Pyridone compound as well as preparation method and application thereof

Abstract

The invention relates to a pyridone compound, a preparation method of the pyridone compound and application of the pyridone compound as a PDE3A-SLFN12 compound inducer. Specifically, the invention provides a method. The invention relates to a pyridone compound as shown in a general formula (I), a stereoisomer, a solvate and a pharmaceutically acceptable salt or prodrug thereof, a preparation method of the pyridone compound and application of the pyridone compound or a pharmaceutical composition containing the pyridone compound in cancer treatment, wherein each group in the general formula (I) is defined in the specification. # imgabs0 #

Description

Pyridone compound and its preparation method and use Technical Field

[0001] The present invention belongs to the technical field of drug synthesis, and in particular relates to a pyridone compound containing a pyridone structure, a preparation method of the pyridone compound, and pharmaceutical applications of the pyridone compound. Background Art

[0002] Cancer is a serious threat to human life and health, causing over 10 million deaths worldwide each year. Currently, numerous breakthroughs have been made in various anti-tumor therapies, including small molecule drugs and biologics, providing improved disease treatment and management for some cancer patients. However, existing therapies also suffer from deficiencies such as insufficient efficacy and safety, and the development of drug resistance. This creates a significant unmet clinical need, and new therapeutic agents and approaches are urgently needed.

[0003] Velcrins are a class of drug molecules discovered through phenotypic screening. Upon binding to the PDE3A protein, they selectively induce the formation of the SLNF12-PDE3A complex, thereby achieving anti-cancer effects. Since the discovery of the first velcrin molecule, 6-(4-(diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (DNMDP), scientists have subsequently discovered a series of small molecules with similar functions, including the human signaling molecule estradiol, the marketed drug anagrelide, and the natural product nauclefine. Recently, Bayer's WO2022184748A1 disclosed a small molecule that selectively induces the formation of a stable PDE3A-SLFN12 complex for the treatment of melanoma. The corresponding small molecule, BAY2666605, has entered Phase I clinical trials. However, like most velcrin molecules, BAY2666605 exhibits strong PDE3A / B inhibitory activity, posing potential risks in clinical application.

[0004] Therefore, there is a continuous need in the art to develop a new PDE3A-SLFN12 complex inducer.

[0005] Summary of the Invention

[0006] The present application aims to provide a pyridone compound containing a pyridone structure that can be used as an inducer of the PDE3A-SLFN12 complex. The compounds of this invention are highly effective in inducing the formation of the PDE3A-SLFN12 complex, yet exhibit minimal inhibitory activity against PDE3A itself, thereby avoiding off-target toxicity and effectively expanding therapeutic potential.

[0007] The purpose of this application is also to provide a method for preparing the pyridone compound as described above.

[0008] The present application also aims to provide a use of the pyridone compound as described above as a PDE3A-SLFN12 complex inducer.

[0009] The present application also aims to provide a pharmaceutical composition comprising the pyridone compound as described above and a pharmaceutically acceptable carrier, adjuvant or excipient.

[0010] The present application also aims to provide a kit comprising the pyridone compound or pharmaceutical composition as described above.

[0011] The present application also aims to provide a use of the pyridone compound as described above in the preparation of a drug for treating tumors or cancers by forming a stable PDE3A-SLFN12 complex.

[0012] The present application also aims to provide a method for preventing or treating tumors or cancers by forming a stable PDE3A-SLFN12 complex.

[0013] In a first aspect, the present application provides a pyridone compound, a stereoisomer, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, wherein the pyridone compound has a structure represented by the following general formula (I):

[0014] Among them, R 30 Selected from -CN, hydrogen, deuterium, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, -C 0-8 Alkyl C 3-12 Cycloalkyl, -C 0-8 Alkyl 3-12 membered heterocyclic group, -C 0-8 Alkyl C 6-10 Aryl, -C 0-8 Alkyl 5-10 membered heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR11 、-C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0-8 Alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 The above groups are independently optionally further substituted by one or more substituents selected from the following: deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 , =C(R 11 )2. -C 0-8 Alkyl-SC(O)R 12 、-C 0-8Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0- 8-alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 ;

[0015] R1 is selected from hydrogen, deuterium, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, -C 0-8 Alkyl C 3-12 Cycloalkyl, -C 0-8 Alkyl 3-12 membered heterocyclic group, -C 0-8 Alkyl C 6-10 Aryl, -C 0-8 Alkyl 5-10 membered heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 、-C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C0-8 Alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 The above groups are independently optionally further substituted by one or more substituents selected from the following: deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 , =C(R 11 )2. -C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0- 8-alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 ;

[0016] R2 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, -C 0-8 Alkyl C 3-12 Cycloalkyl, -C 0-8 Alkyl 3-12 membered heterocyclic group, -C 0-8 Alkyl C 6-10 Aryl, -C 0-8 Alkyl 5-10 membered heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 、-C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0-8 Alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 The above groups are independently optionally further substituted by one or more substituents selected from the following: deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 , =C(R 11 )2. -C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0-8 Alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 ;

[0017] R3 is selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, -C 0-8 Alkyl C 3-12 Cycloalkyl, -C 0-8 Alkyl 3-12 membered heterocyclic group, -C 0-8 Alkyl C 6-10 Aryl, -C 0-8 Alkyl 5-10 membered heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 、-C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0-8 Alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R13 )-C(O)R 12 The above groups are independently optionally further substituted by one or more substituents selected from the following: deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2- 10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 , =C(R 11 )2. -C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0-8 Alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 substituted by a substituent;

[0018] X is selected from a bond, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, -C 0-8 Alkyl C 3-12 Cycloalkyl, -C 0-8 Alkyl 3-12 membered heterocyclic ring, -C 0-8 Alkyl C 6-10 Aromatic ring, -C 0-8 Alkyl 5-10 membered heteroaromatic ring, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 、-C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0-8 Alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 ;

[0019] n is 0, 1, 2, 3 or 4;

[0020] Each R4 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, -C 0-8 Alkyl C 3-12 Cycloalkyl, -C 0-8 Alkyl 3-12 membered heterocyclic group, -C 0-8 Alkyl C 6-10 Aryl, -C 0-8 Alkyl 5-10 membered heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 , =C(R 11 )2、=O、-C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0-8 Alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、=NR 13 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 The above groups are independently optionally further substituted by one or more substituents selected from the following: deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 , =C(R 11 )2. -C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0- 8-alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 ;

[0021] Or two R4 connected to the same atom together with the connected atom form a C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10Aryl or 5-10 membered heteroaryl, the ring structure formed above is independently optionally further substituted by one or more R6;

[0022] Alternatively, two R4 connected to two adjacent atoms and the atoms to which they are connected together form a C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the ring structure formed above is independently optionally further substituted by one or more R6;

[0023] Alternatively, two R4 connected to two non-adjacent atoms together with the atoms to which they are connected form a C 4-12 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the ring structure formed above is independently optionally further substituted by one or more R6;

[0024] R5 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, -C 0-8 Alkyl C 3-12 Cycloalkyl, -C 0-8 Alkyl 3-12 membered heterocyclic group, -C 0-8 Alkyl C 6-10 Aryl, -C 0-8 Alkyl 5-10 membered heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 , =C(R 11 )2、=O、-C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0-8 Alkyl-P(O)(R 12)2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、=NR 13 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 The above groups are independently optionally further substituted by one or more substituents selected from the following: deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 , =C(R 11 )2. -C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0-8 Alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 ;

[0025] Alternatively, R1, R5 and the atoms to which they are connected together form a C 4-12 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the ring structure formed above is independently optionally further substituted by one or more R6;

[0026] Alternatively, R2, R5 and the atoms to which they are connected together form a C 4-12 Cycloalkyl, 4-12 membered heterocycle, the ring structure formed above is independently optionally further substituted by one or more R6;

[0027] Or, R2, R 30 Together with the atoms they are connected to form a C 4-12 Cycloalkyl, 4-12 membered heterocycle, the ring structure formed above is independently optionally further substituted by one or more R6;

[0028] Each R6 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8Alkyl-C(O)SR 11 , =C(R 11 )2、=O、-C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0-8 Alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、=NR 13 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 , or two R6 and the atoms to which they are connected together form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; each of the above groups is independently optionally further substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C0-8 Alkyl-C(O)SR 11 , =C(R 11 )2. -C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0- 8-alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 substituted by a substituent;

[0029] Each R7 is independently selected from hydrogen, deuterium, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, -C 0-8 Alkyl C 3- 12 Cycloalkyl, -C 0-8 Alkyl 3-12 membered heterocyclic group, -C 0-8 Alkyl C 6-10 Aryl, -C 0-8 Alkyl 5-10 membered heteroaryl, -C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)R 12 or -C 0-8 Alkyl-C(O)NR 13 R 14 The above groups are optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6- 10 Aryl, 5-10 membered heteroaryl, -C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 or -C 0-8 Alkyl-N(R 13 )-C(O)R 12 substituted by a substituent;

[0030] Each R8 and each R9 are independently selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, -C 0-8 Alkyl C 3-12 Cycloalkyl, -C 0-8 Alkyl 3-12 membered heterocyclic group, -C 0-8 Alkyl C 6-10 Aryl, -C 0-8 alkyl 5-10 membered heteroaryl, or, R8 and R9 together with the sulfur atom to which they are directly connected form a 3-10 membered heterocyclic group, the above groups are optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10Aryl, 5-10 membered heteroaryl, -C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 or -C 0-8 Alkyl-N(R 13 )-C(O)R 12 substituted by a substituent;

[0031] Each R 10 independently selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, -C 0-8 Alkyl C 3-12 Cycloalkyl, -C 0-8 Alkyl 3-12 membered heterocyclic group, -C 0-8 Alkyl C 6-10 Aryl, -C 0-8 Alkyl 5-10 membered heteroaryl, and -NR 13 R 14 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, C 1-10 Alkyl, C 1-10 Alkoxy, C 3- 12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR 13 R 14 substituted by a substituent;

[0032] Each R11 independently selected from hydrogen, deuterium, C 1-10 Alkyl, C 2-10 Alkenyl, -C 0-8 Alkyl C 3-12 Cycloalkyl, -C 0-8 Alkyl 3-12 membered heterocyclic group, -C 0-8 Alkyl C 6-10 Aryl, -C 0-8 Alkyl 5-10 membered heteroaryl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3- 12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR 13 R 14 substituted by a substituent;

[0033] Each R 12 independently selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, -C 0-8 Alkyl C 3-12 Cycloalkyl, -C 0-8 Alkyl C 3-12 Cycloalkoxy, -C 0-8 Alkyl 3-12 membered heterocyclic group, -C 0-8 Alkyl 3-12 membered heterocyclic oxy group, -C 0-8 Alkyl C 6-10 Aryl, -C 0-8 Alkyl C 6-10 Aryloxy, -C 0-8 Alkyl 5-10 membered heteroaryl, -C 0-8 Alkyl 5-10 membered heteroaryloxy and -NR 13 R 14 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR13 R 14 substituted by a substituent;

[0034] Each R 13 and R 14 are independently selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, -C 0-8 Alkyl C 3-12 Cycloalkyl, -C 0-8 Alkyl 3-12 membered heterocyclic group, -C 0-8 Alkyl C 6-10 Aryl, -C 0-8 Alkyl 5-10 membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl and C 1-10 Alkanoyl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono C 1-10 Alkylamino, di-C 1-10 Alkylamino and C 1-10 substituted with an alkanoyl substituent;

[0035] Or, R 13 and R 14 Together with the nitrogen atom directly connected thereto, a 4-10 membered heterocyclic group or a 5-10 membered heteroaryl group is formed, wherein the 4-10 membered heterocyclic group or the 5-10 membered heteroaryl group is optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, ═O, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono C 1-10 Alkylamino, di-C 1-10 Alkylamino and C 1- 10 substituted with an alkanoyl substituent;

[0036] Each r is independently 0, 1 or 2.

[0037] Compared with the prior art, the beneficial effect of the present application is that the pyridone compound described herein improves the affinity of small molecules to the SLFN12 protein while maintaining weak binding to PDE3A itself, thereby promoting the formation of the PDE3A-SLFN12 protein complex. The preferred embodiment of the pyridone compound has an in vitro anti-tumor proliferation IC 50 The value reaches a level stronger than 10 nM, and the inhibitory activity against PDE3A reaches the micromolar level, with a broad therapeutic window. DETAILED DESCRIPTION

[0038] Definition of terms

[0039] It is to be understood that the terminology used herein is for the purpose of describing particular embodiments and is not intended to be limiting.

[0040] As used herein, the term "acyl" represents hydrogen or alkyl as defined herein, attached to the parent molecular group through a carbonyl as defined herein, and is exemplified by formyl (i.e., formaldehyde group), acetyl, trifluoroacetyl, propionyl, and butyryl. Exemplary unsubstituted acyl groups include from 1 to 6, from 1 to 11, or from 1 to 21 carbon atoms.

[0041] As used herein, the term "alkyl" refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms (such as 1 to 16 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms). Alkylene is a divalent alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n- Heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or various branched chain isomers thereof. 1‐10 "Alkyl" refers to a straight chain alkyl group or a branched chain alkyl group containing 1 to 10 carbon atoms. 1‐4 "Alkyl" refers to straight chain alkyl and branched chain alkyl groups containing 1 to 4 carbon atoms, "C 0‐8 "Alkyl" refers to straight chain alkyl and branched chain alkyl groups including 0 to 8 carbon atoms, "C 0‐4 The term "alkyl" refers to straight-chain and branched-chain alkyl groups having 0 to 4 carbon atoms.

[0042] Alkyl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1‐10 Alkyl, C 2‐10 Alkenyl, C 2‐10 Alkynyl, halogen-substituted C 1‐10 Alkyl, deuterium substituted C 1‐10 Alkyl, C 3‐12 Cycloalkyl, 3-12 membered heterocyclic group, C 5‐10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 , =C(R 11 )2. -C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0-8 Alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 Each r is independently 0, 1 or 2. R7, R8, R9, R 10 、R 11 、R 12 、R 13 and R 14 As defined herein.

[0043] The term "alkenyl" as used herein, alone or in combination with other groups, refers to a straight or branched chain hydrocarbon residue having a carbon-carbon double bond and having 2-20 carbon atoms (e.g., 2-16 carbon atoms, 2-10 carbon atoms, 2-6, or 2 carbon atoms).

[0044] The term "alkynyl" as used herein, alone or in combination with other groups, refers to a straight or branched chain hydrocarbon residue having a carbon-carbon triple bond and having 2-20 carbon atoms (e.g., 2-16 carbon atoms, 2-10 carbon atoms, 2-6, or 2 carbon atoms).

[0045] As used herein, the term "amino" represents -N(RN1)2, wherein each RN1 is independently H, OH, NO2, N(RN2)2, SO2ORN2, SO2RN2, SORN2, N-protecting group, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or other groups described herein), wherein each of these described RN1 groups may be optionally substituted; or two RN1s are combined to form an alkylene or heteroalkylene group, and wherein each RN2 is independently H, alkyl, or aryl. The amino groups of the present invention may be unsubstituted amino groups (i.e., -NH2) or substituted amino groups (i.e., -N(RN1)2).

[0046] As used herein, the term "aryl" refers to an aromatic monocyclic or polycyclic group of 6 to 12 carbon atoms having at least one aromatic ring. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, indanyl, and 1H-indenyl.

[0047] As used herein, the term "aromatic substituent" refers to an unsaturated substituent having aromatic properties, which may be a substituted or unsubstituted group comprising 5 to 12 carbon atoms. For example, the aromatic substituent may be a substituted or unsubstituted five-membered ring or six-membered ring structure, wherein the atoms forming the ring may include one or more of carbon atoms, nitrogen atoms, oxygen atoms, and sulfur atoms.

[0048] As used herein, the term "arylalkyl" represents an alkyl group substituted with an aryl group. Exemplary unsubstituted arylalkyl groups are from 7 to 30 carbon atoms (e.g., from 7 to 16 or from 7 to 20 carbon atoms, such as C1-6 alkyl, C6- 10 Aryl, C1- 10 Alkyl C6- 10 Aryl, or C1- 20 Alkyl C6- 10 In some embodiments, the alkyl and aryl groups can each be further substituted with 1, 2, 3, or 4 substituents as defined herein for the respective groups.

[0049] The term "cyano" as used herein represents a -CN group.

[0050] As used herein, the term "carbocyclyl" refers to a non-aromatic C3- 12 Monocyclic, bicyclic, or tricyclic structures, wherein the rings are formed by carbon atoms. Carbocyclyl structures include cycloalkyl and unsaturated carbocyclyl.

[0051] As used herein, the term "cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent. Partially unsaturated cyclic hydrocarbons refer to cyclic hydrocarbons that may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a completely conjugated π electron system. Cycloalkyl groups can be divided into monocyclic cycloalkyl groups and polycyclic cycloalkyl groups, preferably cycloalkyl groups comprising 3 to 12, 3 to 8 or 3 to 6 carbon atoms, for example, "C 3‐12 "Cycloalkyl" refers to a cycloalkyl group comprising 3 to 12 carbon atoms. Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like. Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups. "Spiroalkyl" refers to a polycyclic group in which a carbon atom (called a spiro atom) is shared between the monocyclic rings. These may contain one or more double bonds (preferably 1, 2, or 3), but no ring has a completely conjugated π electron system. Spiroalkyl groups are divided into monospiroalkyl, bispiroalkyl, or polyspiroalkyl groups according to the number of spiro atoms shared between the rings. Spiroalkyl groups include, but are not limited to:

[0052] "Fused cycloalkyl" refers to an all-carbon polycyclic group in which each ring shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds (preferably 1, 2 or 3), but no ring has a completely conjugated π electron system. Depending on the number of constituent rings, fused cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic or polycyclic. Fused cycloalkyl groups include, but are not limited to:

[0053] "Bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected. These may contain one or more double bonds (preferably 1, 2, or 3), but no ring has a completely conjugated π electron system. Depending on the number of constituent rings, bridged cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic. Bridged cycloalkyl groups include, but are not limited to:

[0054] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl, including but not limited to indanyl, tetrahydronaphthyl, benzocycloheptanyl and the like.

[0055] Cycloalkyl may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1‐10 Alkyl, C 2‐10 Alkenyl, C 2‐10 Alkynyl, halogen-substituted C 1‐10 Alkyl, deuterium substituted C 1‐10 Alkyl, C3‐12 Cycloalkyl, 3-12 membered heterocyclic group, C 5‐10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 , =C(R 11 )2. -C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0- 8-Alkyl-OC(O)R 12 、-C 0-8 Alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 Each r is independently 0, 1 or 2. R7, R8, R9, R 10 、R 11 、R 12 、R 13 and R 14 As defined herein.

[0056] The term "halogen" as used herein refers to a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) group.

[0057] As used herein, the term "heteroalkyl" refers to an alkyl group as defined herein, in which one or more of the constituent carbon atoms has been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkyl group may be further substituted with one, two, three, or four substituents as described herein for alkyl. "Alkoxy" represents all branched and straight chain isomers of a specified number of carbon atoms, with the terminal hydrogen atoms replaced by oxygen atoms. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, and isopropoxy.

[0058] As used herein, the term "heteroalkenyl" refers to an alkenyl group as defined herein, wherein one or more of the constituent carbon atoms has been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkenyl group can be further substituted with 1, 2, 3, or 4 substituents as described herein for alkenyl.

[0059] As used herein, the term "heteroalkynyl" refers to an alkynyl group as defined herein in which one or more of the constituent carbon atoms has been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkynyl group can be further substituted with 1, 2, 3, or 4 substituents as described herein for alkynyl.

[0060] As used herein, the term "heteroaryl" refers to an aromatic monocyclic or polycyclic radical of 5 to 12 atoms having at least one aromatic ring containing 1, 2 or 3 ring heteroatoms selected from N, O and S, with the remaining ring atoms being C. One or two ring carbon atoms of a heteroaryl group may be replaced with a carbonyl group. Examples of heteroaryl groups are pyridyl, pyrazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, oxazolyl, and thiazolyl.

[0061] As used herein, the term "heteroarylalkyl" represents an alkyl group substituted with a heteroaryl group. Exemplary unsubstituted heteroarylalkyl groups are from 7 to 30 carbon atoms (e.g., from 7 to 16 or from 7 to 20 carbon atoms, e.g., C 1-6 Alkyl C 2-9 Heteroaryl, C 1-10 alkyl C2-9 Heteroaryl, or C 1-20 Alkyl C 2-9 In some embodiments, the alkyl and heteroaryl groups can each be further substituted with 1, 2, 3, or 4 substituents as defined herein for the respective groups.

[0062] As used herein, the term "heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent. A partially unsaturated cyclic hydrocarbon refers to a cyclic hydrocarbon that may contain one or more (preferably 1, 2, or 3) double bonds, but no ring has a completely conjugated π electron system. One or more (preferably 1, 2, 3, or 4) ring atoms in the heterocyclyl are selected from nitrogen, oxygen, or S(O)r (wherein r is an integer of 0, 1, or 2), but excluding the ring portion of -O-O-, -O-S-, or -S-S-, and the remaining ring atoms are carbon. Preferably, the heterocyclyl comprises 3 to 12, 3 to 8, or 3 to 6 ring atoms. For example, a "3-12 membered heterocyclyl" refers to a cyclic group comprising 3 to 12 ring atoms. Monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyranyl, homopiperazinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxanyl, and the like.

[0063] Polycyclic heterocyclic groups include spiro rings, fused rings and bridged heterocyclic groups. "Spiro heterocyclic group" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between the monocyclic rings, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O)r (wherein r is an integer 0, 1, 2) heteroatoms, and the remaining ring atoms are carbon. These may contain one or more double bonds, but no ring has a completely conjugated π electron system. Spiro heterocyclic groups are divided into single spiro heterocyclic groups, double spiro heterocyclic groups or multi-spiro heterocyclic groups according to the number of spiro atoms shared between the rings. Spiro heterocyclic groups include but are not limited to:

[0064] "Fused heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more (preferably 1, 2, 3 or 4) rings may contain one or more double bonds (preferably 1, 2 or 3), but no ring has a completely conjugated π electron system, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O)r (wherein r is an integer of 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic alkyl groups, and fused heterocyclic groups include but are not limited to:

[0065] "Bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected. These may contain one or more double bonds (preferably 1, 2 or 3), but no ring has a completely conjugated π electron system, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O)r (where r is an integer of 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Depending on the number of constituent rings, bridged heterocyclic groups can be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups. Bridged heterocyclic groups include but are not limited to:

[0066] The heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, including but not limited to:

[0067] The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1‐10 Alkyl, C 2‐10 Alkenyl, C 2‐10 Alkynyl, halogen-substituted C 1‐10 Alkyl, deuterium substituted C 1‐10 Alkyl, C 3‐12 Cycloalkyl, 3-12 membered heterocyclic group, C 5‐10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 , =C(R 11 )2. -C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0- 8-Alkyl-OC(O)R 12 、-C 0-8 Alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 Each r is independently 0, 1 or 2. R7, R8, R9, R 10 、R 11 、R 12 、R 13 and R 14 As defined herein.

[0068] "Aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group, a polycyclic (i.e., rings with adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably an all-carbon aromatic group containing 6-10 or 6-8 carbon atoms, for example, "C 5‐10 "Aryl" refers to an all-carbon aromatic group containing 5-10 carbon atoms, and "5-10 membered aromatic group" refers to an all-carbon aromatic group containing 5-10 carbon atoms, including but not limited to phenyl and naphthyl. The aromatic ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aromatic ring, including but not limited to:

[0069] Aryl may be substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1‐10 Alkyl, C 2‐10 Alkenyl, C 2‐10 Alkynyl, halogen-substituted C 1‐10 Alkyl, deuterium substituted C 1‐10 Alkyl, C 3‐12 Cycloalkyl, 3-12 membered heterocyclic group, C 5‐10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 , =C(R 11 )2. -C 0-8 Alkyl-SC(O)R12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0-8 Alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 Each r is independently 0, 1 or 2. R7, R8, R9, R 10 、R 11 、R 12 、R 13 and R 14 As defined herein.

[0070] "Heteroaryl" refers to a heteroaromatic system containing one or more (preferably 1, 2, 3 or 4) heteroatoms, including nitrogen, oxygen and S(O)r (wherein r is an integer of 0, 1 or 2), preferably a heteroaromatic system containing 5-10, 5-8 or 5-6 ring atoms, for example, a 5-8 membered heteroaryl refers to a heteroaromatic system containing 5-8 ring atoms, and a 5-10 membered heteroaryl refers to a heteroaromatic system containing 5-10 ring atoms, including but not limited to furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, including but not limited to:

[0071] Heteroaryl may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1‐10 Alkyl, C 2‐10 Alkenyl, C 2‐10 Alkynyl, halogen-substituted C 1‐10 Alkyl, deuterium substituted C 1‐10 Alkyl, C3‐12 Cycloalkyl, 3-12 membered heterocyclic group, C 5‐10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 , =C(R 11 )2. -C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0-8 Alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 Each r is independently 0, 1 or 2. R7, R8, R9, R 10 、R 11 、R 12 、R 13 and R 14 As defined herein.

[0072] "Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably a straight-chain or branched alkenyl group containing 2-10 or 2-4 carbon atoms. For example, C2-10 alkenyl refers to a straight-chain or branched alkenyl group containing 2-10 carbon atoms. Examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like.

[0073] Alkenyl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1‐10 Alkyl, C 2‐10 Alkenyl, C 2‐10 Alkynyl, halogen-substituted C 1‐10 Alkyl, deuterium substituted C 1‐10 Alkyl, C 3‐12 Cycloalkyl, 3-12 membered heterocyclic group, C 5‐10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 , =C(R 11 )2. -C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0-8 Alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 Each r is independently 0, 1 or 2. R7, R8, R9, R 10 、R 11 、R 12 、R 13 and R 14 As defined herein.

[0074] "Alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably a straight-chain or branched alkynyl group containing 2-10 or 2-4 carbon atoms. For example, a C2-10 alkynyl group refers to a straight-chain or branched alkynyl group containing 2-10 carbon atoms. Examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl.

[0075] Alkynyl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1‐10 Alkyl, C 2‐10 Alkenyl, C 2‐10 Alkynyl, halogen-substituted C 1‐10 Alkyl, deuterium substituted C 1‐10 Alkyl, C 3‐12 Cycloalkyl, 3-12 membered heterocyclic group, C 5‐10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 , =C(R 11 )2. -C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C0-8 Alkyl-OC(O)R 12 、-C 0-8 Alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 Each r is independently 0, 1 or 2. R7, R8, R9, R 10 、R 11 、R 12 、R 13 and R 14 As defined herein.

[0076] "Alkoxy" refers to -O-(alkyl), where alkyl is as defined above, for example, "C1-10 alkoxy" refers to an alkyloxy group containing 1-10 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, butoxy, etc.

[0077] Alkoxy may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1‐10 Alkyl, C 2‐10 Alkenyl, C 2‐10 Alkynyl, halogen-substituted C 1‐10 Alkyl, deuterium substituted C 1‐10 Alkyl, C 3‐12 Cycloalkyl, 3-12 membered heterocyclic group, C 5‐10 Aryl, 5-10 membered heteroaryl, -C 0‐8 -SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 , =C(R 11 )2. -C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0-8 Alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )- C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 Each r is independently 0, 1 or 2. R7, R8, R9, R 10 、R 11 、R 12 、R 13 and R 14 As defined herein.

[0078] "Cycloalkoxy" or "cycloalkyloxy" refers to -O-(unsubstituted cycloalkyl), wherein cycloalkyl is defined as above, for example, "C3-12 cycloalkoxy" refers to a cycloalkyloxy group containing 3-12 carbon atoms, including but not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc.

[0079] Cycloalkoxy may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1‐10 Alkyl, C 2‐10 Alkenyl, C 2‐10 Alkynyl, halogen-substituted C 1‐10 Alkyl, deuterium substituted C 1‐10 Alkyl, C 3‐12 Cycloalkyl, 3-12 membered heterocyclic group, C5‐10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 , =C(R 11 )2. -C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0-8 Alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 Each r is independently 0, 1 or 2. R7, R8, R9, R 10 、R 11 、R 12 、R 13 and R 14 As defined herein.

[0080] "3-12 membered heterocyclyl" refers to -O-(unsubstituted 3-12 membered heterocyclyl), wherein the definition of 3-12 membered heterocyclyl is as described above, and 3-12 membered heterocyclyl may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1‐10 Alkyl, C 2‐10 Alkenyl, C 2‐10 Alkynyl, halogen-substituted C 1‐10 Alkyl, deuterium substituted C 1‐10 Alkyl, C 3‐12 Cycloalkyl, 3-12 membered heterocyclic group, C 5‐10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 , =C(R 11 )2. -C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0-8 Alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R12 Each r is independently 0, 1 or 2. R7, R8, R9, R 10 、R 11 、R 12 、R 13 and R 14 As defined herein.

[0081] "C5-10 aryloxy" refers to -O-(unsubstituted C5-10 aryl), wherein the definition of C5-10 aryl is as described above, and C5-10 aryloxy may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1‐10 Alkyl, C 2‐10 Alkenyl, C 2‐10 Alkynyl, halogen-substituted C 1‐10 Alkyl, deuterium substituted C 1‐10 Alkyl, C 3‐12 Cycloalkyl, 3-12 membered heterocyclic group, C 5‐10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 , =C(R 11 )2. -C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0-8 Alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 Each r is independently 0, 1 or 2. R7, R8, R9, R 10 、R 11 、R 12 、R 13 and R 14 As defined herein.

[0082] "5-10 membered heteroaryloxy" refers to -O-(unsubstituted 5-10 membered heteroaryl), wherein the definition of 5-10 membered heteroaryl is as described above, and 5-10 membered heteroaryloxy may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1‐10 Alkyl, C 2‐10 Alkenyl, C 2‐10 Alkynyl, halogen-substituted C 1‐10 Alkyl, deuterium substituted C 1‐10 Alkyl, C 3‐12 Cycloalkyl, 3-12 membered heterocyclic group, C 5‐10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 , =C(R 11 )2. -C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C0-8 Alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 Each r is independently 0, 1 or 2. R7, R8, R9, R 10 、R 11 、R 12 、R 13 and R 14 As defined herein.

[0083] “C 1‐10 "Alkanoyl" refers to C 1‐10 The monovalent atomic group remaining after removing the hydroxyl group from an alkyl acid is usually also expressed as "C0-9-C(O)-". For example, "C1-C(O)-" refers to acetyl; "C2-C(O)-" refers to propionyl; and "C3-C(O)-" refers to butyryl or isobutyryl.

[0084] “C 1‐4 ” refers to “C1-4 alkyl”, “C 0‐4 " means "C 0‐4 Alkyl", "C 1‐8 ” refers to C1-8 alkyl, “C 0‐8 ” refers to a C0-8 alkyl group, as defined above.

[0085] “-C 0‐8 ‐S(O)rR 10 ” refers to ‐S(O)rR 10 The sulfur atom in the 0‐8 On the alkyl group, C 0‐8 The alkyl group is as defined above.

[0086] “-C 0‐8 ‐O‐R 11 ” refers to 11 The oxygen atom in the 0‐8 On the alkyl group, C 0‐8 The alkyl group is as defined above.

[0087] “-C 0‐8 ‐C(O)OR 11 ” means -C(O)OR 11 The carbonyl group is connected to C 0‐8 On the alkyl group, the definition of C0-8 alkyl is as described above.

[0088] “-C 0‐8 ‐C(O)R 12 ” refers to ‐C(O)R 12 The carbonyl group is connected to C 0‐8 On the alkyl group, C 0‐8 The alkyl group is as defined above.

[0089] “-C 0‐8 ‐O‐C(O)R 12 ” refers to ‐O‐C(O)R 12 The oxygen atom in the group is connected to a C0-8 alkyl group, and the definition of C0-8 alkyl group is as described above.

[0090] “-C 0‐8 ‐NR 13 R 14” Refers to NR 13 R 14 The nitrogen atom in the 0‐8 On the alkyl group, C 0‐8 The alkyl group is as defined above.

[0091] “-C 0‐8 -C(=NR 13 )R 12 ” refers to -C(=NR 13 )R 12 The carbonyl group is connected to C 0‐8 On the alkyl group, C 0‐8 The alkyl group is as defined above.

[0092] “-C 0‐8 ‐N(R 13 )-C(=NR 14 )R 12 ” refers to ‐N(R 13 )-C(=NR 14 )R 12 The carbonyl group is connected to C 0‐8 On the alkyl group, C 0‐8 The alkyl group is as defined above.

[0093] “-C 0‐8 ‐C(O)NR 13 R 14 ” refers to ‐C(O)NR 13 R 14 The carbonyl group is connected to C 0‐8On the alkyl group, C 0‐8 The alkyl group is as defined above.

[0094] “-C 0‐8 ‐N(R 13 )-C(O)R 12 ” refers to ‐N(R 13 )-C(O)R 12 The nitrogen atom in the 0‐8 On the alkyl group, C 0‐8 The alkyl group is as defined above.

[0095] "Halogen-substituted C1-10 alkoxy" refers to an alkoxy group with 1-10 carbon atoms, wherein the hydrogen atoms on the alkyl group are optionally replaced by fluorine, chlorine, bromine, or iodine atoms, including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, and tribromomethoxy.

[0096] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur, i.e., includes both substituted and unsubstituted instances. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes both instances where the heterocyclic group is substituted with an alkyl group and where the heterocyclic group is not substituted with an alkyl group.

[0097] "Substituted" means that one or more hydrogen atoms in a group are independently replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated bonds (such as olefins).

[0098] "Stereoisomers," whose English name is stereoisomer, refer to isomers resulting from the different spatial arrangements of atoms in a molecule. They can be divided into two types: cis-trans isomers and enantiomers, or into two major categories: enantiomers and diastereomers. Stereoisomers caused by rotation about single bonds are called conformational isomers, sometimes also called rotational isomers. Stereoisomers caused by bond length, bond angle, the presence of double bonds within the molecule, the presence of rings, etc. are called configurational isomers, which are further divided into two categories. Among them, isomers caused by the inability to rotate freely between double bonds or single bonds of ring carbon atoms are called geometric isomers, also called cis-trans isomers, and are divided into two configurations: Z and E. For example, cis-2-butene and trans-2-butene are a pair of geometric isomers. If the pyridone compounds of the present invention contain double bonds, unless otherwise specified, they can be understood to include E and / or Z forms. Stereoisomers with different optical rotation properties due to the lack of anti-axial symmetry in the molecule are called optical isomers and are divided into R and S configurations. In the present invention, "stereoisomers" are understood to include one or more of the aforementioned enantiomers, configurational isomers, and conformational isomers unless otherwise specified.

[0099] As used herein, the term "solvate" refers to a substance formed by combining a pyridone compound of the present invention with a pharmaceutically acceptable solvent. Pharmaceutically acceptable solvents include water, acetic acid, and the like. Solvates include stoichiometric solvates and non-stoichiometric solvates. Certain pyridone compounds of the present invention may exist in unsolvated or solvated forms. Generally speaking, solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention.

[0100] The term "heterocyclylalkyl" as used herein represents an alkyl group substituted with a heterocyclyl group. Exemplary unsubstituted heterocyclylalkyl groups are from 7 to 30 carbon atoms (e.g., from 7 to 16 or from 7 to 20 carbon atoms, such as C 1-6 Alkyl C 2-9 Heterocyclic group, C 1-10 Alkyl C 2-9 Heterocyclic group, or C 1-20 Alkyl C 2-9 In some embodiments, the alkyl and heterocyclyl groups can each be further substituted with 1, 2, 3, or 4 substituents as defined herein for the respective groups.

[0101] The term "hydroxy" as used herein refers to an -OH group. The term "thiol" as used herein refers to a -SH group.

[0102] Alkyl, alkenyl, alkynyl, assorted alkyl, assorted alkenyl, assorted alkynyl, carbocyclic radical (such as cycloalkyl), aryl, heteroaryl, and heterocyclic radical group can be substituted or unsubstituted.When substituted, usually there will be 1-4 substituents, unless otherwise specified.Substituent includes, for example: aryl (such as substituted and unsubstituted phenyl), carbocyclic radical (such as substituted and unsubstituted cycloalkyl), halogen (such as fluoro), hydroxyl, assorted alkyl (such as substituted and unsubstituted methoxy, ethoxy, or thioalkoxy), heteroaryl, heterocyclic radical, amino (such as NH2 or mono- or dialkylamino), azido, cyano, nitro, or sulfydryl.Aryl, carbocyclic radical (such as cycloalkyl), heteroaryl, and heterocyclic radical also can be substituted with alkyl (unsubstituted and substituted for example arylalkyl (such as substituted and unsubstituted benzyl)).

[0103] In practicing the methods of the present invention, an "effective amount" of any one of the pyridone compounds of the present invention or any combination of pyridone compounds of the present invention or pharmaceutically acceptable salts thereof is administered by any common and acceptable method known in the art (alone or in combination).

[0104] As used herein, the term "pharmaceutical composition" refers to a composition containing a pyridone compound described herein formulated with a pharmaceutically acceptable excipient and approved for manufacture or sale by a governmental regulatory agency as part of a therapeutic regimen for treating a mammalian disease. The pharmaceutical composition can be formulated, for example, as a unit dosage form for oral administration (e.g., tablets, capsules, caplets, softgels, or syrups); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution in a solvent system suitable for intravenous use without particulate emboli); or as any other pharmaceutically acceptable formulation. As used herein, a "pharmaceutically acceptable excipient" refers to any ingredient other than a pyridone compound described herein (e.g., a vehicle capable of suspending or dissolving the active compound) that is substantially non-toxic and non-inflammatory in a patient. Excipients may include, for example, anti-adherents, antioxidants, binders, coatings, tableting aids, disintegrants, dyes (colorants), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavorings, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, and water for hydration. Exemplary excipients include, but are not limited to, butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, cross-linked carboxymethylcellulose, cross-linked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0105] As used herein, the term "pharmaceutically acceptable salt" means any pharmaceutically acceptable salt of a pyridone compound of formula (I). For example, any pharmaceutically acceptable salt of the pyridone compound described herein is included within the scope of reasonable medical judgment, suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reaction and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66: 1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. Salts can be prepared in situ during the final isolation and purification of the pyridone compound described herein or separately by reacting the free base group with a suitable organic acid.

[0106] The pyridone compounds of the present invention may have ionizable groups so that they can be prepared as pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids, or salts may be prepared (in the case of the acid form of the pyridone compounds of the present invention) from inorganic or organic bases. Frequently, the pyridone compounds are prepared as or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases and methods for preparing suitable salts are well known in the art. Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases (including inorganic and organic acids and bases).

[0107] Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.

[0108] "Prodrug" or "prodrug" in the present invention refers to a compound that can be converted or solvent-decomposed into a specific compound or a pharmaceutically acceptable salt of such a compound under physiological conditions before exhibiting its physiological effect. Although not necessarily, the prodrug is usually pharmacologically inactive before being converted into a specific compound (also referred to as a parent drug or parent drug). Typically, the purpose of the prodrug is to improve chemical stability, improve patient acceptance and compliance, improve bioavailability, prolong the duration of action, improve organ selectivity, increase water solubility and / or reduce side effects. The preparation technology of the prodrug can use methods known in the prior art, such as Burger's Medicinal Chemistry and Drug Chemistry, 1, 172-178, 949-982 (1995) and the like.

[0109] As used herein, the term "subject" refers to any organism to which a composition according to the present invention can be administered, e.g., for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). A subject may be a person or animal seeking or requiring treatment, in need of treatment, currently receiving treatment, to be treated in the future, or under the care of a trained professional for a particular disease or condition.

[0110] As used herein, the terms "treat" or "therapeutic" mean both therapeutic treatment and prophylactic or preventative measures, wherein the goal is to prevent or delay (lessen) an unwanted physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical result. Beneficial or desired clinical results include, but are not limited to, relief of symptoms; a reduction in the extent of the condition, disorder, or disease; stabilization of the condition, disorder, or disease state (i.e., not worsening); a delay or slowing of the onset of the condition, disorder, or disease progression; an improvement or alleviation (whether partial or complete) of the condition, disorder, or disease state, whether detectable or undetectable; an improvement in at least one measurable human physiological parameter, which parameter is not necessarily discernible by the patient; or an amelioration or improvement of the condition, disorder, or disease. Treatment includes causing a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival compared to the expected survival if not receiving treatment.

[0111] Compound

[0112] In one embodiment, the present application provides a pyridone compound, a stereoisomer, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, wherein the pyridone compound has a structure represented by the following general formula (I):

[0113] Wherein, each group is as defined above.

[0114] In one embodiment, n is 2, 3 or 4, wherein two R4 attached to the same atom and the attached atom together form a C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the ring structure formed above is independently optionally further substituted by one or more R6;

[0115] Alternatively, two R4 connected to two adjacent atoms and the atoms to which they are connected together form a C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the ring structure formed above is independently optionally further substituted by one or more R6;

[0116] Alternatively, two R4 connected to two non-adjacent atoms together with the atoms to which they are connected form a C 4-12 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the ring structure formed above is independently optionally further substituted by one or more R6.

[0117] In one embodiment, R 30 Selected from CN, hydrogen, deuterium, halogen, C 1-4Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkyl C 3-10 Cycloalkyl, -C 0-4 Alkyl 3-10 membered heterocyclic group, -C 0-4 Alkyl C 6-10 Aryl, -C 0-4 Alkyl 5-10 membered heteroaryl, -C 0-4 Alkyl-S(O) r R 10 、-C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)R 12 、-C 0-4 Alkyl-OC(O)R 12 、-C 0-4 Alkyl-P(O)(R 12 )2. -C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 , the above groups are independently optionally further substituted by one or more substituents selected from deuterium and halogen;

[0118] R1 is selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkyl C 3-6 Cycloalkyl, -C 0-4 Alkyl 3-6 membered heterocyclic group, -C 0-4 Alkyl C 6-10 Aryl, -C 0-4 Alkyl 5-10 membered heteroaryl, -C 1-4 Alkyl-S(O) r R 10 、-C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)SR 11 、-C 0-4 Alkyl-C(O)R 12 、-C0-4 Alkyl-OC(O)R 12 、-C 1-4 Alkyl-P(O)(R 12 )2. -C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, -C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 , =C(R 11 )2. -C 1-4 Alkyl-SC(O)R 12 、-C 0-4 Alkyl-C(O)R 12 、-C 1-4 Alkyl-OC(O)R 12 、-C 0-4 Alkyl-P(O)(R 12 )2. -C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 substituted by a substituent;

[0119] R2 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkyl C 3-10 Cycloalkyl, -C 0-4 Alkyl 3-10 membered heterocyclic group, -C 0-4 Alkyl C 6-10 Aryl, -C 0-4 Alkyl 5-10 membered heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=N-R7)R8, -C0-4 Alkyl-N=S(O)R8R9, -C 0-4 Alkyl-OS(O)2R 10 、-C 0-4 Alkyl-S(O) r R 10 、-C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)SR 11 、-C 0-4 Alkyl-SC(O)R 12 、-C 0-4 Alkyl-C(O)R 12 、-C 0-4 Alkyl-OC(O)R 12 、-C 0-4 Alkyl-P(O)(R 12 )2. -C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(=NR 13 )R 12 、-C 0-4 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-4 Alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=N-R7)R8, -C 0-4 Alkyl-N=S(O)R8R9, -C 0-4 Alkyl-O- S(O)2R 10 、-C 0-4 Alkyl-S(O) rR 10 、-C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)SR 11 , =C(R 11 )2. -C 0-4 Alkyl-SC(O)R 12 、-C 0-4 Alkyl-C(O)R 12 、-C 0-4 Alkyl-OC(O)R 12 、-C 0- 4-alkyl-P(O)(R 12 )2. -C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(=NR 13 )R 12 、-C 0-4 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-4 Alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 substituted by a substituent;

[0120] R3 is selected from hydrogen, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkyl C 3-6 Cycloalkyl, -C 0-4 Alkyl 3-6 membered heterocyclic group, -C 0-4 Alkyl C 6-10 Aryl, -C 0-4 Alkyl 5-10 membered heteroaryl, -C 0-4 Alkyl-S(O) r R 10 、-C 1-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)SR 11 、-C 1-4 Alkyl-SC(O)R 12 、-C0-4 Alkyl-C(O)R 12 、-C 1-4 Alkyl-OC(O)R 12 、-C 0-4 Alkyl-P(O)(R 12 )2. -C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(=NR 13 )R 12 、-C 0-4 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-4 Alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 , the above groups are independently optionally further substituted by one or more substituents selected from deuterium, halogen, and cyano;

[0121] X is selected from a bond, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkyl C 3-12 Cycloalkyl, -C 0-4 Alkyl 3-12 membered heterocyclic ring, -C 0-4 Alkyl C 6-10 Aromatic ring, -C 0-4 Alkyl 5-10 membered heteroaromatic ring, -C 0-4 Alkyl-S(O)(=N-R7)R8, -C 0-4 Alkyl-OS(O)2R 10 、-C 0-4 Alkyl-S(O) r R 10 、-C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)SR 11 、-C 0-4 Alkyl-SC(O)R 12 、-C 0-4 Alkyl-C(O)R 12 、-C 0-4 Alkyl-OC(O)R 12 、-C 0-4 Alkyl-P(O)(R12 )2. -C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(=NR 13 )R 12 、-C 0-4 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-4 Alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=N-R7)R8, -C 0-4 Alkyl-N=S(O)R8R9, -C 0-4 Alkyl-OS(O)2R 10 、-C 0-4 Alkyl-S(O) r R 10 、-C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)SR 11 , =C(R 11 )2. -C 0-4 Alkyl-SC(O)R 12 、-C 0-4 Alkyl-C(O)R 12 、-C 0-4 Alkyl-OC(O)R 12 、-C 0- 4-alkyl-P(O)(R 12 )2. -C 0-4 Alkyl-NR 13 R 14 、-C 0-4Alkyl-C(=NR 13 )R 12 、-C 0-4 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-4 Alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 substituted by a substituent;

[0122] Each R4 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkyl C 3-8 Cycloalkyl, -C 0-4 Alkyl 3-8 membered heterocyclic group, -C 0-4 Alkyl C 6-10 Aryl, -C 0- 4-alkyl 5-10 membered heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=N-R7)R8, -C 0-4 Alkyl-N=S(O)R8R9, -C 0-4 Alkyl-OS(O)2R 10 、-C 0-4 Alkyl-S(O) r R 10 、-C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)SR 11 , =C(R 11 )2、=O、-C 0-4 Alkyl-SC(O)R 12 、-C 0-4 Alkyl-C(O)R 12 、-C 0-4 Alkyl-OC(O)R 12 、-C 0-4 Alkyl-P(O)(R 12 )2. -C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(=NR 13 )R12 、-C 0-4 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-4 Alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=N-R7)R8, -C 0-4 Alkyl-N=S(O)R8R9, -C 0-4 Alkyl-OS(O)2R 10 、-C 0-4 Alkyl-S(O) r R 10 、-C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)SR 11 , =C(R 11 )2. -C 0-4 Alkyl-SC(O)R 12 、-C 0-4 Alkyl-C(O)R 12 、-C 0-4 Alkyl-OC(O)R 12 、-C 0-4 Alkyl-P(O)(R 12 )2. -C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(=NR 13 )R 12 、-C 0-4 Alkyl-N(R 13 )-C(=NR 14 )R 12、-C 0-4 Alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 substituted by a substituent;

[0123] R5 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkyl C 3-8 Cycloalkyl, -C 0-4 Alkyl 3-8 membered heterocyclic group, -C 0-4 Alkyl C 6-10 Aryl, -C 0-4 Alkyl 5-10 membered heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=N-R7)R8, -C 0-4 Alkyl-N=S(O)R8R9, -C 0-4 Alkyl-OS(O)2R 10 、-C 0-4 Alkyl-S(O) r R 10 、-C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)SR 11 , =C(R 11 )2、=O、-C 0-4 Alkyl-SC(O)R 12 、-C 0-4 Alkyl-C(O)R 12 、-C 0-4 Alkyl-OC(O)R 12 、-C 0-4 Alkyl-P(O)(R 12 )2. -C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(=NR 13 )R 12 、-C 0-4 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-4 Alkyl-C(O)NR13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=N-R7)R8, -C 0-4 Alkyl-N=S(O)R8R9, -C 0-4 Alkyl-OS(O)2R 10 、-C 0-4 Alkyl-S(O) r R 10 、-C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)SR 11 , =C(R 11 )2. -C 0-4 Alkyl-SC(O)R 12 、-C 0-4 Alkyl-C(O)R 12 、-C 0-4 Alkyl-OC(O)R 12 、-C 0-4 Alkyl-P(O)(R 12 )2. -C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(=NR 13 )R 12 、-C 0-4 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-4 Alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12substituted by a substituent;

[0124] Alternatively, R1, R5 and the atoms to which they are connected together form a C 4-8 Cycloalkyl, 4-8 membered heterocyclic group, C 6- 10 Aryl or 5-10 membered heteroaryl, the ring structure formed above is independently optionally further substituted by one or more R6;

[0125] Alternatively, R2, R5 and the atoms to which they are connected together form a C 4-8 Cycloalkyl, 4-8 membered heterocyclic group, C 6- 10 Aryl or 5-10 membered heteroaryl, the ring structure formed above is independently optionally further substituted by one or more R6;

[0126] Or, R2, R 30 Together with the atoms they are connected to form a C 4-12 Cycloalkyl, 4-12 membered heterocycle, the ring structure formed above is independently optionally further substituted by one or more R6;

[0127] Each R6 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=N-R7)R8, -C 0-4 Alkyl-N=S(O)R8R9, -C 0-4 Alkyl-OS(O)2R 10 、-C 0-4 Alkyl-S(O) r R 10 、-C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)SR 11 , =C(R 11 )2、=O、-C 0-4 Alkyl-SC(O)R 12 、-C 0-4 Alkyl-C(O)R 12 、-C 0-4 Alkyl-OC(O)R 12 、-C 0-4Alkyl-P(O)(R 12 )2. -C 0-4 Alkyl-NR 13 R 14 、=NR 13 、-C 0-4 Alkyl-C(=NR 13 )R 12 、-C 0-4 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-4 Alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 , or two R6 and the atoms to which they are connected together form C 3-12 Cycloalkyl or 3-12 membered heterocyclic group; each of the above groups is independently optionally further substituted by one or more substituents selected from the following: deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=N-R7)R8, -C 0-4 Alkyl-N=S(O)R8R9, -C 0-4 Alkyl-OS(O)2R 10 、-C 0-4 Alkyl-S(O) r R 10 、-C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)SR 11 , =C(R 11 )2. -C 0-4 Alkyl-SC(O)R 12 、-C 0-4 Alkyl-C(O)R 12 、-C 0-4 Alkyl-OC(O)R 12 、-C 0-4 Alkyl-P(O)(R12 )2. -C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(=NR 13 )R 12 、-C 0-4 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-4 Alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 ;

[0128] Among them, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , r and n are as defined above.

[0129] In one embodiment, each R7 is independently selected from hydrogen, deuterium, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkyl C 3-8 Cycloalkyl, -C 0-4 Alkyl 3-8 membered heterocyclic group, -C 0-4 Alkyl C 6-8 Aryl, -C 0-4 Alkyl 5-8 membered heteroaryl, -C 0-4 Alkyl-S(O) r R 10 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)R 12 or -C 0-4 Alkyl-C(O)NR 13 R 14 The above groups are optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-8 Alkynyl, halogen-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, -C0-4 Alkyl-S(O) r R 10 、-C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)R 12 、-C 0-4 Alkyl-OC(O)R 12 、-C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(=NR 13 )R 12 、-C 0-4 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-4 Alkyl-C(O)NR 13 R 14 or -C 0-4 Alkyl-N(R 13 )-C(O)R 12 substituted by a substituent;

[0130] Each R8 and each R9 are independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkyl C 3-6 Cycloalkyl, -C 0-4 Alkyl 3-8 membered heterocyclic group, -C 0-4 Alkyl C 6-8 Aryl, -C 0-4 alkyl 5-8 membered heteroaryl, or, R8 and R9 together with the sulfur atom to which they are directly connected form a 3-6 membered heterocyclic group, the above groups are optionally further substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, -C 0-4 Alkyl-S(O) r R 10 、-C 0-4 Alkyl-OR 11 、-C0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)R 12 、-C 0-4 Alkyl-OC(O)R 12 、-C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(=NR 13 )R 12 、-C 0-4 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-4 Alkyl-C(O)NR 13 R 14 or -C 0-4 Alkyl-N(R 13 )-C(O)R 12 substituted by a substituent;

[0131] Each R 10 independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl and -NR 13 R 14 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR 13 R 14 substituted by a substituent;

[0132] Each R 11 independently selected from hydrogen, deuterium, C 1-10 Alkyl, C 2-10 Alkenyl, -C 0-8 Alkyl C 3-12 Cycloalkyl, -C 0-8 Alkyl 3-12 membered heterocyclic group, -C 0-8 Alkyl C 6-10 Aryl, -C 0-8Alkyl 5-10 membered heteroaryl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3- 12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR 13 R 14 substituted by a substituent;

[0133] Each R 12 independently selected from hydrogen, deuterium, C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl and 5-8 membered heteroaryl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR 13 R 14 substituted by a substituent;

[0134] Each R 13 and R 14 are independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl and C 1-4 Alkanoyl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono C 1-4 Alkylamino, di-C 1-4 Alkylamino and C 1-4 substituted with an alkanoyl substituent;

[0135] Or, R 13 and R 14 Together with the nitrogen atom directly connected thereto, a 4-8 membered heterocyclic group or a 5-8 membered heteroaryl group is formed, wherein the 4-8 membered heterocyclic group or the 5-8 membered heteroaryl group is optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono C 1-4 Alkylamino, di-C 1-4 Alkylamino and C 1-4 The alkanoyl group is substituted with an alkanoyl substituent.

[0136] In one embodiment of the first aspect, R1 is selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkyl C 3-6 Cycloalkyl, -C 0-4 Alkyl 3-6 membered heterocyclic group, -C 0-4 Alkyl C 6-10 Aryl, -C 0-4 Alkyl 5-10 membered heteroaryl, -C 1-4 Alkyl-S(O) r R 10 、-C 1-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)SR 11 、-C 0-4 Alkyl-C(O)R 12 、-C0-4 Alkyl-OC(O)R 12 、-C 1-4 Alkyl-P(O)(R 12 )2. -C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 , the above groups are independently optionally further substituted by one or more substituents selected from deuterium and halogen;

[0137] R2 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkyl C 3-10 Cycloalkyl, -C 0-4 Alkyl 3-10 membered heterocyclic group, -C 0-4 Alkyl C 6-10 Aryl, -C 0-4 Alkyl 5-10 membered heteroaryl, -C 0-4 Alkyl-S(O) r R 10 、-C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)R 12 、-C 0-4 Alkyl-OC(O)R 12 、-C 0-4 Alkyl-P(O)(R 12 )2. -C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 , the above groups are independently optionally further substituted by one or more substituents selected from deuterium and halogen;

[0138] R3 is selected from hydrogen, C 1-4 Alkyl, -C 3-6 Cycloalkyl, -3-6 membered heterocyclic group, -C 1-4 Alkyl-OR11 、-C 0-4 Alkyl-C(O)OR 11 , the above groups are independently optionally further substituted by one or more substituents selected from deuterium, halogen, and cyano;

[0139] In one embodiment, X is selected from -C 3-10 Cycloalkyl, -3-10 membered heterocycle, -C 6-10 aromatic ring or a 5- to 10-membered heteroaromatic ring.

[0140] In a preferred embodiment, X is selected from benzene ring, naphthalene ring, -5-10 membered heteroaromatic ring; R1 is selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkyl C 3-6 Cycloalkyl, -C 0-4 Alkyl 4-6 membered heterocyclic group, -C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 , the above groups are independently optionally further substituted by one or more substituents selected from deuterium and halogen; R2 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkyl C 3-10 Cycloalkyl, -C 0-4 Alkyl 3-10 membered heterocyclic group, -C 0-4 Alkyl-S(O) r R 10 、-C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-P(O)(R 12 )2. -C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12, the above groups are independently optionally further substituted by one or more substituents selected from deuterium and halogen; R3 is H.

[0141] In a preferred embodiment, the pyridone compound has a structure represented by the following general formula (II):

[0142] Among them, Y 1 N or CR 41 ; Y 2 N or CR 42 ; Z 1 N or CR 51 ; Z 2 N or CR 52 ;

[0143] R 41 、R 42 、R 51 、R 52 Each independently selected from: H, deuterium, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, C 4-8 Heterocyclic group, phenyl group, -N(R 13 )-C(O)R 12 、C 2-6 Alkynyl, -S(O) r R 10 、-NR 13 R 14 , the above groups may be independently optionally further substituted by one or more substituents selected from deuterium and halogen;

[0144] R0 is selected from: H, deuterium, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, -C 0-4 Alkyl 4-8 membered heterocyclic group, -C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C 1-4 Alkoxy, -C 0-4 Alkyl-S(O) r -C 1-4 Alkyl, hydroxyl, -C 0-4 Alkyl-CN, -C 0-4 Alkyl-C(O)NR 13 R 14 、-C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-N(R13 )-C(O)R 12 、-C 0-4 Alkyl-N(R 13 )-S(O) r R 12 、-C 0-4 Alkyl-N(R 13 )-C(=NR 14 )R 12 、C 2-6 Alkenyl, C 2-6 Alkynyl, the above groups may be independently further substituted with one or more substituents selected from deuterium, halogen, and hydroxyl;

[0145] Each R 61 Each independently selected from: H, deuterium, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, -C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C 1-4 Alkoxy, -C 0-4 Alkyl-S(O) r -C 1-4 Alkyl, hydroxyl, -C 0-4 Alkyl-CN, -C 0-4 Alkyl-C(O)NR 13 R 14 、-C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-N(R 13 )-C(O)R 12 、-C 0-4 Alkyl-N(R 13 )-S(O) r R 12 、-C 0-4 Alkyl-N(R 13 )-C(=NR 14 )R 12 、C 2-6 Alkynyl, the above groups may be independently further substituted with one or more substituents selected from deuterium, halogen, and hydroxyl;

[0146] Or, two R 61 Together they form =C(R 15 )2;

[0147] Or, two R 61 Together with the carbon atoms to which they are directly attached, they form a 3-8 membered carbocyclic ring or a 4-8 membered heterocyclic ring containing 1-2 heteroatoms independently selected from O, S, and N;

[0148] Each R 15 Each independently selected from: H, deuterium, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, -C 0-4 Alkyl-C 1-4 Alkoxy, -C 0-4 Alkyl 4-8 membered heterocyclic group, the above groups may be independently further substituted with one or more substituents selected from deuterium, halogen, hydroxyl;

[0149] R1, R2, R 30 、R 10 、R 11 、R 12 、R 13 、R 14 , r is defined as above;

[0150] The condition is that when Y 1 、Y 2 、Z 1 、Z 2 Any three of them are CH, CH and CH or N, CH and CH, and the fourth is CH or C(C 1-6 alkyl), R1 is H or C 1-6 Alkyl, when R2 is H, R0, two R 61 Substituents together with the carbon atom to which they are attached are not C 1-6 alkyl.

[0151] In another preferred embodiment, the pyridone compound has a structure represented by the following general formula (III):

[0152] wherein Ring A is a 3-8 membered carbocyclic ring or a 4-8 membered heterocyclic ring containing 1-2 heteroatoms independently selected from O, S, and N;

[0153] Each R 62 Each independently selected from: H, deuterium, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, -C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C 1-4 Alkoxy, -C 0-4 Alkyl-S(O) r -C 1-4 Alkyl, hydroxyl, -C 0-4 Alkyl-CN, -C 0-4 Alkyl-C(O)NR 13 R 14 、-C 0-4 Alkyl-NR13 R 14 、-C 0-4 Alkyl-N(R 13 )-C(O)R 12 、-C 0-4 Alkyl-N(R 13 )-S(O) r R 12 、-C 0-4 Alkyl-N(R 13 )-C(=NR 14 )R 12 、=O、=C(R 15 ) 2, the above groups may be independently optionally further substituted with one or more substituents selected from deuterium, halogen, and hydroxyl;

[0154] t is 1, 2, 3, or 4; Y 1 、Y 2 、Z 1 、Z 2 、R 41 、R 42 、R 51 、R 52 , R1, R2, R 30 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 , r are defined as before.

[0155] In another preferred embodiment, Ring A is a 3-6 membered carbon ring or a 4-8 membered heterocyclic ring containing 1-2 heteroatoms independently selected from O, S, and N; R1 is selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, -C 1-4 Alkyl-OR 11 and -C 0-4 Alkyl-NR 13 R 14 , the above groups are independently optionally further substituted by one or more substituents selected from deuterium and halogen; R2 is selected from: hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl C 3-10 Cycloalkyl, -C 0-4 Alkyl 3-10 membered heterocyclic group, -C 0-4 Alkyl-NR 13 R 14 and -C 0-4 Alkyl-N(R13 )-C(O)R 12 , the above groups are independently optionally further substituted by one or more substituents selected from deuterium and halogen; R 30 Selected from: -CN, hydrogen, deuterium, halogen, C 1-4 Alkyl, -C 0-4 Alkyl-S(O) r R 10 、-C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)R 12 、-C 0-4 Alkyl-OC(O)R 12 、-C 0-4 Alkyl-P(O)(R 12 )2. -C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 , the above groups are independently optionally further substituted by one or more substituents selected from deuterium and halogen.

[0156] In another preferred embodiment, the pyridone compound has a structure represented by the following general formula (IV), (V) or (VI):

[0157] Among them, R 41 、R 42 、R 51 、R 52 Each independently selected from: H, deuterium, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, C 4-8 Heterocyclic group, phenyl group, -N(R 13 )-C(O)R 12 、C 2-6 Alkynyl, -S(O) r R 10 、-NR 13 R 14 , the above groups may be independently optionally further substituted by one or more substituents selected from deuterium and halogen;

[0158] Ring A, R0, R1, R2, R 10 、R 12 、R 13 、R 14 、R 30 、R 62 The definitions of , t, and r are the same as before.

[0159] In another preferred embodiment, R0 is selected from: H, deuterium, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, -C 0-4 Alkyl 4-8 membered heterocyclic group, -C 0-4 Alkyl-C(O)OR 16 、-C 0-4 Alkyl-C 1-4 Alkoxy, -C 0-4 Alkyl-S(O) r -C 1-4 Alkyl, hydroxyl, -C 0-4 Alkyl-CN, -C 0-4 Alkyl-C(O)N(R 16 )2. -C 0-4 Alkyl-N(R 16 )2. -C 0-4 Alkyl-N(R 16 )-C(O)R 16 、-C 0-4 Alkyl-N(R 16 )-S(O) r R 16 、-C 0-4 Alkyl-N(R 16 )-C(=NR 16 )R 12 、C 2-6 Alkenyl, C 2-6 Alkynyl, the above groups may be independently further substituted with one or more substituents selected from deuterium, halogen, and hydroxyl;

[0160] R 41 、R 42 、R 51 、R 52 Each independently selected from: H, deuterium, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, C 4-8 Heterocyclic group, phenyl group, -N(R 16 )-C(O)R 16 、C 2-6 Alkynyl, -S(O) r R 16 、-N(R16 ) 2, the above groups may be independently optionally further substituted by one or more substituents selected from deuterium and halogen;

[0161] Each R 62 Each independently selected from: H, deuterium, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, -C 0-4 Alkyl-C(O)OR 16 、-C 0-4 Alkyl-C 1-4 Alkoxy, -C 0-4 Alkyl-S(O) r -C 1-4 Alkyl, hydroxyl, -C 0-4 Alkyl-C(O)N(R 16 )2. -C 0- 4-alkyl-N(R 16 )2. -C 0-4 Alkyl-N(R 16 )-C(O)R 16 、-C 0-4 Alkyl-N(R 16 )-S(O) r R 16 、=O、=C(R 15 ) 2, the above groups may be independently optionally further substituted with one or more substituents selected from deuterium, halogen, and hydroxyl;

[0162] Each R 16 Each independently selected from: hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Haloalkyl; R 15 , r is defined as before.

[0163] In another preferred embodiment, R1 is selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy.

[0164] In another preferred embodiment, R2 is selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl.

[0165] In another preferred embodiment, R 30 Select -CN, -N(R 16 )2,-OR 16 、-C(O)OR 16 、-C(O)N(R 16 )2 and -N(R 16 )-C(O)R16 ; Each R 16 Independent of each other and have the same definition as before.

[0166] In another preferred embodiment, ring A is a cyclopropane ring; R1 is selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl; each R 62 Each independently selected from: H, deuterium, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, -C(O)OR 16 、-C 0-4 Alkyl-C 1-4 Alkoxy, hydroxy, -C(O)N(R 16 )2、-N(R 16 )2; t is 0, 1 or 2; each R 16 Independent of each other and with the same definition as before.

[0167] In another preferred embodiment, the pyridone compound has a structure represented by the following general formula (VII):

[0168] wherein Ring B is a 5-8 membered carbocyclic ring or a 5-10 membered heterocyclic ring containing 1-2 heteroatoms independently selected from O, S, and N;

[0169] R1 is selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 haloalkoxy;

[0170] R2 is selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, C 1-4 alkyl halide;

[0171] R 30 Select -CN, -N(R 16 )2,-OR 16 、-C(O)OR 16 、-C(O)N(R 16 )2 and -N(R 16 )-C(O)R 16 ;

[0172] Each R 70 Each independently selected from: H, deuterium, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, -C 0-4 Alkyl-C(O)OR 16 、-C 0-4 Alkyl-C 1-4 Alkoxy, -C 0-4Alkyl-S(O) r R 16 , hydroxyl, -C 0-4 Alkyl-CN, -C 0-4 Alkyl-C(O)N(R 16 )2. -C 0-4 Alkyl-N(R 16 )2. -C 0-4 Alkyl-N(R 16 )-C(O)R 16 、-C 0-4 Alkyl-N(R 16 )-S(O) r R 16 、-C 0-4 Alkyl-N(R 16 )-C(=NR 16 )R 16 、C 2-6 Alkenyl, C 2-6 Alkynyl, the above groups may be independently further substituted with one or more substituents selected from deuterium, halogen, and hydroxyl;

[0173] Two R's attached to the same carbon atom 70 Can form O or =C(R 15 )2;

[0174] Two R's attached to the same carbon atom 70 Together with the carbon atoms to which they are directly attached, they may further form a 3-8 membered carbocyclic ring or a 4-8 membered heterocyclic ring containing 1-2 heteroatoms independently selected from O, S, and N;

[0175] Each Q is independently N or CR 80 ;

[0176] Each R 80 Each independently selected from: H, deuterium, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, C 4-8 Heterocyclic group, phenyl group, -N(R 16 )-C(O)R 16 、C 2-6 Alkynyl, -S(O) r R 16 、-N(R 16 ) 2, the above groups may be independently optionally further substituted by one or more substituents selected from deuterium and halogen;

[0177] Each R 15 Each independently selected from: H, deuterium, halogen, C1-4 Alkyl, C 3-6 Cycloalkyl, -C 0-4 Alkyl-C 1-4 Alkoxy, -C 0-4 Alkyl 4-8 membered heterocyclic group, the above groups may be independently further substituted with one or more substituents selected from deuterium, halogen, hydroxyl;

[0178] Each R 16 Each independently selected from: hydrogen, deuterium, C 1-4 Alkyl, C 1-4 alkyl halide;

[0179] s is 0, 1, 2, 3 or 4; r is 0, 1 or 2.

[0180] In another preferred embodiment, ring B is a 5-6 membered carbocyclic ring or a 5-7 membered heterocyclic ring containing 1 heteroatom selected from O, S, and N;

[0181] Each R 70 Each independently selected from: H, deuterium, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, -C 0-4 Alkyl-C 1-4 Alkoxy, -C 0-4 Alkyl-S(O) r R 16 , hydroxyl, -C 0-4 Alkyl-C(O)N(R 16 )2. -C 0-4 Alkyl-N(R 16 )2. -C 0-4 Alkyl-N(R 16 )-C(O)R 16 、-C 0-4 Alkyl-N(R 16 )-S(O) r R 16 、-C 0-4 Alkyl-N(R 16 )-C(=NR 16 )R 16 、C 2-6 Alkenyl, C 2-6 Alkynyl, the above groups may be independently further substituted with one or more substituents selected from deuterium, halogen, and hydroxyl;

[0182] Two R's attached to the same carbon atom 70 Can form O or =C(R 15 )2;

[0183] Two R's attached to the same carbon atom 70Together with the carbon atoms to which they are directly attached, they may further form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring containing one heteroatom selected from O, S, and N;

[0184] Each Q group has 0 or 1 N.

[0185] In one embodiment, the pyridone compounds described herein, their stereoisomers, solvates, and pharmaceutically acceptable salts or prodrugs include but are not limited to the compounds prepared in the Examples.

[0186] Preparation method of compound

[0187] The pyridone compounds described herein can be prepared in various ways and synthesized via different synthetic routes.

[0188] Shown below are exemplary general routes for the synthesis of the pyridinone compounds described herein.

[0189] The method comprises reacting a first intermediate with a second intermediate to obtain a pyridone compound having a structure as shown in formula (I). The first intermediate has a structure as shown in formula (VA):

[0190] The second intermediate has a structure as shown in the general formula (VIA):

[0191] Wherein, Rx is halogen or trifluoromethanesulfonyl, Ry is the corresponding group required for the coupling reaction containing boron, tin, silicon, zinc, magnesium, etc., preferably, Rx is I, Br, Cl, OTf, Ry is B(OH)2, One or more of BF4, SnMe3, SnBu3, SiMe3, ZnCl, ZnBr, MgCl and MgBr;

[0192] X, R1, R2, R3, R4, R5 and n are as defined above.

[0193] In another embodiment, the first intermediate has a structure as shown in Formula (VIIA):

[0194] The second intermediate has a structure as shown in the general formula (VIIIA):

[0195] Wherein, Rx is halogen or trifluoromethanesulfonyl, Ry is the corresponding group required for the coupling reaction containing boron, tin, silicon, zinc, magnesium, etc., preferably, Rx is I, Br, Cl, OTf, Ry is B(OH)2, One or more of BF4, SnMe3, SnBu3, SiMe3, ZnCl, ZnBr, MgCl and MgBr;

[0196] X, R 30 , R1, R2, R3, R4, R5 and n are as defined above.

[0197] Pharmaceutical composition

[0198] The pyridone compounds, stereoisomers, solvates, pharmaceutically acceptable salts, or prodrugs described herein can be provided in the form of pharmaceutical compositions. Pharmaceutical compositions can include a therapeutically effective amount of the pyridone compound and a pharmaceutically acceptable adjuvant, carrier, or vehicle. Depending on the intended mode of administration, the pharmaceutical composition can be a solid, semisolid, or liquid formulation. Those skilled in the art can select adjuvants, carriers, or vehicles, as well as the dosage form of the pharmaceutical composition, based on actual circumstances, and are not further described herein.

[0199] How to use

[0200] The present application also provides a method for preventing or treating tumors or cancer in a subject by forming a stable PDE3A-SLFN12 complex, the method comprising administering to the subject an effective amount of a pyridone compound or pharmaceutical composition described herein, a stereoisomer, solvate, or pharmaceutically acceptable salt or prodrug thereof. When used in the method, the term "effective amount" refers to an amount of the compound that can achieve the desired pharmacodynamic or other biological effect.

[0201] The pyridone compounds or pharmaceutical compositions described herein can be used to treat human tumors or cancers. In a specific embodiment, the tumor or cancer is selected from lung malignancies or cancers, hepatobiliary malignancies or cancers, gastrointestinal malignancies or cancers, hematological malignancies or cancers, sarcomas, skin malignancies or cancers, bone malignancies or cancers, genitourinary tract malignancies or cancers, nervous system malignancies or cancers, gynecological malignancies or cancers, and adrenal malignancies or cancers. Preferably, the lung malignancies or cancers are selected from bronchial cancer (squamous cell carcinoma, undifferentiated small cells, undifferentiated large cells, or adenocarcinomas), non-small cell lung cancer, bronchial cancer, bronchial adenoma, sarcoma, lymphoma, chondroitinoma, or mesothelioma. The hepatobiliary malignancies or cancers are selected from liver cancer, bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, gallbladder cancer, ampullary cancer, or bile duct cancer. The gastrointestinal malignancy or cancer is selected from the group consisting of esophageal malignancy or cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, or lymphoma), gastric malignancy or cancer (carcinoma, lymphoma, or leiomyosarcoma), pancreatic malignancy or cancer (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, uveal tumor), small intestine (adenocarcinoma, lymphoma, carcinoid, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colorectal malignancy or cancer (adenocarcinoma, adenoma, adenoma, tubular adenoma), or leiomyoma. The hematological malignancy or cancer is selected from the group consisting of acute or chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease, or non-Hodgkin's lymphoma. The sarcoma is selected from the group consisting of angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyosarcoma, fibroma, lipoma, or teratoma. The skin malignancy or cancer is selected from the group consisting of malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus, hyperplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, or psoriasis. The bone malignancy or cancer is selected from the group consisting of osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma, benign enchondroma, chondroblastoma, chondromycofibroma, osteoid osteoma, or giant cell tumor. The genitourinary tract malignancy or cancer is selected from the group consisting of a renal malignancy or cancer (adenocarcinoma, Wilms' tumor, or Wilms' tumor), a lymphoma, a leukemia, a bladder or urethral malignancy or cancer (squamous cell carcinoma, transitional cell carcinoma, or adenocarcinoma), a prostate malignancy or cancer (adenocarcinoma or sarcoma), a testicular malignancy or cancer (leukemia, teratoma, embryonal carcinoma, or teratoma), choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, or lipoma.The nervous system malignancy or cancer is selected from osteoma, hemangioma, granuloma, xanthomas, osteitis deformans, meningioma, meningiosarcoma, glioma, astrocytoma, medulloblastoma, glioma, ependymoma, genital tumor, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor, spinal neurofibroma, meningioma, glioma or sarcoma. The gynecological malignancy or cancer is selected from endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma or unclassified carcinoma), granulosa-theca cell tumor, testicular interstitial cell tumor, sarcoma, malignant teratoma, squamous cell carcinoma, fibroepithelial carcinoma, glandular epithelial carcinoma, melanoma, clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma or fallopian tube cancer. The adrenal malignancy or cancer is selected from neuroblastoma.

[0202] The method of treating or preventing a tumor or cancer in a subject may further comprise administering to the subject a second compound, biomolecule, or composition.The additional agent and the pyridone compound described herein may be injected in any order.

[0203] Reagent test kit

[0204] The present application also provides a kit comprising a pyridone compound, a stereoisomer, solvate, pharmaceutically acceptable salt, or prodrug thereof, or a pharmaceutical composition as described herein. The kit may also include one or more other agents, such as an anti-inflammatory drug. The kit may be an oral formulation or an intravenous formulation made from the pyridone compound or pharmaceutical composition described herein. The kit may also include instructions for use of the kit, a container, a device for injecting the compound or composition, and / or a carrier.

[0205] use

[0206] The present application also relates to the use of the pyridone compounds described herein, their stereoisomers, solvates, pharmaceutically acceptable salts, or prodrugs as PDE3A-SLFN12 complex inducers. The present application also relates to the use of the pyridone compounds described herein, their stereoisomers, solvates, pharmaceutically acceptable salts, or prodrugs in the preparation of medicaments for preventing or treating tumors or cancers by forming a stable PDE3A-SLFN12 complex.

[0207] Example

[0208] The present invention will be further described in detail and completely below with reference to the embodiments, but the present invention is by no means limited thereto, and the present invention is not limited to the contents of the embodiments.

[0209] The structures of the pyridone compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements are performed using a Bruker AVANCE-400 / 500 NMR spectrometer, using deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as the solvents, with tetramethylsilane (TMS) as the internal standard.

[0210] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 6120 mass spectrometer. HPLC was performed using an Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C18 150×4.6 mm column).

[0211] Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0212] The starting materials in the examples of the present invention are known and can be purchased commercially, or can be synthesized using or according to methods known in the art.

[0213] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, with dry solvents and reaction temperatures expressed in degrees Celsius (°C).

[0214] 1. Preparation of intermediates

[0215] Intermediate 1: Preparation of 5-bromo-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile

[0216] 3-Cyano-6-methyl-2(1H)-pyridone (15 g, 111.82 mmol) and N-bromosuccinimide (42.59 g, 239.30 mmol) were added to a reaction flask. The system was evacuated and replaced with nitrogen three times. 1,2-Dichloroethane (150 mL) was added, and the mixture was heated to 80°C and stirred for 16 hours. The reaction system was cooled to room temperature and filtered. The filter cake was washed with methanol and dried to obtain 5-bromo-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile (20 g). The crude product was used directly in the next reaction without purification.

[0217] Intermediate 2: Preparation of 6-methyl-2-carbonyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridine-3-carbonitrile

[0218] To the reaction flask were added 5-bromo-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile (500 mg, 2.35 mmol), bipyraclostrobin (655.62 mg, 2.58 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (342.06 mg, 469.42 μmol), potassium acetate (691.03 mg, 7.04 mmol) in sequence. The system was evacuated and replaced with nitrogen three times. 1,4-dioxane (10 mL) was injected using a syringe, heated to 90 ° C, stirred for 16 hours, filtered, and the filter cake was washed with 1,4-dioxane. The filtrate was collected and used directly in the next reaction without purification.

[0219] Intermediate 3: Preparation of 2-(3-chloro-4-ethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0220] Step 1: Synthesis of 4-bromo-2-chloro-1-ethylbenzene

[0221] 1-(4-Bromo-2-chlorophenyl)ethanone (1 g, 4.28 mmol) and trifluoroacetic acid (5 mL) were added to the reaction flask in sequence. The system was evacuated and replaced with nitrogen three times. Triethylsilane (1.38 mL, 8.57 mmol) was injected using a syringe at 0 ° C. The mixture was stirred at room temperature for 16 hours. After concentration, it was purified using a normal phase column to give 4-bromo-2-chloro-1-ethylbenzene (700 mg, yield: 74.46%).

[0222] The NMR data of this intermediate are as follows: 1 H NMR (400MHz, CDCl3) δ7.49 (d, J = 2.0 Hz, 1H), 7.31 (dd, J = 8.0, 2.0 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 2.70 (q, J = 7.6 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H).

[0223] Step 2: Synthesis of 2-(3-chloro-4-ethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0224] To the reaction flask were added 4-bromo-2-chloro-1-ethylbenzene (200 mg, 0.91 mmol), pinacol diboron (231 mg, 0.91 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (74 mg, 0.091 mmol), and potassium acetate (268 mg, 2.73 mmol). The system was evacuated and replaced with nitrogen three times. 1,4-dioxane (3 mL) and 1,4-dioxane were added. The mixture was heated to 100°C and stirred for 5 hours. The mixture was cooled to room temperature and filtered. The filtrate was concentrated to give 2-(3-chloro-4-ethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (200 mg, crude product). The crude product was used directly in the next reaction without purification.

[0225] Intermediate 4: Preparation of 4-bromo-2-trifluoromethyl-1,1'-biphenyl

[0226] 2-Amino-5-bromobenzotrifluoride (2.5 g, 10.42 mmol) was added to a reaction flask. The system was evacuated and replaced with nitrogen three times. Benzene (10 mL) and n-pentyl nitrite (1.22 g, 10.41 mmol) were added sequentially. The mixture was heated to 50°C and stirred for 1 hour. The temperature was then raised to 80°C, and n-pentyl nitrite (1.22 g, 10.41 mmol) was added. The mixture was stirred at 80°C for 2 hours. The reaction system was cooled to room temperature, and the reaction solution was concentrated and purified using a normal phase column to obtain 4-bromo-2-trifluoromethyl-1,1'-biphenyl (200 mg, yield: 6.38%).

[0227] Intermediate 5: Preparation of 1-bromo-2-chloro-4-ethylbenzene

[0228] 3-Chloro-4-bromoacetophenone (4.60 g, 19.70 mmol) and trifluoroacetic acid (30 mL) were added to a reaction flask. The system was cooled to 0°C and triethylsilane (4.58 g, 39.40 mmol) was added. The mixture was then warmed to room temperature and stirred for 16 hours. After the reaction, the reaction solution was concentrated and purified using a normal phase column to obtain 1-bromo-2-chloro-4-ethylbenzene (2.4 g, yield: 55.5%).

[0229] Intermediate 6: Preparation of 2-(4-ethyl-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0230] 2-(4-ethyl-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane can be prepared by selecting appropriate reagents according to the synthesis method of intermediate 3.

[0231] Intermediate 7: Preparation of 6-ethyl-2-hydroxy-5-iodopyridine-3-carbonitrile

[0232] Step 1: Synthesis of 6-ethyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile

[0233] To a reaction flask, 3-cyano-6-methyl-2(1H)-pyridone (2g, 14.91mmol) and tetrahydrofuran (20ml) were added sequentially. The system was evacuated and replaced with nitrogen three times. After cooling to -78°C, lithium diisopropylamide (22.35mL, 2M, 44.73mmol) was added dropwise. The reaction was stirred at 0°C for 2 hours, and iodomethane (4.55g, 32.06mmol) was added. The temperature was slowly warmed to room temperature and allowed to react for 18 hours. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction, and the product was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product, which was separated using a forward-phase column to afford 6-ethyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile (1.1g, 49.8% yield).

[0234] Step 2: Synthesis of 6-ethyl-2-hydroxy-5-iodopyridine-3-carbonitrile

[0235] To the reaction flask were added 6-ethyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile (550 mg, 3.71 mmol), acetic acid and TFA, N-iodosuccinimide (835 mg, 3.71 mmol), the system was evacuated and replaced with nitrogen three times, heated to 100 ° C, stirred for 3 hours, quenched with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to give 6-ethyl-2-hydroxy-5-iodopyridine-3-carbonitrile (510 mg, yield: 94.8%).

[0236] Intermediate 8: Preparation of 5-methylnaphthalen-2-yltrifluoromethanesulfonic acid

[0237] Step 1: Synthesis of 6-methoxy-1-methylnaphthalene

[0238] To a reaction flask, methyl phenyl sulfone (2.13 g, 13.62 mmol) and tetrahydrofuran (10 mL) were added sequentially. The mixture was cooled to -70°C and n-butyl lithium (2.50 mL, 12.48 mmol) was slowly added dropwise. After stirring for 0.5 hours, 6-methoxytetralone (2 g, 11.35 mmol) and benzoyl chloride (2.39 g, 17.02 mmol) were added sequentially. The reaction system was slowly warmed to room temperature and stirred for 3 hours. Finally, potassium tert-butoxide (6.37 g, 56.75 mmol) was added. The mixture was heated to 60°C and stirred for 3 hours. The mixture was cooled to room temperature and quenched with saturated ammonium chloride. The mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to afford 6-methoxy-1-methylnaphthalene (264 mg, yield: 13.5%).

[0239] Step 2: Synthesis of 5-methyl-2-naphthol

[0240] Dissolve 6-methoxy-1-methylnaphthalene (120 mg, 0.70 mmol) in dichloromethane (3 mL), cool to 0°C, and slowly add boron tribromide (1.05 mL, 1.05 mmol) dropwise. Slowly warm the reaction system to room temperature and stir for 2 hours. Then, add saturated sodium bicarbonate solution to quench the reaction. Extract with dichloromethane, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain crude 5-methyl-2-naphthol (160 mg).

[0241] Step 3: Synthesis of 5-methylnaphthalen-2-yltrifluoromethanesulfonic acid

[0242] 5-Methyl-2-naphthol (190 mg, 1.20 mmol) was dissolved in dichloromethane (8 mL) and cooled to 0°C. 4-Dimethylaminopyridine (14.67 mg, 0.12 mmol), triethylamine (145 mg, 1.44 mmol), and trifluoromethanesulfonic anhydride (406 mg, 1.44 mmol) were added sequentially and allowed to react at room temperature for 2 hours. The mixture was then quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to afford 5-methylnaphthalen-2-yltrifluoromethanesulfonic acid (265 mg, 76% yield).

[0243] Intermediate 9: Preparation of 1-bromo-4-(3,3-difluorocyclobutyl)benzene

[0244] 3-(4-Bromophenyl)cyclobutan-1-one (150 mg, 0.67 mmol) was dissolved in dichloromethane (0.5 mL), cooled to -70°C, and a solution of diethylaminosulfur trifluoride (DAST, 268 mg, 1.67 mmol) in dichloromethane (0.25 mL) was added. The system was stirred at -70°C for 1 hour, then the temperature was raised to 25°C and allowed to react for 40 hours. The reaction was quenched by adding saturated sodium bicarbonate solution (1 mL), extracted with dichloromethane (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified to yield 1-bromo-4-(3,3-difluorocyclobutyl)benzene (120 mg, 73% yield).

[0245] Intermediate 10: Preparation of 1-bromo-4-(1-methylcyclopropyl)benzene

[0246] Diethylzinc (251 mg, 2.03 mmol) was added to dichloromethane (5 mL) at 0°C, followed by the dropwise addition of trifluoroacetic acid (231 mg, 2.03 mmol). After stirring at 0°C for 20 minutes, diiodomethane (544 mg, 2.03 mmol) was added, and the reaction was continued at 0°C with stirring for 20 minutes. 1-Bromo-4-isopropylbenzene (200 mg, 1.01 mmol) was then added dropwise, and the mixture was allowed to react at room temperature for 16 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride and adjusted to neutrality with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to yield 1-bromo-4-(1-methylcyclopropyl)benzene (182 mg, yield: 84.96%), which was used directly in the next step.

[0247] Intermediate 11: Preparation of 1-(1-fluorocyclopropyl)-4-iodobenzene

[0248] Step 1: Synthesis of methyl 5-methyl-4-(tert-butoxycarbonylamino)benzoate

[0249] Methyl 4-aminobenzoate (5 g, 33.08 mmol) was dissolved in acetonitrile (100 mL), and triethylamine (10.04 g, 99.23 mmol), 4-dimethylaminopyridine (404 mg, 3.31 mmol), and di-tert-butyl dicarbonate (10.83 g, 49.61 mmol) were added in sequence. The system was stirred at room temperature for 16 hours, quenched with water, and the system was concentrated to remove acetonitrile. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to give methyl 5-methyl-4-(tert-butoxycarbonylamino)benzoate (2.6 g, yield: 31.28%) as a white solid.

[0250] Step 2: Synthesis of tert-butyl N-[4-(1-hydroxycyclopropyl)phenyl]carbamate

[0251] Methyl 4-(tert-butoxycarbonylamino)benzoate (1 g, 3.98 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to -70°C, and tetraisopropyl titanate (1.58 g, 5.57 mmol) and ethylmagnesium bromide (15.92 mL, 15.92 mmol) were slowly added. The mixture was slowly heated to -10°C and stirred for 0.5 hours, then warmed to room temperature and stirred for 16 hours. After completion, the reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to obtain tert-butyl N-[4-(1-hydroxycyclopropyl)phenyl]carbamate (650 mg, yield: 54.6%).

[0252] Step 3: Synthesis of tert-butyl N-[4-(1-fluorocyclopropyl)phenyl]carbamate

[0253] Dissolve tert-butyl N-[4-(1-hydroxycyclopropyl)phenyl]carbamate (610 mg, 2.45 mmol) in dichloromethane (8 mL), cool to -70°C, and add diethylaminosulfur trifluoride (788 mg, 4.89 mmol) to react for 0.5 hour. Concentrate the mixture to obtain crude tert-butyl N-[4-(1-fluorocyclopropyl)phenyl]carbamate (610 mg).

[0254] Step 4: Synthesis of 4-(1-fluorocyclopropyl)aniline

[0255] Dissolve tert-butyl N-[4-(1-fluorocyclopropyl)phenyl]carbamate (610 mg, 2.43 mmol) in ethyl acetate (10 mL), cool to 0°C, add hydrochloric acid in ethyl acetate (10 mL, 40 mmol), and allow to warm to room temperature with stirring for 3 hours. Saturated sodium bicarbonate was then added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to yield crude 4-(1-fluorocyclopropyl)aniline (480 mg).

[0256] Step 5: Synthesis of 1-(1-fluorocyclopropyl)-4-iodobenzene

[0257] 4-(1-Fluorocyclopropyl)aniline (480 mg, 3.18 mmol) was dissolved in acetonitrile (10 mL), and iodine (805 mg, 3.18 mmol), cuprous iodide (665 mg, 3.49 mmol), and tert-butyl nitrite (491 mg, 4.76 mmol) were added sequentially. The temperature was slowly raised to 80°C and the reaction mixture was allowed to react for 0.5 hours. Saturated sodium thiosulfate solution was then added to quench the reaction. The reaction mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified using a normal phase column to afford 1-(1-fluorocyclopropyl)-4-iodobenzene (270 mg, yield: 32.45%).

[0258] Intermediate 12: Preparation of 4-heptafluoroisopropyliodobenzene

[0259] Step 1: Synthesis of 4-(heptafluoroisopropyl)phenylamine

[0260] To a mixed solution of aniline (3.04 mL, 33.29 mmol) in methyl tert-butyl ether (45 mL) and water (45 mL) were added sodium dithionite (7.24 g, 41.61 mmol), sodium bicarbonate (4.89 g, 58.25 mmol), and tetrabutylammonium hydrogensulfate (565.11 mg, 1.66 mmol) at room temperature. The reaction was stirred at 25°C for 0.5 h, followed by the addition of heptafluoroisopropyl iodide (12.31 g, 41.61 mmol). The mixture was stirred at 25°C for 16 h. The mixture was diluted with ethyl acetate (200 mL), washed with water (2 x 100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to afford 4-(heptafluoroisopropyl)phenylamine (9.10 g, 94.22% yield, 90% purity). The crude product was used directly in the next step without purification.

[0261] Step 2: Synthesis of 4-heptafluoroisopropyliodobenzene

[0262] Under an inert atmosphere, a mixture of 4-(heptafluoroisopropyl)phenylamine (1 g, 3.83 mmol), tert-butyl nitrite (592 mg, 5.74 mmol), iodine (1.49 g, 3.83 mmol), and cuprous iodide (802 mg, 4.21 mmol) in acetonitrile (20 mL) was stirred at 80°C for 3 hours. The mixture was concentrated to obtain a crude product, which was then diluted with ethyl acetate (100 mL), washed sequentially with water (2 x 50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography to yield 4-heptafluoroisopropyliodobenzene (1.10 g, yield: 77.21%).

[0263] Intermediate 13: Preparation of 4,4,5,5-tetramethyl-2-(3-methyl-1-benzothiophen-6-yl)-1,3,2-dioxaborolane

[0264] Step 1: Synthesis of 1-(3-chlorophenylthio)propan-2-one

[0265] Dissolve chloroacetone (4.80 g, 51.86 mmol), 3-chlorothiophenol (5 g, 34.57 mmol), and sodium carbonate (3.66 g, 34.57 mmol) in dichloromethane (15 mL) and stir at room temperature for 4 hours. Filter and dry on a rotary evaporator to obtain the crude product, which is then purified by column chromatography to yield 1-(3-chlorophenylthio)propan-2-one (4.35 g, yield: 62.7%).

[0266] Step 2: Synthesis of 6-chloro-3-methyl-1-benzothiophene

[0267] To a reaction flask, 1-(3-chlorophenylthio)propan-2-one (3 g, 14.95 mmol), polyphosphoric acid (14.42 g, 60.10 mmol), and toluene (5 ml) were added sequentially. The mixture was heated to 130°C and stirred for 12 hours. After cooling to room temperature, the reaction system was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to yield 6-chloro-3-methyl-1-benzothiophene (2 g, yield: 73.24%), which was used directly in the next step.

[0268] Step 3: Synthesis of 4,4,5,5-tetramethyl-2-(3-methyl-1-benzothiophen-6-yl)-1,3,2-dioxaborolane

[0269] To a reaction flask were added 6-chloro-3-methyl-1-benzothiophene (1 g, 5.47 mmol), pinacol diboron (1.95 g, 7.66 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (399 mg, 0.55 mmol), and potassium acetate (1.07 g, 10.95 mmol). The system was evacuated and replaced with nitrogen three times. 1,4-dioxane (5 mL) was added and the reaction was stirred at 100°C for 8 hours. The reaction system was cooled to room temperature, quenched with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by column chromatography to afford 4,4,5,5-tetramethyl-2-(3-methyl-1-benzothiophen-6-yl)-1,3,2-dioxaborolane (195 mg, yield: 13%).

[0270] Intermediate 14: Preparation of 4-bromo-2-chloro-1-(1-methylcyclopropyl)benzene

[0271] Step 1: Synthesis of 4-bromo-2-chloro-1-(prop-1-en-2-yl)benzene

[0272] To a reaction flask were added 4-bromo-2-chloro-1-iodobenzene (1 g, 3.15 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (582 mg, 3.47 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (230 mg, 0.32 mmol), and potassium phosphate (2.01 g, 9.45 mmol). The system was evacuated and replaced with nitrogen three times. 1,4-dioxane (6 mL) and water (2 mL) were added, and the mixture was heated to 95°C with stirring for 3 hours. The reaction system was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography to afford 4-bromo-2-chloro-1-(prop-1-en-2-yl)benzene (487 mg, yield: 67%).

[0273] Step 2: Synthesis of 4-bromo-2-chloro-1-(1-methylcyclopropyl)benzene

[0274] The reaction flask was evacuated and replaced with nitrogen three times, followed by the addition of dichloromethane (10 ml). The mixture was cooled to 0°C, followed by the addition of diethylzinc (533 mg, 4.32 mmol) and the dropwise addition of trifluoroacetic acid (492 mg, 4.32 mmol). The mixture was stirred at this temperature for 20 minutes before the addition of diiodomethane (1.16 g, 4.32 mmol). The reaction mixture was allowed to react for another 20 minutes before the addition of 4-bromo-2-chloro-1-(prop-1-en-2-yl)benzene (200 mg, 1.01 mmol) dropwise. The mixture was then allowed to warm to room temperature and allowed to react for 16 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride, and the pH was adjusted to neutral with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to yield 4-bromo-2-chloro-1-(1-methylcyclopropyl)benzene (420 mg, 79.20% yield). The crude product was used directly in the next reaction.

[0275] Intermediate 15: Preparation of 4-bromo-1-cyclopropyl-2-(trifluoromethyl)benzene

[0276] 1-Bromo-4-iodo-3-(trifluoromethyl)benzene (100 mg, 0.28 mmol), cyclopropylboronic acid (29 mg, 0.34 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (21 mg, 0.029 mmol), and potassium carbonate (118 mg, 0.85 mmol) were added to the reaction flask in sequence. The system was evacuated and replaced with nitrogen three times. 1,4-dioxane (5 mL) and water (1 mL) were added, and the reaction was heated to 90°C with stirring for 16 hours. The reaction system was cooled to room temperature, quenched with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to obtain 4-bromo-1-cyclopropyl-2-(trifluoromethyl)benzene (100 mg).

[0277] Intermediate 16: Preparation of 4-bromo-1-ethyl-2-(trifluoromethyl)benzene

[0278] 4-Bromo-1-ethyl-2-(trifluoromethyl)benzene can be prepared by referring to the preparation method of intermediate 15 and selecting appropriate reagents.

[0279] Intermediate 17: Preparation of 4-bromo-1-cyclopropyl-2-methylbenzene

[0280] 4-Bromo-1-cyclopropyl-2-methylbenzene can be prepared by referring to the preparation method of intermediate 15 and selecting appropriate reagents.

[0281] Intermediate 18: Preparation of 4-bromo-2,6-dichloro-1,1'-biphenyl

[0282] Step 1: Synthesis of 5-bromo-1,3-dichloro-2-iodobenzene

[0283] To a solution of 4-bromo-2,6-dichloroaniline (3 g, 12.45 mmol) in glacial acetic acid (15 mL) at 0°C were added sulfuric acid (10.99 g, 112.08 mmol), sodium nitrite (1.20 g, 17.43 mmol), and water (3 mL). The mixture was stirred at 0°C for 0.5 hours, followed by the addition of potassium iodide (2.27 g, 13.70 mmol) and urea (374 mg, 6.23 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The mixture was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography to yield 5-bromo-1,3-dichloro-2-iodobenzene (2.70 g, yield: 61.6%).

[0284] Step 2: Synthesis of 4-bromo-2,6-dichloro-1,1'-biphenyl

[0285] To the reaction flask were added 5-bromo-1,3-dichloro-2-iodobenzene (2.50 g, 5.33 mmol), phenylboronic acid (975 mg, 7.99 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (388 mg, 0.53 mmol), and potassium carbonate (2.21 g, 15.99 mmol). The system was evacuated and replaced with nitrogen three times. 1,4-dioxane (20 mL) and water (4 mL) were added, and the mixture was heated to 90°C with stirring for 5 hours. The reaction was cooled to room temperature, quenched with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified using a normal phase column to give 4-bromo-2,6-dichloro-1,1'-biphenyl (1.10 g, yield: 68%).

[0286] Intermediate 19: Preparation of 4-bromo-2-cyclopropyl-1-(trifluoromethyl)benzene

[0287] 4-Bromo-2-cyclopropyl-1-(trifluoromethyl)benzene can be prepared by referring to the preparation method of intermediate 15 and selecting appropriate reagents.

[0288] Intermediate 20: Preparation of 1-bromo-4-(cyclopropylmethyl)-benzene

[0289] Dissolve (4-bromophenyl)cyclopropyl ketone (500 mg, 2.22 mmol) in tetrahydrofuran (10 mL). Add borane tetrahydrofuran (6.01 mL, 6.01 mmol) at 0°C. Stir the mixture at 0°C for 0.5 hours, then warm to room temperature for 4 hours. Then, cool the mixture to 0°C and add boron trifluoride etherate (2.74 mL, 22.21 mmol). Warm the mixture again and warm to room temperature for 1 hour. Quench the reaction with water, extract the mixture with ethyl acetate, and wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and filter. The filtrate is concentrated, and the crude product is purified by column chromatography to yield 1-bromo-4-(cyclopropylmethyl)-benzene (240 mg, 51% yield).

[0290] Intermediate 21: Preparation of 1-bromo-4-(2,2-dimethylcyclopropyl)benzene

[0291] Step 1: Synthesis of 1-bromo-4-(2-methylprop-1-en-1-yl)benzene

[0292] Dissolve 4-bromobenzyl diethyl phosphite (200 mg, 1.01 mmol) in tetrahydrofuran (10 ml), cool to 0°C, add sodium hydride (188 mg, 7.81 mmol), and stir for 30 minutes. Then, add acetone (756 mg, 13.02 mmol), maintain the temperature, and continue to react for 30 minutes before warming to room temperature and stirring for 16 hours. The reaction is quenched with water and extracted with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated, and the crude product is purified by column chromatography to yield 1-bromo-4-(2-methylprop-1-en-1-yl)benzene (250 mg, yield: 18%).

[0293] Step 2: Synthesis of 1-bromo-4-(2,2-dimethylcyclopropyl)benzene

[0294] Diethylzinc (293 mg, 2.37 mmol) was added to dichloromethane (10 mL) at 0°C, followed by the dropwise addition of trifluoroacetic acid (270 mg, 2.37 mmol). The mixture was stirred for 20 minutes, followed by the addition of diiodomethane (634 mg, 2.37 mmol). The reaction was continued for another 20 minutes, followed by the dropwise addition of 1-bromo-4-(2-methylprop-1-en-1-yl)benzene (250 mg, 1.01 mmol). The mixture was allowed to warm to room temperature for 16 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution, and the pH was adjusted to neutral with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to afford 1-bromo-4-(2,2-dimethylcyclopropyl)benzene (180 mg, yield: 67.51%). The crude product was used directly in the next step.

[0295] Intermediate 22: Preparation of 1-bromo-4-(2-fluoropropan-2-yl)benzene

[0296] 2-(4-Bromophenyl)propan-2-ol (500 mg, 2.32 mmol) was dissolved in dichloromethane (4.50 mL) and a solution of DAST (749 mg, 4.65 mmol) in dichloromethane (500 μL) was added at -70 ° C. The mixture was stirred at -70 ° C for 1 hour and then warmed to room temperature for 16 hours. Sodium bicarbonate (1 mL) was added to the system to quench the reaction, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel chromatography to obtain 1-bromo-4-(2-fluoropropane-2-yl)benzene (220 mg, 43.6%) as a colorless oil.

[0297] Intermediate 23: Preparation of 1-bromo-4-(2,2-difluoro-1-methylcyclopropyl)benzene

[0298] To a reaction flask, 1-bromo-4-(prop-1-en-2-yl)benzene (1 g, 5.07 mmol), sodium iodide (152.11 mg, 1.01 mmol), and tetrahydrofuran (20 mL) were added sequentially. A solution of (trifluoromethyl)trimethylsilane (1.80 g, 12.69 mmol) in tetrahydrofuran was then added dropwise. The mixture was heated under reflux for 2 hours. The reaction mixture was cooled to room temperature, quenched with water, concentrated to remove most of the tetrahydrofuran, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to yield 1-bromo-4-(2,2-difluoro-1-methylcyclopropyl)benzene (780 mg, yield: 62.22%). The crude product was used directly in the next reaction.

[0299] Intermediate 24: Preparation of 5-bromo-2,2-dimethyl-2,3-dihydro-1H-indene

[0300] Step 1: Synthesis of 6-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-one

[0301] To a solution of 6-bromoindanone (3 g, 14.21 mmol) in THF (90 mL) at 0°C was added sodium hydride (1.42 g, 60%, 35.53 mmol). The mixture was stirred at room temperature for 30 minutes, then cooled to 0°C and iodomethane (5.04 g, 35.53 mmol) was added. The mixture was stirred at 25°C for 2 hours, then diluted with ethyl acetate (200 mL), washed sequentially with water (2 x 100 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel chromatography to afford 6-bromo-2,2-dimethyl-2,3-dihydro-1H-indan-1-one (3.10 g, yield: 91%).

[0302] Step 2: Synthesis of 5-bromo-2,2-dimethyl-2,3-dihydro-1H-indene

[0303] To a solution of 6-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-one (3.10 g, 12.96 mmol) in trifluoroacetic acid (75 mL) was added triethylsilane (3.77 g, 32.41 mmol) at room temperature. The mixture was stirred at 25°C for 16 hours, concentrated to remove volatile components, and then diluted with ethyl acetate (300 mL). The mixture was washed sequentially with sodium bicarbonate (3 x 100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel chromatography to yield 5-bromo-2,2-dimethyl-2,3-dihydro-1H-indene (2.20 g, 75% yield).

[0304] Intermediate 25: Preparation of 5-bromo-2-hydroxy-6-(propan-2-yl)pyridine-3-carbonitrile

[0305] 5-Bromo-2-hydroxy-6-(propan-2-yl)pyridine-3-carbonitrile can be prepared by referring to the preparation method of intermediate 7 and selecting appropriate reagents.

[0306] Intermediate 26: Preparation of 1-bromo-4-(2-methallyl)benzene

[0307] Dissolve (4-bromophenyl)cyclopropyl ketone (1 g, 4.44 mmol) in trifluoroacetic acid (10 mL). Add triethylsilane (1.03 g, 8.89 mmol) at 0°C. Warm the mixture to room temperature and stir for 16 hours. The reaction mixture was concentrated, and the crude product was purified by column chromatography to yield 1-bromo-4-(2-methallyl)benzene (330 mg, 35% yield).

[0308] Intermediate 27: Preparation of 3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one

[0309] 3-Hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one can be prepared by selecting appropriate reagents according to the preparation method of Intermediate 2. ESI-MS: 238.1[M+1] + .

[0310] Intermediate 28: Preparation of 1-ethyl-4-bromo-naphthalene

[0311] 1-Ethylnaphthalene (2 g, 12.80 mmol) was added to a reaction flask. The system was evacuated and replaced with nitrogen three times. Acetonitrile (25 mL) and N-bromosuccinimide (1.73 g, 15.36 mmol) were added sequentially. The mixture was heated to 40°C and stirred for 24 hours. The reaction system was cooled to room temperature, quenched with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified using a normal phase column to obtain 1-ethyl-4-bromo-naphthalene (2.6 g, yield: 86.38%) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ8.19-8.12(m,2H),7.79(d,J=7.6Hz,1H),7.70-7.63 (m,2H),7.29(d,J=7.6Hz,1H),3.05(q,J=7.6Hz,2H),1.28(t,J=7.6Hz,3H).

[0312] Intermediate 29: Preparation of 5-iodo-2-carbonyl-6-(trifluoromethyl)-1,2-dihydropyridine-3-carbonitrile

[0313] Step 1: Synthesis of 2-carbonyl-6-(trifluoromethyl)-1,2-dihydropyridine-3-carbonitrile

[0314] 2-Cyanoacetamide (1 g, 11.90 mmol), potassium carbonate (2.47 g, 17.84 mmol), and toluene (20 mL) were added to the reaction flask and stirred until uniform. (3E)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (2 g, 11.90 mmol) was then added and stirred at 110°C for 10 hours. The mixture was cooled to room temperature, filtered, and the filter cake was washed with toluene. The filter cake was collected and dried to yield 3.5 g of crude 2-carbonyl-6-(trifluoromethyl)-1,2-dihydropyridine-3-carbonitrile, which was used directly in the next reaction. ESI-MS: 189.0 [M+1] + .

[0315] Step 2: Synthesis of 5-iodo-2-carbonyl-6-(trifluoromethyl)-1,2-dihydropyridine-3-carbonitrile

[0316] Dissolve 2-carbonyl-6-(trifluoromethyl)-1,2-dihydropyridine-3-carbonitrile (300 mg, crude) in acetic acid (2 mL) and trifluoroacetic acid (40 uL), add N-iodosuccinimide (263.13 mg, 1.17 mmol), and stir at 100°C for 1 hour. Remove most of the acetic acid solvent by rotary evaporation, then add dichloromethane and saturated sodium thiosulfate aqueous solution for washing and extraction. The organic phase is washed with saturated brine, collected, dried, and concentrated to obtain 5-iodo-2-carbonyl-6-(trifluoromethyl)-1,2-dihydropyridine-3-carbonitrile (130 mg, crude). ESI-MS: 314.9 [M+1] + .

[0317] Intermediate 30: Preparation of 2-chloro-1-(1-fluorocyclopropyl)-4-iodobenzene

[0318] Step 1: Synthesis of methyl 4-{[(tert-butoxy)carbonyl]amino}-2-chlorobenzoate

[0319] Methyl 4-amino-2-chlorobenzoate (5 g, 26.94 mmol), acetonitrile (80 mL), triethylamine (8.18 g, 80.81 mmol), 4-dimethylaminopyridine (329 mg, 2.69 mmol), and di-tert-butyl dicarbonate (8.82 g, 40.41 mmol) were added to a reaction flask in sequence. The system was stirred at 25°C for 16 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to obtain methyl 4-{[(tert-butoxy)carbonyl]amino}-2-chlorobenzoate (6.07 g, yield: 78.86%).

[0320] Step 2: Synthesis of tert-butyl N-[3-chloro-4-(1-hydroxycyclopropyl)phenyl]carbamate

[0321] Methyl 4-{[(tert-butyloxy)carbonyl]amino}-2-chlorobenzoate (1 g, 3.50 mmol) was added to a reaction flask. The system was evacuated and replaced with nitrogen three times. Tetrahydrofuran (20 mL) was injected via syringe and the mixture was cooled to -10°C. Tetraisopropyl titanate (1.39 g, 4.90 mmol) and ethylmagnesium bromide (14 mL, 14 mmol, 1 M in THF) were added sequentially. The temperature was slowly raised to 25°C and stirred for 16 hours. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to afford tert-butyl N-[3-chloro-4-(1-hydroxycyclopropyl)phenyl]carbamate (410 mg, yield: 41.28%) as a light yellow solid.

[0322] Step 3: Synthesis of tert-butyl N-[3-chloro-4-(1-fluorocyclopropyl)phenyl]carbamate

[0323] To the reaction flask was added tert-butyl N-[3-chloro-4-(1-hydroxycyclopropyl)phenyl]carbamate (300 mg, 1.06 mmol), the system was evacuated and replaced with nitrogen three times, dichloromethane (5 mL) was injected using a syringe, the system was cooled to -70°C, diethylaminosulfur trifluoride (340 mg, 2.11 mmol) was added, and the mixture was stirred at -70°C for 1 hour. The mixture was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give tert-butyl N-[3-chloro-4-(1-fluorocyclopropyl)phenyl]carbamate (280 mg, crude product).

[0324] Step 4: Synthesis of 3-chloro-4-(1-fluorocyclopropyl)aniline

[0325] To the reaction flask, tert-butyl N-[3-chloro-4-(1-fluorocyclopropyl)phenyl]carbamate (280 mg, 980 μmol) was added. Ethyl acetate (5 mL) was injected using a syringe. A 4M hydrochloric acid ethyl acetate solution (3 mL, 12 mmol) was added. The mixture was heated to 40°C and stirred for 3 hours. The mixture was cooled to room temperature and concentrated to yield 3-chloro-4-(1-fluorocyclopropyl)aniline (280 mg, crude) as a yellow solid. ESI-MS: 186.1 [M+1] + .

[0326] Step 5: Synthesis of 2-chloro-1-(1-fluorocyclopropyl)-4-iodobenzene

[0327] 3-Chloro-4-(1-fluorocyclopropyl)aniline (280 mg, 905 μmol) was added to a reaction flask. Acetonitrile (2 mL) was injected using a syringe, followed by cuprous iodide (189 mg, 995 μmol), iodine (229 mg, 905 μmol), and tert-butyl nitrite (140 mg, 1.36 mmol). The mixture was heated to 80°C and stirred for 0.5 hours. The mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to afford 2-chloro-1-(1-fluorocyclopropyl)-4-iodobenzene (50 mg, yield: 18.63%).

[0328] Intermediate 31: Preparation of 6-(difluoromethyl)-5-iodo-2-carbonyl-1,2-dihydropyridine-3-carbonitrile

[0329] 6-(Difluoromethyl)-5-iodo-2-carbonyl-1,2-dihydropyridine-3-carbonitrile can be prepared by selecting appropriate reagents according to the preparation method of intermediate 29. ESI-MS: 212.9 [M+1] + .

[0330] Intermediate 32: Preparation of 3-(4-bromophenyl)bicyclo[3.1.0]hexane

[0331] Step 1: Synthesis of 1-bromo-4-(hept-1,6-dien-4-yl)benzene

[0332] Nitromethane (659.82 mg, 10.81 mmol) and dichloromethane (20 mL) were added sequentially to the reaction flask. The system was evacuated and replaced with nitrogen three times. Titanium tetrachloride (820.11 mg, 4.32 mmol) and p-bromobenzaldehyde (500 mg, 2.7 μmol) were added at -70°C. After stirring for 15 minutes, allyltrimethylsilane (926.33 mg, 8.11 mmol) was added dropwise. The reaction was maintained at -70°C for 4 hours and then warmed to room temperature for 8 hours. The reaction was quenched with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to provide 1-bromo-4-(hept-1,6-dien-4-yl)benzene (600 mg, yield: 88.40%). 1 H NMR (400MHz, CDCl3) δ7.42-7.36(m,2H),7.03-6.98(m,2H),5.65-5.55(m,2H) ,4.98-4.88(m,4H),2.73-2.61(m,1H),2.43-2.34(m,2H),2.33-2.23(m,2H).

[0333] Step 2: Synthesis of 1-bromo-4-(cyclopent-3-en-1-yl)benzene

[0334] To the reaction flask were added 1-bromo-4-(hept-1,6-dien-4-yl)benzene (600 mg, 2.39 mmol), dichloromethane (300 mL), and Grubbs second-generation catalyst (101.52 mg, 119.44 μmol) in sequence, stirred at room temperature for 16 hours, quenched with water, extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to give 1-bromo-4-(cyclopent-3-en-1-yl)benzene (350 mg, yield: 65.67%). 1 H NMR (400MHz, DMSO-d6) δ7.49-7.44(m,2H),7.23-7.18(m,2H),5.79(s,2H),3.49-3.37(m,1H),2.83-2.71(m,2H),2.37-2.25(m,2H).

[0335] Step 3: Synthesis of 3-(4-bromophenyl)bicyclo[3.1.0]hexane

[0336] To the reaction flask, diethylzinc (332.12 mg, 2.69 mmol) and dichloromethane (10 mL) were added sequentially. The system was evacuated and replaced with nitrogen three times. Trifluoroacetic acid (306.63 mg, 2.69 mol) was added dropwise at 0°C. After 20 minutes, diiodomethane (720.29 mg, 2.69 mmol) was added. Stirring was continued for 20 minutes before the addition of 1-bromo-4-(cyclopent-3-en-1-yl)benzene (150 mg, 672.31 μmol). The mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 3-(4-bromophenyl)bicyclo[3.1.0]hexane (120 mg).

[0337] Intermediate 33: Preparation of 4,4,5,5-tetramethyl-2-(3-methylbenzo[b]thiophen-4-yl)-1,3,2-dioxaborolane

[0338] 4,4,5,5-Tetramethyl-2-(3-methylbenzo[b]thiophen-4-yl)-1,3,2-dioxaborolane can be prepared by referring to the preparation method of intermediate 13 and selecting appropriate reagents.

[0339] Intermediate 34: Preparation of 6-bromo-3-chloro-1-benzothiophene

[0340] Step 1: Synthesis of 6-bromo-3-chloro-1-benzothiophene-2-carboxylic acid

[0341] 6-Bromo-1-benzothiophene-2-carboxylic acid (2 g, 7.78 mmol) was added to the reaction flask. The system was evacuated and replaced with nitrogen three times. Anhydrous tetrahydrofuran (30 mL) was added and cooled to -70°C. Lithium diisopropylamide (38.9 mL, 77.7 mmol, 2.0 M) was added. The reaction was stirred at -70°C for 1 hour. N-chlorosuccinimide (10.39 g, 77.79 mmol) was then slowly added. The reaction was continued for 1 hour. Saturated ammonium chloride solution was then added to quench the reaction. The reaction was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 6-bromo-3-chloro-1-benzothiophene-2-carboxylic acid (3.2 g, crude product). ESI-MS: 290.8 [M+1]. + .

[0342] Step 2: Synthesis of 6-bromo-3-chloro-1-benzothiophene

[0343] 6-Bromo-3-chloro-1-benzothiophene-2-carboxylic acid (2.45 g, 3.36 mmol), dimethyl sulfoxide (10 mL), and silver carbonate (927 mg, 3.36 mmol) were added to a reaction flask and heated to 120°C for 2 hours. The system was cooled to room temperature, quenched with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified using a normal phase column to obtain 6-bromo-3-chloro-1-benzothiophene (75 mg, yield: 9.01%) as a white solid.

[0344] Intermediate 35: Preparation of 1-tert-butyl-2-fluoro-4-iodobenzene

[0345] 1-tert-Butyl-2-fluoro-4-iodobenzene can be prepared by referring to the preparation method of intermediate 12 and selecting appropriate reagents.

[0346] Intermediate 36: Preparation of 1-bromo-4-(1,1,3,3,3-pentafluoroprop-1-en-2-yl)benzene

[0347] To the reaction flask, 1-(4-bromophenyl)-2,2,2-trifluoro-1-ethanone (1 g, 3.95 mmol), DMF (20 mL), CClF2COONa (732.61 mg, 4.74 mmol), and PPh3 (1.55 g, 1.32 mL, 5.93 mmol) were added sequentially. The system was evacuated and replaced with nitrogen three times, and heated to 100°C for 1 hour. The system was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to obtain 1-bromo-4-(1,1,3,3,3-pentafluoroprop-1-en-2-yl)benzene (500 mg, crude product).

[0348] Intermediate 37: Preparation of 1-bromo-4-(1,1-difluoroprop-1-en-2-yl)benzene

[0349] 1-Bromo-4-(1,1-difluoroprop-1-en-2-yl)benzene can be prepared by referring to the preparation method of intermediate 36 and selecting appropriate reagents.

[0350] Intermediate 38: Preparation of 6-bromo-2-(trifluoromethyl)-1-benzothiophene

[0351] Step 1: Synthesis of (6-bromo-1-benzothiophen-2-yl)boronic acid

[0352] 6-Bromobenzo[b]thiophene (1 g, 4.69 mmol) was added to a reaction flask. The system was evacuated and replaced with nitrogen three times. Anhydrous tetrahydrofuran (15 mL) was added and the mixture was cooled to -70°C. Lithium diisopropylamide (1.29 mL, 5.16 mmol, 2.0 M) was then added. After stirring at -70°C for 1 hour, triisopropyl borate (1.06 g, 5.63 mmol) was slowly added. The reaction was maintained at this temperature for two hours before concentrated sulfuric acid (920 mg, 9.39 mmol) was slowly added. The reaction was allowed to warm to room temperature and stirred for 2 hours. The mixture was cooled to 0°C and quenched with saturated sodium thiosulfate. The mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to afford (6-bromo-1-benzothiophen-2-yl)boronic acid (830 mg, yield: 68.84%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.56 (s, 2H), 8.26 (d, J = 1.6 Hz, 1H), 7.94 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.50 (dd, J = 8.4, 1.6 Hz, 1H).

[0353] Step 2: Synthesis of 6-bromo-2-(trifluoromethyl)-1-benzothiophene

[0354] To a reaction flask, (6-bromo-1-benzothiophen-2-yl)boronic acid (400 mg, 1.56 mmol), methanol / dichloromethane / water (5:5:4) (7 mL), sodium trifluoromethanesulfinate (729 mg, 4.67 mmol), cuprous chloride (154 mg, 1.56 mmol), and tert-butyl hydroperoxide (1.02 g, 7.94 mmol) were added sequentially. The mixture was stirred at room temperature for 2 hours. The mixture was cooled to 0°C, quenched with saturated ammonium chloride, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to afford 6-bromo-2-(trifluoromethyl)-1-benzothiophene (175 mg, yield: 39.99%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.49 (s, 1H), 8.15 (s, 1H), 7.97 (d, J = 8.4Hz, 1H), 7.69 (dd, J = 8.4, 1.6Hz, 1H).

[0355] Intermediate 39: Preparation of 6-bromo-3-chloro-2-methyl-1-benzothiophene

[0356] Step 1: Synthesis of 6-bromo-2-methylbenzothiophene

[0357] 6-Bromobenzothiophene (1.6 g, 7.51 mmol) was added to the reaction flask, the system was evacuated and replaced with nitrogen three times, anhydrous tetrahydrofuran (20 mL), cooled to -70 ° C, added lithium diisopropylamide (1.86 mL, 15.02 mmol), stirred at -70 ° C for 1 hour, and then slowly added iodomethane (9.59 g, 67.58 mmol). After the addition, the temperature was slowly raised to room temperature and stirred for 16 hours. Saturated ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 6-bromo-2-methylbenzothiophene (1.6 g, crude product, purity: 40%).

[0358] Step 2: Synthesis of 6-bromo-3-chloro-2-methyl-1-benzothiophene

[0359] 6-Bromo-2-methylbenzothiophene (200 mg, 880 μmol) was added to a reaction flask, followed by tetrahydrofuran (3 mL) and N-chlorosuccinimide (141 mg, 1.06 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to obtain 6-bromo-3-chloro-2-methyl-1-benzothiophene (70 mg, yield: 30.39%, purity: 83%) as a white solid.

[0360] Intermediate 40: Preparation of 4-bromo-2-methyl-1-(1-methylcyclopropyl)benzene

[0361] 4-Bromo-2-methyl-1-(1-methylcyclopropyl)benzene can be prepared by referring to the preparation method of intermediate 14 and selecting appropriate reagents.

[0362] Intermediate 41: Preparation of {2-[5-bromo-2-(1-methylcyclopropyl)phenyl]ethynyl}trimethylsilane

[0363] Step 1: Synthesis of 5-bromo-2-(prop-1-en-2-yl)aniline

[0364] To the reaction flask were added 5-bromo-2-iodoaniline (5 g, 16.78 mmol), potassium isopropenyl trifluoroborate (2.73 g, 18.46 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.23 g, 1.68 mmol), and cesium carbonate (10.94 g, 33.57 mmol). The system was evacuated and replaced with nitrogen three times, and then 1,4-dioxane (40 mL) and water (10 mL) were added. The reaction was heated to 70 ° C for 16 hours, cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to give 5-bromo-2-(prop-1-en-2-yl)aniline (1.60 g, yield: 44.95%) as a colorless oil. ESI-MS: 212.0 [M+1] + .

[0365] Step 2: Synthesis of 4-bromo-2-iodo-1-(prop-1-en-2-yl)benzene

[0366] To a reaction flask, 5-bromo-2-(prop-1-en-2-yl)aniline (2.10 g, 9.90 mmol), p-toluenesulfonic acid monohydrate (5.65 g, 29.70 mmol), and acetonitrile (20 mL) were added sequentially. The mixture was stirred at 0°C for 1 hour. A solution of potassium iodide (4.11 g, 24.75 mmol) and sodium nitrite (1.37 g, 19.80 mmol) in water (5 mL) was then added, and the mixture was stirred at 25°C for 16 hours. The reaction was quenched by the addition of saturated sodium thiosulfate solution, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to afford 4-bromo-2-iodo-1-(prop-1-en-2-yl)benzene (1.00 g, yield: 31.27%) as a colorless oil.

[0367] Step 3: Synthesis of 4-bromo-2-iodo-1-(1-methylcyclopropyl)benzene

[0368] The reaction flask was evacuated and replaced with nitrogen three times. Dichloromethane (10 ml) and diethylzinc (3.49 g, 28.24 mmol) were added. The mixture was cooled to 0°C and trifluoroacetic acid (3.22 g, 28.24 mmol) was added dropwise. After 20 minutes, diiodomethane (7.56 g, 28.24 mmol) was added. Stirring was continued for 20 minutes before the addition of 4-bromo-2-iodo-1-(prop-1-en-2-yl)benzene (2.28 g, 7.06 mmol). The mixture was allowed to warm to room temperature for 16 hours. The mixture was quenched with saturated aqueous ammonium chloride and the pH was adjusted to neutral with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to afford 4-bromo-2-iodo-1-(1-methylcyclopropyl)benzene (2.2 g, yield: 92.47%) as a colorless oil.

[0369] Step 4: Synthesis of {2-[5-bromo-2-(1-methylcyclopropyl)phenyl]ethynyl}trimethylsilane

[0370] To the reaction flask were added 4-bromo-2-iodo-1-(1-methylcyclopropyl)benzene (300 mg, 890.21 μmol), cuprous iodide (16.95 mg, 89.02 μmol), bistriphenylphosphine palladium dichloride (62.48 mg, 89.02 μmol), and N,N-dimethylformamide (8 mL) in sequence. The reaction flask was evacuated and replaced with nitrogen three times. Trimethylethynylsilane (113.67 mg, 1.16 mmol) was then added, and the mixture was reacted at 80°C for 0.5 h. The mixture was cooled to room temperature, quenched with water, and extracted with petroleum ether. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to give {2-[5-bromo-2-(1-methylcyclopropyl)phenyl]ethynyl}trimethylsilane (210 mg, yield: 76.76%) as a colorless oil.

[0371] Intermediate 42: Preparation of 5-bromo-3-cyclopropyl-1-benzothiophene

[0372] Step 1: Synthesis of methyl 3-amino-5-bromobenzothiophene-2-carboxylate

[0373] 5-Bromo-2-fluorobenzonitrile (2 g, 10 mmol) and N,N-dimethylformamide (15 mL) were added to the reaction flask. The system was evacuated and replaced with nitrogen three times. Methyl thioglycolate (1.11 g, 10.50 mmol) was added at 0°C. After 30 minutes, a solution of sodium hydroxide (599.97 mg, 15 mmol) in water (3 mL) was added. The reaction was continued for 30 minutes, then diluted with water and filtered. The filter cake was collected to yield methyl 3-amino-5-bromobenzothiophene-2-carboxylate (2.80 g, yield: 96.76%) as a white solid. The crude product was used directly in the next reaction. ESI-MS: 286.0 [M+1] + .

[0374] Step 2: Synthesis of methyl 5-bromo-3-iodo-1-benzothiophene-2-carboxylate

[0375] Methyl 3-amino-5-bromobenzo[b]thiophene-2-carboxylate (2 g, 10 mmol) and acetonitrile (30 mL) were added to a reaction flask. The system was evacuated and replaced with nitrogen three times. Iodine (1.11 g, 10.50 mmol) and tert-butyl nitrite (599.97 mg, 15 mmol) were added sequentially, and the mixture was stirred at 80°C for 0.5 hours. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to afford methyl 5-bromo-3-iodo-1-benzothiophene-2-carboxylate (3.2 g, yield: 92.25%) as a brown solid. The crude product was used directly in the next reaction.

[0376] Step 3: Synthesis of 5-bromo-3-iodo-1-benzothiophene-2-carboxylic acid

[0377] Methyl 5-bromo-3-iodo-1-benzothiophene-2-carboxylate (2.90 g, 7.30 mmol) and lithium hydroxide (524.82 mg, 21.91 mmol) were added to a reaction flask, followed by water (4 ml), tetrahydrofuran (8 ml), and methanol (8 ml). The system was evacuated and replaced with nitrogen three times. After stirring at 25°C for 3 hours, the solvent was removed by rotary evaporation and water (10 ml) was added. The filter cake was collected by filtration to obtain 5-bromo-3-iodo-1-benzothiophene-2-carboxylic acid (2.00 g, yield: 71.49%) as a green solid. The crude product was used directly in the next reaction. ESI-MS: 404.9 [M+1] + .

[0378] Step 4: Synthesis of 5-bromo-3-iodo-1-benzothiophene

[0379] To a reaction flask, 5-bromo-3-iodo-1-benzothiophene-2-carboxylic acid (1 g, 2.61 mmol), silver carbonate (719.97 mg, 2.61 mmol), and dimethyl sulfoxide (10 ml) were added sequentially and stirred at 100°C for 5 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with petroleum ether. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to afford 5-bromo-3-iodo-1-benzothiophene (500 mg, yield: 56.49%) as a pink solid, which was used directly in the next reaction. 1 H NMR (400MHz, CDCl3) δ7.92 (d, J = 1.9 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.64 (s, 1H), 7.49 (dd, J = 8.6, 1.9 Hz, 1H).

[0380] Step 5: Synthesis of 5-bromo-3-vinyl-1-benzothiophene

[0381] To a reaction flask were added 5-bromo-3-iodo-1-benzothiophene (150 mg, 442.49 μmol), pinacol vinyl borate (88.60 mg, 575.24 μmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (32.38 mg, 44.25 μmol), and potassium carbonate (183.47 mg, 1.33 mmol). The system was evacuated and replaced with nitrogen three times. 1,4-dioxane (5 mL) and water (0.5 mL) were then added. The reaction was heated to 80°C for 3 hours, cooled to room temperature, quenched with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using normal phase purification to afford 5-bromo-3-vinyl-1-benzothiophene (85 mg, yield: 80.33%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ8.04(d,J=1.8Hz,1H),7.71(d,J=8.5Hz,1H),7.48(s,1H),7.46(dd,J=8.6,1.9Hz ,1H),6.90(ddd,J=17.6,11.1,0.8Hz,1H),5.79(dd,J=17.6,1.2Hz,1H),5.41(dd,J=11.1,1.2Hz,1H).

[0382] Step 6: Synthesis of 5-bromo-3-cyclopropyl-1-benzothiophene

[0383] The reaction flask was evacuated and replaced with nitrogen three times. Dichloromethane (10 ml) and diethylzinc (175.59 mg, 1.42 mmol) were added sequentially. Trifluoroacetic acid (162.12 mg, 1.42 mmol) was added dropwise at 0°C. After 20 minutes, diiodomethane (543.62 mg, 2.03 mmol) was added. Stirring was continued for 20 minutes before the addition of 5-bromo-3-vinyl-1-benzothiophene (200 mg, 1.01 mmol). The mixture was stirred at room temperature for 16 hours. The reaction was quenched with saturated aqueous ammonium chloride and the pH was adjusted to neutral with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to afford 5-bromo-3-cyclopropyl-1-benzothiophene (60 mg, yield: 66.68%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ8.08(d,J=1.9Hz,1H),7.68(d,J=8.5Hz,1H),7.44(dd,J=8.6,1.8Hz,1 H), 6.99 (s, 1H), 1.98 (td, J = 8.4, 4.3Hz, 1H), 1.02-0.95 (m, 3H), 0.69 (p, J = 4.7, 4.1Hz, 2H).

[0384] Intermediate 43: Preparation of 4-bromo-2-cyclopropyl-1-ethylbenzene

[0385] Step 1: Synthesis of 4-bromo-1-ethyl-2-iodobenzene

[0386] To the reaction flask were added acetic acid (10 ml), acetic anhydride (5 ml), sodium periodate (1.86 g, 8.59 mmol), iodine (1.44 g, 5.67 mmol), and sulfuric acid (2 ml) in sequence. The mixture was stirred at room temperature for 10 minutes, and 4-bromoethylbenzene (3 g, 16.21 mmol) was added. The mixture was reacted at room temperature for 2 hours, quenched with ice water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to obtain 4-bromo-1-ethyl-2-iodobenzene (4 g, yield: 79.35%) as a yellow oil. The crude product was used directly in the next reaction.

[0387] Step 2: Synthesis of 4-bromo-2-cyclopropyl-1-ethylbenzene

[0388] To the reaction flask were added 4-bromo-1-ethyl-2-iodobenzene (1 g, 3.22 mmol), cyclopropylboronic acid (359.11 mg, 4.18 mmol), potassium carbonate (1.33 g, 9.65 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (234.34 mg, 321.58 μmol) in sequence. The system was evacuated and replaced with nitrogen three times. 1,4-dioxane (10 mL) and water (2 mL) were then added. The mixture was heated to 90 °C for 16 hours, cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to give 4-bromo-2-cyclopropyl-1-ethylbenzene (500 mg, yield: 69.06%) as a yellow oil. The crude product was used directly in the next reaction.

[0389] Intermediate 44: Preparation of 5'-bromo-2',3'-dihydrospiro[cyclopropano-1,1'-indene]

[0390] Step 1: Synthesis of 5-bromo-1-methylidene-2,3-dihydro-1H-indene

[0391] 5-Bromoindanone (1 g, 4.74 mmol) and methyltriphenylphosphonium bromide (2.54 g, 7.11 mmol) were dissolved in THF (5 mL). Potassium tert-butoxide (797.47 mg, 7.11 mL) was added at 0°C and allowed to react at room temperature for 16 hours. The reaction was quenched by adding saturated ammonium chloride solution, extracted with ethyl acetate, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated, and the crude product was purified by normal phase column chromatography to obtain 5-bromo-1-methylidene-2,3-dihydro-1H-indene (800 mg, yield: 80.75%) as a colorless oil.

[0392] Step 2: Synthesis of 5'-bromo-2',3'-dihydrospiro[cyclopropane-1,1'-indene]

[0393] Under nitrogen, diethylzinc (2.36 g, 19.13 mL, 19.13 mmol) and DCM (40 mL) were added to a reaction flask. Trifluoroacetic acid (2.18 g, 1.42 mL, 19.12 mmol) was added at 0°C. After 0.5 hour, diiodomethane (5.12 g, 1.54 mL, 19.13 mmol) was added and stirring continued for 0.5 hour. 5-Bromo-1-methylene-2,3-dihydro-1H-indene (1 g, 4.78 mmol) was then added. The mixture was reacted at 0°C for 0.5 hour and then at room temperature for 16 hours. The reaction was quenched by addition of saturated Na2S2O3 solution, extracted with DCM, and dried over anhydrous sodium sulfate. The product was filtered, concentrated, and the crude product was purified by normal phase column chromatography to afford 5'-bromo-2',3'-dihydrospiro[cyclopropano-1,1'-indene] (900 mg, yield: 84.34%).

[0394] Intermediate 45: Preparation of 5-bromo-3-chloro-1-benzothiophene

[0395] 5-Bromo-3-chloro-1-benzothiophene can be prepared by partially referring to the preparation method of intermediate 42 and selecting appropriate reagents.

[0396] Intermediate 46: Preparation of 4-bromo-2-chloro-1-(cyclopent-3-en-1-yl)benzene

[0397] 4-Bromo-2-chloro-1-(cyclopent-3-en-1-yl)benzene can be prepared by partially referring to the preparation method of Intermediate 32 and selecting appropriate reagents.

[0398] Intermediate 47: Preparation of 5-bromo-2-cyclopropyl-1,1'-biphenyl

[0399] Step 1: Synthesis of 2-amino-5-bromobiphenyl

[0400] Dissolve o-aminobiphenyl (5 g, 29.55 mmol) in N,N-dimethylformamide (50 mL) and add N-bromosuccinimide (5.52 g, 31.02 mmol) at 0°C. Maintain the reaction at 0°C for 2 hours. The mixture is diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated and the crude product is purified by normal phase column chromatography to yield 2-amino-5-bromobiphenyl (6.30 g, yield: 85.94%). ESI-MS: 248.1 [M+1] + .

[0401] Step 2: Synthesis of 5-bromo-2-iodo-1,1'-biphenyl

[0402] To a solution of 2-amino-5-bromobiphenyl (6.30 g, 25.39 mmol) in acetonitrile (50 mL) was added p-toluenesulfonic acid monohydrate (14.49 g, 76.17 mmol) at 0°C. The mixture was stirred at 0°C for 1 hour. Then, an aqueous solution of sodium nitrite (3.50 g, 50.78 mmol) and potassium iodide (10.54 g, 63.48 mmol) was added dropwise. After warming to room temperature and reacting for 16 hours, the mixture was quenched with a saturated solution of sodium thiosulfate, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated, and the crude product was purified by normal phase column chromatography to give 5-bromo-2-iodo-1,1'-biphenyl (7.20 g, yield: 78.99%).

[0403] Step 3: Synthesis of 5-bromo-2-cyclopropyl-1,1'-biphenyl

[0404] Under nitrogen, 5-bromo-2-iodo-1,1'-biphenyl (1 g, 2.79 mmol), cyclopropylboronic acid (1.20 g, 13.93 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (203.82 mg, 278.55 μmol), and potassium carbonate (1.15 g, 8.36 mmol) were added sequentially to a reaction flask. 1,4-dioxane and 1,4-dioxane were then added, and the mixture was heated to 100°C for 16 hours. After cooling to room temperature, the mixture was directly concentrated to obtain the crude product, which was purified by normal phase column chromatography to afford 5-bromo-2-cyclopropyl-1,1'-biphenyl (350 mg, 46% yield).

[0405] Intermediate 48: Preparation of 5-bromo-1-chloro-3-fluoro-2-(1-methylcyclopropyl)benzene

[0406] 5-Bromo-1-chloro-3-fluoro-2-(1-methylcyclopropyl)benzene can be prepared by referring to the preparation method of intermediate 14 and selecting appropriate reagents. 1 H NMR (400MHz, DMSO-d6) δ7.58-7.56(m,1H),7.54(dd,J=9.6,2.0Hz,1H),1.25(s,3H),0.88-0.82(m,2H),0.80-0.76(m,2H).

[0407] Intermediate 49: Preparation of 5-bromo-3-(trifluoromethyl)-1-benzothiophene

[0408] Step 1: Synthesis of 1-(5-bromo-2-fluorophenyl)-2,2,2-trifluoroethanone

[0409] Dissolve 4-bromofluorobenzene (5 g, 28.57 mmol) in tetrahydrofuran (50 mL). Add lithium diisopropylamide (15.71 mL, 31.43 mmol) at -78°C and stir for 1 hour. Then, add a solution of ethyl trifluoroacetate (4.47 g, 31.43 mmol) in tetrahydrofuran (50 mL) dropwise. After addition, slowly warm the mixture to room temperature and stir for 16 hours. Pour the mixture into saturated ammonium chloride (100 mL) and extract with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated and dried over a normal phase column to obtain 1-(5-bromo-2-fluorophenyl)-2,2,2-trifluoroethanone (3 g, yield: 38.74%) as a yellow oil.

[0410] Step 2: Synthesis of methyl 5-bromo-3-(trifluoromethyl)-1-benzothiophene-2-carboxylate

[0411] 1-(5-Bromo-2-fluorophenyl)-2,2,2-trifluoroethanone (1 g, 3.69 mmol) was dissolved in dimethyl sulfoxide (20 mL), and methyl thioglycolate (391 mg, 0.33 mmol) and triethylamine (260 mg, 0.77 mmol) were added sequentially. The mixture was heated to 80°C and reacted for 7 hours. After cooling to room temperature, the mixture was poured into water (50 mL) and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain methyl 5-bromo-3-(trifluoromethyl)-1-benzothiophene-2-carboxylate (1.17 g, yield: 93.5%) as a crude product.

[0412] Step 3: Synthesis of 5-bromo-3-(trifluoromethyl)-1-benzothiophene-2-carboxylic acid

[0413] Methyl 5-bromo-3-(trifluoromethyl)-1-benzothiophene-2-carboxylate (1.17 g, 3.45 mmol) was dissolved in tetrahydrofuran (15 mL), and water (10 mL) was added, followed by lithium hydroxide monohydrate (217 mg, 5.18 mmol). The mixture was stirred at room temperature for 1 hour. The tetrahydrofuran was removed and the mixture was diluted with water. 2M dilute hydrochloric acid was added to adjust the pH to 1-2. A large amount of solid precipitated. The filter cake was collected by filtration and dried to obtain 5-bromo-3-(trifluoromethyl)-1-benzothiophene-2-carboxylic acid (1.10 g, yield: 98.07%).

[0414] Step 4: Synthesis of 5-bromo-3-(trifluoromethyl)-1-benzothiophene

[0415] 5-Bromo-3-(trifluoromethyl)-1-benzothiophene-2-carboxylic acid (1 g, 3.08 mmol), silver carbonate (848 mg, 3.08 mmol), and dimethyl sulfoxide (8 mL) were added to the reaction flask in sequence, heated to 120 ° C. for 0.5 hour, quenched with water, extracted with petroleum ether, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to give 5-bromo-3-(trifluoromethyl)-1-benzothiophene (654 mg, yield: 75.64%) as a white solid.

[0416] Intermediate 50: Preparation of 4-bromo-2-chloro-1-(1,1,1-trifluoro-2-methylpropan-2-yl)benzene

[0417] Step 1: Synthesis of 2-(4-bromo-2-chlorophenyl)-1,1,1-trifluoropropane-2-ol

[0418] (Trifluoromethyl)trimethylsilane (913.53 mg, 6.42 mmol) was dissolved in tetrahydrofuran (10 mL). Tetrabutylammonium fluoride (27.99 mg, 107.07 μmol) and 1-(4-bromo-2-chlorophenyl)ethanone (500 mg, 2.14 mmol) were added sequentially at 0°C. The mixture was allowed to react at room temperature for 16 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was filtered, concentrated, and purified using a normal phase column to obtain 2-(4-bromo-2-chlorophenyl)-1,1,1-trifluoropropan-2-ol (520 mg, yield: 80.01%).

[0419] Step 2: Synthesis of 2-(4-bromo-2-chlorophenyl)-1,1,1-trifluoropropane-2-yl methanesulfonate

[0420] 2-(4-Bromo-2-chlorophenyl)-1,1,1-trifluoropropan-2-ol (450 mg, 1.48 mmol) was dissolved in tetrahydrofuran (10 mL). Sodium hydride (118.62 mg, 60%, 2.97 mmol) was added at 0°C and heated to 40°C for 1 hour. MsCl (339.66 mg, 2.97 mmol) was then added and the reaction was maintained at 40°C for 4 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The product was filtered, and the filtrate was concentrated and purified using a normal phase column to afford 2-(4-bromo-2-chlorophenyl)-1,1,1-trifluoropropan-2-yl methanesulfonate (425 mg, yield: 75.12%).

[0421] Step 3: Synthesis of 4-bromo-2-chloro-1-(1,1,1-trifluoro-2-methylpropane-2-yl)benzene

[0422] 2-(4-Bromo-2-chlorophenyl)-1,1,1-trifluoropropan-2-yl methanesulfonate (350 mg, 917.21 μmol) was dissolved in dichloromethane (15 mL). Trimethylaluminum (132.24 mg, 1.83 mmol) was added at 0°C and stirred at room temperature for 2 hours. The mixture was cooled to 0°C and quenched with water. Extraction was performed with dichloromethane, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtering and concentration of the filtrate were followed by purification using a normal phase column and then a reverse phase preparative column to afford 4-bromo-2-chloro-1-(1,1,1-trifluoro-2-methylpropan-2-yl)benzene (250 mg, yield: 90.39%).

[0423] Intermediate 51: Preparation of 5-bromo-1-benzothiophene-3-carbonitrile

[0424] 5-Bromo-3-iodo-1-benzothiophene (240 mg, 707.99 μmol) and zinc cyanide (99.74 mg, 849.58 μmol) were added to an 8 mL sample bottle. The system was evacuated and replaced with nitrogen three times. N,N-dimethylformamide (2 mL) was then added and the reaction was stirred at 60°C for 5 hours. After cooling to room temperature, the mixture was quenched with water and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column to obtain 5-bromo-1-benzothiophene-3-carbonitrile (150 mg, crude product, yield: 88.98%).

[0425] Intermediate 52: Preparation of 5-bromo-1-benzothiophene-3-carboxamide

[0426] 5-Bromo-1-benzothiophene-3-carbonitrile (100 mg, 419.99 μmol) was dissolved in dimethyl sulfoxide (2 mL). Hydrogen peroxide (95.23 mg, 30%, 25.74 μL, 839.98 μmol) and potassium carbonate (116.09 mg, 839.98 μmol) were added sequentially and reacted at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated to give the crude product 5-bromo-1-benzothiophene-3-carboxamide (110 mg), which was used directly in the next reaction.

[0427] Intermediate 53: Preparation of [1-(4-bromo-2-chlorophenyl)cyclopropyl]methanol

[0428] Step 1: Synthesis of methyl 1-(4-bromo-2-chlorophenyl)cyclopropane-1-carboxylate

[0429] 1,2-Dibromoethane (5.24 g, 27.89 mmol) and methyl 2-(4-bromo-2-chlorophenyl) acetate (4.90 g, 18.59 mmol) were dissolved in N,N-dimethylformamide (80 mL), cesium carbonate (18.18 g, 55.78 mmol) was added, and the mixture was heated to 150 ° C and stirred for 8 hours. After cooling to room temperature, the system was poured into water (100 mL) and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to obtain methyl 1-(4-bromo-2-chlorophenyl)cyclopropane-1-carboxylate (1.32 g, yield: 24.52%) as a yellow solid.

[0430] Step 2: Synthesis of [1-(4-bromo-2-chlorophenyl)cyclopropyl]methanol

[0431] Methyl 1-(4-bromo-2-chlorophenyl)cyclopropane-1-carboxylate (100 mg, 345 μmol) was dissolved in tetrahydrofuran (3 mL), cooled to 0°C, and lithium aluminum hydride (165 μL, 414 μmol, 2.50 M in THF) was added. The mixture was allowed to warm to room temperature and react for 1 hour. The mixture was poured into water (5 mL) and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to provide [1-(4-bromo-2-chlorophenyl)cyclopropyl]methanol (90 mg, crude product).

[0432] Intermediate 54: Preparation of 2-[1-(4-bromo-2-chlorophenyl)cyclopropyl]acetonitrile

[0433] Step 1: Synthesis of [1-(4-bromo-2-chlorophenyl)cyclopropyl]methyl methanesulfonate

[0434] [1-(4-bromo-2-chlorophenyl)cyclopropyl]methanol (200 mg, 764 μmol) was dissolved in dichloromethane (5 mL), cooled to 0°C, and triethylamine (154 mg, 1.53 mmol) and methanesulfonyl chloride (96 mg, 841 μmol) were added sequentially. The mixture was warmed to room temperature and reacted for 2 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to obtain [1-(4-bromo-2-chlorophenyl)cyclopropyl]methyl methanesulfonate (114 mg, yield: 43.89%).

[0435] Step 2: Synthesis of 2-[1-(4-bromo-2-chlorophenyl)cyclopropyl]acetonitrile

[0436] [1-(4-bromo-2-chlorophenyl)cyclopropyl]methyl methanesulfonate (45 mg, 132 μmol) was dissolved in acetonitrile (3 mL), and trimethylsilyl cyanide (26 mg, 265 μmol) and tetrabutylammonium fluoride (265 μL, 265 μmol, 1 M in THF) were added. The mixture was heated to 80°C for 6 hours. The mixture was poured into water (5 mL) and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 2-[1-(4-bromo-2-chlorophenyl)cyclopropyl]acetonitrile (35 mg, crude product).

[0437] Intermediate 55: Preparation of N-[5-bromo-2-(1-methylcyclopropyl)phenyl]acetamide

[0438] Step 1: Synthesis of N-[5-bromo-2-(prop-1-en-2-yl)phenyl]acetamide

[0439] 5-Bromo-2-(prop-1-en-2-yl)aniline (300 mg, 1.41 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (429.40 mg, 4.24 mmol) and acetyl chloride (122.14 mg, 111.04 μL, 1.56 mmol) were added sequentially at 0°C and allowed to react at room temperature for 16 hours. The reaction solution was evaporated to remove the solvent, and 10 mL of saturated ammonium chloride and 10 mL of dichloromethane were added. The mixture was separated and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain N-[5-bromo-2-(prop-1-en-2-yl)phenyl]acetamide (320 mg, yield: 89.02%). The crude product was used directly in the next reaction. ESI-MS: 254.1 [M+1]. + .

[0440] Step 2: Synthesis of N-[5-bromo-2-(1-methylcyclopropyl)phenyl]acetamide

[0441] Diethylzinc (320.74 mg, 2.60 mmol) and dichloromethane (10 ml) were added sequentially to the reaction flask. Trifluoroacetic acid (296.12 mg, 2.60 mmol) was added dropwise at 0°C. After 20 minutes, diiodomethane (695.61 mg, 2.60 mmol) was added. Stirring was continued for 20 minutes, followed by the addition of N-[5-bromo-2-(prop-1-en-2-yl)phenyl]acetamide (220 mg, 1.01 mmol). The reaction was allowed to react at room temperature for 16 hours. The reaction was quenched with saturated aqueous ammonium chloride and the pH was adjusted to neutral with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to afford N-[5-bromo-2-(1-methylcyclopropyl)phenyl]acetamide (210 mg, yield: 90.46%) as a yellow solid. ESI-MS: 268.1 [M+1] + .

[0442] Intermediate 56: Preparation of 5-bromo-1-(fluoromethylidene)-2,3-dihydro-1H-indene

[0443] 5-Bromo-1-(fluoromethylidene)-2,3-dihydro-1H-indene can be prepared by selecting appropriate reagents according to the preparation method of intermediate 44, and the product is an E / Z mixture.

[0444] Intermediate 57: Preparation of 5-bromo-3-chloro-1-benzothiophene-2-carbonitrile

[0445] Step 1: Synthesis of 5-bromo-3-chloro-1-benzothiophene-2-carboxamide

[0446] To a reaction flask, 5-bromo-3-chloro-1-benzothiophene-2-carboxylic acid (1.50 g, 5.15 mmol), N,N-dimethylformamide (37 mg, 514 μmol), and dichloromethane (5 mL) were added sequentially. The mixture was cooled to 0°C and oxalyl chloride (849 mg, 6.69 mmol) was added. After 15 minutes, the mixture was warmed to room temperature and reacted for 2 hours. The mixture was then cooled to 0°C and ammonia (2.89 g, 82.32 mmol) was added. The mixture was returned to room temperature and the reaction continued for 2 hours. The mixture was filtered and washed with a mixed solvent of ethyl acetate and methanol (1:1 V / V). The filtrate was dried and concentrated to give 5-bromo-3-chloro-1-benzothiophene-2-carboxamide (720 mg, yield: 48.16%).

[0447] Step 2: Synthesis of 5-bromo-3-chloro-1-benzothiophene-2-carbonitrile

[0448] 5-Bromo-3-chloro-1-benzothiophene-2-carboxamide (200 mg, 0.68 mmol) and pyridine (82 mg, 1.03 mmol) were dissolved in dichloromethane (5 mL), cooled to 0 ° C, trifluoromethanesulfonic anhydride (173 mg, 0.82 mmol) was slowly added, and the mixture was heated to 25 ° C and stirred for 1 hour. The mixture was quenched with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to give 5-bromo-3-chloro-1-benzothiophene-2-carbonitrile (100 mg, yield: 53.31%) as a yellow solid.

[0449] Intermediate 58: Preparation of 4-bromo-2-methoxy-1-(1-methylcyclopropyl)benzene

[0450] 4-Bromo-2-methoxy-1-(1-methylcyclopropyl)benzene can be prepared by selecting appropriate reagents according to the preparation method of Intermediate 44. Intermediate 59: Preparation of 4-Bromo-1-(1-methylcyclopropyl)-2-(trifluoromethyl)benzene

[0451] 4-Bromo-1-(1-methylcyclopropyl)-2-(trifluoromethyl)benzene was prepared by selecting appropriate reagents according to the preparation method of Intermediate 44.

[0452] Intermediate 60: Preparation of 2,4-dibromo-1-(prop-1-en-2-yl)benzene

[0453] 2,4-Dibromo-1-(prop-1-en-2-yl)benzene can be prepared by referring to the preparation method of intermediate 14 and selecting appropriate reagents.

[0454] Intermediate 61: Preparation of 1-(4-bromo-2-chlorophenyl)cyclopropane-1-carboxamide

[0455] Step 1: Synthesis of 1-(4-bromo-2-chlorophenyl)cyclopropane-1-carboxylic acid

[0456] Methyl 1-(4-bromo-2-chlorophenyl)cyclopropane-1-carboxylate (1 g, 3.45 mmol) was dissolved in methanol (5 mL), THF (5 mL), and water (2.5 mL). Lithium hydroxide monohydrate (290 mg, 6.91 mmol) was added and allowed to react at room temperature for 16 hours. The mixture was concentrated and adjusted to pH 2 with 1N dilute hydrochloric acid. The solid was filtered and dried under reduced pressure to yield 1-(4-bromo-2-chlorophenyl)cyclopropane-1-carboxylic acid (882 mg, yield: 93%). ESI-MS: 274.9 [M+1] + .

[0457] Step 2: Synthesis of 1-(4-bromo-2-chlorophenyl)cyclopropane-1-carboxamide

[0458] Dissolve 1-(4-bromo-2-chlorophenyl)cyclopropane-1-carboxylic acid (500 mg, 1.81 mmol) in dichloromethane (5 mL). Add oxalyl chloride (414 mg, 3.27 mmol) and N,N-dimethylformamide (13 mg, 181 μmol) at 0°C. Warm the mixture to room temperature for 1 hour, then cool the temperature to 0°C, add ammonia (2.70 g, 77 mmol), and warm the mixture to room temperature again for 2 hours. Quench the mixture with water and extract with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to yield 1-(4-bromo-2-chlorophenyl)cyclopropane-1-carboxamide (480 mg, crude) as a yellow solid. ESI-MS: 274.0 [M+1] + .

[0459] Intermediate 62: Preparation of 4-bromo-2-chloro-1-[1-(methoxymethyl)cyclopropyl]benzene

[0460] [1-(4-Bromo-2-chlorophenyl)cyclopropyl]methanol (150 mg, 573.53 μmol) was dissolved in N,N-dimethylformamide (3 ml). Sodium hydroxide (20.65 mg, 860.29 μmol) and iodomethane (162.81 mg, 1.15 mmol) were added sequentially and allowed to react at room temperature for 16 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to obtain 4-bromo-2-chloro-1-[1-(methoxymethyl)cyclopropyl]benzene (150 mg, yield: 94.91%).

[0461] Intermediate 63: Preparation of 5-bromo-1-benzothiophene-3-amine

[0462] 5-Bromo-1-benzothiophene-3-amine can be prepared by partially referring to the preparation method of intermediate 49 and selecting appropriate reagents.

[0463] Intermediate 64: Preparation of 5-iodo-6-methyl-2-carbonyl-4-(trifluoromethyl)-1,2-dihydropyridine-3-carbonitrile

[0464] To a reaction flask, 2-hydroxy-6-methyl-4-(trifluoromethyl)pyridine-3-carbonitrile (1 g, 4.95 mmol), N-iodosuccinimide (1.45 g, 6.43 mmol), dichloromethane (10 mL), and trifluoroacetic acid (10 mL) were added and stirred at 40°C for 16 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified using a normal phase column to afford 5-iodo-6-methyl-2-carbonyl-4-(trifluoromethyl)-1,2-dihydropyridine-3-carbonitrile (600 mg, yield: 36.97%).

[0465] Intermediate 65: Preparation of 5-bromo-4-ethyl-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile

[0466] Step 1: 4-ethyl-2-hydroxy-6-methylnicotinonitrile

[0467] To a reaction flask were added hex-3-yn-2-one (2 g, 20.81 mmol), 2-cyanoacetamide (2.1 g, 24.94 mmol), ethanol (20 mL), piperidine (431 mg, 5.06 mmol), and acetic acid (375 mg, 6.24 mmol) in sequence. The mixture was heated at 90°C for 16 hours. The reaction solution was concentrated and added to water (20 mL) to precipitate a solid. The solid was collected by filtration, washed with acetonitrile (15 mL), and dried to yield 4-ethyl-2-hydroxy-6-methylnicotinonitrile (2.16 g, yield: 64.01%).

[0468] Step 2: Synthesis of 5-bromo-4-ethyl-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile

[0469] 4-Ethyl-2-hydroxy-6-methylnicotinonitrile (500 mg, 3.08 mmol) was dissolved in 1,2-dichloroethane (10 mL), and N-bromosuccinimide (823 mg, 4.62 mmol) was added. The reaction mixture was heated to 90°C for 2 hours. The mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate. The organic phase was washed with saturated sodium thiosulfate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to provide 5-bromo-4-ethyl-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile (650 mg, yield: 74%).

[0470] Intermediate 66: Preparation of 5-bromo-1,3-difluoro-2-(1-methylcyclopropyl)benzene

[0471] 5-Bromo-1,3-difluoro-2-(1-methylcyclopropyl)benzene can be prepared by referring to the preparation method of intermediate 44 and selecting appropriate reagents.

[0472] Intermediate 67: Preparation of 4-chloro-5-iodo-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile

[0473] 4-Chloro-5-iodo-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile can be prepared by referring to the preparation method of intermediate 64 and selecting appropriate reagents.

[0474] Intermediate 68: Preparation of {[1-(4-bromo-2-chlorophenyl)cyclopropyl]methyl}dimethylamine

[0475] Step 1: Synthesis of 1-(4-bromo-2-chlorophenyl)cyclopropane-1-carbaldehyde

[0476] Dissolve oxalyl chloride (145.60 mg, 1.15 mmol) in dichloromethane (10 ml). Add dimethyl sulfoxide (119.49 mg, 1.53 mmol) at -78°C. After 30 minutes, add [1-(4-bromo-2-chlorophenyl)cyclopropyl]methanol (200 mg, 764.70 μmol). Continue the reaction for 0.5 hour, then add triethylamine (0.64 mL). Maintain the reaction at -78°C for 30 minutes, then slowly warm to room temperature. Quench the reaction by adding saturated sodium bicarbonate solution, and extract with dichloromethane. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 1-(4-bromo-2-chlorophenyl)cyclopropane-1-carbaldehyde (190 mg, yield: 95.74%). The crude product is used directly in the next reaction.

[0477] Step 2: Synthesis of {[1-(4-bromo-2-chlorophenyl)cyclopropyl]methyl}dimethylamine

[0478] 1-(4-Bromo-2-chlorophenyl)cyclopropane-1-carbaldehyde (100 mg, 385.31 μmol) was dissolved in dichloromethane (5 mL). Dimethylamine (34.75 mg, 770.62 μmol) and sodium acetate borohydride (244.99 mg, 1.16 mmol) were added sequentially and stirred at room temperature for 16 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to obtain {[1-(4-bromo-2-chlorophenyl)cyclopropyl]methyl}dimethylamine (100 mg, yield: 89.92%). ESI-MS: 288.0 [M+1] + .

[0479] Intermediate 69: Preparation of 2-[1-(4-bromo-2-chlorophenyl)cyclopropyl]acetamide

[0480] 2-[1-(4-bromo-2-chlorophenyl)cyclopropyl]acetamide can be prepared by referring to the preparation method of intermediate 52 and selecting appropriate reagents.

[0481] Intermediate 70: Preparation of methyl 2-[1-(4-bromo-2-chlorophenyl)cyclopropyl]acetate

[0482] 2-[1-(4-bromo-2-chlorophenyl)cyclopropyl]acetonitrile (200 mg, 740 μmol) and 4M methanolic hydrochloric acid solution (3 mL, 12 mmol) were added sequentially to the reaction flask, and the mixture was heated to 80°C and stirred for 16 hours. The mixture was concentrated, saturated sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified using a normal phase column to obtain methyl 2-[1-(4-bromo-2-chlorophenyl)cyclopropyl]acetate (55 mg, yield: 24.51%).

[0483] Intermediate 71: Preparation of {[1-(4-bromo-2-chlorophenyl)cyclopropyl]methyl}(methyl)amine

[0484] {[1-(4-bromo-2-chlorophenyl)cyclopropyl]methyl}(methyl)amine can be prepared by referring to the preparation method of Intermediate 68 and selecting appropriate reagents.

[0485] Intermediate 72: Preparation of 4-bromo-2-methylsulfonyl-1-(1-methylcyclopropyl)benzene

[0486] Step 1: Synthesis of 1-[4-bromo-2-(methylsulfanyl)phenyl]ethan-1-one

[0487] Sodium methanethiolate (19.54 g, 55.75 mmol, 20% concentration) and N,N-dimethylformamide (120 mL) were added to the reaction flask in sequence. The system was cooled to -45°C, 1-(4-bromo-2-fluorophenyl)ethanone (12.10 g, 55.75 mmol) was added, and the temperature was raised to 25°C. Stirring was continued for 3 hours. The system was then poured into ice water to quench the reaction, filtered, and the solid collected and concentrated to yield 1-[4-bromo-2-(methylsulfanyl)phenyl]ethan-1-one (12.79 g, 93.59% yield) as an off-white solid.

[0488] Step 2: Synthesis of 4-bromo-2-(methylsulfanyl)-1-(prop-1-en-2-yl)benzene

[0489] Methyltriphenylphosphonium bromide (21.40 g, 59.91 mmol) was dissolved in tetrahydrofuran (60 mL), cooled to 0°C, and potassium tert-butoxide (59.91 mL, 59.91 mmol, 1 M in THF) was added. The mixture was stirred at 0°C for 1 hour. 1-[4-bromo-2-(methylsulfanyl)phenyl]ethan-1-one (9.79 g, 39.94 mmol) was then added, and the temperature was slowly raised to 25°C and stirred for 16 hours. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to provide 4-bromo-2-(methylsulfanyl)-1-(prop-1-en-2-yl)benzene (8.23 g, yield: 84.75%).

[0490] Step 3: Synthesis of 4-bromo-2-methylsulfonyl-1-(prop-1-en-2-yl)benzene

[0491] 4-Bromo-2-(methylsulfanyl)-1-(prop-1-en-2-yl)benzene (4 g, 16.45 mmol) was dissolved in dichloromethane (5 mL) under vacuum. m-Chloroperbenzoic acid (4.26 g, 24.68 mmol) was added and stirred at room temperature for 1 hour. m-Chloroperbenzoic acid (1.42 g, 8.23 ​​mmol) was added again and stirred at 25°C for 12 hours. The mixture was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to obtain 4-bromo-2-methylsulfonyl-1-(prop-1-en-2-yl)benzene (3.6 g, yield: 79.53%) as an off-white solid. ESI-MS: 275.0 [M+1] + .

[0492] Step 4: 4-Bromo-2-methylsulfonyl-1-(1-methylcyclopropyl)benzene

[0493] Diethylzinc (538 mg, 4.36 mmol) and dichloromethane (5 mL) were added to the reaction flask in sequence. The mixture was cooled to 0°C, and trifluoroacetic acid (497 mg, 4.36 mmol) was added. After stirring for 0.5 hours, diiodomethane (1.17 g, 4.36 mmol) was added. After stirring for another 0.5 hours, 4-bromo-2-methylsulfonyl-1-(prop-1-en-2-yl)benzene (200 mg, 0.72 mmol) was added. The temperature was raised to 25°C and stirred for 16 hours. The mixture was quenched with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to obtain 4-bromo-2-methylsulfonyl-1-(1-methylcyclopropyl)benzene (720 mg, yield: 71.36%).

[0494] Intermediate 73: Preparation of 5-bromo-N,N-dimethyl-2-(1-methylcyclopropyl)aniline

[0495] Step 1: N-[5-bromo-2-(prop-1-en-2-yl)phenyl]-2,2,2-trifluoroacetamide

[0496] 5-Bromo-2-(prop-1-en-2-yl)aniline (1.64 g, 7.73 mmol) and triethylamine (2.35 g, 23.20 mmol) were dissolved in dichloromethane (10 mL). Trifluoroacetic anhydride (1.95 g, 9.28 mmol) was added under ice bath, and the mixture was stirred at room temperature for 16 hours. The mixture was quenched with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to give N-[5-bromo-2-(prop-1-en-2-yl)phenyl]-2,2,2-trifluoroacetamide (2 g, yield: 83.95%).

[0497] Step 2: N-[5-bromo-2-(1-methylcyclopropyl)phenyl]-2,2,2-trifluoroacetamide

[0498] Diethylzinc (962.10 mg, 7.79 mmol) was mixed with dichloromethane (10 mL). Trifluoroacetic acid (888.18 mg, 7.79 mmol) was added at 0°C. After 30 minutes, diiodomethane (2.09 g, 7.79 mmol) was added. Stirring was continued for 30 minutes, and N-[5-bromo-2-(prop-1-en-2-yl)phenyl]-2,2,2-trifluoroacetamide (600 mg, 1.95 mmol) was added. The mixture was slowly warmed to room temperature and stirred for 16 hours. The mixture was quenched with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to give N-[5-bromo-2-(1-methylcyclopropyl)phenyl]-2,2,2-trifluoroacetamide (200 mg, yield: 31.88%). 1 H NMR (400MHz, CDCl3) δ8.77(s,1H),7.30(dd,J=8.0,2.0Hz,1H),7.22(d,J=8.0Hz,1H),1.31(s,3H),0.92-0.87(m,2H),0.86-0.81(m,2H).

[0499] Step 3: Synthesis of 5-bromo-2-(1-methylcyclopropyl)aniline

[0500] N-[5-Bromo-2-(1-methylcyclopropyl)phenyl]-2,2,2-trifluoroacetamide (200 mg, 620.87 μmol) was dissolved in methanol (10 mL) and water (1 mL). Potassium carbonate (171.62 mg, 70.63 μL, 1.24 mmol) was added and the mixture was heated to 80°C and stirred for 16 hours. The mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified using a normal phase column and then a reverse phase preparative column to obtain 5-bromo-2-(1-methylcyclopropyl)aniline (200 mg, yield: 71.23%). ESI-MS: 226.0 [M+1] + .

[0501] Step 4: 5-Bromo-N,N-dimethyl-2-(1-methylcyclopropyl)aniline

[0502] 5-Bromo-2-(1-methylcyclopropyl)aniline (200 mg, 884.49 μmol) was dissolved in N,N-dimethylformamide (5 mL), and potassium carbonate (366.73 mg, 2.65 mmol) and iodomethane (753.26 mg, 35.31 mmol) were added sequentially. The reaction was heated to 40°C for 16 hours, cooled to room temperature, quenched with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified using a normal phase column and then a reverse phase preparative column to obtain 5-bromo-N,N-dimethyl-2-(1-methylcyclopropyl)aniline (130 mg, yield: 57.83%). ESI-MS: 254.1 [M+1] + .

[0503] Intermediate 74: Preparation of 4-bromo-2-(difluoromethyl)-1-(1-methylcyclopropyl)benzene

[0504] Step 1: 4-Bromo-2-(difluoromethyl)-1-iodobenzene

[0505] Dissolve 5-bromo-2-iodobenzaldehyde (2 g, 6.43 mmol) in dichloromethane (20 mL), cool to -70°C, add diethylaminosulfur trifluoride (2.07 g, 12.87 mmol), and heat to 25°C before stirring for 16 hours. Quench with saturated sodium bicarbonate and extract with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated and purified using a normal phase column to afford 4-bromo-2-(difluoromethyl)-1-iodobenzene (1.55 g, yield: 72.38%).

[0506] The second and third steps can be carried out by selecting appropriate reagents according to the preparation method of intermediate 14 to obtain 4-bromo-2-(difluoromethyl)-1-(1-methylcyclopropyl)benzene.

[0507] Intermediate 75: Preparation of N-{2-[1-(4-bromo-2-chlorophenyl)cyclopropyl]ethyl}acetamide

[0508] Step 1: Synthesis of 2-[1-(4-bromo-2-chlorophenyl)cyclopropyl]ethane-1-amine

[0509] 2-[1-(4-bromo-2-chlorophenyl)cyclopropyl]acetonitrile (500 mg, 1.85 mmol) was dissolved in tetrahydrofuran (2 mL). Borane dimethyl sulfide complex (1.85 mL, 3.70 mmol, 2 M in THF) was added at 0°C and the system was heated to 60°C with stirring for 2 hours. After cooling to room temperature, the system was poured into methanol (10 mL) and concentrated under reduced pressure. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 2-[1-(4-bromo-2-chlorophenyl)cyclopropyl]ethan-1-amine (540 mg, crude) as a yellow solid.

[0510] Step 2: Synthesis of N-{2-[1-(4-bromo-2-chlorophenyl)cyclopropyl]ethyl}acetamide

[0511] 2-[1-(4-bromo-2-chlorophenyl)cyclopropyl]ethan-1-amine (150 mg, 546 μmol) was dissolved in dichloromethane (3 mL). Triethylamine (110 mg, 1.09 mmol) and acetyl chloride (85 mg, 1.09 mmol) were added sequentially at 0°C. The mixture was allowed to warm to room temperature and reacted for 2 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to provide N-{2-[1-(4-bromo-2-chlorophenyl)cyclopropyl]ethyl}acetamide (150 mg, crude product).

[0512] Intermediate 76: Preparation of N-{[1-(4-bromo-2-chlorophenyl)cyclopropyl]methyl}acetamide

[0513] Step 1: Synthesis of 2-(4-bromo-2-chloro-phenyl)-cyclopropanecarbonitrile

[0514] Cyclopropanecarbonitrile (1.60 g, 23.87 mmol) and 4-bromo-2-chloro-1-fluorobenzene (5 g, 23.87 mmol) were dissolved in toluene (50 ml), and potassium bis(trimethylsilyl)amide (5.71 g, 28.65 mmol) was added at 0°C. The mixture was heated to 60°C and stirred for 0.5 hour, then quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to give 2-(4-bromo-2-chloro-phenyl)-cyclopropanecarbonitrile (650 mg, yield: 10.61%) as a brown solid.

[0515] Step 2: 1-[1-(4-bromo-2-chlorophenyl)cyclopropyl]methanamine

[0516] 2-(4-Bromo-2-chloro-phenyl)-cyclopropanecarbonitrile (600 mg, 2.34 mmol) was dissolved in tetrahydrofuran (2 ml), and borane tetrahydrofuran (402.01 mg, 4.68 mmol) was added at 0°C. After stirring at 75°C for 1 hour, water was added to the reaction solution and 1N hydrochloric acid solution was added to adjust the pH to 1. The reaction mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give 1-[1-(4-bromo-2-chlorophenyl)cyclopropyl]methanamine (600 mg, yield: 998.45%) as a yellow solid. ESI-MS: 242.9 [M+1] + .

[0517] Step 3: Synthesis of N-{[1-(4-bromo-2-chlorophenyl)cyclopropyl]methyl}acetamide

[0518] 1-[1-(4-bromo-2-chlorophenyl)cyclopropyl]methanamine (200 mg, 767.58 μmol) was dissolved in dichloromethane (10 ml). Triethylamine (116.51 mg, 1.15 mmol) and acetyl chloride (90.38 mg, 1.15 mmol) were added sequentially under ice-cooling. After stirring at room temperature for 1 hour, saturated sodium bicarbonate was added to quench the reaction. The mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give N-{[1-(4-bromo-2-chlorophenyl)cyclopropyl]methyl}acetamide (200 mg, yield: 86.11%). ESI-MS: 302.0 [M+1]. + .

[0519] Intermediate 77: Preparation of 1-(4-bromo-2,6-difluoro-phenyl)-cyclopropanecarbonitrile

[0520] Step 1: Synthesis of 2-(4-bromo-2,6-difluorophenyl)acetonitrile

[0521] 5-Bromo-2-(bromomethyl)-1,3-difluorobenzene (5 g, 17.49 mmol) was dissolved in ethanol (30 mL) and water (10 mL). Potassium cyanide (1.2 g, 19.23 mmol) was added and heated to 60°C for 3 hours. The mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography to yield 2-(4-bromo-2,6-difluorophenyl)acetonitrile (2.20 g, yield: 54.22%).

[0522] Step 2: Synthesis of 1-(4-bromo-2,6-difluoro-phenyl)-cyclopropanecarbonitrile

[0523] 2-(4-Bromo-2,6-difluorophenyl)acetonitrile (600 mg, 2.59 mmol) was dissolved in toluene (1.5 mL). Sodium hydroxide (2.55 g, 2.55 mL, 63.75 mmol, 24.6521 mmol, 25 M), benzyltriethylammonium chloride (147.25 mg, 646.50 μmol), and 1-bromo-2-chloroethane (741.71 mg, 428.74 μL, 5.17 mmol) were added sequentially at 0°C. The mixture was stirred at 40°C for 18 hours, cooled to room temperature, diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography to afford 1-(4-bromo-2,6-difluorophenyl)-cyclopropanecarbonitrile (600 mg, 89.91% yield).

[0524] Intermediate 78: Preparation of 2-[1-(4-bromo-2-chlorophenyl)cyclopropyl]ethan-1-ol

[0525] Step 1: Synthesis of 2-[1-(4-bromo-2-chlorophenyl)cyclopropyl]acetaldehyde

[0526] Dissolve 2-[1-(4-bromo-2-chlorophenyl)cyclopropyl]acetonitrile (500 mg, 1.85 mmol) in dichloromethane (5 mL), cool to -78°C, add diisobutylaluminum hydride (3.7 mL, 3.70 mmol, 1 M in THF), slowly warm to 25°C, and stir for 2 hours. Pour the mixture into ice water (10 mL) and extract with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to give 2-[1-(4-bromo-2-chlorophenyl)cyclopropyl]acetaldehyde (440 mg).

[0527] Step 2: Synthesis of 2-[1-(4-bromo-2-chlorophenyl)cyclopropyl]ethan-1-ol

[0528] 2-[1-(4-bromo-2-chlorophenyl)cyclopropyl]acetaldehyde (500 mg, 1.83 mmol) was dissolved in methanol (3 mL). Sodium borohydride (138 mg, 3.66 mmol) was added at 0°C and the mixture was stirred at room temperature for 1 hour. The mixture was poured into water (10 mL) and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified using a normal phase column to obtain 2-[1-(4-bromo-2-chlorophenyl)cyclopropyl]ethan-1-ol (480 mg, yield: 95.4%).

[0529] Intermediate 79: Preparation of 2-(4-bromo-2,6-difluorophenyl)-2-methylpropionitrile

[0530] 2-(4-bromo-2,6-difluorophenyl)acetonitrile (300 mg, 1.29 mmol) was dissolved in N,N-dimethylformamide (5 mL), sodium hydride (157.68 mg, 60%, 3.94 mmol) was added at 0°C, stirred at room temperature for 0.5 hours, cooled to 0°C, and iodomethane (551.70 mg, 241.97 μL, 3.89 mmol) was added. The mixture was allowed to warm to room temperature and reacted for 18 hours. Ethyl acetate was added to dilute, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography to give 2-(4-bromo-2,6-difluorophenyl)-2-methylpropionitrile (200 mg, yield 59.47%).

[0531] Intermediate 80: Preparation of 2-(4-bromo-2-chloro-phenyl)-cyclopropanecarbonitrile

[0532] 2-(4-Bromo-2-chloro-phenyl)-cyclopropanecarbonitrile can be prepared by partially referring to the preparation method of intermediate 57 by selecting appropriate reagents.

[0533] Intermediate 81: Preparation of 2-[3-chloro-5-fluoro-4-(1-methylcyclopropyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0534] To a reaction flask were added 5-bromo-1-chloro-3-fluoro-2-(1-methylcyclopropyl)benzene (100 mg, 379.46 μmol), pinacol diboron (125.27 mg, 493.30 μmol), potassium acetate (111.72 mg, 1.14 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (55.53 mg, 75.89 μmol), and 1,4-dioxane (2 mL). The mixture was heated to 80°C and stirred for 16 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to afford 2-[3-chloro-5-fluoro-4-(1-methylcyclopropyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (110 mg, yield: 77.78%).

[0535] Intermediate 82: Preparation of 5-bromo-1,3-dichloro-2-(1-methylcyclopropyl)benzene

[0536] 5-Bromo-1,3-dichloro-2-(1-methylcyclopropyl)benzene can be prepared by partially referring to the preparation methods of intermediates 12 and 14 and selecting appropriate reagents.

[0537] Intermediate 83: Preparation of 6-chloro-5-iodo-2-carbonyl-1,2-dihydropyridine-3-carbonitrile

[0538] Step 1: Synthesis of 6-chloro-5-iodo-2-methoxypyridine-3-carbonitrile

[0539] 6-Chloro-2-methoxy-3-pyridinecarbonitrile (700 mg, 4.15 mmol) was dissolved in dichloromethane (10 mL). N-iodosuccinimide (1.40 g, 6.23 mmol) and trifluoroacetic acid (2 mL) were added sequentially. The mixture was heated to 40°C and stirred for 16 hours. The mixture was diluted with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to obtain 6-chloro-5-iodo-2-methoxypyridine-3-carbonitrile (200 mg, yield: 16.36%). ESI-MS: 294.9 [M+1] + .

[0540] Step 2: Synthesis of 6-chloro-5-iodo-2-carbonyl-1,2-dihydropyridine-3-carbonitrile

[0541] Dissolve 6-chloro-5-iodo-2-methoxypyridine-3-carbonitrile (250 mg, 848.95 μmol) in dichloromethane (2 mL). Add boron tribromide (1.06 g, 4.24 mmol) in an ice bath. Warm the mixture to room temperature and stir for 16 hours. Filter, wash with dichloromethane, and dry the solid to obtain 6-chloro-5-iodo-2-carbonyl-1,2-dihydropyridine-3-carbonitrile (130 mg, yield: 54.60%). ESI-MS: 280.9 [M+1] + .

[0542] Intermediate 84: Preparation of 4-tert-butyl-3,5-difluorophenyltrifluoromethanesulfonic acid

[0543] Step 1: Synthesis of 4-(1,1-dimethylethyl)-3,5-difluorophenol

[0544] 3,5-Difluorophenol (1 g, 7.69 mmol) was dissolved in methyl tert-butyl ether (1.36 g, 15.37 mmol), and zirconium tetrachloride (1.79 g, 7.69 mmol) was added in batches, maintaining the temperature between 35-40°C, and then stirred at room temperature for 16 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to obtain 4-(1,1-dimethylethyl)-3,5-difluorophenol (1.10 g, yield: 76.85%).

[0545] Step 2: Synthesis of 4-tert-butyl-3,5-difluorophenyltrifluoromethanesulfonic acid

[0546] 4-(1,1-Dimethylethyl)-3,5-difluorophenol (1 g, 5.37 mmol) was dissolved in dichloromethane (10 ml), and triethylamine (1.09 g, 10.74 mmol) and trifluoromethanesulfonic anhydride (1.82 g, 6.44 mmol) were added dropwise at 0°C, followed by stirring at room temperature for 16 hours. The mixture was quenched with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to obtain 4-tert-butyl-3,5-difluorophenyltrifluoromethanesulfonic acid (800 mg, yield: 46.80%) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.25 (d, J = 9.8Hz, 2H), 1.91 (t, J = 2.4Hz, 9H).

[0547] Intermediate 85: Preparation of 4-bromo-2-chloro-1-[1-(fluoromethyl)cyclobutyl]benzene

[0548] Dissolve [1-(4-bromo-2-chlorophenyl)cyclopropyl]methanol (300 mg, 1.15 mmol) in dichloromethane (5 ml), cool to -78°C, add diethylaminosulfur trifluoride (369.79 mg, 2.29 mmol), slowly warm to room temperature, and stir for 3 hours. Quench with ice water, extract with dichloromethane, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate and purify it using a normal phase column to obtain 4-bromo-2-chloro-1-[1-(fluoromethyl)cyclobutyl]benzene (170 mg, yield: 56.24%).

[0549] Intermediate 86: Preparation of 1-[4-bromo-2-(difluoromethyl)-6-fluorophenyl]cyclopropane-1-carbonitrile

[0550] Step 1: Synthesis of 5-bromo-1-(difluoromethyl)-2,3-difluorobenzene

[0551] To a solution of 5-bromo-2,3-difluorobenzaldehyde (3.0 g, 13.57 mmol) in dichloromethane (50 mL) was added diethylaminosulfur trifluoride (6.56 g, 40.72 mmol) at -70°C, and the mixture was stirred and allowed to react for half an hour at 0°C. The reaction solution was poured into water, extracted with dichloromethane, washed with aqueous sodium bicarbonate, dried, and concentrated in vacuo to afford crude 5-bromo-1-(difluoromethyl)-2,3-difluorobenzene (2.80 g, 84.88% yield), which was used directly in the next step. 1 H NMR (400MHz, CDCl3) δ7.60-7.39 (m, 2H), 6.85 (t, J = 54.4Hz, 1H).

[0552] Step 2: Synthesis of methyl 2-[4-bromo-2-(difluoromethyl)-6-fluorophenyl]-2-cyanoacetate

[0553] To a solution of methyl 2-cyanoacetate (917.50 mg, 819.20 μL, 9.26 mmol) and 5-bromo-1-(difluoromethyl)-2,3-difluorobenzene (1.50 g, 6.17 mmol) in N,N-dimethylformamide (30 mL) was added potassium carbonate (2.56 g, 1.05 mL, 18.52 mmol), followed by stirring at 80°C for 4 hours. The mixture was poured into saturated aqueous ammonium chloride, extracted with ethyl acetate, washed with water and brine, dried, and concentrated in vacuo to obtain a residue. The crude product was purified by flash silica gel column eluting with 30% ethyl acetate / petroleum ether. A mixture of methyl 2-[4-bromo-2-(difluoromethyl)-6-fluorophenyl]-2-cyanoacetate and methyl 2-[5-bromo-3-(difluoromethyl)-2-fluorophenyl]-2-cyanoacetate was obtained as a colorless oil (1.20 g, yield: 30.18%).1 H NMR (400MHz, CDCl3) δ7.88-7.77(m,1H),7.55(d,J=8.1Hz,1H),6.84(td,J=54.3,29.8Hz,1H),5.25(s,1H),5.03(s,1H),3.90(d,J=2.1Hz,3H).

[0554] Step 3: Synthesis of 2-[4-bromo-2-(difluoromethyl)-6-fluorophenyl]acetonitrile

[0555] Methyl 2-[5-bromo-3-(difluoromethyl)-2-fluorophenyl]-2-cyanoacetate (1.20 g, 1.86 mmol) was added to dimethyl sulfoxide (20 mL), followed by lithium chloride (1.58 g, 37.26 mmol), and the mixture was stirred at 80°C for 4 hours. The mixture was poured into saturated aqueous ammonium chloride, extracted with ethyl acetate, washed with water and brine, dried, and concentrated in vacuo to obtain a residue, which was purified on a flash silica gel column using 0-30% ethyl acetate / petroleum ether. This afforded a mixture of 2-[4-bromo-2-(difluoromethyl)-6-fluorophenyl]acetonitrile and 2-[5-bromo-3-(difluoromethyl)-2-fluorophenyl]acetonitrile as a colorless oil (700 mg, 71.15% yield). 1 H NMR (400MHz, DMSO-d6) δ7.96 (dd, J=9.5, 1.8Hz, 1H), 7.87 (dd, J=15.2, 6.1Hz, 1 H),7.73(s,1H),7.26(td,J=53.8,25.6Hz,2H),4.16(s,1H),4.13-4.08(m,2H).

[0556] Step 4: Synthesis of 1-[4-bromo-2-(difluoromethyl)-6-fluorophenyl]cyclopropane-1-carbonitrile

[0557] To a solution of 2-[4-bromo-2-(difluoromethyl)-6-fluorophenyl]acetonitrile and 2-[5-bromo-3-(difluoromethyl)-2-fluorophenyl]acetonitrile (6600 mg, 1.14 mmol) in toluene (7 mL) were added benzyltriethylammonium chloride (51.76 mg, 227.23 μmol), 1-bromo-2-chloroethane (88.81 mg, 282.55 μL, 3.41 mmol), and sodium hydroxide (2.27 g, 56.81 mmol) dissolved in 2 mL of aqueous solution. The mixture was then stirred at 40°C for 4 hours. Thin-layer chromatography indicated consumption of the starting material and the formation of a new spot. The mixture was poured into water, extracted with ethyl acetate, washed with water and brine, dried, and concentrated in vacuo to yield a residue, which was purified by flash silica gel column chromatography using 0-30% ethyl acetate / petroleum ether as the eluent. A colorless oily product, 1-[4-bromo-2-(difluoromethyl)-6-fluorophenyl]cyclopropane-1-carbonitrile (90 mg, yield: 27.31%), was obtained. 1 H NMR (400MHz, CDCl3) δ7.62 (s, 1H), 7.43 (dd, J = 9.2, 1.9Hz, 1H), 7.06 (t, J = 54.3Hz, 1H), 1.90-1.83 (m, 2H), 1.45-1.40 (m, 2H).

[0558] Intermediate 87: Preparation of 4-bromo-2-chloro-1-[1-(fluoromethyl)cyclopropyl]benzene

[0559] Step 1: Synthesis of 4-bromo-2-chloro-1-(3-fluoroprop-1-en-2-yl)benzene

[0560] To a solution of 4-bromo-2-chloro-1-(prop-1-en-2-yl)benzene (4 g, 17.28 mmol) in N,N-dimethylformamide (80 mL) was added 1-fluoro-4-methyl-1,4-diazabicyclo[2.2.2]octane tetrafluoroborate (6.73 g, 19 mmol), and the mixture was stirred at 100°C for 1 hour. The mixture was diluted with ethyl acetate, washed with water and brine, dried, and concentrated in vacuo to afford the crude product, which was purified on a flash silica gel column to afford 4-bromo-2-chloro-1-(3-fluoroprop-1-en-2-yl)benzene (3.20 g, 74.23% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.57(d,J=2.0Hz,1H),7.39(dd,J=8.2,2.0Hz,1H),7.13(d,J=8.1Hz,1H), 5.62(dq,J=2.7,1.4Hz,1H),5.30(t,J=1.0Hz,1H),5.15(t,J=1.1Hz,1H),5.03(t,J=1.1Hz,1H).

[0561] Step 2: Synthesis of 3-(4-bromo-2-chlorophenyl)-3-(fluoromethyl)-4,5-dihydro-3h-pyrazole

[0562] N-Nitroso-N-methylurea (2.07 g, 20.04 mmol) was suspended in diethyl ether (50 mL). Aqueous potassium hydroxide (2.25 g, 40.08 mmol) was added at 0°C. After the solid dissolved, the aqueous layer was separated and the ether layer was dried over KOH to obtain diazomethane. This diazomethane solution was then added to a solution of 4-bromo-2-chloro-1-(3-fluoroprop-1-en-2-yl)benzene (1 g, 4.01 mmol) in diethyl ether and stirred at room temperature for 16 hours. The mixture was concentrated in vacuo to a residue, which was purified on a flash silica gel column to afford 3-(4-bromo-2-chlorophenyl)-3-(fluoromethyl)-4,5-dihydro-3h-pyrazole as a colorless oil (480 mg, 41.08% yield). 1 H NMR (400MHz, CDCl3) δ7.91(d,J=8.5Hz,1H),7.61(d,J=2.1Hz,1H),7.44(dd,J=8.6,2.1Hz,1H),5.00-4.80(m,2H),4.79-4.71( m,1H),4.52(ddd,J=17.6,9.2,7.9Hz,1H),2.51(dddd,J=13.1,9.3,3.7,1.3Hz,1H),1.82(dddd,J=13.1,10.3,7.7,2.7Hz,1H).

[0563] Step 3: Synthesis of 4-bromo-2-chloro-1-[1-(fluoromethyl)cyclopropyl]benzene

[0564] A solution of 3-(4-bromo-2-chlorophenyl)-3-(fluoromethyl)-4,5-dihydro-3h-pyrazole (200 mg, 685.99 μmol) in xylene (2 mL) was stirred at 150° C. for 6 hours. The mixture was concentrated in vacuo to a residue, which was purified by preparative thin-layer chromatography to give 4-bromo-2-chloro-1-[1-(fluoromethyl)cyclopropyl]benzene (150 mg, 82.97% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.46 (d, J=2.0Hz, 1H), 7.28 (dd, J=8.2, 2.0Hz, 1H), 7.21-7.1 8(m,1H),4.38(s,1H),4.26(s,1H),0.98(tt,J=4.3,2.5Hz,2H),0.91-0.86(m,2H).

[0565] Intermediate 88: Preparation of 5-bromo-1,3-difluoro-2-(1-methoxycyclopropyl)benzene

[0566] Step 1: Synthesis of 1-(4-bromo-2,6-difluorophenyl)cyclopropane-1-ol

[0567] Methyl 4-bromo-2,6-difluorobenzoate (1 g, 3.98 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to -10°C, and tetraisopropyl titanate (1.67 mL, 5.58 mmol) and ethylmagnesium bromide (13.94 mL, 13.94 mmol, 1 M in tetrahydrofuran) were added. After stirring for 1 hour, the mixture was slowly warmed to room temperature and reacted for 16 hours. The mixture was poured into saturated ammonium chloride (20 mL) and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to obtain 1-(4-bromo-2,6-difluorophenyl)cyclopropane-1-ol (168 mg, crude product) as a colorless oil.

[0568] Step 2: Synthesis of 5-bromo-1,3-difluoro-2-(1-methoxycyclopropyl)benzene

[0569] 1-(4-Bromo-2,6-difluorophenyl)cyclopropane-1-ol (280 mg, 1.12 mmol) was dissolved in 1,4-dioxane (5 mL). Tetrabutylammonium bromide (362 mg, 1.12 mmol), potassium hydroxide (252 mg, 4.50 mmol), and iodomethane (478 mg, 3.37 mmol) were added sequentially to the system. The mixture was heated to 80°C and stirred for 4 hours. After cooling, the reaction solution was poured into water (8 mL) and extracted with ethyl acetate. The organic phase was washed four times with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 5-bromo-1,3-difluoro-2-(1-methoxycyclopropyl)benzene (275 mg). The crude product was used directly in the next reaction.

[0570] Intermediate 89: Preparation of 1-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)phenyl]cyclopropane-1-carbonitrile

[0571] Step 1: Methyl 2-cyano-2-[2-fluoro-6-(trifluoromethyl)phenyl]acetate

[0572] To a reaction flask were added 2,3-difluorobenzotrifluoride (5 g, 27.46 mmol), potassium carbonate (11.39 g, 82.38 mmol), methyl cyanoacetate (2.99 g, 30.20 mmol), and N,N-dimethylformamide (70 mL) in that order. The mixture was heated to 90°C for 16 hours. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified using a normal phase column to afford methyl 2-cyano-2-[2-fluoro-6-(trifluoromethyl)phenyl]acetate (2.1 g, yield: 29.28%). 1 H NMR (400MHz, CDCl3) δ7.59 (q, J = 3.4Hz, 2H), 7.42 (ddd, J = 9.6, 5.9, 3.6Hz, 1H), 5.12 (s, 1H), 3.89 (s, 3H).

[0573] Step 2: Synthesis of methyl 2-cyano-2-(2-fluoro-6-(trifluoromethyl)phenyl)acetate

[0574] Methyl 2-cyano-2-[2-fluoro-6-(trifluoromethyl)phenyl]acetate (2.10 g, 8.04 mmol) was dissolved in dimethyl sulfoxide (10 mL) and water (5 mL). Lithium chloride (6.82 g, 160.81 mmol) was added and heated to 140°C for 2 hours. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified using a normal phase column to obtain methyl 2-cyano-2-(2-fluoro-6-(trifluoromethyl)phenyl)acetate (1.5 g, yield: 91.84%). 1 H NMR (400MHz, CDCl3) δ7.58-7.47(m,2H),7.42-7.35(m,1H),3.88-3.85(m,2H).

[0575] Step 3: Synthesis of 1-[2-fluoro-6-(trifluoromethyl)phenyl]cyclopropane-1-carbonitrile

[0576] Methyl 2-cyano-2-(2-fluoro-6-(trifluoromethyl)phenyl)acetate (800 mg, 3.94 mmol) was dissolved in toluene (12 mL). 1-Bromo-2-chloroethane (1.13 g, 7.88 mmol) and benzyltriethylammonium chloride (224.25 mg, 984.54 μmol) were added sequentially. Aqueous sodium hydroxide (3.15 g, 78.76 mmol) (5 mL) was added dropwise under an ice bath. After addition, the mixture was heated to 40°C and reacted for 16 hours. The reaction system was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified using a normal phase column and then a reverse phase preparative column to provide 1-[2-fluoro-6-(trifluoromethyl)phenyl]cyclopropane-1-carbonitrile (500 mg, yield: 55.40%). 1 H NMR (400MHz, CDCl3) δ7.56-7.45(m,2H),7.33(ddd,J=9.8,7.8,2.0Hz,1H),1.89-1.81(m,2H),1.51-1.43(m,2H).

[0577] Step 4: Synthesis of 1-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)phenyl]cyclopropane-1-carbonitrile

[0578] To the reaction flask were added 1-[2-fluoro-6-(trifluoromethyl)phenyl]cyclopropane-1-carbonitrile (200 mg, 872.68 μmol), 4,4'-di-tert-butyl-2,2'-bipyridine (23.42 mg, 87.27 μmol), biboronic acid pinacol ester (221.61 mg, 872.68 μmol) and methoxy(cyclooctadiene)iridium dimer (17.35 mg, 26.18 μmol). The system was evacuated and replaced with nitrogen three times. Tetrahydrofuran (5 mL) was added and the reaction was carried out under microwave at 100 ° C for 4 hours. The mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified using a normal phase column and a reverse phase column to give 1-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)phenyl]cyclopropane-1-carbonitrile (170 mg, yield: 54.85%). 1 H NMR (400MHz, CDCl3) δ7.91 (s, 1H), 7.71 (d, J = 9.9Hz, 1H), 1.87-1.81 (m, 2H), 1.47-1.41 (m, 2H), 1.35 (s, 12H).

[0579] Intermediate 90: Preparation of 5-bromo-3-chloro-2-(1-methylcyclopropyl)pyridine

[0580] 5-Bromo-3-chloro-2-(1-methylcyclopropyl)pyridine was prepared by selecting appropriate reagents according to the preparation method of Intermediate 87. Intermediate 91: Preparation of 6-chloro-3-(1-methylcyclopropyl)-2-(trifluoromethyl)pyridine

[0581] Step 1: Synthesis of [6-chloro-2-(trifluoromethyl)pyridin-3-yl]methanol

[0582] 6-Chloro-2-(trifluoromethyl)nicotinic acid (4.3 g, 18.68 mmol) was dissolved in tetrahydrofuran (50 mL), cooled to 0°C, and borane dimethyl sulfide complex (28 mL, 56.15 mmol, 2 M in THF) was added. The mixture was heated to 70°C for 1 hour. The mixture was poured into saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified using a normal phase column to obtain [6-chloro-2-(trifluoromethyl)pyridin-3-yl]methanol (3.92 g, yield: 99.17%), a colorless oil.

[0583] Step 2: Synthesis of [6-chloro-2-(trifluoromethyl)pyridin-3-yl]methyl methanesulfonate

[0584] Dissolve [6-chloro-2-(trifluoromethyl)pyridin-3-yl]methanol (4 g, 18.91 mmol) in dichloromethane (40 mL), cool to 0°C, add triethylamine (12.77 mL, 113.11 mmol) and methanesulfonic anhydride (10.08 g, 56.72 mmol), and react at room temperature for 1 hour. Pour the mixture into ice water and extract with dichloromethane. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated and purified using a normal phase column to obtain [6-chloro-2-(trifluoromethyl)pyridin-3-yl]methyl methanesulfonate (5.18 g, yield: 94.59%), a yellow oil.

[0585] Step 3: Synthesis of 2-[6-chloro-2-(trifluoromethyl)pyridin-3-yl]acetonitrile

[0586] Dissolve [6-chloro-2-(trifluoromethyl)pyridin-3-yl]methyl methanesulfonate (5 g, 17.26 mmol) in acetonitrile (40 mL), cool to 0°C, add trimethylsilyl cyanide (3.53 g, 34.52 mmol) and tetrabutylammonium fluoride (34.52 mL, 34.52 mmol, 1 M in THF), and heat to 80°C for 1 hour. Pour the mixture into ice water and extract with ethyl acetate. The organic phase is washed five times with water, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated and purified using a normal phase column to obtain 2-[6-chloro-2-(trifluoromethyl)pyridin-3-yl]acetonitrile (3.23 g, yield: 84.83%), a yellow oil.

[0587] Step 4: Synthesis of 1-[6-chloro-2-(trifluoromethyl)pyridin-3-yl]cyclopropane-1-carbonitrile

[0588] 2-[6-chloro-2-(trifluoromethyl)pyridin-3-yl]acetonitrile (3.16 g, 14.33 mmol) was dissolved in toluene (20 mL). Benzyltriethylammonium chloride (489 mg, 2.15 mmol), 1-bromo-2-chloroethane (4.19 g, 28.65 mmol), and a solution of sodium hydroxide (35 g, 840 mmol) in water (35 mL) were added sequentially. The mixture was heated to 50°C and reacted for 16 hours. The mixture was poured into water and adjusted to pH 7 with 2M dilute hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified using a normal phase column to obtain 1-[6-chloro-2-(trifluoromethyl)pyridin-3-yl]cyclopropane-1-carbonitrile (2.7 g, yield: 76.42%) as a yellow solid.

[0589] Step 5: Synthesis of 1-[6-chloro-2-(trifluoromethyl)pyridin-3-yl]cyclopropane-1-carbaldehyde

[0590] 1-[6-chloro-2-(trifluoromethyl)pyridin-3-yl]cyclopropane-1-carbonitrile (2.6 g, 10.54 mmol) was dissolved in dichloromethane (4 mL), cooled to -78°C, and diisobutylaluminum hydride (21.09 mL, 21.09 mmol, 1 M in hexane) was added. The reaction was maintained at -78°C for 1 hour. The mixture was poured into 1 M dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified using a normal phase column to obtain 1-[6-chloro-2-(trifluoromethyl)pyridin-3-yl]cyclopropane-1-carbaldehyde (2.5 g, yield: 95%), as a yellow oil.

[0591] Step 6: Synthesis of {1-[6-chloro-2-(trifluoromethyl)pyridin-3-yl]cyclopropyl}methanol

[0592] Dissolve 1-[6-chloro-2-(trifluoromethyl)pyridin-3-yl]cyclopropane-1-carbaldehyde (2.4 g, 9.61 mmol) in methanol (25 mL). Slowly add sodium borohydride (742 mg, 19.23 mmol) at 0°C. React at room temperature for 1 hour. Pour the mixture into ice water and extract with ethyl acetate. The organic phase is washed five times with water, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated to yield {1-[6-chloro-2-(trifluoromethyl)pyridin-3-yl]cyclopropyl}methanol (2.40 g, yield: 99.20%), as a yellow oil.

[0593] Step 7: Synthesis of {1-[6-chloro-2-(trifluoromethyl)pyridin-3-yl]cyclopropyl}methyl methanesulfonate

[0594] {1-[6-chloro-2-(trifluoromethyl)pyridin-3-yl]cyclopropyl}methanol (2.3 g, 9.14 mmol) was dissolved in dichloromethane (20 mL). Triethylamine (5.61 g, 54.84 mmol) and methanesulfonic anhydride (4.87 g, 27.42 mmol) were added at 0°C and allowed to react at room temperature for 1 hour. The mixture was poured into ice water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified using a normal phase column to obtain {1-[6-chloro-2-(trifluoromethyl)pyridin-3-yl]cyclopropyl}methyl methanesulfonate (2.46 g, yield: 81.63%), as a yellow oil.

[0595] Step 8: Synthesis of 6-chloro-3-(1-methylcyclopropyl)-2-(trifluoromethyl)pyridine

[0596] {1-[6-chloro-2-(trifluoromethyl)pyridin-3-yl]cyclopropyl}methyl methanesulfonate (800 mg, 2.43 mmol) was dissolved in diethyl ether (10 mL), cooled to 0°C, and lithium aluminum hydride (5.82 mL, 14.56 mmol, 2.5 M in THF) was added. The reaction was stirred at room temperature for 3 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to afford 6-chloro-3-(1-methylcyclopropyl)-2-(trifluoromethyl)pyridine (190 mg, yield: 33.23%).

[0597] Intermediate 92: Preparation of 5-bromo-2-hydroxy-6-methyl-nicotinic acid methyl ester

[0598] Step 1: Synthesis of methyl 2-hydroxy-6-methylpyridine-3-carboxylate

[0599] 2-Hydroxy-6-methylnicotinic acid (10 g, 65.3 mmol) was dissolved in methanol (100 mL). Concentrated sulfuric acid (7.05 g, 71.83 mmol) was slowly added dropwise in an ice bath. The temperature was raised to 70°C and stirred for 16 hours. The mixture was concentrated, diluted with water (100 mL), and the pH was adjusted to 7 with saturated sodium bicarbonate. The mixture was extracted with dichloromethane / methanol (10:1) (100 mL x 10). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to yield methyl 2-hydroxy-6-methylpyridine-3-carboxylate (6.5 g, yield: 59.55%) as a white solid.

[0600] Step 2: Synthesis of 5-bromo-2-hydroxy-6-methyl-nicotinic acid methyl ester

[0601] Methyl 2-hydroxy-6-methylpyridine-3-carboxylate (1 g, 5.98 mmol) was dissolved in N,N-dimethylformamide (10 mL), and N-bromosuccinimide (1.12 g, 6.28 mmol) was added. The mixture was heated to 80°C for 2 hours. The mixture was concentrated and poured into water (50 mL). The mixture was stirred thoroughly for 2 hours, filtered, and the solid collected and dried under reduced pressure to yield methyl 5-bromo-2-hydroxy-6-methyl-nicotinate (1.10 g, yield: 74.73%) as a white solid.

[0602] Intermediate 93: Preparation of 5-bromo-1-chloro-2-(2,2-difluoro-1-methylcyclopropyl)-3-fluorobenzene

[0603] Step 1: Synthesis of methyl 4-bromo-2-chloro-6-fluorobenzoate

[0604] 4-Bromo-2-fluoro-6-chlorobenzoic acid (80 g, 315.64 mmol) was dissolved in N,N-dimethylformamide (500 mL), and iodomethane (89.61 g, 39.30 mL, 631.39 mmol) and potassium carbonate (87.25 g, 631.29 mmol) were added sequentially, and stirred at room temperature overnight. After the reaction, the mixture was diluted with petroleum ether, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was purified by silica gel chromatography to obtain methyl 4-bromo-2-chloro-6-fluorobenzoate (81.95 g, 87.51% yield, 90.16% purity) as a pale yellow oil.

[0605] Step 2: Synthesis of 2-(4-bromo-2-chloro-6-fluorophenyl)propan-2-ol

[0606] To a solution of methyl 4-bromo-2-chloro-6-fluorobenzoate (107.59 g, 90.16%, 362.64 mmol) in tetrahydrofuran (500 mL) was added methylmagnesium bromide (362.64 mL, 1.09 mol, 3 eq, 3 M in 2-Me-THF) at 0°C. The mixture was stirred at 50°C for 16 h, cooled to 0°C, quenched by the addition of saturated ammonium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography to give 2-(4-bromo-2-chloro-6-fluorophenyl)propan-2-ol as a yellow oil (42 g, 43.29% yield).

[0607] Step 3: Synthesis of 5-bromo-1-chloro-3-fluoro-2-(prop-1-en-2-yl)benzene

[0608] Under nitrogen, a solution of (4-bromo-2-chloro-6-fluorophenyl)propan-2-ol (41 g, 153.26 mmol) and p-toluenesulfonic acid (2.64 g, 15.33 mmol, 0.1 eq) in toluene (500 mL) was stirred at 100°C for 2 hours. After the reaction, the mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography to yield 5-bromo-1-chloro-3-fluoro-2-(prop-1-en-2-yl)benzene (27.70 g, 65.46% yield, 90.37% purity).

[0609] Step 4: Synthesis of 5-bromo-1-chloro-2-(2,2-difluoro-1-methylcyclopropyl)-3-fluorobenzene

[0610] A solution of 5-bromo-1-chloro-3-fluoro-2-(prop-1-en-2-yl)benzene (5 g, 20.04 mmol), (trifluoromethyl)trimethylsilane (8.55 g, 60.12 mmol), and sodium iodide (600.74 mg, 4.01 mmol) in tetrahydrofuran (50 mL) was stirred at 70°C overnight. The mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography to give 5-bromo-1-chloro-2-(2,2-difluoro-1-methylcyclopropyl)-3-fluorobenzene (1.50 g, yield: 24.99%) as a colorless oil.

[0611] Intermediate 94: Preparation of 2-[3-chloro-5-fluoro-4-(1-methoxycyclopropyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0612] Step 1: Synthesis of {[1-(2-chloro-6-fluorophenyl)vinyl]oxy}trimethylsilane

[0613] Dissolve 2'-chloro-6'-fluoroacetophenone (5 g, 28.98 mmol) in dichloromethane. Add triethylamine (4.40 g, 43.46 mmol) and trimethylsilyl trifluoromethanesulfonate (7.73 g, 34.77 mmol) sequentially under ice-cooling. Slowly warm the mixture to room temperature and stir for 4 hours. Pour the mixture into saturated sodium bicarbonate (3 mL) and extract with dichloromethane. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated to yield {[1-(2-chloro-6-fluorophenyl)vinyl]oxy}trimethylsilane (6.70 g, yield: 94.48%).

[0614] Step 2: Synthesis of [1-(2-chloro-6-fluorophenyl)cyclopropyloxy]trimethylsilane

[0615] Add dichloromethane (30 mL) to the reaction flask, cool to 0°C, and sequentially add diethylzinc (49 mL, 49 mmol) and diiodomethane (13.13 g, 49.03 mmol). After reacting for 15 minutes, add {[1-(2-chloro-6-fluorophenyl)vinyl]oxy}trimethylsilane (2 g, 8.17 mmol). Slowly warm the temperature to 25°C and stir overnight. Quench the reaction with water, extract with dichloromethane, and wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and filter. The filtrate is concentrated to yield [1-(2-chloro-6-fluorophenyl)cyclopropyloxy]trimethylsilane (2.6 g, crude) as a colorless oil.

[0616] Step 3: Synthesis of 1-(2-chloro-6-fluorophenyl)cyclopropane-1-ol

[0617] Dissolve [1-(2-chloro-6-fluorophenyl)cyclopropyloxy]trimethylsilane (1 g, 3.86 mmol) in ethyl acetate (3 mL). Add 4 M hydrochloric acid in ethyl acetate (10 mL). Allow to react at room temperature for 2 hours. Concentrate the mixture to obtain 1-(2-chloro-6-fluorophenyl)cyclopropane-1-ol (615 mg, yield: 85.29%) as a yellow oil.

[0618] Step 4: Synthesis of 1-chloro-3-fluoro-2-(1-methoxycyclopropyl)benzene

[0619] Sodium hydride (141 mg, 3.53 mmol, purity: 60%) was added to a solution of 1-(2-chloro-6-fluorophenyl)cyclopropane-1-ol (549 mg, 2.94 mmol) in N,N-dimethylformamide (5 mL) at 0°C and stirred for 0.5 hours. Methyl iodide (626 mg, 4.41 mmol) was then added and the mixture was allowed to warm to room temperature for 2 hours. The mixture was poured into water (3 mL) and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to afford 1-chloro-3-fluoro-2-(1-methoxycyclopropyl)benzene (540 mg, yield: 91.48%) as a yellow oil.

[0620] Step 5: Synthesis of 2-[3-chloro-5-fluoro-4-(1-methoxycyclopropyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0621] 1-Chloro-3-fluoro-2-(1-methoxycyclopropyl)benzene (200 mg, 996 μmol), bipyraclostrobin (329 mg, 1.3 mmol), methoxy(cyclooctadiene)iridium dimer (20 mg, 30 μmol), 4-tert-butyl-2-(4-tert-butylpyridin-2-yl)pyridine (16 mg, 60 μmol), and tetrahydrofuran (3 mL) were added to the reaction flask in sequence and heated in a microwave at 100 ° C for 3 hours. After cooling, the system was concentrated, diluted with water (3 mL), extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to give 2-[3-chloro-5-fluoro-4-(1-methoxycyclopropyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (80 mg, yield: 24.57%).

[0622] 2. Preparation of Specific Examples

[0623] Example 1: Preparation of 6-methyl-5-(4-methylphenyl)-2-carbonyl-1,2-dihydropyridine-3-carbonitrile

[0624] To the reaction flask were added 5-bromo-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile (150 mg, 0.704 mmol), 4-benzylboronic acid (143.60 mg, 1.06 mmol), XPhos-Pd G3 (59.46 mg, 0.070 mmol), and potassium phosphate (450 mg, 2.11 mmol) in sequence. The system was evacuated and replaced with nitrogen three times. Then 1,4-dioxane (10 mL) and water (1 mL) were added, heated to 100 ° C, stirred for 16 hours, cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using normal phase column and reverse phase preparative purification to give 6-methyl-5-(4-methylphenyl)-2-carbonyl-1,2-dihydropyridine-3-carbonitrile (11.29 mg, yield: 7%). ESI-MS: 225.1[M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.68(s,1H),8.04(s,1H),7.24(s,4H),2.34(s,3H),2.25(s,3H).

[0625] Example 2: Preparation of 6-methyl-2-carbonyl-5-[4-(2,2,2-trifluoroethyl)phenyl]-1,2-dihydropyridine-3-carbonitrile

[0626] To the reaction flask were added 1-bromo-4-(2,2,2-trifluoroethyl)benzene (137.85 mg, 576.70 μmol), 6-methyl-2-carbonyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridine-3-carbonitrile (150 mg, 576.70 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (42.02 mg, 57.67 μmol), potassium carbonate (239.12 mg, 98.40 μL, 1.73 mm Hg). The system was evacuated and replaced with nitrogen three times. 1,4-dioxane (10 mL) and water (1 mL) were injected using a syringe, heated to 80°C, stirred for 16 hours, cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column and a reverse phase preparative column to obtain 6-methyl-2-carbonyl-5-[4-(2,2,2-trifluoroethyl)phenyl]-1,2-dihydropyridine-3-carbonitrile (42.68 mg, yield: 25.27%). ESI-MS: 293.1 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ12.71(s,1H),8.10(s,1H),7.42(d,J=8.0Hz,2H),7.38(d,J=8.0Hz,2H),3.69(q,J=11.6Hz,2H),2.26(s,3H).

[0627] The 2-pyridone derivatives of Example 3-185 can be prepared by selecting appropriate raw materials according to the synthesis method of Example 1 or 2, and their structures are shown in Table 1.

[0628] Table 1. Structural formula, chemical name and mass spectrometry data of Examples 3-185

[0629] The NMR data of the compound prepared in the above example are as follows:

[0630] Example 186: Preparation of 5-[4'-fluoro-2-(trifluoromethyl)-[1,1'-biphenyl]-4-yl]-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile

[0631] Step 1: Synthesis of 5-[4-bromo-3-(trifluoromethyl)phenyl]-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile

[0632] To the reaction flask were added 1-bromo-4-iodo-2-(trifluoromethyl)benzene (500 mg, 1.42 mmol), 6-methyl-2-carbonyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridine-3-carbonitrile (407.67 mg, 1.57 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (103.83 mg, 142.49 μmol), and potassium carbonate (590.79 mg, 4.27 mmol) in sequence. The system was evacuated and replaced with nitrogen three times. 1,4-dioxane (5 mL) and water (1 mL) were injected using a syringe, and the mixture was heated to 90°C and stirred for 6 hours. The reaction mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to obtain 5-[4-bromo-3-(trifluoromethyl)phenyl]-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile (150 mg, yield: 29.48%). ESI-MS: 357.0 [M+1] + .

[0633] Step 2: Synthesis of 5-[4'-fluoro-2-(trifluoromethyl)-[1,1'-biphenyl]-4-yl]-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile

[0634] To the reaction flask were added 4-fluorophenylboric acid (47.01 mg, 336.01 μmol), 5-[4-bromo-3-(trifluoromethyl)phenyl]-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile (100 mg, 280.01 μmol), potassium carbonate (116.10 mg, 840.03 μmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (20.40 mg, 28 μmol). The system was evacuated and replaced with nitrogen three times. 1,4-dioxane (5 mL) and water (1 mL) were injected using a syringe, and the mixture was heated to 90°C and stirred for 16 hours. The reaction mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified using a normal phase column and then a reverse phase preparative column to obtain 5-[4'-fluoro-2-(trifluoromethyl)-[1,1'-biphenyl]-4-yl]-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile (15.54 mg, yield: 14.91%). ESI-MS: 373.1 [M+1] + . 1H NMR: (400MHz, DMSO-d6) δ12.81(s,1H),8.23(s,1H),7.84(s,1H),7.73(d,J=7.9H z, 1H), 7.47 (d, J = 7.9Hz, 1H), 7.43-7.37 (m, 2H), 7.34-7.26 (m, 2H), 2.32 (s, 3H).

[0635] The 2-pyridone derivatives of Examples 187-193 can be prepared by selecting appropriate raw materials according to the synthesis of Example 186, and their structures are shown in Table 2.

[0636] Table 2. Structural formula, chemical name and mass spectrometry data of Examples 187-193

[0637] The NMR data of the compound prepared in the above example are as follows:

[0638] Example 194: Preparation of 5-[3-chloro-4-(prop-1-yn-1-yl)phenyl]-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile

[0639] Step 1: Synthesis of 5-(4-bromo-3-chlorophenyl)-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile

[0640] To the reaction flask were added 4-bromo-3-fluoroiodobenzene (500 mg, 1.66 mmol), 2-hydroxy-6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carbonitrile (327.84 mg, 1.26 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (91.85 mg, 126.04 μmol), and potassium carbonate (522.62 mg, 3.78 mmol) in sequence. The system was evacuated and replaced with nitrogen three times. 1,4-dioxane (10 mL) and water (2 mL) were then added, and the mixture was heated to 100°C for 16 hours. The reaction system was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by normal phase column chromatography to obtain 5-(4-bromo-3-chlorophenyl)-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile (300 mg, yield: 73.56%). ESI-MS: 323.0 [M+1] + .

[0641] Step 2: Synthesis of 5-[3-chloro-4-(prop-1-yn-1-yl)phenyl]-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile

[0642] 1-(Trimethylsilyl)-1-propyne (30.53 mg, 40.70 μL, 271.97 μmol) was dissolved in THF (1.50 mL) and tetrabutylammonium fluoride (258.59 mg, 988.97 μL, 988.99 μmol, 4 eq, 1 M in THF) was added. After reacting at room temperature for 0.5 h, bistriphenylphosphine palladium dichloride (8.68 mg, 12.36 μmol, 12.36 μmol, 0.05 eq) and 5-(4-bromo-3-chlorophenyl)-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile (80 mg, 247.24 μmol, 1 eq) were added. The mixture was reacted at 80°C for 16 h, cooled to room temperature, diluted with EtOAc, washed with water and brine, and dried over anhydrous sodium sulfate. After filtration and concentration of the filtrate, the crude product was purified by normal phase and reverse phase purification to give 5-[3-chloro-4-(prop-1-yn-1-yl)phenyl]-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile (4.97 mg, yield: 7.11%, purity: 99.75%). ESI-MS: 283.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.76(s,1H),8.13(s,1H),7.66-7.46(m,2H),7.31(dd,J=8.0,2.0Hz,1H),2.27(s,3H),2.13(s,3H).

[0643] Example 195: Preparation of 6-methyl-2-carbonyl-5-(piperidin-1-yl)-1,2-dihydropyridine-3-carbonitrile

[0644] To the reaction flask, 5-bromo-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile (400 mg, 1.88 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium (II) (156.67 mg, 187.77 μmol) and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (87.62 mg, 187.77 μmol) were added in sequence. The system was evacuated and replaced with nitrogen three times, followed by piperidine (239.83 mg, 2.82 mmol) and tetrahydrofuran (8 mL) solution. Lithium bistrimethylsilylamide (1 M in THF, 3.76 mL, 3.76 mmol) was added dropwise at 0°C. After addition, the mixture was heated to 50°C for 4 hours. The reaction system was cooled to 0°C and quenched by adding saturated NH4Cl solution. The tetrahydrofuran was removed by concentration and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified using a normal phase column and then a reverse phase preparative column to obtain 6-methyl-2-carbonyl-5-(piperidin-1-yl)-1,2-dihydropyridine-3-carbonitrile (17.50 mg, yield: 4.29%) as a light yellow solid. ESI-MS: 218.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.51 (s, 1H), 8.10 (s, 1H), 2.65 (t, J = 5.2Hz, 4H), 2.26 (s, 3H), 1.62-1.52 (m, 4H), 1.49-1.39 (m, 2H).

[0645] Example 196: Preparation of 1-[2-chloro-4-(5-cyano-2-methyl-6-carbonyl-1,6-dihydropyridin-3-yl)phenyl]cyclopropane-1-carboxylic acid

[0646] Methyl 1-[2-chloro-4-(5-cyano-6-hydroxy-2-methylpyridin-3-yl)phenyl]cyclopropane-1-carboxylate (15 mg, 44 μmol) was dissolved in methanol (2 mL). A solution of lithium hydroxide monohydrate (4 mg, 87 μmol) in water (1 mL) was added. The mixture was heated to 40°C and stirred for 48 hours. The mixture was concentrated and purified using reverse phase preparative chromatography to afford 1-[2-chloro-4-(5-cyano-2-methyl-6-carbonyl-1,6-dihydropyridin-3-yl)phenyl]cyclopropane-1-carboxylic acid (3.34 mg, yield: 23.22%) as an off-white solid. ESI-MS: 329.1 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ12.74(s,1H),12.44(s,1H),8.11(s,1H),7.48(d,J=2.0Hz,1H),7.43(d ,J=8.0Hz,1H),7.28(dd,J=8.0,2.0Hz,1H),2.27(s,3H),1.56-1.55(m,2H),1.21-1.14(m,2H).

[0647] The 2-pyridone derivatives of Examples 197-199 can be prepared by selecting appropriate raw materials with reference to the synthesis of Example 196, and their structures are shown in Table 3.

[0648] Table 3. Structural formula, chemical name and mass spectrometry data of Examples 197-199

[0649] The NMR data of the compound prepared in the above example are as follows:

[0650] Example 200: Preparation of 5-(2-amino-3-chloro-1-benzothiophen-5-yl)-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile

[0651] Step 1: Synthesis of tert-butyl N-(5-bromo-3-chloro-1-benzothiophen-2-yl)carbamate

[0652] 5-Bromo-3-chloro-1-benzothiophene-2-carboxylic acid (410 mg, 1.41 mmol) was dissolved in tert-butanol (5 mL). Triethylamine (213 mg, 2.11 mmol) and diphenylphosphoryl azide (580 mg, 2.11 mmol) were added sequentially. The system was heated to 90°C and stirred for 5 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to obtain tert-butyl N-(5-bromo-3-chloro-1-benzothiophen-2-yl)carbamate (284 mg, yield: 55.68%) as a yellow solid. ESI-MS: 305.8 [M+1] + .

[0653] Step 2: Synthesis of tert-butyl N-[3-chloro-5-(5-cyano-6-hydroxy-2-methylpyridin-3-yl)-1-benzothiophen-2-yl]carbamate

[0654] To the reaction flask were added tert-butyl N-(5-bromo-3-chloro-1-benzothiophen-2-yl)carbamate (150 mg, 414 μmol), 2-hydroxy-6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carbonitrile (129 mg, 496 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30 mg, 41 μmol), and potassium carbonate (114 mg, 0.83 mmol). The system was evacuated and replaced with nitrogen three times, and 1,4-dioxane (2 mL) and water (0.5 mL) were added. The mixture was heated to 80°C and stirred for 1 hour. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to obtain tert-butyl N-[3-chloro-5-(5-cyano-6-hydroxy-2-methylpyridin-3-yl)-1-benzothiophen-2-yl]carbamate (150 mg, yield: 87.20%) as a yellow solid. ESI-MS: 416.1 [M+1] + .

[0655] Step 3: Synthesis of 5-(2-amino-3-chloro-1-benzothiophen-5-yl)-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile

[0656] Tert-butyl N-[3-chloro-5-(5-cyano-6-hydroxy-2-methylpyridin-3-yl)-1-benzothiophen-2-yl]carbamate (142 mg, 341 μmol) was dissolved in ethyl acetate (5 mL). 4 M hydrochloric acid in ethyl acetate (2 mL, 8 mmol) was added and allowed to react at room temperature for 16 hours. The mixture was concentrated and purified using reverse phase preparative chromatography to afford 5-(2-amino-3-chloro-1-benzothiophen-5-yl)-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile (42.44 mg, yield: 38.89%) as a yellow solid. ESI-MS: 316.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.69(s,1H),8.09(s,1H),7.70(d,J=8.0Hz,1H),7.16(d,J=1.6Hz,1H),7.02(dd,J=8.0,1.6Hz,1H),6.47(s,2H),2.25(s,3H).

[0657] Example 201: Preparation of (2-{1-[2-chloro-4-(5-cyano-2-methyl-6-carbonyl-1,6-dihydropyridin-3-yl)phenyl]cyclopropyl}ethyl)urea

[0658] Step 1: Synthesis of 1-benzoyl-3-{2-[1-(4-bromo-2-chlorophenyl)cyclopropyl]ethyl}urea

[0659] Benzoyl isocyanate (185 mg, 1.13 mmol) was dissolved in tetrahydrofuran (2 mL). 2-[1-(4-bromo-2-chlorophenyl)cyclopropyl]ethan-1-amine (2.59 mg, 0.94 mmol) was added at 0°C. The mixture was heated to 25°C and stirred for 1 hour. The mixture was poured into water (10 mL) and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified using a normal phase column to obtain 1-benzoyl-3-{2-[1-(4-bromo-2-chlorophenyl)cyclopropyl]ethyl}urea (185 mg, yield: 46.51%) as a colorless oil. ESI-MS: 420.9 [M+1] + .

[0660] Step 2: Synthesis of 1-benzoyl-3-(2-{1-[2-chloro-4-(5-cyano-6-hydroxy-2-methylpyridin-3-yl)phenyl]cyclopropyl}ethyl)urea

[0661] 1-Benzoyl-3-{2-[1-(4-bromo-2-chlorophenyl)cyclopropyl]ethyl}urea (185 mg, 438 μmol), 2-hydroxy-6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carbonitrile (137 mg, 526 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (32 mg, 44 μmol), potassium carbonate (121 mg, 877 μmol) were added to the reaction flask. The system was evacuated and replaced with nitrogen three times, and 1,4-dioxane (4 mL) and water (1 mL) were added. The mixture was heated to 80°C and stirred for 1 hour. The mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified using a normal phase column to obtain 1-benzoyl-3-(2-{1-[2-chloro-4-(5-cyano-6-hydroxy-2-methylpyridin-3-yl)phenyl]cyclopropyl}ethyl)urea (160 mg, yield: 76.79%) as a yellow solid. ESI-MS: 475.1 [M+1] + .

[0662] Step 3: Synthesis of (2-{1-[2-chloro-4-(5-cyano-2-methyl-6-carbonyl-1,6-dihydropyridin-3-yl)phenyl]cyclopropyl}ethyl)urea

[0663] To a reaction flask, 1-benzoyl-3-(2-{1-[2-chloro-4-(5-cyano-6-hydroxy-2-methylpyridin-3-yl)phenyl]cyclopropyl}ethyl)urea (130 mg, 273 μmol) was added sequentially. Methanol (3 mL) was then injected via syringe. A solution of sodium hydroxide (43 mg, 1.09 mmol) in water (0.5 mL) was added, and the system was heated at 70°C with stirring for 1 hour. The system was concentrated and purified using reverse phase preparative purification to afford (2-{1-[2-chloro-4-(5-cyano-2-methyl-6-carbonyl-1,6-dihydropyridin-3-yl)phenyl]cyclopropyl}ethyl)urea (17.99 mg, yield: 17.72%) as an off-white solid. ESI-MS: 371.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.64(s,1H),8.10(s,1H),7.44(d,J=1.6Hz,1H),7.41(d,J=8.0Hz,1H),7.27(dd,J=8.0,2.0Hz,1H) ,5.79(t,J=5.6Hz,1H),5.34(s,2H),2.86(q,J=7.2Hz,2H),2.25(s,3H),1.65(s,2H),0.84-0.79(m,2H),0.78-0.73(m,2H).

[0664] Example 202: Preparation of 2-[2-chloro-4-(5-cyano-2-methyl-6-carbonyl-1,6-dihydropyridin-3-yl)phenyl]-2-methylcyclopropane-1-carboxylic acid

[0665] Step 1: Synthesis of ethyl (1R,2R)-2-(4-bromo-2-chlorophenyl)-2-methylcyclopropane-1-carboxylate

[0666] 4-Bromo-2-chloro-1-(prop-1-en-2-yl)benzene (2 g, 8.64 mmol) was dissolved in toluene (30 ml), and ethyl diazoacetate (1.48 g, 1.36 mL, 12.96 mmol) and cuprous chloride (855.22 mg, 8.64 mmol) were added in sequence. The mixture was stirred at 50°C for 16 hours and then cooled to room temperature. The reaction solution was directly concentrated, and the crude product was purified using a normal phase column to give ethyl (1R,2R)-2-(4-bromo-2-chlorophenyl)-2-methylcyclopropane-1-carboxylate (300 mg, yield: 10.93%). ESI-MS: 317.0 [M+1] + .

[0667] Step 2: Ethyl 2-[2-chloro-4-(5-cyano-2-methyl-6-carbonyl-1,6-dihydropyridin-3-yl)phenyl]-2-methylcyclopropane-1-carboxylate

[0668] To the reaction flask were added ethyl (1R, 2R)-2-(4-bromo-2-chlorophenyl)-2-methylcyclopropane-1-carboxylate (140 mg, 440.79 μmol), 6-methyl-2-carbonyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridine-3-carbonitrile (137.58 mg, 528.95 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (64.51 mg, 88.16 μmol), potassium carbonate (182.77 mg, 1.3 2mmol), the system was evacuated and replaced with nitrogen three times, 1,4-dioxane (1mL) and water (0.1mL) were added, heated to 80°C, stirred for 1 hour, cooled to room temperature, quenched with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to obtain ethyl 2-[2-chloro-4-(5-cyano-2-methyl-6-carbonyl-1,6-dihydropyridin-3-yl)phenyl]-2-methylcyclopropane-1-carboxylate (180mg, yield: 110.12%). ESI-MS: 371.1[M+1] + .

[0669] Step 3: Synthesis of 2-[2-chloro-4-(5-cyano-2-methyl-6-carbonyl-1,6-dihydropyridin-3-yl)phenyl]-2-methylcyclopropane-1-carboxylic acid

[0670] Ethyl 2-[2-chloro-4-(5-cyano-2-methyl-6-carbonyl-1,6-dihydropyridin-3-yl)phenyl]-2-methylcyclopropane-1-carboxylate (160 mg, 431.46 μmol) was dissolved in a mixed solvent of water (1 mL), tetrahydrofuran (2 mL), and methanol (2 mL). Lithium hydroxide monohydrate (54.36 mg, 1.29 mmol) was added and stirred at 25°C for 5 hours. Water was then added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified using a reverse phase column to afford 2-[2-chloro-4-(5-cyano-2-methyl-6-carbonyl-1,6-dihydropyridin-3-yl)phenyl]-2-methylcyclopropane-1-carboxylic acid (30.46 mg, yield: 20.60%) as a white solid. ESI-MS: 343.1 [M+1]. + . 1H NMR(400MHz,DMSO-d6)δ11.78(s,2H),8.07(s,1H),7.49-7.41(m,2H),7.31(dd,J=8.0,2.0Hz,1 H),2.25(s,3H),1.84(dd,J=8.4,6.0Hz,1H),1.42(s,3H),1.33-1.37(m,1H),1.28-1.30(m,1H).

[0671] Example 203: Preparation of N-(2-{1-[2-chloro-4-(5-cyano-2-methyl-6-carbonyl-1,6-dihydropyridin-3-yl)phenyl]cyclopropyl}ethyl)guanidine

[0672] Step 1: Synthesis of tert-butyl N-{2-[1-(4-bromo-2-chlorophenyl)cyclopropyl]ethyl}carbamate

[0673] 2-[1-(4-bromo-2-chlorophenyl)cyclopropyl]ethan-1-amine (365 mg, 1.33 mmol) was dissolved in dichloromethane (4 mL), and triethylamine (403 mg, 3.99 mmol) and di-tert-butyl dicarbonate (435 mg, 1.99 mmol) were added sequentially. The mixture was warmed to room temperature and reacted for 1 hour. The mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give tert-butyl N-{2-[1-(4-bromo-2-chlorophenyl)cyclopropyl]ethyl}carbamate (580 mg, crude) as a yellow oil. ESI-MS: 374.1 [M+1]. + .

[0674] Step 2: tert-butyl N-(2-{1-[2-chloro-4-(5-cyano-2-methyl-6-carbonyl-1,6-dihydropyridin-3-yl)phenyl]cyclopropyl}ethyl)carbamate

[0675] In the reaction flask, tert-butyl N-{2-[1-(4-bromo-2-chlorophenyl)cyclopropyl]ethyl}carbamate (150 mg, 400 μmol), 2-hydroxy-6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carbonitrile (114 mg, 440 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (29 mg, 40 μmol), and potassium carbonate (110 mg, 800 μmol) were added and the system was extracted. The mixture was vacuumed and replaced with nitrogen three times, and 1,4-dioxane (1 mL) and water (0.2 mL) were added. The mixture was heated to 80°C and stirred for 1 hour. The mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified using a normal phase column to obtain tert-butyl N-(2-{1-[2-chloro-4-(5-cyano-2-methyl-6-carbonyl-1,6-dihydropyridin-3-yl)phenyl]cyclopropyl}ethyl)carbamate (55 mg, yield: 32%) as a yellow solid. ESI-MS: 428.1 [M+1] + .

[0676] Step 3: Synthesis of 5-{4-[1-(2-aminoethyl)cyclopropyl]-3-chlorophenyl}-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile

[0677] Tert-butyl N-(2-{1-[2-chloro-4-(5-cyano-2-methyl-6-carbonyl-1,6-dihydropyridin-3-yl)phenyl]cyclopropyl}ethyl)carbamate (200 mg, 467 μmol) was dissolved in 1,4-dioxane (1 mL), 4M methanolic hydrochloric acid (1.17 mL, 4.67 mmol) was added, and the mixture was heated at 80°C with stirring for 1 hour. The system was cooled to room temperature and concentrated. The crude product was purified using reverse phase preparative method to give 5-{4-[1-(2-aminoethyl)cyclopropyl]-3-chlorophenyl}-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile (170 mg) as a yellow solid. ESI-MS: 328.1 [M+1] + .

[0678] Step 4: Synthesis of N-(2-{1-[2-chloro-4-(5-cyano-2-methyl-6-carbonyl-1,6-dihydropyridin-3-yl)phenyl]cyclopropyl}ethyl)guanidine

[0679] 5-{4-[1-(2-aminoethyl)cyclopropyl]-3-chlorophenyl}-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile (80 mg, 244 μmol) was dissolved in N-dimethylformamide (2 mL). N,N-diisopropylethylamine (157 mg, 1.22 mmol) and pyrazole-1-carboximidamide hydrochloride (54 mg, 488 μmol) were added sequentially. The mixture was heated at 100°C and stirred for 1 hour. The solution was concentrated and purified using reverse phase preparative purification to afford N-(2-{1-[2-chloro-4-(5-cyano-2-methyl-6-carbonyl-1,6-dihydropyridin-3-yl)phenyl]cyclopropyl}ethyl)guanidine (11.89 mg, yield: 13.17%) as an off-white solid. ESI-MS: 370.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ9.76 (s, 1H), 7.38 (s, 1H), 7.28 (d, J = 8.0Hz, 1H), 7.25 (s, 1H), 7.20 (s ,1H),7.06(d,J=8.0Hz,1H),3.18(s,2H),1.78(s,2H),1.62(s,3H),1.00(s,2H),0.72(s,2H).

[0680] Example 204: Preparation of 2-[2-chloro-4-(5-cyano-2-methyl-6-carbonyl-1,6-dihydropyridin-3-yl)phenyl]-2-methylcyclopropane-1-carboxamide

[0681] Ethyl 2-[2-chloro-4-(5-cyano-2-methyl-6-carbonyl-1,6-dihydropyridin-3-yl)phenyl]-2-methylcyclopropane-1-carboxylate (200 mg, 560.52 μmol) was dissolved in N,N-dimethylformamide (3 mL), and sodium methoxide (90.84 mg, 1.68 mmol) and formamide (75.74 mg, 1.68 mmol) were added sequentially. The mixture was heated to 100°C and stirred for 1 hour. The mixture was cooled to room temperature and quenched with water. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by reverse phase column chromatography to give 2-[2-chloro-4-(5-cyano-2-methyl-6-carbonyl-1,6-dihydropyridin-3-yl)phenyl]-2-methylcyclopropane-1-carboxamide (30.14 mg, yield: 15.73%) as a white solid. ESI-MS: 342.3[M+1] + . 1H NMR (400MHz, DMSO-d6) δ12.69(s,1H),8.09(s,1H),7.68(s,1H),7.55(d,J=8.0Hz,1H),7.46(d,J=2.0Hz,1H),7.30(dd,J=8.0,2.0H z,1H),6.99(s,1H),2.25(s,3H),1.88(dd,J=8.4,6.0Hz,1H),1.36(s,3H),1.26(dd,J=6.0,4.4Hz,1H),1.13(dd,J=8.4,4.4Hz,1H).

[0682] Example 205: Preparation of 5-[4-(2-amino-1-methylcyclopropyl)-3-chlorophenyl]-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile

[0683] Step 1: Synthesis of 2-(4-bromo-2-chlorophenyl)-2-methylcyclopropane-1-carboxylic acid

[0684] Ethyl 2-(4-bromo-2-chlorophenyl)-2-methylcyclopropane-1-carboxylate (550 mg, 1.81 mmol) was dissolved in water (1 ml), tetrahydrofuran (2 ml), and methanol (2 ml). Lithium hydroxide (228.28 mg, 5.44 mmol) was added and stirred at room temperature for 5 hours. The solvent was removed by rotary evaporation and the mixture was diluted with water (10 ml). The pH was adjusted to 1 with 1M hydrochloric acid. The mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and analyzed by normal phase column chromatography to obtain 2-(4-bromo-2-chlorophenyl)-2-methylcyclopropane-1-carboxylic acid (450 mg, yield: 85.78%). ESI-MS: 288.7 [M+1] + .

[0685] Step 2: Synthesis of tert-butyl N-[2-(4-bromo-2-chlorophenyl)-2-methylcyclopropyl]carbamate

[0686] 2-(4-Bromo-2-chlorophenyl)-2-methylcyclopropane-1-carboxylic acid (500 mg, 1.73 mmol) was dissolved in toluene (1 ml). Tert-butyl alcohol (1 ml), triethylamine (262.10 mg, 2.59 mmol), and diphenylphosphoryl azide (712.83 mg, 2.59 mmol) were added sequentially. After stirring at 90°C for 1 hour, the mixture was cooled to room temperature, diluted with water (10 ml), and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by normal phase column chromatography to obtain tert-butyl N-[2-(4-bromo-2-chlorophenyl)-2-methylcyclopropyl]carbamate (220 mg, yield: 35.32%).

[0687] Step 3: Synthesis of tert-butyl N-[2-[2-chloro-4-(5-cyano-2-methyl-6-carbonyl-1,6-dihydropyridin-3-yl)phenyl]-2-methylcyclopropyl]carbamate

[0688] To the reaction flask were added tert-butyl N-[2-(4-bromo-2-chlorophenyl)-2-methylcyclopropyl]carbamate (200 mg, 554.51 μmol), 6-methyl-2-carbonyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridine-3-carbonitrile (158.65 mg, 609.96 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (81.15 mg, 110.90 μmol), potassium carbonate (229.92 mg, 1.66 mmol), and the system was stirred for 2 h. The mixture was evacuated and replaced with nitrogen three times, 1,4-dioxane (5 mL) and water (1 mL) were added, heated to 80°C, stirred for 1 hour, cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to give tert-butyl N-[2-[2-chloro-4-(5-cyano-2-methyl-6-carbonyl-1,6-dihydropyridin-3-yl)phenyl]-2-methylcyclopropyl]carbamate (200 mg, yield: 87.14%) as a brown solid. ESI-MS: 414.4 [M+1] + .

[0689] Step 4: Synthesis of 5-[4-(2-amino-1-methylcyclopropyl)-3-chlorophenyl]-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile

[0690] Tert-butyl N-[2-[2-chloro-4-(5-cyano-2-methyl-6-carbonyl-1,6-dihydropyridin-3-yl)phenyl]-2-methylcyclopropyl]carbamate (200 mg, 483.21 μmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at 25°C for 2 hours. The reaction was quenched by adding saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified using a reverse phase column to afford 5-[4-(2-amino-1-methylcyclopropyl)-3-chlorophenyl]-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile (11.47 mg, yield: 7.56%) as a white solid. ESI-MS: 314.4 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ8.08(s,1H),7.41(d,J=2.0Hz,1H),7.38(d,J=8.0Hz,1H),7.24(dd,J=8.0,2.0Hz,1H ),2.36(dd,J=7.6,4.8Hz,1H),2.25(s,3H),1.32(s,3H),0.97(dd,J=7.6,5.2Hz,1H),0.52(t,J=4.8Hz,1H).

[0691] Example 206: Preparation of 5-[3-chloro-4-(1-ethynylcyclopropyl)-5-fluorophenyl]-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile

[0692] Step 1: Synthesis of 2-[1-(2-chloro-6-fluorophenyl)cyclopropyl]-1,3-dioxolane

[0693] 1-(2-chloro-6-fluorophenyl)cyclopropane-1-carbaldehyde (1 g, 5.03 mmol) was dissolved in toluene (10 mL). Ethylene glycol (468.76 mg, 421.17 μL, 7.55 mmol) and p-toluenesulfonic acid (86.70 mg, 503.47 μmol) were added sequentially. The mixture was heated to 110°C and stirred under reflux for 16 hours. After completion, the reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified using a normal phase column to afford 2-[1-(2-chloro-6-fluorophenyl)cyclopropyl]-1,3-dioxolane (780 mg, yield: 63%).

[0694] Step 2: Synthesis of 2-{3-chloro-4-[1-(1,3-dioxolane-2-yl)cyclopropyl]-5-fluorophenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0695] To the reaction flask were added 2-[1-(2-chloro-6-fluorophenyl)cyclopropyl]-1,3-dioxolane (380 mg, 1.57 mmol), bipyraclostrobin (397.65 mg, 397.65 μL, 1.57 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (42.03 mg, 156.59 μmol) and methoxy(cyclooctadiene)iridium dimer (51.90 mg, 78.30 μmol). The system was evacuated and replaced with nitrogen three times. Tetrahydrofuran (10 mL) was added and microwaved at 110 °C for 16 hours. The reaction mixture was cooled to room temperature and concentrated, and the crude product was purified using a normal phase column to give 2-{3-chloro-4-[1-(1,3-dioxolane-2-yl)cyclopropyl]-5-fluorophenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (300 mg, yield: 51.97%).

[0696] Step 3: Synthesis of 5-{3-chloro-4-[1-(1,3-dioxolane-2-yl)cyclopropyl]-5-fluorophenyl}-2-hydroxy-6-methylpyridine-3-carbonitrile

[0697] To the reaction flask were added 5-bromo-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile (312.06 mg, 1.46 mmol), 2-{3-chloro-4-[1-(1,3-dioxolane-2-yl)cyclopropyl]-5-fluorophenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (540 mg, 1.46 mmol), potassium carbonate (607.37 mg, 249.95 μL, 4.39 mmol) and [1,1'-bis(diphenylphosphine) Ferrocene] palladium dichloride (160.77 mg, 219.73 μmol), the system was evacuated and replaced with nitrogen three times, 1,4-dioxane (10 mL) and water (1 mL) were added sequentially, heated to 100°C, stirred for 2 hours, cooled to room temperature, concentrated, and purified using normal phase column and reverse phase preparative purification to obtain 5-{3-chloro-4-[1-(1,3-dioxolane-2-yl)cyclopropyl]-5-fluorophenyl}-2-hydroxy-6-methylpyridine-3-carbonitrile (400 mg, yield: 72%). ESI-MS: 375.3 [M+1] + .

[0698] Step 4: Synthesis of 5-[3-chloro-5-fluoro-4-(1-formylcyclopropyl)phenyl]-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile

[0699] 5-{3-chloro-4-[1-(1,3-dioxolane-2-yl)cyclopropyl]-5-fluorophenyl}-2-hydroxy-6-methylpyridine-3-carbonitrile (200 mg, 533.62 μmol) was dissolved in tetrahydrofuran (5 mL), p-toluenesulfonic acid (183.78 mg, 1.07 mmol) was added, and the mixture was heated to 50°C for 16 hours. After cooling to room temperature, the mixture was concentrated and purified using a normal phase column and then a reverse phase preparative column to obtain 5-[3-chloro-5-fluoro-4-(1-formylcyclopropyl)phenyl]-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile (120 mg). ESI-MS: 331.3 [M+1] + .

[0700] Step 5: Synthesis of 5-[3-chloro-4-(1-ethynylcyclopropyl)-5-fluorophenyl]-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile

[0701] 5-[3-chloro-5-fluoro-4-(1-formylcyclopropyl)phenyl]-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile (240 mg, 725.65 μmol) was dissolved in methanol (10 mL), and dimethyl (1-diazo-2-oxopropyl)phosphonate (209.11 mg, 261.38 μL, 1.09 mmol) and potassium carbonate (200.58 mg, 1.45 mmol) were added sequentially. The mixture was stirred at room temperature for 16 hours, concentrated, and then purified using reverse phase preparative purification to obtain 5-[3-chloro-4-(1-ethynylcyclopropyl)-5-fluorophenyl]-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile (38.69 mg, yield: 13.60%). ESI-MS: 327.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.78(s,1H),8.13(s,1H),7.40(t,J=1.6Hz,1H),7.32(dd, J=10.8,1.6Hz,1H),2.85(s,1H),2.28(s,3H),1.47-1.44(m,2H),1.21-1.18(m,2H).

[0702] Example 207: Preparation of 5-[3-chloro-5-fluoro-4-(1-methylcyclopropyl)phenyl]-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carboxamide

[0703] 5-[3-chloro-5-fluoro-4-(1-methylcyclopropyl)phenyl]-2-hydroxy-6-methylpyridine-3-carboxylic acid (82 mg, 238 μmol), N,N-diisopropylethylamine (92 mg, 715 μmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium hexafluorophosphate (136 mg, 357 μmol), ammonium bicarbonate (23 mg, 286 μmol) were added to the reaction flask in sequence. 1), N,N-dimethylformamide (1 mL), stirred at 25°C for 16 hours, quenched with water, extracted with ethyl acetate, and the organic phase washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated and purified using reverse phase preparative method to obtain 5-[3-chloro-5-fluoro-4-(1-methylcyclopropyl)phenyl]-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carboxamide (16.88 mg, yield: 21.16%) as an off-white solid. ESI-MS: 335.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.56(s,1H),8.97(d,J=4.4Hz,1H),8.13(s,1H),7.56(d,J=4.4Hz,1H), 7.30(d,J=2.0Hz,1H),7.24(dd,J=10.8,1.6Hz,1H),2.29(s,3H),1.30(s,3H),0.89-0.81(m,4H).

[0704] Example 208: Preparation of 5-[3,5-dichloro-4-(1-methylcyclopropyl)phenyl]-3-hydroxy-6-methyl-1,2-dihydropyridin-2-one

[0705] 5-[3,5-Dichloro-4-(1-methylcyclopropyl)phenyl]-3-methoxy-6-methylpyridin-2-ol (40 mg, 118 μmol) was dissolved in dichloromethane (2 mL), and boron tribromide (177 μL, 354 μmol, 2 M in DCM) was added. The reaction was allowed to react at room temperature for 1 hour, quenched with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified using reverse phase preparative purification to afford 5-[3,5-dichloro-4-(1-methylcyclopropyl)phenyl]-3-hydroxy-6-methyl-1,2-dihydropyridin-2-one (6.10 mg, yield: 15.91%) as an off-white solid. ESI-MS: 324.1 [M+1]. + . 1H NMR (400MHz, DMSO-d6) δ11.81(s,1H),8.99(s,1H),7.34(s,2H),6.67(s,1H),2.10(s,3H),1.29(s,3H),1.01-0.91(m,2H),0.91-0.83(m,2H).

[0706] The 2-pyridone derivative of Example 209 can be prepared by selecting appropriate raw materials according to the synthesis of Example 208, and its structure is shown in Table 4.

[0707] Table 4. Structural formula, chemical name and mass spectrometry data of Example 209

[0708] The NMR data of the compound prepared in the above example are as follows:

[0709] Examples 210 and 211: Preparation of optically pure 5-[3-chloro-4-(2,2-difluoro-1-methylcyclopropyl)-5-fluorophenyl]-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile

[0710] 5-[3-Chloro-4-(2,2-difluoro-1-methylcyclopropyl)-5-fluorophenyl]-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile was separated by chiral SFC (Chiral ART Cellulose KCJ (50 mm×250 mm×10 μm), mobile phase CO2 / Methanol=140 / 8 (g / g), flow rate 148 g / min) to obtain a pair of enantiomers as Examples 210 and 211, respectively.

[0711] Optical purity determination: Waters UPCC, Chiral ART Cellulose KCJ (4.6 mm × 100 mm × 3 μm), mobile phase CO2 / Methanol = 90 / 10 (v / v), flow rate 2.0 mL / min. Retention time: Example 210: 1.77 min;

[0712] Example 211: 2.05 minutes.

[0713] Examples 212 and 213: Preparation of optically pure 5-[3-chloro-4-(1-cyano-2,2-difluorocyclopropyl)-5-fluorophenyl]-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile

[0714] 5-[3-Chloro-4-(1-cyano-2,2-difluorocyclopropyl)-5-fluorophenyl]-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile was separated by chiral HPLC (Chiral ART Amylose KBN (30 mm×250 mm×10 μm), mobile phase Hexane / IPA=70 / 30 (V / V), flow rate 60 mL / min) to give a pair of enantiomers as Examples 212 and 213, respectively.

[0715] Optical purity was determined using a Shimadzu LC 20CNZ with UV detector SPD-M20A, Chiral ART Amylose KBN (4.6 mm × 250 mm × 10 μm), mobile phase: Hexane / IPA = 70 / 30 (v / v), flow rate: 2.0 mL / min. Retention times: Example 212: 6.65 min; Example 213: 6.73 min.

[0716] Examples 214 and 215: Preparation of optically pure 5-[3-chloro-4-(1-cyano-2,2-difluorocyclopropyl)-5-fluorophenyl]-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile

[0717] Step 1: Synthesis of 5-[4-(2,2-difluoro-1-methylcyclopropyl)3,5-difluorophenyl]1-(methoxymethyl)6-methyl-2-carbonyl-12-dihydropyridine-3-carbonitrile

[0718] To a solution of 5-[4-(2,2-difluoro-1-methylcyclopropyl)-3,5-difluorophenyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (118 mg, 350.89 μmol) in dichloromethane (4 mL) were added diisopropylethylamine (90.70 mg, 701.78 μmol) and methoxymethyl bromide (43.85 mg, 350.89 μmol) sequentially and allowed to react at room temperature for 1 hour. The mixture was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by normal phase column chromatography and high performance liquid chromatography to yield 5-[4-(2,2-difluoro-1-methylcyclopropyl)-3,5-difluorophenyl]-1-(methoxymethyl)-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile (28 mg). ESI-MS: 381.1 [M+1] + .

[0719] Step 2: Resolution of 5-[4-(2,2-difluoro-1-methylcyclopropyl)3,5-difluorophenyl]1-(methoxymethyl)6-methyl-2-carbonyl-12-dihydropyridine-3-carbonitrile

[0720] 5-[4-(2,2-difluoro-1-methylcyclopropyl)3,5-difluorophenyl]1-(methoxymethyl)6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile was separated by chiral HPLC (Chiral ART Amylose KBN Column (50 mm×250 mm×10 μm), mobile phase Hexane / EtOH=90 / 10 (V / V), flow rate 120 mL / min) to obtain a pair of enantiomers as precursor 1 and precursor 2, respectively.

[0721] Optical purity was determined using a Shimadzu LC 20CND with UV detector SPD-M20A, Chiral ART Amylose KBN (4.6 mm × 250 mm × 10 μm), mobile phase: Hexane / EtOH = 90 / 10 (v / v), flow rate: 1.0 mL / min. Retention times: Precursor 1: 16.04 min; Precursor 2: 20.93 min.

[0722] Step 3: Synthesis of optically pure 5-[3-chloro-4-(1-cyano-2,2-difluorocyclopropyl)-5-fluorophenyl]-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile

[0723] Optically pure 5-[3-chloro-4-(1-cyano-2,2-difluorocyclopropyl)-5-fluorophenyl]-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile can be obtained by deprotecting the corresponding optically pure precursor 5-[4-(2,2-difluoro-1-methylcyclopropyl)-3,5-difluorophenyl]-1-(methoxymethyl)-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile. Enantiomer 1, Example 214, is prepared from precursor 1 by the following specific procedures:

[0724] Optically pure 5-[4-(2,2-difluoro-1-methylcyclopropyl)-3,5-difluorophenyl]-1-(methoxymethyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (60 mg, 157.75 μmol) was dissolved in dioxane (2 mL), and a hydrochloric acid-dioxane solution (457.32 μL, 1.83 mmol, 4 M) was added. The mixture was reacted at 100°C for 1 hour. After cooling to room temperature, the reaction mixture was concentrated in vacuo to obtain the crude product, which was purified by preparative HPLC to afford optically pure 5-[4-(2,2-difluoro-1-methylcyclopropyl)-3,5-difluorophenyl]-6-methyl-2-carbonyl-1,2-dihydropyridine-3-carbonitrile (19.50 mg, yield: 36.76%, purity: 100%) as a white solid. ESI-MS: 337.1[M+1] + . 1H NMR(400MHz,DMSO-d6)δ12.80(s,1H),8.13(s,1H),7.25(s,1H),7.22(s,1H ),2.30(s,3H),1.95-1.88(m,1H),1.83-1.73(m,1H),1.44(d,J=2.6Hz,3H).

[0725] Enantiomer 2 Example 215 can be prepared from Precursor 2 by referring to the procedure of Example 214.

[0726] 3. Biological Test Evaluation

[0727] In vitro antiproliferative test

[0728] This experiment investigated the inhibitory effect of pyridone compounds on cell proliferation in HeLa cells by examining their effects on in vitro cell viability. HeLa cell lines were cultured with the corresponding culture medium in an incubator at 37°C and 5% CO2. Cells were passaged regularly, and cells in the logarithmic growth phase were plated. This experiment used 384-well cell culture plates (NEST 761601) with a plate density of 800 cells / well. After plating, the plates were incubated in an incubator for 24 hours before treatment with the pyridone compounds described herein. The pyridone compound treatment lasted for 72 hours. The pyridone compounds were diluted in a 9-fold 3-fold gradient and treated using a Multidrop Pico 8. A vehicle control and a blank control were also included in the culture plates. After 72 hours, CellTiter-Glo buffer was added to a bottle of CellTiter-Glo substrate to dissolve the substrate, thereby preparing the CellTiter-Glo working solution. Slowly vortex to dissolve the substrate. Remove the cell culture plate and allow it to equilibrate to room temperature for 10 minutes. Add 20 μL of CellTiter-Glo working solution (equal to half the volume of cell culture medium in each well) to each well. Shake the culture plate on an orbital shaker for 2 minutes to induce cell lysis. Incubate the culture plate at room temperature for 10 minutes to stabilize the luminescence signal. Detect the luminescence signal on a SpectraMax Paradigm plate reader. Inhibition rate data are calculated using the following formula:

[0729] Inhibition Rate (Inh%)=100-(RLUDrug-RLUMin) / (RLUMax-RLUMin)*100%.

[0730] The inhibition rates corresponding to different concentrations of pyridone compounds were calculated in EXCEL, and then the inhibition rate curve was plotted using GraphPad Prism software and the relevant parameters were calculated to determine the inhibition rate of 50% (IC50 The results of the in vitro anti-proliferative activity test of the pyridone compounds of the examples are shown in Table 5.

[0731] Table 5: In vitro antiproliferative activity test of the example compounds

[0732] Note: 1. “NT” is the abbreviation of “Not Tested”, which means not tested yet.

[0733] 2. "A" indicates IC50 ≤ 10 nM, "B" indicates 10 nM < IC50 ≤ 50 nM, "C" indicates 50 nM < IC50 ≤ 200 nM, and "D" indicates 200 nM < IC50.

[0734] 3. Positive compound Bay2666605 is Example 135 in patent WO2019 / 025562A1.

[0735] PDE3A enzyme activity test

[0736] PDE3A catalyzes the hydrolysis of cAMP to AMP. In this experiment, a TR-FRET assay (BPS Bioscience) was performed in a 384-well plate format to determine the inhibitory activity of the example compounds against the PDE3A enzyme (NM_000922). The specific procedure was as follows: Purified PDE3A protein (0.25 nM final concentration, 2.5 μL in buffer: 50 mM Tris-HCl, pH 7.5; 8 mM MgCl2; 1.7 mM EDTA; 0.2% BSA) was incubated with the test compound (2.5 μL) at room temperature for 30 minutes, followed by the addition of FAM-cAMP (2.5 μL, 100 nM final concentration) to initiate the enzyme-catalyzed reaction. After 60 minutes, 15 μL of binding reagent was added to terminate the reaction. The mixture was incubated at room temperature for one hour. Luminescence signals were detected on a ViewLux plate reader. PDE3A enzyme activity inhibition rate (Inhibition Rate) data were processed using the following formula:

[0737] Inhibition Rate (Inh%)=100-(RLUDrug-RLUMin) / (RLUMax-RLUMin)*100%.

[0738] The inhibition rates corresponding to different concentrations of pyridone compounds were calculated in EXCEL, and then the inhibition rate curve was plotted using GraphPad Prism software and the relevant parameters were calculated to determine the inhibition rate of 50% (IC 50The results of the PDE3A enzyme activity tests of the pyridone compounds of some examples are shown in Table 6.

[0739] Table 6. PDE3A enzyme inhibitory activity test results of some example compounds

[0740] Note: Positive compound Bay2666605 is Example 135 in patent WO2019 / 025562A1.

[0741] From the activity data of the above specific examples, it can be seen that the series of pyridone compounds of the present invention exhibit excellent anti-tumor activity, and their PDE3A inhibitory activity is very weak, which can effectively avoid the potential off-target toxic side effects caused by PDE3A inhibition. Compared with positive compounds, they have a broader therapeutic window and therefore have good development prospects.

[0742] The above description of the embodiments is intended to facilitate understanding and application of the present application by those skilled in the art. It will be apparent that those skilled in the art can readily make various modifications to these embodiments and apply the general principles described herein to other embodiments without expending any creative effort. Therefore, the present application is not limited to the embodiments described herein, and improvements and modifications made by those skilled in the art based on the disclosure of this application without departing from the scope and spirit of this application are within the scope of this application.

Claims

1. A pyridone compound, its stereoisomer, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: The pyridone compound has a structure represented by the following general formula (I): Among them, R 30 Selected from: -CN, hydrogen, deuterium, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, -C 0-8 Alkyl C 3-12 Cycloalkyl, -C 0-8 Alkyl 3-12 membered heterocyclic group, -C 0-8 Alkyl C 6-10 Aryl, -C 0-8 Alkyl 5-10 membered heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 、-C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0-8 Alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 The above groups are independently optionally further substituted by one or more substituents selected from the following: deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 =C(R 11 )2. -C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0- 8-alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 ; R1 is selected from hydrogen, deuterium, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, -C 0-8 Alkyl C 3-12 Cycloalkyl, -C 0-8 Alkyl 3-12 membered heterocyclic group, -C 0-8 Alkyl C 6-10 Aryl, -C 0-8 Alkyl 5-10 membered heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 、-C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0-8 Alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 The above groups are independently optionally further substituted by one or more substituents selected from the following: deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 =C(R 11 )2. -C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0- 8-alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 ; R2 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, -C 0-8 Alkyl C 3-12 Cycloalkyl, -C 0-8 Alkyl 3-12 membered heterocyclic group, -C 0-8 Alkyl C 6-10 Aryl, -C 0-8 Alkyl 5-10 membered heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 、-C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0-8 Alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、- C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 The above groups are independently optionally further substituted by one or more substituents selected from the following: deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 =C(R 11 )2. -C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0-8 Alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 ; R3 is selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, -C 0-8 Alkyl C 3-12 Cycloalkyl, -C 0-8 Alkyl 3-12 membered heterocyclic group, -C 0-8 Alkyl C 6-10 Aryl, -C 0-8 Alkyl 5-10 membered heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 、-C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0-8 Alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 The above groups are independently optionally further substituted by one or more substituents selected from the following: deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2- 10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 =C(R 11 )2. -C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0-8 Alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 substituted by a substituent; X is selected from a bond, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, -C 0-8 Alkyl C 3-12 Cycloalkyl, -C 0-8 Alkyl 3-12 membered heterocyclic ring, -C 0-8 Alkyl C 6-10 Aromatic ring, -C 0-8 Alkyl 5-10 membered heteroaromatic ring, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 、-C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0-8 Alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 ; n is 0, 1, 2, 3 or 4; Each R4 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, -C 0-8 Alkyl C 3-12 Cycloalkyl, -C 0-8 Alkyl 3-12 membered heterocyclic group, -C 0-8 Alkyl C 6-10 Aryl, -C 0-8 Alkyl 5-10 membered heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 =C(R 11 )2、=O、-C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0-8 Alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、=NR 13 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 The above groups are independently optionally further substituted by one or more substituents selected from the following: deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 alkyl- C(O)SR 11 =C(R 11 )2. -C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0- 8-alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 ; Or two R4 connected to the same atom together with the connected atom form a C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the ring structure formed above is independently optionally further substituted by one or more R6; Alternatively, two R4 connected to two adjacent atoms and the atoms to which they are connected together form a C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the ring structure formed above is independently optionally further substituted by one or more R6; Alternatively, two R4 connected to two non-adjacent atoms together with the atoms to which they are connected form a C 4-12 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the ring structure formed above is independently optionally further substituted by one or more R6; R5 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, -C 0-8 Alkyl C 3-12 Cycloalkyl, -C 0-8 Alkyl 3-12 membered heterocyclic group, -C 0-8 Alkyl C 6-10 Aryl, -C 0-8 Alkyl 5-10 membered heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 =C(R 11 )2、=O、-C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0-8 Alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、=NR 13 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 The above groups are independently optionally further substituted by one or more substituents selected from the following: deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 =C(R 11 )2. -C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0-8 Alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 ; Each R6 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 =C(R 11 )2、=O、-C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0-8 Alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、=NR 13 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 , or two R6 and the atoms to which they are connected together form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; each of the above groups is independently optionally further substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R7)R8, -C 0-8 Alkyl-N=S(O)R8R9, -C 0-8 Alkyl-OS(O)2R 10 、-C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)SR 11 =C(R 11 )2. -C 0-8 Alkyl-SC(O)R 12 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0- 8-alkyl-P(O)(R 12 )2. -C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 and -C 0-8 Alkyl-N(R 13 )-C(O)R 12 substituted by a substituent; Each R7 is independently selected from hydrogen, deuterium, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, -C 0-8 Alkyl C 3- 12 Cycloalkyl, -C 0-8 Alkyl 3-12 membered heterocyclic group, -C 0-8 Alkyl C 6-10 Aryl, -C 0-8 Alkyl 5-10 membered heteroaryl, -C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)R 12 or -C 0-8 Alkyl-C(O)NR 13 R 14 The above groups are optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6- 10 Aryl, 5-10 membered heteroaryl, -C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 or -C 0-8 Alkyl-N(R 13 )-C(O)R 12 substituted by a substituent; Each R8 and each R9 are independently selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, -C 0-8 Alkyl C 3-12 Cycloalkyl, -C 0-8 Alkyl 3-12 membered heterocyclic group, -C 0-8 Alkyl C 6-10 Aryl, -C 0-8 alkyl 5-10 membered heteroaryl, or, R8 and R9 together with the sulfur atom to which they are directly connected form a 3-10 membered heterocyclic group, the above groups are optionally further substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 0-8 Alkyl-S(O) r R 10 、-C 0-8 Alkyl-OR 11 、-C 0-8 Alkyl-C(O)OR 11 、-C 0-8 Alkyl-C(O)R 12 、-C 0-8 Alkyl-OC(O)R 12 、-C 0-8 Alkyl-NR 13 R 14 、-C 0-8 Alkyl-C(=NR 13 )R 12 、-C 0-8 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-8 Alkyl-C(O)NR 13 R 14 or -C 0-8 Alkyl-N(R 13 )-C(O)R 12 substituted by a substituent; Each R 10 independently selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, -C 0-8 Alkyl C 3-12 Cycloalkyl, -C 0-8 Alkyl 3-12 membered heterocyclic group, -C 0-8 Alkyl C 6-10 Aryl, -C 0-8 Alkyl 5-10 membered heteroaryl, and -NR 13 R 14 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, C 1-10 Alkyl, C 1-10 Alkoxy, C 3- 12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR 13 R 14 substituted by a substituent; Each R 11 independently selected from hydrogen, deuterium, C 1-10 Alkyl, C 2-10 Alkenyl, -C 0-8 Alkyl C 3-12 Cycloalkyl, -C 0-8 Alkyl 3-12 membered heterocyclic group, -C 0-8 Alkyl C 6-10 Aryl, -C 0-8 Alkyl 5-10 membered heteroaryl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3- 12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR 13 R 14 substituted by a substituent; Each R 12 independently selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, -C 0-8 Alkyl C 3-12 Cycloalkyl, -C 0-8 Alkyl C 3-12 Cycloalkoxy, -C 0-8 Alkyl 3-12 membered heterocyclic group, -C 0-8 Alkyl 3-12 membered heterocyclic oxy group, -C 0-8 Alkyl C 6-10 Aryl, -C 0-8 Alkyl C 6-10 Aryloxy, -C 0-8 Alkyl 5-10 membered heteroaryl, -C 0-8 Alkyl 5-10 membered heteroaryloxy and -NR 13 R 14 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR 13 R 14 substituted by a substituent; Each R 13 and R 14 are independently selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, -C 0-8 Alkyl C 3-12 Cycloalkyl, -C 0-8 Alkyl 3-12 membered heterocyclic group, -C 0-8 Alkyl C 6-10 Aryl, -C 0-8 Alkyl 5-10 membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl and C 1-10 Alkanoyl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono C 1-10 Alkylamino, di-C 1-10 Alkylamino and C 1-10 substituted with an alkanoyl substituent; Or, R 13 and R 14 Together with the nitrogen atom directly connected thereto, a 4-10 membered heterocyclic group or a 5-10 membered heteroaryl group is formed, wherein the 4-10 membered heterocyclic group or the 5-10 membered heteroaryl group is optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, ═O, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono C 1-10 Alkylamino, di-C 1-10 Alkylamino and C 1- 10 substituted with an alkanoyl substituent; Each r is independently 0, 1 or 2.

2. The pyridone compound according to claim 1, wherein R 30 Selected from -CN, hydrogen, deuterium, halogen, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkyl C 3-10 Cycloalkyl, -C 0-4 Alkyl 3-10 membered heterocyclic group, -C 0- 4-alkyl C 6-10 Aryl, -C 0-4 Alkyl 5-10 membered heteroaryl, -C 0-4 Alkyl-S(O) r R 10 、-C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)R 12 、-C 0-4 Alkyl-OC(O)R 12 、-C 0-4 Alkyl-P(O)(R 12 )2. -C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 , the above groups are independently optionally further substituted by one or more substituents selected from deuterium and halogen; R1 is selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkyl C 3-6 Cycloalkyl, -C 0-4 Alkyl 3-6 membered heterocyclic group, -C 0-4 Alkyl C 6-10 Aryl, -C 0-4 Alkyl 5-10 membered heteroaryl, -C 1-4 Alkyl-S(O) r R 10 、-C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)SR 11 、-C 0-4 Alkyl-C(O)R 12 、-C 0-4 Alkyl-OC(O)R 12 、-C 1-4 Alkyl-P(O)(R 12 )2. -C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, -C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 =C(R 11 )2. -C 1-4 Alkyl-SC(O)R 12 、-C 0-4 Alkyl-C(O)R 12 、-C 1-4 Alkyl-OC(O)R 12 、-C 0-4 Alkyl-P(O)(R 12 )2. -C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 substituted by a substituent; R2 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkyl C 3-10 Cycloalkyl, -C 0-4 Alkyl 3-10 membered heterocyclic group, -C 0-4 Alkyl C 6-10 Aryl, -C 0-4 Alkyl 5-10 membered heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=N-R7)R8, -C 0-4 Alkyl-N=S(O)R8R9, -C 0-4 Alkyl-OS(O)2R 10 、-C 0-4 Alkyl-S(O) r R 10 、-C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)SR 11 、-C 0-4 Alkyl-SC(O)R 12 、-C 0-4 Alkyl-C(O)R 12 、-C 0-4 Alkyl-OC(O)R 12 、-C 0-4 Alkyl-P(O)(R 12 )2. -C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(=NR 13 )R 12 、-C 0-4 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-4 Alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=N-R7)R8, -C 0-4 Alkyl-N=S(O)R8R9, -C 0-4 Alkyl-OS(O)2R 10 、-C 0-4 Alkyl-S(O) r R 10 、-C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)SR 11 =C(R 11 )2. -C 0-4 Alkyl-SC(O)R 12 、-C 0-4 Alkyl-C(O)R 12 、-C 0-4 Alkyl-OC(O)R 12 、-C 0- 4-alkyl-P(O)(R 12 )2. -C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(=NR 13 )R 12 、-C 0-4 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-4 Alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 substituted by a substituent; R3 is selected from hydrogen, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkyl C 3-6 Cycloalkyl, -C 0-4 Alkyl 3-6 membered heterocyclic group, -C 0-4 Alkyl C 6-10 Aryl, -C 0-4 Alkyl 5-10 membered heteroaryl, -C 0-4 Alkyl-S(O) r R 10 、-C 1-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)SR 11 、-C 1-4 Alkyl-SC(O)R 12 、-C 0-4 Alkyl-C(O)R 12 、-C 1-4 Alkyl-OC(O)R 12 、-C 0-4 Alkyl-P(O)(R 12 )2. -C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(=NR 13 )R 12 、-C 0-4 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-4 Alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )- C(O)R 12 , the above groups are independently optionally further substituted by one or more substituents selected from deuterium, halogen, and cyano; X is selected from a bond, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkyl C 3-12 Cycloalkyl, -C 0-4 Alkyl 3-12 membered heterocyclic ring, -C 0-4 Alkyl C 6-10 Aromatic ring, -C 0-4 Alkyl 5-10 membered heteroaromatic ring, -C 0-4 Alkyl-S(O)(=N-R7)R8, -C 0-4 Alkyl-OS(O)2R 10 、-C 0-4 Alkyl-S(O) r R 10 、-C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)SR 11 、-C 0-4 Alkyl-SC(O)R 12 、-C 0-4 Alkyl-C(O)R 12 、-C 0-4 Alkyl-OC(O)R 12 、-C 0-4 Alkyl-P(O)(R 12 )2. -C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(=NR 13 )R 12 、-C 0-4 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-4 Alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=N-R7)R8, -C 0-4 Alkyl-N=S(O)R8R9, -C 0-4 Alkyl-OS(O)2R 10 、-C 0-4 Alkyl-S(O) r R 10 、-C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)SR 11 =C(R 11 )2. -C 0-4 Alkyl-SC(O)R 12 、-C 0-4 Alkyl-C(O)R 12 、-C 0-4 Alkyl-OC(O)R 12 、-C 0- 4-alkyl-P(O)(R 12 )2. -C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(=NR 13 )R 12 、-C 0-4 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-4 Alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 substituted by a substituent; Each R4 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkyl C 3-8 Cycloalkyl, -C 0-4 Alkyl 3-8 membered heterocyclic group, -C 0-4 Alkyl C 6-10 Aryl, -C 0- 4-alkyl 5-10 membered heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=N-R7)R8, -C 0-4 Alkyl-N=S(O)R8R9, -C 0-4 Alkyl-OS(O)2R 10 、-C 0-4 Alkyl-S(O) r R 10 、-C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)SR 11 =C(R 11 )2、=O、-C 0-4 Alkyl-SC(O)R 12 、-C 0-4 Alkyl-C(O)R 12 、-C 0-4 Alkyl-OC(O)R 12 、-C 0-4 Alkyl-P(O)(R 12 )2. -C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(=NR 13 )R 12 、-C 0-4 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-4 Alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=N-R7)R8, -C 0-4 Alkyl-N=S(O)R8R9, -C 0-4 Alkyl-OS(O)2R 10 、-C 0-4 Alkyl-S(O) r R 10 、-C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)SR 11 =C(R 11 )2. -C 0-4 Alkyl-SC(O)R 12 、-C 0-4 Alkyl-C(O)R 12 、-C 0-4 Alkyl-OC(O)R 12 、-C 0-4 Alkyl-P(O)(R 12 )2. -C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(=NR 13 )R 12 、-C 0-4 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-4 Alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 substituted by a substituent; R5 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkyl C 3-8 Cycloalkyl, -C 0-4 Alkyl 3-8 membered heterocyclic group, -C 0-4 Alkyl C 6-10 Aryl, -C 0-4 Alkyl 5-10 membered heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=N-R7)R8, -C 0-4 Alkyl-N=S(O)R8R9, -C 0-4 Alkyl-OS(O)2R 10 、-C 0-4 Alkyl-S(O) r R 10 、-C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)SR 11 =C(R 11 )2、=O、-C 0-4 Alkyl-SC(O)R 12 、-C 0-4 Alkyl-C(O)R 12 、-C 0-4 Alkyl-OC(O)R 12 、-C 0-4 Alkyl-P(O)(R 12 )2. -C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(=NR 13 )R 12 、-C 0-4 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-4 Alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=N-R7)R8, -C 0-4 Alkyl-N=S(O)R8R9, -C 0-4 Alkyl-OS(O)2R 10 、-C 0-4 Alkyl-S(O) r R 10 、-C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)SR 11 =C(R 11 )2. -C 0-4 Alkyl-SC(O)R 12 、-C 0-4 Alkyl-C(O)R 12 、-C 0-4 Alkyl-OC(O)R 12 、-C 0-4 Alkyl-P(O)(R 12 )2. -C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(=NR 13 )R 12 、-C 0-4 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-4 Alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 substituted by a substituent; Each R6 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=N-R7)R8, -C 0-4 Alkyl-N=S(O)R8R9, -C 0-4 Alkyl-OS(O)2R 10 、-C 0-4 Alkyl-S(O) r R 10 、-C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)SR 11 =C(R 11 )2、=O、-C 0-4 Alkyl-SC(O)R 12 、-C 0-4 Alkyl-C(O)R 12 、-C 0-4 Alkyl-OC(O)R 12 、-C 0-4 Alkyl-P(O)(R 12 )2. -C 0-4 Alkyl-NR 13 R 14 、=NR 13 、-C 0-4 Alkyl-C(=NR 13 )R 12 、-C 0-4 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-4 Alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 , or two R6 and the atoms to which they are connected together form C 3-12 Cycloalkyl or 3-12 membered heterocyclic group; each of the above groups is independently optionally further substituted by one or more substituents selected from the following: deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=N-R7)R8, -C 0-4 Alkyl-N=S(O)R8R9, -C 0-4 Alkyl-OS(O)2R 10 、-C 0-4 Alkyl-S(O) r R 10 、-C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)SR 11 =C(R 11 )2. -C 0-4 Alkyl-SC(O)R 12 、-C 0-4 Alkyl-C(O)R 12 、-C 0-4 Alkyl-OC(O)R 12 、-C 0-4 Alkyl-P(O)(R 12 )2. -C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(=NR 13 )R 12 、-C 0-4 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-4 Alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 ; Among them, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , r and n are as defined in claim 1.

3. The pyridone compound according to claim 1, characterized in that Each R7 is independently selected from hydrogen, deuterium, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkyl C 3-8 Cycloalkyl, -C 0-4 Alkyl 3-8 membered heterocyclic group, -C 0-4 Alkyl C 6-8 Aryl, -C 0-4 Alkyl 5-8 membered heteroaryl, -C 0-4 Alkyl-S(O) r R 10 、-C 0-4 Alkyl-C(O)OR 11 、-C 0- 4-alkyl-C(O)R 12 or -C 0-4 Alkyl-C(O)NR 13 R 14 The above groups are optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-8 Alkynyl, halogen-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, -C 0-4 Alkyl-S(O) r R 10 、-C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)R 12 、-C 0-4 Alkyl-OC(O)R 12 、-C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(=NR 13 )R 12 、-C 0-4 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-4 Alkyl-C(O)NR 13 R 14 or -C 0-4 Alkyl-N(R 13 )-C(O)R 12 substituted by a substituent; Each R8 and each R9 are independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkyl C 3-6 Cycloalkyl, -C 0-4 Alkyl 3-8 membered heterocyclic group, -C 0-4 Alkyl C 6-8 Aryl, -C 0-4 alkyl 5-8 membered heteroaryl, or, R8 and R9 together with the sulfur atom to which they are directly connected form a 3-6 membered heterocyclic group, the above groups are optionally further substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, -C 0-4 Alkyl-S(O) r R 10 、-C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)R 12 、-C 0-4 Alkyl-OC(O)R 12 、-C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(=NR 13 )R 12 、-C 0-4 Alkyl-N(R 13 )-C(=NR 14 )R 12 、-C 0-4 Alkyl-C(O)NR 13 R 14 or -C 0-4 Alkyl-N(R 13 )-C(O)R 12 substituted by a substituent; Each R 10 independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl and -NR 13 R 14 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR 13 R 14 substituted by a substituent; Each R 11 independently selected from hydrogen, deuterium, C 1-10 Alkyl, C 2-10 Alkenyl, -C 0-8 Alkyl C 3-12 Cycloalkyl, -C 0-8 Alkyl 3-12 membered heterocyclic group, -C 0-8 Alkyl C 6-10 Aryl, -C 0-8 Alkyl 5-10 membered heteroaryl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3- 12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR 13 R 14 substituted by a substituent; Each R 12 independently selected from hydrogen, deuterium, C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl and 5-8 membered heteroaryl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR 13 R 14 substituted by a substituent; Each R 13 and R 14 are independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl and C 1-4 Alkanoyl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono C 1-4 Alkylamino, di-C 1-4 Alkylamino and C 1-4 substituted with an alkanoyl substituent; Or, R 13 and R 14 Together with the nitrogen atom directly connected thereto, a 4-8 membered heterocyclic group or a 5-8 membered heteroaryl group is formed, wherein the 4-8 membered heterocyclic group or the 5-8 membered heteroaryl group is optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, ═O, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono C 1-4 Alkylamino, di-C 1-4 Alkylamino and C 1-4 The alkanoyl group is substituted with an alkanoyl substituent.

4. The pyridone compound according to any one of claims 1 to 3, characterized in that R1 is selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkyl C 3-6 Cycloalkyl, -C 0-4 Alkyl 3-6 membered heterocyclic group, -C 0-4 Alkyl C 6-10 Aryl, -C 0-4 Alkyl 5-10 membered heteroaryl, -C 1-4 Alkyl-S(O) r R 10 、-C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)SR 11 、-C 0-4 Alkyl-C(O)R 12 、-C 0-4 Alkyl-OC(O)R 12 、-C 1-4 Alkyl-P(O)(R 12 )2. -C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 , the above groups are independently optionally further substituted by one or more substituents selected from deuterium and halogen; R2 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkyl C 3-10 Cycloalkyl, -C 0-4 Alkyl 3-10 membered heterocyclic group, -C 0-4 Alkyl C 6-10 Aryl, -C 0-4 Alkyl 5-10 membered heteroaryl, -C 0-4 Alkyl-S(O) r R 10 、-C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)R 12 、-C 0-4 Alkyl-OC(O)R 12 、-C 0-4 Alkyl-P(O)(R 12 )2. -C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 , the above groups are independently optionally further substituted by one or more substituents selected from deuterium and halogen; R3 is selected from hydrogen, C 1-4 Alkyl, -C 3-6 Cycloalkyl, -3-6 membered heterocyclic group, -C 1-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 , the above groups are independently optionally further substituted by one or more substituents selected from deuterium, halogen, and cyano.

5. The pyridone compound according to any one of claims 1 to 4, characterized in that X is selected from -C 3-10 Cycloalkyl, -3-10 membered heterocycle, -C 6-10 Aromatic ring, -5-10 membered heteroaromatic ring.

6. The pyridone compound according to any one of claims 1 to 5, characterized in that X is selected from a benzene ring, a naphthalene ring, or a 5-10 membered heteroaromatic ring; R1 is selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkyl C 3-6 Cycloalkyl, -C 0-4 Alkyl 4-6 membered heterocyclic group, -C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 , the above groups are independently optionally further substituted by one or more substituents selected from deuterium and halogen; R2 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkyl C 3-10 Cycloalkyl, -C 0-4 Alkyl 3-10 membered heterocyclic group, -C 0-4 Alkyl-S(O) r R 10 、-C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-P(O)(R 12 )2. -C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 , the above groups are independently optionally further substituted by one or more substituents selected from deuterium and halogen; R3 is H.

7. The pyridone compound according to any one of claims 1 to 6, characterized in that It has the structure shown in the following general formula (II): Among them, Y 1 N or CR 41 ; Y 2 N or CR 42 ; Z 1 N or CR 51 ; Z 2 N or CR 52 ; R 41 、R 42 、R 51 、R 52 Each independently selected from: H, deuterium, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, C 4-8 Heterocyclic group, phenyl group, -N(R 13 )-C(O)R 12 、C 2-6 Alkynyl, -S(O) r R 10 、-NR 13 R 14 , the above groups may be independently optionally further substituted by one or more substituents selected from deuterium and halogen; R0 is selected from: H, deuterium, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, -C 0-4 Alkyl 4-8 membered heterocyclic group, -C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C 1-4 Alkoxy, -C 0-4 Alkyl-S(O) r -C 1-4 Alkyl, hydroxyl, -C 0-4 Alkyl-CN, -C 0-4 Alkyl-C(O)NR 13 R 14 、-C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-N(R 13 )-C(O)R 12 、-C 0-4 Alkyl-N(R 13 )-S(O) r R 12 、-C 0-4 Alkyl-N(R 13 )-C(=NR 14 )R 12 、C 2-6 Alkenyl, C 2-6 Alkynyl, the above groups may be independently further substituted with one or more substituents selected from deuterium, halogen, and hydroxyl; Each R 61 Each independently selected from: H, deuterium, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, -C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C 1-4 Alkoxy, -C 0-4 Alkyl-S(O) r -C 1-4 Alkyl, hydroxyl, -C 0-4 Alkyl-CN, -C 0-4 Alkyl-C(O)NR 13 R 14 、-C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-N(R 13 )-C(O)R 12 、-C 0-4 Alkyl-N(R 13 )-S(O) r R 12 、-C 0-4 Alkyl-N(R 13 )-C(=NR 14 )R 12 、C 2-6 Alkynyl, the above groups may be independently further substituted with one or more substituents selected from deuterium, halogen, and hydroxyl; Or, two R 61 Together they form =C(R 15 )2; Or, two R 61 Together with the carbon atoms to which they are directly attached, they form a 3-8 membered carbocyclic ring or a 4-8 membered heterocyclic ring containing 1-2 heteroatoms independently selected from O, S, and N; Each R 15 Each independently selected from: H, deuterium, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, -C 0-4 Alkyl-C 1-4 Alkoxy, -C 0-4 Alkyl 4-8 membered heterocyclic group, the above groups may be independently further substituted with one or more substituents selected from deuterium, halogen, hydroxyl; R1, R2, R 30 、R 10 、R 11 、R 12 、R 13 、R 14 , r is defined as above; The condition is that when Y 1 、Y 2 , Z 1 , Z 2 Any three of them are CH, CH and CH or N, CH and CH, and the fourth is CH or C(C 1-6 Alkyl), R1 is H or C 1-6 Alkyl, when R2 is H, R0, two R 61 Substituents together with the carbon atom to which they are attached are not C 1-6 alkyl.

8. The pyridone compound according to any one of claims 1 to 7, characterized in that It has the structure shown in the following general formula (III): in, Y 1 N or CR 41 ; Y 2 N or CR 42 ; Z 1 N or CR 51 ; Z 2 N or CR 52 ; R 41 、R 42 、R 51 、R 52 Each independently selected from: H, deuterium, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, C 4-8 Heterocyclic group, phenyl group, -N(R 13 )-C(O)R 12 、C 2-6 Alkynyl, -S(O) r R 10 、-NR 13 R 14 , the above groups may be independently optionally further substituted by one or more substituents selected from deuterium and halogen; Ring A is a 3-8 membered carbocyclic ring or a 4-8 membered heterocyclic ring containing 1-2 heteroatoms independently selected from O, S, and N; Each R 62 Each independently selected from: H, deuterium, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, -C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C 1-4 Alkoxy, -C 0-4 Alkyl-S(O) r -C 1-4 Alkyl, hydroxyl, -C 0-4 Alkyl-CN, -C 0-4 Alkyl-C(O)NR 13 R 14 、-C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-N(R 13 )-C(O)R 12 、-C 0-4 Alkyl-N(R 13 )-S(O) r R 12 、-C 0-4 Alkyl-N(R 13 )-C(=NR 14 )R 12 、=O、=C(R 15 ) 2, the above groups may be independently optionally further substituted with one or more substituents selected from deuterium, halogen, and hydroxyl; t is 1, 2, 3, or 4; R1, R2, R 30 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 , r are defined as before.

9. The pyridone compound according to claim 8, characterized in that Ring A is a 3-6 membered carbocyclic ring or a 4-8 membered heterocyclic ring containing 1-2 heteroatoms independently selected from O, S, and N; R1 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-4 Alkyl, -C 1-4 Alkyl-OR 11 and -C 0-4 Alkyl-NR 13 R 14 , the above groups are independently optionally further substituted by one or more substituents selected from deuterium and halogen; R2 is selected from the group consisting of: hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl C 3-10 Cycloalkyl, -C 0-4 Alkyl 3-10 membered heterocyclic group, -C 0-4 Alkyl-NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 , the above groups are independently optionally further substituted by one or more substituents selected from deuterium and halogen; R 30 Selected from: -CN, hydrogen, deuterium, halogen, C 1-4 Alkyl, -C 0-4 Alkyl-S(O) r R 10 、-C 0-4 Alkyl-OR 11 、-C 0-4 Alkyl-C(O)OR 11 、-C 0-4 Alkyl-C(O)R 12 、-C 0-4 Alkyl-OC(O)R 12 、-C 0-4 Alkyl-P(O)(R 12 )2. -C 0-4 Alkyl-NR 13 R 14 、-C 0-4 Alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 , the above groups are independently optionally further substituted by one or more substituents selected from deuterium and halogen.

10. The pyridone compound according to claim 8 or 9, characterized in that It has the structure shown in the following general formula (IV), (V) or (VI): Among them, R 41 、R 42 、R 51 、R 52 Each independently selected from: H, deuterium, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, C 4-8 Heterocyclic group, phenyl group, -N(R 13 )-C(O)R 12 、C 2-6 Alkynyl, -S(O) r R 10 、-NR 13 R 14 , the above groups may be independently optionally further substituted by one or more substituents selected from deuterium and halogen; Ring A, R0, R1, R2, R 10 、R 12 、R 13 、R 14 、R 30 、R 62 The definitions of , t, and r are the same as before.

11. The pyridone compound according to any one of claims 1 to 10, characterized in that R0 is selected from: H, deuterium, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, -C 0-4 Alkyl 4-8 membered heterocyclic group, -C 0-4 Alkyl-C(O)OR 16 、-C 0-4 Alkyl-C 1- 4-alkoxy, -C 0-4 Alkyl-S(O) r -C 1-4 Alkyl, hydroxyl, -C 0-4 Alkyl-CN, -C 0-4 Alkyl-C(O)N(R 16 )2. -C 0-4 Alkyl-N(R 16 )2. -C 0-4 Alkyl-N(R 16 )-C(O)R 16 、-C 0-4 Alkyl-N(R 16 )-S(O) r R 16 、-C 0-4 Alkyl-N(R 16 )-C(=NR 16 )R 12 、C 2-6 Alkenyl, C 2-6 Alkynyl, the above groups may be independently further substituted with one or more substituents selected from deuterium, halogen, and hydroxyl; R 41 、R 42 、R 51 、R 52 Each independently selected from: H, deuterium, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, C 4-8 Heterocyclic group, phenyl group, -N(R 16 )-C(O)R 16 、C 2-6 Alkynyl, -S(O) r R 16 、-N(R 16 ) 2, the above groups may be independently optionally further substituted by one or more substituents selected from deuterium and halogen; Each R 62 Each independently selected from: H, deuterium, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, -C 0-4 Alkyl-C(O)OR 16 、-C 0-4 Alkyl-C 1-4 Alkoxy, -C 0-4 Alkyl-S(O) r -C 1-4 Alkyl, hydroxyl, -C 0-4 Alkyl-C(O)N(R 16 )2. -C 0- 4-alkyl-N(R 16 )2. -C 0-4 Alkyl-N(R 16 )-C(O)R 16 、-C 0-4 Alkyl-N(R 16 )-S(O) r R 16 、=O、=C(R 15 ) 2, the above groups may be independently optionally further substituted with one or more substituents selected from deuterium, halogen, and hydroxyl; Each R 16 Each independently selected from: hydrogen, deuterium, C 1-4 Alkyl, C 1-4 alkyl halide; R 15 , r is defined as before.

12. The pyridone compound according to any one of claims 1 to 11, characterized in that R1 is selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy.

13. The pyridone compound according to claims 1-11, characterized in that R2 is selected from hydrogen, deuterium, halogen, C 1- 4 alkyl, C 1-4 Halogenated alkyl.

14. The pyridone compound according to claims 1-11, characterized in that R 30 Selected from -CN, -N(R 16 )2, -OR 16 , -C(O)OR 16 , -C(O)N(R 16 )2 and -N(R 16 )-C(O)R 16 ; Each R 16 Independent of each other and have the same definition as before.

15. The pyridone compound according to any one of claims 8 to 14, characterized in that Ring A is a cyclopropane ring; R1 is selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, C 1-4 alkyl halide; Each R 62 Each independently selected from: H, deuterium, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, -C(O)OR 16 、-C 0-4 Alkyl-C 1-4 Alkoxy, hydroxy, -C(O)N(R 16 )2、-N(R 16 )2; t is 0, 1, or 2; Each R 16 Independent of each other and have the same definition as before.

16. The pyridone compound according to any one of claims 1 to 6, characterized in that It has the structure shown in the following general formula (VII): wherein Ring B is a 5-8 membered carbocyclic ring or a 5-10 membered heterocyclic ring containing 1-2 heteroatoms independently selected from O, S, and N; R1 is selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 haloalkoxy; R2 is selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, C 1-4 alkyl halide; R 30 Selected from -CN, -N(R 16 )2, -OR 16 , -C(O)OR 16 , -C(O)N(R 16 )2 and -N(R 16 )-C(O)R 16 ; Each R 70 Each independently selected from: H, deuterium, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, -C 0-4 Alkyl-C(O)OR 16 、-C 0-4 Alkyl-C 1-4 Alkoxy, -C 0-4 Alkyl-S(O) r R 16 , hydroxyl, -C 0-4 Alkyl-CN, -C 0-4 Alkyl-C(O)N(R 16 )2. -C 0-4 Alkyl-N(R 16 )2. -C 0-4 Alkyl-N(R 16 )-C(O)R 16 、-C 0-4 Alkyl-N(R 16 )-S(O) r R 16 、-C 0-4 Alkyl-N(R 16 )-C(=NR 16 )R 16 、C 2-6 Alkenyl, C 2-6 Alkynyl, the above groups may be independently further substituted with one or more substituents selected from deuterium, halogen, and hydroxyl; Two R's attached to the same carbon atom 70 Can form O or =C(R 15 )2; Two R's attached to the same carbon atom 70 Together with the carbon atoms to which they are directly attached, they may further form a 3-8 membered carbocyclic ring or a 4-8 membered heterocyclic ring containing 1-2 heteroatoms independently selected from O, S, and N; Each Q is independently N or CR 80 ; Each R 80 Each independently selected from: H, deuterium, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, C 4-8 Heterocyclic group, phenyl group, -N(R 16 )-C(O)R 16 、C 2-6 Alkynyl, -S(O) r R 16 、-N(R 16 ) 2, the above groups may be independently optionally further substituted by one or more substituents selected from deuterium and halogen; Each R 15 Each independently selected from: H, deuterium, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, -C 0-4 Alkyl-C 1-4 Alkoxy, -C 0-4 Alkyl 4-8 membered heterocyclic group, the above groups may be independently further substituted with one or more substituents selected from deuterium, halogen, hydroxyl; Each R 16 Each independently selected from: hydrogen, deuterium, C 1-4 Alkyl, C 1-4 alkyl halide; s is 0, 1, 2, 3, or 4; r is 0, 1, or 2.

17. The pyridone compound according to claim 16, characterized in that Ring B is a 5-6 membered carbocyclic ring or a 5-7 membered heterocyclic ring containing 1 heteroatom selected from O, S, and N; Each R 70 Each independently selected from: H, deuterium, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, -C 0-4 Alkyl-C 1-4 Alkoxy, -C 0-4 Alkyl-S(O) r R 16 , hydroxyl, -C 0-4 Alkyl-C(O)N(R 16 )2. -C 0-4 Alkyl-N(R 16 )2. -C 0-4 Alkyl-N(R 16 )-C(O)R 16 、-C 0-4 Alkyl-N(R 16 )-S(O) r R 16 、-C 0-4 Alkyl-N(R 16 )-C(=NR 16 )R 16 、C 2-6 Alkenyl, C 2-6 Alkynyl, the above groups may be independently further substituted with one or more substituents selected from deuterium, halogen, and hydroxyl; Two R's attached to the same carbon atom 70 Can form O or =C(R 15 )2; Two R's attached to the same carbon atom 70 Together with the carbon atoms to which they are directly attached, they may further form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring containing one heteroatom selected from O, S, and N; Each Q group has 0 or 1 N.

18. The pyridone according to claim 1, wherein The pyridone compound is selected from the following group:

19. Use of the pyridone compound according to any one of claims 1 to 18, or a stereoisomer, solvate, pharmaceutically acceptable salt or prodrug thereof as a PDE3A-SLFN12 complex inducer.

20. A pharmaceutical composition comprising the pyridone compound according to any one of claims 1 to 18, a stereoisomer, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

21. A kit comprising the pyridone compound according to any one of claims 1 to 18, a stereoisomer, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, or the pharmaceutical composition according to claim 20.

22. A pyridone compound according to any one of claims 1 to 18, or use of a stereoisomer, solvate, pharmaceutically acceptable salt or prodrug thereof in the preparation of a medicament for preventing or treating tumors or cancer by forming a stable PDE3A-SLFN12 complex, wherein: The tumor or cancer is selected from the group consisting of lung malignancies or cancers, hepatobiliary malignancies or cancers, gastrointestinal malignancies or cancers, hematological malignancies or cancers, sarcomas, skin malignancies or cancers, bone malignancies or cancers, genitourinary tract malignancies or cancers, nervous system malignancies or cancers, gynecological malignancies or cancers, and adrenal malignancies or cancers; Preferably, the lung malignancy or cancer is selected from bronchogenic carcinoma (squamous cell carcinoma, undifferentiated small cell, undifferentiated large cell or adenocarcinoma), non-small cell lung cancer, bronchogenic carcinoma, bronchial adenoma, sarcoma, lymphoma, cartilaginous hamartoma or mesothelioma; The hepatobiliary malignancy or cancer is selected from the group consisting of liver cancer, bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, gallbladder cancer, ampullary cancer, or bile duct cancer; The gastrointestinal malignancy or cancer is selected from the group consisting of esophageal malignancy or cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, or lymphoma), gastric malignancy or cancer (carcinoma, lymphoma, or leiomyosarcoma), pancreatic malignancy or cancer (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, uveal tumor), small intestine (adenocarcinoma, lymphoma, carcinoid, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colorectal malignancy or cancer (adenocarcinoma, adenoma, adenoma, tubular adenoma), or leiomyoma; The hematological malignancy or cancer is selected from acute or chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease or non-Hodgkin's lymphoma; The sarcoma is selected from the group consisting of angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, or teratoma; The skin malignancy or cancer is selected from malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus mole, hyperplastic nevus, lipoma, hemangioma, dermatofibroma, keloid or psoriasis; The bone malignancy or cancer is selected from osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, multiple myeloma, malignant giant cell tumor chordoma, osteochondroma, benign enchondroma, chondroblastoma, chondromycofibroma, osteoid osteoma or giant cell tumor; The genitourinary tract malignancy or cancer is selected from the group consisting of a renal malignancy or cancer (adenocarcinoma, Wilms' tumor or Nephron cell tumor), lymphoma, leukemia, bladder or urinary tract malignancy or cancer (squamous cell carcinoma, transitional cell carcinoma, or adenocarcinoma), prostate malignancy or cancer (adenocarcinoma or sarcoma), testicular malignancy or cancer (leukemia, teratoma, embryonal carcinoma, or teratoma), choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, or lipoma; The nervous system malignancy or cancer is selected from osteoma, hemangioma, granuloma, xanthomas, osteitis deformans, meningioma, meningiosarcoma, gliomatosis, astrocytoma, medulloblastoma, glioma, ependymoma, genital tumor, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor, spinal neurofibroma, meningioma, glioma or sarcoma; The gynecological malignancy or cancer is selected from endometrial carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma or unclassified carcinoma), granulosa-theca cell tumor, testicular interstitial cell tumor, dysmyoma of the fascia, malignant teratoma, squamous cell carcinoma, fibroepithelial carcinoma, glandular carcinoma, melanoma, clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma or fallopian tube carcinoma; The adrenal gland malignancy or cancer is selected from neuroblastoma.

23. A method for preventing or treating tumors or cancer in a subject by forming a stable PDE3A-SLFN12 complex, the method comprising injecting into the subject an effective amount of the pyridone compound according to any one of claims 1 to 18, its stereoisomer, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition according to claim 20.

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