TW202241862A - Dimethylamide compounds, their preparation methods and medical use - Google Patents

Abstract

The present disclosure relates to dimethylamide compounds, their preparation methods and medical use. Specifically, the present disclosure relates to a dimethylamide compound represented by the general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and its use as a therapeutic agent, especially its use in the preparation of medicaments for inhibiting protein kinases. Wherein, each group in the general formula (I) is as defined in the specification.

Description

Diformamide compound, its preparation method and its application in medicine

The disclosure belongs to the field of medicine, and relates to a dimethylamide compound, its preparation method and its application in medicine. In particular, the disclosure relates to dimethylamide compounds represented by general formula (I), their preparation methods, pharmaceutical compositions containing such compounds, and their use in the preparation of drugs for inhibiting protein kinases.

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

VEGF/VEGFR signaling is the major rate-limiting step in angiogenesis Pathological angiogenesis is a hallmark of tumorigenesis Primary tumor growth and its subsequent metastasis depend on angiogenesis VEGF/VEGFR is found in most solid tumors High expression of VEGFR;

VEGF/VEGFR inhibitor treatment limitations: According to clinical and preclinical data, there are certain limitations in the treatment of simply inhibiting the expression of VEGFR. For example, although monotherapy can delay tumor growth, most of them will not cause tumor growth. Regression, and may induce aggressive or metastatic behavior of the cancer, monotherapy with bevacizumab, Although it can improve the PFS of tumor patients, it cannot effectively increase the overall survival of patients. Moreover, VEGF/VEGFR therapy has primary and secondary drug resistance, and the latter is usually caused by the upregulation of other important genes/proteins. For example, in patients with kidney cancer after VEGFR target therapy, it was found that the high expression of MET and Axl promoted tumor development. Therefore, VEGF/VEGFR therapy usually needs to be used in combination with other drugs.

The TAM subfamily consists of three tyrosine kinases, TYRO3, Axl and Mer. The extracellular ligand-binding domain of 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 binds and activates all three TAM kinases, and PROS1 is a ligand for both Mer and TYRO3 kinases.

Axl (also known as UFO, ARK, JTK11 and TYRO7) was first identified as a transforming gene in the DNA of patients with chronic myeloid leukemia. Binding of GAS6 to Axl can induce its autophosphorylation and activate the tyrosine kinase Axl. Axl can continue to activate proteins in multiple downstream signaling pathways, including PI3K-AKT, Raf-MAPK, PLC-PKC and so on.

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

TYRO3 (also known as DTK, SKY, RSE, BRT, TIF, and ETK2) was first discovered in colonization studies based on PCR technology. Both GAS6 and PROS1 are able to bind to TYRO3 and activate this kinase. Although the downstream signaling pathways activated by TYRO3 are in TAM home The least studied in the family, the current results show that the PI3K-AKT and Raf-MAPK pathways seem to be activated by TYRO3. TYRO3, Axl and Mer were all found to be overexpressed in tumors.

The MET family includes mesenchymal-epithelial transition factor (c-Met), an independent tyrosine kinase receptor expressed on the surface of various 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 of normal cells and wound healing. However, in tumor cells, due to the mutation, overexpression and amplification of c-Met gene, the HGF/c-Met axis is abnormally activated and activates PI3K/AKT, Ras/MAPK, JAK/STAT, SRC and Wnt/β- The catenin signaling pathway enables tumor growth and proliferation. Due to the continuous activation of the c-Met-dependent signaling pathway mentioned above, tumor cells gain more competitive advantages than normal cells, and the possibility of tumor metastasis is greatly increased by contacting blood supply and increasing the ability to detach from tissues. Increase.

Currently published patent applications include WO2005030140A2, WO2010045095A1, WO2010075376A2, WO2019148044A1, CN102212062A and WO2012006960A1, etc. There is still room for improvement in the activities of these patent applications, and there are major unmet medical needs in the relevant patient population.

Therefore, for the treatment of tumors mediated by KDR (VEGFR2), TAM and MET kinases, it is necessary to develop a new class of compounds to better regulate these targets.

The purpose of this disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

in,

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;

G ₁ is N atom or CR ^2a ;

G ₂ is N atom or CR ^2b ;

G ₃ is N atom or CR ^3a ;

Each R is the same or different, and each independently selected from ^a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro, hydroxyl, hydroxyalkyl, ring Alkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from the group consisting of halogen, alkyl, One or more substituents of alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl replaced by

R ² , R ^2a and R ^2b are the same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, Hydroxyalkyl, cycloalkyl and heterocyclyl;

R ³ and R ^3a are the same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl , cycloalkyl and heterocyclyl;

R ^is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group;

R ⁵ is selected from alkyl, -(CH ₂ ) _m R ^a , cycloalkyl and heterocyclyl; wherein the alkyl, cycloalkyl and heterocyclyl are each independently selected from halogen, alkyl, alkane One or more substituents in oxy, haloalkyl, haloalkoxy, cyano, amine, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl replace;

R is cycloalkyl ^or heterocyclyl, wherein the cycloalkyl or heterocyclyl are each independently selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, - NR ^b R ^c , hydroxy and hydroxyalkyl are substituted by one or more substituents;

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;

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

m is 1, 2, 3, 4, 5 or 6.

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:

in,

；環B為環烷基或雜環基；p為0、1、2、3、4、5或6； L is (alkylene) alkylene or

; Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;

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

In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein G ₁ is CR ^2a or N atom; G ₂ is CR ^2b or N atom; G ₃ is CR ^3a ; R ^2a , R ^2b and R ^3a are the same or different, and each independently selected from hydrogen atom, halogen and C _1-6 alkyl; preferably, G ₁ is CR ^2a ; G ₂ is CR ^2b or N atom; G ₃ is CR ^3a ; R ^2a , R ^2b and R ^3a are the same or different, and each independently selected from hydrogen atom, halogen and C _1-6 alkyl; more preferably, G ₁ is CH; G ₂ is CH or N atom; G ₃ is CH; optimally, G ₁ is CH; G ₂ is N atom; G ₃ is CH.

In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein G ₁ is CR ^2a ; G ₂ is CR ^2b ; G ₃ is CR ^3a ; R ^2a , R ^2b and R ^3a are the same or different, and each independently selected from hydrogen atom, halogen and C _1-6 alkyl; or G ₁ is N atom; G ₂ is CR ^2b ; G ₃ is CR ^3a ; R ^2b and R ^3a are the same or different, and each independently selected from hydrogen atom, halogen and C _1-6 alkyl; or G ₁ is GR ^2a ; G ₂ is N atom; G ₃ is CR ^3a ; R ^2a and R ^3a are the same or different, and are each independently selected from a hydrogen atom, a halogen, and a C _1-6 alkyl group.

In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein G ₁ is CR ^2a ; G ₂ is CR ^2b ; G ₃ is CR ^3a ; R ^2a , R ^2b and R ^3a are the same or different, and each independently selected from hydrogen atom, halogen and C _1-6 alkyl; more preferably, G ₁ is CH; G ₂ is CH; G ₃ is CH.

In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein R ^2a , R ^2b and R ^3a are the same or different, and each independently is selected from hydrogen atom, halogen and C _1-6 alkyl; preferably, R ^2a , R ^2b and R ^3a are all hydrogen atoms.

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:

in,

Ring A, R ¹ to R ⁵ and n are as defined in general formula (I).

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

in,

；環B為環烷基或雜環基；p為0、1、2、3、4、5或6； L is (alkylene) alkylene or

; Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;

Ring A, R ¹ to R ⁴ and n are as defined in general formula (I).

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

in,

Ring A, R ¹ to R ⁵ and n are as defined in general formula (I).

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

in,

；環B為環烷基或雜環基；p為0、1、2、3、4、5或6； L is (alkylene) alkylene or

; Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;

Ring A, R ¹ to R ⁴ and n are as defined in general formula (I).

In some embodiments of the present disclosure, the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1) and general formula (III-1) The indicated compound or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl or 5-6 membered heteroaryl; preferably, ring A is phenyl.

In some embodiments of the present disclosure, the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1) and general formula (III-1) The indicated compound or its pharmaceutically acceptable salt, its Ring A is selected from 6 to 10 membered aryl, 5 to 10 membered heteroaryl and 3 to 8 membered cycloalkyl; preferably, ring A is 6 to 10 membered aryl or 3 to 8 membered cycloalkyl; more Preferably, ring A is phenyl or cyclohexyl.

In some embodiments of the present disclosure, the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1) and general formula (III-1) The indicated compound or a pharmaceutically acceptable salt thereof, wherein R ⁴ is C _1-6 alkyl; preferably, R ⁴ is methyl.

。 In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II) and general formula (III) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is C _1-6 alkyl or - (CH ₂ ) _m R ^a ; R ^a is 3 to 6 membered cycloalkyl; wherein the 3 to 6 membered cycloalkyl is optionally selected from one or more of C _1-6 alkyl and -NR ^b R ^c Substituents; R ^b and R ^c are the same or different, and each independently is a hydrogen atom or C _1-6 alkyl; m is 1, 2 or 3; preferably, R ⁵ is methyl or

.

，環B為3至6員環烷基，p為0、1、2或3；較佳地，L為

，環B為環丙基，p為1、2或3；更佳地，L為

，環B為

，p為1。 In some embodiments of the present disclosure, the compound represented by general formula (I-1), general formula (II-1) and general formula (III-1) or a pharmaceutically acceptable salt thereof, wherein L is

, ring B is 3 to 6-membered cycloalkyl, 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.

In some embodiments of the present disclosure, the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1) and general formula (III-1) The shown compound or a pharmaceutically acceptable salt thereof, wherein each R ¹ is the same or different, and each independently selected from hydrogen atom, halogen, 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 heterocyclyl; preferred Preferably, each R ¹ is the same or different, and each independently selected from a hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; more preferably, each R ¹ is the same or different, and each independently selected from hydrogen atom, halogen and C _1-6 alkyl; further preferably, each R ¹ is the same or different, and each independently is a hydrogen atom or halogen; most preferably, each R ¹ is the same or different, and each independently is a hydrogen atom or F.

In some embodiments of the present disclosure, the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1) and general formula (III-1) The indicated compound or a pharmaceutically acceptable salt thereof, wherein R ² is selected from hydrogen atom, halogen and C _1-6 alkyl; preferably, R ² is a hydrogen atom.

In some embodiments of the present disclosure, the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1) and general formula (III-1) The indicated compound or a pharmaceutically acceptable salt thereof, wherein R ³ is selected from hydrogen atom, halogen and C _1-6 alkyl; preferably, R ³ is a hydrogen atom.

In some embodiments of the present disclosure, the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1) and general formula (III-1) The indicated compound or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2; preferably, n is 0 or 1.

；各個R¹相同或不同，且各自獨立地選自氫原子、鹵素、C_1-6烷基和C_1-6鹵烷基；R²選自氫原子、鹵素和C_1-6烷基；R³選自氫原子、鹵素和C_1-6烷基；且n為0或1。 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 is CR ^2a ; G ₂ is CR ^2b ; G ₃ is CR ^3a ; R ^2a , R ^2b and R ^3a are the same or different, and each independently selected from hydrogen atom, halogen and C _1-6 alkyl; R ⁴ is methyl; R ⁵ is methyl or

; Each R ¹ is the same or different, and is independently selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; R ² is selected from hydrogen atom, halogen and C _1-6 alkyl; R ³ is selected from hydrogen atom, halogen and C _1-6 alkyl; and n is 0 or 1.

；各個R¹相同或不同，且各自獨立地選自氫原子、鹵素、C_1-6烷基和C_1-6鹵烷基；R²選自氫原子、鹵素和C_1-6烷基；R³選自氫原子、鹵素和C_1-6烷基；且n為0或1。 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 is CR ^2a ; G ₂ is CR ^2b or N atom; G ₃ is CR ^3a ; R ^2a , R ^2b and R ^3a are the same or different, and each independently selected from hydrogen atom, halogen and C _1-6 alkyl; R ⁴ is methyl; R ⁵ is methyl or

; Each R ¹ is the same or different, and is independently selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; R ² is selected from hydrogen atom, halogen and C _1-6 alkyl; R ³ is selected from hydrogen atom, halogen and C _1-6 alkyl; and n is 0 or 1.

；各個R¹相同或不同，且各自獨立地為氫原子或鹵素；R²選自氫原子、鹵素和C_1-6烷基；R³選自氫原子、鹵素和C_1-6烷基；且n為0或1。 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 is CH; G ₂ is CH or N atom; G ₃ is CH; R ⁴ is methyl; R ⁵ is methyl or

; Each R ¹ is the same or different, and each independently is a hydrogen atom or a halogen; R ² is selected from a hydrogen atom, a halogen and a C _1-6 alkyl group; R ³ is selected from a hydrogen atom, a halogen and a C _1-6 alkyl group; And n is 0 or 1.

；各個R¹相同或不同，且各自獨立地為氫原子或鹵素；R²為氫原子；R³為氫原子；且n為0或1。 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 is CH; G ₂ is CH or N atom; G ₃ is CH; R ⁴ is methyl; R ⁵ is methyl or

each R ¹ is the same or different, and each independently is a hydrogen atom or a halogen; R ² is a hydrogen atom; R ³ is a hydrogen atom; and n is 0 or 1.

；各個R¹相同或不同，且各自獨立地選自氫原子、鹵素、C_1-6烷基和C_1-6鹵烷基；R²選自氫原子、鹵素和C_1-6烷基；R³選自氫原子、鹵素和C_1-6烷基；且n為0或1。 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 is methyl or

; Each R ¹ is the same or different, and is independently selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; R ² is selected from hydrogen atom, halogen and C _1-6 alkyl; R ³ is selected from hydrogen atom, halogen and C _1-6 alkyl; and n is 0 or 1.

； 各個R¹相同或不同，且各自獨立地選自氫原子、鹵素、C_1-6烷基和C_1-6鹵烷基；R²選自氫原子、鹵素和C_1-6烷基；R³選自氫原子、鹵素和C_1-6烷基；且n為0或1。 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 is methyl or

; Each R ¹ is the same or different, and is independently selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; R ² is selected from hydrogen atom, halogen and C _1-6 alkyl; R ³ is selected from hydrogen atom, halogen and C _1-6 alkyl; and n is 0 or 1.

；各個R¹相同或不同，且各自獨立地為氫原子或鹵素；R²為氫原子；R³為氫原子；且n為0或1。 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 is methyl or

each R ¹ is the same or different, and each independently is a hydrogen atom or a halogen; R ² is a hydrogen atom; R ³ is a hydrogen atom; and n is 0 or 1.

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 ¹ is the same or different, and each independently selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; R ² selected from hydrogen atom, halogen and C _1-6 alkyl; R ³ selected from hydrogen atom, halogen and C _1-6 alkyl; and n is 0 or 1.

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 is the same or different, and each independently selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; R ² is selected from hydrogen atom, halogen and C _1-6 alkyl; R ³ selected from hydrogen atom, halogen and C _1-6 alkyl; and n is 0 or 1.

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 is the same or different, and each independently is a hydrogen atom or a halogen; R ² is a hydrogen atom; R ³ is a hydrogen atom; and n is 0 or 1.

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

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

in,

G ₁ , G ₂ , G ₃ and R ² to R ⁵ are as defined in the general formula (I). It is an intermediate for preparing the compound represented by general formula (I).

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

in,

R ^w is an amino protecting group, preferably Boc;

；環B為環烷基或雜環基；p為0、1、2、3、4、5或6； L is (alkylene) alkylene or

; Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;

G ₁ , G ₂ , G ₃ and R ² to R ⁴ are as defined in the general formula (I-1). It is an intermediate for preparing the compound represented by the general formula (I-1).

Another aspect of the present disclosure relates to compounds represented by general formula (IIA) or salts thereof:

in,

R ² to R ⁵ are as defined in the general formula (II). It is an intermediate for preparing the compound represented by general formula (II).

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

in,

R ^w is an amino protecting group, preferably Boc;

；環B為環烷基或雜環基；p為0、1、2、3、4、5或6； L is (alkylene) alkylene or

; Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;

R ² to R ⁴ are as defined in the general formula (II-1). It is an intermediate for preparing the compound represented by the general formula (II-1).

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

in,

R ² to R ⁵ are as defined in the general formula (III). It is an intermediate for preparing the compound represented by general formula (III).

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

in,

R ^w is an amino protecting group, preferably Boc;

；環B為環烷基或雜環基；p為0、1、2、3、4、5或6； L is (alkylene) alkylene or

; Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;

R ² to R ⁴ are as defined in the general formula (III-1). It is an intermediate for preparing the compound represented by general formula (III-1).

Another aspect of the present disclosure relates to compounds represented by general formula (IC) or salts thereof:

in,

Y is a halogen; preferably a bromine atom;

G ₁ , G ₂ , G ₃ and R ² to R ⁵ are as defined in the general formula (I). It is an intermediate for preparing the compound represented by general formula (I).

Another aspect of the present disclosure relates to compounds represented by general formula (IIC) or salts thereof:

in,

R ² to R ⁵ are as defined in the general formula (II). It is an intermediate for preparing the compound represented by general formula (II).

Another aspect of the present disclosure is about the compound represented by the general formula (IIIC) or a salt thereof:

in,

R ² to R ⁵ are as defined in the 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 (IAa) or a salt thereof:

in,

G ₁ , G ₂ , G ₃ and R ² to R ⁵ are as defined in the general formula (I). It is an intermediate for preparing the compound represented by general formula (I).

Another aspect of the present disclosure relates to compounds represented by general formula (IIAa) or salts thereof:

in,

R ² to R ⁵ are as defined in the general formula (II). It is an intermediate for preparing the compound represented by general formula (II).

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

in,

R ² to R ⁵ are as defined in the general formula (III). It is an intermediate for preparing the compound represented by general formula (III).

Table B Typical intermediate compounds of the present disclosure include, but are not limited to:

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:

Acylation reaction of the compound of general formula (IA) or its salt with the compound of general formula (IB) or its salt to obtain the compound of general formula (I) or its pharmaceutically acceptable salt,

in,

X is a halogen; preferably a chlorine atom;

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

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:

Acylation reaction of the compound of general formula (IIA) or its salt with the compound of general formula (IB) or its salt to obtain the compound of general formula (II) or its pharmaceutically acceptable salt,

in,

X is a halogen; preferably a chlorine atom;

Ring A, R ¹ to R ⁵ and n are as defined in general formula (II).

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:

The compound of general formula (IIIA) or its salt is reacted with the compound of general formula (IB) or its salt to produce the compound of general formula (III) or its pharmaceutically acceptable salt,

in,

X is a halogen; preferably a chlorine atom;

Ring A, R ¹ to R ⁵ and n are as defined in general formula (III).

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:

(a) acylation reaction of a compound of general formula (I-1A) or a salt thereof with a compound of general formula (IB) or a salt thereof to obtain a compound of general formula (I-1Aa) or a pharmaceutically acceptable salt thereof;

(b) deprotecting the compound of general formula (I-1Aa) or its pharmaceutically acceptable salt to obtain the compound of general formula (I-1) or its pharmaceutically acceptable salt;

in,

X is a halogen; preferably a chlorine atom;

R ^w is an amino protecting group, preferably Boc;

；環B為環烷基或雜環基；p為0、1、2、3、4、5或6； L is (alkylene) alkylene or

; Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;

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

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, the method comprising:

(a) acylation reaction of a compound of general formula (II-1A) or a salt thereof with a compound of general formula (IB) or a salt thereof to obtain a compound of general formula (II-1Aa) or a pharmaceutically acceptable salt thereof;

(b) deprotecting the compound of general formula (II-1Aa) or its pharmaceutically acceptable salt to obtain the compound of general formula (II-1) or its pharmaceutically acceptable salt;

in,

X is a halogen; preferably a chlorine atom;

R ^w is an amino protecting group, preferably Boc;

；環B為環烷基或雜環基；p為0、1、2、3、4、5或6； L is (alkylene) alkylene or

; Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;

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

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, the method comprising:

(a) acylation reaction of a compound of general formula (III-1A) or a salt thereof with a compound of general formula (IB) or a salt thereof to obtain a compound of general formula (III-1Aa) or a pharmaceutically acceptable salt thereof;

(b) deprotection reaction of the compound of general formula (III-1Aa) or its pharmaceutically acceptable salt to obtain the compound of general formula (III-1) or its pharmaceutically acceptable salt;

in,

X is a halogen; preferably a chlorine atom;

R ^w is an amino protecting group, preferably Boc;

；環B為環烷基或雜環基；p為0、1、2、3、4、5或6； L is (alkylene) alkylene or

; Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;

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

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:

A compound of general formula (IC) or a salt thereof is coupled with a compound of general formula (ID) or a salt thereof to obtain a compound of general formula (I) or a pharmaceutically acceptable salt thereof,

in,

Y is a halogen; preferably a bromine atom;

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

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:

A compound of general formula (IIC) or a salt thereof is coupled with a compound of general formula (ID) or a salt thereof to obtain a compound of general formula (II) or a pharmaceutically acceptable salt thereof,

in,

Y is a halogen; preferably a bromine atom;

Ring A, R ¹ to R ⁵ and n are as defined in general formula (II).

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:

A compound of general formula (IIIC) or a salt thereof is coupled with a compound of general formula (ID) or a salt thereof to obtain a compound of general formula (III) or a pharmaceutically acceptable salt thereof,

in,

Y is a halogen; preferably a bromine atom;

Ring A, R ¹ to R ⁵ and n are as defined in general formula (III).

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:

A compound of general formula (IAa) or a salt thereof and a compound of general formula (IBb) or a salt thereof undergo an amidation reaction to obtain a compound of general formula (I) or a pharmaceutically acceptable salt thereof,

in,

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

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:

A compound of general formula (IIAa) or a salt thereof and a compound of general formula (IBb) or a salt thereof undergo an amidation reaction to obtain a compound of general formula (II) or a pharmaceutically acceptable salt thereof,

in,

Ring A, R ¹ to R ⁵ and n are as defined in general formula (II).

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:

A compound of general formula (IIIAa) or a salt thereof and a compound of general formula (IBb) or a salt thereof undergo an amidation reaction to obtain a compound of general formula (III) or a pharmaceutically acceptable salt thereof,

in,

Ring A, R ¹ to R ⁵ and n are as defined in general formula (III).

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

The present disclosure further relates to general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1) and table A Use of the indicated compound or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising it in the preparation of a medicament for inhibiting protein kinase.

The present disclosure further relates to general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1) and table A The compounds shown or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising them are used in the preparation of medicaments for the treatment and/or prevention of diseases, disorders and syndromes In particular, the use in the preparation of medicaments for treating and/or preventing diseases, disorders and syndromes by inhibiting protein kinases. Wherein the diseases, disorders and syndromes are preferably selected from the group consisting of sarcoma, multiple myeloma, leukemia, myxoma, rhabdomyoma, leiomyoma, fibroma, lipoma, teratoma, throat cancer, oral cavity cancer, lung cancer, alveolar Cancer, lymphoma, mesothelioma, colorectal cancer, small intestine cancer, stomach cancer, esophagus cancer, pancreatic cancer, breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, prostate cancer, Testicular cancer, liver cancer, cholangiocarcinoma, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer, psoriasis, gastrointestinal stromal tumor (GIST), atherosclerosis and pulmonary fibrosis; wherein the throat cancer is preferably nasopharyngeal carcinoma; the sarcoma is preferably osteosarcoma or chondrosarcoma; the colorectal cancer is preferably colon cancer or rectal cancer; The tumor is preferably a neurofibroma.

The present disclosure further relates to general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1) and table A Use of the compound or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, in the preparation of medicines 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, throat cancer, oral cancer, lung cancer, alveolar cancer, lymphoma, mesothelioma, colorectal cancer, small bowel 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 throat 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.

The disclosure further relates to a method of inhibiting protein kinase, which comprises administering a therapeutically effective amount of the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), the compound represented by the general formula (III-1) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same.

The present disclosure further relates to a method of treating and/or preventing diseases, disorders and syndromes, in particular a method of treating and/or preventing diseases, disorders and syndromes treated and/or prevented by inhibiting protein kinases, comprising General formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1) and A compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. Wherein the diseases, disorders and syndromes are preferably selected from the group consisting of sarcoma, multiple myeloma, leukemia, myxoma, rhabdomyoma, leiomyoma, fibroma, lipoma, teratoma, throat cancer, oral cavity cancer, lung cancer, alveolar Cancer, lymphoma, mesothelioma, colorectal cancer, small intestine cancer, stomach cancer, esophagus cancer, pancreatic cancer, breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, prostate cancer, Testicular cancer, liver cancer, cholangiocarcinoma, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer, psoriasis, gastrointestinal stromal tumor (GIST), atherosclerosis and pulmonary fibrosis; wherein the throat cancer is preferably nasopharyngeal carcinoma; the sarcoma is preferably osteosarcoma or chondrosarcoma; the colorectal cancer is preferably colon cancer or rectal cancer; The tumor is preferably a neurofibroma.

The disclosure further relates to a method for treating and/or preventing tumors, which includes administering a therapeutically effective amount of general formula (I), general formula (II), general formula (III), general formula (I-1), A compound represented by general formula (II-1), general formula (III-1) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. Wherein the tumor is preferably cancer, more preferably selected from the group consisting of sarcoma, multiple myeloma, leukemia, myxoma, rhabdomyoma, leiomyoma, fibroma, lipoma, teratoma, throat cancer, oral cavity cancer, lung cancer, lymphoma tumor, mesothelioma, colorectal cancer, small intestine cancer, stomach 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, cholangiocarcinoma, glioma, neuroblastoma, black 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 throat cancer is preferably nasopharyngeal carcinoma; the sarcoma is preferably bone tumor or chondrosarcoma; the colorectal cancer is preferably colon cancer or rectal cancer; the fibroma is preferably neurofibroma.

The disclosure is further related to a general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1) and table A The indicated compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, is used as a medicament.

The disclosure is further related to a general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1) and table A The compound or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising it, is used as a drug for inhibiting protein kinase.

The disclosure is further related to a general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1) and table A Compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, for use as a medicament for the treatment and/or prevention of diseases, disorders and syndromes, in particular for use in the treatment and/or prevention of protein kinases by inhibiting Drugs to treat and/or prevent diseases, conditions and syndromes. Wherein the diseases, disorders and syndromes are preferably selected from the group consisting of sarcoma, multiple myeloma, leukemia, myxoma, rhabdomyoma, leiomyoma, fibroma, lipoma, teratoma, throat cancer, oral cavity cancer, lung cancer, alveolar Cancer, lymphoma, mesothelioma, colorectal cancer, small intestine cancer, stomach cancer, esophagus cancer, pancreatic cancer, breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, prostate cancer, Testicular cancer, liver cancer, cholangiocarcinoma, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer, psoriasis, gastrointestinal stromal tumor (GIST), atherosclerosis and pulmonary fibrosis; wherein the throat cancer is preferably nasopharyngeal carcinoma; the sarcoma is preferably osteosarcoma or chondrosarcoma; the colorectal cancer is preferably colon cancer or rectal cancer; The tumor is preferably a neurofibroma.

The disclosure is further related to a general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1) and table A The compound or its pharmaceutically acceptable salt, or the pharmaceutical composition comprising it, it is used as the medicine for treating and/or preventing tumor, wherein the tumor is preferably cancer, more preferably selected from sarcoma, multiple myeloma, Leukemia, myxoma, rhabdomyoma, leiomyoma, fibroma, lipoma, teratoma, throat cancer, oral cancer, lung cancer, alveolar cancer, lymphoma, mesothelioma, colorectal cancer, small intestine cancer, stomach cancer, esophagus 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 throat 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.

The lymphoma described in this disclosure is preferably Hodgkin's disease or non-Hodgkin's lymphoma (such as mantle cell lymphoma, diffuse large B-cell lymphoma, follicle 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) (such as lung adenocarcinoma, lung squamous cell carcinoma and large cell carcinoma, etc.) or small cell lung cancer (SCLC) The renal cancer is preferably selected from renal cell carcinoma, clear cell tumor and renal oncocytoma; the leukemia is preferably chronic leukemia (such as chronic lymphocytic leukemia) or acute leukemia (such as acute myeloid leukemia).

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

The protein kinases described in this disclosure are receptor tyrosine kinases (RTKs); preferably, the receptor tyrosine kinases (RTKs) are Axl, Mer, TYRO3, MET, KDR or combinations thereof.

The active compounds may be prepared in a form suitable for administration by any suitable route, and the compositions of the present disclosure may be formulated by conventional methods using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure may be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular or subcutaneous), administration by inhalation or insufflation. 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.

As a general guide, the active compound is preferably presented in unit dosage form, or in such a form that the patient can self-administer as a single dose. The unit dosage form of a compound or composition of the present disclosure may be expressed as a tablet, capsule, cachet, bottled solution, powder, granule, lozenge, suppository, reconstitution powder or liquid preparation. A suitable unit dose may be 0.1 to 1000 mg.

In addition to the active compound, the pharmaceutical composition of the present disclosure may contain one or more excipients selected from the following components: fillers (diluents), binders, wetting agents, disintegrants or excipients. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of active compound.

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

Oral formulations can also be provided in soft gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, or where the active ingredient is mixed with a water-soluble carrier or an oil vehicle.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain a or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweeteners.

Oily suspensions can be formulated by suspending the active ingredient in a vegetable or mineral oil. The oily suspensions may contain a thickening agent. Sweetening and flavoring agents as mentioned above may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.

The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase may be vegetable oil, or mineral oil or mixtures thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening agents, flavoring agents, preservatives and antioxidants. Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Among the acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase. The injection or microemulsion can be injected into the patient's bloodstream by local bolus injection. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the disclosed compounds. To maintain this constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM. Model 5400 IV pump.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent. In addition, sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blended and fixed oil may be used. In addition, fatty acids are also used in the preparation of injectables.

Compounds of the disclosure 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.

Aqueous suspensions of dispersible powders and granules can be prepared by the addition of water to administer the disclosed compounds. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.

As is well known to those of ordinary skill in the art, the dosage of a drug to be administered depends on a variety of factors including, but not limited to, the activity of the particular compound used, the age of the patient, the weight of the patient, the state of the patient's health, the patient's behavior, patient’s diet, administration time, administration method, excretion rate, drug combination, disease severity, etc.; in addition, the optimal treatment method such as the mode of treatment, the daily dosage of the compound or the pharmaceutically acceptable The type of salt can be verified according to the traditional treatment plan.

Glossary

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

The term "alkyl" refers to a saturated linear or branched aliphatic hydrocarbon group having 1 to 20 carbon atoms (ie, C _1-20 alkyl). The alkyl group is preferably an alkyl group having 1 to 12 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (ie C _1-12 alkyl ), more preferably an alkyl group having 1 to 6 carbon atoms (ie C _1-6 alkyl). Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, second-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-di Methylpentyl, 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 isomers thereof. Preferably lower alkyl having 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, second-butyl Base, 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-dimethyl Dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl group, 2,3-dimethylbutyl group, etc. Alkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, substituents are preferably selected from D atoms, halogen, alkoxy, haloalkyl, haloalkane One or more of oxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl .

The term "(alkylene)" refers to a divalent alkyl group, wherein the alkyl group is as defined above, which has 1 to 20 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie C _1-20 alkylene). The (alkylene)alkylene preferably has 1 to 12 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (ie C _1-12 (alkylene)), more preferably having 1 to 6 carbon atoms (ie C _1-6 (alkylene)). Non-limiting examples of alkylene include, but are not limited to, methylene ( _-CH2- ), 1,1-ethylene (-CH( _CH3 )-), 1,2-ethylene ( -CH ₂ CH ₂ )-, 1,1-propylene (-CH(CH ₂ CH ₃ )-), 1,2-propylidene (-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. Alkylene may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably the substituent is selected from alkenyl, alkynyl, alkoxy, halo Alkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl One or more of group, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and pendant oxygen.

The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein the definition of the alkyl group is as described above, and it has 2 to 12 (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (ie C _2-12 alkenyl). The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (ie, a C _2-6 alkenyl group). Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, and the like. Alkenyl may be substituted or unsubstituted, and when substituted, it is preferably selected from alkoxy, halo, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, One or more of hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein the definition of the alkyl group is as described above, and it has 2 to 12 (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (ie C _2-12 alkynyl). The alkynyl group preferably has 2 to 6 carbon atoms (ie C _2-6 alkynyl). Alkynyl may be substituted or unsubstituted, and when substituted, it is preferably selected from alkoxy, halo, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, One or more of hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy, and butoxy, and the like. Alkoxy may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, substituents are preferably selected from deuterium atoms, halogen, alkoxy, haloalkyl, haloalkane One or more of oxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl .

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent 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 (ie 3 to 20 membered cycloalkyl), preferably with 3 to 14 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14) carbon atoms (ie 3 to 14 membered cycloalkyl), more preferably 3 to 8 carbon atoms (ie 3 to 8 membered cycloalkyl ), further preferably has 3 to 6 carbon atoms (ie 3 to 6 membered cycloalkyl), most preferably has 5 or 6 carbon atoms (ie 5 to 6 membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Base and cyclooctyl, etc.; polycyclic cycloalkyl includes spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl.

The term "spirocycloalkyl" refers to a polycyclic group with 5 to 20 members that shares one carbon atom (called a spiro atom) between monocyclic rings, which may contain one or more double bonds. Preferably 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of spiro atoms shared between the ring and the ring, the spirocycloalkyl group is divided into a single spirocycloalkyl group or a multi-spirocycloalkyl group (such as a double spirocycloalkyl group), preferably a single spirocycloalkyl group. Cycloalkyl or double spirocycloalkyl. More preferably 3/5 members, 3/6 members, 4/4 members, 4/5 members, 4/6 members, 5/5 members, 5/6 members or 6/6 members Single spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

The term "fused cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, each ring of which shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or multiple double bonds. Preferably it is 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic fused cycloalkyl groups, more preferably 3-membered/4-membered, 3-membered/5-membered, 3 people/6 people, 4 people/4 people, 4 people/5 people, 4 people/6 people, 5 people/3 people, 5 people/4 people, 5 people/5 people, 5 people/6 people, 6 people /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 bicycloalkyl. Non-limiting examples of fused cycloalkyl groups include:

The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds. Preferably it is 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyl, more preferably bicyclic or tricyclic bridged cycloalkyl. Non-limiting examples of bridged cycloalkyl groups include:

、

和

等；較佳

和

。 The cycloalkyl ring includes a cycloalkyl group as described above (including monocyclic, spiro, fused and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring wherein the bond to the parent structure is at The rings together are cycloalkyl, non-limiting examples include

,

with

etc; better

with

.

Cycloalkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, halo One or more of alkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl indivual.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic ring substituent having 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur, The sulfur can be optionally oxidized (ie to form argon or sulfur) and the remaining ring atoms are carbon. Preferably having 3 to 14 (for example 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14) ring atoms, wherein 1 to 4 (for example 1, 2, 3 and 4) are heteroatoms (ie 3 to 14 membered heterocyclyl); more preferably 3 to 8 (eg 3, 4, 5, 6, 7 and 8) ring atoms, of which 1-3 (eg 1 , 2 and 3) are heteroatoms (ie 3 to 8 membered heterocyclyl) or 6 to 14 ring atoms (eg 6, 7, 8, 9, 10, 11, 12, 13 and 14), wherein 1 - 3 (eg 1, 2 and 3) are heteroatoms (ie 6 to 14 membered heterocyclyl); more preferably have 3 to 6 ring atoms sub, wherein 1-3 (eg 1, 2 and 3) are heteroatoms (ie 3 to 6 membered heterocyclyl); optimally contain 5 or 6 ring atoms, of which 1-3 are heteroatoms (ie 5 to 6 membered heterocyclyl). Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl , Homopiperazinyl, etc. Polycyclic heterocyclyls include spiroheterocyclyls, fused heterocyclyls and bridged heterocyclyls.

The term "spiroheterocyclyl" refers to a multi-ring heterocyclic group with 5 to 20 members sharing one atom (called spiro atom) between monocyclic rings, wherein one or more ring atoms are heterocyclic groups selected from nitrogen, oxygen and sulfur atoms, the sulfur can be oxidized (ie to form argon or sulfur) if desired, and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably 6 to 14 members (eg 6, 7, 8, 9, 10, 11, 12, 13 and 14 members), more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of spiro atoms shared between the ring and the ring, the spiroheterocyclyl is divided into a single spiroheterocyclyl or a polyspiroheterocyclyl (such as a double spiroheterocyclyl), preferably a single spiroheterocyclyl or a double spiroheterocyclyl Ring base. Most preferably 3/5, 3/6, 4/4, 4/5, 4/6, 5/5, 5/6 or 6/6 member monospiroheterocyclyl. Non-limiting examples of spiroheterocyclyls include:

The term "fused heterocyclyl" refers to 5 to 20 membered polycyclic heterocyclic groups in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more Double bonds in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur being optionally oxidized (ie to form argon or thionium), and the remaining ring atoms being carbon. Preferably 6 to 14 members (such as 6, 7, 8, 9, 10, 11, 12, 13 and 14 members), more preferably 7 to 10 members (such as 7, 8, 9 or 10 members). According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic fused heterocyclic groups, more preferably 3-membered/4-membered, 3-membered/5-membered, 3 people/6 people, 4 people/4 people, 4 people/5 people, 4 people/6 people, 5 people/3 people, 5 people/4 people, 5 people/5 people, 5 people/6 people, 6 people /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 heterocyclyl. Non-limiting examples of fused heterocyclic groups include:

The term "bridged heterocyclyl" refers to a 5 to 20-membered polycyclic heterocyclic group in which any two rings share two atoms not directly connected, which may contain one or more double bonds, in which one or more ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, the sulfur optionally being oxidized (ie to form argon or argon), and the remaining ring atoms being carbon. Preferably 6 to 14 members (eg 6, 7, 8, 9, 10, 11, 12, 13 and 14 members), more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic bridged heterocyclic groups. Non-limiting examples of bridged heterocyclyl groups include:

The heterocyclyl ring includes a heterocyclyl as described above (including monocyclic, spiroheterocycle, fused heterocycle and bridged heterocycle) fused to an aryl, heteroaryl or cycloalkyl ring wherein the parent structure The rings joined together are heterocyclyl, non-limiting examples of which include:

和

等。

with

Wait.

The heterocyclyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, halo One or more of alkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl indivual.

The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (a fused polycyclic is a ring that shares adjacent pairs of carbon atoms) group, preferably 6 to 10 membered, having a conjugated π-electron system. , 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 bonded to the parent structure is an aryl ring, non-limiting examples of which include:

Aryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, substituents are preferably selected from halogen, alkyl, alkoxy, haloalkane In radical, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl one or more.

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms (eg 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 membered (eg 5, 6, 7, 8, 9 or 10 membered), more preferably 5 or 6 membered (ie 5 to 6 membered heteroaryl), eg furyl, thiophene Base, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes a heteroaryl as described above fused to an aryl, heterocyclyl or cycloalkyl ring wherein the ring bonded to the parent structure is a heteroaryl ring, non-limiting examples of which include:

Heteroaryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, halo One or more of alkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl indivual.

The above cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived from a parent ring atom by removing a hydrogen atom, or from the same parent ring atom or two different ring atoms Residues derived by removing two hydrogen atoms from above are "(extended) cycloalkylene", "(extended) heterocyclyl", "(extended) aryl", "(extended) heteroaryl" .

The term "amino group protecting group" is used to protect the amine group by the easy-to-remove group introduced on the amine group to keep the amine group unchanged when other parts of the molecule react. Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl (Boc), acetyl, benzyl, benzyloxycarbonyl (Cbz), allyl and p-methoxybenzyl et al. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy or nitro.

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

The term "cycloalkyloxy" refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.

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

The term "alkylthio" refers to alkyl-S-, wherein alkyl is as defined above.

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

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

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

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

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

The term "hydroxyl" refers to -OH.

The term "mercapto" refers to -SH.

The term "amino" refers to _-NH2 .

The term "cyano" refers to -CN.

The term "nitro" refers to _-NO2 .

The term "side oxygen" refers to "=0".

The term "carbonyl" refers to C=O.

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

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.

Compounds of the present disclosure include isotopic derivatives thereof. The term "isotopically derivative" refers to compounds that differ in structure only by the presence of one or more isotopically enriched atoms. For example, with the structure of the present disclosure, hydrogen is replaced by "deuterium" or "tritium", or fluorine is replaced by ¹⁸ F-fluorine label ( ¹⁸ F isotope), or ¹¹ C-, ¹³ C-, or ¹⁴ C-enriched Compounds in which carbon atoms are replaced by carbon ( ¹¹ C-, ¹³ C-, or ¹⁴ C-carbon labels; ¹¹ C-, ¹³ C-, or ¹⁴ C-isotopes) are within the scope of the present disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies. Various deuterated forms of compounds of the present disclosure mean that each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can refer to the relevant literature to synthesize the deuterated form of the compound. Commercially available deuterated starting materials can be used in the preparation of deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including but not limited to deuterated borane, trideuterioborane in tetrahydrofuran , deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc. Deuterated compounds generally retain comparable activity to undeuterated compounds, and can achieve better metabolic stability when deuterated at certain sites, thereby gaining certain therapeutic advantages.

Compounds of the present disclosure may exist in certain stereoisomeric forms. The term "stereoisomer" refers to isomers that are identical in structure but differ in the arrangement of the atoms in space. It includes cis and trans (or Z and E ) isomers, (-)- and (+)-isomers, ( R )- and ( S )-enantiomers, diastereomers isomers, (D )- and ( L )-isomers, tautomers, atropisomers, conformers and mixtures thereof (eg racemates, mixtures of diastereomers). Substituents in compounds of the present disclosure may be present with additional asymmetric atoms. All such stereoisomers, as well as mixtures thereof, are included within the scope of the present disclosure. Optically active (-)- and (+)-isomers, ( R )- and ( S )-enantiomers and (D )- and ( L )-isomers. An isomer of a compound disclosed in this disclosure can be prepared by asymmetric synthesis or chiral auxiliary agents, or, when the molecule contains a basic functional group (such as an amine group) or an acidic functional group (such as a carboxyl group), it can be prepared with an appropriate Optically active acids or bases form diastereomeric salts, which are then resolved by conventional methods well known in the art to obtain the pure isomers. Furthermore, separation of enantiomers and diastereomers is usually accomplished by chromatography.

”或“

”，或者同時包含“

”和“

”兩種構型。 In the chemical structure of the compound described in this disclosure, 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"

, or both "

"with"

"Two configurations.

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 structural isomers that exist in equilibrium and are readily converted from one isomeric form to the other. It includes all possible tautomers, ie present as single isomers or as mixtures of such tautomers in any ratio. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactimine, and the like. An example of a lactam-lactimine equilibrium is shown below:

For example, when referring to pyrazolyl, it should be understood to include any one of the following two structures or a mixture of two tautomers:

All tautomeric forms are within the scope of the disclosure, and the naming of compounds does not exclude any tautomers.

"Optionally" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur. For example, "C _1-6 alkyl optionally substituted by halogen or cyano" means that halogen or cyano may but not necessarily exist, and this description includes the case where the alkyl is substituted by halogen or cyano and the alkyl is not substituted by halogen. And the case of cyano substitution.

"Substituted" means that one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. Those skilled in the art can determine (by experiment or theory) without undue effort Possible or impossible substitution. For example, an amine or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.

"Pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof and other chemical components, and other components such as a physiologically/pharmaceutically acceptable carrier and excipients. The purpose of the pharmaceutical composition is to promote the administration to the living body, facilitate the absorption of the active ingredient and thus exert the biological activity.

"Pharmaceutically acceptable salt" refers to a salt of a compound 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 proper biological activity. Salts can be prepared separately during the final isolation and purification of the compounds, or by reacting the appropriate 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 amines. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

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 the therapeutically effective dose varies from person to person, depending on the age and general condition of the subject, and also depends on the specific active substance. The appropriate therapeutically effective dose in individual cases can be determined by those skilled in the art according to routine experiments.

As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with patient tissues without undue toxicity, irritation, allergic reaction or Other problems or complications that have a reasonable benefit/risk ratio and are valid for the intended use.

As used herein, the singular forms "a", "an" and "the" include plural references and vice versa unless the context clearly dictates otherwise.

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

The synthetic method of the disclosed compound

In order to accomplish the purpose of this disclosure, this disclosure adopts the following technical solutions:

Option One

The present disclosure discloses a compound represented by general formula (I), or a preparation method of a pharmaceutically acceptable salt thereof, the method comprising:

A compound of general formula (IA) or a salt thereof and a compound of general formula (IB) or a salt thereof, under alkaline conditions, undergo an acylation reaction to obtain a compound of general formula (I) or a pharmaceutically acceptable salt thereof,

in,

X is a halogen; preferably a chlorine atom;

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

Option II

The present disclosure discloses a compound represented by general formula (II), or a preparation method of a pharmaceutically acceptable salt thereof, the method comprising:

A compound of general formula (IIA) or a salt thereof and a compound of general formula (IB) or a salt thereof, under alkaline conditions, undergo an acylation reaction to obtain a compound of general formula (II) or a pharmaceutically acceptable salt thereof,

in,

X is a halogen; preferably a chlorine atom;

Ring A, R ¹ to R ⁵ and n are as defined in general formula (II).

third solution

The present disclosure discloses a compound represented by general formula (III), or a preparation method of a pharmaceutically acceptable salt thereof, the method comprising:

A compound of general formula (IIIA) or a salt thereof and a compound of general formula (IB) or a salt thereof, under alkaline conditions, undergo an acylation reaction to obtain a compound of general formula (III) or a pharmaceutically acceptable salt thereof,

in,

X is a halogen; preferably a chlorine atom;

Ring A, R ¹ to R ⁵ and n are as defined in general formula (III).

Option four

The present disclosure discloses a compound represented by general formula (I-1), or a preparation method of a pharmaceutically acceptable salt thereof, the method comprising:

(a) a compound of general formula (I-IA) or a salt thereof and a compound of general formula (IB) or a salt thereof undergo an acylation reaction under alkaline conditions to obtain a compound of general formula (I-1Aa) or a compound thereof medicinal salts;

(b) deprotecting the compound of general formula (I-1Aa) or its pharmaceutically acceptable salt under acidic conditions to obtain the compound of general formula (I-1) or its pharmaceutically acceptable salt;

in,

X is a halogen; preferably a chlorine atom;

R ^w is an amino protecting group, preferably Boc;

；環B為環烷基或雜環基；p為0、1、2、3、4、5或6； L is (alkylene) alkylene or

; Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;

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

Option five

The present disclosure discloses a compound represented by general formula (II-1), or a preparation method of a pharmaceutically acceptable salt thereof, the method comprising:

(a) the compound of general formula (II-1A) 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-1Aa) or its equivalent medicinal salts;

(b) The compound of general formula (II-1Aa) or its pharmaceutically acceptable salt undergoes a deprotection reaction under acidic conditions to obtain the compound of general formula (II-1) or its pharmaceutically acceptable salt;

in,

X is a halogen; preferably a chlorine atom;

R ^w is an amino protecting group, preferably Boc;

；環B為環烷基或雜環基；p為0、1、2、3、4、5或6； L is (alkylene) alkylene or

; Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;

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

Option six

The present disclosure discloses a compound represented by general formula (III-1), or a preparation method of a pharmaceutically acceptable salt thereof, the method comprising:

(a) the compound of general formula (III-1A) 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-1Aa) or its equivalent medicinal salts;

(b) The compound of general formula (III-1Aa) or its pharmaceutically acceptable salt undergoes a deprotection reaction under acidic conditions to obtain the compound of general formula (III-1) or its pharmaceutically acceptable salt;

in,

X is a halogen; preferably a chlorine atom;

R ^w is an amino protecting group, preferably Boc;

；環B為環烷基或雜環基；p為0、1、2、3、4、5或6； L is (alkylene) alkylene or

; Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;

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

Option seven

The present disclosure discloses a preparation method of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (IC) or its salt and the compound of general formula (ID) or its salt, under alkaline conditions, in the presence of a catalyst, a coupling reaction occurs to obtain the compound of general formula (I) or its druggable the salt used,

in,

Y is a halogen; preferably a bromine atom;

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

Option eight

The present disclosure discloses a preparation method of a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

A compound of general formula (IIC) or a salt thereof and a compound of general formula (ID) or a salt thereof are subjected to a coupling reaction under alkaline conditions in the presence of a catalyst to obtain a compound of general formula (II) or a pharmaceutically acceptable the salt used,

in,

Y is a halogen; preferably a bromine atom;

Ring A, R ¹ to R ⁵ and n are as defined in general formula (II).

Option nine

The present disclosure discloses a preparation method of a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

A compound of general formula (IIIC) or a salt thereof and a compound of general formula (ID) or a salt thereof are subjected to a coupling reaction under alkaline conditions in the presence of a catalyst to obtain a compound of general formula (III) or a pharmaceutically acceptable the salt used,

in,

Y is a halogen; preferably a bromine atom;

Ring A, R ¹ to R ⁵ and n are as defined in general formula (III).

Plan ten

The present disclosure discloses a preparation method of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

A compound of general formula (IAa) or a salt thereof and a compound of general formula (IBb) or a salt thereof undergo an amidation reaction under a condensing agent (preferably HATU) and alkaline conditions to obtain a compound of general formula (I) or its pharmaceutically acceptable salts,

in,

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

Plan Eleven

The present disclosure discloses a preparation method of a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

A compound of general formula (IIAa) or a salt thereof and a compound of general formula (IBb) or a salt thereof undergo an amidation reaction under a condensing agent (preferably HATU) and alkaline conditions to obtain a compound of general formula (II) or its pharmaceutically acceptable salts,

in,

Ring A, R ¹ to R ⁵ and n are as defined in general formula (II).

Plan twelve

The present disclosure discloses a preparation method of a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

A compound of general formula (IIIAa) or a salt thereof and a compound of general formula (IBb) or a salt thereof undergo an amidation reaction under a condensing agent (preferably HATU) and alkaline conditions to obtain a compound of general formula (III) or its pharmaceutically acceptable salts,

in,

Ring A, R ¹ to R ⁵ and n are as defined in general formula (III).

The reagents providing basic conditions in the above synthesis scheme include organic bases and inorganic bases, the organic bases include but not limited to triethylamine, pyridine, N,N -diisopropylethylamine, n-butyl lithium, diiso Lithium propylamide, 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 hydrogenation Sodium, 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 one to six is preferably pyridine; scheme The reagent providing basic conditions in Schemes 7 to 9 is preferably cesium carbonate; the reagent providing basic conditions in Schemes 10 to 12 is preferably N,N -diisopropylethylamine.

Catalysts in the above synthesis schemes 7 to 9 include but are not limited to bis(dibenzylideneacetone)palladium, bis(dibenzylideneacetone)palladium/4,5-bisdiphenylphosphine-9,9-dimethyl Xanthene, tetrakis-triphenylphosphonium palladium, palladium dichloride, palladium acetate, methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2,4',6'-tri Isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), 1,1'-bis(dibenzylphosphine)dichloro Dipentyl iron palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride Dichloromethane complex, tris(dibenzylideneacetone)dipalladium, preferably bis(dibenzylideneacetone)palladium or bis(dibenzylideneacetone)palladium/4,5-bisdiphenylphosphonium -9,9-Dimethylxanthene.

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

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

The reaction of 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, dimethylsulfoxide, 1,4-dioxane, water, N,N -dimethylformamide, N,N -dimethylacetamide, 1,2- Dibromoethane and its mixtures.

The following examples are used to further describe the present disclosure, but these examples do not limit the scope of the present disclosure.

Example

Compound structures were determined by nuclear magnetic resonance (NMR) or/and mass spectroscopy (MS). NMR shifts (d) are given in units of 10-6 (ppm). The determination of NMR is carried out with a Bruker AVANCE NEO 500M nuclear magnetic instrument, and the determination solvent is deuterated dimethyl sulfide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard is four Methylsilane (TMS).

The determination of MS uses Agilent 1200/1290 DAD-6110/6120 Quadrupole MS liquid mass spectrometer (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS Model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

High-performance liquid chromatography (HPLC) was analyzed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high-performance liquid chromatography.

Chiral HPLC analysis and determination using Agilent 1260 DAD high performance liquid chromatography.

For HPLC preparation, Waters 2545-2767, Waters 2767-SQ Detecor 2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs were used.

Chiral preparation A Shimadzu LC-20AP preparative chromatograph was used.

The CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).

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

Silica gel column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as the carrier.

Kinase average inhibition rate and IC50 value were determined with NovoStar microplate reader (BMG Company, Germany).

The known starting materials of the present disclosure can be used or synthesized according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Darui Chemicals and other companies.

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

The argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.

The hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

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

The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.

For the microwave reaction, a CEM Discover-S 908860 microwave reactor was used.

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

Unless otherwise specified in the examples, the temperature of the reaction is room temperature, which is 20° C. to 30° C.

The monitoring of the reaction process in the embodiment adopts thin-layer chromatography (TLC), the developing agent used in the reaction, the system of the eluting agent of the column chromatography adopted by the purified compound and the developing agent 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 it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.

Example 1

N -(4-fluorophenyl) -N '-(5-((7-methoxy-6-(methylaminoformyl)quinolin-4-yl)oxy)pyridin-2-yl ) cyclopropane-1,1-dimethylamide 1

first step

4-((6-aminopyridin-3-yl)oxy)-7-methoxy- N -methylquinoline-6-formamide 1b

Compound 4-chloro-7-methoxy- N -methylquinoline-6-formamide 1a (501mg, 1.99mmol, using the method disclosed in the patent application "Example Intermediate 29 on page 168 of the specification in WO2019148043A1" Prepared) was dissolved in dimethylsulfoxide (5mL), added 6-aminopyridin-3-ol (220mg, 1.99mmol) and potassium hydroxide solution (2M, 0.1mL), heated to 85 ℃ 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%).

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

second step

N -(4-fluorophenyl) -N '-(5-((7-methoxy-6-(methylaminoformyl)quinolin-4-yl)oxy)pyridin-2-yl ) cyclopropane-1,1-dimethylamide 1

Compound 1b (170 mg, 524.15 μmol), compound 1-((4-fluorophenyl)aminoformyl)cyclopropane-1-formyl chloride 1c (130mg, 537.98 μmol) were prepared by using the patent application "EP3750893A1 in the specification No. 14 (prepared by the method disclosed in the examples on page Common Intermediates)) was dissolved in pyridine (10 mL), and stirred for 12 hours. After the reaction solution was concentrated under reduced pressure, use high performance liquid chromatography (Gilson281, chromatographic column: SharpSil-T C18 150*30mm, 5 μm; mobile phase 1: water (containing 10mmol/L ammonium bicarbonate); mobile phase 2: Acetonitrile; 15 minutes gradient: acetonitrile 38%-90%, flow rate: 30mL/min) to obtain the title product 1 (98mg, yield: 35.0%).

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

¹ H NMR (500MHz,DMSO- d ₆ )δ 11.18(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,1H),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).

Example 2

N -(4-fluorophenyl) -N' -[5-[[7-methoxy-6-(methylaminoformyl)-quinolin-4-yl]oxy]pyrazine-2 -yl]cyclopropane-1,1-dimethylamide 2

first step

N- (4-fluorophenyl)cyclopropane-1,1-dimethylamide 2a

1c (2g, 8.27mmol) was dissolved in tetrahydrofuran (20mL), and 25-28% amine water (30mL) was dropped into the reaction flask under ice-cooling, raised to room temperature, and stirred for 1 hour. Extract with dichloromethane (100mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, the filtrate is concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to obtain the title product 2a (1.8g, yield : 97.8%).

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

second step

4-Hydroxy-7-methoxy- N -methylquinoline-6-carboxamide 2c

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

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

third step

4-((5-bromopyrazin-2-yl)oxy)-7-methoxy- N -methylquinoline-6-formamide 2d

Dissolve compound 2c (2.5g, 10.76mmol) in N,N -dimethylformamide (100mL), add cesium carbonate (8.7g, 26.9mmol, Shanghai Shaoyuan Reagent Co., Ltd.), stir, and react at 80°C For 1 hour, 2,5-dibromopyrazine (2.5g, 10.76mmol, Shanghai Shaoyuan Reagent Co., Ltd.) was dissolved in N , N -dimethylformamide (2mL), and added dropwise to the reaction at 80°C In the bottle, the reaction was continued for 1 hour. Cool the reaction solution to room temperature, slowly pour it into 800mL of water, add ethyl acetate for extraction (300mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and use silica gel column chromatography to elute Purification of reagent system A afforded the title product 2d (840 mg, yield: 20%).

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

the fourth step

N -(4-fluorophenyl) -N' -[5-[[7-methoxy-6-(methylaminoformyl)-quinolin-4-yl]oxy]pyrazine-2 -yl]cyclopropane-1,1-dimethylamide 2

Compound 2d (810mg, 2.08mmol) was dissolved in toluene (150mL), and compound 2a (925mg, 4.16mmol), cesium carbonate (2.0g, 6.24mmol, Shanghai Shaoyuan Reagent Co., Ltd.), 4,5-bisbis Phenylphosphonium-9,9-dimethylxanthene (721mg, 1.24mmol, Shanghai Shaoyuan Reagent Co., Ltd.), nitrogen was passed through twice, and the air was exhausted, and bis(dibenzylideneacetone)palladium (571mg, 0.62mmol, Beijing Bailingwei Technology Co., Ltd.), nitrogen gas was introduced three times, the air was exhausted, and the mixture was added to a pre-heated 90°C oil bath, and stirred for 16 hours. After being cooled to room temperature, the reaction solution was concentrated under reduced pressure and then subjected to high performance liquid chromatography (Gilson281, chromatographic column: SharpSil-T C18 150*30mm, 5 μm; mobile phase 1: water (containing 10mmol/L ammonium bicarbonate); Mobile phase 2: acetonitrile; 20 minutes gradient: 25%-45%, flow rate: 30mL/min) was purified to obtain the title product 2 (410mg, yield: 37.1%).

MS m/z (ESI): 531.2 [M+1].

¹ H NMR (500MHz,DMSO- d ₆ )δ 11.39(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).

Example 3

N -cyclohexyl- N- (5-((7-methoxy-6-(methylaminoformyl)quinolin-4-yl)oxy)pyridin-2-yl)cyclopropane-1, 1-Diformamide 3

first step

1-((5-((7-methoxy-6-(methylaminoformyl)quinolin-4-yl)oxy)pyridin-2-yl)aminoformyl)cyclopropane-1 - Methyl carboxylate 3b

Compound 1b (200mg, 0.62mmol), 1,1-cyclopropyl dicarboxylic acid monomethyl ester 3a (106mg, 0.74mmol) was dissolved in N,N -dimethylformamide (5mL), and O- (7 -Azabenzotriazol-1-yl) -N,N,N',N' -tetramethyluronium hexafluorophosphate (282mg, 0.74mmol, Shanghai Shaoyuan Reagent Co., Ltd.), N,N -di Isopropylethylamine (240 mg, 1.86 mmol, Adamas Reagent Co., Ltd.), 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 with eluent system A to obtain the title product 3b (180 mg, yield: 64.8%).

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

second step

1-((5-((7-methoxy-6-(methylaminoformyl)quinolin-4-yl)oxy)pyridin-2-yl)aminoformyl)cyclopropane-1 -Carboxylic acid 3c

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 Stir warm for 2 hours. Concentrate under reduced pressure to remove most of the solvent, add 1M hydrochloric acid until the pH of the reaction solution is 3~4, a solid precipitates, filter, collect the filter cake, and dry in vacuo to obtain the title product 3c (77 mg, yield: 99%).

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

third step

N -cyclohexyl- N- (5-((7-methoxy-6-(methylaminoformyl)quinolin-4-yl)oxy)pyridin-2-yl)cyclopropane-1, 1-Diformamide 3

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

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

¹ H NMR (500MHz, 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,1H),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).

Example 4

N -(5-((7-((1-aminocyclopropyl)methoxy)-6-(methylaminoformyl)quinolin-4-yl)oxy)pyridin-2-yl )-N-(4-fluorophenyl)cyclopropane-1,1- dimethylamide 4

first step

(1-((tertiary butoxycarbonyl)amino)cyclopropyl)methyl mesylate 4b

Compound (tert-butyl 1-(hydroxymethyl)cyclopropyl)carbamate 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 reacted at room temperature for 0.5 hours. Extracted with ethyl acetate (30 mL×3), combined the organic phases, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product of the title product 4b (2.5 g, yield: 98%).

second step

4-Chloro-7-hydroxy- N -methylquinoline-6-carboxamide 4c

Compound 1a (1 g, 3.98 mmol) was dissolved in dichloromethane (50 mL), and boron tribromide dichloromethane solution (1M, 39.89 mL) was added dropwise at 0°C. Rise to room temperature and react for 5 hours. The reaction was quenched by adding 10 mL of methanol, and the pH of the solution was adjusted to weak acidity with 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%).

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

third step

Tertiary butyl (1-(((4-chloro-6-(methylaminoformyl)quinolin-7-yl)oxy)methyl)cyclopropyl)carbamate 4d

Compound 4c (900mg, 3.80mmol) and compound 4b (2.0g, 7.53mmol) were dissolved in N,N -dimethylformamide (10mL), anhydrous potassium carbonate (2.6g, 18.81mmol) and potassium iodide (1.8 g, 10.84 mmol). 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%).

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

the fourth step

(1-(((4-((6-aminopyridin-3-yl)oxy)-6-(methylaminoformyl)quinolin-7-yl)oxy)methyl)cyclopropyl Tertiary butyl carbamate 4e

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

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

the fifth step

(1-(((4-((6-(1-((4-fluorophenyl)aminoformyl)cyclopropane-1-formamido)pyridin-3-yl)oxy)-6 -(Methylaminoformyl)quinolin-7-yl)oxy)methyl)cyclopropyl)carbamate tertiary butyl ester 4f

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 with eluent system A to obtain the title product 4f (130 mg, yield: 70%).

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

step six

N -(5-((7-((1-aminocyclopropyl)methoxy)-6-(methylaminoformyl)quinolin-4-yl)oxy)pyridin-2-yl )-N-(4-fluorophenyl)cyclopropane-1,1- dimethylamide 4

Compound 4f (130 mg, 189.86 μmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added dropwise at 0° C., and reacted at room temperature for 1 hour. Concentrate the reaction solution at room temperature, adjust the pH of the reaction solution to 8 with saturated sodium bicarbonate solution, concentrate, and use high performance liquid chromatography (Waters-2545, chromatographic column: YMC Triar-Exrs Prep C18 150*30mm, 5 μm; Mobile phase 1: water (ammonium bicarbonate containing 10mmol/L); Mobile phase 2: acetonitrile; 15 minutes gradient: acetonitrile: 35%-47%, flow rate: 30mL/min) purify title product 4 (86mg, productive rate 77%).

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

¹ H NMR (500MHz,DMSO- d ₆ )δ 1.18(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).

Comparative example A

N -(4-fluorophenyl ) -N-(2-((7-methoxy-6-(methylaminoformyl)quinolin-4-yl)oxy)pyrimidin-5-yl)

Cyclopropane-1,1-dimethylamide A

first step

7-methoxy- N -methyl-4-((5-nitropyrimidin-2-yl)oxy)quinoline-6-formamide A2

Disperse compound 2c (1g, 4.31mmol) in N,N -dimethylformamide (10mL), add 2-chloro-5-nitropyrimidine A1 (690mg, 4.33mmol, Shanghai Pide Pharmaceutical Technology Co., Ltd. ), triethylamine (0.48g, 4.74mmol), reacted at room temperature for 5 minutes, concentrated under reduced pressure to remove the solvent, and the resulting residue was purified with silica gel column chromatography to obtain the title product A2 (200mg, yield : 13.1%).

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

second step

4-((5-aminopyrimidin-2-yl)oxy)-7-methoxy- N -methyl-quinoline-6-formamide A3

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

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

third step

N -(4-fluorophenyl ) -N-(2-((7-methoxy-6-(methylaminoformyl)quinolin-4-yl)oxy)pyrimidin-5-yl)

Cyclopropane-1,1-dimethylamide A

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. After the reaction solution was concentrated under reduced pressure, use high-performance liquid chromatography (chromatographic column: SharpSil-T C18 150*30mm, 5 μm; mobile phase 1: water (containing 10mmol/L ammonium bicarbonate); mobile phase 2: acetonitrile; 22 minutes, acetonitrile: 36%-46%, flow rate: 30mL/min) to obtain the title product A (60mg, yield: 36.8%).

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

¹ H NMR (500MHz,DMSO- d ₆ )δ 10.44(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).

biological evaluation

Test Example 1. The disclosed compound has inhibitory effect on Axl, Mer, KDR and MET kinase activities

The purpose of this experiment is to test the inhibitory effect of the compound on the kinase activity of Axl, Mer, KDR and MET, and evaluate the in vitro activity of the compound according to the IC ₅₀ size.

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

1. Experimental materials and instruments

laboratory apparatus

Experimental Materials

2. Experimental steps

1. Dissolve the compound to 10mM in DMSO, and serially dilute 9 concentrations by 5 times. Each gradient compound previously diluted in DMSO was diluted again with PBS, and the compound was diluted to an initial concentration of 50 μM, and 5-fold gradient dilution was performed at 9 concentration points. Another 2 μL of the compound was added to a 384-well plate (PE, 6005620).

2. According to the instructions of the HTRF KinEASE-TK kit (Cisbio, 62TKOPEC), configure the enzyme activity reaction buffer.

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 in sequence To 0.025ng/μL, 0.125ng/μL, 0.01ng/μL and 0.05ng/μL, respectively take 4μL into 384 wells. Incubate at room temperature for 15 minutes.

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 100 μM, and the substrate concentration is 1 μM. 4 μL of the reaction substrate mixture was added to a 384-well plate, and reacted at 37°C for 0.5 hours.

5. According to the instructions of the HTRF KinEASE-TK kit, configure the detection mixture. Take 10 μL of the detection mixture and add it to a 384-well plate, and incubate at room temperature for 1 hour.

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 .

7. Use the log(inhibitor) vs. response-variable slope of the graphpad prism5.0 software to calculate the inhibition rate based on the logarithmic value of the compound concentration and the corresponding ratio, draw the dose-effect curve and calculate the IC ₅₀ value.

The inhibition of the kinase activity of Axl, Mer, KDR and MET by the compounds disclosed in this disclosure was determined by the above tests, and the measured IC ₅₀ values are shown in Table 1.

Table 1 The IC ₅₀ values of the inhibitory effects of the compounds in this disclosure on Axl, Mer, KDR and MET kinase activities

Conclusion: The compounds disclosed in this disclosure have obvious inhibitory effects on the binding of KDR, MET, Axl, and Mer, and have better inhibitory effects than Control Example A.

Test Example 2: Identification of Reactive Metabolites of Compounds Disclosed in Human Liver Microsomes

The identification of reactive metabolites of the disclosed compounds in human liver microsomes adopts the following experimental methods:

1. Experimental materials and instruments

1. Phosphate buffer (purchased from Shanghai Sangong)

2. NADPH (ACROS, A2646-71-1)

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

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

5. Acquity BEH C ₁₈ column, 2.1×100mm, 1.7μm (Waters, USA)

6. Positive control compound (Diclofenac, Diclofenac).

2. Experimental Drugs

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

3. Experimental steps

1. Preparation of the test compound solution: take an appropriate amount of the test compound, accurately weigh it, add an appropriate amount of DMSO to dissolve and mix evenly to obtain a stock solution with a concentration of 30 mM. The stock solution with a concentration of 10 mM was diluted 10 times with 50% acetonitrile/water (v/v) to obtain a working solution with a concentration of 3.0 mM. Liquid 1. Working solution 1 with a concentration of 3.0 mM was diluted 10 times with PBS to obtain 300 μM working solution 2, which was stored at 4°C before use.

2. Preparation of phosphate buffer solution: Weigh appropriate amount of K ₂ HPO ₄ and KH ₂ PO ₄ respectively, dissolve them in 4L of pure water to make a buffer solution with a concentration of 100mM, and then adjust the pH value to 7.4 with phosphoric acid or sodium hydroxide .

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

4. Preparation of NADPH cofactor solution: Weigh an appropriate amount of NADPH and magnesium chloride, dissolve in an appropriate amount of phosphate buffer (pH 7.4) with a concentration of 100 mM, so that the concentrations of NADPH and magnesium chloride are 10 mM and 30 mM respectively, and set aside.

5. Preparation of glutathione (GSH) solution: Take an appropriate amount of GSH, dissolve it in an appropriate amount of 100 mM phosphate buffer (pH 7.4), so that the concentration of GSH is 50 mM, and set aside.

6. The incubation system is as follows:

Precisely 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 microsomal solution with a concentration of 1.43 mg/mL, so that the concentration of liver microsomal protein in the incubation system is 1 mg/mL. After adding 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 into a constant temperature incubator at 37° C. for shaking incubation, and start timing. After 60 minutes of incubation, the incubation samples were taken out from the incubator, and 1000 μL of ice-cold acetonitrile solution was added to terminate the reaction and left at room temperature for 10 minutes, then centrifuged at 12000 rpm for 10 minutes. Pipette all supernatants into centrifuge tubes and concentrate to dryness in vacuo at 37°C. The residue was redissolved in 200 μL of 25% acetonitrile/water solution, centrifuged at 12000 rpm for 10 min, the supernatant was transferred to a 96-well plate, and 5 μL was pipetted for LC/MS analysis. For blank samples, add 20 μL PBS instead of working solution 2. For NCF samples, add 20 µL of PBS instead of GSH solution. The positive control diclofenac (10 μM) was the same as the test compound. The collected data is processed and analyzed by Xcalibur software, and according to the accurate molecular weight, the fragmentation of MS/MS is used to analyze whether the disclosed compound will undergo metabolic activation to produce reactive metabolites.

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

Conclusion: GSH conjugates related to the compound of Example 2 of the present disclosure were not detected in the experiment, but GSH conjugates related to the compound XL-092 were detected. It can be seen that the compound of the present disclosure shows more good security.

Claims (22)

A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof,

in, 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; G ₁ is N atom or CR ^2a ; G ₂ is N atom or CR ^2b ; G ₃ is N atom or CR ^3a ; Each R is the same or different, and each independently selected from ^a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro, hydroxyl, hydroxyalkyl, ring Alkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from the group consisting of halogen, alkyl, One or more substituents of alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl replaced by R ² , R ^2a and R ^2b are the same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, Hydroxyalkyl, cycloalkyl and heterocyclyl; R ³ and R ^3a are the same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl , cycloalkyl and heterocyclyl; R ^is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group; R ⁵ is selected from alkyl, -(CH ₂ ) _m R ^a , cycloalkyl and heterocyclyl; wherein the alkyl, cycloalkyl and heterocyclyl are each independently selected from halogen, alkyl, alkane One or more substituents in oxy, haloalkyl, haloalkoxy, cyano, amine, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl replace; R is cycloalkyl ^or heterocyclyl, wherein the cycloalkyl or heterocyclyl are each independently selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, - NR ^b R ^c , hydroxy and hydroxyalkyl are substituted by one or more substituents; 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; n is 0, 1, 2, 3, 4 or 5; and m is 1, 2, 3, 4, 5 or 6. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as claimed in item 1, wherein G ₁ is CR ^2a ; G ₂ is CR ^2b or N atom; G ₃ is CR ^3a ; R ^2a , R ^2b and R ^3a are the same or different, and are each independently selected from hydrogen atom, halogen and C _1-6 alkyl; preferably, G ₁ is CR ^2a ; G ₂ is CR ^2b ; G ₃ is CR ^3a ; R ^2a , R ^2b and R ^3a are the same or different, and are each independently selected from a hydrogen atom, a halogen and a C _1-6 alkyl group. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof as described in Claim 1 or 2, which is the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof,

in, Ring A, R ¹ to R ⁵ and n are as defined in claim 1. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 3, wherein ring A is phenyl or cyclohexyl. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 4, wherein R ⁴ is C _1-6 alkyl; preferably, R ⁴ is methyl . A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 5, wherein R ⁵ is 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 substituted by one or more substituents selected from C _1-6 alkyl and -NR ^b R ^c ; R ^b and R ^c are the same or different, and each independently is a hydrogen atom or a C _1-6 alkyl group; m is 1, 2 or 3; preferably, R ⁵ is methyl or

. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 6, wherein each R ¹ is the same or different, and each independently selected from hydrogen atom, halogen, 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 is the same or different, and each independently selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 halogen alkyl. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 7, wherein R ² is selected from hydrogen atom, halogen and C _1-6 alkyl. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 8, wherein R ³ is selected from hydrogen atom, halogen and C _1-6 alkyl. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 9, wherein n is 0 or 1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 10, which is selected from the following compounds:

A compound represented by general formula (IA) or a salt thereof,

in, G ₁ , G ₂ , G ₃ and R ² to R ⁵ are as defined in claim 1. A compound selected from the following structures,

A compound represented by general formula (IC) or a salt thereof,

in, Y is a halogen; preferably a bromine atom; G ₁ , G ₂ , G ₃ and R ² to R ⁵ are as defined in claim 1. The compound represented by the general formula (IC) or its salt as claimed in item 14, which is selected from the following compounds:

A method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, the method comprising:

Acylation reaction of the compound of general formula (IA) or its salt with the compound of general formula (IB) or its salt to obtain the compound of general formula (I) or its pharmaceutically acceptable salt, in, X is a halogen; preferably a chlorine atom; Ring A, G ₁ , G ₂ , G ₃ , R ¹ to R ⁵ and n are as defined in claim 1. A method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, the method comprising:

A compound of general formula (IC) or a salt thereof is coupled with a compound of general formula (ID) or a salt thereof to obtain a compound of general formula (I) or a pharmaceutically acceptable salt thereof, in, Y is a halogen; preferably a bromine atom; Ring A, G ₁ , G ₂ , G ₃ , R ¹ to R ⁵ and n are as defined in claim 1. A pharmaceutical composition, which contains a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claim items 1 to 11, and one or more pharmaceutically acceptable carriers , diluent or excipient. A compound represented by general formula (I) as described in any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in claim 18 in the preparation of a drug for inhibiting protein kinase Use in; preferably, wherein the protein kinases are receptor tyrosine kinases (RTKs). The use as claimed in claim 19, wherein the receptor tyrosine kinases (RTKs) are Axl, Mer, TYRO3, MET, KDR or a combination thereof. A compound represented by general formula (I) as described in any one of claim items 1 to 11 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in claim item 18 is used for treatment and/or prevention Use in medicine for diseases, disorders and syndromes; wherein the diseases, disorders and syndromes are selected from the group consisting of sarcoma, multiple myeloma, leukemia, myxoma, rhabdomyoma, leiomyoma, fibroma, lipoma, teratoma , throat cancer, oral cancer, lung cancer, alveolar cancer, lymphoma, mesothelioma, colorectal cancer, small intestine cancer, stomach 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, cholangiocarcinoma, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer , psoriasis, gastrointestinal stromal tumor, atherosclerosis and pulmonary fibrosis; wherein the throat cancer is preferably nasopharyngeal carcinoma; the sarcoma is preferably osteosarcoma or chondrosarcoma; the colorectal cancer is preferably colon Carcinoma or rectal cancer; the fibroma is preferably a neurofibroma. A compound represented by general formula (I) as described in any one of claim items 1 to 11 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in claim item 18 is used for treating and or preventing tumors wherein the tumor is selected from the group consisting of sarcoma, multiple myeloma, leukemia, myxoma, rhabdomyoma, leiomyoma, fibroma, lipoma, teratoma, throat cancer, oral cavity cancer, lung cancer, alveolar cancer , lymphoma, mesothelioma, colorectal cancer, small intestine cancer, stomach cancer, esophagus cancer, pancreatic cancer, breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer Carcinoma, prostate cancer, testicular cancer, liver cancer, cholangiocarcinoma, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer, and gastrointestinal stromal cancer Wherein the throat 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.