Pyrazole derivatives, their manufacturing methods, and pharmaceutical applications

Abstract

The present invention relates to pyrazole derivatives, their preparation methods and pharmaceutical applications. In particular, the present invention relates to PRMT5 inhibitors having the structure of formula (I), their preparation methods, pharmaceutical compositions containing them, their use as PRMT5 inhibitors, and their use in treating and / or preventing diseases mediated by PRMT5. The definitions of each substituent in formula (I) are the same as those in the specification.

Description

[Technical Field]

[0001] This invention belongs to the field of drug synthesis, and more particularly to pyrazole derivatives, methods for producing the same, and their applications in pharmaceuticals. [Background technology]

[0002] Epigenetic gene regulation is a crucial biological regulatory mechanism for protein synthesis and cell differentiation, and plays a vital role in many human diseases. Epigenetic regulation involves the modification of heritable genetic material without altering nucleic acid sequences. Typically, epigenetic regulation controls the conversion between transcriptionally active and inactive states in chromatin conformations through selective and reversible modifications (e.g., 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 genetic alterations in many human disease-causing genes. PRMT5 plays a crucial role in many diseases, such as tumors, metabolic disorders, and hematological disorders.

[0003] Homozygous deletions of tumor suppressor genes are a driving factor for tumors and often lead to deletions of passenger genes near the suppressor gene. These passenger gene deletions result in specific vulnerabilities in tumor cells and can be targeted with targeted therapies. Homozygous deletions at the chromosome 9p21 site, including the well-known tumor suppressor gene CDKN2A, occur in 15% of tumors and often involve deletions of the passenger gene MTAP. MTAP is a key enzyme in the methionine and adenine recycling pathway. Deletion of MTAP leads to the accumulation of its substrate, MTA. MTA is structurally similar to S-adenosylmethionine (SAM), a methyl substrate donor for the type II methyltransferase PRMT5. Increased MTA levels due to MTAP deletion can selectively compete with SAM for binding to PRMT5, rendering the methyltransferase ineffective and making it more susceptible to PRMT5 inhibition. Numerous genome-wide shRNA screenings using a wide range of tumor cell lines have shown a correlation between MTAP deletion and PRMT5 dependence of cell lines, bringing attention to the effects of this metabolic sensitivity. However, PRMT5 is a very important gene for cells, and all studies on conditional knockout or siRNA knockout of PRMT5 suggest that inhibiting PRMT5 in normal tissues leads to serious side effects (e.g., cytopenia, infertility, skeletal muscle loss, cardiac hypertrophy, etc.). Therefore, a new strategy is needed to apply and explore metabolic sensitivity that selectively targets PRMT5 in MTAP-deficient tumors while avoiding its effects in normal tissues (MTAP wild-type).

[0004] Small molecule inhibitors targeting PRMT5 in cooperation with MTA can selectively target only PRMT5, which is enriched only in MTAP-deficient tumor cells that are bound to MTA. Therefore, if MTA levels are very low in completely normal cells, PRMT5 will not be targeted, thereby providing a better therapeutic window. [Overview of the Initiative]

Problems to be Solved by the Invention

[0005] The object of the present invention is to provide a pyrazole derivative, a method for producing the same, and an application in pharmacy. A series of compounds of the present invention have a strong inhibitory effect on PRMT5 and can be widely applied to the production of drugs for treating and / or preventing diseases mediated by PRMT5, and the development of a new generation of PRMT5 inhibitors can be expected.

Means for Solving the Problems

[0006] The first aspect of the present invention provides a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0007]

Chemical formula

[0008] Here, L is a 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 where X1, X2 and X3 are each independently N or CR 15 where R1 is hydrogen, deuterium, a hydroxy group, C 1-10 alkyl group, C 2-10 alkenyl group, C 3-12 cycloalkyl group, 3- to 12-membered heterocyclic group, C 6-10 aryl group and 5- to 10-membered heteroaryl group, and the said groups are independently deuterium, halogen, hydroxy group, =O, C 1-10 alkyl group, C 1-10 alkoxy group, C 3-12 cycloalkyl group, C 3-12 cycloalkoxy group, 3- to 12-membered heterocyclic group, 3- to 12-membered heterocyclic oxy group, C 6-10 aryl group, C 6-10 aryloxy group, 5- to 10-membered heteroaryl group, 5- to 10-membered heteroaryloxy group and -NR 22R 23 Optionally further substituted by one or more substituents selected from, R2 is hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halosubstituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl alkyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclic group, C 6-10 Aryl group, 5-10 membered heteroaryl group, -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(=NR23 )R 21 、 -C 0-8 alkyl - C(O)NR 22 R 23 and -C 0-8 alkyl - N(R 22 ) - C(O)R 21 selected from, R3, R4, R5, R6 and R7 are each independently hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group, C 3-12 cycloalkyl group, 3 - 12 member heterocyclic group, C 6-10 aryl group, 5 - 10 member heteroaryl group, -C 0-8 alkyl - SF5, -C 0-8 alkyl - S(O)(=N - R 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 - O - S(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 - O - R 20 、 -C 0-8 alkyl - C(O)OR 20 、 -C 0-8 alkyl - C(O)SR 20 、 -C 0-8 alkyl - S - C(O)R 21 、 -C 0-8 alkyl - C(O)R 21 、 -C 0-8 alkyl - O - C(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 Either selected from or two adjacent substituents from R3, R4, R5, R6, R7 form a 4-8 membered carbon ring, a 4-8 membered hetero ring, a 6-8 membered aromatic ring, or a 5-8 membered heteroaromatic ring with the directly linked moiety, and the group independently consists of deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl, halo-substituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclic group, C 6-10 Aryl group, 5-10 membered heteroaryl group, =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 Optionally further substituted by one or more substituents selected from, R8 consists of hydrogen, deuterium, a hydroxyl group, and C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclic group, C 6-10 Selected from aryl groups and 5-10 membered heteroaryl groups, the group can independently be deuterium, halogen, hydroxyl, =O, C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group and -NR 22 R 23 Optionally further substituted by one or more substituents selected from, R9 consists of hydrogen, deuterium, halogen, cyano group, nitro group, azide group, and C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halosubstituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl alkyl group, C 3-12Cycloalkyl group, 3-12 membered heterocyclic group, C 6-10 Aryl group, 5-10 membered heteroaryl group, -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 Selected from, R 10 and R 11These are, independently, hydrogen, deuterium, halogen, cyano group, nitro group, azide group, and C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclic group, C 6-10 Aryl group, 5-10 membered heteroaryl group, -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(R22 )-C(O)R 21 Selected from, or R 10 and R 11 These are directly linked carbon atoms and C(O), C 3-10 Cycloalkyl group, 3-10 membered heterocyclic group, C 6-10 An aryl group or a 5-8 membered heteroaryl group is formed, and the group can independently be deuterium, halogen, cyano group, nitro group, azide group, or C 1-10 Alkyl, halo-substituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclic group, C 6-10 Aryl group, 5-10 membered heteroaryl group, =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 R23 , -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 Optionally further substituted by one or more substituents selected from, R 12 is hydrogen, deuterium, hydroxyl group, C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclic group, C 6-10 Selected from aryl groups and 5-10 membered heteroaryl groups, the group can independently be deuterium, halogen, hydroxyl, =O, C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group and -NR 22 R 23 Optionally further substituted by one or more substituents selected from, R 13 and R 14 These are, independently, hydrogen, deuterium, halogen, cyano group, nitro group, azide group, and C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclic group, C 6-10 Aryl group, 5-10 membered heteroaryl group, -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 Selected from, or R 13 and R 14 These are directly linked carbon atoms and C(O), C 3-10 Cycloalkyl group, 3-10 membered heterocyclic group, C 6-10 An aryl group or a 5-8 membered heteroaryl group is formed, and the group can independently be deuterium, halogen, cyano group, nitro group, azide group, or C 1-10 Alkyl, halo-substituted C 1-10 Alkyl, deuterium-substituted C1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclic group, C 6-10 Aryl group, 5-10 membered heteroaryl group, =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 21Optionally further substituted by one or more substituents selected from, Each R 15 These are independently hydrogen, deuterium, halogen, cyano group, nitro group, azide group, and C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclic group, C 6-10 Aryl group, 5-10 membered heteroaryl group, -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 Selected from, the group is independently deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl, halo-substituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclic group, C 6-10 Aryl group, 5-10 membered heteroaryl group, =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 0-8Alkyl-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 R is optionally further substituted by one or more substituents selected from the above, and 15 If is hydrogen, then at least one of R3, R4, R5, R6, and R7 is a 3-8 member nitrogen-containing heterocyclic group, and the nitrogen atom is linked to a benzene ring. Each R 16 These are hydrogen, deuterium, and C, respectively, independently. 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-10 Cycloalkyl group, 3-10 membered heterocyclic group, C 6-10 Aryl group, 5-10 membered heteroaryl group, -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 Selected from, the group is deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl, halo-substituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclic group, C 6-10 Aryl group, 5-10 membered heteroaryl group, =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 Optionally further substituted by one or more substituents selected from, Each R 17 and R 18 These are, independently, hydrogen, deuterium, a hydroxyl group, and C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-10 Cycloalkyl group, 3-10 membered heterocyclic group, C 6-10 Selected from an aryl group or a 5-10 membered heteroaryl group, or R 17 and R18 It forms a 3-10 membered heterocyclic group with a directly linked sulfur atom, and the group consists of deuterium, halogen, cyano group, nitro group, azide group, and C 1-10 Alkyl, halo-substituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclic group, C 6-10 Aryl group, 5-10 membered heteroaryl group, =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 Optionally further substituted by one or more substituents selected from, Each R 19 These are independently hydrogen, deuterium, hydroxyl group, and C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclic group, C 6-10 Aryl groups, 5-10 membered heteroaryl groups, and -NR 22 R 23 Selected from, the group is independently deuterium, halogen, hydroxyl group, =O, C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group and -NR 22 R 23 Optionally further substituted by one or more substituents selected from, Each R 20 These are hydrogen, deuterium, and C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclic group, C 6-10 Selected from aryl groups and 5-10 membered heteroaryl groups, the group can independently be deuterium, halogen, hydroxyl group, =O, cyano group, or C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group and -NR 22 R23 Optionally further substituted by one or more substituents selected from, Each R 21 These are independently hydrogen, deuterium, hydroxyl group, and C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group and -NR 22 R 23 Selected from, the group is independently deuterium, halogen, hydroxyl group, =O, cyano group, C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group and -NR 22 R 23 Optionally further substituted by one or more substituents selected from, Each R 22 and R 23 These are, independently, hydrogen, deuterium, a hydroxyl group, and C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclic group, C 6-10 Aryl group, 5-10 membered heteroaryl group, sulfinyl group, sulfonyl group, methylsulfonyl group, isopropylsulfonyl group, cyclopropylsulfonyl group, p-toluenesulfonyl group, aminosulfonyl group, dimethylaminosulfonyl group and C 1-10 Selected from alkanoyl groups, the group is independently deuterium, halogen, hydroxyl, =O, C 1-10 Alkyl alkyl group, C2-10 Alkenyl group, C 2-10 Alkynyl group, halosubstituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group, amino group, C 1-10 Alkyl mono-substituted amino group, C 1-10 Alkyl bis-substituted amino group and C 1-10 The group may be further optionally substituted with one or more substituents selected from the alkanoyl group, or R 22 and R 23 It forms a 4-10 membered heterocyclic group or a 5-10 membered heteroaryl group with a directly bonded nitrogen atom, and the 4-10 membered heterocyclic group or 5-10 membered heteroaryl group consists of deuterium, halogen, hydroxyl group, =O, C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halosubstituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group, amino group, C 1-10 Alkyl monosubstituted amino group, C 1-10 Alkyl disubstituted amino group and C 1-10 They may be further optionally substituted with one or more substituents selected from the alkanoyl group. Each r is independently 0, 1, or 2.

[0009] More preferably, in the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, L is a bond, O, S, C(O), S(O), S(O)2, NR 12 or CR 13 R 14 And, X1, X2, and X3 are each independently N or CR 15 And, R1 is hydrogen, deuterium, hydroxyl group, C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, C 6-8 Selected from aryl groups and 5-8 membered heteroaryl groups, the group can independently be deuterium, halogen, hydroxyl, =O, C 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl group, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -NR 22 R 23 Optionally further substituted by one or more substituents selected from, R2 is hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halosubstituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl alkyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, C 6-8 Aryl group, 5-8 membered heteroaryl group, -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 R18 , -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 Selected from, R3, R4, R5, R6, and R7 are each independently hydrogen, deuterium, halogen, cyano group, nitro group, azide group, and C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclic group, C 6-8 Aryl group, 5-8 membered heteroaryl group, -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 - O - S(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 - O - R 20 、 -C 0-4 alkyl - C(O)OR 20 、 -C 0-4 alkyl - C(O)SR 20 、 -C 0-4 alkyl - S - C(O)R 21 、 -C 0-4 alkyl - C(O)R 21 、 -C 0-4 alkyl - O - C(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 selected from, or two adjacent substituents of R3, R4, R5, R6, R7 form a directly - connecting part and a 5 - 8 - membered carbon ring, 5 - 8 - membered heterocyclic ring, 6 - membered aromatic ring or 5 - 6 - membered hetero - aromatic ring, and the groups are independently deuterium, halogen, cyano group, nitro group, azide group, C 1-4 alkyl group, halo - substituted C 1-4 alkyl group, deuterium - substituted C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 3-8Cycloalkyl group, 3-8 membered heterocyclic group, C 6-8 Aryl group, 5-8 membered heteroaryl group, =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 Optionally further substituted by one or more substituents selected from, R8 consists of hydrogen, deuterium, a hydroxyl group, and C 1-4An alkyl group, C 2-4 An alkenyl group, C 3-6 A cycloalkyl group, a 3- to 6-membered heterocyclic group, C 6-8 Selected from an aryl group and a 5- to 8-membered heteroaryl group, and the said groups are independently deuterium, halogen, a hydroxy group, =O, C 1-4 An alkyl group, C 1-4 An alkoxy group, C 3-6 A cycloalkyl group, C 3-6 A cycloalkoxy group, a 3- to 6-membered heterocyclic group, a 3- to 6-membered heterocyclic oxy group, C 6-8 An aryl group, C 6-8 An aryloxy group, a 5- to 8-membered heteroaryl group, a 5- to 8-membered heteroaryloxy group and -NR 22 R 23 Optionally further substituted by one or more substituents selected from R9 is hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-4 An alkyl group, C 2-4 An alkenyl group, C 2-4 An alkynyl group, a halo-substituted C 1-4 An alkyl group, a deuterium-substituted C 1-4 An alkyl group, C 3-6 A cycloalkyl group, a 3- to 6-membered heterocyclic group, C 6-8 An aryl group, a 5- to 8-membered heteroaryl group, -C 0-4 An alkyl-SF5, -C 0-4 An alkyl-S(O)(=N-R 16 )R 17 , -C 0-4 An alkyl-N=S(O)R 17 R 18 , -C 0-4 An alkyl-N=SR 17 R 18 , -C 0-4 An alkyl-O-S(O)2R 19 , -C 0-4 An alkyl-S(O) r R 19 , -C 0-4 An alkyl-P(O)(OR 20 )R 19 , -C 0-4 An alkyl-O-R 20 , -C 0-4 An 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 Selected from, R 10 and R 11 These are, independently, hydrogen, deuterium, halogen, cyano group, nitro group, azide group, and C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, C 6-8 Aryl group, 5-8 membered heteroaryl group, -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 Selected from, or R 10 and R 11 These are directly linked carbon atoms and C(O), C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, C 6-8 An aryl group or a 5-6 membered heteroaryl group is formed, and the group can independently be deuterium, halogen, cyano group, nitro group, azide group, or C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, C 6-8 Aryl group, 5-8 membered heteroaryl group, =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 R18 , -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 Optionally further substituted by one or more substituents selected from, R 12 is hydrogen, deuterium, hydroxyl group, C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, C 6-8 Selected from aryl groups and 5-8 membered heteroaryl groups, the group can independently be deuterium, halogen, hydroxyl, =O, C 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, C3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl group, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -NR 22 R 23 Optionally further substituted by one or more substituents selected from, R 13 and R 14 These are, independently, hydrogen, deuterium, halogen, cyano group, nitro group, azide group, and C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, C 6-8 Aryl group, 5-8 membered heteroaryl group, -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 0-4Alkyl-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 Selected from, or R 13 and R 14 These are directly linked carbon atoms and C(O), C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, C 6-8 An aryl group or a 5-6 membered heteroaryl group is formed, and the group can independently be deuterium, halogen, cyano group, nitro group, azide group, or C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, C 6-8 Aryl group, 5-8 membered heteroaryl group, =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 , -C0-4 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 Optionally further substituted by one or more substituents selected from, Each R 15 These are independently hydrogen, deuterium, halogen, cyano group, nitro group, azide group, and C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, C 6-8 Aryl group, 5-8 membered heteroaryl group, -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 0-4alkyl-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 Selected from, the group is independently deuterium, halogen, cyano group, nitro group, azide group, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, C 6-8 Aryl group, 5-8 membered heteroaryl group, =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 0-4Alkyl-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 R is optionally further substituted by one or more substituents selected from the above, and 15 If is hydrogen, then at least one of R3, R4, R5, R6, and R7 is a 3-8 member nitrogen-containing heterocyclic group, and the nitrogen atom is linked to a benzene ring. Here, R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 And r are as described for the compound of formula (I).

[0010] A more preferred form is a compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, wherein each R 16 These are hydrogen, deuterium, and C, respectively, independently. 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, C 6-8 Aryl group, 5-8 membered heteroaryl group, -S(O) r R 19 , -C(O)OR 20 , -C(O)R 21 or -C(O)NR 22 R 23 Selected from, the group is deuterium, halogen, cyano group, nitro group, azide group, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, C 6-8 Aryl group, 5-8 member heteroaryl group, =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 22R 23 and Il-N(R 22 )-C(O)R 21 Optionally further substituted by one or more substituents selected from, Each R 17 and R 18 These are, independently, hydrogen, deuterium, a hydroxyl group, and C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, C 6-8 Selected from an aryl group or a 5-8 membered heteroaryl group, or R 17 and R 18 It forms a 4-6 membered heterocyclic group with a directly linked sulfur atom, and the group consists of deuterium, halogen, cyano group, nitro group, azide group, and C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, C 6-8 Aryl group, 5-8 member heteroaryl group, =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 )R21 -C(O)NR 22 R 23 and -N(R 22 )-C(O)R 21 Optionally further substituted by one or more substituents selected from, Each R 19 These are independently hydrogen, deuterium, hydroxyl group, and C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, and -NR 22 R 23 Selected from, the group is independently deuterium, halogen, hydroxyl group, =O, C 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl group, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -NR 22 R 23 Optionally further substituted by one or more substituents selected from, Each R 20 These are hydrogen, deuterium, and C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, C 6-8 Selected from aryl groups and 5-8 membered heteroaryl groups, the group can independently be deuterium, halogen, hydroxyl group, =O, cyano group, or C 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl group, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -NR 22 R 23Optionally further substituted by one or more substituents selected from, Each R 21 These are independently hydrogen, deuterium, hydroxyl group, and C 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl group, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -NR 22 R 23 Selected from, the group is independently deuterium, halogen, hydroxyl group, =O, cyano group, C 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl group, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -NR 22 R 23 Optionally further substituted by one or more substituents selected from, Each R 22 and R 23 These are, independently, hydrogen, deuterium, a hydroxyl group, and C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, C 6-8 Aryl group, 5-8 membered heteroaryl group, sulfinyl group, sulfonyl group, methylsulfonyl group, isopropylsulfonyl group, cyclopropylsulfonyl group, p-toluenesulfonyl group, aminosulfonyl group, dimethylaminosulfonyl group, and C 1-4 Selected from alkanoyl groups, the group is independently deuterium, halogen, hydroxyl, =O, C 1-4Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halosubstituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl group, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group, amino group, C 1-4 Alkyl monosubstituted amino group, C 1-4 Alkyl disubstituted amino group and C 1-4 The group may be further optionally substituted with one or more substituents selected from the alkanoyl group, or R 22 and R 23 It forms a 4-6 membered heterocyclic group or a 5-6 membered heteroaryl group with a directly bonded nitrogen atom, and the 4-6 membered heterocyclic group or 5-6 membered heteroaryl group contains deuterium, halogen, hydroxyl group, =O, C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halosubstituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl group, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group, amino group, C 1-4 Alkyl monosubstituted amino group, C 1-4 Alkyl disubstituted amino group and C 1-4 They may be further optionally substituted with one or more substituents selected from the alkanoyl group. Each r is independently 0, 1, or 2.

[0011] A more preferred embodiment is a compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) has the structure of the compound of formula (II) below,

[0012] [ka]

[0013] Here, X1 is N or CH, and X2 is N or CR. 15 And, R1 is hydrogen, deuterium, C 1-4 Alkyl alkyl group, C 3-6 Selected from cycloalkyl groups and 3-6 membered heterocyclic groups, the group can independently be deuterium, halogen, hydroxyl group, =O, C 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl group, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -NR 22 R 23 Optionally further substituted by one or more substituents selected from, R3, R4, R5, R6, and R7 are each independently hydrogen, deuterium, halogen, cyano group, and C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclic group, C 6-8 Aryl group, 5-8 membered heteroaryl group, -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 0-4Alkyl-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 Either selected from or two adjacent substituents from R3, R4, R5, R6, R7 form a 5-8 membered carbon ring, a 5-8 membered hetero ring, a 6 membered aromatic ring, or a 5-6 membered heteroaromatic ring with the directly linked moiety, and the group is independently deuterium, halogen, cyano group, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclic group, C 6-8 Aryl group, 5-8 membered heteroaryl group, =O, =S, -C 0-4 Alkyl-SF5, -C 0-4Alkyl-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 Optionally further substituted by one or more substituents selected from, R 10 and R 11 These are, independently, hydrogen, deuterium, halogen, cyano group, and C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6Cycloalkyl group, 3-6 membered heterocyclic group, C 6-8 Aryl group, 5-8 membered heteroaryl group, -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 Selected from, or R 10 and R 11 These are directly linked carbon atoms and C(O), C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, C 6-8 An aryl group or a 5-6 membered heteroaryl group is formed, and the group can independently be deuterium, halogen, cyano group, or C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, C 6-8 Aryl group, 5-8 membered heteroaryl group, =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 R23 and -C 0-4 Alkyl-N(R 22 )-C(O)R 21 Optionally further substituted by one or more substituents selected from, R 15 It consists of hydrogen, deuterium, cyano group, and C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclic group, C 6-8 Aryl group, 5-8 membered heteroaryl group, -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 Selected from, the group is independently deuterium, halogen, cyano group, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclic group, C 6-8 Aryl group, 5-8 membered heteroaryl group, =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 R is optionally further substituted by one or more substituents selected from the above, and 15 When is hydrogen, at least one of R3, R4, R5, R6, and R7 is a 3-8 member nitrogen-containing heterocyclic group, and the nitrogen atom is linked to a benzene ring. Here, R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 And r are as described for the compound of formula (I).

[0014] A more preferred embodiment is a compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) has the structure of the compound of formula (III) below,

[0015] [ka]

[0016] Here, ring A has the following structure,

[0017] [ka] or

[0018] [ka] And,

[0019] R1 is selected from hydrogen, deuterium, methyl group, ethyl group, isopropyl group and cyclopropyl group. Each of R3 and R7 independently consists of hydrogen, deuterium, fluorine, chlorine, cyano group, and C. 1-4 Alkyl alkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclic group, hydroxyl group, methoxy group, ethoxy group, isopropoxy group, C 3-8 Selected from cycloalkoxy groups, 3-8 membered heterocyclic oxy groups, methylthio groups, ethylthio groups, carboxyl groups, methoxycarbonyl groups, ethoxycarbonyl groups, isopropoxycarbonyl groups, acetyl groups, acetoxy groups, amino groups, dimethylamino groups, acetylamino groups, and carbamoyl groups, R 15 This is selected from a cyano group, an ethynyl group, a cyclopropyl group, or hydrogen.

[0020] R 15 The group is selected from a cyano group, an ethynyl group, or a cyclopropyl group, and ring A is

[0021] [ka] If so, R4 and R 6a These are halogen and C, respectively, independently. 1-4 Alkoxy group, C 3-8 Selected from a cycloalkoxy group, a 3-8 membered heterocyclic group, or a 3-8 membered heterocyclic oxy group, the C 1-4 Alkoxy group, C 3-8 The cycloalkoxy group, 3-8 membered heterocyclic group, or 3-8 membered heterocyclic oxy group can each independently be deuterium, halogen, cyano group, or C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclic group, C 6-8 Aryl group, 5-8 membered heteroaryl group, =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 Optionally further substituted by one or more substituents selected from,

[0022] R 15 The group is selected from a cyano group, an ethynyl group, or a cyclopropyl group, and ring A is

[0023] [ka] If R 6b These are hydrogen, deuterium, fluorine, chlorine, cyano group, and C 1-4 Alkyl alkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclic group, hydroxyl group, methoxy group, ethoxy group, isopropoxy group, C 3-8 Selected from cycloalkoxy groups, 3-8 membered heterocyclic oxy groups, carboxyl groups, amino groups, and dimethylamino groups,

[0024] R 15 A is selected from hydrogen, and ring A is

[0025] [ka] If so, R4 and R 6a These are halogen and C, respectively, independently. 1-4 Alkoxy group, C 3-8 Selected from a cycloalkoxy group, a 3-8 membered heterocyclic group, or a 3-8 membered heterocyclic oxy group, the C 1-4 Alkoxy group, C 3-8 The cycloalkoxy group, 3-8 membered heterocyclic group, or 3-8 membered heterocyclic oxy group can each independently be deuterium, halogen, cyano group, or C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclic group, C 6-8 Aryl group, 5-8 membered heteroaryl group, =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 optionally further substituted by one or more substituents selected from, and R4 and R 6a Of these, at least one is a 3-8 member nitrogen-containing heterocyclic group, the nitrogen atom is linked to a benzene ring, and the 3-8 member nitrogen-containing heterocyclic group is deuterium, halogen, cyano group, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclic group, C6-8 Aryl group, 5-8 membered heteroaryl group, =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 Provided that it is optionally further substituted by one or more substituents selected from,

[0026] Here, R 20 , R 21 , R 22 and R 23 This is as described for the compound of formula (I). A more preferred embodiment is a compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) has the structure of the compound of formula (IVa) below,

[0027] [ka]

[0028] Here, R 15 This is selected from a cyano group, an ethynyl group, or a cyclopropyl group. Ring A has the following structure:

[0029] [ka] or

[0030] [ka] And,

[0031] R4 and R 6a These are halogen and C, respectively, independently. 1-4 Alkoxy group, C 3-8Selected from a cycloalkoxy group, a 3-8 membered heterocyclic group, or a 3-8 membered heterocyclic oxy group, the C 1-4 Alkoxy group, C 3-8 The cycloalkoxy group, 3-8 membered heterocyclic group, or 3-8 membered heterocyclic oxy group can each independently be deuterium, halogen, cyano group, or C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclic group, C 6-8 Aryl group, 5-8 membered heteroaryl group, =O, =S, -SF5, -OR 20 and -NR 22 R 23 Optionally further substituted by one or more substituents selected from, R 6b These are hydrogen, deuterium, fluorine, chlorine, cyano group, and C 1-4 Alkyl alkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclic group, hydroxyl group, methoxy group, ethoxy group, isopropoxy group, C 3-8 Selected from a cycloalkoxy group, a 3-8 membered heterocyclic oxy group, a carboxyl group, an amino group, and a dimethylamino group, where R 20 , R 22 and R 23 This is as described for the compound of formula (I).

[0032] A more preferred embodiment is a compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, wherein R4 and R 6aEach is independently selected from fluorine, chlorine, cyclopropoxy group, cyclobutoxy group, or 3-8 member nitrogen-containing heterocyclic group, and each of the cyclopropoxy group, cyclobutoxy group, or 3-8 member nitrogen-containing heterocyclic group is independently selected from deuterium, fluorine, chlorine, cyano group, methyl group, ethyl group, n-propyl group, isopropyl group, trifluoromethyl group, difluoromethyl group, trideuteromethyl group, diduteromethyl group, vinyl group, ethynyl group, cyclopropyl group, cyclobutyl group, oxetanyl group, azetidinyl group, phenyl group, -SF5, =O, hydroxyl group, methoxy group, ethoxy group, n-propyloxy group, isopropyloxy group, amino group, monoC 1-4 Alkylamino group and diC 1-4 Optionally further substituted with one or more substituents selected from alkylamino groups, R 6b The group is selected from hydrogen, deuterium, fluorine, chlorine, cyano group, methyl group, ethyl group, n-propyl group, isopropyl group, cyclopropyl group, cyclobutyl group, oxetanyl group, azetidinyl group, hydroxyl group, methoxy group, ethoxy group, isopropoxy group, cyclopropoxy group, cyclobutoxy group, carboxyl group, amino group, and dimethylamino group.

[0033] A more preferred embodiment is a compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) has the structure of the compound of formula (IVb) below,

[0034] [ka]

[0035] Here, R4 and R 6a These are halogen and C, respectively, independently. 1-4 Alkoxy group, C 3-8 Selected from a cycloalkoxy group, a 3-8 membered heterocyclic group, or a 3-8 membered heterocyclic oxy group, the C 1-4 Alkoxy group, C 3-8 The cycloalkoxy group, 3-8 membered heterocyclic group, or 3-8 membered heterocyclic oxy group can each independently be deuterium, halogen, cyano group, or C1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclic group, C 6-8 Aryl group, 5-8 membered heteroaryl group, =O, =S, -SF5, -OR 20 and -NR 22 R 23 The substituents are optionally further substituted by one or more substituents selected from, and R4 and R 6a At least one of these is a 3-8 member nitrogen-containing heterocyclic group, the nitrogen atom is linked to a benzene ring, and each of the 3-8 member nitrogen-containing heterocyclic groups is independently a deuterium, halogen, cyano group, and C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclic group, C 6-8 Aryl group, 5-8 membered heteroaryl group, =O, =S, -SF5, -OR 20 and -NR 22 R 23 Provided that it is optionally further substituted by one or more substituents selected from, Here, R 20 , R 22 and R 23 This is as described for the compound of formula (I).

[0036] A more preferred embodiment is a compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, wherein R4 and R 6aEach is independently selected from fluorine, chlorine, cyclopropoxy group, cyclobutoxy group, or 3-8 member nitrogen-containing heterocyclic group, and each of the cyclopropoxy group, cyclobutoxy group, or 3-8 member nitrogen-containing heterocyclic group is independently selected from deuterium, fluorine, chlorine, cyano group, methyl group, ethyl group, n-propyl group, isopropyl group, trifluoromethyl group, difluoromethyl group, trideuteromethyl group, diduteromethyl group, vinyl group, ethynyl group, cyclopropyl group, cyclobutyl group, oxetanyl group, azetidinyl group, phenyl group, -SF5, =O, hydroxyl group, methoxy group, ethoxy group, n-propyloxy group, isopropyloxy group, amino group, monoC 1-4 Alkylamino group and diC 1-4 It is optionally further substituted with one or more substituents selected from alkylamino groups, R4 and R 6a At least one of these is a 3-8 member nitrogen-containing heterocyclic group, the nitrogen atom is linked to a benzene ring, and each of the 3-8 member nitrogen-containing heterocyclic groups is independently one or more deuterium, fluorine, chlorine, cyano group, methyl group, ethyl group, n-propyl group, isopropyl group, trifluoromethyl group, difluoromethyl group, tridueteromethyl group, didueteromethyl group, vinyl group, ethynyl group, cyclopropyl group, cyclobutyl group, oxetanyl group, azetidinyl group, phenyl group, -SF5, =O, hydroxyl group, methoxy group, ethoxy group, n-propyloxy group, isopropyloxy group, amino group, monoC 1-4 Alkylamino group and diC 1-4 The condition is that it may be further optionally substituted with substituents selected from the alkylamino group.

[0037] In a more preferred form, in the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, the 3-8 membered nitrogen-containing heterocyclic group is selected from the following structures.

[0038] [ka]

[0039] The most preferred forms of the compound of formula (I), its stereoisomers, or its pharmaceutically acceptable salts include, but are not limited to, the following compounds.

[0040] [ka] TIFF0007897619000015.tif231170TIFF0007897619000016.tif110168

[0041] A second aspect of the present invention provides a method for producing a compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, the method comprising the step of synthesizing a compound of formula (IA) or a salt thereof with a compound of formula (IB) or a salt thereof by a condensation reaction to obtain a compound of formula (I) or a salt thereof, the reaction pathway being as follows.

[0042] [ka]

[0043] The above manufacturing method can be used to produce L using a general condensation reaction in the art, for example,

[0044] If L is a bond, then R a It is halogen, R b is -B(OH)2 or [ka] is or, R a is -B(OH)2 or [ka] With halogen, R b It is a halogen,

[0045] If L is O, then R a R is a hydroxyl group or an alkoxy group. b is either halogen or R aIt is halogen, R b is a hydroxyl group or an alkoxy group, If L is S, then R a R is a mercapto group or an alkylthio group. b is either halogen or R a It is halogen, R b This is a mercapto group or an alkylthio group, If L is C(O), C(O)O, or C(O)NH, then R a R consists of a carboxyl group and an alkoxycarbonyl group. b is a halogen, a hydroxyl group, or an amino group, or R a R is a halogen, hydroxyl group, or amino group. b These are carboxyl groups and alkoxycarbonyl groups, Here, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 X1, X2, and X3 are defined as in the compound of formula (I).

[0046] A third aspect of the present invention provides a drug composition comprising a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. A fourth aspect of the present invention provides applications of the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof in the manufacture of a drug for treating MATP-related cancer or tumor.

[0047] Preferred forms of tumors or cancers include endometrial adenocarcinoma, granuloflorous cell tumor, testicular Sertoli cell tumor, germ cell tumor, malignant teratoma, squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma, clear cell carcinoma, squamous cell carcinoma, staphyloid sarcoma, fallopian tube cancer, adenocarcinoma, nephroblastoma, lymphoma, leukemia, bladder cancer, squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, prostate cancer, seminocarcinoma, teratoma, fetal cancer, teratoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma, and liver cancer. Cancer, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, gallbladder cancer, ampulla cancer, cholangiocarcinoma, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, birthmark, 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 lymphoma, osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, multiple Myeloma, malignant giant cell tumor, chordoma, osteochondroma, benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, giant cell tumor, angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyocele, fibroma, lipoma and teratoma, bronchopulmonary cancer, alveolar carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatoid hamartoma, mesothelioma, squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma, gastric cancer, lymphoma, leiomyosarcoma, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid The following are selected from tumors, snake venomous tumors, adenocarcinomas, lymphomas, carcinoid tumors, Kaposi's sarcoma, leiomyomas, hemangiomas, lipomas, neurofibromas, fibromas, colorectal adenocarcinomas, tubular adenomas, chorioadenomas, hamartomas, leiomyomas, craniomas, hemangiomas, granulomas, xanthomas, degenerative osteitis, meningiomas, meningiosarcomas, gliomas, astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors, glioblastoma multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors, spinal neurofibromas, meningiomas, gliomas, and sarcomas.

[0048] In a more preferred form, the cancer or tumor is selected from breast cancer, pancreatic cancer, skin cancer, bladder cancer, liver cancer, or head and neck cancer. The present invention also relates to a compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, used as a PRMT5 inhibitor drug.

[0049] The present invention also relates to the use of the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof in the manufacture of a drug for treating and / or preventing a PRMT5-mediated disease.

[0050] The present invention also relates to a method for treating and / or preventing PRMT5-mediated diseases, comprising administering to a patient in need a therapeutically effective amount of the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof. [Modes for carrying out the invention]

[0051] The inventors of this invention, through extensive and in-depth research, have for the first time researched and developed a PRMT5 inhibitor having the structure of formula (I) below. The series of compounds of the present invention can be widely applied to the manufacture of drugs that treat and / or prevent PRMT5-mediated diseases, and are expected to be developed as a new generation of PRMT5 inhibitors. Based on this, the present invention has been completed.

[0052] Detailed explanation: Unless otherwise stated or otherwise explained, the following terms used in the specification and claims have the following meanings: "Alkyl group" refers to a saturated aliphatic hydrocarbon group containing a linear or branched chain, preferably a linear alkyl group containing 1 to 10 or 1 to 6 carbon atoms or 1 to 4 carbon atoms, and branched alkyl groups, including methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, s-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methyl This includes, but is not limited to, the following: rupentyl group, 4-methylpentyl group, 2,3-dimethylbutyl group, n-heptyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 5-methylhexyl group, 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, n-octyl group, 2,3-dimethylhexyl group, 2,4-dimethylhexyl group, 2,5-dimethylhexyl group, 2,2-dimethylhexyl group, 3,3-dimethylhexyl group, 4,4-dimethylhexyl group, 2-ethylhexyl group, 3-ethylhexyl group, 4-ethylhexyl group, 2-methyl-2-ethylpentyl group, 2-methyl-3-ethylpentyl group, or various branched isomers thereof. 1-10 "Alkyl alkyl group" refers to a linear alkyl group containing 1 to 10 carbon atoms and a branched alkyl group containing C 1-4 "Alkyl alkyl group" refers to a linear alkyl group containing 1 to 4 carbon atoms and a branched alkyl group containing C 0-8 "Alkyl alkyl group" refers to a linear alkyl group containing 0 to 8 carbon atoms and a branched alkyl group containing C 0-4 "Alkyl group" refers to a linear alkyl group containing 0 to 4 carbon atoms, as well as a branched alkyl group.

[0053] The alkyl group may be optionally substituted or unsubstituted, but if substituted, the substituents may independently be deuterium, halogen, cyano group, nitro group, azide group, or C 1-10 Alkyl, halo-substituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclic group, C 6-10 Aryl group, 5-10 membered heteroaryl group, =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 )R21 , -C 0-8 Alkyl-C(O)NR 22 R 23 and -C 0-8 Alkyl-N(R 22 )-C(O)R 21 It is preferable that the group consists of one or more (preferably one, two, three, or four) selected from the above.

[0054] "Cycloalkyl group" or "carbocyclic group" refers to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents. A partially unsaturated cyclic hydrocarbon is one in which a cyclic hydrocarbon may contain one or more (preferably one, two, or three) double bonds, but none of the rings have a fully conjugated π-electron system. Cycloalkyl groups are divided into monocyclic cycloalkyl groups and polycyclic cycloalkyl groups, and are preferably cycloalkyl groups containing 3 to 12, 3 to 8, or 3 to 6 carbon atoms, for example, "C 3-12 A "cycloalkyl group" refers to a cycloalkyl group containing 3 to 12 carbon atoms, and is called "C 4-8 A "cycloalkyl group" refers to a cycloalkyl group containing 4 to 8 carbon atoms, and is called "C 3-8 A "cycloalkyl group" refers to a cycloalkyl group containing 3 to 8 carbon atoms, and is called "C 3-6 A "cycloalkyl group" refers to a cycloalkyl group containing 3 to 6 carbon atoms, and among them, Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl groups.

[0055] Polycyclic cycloalkyl groups include cycloalkyl groups of spiro rings, fused rings, and crosslinked rings. A "spirocycloalkyl group" is a polycyclic group that shares one carbon atom (called a spiro atom) between monocyclic rings. These groups may contain one or more (preferably one, two, or three) double bonds, but do not have rings with a fully conjugated π-electron system. Depending on the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified into monospirocycloalkyl groups, dispirocycloalkyl groups, or polyspirocycloalkyl groups. Spirocycloalkyl groups include, but are not limited to, the following:

[0056] [ka]

[0057] A "condensed cycloalkyl group" is a polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with another ring in the system. One or more of these rings may contain one or more (preferably one, two, or three) double bonds, but there are no rings with a fully conjugated π-electron system. Depending on the number of constituent rings, condensed cycloalkyl groups can be classified into dicyclic, tricyclic, tetracyclic, or polycyclic groups. Condensed cycloalkyl groups include, but are not limited to, the following:

[0058] [ka]

[0059] A "crosslinked cycloalkyl group" refers to a polycyclic group of all carbon atoms sharing two carbon atoms that are not directly linked to any two rings. These groups may contain one or more (preferably one, two, or three) double bonds, but they do not have rings with a fully conjugated π-electron system. Depending on the number of constituent rings, crosslinked cycloalkyl groups can be classified into dicyclic, tricyclic, tetracyclic, or polycyclic crosslinked cycloalkyl groups. Crosslinked cycloalkyl groups include, but are not limited to, the following:

[0060] [ka]

[0061] The cycloalkyl ring may be condensed with an aryl group, a heteroaryl group, or a heterocycloalkyl ring. Here, the ring linked to the parent structure is a cycloalkyl group, and includes, but is not limited to, an indanyl group, a tetrahydronaphthyl group, a benzocycloheptyl group, etc.

[0062] The "cycloalkyl group" or "carbon ring" may be optionally substituted or unsubstituted, but if substituted, the substituents may independently be deuterium, halogen, cyano group, nitro group, azide group, or C 1-10 Alkyl, halo-substituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclic group, C 6-10 Aryl group, 5-10 membered heteroaryl group, =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 It is preferable that the group consists of one or more (preferably one, two, three, or four) selected from the above.

[0063] A "heterocyclic group" or "heterocyclic ring" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. A partially unsaturated cyclic hydrocarbon is one in which a cyclic hydrocarbon may contain one or more (preferably one, two, or three) double bonds, but none of the rings have a fully conjugated π-electron system. One or more (preferably one, two, three, or four) ring atoms of the heterocyclic group are N, O, N·O, or S(O). r The heteroatom is selected from (where r is an integer 0, 1, or 2), but does not contain the -OO-, -OS-, or -SS- ring portion, and the remaining ring atom is carbon. Preferably, it is a heterocyclic group containing 3 to 12, 3 to 8, or 3 to 6 ring atoms. For example, "3-6 member heterocyclic group" means a heterocyclic group containing 3 to 6 ring atoms, "3-8 member heterocyclic group" means a heterocyclic group containing 3 to 8 ring atoms, "4-8 member heterocyclic group" means a heterocyclic group containing 4 to 8 ring atoms, "4-10 member heterocyclic group" means a heterocyclic group containing 4 to 10 ring atoms, "5-8 member heterocyclic group" means a heterocyclic group containing 5 to 8 ring atoms, and "3-12 member heterocyclic group" means a heterocyclic group containing 3 to 12 ring atoms.

[0064] Monocyclic heterocyclic groups include, but are not limited to, pyrrolidyl groups, piperidyl groups, piperadyl groups, morpholyl groups, thiomorpholyl groups, homopiperazyl groups, oxetane groups, and tetrahydrofuran groups.

[0065] Polycyclic heterocycles include heterocyclic groups such as spiro rings, fused rings, and bridging rings. A "spiroheterocyclic group" is a polycyclic heterocyclic group that shares one atom (called a spiro atom) between monocyclic rings, and one or more (preferably 1, 2, 3, or 4) of its ring atoms are N, O, N·O, or S(O). r A spiroheterocyclic group is a heteroatom selected from (where r is an integer 0, 1, or 2), with the remaining ring atom being carbon. These groups may contain one or more double bonds (preferably one, two, or three), but do not have a ring with a fully conjugated π-electron system. Depending on the number of spiro atoms shared between the rings, spiroheterocyclic groups are classified into monospiroheterocyclic groups, dispiroheterocyclic groups, or polyspiroheterocyclic groups. Spiroheterocyclic groups include, but are not limited to, the following:

[0066] [ka]

[0067] A "condensed heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares a pair of adjacent atoms with another ring 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 there are no rings with a fully conjugated π-electron system, and one or more (preferably 1, 2, 3, or 4) ring atoms are N, O, N·O, or S(O). r A heteroatom selected from (where r is an integer 0, 1, or 2), with the remaining ring atom being carbon. Depending on the number of constituent rings, it can be divided into dicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, which include, but are not limited to, the following:

[0068] [ka]

[0069] A "bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly linked. These rings may contain one or more (preferably one, two, or three) double bonds, but there are no rings with a fully conjugated π-electron system, and one or more (preferably one, two, three, or four) ring atoms are N, O, N·O, or S(O). r A heteroatom selected from (where r is an integer 0, 1, or 2), with the remaining ring atom being carbon. Depending on the number of constituent rings, it can be divided into dicyclic, tricyclic, tetracyclic, or polycyclic bridging heterocyclic groups, which include, but are not limited to, the following:

[0070] [ka]

[0071] The ring of the heterocyclic group may be fused to an aryl group, a heteroaryl group, or a cycloalkyl group, where the ring linked to the parent structure is a heterocyclic group and includes, but is not limited to, the following.

[0072] [ka]

[0073] The "heterocyclic group" or "heterocyclic ring" may be optionally substituted or unsubstituted, but if substituted, the substituents may independently be deuterium, halogen, cyano group, nitro group, azide group, or C 1-10 Alkyl, halo-substituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclic group, C 6-10 Aryl group, 5-10 membered heteroaryl group, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR) 16 )R17 , -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 It is preferable that the group consists of one or more (preferably one, two, three, or four) selected from the above.

[0074] An "aryl group" or "aromatic ring" is a monocyclic or polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group of all carbon atoms, and is a polycyclic (i.e., a ring having adjacent carbon atom pairs) group having a conjugated π-electron system. Preferably, it is an all-carbon aryl group containing 6-10 or 6-8 carbon atoms. For example, "C 6-10 An "aryl group" refers to a total carbon aryl group containing 6-10 carbon atoms, and includes, but is not limited to, phenyl and naphthyl groups. 6-8 An "aryl group" refers to a total carbon aryl group containing 6-8 carbon atoms. The ring of the aryl group may be fused to a heteroaryl group, a heterocyclic group, or a cycloalkyl ring, but the ring linked to the parent structure is an aryl ring and includes, but is not limited to, the following.

[0075] [ka]

[0076] The "aryl group" or "aromatic ring" may be substituted or unsubstituted, but if substituted, the substituents can independently be deuterium, halogen, cyano group, nitro group, azide group, or C 1-10 Alkyl, halo-substituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclic group, C 6-10 Aryl group, 5-10 membered heteroaryl group, =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 R19 , -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 It is preferable that the group consists of one or more (preferably one, two, three, or four) selected from the above.

[0077] A "heteroaryl group" or "heteroaromatic ring" refers to a heteroaromatic system containing one or more (preferably 1, 2, 3, or 4) heteroatoms, wherein the heteroatoms include N, O, N·O, and S(O)r (where r is an integer 0, 1, or 2), but more preferably a heteroaromatic system containing 5-10, 5-8, or 5-6 ring atoms. For example, a "5-8 membered heteroaryl group" refers to a heteroaromatic system containing 5-8 ring atoms, and a "5-10 membered heteroaryl group" refers to a heteroaromatic system containing 5-10 ring atoms, including but not limited to furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, and tetrazolyl groups. The heteroaryl ring may be fused to an aryl group, a heterocyclic group, or a cycloalkyl ring, where the ring linked to the parent structure is a heteroaryl ring and includes, but is not limited to, the following.

[0078] [ka]

[0079] The "heteroaryl group" or "heteroaromatic ring" may be optionally substituted or unsubstituted, but if substituted, the substituents may independently be deuterium, halogen, cyano group, nitro group, azide group, or C 1-10 Alkyl, halo-substituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclic group, C 6-10 Aryl group, 5-10 membered heteroaryl group, =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 R18 , -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 It is preferable that the group consists of one or more (preferably one, two, three, or four) selected from the above.

[0080] An "alkenyl group" refers to an alkyl group defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, but preferably a linear or branched alkenyl group containing 2-10 or 2-4 carbon atoms. For example, "C 2-10 An "alkenyl group" refers to a linear or branched alkenyl group containing 2 to 10 carbon atoms, and is defined as "C 2-4An "alkenyl group" refers to a linear or branched alkenyl group containing 2-4 carbon atoms. This includes, but is not limited to, vinyl groups, 1-propenyl groups, 2-propenyl groups, 1-butenyl groups, 2-butenyl groups, and 3-butenyl groups.

[0081] The "alkenyl group" may be substituted or unsubstituted, but if substituted, the substituents can be independently deuterium, halogen, cyano group, nitro group, azide group, or C 1-10 Alkyl, halo-substituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclic group, C 6-10 Aryl group, 5-10 membered heteroaryl group, =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-NR22 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 It is preferable that the group consists of one or more (preferably one, two, three, or four) selected from the above.

[0082] An "alkynyl group" refers to an alkyl group defined above, consisting of at least two carbon atoms and at least one carbon-carbon triple bond, but preferably a linear or branched alkynyl group containing 2-10 or 2-4 carbon atoms. For example, "C 2-10 An "alkynyl group" refers to a linear or branched alkynyl group containing 2-10 carbon atoms, and is defined as "C 2-4 An "alkynyl group" refers to a linear or branched alkynyl group containing 2-4 carbon atoms. This includes, but is not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0083] The "alkynyl group" may be substituted or unsubstituted, but in the case of a substituted group, the substituents can be independently deuterium, halogen, cyano group, nitro group, azide group, or C 1-10 Alkyl, halo-substituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclic group, C 6-10 Aryl group, 5-10 membered heteroaryl group, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR) 16 )R17 , -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 It is preferable that the group consists of one or more (preferably one, two, three, or four) selected from the above.

[0084] An "alkoxy group" refers to an -O-alkyl group, and the definition of an alkyl group is as described above. For example, "C 1-10 An "alkoxy group" refers to an alkyloxy group containing 1 to 10 carbon atoms. 1-4An "alkoxy group" refers to an alkyloxy group containing 1 to 4 carbon atoms. 1-2 An "alkoxy group" refers to an alkyloxy group containing one or two carbon atoms, and includes, but is not limited to, methoxy, ethoxy, propoxy, and butoxy groups.

[0085] The "alkoxy group" may be optionally substituted or unsubstituted, but if substituted, the substituents can independently be deuterium, halogen, cyano group, nitro group, azide group, or C 1-10 Alkyl, halo-substituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclic group, C 6-10 Aryl group, 5-10 membered heteroaryl group, =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 , -C0-8 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 It is preferable that the group consists of one or more (preferably one, two, three, or four) selected from the above.

[0086] A "cycloalkoxy group" or "cycloalkyloxy group" refers to an -O-cycloalkyl group, and the definition of a cycloalkyl group is as described above. For example, "C 3-12 A "cycloalkoxy group" refers to a cycloalkyloxy group containing 3 to 12 carbon atoms, and is defined as "C 3-6 A "cycloalkoxy group" refers to a cycloalkyloxy group containing 3 to 6 carbon atoms, and includes, but is not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy groups.

[0087] The "cycloalkoxy group" or "cycloalkyloxy group" may be optionally substituted or unsubstituted, but if substituted, the substituents may independently be deuterium, halogen, cyano group, nitro group, azide group, or C 1-10 Alkyl, halo-substituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclic group, C 6-10 Aryl group, 5-10 membered heteroaryl group, =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 It is preferable that the group consists of one or more (preferably one, two, three, or four) selected from the above.

[0088] A "heterocyclooxy group" or "heterocyclic oxy group" refers to an -O-heterocyclic group. The definition of a heterocyclic group is as described above and includes, but is not limited to, azetidinyloxy groups, oxetanyloxy groups, azacyclopentaoxy groups, nitrogen, oxanyloxy groups, etc.

[0089] The "heterocyclooxy group" or "heterocyclic oxy group" may be optionally substituted or unsubstituted, but if substituted, the substituents may independently be deuterium, halogen, cyano group, nitro group, azide group, or C 1-10 Alkyl, halo-substituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclic group, C 6-10 Aryl group, 5-10 membered heteroaryl group, =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 , -C0-8 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 It is preferable that the group consists of one or more (preferably one, two, three, or four) selected from the above.

[0090] "C 1-10 "Alkanoyl group" refers to C 1-10 It refers to the monovalent group of atoms remaining after removing the hydroxyl group from an alkyl acid, but is usually "C 0-9 It is also expressed as "alkyl-C(O)-", for example, "C1 alkyl-C(O)-" refers to an acetyl group, "C2 alkyl-C(O)-" refers to a propionyl group, and "C3 alkyl-C(O)-" refers to a butyryl group or isobutyryl group.

[0091] "-C 0-8 Alkyl-S(O)(=NR) 16 )R 17 " is -S(O)(=NR 16 )R 17 The sulfur atom in C 0-8 It refers to something that is linked to an alkyl group, but the C 0-8 The definition of alkyl groups is as stated above.

[0092] "-C 0-8 Alkyl-N=S(O)R 17 R 18 " is -N=S(O)R 17 R 18 The nitrogen atom in C 0-8 It refers to something that is linked to an alkyl group, but the C 0-8 The definition of alkyl groups is as stated above.

[0093] "-C 0-8 Alkyl-N=SR 17 R 18 " means -N=SR 17 R 18The nitrogen atom in C 0-8 It refers to something that is linked to an alkyl group, but the C 0-8 The definition of alkyl groups is as stated above.

[0094] "-C 0-8 Alkyl-OS(O)2R 19 " is -OS(O)2R 19 The oxygen atom in C 0-8 It refers to something that is linked to an alkyl group, but the C 0-8 The definition of alkyl groups is as stated above.

[0095] "-C 0-8 Alkyl-S(O) r R 19 " is -S(O) r R 19 The sulfur atom in C 0-8 It refers to something that is linked to an alkyl group, but the C 0-8 The definition of alkyl groups is as stated above.

[0096] "-C 0-8 alkyl-P(O)(OR 20 )R 19 " is -P(O)(OR 20 )R 19 The phosphorus atom in C 0-8 It refers to something that is linked to an alkyl group, but the C 0-8 The definition of alkyl groups is as stated above.

[0097] "-C 0-8 Alkyl-OR 20 " is -OR 20 The oxygen atom in C 0-8 It refers to something that is linked to an alkyl group, but the C 0-8 The definition of alkyl groups is as stated above.

[0098] "-C 0-8 Alkyl-C(O)OR 20 " is -C(O)OR 20 The carbonyl group in C 0-8 It refers to something that is linked to an alkyl group, but the C 0-8The definition of alkyl groups is as stated above.

[0099] "-C 0-8 Alkyl-C(O)SR 20 " is -C(O)SR 20 The carbonyl group in C 0-8 It refers to something that is linked to an alkyl group, but the C 0-8 The definition of alkyl groups is as stated above.

[0100] "-C 0-8 Alkyl-SC(O)R 21 " is -SC(O)R 21 The sulfur atom in C 0-8 It refers to something that is linked to an alkyl group, but the C 0-8 The definition of alkyl groups is as stated above.

[0101] "-C 0-8 Alkyl-C(O)R 21 " is -C(O)R 21 The carbonyl group in C 0-8 It refers to something that is linked to an alkyl group, but the C 0-8 The definition of alkyl groups is as stated above.

[0102] "-C 0-8 Alkyl-OC(O)R 21 " is -OC(O)R 21 The oxygen atom in C 0-8 It refers to something that is linked to an alkyl group, but the C 0-8 The definition of alkyl groups is as stated above.

[0103] "-C 0-8 Alkyl-NR 22 R 22 " is -NR 21 R 22 The nitrogen atom in C 0-8 It refers to something that is linked to an alkyl group, but the C 0-8 The definition of alkyl groups is as stated above.

[0104] "-C 0-8 Alkyl-C(=NR) 22)R 21 " is -C(=NR 22 )R 21 The carbon atoms in C 0-8 It refers to something that is linked to an alkyl group, but the C 0-8 The definition of alkyl groups is as stated above.

[0105] "-C 0-8 Alkyl-N(R 22 )-C(=NR 23 )R 21 " is -N(R 22 )-C(=NR 23 )R 21 The nitrogen atom in C 0-8 It refers to something that is linked to an alkyl group, but the C 0-8 The definition of alkyl groups is as stated above.

[0106] "-C 0-8 Alkyl-C(O)NR 22 R 23 " is -C(O)NR 22 R 23 The carbonyl group in C 0-8 It refers to something that is linked to an alkyl group, but the C 0-8 The definition of alkyl groups is as stated above.

[0107] "-C 0-8 Alkyl-N(R 22 )-C(O)R 21 " is -N(R 22 )-C(O)R 21 The nitrogen atom in C 0-8 It refers to something that is linked to an alkyl group, but the C 0-8 The definition of alkyl groups is as stated above.

[0108] "Halo substitution C 1-10 An "alkyl group" refers to a 1-10 carbon alkyl group in which the hydrogen atoms in the alkyl group are optionally substituted with fluorine, chlorine, bromine, or iodine atoms. This includes, but is not limited to, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, and tribromomethyl groups.

[0109] "Halo substitution C 1-10 An "alkoxy group" refers to a carbon alkoxy group consisting of 1 to 10 atoms, in which the hydrogen atoms in the alkyl group are optionally substituted with fluorine, chlorine, bromine, or iodine atoms. This includes, but is not limited to, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, and tribromomethoxy groups.

[0110] Deuterium-substituted C 1-10 An "alkyl group" refers to a 1-10 carbon alkyl group in which hydrogen atoms in the alkyl group are optionally substituted with deuterium atoms. This includes, but is not limited to, deuteromethyl, diduteromethyl, and trideuteromethyl groups.

[0111] "Halogen" refers to fluorine, chlorine, bromine, or iodine. "n-BuLi" refers to n-butyllithium. "THF" refers to tetrahydrofuran. "m-CPBA" refers to metachloroperbenzoic acid. "CuCN" refers to copper cyanide no. 1. "DMF" refers to dimethylformamide. "K2CO3" refers to potassium carbonate. "Dioxane" refers to dioxane. "NBS" refers to N-bromosuccinimide. "MeCN" refers to acetonitrile. "DMSO" refers to dimethyl sulfoxide.

[0112] "Optional" or "at will" means that it is possible by the following circumstances or environment, but does not necessarily occur, and the description includes cases where the circumstances or environment occur or do not occur, that is, both when substitution occurs and when it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may be present but does not necessarily exist, and the 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.

[0113] "Substitution" refers to the substitution of one or more hydrogen atoms in a group by a corresponding number of substituents that are independent of each other. Of course, the substituents are only those that are chemically possible, and they conform to the theory of chemical valence bonding. Those skilled in the art can verify whether substitution is possible or impossible (experimentally or theoretically) without special effort. For example, an amino group or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated bond (e.g., an olefin).

[0114] "Stereoisomers" are isomers that arise from differences in the spatial arrangement of atoms within a molecule. They can be divided into two types: cis-trans isomers and enantiomers, or enantiomers and diastereoisomers. Stereoiomers that arise from the rotation of single bonds are called conformational stereoisomers, also known as rotamers. Stereoiomers that arise from bond length, bond angles, the presence of double bonds or rings within a molecule are called structural stereoisomers, and structural stereoisomers are divided into two types. Among these, isomers that arise when the single bond of a double bond or ring-forming carbon atom cannot freely rotate are called geometric isomers, also known as cis-trans isomers, and are divided into two structures, Z and E. For example, cis-2-butene and trans-2-butene are a pair of geometric isomers, and stereoisomers that have different optical properties due to the lack of antiaxial symmetry within a molecule are called optical isomers, and are divided into structural R and S. In the present invention, unless otherwise specified, the term "stereoisomer" may be understood to include one or more of the enantiomers, structural stereoisomers, and conformational isomers.

[0115] In the present invention, "pharmaceutically acceptable salt" means a pharmaceutically acceptable acid addition salt, and includes inorganic salts and organic salts, which can be produced by methods known in the art.

[0116] "Drug composition" refers to a mixture of one or more compounds described herein or their physiologically / medicinal salts or prodrugs with other chemical components, and other components, such as physiologically / medicinal carriers and excipients. The purpose of a drug composition is to exert biological activity by facilitating administration to a living organism and contributing to the absorption of the active ingredient.

[0117] The present invention will be described in more detail and comprehensively below with reference to examples, but this is not intended to limit the present invention, nor is it limited to the contents of the examples. The structures of the compounds of the present invention were confirmed by nuclear magnetic resonance (NMR) and / or liquid-phase mass spectrometry (LC-MS). The chemical shift (δ) of the NMR is expressed in parts per million (ppm). A Bruker AVANCE-400 / 500 nuclear magnetic resonance spectrometer was used for the NMR measurements, and the solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3), with tetramethylsilane (TMS) as the internal standard.

[0118] Liquid-phase mass spectrometry (LC-MS) measurements were performed using an Agilent 6120 mass spectrometer. HPLC measurements were performed using an Agilent 1200DAD high-pressure liquid-phase chromatograph (Sunfire C18 150 × 4.6 mm chromatographic column) and a Waters 2695-2996 high-pressure liquid-phase chromatograph (Gimini C18 150 × 4.6 mm chromatographic column).

[0119] For thin-layer chromatography, silica gel plates from Yantai Huanghai HSGF254 or Qingdao GF254 were used. The size used for TLC was 0.15 mm to 0.20 mm, while the size used for product separation and purification by thin-layer chromatography was 0.4 mm to 0.5 mm. For column chromatography, 200 to 300 mesh silica gel from Yantai Huanghai Silica Gel was typically used as the support.

[0120] The starting materials used in the embodiments of this invention can be known commercially available products or synthesized by methods known in the art. Unless otherwise specified, all reactions of the present invention are carried out by continuous magnetic stirring in an atmosphere of dry nitrogen or argon, using a dry solvent, and the reaction temperature is measured in degrees Celsius (°C).

[0121] 1. Production of intermediates Preparation of intermediate 1: 2-(4-bromo-1-methyl-1H-pyrazole-5-yl)-3-fluoro-1-naphthonitrile

[0122] [ka]

[0123] Step 1: Synthesis of 5-bromo-7-fluoro-9-methyl-1,4-dihydro-1,4-epiminonaphthalene

[0124] [ka]

[0125] 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 gas protection. After the addition was complete, the mixture was stirred at -30°C for 0.5 hours, and then stirred at 25°C for 12 hours. The reaction mixture was slowly poured into 1000 mL of water, extracted with ethyl acetate (1000 mL x 3), washed with saturated sodium chloride aqueous solution (1000 mL), dried the organic phase over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was separated by high-performance silica gel column to obtain 5-bromo-7-fluoro-9-methyl-1,4-dihydro-1,4-epiminonaphthalene (19.0 g, yield 48%). 1H NMR (400MHz, CDCl3) δ 7.16-6.62 (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).

[0126] Step 2: Synthesis of 1-bromo-3-fluoronaphthalene

[0127] [ka]

[0128] 5-Bromo-7-fluoro-9-methyl-1,4-dihydro-1,4-epiminonaphthalene (44.0 g, 173 mmol) was dissolved in chloroform (450 mL), and m-CPBA (70.2 g, 85% purity, 346 mmol) was slowly added in several batches at 0°C. The reaction mixture was allowed to react at 25°C for 14 hours. The reaction mixture was slowly poured into 500 mL of water, extracted with dichloromethane (500 mL x 3), washed with saturated sodium sulfite aqueous solution (400 mL x 2), then washed with saturated brine (400 mL), dried the organic phase over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and separated the residue by high-speed silica gel column to obtain 1-bromo-3-fluoronaphthalene (34.0 g, yield 87%).

[0129] 1 H NMR (400MHz, CDCl3) δ 8.29-8.19 (m, 1H), 7.78 (br dd, J=2.9, 4.5 Hz, 1H), 7.67-7.52 (m, 3H), 7.50-7.41 (m, 1H).

[0130] Step 3: Synthesis of 3-fluoro-1-naphthonitrile

[0131] [ka]

[0132] 1-Bromo-3-fluoronaphthalene (34.0 g, 151 mmol) was dissolved in DMF (450 mL), and copper cyanide (23.2 mL, 755 mmol) was slowly added under nitrogen gas protection at 0°C. The mixture was reacted at 145°C for 12 hours under nitrogen gas protection. The reaction solution was slowly poured into 250 mL of saturated brine, extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to remove the solvent. The residue was separated by high-speed silica gel column to obtain 3-fluoro-1-naphthonitrile (19.0 g, 66% yield).

[0133] 1 H NMR (400 MHz, CDCl3) δ 8.17 (m, 1H) 7.81 (m, 1H) 7.62 (m, 4H). Step 4: Synthesis of 3-fluoro-2-iodo-1-naphthonitrile

[0134] [ka]

[0135] 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 the protection of nitrogen gas. After the addition was complete, the reaction was allowed to proceed at -70°C for 30 minutes under the protection of nitrogen gas. Iodine (28.3 mL, 114 mmol) was dissolved in tetrahydrofuran (200 mL), and then added to the reaction mixture at -70°C under the protection of nitrogen gas. The mixture was stirred at -70°C for 30 minutes, and then allowed to proceed at 25°C for 17 hours. After the reaction was complete, the solution was diluted with water (300 mL), extracted with ethyl acetate (3 * 300 mL), washed with saturated sodium chloride aqueous solution (400 mL), dried the organic phase over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was separated by high-performance silica gel column to obtain 3-fluoro-2-iodo-1-naphthonitrile (16.0 g, yield 52%).

[0136] 1 H NMR (400MHz, CDCl3) δ 8.29-8.22 (m, 1H), 7.91-7.84 (m, 1H), 7.76-7.64 (m, 3H).

[0137] Step 5: Synthesis of 3-fluoro-2-(1-methyl-1H-pyrazole-5-yl)-1-naphthonitrile

[0138] [ka]

[0139] 3-Fluoro-2-iodo-1-naphthonitrile (8.00 g, 26.9 mmol) was dissolved in 1,4-dioxane (80 mL) and water (16 mL). Sodium bicarbonate (42.4 g, 505 mmol), potassium carbonate (608 mg, 4.40 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (14.0 g, 67.3 mmol), and Pd-118 (0.88 g, 1.34 mmol) were added to the reaction mixture under the protection of nitrogen gas. The reaction mixture was allowed to react at 80°C for 2 hours under the protection of nitrogen gas. The reaction mixture was extracted with ethyl acetate (80 mL x 3), washed with saturated sodium chloride aqueous solution (200 mL), dried the organic phase over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and separated the residue by high-performance silica gel column to obtain 3-fluoro-2-(1-methyl-1H-pyrazole-5-yl)-1-naphthonitrile (6.0 g, yield 76%). MS m / z (ESI): 252 [M+H] + .

[0140] 1 H NMR (400MHz, CDCl3) δ 8.36-8.30 (m, 1H), 7.98-7.92 (m, 1H), 7.88 (d, J = 9.8 Hz, 1H), 7.77-7.73 (m, 2H), 7.69 (d, J = 2.0 Hz, 1H), 7.28 (s, 1H), 6.63 (d, J = 2.0 Hz, 1H), 3.86 (d, J = 1.5 Hz, 3H).

[0141] Step 6: Synthesis of 2-(4-bromo-1-methyl-1H-pyrazole-5-yl)-3-fluoro-1-naphthonitrile

[0142] [ka]

[0143] 3-Fluoro-2-(1-methyl-1H-pyrazole-5-yl)-1-naphthonitrile (6.00 g, 23.8 mmol) was dissolved in acetonitrile (500 mL), NBS (7.65 g, 42.9 mmol) was added, and the reaction mixture was allowed to react 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 x 3), washed with saturated sodium chloride aqueous solution (200 mL), dried the organic phase over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and separated the residue by high-performance silica gel column to obtain 2-(4-bromo-1-methyl-1H-pyrazole-5-yl)-3-fluoro-1-naphthonitrile (8.00 g, yield 91%).

[0144] 1 H NMR (400MHz, DMSO-d6) δ 8.49 (d, J = 10.4 Hz, 1H), 8.27-8.19 (m, 2H), 7.93-7.85 (m, 3H), 3.81 (s, 3H).

[0145] Intermediate 2: Preparation of tert-butyl((3-bromo-8-oxo-7,8-dihydropyrido[2,3-d]pyridazin-5-yl)methyl)carbamate

[0146] [ka]

[0147] Step 1: Synthesis of methyl 5-bromo-3-(bromomethyl)pyridine-2-carboxylate

[0148] [ka]

[0149] 5-Bromo-3-methylpyridine-2-carboxylate methyl (3.0 g, 13.04 mmol) and NBS (3.48 g, 19.56 mmol) were placed in carbon tetrachloride (50 mL), and the mixture was stirred at 80°C for 18 hours under the protection of nitrogen gas. After concentrating the reaction mixture, it was separated by column chromatography to obtain 5-bromo-3-(bromomethyl)pyridine-2-carboxylate methyl (4.0 g, 90% yield).

[0150] 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).

[0151] Step 2: Synthesis of 3-bromoflou[3,4-b]pyridine-7(5H)-one

[0152] [ka]

[0153] 5-Bromo-3-(bromomethyl)pyridine-2-carboxylate methyl (2000 mg, 6.47 mmol) and water (10 mL) were added to 1,4-dioxane (50 mL), and the mixture was stirred at 100°C for 18 hours under the protection of nitrogen gas. After concentrating the reaction mixture, it was separated by column chromatography to obtain 3-bromoflou[3,4-b]pyridine-7(5H)-one (1.0 g, yield 61%). MS m / z (ESI): 213 / 215 [M+H] + .

[0154] Step 3: Synthesis of (Z)-3-bromo-5-((dimethylamino)methylene)flu[3,4-b]pyridine-7(5H)-one

[0155] [ka]

[0156] 3-Bromoflou[3,4-b]pyridine-7(5H)-one (1.0 g, 4.67 mmol) and potassium tert-butoxide (52 mg, 0.47 mmol) were added to DMFDMA, and the mixture was stirred at 100°C for 18 hours under the protection of nitrogen gas. After concentrating the reaction mixture, it was beaten with PE to obtain (Z)-3-bromo-5-((dimethylamino)methylene)flou[3,4-b]pyridine-7(5H)-one (1.0 g, 70% yield). MS m / z (ESI): 269 / 271 [M+H] + .

[0157] Step 4: Synthesis of 3-bromo-5-((dimethylamino)methyl)pyrido[2,3-d]pyridazine-8(7H)-one

[0158] [ka]

[0159] (Z)-3-bromo-5-((dimethylamino)methylene)flou[3,4-b]pyrididine-7(5H)-one (7.0 g, 26.0 mmol) and hydrazine hydrate (7.44 mL, 130.1 mmol) were added to ethanol (50 mL), and the mixture was stirred at 80°C for 18 hours under the protection of nitrogen gas. After concentrating the reaction mixture, it was separated by column chromatography to obtain 3-bromo-5-((dimethylamino)methyl)pyrido[2,3-d]pyridazin-8(7H)-one (3.0 g, yield 25%). MS m / z (ESI): 283 / 285 [M+H] + .

[0160] Step 5: Synthesis of 3-bromo-5-(chlormethyl)pyrido[2,3-d]pyridazine-8(7H)-one

[0161] [ka]

[0162] 3-Bromo-5-((dimethylamino)methyl)pyrido[2,3-d]pyridazine-8(7H)-one (300 mg, 1.06 mmol) and 2-methylpropyl chloromethaneate (0.28 mL, 2.12 mmol) were placed in THF (10 mL), and the mixture was stirred at room temperature for 4 hours under the protection of nitrogen gas. After concentrating the reaction mixture, it was beaten with PE to obtain 3-bromo-5-(chloromethyl)pyrido[2,3-d]pyridazine-8(7H)-one (250 mg, yield 38%). MS m / z (ESI): 275 / 277 [M+H] + .

[0163] Step 6: Synthesis of 2-((3-bromo-8-oxo-7,8-dihydropyrido[2,3-d]pyridazin-5-yl)methyl)isoindoline-1,3-dione

[0164] [ka]

[0165] 3-Bromo-5-(chloromethyl)pyrido[2,3-d]pyridazine-8(7H)-one (1.5 g, 5.46 mmol) and potassium phthalimide salt (1.52 g, 8.20 mmol) were placed in DMF (50 mL), and the mixture was stirred at 90°C for 2 hours under the protection of nitrogen gas. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain 2-((3-bromo-8-oxo-7,8-dihydropyrido[2,3-d]pyridazine-5-yl)methyl)isoindorin-1,3-dione (2.0 g, 95% yield). MS m / z (ESI): 385 / 387 [M+H] + .

[0166] Step 7: Synthesis of 5-(aminomethyl)-3-bromopyrido[2,3-d]pyridazine-8(7H)-one

[0167] [ka]

[0168] 2-((3-bromo-8-oxo-7,8-dihydropyrido[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 the mixture was stirred at 70°C for 18 hours under the protection of nitrogen gas. After concentrating the reaction mixture, 5-(aminomethyl)-3-bromopyrido[2,3-d]pyridazin-8(7H)-one (900 mg, yield 67%) was obtained. MS m / z (ESI): 256 / 258 [M+H] + .

[0169] Step 8: Synthesis of ((3-bromo-8-oxo-7,8-dihydropyrido[2,3-d]pyridazin-5-yl)methyl)carbamate tert-butyl

[0170] [ka]

[0171] 5-(aminomethyl)-3-bromopyrido[2,3-d]pyridazine-8(7H)-one (900 mg, 3.53 mmol) and triethylamine (2.45 mL, 17.64 mmol) were added to dichloromethane (100 mL). Under the protection of nitrogen gas, di-tert-butyl dicarbonate (3.02 mL, 14.11 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain tert-butyl((3-bromo-8-oxo-7,8-dihydropyrido[2,3-d]pyridazine-5-yl)methyl)carbamate (300 mg, yield 23%). MS m / z (ESI): 355 / 357 [M+H] + .

[0172] Intermediate 3: Preparation of (4-((bis(tert-butoxycarbonyl)amino)methyl)-8-cyano-1-oxo-1,2-dihydrophthalazine-6-yl)boronic acid

[0173] [ka]

[0174] Step 1: Synthesis of 4-bromo-2-iodo-6-methylbenzoic acid 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. The mixture was then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to obtain 4-bromo-2-iodo-6-methylbenzoic acid (120 g, yield 57%).

[0175] Step 2: Synthesis of 5-bromo-7-iodo-1,3-dihydro-2-benzofuran-1-one

[0176] [ka]

[0177] 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 each added to a solution of CH3CN (600 mL). The mixture was stirred at 80°C for 24 hours. After confirming that the reaction was complete by TLC, the reaction solution was extracted with ethyl acetate (600 mL) and water (600 mL), washed with saturated brine (600 mL), dried the organic phase over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and separated the residue by column chromatography to obtain 5-bromo-7-iodo-1,3-dihydro-2-benzofuran-1-one (20 g, 33% yield).

[0178] 1 H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J = 0.72 Hz, 1H), 8.04 (d, J = 1.07 Hz, 1H), 5.35 (s, 2H).

[0179] Step 3: Synthesis of (3Z)-5-bromo-3-[(dimethylamino)methylethenyl]-7-iodo-1,3-dihydro-2-benzofuran-1-one

[0180] [ka]

[0181] To a flask containing 5-bromo-7-iodo-1,3-dihydro-2-benzofuran-1-one (33.5 g, 98.8 mmol), toluene (330 mL) was added, followed by the addition of [(tert-butoxy)(dimethylamino)methyl]dimethylamine (26.5 mL, 128.5 mmol). The mixture was stirred at 90°C for 5 hours. After confirming the completion of the reaction by TLC, the mixture was filtered, and the filter cake was dried to obtain compound (3Z)-5-bromo-3-[(dimethylamino)methylethenyl]-7-iodo-1,3-dihydro-2-benzofuran-1-one (20.1 g, 52% yield) as a yellow solid.

[0182] 1 H NMR (400 MHz, DMSO-d6) δ 7.96 (d, J = 1.19 Hz, 1H), 7.68 (d, J = 1.07 Hz, 1H), 7.07 (s, 1H), 3.12 (s, 6H).

[0183] Step 4: Synthesis of 6-bromo-4-[(dimethylamino)methyl]-8-iodo-1,2-dihydrophthalazine-1-one

[0184] [ka]

[0185] Add 180 mL of ethanol solution of (3Z)-5-bromo-3-[(dimethylamino)methylethenyl]-7-iodo-1,3-dihydro-2-benzofuran-1-one (18 g, 45.7 mmol) to a 500 mL flask, and 0 o Hydrazine hydrate (5.2 mL, 105.1 mmol) was added in 14C, and the mixture was stirred at 25°C for 0.5 hours, followed by stirring at 50°C for 18 hours. The precipitate was filtered directly and dried under reduced pressure to obtain 6-bromo-4-[(dimethylamino)methyl]-8-iodo-1,2-dihydrophthalazine-1-one (11.73 g, yield 63%) as a white solid.

[0186] 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 1.67 Hz, 1H), 8.35 (d, J = 1.67 Hz, 1H), 3.56 (s, 2H), 2.18 (s, 6H).

[0187] Step 5: Synthesis of 6-bromo-4-(chloromethyl)-8-iodo-1,2-dihydrophthalazine-1-one

[0188] [ka]

[0189] A mixture of 6-bromo-4-[(dimethylamino)methyl]-8-iodo-1,2-dihydrophthalazine-1-one (12 g, 29.48 mmol) in THF (140 mL) was degassed several times with N2 and cooled to 0°C. Chloro(2-methylpropoxy)methane (13.8 mL, 106.1 mmol) was then added dropwise, and the mixture was stirred under nitrogen at 25°C for 16 hours. The reaction mixture 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. The mixture was then concentrated under reduced pressure to obtain a white crude product. The crude product and MTBE (20 mL) were stirred at 25°C for 30 minutes. The mixture was filtered, and the filtered cake was then dried to obtain compound 6-bromo-4-(chloromethyl)-8-iodo-1,2-dihydrophthalazine-1-one (9.2 g, yield 78%) as a white solid.

[0190] 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.88 (s, 1H), 8.59 (d, J = 1.76 Hz, 1H), 8.27 (d, J = 1.76 Hz, 1H), 5.02 (s, 2H).

[0191] Step 6: Synthesis of tert-butyl N-[(7-bromo-5-iodo-4-oxo-3,4-dihydrophthalazine-1-yl)methyl]-N-[(tert-butyl)carbonyl]carbamate

[0192] [ka]

[0193] Bis(tert-butoxycarbonyl)amine (5.16 g, 23.73 mmol) was added to THF (100 mL), and lithium bis(trimethylsilyl)amide (25.7 mL, 25.71 mmol) was added at 0°C under an N2 atmosphere. The mixture was stirred at -70°C for 1 hour under an N2 atmosphere. Then, a mixture of 6-bromo-4-(chloromethyl)-8-iodo-1,2-dihydrophthalazine-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 hours. The reaction mixture was quenched with saturated NH4Cl (100 ml), extracted with ethyl acetate (80 ml) and water (100 ml), washed with saturated saline (100 ml), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to obtain tert-butyl N-[(7-bromo-5-iodo-4-oxo-3,4-dihydrophthalazine-1-yl)methyl]-N-[(tert-butyl)carbonyl]carbamate (4.09 g, yield 33%).

[0194] 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.69 (s, 1H), 8.60 (d, J = 1.76 Hz, 1H), 8.26 (d, J = 1.76 Hz, 1H), 4.98 (s, 2H), 1.39 (s, 18H). Step 7: Synthesis of tert-butyl((7-bromo-5-cyano-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)(tert-butoxycarbonyl)carbamate

[0195] [ka]

[0196] In a 250 mL neck flask, tert-butyl N-[(7-bromo-5-iodo-4-oxo-3,4-dihydrophthalazine-1-yl)methyl]-N-[(tert-butyl)carbonyl]carbamate (1.4 g, 2.17 mmol), N,N-dimethylformamide (20 mL), and copper cyanide (194 mg, 2.17 mmol) were added, and the mixture was stirred at 80°C for 3 hours. The reaction mixture was concentrated under reduced pressure, the residue was diluted with dichloromethane, and washed with 5% aqueous ammonia and saturated brine, respectively. The organic phase was dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure to obtain tert-butyl((7-bromo-5-cyano-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)(tert-butoxycarbonyl)carbamate (1.1 g, purity 88%, yield 93%). MS m / z (ESI): 479 / 481 [M+H] + .

[0197] Step 8: Synthesis of (4-((bis(tert-butoxycarbonyl)amino)methyl)-8-cyano-1-oxo-1,2-dihydrophthalazine-6-yl)boronic acid

[0198] [ka]

[0199] In a 100 mL necked flask, tert-butyl((7-bromo-5-cyano-4-oxo-3,4-dihydrophthalazine-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(diphenylphosphino)ferocenedichloropalladium (213 mg, 0.29 mmol), and bis(pinacolate)diborone (2.22 g, 8.73 mmol) were added and the mixture was stirred at 80°C and reacted for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was separated by reverse-phase column chromatography to obtain (4-((bis(tert-butoxycarbonyl)amino)methyl)-8-cyano-1-oxo-1,2-dihydrophthalazine-6-yl)boronic acid (1090 mg, purity 65%, yield 55%). MS m / z (ESI): 445 [M+H] + .

[0200] Intermediates 4 to 7 can be produced by selecting the corresponding raw materials, referring to all or part of the synthesis method for intermediate 1, intermediate 2, or intermediate 3.

[0201] [Table 1] Preparation of intermediate 8: 2-(4-bromo-1-methyl-1H-pyrazole-5-yl)-4-chloro-6-(3,3-difluoroazetidine-1-yl)-3-fluorobenzonitrile

[0202] [ka] Step 1: Synthesis of 2-bromo-4-chloro-6-(3,3-difluoroazetidine-1-yl)-3-fluorobenzonitrile

[0203] [ka]

[0204] 2-Bromo-4-chloro-3,6-difluorobenzonitrile (100 mg, 0.40 mmol), potassium carbonate (219 mg, 1.58 mmol), and 3,3-difluoroazetidine hydrochloride (103 mg, 0.792 mmol) were dissolved in N-methylpyrrolidone (2 mL), stirred overnight at 75°C, and after the reaction was complete, the mixture was cooled to room temperature, water (20 mL) was added, and the reaction mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the crude product was separated by column chromatography to obtain 2-bromo-4-chloro-6-(3,3-difluoroazetidine-1-yl)-3-fluorobenzonitrile (50 mg, yield 39%). 1 H NMR (400 MHz, CDCl3) δ 6.49 (d, J = 5.6 Hz, 1H), 4.53 (t, J = 11.7 Hz, 4H).

[0205] Step 2: Synthesis of 4-chloro-6-(3,3-difluoroazetidine-1-yl)-3-fluoro-2-(1-methyl-1H-pyrazole-5-yl)benzonitrile

[0206] [ka]

[0207] 2-Bromo-4-chloro-6-(3,3-difluoroazetidine-1-yl)-3-fluorobenzonitrile (300 mg, 0.92 mmol), 1-methyl-5-(tetramethyl-1,3,2-dioxaborolan-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 gas protection. The reaction was stirred at 60°C for 40 hours under nitrogen gas protection. Saturated sodium bicarbonate solution (30 mL) was added to the reaction mixture, and then it was extracted with dichloromethane (30 mL x 3). The organic phases were combined and concentrated, and the crude product was separated by column chromatography to obtain 4-chloro-6-(3,3-difluoroazetidine-1-yl)-3-fluoro-2-(1-methyl-1H-pyrazole-5-yl)benzonitrile (120 mg, 40% yield). MS m / z (ESI): 327 [M+H] + .

[0208] Step 3: Synthesis of 2-(4-bromo-1-methyl-1H-pyrazole-5-yl)-4-chloro-6-(3,3-difluoroazetidine-1-yl)-3-fluorobenzonitrile

[0209] [ka]

[0210] 4-chloro-6-(3,3-difluoroazetidine-1-yl)-3-fluoro-2-(1-methyl-1H-pyrazole-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 C18 reverse-phase column to obtain 2-(4-bromo-1-methyl-1H-pyrazole-5-yl)-4-chloro-6-(3,3-difluoroazetidine-1-yl)-3-fluorobenzonitrile (120 mg, yield 80.6%). MS m / z (ESI): 405 / 407 [M+1] + .

[0211] Intermediates 9 to 21 can be produced by selecting the corresponding raw materials, referring to all or part of the synthesis method for intermediate 8.

[0212] [Table 2] TIFF0007897619000059.tif232162TIFF0007897619000060.tif139162

[0213] Intermediate 24: Synthesis of 2-(4-bromo-1-methyl-1H-pyrazole-5-yl)-6-cyclopropoxy-3-fluoro-4-(3-methoxypyrrolidine-1-yl)benzonitrile

[0214] [ka]

[0215] Step 1: Synthesis of 2-bromo-4-chloro-3,6-difluorobenzonitrile

[0216] [ka]

[0217] A mixture of 4-chloro-2,5-difluorobenzonitrile (25 g, 144.1 mmol), NBS (51.28 g, 288.1 mmol), palladium acetate (3.23 g, 14.4 mmol), and p-toluenesulfonic acid (11.59 mL, 72.0 mmol) 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), dried the organic phase over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and separated the residue by column chromatography to obtain 2-bromo-4-chloro-3,6-difluorobenzonitrile (13.33 g, yield 38%).

[0218] Step 2: Synthesis of 2-bromo-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile

[0219] [ka]

[0220] 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, then 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. The mixture was then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to obtain 2-bromo-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile (8.1 g, yield 47%).

[0221] 1 H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 5.63 Hz, 1H) 3.77 (dt, J = 8.63, 4.44 Hz, 1H) 0.83 (br d, J = 4.63 Hz, 4H). Step 3: Synthesis of 4-chloro-6-cyclopropoxy-3-fluoro-2-(1-methyl-1H-pyrazole-5-yl)benzonitrile

[0222] [ka]

[0223] 2-Bromo-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile (5.0 g, 17.21 mmol), 1-methyl-5-tetramethyl-1,3,2-dioxaborolan-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 mixture 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. The solvent was removed by reducing the pressure and 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%).

[0224] 1 H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 2.01 Hz, 1H), 7.50 (d, J = 5.77 Hz, 1H), 6.52 (d, J = 1.76 Hz, 1H), 3.89 (dt, J = 8.91, 4.33 Hz, 1H), 3.83 (d, J = 1.00 Hz, 3H), 0.96 (m, 4H). Step 4: Synthesis of 2-(4-bromo-1-methyl-1H-pyrazole-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile

[0225] [ka]

[0226] 4-chloro-6-cyclopropoxy-3-fluoro-2-(1-methyl-1H-pyrazole-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 mixture 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. The mixture was then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to obtain 2-(4-bromo-1-methyl-1H-pyrazole-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile (5 g, purity: 93%, yield: 76%).

[0227] 1 H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 7.48 (d, J = 5.88 Hz, 1H), 3.82 (m, 1H), 3.73 (s, 3H), 0.92-0.83 (m, 4H). Step 5: Synthesis of 2-(4-bromo-1-methyl-1H-pyrazole-5-yl)-6-cyclopropoxy-3-fluoro-4-(3-methoxypyrrolidine-1-yl)benzonitrile

[0228] [ka]

[0229] 2-(4-bromo-1-methyl-1H-pyrazole-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 stirred overnight in a sealed tube at 130°C. After the reaction was complete, water was added to quench the mixture, and it was extracted with ethyl acetate. The organic phases were combined and washed with water, dried, concentrated, and the crude product was separated by column chromatography to obtain 2-(4-bromo-1-methyl-1H-pyrazole-5-yl)-6-cyclopropoxy-3-fluoro-4-(3-methoxypyrrolidine-1-yl)benzonitrile (85 mg, 79% yield). MS m / z (ESI): 435 / 437 [M+H] + .

[0230] Intermediates 25-34 can be produced by referring to all or part of the synthesis method for intermediate 24 and selecting the corresponding raw materials.

[0231] [Table 3] TIFF0007897619000068.tif199161

[0232] 2. Manufacturing of specific examples Experiment 1: Preparation of 1-(aminomethyl)-7-(5-(1-cyano-3-fluoronaphthalene-2-yl)-1-methyl-1H-pyrazole-4-yl)-4-oxo-3,4-dihydrophthalazine-5-carbonitrile

[0233] [ka]

[0234] Step 1: Synthesis of tert-butyl(tert-butoxycarbonyl)((5-cyano-7-(5-(1-cyano-3-fluoronaphthalene-2-yl)-1-methyl-1H-pyrazole-4-yl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)carbamate

[0235] [ka]

[0236] (4-((bis(tert-butoxycarbonyl)amino)methyl)-8-cyano-1-oxo-1,2-dihydrophthalazine-6-yl)boronic acid (1.0 g, 70% purity, 1.58 mmol), 2-(4-bromo-1-methyl-1H-pyrazole-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(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (230 mg, 0.32 mmol) were added to a 25 mL necked flask, and the reaction mixture was stirred at 80°C and reacted for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was separated by column chromatography to obtain tert-butyl(tert-butoxycarbonyl)((5-cyano-7-(5-(1-cyano-3-fluoronaphthalene-2-yl)-1-methyl-1H-pyrazole-4-yl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)carbamate (450 mg, yield 43%). MS m / z (ESI): 650 [M+H] + .

[0237] Step 2: Synthesis of 1-(aminomethyl)-7-(5-(1-cyano-3-fluoronaphthalene-2-yl)-1-methyl-1H-pyrazole-4-yl)-4-oxo-3,4-dihydrophthalazine-5-carbonitrile

[0238] [ka]

[0239] 135 mg, 0.015 mmol of tert-butyl(tert-butoxycarbonyl)((5-cyano-7-(5-(1-cyano-3-fluoronaphthalene-2-yl)-1-methyl-1H-pyrazole-4-yl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)carbamate was dissolved in 3.0 mL of dichloromethane, 2.0 mL of trifluoroacetic acid was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate, the pH was adjusted to 9-10 with saturated sodium bicarbonate, and the aqueous phase was extracted with ethyl acetate after liquid-liquid separation. The organic phase was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was swiftly evaporated under reduced pressure to obtain 1-(aminomethyl)-7-(5-(1-cyano-3-fluoronaphthalene-2-yl)-1-methyl-1H-pyrazole-4-yl)-4-oxo-3,4-dihydrophthalazine-5-carbonitrile (96 mg, 97% yield). MS m / z (ESI): 450 [M+H] + .

[0240] 1 H NMR (400 MHz, DMSO-d6) δ 12.75 (brs, 1H), 8.56 (d, J = 10.2 Hz, 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). tert-butyl(tert-butoxycarbonyl)((5-cyano-7-(5-(1-cyano-3-fluoronaphthalene-2-yl)-1-methyl-1H-pyrazole-4-yl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)carbamate (380 mg, 0.585 mmol) was separated by chiral column to obtain tert-butyl(M)-(tert-butoxycarbonyl)((5-cyano-7-(5-(1-cyano-3-fluoronaphthalene-2-yl)-1-methyl-1H-pyrazole-4-yl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)carbamate (135 182 mg (yield: 35%) and tert-butyl(P)-(tert-butoxycarbonyl)((5-cyano-7-(5-(1-cyano-3-fluoronaphthalene-2-yl)-1-methyl-1H-pyrazole-4-yl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)carbamate were obtained (yield: 46%). Subsequently, tert-butoxycarbonyl was removed with trifluoroacetic acid to obtain the corresponding final products, Examples 4 and 5, and the specific data are shown in the table below.

[0241] Examples 2 to 37 can be manufactured by referring to all or part of the synthesis method of Example 1 and selecting the corresponding raw materials.

[0242] [Table 4] TIFF0007897619000073.tif238161TIFF0007897619000074.tif238162TIFF0007897619000075.tif240162TIFF0007897619000076.tif239162TIFF0007897619000077.tif240161TIFF0007897619000078.tif46161The nuclear magnetic data of the compounds produced in the above examples are as follows.

[0243] [Table 5] TIFF0007897619000080.tif239161TIFF0007897619000081.tif239161TIFF0007897619000082.tif239161 TIFF0007897619000083.tif243161TIFF0007897619000084.tif239161TIFF0007897619000085.tif106161

[0244] [Biological Measurement and Evaluation] 1. Human colorectal cancer HCT116 cell proliferation inhibition test 1. HCT 116 MTAP knockout cells and MTAP wild-type cells were seeded in 96-well flat-bottom plates and cultured overnight at 37°C and 5% CO2 in McCoy's 5A medium containing 10% fetal bovine serum + 1% penicillin-streptomycin.

[0245] 2. The following day, the compound was dissolved in DMSO, then diluted sequentially with DMSO and culture medium, and transferred to a cell plate. The final concentration of the compound was 10 μM, a 4-fold dilution, and nine concentration gradients were prepared, along with a DMSO control.

[0246] 3. Cells that had not been treated with the compound were isolated, and cell activity was detected using the CellTiter-Glo Luminescent Cell Viability Assay (Promega), following the procedure in the kit's instructions. Subsequently, the cell plate was placed on an EnVision Multilabel Reader and the cold light signal was detected.

[0247] 4. Simultaneously, cell plates treated with the compound were cultured continuously for 6 days at 37°C under conditions of 5% CO2. 5. Subsequently, cell activity was detected using CellTiter-Glo in the same manner.

[0248] 6. Finally, the dose-response curve was plotted using the 4-parameter dose-response curve module of GraphPad Prism v 9.2.0 software, and growth-inhibiting IC was calculated. 50 The value (in nM) was calculated.

[0249] [Table 6] Based on the biological activity data of the compounds in specific examples, the series of compounds of the present invention exhibits potent inhibitory activity against the proliferation of human colorectal cancer HCT116 MTAP knockout cells at the cellular level, while exhibiting weak inhibitory activity against MTAP wild-type HCT116 cells and having higher selectivity compared to the positive compound MRTX-1979.

[0250] [Mouse Pharmacokinetic Measurement] 1. Research Objectives The purpose of this study is to investigate the pharmacokinetic behavior of some of the compounds of the present invention, and the administration method for each compound is a single oral (PO) dose to ICR mice.

[0251] 2. Experimental Plan 2.1 Experimental drugs The compounds used in this test are derived from the compounds in the specific examples of the present invention.

[0252] 2.2 Laboratory animals ICR mouse, male, N=3. Origin: Shanghai Xipur-Bikay Laboratory Animal Co., Ltd. 2.3 Preparation and Administration of Drugs The compounds were weighed and dissolved in a solvent of 20% PG + 10% Solutol HS15 + 70% pH3 citrate buffer. The mixture was then shaken and sonicated to obtain a colorless, transparent solution or suspension. Nine mice were fasted overnight, and then orally administered at a dose of 10 mg / kg.

[0253] 2.4 Sample Collection: Blood was collected from the submandibular vein at approximately 90 μL / time, treated with heparin sodium for anticoagulation, placed on ice after collection, and centrifuged within 1 hour to separate the plasma (centrifugation conditions: 8000 rpm, 6 minutes, 2-8°C). Blood collection time points were 0, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours. Samples were stored in a refrigerator at -20°C.

[0254] A 40 μL plasma sample was added to 160 μL of chilled acetonitrile containing an internal standard, vortexed for 3 minutes, and centrifuged at 11,000 rpm for 5 minutes. 100 μL of the supernatant was added to 100 μL of water, and 5 μL was injected into LC / MS / MS for analysis (results are shown in the table below).

[0255] 2.5 Test Results: PK results after single oral administration (PO) of a compound at 10 mg / kg to mice.

[0256] [Table 7]

[0257] Experimental conclusion: In a mouse pharmacokinetic study, under oral administration conditions, the compounds of the present invention examples showed a C value compared to the positive compound MRTX-1979. max Furthermore, the AUC increased significantly, indicating favorable pharmacokinetic properties and a better prospect for development. [Liver microsome stability experiment] 1. Manufacturing of reagents 1. Preparation of buffer solution C: Buffer A: 1.0 L of 0.1 M potassium dihydrogen phosphate buffer (containing 1.0 mM EDTA).

[0258] Buffer B: 1.0 L of 0.1 M dipotassium hydrogen phosphate buffer (containing 1.0 mM EDTA). Buffer C: Add 700 mL of Buffer A to Buffer B, and stop when the pH reaches 7.4.

[0259] 2. Preparation of 10 mM stock solution: The selected example compounds and the control samples were dissolved in DMSO to prepare 10 mM stock solutions.

[0260] • 500 μM solution: 10 μL of 10 mM stock solution was added to 190 μL of ACN. • 1.5 μM administration solution (dissolved in liver microsome solution; human liver microsomes purchased from Xenotech): 18.75 μL of 20 mg / mL liver microsomes were added to 479.75 μL of buffer C, then 1.5 μL of 500 μM solution was added, and the mixture was shaken gently to ensure uniformity.

[0261] Preparation of 4.6 mM NADPH solution: NADPH was weighed, and then an appropriate amount of buffer C was added to make a 6 mM NADPH solution.

[0262] 2. Specific experimental plan 1. 30 μL of 1.5 μM dose solution was added to wells set at different time points (0 min, 5 min, 15 min, 30 min, 45 min) on a 96-well plate, with 2 replicates.

[0263] 2. Prepare the 0-minute sample: First, add 135 μL of ACN (containing internal standard) to the 0-minute well, followed by 15 μL of 6 mM NADPH solution.

[0264] 3. A 96-well plate containing the 1.5 μM administration solution and the NADPH solution were preheated in a 37°C water bath for 5 minutes.

[0265] 4. Preheated 15 μL of 6 mM NADPH solution was added to the wells at the designated time points of 5 minutes, 15 minutes, 30 minutes, and 45 minutes to start the reaction and begin timing.

[0266] 5. When the timer showed 5 minutes, 15 minutes, 30 minutes, and 45 minutes, 135 μL of ACN (containing internal standard) was added to terminate the reaction. The mixture was vortexed for 10 minutes, and the sample was centrifuged at 5594 × g for 15 minutes.

[0267] 6. 50 μL of supernatant was taken from the centrifuged sample, transferred to a 96-well sample plate with 50 μL of water added, and mixed. Finally, the sample was sent to LC-MS / MS for analysis, and the half-life was calculated from the test results. The experimental results are shown in the table below.

[0268] [Table 8]

[0269] Experimental conclusion: In in vitro human liver microsome stability experiments, the compounds of the present invention demonstrated a half-life T compared to the positive compound MRTX-1979. 1 / 2 This showed a significant improvement, demonstrating better in vitro metabolic stability and indicating a more promising outlook for development.

[0270] All documents relating to the present invention are cited herein by reference, so that each document may be cited independently. Furthermore, after reading the above, those skilled in the art will understand that various variations and modifications of the present invention may be made, and that equivalent forms thereof are included within the scope of the claims of the present invention.

Claims

1. A compound of formula (III), its stereoisomer, or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 Here, ring A has the following structure, 【Chemistry 2】 or 【Transformation 3】 And, R １ It is selected from hydrogen, deuterium, methyl group, ethyl group, isopropyl group and cyclopropyl group, Each R ３ and R ７ These are, independently, hydrogen, deuterium, fluorine, chlorine, cyano group, and C. １－４ alkyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclic group, hydroxyl group, methoxy group, ethoxy group, isopropoxy group, C ３－８ Selected from cycloalkoxy groups, 3-8 membered heterocyclic oxy groups, methylthio groups, ethylthio groups, carboxyl groups, methoxycarbonyl groups, ethoxycarbonyl groups, isopropoxycarbonyl groups, acetyl groups, acetoxy groups, amino groups, dimethylamino groups, acetylamino groups, and carbamoyl groups, R １５ This is selected from a cyano group, an ethynyl group, a cyclopropyl group, or hydrogen. R １５ The group is selected from a cyano group, an ethynyl group, or a cyclopropyl group, and ring A is 【Chemistry 4】 When it is, R ４ and R ６ａ are each independently selected from halogen, C １－４ alkoxy group, C ３－８ cycloalkoxy group, 3- to 8-membered heterocyclic group or 3- to 8-membered heterocyclic oxy group, and the C １－４ alkoxy group, C ３－８ cycloalkoxy group, 3- to 8-membered heterocyclic group or 3- to 8-membered heterocyclic oxy group is each independently deuterium, halogen, cyano group, C １－４ alkyl group, halo-substituted C １－４ alkyl group, deuterium-substituted C １－４ alkyl group, C ２－４ alkenyl group, C ２－４ alkynyl group, C ３－８ cycloalkyl group, 3- to 8-membered heterocyclic group, C ６－８ aryl group, 5- to 8-membered heteroaryl group, =O, =S, -SF ５ , -O-R ２０ , -C(O)OR ２０ , -C(O)R ２１ , -O-C(O)R ２１ , -NR ２２ R ２３ , -C(O)NR ２２ R ２３ and -N(R ２２ )-C(O)R ２１ and is optionally further substituted by one or more substituents selected from R １５ The group is selected from a cyano group, an ethynyl group, or a cyclopropyl group, and ring A is 【Transformation 5】 If R ６ｂ It is hydrogen, deuterium, fluorine, chlorine, cyano group, C １－４ alkyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclic group, hydroxyl group, methoxy group, ethoxy group, isopropoxy group, C ３－８ Selected from cycloalkoxy groups, 3-8 membered heterocyclic oxy groups, carboxyl groups, amino groups, and dimethylamino groups, R １５ is selected from hydrogen, and ring A is 【Transformation 6】 If R ４ and R ６ａ These are halogen and C, respectively, independently. １－４ Alkoxy group, C ３－８ Selected from a cycloalkoxy group, a 3-8 membered heterocyclic group, or a 3-8 membered heterocyclic oxy group, the C １－４ Alkoxy group, C ３－８ The cycloalkoxy group, 3-8 membered heterocyclic group, or 3-8 membered heterocyclic oxy group can each independently be deuterium, halogen, cyano group, or C １－４ Alkyl, halo-substituted C １－４ Alkyl, deuterium-substituted C １－４ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclic group, C ６－８ Aryl group, 5-8 membered heteroaryl group, =O, =S, -SF ５ , -O-R ２０ , -C(O)OR ２０ , -C(O)R ２１ , -O-C(O)R ２１ , -NR ２２ R ２３ , -C(O)NR ２２ R ２３ and -N(R ２２ )-C(O)R ２１ R is optionally further substituted by one or more substituents selected from the above, ４ and R ６ａ At least one of them is a 3-8 member nitrogen-containing heterocyclic group, the nitrogen atom is linked to a benzene ring, and the 3-8 member nitrogen-containing heterocyclic group is deuterium, halogen, cyano group, C １－４ Alkyl, halo-substituted C １－４ Alkyl, deuterium-substituted C １－４ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclic group, C ６－８ Aryl group, 5-8 membered heteroaryl group, =O, =S, -SF ５ , -O-R ２０ , -C(O)OR ２０ , -C(O)R ２１ , -O-C(O)R ２１ , -NR ２２ R ２３ , -C(O)NR ２２ R ２３ and -N(R ２２ )-C(O)R ２１ Provided that it is optionally further substituted by one or more substituents selected from, R15 is selected from hydrogen, and ring A is 【Transformation 7】 If not, Each R ２０ is independently selected from hydrogen, deuterium, C １－４ alkyl group, C ２－４ alkenyl group, C ３－６ cycloalkyl group, C ３－６ cycloalkyl group, 3- to 6-membered heterocyclic group, C ６－８ aryl group and 5- to 8-membered heteroaryl group, and the said groups are optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy group, =O, cyano group, C １－４ alkyl group, C １－４ alkoxy group, C ３－６ cycloalkyl group, C ３－６ cycloalkoxy group, 3- to 6-membered heterocyclic group, 3- to 6-membered heterocyclic oxy group, C ６－８ aryl group, C ６－８ aryloxy group, 5- to 8-membered heteroaryl group, 5- to 8-membered heteroaryloxy group and -NR ２２ R ２３ and is optionally further substituted by one or more substituents selected therefrom, Each R ２１ is independently hydrogen, deuterium, a hydroxy group, C １－４ alkyl group, C １－４ alkoxy group, C ２－４ alkenyl group, C ２－４ alkynyl group, C ３－６ cycloalkyl group, C ３－６ cycloalkoxy group, a 3- to 6-membered heterocyclic group, a 3- to 6-membered heterocyclic oxy group, C ６－８ aryl group, C ６－８ aryloxy group, a 5- to 8-membered heteroaryl group, a 5- to 8-membered heteroaryloxy group, and -NR ２２ R ２３ is selected from, and the groups are independently deuterium, halogen, a hydroxy group, =O, a cyano group, C １－４ alkyl group, C １－４ alkoxy group, C ３－６ cycloalkyl group, C ３－６ cycloalkoxy group, a 3- to 6-membered heterocyclic group, a 3- to 6-membered heterocyclic oxy group, C ６－８ aryl group, C ６－８ aryloxy group, a 5- to 8-membered heteroaryl group, a 5- to 8-membered heteroaryloxy group, and -NR ２２ R ２３ is optionally further substituted by one or more substituents selected from, Each R ２２ and R ２３ These are, independently, hydrogen, deuterium, a hydroxyl group, and C １－４ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－６ Cycloalkyl group, 3-6 membered heterocyclic group, C ６－８ Aryl group, 5-8 membered heteroaryl group, sulfinyl group, sulfonyl group, methylsulfonyl group, isopropylsulfonyl group, cyclopropylsulfonyl group, p-toluenesulfonyl group, aminosulfonyl group, dimethylaminosulfonyl group and C １－４ Selected from alkanoyl groups, the group can independently be deuterium, halogen, hydroxyl, =O, C １－４ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, halosubstituted C １－４ Alkyl, deuterium-substituted C １－４ alkyl group, C １－４ Alkoxy group, C ３－６ Cycloalkyl groups, C ３－６ Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C ６－８ Aryl group, C ６－８ Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group, amino group, C １－４ Alkyl monosubstituted amino group, C １－４ Alkyl disubstituted amino group and C １－４ The group may be further optionally substituted with one or more substituents selected from the alkanoyl group, or R ２２ and R ２３ It forms a 4-6 membered heterocyclic group or a 5-6 membered heteroaryl group with a directly bonded nitrogen atom, and the 4-6 membered heterocyclic group or 5-6 membered heteroaryl group contains deuterium, halogen, hydroxyl group, =O,C １－４ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, halosubstituted C １－４ Alkyl, deuterium-substituted C １－４ alkyl group, C １－４ Alkoxy group, C ３－６ Cycloalkyl groups, C ３－６ Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C ６－８ Aryl group, C ６－８ Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group, amino group, C １－４ Alkyl monosubstituted amino group, C １－４ Alkyl disubstituted amino group and C １－４ They may be further optionally substituted with one or more substituents selected from the alkanoyl group. A compound of formula (III), its stereoisomer, or a pharmaceutically acceptable salt thereof, characterized in that each r is independently 0, 1, or 2.

2. The compound of formula (III) has the structure of the compound of formula (IVa) below, 【Transformation 8】 Here, R １５ This is selected from a cyano group, an ethynyl group, or a cyclopropyl group. Ring A has the following structure: 【Chemistry 9】 or 【Chemistry 10】 And, R ４ and R ６ａ These are halogen and C, respectively, independently. １－４ Alkoxy group, C ３－８ Selected from a cycloalkoxy group, a 3-8 membered heterocyclic group, or a 3-8 membered heterocyclic oxy group, the C １－４ Alkoxy group, C ３－８ The cycloalkoxy group, 3-8 membered heterocyclic group, or 3-8 membered heterocyclic oxy group can each independently be deuterium, halogen, cyano group, or C １－４ Alkyl, halo-substituted C １－４ Alkyl, deuterium-substituted C １－４ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclic group, C ６－８ Aryl group, 5-8 membered heteroaryl group, =O, =S, -SF ５ , -O-R ２０ and -NR ２２ R ２３ Optionally further substituted by one or more substituents selected from, R ６ｂ It is hydrogen, deuterium, fluorine, chlorine, cyano group, C １－４ alkyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclic group, hydroxyl group, methoxy group, ethoxy group, isopropoxy group, C ３－８ Selected from cycloalkoxy groups, 3-8 membered heterocyclic oxy groups, carboxyl groups, amino groups, and dimethylamino groups, Here, R ２０ , R ２２ and R ２３ The features are as defined in claim 1. A compound of formula (III) as described in claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

3. R ４ and R ６ａ Each is independently selected from fluorine, chlorine, cyclopropoxy group, cyclobutoxy group, or 3-8 membered nitrogen-containing heterocyclic group, and each of the cyclopropoxy group, cyclobutoxy group, or 3-8 membered nitrogen-containing heterocyclic group is independently selected from deuterium, fluorine, chlorine, cyano group, methyl group, ethyl group, n-propyl group, isopropyl group, trifluoromethyl group, difluoromethyl group, tridueteromethyl group, didueteromethyl group, vinyl group, ethynyl group, cyclopropyl group, cyclobutyl group, oxetanyl group, azetidinyl group, phenyl group, -SF ５ , =O, hydroxyl group, methoxy group, ethoxy group, n-propyloxy group, isopropyloxy group, amino group, monoC １－４ Alkylamino group and diC １－４ Optionally further substituted with one or more substituents selected from alkylamino groups, R ６ｂ It is characterized by being selected from hydrogen, deuterium, fluorine, chlorine, cyano group, methyl group, ethyl group, n-propyl group, isopropyl group, cyclopropyl group, cyclobutyl group, oxetanyl group, azetidinyl group, hydroxyl group, methoxy group, ethoxy group, isopropoxy group, cyclopropoxy group, cyclobutoxy group, carboxyl group, amino group, and dimethylamino group. A compound of formula (III) as described in claim 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

4. The compound of formula (III) has the structure of the compound of formula (IVb) below, 【Chemistry 11】 Here, R ４ and R ６ａ These are halogen and C, respectively, independently. １－４ Alkoxy group, C ３－８ Selected from a cycloalkoxy group, a 3-8 membered heterocyclic group, or a 3-8 membered heterocyclic oxy group, the C １－４ Alkoxy group, C ３－８ The cycloalkoxy group, 3-8 membered heterocyclic group, or 3-8 membered heterocyclic oxy group can each independently be deuterium, halogen, cyano group, or C １－４ Alkyl, halo-substituted C １－４ Alkyl, deuterium-substituted C １－４ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclic group, C ６－８ Aryl group, 5-8 membered heteroaryl group, =O, =S, -SF ５ , -O-R ２０ and -NR ２２ R ２３ R is optionally further substituted by one or more substituents selected from the above, ４ and R ６ａ At least one of these is a 3-8 member nitrogen-containing heterocyclic group, the nitrogen atom is linked to a benzene ring, and each of the 3-8 member nitrogen-containing heterocyclic groups is independently a deuterium, halogen, cyano group, and C １－４ Alkyl, halo-substituted C １－４ Alkyl, deuterium-substituted C １－４ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclic group, C ６－８ Aryl group, 5-8 membered heteroaryl group, =O, =S, -SF ５ , -O-R ２０ and -NR ２２ R ２３ Provided that it is optionally further substituted by one or more substituents selected from, Here, R ２０ , R ２２ and R ２３ The features are as defined in claim 1. A compound of formula (III) as described in claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

5. R ４ and R ６ａ Each is independently selected from fluorine, chlorine, cyclopropoxy group, cyclobutoxy group, or 3-8 membered nitrogen-containing heterocyclic group, and each of the cyclopropoxy group, cyclobutoxy group, or 3-8 membered nitrogen-containing heterocyclic group is independently selected from deuterium, fluorine, chlorine, cyano group, methyl group, ethyl group, n-propyl group, isopropyl group, trifluoromethyl group, difluoromethyl group, tridueteromethyl group, didueteromethyl group, vinyl group, ethynyl group, cyclopropyl group, cyclobutyl group, oxetanyl group, azetidinyl group, phenyl group, -SF ５ , =O, hydroxyl group, methoxy group, ethoxy group, n-propyloxy group, isopropyloxy group, amino group, monoC １－４ Alkylamino group and diC １－４ R is optionally further substituted with one or more substituents selected from alkylamino groups, ４ and R ６ａ At least one of them is a 3-8 member nitrogen-containing heterocyclic group, the nitrogen atom is linked to a benzene ring, and each of the 3-8 member nitrogen-containing heterocyclic groups is independently a deuterium, fluorine, chlorine, cyano group, methyl group, ethyl group, n-propyl group, isopropyl group, trifluoromethyl group, difluoromethyl group, tridueteromethyl group, didueteromethyl group, vinyl group, ethynyl group, cyclopropyl group, cyclobutyl group, oxetanyl group, azetidinyl group, phenyl group, -SF ５ , =O, hydroxyl group, methoxy group, ethoxy group, n-propyloxy group, isopropyloxy group, amino group, monoC １－４ Alkylamino group and diC １－４ This is characterized by being further optionally substituted with one or more substituents selected from alkylamino groups. A compound of formula (III) as described in claim 4, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

6. The aforementioned 3-8 membered nitrogen-containing heterocyclic group is characterized by being selected from the following structures: A compound of formula (III) as described in claim 5, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: 【Chemistry 12】

7. A compound of formula (III) according to any one of claims 1 to 6, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized by being selected from the following compounds. 【Chemistry 13】 【change】

8. A drug composition comprising a compound of formula (III) as described in claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

9. Use of a compound of formula (III) according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a drug for treating MATP-related cancer or tumor.

10. The aforementioned tumors or cancers include endometrial adenocarcinoma, granuloflorous cell tumor, testicular Sertoli cell tumor, germ cell tumor, malignant teratoma, squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma, clear cell carcinoma, squamous cell carcinoma, staphyloid sarcoma, fallopian tube cancer, adenocarcinoma, nephroblastoma, lymphoma, leukemia, bladder cancer, squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, prostate cancer, seminocarcinoma, teratoma, fetal cancer, teratoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma, liver cancer, bile duct cancer, and hepatoblastoma. Angiosarcoma, hepatocellular adenoma, hemangioma, gallbladder cancer, ampulla cancer, cholangiocarcinoma, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, birthmark, 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 lymphoma, osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, multiple myeloma, malignant megaloblastic leukemia Cystomas, chordomas, osteochondromas, benign chondromas, chondroblastomas, chondromyxofibromas, osteoid osteomas, giant cell tumors, angiosarcomas, fibrosarcomas, rhabdomyosarcomas, liposarcomas, myxomas, rhabdomyoceles, fibromas, lipomas and teratomas, bronchopulmonary cancer, alveolar carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatoid hamartoma, mesothelioma, squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma, gastric cancer, lymphoma, leiomyosarcoma, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, snake venom tumors, adenocarcinomas, Characterized by being selected from lymphoma, carcinoid, Kaposi's sarcoma, leiomyomere, hemangioma, lipoma, neurofibroma, fibroma, colorectal adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, leiomyomere, cranioma, hemangioma, granuloma, xanthomas, degenerative osteitis, meningioma, meningiosarcoma, glioma, astrocytoma, medulloblastoma, glioma, ependymoma of the ventricle, germ cell tumor, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor, spinal neurofibroma, meningioma, glioma, and sarcoma. The use described in claim 9.

11. The cancer or tumor is characterized by being selected from breast cancer, pancreatic cancer, skin cancer, bladder cancer, liver cancer, or head and neck cancer. The use described in claim 9.

12. A compound of formula (III) according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use as a PRMT5 inhibitor.

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