A pyrazole derivative, a process for its preparation and its use in pharmacy

Abstract

A pyrazole derivative, a preparation method thereof and a pharmaceutical use thereof. In particular, a PRMT5 inhibitor having a structure of formula (I), a preparation method thereof, a pharmaceutical composition containing the same, and a use thereof as a PRMT5 inhibitor and a use thereof in treating and / or preventing a PRMT5-mediated disease.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically relating to a pyrazole derivative, its preparation method and pharmaceutical application. Background Technology

[0002] Epigenetic gene regulation is an important biological regulatory mechanism for protein synthesis and cell differentiation, and plays a vital role in many human diseases.

[0003] Epigenetic regulation involves modulating inheritable genetic material without altering its nucleic acid sequence. Typically, epigenetic regulation controls the switching between transcriptionally active and inactive states in chromatin conformation through selective, reversible modifications (such as methylation) of DNA and proteins (e.g., histones). These covalent modifications can be controlled by enzymes, such as methyltransferases (e.g., PRMT5), many of which are associated with specific gene alterations in many human disease-causing genes. PRMT5 plays a crucial role in many diseases, including cancer, metabolic disorders, and hematologic diseases.

[0004] Homozygous deletion of tumor suppressor genes is a driver of tumor development, often resulting in the deletion of passenger genes near the suppressor genes. The deletion of these passenger genes creates tumor-cell-specific vulnerabilities, making them targetable for specific therapies. Homozygous deletion at chromosome 9p21 includes the well-known tumor suppressor gene CDKN2A, which occurs in 15% of tumors and often involves the deletion of the passenger gene MTAP. MTAP is a key enzyme in the methionine and adenine reprocessing pathway. The deletion of MTAP leads to the accumulation of its substrate, MTA. MTA and S-adenosylmethionine (SAM) are structurally similar, and the latter is the methyl substrate donor for the type-2 methyltransferase PRMT5. The increased MTA levels resulting from MTAP deletion selectively compete with SAM for PRMT5 binding, rendering the methyltransferase inactive and more susceptible to PRMT5 inhibition. Extensive shRNA screening across various genome-wide tumor cell lines has demonstrated a correlation between MTAP deficiency and PRMT5 dependence, bringing the impact of this metabolic susceptibility into the spotlight. However, PRMT5 is a crucial cellular gene, and studies of conditional PRMT5 knockout or siRNA knockout have shown that inhibiting PRMT5 in normal tissues can have significant side effects (e.g., cytopenia, infertility, skeletal muscle loss, cardiac hypertrophy, etc.). Therefore, new strategies are needed to explore this metabolic susceptibility, selectively targeting PRMT5 in MTAP-deficient tumors while avoiding its effects in normal tissues (MTAP wild-type).

[0005] Small molecule inhibitors that target PRMT5 in synergy with MTA can selectively target PRMT5 in its MTA-bound state. This PRMT5 is enriched only in MTAP-deficient tumor cells. Therefore, in normal cells with intact MTAP, when MTA levels are very low, PRMT5 will not be targeted, thus providing a better therapeutic window. Summary of the Invention

[0006] The purpose of this invention is to provide a pyrazole derivative, its preparation method, and its pharmaceutical applications. The compounds of this invention exhibit strong inhibitory activity against PRMT5 and can be widely used in the preparation of drugs for the treatment and / or prevention of PRMT5-mediated diseases, thus holding promise for the development of a new generation of PRMT5 inhibitors.

[0007] The first aspect of the present invention provides a compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof:

[0008]

[0009] Where L represents bond, O, S, C(O), C(O)O, C(O)NH, CH=CH, C≡C, S(O), S(O)2, NR 12 , S(O)2NH or CR 13 R 14 ;

[0010] X1, X2, and X3 are each independently N or CR 15 ;

[0011] R1 is selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the above groups are independently and optionally further selected by one or more radicals selected from deuterium, halogen, hydroxyl, =O, 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 6-10 Aryl, C 6-10 aryloxy groups, 5-10 heteroaryl groups, 5-10 heteroaryloxy groups and -NR 22 R 23 The substituents are replaced;

[0012] R2 is selected from hydrogen, deuterium, halogen, cyano, nitro, azide, and C. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR) 16 )R 17 -C 0-8 Alkyl-N=S(O)R 17 R 18 -C 0-8 Alkyl-N=SR 17 R 18 -C 0-8 Alkyl-OS(O)2R 19 -C 0-8 Alkyl-S(O) r R 19 -C 0-8 Alkyl-P(O)(OR) 20 )R 19 -C 0-8 Alkyl-OR 20 -C 0-8 Alkyl-C(O)OR 20 -C 0-8 Alkyl-C(O)SR 20 -C 0-8 Alkyl-SC(O)R 21 -C 0-8 Alkyl-C(O)R 21 -C 0-8 Alkyl-OC(O)R 21 -C 0-8 Alkyl-NR 22 R 23 -C 0-8 Alkyl-C (=NR) 22 )R 21 -C 0-8 Alkyl-N(R) 22 )-C(=NR 23 )R 21 -C 0-8 Alkyl-C(O)NR 22 R 23 and -C 0-8 Alkyl-N(R) 22 )-C(O)R 21 ;

[0013] R3, R4, R5, R6, and R7 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, and C. 1-10Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR) 16 )R 17 -C 0-8 Alkyl-N=S(O)R 17 R 18 -C 0-8 Alkyl-N=SR 17 R 18 -C 0-8 Alkyl-OS(O)2R 19 -C 0-8 Alkyl-S(O) r R 19 -C 0-8 Alkyl-P(O)(OR) 20 )R 19 -C 0-8 Alkyl-OR 20 -C 0-8 Alkyl-C(O)OR 20 -C 0-8 Alkyl-C(O)SR 20 -C 0-8 Alkyl-SC(O)R 21 -C 0-8 Alkyl-C(O)R 21 -C 0-8 Alkyl-OC(O)R 21 -C 0-8 Alkyl-NR 22 R 23 -C 0-8 Alkyl-C (=NR) 22 )R 21 -C 0-8 Alkyl-N(R) 22 )-C(=NR 23 )R 21 -C 0-8 Alkyl-C(O)NR 22 R 23 and -C 0-8 Alkyl-N(R) 22 )-C(O)R 21Alternatively, two adjacent substituents of R3, R4, R5, R6, and R7, along with their directly attached portions, form a 4-8 membered carbon ring, a 4-8 membered heterocyclic ring, a 6-8 membered aromatic ring, or a 5-8 membered heteroaromatic ring. These groups are independently and optionally further substituents selected from one or more elements chosen from deuterium, halogen, cyano, nitro, azide, C... 1-10 Alkyl, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR) 16 )R 17 -C 0-8 Alkyl-N=S(O)R 17 R 18 -C 0-8 Alkyl-N=SR 17 R 18 -C 0-8 Alkyl-OS(O)2R 19 -C 0-8 Alkyl-S(O) r R 19 -C 0-8 Alkyl-P(O)(OR) 20 )R 19 -C 0-8 Alkyl-OR 20 -C 0-8 Alkyl-C(O)OR 20 -C 0-8 Alkyl-C(O)SR 20 -C 0-8 Alkyl-SC(O)R 21 -C 0-8 Alkyl-C(O)R 21 -C 0-8 Alkyl-OC(O)R 21 -C 0-8 Alkyl-NR 22 R 23 -C 0-8 Alkyl-C (=NR) 22 )R 21 -C 0-8 Alkyl-N(R) 22 )-C(=NR 23 )R 21 -C 0-8 Alkyl-C(O)NR22 R 23 and -C 0-8 Alkyl-N(R) 22 )-C(O)R 21 The substituents are replaced;

[0014] R8 is selected from hydrogen, deuterium, hydroxyl, and C. 1-10 Alkyl, C 2-10 Alkenyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the above groups are independently and optionally further selected by one or more radicals selected from deuterium, halogen, hydroxyl, =O, 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 6-10 Aryl, C 6-10 aryloxy groups, 5-10 heteroaryl groups, 5-10 heteroaryloxy groups and -NR 22 R 23 The substituents are replaced;

[0015] R9 is selected from hydrogen, deuterium, halogen, cyano, nitro, azide, and C. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR) 16 )R 17 -C 0-8 Alkyl-N=S(O)R 17 R 18 -C 0-8 Alkyl-N=SR 17 R 18 -C 0-8 Alkyl-OS(O)2R 19 -C 0-8 Alkyl-S(O) r R 19 -C 0-8 Alkyl-P(O)(OR) 20 )R 19 -C 0-8 Alkyl-OR 20 -C 0-8Alkyl-C(O)OR 20 -C 0-8 Alkyl-C(O)SR 20 -C 0-8 Alkyl-SC(O)R 21 -C 0-8 Alkyl-C(O)R 21 -C 0-8 Alkyl-OC(O)R 21 -C 0-8 Alkyl-NR 22 R 23 -C 0-8 Alkyl-C (=NR) 22 )R 21 -C 0-8 Alkyl-N(R) 22 )-C(=NR 23 )R 21 -C 0-8 Alkyl-C(O)NR 22 R 23 and -C 0-8 Alkyl-N(R) 22 )-C(O)R 21 ;

[0016] R 10 and R 11 Each is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, and C. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR) 16 )R 17 -C 0-8 Alkyl-N=S(O)R 17 R 18 -C 0-8 Alkyl-N=SR 17 R 18 -C 0-8 Alkyl-OS(O)2R 19 -C 0-8 Alkyl-S(O) r R 19 -C 0-8 Alkyl-P(O)(OR) 20 )R 19 -C 0-8 Alkyl-OR 20 -C0-8 Alkyl-C(O)OR 20 -C 0-8 Alkyl-C(O)SR 20 -C 0-8 Alkyl-SC(O)R 21 -C 0-8 Alkyl-C(O)R 21 -C 0-8 Alkyl-OC(O)R 21 -C 0-8 Alkyl-NR 22 R 23 -C 0-8 Alkyl-C (=NR) 22 )R 21 -C 0-8 Alkyl-N(R) 22 )-C(=NR 23 )R 21 -C 0-8 Alkyl-C(O)NR 22 R 23 and -C 0-8 Alkyl-N(R) 22 )-C(O)R 21 Or, R 10 and R 11 The carbon atoms directly bonded to it form C(O), C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl or 5-8 heteroaryl, wherein the above groups are independently and optionally further selected from one or more radicals selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR) 16 )R 17 -C 0-8 Alkyl-N=S(O)R 17 R 18 -C 0-8 Alkyl-N=SR 17 R 18 -C 0-8 Alkyl-OS(O)2R 19 -C 0-8 Alkyl-S(O)r R 19 -C 0-8 Alkyl-P(O)(OR) 20 )R 19 -C 0-8 Alkyl-OR 20 -C 0-8 Alkyl-C(O)OR 20 -C 0-8 Alkyl-C(O)SR 20 -C 0-8 Alkyl-SC(O)R 21 -C 0-8 Alkyl-C(O)R 21 -C 0-8 Alkyl-OC(O)R 21 -C 0-8 Alkyl-NR 22 R 23 -C 0-8 Alkyl-C (=NR) 22 )R 21 -C 0-8 Alkyl-N(R) 22 )-C(=NR 23 )R 21 -C 0-8 Alkyl-C(O)NR 22 R 23 and -C 0-8 Alkyl-N(R) 22 )-C(O)R 21 The substituents are replaced;

[0017] R 12 Selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the above groups are independently and optionally further selected by one or more radicals selected from deuterium, halogen, hydroxyl, =O, 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 6-10 Aryl, C 6-10 aryloxy groups, 5-10 heteroaryl groups, 5-10 heteroaryloxy groups and -NR 22 R 23 The substituents are replaced;

[0018] R 13 and R 14Each is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, and C. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR) 16 )R 17 -C 0-8 Alkyl-N=S(O)R 17 R 18 -C 0-8 Alkyl-N=SR 17 R 18 -C 0-8 Alkyl-OS(O)2R 19 -C 0-8 Alkyl-S(O) r R 19 -C 0-8 Alkyl-P(O)(OR) 20 )R 19 -C 0-8 Alkyl-OR 20 -C 0-8 Alkyl-C(O)OR 20 -C 0-8 Alkyl-C(O)SR 20 -C 0-8 Alkyl-SC(O)R 21 -C 0-8 Alkyl-C(O)R 21 -C 0-8 Alkyl-OC(O)R 21 -C 0-8 Alkyl-NR 22 R 23 -C 0-8 Alkyl-C (=NR) 22 )R 21 -C 0-8 Alkyl-N(R) 22 )-C(=NR 23 )R 21 -C 0-8 Alkyl-C(O)NR 22 R 23 and -C 0-8 Alkyl-N(R) 22 )-C(O)R 21 Or, R 13 and R 14The carbon atoms directly bonded to it form C(O), C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl or 5-8 heteroaryl, wherein the above groups are independently and optionally further selected from one or more radicals selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR) 16 )R 17 -C 0-8 Alkyl-N=S(O)R 17 R 18 -C 0-8 Alkyl-N=SR 17 R 18 -C 0-8 Alkyl-OS(O)2R 19 -C 0-8 Alkyl-S(O) r R 19 -C 0-8 Alkyl-P(O)(OR) 20 )R 19 -C 0-8 Alkyl-OR 20 -C 0-8 Alkyl-C(O)OR 20 -C 0-8 Alkyl-C(O)SR 20 -C 0-8 Alkyl-SC(O)R 21 -C 0-8 Alkyl-C(O)R 21 -C 0-8 Alkyl-OC(O)R 21 -C 0-8 Alkyl-NR 22 R 23 -C 0-8 Alkyl-C (=NR) 22 )R 21 -C 0-8 Alkyl-N(R) 22 )-C(=NR 23 )R 21 -C 0-8 Alkyl-C(O)NR22 R 23 and -C 0-8 Alkyl-N(R) 22 )-C(O)R 21 The substituents are replaced;

[0019] Each R 15 Independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR) 16 )R 17 -C 0-8 Alkyl-N=S(O)R 17 R 18 -C 0-8 Alkyl-N=SR 17 R 18 -C 0-8 Alkyl-OS(O)2R 19 -C 0-8 Alkyl-S(O) r R 19 -C 0-8 Alkyl-P(O)(OR) 20 )R 19 -C 0-8 Alkyl-OR 20 -C 0-8 Alkyl-C(O)OR 20 -C 0-8 Alkyl-C(O)SR 20 -C 0-8 Alkyl-SC(O)R 21 -C 0-8 Alkyl-C(O)R 21 -C 0-8 Alkyl-OC(O)R 21 -C 0-8 Alkyl-NR 22 R 23 -C 0-8 Alkyl-C (=NR) 22 )R 21 -C 0-8 Alkyl-N(R) 22 )-C(=NR 23 )R 21 -C 0-8Alkyl-C(O)NR 22 R 23 and -C 0-8 Alkyl-N(R) 22 )-C(O)R 21 The aforementioned groups are independently and optionally further selected by one or more radicals selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR) 16 )R 17 -C 0-8 Alkyl-N=S(O)R 17 R 18 -C 0-8 Alkyl-N=SR 17 R 18 -C 0-8 Alkyl-OS(O)2R 19 -C 0-8 Alkyl-S(O) r R 19 -C 0-8 Alkyl-P(O)(OR) 20 )R 19 -C 0-8 Alkyl-OR 20 -C 0-8 Alkyl-C(O)OR 20 -C 0-8 Alkyl-C(O)SR 20 -C 0-8 Alkyl-SC(O)R 21 -C 0-8 Alkyl-C(O)R 21 -C 0-8 Alkyl-OC(O)R 21 -C 0-8 Alkyl-NR 22 R 23 -C 0-8 Alkyl-C (=NR) 22 )R 21 -C 0-8 Alkyl-N(R) 22 )-C(=NR 23 )R 21-C 0-8 Alkyl-C(O)NR 22 R 23 and -C 0-8 Alkyl-N(R) 22 )-C(O)R 21 The substituent is replaced by the substituent, provided that when R 15 When the nitrogen atom is hydrogen, at least one of R3, R4, R5, R6 and R7 is a 3-8 member nitrogen-containing heterocyclic group, wherein the nitrogen atom is attached to the benzene ring;

[0020] Each R 16 Each is independently selected from hydrogen, deuterium, and C. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -C 0-8 Alkyl-S(O) r R 19 -C 0-8 Alkyl-C(O)OR 20 -C 0-8 Alkyl-C(O)R 21 or -C 0-8 Alkyl-C(O)NR 22 R 23 The above-mentioned groups may optionally be further divided by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR) 16 )R 17 -C 0-8 Alkyl-N=S(O)R 17 R 18 -C 0-8 Alkyl-N=SR 17 R 18 -C 0-8 Alkyl-OS(O)2R 19 -C 0-8 Alkyl-S(O) r R 19 -C 0-8 Alkyl-P(O)(OR)20 )R 19 -C 0-8 Alkyl-OR 20 -C 0-8 Alkyl-C(O)OR 20 -C 0-8 Alkyl-C(O)SR 20 -C 0-8 Alkyl-SC(O)R 21 -C 0-8 Alkyl-C(O)R 21 -C 0-8 Alkyl-OC(O)R 21 -C 0-8 Alkyl-NR 22 R 23 -C 0-8 Alkyl-C (=NR) 22 )R 21 -C 0-8 Alkyl-N(R) 22 )-C(=NR 23 )R 21 -C 0-8 Alkyl-C(O)NR 22 R 23 and -C 0-8 Alkyl-N(R) 22 )-C(O)R 21 The substituents are replaced;

[0021] Each R 17 and R 18 Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, or, R 17 and R 18 Together with the sulfur atom directly attached thereto, a 3-10 membered heterocyclic group is formed, which may be further selected by one or more elements selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8Alkyl-S(O)(=NR) 16 )R 17 -C 0-8 Alkyl-N=S(O)R 17 R 18 -C 0-8 Alkyl-N=SR 17 R 18 -C 0-8 Alkyl-OS(O)2R 19 -C 0-8 Alkyl-S(O) r R 19 -C 0-8 Alkyl-P(O)(OR) 20 )R 19 -C 0-8 Alkyl-OR 20 -C 0-8 Alkyl-C(O)OR 20 -C 0-8 Alkyl-C(O)SR 20 -C 0-8 Alkyl-SC(O)R 21 -C 0-8 Alkyl-C(O)R 21 -C 0-8 Alkyl-OC(O)R 21 -C 0-8 Alkyl-NR 22 R 23 -C 0-8 Alkyl-C (=NR) 22 )R 21 -C 0-8 Alkyl-N(R) 22 )-C(=NR 23 )R 21 -C 0-8 Alkyl-C(O)NR 22 R 23 and -C 0-8 Alkyl-N(R) 22 )-C(O)R 21 The substituents are replaced;

[0022] Each R 19 Independently selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl and -NR 22 R 23The above-mentioned groups are independently and optionally further selected by one or more elements chosen from deuterium, halogen, hydroxyl, =O, 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 6-10 Aryl, C 6-10 aryloxy groups, 5-10 heteroaryl groups, 5-10 heteroaryloxy groups and -NR 22 R 23 The substituents are replaced;

[0023] Each R 20 Independently selected from hydrogen, deuterium, and C 1-10 Alkyl, C 2-10 Alkenyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the above groups are independently and optionally further selected by one or more radicals selected from deuterium, halogen, hydroxyl, =O, 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 6-10 Aryl, C 6-10 aryloxy groups, 5-10 heteroaryl groups, 5-10 heteroaryloxy groups and -NR 22 R 23 The substituents are replaced;

[0024] Each R 21 Independently selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 aryloxy groups, 5-10 heteroaryl groups, 5-10 heteroaryloxy groups and -NR 22 R 23 The above-mentioned groups may independently and optionally be further selected by one or more groups selected from deuterium, halogen, hydroxyl, =O, 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 6-10 Aryl, C 6-10aryloxy groups, 5-10 heteroaryl groups, 5-10 heteroaryloxy groups and -NR 22 R 23 The substituents are replaced;

[0025] Each R 22 and R 23 Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropanesulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, and C 1-10 Alkyl group, wherein the above groups are independently and optionally further divided by one or more groups selected from deuterium, halogen, hydroxyl, =O, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated 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 6-10 Aryl, C 6-10 Aryloxy, 5-10 heteroaryl, 5-10 heteroaryloxy, amino, C 1-10 Alkyl monosubstituted amino, C 1-10 Alkyl disubstituted amino and C 1-10 The alkyl group is substituted by a substituent, or R 22 and R 23 Together with the nitrogen atom directly attached thereto, a 4-10 membered heterocyclic group or a 5-10 membered heteroaryl group is formed, wherein the 4-10 membered heterocyclic group or the 5-10 membered heteroaryl group is optionally further surrounded by one or more elements selected from deuterium, halogen, hydroxyl, =O, C. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated 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 6-10 Aryl, C 6-10 Aryloxy, 5-10 heteroaryl, 5-10 heteroaryloxy, amino, C 1-10 Alkyl monosubstituted amino, C 1-10Alkyl disubstituted amino and C 1-10 The alkyl acyl group is substituted by a substituent; and

[0026] Each r is independently 0, 1, or 2.

[0027] As a more preferred embodiment, in the compound of formula (I), its stereoisomers, or its pharmaceutically acceptable salt, L represents a bond, O, S, C(O), S(O), S(O)2, NR 12 or CR 13 R 14 ;

[0028] X1, X2, and X3 are each independently N or CR 15 ;

[0029] R1 is selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 aryl and 5-8 heteroaryl groups, wherein the above groups are independently and optionally further selected by one or more radicals selected from deuterium, halogen, hydroxyl, =O, 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 6-8 Aryl, C 6-8 aryloxy, 5-8 heteroaryl, 5-8 heteroaryloxy and -NR 22 R 23 The substituents are replaced;

[0030] R2 is selected from hydrogen, deuterium, halogen, cyano, nitro, azide, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 quinone heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR) 16 )R 17 -C 0-4 Alkyl-N=S(O)R 17 R 18 -C 0-4 Alkyl-N=SR 17 R 18 -C 0-4 Alkyl-OS(O)2R19 -C 0-4 Alkyl-S(O) r R 19 -C 0-4 Alkyl-P(O)(OR) 20 )R 19 -C 0-4 Alkyl-OR 20 -C 0-4 Alkyl-C(O)OR 20 -C 0-4 Alkyl-C(O)SR 20 -C 0-4 Alkyl-SC(O)R 21 -C 0-4 Alkyl-C(O)R 21 -C 0-4 Alkyl-OC(O)R 21 -C 0-4 Alkyl-NR 22 R 23 -C 0-4 Alkyl-C (=NR) 22 )R 21 -C 0-4 Alkyl-N(R) 22 )-C(=NR 23 )R 21 -C 0-4 Alkyl-C(O)NR 22 R 23 and -C 0-4 Alkyl-N(R) 22 )-C(O)R 21 ;

[0031] R3, R4, R5, R6, and R7 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-8 Aryl, 5-8 quinone heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR) 16 )R 17 -C 0-4 Alkyl-N=S(O)R 17 R 18 -C 0-4 Alkyl-N=SR 17 R 18 -C 0-4 Alkyl-OS(O)2R19 -C 0-4 Alkyl-S(O) r R 19 -C 0-4 Alkyl-P(O)(OR) 20 )R 19 -C 0-4 Alkyl-OR 20 -C 0-4 Alkyl-C(O)OR 20 -C 0-4 Alkyl-C(O)SR 20 -C 0-4 Alkyl-SC(O)R 21 -C 0-4 Alkyl-C(O)R 21 -C 0-4 Alkyl-OC(O)R 21 -C 0-4 Alkyl-NR 22 R 23 -C 0-4 Alkyl-C (=NR) 22 )R 21 -C 0-4 Alkyl-N(R) 22 )-C(=NR 23 )R 21 -C 0-4 Alkyl-C(O)NR 22 R 23 and -C 0-4 Alkyl-N(R) 22 )-C(O)R 21 Alternatively, two adjacent substituents of R3, R4, R5, R6, and R7, along with their directly attached portions, form a 5-8 membered carbon ring, a 5-8 membered heterocyclic ring, a 6-membered aromatic ring, or a 5-6 membered heteroaromatic ring. These groups are independently and optionally further substituents selected from one or more elements chosen from deuterium, halogen, cyano, nitro, azide, C... 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-8 Aryl, 5-8 heteroaryl, =O, =S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR) 16 )R 17 -C 0-4 Alkyl-N=S(O)R 17 R 18-C 0-4 Alkyl-N=SR 17 R 18 -C 0-4 Alkyl-OS(O)2R 19 -C 0-4 Alkyl-S(O) r R 19 -C 0-4 Alkyl-P(O)(OR) 20 )R 19 -C 0-4 Alkyl-OR 20 -C 0-4 Alkyl-C(O)OR 20 -C 0-4 Alkyl-C(O)SR 20 -C 0-4 Alkyl-SC(O)R 21 -C 0-4 Alkyl-C(O)R 21 -C 0-4 Alkyl-OC(O)R 21 -C 0-4 Alkyl-NR 22 R 23 -C 0-4 Alkyl-C (=NR) 22 )R 21 -C 0-4 Alkyl-N(R) 22 )-C(=NR 23 )R 21 -C 0-4 Alkyl-C(O)NR 22 R 23 and -C 0-4 Alkyl-N(R) 22 )-C(O)R 21 The substituents are replaced;

[0032] R8 is selected from hydrogen, deuterium, hydroxyl, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 aryl and 5-8 heteroaryl groups, wherein the above groups are independently and optionally further selected by one or more radicals selected from deuterium, halogen, hydroxyl, =O, 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 6-8 Aryl, C 6-8aryloxy, 5-8 heteroaryl, 5-8 heteroaryloxy and -NR 22 R 23 The substituents are replaced;

[0033] R9 is selected from hydrogen, deuterium, halogen, cyano, nitro, azide, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 quinone heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR) 16 )R 17 -C 0-4 Alkyl-N=S(O)R 17 R 18 -C 0-4 Alkyl-N=SR 17 R 18 -C 0-4 Alkyl-OS(O)2R 19 -C 0-4 Alkyl-S(O) r R 19 -C 0-4 Alkyl-P(O)(OR) 20 )R 19 -C 0-4 Alkyl-OR 20 -C 0-4 Alkyl-C(O)OR 20 -C 0-4 Alkyl-C(O)SR 20 -C 0-4 Alkyl-SC(O)R 21 -C 0-4 Alkyl-C(O)R 21 -C 0-4 Alkyl-OC(O)R 21 -C 0-4 Alkyl-NR 22 R 23 -C 0-4 Alkyl-C (=NR) 22 )R 21 -C 0-4 Alkyl-N(R) 22 )-C(=NR 23 )R 21 -C 0-4 Alkyl-C(O)NR22 R 23 and -C 0-4 Alkyl-N(R) 22 )-C(O)R 21 ;

[0034] R 10 and R 11 Each is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 quinone heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR) 16 )R 17 -C 0-4 Alkyl-N=S(O)R 17 R 18 -C 0-4 Alkyl-N=SR 17 R 18 -C 0-4 Alkyl-OS(O)2R 19 -C 0-4 Alkyl-S(O) r R 19 -C 0-4 Alkyl-P(O)(OR) 20 )R 19 -C 0-4 Alkyl-OR 20 -C 0-4 Alkyl-C(O)OR 20 -C 0-4 Alkyl-C(O)SR 20 -C 0-4 Alkyl-SC(O)R 21 -C 0-4 Alkyl-C(O)R 21 -C 0-4 Alkyl-OC(O)R 21 -C 0-4 Alkyl-NR 22 R 23 -C 0-4 Alkyl-C (=NR) 22 )R 21 -C 0-4 Alkyl-N(R) 22 )-C(=NR 23 )R 21 -C 0-4Alkyl-C(O)NR 22 R 23 and -C 0-4 Alkyl-N(R) 22 )-C(O)R 21 Or, R 10 and R 11 The carbon atoms directly bonded to it form C(O), C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 aryl or 5-6 heteroaryl, wherein the above groups are independently and optionally further selected from one or more radicals selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 heteroaryl, =O, =S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR) 16 )R 17 -C 0-4 Alkyl-N=S(O)R 17 R 18 -C 0-4 Alkyl-N=SR 17 R 18 -C 0-4 Alkyl-OS(O)2R 19 -C 0-4 Alkyl-S(O) r R 19 -C 0-4 Alkyl-P(O)(OR) 20 )R 19 -C 0-4 Alkyl-OR 20 -C 0-4 Alkyl-C(O)OR 20 -C 0-4 Alkyl-C(O)SR 20 -C 0-4 Alkyl-SC(O)R 21 -C 0-4 Alkyl-C(O)R 21 -C 0-4 Alkyl-OC(O)R 21 -C 0-4 Alkyl-NR 22 R 23 -C 0-4 Alkyl-C (=NR)22 )R 21 -C 0-4 Alkyl-N(R) 22 )-C(=NR 23 )R 21 -C 0-4 Alkyl-C(O)NR 22 R 23 and -C 0-4 Alkyl-N(R) 22 )-C(O)R 21 The substituents are replaced;

[0035] R 12 Selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 aryl and 5-8 heteroaryl groups, wherein the above groups are independently and optionally further selected by one or more radicals selected from deuterium, halogen, hydroxyl, =O, 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 6-8 Aryl, C 6-8 aryloxy, 5-8 heteroaryl, 5-8 heteroaryloxy and -NR 22 R 23 The substituents are replaced;

[0036] R 13 and R 14 Each is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 quinone heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR) 16 )R 17 -C 0-4 Alkyl-N=S(O)R 17 R 18 -C 0-4 Alkyl-N=SR 17 R 18 -C 0-4 Alkyl-OS(O)2R 19 -C 0-4 Alkyl-S(O) r R19 -C 0-4 Alkyl-P(O)(OR) 20 )R 19 -C 0-4 Alkyl-OR 20 -C 0-4 Alkyl-C(O)OR 20 -C 0-4 Alkyl-C(O)SR 20 -C 0-4 Alkyl-SC(O)R 21 -C 0-4 Alkyl-C(O)R 21 -C 0-4 Alkyl-OC(O)R 21 -C 0-4 Alkyl-NR 22 R 23 -C 0-4 Alkyl-C (=NR) 22 )R 21 -C 0-4 Alkyl-N(R) 22 )-C(=NR 23 )R 21 -C 0-4 Alkyl-C(O)NR 22 R 23 and -C 0-4 Alkyl-N(R) 22 )-C(O)R 21 Or, R 13 and R 14 The carbon atoms directly bonded to it form C(O), C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 aryl or 5-6 heteroaryl, wherein the above groups are independently and optionally further selected from one or more radicals selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 heteroaryl, =O, =S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR) 16 )R 17 -C 0-4 Alkyl-N=S(O)R 17 R 18 -C 0-4Alkyl-N=SR 17 R 18 -C 0-4 Alkyl-OS(O)2R 19 -C 0-4 Alkyl-S(O) r R 19 -C 0-4 Alkyl-P(O)(OR) 20 )R 19 -C 0-4 Alkyl-OR 20 -C 0-4 Alkyl-C(O)OR 20 -C 0-4 Alkyl-C(O)SR 20 -C 0-4 Alkyl-SC(O)R 21 -C 0-4 Alkyl-C(O)R 21 -C 0-4 Alkyl-OC(O)R 21 -C 0-4 Alkyl-NR 22 R 23 -C 0-4 Alkyl-C (=NR) 22 )R 21 -C 0-4 Alkyl-N(R) 22 )-C(=NR 23 )R 21 -C 0-4 Alkyl-C(O)NR 22 R 23 and -C 0-4 Alkyl-N(R) 22 )-C(O)R 21 The substituents are replaced;

[0037] Each R 15 Independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 quinone heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR) 16 )R 17 -C 0-4 Alkyl-N=S(O)R 17 R 18 -C 0-4Alkyl-N=SR 17 R 18 -C 0-4 Alkyl-OS(O)2R 19 -C 0-4 Alkyl-S(O) r R 19 -C 0-4 Alkyl-P(O)(OR) 20 )R 19 -C 0-4 Alkyl-OR 20 -C 0-4 Alkyl-C(O)OR 20 -C 0-4 Alkyl-C(O)SR 20 -C 0-4 Alkyl-SC(O)R 21 -C 0-4 Alkyl-C(O)R 21 -C 0-4 Alkyl-OC(O)R 21 -C 0-4 Alkyl-NR 22 R 23 -C 0-4 Alkyl-C (=NR) 22 )R 21 -C 0-4 Alkyl-N(R) 22 )-C(=NR 23 )R 21 -C 0-4 Alkyl-C(O)NR 22 R 23 and -C 0-4 Alkyl-N(R) 22 )-C(O)R 21 The aforementioned groups are independently and optionally further selected by one or more radicals selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 heteroaryl, =O, =S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR) 16 )R 17 -C 0-4 Alkyl-N=S(O)R 17 R 18 -C0-4 Alkyl-N=SR 17 R 18 -C 0-4 Alkyl-OS(O)2R 19 -C 0-4 Alkyl-S(O) r R 19 -C 0-4 Alkyl-P(O)(OR) 20 )R 19 -C 0-4 Alkyl-OR 20 -C 0-4 Alkyl-C(O)OR 20 -C 0-4 Alkyl-C(O)SR 20 -C 0-4 Alkyl-SC(O)R 21 -C 0-4 Alkyl-C(O)R 21 -C 0-4 Alkyl-OC(O)R 21 -C 0-4 Alkyl-NR 22 R 23 -C 0-4 Alkyl-C (=NR) 22 )R 21 -C 0-4 Alkyl-N(R) 22 )-C(=NR 23 )R 21 -C 0-4 Alkyl-C(O)NR 22 R 23 and -C 0-4 Alkyl-N(R) 22 )-C(O)R 21 The substituent is replaced by the substituent, provided that when R 15 When the nitrogen atom is hydrogen, at least one of R3, R4, R5, R6 and R7 is a 3-8 member nitrogen-containing heterocyclic group, wherein the nitrogen atom is attached to the benzene ring;

[0038] Among them, R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 And r as described in compound (I).

[0039] As a more preferred embodiment, in the compound of formula (I), its stereoisomers, or its pharmaceutically acceptable salts, each R16 Each is independently selected from hydrogen, deuterium, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 quinone heteroaryl, -S(O) r R 19 -C(O)OR 20 -C(O)R 21 or -C(O)NR 22 R 23 The above-mentioned groups may optionally be further divided by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 heteroaryl, =O, =S, -SF5, -S(O)(=NR) 16 )R 17 -N=S(O)R 17 R 18 -N=SR 17 R 18 -OS(O)2R 19 -S(O) r R 19 -P(O)(OR) 20 )R 19 -OR 20 -C(O)OR 20 -C(O)SR 20 -SC(O)R 21 -C(O)R 21 -OC(O)R 21 -NR 22 R 23 -C(=NR) 22 )R 21 -N(R) 22 )-C(=NR 23 )R 21 -C(O)NR 22 R 23 and base-N(R) 22 )-C(O)R 21 The substituents are replaced;

[0040] Each R 17 and R18 Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 aryl or 5-8 quinone heteroaryl, or, R 17 and R 18 Together with the sulfur atom directly attached thereto, a 4-6 membered heterocyclic group is formed, which may be further selected by one or more elements selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 heteroaryl, =O, =S, -SF5, -S(O)(=NR) 16 )R 17 -N=S(O)R 17 R 18 -N=SR 17 R 18 -OS(O)2R 19 -S(O) r R 19 -P(O)(OR) 20 )R 19 -OR 20 -C(O)OR 20 -C(O)SR 20 -SC(O)R 21 -C(O)R 21 -OC(O)R 21 -NR 22 R 23 -C(=NR) 22 )R 21 -N(R) 22 )-C(=NR 23 )R 21 -C(O)NR 22 R 23 and -N(R) 22 )-C(O)R 21 The substituents are replaced;

[0041] Each R 19 Independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 quinone heteroaryl and -NR 22 R 23 The above-mentioned groups are independently and optionally further selected by one or more elements chosen from deuterium, halogen, hydroxyl, =O, 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 6-8 Aryl, C 6-8 aryloxy, 5-8 heteroaryl, 5-8 heteroaryloxy and -NR 22 R 23 The substituents are replaced;

[0042] Each R 20 Independently selected from hydrogen, deuterium, and C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 aryl and 5-8 heteroaryl groups, wherein the above groups are independently and optionally further selected by one or more radicals selected from deuterium, halogen, hydroxyl, =O, 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 6-8 Aryl, C 6-8 aryloxy, 5-8 heteroaryl, 5-8 heteroaryloxy and -NR 22 R 23 The substituents are replaced;

[0043] Each R 21 Independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, C 6-8 aryloxy, 5-8 heteroaryl, 5-8 heteroaryloxy and -NR 22 R 23 The above-mentioned groups may independently and optionally be further selected by one or more groups selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, C 6-8 aryloxy, 5-8 heteroaryl, 5-8 heteroaryloxy and -NR 22 R 23 The substituents are replaced;

[0044] Each R 22 and R 23 Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropanesulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, and C 1-4 Alkyl group, wherein the above groups are independently and optionally further divided by one or more groups selected from deuterium, halogen, hydroxyl, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated 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 6-8 Aryl, C 6-8 Aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy, amino, C 1-4 Alkyl monosubstituted amino, C 1-4 Alkyl disubstituted amino and C 1-4 The alkyl group is substituted by a substituent, or R 22 and R 23 Together with the nitrogen atom directly attached thereto, a 4-6 membered heterocyclic group or a 5-6 membered heteroaryl group is formed, wherein the 4-6 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally further surrounded by one or more elements selected from deuterium, halogen, hydroxyl, =O, C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated 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 6-8 Aryl, C 6-8 Aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy, amino, C1-4 Alkyl monosubstituted amino, C 1-4 Alkyl disubstituted amino and C 1-4 The alkyl acyl group is substituted by a substituent; and

[0045] Each r is independently 0, 1, or 2.

[0046] As a further preferred embodiment, the compound of formula (I), its stereoisomers, or its pharmaceutically acceptable salts, wherein the compound of formula (I) has the structure of the compound of formula (II) as follows:

[0047]

[0048] Where X1 is N or CH; X2 is N or CR 15 ;

[0049] R1 is selected from hydrogen, deuterium, and C. 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, the above groups optionally further selected by one or more radicals selected from deuterium, halogen, hydroxyl, =O, 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 6-8 Aryl, C 6-8 aryloxy, 5-8 heteroaryl, 5-8 heteroaryloxy and -NR 22 R 23 The substituents are replaced;

[0050] R3, R4, R5, R6, and R7 are each independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-8 Aryl, 5-8 quinone heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR) 16 )R 17 -C 0-4 Alkyl-N=S(O)R 17 R 18 -C 0-4 Alkyl-N=SR 17 R 18 -C 0-4 Alkyl-OS(O)2R 19 -C 0-4 Alkyl-S(O) r R19 -C 0-4 Alkyl-P(O)(OR) 20 )R 19 -C 0-4 Alkyl-OR 20 -C 0-4 Alkyl-C(O)OR 20 -C 0-4 Alkyl-C(O)SR 20 -C 0-4 Alkyl-SC(O)R 21 -C 0-4 Alkyl-C(O)R 21 -C 0-4 Alkyl-OC(O)R 21 -C 0-4 Alkyl-NR 22 R 23 -C 0-4 Alkyl-C (=NR) 22 )R 21 -C 0-4 Alkyl-N(R) 22 )-C(=NR 23 )R 21 -C 0-4 Alkyl-C(O)NR 22 R 23 and -C 0-4 Alkyl-N(R) 22 )-C(O)R 21 Alternatively, two adjacent substituents of R3, R4, R5, R6, and R7, along with their directly attached portions, form a 5-8 membered carbon ring, a 5-8 membered heterocyclic ring, a 6-membered aromatic ring, or a 5-6 membered heteroaromatic ring. These groups are independently and optionally further substituents selected from one or more groups chosen from deuterium, halogens, cyano groups, and C. 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-8 Aryl, 5-8 heteroaryl, =O, =S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR) 16 )R 17 -C 0-4 Alkyl-N=S(O)R 17 R 18 -C 0-4 Alkyl-N=SR 17 R 18 -C0-4 Alkyl-OS(O)2R 19 -C 0-4 Alkyl-S(O) r R 19 -C 0-4 Alkyl-P(O)(OR) 20 )R 19 -C 0-4 Alkyl-OR 20 -C 0-4 Alkyl-C(O)OR 20 -C 0-4 Alkyl-C(O)SR 20 -C 0-4 Alkyl-SC(O)R 21 -C 0-4 Alkyl-C(O)R 21 -C 0-4 Alkyl-OC(O)R 21 -C 0-4 Alkyl-NR 22 R 23 -C 0-4 Alkyl-C (=NR) 22 )R 21 -C 0-4 Alkyl-N(R) 22 )-C(=NR 23 )R 21 -C 0-4 Alkyl-C(O)NR 22 R 23 and -C 0-4 Alkyl-N(R) 22 )-C(O)R 21 The substituents are replaced;

[0051] R 10 and R 11 Each is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 quinone heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-OR 20 -C 0-4 Alkyl-C(O)OR 20 -C 0-4 Alkyl-C(O)R 21 -C 0-4 Alkyl-OC(O)R 21 -C0-4 Alkyl-NR 22 R 23 -C 0-4 Alkyl-C(O)NR 22 R 23 and -C 0-4 Alkyl-N(R) 22 )-C(O)R 21 Or, R 10 and R 11 The carbon atoms directly bonded to it form C(O), C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl or 5-6 heteroaryl groups, wherein the above groups are independently and optionally further selected by one or more radicals selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 heteroaryl, =O, =S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-OR 20 -C 0-4 Alkyl-C(O)OR 20 -C 0-4 Alkyl-C(O)R 21 -C 0-4 Alkyl-OC(O)R 21 -C 0-4 Alkyl-NR 22 R 23 -C 0-4 Alkyl-C(O)NR 22 R 23 and -C 0-4 Alkyl-N(R) 22 )-C(O)R 21 The substituents are replaced;

[0052] R 15 Selected from hydrogen, deuterium, cyano, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-8 Aryl, 5-8 quinone heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR) 16 )R 17 -C 0-4 Alkyl-N=S(O)R17 R 18 -C 0-4 Alkyl-N=SR 17 R 18 -C 0-4 Alkyl-OS(O)2R 19 -C 0-4 Alkyl-S(O) r R 19 -C 0-4 Alkyl-P(O)(OR) 20 )R 19 -C 0-4 Alkyl-OR 20 -C 0-4 Alkyl-C(O)OR 20 -C 0-4 Alkyl-C(O)SR 20 -C 0-4 Alkyl-SC(O)R 21 -C 0-4 Alkyl-C(O)R 21 -C 0-4 Alkyl-OC(O)R 21 -C 0-4 Alkyl-NR 22 R 23 -C 0-4 Alkyl-C (=NR) 22 )R 21 -C 0-4 Alkyl-N(R) 22 )-C(=NR 23 )R 21 -C 0-4 Alkyl-C(O)NR 22 R 23 and -C 0-4 Alkyl-N(R) 22 )-C(O)R 21 The aforementioned groups are independently and optionally further selected by one or more radicals selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-8 Aryl, 5-8 heteroaryl, =O, =S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-OR 20 -C 0-4 Alkyl-C(O)OR 20 -C0-4 Alkyl-C(O)R 21 -C 0-4 Alkyl-OC(O)R 21 -C 0-4 Alkyl-NR 22 R 23 -C 0-4 Alkyl-C(O)NR 22 R 23 and -C 0-4 Alkyl-N(R) 22 )-C(O)R 21 The substituent is replaced by the substituent, provided that when R 15 When the nitrogen atom is hydrogen, at least one of R3, R4, R5, R6 and R7 is a 3-8 member nitrogen-containing heterocyclic group, wherein the nitrogen atom is attached to the benzene ring;

[0053] Among them, R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 And r as described in compound (I).

[0054] As a further preferred embodiment, the compound of formula (I), its stereoisomers, or its pharmaceutically acceptable salts, wherein the compound of formula (I) has the following structure as a compound of formula (III):

[0055]

[0056] Ring A has the following structure:

[0057]

[0058] R1 is selected from hydrogen, deuterium, methyl, ethyl, isopropyl, and cyclopropyl;

[0059] Each R3 and R7 is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, and C. 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, hydroxyl, methoxy, ethoxy, isopropoxy, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic hydroxyl, methylthio, ethylthio, carboxyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, acetyl, acetoxy, amino, dimethylamino, acetamino and carbamoyl;

[0060] R 15 Selected from cyano, ethynyl, cyclopropyl, or hydrogen, and

[0061] When R 15When selected from cyano, ethynyl, or cyclopropyl, and ring A is... At that time, R4 and R 6a Each is independently selected from halogens, C 1-4 Alkoxy, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic group or 3-8 membered heterocyclic group, wherein the C 1-4 Alkoxy, C 3-8 The cycloalkoxy, 3-8 membered heterocyclic group, or 3-8 membered heterocyclic group is each independently and optionally further selected by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-8 aryl, 5-8 heteroaryl, =O, =S, -SF5, -OR 20 -C(O)OR 20 -C(O)R 21 -OC(O)R 21 -NR 22 R 23 -C(O)NR 22 R 23 and -N(R) 22 )-C(O)R 21 The substituents are replaced;

[0062] When R 15 When selected from cyano, ethynyl, or cyclopropyl, and ring A is... hour,

[0063] R 6b Selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, hydroxyl, methoxy, ethoxy, isopropoxy, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic alkyl groups, carboxyl groups, amino groups, and dimethylamino groups;

[0064] When R 15 When selected from hydrogen, and ring A is At that time, R4 and R 6a Each is independently selected from halogens, C 1-4 Alkoxy, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic group or 3-8 membered heterocyclic group, wherein the C 1-4 Alkoxy, C 3-8 The cycloalkoxy, 3-8 membered heterocyclic group, or 3-8 membered heterocyclic group is each independently and optionally further selected by one or more groups selected from deuterium, halogen, cyano, C1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-8 aryl, 5-8 heteroaryl, =O, =S, -SF5, -OR 20 -C(O)OR 20 -C(O)R 21 -OC(O)R 21 -NR 22 R 23 -C(O)NR 22 R 23 and -N(R) 22 )-C(O)R 21 The substituents are replaced by R4 and R. 6a At least one of them is a 3-8 membered nitrogen-containing heterocyclic group, wherein the nitrogen atom is attached to the benzene ring, and the 3-8 membered nitrogen-containing heterocyclic group is optionally further composed of one or more elements selected from deuterium, halogen, cyano, C. 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-8 aryl, 5-8 heteroaryl, =O, =S, -SF5, -OR 20 -C(O)OR 20 -C(O)R 21 -OC(O)R 21 -NR 22 R 23 -C(O)NR 22 R 23 and -N(R) 22 )-C(O)R 21 The substituents are replaced;

[0065] Among them, R 20 R 21 R 22 and R 23 As described in compound (I).

[0066] As a further preferred embodiment, the compound of formula (I), its stereoisomers, or its pharmaceutically acceptable salts, wherein the compound of formula (I) has the structure of a compound of formula (IVa):

[0067]

[0068] Among them, R 15 Selected from cyano, ethynyl, or cyclopropyl;

[0069] Ring A has the following structure:

[0070]

[0071] R4 and R 6a Each is independently selected from halogens, C 1-4 Alkoxy, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic group or 3-8 membered heterocyclic group, wherein the C 1-4 Alkoxy, C 3-8 The cycloalkoxy, 3-8 membered heterocyclic group, or 3-8 membered heterocyclic group is each independently and optionally further selected by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-8 aryl, 5-8 heteroaryl, =O, =S, -SF5, -OR 20 and -NR 22 R 23 The substituents are replaced;

[0072] R 6b Selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, hydroxyl, methoxy, ethoxy, isopropoxy, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic alkyl groups, carboxyl groups, amino groups, and dimethylamino groups; among which, R 20 R 22 and R 23 As described in compound (I).

[0073] As a further preferred embodiment, in the compound of formula (I), its stereoisomers, or its pharmaceutically acceptable salts, R4 and R 6a Each of the following groups is independently selected from fluorine, chlorine, cyclopropoxy, cyclobutoxy, or a 3-8 member nitrogen-containing heterocyclic group, wherein each of the cyclopropoxy, cyclobutoxy, or 3-8 member nitrogen-containing heterocyclic group is optionally further selected from one or more groups selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, trideutermethyl, dideutermethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetyl, aziridine, phenyl, -SF5, =O, hydroxyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, amino, mono-C1-4 Alkylamino and diC 1-4 Substituents of alkylamino groups;

[0074] R 6b Selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, oxacyclobutyl, aziroxy, hydroxyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutoxy, carboxyl, amino, and dimethylamino.

[0075] As a further preferred embodiment, the compound of formula (I), its stereoisomers, or its pharmaceutically acceptable salts, wherein the compound of formula (I) has the following structure:

[0076]

[0077] Among them, R4 and R 6a Each is independently selected from halogens, C 1-4 Alkoxy, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic group or 3-8 membered heterocyclic group, wherein the C 1-4 Alkoxy, C 3-8 The cycloalkoxy, 3-8 membered heterocyclic group, or 3-8 membered heterocyclic group is each independently and optionally further selected by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-8 aryl, 5-8 heteroaryl, =O, =S, -SF5, -OR 20 and -NR 22 R 23 The substituents are replaced by R4 and R. 6a At least one of them is a 3-8 membered nitrogen-containing heterocyclic group, wherein the nitrogen atom is attached to the benzene ring, and each of the 3-8 membered nitrogen-containing heterocyclic groups is independently and optionally further selected by one or more elements selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-8 aryl, 5-8 heteroaryl, =O, =S, -SF5, -OR 20 and -NR 22 R 23 The substituents are replaced;

[0078] Among them, R 20 R 22 and R 23 As described in compound (I).

[0079] As a further preferred embodiment, in the compound of formula (I), its stereoisomers, or its pharmaceutically acceptable salts, R4 and R 6a Each of the following groups is independently selected from fluorine, chlorine, cyclopropoxy, cyclobutoxy, or a 3-8 member nitrogen-containing heterocyclic group, wherein each of the cyclopropoxy, cyclobutoxy, or 3-8 member nitrogen-containing heterocyclic group is optionally further selected from one or more groups selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, trideutermethyl, dideutermethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetyl, aziridine, phenyl, -SF5, =O, hydroxyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, amino, mono-C 1-4 Alkylamino and diC 1-4 The alkylamino group is substituted, provided that...

[0080] R4 and R 6a At least one of them is a 3-8 membered nitrogen-containing heterocyclic group, wherein the nitrogen atom is attached to the benzene ring, and each of the 3-8 membered nitrogen-containing heterocyclic groups is independently and optionally further selected from one or more of the following: deuterium, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuterylmethyl, dideuterylmethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxobutyl, aziroxybutyl, phenyl, -SF5, =O, hydroxyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, amino, mono-C 1-4 Alkylamino and diC 1-4 Substituents of alkylamino groups.

[0081] As a further preferred embodiment, in the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof, the 3-8 membered nitrogen-containing heterocyclic group is selected from the following structures:

[0082]

[0083] 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:

[0084]

[0085]

[0086] A second aspect of the present invention provides a method for preparing a compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, the method comprising the following steps: synthesizing a compound of formula (I) or a salt thereof by a condensation reaction with a compound of formula (IB) or a salt thereof, wherein the reaction route is as follows:

[0087]

[0088] The preparation method can be based on the definition of L and employ general condensation reactions in the art, for example,

[0089] When L is the bond, R a For halogens, R b -B(OH)2 or Or, R a -B(OH)2 or Halogen, R b It is a halogen;

[0090] When L is 0, R a hydroxyl or alkoxy, R b For halogen, or, R a For halogens, R b It is a hydroxyl or alkoxy group;

[0091] When L is S, R a It is a mercapto or alkylthio group, R b For halogen, or, R a For halogens, R b It is a mercapto or alkylthio group;

[0092] When L is C(O), C(O)O, or C(O)NH, R a For carboxyl, alkoxycarbonyl, R b It is a halogen, hydroxyl or amino group, or R a Halogen, hydroxyl or amino, R b It consists of carboxyl and alkoxycarbonyl groups;

[0093] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 X1, X2, and X3 are as defined in compound (I).

[0094] A 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.

[0095] The fourth aspect of the present invention provides the use of the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating MATP-related cancers or tumors.

[0096] As a preferred embodiment, the tumor or cancer is selected from endometrial adenocarcinoma, granulosa-theca cell carcinoma, Sertoli cell carcinoma of the testis, germ cell tumor, malignant teratoma, squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma, clear cell carcinoma, squamous cell carcinoma, staphylococcal sarcoma, fallopian tube cancer, adenocarcinoma, nephroblastoma, lymphoma, leukemia, bladder cancer, squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, prostate cancer, seminoma, teratoma, embryonal carcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, and adenomatoid tumor. Lipoma; Liver cancer, bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, gallbladder cancer, ampullary cancer, bile duct cancer, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus, dysplastic nevus, lipoma, hemangioma, acute and chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma, osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma Multiple myeloma, malignant giant cell tumor chordoma, osteochondroma, benign chondroma, chondroblastoma, chondromycinoma, osteoid osteoma, giant cell tumor, angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma, bronchogenic carcinoma, alveolar carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma-like hamartoma, mesothelioma, squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma, gastric cancer, lymphoma, leiomyosarcoma, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor Snake tumor, adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma, colorectal adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma, skull tumor, hemangioma, granuloma, xanthomas, osteitis deformans, meningioma, meningeal sarcoma, gliomatosis, astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal neurofibroma, meningioma, glioma, and sarcoma.

[0097] As a more preferred option, the cancer or tumor is selected from breast cancer, pancreatic cancer, skin cancer, bladder cancer, liver cancer, or head and neck cancer.

[0098] The present invention also relates to compounds of formula (I), their stereoisomers or pharmaceutically acceptable salts thereof, which are used as PRMT5 inhibitor drugs.

[0099] 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 medicaments for the treatment and / or prevention of PRMT5-mediated diseases.

[0100] The present invention also relates to a method for treating and / or preventing PRMT5-mediated diseases, comprising administering to a desired patient a therapeutically effective amount of the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof. Detailed Implementation

[0101] Through extensive and in-depth research, the inventors of this application have, for the first time, developed a PRMT5 inhibitor having the structure of formula (I). This series of compounds can be widely used in the preparation of drugs for the treatment and / or prevention of PRMT5-mediated diseases, and is expected to be developed into a new generation of PRMT5 inhibitors. Based on this, the present invention was completed.

[0102] Detailed explanation: Unless otherwise stated or specifically stated, the terms used in the specification and claims shall have the following meanings.

[0103] "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group, preferably including straight-chain alkyl groups with 1 to 10, 1 to 6, or 1 to 4 carbon atoms, and branched alkyl groups, 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, and 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 their various branched isomers, etc. "C 1-10 "Alkyl" refers to straight-chain alkyl groups comprising 1 to 10 carbon atoms and branched alkyl groups. 1-4 "Alkyl" refers to straight-chain alkyl groups comprising 1 to 4 carbon atoms and branched alkyl groups. 0-8 "Alkyl" refers to straight-chain alkyl groups comprising 0 to 8 carbon atoms and branched alkyl groups. 0-4 "Alkyl" refers to straight-chain alkyl groups containing 0 to 4 carbon atoms and branched alkyl groups.

[0104] The alkyl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C64, halogen, cyano, nitro, azido, halogen, cyano ... 1-10 Alkyl, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR) 16 )R 17 -C 0-8 Alkyl-N=S(O)R 17 R 18 -C 0-8 Alkyl-N=SR 17 R 18 -C 0-8 Alkyl-OS(O)2R 19 -C 0-8 Alkyl-S(O) r R 19 -C 0-8 Alkyl-P(O)(OR) 20 )R 19 -C 0-8 Alkyl-OR 20 -C 0-8 Alkyl-C(O)OR 20 -C 0-8 Alkyl-C(O)SR 20 -C 0-8 Alkyl-SC(O)R 21 -C 0-8 Alkyl-C(O)R 21 -C 0-8 Alkyl-OC(O)R 21 -C 0-8 Alkyl-NR 22 R 23 -C 0-8 Alkyl-C (=NR) 22 )R 21 -C 0-8 Alkyl-N(R) 22 )-C(=NR 23 )R 21 -C 0-8 Alkyl-C(O)NR 22 R 23 and -C0-8 Alkyl-N(R) 22 )-C(O)R 21 The substituents are replaced by the substituents.

[0105] "Cycloalkyl" or "carbocyclic" refers to a substituent in a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon. A partially unsaturated cyclic hydrocarbon is one that may contain one or more (preferably 1, 2, or 3) double bonds, but none of the rings has a fully conjugated π-electron system. Cycloalkyl groups are classified as monocyclic or polycyclic, and preferably include 3 to 12, 3 to 8, or 3 to 6 carbon atoms. For example, "C..." 3-12 "Cycloalkyl" refers to a cycloalkyl group consisting of 3 to 12 carbon atoms, "C 4-8 "Cycloalkyl" refers to a cycloalkyl group consisting of 4 to 8 carbon atoms, "C 3-8 "Cycloalkyl" refers to a cycloalkyl group consisting of 3 to 8 carbon atoms, "C 3-6 "Cycloalkyl" refers to a cycloalkyl group comprising 3 to 6 carbon atoms, wherein:

[0106] Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptanetrienyl, and cyclooctyl.

[0107] Polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups. "Spirocycloalkyl" refers to a polycyclic group in which a single carbon atom (called a spiro atom) is shared between the rings. These groups may contain one or more (preferably 1, 2, or 3) double bonds, but none of the rings has a fully conjugated π-electron system. Based on the number of shared spiro atoms between the rings, spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups. Spirocycloalkyl groups include, but are not limited to:

[0108]

[0109] "Fused cyclic alkyl" refers to a polycyclic aromatic hydrocarbon group in which each ring shares an adjacent pair of carbon atoms with the other rings in the system. One or more rings may contain one or more (preferably 1, 2, or 3) double bonds, but no ring has a fully conjugated π-electron system. Based on the number of constituent rings, fused cyclic alkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic. Fused cyclic alkyl groups include, but are not limited to:

[0110]

[0111] "Bridged cycloalkyl" refers to a polycyclic aromatic hydrocarbon group in which any two rings share two non-directly bonded carbon atoms. These groups may contain one or more (preferably 1, 2, or 3) double bonds, but none of the rings has a fully conjugated π-electron system. Based on the number of constituent rings, bridged cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic. Bridged cycloalkyl groups include, but are not limited to:

[0112]

[0113] The cycloalkyl ring can be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl ring, including but not limited to indanyl, tetrahydronaphthyl, benzocycloheptyl, etc.

[0114] The "cycloalkyl" or "carbocyclic" group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C64, etc. 1-10 Alkyl, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR) 16 )R 17 -C 0-8 Alkyl-N=S(O)R 17 R 18 -C 0-8 Alkyl-N=SR 17 R 18 -C 0-8 Alkyl-OS(O)2R 19 -C 0-8 Alkyl-S(O) r R 19 -C 0-8 Alkyl-P(O)(OR) 20 )R 19 -C 0-8 Alkyl-OR 20 -C 0-8 Alkyl-C(O)OR 20 -C 0-8 Alkyl-C(O)SR 20 -C 0-8 Alkyl-SC(O)R 21 -C 0-8 Alkyl-C(O)R 21 -C 0-8 Alkyl-OC(O)R 21 -C 0-8 Alkyl-NR 22 R 23 -C 0-8 Alkyl-C (=NR)22 )R 21 -C 0-8 Alkyl-N(R) 22 )-C(=NR 23 )R 21 -C 0-8 Alkyl-C(O)NR 22 R 23 and -C 0-8 Alkyl-N(R) 22 )-C(O)R 21 The substituents are replaced by the substituents.

[0115] "Heterocyclic group" or "heterocyclic" refers to a substituent for a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon. The partially unsaturated cyclic hydrocarbon is one that may contain one or more (preferably 1, 2, or 3) double bonds, but none of the rings has a fully conjugated π-electron system. The one or more (preferably 1, 2, 3, or 4) ring atoms in the heterocyclic group are selected from N, O, N·O, or S(O). r (where r is an integer 0, 1, or 2) heteroatoms, excluding the ring portions of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Preferably, the heterocyclic group includes 3 to 12, 3 to 8, or 3 to 6 ring atoms. For example, "3-6 membered heterocyclic group" refers to a heterocyclic group containing 3 to 6 ring atoms, "3-8 membered heterocyclic group" refers to a heterocyclic group containing 3 to 8 ring atoms, "4-8 membered heterocyclic group" refers to a heterocyclic group containing 4 to 8 ring atoms, "4-10 membered heterocyclic group" refers to a heterocyclic group containing 4 to 10 ring atoms, "5-8 membered heterocyclic group" refers to a heterocyclic group containing 5 to 8 ring atoms, and "3-12 membered heterocyclic group" refers to a heterocyclic group containing 3 to 12 ring atoms.

[0116] Monocyclic heterocyclic groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, oxobutyl, tetrahydrofuranyl, etc.

[0117] Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups. A "spiroheterocyclic group" refers to a polycyclic heterocyclic group in which one or more (preferably 1, 2, 3, or 4) ring atoms are selected from N, O, N·O, or S(O). r (Where r is an integer 0, 1, or 2) heteroatoms, with the remaining ring atoms being carbon. These may contain one or more double bonds (preferably 1, 2, or 3), but none of the rings has a fully conjugated π-electron system. Spiroheterocyclic groups are classified into monospirocyclic, bispirocyclic, or polyspirocyclic groups based on the number of shared spiroatoms between rings. Spiroheterocyclic groups include, but are not limited to:

[0118]

[0119] "Fused heterocyclic group" 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 fully conjugated π-electron system. The one or more (preferably 1, 2, 3, or 4) ring atoms are selected from N, O, N·O, or S(O). r (where r is an integer 0, 1, or 2) heteroatoms, with the remaining ring atoms being carbon. Based on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic alkyl groups. Fused heterocyclic groups include, but are not limited to:

[0120]

[0121] "Bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected. These groups may contain one or more (preferably 1, 2, or 3) double bonds, but none of the rings has a fully conjugated π-electron system. The one or more (preferably 1, 2, 3, or 4) ring atoms are selected from N, O, N·O, or S(O). r Bridged heterocyclic groups consist of heteroatoms (where r is an integer of 0, 1, or 2) and the remaining ring atoms are carbon. Based on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups. Bridged heterocyclic groups include, but are not limited to:

[0122]

[0123] The heterocyclic ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, including but not limited to:

[0124]

[0125] The "heterocyclic group" or "heterocycle" can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR) 16 )R 17 -C 0-8 Alkyl-N=S(O)R 17 R18 -C 0-8 Alkyl-N=SR 17 R 18 -C 0-8 Alkyl-OS(O)2R 19 -C 0-8 Alkyl-S(O) r R 19 -C 0-8 Alkyl-P(O)(OR) 20 )R 19 -C 0-8 Alkyl-OR 20 -C 0-8 Alkyl-C(O)OR 20 -C 0-8 Alkyl-C(O)SR 20 -C 0-8 Alkyl-SC(O)R 21 -C 0-8 Alkyl-C(O)R 21 -C 0-8 Alkyl-OC(O)R 21 -C 0-8 Alkyl-NR 22 R 23 -C 0-8 Alkyl-C (=NR) 22 )R 21 -C 0-8 Alkyl-N(R) 22 )-C(=NR 23 )R 21 -C 0-8 Alkyl-C(O)NR 22 R 23 and -C 0-8 Alkyl-N(R) 22 )-C(O)R 21 The substituents are replaced by the substituents.

[0126] "Aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group, a polycyclic (i.e., a ring with adjacent carbon atom pairs) group with a conjugated π-electron system, preferably an all-carbon aryl group containing 6-10 or 6-8 carbons, for example, "C 6-10 "Aryl" refers to a full-carbon aryl group containing 6-10 carbons, including but not limited to phenyl and naphthyl groups. 6-8 "Aryl" refers to a fully carbon-based aryl group containing 6-8 carbons. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, including but not limited to:

[0127]

[0128] The "aryl" or "aromatic ring" can be substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR) 16 )R 17 -C 0-8 Alkyl-N=S(O)R 17 R 18 -C 0-8 Alkyl-N=SR 17 R 18 -C 0-8 Alkyl-OS(O)2R 19 -C 0-8 Alkyl-S(O) r R 19 -C 0-8 Alkyl-P(O)(OR) 20 )R 19 -C 0-8 Alkyl-OR 20 -C 0-8 Alkyl-C(O)OR 20 -C 0-8 Alkyl-C(O)SR 20 -C 0-8 Alkyl-SC(O)R 21 -C 0-8 Alkyl-C(O)R 21 -C 0-8 Alkyl-OC(O)R 21 -C 0-8 Alkyl-NR 22 R 23 -C 0-8 Alkyl-C (=NR) 22 )R 21 -C 0-8 Alkyl-N(R) 22 )-C(=NR 23 )R 21 -C 0-8 Alkyl-C(O)NR22 R 23 and -C 0-8 Alkyl-N(R) 22 )-C(O)R 21 The substituents are replaced by the substituents.

[0129] "Heteroaryl" or "heteroary ring" refers to a heteroaryl system containing one or more (preferably 1, 2, 3, or 4) heteroatoms, including N, O, N·O, and S(O)r (where r is an integer 0, 1, or 2), preferably a heteroaryl system containing 5-10, 5-8, or 5-6 ring atoms. For example, "5-8-membered heteroaryl" refers to a heteroaryl system containing 5-8 ring atoms, and "5-10-membered heteroaryl" refers to a heteroaryl system containing 5-10 ring atoms, including but not limited to furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring can be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, including but not limited to:

[0130]

[0131] The "heteroaryl" or "heteroary ring" can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR) 16 )R 17 -C 0-8 Alkyl-N=S(O)R 17 R 18 -C 0-8 Alkyl-N=SR 17 R 18 -C 0-8 Alkyl-OS(O)2R 19 -C 0-8 Alkyl-S(O) r R 19 -C 0-8 Alkyl-P(O)(OR) 20 )R 19 -C0-8 Alkyl-OR 20 -C 0-8 Alkyl-C(O)OR 20 -C 0-8 Alkyl-C(O)SR 20 -C 0-8 Alkyl-SC(O)R 21 -C 0-8 Alkyl-C(O)R 21 -C 0-8 Alkyl-OC(O)R 21 -C 0-8 Alkyl-NR 22 R 23 -C 0-8 Alkyl-C (=NR) 22 )R 21 -C 0-8 Alkyl-N(R) 22 )-C(=NR 23 )R 21 -C 0-8 Alkyl-C(O)NR 22 R 23 and -C 0-8 Alkyl-N(R) 22 )-C(O)R 21 The substituents are replaced by the substituents.

[0132] "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-chain or branched alkenyl group containing 2-10 or 2-4 carbons, for example, "C 2-10 "Alkenyl" refers to a straight-chain or branched alkenyl group containing 2-10 carbons. 2-4 "Alkenyl" refers to straight-chain or branched alkenyl groups containing 2-4 carbons. These include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl groups.

[0133] The "alkenyl" group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8Alkyl-S(O)(=NR) 16 )R 17 -C 0-8 Alkyl-N=S(O)R 17 R 18 -C 0-8 Alkyl-N=SR 17 R 18 -C 0-8 Alkyl-OS(O)2R 19 -C 0-8 Alkyl-S(O) r R 19 -C 0-8 Alkyl-P(O)(OR) 20 )R 19 -C 0-8 Alkyl-OR 20 -C 0-8 Alkyl-C(O)OR 20 -C 0-8 Alkyl-C(O)SR 20 -C 0-8 Alkyl-SC(O)R 21 -C 0-8 Alkyl-C(O)R 21 -C 0-8 Alkyl-OC(O)R 21 -C 0-8 Alkyl-NR 22 R 23 -C 0-8 Alkyl-C (=NR) 22 )R 21 -C 0-8 Alkyl-N(R) 22 )-C(=NR 23 )R 21 -C 0-8 Alkyl-C(O)NR 22 R 23 and -C 0-8 Alkyl-N(R) 22 )-C(O)R 21 The substituents are replaced by the substituents.

[0134] "Alkyne group" 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-chain or branched alkynyl group containing 2-10 or 2-4 carbon atoms, for example, "C 2-10 "Alkyne group" refers to a straight-chain or branched alkynyl group containing 2-10 carbons. 2-4 "Alynyl" refers to a straight-chain or branched alkynyl group containing 2-4 carbon atoms. It includes, but is not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, etc.

[0135] The "alkynyl group" can be substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR) 16 )R 17 -C 0-8 Alkyl-N=S(O)R 17 R 18 -C 0-8 Alkyl-N=SR 17 R 18 -C 0-8 Alkyl-OS(O)2R 19 -C 0-8 Alkyl-S(O) r R 19 -C 0-8 Alkyl-P(O)(OR) 20 )R 19 -C 0-8 Alkyl-OR 20 -C 0-8 Alkyl-C(O)OR 20 -C 0-8 Alkyl-C(O)SR 20 -C 0-8 Alkyl-SC(O)R 21 -C 0-8 Alkyl-C(O)R 21 -C 0-8 Alkyl-OC(O)R 21 -C 0-8 Alkyl-NR 22 R 23 -C 0-8 Alkyl-C (=NR) 22 )R 21 -C 0-8 Alkyl-N(R) 22 )-C(=NR 23 )R 21 -C 0-8 Alkyl-C(O)NR22 R 23 and -C 0-8 Alkyl-N(R) 22 )-C(O)R 21 The substituents are replaced by the substituents.

[0136] "Alkoxy" refers to -O-alkyl, where alkyl is defined as described above, for example, "C 1-10 "Alkoxy" refers to an alkyloxy group containing 1-10 carbon atoms. 1-4 "Alkoxy" refers to an alkyloxy group containing 1-4 carbons, "C 1-2 "Alkoxy" refers to alkyloxy groups containing 1-2 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, butoxy, etc.

[0137] The "alkoxy group" can be optionally substituted or unsubstituted. When substituted, the substituent, preferably one or more (preferably 1, 2, 3, or 4) groups, is independently selected from deuterium, halogen, cyano, nitro, azido, C... 1-10 Alkyl, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR) 16 )R 17 -C 0-8 Alkyl-N=S(O)R 17 R 18 -C 0-8 Alkyl-N=SR 17 R 18 -C 0-8 Alkyl-OS(O)2R 19 -C 0-8 Alkyl-S(O) r R 19 -C 0-8 Alkyl-P(O)(OR) 20 )R 19 -C 0-8 Alkyl-OR 20 -C 0-8 Alkyl-C(O)OR 20 -C 0-8 Alkyl-C(O)SR 20 -C 0-8 Alkyl-SC(O)R 21 -C 0-8Alkyl-C(O)R 21 -C 0-8 Alkyl-OC(O)R 21 -C 0-8 Alkyl-NR 22 R 23 -C 0-8 Alkyl-C (=NR) 22 )R 21 -C 0-8 Alkyl-N(R) 22 )-C(=NR 23 )R 21 -C 0-8 Alkyl-C(O)NR 22 R 23 and -C 0-8 Alkyl-N(R) 22 )-C(O)R 21 The substituents are replaced by the substituents.

[0138] "Cycloalkoxy" or "cycloalkyloxy" refers to -O-cycloalkyl, where cycloalkyl is defined as described above, for example, "C 3-12 "Cycloalkoxy" refers to a cycloalkyloxy group containing 3-12 carbons, "C 3-6 "Cycloalkoxy" refers to cycloalkyloxy groups containing 3-6 carbons, including but not limited to cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, etc.

[0139] "Cycloalkoxy" or "cycloalkyloxy" may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR) 16 )R 17 -C 0-8 Alkyl-N=S(O)R 17 R 18 -C 0-8 Alkyl-N=SR 17 R 18 -C 0-8 Alkyl-OS(O)2R 19 -C 0-8Alkyl-S(O) r R 19 -C 0-8 Alkyl-P(O)(OR) 20 )R 19 -C 0-8 Alkyl-OR 20 -C 0-8 Alkyl-C(O)OR 20 -C 0-8 Alkyl-C(O)SR 20 -C 0-8 Alkyl-SC(O)R 21 -C 0-8 Alkyl-C(O)R 21 -C 0-8 Alkyl-OC(O)R 21 -C 0-8 Alkyl-NR 22 R 23 -C 0-8 Alkyl-C (=NR) 22 )R 21 -C 0-8 Alkyl-N(R) 22 )-C(=NR 23 )R 21 -C 0-8 Alkyl-C(O)NR 22 R 23 and -C 0-8 Alkyl-N(R) 22 )-C(O)R 21 The substituents are replaced by the substituents.

[0140] "Heterocyclic oxy group" or "heterocyclic oxy group" refers to -O-heterocyclic groups, wherein the definition of heterocyclic groups is as described above, including but not limited to azirrocyclobutyoxy, oxocyclobutyoxy, azirrocyclopentyloxy, nitrogen, oxocyclohexyloxy, etc.

[0141] The "heterocyclic oxy group" or "heterocyclic oxy group" can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8Alkyl-S(O)(=NR) 16 )R 17 -C 0-8 Alkyl-N=S(O)R 17 R 18 -C 0-8 Alkyl-N=SR 17 R 18 -C 0-8 Alkyl-OS(O)2R 19 -C 0-8 Alkyl-S(O) r R 19 -C 0-8 Alkyl-P(O)(OR) 20 )R 19 -C 0-8 Alkyl-OR 20 -C 0-8 Alkyl-C(O)OR 20 -C 0-8 Alkyl-C(O)SR 20 -C 0-8 Alkyl-SC(O)R 21 -C 0-8 Alkyl-C(O)R 21 -C 0-8 Alkyl-OC(O)R 21 -C 0-8 Alkyl-NR 22 R 23 -C 0-8 Alkyl-C (=NR) 22 )R 21 -C 0-8 Alkyl-N(R) 22 )-C(=NR 23 )R 21 -C 0-8 Alkyl-C(O)NR 22 R 23 and -C 0-8 Alkyl-N(R) 22 )-C(O)R 21 The substituents are replaced by the substituents.

[0142] “C 1-10 "alkylyl" refers to C 1-10 The monovalent group remaining after removing the hydroxyl group from an alkyl acid is usually also represented as "C". 0-9 "alkyl-C(O)-", for example, "C1 alkyl-C(O)-" refers to acetyl; "C2 alkyl-C(O)-" refers to propionyl; "C3 alkyl-C(O)-" refers to butyryl or isobutyryl.

[0143] -C0-8 Alkyl-S(O)(=NR) 16 )R 17 "Refers to -S(O)(=NR)" 16 )R 17 The sulfur atom in C is attached to C 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.

[0144] -C 0-8 Alkyl-N=S(O)R 17 R 18 "Refers to -N = S(O)R" 17 R 18 The nitrogen atom in C is attached to C 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.

[0145] -C 0-8 Alkyl-N=SR 17 R 18 "Refers to -N = SR" 17 R 18 The nitrogen atom in C is attached to C 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.

[0146] -C 0-8 Alkyl-OS(O)2R 19 "referring to -OS(O)2R" 19 The oxygen atom in C is attached to C 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.

[0147] -C 0-8 Alkyl-S(O) r R 19 "Referring to -S(O)" r R 19 The sulfur atom in C is attached to C 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.

[0148] -C 0-8 Alkyl-P(O)(OR) 20 )R 19 "Refers to -P(O)(OR)" 20 )R 19 The phosphorus atom in C is linked to 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.

[0149] -C 0-8 Alkyl-OR20 "referring to -OR" 20 The oxygen atom in C is attached to C 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.

[0150] -C 0-8 Alkyl-C(O)OR 20 "Refers to -C(O)OR 20 The carbonyl group in the C10 group is linked to the carbonyl group in the C10 group. 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.

[0151] -C 0-8 Alkyl-C(O)SR 20 "Refers to -C(O)SR 20 The carbonyl group in the C10 group is linked to the carbonyl group in the C10 group. 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.

[0152] -C 0-8 Alkyl-SC(O)R 21 "Referring to -SC(O)R" 21 The sulfur atom in C is attached to C 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.

[0153] -C 0-8 Alkyl-C(O)R 21 "Referring to -C(O)R" 21 The carbonyl group in the C10 group is linked to the carbonyl group in the C10 group. 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.

[0154] -C 0-8 Alkyl-OC(O)R 21 "Refers to -OC(O)R 21 The oxygen atom in C is attached to C 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.

[0155] -C 0-8 Alkyl-NR 22 R 22 "Referring to -NR" 21 R 22 The nitrogen atom in C is attached to C 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.

[0156] -C 0-8 Alkyl-C (=NR) 22 )R21 "Refers to -C(=NR)" 22 )R 21 The carbon atom in C is attached to C 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.

[0157] -C 0-8 Alkyl-N(R) 22 )-C(=NR 23 )R 21 "Referring to -N(R)" 22 )-C(=NR 23 )R 21 The nitrogen atom in C is attached to C 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.

[0158] -C 0-8 Alkyl-C(O)NR 22 R 23 "Referring to -C(O)NR" 22 R 23 The carbonyl group in the C10 group is linked to the carbonyl group in the C10 group. 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.

[0159] -C 0-8 Alkyl-N(R) 22 )-C(O)R 21 "Referring to -N(R)" 22 )-C(O)R 21 The nitrogen atom in C is attached to C 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.

[0160] "Hydrogen replaces C" 1-10 "Alkyl" refers to 1-10 carbon alkyl groups on an alkyl group in which the hydrogen atoms are optionally replaced by fluorine, chlorine, bromine, or iodine atoms, including but not limited to difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, etc.

[0161] "Hydrogen replaces C" 1-10 "Alkoxy" refers to 1-10 carbon alkoxy groups on an alkyl group, where the hydrogen atom is optionally replaced by a fluorine, chlorine, bromine, or iodine atom. These include, but are not limited to, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, and tribromomethoxy.

[0162] "Deuterium replaces C" 1-10 "Alkyl" refers to a 1-10 carbon alkyl group on an alkyl group in which the hydrogen atoms are optionally replaced by deuterium atoms. This includes, but is not limited to, monodeuterylmethyl, dideuterylmethyl, trideuterylmethyl, etc.

[0163] "Halogen" refers to fluorine, chlorine, bromine, or iodine; "n-BuLi" refers to n-butyllithium; "THF" refers to tetrahydrofuran; "m-CPBA" refers to m-chloroperoxybenzoic acid; "CuCN" refers to cuprous cyanide; "DMF" refers to dimethylformamide; "K2CO3" refers to potassium carbonate; "dioxane" refers to dioxane; "NBS" refers to N-bromosuccinimide; "MeCN" refers to acetonitrile; and "DMSO" refers to dimethyl sulfoxide.

[0164] "Optional" or "optionally" means that the event or environment described below may but does not have to occur. This description includes the possibility that the event or environment may or may not occur, that is, it includes both substituted and unsubstituted cases. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present. This description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0165] "Substituted" means that one or more "hydrogen atoms" in a group are independently replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, conforming to the valence bond theory in chemistry, and that a person skilled in the art can determine (through experiment or theory) possible or impossible substitutions without much 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 alkene).

[0166] Stereoisomers, also known as cis-trans isomers, are isomers formed by different spatial arrangements of atoms in a molecule. They can be classified into two main categories: cis-trans isomers and enantiomers, or enantiomers and diastereomers. Stereoisomers resulting from the rotation of single bonds are called conformational stereo-isomers, sometimes also called rotamers. Stereoisomers resulting from bond length, bond angle, the presence of double bonds, or rings within the molecule are called configurational stereo-isomers. Configurational stereo-isomers are further divided into two categories. Those resulting from the inability of single bonds in double bonds or cyclic carbon atoms to rotate freely are called geometrical isomers, also known as cis-trans isomers, and have 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 lack of antiaxial symmetry in their molecules are called optical isomers, which are classified into R and S configurations. In this invention, unless otherwise specified, "stereoisomer" can be understood to include one or more of the enantiomers, configuration isomers, and conformational isomers described above.

[0167] In this invention, "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable acid addition salt, including inorganic acid salts and organic acid salts, which can be prepared by methods known in the art.

[0168] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0169] The present invention will be further described in detail and completely below with reference to the embodiments, but this is by no means a limitation of the present invention, nor is the present invention limited to the contents of the embodiments.

[0170] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 / 500 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0171] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 6120 mass spectrometer. HPLC was performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C18 150×4.6 mm column).

[0172] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The standard size for TLC is 0.15mm to 0.20mm, while the standard size for separating and purifying products using TLC is 0.4mm to 0.5mm. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0173] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0174] Unless otherwise specified, all reactions in this invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature is expressed in degrees Celsius (°C).

[0175] I. Preparation of intermediates

[0176] Preparation of Intermediate 1: 2-(4-bromo-1-methyl-1H-pyrazol-5-yl)-3-fluoro-1-naphthyl nitrile

[0177]

[0178] Step 1: Synthesis of 5-bromo-7-fluoro-9-methyl-1,4-dihydro-1,4-cycloiminonaphthalene

[0179]

[0180] 1,3-Dibromo-2-chloro-5-fluorobenzene (45.0 g, 156 mmol) and N-methyl-2-pyrrole (27.8 mL, 312 mmol) were dissolved in tetrahydrofuran (1000 mL), and n-butyllithium (65 mL, 162 mmol) was added dropwise at -30 °C under nitrogen protection. After the addition was complete, the mixture was stirred at -30 °C for 0.5 h, and then at 25 °C for 12 h. The reaction mixture was slowly poured into 1000 mL of water, extracted with ethyl acetate (1000 mL * 3), washed with saturated sodium chloride aqueous solution (1000 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was separated by rapid silica gel column chromatography to obtain 5-bromo-7-fluoro-9-methyl-1,4-dihydro-1,4-cycloiminonaphthalene (19.0 g, yield 48%).

[0181] 1 H NMR (400MHz, CDCl3) δ7.16-6.62(m,4H),4.85-4.44(m,2H),2.32(br s,1H),2.16(br s,1H),2.06(s,1H),1.81(br s,1H).

[0182] Step 2: Synthesis of 1-bromo-3-fluoronaphthalene

[0183]

[0184] 44.0 g (173 mmol) of 5-bromo-7-fluoro-9-methyl-1,4-dihydro-1,4-cycloiminonaphthalene was dissolved in chloroform (450 mL). m-CPBA (70.2 g, 85% purity, 346 mmol) was slowly added in portions at 0 °C. The reaction mixture was reacted at 25 °C for 14 hours. The reaction mixture was slowly poured into 500 mL of water and extracted with dichloromethane (500 mL x 3). The extract was washed with saturated sodium sulfite aqueous solution (400 mL x 2), followed by washing with saturated brine (400 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. The residue was separated by rapid silica gel column chromatography to obtain 1-bromo-3-fluoronaphthalene (34.0 g, 87% yield).

[0185] 1H NMR (400MHz, CDCl3) δ8.29-8.19(m,1H),7.78(br dd,J=2.9,4.5Hz,1H),7.67-7.52(m,3H),7.50-7.41(m,1H).

[0186] Step 3: Synthesis of 3-fluoro-1-naphthyl nitrile

[0187]

[0188] 1-Bromo-3-fluoronaphthalene (34.0 g, 151 mmol) was dissolved in DMF (450 mL), and cuprous cyanide (23.2 mL, 755 mmol) was slowly added under nitrogen protection at 0 °C. The mixture was reacted at 145 °C for 12 hours under nitrogen protection. The reaction solution was slowly poured into 250 mL of saturated brine, extracted with ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was separated by rapid silica gel column chromatography to give 3-fluoro-1-naphthonitrile (19.0 g, 66% yield).

[0189] 1 H NMR (400MHz, CDCl3) δ8.17(m,1H)7.81(m,1H)7.62(m,4H).

[0190] Step 4: Synthesis of 3-fluoro-2-iodo-1-naphthyl nitrile

[0191]

[0192] 3-Fluoro-1-naphthonitrile (1.89 g, 3.57 mmol) was dissolved in tetrahydrofuran (200 mL), and LDA (48.2 mL, 96.4 mmol) was slowly added dropwise under nitrogen protection. After the addition was complete, the reaction was carried out at -70 °C for 30 minutes under nitrogen protection. Iodine (28.3 mL, 114 mmol) was dissolved in tetrahydrofuran (200 mL) and added to the reaction mixture at -70 °C under nitrogen protection. The mixture was stirred at -70 °C for 30 minutes and then reacted at 25 °C for 17 hours. After the reaction was complete, the mixture was diluted with water (300 mL), extracted with ethyl acetate (3 x 300 mL), washed with saturated sodium chloride aqueous solution (400 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was separated by rapid silica gel column chromatography to obtain 3-fluoro-2-iodo-1-naphthonitrile (16.0 g, yield 52%).

[0193] 1 H NMR (400MHz, CDCl3) δ8.29-8.22(m,1H),7.91-7.84(m,1H),7.76-7.64(m,3H).

[0194] Step 5: Synthesis of 3-fluoro-2-(1-methyl-1H-pyrazol-5-yl)-1-naphthyl nitrile

[0195]

[0196] 3-Fluoro-2-iodo-1-naphthionitrile (8.00 g, 26.9 mmol) was dissolved in 1,4-dioxane (80 mL) and water (16 mL). Under nitrogen protection, sodium bicarbonate (42.4 g, 505 mmol), potassium carbonate (608 mg, 4.40 mmol), 1-methyl-1H-pyrazole-5-boronic acid linalool ester (14.0 g, 67.3 mmol), and Pd-118 (0.88 g, 1.34 mmol) were added to the reaction solution. The reaction solution was reacted at 80 °C for 2 hours under nitrogen protection. The reaction solution was extracted with ethyl acetate (80 mL * 3), washed with saturated sodium chloride aqueous solution (200 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. The residue was separated by rapid silica gel column chromatography to obtain 3-fluoro-2-(1-methyl-1H-pyrazole-5-yl)-1-naphthionitrile (6.0 g, yield 76%). MS m / z(ESI): 252 [M+H] + .

[0197] 1 H NMR (400MHz, CDCl3) δ8.36-8.30(m,1H),7.98-7.92(m,1H),7.88(d,J=9.8Hz,1H),7.77-7. 73(m,2H),7.69(d,J=2.0Hz,1H),7.28(s,1H),6.63(d,J=2.0Hz,1H),3.86(d,J=1.5Hz,3H).

[0198] Step 6: Synthesis of 2-(4-bromo-1-methyl-1H-pyrazol-5-yl)-3-fluoro-1-naphthyl nitrile

[0199]

[0200] 3-Fluoro-2-(1-methyl-1H-pyrazole-5-yl)-1-naphthonitrile (6.00 g, 23.8 mmol) was dissolved in acetonitrile (500 mL), and NBS (7.65 g, 42.9 mmol) was added. The reaction mixture was reacted at 25 °C for 24 hours. After the reaction was complete, the reaction mixture was extracted with water (100 mL) and ethyl acetate (100 mL * 3), washed with saturated sodium chloride aqueous solution (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was separated by rapid silica gel column chromatography to obtain 2-(4-bromo-1-methyl-1H-pyrazole-5-yl)-3-fluoro-1-naphthonitrile (8.00 g, yield 91%).

[0201] 1 H NMR (400MHz, DMSO-d6) δ8.49 (d, J = 10.4Hz, 1H), 8.27-8.19 (m, 2H), 7.93-7.85 (m, 3H), 3.81 (s, 3H).

[0202] Intermediate 2: Preparation of tert-butyl carbamate ((3-bromo-8-oxo-7,8-dihydropyrido[2,3-d]pyridazin-5-yl)methyl)carbamate

[0203]

[0204] Step 1: Synthesis of methyl 5-bromo-3-(bromomethyl)pyridine-2-carboxylate

[0205]

[0206] Methyl 5-bromo-3-methylpyridine-2-carboxylate (3.0 g, 13.04 mmol) and NBS (3.48 g, 19.56 mmol) were placed in carbon tetrachloride (50 mL) and stirred at 80 °C for 18 hours under nitrogen protection. The reaction solution was concentrated and separated by column chromatography to obtain methyl 5-bromo-3-(bromomethyl)pyridine-2-carboxylate (4.0 g, 90% yield).

[0207] 1 H NMR (400MHz, DMSO-d6) δ 8.69 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 4.89 (s, 2H), 4.02 (s, 3H).

[0208] Step 2: Synthesis of 3-bromofurano[3,4-b]pyridin-7(5H)-one

[0209]

[0210] Methyl 5-bromo-3-(bromomethyl)pyridine-2-carboxylate (2000 mg, 6.47 mmol), water (10 mL), and 1,4-dioxane (50 mL) were placed in a nitrogen atmosphere and stirred at 100 °C for 18 hours. The reaction mixture was concentrated and separated by column chromatography to obtain 3-bromofurano[3,4-b]pyridine-7(5H)-one (1.0 g, yield 61%). MS m / z (ESI): 213 / 215 [M+H] + Step 3: Synthesis of (Z)-3-bromo-5-((dimethylamino)methylene)furano[3,4-b]pyridin-7(5H)-one

[0211]

[0212] 3-Bromofurano[3,4-b]pyridin-7(5H)-one (1.0 g, 4.67 mmol) and potassium tert-butoxide (52 mg, 0.47 mmol) were placed in DMFDMA and stirred at 100 °C for 18 hours under nitrogen protection. The reaction mixture was concentrated and slurried with PE to obtain (Z)-3-bromo-5-((dimethylamino)methylene)furano[3,4-b]pyridin-7(5H)-one (1.0 g, 70% yield). MS m / z (ESI): 269 / 271 [M+H] + .

[0213] Step 4: Synthesis of 3-bromo-5-((dimethylamino)methyl)pyrido[2,3-d]pyridazin-8(7H)-one

[0214]

[0215] (Z)-3-bromo-5-((dimethylamino)methylene)furano[3,4-b]pyridin-7(5H)-one (7.0 g, 26.0 mmol) and hydrazine hydrate (7.44 mL, 130.1 mmol) were placed in ethanol (50 mL) and stirred at 80 °C for 18 hours under nitrogen protection. The reaction mixture was concentrated and separated by column chromatography to obtain 3-bromo-5-((dimethylamino)methyl)pyrido[2,3-d]pyridazine-8(7H)-one (3.0 g, yield 25%). MS m / z (ESI): 283 / 285 [M+H] + .

[0216] Step 5: Synthesis of 3-bromo-5-(chloromethyl)pyrido[2,3-d]pyridazin-8(7H)-one

[0217]

[0218] 3-Bromo-5-((dimethylamino)methyl)pyrido[2,3-d]pyridazin-8(7H)-one (300 mg, 1.06 mmol) and 2-methylpropyl chloromethane (0.28 mL, 2.12 mmol) were placed in 10 mL of THF and stirred at room temperature for 4 hours under nitrogen protection. The reaction mixture was concentrated and slurried with PE to obtain 3-bromo-5-(chloromethyl)pyrido[2,3-d]pyridazin-8(7H)-one (250 mg, yield 38%). MS m / z (ESI): 275 / 277 [M+H] + .

[0219] Step 6: Synthesis of 2-((3-bromo-8-oxo-7,8-dihydropyrido[2,3-d]pyridazin-5-yl)methyl)isoindoline-1,3-dione

[0220]

[0221] 3-Bromo-5-(chloromethyl)pyrido[2,3-d]pyridazin-8(7H)-one (1.5 g, 5.46 mmol) and potassium phthalimide (1.52 g, 8.20 mmol) were placed in DMF (50 mL) and stirred at 90 °C for 2 hours under nitrogen protection. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give 2-((3-bromo-8-oxo-7,8-dihydropyrido[2,3-d]pyridazin-5-yl)methyl)isoindoline-1,3-dione (2.0 g, 95% yield). MS m / z (ESI): 385 / 387 [M+H] + .

[0222] Step 7: Synthesis of 5-(aminomethyl)-3-bromopyrido[2,3-d]pyridazine-8(7H)-one

[0223]

[0224] 2-((3-bromo-8-oxo-7,8-dihydropyridano[2,3-d]pyridazin-5-yl)methyl)isoindoline-1,3-dione (1.0 g, 4.67 mmol) and hydrazine hydrate (498 mg, 15.58 mmol) were placed in ethanol (200 mL) and stirred at 70 °C for 18 hours under nitrogen protection. The reaction mixture was concentrated to give 5-(aminomethyl)-3-bromopyridano[2,3-d]pyridazin-8(7H)-one (900 mg, yield 67%). MS m / z (ESI): 256 / 258 [M+H] + .

[0225] Step 8: Synthesis of tert-butyl ((3-bromo-8-oxo-7,8-dihydropyridino[2,3-d]pyridazin-5-yl)methyl)carbamate

[0226]

[0227] 5-(aminomethyl)-3-bromopyrido[2,3-d]pyridazin-8(7H)-one (900 mg, 3.53 mmol) and triethylamine (2.45 mL, 17.64 mmol) were placed in dichloromethane (100 mL) under nitrogen protection, and di-tert-butyl dicarbonate (3.02 mL, 14.11 mmol) was added. The mixture was stirred at room temperature for 18 hours. The reaction solution was diluted with water and extracted with EtOAc. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the solution was separated by column chromatography to obtain ((3-bromo-8-oxo-7,8-dihydropyrido[2,3-d]pyridazin-5-yl)methyl)tert-butyl carbamate (300 mg, yield 23%). MS m / z (ESI): 355 / 357 [M+H] + .

[0228] Preparation of Intermediate 3: (4-((bis(tert-butoxycarbonyl)amino)methyl)-8-cyano-1-oxo-1,2-dihydrodiazanaphthalene-6-yl)boronic acid

[0229]

[0230] Step 1: Synthesis of 4-bromo-2-iodo-6-methylbenzoic acid

[0231] A mixture of 4-bromo-2-methylbenzoic acid (100 g, 465.1 mmol), NIS (156.93 g, 697.5 mmol), and Pd(OAc)₂ (10.44 g, 46.5 mmol) in DMF (600 mL) was degassed with nitrogen and then stirred at 100 °C for 3 hours. The reaction mixture was extracted with ethyl acetate (1 L) and water (1 L), washed with saturated brine (1 L), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to obtain 4-bromo-2-iodo-6-methylbenzoic acid (120 g, yield 57%).

[0232] Step 2: Synthesis of 5-bromo-7-iodo-1,3-dihydro-2-benzofuran-1-one

[0233]

[0234] 4-Bromo-2-iodo-6-methylbenzoic acid (60 g, 176.0 mmol), TBAB (109.2 mL, 352.0 mmol), and Na₂O₈S₂ (99.5 mL, 1003.1 mmol) were added separately to a CH₃CN (600 mL) solution. The mixture was stirred at 80 °C for 24 hours. TLC showed that the reaction was complete. The reaction solution was extracted with ethyl acetate (600 mL) and water (600 mL), washed with saturated brine (600 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to give 5-bromo-7-iodo-1,3-dihydro-2-benzofuran-1-one (20 g, yield 33%).

[0235] 1 H NMR (400MHz, DMSO-d6) δ 8.31 (d, J = 0.72 Hz, 1H), 8.04 (d, J = 1.07 Hz, 1H), 5.35 (s, 2H).

[0236] Step 3: Synthesis of (3Z)-5-bromo-3-[(dimethylamino)methylethylene]-7-iodo-1,3-dihydro-2-benzofuran-1-one

[0237]

[0238] Toluene (330 mL) was added to a flask containing 5-bromo-7-iodo-1,3-dihydro-2-benzofuran-1-one (33.5 g, 98.8 mmol), followed by [(tert-butoxy)(dimethylamino)methyl]dimethylamine (26.5 mL, 128.5 mmol). The mixture was stirred at 90 °C for 5 hours. TLC showed that the reaction was complete. The mixture was filtered, and the filter cake was dried to give compound (3Z)-5-bromo-3-[(dimethylamino)methylethylene]-7-iodo-1,3-dihydro-2-benzofuran-1-one as a yellow solid (20.1 g, 52% yield).

[0239] 1 H NMR (400MHz, DMSO-d6) δ7.96 (d, J = 1.19 Hz, 1H), 7.68 (d, J = 1.07 Hz, 1H), 7.07 (s, 1H), 3.12 (s, 6H).

[0240] Step 4: Synthesis of 6-bromo-4-[(dimethylamino)methyl]-8-iodo-1,2-dihydrophthalazin-1-one

[0241]

[0242] In a 500 mL flask, an ethanol solution (180 mL) of (3Z)-5-bromo-3-[(dimethylamino)methylethylene]-7-iodo-1,3-dihydro-2-benzofuran-1-one (18 g, 45.7 mmol) was added. Hydrazine hydrate (5.2 mL, 105.1 mmol) was added at 0 °C, followed by stirring at 25 °C for 0.5 h, and then at 50 °C for 18 h. The precipitate was directly filtered and dried under reduced pressure to give 6-bromo-4-[(dimethylamino)methyl]-8-iodo-1,2-dihydrophthalazine-1-one as a white solid (11.73 g, yield 63%).

[0243] 1 H NMR (400MHz, DMSO-d6) δ8.53 (d, J = 1.67 Hz, 1H), 8.35 (d, J = 1.67 Hz, 1H), 3.56 (s, 2H), 2.18 (s, 6H).

[0244] Step 5: Synthesis of 6-bromo-4-(chloromethyl)-8-iodo-1,2-dihydrophthalazin-1-one

[0245]

[0246] A mixture of 6-bromo-4-[(dimethylamino)methyl]-8-iodo-1,2-dihydrophthalazin-1-one (12 g, 29.48 mmol) in THF (140 mL) was degassed repeatedly with N2, cooled to 0 °C, and then chloro(2-methylpropoxy)methane (13.8 mL, 106.1 mmol) was added dropwise. The mixture was then stirred under nitrogen at 25 °C for 16 h. The reaction solution was extracted with ethyl acetate (100 mL) and water (100 mL), washed with saturated brine (100 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a white crude product. The crude product was stirred with MTBE (20 mL) at 25 °C for 30 min. The mixture was filtered, and the filter cake was dried to give 6-bromo-4-(chloromethyl)-8-iodo-1,2-dihydrophthalazin-1-one as a white solid (9.2 g, 78% yield).

[0247] 1 H NMR (400MHz, DMSO-d6) δppm 12.88 (s, 1H), 8.59 (d, J = 1.76 Hz, 1H), 8.27 (d, J = 1.76 Hz, 1H), 5.02 (s, 2H).

[0248] Step 6: Synthesis of tert-butyl N-[(7-bromo-5-iodo-4-oxo-3,4-dihydrophthalazin-1-yl)methyl]-N-[(tert-butyl)carbonyl]carbamate

[0249]

[0250] Bis(tert-butoxycarbonyl)amine (5.16 g, 23.73 mmol) was added to THF (100 mL), and lithium di(trimethylsilyl)amino (25.7 mL, 25.71 mmol) was added at 0 °C under N2 atmosphere. The mixture was stirred at -70 °C for 1 h under N2 atmosphere. Then, a mixture of 6-bromo-4-(chloromethyl)-8-iodo-1,2-dihydrophthalazin-1-one (7.9 g, 19.80 mmol) in tetrahydrofuran (100 mL) was added to the mixture. The resulting mixture was stirred at -70 °C for 2 h. The reaction solution was quenched with saturated NH4Cl (100 ml), extracted with ethyl acetate (80 ml) and water (100 ml), washed with saturated brine (100 ml), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to obtain tert-butyl N-[(7-bromo-5-iodo-4-oxo-3,4-dihydrophthalazin-1-yl)methyl]-N-[(tert-butyl)carbonyl]carbamate (4.09 g, yield 33%).

[0251] 1 H NMR (400MHz, DMSO-d6) δppm 12.69 (s, 1H), 8.60 (d, J = 1.76Hz, 1H), 8.26 (d, J = 1.76Hz, 1H), 4.98 (s, 2H), 1.39 (s, 18H).

[0252] Step 7: Synthesis of tert-butyl ((7-bromo-5-cyano-4-oxo-3,4-dihydrodiazanaphthyl-1-yl)methyl)(tert-butyloxycarbonyl)carbamate

[0253]

[0254] To a 250 mL single-necked flask, add tert-butyl N-[(7-bromo-5-iodo-4-oxo-3,4-dihydrophthalazin-1-yl)methyl]-N-[(tert-butyl)carbonyl]carbamate (1.4 g, 2.17 mmol), N,N-dimethylformamide (20 mL), and cuprous cyanide (194 mg, 2.17 mmol). Stir at 80 °C for three hours. Concentrate the reaction solution under reduced pressure. Dilute the residue with dichloromethane, wash with 5% ammonia solution and saturated brine, respectively. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain tert-butyl ((7-bromo-5-cyano-4-oxo-3,4-dihydrodiazanaphthyl)methyl)(tert-butyloxycarbonyl)carbamate (1.1 g, purity 88%, yield 93%). MS m / z (ESI): 479 / 481 [M+H] + .

[0255] Step 8: Synthesis of (4-((bis(tert-butoxycarbonyl)amino)methyl)-8-cyano-1-oxo-1,2-dihydrodiazanaphthalene-6-yl)boronic acid

[0256]

[0257] To a 100 mL single-necked flask, add tert-butyl ((7-bromo-5-cyano-4-oxo-3,4-dihydrodiazanaphthalene-1-yl)methyl)(tert-butoxycarbonyl)carbamate (1.5 g, 93% purity, 2.91 mmol), 1,4-dioxane (20 mL), potassium acetate (857 mg, 8.73 mmol), 1,1-bis(diphenylphosphine)dimerferropalladium dichloride (213 mg, 0.29 mmol), and pinacol diborate (2.22 g, 8.73 mmol), and stir at 80 °C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was separated by reversed-phase column chromatography to obtain (4-((bis(tert-butoxycarbonyl)amino)methyl)-8-cyano-1-oxo-1,2-dihydrodiazanaphthalene-6-yl)boronic acid (1090 mg, 65% purity, 55% yield). MS m / z(ESI): 445 [M+H] + .

[0258] Intermediates 4-7 can be prepared by selecting appropriate raw materials, referring to the synthesis methods of all or part of intermediates 1, 2, or 3.

[0259]

[0260] Preparation of intermediate 8 2-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-(3,3-difluoroacetidin-1-yl)-3-fluorobenzonitrile

[0261]

[0262] Step 1: Synthesis of 2-bromo-4-chloro-6-(3,3-difluoroacetidin-1-yl)-3-fluorobenzonitrile

[0263]

[0264] 2-Bromo-4-chloro-3,6-difluorobenzonitrile (100 mg, 0.40 mmol), potassium carbonate (219 mg, 1.58 mmol), and 3,3-difluoroacetidine hydrochloride (103 mg, 0.792 mmol) were dissolved in N-methylpyrrolidone (2 mL). The mixture was stirred overnight at 75 °C. After the reaction was completed, the mixture was cooled to room temperature, and water (20 mL) was added. The reaction solution was extracted with ethyl acetate (30 mL * 3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure. The crude product was separated by column chromatography to obtain 2-bromo-4-chloro-6-(3,3-difluoroacetidine-1-yl)-3-fluorobenzonitrile (50 mg, yield 39%). 1 H NMR (400MHz, CDCl3) δ6.49 (d, J = 5.6 Hz, 1H), 4.53 (t, J = 11.7 Hz, 4H).

[0265] Step 2: Synthesis of 4-chloro-6-(3,3-difluoroacetidin-1-yl)-3-fluoro-2-(1-methyl-1H-pyrazol-5-yl)benzonitrile

[0266]

[0267] 2-Bromo-4-chloro-6-(3,3-difluoroacetidin-1-yl)-3-fluorobenzonitrile (300 mg, 0.92 mmol), 1-methyl-5-(tetramethyl-1,3,2-dioxoboropentane-2-yl)-1H-pyrazole (249 mg, 1.20 mmol), and sodium bicarbonate (310 mg, 3.69 mmol) were dissolved in 1,4-dioxane (16 mL) and water (4 mL). CataCXium A Pd G3 (67 mg, 0.09 mmol) was added under nitrogen protection. The reaction mixture was stirred at 60 °C for 40 hours under nitrogen protection. After adding saturated sodium bicarbonate solution (30 mL), the mixture was extracted with dichloromethane (30 mL x 3). After concentrating the combined organic phases, the crude product was separated by column chromatography to obtain 4-chloro-6-(3,3-difluoroacetidin-1-yl)-3-fluoro-2-(1-methyl-1H-pyrazol-5-yl)benzonitrile (120 mg, yield 40%). MS m / z (ESI): 327 [M+H] + .

[0268] Step 3: Synthesis of 2-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-(3,3-difluoroacetidin-1-yl)-3-fluorobenzonitrile

[0269]

[0270] 4-Chloro-6-(3,3-difluoroacridin-1-yl)-3-fluoro-2-(1-methyl-1H-pyrazol-5-yl)benzonitrile (120 mg, 0.37 mmol) was dissolved in anhydrous acetonitrile (5 mL), and NBS (98.0 mg, 0.55 mmol) was added. The reaction was stirred overnight at 50 °C. After the reaction was complete, the reaction system was concentrated, and the crude product was separated by reverse-phase column chromatography on a C18 column to obtain 2-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-(3,3-difluoroacridin-1-yl)-3-fluorobenzonitrile (120 mg, yield 80.6%). MS m / z (ESI): 405 / 407 [M+1] + .

[0271] Intermediates 9-21 can be prepared by selecting appropriate raw materials, referring to the synthesis method of intermediate 8 (either fully or partially).

[0272]

[0273]

[0274]

[0275] Preparation of intermediate 24: 2-(4-bromo-1-methyl-1H-pyrazol-5-yl)-6-cyclopropoxy-3-fluoro-4-(3-methoxypyrrolidine-1-yl)benzonitrile

[0276]

[0277] Step 1: Synthesis of 2-bromo-4-chloro-3,6-difluorobenzonitrile

[0278]

[0279] A mixture of 25 g (144.1 mmol) of 4-chloro-2,5-difluorobenzonitrile, 51.28 g (288.1 mmol) of NBS, 3.23 g (14.4 mmol) of palladium acetate, and 11.59 mL (72.0 mmol) of p-toluenesulfonic acid in dichloroethane (250 mL) was degassed with nitrogen and then stirred at 75 °C for 12 hours. The reaction mixture was extracted with dichloroethane (300 mL) and water (300 mL), washed with saturated brine (300 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to give 2-bromo-4-chloro-3,6-difluorobenzonitrile (13.33 g, yield 38%).

[0280] Step 2: Synthesis of 2-bromo-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile

[0281]

[0282] A mixture of 2-bromo-4-chloro-3,6-difluorobenzonitrile (15 g, 59.4 mmol), cyclopropanol (5.18 g, 89.1 mmol), and potassium carbonate (20.53 g, 148.6 mmol) in DMF (200 mL) was degassed with nitrogen and stirred at 75 °C for 2 hours. The reaction mixture was extracted with ethyl acetate (200 mL) and water (200 mL), washed with saturated brine (200 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to obtain 2-bromo-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile (8.1 g, yield 47%).

[0283] 1 H NMR (400MHz, CDCl3) δ7.28 (d, J = 5.63Hz, 1H) 3.77 (dt, J = 8.63, 4.44Hz, 1H) 0.83 (br d, J = 4.63Hz, 4H).

[0284] Step 3: Synthesis of 4-chloro-6-cyclopropoxy-3-fluoro-2-(1-methyl-1H-pyrazol-5-yl)benzonitrile

[0285]

[0286] 2-Bromo-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile (5.0 g, 17.21 mmol), 1-methyl-5-tetramethyl-1,3,2-dioxaborane-2-pyrazole, and cesium carbonate (16.82 g, 51.63 mmol) were dissolved in water (20 mL) and dioxane (100 mL), degassed with nitrogen, and Pd-118 (1.12 g, 1.72 mmol) was added. The mixture was stirred at 80 °C for 12 hours. The reaction solution was extracted with ethyl acetate (50 mL) and water (50 mL), washed with saturated brine (50 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to obtain 4-chloro-6-cyclopropoxy-3-fluoro-2-(1-methyl-1H-pyrazole-5-yl)benzonitrile (2.5 g, purity 80%, yield 50%).

[0287] 1 H NMR (400MHz, CDCl3) δ7.63 (d, J=2.01Hz, 1H), 7.50 (d, J=5.77Hz, 1H), 6.52 (d, J= 1.76Hz, 1H), 3.89 (dt, J=8.91, 4.33Hz, 1H), 3.83 (d, J=1.00Hz, 3H), 0.96 (m, 4H).

[0288] Step 4: Synthesis of 2-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile

[0289]

[0290] 4-Chloro-6-cyclopropoxy-3-fluoro-2-(1-methyl-1H-pyrazol-5-yl)benzonitrile (4.8 g, 16.46 mmol) and NBS (5.86 g, 32.91 mmol) were dissolved in acetonitrile (50 mL) and stirred at 40 °C under a nitrogen atmosphere for 2 hours. The reaction solution was extracted with ethyl acetate (50 mL) and water (50 mL), washed with saturated brine (50 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to obtain 2-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile (5 g, purity: 93%, yield: 76%).

[0291] 1 H NMR (400MHz, CDCl3) δ7.54 (s, 1H), 7.48 (d, J = 5.88Hz, 1H), 3.82 (m, 1H), 3.73 (s, 3H), 0.92-0.83 (m, 4H).

[0292] Step 5: Synthesis of 2-(4-bromo-1-methyl-1H-pyrazol-5-yl)-6-cyclopropoxy-3-fluoro-4-(3-methoxypyrrolidine-1-yl)benzonitrile

[0293]

[0294] 2-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile (80 mg, 0.22 mmol) was dissolved in N-methylpyrrolidone (2 mL), and 3-methoxypyrrolidine (59 mg, 0.43 mmol) and N,N-diisopropylethylamine (134 mg, 1.08 mmol) were added. The reaction was carried out overnight in a sealed tube with stirring at 130 °C. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with water, dried, and concentrated. The crude product was separated by column chromatography to give 2-(4-bromo-1-methyl-1H-pyrazol-5-yl)-6-cyclopropoxy-3-fluoro-4-(3-methoxypyrrolidine-1-yl)benzonitrile (85 mg, yield 79%). MS m / z (ESI): 435 / 437 [M+H] + .

[0295] Intermediates 25-34 can be prepared by selecting appropriate raw materials, referring to the synthesis method of all or part of intermediate 24.

[0296]

[0297]

[0298] II. Preparation of Specific Embodiments

[0299] Example 1: Preparation of 1-(aminomethyl)-7-(5-(1-cyano-3-fluoronaphthyl-2-yl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazine-5-carboxynitrile

[0300]

[0301] Step 1: Synthesis of tert-butyl carbamate (tert-butyloxycarbonyl)((5-cyano-7-(5-(1-cyano-3-fluoronaphthyl-2-yl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)carbamate

[0302]

[0303] Add (4-((bis(tert-butoxycarbonyl)amino)methyl)-8-cyano-1-oxo-1,2-dihydrodiazanaphthalene-6-yl)boronic acid (1.0 g, 70% purity, 1.58 mmol), 2-(4-bromo-1-methyl-1H-pyrazol-5-yl)-3-fluoro-1-naphthonitrile (594 mg, 1.58 mmol), 1,4-dioxane (20 mL), water (5 mL), sodium carbonate (501 mg, 4.73 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (230 mg, 0.32 mmol) to a 25 mL single-necked flask. Stir the reaction mixture at 80 °C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated by column chromatography to obtain tert-butyl carbamate (450 mg, yield 43%), consisting of (tert-butyloxycarbonyl)((5-cyano-7-(5-(1-cyano-3-fluoronaphthyl-2-yl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate. MS m / z (ESI): 650 [M+H] + .

[0304] Step 2: Synthesis of 1-(aminomethyl)-7-(5-(1-cyano-3-fluoronaphthyl-2-yl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazine-5-carboxynitrile

[0305]

[0306] 135 mg (0.015 mmol) of tert-butyl carbamate (tert-butyloxycarbonyl)((5-cyano-7-(5-(1-cyano-3-fluoronaphthyl-2-yl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate was dissolved in dichloromethane (3.0 mL), and trifluoroacetic acid (2.0 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The pH was adjusted to 9–10 with saturated sodium bicarbonate. The mixture was separated, and the aqueous phase was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated under reduced pressure to give 1-(aminomethyl)-7-(5-(1-cyano-3-fluoronaphthyl-2-yl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazine-5-carboxynitrile (96 mg, yield 97%). MS m / z (ESI): 450 [M+H] + .

[0307] 1 H NMR (400MHz, DMSO-d6) δ12.75 (brs, 1H), 8.56 (d, J = 10.2Hz, 1H), 8.48 (s, 1H), 8. 30-8.24(m,2H),8.20-8.12(m,1H),7.91-7.85(m,3H),3.83(s,3H),3.46(s,2H).

[0308] (tert-Butoxycarbonyl)((5-cyano-7-(5-(1-cyano-3-fluoronaphthyl-2-yl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)tert-butyl carbamate (380 mg, 0.585 mmol) was separated by chiral column chromatography to give (M)-(tert-Butoxycarbonyl)((5-cyano-7-(5-(1-cyano-3-fluoronaphthyl-2-yl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (380 mg, 0.585 mmol). H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)tert-butyl carbamate (135 mg, yield: 35%) and (P)-(tert-butyloxycarbonyl)((5-cyano-7-(5-(1-cyano-3-fluoronaphthyl-2-yl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)tert-butyl carbamate (182 mg, yield: 46%) were subsequently de-tert-butyloxycarbonylated with trifluoroacetic acid to obtain the corresponding final products in Examples 4 and 5. Specific data are shown in the table below.

[0309] Examples 2-37 can be prepared by selecting appropriate raw materials, referring to all or part of the synthesis method in Example 1:

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316] The NMR data of the compounds prepared in the above examples are as follows:

[0317]

[0318]

[0319]

[0320] Biological test evaluation

[0321] I. Human colon cancer HCT116 cell proliferation inhibition assay

[0322] 1. HCT 116MTAP knockout and MTAP wild-type cells were seeded in 96-well plates and cultured overnight at 37°C and 5% CO2 in McCoy's 5A culture medium containing 10% fetal bovine serum and 1% penicillin-streptomycin.

[0323] 2. On the second day, the compound was dissolved in DMSO, and then diluted with DMSO and culture medium in sequence and transferred to cell plates. The final concentration of the compound was 10 μM, 4-fold dilution, 9 concentration gradients, and DMSO control.

[0324] 3. Remove cells that have not been treated with the compound and detect cell viability using the CellTiter-Glo Luminescent Cell Viability Assay (Promega). Follow the instructions in the kit manual. Then place the cell plate on an EnVisionMultilabel Reader to detect the cold light signal.

[0325] 4. Simultaneously, the cell plates treated with the added compound were cultured continuously at 37°C and 5% CO2 for 6 days.

[0326] 5. Then, cell viability was detected using CellTiter-Glo.

[0327] 6. Finally, the dose-response curve was plotted using the four-parameter dose-response curve module of GraphPad Prism v 9.2.0 software, and the proliferation inhibition IC50 was calculated. 50(Unit: nM)

[0328]

[0329] Based on the bioactivity data of the compounds in the specific embodiments, the series of compounds of the present invention have a strong inhibitory effect on the proliferation of human colon cancer HCT116 MTAP knockout cells at the cellular level, and a weaker inhibitory effect on MTAP wild-type HCT116 cells, showing higher selectivity compared to the positive compound MRTX-1979.

[0330] Mouse pharmacokinetics assay

[0331] 1. Research Objectives

[0332] The purpose of this experiment was to study the pharmacokinetic behavior of some compounds of this invention. The administration routes were as follows: ICR mice were administered a single oral dose (PO):

[0333] 2. Experimental Design

[0334] 2.1 Experimental reagents

[0335] The compounds used in this experiment are derived from compounds in specific embodiments of this invention.

[0336] 2.2 Laboratory Animals

[0337] Male ICR mice (N=3) Original source: Shanghai Xipu-Bikai Experimental Animal Co., Ltd.

[0338] 2.3 Drug Preparation and Administration

[0339] The compounds were weighed and dissolved in 20% PG + 10% Solutol HS15 + 70% pH3 citrate buffer, respectively. The solutions were shaken and sonicated to prepare colorless, clear solutions or suspensions. Nine mice were fasted overnight and then administered the solution orally at a dose of 10 mg / kg.

[0340] 2.4 Sample Collection:

[0341] Approximately 90 μL of blood was collected via the submandibular vein at each time point. Heparin sodium was used for anticoagulation. After collection, the samples were placed on ice and centrifuged within 1 hour to separate the plasma (centrifugation conditions: 8000 rpm, 6 minutes, 2-8 degrees Celsius). Blood collection time points were 0, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours. Samples were stored at -20 degrees Celsius.

[0342] Add 160 μL of ice-cold acetonitrile containing internal standard to 40 μL of plasma sample, vortex for 3 minutes, and centrifuge at 11,000 rpm for 5 minutes. Take 100 μL of the supernatant and add it to 100 μL of water. Inject 5 μL of the supernatant into LC / MS / MS for analysis (results are shown in the table below).

[0343] 2.5 Test Results:

[0344] PK results of single oral administration (PO) of 10 mg / kg compound in mice

[0345]

[0346] Experimental conclusion: In in vivo pharmacokinetic tests in mice, under oral administration, the compound of the present invention, compared with the positive compound MRTX-1979, showed C... max It shows a significant improvement in AUC, indicating better pharmacokinetic properties and better development prospects.

[0347] Liver microsomal stability test

[0348] I. Preparation of Reagents

[0349] 1. Preparation of buffer C:

[0350] Buffer A: 1.0 L of 0.1 M potassium dihydrogen phosphate buffer (containing 1.0 mM EDTA);

[0351] Buffer B: 1.0 L of 0.1 M dipotassium hydrogen phosphate buffer (containing 1.0 mM EDTA);

[0352] Buffer C: Add buffer A to 700 mL of buffer B, and stop when the pH reaches 7.4.

[0353] 2. Preparation of 10mM stock solution:

[0354] The selected compounds and reference standards were dissolved in DMSO to prepare 10 mM stock solutions.

[0355] 3. Preparation of the drug administration solution:

[0356] ■500μM solution: Add 10μL of 10mM stock solution to 190μL of ACN;

[0357] ■ 1.5 μM Dosage Solution (dissolved in liver microsome solution, human liver microsomes purchased from Xenotech): Add 18.75 μL of 20 mg / mL liver microsomes to 479.75 μL of buffer C, then add 1.5 μL of 500 μM solution and gently vortex to mix.

[0358] 4. Preparation of 6mM NADPH solution:

[0359] Weigh out NADPH and add an appropriate amount of buffer C to prepare a 6mM NADPH solution.

[0360] II. Specific Experimental Scheme

[0361] 1. Add 30 μL of 1.5 μM drug solution to wells of a 96-well plate set at different time points (0 min, 5 min, 15 min, 30 min, 45 min), with a duplication rate of 2.

[0362] 2. Preparation of 0-minute sample: First, add 135 μL of ACN (including internal standard) to the 0-minute well, then add 15 μL of 6 mM NADPH solution.

[0363] 3. Preheat the 96-well plate containing 1.5 μM drug solution and NADPH solution in a 37°C water bath for 5 minutes.

[0364] 4. Add 15 μL of preheated 6 mM NADPH solution to the wells set for 5 minutes, 15 minutes, 30 minutes, and 45 minutes, start the reaction and begin timing.

[0365] 5. When the timer displays 5 minutes, 15 minutes, 30 minutes, and 45 minutes, add 135 μL of ACN (containing internal standard) to terminate the reaction. Vortex for 10 minutes, then centrifuge the sample at 5594 × g for 15 minutes.

[0366] 6. Take 50 μL of supernatant from the centrifuged sample and transfer it to a 96-well plate containing 50 μL of water. Mix well and then analyze the sample by LC-MS / MS. Calculate the half-life based on the test results. The experimental results are shown in the table below:

[0367] Example 1 202 Example 2 43 Example 6 123 Example 8 52 Example 9 38 Example 28 27 MRTX-1979 20

[0368] Experimental conclusion: In the in vitro human liver microsomal stability experiment, the half-life T of the compound in this embodiment of the invention was longer than that of the positive compound MRTX-1979. 1 / 2 It shows significant improvement, demonstrating better in vitro metabolic stability and promising development prospects.

[0369] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the above disclosure of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. Compounds of formula (III), their stereoisomers or pharmaceutically acceptable salts thereof: ， in, Ring A has the following structure: or , R1 is selected from hydrogen, deuterium, methyl, ethyl, and isopropyl; Each R3 and R7 is independently selected from hydrogen, deuterium, fluorine, chlorine, and cyano; R 15 Selected from cyano, ethynyl, cyclopropyl, or hydrogen, and When R 15 When selected from cyano, ethynyl, or cyclopropyl, and ring A is... At that time, R4 and R 6a Each is independently selected from halogens, C 3-8 Cycloalkoxy groups and 3-8 membered heterocyclic groups; When R 15 When selected from cyano, ethynyl, or cyclopropyl, and ring A is... At that time, R 6b It is hydrogen; When R 15 When selected from hydrogen, and ring A is At that time, R4 and R 6a Each is independently selected from halogens, C 3-8 Cycloalkoxy and 3-8 membered heterocyclic groups, provided that R4 and R 6a At least one of them is a 3-8 membered nitrogen-containing heterocyclic group, wherein the nitrogen atom is attached to the benzene ring, and the 3-8 membered nitrogen-containing heterocyclic group is optionally further composed of one or more elements selected from deuterium, halogen, C. 1-4 Alkyl, halogenated C 1-4 Alkyl, -OR 20 and -NR 22 R 23 The substituents are replaced; R 20 Selected from hydrogen and C 1-4 alkyl; R 22 and R 23 Each is independently selected from hydrogen and C. 1-4 alkyl.

2. The compound of formula (III) according to claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that, Compound (III) has the structure of compound (IVa) as follows: ， Among them, R 15 Selected from cyano, ethynyl, or cyclopropyl; Ring A has the following structure: or , R4 and R 6a Each is independently selected from halogens, C 3-8 Cycloalkoxy groups and 3-8 membered heterocyclic groups; R 6b It is hydrogen.

3. The compound of formula (III) according to claim 2, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that, R4 and R 6a Each is independently selected from fluorine, chlorine, cyclopropoxy, cyclobutoxy, or 3-8 member nitrogen-containing heterocyclic groups; R 6b It is hydrogen.

4. The compound of formula (III) according to claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that, Compound (III) has the structure of compound (IVb) as follows: ， Among them, R4 and R 6a Each is independently selected from halogens, C 3-8 Cycloalkoxy and 3-8 membered heterocyclic groups, provided that R4 and R 6a At least one of them is a 3-8 membered nitrogen-containing heterocyclic group, wherein the nitrogen atom is attached to the benzene ring, and each of the 3-8 membered nitrogen-containing heterocyclic groups is independently and optionally further selected by one or more elements selected from deuterium, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, -OR 20 and -NR 22 R 23 The substituents are replaced; Among them, R 20 R 22 and R 23 As defined in claim 1.

5. The compound of formula (III) according to claim 4, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that, R4 and R 6a Each is independently selected from fluorine, chlorine, cyclopropoxy, cyclobutoxy, or 3-8 membered nitrogen-containing heterocyclic groups, provided that R4 and R 6a At least one of them is a 3-8 membered nitrogen-containing heterocyclic group, wherein the nitrogen atom is attached to the benzene ring, and each of the 3-8 membered nitrogen-containing heterocyclic groups is independently and optionally further selected from one or more of deuterium, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, hydroxyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, amino, mono-C 1-4 Alkylamino and diC 1-4 Substituents of alkylamino groups.

6. The compound of formula (III) according to claim 5, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that, The 3-8 member nitrogen-containing heterocyclic group is selected from the following structures: 。 7. The compound of formula (III) according to claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that, Selected from the following compounds: and .

8. A pharmaceutical composition comprising a compound of formula (III) according to any one of claims 1-7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

9. The use of the compound of formula (III) according to any one of claims 1-7, its stereoisomer or pharmaceutically acceptable salt thereof in the preparation of a medicament for treating MTAP-related cancers or tumors.

10. The application according to claim 9, characterized in that, The tumors or cancers mentioned are selected from granulosa-theca cell tumors, Sertoli cell tumors of the testis, germ cell tumors, squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, melanoma, clear cell carcinoma, fallopian tube cancer, nephroblastoma, lymphoma, leukemia, bladder cancer, transitional cell carcinoma, seminoma, teratoma, embryonal carcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoma-like tumor, and lipoma. Liver cancer, bile duct cancer, hepatoblastoma, hepatocellular adenoma, hemangioma, gallbladder cancer, ampullary cancer, basal cell carcinoma, dysplastic nevus, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease, malignant fibrous histiocytoma, malignant giant cell tumor chordoma, osteochondroma, benign chondroma, chondroblastoma, osteoid osteoma, giant cell tumor, myxoma, rhabdomyosarcoma, bronchogenic carcinoma, alveolar carcinoma, bronchial adenoma, chondroma-like hamartoma, mesothelioma, gastric cancer, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, leiomyoma, tubular adenoma, villous adenoma, hamartoma, skull tumor, xanthoma, meningioma, astrocytoma, medulloblastoma, glioma, ependymoma, schwannoma, retinoblastoma, or congenital tumors.

11. The application according to claim 10, characterized in that, The glioma mentioned is glioblastoma multiforme or oligodendroglioma.

12. The application according to claim 10, characterized in that, The adenocarcinoma is endometrial adenocarcinoma, prostate cancer, ductal adenocarcinoma, or colorectal adenocarcinoma; The lymphoma is non-Hodgkin's lymphoma; The teratoma is a malignant teratoma; The sarcoma is fibrosarcoma, botryoid sarcoma, angiosarcoma, Kaposi's sarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, rhabdomyosarcoma, liposarcoma, leiomyosarcoma, or meningeal sarcoma. The leukemia mentioned refers to acute or chronic myeloid leukemia, acute lymphoblastic leukemia, or chronic lymphoblastic leukemia. The fibroma is either chondromycinous fibroma or neurofibroma.

13. The application according to claim 12, characterized in that, The neurofibroma is a spinal neurofibroma.

14. The application according to claim 9, characterized in that, The cancer or tumor is selected from breast cancer, pancreatic cancer, skin cancer, bladder cancer, liver cancer, or head and neck cancer.

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