A 1H-pyrazole-4-amide derivative, its preparation method and application

Abstract

A 1H-pyrazole-4-amide derivative having a structure of formula (I), a preparation method thereof, a pharmaceutical composition containing the same, and its use as an inhibitor of FGFR and its mutations, and its use in preparing a drug for treating and / or preventing a tumor or cancer at least partially mediated by FGFR kinase and a tumor patient with tolerance to FGFR inhibitors, and its use in preparing a drug for treating and / or preventing a tumor patient with mutations in V561, V565, N550, N540, V555, E566, K660 and / or V550 of the FGFR signaling pathway. #imgabs0#

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis, and specifically relates to a 1H-pyrazole-4-amide derivative, a preparation method and application thereof. Background Art

[0002] Fibroblast growth factor receptor (FGFR) is a tyrosine kinase receptor that binds to fibroblast growth factor ligands. Four FGFR receptors have been found to bind to ligands. The fibroblast growth factor (FGF) signaling pathway is believed to play an important role in many processes, such as embryogenesis, tissue differentiation, wound healing, metabolic regulation, and is also believed to be strongly associated with the characteristics of many tumors. When FGF binds to its receptor, the receptor dimerizes and phosphorylates, stimulating protein kinase activity and facilitating the activation of a series of intracellular signaling pathways, including Ras-MAPK, AKT-PI3K, and phosphatase C, which are very important for cell growth, proliferation, and survival.

[0003] Genetic changes in FGFR family members are often associated with tumor growth, metastasis, angiogenesis, and survival. Many FGFR inhibitors have shown clinical responses in patients with FGFR abnormalities in clinical trials, and FGFR inhibitors have recently been approved for marketing. However, in clinical trials, it was found that acquired resistance to FGFR inhibitors emerged rapidly, resulting in a relatively short progression-free survival. Mutations affecting FGFR amino acids may cause resistance to FGFR inhibitors or reduce the activity of FGFR inhibitors. Secondary FGFR kinase domain mutations generated under the action of FGFR inhibitors are an important mechanism for acquiring resistance to FGFR inhibition. Corresponding FGFR point mutations also exist in tumors. Gatekeeper mutations have been reported to be one of the main mechanisms for resistance to tyrosine kinases, and FGFR resistance mutations have been reported in both in vitro cell systems and clinical trials. Gatekeeper mutations include FGFR3V555M, FGFR2V565F / V565I / V565L, etc. Recent studies have reported that three patients with cholangiocarcinoma treated with BGJ398 had gatekeeper mutations of FGFR2V565F, and two of them had other mutations in the FGFR2 kinase region. Therefore, in order to break through the acquired resistance to first-generation FGFR inhibitors in the clinic, a new generation of FGFR inhibitors is urgently needed to have more persistent activity in tumors with gene mutations in the FGFR signaling pathway. Such second-generation FGFR inhibitors need to be able to maintain the same activity against gatekeeper mutations that weaken the activity of first-generation inhibitors while maintaining the inhibitory activity against FGFR. Summary of the invention

[0004] The inventors of the present application have developed a 1H-pyrazole-4-amide derivative for the first time after extensive and in-depth research, and its preparation method and application. The series of compounds of the present invention have good activity against mutated FGFRs, especially against FGFRs with gatekeeper mutations, especially against FGFR3 V555M, FGFR2 V565I, FGFR2 V565F, FGFR2 V565L and non-gatekeeper mutation FGFR2 N550K mutations, and are expected to develop a new generation of FGFR inhibitors.

[0005] The first aspect of the present invention provides a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0006]

[0007] in, is a single bond or a double bond;

[0008] X is C or N; Y is CR 6a , N, NR 6b , O or S;

[0009] Ring A is a 3-12-membered nitrogen-containing heterocyclic group, wherein the nitrogen atom is connected to the carbonyl group;

[0010] R 1 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 Alkyl-SF 5 , -C 0-8 Alkyl-S(O) r R 8 , -C 0-8 Alkyl-OR 9 , -C 0-8 Alkyl-C(O)OR 9 , -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 The above groups are optionally further substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, =O, -C 0-8 Alkyl-SF 5 , -C 0-8 Alkyl-S(O) r R 8 , -C 0-8 Alkyl-OR 9 , -C 0-8 Alkyl-C(O)OR 9 , -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 substituted by a substituent;

[0011] Each R 2 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 Alkyl-SF 5 , -C 0-8 Alkyl-S(O) r R 8 , -C 0-8 Alkyl-OR 9 , -C 0-8 Alkyl-C(O)OR 9 , -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 ;

[0012] Each R 3 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 Alkyl-SF 5 , -C 0-8 Alkyl-S(O) r R 8 , -C 0-8 Alkyl-OR 9 , -C 0-8 Alkyl-C(O)OR 9 , -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 ;

[0013] R 4 is selected from vinyl or ethynyl, the above groups are independently optionally further substituted by one or more selected from hydrogen, deuterium, halogen, cyano, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, -C 0-8 Alkyl-C(O)OR 9 , -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-C(O)-NR 7a R 7b and -C 0-8 Alkyl-NR 7a R 7b substituted by a substituent;

[0014] R 5a and R 5b are each independently selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, -C 0-8 Alkyl-C(O)OR 9 , -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-C(=NR 11 )R 10 and -C 0-8 Alkyl-C(O)NR 11 R 12 , or, R 5a and R 5bTogether with the nitrogen atom directly connected thereto, it forms a 4-10 membered heterocyclic group, wherein the above group is optionally further substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, =O, -C 0-8 Alkyl-SF 5 , -C 0-8 Alkyl-S(O) r R 8 , -C 0-8 Alkyl-OR 9 , -C 0-8 Alkyl-C(O)OR 9 , -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 substituted by a substituent;

[0015] R 6a is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 Alkyl-SF 5 , -C 0-8 Alkyl-S(O) r R8 , -C 0-8 Alkyl-OR 9 , -C 0-8 Alkyl-C(O)OR 9 , -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 ;

[0016] R 6b Selected from hydrogen, deuterium, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 5-10 Aryl and 5-10 membered heteroaryl, the above groups are optionally further substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, =O, -C 0-8 Alkyl-SF 5 , -C 0-8 Alkyl-S(O) r R 8 , -C 0-8 Alkyl-OR 9 , -C 0-8 Alkyl-C(O)OR 9 , -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 substituted by a substituent;

[0017] R 7a and R 7b are each independently selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, -C 0-8 Alkyl-C(O)OR 9 , -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-C(=NR 11 )R 10 and -C 0-8 Alkyl-C(O)NR 11 R 12 , or, R 7a and R 7b Together with the nitrogen atom directly connected thereto, it forms a 4-10 membered heterocyclic group, wherein the above group is optionally further substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, =O, -C 0-8 Alkyl-SF 5 , -C 0-8 Alkyl-S(O) r R 8 , -C 0-8 Alkyl-OR 9 , -C 0-8 Alkyl-C(O)OR 9 , -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 substituted by a substituent;

[0018] Each R 8 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl and -NR 11 R 12 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, oxo, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 5-10 Aryl, C 5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR 11 R 12 substituted by a substituent;

[0019] Each R 9 are each independently selected from hydrogen, deuterium, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 5-10 Aryl and 5-10 membered heteroaryl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, oxo, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 5-10 Aryl, C 5-10aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR 11 R 12 substituted by a substituent;

[0020] Each R 10 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 5-10 Aryl, C 5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR 11 R 12 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 5-10 Aryl, C 5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR 11 R 12 substituted by a substituent;

[0021] Each R 11 and R 12 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-10 Alkylamino, di-C 1-10 Alkylamino and C 1-10 Alkanoyl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3-12Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 5-10 Aryl, C 5-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono-C 1-10 Alkylamino, di-G 1-10 Alkylamino and C 1-10 substituted with an alkanoyl substituent;

[0022] Or, R 11 and R 12 The nitrogen atom directly connected thereto forms a 4-10 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 4-10 membered heterocyclic group or the 5-10 membered heteroaryl group is optionally further substituted by one or more selected from deuterium, halogen, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted G 1-10 Alkyl, G 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 5-10 Aryl, C 5-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono C 1-10 Alkylamino, di-C 1-10 Alkylamino and C 1-10 substituted with an alkanoyl substituent;

[0023] m is 0, 1, 2 or 3;

[0024] n is 0, 1, 2, 3 or 4; and

[0025] Each r is independently 0, 1 or 2.

[0026] As a preferred embodiment, in the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, R 1 Selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 5-8 Aryl, 5-8 membered heteroaryl, -C 0-4 Alkyl-SF 5 , -C 0-4 Alkyl-S(O) r R 8 , -C 0-4 Alkyl-OR 9 , -C0-4 Alkyl-C(O)OR 9 , -C 0-4 Alkyl-C(O)R 10 , -C 0-4 Alkyl-OC(O)R 10 , -C 0-4 Alkyl-NR 11 R 12 , -C 0-4 Alkyl-C(=NR 11 )R 10 , -C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R 11 )-C(O)R 10 The above groups are optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 5-8 Aryl, 5-8 membered heteroaryl, =O, -C 0-4 Alkyl-SF 5 , -C 0-4 Alkyl-S(O) r R 8 , -C 0-4 Alkyl-OR 9 , -C 0-4 Alkyl-C(O)OR 9 , -C 0-4 Alkyl-C(O)R 10 , -C 0-4 Alkyl-OC(O)R 10 , -C 0-4 Alkyl-NR 11 R 12 , -C 0-4 Alkyl-C(=NR 11 )R 10 , -C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 Alkyl-C(O)NR 11 R12 and -C 0-4 Alkyl-N(R 11 )-C(O)R 10 substituted by a substituent;

[0027] Each R 2 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 5-8 Aryl, 5-8 membered heteroaryl, -C 0-4 Alkyl-SF 5 , -C 0-4 Alkyl-S(O) r R 8 , -C 0-4 Alkyl-OR 9 , -C 0-4 Alkyl-C(O)OR 9 , -C 0-4 Alkyl-C(O)R 10 , -C 0-4 Alkyl-OC(O)R 10 , -C 0-4 Alkyl-NR 11 R 12 , -C 0-4 Alkyl-C(=NR 11 )R 10 , -C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R 11 )-C(O)R 10 ;

[0028] Each R 3 are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 5-8 Aryl, 5-8 membered heteroaryl, -C0-4 Alkyl-SF 5 , -C 0-4 Alkyl-S(O) r R 8 , -C 0-4 Alkyl-OR 9 , -C 0-4 Alkyl-C(O)OR 9 , -C 0-4 Alkyl-C(O)R 10 , -C 0-4 Alkyl-OC(O)R 10 , -C 0-4 Alkyl-NR 11 R 12 , -C 0-4 Alkyl-C(=NR 11 )R 10 , -C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R 11 )-C(O)R 10 ;

[0029] R 5a and R 5b are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -C 0-4 Alkyl-C(O)OR 9 , -C 0-4 Alkyl-C(O)R 10 , -C 0-4 Alkyl-C(=NR 11 )R 10 and -C 0-4 Alkyl-C(O)NR 11 R 12 , or, R 5a and R 5b Together with the nitrogen atom directly connected thereto, it forms a 4-8 membered heterocyclic group, wherein the above group is optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C5-8 Aryl, 5-8 membered heteroaryl, =O, -C 0-4 Alkyl-SF 5 , -C 0-4 Alkyl-S(O) r R 8 , -C 0-4 Alkyl-OR 9 , -C 0-4 Alkyl-C(O)OR 9 , -C 0-4 Alkyl-C(O)R 10 , -C 0-4 Alkyl-OC(O)R 10 , -C 0-4 Alkyl-NR 11 R 12 , -C 0-4 Alkyl-C(=NR 11 )R 10 , -C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R 11 )-C(O)R 10 substituted by a substituent;

[0030] R 6a Selected from hydrogen, deuterium, halogen, cyano, nitro, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 5-8 Aryl, 5-8 membered heteroaryl, -C 0-4 Alkyl-SF 5 , -C 0-4 Alkyl-S(O) r R 8 , -C 0-4 Alkyl-OR 9 , -C 0-4 Alkyl-C(O)OR 9 , -C 0-4 Alkyl-C(O)R 10 , -C 0-4 Alkyl-OC(O)R 10 , -C 0-4 Alkyl-NR11 R 12 , -C 0-4 Alkyl-C(=NR 11 )R 10 , -C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R 11 )-C(O)R 10 ;

[0031] R 6b Selected from hydrogen, deuterium, C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 5-8 Aryl and 5-8 membered heteroaryl, the above groups are optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 5-8 Aryl, 5-8 membered heteroaryl, =O, -C 0-4 Alkyl-SF 5 , -C 0-4 Alkyl-S(O) r R 8 , -C 0-4 Alkyl-OR 9 , -C 0-4 Alkyl-C(O)OR 9 , -C 0-4 Alkyl-C(O)R 10 , -C 0-4 Alkyl-OC(O)R 10 , -C 0-4 Alkyl-NR 11 R 12 , -C 0-4 Alkyl-C(=NR 11 )R 10 , -C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 Alkyl-C(O)NR 11 R12 and -C 0-4 Alkyl-N(R 11 )-C(O)R 10 substituted by a substituent;

[0032] R7 a and R7 b are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, -C 0-4 Alkyl-C(O)OR 9 , -C 0-4 Alkyl-C(O)R 10 , -C 0-4 Alkyl-C(=NR 11 )R 10 and -C 0-4 Alkyl-C(O)NR 11 R 12 , or, R 7a and R7 b Together with the nitrogen atom directly connected thereto, it forms a 4-8 membered heterocyclic group, wherein the above group is optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 5-8 Aryl, 5-8 membered heteroaryl, =O, -C 0-4 Alkyl-SF 5 , - C 0-4 Alkyl-S(O) r R 8 , -C 0-4 Alkyl-OR 9 , -C 0-4 Alkyl-C(O)OR 9 , -C 0-4 Alkyl-C(O)R 10 , -C 0-4 Alkyl-OC(O)R 10 , -C 0-4 Alkyl-NR 11 R 12 , -C 0-4 Alkyl-C(=NR 11 )R 10 , -C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R 11 )-C(O)R 10 substituted by a substituent;

[0033] Among them, R 8 , R 9 , R 10 , R 11 , R 12 and r are as defined in the compound of formula (I).

[0034] As a further preferred embodiment, the compound of formula (I) is a compound of formula (IIa) or formula (IIb):

[0035]

[0036] Wherein, in the compound of formula (IIa), Y 1 NR 6b , O or S; in the compound of formula (IIb), Y 2 CR 6a or N;

[0037] Each ring A is independently a 3-8 membered nitrogen-containing heterocyclic group, wherein the nitrogen atom is connected to the carbonyl group;

[0038] Each R 1 are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -SF 5 、-S(O) r R 8 、-OR 9 、-C(O)OR 9 、-C(O)R 10 、-OC(O)R 10 、-NR 11 R 12 、-C(=NR 11 )R 10 、-N(R 11 )-C(=NR 12 )R 10 、-C(O)NR 11 R 12 and -N(R 11 )-C(O)R 10 The above groups are optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 5-8 Aryl, 5-8 membered heteroaryl, =O, -SF 5 、-S(O) r R 8 、-OR 9 、-C(O)OR 9 、-C(O)R 10 、-OC(O)R 10 、-NR 11 R 12 、-C(=NR 11 )R 10 、-N(R 11 )-C(=NR 12 )R 10 、-C(O)NR 11 R 12 and -N(R 11 )-C(O)R 10 substituted by a substituent;

[0039] Each R 2a and R 2b are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -SF 5 、-S(O) r R 8 、-OR 9 、-C(O)OR 9 、-C(O)R 10 、-OC(O)R 10 、-NR 11 R 12 、-C(=NR 11 )R 10 、-N(R 11 )-C(=NR 12 )R 10 、-C(O)NR 11 R 12 and -N(R11)-C(O)R 10 ;

[0040] Each R4 Each of them is independently vinyl, and the above groups are independently optionally further substituted with one or more selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -C 0-4 Alkyl-C(O)OR 9 , -C 0-4 Alkyl-C(O)R 10 , -C 0-4 Alkyl-C(O)-NR 7a R 7b and -C 0-4 Alkyl-NR 7a R 7b substituted by a substituent;

[0041] Each R 5a and R 5b are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -C(O)OR 9 、-C(O)R 10 、-C(=NR 11 )R 10 and -C(O)NR 11 R 12 , or, R 5a and R 5b Together with the nitrogen atom directly connected thereto, it forms a 4-6 membered heterocyclic group, wherein the above group is optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -SF 5 、-S(O) r R 8 、-OR 9 、-C(O)OR 9 、-C(O)R 10 、-OC(O)R 10 、-NR 11 R 12 、-C(=NR 11 )R 10 、-N(R 11 )-C(=NR 12 )R 10 、-C(O)NR11 R 12 and -N(R 11 )-C(O)R 10 substituted by a substituent;

[0042] R 6a Selected from hydrogen, deuterium, halogen, cyano, nitro, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -SF 5 、-S(O) r R 8 、-OR 9 、-C(O)OR 9 、-C(O)R 10 、-OC(O)R 10 、-NR 11 R 12 、-C(=NR 11 )R 10 、-N(R 11 )-C(=NR 12 )R 10 、-C(O)NR 11 R 12 and -N(R 11 )-C(O)R 10 ;

[0043] R 6b Selected from hydrogen, deuterium, C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, the above groups are optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, =O, -SF 5 、-S(O) r R 8 、-OR 9 、-C(O)OR 9 、-C(O)R 10 、-OC(O)R 10 、-NR 11 R 12 、-C(=NR 11)R 10 、-N(R 11 )-C(=NR 12 )R 10 、-C(O)NR 11 R 12 and -N(R 11 )-C(O)R 10 substituted by a substituent;

[0044] Each R 7a and R 7b are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, -C(O)OR 9 、-C(O)R 10 、-C(=NR 11 )R 10 and -C(O)NR 11 R 12 , or, R 7a and R 7b Together with the nitrogen atom directly connected thereto, it forms a 4-6 membered heterocyclic group, wherein the above group is optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -SF 5 、-S(O) r R 8 、-OR 9 、-C(O)OR 9 、-C(O)R 10 、-OC(O)R 10 、-NR 11 R 12 、-C(=NR 11 )R 10 、-N(R 11 )-C(=NR 12 )R 10 、-C(O)NR 11 R 12 and -N(R 11 )-C(O)R 10 substituted by a substituent;

[0045] Among them, R 4 , R 8 , R 9 , R 10 , R 11 , R 12and r are as defined in the compound of formula (I).

[0046] As a further preferred embodiment, in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, each ring A is independently:

[0047] As a further preferred embodiment, the compound of formula (I) is a compound of formula (IIIa) or (IIIb):

[0048]

[0049] Wherein, in the compound of formula (IIIa), Y 1 O or S;

[0050] Each R 1 are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-2 Alkyl, C 3-4 Cycloalkyl, 3-4 membered heterocyclic group, -SF 5 、-OR 9 、-C(O)OR 9 、-C(O)R 10 、-OC(O)R 10 and-NR 11 R 12 The above groups are optionally further substituted with one or more selected from deuterium, fluorine, chlorine, bromine, cyano, C 1-2 Alkyl, halogen substituted C 1-2 Alkyl, deuterium substituted C 1-2 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, =O, -SF 5 、-OR 9 、-C(O)OR 9 、-C(O)R 10 、-OC(O)R 10 and-NR 11 R 12 substituted by a substituent;

[0051] Each R 2a and R 2b are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, -SF 5 、-OR 9 、-C(O)OR 9 、-C(O)R 10 、-OC(O)R 10and-NR 11 R 12 ;

[0052] Among them, R 9 , R 10 , R 11 and R 12 As defined in the compounds of formula (I).

[0053] As a further preferred embodiment, in the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, each R 8 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 5-8 Aryl, 5-8 membered heteroaryl and -NR 11 R 12 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 5-8 Aryl, C 5-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR 11 R 12 substituted by a substituent;

[0054] Each R 9 are each independently selected from hydrogen, deuterium, C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 5-8 Aryl and 5-8 membered heteroaryl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, oxo, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 5-8 Aryl, C 5-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR 11 R 12 substituted by a substituent;

[0055] Each R 10 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 5-8 Aryl, C 5-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR 11 R 12 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 5-8 Aryl, C 5-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR 11 R 12 substituted by a substituent;

[0056] Each R 11 and R 12 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 5-8 Aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-4 Alkylamino, di-C 1-4 Alkylamino and C 1-4 Alkanoyl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 5-8 Aryl, C 5-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono C 1-4 Alkylamino, di-C 1-4 Alkylamino and C 1-4 substituted with an alkanoyl substituent;

[0057] Or, R 11 and R 12 The nitrogen atom directly connected thereto forms a 4-10 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 4-10 membered heterocyclic group or the 5-10 membered heteroaryl group is optionally further substituted by one or more selected from deuterium, halogen, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 5-8 Aryl, C 5-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono C 1-4 Alkylamino, di-C 1-4 Alkylamino and C 1-4 The alkanoyl group is substituted with an alkanoyl substituent.

[0058] As a further preferred embodiment, in the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, each R 1 are each independently selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, -SF 5 , methoxy, ethoxy, carboxyl, acetyl, acetoxy, amino, methylamino and dimethylamino, the above groups are optionally further substituted by one or more selected from deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, difluoromethyl, trideuterium, dideuterium, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, =O, -SF 5 , methoxy, ethoxy, carboxyl, acetyl, acetoxy, amino, methylamino and dimethylamino substituents;

[0059] Each R 2a and R 2b are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteriomethyl, dideuteriomethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, -SF 5 , methoxy, ethoxy, carboxyl, acetyl, acetoxy, amino, methylamino and dimethylamino.

[0060] As the most preferred embodiment, the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof include but are not limited to the following compounds:

[0061]

[0062]

[0063]

[0064] The second aspect of the present invention provides a method for preparing a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0065]

[0066] Among them, ring A, X, Y, R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , m and n are as defined in the compound of formula (I).

[0067] The third aspect of the present invention provides a pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0068] The present invention also relates to the use of the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof in the preparation of a drug for treating tumor patients resistant to FGFR inhibitors.

[0069] As a preferred solution, the tumor patient is a tumor patient with mutations in FGFR V561, V565, N550, N540, V555, E566, K660 and / or V550;

[0070] As a further preferred embodiment, the tumor patient is preferably a tumor patient having FGFR2 V565F, V565I, V565L, V565M, N550K, N550H, E566A, E566G, K660M and / or K660Q mutations;

[0071] As a further preferred embodiment, the tumor patient is a tumor patient having FGFR3 V555M / L and / or N540K mutations.

[0072] The present invention also relates to a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof for use in preventing or treating a disease state or condition mediated by FGFR kinase.

[0073] The present invention also relates to a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, for use in preventing or treating tumors or cancers mediated by FGFR kinase.

[0074] As a preferred embodiment, the tumor or cancer is selected from bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, thyroid cancer, skin cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, acute myeloid leukemia, Hodgkin's lymphoma or non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, hairy lymphoma, cell lymphoma, Burkitt's lymphoma, glioblastoma, melanoma or rhabdomyosarcoma.

[0075] The present invention also relates to the use of the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof in the preparation of drugs for treating myeloproliferative diseases, bone or cartilage cell disorders, or hypophosphatemia.

[0076] The present invention also relates to the myeloproliferative disease selected from polycythemia, essential thrombocythemia or primary myelofibrosis; the bone or cartilage cell disorder selected from dysplasia, chondrodysplasia, dwarfism, lethal teratogenicity (TD), Appel's syndrome, Cruzon's syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutaneous striated syndrome, Pfeiffer syndrome or cranial muscular dystrophy syndrome; the hypophosphatemia selected from X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets or tumor-induced ovarian softening.

[0077] The present invention also relates to the use of the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, or the aforementioned pharmaceutical composition as a selective FGFR 2 and / or FGFR 3 inhibitor to treat diseases associated with abnormal expression, mutation of FGFR2 or FGFR3 receptors or abnormal expression and activity of the corresponding ligands.

[0078] The present invention also relates to a method for treating tumor patients who are resistant to FGFR inhibitors, comprising administering a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0079] The present invention also relates to a method for treating patients with tumors having mutations in FGFR2 V565F, V565I, V565L, V565M, N550K, N550H, E566A, E566G, K660M and / or K660Q, comprising administering a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof to a patient in need thereof. DETAILED DESCRIPTION

[0080] The inventors of the present application have developed a 1H-pyrazole-4-amide derivative, its preparation method and application for the first time after extensive and in-depth research. The series of compounds of the present invention have good activity against mutated FGFRs, especially against FGFRs with gatekeeper mutations, especially against FGFR3 V555M, FGFR2 V565I, FGFR2 V565F, FGFR2 V565L and FGFR2 N550K mutations.

[0081] Detailed Description: Unless stated to the contrary or specifically indicated, the following terms used in the specification and claims have the following meanings.

[0082] The term "alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group, preferably a straight or branched alkyl group having 1 to 10, 1 to 6, or 1 to 4 carbon atoms, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, , 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or various branched chain isomers thereof. 1-10 "Alkyl" refers to straight chain alkyl and branched chain alkyl groups including 1 to 10 carbon atoms. 1-4 "Alkyl" refers to straight chain alkyl and branched chain alkyl groups including 1 to 4 carbon atoms. 1-2 "Alkyl" refers to straight chain alkyl and branched chain alkyl groups containing 1 to 2 carbon atoms. 0-8 "Alkyl" refers to straight chain alkyl and branched chain alkyl groups including 0 to 8 carbon atoms. 0-4 "Alkyl" refers to straight chain alkyl and branched chain alkyl groups including 0 to 4 carbon atoms. 0-2 The term "alkyl" refers to straight chain alkyl groups and branched chain alkyl groups having 0 to 2 carbon atoms.

[0083] The alkyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, =O, -C 0-8 Alkyl-SF 5 , -C 0-8 Alkyl-S(O) r R 8 , -C 0-8 Alkyl-OR 9 , -C 0-8 Alkyl-C(O)OR 9 , -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 or -C 0-8 Alkyl-N(R 11 )-C(O)R 10 substituted by a substituent.

[0084] "Cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the partially unsaturated cyclic hydrocarbon refers to a cyclic hydrocarbon that may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a completely conjugated π electron system, and the cycloalkyl group is divided into a monocyclic cycloalkyl group and a polycyclic cycloalkyl group, preferably a cycloalkyl group containing 3 to 12, 3 to 8 or 3 to 6 carbon atoms, for example, "C 3-12 "Cycloalkyl" refers to a cycloalkyl group containing 3 to 12 carbon atoms. 3-8 "Cycloalkyl" refers to a cycloalkyl group containing 3 to 8 carbon atoms. 3-6 "Cycloalkyl" refers to a cycloalkyl group containing 3 to 6 carbon atoms.3-4 "Cycloalkyl" refers to a cycloalkyl group comprising 3 to 4 carbon atoms, wherein:

[0085] Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.

[0086] Polycyclic cycloalkyl groups include cycloalkyl groups of spiro rings, fused rings and bridged rings. "Spiroalkyl" refers to a polycyclic group in which a carbon atom (called a spiro atom) is shared between the single rings. These may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a completely conjugated π electron system. Spiroalkyl groups are divided into monospiroalkyl, dispiroalkyl or polyspiroalkyl groups according to the number of spiro atoms shared between the rings. Spiroalkyl groups include but are not limited to:

[0087]

[0088] "Fused cycloalkyl" refers to a full-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a completely conjugated π electron system. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, and fused cycloalkyl includes but is not limited to:

[0089]

[0090] "Bridged cycloalkyl" refers to a full-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected. These may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a completely conjugated π electron system. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl. Bridged cycloalkyl includes but is not limited to:

[0091]

[0092] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl, including but not limited to indanyl, tetrahydronaphthyl, benzocycloheptanyl and the like.

[0093] Cycloalkyl may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12Cycloalkyl, 3-12 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, =O, -C 0-8 Alkyl-SF 5 , -C 0-8 Alkyl-S(O) r R 8 , -C 0-8 Alkyl-OR 9 , -C 0-8 Alkyl-C(O)OR 9 , -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 or -C 0-8 Alkyl-N(R 11 )-C(O)R 10 substituted by a substituent.

[0094] "Heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the partially unsaturated cyclic hydrocarbon means that the cyclic hydrocarbon may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a completely conjugated π electron system, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen, S(O)(=NH) or S(O) r (wherein r is an integer of 0, 1, 2) heteroatoms, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms are carbon, preferably a heterocyclyl group containing 3 to 12 or 3 to 8 or 3 to 6 ring atoms, for example, "3-4 membered heterocyclyl" refers to a cyclyl group containing 3 to 4 ring atoms, "4-6 membered heterocyclyl" refers to a cyclyl group containing 4 to 6 ring atoms, "3-6 membered heterocyclyl" refers to a cyclyl group containing 3 to 6 ring atoms, "3-8 membered heterocyclyl" refers to a cyclyl group containing 3 to 8 ring atoms, "3-12 membered heterocyclyl" refers to a cyclyl group containing 3 to 12 ring atoms, "4-8 membered heterocyclyl" refers to a cyclyl group containing 4 to 8 ring atoms, and "4-10 membered heterocyclyl" refers to a cyclyl group containing 4 to 10 ring atoms.

[0095] Monocyclic heterocyclic groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.

[0096] Polycyclic heterocyclic groups include spirocyclic, fused and bridged heterocyclic groups. "Spiro heterocyclic group" refers to a polycyclic heterocyclic group in which the single rings share one atom (called a spiro atom), wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen, S(O)(=NH) or S(O) r (where r is an integer of 0, 1, or 2) with the remaining ring atoms being carbon. These may contain one or more double bonds (preferably 1, 2, or 3), but no ring has a completely conjugated π electron system. Spiro heterocyclic groups are classified into mono-, di-, or poly-spiro heterocyclic groups according to the number of spiro atoms shared between the rings. Spiro heterocyclic groups include, but are not limited to:

[0097]

[0098] "Fused heterocyclyl" refers to a polycyclic heterocyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more (preferably 1, 2, 3 or 4) rings may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a completely conjugated π electron system, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen, S(O)(=NH) or S(O) r (where r is an integer of 0, 1, or 2) and the remaining ring atoms are carbon. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic alkyl groups, and fused heterocyclic groups include but are not limited to:

[0099]

[0100] "Bridged heterocyclyl" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, these may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a completely conjugated π electron system, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen, S(O)(=NH) or S(O) r (where r is an integer of 0, 1, or 2) and the remaining ring atoms are carbon. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, and bridged heterocyclic groups include but are not limited to:

[0101]

[0102] The heterocyclic ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic ring, including but not limited to:

[0103]

[0104] The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3 - 12 Cycloalkyl, 3-12 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, =O, -C 0-8 Alkyl-SF 5 , -C 0-8 Alkyl-S(O) r R 8 , -C 0-8 Alkyl-OR 9 , -C 0-8 Alkyl-C(O)OR 9 , -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 or -C 0-8 Alkyl-N(R 11 )-C(O)R 10 substituted by a substituent.

[0105] "Aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group, a polycyclic (i.e., rings with adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably an all-carbon aromatic group containing 5-10 or 5-8 carbon atoms, for example, "C 5-10 "Aryl" refers to a carbon-containing aromatic group containing 5 to 10 carbon atoms. 5-8"Aryl" refers to an all-carbon aromatic group containing 5-8 carbon atoms, including but not limited to phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, including but not limited to:

[0106]

[0107] "Aryl" may be substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, =O, -C 0-8 Alkyl-SF 5 , -C 0-8 Alkyl-S(O) r R 8 , -C 0-8 Alkyl-OR 9 , -C 0-8 Alkyl-C(O)OR 9 , -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 or -C 0-8 Alkyl-N(R 11 )-C(O)R 10 substituted by a substituent.

[0108] "Heteroaryl" refers to a heteroaromatic system containing one or more (preferably 1, 2, 3 or 4) heteroatoms, including nitrogen, oxygen and S(O)r (wherein r is an integer of 0, 1, 2), preferably a heteroaromatic system containing 5-10 or 5-8 or 5-6 ring atoms, for example, "5-8 membered heteroaryl" refers to a heteroaromatic system containing 5-8 ring atoms, and "5-10 membered heteroaryl" refers to a heteroaromatic system containing 5-10 ring atoms, including but not limited to furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, including but not limited to:

[0109]

[0110] "Heteroaryl" may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, =O, -C 0-8 Alkyl-SF 5 , -C 0-8 Alkyl-S(O) r R 8 , -C 0-8 Alkyl-OR 9 , -C 0-8 Alkyl-C(O)OR 9 , -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 or -C0-8 Alkyl-N(R 11 )-C(O)R 10 substituted by a substituent.

[0111] "Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably a straight or branched alkenyl group containing 2-10 or 2-4 carbon atoms, for example, "C 2-10 "Alkenyl" refers to a straight or branched chain alkenyl group containing 2 to 10 carbon atoms. 2-4 "Alkenyl" refers to a straight or branched alkenyl group containing 2 to 4 carbon atoms, including but not limited to ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc.

[0112] "Alkenyl" may be substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, =O, -C 0-8 Alkyl-SF 5 , -C 0-8 Alkyl-S(O) r R 8 , -C 0-8 Alkyl-OR 9 , -C 0-8 Alkyl-C(O)OR 9 , -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 or -C 0-8 Alkyl-N(R 11 )-C(O)R10 substituted by a substituent.

[0113] "Alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably a straight or branched chain alkynyl group containing 2-10 or 2-4 carbon atoms, for example, "C 2-10 "Alkynyl" refers to a straight or branched chain alkynyl group containing 2 to 10 carbon atoms. 2-4 "Alkynyl" refers to a straight or branched chain alkynyl group containing 2-4 carbon atoms, including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, etc.

[0114] "Alkynyl" may be substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, =O, -C 0-8 Alkyl-SF 5 , -C 0-8 Alkyl-S(O) r R 8 , -C 0-8 Alkyl-OR 9 , -C 0-8 Alkyl-C(O)OR 9 , -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 or -C 0-8 Alkyl-N(R 11 )-C(O)R 10 substituted by a substituent.

[0115] "Alkoxy" refers to an -O-alkyl group in which alkyl is as defined above, for example, "C 1-10 "Alkoxy" refers to an alkyloxy group containing 1 to 10 carbon atoms, C 1-4 The term "alkoxy" refers to an alkyloxy group containing 1 to 4 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, butoxy, and the like.

[0116] "Alkoxy" may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, =O, -C 0-8 Alkyl-SF 5 , -C 0-8 Alkyl-S(O) r R 8 , -C 0-8 Alkyl-OR 9 , -C 0-8 Alkyl-C(O)OR 9 , -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 or -C 0-8 Alkyl-N(R 11 )-C(O)R 10 substituted by a substituent.

[0117] "Cycloalkoxy" refers to an -O-cycloalkyl group, wherein cycloalkyl is as defined above, for example, "C 3-12 "Cycloalkyloxy" refers to a cycloalkyloxy group containing 3 to 12 carbon atoms. 3-6The term "cycloalkyloxy" refers to cycloalkyloxy groups containing 3 to 6 carbon atoms, including but not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0118] "Cycloalkoxy" may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, =O, -C 0-8 Alkyl-SF 5 , -C 0-8 Alkyl-S(O) r R 8 , -C 0-8 Alkyl-OR 9 , -C 0-8 Alkyl-C(O)OR 9 , -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 or -C 0-8 Alkyl-N(R 11 )-C(O)R 10 substituted by a substituent.

[0119] "Heterocyclyloxy" refers to an -O-heterocyclyl group, wherein the heterocyclyl group is as defined above, and heterocyclyloxy includes but is not limited to azetidinyloxy, oxetanyloxy, azepentyloxy, nitrogen, oxhexyloxy, and the like.

[0120] "Heterocyclyloxy" may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, =O, -C 0-8 Alkyl-SF 5 , -C 0-8 Alkyl-S(O) r R 8 , -C 0-8 Alkyl-OR 9 , -C 0-8 Alkyl-C(O)OR 9 , -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 or -C 0-8 Alkyl-N(R 11 )-C(O)R 10 substituted by a substituent.

[0121] “C 1-10 "Alkanoyl" refers to C 1-10 The monovalent atomic group remaining after removing the hydroxyl group from the alkyl acid is usually expressed as "C 0-9 -C(O)-", for example, "C 1 -C(O)-" refers to acetyl; "C 2 -C(O)-" refers to propionyl; "C 3 -C(O)-" means butyryl or isobutyryl.

[0122] "-C 0-8 Alkyl-S(O) r R8 ” refers to -S(O) r R 8 The sulfur atom in the 0-8 On the alkyl group, where C 0-8 Alkyl is as defined above.

[0123] "-C 0-8 Alkyl-OR 9 "refers to -OR 9 The oxygen atom in the 0-8 On the alkyl group, where C 0-8 Alkyl is as defined above.

[0124] "-C 0-8 Alkyl-C(O)OR 9 ” means -C(O)OR 9 The carbonyl group in 0-8 On the alkyl group, where C 0-8 Alkyl is as defined above.

[0125] "-C 0-8 Alkyl-C(O)R 10 ” refers to -C(O)R 10 The carbonyl group in 0-8 On the alkyl group, where C 0-8 Alkyl is as defined above.

[0126] "-C 0-8 -OC(O)R 10 ” refers to -OC(O)R 10 The oxygen atom in the 0-8 On the alkyl group, where C 0-8 Alkyl is as defined above.

[0127] "-C 0-8 -NR 11 R 12 ” refers to -NR 11 R 12 The nitrogen atom in the 0-8 On the alkyl group, where C 1-8 Alkyl is as defined above.

[0128] "-C 0-8 -C(=NR 11 )R 10 " refers to -C(=NR 11 )R 10 The nitrogen atom in the 0-8 On the alkyl group, where C 0-8 Alkyl is as defined above.

[0129] "-C 0-8-N(R 11 )-C(=NR 12 )R 10 ” refers to -N(R 11 )-C(=NR 12 )R 10 The nitrogen atom in the 0-8 On the alkyl group, where C 0-8 Alkyl is as defined above.

[0130] "-C 0-8 -C(O)NR 11 R 12 ” refers to -C(O)NR 11 R 12 The carbonyl group in 0-8 On the alkyl group, where C 0-8 Alkyl is as defined above.

[0131] "-C 0-8 -N(R 11 )-C(O)R 10 ” refers to -N(R 11 )-C(O)R 10 The nitrogen atom in the 0-8 On the alkyl group, where C 0-8 Alkyl is as defined above.

[0132] "Halogen-substituted C 1-10 The term "alkyl" refers to an alkyl group of 1 to 10 carbon atoms in which the hydrogen atoms on the alkyl group are optionally replaced by fluorine, chlorine, bromine or iodine atoms, including but not limited to difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl and the like.

[0133] "Halogen-substituted C 1-10 The term "alkoxy" refers to an alkoxy group of 1 to 10 carbon atoms in which the hydrogen atoms on the alkyl group are optionally replaced by fluorine, chlorine, bromine or iodine atoms. It includes but is not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy and the like.

[0134] "Deuterium replaces C 1-10 "Alkyl" refers to an alkyl group of 1 to 10 carbon atoms in which the hydrogen atoms on the alkyl group are optionally replaced by deuterium atoms, including but not limited to monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl, etc.

[0135] "Halogen" refers to fluorine, chlorine, bromine or iodine. "PE" refers to petroleum ether. "EtOAc" refers to ethyl acetate. "DCM" refers to dichloromethane.

[0136] "Optional" or "optionally" means that the event or circumstance described later may but need not occur, and the description includes the occasions where the event or circumstance occurs or does not occur, that is, both substituted and unsubstituted situations are included. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes the situation where the heterocyclic group is substituted with an alkyl group and the situation where the heterocyclic group is not substituted with an alkyl group.

[0137] "Substituted" means that one or more "hydrogen atoms" in a group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, in accordance with the valence bond theory in chemistry, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond (such as an olefin).

[0138] "Stereoisomers" are called stereoisomers in English. They refer to isomers produced by different spatial arrangements of atoms in molecules. They can be divided into two types: cis-trans isomers and enantiomers, or into two major categories: enantiomers and diastereomers. Stereoisomers caused by the rotation of single bonds are called conformational stereo-isomers, sometimes also called rotamers. Stereoisomers caused by bond length, bond angle, double bonds in molecules, rings, etc. are called configuration stereo-isomers, and configuration isomers are divided into two categories. Among them, isomers caused by the inability of double bonds or single bonds of ring carbon atoms to rotate freely are called geometric isomers, also called cis-trans isomers, and are divided into two configurations: Z and E. For example, cis-2-butene and trans-2-butene are a pair of geometric isomers. Stereoisomers with different optical properties due to the absence of anti-axial symmetry in the molecule are called optical isomers, which are divided into R and S configurations. In the present invention, the "stereoisomer" is understood to include one or more of the above-mentioned enantiomers, configurational isomers and conformational isomers unless otherwise specified.

[0139] "Pharmaceutically acceptable salt" in the present invention refers to pharmaceutically acceptable acid addition salts or base addition salts, including inorganic acid salts and organic acid salts, which can be prepared by methods known in the art.

[0140] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0141] The present invention is further described in detail and completely below in conjunction with the embodiments, but the present invention is by no means limited to the contents of the embodiments.

[0142] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (δ) is given in parts per million (ppm). The NMR measurement is performed using a Bruker AVANCE-400 nuclear magnetic spectrometer, and the measurement solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), and the internal standard was tetramethylsilane (TMS).

[0143] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 6120 mass spectrometer, and HPLC was performed using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (GJimini C18 150×4.6 mm column).

[0144] Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0145] The starting materials in the examples of the present invention are known and can be purchased on the market, or can be synthesized by or according to methods known in the art.

[0146] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature is in degrees Celsius (°C).

[0147] 1. Preparation of intermediates

[0148] Intermediate 1: Preparation of 2-cyclopropyl-7-ethynyl-6,8-difluoroimidazo[1,2-a]pyridine

[0149]

[0150] Step 1: Synthesis of 2-cyclopropyl-6,8-difluoro-7-iodoimidazo[1,2-a]pyridine

[0151]

[0152] 3,5-difluoro-4-iodopyridin-2-amine (1.0 g, 4.0 mmol) was dissolved in DMF (10 mL) and 2-bromo-1-cyclopropylethane-1-one (0.98 g, 6.0 mmol) was added. The mixture was stirred at 60°C for 16 hours. After cooling to room temperature, 2-cyclopropyl-6,8-difluoro-7-iodoimidazo[1,2-a]pyridine (640 mg, yield: 50%) was obtained by filtration. MS m / z (ESI): 321 [M+H] + .

[0153] Step 2: Synthesis of 2-cyclopropyl-7-ethynyl-6,8-difluoroimidazo[1,2-a]pyridine

[0154]

[0155] Dissolve 2-cyclopropyl-6,8-difluoro-7-iodoimidazo[1,2-a]pyridine (320 mg, 1.0 mmol) in DMF (5 mL), add tributyl(ethynyl)stannane (472 mg, 1.5 mmol) and tetrakistriphenylphosphine palladium (115.5 mg, 0.1 mmol). Stir the mixture at 130°C for 1 hour in a microwave oven. Cool to room temperature, concentrate and separate by column chromatography to obtain 2-cyclopropyl-7-ethynyl-6,8-difluoroimidazo[1,2-a]pyridine (120 mg, yield: 55%). MS m / z (ESI): 219 [M+H] + .

[0156] Intermediate 2: Preparation of 2-cyclopropyl-7-ethynyl-6-fluoroimidazo[1,2-a]pyridine

[0157]

[0158] Step 1: Synthesis of 2-cyclopropyl-6-fluoro-7-iodoimidazo[1,2-a]pyridine

[0159]

[0160] 5-Fluoro-4-iodopyridin-2-amine (2.38 g, 10.0 mmol) was dissolved in DMF (20 mL) and 2-bromo-1-cyclopropylethane-1-one (2.44 g, 15.0 mmol) was added. The mixture was stirred at 60°C for 16 hours. After cooling to room temperature, 2-cyclopropyl-6-fluoro-7-iodoimidazo[1,2-a]pyridine (2.20 mg, yield: 73%) was obtained by filtration. MS m / z (ESI): 303 [M+H] + .

[0161] Step 2: Synthesis of 2-cyclopropyl-7-ethynyl-6-fluoroimidazo[1,2-a]pyridine

[0162]

[0163] Dissolve 2-cyclopropyl-6-fluoro-7-iodoimidazo[1,2-a]pyridine (540 mg, 2.0 mmol) in DMF (10 mL), add tributyl(ethynyl)stannane (1260 mg, 4.0 mmol) and tetrakistriphenylphosphine palladium (116 mg, 0.1 mmol). Stir the mixture at 60°C for 16 hours. Cool to room temperature, concentrate and separate by column chromatography to obtain 2-cyclopropyl-7-ethynyl-6-fluoroimidazo[1,2-a]pyridine (140 mg, yield: 40%). MS m / z (ESI): 175 [M+H] + .

[0164] Intermediate 3 is prepared by selecting corresponding raw materials according to all or part of the synthetic method of Intermediate 2:

[0165]

[0166] Intermediate 4: Preparation of 2-cyclopropyl-5-ethynylbenzo[d]oxazole

[0167]

[0168] Step 1: Synthesis of N-(5-bromo-2-hydroxyphenyl)cyclopropanecarboxamide

[0169]

[0170] 2-Amino-4-bromophenol (2.0 g, 10.6 mmol) was dissolved in DCM (30 mL), and triethylamine (1.29 g, 12.8 mmol) and cyclopropylcarbonyl chloride (1.11 g, 10.6 mmol) were added in sequence at 0°C. The mixture was stirred at 0°C for 1 hour, diluted with aqueous sodium bicarbonate solution and extracted with DCM. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, column chromatography was performed to obtain N-(5-bromo-2-hydroxyphenyl)cyclopropylcarboxamide (1.34 g, yield: 49%). MS m / z (ESI): 256 / 258 [M+H] + Step 2: Synthesis of 5-bromo-2-cyclopropylbenzo[d]oxazole

[0171]

[0172] N-(5-bromo-2-hydroxyphenyl)cyclopropanecarboxamide (1.04 g, 4.06 mmol) was dissolved in acetonitrile (30 mL), and triphenylphosphine (4.26 g, 16.2 mmol) and carbon tetrachloride (1.25 g, 8.1 mmol) were added in sequence at room temperature. The mixture was stirred at 60°C for 1 hour, diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, 5-bromo-2-cyclopropylbenzo[d]oxazole (548 mg, yield: 55%) was obtained by column chromatography. MS m / z (ESI): 238 / 240 [M+H] + .

[0173] Step 3: Synthesis of 2-cyclopropyl-5-((trimethylsilyl)ethynyl)benzo[d]oxazole

[0174]

[0175] 5-Bromo-2-cyclopropylbenzo[d]oxazole (200 mg, 0.84 mmol) was placed in DMF (3 mL), and triethylamine (1 mL), cuprous iodide (16 mg, 0.084 mmol), trimethylsilyl acetylene (825 mg, 8.4 mmol), and tetrakistriphenylphosphine palladium (49 mg, 0.042 mmol) were added in sequence at room temperature. The mixture was stirred at 80°C for 16 hours, diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, 2-cyclopropyl-5-((trimethylsilyl)ethynyl)benzo[d]oxazole (204 mg, yield: 95%) was obtained by column chromatography. MS m / z (ESI): 256 [M+H] + .

[0176] Step 4: Synthesis of 2-cyclopropyl-5-ethynylbenzo[d]oxazole

[0177]

[0178] 2-Cyclopropyl-5-((trimethylsilyl)ethynyl)benzo[d]oxazole (204 mg, 0.8 mmol) was dissolved in methanol (8 mL), and potassium carbonate (1.1 g, 8 mmol) was added at room temperature. The mixture was stirred at room temperature for 1 hour, diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, 2-cyclopropyl-5-ethynylbenzo[d]oxazole (112 mg, yield: 76%) was separated by column chromatography. MS m / z (ESI): 184 [M+H] + .

[0179] Intermediates 5-8 are prepared by selecting corresponding raw materials according to all or part of the synthetic method of Intermediate 4:

[0180]

[0181] Intermediate 9: Preparation of 2-cyclopropyl-5-ethynyl-6-fluorobenzo[d]thiazole

[0182]

[0183] Step 1: Synthesis of N-(5-bromo-2,4-difluorophenyl)cyclopropanecarboxamide

[0184]

[0185] Dissolve 5-bromo-2,4-difluoroaniline (1.04 g, 5.0 mmol) in dichloromethane (20 mL), add cyclopropanoyl chloride (572 mg, 5.5 mmol), stir overnight at room temperature, spin dry directly and separate by column chromatography to obtain N-(5-bromo-2,4-difluorophenyl)cyclopropanecarboxamide (1.0 g, yield: 72%). MS m / z (ESI): 276 / 278 [M+H] + .

[0186] Step 2: Synthesis of N-(5-bromo-2,4-difluorophenyl)cyclopropylmethylthioamide

[0187]

[0188] Dissolve N-(5-bromo-2,4-difluorophenyl)cyclopropanecarboxamide (1.0 g, 3.6 mmol) and Lawesson's reagent (750 mg, 1.85 mmol) in acetonitrile (25 mL), heat to 85°C, and stir overnight. After the reaction, the N-(5-bromo-2,4-difluorophenyl)cyclopropanecarboxamide solution was directly used for the next experiment. MS m / z (ESI): 292 / 294 [M+H] + .

[0189] Step 3: Synthesis of 5-bromo-2-cyclopropyl-6-fluorobenzo[d]thiazole

[0190]

[0191] Sodium tert-butoxide (1.7 g, 18 mmol) was added to the cooled N-(5-bromo-2,4-difluorophenyl)cyclopropylmethylthioamide solution, and the mixture was heated to 50°C and stirred for 16 hours. After concentration, 5-bromo-2-cyclopropyl-6-fluorobenzo[d]thiazole (0.82 g, yield: 83%) was obtained by column chromatography. MS m / z (ESI): 2712 / 274 [M+H] + .

[0192] Step 4: Synthesis of 2-cyclopropyl-5-ethynyl-6-fluorobenzo[d]thiazole

[0193]

[0194] 5-Bromo-2-cyclopropyl-6-fluorobenzo[d]thiazole (0.82 g, 3.0 mmol) was dissolved in DMF (15 mL), tributyl(ethynyl)stannane (1.9 g, 6.0 mmol) and tetrakistriphenylphosphine palladium (173 mg, 0.15 mmol) were added and stirred at 130 ° C in a microwave reactor for 0.5 hours. After concentration, column chromatography was performed to obtain 2-cyclopropyl-5-ethynyl-6-fluorobenzo[d]thiazole (0.16 g, yield: 25%). MS m / z (ESI): 218 [M+H] + .

[0195] Intermediates 10-14 are prepared by selecting corresponding raw materials according to all or part of the synthetic method of intermediate 9:

[0196]

[0197] Intermediate 15: Preparation of 2-cyclopropyl-5-ethynyl-4,6-difluorobenzo[d]thiazole

[0198]

[0199] Step 1: Synthesis of N-(2,4-difluorophenyl)cyclopropanecarboxamide

[0200]

[0201] Dissolve 2,4-difluoroaniline (10 g, 77.45 mmol) in dichloromethane (100 mL), add triethylamine (15.64 g, 154.9 mmol), add cyclopropylcarbonyl chloride (8.1 g, 77.45 mmol) dropwise under ice bath, and stir overnight at room temperature. The reaction solution is washed with appropriate amount of saturated ammonium chloride aqueous solution and saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography to obtain N-(2,4-difluorophenyl)cyclopropylcarboxamide (10.1 g, yield: 66%). MS m / z (ESI): 196 [M+H] + .

[0202] Step 2: Synthesis of N-(2,4-difluorophenyl)cyclopropylmethylthioamide

[0203]

[0204] Dissolve N-(2,4-difluorophenyl)cyclopropylcarboxamide (5 g, 25.36 mmol) in xylene (80 mL), add Lawesson's reagent (7.18 g, 17.75 mmol), heat to 120°C and stir overnight. After concentration, directly separate by silica gel column chromatography to obtain N-(2,4-difluorophenyl)cyclopropylcarboxamide (4.1 g, yield: 75%). MS m / z (ESI): 212 [M+H] + .

[0205] Step 3: Synthesis of 2-cyclopropyl-4,6-difluorobenzo[d]thiazole

[0206]

[0207] N-(2,4-difluorophenyl)cyclopropylmethylthioamide (1g, 4.69mmol) was dissolved in sodium hydroxide solution (1.69g, 42.2mmol, 5mL ethanol and 10mL water), and the resulting solution was added dropwise to a K3Fe(CN)6 aqueous solution (6.18g, 18.78mmol, 10mL water) preheated to 90°C. After stirring for 2 hours, the heating was immediately stopped, and after cooling, the solution was adjusted to weak acidity with concentrated hydrochloric acid, extracted with ethyl acetate, and the resulting extract was washed with saturated brine, concentrated, and separated by silica gel column chromatography to obtain 2-cyclopropyl-4,6-difluorobenzo[d]thiazole (500mg, yield: 51%). MS m / z(ESI): 212[M+H] + .

[0208] Step 4: Synthesis of 2-cyclopropyl-4,6-difluorobenzo[d]thiazole-5-carboxaldehyde

[0209]

[0210] 2-Cyclopropyl-4,6-difluorobenzo[d]thiazole (980 mg, 4.64 mmol) was dissolved in tetrahydrofuran (15 mL) and cooled to -70°C. LDA (2.55 mL, 5.10 mmol, 2 M) was added dropwise. After maintaining the temperature for 2 hours, DMF (1.01 g, 13.92 mmol) was added. After maintaining the temperature for 2 hours, the reaction was completed by LCMS monitoring. An appropriate amount of ammonium chloride aqueous solution was added to quench the reaction and the temperature was raised to room temperature. The reaction solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated, and separated by silica gel column chromatography to obtain 2-cyclopropyl-4,6-difluorobenzo[d]thiazole-5-carboxaldehyde (675 mg, yield: 65%). MS m / z (ESI): 240 [M+H] + .

[0211] Step 5: Synthesis of 2-cyclopropyl-5-ethynyl-4,6-difluorobenzo[d]thiazole

[0212]

[0213] 2-Cyclopropyl-4,6-difluorobenzo[d]thiazole-5-carboxaldehyde (122 mg, 0.51 mmol) was dissolved in methanol (10 mL), potassium carbonate (211 mg, 1.53 mmol) and (1-diazo-2-oxo-propanol)-phosphonic acid dimethyl ester (159 mg, 0.76 mmol) were added in sequence, and stirred at room temperature overnight. After direct concentration, 2-cyclopropyl-5-ethynyl-4,6-difluorobenzo[d]thiazole (73 mg, yield: 61%) was obtained by separation by silica gel column chromatography. MS m / z (ESI): 236 [M+H] + .

[0214] Intermediate 16 is prepared by selecting corresponding raw materials according to all or part of the synthetic method of intermediate 15:

[0215]

[0216]

[0217] Intermediate 17: Preparation of 5-ethynyl-6-fluoro-N-methylbenzo[d]oxazol-2-amine

[0218]

[0219] Step 1: Synthesis of 2-amino-4-bromo-5-fluorophenol

[0220]

[0221] 4-Bromo-5-fluoro-2-nitrophenol (5.00 g, 21.2 mmol) was dissolved in tetrahydrofuran / water (60 mL / 30 mL), and ammonium chloride (5.66 g, 105.9 mmol) and zinc powder (6.89 g, 105.9 mmol) were added in sequence at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction solution was filtered, washed with ethyl acetate (50 mL), separated and extracted, and the organic phase was concentrated and separated by column chromatography to obtain 2-amino-4-bromo-5-fluorophenol (3.2 g, yield: 73%). MS m / z (ESI): 206 / 208 [M+H] + .

[0222] Step 2: Synthesis of 5-bromo-6-fluorobenzo[d]oxazole-2(3H)-thione

[0223]

[0224] 2-Amino-4-bromo-5-fluorophenol (3.2 g, 15.5 mmol) was placed in ethanol (50 mL), and potassium ethylsulfonate (2.48 g, 15.5 mmol) was added at room temperature. The mixture was stirred at 80°C for 17 hours. The reaction solution was directly concentrated and separated by column chromatography to obtain 5-bromo-6-fluorobenzo[d]oxazole-2(3H)-thione (1.80 g, yield: 47%). MS m / z (ESI): 248 / 250 [M+H] + Step 3: Synthesis of 5-bromo-2-chloro-6-fluorobenzo[d]oxazole

[0225]

[0226] 5-Bromo-6-fluorobenzo[d]oxazole-2(3H)-thione (1.76 g, 7.1 mmol) was dissolved in dichloromethane (15 mL), and N,N-dimethylformamide (0.5 mL) and thionyl chloride (5.0 mL, 68.9 mmol) were added successively at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was diluted with dichloromethane (100 mL), washed with saturated sodium bicarbonate solution (50 mL) and brine (50 mL) successively, and dried over anhydrous sodium sulfate. After suction filtration, the filtrate was concentrated and separated by column chromatography to obtain 5-bromo-2-chloro-6-fluorobenzo[d]oxazole (1.30 g, yield: 73%).

[0227] Step 4: Synthesis of 5-bromo-6-fluoro-N-methylbenzo[d]oxazol-2-amine

[0228]

[0229] 5-Bromo-2-chloro-6-fluorobenzo[d]oxazole (250 mg, 1.0 mmol) was placed in acetonitrile (5 mL), and methylamine aqueous solution (1.0 mL, mass fraction 25-30%) was added at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with brine, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain 5-bromo-6-fluoro-N-methylbenzo[d]oxazol-2-amine (245 mg, yield: 100%). MS m / z (ESI): 245 / 247 [M+H] + .

[0230] Step 5: Synthesis of 6-fluoro-N-methyl-5-((trimethylsilyl)ethynyl)benzo[d]oxazol-2-amine

[0231]

[0232] 5-Bromo-6-fluoro-N-methylbenzo[d]oxazol-2-amine (190 mg, 0.78 mmol) was placed in 1,4-dioxane / N,N-dimethylformamide (10 mL / 1 mL), and tributyl(trimethylsilylethynyl)tin (600 mg, 1.55 mmol) and tetrakistriphenylphosphine palladium (90 mg, 0.08 mmol) were added at room temperature. The mixture was reacted at 120°C in a microwave for 6 hours. The reaction solution was directly concentrated and separated by column chromatography to obtain 6-fluoro-N-methyl-5-((trimethylsilyl)ethynyl)benzo[d]oxazol-2-amine (158 mg, yield: 78%). MS m / z (ESI): 263 [M+H] + .

[0233] Step 6: Synthesis of 5-ethynyl-6-fluoro-N-methylbenzo[d]oxazol-2-amine

[0234]

[0235] 6-Fluoro-N-methyl-5-((trimethylsilyl)ethynyl)benzo[d]oxazol-2-amine (158 mg, 0.60 mmol) was placed in methanol (10 mL), and potassium carbonate (248 mg, 1.80 mmol) was added at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction solution was directly concentrated and separated by column chromatography to obtain 5-ethynyl-6-fluoro-N-methylbenzo[d]oxazol-2-amine (95 mg, yield: 83%). MS m / z (ESI): 191 [M+H] + .

[0236] Intermediates 18-20 are prepared by selecting corresponding raw materials according to all or part of the synthetic method of intermediate 17:

[0237]

[0238] Intermediate 21: Preparation of 2-(azetidin-1-yl)-5-ethynyl-4,6-difluorobenzo[d]oxazole

[0239]

[0240] Step 1: Synthesis of 2-amino-3,5-difluorophenol

[0241]

[0242] Dissolve 3,5-difluoro-2-nitrophenol (10 g, 57.11 mmol) in methanol (100 mL), add palladium carbon (1 g), stir overnight at room temperature, filter, and spin-dry the filtrate to obtain 2-amino-3,5-difluorophenol (8.5 g, yield: 100%). MS m / z (ESI): 146 [M+H] + .

[0243] Step 2: Synthesis of 4,6-difluorobenzo[d]oxazole-2-thiol

[0244]

[0245] Dissolve 2-amino-3,5-difluorophenol (8.5 g, 58.62 mmol) in ethanol (100 mL), add potassium O-ethyl disulfate (1.13 g, 70.34 mmol), and heat to 95°C overnight. Cool and filter, concentrate the filtrate, and separate by silica gel column chromatography to obtain 4,6-difluoro-1,3-benzoxazole-2-thiol (11 g, yield: 95.31%). MS m / z (ESI): 188 [M+H] + .

[0246] Step 3: Synthesis of 2-chloro-4,6-difluorobenzo[d]oxazole

[0247]

[0248] 4,6-difluoro-1,3-benzoxazole-2-thiol (4 g, 21.37 mmol) was dissolved in dichloromethane (50 mL), oxalyl chloride (10.85 g, 85.48 mmol) and N,N-dimethylformamide (0.16 g, 2.14 mmol) were added, stirred at room temperature for 2 hours, and then dried to obtain crude 2-chloro-4,6-difluorobenzo[d]oxazole (4.05 g, yield: 100%), which was directly used in the next step. MSm / z(ESI): 190[M+H] + .

[0249] Step 4: Synthesis of 2-(azetidin-1-yl)-4,6-difluorobenzo[d]oxazole

[0250]

[0251] The crude product of 2-chloro-4,6-difluorobenzo[d]oxazole (4.05 g, 21.36 mmol) was dissolved in tetrahydrofuran (50 mL), and N,N-diisopropylethylamine (5.51 g, 42.72 mmol) and azocyclobutane hydrochloride (2.40 g, 25.63 mmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction solution was dried by rotary evaporation, ethyl acetate was added, and the mixture was washed twice with saturated aqueous ammonium chloride solution and saturated brine. The mixture was dried with sodium sulfate and filtered. The filtrate was concentrated and separated by silica gel column chromatography to obtain 2-(azetidine-1-yl)-4,6-difluorobenzo[d]oxazole (3.2 g, yield: 72%). MS m / z (ESI): 211 [M+H] + .

[0252] Step 5: Synthesis of 2-(azetidin-1-yl)-4,6-difluorobenzo[d]oxazole-5-carboxaldehyde

[0253]

[0254] 2-(azetidine-1-yl)-4,6-difluorobenzo[d]oxazole (3 g, 14.28 mmol) was dissolved in tetrahydrofuran (100 ml), cooled to -70°C, and a solution of lithium diisopropylamide in tetrahydrofuran (10.7 mL, 21.41 mmol, 2 M) was added dropwise. The mixture was stirred at low temperature for 1 hour, and then N,N-dimethylformamide (11.04 mL, 142.73 mmol) was added at once. The mixture was stirred at low temperature for 2 hours. An appropriate amount of saturated aqueous ammonium chloride solution was added to quench the reaction. After warming to room temperature, the mixture was extracted twice with ethyl acetate. The ethyl acetate phases were combined, washed twice with saturated brine, dried over sodium sulfate, and filtered to obtain a filtrate. After concentration, the mixture was separated by silica gel column chromatography to obtain 2-(azetidine-1-yl)-4,6-difluorobenzo[d]oxazole-5-carboxaldehyde (0.8 g, yield: 24%). MS m / z (ESI): 239 [M+H] + .

[0255] Step 6: Synthesis of 2-(azetidin-1-yl)-5-ethynyl-4,6-difluorobenzo[d]oxazole

[0256]

[0257] 2-(azetidine-1-yl)-4,6-difluorobenzo[d]oxazole-5-carboxaldehyde (0.8 g, 3.40 mmol) was dissolved in methanol (10 mL) and tetrahydrofuran (10 mL), potassium carbonate (1.17 g, 8.5 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (1.31 g, 6.801 mmol) were added, stirred at room temperature for two hours, concentrated, and an appropriate amount of saturated aqueous ammonium chloride solution was added to quench the reaction. After warming to room temperature, the mixture was extracted twice with ethyl acetate, combined, washed twice with saturated brine, dried with sodium sulfate, and filtered to obtain a filtrate, which was concentrated and separated by silica gel column chromatography to obtain 2-(azetidine-1-yl)-5-ethynyl-4,6-difluorobenzo[d]oxazole (0.75 g, yield: 94%). MSm / z(ESI): 235[M+H] + .

[0258] Intermediate 22 is prepared by selecting corresponding raw materials according to all or part of the synthetic method of intermediate 21:

[0259]

[0260] Intermediate 23: Preparation of (S)-1-(1-acryloylpyrrolidin-3-yl)-5-amino-3-bromo-1H-pyrazole-4-carboxamide

[0261]

[0262] Step 1: Synthesis of 3-amino-5-bromo-1H-pyrazole-4-carbonitrile

[0263]

[0264] 3-amino-1H-pyrazole-4-carbonitrile (25.0 g, 231 mmol) was dissolved in DMF (200 mL), and N-bromosuccinimide (42.0 g, 236 mmol) was added in batches under an ice bath. After the addition, the temperature was slowly raised to room temperature and stirring was continued for 2 hours. After the reaction was completed, water was added, and ethyl acetate was extracted. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by column chromatography to obtain 3-amino-5-bromo-1H-pyrazole-4-carbonitrile (14.7 g, yield: 34%). MS m / z (ESI): 187 / 189 [M+H] + .

[0265] Step 2: Synthesis of tert-butyl (S)-3-(5-amino-3-bromo-4-cyano-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate

[0266]

[0267] 3-Amino-5-bromo-1H-pyrazole-4-carbonitrile (14.7 g, 78.6 mmol) and tert-butyl (R)-3-(tosyloxy)pyrrolidine-1-carboxylate (322 g, 94.3 mmol) were dissolved in DMF (200 mL) and cesium carbonate (51.2 g, 1572 mmol) was added. The reaction was stirred at 90 ° C for 18 hours. After the reaction was completed, it was cooled to room temperature, water was added, and extracted with ethyl acetate. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by column chromatography to obtain tert-butyl (S)-3-(5-amino-3-bromo-4-cyano-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (7.5 g, yield: 26.8%). MS m / z (ESI): 300 / 302 [M+H] + Step 3: Synthesis of tert-butyl (S)-3-(5-amino-3-bromo-4-carbamoyl-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate

[0268]

[0269] Tert-butyl (S)-3-(5-amino-3-bromo-4-cyano-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (1.85 g, 5.19 mmol) was dissolved in DMSO (30 mL), and sodium hydroxide (208 mg, 5.19 mmol) aqueous solution (10 mL) was added. Hydrogen peroxide solution (30 wt%, 16.4 mL) was slowly added under ice bath cooling. After the addition, the mixture was warmed to room temperature and stirred for 2 hours. After the reaction was completed, saturated brine was added and extracted with ethyl acetate. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was separated by column chromatography to obtain tert-butyl (S)-3-(5-amino-3-bromo-4-carbamoyl-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (1.24 g, yield: 63.8%). MS m / z (ESI): 374 / 376 [M+H] + .

[0270] Step 4: Synthesis of (S)-5-amino-3-bromo-1-(pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide hydrochloride

[0271]

[0272] Tert-butyl (S)-3-(5-amino-3-bromo-4-carbamoyl-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (1.24 g, 3.31 mmol) was dissolved in dichloromethane (15 mL), and hydrochloric acid ethanol solution (10 M, 3.3 mL, 33 mmol) was added at room temperature. After the addition, stirring was continued for 30 minutes until the reaction was completed, and the reaction system was directly concentrated. The crude product can be directly used in the next step without separation to obtain (S)-5-amino-3-bromo-1-(pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide hydrochloride (1.03 g, yield: 100%). MS m / z (ESI): 274 / 276 [M+H] + .

[0273] Step 5: Synthesis of (S)-1-(1-acryloylpyrrolidin-3-yl)-5-amino-3-bromo-1H-pyrazole-4-carboxamide

[0274]

[0275] (S)-5-amino-3-bromo-1-(pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide hydrochloride (1.03 g, 3.31 mmol) and sodium bicarbonate (836 mg, 9.95 mmol) were dissolved in THF / water (10 / 2 mL), and acryloyl chloride (300 mg, 3.31 mmol) was slowly added dropwise under ice bath. After the addition was completed, the ice bath was removed and stirring was continued for 30 minutes. After the reaction was completed, saturated brine was added and extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the target product (S)-1-(1-acryloylpyrrolidin-3-yl)-5-amino-3-bromo-1H-pyrazole-4-carboxamide (930 mg, yield: 85.5%). MS m / z (ESI): 328 / 330 [M+H] + .

[0276] 2. Preparation of Specific Embodiments

[0277] Example 1: Preparation of (S)-1-(1-acryloylpyrrolidin-3-yl)-5-amino-3-((2-cyclopropyl-6-fluorobenzo[d]thiazol-5-yl)ethynyl)-1H-pyrazole-4-carboxamide

[0278]

[0279] (S)-1-(1-acryloylpyrrolidin-3-yl)-5-amino-3-bromo-1H-pyrazole-4-carboxamide (200 mg, 0.61 mmol), 2-cyclopropyl-5-ethynyl-6-fluorobenzo[d]thiazole (170 mg, 0.79 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (35.2 mg, 0.03 mmol) and cuprous iodide (11.4 mg, 0.06 mmol) were dissolved in N,N-dimethylformamide (5 mL), and triethylamine (1 mL) was added. The mixture was stirred in a microwave at 130° C. for 2 hours. After concentration, column chromatography was used to separate (S)-1-(1-acryloylpyrrolidin-3-yl)-5-amino-3-((2-cyclopropyl-6-fluorobenzo[d]thiazol-5-yl)ethynyl)-1H-pyrazole-4-carboxamide (130 mg, yield: 45.8%). MS m / z (ESI): 465 [M+H] + .

[0280] 1 H NMR (400 MHz, DMSO-d 6 ): δ8.12 (dd, J=9.6, 7.6Hz, 2H), 7.35 (brs, 1H), 6.76-6.51 (m, 3H), 6.22-6.13 (m, 1H), 5.80-5.61 (m, 1H), 5.09 -4.90 (m, 1H), 4.08-3.76 (m, 2H), 3.76-3.47 (m, 2H), 2.63-2.53 (m, 1H), 2.47-2.10 (m, 2H), 1.38-1.05 (m, 4H).

[0281] Examples 2 to 22 are prepared by selecting corresponding raw materials according to all or part of the synthesis method of Example 1:

[0282]

[0283]

[0284]

[0285]

[0286]

[0287] The NMR data of the compound prepared in the above example are as follows:

[0288]

[0289]

[0290] Biological test evaluation

[0291] 1. BaF3-Tel-FGFR2 WT and various mutant FGFR2 cell proliferation assays

[0292] The compounds of the embodiments of the present invention are used to stably express TEL-FGFR2 WT intracellular kinase domain fusion protein or cell lines containing FGFR2 V564I, V564F, V564L, N549K, K659M mutant intracellular domain fusion protein in Baf cells by transfection to determine the proliferation effect of Baf3-Tel-FGFR2 WT and various mutant FGFR2 cells. The specific test process is as follows:

[0293] 1) 90 μL of cell suspension in growth medium (DMEM containing 1% Glutamax, 10% FBS and 1% Pen / Strep) (a total of 2000-4000 cells per well) was seeded in a 96-well plate and then incubated at 37°C and 5% CO 2 Incubate overnight.

[0294] 2) Add 10 μL of growth medium containing 10x stock solution of test compound to the cell culture (9 dose points, 3x serial dilutions, starting from 1 μM, final 0.3% DMSO).

[0295] 3) At 37°C and 5% CO 2 Incubate for 48 hours.

[0296] 4) A volume of 50 μL of CellTiter Glo (CTG) reagent was added to the 96-well plate containing the cells and the plate was incubated at room temperature for 10 minutes.

[0297] 5) RLU (Relative Light Units) were measured on a microplate reader with a luminescence detection module. RLU values ​​were normalized to % survival and concentration-response curves were plotted using Prism to calculate IC 50 (Unit: nM), the test results are shown in the following table.

[0298]

[0299]

[0300] II. BaF3-Tel-FGFR3 WT and FGFR3V555M Cell Proliferation Assay

[0301] The compounds of the present invention are used to stably express TEL-FGFR3WT intracellular kinase domain fusion protein or cell lines containing FGFR3V555M mutated intracellular domain fusion protein in Baf cells by transfection to determine the proliferation effect of BaF3-Tel-FGFR3 WT and R3V555M cells. The specific test process is as follows:

[0302] 1) 90 μL of cell suspension in growth medium (DMEM containing 1% Glutamax, 10% FBS and 1% Pen / Strep) (a total of 2000-4000 cells per well) was seeded in a 96-well plate and then incubated at 37°C and 5% CO 2 Incubate overnight.

[0303] 2) Add 10 μL of growth medium containing 10x stock solution of test compound to the cell culture (9 dose points, 3x serial dilutions, starting from 1 μM, final 0.3% DMSO).

[0304] 3) At 37°C and 5% CO 2 Incubate for 48 hours.

[0305] 4) A volume of 50 μL of CellTiter Glo (CTG) reagent was added to the 96-well plate containing the cells and the plate was incubated at room temperature for 10 minutes.

[0306] 5) RLU (Relative Light Units) were measured on a microplate reader with a luminescence detection module. RLU values ​​were normalized to % survival and concentration-response curves were plotted using Prism to calculate IC 50 (Unit: nM), the test results are shown in the following table.

[0307]

[0308]

[0309] From the biological activity data of the compounds in the specific examples, it can be seen that the series of compounds of the present invention have a strong inhibitory effect on both wild-type FGFR and mutant FGFR at the cellular level, and the inhibitory effect is not weakened in the mutant.

[0310] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as references separately. In addition, it should be understood that after reading the above disclosure of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: The compound of formula (I) has the structure of formula (IIIa) or formula (IIIb): in, In the compound of formula (IIIa), Y1 is O or S; Each R1 is independently selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, -SF5, methoxy, ethoxy, carboxyl, acetyl, acetoxy, amino, methylamino and dimethylamino, and the above groups are optionally further substituted with one or more substituents selected from deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, difluoromethyl, trideuteriummethyl, dideuteriummethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, =O, -SF5, methoxy, ethoxy, carboxyl, acetyl, acetoxy, amino, methylamino and dimethylamino; Each R 2a and R 2b Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteriomethyl, dideuteriomethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, -SF5, methoxy, ethoxy, carboxyl, acetyl, acetoxy, amino, methylamino and dimethylamino.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: Selected from the following compounds:

3. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, comprising the following steps: or, in, A,X,Y,R1,R2,R3,R4,R 5a , R 5b , m and n are as defined in claim 1.

4. A pharmaceutical composition comprising: A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2; and A pharmaceutically acceptable carrier.

5. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2 in the preparation of a medicament for treating a tumor patient resistant to an FGFR inhibitor, wherein the tumor patient is a tumor patient having FGFR2 V565F, V565I, V565L, V565M, N550K, N550H, E566A, E566G, K660M and / or K660Q mutations; or the tumor patient is a tumor patient having FGFR3 V555M, V555L and / or N540K mutations.

6. Use of a compound of formula (I) according to claim 1 or 2 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a tumor mediated by FGFR2 and / or FGFR3 kinase, wherein the tumor is selected from bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, thyroid cancer, skin cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, B-cell lymphoma, Hodgkin's lymphoma or non-Hodgkin's lymphoma, hair-like lymphoma, glioblastoma, melanoma or rhabdomyosarcoma.

7. The use according to claim 6, wherein the leukemia is adult T-cell leukemia, acute myeloid leukemia or Waldenstrom's macroglobulinemia.

8. The use according to claim 6, wherein the non-Hodgkin's lymphoma is Burkitt's lymphoma.

9. Use of a compound of formula (I) according to claim 1 or 2 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating myeloproliferative diseases, bone or cartilage cell disorders, or hypophosphatemia mediated by FGFR2 and / or FGFR3 kinases; wherein, The myeloproliferative disease is selected from polycythemia vera, essential thrombocythemia or primary myelofibrosis; The bone or cartilage cell disorder is selected from dysplasia, dwarfism, lethal teratogenicity (TD), Appel's syndrome, Crouzon's syndrome, Jackson-Weiss syndrome, Beare-Stevenson skin fold syndrome, Pfeiffer syndrome or cranial muscular dystrophy syndrome; The hypophosphatemia is selected from X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets or tumor-induced ovarian softening.

10. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2 in the preparation of a medicament for treating chondrodysplasia mediated by FGFR2 and / or FGFR3 kinases.

11. Use of a compound of formula (I) according to claim 1 or 2 or a pharmaceutically acceptable salt thereof in the preparation of a selective FGFR2 and / or FGFR3 inhibitor, wherein the inhibitor is used to treat diseases associated with abnormal expression or mutation of FGFR2 or FGFR3 receptors or abnormal expression and activity of the corresponding ligands.

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