Protein degradation agent and application thereof

Abstract

The invention discloses a protein degradation agent, such as a GSPT1 degradation agent, and applications thereof, especially applications in prevention and / or treatment of diseases.

Description

[0001] This application claims priority to Chinese patent application CN202210654080.7 filed on June 10, 2022, the entire contents of which are incorporated by reference in their entirety for all purposes. Technical Field

[0002] The present invention relates to the field of biomedical technology, and in particular to a protein degrader and applications thereof, such as a GSPT1 degrader and applications thereof. Background Art

[0003] Protein dysfunction and / or protein imbalance are hallmarks of many disease states. For example, immune system function is finely balanced through the activity of pro- and anti-inflammatory mediators or cytokines. Impaired protein synthesis can lead to uncontrolled cell growth, proliferation, and migration, potentially leading to cancer. For example, the translation termination factor GSPT1 (eRF3a) mediates stop codon recognition, facilitating the release of nascent peptides from the ribosome. In addition to its role in translation termination, GSPT1 is involved in several other key cellular processes, such as cell cycle regulation, cytoskeletal organization, and apoptosis. GSPT1 is considered an oncogenic driver for several different types of cancer, including breast, hepatocellular, gastric, and prostate cancers. GSPT1 has also been implicated in glial scar formation and astrocyte proliferation following central nervous system injury.

[0004] One approach to disrupting disease-driving proteins is to reduce their cellular concentrations. For example, proteolytic degradation of cellular proteins is crucial for normal cell function. Approaches to target specific disease-associated proteins offer a novel mechanism for treating disease. The irreversible nature of proteolysis makes them well-suited as regulatory switches for controlling unidirectional processes.

[0005] Currently, there are not many reports on GSPT1-targeted degraders. The development of new GSPT1 degrader compounds would be beneficial for identifying candidates and drugs for treating GSPT1-related diseases.

[0006] Overview

[0007] In various embodiments, the present invention generally relates to protein degraders, such as GSPT1 degraders. Without wishing to be bound by theory, it is believed that the compounds of the present disclosure can act as molecular glues that are capable of binding to E3 ligases, which can lead to the recruitment, ubiquitination, and subsequent degradation of various substrates that are not normally substrates for the ligase. Without wishing to be bound by theory, it is also believed that the compounds of the present disclosure can be viewed as containing an E3 ligase binding moiety, typically a glutarimide-containing moiety or other moiety capable of binding to a small head, linked to a structure capable of binding to a protein substrate.

[0008] In some embodiments, the present invention provides compounds useful as GSPT1 degraders, as well as pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates, and deuterated compounds thereof, as well as methods for their preparation and uses, particularly their use in preventing and / or treating diseases. In some embodiments, the compounds described herein can also be used as degraders of proteins other than GSPT1.

[0009] In various embodiments, the compounds of the present disclosure can be characterized as having a structure according to Formula (I), Formula A, Formula B, Formula C, or substructures thereof, as defined herein.

[0010] In a first aspect, the present invention provides a compound having the following structure:

[0011]

[0012] in,

[0013] W is selected from: C 0-10 Alkyl, C 3-6 cycloalkyl, heterocycloalkyl, and heteroaryl;

[0014] R1 is one or more independent substituents of ring A, selected from: halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 alkyl) and L' is selected from: single bond, C 1-10 Alkylene, -O-, -OC 1-10 Alkylene-, -S-, -SC 1-10 Alkylene-, -SO-, -SO-C 1-10Alkylene-, -SO 2- 、-SO 2- C 1-10 Alkylene-, -N(C 0-10 Alkyl)-, -N-(C 0-10 Alkyl) alkylene-, -CO-, -CO-C 1-10 Alkylene-, -CONH- and -CONH-C 1-10 Alkylene-; R6 is one or more independent substituents on ring B, -CN, -NO2, -CF3, -OCF3, C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 Alkyl), C 3-6 cycloalkyl, heterocycloalkyl, and heteroaryl;

[0015] R2 is one or more independent substituents of the benzene ring selected from: halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 Alkyl), C 3-6 cycloalkyl, aryl, heterocycloalkyl, and heteroaryl;

[0016] V is selected from: O, S, where R v1 、R v2 Independently selected from: C 0–10 Alkyl, C 3–6 cycloalkyl and heterocycloalkyl groups;

[0017] Q is H or a single bond (when Q is a single bond, Q is connected to R2 or L through a site in the benzene ring), or Q and V together with the carbon atoms therebetween form an aryl or heteroaryl group;

[0018] L has the following structure: in,

[0019] L1 is selected from: -NR L1 - (C 0-10 Alkylene)-, -O-(C 0-10 Alkylene)-, -S-(C 0-10 Alkylene)-、-NR L1 CO-(C 0-10 Alkylene)-, -CONR L1 - (C 0-10 Alkylene)-, -CO-(C 0-10 Alkylene)-、-NR L1 CONH-(C 0-10 Alkylene)-, -(C 1-10 Alkylene)-, -SO 2- (C 0-10 Alkylene)-, -SO-(C 0-10 Alkylene)-,

[0020] where R L1 Selected from: H, -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl and heterocycloalkyl, where C 1-6 One or more H, C 3-6 Cycloalkyl or heterocycloalkyl may be selected from: halogen (especially F), -OH, -NH2, alkoxy, alkylamino, C 3-6Substituents of cycloalkyl and heterocycloalkyl; R L1 ' and R L1 " is independently selected from: halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and heterocycloalkyl, wherein C 1-6 One or more H, C 3-6 The cycloalkyl or heterocycloalkyl group may be substituted by a substituent selected from the group consisting of: halogen (especially F), -OH, -NH2, alkoxy, alkylamino, C3-cycloalkyl and heterocycloalkyl; or R L1 ' and R L1 ” together with the carbon atom to which it is attached, form a cycloalkyl or heterocyclyl group;

[0021] L3 is selected from: -(C 0-10 Alkylene)-, -(C 0-10 Alkylene)-NR L3 - 、-(C 0-10 Alkylene)-O-, -(C 0-10 Alkylene)-S-, -(C 0-10 Alkylene)-NR L3 CO-、-(C 0-10 alkylene)-CONR L3 - 、-(C 0-10 Alkylene)-CO-, -(C 0-10 alkylene)-NHCONR L3 - 、-(C 0-10 Alkylene)-SO 2- 、-(C 0-10 Alkylene)-SO-,

[0022] -NR L3 - (C 0-10 Alkylene)-, -O-(C 0-10 Alkylene)-, -S-(C 0-10 Alkylene)-、-NR L3 CO-(C 0-10 Alkylene)-, -CONR L3 - (C0-alkylene)-, -CO-(C 0-10 Alkylene)-, -NHCONR L3 - (C 0-10 Alkylene)-, -SO 2- (C 0-10 Alkylene)-, -SO-(C 0-10Alkylene)-, where R L3 Selected from: H, -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl and heterocycloalkyl, where C 1-6 One or more H, C 3-6 Cycloalkyl or heterocycloalkyl may be selected from: halogen (especially F), -OH, -NH2, alkoxy, alkylamino, C 3-6 Substituents of cycloalkyl and heterocycloalkyl; R L3 ' and R L3 "Alcohol is independently selected from: halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and heterocycloalkyl, where C 1-6 One or more H, C 3-6 Cycloalkyl or heterocycloalkyl may be selected from: halogen (especially F), -OH, -NH2, alkoxy, alkylamino, C 3-6 Substituents of cycloalkyl and heterocycloalkyl; or R L3 ' and R L3 ” together with the carbon atom to which it is attached, form a cycloalkyl or heterocyclyl group;

[0023] L2 is a covalent bond, or a divalent, saturated or unsaturated linear or branched C 1-50 (e.g. C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 、C 12 、C 13 、C 14 、C 15 、C 16 、C 17 、C 18 、C 19 、C 20 、C 25 、C 30 、C 35 、C 40 、C 45 or C 50 ) hydrocarbon chain, wherein 0-6 methylene units are independently replaced by: -CY-, -O-, -NR L2 - , -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NR L2 S(O)2-、-S(O)2-R L2 -、-NRL2R L2 -C(O)-, -C(O)NR L2 -、-OC(O)NR L2-、-NR L2 -C(O)O-, wherein m is an integer selected from 0-10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), and each -C y - is independently selected from the following optionally substituted divalent rings: arylene, cycloalkylene and heterocyclylene; RL2 is selected from: H, -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl and heterocycloalkyl, wherein C 1-6 One or more H, C 3-6 Cycloalkyl or heterocycloalkyl may be selected from halogen (especially F), -OH, -NH2, alkoxy, alkylamino, C 3-6 Substituents of the cycloalkyl and heterocycloalkyl groups are substituted.

[0024] In one embodiment of the present invention, Q is a single bond, and the above compound may have the following structure:

[0025]

[0026] where R 201 、R 202 and R 203 Each has the same definition as described above for R2.

[0027] In another embodiment of the present invention, Q and V together with the carbon atoms between them form an aryl or heteroaryl group, in particular a six-membered aryl or heteroaryl group; for example, the above compound can have the following structure:

[0028]

[0029] wherein Y1 and Y2 are independently selected from: CH and N.

[0030] Specifically, the compound may have the following structure:

[0031]

[0032] where R 201 、R 202 and R 203 Each has the same definition as described above for R2.

[0033] In some embodiments of the present invention, Y 1 and Y 2 All CH

[0034] In other embodiments of the present invention, Y 1 CH, Y 2 N

[0035] In other embodiments of the present invention, Y 1 N, Y 2 CH

[0036] In other embodiments of the present invention, Y 1 and Y 2 All are N

[0037] In some embodiments of the present invention, R 201 、R 202 and R 203 are independently selected from: cycloalkyl, aryl, heterocycloalkyl and heteroaryl; in other embodiments of the present invention, R 201 、R 202 and R 203 Independently selected from: halogen, -CN, -NO2, -CF3, -OCF3, -H, C 1-6 Alkyl (e.g., -CH3 or -CH2CH3), -OH, -NH2, and -N(C 1-3 Alkyl)(C 1-3 alkyl); in particular, R 201 、R 202 and R 203 All are -H;

[0038] In some embodiments of the present invention, w is Wherein R3 is selected from: C 0-10 Alkyl, C 3-6 cycloalkyl, heterocycloalkyl, and heteroaryl;

[0039] R4 and R5 are independently selected from: halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 Alkyl, -O(C0-alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C0-10 Alkyl), C 3-6 Cycloalkyl, heterocycloalkyl and heteroaryl. Specifically, V can be selected from: -CH2-, and -NH-; In some embodiments of the present invention, V is

[0040] Specifically, R3 can be selected from: -H, and C 1-6 Alkyl (eg, -CH3 or -CH2CH3); in some embodiments of the invention, R3 is -H.

[0041] Specifically, R4 can be selected from: halogen, -CN, -NO2, -CF3, -OCF3, -H, C 1-6 Alkyl (e.g., -CH3, or -CH2CH3), -OH, -NH2, and -N(C 1-3 Alkyl)(C 1-3 alkyl); in some embodiments of the present invention, R4 is -H

[0042] Specifically, R5 can be selected from: halogen, -CN, -NO2, -CF3, -OCF3, -H, C 1-6 Alkyl (e.g., -CH3 or -CH2CH3), -OH, -NH2, and -N(C 1-3 Alkyl)(C 1-3 alkyl); in some embodiments of the present invention, R5 is -H.

[0043] In particular, W is

[0044] Specifically, R2 can be selected from: halogen, -CN, -NO2, -CF3, -OCF3, -H, C 1-6 Alkyl (e.g., -CH3 or -CH2CH3), -OH, -NH2, and -N(C 1-3 Alkyl)(C 1-3 alkyl); in some embodiments of the present invention, R2 is -H.

[0045] Furthermore, the above compound may have the following structure:

[0046]

[0047] Furthermore, the above compound may have the following structure:

[0048]

[0049] Furthermore, the above compound may also have the following structure:

[0050]

[0051] Furthermore, the above compound may also have the following structure:

[0052]

[0053] Specifically, each -Cy- is independently an optionally substituted bivalent ring selected from: phenylene, bicyclic arylene, tricyclic arylene, monocyclic cycloalkylene, bicyclic cycloalkylene, tricyclic cycloalkylene, monocyclic heteroarylene, bicyclic heteroaryl, tricyclic heteroaryl, monocyclic heterocycloalkylene, bicyclic heterocycloalkylene and tricyclic heterocycloalkylene; in particular, phenylene, 8- to 10-membered bicyclic arylene, 3- to 7-membered monocyclic saturated or partially unsaturated carbocycle, 4- to 7-membered saturated or partially unsaturated spirocarbocycle, 8- to 10-membered saturated or partially unsaturated fused carbocycle, 3- to 7-membered monocyclic saturated or partially unsaturated heterocyclyl, 4- to 7-membered saturated or partially unsaturated spiroheterocyclyl, 8- to 10-membered saturated or partially unsaturated fused heterocyclyl.

[0054] Specifically, each -Cy- can be independently selected from:

[0055]

[0056]

[0057]

[0058]

[0059] where R L4 is one or more independent substituents on the ring selected from: halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 alkyl), -OCO(C0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 alkyl) and three to six-membered heterocycloalkyl;

[0060] R L5 Selected from: halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 alkyl)(C0-alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 alkyl);

[0061] R L6 and R L7 Independently selected from: C 0-10 Alkyl, C 3-6 cycloalkyl, heterocycloalkyl, and heteroaryl;

[0062] R L8 and R L9 Independently selected from: halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 alkyl), -N(C0-alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl) and -CO(C 0-10 alkyl); or R L8 and R L9 With R L8 and R L9 The connected carbon atoms together form a substituted or unsubstituted cycloalkyl or heterocyclic group. Further, each -Cy- can be independently selected from:

[0063] (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ),and (For example ).

[0064] More specifically, R L4 Can be selected from: -H, halogen (especially F), -OH, C 1-6 Alkyl (e.g. -CH3 or -CH2CH3), -O(C 1-6 alkyl) (such as methoxy or ethoxy) and four to six-membered nitrogen-containing heterocyclic alkyl; in some embodiments of the present invention, R L4 Selected from -H, F, methoxy, ethoxy,

[0065] More specifically, R L5 Can be selected from: -H, halogen (especially F), -OH, C 1-6 Alkyl (e.g. -CH3 or -CH2CH3) and -O(C 1-6 alkyl) (e.g., methoxy or ethoxy); in some embodiments of the present invention, R L5 Yes -H.

[0066] More specifically, R L6 Can be selected from: -H, C 1-6 Alkyl (e.g. -CH3 or -CH2CH3) and C 3-6 Cycloalkyl; In some embodiments of the present invention, R L6 Selected from: -H, -CH3, -CH2CH3, cyclopropyl and cyclobutyl.

[0067] In some embodiments of the present invention, each -Cy- can be independently selected from:

[0068]

[0069] Specifically, R L1 Can be selected from: H, C 1-6 Alkyl, wherein one or more H in the alkyl can be substituted by the following groups: halogen (especially F), -OH, -NH2, C 1-6 Alkoxy (such as methoxy or ethoxy) and C 1-6 Alkylamino groups (e.g. ); More specifically, R L1 Available from: H, C 1-3 alkyl,

[0070] Specifically, R L1 ' and R L1 " can be independently selected from: halogen and C 1-6Alkyl, wherein one or more H in the alkyl group may be substituted by a substituent selected from the group consisting of halogen (especially F), -OH, -NH2, C 1-6 Alkoxy (such as methoxy or ethoxy) and C 1-6 Alkylamino groups (e.g. ); More specifically, R L1 ' and R L1 " can be independently selected from: H, C 1-3 alkyl,

[0071] Specifically, R L1 ' and R L1 "Together with the carbon atoms attached to it, it can form C 3-6 Cycloalkyl groups, e.g. or a 4- to 6-membered heterocyclic group, such as In some embodiments of the present invention, L1 is selected from -NR L1 -(C 0–6 Alkylene)-, -O-(C 0–6 Alkylene)-, -S-(C 0–6 Alkylene)-, -(C 0–6 Alkylene)-, For example, L1 can be -NH-, -NH-CH2-, -NH-CH2CH2-, -NH-CH2CH2CH2-, -O-, -O-CH2-, -O-CH2CH2-, -O-CH2CH2CH2-, -S-, -S-CH2-, -S-CH2CH2-, -S-CH2CH2CH2-, single bond, -CH2-, -CH2CH2-, -CH2CH2CH2- or

[0072] Specifically, R L3 Can be selected from: H, C 1-6 Alkyl, wherein one or more H in the alkyl may be substituted by the following groups: halogen (especially F), -OH, -NH2, C 1-6 Alkoxy (such as methoxy or ethoxy) and C 1-6 Alkylamino groups (e.g. ); More specifically, R L3 Available from: H, C 1-3 alkyl, Specifically, R L3' and R L3” The rings may be independently selected from: halogen and C 1-6 Alkyl, wherein one or more H in the alkyl group may be selected from: halogen (especially F), -OH, -NH2, C1-6 Alkoxy (such as methoxy or ethoxy) and C 1-6 Alkylamino groups (e.g. ); More specifically, R L3 ' and R L3 " can be independently selected from: H, C 1-3 alkyl,

[0073] Specifically, R L3 ' and R L3 "Together with the carbon atoms to which it is attached, it can form C 3-6 Cycloalkyl groups, such as: or a 4- to 6-membered heterocyclic group, such as

[0074] In some embodiments of the present invention, L3 is selected from -(C 0–6 Alkylene)-NR L3 CO-、-(C 0–6 alkylene)-CONR L3 -、-(C 0–6 Alkylene)-CO-, -(C 0–6 Alkylene)-NH-, -(C 0–6 Alkylene)-, -NR L3 -(C 0–6 Alkylene)-, -O-(C 0–6 Alkylene)-, -S-(C 0–6 Alkylene)-、-NR L3 CO-(C 0–6 Alkylene)-, -CONR L3 -(C 0–6 Alkylene)- or -CO-(C 0–6 Alkylene)-; For example, L3 can be -CONH-, -CH2-CONH-, -CH2CH2-CONH-, -CH2CH2CH2-CONH-, -NH-, -CH2-NH-, -CH2CH2-NH-, -CH2CH2CH2-NH-, single bond, -NHCO-, -NHCO-CH2-, -CO-, -CO-CH2-, -NH-CH2-, -O-CH2- or -S-CH2-.

[0075] Specifically, L2 can be selected from: C1-C20 straight chain alkylene (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C18 or C20 straight chain alkyl), -(CH2CH2O) m2 - and -Cy-, wherein m2 is an integer selected from 0-5 (eg, 0, 1, 2, 3, 4 or 5).

[0076] In some embodiments of the present invention, L is selected from:

[0077]

[0078]

[0079]

[0080] Specifically, Ring A can be an aliphatic ring, an aromatic ring or a heterocyclic ring, such as a monocyclic saturated aliphatic ring, a bicyclic saturated aliphatic ring, a monocyclic aromatic ring, a bicyclic aromatic ring, a monocyclic heterocyclic ring or a bicyclic heterocyclic ring (e.g., a benzene ring, an 8-10 membered bicyclic aromatic ring, a 3-7 membered monocyclic saturated aliphatic ring, a 4-7 membered saturated spiro alicyclic ring, an 8-10 membered saturated fused alicyclic ring, an 8-10 membered saturated bridged alicyclic ring, a 4-7 membered monocyclic saturated heterocyclic ring, a 4-7 membered saturated spiro heterocyclic ring, 8-10 membered saturated fused heterocycle, or 8-10 membered saturated bridged heterocycle), in particular a saturated carbocycle or heterocycle (e.g., a 3-7 membered monocyclic saturated carbocycle, a 4-7 membered saturated spiro carbocycle, an 8-10 membered fused carbocycle, an 8-10 membered saturated bridged carbocycle, a 4-7 membered monocyclic saturated heterocycle, a 4-7 membered saturated spiro heterocycle, an 8-10 membered saturated fused heterocycle or an 8-10 membered saturated bridged heterocycle); in some embodiments of the present invention, It is a 3-7 membered monocyclic saturated carbocycle, a 4-7 membered saturated spirocarbocycle, an 8-10 membered saturated fused carbocycle, a 3-7 membered monocyclic saturated heterocycle, a 4-7 membered saturated spiroheterocyclic ring, or an 8-10 membered saturated fused heterocyclic ring.

[0081] More specifically, the group Can be selected from: In some embodiments of the present invention, the group Selected from Specifically,

[0082] In one embodiment of the present invention, in the above compounds, R1 is one or more independent substituents of ring A and is selected from: H, halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl) and -CO(C 0-10 alkyl), and L2 is -Cy-; more specifically, the group is a 3-7 membered monocyclic saturated carbocycle, a 4-7 membered saturated spirocarbocycle, an 8-10 membered saturated fused carbocycle, a 3-7 membered monocyclic saturated heterocycle, a 4- to 7-membered saturated spiroheterocyclylene group or an 8- to 10-membered saturated fused heterocyclyl group, for example, -Cy- may be a substituted or unsubstituted arylene or heteroarylene group, such as a substituted or unsubstituted phenylene group, for example, (For example, ). In some embodiments of the present invention, the group yes where R 101 、R 102 、R 103 、R 104 、R 105 and R 106 Each has the definition of R1; in particular, R 103 、R 104 、R 105 and R 106 Both can be H (i.e. yes ); specifically, R 101 and R 102Independently selected from: -H, halogen (such as F), -OH, C 1-6 Alkyl (e.g. -CH3 or -CH2CH3) and -O(C 1-6 alkyl) (e.g., methoxy or ethoxy); more specifically, Can be In another embodiment of the present invention, R1 is

[0083] In some embodiments of the present invention, the above compound may have the following structure:

[0084]

[0085] In one embodiment of the present invention, L' is a single bond; that is:

[0086] Specifically, ring B may be an aromatic ring or a heteroaromatic ring, such as a benzene ring, a bicyclic aromatic ring, a tricyclic aromatic ring, a monocyclic heteroaromatic ring, a bicyclic heteroaromatic ring, or a tricyclic heteroaromatic ring.

[0087] In one embodiment of the present invention, ring B is a benzene ring and yes where R 601 、R 602 、R 603 、R 604 and R 605 Each has a structure as defined by R6 and is independently selected from: halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10alkyl), cycloalkyl, heterocycloalkyl and heteroaryl, wherein the H at the carbon atom may be substituted by one or more groups selected from the following: halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 Alkyl), C 3-6 Specifically, in Formula VI, R 601 、R 602 、R 603 、R 604 and R 605 Independently selected from: -H, halogen, -OH, C 1-6 Alkyl (e.g., -CH3, -CH2CH3) and -O(C 1-6 alkyl) (e.g., methoxy or ethoxy); in some embodiments of the present invention, R 601 、R 602 、R 603 、R 604 and R 605 All are -H.

[0088] In another embodiment of the present invention, Ring B is a monocyclic heteroaromatic ring, such as the group Can be wherein A1, A2, A3, A4, A5 and A6 are independently selected from C and N, and at least one of A1, A2, A3, A4, A5 and A6 is N; when any one of A2, A3, A4, A5 and A6 is N, R 601 、R 602 、R 603 、R 604 and R 605There is no corresponding group; R 601 、R 602 、R 603 、R 604 and R 605 Each has the same definition as above for R6 and is independently selected from: halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 Alkyl), C 3-6 Cycloalkyl, heterocycloalkyl and heteroaryl, wherein the H at the carbon atom may be substituted by one or more groups selected from the group consisting of halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10Alkyl)(C 0-10 alkyl), -CO(C 0-10 Alkyl), C 3-6 Cycloalkyl, heterocycloalkyl, and heteroaryl.

[0089] Specifically, in Formula VII, one of A1, A2, A3, A4, A5 and A6 is N, and the rest are C; or A1, A2, A3, A4, A5, A6 are N, and the rest are C; three of A1, A2, A3, A4, A5 and A6 are N, and the rest are C.

[0090] More specifically, A section can have the following structure:

[0091]

[0092]

[0093] More specifically, in Formula VII, R 601 、R 602 、R 603 and R 604 Independently selected from: -H, -D, -F, -Cl, -Br, -I, -CF3, -CHF2, -CH2F, -CH2CF3, -CN, -NO2, -CH3, -OH, -NH2,

[0094]

[0095]

[0096]

[0097] In another embodiment of the present invention, Ring B is a bicyclic heteroaryl ring.

[0098] Specifically, A section can have the following structure: wherein A1, A2 and A3 are independently selected from C, N, O and S; B1, B2 and B3 are independently selected from C and N; B4 is C, N or absent, and satisfies valence saturation; R 601 、R 602 、R 603 、R 604 、R 605 、R 606 and R 607 May not exist under appropriate circumstances; R601 、R 602 、R 603 、R 604 、R 605 、R 606 and R607 are independently selected from: halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 Alkyl), C 3-6 Cycloalkyl, heterocycloalkyl and heteroaryl, wherein the H at the carbon atom may be substituted by one or more groups selected from the group consisting of halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C0-10 alkyl), -CO(C 0-10 Alkyl), C 3-6 In some embodiments of the present invention, B1, B2, B3, and B4 are all C; or B1 is N, and B2, B3, and B4 are all C; or B2 is N, and B1, B3, and B4 are all C; or B3 is N, and B1, B2, and B4 are all C; or B4 is N, and B2, B3, and B1 are all C.

[0099] More specifically, A section can have the following structure:

[0100]

[0101]

[0102]

[0103]

[0104] More specifically, in VIII, R 601 、R 602 、R 603 、R 604 、R 605 、R 606 and R 607 Independently selected from: -H, -D, -F, -Cl, -Br, -I, -CF3, -CHF2, -CH2F, -CH2CF3, -CN, -NO2, -CH3, -OH, -NH2,

[0105]

[0106]

[0107]

[0108] More specifically, in Formula VIII, R 601 Available from: -H, C 1-6 Alkyl (e.g., methyl, ethyl, n-propyl or isopropyl), C 3-6 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), heterocycloalkyl (e.g. ), wherein the C 1-6 Alkyl, C 3-6One or more H in the cycloalkyl or heterocycloalkyl group may be substituted by a substituent selected from the group consisting of halogen (particularly F), -OH, -NH2, alkoxy, alkylamino, and C 3-6 Cycloalkyl; In addition, R 601 Can be selected from: -H and C 1-6 Alkyl (e.g., methyl, ethyl, n-propyl or isopropyl), wherein C 1-6 One or more H in the alkyl group may be substituted by a substituent selected from the group consisting of halogen (especially F), -OH, -NH2, C 1-6 Alkoxy (such as methoxy or ethoxy) and C 1-6 Alkylamino groups (e.g., ); In some embodiments of the present invention, R 601 Selected from: -H, C 1–3 alkyl,

[0109] In some embodiments of the present invention, in Formula VIII, R 602 Yes -H.

[0110] In some embodiments of the present invention, in Formula VIII, R 605 Yes -H.

[0111] In some embodiments of the present invention, in Formula VIII, R 606 Yes -H.

[0112] More specifically, in Formula VIII, R 603 Can be selected from: -H, C 1-6 Alkyl (such as methyl, ethyl, n-propyl or isopropyl), -OH, C 1-6 Alkoxy (such as methoxy or ethoxy), -NH2, C 1-6 Alkylamino groups (e.g. ), C 3–6 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) and heterocycloalkyl (e.g., ), wherein the C 1-6 Alkyl, C 3-6 One or more H in the cycloalkyl or heterocycloalkyl group may be substituted by a substituent selected from the group consisting of halogen (particularly F), -OH, -NH2, alkoxy, alkylamino, and C 3-6 Cycloalkyl; In addition, R 603 Can be selected from: -H, C 1-6 Alkoxy (such as methoxy or ethoxy), -NH2 and C 1-6 Alkylamino groups (e.g. ); In some embodiments of the present invention, R 603Selected from: -H, methoxy, and

[0113] More specifically, in Formula VIII, R 604 Can be selected from: -H, C 1-6 Alkyl (such as methyl, ethyl, n-propyl or isopropyl), -OH, C 1-6 Alkoxy (such as methoxy or ethoxy), -NH2, C 1-6 Alkylamino groups (e.g. ), C 3–6 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), heterocycloalkyl (e.g., ), where C 1-6 Alkyl, C 3-6 One or more H in the cycloalkyl or heterocycloalkyl group may be substituted by a substituent selected from the group consisting of halogen (particularly F), -OH, -NH2, alkoxy, alkylamino, and C 3-6 Cycloalkyl; In addition, R 604 Can be selected from: -H, C 1-6 Alkoxy (such as methoxy or ethoxy), -NH2 and C 1-6 Alkylamino groups (e.g. ); In some embodiments of the present invention, R 604 Selected from: -H, methoxy and In another embodiment of the present invention, ring b is a tricyclic heteroaryl ring.

[0114] Specifically, A section can have the following structure: wherein A1, A2 and A3 are independently selected from C, N, O and S; B1, B2 and B3 are independently selected from C and N; B4 is C, N or absent; X1, X2 and X3 are independently selected from C, N, O and S and satisfy valence saturation; R 601 、R 602 、R 603 、R 604 、R 605 、R 606 and R 607 May not exist under appropriate circumstances; R 601 、R 602 、R 603 、R 604 、R 605 、R 606 and R 607 Independently selected from: halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 alkyl)

[0115] (C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C0- 10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 Alkyl), C 3-6 Cycloalkyl, heterocycloalkyl and heteroaryl, wherein the H on the carbon atom of the group can be substituted by one or more groups selected from the following: halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 Alkyl), C 3-6 Cycloalkyl, heterocycloalkyl, and heteroaryl.

[0116] Specifically, in Formula IX, A1, A2 and A3 are independently selected from C and N.

[0117] In some embodiments of the present invention, in Formula IX, B1, B2, B3 and B4 are all C; or B1 is N, and B2, B3 and B4 are all C; or B2 is N, and B1, B3, B4 are all C; or B3 is N, and B1, B2, B4 are all C; or B4 is N, and B2, B3, B1 are all C.

[0118] Specifically, in Formula IX, X1, X2 and X3 are independently selected from C and N.

[0119] In some embodiments of the present invention, in Formula IX, X1 is C, X2 is C, and X3 is N.

[0120] More specifically, The following structures can be selected:

[0121]

[0122]

[0123] More specifically, in Formula IX, R 601 、R 602 、R 603 、R 604 、R 605 、R 606 and R 607 Independently selected from: -H, -D, -F, -Cl, -Br, -I, -CF3, -CHF2, -CH2F, -CH2CF3, -CN, -NO2, -CH3, -OH, -NH2,

[0124]

[0125]

[0126]

[0127] In some embodiments of the present invention, in Formula IX, R 601 Selected from: -H, C 1-6 Alkyl (such as methyl, ethyl, n-propyl or isopropyl) and C 3-6 Cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl).

[0128] In some embodiments of the present invention, in Formula IX, R 603 is -H.

[0129] In some embodiments of the present invention, in Formula IX, R 604 Selected from: -H, C 1-6 Alkyl (such as methyl, ethyl, n-propyl or isopropyl) and C 3-6 Cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl).

[0130] In some embodiments of the present invention, in Formula IX, R 606 Yes -H.

[0131] In some embodiments of the present invention, in Formula IX, R 607 Selected from: -H, C 1-6 Alkyl (such as methyl, ethyl, n-propyl or isopropyl) and C 3-6 Cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl).

[0132] In some embodiments of the present invention, in Formula IX, R 602 Selected from:

[0133]

[0134] In some embodiments of the present invention, Can be selected from:

[0135]

[0136]

[0137]

[0138]

[0139] The H attached to the carbon atom may be optionally substituted by one or more groups selected from the following: halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0- Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0- Alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 Alkyl), C 3-6 Cycloalkyl, heterocycloalkyl, and heteroaryl.

[0140] Specifically, R1 can be selected from: H, halogen, -CN, -NO2, -CF3, -OCF3, C 1-6 Alkyl, -O(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -COOH, -COO(C 1-6 alkyl), -OCOH, -OCO(C 1-6 alkyl), -CONH(C 1-6 alkyl), -CON(C 1-6 Alkyl)(C 1-6 alkyl),

[0141]

[0142]

[0143]

[0144] In some embodiments, the present invention provides the following listed Examples 1-56:

[0145] Example 1. The compound has a structure of Formula A or a pharmaceutically acceptable salt thereof,

[0146]

[0147] in:

[0148] T 1 is a glutarimide-containing group;

[0149] T 2 is hydrogen or an optionally substituted fused 8-14 membered bicyclic or tricyclic heteroaryl having 1-6 ring heteroatoms each independently selected from N, S and O, preferably T 2 It is not hydrogen;

[0150] Ring A1 is a 4-10 membered monocyclic or bicyclic carbon ring or heterocyclic ring, which is substituted by one or more substituents, each of which is independently halogen, OH, CN, oxo, NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl or selected from C 3-7 Carbocyclic ring, 3-7 membered heterocyclic ring, phenyl or 5- or 6-membered heteroaryl 3-7 membered ring, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 The heteroalkyl group or the 3-7 membered ring is optionally substituted;

[0151] Y 1 toY 7 It has the following definitions (1)-(11):

[0152] (1)Y 1 Selected from NH, O, S, S(O), SO2, C(G A )(G B ), C(O) or N(G C );

[0153] Y 2 Selected from NH, O, S, S(O), SO2, C(G A )(G B ), C(O) or N(G C );

[0154] Y 3 Selected from NH, O, S, S(O), SO2, C(G A )(G B ), C(O) or N(G C );

[0155] Y 4 Selected from NH, O, S, S(O), SO2, C(G A )(G B ), C(O) or N(G C );

[0156] Y 5 Selected from NH, O, S, S(O), SO2, C(G A )(G B ), C(O) or N(G C );

[0157] Y 6 Selected from NH, O, S, S(O), SO2, C(G A )(G B), C(O) or N(G C );

[0158] Y 7 Selected from NH, O, S, S(O), SO2, C(G A )(G B ), C(O) or N(G C );

[0159] Among them G A and G B are each independently selected from hydrogen, deuterium, halogen, OH, C 1-4 Alkyl or C optionally substituted by halogen and / or OH 1-4 Heteroalkyl, or two adjacent G A Connect to form a double bond, or two adjacent C (G A )(G B ) represents a triple bond, or G A and G B Together with the carbon atoms to which they are attached, they form an optionally substituted 3-7 membered carbocyclic or heterocyclic ring; G C Independently selected from C 1-4 Alkyl, C 1-4 heteroalkyl or an optionally substituted group of a 3-8 membered ring;

[0160] The method comprises:

[0161] (i) Two adjacent Y 1 To Y 7 Not all selected from NH, O, S or N(G C );

[0162] (ii) Two adjacent Y 1 To Y 7 Not uniformly selected from S(O), SO2 or C(O);

[0163] (iii) up to three selected from Y 1 To Y 7 The group can be S(O), SO2 or C(O);

[0164] (iv) at most two selected from Y 1 To Y 7 The group can be C(G A )(G B ), where G A and G B Together with the carbon atoms to which they are attached, they form an optionally substituted 3-6 membered carbocyclic or heterocyclic ring;

[0165] (v)Y 1 To Y 7The combination does not contain a bond selected from SS(O), S-SO2 and SC(O);

[0166] (2)Y 3 、Y 4 and Y 5 Together they represent an optionally substituted 3-8 membered ring, Y 1 、Y 2 、Y 6 and Y 7 As defined in (1);

[0167] (3)Y 4 、Y 5 and Y 6 Together they represent an optionally substituted 3-8 membered ring, Y 1 、Y 2 、Y 3 and Y 7 As defined in (1);

[0168] (4)Y 5 、Y 6 and Y 7 Together they represent an optionally substituted 3-8 membered ring, Y 1 、Y 2 、Y 3 and Y 4 As defined in (1);

[0169] (5)Y 3 、Y 4 、Y 5 and Y 6 Together they represent an optionally substituted 3-10 membered ring, Y 1 、Y 2 and Y 7 As defined in (1);

[0170] (6)Y 4 、Y 5 、Y 6 and Y 7 Together they represent an optionally substituted 3-10 membered ring, Y 1 、Y 2 and Y 3 As defined in (1);

[0171] (7)Y 2 、Y 3 and Y 4 Together they represent an optionally substituted 3-8 membered ring, Y 1 、Y 5 、Y 6 and Y 7 As defined in (1);

[0172] (8)Y2 、Y 3 、Y 4 and Y 5 Together they represent an optionally substituted 3-10 membered ring, Y 1 、Y 6 and Y 7 As defined in (1);

[0173] (9)Y 2 、Y 3 、Y 4 、Y 5 and Y 6 Together they represent an optionally substituted 3-10 membered ring, Y 1 and Y 7 As defined in (1);

[0174] (10)Y 3 、Y 4 、Y 5 、Y 6 and Y 7 together represent an optionally substituted 3-10 membered ring, preferably an 8-10 membered heterocyclic or heteroaromatic ring, Y 1 and Y 2 As defined in (1);

[0175] (11)Y 2 、Y 3 、Y 4 、Y 5 、Y 6 , and Y 7 can be selected from substituted 3-10 membered rings, preferably 8-10 membered heterocyclic rings or heteroaryl rings, Y 1 As defined in (1);

[0176] Y 8 is empty, O, NH, C(O), optionally substituted C 1-6 Alkylene or optionally substituted C 1-6 Heteroalkylene.

[0177] Example 2. The compound of Example 1 or a pharmaceutically acceptable salt thereof, wherein T 1 Has the following structure:

[0178]

[0179] in:

[0180] X is CH2 or C(=O),

[0181] n1 is an integer from 0 to 2,

[0182] G 1independently selected from halogen, CN, OH, NH2, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 heteroalkyl, an optionally substituted 3-8 membered carbocyclic or heterocyclic ring, an optionally substituted phenyl group or an optionally substituted heteroaryl group.

[0183] Example 3. The compound of Example 2 or a pharmaceutically acceptable salt thereof, characterized in that it has the structure shown in Formula A1:

[0184]

[0185] Embodiment 4. The compound according to any one of Embodiments 2 or 3, or a pharmaceutically acceptable salt thereof, wherein n1 is 0.

[0186] Embodiment 5. The compound according to any one of embodiments 1-4 or a pharmaceutically acceptable salt thereof, wherein Y 1 Selected from NH, O or N(G C ), preferably, Y 1 Selected from NH or O.

[0187] Embodiment 6. The compound according to any one of embodiments 1-5 or a pharmaceutically acceptable salt thereof, wherein Y 2 C(G A )(G B ), preferably, G A and G B are each independently hydrogen, deuterium, halogen or C 1-4 Alkyl (eg methyl) or G A and G B Together with the carbon atoms to which they are attached, they form a 3-6 membered carbocyclic or heterocyclic ring, wherein said groups are independently optionally substituted by one or more halogen, OH and C 1-4 Alkyl (eg methyl) substituted, such as Y 2 For CH2, CH(CH3), C(CH3)2, Preferably, Y 1 -Y 2 It is -NHCH2- or -OCH2-.

[0188] Embodiment 7. The compound according to any one of embodiments 1-6 or a pharmaceutically acceptable salt thereof, wherein Y 3 、Y 4 , and Y 5 is an optionally substituted 3-8 membered ring, wherein the 3-8 membered ring is selected from a 3-8 membered carbocyclic ring, a 3-8 membered heterocyclic ring, a benzene ring, or a 5- or 6-membered heteroaromatic ring, preferably Y 3 、Y 4 and Y 5 is an optionally substituted phenylene group or an optionally substituted 5- or 6-membered heteroaryl group.

[0189] Example 8. According to the embodiment 1-6 Any one of the compounds or pharmaceutically acceptable salts thereof, wherein Y 3 、Y 4 , and Y 5 is optionally substituted phenylene or optionally substituted 5 or 6 -membered heteroaryl, wherein when Y 2 and Y 6 When on the phenyl or heteroaryl ring, Y is not in ortho position to each other. 2 and Y 6 In between each other.

[0190] Embodiment 9. The compound according to any one of embodiments 1-6 or a pharmaceutically acceptable salt thereof, wherein Y 3 、Y 4 and Y 5 is 1,3-phenylene, wherein 1 , 3 -H on the phenylene group may be substituted by one or more substituents, each substituent being independently selected from halogen, CN, G 2 、OH、NH2、OG 2 NHG 2 NG 2 G 2 、COOH、CONH2、C(O)OG 2 、C(O)NHG 2 or C(O)NG 2 G 2 , where G 2 Independently selected from optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 1-4 heteroalkyl, or an optionally substituted 3-7 membered ring (preferably a 3-7 membered carbocyclic or heterocyclic ring), preferably, when substituted, one or more H in the above groups may be substituted by a substituent selected from the following: oxo (if applicable), halogen, OH, CN, NH2, optionally substituted C 1-4 Alkyl, optionally substituted C 1-4 Heteroalkyl, or optionally substituted 3-4 membered carbocyclic or heterocyclic ring; More preferably, G 2 Independently selected from the following groups: 1-3 G S1 Any substituted C 1-4 Alkyl, 1-3 G S2 Any substituted C 1-4 Heteroalkyl, or 1-3G S2substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 Independently selected from: halogen, OH, C optionally substituted by F 1-4 Heteroalkyl or 3-4 membered carbocyclic or heterocyclic ring optionally substituted by F and / or methyl; G S2 are independently selected from oxo (if applicable), halogen, OH, NH2, C optionally substituted by F 1-4 Alkyl, C optionally substituted by F 1-4 heteroalkyl or a 3-4 membered carbocyclic or heterocyclic ring optionally substituted by F and / or methyl.

[0191] Embodiment 10. The compound according to any one of embodiments 1-6 or a pharmaceutically acceptable salt thereof, wherein Y 3 、Y 4 and Y 5 Together they represent a 5- or 6-membered heteroaryl group, such as 2,5-thienyl (i.e., ), 2,5-furandiene, 2,4-pyridinediene, 2,6-pyridinyl, 3,5-pyridinyl, 2,4-pyrimidinyl, 2,6-pyrimidinyl, or 4,6-pyrimidinyl, etc. wherein the 5- or 6-membered heteroaryl is optionally substituted with one or more substituents, each substituent being independently selected from halogen, CN, G 2 、OH、NH2、OG 2 、NHG2、NG 2 G 2 、COOH、CONH2、C(O)OG 2 、C(O)NHG 2 or C(O)NG 2 G 2 , where G 2 Independently selected from optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 1-4 heteroalkyl or an optionally substituted 3-7 membered ring (preferably a 3-7 membered carbocyclic or heterocyclic ring), preferably, when substituted, one or more H in the above groups may be substituted by a substituent selected from the following: oxo (if applicable), halogen, OH, CN, NH2, optionally substituted C 1-4 Alkyl, optionally substituted C 1-4 Heteroalkyl or optionally substituted 3-4 membered carbocyclic or heterocyclic ring; more preferably, G 2 Independently selected from the following groups: 1-3 G S1 Any substituted C 1-4 Alkyl, 1-3 G S2 Any substituted C 1-4 Heteroalkyl or 1-3G S2substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 Independently selected from: halogen, OH, C optionally substituted by F 1-4 Heteroalkyl or 3-4 membered carbocyclic or heterocyclic ring optionally substituted by F and / or methyl; G S2 are independently selected from oxo (if applicable), halogen, OH, NH2, C optionally substituted by F 1-4 Alkyl, C optionally substituted by F 1-4 heteroalkyl or a 3-4 membered carbocyclic or heterocyclic ring optionally substituted by F and / or methyl.

[0192] Embodiment 11. The compound according to any one of embodiments 1-6 or a pharmaceutically acceptable salt thereof, wherein Y 3 、Y 4 , and Y 5 Together they represent a 3-6 membered carbocyclic or heterocyclic ring, wherein the H on the carbon atom may be substituted by one or more of the following substituents: halogen, OH, NH2, C 2 ... 1-4 Alkyl, C optionally substituted by F 1-4 Alkoxy or 3-4 membered carbon ring or heterocycle optionally substituted by F and / or methyl, for example, Y 3 、Y 4 and Y 5 Together

[0193] Embodiment 12. The compound according to any one of embodiments 1-6 or a pharmaceutically acceptable salt thereof, wherein Y 3 C(G A )(G B ), preferably, G A and G B are each independently selected from hydrogen, deuterium, halogen or C 1-4 Alkyl (eg methyl) or G A and G B Together with the carbon atoms to which they are attached, they form a 3-6 membered carbocyclic or heterocyclic ring, wherein one or more H on the carbon atom may be substituted by a substituent selected from the group consisting of OH and C 1-4 Alkyl (e.g., methyl), for example: Y 3 Selected from CH2,

[0194] Embodiment 13. The compound according to any one of embodiments 1-6 and 12, or a pharmaceutically acceptable salt thereof, wherein Y 4 Selected from O, NH, N(C 1-4 Alkyl) or C(G A )(G B ), preferably, G A and GB are each independently selected from hydrogen, deuterium, halogen or C1-4 alkyl (such as methyl) or G A and G B Together with the carbon atoms to which they are attached, they form a 3-6 membered carbocyclic or heterocyclic ring, wherein one or more H on the carbon atom may be substituted by a substituent selected from the group consisting of OH and C 1-4 Alkyl (e.g., methyl), for example: Y 4 Selected from O, CH2, CH(CH3), C(CH3)2,

[0195] Embodiment 14. The compound according to any one of embodiments 1-6 and 12-13, or a pharmaceutically acceptable salt thereof, wherein Y 5 Selected from O, NH, N(C 1-4 Alkyl), C(G A )(G B ), preferably, G A and G B are each independently selected from hydrogen, deuterium, halogen or C 1-4 Alkyl (eg methyl), or G A and G B Together with the carbon atoms to which they are attached, they form a 3-6 membered carbocyclic or heterocyclic ring, wherein one or more H on the carbon atom may be substituted by a substituent selected from the group consisting of OH and C 1-4 Alkyl (e.g., methyl), for example: Y 5 Selected from O or CH2.

[0196] Embodiment 15. The compound according to any one of embodiments 1-6 and 12-13 or a pharmaceutically acceptable salt thereof, wherein Y 5 , Y 6 , and Y 7 is an optionally substituted 3-8 membered ring selected from a 3-8 membered carbocyclic ring, a 3-8 membered heterocyclic ring, a phenyl ring or a heteroaryl ring, for example, Y 5 、Y 6 , and Y 7 Together for

[0197] Example 16. The compound according to any one of Examples 1-6 and 12-14, or a pharmaceutically acceptable salt thereof, wherein Y 6 is O, C(O) or C(G A) (G B ), preferably, G A and G B are each independently selected from hydrogen, deuterium, halogen or C1-4 alkyl (eg methyl), for example, Y 6 Selected from O, C(O) or CH2.

[0198] Embodiment 17. The compound according to any one of embodiments 1-6, 12-14 and 16, or a pharmaceutically acceptable salt thereof, wherein Y 7 Selected from O, C(O), NH, N(G C ) or C(G A )(G B ), preferably, G A and G B are each independently selected from hydrogen, deuterium, halogen or C 1-4 Alkyl (eg methyl), preferably, G C C 1-6 Alkyl (such as methyl) or C 1-6 Heteroalkyl, for example, Y 7 is selected from NH, O, CH2 or N(CH3).

[0199] Embodiment 18. The compound according to any one of embodiments 1-6 and 12-14, or a pharmaceutically acceptable salt thereof, wherein Y 6 -Y 7 Selected from -C(O)NH-, -C(O)-N(G C )-, -NHCH2- or -OCH2-, wherein G C C 1-6 Alkyl (such as methyl) or C 1-6 Heteroalkyl, for example, Y 6 -Y 7 Selected from -C(O)NH-, -C(O)-N(CH3)-, -NHCH2- or -OCH2-.

[0200] Embodiment 19. The compound according to any one of embodiments 1-6 and 12, or a pharmaceutically acceptable salt thereof, wherein Y 4 、Y 5 、Y 6 and Y 7 Together they represent an optionally substituted 3-8 membered ring selected from a 3-8 membered carbocyclic ring, a 3-8 membered heterocyclic ring, a benzene ring or a heteroaryl ring, for example, Y 4 、Y 5 、Y 6 and Y 7 Together expressed as

[0201] Example 20. The compound according to any one of Examples 1-5 or a pharmaceutically acceptable salt thereof, characterized in that Y 2 、Y 3 、Y 4 、Y 5 、Y 6 and Y 7Together they represent an optionally substituted 8-10 membered heterocyclic or heteroaryl ring.

[0202] Example 21. The compound according to any one of Examples 1-6 or a pharmaceutically acceptable salt thereof, characterized in that Y 3 , Y 4 , Y 5 , Y 6 and Y 7 Together they represent an optionally substituted 8-10 membered heterocyclic or heterocyclic aromatic group, preferably, the 8-10 membered heterocyclic or heterocyclic aromatic group is selected from a 6,5-fused or 6,6-fused heterocyclic or heterocyclic aromatic group having 1-5 heteroatoms, wherein each heteroatom is independently selected from O, N or S.

[0203] Example 22. The compound according to any one of Examples 1-6 or a pharmaceutically acceptable salt thereof, characterized in that Y 3 , Y 4 , Y 5 , Y 6 and Y 7 Together they represent an optionally substituted 6,5-fused or 6,6-fused heterocycle, wherein a benzene ring or a 6-membered heterocyclic aromatic group is fused to a 5- or 6-membered heterocycle having 1 or 2 ring heteroatoms, each heteroatom being independently selected from O, N or S, and further preferably, the heteroatom is a N atom, for example, Y 4 , Y 5 , Y 6 and Y 7 Together for

[0204] Embodiment 23. The compound according to any one of embodiments 1-6 or a pharmaceutically acceptable salt thereof, wherein Y 3 、Y 4 、Y 5 、Y 6 and Y 7 Together, they represent an optionally substituted 6,5- or 6,6-fused heteroaromatic ring having 1-5 ring atoms, each heteroatom being independently selected from O, N or S, for example, an optionally substituted benzimidazole, indazole, benzothiophene, etc., wherein the H on the carbon atom of the 6,5 or 6,6-fused heteroaromatic ring may be substituted by one to three groups selected from the following: halogen, CN, G 2 、OH、NH2、OG 2 NHG 2 NG 2 G 2 、COOH、CONH2、C(O)OG 2 、C(O)NHG 2 or C(O)NG 2 G 2 , where G2 Independently selected from optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, substituted C 2-4 Alkynyl, substituted C 1-4 Heteroalkyl, substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic); preferably, the H on the carbon atom may be substituted by one or more of the following groups: oxo (if applicable), halogen, OH, CN, NH2, substituted C 1-4 Alkyl, substituted C 1-4 Heteroalkyl, or an optionally substituted 3-4 membered carbocyclic or heterocyclic ring; More preferably, G 2 Independently selected from 1-3 G S1 Substituted C 1-4 Alkyl, 1-3 G S2 Substituted C 1-4 Heteroalkyl or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 are independently selected from halogen, OH, C substituted with one or more F 1-4 Heteroalkyl, or a 3-4 membered carbocyclic or heterocyclic ring substituted by one or more F and / or methyl groups; G S2 independently selected from oxo (if applicable), halogen, OH, NH2, C substituted with one or more F 1-4 Alkyl, one or more F-substituted C 1-4 heteroalkyl, or a 3-4 membered carbocyclic or heterocyclic ring optionally substituted by F and / or methyl.

[0205] Embodiment 24. The compound according to any one of embodiments 1-23 or a pharmaceutically acceptable salt thereof, characterized in that Y 8 Empty.

[0206] Embodiment 25. The compound according to any one of embodiments 1-23 or a pharmaceutically acceptable salt thereof, characterized in that Y 8 Selected from O, NH, C(O), C 1-2 Alkylene, or C with 1-3 heteroatoms 1-6 Heteroalkylene, wherein the heteroatom is selected from O, N and S, wherein the S can be oxidized, the C 1-6 The heteroalkylene group may be substituted with 1 or 2 oxo groups.

[0207] Example 26. The compound according to any one of Examples 1-25 or a pharmaceutically acceptable salt thereof, characterized in that the A1 ring is a 4-8 membered monocyclic carbocyclic ring or heterocyclic ring, wherein the H on the carbon atom can be substituted by one or more of the following groups: halogen, OH, CN, oxo, C substituted by F 1-4 Alkyl or C substituted by F1-4 Heteroalkyl.

[0208] Example 27. The compound according to any one of Examples 1-25 or a pharmaceutically acceptable salt thereof, characterized in that Ring A1 is C 4-7 Cycloalkyl, wherein the H on the carbon atom may be substituted by one or more of the following groups: halogen, OH, CN, oxo, C substituted by F 1-4 Alkyl or C substituted by F 1-4 Heteroalkyl.

[0209] Example 28. The compound according to any one of Examples 1-25 or a pharmaceutically acceptable salt thereof, characterized in that ring A1 is cyclohexylene, preferably, ring A1 is 1,4-trans-cyclohexylene,

[0210] Embodiment 29. The compound according to any one of embodiments 1-28 or a pharmaceutically acceptable salt thereof, characterized in that T 2 is a 5,5- or 6,5-fused aromatic heterocycle which may be substituted, wherein the 5,5- or 6,5-fused aromatic heterocycle has 1 to 5 ring heteroatoms, each heteroatom being independently selected from O, N or S, for example, T 2 Selected from substituted thiazolopyridine, imidazopyridine, benzimidazole, pyrazolopyridine, oxazolopyridine, benzoxazole, indole, benzothiophene, benzothiazole, thienopyridine, thienopyrimidine, thienothiophene, etc., wherein the H on the carbon atom can be substituted by 1-3 groups of the following: halogen, CN, G 2 、OH、NH2、OG 2 NHG 2 NG2G 2 、COOH、CONH2、C(O)OG 2 、C(O)NHG 2 or C(O)NG 2 G 2 , where G 2 Independently selected from substituted C 1-4 Alkyl, substituted C 2-4 Alkenyl, substituted C 2-4 Alkynyl, substituted C 1-4 Heteroalkyl, or an optionally substituted 3-7 membered ring (preferably a 3-7 membered carbocyclic or heterocyclic ring), preferably, the H on the carbon atom may be substituted by one or more of the following groups: oxo (if applicable), halogen, OH, CN, NH2, substituted C 1-4 Alkyl, substituted C 1-4 Heteroalkyl, or substituted 3-4 membered carbocyclic or heterocyclic ring; More preferably, G 2 Independently selected from 1-3 G S1 Substituted C1-4 Alkyl, 1-3 G S2 Substituted C 1-4 Heteroalkyl or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 independently selected from halogen, OH, C substituted by F 1-4 heteroalkyl, or a 3-4 membered carbocyclic or heterocyclic ring substituted with F and / or methyl; wherein G S2 independently selected from oxo (if applicable), halogen OH, NH2, F substituted C 1-4 Alkyl, F-substituted C 1-4 heteroalkyl or a 3-4 membered carbocyclic or heterocyclic ring substituted by F and / or methyl.

[0211] Embodiment 30. The compound according to any one of embodiments 1-28 or a pharmaceutically acceptable salt thereof, characterized in that T 2 is a substituted 6,5-fused aromatic heterocycle having 1-5 heteroatoms, wherein each heteroatom is independently selected from O, N or S, wherein one ring is selected from furan, thiophene, pyrrole, pyrazole, imidazole, oxazole, thiazole, isoxazole or isothiazole, and the ring is fused with benzene, pyridine, pyrimidine, pyridazine or pyrazine, and when the 6,5-fused aromatic heterocycle is substituted, it is preferably substituted with 1-3 substituents, each substituent being independently selected from halogen, CN, G 2 、OH、NH2、OG 2 NHG 2 NG 2 G 2 、COOH、CONH2、C(O)OG 2 、C(O)NHG 2 or C(O)NG 2 G 2 , where G 2 Each occurrence is independently optionally substituted C1 4 alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 1-4 heteroalkyl, or an optionally substituted 3-7 membered ring (preferably a 3-7 membered carbocyclic or heterocyclic ring), preferably when substituted, the optionally substituted group is substituted by one or more substituents, each substituent being independently oxo (as applicable), halogen, CN, G 2 、OH、NH2、OG 2 NHG 2 NG 2 G 2 、COOH、CONH2、C(O)OG 2 、C(O)NHG 2 or C(O)NG2 G 2 , where G 2 Independently selected from substituted C 1-4 Alkyl, substituted C 1-4 Heteroalkyl, or optionally substituted 3-4 membered carbocyclic or heterocyclic ring; More preferably, G 2 Independently selected from 1-3 G S1 Substituted C 1-4 Alkyl, 1-3 G S2 Substituted C 1-4 Heteroalkyl, or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 independently selected from halogen, OH, C substituted by F 1-4 Heteroalkyl, or a 3-4 membered carbocyclic or heterocyclic ring optionally substituted by F and / or methyl; G S2 are independently selected from oxo (if applicable), halogen OH, NH2, C substituted by F 1-4 Alkyl, C substituted by F 1-4 Heteroalkyl, or a 3-4 membered carbocyclic or heterocyclic ring substituted with F and / or methyl, preferably, T 2 Connected to ring A1 via a ring atom on the 5-membered ring, for example, T 2 Selected from the following aromatic heterocycles: etc.

[0212] Embodiment 31. The compound according to any one of embodiments 1-28 or a pharmaceutically acceptable salt thereof, characterized in that T 2 is a substituted 5,6,5-fused, 6,5,5-fused or 5,6,6-fused tricyclic aromatic heterocycle, wherein the fused tricyclic aromatic heterocycle has 1-5 ring heteroatoms, wherein the heteroatoms are independently selected from O, N or S, wherein the 5-membered ring in the fused ring is independently selected from furan, thiophene, pyrrole, pyrazole, imidazole, oxazole, thiazole, isoxazole or isothiazole, and the 6-membered ring in the fused ring is independently selected from benzene, pyridine, pyrimidine, pyridazine or pyrazine; wherein the H on the carbon atom of the 5,6,5-fused, 6,5,5-fused or 5,6,6-fused tricyclic aromatic heterocycle is preferably substituted by 1-3 of the following groups: CN, G 2 、OH、NH2、OG 2 NHG 2 NG 2 G 2 、COOH、CONH2、C(O)OG 2 、C(O)NHG 2 or C(O)NG 2 G 2 , where G 2 Independently selected from substituted C1-4 Alkyl, substituted C 2-4 Alkenyl, substituted C 2-4 Alkynyl, substituted C 1-4 Heteroalkyl, or substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), when substituted, the H on the carbon atom may be substituted by one or more of the following substituents: oxo (if applicable), halogen, OH, CN, NH2, substituted C 1-4 Alkyl, substituted C 1-4 Heteroalkyl, or substituted 3-4 membered carbocyclic or heterocyclic ring; More preferably, G 2 Independently selected from 1-3 G S1 Substituted C 1-4 Alkyl, 1-3 G S2 Substituted C 1-4 Heteroalkyl, or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 independently selected from halogen, OH, C substituted by F 1-4 heteroalkyl, 3-4 membered carbocyclic or heterocyclic ring substituted by F and / or methyl; G S2 are independently selected from oxo (if applicable), halogen, OH, NH2, C substituted by F 1-4 Alkyl, C substituted by F 1-4 Heteroalkyl or 3-4 membered carbocyclic or heterocyclic ring substituted by F and / or methyl, for example, T 2 Selected from the following aromatic heterocycles: wait.

[0213] Embodiment 32. A compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula B:

[0214]

[0215] in,

[0216] T 1 is a glutarimide-containing group;

[0217] T 3 is an 8-14 membered bicyclic or tricyclic fused heterocyclic aromatic group having 1-6 ring heteroatoms independently selected from N, S and O;

[0218] n2 is an integer from 0 to 2, G 3 independently selected from halogen, OH, CN, oxo, C substituted by F 1-4 Alkyl, or C substituted by F 1-4 Heteroalkyl; preferably, n2 is 0;

[0219] LNK is connected to T1 and a cyclohexyl ring, the linker can be a chain, a ring or a ring-chain structure, wherein the number of atoms constituting the shortest chain or ring of the linker is at least 4 (e.g., 4, 5, 6, 7, 8 or 9), wherein the atoms constituting the chain or ring are independently selected from C, N, O and S, wherein the minimum number of atoms is T 1 The minimum number of linker atoms required to connect the cyclohexyl ring, from the bond to T 1 and ends with the atom that is bonded to the cyclohexyl ring.

[0220] Example 33. The compound according to Example 32 or a pharmaceutically acceptable salt thereof, characterized in that it has the structure shown in Formula b1:

[0221]

[0222] Embodiment 34. The compound according to any one of Embodiments 32 or 33 or a pharmaceutically acceptable salt thereof, characterized in that T 3 is a 6,5-fused heterocyclic aromatic group having 1-5 heteroatoms, each heteroatom independently selected from O, N or S, wherein one fused ring is selected from furan, thiophene, pyrrole, pyrazole, imidazole, oxazole, thiazole, isoxazole or isothiazole, fused with a group selected from the following: benzene, pyridine, pyrimidine, pyridazine or pyrazine, when substituted, the 5-fused heterocyclic aromatic group is preferably substituted with 1-3 substituents, each substituent independently selected from halogen, CN, G 2 、OH、NH2、OG 2 NHG 2 NG 2 G 2 、COOH、CONH2、C(O)OG 2 、C(O)NHG 2 or C(O)NG 2 G 2 , where G 2 Independently selected from substituted C 1-4 Alkyl, substituted C 2-4 Alkenyl, substituted C 2-4 Alkynyl, substituted C 1-4 Heteroalkyl, or substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), when substituted, the H on the carbon atom may be substituted by one or more of the following substituents: oxo (if applicable), halogen, OH, CN, NH2, substituted C 1-4 Alkyl, substituted C 1-4 Heteroalkyl, or substituted 3-4 membered carbocyclic or heterocyclic ring; More preferably, G 2 Independently selected from 1-3 G S1 Substituted C 1-4 Alkyl, 1-3 GS2 Substituted C 1-4 Heteroalkyl, or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 independently selected from halogen, OH, C substituted by F 1-4 heteroalkyl, 3-4 membered carbocyclic or heterocyclic ring substituted by F and / or methyl; G S2 are independently selected from oxo (if applicable), halogen, OH, NH2, C substituted by F 1-4 Alkyl, C substituted by F 1-4 heteroalkyl or a 3-4 membered carbon ring or heterocycle substituted by F and / or methyl, T 3 By attaching to the cyclohexyl group via a ring atom on the 5-membered ring, for example, T 3 Selected from the following substituted or unsubstituted heterocyclic aromatic groups: wait.

[0223] Embodiment 35. The compound according to any one of Embodiments 32 or 33 or a pharmaceutically acceptable salt thereof, characterized in that T 3 is a 5,6,5-fused, 6,5,5-fused or 5,6,6-fused three-membered heterocyclic aromatic group, wherein the ring has 1-5 ring heteroatoms, each heteroatom is independently selected from O, N or S, wherein the 5-membered ring of the fused ring is independently selected from furan, thiophene, pyrrole, pyrazole, imidazole, oxazole, thiazole, isoxazole or isothiazole, and the 6-membered ring of the fused ring is independently selected from benzene, pyridine, pyrimidine, pyridazine or pyrazine, and when substituted, the fused three-membered heterocyclic aromatic group is preferably substituted with 1-3 of the following substituents: halogen, CN, G 2 、OH、NH2、OG 2 NHG 2 NG 2 G 2 、COOH、CONH2、C(O)OG 2 、C(O)NHG 2 or C(O)NG 2 G 2 , where G 2 Independently selected from substituted C 1-4 Alkyl, substituted C 2-4 Alkenyl, substituted C 2-4 Alkynyl, substituted C 1-4 Heteroalkyl, or substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), when substituted, the H on the carbon atom may be substituted by one or more of the following substituents: oxo (if applicable), halogen, OH, CN, NH2, substituted C 1-4 Alkyl, substituted C 1-4Heteroalkyl, or substituted 3-4 membered carbocyclic or heterocyclic ring; More preferably, G 2 Independently selected from 1-3 G S1 Substituted C 1-4 Alkyl, 1-3 G S2 Substituted C 1-4 Heteroalkyl, or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 independently selected from halogen, OH, C substituted by F 1-4 heteroalkyl, 3-4 membered carbocyclic or heterocyclic ring substituted by F and / or methyl; G S2 are independently selected from oxo (if applicable), halogen, OH, NH2, C substituted by F 1-4 Alkyl, C substituted by F 1-4 heteroalkyl, or a 3-4 membered carbocyclic or heterocyclic ring substituted with F and / or methyl, T 3 By attaching to the cyclohexyl group via a ring atom on the 5-membered ring, for example, T 3 Selected from the following substituted or unsubstituted heterocyclic aromatic groups: wait.

[0224] Example 36. The compound according to any one of Examples 32-35 or a pharmaceutically acceptable salt thereof, characterized in that T 1 Has the following structure:

[0225]

[0226] in:

[0227] X is selected from CH2 or C(=O),

[0228] n1 is an integer from 0 to 2,

[0229] G 1 independently selected from halogen, CN, OH, NH2, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 heteroalkyl, substituted or substituted 3-8 membered carbocyclic or heterocyclic ring, substituted or substituted phenyl, substituted or substituted aromatic heterocyclic ring.

[0230] Example 37. The compound according to any one of Example 36 or a pharmaceutically acceptable salt thereof, characterized in that it has the structure of Formula B2:

[0231]

[0232] Embodiment 38. The compound according to any one of Embodiments 36 or 37, or a pharmaceutically acceptable salt thereof, characterized in that n1 is 0.

[0233] Example 39. The compound according to any one of Examples 32-38 or a pharmaceutically acceptable salt thereof, characterized in that LNK is a linker defined in this application, for example, a linker defined in Examples 5-25: or is or any chain structure as defined herein for formula (I) for 1.

[0234] Example 40. A compound having the structure of Formula C or a pharmaceutically acceptable salt thereof,

[0235]

[0236] in:

[0237] T 1 is a glutarimide-containing group;

[0238] LNK is connected to T 1 and a linker of ring A1, the linker being a chain, a ring or a ring-chain structure, wherein the number of atoms constituting the shortest chain or ring of the linker is at least 4 (e.g., 4, 5, 6, 7, 8 or 9), wherein the atoms constituting the chain or ring are independently selected from C, N, O and S, wherein the minimum number of atoms is T 1 The minimum number of linker atoms required to connect the cyclohexyl ring, from the bond to T 1 and ends with the atom bonded to the cyclohexyl ring;

[0239] Ring A1 is selected from an optionally substituted 4-10 membered monocyclic or bicyclic carbocyclic or heterocyclic ring;

[0240] T 4 is an optionally substituted 5,5- or 6,5-fused heterocyclic aromatic group, wherein the heterocyclic ring has 1-5 ring heteroatoms, each independently selected from O, N or S; or an optionally substituted 5,6,5-fused, 6,5,5-fused or 5,6,6-fused aromatic three-membered heterocyclic ring, wherein the ring has 1-6 ring heteroatoms, each independently selected from O, N or S. Preferably, T 4 A ring atom on the 5-membered ring is bonded to Ring A1.

[0241] Embodiment 41. The compound according to any one of Embodiment 40 or a pharmaceutically acceptable salt thereof, characterized in that T 4is a substituted or unsubstituted 6,5-fused heterocyclic aromatic group having 1-5 ring heteroatoms, wherein the ring heteroatoms are each independently selected from O, N or S, wherein one fused ring is selected from furan, thiophene, pyrrole, pyrazole, imidazole, oxazole, thiazole, isoxazole or isothiazole, which is fused with benzene, pyridine, pyrimidine, pyridazine or pyrazine, and when the 6,5-fused heterocyclic aromatic group is substituted, the 5-fused heterocyclic aromatic group is preferably substituted with 1-3 substituents, each substituent being independently selected from halogen, CN, G 2 、OH、NH2、OG 2 NHG 2 NG 2 G 2 、COOH、CONH2、C(O)OG 2 、C(O)NHG 2 or C(O)NG 2 G 2 , where G 2 Independently selected from substituted C 1-4 Alkyl, substituted C 2-4 Alkenyl, substituted C 2-4 Alkynyl, substituted C 1-4 Heteroalkyl, or substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), when substituted, the H on the carbon atom may be substituted by one or more of the following substituents: oxo (if applicable), halogen, OH, CN, NH2, substituted C 1-4 Alkyl, substituted C 1-4 Heteroalkyl, or substituted 3-4 membered carbocyclic or heterocyclic ring; More preferably, G 2 Independently selected from 1-3 G S1 Substituted C 1-4 Alkyl, 1-3 G S2 Substituted C 1-4 Heteroalkyl, or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 independently selected from halogen, OH, C substituted by F 1-4 heteroalkyl, 3-4 membered carbocyclic or heterocyclic ring substituted by F and / or methyl; G S2 are independently selected from oxo (if applicable), halogen, OH, NH2, C substituted by F 1-4 Alkyl, C substituted by F 1-4 heteroalkyl or a 3-4 membered carbon ring or heterocycle substituted by F and / or methyl, T 4 Selected from the following substituted or unsubstituted heterocyclic aromatic groups: etc.

[0242] Embodiment 42. The compound according to any one of Embodiment 40 or a pharmaceutically acceptable salt thereof, characterized in that T 4 is an optionally substituted 5,6,5-fused, 6,5,5-fused or 5,6,6-fused three-membered heterocyclic aromatic group having 1-5 ring heteroatoms, each of which is independently selected from O, N or S, wherein the 5-membered ring of the fused ring is independently selected from furan, thiophene, pyrrole, pyrazole, imidazole, oxazole, thiazole, isoxazole or isothiazole, and the 6-membered ring of the fused ring is independently selected from benzene, pyridine, pyrimidine, pyridazine or pyrazine, and when substituted, the fused three-membered heterocyclic aromatic group is preferably substituted with 1-3 of the following substituents: halogen, CN, G 2 、OH、NH2、OG 2 NHG 2 NG 2 G 2 、COOH、CONH2、C(O)OG 2 、C(O)NHG 2 or C(O)NG 2 G 2 , where G 2 Independently selected from substituted C 1-4 Alkyl, substituted C 2-4 Alkenyl, substituted C 2-4 Alkynyl, substituted C 1-4 Heteroalkyl, or substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), when substituted, the H on the carbon atom may be substituted by one or more of the following substituents: oxo (if applicable), halogen, OH, CN, NH2, substituted C 1-4 Alkyl, substituted C 1-4 Heteroalkyl, or substituted 3-4 membered carbocyclic or heterocyclic ring; More preferably, G 2 Independently selected from 1-3 G S1 Substituted C 1-4 Alkyl, 1-3 G S2 Substituted C 1-4 Heteroalkyl, or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 independently selected from halogen, OH, C substituted by F 1-4 heteroalkyl, 3-4 membered carbocyclic or heterocyclic ring substituted by F and / or methyl; G S2 are independently selected from oxo (if applicable), halogen, OH, NH2, C substituted by F 1-4 Alkyl, C substituted by F 1-4 heteroalkyl or a 3-4 membered carbocyclic or heterocyclic ring substituted with F and / or methyl, T4 is selected from the following substituted or unsubstituted heterocyclic aromatic groups: wait.

[0243] Embodiment 43. The compound according to any one of embodiments 40-42 or a pharmaceutically acceptable salt thereof, characterized in that T 1 Has the following structure:

[0244]

[0245] in,

[0246] x is ch2 or c(=o),

[0247] n1 is an integer from 0 to 2,

[0248] G 1 independently selected from halogen, CN, OH, NH2, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 heteroalkyl, substituted or unsubstituted 3-8 membered carbocyclic or heterocyclic ring, substituted or unsubstituted phenyl or substituted or unsubstituted heteroaryl.

[0249] Example 44. The compound according to any one of Example 43 or a pharmaceutically acceptable salt thereof, characterized in that it has the structure shown in Formula C1:

[0250]

[0251] Embodiment 45. The compound of Embodiment 43 or 44, or a pharmaceutically acceptable salt thereof, wherein n1 is 0.

[0252] Embodiment 46. The compound of any one of embodiments 40-45, or a pharmaceutically acceptable salt thereof, wherein lnk is any linker defined herein, for example, as defined in any one of embodiments 5-25. The structure or the structure of L defined in the present application connected to formula (I) serves as a linker.

[0253] Embodiment 47. The compound of any one of Embodiments 40-46, or a pharmaceutically acceptable salt thereof, wherein Ring A1 is an optionally substituted 4-8 membered monocyclic carbocyclic or heterocyclic ring.

[0254] Embodiment 48. The compound of any one of Embodiments 40-46 or a pharmaceutically acceptable salt thereof, wherein Ring A1 is substituted or unsubstituted C 4-7 Cycloalkyl.

[0255] Embodiment 49. The compound of any one of Embodiments 40-46 or a pharmaceutically acceptable salt thereof, wherein Ring A1 is cyclohexylene, preferably 1,4-trans-cyclohexylene,

[0256] Example 50. The compound according to any one of Examples 1 to 150 or a pharmaceutically acceptable salt thereof. The structures of Examples 1 to 150 can be found in the Synthetic Examples section.

[0257] Example 51. A pharmaceutical composition according to any one of the compounds described in Examples 1-50 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0258] Example 52. A method of inducing protein degradation in a cell, comprising contacting the cell with any one of the compounds of Examples 1-50 or a pharmaceutically acceptable salt thereof.

[0259] Example 53. The method of Example 52, wherein the protein is GSPT1.

[0260] Embodiment 54. The method of embodiment 52 or 53, wherein the cell is a cancer cell.

[0261] Embodiment 55. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1-50 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in Embodiment 51.

[0262] Example 56. The method of Example 55, wherein the cancer is associated with GSPT1 activity.

[0263] In some embodiments of the present invention, the compounds of the present invention are selected from the following structures:

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273] In a second aspect, the present invention provides pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds of the above-mentioned compounds.

[0274] In some embodiments of the present invention, the stereoisomer has the following structure:

[0275]

[0276]

[0277]

[0278]

[0279]

[0280] In some embodiments, the present invention comprises a compound selected from the group consisting of:

[0281]

[0282]

[0283] or a pharmaceutically acceptable salt thereof.

[0284] In a third aspect of the present invention, a pharmaceutical composition is provided, comprising the compound according to the first aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof.

[0285] Specifically, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0286] Specifically, the pharmaceutically acceptable excipients may be selected from fillers, binders, lubricants and the like.

[0287] Specifically, in the pharmaceutical composition, the pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates, and deuterated compounds of the compound described in the first aspect can be used alone or in combination with other types of active ingredients. Specifically, the pharmaceutical composition may also include an antioxidant, a buffer, an antibacterial agent, a solute that makes the formulation isotonic with the subject's blood, and aqueous and non-aqueous sterile suspensions, which may include suspending agents, solubilizers, thickeners, stabilizers, and preservatives.

[0288] In particular, the pharmaceutical composition is suitable for enteral or parenteral administration, such as administration via intravenous, intramuscular, intradermal and subcutaneous routes.

[0289] Specifically, the pharmaceutical composition can be prepared into pharmaceutical preparations in the following forms: injection, syrup, elixir, suspension, powder, granule, tablet, capsule, lozenge, cream, ointment, lotion, gel, emulsion, etc.

[0290] When preparing injections, any commonly used carrier in the art can be used, such as water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyethoxylated isostearyl alcohol, and fatty acid esters of polyethylene sorbitan, etc. In addition, commonly used solvents and buffers can also be added.

[0291] Specifically, the pharmaceutical composition is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate amounts of the active ingredient. The unit dosage form can be a capsule, tablet, or any other dosage form; in addition, the unit dosage form can also be a packaged preparation, such as tablets, capsules, and powders packaged in vials or ampoules.

[0292] In a fourth aspect, the present invention provides use of the compound of the first aspect, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof, in the preparation of a medicament for preventing and / or treating a GSPT1-related disease. Specifically, the GSPT1-related disease is selected from the group consisting of autoimmune diseases, inflammatory diseases, heteroimmune diseases, neurodegenerative diseases, and tumors.

[0293] Specifically, the above-mentioned autoimmune diseases include, but are not limited to, one or more of organ-specific autoimmune diseases, systemic lupus erythematosus, rheumatoid arthritis, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, autoimmune hemolytic anemia, thyroid autoimmune disease, and ulcerative colitis.

[0294] Specifically, the above-mentioned inflammatory diseases include but are not limited to: one or more of osteoarthritis, gout, chronic obstructive pulmonary disease, periodic fever, rash, lymphadenopathy, sepsis, osteoarthritis, ankylosing spondylitis, psoriasis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, uveitis, asthma, and allergies.

[0295] Specifically, the aforementioned xenoimmune disease is a rejection reaction after organ transplantation.

[0296] Specifically, the above-mentioned neurodegenerative diseases include but are not limited to: Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), different types of spinocerebellar ataxia (SCA), Pick's disease, etc.

[0297] Specifically, the above tumors include but are not limited to: adrenal cancer, anal cancer, angiosarcoma, appendix cancer, bile duct cancer, bladder cancer, breast cancer, brain cancer, bronchial cancer, carcinoid tumor, cervical cancer, choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer, connective tissue cancer, epithelial cancer, ependymoma, endothelial sarcoma, endometrial cancer, esophageal cancer, Ewing's sarcoma, eye cancer, gallbladder cancer, gastric cancer, gastrointestinal stromal tumor (GIST), germ cell cancer, head and neck cancer, hematological malignancies, hemangioblastoma, hypopharyngeal cancer, inflammatory myofibroblastic tumor , immune cell amyloidosis, kidney cancer, liver cancer, lung cancer, leiomyosarcoma (LMS), muscle cancer, mesothelioma, myeloproliferative disorders (MPD), neuroblastoma, neurofibroma, neuroendocrine cancer, osteosarcoma, ovarian cancer, papillary adenocarcinoma, pancreatic cancer, penile cancer, pineal tumor, primitive neuroectodermal tumor (PNT), prostate cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer, small intestine cancer, soft tissue sarcoma, sebaceous gland cancer, sweat gland cancer, synovioma, testicular cancer, thyroid cancer, urethra cancer, vaginal cancer, vulvar cancer.

[0298] More specifically, the tumor is a hematological malignancy, such as leukemia, lymphoma, and multiple myeloma (MM).

[0299] Specifically, the leukemia may be chronic lymphocytic leukemia (CLL) (e.g., B cell CLL, T cell CLL), chronic myeloid leukemia (CML) (e.g., B cell CML, T cell CML), acute lymphocytic leukemia (ALL) (e.g., B cell ALL, T cell ALL), acute myeloid leukemia (AML)

[0300] (e.g., B cell AML, T cell AML), acute monocytic leukemia, especially acute myeloid leukemia. Specifically, the leukemia can be relapsed, refractory or drug-resistant.

[0301] Specifically, the lymphoma can be Hodgkin lymphoma (HL) (e.g., B cell HL, T cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodular marginal zone B cell lymphoma, splenic marginal zone B cell lymphoma), primary mediastinal B cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenstrom's giant cell lymphoma), globulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma and T-cell NHL, such as precursor T lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma and anaplastic large cell lymphoma, NK / T-cell lymphoma, in particular diffuse large B-cell lymphoma (DLBCL).

[0302] More specifically, the above tumors are multiple myeloma (MM), diffuse large B-cell lymphoma (DLBCL), and acute monocytic leukemia.

[0303] In a fifth aspect of the present invention, a method for preventing and / or treating a GSPT1-related disease is provided, comprising the step of administering to a subject in need thereof the compound of the first aspect of the present invention or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, or the pharmaceutical composition of the third aspect of the present invention.

[0304] Specifically, in the above method, the GSPT1-related disease has the corresponding definition described in the fourth aspect of the present invention.

[0305] Specifically, the above-mentioned subject can be a mammal, especially a human. Background of the Invention

[0307] The compounds disclosed herein can generally be characterized as having any of the general structural formulas of Formula (I) (including subformulas thereof such as Formulas I-1 to I-8, (II), (III), (IV), or (V)), Formula A, Formula B, Formula C, and subformulas thereof. The compounds of Formula (I) and their subformulas are described in detail in the Summary of the Invention section.

[0308] In some embodiments, the present disclosure provides compounds of Formula A as defined in Examples 1-31. In some embodiments, the present disclosure provides compounds of Formula B as defined in Examples 32-39. In some embodiments, the present disclosure provides compounds of Formula C as defined in Examples 40-49. In some embodiments, the variables of Formula A, B, or C are selected from any structure defined in the present disclosure, for example, selected from the compound structures defined in Examples 1-150.

[0309] Formula A

[0310] In the embodiment described according to Formula A, T 1 A glutarimide-containing group is a group that can typically bind to the cereblon pocket of an E3 ligase. The glutarimide-containing group used in the present invention refers to a group derived from a substituted or unsubstituted glutarimide. For example, in some embodiments, T 1 A structure having the following general formula:

[0311]

[0312] in:

[0313] X is CH2 or C(=O),

[0314] n1 is an integer from 0 to 2,

[0315] G 1 independently selected from halogen, CN, OH, NH2, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 In some embodiments, n1 is 0. In some embodiments, n1 is 1 and G 1 is halogen (such as F), C substituted or unsubstituted by F 1-4 Alkyl or C 1-4 Heteroalkyl (e.g. C 1-4 Alkoxy or C 1-4 In some embodiments, X is C(O). In some embodiments, X is CH2. The remainder of the molecule may be attached to T at any position of the benzene ring. 1 However, in some preferred embodiments, the compound of Formula A is characterized by having a structure of Formula A1:

[0316]

[0317] wherein the variables are as defined in the present invention.

[0318] In some embodiments according to Formula A (eg, A1), Y 1 to Y 7 represents a chain structure, for example, in some embodiments, Y 1 -Y 7 It may represent a heteroalkylene chain having 7 atoms in the chain, such as In some embodiments, Y 1 to Y 7 Having any of the structures defined in Examples 5, 6, 12-14 and 16-18.

[0319] In some embodiments according to Formula A (eg, A1), Y 1 to Y 7 In other words, Y 1 to Y 7 At least some of the representations consist of ring structures, and Y 1 to Y 7 The ring-chain structure is not particularly limited.

[0320] For example, in some embodiments, Y 3 、Y 4 and Y 5 Together they form a substituted or unsubstituted 3-8 membered ring, Y 1 、Y 2 、Y 6 and Y 7 is the structure defined above in this application, such as the structure listed in Example 1-(1). In some embodiments, Y 1 、Y 2 、Y 6 and Y 7 Can be selected from the structures defined in Examples 5, 6 and 16-18, respectively. In some preferred embodiments, Y 1 -Y 2 is an NHCH2 or OCH2 linker, and Y 6 -Y 7 It can be selected from -C(O)NH-, -C(O)-N(CH3)-, -NHCH2- or -OCH2-. It should be noted that these divalent linkers are not limited to any particular orientation and can be connected to the rest of the molecule in either direction (from left to right or from right to left). For example, in some embodiments, the compound of formula A can be characterized as having a structure of formula A1a, A1b, A1c, A1d, A1e, A1f, A1g or A1h

[0321]

[0322] wherein the variables are as defined above.

[0323] According to the embodiment described in Formula A (such as Formula A1a, A1b, A1c, A1d, A1e, A1f, A1g or A1h), Y 3 、Y 4 and Y 5 Together they represent a substituted or unsubstituted phenylene, or a substituted or unsubstituted 5- or 6-membered heteroaryl (e.g., the structures defined in any one of Examples 8-10). For example, in some embodiments, Y 3 、Y 4 and Y 5 Together they represent substituted or unsubstituted 1,3-phenylene, i.e., Y 2 and Y 6 They are in the meta position relative to each other, as shown in formula A1i:

[0324]

[0325] Where j is 0, 1 or 2, G 10 Selected from halogen, CNG 2 、OH、NH2、OG 2 NHG 2 NG 2 G 2 、COOH、CONH2、C(O)OG 2 、C(O)NHG 2 or C(O)NG 2 G 2 , where G 2 Independently selected from substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 2-4 Alkenyl, substituted or unsubstituted C 2-4 Alkynyl, substituted or unsubstituted C 1-4 Heteroalkyl or selected from substituted or unsubstituted 3-7 membered rings (preferably 3-7 membered carbocyclic or heterocyclic rings), preferably, the carbon atoms may be substituted by one or more substituents, each substituent being independently selected from oxo (if applicable), halogen, OH, CN, NH2, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 1-4 Heteroalkyl, or substituted or unsubstituted 3-4 membered carbocyclic or heterocyclic ring; More preferably, G 2 Independently selected from 1-3 G S1 Substituted or unsubstituted C 1-4 Alkyl, 1-3 G S2 Substituted or unsubstituted C 1-4 Heteroalkyl or 1-3 G S2 a substituted or unsubstituted 3-7 membered ring (preferably a 3-7 membered carbocyclic or heterocyclic ring), wherein G S1are independently selected from halogen, OH, C substituted or unsubstituted by F 1-4 heteroalkyl, or a 3-4 membered carbocyclic or heterocyclic ring which may be substituted by F and / or methyl; G S2 are independently selected from oxo (if applicable), halogen, OH, NH2, C substituted or unsubstituted by F 1-4 Alkyl, optionally substituted by F or unsubstituted C 1-4 In some embodiments, G 10 is selected from halogen, OH, NH2, CN, C substituted or unsubstituted by F 1-4 Alkyl or C 1-4 Heteroalkyl, such as C optionally substituted by F 1-4 Alkoxy.

[0326] According to some embodiments of Formula A (e.g., Formula A1a, A1b, A1c, A1d, A1e, A1f, A1g, or A1h), Y 3 、Y 4 and Y 5 Together they represent a substituted or unsubstituted 5- or 6-membered heterocyclic aromatic group, for example 2,5-thienyl (ie, ), 2,5-furandiene, 2,4-pyridinediene, 2,6-pyridyl, 3,5-pyridyl, 2,4-pyrimidinyl, 2,6-pyrimidinyl or 4,6-pyrimidinyl. In some preferred embodiments, Y 3 、Y 4 and Y 5 Together they represent a substituted or unsubstituted 6-membered heterocyclic aromatic group. In some embodiments, Y 3 、Y 4 and Y 5 Together they represent an unsubstituted 6-membered heterocyclic aromatic group, such as an unsubstituted 2,4-pyridyl group (i.e. ), 2,6-pyridinediene (ie ), 3,5-pyridinediene (ie ), 2,4-pyrimidinediene (ie ), 2,6-pyrimidinediene (ie ) or 4,6-pyrimidinediene (ie In some embodiments, Y 3 、Y 4 and Y 5 Together they represent a 5- or 6-membered heterocyclic aromatic group (as described herein), wherein the carbon atoms may be substituted by one or two of the following substituents: halogen, CN, G 2 、OH、NH2、OG 2 NHG 2 NG 2 G 2、COOH、CONH2、C(O)OG 2 、C(O)NHG 2 or C(O)NG 2 G 2 , where G 2 Independently selected from substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 2-4 Alkenyl, substituted or unsubstituted C 2-4 Alkynyl, substituted or unsubstituted C 1-4 Heteroalkyl is or is selected from substituted or unsubstituted 3-7 membered rings (preferably 3-7 membered carbocyclic or heterocyclic rings). In some embodiments, when the carbon atom is substituted, G 2 It may be unsubstituted or substituted with one or more of the following groups (e.g., 1, 2, or 3 substituents): oxo (if applicable), halogen, OH, CN, NH2, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 1-4 In some preferred embodiments, G2 is independently selected from 1-3 G S1 Substituted or unsubstituted C 1-4 Alkyl, 1-3 G S2 Substituted or unsubstituted C 1-4 Heteroalkyl or 1-3 G S2 a substituted or unsubstituted 3-7 membered ring (preferably a 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 are independently selected from halogen, OH, C substituted or unsubstituted by F 1-4 heteroalkyl, or a 3-4 membered carbocyclic or heterocyclic ring which may be substituted by F and / or methyl.

[0327] According to some embodiments described by formula A (such as formula 1aA1a, A1b, A1c, A1d, A1e, A1f, A1g or A1h), Y 3 、Y 4 and Y 5 Together, they can also represent a 3-6 membered carbocyclic or heterocyclic ring, wherein the carbon atoms in the carbocyclic or heterocyclic ring can be replaced by one or more of the following: oxo, halogen, OH, CN, NH2, C substituted or unsubstituted by F 1-4 Alkyl, C substituted or unsubstituted by F 1-4 Alkoxy or 3-4 membered carbocyclic or heterocyclic ring substituted or unsubstituted by F and / or methyl. For example, in some embodiments, Y 3 、Y 4 and Y 5 Can be expressed together

[0328] According to some embodiments described in Formula A, I (e.g., Formula A1), Y2 、Y 3 and Y 4 Together they represent an optionally substituted 3-8 membered ring; Y 1 、Y 5 、Y 6 and Y 7 is selected from the groups defined herein, such as the groups listed in Example 1-(1). In some embodiments, Y 1 、Y 5 、Y 6 and Y 7 can be selected from the groups defined in Examples 5, 14, and 16-18, respectively.

[0329] According to some embodiments described in Formula A (eg, A1), Y 2 、Y 3 、Y 4 and Y 5 Together they represent an optionally substituted 3-10 membered ring; Y 1 、Y 6 and Y 7 As defined herein, for example, selected from the groups defined in Example 1-(1). In some embodiments, Y 1 、Y 6 and Y 7 can be selected from the groups defined in Examples 5 and 16-18, respectively.

[0330] In some embodiments according to formula A (eg, A1), Y 2 、Y 3 、Y 4 、Y 5 and Y 6 Together they represent an optionally substituted 3-10 membered ring, Y 1 and Y 7 As defined herein, for example, selected from the groups defined in Example 1-(1). In some embodiments, Y 1 and Y 7 can be selected from the groups defined in Examples 5 and 17, respectively.

[0331] In some embodiments according to formula A (eg, A1), Y 4 、Y 5 and Y 6 Together they represent an optionally substituted 3-8 membered ring, Y 1 、Y 2 、Y 3 and Y 7 is selected from the groups defined herein, for example, selected from the groups defined in Example 1-(1). In some embodiments, Y 1 、Y 2 、Y 3and Y 7 can be selected from the groups defined in Examples 5, 6, 12 and 17, respectively. In some preferred embodiments, Y 1 -Y 2 Can be NHCH2 or OCH2 linker, Y 7 Can be selected from -C(O)-, -N(CH3)-, -CH2- or -O-. In some embodiments, Y 4 、Y 5 and Y 6 Together they represent an optionally substituted 3- to 6-membered carbocyclic or heterocyclic ring, an optionally substituted phenylene group, or an optionally substituted 5- or 6-membered heterocyclic aromatic group.

[0332] In some embodiments according to formula A (eg, A1), Y 5 、Y 6 and Y 7 Together they represent an optionally substituted 3-8 membered ring, Y 1 、Y 2 、Y 3 and Y 4 As defined herein, for example, can be selected from the groups defined in Example 1-(1). In some embodiments, Y 1 、Y 2 、Y 3 and Y 4 can be selected from the groups defined in Examples 5, 6, 12 and 13, respectively. In some embodiments, Y 1 -Y 2 Can be NHCH2 or OCH2 linker, Y 3 -Y 4 Can be -C(O)NH-, -C(O)-N(CH3)-, -NHCH2- or -OCH2-. In some embodiments, Y 5 、Y 6 and Y 7 Together they represent an optionally substituted 3-8 membered carbocyclic ring, 3-8 membered heterocyclic ring, benzene ring or heterocyclic aromatic ring. For example, in some embodiments, Y 5 、Y 6 and Y 7 Together Preferably, the nitrogen of the pyridin-2-one is linked to Y 8 .

[0333] According to some embodiments described in formula A (eg, A1), Y 2 、Y 3 、Y 4 、Y 5 、Y 6 and Y 7 Together they represent an optionally substituted 8-10 membered heterocyclic or heteroaryl ring.1 As defined herein, for example, can be selected from the groups defined in Example 1-(1). In some embodiments, Y 1 can be selected from the groups defined in Example 5. In some embodiments, Y 1 is NH or O.

[0334] According to some embodiments described in formula A (eg, A1), Y 3 、Y 4 、Y 5 、Y 6 and Y 7 Together they represent an optionally substituted 8-10 membered heterocyclic or heterocyclic aromatic group, preferably, the heterocyclic or heterocyclic aromatic group is a 5-fused or 6,6-fused heterocyclic or heterocyclic aromatic group, wherein the heterocyclic ring has 1-5 ring heteroatoms, each heteroatom being independently selected from O, N or S, Y 1 and Y 2 As defined herein, for example, can be selected from the groups defined in Example 1-(1). In some embodiments, Y 1 and Y 2 Can be selected from the groups defined in Examples 5 and 6, respectively. In some embodiments, Y 1 -Y 2 Can be NHCH2 or OCH2 linker. In some embodiments, Y 3 、Y 4 、Y 5 、Y 6 , and Y 7 Together they represent an optionally substituted 6,5-fused or 6,6-fused heterocyclic ring in which a benzene ring or a 6-membered heterocyclic aromatic group is fused to a 5- or 6-membered heterocyclic ring having 1 or 2 ring heteroatoms, each heteroatom being independently selected from O, N or S, preferably 1 ring nitrogen atom, for example Y 3 、Y 4 、Y 5 、Y 6 and Y 7 Together For example, in some embodiments, the compound of Formula A can have the structure of Formula A1j or A1k:

[0335]

[0336] wherein the variables are as defined in this application.

[0337] In some embodiments, Y 3 、Y 4 、Y 5 、Y 6 and Y 7Together, they represent an optionally substituted 6,5-fused or 6,6-fused heterocyclic aromatic group having 1-5 ring heteroatoms, each heteroatom independently selected from O, N, or S. For example, in some embodiments, Y 3 、Y 4 、Y 5 、Y 6 and Y 7 Together, they can be selected from optionally substituted benzimidazoles, indazoles, benzothiophenes, and the like. In some embodiments, the benzimidazoles, indazoles, or benzothiophenes can be unsubstituted. When substituted, the H on the carbon atoms of the 6, 5, or 6, 6-fused heteroaromatic ring can be substituted with one to three groups selected from the following: halogen, CN, G 2 、OH、NH2、OG 2 NHG 2 NG 2 G 2 、COOH、CONH2、C(O)OG 2 、C(O)NHG 2 or C(O)NG 2 G 2 , where G 2 Independently selected from optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 1-4 Heteroalkyl or an optionally substituted 3-7 membered ring (preferably a 3-7 membered carbocyclic or heterocyclic ring); preferably, the H on the carbon atom may be substituted by one or more of the following groups: oxo (if applicable), halogen, OH, CN, NH2, substituted C 1-4 Alkyl, substituted C 1-4 Heteroalkyl, or an optionally substituted 3-4 membered carbocyclic or heterocyclic ring; More preferably, G 2 Independently selected from 1-3 G S1 Substituted C 1-4 Alkyl, 1-3 G S2 Substituted C 1-4 Heteroalkyl or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 are independently selected from halogen, OH, C substituted with one or more F 1-4 Heteroalkyl or 3-4 membered carbocyclic or heterocyclic ring substituted by one or more F and / or methyl groups; G S2 independently selected from oxo (if applicable), halogen, OH, NH2, C substituted with one or more F 1-4 Alkyl, one or more F-substituted C 1-4 heteroalkyl, or a 3-4 membered carbocyclic or heterocyclic ring optionally substituted by F and / or methyl.

[0338] According to some embodiments described by formula A (eg, A1), Y 1 -Y 7 Together, they can be selected from linkers as described in Examples 1-150.

[0339] Typically, according to some embodiments described by formula A (eg, A1, A1a to A1k), Y 8 However, in some embodiments, Y 8 can be selected from O, NH, C(O), optionally substituted C 1-2 Alkylene, or C with 1-3 heteroatoms 1-6 Heteroalkylene, wherein the heteroatom is selected from O, N and S, wherein S can be oxidized, the C 1-6 The heteroalkylene group may be substituted with 1 or 2 oxo groups.

[0340] According to some embodiments described in formula A (e.g., A1, A1a to A1k), ring A1 is preferably selected from 4-8 membered monocyclic carbon rings or heterocycles substituted by one or more (e.g., 1 or 2) of the following substituents: halogen, OH, CN, oxo, C optionally substituted by F 1-4 Alkyl or C optionally substituted by F 1-4 Heteroalkyl.

[0341] According to some preferred embodiments of formula A (e.g., A1, A1a to A1k), ring A1 is C 4-7 Cycloalkyl, wherein the H on the carbon atom may be substituted by one or more of the following groups: halogen, OH, CN, oxo, C substituted by F 1-4 Alkyl or C substituted by F 1-4 In some embodiments, ring A1 is an unsubstituted C 4-7 For example, preferably, ring A1 is cyclohexylene, preferably 1, 4-trans cyclohexylene,

[0342] According to the compound described in formula A (including all subformulas), T 2 As described herein, the inventors have found that T 2 Selected from a fused bicyclic or tricyclic heteroaromatic group, which can provide compounds with good efficacy, such as lower DC50 values ​​relative to GSPT1.

[0343] According to some embodiments of formula A (e.g., A1, A1a to A1k), T2 is preferably selected from an optionally substituted 5,5-fused or 6,5-fused heterocyclic aromatic group having 1-5 ring heteroatoms, wherein each heteroatom is independently selected from O, N or S. More preferably, T 2It is connected to ring A1 through a ring atom on the 5-membered ring. In some embodiments, T 2 is an optionally substituted thiazolopyridine, imidazopyridine, benzimidazole, pyrazolopyridine, oxazolopyridine, benzothiazole, indole, benzothiophene, benzothiazole, thienopyridine, thienopyrimidine or thienothiophene. Preferably, when substituted, the 5,5-fused or 6,5-fused heterocyclic aromatic group may be substituted by 1-3 of the following substituents: halogen, CN, G 2 、OH、NH2、OG 2 NHG 2 NG 2 G 2 、COOH、CONH2、C(O)OG 2 、C(O)NHG 2 or C(O)NG 2 G 2 , where G 2 Independently selected from optionally substituted C1-4 alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C1-4 heteroalkyl or optionally substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring); preferably, the H on the carbon atom may be substituted by one or more of the following groups: oxo (if applicable), halogen, OH, CN, NH2, substituted C 1-4 Alkyl, substituted C 1-4 Heteroalkyl, or an optionally substituted 3-4 membered carbocyclic or heterocyclic ring; More preferably, G2 is independently selected from 1-3 G S1 Substituted C 1-4 Alkyl, 1-3 G S2 Substituted C 1-4 Heteroalkyl or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 are independently selected from halogen, OH, C substituted with one or more F 1-4 Heteroalkyl or 3-4 membered carbocyclic or heterocyclic ring substituted by one or more F and / or methyl groups; G S2 independently selected from oxo (if applicable), halogen, OH, NH2, C substituted with one or more F 1-4 Alkyl, one or more F-substituted C 1-4 heteroalkyl, or a 3-4 membered carbocyclic or heterocyclic ring optionally substituted by F and / or methyl.

[0344] According to some preferred embodiments described in Formula A (eg, A1, eg, A1a to A1k), T 2is an optionally substituted 6,5-fused heterocyclic aromatic group having 1-5 ring heteroatoms, each heteroatom independently selected from O, N or S, characterized in that one of the fused rings is furan, thiophene, pyrrole, pyrazole, imidazole, oxazole, thiazole, isoxazole or isothiazole, which is fused with benzene, pyridine, pyrimidine, pyridazine or pyrazine. Preferably, T 2 It is connected to ring A1 through a ring atom on the 5-membered ring. It should be noted that in the embodiments of the present application, the bicyclic fused heterocyclic aromatic group or the tricyclic fused heterocyclic aromatic group can be described by, for example, the name of a single ring. For example, when it is described that in a bicyclic fused heterocyclic aromatic group, one of the fused rings is imidazole, which is fused to a pyrazine ring, it should be understood that the bicyclic fused heterocyclic aromatic group includes The same group, i.e., the bicyclic fused heterocyclic aromatic group includes all possible imidazopyrazines, imidazo[1,2-a]pyrazines, imidazo[1,5-a]pyrazines or imidazo[4,5-b]pyrazines. Similar expressions of other fused bicyclic or tricyclic heterocyclic aromatic groups should be understood in the same way. In some preferred embodiments, the 6,5-fused heterocyclic aromatic group is a thiazole fused with benzene, pyridine, pyrimidine, pyridazine or pyrazine, more preferably a pyridine-fused thiazole, which can be selected from

[0345] The group may be substituted with one or more suitable substituents described herein. In some preferred embodiments, the 6,5-fused heterocyclic aromatic group is an imidazole fused with benzene, pyridine, pyrimidine, pyridazine or pyrazine, and the 6,5-fused heterocyclic aromatic group may be selected from the group consisting of: In some embodiments, the 6,5-fused heterocyclic aromatic group is unsubstituted. In some embodiments, the H on the carbon atom of the 6,5-fused heterocyclic aromatic group may be substituted by one to three groups selected from the following: halogen, CN, G 2 、OH、NH2、OG 2 NHG 2 NG 2 G 2 、COOH、CONH2、C(O)OG 2 、C(O)NHG 2 or C(O)NG 2 G 2 , where G 2 Independently selected from optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 1-4Heteroalkyl or an optionally substituted 3-7 membered ring (preferably a 3-7 membered carbocyclic or heterocyclic ring), preferably, the H on the carbon atom may be substituted by one or more of the following groups: oxo (if applicable), halogen, OH, CN, NH2, substituted C 1-4 Alkyl, substituted C 1-4 Heteroalkyl, or an optionally substituted 3-4 membered carbocyclic or heterocyclic ring; More preferably, G 2 Independently selected from 1-3 G S1 Substituted C 1-4 Alkyl, 1-3 G S2 Substituted C 1-4 Heteroalkyl or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 are independently selected from halogen, OH, C substituted with one or more F 1-4 Heteroalkyl or 3-4 membered carbocyclic or heterocyclic ring substituted by one or more F and / or methyl groups; G S2 independently selected from oxo (if applicable), halogen, OH, NH2, C substituted with one or more F 1-4 Alkyl, one or more F-substituted C 1-4 Heteroalkyl, or a 3-4 membered carbocyclic or heterocyclic ring optionally substituted with F and / or methyl. In some embodiments, the H on the carbon atom of the 6,5-fused heterocyclic aromatic group may be substituted with 1 to 2 groups selected from the following: halogen, CN, OH, NH2, 1-3 G S1 Substituted C 1-4 Alkyl, 1-3 G S2 Substituted C 1-4 Heteroalkyl or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 and G S2 As defined herein. In some embodiments, the 6,5-fused heterocyclic aromatic group is unsubstituted or substituted with a substituent selected from C, C-, C-, and C-substituted groups. 1-4 Alkyl or heteroalkyl which may be substituted by 1-3 F atoms, such as methoxy. In some embodiments, the 6,5-fused heterocyclic aromatic group is unsubstituted or substituted by one or two substituents selected from the following: halogen, CN, OH, NH2, C substituted by 1-3 F 1-4 Alkyl or C substituted with 1-3 F 1-4 Heteroalkyl, such as methoxy.

[0346] In some embodiments described in Formula A (e.g., A1, A1a to A1k), T 2 is an optionally substituted 6,5-fused heterocyclic aromatic group selected from the following structures: The group may be substituted with 1-3 substituents selected from the following groups: halogen, CN, G 2 、OH、NH2、OG 2 NHG 2 NG 2 G 2 、COOH、CONH2、C(O)OG 2 、C(O)NHG 2 or C(O)NG 2 G 2 , where G 2 As defined in this application. It should be noted that when there is a substituent, the substituent may be attached to a carbon atom or a nitrogen atom on the ring. In some embodiments, the aforementioned 6,5-fused heterocyclic aromatic group is unsubstituted or substituted with one or two substituents selected from the following: halogen, CN, OH, NH2, 1-3 G S1 Substituted C 1-4 Alkyl, 1-3 G S2 Substituted C 1-4 Heteroalkyl or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 and G S2 As defined herein. In some embodiments, the 6,5-fused heterocyclic aromatic group is unsubstituted or substituted with a substituent selected from C, C, or C-substituted groups which may be optionally substituted with 1-3 F atoms or C atoms. 1-4 Alkyl or heteroalkyl optionally substituted by 1-3 F atoms, such as methoxy. In some embodiments, the 6,5-fused heterocyclic aromatic group is unsubstituted or substituted by one or two substituents selected from the following: halogen, CN, OH, NH2, C optionally substituted by 1-3 F atoms, 1-4 Alkyl or C substituted with 1-3 F 1-4 In some more specific embodiments, according to any compound described in Formula A (eg, A1, A1a to A1k), T 2 is any 6,5-fused heterocyclic aromatic group selected from the group consisting of those described in Example 50.

[0347] In some embodiments, according to any compound of Formula A (eg, A1, A1a to A1k), T 2is an optionally substituted 5,6,5-fused, 6,5,5-fused, or 5,6,6-fused three-membered heterocyclic aromatic group having 1-5 ring heteroatoms independently selected from O, N, or S, wherein the 5-membered ring in the fused ring is independently selected from furan, thiophene, pyrrole, pyrazole, imidazole, oxazole, thiazole, isoxazole, or isothiazole, and the 6-membered ring in the fused ring is independently selected from benzene, pyridine, pyrimidine, pyridazine, or pyrazine. In some embodiments, the 5-membered ring is imidazole. In some embodiments, the 5-membered ring is pyrrole. In some embodiments, the 6-membered ring is pyridine. In some embodiments, the 5,6,5-fused, 6,5,5-fused, or 5,6,6-fused three-membered heterocyclic aromatic group has no substituents. In some embodiments, the H on the carbon atom of the 5,6,5-fused, 6,5,5-fused or 5,6,6-fused three-membered heterocyclic aromatic ring is substituted with a substituent as defined herein. In some embodiments, the H on the carbon atom of the 5,6,5-fused, 6,5,5-fused or 5,6,6-fused three-membered heterocyclic aromatic ring is substituted with 1-3 of the following groups: CN, G 2 、OH、NH2、OG 2 NHG 2 NG 2 G 2 、COOH、CONH2、C(O)OG 2 、C(O)NHG 2 or C(O)NG 2 G 2 , where G 2 Independently selected from optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 1-4 heteroalkyl or substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), preferably, when substituted, the H on the carbon atom may be substituted by one or more of the following substituents: oxo (if applicable), halogen, OH, CN, NH2, substituted C 1-4 Alkyl, substituted C 1-4 Heteroalkyl, or substituted 3-4 membered carbocyclic or heterocyclic ring; More preferably, G 2 Independently selected from 1-3 G S1 Substituted C 1-4 Alkyl, 1-3 G S2 Substituted C 1-4 Heteroalkyl, or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 independently selected from halogen, OH, C substituted by F 1-4 heteroalkyl, 3-4 membered carbocyclic or heterocyclic ring substituted by F and / or methyl; GS2 are independently selected from oxo (if applicable), halogen, OH, NH2, C substituted by F 1-4 Alkyl, C substituted by F 1-4 In some embodiments, the 5,6,5-fused, 6,5,5-fused or 5,6,6-fused three-membered heterocyclic aromatic ring has no substituents or the hydrogen on the carbon atom is substituted by 1 or 2 of the following substituents: halogen, OH, NH2, 1-3 G S1 Substituted C1-4 alkyl, 1-3 G S2 Substituted C1-4 heteroalkyl or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 and G S2 As defined herein. In some embodiments, T 2 Selected from the following aromatic heterocycles: The hydrogen atoms on the aromatic heterocyclic carbon atoms may be substituted by substituents selected from the following: halogen, CN, OH, NH2, 1-3 G S1 Substituted C 1-4 Alkyl, 1-3 G S2 Substituted C 1-4 Heteroalkyl or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 and G S2 As defined herein. In some more specific embodiments, according to any embodiment of Formula A (such as Formulas A1, A1a to A1k), T 2 The 5,6,5-fused heterocyclic aromatic group may be selected from the 5,6,5-fused heterocyclic aromatic groups described in Examples 1-150.

[0348] Formula B

[0349] In some embodiments, the present disclosure also provides a compound according to Formula B, such as the compounds defined in Examples 32-39, or a pharmaceutically acceptable salt thereof.

[0350] In formula B, LNK is not particularly limited and can be a chain, ring or ring-chain structure. In some embodiments, LNK is a linker of a chain structure, which means that the linker can connect T1 to the cyclohexene ring without using any ring-forming atoms (or short ring atoms). It should be noted that this linker is selected from a ring having one or more substituents. In some embodiments, LNK is a linker of a ring-chain structure, which means that the linker uses at least one chain atom and at least one ring atom to connect T1 to the cyclohexene ring. In some embodiments, LNK is a linker of a ring structure, which means that the linker connects T1 to the cyclohexene ring without using chain atoms. It should be noted that this ring structure linker can be arbitrarily substituted with a substituent having one or more chain atoms. For example, are considered to be the ring-chain structures of the linkers used in this article, and This will be considered the chain structure of the linker, and is a ring structure of a linker as used herein. Generally, LNK is characterized by having a certain "length", which represents the minimum number of atoms constituting a chain or ring of the linker, and the length is at least 4 (e.g., 4, 5, 6, 7, 8 or 9), wherein the atoms forming the chain or ring are independently selected from C, N, O and S, the minimum number of which is from T 1 The minimum number of atoms required to link the cyclohexyl ring from the bond to T 1 and ends with the atom bonded to the cyclohexyl ring. The minimum number of atoms to form a chain or ring is 7, which is connected by T 1 The calculation starts from the bold N in the group and includes the minimum number of atoms, that is, the carbon atom in the chain or ring of the bold bond below, to the bold N atom bonded to the cyclohexylene group:

[0351]

[0352] It is obvious that the atom count of the path through the other three ring atoms of the benzene ring (non-bold bonds) will increase to 9, not from T 1The minimum number of atoms connected to the cyclohexyl ring. Based on this, it can also be clear that any substituent on the phenyl ring or N atom or methylene in the above-mentioned linker is not counted in the minimum number of atoms. The linkers of other structures are also the same definition. In some embodiments, the minimum number of atoms forming a chain or ring is 4-10, and in particular, the minimum number of atoms forming a chain or ring is at most 6, wherein at most 6 are from ring atoms. In some embodiments, the minimum number of atoms forming a chain or ring can also be greater than 10, for example 12, 15 or 20, or any range therebetween. Typically, the molecular weight of LNK is about 50-350Da, preferably 50-250Da, such as about 80-180Da or about 100-200Da. Typically, LNK contains no more than 8 heteroatoms. For example, in some embodiments, LNK has 2-6 (for example 2, 3, 4 or 5) heteroatoms, each independently selected from O, N or S, and the remaining atoms can be selected from C, H, D or halogen. Typically, LNK has up to three rings, such as one or two monocyclic rings, one bicyclic ring, or one monocyclic and one bicyclic ring. In some embodiments, LNK has one 5- or 6-membered ring, which can be selected from a carbocyclic ring, a heterocyclic ring, a phenyl group, or a heteroaromatic group. In some embodiments, LNK can be a bicyclic heterocyclic ring or a heteroaromatic group. In some embodiments, LNK is a 3- to 6-membered spirocyclic ring, such as a spiropropyl ring.

[0353] According to any compound described in Formula B (including any substructure thereof), LNK has The structures defined herein include any one of the compounds defined in Examples 5-25.

[0354] According to any compound of Formula B (including any substructures thereof), LNK has the structure where L is defined in Formula (I).

[0355] According to any compound described by Formula B (including any substructures thereof), LNK can have the structure of any linker as described in the specific compounds herein, such as the compounds shown in Examples 1-150.

[0356] Typically, in Formula B, n2 is 0, and the compound has the structure of Formula B1, wherein the cyclohexylene is 1,4-trans-cyclohexylene.

[0357] In some embodiments, the cyclohexylene group (preferably 1,4-trans cyclohexylene) in any compound according to formula B has one or two G 3 Substituents. In particular, when substituted, G 3 Substituents are not connected to LNK or T 3 When there is a substituent, G 3 Usually selected from F, OH, CN, C which can be arbitrarily substituted by F 1-2 Alkyl or C optionally substituted by F1-3 Heteroalkyl.

[0358] Typically, in any compound according to Formula B (eg, Formula B1 or B2), T 3 is an optionally substituted 5,5-fused or 6,5-fused heterocyclic aromatic group having 1 to 5 ring heteroatoms, each heteroatom being independently selected from O, N or S, more preferably, T 3 The cyclohexylene group is connected to the cyclohexylene group through a ring atom on the 5-membered ring. 3 is selected from an optionally substituted thiazolopyridine, imidazopyridine, benzimidazole, pyrazolopyridine, oxazolopyridine, benzoxazole, indole|benzothiophene, benzothiazole, thienopyridine, thienopyrimidine or thienothiophene. Preferably, when substituted, the 5,5-fused or 6,5-fused heteroaromatic ring herein is substituted with 1-3 substituents, each substituent being independently selected from halogen, CN, G 2 、OH、NH2、OG 2 NHG 2 NG 2 G 2 、COOH、CONH2、C(O)OG 2 、C(O)NHG 2 or C(O)NG 2 G 2 , where G 2 Independently selected from optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 1-4 heteroalkyl or an optionally substituted 3-7 membered ring (preferably a 3-7 membered carbocyclic or heterocyclic ring), preferably, when substituted, the H on the carbon atom may be substituted by one or more of the following substituents: oxo (if applicable), halogen, OH, CN, NH2, substituted C 1-4 Alkyl, substituted C 1-4 Heteroalkyl, or substituted 3-4 membered carbocyclic or heterocyclic ring; More preferably, G 2 Independently selected from 1-3 G S1 Substituted C 1-4 Alkyl, 1-3 G S2 Substituted C 1-4 Heteroalkyl, or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 independently selected from halogen, OH, C optionally substituted by F 1-4 Heteroalkyl, 3-4 membered carbocyclic or heterocyclic ring optionally substituted by F and / or methyl; G S2independently selected from oxo (if applicable), halogen, OH, NH2, C optionally substituted by F 1-4 Alkyl, C optionally substituted by F 1-4 heteroalkyl or a 3-4 membered carbocyclic or heterocyclic ring optionally substituted by F and / or methyl.

[0359] In some preferred embodiments, according to any compound described by Formula B (eg, Formula B1 or B2), T 3 is a 6,5-fused heterocyclic aromatic group having 1-5 heterocyclic atoms, each heteroatom independently selected from O, N or S, wherein one fused ring is selected from furan, thiophene, pyrrole, pyrazole, imidazole, oxazole, thiazole, isoxazole or isothiazole, and is fused with a group selected from the following: benzene, pyridine, pyrimidine, pyridazine or pyrazine. Preferably, T 3 The 6,5-fused heterocyclic aromatic group is connected to the cyclohexylene group through a ring atom on the 5-membered ring. In some preferred embodiments, the 6,5-fused heterocyclic aromatic group is selected from thiazole fused to benzene, pyridine, pyrimidine, pyridazine or pyrazine, more preferably, selected from thiazole fused to pyridine, which can be: The group may be substituted by one or more other substituents defined in this application. In some preferred embodiments, the 6,5-fused heterocyclic aromatic group is selected from imidazole fused with benzene, pyridine, pyrimidine, pyridazine or pyrazine, which can be Said group may be substituted by one or more other substituents defined in this application. In some preferred embodiments, the 6,5-fused heterocyclic aromatic group has no substituent. In some preferred embodiments, the 6,5-fused heterocyclic aromatic group is substituted by 1-3 substituents, each of which is independently selected from halogen, CN, G 2 、OH、NH2、OG 2 NHG 2 NG 2 G 2 、COOH、CONH2、C(O)OG 2 、C(O)NHG 2 or C(O)NG 2 G 2 , where G 2 Independently selected from substituted C 1-4 Alkyl, substituted C 2-4 Alkenyl, substituted C 2-4 Alkynyl, substituted C 1-4 Heteroalkyl, or substituted 3-7 Membered ring (preferably 3-7 Preferably, when substituted, the H on the carbon atom may be substituted by one or more of the following substituents: oxo (if applicable), halogen, OH, CN, NH2, substituted C 1-4 Alkyl, substituted C1-4 Heteroalkyl, or substituted 3-4 membered carbocyclic or heterocyclic ring; More preferably, G 2 Independently selected from 1-3 G S1 Substituted C 1-4 Alkyl, 1-3 G S2 Substituted C 1-4 Heteroalkyl, or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 G is independently selected from halogen, OH, C1-4 heteroalkyl substituted by F, 3-4 membered carbocyclic or heterocyclic ring substituted by F and / or methyl; S2 are independently selected from oxo (if applicable), halogen, OH, NH2, C substituted by F 1-4 Alkyl, C substituted by F 1-4 Heteroalkyl or 3-4 membered carbocyclic or heterocyclic ring substituted with F and / or methyl. In some embodiments, the 6,5-fused heterocyclic aromatic group has no substituent or is substituted with 1-2 substituents, each of which is independently selected from 1-3 G S1 Substituted C 1-4 Alkyl, 1-3 G S2 Substituted C 1-4 Heteroalkyl, or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 and G S2 As defined in this application. In some preferred embodiments, the 6,5-fused heterocyclic aromatic group is not substituted or is substituted with a substituent selected from C substituted with 1-3 F atoms. 1-4 Alkyl or heteroalkyl substituted by 1-3 F atoms, such as methoxy. In some embodiments, the 6,5-fused heterocyclic aromatic group is unsubstituted or substituted by one or two substituents selected from the following: halogen, CN, OH, NH2, C substituted by 1-3 F 1-4 Alkyl or C substituted with 1-3 F 1-4 Heteroalkyl, such as methoxy.

[0360] In some embodiments described by Formula B (eg, B1 or B2), T 3 is an optionally substituted 6,5-fused heterocyclic aromatic group selected from the following structures: The group may be substituted with 1-3 substituents selected from the following groups: halogen, CN, G 2 、OH、NH2、OG 2 NHG 2 NG 2 G 2、COOH、CONH2、C(O)OG 2 、C(O)NHG 2 or C(O)NG 2 G 2 , where G 2 As defined in this application. It should be noted that when there is a substituent, the substituent may be attached to a carbon atom or a nitrogen atom on the ring. In some embodiments, the aforementioned 6,5-fused heterocyclic aromatic group is unsubstituted or substituted by one or two substituents, each of which is independently selected from: halogen, CN, OH, NH2, 1-3 G S1 Substituted C 1-4 Alkyl, 1-3 G S2 Substituted C 1-4 Heteroalkyl, or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 and G S2 As defined in this application. In some embodiments, the 6,5-fused heterocyclic aromatic group is unsubstituted or substituted with a substituent selected from C, C- ... 1-4 Alkyl or heteroalkyl optionally substituted by 1-3 F atoms, such as methoxy. In some embodiments, the 6,5-fused heterocyclic aromatic group is unsubstituted or substituted by one or two substituents selected from the following: halogen, CN, OH, NH2, C optionally substituted by 1-3 F atoms, 1-4 Alkyl or C substituted with 1-3 F 1-4 In some more specific embodiments, according to formula B (such as B1 or B2), T 3 is any 6,5-fused heterocyclic aromatic group selected from Examples 1-150.

[0361] In some embodiments, according to any compound described by Formula B (eg, B1 or B2), T 3is an optionally substituted 5,6,5-fused, 6,5,5-fused, or 5,6,6-fused three-membered heterocyclic aromatic group having 1-5 ring heteroatoms independently selected from O, N, or S, wherein the 5-membered ring in the fused ring is independently selected from furan, thiophene, pyrrole, pyrazole, imidazole, oxazole, thiazole, isoxazole, or isothiazole, and the 6-membered ring in the fused ring is independently selected from benzene, pyridine, pyrimidine, pyridazine, or pyrazine. In some embodiments, the 5-membered ring is imidazole. In some embodiments, the 5-membered ring is pyrrole. In some embodiments, the 6-membered ring is pyridine. In some embodiments, the 5,6,5-fused, 6,5,5-fused, or 5,6,6-fused three-membered heterocyclic aromatic group has no substituents. In some embodiments, the H on the carbon atom of the 5,6,5-fused, 6,5,5-fused or 5,6,6-fused three-membered heterocyclic aromatic ring is substituted with a substituent as defined herein. In some embodiments, the H on the carbon atom of the 5,6,5-fused, 6,5,5-fused or 5,6,6-fused three-membered heterocyclic aromatic ring is substituted with 1-3 of the following groups: halogen, CN, G 2 、OH、NH2、OG 2 NHG 2 NG 2 G 2 、COOH、CONH2、C(O)OG 2 、C(O)NHG 2 or C(O)NG 2 G 2 , where G 2 Independently selected from optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 1-4 heteroalkyl or substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), preferably, when substituted, the H on the carbon atom may be substituted by one or more of the following substituents: oxo (if applicable), halogen, OH, CN, NH2, substituted C 1-4 Alkyl, substituted C 1-4 Heteroalkyl, or substituted 3-4 membered carbocyclic or heterocyclic ring; More preferably, G 2 Independently selected from 1-3 G S1 Substituted C 1-4 Alkyl, 1-3 G S2 Substituted C 1-4 Heteroalkyl, or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 independently selected from halogen, OH, C substituted by F 1-4 heteroalkyl, 3-4 membered carbocyclic or heterocyclic ring substituted by F and / or methyl; GS2 are independently selected from oxo (if applicable), halogen, OH, NH2, C substituted by F 1-4 Alkyl, C substituted by F 1-4 In some embodiments, the 5,6,5-fused, 6,5,5-fused or 5,6,6-fused three-membered heterocyclic aromatic ring has no substituents or the hydrogen on the carbon atom is substituted by 1 or 2 of the following substituents: halogen, OH, NH2, 1-3 G S1 Substituted C 1-4 Alkyl, 1-3 G S2 Substituted C 1-4 Heteroalkyl or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 and G S2 As defined herein. In some embodiments, T 3 Selected from the following aromatic heterocycles: The hydrogen atoms on the aromatic heterocyclic carbon atoms may be independently substituted by substituents selected from the following groups: halogen, CN, OH, NH2, 1-3 G S1 Substituted C 1-4 Alkyl, 1-3 G S2 Substituted C 1-4 Heteroalkyl or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 and G S2 As defined herein. In some more specific embodiments, according to any embodiment of Formula B (such as Formula B1 or B2), T 3 The 5,6,5-fused heterocyclic aromatic group may be selected from the 5,6,5-fused heterocyclic aromatic groups described in Examples 1-150.

[0362] T in Formula B (e.g., Formula B1 or B2) 1 , characterized in that it is selected from any structure described in the present application and connected to formula (I) or formula A. In some embodiments, T in formula B (e.g., formula B1 or B2) 1 is selected from any one of the structures defined in Examples 36-38. In some embodiments, T in Formula B (e.g., Formula B1 or B2) 1 Any glutarimide group selected from the compounds described in Examples 1-150.

[0363] Formula C

[0364] In some embodiments, the present disclosure further provides a compound according to Formula C, which is selected from the compounds defined in any one of Examples 40-49, or a pharmaceutically acceptable salt thereof.

[0365] According to some embodiments described in Formula C, T 4 is selected from an optionally substituted 5,5-fused or 6,5-fused heterocyclic aromatic group having 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from O, N or S, T 2 The ring is connected to the ring A1 through a ring atom on the 5-membered ring. According to some embodiments described in formula C, T 4 is selected from an optionally substituted thiazolopyridine, imidazopyridine, benzimidazole, pyrazolopyridine, oxazolopyridine, benzothiazole, indole, benzothiophene, benzothiazole, thienopyridine, thienopyrimidine or thienothiophene. Preferably, when substituted, the H on the carbon atom of the 5,5-fused or 6,5-fused heterocyclic aromatic group may be substituted by 1-3 of the following substituents: halogen, CN, G 2 、OH、NH2、OG 2 NHG 2 NG 2 G 2 、COOH、CONH2、C(O)OG 2 、C(O)NHG 2 or C(O)NG 2 G 2 , where G 2 Independently selected from optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 1-4 heteroalkyl or an optionally substituted 3-7 membered ring (preferably a 3-7 membered carbocyclic or heterocyclic ring), preferably, when substituted, the H on the carbon atom may be substituted by one or more of the following groups: oxo (if applicable), halogen, OH, CN, NH2, substituted C 1-4 Alkyl, substituted C 1-4 Heteroalkyl, or an optionally substituted 3-4 membered carbocyclic or heterocyclic ring; More preferably, G 2 Independently selected from 1-3 G S1 Substituted C 1-4 Alkyl, 1-3 G S2 Substituted C 1-4 Heteroalkyl or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 are independently selected from halogen, OH, C substituted with one or more F 1-4 Heteroalkyl or 3-4 membered carbocyclic or heterocyclic ring substituted by one or more F and / or methyl groups; G S2 independently selected from oxo (if applicable), halogen, OH, NH2, C substituted with one or more F 1-4Alkyl, one or more F-substituted C 1-4 heteroalkyl, or a 3-4 membered carbocyclic or heterocyclic ring optionally substituted by F and / or methyl.

[0366] According to some preferred embodiments described by Formula C (e.g., Formula C1), T 4 is selected from an optionally substituted 6,5-fused heterocyclic aromatic group having 1-5 ring heteroatoms, each heteroatom being independently selected from O, N or S, characterized in that one of the fused rings is selected from furan, thiophene, pyrrole, pyrazole, imidazole, oxazole, thiazole, isoxazole or isothiazole, which is fused with benzene, pyridine, pyrimidine, pyridazine or pyrazine. Preferably, T 4 The 6,5-fused heterocyclic aromatic group is connected to the ring A1 through a ring atom on the 5-membered ring. In some preferred embodiments, the 6,5-fused heterocyclic aromatic group is a thiazole fused with benzene, pyridine, pyrimidine, pyridazine or pyrazine, more preferably a pyridine-fused thiazole, which can be selected from The group may be substituted with one or more suitable substituents described herein. In some preferred embodiments, the 6,5-fused heterocyclic aromatic group is selected from imidazole-fused benzene, pyridine, pyrimidine, pyridazine or pyrazinyl, that is, the fused heterocyclic aromatic group may be selected from the group substituted with one or more suitable substituents described herein. In some embodiments, the 6,5-fused heterocyclic aromatic group is unsubstituted. In some embodiments, the H on the carbon atom of the 6,5-fused heterocyclic aromatic group may be substituted by one to three groups selected from the following: halogen, CN, G 2 、OH、NH2、OG 2 NHG 2 NG 2 G 2 、COOH、CONH2、C(O)OG 2 、C(O)NHG 2 or C(O)NG 2 G 2 , where G 2 Independently selected from optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 1-4 Heteroalkyl or an optionally substituted 3-7 membered ring (preferably a 3-7 membered carbocyclic or heterocyclic ring), preferably, the H on the carbon atom may be substituted by one or more of the following groups: oxo (if applicable), halogen, OH, CN, NH2, substituted C 1-4 Alkyl, substituted C 1-4 Heteroalkyl, or an optionally substituted 3-4 membered carbocyclic or heterocyclic ring; More preferably, G 2 Independently selected from 1-3 G S1 Substituted C 1-4Alkyl, 1-3 G S2 Substituted C 1-4 Heteroalkyl or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 are independently selected from halogen, OH, C substituted with one or more F 1-4 Heteroalkyl or 3-4 membered carbocyclic or heterocyclic ring substituted by one or more F and / or methyl groups; G S2 independently selected from oxo (if applicable), halogen, OH, NH2, C substituted with one or more F 1-4 Alkyl, one or more F-substituted C 1-4 Heteroalkyl, or a 3-4 membered carbocyclic or heterocyclic ring optionally substituted with F and / or methyl. In some embodiments, the 6,5-fused heterocyclic aromatic group is not substituted or the H on the carbon atom may be substituted with 1 to 2 groups selected from the following: halogen, CN, OH, NH2, 1-3 G S1 Substituted C 1-4 Alkyl, 1-3 G S2 Substituted C 1-4 Heteroalkyl or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 and G S2 As defined herein. In some embodiments, the 6,5-fused heterocyclic aromatic group is unsubstituted or substituted with a substituent selected from C, C-, C-, and C-substituted groups. 1-4 Alkyl or heteroalkyl which may be optionally substituted by 1-3 F atoms, for example methoxy.

[0367] In some embodiments, the 6,5-fused heterocyclic aromatic group is unsubstituted or substituted with one or two substituents selected from the following: halogen, CN, OH, NH2, C substituted with 1-3 F 1-4 Alkyl or C substituted with 1-3 F 1-4 Heteroalkyl, such as methoxy.

[0368] According to some embodiments described by Formula C (e.g., Formula C1), T 4 is an optionally substituted 6,5-fused heterocyclic aromatic group selected from the following structures: The group may be substituted with 1-3 substituents selected from the following groups: halogen, CN, G 2 、OH、NH2、OG 2 NHG 2 NG 2 G 2 、COOH、CONH2、C(O)OG2 、C(O)NHG 2 or C(O)NG 2 G 2 , where G 2 As defined in this application. It should be noted that when there is a substituent, the substituent may be attached to a carbon atom or a nitrogen atom on the ring. In some embodiments, the aforementioned 6,5-fused heterocyclic aromatic group is unsubstituted or substituted with one or two substituents selected from the following: halogen, CN, OH, NH2, 1-3 G S1 Substituted C 1-4 Alkyl, 1-3 G S2 Substituted C 1-4 Heteroalkyl or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 and G S2 As defined herein. In some embodiments, the 6,5-fused heterocyclic aromatic group is unsubstituted or substituted with a substituent selected from C, C, or C-substituted groups which may be optionally substituted with 1-3 F atoms or C atoms. 1-4 Alkyl or C optionally substituted by 1-3 F atoms 1-4 In some embodiments, the 6,5-fused heterocyclic aromatic group is unsubstituted or substituted with one or two substituents selected from the following: halogen, CN, OH, NH2, C 2 substituted with 1-3 F 1-4 Alkyl or C substituted with 1-3 F 1-4 In some more specific embodiments, according to formula C (eg, C1), T 4 is any 6,5-fused heterocyclic aromatic group selected from Examples 1-150

[0369] According to some embodiments described in Formula C, T 4 is an optionally substituted 5,6,5-fused, 6,5,5-fused or 5,6,6-fused three-membered heterocyclic aromatic group having 1 to 6 ring heteroatoms independently selected from O, N or S, wherein T 4The 5-membered ring of the fused ring is bonded to Ring A1 through a ring atom. In some embodiments, the 5-membered ring of the fused ring is independently selected from furan, thiophene, pyrrole, pyrazole, imidazole, oxazole, thiazole, isoxazole, or isothiazole, and the 6-membered ring of the fused ring is independently selected from benzene, pyridine, pyrimidine, pyridazine, or pyrazine. In some embodiments, the 5-membered ring is imidazole. In some embodiments, the 5-membered ring is pyrrole. In some embodiments, the 6-membered ring is pyridine. In some embodiments, the 5,6,5-fused, 6,5,5-fused, or 5,6,6-fused three-membered heterocyclic aromatic group has no substituents. In some embodiments, the H groups on the ring carbon atoms of the 5,6,5-fused, 6,5,5-fused, or 5,6,6-fused three-membered heterocyclic aromatic group are substituted with one or more substituents as defined herein. In some embodiments, the H on the carbon atom of the 5,6,5-fused, 6,5,5-fused or 5,6,6-fused three-membered heterocyclic aromatic ring is substituted by 1-3 groups: halogen, CN, G 2 、OH、NH2、OG 2 NHG 2 NG 2 G 2 、COOH、CONH2、C(O)OG 2 、C(O)NHG 2 or C(O)NG 2 G 2 , where G 2 Independently selected from optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 1-4 heteroalkyl or substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), preferably, when substituted, the H on the carbon atom may be substituted by one or more of the following substituents: oxo (if applicable), halogen, OH, CN, NH2, substituted C 1-4 Alkyl, substituted C 1-4 Heteroalkyl, or substituted 3-4 membered carbocyclic or heterocyclic ring; More preferably, G 2 Independently selected from 1-3 G S1 Substituted C 1-4 Alkyl, 1-3 G S2 Substituted C 1-4 Heteroalkyl, or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 independently selected from halogen, OH, C substituted by F 1-4 heteroalkyl, 3-4 membered carbocyclic or heterocyclic ring substituted by F and / or methyl; G S2 are independently selected from oxo (if applicable), halogen, OH, NH2, C substituted by F1-4 Alkyl, C substituted by F 1-4 In some embodiments, the 5,6,5-fused, 6,5,5-fused or 5,6,6-fused three-membered heterocyclic aromatic ring has no substituents or the hydrogen on the carbon atom is substituted by 1 or 2 of the following substituents: halogen, OH, NH2, 1-3 G S1 Substituted C 1-4 Alkyl, 1-3 G S2 Substituted C 1-4 Heteroalkyl or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 and G S2 As defined herein. In some embodiments, T 3 Selected from the following aromatic heterocycles: The hydrogen atoms on the aromatic heterocyclic carbon atoms may be independently substituted by substituents selected from the following groups: halogen, CN, OH, NH2, 1-3 G S1 Substituted C 1-4 Alkyl, 1-3 G S2 Substituted C 1-4 Heteroalkyl or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 and G S2 As defined herein. In some more specific embodiments, according to any embodiment of Formula C (such as Formula C1), T 4 The 5,6,5-fused heterocyclic aromatic group may be selected from the 5,6,5-fused heterocyclic aromatic groups described in Examples 1-150.

[0370] T in Formula C (e.g., Formula C1) 1 and LNK can be selected from the groups described in the present disclosure and connected to Formula B. For example, in some embodiments, LNK has The structures defined in Examples 5-25 or the structures of L as defined in this disclosure and linked to Formula (I).

[0371] In Formula C (e.g., Formula C1), Ring A1 can be selected from the structures described in the present disclosure and connected to Formula A. For example, it is characterized in that Ring A1 can be selected from substituted or unsubstituted 4-8 membered carbon monocyclic or heterocyclic rings. In some preferred embodiments, Ring A1 can be an optionally substituted C 4-7 Cycloalkylene, such as unsubstituted C 4-7 Cycloalkylene, preferably cyclohexylene, such as 1,4-trans-cyclohexylene

[0372] In some embodiments, the present disclosure provides pharmaceutical compositions comprising one or more compounds (e.g., any compound according to Formula (I), Formula A, Formula B, Formula C, or any substructure thereof, or any compound shown in the tables herein, or any compound in Examples 1-150, a deuterated analog, stereoisomer, a solvate or hydrate thereof, or a pharmaceutically acceptable salt thereof). In some embodiments, the pharmaceutical compositions comprise one or more compounds of the present disclosure, wherein the compounds have a DC50 of less than 100 nM for GSPT1 according to the methods described herein. The pharmaceutical compositions of the present invention can be formulated for any suitable route of administration, such as oral or parenteral administration.

[0373] In some embodiments, the present disclosure provides a method for inducing protein degradation (particularly GSPT1) in a cell, the method comprising contacting the cell with one or more compounds of the present disclosure (e.g., any compound according to Formula (I), Formula A, Formula B, Formula C, or substructures thereof, or any compound shown in the tables herein, or any compound of Examples 1-150, a deuterated analog, stereoisomer, a solvate or hydrate thereof, or a pharmaceutically acceptable salt thereof). In some embodiments, the cell is a cancer cell.

[0374] In some embodiments, the present disclosure provides a method for treating a GSPT1-related disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of one or more compounds of the present invention (e.g., compounds according to Formula (I), Formula A, Formula B, Formula C, or any substructure thereof, or any compound shown in the tables herein, or any compound in Examples 1-150, deuterated analogs, stereoisomers, solvates or hydrates thereof, or pharmaceutically acceptable salts thereof) or pharmaceutical compositions. Associated diseases or conditions include any of the diseases described herein. In some embodiments, one or more compounds used in the present disclosure are selected from the group consisting of those with a DC affinity for GSPT1 measured according to the methods described herein. 50 Compounds at less than 100 nM.

[0375] In some embodiments, the present disclosure provides a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of one or more compounds of the present disclosure (e.g., compounds according to Formula (I), Formula A, Formula B, Formula C, or any substructure thereof, or any compound shown in the tables herein, or any compound of Examples 1-150, a deuterated analog, stereoisomer, a solvate or hydrate thereof, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition. In some embodiments, the cancer is associated with GSPT1 activity. The type of cancer treated by the methods herein is not particularly limited and may include any of the cancer cell lines described herein, including the cancer cell lines tested herein. In some embodiments, the one or more compounds used in the present disclosure are selected from the group consisting of those with DCs for GSPT1 measured according to the methods described herein. 50 Compounds at less than 100 nM.

[0376] According to the methods of treatment described herein, one or more compounds of the invention may be formulated and administered by any suitable route of administration, such as oral or parenteral administration.

[0377] The compounds disclosed herein can be used as monotherapy or combination therapy. In some embodiments, according to the methods described herein, one or more compounds of the present invention can be administered as the sole active ingredient. In some embodiments, the methods herein further comprise administering to the subject an additional therapeutic agent, such as a drug as described herein before. When used in combination with one or more additional therapeutic agents, the compounds of the present invention or the pharmaceutical compositions herein can be administered to the subject simultaneously or concurrently with the use of such additional therapeutic agents in any order. In some embodiments, the pharmaceutical composition may comprise one or more compounds of the present invention and one or more additional monotherapy compositions. In some embodiments, a pharmaceutical composition comprising one or more compounds of the present invention may be included in a kit further comprising a separate pharmaceutical composition comprising the one or more additional pharmaceutical composition drugs.

[0378] The dosage regimens described herein, including dosages, can be varied and adjusted depending on the subject being treated, the condition, disorder or disease being treated and its severity, the composition comprising the compound, the time of administration, the route of administration, the duration of treatment, the efficacy of the compound, its rate of clearance, and whether additional drugs are co-administered.

[0379] Interpretation

[0380] Unless otherwise defined, all scientific and technical terms used in the present invention have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention relates.

[0381] In the present invention, the term "alkyl" refers to a straight or branched hydrocarbon chain radical that does not contain unsaturated bonds and is connected to the rest of the molecule by a single bond. Typical alkyl groups contain 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, etc. If the alkyl group is substituted by a cycloalkyl group, it is correspondingly a "cycloalkylalkyl" group, such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc. If the alkyl group is substituted by an aryl group, it is correspondingly an "aralkyl" group, such as benzyl, diphenylmethyl, or phenethyl. If the alkyl group is substituted by a heterocyclyl group, it is correspondingly a "heterocyclylalkyl" group. In the present invention, C0 alkyl refers to H, that is, C0-10 alkyl includes H and C1-10 alkyl.

[0382] The term "alkylene" refers to a hydrocarbon group (divalent alkyl) formed by losing two hydrogen atoms from an alkane molecule. It can be straight or branched and is connected to the rest of the molecule by a single bond. Typical alkylene groups herein have 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms, such as methylene (-CH2-), ethylene, propylene, butylene, etc. In the present invention, C0-10 alkylene refers to a single bond, i.e., C0-10 alkylene includes a single bond and C1-10 alkylene.

[0383] The term "cycloalkyl" refers to alicyclic hydrocarbons, such as those containing 1 to 4 single rings and / or condensed rings, containing 3-18 carbon atoms, preferably 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl, etc.

[0384] The term "alkoxy" refers to a substituent formed by replacing the hydrogen of a hydroxy group with an alkyl group, such as an alkoxy group containing 1 to 10 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, and the like.

[0385] The term "alkylamino" refers to a substituent formed when one or both hydrogen atoms in an amino group (-NH2) are replaced by an alkyl group, such as an alkylamino group containing 1 to 10 carbon atoms, for example

[0386] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0387] The term "haloalkyl" refers to a group in which one or more hydrogen atoms in an alkyl group are replaced by a halogen atom (e.g., fluorine, chlorine, bromine or iodine), for example, -CHF2, -CH2F, -CF3, -CH2-CF3, -CH2CH2-CF3, -CH2CH2CH2-CF3.

[0388] The term "aryl" refers to a monocyclic or polycyclic free radical, including a polycyclic free radical containing a monocyclic aromatic group and / or a condensed aromatic group, such as a radical containing 1-3 monocyclic or condensed rings and 6-18 (e.g., 6, 8, 10, 12, 14, 16, 18) carbon ring atoms. The C6-C12 aryl group mentioned in the present invention refers to an aryl group containing 6-12 carbon ring atoms, such as phenyl, naphthyl, biphenyl, indenyl, etc.

[0389] The term "heterocyclyl" refers to a 3- to 18-membered non-aromatic ring group containing 2 to 17 carbon atoms and 1 to 10 heteroatoms. A heterocyclyl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused, spirocyclic, or bridged ring systems. A heterocyclyl group can be partially saturated (heteroaryl) or fully saturated (heterocycloalkyl). Suitable heteroaryl groups in the compounds of the present invention contain 1, 2 or 3 heteroatoms selected from N, O or S atoms and include, for example, coumarin, including 8-coumarin, quinolyl, including 8-quinolyl, isoquinolyl, pyridinyl, pyrazinyl, pyrazolyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazolyl, indolyl, isoindolyl, indazolyl, indolizinyl, phthalazinyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazolyl, pyridazinyl, triazinyl, cinnolinyl, benzimidazolyl, benzofuranyl, benzofurazolyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridinyl. Suitable heterocycloalkyl groups in the compounds of the present invention contain 1, 2 or 3 heteroatoms selected from N, O or S atoms, and include, for example, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, oxathianyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxirane, thiirane, azepine, oxazepine, diazepine, 1-Hydroxy-1,1-dopamine, 1-dopamine-2,1-dopamine-3,1-dopamine-4,1-dopamine-5,1-dopamine-6,1-dopamine-7,1-dopamine-8,1-dopamine-9,1-dopamine-10,1-dopamine-11,1-dopamine-12,1-dopamine-13,1-dopamine-14,1-dopamine-15,1-dopamine-16,1-dopamine-17,1-dopamine-18,1-dopamine-19,1-dopamine-20,1-dopamine-21,1-dopamine-22,1-dopamine-23,1-dopamine-24,1-dopamine-25,1-dopamine-26,1-dopamine-27,1-dopamine-3

[0390] However, as used in conjunction with Examples 1-56 recited herein or in discussions involving Formulas A, B, C, or substructures thereof, the terms "heterocyclyl" or "heterocycle" when used by themselves or as part of another group refer to a 3-membered or larger, e.g., 3- to 14-membered, non-aromatic ring system having ring carbon atoms and at least one ring heteroatom, e.g., 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In other words, in recited Examples 1-56, the terms heterocyclyl and heteroaryl are defined separately. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence permits. The heterocyclyl group may be a single ring (monocyclic heterocyclyl) or a fused, bridged or spiro ring system, for example a bicyclic ring system (bicyclic heterocyclyl), and may be saturated or may be partially unsaturated. Bicyclic ring systems may include one or more heteroatoms in one or both rings, and the point of attachment may be on either ring. The term "heterocyclylene" as used herein, by itself or as part of another group, refers to a divalent radical derived from a heterocyclyl group as defined herein. A heterocyclyl or heterocyclylmethylene group may optionally be attached to the remainder of the molecule through a carbon or nitrogen atom.

[0391] In the present invention, "D" refers to deuterium; "substituted by deuterium" means replacing one or more hydrogen atoms with a corresponding number of deuterium atoms.

[0392] It will be appreciated that, depending on the source of the chemical materials used in the synthesis, some variation in natural isotopic abundance will exist in the synthesized compounds. Thus, the compounds of the present invention will inherently contain small amounts of deuterated isotopologues. Despite this variation, the concentrations of such naturally abundant stable hydrogen and carbon isotopes are low and insignificant compared to the degree of stable isotopic substitution in the compounds of the present invention. See, e.g., Wada, E. et al., Seikagaku, 1994, 66:15;

[0393] Gannes, LZ et al., CompBiochemPhysiolMolIntegrPhysiol, 1998, 119:725.

[0394] In the compounds of the present invention, any atom not designated as deuterium is present at its natural isotopic abundance. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen," the position is understood to have hydrogen at its natural abundance isotopic composition. Similarly, unless otherwise indicated, when a position is specifically designated as "D" or "deuterium," the position is understood to have deuterium at an abundance of at least 3000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 45% deuterium incorporation).

[0395] As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance and the natural abundance of a particular isotope.

[0396] In other embodiments, the compounds of the invention have an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0397] The term "isotopologue" refers to a substance wherein the chemical structure differs from a specific compound of the present invention only in its isotopic composition.

[0398] The term "pharmaceutically acceptable salts" includes acid addition salts and base addition salts.

[0399] The term "acid addition salt" includes, but is not limited to, salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic and phosphonic acids, and salts derived from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids and aliphatic and aromatic sulfonic acids. The present invention relates to the preparation of the present invention and the like.Therefore, these salts include but are not limited to sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, iodate, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate and mesylate, also comprise amino acid whose salt such as arginate, gluconate, galacturonate etc.Acid addition salts can be prepared by making free alkali form contact with sufficient amount of required acid in a conventional manner.Free alkali form can be regenerated by making salt form contact with alkali, and separate this free alkali in a conventional manner.

[0400] The term "base addition salt" refers to salts formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides, or with organic amines. Examples of metals used as cations include, but are not limited to, sodium, potassium, magnesium, and calcium. Examples of suitable amines include, but are not limited to, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane-1,2-diamine), N-methylglucamine, and procaine. Base addition salts can be prepared by contacting the free acid form with a sufficient amount of the desired base to form the salt in a conventional manner. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner.

[0401] The term "stereoisomer" includes the presence of enantiomers, diastereomers and geometric isomers. Some compounds of the present invention have cyclic hydrocarbon groups that may be substituted on more than one carbon atom, in which case all geometric forms, including cis and trans forms, and mixtures thereof, are within the scope of the present invention.

[0402] The term "solvate" refers to a physical association of a compound of the invention with one or more solvent molecules. This physical association includes varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Solvates include both solution-phase and isolatable solvates. Representative solvates include ethanolates, methanolates, and the like.

[0403] The term "prodrug" refers to a form of a compound of Formula I that is suitable for administration to a patient without undue toxicity, irritation, allergic reactions, etc., and is effective for its intended use, including acetal, ester, and zwitterion forms. The prodrug is transformed in vivo, for example, by hydrolysis in the blood, to yield the parent compound.

[0404] The terms "patient" or "subject" and the like are used interchangeably herein to refer to any animal or cell thereof to be treated according to the methods described herein, whether in vitro or in situ. Specifically, the aforementioned animals include mammals, e.g., rats, mice, guinea pigs, rabbits, dogs, monkeys or humans, particularly humans.

[0405] The term "treating" refers to preventing, curing, reversing, attenuating, alleviating, minimizing, inhibiting, suppressing and / or halting one or more clinical symptoms of a disease after onset of the disease.

[0406] The term "prevent" or "prevent" refers to treating a disease before it occurs to avoid, minimize, or make the onset or development of the disease more difficult.

[0407] The term "tumor" refers to an abnormal mass of tissue, wherein the growth of the mass exceeds the growth of normal tissue and is not coordinated with the growth of normal tissue. Tumors can be "benign" or "malignant", depending on the following characteristics: the degree of cell differentiation (including morphology and function), growth rate, local invasion and metastasis. "Benign tumors" are usually well differentiated, characterized in that they grow slower than malignant tumors and remain confined to the site of origin. In addition, benign tumors do not have the ability to infiltrate, invade or metastasize to distant sites. In some cases, certain "benign" tumors may later lead to malignant tumors, which may be due to additional genetic changes in a subpopulation of the tumor's neoplastic cells, and these tumors are called "precancerous tumors". "Malignant tumors" are usually poorly differentiated (anaplastic) and have a characteristic rapid growth, accompanied by progressive infiltration, invasion and destruction of surrounding tissues. In addition, malignant tumors usually have the ability to metastasize to distant sites.

[0408] The term "cancer" refers to a malignant tumor (Stedman's Medical Dictionary, 25th ed.; Hensyled.; Williams & Wilkins: Philadelphia, 1990). Exemplary cancers include, but are not limited to, adrenal cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, angiosarcoma); appendix cancer; bile duct cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., breast adenocarcinoma, breast papillary carcinoma, mammary cancer, medullary breast cancer); brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchogenic carcinoma; carcinoid tumor; cervical cancer. (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial cancer; ependymoma; endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcomas); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma); Ewing's sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); gallbladder cancer; gastric cancer (e.g., gastric adenocarcinoma); gastrointestinal stromal tumor (GIST) ; Germ cell cancer; Head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), laryngeal cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); Hematologic malignancies (e.g., leukemias such as acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); Lymphomas, such as Hodgkin's lymphoma lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodular marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenstrom's macroglobulinemia ( smacroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and T-cell NHL, such as precursor T lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); one or more leukemias / lymphomas as described above mixed; and multiple myeloma (MM)), hemangioblastoma; hypopharyngeal cancer; inflammatory myofibroblastic tumor; immune cell amyloidosis; kidney cancer (e.g., Wilms' tumor or renal cell carcinoma); liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; mesothelioma; myeloproliferative disorders (MPD) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), unexplained myeloid metaplasia (AM) myelofibrosis (MF), also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibromas (e.g., neurofibromatosis type 1 or type 2, schwannomatosis); neuroendocrine cancers (e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic cancer, intraductal papillary mucinous neoplasm (IPMN), islet cell tumor); penile cancer (e.g., Paget's disease of the penis and scrotum); isease); pinealoma; primitive neuroectodermal tumor (PNT); prostate cancer (e.g., prostate adenocarcinoma); rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcomas (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma); urethral cancer; vaginal cancer;and vulvar cancer (e.g., Paget's disease of the vulva).

[0409] In the present invention, the term "heteroalkyl" by itself or in combination with another term, unless otherwise indicated, is a stable straight or branched chain alkyl group, for example, having 2-14 carbons, such as 2-10 carbons in the chain, wherein one or more carbons are substituted with heteroatoms such as S, O, P, and N, and wherein the nitrogen, phosphorus, and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatoms S, O, P, and N may be substituted at any interior position of the heteroalkyl group or at the position where the alkyl group is attached to the molecule. When the heteroalkyl group is said to be substituted, the substituent may replace one or more hydrogen atoms attached to the carbon atoms and / or heteroatoms of the heteroalkyl group. In some embodiments, the heteroalkyl group is C 1-4 Heteroalkyl refers to a heteroalkyl group having 1 to 4 carbon atoms as defined herein. 1-4 Examples of heteroalkyl groups include, but are not limited to, C4 heteroalkyl groups such as -CH2-CH2-N(CH3)-CH3, C3 heteroalkyl groups such as -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, C2 heteroalkyl groups such as -CH2-CH2-OH, -CH2-CH2-NH2, -CH2-NH(CH3), -O-CH2-CH3 and C1 heteroalkyl groups such as -CH2-OH, -CH2-NH2, -O-CH3. Preferably, C in the present invention is 1-4 Heteroalkyl (or C 1-4 Heteroalkylene) contains 1 or 2 heteroatoms, such as one oxygen atom, one nitrogen atom, two oxygen atoms, two nitrogen atoms, or one oxygen atom and one nitrogen atom. In some preferred embodiments, unless otherwise specified or specifically constrained, any C 1-4 Heteroalkyl (or C 1-4 The heteroalkylene) chain terminal positions may contain an oxygen or a nitrogen, for example, C 1-4 Alkoxy, NH(C 1-4alkyl) or a dialkylamino group having a total of four carbon atoms. Similarly, the term "heteroalkylene" by itself or as part of another substituent refers to a divalent radical derived from a heteroalkyl group, such as, but not limited to, -CH2-CH2-O-CH2-CH2- and -O-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms may also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Furthermore, for alkylene and heteroalkylene linking groups, the orientation of the linking group is not implied by the direction in which the general formula of the linking group is written. Where "heteroalkyl" is recited, followed by a specific heteroalkyl group, such as -NR'R", it is understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, reciting the specific heteroalkyl groups provides clarity in the definition of the terms. Therefore, the term "heteroalkyl" herein should not be construed as excluding specific heteroalkyl groups, such as -NR'R", etc.

[0410] In the present invention, unless otherwise specified or excepted, "ring structure", "cyclic structure" or simply "ring", having a specified number of ring atoms, such as "3-10 membered ring structure", "3-12 membered ring structure" or "5- or 6-membered ring" shall be understood to include any ring atoms (e.g., carbocycle, heterocycle, aryl, heteroaryl, etc.) having the specified number of ring members, which can be (1) monocyclic or polycyclic (as chemically feasible), such as monocyclic or bicyclic (including fused rings, spirocyclic and bridged bicyclic rings, and ring systems in which two monocyclic rings are connected by a single bond or a double bond); (2) aromatic, partially unsaturated or fully saturated; and in the case of a polycyclic structure, each ring can independently be aromatic, partially unsaturated or fully saturated; and (3) contain no heteroatoms (i.e., all ring members are carbon atoms) or 1-4 heteroatoms; in the case of a polycyclic structure, each ring can independently have no ring heteroatoms or 1-4 ring heteroatoms (e.g., O, N, S, etc.). When the ring contains a ring sulfur or nitrogen atom, the sulfur atom or nitrogen atom may be optionally oxidized. One or more ring carbon atoms in the ring structure may be present as C(=O). A fully saturated ring is one in which none of the ring carbon atoms and the ring heteroatom (e.g., nitrogen), if present, form a double or triple bond with any other atom. The ring structure may be optionally substituted with one or more substituents as described herein. The substituents of the ring structure herein may also have a ring structure, and in some cases, two substituents of the ring structure may be described as being linked to form a ring structure.

[0411] Unless otherwise specified or contradicted by the context, a heteroatom herein refers to an atom selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon.

[0412] "Optionally substituted" groups, such as optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, refer to unsubstituted or substituted corresponding groups. Generally, the term "substituted", whether or not preceded by the term "arbitrary", refers to the presence of at least one hydrogen on a group (such as a carbon or nitrogen atom) that is replaced by a substituent that is allowed, such as a substituent that produces a stable compound when substituted, such as a compound that is not spontaneously transformed by rearrangement, cyclization, elimination or other reactions. Unless otherwise stated, a "substituted" group carries out a substituent on one or more substitutable positions of the group, and when more than one position is substituted in any given structure, the substituent can be the same or different at each position. Generally, when substituted, the optionally substituted group herein can be substituted by 1-5 substituents. The substituent can be a carbon atom substituted, a nitrogen atom substituted, an oxygen atom substituted or a sulfur atom substituted, and any of the above atoms can be isotopically labeled, such as deuterated. Two arbitrarily substituents can be connected to form a ring structure, for example arbitrarily substituted cycloalkyl, heterocyclic radical, aryl or heteroaryl ring. Replacement can occur on any available carbon, oxygen or nitrogen-atoms, and can form a spirocycle. Usually, replacement herein does not form OO, ON, SS, SN (except SO2-N key), heteroatom-halogen or-C (O)-SBOND or three or more continuous heteroatoms, except O-SO2-O, O-SO2-N and N-SO2-N, except that some such keys or connections can be allowed in stable aromatic systems.

[0413] In a broad aspect, the permissible substituents herein include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents may be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents may include any substituent described herein, for example, halogen, hydroxy, carbonyl (e.g., carboxy, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxy, cycloalkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, thiol, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aryl, or heteroaryl, each of which can be substituted as appropriate.

[0414] Exemplary substituents include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkylene-aryl, -arylene-alkyl, -alkylene-heteroaryl, -alkenylene-heteroaryl, -alkynylene-heteroaryl, -OH, hydroxyalkyl, haloalkyl, -O-alkyl, -O-haloalkyl, -alkylene-O-alkyl, -O-aryl, -O-alkylene-aryl, acyl, -C(O)-aryl, halogen, -NO2, -CN, -SF5, -C(O)OH, -C(O)O-alkyl, -C(O)O-aryl, -C(O)O-alkylene-aryl, -S(O)-alkyl , -S(O)2-alkyl, -S(O)-aryl, -S(O)2-aryl, -S(O)-heteroaryl, -S(O)2-heteroaryl, -S-alkyl, -S-aryl, -S-heteroaryl, -S-alkylene-aryl, -S-alkylene-heteroaryl, -S(O)2-alkylene-aryl, -S(O)2-alkylene-heteroaryl, cycloalkyl, heterocycloalkyl, -OC(O)-alkyl, -OC(O)-aryl, -OC(O)-cycloalkyl, -C(=N-CN)-NH2, -C(=NH)-NH2, -C(=NH)-NH(alkyl), -N(Y 1 )(Y 2 ), -alkylene-N(Y 1 )(Y 2 )、-C(O)N(Y 1 )(Y 2 ) and -S(O) 2 N(Y 1 )(Y 2 ), where Y 1 and Y 2 and -alkyl-aryl groups may be the same or different and are independently selected from hydrogen, alkyl, aryl, cycloalkyl, and -alkylene-aryl groups.

[0415] Some examples of suitable substituents include, but are not limited to, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C 10) cycloalkyl, halogen (F, Cl, BR or I), halo(C1-C8)alkyl (such as but not limited to -CF3), -O-(C1-C8)alkyl, -OH, -S-(C1-C8)alkyl, -SH, -NH(C1-C8)alkyl, -N((C1-C8)alkyl)2 group, -NH2, -C(O)NH2, -C(O)NH(C1-C8)alkyl, -C(O)N((C1-C8)alkyl)2, -NHC(O)H, -NHC(O)(C1-C8)alkyl, -NHC(O)(C3-C8)cycloalkyl, -N((C1-C8)alkyl)C(O)H, -N((C1-C8)alkyl)C(O) (C1-C8) alkyl, -NHC(O)NH2, -NHC(O)NH(C1-C8) alkyl, -N((C1-C8) alkyl)C(O)NH2 group, -NHC(O)N((C1-C8) alkyl)2 group, -N((C1-C8) alkyl)C(O)N((C1-C8) alkyl)2 group, -N((C1-C8) alkyl)C(O)NH((C1-C8) alkyl), -C(O)H, -C(O)(C1-C8) alkyl, -CN, -NO2, -S(O)(C1-C8) alkyl, -S(O)2(C1-C8) alkyl, -S(O)2N((C1-C8) alkyl)2 group, -S( -C1-C8)alkyl, -C(O)OH, -C(O)O(C1-C8)alkyl, NHOH, NHO(C1-C8)alkyl, -O-halo(C1-C8)alkyl (such as, but not limited to, -OCF3), -S(O)2-halo(C1-C8)alkyl (such as, but not limited to, -S (O)2CF3), -S-halo(C1-C8)alkyl (for example, but not limited to -SCF3), -(C1-C6)heterocycle (for example, but not limited to pyrrolidine, tetrahydrofuran, pyran or morpholine), -(C1-C6)heteroaryl (for example, but not limited to tetrazole, imidazole, furan, pyrazine or pyrazole), -phenyl, -NHC(O)O-(C1-C6)alkyl, -N((C1-C6)alkyl)C(O)O-(C1-C6)alkyl, -C(=NH)-(C1-C6)alkyl, -C(=NOH)-(C1-C6)alkyl or -C(=NO-(C1-C6)alkyl)-(C1-C6)alkyl)-(C1-C6)alkylGROUP.EXPLAQUE carbon atom substituents include, but are not limited to, deuterium, halogen, -CN, -NO2, -N3, hydroxyl, alkoxy, cycloalkoxy, aryloxy, amino, monoalkylamino, dialkylamino, amide, sulfonamide, thiol, acyl, carboxylic acid, ester, sulfone, sulfoxide, alkyl, haloalkyl, alkenyl, alkynyl, C. 3-10 Carbocyclic group, C 6-10 Aryl, 3-10 membered heterocyclic group, 5-10 membered heteroaryl, etc. For example, exemplary carbon atom substituents may include F, CL, -CN, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -NH2, -N(C 1-6 Alkyl)2, -NH(C 1-6 alkyl), -SH, -SC1-6 alkyl, -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 Alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 Alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 Alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)2, -SO2NH(C 1-6 Alkyl), -SO2NH2, -SO2C1-6 alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, C 6-10 Aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two para-substituents may be linked to form =0.

[0416] The nitrogen atoms may be substituted or unsubstituted as valence permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, acyl, ester, sulfone, sulfoxide, C1-alkyl, C 1-10 Halogenated alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, C 3-14 Heterocyclic group, C 6-14 The aryl group and the 5-14 membered heteroaryl group or the two substituents attached to the nitrogen atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group may be further substituted as defined herein. In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also known as an amino protecting group). Nitrogen protecting groups are well known in the art and include the groups described in detail in Organic Synthesis, TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, which are incorporated herein by reference. Exemplary nitrogen protecting groups include, but are not limited to, those that form carbamates, such as carbobenzyloxy (Cbz) groups, p-methoxybenzylcarbonyl (Moz or MeOZ) groups, tert-butyloxycarbonyl (BOC) groups, troc, 9-fluorenylmethoxycarbonyl (Fmoc) groups, and the like, those that form amides, such as acetyl, benzoyl, and the like, those that form benzylamines, such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, and the like, those that form sulfonamides, such as tosyl, Nosyl, and the like, and others such as p-methoxyphenyl sulfonamides.

[0417] Exemplary oxygen atom substitutions include, but are not limited to, acyl, ester, sulfonate, C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14Aryl and 5-14 yuan heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic radical, heterocyclic radical, aryl and heteroaryl can be further substituted as defined in the present invention.In some embodiments, the oxygen atom substituent present on the oxygen atom is an oxygen protecting group (also referred to as a hydroxy protecting group).Oxygen protecting groups are well known in the art, including those described in detail in Organic Synthesis, TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, which are incorporated herein by reference. Exemplary oxygen protecting groups include but are not limited to the groups forming alkyl ethers or substituted alkyl ethers, such as methyl, allyl, benzyl, substituted benzyl such as 4-methoxybenzyl, methoxymethyl (MOM), benzyloxymethyl (BOM), 2-methoxyethoxymethyl (MEM) etc., the groups forming silyl ethers, such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS) etc. Acetal- or ketal-forming groups, such as tetrahydropyranyl (THP), ester-forming groups such as formates, acetates, chloroacetates, dichloroacetates, trichloroacetates, trifluoroacetates, methoxyacetates, etc., carbonate- or sulfonate-forming groups, such as methanesulfonate (mesylate), benzylsulfonate, and toluenesulfonate (Ts), etc.

[0418] Unless explicitly stated otherwise, combinations of substituents and / or variables are permissible only if such combinations are chemically allowed and the resulting compound is stable. A "stable" compound is one that can be prepared and isolated while its structure and properties remain unchanged or remain substantially unchanged for a sufficient period of time while the compound is used for its intended purpose, e.g., therapeutic administration to a subject.

[0419] The disclosures of the various publications, patents, and published patent specifications cited herein are hereby incorporated by reference in their entireties. To the extent that any meaning or definition of a term in this document conflicts with any meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to the term in this document shall govern.

[0420] The following is a clear and complete description of the technical solutions of the present invention in conjunction with the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0421] Synthesis Example

[0422] Example 1

[0423]

[0424] Preparation steps:

[0425] Step 1:

[0426]

[0427] At room temperature, 01 (29 mg, 0.189 mmol) was dissolved in N,N-dimethylformamide (1 mL), and 02 (50 mg, 0.123 mmol), HATU (70 mg, 0.184 mmol), and N,N-diisopropylethylamine (79 mg, 0.611 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour. The reaction solution was purified by high-performance liquid chromatography to obtain a yellow-green solid (43.66 mg, yield: 70.2%). LC-MS: 507.3 [M+H] + , 1 HNMR (400MHz, DMSO-d6) δ11.10 (s, 1H), 8.30 (dd, J=34.7, 8.0Hz, 1H), 7.85 (s, 1H), 7.71 (d, J=7.7Hz, 1 H), 7.53–7.47(m, 2H), 7.41(t, J=7.6Hz, 1H), 7.29(t, J=6.2Hz, 1H), 7.03(d, J=7.1Hz, 1H), 6.94(d, J=8 .6Hz, 1H), 5.07 (dd, J=12.8, 5.4Hz, 1H), 4.60 (d, J=6.1Hz, 2H), 4.15–3.78 (m, 1H), 2.96–2.83 (m, 1H), 2 .57 (dd, J=17.7, 10.5Hz, 2H), 2.04 (d, J=5.4Hz, 2H), 1.77 (dd, J=37.4, 20.0Hz, 3H), 1.64–1.25 (m, 5H).

[0428] Example 2

[0429]

[0430] Preparation steps:

[0431] Step 1:

[0432]

[0433] To a 100 mL single-necked flask, 01 (30 mg, 0.181 mmol), 02 (73 mg, 0.181 mmol), HATU (103 mg, 0.272 mmol), N,N-diisopropylethylamine (70 mg, 0.543 mmol), and N,N-dimethylformamide (2 mL) were added. The mixture was reacted at room temperature for 16 hours. Reverse phase preparative purification afforded the desired product as a yellow solid (65.9 mg, yield: 70.2%). LC-MS: 519.1 [M+H] + 、 1 HNMR (400MHz, DMSO-d6) δ11.09 (s, 1H), 8.25 (d, J = 4.0Hz, 1H), 8.14 (d, J = 4.0Hz, 1H), 7.84 (s, 1H), 7.70 (d, J = 7.0 Hz, 1H), 7.55–7.45 (m, 2H), 7.40 (td, J=7.6, 3.0Hz, 1H), 7.27 (t, J=6.1Hz, 1H), 7.03 (d, J=7.1Hz, 1H), 6.94 (d, J=8 .6Hz, 1H), 5.07 (dd, J=12.9, 5.4Hz, 1H), 4.60 (d, J=6.1Hz, 2H), 4.14–3.99 (m, 1H), 3.79 (s, 1H), 3.23 (d, J=4.8Hz, 3H), 2.95–2.83(m, 1H), 2.64–2.54(m, 2H), 2.21–1.91(m, 3H), 1.74(s, 2H), 1.58–1.41(m, 2H), 1.35–1.15(m, 2H).

[0434] Example 3

[0435]

[0436] Preparation steps:

[0437] Step 1:

[0438]

[0439] At room temperature, 01 (71 mg, 0.175 mmol) was dissolved in N,N-dimethylformamide (2 mL), and HATU (100 mg, 0.263 mmol), N,N-diisopropylethylamine (68 mg, 0.526 mmol), and 02 (30 mg, 0.175 mmol) were added sequentially. The mixture was stirred at room temperature for 16 hours. The reaction solution was purified by high-performance liquid chromatography to obtain a yellow solid as the desired product (50.92 mg, yield: 55.5%). LC-MS: 525.19 [M+H] + 、 1HNMR (400MHz, DMSO-d6) δ11.10 (s, 1H), 8.39 (d, J = 7.9Hz, 1H), 7.85 (s, 1H), 7.71 (d, J = 7.7Hz, 1H), 7.51 (t, J=7.8Hz, 2H), 7.42 (t, J=7.6Hz, 1H), 7.30 (t, J=6.1Hz, 1H), 7.03 (d, J=7.0Hz, 1H), 6.94 (d, J=8.6Hz, 1H), 5.07(dd, J=13.0, 5.4Hz, 1H), 4.61(d, J=6.3Hz, 2H), 4.00(s, 1H), 2.95–2.84(m, 1H), 2.60-2.51(m, 2H), 2.29-2.23(m, 1H), 2.04(d, J=7.4Hz, 2H), 1.88-1.77(m, 3H), 1.41-1.25(m, 2H).

[0440] Example 4

[0441]

[0442] Preparation steps:

[0443] Step 1:

[0444]

[0445] At room temperature, 02 (30.0 mg, 0.074 mmol) was dissolved in N,N-dimethylformamide (1 mL), and 01 (13.0 mg, 0.074 mmol), HATU (42.2 mg, 0.111 mmol), and N,N-diisopropylethylamine (28.7 mg, 0.222 mmol) were added sequentially. The mixture was stirred at room temperature for 16 hours. The reaction solution was purified by high-performance liquid chromatography to obtain a yellow-green solid (22.7 mg, yield: 54.6%). LC-MS: 565.2 [M+H] + 、 1HNMR (400MHz, DMSO-d6) δ11.09 (s, 1H), 8.19 (dd, J=50.5, 7.9Hz, 1H), 7.85 (d, J=17.0Hz, 1H), 7.73 ( d, J=7.5Hz, 1H), 7.54–7.48 (m, 2H), 7.42 (dt, J=10.7, 5.3Hz, 1H), 7.32–7.25 (m, 5H), 7.18 (d, J=6.3 Hz, 1H), 7.03 (dd, J=6.9, 3.3Hz, 1H), 6.96 (dd, J=8.5, 3.4Hz, 1H), 5.07 (dd, J=12.7, 5.1Hz, 1H), 4.6 2(s, 2H), 3.85(s, 1H), 2.89(s, 1H), 2.56(s, 2H), 1.95(dd, J=50.7, 38.5Hz, 6H), 1.69–1.47(m, 4H).

[0446] Example 5

[0447]

[0448] Preparation steps:

[0449] Step 1:

[0450]

[0451] To a 100 ml single-necked flask were added 1 (200 mg, 0.724 mmol), 2 (150.5 mg, 0.87 mmol), and N-methylpyrrolidone (5 ml). The mixture was stirred thoroughly, and DIEA (468 mg, 3.62 mmol) was added. The mixture was reacted at 110°C for 18 hours, concentrated, and dried. The mixture was purified by column chromatography to give the desired product as a yellow-green solid (171 mg, 55%). LC-MS: 430 [M+H]+.

[0452] Step 2

[0453]

[0454] In a 100 ml single-necked flask, 3 (171 mg, 0.323 mmol) was dissolved in DCM (4 ml). TFA (0.8 ml) was added and the mixture was allowed to react at room temperature for 16 h. The mixture was concentrated and dried by spin drying. The desired product was purified by column chromatography to give a yellow-green solid (135 mg, 91%). LC-MS: 374 [M+H]+.

[0455] Step 3

[0456]

[0457] To a 250 ml single-necked flask, 5 (1 g, 9.25 mmol), 6 (3 g, 13.2 mmol), and methanol (100 ml) were added and stirred. AcOH (8 ml) was added and the mixture was reacted overnight at 50°C under an oxygen balloon. The mixture was concentrated and dried by spin drying. The desired product was purified by column chromatography to obtain a white solid (440 mg, 15.1%). LC-MS: 316 [M+H]+.

[0458] Step 4

[0459]

[0460] In a 100 ml single-necked flask, 7 (440 mg, 1.395 mmol) was dissolved in DCM (4 ml). TFA (0.8 ml) was added and the mixture was allowed to react at room temperature for 16 h. The mixture was concentrated and dried by spin drying. The desired product was purified by column chromatography to give a yellow-green solid (235 mg, 78.2%). LC-MS: 216 [M+H]+.

[0461] Step 5

[0462]

[0463] In a 100 ml single-necked bottle, 4 (135 mg, 0.362 mmol) and 8 (93.4 mg, 0.434 mmol) were dissolved in DMF (4 ml) and stirred evenly. HATU (206.5 mg, 0.543 mmol) and DIEA (140 mg, 1.086 mmol) were added and reacted at room temperature for 18 hours. The mixture was concentrated and dried by spin drying. The target product (17.3 mg, yield: 8.38%) was obtained by HPLC. LC-MS: 571 [M+H] + 1H NMR (400 MHz, DMSO) δ 11.11 (s, 1H), 7.81 (m, 3H), 7. 56 (m, 3H), 7.11 (d, J = 8.6Hz, 1H), 7.03 (d, J = 7.0Hz, 1H), 6.59 (s, 1H), 5.06 (dd, J = 12.9, 5.3Hz, 1H), 3.62 (m, 1H), 3.17 (t, J = 12.1 Hz, 1H), 2.89 (dd, J=15.6, 10.5Hz, 1H), 2.58 (m, 2H), 2.05 (d, J=37.6, 29.3, 15.3Hz, 8H), 1.77 (m, 2H), 1.58 (s, 4H), 1.32 (m, 3H).

[0464] Example 6

[0465]

[0466] Preparation steps:

[0467] Step 1:

[0468]

[0469] To a 500 mL single-necked flask, 01 (7 g, 28.8 mmol), 02 (3.14 g, 28.8 mmol), HATU (16.4 g, 43.1 mmol), DIEA (11.15 g, 86.3 mmol), and DMF (200 mL) were added and reacted at room temperature for 16 hours. Water (300 mL) was added, and the mixture was extracted with ethyl acetate (40 mL), washed with saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, and purified by column chromatography (dichloromethane:methanol = 10:1) to obtain the desired product as a brown solid (5 g, yield: 51.97%). LC-MS: 335.1 [M+H] +

[0470] Step 2:

[0471]

[0472] In a 100 mL single-necked round-bottom flask, 03 (5 g, 15.0 mmol) and NaOH (1.79 g, 44.8 mmol) were dissolved in ethanol (50 mL) and reacted at 80°C for 48 hours. The mixture was spin-dried, water (50 mL) was added, and the mixture was extracted with ethyl acetate (40 mL), washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, and spin-dried. Column chromatography (dichloromethane:methanol = 10:1) afforded the desired product as a pale yellow solid (1.3 g, yield: 27.48%). LC-MS: 317.1 [M+H] +

[0473] Step 3:

[0474]

[0475] In a 100 mL single-necked bottle, 04 (100 mg, 0.316 mmol) was dissolved in dichloromethane:trifluoroacetic acid (4 mL, 3:1) and stirred at room temperature for 2 h. Reverse phase chromatography yielded the desired product as a brown solid (40 mg, yield: 58.52%). LC-MS: 217.0 [M+H] +

[0476] Step 4:

[0477]

[0478] In a 100 mL single-necked flask, 05 (40 mg, 0.185 mmol), 06 (70 mg, 0.187 mmol), HATU (105 mg, 0.276 mmol), DIEA (72 mg, 0.557 mmol), and DMF (2 mL) were added and reacted at room temperature for 16 hours. Reverse phase chromatography yielded the desired product as a yellow-green solid (11.44 mg, yield: 10.82%). LC-MS: 572.3 [M+H] + , 1 HNMR (400MHz, DMSO-d6) δ12.78 (s, 1H), 11.10 (d, J = 8.8Hz, 1H), 10.84–10.81 (m, 1H), 8.90 (s, 1H), 8.29 (s, 1H) , 7.74 (dd, J=12.8, 7.9Hz, 1H), 7.65–7.51 (m, 2H), 7.10 (d, J=8.7Hz, 1H), 7.03 (d, J=7.0Hz, 1H), 6.57 (t, J=5.8H z, 1H), 5.05 (dd, J=12.8, 5.4Hz, 1H), 3.61 (d, J=4.5Hz, 1H), 3.34 (s, 2H), 2.86 (d, J=9.3Hz, 2H), 2.62–2.54 (m, 2H), 2.10 (d, J=6.9Hz, 3H), 2.02 (d, J=7.7Hz, 1H), 1.91 (d, J=9.6Hz, 3H), 1.68–1.57 (m, 6H), 1.37–1.29 (m, 2H).

[0479] Example 7

[0480]

[0481] Preparation steps:

[0482] Step 1:

[0483]

[0484] 06 (700 g, 2.53 mmol), 07 (418 mg, 3.04 mmol), and N,N-diisopropylethylamine (982 mg, 7.60 mmol) were mixed in anhydrous dimethyl sulfoxide (5 mL). The reaction mixture was stirred at 90°C for 16 hours. After cooling to 20°C, the mixture was directly passed through a reverse phase column (C18, 10-100% acetonitrile / water as the mobile phase, 0.1% formic acid) to obtain the desired product as a brown-yellow solid (600 mg, yield: 66.3%). LC-MS: 358.1 [M+H] + ; 380.1[M+Na] + .

[0485] Step 2:

[0486]

[0487] At room temperature, 08 (600 mg, 1.68 mmol) was dissolved in anhydrous dichloromethane (10 mL), and pyridinium chlorochromate (724 mg, 3.36 mmol) was added. The mixture was stirred at room temperature for 3 hours. The mixture was separated by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain the desired product as a yellow solid (400 mg, yield: 67.0%). LC-MS: 356.3 [M+H] + .

[0488] Step 3:

[0489]

[0490] At room temperature, 01 (750 mg, 6.09 mmol), 02 (1.57 g, 6.09 mmol), and N,N-diisopropylethylamine (2.36 g, 18.3 mmol) were mixed in anhydrous N,N-dimethylformamide (10 mL). (7-Azobenzotriazole)-tetramethyluronium hexafluorophosphate (3.47 g, 9.14 mmol) was added with stirring at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The mixture was separated by reverse phase column (C18, 10-100% acetonitrile / water as mobile phase, 0.1% formic acid) to obtain the desired product as a white solid (700 mg, yield: 33.4%). LC-MS: [M+H] +

[0491] Step 4:

[0492]

[0493] At room temperature, 03 (160 mg, 0.464 mmol) was dissolved in dichloromethane (2 mL), and then a solution of hydrogen chloride in dioxane (2 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. The product was dried to give a white solid as the target product (167 mg, crude product). LC-MS: 245.1 [M+H] + .

[0494] Step 5:

[0495]

[0496] At room temperature, 04 (20.0 mg, 0.071 mmol), 05 (25.2 mg, 0.071 mmol), and sodium acetate (19.3 mg, 0.142 mmol) were dissolved in dichloroethane (2 mL). After stirring at room temperature for 30 minutes, sodium acetate borohydride (45.1 mg, 0.213 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The mixture was separated by preparative chromatography (C18, 5-100% acetonitrile / water as mobile phase, 0.1% formic acid) to obtain the desired product as a green solid (7.80 mg, yield: 18.7%). LC-MS: 584.3 [M+H] + , 1 HNMR (400MHz, DMSO-d6) δ11.15 (s, 1H), 8.92 (s, 1H), 8.34–8.31 (m, 2H), 7.67–7.57 (m, 2H), 7.22– 7.14 (m, 1H), 7.11–7.06 (m, 1H), 6.65–6.53 (m, 1H), 5.11 (dd, J=12.4, 5.3Hz, 1H), 3.93–3.89 (m, 3 H), 3.47–3.44(m, 1H), 3.41–3.37(m, 1H), 3.25–3.19(m, 1H), 3.08–2.88(m, 2H), 2.68–2.59(m, 2H ), 2.53–2.43(m, 2H), 2.39–2.22(m, 2H), 2.10–1.84(m, 6H), 1.83–1.50(m, 6H), 1.22–1.11(m, 1H).

[0497] Example 8

[0498]

[0499] Preparation steps:

[0500]

[0501] To a 100 mL single-necked flask, 01 (30 mg, 0.130 mmol), 02 (49 mg, 0.131 mmol), HATU (74 mg, 0.195 mmol), DIEA (51 mg, 0.395 mmol), and DMF (1 mL) were added and allowed to react at room temperature for 1 hour. Preparative liquid chromatography yielded the desired product as a yellow-green solid (51.59 mg, yield: 67.6%). LC-MS: 586.4 [M+H] +

[0502] 1HNMR (400MHz, DMSO-d6) δ11.09 (s, 1H), 8.86 (s, 1H), 8.27 (d, J = 5.5Hz, 1H), 8.20 (s, 1H), 7.78 (d, J = 7.5Hz, 1H), 7.6 1–7.56 (m, 1H), 7.54 (d, J = 5.4Hz, 1H), 7.10 (d, J = 8.7Hz, 1H), 7.02 (d, J = 7.0Hz, 1H), 6.58 (s, 1H), 5.05 (dd, J = 12.9, 5.4Hz, 1H), 3.86 (d, J=4.1Hz, 3H), 3.60 (s, 1H), 2.98 (t, J=11.8Hz, 1H), 2.92–2.82 (m, 1H), 2.60 (dd, J=33.5, 16.9H z, 2H), 2.12 (s, 2H), 1.94 (dd, J=28.3, 11.6Hz, 6H), 1.79–1.61 (m, 3H), 1.58 (s, 4H), 1.35 (dd, J=23.7, 10.8Hz, 2H).

[0503] Example 9

[0504]

[0505] Preparation steps:

[0506] Step 1:

[0507]

[0508] In a 100 mL single-necked flask, 01 (400 mg, 3.25 mmol), 02 (664 mg, 3.08 mmol), HATU (1.85 g, 4.87 mmol), N,N-diisopropylethylamine (1.26 g, 9.75 mmol), and N,N-dimethylformamide (20 mL) were added and reacted at room temperature for 2 hours. The mixture was quenched with water (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL × 3), and dried by spin drying. Column chromatography (dichloromethane: methanol = 20:1) gave the desired product as a yellow solid (300 mg, yield: 28.8%). LC-MS: 321.2 [M+H]+

[0509] Step 2:

[0510]

[0511] In a 100 mL single-necked round-bottom flask, 03 (300 mg, 0.936 mmol) was dissolved in acetic acid (5 mL) and reacted at 70°C for 2.5 hours. The mixture was spin-dried and purified by column chromatography (dichloromethane:methanol = 10:1) to obtain the desired product as a pale yellow solid (250 mg, yield: 88.3%). LC-MS: 303.2 [M+H] +

[0512] Step 3:

[0513]

[0514] In a 50 mL single-necked bottle, 04 (150 mg, 0.496 mmol) was dissolved in dichloromethane (5 mL). 1,4-Dioxane hydrochloride (0.5 mL) was added and the reaction was stirred at room temperature for 1 h. The yellow solid obtained by spin drying the solvent was the desired product (100 mg, yield: 99.7%) and was used directly in the next step without further purification. LC-MS: 203.1 [M+H]+

[0515] Step 4:

[0516]

[0517] At room temperature, 05 (40 mg, 0.198 mmol) was dissolved in N, N-dimethylformamide (5 mL), followed by 06 (81 mg, 0.199 mmol), HATU (112 mg, 0.294 mmol), and N, N-diisopropylethylamine (77 mg, 0.596 mmol). The mixture was stirred at room temperature for 1 hour. The reaction solution was purified by high-performance liquid chromatography to obtain a yellow-green solid (65 mg, yield: 55.6%). LC-MS: 592.3 [M+H] + , 1HNMR (400MHz, DMSO-d6) δ11.11 (s, 1H), 9.43 (d, J=5.0Hz, 1H), 8.91–8.80 (m, 1H), 8.60 (dd, J=8.8, 6.6Hz, 1H), 8.21 (dd, J=31.7, 6.5Hz, 1H), 7.89 (d, J = 4.9Hz, 1H), 7.77 (d, J = 7.9Hz, 1H), 7.62–7.48 (m, 2H), 7.44 (dt, J = 11.4, 7.6Hz, 1H), 7.30 (d, J = 4.3Hz, 1H), 7.03 (dd, J=7.0, 2.5Hz, 1H), 6.95 (dd, J=8.6, 5.0Hz, 1H), 5.08 (dd, J=12.8, 5.2Hz, 1H), 4.77 (d, J=6.4Hz, 1H), 4.62 (t, J=5.8Hz, 2H), 4.04–3.97(m, 1H), 3.93(d, J=13.0Hz, 3H), 3.83–3.71(m, 1H), 2.95–2.71(m, 4H), 2.63–2.54(m, 2H), 2.06(d, J=13.5Hz, 1H).

[0518] Example 10

[0519]

[0520] Preparation steps:

[0521] Step 1:

[0522]

[0523] 01 (100 mg, 0.604 mmol) was dissolved in dimethyl sulfoxide (1 mL), and 02 (167 mg, 0.604 mmol) and N,N-diisopropylethylamine (234 mg, 1.81 mmol) were added sequentially. The reaction system was heated to 120°C under an argon atmosphere and stirred for 16 hours. The reaction solution was purified by high-performance liquid chromatography to obtain a yellow-green solid (100 mg, yield: 42.9%). LC-MS: 386.2 [M+H] +

[0524] Step 2:

[0525]

[0526] At room temperature, 03 (50 mg, 0.13 mmol) was dissolved in N, N-dimethylformamide (1 mL), followed by 04 (30 mg, 0.13 mmol), HATU (74 mg, 0.195 mmol), and N, N-diisopropylethylamine (51 mg, 0.395 mmol). The mixture was stirred at room temperature for 1 hour. The reaction solution was purified by high-performance liquid chromatography to obtain a yellow-green solid (45.90 mg, yield: 55.8%). LC-MS: 598.3 [M+H] +

[0527] 1 HNMR (400MHz, DMSO-d6) δ11.09 (s, 1H), 8.86 (s, 1H), 8.27 (d, J = 5.3Hz, 1H), 8.18 (s, 1H), 7.69–7.62 (m, 1H), 7.6 1–7.52 (m, 2H), 7.13 (t, J=8.2Hz, 1H), 7.03 (dd, J=7.0, 2.8Hz, 1H), 6.53 (d, J=25.7Hz, 1H), 5.05 (dd, J=12.7, 5.2 Hz, 1H), 3.86 (d, J=5.0Hz, 3H), 3.59 (s, 1H), 3.42–3.37 (m, 1H), 3.05–2.81 (m, 3H), 2.62–2.53 (m, 2H), 2.25–2.11 (m, 2H), 2.01 (dd, J=23.0, 9.7Hz, 4H), 1.89 (s, 4H), 1.71 (dt, J=24.7, 9.7Hz, 3H), 1.36 (dd, J=25.8, 14.0Hz, 2H).

[0528] Example 11

[0529]

[0530] Preparation steps:

[0531] Step 1:

[0532]

[0533] In a 100 mL single-necked bottle, 01 (200 mg, 0.56 mmol) was dissolved in dioxane (5 mL), and 02 (165 mg, 0.56 mmol), potassium carbonate (232 mg, 1.68 mmol), Pd(dppf)Cl2 (41 mg, 0.056 mmol) and water (1.2 mL) were added. The mixture was stirred at 100 ° C for 16 hours under nitrogen protection. Cooled to room temperature, quenched with water (10 mL), extracted with ethyl acetate (15 mL × 2), and the organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and dried to obtain a crude product. The crude product was purified by Pre-TLC (PE: EA = 20: 1) to obtain a white solid product (160 mg, yield: 64%).

[0534] LC-MS: 469.1[M+Na] + 、391.0[M-56+H] +

[0535] Step 2:

[0536]

[0537] In a 100 mL single-necked flask, 03 (120 mg, 0.27 mmol) was dissolved in methanol (5 mL). 10% palladium on carbon (10 mg) and ammonium formate (339 mg, 5.38 mmol) were added. The mixture was stirred at 25°C for 16 hours. Filtered, dried, and purified by pre-TLC (DCM:MeOH = 12:1) to obtain the product as a white solid (50 mg, yield: 59.5%).

[0538] LC-MS: 315.3 [M+H] +

[0539] Step 3:

[0540]

[0541] At room temperature, 04 (50 mg, 0.16 mmol) was dissolved in pyridine (2 mL), and 05 (65 mg, 0.16 mmol) and EDCI (92 mg, 0.48 mmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated and purified by Pre-TLC (DCM:MeOH = 30:1) to obtain the desired product as a yellow solid (20 mg, yield: 17.9%). LC-MS: 726.3 [M+Na] +

[0542] Step 4:

[0543]

[0544] At room temperature, 06 (20 mg, 0.028 mmol) was dissolved in DCM (3 mL), TFA (0.5 mL) was added, and the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated and purified by HPLC to give a yellow solid product (2.06 mg, yield: 12.2%). LC-MS: 604.1 [M+H] + , 1 HNMR (400MHz, DMSO-d6) δ11.11 (s, 1H), 10.89-10.86 (m, 1H), 8.30 (d, J = 7.5Hz, 1H), 8.11 (s, 1H), 7.86 (d, J = 16.9 Hz, 1H), 7.73 (dd, J=16.1, 7.4Hz, 1H), 7.51 (dd, J=17.8, 9.6Hz, 3H), 7.42 (dd, J=17.8, 7.2Hz, 2H), 7.34–7.25 (m, 2 H), 6.99-6.92(m, 4H), 6.24(s, 1H), 6.14(s, 1H), 5.08(dd, J=12.8, 5.9Hz, 1H), 4.67-4.57(m, 3H), 4.03-3.96(m, 2H), 3.85(s, 3H), 2.68(s, 1H), 2.54(s, 3H), 2.10(d, J=12.1Hz, 2H), 1.99(s, 1H), 1.71(s, 1H), 1.63–1.50(m, 2H).

[0545] Example 12

[0546]

[0547] Preparation steps:

[0548] Step 1:

[0549]

[0550] At room temperature, 01 (300 mg, 0.840 mmol) was dissolved in dioxane (10 mL) and water (2 mL). 2-Bromo-1-benzofuran (166 mg, 0.840 mmol), potassium carbonate (348 mg, 2.52 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (61.5 mg, 0.084 mmol) were added sequentially. The mixture was stirred at 90°C under an argon atmosphere for 16 hours. The mixture was then dried by spin drying, water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) and preparative plate chromatography (petroleum ether:ethyl acetate = 8:1) to obtain the desired product as a white solid (77 mg, yield: 26.4%). LC-MS: 348.2 [M+H] + .

[0551] Step 2:

[0552]

[0553] At room temperature, 03 (77 mg, 0.222 mmol) was dissolved in tetrahydrofuran (3 mL), and then palladium hydroxide / carbon (20% palladium, 20 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. Filter and spin dry to obtain a brown oil as the desired product (48 mg, crude product). LC-MS: 216.1 [M+H] +

[0554] Step 3:

[0555]

[0556] At room temperature, 05 (90.8 mg, 0.223 mmol), 04 (48 mg, 0.223 mmol), and N,N-diisopropylethylamine (86.5 mg, 0.669 mmol) were mixed in anhydrous N,N-dimethylformamide (1 mL). (7-Azobenzotriazole)-tetramethyluronium hexafluorophosphate (127 mg, 0.335 mmol) was added with stirring at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The mixture was separated by preparative chromatography (C18, 5-100% acetonitrile / water as the mobile phase, 0.1% formic acid) to obtain the desired product as a yellow solid (31.12 mg, yield: 23.1%). LC-MS: 605.3 [M+H] + . 1HNMR (400MHz, DMSO-d6) δ11.13–10.96(m, 1H), 8.35–8.12(m, 1H), 7.89–7.82(m, 1H), 7.77–7.67( m, 1H), 7.61–7.35 (m, 5H), 7.33–7.25 (m, 1H), 7.24–7.15 (m, 2H), 7.12–6.98 (m, 1H), 6.98–6.85 (m, 1H), 6.70–6.56(m, 1H), 5.12–5.03(m, 1H), 4.77–4.56(m, 2H), 3.90–3.79(m, 1H), 2.96–2.72(m, 2H ), 2.64–2.51(m, 2H), 2.19–2.09(m, 2H), 2.07–1.80(m, 3H), 1.75–1.63(m, 1H), 1.63–1.46(m, 3H).

[0557] Example 13

[0558]

[0559] Preparation steps:

[0560] Step 1:

[0561]

[0562] The raw materials 01 (200 mg, 0.56 mmol), 02 (144 mg, 0.73 mmol), and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (41 mg, 0.06 mmol) were dissolved in 1,4-dioxane (4 mL), and a solution of potassium carbonate (194 mg, 1.4 mmol) in water (1 mL) was added. The reaction mixture was stirred at 90°C under argon for 3 hours. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The mixture was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and dried. The residue was separated by silica gel column (petroleum ether:ethyl acetate = 100:0 to 80:20) and reverse column (C18, water:acetonitrile = 100:0 to 35:65, 0.1% formic acid) to obtain the desired product as a white solid (50 mg, yield: 26.0%). LC-MS: 348.2[M+H] + .

[0563] Step 2:

[0564]

[0565] At room temperature, 03 (50 mg, 0.14 mmol) was dissolved in tetrahydrofuran (3 mL), wet palladium on carbon (25 mg) was added, and the hydrogen atmosphere was replaced twice. The mixture was stirred under a hydrogen balloon at room temperature for 16 hours. The mixture was filtered and the filtrate was dried to obtain a white solid, which was the desired product (13 mg, yield: 44.0%). LC-MS: 216.1 [M+H] + .

[0566] Step 3:

[0567]

[0568] At room temperature, 04 (13 mg, 0.06 mmol), 05 (25 mg, 0.06 mmol), and N,N-diisopropylethylamine (24 mg, 0.18 mmol) were dissolved in N,N-dimethylformamide (0.5 mL). (7-Azobenzotriazole)-tetramethyluronium hexafluorophosphate (28 g, 0.07 mmol) was added with stirring at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The mixture was separated by preparative chromatography (C18, 5-100% acetonitrile / water as mobile phase, 0.1% formic acid) to obtain the desired product as a yellow solid (9.65 mg, yield: 26.6%). LC-MS: 605.3 [M+H] + . 1 HNMR (400MHz, DMSO-d6) δ11.04 (s, 1H), 8.23 ​​(dd, J=64.4, 7.6Hz, 1H), 7.85 (d, J=16.9Hz, 1H), 7.72 (dd, J=18.5 ,7.6Hz,1H),7.58–7.45(m,4H),7.44–7.35(m,1H),7.32–7.25(m,1H),7.24–7.16(m,2H),7.02(t,J=7.7Hz,1H) , 6.94 (t, 1H), 6.63 (d, J = 41.4Hz, 1H), 5.07 (dt, J = 11.1, 5.4Hz, 1H), 4.60 (dd, J = 12.8, 6.0Hz, 2H), 3.91 (d, J = 5 8.3Hz, 1H), 2.96–2.84 (m, 1H), 2.81–2.55 (m, 2H), 2.15 (d, J=9.4Hz, 2H), 2.08–1.78 (m, 4H), 1.74–1.46 (m, 4H).

[0569] Example 14

[0570]

[0571] Preparation steps:

[0572] Step 1:

[0573]

[0574] In a 50 mL single-necked flask, 01 (431 mg, 1.23 mmol), 02 (300 mg, 1.23 mmol), Pd(dppf)Cl2 (90 mg, 0.12 mmol), K2CO3 (509 mg, 3.69 mmol), 1,4-dioxane (4 mL), and water (1 mL) were added. The mixture was reacted at 100°C under a nitrogen atmosphere for 16 hours. After cooling to room temperature, the mixture was quenched with water (10 mL), extracted with ethyl acetate (40 mL × 3), washed with saturated brine (20 mL × 3), and dried to give a crude product. Pre-TLC (petroleum ether:ethyl acetate = 1:1) revealed the desired product as a yellow solid (173 mg, yield: 57.7%). LC-MS: 348.1 [M+H] +

[0575] Step 2:

[0576]

[0577] In a 100 mL single-necked round-bottom flask, 03 (173 mg, 0.50 mmol) and formic acid (2 mL) were dissolved in methanol (3 mL) and palladium on carbon (10 mg) was added. The mixture was reacted at room temperature under a hydrogen atmosphere for 16 hours. Filtered and dried to obtain a crude product, which was analyzed by pre-TLC (dichloromethane:methanol = 5:1) to obtain a white solid as the desired product (86 mg, yield: 41.3%). LC-MS: 216.1 [M+H] +

[0578] Step 3:

[0579]

[0580] In a 100 mL single-necked bottle, 04 (80 mg, 0.37 mmol) was dissolved in pyridine (2 mL), and 05 (151 mg, 0.37 mmol) and EDCI (212 mg, 1.11 mmol) were added. The mixture was stirred at room temperature for 16 hours.

[0581] The mixture was subjected to reverse phase purification to obtain a yellow solid as the target product 1 (1.04 mg, yield: 1.3%). LC-MS: 605.1 [M+H] + , 1HNMR (400MHz, DMSO-d6) δ12.61 (s, 1H), 11.10 (s, 1H), 8.31 (d, J = 8.0Hz, 1H), 7.88 (s, 1H), 7.83 (d, J =7.8Hz, 1H), 7.75 (d, J = 8.0Hz, 1H), 7.51 (d, J = 7.5Hz, 2H), 7.44 (t, J = 8.2Hz, 2H), 7.30 (s, 2H), 7.04 ( d, J=7.1Hz, 2H), 6.97 (d, J=9.0Hz, 1H), 5.08 (d, J=8.1Hz, 1H), 4.62 (d, J=5.5Hz, 2H), 3.91 (s, 1H), 3 .02(s, 1H), 2.89(s, 1H), 2.67(s, 1H), 2.06-1.98(m, 6H), 1.79(d, J=13.0Hz, 2H), 1.66–1.53(m, 3H).

[0582] Example 15

[0583] The mixture obtained in step 3 of Example 14 was subjected to reverse phase reaction to obtain a yellow solid as the target product 2 (2.20 mg, yield: 2.8%). LC-MS: 605.1 [M+H] +

[0584] 1 HNMR (400MHz, DMSO-d6) δ12.62 (s, 1H), 11.09 (s, 1H), 8.20 (d, J = 6.8Hz, 1H), 7.86 (s, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.73 (d, J=7.4Hz, 1H), 7.53–7.44 (m, 3H), 7.39 (t, J=7.6Hz, 1H), 7.32–7.26 (m, 2H), 7.04 (dd, J= 17.5, 7.2Hz, 2H), 6.95 (d, J=8.7Hz, 1H), 5.07 (dd, J=12.7, 5.2Hz, 1H), 4.60 (d, J=5.8Hz, 2H), 4.02 (s, 1H ), 2.87 (d, J = 13.3Hz, 1H), 2.61 (s, 2H), 2.24 (s, 2H), 2.06 (s, 1H), 1.88 (s, 4H), 1.71 (s, 2H), 1.24 (s, 1H).

[0585] Example 16

[0586]

[0587] Preparation steps:

[0588] Step 1:

[0589]

[0590] In a 50 mL single-necked flask, 01 (227 mg, 0.64 mmol), 02 (100 mg, 0.64 mmol), Pd(dppf)Cl2 (45.4 mg, 0.06 mmol), K2CO3 (263 mg, 1.90 mmol), 1,4-dioxane (2 mL), and water (1 mL) were added. The mixture was reacted at 100°C under nitrogen for 16 hours. After cooling to room temperature, the mixture was quenched with water (10 mL), extracted with ethyl acetate (40 mL × 3), washed with saturated brine (20 mL × 3), and dried by spin drying. Pre-TLC (petroleum ether:ethyl acetate = 5:1) revealed the desired product as a yellow solid (116 mg, yield: 51.1%). LC-MS: 349.0 [M+H] +

[0591] Step 2:

[0592]

[0593] In a 100 mL single-necked round-bottom flask, 03 (116 mg, 0.33 mmol) was dissolved in tetrahydrofuran (3 mL). A mixture of palladium hydroxide on carbon (10 mg) was added and reacted at room temperature under a hydrogen atmosphere for 16 hours. The mixture was filtered and dried to give the crude product. Pre-TLC (petroleum ether:ethyl acetate = 3:1) revealed the desired product as a white solid (48 mg, yield: 41.3%). LC-MS: 217.2 [M+H] +

[0594] Step 3:

[0595]

[0596] In a 100 mL single-necked bottle, 04 (48 mg, 0.14 mmol) was dissolved in N,N-dimethylformamide (2 mL), and HATU (126 mg, 0.21 mmol), DIEA (85 mg, 0.42 mmol) and 05 (48 mg, 0.14 mmol) were added. The mixture was stirred at room temperature for 16 hours.

[0597] The mixture was subjected to reverse phase purification to obtain a yellow solid as the target product 1 (5.25 mg, yield: 11.0%). LC-MS: 606.0 [M+H] + , 1HNMR (400MHz, CD3OD) δ7.86 (s, 1H), 7.72 (d, J=7.7Hz, 1H), 7.67–7.62 (m, 1H), 7.60–7.54 (m, 2H), 7.51–7.41 (m, 2H), 7.39–7.33 (m, 2H), 7.06 (d, J=7.1Hz, 1H), 6.94 (d, J=8.5Hz, 1H), 5.0 8(dd, J=12.4, 5.5Hz, 1H), 4.63(s, 2H), 3.98(s, 1H), 3.01(s, 1H), 2.90–2.81(m, 1H), 2.80–2 .69 (m, 2H), 2.31 (d, J=12.2Hz, 2H), 2.19-2.09 (m, 3H), 1.90-1.75 (m, 2H), 1.59-1.50 (m, 2H).

[0598] Example 17

[0599] The mixture obtained in step 3 of Example 16 was subjected to reverse phase reaction to obtain a yellow solid as the target product 2 (2.16 mg, yield: 4.5%). LC-MS: 606.1 [M+H] +

[0600] 1 HNMR (400MHz, CD3OD) δ7.81 (s, 1H), 7.66 (dd, J=11.3, 5.5Hz, 2H), 7.60–7.56 (m, 1H), 7.52 (d, J=7.9Hz, 1H), 7.45 (d, J=7.9Hz, 1H), 7.43–7.39 (m, 1H), 7.37–7.33 (m, 2H), 7.03 (d, J=7.1Hz, 1H), 6.92 (d, J=8.5H z, 1H), 5.07–5.02 (m, 1H), 4.59 (s, 2H), 4.56 (s, 2H), 4.07 (d, J=4.6Hz, 1H), 2.83 (dd, J=18.2, 4.8Hz, 1H) , 2.75-2.60(m, 2H), 2.40(d, J=9.5Hz, 2H), 2.03(dd, J=9.1, 4.9Hz, 3H), 1.89(s, 2H), 1.83–1.73(m, 2H).

[0601] Example 18

[0602]

[0603] Preparation steps:

[0604] Step 1:

[0605]

[0606] In a 100 mL single-necked flask, 01 (150 mg, 0.42 mmol), 02 (64 mg, 0.42 mmol), potassium carbonate (173 mg, 1.26 mmol), Pd(dtbpf)Cl2 (27 mg, 0.028 mmol), dioxane (4 mL), and water (1 mL) were added. The mixture was stirred at 100°C under nitrogen for 16 h. The mixture was cooled to room temperature and dried to give a crude product. The crude product was purified by Pre-TLC (PE:EA = 1:3) to afford the desired product as a brown solid (65 mg, yield: 44.4%). LC-MS: 349.0 [M+H] +

[0607] Step 2:

[0608]

[0609] In a 100 mL single-necked flask, 03 (55 mg, 0.16 mmol) was dissolved in methanol (3 mL). Trifluoroacetic acid (1 mL) and palladium on carbon (10 mg) were added and stirred under a hydrogen atmosphere for 16 hours. The mixture was filtered and dried to obtain a yellow oil as the desired product, which was used directly in the next step (36 mg, yield: 100%). LC-MS: 217.2 [M+H] +

[0610] Step 3:

[0611]

[0612] At room temperature, 04 (36 mg, 0.166 mmol) was dissolved in pyridine (1 mL), and 05 (67 mg, 0.166 mmol) and EDCI (96 mg, 0.499 mmol) were added. The mixture was stirred at room temperature for 16 hours and concentrated to obtain a crude product. The crude product was purified by HPLC to obtain the desired product as a yellow solid (4.93 mg, yield: 4.9%). LC-MS: 606.1 [M+H] + , 1HNMR (400MHz, DMSO-d6) δ12.79 (s, 1H), 12.44 (s, 1H), 11.10 (s, 1H), 8.34–8.08 (m, 2H), 7.88 (s, 1H), 7.84 (s, 1H), 7.72 (dd, J=14. 8, 7.7Hz, 1H), 7.54–7.42 (m, 2H), 7.38 (dd, J=15.4, 7.6Hz, 1H), 7.28 (dd, J=12.5, 6.4Hz, 1H), 7.16 (s, 1H), 7.02 (dd, J=9.6, 7.1Hz , 1H), 6.94 (dd, J=11.9, 8.7Hz, 1H), 5.07 (dd, J=12.8, 5.5Hz, 1H), 4.60 (dd, J=16.3, 6.3Hz, 2H), 4.05–3.81 (m, 1H), 3.13 (s, 1H), 2 .87(d, J=12.4Hz, 1H), 2.69–2.55(m, 2H), 2.33(s, 1H), 2.12(s, 1H), 2.03(d, J=7.1Hz, 2H), 1.86(s, 1H), 1.71(s, 3H), 1.54(s, 1H).

[0613] Example 19

[0614]

[0615] Preparation steps:

[0616] Step 1:

[0617]

[0618] At room temperature, 01 (1 g, 4.11 mmol) was dissolved in N,N-dimethylformamide (10 mL), and HATU (3.12 g, 8.22 mmol) was added. After the mixture was stirred at room temperature for 30 minutes, 02 (444 mg, 4.11 mmol) and DIEA (1.59 g, 12.33 mmol) were added. The reaction solution was stirred at room temperature for 16 hours, diluted with 50 mL of water, extracted with ethyl acetate (50 mL × 3), washed with saturated brine (50 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography (dichloromethane: methanol = 15:1) to obtain a yellow-white solid (140 mg, yield: 10.2%). LC-MS: 333.4 [M+H] +

[0619] Step 2:

[0620]

[0621] At room temperature, 03 (80 mg, 0.24 mmol) was dissolved in acetic acid (5 mL), and the mixture was heated to 80°C and stirred for 3 hours under nitrogen. After cooling to room temperature, the reaction solution was diluted with 10 mL of water, extracted with ethyl acetate (10 mL × 3), and washed with saturated brine (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a yellow-brown solid (140 mg, crude product). LC-MS: 315.4 [M+H] +

[0622] Step 3:

[0623]

[0624] In a 50 mL single-necked flask, 04 (100 mg, 0.32 mmol), dichloromethane (6 mL) and trifluoroacetic acid (3 mL) were added. The mixture was stirred at room temperature for 1 hour under nitrogen protection and dried to obtain a yellow-brown solid (75 mg, crude product).

[0625] Step 4:

[0626]

[0627] At room temperature, in a 50 mL single-necked flask, 05 (75 mg, 0.35 mmol) was dissolved in N, N-dimethylformamide (2 mL), and N, N-diisopropylethylamine (136 mg, 1.05 mmol) was added, and the reaction was stirred at room temperature for 30 minutes. At the same time, another 50 mL single-necked flask was used to dissolve 06 (143 mg, 0.35 mmol) in N, N-dimethylformamide (2 mL), and HATU (266 mg, 0.70 mmol) was added, and the reaction was stirred at room temperature for 30 minutes. The two mixed solutions were mixed and reacted at room temperature for 16 hours. The reaction solution was prepared to obtain a white solid as the product (22.03 mg, yield: 10.4%). LC-MS: 605.6 [M+H] +, 1HNMR (400MHz, DMSO-d6) δ11.11 (s, 1H), 8.59–8.55 (m, 2H), 8.27 (s, 1H), 8.05 (s, 1H), 7.63 (dd, J=5.8, 3.2Hz, 2H) , 7.57 (d, J = 4.8Hz, 1H), 7.46 (dd, J = 15.1, 7.3Hz, 2H), 7.33 (dd, J = 5.8, 3.1Hz, 2H), 7.05 (d, J = 7.0Hz, 1H), 6.86 (d , J=8.5Hz, 1H), 5.09 (dd, J=12.6, 5.2Hz, 1H), 4.71 (d, J=6.3Hz, 2H), 3.90 (d, J=8.3Hz, 2H), 2.64–2.54 (m, 3H), 2. 18 (d, J=11.8Hz, 2H), 2.08 (d, J=11.1Hz, 1H), 2.00 (d, J=10.5Hz, 2H), 1.83–1.74 (m, 2H), 1.66 (d, J=12.0Hz, 2H).

[0628] Example 20

[0629]

[0630] Preparation steps:

[0631] Step 1:

[0632]

[0633] At room temperature, 01 (500 mg, 2.54 mmol), 2-(trimethylsilyl)ethoxymethyl chloride (0.4 mL), and cesium carbonate (820 mg, 2.54 mmol) were dissolved in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at room temperature for 16 hours. Water (100 mL) was added, and extraction with ethyl acetate (100 mL × 3) was performed. The mixture was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and dried to obtain the desired product as a yellow solid (360 mg, yield: 43.4%). LC-MS: 328.1 [M+H] + .

[0634] Step 2:

[0635]

[0636] At room temperature, 02 (360 mg, 1.10 mmol), 03 (323 mg, 1.65 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (161 mg, 0.22 mmol), and potassium carbonate (303 mg, 2.20 mmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL). The reaction mixture was stirred at 90°C for 16 hours. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The mixture was washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and dried to obtain a yellow solid as the desired product (260 mg, yield: 53.3%). LC-MS: 445.2 [M+H] + .

[0637] Step 3:

[0638]

[0639] At room temperature, 03 (240 mg, 0.54 mmol) was dissolved in tetrahydrofuran (5 mL), wet palladium on carbon (100 mg) was added, and the hydrogen atmosphere was replaced twice. The reaction was stirred under a hydrogen balloon at room temperature for 16 hours. The filtrate was filtered and dried to give the desired product as a yellow solid (100 mg, crude product). LC-MS: 447.2 [M+H]+.

[0640] Step 4:

[0641]

[0642] At room temperature, 05 (80 mg, 0.18 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 6 hours. The solvent was removed by swirl to obtain the desired product (80 mg, crude) as a yellow oil. LC-MS: 217.2 [M+H] + .

[0643] Step 5:

[0644]

[0645] At room temperature, 05 (70 mg, 0.32 mmol), 06 (146 mg, 0.38 mmol), N,N-diisopropylethylamine (82 mg, 0.64 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (243 mg, 0.64 mmol) were dissolved in N,N-dimethylformamide (2 mL). The reaction mixture was stirred at room temperature for 16 hours. The desired product (29.87 mg, 15.3% yield) was isolated as a yellow solid by preparative chromatography (C18, 5-100% acetonitrile / water as the mobile phase, 0.1% formic acid). LC-MS: 606.2 [M+H] + . 1 HNMR (400MHz, DMSO) δ11.28–10.88 (m, 1H), 9.76–9.33 (m, 1H), 8.80–8.43 (m, 1H), 8 .36–8.14(m, 1H), 7.97–7.63(m, 3H), 7.57–7.36(m, 3H), 7.34–7.23(m, 1H), 7.07–6. 90 (m, 2H), 5.14–4.99 (m, 1H), 4.71–4.53 (m, 2H), 3.30–3.29 (m, 1H), 2.96–2.82 (m, 3 H), 2.56 (d, J=8.6Hz, 1H), 2.28–1.97 (m, 5H), 1.93–1.79 (m, 3H), 1.68–1.54 (m, 1H).

[0646] Example 21

[0647]

[0648] Preparation steps:

[0649] Step 1:

[0650]

[0651] In a 100 mL single-necked flask, 01 (200 mg, 0.771 mmol) was dissolved in acetic acid (2 mL), stirred, and heated to 70°C. After the reaction system was dissolved, dichloromethane (5 mL) and 02 (232 mg, 1.54 mmol) were slowly added and reacted at room temperature for 0.5 hours. Sodium acetate borohydride (490 mg, 2.31 mmol) was added and the reaction was continued with stirring at room temperature for 16 hours. Water (15 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (dichloromethane: methanol = 10:1) gave the target product as a yellow solid (35 mg, yield: 11.5%).

[0652] LC-MS: 394.3 [M+H] +

[0653] Step 2:

[0654]

[0655] At room temperature, 03 (35 mg, 0.0890 mmol) was dissolved in N,N-dimethylformamide (0.5 mL), and HATU (51 mg, 0.133 mmol), N,N-diisopropylethylamine (34 mg, 0.267 mmol), and 04 (24 mg, 0.0890 mmol) were added sequentially. The mixture was stirred at room temperature for 2 hours. The reaction solution was purified by preparative high-performance liquid chromatography (HPLC) to obtain the desired product as a white solid (8.34 mg, yield: 15.5%).

[0656] LC-MS: 606.2[M+H] + ,

[0657] 1 HNMR (400MHz, DMSO-d6) δ11.01 (s, 1H), 8.87 (s, 1H), 8.35–8.20 (m, 2H), 7.89 (s, 1H), 7.72 (d, J=7.2Hz, 1H), 7.54 ( dd, J=12.4, 6.5Hz, 2H), 7.40 (t, J=7.9Hz, 1H), 7.21 (t, J=7.8Hz, 1H), 6.94 (d, J=7.2Hz, 1H), 6.65 (d, J=8.2Hz, 1H), 6.41 (d, J=5.9Hz, 1H), 5.22–4.97 (m, 1H), 4.44 (s, 2H), 4.27 (dd, J=44.7, 17.1Hz, 2H), 3.88 (d, J=7.6Hz, 3H), 3.02 –2.78 (m, 2H), 2.63 (d, J=15.1Hz, 1H), 2.38–2.26 (m, 1H), 2.15–1.89 (m, 6H), 1.81–1.69 (m, 2H), 1.65–1.47 (m, 2H).

[0658] Example 22:

[0659]

[0660] Preparation steps:

[0661] Step 1:

[0662]

[0663] In a 50 mL single-necked flask, 01 (500 mg, 1.40 mmol), 02 (215 mg, 1.40 mmol), Pd(dppf)Cl2 (102 mg, 0.14 mmol), K2CO3 (580 mg, 4.20 mmol), 1,4-dioxane (8 ml), and water (2 mL) were added. The mixture was reacted at 100°C under a nitrogen atmosphere for 16 hours. After cooling to room temperature, the mixture was quenched with water (20 mL), extracted with ethyl acetate (20 mL × 3), washed with saturated brine (20 mL × 3), and dried by spin drying. Pre-TLC (petroleum ether:ethyl acetate = 5:1) revealed the desired product as a yellow solid (227 mg, yield: 45.4%). LC-MS: 349.1 [M+H] +

[0664] Step 2:

[0665]

[0666] In a 100 mL single-necked round-bottom flask, 03 (227 mg, 0.65 mmol) and palladium hydroxide / carbon (10 mg) were placed in tetrahydrofuran (3 mL) and reacted at room temperature under a hydrogen atmosphere for 16 hours. The crude product was filtered and dried to dryness. Pre-TLC (petroleum ether:ethyl acetate = 3:1) revealed a white solid as the desired product (192 mg, yield: 84.6%). LC-MS: 217.1 [M+H] +

[0667] Step 3:

[0668]

[0669] In a 100 mL single-necked flask, 04 (90 mg, 0.42 mmol) was dissolved in N,N-dimethylformamide (4 mL). HATU (236 mg, 0.63 mmol), DIEA (161 mg, 1.26 mmol), and 05 (169 mg, 0.42 mmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was subjected to reverse phase purification to obtain a yellow solid as the desired product (38.81 mg, yield: 43.1%). LC-MS: 607.1 [M+H] +, 1HNMR (400MHz, DMSO-d6) δ11.12 (s, 1H), 8.58 (t, J = 6.0Hz, 2H), 8.03 (d, J = 12.8Hz, 1H), 7.76–7.62 ( m, 2H), 7.52 (dt, J=13.5, 5.0Hz, 3H), 7.35 (dd, J=6.5, 2.9Hz, 2H), 7.05 (d, J=7.0Hz, 1H), 6.86 (t, J=8 .9Hz, 1H), 5.10 (dd, J=12.8, 5.3Hz, 1H), 4.70 (t, J=7.4Hz, 2H), 3.86 (dd, J=1.5, 7.8Hz, 1H), 3.02–2. 82 (m,, 2H), 2.22 (d, J=13.1Hz, 2H), 2.08 (d, J=4.9Hz, 1H), 1.95 (d, J=12.0Hz, 2H), 1.78–1.58 (m, 4H).

[0670] Example 23:

[0671]

[0672] Preparation steps:

[0673] Step 1:

[0674]

[0675] In a 100 mL single-necked flask, 01 (400 mg, 1.64 mmol) was dissolved in N,N-dimethylformamide (5 mL). 02 (179 mg, 1.64 mmol), HATU (938 g, 2.47 mmol), and N,N-diisopropylethylamine (637 g, 4.93 mmol) were added and reacted at room temperature for 16 hours. The mixture was quenched with water (15 mL), extracted with ethyl acetate (20 mL × 3), washed with saturated brine (20 mL × 3), and dried. 03 (500 mg, yield: 90.9%), was purified by column chromatography (dichloromethane:methanol = 20:1) to obtain a brown solid.

[0676] LC-MS: 335.1[M+H] +

[0677] Step 2:

[0678]

[0679] In a 100 mL single-necked bottle, 03 (200 mg, 0.598 mmol) was dissolved in acetic acid (2 mL) and reacted at 80°C for 2.5 hours. The reaction mixture was adjusted to pH 8-9 with saturated sodium bicarbonate solution, extracted with ethyl acetate (20 mL x 3), washed with saturated brine (20 mL x 3), dried, and concentrated to afford 04 (170 mg, yield: 89.84%) as a yellow solid.

[0680] LC-MS: 317.4[M+H] +

[0681] Step 3:

[0682]

[0683] In a 50 mL single-necked bottle, 04 (170 mg, 0.537 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was reacted at room temperature for 2 hours. The mixture was then spin-dried to obtain crude 05 (130 mg, crude product, yellow solid).

[0684] LC-MS: 217.4[M+H] +

[0685] Step 4:

[0686]

[0687] At room temperature, 06 (40 mg, 0.0980 mmol) was dissolved in N,N-dimethylformamide (1 mL). Crude 05 (21 mg, 0.0980 mmol), HATU (56 mg, 0.147 mmol), and N,N-diisopropylethylamine (38 mg, 0.294 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour. The reaction solution was purified by HPLC (formic acid) to obtain the desired product (10.04 mg, 16.9% yield, as a yellow solid).

[0688] LC-MS: 607.3[M+H] + ,

[0689] 1HNMR (400MHz, DMSO-d6) δ12.85 (s, 1H), 11.11 (s, 1H), 8.91 (s, 1H), 8.62–8.52 (m, 2H), 8.30 (s , 1H), 8.04 (s, 1H), 7.64–7.54 (m, 2H), 7.49 (dd, J=16.0, 8.1Hz, 2H), 7.05 (d, J=7.1Hz, 1H), 6. 87 (d, J=8.5Hz, 1H), 5.09 (dd, J=12.8, 5.4Hz, 1H), 4.71 (d, J=6.3Hz, 2H), 3.94–3.80 (m, 1H), 2 .97–2.84(m, 2H), 2.65–2.53(m, 2H), 2.18–2.04(m, 3H), 2.00–1.91(m, 2H), 1.81–1.56(m, 4H).

[0690] Example 24

[0691]

[0692] Example 25

[0693]

[0694] Preparation steps:

[0695] Step 1:

[0696]

[0697] In a 25 mL single-necked flask, 01 (40 mg, 0.26 mmol), HATU (200 mg, 0.52 mmol), and DMF (2 mL) were added, followed by 02 (70 mg, 0.26 mmol) and DIEA (102 mg, 0.78 mmol). The mixture was stirred at room temperature for 16 h. After the reaction was complete, the product was purified by reverse phase purification (acetonitrile / water = 50%) to obtain a white solid as the target product (180 mg, yield: 70.1%).

[0698] LC-MS: 366.3 [M+H] +

[0699] Step 2:

[0700]

[0701] In a 50 mL single-necked bottle, 03 (150 mg, 0.4 mmol) was dissolved in methanol (5 mL). Manganese dioxide (715 mg, 8.2 mmol) was added. The mixture was reacted at room temperature for 16 h under nitrogen protection. The mixture was filtered and dried to give a yellow solid as the desired product (156 mg, yield: 97.9%). LC-MS: 364.1 [M+H] +

[0702] Step 3:

[0703]

[0704] In a 50 mL single-necked flask, 05 (105 mg, 0.4 mmol) dissolved in N,N-dimethylformamide / acetic acid (6 mL / 4.8 mL) was added, followed by 04 (147 mg, 0.4 mmol). Sodium triacetoxyborohydride (257.5 mg, 1.2 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 16 h. The reaction mixture was filtered, and HPLC analysis revealed the desired product as a yellow solid (12.76 mg, yield: 4.9%). LC-MS: 607.1 [M+H] + , 1 HNMR (400MHz, DMSO-d6) δ11.02 (s, 1H), 9.32 (s, 1H), 8.59-8.53 (m, 3H), 8.07 (s, 2H), 7.60 (s, 1H), 7.20 (s, 1H), 6.96 (s, 1H), 6.57 (s, 2H) , 5.15(s, 1H), 4.55(s, 2H), 4.33-4.26(m, 2H), 4.00(s, 3H), 2.94(s, 1H), 2.66(s, 2H), 2.33(s, 1H), 2.11–1.90(m, 6H), 1.81-1.69(m, 4H).

[0705] Example 26

[0706]

[0707] Preparation steps:

[0708] Step 1:

[0709]

[0710] To a 250 mL three-necked flask, 01 (5 g, 36.46 mmol), THF (50 ml), and DMAP (445 mg, 3.65 mmol) were added. Di-tert-butyl dicarbonate (11.9 g, 54.69 mmol) was added under an ice bath and allowed to react at room temperature for 12 hours. The mixture was quenched with water (50 mL), extracted with ethyl acetate (50 mL × 2), washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and spin-dried. The mixture was purified by column chromatography (ethyl acetate:petroleum ether = 1:2) to obtain a yellow oily liquid (4.37 g, yield: 62.1%). LC-MS: 194.1 [M+H] +

[0711] Step 2:

[0712]

[0713] To a 100 mL single-necked flask, add 02 (500 mg, 2.59 mmol), NBS (460 mg, 2.59 mmol), AIBN (85 mg, 0.5174 mmol), and carbon tetrachloride (5 mL). The mixture was reacted at 90°C under argon for 3 hours. The mixture was cooled to room temperature and quenched with water (10 mL). The mixture was extracted with dichloromethane (10 mL x 2), washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, and spin-dried. The mixture was purified by column chromatography (ethyl acetate:petroleum ether = 1:2) to afford a brown oily liquid (386 mg, yield: 54.9%). LC-MS: 274.0 [M+H] +

[0714] Step 3:

[0715]

[0716] To a 50 mL single-necked flask, 03 (104 mg, 0.384 mmol), 04 (100 mg, 0.384 mmol), potassium bicarbonate (115 mg, 1.152 mmol), and DMF (5 mL) were added and reacted at 30°C for 12 hours. The mixture was quenched with water (10 mL), extracted with ethyl acetate (10 mL × 2), washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, and spin-dried. A brown solid (69 mg, yield: 39.8%) was obtained by column chromatography (methanol:dichloromethane = 1:10). LC-MS: 452.4 [M+H] +

[0717] Step 4:

[0718]

[0719] Add 05 (30 mg, 0.066 mmol), TFA (2 mL), and DCM (2 mL) to a 50 mL single-necked bottle, react at room temperature for 2 hours, and spin dry to obtain a brown oily liquid (69 mg, crude product). LC-MS: 396.3 [M+H] +

[0720] Step 5:

[0721]

[0722] In a 50 mL single-necked bottle, 06 (30 mg, 0.066 mmol), 08 (15 mg, 0.0683 mmol), HATU (43.34 mg, 0.114 mmol), DIEA (29.46 mg, 0.228 mmol), and DMF (2 ml) were added. The mixture was allowed to react at room temperature for 12 hours. The reaction solution was purified by high-performance liquid chromatography to obtain a white solid (1.37 mg, yield: 3%). LC-MS: 608.3 [M+H] + 1HNMR (400MHz, DMSO-d6) δ11.00 (s, 1H), 9.05 (s, 0.62H), 8.68–8.64 (m, 2H), 8.37 (s, 0.51H), 8.14(s, 1H), 7.72–7.71(m, 2H), 7.50(t, J=4.9Hz, 1H), 7.37(d, J=3.8Hz, 1H), 7.29(d, J=3.8H z, 1H), 7.20–7.07 (m, 1H), 5.46 (s, 2H), 5.14 (dd, J=12.9, 5.3Hz, 1H), 4.51 (d, J=17.6Hz, 1H), 4.35 (d, J=17.0Hz, 1H), 3.94 (s, 4H), 3.07–2.90 (m, 2H), 2.08–1.99 (m, 4H), 1.81–1.67 (m, 4H).

[0723] Example 27

[0724]

[0725] Example 28

[0726]

[0727] Preparation steps:

[0728] Step 1:

[0729]

[0730] At room temperature, 01 (3 g, 11.67 mmol), 02 (2.24 g, 17.51 ​​mmol), 1-ethyl-3-(3-dimethylpropylamino)carbodiimide (2.89 g, 15.18 mmol), and 4-dimethylaminopyridine (1.85 g, 15.18 mmol) were dissolved in N,N-dimethylformamide (15 mL). The reaction mixture was stirred at room temperature for 2 hours. Water (20 mL) was added to precipitate a solid, which was filtered and slurried with anhydrous ether to obtain the desired product as a white solid (1.3 g, yield: 30.4%). LC-MS: 312.1 [M+H-56] + .

[0731] Step 2:

[0732]

[0733] At room temperature, 03 (1.3 g, 3.54 mmol) was dissolved in tetrahydrofuran (10 mL), and Lawes' reagent (2.15 g, 5.31 mmol) was added. The reaction mixture was stirred at 60°C under argon for 16 hours. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The mixture was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and dried. The residue was purified on a silica gel column (petroleum ether:ethyl acetate = 100:0 to 70:30) to obtain the desired product as a white solid (850 mg, yield: 69.2%). LC-MS: 348.1 [M+H] + .

[0734] Step 3:

[0735]

[0736] At room temperature, 04 (400 mg, 1.15 mmol) was dissolved in dichloromethane (4 mL), and then 1,4-dioxane hydrochloride (4 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was dried to give a white solid as the desired product (325 mg, yield: 99.5%). LC-MS: 248.1 [M+H] + .

[0737] Step 4:

[0738]

[0739] At room temperature, 05 (250 mg, 1.01 mmol), 06 (140 mg, 1.01 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (76 mg, 0.13 mmol), bis(dibenzylideneacetonepalladium) (29 mg, 0.05 mmol), and cesium carbonate (657 mg, 2.02 mmol) were dissolved in anhydrous 1,4-dioxane (5 mL). The reaction mixture was stirred at 80°C under argon for 3 hours. The reaction mixture was dried by rotary evaporation, and the residue was separated by reverse column chromatography (C18, water:acetonitrile = 100:0-40:60, 0.1% formic acid) to obtain the desired product as a white solid (50 mg, yield: 14.2%). LC-MS: 350.1 [M+H] + .

[0740] Step 5:

[0741]

[0742] At room temperature, 07 (50 mg, 0.14 mmol) was dissolved in tetrahydrofuran (2 mL). Raney nickel (20 mg) and a drop of aqueous ammonia were added at room temperature. The hydrogen atmosphere was replaced twice, and the mixture was stirred under a hydrogen balloon at room temperature for 6 hours. The mixture was filtered and dried to obtain a colorless viscous liquid as the desired product (50 mg, yield: 99.1%). LC-MS: 354.1 [M+H] + .

[0743] Step 6:

[0744]

[0745] At room temperature, 08 (50 mg, 0.14 mmol), 09 (39 mg, 0.14 mmol), and N,N-diisopropylethylamine (54 mg, 0.42 mmol) were dissolved in dimethyl sulfoxide (1 mL). The reaction mixture was stirred at 110°C for 16 hours. After cooling to 20°C, the mixture was separated by preparative chromatography (C18, 5-100% acetonitrile / water as the mobile phase, 0.1% formic acid) to afford the desired product as a yellow solid (2.89 mg, yield: 3.39%). LC-MS: [M+H] + 610.4.

[0746] 1HNMR (400MHz, DMSO-d6) δ11.10 (s, 1H), 8.56 (s, 1H), 8.31 (d, J = 7.7Hz, 1H), 7.88 (d, J = 4.9Hz, 1H), 7.59–7.48 (m, 2H), 7.27–7.17(m, 1H), 7.04(d, J=7.1Hz, 1H), 6.85(d, J=8.4Hz, 1H), 6.63–6.53(m, 1H), 6.45–6.36(m, 2H), 5.08( dd, J=12.7, 5.1Hz, 1H), 4.43 (d, J=5.8Hz, 2H), 3.13–3.08 (m, 3H), 2.94–2.84 (m, 1H), 2.59 (d, J=20.9Hz, 2H), 2.1 7 (d, J=11.0Hz, 2H), 2.09–2.00 (m, 1H), 1.89 (d, J=11.1Hz, 2H), 1.60–1.48 (m, 3H), 1.12 (dd, J=24.4, 12.0Hz, 2H).

[0747] Example 29:

[0748]

[0749] Preparation steps:

[0750]

[0751] In a 100 mL single-necked flask, 10 (200 mg, 0.41 mmol), trifluoroacetic acid (3 mL), and dichloromethane (10 mL) were added and allowed to react at room temperature for 16 hours. Concentration afforded a crude yellow oil (150 mg). Ammonia (2 mL) and dioxane (10 mL) were then added and the mixture was allowed to react at 70°C for 16 hours. The product was concentrated, dried, and purified by Prep-HPLC (ACN-H2O, TFA) to afford the desired product as a yellow oil (53 mg, 51.21%). LC-MS: 256 [M+H] +

[0752] Step 2:

[0753]

[0754] In a 100 ml single-necked flask, 3 (500 mg, 1.81 mmol), 4 (376 mg, 2.17 mmol), and N-methylpyrrolidone (5 mL) were added and stirred. DIEA (468 mg, 3.62 mmol) was added and the mixture was reacted at 110°C for 18 hours. The mixture was concentrated and dried by rotary evaporation. The desired product (341 mg, 43.91%) was purified by column chromatography to obtain a yellow-green solid. LC-MS: 430 [M+H] +

[0755] Step 3:

[0756]

[0757] In a 100 mL single-necked bottle, 5 (341 mg, 0.79 mmol) was dissolved in DCM (10 mL). TFA (1 mL) was added and the mixture was reacted at room temperature for 16 hours. The mixture was concentrated and dried by spin drying. Purification by column chromatography gave a yellow-green solid as the desired product (210 mg, 71.07%). LC-MS: 374 [M+H] +

[0758] Step 4:

[0759]

[0760] Compound 6 (75 mg, 0.2 mmol), compound 2 (53 mg, 0.20 mmol), HATU (114 mg, 0.3 mmol), and DIEA (77.4 mg, 0.6 mmol) were added to a flask containing dichloromethane and stirred overnight at room temperature. After rotary evaporation of the solvent, the crude product was purified by Prep-HPLC to obtain the product as a yellow solid (15 mg, 12.29%). LC-MS: 611 [M+H] + , 1NMR (400MHz, DMSO) δ11.61 (s, 1H), 11.08 (s, 1H), 8.42 (s, 1H), 7.75 (d, J=7.7Hz, 1H), 7.60–7.52 (m, 1H), 7.34 (s, 1H), 7.07 (d, J=8.6Hz, 1H), 6.99 (d, J=7.0Hz, 1H), 6.58–6.50 (m, 2H), 5.02 (dd, J=1 2.9, 5.3Hz, 1H), 3.65–3.53 (m, 1H), 2.90–2.79 (m, 2H), 2.55 (d, J=16.8Hz, 2H), 2.08 (s, 4H), 2.02– 1.97 (m, 1H), 1.89 (d, J=10.4Hz, 2H), 1.74–1.62 (m, 2H), 1.58 (d, J=28.0Hz, 5H), 1.38–1.19 (m, 3H).

[0761] Example 30:

[0762]

[0763] Preparation steps:

[0764] Step 1:

[0765]

[0766] At room temperature, 01 (20.0 mg, 0.074 mmol), 02 (37.7 mg, 0.074 mmol), and N,N-diisopropylethylamine (38.3 mg, 0.296 mmol) were mixed in anhydrous N,N-dimethylformamide (1 mL). (7-Azobenzotriazole)-tetramethyluronium hexafluorophosphate (42.2 mg, 0.111 mmol) was added portionwise with stirring at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The mixture was separated by preparative chromatography (C18, 5-100% acetonitrile / water as the mobile phase, 0.1% formic acid) to obtain the desired product as a white solid (10.4 mg, yield: 22.9%). LC-MS: 611.4 [M+H] + , 1 HNMR (400MHz, DMSO-d6) δ10.99 (s, 1H), 8.67 (d, J = 5.0Hz, 1H), 8.62 (d, J = 8.5Hz, 1H), 8.58 (dd, J = 4.6, 1.4Hz, 1H), 8.35 (dd, J = 8.2 , 1.5Hz, 1H), 8.13 (s, 1H), 7.71 (d, J=5.0Hz, 1H), 7.56 (dd, J=8.2, 4.7Hz, 1H), 7.50 (t, J=7.8Hz, 1H), 7.36 (d, J=7.4Hz, 1H), 7.28(d , J=8.1Hz, 1H), 5.46 (s, 2H), 5.14 (dd, J=13.3, 5.1Hz, 1H), 4.51 (d, J=17.5Hz, 1H), 4.35 (d, J=17.4Hz, 1H), 3.97–3.87 (m, 1H), 3.1 8–3.09(m, 1H), 2.98–2.87(m, 1H), 2.64–2.56(m, 1H), 2.46–2.41(m, 1H), 2.28–2.20(m, 2H), 2.05–1.96(m, 3H), 1.81–1.63(m, 4H).

[0767] Example 31

[0768]

[0769] Preparation steps:

[0770] Step 1:

[0771]

[0772] 1 (2.00 g, 7.24 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL), and lithium aluminum hydride (1.37 g, 36.2 mmol) was added in batches with stirring at room temperature. The reaction mixture was stirred at 60 ° C for 16 hours. Water (1.5 mL), 10% sodium hydroxide aqueous solution (1.5 mL), and water (5 mL) were slowly added at 0 ° C. Filter, wash the filter cake three times with tetrahydrofuran (20 mL), and the filtrate was dried. The residue was purified by rapid silica gel column (petroleum ether: ethyl acetate = 0-50%) to obtain a light yellow solid as the target product (1.20 g, yield: 66.8%). LC-MS: 249.4 [M+H] +

[0773] Step 2:

[0774]

[0775] 2 (150 mg, 0.60 mmol), 3 (86 mg, 0.72 mmol), and triphenylphosphine (314 mg, 1.20 mmol) were dissolved in anhydrous tetrahydrofuran (15 mL). Diisopropyl azodicarboxylate (242 mg, 1.20 mmol) was added with stirring at 0°C. The reaction mixture was stirred at 0°C for 16 hours. The product was then dried and purified by reverse-phase column chromatography (C18, 10-100% acetonitrile / water as the mobile phase, 0.1% formic acid) to afford the desired product as a white solid (130 mg, yield: 61.9%). LC-MS: 351.2 [M+H]+.

[0776] Step 3:

[0777]

[0778] At room temperature, 4 (130 mg, 0.369 mmol) was dissolved in tetrahydrofuran (10 mL). Raney nickel (100 mg) was added at room temperature, and the reaction mixture was stirred under a hydrogen balloon for 6 hours. Filtered and dried to give the desired product (80 mg, crude) as a colorless viscous liquid. LC-MS: 355.3 [M+H]+.

[0779] Step 4:

[0780]

[0781] At room temperature, 5 (80 mg, 0.22 mmol), 6 (63 mg, 0.22 mmol), and N,N-diisopropylethylamine (38 mg, 0.44 mmol) were dissolved in dimethyl sulfoxide (2 mL). The reaction mixture was stirred at 120°C for 2 hours. After cooling to room temperature, the mixture was purified by preparative chromatography (C18, 5-100% acetonitrile / water as the mobile phase, 0.1% formic acid) to afford the desired product (10.08 mg, 7.2% yield) as a yellow solid. LC-MS: 611.4[M+H]+, 1HNMR (400MHz, DMSO) δ11.10 (s, 1H), 8.57 (dd, J=4.6, 1.4Hz, 1H), 8.37 (d, J=5.7Hz, 1H), 8.33 (dd, J=8.2, 1.4Hz, 1H), 7.60–7.53 (m, 2H), 7.45 (t, J=5.7Hz, 1H), 7.06 (d, J=7.0Hz, 1H), 7.02 (d, J=8.6Hz, 1H), 6.98 (d, J=2.1Hz, 1H), 6.92 (dd, J=5.8, 2. 4Hz, 1H), 5.08 (dd, J=12.8, 5.3Hz, 1H), 4.57 (d, J=5.7Hz, 2H), 3.93 (d, J=6.3Hz, 2H), 3.13 (tt, J=12.0, 3.3Hz, 1H), 2.94–2.84 (m, 1H), 2.62–2.53(m,2H), 2.25–2.17(m,2H), 2.08–2.00(m,1H), 2.00–1.92(m,2H), 1.90–1.81(m,1H), 1.69–1.58(m,2H), 1.33–1.22(m,2H).

[0782] Example 32

[0783]

[0784] Preparation steps:

[0785] Step 1:

[0786]

[0787] In a 250 mL single-necked flask, 01 (3 g, 25.64 mmol) was dissolved in DCM (30 mL). Di-tert-butyl dicarbonate (6 g, 25.64 mmol) and DMAP (600 mg, 4.92 mmol) were added. The mixture was reacted at room temperature under nitrogen for 16 hours. The mixture was quenched with water (20 mL), extracted with DCM (50 mL × 3), washed with saturated brine (20 mL × 3), and dried by spin drying. Column chromatography (ethyl acetate / petroleum ether = 1:10) afforded the desired product as a yellow solid (4.5 g, yield: 80.9%). LC-MS: 218.1 [M+H] +

[0788] Step 2:

[0789]

[0790] In a 500mL three-necked round-bottom flask, 02 (4.5g, 20.74mmol) was dissolved in tetrahydrofuran (45mL). LDA (2mol / L, 11.7mL) was slowly added dropwise at -75°C. After reacting at -75°C for 30 minutes, cyanogen bromide (8.1g, 78.59mmol) was added and the temperature was slowly warmed to room temperature for 16 hours. The mixture was quenched with water (20mL), extracted with ethyl acetate (40mL), washed with saturated brine (20mL x 3), and dried by spin drying. The product was purified by column chromatography (ethyl acetate / petroleum ether = 1:10) to obtain a yellow solid (2.6g, yield: 58%). LC-MS: 296.0 / 298.0 [M+H] +

[0791] Step 3:

[0792]

[0793] In a 100 mL single-necked bottle, 03 (2.6 g, 8.81 mmol) was dissolved in MeOH (13 mL) and H2O (13 mL), and NaOH (1.67 g, 17.62 mmol) was added. The mixture was stirred at 90°C for 2 hours. After cooling to room temperature, the mixture was quenched with water (20 mL), extracted with ethyl acetate (40 mL), washed with saturated brine (20 mL × 3), and dried. The product was purified by column chromatography (ethyl acetate / petroleum ether = 1:5) to obtain a yellow solid product (1.1 g, yield: 42.3%). LC-MS: 196.0 / 198.0 [M+H] +

[0794] Step 4:

[0795]

[0796] In a 250 mL single-necked bottle, 04 (1.1 g, 5.67 mmol) was dissolved in acetonitrile (11 mL), CH3I (8.8 mL) and Cs2CO3 (5.5 g, 16.88 mmol) were added, and the mixture was stirred at 100°C for 16 hours. After cooling to room temperature, the mixture was quenched with water (20 mL), extracted with ethyl acetate (40 mL), washed with saturated brine (20 mL × 3), and dried. The product was purified by column chromatography (ethyl acetate / petroleum ether = 1:6) to obtain a yellow solid product (301 mg, yield: 27.3%). LC-MS: 210.0 / 212.0 [M+H] +

[0797] Step 5:

[0798]

[0799] To a 50 mL single-necked flask were added 05 (301 mg, 1.44 mmol), 06 (513 mg, 1.44 mmol), Pd(dppf)Cl2 (108 mg, 0.14 mmol), K2CO3 (602 mg, 4.32 mmol), 1,4-dioxane (8 mL), and water (2 mL). The mixture was reacted at 100°C under a nitrogen atmosphere for 16 hours. After cooling to room temperature, the mixture was quenched with water (20 mL), extracted with ethyl acetate (40 mL), washed with saturated brine (20 mL × 3), and dried by spin drying. The product was purified by column chromatography (ethyl acetate / petroleum ether = 1:6) to obtain a yellow solid (158 mg, yield: 52.5%). LC-MS: 361.2 [M+H] +

[0800] Step 6:

[0801]

[0802] In a 50 mL round-bottom flask, 07 (158 mg, 0.44 mmol) was dissolved in methanol (3 mL). 10% palladium on carbon (10 mg) and ammonium formate (50 mg) were added, and the mixture was reacted at room temperature for 16 hours. The mixture was filtered, dried, and analyzed by pre-TLC (petroleum ether:ethyl acetate = 3:1) to obtain the desired product as a white solid (50 mg, yield: 32%). LC-MS: 229.1 [M+H] +

[0803] Step 7:

[0804]

[0805] In a 50 mL single-necked bottle, 08 (45.6 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (2 mL). HATU (114 mg, 0.3 mmol), DIEA (77 mg, 0.6 mmol), and 09 (81.4 mg, 0.20 mmol) were added. The mixture was stirred at room temperature for 16 hours. Example 32 (2.30 mg, 1.9% yield) was obtained as a yellow solid by reversed-phase liquid chromatography. LC-MS: 618.2 [M+H] + 1 HNMR (400MHz, DMSO-d6) δ11.09 (s, 1H), 8.30-8.15 (m, 1H), 7.86 (d, J=12.5Hz, 1H), 7.73 (s, 1H), 7. 50 (s, 2H), 7.44 (s, 2H), 7.37 (d, J = 8.6Hz, 1H), 7.29 (s, 1H), 7.05 (d, J = 7.9Hz, 2H), 6.96 (d, J = 7.7H z, 2H), 6.28-6.25 (m, 1H), 5.06 (s, 1H), 4.62 (s, 2H), 3.70 (d, J=4.9Hz, 3H), 2.88 (s, 2H), 2.65 (d, J =19.4Hz, 2H), 2.33(s, 1H), 2.06(s, 2H), 1.90(s, 2H), 1.85–1.74(m, 2H), 1.57(s, 2H), 1.24(s, 1H)

[0806] Example 33:

[0807]

[0808] Preparation steps:

[0809] Step 1:

[0810]

[0811] 2-Bromo-1H-benzimidazole (500 mg, 2.54 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL), and 60% sodium hydroxide (183 mg, 4.57 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 15 minutes, followed by the addition of iodomethane (378 mg, 2.67 mmol), and the mixture was stirred at room temperature for 16 hours. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The mixture was purified by reverse-phase column chromatography (C18, 5%-100% acetonitrile / water as mobile phase, 0.1% formic acid) to obtain the desired product as a white solid (250 mg, yield: 46.7%). LC-MS: 211.0, 213.0 [M+H] +

[0812] Step 2:

[0813]

[0814] 02 (150 mg, 0.710 mmol), 03 (304 mg, 0.850 mmol), potassium carbonate (294 mg, 2.13 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (52.0 mg, 0.071 mmol) were mixed in dioxane (5 mL) and water (1 mL). After argon was replaced, the mixture was stirred at 90°C under argon protection for 16 hours. After cooling the mixture to room temperature, the solvent was removed under reduced pressure, water (20 mL) was added, and the mixture was extracted with ethyl acetate (10 mL×2), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and dried. The residue was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the desired product as a white solid (139 mg, yield: 54.1%). LC-MS: 362.1 [M+H] +

[0815] Step 3:

[0816]

[0817] Dissolve 04 (139 mg, 0.385 mmol) in tetrahydrofuran (3 mL), then add 20% palladium hydroxide / carbon (40 mg, 0.285) and stir at room temperature for 16 h. Filter and spin dry to obtain the desired product as a brown oil (75.0 mg, yield: 85.0%). LC-MS: 230.2 [M+H] +

[0818] Step 4:

[0819]

[0820] At room temperature, 05 (75.0 mg, 0.327 mmol), 06 (133 mg, 0.327 mmol), and N,N-diisopropylethylamine (127 mg, 0.981 mmol) were mixed in anhydrous N,N-dimethylformamide (2 mL). (7-Azobenzotriazole)-tetramethyluronium hexafluorophosphate (149 mg, 0.392 mmol) was added portionwise with stirring at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The mixture was separated by preparative chromatography (C18, 5-100% acetonitrile / water as the mobile phase, 0.1% formic acid) to obtain the desired product as a yellow solid (73.7 mg, yield: 36.4%). LC-MS: 619.2 [M+H] + .

[0821] Example 34:

[0822]

[0823] Preparation steps:

[0824] Step 1:

[0825]

[0826] 3-Bromo-4-nitropyridine-N-oxide (5.00 g, 22.8 mmol) was dissolved in tetrahydrofuran (150 mL) at room temperature. A 30% methylamine alcohol solution (3.54 g, 114 mmol) was added with stirring at room temperature. The reaction mixture was stirred at 60°C for 2 hours. The solvent was removed from the mixture under reduced pressure. The crude product was purified by flash silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain the desired product as an orange-red solid (3.22 g, yield: 83.4%). LC-MS: 170.0 [M+H] + ;211.0[M+H+41] + .

[0827] Step 2:

[0828]

[0829] 02 (3.22 g, 19.0 mmol) was dissolved in tetrahydrofuran (150 mL) at room temperature. Raney nickel (1 g) was added, and the hydrogen atmosphere was replaced twice. The reaction mixture was stirred under a hydrogen balloon at room temperature for 16 hours. The mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain a brown-black solid as the desired product (2.18 g, yield: 93%). LC-MS: 124.1 [M+H] + .

[0830] Step 3:

[0831]

[0832] 03 (500 mg, 4.06 mmol), trans-4-(Boc-amino)cyclohexanecarboxylic acid (938 mg, 3.86 mmol), and N,N-diisopropylethylamine (1.57 g, 12.2 mmol) were dissolved in anhydrous N,N-dimethylformamide (10 mL). (7-Azobenzotriazole)-tetramethyluronium hexafluorophosphate (2.32 g, 6.09 mmol) was added portionwise with stirring at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The mixture was purified by reverse phase column (C18, 5-100% acetonitrile / water as mobile phase, 0.1% trifluoroacetic acid) to obtain the desired product (1.20 g, yield: 84.8%) as a yellow oil (Note: The unring-closed product was completely ring-closed during the concentration of the components purified by reverse phase column). LC-MS: 331.3 [M+H]+ ; 372.2[M+H+41] + ; 275.2[M+H-56] + .

[0833] Step 4:

[0834]

[0835] Dissolve 04 (564 mg, 1.71 mmol) in anhydrous dichloromethane (2.5 mL) and add 4M hydrogen chloride solution in dioxane (2 mL) dropwise with stirring at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The mixture was dried to give an off-white solid as the desired product (400 mg, yield: 87.8%). LC-MS: 231.1 [M+H] + ; 272.1[M+H+41] + .

[0836] Step 5:

[0837]

[0838] 05 (32.8 mg, 0.123 mmol), 06 (50 mg, 0.123 mmol), and N,N-diisopropylethylamine (79.5 mg, 0.615 mmol) were dissolved in anhydrous N,N-dimethylformamide (2 mL). (7-Azobenzotriazole)-tetramethyluronium hexafluorophosphate (56.3 mg, 0.148 mmol) was added portionwise with stirring at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The mixture was separated by reverse phase liquid chromatography (C18, 5-100% acetonitrile / water as mobile phase, 0.1% formic acid) to obtain the desired product as a yellow solid (27 mg, yield: 35.5%). LC-MS: 620.4 [M+H] + . 1HNMR (400MHz, DMSO-d6) δ11.11 (s, 1H), 9.36 (s, 1H), 8.54 (d, J = 6.4Hz, 1H), 8.35 (d, J = 7.7Hz, 1H), 8.10 (d, J = 6.1Hz, 1H), 7.86 (s, 1H), 7.74 (d, J=7.8Hz, 1H), 7.55–7.48 (m, 2H), 7.43 (t, J=7.6Hz, 1H), 7.30 (t, J=6.3Hz, 1H), 7.04 (d, J=7 .0Hz, 1H), 6.96 (d, J=8.7Hz, 1H), 5.08 (dd, J=12.8, 5.4Hz, 1H), 4.62 (d, J=6.1Hz, 2H), 4.02 (s, 3H), 3.92–3.83 (m, 1H ), 3.19–3.14(m, 1H), 2.94–2.84(m, 1H), 2.64–2.54(m, 2H), 2.13–1.97(m, 5H), 1.84–1.72(m, 2H), 1.64–1.53(m, 2H).

[0839] Example 35:

[0840]

[0841] Preparation steps:

[0842] Step 1:

[0843]

[0844] To a 100 mL single-necked flask, 01 (200 mg, 1.64 mmol), 02 (400 mg, 1.64 mmol), HATU (810 mg, 2.13 mmol), DIEA (634 mg, 4.9 mmol), and DMF (10 mL) were added and allowed to react at room temperature for 2 hours. The mixture was quenched with water (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL × 3), and dried by spin drying. Column chromatography (dichloromethane:methanol = 20:1) afforded the desired product as a white solid (500 mg, yield: 88%). LC-MS: 348.2 [M+H] +

[0845] Step 2:

[0846]

[0847] In a 100 mL single-necked round-bottom flask, 03 (250 mg, 0.720 mmol) was dissolved in acetic acid (2 mL) and reacted at 70°C for 3 hours. The mixture was spin-dried and purified by column chromatography (dichloromethane:methanol = 10:1) to obtain the desired product as a pale yellow solid (220 mg, yield: 93%). LC-MS: 330.2 [M+H] +

[0848] Step 3:

[0849]

[0850] In a 50 mL single-necked bottle, dissolve 04 (50 mg, 0.152 mmol) in dichloromethane (2 mL). Add 1,4-dioxane hydrochloride (0.5 mL) and stir at room temperature for 1 h. The reaction solution was spin-dried and directly used in the next step. LC-MS: 230.2 [M+H] +

[0851] Step 4:

[0852]

[0853] At room temperature, 06 (31 mg, 0.135 mmol) was dissolved in N,N-dimethylformamide (1 mL), and 07 (55 mg, 0.135 mmol), HATU (67 mg, 0.176 mmol), and N,N-diisopropylethylamine (87 mg, 0.673 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour. The reaction solution was purified by high-performance liquid chromatography to obtain a yellow-green solid (30.79 mg, two-step yield: 37%). LC-MS: 620.3 [M+H] +, 1HNMR (400MHz, DMSO-d6) δ11.11 (s, 1H), 8.70 (d, J = 8.4Hz, 1H), 8.60 (d, J = 5.0Hz, 1H), 8.04 (s, 1H), 7.98 (dd, J = 6.3, 2.8Hz, 1H), 7.81 (dd, J=6.2, 2.9Hz, 1H), 7.64–7.57 (m, 3H), 7.53–7.46 (m, 2H), 7.06 (d, J=7.1Hz, 1H), 6.87 (d, J=8.6Hz, 1H), 5.10 (dd, J=12.8 , 5.4Hz, 1H), 4.72 (d, J=5.5Hz, 2H), 4.04 (s, 3H), 3.97–3.86 (m, 1H), 3.34 (t, J=12.0Hz, 1H), 2.98–2.81 (m, 1H), 2.65–2.53 (m, 2H) , 2.17 (d, J=11.8Hz, 2H), 2.13–2.04 (m, 1H), 2.00 (d, J=10.5Hz, 2H), 1.82 (dd, J=24.2, 11.6Hz, 2H), 1.70 (dd, J=22.9, 11.8Hz, 2H).

[0854] Example 36:

[0855]

[0856] Preparation steps:

[0857] Step 1:

[0858]

[0859] 01 (1.00 g, 8.12 mmol), 02 (1.51 g, 8.12 mmol), and N,N-diisopropylethylamine (3.15 mg, 24.4 mmol) were dissolved in anhydrous N,N-dimethylformamide (30 mL). (7-Azobenzotriazole)-tetramethyluronium hexafluorophosphate (4.63 g, 12.2 mmol) was added portionwise with stirring at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The mixture was separated by reverse phase column (C18, 10-100% acetonitrile / water as mobile phase, 0.1% ammonia water) to obtain the desired product as a white solid (1.46 g, yield: 61.7%). LC-MS: 292.4 [M+H] +

[0860] Step 2:

[0861]

[0862] 03 (200 mg, 0.686 mmol) was added to the sealed tube and dissolved in acetic acid (3 mL). The reaction mixture was stirred at 140°C for 16 hours. The solvent was removed from the mixture under reduced pressure to obtain the desired product as a white solid (165 mg, yield: 87.9%). LC-MS: 274.3 [M+H] + .

[0863] Step 3:

[0864]

[0865] At room temperature, 04 (165 mg, 0.604 mmol) was dissolved in tetrahydrofuran (2 mL) and water (0.5 mL). Lithium hydroxide (50.7 mg, 1.21 mmol) was then added, and the mixture was stirred at room temperature for 16 hours. An appropriate amount of hydrochloric acid (2 M) was added to adjust the pH of the reaction solution to 3-4, and the mixture was then dried to obtain a white solid as the desired product (165 mg, crude product). LC-MS: 260.3 [M+H] + .

[0866] Step 4:

[0867]

[0868] 05 (50.0 mg, 0.193 mmol), 06 (73.0 mg, 0.193 mmol), and N,N-diisopropylethylamine (74.8 mg, 0.579 mmol) were dissolved in anhydrous N,N-dimethylformamide (2 mL). (7-Azobenzotriazole)-tetramethyluronium hexafluorophosphate (110 mg, 0.289 mmol) was added portionwise with stirring at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The mixture was separated by reverse phase liquid chromatography (C18, 5-100% acetonitrile / water as the mobile phase, 0.1% formic acid) to obtain the desired product as a yellow-green solid (12.20 mg, yield: 10.2%). LC-MS: 620.4 [M+H] + 、 1HNMR (400MHz, DMSO-d6) δ11.10 (s, 1H), 9.92 (s, 1H), 8.83 (s, 1H), 8.29 (d, J=5.5Hz, 1H) , 7.62–7.50 (m, 4H), 7.29–7.21 (m, 2H), 7.04 (d, J=7.0Hz, 2H), 6.92 (d, J=8.6Hz, 1H), 5.0 8(dd, J=12.8, 5.3Hz, 1H), 4.54(d, J=5.9Hz, 2H), 3.81(s, 3H), 3.11–3.04(m, 1H), 2.95– 2.85(m, 1H), 2.62–2.56(m, 2H), 2.12–2.00(m, 4H), 1.99–1.91(m, 2H), 1.73–1.61(m, 4H)

[0869] Example 37:

[0870]

[0871] Preparation steps:

[0872] Step 1:

[0873]

[0874] At room temperature, 01 (500 mg, 4.06 mmol), 02 (680 mg, 3.15 mmol), and N,N-diisopropylethylamine (1049 mg, 8.12 mmol) were dissolved in N,N-dimethylformamide (8 mL). (7-Azobenzotriazole)-tetramethyluronium hexafluorophosphate (1852 mg, 4.87 mmol) was added with stirring at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The desired product was separated by reverse column chromatography (C18, water:acetonitrile = 100:0-35:65, 0.1% formic acid) to obtain a white solid (190 mg, yield: 20.7%). LC-MS: 292.4 [M+H] + .

[0875] Step 2:

[0876]

[0877] At room temperature, 03 (190 mg, 0.65 mmol) was dissolved in acetic acid (2 mL), and the reaction mixture was stirred at 70°C under argon for 2 hours. The mixture was dried to give a yellow oil as the desired product (140 mg, yield: 78.9%). LC-MS: 274.2 [M+H] + .

[0878] Step 3:

[0879]

[0880] At room temperature, 04 (140 mg, 0.51 mmol) was dissolved in tetrahydrofuran (2 mL) and water (2 mL). Lithium hydroxide monohydrate (52 mg, 1.23 mmol) was added at room temperature and stirred at room temperature for 3 hours. The reaction solution was dried by rotary evaporation, and water (20 mL) and ethyl acetate (20 mL) were added. After separation, the pH of the aqueous phase was adjusted to less than 7, and extracted with ethyl acetate (30 mL). The product was dried by rotary evaporation to obtain a white solid as the target product (90 mg, yield: 68.1%). LC-MS: 260.2 [M+H] + .

[0881] Step 4:

[0882]

[0883] At room temperature, 05 (90 mg, 0.35 mmol), 06 (133 mg, 0.35 mmol), and N,N-diisopropylethylamine (136 mg, 1.05 mmol) were dissolved in N,N-dimethylformamide (1 mL). (7-Azobenzotriazole)-tetramethyluronium hexafluorophosphate (160 mg, 0.42 mmol) was added with stirring at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The mixture was separated by preparative chromatography (C18, 5-100% acetonitrile / water as mobile phase, 0.1% formic acid) to obtain the desired product as a yellow solid (1.83 mg, yield: 0.8%). LC-MS: 620.5 [M+H] + .

[0884] 1 HNMR (400MHz, DMSO-d6) δ11.11 (s, 1H), 9.93 (s, 1H), 8.87 (s, 1H), 8.28 (d, J=5.5Hz, 1H), 7 .61(d, J=9.3Hz, 1H), 7.58–7.49(m, 3H), 7.30–7.21(m, 2H), 7.04(d, J=7.0Hz, 2H), 6.92(d , J=8.7Hz, 1H), 5.08(dd, J=13.0, 5.5Hz, 1H), 4.54(d, J=5.8Hz, 2H), 3.88(s, 3H), 3.08(s, 1H), 2.96–2.84 (m, 1H), 2.65 (d, J=19.2Hz, 2H), 2.07–1.93 (m, 6H), 1.67 (t, J=9.8Hz, 4H).

[0885] Example 38:

[0886]

[0887] Preparation steps:

[0888] Step 1:

[0889]

[0890] At room temperature, 01 (65 mg, 0.369 mmol), 02 (100 mg, 0.370 mmol), and triethylamine (75 mg, 0.742 mmol) were dissolved in isopropanol (10 mL). The reaction mixture was stirred at 80°C under nitrogen for 4 hours and then cooled to room temperature. A solution of tri-n-butylphosphine (225 mg, 1.11 mmol) in isopropanol (1 mL) was then added at room temperature, and the mixture was stirred at 80°C for 16 hours before being cooled to room temperature. The reaction mixture was filtered, and the filter cake was washed with isopropanol and dried to obtain the desired product as a pale yellow solid (100 mg, yield: 75.5%). LC-MS: 360.1 [M+H] + .

[0891] Step 2:

[0892]

[0893] At room temperature, 03 (30 mg, 0.0836 mmol) was dissolved in tetrahydrofuran (5 mL). Raney nickel (50 mg) was added at room temperature. The hydrogen atmosphere was replaced three times, and the mixture was stirred under a hydrogen balloon at room temperature for 16 hours. The filtrate was filtered and dried to give the desired product as a white solid (20 mg, yield: 65.9%). LC-MS: 364.0 [M+H] + .

[0894] Step 3:

[0895]

[0896] At room temperature, 04 (20 mg, 0.0551 mmol), 05 (15 mg, 0.0543 mmol), and N,N-diisopropylethylamine (21 mg, 0.163 mmol) were dissolved in anhydrous dimethyl sulfoxide (1 mL). The reaction mixture was stirred at 80°C for 16 hours. The mixture was cooled to 20°C and isolated using a preparative chromatography (C18, 5-100% acetonitrile / water as the mobile phase, 0.1% formic acid) to afford the desired product as a yellow solid (3.08 mg, yield: 9.03%). LC-MS: 620.2 [M+H] + . 1HNMR (400MHz, DMSO-d6) δ11.11 (s, 1H), 8.60 (d, J = 4.6Hz, 1H), 8.39 (s, 1H), 8.37 (d, J = 8.2Hz, 1H), 7.68 (d, J = 8.6Hz, 1 H), 7.61–7.57 (m, 1H), 7.56 (s, 1H), 7.54–7.47 (m, 1H), 7.28 (t, J=6.0Hz, 1H), 7.06 (t, J=9.3Hz, 2H), 7.02 (d, J=7.1Hz , 1H), 5.08 (dd, J=12.8, 5.4Hz, 1H), 4.64 (d, J=6.2Hz, 3H), 2.89 (dd, J=21.6, 9.9Hz, 1H), 2.61 (dd, J=29.5, 12.5Hz, 3H ), 2.36 (d, J = 13.3Hz, 2H), 2.27 (d, J = 9.6Hz, 2H), 2.15 (dd, J = 24.8, 12.5Hz, 2H), 2.09–1.97 (m, 1H), 1.97–1.83 (m, 2H).

[0897] Example 39:

[0898]

[0899] Preparation steps:

[0900] Step 1:

[0901]

[0902] 01 (465 mg, 1.14 mmol), 02 (263 mg, 1.14 mmol), and N,N-diisopropylethylamine (442 mg, 3.42 mmol) were dissolved in anhydrous N,N-dimethylformamide (15 mL). (7-Azobenzotriazole)-tetramethyluronium hexafluorophosphate (650 mg, 1.71 mmol) was added portionwise with stirring at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The mixture was separated by reverse phase column (C18, 5-100% acetonitrile / water as mobile phase, 0.1% formic acid) and silica gel column (methanol / dichloromethane = 1:10) to obtain the desired product as a yellow solid (330 mg, yield: 46.7%). LC-MS: 621.4 [M+H] + . 1HNMR (400MHz, DMSO-d6) δ11.12 (s, 1H), 9.09 (s, 1H), 8.66–8.52 (m, 2H), 8.39 (d, J=5.7Hz, 1H), 8.04 (s, 1H), 7.79 (d, J=5.9Hz, 1H), 7.57 (d, J=3.7Hz, 1H), 7.53–7.43 (m, 2H), 7.05 (d, J=7.0Hz, 1H), 6.8 7 (d, J=8.6Hz, 1H), 5.10 (dd, J=12.8, 5.4Hz, 1H), 4.71 (d, J=6.3Hz, 2H), 3.94 (s, 3H), 3.91–3.83 (m, 1H), 3.11–3.03(m, 1H), 2.96–2.85(m, 1H), 2.64–2.52(m, 2H), 2.12–1.94(m, 5H), 1.83–1.61(m, 4H).

[0903] Example 40

[0904]

[0905] Preparation steps:

[0906] Step 1:

[0907]

[0908] 6-Methyl-2-pyridinecarboxylic acid (500 mg, 3.65 mmol) and 4-dimethylaminopyridine (223 mg, 1.82 mmol) were dissolved in anhydrous tetrahydrofuran (10 mL). Di-tert-butyl dicarbonate (1.03 g, 4.74 mmol) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 20 hours. The solvent was removed under reduced pressure, and water (30 mL) was added. The mixture was extracted with ethyl acetate (10 mL x 2), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and dried. The residue was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to afford the desired product as a colorless, transparent oil (570 mg, yield: 80.9%). LC-MS: 194.2 [M+H] + ; 138.2[M+H] + .

[0909] Step 2:

[0910]

[0911] 02 (570 mg, 2.95 mmol), N-bromosuccinimide (577 mg, 3.24 mmol), and azobisisobutyronitrile (48.4 mg, 0.295 mmol) were mixed in carbon tetrachloride (5 mL). The reaction mixture was stirred at 90°C for 3 hours. After the mixture was cooled to room temperature, the solvent was removed under reduced pressure. The residue was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the desired product as a white solid (390 mg, yield: 48.6%). LC-MS: 272.2, 274.2 [M+H] + ; 216.1, 218.1 [M+H-56] + .

[0912] Step 3:

[0913]

[0914] 03 (390 mg, 1.43 mmol) was dissolved in anhydrous dimethyl sulfoxide (5 mL), and sodium azide (140 mg, 2.15 mmol) was added in batches with stirring at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into water (50 mL), extracted with ethyl acetate (10 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and dried. The residue was purified by flash silica gel column (petroleum ether: ethyl acetate = 10:1) to obtain a yellow oil as the target product (310 mg, yield: 92.3%). LC-MS: 235.3 [M+H] + ; 179.2[M+H-56] + .

[0915] Step 4:

[0916]

[0917] 05 (160 mg, 0.683 mmol) was dissolved in methanol (5 mL), and wet palladium on carbon (100 mg, 10% palladium content, 50% water content) was added. After replacing the hydrogen atmosphere, the reaction was stirred under a hydrogen balloon at room temperature for 16 hours. The mixture was filtered and dried to give a yellow solid as the desired product (116 mg, yield: 81.6%). LC-MS: 209.3 [M+H] + ; 153.3[M+H-56] + .

[0918] Step 5:

[0919]

[0920] 05 (110 mg, 0.528 mmol), 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione (146 mg, 0.528 mmol), and N,N-diisopropylethylamine (273 mg, 2.11 mmol) were dissolved in dimethyl sulfoxide (2 mL) and stirred at 120°C for 5 hours. The mixture was cooled to room temperature and purified on a reverse phase column (C18, 10-100 acetonitrile / water as mobile phase, 0.1% formic acid) to obtain the desired product as a yellow solid (90.0 mg, yield: 36.7%). LC-MS: 465.4 [M+H] + ; 409.3[M+H-56] + .

[0921] Step 6:

[0922]

[0923] 07 (50 mg, 0.108 mmol) was dissolved in dichloromethane (2.5 mL) and trifluoroacetic acid (0.5 mL) was added dropwise with stirring at room temperature. The reaction mixture was stirred at room temperature for 14 hours. The solvent was removed from the mixture under reduced pressure to obtain the desired product as a yellow solid (40.0 mg, yield: 98.0%). LC-MS: 409.3 [M+H] + ; 431.3[M+Na] + .

[0924] Step 7:

[0925]

[0926] 08 (40.0 mg, 0.0980 mmol), 09 (26.1 mg, 0.0980 mmol) and N, N-diisopropylethylamine (50.7 mg, 0.392 mmol) were dissolved in anhydrous N, N-dimethylformamide (1 mL). (7-Azobenzotriazole)-tetramethyluronium hexafluorophosphate (44.9 mg, 0.118 mmol) was added portionwise with stirring at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The mixture was separated by preparative chromatography (C18, 5-100% acetonitrile / water as the mobile phase, 0.1% formic acid) to obtain the desired product as a yellow solid (two components P1: 5.9 mg, P2: 13.06 mg, combined yield: 31.2%).

[0927] P1: LC-MS: 621.4 [M+H] + . 1HNMR (400MHz, DMSO-d6) δ11.09 (s, 1H), 8.95 (s, 1H), 8.30 (d, J=5.4Hz, 1H), 8.21 (d, J =6.7Hz, 1H), 8.03–7.95 (m, 2H), 7.65–7.56 (m, 4H), 7.14 (d, J=8.6Hz, 1H), 6.96 (d, J=7 .0Hz, 1H), 5.01 (dd, J=12.8, 5.3Hz, 1H), 4.77 (d, J=5.5Hz, 2H), 4.10–4.01 (m, 1H), 3.9 0(s, 3H), 2.79–2.66(m, 2H), 2.46–2.32(m, 2H), 2.11–2.02(m, 2H), 1.91–1.77(m, 7H).

[0928] P2: LC-MS: 621.4 [M+H] + . 1 HNMR (400MHz, DMSO-d6) δ11.18 (s, 1H), 8.94 (s, 1H), 8.31 (d, J = 5.6Hz, 1H), 8.18 (d, J = 8.1H z, 1H), 8.04–7.97 (m, 2H), 7.76 (t, J=5.6Hz, 1H), 7.65–7.59 (m, 3H), 7.14 (s, 1H), 7.12 (s, 1H ), 5.14 (dd, J=12.7, 5.2Hz, 1H), 4.78 (d, J=5.2Hz, 2H), 3.92 (s, 3H), 3.91–3.86 (m, 1H), 3.0 0–2.88(m, 2H), 2.65–2.57(m, 2H), 2.12–2.00(m, 5H), 1.83–1.74(m, 2H), 1.59–1.50(m, 2H).

[0929] Example 41:

[0930]

[0931] Preparation steps:

[0932] Step 1:

[0933]

[0934] Sodium hydroxide (153 mg, 3.82 mmol, 60%) was added to a 100 mL three-necked flask. Under argon, the mixture was cooled to 0°C. 01 (500 mg, 2.538 mmol) was dissolved in DMF (5 mL) and added to the reaction system. After reacting at 0°C for 0.5 hours, iodomethane (432 mg, 3.04 mmol) was added and the reaction was continued at 0°C for 3 hours. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, and spin-dried. The desired product (420 mg, yield: 78.4%) was obtained as a white solid by column chromatography (petroleum ether:ethyl acetate = 3:1). LC-MS: 211.0 / 213.0 [M+H] +

[0935] Step 2:

[0936]

[0937] A 100 mL single-necked round-bottom flask was charged with 02 (100 mg, 0.474 mmol), 03 (95 mg, 0.474 mmol), DIEA (306 mg, 2.31 mmol), and DMSO (10 mL). The mixture was reacted at 120°C under nitrogen for 16 hours. Water (20 mL) was added for dilution, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, and purified by spin column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain a brown solid (130 mg, yield: 83.0%). LC-MS: 331.4 [M+H] +

[0938] Step 3:

[0939]

[0940] In a 100 mL single-necked flask, add 04 (130 mg, 0.393 mmol), hydrochloric acid (4 M) (2 mL), and dichloromethane (5 mL) and react at room temperature for 2 hours. Concentrate to obtain a white solid, which can be used directly in the next step. LC-MS: 231.2 [M+H] +

[0941] Step 4:

[0942]

[0943] In a 100 mL single-necked flask, 05 (20 mg, 0.087 mmol), 06 (36 mg, 0.088 mmol), HATU (50 mg, 0.131 mmol), DIEA (57 mg, 0.44 mmol), and DMF (1 mL) were added and reacted at room temperature for 2 hours. HPLC analysis yielded the desired product as a yellow solid (14.46 mg, yield: 26.8%). LC-MS: 621.3 [M+H] + . 1 HNMR (400MHz, DMSO-d6) δ11.12 (s, 1H), 8.79 (d, J = 8.2Hz, 1H), 8.59 (d, J = 4.9Hz, 1H), 8.06 (s, 1H), 7.67 (d , J=8.5Hz, 1H), 7.59 (d, J=4.2Hz, 1H), 7.55–7.45 (m, 3H), 7.45–7.36 (m, 2H), 7.06 (d, J=7.0Hz, 1H), 6.87 ( d, J=8.6Hz, 1H), 5.10 (dd, J=12.9, 5.3Hz, 1H), 4.71 (d, J=5.5Hz, 2H), 4.16 (s, 1H), 3.92 (d, J=12.7Hz, 2H) , 3.76 (s, 3H), 3.46 (t, J = 10.5Hz, 2H), 2.91 (t, J = 13.0Hz, 1H), 2.68–2.52 (m, 2H), 1.95 (t, J = 21.9Hz, 5H).

[0944] Example 42:

[0945]

[0946] Preparation steps:

[0947] Step 1:

[0948]

[0949] 01 (100 mg, 0.812 mmol), 02 (198 mg, 0.812 mmol), and N,N-diisopropylethylamine (315 mg, 2.44 mmol) were dissolved in anhydrous N,N-dimethylformamide (3 mL). (7-Azobenzotriazole)-tetramethyluronium hexafluorophosphate (464 mg, 1.22 mmol) was added portionwise with stirring at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The mixture was separated by reverse phase column (C18, 10-100% acetonitrile / water as mobile phase, 0.03% trifluoroacetic acid) to obtain the desired product as a brown oil (260 mg, yield: 91.8%). LC-MS: 349.4 [M+H] +

[0950] Step 2:

[0951]

[0952] 03 (260 mg, 0.746 mmol) was dissolved in acetic acid (2 mL), and the reaction mixture was stirred at 70°C for 3 hours. The solvent was removed from the mixture under reduced pressure to obtain the desired product as a brown oil (246 mg, crude product). LC-MS: 331.4 [M+H] + .

[0953] Step 3:

[0954]

[0955] 04 (246 mg, 0.744 mmol) was dissolved in dichloromethane (2 mL) and methanol (1 mL). A solution of hydrogen chloride in dioxane (2 mL) was added with stirring at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed from the mixture under reduced pressure to obtain the desired product as a white solid (131 mg, two-step yield: 76.2%). LC-MS: 231.3 [M+H] + .

[0956] Step 4:

[0957]

[0958] 05 (22.6 mg, 0.098 mmol), 06 (40.0 mg, 0.098 mmol), and N,N-diisopropylethylamine (38.0 mg, 0.294 mmol) were dissolved in anhydrous N,N-dimethylformamide (1 mL). (7-Azobenzotriazole)-tetramethyluronium hexafluorophosphate (55.9 mg, 0.147 mmol) was added portionwise with stirring at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The mixture was separated by reverse phase liquid chromatography (C18, 5-100% acetonitrile / water as the mobile phase, 0.1% formic acid) to obtain the desired product as a yellow-green solid (13.3 mg, yield: 21.6%). LC-MS: 621.3 [M+H] +, 1HNMR (400MHz, DMSO) δ11.12 (s, 1H), 8.64–8.56 (m, 2H), 8.39 (s, 1H), 8.13 (s, 1H), 8.09–8.00 (m, 2H ), 7.57(d, J=4.7Hz, 1H), 7.54–7.45(m, 2H), 7.28(dd, J=8.2, 4.6Hz, 1H), 7.05(d, J=7.0Hz, 1H), 6.87( d, J=8.6Hz, 1H), 5.10 (dd, J=12.9, 5.3Hz, 1H), 4.71 (d, J=6.4Hz, 2H), 3.94–3.81 (m, 4H), 3.08–3.00 (m , 1H), 2.95–2.86(m, 1H), 2.64–2.54(m, 2H), 2.11–1.94(m, 5H), 1.83–1.73(m, 2H), 1.71–1.61(m, 2H).

[0959] Example 43:

[0960]

[0961] Preparation steps:

[0962] Step 1:

[0963]

[0964] 01 (200 mg, 1.62 mmol), 02 (355 mg, 1.46 mmol), and N,N-diisopropylethylamine (628 mg, 4.86 mmol) were dissolved in anhydrous N,N-dimethylformamide (3 mL). (7-Azobenzotriazole)-tetramethyluronium hexafluorophosphate (924 mg, 2.43 mmol) was added portionwise with stirring at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The mixture was separated by reverse phase column (C18, 10-100% acetonitrile / water as mobile phase, 0.03% trifluoroacetic acid) to obtain a red solid as the desired product (290 mg, yield: 51.2%). LC-MS: 349.4 [M+H] +

[0965] Step 2:

[0966]

[0967] 03 (290 mg, 0.832 mmol) and acetic acid (2 mL) were added to the sealed tube. The reaction mixture was stirred at 130°C for 16 hours under sealed conditions. The solvent was removed from the mixture under reduced pressure to obtain the desired product as a gray solid (117 mg, yield: 61.0%). LC-MS: 231.4 [M+H] +.

[0968] Step 3:

[0969]

[0970] 04 (30.0 mg, 0.112 mmol), 05 (45.7 mg, 0.112 mmol), and N,N-diisopropylethylamine (43.4 mg, 0.336 mmol) were dissolved in anhydrous N,N-dimethylformamide (1 mL). (7-Azobenzotriazole)-tetramethyluronium hexafluorophosphate (63.9 mg, 0.168 mmol) was added portionwise with stirring at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The mixture was separated by reverse phase liquid chromatography (C18, 5-100% acetonitrile / water as mobile phase, 0.1% formic acid) to obtain the desired product as a yellow-green solid (21.06 mg, yield: 30.2%). LC-MS: 621.2 [M+H] + , 1HNMR (400MHz, DMSO) δ11.12 (s, 1H), 8.65–8.56 (m, 2H), 8.35 (d, J=4.9Hz, 1H), 8.07–7.99 (m , 2H), 7.61–7.55(m, 1H), 7.53–7.45(m, 2H), 7.33–7.26(m, 1H), 7.05(d, J=7.0Hz, 1H), 6.87(d , J=8.6Hz, 1H), 5.10 (dd, J=12.8, 5.4Hz, 1H), 4.71 (d, J=6.2Hz, 2H), 3.92–3.80 (m, 4H), 3.07( t, J=11.9Hz, 1H), 2.95–2.84 (m, 1H), 2.63–2.53 (m, 2H), 2.09–1.89 (m, 5H), 1.83–1.61 (m, 4H).

[0971] Example 44:

[0972]

[0973] Preparation steps:

[0974] Step 1:

[0975]

[0976] In a 25 mL single-necked flask, 01 (100 mg, 0.280 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL). 02 (72 mg, 0.336 mmol), potassium carbonate (116 mg, 0.840 mmol), and Pd(dppf)Cl2 (41 mg, 0.0560 mmol) were added. The mixture was reacted at 80°C under an argon atmosphere for 16 hours. Column chromatography (petroleum ether:ethyl acetate = 5:1) afforded the desired product as a pale yellow solid (89 mg, yield: 87.5%). LC-MS: 364.1 [M+H] +

[0977] Step 2:

[0978]

[0979] In a 50 mL single-necked flask, 03 (89 mg, 0.245 mmol) was dissolved in a mixture of methanol (5 mL) and tetrahydrofuran (1 mL). Palladium on carbon (15 mg) was added and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. Filter and spin dry to obtain the desired product as a yellow solid (82 mg, yield: 91.8%). LC-MS: 366.1 [M+H] +

[0980] Step 3:

[0981]

[0982] In a 50 mL single-necked vial, 04 (82 mg, 0.224 mmol) was dissolved in trifluoroacetic acid (2 mL) and the mixture was heated to 70°C with stirring for 2 hours. The mixture was spin-dried and purified by reverse phase purification (acetonitrile:water = 65%) to obtain the desired product as a pale yellow solid (24 mg, yield: 46.2%). LC-MS: 232.1 [M+H] +

[0983] Step 4:

[0984]

[0985] In a 25 mL single-necked flask, 06 (42 mg, 0.104 mmol) was dissolved in N,N-dimethylformamide (1 mL). HATU (59 mg, 0.156 mmol), N,N-diisopropylethylamine (27 mg, 0.207 mmol), and 05 (24 mg, 0.104 mmol) were added and allowed to react at room temperature for 2 hours. High-performance liquid chromatography (HPLC) yielded the desired product as a yellow solid (10.34 mg, yield: 16.1%). LC-MS: 621.2 [M+H] +

[0986] 1 HNMR (400MHz, DMSO-d6) δ11.09 (s, 1H), 8.22 (dd, J=59.7, 7.6Hz, 1H), 7.87 (t, J=12.2Hz, 2H), 7.72 (dd, J=15.1, 6.9Hz , 2H), 7.55–7.46 (m, 2H), 7.41 (dd, J=15.9, 7.9Hz, 1H), 7.36–7.31 (m, 1H), 7.30–7.25 (m, 2H), 7.20 (s, 1H), 7.02 (t, J=8 .1Hz, 1H), 6.95 (t, J=8.9Hz, 1H), 5.20–4.96 (m, 1H), 4.72–4.50 (m, 2H), 3.93 (d, J=67.5Hz, 1H), 3.40 (s, 1H), 3.14 (s, 1 H), 2.97–2.81(m, 2H), 2.64–2.57(m, 1H), 2.14–2.04(m, 2H), 2.01–1.87(m, 2H), 1.84–1.68(m, 2H), 1.65–1.49(m, 2H).

[0987] Example 45:

[0988]

[0989] (1) Preparation steps:

[0990] Step 1:

[0991]

[0992] The raw materials 01 (200 mg, 0.56 mmol), 02 (143 mg, 0.67 mmol), and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (41 mg, 0.06 mmol) were dissolved in 1,4-dioxane (4 mL), and a solution of potassium carbonate (194 mg, 1.4 mmol) in water (1 mL) was added. The reaction mixture was stirred at 90°C under argon for 3 hours. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The mixture was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and dried. The residue was separated by silica gel column (petroleum ether:ethyl acetate = 100:0 to 80:20) and reverse column (C18, water:acetonitrile = 100:0 to 35:65, 0.1% formic acid) to obtain the desired product as a white solid (110 mg, yield: 54.1%). LC-MS: 364.1[M+H] + .

[0993] Step 2:

[0994]

[0995] At room temperature, 03 (110 mg, 0.30 mmol) was dissolved in tetrahydrofuran (1 mL) and isopropanol (1 mL). Palladium hydroxide on carbon (50 mg) was added, and the hydrogen atmosphere was replaced twice. The mixture was stirred under a hydrogen balloon at room temperature for 16 hours. The mixture was filtered, the filtrate was dried, and the residue was separated by TLC (petroleum ether:ethyl acetate = 4:1) to obtain the desired product (upper spot) as a white solid (55 mg, yield: 50.2%). LC-MS: 366.1 [M+H] + .

[0996] Step 3:

[0997]

[0998] 04 (55 mg, 0.15 mmol) was dissolved in trifluoroacetic acid (1 mL) at room temperature. The reaction mixture was stirred at 70°C under argon for 0.5 hours. The solvent was removed by swirl, and the residue was purified by reverse-phase column chromatography (C18, water:acetonitrile = 100:0 to 50:50, 0.1% formic acid) to afford the desired product as a white solid (15 mg, yield: 43.3%). LC-MS: 232.3 [M+H] + .

[0999] Step 4:

[1000]

[1001] At room temperature, 05-P1 (15 mg, 0.065 mmol), 06 (27 mg, 0.065 mmol), and N,N-diisopropylethylamine (26 mg, 0.195 mmol) were dissolved in N,N-dimethylformamide (0.5 mL). (7-Azobenzotriazole)-tetramethyluronium hexafluorophosphate (30 mg, 0.078 mmol) was added with stirring at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The mixture was separated by preparative chromatography (C18, 5-100% acetonitrile / water as mobile phase, 0.1% formic acid) to obtain the desired product as a yellow solid (11.06 mg, yield: 27.4%). LC-MS: 621.3 [M+H] + . 1HNMR (400MHz, DMSO-d6) δ11.09 (s, 1H), 8.15 (d, J=6.8Hz, 1H), 7.97 (d, J=7.6Hz, 1H), 7.90–7.81 (m, 2H), 7.74 (d, J=7.6Hz, 1H), 7.54–7.48 (m, 2H), 7.45–7.34 (m, 4H), 7.29 (t, J=5.9Hz, 1H), 7.02 (d, J=7.0Hz, 1H) , 6.96 (d, J = 8.6Hz, 1H), 5.06 (dd, J = 12.8, 5.3Hz, 1H), 4.62 (d, J = 5.9Hz, 2H), 4.19–4.11 (m, 1H), 3.14–3.0 3(m, 1H), 2.93–2.82(m, 1H), 2.63–2.53(m, 2H), 2.07–2.01(m, 1H), 1.99–1.88(m, 4H), 1.87–1.74(m, 4H).

[1002] Example 46:

[1003]

[1004] Preparation steps:

[1005] Step 1:

[1006]

[1007] At room temperature, 03 (110 mg, 0.30 mmol) was dissolved in tetrahydrofuran (1 mL) and isopropanol (1 mL). Palladium hydroxide on carbon (50 mg) was added, and the hydrogen atmosphere was replaced twice. The mixture was stirred under a hydrogen balloon at room temperature for 16 hours. The mixture was filtered, the filtrate was dried, and the residue was separated by TLC (petroleum ether:ethyl acetate = 4:1) to obtain the desired product (lower spot) as a white solid (25 mg, yield: 22.7%). LC-MS: 366.1 [M+H] + .

[1008] Step 2:

[1009]

[1010] 04 (25 mg, 0.0684 mmol) was dissolved in trifluoroacetic acid (1 mL) at room temperature. The reaction mixture was stirred at 70°C under argon for 0.5 hours. The solvent was removed by swirl, and the residue was purified by reverse-phase column chromatography (C18, water:acetonitrile = 100:0 to 50:50, 0.1% formic acid) to afford the desired product as a white solid (10 mg, yield: 63.2%). LC-MS: 232.3 [M+H] + .

[1011] Step 3:

[1012]

[1013] At room temperature, 05-P2 (10 mg, 0.043 mmol), 06 (17.6 mg, 0.043 mmol), and N,N-diisopropylethylamine (16.6 mg, 0.129 mmol) were dissolved in N,N-dimethylformamide (0.5 mL). (7-Azobenzotriazole)-tetramethyluronium hexafluorophosphate (19.6 mg, 0.0516 mmol) was added with stirring at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The mixture was separated by preparative chromatography (C18, 5-100% acetonitrile / water as the mobile phase, 0.1% formic acid) to obtain the desired product as a yellow solid (product 2: 7.27 mg, yield: 27.2%). LC-MS: 621.3 [M+H] + .

[1014] 1 HNMR (400MHz, DMSO-d6) δ11.10 (s, 1H), 8.32 (d, J = 8.1Hz, 1H), 7.97 (d, J = 7.4Hz, 1H), 7.91–7.86 (m, 2H), 7.75 (d, J=6.9Hz, 1H), 7.54–7.49 (m, 2H), 7.45–7.34 (m, 4H), 7.32–7.27 (m, 1H), 7.04 (d, J=7.1Hz, 1H), 6 .96 (d, J=8.3Hz, 1H), 5.08 (dd, J=12.6, 5.2Hz, 1H), 4.62 (d, J=5.8Hz, 2H), 3.95–3.84 (m, 1H), 2.98–2.91 (m, 1H), 2.91–2.84 (m, 1H), 2.65–2.56 (m, 2H), 2.08–2.04 (m, 2H), 2.02–1.96 (m, 3H), 1.67–1.59 (m, 4H).

[1015] Example 47:

[1016]

[1017] Preparation steps:

[1018] Step 1:

[1019]

[1020] 01 (854 mg, 2.864 mmol) and cuprous cyanide (1282 mg, 14.32 mmol) were dissolved in N,N-dimethylformamide (25 mL) at room temperature. The reaction mixture was stirred at 149°C for 16 hours. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain the desired product as a white solid (249 mg, yield: 35.5%). LC-MS: 189.1 [M+H-56] +

[1021] Step 2:

[1022]

[1023] At room temperature, 02 (100 mg, 0.41 mmol) was dissolved in dichloromethane (4 mL) and trifluoro acid (0.8 mL) and stirred at room temperature for 2 hours. The reactants were dried to give the desired product as a white solid (100 mg, crude product). LC-MS: 145.1 [M+H] + .

[1024] Step 3:

[1025]

[1026] At room temperature, 03 (100 mg, 0.69 mmol) and 04 (161 mg, 0.69 mmol) were dissolved in dichloroethane (5 mL), and sodium triacetylborohydride (441 mg, 2.08 mmol) was added with stirring at room temperature. The reaction mixture was stirred at room temperature for 12 hours. The residue was dried and purified on a silica gel column (petroleum ether:ethyl acetate = 2:1) to obtain the desired product as a white solid (100 mg, two-step yield: 94.5%). LC-MS: 361.3 [M+H] + .

[1027] Step 4:

[1028]

[1029] 05 (100 mg, 0.25 mmol) was dissolved in methanol (2.5 mL) at room temperature. Tetrahydrofuran (2.5 mL), aqueous ammonia (0.5 mL), and Raney-Ni were added. The reaction mixture was stirred under hydrogen protection at room temperature for 2 hours. Filtered and dried to obtain the desired product as a white solid (100 mg, yield: 99%). LC-MS: 365.4 [M+H] + .

[1030] Step 5:

[1031]

[1032] At room temperature, 06 (100 mg, 0.27 mmol) and 07 (76 mg, 0.27 mmol) were dissolved in dimethyl sulfoxide (1.5 mL), and N,N-diisopropylethylamine (106 mg, 0.82 mmol) was added. The reaction mixture was stirred at 100°C for 12 hours. The mixture was separated by preparative separation to obtain the desired product as a green solid (3.15 mg, yield: 1.9%). LC-MS: 621.3 [M+H] + .

[1033] 1 HNMR (400MHz, DMSO-d6) δ11.09 (s, 1H), 8.59–8.53 (m, 1H), 8.35–8.28 (m, 1H), 7.58–7.48 (m, 2H), 7.21 (dd, J=18.8, 12.5Hz, 4H), 7.02 (t, J=5.4Hz, 1H), 6.96 (d, J=8.6Hz, 1H), 5.0 6 (dd, J=12.9, 5.4Hz, 1H), 4.53 (d, J=5.9Hz, 2H), 3.87 (d, J=19.5Hz, 4H), 2.87 (d, J=13.7 Hz, 1H), 2.59 (d, J=16.0Hz, 4H), 2.18–1.99 (m, 4H), 1.91 (s, 3H), 1.71 (t, J=12.4Hz, 2H).

[1034] Example 48:

[1035]

[1036] Preparation steps:

[1037] Step 1:

[1038]

[1039] To a 50 mL single-necked flask, 01 (78 mg, 0.287 mmol), 02 (78.7 mg, 0.287 mmol), potassium carbonate (39.7 mg, 0.287 mmol), and N,N-dimethylformamide (2 mL) were added and reacted at room temperature for 2 hours. The mixture was quenched with water (10 mL), extracted with ethyl acetate (10 mL × 2), washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, and spin-dried. A yellow solid (60 mg, yield: 44.9%) was obtained by column chromatography (methanol: dichloromethane = 10:1). LC-MS: 466.4 [M+H] +

[1040] Step 2:

[1041]

[1042] In a 50 mL single-necked flask, 03 (30 mg, 0.064 mmol), dichloromethane (3 mL), and trifluoroacetic acid (1 mL) were added and reacted at room temperature for 12 hours. The solvent was evaporated to obtain the desired product (20 mg, yield: 76.3%). LC-MS: 410.3 [M+H] +

[1043] Step 3:

[1044]

[1045] In a 50 mL single-necked flask, 04 (20 mg, 0.0489 mmol), 05 (13.5 mg, 0.0587 mmol), HATU (27.9 mg, 0.0733 mmol), DIEA (19.0 mg, 0.147 mmol), and DMF (1 mL) were added and reacted at room temperature for 2 hours. The reaction solution was purified by HPLC to obtain a white solid (10.93 mg, yield: 35.9%). LC-MS: 622.5 [M+H] + . 1 HNMR (400MHz, DMSO-d6) δ11.12(s, 1H), 9.42(s, 1H), 8.78–8.42(m, 3H), 8.27–8.08(m , 2H), 7.86 (t, J=7.9Hz, 1H), 7.76 (t, J=5.9Hz, 1H), 7.55 (dd, J=19.2, 7.9Hz, 2H), 5.56 (s, 2H), 5.13 (dd, J=12.9, 5.3Hz, 1H), 4.14–3.99 (m, 3H), 3.99–3.87 (m, 1H), 3.23–3.1 0(m, 1H), 2.96–2.84(m, 1H), 2.68–2.55(m, 2H), 2.16–1.94(m, 5H), 1.93–1.60(m, 4H).

[1046] Example 49:

[1047]

[1048] Preparation steps:

[1049] Step 1:

[1050]

[1051] Dissolve 4-(Benzyloxyamido)cyclohexanone (12 g, 48.5 mmol) in tetrahydrofuran (150 mL). Add a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (97.0 mL, 97.0 mmol) at -65°C. After stirring the reaction mixture at -65°C for 1 hour, add a solution of N-phenylbis(trifluoromethanesulfonyl)imide (17.3 g, 48.5 mmol) in tetrahydrofuran (40 mL) dropwise. Stir the reaction mixture at room temperature for 16 hours. Slowly pour the mixture into water (150 mL) to quench the mixture, extract with ethyl acetate (150 mL x 2), wash with saturated brine (200 mL x 2), dry over anhydrous sodium sulfate, filter, and spin dry. The residue was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain a crude product, which was then slurried in petroleum ether:ethyl acetate (102 mL, 50:1) to obtain a white solid as the desired product (5.5 g, yield: 29.9%). LC-MS: 380.2 [M+H] +

[1052] Step 2:

[1053]

[1054] 03 (9.0 g, 23.7 mmol), bis(pinacol diboronate) (7.23 g, 28.5 mmol), potassium acetate (6.99 g, 71.2 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (868 mg, 1.19 mmol) were mixed in anhydrous dioxane (150 mL). After argon replacement, the mixture was stirred at 90°C under argon for 3 hours. After cooling to room temperature, the solvent was removed under reduced pressure, diluted with ethyl acetate (300 mL), and filtered. The filtrate was washed with water (150 mL) and saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and dried. The residue was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the desired product as an off-white solid (6.3 g, yield: 74.3%). LC-MS: 358.2 [M+H] +

[1055] Step 3:

[1056]

[1057] 05 (100 mg, 0.280 mmol), 2-bromobenzothiazole (59.9 mg, 0.280 mmol), potassium carbonate (116 mg, 0.840 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (20.4 mg, 0.0280 mmol) were mixed in dioxane (5 mL) and water (1 mL). After argon was replaced, the mixture was stirred at 100°C under argon protection for 7 hours. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. Water (10 mL) was added and the mixture was extracted with ethyl acetate (5 mL x 2), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and dried. The residue was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain the desired product as a yellow solid (60 mg, yield: 58.8%). LC-MS: 365.2 [M+H] +

[1058] Step 4:

[1059]

[1060] 07 (60 mg, 0.165 mmol) was dissolved in tetrahydrofuran (2 mL) and methanol (0.5 mL). Wet palladium on carbon (20 mg, 10% palladium content, 50% water content) was added. After replacing the hydrogen atmosphere, the reaction was stirred under a hydrogen balloon at room temperature for 14 hours. The mixture was filtered and dried to give a yellow solid as the desired product (55 mg, yield: 91.2%). LC-MS: 367.3 [M+H] +

[1061] Step 5:

[1062]

[1063] 08 (55 mg, 0.150 mmol) was dissolved in trifluoroacetic acid (1 mL) and stirred at 70°C for 1 hour. The mixture was stripped of solvent under reduced pressure to give the desired product as a brown oil (52.0 mg, yield: 100%). LC-MS: 233.3 [M+H] +

[1064] Step 6:

[1065]

[1066] 09 (52.0 mg, 0.150 mmol), 10 (61.1 mg, 0.150 mmol), and N,N-diisopropylethylamine (96.9 mg, 0.750 mmol) were dissolved in anhydrous N,N-dimethylformamide (1 mL). (7-Azobenzotriazole)-tetramethyluronium hexafluorophosphate (68.4 mg, 0.180 mmol) was added portionwise with stirring at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The mixture was separated by preparative chromatography (C18, 5-100% acetonitrile / water as the mobile phase, 0.1% hydrochloric acid) to obtain the desired product as a yellow solid (45 mg, yield: 48.2%). LC-MS: 622.1 [M+H] + . 1 HNMR (400MHz, DMSO-d6) δ11.13–11.08 (m, 1H), 8.35–8.14 (m, 1H), 8.10–8.05 (m, 1H), 7.99–7.93 (m, 1H), 7. 89–7.83(m, 1H), 7.76–7.67(m, 1H), 7.54–7.45(m, 3H), 7.44–7.34(m, 2H), 7.33–7.23(m, 1H), 7.06–6.99(m, 1H), 6.98–6.91(m, 1H), 5.13–5.03(m, 1H), 4.66–4.54(m, 2H), 4.04–3.86(m, 1H), 3.39–3.08(m, 1H), 2.96–2 .83(m, 1H), 2.66–2.52(m, 2H), 2.35–2.19(m, 2H), 2.09–1.95(m, 3H), 1.80–1.67(m, 3H), 1.62–1.51(m, 1H).

[1067] Example 50

[1068]

[1069] Preparation steps:

[1070] Step 1:

[1071]

[1072] In a 100 mL single-necked flask, 01 (100 mg, 0.279 mmol), 02 (60 mg, 0.279 mmol), potassium carbonate (116 mg, 0.839 mmol), Pd(dppf)Cl2 (20 mg, 0.0279 mmol), dioxane (4 mL), and water (1 mL) were added. The mixture was stirred at 100°C under nitrogen for 16 h. After cooling to room temperature, the reaction mixture was evaporated to dryness to obtain a crude product. The crude product was purified by Pre-TLC (PE:EA = 1:3) to obtain the desired product as a white solid (83 mg, yield: 81.4%). LC-MS: 365.1 [M+H] +

[1073] Step 2:

[1074]

[1075] In a 100 mL single-necked flask, 03 (40 mg, 0.109 mmol) was dissolved in methanol (3 mL). Palladium on carbon (10 mg) was added and stirred under a hydrogen atmosphere for 16 hours. The mixture was filtered and dried to give the desired product as a white solid (35 mg, 87.0% yield), which was used directly in the next step.

[1076] LC-MS: 367.1[M+H] +

[1077] Step 3:

[1078]

[1079] At room temperature, 04 (35 mg, 0.095 mmol) was dissolved in trifluoroacetic acid (3 mL) and stirred at 70°C under nitrogen for 3 h. The reaction mixture was evaporated to dryness to obtain the desired product as a yellow oil (20 mg, yield: 90.1%). LC-MS: 233.1 [M+H] +

[1080] Step 4:

[1081]

[1082] At room temperature, 05 (20 mg, 0.086 mmol) was dissolved in pyridine (1 mL), and 06 (35 mg, 0.086 mmol) and EDCI (49 mg, 0.258 mmol) were added. The mixture was stirred at room temperature for 16 hours and concentrated to obtain a crude product. The crude product was purified by HPLC to obtain the desired product as a yellow solid (6.35 mg, 11.9% yield). LC-MS: 622.1 [M+H] + , 1HNMR (400MHz, DMSO-d6) δ11.10(s,1H),9.13(s,1H),8.42(d,J=5.4Hz,2H),8.32(d,J=7.8Hz,1H),8.16(d,J= 7.2Hz,1H),7.85(d,J=8.0Hz,1H),7.77-7.66(m,2H),7.52-7.50(m,2H),7.45-7.36(m,2H),7.34-7.24(m,2H ),7.03(t,J=7.4Hz,1H),6.95(t,J=8.9Hz,1H),5.16-5.00(m,1H),4.61(dd,J=10.1,6.3Hz,2H),3.99-3.85( m,1H),3.00(s,1H),2.89-2.80(m,1H),2.64-2.54(m,2H),2.10-1.80(m,5H),1.76(s,2H),1.68-1.52(m,2H).

[1083] Example 51

[1084]

[1085] Preparation steps:

[1086] Step 1:

[1087]

[1088] In a 100 mL single-necked flask, 01 (166 mg, 0.467 mmol), 02 (100 mg, 0.467 mmol), potassium carbonate (193 mg, 1.401 mmol), Pd(dppf)Cl2 (34 mg, 0.0467 mmol), dioxane (4 mL), and water (1 mL) were added. The mixture was stirred at 100°C for 16 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature and dried to give a crude product. The crude product was purified by Pre-TLC (PE:EA = 1:3) to afford the desired product as a white solid (120 mg, yield: 70.9%). LC-MS: 365.0 [M+H] + .

[1089] Step 2:

[1090]

[1091] In a 100 mL single-necked flask, 03 (120 mg, 0.329 mmol) was dissolved in methanol (3 mL). Palladium on carbon (10 mg) was added and stirred under a hydrogen atmosphere for 16 hours. Filter and spin dry to obtain a white solid as the desired product (103 mg, yield: 85.4%), which was used directly in the next step. LC-MS: 367.0 [M+H] +

[1092] Step 3:

[1093]

[1094] At room temperature, 04 (103 mg, 0.281 mmol) was dissolved in trifluoroacetic acid (5 mL) and stirred at 70°C for 3 h under nitrogen. The reaction mixture was evaporated to dryness to obtain the desired product as a yellow oil (55 mg, yield: 84.2%). LC-MS: 233.1 [M+H] +

[1095] Step 4:

[1096]

[1097] At room temperature, 05 (55 mg, 0.237 mmol) was dissolved in pyridine (2 mL), and 06 (96 mg, 0.237 mmol) and EDCI (161 mg, 0.711 mmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction solution was dried and purified by HPLC to obtain the desired product as a yellow solid (1.46 mg, yield: 0.99%). LC-MS: 622.1 [M+H] + , 1 HNMR(400MHz,DMSO-d6)δ11.10(s,1H),9.00(s,1H),8.45–8.42(m,1H),8. 34(s,2H),7.97(s,1H),7.88(s,1H),7.75(s,1H),7.52(s,2H),7.49-7.39( m,2H),7.30(s,1H),7.03(s,1H),6.97(s,1H),5.07(s,1H),4.62(s,2H),3. 86(s,2H),2.97(s,2H),2.62(s,1H),2.25-1.80(m,6H),1.64-1.47(s,3H).

[1098] Example 52

[1099]

[1100] (1) Preparation steps

[1101] Step 1:

[1102]

[1103] To a 100 mL single-necked flask, 01 (142.49 mg, 0.84 mmol), 02 (200 mg, 0.56 mmol), potassium phosphate (237.73 mg, 1.12 mmol), tetrahydrofuran (10 mL), water (2 mL), and the catalyst Ruphos-Pd (50 mg, 0.0612 mmol) were added. The mixture was then reacted at 90°C for 3 hours under argon atmosphere. The mixture was then dried and column chromatography was performed to obtain the products of both molecular weights (03-P1: 50 mg, yield: 16.3%; 03-P2: 60 mg, yield: 19.6%). LC-MS: 365.2 [M+H] +

[1104] 03-P1:1HNMR(400MHz,CD3OD)δ8.24(d,J=8.2Hz,1H),8.06(d,J=8.2Hz,1H), 7.60(t,J=7.2Hz,1H),7.51(t,J=7.3Hz,1H),7.37(dt,J=22.2,7.4Hz,5H),6. 41(s,1H),5.14(s,2H),3.90(s,1H),2.87(d,J=16.7Hz,1H),2.72(d,J=16.7 Hz,2H),2.36–2.24(m,1H),2.11(s,1H),1.83(ddd,J=22.9,10.3,5.6Hz,1H).

[1105] 03-P2:1HNMR(400MHz,CD3OD)δ7.74(dd,J=7.7,1.0Hz,1H),7.65–7.60(m,1H),7.49(d,J=7.8Hz,1H),7.41(dd,J=6.6,5.7Hz,1H),7.39–7.31(m,5H), 6.16(s,1H),5.10(s,2H),3.78(s,1H),2.56(d,J=18.8Hz,1H),2.31(d,J= 16.4Hz,1H),2.28–2.16(m,2H),1.98(d,J=12.0Hz,1H),1.82–1.69(m,1H).

[1106] Step 2:

[1107]

[1108] In a 50 mL single-necked vial, 03-P1 (60 mg, 0.165 mmol), Pd(OH)2 / C (50 mg, 10%), and tetrahydrofuran (10 mL) were added and reacted at room temperature under a hydrogen atmosphere for 5 days. Filtration and concentration afforded the desired product (04-P1: 18 mg, yield: 29.7%). LC-MS: 367.3 [M+H] +

[1109] Step 3:

[1110]

[1111] 04-P1 (18 mg, 0.0491 mmol) and trifluoroacetic acid (2 mL) were added to a 50 mL single-necked bottle and reacted at 70°C for 1 hour. The mixture was then dried in a rotary evaporation chamber to obtain the tar...

Claims

1. A compound having a structure of formula A or a pharmaceutically acceptable salt thereof, in: T 1 is a glutarimide-containing group; T 2 is hydrogen or an optionally substituted fused 8-14 membered bicyclic or tricyclic heteroaryl having 1-6 ring heteroatoms each independently selected from N, S and O; preferably T 2 It is not hydrogen; Ring A1 is a 4-10 membered monocyclic or bicyclic carbocyclic or heterocyclic ring, which is arbitrarily substituted by one or more substituents, each of which is independently halogen, OH, CN, oxo, NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl or selected from C 3-7 A 3-7 membered ring of a carbocyclic ring, a 3-7 membered heterocyclic ring, a phenyl ring, or a 5- or 6-membered heteroaryl ring, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 The heteroalkyl or 3-7 membered ring is optionally substituted; Y 1 To Y 7 It has the following definitions (1)-(11): (1)Y 1 Selected from NH, O, S, S(O), SO2, C(G A )(G B ), C(O) or N(G C ); Y 2 Selected from NH, O, S, S(O), SO2, C(G A )(G B ), C(O) or N(G C ); Y 3 Selected from NH, O, S, S(O), SO2, C(G A )(G B ), C(O) or N(G C ); Y 4 Selected from NH, O, S, S(O), SO2, C(G A )(G B ), C(O) or N(G C ); Y 5 Selected from NH, O, S, S(O), SO2, C(G A )(G B ), C(O) or N(G C ); Y 6 Selected from NH, O, S, S(O), SO2, C(G A )(G B ), C(O) or N(G C ); Y 7 Selected from NH, O, S, S(O), SO2, C(G A )(G B ), C(O) or N(G C ); Among them G A and G B are each independently selected from hydrogen, deuterium, halogen, OH, C arbitrarily substituted by halogen and / or OH 1-4 Alkyl or C substituted by halogen and / or OH 1-4 Heteroalkyl, or two adjacent G A Connect to form a double bond or two adjacent C (G A )(G B ) represents a triple bond or G A and G B Together with the carbon atoms to which they are attached, they form an optionally substituted 3-7 membered carbocyclic or heterocyclic ring; G C Independently selected from C 1-4 Alkyl, C 1-4 heteroalkyl or an optionally substituted group of a 3-8 membered ring; The premise is: (ii) Two adjacent Y 1 To Y 7 Not all selected from NH, O, S or N(G C ); (iii) Two adjacent Y 1 To Y 7 are not all selected from S(O), SO2 or C(O); (iv) at most three selected from Y 1 To Y 7 The group can be S(O), SO2 or C(O); (v) at most two selected from Y 1 To Y 7 The group can be C(G A )(G B ), where G A and G B Together with the carbon atoms to which they are attached, they form an optionally substituted 3-6 membered carbocyclic or heterocyclic ring; (vi)Y 1 To Y 7 The combination does not include a bond selected from SS(O), S-SO2 and SC(O); (2)Y 3 , Y 4 and Y 5 Together they represent an optionally substituted 3-8 membered ring, Y 1 , Y 2 , Y 6 and Y 7 As defined in (1); (3)Y 4 , Y 5 and Y 6 Together they represent an optionally substituted 3-8 membered ring, Y 1 , Y 2 , Y 3 and Y 7 As defined in (1); (4)Y 5 , Y 6 and Y 7 Together they represent an optionally substituted 3-8 membered ring, Y 1 , Y 2 , Y 3 and Y 4 As defined in (1); (5)Y 3 , Y 4 , Y 5 and Y 6 Together they represent an optionally substituted 3-10 membered ring, Y 1 , Y 2 and Y 7 As defined in (1); (6)Y 4 , Y 5 , Y 6 and Y 7 Together they represent an optionally substituted 3-10 membered ring, Y 1 , Y 2 and Y 3 As defined in (1); (7)Y 2 , Y 3 and Y 4 Together they represent an optionally substituted 3-8 membered ring, Y 1 , Y 5 , Y 6 and Y 7 As defined in (1); (8)Y 2 , Y 3 , Y 4 and Y 5 Together they represent an optionally substituted 3-10 membered ring, Y 1 , Y 6 and Y 7 As defined in (1); (9)Y 2 , Y 3 , Y 4 , Y 5 and Y 6 Together they represent an optionally substituted 3-10 membered ring, Y 1 and Y 7 As defined in (1); (10)Y 3 , Y 4 , Y 5 , Y 6 and Y 7 together represent an optionally substituted 3-10 membered ring; preferably, selected from an 8-10 membered heterocyclic or heteroaromatic ring, Y 1 and Y 2 As defined in (1); (11)Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , and Y 7 can be selected from substituted 3-10 membered rings; preferably, selected from 8-10 membered heterocyclic or heteroaryl rings, Y 1 As defined in (1); Y 8 is absent, O, NH, C(O), optionally substituted C 1-6 Alkylene or optionally substituted C 1-6 Heteroalkylene.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein T 1 Has the following structure: in: X is CH2 or C(=O), n1 is an integer from 0 to 2, G 1 independently selected from halogen, CN, OH, NH2, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 heteroalkyl, an optionally substituted 3-8 membered carbocyclic or heterocyclic ring, an optionally substituted phenyl or an optionally substituted heterocyclic aromatic group.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, characterized in that: It has the structure shown in formula A1: 4 . The compound or pharmaceutically acceptable salt thereof according to claim 2 , wherein n1 is 0.

5. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein Y 1 Selected from NH, O or N(G C ); preferably, Y 1 Selected from NH or O.

6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein Y 2 C(G A )(G B ); preferably, G A and G B are each independently hydrogen, deuterium, halogen or C 1-4 Alkyl (eg methyl) or G A and G B Together with the carbon atoms to which they are attached, they form a 3-6 membered carbocyclic or heterocyclic ring, wherein the groups are independently optionally substituted by one or more halogen, OH and C 1-4 Alkyl (eg methyl) substitution, such as Y 2 CH2, CH(CH3), C(CH3)2, Preferably, Y 1 -Y 2 It is -NHCH2- or -OCH2-.

7. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein Y 3 , Y 4 , and Y 5 is an optionally substituted 3-8 membered ring, wherein the 3-8 membered ring is selected from a 3-8 membered carbocyclic ring, a 3-8 membered heterocyclic ring, a benzene ring, or a 5- or 6-membered heteroaromatic ring; preferably, Y 3 , Y 4 and Y 5 is an optionally substituted phenylene group or an optionally substituted 5- or 6-membered heteroaryl group.

8. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein Y 3 , Y 4 , and Y 5 is an optionally substituted phenylene or an optionally substituted 5- or 6-membered heteroaryl, wherein when Y 2 and Y 6 When on the phenyl or heteroaryl ring, Y is not in ortho position to each other. 2 and Y 6 In between each other.

9. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein Y 3 , Y 4 and Y 5 is 1,3-phenylene, wherein the H on the 1,3-phenylene may be substituted by one or more substituents, each of which is independently selected from halogen, CN, G 2 , OH, NH2, OG 2 , NHG 2 NG 2 G 2 、COOH、CONH2、C(O)OG 2 、C(O)NHG 2 or C(O)NG 2 G 2 , where G 2 Independently selected from optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 1-4 heteroalkyl, or an optionally substituted 3-7 membered ring (preferably a 3-7 membered carbocyclic or heterocyclic ring), preferably, when substituted, one or more H in the above groups may be substituted by a substituent selected from the following: oxo (if applicable), halogen, OH, CN, NH2, optionally substituted C 1-4 Alkyl, optionally substituted C 1-4 Heteroalkyl, or an optionally substituted 3-4 membered carbocyclic or heterocyclic ring; More preferably, G 2 Independently selected from the following groups: 1-3 G S1 Any substituted C 1-4 Alkyl, 1-3 G S2 Any substituted C 1-4 Heteroalkyl, or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 are independently selected from: halogen, OH, C optionally substituted by F 1-4 Heteroalkyl or a 3-4 membered carbocyclic or heterocyclic ring optionally substituted by F and / or methyl; G S2 independently selected from oxo (if applicable), halogen, OH, NH2, C optionally substituted by F 1-4 Alkyl, C arbitrarily substituted by F 1-4 Heteroalkyl or a 3-4 membered carbocyclic or heterocyclic ring optionally substituted by F and / or methyl.

10. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein Y 3 , Y 4 and Y 5 Together they represent a 5- or 6-membered heteroaryl group, such as 2,5-thienyl (i.e. ), 2,5-furandiene, 2,4-pyridinediene, 2,6-pyridyl, 3,5-pyridyl, 2,4-pyrimidyl, 2,6-pyrimidyl, or 4,6-pyrimidyl, etc. wherein the 5- or 6-membered heteroaryl is optionally substituted by one or more substituents, each of which is independently selected from halogen, CN, G 2 , OH, NH2, OG 2 , NHG2, NG 2 G 2 、COOH、CONH2、C(O)OG 2 、C(O)NHG 2 or C(O)NG 2 G 2 , where G 2 Independently selected from optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 1-4 heteroalkyl or an optionally substituted 3-7 membered ring (preferably a 3-7 membered carbocyclic or heterocyclic ring); preferably, when substituted, one or more H in the above groups may be substituted by a substituent selected from the following: oxo (if applicable), halogen, OH, CN, NH2, optionally substituted C 1-4 Alkyl, optionally substituted C 1-4 Heteroalkyl or an optionally substituted 3-4 membered carbocyclic or heterocyclic ring; More preferably, G 2 Independently selected from the following groups: 1-3 G S1 Any substituted C 1-4 Alkyl, 1-3 G S2 Any substituted C 1-4 Heteroalkyl or 1- 3G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 are independently selected from: halogen, OH, C optionally substituted by F 1-4 Heteroalkyl or a 3-4 membered carbocyclic or heterocyclic ring optionally substituted by F and / or methyl; G S2 independently selected from oxo (if applicable), halogen, OH, NH2, C optionally substituted by F 1-4 Alkyl, C arbitrarily substituted by F 1-4 Heteroalkyl or a 3-4 membered carbocyclic or heterocyclic ring optionally substituted by F and / or methyl.

11. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein Y 3 , Y 4 , and Y 5 The carbon atoms of the carbon atoms may be substituted by one or more of the following substituents: halogen, OH, NH2, C substituted by any of the following: 1-4 Alkyl, C arbitrarily substituted by F 1-4 Alkoxy or 3-4 membered carbon or heterocyclic ring optionally substituted by F and / or methyl, for example, Y 3 , Y 4 and Y 5 Together 12. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein Y 3 C(G A )(G B ); preferably, G A and G B are each independently selected from hydrogen, deuterium, halogen or C 1-4 Alkyl (eg methyl) or G A and G B Together with the carbon atoms to which they are attached, they form a 3-6 membered carbocyclic or heterocyclic ring, wherein one or more H on the carbon atom may be substituted by a substituent selected from the group consisting of OH and C 1-4 Alkyl (eg methyl), for example: Y 3 Selected from CH2, 13. A compound according to any one of claims 1 to 6 and 12 or a pharmaceutically acceptable salt thereof, wherein Y 4 Selected from O, NH, N(C 1-4 Alkyl) or C(G A )(G B ); preferably, G A and G B are each independently selected from hydrogen, deuterium, halogen or C 1-4 Alkyl (eg methyl) or G A and G B Together with the carbon atoms to which they are attached, they form a 3-6 membered carbocyclic or heterocyclic ring, wherein one or more H on the carbon atom may be substituted by a substituent selected from the group consisting of OH and C 1-4 Alkyl (eg methyl), for example: Y 4 Selected from O, CH2, CH(CH3), C(CH3)2, 14. A compound according to any one of claims 1-6 and 12-13 or a pharmaceutically acceptable salt thereof, wherein Y 5 Selected from O, NH, N(C 1-4 Alkyl), C(G A )(G B ); preferably, G A and G B are each independently selected from hydrogen, deuterium, halogen or C 1-4 Alkyl (eg methyl), or G A and G B Together with the carbon atoms to which they are attached, they form a 3-6 membered carbocyclic or heterocyclic ring, wherein one or more H on the carbon atom may be substituted by a substituent selected from the group consisting of OH and C 1-4 Alkyl (eg methyl), for example: Y 5 Selected from O or CH2.

15. A compound according to any one of claims 1 to 6 and 12 to 13 or a pharmaceutically acceptable salt thereof, wherein Y 5 , Y 6 , and Y 7 is an optionally substituted 3-8 membered ring selected from a 3-8 membered carbocyclic ring, a 3-8 membered heterocyclic ring, a phenyl ring or a heteroaryl ring, for example, 5 , Y 6 , and Y 7 Both 16. A compound according to any one of claims 1 to 6 and 12 to 14 or a pharmaceutically acceptable salt thereof, wherein Y 6 is O, C(O) or C(G A )(G B ); preferably, G A and G B are each independently selected from hydrogen, deuterium, halogen or C1-4 alkyl (eg methyl), for example, Y 6 Selected from O, C(O) or CH2.

17. A compound according to any one of claims 1-6, 12-14 and 16 or a pharmaceutically acceptable salt thereof, wherein Y 7 Selected from O, C(O), NH, N(G C ) or C(G A )(G B ); preferably, G A and G B are each independently selected from hydrogen, deuterium, halogen or C 1-4 Preferably, G C C 1-6 Alkyl (such as methyl) or C 1-6 Heteroalkyl, for example, Y 7 is selected from NH, O, CH2 or N(CH3).

18. A compound according to any one of claims 1-6 and 12-14 or a pharmaceutically acceptable salt thereof, wherein Y 6 -Y 7 Selected from -C(O)NH-, -C(O)-N(G C )-, -NHCH2- or -OCH2-, wherein G C C 1-6 Alkyl (such as methyl) or C 1-6 Heteroalkyl, for example, Y 6 -Y 7 Selected from -C(O)NH-, -C(O)-N(CH3)-, -NHCH2- or -OCH2-.

19. A compound according to any one of claims 1 to 6 and 12 or a pharmaceutically acceptable salt thereof, wherein Y 4 , Y 5 , Y 6 and Y 7 Together they represent an optionally substituted 3-8 membered ring selected from a 3-8 membered carbocyclic ring, a 3-8 membered heterocyclic ring, a benzene ring or a heteroaryl ring, for example, Y 4 , Y 5 , Y 6 and Y 7 Both 20. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, characterized in that: Y 2 , Y 3 , Y 4 , Y 5 , Y 6 and Y 7 Together they represent an optionally substituted 8-10 membered heterocyclic or heteroaryl ring.

21. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, characterized in that: Y 3 , Y 4 , Y 5 , Y 6 and Y 7 Together they represent an optionally substituted 8-10 membered heterocyclic or heterocyclic aromatic group, preferably, the 8-10 membered heterocyclic or heterocyclic aromatic group is selected from a 6,5-fused or 6,6-fused heterocyclic or heterocyclic aromatic group having 1-5 heteroatoms, wherein each heteroatom is independently selected from O, N or S.

22. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, characterized in that: Y 3 , Y 4 , Y 5 , Y 6 and Y 7 Together, they represent an optionally substituted 6,5-fused or 6,6-fused heterocyclic ring, wherein a benzene ring or a 6-membered heterocyclic aromatic group is fused to a 5- or 6-membered heterocyclic ring having 1 or 2 ring heteroatoms, each heteroatom being independently selected from O, N or S, and further preferably, the heteroatom is a N atom, for example, Y 4 , Y 5 , Y 6 and Y 7 Together for 23. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein Y 3 , Y 4 , Y 5 , Y 6 and Y 7 The 6,5- or 6,6-fused heteroaromatic rings are represented by any substitutions of 1 to 5 ring atoms, each heteroatom is independently selected from O, N or S, for example, any substitutions of benzimidazole, indazole, benzothiophene, etc., wherein the H on the carbon atom of the 6,5- or 6,6-fused heteroaromatic ring can be substituted by one to three groups selected from the following: halogen, CN, G 2 , OH, NH2, OG 2 , NHG 2 NG 2 G 2 、COOH、CONH2、C(O)OG 2 、C(O)NHG 2 or C(O)NG 2 G 2 ,in, G 2 Independently selected from optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, substituted C 2-4 Alkynyl, substituted C 1-4 Heteroalkyl, substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring); preferably, the H on the carbon atom may be substituted by one or more of the following groups: oxo (if applicable), halogen, OH, CN, NH2, substituted C 1-4 Alkyl, substituted C 1-4 Heteroalkyl, or an optionally substituted 3-4 membered carbocyclic or heterocyclic ring; More preferably, G 2 Independently selected from 1-3 G S1 Substituted C 1-4 Alkyl, 1-3 G S2 Substituted C 1-4 Heteroalkyl or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 independently selected from halogen, OH, C substituted with one or more F 1-4 Heteroalkyl, or a 3-4 membered carbocyclic or heterocyclic ring substituted by one or more F and / or methyl groups; G S2 independently selected from oxo (if applicable), halogen, OH, NH2, C substituted with one or more F 1-4 Alkyl, one or more F substituted C 1-4 heteroalkyl, or a 3-4 membered carbocyclic or heterocyclic ring optionally substituted by F and / or methyl.

24. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 23, characterized in that: Y 8 Does not exist.

25. The compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, wherein: Y 8 Selected from O, NH, C(O), C 1-2 Alkylene, or C 1-6 wherein the heteroatom is selected from O, N and S, wherein the S can be oxidized, the C 1-6 The heteroalkylene group may be substituted with 1 or 2 oxo groups.

26. The compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, wherein: A1 ring is a 4-8 membered monocyclic carbocyclic or heterocyclic ring, wherein the H on the carbon atom may be substituted by one or more of the following groups: halogen, OH, CN, oxo, C substituted by F 1-4 Alkyl or C substituted by F 1-4 Heteroalkyl.

27. The compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, wherein: Ring A1 is C 4-7 Cycloalkyl, wherein the H on the carbon atom may be substituted by one or more of the following groups: halogen, OH, CN, oxo, C substituted by F 1-4 Alkyl or C substituted by F 1-4 Heteroalkyl.

28. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 25, characterized in that: Ring A1 is cyclohexylene, preferably, ring A1 is 1,4-trans-cyclohexylene, 29. The compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof, characterized in that T 2 is a 5,5- or 6,5-fused aromatic heterocycle which may be substituted, wherein the 5,5- or 6,5-fused aromatic heterocycle has 1 to 5 ring heteroatoms, each heteroatom being independently selected from O, N or S. For example, T 2 is selected from substituted thiazolopyridine, imidazopyridine, benzimidazole, pyrazolopyridine, oxazolopyridine, benzoxazole, indole, benzothiophene, benzothiazole, thienopyridine, thienopyrimidine, thienothiophene, etc., wherein the H on the carbon atom can be substituted by 1-3 groups of the following: halogen, CN, G 2 , OH, NH2, OG 2 , NHG 2 NG2G 2 、COOH、CONH2、C(O)OG 2 、C(O)NHG 2 or C(O)NG 2 G 2 , where G 2 Independently selected from substituted C 1-4 Alkyl, substituted C 2-4 Alkenyl, substituted C 2-4 Alkynyl, substituted C 1-4 heteroalkyl, or an optionally substituted 3-7 membered ring (preferably a 3-7 membered carbocyclic or heterocyclic ring); preferably, the H on the carbon atom may be substituted by one or more of the following groups: oxo (if applicable), halogen, OH, CN, NH2, substituted C 1-4 Alkyl, substituted C 1-4 Heteroalkyl, or substituted 3-4 membered carbocyclic or heterocyclic ring; More preferably, G 2 Independently selected from 1-3 G S1 Substituted C 1-4 Alkyl, 1-3 G S2 Substituted C 1-4 Heteroalkyl or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 independently selected from halogen, OH, C substituted by F 1-4 heteroalkyl, or a 3-4 membered carbocyclic or heterocyclic ring substituted with F and / or methyl; wherein G S2 independently selected from oxo (if applicable), halogen OH, NH2, F substituted C 1-4 Alkyl, F-substituted C 1-4 Heteroalkyl or a 3-4 membered carbocyclic or heterocyclic ring substituted by F and / or methyl.

30. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 28, characterized in that: T 2 is a substituted 6,5-fused aromatic heterocycle having 1-5 heteroatoms, wherein each heteroatom is independently selected from O, N or S, wherein one ring is selected from furan, thiophene, pyrrole, pyrazole, imidazole, oxazole, thiazole, isoxazole or isothiazole, and the ring is fused with benzene, pyridine, pyrimidine, pyridazine or pyrazine, and when the 6,5-fused aromatic heterocycle is substituted, it is preferably substituted with 1-3 substituents, each of which is independently selected from halogen, CN, G 2 , OH, NH2, OG 2 , NHG 2 NG 2 G 2 、COOH、CONH2、C(O)OG 2 、C(O)NHG 2 or C(O)NG 2 G 2 , where G 2 Each occurrence is independently selected from any substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 1-4 heteroalkyl or an optionally substituted 3-7 membered ring (preferably a 3-7 membered carbocyclic or heterocyclic ring), preferably, when substituted, the optionally substituted group is substituted by one or more substituents, each of which is independently oxo (as applicable), halogen, CN, G 2 , OH, NH2, OG 2 , NHG 2 NG 2 G 2 、COOH、CONH2、C(O)OG 2 、C(O)NHG 2 or C(O)NG 2 G 2 , where G 2 Independently selected from optionally substituted C 1-4 Alkyl, optionally substituted C 1-4 Heteroalkyl or an optionally substituted 3-4 membered carbocyclic or heterocyclic ring; More preferably, G 2 Independently selected from 1-3 G S1 Substituted C 1-4 Alkyl, 1-3 G S2 Substituted C 1-4 Heteroalkyl, or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 independently selected from halogen, OH, C substituted by F 1-4 Heteroalkyl, or a 3-4 membered carbocyclic or heterocyclic ring optionally substituted by F and / or methyl; G S2 independently selected from oxo (if applicable), halogen OH, NH2, C substituted with F 1-4 Alkyl, C substituted by F 1-4 heteroalkyl, or a 3-4 membered carbocyclic or heterocyclic ring substituted with F and / or methyl, preferably, T 2 Connected to ring A1 via a ring atom in the 5-membered ring, for example, T 2 Selected from the following aromatic heterocycles: wait.

31. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 28, characterized in that: T 2 is a substituted 5,6,5-fused, 6,5,5-fused or 5,6,6-fused tricyclic aromatic heterocycle, wherein the fused tricyclic aromatic heterocycle has 1-5 ring heteroatoms, wherein the heteroatoms are independently selected from O, N or S, wherein the 5-membered ring in the fused ring is independently selected from furan, thiophene, pyrrole, pyrazole, imidazole, oxazole, thiazole, isoxazole or isothiazole, and the 6-membered ring in the fused ring is independently selected from benzene, pyridine, pyrimidine, pyridazine or pyrazine; wherein the H on the carbon atom of the 5,6,5-fused, 6,5,5-fused or 5,6,6-fused tricyclic aromatic heterocycle is preferably substituted by 1-3 of the following groups: CN, G 2 , OH, NH2, OG 2 , NHG 2 NG 2 G 2 、COOH、CONH2、C(O)OG 2 、C(O)NHG 2 or C(O)NG 2 G 2 , where G 2 Independently selected from substituted C 1-4 Alkyl, substituted C 2-4 Alkenyl, substituted C 2-4 Alkynyl, substituted C 1-4 heteroalkyl, or a substituted 3-7 membered ring (preferably a 3-7 membered carbocyclic or heterocyclic ring), when substituted, the H on the carbon atom may be substituted by one or more of the following substituents: oxo (if applicable), halogen, OH, CN, NH2, substituted C 1-4 Alkyl, substituted C 1-4 Heteroalkyl, or substituted 3-4 membered carbocyclic or heterocyclic ring; More preferably, G 2 Independently selected from 1-3 G S1 Substituted C 1-4 Alkyl, 1-3 G S2 Substituted C 1-4 Heteroalkyl, or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 independently selected from halogen, OH, C substituted by F 1-4 Heteroalkyl, 3-4 membered carbocyclic or heterocyclic ring substituted by F and / or methyl; G S2 independently selected from oxo (if applicable), halogen, OH, NH2, C substituted with F 1-4 Alkyl, C substituted by F 1-4 heteroalkyl or a 3-4 membered carbocyclic or heterocyclic ring substituted with F and / or methyl, for example, T 2 Selected from the following aromatic heterocycles: wait.

32. A compound having the structure of the following formula B or a pharmaceutically acceptable salt thereof, in, T 1 is a glutarimide-containing group; T 3 is an 8-14 membered bicyclic or tricyclic fused heterocyclic aromatic group, wherein the fused heterocyclic aromatic group has 1-6 ring heteroatoms and is independently selected from N, S and O; n2 is an integer from 0 to 2, G 3 independently selected from halogen, OH, CN, oxo, C substituted by F 1-4 Alkyl, or C substituted by F 1-4 Heteroalkyl; preferably, n2 is 0; LNK is connected to T 1 and a cyclohexyl ring, the linker can be a chain, a ring or a ring-chain structure, wherein the number of atoms constituting the shortest chain or ring of the linker is at least 4 (e.g., 4, 5, 6, 7, 8 or 9), wherein the atoms constituting the chain or ring are independently selected from C, N, O and S, wherein the minimum number of atoms is T 1 The minimum number of linker atoms required to connect the cyclohexyl ring, from the bond to T 1 The residue is preferably cyclohexyl. It begins with the atom that is bonded to the cyclohexyl ring and ends with the atom that is bonded to the cyclohexyl ring.

33. The compound according to claim 32 or a pharmaceutically acceptable salt thereof, characterized in that: It has the structure shown in formula B1:

34. The compound according to claim 32 or 33 or a pharmaceutically acceptable salt thereof, characterized in that T 3 is a 6,5-fused heterocyclic aromatic group having 1-5 heterocyclic atoms, each heteroatom independently selected from O, N or S, wherein one fused ring is selected from furan, thiophene, pyrrole, pyrazole, imidazole, oxazole, thiazole, isoxazole or isothiazole, fused with a group selected from the following: benzene, pyridine, pyrimidine, pyridazine or pyrazine, and when substituted, the 5-fused heterocyclic aromatic group is preferably substituted with 1-3 substituents, each substituent independently selected from halogen, CN, G 2 , OH, NH2, OG 2 , NHG 2 NG 2 G 2 、COOH、CONH2、C(O)OG 2 、C(O)NHG 2 or C(O)NG 2 G 2 , where G 2 Independently selected from substituted C 1-4 Alkyl, substituted C 2-4 Alkenyl, substituted C 2-4 Alkynyl, substituted C 1-4 heteroalkyl, or a substituted 3-7 membered ring (preferably a 3-7 membered carbocyclic or heterocyclic ring), when substituted, the H on the carbon atom may be substituted by one or more of the following substituents: oxo (if applicable), halogen, OH, CN, NH2, substituted C 1-4 Alkyl, substituted C 1-4 Heteroalkyl, or substituted 3-4 membered carbocyclic or heterocyclic ring; More preferably, G 2 Independently selected from 1-3 G S1 Substituted C 1-4 Alkyl, 1-3 G S2 Substituted C 1-4 Heteroalkyl, or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 independently selected from halogen, OH, C substituted by F 1-4 Heteroalkyl, 3-4 membered carbocyclic or heterocyclic ring substituted by F and / or methyl; G S2 independently selected from oxo (if applicable), halogen, OH, NH2, C substituted with F 1-4 Alkyl, C substituted by F 1-4 heteroalkyl or a 3-4 membered carbocyclic or heterocyclic ring substituted with F and / or methyl, T 3 By connecting to the cyclohexyl group via a ring atom on the 5-membered ring, for example, T 3 Selected from the following substituted or unsubstituted heterocyclic aromatic groups: wait.

35. The compound according to any one of claims 32 or 33 or a pharmaceutically acceptable salt thereof, characterized in that: T 3 is a 5,6,5-fused, 6,5,5-fused or 5,6,6-fused three-membered heterocyclic aromatic group, the ring has 1-5 ring heteroatoms, each of which is independently selected from O, N or S, wherein the 5-membered ring of the fused ring is independently selected from furan, thiophene, pyrrole, pyrazole, imidazole, oxazole, thiazole, isoxazole or isothiazole, and the 6-membered ring in the fused ring is independently selected from benzene, pyridine, pyrimidine, pyridazine or pyrazine, and when substituted, the fused three-membered heterocyclic aromatic group is preferably substituted by 1-3 of the following substituents: halogen, CN, G 2 , OH, NH2, OG 2 , NHG 2 NG 2 G 2 、COOH、CONH2、C(O)OG 2 、C(O)NHG 2 or C(O)NG 2 G 2 , where G 2 Independently selected from substituted C 1-4 Alkyl, substituted C 2-4 Alkenyl, substituted C 2-4 Alkynyl, substituted C 1-4 heteroalkyl, or a substituted 3-7 membered ring (preferably a 3-7 membered carbocyclic or heterocyclic ring), when substituted, the H on the carbon atom may be substituted by one or more of the following substituents: oxo (if applicable), halogen, OH, CN, NH2, substituted C 1-4 Alkyl, substituted C 1-4 Heteroalkyl, or substituted 3-4 membered carbocyclic or heterocyclic ring; More preferably, G 2 Independently selected from 1-3 G S1 Substituted C 1-4 Alkyl, 1-3 G S2 Substituted C 1-4 Heteroalkyl, or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 independently selected from halogen, OH, C substituted by F 1-4 Heteroalkyl, 3-4 membered carbocyclic or heterocyclic ring substituted by F and / or methyl; G S2 independently selected from oxo (if applicable), halogen, OH, NH2, C substituted with F 1-4 Alkyl, C substituted by F 1-4 heteroalkyl or a 3-4 membered carbocyclic or heterocyclic ring substituted with F and / or methyl, T 3 The 5-membered ring is connected to the cyclohexyl group, for example, 3 Selected from the following substituted or unsubstituted heterocyclic aromatic groups: wait.

36. The compound according to any one of claims 32 to 35 or a pharmaceutically acceptable salt thereof, characterized in that: T 1 Has the following structure: in: X is selected from CH2 or C(=O), n1 is an integer from 0 to 2, G 1 are independently selected from halogen, CN, OH, NH2, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 heteroalkyl, substituted or substituted 3-8 membered carbocyclic or heterocyclic ring, substituted or substituted phenyl, substituted or substituted aromatic heterocyclic ring.

37. The compound or pharmaceutically acceptable salt thereof according to any one of claims 36, characterized in that: It has the structure of formula B2:

38. The compound or pharmaceutically acceptable salt thereof according to any one of claims 36 or 37, characterized in that: n1 is 0.

39. The compound according to any one of claims 32 to 38 or a pharmaceutically acceptable salt thereof, characterized in that: LNK is a linker defined in the present application, for example, a linker defined in claims 5-25: or is or is any chain structure as defined herein for formula (I) for l.

40. A compound having a structure of formula C or a pharmaceutically acceptable salt thereof, in: T 1 is a glutarimide-containing group; LNK is connected to T 1 and a linker of ring A1, the linker being a chain, a ring or a ring-chain structure, wherein the number of atoms constituting the shortest chain or ring of the linker is at least 4 (e.g., 4, 5, 6, 7, 8 or 9), wherein the atoms constituting the chain or ring are independently selected from C, N, O and S, wherein the minimum number of atoms is the minimum number of atoms of the linker required for T1 to connect to the cyclohexyl ring, starting from the atom bonded to T1 and ending with the atom bonded to the cyclohexyl ring; Ring A1 is selected from an optionally substituted 4-10 membered monocyclic or bicyclic carbocyclic or heterocyclic ring; T 4 is an optionally substituted 5,5- or 6,5-fused heterocyclic aromatic group, the heterocyclic ring having 1-5 ring heteroatoms, each independently selected from O, N or S; or an optionally substituted 5,6,5-fused, 6,5,5-fused or 5,6,6-fused aromatic three-membered heterocyclic ring, the ring having 1-6 ring heteroatoms, each independently selected from O, N or S; preferably, T 4 A ring atom on the 5-membered ring is bonded to Ring A1.

41. The compound according to any one of claims 40 or a pharmaceutically acceptable salt thereof, characterized in that: T 4 is a substituted or unsubstituted 6,5-fused heterocyclic aromatic group having 1 to 5 ring heteroatoms, wherein the ring heteroatoms are each independently selected from O, N or S, wherein one of the fused rings is selected from furan, thiophene, pyrrole, pyrazole, imidazole, oxazole, thiazole, isoxazole or isothiazole, which is fused with benzene, pyridine, pyrimidine, pyridazine or pyrazine, and when the 6,5-fused heterocyclic aromatic group is substituted, the 5-fused heterocyclic aromatic group is preferably substituted with 1 to 3 substituents, each of which is independently selected from halogen, CN, G 2 , OH, NH2, OG 2 , NHG 2 NG 2 G 2 、COOH、CONH2、C(O)OG 2 、C(O)NHG 2 or C(O)NG 2 G 2 , where G 2 Independently selected from substituted C 1-4 Alkyl, substituted C 2-4 Alkenyl, substituted C 2-4 Alkynyl, substituted C 1-4 heteroalkyl, or a substituted 3-7 membered ring (preferably a 3-7 membered carbocyclic or heterocyclic ring), when substituted, the H on the carbon atom may be substituted by one or more of the following substituents: oxo (if applicable), halogen, OH, CN, NH2, substituted C 1-4 Alkyl, substituted C 1-4 Heteroalkyl, or substituted 3-4 membered carbocyclic or heterocyclic ring; More preferably, G 2 Independently selected from 1-3 G S1 Substituted C 1-4 Alkyl, 1-3 G S2 Substituted C 1-4 Heteroalkyl, or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 independently selected from halogen, OH, C substituted by F 1-4 Heteroalkyl, 3-4 membered carbocyclic or heterocyclic ring substituted by F and / or methyl; G S2 independently selected from oxo (if applicable), halogen, OH, NH2, C substituted with F 1-4 Alkyl, C substituted by F 1-4 heteroalkyl or a 3-4 membered carbocyclic or heterocyclic ring substituted with F and / or methyl, T 4 Selected from the following substituted or unsubstituted heterocyclic aromatic groups: wait.

42. The compound according to any one of claims 40 or a pharmaceutically acceptable salt thereof, characterized in that: T 4 is an optionally substituted 5,6,5-fused, 6,5,5-fused or 5,6,6-fused three-membered heterocyclic aromatic group, the ring having 1-5 ring heteroatoms, each of which is independently selected from O, N or S, wherein the 5-membered ring of the fused ring is independently selected from furan, thiophene, pyrrole, pyrazole, imidazole, oxazole, thiazole, isoxazole or isothiazole, and the 6-membered ring in the fused ring is independently selected from benzene, pyridine, pyrimidine, pyridazine or pyrazine, and when substituted, the fused three-membered heterocyclic aromatic group is preferably substituted by 1-3 of the following substituents: halogen, CN, G 2 , OH, NH2, OG 2 , NHG 2 NG 2 G 2 、COOH、CONH2、C(O)OG 2 、C(O)NHG 2 or C(O)NG 2 G 2 , where G 2 Independently selected from substituted C 1-4 Alkyl, substituted C 2-4 Alkenyl, substituted C 2-4 Alkynyl, substituted C 1-4 heteroalkyl, or a substituted 3-7 membered ring (preferably a 3-7 membered carbocyclic or heterocyclic ring), when substituted, the H on the carbon atom may be substituted by one or more of the following substituents: oxo (if applicable), halogen, OH, CN, NH2, substituted C 1-4 Alkyl, substituted C 1-4 Heteroalkyl, or substituted 3-4 membered carbocyclic or heterocyclic ring; More preferably, G 2 Independently selected from 1-3 G S1 Substituted C 1-4 Alkyl, 1-3 G S2 Substituted C 1-4 Heteroalkyl, or 1-3 G S2 substituted 3-7 membered ring (preferably 3-7 membered carbocyclic or heterocyclic ring), wherein G S1 independently selected from halogen, OH, C substituted by F 1-4 Heteroalkyl, 3-4 membered carbocyclic or heterocyclic ring substituted by F and / or methyl; G S2 independently selected from oxo (if applicable), halogen, OH, NH2, C substituted with F 1-4 Alkyl, C substituted by F 1-4 heteroalkyl or a 3-4 membered carbocyclic or heterocyclic ring substituted with F and / or methyl, T4 is selected from the following substituted or unsubstituted heterocyclic aromatic groups: wait.

43. The compound according to any one of claims 40 to 42 or a pharmaceutically acceptable salt thereof, characterized in that: T 1 Has the following structure: in, X is CH2 or C(=O), n1 is an integer from 0 to 2, G 1 independently selected from halogen, CN, OH, NH2, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 heteroalkyl, substituted or unsubstituted 3-8 membered carbocyclic or heterocyclic ring, substituted or unsubstituted phenyl or substituted or unsubstituted heteroaryl.

44. The compound according to any one of claims 43 or a pharmaceutically acceptable salt thereof, characterized in that: It has the structure shown in formula C1:

45. The compound according to claim 43 or 44, or a pharmaceutically acceptable salt thereof, wherein n1 is 0.

46. ​​A compound according to any one of claims 40-45, or a pharmaceutically acceptable salt thereof, wherein LNK is any linker as defined herein, for example, as defined in any one of claims 5-25. The structure or the structure of L defined in the present application connected to formula (I) serves as a linker.

47. The compound or pharmaceutically acceptable salt thereof according to any one of claims 40 to 46, wherein Ring A1 is an optionally substituted 4-8 membered monocyclic carbocyclic or heterocyclic ring.

48. The compound or pharmaceutically acceptable salt thereof according to any one of claims 40 to 46, wherein Ring A1 is substituted or unsubstituted C 4-7 Cycloalkyl.

49. The compound or pharmaceutically acceptable salt thereof according to any one of claims 40 to 46, wherein Ring A1 is cyclohexylene, preferably 1,4-trans-cyclohexylene, 50. A compound selected from Examples 1-150 or a pharmaceutically acceptable salt thereof.

51. A pharmaceutical composition according to any one of claims 1 to 50 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

52. A method for inducing protein degradation in a cell, the method comprising contacting the cell with any one of the compounds of claims 1-50 or a pharmaceutically acceptable salt thereof.

53. The method of claim 52, wherein: The protein is GSPT1.

54. The method of claim 52 or 53, wherein the cell is a cancer cell.

55. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 50 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 51 56. The method of claim 55, wherein the cancer is associated with GSPT1 activity.

57. A compound or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof, wherein the compound has the structure: in, W is selected from: C 0-10 Alkyl, C 3-6 Cycloalkyl, heterocycloalkyl, and heteroaryl; R1 is one or more independent substituents of ring A, selected from: halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 Alkyl)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CO(C 0-10 Alkyl) and L' is selected from: single bond, C 1-10 Alkylene, -O-, -OC 1-10 Alkylene-, -S-, -SC 1-10 Alkylene-, -SO-, -SO-C 1-10 Alkylene-, -SO 2- 、-SO 2- C 1-10 Alkylene-, -N(C 0-10 Alkyl)-, -N-(C 0-10 alkyl) alkylene-, -CO-, -CO-C 1-10 Alkylene-, -CONH- and -CONH-C 1-10 Alkylene-; R6 is one or more independent substituents on ring B, -CN, -NO2, -CF3, -OCF3, C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 Alkyl)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CO(C 0-10 Alkyl), C 3-6 Cycloalkyl, heterocycloalkyl, and heteroaryl; R2 is one or more independent substituents of the benzene ring selected from: halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 Alkyl)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CO(C 0-10 Alkyl), C 3-6 Cycloalkyl, aryl, heterocycloalkyl, and heteroaryl; V is selected from: O, S, Where R v1 , R v2 Independently selected from: C 0–10 Alkyl, C 3–6 Cycloalkyl and heterocycloalkyl groups; Q is H or a single bond or Q and V together with the carbon atom between them form an aryl or heteroaryl group; L has the following structure: in L1 is selected from: -NR L1 - (C 0-10 Alkylene)-, -O-(C 0-10 Alkylene)-, -S-(C 0-10 Alkylene)-, -NR L1 CO-(C 0-10 Alkylene)-, -CONR L1 - (C 0-10 Alkylene)-, -CO-(C 0-10 Alkylene)-, -NR L1 CONH-(C 0-10 Alkylene)-, -(C 1-10 Alkylene)-, -SO 2- (C 0-10 Alkylene)-, -SO-(C 0-10 Alkylene)-, Where R L1 Selected from: H, -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl and heterocycloalkyl, wherein C 1-6 One or more H, C 3-6 Cycloalkyl or heterocycloalkyl may be selected from: halogen (especially F), -OH, -NH2, alkoxy, alkylamino, C 3-6 Substituents of cycloalkyl and heterocycloalkyl; R L1 ' and R L1 " is independently selected from: halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and heterocycloalkyl, wherein C 1-6 One or more H, C 3-6 The cycloalkyl or heterocycloalkyl may be substituted by a substituent selected from: halogen (especially F), -OH, -NH2, alkoxy, alkylamino, C3-cycloalkyl and heterocycloalkyl; or R L1' and R L1” Together with the carbon atom attached thereto, it forms a cycloalkyl or heterocyclic group; L3 is selected from: -(C 0-10 Alkylene)-, -(C 0-10 Alkylene)-NR L3 - 、-(C 0-10 Alkylene)-O-, -(C 0-10 Alkylene)-S-, -(C 0-10 Alkylene)-NR L3 CO-、-(C 0-10 Alkylene)-CONR L3 - 、-(C 0-10 Alkylene)-CO-, -(C 0-10 Alkylene)-NHCONR L3 - 、-(C 0-10 Alkylene)-SO 2- 、-(C 0-10 Alkylene)-SO-, -NR L3 - (C 0-10 Alkylene)-, -O-(C 0-10 Alkylene)-, -S-(C 0-10 Alkylene)-, -NR L3 CO-(C 0-10 Alkylene)-, -CONR L3 - (C0-alkylene)-, -CO-(C 0-10 Alkylene)-, -NHCONR L3 - (C 0-10 Alkylene)-, -SO 2- (C 0-10 Alkylene)-, -SO-(C 0-10 Alkylene)-, Where R L3 Selected from: H, -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl and heterocycloalkyl, wherein C 1-6 One or more H, C 3-6 Cycloalkyl or heterocycloalkyl may be selected from: halogen (especially F), -OH, -NH2, alkoxy, alkylamino, C 3-6 Substituents of cycloalkyl and heterocycloalkyl; R L3' and R L3” Alcohols are independently selected from: halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and heterocycloalkyl, wherein C 1-6 One or more H, C 3-6 Cycloalkyl or heterocycloalkyl may be selected from: halogen (especially F), -OH, -NH2, alkoxy, alkylamino, C 3-6 Substituents of cycloalkyl and heterocycloalkyl are substituted; or R L3' and R L3” Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclyl group; L2 is a covalent bond or a divalent, saturated or unsaturated straight or branched chain C 1-50 (e.g. C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 25 , C 30 , C 35 , C 40 , C 45 or C 50 ) hydrocarbon chain, wherein 0-6 methylene units are independently replaced by: -CY-, -O-, -NR L2 - , -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NR L2 S(O)2-、-S(O)2-R L2 -、-NRL2R L2 -C(O)-, -C(O)NR L2 -、-OC(O)NR L2 -、-NR L2 -C(O)O-, wherein M is an integer selected from 0-10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10), and each -C y - is independently selected from the following optionally substituted divalent rings: arylene, cycloalkylene and heterocyclylene; R L2 Selected from: H, -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl and heterocycloalkyl, wherein C 1-6 One or more H, C 3-6 Cycloalkyl or heterocycloalkyl may be selected from halogen (especially F), -OH, -NH2, alkoxy, alkylamino, C 3-6 The substituents of the cycloalkyl and heterocycloalkyl groups are substituted.

58. The compound according to claim 57, wherein W is Wherein R3 is selected from: C0-10 alkyl, C3-6 cycloalkyl, heterocycloalkyl and heteroaryl; R4 and R5 are independently selected from: halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 Alkyl, -O(C0-alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 Alkyl)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CO(C 0-10 Alkyl), C 3-6 Cycloalkyl, heterocycloalkyl, and heteroaryl; Preferably, W is 59. The compound according to claim 57 or 58, wherein V is selected from: -CH2-, and -NH-; preferably, V is 60. A compound according to any one of claims 57-59 having the following structural formula: Where R 201 , R 202 and R 203 are independently selected from cycloalkyl, aryl, heterocycloalkyl and heteroaryl; or R 201 , R 202 and R 203 Independently selected from: halogen, -CN, -NO2, -CF3, -OCF3, -H, C 1–6 Alkyl, -OH, -NH2, and -N(C 1–3 Alkyl)(C 1–3 alkyl); Preferably, R 201 , R 202 and R 203 All are H.

61. The compound according to claim 57 or 58, having the following structure: Wherein Y1 and Y2 are independently selected from: CH and N; R 201 , R 202 and R 203 are independently selected from: cycloalkyl, aryl, heterocycloalkyl and heterocycloaryl; or R 201 , R 202 and R 203 Independently selected from: halogen, -CN, -NO2, -CF3, -OCF3, -H, C 1–6 Alkyl, -OH, -NH2, and -N(C 1–3 Alkyl)(C 1–3 alkyl); Preferably, Y1 and Y2 are both CH; or Y1 is CH and Y2 is N; or Y1 is N and Y2 is CH; or Y1 and Y2 are both N; Preferably, R 201 , R 202 and R 203 All are H.

62. The compound of claims 57-61, wherein Ring A is a benzene ring, an 8-10 membered bicyclic aromatic ring, a 3-7 membered monocyclic saturated aliphatic ring, a 4-7 membered saturated spiro alicyclic ring, an 8-10 membered saturated fused alicyclic ring, an 8-10 membered saturated bridged alicyclic ring, a 4-7 membered monocyclic saturated heterocyclic ring, a 4-7 membered saturated spiro heterocyclic ring, an 8-10 membered saturated fused heterocyclic ring, or an 8-10 membered saturated bridged heterocyclic ring; Preferably, the group Selected from: More preferably, the group Selected from More preferably, the group yes 63. The compound according to any one of claims 57 to 62, wherein Ring B is a benzene ring, a bicyclic aromatic ring, a tricyclic aromatic ring, a monocyclic heteroaromatic ring, a bicyclic heteroaromatic ring or a tricyclic heteroaromatic ring.

64. A compound according to any one of claims 57-63, wherein yes Where R 601 , R 602 , R 603 , R 604 and R 605 Independently selected from: halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 Alkyl)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CO(C 0-10 alkyl), cycloalkyl, heterocycloalkyl and heteroaryl, wherein The H at the carbon atom may be substituted by one or more groups selected from the following: halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 Alkyl)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CO(C 0-10 Alkyl), C 3-6 Cycloalkyl, heterocycloalkyl, and heteroaryl; Preferably, R 601 , R 602 , R 603 , R 604 and R 605 Independently selected from: -H, halogen, -OH, C 1-6 Alkyl and -O(C 1-6 alkyl).

65. A compound according to any one of claims 57-63, wherein The section has the following structure: wherein A1, A2, A3, A4, A5 and A6 are independently selected from C and N, and at least one of A1, A2, A3, A4, A5 and A6 is N; when any one of A2, A3, A4, A5 and A6 is N, R 601 , R 602 , R 603 , R 604 and R 605 There is no corresponding group; R 601 , R 602 , R 603 , R 604 and R 605 Independently selected from: halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 Alkyl)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 Alkyl), C 3-6 Cycloalkyl, heterocycloalkyl and heteroaryl, wherein the H at the carbon atom may be substituted by one or more groups selected from the following: halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 Alkyl)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CO(C 0-10 Alkyl), C 3-6 Cycloalkyl, heterocycloalkyl, and heteroaryl; Preferably, Select from the following structures: Preferably, in Formula VII, R 601 , R 602 , R 603 , R 604 and R 605 Independently selected from: -H, -D, -F, -Cl, -Br, -I, -CF3, -CHF2, -CH2F, -CH2CF3, -CN, -NO2, -CH3, -OH, -NH2, 66. A compound according to any one of claims 57 to 63, wherein Has the following structure: wherein A1, A2 and A3 are independently selected from C, N, O and S; B1, B2 and B3 are independently selected from C and N; B4 is C, N or does not exist, and satisfies valence saturation; R 601 , R 602 , R 603 , R 604 , R 605 , R 606 and R 607 May not exist under appropriate circumstances; R 601 , R 602 , R 603 , R 604 , R 605 , R 606 and R 607 Independently selected from: halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 Alkyl)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CO(C 0-10 Alkyl), C 3-6 Cycloalkyl, heterocycloalkyl and heteroaryl, wherein the H at the carbon atom may be substituted by one or more groups selected from the following: halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 Alkyl)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CO(C 0-10 Alkyl), C 3-6 Cycloalkyl, heterocycloalkyl, and heteroaryl; Preferably, Select from the following structures: Preferably, in Formula VIII, R 601 , R 602 , R 603 , R 604 , R 605 , R 606 and R 607 Independently selected from: -H, -D, -F, -Cl, -Br, -I, -CF3, -CHF2, -CH2F, -CH2CF3, -CN, -NO2, -CH3, -OH, -NH2, More preferably, R 601 Selected from: -H, C 1-6 Alkyl (e.g., methyl, ethyl, n-propyl or isopropyl), C 3-6 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), heterocycloalkyl (e.g. ), wherein the C 1-6 Alkyl, C 3-6 One or more H in the cycloalkyl or heterocycloalkyl group may be substituted by a substituent selected from the group consisting of halogen (especially F), -OH, -NH2, alkoxy, alkylamino and C 3-6 More preferably, R 601 Selected from: -H, C 1–3 alkyl, More preferably, R 603 Selected from: -H, C 1-6 Alkyl (e.g., methyl, ethyl, n-propyl, or isopropyl), -OH, C 1-6 Alkoxy (e.g. methoxy or ethoxy), -NH2, C 1-6 Alkylamino (e.g. ), C 3–6 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) and heterocycloalkyl (e.g., ), wherein the C 1-6 Alkyl, C 3-6 One or more H in the cycloalkyl or heterocycloalkyl group may be substituted by a substituent selected from the group consisting of halogen (particularly F), -OH, -NH2, alkoxy, alkylamino, and C 3-6 More preferably, R 603 Selected from: -H, methoxy and More preferably, R 604 Selected from: -H, C 1-6 Alkyl (e.g., methyl, ethyl, n-propyl, or isopropyl), -OH, C 1-6 Alkoxy (e.g. methoxy or ethoxy), -NH2, C 1-6 Alkylamino (e.g. ), C 3–6 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), heterocycloalkyl (e.g., ), where C 1-6 Alkyl, C 3-6 One or more H in the cycloalkyl or heterocycloalkyl group may be substituted by a substituent selected from the group consisting of halogen (especially F), -OH, -NH2, alkoxy, alkylamino and C 3-6 More preferably, R 604 Selected from: -H, methoxy and 67. A compound according to any one of claims 57 to 63, wherein Has the following structure: wherein A1, A2 and A3 are independently selected from C, N, O and S; B1, B2 and B3 are independently selected from C and N; B4 is C, N or absent; X1, X2 and X3 are independently selected from C, N, O and S and satisfy valence saturation; R 601 , R 602 , R 603 , R 604 , R 605 , R 606 and R 607 May not exist in appropriate circumstances; R 601 , R 602 , R 603 , R 604 , R 605 , R 606 and R 607 Independently selected from: halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 Alkyl)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CO(C 0-10 Alkyl), C 3-6 Cycloalkyl, heterocycloalkyl and heteroaryl, wherein the H on the carbon atom of the group can be substituted by one or more groups selected from the following: halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 Alkyl)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CO(C 0-10 Alkyl), C 3-6 Cycloalkyl, heterocycloalkyl, and heteroaryl; Preferably, Select from the following structures: More preferably, R 601 , R 602 , R 603 , R 604 , R 605 , R 606 and R 607 Independently selected from: -H, -D, -F, -Cl, -Br, -I, -CF3, -CHF2, -CH2F, -CH2CF3, -CN, -NO2, -CH3, -OH, -NH2, More preferably, R 601 Selected from: -H, C 1-6 Alkyl (e.g., methyl, ethyl, n-propyl or isopropyl) and C 3-6 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl); More preferably, R 604 Selected from: -H, C 1-6 Alkyl (e.g., methyl, ethyl, n-propyl or isopropyl) and C 3-6 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl); More preferably, R 607 Selected from: -H, C 1-6 Alkyl (e.g., methyl, ethyl, n-propyl or isopropyl) and C 3-6 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl); More preferably, R 602 Selected from:

68. A compound according to any one of claims 57 to 63, wherein Selected from: The H attached to the carbon atom may be optionally substituted by one or more groups selected from the following: halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0- Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 Alkyl)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0- Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CO(C 0-10 Alkyl), C 3-6 Cycloalkyl, heterocycloalkyl and heteroaryl.

69. The compound according to claim 1, wherein R1 is selected from the group consisting of: H, halogen, -CN, -NO2, -CF3, -OCF3, C 1-6 Alkyl, -O(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -COOH, -COO(C 1-6 alkyl), -OCOH, -OCO(C 1-6 alkyl), -CONH(C 1-6 Alkyl), -CON(C 1-6 Alkyl)(C 1-6 alkyl), 70. A compound according to any one of claims 57 to 69, wherein each -Cy- is independently selected from: Where R L4 is one or more independent substituents on the ring selected from: halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 Alkyl)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CO(C 0-10 alkyl) and three to six-membered heterocycloalkyl; Selected from: halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 Alkyl)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 alkyl)(C0-alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CO(C 0-10 alkyl); R L6 and R L7 Independently selected from: C 0-10 Alkyl, C 3-6 Cycloalkyl, heterocycloalkyl, and heteroaryl; R L8 and R L9 Independently selected from: halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 alkyl), -N(C0-alkyl)CON(C 0-10 Alkyl), -N(C 0-10 Alkyl)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl) and -CO(C 0-10 alkyl); or R L8 and R L9 With R L8 and R L9 The connected carbon atoms together form a substituted or unsubstituted cycloalkyl or heterocyclic group; Preferably, each -Cy- can be independently selected from: (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ),and (For example ); More preferably, each -Cy- is independently selected from:

71. Any one of the compounds according to claims 57 to 70, wherein L1 is selected from -NR L1 -(C 0–6 Alkylene)-, -O-(C 0–6 Alkylene)-, -S-(C 0–6 Alkylene)-, -(C 0–6 Alkylene)-, Where R L1 Selected from: H, C 1–6 Alkyl, wherein the H atom on the alkyl may be substituted by one or more of the following groups: halogen (especially F), -OH, -NH2, C 1-6 Alkoxy (such as methoxy or ethoxy) and C 1-6 Alkylamino (e.g. ); Preferably, L1 is selected from: -NH-, -NH-CH2-, -NH-CH2CH2-, -NH-CH2CH2CH2-, -O-, -O-CH2-, -O-CH2CH2-, -O-CH2CH2CH2-, -S-, -S-CH2-, -S-CH2CH2-, -S-CH2CH2CH2-, single bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, and 72. According to any one of claims 57 to 71, wherein L3 is selected from -(C 0–6 Alkylene)-NR L3 CO-、-(C 0–6 Alkylene)-CONR L3 -、-(C 0–6 Alkylene)-CO-, -(C 0–6 Alkylene)-NH-, -(C 0–6 Alkylene)-, -NR L3 -(C 0–6 Alkylene)-, -O-(C 0–6 Alkylene)-, -S-(C 0–6 Alkylene)-, -NR L3 CO-(C 0–6 Alkylene)-,- CONR L3 -(C 0–6 Alkylene)- or -CO-(C 0–6 Alkylene)-, wherein R L3 Selected from: H and C 1–6 Alkyl, wherein the H on the alkyl may be substituted by one or more groups selected from the following: halogen (especially F), -OH, -NH2, C 1-6 Alkoxy (such as methoxy or ethoxy) and C 1-6 Alkylamino (e.g. ); Preferably, L3 is selected from: -CONH-, -CH2-CONH-, -CH2CH2-CONH-, -CH2CH2CH2-CONH-, -NH-, -CH2-NH-, -CH2CH2-NH-, -CH2CH2CH2-NH-, single bond, -NHCO-, -NHCO-CH2-, -CO-, -CO-CH2-, -NH-CH2-, -O-CH2- and -S-CH2-.

73. Any compound according to claim 57 to 72, wherein L2 is selected from: C1-C20 straight chain alkylene, - (CH2CH2O) m2 - and -Cy-, wherein m2 is selected from 0, 1, 2, 3, 4 or 5.

74. A compound according to any one of claims 57 to 69, wherein L is selected from:

75. The compound according to claim 57, selected from the following structures:

76. The compound according to claim 57, wherein the stereoisomers are selected from the following structures:

77. A compound according to any one of claims 57 to 76, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof.

78. Use of any one of the compounds of claims 57 to 76 or pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds thereof in the preparation of a medicament for preventing and / or treating a GSPT1-related disease.

79. The use according to claim 78, wherein the GSPT1-related disease is selected from the group consisting of: autoimmune diseases, inflammatory diseases, heteroimmune diseases, neurodegenerative diseases, tumors; Preferably, the autoimmune disease is selected from the group consisting of organ-specific autoimmune disease, systemic lupus erythematosus, rheumatoid arthritis, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, autoimmune hemolytic anemia, thyroid autoimmune disease, and ulcerative colitis; Preferably, the inflammatory disease is selected from the group consisting of osteoarthritis, gout, chronic obstructive pulmonary disease, periodic fever, rash, lymphadenopathy, sepsis, osteoarthritis, ankylosing spondylitis, psoriasis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, uveitis, asthma, allergy; Preferably, the neurodegenerative disease is selected from: Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, different types of spinocerebellar ataxia, Pick's disease, etc.; Preferably, the tumor is selected from the group consisting of adrenal cancer, anal cancer, angiosarcoma, appendix cancer, bile duct cancer, bladder cancer, breast cancer, brain cancer, bronchial cancer, carcinoid tumor, cervical cancer, choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer, connective tissue cancer, epithelial cancer, ependymoma, endothelial sarcoma, endometrial cancer, esophageal cancer, Ewing's sarcoma, eye cancer, gallbladder cancer, gastric cancer, gastrointestinal stromal tumor (GIST), germ cell cancer, head and neck cancer, hematological malignancies, hemangioblastoma, hypopharyngeal cancer, inflammatory myofibroblastic tumor, immune Immunoblastic amyloidosis, renal cancer, liver cancer, lung cancer, leiomyosarcoma (LMS), muscle cancer, mesothelioma, myeloproliferative disease (MPD), neuroblastoma, neurofibroma, neuroendocrine cancer, osteosarcoma, ovarian cancer, papillary adenocarcinoma, pancreatic cancer, penile cancer, pineal tumor, primitive neuroectodermal tumor (PNT), prostate cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer, small intestine cancer, soft tissue sarcoma, sebaceous gland cancer, sweat gland cancer, synovioma, testicular cancer, thyroid cancer, urethral cancer, vaginal cancer, vulvar cancer.

80. The use according to claim 78, wherein the GSPT1-related disease is a hematological malignancy; Preferably, the hematological malignancy is selected from the group consisting of leukemia, lymphoma and multiple myeloma; Preferably, the leukemia is chronic lymphocytic leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, acute myeloid leukemia or acute monocytic leukemia, in particular acute myeloid leukemia; Preferably, the lymphoma is B-cell lymphoma, T-cell lymphoma or NK / T-cell lymphoma, in particular diffuse large B-cell lymphoma.

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