Diformamide compounds, preparation methods thereof and their medical applications

Abstract

The present disclosure relates to diformamide compounds, preparation methods thereof and their applications in medicine. Specifically, the present disclosure relates to a diformamide compound represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and its application as a therapeutic agent, in particular, its application in the preparation of a drug for inhibiting protein kinase. The groups in general formula (I) are as defined in the specification.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and relates to a diformamide compound, a preparation method thereof, and its application in medicine. In particular, the present invention relates to a diformamide compound represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the diformamide compound, and its application in preparing a drug for inhibiting protein kinase. Background Art

[0002] Receptor tyrosine kinases (RTKs) belong to a family of transmembrane proteins on the cell membrane surface. Their main function is to transmit extracellular signals into cells and participate in regulating a series of processes such as survival, growth, proliferation, differentiation, adhesion and migration.

[0003] VEGF / VEGFR signaling is the major rate-limiting step in angiogenesis. Pathological angiogenesis is a hallmark of tumorigenesis. The growth of primary tumors and their subsequent metastasis depend on angiogenesis. High expression of VEGF / VEGFR is found in most solid tumors.

[0004] Treatment limitations of VEGF / VEGFR inhibitors: Based on clinical and preclinical data, treatment methods that simply inhibit VEGFR expression have certain limitations. For example, although monotherapy can delay tumor growth, most of them will not lead to tumor regression and may induce invasive or metastatic behavior of cancer. Although bevacizumab monotherapy can improve the PFS of tumor patients, it cannot effectively increase the overall survival of patients. In addition, VEGF / VEGFR therapy has primary and secondary drug resistance, the latter of which is usually caused by the upregulation of other important genes / proteins. For example, in renal cancer patients after VEGFR target treatment, it was found that high expression of MET and Axl promoted tumor development. Therefore, VEGF / VEGFR therapy usually needs to be used in combination with other drugs.

[0005] The TAM subfamily is composed of three tyrosine kinases: TYRO3, Axl, and Mer. The extracellular ligand binding domain of the TAM family kinases consists of two immunoglobulin-like domains and two fibronectin III domains. It has been confirmed that the natural ligands of TAM are growth arrest-specific protein 6 (GAS6) and protein S (PROS1). GAS6 can bind to and activate all three TAM kinases, while PROS1 is a ligand for both Mer and TYRO3 kinases.

[0006] Axl (also known as UFO, ARK, JTK11 and TYRO7) was first discovered as a transforming gene in the DNA of patients with chronic myeloid leukemia. GAS6 binds to Axl and induces its autophosphorylation and activation of tyrosine kinase Axl. Axl can continue to activate proteins in multiple downstream signal transduction pathways including PI3K-AKT, Raf-MAPK, PLC-PKC, etc.

[0007] Mer (also known as MERTK, EYK, RYK, RP38, NYK and TYRO12) was first discovered as a phosphoprotein in a lymphoblastoid cell expression library. Both GAS6 and PROS1 can bind to Mer and induce its phosphorylation and activation of Mer kinase. Similar to Axl, after activation, Mer can also continue to transmit signals downstream, such as activating the PI3K-AKT and Raf-MAPK pathways.

[0008] TYRO3 (also known as DTK, SKY, RSE, BRT, TIF, and ETK2) was first discovered by PCR-based cloning studies. Both GAS6 and PROS1 can bind to TYRO3 and activate this kinase. Although the downstream signaling pathways activated by TYRO3 are the least studied in the TAM family, current results show that the PI3K-AKT and Raf-MAPK pathways appear to be activated by TYRO3. TYRO3, AXL, and Mer have all been found to be overexpressed in tumors.

[0009] The MET family includes mesenchymal-epithelial transition factor (c-Met), an independent tyrosine kinase receptor expressed on the surface of a variety of epithelial cells; its natural ligand is hepatocyte growth factor / scatter factor (HGF / SF). After the natural ligand HGF binds to c-Met, it will start a series of intracellular signal transduction processes, including embryonic development and wound healing of normal cells. However, in tumor cells, due to mutation, overexpression and amplification of the c-Met gene, the HGF / c-Met axis is abnormally activated and the PI3K / AKT, Ras / MAPK, JAK / STAT, SRC and Wnt / β-catenin signaling pathways are activated, resulting in tumor growth and proliferation. Due to the continuous activation of the above-mentioned c-Met-dependent signaling pathways, tumor cells gain more competitive advantages than normal cells, and the possibility of tumor metastasis is greatly increased by contacting the blood supply and increasing the ability to detach from tissues.

[0010] The patent applications that have been published so far include WO2005030140A2, WO2010045095A1, WO2010075376A2, WO2019148044A1, CN102212062A and WO2012006960A1. The activities in these patent applications still have room for improvement, and there are major unmet medical needs in the relevant patient populations.

[0011] Therefore, a new class of compounds needs to be developed to better regulate these targets for the treatment of KDR (VEGFR2), TAM and MET kinase-mediated tumors. Summary of the invention

[0012] The purpose of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0013]

[0014] in:

[0015] Ring A is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclyl;

[0016] G 1 N atom or CR 2a ;

[0017] G 2 N atom or CR 2b ;

[0018] G 3 N atom or CR 3a ;

[0019] Each R 1 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0020] R 2 , R 2a and R 2b are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclic groups;

[0021] R 3 and R3a are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclic groups;

[0022] R 4 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group;

[0023] R 5 Selected from alkyl, -(CH 2 ) m R a , cycloalkyl and heterocyclyl; wherein the alkyl, cycloalkyl and heterocyclyl are each independently substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0024] R a is a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is independently selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR b R c , hydroxyl and hydroxyalkyl;

[0025] R b and R c are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group;

[0026] n is 0, 1, 2, 3, 4 or 5; and

[0027] m is 1, 2, 3, 4, 5 or 6.

[0028] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (I-1), or a pharmaceutically acceptable salt thereof:

[0029]

[0030] in:

[0031] L is an alkylene group or Ring B is a cycloalkyl group or a heterocyclyl group; p is 0, 1, 2, 3, 4, 5 or 6;

[0032] Ring A, G 1 , G 2 , G 3 , R 1 To R 4 and n are as defined in the general formula (I).

[0033] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein G 1 CR 2a or N atom; G 2 CR 2b or N atom; G 3 CR 3a ; R 2a , R 2b and R 3a are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; preferably, G 1 CR 2a ; G 2 CR 2b or N atom; G 3 CR 3a ; R 2a , R 2b and R 3a are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 More preferably, G 1 CH; G 2 is a CH or N atom; G 3 is CH; most preferably, G 1 CH; G 2 is N atom; G 3 For CH.

[0034] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein G 1 CR 2a ; G 2 CR 2b ; G 3 CR 3a ; R 2a , R 2b and R 3a are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; or G 1 is N atom; G 2 CR 2b ; G 3 CR 3a ; R 2b and R 3a are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; or G 1 CR 2a ; G 2 is N atom; G3 CR 3a ; R 2a and R 3a are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl.

[0035] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein G 1 CR 2a ; G 2 CR 2b ; G 3 CR 3a ; R 2a , R 2b and R 3a are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 More preferably, G 1 CH; G 2 CH; G 3 For CH.

[0036] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein R 2a , R 2b and R 3a are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; preferably, R 2a , R 2b and R 3a All are hydrogen atoms.

[0037] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II), or a pharmaceutically acceptable salt thereof:

[0038]

[0039] in:

[0040] Ring A, R 1 To R 5 and n are as defined in the general formula (I).

[0041] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1) or general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II-1), or a pharmaceutically acceptable salt thereof:

[0042]

[0043] in:

[0044] L is an alkylene group or Ring B is a cycloalkyl group or a heterocyclyl group; p is 0, 1, 2, 3, 4, 5 or 6;

[0045] Ring A, R 1 To R 4 and n are as defined in the general formula (I).

[0046] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (I-1) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III), or a pharmaceutically acceptable salt thereof:

[0047]

[0048] in:

[0049] Ring A, R 1 To R 5 and n are as defined in the general formula (I).

[0050] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1) or general formula (III) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III-1), or a pharmaceutically acceptable salt thereof:

[0051]

[0052] in:

[0053] L is an alkylene group or Ring B is a cycloalkyl group or a heterocyclyl group; p is 0, 1, 2, 3, 4, 5 or 6;

[0054] Ring A, R 1 To R 4 and n are as defined in the general formula (I).

[0055] In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1) and general formula (III-1) or their pharmaceutically acceptable salts, wherein ring A is phenyl or a 5- to 6-membered heteroaryl group; preferably, ring A is phenyl.

[0056] In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1) and general formula (III-1) or their pharmaceutically acceptable salts, wherein ring A is selected from 6- to 10-membered aryl groups, 5- to 10-membered heteroaryl groups and 3- to 8-membered cycloalkyl groups; preferably, ring A is a 6- to 10-membered aryl group or a 3- to 8-membered cycloalkyl group; more preferably, ring A is phenyl or cyclohexyl.

[0057] In some embodiments of the present disclosure, the compounds represented by the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1) and general formula (III-1) or their pharmaceutically acceptable salts, wherein R 4 C 1-6 Alkyl; preferably, R 4 It is methyl.

[0058] In some embodiments of the present disclosure, the compounds represented by the general formula (I), general formula (II) and general formula (III) or their pharmaceutically acceptable salts, wherein R 5 C 1-6 Alkyl or -(CH 2 ) m R a ; R a is a 3- to 6-membered cycloalkyl group; wherein the 3- to 6-membered cycloalkyl group is optionally selected from C 1-6 Alkyl and -NR b R c is substituted by one or more substituents; R b and R c are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl; m is 1, 2 or 3; preferably, R 5 Methyl or

[0059] In some embodiments of the present disclosure, the compounds represented by the general formula (I-1), the general formula (II-1) and the general formula (III-1) or their pharmaceutically acceptable salts, wherein L is Ring B is a 3- to 6-membered cycloalkyl group, p is 0, 1, 2 or 3; preferably, L is Ring B is cyclopropyl, p is 1, 2 or 3; more preferably, L is Ring B is p is 1.

[0060] In some embodiments of the present disclosure, the compounds represented by the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1) and general formula (III-1) or their pharmaceutically acceptable salts, wherein each R 1 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, cyano, amino, nitro, hydroxyl, C 1-6 hydroxyalkyl, 3 to 6-membered cycloalkyl and 3 to 6-membered heterocyclic group; preferably, each R 1 are the same or different and are each independently selected from hydrogen atoms, halogens, C1-6 Alkyl and C 1-6 More preferably, each R 1 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; further preferably, each R 1 The same or different, and each independently is a hydrogen atom or a halogen; most preferably, each R 1 are the same or different and are each independently a hydrogen atom or F.

[0061] In some embodiments of the present disclosure, the compounds represented by the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1) and general formula (III-1) or their pharmaceutically acceptable salts, wherein R 2 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; preferably, R 2 A hydrogen atom.

[0062] In some embodiments of the present disclosure, the compounds represented by the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1) and general formula (III-1) or their pharmaceutically acceptable salts, wherein R 3 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; preferably, R 3 A hydrogen atom.

[0063] In some embodiments of the present disclosure, the compounds represented by formula (I), formula (II), formula (III), formula (I-1), formula (II-1) and formula (III-1) or their pharmaceutically acceptable salts, wherein n is 0, 1 or 2; preferably, n is 0 or 1.

[0064] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl; G 1 CR 2a ; G 2 CR 2b ; G 3 CR 3a ; R 2a , R 2b and R 3a are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; R 4 is methyl; R 5 Methyl or Each R 1 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R2 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; R 3 Selected from hydrogen atoms, halogens and C 1-6 alkyl; and n is 0 or 1.

[0065] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl or cyclohexyl; G 1 CR 2a ; G 2 CR 2b or N atom; G 3 CR 3a ; R 2a , R 2b and R 3a are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; R 4 is methyl; R 5 Methyl or Each R 1 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R 2 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; R 3 Selected from hydrogen atoms, halogens and C 1-6 alkyl; and n is 0 or 1.

[0066] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl or cyclohexyl; G 1 CH; G 2 is a CH or N atom; G 3 CH; R 4 is methyl; R 5 Methyl or Each R 1 are the same or different and are each independently a hydrogen atom or a halogen; R 2 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; R 3 Selected from hydrogen atoms, halogens and C 1-6 alkyl; and n is 0 or 1.

[0067] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl or cyclohexyl; G 1 CH; G 2 is a CH or N atom; G 3 CH; R 4 is methyl; R5 Methyl or Each R 1 are the same or different and are each independently a hydrogen atom or a halogen; R 2 is a hydrogen atom; R 3 is a hydrogen atom; and n is 0 or 1.

[0068] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl; R 4 is methyl; R 5 Methyl or Each R 1 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R 2 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; R 3 Selected from hydrogen atoms, halogens and C 1-6 alkyl; and n is 0 or 1.

[0069] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl or cyclohexyl; R 4 is methyl; R 5 Methyl or Each R 1 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R 2 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; R 3 Selected from hydrogen atoms, halogens and C 1-6 alkyl; and n is 0 or 1.

[0070] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl or cyclohexyl; R 4 is methyl; R 5 Methyl or Each R 1 are the same or different and are each independently a hydrogen atom or a halogen; R 2 is a hydrogen atom; R 3 is a hydrogen atom; and n is 0 or 1.

[0071] In some embodiments of the present disclosure, the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl; R 4 is methyl; R 5 is methyl; each R 1are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R 2 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; R 3 Selected from hydrogen atoms, halogens and C 1-6 alkyl; and n is 0 or 1.

[0072] In some embodiments of the present disclosure, the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl or cyclohexyl; R 4 is methyl; R 5 is methyl; each R 1 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R 2 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; R 3 Selected from hydrogen atoms, halogens and C 1-6 alkyl; and n is 0 or 1.

[0073] In some embodiments of the present disclosure, the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl or cyclohexyl; R 4 is methyl; R 5 is methyl; each R 1 are the same or different and are each independently a hydrogen atom or a halogen; R 2 is a hydrogen atom; R 3 is a hydrogen atom; and n is 0 or 1.

[0074] Table A Typical compounds of the present disclosure include, but are not limited to:

[0075]

[0076] Another aspect of the present disclosure relates to a compound represented by general formula (IA) or a salt thereof:

[0077]

[0078] in:

[0079] G 1 , G 2 , G 3 and R 2 To R 5 As defined in the general formula (I). It is an intermediate for preparing the compound represented by the general formula (I).

[0080] Another aspect of the present disclosure relates to a compound represented by general formula (I-1A) or a salt thereof:

[0081]

[0082] in:

[0083] R w is an amino protecting group, preferably Boc;

[0084] L is an alkylene group or Ring B is a cycloalkyl group or a heterocyclyl group; p is 0, 1, 2, 3, 4, 5 or 6;

[0085] G 1 , G 2 , G 3 and R 2 To R 4 As defined in the general formula (I-1). It is an intermediate for preparing the compound represented by the general formula (I-1).

[0086] Another aspect of the present disclosure relates to a compound represented by general formula (IIA) or a salt thereof:

[0087]

[0088] in:

[0089] R 2 To R 5 As defined in the general formula (II), it is an intermediate for preparing the compound represented by the general formula (II).

[0090] Another aspect of the present disclosure relates to a compound represented by general formula (II-1A) or a salt thereof:

[0091]

[0092] in:

[0093] R w is an amino protecting group, preferably Boc;

[0094] L is an alkylene group or Ring B is a cycloalkyl group or a heterocyclyl group; p is 0, 1, 2, 3, 4, 5 or 6;

[0095] R 2 To R 4 As defined in the general formula (II-1), it is an intermediate for preparing the compound represented by the general formula (II-1).

[0096] Another aspect of the present disclosure relates to a compound represented by general formula (IIIA) or a salt thereof:

[0097]

[0098] in:

[0099] R 2 To R 5 As defined in general formula (III). It is an intermediate for preparing the compound represented by general formula (III). Another aspect of the present disclosure relates to a compound represented by general formula (III-1A) or a salt thereof:

[0100]

[0101] in:

[0102] R w is an amino protecting group, preferably Boc;

[0103] L is an alkylene group or Ring B is a cycloalkyl group or a heterocyclyl group; p is 0, 1, 2, 3, 4, 5 or 6;

[0104] R 2 To R 4 As defined in the general formula (III-1), it is an intermediate for preparing the compound represented by the general formula (III-1).

[0105] Another aspect of the present disclosure relates to a compound represented by the general formula (IC) or a salt thereof:

[0106]

[0107] in:

[0108] Y is a halogen; preferably a bromine atom;

[0109] G 1 , G 2 , G 3 and R 2 To R 5 As defined in the general formula (I). It is an intermediate for preparing the compound represented by the general formula (I).

[0110] Another aspect of the present disclosure relates to a compound represented by general formula (IIC) or a salt thereof:

[0111]

[0112] in:

[0113] R 2 To R 5 As defined in the general formula (II), it is an intermediate for preparing the compound represented by the general formula (II).

[0114] Another aspect of the present disclosure relates to a compound represented by general formula (IIIC) or a salt thereof:

[0115]

[0116] in:

[0117] R 2 To R 5 As defined in the general formula (III), it is an intermediate for preparing the compound represented by the general formula (III).

[0118] Another aspect of the present disclosure relates to a compound represented by the general formula (IAa) or a salt thereof:

[0119]

[0120] in:

[0121] G 1 , G 2 , G 3 and R 2 To R 5 As defined in the general formula (I). It is an intermediate for preparing the compound represented by the general formula (I).

[0122] Another aspect of the present disclosure relates to a compound represented by general formula (IIAa) or a salt thereof:

[0123]

[0124] in:

[0125] R 2 To R 5 As defined in the general formula (II), it is an intermediate for preparing the compound represented by the general formula (II).

[0126] Another aspect of the present disclosure relates to a compound represented by general formula (IIIAa) or a salt thereof:

[0127]

[0128] in:

[0129] R 2 To R 5 As defined in the general formula (III), it is an intermediate for preparing the compound represented by the general formula (III).

[0130] Table B Typical intermediate compounds disclosed herein include but are not limited to:

[0131]

[0132]

[0133] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0134]

[0135] A compound of the general formula (IA) or a salt thereof undergoes an acylation reaction with a compound of the general formula (IB) or a salt thereof to obtain a compound of the general formula (I) or a pharmaceutically acceptable salt thereof,

[0136] in:

[0137] X is a halogen; preferably a chlorine atom;

[0138] Ring A, G 1 , G 2 , G 3 , R 1 To R 5 and n are as defined in the general formula (I).

[0139] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0140]

[0141] A compound of general formula (IIA) or a salt thereof undergoes acylation reaction with a compound of general formula (IB) or a salt thereof to obtain a compound of general formula (II) or a pharmaceutically acceptable salt thereof,

[0142] in:

[0143] X is a halogen; preferably a chlorine atom;

[0144] Ring A, R 1 To R 5 and n are as defined in the general formula (II).

[0145] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0146]

[0147] A compound of the general formula (IIIA) or a salt thereof undergoes an acylation reaction with a compound of the general formula (IB) or a salt thereof to obtain a compound of the general formula (III) or a pharmaceutically acceptable salt thereof,

[0148] in:

[0149] X is a halogen; preferably a chlorine atom;

[0150] Ring A, R 1 To R 5 and n are as defined in the general formula (III).

[0151] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-1), or a pharmaceutically acceptable salt thereof, the method comprising:

[0152]

[0153] (a) Acetylation reaction of a compound of the general formula (I-1A) or a salt thereof with a compound of the general formula (IB) or a salt thereof to obtain a compound of the general formula (I-1Aa) or a pharmaceutically acceptable salt thereof;

[0154] (b) subjecting the compound of the general formula (I-1Aa) or a pharmaceutically acceptable salt thereof to a deprotection reaction to obtain a compound of the general formula (I-1) or a pharmaceutically acceptable salt thereof;

[0155] in:

[0156] X is a halogen; preferably a chlorine atom;

[0157] R w is an amino protecting group, preferably Boc;

[0158] L is an alkylene group or Ring B is a cycloalkyl group or a heterocyclyl group; p is 0, 1, 2, 3, 4, 5 or 6;

[0159] Ring A, G 1 , G 2 , G 3 , R 1 To R 4 and n are as defined in the general formula (I-1).

[0160] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-1), or a pharmaceutically acceptable salt thereof, comprising:

[0161]

[0162] (a) Acylation reaction of a compound of formula (II-1A) or a salt thereof with a compound of formula (IB) or a salt thereof to obtain a compound of formula (II-1Aa) or a pharmaceutically acceptable salt thereof;

[0163] (b) subjecting the compound of the general formula (II-1Aa) or a pharmaceutically acceptable salt thereof to a deprotection reaction to obtain a compound of the general formula (II-1) or a pharmaceutically acceptable salt thereof;

[0164] in:

[0165] X is a halogen; preferably a chlorine atom;

[0166] R w is an amino protecting group, preferably Boc;

[0167] L is an alkylene group or Ring B is a cycloalkyl group or a heterocyclyl group; p is 0, 1, 2, 3, 4, 5 or 6;

[0168] Ring A, R 1 To R 4 and n are as defined in the general formula (II-1).

[0169] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-1), or a pharmaceutically acceptable salt thereof, comprising:

[0170]

[0171] (a) Acylation reaction of a compound of formula (III-1A) or a salt thereof with a compound of formula (IB) or a salt thereof to obtain a compound of formula (III-1Aa) or a pharmaceutically acceptable salt thereof;

[0172] (b) subjecting the compound of the general formula (III-1Aa) or a pharmaceutically acceptable salt thereof to a deprotection reaction to obtain a compound of the general formula (III-1) or a pharmaceutically acceptable salt thereof;

[0173] in:

[0174] X is a halogen; preferably a chlorine atom;

[0175] R w is an amino protecting group, preferably Boc;

[0176] L is an alkylene group or Ring B is a cycloalkyl group or a heterocyclyl group; p is 0, 1, 2, 3, 4, 5 or 6;

[0177] Ring A, R 1 To R 4 and n are as defined in the general formula (III-1).

[0178] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0179]

[0180] The compound of general formula (IC) or its salt undergoes coupling reaction with the compound of general formula (ID) or its salt to obtain the compound of general formula (I) or its pharmaceutically acceptable salt,

[0181] in:

[0182] Y is a halogen; preferably a bromine atom;

[0183] Ring A, G 1 , G 2 , G 3 , R1 To R 5 and n are as defined in the general formula (I).

[0184] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0185]

[0186] The compound of general formula (IIC) or its salt undergoes coupling reaction with the compound of general formula (ID) or its salt to obtain the compound of general formula (II) or its pharmaceutically acceptable salt,

[0187] in:

[0188] Y is a halogen; preferably a bromine atom;

[0189] Ring A, R 1 To R 5 and n are as defined in the general formula (II).

[0190] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0191]

[0192] The compound of general formula (IIIC) or its salt undergoes coupling reaction with the compound of general formula (ID) or its salt to obtain the compound of general formula (III) or its pharmaceutically acceptable salt,

[0193] in:

[0194] Y is a halogen; preferably a bromine atom;

[0195] Ring A, R 1 To R 5 and n are as defined in the general formula (III).

[0196] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0197]

[0198] The compound of the general formula (IAa) or its salt undergoes an amidation reaction with the compound of the general formula (IBb) or its salt to obtain the compound of the general formula (I) or its pharmaceutically acceptable salt,

[0199] in:

[0200] Ring A, G 1 , G 2 , G 3 , R1 To R 5 and n are as defined in the general formula (I).

[0201] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0202]

[0203] The compound of general formula (IIAa) or its salt undergoes amidation reaction with the compound of general formula (IBb) or its salt to obtain the compound of general formula (II) or its pharmaceutically acceptable salt,

[0204] in:

[0205] Ring A, R 1 To R 5 and n are as defined in the general formula (II).

[0206] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0207]

[0208] The compound of the general formula (IIIAa) or its salt undergoes an amidation reaction with the compound of the general formula (IBb) or its salt to obtain the compound of the general formula (III) or its pharmaceutically acceptable salt,

[0209] in:

[0210] Ring A, R 1 To R 5 and n are as defined in the general formula (III).

[0211] Another aspect of the present disclosure relates to a pharmaceutical composition, which contains a compound shown in the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1) and Table A of the present disclosure, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0212] The present disclosure further relates to the use of compounds shown in general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1) and Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same in the preparation of drugs for inhibiting protein kinases.

[0213] The present disclosure further relates to the use of compounds shown in general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1) and Table A or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising the same in the preparation of drugs for treating and / or preventing diseases, conditions and syndromes; specifically, in the preparation of drugs for treating and / or preventing diseases, conditions and syndromes by inhibiting protein kinases. The diseases, disorders and syndromes are preferably selected from sarcoma, multiple myeloma, leukemia, myxoma, rhabdomyomas, leiomyomas, fibromas, lipomas, teratomas, pharyngeal cancer, oral cancer, lung cancer, alveolar cancer, lymphoma, mesothelioma, colorectal cancer, small intestine cancer, gastric cancer, esophageal cancer, pancreatic cancer, breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, liver cancer, bile duct cancer, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer, psoriasis, gastrointestinal stromal tumors (GIST), atherosclerosis and pulmonary fibrosis; wherein the pharyngeal cancer is preferably nasopharyngeal carcinoma; the sarcoma is preferably osteosarcoma or chondrosarcoma; the colorectal cancer is preferably colon cancer or rectal cancer; the fibroma is preferably neurofibroma.

[0214] The present disclosure further relates to the use of compounds shown in general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1) and Table A or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising the same in the preparation of drugs for treating and / or preventing tumors, wherein the tumor is preferably cancer, more preferably selected from sarcoma, multiple myeloma, leukemia, myxoma, rhabdomyomas, leiomyomas, fibromas, lipomas, teratomas, laryngeal cancer, oral cancer, lung cancer, alveolar cancer, lymphoma, mesothelioma, colorectal cancer The invention relates to cancer of the present invention to a kind of cancer of the present invention, wherein the cancer of the present invention is preferably nasopharyngeal cancer, the cancer of the small intestine, the cancer of the stomach, the cancer of the esophagus, the cancer of the pancreas, the cancer of the breast, the cancer of the endometrium, the cancer of the ovary, the cancer of the fallopian tube, the cancer of the cervix, the cancer of the kidney, the cancer of the bladder, the cancer of the prostate, the cancer of the testis, the cancer of the liver, the cancer of the bile duct, the glioma, the neuroblastoma, the melanoma, the cancer of the skin, the basal cell carcinoma, the squamous cell carcinoma, the cancer of the thyroid, the cancer of the head and neck, the salivary gland cancer and the gastrointestinal stromal tumor (GIST); wherein the pharyngeal cancer is preferably nasopharyngeal carcinoma; wherein the sarcoma is preferably osteosarcoma or chondrosarcoma; wherein the colorectal cancer is preferably colon cancer or rectal cancer; wherein the fibroma is preferably neurofibroma.

[0215] The present disclosure further relates to a method for inhibiting protein kinase, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (III), formula (I-1), formula (II-1), formula (III-1) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0216] The present disclosure further relates to a method for treating and / or preventing diseases, conditions and syndromes, specifically a method for treating and / or preventing diseases, conditions and syndromes that are treated and / or prevented by inhibiting protein kinases, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (III), formula (I-1), formula (II-1), formula (III-1) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. The diseases, disorders and syndromes are preferably selected from sarcoma, multiple myeloma, leukemia, myxoma, rhabdomyomas, leiomyomas, fibromas, lipomas, teratomas, pharyngeal cancer, oral cancer, lung cancer, alveolar cancer, lymphoma, mesothelioma, colorectal cancer, small intestine cancer, gastric cancer, esophageal cancer, pancreatic cancer, breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, liver cancer, bile duct cancer, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer, psoriasis, gastrointestinal stromal tumors (GIST), atherosclerosis and pulmonary fibrosis; wherein the pharyngeal cancer is preferably nasopharyngeal carcinoma; the sarcoma is preferably osteosarcoma or chondrosarcoma; the colorectal cancer is preferably colon cancer or rectal cancer; the fibroma is preferably neurofibroma.

[0217] The present disclosure further relates to a method for treating and / or preventing tumors, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (III), formula (I-1), formula (II-1), formula (III-1) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. The tumor is preferably cancer, more preferably selected from sarcoma, multiple myeloma, leukemia, myxoma, rhabdomyomas, leiomyomas, fibromas, lipomas, teratomas, pharyngeal cancer, oral cancer, lung cancer, lymphoma, mesothelioma, colorectal cancer, small intestine cancer, gastric cancer, esophageal cancer, pancreatic cancer, breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, liver cancer, bile duct cancer, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer and gastrointestinal stromal tumor (GIST); wherein the pharyngeal cancer is preferably nasopharyngeal carcinoma; the sarcoma is preferably osteosarcoma or chondrosarcoma; the colorectal cancer is preferably colon cancer or rectal cancer; the fibroma is preferably neurofibroma.

[0218] The present disclosure further relates to a compound shown in general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a drug.

[0219] The present disclosure further relates to a compound shown in general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a drug for inhibiting protein kinase.

[0220] The present disclosure further relates to a compound shown in general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a drug for treating and / or preventing diseases, conditions and syndromes, specifically as a drug for treating and / or preventing diseases, conditions and syndromes treated and / or prevented by inhibiting protein kinases. The diseases, disorders and syndromes are preferably selected from sarcoma, multiple myeloma, leukemia, myxoma, rhabdomyomas, leiomyomas, fibromas, lipomas, teratomas, pharyngeal cancer, oral cancer, lung cancer, alveolar cancer, lymphoma, mesothelioma, colorectal cancer, small intestine cancer, gastric cancer, esophageal cancer, pancreatic cancer, breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, liver cancer, bile duct cancer, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer, psoriasis, gastrointestinal stromal tumors (GIST), atherosclerosis and pulmonary fibrosis; wherein the pharyngeal cancer is preferably nasopharyngeal carcinoma; the sarcoma is preferably osteosarcoma or chondrosarcoma; the colorectal cancer is preferably colon cancer or rectal cancer; the fibroma is preferably neurofibroma.

[0221] The present disclosure further relates to a compound represented by formula (I), formula (II), formula (III), formula (I-1), formula (II-1), formula (III-1) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a drug for treating and / or preventing tumors, wherein the tumor is preferably cancer, more preferably selected from sarcoma, multiple myeloma, leukemia, myxoma, rhabdomyoma, leiomyoma, fibroma, lipoma, teratoma, laryngeal cancer, oral cancer, lung cancer, alveolar cancer, lymphoma, mesothelioma, colorectal cancer, Small intestine cancer, gastric cancer, esophageal cancer, pancreatic cancer, breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, liver cancer, bile duct cancer, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer and gastrointestinal stromal tumor (GIST); wherein the laryngeal cancer is preferably nasopharyngeal carcinoma; the sarcoma is preferably osteosarcoma or chondrosarcoma; the colorectal cancer is preferably colon cancer or rectal cancer; the fibroma is preferably neurofibroma.

[0222] The lymphoma described in the present disclosure is preferably Hodgkin's disease or non-Hodgkin's lymphoma (e.g., mantle cell lymphoma, diffuse large B-cell lymphoma, follicular center lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma and peripheral T-cell lymphoma); the lung cancer is preferably non-small cell lung cancer (NSCLC) (e.g., lung adenocarcinoma, lung squamous cell carcinoma and large cell carcinoma, etc.) or small cell lung cancer (SCLC); the kidney cancer is preferably selected from renal cell carcinoma, clear cell tumor and renal oncocytoma; the leukemia is preferably chronic leukemia (e.g., chronic lymphocytic leukemia) or acute leukemia (e.g., acute myeloid leukemia).

[0223] The protein kinases described in the present disclosure are preferably receptor tyrosine kinases (RTKs); preferably, the receptor tyrosine kinases (RTKs) are TAM, MET, KDR or a combination thereof.

[0224] The protein kinases described in the present disclosure are receptor tyrosine kinases (RTKs); preferably, the receptor tyrosine kinases (RTKs) are Axl, Mer, TYRO3, MET, KDR or a combination thereof.

[0225] The active compound can be prepared into a form suitable for administration by any appropriate route, and the composition of the present disclosure can be prepared by conventional methods using one or more pharmaceutically acceptable carriers. Therefore, the active compound of the present disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular or subcutaneous) administration, inhalation or insufflation administration. The compounds of the present disclosure can also be formulated into dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges or syrups.

[0226] As a general guide, the active compound is preferably in a unit dose form, or in a form that a patient can self-administer in a single dose. The unit dose of the disclosed compound or composition can be expressed in tablets, capsules, cachets, bottled liquids, powders, granules, lozenges, suppositories, reconstituted powders or liquid preparations. Suitable unit doses can be 0.1 to 1000 mg.

[0227] The pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, and the excipients are selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0228] Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for preparing tablets. These excipients may be inert excipients, granulating agents, disintegrants, binders and lubricants. These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.

[0229] Oral preparations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water-soluble carrier or an oily vehicle.

[0230] Aqueous suspensions contain the active substance and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, dispersants or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.

[0231] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil, or a mineral oil. The oil suspension may contain a thickener. The above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding an antioxidant.

[0232] Pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such preparations may also contain a demulcent, a preservative, a coloring agent, and an antioxidant.

[0233] The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. The injection or microemulsion may be injected into the patient's bloodstream by local mass injection. Alternatively, it is preferred that the solution and microemulsion be administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain such a constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous injection pump.

[0234] Pharmaceutical compositions of the present disclosure can be in the form of sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be prepared with suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injection preparations can also be sterile injection solutions or suspensions prepared in parenteral acceptable nontoxic diluents or solvents. In addition, sterile fixed oils can be conveniently used as solvents or suspension media. For this purpose, any blended fixed oils can be used. In addition, fatty acids can also be used to prepare injections.

[0235] The disclosed compounds may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

[0236] The compounds of the present disclosure can be administered by preparing water-suspended dispersible powders and granules by the addition of water. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent, or one or more preservatives.

[0237] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the best treatment method such as the mode of treatment, the daily dosage of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

[0238] Terminology

[0239] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0240] The term "alkyl" refers to a saturated straight or branched aliphatic hydrocarbon group having 1 to 20 carbon atoms (i.e., C 1-20 The alkyl group is preferably an alkyl group having 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e., C 1-12 alkyl), more preferably an alkyl group having 1 to 6 carbon atoms (i.e., C 1-6alkyl). Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. Most preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. The substituent is preferably selected from one or more of a D atom, a halogen, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0241] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 The alkylene group preferably has 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e., C1-12 Alkylene), more preferably having 1 to 6 carbon atoms (i.e., C 1-6 Non-limiting examples of alkylene include, but are not limited to, methylene (—CH 2 -), 1,1-ethylene (-CH(CH 3 )-), 1,2-ethylene (-CH 2 CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), etc. The alkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, and oxo.

[0242] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein the definition of alkyl is as described above, and an alkenyl group (i.e., C 2 to 12) carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) 2-12 The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C 2-6 The term "alkenyl" refers to an alkylene group (alkylene group). Non-limiting examples include ethenyl, propenyl, isopropenyl, butenyl, etc. Alkenyl may be substituted or unsubstituted, and when substituted, it is preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0243] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e., C 2-12 The alkynyl group preferably has 2 to 6 carbon atoms (i.e., C 2-6The alkynyl group may be substituted or unsubstituted and, when substituted, is preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0244] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy and butoxy, etc. Alkoxy can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of a deuterium atom, a halogen, an alkoxy, a haloalkyl, a haloalkoxy, a cycloalkyloxy, a heterocyclyloxy, a hydroxyl, a hydroxyalkyl, a cyano, an amino, a nitro, a cycloalkyl, a heterocyclyl, an aryl and a heteroaryl.

[0245] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., 3-20 membered cycloalkyl), preferably having 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14) carbon atoms (i.e., 3-14 membered cycloalkyl), more preferably having 3 to 8 carbon atoms (i.e., 3-8 membered cycloalkyl), further preferably having 3 to 6 carbon atoms (i.e., 3-6 membered cycloalkyl), and most preferably having 5 or 6 carbon atoms (i.e., 5-6 membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl, and the like; polycyclic cycloalkyl groups include spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl groups.

[0246] The term "spirocycloalkyl" refers to a polycyclic group of 5 to 20 yuan, a carbon atom (called spiral atom) shared between monocyclic rings, which may contain one or more double bonds. Preferably 6 to 14 yuan, more preferably 7 to 10 yuan (e.g. 7, 8, 9 or 10 yuan). According to the number of spiral atoms shared between rings, spirocycloalkyl is divided into single spirocycloalkyl or multi-spirocycloalkyl (e.g. double spirocycloalkyl), preferably single spirocycloalkyl or double spirocycloalkyl. More preferably 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan or 6 yuan / 6 yuan single spirocycloalkyl. Non-limiting examples of spirocycloalkyl include:

[0247]

[0248] The term "condensed cycloalkyl" refers to 5 to 20 yuan, and each ring in the system shares a pair of adjacent carbon atoms with other rings in the system. All carbon polycyclic groups, wherein one or more rings can contain one or more double bonds. Preferably 6 to 14 yuan, more preferably 7 to 10 yuan (such as 7,8,9 or 10 yuan). According to the number of the composition ring, it can be divided into polycyclic condensed cycloalkyls such as bicyclic, tricyclic, tetracyclic, preferably bicyclic or tricyclic condensed cycloalkyl, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan bicyclic alkyl. The limiting examples of condensed cycloalkyl include:

[0249]

[0250] The term "bridged cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, and which may contain one or more double bonds. Preferably, it is 6 to 14 members, and more preferably, it is 7 to 10 members (e.g., 7, 8, 9, or 10 members). According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably a bicyclic, tricyclic, or tetracyclic bridged cycloalkyl, and more preferably a bicyclic or tricyclic bridged cycloalkyl. Non-limiting examples of bridged cycloalkyl include:

[0251]

[0252] The cycloalkyl ring includes a cycloalkyl group as described above (including a monocyclic ring, a spirocyclic ring, a condensed ring and a bridged ring) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include etc.; preferred

[0253] The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. The substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0254] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent having 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, wherein the sulfur may be optionally oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it has 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14) ring atoms, wherein 1 to 4 (e.g., 1, 2, 3 and 4) are heteroatoms (i.e., 3 to 14-membered heterocyclyl); more preferably, it has 3 to 8 (e.g., 3, 4, 5, 6, 7 and 8) ring atoms, wherein 1-3 (e.g., 1, 2 and 3) are heteroatoms (i.e., 3 to 8-membered heterocyclyl) or 6 to 1 4 ring atoms (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14), of which 1-3 (e.g., 1, 2 and 3) are heteroatoms (i.e., 6 to 14-membered heterocyclyl); more preferably, there are 3 to 6 ring atoms, of which 1-3 (e.g., 1, 2 and 3) are heteroatoms (i.e., 3 to 6-membered heterocyclyl); most preferably, there are 5 or 6 ring atoms, of which 1-3 are heteroatoms (i.e., 5 to 6-membered heterocyclyl). Non-limiting examples of monocyclic heterocyclyls include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclyls include spiro heterocyclyls, fused heterocyclyls and bridged heterocyclyls.

[0255] The term "spiro heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 yuan, one atom (called spiral atom) shared between monocyclic rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably 6 to 14 yuan (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 yuan), more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of spiral atoms shared between rings, the spiral heterocyclic group is divided into a single spiral heterocyclic group or a multi-spiro heterocyclic group (such as a double spiral heterocyclic group), preferably a single spiral heterocyclic group or a double spiral heterocyclic group. Most preferably, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan or 6 yuan / 6 yuan single spiral heterocyclic group. Non-limiting examples of spiral heterocyclic groups include:

[0256]

[0257] The term "fused heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 members, each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14 members (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 members), more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into polycyclic fused heterocyclic groups such as bicyclic, tricyclic, and tetracyclic, preferably bicyclic or tricyclic fused heterocyclic groups, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0258]

[0259] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 members, any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14 members (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 members), more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into polycyclic bridged heterocyclic groups such as bicyclic, tricyclic, tetracyclic, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic bridged heterocyclic groups. Non-limiting examples of bridged heterocyclic groups include:

[0260]

[0261] The heterocyclic ring includes a heterocyclic group as described above (including a monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples of which include:

[0262] wait.

[0263] The heterocyclic group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic groupoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic group, aryl and heteroaryl.

[0264] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent carbon atom pairs) group with a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and its non-limiting examples include:

[0265]

[0266] The aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0267] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms (e.g., 1, 2, 3, and 4), 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 yuan (e.g., 5, 6, 7, 8, 9, or 10 yuan), more preferably 5 yuan or 6 yuan (i.e., 5 to 6 yuan heteroaryl), such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include:

[0268]

[0269] The heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0270] The above-mentioned cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived from a parent ring atom by removing a hydrogen atom, or residues derived from the same ring atom or two different ring atoms of the parent by removing two hydrogen atoms, namely "cycloalkylene", "heterocyclylene", "arylene" and "heteroarylene".

[0271] The term "amino protecting group" is a group that is easily removed and introduced on the amino group to protect the amino group in order to keep the amino group unchanged when other parts of the molecule react. Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butyloxycarbonyl (Boc), acetyl, benzyl, benzyloxycarbonyl (Cbz), allyl and p-methoxybenzyl. These groups can be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro.

[0272] The term "hydroxy protecting group" refers to a hydroxy derivative that is usually used to block or protect the hydroxy group while reacting on other functional groups of the compound. Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.

[0273] The term "cycloalkyloxy" refers to a cycloalkyl-O- group in which cycloalkyl is as defined above.

[0274] The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

[0275] The term "alkylthio" refers to an alkyl-S- group in which alkyl is as defined above.

[0276] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0277] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0278] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

[0279] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0280] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0281] The term "hydroxy" refers to -OH.

[0282] The term "thiol" refers to -SH.

[0283] The term "amino" refers to -NH 2 .

[0284] The term "cyano" refers to -CN.

[0285] The term "nitro" refers to -NO 2.

[0286] The term "oxo" refers to "=0".

[0287] The term "carbonyl" refers to C=O.

[0288] The term "carboxy" refers to -C(O)OH.

[0289] The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O)O-, wherein alkyl and cycloalkyl are as defined above.

[0290] The compounds of the present disclosure include isotopic derivatives thereof. The term "isotopic derivative" refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms. For example, a compound having a structure of the present disclosure, with "deuterium" or "tritium" replacing hydrogen, or with 18 F-fluorine labeling ( 18 F isotope) instead of fluorine, or with 11 C-, 13 C-, or 14 C-enriched carbon ( 11 C-, 13 C-, or 14 C-carbon labeling; 11 C-, 13 C-, or 14 Compounds in which a carbon atom is replaced by a C-isotope) are within the scope of the present disclosure. Such compounds can be used as analytical tools or probes in, for example, biological assays, or can be used as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamics, pharmacokinetics or receptor studies. The various deuterated forms of the compounds disclosed herein refer to compounds in which each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of compounds with reference to relevant literature. Commercially available deuterated starting materials can be used when preparing deuterated forms of compounds, or they can be synthesized using deuterated reagents using conventional techniques, and deuterated reagents include but are not limited to deuterated borane, trideuterated borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc. Deuterated substances can generally retain activity comparable to undeuterated compounds, and when deuterated at certain specific sites, better metabolic stability can be achieved, thereby obtaining certain therapeutic advantages.

[0291] The disclosed compounds may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers with identical structures but different arrangements of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (such as racemates, mixtures of diastereomers). Substituents in the disclosed compounds may have additional asymmetric atoms. All of these stereoisomers and their mixtures are included within the scope of the present disclosure. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers and (D)- and (L)-isomers may be prepared by chiral synthesis, chiral reagents or other conventional techniques. An isomer of a compound disclosed herein can be prepared by asymmetric synthesis or chiral auxiliary, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereoisomer salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art to obtain pure isomers. In addition, the separation of enantiomers and diastereoisomers is usually completed by chromatography.

[0292] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond Can be or include both Two configurations.

[0293] The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and is easily converted from one isomeric form to another isomeric form. It includes all possible tautomers, i.e., in the form of a single isomer or in the form of a mixture of any proportions of the tautomers. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, etc. Examples of lactam-lactim equilibrium are shown below:

[0294]

[0295] For example, when referring to pyrazolyl, it is understood to include either or a mixture of two tautomers of the following two structures:

[0296]

[0297] All tautomeric forms are within the scope of the present disclosure, and the naming of compounds does not exclude any tautomer.

[0298] "Optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "optionally C substituted with halogen or cyano 1-6 The term "alkyl" means that halogen or cyano may but need not be present, and the description includes the case where the alkyl is substituted with halogen or cyano and the case where the alkyl is not substituted with halogen and cyano.

[0299] "Substituted" refers to one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, which are independently replaced by a corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions (by experiment or theory) without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0300] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0301] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals and have the desired biological activity. Salts may be prepared separately during the final isolation and purification of the compounds, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.

[0302] With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to an amount of the drug or agent sufficient to achieve or at least partially achieve the desired effect. The determination of a therapeutically effective amount varies from person to person, depending on the age and general condition of the recipient and on the specific active substance, and the appropriate therapeutically effective amount in an individual case can be determined by a person skilled in the art based on routine experiments.

[0303] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0304] As used herein, the singular form of "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0305] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, numbers are generally given only for illustrative purposes and not for limitation.

[0306] Synthesis method of the disclosed compound

[0307] In order to achieve the purpose of this disclosure, this disclosure adopts the following technical solutions:

[0308] Solution 1

[0309] The present invention discloses a method for preparing a compound represented by general formula (I), or a pharmaceutically acceptable salt thereof, the method comprising:

[0310]

[0311] The compound of general formula (IA) or its salt and the compound of general formula (IB) or its salt undergo acylation reaction under alkaline conditions to obtain the compound of general formula (I) or its pharmaceutically acceptable salt.

[0312] in:

[0313] X is a halogen; preferably a chlorine atom;

[0314] Ring A, G 1 , G 2 , G 3 , R 1 To R 5 and n are as defined in the general formula (I).

[0315] Solution 2

[0316] The present invention discloses a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0317]

[0318] The compound of general formula (IIA) or its salt and the compound of general formula (IB) or its salt undergo acylation reaction under alkaline conditions to obtain the compound of general formula (II) or its pharmaceutically acceptable salt.

[0319] in:

[0320] X is a halogen; preferably a chlorine atom;

[0321] Ring A, R 1 To R5 and n are as defined in the general formula (II).

[0322] Option 3

[0323] The present invention discloses a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0324]

[0325] The compound of general formula (IIIA) or its salt and the compound of general formula (IB) or its salt undergo acylation reaction under alkaline conditions to obtain the compound of general formula (III) or its pharmaceutically acceptable salt.

[0326] in:

[0327] X is a halogen; preferably a chlorine atom;

[0328] Ring A, R 1 To R 5 and n are as defined in the general formula (III).

[0329] Option 4

[0330] The present invention discloses a method for preparing a compound represented by general formula (I-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0331]

[0332] (a) A compound of the general formula (I-1A) or a salt thereof undergoes an acylation reaction with a compound of the general formula (IB) or a salt thereof under alkaline conditions to obtain a compound of the general formula (I-1Aa) or a pharmaceutically acceptable salt thereof;

[0333] (b) subjecting the compound of the general formula (I-1Aa) or a pharmaceutically acceptable salt thereof to a deprotection reaction under acidic conditions to obtain a compound of the general formula (I-1) or a pharmaceutically acceptable salt thereof;

[0334] in:

[0335] X is a halogen; preferably a chlorine atom;

[0336] R w is an amino protecting group, preferably Boc;

[0337] L is an alkylene group or Ring B is a cycloalkyl group or a heterocyclyl group; p is 0, 1, 2, 3, 4, 5 or 6;

[0338] Ring A, G 1 , G 2 , G 3 , R 1 To R 4and n are as defined in the general formula (I-1).

[0339] Option 5

[0340] The present invention discloses a method for preparing a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0341]

[0342] (a) A compound of the general formula (II-1A) or a salt thereof undergoes an acylation reaction with a compound of the general formula (IB) or a salt thereof under alkaline conditions to obtain a compound of the general formula (II-1Aa) or a pharmaceutically acceptable salt thereof;

[0343] (b) subjecting the compound of the general formula (II-1Aa) or a pharmaceutically acceptable salt thereof to a deprotection reaction under acidic conditions to obtain a compound of the general formula (II-1) or a pharmaceutically acceptable salt thereof;

[0344] in:

[0345] X is a halogen; preferably a chlorine atom;

[0346] R w is an amino protecting group, preferably Boc;

[0347] L is an alkylene group or Ring B is a cycloalkyl group or a heterocyclyl group; p is 0, 1, 2, 3, 4, 5 or 6;

[0348] Ring A, R 1 To R 4 and n are as defined in the general formula (II-1).

[0349] Option 6

[0350] The present invention discloses a method for preparing a compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0351]

[0352] (a) A compound of the general formula (III-1A) or a salt thereof undergoes an acylation reaction with a compound of the general formula (IB) or a salt thereof under alkaline conditions to obtain a compound of the general formula (III-1Aa) or a pharmaceutically acceptable salt thereof;

[0353] (b) subjecting the compound of the general formula (III-1Aa) or a pharmaceutically acceptable salt thereof to a deprotection reaction under acidic conditions to obtain a compound of the general formula (III-1) or a pharmaceutically acceptable salt thereof;

[0354] in:

[0355] X is a halogen; preferably a chlorine atom;

[0356] R w is an amino protecting group, preferably Boc;

[0357] L is an alkylene group or Ring B is a cycloalkyl group or a heterocyclyl group; p is 0, 1, 2, 3, 4, 5 or 6;

[0358] Ring A, R 1 To R 4 and n are as defined in the general formula (III-1).

[0359] Option 7

[0360] The present invention discloses a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0361]

[0362] The compound of the general formula (IC) or its salt and the compound of the general formula (ID) or its salt undergo coupling reaction under alkaline conditions in the presence of a catalyst to obtain the compound of the general formula (I) or its pharmaceutically acceptable salt.

[0363] in:

[0364] Y is a halogen; preferably a bromine atom;

[0365] Ring A, G 1 , G 2 , G 3 , R 1 To R 5 and n are as defined in the general formula (I).

[0366] Option 8

[0367] The present invention discloses a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0368]

[0369] The compound of general formula (IIC) or its salt and the compound of general formula (ID) or its salt undergo coupling reaction under alkaline conditions in the presence of a catalyst to obtain the compound of general formula (II) or its pharmaceutically acceptable salt.

[0370] in:

[0371] Y is a halogen; preferably a bromine atom;

[0372] Ring A, R 1 To R 5 and n are as defined in the general formula (II).

[0373] Option 9

[0374] The present invention discloses a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0375]

[0376] The compound of general formula (IIIC) or its salt and the compound of general formula (ID) or its salt undergo coupling reaction under alkaline conditions in the presence of a catalyst to obtain the compound of general formula (III) or its pharmaceutically acceptable salt.

[0377] in:

[0378] Y is a halogen; preferably a bromine atom;

[0379] Ring A, R 1 To R 5 and n are as defined in the general formula (III).

[0380] Plan 10

[0381] The present invention discloses a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0382]

[0383] The compound of the general formula (IAa) or its salt and the compound of the general formula (IBb) or its salt undergo an amidation reaction in the presence of a condensing agent (preferably HATU) and alkaline conditions to obtain a compound of the general formula (I) or its pharmaceutically acceptable salt,

[0384] in:

[0385] Ring A, G 1 , G 2 , G 3 , R 1 To R 5 and n are as defined in the general formula (I).

[0386] Plan 11

[0387] The present invention discloses a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0388]

[0389] The compound of the general formula (IIAa) or its salt and the compound of the general formula (IBb) or its salt undergo amidation reaction in the presence of a condensing agent (preferably HATU) and alkaline conditions to obtain a compound of the general formula (II) or its pharmaceutically acceptable salt,

[0390] in:

[0391] Ring A, R 1To R 5 and n are as defined in the general formula (II).

[0392] Plan 12

[0393] The present invention discloses a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0394]

[0395] The compound of the general formula (IIIAa) or its salt and the compound of the general formula (IBb) or its salt undergo amidation reaction in the presence of a condensing agent (preferably HATU) and alkaline conditions to obtain a compound of the general formula (III) or its pharmaceutically acceptable salt,

[0396] in:

[0397] Ring A, R 1 To R 5 and n are as defined in the general formula (III).

[0398] The reagents providing alkaline conditions in the above synthesis schemes include organic bases and inorganic bases, the organic bases include but are not limited to triethylamine, pyridine, N, N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide or 1,8-diazabicycloundec-7-ene, the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, lithium hydroxide monohydrate and potassium hydroxide; wherein the reagent providing alkaline conditions in schemes 1 to 6 is preferably pyridine; the reagent providing alkaline conditions in schemes 7 to 9 is preferably cesium carbonate; the reagent providing alkaline conditions in schemes 10 to 12 is preferably N, N-diisopropylethylamine.

[0399] The catalysts in the above synthesis schemes 7 to 9 include, but are not limited to, bis(dibenzylideneacetone)palladium, bis(dibenzylideneacetone)palladium / 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene, tetrakis-triphenylphosphine palladium, palladium dichloride, palladium acetate, methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2,4′,6′-triisopropyl-1,1′-biphenyl) (2′-amino-1,1′-biphenyl- 2-yl) palladium (II), 1,1'-bis(dibenzylphosphine)dichlorodipentylferropalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, tris(dibenzylideneacetone)dipalladium, preferably bis(dibenzylideneacetone)palladium or bis(dibenzylideneacetone)palladium / 4,5-bisdiphenylphosphine-9,9-dimethylxanthene.

[0400] The amidation reaction in the above synthesis schemes 10 to 12 is carried out in the presence of a condensing agent, and the condensing agent is preferably O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU).

[0401] The deprotection reaction in the above synthesis schemes 4 to 6 is preferably carried out under acidic conditions, and the reagent providing the acidic conditions is preferably trifluoroacetic acid.

[0402] The reaction in the above steps is preferably carried out in a solvent, and the solvent used includes but is not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane and a mixture thereof. DETAILED DESCRIPTION

[0403] The following embodiments are used to further describe the present disclosure, but these embodiments are not intended to limit the scope of the present disclosure.

[0404] Example

[0405] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (d) are given in units of 10-6 (ppm). NMR measurements were performed using a Bruker AVANCE NEO 500M NMR spectrometer, and the solvent used was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was tetramethylsilane (TMS).

[0406] MS was measured using Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS LC / MS (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), Waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector), and THERMOUltimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0407] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489.

[0408] Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.

[0409] High performance liquid chromatography was performed using Waters 2545-2767, Waters 2767-SQ Detecor 2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

[0410] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0411] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0412] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0413] Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0414] The average kinase inhibition rate and IC50 value were determined using NovoStar microplate reader (BMG, Germany).

[0415] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Darui Chemicals, and other companies.

[0416] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0417] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

[0418] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1L.

[0419] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or a HC2-SS hydrogenator.

[0420] The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.

[0421] The microwave reaction was carried out using a CEM Discover-S 908860 microwave reactor.

[0422] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0423] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0424] The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), and the developing solvent used in the reaction, the column chromatography eluent system used for purifying the compound and the developing solvent system of the thin layer chromatography include: A: dichloromethane / methanol system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0425] Example 1

[0426] N-(4-Fluorophenyl)-N′-(5-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)pyridin-2-yl)cyclopropane-1,1-dicarboxamide 1

[0427]

[0428] first step

[0429] 4-((6-aminopyridin-3-yl)oxy)-7-methoxy-N-methylquinoline-6-carboxamide 1b

[0430] Compound 4-chloro-7-methoxy-N-methylquinoline-6-carboxamide 1a (501 mg, 1.99 mmol, prepared by the method disclosed in the patent application "Example intermediate 29 on page 168 of the specification of WO2019148043A1") was dissolved in dimethyl sulfoxide (5 mL), 6-aminopyridine-3-ol (220 mg, 1.99 mmol) and potassium hydroxide solution (2M, 0.1 mL) were added, and heated to 85 ° C for 2 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 1b (400 mg, yield: 62%).

[0431] MS m / z(ESI):325.1[M+1]

[0432] Step 2

[0433] N-(4-Fluorophenyl)-N′-(5-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)pyridin-2-yl)cyclopropane-1,1-dicarboxamide 1

[0434] Compound 1b (170 mg, 524.15 μmol) and compound 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carbonyl chloride 1c (130 mg, 537.98 μmol, prepared by the method disclosed in the patent application "Example Common Intermediate on page 14 of the specification of EP3750893A1") were dissolved in pyridine (10 mL) and stirred for 12 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by high performance liquid chromatography (Gilson 281, chromatographic column: SharpSil-T C18 150*30 mm, 5 μm; mobile phase 1: water (containing 10 mmol / L ammonium bicarbonate); mobile phase 2: acetonitrile; 15-minute gradient: acetonitrile 38%-90%, flow rate: 30 mL / min) to obtain the title product 1 (98 mg, yield: 35.0%).

[0435] MS m / z(ESI):530.2[M+1]

[0436] 1 H NMR (500 MHz, DMSO-d 6 )δ11.18 (s, 1H), 9.76 (s, 1H), 8.68 (d, J=5.3Hz, 1H), 8.63 (s, 1H), 8.40-8.35 (m, 2H), 8.23 ​​(d, J=9.0Hz, 1H), 7.85 (dd, J=9.0, 2.9Hz, 1 H), 7.65-7.59 (m, 2H), 7.54 (s, 1H), 7.23-7.14 (m, 2H), 6.56 (d, J=5.3Hz, 1H), 4.03 (s, 3H), 2.85 (d, J=4.6Hz, 3H), 1.65-1.53 ​​(m, 4H).

[0437] Example 2

[0438] N-(4-Fluorophenyl)-N′-[5-[[7-methoxy-6-(methylcarbamoyl)-quinolin-4-yl]oxy]pyrazin-2-yl]cyclopropane-1,1-dicarboxamide 2

[0439]

[0440] first step

[0441] N-(4-Fluorophenyl)cyclopropane-1,1-dicarboxamide 2a

[0442] 1c (2 g, 8.27 mmol) was dissolved in tetrahydrofuran (20 mL), and 25-28% aqueous ammonia (30 mL) was dripped into the reaction flask under ice bath, warmed to room temperature, and stirred for 1 hour. The mixture was extracted with dichloromethane (100 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to obtain the title product 2a (1.8 g, yield: 97.8%).

[0443] MS m / z(ESI):223.1[M+1].

[0444] Step 2

[0445] 4-Hydroxy-7-methoxy-N-methylquinoline-6-carboxamide 2c

[0446] Compound 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxylic acid methyl ester 2b (10 g, 42.87 mmol, Shanghai Shaoyuan Reagent Co., Ltd.) was dissolved in 30% methylamine ethanol solution (200 mL, Shanghai Titan Technology Co., Ltd.) and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title product 2c (9.7 g, yield: 97.4%), which was used directly in the next step without purification.

[0447] MS m / z(ESI):233.1[M+1].

[0448] Step 3

[0449] 4-((5-bromopyrazin-2-yl)oxy)-7-methoxy-N-methylquinoline-6-carboxamide 2d

[0450] Compound 2c (2.5 g, 10.76 mmol) was dissolved in N, N-dimethylformamide (100 mL), cesium carbonate (8.7 g, 26.9 mmol, Shanghai Shaoyuan Reagent Co., Ltd.) was added, stirred, reacted at 80°C for 1 hour, 2,5-dibromopyrazine (2.5 g, 10.76 mmol, Shanghai Shaoyuan Reagent Co., Ltd.) was dissolved in N, N-dimethylformamide (2 mL), added dropwise to the reaction bottle at 80°C, and the reaction was continued for 1 hour. The reaction solution was cooled to room temperature, slowly poured into 800 mL of water, extracted with ethyl acetate (300 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to obtain the title product 2d (840 mg, yield: 20%).

[0451] MS m / z(ESI):391.0[M+1].

[0452] Step 4

[0453] N-(4-Fluorophenyl)-N′-[5-[[7-methoxy-6-(methylcarbamoyl)-quinolin-4-yl]oxy]pyrazin-2-yl]cyclopropane-1,1-dicarboxamide 2

[0454] Compound 2d (810 mg, 2.08 mmol) was dissolved in toluene (150 mL), and compound 2a (925 mg, 4.16 mmol), cesium carbonate (2.0 g, 6.24 mmol, Shanghai Shaoyuan Reagent Co., Ltd.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (721 mg, 1.24 mmol, Shanghai Shaoyuan Reagent Co., Ltd.) were added, nitrogen was introduced twice, and the air was exhausted. Bis(dibenzylideneacetone)palladium (571 mg, 0.62 mmol, Beijing Bailingwei Technology Co., Ltd.) was added, nitrogen was introduced three times, and the air was exhausted. The mixture was added to a preheated 90°C oil bath and stirred for 16 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and purified by high performance liquid chromatography (Gilson 281, chromatographic column: SharpSil-T C18 150*30mm, 5μm; mobile phase 1: water (containing 10mmol / L ammonium bicarbonate); mobile phase 2: acetonitrile; 20-minute gradient: 25%-45%, flow rate: 30mL / min) to obtain the title product 2 (410mg, yield: 37.1%). MS m / z (ESI): 531.2 [M+1].

[0455] 1 H NMR (500 MHz, DMSO-d 6 )δ11.39(d,1H),9.80(s,1H),9.01(s,1H),8.80(d,1H),8.60(s,1H),8.48(s,1H),8.40-8.35(m,1H),7 .60-7.65(m, 2H), 7.57(s, 1H), 7.18(t, 2H), 7.04(d, 1H), 4.04(s, 3H), 2.83(d, 3H), 1.60-1.64(m, 4H).

[0456] Example 3

[0457] N-cyclohexyl-N-(5-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)pyridin-2-yl)cyclopropane-1,1-dicarboxamide

[0458]

[0459]

[0460] first step

[0461] Methyl 1-((5-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)pyridin-2-yl)carbamoyl)cyclopropane-1-carboxylate 3b

[0462] Compound 1b (200 mg, 0.62 mmol) and 1,1-cyclopropyldicarboxylic acid monomethyl ester 3a (106 mg, 0.74 mmol) were dissolved in N,N-dimethylformamide (5 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (282 mg, 0.74 mmol, Shanghai Shaoyuan Reagent Co., Ltd.) and N,N-diisopropylethylamine (240 mg, 1.86 mmol, Adamas Reagent Co., Ltd.) were added, and stirred at room temperature for 4 hours. The solvent was removed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system A to obtain the title product 3b (180 mg, yield: 64.8%).

[0463] MS m / z(ESI):451.1[M+1].

[0464] Step 2

[0465] 1-((5-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)pyridin-2-yl)carbamoyl)cyclopropane-1-carboxylic acid 3c

[0466] Compound 3b (80 mg, 0.18 mmol) was dissolved in 6.6 mL of a mixed solvent of methanol, tetrahydrofuran and water (V / V / V=5:5:1), lithium hydroxide monohydrate (37 mg, 0.88 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Most of the solvent was removed by concentration under reduced pressure, and 1 M hydrochloric acid was added until the pH of the reaction solution was 3-4. Solid precipitated, and the filter cake was collected by filtration and vacuum drying to obtain the title product 3c (77 mg, yield: 99%).

[0467] MS m / z(ESI):437.1[M+1].

[0468] Step 3

[0469] N-cyclohexyl-N-(5-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)pyridin-2-yl)cyclopropane-1,1-dicarboxamide

[0470] Compound 3c (77 mg, 0.18 mmol) and cyclohexylamine (21 mg, 0.21 mmol, Adamas Reagent Co., Ltd.) were dissolved in N,N-dimethylformamide (3 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (81 mg, 0.21 mmol, Shanghai Shaoyuan Reagent Co., Ltd.) and N,N-diisopropylethylamine (182 mg, 1.41 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The mixture was filtered and concentrated under reduced pressure to remove the solvent. The residue was purified by high performance liquid chromatography (Waters-2545, chromatographic column: SharpSil-T, 30*150 mm, 5 μm; mobile phase 1: water (containing 10 mmol / L ammonium bicarbonate); mobile phase 2: acetonitrile; 12 min gradient: acetonitrile: 35%-50%, flow rate: 30 mL / min) to give the title product 3 (11 mg, yield: 12.0%).

[0471] MS m / z(ESI):518.2[M+1].

[0472] 1 H NMR (500 MHz, DMSO-d 6 ): 10.82 (s, 1H), 8.67 (d, 1H), 8.61 (s, 1H), 8.30-8.44 (m, 2H), 8.18 (d, 1H), 7.82 (dd, 1H), 7.60 (d, 1H), 7.52 (s, 1H), 6.55 (d, 1 H), 4.02 (s, 3H), 3.58-3.69 (m, 1H), 2.84 (d, 3H), 1.62-1.79 (m, 4H), 1.55-1.61 (m, 1H), 1.39-1.54 (d, 4H), 1.21-1.26 (m, 5H).

[0473] Example 4

[0474] N-(5-((7-((1-aminocyclopropyl)methoxy)-6-(methylcarbamoyl)quinolin-4-yl)oxy)pyridin-2-yl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

[0475]

[0476] first step

[0477] (1-((tert-Butyloxycarbonyl)amino)cyclopropyl)methyl methanesulfonate 4b

[0478] Compound (1-(hydroxymethyl)cyclopropyl)carbamic acid tert-butyl ester 4a (1.8 g, 9.6 mmol) was dissolved in dichloromethane (15 mL), and triethylamine (2.91 g, 28.75 mmol) was added. Methanesulfonyl chloride (1.31 g, 11.49 mmol) was added dropwise at 0°C, and the mixture was reacted at room temperature for 0.5 hours. The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude title product 4b (2.5 g, yield: 98%).

[0479] Step 2

[0480] 4-Chloro-7-hydroxy-N-methylquinoline-6-carboxamide 4c

[0481] Compound 1a (1 g, 3.98 mmol) was dissolved in dichloromethane (50 mL), and a dichloromethane solution of boron tribromide (1 M, 39.89 mL) was added dropwise at 0°C. The mixture was heated to room temperature and reacted for 5 hours. 10 mL of methanol was added to quench the reaction, and the pH of the solution was adjusted to weak acidity with a saturated sodium bicarbonate solution. After concentration under reduced pressure, the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 4c (944 mg, yield: 99%).

[0482] MS m / z(ESI):237.1[M+1].

[0483] Step 3

[0484] tert-Butyl (1-(((4-chloro-6-(methylcarbamoyl)quinolin-7-yl)oxy)methyl)cyclopropyl)carbamate 4d

[0485] Compound 4c (900 mg, 3.80 mmol) and compound 4b (2.0 g, 7.53 mmol) were dissolved in N,N-dimethylformamide (10 mL), and anhydrous potassium carbonate (2.6 g, 18.81 mmol) and potassium iodide (1.8 g, 10.84 mmol) were added. Stir at 85°C for 16 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to obtain the title product 4d (600 mg, yield: 38.8%).

[0486] MS m / z(ESI):406.2[M+1].

[0487] Step 4

[0488] Tert-butyl (1-(((4-((6-aminopyridin-3-yl)oxy)-6-(methylcarbamoyl)quinolin-7-yl)oxy)methyl)cyclopropylcarbamate 4e

[0489] Compound 4d (600 mg, 1.47 mmol) was dissolved in dimethyl sulfoxide (10 mL), 6-aminopyridine-3-ol (162 mg, 1.47 mmol) was added, potassium hydroxide solution (1 M, 3 mL) was added, and the mixture was heated to 85°C for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to give the title product 4e (300 mg, yield: 42%).

[0490] MS m / z(ESI):480.1[M+1].

[0491] Step 5

[0492] tert-Butyl (1-(((4-((6-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxamido)pyridin-3-yl)oxy)-6-(methylcarbamoyl)quinolin-7-yl)oxy)methyl)cyclopropyl)carbamate 4f

[0493] Compound 4e (130 mg, 271.10 μmol) and compound 1c (130 mg, 537.97 μmol) were dissolved in pyridine (10 mL) and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography using eluent system A to obtain the title product 4f (130 mg, yield: 70%).

[0494] MS m / z(ESI):685.3[M+1].

[0495] Step 6

[0496] N-(5-((7-((1-aminocyclopropyl)methoxy)-6-(methylcarbamoyl)quinolin-4-yl)oxy)pyridin-2-yl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

[0497] Compound 4f (130 mg, 189.86 μmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added dropwise at 0°C, and the mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated at room temperature, the pH of the reaction solution was adjusted to 8 with saturated sodium bicarbonate solution, and the residue was purified by high performance liquid chromatography (Waters-2545, column: YMC Triar-Exrs Prep C18 150*30 mm, 5 μm; mobile phase 1: water (containing 10 mmol / L ammonium bicarbonate); mobile phase 2: acetonitrile; 15-minute gradient: acetonitrile: 35%-47%, flow rate: 30 mL / min) to obtain the title product 4 (86 mg, yield 77%).

[0498] MS m / z(ESI):585.2[M+1].

[0499] 1 H NMR (500 MHz, DMSO-d 6 )δ11.18(s, 1H), 9.76(s, 1H), 8.77-8.58(m, 3H), 8.38(d, 1H), 8.22(d, 1H), 7.85(dd, 1H), 7.67-7.59(m, 2H), 7.51(s, 1H), 7.17(t, 2H), 6.55(d, 1H), 4.17(s, 2H), 2.87(d, 3H), 2.15(s, 2H), 1.58(dt, 4H), 0.67(dt, 2H), 0.65-0.59(m, 2H).

[0500] Comparative Example A

[0501] N-(4-Fluorophenyl)-N-(2-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)pyrimidin-5-yl)cyclopropane-1,1-dicarboxamide A

[0502]

[0503] first step

[0504] 7-Methoxy-N-methyl-4-((5-nitropyrimidin-2-yl)oxy)quinoline-6-carboxamide A2

[0505] Compound 2c (1 g, 4.31 mmol) was dispersed in N,N-dimethylformamide (10 mL), and 2-chloro-5-nitropyrimidine A1 (690 mg, 4.33 mmol, Shanghai Bid Pharmaceutical Technology Co., Ltd.) and triethylamine (0.48 g, 4.74 mmol) were added. The mixture was reacted at room temperature for 5 minutes, and the solvent was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title product A2 (200 mg, yield: 13.1%).

[0506] MS m / z(ESI):356.1[M+1].

[0507] Step 2

[0508] 4-((5-aminopyrimidin-2-yl)oxy)-7-methoxy-N-methyl-quinoline-6-carboxamide A3

[0509] Compound A2 (180 mg, 0.51 mmol) was dissolved in a mixed solvent of 25 mL of ethanol and water (V / V=4:1), 170 mg of iron powder was added, and 170 mg of ammonium chloride was added. The mixture was heated to 90°C for 2 hours, and the solvent was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to obtain the title product A3 (160 mg, yield: 97.1%).

[0510] MS m / z(ESI):326.2[M+1].

[0511] Step 3

[0512] N-(4-Fluorophenyl)-N-(2-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)pyrimidin-5-yl)cyclopropane-1,1-dicarboxamide A

[0513] Compound A3 (100 mg, 0.31 mmol) and compound 1c (90 mg, 0.37 mmol) were dissolved in pyridine (10 mL) and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and purified by high performance liquid chromatography (chromatographic column: SharpSil-T C18150*30 mm, 5 μm; mobile phase 1: water (containing 10 mmol / L ammonium bicarbonate); mobile phase 2: acetonitrile; 22 minutes, acetonitrile: 36%-46%, flow rate: 30 mL / min) to obtain the title product A (60 mg, yield: 36.8%).

[0514] MS m / z(ESI):531.9[M+1].

[0515] 1 H NMR (500 MHz, DMSO-d 6 )δ10.44(s,1H),10.10(s,1H),8.91(s,2H),8.87-8.89(d,1H),8.34-8.37(dd,1H),8.28(s,1H)7.62-7.65 (dd, 2H), 7.59 (s, 1H), 7.26-7.27 (d, 1H), 7.13-7.16 (t, 2H), 4.03 (s, 3H), 2.80-2.81 (d, 3H), 1.47 (s, 4H).

[0516] Biological evaluation

[0517] Test Example 1: The compounds disclosed herein have an inhibitory effect on the kinase activity of Axl, Mer, KDR and MET

[0518] The purpose of this experiment is to test the inhibitory effect of compounds on the kinase activity of Axl, Mer, KDR and MET. 50 Size evaluation of the in vitro activity of compounds.

[0519] The inhibitory effects of the disclosed compounds on the kinase activities of Axl, Mer, KDR and MET were tested by the following method.

[0520] 1. Experimental Materials and Instruments

[0521] Experimental instruments

[0522]

[0523] Experimental Materials

[0524]

[0525]

[0526] 2. Experimental steps

[0527] 1. Dissolve the compound in DMSO to 10 mM, and dilute it 5-fold to 9 concentrations. Dilute the compound diluted in DMSO again with PBS, dilute the compound to a first concentration of 50 μM, and dilute it 5-fold to 9 concentrations. Take 2 μL of the compound and add it to a 384-well plate (PE, 6005620).

[0528] 2. Prepare enzyme activity reaction buffer according to the instructions of HTRF KinEASE-TK kit (Cisbio, 62TKOPEC).

[0529] 3. Use enzyme activity buffer to dilute Axl (Carna Biosciences, 08-107), Mer (Carna Biosciences, 08-108), KDR (Carna Biosciences, 08-191) and MET (Carna Biosciences, 08-151) proteins to 0.025 ng / μL, 0.125 ng / μL, 0.01 ng / μL and 0.05 ng / μL, respectively, and add 4 μL to 384 wells. Incubate at room temperature for 15 minutes.

[0530] 4. According to the instructions of the HTRF KinEASE-TK kit, use the enzyme activity buffer to prepare the reaction substrate mixture of ATP and substrate. The ATP concentration is 100μM and the substrate concentration is 1μM. Take 4μL of the reaction substrate mixture and add it to the 384-well plate, and react at 37℃ for 0.5 hours.

[0531] 5. Prepare the detection mixture according to the instructions of the HTRF KinEASE-TK kit. Take 10 μL of the detection mixture and add it to the 384-well plate and incubate at room temperature for 1 hour.

[0532] 6. Use the HTRF module in the Envision microplate reader to read the fluorescence signal values ​​excited at 665nm and 620nm, and calculate the ratio Ratio = (665nm / 620nm) × 10 4 .

[0533] 7. Using the log(inhibitor) vs. response-variable slope of GraphPad Prism5.0 software, the inhibition rate was calculated based on the logarithmic value of the compound concentration and the corresponding ratio, and the dose-effect curve was drawn and the IC was calculated. 50 value.

[0534] The inhibition of the kinase activities of Axl, Mer, KDR and MET by the compounds disclosed in the present invention was determined by the above test, and the measured IC 50 See Table 1 for values.

[0535] Table 1 IC values ​​of the compounds disclosed herein for the inhibition of Axl, Mer, KDR and MET kinase activities 50 value

[0536]

[0537]

[0538] Conclusion: The disclosed compounds have significant inhibitory effects on the binding of KDR, MET, Axl, and Mer, and have better inhibitory effects than control example A.

[0539] Test Example 2: Identification of Reactive Metabolites of the Disclosed Compounds in Human Liver Microsomes

[0540] The reactive metabolites of the disclosed compounds in human liver microsomes were identified using the following experimental methods:

[0541] 1. Experimental Materials and Instruments

[0542] 1. Phosphate buffer (purchased from Shanghai Biotech)

[0543] 2. NADPH (ACROS, A2646-71-1)

[0544] 3. Human liver microsomes (Corning Gentest, catalog number 452161, batch number 905002)

[0545] 4. Thermo UHPLC-Q-Exactive Orbitrap mass spectrometer (Thermo Fisher Scientific)

[0546] 5. Acquity BEH C 18 Column, 2.1×100 mm, 1.7 μm (Waters, USA)

[0547] 6. Positive control compound (Diclofenac).

[0548] 2. Experimental Drugs

[0549] The compound of Example 2, compound XL-092 (see the compound of Example 8 on page 162 of WO2019148044A1), has the following structure:

[0550]

[0551] 3. Experimental steps

[0552] 1. Preparation of test compound solution: Take an appropriate amount of the test compound, weigh it accurately, add an appropriate amount of DMSO to dissolve it and mix it evenly to obtain a stock solution with a concentration of 30mM. Dilute the stock solution with a concentration of 10mM 10 times with 50% acetonitrile / water (v / v) to obtain a working solution 1 with a concentration of 3.0mM. Dilute the working solution 1 with a concentration of 3.0mM 1 10 times with PBS to obtain a working solution 2 with a concentration of 300μM, and store it at 4℃ before use.

[0553] 2. Preparation of phosphate buffer: weigh K 2 HPO 4 and KH 2 PO 4 Dissolve an appropriate amount in 4L of pure water to prepare a 100mM buffer solution, and then adjust the pH to 7.4 with phosphoric acid or sodium hydroxide.

[0554] 3. Preparation of liver microsome solution: Take an appropriate amount of liver microsome storage solution (concentration of 20 mg / mL) of each species and dilute it to 1.43 mg / mL microsome solution with 100 mM phosphate buffer (pH 7.4).

[0555] 4. Preparation of NADPH cofactor solution: Weigh appropriate amounts of NADPH and magnesium chloride, dissolve them in an appropriate amount of 100 mM phosphate buffer (pH 7.4) to make the concentrations of NADPH and magnesium chloride 10 mM and 30 mM respectively, and set aside.

[0556] 5. Preparation of glutathione (GSH) solution: Weigh an appropriate amount of GSH and dissolve it in an appropriate amount of 100 mM phosphate buffer (pH 7.4) to make the concentration of GSH 50 mM and set aside.

[0557] 6. The incubation system is as follows:

[0558]

[0559]

[0560] Accurately pipette 20 μL of working solution 2 with a concentration of 300 μM, add it to a 1.5 mL centrifuge tube, and then add 140 μL of liver microsome solution with a concentration of 1.43 mg / mL, so that the liver microsome protein concentration in the incubation system is 1 mg / mL. Then add 20 μL of NADPH solution with a concentration of 10 mM and 20 μL of GSH solution with a concentration of 50 mM, put it in a 37 ° C constant temperature incubator for shaking incubation, and start timing. 60 minutes after the start of incubation, remove the incubation sample from the incubator, add 1000 μL of ice-cold acetonitrile solution, stop the reaction, leave it at room temperature for 10 minutes, and centrifuge it at 12000 rpm for 10 minutes. Pipette all the supernatant into a centrifuge tube and concentrate it to dryness in a vacuum at 37 ° C. The residue is reconstituted with 200 μL of 25% acetonitrile / water solution, centrifuged at 12000 rpm for 10 minutes, and the supernatant is transferred to a 96-well plate, and 5 μL is aspirated for LC / MS analysis. For blank samples, 20 μL PBS was added to replace working solution 2. For NCF samples, 20 μL PBS was added to replace GSH solution. The positive control diclofenac (10 μM) was the same as the test compound. The collected data was processed and analyzed by Xcalibur software, and the secondary mass spectrometry fragmentation analysis was performed based on the accurate molecular weight to determine whether the disclosed compounds would undergo metabolic activation to produce reactive metabolites.

[0561] Table 2 Identification of reactive metabolites of the disclosed compounds in human liver microsomes

[0562]

[0563] Conclusion: No GSH conjugates related to the compound of Example 2 of the present disclosure were detected in the experiment, but GSH conjugates related to compound XL-092 were detected. Therefore, it can be seen that the compound of the present disclosure exhibits better safety than compound XL-092.

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof: in: Ring A is phenyl or cyclohexyl; G1 is CR 2a ; G2 is N atom or CR 2b ; G3 is CR 3a ; Each R 1 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl; R 2 , R 2a and R 2b are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl; R 3 and R 3a are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl; R 4 C 1-6 alkyl; R 5 Methyl or and n is 0, 1 or 2.

2. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein G1 is CR 2a ; G2 is CR 2b ; G3 is CR 3a ; R 2a , R 2b and R 3a are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl.

3. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein G1 is CH; G2 is CH or a N atom; and G3 is CH.

4. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, in: Ring A, R 1 To R 5 and n is as defined in claim 1.

5. The compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 It is methyl.

6. The compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 1 are the same or different and are each independently a hydrogen atom or a halogen.

7. The compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 1 are the same or different and are each independently a hydrogen atom or F.

8. The compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 A hydrogen atom.

9. The compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 A hydrogen atom. 10 . The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 , wherein n is 0 or 1.

11. The compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the following compounds:

12. A compound represented by the general formula (IA) or a salt thereof: in: G1, G2, G3 and R 2 To R 5 As defined in claim 1.

13. A compound selected from the following structures:

14. A compound represented by the general formula (IC) or a salt thereof: in: Y is halogen; G1, G2, G3 and R 2 To R 5 As defined in claim 1. 15 . The compound represented by the general formula (IC) or a salt thereof according to claim 14 , wherein Y is a bromine atom.

16. The compound represented by the general formula (IC) according to claim 14 or a salt thereof, which is selected from the following compounds:

17. A method for preparing the compound represented by general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, the method comprising: A compound of the general formula (IA) or a salt thereof undergoes an acylation reaction with a compound of the general formula (IB) or a salt thereof to obtain a compound of the general formula (I) or a pharmaceutically acceptable salt thereof, in: X is a halogen; Ring A, G1, G2, G3, R 1 To R 5 and n is as defined in claim 1.

18. The method according to claim 17, wherein X is a chlorine atom.

19. A method for preparing the compound represented by general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, the method comprising: The compound of general formula (IC) or its salt undergoes coupling reaction with the compound of general formula (ID) or its salt to obtain the compound of general formula (I) or its pharmaceutically acceptable salt, in: Y is halogen; Ring A, G1, G2, G3, R 1 To R 5 and n is as defined in claim 1.

20. The method according to claim 19, wherein Y is a bromine atom.

21. A pharmaceutical composition comprising a compound represented by general formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

22. Use of a compound represented by general formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 21 in the preparation of a medicament for inhibiting protein kinase.

23. The use according to claim 22, wherein the protein kinase is a receptor tyrosine kinase (RTKs).

24. The use according to claim 23, wherein the receptor tyrosine kinases (RTKs) are Axl, Mer, TYRO3, MET, KDR or a combination thereof.

25. Use of a compound of formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 21 in the preparation of a medicament for treating and / or preventing a disease, disorder or syndrome; wherein the disease, disorder or syndrome is selected from sarcoma, multiple myeloma, leukemia, myxoma, rhabdomyomas, leiomyomas, fibromas, lipomas, teratomas, pharyngeal cancer, oral cancer, lung cancer, lymphoma, mesothelioma, colorectal cancer, small intestine cancer, gastric cancer, esophageal cancer, pancreatic cancer, breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, liver cancer, bile duct cancer, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer and gastrointestinal stromal tumors.

26. The use according to claim 25, wherein the laryngeal cancer is nasopharyngeal carcinoma; the sarcoma is osteosarcoma or chondrosarcoma; the colorectal cancer is colon cancer or rectal cancer; the fibroma is neurofibroma; and the lung cancer is alveolar carcinoma.

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