-NR eR f、-SO 2R g；或任选被取代基取代的C 1-6烷基、-C 1-6烷基-R’、-C(O)-R’、-SO 2-R’、3-8元环烷基、3-8元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基；
    R d不存在，或者在每次出现时，各自独立地选自氢原子、-NR eR f、-NR eC(O)OR g、-NR eC(O)R g、-NR eSO 2R g；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基、-C 1-6烷基-R’、-C 1-6烷氧基-R’、-O-R’、-NR eC(O)-R’、3-8元环烷基、3-8元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基；
    R e、R f不存在，或者在每次出现时，独立的选自氢原子、羟基、羧基、氰基、硝基、卤素原子；或任选被取代基取代的C 1-6烷基、-C 1-6烷基-R’、-C(O)-R’、-SO 2-R’、3-12元环烷基、3-12元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基；
    R g不存在，或者在每次出现时，独立的选自氢原子，或任选被取代基取代的C 1-6烷基、C 1-6烷氧基、-C 1-6烷基-R’、-C(O)-R’、-SO 2-R’、3-12元环烷基、3-12元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基；
    R’为3-8元环烷基、3-8元环烯基、3-14元杂环基、6-14元芳基、5-10元杂芳基；
    n为0-3的整数；
    所述“任选被取代基取代”中的取代基各自独立地选自：羟基、巯基、氨基、羧基、氰基、硝基、卤素原子、C 1-6烷基、C 1-6烷氧基C 1-6烷基、C 1-6烷氧基、C 1-6烷基C 1-6烷氧基、C 1-6烷氧基C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷基氨基羰基、(C 1-6烷基) 2氨基羰基、C 1-6烷基羰基、C 1-6烷基羰基氧基、C 1-6烷基羰基氨基、C 1-6烷基磺酰氨基、 卤代C 1-6烷基、卤代C 1-6烷氧基、C 1-6烷基磺酰基、C 1-6烷基硫基、3-8元环烷基、6-14元芳基、3-8元杂环基、5-10元杂芳基和氧代基；
    优选地，X 1为N，X 2为CR a，X 3为C＝O；
    优选地，X 1为CR a，X 2为N，X 3为C＝O；
    优选地，X 1为CR a，X 2为CR a，X 3为C＝O。
  3. 如权利要求2所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体，
    其中，X 1、X 2、X 3分别独立地选自CR a、C＝O、NR b，且其中至少一个为C＝O；
    X 4选自C，X 5选自C；
    M 3选自氢原子、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-NR bC(O)R d；或任选被取代基取代的C 1-6烷基、C 2-8烯基、C 2-8炔基、3-8元环烷基、3-8元杂环基；
    Cy 2选自任选被一至多个R 2取代的苯基、5-6元杂芳基，R 2各自独立地选自氢原子、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-NR bC(O)R d；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基；
    Cy 3选自任选被一至多个R 3取代的5-6元杂芳基，R 3各自独立地选自氢原子、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-NR bC(O)R d；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基；
    Cy 4选自任选被一至多个R 4取代的5-6元杂芳基或9元并杂芳基，R 4各自独立地选自氢原子、羟基、卤素原子、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-NR bC(O)R d；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基、5-10元杂芳基，或者，两个R 4可以与所连接的原子形成5-6元含氧环状基团；
    L选自-O-；
    R a不存在，或者在每次出现时，各自独立地选自氢原子，或任选被取代基取代的C 1-6烷基；
    R b、R c不存在，或者在每次出现时，各自独立地选自氢原子，或任选被取代基取代的C 1-6烷基；
    R d不存在，或者在每次出现时，各自独立地选自氢原子，或任选被取代基取代的C 1-6烷基；
    n为0-2的整数；
    所述“任选被取代基取代”中的取代基各自独立地选自：羟基、氨基、羧基、氰基、硝基、卤素原子、C 1-6烷基、C 1-6烷氧基；
    优选地，X 1为N，X 2为CR a，X 3为C＝O；
    优选地，X 1为CR a，X 2为N，X 3为C＝O；
    优选地，X 1为CR a，X 2为CR a，X 3为C＝O；
    优选地，Cy 3为
    Figure PCTCN2020117074-appb-100007
    Y 2、Y 3、Y 6、Y 7分别独立的选自CH或N，并且至少有一个为N。
  4. 如权利要求3所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体，
    其中，X 1、X 2、X 3分别独立地选自CR a、C＝O、NR b，且其中至少一个为C＝O；
    X 4选自C，X 5选自C；
    M 3选自氢；或任选被取代基取代的C 1-6烷基、C 2-8烯基、C 2-8炔基、3-8元环烷基、5-6元杂环基；
    Cy 2选自任选被一至多个R 2取代的苯基、5-6元杂芳基；
    Cy 3表示任选被一至多个R 3取代的
    Figure PCTCN2020117074-appb-100008
    Y 2、Y 3、Y 6和Y 7各自独立地选自CH或N，且至少一个为N；
    Cy 4选自任选被一至多个R 4取代的6元杂芳基或9元并杂芳基；
    R 2各自独立地选自氢原子、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-NR bC(O)R d；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基；
    R 3各自独立地选自氢原子、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-NR bC(O)R d；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基；
    R 4各自独立地选自氢原子、羟基、卤素原子、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-NR bC(O)R d、5-10元杂芳基；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基；
    L选自-O-；
    R a不存在，或者在每次出现时，各自独立地选自氢原子、C 1-6烷基、卤代C 1-6烷基；
    R b、R c不存在，或者在每次出现时，各自独立地选自氢原子、C 1-6烷基；
    R d不存在，或者在每次出现时，各自独立地选自氢原子、C 1-6烷基；
    n为0-2的整数；
    所述“任选被取代基取代”中的取代基各自独立地选自：羟基、巯基、氨基、羧基、氰基、硝基、卤素原子、C 1-6烷基、C 1-6烷氧基；
    优选地，X 1为N，X 2为CR a，X 3为C＝O；
    优选地，X 1为CR a，X 2为N，X 3为C＝O；
    优选地，X 1为CR a，X 2为CR a，X 3为C＝O；
    优选地，Cy 4选自任选被一至多个R 4取代的6元含N杂芳基或9元含N并杂芳基。
  5. 如权利要求4所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体，
    其中，X 1、X 2分别独立地选自CR a或NR b，X 3为C＝O；
    M 3选自氢原子、C 1-6烷基、C 2-8烯基、C 2-8炔基、3-6元环烷基、5-6元杂环基；
    Cy 2选自任选被一至多个R 2取代的苯基；
    Cy 3表示任选被一至多个R 3取代的
    Figure PCTCN2020117074-appb-100009
    Y 2、Y 3、Y 6和Y 7独立地选自CH或N，且至少一个为N；
    Cy 4选自任选被一至多个R 4取代的
    Figure PCTCN2020117074-appb-100010
    Figure PCTCN2020117074-appb-100011
    R 2各自独立地选自氢原子、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-NR bC(O)R d；或任选被取代基取代的C 1-6烷基C 1-6烷氧基；
    R 3各自独立地选自氢原子、羟基、卤素原子、羧基、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-NR bC(O)R d；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基；
    R 4各自独立地选自氢原子、羟基、卤素原子、硝基、-NR bR c、-C(O)R d、-C(O)NR bR c、-NR bC(O)R d；或任选被取代基取代的C 1-6烷基、C 1-6烷氧基、5-6元杂芳基；
    L选自-O-；
    R a不存在，或者在每次出现时，各自独立地选自氢原子、C 1-6烷基、卤代C 1-6烷基；
    R b、R c不存在，或者在每次出现时，各自独立地选自氢原子、C 1-6烷基；
    R d不存在，或者在每次出现时，各自独立地选自氢原子、C 1-6烷基；
    n为0-1的整数；
    所述“任选被取代基取代”中的取代基各自独立地选自：羟基、巯基、氨基、羧基、氰基、硝基、卤素原子。
  6. 如权利要求1所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体，
    其中，W选自氢原子；
    R表示如下通式(b)所示的基团：
    Figure PCTCN2020117074-appb-100012
    Figure PCTCN2020117074-appb-100013
    部分通过连接基团与M 3基团连接；
    X 1、X 2分别独立地选自CR a或NR b，X 3为C＝O；
    X 4选自C；X 5选自C；
    M 3选自：氢原子、羟基、卤素原子、硝基、C 1-4烷基、C 2-6烯基、C 2-6炔基、3-6元环烷基、5-6元杂环基；
    Cy 2选自任选被一至多个R 2取代的
    Figure PCTCN2020117074-appb-100014
    R 2各自独立地 选自氢原子、羟基、氟、氯、溴、C 1-4烷基；
    Cy 3选自任选被一至多个R 3取代的
    Figure PCTCN2020117074-appb-100015
    Figure PCTCN2020117074-appb-100016
    R 3各自独立地选自氢原子、羟基、氟、氯、溴、C 1-4烷基；
    Cy 4选自任选被一至多个R 4取代的
    Figure PCTCN2020117074-appb-100017
    Figure PCTCN2020117074-appb-100018
    R 4各自独立地选自氢原子、羟基、卤素原子、氨基、(C 1-4烷基) 1-2氨基-、C 1-4烷基、卤代C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷氧基、3-14元杂环基、5-6元杂芳基；
    L为-O-；
    R a不存在，或者在每次出现时，各自独立地选自氢原子、C 1-6烷基、卤代C 1-6烷基；
    R b不存在，或者在每次出现时，各自独立地选自氢原子、C 1-6烷基；
    n为0-1的整数；
    优选地，X 1为N，X 2为CR a，X 3为C＝O；
    优选地，X 1为CR a，X 2为N，X 3为C＝O；
    优选地，X 1为CR a，X 2为CR a，X 3为C＝O。
  7. 如权利要求1所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体，其为选自如下结构的化合物：
    Figure PCTCN2020117074-appb-100019
    Figure PCTCN2020117074-appb-100020
    Figure PCTCN2020117074-appb-100021
    Figure PCTCN2020117074-appb-100022
    Figure PCTCN2020117074-appb-100023
  8. 包含权利要求1-7任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体的药物组合物，其任选地含有一种或多种药用载体。
  9. 如权利要求8所述的药物组合物，还可以包括一种或多种第二活性治疗剂，所述的第二治疗活性剂为抗代谢物、生长因子抑制剂、有丝分类抑制剂、抗肿瘤激素类、烷化剂类、金属铂类、拓扑异构酶抑制剂、激素药、免疫调节剂、肿瘤抑制基因、癌疫苗、免疫检查点 抑制剂、肿瘤免疫治疗相关的抗体或肿瘤免疫治疗相关的小分子药物。
  10. 权利要求1-7任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体和权利要求8所述的药物组合物在制备治疗和/或预防由TAM家族受体及/或其配体异常表达所导致的信号通路异常而引发的相关疾病的药物中的用途，所述TAM家族受体及/或其配体异常表达所导致的信号通路异常而引发的相关疾病包括以下疾病中的至少一种肿瘤、子宫内膜异位、血管疾病/损伤、牛皮癣、视觉缺陷/病变、肾脏疾病、类风湿性关节炎、骨质疏松症。
  11. 权利要求1-7任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体和权利要求8所述的药物组合物在制备治疗和/或预防由TAM家族激酶/和Ron激酶受体和/或其配体异常表达所介导的疾病的药物中的用途，所述的TAM家族激酶/和Ron激酶受体和/或其配体异常表达所介导的疾病包括以下疾病中的至少一种：肿瘤、肿瘤免疫、子宫内膜异位、血管疾病/损伤、牛皮癣、视觉缺陷/病变、肾脏疾病、类风湿性关节炎、骨质疏松症。
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