Compounds containing trifluoromethyl groups

Abstract

Provided are compounds containing a trifluoromethyl group, specifically compounds of formula I-0 or pharmaceutically acceptable salts thereof, methods for preparing the compounds, pharmaceutical compositions containing the compounds, and uses thereof in treating tumor diseases.

Description

Compounds containing a trifluoromethyl group

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority and benefits of Chinese Patent Application No. 202210817391.0 filed with the State Intellectual Property Office of China on July 12, 2022, Chinese Patent Application No. 202310226014.4 filed with the State Intellectual Property Office of China on January 16, 2023, and Chinese Patent Application No. 202310815128.2 filed with the State Intellectual Property Office of China on July 4, 2023, and the contents disclosed in said applications are incorporated herein by reference in their entirety. Technical Field

[0003] The present application relates to a compound containing a trifluoromethyl group, a preparation method thereof, a pharmaceutical composition containing the compound, and use thereof in treating tumor diseases. Background Art

[0004] The B-cell lymphoma 2 (Bcl-2) family of proteins, composed of pro-apoptotic and anti-apoptotic members, plays a key role in determining cell fate by regulating the intrinsic apoptotic pathway. Anti-apoptotic Bcl-2 family proteins (such as Bcl-2, Bcl-xL, Bcl-W, and Mcl-1) are upregulated in many cancers and are associated with tumor initiation, progression, and resistance to chemotherapy and targeted therapies. Because the growth of most solid tumors is independent of BCL-2 proteins, simply targeting BCL-2 inhibitors has no significant effect in the treatment of solid tumors. However, BCL-XL protein expression is significantly elevated in many leukemia cells and solid tumors. Studies have shown that BCL-XL expression in tumor tissues is positively correlated with tumor drug resistance. Targeting BCL-XL is a potential ideal anti-tumor molecular target.

[0005] PROTAC (proteolysis targeting chimera) molecules are a class of bifunctional compounds that can simultaneously bind to target proteins and E3 ubiquitin ligases. These compounds can induce the target protein to be recognized by the cell's proteasome, causing the degradation of the target protein and effectively reducing the target protein's content in the cell. By introducing ligands that can bind to different target proteins into PROTAC molecules, PROTAC technology has become possible for the treatment of various diseases. This technology has also received widespread attention in recent years.

[0006] Summary of the Invention

[0007] The present application relates to a compound of formula I-0 or a pharmaceutically acceptable salt thereof,

[0008] in,

[0009] Every R 1 are independently selected from hydrogen, halogen, OH, NH2, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl OCO-, C 1-6 Alkyl C(O)O-, C 1-6 Alkyl NHCO-, C 1-6 AlkylCONH-, (C 1-6 Alkyl)2NCO-, C 1-6 Alkyl NHS(O)-, C 1-6 Alkyl S(O)NH-, (C 1-6 Alkyl) 2NS(O)-, C 1-6 Alkyl NHS(O)2-, C 1-6 Alkyl S(O)2NH-, (C 1-6 alkyl)2NS(O)2-、C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 Aryl or 5-12 membered heteroaryl;

[0010] n1 is selected from 1, 2, 3 or 4;

[0011] q is selected from 0, 1, 2, 3, 4, 5 or 6;

[0012] Every R 2 are independently selected from halogen, OH, NH2, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl OCO-, C 1-6 Alkyl C(O)O-, C 1-6 Alkyl NHCO-, C 1-6 AlkylCONH-, (C 1-6 Alkyl)2NCO-, C 1-6 AlkylNHS(O)-, C 1-6 Alkyl S(O)NH-, (C 1-6 Alkyl) 2NS(O)-, C 1-6Alkyl NHS(O)2-, C 1-6 Alkyl S(O)2NH-, (C 1-6 alkyl)2NS(O)2-、C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 Aryl or 5-12 membered heteroaryl;

[0013] m is selected from 0, 1, 2, 3, 4, 5 or 6;

[0014] Ring A is selected from C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 Aryl or 5-12 membered heteroaryl;

[0015] L is a linking group;

[0016] Every R 3 are independently selected from halogen, OH, NH2, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl OCO-, C 1-6 Alkyl C(O)O-, C 1-6 Alkyl NHCO-, C 1-6 AlkylCONH-, (C 1-6 Alkyl)2NCO-, C 1-6 AlkylNHS(O)-, C 1-6 Alkyl S(O)NH-, (C 1-6 Alkyl) 2NS(O)-, C 1-6 Alkyl NHS(O)2-, C 1-6 Alkyl S(O)2NH-, (C 1-6 alkyl)2NS(O)2-、C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 Aryl or 5-12 membered heteroaryl;

[0017] p is selected from 0, 1, 2 or 3;

[0018] R 4 and R 5 are independently selected from hydrogen, halogen, OH, NH2, CN, C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl OCO-, C 1-6 Alkyl C(O)O-, C 1-6 Alkyl NHCO-, C 1-6 AlkylCONH-, (C 1-6 Alkyl)2NCO-, C 1-6 AlkylNHS(O)-, C 1-6 Alkyl S(O)NH-, (C 1-6 Alkyl) 2NS(O)-, C 1-6 Alkyl NHS(O)2-, C 1-6 Alkyl S(O)2NH-, (C 1-6 alkyl)2NS(O)2-、C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl,

[0019] Or, R 4 and R 5 Connected to each other and connected carbon atoms together to form C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl;

[0020] X is selected from CR a R a’ or C=O;

[0021] X 1 Selected from CR b or N;

[0022] R a and R a ' may be the same or different, and are independently selected from hydrogen, halogen, OH, NH2, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl OCO-, C 1-6 Alkyl C(O)O-, C 1-6 Alkyl NHCO-, C 1-6 AlkylCONH-, (C 1-6Alkyl)2NCO-, C 1-6 AlkylNHS(O)-, C 1-6 Alkyl S(O)NH-, (C 1-6 Alkyl) 2NS(O)-, C 1-6 Alkyl NHS(O)2-, C 1-6 Alkyl S(O)2NH-, (C 1-6 alkyl)2NS(O)2-、C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 Aryl or 5-12 membered heteroaryl;

[0023] R b Selected from hydrogen, halogen, OH, NH2, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl OCO-, C 1-6 Alkyl C(O)O-, C 1-6 Alkyl NHCO-, C 1-6 AlkylCONH-, (C 1-6 Alkyl)2NCO-, C 1-6 AlkylNHS(O)-, C 1-6 Alkyl S(O)NH-, (C 1-6 Alkyl) 2NS(O)-, C 1-6 Alkyl NHS(O)2-, C 1-6 Alkyl S(O)2NH-, (C 1-6 alkyl)2NS(O)2-、C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 Aryl or 5-12 membered heteroaryl;

[0024] The R 1 、R 2 , Ring A, R 3 、R 4 、R 5 、R a 、R a’ or R b Optionally substituted with one or more substituents.

[0025] In some embodiments, n1 is 1 or 2. In some embodiments, n1 is 1.

[0026] In some embodiments, each R 1 are independently selected from hydrogen, halogen, OH, NH2, CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkyl NH-, (C 1-4 Alkyl)2N-, C 1-4 Alkyl OCO-, C 1-4 Alkyl C(O)O-, C 1-4 Alkyl NHCO-, C 1-4 AlkylCONH-, (C 1-4 Alkyl)2NCO-, C 1-4 AlkylNHS(O)-, C 1-4 Alkyl S(O)NH-, (C 1-4 Alkyl) 2NS(O)-, C 1-4 Alkyl NHS(O)2-, C 1-4 Alkyl S(O)2NH-, (C 1-4 alkyl)2NS(O)2-、C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, said R 1 Optionally substituted with one or more substituents.

[0027] In some embodiments, each R 1 are independently selected from hydrogen, halogen, OH, NH2, CN, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkyl NH-, (C 1-3 Alkyl)2N-, C 1-3 Alkyl OCO-, C 1-3 Alkyl C(O)O-, C 1-3 Alkyl NHCO-, C 1-3 AlkylCONH-, (C 1-3 Alkyl)2NCO-, C 1-3 AlkylNHS(O)-, C 1-3 Alkyl S(O)NH-, (C 1-3 Alkyl) 2NS(O)-, C 1-3 Alkyl NHS(O)2-, C1-3 Alkyl S(O)2NH-, (C 1-3 alkyl)2NS(O)2-、C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, said R 1 Optionally substituted with one or more substituents.

[0028] In some embodiments, each R 1 independently selected from hydrogen, halogen, OH, NH2, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl OCO-, C 1-6 Alkyl C(O)O-, C 1-6 Alkyl NHCO-, C 1-6 AlkylCONH-, (C 1-6 Alkyl)2NCO-, C 1-6 AlkylNHS(O)-, C 1-6 Alkyl S(O)NH-, (C 1-6 Alkyl) 2NS(O)-, C 1-6 Alkyl NHS(O)2-, C 1-6 Alkyl S(O)2NH- or (C 1-6 alkyl) 2NS(O) 2-, the R 1 Optionally substituted with one or more substituents.

[0029] In some embodiments, each R 2 are independently selected from halogen, OH, NH2, CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkyl NH-, (C 1-4 Alkyl)2N-, C 1-4 Alkyl OCO-, C 1-4 Alkyl C(O)O-, C 1-4 Alkyl NHCO-, C 1-4 AlkylCONH-, (C 1-4 Alkyl)2NCO-, C 1-4 AlkylNHS(O)-, C1-4 Alkyl S(O)NH-, (C 1-4 Alkyl) 2NS(O)-, C 1-4 Alkyl NHS(O)2-, C 1-4 Alkyl S(O)2NH-, (C 1-4 alkyl)2NS(O)2-、C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, said R 2 Optionally substituted with one or more substituents.

[0030] In some embodiments, each R 2 are independently selected from halogen, OH, NH2, CN, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkyl NH-, (C 1-3 Alkyl)2N-, C 1-3 Alkyl OCO-, C 1-3 Alkyl C(O)O-, C 1-3 Alkyl NHCO-, C 1-3 AlkylCONH-, (C 1-3 Alkyl)2NCO-, C 1-3 AlkylNHS(O)-, C 1-3 Alkyl S(O)NH-, (C 1-3 Alkyl) 2NS(O)-, C 1-3 Alkyl NHS(O)2-, C 1-3 Alkyl S(O)2NH-, (C 1-3 alkyl)2NS(O)2-、C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, said R 2 Optionally substituted with one or more substituents.

[0031] In some embodiments, each R 2 Independently selected from halogen, OH, NH2, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl NH-, (C1-6 Alkyl)2N-, C 1-6 Alkyl OCO-, C 1-6 Alkyl C(O)O-, C 1-6 Alkyl NHCO-, C 1-6 AlkylCONH-, (C 1-6 Alkyl)2NCO-, C 1-6 AlkylNHS(O)-, C 1-6 Alkyl S(O)NH-, (C 1-6 Alkyl) 2NS(O)-, C 1-6 Alkyl NHS(O)2-, C 1-6 Alkyl S(O)2NH- or (C 1-6 alkyl) 2NS(O) 2-, the R 2 Optionally substituted with one or more substituents.

[0032] In some embodiments, each R 3 are independently selected from halogen, OH, NH2, CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkyl NH-, (C 1-4 Alkyl)2N-, C 1-4 Alkyl OCO-, C 1-4 Alkyl C(O)O-, C 1-4 Alkyl NHCO-, C 1-4 AlkylCONH-, (C 1-4 Alkyl)2NCO-, C 1-4 AlkylNHS(O)-, C 1-4 Alkyl S(O)NH-, (C 1-4 Alkyl) 2NS(O)-, C 1-4 Alkyl NHS(O)2-, C 1-4 Alkyl S(O)2NH-, (C 1-4 alkyl)2NS(O)2-、C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, said R 3 Optionally substituted with one or more substituents.

[0033] In some embodiments, each R 3 are independently selected from halogen, OH, NH2, CN, C 1-3 Alkyl, C 2-3 Alkenyl, C2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkyl NH-, (C 1-3 Alkyl)2N-, C 1-3 Alkyl OCO-, C 1-3 Alkyl C(O)O-, C 1-3 Alkyl NHCO-, C 1-3 AlkylCONH-, (C 1-3 Alkyl)2NCO-, C 1-3 AlkylNHS(O)-, C 1-3 Alkyl S(O)NH-, (C 1-3 Alkyl) 2NS(O)-, C 1-3 Alkyl NHS(O)2-, C 1-3 Alkyl S(O)2NH-, (C 1-3 alkyl)2NS(O)2-、C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, said R 3 Optionally substituted with one or more substituents.

[0034] In some embodiments, each R 3 Independently selected from halogen, OH, NH2, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl OCO-, C 1-6 Alkyl C(O)O-, C 1-6 Alkyl NHCO-, C 1-6 AlkylCONH-, (C 1-6 Alkyl)2NCO-, C 1-6 AlkylNHS(O)-, C 1-6 Alkyl S(O)NH-, (C 1-6 Alkyl) 2NS(O)-, C 1-6 Alkyl NHS(O)2-, C 1-6 Alkyl S(O)2NH- or (C 1-6 alkyl) 2NS(O) 2-, the R 3 Optionally substituted with one or more substituents.

[0035] In some embodiments, each R4 or R 5 are independently selected from hydrogen, halogen, OH, NH2, CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkyl NH-, (C 1-4 Alkyl)2N-, C 1-4 Alkyl OCO-, C 1-4 Alkyl C(O)O-, C 1-4 Alkyl NHCO-, C 1-4 AlkylCONH-, (C 1-4 Alkyl)2NCO-, C 1-4 AlkylNHS(O)-, C 1-4 Alkyl S(O)NH-, (C 1-4 Alkyl) 2NS(O)-, C 1-4 Alkyl NHS(O)2-, C 1-4 Alkyl S(O)2NH-, (C 1-4 alkyl)2NS(O)2-、C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl,

[0036] Or, R 4 and R 5 Connected to each other and connected carbon atoms together to form C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl; said R 4 or R 5 Optionally substituted with one or more substituents.

[0037] In some embodiments, each R 4 or R 5 are independently selected from hydrogen, halogen, OH, NH2, CN, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkyl NH-, (C 1-3 Alkyl)2N-, C 1-3 Alkyl OCO-, C 1-3 Alkyl C(O)O-, C 1-3 Alkyl NHCO-, C 1-3 AlkylCONH-, (C 1-3 Alkyl)2NCO-, C1-3 AlkylNHS(O)-, C 1-3 Alkyl S(O)NH-, (C 1-3 Alkyl) 2NS(O)-, C 1-3 Alkyl NHS(O)2-, C 1-3 Alkyl S(O)2NH-, (C 1-3 alkyl)2NS(O)2-、C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl,

[0038] Or, R 4 and R 5 Connected to each other and connected carbon atoms together to form C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl; said R 4 or R 5 Optionally substituted with one or more substituents.

[0039] In some embodiments, R 4 and R 5 are independently selected from hydrogen, halogen, OH, NH2, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl OCO-, C 1-6 Alkyl C(O)O-, C 1-6 Alkyl NHCO-, C 1-6 AlkylCONH-, (C 1-6 Alkyl)2NCO-, C 1-6 AlkylNHS(O)-, C 1-6 Alkyl S(O)NH-, (C 1-6 Alkyl) 2NS(O)-, C 1-6 Alkyl NHS(O)2-, C 1-6 Alkyl S(O)2NH- or (C 1-6 alkyl) 2NS(O) 2-, the R 4 or R 5 Optionally substituted with one or more substituents.

[0040] In some embodiments, R 4 and R 5 are independently selected from C 1-3 Alkyl, or R 4and R 5 Connected to each other and connected carbon atoms together to form C 3-4 In some embodiments, R 4 and R 5 are independently selected from methyl, or R 4 and R 5 Connected to each other and connected carbon atoms together to form C 3-4 In some embodiments, R 4 and R 5 are each independently selected from methyl.

[0041] In some embodiments, R a and R a’ may be the same or different and independently selected from hydrogen, halogen, OH, NH2, CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkyl NH-, (C 1-4 Alkyl)2N-, C 1-4 Alkyl OCO-, C 1-4 Alkyl C(O)O-, C 1-4 Alkyl NHCO-, C 1-4 AlkylCONH-, (C 1-4 Alkyl)2NCO-, C 1-4 AlkylNHS(O)-, C 1-4 Alkyl S(O)NH-, (C 1-4 Alkyl) 2NS(O)-, C 1-4 Alkyl NHS(O)2-, C 1-4 Alkyl S(O)2NH-, (C 1-4 alkyl)2NS(O)2-、C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, said R a or R a’ Optionally substituted with one or more substituents.

[0042] In some embodiments, R a and R a’ may be the same or different and independently selected from hydrogen, halogen, OH, NH2, CN, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C1-3 Alkylthio, C 1-3 Alkyl NH-, (C 1-3 Alkyl)2N-, C 1-3 Alkyl OCO-, C 1-3 Alkyl C(O)O-, C 1-3 Alkyl NHCO-, C 1-3 AlkylCONH-, (C 1-3 Alkyl)2NCO-, C 1-3 AlkylNHS(O)-, C 1-3 Alkyl S(O)NH-, (C 1-3 Alkyl) 2NS(O)-, C 1-3 Alkyl NHS(O)2-, C 1-3 Alkyl S(O)2NH-, (C 1-3 alkyl)2NS(O)2-、C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, said R a or R a’ Optionally substituted with one or more substituents.

[0043] In some embodiments, R a and R a ' may be the same or different, and are independently selected from hydrogen, halogen, OH, NH2, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl OCO-, C 1-6 Alkyl C(O)O-, C 1-6 Alkyl NHCO-, C 1-6 AlkylCONH-, (C 1-6 Alkyl)2NCO-, C 1-6 AlkylNHS(O)-, C 1-6 Alkyl S(O)NH-, (C 1-6 Alkyl) 2NS(O)-, C 1-6 Alkyl NHS(O)2-, C 1-6 Alkyl S(O)2NH- or (C 1-6 alkyl) 2NS(O) 2-, the R a and R a ' is optionally substituted with one or more substituents.

[0044] In some embodiments, R a and R a’ may be the same or different and are independently selected from hydrogen or halogen.

[0045] In some embodiments, R a and R a’ are the same and are each independently selected from hydrogen.

[0046] In some embodiments, R b Selected from hydrogen, halogen, OH, NH2, CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkyl NH-, (C 1-4 Alkyl)2N-, C 1-4 Alkyl OCO-, C 1-4 Alkyl C(O)O-, C 1-4 Alkyl NHCO-, C 1-4 AlkylCONH-, (C 1-4 Alkyl)2NCO-, C 1-4 AlkylNHS(O)-, C 1-4 Alkyl S(O)NH-, (C 1-4 Alkyl) 2NS(O)-, C 1-4 Alkyl NHS(O)2-, C 1-4 Alkyl S(O)2NH-, (C 1-4 alkyl)2NS(O)2-、C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, said R b Optionally substituted with one or more substituents.

[0047] In some embodiments, R b Selected from hydrogen, halogen, OH, NH2, CN, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkyl NH-, (C 1-3 Alkyl)2N-, C 1-3 Alkyl OCO-, C 1-3 Alkyl C(O)O-, C 1-3 Alkyl NHCO-, C 1-3 AlkylCONH-, (C1-3 Alkyl)2NCO-, C 1-3 AlkylNHS(O)-, C 1-3 Alkyl S(O)NH-, (C 1-3 Alkyl) 2NS(O)-, C 1-3 Alkyl NHS(O)2-, C 1-3 Alkyl S(O)2NH-, (C 1-3 alkyl)2NS(O)2-、C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, said R b Optionally substituted with one or more substituents.

[0048] In some embodiments, R b Selected from hydrogen, halogen, OH, NH2, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl OCO-, C 1-6 Alkyl C(O)O-, C 1-6 Alkyl NHCO-, C 1-6 AlkylCONH-, (C 1-6 Alkyl)2NCO-, C 1-6 AlkylNHS(O)-, C 1-6 Alkyl S(O)NH-, (C 1-6 Alkyl) 2NS(O)-, C 1-6 Alkyl NHS(O)2-, C 1-6 Alkyl S(O)2NH- or (C 1-6 alkyl) 2NS(O) 2-, the R b Optionally substituted with one or more substituents.

[0049] In some embodiments, R b is selected from hydrogen or halogen.

[0050] In some embodiments, R b Selected from hydrogen.

[0051] In some embodiments, Ring A is selected from C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6-10In some embodiments, the 3-4 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, 3-10 membered heterocycloalkyl, 3-12 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, 3-10 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl, 5-10 membered heteroaryl and 5-12 membered heteroaryl each independently contain 1, 2 or 3 heteroatoms independently selected from N, O and S.

[0052] In some embodiments, the R 1 、R 2 , Ring A, R 3 、R 4 、R 5 、R a 、R a’ or R b Optionally substituted with one or more substituents selected from the group consisting of -OH, -SH, halogen, -NH2, nitro, nitroso, -CN, an azide group, a sulfoxide group, a sulfone group, a sulfonamide group, a carboxyl group, a carboxaldehyde group, an imine group, an alkyl group, a halo-alkyl group, a cycloalkyl group, a halo-cycloalkyl group, an alkenyl group, a halo-alkenyl group, a cycloalkenyl group, a halo-cycloalkenyl group, an alkynyl group, a halo-alkynyl group, a cycloalkynyl group, a halo-cycloalkynyl group, a heteroalkyl group, a halo - heteroalkyl group, alkoxy group, alkylthio group, aryl group, aryloxy group, arylthio group, aralkyl group, arylalkoxy group, arylalkylthio group, heteroaryl group, heteroaryloxy group, heteroarylthio group, heteroaralkyl group, heteroarylalkoxy group, heteroarylalkylthio group, heterocyclyl group, heterocyclyloxy group, heterocyclylthio group, heterocyclylalkyl group, heterocyclylalkoxy group, heterocyclylalkylthio group, acyl group, acyloxy group, carbamate group, amide group, urea group, epoxy group and ester group, etc.

[0053] In some embodiments, the compound of formula I-0 or a pharmaceutically acceptable salt thereof is selected from a compound of formula I or a pharmaceutically acceptable salt thereof:

[0054] in:

[0055] R 1 Selected from hydrogen, halogen or C 1-3 alkyl;

[0056] q is selected from 0, 1, 2, 3, 4, 5 or 6;

[0057] Every R 2 are independently selected from OH, NH2, CN, halogen, C 1-3 Alkyl or C 1-3 alkoxy;

[0058] m is selected from 0, 1, 2 or 3;

[0059] Ring A is selected from C4-10 Cycloalkyl or 4-10 membered heterocycloalkyl;

[0060] L is a linking group;

[0061] Every R 3 are independently selected from OH, NH2, CN, halogen, C 1-3 Alkyl or C 1-3 alkoxy;

[0062] p is selected from 0, 1, 2 or 3;

[0063] X is selected from CH2 or C=O;

[0064] X 1 selected from CH or N;

[0065] The R 1 、R 2 , Ring A, R 3 , X, or X 1 Optionally substituted with one or more substituents.

[0066] The compound of formula I-0 and the compound of formula I each independently include the following embodiments.

[0067] In some embodiments,

[0068] R 1 Selected from hydrogen, halogen or C 1-3 alkyl;

[0069] q is selected from 0, 1, 2, 3, 4, 5 or 6;

[0070] Every R 2 are independently selected from OH, NH2, CN, halogen, C 1-3 Alkyl or C 1-3 alkoxy;

[0071] m is selected from 0, 1, 2 or 3;

[0072] Ring A is selected from C 4-10 Cycloalkyl or 4-10 membered heterocycloalkyl;

[0073] L is a linking group;

[0074] Every R 3 are independently selected from OH, NH2, CN, halogen, C 1-3 Alkyl or C 1-3 alkoxy;

[0075] p is selected from 0, 1, 2 or 3;

[0076] X is selected from CH2 or C=O;

[0077] X 1 is selected from CH or N.

[0078] In some embodiments, each R 1 are independently selected from hydrogen, halogen or C 1-3 Alkyl, the R 1 Optionally substituted with one or more substituents.

[0079] In some embodiments, each R 1 are independently selected from hydrogen, halogen or C 1-2 Alkyl, the R 1 Optionally substituted with one or more substituents.

[0080] In some embodiments, each R 1 are independently selected from hydrogen, fluorine, chlorine, bromine or methyl, and the R 1 Optionally substituted with one or more substituents.

[0081] In some embodiments, each R 1 are independently selected from hydrogen, chlorine or methyl, said R 1 Optionally substituted with one or more substituents.

[0082] In some embodiments, R 1 Selected from hydrogen, halogen or C 1-3 alkyl.

[0083] In some embodiments, R 1 Selected from hydrogen, halogen or C 1-2 alkyl.

[0084] In some embodiments, R 1 is selected from hydrogen, fluorine, chlorine, bromine or methyl.

[0085] In some embodiments, R 1 is selected from hydrogen, chlorine or methyl.

[0086] In some embodiments, R 1 For hydrogen.

[0087] In some embodiments, the structural fragment for

[0088] In some embodiments, the structural fragment Selected from

[0089] In some embodiments, q is selected from 0, 1, 2, or 3. In some embodiments, q is selected from 0, 1, or 2. In some embodiments, q is 1.

[0090] In some embodiments, each R 2 are independently selected from OH, NH2, CN, halogen, C 1-3 Alkyl or C 1-3 Alkoxy, the R 2 Optionally substituted with one or more substituents.

[0091] In some embodiments, each R 2 are independently selected from CN, halogen or C 1-3 Alkyl, the R 2 Optionally substituted with one or more substituents.

[0092] In some embodiments, each R 2 are independently selected from OH, NH2, CN, halogen, C 1-3 Alkyl or C 1-3 Alkoxy.

[0093] In some embodiments, each R 2 are independently selected from OH, NH2, CN, halogen, C 1-2 Alkyl or C 1-2 Alkoxy.

[0094] In some embodiments, each R 2 are independently selected from CN, halogen or C 1-3 alkyl.

[0095] In some embodiments, each R 2 are independently selected from CN, halogen or C 1-2 alkyl.

[0096] In some embodiments, m is selected from 0, 1, 2, or 3.

[0097] In some embodiments, m is selected from 0, 1, or 2. In some embodiments, m is selected from 0 or 1. In some embodiments, m is 0.

[0098] In some embodiments, Ring A is selected from C 4-10 Cycloalkyl or 4-10 membered heterocycloalkyl.

[0099] In some embodiments, Ring A is selected from C 4-8 Cycloalkyl or 4-8 membered heterocycloalkyl.

[0100] In some embodiments, Ring A is selected from C 4-6 Cycloalkyl or 4-6 membered heterocycloalkyl.

[0101] In some embodiments, Ring A is selected from C 5-6 Cycloalkyl or 5-6 membered heterocycloalkyl.

[0102] In some embodiments, Ring A is selected from C6 cycloalkyl or 6-membered heterocycloalkyl.

[0103] In some embodiments, Ring A is selected from C6 cycloalkyl or 6-membered N-containing heterocycloalkyl.

[0104] In some embodiments, Ring A is selected from cyclohexyl or piperidinyl.

[0105] In some embodiments, Ring A is selected from

[0106] In some embodiments, the structural fragment Selected from

[0107] In some embodiments, L is selected from -Cy-L 1 -or-L 2 -; wherein Cy is selected from C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl, the C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl is optionally substituted with one or more substituents;

[0108] Among them, -L 1 -or-L 2 - are independently selected from one or more -CH2-, optionally selected from -O-, phenyl (such as )、-NH-、-N(C 1-6 Alkyl)- or -S-substituted-C 1-20 Alkyl-, one or more -CH2- are optionally selected from -O-, phenyl (such as )、-NH-、-N(C 1-6 Alkyl)- or -S-substituted-C 2-20 Alkenyl-, or one or more -CH2- are optionally selected from -O-, phenyl (such as )、-NH-、-N(C 1-6 Alkyl)- or -S-substituted-C 2-20 Alkynyl-, the-C 1-20 Alkyl-, -C 2-20 Alkenyl-, or -C 2-20 Alkynyl- is optionally substituted with one or more substituents.

[0109] In some embodiments, the substituent is selected from =O, OH, NH2, halogen, CN, C 1-6 Alkyl or C 1-6 Alkoxy.

[0110] In some embodiments, the substituent is selected from ═O, OH, NH 2 , halogen, or CN.

[0111] In other embodiments, L is selected from -Cy-L 1 -or-L 2 -; wherein Cy is selected from C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl, the C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl is optionally substituted by one or more groups selected from: =O, OH, NH2, halogen, CN, C 1-6 Alkyl or C 1-6 alkoxy;

[0112] Among them, -L 1 -or-L 2 - are independently selected from one or more -CH2-, optionally selected from -O-, -NH-, -N(C 1-6 Alkyl)- or -S-substituted-C 1-20 Alkyl-, one or more -CH2- are optionally selected from -O-, -NH-, -N(C 1-6 Alkyl)- or -S-substituted-C 2-20 Alkenyl-, or one or more -CH2- are optionally selected from -O-, -NH-, -N(C 1-6 Alkyl)- or -S-substituted-C 2-20 Alkynyl-, the-C 1-20 Alkyl-, -C 2-20 Alkenyl-, or -C 2-20 Alkynyl- is optionally substituted with one or more groups selected from: =0, OH, NH2, halogen or CN.

[0113] In some embodiments, the -L 1 -or-L 2 - are independently selected from one or more -CH2-, optionally selected from -O-, phenyl (such as )、-NH-、-N(C 1-6 Alkyl)- or -S-substituted-C 1-15 Alkyl-, one or more -CH2- are optionally selected from -O-, phenyl (such as )、-NH-、-N(C 1-6 Alkyl)- or -S-substituted-C 2-15 Alkenyl-, or one or more -CH2- are optionally selected from -O-, phenyl (such as )、-NH-、-N(C 1-6 Alkyl)- or -S-substituted-C 2-15 Alkynyl-, the-C 1-15 Alkyl-, -C 2-15 Alkenyl-, or -C 2-15Alkynyl- is optionally substituted with one or more of the following: =0, OH, NH2, halogen, or CN.

[0114] In other embodiments, the -L 1 -or-L 2 - are independently selected from one or more -CH2-, optionally selected from -O-, -NH-, -N(C 1-6 Alkyl)- or -S-substituted-C 1-15 Alkyl-, one or more -CH2- are optionally selected from -O-, -NH-, -N(C 1-6 Alkyl)- or -S-substituted-C 2-15 Alkenyl-, or one or more -CH2- are optionally selected from -O-, -NH-, -N(C 1-6 Alkyl)- or -S-substituted-C 2-15 Alkynyl-, the-C 1-15 Alkyl-, -C 2-15 Alkenyl-, or -C 2-15 Alkynyl- is optionally substituted with one or more of the following: =0, OH, NH2, halogen, or CN.

[0115] In some embodiments, the -L 1 -or-L 2 - independently selected from -1 or more -CH2- optionally selected from -O-, phenyl (such as )、-NH-、-N(C 1-6 Alkyl)- or -S-substituted-C 1-12 Alkyl-, one or more -CH2- are optionally selected from -O-, phenyl (such as )、-NH-、-N(C 1-6 Alkyl)- or -S-substituted-C 2-12 Alkenyl-, or one or more -CH2- are optionally selected from -O-, phenyl (such as )、-NH-、-N(C 1-6 Alkyl)- or -S-substituted-C 2-12 Alkynyl-, the-C 1-12 Alkyl-, -C 2-12 Alkenyl-, or -C 2-12 Alkynyl- is optionally substituted with one or more of the following: =0, OH, NH2, halogen, or CN.

[0116] In other embodiments, the -L 1 -or-L 2 - are independently selected from -1 or more -CH2-, optionally selected from -O-, -NH-, -N(C 1-6Alkyl)- or -S-substituted-C 1-12 Alkyl-, one or more -CH2- are optionally selected from -O-, -NH-, -N(C 1-6 Alkyl)- or -S-substituted-C 2-12 Alkenyl-, or one or more -CH2- are optionally selected from -O-, -NH-, -N(C 1-6 Alkyl)- or -S-substituted-C 2-12 Alkynyl-, the-C 1-12 Alkyl-, -C 2-12 Alkenyl-, or -C 2-12 Alkynyl- is optionally substituted with one or more of the following: =0, OH, NH2, halogen, or CN.

[0117] In some embodiments, the Cy is selected from C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl, the C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl is optionally substituted by one or more groups selected from: =O, OH, NH2, halogen, CN, C 1-6 Alkyl or C 1-6 Alkoxy.

[0118] In some embodiments, the Cy is selected from C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, the C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted by one or more groups selected from: =O, OH, NH2, halogen, CN, C 1-3 Alkyl or C 1-3 Alkoxy.

[0119] In some embodiments, the Cy is selected from C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, the C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted by one or more groups selected from: =O, OH, NH2, fluorine, chlorine, bromine, CN, C 1-3 Alkyl or C 1-3 Alkoxy.

[0120] In some embodiments, the Cy is selected from C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl.

[0121] In some embodiments, the Cy is selected from C 5-6 Cycloalkyl or 5-6 membered heterocycloalkyl.

[0122] In some embodiments, the Cy is selected from 5-6 membered heterocycloalkyl.

[0123] In some embodiments, the Cy is selected from 6-membered heterocycloalkyl.

[0124] In some embodiments, the Cy is selected from piperidinyl or piperazinyl.

[0125] In some embodiments, the Cy is selected from In some embodiments, the Cy is selected from

[0126] In some embodiments, the structural fragment -Cy-L 1 -Selected In some embodiments, the structural fragment -Cy-L 1 -for

[0127] In some embodiments, the -L 1 - is selected from one or more -CH2- optionally selected from phenyl (such as ), or -N(C 1-6 alkyl)-substituted-C 1-20 Alkyl-, -C 1-19 Alkyloxy-, -C 1-19 Alkylthio-, -C 1-19 Alkylamino-, -C 2-20 Alkenyl- or -C 2-20 Alkynyl-, the-C 1-20 Alkyl-, -C 1-19 Alkyloxy-, -C 1-19 Alkylthio-, -C 1-19 Alkylamino-, -C 2-20 Alkenyl- or -C 2-20 Alkynyl- is optionally substituted with one or more substituents.

[0128] In some embodiments, the -L 1 - is selected from one or more -CH2- optionally selected from phenyl (such as ), or -N(C 1-6 alkyl)-substituted-C 1-15 Alkyl-, -C 1-14 Alkyloxy-, -C 1-14 Alkylthio-, -C 1-14 Alkylamino-, -C 2-15 Alkenyl- or -C 2-15 Alkynyl-, the-C 1-15 Alkyl-, -C 1-14 Alkyloxy-, -C 1-14 Alkylthio-, -C 1-14 Alkylamino-, -C 2-15 Alkenyl- or -C2-15 Alkynyl- is optionally substituted with one or more substituents.

[0129] In some embodiments, the -L 1 - is selected from one or more -CH2- optionally selected from phenyl (such as ), or -N(C 1-6 alkyl)-substituted-C 1-12 Alkyl-, -C 1-11 Alkyloxy-, -C 1-11 Alkylthio-, -C 1-11 Alkylamino-, -C 2-12 Alkenyl- or -C 2-12 Alkynyl-, the-C 1-12 Alkyl-, -C 1-11 Alkyloxy-, -C 1-11 Alkylthio-, -C 1-11 Alkylamino-, -C 2-12 Alkenyl- or -C 2-12 Alkynyl- is optionally substituted with one or more substituents.

[0130] In some embodiments, the substituent is selected from ═O, OH, NH 2 , halogen, or CN.

[0131] In some other embodiments, the -L 1 -Selected from-C 1-20 Alkyl-, -C 1-19 Alkyloxy-, -C 1-19 Alkylthio-, -C 1-19 Alkylamino-, -C 2-20 Alkenyl- or -C 2-20 Alkynyl-, the-C 1-20 Alkyl-, -C 1-19 Alkyloxy-, -C 1-19 Alkylthio-, -C 1-19 Alkylamino-, -C 2-20 Alkenyl- or -C 2-20 Alkynyl- is optionally substituted with one or more groups selected from: =0, OH, NH2, halogen or CN.

[0132] In some other embodiments, the -L 1 -Selected from-C 1-15 Alkyl-, -C 1-14 Alkyloxy-, -C 1-14 Alkylthio-, -C 1-14 Alkylamino-, -C 2-15 Alkenyl- or -C 2-15 Alkynyl-, the-C 1-15 Alkyl-, -C 1-14Alkyloxy-, -C 1-14 Alkylthio-, -C 1-14 Alkylamino-, -C 2-15 Alkenyl- or -C 2-15 Alkynyl- is optionally substituted with one or more groups selected from: =0, OH, NH2, halogen or CN.

[0133] In some other embodiments, the -L 1 -Selected from-C 1-12 Alkyl-, -C 1-11 Alkyloxy-, -C 1-11 Alkylthio-, -C 1-11 Alkylamino-, -C 2-12 Alkenyl- or -C 2-12 Alkynyl-, the-C 1-12 Alkyl-, -C 1-11 Alkyloxy-, -C 1-11 Alkylthio-, -C 1-11 Alkylamino-, -C 2-12 Alkenyl- or -C 2-12 Alkynyl- is optionally substituted with one or more groups selected from: =0, OH, NH2, halogen or CN.

[0134] In some embodiments, the -L 1 -or-L 2 - are independently selected from -(CH2) n O-, -(CH2) n S-, -C(O)-(CH2) n O-, -C(O)-(CH2) n S-, -(CH2) n C≡C-, -C(O)-(CH2) n C≡C-, -(CH2)2N(CH3)-(CH2) n C≡C-, -(CH2)2N(CH3)-(CH2) n O-, -CH2N(CH3)-(CH2) n C≡C-, -CH2N(CH3)-(CH2) n O-, -(CH2)3N(CH3)-(CH2) n C≡C- or -(CH2)3N(CH3)-(CH2) n O-, wherein n is selected from 1 to 12. In some embodiments, the -L 1 -or-L 2 - are independently selected from -(CH2) n NH- or -CH2-phenyl-(CH2) nO-, wherein n is selected from 1-12. In some embodiments, n is selected from 1-10; or n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or an integer range consisting of any two of them. In some embodiments, n is 3-5. In some embodiments, n is 3-7. In some embodiments, n is 3-9. In some embodiments, n is 3-10.

[0135] In some embodiments, the -L 1 -selected from -(CH2) n O-, -(CH2) n S-, -C(O)-(CH2) n O-, -C(O)-(CH2) n S-, -(CH2) n C≡C- or -C(O)-(CH2) n C≡C-, wherein n is selected from 1 to 12. In some embodiments, the -L 1 -selected from -(CH2) n NH-, -(CH2)2N(CH3)-(CH2) n C≡C-, or -CH2-phenyl-(CH2) n O-, wherein n is selected from 1 to 12. In some embodiments, the -L 1 -selected from -(CH2) n NH-, -(CH2) n O-, -(CH2) n S-, -(CH2) n C≡C-, -(CH2)3N(CH3)-(CH2) n C≡C- or -CH2-phenyl-(CH2) n O-, wherein n is selected from 1 to 12. In some embodiments, the -L 1 -selected from -(CH2) n O-, -(CH2) n S- or -(CH2) n C≡C-, wherein n is selected from 1-12. In some embodiments, n is selected from 1-10; or n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or an integer range consisting of any two of them. In some embodiments, n is selected from 3-7. In some embodiments, n is 3-5. In some embodiments, n is 3-7. In some embodiments, n is 3-9. In some embodiments, n is 3-10.

[0136] In some embodiments, the -L 2 -selected from -(CH2)2N(CH3)-(CH2)n C≡C-, -(CH2)2N(CH3)-(CH2) n O-, -CH2N(CH3)-(CH2) n C≡C-, -CH2N(CH3)-(CH2) n O-, -(CH2)3N(CH3)-(CH2) n C≡C- or -(CH2)3N(CH3)-(CH2) n O-, wherein n is selected from 1 to 12. In some embodiments, the -L 2 -selected from -(CH2) n O-, -(CH2) n S-, -(CH2) n NH-, -(CH2) n C≡C-, -(CH2) n N(CH3)(CH2) n C≡C- or -(CH2) n -phenyl-(CH2) n O-, wherein n is selected from 1-12. In some embodiments, n is selected from 1-10; or n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or an integer range consisting of any two of them. In some embodiments, n is 3-5. In some embodiments, n is 3-7. In some embodiments, n is 3-9. In some embodiments, n is 3-10.

[0137] In some embodiments, L is selected from -Cy-L 3 -X 2 -or-L 2 -, where Cy and L 2 As mentioned above; L 3 Selected from one or more -CH2- optionally selected from -O-, phenyl (such as )、-NH-、-N(C 1-6 Alkyl)- or -S-substituted-C 1-20 Alkyl-, -C 2-20 Alkenyl- or -C 2-20 Alkynyl-, the-C 1-20 Alkyl-, -C 2-20 Alkenyl- or -C 2-20 Alkynyl-optionally substituted with one or more of the following groups: =O, OH, NH2, halogen or CN; X 2 is selected from a bond, O, S or NH.

[0138] In other embodiments, L is selected from -Cy-L 3 -X 2 -or-L2 -, where Cy and L 2 As mentioned above; L 3 Selected from -C 1-20 Alkyl-, -C 2-20 Alkenyl- or -C 2-20 Alkynyl-, the-C 1-20 Alkyl-, -C 2-20 Alkenyl- or -C 2-20 Alkynyl-optionally substituted with one or more of the following groups: =O, OH, NH2, halogen or CN; X 2 is selected from a bond, O or S.

[0139] In other embodiments, L is selected from -Cy-L 3 -X 2 -or-L 2 -, where Cy and L 2 As mentioned above; L 3 Selected from one or more -CH2- optionally selected from -O-, phenyl (such as )、-NH-、-N(C 1-6 Alkyl)- or -S-substituted-C 1-20 Alkyl-, -C 2-20 Alkenyl- or -C 2-20 Alkynyl-, the-C 1-20 Alkyl-, -C 2-20 Alkenyl- or -C 2-20 Alkynyl-optionally substituted with one or more substituents; optionally said substituents are selected from the group consisting of: =O, OH, NH2, halogen or CN; X 2 is selected from a bond, O or S.

[0140] In some embodiments, L is selected from -Cy-L 3 -X 2 -or-L 2 -, wherein Cy is selected from 3-10 membered heterocycloalkyl, L 3 Selected from one or more -CH2- optionally selected from -O-, phenyl (such as )、-NH-、-N(C 1-4 Alkyl)- or -S-substituted-C 1-20 Alkyl- or -C 2-20 Alkynyl-, L 2 Selected from -C 1-20 Alkyl NH-; X 2 is selected from a bond, O, S or NH.

[0141] In some embodiments, L is selected from -Cy-L 3 -X 2 -or-L 2-, wherein Cy is selected from 3-6 membered heterocycloalkyl, L 3 Selected from one or more -CH2- optionally selected from phenyl (such as ) or -N(C 1-4 alkyl)-substituted-C 3-15 Alkyl- or -C 3-15 Alkynyl-, L 2 Selected from -C 3-15 Alkyl NH-; X 2 is selected from a bond, O, S or NH.

[0142] In some embodiments, L is selected from -Cy-L 3 -X 2 -or-L 2 -, wherein Cy is selected from 6-membered heterocycloalkyl, L 3 Selected from one or more -CH2- optionally selected from phenyl (such as ) or -N(C 1-3 alkyl)-substituted-C 3-10 Alkyl- or -C 5-11 Alkynyl-, L 2 Selected from -C 3-10 Alkyl NH-; X 2 is selected from a bond, O, S or NH.

[0143] In some embodiments, the moiety -Cy-L 3 -X 2 -piperidinyl-(CH2)3S-, -piperidinyl-(CH2)4S-, -piperidinyl-(CH2)5S-, -piperidinyl-(CH2)6S-, -piperidinyl-(CH2)7S-, -piperidinyl-(CH2)8S-, -piperidinyl-(CH2)9S-, -piperidinyl-(CH2)3O-, -piperidinyl-(CH2)4O-, -piperidinyl-(CH2)5O-, -piperidinyl-(CH2)6O-, -piperidinyl-(CH2)7O-, -piperidinyl-(CH2)8O-, -piperidinyl-(CH2) 10 O-, -piperidinyl-(CH2)9O-, -piperidinyl-(CH2)3NH-, -piperidinyl-(CH2)4NH-, -piperidinyl-(CH2)5NH-, -piperidinyl-(CH2)3C≡C-, -piperidinyl-(CH2)4C≡C-, -piperidinyl-(CH2)5C≡C-, -piperidinyl-(CH2)6C≡C-, -piperidinyl-(CH2)7C≡C-, -piperidinyl-(CH2)8C≡C-, -piperidinyl-(CH2)9C≡C-, -piperidinyl-(CH2)2N(CH3)(CH2)3C≡C-, or -piperidinyl-CH2-phenyl-CH2O-. In some embodiments, the moiety -L 2- is selected from -(CH2)5NH-.

[0144] In some embodiments, the moiety -L 3 -X 2 -or-L 2 -Selected from -(CH2)3NH-, -(CH2)4NH-, -(CH2)5NH-, -(CH2)3O-, -(CH2)4O-, -(CH2)5O-, -(CH2)6O-, -(CH2)7O-, -(CH2)8O-, -(CH2)9O-, -(CH2) 10 O-, -(CH2)3S-, -(CH2)4S-, -(CH2)5S-, -(CH2)6S-, -(CH2)7S-, -(CH2)8S-, -(CH2)9S-, -(CH2)3C≡C-, -(CH2)4C≡C-, -(CH2)5C≡C-, -(CH2)6C≡C-, -(CH2)7C≡C-, -(CH2)8C≡C-, -(CH2)9C≡C-, -(CH2)2N(CH3)(CH2)3C≡C-, or -CH2-phenyl-CH2O-. In some embodiments, the moiety -L 3 -X 2 -or-L 2 -Selected from -(CH2)3O-, -(CH2)4O-, -(CH2)5O-, -(CH2)6O-, -(CH2)7O-, -(CH2)8O-, -(CH2)9O-, -(CH2) 10 O-, -(CH2)3S-, -(CH2)4S-, -(CH2)5S-, -(CH2)6S-, -(CH2)7S-, -(CH2)8S-, -(CH2)9S-, -(CH2 )3C≡C-, -(CH2)4C≡C-, -(CH2)5C≡C-, -(CH2)6C≡C-, -(CH2)7C≡C-, -(CH2)8C≡C- or -(CH2)9C≡C-.

[0145] In some embodiments, L is selected from

[0146] In some embodiments, L 3 Selected from -C 1-15 Alkyl-, -C 2-15 Alkenyl- or -C 2-15 Alkynyl-, the-C 1-15 Alkyl-, -C 2-15 Alkenyl- or -C 2-15 Alkynyl- is optionally substituted with one or more =0. In some embodiments, L3 Selected from -C 1-12 Alkyl-, -C 2-12 Alkenyl- or -C 2-12 Alkynyl-, the-C 1-12 Alkyl-, -C 2-12 Alkenyl- or -C 2-12 Alkynyl- is optionally substituted with one or more =0. In some embodiments, L 3 Selected from -C 3-12 Alkyl- or -C 3-12 Alkynyl-, the-C 3-12 Alkyl- or -C 3-12 Alkynyl- is optionally substituted with one or more =0. In some embodiments, L 3 Selected from -C 3-10 Alkyl- or -C 3-10 Alkynyl-, the-C 3-10 Alkyl- or -C 3-10 Alkynyl- is optionally substituted with one or more =0. In some embodiments, L 3 Selected from -C 3-7 Alkyl- or -C 3-7 Alkynyl-, the-C 3-7 Alkyl- or -C 3-7 Alkynyl- is optionally substituted with one or more =0.

[0147] In some embodiments, L is selected from n is as defined above. In some embodiments, n is 3-5. In some embodiments, n is 3-7. In some embodiments, n is 3-9. In some embodiments, n is 3-10. In some embodiments, L is selected from n is as defined above. In some embodiments, L is selected from n is as defined above. In some embodiments, n is 3-5. In some embodiments, n is 3-7. In some embodiments, n is 3-9. In some embodiments, n is 3-10.

[0148] In some embodiments, L is selected from n is as defined above. In some embodiments, n is 3-5. In some embodiments, n is 3-7. In some embodiments, n is 3-9. In some embodiments, n is 3-10.

[0149] In some embodiments, L is selected from -(CH2) n-NH- or n is as defined above. In some embodiments, n is 3-5. In some embodiments, n is 3-7. In some embodiments, n is 3-9. In some embodiments, n is 3-10.

[0150] In other embodiments, L is selected from n is as defined above. In some embodiments, n is 3-5. In some embodiments, n is 3-7. In some embodiments, n is 3-9. In some embodiments, n is 3-10.

[0151] In some embodiments, each R 3 are independently selected from OH, NH2, CN, halogen, C 1-3 Alkyl or C 1-3 Alkoxy.

[0152] In some embodiments, each R 3 are independently selected from OH, NH2, CN, halogen, C 1-2 Alkyl or C 1-2 In some embodiments, each R 3 are independently selected from OH, NH2, fluorine, chlorine or methyl. In some embodiments, each R 3 are each independently selected from fluorine.

[0153] In some embodiments, p is selected from 0, 1, or 2. In some embodiments, p is selected from 0 or 1. In some embodiments, p is selected from 0.

[0154] In some embodiments, X is selected from CH2 or C=O.

[0155] In some embodiments, X is selected from CH2. In some embodiments, X is selected from C=O.

[0156] In some embodiments, X 1 is selected from CH or N.

[0157] In some embodiments, X 1 In some embodiments, X 1 Selected from N.

[0158] In some embodiments, the structural fragment Selected from

[0159] In some embodiments, R 1 is hydrogen; structural fragment for m is 0; L is selected from -(CH2) n -NH- or n is 3-5 or 3-9 or 3-10; q is 1 or 2; and the structural fragment Selected from

[0160] In some embodiments, R 1 is hydrogen; structural fragment for m is 0; L is selected from q is 1 or 2; and the structural fragment Selected from

[0161] The compound of formula I of the present application or a pharmaceutically acceptable salt thereof is selected from the compound of formula II, II-A or II-B or a pharmaceutically acceptable salt thereof,

[0162] Among them, R 1 、R 2 , m, L, R 3 , p or X are as defined in this application;

[0163] X 3 and X 4 are independently selected from N, NH, CH or CH2;

[0164] Optionally, the R 1 、R 2 、R 3 ,X,X 3 and X 4 Optionally substituted with one or more substituents.

[0165] In some embodiments, the compound of Formula I, II, II-A or II-B or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 , m, L, R 3 , p or X are as defined in this application, X 3 and X 4 are independently selected from N, NH, CH or CH2.

[0166] In some embodiments, X 3 and X 4 are independently selected from NH or CH2.

[0167] In another aspect, the present application relates to a compound of formula III or a pharmaceutically acceptable salt thereof,

[0168] Among them, q, R 2 、R 4 、R 5 ,m,ring A,R 3 ,p,X,X 1 is as defined in this application;

[0169] Every R 11 are independently selected from hydrogen, halogen, OH, NH2, CN, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl OCO-, C 1-6 Alkyl C(O)O-, C 1-6 Alkyl NHCO-, C 1-6 AlkylCONH-, (C 1-6 Alkyl)2NCO-, C 1-6 AlkylNHS(O)-, C 1-6 Alkyl S(O)NH-, (C 1-6 Alkyl) 2NS(O)-, C 1-6 Alkyl NHS(O)2-, C 1-6 Alkyl S(O)2NH-, (C 1-6 alkyl)2NS(O)2-、C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl, said R 11 is optionally substituted with one or more substituents;

[0170] k is selected from 0, 1, 2 or 3;

[0171] L is selected from -Cy-L 1 -; wherein Cy is selected from C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl, the C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl is optionally substituted with one or more substituents;

[0172] -L 1 -selected from one or more -CH2- 6-10Aryl or 5-10 membered heteroaryl (such as phenyl, ) is replaced, and optionally one or more -CH2- is selected from -O-, -NH-, -N(C 1-6 Alkyl)- or -S-substituted groups: -C 1-20 Alkyl-, -C 2-20 Alkenyl- or -C 2-20 Alkynyl-, the-C 1-20 Alkyl-, -C 2-20 Alkenyl-, or -C 2-20 Alkynyl- is optionally substituted with one or more substituents.

[0173] In some embodiments, each R 11 are independently selected from hydrogen, halogen, OH, NH2, CN, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkyl NH-, (C 1-4 Alkyl)2N-, C 1-4 Alkyl OCO-, C 1-4 Alkyl C(O)O-, C 1-4 Alkyl NHCO-, C 1-4 AlkylCONH-, (C 1-4 Alkyl)2NCO-, C 1-4 AlkylNHS(O)-, C 1-4 Alkyl S(O)NH-, (C 1-4 Alkyl) 2NS(O)-, C 1-4 Alkyl NHS(O)2-, C 1-4 Alkyl S(O)2NH-, (C 1-4 alkyl)2NS(O)2-、C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, said R 11 Optionally substituted with one or more substituents.

[0174] In some embodiments, each R 11 are independently selected from hydrogen, halogen, OH, NH2, CN, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3Alkylthio, C 1-3 Alkyl NH-, (C 1-3 Alkyl)2N-, C 1-3 Alkyl OCO-, C 1-3 Alkyl C(O)O-, C 1-3 Alkyl NHCO-, C 1-3 AlkylCONH-, (C 1-3 Alkyl)2NCO-, C 1-3 AlkylNHS(O)-, C 1-3 Alkyl S(O)NH-, (C 1-3 Alkyl) 2NS(O)-, C 1-3 Alkyl NHS(O)2-, C 1-3 Alkyl S(O)2NH-, (C 1-3 alkyl)2NS(O)2-、C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, said R 11 Optionally substituted with one or more substituents.

[0175] In some embodiments, each R 11 are independently selected from hydrogen, halogen, OH, NH2, CN, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkyl NH-, (C 1-3 Alkyl)2N-, C 1-3 Alkyl OCO-, C 1-3 Alkyl C(O)O-, C 1-3 Alkyl NHCO-, C 1-3 AlkylCONH-, (C 1-3 Alkyl)2NCO-, C 1-3 AlkylNHS(O)-, C 1-3 Alkyl S(O)NH-, (C 1-3 Alkyl) 2NS(O)-, C 1-3 Alkyl NHS(O)2-, C 1-3 Alkyl S(O)2NH- or (C 1-3 alkyl) 2NS(O) 2-, the R 11 is optionally substituted with one or more substituents. 11 are independently selected from halogen or C 1-3 Alkyl, the C1-3 Alkyl is optionally substituted with one or more substituents. In some embodiments, each R 11 are independently selected from halogen or C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with one or more halogens.

[0176] In some embodiments, each R 11 are each independently selected from fluoro, chloro or methyl, said methyl being optionally substituted with one or more halogens.

[0177] In some embodiments, each R 11 are independently selected from chlorine or methyl, and the methyl group is optionally substituted with one or more fluorine or chlorine. 11 is selected from chloro, methyl or trifluoromethyl.

[0178] In some embodiments, R 4 and R 5 are independently selected from C 1-3 Alkyl, or R 4 and R 5 Connected to each other and connected carbon atoms together to form C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-3 Alkyl, C 3-6 The cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with one or more substituents.

[0179] In some embodiments, R 4 and R 5 are independently selected from C 1-3 Alkyl, or R 4 and R 5 Connected to each other and connected carbon atoms together to form C 3-4 In some embodiments, R 4 and R 5 are independently selected from methyl, or R 4 and R 5 Connected to each other and connected carbon atoms together to form C 3-4 In some embodiments, R 4 and R 5 are each independently selected from methyl.

[0180] In some embodiments, k is selected from 0, 1, or 2. In some embodiments, k is selected from 1.

[0181] In some embodiments, the -L 1 -selected from one or more -CH2-C6 aryl or 5-6 membered heteroaryl (such as phenyl, ) is replaced, and optionally one or more -CH2- is selected from -O-, -NH-, -N(C 1-6 Alkyl)- or -S-substituted groups: -C 1-15 Alkyl-, -C 2-15 Alkenyl-, or -C 2-15 Alkynyl-, the-C 1-15 Alkyl-, -C 2-15 Alkenyl-, or -C 2-15 Alkynyl- is optionally substituted with one or more of the following: =0, OH, NH2, halogen, or CN.

[0182] In some embodiments, the Cy is defined as described herein.

[0183] In some embodiments, the structural fragment -Cy-L 1 -Selected

[0184] In some embodiments, the -L 1 - as defined in this application.

[0185] In some embodiments, the -L 1 -Selected from one or more -CH2-phenyl groups (such as ) and optionally one or more -CH2- are replaced by -N(C 1-6 Alkyl)-substituted following groups: -C 1-20 Alkyl-, -C 1-19 Alkyloxy-, -C 1-19 Alkylthio-, -C 1-19 Alkylamino-, -C 2-20 Alkenyl- or -C 2-20 Alkynyl-, the-C 1-20 Alkyl-, -C 1-19 Alkyloxy-, -C 1-19 Alkylthio-, -C 1-19 Alkylamino-, -C 2-20 Alkenyl- or -C 2-20 Alkynyl- is optionally substituted with one or more substituents.

[0186] In some embodiments, the -L 1 -Selected from one or more -CH2-phenyl groups (such as ) and optionally one or more -CH2- are replaced by -N(C 1-6 Alkyl)-substituted following groups: -C 1-15 Alkyl-, -C 1-14 Alkyloxy-, -C 1-14 Alkylthio-, -C1-14 Alkylamino-, -C 2-15 Alkenyl- or -C 2-15 Alkynyl-, the-C 1-15 Alkyl-, -C 1-14 Alkyloxy-, -C 1-14 Alkylthio-, -C 1-14 Alkylamino-, -C 2-15 Alkenyl- or -C 2-15 Alkynyl- is optionally substituted with one or more substituents.

[0187] In some embodiments, the -L 1 -Selected from one or more -CH2-phenyl groups Replaced, and optionally one or more -CH2- by -N(C 1-6 Alkyl)-substituted following groups: -C 1-12 Alkyl-, -C 1-11 Alkyloxy-, -C 1-11 Alkylthio-, -C 1-11 Alkylamino-, -C 2-12 Alkenyl- or -C 2-12 Alkynyl-, the-C 1-12 Alkyl-, -C 1-11 Alkyloxy-, -C 1-11 Alkylthio-, -C 1-11 Alkylamino-, -C 2-12 Alkenyl- or -C 2-12 Alkynyl- is optionally substituted with one or more substituents.

[0188] In some embodiments, the substituent is selected from ═O, OH, NH 2 , halogen, or CN.

[0189] In some embodiments, the -L 1 -selected from -CH2-phenyl-(CH2) n O-, wherein n is selected from 1-12. In some embodiments, n is selected from 1-10; or n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or an integer range consisting of any two thereof. In some embodiments, n is selected from 1-8.

[0190] In some embodiments, L is selected from -Cy-L 3 -X 2 -, where Cy is as described above; L 3 One or more -CH2- are selected from C 6-10 aryl or 5-10 membered heteroaryl, and optionally one or more -CH2- are selected from -O-, -NH-, -N(C 1-6Alkyl)- or -S-substituted groups: -C 1-20 Alkyl-, -C 2-20 Alkenyl- or -C 2-20 Alkynyl-, the-C 1-20 Alkyl-, -C 2-20 Alkenyl- or -C 2-20 Alkynyl-optionally substituted with one or more of the following groups: =O, OH, NH2, halogen or CN; X 2 is selected from a bond, O, S or NH.

[0191] In some embodiments, L is selected from -Cy-L 3 -X 2 -, wherein Cy is selected from 3-10 membered heterocycloalkyl, L 3 One or more -CH2- are selected from C6 aryl or 5-6 membered heteroaryl replaced, and optionally one or more -CH2- are selected from -O-, -NH-, -N(C 1-4 Alkyl)- or -S-substituted groups: -C 1-20 Alkyl- or -C 2-20 Alkynyl-; X 2 is selected from a bond, O, S or NH.

[0192] In some embodiments, L is selected from -Cy-L 3 -X 2 -, wherein Cy is selected from 3-6 membered heterocycloalkyl, L 3 One or more -CH2- are selected from C6 aryl or 6-membered heteroaryl replaced, and optionally one or more -CH2- are selected from -N(C 1-4 Alkyl)-substituted following groups: -C 3-15 Alkyl- or -C 3-15 Alkynyl-; X 2 is selected from a bond, O, S or NH.

[0193] In some embodiments, L is selected from -Cy-L 3 -X 2 -, wherein Cy is selected from 6-membered heterocycloalkyl, L 3 One or more -CH2- are selected from -N(C 1-3 Alkyl)-substituted following groups: -C 3-10 Alkyl-; X 2 is selected from a bond, O, S or NH.

[0194] In some embodiments, the moiety -Cy-L 3 -X 2 -Selected from -piperidinyl-CH2-phenyl-(CH2) nO-, n are as defined herein. In some embodiments, the moiety -Cy-L 3 -X 2 - is selected from -piperidinyl-CH2-phenyl-CH2O-.

[0195] In some embodiments, the moiety -L 3 -X 2 - is selected from -CH2-phenyl-CH2O-. In some embodiments, L is selected from

[0196] In some embodiments, L is selected from The definition of n is as described above.

[0197] The present application relates to the following compounds or pharmaceutically acceptable salts thereof,

[0198] wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0199] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0200] wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0201] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0202] wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0203] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0204] wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0205] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0206] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0207] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0208] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0209] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0210] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0211] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0212] wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0213] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0214] wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0215] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0216] wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0217] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0218] wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0219] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0220] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0221] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0222] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0223] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0224] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0225] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0226] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0227] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0228] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0229] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0230] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0231] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0232] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0233] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0234] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0235] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0236] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0237] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0238] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0239] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0240] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0241] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0242] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0243] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0244] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0245] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0246] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0247] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0248] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0249] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0250] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0251] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0252] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0253] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0254] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0255] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0256] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0257] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0258] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0259] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0260] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0261] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0262] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0263] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0264] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0265] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0266] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0267] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0268] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0269] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0270] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0271] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0272] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0273] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0274] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0275] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0276] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0277] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0278] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0279] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0280] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0281] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0282] wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11;

[0283] wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11;

[0284] wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11;

[0285] wherein n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0286] The present application relates to the following compounds or pharmaceutically acceptable salts thereof,

[0287] On the other hand, the present application relates to a compound of formula I-0 or a pharmaceutically acceptable salt thereof, wherein R 1 , n, q, R 2 ,m,ring A,L,R 3 ,p,R 4 、R 5 ,X,X 1、R a 、R a ' or R b The definition of is as described in the present application, and the structural fragment in the structure shown in the compound of formula I-0 Optionally substituted with one or more substituents.

[0288] In some embodiments, the structural fragments in the structure shown in the compound of formula I-0 The piperazinyl or methylene group in the group is optionally substituted by one or more substituents.

[0289] In some embodiments, the structural fragments in the structure shown in the compound of formula I-0 The phenyl group or the -NH- linking fragment in is optionally substituted with one or more substituents.

[0290] On the other hand, the present application relates to a pharmaceutical composition, which contains the above-mentioned compound of the present application or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition of the present application also includes a pharmaceutically acceptable excipient.

[0291] On the other hand, the present application relates to the use of the above-mentioned compound or its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for preventing or treating a disease that is treated by degrading a target protein bound to a targeting ligand.

[0292] On the other hand, the present application relates to the use of the above-mentioned compound or its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for preventing or treating a disease that is treated by binding to a cerebellar protein in vivo.

[0293] On the other hand, the present application relates to the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating a disease associated with BCL-XL.

[0294] The present application relates to a method for treating or preventing a disease in a mammal by degrading a target protein bound to a targeting ligand, comprising administering a therapeutically effective amount of the above-mentioned compound of the present application or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

[0295] The present application relates to a method for treating or preventing a disease that is treated by binding to a cerebellar protein in vivo, comprising administering a therapeutically effective amount of the above-mentioned compound of the present application or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

[0296] In another aspect, the present application relates to a method for treating a BCL-XL-related disease in a mammal, comprising administering a therapeutically effective amount of the above-mentioned compound of the present application or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

[0297] On the other hand, the present application relates to the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating a disease that is treated by degrading a target protein bound to a targeting ligand.

[0298] On the other hand, the present application relates to the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt, or pharmaceutical composition thereof for preventing or treating diseases that are treated by binding to cerebellar proteins in vivo.

[0299] On the other hand, the present application relates to the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating diseases associated with BCL-XL.

[0300] On the other hand, the present application relates to the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating a disease that is treated by degrading a target protein bound to a targeting ligand.

[0301] On the other hand, the present application relates to the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating a disease that is treated by binding to a cerebellar protein in vivo.

[0302] On the other hand, the present application relates to the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating diseases associated with BCL-XL.

[0303] On the other hand, the present application relates to the use of the above-mentioned compound or its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for preventing or treating cancer.

[0304] On the other hand, the present application relates to the use of the above-mentioned compound or its pharmaceutically acceptable salt, or its pharmaceutical composition in preventing or treating cancer.

[0305] On the other hand, the present application relates to the above-mentioned compound or its pharmaceutically acceptable salt, or its pharmaceutical composition for preventing or treating cancer.

[0306] On the other hand, the present application relates to a method for treating or preventing cancer in a mammal, comprising administering a therapeutically effective amount of the above-mentioned compound of the present application or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

[0307] In some embodiments, the BCL-XL-related disease is selected from a disorder treated by degrading and / or inhibiting proteins that bind to BCL-XL target protein ligands; in some embodiments, the BCL-XL-related disease is selected from a disorder treated by binding to cerebellum protein in vivo; in some embodiments, the disease or disorder is selected from cancer.

[0308] In some embodiments, the conditions treated by binding to cerebellar proteins in vivo are selected from BCL-XL-related diseases; in some embodiments, the BCL-XL-related diseases are selected from cancers; in some embodiments, the cancers are selected from leukemias; in some embodiments, the cancers are selected from lymphoid leukemias.

[0309] In some embodiments, the "one or more" is selected from one, two, three, four, five, or six. In some embodiments, the "one or more" is selected from one, two, or three. In some embodiments, the "one or more" is selected from one, or two.

[0310] In some embodiments, the substituents in the "optionally substituted with one or more substituents" are selected from hydroxyl, thiol, halogen, amino, nitro, nitroso, cyano, carboxyl, aldehyde, C 1-12 Alkyl, halo-C 1-12 Alkyl, 3-12 membered cycloalkyl, halogenated 3-12 membered cycloalkyl, C 2-12 Alkenyl, halo-C 2-12 Alkenyl, 3-12 membered cycloalkenyl, halogenated 3-12 membered cycloalkenyl, C 2-12 Alkynyl, halo-C 2-12 Alkynyl, 8-12 membered cycloalkynyl, halogenated 8-12 membered cycloalkynyl, C 1-12 Heteroalkyl, halo-C 1-12 Heteroalkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclic group, C 1-12 Acyl, C 1-12 Acyloxy or C 1-12 Amide group.

[0311] In some embodiments, the present application encompasses the above-defined variables and embodiments thereof, and any combination thereof.

[0312] Technical Effects

[0313] The compounds of the present application have proliferation inhibitory effects on RS4;11 cells and MOLT-4 cells; can degrade BCL-XL protein, such as BCL-XL protein in MOLT-4 cells; have binding inhibitory activity against BCL-XL / BAK; are metabolically stable in vitro (e.g., in human, monkey, dog, rat, or mouse liver microsomes); and have good in vivo pharmacokinetic properties (in mice, rats, or dogs) and in vivo efficacy data; and have low platelet toxicity (in dog or human platelets) and few toxic side effects.

[0314] definition

[0315] Unless otherwise indicated, the following terms used in this application have the following meanings. A particular term should not be construed as undefined or unclear unless specifically defined, but rather should be understood according to its ordinary meaning in the art. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0316] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo (i.e., =O), it means that two hydrogen atoms are replaced. Oxo does not occur on aromatic groups.

[0317] The term "optionally" or "optionally" means that the event or circumstance described subsequently may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. For example, an ethyl group is "optionally" substituted with a halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (such as CH2CH2F), polysubstituted (such as CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that would be sterically impossible and / or incomposable to synthesize will be introduced.

[0318] The “substituents” described herein include all substituents mentioned herein, including but not limited to the terms “alkyl”, “alkoxy”, “heteroalkyl”, “alkenyl”, “alkynyl”, “cycloalkenyl”, “cycloalkyl”, “heterocycloalkyl”, “heterocycloalkenyl”, “heterocyclyl”, “heteroaryl”, etc., and corresponding non-limiting or exemplary groups, wherein some non-limiting examples of the “substituents” include deuterium, tritium, -OH, -SH, halogen, -NH2, nitro, nitroso, -CN, azide, sulfoxide, sulfone, sulfone, sulfonamide, carboxyl, carboxaldehyde, imine, alkyl, halo-alkyl, cycloalkyl, halo-cycloalkyl, alkenyl, halo-alkenyl, cycloalkenyl, halo-cycloalkenyl, alkynyl, halo-alkynyl , cycloalkynyl, halo-cycloalkynyl, heteroalkyl, halo-heteroalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, aralkyl, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroaralkyl, heteroarylalkoxy, heteroarylalkylthio, heterocyclyl, heterocyclyloxy, heterocyclylthio, heterocyclylalkyl, heterocyclylalkoxy, heterocyclylalkylthio, acyl, acyloxy, carbamate group, amide group, urea group , epoxy groups and ester groups, etc., which are optionally substituted by one or more substituents selected from the following: oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyl, heterocyclylalkyl, heterocyclyloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, aryl, arylalkyl or aryloxy.

[0319] In this article, C m-n , means that the moiety has an integer number of carbon atoms in a given range. For example, "C 1-6 " means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. For example, C 1-3 It means that the group may have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

[0320] In some embodiments herein, the substituent is selected from hydroxyl, sulfhydryl, halogen, amino, nitro, nitroso, cyano, azide, sulfoxide, sulfone, sulfone, sulfonamide, carboxyl, aldehyde, imine, C 1-12 Alkyl, halo-C1-12 Alkyl, 3-12 membered cycloalkyl, halogenated 3-12 membered cycloalkyl, C 2-12 Alkenyl, halo-C 2-12 Alkenyl, 3-12 membered cycloalkenyl, halogenated 3-12 membered cycloalkenyl, C 2-12 Alkynyl, halo-C 2-12 Alkynyl, 8-12 membered cycloalkynyl, halogenated 8-12 membered cycloalkynyl, C 1-12 Heteroalkyl, halo-C 1-12 Heteroalkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, 6-10 membered aryl, 6-10 membered aryloxy, 6-10 membered arylthio, 6-10 membered arylC 1-12 Alkylene, 6-10 membered aryl C 1-12 Alkoxy, 6-10 membered aryl C 1-12 alkylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, 5-10 membered heteroarylalkylene, 5-10 membered heteroarylalkoxy, 5-10 membered heteroarylalkylthio, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, 3-12 membered heterocyclylthio, 3-12 membered heterocyclylC 1-12 Alkylene, 3-12 membered heterocyclic group C 1-12 Alkoxy, 3-12 membered heterocyclic group C 1-12 Alkylthio, C 1-12 Acyl, C 1-12 Acyloxy, carbamate group, C 1-12 Amide group, urea group, epoxy group, C 2-12 Ester group and oxo, said substituent being optionally substituted by one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, carboxyl, -C(O)OC 1-12 Alkyl, -OC(O)-C 1-12 Alkyl, -C(O)NH2, -C(O)NH-C 1-12 Alkyl, -C(O)N(C 1-12 Alkyl)2, -NHC(O)-C 1-12 Alkyl, -C(O)-C 1-12 Alkyl, -S(O)-C 1-12 Alkyl, -S(O)2-C1-12 Alkyl, -S(O)2NH2, -S(O)2NH-C 1-12 Alkyl, -S(O)2N(C 1-12 alkyl) 2, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12 Alkylene, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group C 1-12 Alkylene, 3-12 membered heterocyclyloxy, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkylC 1-12 Alkylene, 3-12 membered heterocycloalkyloxy, 5-10 membered heteroaryl, 5-10 membered heteroarylC 1-12 Alkylene, 5-10 membered heteroaryloxy, 6-10 membered aryl, 6-10 membered arylC 1-12 an alkylene group or a 6- to 10-membered aryloxy group.

[0321] As used herein, "one or more" refers to an integer from one to ten. For example, "one or more" refers to one, two, three, four, five, six, seven, eight, nine, or ten; or, "one or more" refers to one, two, three, four, five, or six; or, "one or more" refers to one, two, or three.

[0322] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. For example, if a group contains two R's, each R has an independent option.

[0323] When a bond crosses two atoms in a ring (including a monocyclic, paracyclic, or spirocyclic ring), the bond can be bonded to any atom in the ring (including a monocyclic, paracyclic, or spirocyclic ring). For example, the bonds on both sides of the ring A can be connected to any two different atoms in the ring A.

[0324] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0325] The term "hydroxy" refers to an -OH group.

[0326] The term "amino" refers to a -NH2 group.

[0327] The term "cyano" refers to a -CN group.

[0328] The term "mercapto" refers to a -SH group.

[0329] The term "nitro" refers to a -NO2 group.

[0330] The term "heteroatom" includes atoms of any element other than carbon or hydrogen. Preferred heteroatoms are boron, nitrogen, oxygen, sulfur, silicon, and phosphorus. In one embodiment, the heteroatom is selected from N, O, and S. In some embodiments, the number of heteroatoms is 1, 2, 3, or 4.

[0331] The term "alkyl" refers to a group of the formula C n H 2n+1 The term "alkyl" refers to an alkyl group having 1 to 6 carbon atoms. The alkyl group may contain 1 to 20, 1 to 15, 1 to 12, 1 to 10, 1 to 8, 1 to 6, or 1 to 3 carbon atoms. The alkyl group may be straight or branched. For example, the term "C1-6 alkyl" refers to an alkyl group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (i.e., alkyl) of an alkoxyl group, an alkylamino group, a dialkylamino group, an alkylsulfonyl group, and an alkylthio group has the same definition as above. For another example, the term "C1-3 alkyl" refers to an alkyl group having 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl, and isopropyl).

[0332] The term "alkoxy" refers to an -O-alkyl group.

[0333] The term "heteroalkyl" refers to an alkyl structure containing heteroatoms. Unless otherwise indicated, the heteroalkyl group is typically an alkyl group containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and / or nitrogen. Typically, where there is more than one heteroatom, the heteroatoms are not adjacent to each other. Exemplary heteroalkyl groups include alkoxy, alkoxyalkyl, alkylamino, alkylaminoalkyl, dialkylamino, dialkylaminoalkyl, etc.

[0334] The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one double bond. The alkenyl group may contain 2-20, 2-15, 2-12, 2-10, 2-8, 2-6, or 2-3 carbon atoms. Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.

[0335] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one triple bond. The alkynyl group may contain 2-20, 2-15, 2-12, 2-10, 2-8, 2-6, or 2-3 carbon atoms. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡C-CH3), 2-propynyl (-CH2-C≡CH), 1,3-butadiynyl (-C≡C≡CH), and the like.

[0336] The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and can exist as a monocyclic, bicyclic bridged ring or spirocycle. Unless otherwise indicated, the carbocyclic ring is typically 4 to 20 rings, 4 to 15 rings, 4 to 10 rings, 4 to 8 rings, 3 to 12 rings, 3 to 10 rings or 3 to 6 rings. Non-limiting examples of cycloalkenyl include but are not limited to cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl etc.

[0337] The term "cycloalkyl" refers to a fully saturated carbocyclic ring that can exist as a monocycle, a bridged ring or a spirocycle. Unless otherwise indicated, the carbocyclic ring is typically 3 to 20 rings, 3 to 15 rings, 3 to 12 rings, 3 to 10 rings (e.g., 5 to 8 rings), 3 to 6 rings, 4 to 10 rings, 4 to 8 rings, 4 to 6 rings, 5 to 6 rings or 6 rings. Non-limiting examples of cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo [2.2.1] heptyl), bicyclo [2.2.2] octyl, adamantyl etc.

[0338] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3 to 20-membered ring, a 3 to 15-membered ring, a 3 to 10-membered ring, a 3 to 7-membered ring, a 3 to 6-membered ring, a 3 to 5-membered ring, a 4 to 10-membered ring, a 4 to 8-membered ring, a 4 to 6-membered ring, a 5 to 6-membered ring or a 6-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and / or nitrogen. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxirane, thioethane, and aziridine groups; non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl groups; examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl groups; examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl groups; examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxetanyl, and thiepanyl groups. Preferably, the heterocycloalkyl group is a monocyclic group having 5 or 6 ring atoms.

[0339] The term "heterocycloalkenyl" includes cycloalkenyl groups in which up to 3 carbon atoms, in one embodiment up to 2 carbon atoms, in another embodiment 1 carbon atom is independently replaced by O, S(O) or N, provided that at least one cycloalkenyl carbon-carbon double bond is retained. The cyclic group may be present as a monocyclic, bridged or spirocyclic ring and may be a 3 to 20-membered ring, a 3 to 15-membered ring, a 3 to 12-membered ring, a 3 to 10-membered ring (e.g., a 5 to 8-membered ring), or a 3 to 6-membered ring. Examples of heterocycloalkenyl groups include, but are not limited to, dihydropyrrolyl, tetrahydropyridyl, tetrahydroazepine or azaspirocyclooctene.

[0340] Term " heterocyclic radical " refers to the non-aromatic ring that is fully saturated or partially undersaturated (but not fully undersaturated heteroaromatic) and can exist with monocycle, bridged ring or spirocycle.Unless otherwise indicated, this heterocycle is generally 3 to 20 rings, 3 to 15 rings, 3 to 12 rings, 3 to 10 rings or 3 to 7 rings containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulphur, oxygen and / or nitrogen.The limiting examples of heterocyclic radical include but not limited to oxiranyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl etc.

[0341] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, 6-12 carbon atoms, or 6-10 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.

[0342] The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system containing at least one (e.g., 1, 2, or 3) ring atom selected from N, O, or S, with the remaining ring atoms being C and having at least one aromatic ring. Preferred heteroaryls have single 4 to 8-membered rings, particularly 5 to 8-membered rings, 5 to 10-membered rings, 5 to 12-membered rings, or multiple fused rings containing 6 to 20, 6 to 15, or 6 to 14, particularly 6 to 10 ring atoms, or 5- or 6-membered monocyclic rings. Non-limiting examples of heteroaryls include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.

[0343] The "ring A" groups in this application are all divalent groups, so it should be understood that the options for "ring A" are also divalent groups. For example, the "cycloalkyl" in ring A can be understood as "cycloalkylene", and the C in ring A 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12Cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 Aryl or 5-12 membered heteroaryl can be understood as C 3-12 Cycloalkylene, 3-12 membered heterocycloalkylene, C 3-12 Cycloalkenylene, 3-12 membered heterocycloalkenylene, C 6-12 Arylene or 5-12 membered heteroarylene; C in ring A 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl can be understood as C 3-6 Cycloalkylene, 3-6 membered heterocycloalkylene, C 3-6 Cycloalkenylene, 3-6 membered heterocycloalkenylene, C 6-10 Arylene or 5-10 membered heteroarylene; C in ring A 4-10 Cycloalkyl or 4-10 membered heterocycloalkyl can be understood as C 4-10 Cycloalkylene or 4-10 membered heterocycloalkylene; C in ring A 4-6 Cycloalkyl or 4-6 membered heterocycloalkyl can be understood as C 4-6 Cycloalkylene or 4-6 membered heterocycloalkylene; C in ring A 5-6 Cycloalkyl or 5-6 membered heterocycloalkyl can be understood as C 5-6 Cycloalkylene or 5-6 membered heterocycloalkylene; C6 cycloalkyl or 6 membered heterocycloalkyl in ring A may be understood as C6 cycloalkylene or 6 membered heterocycloalkylene; C6 cycloalkyl or 6 membered N-containing heterocycloalkyl in ring A may be understood as C6 cycloalkylene or 6 membered N-containing heterocycloalkylene; cyclohexyl or piperidinyl in ring A may be understood as cyclohexylene or piperidinylene.

[0344] The "Cy" groups in this application are all divalent groups, so it should be understood that the options of the "Cy" group are also divalent groups. For example, the C in Cy 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl can be understood as C 3-10 Cycloalkylene or 3-10 membered heterocycloalkylene; C in Cy 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl can be understood as C 3-8 Cycloalkylene or 3-8 membered heterocycloalkylene; C in Cy 5-6 Cycloalkyl or 5-6 membered heterocycloalkyl can be understood as C 5-6 Cycloalkylene or 5-6 membered heterocycloalkylene; 3-6 membered heterocycloalkyl in Cy can be understood as 3-6 membered heterocycloalkylene; 6 membered heterocycloalkyl in Cy can be understood as 6 membered heterocycloalkylene; piperidinyl or piperazinyl in Cy can be understood as piperidinylene or piperazinylene.

[0345] The groups or structural fragments in this application, such as ring A, -Cy-L3 -X 2 -、-Cy-、-L 1 -、-X 2 -、-Cy-L 1 -or-L 2 - and its specific options, optionally can be read from left to right, corresponding to the group on the left and right of the group or fragment in the general formula, for example, when -Cy-L 1 -(ie L) is selected from Reading from left to right, -Cy-L 1 -The left side corresponds to the fragment on the left side of the general formula Connect, right side to right side segment Connect, the resulting fragments are Optionally, the groups or structural fragments in the present application, such as ring A, -Cy-L 3 -X 2 -、-Cy-、-L 1 -、-X 2 -、-Cy-L 1 -or-L 2 - and its specific options can be read from right to left, and are connected to the left and right groups of the group or fragment in the general formula, respectively. For example, when -Cy-L 1 -(ie L) is selected from According to the reading order from right to left, -Cy-L 1 - The right side corresponds to the fragment on the left side of the general formula Connect the left side with the corresponding right side fragment in the general formula The ligated fragments are Other groups are the same as described above.

[0346] The term "treatment" means administering the compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0347] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0348] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0349] The term "prevention" means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, including preventing the occurrence of a disease or disease state in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0350] The term "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and this disclosure.

[0351] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0352] As the pharmaceutically acceptable salt, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned.

[0353] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

[0354] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0355] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0356] The compounds and intermediates of the present application can also exist in different tautomeric forms, and all such forms are included in the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. The specific example of a proton tautomer is the imidazole moiety, in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions by reorganization of some bonding electrons.

[0357] The present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0358] Certain isotope-labeled compounds of the present application (e.g. 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as 15 O. 13 N. 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0359] In addition, the use of heavier isotopes such as deuterium (i.e. 2 H)) substitution may offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium.

[0360] The compounds of the present invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds of the present invention containing asymmetric carbon atoms can be isolated in optically pure forms or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

[0361] The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

[0362] Typical routes of administration of the compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0363] The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0364] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, and the like for oral administration to a patient.

[0365] Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be prepared by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients as needed, and then granulating the mixture to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0366] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0367] In all methods of administration described herein, the compounds of formula I are administered at a dosage of 0.01 to 200 mg / kg body weight per day in single or divided doses.

[0368] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0369] The chemical reactions described in the specific embodiments of the present application are carried out in a suitable solvent that is compatible with the chemical transformations described herein and the reagents and materials required. To obtain the compounds described herein, it may sometimes be necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0370] An important consideration in synthetic route planning in this field is the selection of an appropriate protecting group for a reactive functional group (such as an amino group in this application). For example, reference can be made to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.

[0371] Among them, q, R 2 ,m,ring A,R 1 , L, R 3 ,p,X,X 1 The definition of is as described above, and Z is selected from reactive site groups, including but not limited to F, Cl, Br, I or -CHO, etc.

[0372] This application uses the following abbreviations:

[0373] EDCI represents carbodiimide hydrochloride; DMAP represents 4-dimethylaminopyridine; Pd(PPh3)2Cl2 represents bistriphenylphosphine palladium dichloride; AcOH represents acetic acid; NaBH3CN represents sodium cyanoborohydride; and NaCl represents sodium chloride.

[0374] For the sake of clarity, the present invention is further illustrated by examples, but the examples do not limit the scope of this application. All reagents used in this application are commercially available and can be used without further purification. DETAILED DESCRIPTION

[0375] Example 1: Preparation of Compound 1

[0376] 1) Preparation of Intermediate 1-1

[0377] 4-Fluoro-3-nitrobenzenesulfonamide (10 g) was dissolved in tetrahydrofuran (20 mL), and 1-tert-butyloxycarbonyl-4-aminomethylpiperidine (9.7 g) and triethylamine (6.8 g) were added sequentially. The mixture was stirred at room temperature for 12 h until the reaction was complete. The solvent was evaporated under reduced pressure to obtain Intermediate 1-1 (14 g).

[0378] 2) Preparation of intermediate 1-2

[0379] Dissolve compound Intermediate 1-1 (5.0 g) in dichloromethane (50 mL) and add trifluoroacetic acid (5 mL). Stir and react at room temperature for 3 h until the reaction is complete. Evaporate the solvent and trifluoroacetic acid under reduced pressure. Add water (50 mL) and acetonitrile (10 mL) to dissolve the mixture. Add saturated aqueous NaHCO3 dropwise and adjust the pH to 8-9. A solid precipitates and is filtered to obtain Intermediate 1-2 (4.9 g).

[0380] 3) Preparation of Intermediate 1-3

[0381] Intermediate 1-2 (1.0 g) was dissolved in methanol (50 mL), and N-tert-butyloxycarbonyl-4-piperidone (0.95 g) was added. The mixture was stirred at room temperature for 30 min, and AcOH (1 mL) was added. The mixture was stirred at room temperature for 30 min, and NaBH3CN (0.60 g) was added. The reaction was stirred at room temperature for 12 h. The reaction was quenched by the addition of saturated sodium bicarbonate. The aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, the solvent was evaporated under reduced pressure, and column chromatography (developing solvent: dichloromethane:methanol = 10:1) was performed to obtain Intermediate 1-3 (0.5 g).

[0382] 4) Preparation of Intermediate 1-5

[0383] Intermediate 1-3 (1.2 g) and compound 1-4 (1.46 g) were dissolved in dichloromethane (20 mL), and EDCI (0.64 g) and DMAP (0.58 g) were added. The mixture was stirred at room temperature for 12 h, and the reaction was complete. Dichloromethane (30 mL) was added, and the mixture was washed with saturated aqueous NaCl. The solvent was evaporated under reduced pressure, and column chromatography (developing solvent: dichloromethane:methanol = 30:1) was performed to obtain Intermediate 1-5 (1.2 g).

[0384] 5) Preparation of Intermediate 1-6

[0385] The obtained intermediate 1-5 (1.0 g) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 2 h. The solvent and trifluoroacetic acid were evaporated under reduced pressure to obtain intermediate 1-6 (800 mg).

[0386] 6) Preparation of Intermediate 1-8

[0387] Sodium thiosulfate pentahydrate (53.7 g), benzyl chloride (27.4 g), copper sulfate pentahydrate (77.4 mg), and bipyridine (0.72 g) were dissolved in methanol (120 mL) and water (120 mL). The temperature was slowly raised to 80°C and stirred for 2 h. The reaction mixture was cooled to room temperature, compound 1-7 (8.0 g) was added, and tert-butyl nitrite (4.78 g) was slowly added dropwise. After completion of the dropwise addition, the temperature was raised to 80°C and stirred for 8 h. After the reaction was complete, the reaction mixture was cooled to room temperature and water (200 mL) was added. The aqueous phase was extracted with ethyl acetate (200 mL x 2). The organic phases were combined, washed with water and saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The mixture was purified by column chromatography (developing solvent: petroleum ether:ethyl acetate = 1:2) to obtain intermediate 1-8 (6.8 g).

[0388] LC-MS: m / z=367.11[M+H] + .

[0389] 7) Preparation of Intermediate 1-9

[0390] Anhydrous aluminum chloride (2.61 g) was dissolved in anhydrous toluene (70 mL), and intermediate 1-8 (1.8 g) was slowly added with stirring. After the addition was complete, the reaction was stirred at 35°C for 7 h. After the reaction was complete, 20% aqueous citric acid solution was slowly added with stirring until no solid precipitated. The mixture was filtered, and the filter cake was rinsed with water and ethyl acetate, respectively, and dried to obtain intermediate 1-9 (1.15 g).

[0391] LC-MS: m / z = 277.06 [M+H] + .

[0392] 8) Preparation of Intermediate 1-10

[0393] Intermediate 1-9 (1.0 g) and anhydrous potassium carbonate (1.0 g) were dissolved in anhydrous N,N-dimethylformamide (10 mL). 1,3-Dibromopropane (0.87 g) was slowly added with stirring and the mixture was stirred at room temperature for 1 h. After completion of the reaction, water was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phases were combined and the solvent was evaporated under reduced pressure to obtain Intermediate 1-10 (150 mg).

[0394] LC-MS: m / z=397.02[M+H] + .

[0395] 9) Preparation of Compound 1

[0396] Intermediate 1-6 (0.15 g) was dissolved in N,N-dimethylformamide (10 mL), and potassium carbonate (0.14 g), sodium iodide (0.15 g) and intermediate 1-10 (0.12 g) were added in sequence. The mixture was stirred at 50°C for 8 h. The reaction solution was subjected to preparative liquid chromatography to obtain compound 1 (13 mg).

[0397] LC-MS: m / z=651.2[M+2H] 2+ .

[0398] 1 H NMR(500MHz, CDCl3)δ8.86(d,1H),8.56(s,1H),8.44(s,1H),8.15(d,1H),8.05(d,1H),7.94( d,1H),7.65(d,1H),7.43(dd,3H),7.09(d,2H),7.03(d,1H),7.00(d,1H),6.55(dd,2H),6.02 (s,1H),5.24(dd,1H),4.44(d,1H),4.31(d,1H),4.07–4.01(m,2H),3.20(m,2H),3.06(m,4H) ,2.93–2.83(m,5H),2.73–2.22(m,15H),1.98–1.79(m,12H),1.52–1.26(m,10H),0.95(s,6H).

[0399] Example 2: Preparation of Compound 2

[0400] 1) Preparation of Intermediate 2-1

[0401] Referring to the preparation method of intermediate 1-10 in step 8) of Example 1, 1,3-dibromopropane was replaced with 1,4-dibromobutane to obtain intermediate 2-1 (166 mg).

[0402] LC-MS: m / z = 411.0 [M+H] + .

[0403] 2) Preparation of Compound 2

[0404] Refer to the preparation method of Example 1 in step 9) of Example 1, replacing the intermediate 1-10 with intermediate 2-1 to obtain compound 2 (62 mg).

[0405] LC-MS: m / z=657.6[M+2H] 2+ .

[0406] 1H NMR(500MHz, CDCl3)δ8.87(d,1H),8.57(s,1H),8.45(s,1H),8.15(d,1H),8.07(d,1H),7.95( d,1H),7.65(d,1H),7.44(dd,3H),7.10(d,2H),7.03(d,1H),7.00(d,1H),6.56(dd,2H),6.03 (s,1H),5.25(dd,1H),4.44(d,1H),4.30(d,1H),4.07–4.00(m,2H),3.21(m,2H),3.06(m,4H) ,2.93–2.83(m,6H),2.73–2.22(m,14H),1.98–1.79(m,14H),1.52–1.26(m,10H),0.95(s,6H).

[0407] Example 3: Preparation of Compound 3

[0408] 1) Preparation of Intermediate 3-1

[0409] Referring to the preparation method of intermediate 1-10 in step 8) of Example 1, 1,3-dibromopropane was replaced with 1,5-dibromopentane to obtain intermediate 3-1 (210 mg).

[0410] LC-MS: m / z = 425.0 [M+H] + .

[0411] 2) Preparation of Compound 3

[0412] Referring to the preparation method of Example 1 in step 9) of Example 1, intermediate 1-10 was replaced with intermediate 3-1 to obtain compound 3 (21 mg).

[0413] LC-MS: m / z=664.7[M+2H] 2+ .

[0414] 1H NMR(500MHz, CDCl3)δ8.86(d,1H),8.57(s,1H),8.43(s,1H),8.14(d,1H),8.07(d,1H),7.93( d,1H),7.66(d,1H),7.45(dd,3H),7.10(d,2H),7.02(d,1H),7.00(d,1H),6.56(dd,2H),6.02 (s,1H),5.24(dd,1H),4.44(d,1H),4.30(d,1H),4.07–4.00(m,2H),3.21(m,2H),3.06(m,4H) ,2.93–2.83(m,8H),2.73–2.22(m,12H),1.98–1.79(m,15H),1.52–1.26(m,11H),0.95(s,6H).

[0415] Example 4: Preparation of Compound 4

[0416] 1) Preparation of intermediate 4-2

[0417] Compound 4-1 (1.0 g), 1,4-dibromobutane (2.49 g) and potassium carbonate (0.58 g) were stirred in acetonitrile (20 mL) at 80° C. for 9 h, filtered, and the filter cake was rinsed with dichloromethane. The solvent was evaporated from the filtrate under reduced pressure, and the intermediate 4-2 (670 mg) was obtained by column chromatography (developing solvent: dichloromethane: methanol = 150:1 to 100:1).

[0418] LC-MS: m / z=396.9[M+H] + .

[0419] 1 H NMR(500MHz, CDCl3)δ8.86(d,1H),8.54(s,1H),8.43(s,1H),8.13(d,1H),8.07(d,1H),7.96( d,1H),7.64(d,1H),7.43(dd,3H),7.08(d,2H),7.03(d,1H),7.00(d,1H),6.55(dd,2H),6.04 (s,1H),5.25(dd,1H),4.43(d,1H),4.31(d,1H),4.07–4.02(m,2H),3.22(m,2H),3.06(m,4H) ,2.93–2.83(m,6H),2.73–2.22(m,14H),1.98–1.79(m,14H),1.52–1.26(m,10H),0.95(s,6H).

[0420] 2) Preparation of Compound 4

[0421] Refer to the preparation method of Example 1 in step 9) of Example 1, replacing Intermediate 1-10 with Intermediate 4-2 to obtain Compound 4 (88 mg).

[0422] LC-MS: m / z=649.8[M+2H] 2+ .

[0423] Example 5: Preparation of Compound 5

[0424] 1) Preparation of Intermediate 5-1

[0425] Referring to the preparation method of intermediate 4-2 in step 1) of Example 4, 1,4-dibromobutane was replaced with 1,5-dibromopentane to obtain intermediate 5-1 (980 mg).

[0426] LC-MS: m / z = 411.0 [M+H] + .

[0427] 2) Preparation of Compound 5

[0428] Refer to the preparation method of Example 1 in step 9) of Example 1, replacing the intermediate 1-10 with intermediate 5-1 to obtain compound 5 (32 mg).

[0429] LC-MS: m / z = 656.8 [M+2H] 2+

[0430] 1 H NMR(500MHz, CDCl3)δ8.87(d,1H),8.55(s,1H),8.43(s,1H),8.13(d,1H),8.07(d,1H),7.9 5(d,1H),7.66(d,1H),7.44(dd,3H),7.10(d,2H),7.02(d,1H),7.00(d,1H),6.55(dd,2H),6 .03(s,1H),5.24(dd,1H),4.44(d,1H),4.30(d,1H),4.07–4.00(m,2H),3.21–3.06(m,7H),2 .93–2.83(m,8H),2.73–2.22(m,13H),1.98–1.79(m,14H),1.52–1.26(m,10H),0.95(s,6H).

[0431] Example 6: Preparation of Compound 6

[0432] 1) Preparation of Intermediate 6-2

[0433] Refer to the preparation method of intermediate 1-6 in step 5) of Example 1, and replace intermediate 1-5 with intermediate 6-1 to obtain intermediate 6-2 (850 mg).

[0434] LC-MS: m / z = 958.4 [M+H] + .

[0435] 2) Preparation of Intermediate 6-4

[0436] Compound 6-3 (0.50 g) was dissolved in N,N-dimethylformamide (5 mL), and 4-pentyn-1-ol (0.21 g), Pd(PPh3)2Cl2 (0.10 g), and CuI (57 mg) were added sequentially. The mixture was stirred at room temperature for 5 min, and triethylamine (2.5 mL) was added. The reaction was stirred at 80°C under N2 protection for 16 h. The mixture was cooled to room temperature and quenched with water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with water (30 mL × 2), then washed with saturated aqueous NaCl (50 mL × 3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The mixture was purified by column chromatography (developing solvent: dichloromethane:methanol = 5:1) to obtain intermediate 6-4 (350 mg).

[0437] LC-MS: m / z=327.13[M+H] + .

[0438] 3) Preparation of Intermediate 6-5

[0439] Intermediate 6-4 (50 mg) and phosphorus tribromide (42 mg) were stirred in N-methylpyrrolidone (2 mL) at 70°C for 12 h. The mixture was cooled to room temperature and quenched with water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with water and saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The mixture was purified by column chromatography (developing solvent: dichloromethane:methanol = 100:1) to obtain Intermediate 6-5 (120 mg).

[0440] LC-MS: m / z = 389.2 [M+H] + .

[0441] 4) Preparation of Compound 6

[0442] Refer to the preparation method of Example 1 in step 9) of Example 1, replace Intermediate 1-6 with Intermediate 6-2, and replace Intermediate 1-10 with Intermediate 6-5 to obtain Compound 6 (22 mg).

[0443] LC-MS: m / z = 634.0 [M+2H] 2+ .

[0444] 1 H NMR (500MHz, CDCl3) δ10.74(s,1H),8.80(d,1H),8.41(s,1H),8.07(d,1H),7.98(d,1H),7.88 (d,1H),7.77(d,1H),7.68(d,1H),7.53(t,2H),7.43(m,3H),7.10(d,2H),6.78(d,1H),6.53( dd,1H),6.50(d,1H),5.97(s,1H),5.23(dd,1H),4.50(d,1H),4.38(d,1H),3.22–3.10(m,10H ),2.97–2.78(m,7H),2.57–2.43(m,12H),2.00–1.83(m,8H),1.63–1.26(m,9H),0.95(s,6H).

[0445] Example 7: Preparation of Compound 7

[0446] 1) Preparation of Intermediate 7-2

[0447] Compound 7-1 (1.0 g) was dissolved in anhydrous N,N-dimethylformamide (10 mL), and anhydrous potassium carbonate (1.1 g) and sodium iodide (1.1 g) were added in sequence. 1,3-dibromopropane (0.87 g, 4.34 mmol) was slowly added under stirring at room temperature, and heated at 60°C for 6 h. Liquid phase preparation was performed to obtain intermediate 7-2.

[0448] LC-MS: m / z = 393.9 [M+H] +

[0449] 2) Preparation of Compound 7

[0450] Intermediate 1-6 (0.50 g) was dissolved in 10 mL DMF, and potassium carbonate (0.14 g), sodium iodide (0.15 g) and intermediate 7-2 (0.33 g) were added in sequence. The mixture was heated at 50° C. for 8 h. Liquid phase preparation was performed to obtain compound 7 (88 mg).

[0451] LC-MS: m / z = 1297.54 [M+H] +

[0452] Example 8: Preparation of Compound 8

[0453] 1) Preparation of Intermediate 8-1

[0454] Referring to the preparation method of intermediate 7-2 in step 1) of Example 7, 1,3-dibromopropane was replaced with 1,4-dibromobutane to obtain intermediate 8-1 (166 mg).

[0455] LC-MS: m / z = 408.2 [M+H] + .

[0456] 2) Preparation of Compound 8

[0457] Refer to the preparation method of compound 7 in step 2) of Example 7, replacing intermediate 7-2 with intermediate 8-1 to obtain compound 8 (62 mg).

[0458] LC-MS: m / z=656.3[M+2H] 2+ .

[0459] Example 9: Preparation of Compound 9

[0460] 1) Preparation of Intermediate 9-1

[0461] Referring to the preparation method of intermediate 7-2 in step 1) of Example 7, 1,3-dibromopropane was replaced with 1,5-dibromopentane to obtain intermediate 9-1 (180 mg).

[0462] LC-MS: m / z = 422.1 [M+H] + .

[0463] 2) Preparation of Compound 9

[0464] Refer to the preparation method of compound 7 in step 2) of Example 7, replacing intermediate 7-2 with intermediate 9-1 to obtain compound 9 (80 mg).

[0465] LC-MS: m / z=663.3[M+2H] 2+ .

[0466] Example 10: Preparation of Compound 10

[0467] 1) Preparation of Intermediate 10-1

[0468] Refer to the preparation method of intermediate 1-5 in step 4) of Example 1, and replace intermediate 1-3 with intermediate 1-1 to obtain intermediate 10-1 (800 mg).

[0469] 2) Preparation of Intermediate 10-2

[0470] Refer to the preparation method of intermediate 1-6 in step 5) of Example 1, and replace intermediate 1-5 with intermediate 10-1 to obtain intermediate 10-2 (600 mg).

[0471] 3) Preparation of Compound 10

[0472] Refer to the preparation method of compound 9 in step 2) of Example 9, replacing intermediate 1-6 with intermediate 10-2 to obtain compound 10 (120 mg).

[0473] LC-MS: m / z = 621.8 [M+2H] 2+ .

[0474] Example 11: Preparation of Compound 11

[0475] 1) Preparation of Intermediate 11-1

[0476] Referring to the preparation method of intermediate 8-1 in step 1) of Example 8, compound 7-1 was replaced with lenalidomide to obtain intermediate 11-1 (180 mg).

[0477] LC-MS: m / z=394.1[M+H] + .

[0478] 2) Preparation of Compound 11

[0479] Refer to the preparation method of compound 7 in step 2) of Example 7, and replace intermediate 7-2 with intermediate 11-1 to obtain compound 11 (45 mg).

[0480] LC-MS: m / z=649.3[M+2H] 2+ .

[0481] Example 12: Preparation of Compound 12

[0482] 1) Preparation of Intermediate 12-1

[0483] 1g of compound 12A, 871mg of bistriphenylphosphine palladium dichloride, and 118mg of cuprous iodide were weighed and dissolved in 20mL of N,N-dimethylformamide. The mixture was stirred at room temperature, followed by the addition of 783mg of 7-octyn-1-ol and 1.539mL of N,N-diisopropylethylamine. Under nitrogen, the mixture was heated to 70°C and stirred for 5 hours. 40mL of water was added to the reaction solution, which was then extracted with 50mL of ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated at 38°C. The crude product was purified by silica gel column chromatography (dichloromethane:methanol) to afford 795mg of intermediate 12-1.

[0484] ESI-MS: m / z = 369.1 [M+H] +

[0485] 2) Preparation of Intermediate 12-2

[0486] Disperse 200 mg of Intermediate 12-1 in 5 mL of dichloromethane, add 345 mg of Dess-Martin reagent, and stir at 40°C under nitrogen for 3 hours. Cool to room temperature, add 45 mL of dichloromethane, 25 mL of saturated sodium bicarbonate solution, and 25 mL of saturated sodium thiosulfate solution to the reaction solution. Stir at room temperature for 10 minutes, then separate the layers. The aqueous phase is extracted with 50 mL of dichloromethane. The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated at 38°C to obtain 246 mg of Intermediate 12-2.

[0487] ESI-MS: m / z = 367.33 [M+H] +

[0488] 3) Preparation of Compound 12

[0489] 156 mg of intermediate 12-2 and 419 mg of intermediate 1-6 were dispersed in 8 mL of dichloromethane, 0.037 mL of glacial acetic acid was added, and the mixture was stirred at room temperature for 30 minutes. 37 mg of sodium cyanoborohydride was then added, and the mixture was stirred at room temperature for 3 hours. 25 mL of dichloromethane, 25 mL of saturated ammonium chloride solution, 25 mL of saturated brine, and 25 mL of water were added to the reaction mixture, and the mixture was stirred at room temperature for 5 minutes. After separation, the aqueous phase was extracted with dichloromethane:methanol = 3:2 (v:v). The organic phases were combined and concentrated at 38°C. The crude product was purified by preparative liquid chromatography to obtain 85 mg of compound 12.

[0490] ESI-MS: m / z = 667.8 [M+2H] 2+

[0491] 1H NMR (500MHz, DMSO) δ11.53(d,J=2.4Hz,1H),11.03–10.99(m,1H),8.40(d,J=2.2Hz,2H),8.15(s,2H),7.93(d ,J=2.6Hz,1H),7.71(dd,J=7.6,1.0Hz,1H),7.69–7.64(m,3H),7.62(dd,J=7.6,1.0Hz,1H),7.58(d,J=8.8Hz, 1H),7.52(t,J=7.6Hz,1H),7.42(t,J=3.0Hz,1H),7.30(d,J=2.6Hz,1H),7.26(d,J=7.9Hz,2H),6.87(d,J=9.3 Hz,1H),6.62(dd,J=8.9,2.4Hz,1H),6.30(dd,J=3.4,1.9Hz,1H),6.23(d,J=2.3Hz,1H),5.15(dd,J=13.4,5.2 Hz,1H),4.44(d,J=17.6Hz,1H),4.30(d,J=17.5Hz,1H),3.28(d,J=12.7Hz,5H),3.10(d,J=11.1Hz,5H),3.03– 2.97(m,4H),2.92(ddd,J=17.2,13.7,5.4Hz,2H),2.72(s,2H),2.59(ddd,J=17.4,4.5,2.3Hz,2H),2.47(d,J= 7.0Hz,2H),2.25–2.15(m,8H),1.98(s,2H),1.84(d,J=12.3Hz,2H),1.78(d,J=13.1Hz,2H),1.57(p,J=6.7Hz, 4H),1.53–1.46(m,2H),1.44(d,J=7.9Hz,2H),1.41(t,J=6.5Hz,3H),1.30(p,J=8.5,7.8Hz,4H),0.94(s,6H).

[0492] Example 13: Preparation of Compound 13

[0493] 1) Preparation of Intermediate 13-1

[0494] Refer to the preparation method of intermediate 12-1 in step 1) of Example 12, and replace 7-octyne-1-ol with 4-pentyne-1-ol to obtain intermediate 13-1.

[0495] ESI-MS: m / z = 327.1 [M+H] +

[0496] 2) Preparation of Intermediate 13-2

[0497] Refer to the preparation method of intermediate 12-2 in step 2) of Example 12, and replace intermediate 12-1 with intermediate 13-1 to obtain intermediate 13-2.

[0498] ESI-MS: m / z = 325.1 [M+H] +

[0499] 3) Preparation of Compound 13

[0500] Refer to the preparation method of compound 12 in step 3) of Example 12, and replace intermediate 12-2 with intermediate 13-2 to obtain compound 13.

[0501] LC-MS: m / z=646.8[M+2H] 2+ .

[0502] 1 H NMR (500MHz, DMSO) δ11.55(d,J=2.4Hz,1H),11.01(s,1H),8.49–8.41(m,2H),8.15(s,3H),7.95(d,J=2.6Hz,1H),7.75–7.60(m,5H),7.5 9–7.49(m,2H),7.44(m,1H),7.34(m,1H),7.26(d,J=8.0Hz,2H),6.93(d,J=9.2Hz,1H),6.63(m,1H),6.32(m,1H),6.22(d,J=2.3Hz,1H),5 .16(m,1H),4.46(d,J=17.6Hz,2H),4.30(d,J=17.5Hz,2H),3.31(m,3H),3.24(m,3H),3.05(m,3H),3.00(m,3H),2.72(s,2H),2.70–2.61( m,3H),2.41(m,1H),2.18(m,5H),2.12–2.00(m,3H),1.98(s,2H),1.92–1.81(m,5H),1.76(m,2H),1.59(m,2H),1.39(m,4H),0.94(s,6H).

[0503] Example 14: Preparation of Compound 14

[0504] 1) Preparation of Intermediate 14-1

[0505] Refer to the preparation method of intermediate 12-1 in step 1) of Example 12, and replace 7-octyne-1-ol with 6-heptyne-1-ol to obtain intermediate 14-1.

[0506] ESI-MS: m / z = 355.2 [M+H] +

[0507] 2) Preparation of Intermediate 14-2

[0508] Refer to the preparation method of intermediate 12-2 in step 2) of Example 12, and replace intermediate 12-1 with intermediate 14-1 to obtain intermediate 14-2.

[0509] ESI-MS: m / z = 353.1 [M+H] +

[0510] 3) Preparation of Compound 14

[0511] Refer to the preparation method of compound 12 in step 3) of Example 12, and replace intermediate 12-2 with intermediate 14-2 to obtain compound 14.

[0512] LC-MS: m / z = 660.8 [M+2H] 2+ .

[0513] 1H NMR (500MHz, DMSO) δ11.50 (s, 1H), 11.02 (s, 1H), 8.41–8.36 (m, 1H), 7.91 (d, J = 2.6Hz, 1H), 7. 71(dd,J=7.5,1.0Hz,1H),7.65(s,1H),7.66–7.59(m,3H),7.57(d,J=8.8Hz,1H),7.51(t,J=7. 6Hz,1H),7.41(t,J=3.0Hz,1H),7.30–7.23(m,3H),6.82(d,J=9.2Hz,1H),6.60(dd,J=8.9,2.4 Hz,1H),6.30(dd,J=3.3,1.9Hz,1H),6.24(d,J=2.4Hz,1H),5.13(dd,J=13.3,5.2Hz,1H),4.43 (d,J=17.6Hz,1H),4.29(d,J=17.6Hz,1H),3.06(s,2H),3.03–2.97(m,4H),2.91(ddd,J=17.1, 13.7,5.5Hz,1H),2.72(s,2H),2.59(ddd,J=17.3,4.4,2.3Hz,2H),2.54(s,4H),2.47(d,J=7.0 Hz,2H),2.42(dd,J=13.2,4.6Hz,2H),2.22–2.15(m,6H),1.97(s,2H),1.90(s,8H),1.79(dd,J =25.1,12.6Hz,4H),1.57(p,J=7.1Hz,4H),1.45–1.37(m,4H),1.30–1.20(m,5H),0.94(s,6H).

[0514] Example 15: Preparation of Compound 15

[0515] 1) Preparation of Intermediate 15-1

[0516] Refer to the preparation method of intermediate 12-1 in step 1) of Example 12, and replace 7-octyne-1-ol with 8-nonyne-1-ol to obtain intermediate 15-1.

[0517] ESI-MS: m / z = 383.2 [M+H] +

[0518] 2) Preparation of Intermediate 15-2

[0519] Refer to the preparation method of intermediate 12-2 in step 2) of Example 12, and replace intermediate 12-1 with intermediate 15-1 to obtain intermediate 15-2.

[0520] ESI-MS: m / z = 381.1 [M+H] +

[0521] 3) Preparation of Compound 15

[0522] Refer to the preparation method of compound 12 in step 3) of Example 12, and replace intermediate 12-2 with intermediate 15-2 to obtain compound 15.

[0523] LC-MS: m / z=674.3[M+2H] 2+ .

[0524] 1 H NMR (500MHz, DMSO) δ11.52(s,1H),11.03(s,1H),8.39(dd,J=7.5,4.1Hz,2H),8.15(s,3H),7.92(d,J=2.6Hz,1H),7.73–7.6 8(m,1H),7.65(t,J=6.8Hz,3H),7.63–7.60(m,1H),7.58(d,J=8.8Hz,1H),7.52(t,J=7.6Hz,1H),7.41(t,J=3.0Hz,1H),7.31 –7.23(m,3H),6.85(d,J=9.2Hz,1H),6.61(dd,J=8.9,2.4Hz,1H),6.30(dd,J=3.4,1.9Hz,1H),6.24(d,J=2.3Hz,1H),5.15( dd,J=13.3,5.2Hz,1H),4.44(d,J=17.6Hz,1H),4.30(d,J=17.6Hz,1H),3.27(t,J=6.3Hz,5H),3.08(d,J=10.9Hz,5H),3.03– 2.97(m,4H),2.92(ddd,J=17.2,13.7,5.4Hz,2H),2.72(s,2H),2.60(ddd,J=17. 3,4.5,2.3Hz,2H),2.43(dd,J=13.0,4.6Hz,2H),2.19(q,J=8.4,6.6Hz,8H),2.06 –1.97(m,3H),1.80(s,1H),1.77(d,J=13.1Hz,2H),1.72(s,1H),1.57(p,J=6.9Hz ,4H),1.43(dt,J=22.9,6.6Hz,6H),1.30(s,1H),1.30–1.22(m,4H),0.94(s,6H).

[0525] Example 16: Preparation of Compound 16

[0526] 1) Preparation of Intermediate 16-1

[0527] Refer to the preparation method of intermediate 12-1 in step 1) of Example 12, and replace 7-octyne-1-ol with 9-decyne-1-ol to obtain intermediate 16-1.

[0528] ESI-MS: m / z = 397.2 [M+H] +

[0529] 2) Preparation of Intermediate 16-2

[0530] Refer to the preparation method of intermediate 12-2 in step 2) of Example 12, and replace intermediate 12-1 with intermediate 16-1 to obtain intermediate 16-2.

[0531] ESI-MS: m / z = 395.1 [M+H] +

[0532] 3) Preparation of Compound 16

[0533] Refer to the preparation method of compound 12 in step 3) of Example 12, and replace intermediate 12-2 with intermediate 16-2 to obtain compound 16.

[0534] LC-MS: m / z = 681.8 [M+2H] 2+ .

[0535] 1H NMR (500MHz, DMSO) δ11.53(t,J=2.4Hz,1H),11.02(s,1H),8.43–8.38(m,2H),8.15(s,3H),7.93(d,J=2.6Hz,1H),7.71 (dd,J=7.6,1.0Hz,1H),7.67(d,J=2.2Hz,1H),7.64(ddd,J=17.2,6.3,1.7Hz,3H),7.58(d,J=8.7Hz,1H),7.52(t,J=7. 6Hz,1H),7.42(t,J=3.0Hz,1H),7.31(d,J=2.6Hz,1H),7.26(d,J=7.9Hz,2H),6.88(d,J=9.2Hz,1H),6.62(dd,J=8.9,2 .4Hz,1H),6.31(dd,J=3.4,1.9Hz,1H),6.23(d,J=2.4Hz,1H),5.15(dd,J=13.3,5.1Hz,1H),4.44(d,J=17.6Hz,1H),4.3 0(d,J=17.6Hz,1H),3.28(t,J=6.3Hz,3H),3.11(d,J=12.1Hz,4H),3.00(t,J=4.8Hz,4H),2.92(ddd,J=17.2,13.6,5.4 Hz,2H),2.72(s,2H),2.60(ddd,J=17.3,4.4,2.3Hz,2H),2.47(d,J=7.0Hz,2H),2.43(dd,J=13.1,4.6Hz,1H),2.18(q,J =7.8,6.3Hz,8H),2.02(ddt,J=9.9,5.4,2.2Hz,1H),1.98(s,2H),1.87–1.81(m,2H),1.78(d,J=13.3Hz,2H),1.72(d,J =10.6Hz,1H),1.57(p,J=7.1Hz,4H),1.45(d,J=7.6Hz,2H),1.41(q,J=7.3,6.6Hz,4H),1.32–1.22(m,8H),0.94(s,6H).

[0536] Example 17: Preparation of Compound 17

[0537] 1) Preparation of Intermediate 17-1

[0538] Refer to the preparation method of intermediate 12-1 in step 1) of Example 12, and replace 7-octyne-1-ol with 10-undecyne-1-ol to obtain intermediate 17-1.

[0539] ESI-MS: m / z = 411.2 [M+H] +

[0540] 2) Preparation of Intermediate 17-2

[0541] Refer to the preparation method of intermediate 12-2 in step 2) of Example 12, and replace intermediate 12-1 with intermediate 17-1 to obtain intermediate 17-2.

[0542] ESI-MS: m / z = 409.2 [M+H] +

[0543] 3) Preparation of Compound 17

[0544] Refer to the preparation method of compound 12 in step 3) of Example 12, and replace intermediate 12-2 with intermediate 17-2 to obtain compound 17.

[0545] LC-MS: m / z = 688.8 [M+2H] 2+ .

[0546] 1H NMR(500MHz,DMSO)δ11.51(s,1H),11.03(s,1H),8.41–8.37(m,1H),7.92(d,J=2.6Hz,1H),7.7 1(dd,J=7.5,1.0Hz,1H),7.66(s,1H),7.66–7.60(m,3H),7.58(d,J=8.8Hz,1H),7.51(t,J=7.6 Hz,1H),7.41(t,J=3.0Hz,1H),7.30–7.23(m,3H),6.84(d,J=9.2Hz,1H),6.61(dd,J=8.9,2.4H z,1H),6.30(dd,J=3.3,1.9Hz,1H),6.24(d,J=2.4Hz,1H),5.15(dd,J=13.3,5.2Hz,1H),4.44( d,J=17.6Hz,1H),4.29(d,J=17.6Hz,1H),3.07(s,2H),3.03–2.97(m,4H),2.92(ddd,J=17.1,1 3.7,5.5Hz,1H),2.72(s,2H),2.59(ddd,J=17.3,4.4,2.3Hz,2H),2.54(s,4H),2.47(d,J=7.0H z,2H),2.42(dd,J=13.2,4.6Hz,2H),2.22–2.16(m,6H),1.98(s,2H),1.91(s,10H),1.79(dd,J =25.1,12.6Hz,4H),1.57(p,J=7.1Hz,4H),1.45–1.37(m,6H),1.30–1.20(m,9H),0.94(s,6H).

[0547] Example 18: Preparation of Compound 18

[0548] 1) Preparation of Intermediate 18-1

[0549] Refer to the preparation method of intermediate 12-1 in step 1) of Example 12, and replace 7-octyne-1-ol with 5-hexyne-1-ol to obtain intermediate 18-1.

[0550] ESI-MS: m / z = 341.1 [M+H] +

[0551] 2) Preparation of Intermediate 18-2

[0552] Refer to the preparation method of intermediate 12-2 in step 2) of Example 12, and replace intermediate 12-1 with intermediate 18-1 to obtain intermediate 18-2.

[0553] ESI-MS: m / z = 339.1 [M+H] +

[0554] 3) Preparation of Compound 18

[0555] Refer to the preparation method of Example 12 in step 3) of Example 12, and replace the intermediate 12-2 with intermediate 18-2 to obtain compound 18.

[0556] LC-MS: m / z=653.8[M+2H] 2+ .

[0557] 1 H NMR(500MHz,DMSO)δ11.53(s,1H),11.00(s,1H),8.44–8.39(m,2H),8.14(s,4H),7.93(d,J=2.6Hz,1 H),7.74–7.60(m,5H),7.57(d,J=8.8Hz,1H),7.52(t,J=7.6Hz,1H),7.42(t,J=3.0Hz,1H),7.32(d,J =2.6Hz,1H),7.26(d,J=7.9Hz,2H),6.89(d,J=9.2Hz,1H),6.62(dd,J=8.9,2.4Hz,1H),6.31(dd,J=3 .4,1.9Hz,1H),6.23(d,J=2.3Hz,1H),5.16(dd,J=13.3,5.1Hz,1H),4.45(d,J=17.6Hz,1H),4.30(d,J =17.6Hz,1H),3.29(d,J=6.9Hz,3H),3.16(d,J=10.9Hz,3H),3.09(d,J=11.1Hz,3H),3.00(t,J=5.1H z,4H),2.93(ddd,J=17.0,13.5,5.2Hz,2H),2.74(d,J=16.8Hz,3H),2.61(d,J=3.5Hz,1H),2.54(s,3H ),2.46–2.37(m,1H),2.19(d,J=5.8Hz,6H),2.02(dq,J=7.3,2.9,2.4Hz,1H),1.99(s,2H),1.89–1.7 8(m,4H),1.65–1.55(m,5H),1.41(t,J=6.5Hz,2H),1.34(d,J=12.5Hz,1H),1.24(s,1H),0.94(s,6H).

[0558] Example 19: Preparation of Compound 19

[0559] 1) Preparation of Intermediate 19-1

[0560] Compound 19A (2.0 g) was dissolved in acetonitrile (40 mL), and anhydrous potassium carbonate (1.17 g) and 1,6-dibromohexane (5.62 g) were added in sequence. The mixture was reacted at 60° C. for 6 h to obtain intermediate 19-1 via liquid phase reaction.

[0561] ESI-MS: m / z = 423.1 [M+H] +

[0562] 2) Preparation of Compound 19

[0563] Refer to the preparation method of compound 7 in step 2) of Example 7, and replace intermediate 7-2 with intermediate 19-1 to obtain compound 19.

[0564] LC-MS: m / z = 663.8 [M+2H] 2+ .

[0565] 1 H NMR(500MHz, CDCl3)δ8.86(d,1H),8.56(s,1H),8.44(s,1H),8.15(d,1H),8.05(d,1H),7.94(d,1H ),7.65(d,1H),7.43(dd,3H),7.09(d,2H),7.03(d,1H),7.00(d,1H),6.55(dd,2H),6.02(s,1H),5. 24(dd,1H),4.44(d,1H),4.31(d,1H),4.07–4.01(m,2H),3.20(m,2H),3.06(m,4H),2.93–2.83(m, 4H),2.73(m,2H),2.42(m,4H),2.22(dd,9H),1.98–1.79(m,15H),1.52–1.26(m,14H),0.95(s,6H).

[0566] Example 20: Preparation of Compound 20

[0567] 1) Preparation of Intermediate 20-1

[0568] Refer to the preparation method of intermediate 19-1 in step 1) of Example 19, replacing 1,6-dibromohexane with 1,7-dibromoheptane to obtain intermediate 20-1.

[0569] ESI-MS: m / z = 437.1 [M+H] +

[0570] 2) Preparation of Compound 20

[0571] Refer to the preparation method of compound 7 in step 2) of Example 7, replacing intermediate 7-2 with intermediate 20-1 to obtain compound 20.

[0572] LC-MS: m / z = 670.8 [M+2H] 2+ .

[0573] 1 H NMR(500MHz, CDCl3)δ8.81(d,1H),8.41(s,1H),8.11(d,1H),7.97(d,1H),7.91(d,1H),7.62(d,1H) ,7.52(t,2H),7.43(dd,3H),7.10(d,2H),7.00(d,1H),6.75(d,1H),6.55(dd,1H),6.47(d,1H),6.04 (s,1H),5.24(dd,1H),4.43(d,1H),4.30(d,1H),4.07–4.02(m,3H),3.19(m,2H),3.07(m,4H),2.93– 2.83(m,3H),2.73(m,2H),2.42–2.22(m,14H),1.98–1.79(m,15H),1.52–1.26(m,14H),0.95(s,6H).

[0574] Example 21: Preparation of Compound 21

[0575] 1) Preparation of Intermediate 21-1

[0576] Refer to the preparation method of intermediate 19-1 in step 1) of Example 19, and replace 1,6-dibromohexane with 1,8-dibromooctane to obtain intermediate 21-1.

[0577] ESI-MS: m / z = 451.1 [M+H] +

[0578] 2) Preparation of Compound 21

[0579] Refer to the preparation method of compound 7 in step 2) of Example 7, and replace intermediate 7-2 with intermediate 21-1 to obtain compound 21.

[0580] LC-MS: m / z=677.8[M+2H] 2+ .

[0581] 1H NMR(500MHz, CDCl3)δ8.79(d,1H),8.38(s,1H),8.11(d,1H),7.97(d,1H),7.91(d,1H),7.59(d,1H),7 .51(t,2H),7.43(dd,3H),7.10(d,2H),7.01(d,1H),6.72(d,1H),6.54(dd,1H),6.45(d,1H),6.06(s, 1H),5.24(dd,1H),4.43(d,1H),4.30(d,1H),4.08–4.00(m,4H),3.16(m,2H),3.07(m,6H),2.93–2 .83(m,2H),2.74(m,2H),2.40–2.22(m,13H),1.98–1.77(m,13H),1.52–1.26(m,17H),0.95(s,6H).

[0582] Example 22: Preparation of Compound 22

[0583] 1) Preparation of Intermediate 22-1

[0584] Refer to the preparation method of intermediate 19-1 in step 1) of Example 19, and replace 1,6-dibromohexane with 1,9-dibromononane to obtain intermediate 22-1.

[0585] ESI-MS: m / z = 465.1 [M+H] +

[0586] 2) Preparation of Compound 22

[0587] Refer to the preparation method of compound 7 in step 2) of Example 7, replacing intermediate 7-2 with intermediate 22-1 to obtain compound 22.

[0588] LC-MS: m / z = 684.8 [M+2H] 2+ .

[0589] 1H NMR(500MHz, CDCl3)δ8.81(d,1H),8.40(s,1H),8.11(d,1H),7.99(d,1H),7.91(d,1H),7.62(d,1H) ,7.51(t,2H),7.43(dd,3H),7.10(d,2H),7.01(d,1H),6.75(d,1H),6.55(dd,1H),6.46(d,1H),6.04 (s,1H),5.24(dd,1H),4.43(d,1H),4.30(d,1H),4.09–4.01(m,4H),3.18(m,2H),3.07(m,6H),2.91– 2.83(m,2H),2.74(m,2H),2.38–2.20(m,13H),1.98–1.76(m,13H),1.56–1.28(m,19H),0.95(s,6H).

[0590] Example 23: Preparation of Compound 23

[0591] 1) Preparation of Intermediate 23-1

[0592] Refer to the preparation method of intermediate 19-1 in step 1) of Example 19, and replace 1,6-dibromohexane with 1,10-dibromodecane to obtain intermediate 23-1.

[0593] ESI-MS: m / z = 479.1 [M+H] +

[0594] 2) Preparation of Compound 23

[0595] Refer to the preparation method of compound 7 in step 2) of Example 7, replacing intermediate 7-2 with intermediate 23-1 to obtain compound 23.

[0596] LC-MS: m / z = 691.8 [M+2H] 2+ .

[0597] 1H NMR(500MHz, CDCl3)δ8.73(d,1H),8.44(s,1H),8.07(d,1H),7.84(m,2H),7.55(d,1H),7.50( t,2H),7.40(dd,3H),7.10(d,2H),6.98(d,1H),6.74(d,1H),6.52(dd,1H),6.40(d,1H),6.03( s,1H),5.20(dd,1H),4.43(d,1H),4.30(d,1H),4.02(m,2H),3.60–3.07(m,10H),2.96–2.77( m,2H),2.74(m,2H),2.38–2.20(m,13H),1.98–1.76(m,13H),1.56–1.28(m,21H),0.94(s,6H).

[0598] Example 24: Preparation of Compound 24

[0599] 1) Preparation of Intermediate 24-1

[0600] Refer to the preparation method of intermediate 19-1 in step 1) of Example 19, replace compound 19A with compound 24A, and replace 1,6-dibromohexane with 1,3-dibromopropane to obtain intermediate 24-1.

[0601] ESI-MS: m / z = 395.1 [M+H] +

[0602] 2) Preparation of Compound 24

[0603] Refer to the preparation method of compound 7 in step 2) of Example 7, replacing intermediate 7-2 with intermediate 24-1 to obtain compound 24.

[0604] LC-MS: m / z=649.8[M+2H] 2+ .

[0605] 1H NMR (500MHz, CDCl3) δ9.92 (s, 1H), 8.87 (d, J = 2.3Hz, 1H), 8.48 (t, J = 5.5Hz, 1H), 8.11 (d, J = 2. 6Hz,1H),8.03(dd,J=9.2,2.3Hz,1H),7.93(d,J=9.2Hz,1H),7.78–7.61(m,2H),7.51(d,J=7.9 Hz,2H),7.48–7.38(m,2H),7.23(d,J=8.5Hz,1H),7.10(d,J=7.9Hz,2H),6.82(d,J=9.3Hz,1H) ,6.62–6.45(m,2H),5.99(d,J=2.4Hz,1H),4.94(dd,J=12.2,5.4Hz,1H),4.25(t,J=5.9Hz,2H) ,3.35–3.11(m,7H),3.07(t,J=5.1Hz,4H),2.90(d,J=3.6Hz,1H),2.87(t,J=3.1Hz,1H),2.82 (d,J=4.4Hz,1H),2.79(d,J=3.7Hz,1H),2.74(s,2H),2.72(d,J=3.9Hz,1H),2.71–2.64(m,3H) ,2.35(q,J=12.4Hz,4H),2.22(t,J=5.1Hz,3H),2.18(d,J=7.7Hz,2H),2.12(d,J=12.4Hz,2H), 2.06(s,3H),1.98(s,3H),1.86(s,4H),1.64–1.51(m,2H),1.43(t,J=6.4Hz,2H),0.95(s,6H).

[0606] Example 25: Preparation of Compound 25

[0607] 1) Preparation of Intermediate 25-1

[0608] Refer to the preparation method of intermediate 24-1 in step 1) of Example 24, and replace 1,3-dibromopropane with 1,4-dibromobutane to obtain intermediate 25-1.

[0609] ESI-MS: m / z = 409.0 [M+H] +

[0610] 2) Preparation of Compound 25

[0611] Refer to the preparation method of compound 7 in step 2) of Example 7, replacing intermediate 7-2 with intermediate 25-1 to obtain compound 25.

[0612] LC-MS: m / z = 656.8 [M+2H] 2+ .

[0613] 1 H NMR (500MHz, CDCl3) δ8.85(s,1H),8.44(s,1H),8.10(d,J=2.6Hz,1H),7.98(d,J=9.2Hz,1H),7.94(d,J=9.1Hz,1H),7.70–7.62(m,2H),7. 52(d,J=7.9Hz,3H),7.48–7.38(m,3H),7.21(d,J=8.5Hz,2H),7.10(d,J=8.0Hz,2H),6.75(s,1H),6.58–6.53(m,1H),6.50(s,1H),6.04(s, 1H),4.94(dd,J=12.1,5.4Hz,1H),4.23(d,J=6.1Hz,1H),4.16(d,J=6.9Hz,1H),3.20(s,5H),3.06(d,J=5.6Hz,5H),2.75(d,J=7.5Hz,4H) ,2.62(s,1H),2.30(d,J=11.2Hz,3H),2.21(d,J=17.4Hz,12H),2.05(s,6H),1.51(m,4H),1.43(t,J=6.4Hz,2H),1.25(m,4H),0.95(s,6H).

[0614] Example 26: Preparation of Compound 26

[0615] 1) Preparation of Intermediate 26-1

[0616] Refer to the preparation method of intermediate 24-1 in step 1) of Example 24, and replace 1,3-dibromopropane with 1,6-dibromohexane to obtain intermediate 26-1.

[0617] ESI-MS: m / z = 437.1 [M+H] +

[0618] 2) Preparation of Compound 26

[0619] Refer to the preparation method of compound 7 in step 2) of Example 7, replacing intermediate 7-2 with intermediate 26-1 to obtain compound 26.

[0620] LC-MS: m / z = 670.8 [M+2H] 2+ .

[0621] 1H NMR (500MHz, CDCl3) δ8.82(s,1H),8.39(s,1H),8.13(d,J=2.6Hz,1H),7.96(s,1H),7.67(t,J=7.9Hz,1H),7.60(s,1H),7.52 (d,J=7.9Hz,3H),7.46–7.40(m,3H),7.37(s,1H),7.22(d,J=8.5Hz,1H),7.11(d,J=7.9Hz,2H),6.70(s,1H),6.57(d,J=9.2H z,1H),6.49(d,J=3.5Hz,1H),6.07(s,1H),5.35(d,J=4.7Hz,3H),4.17(d,J=6.5Hz,3H),3.62(s,4H),3.34(s,1H),3.12–3.0 4(m,6H),2.81(d,J=1.4Hz,2H),2.75(s,4H),2.45(s,4H),2.39(s,3H),2.04–1.97(m,13H),1.44–1.04(m,11H),0.95(s,6H).

[0622] Example 27: Preparation of Compound 27

[0623] 1) Preparation of Intermediate 27-1

[0624] Refer to the preparation method of intermediate 24-1 in step 1) of Example 24, and replace 1,3-dibromopropane with 1,7-dibromoheptane to obtain intermediate 27-1.

[0625] ESI-MS: m / z = 451.1 [M+H] +

[0626] 2) Preparation of Compound 27

[0627] Refer to the preparation method of compound 7 in step 2) of Example 7, replacing intermediate 7-2 with intermediate 27-1 to obtain compound 27.

[0628] LC-MS: m / z=677.8[M+2H] 2+ .

[0629] 1H NMR (500MHz, CDCl3) δ8.84(d,J=2.2Hz,1H),8.41(s,1H),8.14(d,J=2.6Hz,1H),8.01(d,J=9.3Hz,1H),7.95(d,J=9.1Hz,1H),7.70–7.63(m,2 H),7.52(d,J=7.9Hz,2H),7.47–7.43(m,2H),7.21(d,J=8.5Hz,1H),7.10(d,J=7.9Hz,3H),6.72(s,1H),6.56(dd,J=9.1,2.4Hz,1H),6.54–6.5 0(m,1H),6.04(s,1H),4.94(dd,J=12.1,5.4Hz,1H),4.23–4.12(m,2H),3.19(d,J=17.8Hz,4H),3.08(t,J=5.0Hz,5H),2.74(s,3H),2.53(s,4 H),2.23(d,J=5.3Hz,8H),2.19(s,4H),2.06(s,4H),1.99(s,3H),1.81(s,5H),1.53(dd,J=14.7,7.5Hz,4H),1.43–1.26(m,10H),0.95(s,6H).

[0630] Example 28: Preparation of Compound 28

[0631] 1) Preparation of Intermediate 28-1

[0632] Refer to the preparation method of intermediate 24-1 in step 1) of Example 24, and replace 1,3-dibromopropane with 1,5-dibromopentane to obtain intermediate 28-1.

[0633] ESI-MS: m / z = 423.1 [M+H] +

[0634] 2) Preparation of Compound 28

[0635] Refer to the preparation method of compound 7 in step 2) of Example 7, replacing intermediate 7-2 with intermediate 28-1 to obtain compound 28.

[0636] LC-MS: m / z = 663.8 [M+2H] 2+ .

[0637] 1H NMR(500MHz, CDCl3)δ9.60(s,1H),8.87(d,J=2.3Hz,1H),8.55–8.42(m,2H),8.10(d,J=2.6Hz,1H),7.98–7.88(m,2H),7.73–7.61(m,2H), 7.52(d,J=8.0Hz,2H),7.49–7.42(m,2H),7.20(d,J=8.4Hz,1H),7.10(d,J=7.9Hz,2H),6.76(d,J=9.3Hz,1H),6.60–6.48(m,2H),6.02(d,J =2.4Hz,1H),4.93(dd,J=12.2,5.6Hz,1H),4.29–4.10(m,3H),3.27(d,J=15.4Hz,5H),3.08(t,J=5.1Hz,4H),2.90–2.80(m,3H),2.73(d,J =12.7Hz,5H),2.48(s,4H),1.99(s,8H),1.94–1.83(m,6H),1.77–1.60(m,9H),1.43(t,J=6.5Hz,3H),1.28(d,J=21.4Hz,1H),0.95(s,6H).

[0638] Example 29: Preparation of Compound 29

[0639] 1) Preparation of Intermediate 29-1

[0640] Sodium thiosulfate pentahydrate (53.7 g), benzyl chloride (27.4 g), copper sulfate pentahydrate (77.4 mg), and bipyridine (0.72 g) were added to a reaction flask containing methanol (120 mL) and water (120 mL). The temperature was then slowly raised to 80°C and stirred for 2 h. The reaction solution was then cooled to room temperature, compound 29A (8.0 g) was added, and finally tert-butyl nitrite (4.78 g) was slowly added dropwise. After the addition, the temperature was again raised to 80°C and stirred for 8 h. After the reaction was completed, the reaction solution was cooled to room temperature, water (200 mL) was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:2) and liquid phase chromatography to obtain intermediate 29-1 (6.8 g).

[0641] ESI-MS: m / z = 367.11 [M+H] +

[0642] 2) Preparation of Intermediate 29-2

[0643] Anhydrous aluminum chloride (2.61 g) and anhydrous toluene (70 mL) were added to a 250 mL egg-shaped flask. Intermediate 29-1 (1.8 g) was slowly added with stirring. The mixture was allowed to react at 35°C for 7 h. After the reaction, 20% aqueous citric acid solution was slowly added with stirring. The mixture was then filtered and the filter cake was washed with water and ethyl acetate, respectively. The filter cake was dried to obtain Intermediate 29-2 (1.15 g).

[0644] ESI-MS: m / z = 277.06 [M+H] +

[0645] 3) Preparation of Intermediate 29-3

[0646] Refer to the preparation method of Intermediate 19-1 in Step 1) of Example 19, and replace Compound 19A with Intermediate 29-2 to obtain Intermediate 29-3.

[0647] ESI-MS: m / z = 439.02 [M+H] +

[0648] 4) Preparation of Compound 29

[0649] Refer to the preparation method of compound 7 in step 2) of Example 7, replacing intermediate 7-2 with intermediate 29-3 to obtain compound 29.

[0650] LC-MS: m / z = 671.8 [M+2H] 2+ .

[0651] 1 H NMR(500MHz, CDCl3)δ8.86(d,1H),8.57(s,1H),8.43(s,1H),8.14(d,1H),8.07(d,1H),7.93( d,1H),7.66(d,1H),7.45(dd,3H),7.10(d,2H),7.02(d,1H),7.00(d,1H),6.56(dd,2H),6.02 (s,1H),5.24(dd,1H),4.44(d,1H),4.30(d,1H),4.07–4.00(m,2H),3.21(m,3H),3.06(m,4H) ,2.93–2.83(m,9H),2.73–2.22(m,12H),1.98–1.79(m,14H),1.52–1.26(m,12H),0.95(s,6H).

[0652] Example 30: Preparation of Compound 30

[0653] 1) Preparation of Intermediate 30-1

[0654] Refer to the preparation method of intermediate 29-3 in step 3) of Example 29, and replace 1,6-dibromohexane with 1,7-dibromoheptane to obtain intermediate 30-1.

[0655] ESI-MS: m / z = 453.1 [M+H] +

[0656] 2) Preparation of Example 30

[0657] Refer to the preparation method of compound 7 in step 2) of Example 7, and replace intermediate 7-2 with intermediate 30-1 to obtain Example 30.

[0658] LC-MS: m / z = 678.8 [M+2H] 2+ .

[0659] 1 H NMR(500MHz, CDCl3)δ8.87(d,1H),8.58(s,1H),8.43(s,1H),8.16(d,1H),8.07(d,1H),7.95( d,1H),7.67(d,1H),7.44(dd,3H),7.10(d,2H),7.03(d,1H),7.01(d,1H),6.55(dd,2H),6.03 (s,1H),5.25(dd,1H),4.44(d,1H),4.31(d,1H),4.09–4.02(m,2H),3.23(m,3H),3.08(m,4H) ,2.98–2.79(m,9H),2.76–2.20(m,13H),1.98–1.78(m,15H),1.53–1.22(m,12H),0.94(s,6H).

[0660] Example 31: Preparation of Compound 31

[0661] 1) Preparation of Intermediate 31-1

[0662] Refer to the preparation method of intermediate 29-3 in step 3) of Example 29, and replace 1,6-dibromohexane with 1,8-dibromooctane to obtain intermediate 31-1.

[0663] ESI-MS: m / z = 467.1 [M+H] +

[0664] 2) Preparation of Compound 31

[0665] Refer to the preparation method of compound 7 in step 2) of Example 7, replacing intermediate 7-2 with intermediate 31-1 to obtain compound 31.

[0666] LC-MS: m / z = 685.8 [M+2H] 2+ .

[0667] 1H NMR (500MHz, DMSO) δ11.50(d,J=2.7Hz,1H),10.99(s,1H),8.39–8.31(m,2H),7.91(d,J=2.6Hz,1H),7.72–7. 49(m,8H),7.40(m,1H),7.29–7.24(m,4H),6.81(d,J=9.2Hz,1H),6.61(m,1H),6.31–6.21(m,2H),5.13(m,1H) ,4.35(m,1H),4.21(m,1H),3.25(m,2H),3.07(m,3H),3.00(m,6H),2.72(s,3H),2.59–2.51(m,4H),2.39(s,1 H),2.19(m,6H),1.99(s,3H),1.91(s,6H),1.74(m,3H),1.59(m,2H),1.41(m,6H),1.24(s,10H),0.94(s,6H).

[0668] Example 32: Preparation of Compound 32

[0669] 1) Preparation of Intermediate 32-1

[0670] Refer to the preparation method of intermediate 29-3 in step 3) of Example 29, and replace 1,6-dibromohexane with 1,9-dibromononane to obtain intermediate 32-1.

[0671] ESI-MS: m / z = 481.1 [M+H] +

[0672] 2) Preparation of Compound 32

[0673] Refer to the preparation method of compound 7 in step 2) of Example 7, replacing intermediate 7-2 with intermediate 32-1 to obtain compound 32.

[0674] LC-MS: m / z=692.8[M+2H] 2+ .

[0675] 1H NMR(500MHz,DMSO)δ11.55(s,1H),10.99(s,1H),8.43(s,2H),8.16(s,3H),7.95(s,1H), 7.78–7.48(m,7H),7.46–7.19(m,4H),6.90(s,1H),6.63(s,1H),6.27(d,J=42.8Hz,2H),5 .13(s,1H),4.43–4.12(m,4H),3.28(s,2H),3.04(m,12H),2.72(s,3H),2.32(s,3H),2.1 9(s,6H),1.98(s,3H),1.82(m,5H),1.59(s,4H),1.40(s,6H),1.23(s,10H),0.94(s,6H).

[0676] Example 33: Preparation of Compound 33

[0677] 1) Preparation of Intermediate 33-1

[0678] Refer to the preparation method of intermediate 13-1 in step 1) of Example 13, and replace compound 12A with compound 33A to obtain intermediate 33-1.

[0679] ESI-MS: m / z = 341.1 [M+H] + .

[0680] 2) Preparation of Intermediate 33-2

[0681] Refer to the preparation method of intermediate 13-2 in step 2) of Example 13, and replace intermediate 13-1 with intermediate 33-1 to obtain intermediate 33-2.

[0682] ESI-MS: m / z = 338.1 [M+H] +

[0683] 3) Preparation of Compound 33

[0684] Refer to the preparation method of compound 13 in step 3) of Example 13, replacing intermediate 13-2 with intermediate 33-2 to obtain compound 33.

[0685] LC-MS: m / z=653.8[M+2H] 2+ .

[0686] Example 34: Preparation of Compound 34

[0687] 1) Preparation of Intermediate 34-1

[0688] Refer to the preparation method of intermediate 19-1 in step 1) of Example 19, and replace 1,6-dibromohexane with 1,4-di(bromomethyl)benzene to obtain intermediate 34-1.

[0689] ESI-MS: m / z = 443.1 [M+H] +

[0690] 2) Preparation of Compound 34

[0691] Refer to the preparation method of compound 7 in step 2) of Example 7, replacing intermediate 7-2 with intermediate 34-1 to obtain compound 34.

[0692] LC-MS: m / z=673.8[M+2H] 2+ .

[0693] 1 H NMR(500MHz, CDCl3)δ8.81(d,1H),8.46(s,1H),8.42(s,1H),8.09(d,1H),7.95(d,1H),7.93(d,1H),7. 90(d,1H),7.67(d,1H),7.50(t,2H),7.43(dd,4H),7.10(d,3H),6.78(d,1H),6.55(dd,1H),6.51(d,1H ),6.01(s,1H),5.23(dd,1H),5.13(s,2H),4.43(d,1H),4.30(d,1H),3.63(m,2H),3.38–3.01(m,4H),2 .98–2.75(m,9H),2.60(m,2H),2.37–2.15(m,11H),1.98–1.82(m,12H),1.42–1.24(m,6H),0.95(s,6H).

[0694] Test Example 1: In vitro RS4;11 cell proliferation inhibition

[0695] RS4;11 cells (from Nanjing Kebai) in good exponential growth phase were collected into a centrifuge tube and centrifuged at 1000 rpm for 5 min. The supernatant was discarded and 3 mL of seed culture medium (RPMI basal medium + 5% fetal bovine serum) was added with a pipette to resuspend. The cells were counted using a cell counter and diluted with seed culture medium to adjust the cell density to 1×10 5 / mL, inoculated on a 96-well plate using a spray gun, 100μL / well, and cultured in a cell culture incubator at 37°C and 5% CO2 saturated humidity. After culturing for 24 hours, the compound was added using a nanoliter pipette to a final concentration of 2000nM-0.91nM, with 2 replicates, and a control was set up at the same time. After continuing to culture in the cell culture incubator for 72 hours, the detection reagent CCK-8 (manufacturer: Japan Dojin Chemical) was added at 10μL / well. After incubation in the cell culture incubator for 4 hours, the absorbance was detected at 450nm by an Envision microplate reader, and the inhibition rate was calculated. The inhibition rate (%) = (average value of the negative control group - average value of the experimental group) / (average value of the negative control group - average value of the blank group) * 100%, with the logarithm of the compound concentration as the horizontal axis and the inhibition rate as the vertical axis. Four-parameter analysis was performed, and the dose-effect curve was fitted to calculate the IC 50 The results are shown in Table 1.

[0696] Table 1. In vitro RS4;11 cell inhibitory activity test results of compounds

[0697] The compounds disclosed herein have an inhibitory effect on RS4;11 cell proliferation in vitro.

[0698] Test Example 2: In vitro MOLT-4 cell proliferation inhibition

[0699] Take a MOLT-4 cell dish in good exponential growth phase, collect the cells into a centrifuge tube, centrifuge at a low speed of 1500 rpm for 3 minutes, discard the supernatant, and use a pipette to add 5 mL of complete medium (RPMI basal medium + 10% FBS) to resuspend the cells. Count the cells using a cell counter and dilute with complete medium to adjust the cell density to 1.6*10 5 / mL, and then add an equal amount of RPMI basal medium to adjust the serum concentration to 5% and the cell density to 8*10 4 / mL seed plate. Use a spray gun to inoculate on a 96-well plate, 100μL / well, and culture in a cell culture incubator at 37℃ and 5% CO2 saturated humidity. After culturing for 24h, use a nanoliter sampler to add the compound to a final concentration of 1000nM-0.46nM. Set up 2 replicates for each concentration, and use cells without compound as a negative control. After 72 hours, add CCK-8 (Japan Dojin Chemical) at 10μL / well. After 3.5 hours, use Envision enzyme reader to detect its absorbance at 450nm, and calculate the inhibition rate. Inhibition rate (%) = (average value of negative control group - experimental group) / (average value of negative control group - average value of blank group) × 100%. The logarithm of compound concentration is used as the horizontal axis and the inhibition rate is used as the vertical axis. Four-parameter analysis is performed, and the dose-effect curve is fitted to calculate IC 50 The results are shown in Table 2.

[0700] Table 2. Compound inhibitory activity test results

[0701] The compounds disclosed herein have an inhibitory effect on MOLT-4 cell proliferation in vitro.

[0702] Experimental Example 3: Degradation of BCL-XL protein in MOLT-4 cells in vitro

[0703] Take a MOLT-4 cell dish in good exponential growth phase, collect the cells into a centrifuge tube, centrifuge at a low speed of 1500 rpm for 3 minutes, discard the supernatant, and use a pipette to add 5 mL of complete medium (RPMI basal medium + 10% FBS) to resuspend the cells. Count the cells using a cell counter and dilute with complete medium to adjust the cell density to 1*10 7 100 μL / well was inoculated onto a 96-well plate using a dispenser. Compounds were added using a nanoliter pipette to a final concentration of 1000 nM to 1 nM. Two replicate wells were set for each concentration and cultured in a 37°C, 5% CO2, saturated humidity incubator.

[0704] After culturing for 24 hours, cells were collected for flow cytometry. After washing with PBS containing 2% BSA, the cells were first fixed with 80% methanol, then permeabilized with PBS containing 0.1% Tween20, and then blocked with PBS containing 10% BSA, and finally labeled with antibodies. The cells were incubated with BCL-XL (54H6) Rabbit mAb (CST, 2764S) primary antibody at room temperature for 0.5 hours, and then washed with PBS containing 2% BSA, and then labeled with Anti-rabbit IgG (H+L), F(ab')2Fragment (Alexa 488 Conjugate) (CST, 4412S) were incubated at room temperature for 0.5 h. After incubation, the cells were washed and resuspended with PBS containing 2% BSA and detected using IQue3 (Sartorius).

[0705] The group labeled with only the secondary antibody was used as the background group, and the cells without compound addition were used as the negative control group. The mean fluorescence intensity (MFI) was used to measure BCL-XL protein expression and calculate the inhibition rate. Degradation rate (%) = (mean MFI of negative control group - MFI of compound group) / (mean MFI of negative control group - mean MFI of background group) × 100%. The logarithm of compound concentration was used as the horizontal axis and the degradation rate was used as the vertical axis. Four-parameter analysis was performed, and the dose-effect curve was fitted to calculate DC. 50 (half-maximal degradation concentration). The results are shown in Table 3.

[0706] Table 3. Compound degradation activity test results

[0707] The compounds disclosed herein have an effect of degrading BCL-XL protein in MOLT-4 cells in vitro.

[0708] Experimental Example 4: Evaluation of BCL-XL / BAK Binding Inhibitory Activity

[0709] The Tag1-BCL-XL protein stock solution was diluted to 8 nM using the dilution buffer in the kit (cisbio, 63ADK000CB04PEG), and the Tag2-BAK protein stock solution was diluted to 20 nM. 5 μL / well of the Tag1-BCL-XL protein dilution solution was added to a 384-well plate. The compound was added using a nanoliter pipette to make the final concentration of the compound 1000 nM-0.24 nM. Two replicate wells were used, and a control was set up at the same time. 5 μL / well of the Tag2-BAK protein dilution solution was added, centrifuged and mixed, and incubated at room temperature for 15 minutes. Anti-Tag1-Eu was diluted with the detection buffer in the kit (cisbio, 63ADK000CB04PEG). 3+ Antibodies and Anti-Tag2-XL665 antibodies were diluted to 1X concentration, and Anti-Tag1-Eu 3+ Mix the Anti-Tag2-XL665 antibody dilution at a 1:1 volume ratio, add 10 μL / well of the antibody mixture, centrifuge to mix, and incubate at room temperature for 2 hours. Detect the fluorescence value at 665nm / 620nm using an Envision microplate reader, perform a four-parameter analysis, fit the dose-effect curve, and calculate the IC 50 .

[0710] The compounds disclosed herein possess BCL-XL / BAK binding inhibitory activity.

[0711] Test Example 5: In vitro liver microsome stability

[0712] Liver microsomal incubation samples (species: human, monkey, rat, and mouse) were prepared by mixing PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / mL), test compound, and NADPH + MgCl₂ solution at 37°C and 300 rpm for 1 hour. The 0-hour sample was prepared by mixing PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / mL), and test compound. The sample was added to acetonitrile containing an internal standard for protein precipitation, and the supernatant was prepared. The supernatant was diluted and analyzed by LC / MS / MS. The results are shown in Table 4.

[0713] Table 4. In vitro liver microsome metabolic stability results

[0714] The compounds of the present disclosure are metabolically stable in liver microsomes in vitro.

[0715] Test Example 6: Pharmacokinetics in mice

[0716] ICR mice weighing 18-22 g were randomly divided into groups of 9 after acclimation for 3-5 days and injected intravenously with the test compound solution at a dose of 1 mg / kg. Blood was collected from the eye socket at 5, 15, 30, 1, 2, 3, 4, 6, 8, 10, and 24 hours. Twenty μL of the test plasma sample and the standard curve were aspirated and protein precipitated with acetonitrile containing an internal standard. The supernatant was diluted and used for LC / MS / MS analysis. Pharmacokinetic parameters were fitted using a non-compartmental model.

[0717] The compounds disclosed herein have good in vivo pharmacokinetic properties, such as AUC, C max 、T 1 / 2 and T max Parameters showed excellent performance.

[0718] Test Example 7

[0719] 7.1 Canine Platelet Proliferation Inhibitory Activity Assay

[0720] Collect whole blood from dogs, separate canine platelets, resuspend in acid citrate buffer and count, and adjust platelet density to 10 with Tyrode's solution. 8 / ml, inoculated in a 96-well U-bottom plate (manufacturer: Costar), 90 μl per well, and 10 μl FBS was added to all wells after plating. Use a nanoliter sampler to add the compound to a final concentration of 5000nM-13nM, 2 replicates, and set up a control at the same time. Then, seal the plate with a sealing film and place it on a microplate constant temperature oscillator, incubate at 20°C and 300rpm for 72 hours. Finally, add the detection reagent CCK-8 (manufacturer: Japan Tongren Chemical, 10 μL / well), incubate in a cell culture incubator for 1.5 hours, and detect its absorbance at 450nm using an Envision enzyme reader. Four-parameter analysis, fitting of the dose-effect curve, and calculation of IC 50 .

[0721] 7.2 Human platelet proliferation inhibitory activity assay

[0722] Collect human whole blood, separate human platelets, resuspend in acid citrate buffer and count, and adjust platelet density to 10 with Tyrode's solution. 8 / ml, inoculated in a 96-well U-bottom plate (manufacturer: Costar), 90 μl per well, and 10 μl FBS was added to all wells after plating. Use a nanoliter sampler to add the compound to a final concentration of 5000nM-13nM, 2 replicates, and set up a control at the same time. Then, seal the plate with a sealing film and place it on a microplate constant temperature oscillator, incubate at 20°C and 300rpm for 72 hours. Finally, add the detection reagent CCK-8 (manufacturer: Japan Tongren Chemical, 10 μL / well), incubate in a cell culture incubator for 1.5 hours, and detect its absorbance at 450nm using an Envision enzyme reader. Four-parameter analysis, fitting of the dose-effect curve, and calculation of IC 50 .

[0723] The compounds of the present disclosure have low platelet toxicity (canine or human platelets).

Claims

1. A compound of formula I-0 or a pharmaceutically acceptable salt thereof, in, Every R 1 are independently selected from hydrogen, halogen, OH, NH2, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl OCO-, C 1-6 Alkyl C(O)O-, C 1-6 Alkyl NHCO-, C 1-6 AlkylCONH-, (C 1-6 Alkyl)2NCO-, C 1-6 Alkyl NHS(O)-, C 1-6 Alkyl S(O)NH-, (C 1-6 Alkyl) 2NS(O)-, C 1-6 Alkyl NHS(O)2-, C 1-6 Alkyl S(O)2NH-, (C 1-6 alkyl)2NS(O)2-、C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 Aryl or 5-12 membered heteroaryl; n1 is selected from 1, 2, 3 or 4; q is selected from 0, 1, 2, 3, 4, 5 or 6; Every R 2 are independently selected from halogen, OH, NH2, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl OCO-, C 1-6 Alkyl C(O)O-, C 1-6 Alkyl NHCO-, C 1-6 AlkylCONH-, (C 1-6 Alkyl)2NCO-, C 1-6 AlkylNHS(O)-, C 1-6 Alkyl S(O)NH-, (C 1-6 Alkyl) 2NS(O)-, C 1-6 Alkyl NHS(O)2-, C 1-6 Alkyl S(O)2NH-, (C 1-6 alkyl)2NS(O)2-、C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 Aryl or 5-12 membered heteroaryl; m is selected from 0, 1, 2, 3, 4, 5 or 6; Ring A is selected from C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 Aryl or 5-12 membered heteroaryl; L is a linking group; Every R 3 are independently selected from halogen, OH, NH2, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl OCO-, C 1-6 Alkyl C(O)O-, C 1-6 Alkyl NHCO-, C 1-6 AlkylCONH-, (C 1-6 Alkyl)2NCO-, C 1-6 AlkylNHS(O)-, C 1-6 Alkyl S(O)NH-, (C 1-6 Alkyl) 2NS(O)-, C 1-6 Alkyl NHS(O)2-, C 1-6 Alkyl S(O)2NH-, (C 1-6 alkyl)2NS(O)2-、C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 Aryl or 5-12 membered heteroaryl; p is selected from 0, 1, 2 or 3; R 4 and R 5 are independently selected from hydrogen, halogen, OH, NH2, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl OCO-, C 1-6 Alkyl C(O)O-, C 1-6 Alkyl NHCO-, C 1-6 AlkylCONH-, (C 1-6 Alkyl)2NCO-, C 1-6 AlkylNHS(O)-, C 1-6 Alkyl S(O)NH-, (C 1-6 Alkyl) 2NS(O)-, C 1-6 Alkyl NHS(O)2-, C 1-6 Alkyl S(O)2NH-, (C 1-6 alkyl)2NS(O)2-、C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl, Or, R 4 and R 5 Connected to each other and connected carbon atoms together to form C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl; X is selected from CR a R a’ or C=O; X 1 Selected from CR b or N; R a and R a 'same or different, independently selected from hydrogen, halogen, OH, NH2, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl OCO-, C 1-6 Alkyl C(O)O-, C 1-6 Alkyl NHCO-, C 1-6 AlkylCONH-, (C 1-6 Alkyl)2NCO-, C 1-6 AlkylNHS(O)-, C 1-6 Alkyl S(O)NH-, (C 1-6 Alkyl) 2NS(O)-, C 1-6 Alkyl NHS(O)2-, C 1-6 Alkyl S(O)2NH-, (C 1-6 alkyl)2NS(O)2-、C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 Aryl or 5-12 membered heteroaryl; R b Selected from hydrogen, halogen, OH, NH2, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl OCO-, C 1-6 Alkyl C(O)O-, C 1-6 Alkyl NHCO-, C 1-6 AlkylCONH-, (C 1-6 Alkyl)2NCO-, C 1-6 AlkylNHS(O)-, C 1-6 Alkyl S(O)NH-, (C 1-6 Alkyl) 2NS(O)-, C 1-6 Alkyl NHS(O)2-, C 1-6 Alkyl S(O)2NH-, (C 1-6 alkyl)2NS(O)2-、C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 Aryl or 5-12 membered heteroaryl; The R 1 、R 2 , Ring A, R 3 、R 4 、R 5 、R a 、R a’ or R b Optionally substituted with one or more substituents.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from a compound of formula I or a pharmaceutically acceptable salt thereof, in, R 1 Selected from hydrogen, halogen or C 1-3 alkyl; q is selected from 0, 1, 2, 3, 4, 5 or 6; Every R 2 are independently selected from OH, NH2, CN, halogen, C 1-3 Alkyl or C 1-3 alkoxy; m is selected from 0, 1, 2 or 3; Ring A is selected from C 4-10 Cycloalkyl or 4-10 membered heterocycloalkyl; L is a linking group; Every R 3 are independently selected from OH, NH2, CN, halogen, C 1-3 Alkyl or C 1-3 alkoxy; p is selected from 0, 1, 2 or 3; X is selected from CH2 or C=O; X 1 selected from CH or N; The R 1 、R 2 , Ring A, R 3 ,X,X 1 or X 2 Optionally substituted with one or more substituents.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from hydrogen, halogen or C 1-2 alkyl; Or, R 1 is selected from hydrogen, fluorine, chlorine, bromine or methyl; Or, R 1 is selected from hydrogen, chlorine or methyl; Alternatively, a structural fragment for Alternatively, a structural fragment Selected from 4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein q is selected from 0, 1, 2 or 3; Alternatively, q is selected from 0, 1 or 2; Alternatively, q is 1.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein each R 2 are independently selected from OH, NH2, CN, halogen, C 1-2 Alkyl or C 1-2 alkoxy; Or, each R 2 are independently selected from CN, halogen or C 1-3 alkyl.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein m is selected from 0, 1 or 2; Alternatively, m is selected from 0 or 1; Alternatively, m is 0.

7. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein ring A is selected from C 4-8 Cycloalkyl or 4-8 membered heterocycloalkyl; Alternatively, Ring A is selected from C 4-6 Cycloalkyl or 4-6 membered heterocycloalkyl; Alternatively, Ring A is selected from C 5-6 Cycloalkyl or 5-6 membered heterocycloalkyl; Alternatively, ring A is selected from C6 cycloalkyl or 6-membered heterocycloalkyl; Alternatively, ring A is selected from C6 cycloalkyl or 6-membered N-containing heterocycloalkyl; Alternatively, Ring A is selected from cyclohexyl or piperidinyl; Alternatively, Ring A is selected from Alternatively, a structural fragment Selected from 8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein L is selected from -Cy-L 1 -or-L 2 -;in, -Cy-L 1 -or-L 2 -; wherein Cy is selected from C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl, the C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl is optionally substituted with one or more substituents; wherein, -L 1 -or-L 2 - are independently selected from one or more -CH2-, optionally selected from -O-, phenyl, -NH-, -N(C 1-6 Alkyl)- or -S-substituted-C 1-20 Alkyl-, one or more -CH2- are optionally selected from -O-, phenyl, -NH-, -N(C 1-6 Alkyl)- or -S-substituted-C 2-20 Alkenyl-, or one or more -CH2- are optionally selected from -O-, phenyl, -NH-, -N(C 1-6 Alkyl)- or -S-substituted-C 2-20 Alkynyl-, the-C 1-20 Alkyl-, -C 2-20 Alkenyl-, or -C 2-20 Alkynyl - optionally substituted with one or more substituents; Cy is selected from C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl, the C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl is optionally substituted by one or more groups selected from: =O, OH, NH2, halogen, CN, C 1-6 Alkyl or C 1-6 alkoxy; Among them, L 1 or L 2 Each independently selected from one or more -CH2-, optionally selected from -O-, phenyl, -NH-, -N(C 1-6 Alkyl)- or -S-substituted-C 1-20 Alkyl-, one or more -CH2- are optionally selected from -O-, phenyl, -NH-, -N(C 1-6 Alkyl)- or -S-substituted-C 2-20 Alkenyl-, or one or more -CH2- are optionally selected from -O-, phenyl, -NH-, -N(C 1-6 Alkyl)- or -S-substituted-C 2-20 Alkynyl-, the-C 1-20 Alkyl-, -C 2-20 Alkenyl-, or -C 2-20 Alkynyl-optionally substituted with one or more groups selected from: =O, OH, NH2, halogen or CN; Alternatively, the L 1 or L 2 Each independently selected from one or more -CH2-, optionally selected from -O-, phenyl, -NH-, -N(C 1-6 Alkyl)- or -S-substituted-C 1-15 Alkyl-, one or more -CH2- are optionally selected from -O-, phenyl, -NH-, -N(C 1-6 Alkyl)- or -S-substituted-C 2-15 Alkenyl-, or one or more -CH2- are optionally selected from -O-, phenyl, -NH-, -N(C 1-6 Alkyl)- or -S-substituted-C 2-15 Alkynyl-, the-C 1-15 Alkyl-, -C 2-15 Alkenyl-, or -C 2-15 Alkynyl-optionally substituted with one or more of the following: =O, OH, NH2, halogen or CN; Alternatively, the L 1 or L 2 Each independently selected from -1 or more -CH2- optionally selected from -O-, phenyl, -NH-, -N(C 1-6 Alkyl)- or -S-substituted-C 1-12 Alkyl-, one or more -CH2- are optionally selected from -O-, phenyl, -NH-, -N(C 1-6 Alkyl)- or -S-substituted-C 2-12 Alkenyl-, or one or more -CH2- are optionally selected from -O-, phenyl, -NH-, -N(C 1-6 Alkyl)- or -S-substituted-C 2-12 Alkynyl-, the-C 1-12 Alkyl-, -C 2-12 Alkenyl-, or -C 2-12 Alkynyl-optionally substituted with one or more of the following: =O, OH, NH2, halogen or CN; Optionally, the Cy is selected from C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl, the C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl is optionally substituted by one or more groups selected from: =O, OH, NH2, halogen, CN, C 1-6 Alkyl or C 1-6 alkoxy; Alternatively, the Cy is selected from C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, the C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted with One or more groups selected from the following: =O, OH, NH2, halogen, CN, C 1-3 Alkyl or C 1-3 alkoxy; Alternatively, the Cy is selected from C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, the C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted by one or more groups selected from: =O, OH, NH2, fluorine, chlorine, bromine, CN, C 1-3 Alkyl or C 1-3 alkoxy; Alternatively, the Cy is selected from C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl; Alternatively, the Cy is selected from C 5-6 Cycloalkyl or 5-6 membered heterocycloalkyl; Alternatively, the Cy is selected from a 5-6 membered heterocycloalkyl group; Alternatively, the Cy is selected from a 6-membered heterocycloalkyl group; Alternatively, the Cy is selected from piperidinyl or piperazinyl; Alternatively, the Cy is selected from Alternatively, the structural fragment -Cy-L 1 -Selected Optionally, the L 1 Selected from one or more -CH2- optionally selected from phenyl or -N(C 1-6 alkyl)-substituted-C 1-20 Alkyl-, -C 1-19 Alkyloxy-, -C 1-19 Alkylthio-, -C 1-19 Alkylamino-, -C 2-20 Alkenyl- or -C 2-20 Alkynyl-, the-C 1-20 Alkyl-, -C 1-19 Alkyloxy-, -C 1-19 Alkylthio-, -C 1-19 Alkylamino-, -C 2-20 Alkenyl- or -C 2-20 Alkynyl - optionally substituted with one or more substituents; Alternatively, the L 1 Selected from one or more -CH2- optionally selected from phenyl or -N(C 1-6 Alkyl)-substituted--C 1-15 Alkyl-, -C 1-14 Alkyloxy-, -C 1-14 Alkylthio-, -C 1-14 Alkylamino-, -C 2-15 Alkenyl- or -C 2-15 Alkynyl-, the-C 1-15 Alkyl-, -C 1-14 Alkyloxy-, -C 1-14 Alkylthio-, -C 1-14 Alkylamino-, -C 2-15 Alkenyl- or -C 2-15 Alkynyl - optionally substituted with one or more substituents; Alternatively, the L 1 Selected from one or more -CH2- optionally selected from phenyl or -N(C 1-6 Alkyl)-substituted--C 1-12 Alkyl-, -C 1-11 Alkyloxy-, -C 1-11 Alkylthio-, -C 1-11 Alkylamino-, -C 2-12 Alkenyl- or -C 2-12 Alkynyl-, the-C 1-12 Alkyl-, -C 1-11 Alkyloxy-, -C 1-11 Alkylthio-, -C 1-11 Alkylamino-, -C 2-12 Alkenyl- or -C 2-12 Alkynyl - optionally substituted with one or more substituents; Optionally, the substituent is selected from =O, OH, NH2, halogen or CN; Alternatively, the L 1 or L 2 are independently selected from -(CH2) n O-, -(CH2) n S-, -C(O)-(CH2) n O-, -C(O)-(CH2) n S-, -(CH2) n C≡C-, -C(O)-(CH2) n C≡C-, -(CH2)2N(CH3)-(CH2) n C≡C-, -(CH2)2N(CH3)-(CH2) n O-, -CH2N(CH3)-(CH2) n C≡C-, -CH2N(CH3)-(CH2) n O-, -(CH2)3N(CH3)-(CH2) n C≡C-, -(CH2)3N(CH3)-(CH2) n O-, -(CH2) n NH- or -CH2-phenyl-(CH2) n O-, wherein n is selected from 1-12; or, n is selected from 1-10; or n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or an integer range consisting of any two; Alternatively, the L 1 Selected from -(CH2) n O-, -(CH2) n S-, -C(O)-(CH2) n O-, -C(O)-(CH2) n S-, -(CH2) n C≡C-, -C(O)-(CH2) n C≡C-, -(CH2) n NH-, -(CH2)2N(CH3)-(CH2) n C≡C-, or -CH2-phenyl-(CH2) n O-, wherein n is selected from 1-12; or, n is selected from 1-10; or n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or an integer range consisting of any two; Alternatively, the L 2 Selected from -(CH2)2N(CH3)-(CH2) n C≡C-, -(CH2)2N(CH3)-(CH2) n O-, -CH2N(CH3)-(CH2) n C≡C-, -CH2N(CH3)-(CH2) n O-, -(CH2)3N(CH3)-(CH2) n C≡C-, -(CH2)3N(CH3)-(CH2) n O-, -(CH2) n O-, -(CH2) n S-, -(CH2) n NH-, -(CH2) n C≡C-, -(CH2) n N(CH3)(CH2) n C≡C- or -(CH2) n -phenyl-(CH2) n O-, wherein n is selected from 1-12; or, n is selected from 1-10; or n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or an integer range consisting of any two of them.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein L is selected from -Cy-L 3 -X 2 -or-L 2 -, where Cy and L 2 As claimed in claim 7; L 3 One or more -CH2- are optionally selected from -O-, phenyl, -NH-, -N(C 1-6 Alkyl)- or -S-substituted-C 1-20 Alkyl-, -C 2-20 Alkenyl- or -C 2-20 Alkynyl-, the-C 1-20 Alkyl-, -C 2-20 Alkenyl- or -C 2-20 Alkynyl-optionally substituted with one or more substituents; optionally said substituents are selected from the group consisting of: =O, OH, NH2, halogen or CN; X 2 is selected from a bond, O or S; Or, L 3 Selected from -C 1-15 Alkyl-, -C 2-15 Alkenyl- or -C 2-15 Alkynyl-, the-C 1-15 Alkyl-, -C 2-15 Alkenyl- or -C 2-15 Alkynyl-any is optionally substituted with one or more =O; Optionally, L 3 Selected from -C 1-12 Alkyl-, -C 2-12 Alkenyl- or -C 2-12 Alkynyl-, the-C 1-12 Alkyl-, -C 2-12 Alkenyl- or -C 2-12 Alkynyl-optionally substituted with one or more ═O; Optionally, L is selected from Optionally, the moiety -L 3 -X 2 -or-L 2 -Selected from -(CH2)3NH-, -(CH2)4NH-, -(CH2)5NH-, -(CH2)3O-, -(CH2)4O-, -(CH2)5O-, -(CH2)6O-, -(CH2)7O-, -(CH2)8O-, -(CH2)9O-, -(CH2) 10 O-, -(CH2)3S-, -(CH2)4S-, -(CH2)5S-, -(CH2)6S-, -(CH2)7S-, -(CH2)8S-, -(CH2)9S-, -(CH2)3C≡C-, -(CH2)4C≡C-, -(CH2)5C≡C-, -(CH2)6C≡C-, -(CH2)7C≡C-, -(CH2)8C≡C-, -(CH2)9C≡C-, -(CH2)2N(CH3)(CH2)3C≡C- or -CH2-phenyl-CH2O-.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein each R 3 are independently selected from OH, NH2, CN, halogen, C 1-2 Alkyl or C 1-2 alkoxy; Or, each R 3 are independently selected from OH, NH2, fluorine, chlorine or methyl.

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein p is selected from 0, 1 or 2; Alternatively, p is selected from 0 or 1; Alternatively, p is selected from 0.

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein X is selected from CH2; or X is selected from C=O.

13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein X 1 selected from CH; or X 1 Selected from N.

14. The compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein the structural fragment Selected from 15. A compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, which is selected from a compound of formula II, II-A or II-B or a pharmaceutically acceptable salt thereof, X 3 and X 4 are independently selected from N, NH, CH or CH2.

16. A compound of formula III or a pharmaceutically acceptable salt thereof, in, q, R 2 、R 4 、R 5 ,m,ring A,R 3 ,p,X,X 1 The definition as described in any one of claims 1 to 15; Every R 11 are independently selected from hydrogen, halogen, OH, NH2, CN, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl OCO-, C 1-6 Alkyl C(O)O-, C 1-6 Alkyl NHCO-, C 1-6 AlkylCONH-, (C 1-6 Alkyl)2NCO-, C 1-6 AlkylNHS(O)-, C 1-6 Alkyl S(O)NH-, (C 1-6 Alkyl) 2NS(O)-, C 1-6 Alkyl NHS(O)2-, C 1-6 Alkyl S(O)2NH-, (C 1-6 alkyl)2NS(O)2-、C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl, said R 11 is optionally substituted with one or more substituents; k is selected from 0, 1, 2 or 3; L is selected from -Cy-L 1 -; wherein Cy is selected from C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl, the C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl is optionally substituted with one or more substituents; -L 1 -selected from one or more -CH2- 6-10 aryl or 5-10 membered heteroaryl, and optionally one or more -CH2- are selected from -O-, -NH-, -N(C 1-6 Alkyl)- or -S-substituted groups: -C 1-20 Alkyl-, -C 2-20 Alkenyl- or -C 2-20 Alkynyl-, the-C 1-20 Alkyl-, -C 2-20 Alkenyl-, or -C 2-20 Alkynyl- is optionally substituted with one or more substituents.

17. The following compound or a pharmaceutically acceptable salt thereof, in, n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11; wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11; wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8.

18. The following compound or a pharmaceutically acceptable salt thereof, 19. A pharmaceutical composition comprising the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof.

20. Use of the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19, in the preparation of a medicament for preventing or treating a disease that is treated by degrading a target protein bound to a targeting ligand.

21. Use of the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19, in the preparation of a medicament for preventing or treating a disease that is treated by binding to a cerebellar protein in vivo.

22. Use of the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19, in the preparation of a medicament for preventing or treating tumors.

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