Compound containing tricyclic ring

Abstract

The present invention relates to a compound containing a tricyclic ring, and specifically relates to a compound of formula I, a preparation method therefor, a pharmaceutical composition containing the compound, and the use thereof in the treatment of related diseases (e.g., cancer). Formula I is PTM-L-CLM, wherein CLM is an E3 ubiquitin ligase binding moiety, L is a linking group, and PTM is a binding moiety targeting a target protein (e.g., GSPT1).

Description

Compounds containing tricyclic rings Technical Field

[0001] The present application relates to a compound containing a tricyclic ring, a preparation method thereof, a pharmaceutical composition containing the compound, and its use in treating related diseases (such as cancer). Background Art

[0002] G1 to S phase transition 1 (GSPT1) is a transcription factor that mediates the recognition of stop codons and promotes the release of transcribed peptide chains from ribosomes. In addition to its role in transcription termination, GSPT1 is also closely involved in various important cellular processes, such as cell cycle regulation, cytoskeleton formation, and apoptosis. GSPT1 is considered an oncogenic factor in various tumors and has become one of the most attractive potential anti-tumor targets. Furthermore, downregulating GSPT1 can also affect the expression of proteins such as AR and AR-V7.

[0003] The androgen receptor (AR) belongs to the steroid receptor family of the nuclear receptor superfamily. Upon binding to androgens (such as testosterone and dihydrotestosterone), AR is released from the heat shock protein complex, undergoes phosphorylation, forms a dimer, and translocates to the cell nucleus, where it binds to its associated DNA fragments, thereby stimulating the transcription of its target genes. The transcriptional activity of the AR activated by ligand binding is coordinated by proteins called co-activators. AR antagonists primarily act by directly preventing testosterone or dihydrotestosterone from binding to the AR, blocking the effects of androgens on cells. This leads to anti-androgenic and anti-cell growth effects, ultimately inducing cell apoptosis, achieving a crucial role in the treatment of prostate cancer. Second-generation AR signaling inhibitors, abiraterone and enzalutamide, have achieved some success in clinical treatment, but resistance has emerged. The F876L mutation in the ligand binding region is a missense mutation that confers resistance to enzalutamide, converting it from an antagonist to an agonist. In addition, AR splicing mutants, especially AR-v7 mutations lacking the ligand binding region, are important mediators of second-generation drug resistance. The treatment of drug-resistant cancers remains a key challenge in cancer therapy. Current drug therapies induce drug resistance, with AR mutations (including point mutations and splicing mutations) being a key factor. Therefore, the development of new drugs to treat drug-resistant cancers is crucial.

[0004] PROTAC (proteolysis targeting chimera) molecules are a class of bifunctional compounds that can simultaneously bind to target proteins and E3 ubiquitin ligases. These compounds can induce the recognition of target proteins by the cell's proteasome, causing their degradation and effectively reducing their levels in cells. By introducing ligands that can bind to different target proteins into PROTAC molecules, PROTAC technology has become possible for the treatment of various diseases and has received widespread attention in recent years.

[0005] The applicant used PROTAC technology to develop a series of compounds with GSPT1 degradation / inhibition activity to treat related diseases.

[0006] Detailed Description of the Invention

[0007] In one aspect, the present application relates to a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0008] PTM-L-CLM

[0009] in,

[0010] CLM was selected from the E3 ubiquitin ligase binding moiety;

[0011] L is selected from a linking group;

[0012] The PTM is selected from a binding moiety that targets a target protein (eg, GSPT1).

[0013] In some embodiments, the E3 ubiquitin ligase binding moiety is selected from a cereblon E3 ubiquitin ligase binding moiety, a VHL E3 ubiquitin ligase binding moiety, an IAP E3 ubiquitin ligase binding moiety, or an MDM2 E3 ubiquitin ligase binding moiety. In some embodiments, the E3 ubiquitin ligase binding moiety is selected from a cereblon E3 ubiquitin ligase binding moiety.

[0014] In some embodiments, the CLM is selected from small molecule compounds. In some embodiments, the PTM is selected from small molecule compounds.

[0015] In some embodiments, the CLM is covalently linked to L. In some embodiments, the PTM is covalently linked to L.

[0016] In one aspect, the present application relates to a compound of formula II, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0017] in,

[0018] represents a single bond or a double bond;

[0019] Ring W is selected from:

[0020] Ring A is absent or selected from C 3-15 Cycloalkenyl, 3-15 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl;

[0021] Ring B is selected from phenyl or 5-6 membered heteroaryl;

[0022] Ring C is absent or selected from 5-6 membered heteroaryl;

[0023] X 8 Selected from -C(O)- or -CH2-;

[0024] X 9 Selected from -C(R d R e )-、-N(R e )-, -O-, or -S-;

[0025] X 10 is selected from a bond, -CH2-, -NH-, -O- or -S-;

[0026] R d and R e are independently selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN, C 1-10 Alkyl, C 1-10 Alkoxy, (C 1-10 Alkyl)NH-, (C 1-10 Alkyl) 2N- or halogenated C 1-10 Alkyl, or R d and R e Connect to form C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl;

[0027] Each R 1 independently selected from deuterium, halogen, -OH, -NH2, -CN, the following groups optionally substituted with one or more substituents: C 1-10 Alkyl, C 1-10 Alkoxy, (C 1-10 Alkyl)NH-, (C 1-10 Alkyl) 2N-, halogenated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl;

[0028] n is selected from 0, 1, 2 or 3;

[0029] X 5 Selected from C(R f ) or N;

[0030] R f is selected from H, halogen, deuterium or C optionally substituted by one or more substituents 1-6 alkyl;

[0031] L 1 is selected from a bond, -NH-, -O-, -S-, -CONH- or -CON(C 1-6 alkyl)-;

[0032] L is selected from a linking group;

[0033] The PTM is selected from small molecule compounds that target a target protein (eg, GSPT1).

[0034] In one aspect, the present application also relates to a compound of formula III, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0035] in,

[0036] Ring W, L 1 、R 1 , n and X 5 As defined in this application,

[0037] L is selected from a linking group;

[0038] X 6 Selected from bond, -O-, -S-, -N(R t )-、-C 1-6 Alkylene-, -C 2-6 Alkenylene-, -C 2-6 Alkynylidene-, -N(R t )C 1-6 Alkylene-, -OC 1-6 Alkylene-, -SC 1-6 Alkylene-, or -N(R t )C(O)-;

[0039] R t Selected from H or C 1-6 alkyl;

[0040] Each R 2 、R 3 and R 4 are independently selected from halogen, -CN, the following groups optionally substituted by one or more substituents: R v -、R v O-、R v S-、R s R v N-、R v C(O)-、Rv S(O)2-、R v S(O)-、R v ＝ N-、R v OC(O)-、R v C(O)O-、R v S(O)O-、R v OS(O)-、R v S(O)2O-、R v OS(O)2-、R s R v NC(O)-、R v C(O)NH-、R v OC(O)NH-、R v NHC(O)O-、R v S(O)NH-、R s R v NS(O)-、R v S(O)2NH-、R s R v NS(O)2-or R s R v S(O) ＝ N-;

[0041] R s and R v are independently selected from H, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkyl C 1-3 Alkylene-, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl C 1-3 Alkylene-, C 3-12 Cycloalkenyl, C 3-12 Cycloalkenyl C 1-3 Alkylene-, 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl C 1-3 Alkylene-, C 6-12 Aryl, C 6-12 Aryl C 1-3 Alkylene-, 5-12 membered heteroaryl, or 5-12 membered heteroarylC 1-3 Alkylene-;

[0042] m, p and k are each independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0043] Ring G is selected from C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12Aryl, or 5-12 membered heteroaryl;

[0044] Ring E and Ring F are independently selected from C 6-12 Aryl or 5-12 membered heteroaryl;

[0045] Z is selected from -C-, -O-, -S-, -N-, -OC 1-6 Alkylene- or -NC(O)-;

[0046] R 5 and R 6 are independently absent, or are independently selected from H, =O, halogen, -OH, -NH2, -CN, C 1-10 Alkyl, C 2-10 Alkenyl or C 2-10 Alkynyl, or R 5 and R 6 are connected to each other to form the following group which is optionally substituted by one or more substituents: C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl.

[0047] In some embodiments, the CLM is selected from in Ring W, R 1 、n、L 1 and X 5 The definition of is as described in this application.

[0048] In some embodiments, the CLM is selected from in Ring A, Ring B, Ring C, R 1 、n、L 1 and X 5 The definition of is as described in this application.

[0049] In some embodiments, the PTM is selected from where X 6 , Z, R 2 、R 3 、R 4 , m, p, k, ring G, ring E, ring F, R 5 and R 6 The definition of is as described in this application.

[0050] In some embodiments, Ring W is selected from: Among them, ring A, ring B, ring C, X 8 、X 9 and X 10 The definition of is as described in this application.

[0051] In some embodiments, Ring A is absent, or is selected from C 3-12In some embodiments, C 3-12 Cycloalkenyl is selected from C 3-6 In some embodiments, the 3-12 membered heterocycloalkenyl group is selected from a 4-9 membered heterocycloalkenyl group.

[0052] In some embodiments, Ring A is absent or is selected from C 5-15 cycloalkenyl, 5-15 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0053] In some embodiments, Ring A is absent or is selected from C 5-10 cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0054] In some embodiments, Ring A is absent or is selected from C 5-9 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0055] In some embodiments, Ring A is absent or is selected from C 5-7 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0056] In some embodiments, Ring A is absent or is selected from C 5-6 cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0057] In some embodiments, Ring A is absent or is selected from C 5-6 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0058] In some embodiments, Ring A is absent or is selected from C 5-6 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5 membered heteroaryl.

[0059] In some embodiments, Ring A is absent or is selected from C 5-6 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl, pyrrolyl, pyrazolyl, furyl, or oxazolyl.

[0060] In some embodiments, Ring A is absent or is selected from C5 cycloalkenyl, C6 cycloalkenyl, 5-membered, 6-membered, 7-membered, 8-membered, or 9-membered heterocycloalkenyl, phenyl, pyrrolyl, pyrazolyl, furanyl, or oxazolyl.

[0061] In some embodiments, Ring A is absent or is selected from cyclopentenyl, monocyclohexenyl, bicyclohexenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine In some embodiments, ring A is selected from cyclopentenyl, or monocyclohexenyl. In some embodiments, ring A is selected from dihydropyrrolyl, tetrahydropyridinyl, or tetrahydroazapyridine. base.

[0062] In some embodiments, Ring A is selected from C 5-10 cycloalkenyl or 5-10 membered heterocycloalkenyl.

[0063] In some embodiments, Ring A is selected from C 5-7 In some embodiments, ring A is selected from C 5-7 cycloalkenyl or a 5-10 membered heterocycloalkenyl containing 1-3 heteroatoms selected from N, O or S.

[0064] In some embodiments, Ring A is selected from C 5-6 In some embodiments, ring A is selected from C 5-6 In some embodiments, Ring A is selected from a C5 cycloalkenyl or a 5-6 membered heterocycloalkenyl. In some embodiments, Ring A is selected from a C5 cycloalkenyl or a 5-6 membered heterocycloalkenyl. In some embodiments, Ring A is selected from a C5 cycloalkenyl or a 5-6 membered heterocycloalkenyl containing 1-2 N atoms or O atoms. In some embodiments, Ring A is selected from a dihydropyrrolyl or a tetrahydropyridinyl.

[0065] In some embodiments, Ring B is selected from phenyl or a 6-membered heteroaryl. In some embodiments, Ring B is selected from phenyl or a 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O, or S. In some embodiments, Ring B is selected from phenyl or a 6-membered heteroaryl containing 1-2 N atoms. In some embodiments, Ring B is selected from phenyl or pyridyl. In some embodiments, Ring B is phenyl.

[0066] In some embodiments, Ring C is absent or selected from a 5-membered heteroaryl group. In some embodiments, Ring C is selected from a 5-membered heteroaryl group. In some embodiments, Ring C is selected from a 5-membered heteroaryl group containing 1-3 (e.g., 1-2) heteroatoms selected from N, O, or S. In some embodiments, Ring C is absent or selected from isoxazolyl, pyrazolyl, or furanyl. In some embodiments, Ring C is selected from isoxazolyl or furanyl. In some embodiments, Ring C is isoxazolyl. In some embodiments, Ring C is absent.

[0067] In some embodiments, R 1 The substitution position of is selected from Ring A or Ring B. In some embodiments, R 1The substitution position of is selected from Ring A. In some embodiments, R 1 The substitution position of is selected from Ring B. In some embodiments, R 1 The substitution position of is selected from ring C. In some embodiments, R 1 Does not exist (ie, n is 0).

[0068] In some embodiments, Ring A is linked to L. In some embodiments, Ring B is linked to L. In some embodiments, Ring C is linked to L. In some embodiments, Ring A is linked to L 1 In some embodiments, ring B is connected to L 1 In some embodiments, ring C and L 1 In some embodiments, ring A is connected to the fragment Connection (When L 1 In some embodiments, ring B and fragment Connection (When L 1 In some embodiments, ring C and fragment Connection (When L 1 Select from keys).

[0069] In some embodiments, the structural fragment Selected from

[0070] In some embodiments, the structural fragment Selected from

[0071] In some embodiments, the structural fragment Selected from

[0072] In some embodiments, the structural fragment Selected from Phenyl, pyridyl,

[0073] In some embodiments, the structural fragment Selected from Phenyl, pyridyl,

[0074] In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment In some embodiments, the structural fragment Selected from

[0075] In some embodiments, the structural fragment Selected from Phenyl, pyridyl,

[0076] In some embodiments, the structural fragment Selected from

[0077] In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment In some embodiments, the structural fragment Selected from

[0078] In some embodiments, the structural fragment By n R 1 In some embodiments, n is 0 or 1. In some embodiments, n is 0.

[0079] In some embodiments, the structural fragment By n R 1 Replace each independently.

[0080] In some embodiments, the structural fragment Selected from

[0081] In some embodiments, X 9 Selected from -C(R d R e )-、-N(R e )-or-O-.

[0082] In some embodiments, X 9 Selected from -C(R d R e )-or-O-.

[0083] In some embodiments, X 10 is selected from a bond or -O-.

[0084] In some embodiments, R d and R e are independently selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, (C 1-6 Alkyl)NH-, (C 1-6 Alkyl) 2N- or halogenated C 1-6 Alkyl, or R d and R e Connect to form C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl.

[0085] In some embodiments, R d and R e are independently selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, or R d and R e Connect to form C 3-4 Cycloalkyl.

[0086] In some embodiments, R d and R e are independently selected from hydrogen, F, or methyl, or R d and R e They are connected to each other to form a cyclopropyl group.

[0087] In some embodiments, the structural fragment Selected from

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

[0089] In some embodiments, each R 1 independently selected from deuterium, halogen, -OH, -NH2, -CN, the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, C 1-6 Alkoxy, (C 1-10 Alkyl)NH-, (C 1-10 Alkyl) 2N-, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl.

[0090] In some embodiments, each R 1 independently selected from deuterium, halogen, -OH, -NH2, -CN, the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 alkyl.

[0091] In some embodiments, each R 1 independently selected from halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy or halogenated C 1-4 alkyl.

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

[0093] In some embodiments, n is selected from 0, 1, or 2. In some embodiments, n is selected from 0 or 1.

[0094] In some specific embodiments, n is selected from 0.

[0095] In some embodiments, the structural fragment Selected from Phenyl, Pyridyl,

[0096] In some embodiments, the structural fragment Selected from More preferably selected from

[0097] In some embodiments, X 5 Selected from C(R f ).

[0098] In some embodiments, R f is selected from H, fluorine, chlorine, bromine, deuterium or C optionally substituted by one or more substituents 1-3 alkyl.

[0099] In some embodiments, R f Selected from H, fluorine, chlorine, bromine, deuterium or C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with one or more of the following groups: halogen, -OH, -NH2, or -CN.

[0100] In some embodiments, R f Selected from H, fluorine, chlorine, bromine, deuterium or C 1-3 In some embodiments, R f is selected from H, fluorine, deuterium or methyl. In some embodiments, R f Selected from H.

[0101] In some embodiments, X 5 is selected from CH or N.

[0102] In some embodiments, X 5 Selected from CH.

[0103] In some embodiments, Selected from

[0104] In some embodiments, CLM, Selected from

[0105] In some embodiments, CLM or Selected from

[0106] In some embodiments, CLM, Selected from

[0107] In some embodiments, CLM, Selected from

[0108] In some embodiments, CLM or Selected from In some embodiments, CLM or Selected from In some embodiments, CLM or Selected from

[0109] In some embodiments, the L 1 In some embodiments, the L 1 Select from keys.

[0110] In some embodiments, the L is selected from the following groups optionally substituted with one or more substituents: C 1-50 Alkylene, C 2-50 Alkenylene or C 2-50 Alkynylidene, optionally, the C 1-50 Alkylene, C 2-50 Alkenylene or C 2-50 One or more -CH2- in the alkynylene group are independently optionally replaced by -O-, C 3-15 Cycloalkyl, 3-15 membered heterocycloalkyl, 4-15 membered heterocycloalkenyl, C 6-15 Aryl, 5-15 membered heteroaryl, -NH-, -N(C 1-6 alkyl)- or -S-substituted.

[0111] In some embodiments, the L is selected from the following groups optionally substituted with one or more substituents: C 1-30 Alkylene, C 2-30 Alkenylene or C 2-30 Alkynylidene, optionally, the C 1-30 Alkylene, C 2-30 Alkenylene or C 2-30One or more -CH2- in the alkynylene group are independently optionally replaced by -O-, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl, 5-12 membered heteroaryl, -NH-, -N(C 1-6 alkyl)- or -S-substituted.

[0112] In some embodiments, the L is selected from the following groups optionally substituted with one or more substituents: C 1-20 Alkylene, C 2-20 Alkenylene or C 2-20 Alkynylidene, optionally, the C 1-20 Alkylene, C 2-20 Alkenylene or C 2-20 One or more -CH2- in the alkynylene group are independently optionally replaced by -O-, C 3-10 Cycloalkyl, 3-11 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-10 Aryl, any 5-10 membered heteroaryl, -NH-, -N(C 1-6 alkyl)- or -S-substituted.

[0113] In some embodiments, the L is selected from the following groups optionally substituted with one or more substituents: C 1-15 Alkylene, C 2-15 Alkenylene or C 2-15 Alkynylidene, optionally, the C 1-15 Alkylene, C 2-15 Alkenylene or C 2-15 One or more -CH2- in the alkynylene group are independently optionally replaced by -O-, C 3-9 Cycloalkyl, 3-11 membered heterocycloalkyl, 4-8 membered heterocycloalkenyl, C 6-8 Aryl, 5-8 membered heteroaryl, -NH-, -N(C 1-4 alkyl)- or -S-substituted.

[0114] In some embodiments, the L is selected from the following groups optionally substituted with one or more substituents: C 1-10 Alkylene, C 2-10 Alkenylene or C 2-10 Alkynylidene, optionally, the C 1-10 Alkylene, C 2-10 Alkenylene or C 2-10 One or more -CH2- in the alkynylene group are independently optionally replaced by -O-, C 3-9 Cycloalkyl, 3-11 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, -NH-, -N(C 1-3 alkyl)- or -S-substituted.

[0115] In some embodiments, the L is selected from the following groups optionally substituted with one or more substituents: C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkynylidene, optionally, the C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 One or more -CH2- in the alkynylene group are independently optionally replaced by -O-, C 3-9 Cycloalkyl, 3-11 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, -NH-, -N(C 1-3 alkyl)- or -S-substituted.

[0116] In some embodiments, the L is selected from the following groups optionally substituted with one or more substituents: C 1-4 Alkylene, C 2-4 Alkenylene or C 2-4 Alkynylidene, optionally, the C 1-4 Alkylene, C 2-4 Alkenylene or C 2-4 One or more (e.g., one or two, one or three, etc.) -CH2- in the alkynylene group are independently optionally replaced by -O-, C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, -NH-, -N(C 1-3 alkyl)- or -S-substituted.

[0117] In some embodiments, the L is selected from C optionally substituted with one or more substituents. 1-10 Alkylene or C 2-10 Alkynylidene, optionally, the C 1-10 Alkylene or C 2-10 One or more -CH2- in the alkynylene group are independently optionally selected from -O-, C 3-12 Cycloalkyl, 4-12 membered heterocycloalkyl, 4-12 membered heterocycloalkenyl, -NH-, -N(C 1-6 alkyl)- or -S-substituted.

[0118] In some embodiments, the L is selected from C optionally substituted with one or more substituents. 1-6 Alkylene or C 2-6 Alkynylidene, optionally, the C 1-6 Alkylene or C 2-6 One or more -CH2- in the alkynylene group are independently optionally selected from -O-, C 3-10 Cycloalkyl, 4-11 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl, -NH-, -N(C 1-3alkyl)- or -S-substituted.

[0119] In some embodiments, the L is selected from C optionally substituted with one or more substituents. 1-6 Alkylene (e.g., C1, C2, C3, C4, C5, or C6 alkylene) or C 2-6 Alkyne (e.g., C2, C3, C4, C5 or C6 alkynyl), optionally, the C 1-6 Alkylene (e.g., C1, C2, C3, C4, C5, or C6 alkylene) or C 2-6 One or more -CH2- in an alkynylene group (e.g., a C2, C3, C4, C5, or C6 alkynylene group) are independently optionally selected from -O-, C 3-10 Cycloalkyl (e.g., C3, C4, C5, C6, C7, C8, C9, or C 10 cycloalkyl) or 4-11 membered heterocycloalkyl (e.g., 4-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-membered heterocycloalkyl), -NH-, -N(C 1-3 alkyl)- or -S-substituted.

[0120] In some embodiments, in the definition of L, the substituent is selected from halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl, C 1- 6 Alkoxy, halogenated C 1-6 Alkyl, (C 1-6 Alkyl)NH-, (C 1-6 Alkyl)2N-, C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl.

[0121] In some embodiments, in the definition of L, the substituent is selected from halogen, =O, -OH, -NH2, -CN, C 1-4 Alkyl, C 1- 4 Alkoxy, halogenated C 1-4 Alkyl, (C 1-4 Alkyl)NH-, (C 1-4 Alkyl)2N-, C 3-10 Cycloalkyl or 4-10 membered heterocycloalkyl.

[0122] In some embodiments, in the definition of L, the substituent is selected from halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl or C 1- In some embodiments, in the definition of L, the substituent is selected from =O, -OH, -NH2, halogen or -CN. In some embodiments, in the definition of L, the substituent is =O.

[0123] In some embodiments, in the definition of L: the cycloalkyl group is selected from cyclobutyl, cyclopentyl, cyclohexyl or spirononanyl.

[0124] In some embodiments, in the definition of L: the heterocycloalkyl group is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, monoazaspiroheptane, monoazaspirooctane, monoazaspironanyl, diazaspirononanyl, monoazaspirodecanyl, diazaspirodecane, monoazaspiroundecyl, diazaspiroundecyl, monoazabicyclohexane, octahydrocyclopentapyrrolyl, diazabicyclooctanyl or monoazabicyclononanyl.

[0125] In some embodiments, in the definition of L: the heterocycloalkenyl group is selected from tetrahydropyridinyl.

[0126] In some embodiments, in the definition of L, the heteroaryl group is selected from pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl, triazolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, furanyl, thienyl or pyrrolyl, etc.

[0127] In some embodiments, in the definition of L: the aryl group is selected from phenyl.

[0128] In some embodiments, the L is selected from -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -Cy 3 -,in,

[0129] Cy 1 、Cy 2 or Cy 3 are independently selected from a bond, or optionally substituted by one or more R b Substituted with the following groups: C 3-12 Cycloalkyl, 4-12 membered heterocycloalkyl or 4-12 membered heterocycloalkenyl;

[0130] LNK, LNK 1 and LNK 2 are independently selected from a bond, -NH-, -O-, -S-, or optionally substituted by one or more R c Substituted with the following groups: C 1-12 Alkylene, C 2-12 Alkenylene, C 2-12 Alkynylidene or C 1-12 heteroalkylene;

[0131] Each R b and R c Each independently selected from halogen, =O, -OH, -NH2, -CN, C 1-6Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, (C 1- 6 alkyl)NH-, (C 1-6 Alkyl)2N-, C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl.

[0132] In some embodiments, Cy 1 、Cy 2 and Cy 3 In some embodiments, Cy 2 and Cy 3 In some embodiments, LNK 1 and LNK 2 Select from keys.

[0133] In some embodiments, the L is selected from -Cy 1 -、-Cy 2 -、-LNK 1 -、-Cy 1 -LNK-, -Cy 1 -Cy 2 -、-LNK 1 -Cy 1 -LNK-, -LNK-Cy 2 -LNK 2 -、-Cy 1 -Cy 2 -LNK 2 -、-LNK 1 -Cy 1 -Cy 2 -、-Cy 1 -LNK-Cy 2 -、-LNK 1 -Cy 1 -Cy 2 -LNK 2 -、-LNK 1 -Cy 1 -LNK-Cy 2 -、-Cy 1 -LNK-Cy 2 -LNK 2 -、-Cy 1 -Cy 2 -Cy 3 -or-Cy 1 -Cy 2 -LNK 2 -Cy 3 -.

[0134] In some embodiments, LNK, LNK1 and LNK 2 are independently selected from a bond, -NH-, -O-, -S-, or optionally substituted by one or more R c Substituted with the following groups: C 1-10 Alkylene, C 2-10 Alkenylene, C 2-10 Alkynylidene or C 1-10 Heteroalkylene.

[0135] In some embodiments, LNK, LNK 1 and LNK 2 are independently selected from a bond, -NH-, -O-, -S-, or optionally substituted by one or more R c Substituted with the following groups: C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene or C 1-6 Heteroalkylene.

[0136] In some embodiments, LNK, LNK 1 and LNK 2 are independently selected from a bond, -NH-, -O-, -S-, or optionally substituted by one or more R c Substituted with the following groups: C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene or C 1-4 Heteroalkylene.

[0137] In some embodiments, LNK, LNK 1 and LNK 2 are independently selected from a bond, -NH-, -O-, -S-, or optionally substituted by one or more R c Substituted with the following groups: C 1-6 Alkylene, C 2-6 Alkynylidene or C 1-6 Heteroalkylene.

[0138] In some embodiments, LNK, LNK 1 and LNK 2 are independently selected from a bond, -NH-, -O-, -S-, or optionally substituted by one or more R c Substituted with the following groups: C 1-4 Alkylene, C 2-4 Alkynylidene or C 1-4 Heteroalkylene.

[0139] In some embodiments, LNK, LNK 1 and LNK 2are independently selected from a bond, -NH-, -O-, or optionally substituted by one or more R c Substituted with the following groups: C 1-3 Alkylene, C 2-3 Alkynylidene or C 1-3 Heteroalkylene.

[0140] In some embodiments, LNK, LNK 1 and LNK 2 are independently selected from a bond, -NH-, -O-, or optionally substituted by one or more R c Substituted with the following groups: C 1-2 Alkylene, C2 alkynylene or C 1-2 Heteroalkylene.

[0141] In some embodiments, LNK, LNK 1 and LNK 2 Each is independently selected from a bond, -NH-, -O-, -NHCH2-, -CH2NHCH2-, -CH2-, -CH2CH2-, ethynylene, -C(O)- or -C(O)CH2-.

[0142] In some embodiments, Cy 1 、Cy 2 or Cy 3 are independently selected from a bond, or optionally substituted by one or more R b Substituted with the following groups: C 3-11 cycloalkyl, 4-12 membered heterocycloalkyl or 4-11 membered heterocycloalkenyl.

[0143] In some embodiments, Cy 1 、Cy 2 or Cy 3 are independently selected from a bond, or optionally substituted by one or more R b Substituted with the following groups: C 4-10 cycloalkyl, 4-11 membered heterocycloalkyl or 5-6 membered heterocycloalkenyl.

[0144] In some embodiments, Cy 1 、Cy 2 or Cy 3 are independently selected from a bond, or optionally substituted by one or more R b Substituted with the following groups: C 4-9 cycloalkyl, 4-11 membered heterocycloalkyl or 5-6 membered heterocycloalkenyl.

[0145] In some embodiments, Cy 1 、Cy 2 or Cy 3 are independently selected from a bond, or optionally substituted by one or more Rb Substituted with the following groups: C 4-6 Cycloalkyl, C9 cycloalkyl, 4-11 membered heterocycloalkyl or 6 membered heterocycloalkenyl.

[0146] In some embodiments, Cy 1 、Cy 2 or Cy 3 are independently selected from a bond, or optionally substituted by one or more R b Substituted with the following groups: C 4-6 Cycloalkyl or 4-6 membered heterocycloalkyl.

[0147] In some embodiments, Cy 1 、Cy 2 or Cy 3 are independently selected from a bond, or optionally substituted by one or more R b Substituted from the following groups: cyclobutyl, cyclopentyl, cyclohexyl, spironanyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyridinyl, piperazinyl, monoazaspiroheptanyl, monoazaspirooctanyl, monoazaspironanyl, diazaspironanyl, monoazaspirodecanyl, diazaspirodecane, monoazaspiroundecyl, diazaspiroundecyl, monoazabicyclohexane, octahydrocyclopentapyrrolyl, diazabicyclooctanyl or monoazabicyclononanyl.

[0148] In some embodiments, Cy 1 、Cy 2 or Cy 3 are independently selected from a bond,

[0149] In some embodiments, Cy 1 、Cy 2 or Cy 3 are independently selected from a bond,

[0150] In some embodiments, each R b and R c Each independently selected from halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, (C 1-6 Alkyl)NH-, (C 1-6 Alkyl)2N-, C 3-10 Cycloalkyl or 4-10 membered heterocycloalkyl.

[0151] In some embodiments, each R b and R cEach independently selected from halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, (C 1-6 alkyl)NH- or (C 1-6 Alkyl)2N-.

[0152] In some embodiments, each R b and R c Each independently selected from halogen, =O, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, (C 1-4 Alkyl)NH-, or (C 1-4 Alkyl)2N-.

[0153] In some embodiments, each R b and R c Each independently selected from halogen, =O, -OH, -NH2, -CN or C 1-3 alkyl.

[0154] In some embodiments, each R b and R c Each is independently selected from halogen, =O, -OH, -NH2 or -CN.

[0155] In some embodiments, each R b and R c are each independently selected from =0.

[0156] In some embodiments, L or -LNK 1 - is selected from a bond, -O-, -NHCH2-, -CH2NHCH2-, -CH2-, -CH2CH2-, ethynylene, -C(O)- or -C(O)CH2-.

[0157] In some embodiments, L is selected from a bond, -NHCH2-, -CH2NHCH2-, -CH2-, -C(O)CH2-,

[0158] In some embodiments, the L is selected from

[0159] In some embodiments, L is selected from In some embodiments, the L is selected from In some embodiments, the L is selected from In some embodiments, the L is selected from In some embodiments, the L is selected from

[0160] In some embodiments, Ring F is linked to L.

[0161] In some embodiments, the PTM is selected from where X 6 , Z, R 2 、R 3 、R 4 , m, p, k, ring G, ring E, ring F, R 5 and R 6 The definition of is as described in this application; Optionally, the structural part The definition of is as described in this application.

[0162] In some embodiments, X 6 Selected from bond, -O-, -S-, -N(R t )-、-C 1-4 Alkylene-, -C 2-4 Alkenylene-, -C 2-4 Alkynylidene-, -N(R t )C 1- 4-alkylene-、-OC 1-4 Alkylene-, -SC 1-4 Alkylene- or -N(R t )C(O)-.

[0163] In some embodiments, X 6 Selected from bond, -O-, -S-, -N(R t )-、-C 1-3 Alkylene-, -C 2-3 Alkenylene-, -C 2-3 Alkynylidene-, -N(R t )C 1- 3-alkylene-, -OC 1-3 Alkylene-, -SC 1-3 Alkylene- or -N(R t )C(O)-.

[0164] In some embodiments, X 6 Selected from bond, -O-, -S-, -N(R t )-、-C 1-3 Alkylene-, -C 2-3 Alkenylene-, -C 2-3Alkynylidene-, -N(R t )C 1- 3-alkylene-, -OC 1-3 Alkylene- or -N(R t )C(O)-.

[0165] In some embodiments, X 6 Selected from bond, -O-, -S-, -N(R t )-、-CH2-、-C2alkynylene-、-N(R t )C 1-2 Alkylene-, -OC 1-2 Alkylene- or -N(R t )C(O)-.

[0166] In some embodiments, X 6 is selected from a bond, -O-, -S-, -NH-, -CH2-, -NHCH2-, -N(CH3)CH2-, -OCH2-, -OCH(CH3)-, or -NHC(O)-.

[0167] In some embodiments, X 6 Selected from -O-, -S-, -NH-, -C 2-4 Alkynylidene-, -NHC 1-4 Alkylene- or -OC 1-4 Alkylene-.

[0168] In some embodiments, X 6 Selected from bond, -O-, -C 2-3 Alkynylidene- or -OC 1-3 In some embodiments, X 6 Selected from bond, -O-, -C 2-3 Alkynylidene- or -C 2-3 Alkenylene-.

[0169] In some embodiments, X 6 is selected from a bond, -O-, -ethynylene- or -OCH2-.

[0170] In some specific embodiments, X 6 Selected from bond, -O-, -NHC 1-3 Alkylene- or -OC 1-3 Alkylene-.

[0171] In some specific embodiments, X 6 is selected from a bond, -O-, -NHCH2- or -OCH2-.

[0172] In some specific embodiments, X 6 Selected from -O-, -C 2-3Alkynylidene- or -OC 1-3 In some embodiments, X 6 In some embodiments, X 6 In some embodiments, X 6 In some embodiments, X 6 In some embodiments, X 6 Selected from -ethynylene-.

[0173] In some embodiments, the R t Selected from H or C 1-6 In some embodiments, the R t Selected from H or C 1-3 In some embodiments, the R t Selected from H or methyl.

[0174] In some embodiments, each R 2 are independently selected from halogen, -CN, the following groups optionally substituted with one or more R': R v -、R v O-、R v S-、R s R v N-、R v C(O)-、R v S(O)2-、R v S(O)-、R v =N-、R v OC(O)-、R v C(O)O-、R v S(O)O-、R v OS(O)-、R v S(O)2O-、R v OS(O)2-、R s R v NC(O)-、R v C(O)NH-、R v OC(O)NH-、R v NHC(O)O-、R v S(O)NH-、R s R v NS(O)-、R v S(O)2NH-、R s R v NS(O)2-or R s R v S(O)=N-.

[0175] In other embodiments, each R 2 are independently selected from halogen, -CN, the following groups optionally substituted with one or more R': R v -、R v O-、R v C(O)-、R v =N-、R v S(O)2NH- or R s R v S(O)=N-.

[0176] In some embodiments, the R' substitution is in R s or R v superior.

[0177] In some embodiments, R s and R v are independently selected from H, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkyl C 1-3 Alkylene-, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl C 1-3 Alkylene-, C 3-12 Cycloalkenyl, C 3-12 Cycloalkenyl C 1-3 Alkylene-, 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl C 1-3 Alkylene-, C 6-10 Aryl, C 6-10 Aryl C 1-3 Alkylene, 5-10 membered heteroaryl or 5-10 membered heteroarylC 1-3 Alkylene-.

[0178] In some embodiments, R s and R v are independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl C 1-3 Alkylene-, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkylC 1-3 Alkylene-, C 3-10 Cycloalkenyl, C 3-10 Cycloalkenyl C 1-3 Alkylene-, 3-10 membered heterocycloalkenyl, 3-10 membered heterocycloalkenyl C 1-3 Alkylene-, C 6-10 Aryl, C 6-10 Aryl C1-3 Alkylene-, 5-10 membered heteroaryl or 5-10 membered heteroarylC 1-3 Alkylene-.

[0179] In some embodiments, R s and R v are independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-6 membered heteroaryl.

[0180] In some specific embodiments, R s are independently selected from H or C 1-6 In some embodiments, R s are independently selected from H.

[0181] In some embodiments, R s and R v are independently selected from H, methyl, ethyl, n-propyl, isopropyl, isobutyl, vinyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrothiophenyl, Piperidinyl, Morpholinyl, piperazinyl, 1,4-oxathiyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl, thiadiazolyl, or phenyl.

[0182] In some embodiments, R s and R v are independently selected from H, methyl, ethyl, n-propyl, isopropyl, isobutyl, vinyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl (such as ), azetidinyl (such as ), pyrrolidino (such as ), Piperidinyl (such as ), Morpholinyl (such as ), piperazinyl (such as Pyrazolyl (such as ), imidazole (such as ), oxazolyl (such as ), isoxazolyl (such as ), triazole (such as ), oxadiazole (such as ), thiadiazolyl (such as ), phenyl.

[0183] In other embodiments, R s and R v are independently selected from H, C 1-4 Alkyl, C 3-4 cycloalkyl, 4-7 membered heterocycloalkyl or 5-6 membered heteroaryl.

[0184] In other embodiments, R s and R v are independently selected from H, methyl, ethyl, isopropyl, tetrahydrothienyl, 1,4-oxathiohexyl, cyclopropyl, oxetanyl, azetidinyl, pyrrolidinyl, morpholinyl, or oxadiazolyl.

[0185] In some embodiments, each R 2 are independently selected from halogen, -OH, -NH2, -CN, the following groups optionally substituted by one or more substituents R': C 1-6 Alkyl, C 1-6 Alkyl O-, 4-10 membered heterocycloalkyl O-, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-10 CycloalkylNH-, 4-10 membered heterocycloalkylNH-, C 1-6 Alkyl C(O)-, C 3-10 Cycloalkyl C (O) -, 5-10 membered heterocycloalkyl C (O) -, C 1-6 Alkyl S(O)2-, H2NC(O)-, C 1-6 Alkyl NHC(O)-, (C 1-6 Alkyl) 2NC(O)-, C 2-6 Alkenyl C(O)NH-, C 1-6 Alkyl S(O)2NH-, C 3- 10 Cycloalkyl-S(O)2NH-, H2NS(O)2-, (C 1-6 alkyl)2S(O)=N-, 4-12 membered heterocycloalkyl=N-, C 3-10 cycloalkyl, 4-12 membered heterocycloalkyl or 5-10 membered heteroaryl.

[0186] In some embodiments, each R 2 are independently selected from halogen, -OH, -NH2, -CN, the following groups optionally substituted by one or more substituents R': C 1-6 Alkyl, C 1-6 Alkyl O-, 4-6 membered heterocycloalkyl O-, C 1-6 Alkyl S-, C1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 CycloalkylNH-, 4-6 membered heterocycloalkylNH-, C 1-6 Alkyl C(O)-, C 3-6 Cycloalkyl C (O) -, 5-6 membered heterocycloalkyl C (O) -, C 1-6 Alkyl S(O)2-, H2NC(O)-, C 1-6 Alkyl NHC(O)-, (C 1-6 Alkyl) 2NC(O)-, C 2-6 Alkenyl C(O)NH-, C 1-6 Alkyl S(O)2NH-, C 3-6 Cycloalkyl-S(O)2NH-, H2NS(O)2-, (C 1-6 alkyl)2S(O)=N-, 4-10 membered heterocycloalkyl=N-, C 3-6 cycloalkyl, 4-10 membered heterocycloalkyl or 5-6 membered heteroaryl.

[0187] In some embodiments, each R 2 are independently selected from halogen, -OH, -NH2, -CN, the following groups optionally substituted by one or more substituents R': methyl, ethyl, n-propyl, isopropyl, isobutyl, CH3S-, CH3NH-, CH3CH2NH-, (CH3)2CHNH-, (CH3)2N-, Cyclopropyl-NH-, CH3C(O)-、CH3CH2C(O)-、(CH3)2CHC(O)-、cyclopropyl-C(O)-、cyclobutyl-C(O)-、cyclopentyl-C(O)-、 CH3S(O)2-, H2NC(O)-, CH3NHC(O)-, CH3CH2NHC(O)-, (CH3)2NC(O)-, CH3S(O)2NH-, cyclopropyl-S(O)2NH-, H2NS(O)2-, (CH3)2S(O) ＝ N-、 Cyclopropyl, Azetidine (such as ), pyrrolidino (such as ), Piperidinyl (such as ), Morpholinyl (such as ), piperazinyl (such as ), Pyrazolyl (such as ), imidazole (such as ), oxazolyl (such as ), isoxazolyl (such as ), triazole (such as ), oxadiazole (such as ) or thiadiazole (such as ); In some embodiments, each R 2 are independently selected from the following groups optionally substituted by one or more substituents R': CH3O-, CH3CH2O-,

[0188] In some embodiments, each R' is independently selected from halogen, -OH, -NH2, -CN, =O, or the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, C 1-6 Alkyl OC 1-6 Alkyl-, C 1-6 Alkyl O-, C 1-6 Alkyl S-, (C 1-6 Alkyl)NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl C(O)-, C 1-6 Alkyl S(O)2-, C 1-6 Alkyl C(O)NH-, C 1-6 Alkyl S(O)2NH-, C 1-6 Alkyl S(O)NH-, (C 1-6 alkyl)2S(O)=N-、C 1-6 Alkyl NHC(O)-, C 1-6 Alkyl NHS(O)2-, C 1-6 AlkylNHS(O)-, C 1-6 Alkyl C(O)O-, C 1-6 Alkyl S(O)2O-, C 1-6 Alkyl S(O)O-, C 1-6 Alkyl OC(O)-, C 1-6 Alkyl OS(O)2-, C 1-6 Alkyl OS(O)-, C 1-6 Alkyl NHC(O)O-, C 1-6 Alkyl OC(O)NH-, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl.

[0189] In some embodiments, each R' is independently selected from halogen, -OH, -NH2, -CN, =O, C optionally substituted with one or more hydroxyl or halogen. 1-6 Alkyl, C 1-6 Alkyl OC 1-6 Alkylene-, C 1-6 Alkyl O-, (C 1-6 Alkyl)NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl S(O)2-, C 1-6 Alkyl S(O)2NH-, C 3-6 cycloalkyl, or 3-6 membered heterocycloalkyl optionally substituted with one or more halogens (eg, F, Cl, Br, or I).

[0190] In some embodiments, each R' is independently selected from -F, -OH, -NH2, -CN, =O, methyl, ethyl, HOCH2-, CH3OCH2-, CH3CH2O-, (CH3)2N-, CH3S(O)2-, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl (such as )or In some embodiments, each R' is independently selected from -Cl or CH3S(O)2NH-.

[0191] In some embodiments, each R' is optionally substituted with one or more substituents. In some embodiments, each R' is optionally substituted with one or more of the following substituents: halogen, -OH, -NH2, -CN, =O, C 1-6 Alkyl, C 1-6 Alkyl O-, C 1-6 Alkyl S-, (C 1-6 Alkyl)NH-, (C 1-6 Alkyl)2N-, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl.

[0192] In some embodiments, each R' is optionally substituted with one or more of the following substituents: halogen, -OH, -NH2, -CN, =O, C 1-6 Alkyl, C 1-6 Alkyl O-, C 1-6 Alkyl S-, (C 1-6 alkyl)NH- or (C 1-6 Alkyl)2N-.

[0193] In some embodiments, each R' is optionally substituted with one or more of the following substituents: halogen, -OH, -NH2, or -CN.

[0194] In some embodiments, each R 2 are independently selected from halogen, halogenated C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkyl O-, halogenated C 1-6 Alkyl O-, hydroxy substituted C 1-6 Alkyl-, optionally hydroxy-substituted C 3-6 Cycloalkyl, C 1-6 Alkyl S(O)2NH-, C 3-6 Cycloalkyl-S(O)2NH-, 4-9 membered heterocycloalkyl (including monocyclic or spirocyclic) containing 1-3 heteroatoms selected from N or O or S, C 1-6 Alkyl-substituted 4-8 membered heterocyclic alkyl (including monocyclic or spirocyclic) containing 1-3 heteroatoms selected from N, O or S, C 1-6 Alkyl S (O) 2NH-heterocycloalkyl- (wherein, heterocycloalkyl is a 4-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N or O or S), C 1-6 Alkyl S (O) 2-heterocycloalkyl - (wherein the heterocycloalkyl is a 4-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N or O or S), hydroxy substituted azetidinyl, hydroxy substituted oxetane, 3-hydroxy-thietanyl,

[0195] In some embodiments, each R 2 Each independently selected from -F, -CN, -NH2, methyl, CH3CH2-, CH3CH(NH2)-, CH3CH(OH)-, (CH3)2C(OH)-, CH3CH2CH(OH)-, (CH3)2CHCH(OH)-, CH3S-, CH3NH-, CH3CH2NH-, (CH3)2CHNH-, (CH3)2N-, Cyclopropyl-NH-, CH3C(O)-、CH3CH2C(O)-、(CH3)2CHC(O)-、cyclopropyl-C(O)-、cyclobutyl-C(O)-、cyclopentyl-C(O)-、 CH3S(O)2-, H2NC(O)-, CH3NHC(O)-, CH3CH2NHC(O)-, (CH3)2NC(O)-, CH3S(O)2NH-, cyclopropyl-S(O)2NH-, H2NS(O)2-, (CH3)2S(O)=N-, Cyclopropyl, Azetidine (such as ), Pyrrolidino (eg ), Piperidinyl (such as ), Morpholinyl (such as ), Piperazine (eg ), Pyrazolyl (such as ), imidazole (such as ), oxazolyl (such as ), isoxazolyl (such as ), triazole (such as 、), oxadiazole (such as ), thiadiazolyl (such as ), In some embodiments, each R 2 Each independently selected from -Cl, -CHF2, -CF3, CH3O-, CHF2O-, CF3O-, CF3CH2O-,

[0196] In some embodiments, each R 2 are independently selected from halogen, or the following groups optionally substituted by one or more R': C 1- 6 alkyl, C 1-6 Alkyl O-, C 1-6 Alkyl C(O)-, C 1-6 Alkyl S(O)2NH-, (C 1-6 alkyl)2S(O)=N-、C 3-6 In other embodiments, each R 2 are independently selected from halogen, or the following groups optionally substituted by one or more R': C 1-4 Alkyl, C 1-4 Alkyl O-, C 1-3 Alkyl C(O)-, C 1-3 Alkyl S(O)2NH-, (C 1-3 alkyl)2S(O)=N-、C3-4 The present invention can be any of a 4- to 7-membered cycloalkyl group, a 4- to 7-membered heterocycloalkyl group (such as a 6- to 7-membered heterocycloalkyl group), or a 5-membered heteroaryl group.

[0197] In some embodiments, R 2 Selected from halogen, -CHF2, -CF3, methyl, CH3O-, CHF2O-, CF3O-, CF3CH2O-, CH3CH(OH)-, (CH3)2C(OH)-, CH3CH2CH(OH)-, cyclopropyl, CH3S(O)2NH- or cyclopropyl-S(O)2NH-. In some embodiments, each R 2 are independently selected from -F, -Cl, CH3O-, CH3CH(OH)-, (CH3)2C(OH)-, cyclopropyl, CHF2O-, CF3O-, CF3CH2O-, -CF3, -CHF2 or CH3S(O)2NH-.

[0198] In other embodiments, R' is selected from halogen, -OH, -NH2, -CN, =O, C 1-6 Alkyl, C 1-6 Alkyl O-, (C 1-6 Alkyl)NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl S(O)2NH-, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl.

[0199] In other embodiments, each R' is independently selected from halogen (eg, F, Cl, Br, or I), -OH, -NH2, -CN, ═O, C 1-6 Alkyl, C 1-6 Alkyl O-, (C 1-6 Alkyl)NH-, C 1-6 Alkyl S(O)2NH-, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl.

[0200] In other embodiments, R' is selected from halogen, -OH, -NH2, -CN, =O, C 1-3 Alkyl, C 1-3 Alkyl O-, (C 1-3 Alkyl)NH-, C 1-3 Alkyl S(O)2NH-, or (C 1-3 Alkyl)2N-.

[0201] In other embodiments, each R' is independently selected from halogen (eg, F, Cl, Br, or I), -OH, -NH2, -CN, ═O, C 1-4 Alkyl or C 1-4 Alkyl S(O)2NH-.

[0202] In other embodiments, each R' is independently selected from -F, -Cl, -OH, =O, methyl, or CH3S(O)2NH-.

[0203] In some embodiments, R' is selected from halogen (F, Cl, Br or I), -OH, -NH2, -CN or C 1-3 In some embodiments, the R' is selected from =O, or C 1-3 Alkyl S(O)2NH-.

[0204] In other embodiments, each R 2 are independently selected from halogen, or the following groups optionally substituted by one or more R': C 1-6 Alkyl, C 1-6 Alkyl O-, C 1-6 Alkyl C(O)-, C 1-6 Alkyl S(O)2NH-, (C 1-6 alkyl)2S(O)=N-, 5-7 membered heterocycloalkyl=N-, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl or 5-6 membered heteroaryl.

[0205] In other embodiments, each R 2 are independently selected from the following groups: halogen, C 1-4 Alkyl, C 1-4 Alkyl O-, C 1-3 Alkyl C(O)-, C 1-3 Alkyl S(O)2NH-, (C 1-3 alkyl)2S(O)=N-, 5-6 membered heterocycloalkyl=N-, C 3-4 Cycloalkyl, 4-7 membered heterocycloalkyl or 5 membered heteroaryl, the C 1-4 Alkyl, C 1-4 Alkyl O-, C 1-3 Alkyl C(O)-, C 1-3 Alkyl S(O)2NH-, (C 1-3 alkyl)2S(O)=N-, 5-6 membered heterocycloalkyl=N-, C 3- 4-membered cycloalkyl, 4-7-membered heterocycloalkyl or 5-membered heteroaryl are optionally substituted with one or more of the following groups: halogen (e.g., F, Cl, Br or I), -OH, -NH2, -CN, C 1-3 Alkyl, =O or C1-3 Alkyl S(O)2NH-.

[0206] In other embodiments, each R 2 Each independently selected from -F, CH3CH(OH)-, (CH3)2C(OH)-, -CHF2, -CF3, CH3O-, CHF2O-, CF3O-, CF3CH2O-, CH3C(O)-, CH3S(O)2NH-, (CH3)2S(O)=N-, Cyclopropyl,

[0207] In some embodiments, each R 2 are independently selected from the following groups: C 1-4 Alkyl, C 1-3 Alkyl C(O)-, C 1-3 Alkyl S(O)2NH-, (C 1-3 alkyl)2S(O)=N-, 6-7 membered heterocycloalkyl or 5 membered heteroaryl, the C 1-4 Alkyl, 6-7 membered heterocycloalkyl or 5 membered heteroaryl are optionally substituted with one or more of the following groups: halogen, -OH, -NH2, -CN or C 1-3 alkyl.

[0208] In some embodiments, each R 2 are independently selected from the following groups: C 1-3 Alkyl, C 1-2 Alkyl C(O)-, C 1-2 Alkyl S(O)2NH-, (C 1-2 alkyl)2S(O)=N-, 7-membered heterocycloalkyl or 5-membered heteroaryl, the C 1-3 The alkyl or 5-membered heteroaryl group is optionally substituted with one or more of the following groups: -OH or C 1-3 alkyl.

[0209] In some embodiments, each R 2 are independently selected from the following groups: CH3CH2-, CH3C(O)-, CH3S(O)2NH-, (CH3)2S(O)=N-, The CH3CH2- or Optionally substituted with one or more of the following groups: -OH or methyl.

[0210] In some embodiments, each R 2 Each independently selected from CH3CH(OH)-, CH3C(O)-, CH3S(O)2NH-, (CH3)2S(O)=N-, In some embodiments, each R2 are independently selected from CH3CH(OH)-, or CH3C(O)-. In some embodiments, each R 2 are independently selected from CH3S(O)2NH-, or (CH3)2S(O)=N-. In some embodiments, each R 2 are independently selected from

[0211] In some embodiments, each R 3 are independently selected from halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1- 6 alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl or 5-6 membered heteroaryl.

[0212] In some embodiments, each R 3 are independently selected from halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1- 6 alkyl.

[0213] In some embodiments, each R 3 are independently selected from halogen, -OH, -NH2, -CN or methyl.

[0214] In some embodiments, each R 3 are independently selected from halogen. 3 are independently selected from F.

[0215] In some embodiments, each R 4 are independently selected from halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1- 6 alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl or 5-6 membered heteroaryl.

[0216] In some embodiments, each R 4 are independently selected from halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1- 6 alkyl.

[0217] In some embodiments, each R 4are independently selected from halogen, -OH, -NH2, -CN or methyl.

[0218] In some embodiments, each R 4 are independently selected from halogen, -OH, -NH2 or -CN.

[0219] In some embodiments, each R 4 are independently selected from halogen or -CN.

[0220] In some embodiments, each R 4 are independently selected from -F, -Cl or -CN.

[0221] In some embodiments, m is selected from 0, 1, 2, or 3. In some embodiments, m is selected from 1 or 2. In some embodiments, m is 1.

[0222] In some embodiments, p is selected from 0, 1, or 2. In some embodiments, p is selected from 0 or 1. In some embodiments, p is 0.

[0223] In some embodiments, k is selected from 0, 1, 2, or 3. In some embodiments, k is selected from 0, 1, or 2. In some embodiments, k is 0 or 1.

[0224] In some embodiments, m is selected from 1, p is selected from 0, and k is selected from 0, 1, or 2.

[0225] In some embodiments, ring G is selected from C 4-6 In some embodiments, ring G is selected from C 4-6 In some embodiments, ring G is selected from C 4-6 Cycloalkyl, 4-9 membered heterocycloalkyl, phenyl, 5-8 membered heteroaryl, tetrahydroisoquinolinyl, tetrahydropyridopyrimidinyl, tetrahydropyridopyrazinyl, pyrrolopyrimidinyl or pyrimidopyrrolidinyl.

[0226] In some embodiments, the ring G is selected from phenyl, 5-6 membered heteroaryl or 9-10 membered heterocycloalkenyl. In some embodiments, the ring G is selected from pyrimidine or tetrahydropyridopyrimidinyl.

[0227] In some embodiments, the ring G is selected from cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, dioxane, phenyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,

[0228] In some embodiments, the ring G is selected from cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, dioxane,

[0229] In some embodiments, the ring G is selected from phenyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, In some embodiments, the ring G is selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, In some embodiments, the ring G is selected from pyridinyl, pyrimidinyl, pyridazinyl, In some embodiments, the ring G is selected from In some embodiments, the ring G is selected from pyrimidinyl or pyridazinyl. In some embodiments, the ring G is selected from In some embodiments, the ring G is selected from

[0230] In some embodiments, ring G is selected from phenyl or a 5-10 membered heteroaryl. In some embodiments, ring G is selected from phenyl or a 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S.

[0231] In some embodiments, the ring G is selected from phenyl or a 6-membered heteroaryl. In some embodiments, the ring G is selected from phenyl or a 6-membered N-containing heteroaryl. In some embodiments, the ring G is selected from phenyl or a 5-6-membered heteroaryl containing 1-3 N atoms.

[0232] In some embodiments, the ring G is selected from phenyl, pyrimidinyl, pyridazinyl, pyridinyl, or pyrazinyl.

[0233] In some embodiments, the ring G is selected from

[0234] In some embodiments, ring G is selected from

[0235] In some embodiments, Ring E is selected from C6-12 In some embodiments, ring E is selected from phenyl or 5-6 membered heteroaryl. In some embodiments, ring E is selected from phenyl or 6 membered heteroaryl. In some embodiments, ring E is selected from phenyl or 6 membered N-containing heteroaryl. In some embodiments, ring E is selected from phenyl or 6 membered heteroaryl containing 1-2 N atoms. In some embodiments, ring E is selected from phenyl or pyridyl. In some embodiments, ring E is selected from In some embodiments, Ring E is selected from

[0236] In some embodiments, Ring F is selected from C 6-12 In some embodiments, ring F is selected from phenyl or 5-6 membered heteroaryl. In some embodiments, ring F is selected from phenyl or 6 membered heteroaryl. In some embodiments, ring F is selected from phenyl or 6 membered N-containing heteroaryl. In some embodiments, ring F is selected from phenyl or 6 membered heteroaryl containing 1-2 N atoms. In some embodiments, ring F is selected from phenyl or pyridyl. In some embodiments, ring F is selected from In some embodiments, Ring F is selected from

[0237] In some embodiments, Selected from

[0238] In some embodiments, Selected from

[0239] In some embodiments, Z is selected from -C-.

[0240] In some embodiments, R 5 and R 6 are independently selected from H, =O, halogen, -OH, -NH2, -CN, C 1-6 Alkyl or C 2-6 Alkenyl, or R 5 and R 6 are linked to each other to form the following group which is optionally substituted by one or more substituents such as R": 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl.

[0241] In some embodiments, R 5 and R 6 are independently selected from H, C 1-3 Alkyl or C 2-3 Alkenyl, or R 5 and R 6are linked to each other to form the following group optionally substituted by one or more R": 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl.

[0242] In some embodiments, R 5 and R 6 are independently selected from H, methyl, ethyl or vinyl, or R 5 and R 6 are linked to each other to form the following groups which are optionally substituted by one or more R″: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl or oxetanyl.

[0243] In some embodiments, the R" is selected from halogen, -OH, -NH2, -CN, C 1-3 Alkyl or halogenated C 1-3 alkyl.

[0244] In some embodiments, R 5 and R 6 are independently selected from H, methyl, ethyl or vinyl, or R 5 and R 6 They are linked to each other to form the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl or oxetanyl.

[0245] In some embodiments, R 5 and R 6 are independently selected from H or C 1-6 Alkyl, or R 5 and R 6 Connected to form the following groups: C 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl.

[0246] In some embodiments, R 5 and R 6 are independently selected from H or C 1-3 Alkyl, or R 5 and R 6 Connected to form the following groups: C 3-4 In some embodiments, R 5 and R 6 are independently selected from H or C 1-3 Alkyl, or R 5 and R 6 are connected to form a 4-membered heterocycloalkyl. 5 and R 6 are independently selected from H or C 1-3 alkyl.

[0247] In some embodiments, R5 and R 6 are independently selected from methyl, or, R 5 and R 6 They are connected to each other to form oxetane groups.

[0248] In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from

[0249] In some embodiments, the moiety Selected from Optionally, the left ring in the fragment is ring E and the right ring is ring F.

[0250] In some embodiments, the moiety Selected from

[0251] In some embodiments, the moiety Selected from

[0252] In some embodiments, the moiety Selected from

[0253] In some embodiments, the moiety Selected from

[0254] In some embodiments, the moiety (or PTM) selected from In some embodiments, the moiety Or PTM is

[0255] In some embodiments, the moiety (or PTM) selected from

[0256] In some embodiments, the moiety (or PTM) selected from

[0257] In some embodiments, the moiety (or PTM) selected from

[0258] In some embodiments, the moiety (or PTM) selected from

[0259] In some embodiments, the moiety (or PTM) or Selected from

[0260] In some embodiments, the moiety (or PTM) selected from Among them, T 1 、T 2 、T 3 、T 4 、T 5 、T 7 、T 8 、T 9 and T 10 are independently selected from CH or N, wherein one or more are selected from N, X 6 is selected from O or a bond; when X 6 Selected from O, T 7 、T 8 and T 10 One or more of them are selected from N; wherein R 2 、R 3 、R 4 ,m,p,k,R 5 and R 6 is as defined herein. In some embodiments, the moiety (or PTM) selected from Among them, T 1 、T 2 、T 3 、T 4 、T 5 、T 7 、T 8 and T 10 are independently selected from CH or N, T 7 、T 8 and T 10 One or more selected from N, wherein R 2 、R 3 、R 4,m,p,k,R 5 and R 6 The definition of is as described in this application.

[0261] In some embodiments, the moiety (or PTM) selected from Where T 1 、T 2 、T 3 、T 4 、T 5 、T 7 、T 8 、T 9 and T 10 are independently selected from CH or N, wherein one or more are selected from N, wherein R 2 、R 3 、R 4 ,m,p,k,R 5 and R 6 The definition of is as described in this application.

[0262] In some embodiments, T 1 、T 2 、T 3 、T 4 and T 5 are independently selected from CH or N, wherein one or more are selected from N.

[0263] In some embodiments, T 1 、T 2 、T 3 、T 4 and T 5 One or two of them are selected from N, and the rest are selected from CH.

[0264] In some embodiments, T 2 and T 4 are independently selected from N, T 1 、T 3 and T 5 are independently selected from CH or N.

[0265] In some embodiments, T 7 、T 8 、T 9 and T 10 are independently selected from CH or N, one or two of which are selected from N, and the rest are selected from CH.

[0266] In some embodiments, T 7 and T 8 are independently selected from CH or N, one of which is selected from CH and the other is selected from CH or N.

[0267] In some embodiments, T 7 and T 8 is selected from CH or N, one of which is selected from CH and the other is selected from N.

[0268] In some embodiments, T 7 and T 8 Selected from CH.

[0269] In some embodiments, T 9 and T 10 are independently selected from CH or N, one of which is selected from CH and the other is selected from CH or N.

[0270] In some embodiments, T 9 and T 10 is selected from CH or N, one of which is selected from CH and the other is selected from N.

[0271] In some embodiments, T 9 and T 10 Selected from CH.

[0272] In some embodiments, T 10 Selected from N.

[0273] In some embodiments, T 10 Selected from CH.

[0274] In some embodiments, Selected from

[0275] In some embodiments, the moiety (or PTM) selected from

[0276] In some embodiments, the moiety (or PTM) selected from

[0277] In some embodiments, the compound of formula II, its stereoisomers, or pharmaceutically acceptable salts thereof is selected from the compound of formula IIA, its stereoisomers, or pharmaceutically acceptable salts thereof,

[0278] Among them, ring A, ring B, ring C, R 1 ,n,X 5 , L 1 , L and PTM are defined as described in this application.

[0279] In some embodiments, in the compound of Formula IIA,

[0280] X 5 C(R f ), R f Selected from H, halogen, deuterium or C 1-3 Alkyl; preferably, X 5 C(R f ), R f is H or deuterium; more preferably, X 5 for CH;

[0281] represents a single bond;

[0282] L 1 is the key;

[0283] Ring A is selected from a 5-6 membered heterocycloalkenyl group containing 1-2 N atoms or O atoms (e.g., dihydropyrrolyl or tetrahydropyridinyl), Ring B is selected from a phenyl group or a pyridinyl group (e.g., phenyl), and Ring C is a 5 membered heteroaryl group containing 1-2 heteroatoms selected from N, O, or S (e.g., isoxazolyl, pyrazolyl, or furanyl); preferably, Selected from More preferably, Selected from

[0284] R 1 Selected from deuterium, halogen, -OH or -NH2 (preferably R 1 is selected from deuterium); n is 0 or 1 (preferably n is 0); preferably, Selected from

[0285] L is selected from Preferably, L is selected from More preferably, L is selected from

[0286] PTM is Preferably More preferably

[0287] Preferably,

[0288] R 2Selected from halogen, -CHF2, -CF3, methyl, CH3O-, CHF2O-, CF3O-, CF3CH2O-, CH3CH(OH)-, (CH3)2C(OH)-, CH3CH2CH(OH)-, cyclopropyl, CH3S(O)2NH- or cyclopropyl-S(O)2NH-; preferably, R 2 Selected from -CHF2, -CF3, CH3O-, CHF2O-, CF3O-, CF3CH2O-, CH3CH(OH)-, (CH3)2C(OH)-, Cyclopropyl, (CH3)2S(O)=N-, -F or -Cl; m is 1;

[0289] Ring G is selected from phenyl or 5-6 membered heteroaryl containing 1-3 N atoms; preferably, ring G is selected from

[0290] X 6 Selected from bond, -O-, -S-, -C 2-3 Alkenylene- or -C 2-3 Alkynylidene-(e.g. X 6 is selected from a bond, -O-, -S- or -ethynylene-); preferably, X 6 is selected from -O-, a bond (e.g., a single bond) or -ethynylene-;

[0291] Ring E is selected from phenyl or a 6-membered heteroaryl group containing 1-2 N atoms; preferably, ring E is selected from

[0292] p is 0;

[0293] Z is selected from -C-;

[0294] R 5 and R 6 are independently selected from C 1-3 Alkyl or C 2-3 alkenyl (eg, methyl, ethyl or propyl); preferably, R 5 and R 6 C 1-3 Alkyl; More preferably, R 5 and R 6 are each independently a methyl group;

[0295] Ring F is selected from phenyl or a 6-membered heteroaryl group containing 1-2 N atoms; preferably, ring F is selected from

[0296] R 4 is selected from halogen or -CN; preferably, R 4 Selected from -F or -CN;

[0297] k is 0 or 1 (preferably, Selected from ).

[0298] In some embodiments, the PTM is selected from

[0299] In some embodiments, the compound of formula III, its stereoisomers, or pharmaceutically acceptable salts thereof is selected from the compound of formula IIIA, its stereoisomers, or pharmaceutically acceptable salts thereof,

[0300] Among them, ring A, ring B, ring C, R 1 ,n,X 5 , L 1 , L, X 6 , Z, R 2 、R 3 、R 4 , m, p, k, ring G, ring E, ring F, R 5 and R 6 The definition of is as described in this application.

[0301] In some embodiments, the compound of Formula I, Formula II or Formula III, its stereoisomers or pharmaceutically acceptable salts thereof is selected from the compound of Formula IIIB, its stereoisomers or pharmaceutically acceptable salts thereof,

[0302] Among them, ring A, ring B, ring C, R 1 ,n,X 5 , L, X 6 、R 2 、R 3 、R 4 , m, p, k, ring G, ring E, ring F, R 5 and R 6 The definition of is as described in this application.

[0303] In some embodiments, in the compound of Formula IIIB, represents a single bond; X 5 C(R f ), R f is H or deuterium, preferably, X 5 for CH;

[0304] Selected from More preferably, Selected from

[0305] n is 0;

[0306] L is selected from Preferably, L is selected from

[0307] R 2 Selected from -CHF2, -CF3, CH3O-, CHF2O-, CF3O-, CF3CH2O-, CH3CH(OH)-, (CH3)2C(OH)-, Cyclopropyl, (CH3)2S(O)=N-, -F or -Cl;

[0308] m is 1;

[0309] Ring G is selected from phenyl or 5-6 membered heteroaryl containing 1-3 N atoms; preferably, ring G is selected from

[0310] X 6 Selected from bond, -O-, -S-, -C 2-3 Alkenylene- or -C 2-3 Alkynylidene-(e.g. X 6 is selected from a bond, -O-, -S- or -ethynylene-); preferably, X 6 is selected from -O-, a bond (e.g., a single bond) or -ethynylene-;

[0311] Ring E is selected from phenyl or a 6-membered heteroaryl group containing 1-2 N atoms; preferably, ring E is selected from

[0312] p is 0;

[0313] R 5 and R 6 C 1-3 Alkyl; preferably, R 5 and R 6 are each independently a methyl group;

[0314] Preferably, ring F is selected from

[0315] R 4 is selected from halogen or -CN; preferably, R 4 Selected from -F or -CN;

[0316] k is 0 or 1.

[0317] In some embodiments, the compound of Formula I, Formula II, Formula III or IIIA, its stereoisomers or pharmaceutically acceptable salts thereof are selected from Formula IV, Formula V, Formula VI, Formula VII, Formula VIII-1, Formula VIII-2, Formula VIII-3 or Formula VIII-4, its stereoisomers or pharmaceutically acceptable salts thereof,

[0318] Among them, ring A, ring B, ring C, R 1 ,n,X 5 , L, X 6 、R 2 、R 3 、R 4 , m, p, k, ring G, ring E, ring F, R 5 and R 6 is as defined in this application;

[0319] Where T 1 、T 2 、T 3 、T 4 、T 5 and T 6 are independently selected from CH or N;

[0320] X 7 selected from CH or N;

[0321] T 7 、T 8 、T 9 and T 10 are independently selected from CH or N.

[0322] In some embodiments, T 1 、T 2 、T 3 、T 4 、T 5 and T 6 Two of them are selected from N, and the others are selected from CH.

[0323] In some embodiments, T 7 and T 8 are independently selected from CH or N, one of which is selected from CH and the other is selected from CH or N.

[0324] In some embodiments, T 7 and T 8 is selected from CH or N, one of which is selected from CH and the other is selected from N.

[0325] In some embodiments, T 7 and T 8 Selected from CH.

[0326] In some embodiments, T 9 and T 10 are independently selected from CH or N, one of which is selected from CH and the other is selected from CH or N.

[0327] In some embodiments, T 9 and T 10 is selected from CH or N, one of which is selected from CH and the other is selected from N.

[0328] In some embodiments, T 9 and T 10 Selected from CH.

[0329] In some embodiments, Selected from T 1 、T 2 、T 3 and T 4 are independently selected from CH or N. In some embodiments, In some embodiments, Selected from

[0330] Others such as structural parts As described in this application.

[0331] In some embodiments, the above-mentioned heterocycloalkenyl, heteroaryl, heterocycloalkyl or heteroalkylene group contains one or more heteroatoms or heteroatoms independently selected from -O-, -NH-, -N-, -S-, -C(=O)-, -C(=O)NH-, -C(=O)O-, -S(=O)- or -S(=O)2-; in some embodiments, the above-mentioned heterocycloalkenyl, heteroaryl, heterocycloalkyl or heteroalkylene group contains one or more heteroatoms or heteroatoms independently selected from -O-, -NH-, -N- or -S-; in some embodiments, the above-mentioned heterocycloalkenyl, heteroaryl, heterocycloalkyl or heteroalkylene group contains one or more heteroatoms or heteroatoms independently selected from -O-, -NH- or -N-. In some embodiments, the number of the heteroatoms or heteroatoms is independently selected from 1, 2, 3, 4, 5 or 6; or selected from 1, 2, 3 or 4; or selected from 1, 2 or 3; or selected from 1 or 2.

[0332] In some embodiments, the heteroatoms in the heterocycloalkenyl group are selected from N, NH, O, or S. In some embodiments, the heteroatoms in the heterocycloalkenyl group are selected from N, O, or S. In some specific embodiments, the heteroatoms in the heterocycloalkenyl group are selected from N or O. In some embodiments, the number of heteroatoms in the heterocycloalkenyl group is selected from 1, 2, 3, 4, 5, or 6. In some embodiments, the number of heteroatoms in the heterocycloalkenyl group is selected from 1, 2, 3, or 4. In some embodiments, the number of heteroatoms in the heterocycloalkenyl group is selected from 1, 2, or 3. In some specific embodiments, the number of heteroatoms in the heterocycloalkenyl group is selected from 1 or 2.

[0333] In some embodiments, the halo is selected from fluoro, chloro, or bromo. In some embodiments, the halo is selected from fluoro or chloro. In some embodiments, the halo is selected from fluoro.

[0334] In some embodiments, the C 1-10 Selected from C 1-9 、C 1-8 、C 1-7 、C 1-6 、C 1-4 、C 1-3 , or C 1-2 In some embodiments, C 1- 6 from C 1-4 、C 1-3 , or C 1-2 In some embodiments, the C 1-4 is selected from C4, C3, C2, or C1. In some embodiments, the C 1-3 Selected from C3, C2, or C1.

[0335] In some embodiments, the C 2-10 Selected from C 2-8 、C 2-6 、C 2-5 、C 2-4 、C 2-3 In some embodiments, the C 2-6 Selected from C 2- 4. or C 2-3 In some embodiments, the C 2-4 Selected from C4, C3, or C2.

[0336] In some embodiments, the C 3-6 Selected from C 3-5 、C 3-4 、C 4-6 、C 4-5 , or C 5-6 In some embodiments, the C 6-10 Selected from C6-9 、C 6-8 、C 6-7 、C 7-10 、C 7-9 、C 7-8 、C 8-10 、C 8-9 , or C 9-10 In some embodiments, the C 3-10 Selected from C 3-9 、C 3-8 、C 3- 7. C 3-6 、C 3-5 、C 3-4 、C 4-10 、C 4-9 、C 4-8 、C 4-7 、C 4-6 、C 4-5 、C 5-10 、C 5-9 、C 5-8 、C 5-7 、C 5-6 、C 6-10 、C 6-9 、C 6-8 、C 6- 7. C 7-12 、C 7-10 、C 7-9 、C 7-8 、C 8-12 、C 8-10 、C 8-9 、C 9-12 , or C 9-10 In some embodiments, the C 3-15 Selected from C 3-12 or C 3- 10 In some embodiments, the C 3-12 Selected from C 3-10 In some embodiments, the C 6-12 Selected from C 6-10 .

[0337] In some embodiments, the 3-6 yuan is selected from 3-5 yuan, 3-4 yuan, 4-6 yuan, 4-5 yuan, or 5-6 yuan. In some embodiments, the 5-10 yuan is selected from 5-8 yuan, 5-7 yuan, 5-6 yuan, 6-10 yuan, 6-9 yuan, 6-8 yuan, 6-7 yuan, 7-10 yuan, 7-9 yuan, 7-8 yuan, 8-10 yuan, 8-9 yuan, and 9-10 yuan. In some embodiments, the 3-10 yuan is selected from 3-9 yuan, 3-8 yuan, 3-7 yuan, 3-6 yuan, 3-5 yuan, 3-4 yuan, 4-10 yuan, 4-9 yuan, 4-8 yuan, 4-7 yuan, 4-6 yuan, 4-5 yuan, 5-10 yuan, 5-9 yuan, 5-8 yuan, 5-7 yuan, 5-6 yuan, 6-10 yuan, 6-9 yuan, 6-8 yuan, 6-7 yuan, 7-10 yuan, 7-9 yuan, 7-8 yuan, 8-10 yuan, 8-9 yuan, 9-10 yuan. In some embodiments, the 3-15 yuan is selected from 3-12 yuan or 3-10 yuan. In some embodiments, the 3-12 yuan is selected from 3-10 yuan. In some embodiments, the 5-12 yuan is selected from 5-10 yuan.

[0338] It should be understood that any embodiment of the compounds of the present application as described above and the specific rings A, B, C, R, and R in the compounds of the present application as described above are not limited to the embodiments of the compounds of the present application as described above. 1 ,n,X 5 , L, X 6 、R 2 、R 3 、R 4 , Ring G, Ring E, Ring F, R 5 and R 6 Any specific substituent described in the substituents may be independently combined with other embodiments and / or substituents of the compounds of the present application to form embodiments of the invention not specifically described above. In addition, any specific ring A, ring B, ring C, R 1 ,n,X 5 , L, X 6 、R 2 、R 3 、R 4 , Ring G, Ring E, Ring F, R 5 and R 6 Where a range of substituents is disclosed, it is understood that one or more substituents may be deleted from the range and the remaining range of substituents is considered an embodiment of the present application.

[0339] In some embodiments, the VHL E3 ubiquitin ligase binding moiety is selected from the group consisting of:

[0340] In some embodiments, the IAP E3 ubiquitin ligase binding moiety is selected from the group consisting of:

[0341] In some embodiments, the MDM2 E3 ubiquitin ligase binding moiety is selected from the group consisting of:

[0342] In some embodiments, the CLM is selected from the following structural fragments:

[0343] wherein j and j1 are independently selected from 0, 1 or 2;

[0344] Ring D is selected from a 5-20 membered ring (eg, aryl, heteroaryl, cycloalkyl, partially unsaturated heterocyclyl or heterocycloalkyl);

[0345] R 7 are independently selected from H or C 1-6 alkyl;

[0346] X 11 is selected from a bond, O, S, CH2 or NH;

[0347] R 1 、n、L 1 The definition of is as described in this application.

[0348] In some embodiments, the ring D is selected from a 5-15 membered ring; in some embodiments, the ring D is selected from a 5-12 membered ring; in some embodiments, the ring D is selected from a 5-10 membered ring; in some embodiments, the ring D is selected from a 5-7 membered ring; in some embodiments, the ring D is selected from a 5-15 membered ring, C 6-15 Aryl, 5-15 membered heteroaryl, C 5-15 Cycloalkyl or 5-15 membered heterocycloalkyl; In some embodiments, the ring D is selected from a 5-12 membered ring, C 6-12 Aryl, 5-12 membered heteroaryl, C 5-12 Cycloalkyl or 5-12 membered heterocycloalkyl; In some embodiments, the ring D is selected from a 5-10 membered ring, C 6-10 Aryl, 5-10 membered heteroaryl, C 5-10 Cycloalkyl or 5-10 membered heterocycloalkyl; In some embodiments, the ring D is selected from a 5-7 membered ring, C 6-10 Aryl, 5-7 membered heteroaryl, C 5-7 Cycloalkyl or 5-7 membered heterocycloalkyl.

[0349] In some embodiments, the R 7 are independently selected from H or C 1-3 Alkyl; In some embodiments, the R 7are independently selected from H. The heteroatoms in the heteroaryl, heterocyclic group and heterocycloalkyl group are selected from nitrogen, oxygen or sulfur, and the number of heteroatoms is optionally 1, 2, 3, 4, 5 or 6.

[0350] In some embodiments, the CLM is selected from the following structural fragments:

[0351] Among them, R a are independently selected from hydroxy, halogen, amino, cyano or C 1-8 alkyl;

[0352] q is selected from 0, 1, 2 or 3;

[0353] X 4 is selected from N or optionally substituted CH.

[0354] In some embodiments, wherein R a are independently selected from hydroxy, halogen, amino, cyano or C 1-6 alkyl.

[0355] In some embodiments, wherein R a are independently selected from hydroxy, halogen, amino, cyano or C 1-4 alkyl.

[0356] In some embodiments, wherein R a are independently selected from hydroxy, halogen, amino, cyano or C 1-3 alkyl.

[0357] In some embodiments, wherein R a are independently selected from hydroxy, halogen, amino or cyano.

[0358] In some embodiments, wherein R a are independently selected from halogen or amino.

[0359] In some embodiments, q is selected from 0, 1, or 2. In some embodiments, q is selected from 0 or 1.

[0360] In some embodiments, X 4 is selected from N or CH, wherein CH is optionally substituted by hydroxy, halogen, amino, cyano or C 1-4 alkyl.

[0361] In some embodiments, X 4 In some embodiments, X 4 Selected from CH.

[0362] In some embodiments, the CLM is selected from the following structural fragments:

[0363] The present application also relates to the following compounds, their stereoisomers or pharmaceutically acceptable salts thereof:

[0364] The present application relates to a compound of formula Ia, a structural portion thereof, a derivative thereof (e.g., Protac), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0365] in,

[0366] T 1 、T 2 、T 3 、T 4 、T 5 、T 7 、T 8 、T 9 and T 10 are independently selected from CH or N, X 6 is selected from O or a bond; provided that when X 6 Selected from O, T 7 、T 8 and T 10 One or more of which are selected from N;

[0367] R 8 Selected from hydrogen, C 3-12 Cycloalkyl, 4-12 membered heterocycloalkyl, -OC 3-12 Cycloalkyl, -NHC 3-12 Cycloalkyl or -SC 3-12 Cycloalkyl, the C 3- 12 Cycloalkyl, 4-12 membered heterocycloalkyl, -OC 3-12 Cycloalkyl, -NHC 3-12 Cycloalkyl or -SC 3-12 The cycloalkyl group is optionally replaced by HC(O)- or C 1-6 Alkyl OC(O)-substituted;

[0368] where R 2 、R 3 、R4 ,m,p,k,R 5 and R 6 The definition of is as described in this application.

[0369] In some embodiments, X 6 Select from keys.

[0370] In some embodiments, T 1 、T 2 、T 3 、T 4 、T 5 、T 7 、T 8 、T 9 and T 10 At least one of is selected from N.

[0371] In some embodiments, T 1 、T 2 、T 3 、T 4 and T 5 One or two of them are selected from N, and the rest are selected from CH.

[0372] In some embodiments, T 7 、T 8 、T 9 and T 10 are independently selected from CH or N, one or two of which are selected from N, and the rest are selected from CH.

[0373] In some embodiments, T 1 is selected from N. In some embodiments, T 2 is selected from N. In some embodiments, T 3 is selected from N. In some embodiments, T 4 is selected from N. In some embodiments, T 5 is selected from N. In some embodiments, T 6 is selected from N. In some embodiments, T 7 is selected from N. In some embodiments, T 8 is selected from N. In some embodiments, T 9 is selected from N. In some embodiments, T 10 Selected from N.

[0374] In some embodiments, R 8 Selected from hydrogen, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, -OC 3-9 Cycloalkyl, -NHC 3-10 Cycloalkyl or -SC 3- 10 Cycloalkyl, the C3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, -OC 3-9 Cycloalkyl, -NHC 3-10 Cycloalkyl or -SC 3-10 The cycloalkyl group is optionally replaced by HC(O)- or C 1-4 AlkylOC(O)-.

[0375] In some embodiments, R 8 Selected from hydrogen, C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -OC 3-6 Cycloalkyl, -NHC 3-6 Cycloalkyl or -SC 3-6 Cycloalkyl, the C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -OC 3-6 Cycloalkyl, -NHC 3-6 Cycloalkyl or -SC 3-6 The cycloalkyl group is optionally replaced by HC(O)- or C 1-4 AlkylOC(O)-.

[0376] In some embodiments, R 8 Selected from hydrogen, 4-6 membered heterocycloalkyl or -OC 3-6 Cycloalkyl, the 4-6 membered heterocycloalkyl or -OC 3-6 The cycloalkyl group is optionally replaced by HC(O)- or C 1-2 AlkylOC(O)-.

[0377] In some embodiments, R 8 Selected from hydrogen.

[0378] The present application also relates to the following compounds, their structural parts, their derivatives (such as Protac), their stereoisomers or their pharmaceutically acceptable salts:

[0379] On the other hand, the present application relates to a Protac molecule comprising a compound of formula Ia, a structural portion thereof, a derivative thereof, or a related specific compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0380] Use of a compound of Formula Ia, a structural portion thereof, a derivative thereof, or a related specific compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the preparation of Protac (or a protein degrader). Use of a compound of Formula Ia, a structural portion thereof, a derivative thereof, or a related specific compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in a Protac molecule, for example, as a structural portion of a Protac molecule, in the form of a Protac molecule; use for protein degradation, i.e., degradation of related proteins in the form of a Protac molecule.

[0381] This application also covers solutions obtained by any combination, deletion or replacement of the above embodiments.

[0382] On the other hand, the present application relates to a pharmaceutical composition, which contains the above-mentioned compound, its structural part, its derivative, its stereoisomer or its pharmaceutically acceptable salt. Optionally, the pharmaceutical composition of the present application also includes a pharmaceutically acceptable excipient.

[0383] On the other hand, the present application relates to the use of the above-mentioned compound, its structural part, its derivative, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for preventing or treating a disease (such as cancer).

[0384] On the other hand, the present application relates to the use of the above-mentioned compounds, their structural parts, their derivatives, their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutical compositions in the preparation of medicaments for preventing or treating diseases treated by degrading and / or inhibiting target proteins (e.g., GSPT1) bound to targeting ligands. Alternatively, the present application relates to the use of the above-mentioned compounds, their structural parts, their derivatives, their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutical compositions in the preparation of medicaments for degrading and / or inhibiting target proteins (e.g., GSPT1) bound to targeting ligands.

[0385] On the other hand, the present application relates to the use of the above-mentioned compound, its structural part, its derivative, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for preventing or treating a disease that is treated by binding to cerebellar proteins in vivo.

[0386] On the other hand, the present application relates to the use of the above-mentioned compound, its structural part, its derivative, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for preventing or treating GSPT1-related diseases.

[0387] On the other hand, the present application relates to the use of the above-mentioned compounds, their structural parts, their derivatives, their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutical compositions in the preparation of drugs for preventing or treating diseases related to AR or ARv7.

[0388] The present application relates to a method for treating or preventing a disease (e.g., cancer), comprising administering a therapeutically effective amount of the above-mentioned compound of the present application, its structural portion, its derivative, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition to a mammal (preferably a human) in need of such treatment.

[0389] The present application relates to a method for treating or preventing a condition in a mammal treated by degrading and / or inhibiting a target protein (e.g., GSPT1) bound to a targeting ligand, comprising administering to a mammal (preferably a human) in need of such treatment a therapeutically effective amount of the above-mentioned compound of the present application, its structural portion, its derivative, its stereoisomer, or its pharmaceutically acceptable salt, or a pharmaceutical composition thereof. The present application relates to a method for degrading and / or inhibiting a target protein (e.g., GSPT1) bound to a targeting ligand in a mammal, comprising administering to a mammal (preferably a human) in need of such treatment a therapeutically effective amount of the above-mentioned compound of the present application, its structural portion, its derivative, its stereoisomer, or its pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

[0390] The present application relates to a method for treating or preventing a disease that is treated by binding to a cerebellar protein in vivo, comprising administering a therapeutically effective amount of the above-mentioned compound of the present application, its structural portion, its derivative, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition to a mammal (preferably a human) in need of such treatment.

[0391] On the other hand, the present application relates to a method for treating a disease associated with GSPT1, comprising administering a therapeutically effective amount of the above-mentioned compound of the present application, its structural portion, its derivative, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition to a mammal (preferably a human) in need of such treatment.

[0392] On the other hand, the present application relates to a method for treating diseases related to AR or ARv7 in mammals, comprising administering a therapeutically effective amount of the above-mentioned compound of the present application, its structural portion, its derivative, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition to a mammal (preferably a human) in need of such treatment.

[0393] On the other hand, the present application relates to the above-mentioned compound, its structural part, its derivative, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition for preventing or treating diseases (such as cancer).

[0394] On the other hand, the present application relates to the above-mentioned compounds, their structural parts, their derivatives, their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutical compositions for preventing or treating diseases treated by degrading and / or inhibiting the target protein (e.g., GSPT1) bound to the targeting ligand.

[0395] On the other hand, the present application relates to the above-mentioned compound, its structural part, its derivative, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition for degrading and / or inhibiting the target protein (such as GSPT1) binding to the targeting ligand.

[0396] On the other hand, the present application relates to the above-mentioned compound, its structural part, its derivative, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition for preventing or treating diseases treated by binding to cerebellar proteins in vivo.

[0397] On the other hand, the present application relates to the above-mentioned compound, its structural part, its derivative, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition for preventing or treating diseases related to GSPT1.

[0398] On the other hand, the present application relates to the above-mentioned compounds, their structural parts, their derivatives, their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutical compositions for preventing or treating diseases related to AR or ARv7.

[0399] On the other hand, the present application relates to the use of the above-mentioned compound, its structural part, its derivative, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition in preventing or treating diseases (such as cancer).

[0400] On the other hand, the present application relates to the use of the above-mentioned compounds, their structural parts, their derivatives, their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutical compositions in preventing or treating diseases that are treated by degrading and / or inhibiting target proteins (such as GSPT1) that bind to targeting ligands.

[0401] On the other hand, the present application relates to the use of the above-mentioned compounds, their structural parts, their derivatives, their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutical compositions in degrading and / or inhibiting target proteins (e.g., GSPT1) that bind to targeting ligands.

[0402] On the other hand, the present application relates to the use of the above-mentioned compound, its structural part, its derivative, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition in preventing or treating diseases that are treated by binding to cerebellar proteins in vivo.

[0403] On the other hand, the present application relates to the use of the above-mentioned compound, its structural part, its derivative, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition in preventing or treating diseases related to GSPT1.

[0404] On the other hand, the present application relates to the use of the above-mentioned compounds, their structural parts, their derivatives, their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutical compositions in preventing or treating diseases related to AR or ARv7.

[0405] In some embodiments, the above-mentioned diseases or conditions are diseases that are treated by degradation and / or inhibition of a target protein (e.g., GSPT1), or by binding to cerebellum to ubiquitinate the target protein. In some embodiments, the above-mentioned diseases are selected from conditions that are treated by degradation and / or inhibition of a protein (e.g., GSPT1) to which a target protein ligand binds; in some embodiments, the above-mentioned diseases are selected from conditions that are treated by binding to cerebellum in vivo; in some embodiments, the above-mentioned diseases or conditions are selected from cancer, such as prostate cancer.

[0406] In some embodiments, the above-mentioned conditions treated by binding to cerebellum proteins in vivo and / or conditions treated by degrading and / or inhibiting target proteins bound to targeting ligands are selected from GSPT1-related diseases, or AR or ARv7-related diseases; in some embodiments, the above-mentioned GSPT1-related diseases, or AR or ARv7-related diseases are selected from cancer, such as prostate cancer. In some embodiments, the above-mentioned conditions treated by binding to cerebellum proteins in vivo and / or conditions treated by degrading target proteins bound to targeting ligands are selected from cancer, such as prostate cancer. In some schemes, the target protein bound to the targeting ligand is selected from GSPT1. In some embodiments, the disease or condition is selected from AR or ARv7-related diseases. In some embodiments, the disease or condition is selected from GSPT1-related diseases.

[0407] In some embodiments, the above-mentioned disease or disorder is a disease that can be treated by degradation and / or inhibition of GSPT1, or by binding to cerebellin to ubiquitinate the target protein.

[0408] In some aspects, the present application comprises the above-defined variables and embodiments thereof, and any combination thereof.

[0409] Technical Effects

[0410] The compounds of the present application may exhibit GSPT1 degradation activity and anti-proliferative activity against VCaP and / or 22RV1 cells. Furthermore, the compounds of the present application exhibit good in vitro liver microsomal stability and in vivo pharmacokinetic properties (specifically, parameters such as AUC) in mammals (e.g., mice, rats, dogs, or humans), and can inhibit tumor growth in vivo, demonstrating promising drug development.

[0411] definition

[0412] Unless otherwise indicated, the following terms used in this application have the following meanings. A particular term should not be construed as undefined or unclear unless specifically defined, but rather should be understood according to its ordinary meaning in the art. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0413] As used herein, "one or more" refers to an integer from one to ten. For example, "one or more" refers to one, two, three, four, five, six, seven, eight, nine, or ten; in some embodiments, the "one or more" is selected from one, two, three, four, five, or six. In some embodiments, the "one or more" is selected from one, two, or three. In some embodiments, the "one or more" is selected from one, or two.

[0414] Unless otherwise specified, It is used to indicate that the hydrogen atom at any position of the group in [] can be replaced by a group connected by "—", for example, by L.

[0415] The term "substituted" means that any one or more hydrogen atoms or lone pairs of electrons on a particular atom are replaced by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo group (i.e., =O), it means that two hydrogen atoms are replaced. Oxo groups do not occur on aromatic groups. For example, for It can be represented by one or more R 1 Substituent substituted, wherein the R 1 It can be substituted on ring B or on another ring, such as X on the ring 8 、X 9 、X 10 and its substituents, and -NH-.

[0416] The term "optionally" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes both the occurrence of the event or situation and the non-occurrence of the event or situation. "Optionally substituted" includes unsubstituted and substituted. For example, an ethyl group is "optionally" substituted with a halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (such as CH2CH2F), polysubstituted (such as CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible and / or cannot be synthesized will be introduced.

[0417] In this article, C m-n , means that the moiety has an integer number of carbon atoms in a given range. For example, "C 1-6 ” means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0418] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. For example, if a group contains two R's, each R has an independent option.

[0419] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a covalent bond.

[0420] When one of the variables is selected from a covalent bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a covalent bond, it means that the structure is actually AZ.

[0421] When a bond cross-links two atoms in a ring (including a monocyclic, fused, or spirocyclic ring), the bond can be bonded to any atom in the ring (including a monocyclic, fused, or spirocyclic ring). Indicates that the bonds on both sides can be connected to any two different atoms on ring A, ring B or ring C; for example Indicates that the bonds on both sides can be connected to any two different atoms on ring A, the middle benzene ring or ring C; further, for example It means that the bonds on both sides can be connected to any two different atoms in the four rings in the system.

[0422] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0423] The term "hydroxy" refers to an -OH group.

[0424] The term "amino" refers to a -NH2 group.

[0425] The term "cyano" refers to a -CN group.

[0426] The term "alkyl" refers to a group of the formula C n H 2n+1 The alkyl group may be straight chain or branched. For example, the term "C 1-6 The term "alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio has the same definition as above.

[0427] The term "alkylene" refers to a divalent group formed by removing a hydrogen from any position of an alkyl group, for example, the term "C 1-6 "Alkyl" refers to an alkylene group containing 1 to 6 carbon atoms; the term "C 1-4 "Alkyl" refers to an alkylene group containing 1 to 4 carbon atoms, including but not limited to -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-.

[0428] The term "alkenylene" refers to a divalent group formed by removing a hydrogen atom from any position of an alkenyl group, for example, the term "C 2-6 "Alkenyl" refers to an alkenylene group containing 2 to 6 carbon atoms; the term "C 2-4 "Alkenyl" refers to an alkenylene group containing 2 to 4 carbon atoms, including but not limited to -CH2CH=CH-, -CH2CH2CH=CH- or -CH2CH=CHCH2-.

[0429] The term "alkynylene" refers to a divalent group formed by removing a hydrogen atom from any position of an alkynyl group, for example, the term "C 2-6 "Alkynyl" refers to an alkynylene group containing 2 to 6 carbon atoms; the term "C 2-4 The term "alkynyl" refers to an alkynylene group containing 2 to 4 carbon atoms, including but not limited to -C≡C-, -H2C-C≡C-, -H2C-H2C-C≡C- or -H2C-C≡C-CH2-.

[0430] The term "heteroalkyl" refers to a straight or branched chain alkyl group consisting of a certain number of carbon atoms and at least one heteroatom, preferably having 1 to 14 carbon atoms, more preferably 1 to 10 carbon atoms, even more preferably 1 to 6 carbon atoms, and most preferably 1 to 3 carbon atoms in the chain, wherein the heteroatom is selected from the group consisting of Si, P, B, S, O, and N; and preferably has 1, 2, or 3 heteroatoms selected from S, O, and N. For example, C mHeteroalkyl refers to an alkyl group consisting of m carbon atoms and at least one heteroatom (e.g., 1-3 heteroatoms selected from S, O, and N) between any two carbon atoms, with heteroatoms inserted in the chain. The nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. The heteroatom or heteroatom group can be located at any interior position of the heteroalkyl group, including the position where the hydrocarbon group is attached to the rest of the molecule. Exemplary heteroalkyl groups include alkyl ethers, secondary and tertiary alkylamines, amides, sulfides, and the like, including alkoxy, alkylthio, and alkylamino groups; unless otherwise specified, C 1-6 Heteroalkyl groups include C1, C2, C3, C4, C5 and C6 heteroalkyl groups, such as C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino.

[0431] The term "heteroalkylene" refers to a divalent group formed by removing one hydrogen from any position of a heteroalkyl group, for example, -NHCH2- or -CH2NHCH2-.

[0432] The term "alkoxy" refers to an -O-alkyl group.

[0433] The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. Non-limiting examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.

[0434] The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and can exist as a monocyclic, bicyclic bridged ring or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 4 to 16-membered ring, a 4 to 12-membered ring, a 4 to 10-membered ring or a 4 to 8-membered ring. Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, etc.

[0435] The term "cycloalkyl" refers to a fully saturated carbocyclic ring that can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically 3 to 16 rings (e.g., 3 to 10 rings, or 5 to 8 rings). Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo [2.2.1] heptyl), bicyclo [2.2.2] octyl, adamantyl, etc.

[0436] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the heterocycle typically contains heteroatoms selected from Si, P, B, S, O, and N; preferably, it is a 3- to 16-membered ring, a 3- to 11-membered ring, a 3- to 10-membered ring, a 3- to 7-membered ring, a 3- to 6-membered ring, or a 3- to 5-membered ring containing 1 to 3 heteroatoms independently selected from sulfur, oxygen, and / or nitrogen (preferably 1 or 2 heteroatoms). Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxirane, thioethane, and aziridine groups; non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl groups; examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl groups; examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl groups; examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxetanyl, and thiepanyl groups. Preferably, the heterocycloalkyl group is a monocyclic group having 5 or 6 ring atoms.

[0437] The term "spirocycle" refers to a fully saturated or partially unsaturated polycyclic ring system in which the monocyclic rings share a carbon atom (called a spiro atom), including carbocycles and heterocycles. Unless otherwise indicated, the spirocycle is 5 to 20 members, preferably 6 to 14 members, and more preferably 8 to 12 members. When the spirocycle is a heterocycle, one or more ring atoms in the polycyclic ring are selected from N, O, S(O) n 、P(O) n (wherein n is 0, 1 or 2) heteroatoms (preferably 1 or 2 heteroatoms), and the remaining ring atoms are carbon atoms.

[0438] The term "spiroalkyl" refers to a fully saturated, all-carbon polycyclic ring that shares a carbon atom (called a spiro atom) between monocyclic rings. Unless otherwise indicated, the spiroalkyl is 5 to 20 yuan, preferably 6 to 14 yuan, and more preferably 8 to 12 yuan. According to the number of spiro atoms shared between the rings, the spiroalkyl is divided into a single spiroalkyl, a double spiroalkyl or a multi-spiroalkyl, preferably a single spiroalkyl and a double spiroalkyl, more preferably a 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or a 5 yuan / 6 yuan single spiroalkyl. Non-limiting examples of spiroalkyl include

[0439] The term "spiroheterocycloalkyl" refers to a fully saturated polycyclic ring in which the monocyclic rings share a carbon atom (called a spiro atom), and one or more ring atoms in the polycyclic ring are selected from N, O, S(O) n 、P(O) n(wherein n is 0, 1 or 2) heteroatoms (preferably 1 or 2 heteroatoms), and the remaining ring atoms are carbon atoms. Unless otherwise indicated, the spiro heterocycloalkyl is 5 to 20 yuan, preferably 6 to 14 yuan, more preferably 6 to 10 yuan. According to the number of shared spiro atoms between the rings, the spiro heterocycle is divided into a monospiro heterocycle, a dispiro heterocycle or a polyspiro heterocycle, preferably a monospiro heterocycle or a dispiro heterocycle, more preferably a 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or a 5 yuan / 6 yuan monospiro heterocycle. Non-limiting examples of spiro heterocycloalkyl include wait.

[0440] The term "heterocycloalkenyl" includes cycloalkenyl groups in which one or more carbon atoms (e.g., 1-5, 1-4, 1-3, 1-2) are replaced by heteroatoms selected from Si, P, B, S, O, and N; specifically, cycloalkenyl groups in which up to 3 carbon atoms, in one embodiment up to 2 carbon atoms, in another embodiment 1 carbon atom are independently replaced by O, S, S(O), or N, provided that at least one cycloalkenyl carbon-carbon double bond is retained. Cyclic groups that may exist as monocyclic, bridged, or spirocyclic rings may be 3 to 20-membered, 3 to 16-membered (e.g., 3 to 12-membered, 5 to 8-membered, specifically 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, or 11-membered) rings. Examples of heterocycloalkenyl groups include, but are not limited to, dihydropyrrolyl, tetrahydropyridyl, tetrahydroazepine, pyrrolidine ... Base, azaspirocyclooctene, wait.

[0441] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and 1,2,3,4-tetrahydronaphthalene.

[0442] The term "heterocyclyl" refers to a monocyclic or fused polycyclic ring system containing heteroatoms selected from Si, P, B, S, O and N; preferably, an unsaturated non-aromatic ring system containing at least one (e.g., 1-5, 1-4, 1-3, 1-2) ring atom selected from N, O, S, and the remaining ring atoms being C, which may be free of double bonds or have at least one or more double bonds. Preferred heterocyclyl groups have a single 4- to 8-membered ring, especially a 5- to 8-membered ring (e.g., 5-, 6-, 7- or 8-membered), or multiple fused rings containing 6 to 14, especially 6 to 10 (e.g., 6, 7, 8, 9 or 10) ring atoms.

[0443] The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system containing at least one (e.g., 1-5, 1-4, 1-3, 1-2) ring atom selected from N, O, S, with the remaining ring atoms being C, and having at least one aromatic ring. Preferred heteroaryl groups have single 4 to 8-membered rings, especially 5 to 8-membered rings (e.g., 5-, 6-, 7-, or 8-membered), or multiple fused rings containing 6 to 14, especially 6 to 10 (e.g., 6, 7, 8, 9, or 10) ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.

[0444] The term "substituent", "optionally substituted with one or more substituents" or "optionally substituted", the substitution or substituent substitution, include all substituents mentioned herein, for example, the terms "halogen", "deuterium", "-NH2", "-NH(C 1-4 Alkyl)", "-N(C 1-4 Alkyl)2", "-OH", "-OC 1-4 Alkyl", "-CN", "C 1-4alkyl", "3-6 membered heterocycloalkyl", etc., and corresponding non-limiting or exemplary groups, wherein some non-limiting examples of the "substituent" include thiol, nitro, nitroso, cyano, azide, sulfoxide, sulfone, sulfonamide, carboxyl, aldehyde, imine, alkyl, halo-alkyl, cycloalkyl, halo-cycloalkyl, alkenyl, halo-alkenyl, cycloalkenyl, halo-cycloalkenyl, alkynyl, halo-alkynyl, cycloalkynyl, halo-cycloalkynyl , heteroalkyl, halo-heteroalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, arylalkylene, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroarylalkylene, heteroarylalkoxy, heteroarylalkylthio, heterocyclyl, heterocyclyloxy, heterocyclylthio, heterocyclylalkylene, heterocyclylalkoxy, heterocyclylalkylthio, acyl, acyloxy, carbamate group, amide group, urea group, epoxy group, ester group and oxo, etc., wherein the substituent is optionally substituted by one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC( -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0445] In some embodiments herein, the substituent is selected from deuterium, tritium, hydroxyl, sulfhydryl, halogen, amino, nitro, nitroso, cyano, azide, sulfoxide, sulfone, sulfone, sulfonamide, carboxyl, aldehyde, imine, C 1-12 Alkyl, halo-C 1-12 Alkyl, 3-12 membered cycloalkyl, halogenated 3-12 membered cycloalkyl, C 2-12 Alkenyl, halo-C 2-12 Alkenyl, 3-12 membered cycloalkenyl, halogenated 3-12 membered cycloalkenyl, C 2-12 Alkynyl, halo-C 2-12 Alkynyl, 8-12 membered cycloalkynyl, halogenated 8-12 membered cycloalkynyl, C 1-12 Heteroalkyl, halo-C 1-12 Heteroalkyl, C 1-12 Alkoxy, C 1-12Alkylthio, 6-10 membered aryl, 6-10 membered aryloxy, 6-10 membered arylthio, 6-10 membered arylC 1-12 Alkylene, 6-10 membered aryl C 1-12 Alkoxy, 6-10 membered aryl C 1-12 alkylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, 5-10 membered heteroarylalkylene, 5-10 membered heteroarylalkoxy, 5-10 membered heteroarylalkylthio, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, 3-12 membered heterocyclylthio, 3-12 membered heterocyclylC 1-12 Alkylene, 3-12 membered heterocyclic group C 1-12 Alkoxy, 3-12 membered heterocyclic group C 1-12 Alkylthio, C 1-12 Acyl, C 1-12 Acyloxy, carbamate group, C 1-12 Amide group, urea group, epoxy group, C 2-12 Ester group and oxo, said substituent being optionally substituted by one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, carboxyl, -C(O)OC 1-12 Alkyl, -OC(O)-C 1-12 Alkyl, -C(O)NH2, -C(O)NH-C 1-12 Alkyl, -C(O)N(C 1-12 Alkyl)2, -NHC(O)-C 1-12 Alkyl, -C(O)-C 1-12 Alkyl, -S(O)-C 1-12 Alkyl, -S(O)2-C 1-12 Alkyl, -S(O)2NH2, -S(O)2NH-C 1-12 Alkyl, -S(O)2N(C 1-12 alkyl) 2, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12 Alkylene, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group C 1-12 Alkylene, 3-12 membered heterocyclyloxy, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkylC 1-12Alkylene, 3-12 membered heterocycloalkyloxy, 5-10 membered heteroaryl, 5-10 membered heteroarylC 1-12 Alkylene, 5-10 membered heteroaryloxy, 6-10 membered aryl, 6-10 membered arylC 1-12 an alkylene group or a 6- to 10-membered aryloxy group.

[0446] Unless otherwise specified, the term "hetero" refers to a heteroatom or heteroatom group (i.e., a group containing heteroatoms), including atoms other than carbon (C) and hydrogen (H) and groups containing these heteroatoms. For example, heteroatoms include, but are not limited to, oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), silicon (Si), germanium (Ge), aluminum (Al), and boron (B). Specific heteroatoms or heteroatom groups include: -O-, -S-, -N=, =O, =S, -P(=O)-, -P(=O)2-, -P(=O)O-, -P(=O)2O-, -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, and optionally substituted -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)-, or -S(=O)N(H)-. Preferably, the term "hetero" denotes a heteroatom or a heteroatom group (ie a group containing a heteroatom) wherein the heteroatom is selected from oxygen, nitrogen or sulfur.

[0447] The term "derivative" refers to a new compound or a group of new compounds produced by one or more chemical reactions or structural evolution, retaining the basic structure of the parent compound and only undergoing changes or modifications in the side chains, functional groups or substituents.

[0448] In this application, wavy lines are used represents one of the absolute configurations of a stereocenter (e.g. one, specific express ) or one of the relative configurations (e.g. express or When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, they are intended to include both E and Z geometric isomers. Likewise, all tautomeric forms are encompassed within the scope of this application.

[0449] The groups or structural fragments in this application such as -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -、-Cy 1 -Cy 2 -LNK 2 -、LNK、Cy 1 、Cy2 、-Cy 1 -LNK-Cy 2 -、-Cy 1 -LNK- or -LNK-Cy 2 - and its specific options, optionally can be read from left to right, corresponding to the group or fragment in the general formula on the left and right groups connected, for example, when L is selected from -Cy 1 -LNK-, when Cy 1 Selected from Reading from left to right, Cy 1 The left side corresponds to the fragment on the left side of the general formula Connect, right side to right side segment The resulting fragments are Optionally, the groups or structural fragments in this application such as -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -、-Cy 1 -Cy 2 -LNK 2 -、LNK、Cy 1 、Cy 2 、-Cy 1 -LNK-Cy 2 -、-Cy 1 -LNK- or -LNK-Cy 2 - and its specific options, can be read in order from right to left, and are respectively connected to the left and right groups of the group or fragment in the general formula, for example, when L is selected from -Cy 1 -LNK-, when Cy 1 Selected from According to the reading order from right to left, Cy 1 The right side corresponds to the fragment on the left side of the general formula Connect the left side with the corresponding right side fragment in the general formula The fragments formed by the connection are Other groups are the same as described above.

[0450] The term "treating" means administering the compounds or formulations described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes: (i) inhibiting the disease or disease state, i.e., curbing its development; (ii) alleviating the disease or disease state, i.e., causing the disease or disease state to regress.

[0451] The term "prevention" means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, including preventing the occurrence of a disease or disease state in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0452] The term "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and this disclosure.

[0453] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0454] As the pharmaceutically acceptable salt, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned.

[0455] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

[0456] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0457] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0458] Unless the context clearly indicates otherwise, singular terms herein include plural referents and vice versa. Similarly, the word "or" herein is intended to include "and" unless the context clearly indicates otherwise.

[0459] Unless otherwise indicated, all numbers used herein expressing amounts of ingredients, measurements, or reaction conditions are to be understood as modified in all instances by the term "about." When used in conjunction with a percentage, the term "about" can mean, for example, ±1%, preferably ±0.5%, and more preferably ±0.1%.

[0460] The compounds and intermediates of the present application may also exist in different tautomeric forms, and all such forms are included within the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety, in which the proton can migrate between two ring nitrogens. Valence tautomers include interconversions by reorganization of some bonding electrons. For example, any compound of the present disclosure, such as pyrazole alone or as part of a heterocyclic group, may exist as a mixture of two tautomers or any number of two tautomers, i.e. or The present disclosure includes all possible tautomers of the disclosed compounds, either as single tautomers or as any mixture of such tautomers in any ratio.

[0461] In the absence of any indication to the contrary, the substituents herein (e.g., L 1 、X 6 ) in the definition refers to a single bond.

[0462] The present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0463] Certain isotope-labeled compounds of the present application (e.g. 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as 15 O. 13 N. 11 C and 18 F can be used for positron emission tomography (PET) research to determine substrate occupancy. Isotope-labeled compounds of the present invention can usually be prepared by replacing an isotope-labeled reagent with an isotope-labeled reagent by the following procedures similar to those disclosed in the schemes and / or examples below. The compounds of the present invention can be asymmetric, for example, having one or more stereoisomers (such as cis-trans isomers, etc.). Unless otherwise indicated, all stereoisomers include enantiomers and diastereomers. The compounds containing asymmetric carbon atoms of the present application can be separated in optically pure form or racemic form. Optically pure forms can be resolved from racemic mixtures, or synthesized by using chiral raw materials or chiral reagents.

[0464] The pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients.

[0465] Typical routes of administration of the compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0466] The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0467] In some embodiments, the pharmaceutical composition is in oral form.

[0468] Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets or dragee cores.

[0469] The pharmaceutical composition may also be suitable for parenteral administration.

[0470] In all methods of administration described herein, the compounds of formula I are administered at a dosage of 0.001 to 2000 mg / kg body weight per day in single or divided doses.

[0471] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0472] The chemical reactions described in the specific embodiments of the present application are carried out in a suitable solvent that is compatible with the chemical transformations described herein and the reagents and materials required. To obtain the compounds described herein, it may sometimes be necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0473] An important consideration in synthetic route planning in this field is the selection of an appropriate protecting group for a reactive functional group (such as an amino group in this application). For example, reference can be made to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.

[0474] In some embodiments, the compounds of the present application can be prepared by those skilled in the art of organic synthesis using the following intermediates or their salts through the following routes:

[0475] Among them, ring A, ring B, ring C, R 1 ,n,X 5 , L, X 6 、R 2 、R 3 、R 4 ,m,p,k,R 5 、R 6 、T 1 、T 2 、T 3 、T 4 、T 5 and T 6 The definition of is as described in this application.

[0476] The compound of general formula IV-1 is obtained by Mitsunobu reaction to obtain the compound of general formula IV-2, the compound of general formula IV-2 is obtained by coupling reaction to obtain the compound of general formula IV-3, and then the compound of general formula IV-4 is obtained by deprotection group Boc reaction, and the compound of general formula IV-4 is obtained by reductive amination reaction to obtain the compound of general formula IV.

[0477] The compound of general formula IV-1 is obtained through Mitsunobu reaction to obtain the compound of general formula IV-6, the compound of general formula IV-2 is obtained through coupling reaction to obtain the compound of general formula IV-7, and then through oxidation reaction to obtain the compound of general formula IV-8, and the compound of general formula IV-8 is obtained through reductive amination reaction to obtain the compound of general formula IV.

[0478] This application uses the following abbreviations:

[0479] DMSO stands for dimethyl sulfoxide; DMF stands for N,N-dimethylformamide; DIPEA stands for N,N'-diisopropylethylamine; HATU stands for 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; DCE stands for dichloroethane; Boc stands for tert-butyloxycarbonyl; DCM stands for dichloromethane; DEAD stands for diethyl azodicarboxylate; EA stands for ethyl acetate; DMAP stands for 4-dimethylaminopyridine; TBS stands for tert-butyldimethylsilyl; Tf stands for trifluoromethanesulfonyl; THF stands for tetrahydrofuran; Dess-martin reagent stands for 1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benzidoxyl-3-(1H)-one; DC 50 It indicates the drug concentration when the degradation rate reaches 50%; Dmax indicates the maximum degradation rate.

[0480] PdCl2(PPh3)2 represents bistriphenylphosphine palladium dichloride; XPhos-Pd-G3 represents methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II); Xphos represents 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; Pd2(dba)3 represents trisdibenzylideneacetone dipalladium; TBAF represents tetrabutylammonium fluoride; DMF represents N,N-dimethylaminobenzoate 4-[4-(2-(diphenylphosphino)ferrocene)]dichloropalladium dichloromethane complex; DIAD stands for diisopropyl azodicarboxylate; RuPhos stands for 2-dicyclohexylphosphino-2',6'-diisopropyl-1,1'-biphenyl.

[0481] For the sake of clarity, the present invention is further illustrated by examples, but the examples are not intended to limit the scope of this application. All reagents used in this application are commercially available and can be used without further purification. DETAILED DESCRIPTION

[0482] Preparation Example 1

[0483] Synthesis of intermediate z8

[0484] The intermediate 5-chloro-2-iodopyrimidine (8.04 g), cesium carbonate (21.68 g), XPhos-Pd-G3 (2.64 g), 1-aminoylidene tetrahydrothiophene (7.93 g), and 1,4-dioxane (100 mL) were added to the reaction flask in sequence. The mixture was reacted at 110°C for 2 h under nitrogen protection. The reaction was complete and purified by silica gel column chromatography to obtain compound z8 (6.8 g). MS (ESI, [M+H] + )m / z:232.10.

[0485] The synthesis of intermediates z9-z17 was carried out by referring to the synthesis method of intermediate z8 to synthesize the following compounds:

[0486] Preparation Example 2 Synthesis of Intermediate z18

[0487] Step 1: Preparation of compound z18b

[0488] To the reaction flask, z18a (1.0 g), triethylamine (1.5 g), and dichloromethane (20 mL) were added sequentially. The temperature was lowered to 0°C, and methylsulfonic anhydride (1.3 g) was slowly added. The reaction was allowed to react at 0°C for 2 h. Once the reaction was complete, water was added to quench the reaction solution. The organic phase was separated, washed with saturated brine, and concentrated to afford z18b (1.2 g).

[0489] Step 2: Preparation of compound z18c

[0490] To the reaction flask, z18b (1.2 g), dichloromethane (20 mL), and trifluoroacetic acid (5 mL) were added sequentially and allowed to react at room temperature for 2 h. After the reaction was complete, the product was concentrated to give z18c (0.8 g).

[0491] Step 3: Preparation of compound z18

[0492] z18c (0.2 g), 2,5-dichloropyrazine (0.17 g), potassium carbonate (0.3 g), and acetonitrile (5 mL) were added to the reaction flask in sequence and reacted at 50°C for 2 h. The reaction was complete and purified by silica gel column chromatography to give compound z18 (0.12 g). MS (ESI, [M+H] + )m / z:263.21.

[0493] Synthesis of intermediates z19-z23: The following compounds were synthesized by referring to the synthesis method of intermediate z18:

[0494] Example 1 Synthesis of Compound 1

[0495] Step 1: Preparation of intermediate 1b

[0496] Intermediate 1a (2 g), N-Boc-3-hydroxyazetidine (1.5 g), triphenylphosphine (2.8 g), and THF (30 mL) were mixed. Under N2 protection, diethyl azodicarboxylate (1.8 g) was slowly added dropwise to the reaction system. The reaction was allowed to proceed at 60°C for 16 h. After the reaction was complete, the reaction solution was concentrated and purified by silica gel column chromatography to obtain intermediate 1b (1.37 g). MS (ESI) m / z [M+H] + :384.1.

[0497] Step 2: Preparation of intermediate 1c

[0498] Intermediate 1b (500 mg), 5-bromo-2-cyanopyrimidine (360 mg), cuprous iodide (49 mg), 2-picolinic acid (32 mg), potassium phosphate (454 mg), and DMSO (10 mL) were mixed and reacted at 100°C for 16 h under N2 protection. After the reaction was complete, the reaction solution was extracted with ethyl acetate and saturated aqueous ammonium chloride. The organic phase was concentrated and purified by silica gel column chromatography to obtain intermediate 1c (530 mg). MS (ESI) m / z [M+H] + :487.3.

[0499] Step 3: Preparation of intermediate 1d

[0500] Intermediate 1c (530 mg) and THF (10 mL) were mixed. Under N2 protection, methylmagnesium bromide (3.27 mL, 1 M THF solution) was slowly added dropwise to the reaction system. The reaction was allowed to proceed at 25°C for 3 h. After the reaction was complete, the reaction solution was extracted with ethyl acetate and saturated aqueous ammonium chloride. The organic phase was concentrated and purified by silica gel column chromatography to obtain intermediate 1d (480 mg). MS (ESI) m / z [M+H] + :504.4.

[0501] Step 4: Preparation of intermediate 1e

[0502] Intermediate 1d (480 mg) and methanol (10 mL) were mixed and sodium borohydride (108 mg) was added to the reaction system under an ice-water bath. The reaction was allowed to react for 1 h. After the reaction was complete, the reaction solution was quenched with ammonium chloride and extracted with ethyl acetate. The organic phase was concentrated and purified by silica gel column chromatography to obtain intermediate 1e (420 mg). MS (ESI) m / z [M+H] + :506.4.

[0503] Step 5: Preparation of Intermediate 1f

[0504] Intermediate 1e (420 mg) and dichloromethane (10 mL) were mixed, trifluoroacetic acid (2 mL) was added to the reaction system, and the reaction was allowed to react for 1 h. After the reaction was complete, the reaction solution was concentrated to obtain Intermediate 1f (430 mg). MS (ESI) m / z [M+H] + :406.5.

[0505] Step 6: Preparation of Compound 1

[0506] Intermediate 1f (120 mg), z4 (70 mg, i.e., intermediate 40e in Example 40 of WO2023088406, refer to its preparation process), and dichloromethane / isopropanol (v:v 5 / 1, 10 mL) were mixed, and sodium triacetoxyborohydride (148 mg) was added to the reaction system and reacted for 1 h. After the reaction was complete, the reaction solution was concentrated and purified by silica gel column chromatography to obtain compound 1 (53 mg). MS (ESI) m / z [M+H] + :688.5. 1 H NMR(500MHz,DMSO)δ11.07(s,1H),8.57(s,2H),7.60(d,J=8.0Hz,1H),7.32–7.18(m,3H),7.18–7.07(m,2H),7 .07–6.95(m,2H),6.75(d,J=8.8Hz,2H),5.21(d,J=5.5Hz,1H),4.78(dp,J=17.2,6.0Hz,2H),4.56(dd,J=11.8, 5.0Hz,1H),3.85–3.72(m,2H),3.17(ddd,J=35.9,16.3,7.8Hz,2H),3.04–2.96(m,2H),2.92–2.70(m,3H),2.6 8–2.52(m,4H),2.46(dd,J=12.0,4.4Hz,1H),2.18(dd,J=12.6,5.6Hz,1H),1.61(s,6H),1.41(d,J=6.5Hz,3H).

[0507] Example 2 Synthesis of Compound 2

[0508] Step 1: Preparation of intermediate 2b

[0509] Intermediate 2a (30 g) and methanol (300 mL) were mixed, and sodium borohydride (1.56 g) was added to the reaction system under ice-cooling. The reaction was allowed to proceed at 0°C for 1 h until the reaction was complete. The mixture was quenched with saturated ammonium chloride solution and extracted with DCM. The organic phases were combined, dried, and concentrated to give Intermediate 2b (g). MS (ESI) m / z [M+H] + :203.1.

[0510] Step 2: Preparation of intermediate 2c

[0511] Intermediate 2b (15 g), imidazole (15 g), and DCM (200 mL) were mixed and TBSCl (16.7 g) was added to the reaction system under ice-cooling. The reaction was allowed to proceed at 25°C for 16 h until the reaction was complete. The reaction solution was concentrated and purified by silica gel column chromatography to obtain intermediate 2c (17.3 g). MS (ESI) m / z [M+H] + :317.2.

[0512] Step 3: Preparation of intermediate 2e

[0513] Mix 2d (15 g) and THF (150 mL) and cool to -20°C. Under N2 protection, add 1M isopropylmagnesium chloride in THF (60 mL) dropwise to the reaction system and react at -20°C for 1 hour. Add acetone (4.95 g) and warm to room temperature for complete reaction. Pour the reaction solution into saturated aqueous ammonium chloride solution, extract with ethyl acetate, concentrate, and purify by silica gel column chromatography to obtain intermediate 2e (5.54 g). MS (ESI) m / z [M+H] + :195.1.

[0514] Step 4: Preparation of intermediate 2f

[0515] Intermediate 2e (5.54 g), phenol (2.81 g), and carbon tetrachloride (100 mL) were mixed and cooled to -20°C. Boron trifluoride etherate (23.82 g) was added dropwise to the reaction system under N2 protection and the temperature was raised to room temperature for complete reaction. The reaction solution was poured into water, extracted with ethyl acetate, concentrated, and purified by silica gel column chromatography to obtain intermediate 2f (5.69 g). MS (ESI) m / z [M+H] + :271.2.

[0516] Step 5: Preparation of Intermediate 2g

[0517] Intermediate 2c (2 g), intermediate 2f (1.74 g), CuI (600 mg), 2-picolinic acid (388 mg), potassium phosphate (4 g), and DMSO (20 mL) were mixed and reacted at 100°C for 16 h under N2 protection. The reaction was complete. Saturated brine and EA were added for extraction. The organic phase was dried and concentrated to obtain a crude product. Intermediate 2g (730 mg) was separated by silica gel column chromatography. MS (ESI) m / z [M+H] + :507.3.

[0518] Step 6: Preparation of intermediate 2h

[0519] Intermediate 2g (300 mg) and THF (10 mL) were mixed, and LiAlH4 (22 mg) was added to the reaction system under ice-cooling. The reaction was allowed to proceed at 0°C for 1 h until the reaction was complete. The reaction was quenched by adding 5% aqueous sodium hydroxide solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain Intermediate 2h (210 mg). MS (ESI) m / z [M+H] + :479.2.

[0520] Step 7: Preparation of intermediate 2i

[0521] Intermediate 2h (210 mg) and DCM (10 mL) were mixed and Dess-martin oxidant (279 mg) was added to the reaction system under ice-cooling. The reaction was allowed to proceed at 25°C for 1 hour until completion. The reaction was quenched by the addition of a saturated sodium thiosulfate solution and extracted with DCM. The organic phase was dried and concentrated, and then separated by silica gel column chromatography to afford intermediate 2i (180 mg). MS (ESI) m / z [M+H] + :477.5.

[0522] Step 8: Preparation of intermediate 2j

[0523] Intermediate z2 (260 mg), tert-butyl 3-formylazetidine-1-carboxylate (150 mg), sodium acetate (66 mg), and isopropanol / DCM (1:5, 10 mL) were mixed. Sodium triacetoxyborohydride (515 mg) was added to the reaction system and allowed to react at 25°C for 1 h. The reaction was complete. The reaction solution was concentrated and separated by silica gel column chromatography to obtain intermediate 2j (370 mg). MS (ESI) m / z [M+H] + :455.3.

[0524] Step 9: Preparation of intermediate 2k

[0525] Intermediate 2j (370 mg) and solvent DCM (10 mL) were mixed, trifluoroacetic acid (2 mL) was added, and the mixture was allowed to react at 25°C for 1 h until the reaction was complete. The reaction solution was concentrated to obtain intermediate 2k (420 mg). MS (ESI) m / z [M+H] + :355.2.

[0526] Step 10: Preparation of intermediate 21

[0527] Intermediate 2k (177 mg), intermediate 2i (180 mg), and isopropanol / DCE (v:v = 1:5, 10 mL) were mixed, and sodium triacetoxyborohydride (240 mg) was added to the reaction system. The mixture was allowed to react at 70°C for 16 h until the reaction was complete. The reaction solution was concentrated and separated by silica gel column chromatography to obtain intermediate 2l (85 mg). MS (ESI) m / z [M+H] + :815.5.

[0528] Step 11: Preparation of Compound 2

[0529] Intermediate 21 (85 mg), formic acid (2 mL), and water (2 mL) were mixed and reacted at 25°C for 1 h. The reaction was complete. The reaction solution was quenched by adding saturated sodium bicarbonate solution and extracted with DCM. The organic phase was filtered, concentrated, and separated by silica gel column chromatography to obtain compound 2 (62 mg).

[0530] MS (ESI) m / z [M+H] + :701.5. 1 H NMR (500MHz, DMSO) δ11.07(s,1H),8.57(s,2H),7.56(d,J=8.2Hz,1H),7.29–7.22(m,2H),7.21–7.12(m,4H),7.07(d ,J=8.3Hz,1H),7.04–6.97(m,2H),5.20(d,J=5.5Hz,1H),4.79(p,J=6.4Hz,1H),4.54(dd,J=11.9,5.0Hz,1H),3.65(s ,2H),3.50(s,2H),3.37(d,J=8.0Hz,2H),2.95(t,J=5.9Hz,2H),2.81(d,J=19.2Hz,2H),2.77–2.66(m,6H),2.60(dt ,J=17.3,4.2Hz,1H),2.46(dt,J=12.3,6.3Hz,1H),2.17(dq,J=13.6,4.9Hz,1H),1.62(s,6H),1.41(d,J=6.6Hz,3H).

[0531] Example 3 Synthesis of Compound 3

[0532] Step 1: Preparation of intermediate 3a

[0533] Intermediate z1 (200 mg), tert-butyl 3-formylazetidine-1-carboxylate (180 mg), sodium acetate (270 mg), and DCE / isopropanol (v:v = 5:1, 20 mL) were mixed, and sodium triacetoxyborohydride (110 mg) was added. The reaction was allowed to complete at room temperature. The reaction solution was concentrated and purified by silica gel column chromatography to obtain intermediate 3a (210 mg). MS (ESI) m / z [M+H] + :441.1.

[0534] Step 2: Preparation of intermediate 3b

[0535] Intermediate 3a (210 mg), DCM (5 mL) and trifluoroacetic acid (2 mL) were mixed and reacted at room temperature until complete. The reaction solution was concentrated to obtain Intermediate 3b (170 mg). MS (ESI) m / z [M+H] + :341.1.

[0536] Step 3: Preparation of intermediate 3c

[0537] Intermediate 2g (400 mg), methanol (10 mL), water (2 mL), and sodium hydroxide (158 mg) were mixed and reacted at 70°C for 5 h. After the reaction was complete, the reaction solution was adjusted to an acidic pH by adding 1M aqueous hydrochloric acid. The mixture was then extracted with ethyl acetate. The organic phase was dried and concentrated to afford Intermediate 3c (340 mg). MS (ESI) m / z [M+H] + :493.1.

[0538] Step 4: Preparation of intermediate 3d

[0539] Intermediate 3b (120 mg), intermediate 3c (110 mg), DIPEA (150 mg), and DMF (5 mL) were mixed, and HATU (110 mg) was added. The reaction was allowed to complete at room temperature. The reaction solution was poured into water, extracted with ethyl acetate, and purified by silica gel column chromatography to obtain intermediate 3d (150 mg). MS (ESI) m / z [M+H] + :815.4.

[0540] Step 5: Preparation of compound 3

[0541] Intermediate 3d (150 mg), water (2 mL) and formic acid (2 mL) were mixed and reacted at room temperature for completion, and then purified by silica gel column chromatography to obtain compound 3 (80 mg).

[0542] MS (ESI) m / z [M+H] + :701.5. 1H NMR (500MHz, DMSO) δ11.08(s,1H),8.58(s,2H),7.71(d,J=8.0Hz,1H),7.61–7.56(m,2H),7.33–7.27(m,4H),7.26(d,J=2.1Hz,1H ),7.05–7.01(m,2H),5.21(d,J=5.5Hz,1H),4.82–4.77(m,1H),4.60(dd,J=11.9,5.0Hz,1H),4.44(t,J=8.2Hz,1H),4.16(d,J=8. 4Hz, 3H), 4.04 (t, J = 2.5Hz, 3H), 3.77 (dd, J = 9.9, 5.5Hz, 1H), 3.00 (d, J = 8.4Hz, 2H), 2.92 (p, J = 6.8Hz, 1H), 2.77 (ddd, J = 17.2, 12. 0,5.3Hz,1H),2.61(dt,J=17.3,4.3Hz,1H),2.49–2.45(m,1H),2.20(dt,J=13.1,4.7Hz,1H),1.66(s,6H),1.41(d,J=6.5Hz,3H).

[0543] Example 4 Synthesis of Compound 4

[0544] Step 1: Preparation of intermediate 4a

[0545] Intermediate z1 (200 mg), 1-Boc-3-azetidinone (160 mg), sodium acetate (270 mg), and DCE / isopropanol (v:v = 5:1, 20 mL) were mixed, and sodium triacetoxyborohydride (110 mg) was added. The reaction was allowed to complete at room temperature. The reaction solution was concentrated and purified by silica gel column chromatography to obtain Intermediate 4a (180 mg). MS (ESI) m / z [M+H] + :427.3.

[0546] Step 2: Preparation of intermediate 4b

[0547] Intermediate 4a (180 mg), DCM (5 mL) and trifluoroacetic acid (2 mL) were mixed and reacted at room temperature until complete. The reaction solution was concentrated to obtain intermediate 4b (160 mg). MS (ESI) m / z [M+H] + :327.1.

[0548] Step 3: Preparation of intermediate 4c

[0549] Intermediate 3c (130 mg), intermediate 4b (110 mg), DIPEA (140 mg), and DMF (5 mL) were mixed, and HATU (110 mg) was added. The reaction was allowed to complete at room temperature. The reaction solution was poured into water, extracted with ethyl acetate, and purified by silica gel column chromatography to obtain intermediate 4c (120 mg). MS (ESI) m / z [M+H] + :801.4.

[0550] Step 4: Preparation of compound 4

[0551] Intermediate 4c (120 mg), water (2 mL) and formic acid (2 mL) were mixed and reacted at room temperature until completion, followed by silica gel column chromatography to obtain compound 4 (60 mg).

[0552] MS (ESI) m / z [M+H] + :687.5. 1 H NMR (500MHz, DMSO) δ11.09 (s, 1H), 8.59 (s, 2H), 7.73 (d, J = 8.1Hz, 1H), 7.62–7.58 (m, 2H), 7.34–7.26 (m, 5H), 7.06–7. 02(m,2H),5.21(d,J=5.5Hz,1H),4.83–4.77(m,1H),4.60(dd,J=11.9,5.0Hz,1H),4.42(t,J=8.1Hz,1H),4.34(s,1H) ,4.21(d,J=18.9Hz,3H),4.13–4.03(m,3H),3.82(dq,J=9.8,3.7Hz,1H),2.77(ddd,J=17.2,12.0,5.4Hz,1H),2.61(d t,J=17.3,4.1Hz,1H),2.53(dd,J=12.3,4.3Hz,1H),2.20(dq,J=13.5,4.6Hz,1H),1.67(s,6H),1.41(d,J=6.5Hz,3H).

[0553] Example 5 Synthesis of Compound 5

[0554] Step 1: Preparation of intermediate 5a

[0555] Intermediate 3c (130 mg), Intermediate 2k (110 mg), DIPEA (140 mg), and DMF (5 mL) were mixed, and HATU (110 mg) was added. The reaction was allowed to complete at room temperature. The reaction solution was poured into water, extracted with ethyl acetate, and purified by silica gel column chromatography to obtain Intermediate 5a (100 mg). MS (ESI) m / z [M+H] + :829.3.

[0556] Step 2: Preparation of compound 5

[0557] Intermediate 5a (100 mg) and formic acid / water (v:v = 1:1, 3 mL) were mixed and reacted at room temperature. After completion of the reaction, dichloromethane and water were added to dilute the system, and the pH was adjusted to a weakly alkaline state by adding saturated sodium bicarbonate aqueous solution. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The mixture was purified by silica gel column chromatography to obtain compound 5 (40 mg).

[0558] MS (ESI, [M+H] + )m / z:715.3. 1 H NMR (500MHz, DMSO-d6) δ11.07(s,1H),8.58(d,J=1.5Hz,2H),7.57(d,J=8.1Hz,3H),7.33–7.24(m,4H),7.08(d,J=8.2Hz, 1H),7.03(dd,J=8.5,1.6Hz,2H),5.21(d,J=5.5Hz,1H),4.79(p,J=6.3Hz,1H),4.55(dd,J=11.9,4.9Hz,1H),4.42(t,J=8 .5Hz,1H),4.14(t,J=9.2Hz,1H),4.00(t,J=7.2Hz,1H),3.82–3.66(m,3H),2.97(t,J=5.6Hz,3H),2.85–2.71(m,5H),2.6 0(dt,J=17.3,4.4Hz,1H),2.46(dd,J=12.2,4.4Hz,1H),2.18(dq,J=13.8,4.8Hz,1H),1.65(s,6H),1.41(d,J=6.7Hz,3H).

[0559] Example 6 Synthesis of Compound 6

[0560] Step 1: Preparation of compound 6

[0561] Intermediate 1f (200 mg), intermediate z3 (140 mg), sodium acetate (40 mg), and DCE / isopropanol (v:v = 5:1, 5 mL) were mixed, and sodium triacetoxyborohydride (314 mg) was added. The mixture was reacted at room temperature. After completion of the reaction, the solvent was evaporated under reduced pressure, and the product was purified by silica gel column chromatography to obtain compound 6 (70 mg). MS (ESI, [M+H] + )m / z:674.3. 1H NMR (500MHz, DMSO-d6) δ11.07(s,1H),8.57(s,2H),7.61(dd,J=8.1,2.5Hz,1H),7.25(dd,J=8.6,2.0Hz,3H),7.16–7.09(m ,2H),7.05–6.98(m,2H),6.78–6.70(m,2H),5.21(d,J=5.5Hz,1H),4.79(p,J=6.4Hz,1H),4.70(p,J=5.7Hz,1H),4.56(dd, J=11.8,4.9Hz,1H),3.81–3.70(m,2H),3.45–3.37(m,1H),3.34(s,1H),3.12(dd,J=14.4,6.4Hz,1H),3.05(dt,J=12.9,6. 4Hz,2H),2.90–2.72(m,3H),2.65–2.57(m,1H),2.49–2.43(m,1H),2.25–2.14(m,1H),1.61(s,6H),1.41(d,J=6.5Hz,3H).

[0562] Example 7 Synthesis of Compound 7

[0563] Step 1: Preparation of intermediate 7a

[0564] Intermediate 7-1 (2 g), intermediate 7-2 (1.16 g), triphenylphosphine (3.45 g) and tetrahydrofuran (20 mL) were mixed, replaced with nitrogen, and DEAD (2.56 mL) was slowly added under ice bath conditions. After the addition was complete, the mixture was heated to 65°C for reaction. After the reaction was completed, the reaction solution was cooled to room temperature, the solvent was evaporated under reduced pressure, and the reaction solution was purified by silica gel column chromatography to obtain intermediate 7a (700 mg). MS (ESI, [M+H] + )m / z:343.2.

[0565] Step 2: Preparation of intermediate 7b

[0566] Intermediate 7a (700 mg), intermediate 2c (650 mg), cuprous iodide (540 mg), 2-pyridine carboxylate (350 mg) and DMSO (10 mL) were mixed, replaced with nitrogen, and the mixture was heated to 100°C for reaction. After the reaction was completed, ethyl acetate and water were added to the system for extraction. The organic phase was separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The product was purified by silica gel column chromatography to obtain intermediate 7b (160 mg). MS (ESI, [M+H] + )m / z:579.2.

[0567] Step 3: Preparation of intermediate 7c

[0568] Intermediate 7b (160 mg) and formic acid / water (v:v = 1:1, 3 mL) were mixed and the mixture was heated to 90°C for reaction. After the reaction was completed, dichloromethane and water were added to the system for dilution, and saturated sodium bicarbonate aqueous solution was added to adjust the pH to a weak alkaline state. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The product was purified by silica gel column chromatography to obtain Intermediate 7c (90 mg). MS (ESI, [M+H] + )m / z:419.1.

[0569] Step 4: Preparation of compound 5

[0570] Intermediate 7c (90 mg), intermediate z2 (74 mg), sodium acetate (14 mg), methanol (2 mL) and sodium cyanoborohydride (41 mg) were mixed and heated to 60°C for reaction. After completion of the reaction, the solvent was evaporated under reduced pressure and the product was purified by silica gel column chromatography to obtain compound 7 (25 mg). MS (ESI, [M+H] + )m / z:688.3. 1 H NMR (500MHz, DMSO-d6) δ11.07(s,1H),8.57(s,2H),7.57(d,J=8.2Hz,1H),7.25(d,J=8.3Hz,2H),7.11(t,J=7.2Hz,3H ),7.01(d,J=8.3Hz,2H),6.78(d,J=8.3Hz,2H),5.21(d,J=5.5Hz,1H),4.79(p,J=6.3Hz,1H),4.51(ddd,J=40.8,13.0 ,6.1Hz,2H),3.64(s,2H),2.99(t,J=5.9Hz,2H),2.74(ddq,J=28.5,17.2,5.6Hz,6H),2.60(dt,J=17.4,4.3Hz,1H),2 .46(dd,J=12.2,4.4Hz,1H),2.18(dq,J=13.7,4.8Hz,1H),1.94(q,J=10.4Hz,2H),1.61(s,6H),1.41(d,J=6.5Hz,3H).

[0571] Example 8 Synthesis of Compound 8

[0572] Step 1: Preparation of compound 8a

[0573] Intermediate 2c (3.50 g), intermediate 7-1 (4.03 g), cuprous iodide (1.05 g), 2-picolinic acid (0.68 g), potassium phosphate (7.02 g), and DMSO (70 mL) were mixed and reacted at 90°C for 4 h under N2 protection. After the reaction was complete, water and EA were added to the reaction solution for dilution. The organic phase was separated, washed with saturated brine, concentrated, and purified by silica gel column chromatography to obtain compound 8a (2.8 g). MS (ESI, [M+H] + )m / z:465.3.

[0574] Step 2: Preparation of compound 8b

[0575] To the reaction flask, intermediate 8a (2.7 g), pyridine (0.76 g), DMAP (0.04 g), and DCM (50 mL) were added in sequence. The temperature was lowered to 0°C, and trifluoromethanesulfonic anhydride (0.81 g) was slowly added. The mixture was reacted at 0°C for 2 h. After the reaction was complete, water was added to quench the reaction solution. The organic phase was separated, washed with saturated brine, concentrated, and purified by silica gel column chromatography to obtain compound 8b (2.2 g). MS (ESI, [M+H] + )m / z:597.3.

[0576] Step 3: Preparation of compound 8c

[0577] Intermediate 8b (600 mg), 4-(dimethoxymethyl)-piperidine (400 mg), tris(dibenzylideneacetone)dipalladium (90 mg), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (500 mg), cesium carbonate (660 mg), and 1,4-dioxane (15 mL) were mixed and reacted at 110°C for 2 h under N2 protection. The reaction was complete, and the reaction solution was purified by silica gel column chromatography to obtain compound 8c (420 mg). MS (ESI, [M+H] + )m / z:606.4.

[0578] Step 4: Preparation of compound 8d

[0579] Intermediate 8c (400 mg), formic acid (4 mL), and water (4 mL) were mixed and reacted at 80°C for 2 h. After the reaction was complete, water and EA were added to dilute the reaction solution. The organic phase was separated, washed with saturated brine, concentrated, and purified by silica gel column chromatography to obtain compound 8d (320 mg). MS (ESI, [M+H] + )m / z:446.1.

[0580] Step 5: Preparation of compound 8

[0581] Intermediate 8d (100 mg), intermediate z1 (80 mg), sodium acetate (40 mg), 1,2-dichloroethane (10 mL), and isopropanol (2 mL) were mixed and stirred at room temperature for 10 min. Sodium triacetoxyborohydride (100 mg) was then added and allowed to react at room temperature for 1 h. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, washed with saturated brine, concentrated, and purified by silica gel column chromatography to obtain compound 8 (32 mg). MS (ESI, [M+H] + )m / z:701.3. 1 H NMR (500MHz, DMSO) δ11.09(s,1H),8.57(s,2H),7.71(d,J=8.0Hz,1H),7.28(dd,J=24.5,8.2Hz,3H),7.03(dd,J=23.5 ,8.3Hz,4H),6.86(d,J=8.4Hz,2H),5.21(d,J=5.5Hz,1H),4.79(p,J=6.3Hz,1H),4.60(dd,J=11.9,4.9Hz,1H),4.15( s,2H),4.04(s,2H),3.65(d,J=11.8Hz,2H),2.77(ddd,J=17.3,11.9,5.3Hz,1H),2.70–2.58(m,5H),2.53(d,J=10.1H z,1H),2.26–2.15(m,1H),1.87(d,J=12.7Hz,2H),1.70(s,1H),1.60(s,6H),1.41(d,J=6.6Hz,3H),1.33–1.22(m,2H).

[0582] Example 9 Synthesis of Compound 9

[0583] Step 1: Preparation of compound 9

[0584] Referring to the method described in step 5 of Example 8, intermediate z2 was substituted for intermediate z1 to synthesize compound 9 (70 mg). MS (ESI, [M+H] + )m / z:715.1. 1H NMR (500MHz, DMSO) δ11.07(s,1H),8.57(s,2H),7.57(d,J=8.1Hz,1H),7.29–7.22(m,2H),7.10(d,J=8.2Hz,1H),7.08–6.98(m ,4H),6.84(dd,J=9.2,2.6Hz,2H),5.20(d,J=5.5Hz,1H),4.79(p,J=6.4Hz,1H),4.55(dd,J=11.8,5.0Hz,1H),3.70(s,2H),3.6 3(d,J=12.3Hz,2H),2.99(t,J=5.9Hz,2H),2.77(dh,J=12.5,5.4Hz,3H),2.67–2.57(m,3H),2.46(dd,J=12.2,4.4Hz,1H),2.40 (d,J=6.8Hz,2H),2.18(dq,J=13.7,4.7Hz,1H),1.81(t,J=11.8Hz,3H),1.59(s,6H),1.41(d,J=6.6Hz,3H),1.29–1.22(m,2H).

[0585] Example 10 Synthesis of Compound 10

[0586] Step 1: Preparation of intermediate 10a

[0587] Intermediate 8b (350 mg), tert-butyl 3-ethynyl-1-azetidinecarboxylate (90 mg), bistriphenylphosphine palladium dichloride (40 mg), cuprous iodide (20 mg), tetrabutylammonium iodide (240 mg), triethylamine (5 mL), and DMF (5 mL) were mixed and heated to 100°C under N2 protection for 3 h. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, and purified by silica gel column chromatography to obtain intermediate 10a (330 mg). MS (ESI) m / z [M+H] + :628.3.

[0588] Step 2: Preparation of Intermediate 10b

[0589] Intermediate 10a (330 mg), DCM (5 mL), and trifluoroacetic acid (2 mL) were mixed and reacted at room temperature until complete. The pH of the reaction solution was adjusted to approximately 7-8 with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, and purified by silica gel column chromatography to obtain Intermediate 10b (170 mg). MS (ESI) m / z [M+H] + :528.2.

[0590] Step 3: Preparation of intermediate 10c

[0591] Intermediate 10b (170 mg), intermediate z3 (90 mg), and DCE / isopropanol (v:v = 5:1, 10 mL) were mixed, and sodium triacetoxyborohydride (150 mg) was added. The reaction was allowed to complete at room temperature. The reaction solution was concentrated and purified by silica gel column chromatography to obtain intermediate 10c (130 mg). MS (ESI) m / z [M+H] + :796.4.

[0592] Step 4: Preparation of compound 10

[0593] Intermediate 10c (130 mg), water (2 mL) and formic acid (2 mL) were mixed and reacted at room temperature until complete. Compound 10 (70 mg) was obtained by silica gel column chromatography. MS (ESI) m / z [M+H] + :682.1. 1 H NMR (500MHz, DMSO) δ11.07(s,1H),8.58(s,2H),7.61(dd,J=8.1,3.1Hz,1H),7.32(d,J=8.1Hz,2H),7.27–7.23(m ,3H),7.20(d,J=8.3Hz,2H),7.04–7.00(m,2H),5.21(d,J=5.6Hz,1H),4.79(p,J=6.4Hz,1H),4.56(dd,J=11.8,5 .0Hz,1H),3.64–3.56(m,2H),3.35(q,J=7.7Hz,2H),3.16–3.03(m,4H),2.84(dd,J=16.2,3.1Hz,1H),2.81–2.72 (m,2H),2.64–2.57(m,1H),2.49–2.43(m,1H),2.18(dp,J=13.3,4.4Hz,1H),1.62(s,6H),1.41(d,J=6.5Hz,3H).

[0594] Example 11 Synthesis of Compound 11

[0595] Step 1: Preparation of intermediate 11a

[0596] To a three-necked flask, bisphenol A (10 g), intermediate 11a-1 (5.7 g), triphenylphosphine (17.23 g), and dioxane (150 mL) were added in sequence. DEAD (12.78 mL) was slowly added under a nitrogen atmosphere and in an ice bath. After the addition was complete, the mixture was heated to 80°C for reaction. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography to obtain intermediate 11a (5.5 g). MS (ESI, [M+H] +)m / z:341.25.

[0597] Step 2: Preparation of intermediate 11b

[0598] To a single-necked flask, intermediate 11a (1.5 g), intermediate 11a-2 (0.846 g), potassium carbonate (1.745 g), and DMF (15 mL) were added in sequence. Under N2 protection, the mixture was heated to 80°C for reaction. After the reaction was completed, ethyl acetate and water were added to the system for extraction. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain intermediate 11b (0.8 g). MS (ESI, [M+H] + )m / z:461.28.

[0599] Step 3: Preparation of intermediate 11c

[0600] To a single-necked flask, intermediate 11b (0.8 g), methanol (5 mL), and sodium borohydride (0.032 g) were added sequentially, and the mixture was reacted at room temperature. After the reaction, the reaction solution was slowly poured into a saturated aqueous ammonium chloride solution. The aqueous phase was extracted with dichloromethane. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate 11c (0.79 g). MS (ESI, [M+H] + )m / z:463.35.

[0601] Step 4-5: Preparation of compound 11

[0602] Referring to the reaction of steps 9-10 of Example 17, 17h was replaced by 11c to obtain compound 11 (60 mg).

[0603] Compound 11d: MS (ESI, [M+H] + )m / z:433.12.

[0604] Compound 11: MS (ESI, [M+H] + )m / z:702.33. 1H NMR(500MHz,DMSO-d6)δ11.07(s,1H),8.57(s,2H),7.57(d,J=8.2Hz,1H),7.31–7.21(m,2H),7.10 (dd,J=8.7,6.9Hz,3H),7.06–6.96(m,2H),6.79–6.69(m,2H),5.21(d,J=5.6Hz,1H),4.79(p,J=6.3 Hz,2H),4.55(dd,J=11.9,5.0Hz,1H),3.70(s,2H),2.99(t,J=5.7Hz,2H),2.87–2.71(m,3H),2.71 –2.56(m,4H),2.46(dd,J=12.1,4.4Hz,1H),2.34–2.12(m,5H),1.61(s,6H),1.41(d,J=6.6Hz,3H).

[0605] Example 12 Synthesis of Compound 12

[0606] Step 1: Preparation of compound 12a

[0607] To the reaction flask were added intermediate 8b (2.60 g), 3-methylformate azetidine hydrochloride (3.01 g), Pd2(dba)3 (0.40 g), RuPhos (0.31 g), cesium carbonate (2.84 g), and 1,4-dioxane (26 mL) in sequence. Under N2 protection, the mixture was reacted at 110°C for 2 h. The reaction was complete, and the reaction solution was purified by silica gel column chromatography to obtain compound 12a (1.6 g). MS (ESI, [M+H] + )m / z:562.21.

[0608] Step 2: Preparation of compound 12b

[0609] Referring to the reaction in step 9 of Example 17, compound 12a was used to replace compound 17h to obtain compound 12b (1.8 g). MS (ESI, [M+H] + )m / z:532.33.

[0610] Step 3: Preparation of compound 12c

[0611] Referring to the reaction in step 6 of Example 17, compound 12b was used to replace compound 17e to obtain compound 12c (1.1 g). MS (ESI, [M+H] + )m / z:418.31.

[0612] Step 4: Preparation of compound 12

[0613] Referring to the reaction in step 5 of Example 8, compound 12c was used in place of compound 8d to obtain compound 12 (0.32 g). MS (ESI, [M+H]+) m / z: 673.19. 1 H NMR (500MHz, DMSO) δ11.07(s,1H),8.57(s,2H),7.71(d,J=8.0Hz,1H),7.30(d,J=8.1Hz,1H),7.27–7.22(m,2H),7.0 6–6.98(m,4H),6.37(d,J=8.3Hz,2H),5.19(d,J=5.5Hz,1H),4.79(p,J=6.3Hz,1H),4.60(dd,J=11.8,5.0Hz,1H),4. 17(s,2H),4.06(s,2H),3.95(t,J=7.1Hz,2H),3.51(t,J=6.1Hz,2H),3.00(q,J=7.1Hz,3H),2.77(ddd,J=17.2,11.9 ,5.3Hz,1H),2.61(dt,J=17.3,4.2Hz,1H),2.56–2.52(m,1H),2.25–2.16(m,1H),1.59(s,6H),1.41(d,J=6.5Hz,3H).

[0614] Example 13-16 Synthesis of Compound 13-16

[0615] The synthesis method of reference compound 12 was to use compound 12c as the starting material and replace z1 with the following intermediate to synthesize the following compound:

[0616] Example 17 Synthesis of Compound 17

[0617] Step 1: Preparation of intermediate 17a

[0618] 17a-1 (10 g), DCM (100 mL), pyridine (13 mL) and DMAP (0.7 g) were added to a single-necked flask in sequence. Under ice bath protection, trifluoromethanesulfonic anhydride (10 mL) was slowly added and the mixture was reacted at room temperature. After the reaction was completed, DCM and water were added to the system for extraction, and the organic phase was separated. After washing with saturated brine, the mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate 17a (16.5 g). MS (ESI, [M+H] + )m / z:303.21.

[0619] Step 2: Preparation of intermediate 17b

[0620] 17a (16.5 g) and toluene (200 mL) were added to a three-necked flask in sequence. Methylmagnesium bromide (45 mL) was slowly added under nitrogen protection and in an ice bath, and the mixture was reacted at room temperature. After the reaction, the reaction solution was slowly poured into an aqueous ammonium chloride solution. The aqueous phase was extracted with ethyl acetate. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain intermediate 17b (9.1 g). MS (ESI, [M+H] + )m / z:303.13.

[0621] Step 3: Preparation of intermediate 17c

[0622] 17b (9.1 g), phenol (5.6 g), 1,2-dichloroethane (100 mL), and trifluoromethanesulfonic acid (5.2 mL) were added sequentially to a single-necked flask and the mixture was reacted at room temperature. After the reaction was complete, DCM and water were added to the system for extraction. The organic phase was separated, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain intermediate 17c (9.5 g). MS (ESI, [M+H] + )m / z:379.24.

[0623] Step 4: Preparation of Intermediate 17d

[0624] 17c (2 g), DMF (20 mL), imidazole (1 g), and TIPS-Cl (1.5 g) were added sequentially to a single-necked flask, and the mixture was heated to 50°C for reaction. After completion of the reaction, ethyl acetate and water were added to the system for extraction. The organic phase was separated, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain intermediate 17d (3.9 g). MS (ESI, [M+H] + )m / z:535.32.

[0625] Step 5: Preparation of intermediate 17e

[0626] To a single-necked flask, 17d (2 g), methyl azetidine-3-carboxylate hydrochloride (1.05 g), Pd2(dba)3 (0.3 g), Xphos (0.3 g), Cs2CO3 (4.8 g), and 1,4-dioxane (20 mL) were added sequentially. Under nitrogen protection, the mixture was heated to 120°C for reaction. After completion of the reaction, the solvent was evaporated under reduced pressure, and the intermediate 17e (0.85 g) was purified by silica gel column chromatography. MS (ESI, [M+H] + )m / z:500.25.

[0627] Step 6: Preparation of intermediate 17f

[0628] 17e (0.85 g), tetrahydrofuran (10 mL), and TBAF (5 mL) were added sequentially to a single-necked flask, and the mixture was reacted at room temperature. After the reaction was complete, ethyl acetate and water were added to the system for extraction. The organic phase was separated, and the solvent was evaporated under reduced pressure. The intermediate 17f (0.5 g) was purified by silica gel column chromatography. MS (ESI, [M+H] + )m / z:344.33.

[0629] Step 7: Preparation of Intermediate 17g

[0630] To a single-necked flask, 17f (0.5 g), 11a-2 (0.33 g), potassium carbonate (1.5 g), and DMF (15 mL) were added sequentially. Under N2 protection, the mixture was heated to 80°C for reaction. After the reaction was complete, ethyl acetate and water were added to the system for extraction. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The intermediate 17g (0.3 g) was purified by silica gel column chromatography. MS (ESI, [M+H] + )m / z:464.51.

[0631] Step 8: Preparation of Intermediate 17h

[0632] 17g (0.3g), methanol (5mL), and sodium borohydride (12mg) were added to a single-necked flask in sequence, and the mixture was reacted at room temperature. After the reaction, the reaction solution was slowly poured into a saturated aqueous ammonium chloride solution. The aqueous phase was extracted with dichloromethane. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain intermediate 17h (0.25g). MS (ESI, [M+H] + )m / z:466.32.

[0633] Step 9: Preparation of intermediate 17i

[0634] To a three-necked flask, 17h (0.25 g) and dichloromethane (5 mL) were added sequentially. Under nitrogen protection, DIBAL-H (0.55 mL) was added dropwise at -78°C, and the mixture was reacted at -78°C. After the reaction was completed, the reaction solution was poured into a saturated aqueous ammonium chloride solution, and the aqueous phase was extracted with dichloromethane. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain intermediate 17i (0.18 g). MS (ESI, [M+H] + )m / z:436.32.

[0635] Step 10: Preparation of compound 17

[0636] To a single-necked flask, intermediate 17i (180 mg), intermediate z2 (140 mg), sodium acetate (35 mg), DCE / iPrOH = 5:1 (5 mL, v:v), and sodium triacetoxyborohydride (260 mg) were added sequentially, and the mixture was reacted at room temperature. After completion of the reaction, the product was purified by silica gel column chromatography to obtain compound 17 (75 mg). MS (ESI, [M+H] + )m / z:705.41. 1 H NMR (500MHz, DMSO-d6) δ11.07(s,1H),8.58(s,2H),7.58(d,J=8.2Hz,1H),7.25(d,J=8.7Hz,2H),7.06(dd,J= 41.9,8.5Hz,3H),6.90–6.79(m,2H),6.47(t,J=9.1Hz,1H),5.21(d,J=5.5Hz,1H),4.79(p,J=6.4Hz,1H),4.56 (dd,J=11.9,5.0Hz,1H),4.15–3.95(m,2H),3.72(s,2H),3.58(t,J=6.6Hz,2H),3.00(q,J=10.5Hz,3H),2.89 –2.69(m,5H),2.60(dt,J=17.3,4.3Hz,1H),2.18(dq,J=14.1,5.0Hz,1H),1.59(s,6H),1.41(d,J=6.6Hz,3H).

[0637] Example 18 Synthesis of Compound 18

[0638] Referring to the reaction of step 1-10 of Example 17b, 17a-1 was replaced with 18a-1 to finally prepare compound 18.

[0639] 18a: MS (ESI, [M+H] + )m / z:310.05.

[0640] 18b: MS (ESI, [M+H] + )m / z:310.12.

[0641] 18c: MS (ESI, [M+H] + )m / z:386.12.

[0642] 18d: MS (ESI, [M+H] + )m / z:542.31.

[0643] 18e:MS(ESI,[M+H] + )m / z:507.43.

[0644] 18f: MS (ESI, [M+H] + )m / z:351.33.

[0645] 18g: MS (ESI, [M+H] + )m / z:471.21.

[0646] 18h: MS (ESI, [M+H] + )m / z:473.24.

[0647] 18i:MS(ESI,[M+H] + )m / z:443.31.

[0648] Compound 18: MS (ESI, [M+H] + )m / z:712.32. 1 H NMR (500MHz, DMSO-d6) δ11.07(s,1H),8.58(s,2H),7.58(d,J=8.1Hz,1H),7.33(d,J=2.3Hz,1H),7.25(d,J=8.4Hz,2H),7.21(dd,J= 8.9,2.3Hz,1H),7.10(d,J=8.2Hz,1H),7.02(d,J=8.3Hz,2H),6.52(d,J=8.9Hz,1H),5.21(d,J=5.5Hz,1H),4.80(p,J=6.3Hz,1H),4 .56(dd,J=11.9,5.0Hz,1H),4.22(t,J=7.8Hz,2H),3.85–3.68(m,4H),3.03(dt,J=33.5,6.6Hz,3H),2.78(ddd,J=29.3,11.4,6.2Hz ,5H),2.60(dt,J=17.4,4.2Hz,1H),2.46(dd,J=12.1,4.4Hz,1H),2.19(dq,J=13.7,4.8Hz,1H),1.59(s,6H),1.41(d,J=6.5Hz,3H).

[0649] Example 19 Synthesis of Compound 19

[0650] Referring to the reaction of steps 7-10 of Example 17, intermediate 21e was used to replace intermediate 17f to finally prepare compound 19.

[0651] 19a:MS(ESI,[M+H] + )m / z:447.31.

[0652] 19b: MS (ESI, [M+H] + )m / z:449.23.

[0653] 19c:MS(ESI,[M+H] + )m / z:419.34.

[0654] Compound 19: MS (ESI, [M+H] + )m / z:688.33. 1 H NMR (500MHz, DMSO-d6) δ11.07(s,1H),8.57(s,2H),7.98(d,J=2.5Hz,1H),7.58(d,J=8.1Hz,1H),7.31(dd,J=8.6,2.5Hz,1H),7.2 9–7.23(m,2H),7.10(d,J=8.3Hz,1H),7.06–6.96(m,2H),6.31(d,J=8.7Hz,1H),5.21(d,J=5.5Hz,1H),4.83–4.74(m,1H),4.56(dd ,J=11.9,4.9Hz,1H),4.03(t,J=7.9Hz,2H),3.73(s,2H),3.61(dd,J=7.9,5.6Hz,2H),3.01(dt,J=20.7,6.5Hz,3H),2.93–2.70(m, 5H), 2.60 (dt, J=17.3, 4.2Hz, 1H), 2.46 (dd, J=12.1, 4.4Hz, 1H), 2.18 (dq, J=13.6, 4.9Hz, 1H), 1.61 (s, 6H), 1.41 (d, J=6.5Hz, 3H).

[0655] Example 20 Synthesis of Compound 20

[0656] Step 1: Preparation of intermediate 20a

[0657] Referring to the reaction of step 2 of Example 17, 20a was prepared by replacing 17a with intermediate 20a-1.

[0658] MS (ESI, [M+H] + )m / z:154.37.

[0659] Step 2: Preparation of intermediate 20b

[0660] To a single-necked flask, 20a (18 g), anisole (50 mL), and trifluoromethanesulfonic acid (16 mL) were added sequentially, and the mixture was reacted at room temperature. After completion of the reaction, dichloromethane and water were added to the system for extraction. The organic phase was separated and purified by silica gel column chromatography to obtain intermediate 20b (8.5 g).

[0661] MS (ESI, [M+H] + )m / z:244.34.

[0662] Step 3: Preparation of intermediate 20c

[0663] By referring to the reaction of step 1 of Example 17, 20b was used to replace 17a-1 to obtain intermediate 20c (9.3 g).

[0664] MS (ESI, [M+H] + )m / z:376.33.

[0665] Step 4: Preparation of intermediate 20d

[0666] 20c (9.3 g), dichloromethane (100 mL), and boron tribromide (2 M, 37 mL) were added sequentially to a single-necked flask and the mixture was reacted at room temperature. After the reaction was complete, dichloromethane and water were added to the system for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain intermediate 20d (7.8 g). MS (ESI, [M+H] + )m / z:362.52.

[0667] Referring to the reaction of steps 4-10 of Example 17, compound 20 was prepared by replacing 17c with 20d and replacing Xphos in step 5 of Example 17 with BINAP.

[0668] 20e:MS(ESI,[M+H] + )m / z:518.32.

[0669] 20f: MS (ESI, [M+H] + )m / z:483.31.

[0670] 20g: MS (ESI, [M+H] + )m / z:327.25

[0671] 20h: MS (ESI, [M+H] + )m / z:447.33.

[0672] 20i:MS(ESI,[M+H] + )m / z:449.32.

[0673] 20j:MS(ESI,[M+H] + )m / z:419.33.

[0674] Compound 20: MS (ESI, [M+H] + )m / z:688.50. 1 H NMR (500MHz, DMSO-d6) δ11.07(s,1H),8.64(s,2H),8.40(d,J=2.9Hz,1H),7.58(d,J=8.2Hz,1H),7.44(dd,J=8.8,3.0Hz,1H),7 .17(d,J=8.8Hz,1H),7.09(d,J=8.3Hz,1H),7.06–7.01(m,2H),6.39–6.33(m,2H),5.23(d,J=5.5Hz,1H),4.85–4.77(m,1H),4.5 5(dd,J=11.9,5.0Hz,1H),3.92(t,J=7.4Hz,2H),3.72(s,2H),3.47(dd,J=7.2,5.6Hz,2H),3.01(dt,J=17.2,6.2Hz,3H),2.85– 2.73(m,5H),2.60(dt,J=17.3,4.2Hz,1H),2.46(dd,J=12.1,4.5Hz,1H),2.23–2.15(m,1H),1.64(s,6H),1.41(d,J=6.5Hz,3H).

[0675] Example 21 Synthesis of Compound 21

[0676] Step 1-5: Preparation of intermediate 21e

[0677] Referring to the reaction of steps 2-6 of Example 17, 17a was replaced with 6-bromonicotinate, and Xphos in step 5 of Example 17 was replaced with BINAP to prepare 21e.

[0678] 21a:MS(ESI,[M+H] + )m / z:216.05.

[0679] 21b:MS(ESI,[M+H] + )m / z:292.06.

[0680] 21c:MS(ESI,[M+H] + )m / z:448.45.

[0681] 21d: MS (ESI, [M+H] +)m / z:483.30.

[0682] 21e:MS(ESI,[M+H] + )m / z:327.22.

[0683] Step 6: Preparation of intermediate 21f

[0684] Referring to the reaction of step 1 of Example 17, 21e was used to replace 17a-1 to obtain intermediate 21f (2.0 g). 21f: MS (ESI, [M+H] + )m / z:459.09.

[0685] Step 7: Preparation of Intermediate 21g

[0686] 21f (2 g), neopentyl glycol diboronate (1.183 g), PdCl2(dppf)-CH2Cl2 (0.713 g), potassium acetate (1.284 g), and 1,4-dioxane (30 mL) were added sequentially to a single-necked flask. Under nitrogen protection, the mixture was heated to 100°C for reaction. After the reaction, ethyl acetate and water were added to the system for extraction. The organic phase was separated and purified by silica gel column chromatography to obtain intermediate 21g (1.3 g). MS (ESI, [M+H] + )m / z:423.31.

[0687] Step 8: Preparation of Intermediate 21h

[0688] To a single-necked flask, 21g (500 mg), intermediate z8 (274 mg), Pd2(dba)3 (217 mg), Xphos (226 mg), Cs2CO3 (1157 mg), and 1,4-dioxane (5 mL) were added sequentially. Under nitrogen protection, the mixture was heated to 100°C for reaction. After completion of the reaction, intermediate 21h (0.59 g) was purified by silica gel column chromatography. MS (ESI, [M+H] + )m / z:506.25.

[0689] Steps 9-10: Preparation of compound 21

[0690] Referring to the reaction of steps 9-10 of Example 17, 17h was replaced by 21h to finally obtain compound 21 (100 mg).

[0691] 21i:MS(ESI,[M+H] + )m / z:476.34Compound 21: MS (ESI, [M+H] + )m / z:745.32. 1H NMR (500MHz, DMSO-d6) δ11.07(s,1H),8.77(s,2H),8.02(d,J=2.5Hz,1H),7.58(dd,J=8.1,5.8Hz,3H),7. 37–7.28(m,3H),7.10(d,J=8.3Hz,1H),6.31(d,J=8.7Hz,1H),4.56(dd,J=11.9,5.0Hz,1H),4.03(t,J=7.9 Hz,2H),3.73(s,2H),3.68–3.57(m,4H),3.38(dt,J=14.1,7.2Hz,2H),3.01(dt,J=21.1,6.5Hz,3H),2.87 –2.71(m,5H),2.60(dt,J=17.3,4.3Hz,1H),2.46(dd,J=12.2,4.3Hz,1H),2.29–2.06(m,5H),1.63(s,6H).

[0692] Example 22 Synthesis of Compound 22

[0693] Step 1: Preparation of intermediate 22a

[0694] Referring to the reaction of step 1 of Example 17, 20 g was used to replace 17a-1 to obtain intermediate 22a (2.1 g). MS (ESI, [M+H] + )m / z:459.09.

[0695] Step 2-5: Preparation of intermediate 22c

[0696] Referring to the reaction of steps 7-8 of Example 21, 21f was replaced with 22a to finally obtain compound 22 (83 mg).

[0697] 22b: MS (ESI, [M+H] + )m / z:423.33.

[0698] 22c: MS (ESI, [M+H] + )m / z:506.31.

[0699] 22d: MS (ESI, [M+H] + )m / z:476.34.

[0700] Compound 22: MS (ESI, [M+H] + )m / z:745.32. 1H NMR (500MHz, DMSO) δ11.07(s,1H),8.75(s,2H),7.76(d,J=2.9Hz,1H),7.60–7.52(m,3H),7.32–7.25(m,2H),7.07(d d,J=24.7,8.4Hz,2H),6.76(dd,J=8.6,2.9Hz,1H),4.55(dd,J=11.9,4.9Hz,1H),3.99(t,J=7.5Hz,2H),3.73(s,2H), 3.63(dt,J=13.6,7.1Hz,2H),3.56(dd,J=7.3,5.6Hz,2H),3.38(dt,J=14.1,7.2Hz,2H),3.08(p,J=6.9Hz,1H),2.99( t,J=5.8Hz,2H),2.87–2.72(m,5H),2.60(dt,J=17.3,4.3Hz,1H),2.48–2.42(m,1H),2.28–2.06(m,5H),1.66(s,6H).

[0701] Example 23 Synthesis of Compound 23

[0702] Step 1: Preparation of intermediate 23a

[0703] To a single-necked flask, intermediate 21c (6.5 g), 2-chloropyrimidine-5-boronic acid pinacol ester (5.23 g), PdCl2(dppf)-CH2Cl2 (2.367 g), K2CO3 (6.01 g), 1,4-dioxane (60 mL), and water (12.00 mL) were added sequentially. Under nitrogen protection, the mixture was heated to 85°C for reaction. After completion of the reaction, ethyl acetate and water were added to the system for extraction. The organic phase was separated and purified by silica gel column chromatography to obtain intermediate 23a (0.88 g). MS (ESI, [M+H] + )m / z:482.31.

[0704] Step 2: Preparation of intermediate 23b

[0705] 23a (0.88 g), 1-aminotetrahydrothiophene 1-oxide (0.435 g), XPhos-Pd-G3 (0.154 g), Cs2CO3 (1.784 g), and 1,4-dioxane (10 mL) were added sequentially to a single-necked flask. Under nitrogen protection, the mixture was heated to 100°C for reaction. After completion of the reaction, intermediate 23b (0.9 g) was purified by silica gel column chromatography. MS (ESI, [M+H] + )m / z:565.25.

[0706] Step 3: Preparation of intermediate 23c

[0707] Referring to the reaction of step 6 of Example 17, 17e was replaced with 23b to obtain intermediate 23c (0.62 g). MS (ESI, [M+H] + )m / z:409.21.

[0708] Step 4: Preparation of intermediate 23d

[0709] Referring to the reaction of step 1 of Example 17, 17a-1 was replaced with 23c to obtain intermediate 23d (0.7 g). MS (ESI, [M+H] + )m / z:541.08.

[0710] Step 5: Preparation of intermediate 23e

[0711] Referring to the reaction in step 5 of Example 17, 17d was replaced with 23d to obtain intermediate 23e (0.22 g). MS (ESI, [M+H] + )m / z:506.40.

[0712] Steps 6-7: Preparation of intermediate 23f

[0713] Referring to the reaction of steps 9-10 of Example 17, 17h was replaced by 23e to finally obtain compound 23 (15 mg).

[0714] 23f: MS (ESI, [M+H] + )m / z:476.62.

[0715] Compound 23: MS (ESI, [M+H] + )m / z:745.33. 1H NMR (500MHz, DMSO-d6) δ11.07(s,1H),9.07(s,2H),8.50(d,J=2.5Hz,1H),7.85(d,J=8.4Hz,1H),7.65(dd,J=8.4,2. 4Hz,1H),7.58(d,J=8.2Hz,1H),7.09(dd,J=13.0,8.3Hz,3H),6.38(d,J=8.2Hz,2H),4.56(dd,J=11.9,5.0Hz,1H),3. 93(t,J=7.4Hz,2H),3.73(s,2H),3.63(dt,J=13.6,6.9Hz,2H),3.48(t,J=6.4Hz,2H),3.40(dt,J=13.6,6.8Hz,2H),3 .01(d,J=22.0Hz,3H),2.87–2.71(m,5H),2.60(dd,J=17.7,4.5Hz,1H),2.47(s,1H),2.27–2.06(m,5H),1.65(s,6H).

[0716] Example 24 Synthesis of Compound 24

[0717] Step 1: Preparation of intermediate 24a

[0718] 20e (2.0 g), neopentyl glycol diboronate (2.9 g), potassium acetate (2.1 g), Pd(dppf)Cl2 (1.1 g), and 1,4-dioxane (50 mL) were added to the reaction flask in sequence and reacted at 100°C for 2 h. After the reaction was complete, the mixture was filtered, extracted with ethyl acetate, and the organic phase was separated, washed with saturated brine, concentrated, and purified by silica gel column chromatography to obtain intermediate 24a (1.7 g). MS (ESI, [M+H] + )m / z:482.31.

[0719] Step 2: Preparation of compound 24b

[0720] Referring to the reaction in step 8 of Example 21, 24a was substituted for 21g to obtain compound 24b (1.12 g). MS (ESI, [M+H] + )m / z:565.31.

[0721] Step 3: Preparation of intermediate 24c

[0722] Referring to the reaction in step 6 of Example 17, 24b was substituted for 17e to obtain compound 24c (0.74 g). MS (ESI, [M+H] + )m / z:409.19.

[0723] Step 4: Preparation of intermediate 24d

[0724] To the reaction flask were added intermediate 24c (0.48 g), 4-dimethylaminopyridine (17.7 mg), triethylamine (391 mg), N-phenylbis(trifluoromethylsulfonyl)imide (514 mg), and dichloromethane (25 mL) in sequence and allowed to react at room temperature for 2 h. After the reaction was complete, water was added to the reaction solution, and the organic phase was separated, washed with saturated brine, concentrated, and purified by silica gel column chromatography to give compound 24d (0.52 g). MS (ESI, [M+H] + )m / z:541.12.

[0725] Step 5: Preparation of intermediate 24e

[0726] Referring to the reaction in step 5 of Example 17, 24d was used to replace 17d to obtain compound 24e (0.28 g). MS (ESI, [M+H] + )m / z:506.21.

[0727] Steps 6-7: Preparation of compound 24

[0728] Referring to the reaction of steps 9-10 of Example 17, 17h was replaced by 24e to finally obtain compound 24 (0.12 g).

[0729] 24f: MS (ESI, [M+H] + )m / z:476.21.

[0730] Compound 24: MS (ESI, [M+H] + )m / z:745.18. 1 H NMR (500MHz, DMSO) δ11.07(s,1H),8.86–8.79(m,3H),7.96(dd,J=8.4,2.5Hz,1H),7.58(d,J=8.2Hz,1H),7.20(d ,J=8.3Hz,1H),7.12–7.04(m,3H),6.39–6.33(m,2H),4.55(dd,J=11.9,5.0Hz,1H),3.92(t,J=7.4Hz,2H),3.72( s,2H),3.64(dt,J=13.6,7.0Hz,2H),3.47(dd,J=7.1,5.6Hz,2H),3.39(dt,J=13.6,6.8Hz,2H),3.01(dt,J=18.1 ,6.5Hz,3H),2.83–2.73(m,5H),2.60(dt,J=17.3,4.4Hz,1H),2.49–2.43(m,1H),2.29–2.08(m,5H),1.66(s,6H).

[0731] The synthesis method of reference compound 22 was to use 22b as the starting material and replace z8 with the structure shown in the table below to synthesize the following compound:

[0732] Example 34 Synthesis of Compound 34

[0733] Step 1: Preparation of compound 34a

[0734] 2-Chloro-5-iodopyrimidine (3.7 g), triethylsilyl acetylene (1.5 g), PdCl2(PPh3)2 (0.85 g), cuprous iodide (0.46 g), and DMF / triethylamine = 2:1 (50 mL, v:v) were added to the reaction flask in sequence. Under nitrogen protection, the mixture was reacted at 100°C for 2 h. Water and ethyl acetate were added to the reaction solution, and the organic phase was separated, washed with saturated brine, concentrated, and purified by silica gel column chromatography to obtain compound 34a (1.6 g). MS (ESI, [M+H] + )m / z:253.31.

[0735] Step 2: Preparation of compound 34b

[0736] To the reaction flask were added 22a (450 mg), 34a (400 mg), PdCl2(PPh3)2 (71 mg), cuprous iodide (38 mg), triethylamine (0.5 mL), potassium fluoride (177 mg), and DMF (10 mL) in sequence. The mixture was reacted at 100°C under nitrogen atmosphere for 2 h. The reaction solution was diluted with water and EA, and the organic phase was separated, washed with saturated brine, concentrated, and purified by silica gel column chromatography to obtain compound 34b (496 mg). MS (ESI, [M+H] + )m / z:447.31.

[0737] Step 3: Preparation of intermediate 34c

[0738] Referring to the preparation of z8 in Preparation Example 1, 34b was used to replace 5-chloro-2-iodopyrimidine to obtain compound 34c (533 mg). MS (ESI, [M+H] + )m / z:530.10.

[0739] Step 4-5: Preparation of compound 35

[0740] Referring to the reaction of steps 9-10 of Example 17, 17i was replaced with 34c to finally obtain compound 34 (75 mg).

[0741] 34d: MS (ESI, [M+H]+ )m / z:500.34.

[0742] Compound 34: MS (ESI, [M+H] + )m / z:769.32. 1 H NMR (500MHz, DMSO) δ11.07(s,1H),8.63(s,2H),7.75(d,J=2.9Hz,1H),7.58(d,J=8.1Hz,1H),7.47–7.37(m,2H),7.29–7.20(m,2H),7 .10(d,J=8.2Hz,1H),7.02(d,J=8.6Hz,1H),6.76(dd,J=8.6,2.9Hz,1H),4.56(dd,J=11.9,5.0Hz,1H),3.99(t,J=7.5Hz,2H),3.73(s, 2H),3.62(dt,J=12.3,6.5Hz,2H),3.56(dd,J=7.3,5.6Hz,2H),3.40(dt,J=14.0,7.1Hz,2H),3.08(p,J=7.0Hz,1H),2.99(d,J=5.8Hz, 2H), 2.78(ddd,J=29.1,10.9,6.2Hz,5H),2.60(dt,J=17.3,4.3Hz,1H),2.46(dd,J=12.2,4.5Hz,1H),2.28–2.06(m,5H),1.64(s,6H).

[0743] Example 35 Synthesis of Compound 35

[0744] Step 1: Preparation of intermediate 35a

[0745] 20e (3.0 g), tetrahydrofuran (100 mL), and lithium tri-sec-butylborohydride (3.3 g) were added to a three-necked flask in sequence, and the mixture was heated to 80°C for reaction. After the reaction was completed, the reaction solution was cooled to room temperature and purified by silica gel column chromatography to obtain intermediate 35a (2.0 g). MS (ESI, [M+H] + )m / z:386.21.

[0746] Step 2: Preparation of intermediate 35b

[0747] To a three-necked flask, 35a (1.9 g), cis-tert-butyl 3-hydroxycyclobutanecarboxylate (1.3 g), triphenylphosphine (2.6 g), and dioxane (20 mL) were added sequentially. The atmosphere was replaced with nitrogen. DEAD (1.94 mL) was slowly added under ice-bath conditions, and the mixture was heated to 80°C for reaction. After completion of the reaction, intermediate 35b (1.85 g) was obtained by purification via silica gel column chromatography. MS (ESI, [M+H] + )m / z:498.25.

[0748] Step 3: Preparation of intermediate 35c

[0749] Referring to the reaction of step 6 of Example 17, 17e was replaced with 35b to obtain intermediate 35c (1.5 g). MS (ESI, [M+H] + )m / z:342.21.

[0750] Step 4: Preparation of intermediate 35d

[0751] Referring to the reaction of step 1 of Example 17, 17a-1 was replaced with 35c to obtain intermediate 35d (1.05 g). MS (ESI, [M+H] + )m / z:474.31.

[0752] Steps 5-6: Preparation of intermediate 35f

[0753] The reaction of step 7-8 of reference example 21, wherein 21f was replaced with 35d, gave intermediate 35f (0.23 g).

[0754] 35e:MS(ESI,[M+H] + )m / z:438.31.

[0755] 35f: MS (ESI, [M+H] + )m / z:521.25.

[0756] Steps 7-8: Preparation of compound 35

[0757] Refer to the reaction of steps 9-10 of Example 17, wherein 17h was replaced with 35f to obtain compound 35 (78 mg).

[0758] 35g: MS (ESI, [M+H] + )m / z:491.34.

[0759] Compound 35: MS (ESI, [M+H] + )m / z:760.32. 1H NMR (500MHz, DMSO-d6) δ11.07(s,1H),8.75(s,2H),8.13(t,J=1.8Hz,1H),7.63–7.50(m,3H),7.29(d, J=8.3Hz,2H),7.17(d,J=1.8Hz,2H),7.09(d,J=8.3Hz,1H),4.89(p,J=6.1Hz,1H),4.55(dd,J=11.9,5 .0Hz,1H),3.71(s,2H),3.62(dt,J=13.5,6.9Hz,2H),3.38(dt,J=13.5,6.8Hz,2H),3.04–2.85(m,2H) ,2.83–2.72(m,3H),2.71–2.55(m,4H),2.46(dd,J=12.2,4.4Hz,1H),2.37–2.02(m,9H),1.68(s,6H).

[0760] Example 36 Synthesis of Compound 36

[0761] Step 1: Preparation of intermediate 36a

[0762] Referring to the reaction in step 8 of Example 21, 21g was replaced with 35e and z8 was replaced with intermediate z18 to obtain intermediate 36a (0.24 g). MS (ESI, [M+H] + )m / z:552.25.

[0763] Step 2-3: Preparation of compound 36

[0764] Referring to the reaction of steps 9-10 of Example 17, 17h was replaced by 36a to obtain compound 36 (73 mg).

[0765] 36b:MS(ESI,[M+H] + )m / z:522.31.

[0766] Compound 36: MS (ESI, [M+H] + )m / z:791.21. 1H NMR (500MHz, DMSO-d6) δ11.07(s,1H),8.60(d,J=1.5Hz,1H),8.13(dd,J=2.7,0.9Hz,1H),7.97(d,J=1.5Hz,1H),7.90–7.86(m, 1H),7.85–7.81(m,2H),7.57(d,J=8.1Hz,1H),7.29–7.25(m,2H),7.18–7.12(m,2H),7.09(d,J=8.2Hz,1H),4.88(p,J=6.2Hz,1 H),4.55(dd,J=11.8,5.0Hz,1H),4.39(d,J=5.2Hz,3H),3.94(q,J=3.0Hz,2H),3.70(s,2H),2.95(s,5H),2.77(dp,J=17.2,6.0 Hz,3H),2.69–2.57(m,4H),2.47(dd,J=5.2,3.2Hz,1H),2.27(d,J=7.1Hz,2H),2.19(ddd,J=18.0,9.7,5.2Hz,3H),1.68(s,6H).

[0767] Example 37 Synthesis of Compound 37

[0768] Step 1: Preparation of intermediate 37a

[0769] To a single-necked flask, bisphenol A (20 g), dichloromethane (200 mL), and DIPEA (46 mL) were added sequentially. Trifluoromethanesulfonic anhydride (37 g) was slowly added under an ice bath, and the mixture was reacted at room temperature. After the reaction was complete, dichloromethane and water were added to the system for extraction, and the organic phase was separated. After washing with saturated brine, the mixture was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain intermediate 37a (18 g). MS (ESI, [M+H] + )m / z:361.45.

[0770] Step 2-4: Preparation of intermediate 37d

[0771] The reaction of step 4-6 of reference example 17, wherein 17c was replaced with 37a, gave intermediate 37d (1.5 g).

[0772] 37b:MS(ESI,[M+H] + )m / z:517.23.

[0773] 37c:MS(ESI,[M+H] + )m / z:482.30.

[0774] 37d: MS (ESI, [M+H] + )m / z:326.22.

[0775] Step 5: Preparation of intermediate 37e

[0776] Referring to the reaction of step 1 of Example 17, 17a-1 was replaced with 37d to obtain intermediate 37e (2.1 g). MS (ESI, [M+H] + )m / z:458.09.

[0777] Step 6: Preparation of Intermediate 37f

[0778] Referring to the reaction of step 7 of Example 21, 21f was replaced with 37e to obtain intermediate 37f (1.3 g). MS (ESI, [M+H] + )m / z:422.31.

[0779] Step 7: Preparation of Intermediate 37g

[0780] Referring to the reaction in step 8 of Example 21, 21g was replaced with 37f and z8 was replaced with z21 to obtain intermediate 37g (0.66 g). MS (ESI, [M+H] + )m / z:485.34.

[0781] Steps 8-9: Preparation of compound 37

[0782] Refer to the reaction of steps 9-10 of Example 17, wherein 17h was replaced by 37g to obtain compound 37 (53 mg).

[0783] 37h: MS (ESI, [M+H] + )m / z:455.21.

[0784] Compound 37: MS (ESI, [M+H] + )m / z:724.41. 1H NMR (500MHz, DMSO) δ11.07(s,1H),8.59(d,J=1.5Hz,1H),7.93(d,J=1.5Hz,1H),7.81(d,J=8.2Hz,2H), 7.58(d,J=8.1Hz,1H),7.26(d,J=8.2Hz,2H),7.07(dd,J=31.7,8.3Hz,3H),6.35(d,J=8.3Hz,2H),4.73( s,4H),4.56(dd,J=11.9,5.0Hz,1H),4.24(s,4H),3.92(t,J=7.4Hz,2H),3.73(s,2H),3.48(q,J=9.1Hz ,2H),3.00(s,3H),2.91–2.70(m,5H),2.62(t,J=4.1Hz,1H),2.18(dq,J=13.6,4.7Hz,1H),1.60(s,6H).

[0785] The synthesis method of reference compound 37 is to use 37f as the starting material, and z21 is replaced with the structure in the table below (or, z2 is replaced with z24, etc.) to synthesize the following examples:

[0786] Example 49 Synthesis of Compound 49

[0787] Step 1: Preparation of intermediate 49a

[0788] Referring to the reaction of step 7 of Example 21, 21f was replaced with 37b to obtain intermediate 49a (15.3 g). MS (ESI, [M+H] + )m / z:481.31.

[0789] Step 2: Preparation of intermediate 49b

[0790] Referring to the reaction in step 8 of Example 21, 21g was replaced with 49a to obtain intermediate 49b (0.67g). MS (ESI, [M+H] + )m / z:564.33.

[0791] Step 3: Preparation of intermediate 49c

[0792] Referring to the reaction in step 6 of Example 17, 17e was replaced with 49b to obtain compound 49c (0.53 g). MS (ESI, [M+H] + )m / z:408.19.

[0793] Step 4: Preparation of intermediate 49d

[0794] Intermediate 49c (0.48 g), 4-dimethylaminopyridine (13 mg), triethylamine (500 mg), N-phenylbis(trifluoromethylsulfonyl)imide (514 mg), and dichloromethane (25 mL) were added to the reaction flask in sequence and reacted at room temperature for 2 h. The reaction was complete and purified by silica gel column chromatography to give compound 49d (0.52 g). MS (ESI, [M+H] + )m / z:540.15.

[0795] Step 5: Preparation of intermediate 49e

[0796] To the reaction flask were added intermediate 49d (0.46 g), (R)-methylpyrrolidine-3-methyl ester hydrochloride (0.21 g), Pd2(dba)3 (83 mg), Ruphos (87 mg), cesium carbonate (0.7 g), and 1,4-dioxane (10 mL) in sequence. The mixture was reacted at 110°C for 2 h under nitrogen protection. The reaction was complete and purified by silica gel column chromatography to give compound 49e (0.33 g). MS (ESI, [M+H] + )m / z:519.21.

[0797] Step 6: Preparation of Intermediate 49f

[0798] To the reaction flask, intermediate 49e (0.25 g) and dichloromethane (20 mL) were added sequentially, and the temperature was lowered to -78°C. Under nitrogen protection, DIBAL-H (0.68 mL, 1.5 M) was slowly added, and the reaction was continued at -78°C for 1 h. After the reaction was complete, the reaction solution was poured into saturated ammonium chloride solution to quench, and saturated potassium sodium tartrate solution was added and stirred thoroughly. The organic phase was separated, washed with saturated brine, and concentrated to obtain 49f (0.23 g). MS (ESI, [M+H] + )m / z:489.33.

[0799] Step 7: Preparation of compound 49

[0800] Referring to the reaction in step 10 of Example 17, 17i was replaced with 49f to obtain compound 49 (73 mg). HRMS (ESI, [M+H] + )m / z:758.35. 1H NMR (500MHz, DMSO-d6) δ11.07(s,1H),8.75(s,2H),7.56(dd,J=12.9,8.3Hz,3H),7.30–7.21(m,2H),7.10(d,J=8.2Hz,1H),7.06– 7.00(m,2H),6.45(d,J=8.7Hz,2H),4.56(dd,J=11.9,5.0Hz,1H),3.76(q,J=16.0Hz,2H),3.62(dt,J=13.7,7.2Hz,2H),3.37(ddd, J=10.8,8.8,4.2Hz,3H),3.30–3.26(m,1H),3.21(dt,J=9.3,7.4Hz,1H),3.00(q,J=5.8Hz,3H),2.89–2.65(m,4H),2.65–2.53(m,3 H),2.49–2.43(m,1H),2.21(dtt,J=13.4,8.5,4.5Hz,3H),2.12(qd,J=7.6,3.1Hz,3H),1.74(dq,J=12.1,7.6Hz,1H),1.60(s,6H).

[0801] Example 50 Synthesis of Compound 50

[0802] Referring to the reaction of step 5-7 of Example 49, (R)-methylpyrrolidine-3-methyl ester hydrochloride was replaced with (S)-methylpyrrolidine-3-methyl ester hydrochloride to finally prepare compound 50.

[0803] 50a:MS(ESI,[M+H] + )m / z:519.33.

[0804] 50b:MS(ESI,[M+H] + )m / z:489.15.

[0805] Compound 50: HRMS (ESI, [M+H] + )m / z:758.3498. 1H NMR (500MHz, DMSO-d6) δ11.07(s,1H),8.75(s,2H),7.56(dd,J=12.9,8.3Hz,3H),7.30–7.21(m,2H),7.10(d,J=8.2Hz,1H),7.06– 7.00(m,2H),6.45(d,J=8.7Hz,2H),4.56(dd,J=11.9,5.0Hz,1H),3.76(q,J=16.0Hz,2H),3.62(dt,J=13.7,7.2Hz,2H),3.37(ddd, J=10.8,8.8,4.2Hz,3H),3.30–3.26(m,1H),3.21(dt,J=9.3,7.4Hz,1H),3.00(q,J=5.8Hz,3H),2.89–2.65(m,4H),2.65–2.53(m,3 H),2.49–2.43(m,1H),2.21(dtt,J=13.4,8.5,4.5Hz,3H),2.12(qd,J=7.6,3.1Hz,3H),1.74(dq,J=12.1,7.6Hz,1H),1.60(s,6H).

[0806] Example 51 Synthesis of Compound 51

[0807] Step 1: Preparation of intermediate 51a

[0808] Referring to the reaction of step 1 of Example 11, bisphenol A was replaced with 49c to obtain intermediate 51a (1.73 g). MS (ESI, [M+H] + )m / z:520.11.

[0809] Step 2-3: Preparation of intermediate 51b

[0810] The reaction of step 9-10 of reference example 17 was carried out, wherein 17h was replaced by 51a to obtain compound 51 (55 mg).

[0811] 51b:MS(ESI,[M+H] + )m / z:490.34.

[0812] Compound 51: MS (ESI, [M+H] + )m / z:759.33. 1H NMR (500MHz, DMSO) δ11.07(s,1H),8.76(s,2H),7.57(d,J=8.3Hz,3H),7.31–7.26(m,2H),7.16– 7.07(m,3H),6.77–6.71(m,2H),4.80(p,J=6.2Hz,1H),4.56(dd,J=11.8,5.0Hz,1H),3.71(s,1H ),3.64–3.58(m,2H),3.38(dt,J=13.7,6.9Hz,2H),2.99(s,2H),2.76(ddd,J=17.2,11.9,5.3Hz ,3H),2.72–2.56(m,4H),2.49–2.44(m,1H),2.33–2.16(m,7H),2.15–2.03(m,2H),1.63(s,6H).

[0813] The following Examples 52-70 refer to the synthesis method of compound 37, using 37f as the starting material and replacing z21 with the structure shown in the table below:

[0814] Example 71 Synthesis of Compound 71

[0815] Step 1: Preparation of intermediate 71a

[0816] To a single-necked flask were added intermediate 21c (684 mg), 4-(2-hydroxy-2-propyl)phenylboronic acid pinacol ester (400 mg), PdCl2(dppf)-CH2Cl2 (125 mg), K2CO3 (633 mg), dioxane (5 mL), and water (1 mL). Under nitrogen protection, the mixture was heated to 85°C for reaction. Upon completion of the reaction, a reaction solution containing 71a was obtained, which was used directly in the next step. MS (ESI, [M+H] + )m / z:504.25.

[0817] Step 2: Preparation of intermediate 71b

[0818] TBAF (6.08 mL) was added to the reaction solution containing intermediate 71a obtained in the previous step, and the mixture was reacted at room temperature. After the reaction was completed, ethyl acetate and water were added to the system for extraction. The organic phase was separated and purified by silica gel column chromatography to obtain intermediate 71b (0.32 g). MS (ESI, [M+H] + )m / z:348.30.

[0819] Step 3: Preparation of intermediate 71c

[0820] To a single-necked flask, 71b (0.32 g), dichloromethane (5 mL), triethylamine (0.385 mL), and DMAP (92 mg) were added sequentially, followed by N-phenylbis(trifluoromethanesulfonyl)imide (0.362 g), and the mixture was reacted at room temperature. After completion of the reaction, intermediate 71c (0.36 g) was obtained by purification via silica gel column chromatography. MS (ESI, [M+H] + )m / z:480.18.

[0821] Step 4: Preparation of Intermediate 71d

[0822] Referring to the reaction in step 5 of Example 17, 17d was replaced with 71c to obtain intermediate 71d (0.32 g). MS (ESI, [M+H] + )m / z:445.27.

[0823] Steps 6-7: Preparation of compound 71

[0824] The reaction of step 9-10 of reference example 17 was carried out, wherein 17h was replaced by 71d to obtain compound 71 (50 mg).

[0825] 71e:MS(ESI,[M+H] + )m / z:415.33.

[0826] Compound 71: HRMS (ESI, [M+H] + )m / z:684.3519. 1 H NMR (500MHz, DMSO-d6) δ11.07(s,1H),8.50(d,J=2.5Hz,1H),8.00–7.92(m,2H),7.80(d,J=8.2Hz,1H),7.63(dd,J=8 .3,2.5Hz,1H),7.56(dd,J=14.2,8.3Hz,3H),7.09(t,J=8.9Hz,3H),6.41–6.33(m,2H),5.04(s,1H),4.56(dd,J=11.9 ,5.0Hz,1H),3.93(t,J=7.4Hz,2H),3.72(s,2H),3.55–3.44(m,2H),3.01(dt,J=19.5,6.2Hz,3H),2.89–2.68(m,5H) ,2.60(dt,J=17.3,4.2Hz,1H),2.46(dd,J=12.1,4.4Hz,1H),2.18(dq,J=13.6,4.3Hz,1H),1.66(s,6H),1.45(s,6H).

[0827] Example 72 Synthesis of Compound 72

[0828] Step 1: Preparation of intermediate 72a

[0829] Refer to the reaction in step 1 of Example 24, replacing 20e with 72a-1. After the reaction is completed, the reaction solution is filtered and concentrated to obtain intermediate 72a, which is directly used in the next step.

[0830] Step 2: Preparation of compound 72b

[0831] Intermediate 72a (3.2 g), intermediate 21c (4.1 g), potassium carbonate (2.5 g), Pd(dppf)Cl2 (0.67 g), 1,4-dioxane (20 mL), and water (4 mL) were added to the reaction flask in sequence and reacted at 100°C for 2 h. The reaction was complete and purified by silica gel column chromatography to give compound 72b (3.5 g). MS (ESI, [M+H] + )m / z:505.27.

[0832] Step 3: Preparation of compound 72c

[0833] Referring to the reaction in step 6 of Example 17, 17e was replaced with 72b to obtain compound 72c (2.7 g). MS (ESI, [M+H] + )m / z:349.31.

[0834] Step 4: Preparation of compound 72d

[0835] Referring to the reaction in step 3 of Example 71, 72c was used to replace 71b, and the reaction was carried out at 0°C to obtain compound 72d (0.5 g). MS (ESI, [M+H] + )m / z:481.16.

[0836] Step 5: Preparation of compound 72e

[0837] Referring to the reaction in step 5 of Example 17, 17d was replaced with 72d and Xphos was replaced with Ruphos to obtain compound 72e (0.26 g). MS (ESI, [M+H] + )m / z:446.24.

[0838] Step 6: Preparation of Intermediate 72f

[0839] Referring to the reaction of step 9 of Example 17, 17h was replaced with 72e to give 72f (0.21 g). MS (ESI, [M+H] + )m / z:416.24

[0840] Step 7: Preparation of Compound 72

[0841] Referring to the reaction of step 10 of Example 17, 17i was replaced with 72f to obtain compound 72 (0.08 g). MS (ESI, [M+H] + )m / z:685.31. 1 H NMR (500MHz, DMSO) δ11.07(s,1H),9.11(d,J=2.3Hz,1H),8.55(d,J=2.5Hz,1H),8.35(dd,J=8.3,2.3Hz,1H),7.89(d,J=8.3Hz ,1H),7.74(d,J=8.3Hz,1H),7.68(dd,J=8.4,2.5Hz,1H),7.58(d,J=8.1Hz,1H),7.13–7.05(m,3H),6.43–6.36(m,2H),5.26(s, 1H),4.55(dd,J=11.9,5.0Hz,1H),3.93(t,J=7.4Hz,2H),3.72(s,2H),3.48(dd,J=7.2,5.6Hz,2H),3.01(dt,J=19.8,6.2Hz,3H ),2.84–2.73(m,5H),2.64–2.58(m,1H),2.46(dd,J=12.0,4.3Hz,1H),2.18(dq,J=13.6,4.6Hz,1H),1.66(s,6H),1.47(s,6H).

[0842] Example 73 Synthesis of Compound 73

[0843] Referring to Step 1-7 of Example 72, compound 73 (0.1 g) was obtained by substituting 73a-1 for 72a-1.

[0844] 73b:MS(ESI,[M+H] + )m / z:506.27.

[0845] 73c:MS(ESI,[M+H] + )m / z:350.3.

[0846] 73d:MS(ESI,[M+H] + )m / z:482.16.

[0847] 73e:MS(ESI,[M+H] + )m / z:447.29.

[0848] 73f:MS(ESI,[M+H]+ )m / z:417.33.

[0849] Compound 73: MS (ESI, [M+H] + )m / z:686.31. 1 H NMR (500MHz, DMSO) δ11.07(s,1H),9.36(s,2H),8.58(d,J=2.4Hz,1H),8.00(d,J=8.3Hz,1H),7.75(dd,J=8.3,2 .5Hz,1H),7.57(d,J=8.1Hz,1H),7.14–7.05(m,3H),6.41–6.36(m,2H),5.12(s,1H),4.55(dd,J=11.9,5.0Hz,1 H),3.93(t,J=7.4Hz,2H),3.72(s,2H),3.52–3.45(m,2H),3.01(dt,J=20.9,6.6Hz,3H),2.84–2.71(m,5H),2.6 0(dt,J=17.3,4.3Hz,1H),2.46(dd,J=12.3,4.3Hz,1H),2.18(dq,J=13.8,4.8Hz,1H),1.67(s,6H),1.53(s,6H).

[0850] Example 74 Synthesis of Compound 74

[0851] Step 1: Preparation of compound 74a

[0852] 73c (0.5 g), triphenylphosphine (1.12 g), cis-tert-butyl 3-hydroxycyclobutanecarboxylate (0.56 g), and dioxane (10 mL) were added to the reaction flask in sequence. Under N2 protection, diisopropyl azodicarboxylate (0.86 g) was slowly added at room temperature and the mixture was allowed to react at 100°C for 3 h. After the reaction was complete, the reaction solution was directly added to silica gel and purified by silica gel column chromatography to obtain compound 74a (0.18 g). MS (ESI, [M+H] + )m / z:462.30.

[0853] Step 2-3: Preparation of compound 74

[0854] Referring to the reaction of step 2-3 of Example 51, 51a was replaced with 74a to give compound 74 (0.1 g).

[0855] 74b:MS(ESI,[M+H] + )m / z:432.31.

[0856] Compound 74: MS (ESI, [M+H]+ )m / z:701.28. 1 H NMR (500MHz, DMSO) δ11.07(s,1H),9.36(s,2H),8.59(d,J=2.5Hz,1H),8.01(d,J=8.3Hz,1H),7.76(dd,J=8 .3,2.5Hz,1H),7.57(d,J=8.2Hz,1H),7.17(d,J=8.5Hz,2H),7.09(d,J=8.2Hz,1H),6.77(d,J=8.4Hz,2H),5 .12(s,1H),4.81(p,J=6.2Hz,1H),4.55(dd,J=11.9,5.0Hz,1H),3.70(s,2H),2.98(t,J=5.9Hz,2H),2.83– 2.72(m,3H),2.69–2.57(m,4H),2.46(dd,J=12.2,4.3Hz,1H),2.30–2.14(m,5H),1.69(s,6H),1.53(s,6H).

[0857] Example 75 Synthesis of Compound 75

[0858] By referring to the method described in steps 1-3 of Example 74, wherein intermediate 72c was substituted for intermediate 73c, compound 75 (0.06 g) was finally obtained.

[0859] 75a:MS(ESI,[M+H] + )m / z:461.33.

[0860] 75b:MS(ESI,[M+H] + )m / z:431.33.

[0861] Compound 75: MS (ESI, [M+H] + )m / z:700.71.

[0862] 1H NMR (500MHz, DMSO) δ11.07(s,1H),9.13–9.08(m,1H),8.55(d,J=2.5Hz,1H),8.35(dd,J=8.3,2.3Hz,1H),7.90(d,J=8. 4Hz,1H),7.74(dd,J=8.3,0.8Hz,1H),7.70(dd,J=8.4,2.5Hz,1H),7.57(d,J=8.2Hz,1H),7.21–7.15(m,2H),7.09(d,J =8.2Hz,1H),6.80–6.74(m,2H),5.26(s,1H),4.81(p,J=6.1Hz,1H),4.55(dd,J=11.9,5.0Hz,1H),3.70(s,2H),2.98(t ,J=5.9Hz,2H),2.83–2.72(m,3H),2.69–2.56(m,4H),2.48–2.44(m,1H),2.30–2.14(m,5H),1.68(s,6H),1.47(s,6H).

[0863] Experimental Example 1: Effect of Compounds on Inhibition or Degradation of Proteins in Cells

[0864] 1.1 Assay for AR-V7 protein inhibition or degradation activity in 22RV1 cells

[0865] 22RV1 cells in good growth condition were taken, washed with PBS, digested with trypsin, and digested with 1640 complete medium containing 10% FBS to stop the digestion. The cells were collected into a centrifuge tube and the cell density was adjusted to 2×10 5 Cells were plated at 40 μL / well and incubated at 37°C overnight. Compounds were added using a nanoliter pipette to a final concentration of 1000 nM-0.061 nM, with two replicates, and a control was set up. After the cells were cultured for 24 hours, the supernatant was discarded, and 40 μL of paraformaldehyde (manufacturer: Sangon Biotech) was added to each well and incubated at room temperature for 20 minutes. The supernatant was discarded, and each well was washed twice with 40 μL of PBS, and then 40 μL of ice-cold methanol (manufacturer: Merck) was added to each well and incubated at room temperature for 10 minutes. The supernatant was discarded, and each well was washed twice with 40 μL of TBST, and then 40 μL of 2% Incubate at room temperature for 60 minutes with BSA-TBST blocking solution; discard the supernatant, add 20 μL of GAPDH mouse anti-antibody (manufacturer: R&D) and AR-V7 rabbit anti-antibody mixture (manufacturer: CST) prepared with blocking solution to each well, and incubate at 4°C overnight; discard the supernatant, add 40 μL of TBST to each well, wash twice, and add 20 μL of Anti-mouse IgG (H+L) (Dylight TM680Conjugate) antibody and Anti-rabbit IgG (H+L) (Dylight TM 800 4×PEG Conjugate) antibody mixture (manufacturer: CST), incubate at room temperature in the dark for 45 minutes; discard the supernatant, add 40μL TBST to each well and wash twice, then add 40μL PBS to each well and wash once, Azure Sapphire TM Dual-mode multispectral laser imaging system for detection (In-Cell WB-800nm, 680nm), four-parameter analysis, dose-effect curve fitting, and IC calculation 50 or DC 50 .

[0866] 1.2 Determination of AR protein inhibitory or degradation activity in VCaP cells

[0867] Detection was performed using the HTRF HUMAN ANDROGEN RECEPTOR DETECTION KIT (cisbio, 64ANDRPEG). 4× supplemented lysis buffer was prepared using blocking reagent stock solution (100×) and lysis buffer stock solution (4×), and 1× supplemented lysis buffer was prepared using 4× supplemented lysis buffer and ddH2O. Premixed antibody solutions were prepared using detection buffer, androgen receptor Eu cryptate antibody, and androgen receptor d2 antibody.

[0868] VCaP cells in good growth condition were taken, washed with PBS, digested with trypsin, and digested with phenol red-free DMEM complete medium containing 2% CSS-FBS to stop the digestion. The cells were collected into a centrifuge tube and the cell density was adjusted to 1×10 6Cells were plated at 100 μL / well in a 96-well plate and incubated overnight in a cell culture incubator. Compounds were added using a nanoliter pipette to a final concentration of 1000 nM to 0.32 nM, with two replicates. A control was also set up. After 24 hours of incubation in the cell culture incubator, the culture medium was aspirated and 40 μL / well of 1× Supplemented Lysis buffer was added to lyse the cells. After shaking at room temperature for 40 minutes, 16 μL of cell lysate was added to a 384-well plate. 4 μL / well of premixed antibody solutions was added and the plate was incubated at 25°C for 2 hours. Fluorescence values ​​were measured at 665 nm / 620 nm using an Envision microplate reader. Four-parameter analysis was performed, and a dose-effect curve was fitted to calculate the IC. 50 Or DC50 (drug concentration at which the degradation rate reaches 50%).

[0869] 1.3 Assay for GSPT1 protein degradation activity in 22RV1 cells

[0870] 22RV1 cells in good growth condition were taken, washed with PBS, digested with trypsin, and digested with 1640 complete medium containing 10% FBS. The cells were collected into centrifuge tubes and the cell density was adjusted to 8×10 5Cells were inoculated with 1 mL / well of 1640 complete medium containing 10% FBS and incubated overnight at 37°C. Compounds were prepared in 1640 complete medium supplemented with 10% FBS and added to the cells (1 mL / well) to final concentrations of 1000 nM to 8 nM (4 concentration points) and 200 nM to 0.32 nM (5 concentration points). A DMSO control group was also included. After 6 hours of cell culture, the supernatant was discarded, the cells were washed twice with PBS, and 50 μL of RIPA lysis buffer (containing 1× phosphatase inhibitor and 1× PMSF) was added. The cells were lysed on ice for 30 minutes and centrifuged at 12,000 rpm for 20 minutes at 4°C. The supernatant protein sample was collected, the protein concentration was adjusted to 0.7 μg / μL using BCA quantification, and the cells were stored in a -80°C ultra-low temperature freezer. GSPT1 protein expression was detected using a fully automated protein expression quantitative assay. 3.0 μL of cell protein storage solution was added to 3 μL of 0.1× Sample Buffer (ProteinSimple), followed by 1.5 μL of 5× Master Mix (ProteinSimple) to a final concentration of 0.28 μg / μL of cell protein. The prepared sample was denatured at 95°C for 5 minutes. After denaturation, the sample was removed, cooled on ice for 5 minutes, vortexed, and briefly centrifuged before being placed on ice for later use. The primary antibody was diluted with Antibody Diluent After dilution, place on ice until ready to use. Primary antibodies were GSPT1 (manufacturer: CST, 1:20) and GAPDH (manufacturer: CST, 1:400); secondary antibodies were goat anti-rabbit secondary antibodies (manufacturer: ProteinSimple), and the color development solution was a 1:1 mixture of Lumino-S and Peroxide. The prepared reagents were sequentially added to the assay plate (manufacturer: ProteinSimple), centrifuged at 1000g for 10 minutes at room temperature, and analyzed on an analyzer. Western blot analysis was performed using the fully automated protein expression analysis software Compass for SW. Electropherograms were automatically simulated based on the signals, and degradation rate (%) was calculated using the formula: (GSPT1 / GAPDH in control group - GSPT1 / GAPDH in treatment group) / GSPT1 / GAPDH in control group × 100%. GraphPad Prism 8 software was used to plot inhibition rate against sample concentration.

[0871] The test results show that the compounds of the present application (such as Example compounds 41, 42, 73 and 74, etc.) have degradation activity on GSPT1 protein.

[0872] Test Example 2: In vitro cell proliferation inhibitory activity

[0873] 2.1 VCaP cell proliferation inhibitory activity assay

[0874] VCaP cells in good growth condition were taken, washed with PBS, digested with trypsin, and digested with phenol red-free DMEM complete medium containing 5% CSS-FBS to stop the digestion. The cells were collected into a centrifuge tube and the cell density was adjusted to 1×10 5 Cells were plated at 100 μL / mL in a 96-well plate (100 μL / well). Compounds were added using a nanoliter pipette, using a two-fold serial dilution to a final concentration of 1000 nM to 0.061 nM. A control was also included. Cells were cultured for 168 hours in a cell culture incubator. The detection reagent, CCK-8 (Dojindo, 10 μL / well), was added. After incubation for 7 hours in a cell culture incubator, absorbance was measured at 450 nm using a PerkinElmer Envision microplate reader. Four-parameter analysis was performed, and dose-response curves were fitted to calculate IC50 values. Results are shown in Table 1A.

[0875] 2.2 22RV1 cell proliferation inhibitory activity assay

[0876] 22RV1 cells in good growth condition were taken, washed with PBS, digested with trypsin, and digested with 1640 complete medium containing 5% FBS. The cells were collected into centrifuge tubes and the cell density was adjusted to 5×10 4 Cells were plated at 100 μL / well in a 96-well white plate. Compounds were added using a nanoliter pipette, using a two-fold serial dilution to a final concentration of 1000 nM to 0.061 nM. A control was also included. After 168 hours of incubation in a cell culture incubator, the detection reagent CellCounting-Lite 2.0 (Vazyme) was added at 50 μL / well. After incubation at room temperature for 10 minutes, luminescence values ​​were measured using a PerkinElmer Envision microplate reader. Four-parameter analysis was performed, and a dose-response curve was fitted to calculate the IC50. The results are shown in Table 1.

[0877] Table 1. Antiproliferation activity of compounds on 22RV1 cells

[0878] Table 1A. Antiproliferation activity of compounds on VCaP cells

[0879] The test results show that the compounds of the present application, such as the compounds in the examples, have the activity of inhibiting the proliferation of VCaP cells and 22RV1 cells.

[0880] Test Example 3: In vitro metabolic stability

[0881] Liver microsomal incubation samples were prepared by mixing PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / ml, species: human, rat, or mouse), test compound, and NADPH+MgCl2 solution. The mixture was incubated at 37°C and 300 rpm for 1 hour. The 0-hour sample was prepared by mixing PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / ml), and test compound. The sample was added to acetonitrile solution containing internal standard for protein precipitation to prepare the supernatant, which was diluted and used for LC / MS / MS analysis. The results are shown in Tables 2 and 3.

[0882] Table 2

[0883] Table 3

[0884] The test results show that the compounds of the present application, including the compounds in the examples, are metabolically stable in vitro.

[0885] Test Example 4: In vivo pharmacokinetic properties

[0886] ICR mice weighing 18-22 g were acclimated for 3-5 days and randomly divided into groups of 6. The oral administration group was given a 10 mg / kg dose of the test compound solution by oral administration, and the intravenous administration group was given a 1 mg / kg dose of the test compound solution by intravenous injection.

[0887] The blood samples for the oral administration group were collected at 15 min, 1 h, 4 h, 6 h, 8 h, 10 h, and 24 h after administration, and the blood samples for the intravenous administration group were collected at 5 min, 0.25 h, 1 h, 4 h, 6 h, 10 h, and 24 h after administration. Blood was collected from the eye sockets to prepare plasma samples for testing.

[0888] 30 μL of the plasma sample to be tested and the standard curve sample were aspirated and added to an acetonitrile solution containing the internal standard for protein precipitation. The resulting supernatant was diluted and used for LC / MS / MS analysis. Pharmacokinetic parameters were fitted using a non-compartmental model. The results are shown in Table 4.

[0889] Table 4 Results of pharmacokinetic tests on compounds in mice

[0890] The test results show that the compounds of the present application, such as the example compounds, have good pharmacokinetic properties in animals such as mice, preferably with AUC (0-24h) > 10000 ng*h / mL; and / or bioavailability F > 30%.

[0891] Experimental Example 5: Pharmacodynamic evaluation in a 22RV1 human prostate cancer cell subcutaneous transplant tumor model in castrated nude mice

[0892] 22RV1 cells were subcutaneously inoculated in the right axilla of SPF male nude mice (source: Shanghai Lingchang Biotechnology Co., Ltd.) at a rate of 5 × 10 6 When the average tumor volume reaches 200mm 3 The animals were castrated and the tumor continued to grow to 300 mm. 3 When about 30 seconds, divide the animals into groups.

[0893] The day of grouping is designated Day 0. Starting from Day 0 (d0), administer the drug once daily by gavage (dose 0.5-3 mpk). Tumor volume is measured 2-3 times per week, and mice are weighed and recorded. The general condition of the mice is observed and recorded daily. At the end of the experiment (e.g., Day 17), tumors are removed, weighed, and photographed.

[0894] The detection indicators and calculation formulas are as follows:

[0895] Tumor volume, TV (mm 3 )=1 / 2×(a×b 2 ), where a is the long diameter of the tumor and b is the short diameter of the tumor.

[0896] Relative tumor volume, RTV = TV t / TV0; TV0 is the tumor volume on day 0, TV t is the tumor volume at each measurement.

[0897] Relative tumor growth rate, T / C (%) = T RTV / C RTV ×100%; where T RTV RTV for the treatment group; C RTV The vehicle control group was RTV.

[0898] Tumor volume inhibition rate, TGI(TV) (%), TGI(%) = [1-(T-T0) / (C-C0)] × 100%; where T is the mean tumor volume of the treatment group; T0 is the mean tumor volume of the treatment group on day 0; C is the mean tumor volume of the control group; C0 is the mean tumor volume of the control group on day 0.

[0899] Tumor weight inhibition rate, TGI(TW)(%), TGI(%)=(1-TWt / TWc)×100%; wherein, TWt is the tumor weight of the treatment group; TWc is the tumor weight of the control group.

[0900] Body weight change rate, WCR (%) = (Wt t -Wt0) / Wt0×100%; where Wt0 is the weight of mice on day 0, Wt t= represents the weight of the mice at each measurement. Test results demonstrate that the compounds of the present application (e.g., Examples 41, 42, 73, and 74) exhibit tumor-suppressing activity in vivo. At a dose of 2 mpk, TGI (TW) ≥ 85% and TGI (TV) ≥ 95% on day 19. Furthermore, the weights of the mice in each dosing group remained relatively stable.

Claims

1. A compound of formula II, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in, Indicates a single bond or a double bond; Ring W is selected from: Ring A is absent or selected from C 3-15 Cycloalkenyl, 3-15 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; Ring B is selected from phenyl or 5-6 membered heteroaryl; Ring C is absent or selected from 5-6 membered heteroaryl; X 8 Selected from -C(O)- or -CH2-; X 9 Selected from -C(R d R e )-、-N(R e )-, -O-, or -S-; X 10 is selected from a bond, -CH2-, -NH-, -O- or -S-; R d and R e are independently selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN, C 1-10 Alkyl, C 1-10 Alkoxy, (C 1-10 Alkyl)NH-, (C 1-10 Alkyl) 2N- or halogenated C 1-10 Alkyl, or R d and R e Connect to form C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl; Each R 1 independently selected from deuterium, halogen, -OH, -NH2, -CN, the following groups optionally substituted with one or more substituents: C 1-10 Alkyl, C 1-10 Alkoxy, (C 1-10 Alkyl)NH-, (C 1-10 Alkyl) 2N-, halogenated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl; n is selected from 0, 1, 2 or 3; X 5 Selected from C(R f ) or N; R f is selected from H, halogen, deuterium or C optionally substituted by one or more substituents 1-6 alkyl; L 1 is selected from a bond, -NH-, -O-, -S-, -CONH- or -CON(C 1-6 alkyl)-; L is selected from a linking group; The PTMs were selected from small molecule compounds targeting GSPT1.

2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, which is selected from the compound of formula III, its stereoisomer or a pharmaceutically acceptable salt thereof, in, X 6 Selected from bond, -O-, -S-, -N(R t )-、-C 1-6 Alkylene-, -C 2-6 Alkenylene-, -C 2-6 Alkynylidene-, -N(R t )C 1-6 Alkylene-, -OC 1- 6-alkylene-、-SC 1-6 Alkylene-, or -N(R t )C(O)-; R t Selected from H or C 1-6 alkyl; Each R 2 、R 3 and R 4 are independently selected from halogen, -CN, the following groups optionally substituted by one or more substituents: R v -、R v O-、R v S-、R s R v N-、R v C(O)-、R v S(O)2-、R v S(O)-、R v =N-、R v OC(O)-、R v C(O)O-、R v S(O)O-、R v OS(O)-、R v S(O)2O-、R v OS(O)2-、R s R v NC(O)-、R v C(O)NH-、R v OC(O)NH-、R v NHC(O)O-、R v S(O)NH-、R s R v NS(O)-、R v S(O)2NH-、R s R v NS(O)2-or R s R v S(O)=N-; R s and R v are independently selected from H, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkyl C 1-3 Alkylene-, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl C 1-3 Alkylene-, C 3-12 Cycloalkenyl, C 3-12 Cycloalkenyl C 1-3 Alkylene-, 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl C 1-3 Alkylene-, C 6-12 Aryl, C 6-12 Aryl C 1-3 Alkylene-, 5-12 membered heteroaryl, or 5-12 membered heteroarylC 1-3 Alkylene-; m, p and k are each independently selected from 0, 1, 2, 3, 4, 5 or 6; Ring G is selected from C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 Aryl, or 5-12 membered heteroaryl; Ring E and Ring F are independently selected from C 6-12 Aryl or 5-12 membered heteroaryl; Z is selected from -C-, -O-, -S-, -N-, -OC 1-6 Alkylene- or -NC(O)-; R 5 and R 6 are independently absent, or are independently selected from H, =O, halogen, -OH, -NH2, -CN, C 1-10 Alkyl, C 2-10 Alkenyl or C 2-10 Alkynyl, or R 5 and R 6 are connected to each other to form the following group which is optionally substituted by one or more substituents: C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl.

3. The compound according to claim 1 or 2, its stereoisomer or pharmaceutically acceptable salt thereof, wherein Ring A is absent or selected from C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; Alternatively, Ring A is absent or selected from C 5-15 Cycloalkenyl, 5-15 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; Alternatively, Ring A is absent or selected from C 5-10 Cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; Alternatively, Ring A is absent or selected from C 5-9 Cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; Alternatively, Ring A is absent or selected from C 5-7 Cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; Alternatively, Ring A is absent or selected from C 5-6 Cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; Alternatively, Ring A is absent or selected from C 5-6 Cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; Alternatively, Ring A is absent or selected from C 5-6 Cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5 membered heteroaryl; Alternatively, Ring A is absent or selected from C 5-6 Cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl, pyrrolyl, pyrazolyl, furanyl, or oxazolyl; Alternatively, Ring A is absent or is selected from C5 cycloalkenyl, C6 cycloalkenyl, 5-membered, 6-membered, 7-membered, 8-membered or 9-membered heterocycloalkenyl, phenyl, pyrrolyl, pyrazolyl, furanyl or oxazolyl; Alternatively, ring A is absent or is selected from cyclopentenyl, monocyclohexenyl, bicyclohexenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine 1-Hydroxy, ... Alternatively, the ring B is selected from phenyl or pyridyl; Alternatively, the ring B is selected from phenyl; and / or, Alternatively, ring C is absent or selected from a 5-membered heteroaryl group; Alternatively, the ring C is absent or selected from isoxazolyl, pyrazolyl or furyl; Optionally, the structural fragment Selected from Alternatively, a structural fragment Selected from Alternatively, a structural fragment Selected from Alternatively, a structural fragment Selected from Phenyl, pyridyl, 4. The compound according to any one of claims 1 to 3, its stereoisomer or pharmaceutically acceptable salt, structural fragment Selected from Optionally, X 9 Selected from -C(R d R e )-、-N(R e )-or-O-; and / or, X 10 is selected from a bond or -O-; Optionally, R d and R e are independently selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, (C 1-6 Alkyl)NH-, (C 1-6 Alkyl) 2N- or halogenated C 1-6 Alkyl, or R d and R e Connect to form C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl; Or, R d and R e are independently selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, or R d and R e Connect to form C 3-4 Cycloalkyl; Or, R d and R e are independently selected from hydrogen, F, or methyl, or R d and R e They are connected to each other to form a cyclopropyl group.

5. The compound according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein each R 1 independently selected from deuterium, halogen, -OH, -NH2, -CN, the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, C 1-6 Alkoxy, (C 1-10 Alkyl)NH-, (C 1-10 Alkyl) 2N-, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl; Or, each R 1 independently selected from deuterium, halogen, -OH, -NH2, -CN, the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 alkyl; Or, each R 1 independently selected from halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy or halogenated C 1-4 alkyl; Or, each R 1 independently selected from halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy or halogenated C 1-3 alkyl; Or, each R 1 independently selected from halogen, -OH, -NH2, -CN or C 1-3 alkyl; Or, each R 1 independently selected from halogen or C 1-3 alkyl; Or, each R 1 independently selected from fluorine, chlorine, bromine, -OH, -NH2 or -CN; Optionally, n is selected from 0, 1 or 2; Alternatively, n is selected from 0 or 1.

6. The compound according to any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R f is selected from H, fluorine, chlorine, bromine, deuterium or C optionally substituted by one or more substituents 1-3 alkyl; Or, R f Selected from H, fluorine, chlorine, bromine, deuterium or C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with one or more of the following groups: halogen, -OH, -NH2, or -CN; Or, R f Selected from H, fluorine, chlorine, bromine, deuterium or C 1-3 Alkyl; or, R f is selected from H, fluorine, deuterium or methyl; Or, R f Selected from H; Optionally, X 5 is selected from CH or N.

7. The compound according to any one of claims 1 to 6, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein said L 1 is selected from a bond, -NH- or -CONH-; or, said L 1 Select from keys.

8. The compound according to any one of claims 1 to 7, its stereoisomer or pharmaceutically acceptable salt thereof, wherein L is selected from the following groups optionally substituted with one or more substituents: C 1-50 Alkylene, C 2-50 Alkenylene or C 2-50 Alkynylidene, optionally, the C 1-50 Alkylene, C 2-50 Alkenylene or C 2-50 One or more -CH2- in the alkynylene group are independently optionally replaced by -O-, C 3-15 Cycloalkyl, 3-15 membered heterocycloalkyl, 4-15 membered heterocycloalkenyl, C 6-15 Aryl, 5-15 membered heteroaryl, -NH-, -N(C 1-6 alkyl)- or -S-substituted; Alternatively, said L is selected from the following groups optionally substituted by one or more substituents: C 1-30 Alkylene, C 2-30 Alkenylene or C 2-30 Alkynylidene, optionally, the C 1-30 Alkylene, C 2-30 Alkenylene or C 2-30 One or more -CH2- in the alkynylene group are independently optionally replaced by -O-, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl, 5-12 membered heteroaryl, -NH-, -N(C 1-6 alkyl)- or -S-substituted; Alternatively, said L is selected from the following groups optionally substituted by one or more substituents: C 1-20 Alkylene, C 2-20 Alkenylene or C 2-20 Alkynylidene, optionally, the C 1-20 Alkylene, C 2-20 Alkenylene or C 2-20 One or more -CH2- in the alkynylene group are independently optionally replaced by -O-, C 3-10 Cycloalkyl, 3-11 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-10 Aryl, any 5-10 membered heteroaryl, -NH-, -N(C 1-6 alkyl)- or -S-substituted; Alternatively, said L is selected from the following groups optionally substituted by one or more substituents: C 1-15 Alkylene, C 2-15 Alkenylene or C 2-15 Alkynylidene, optionally, the C 1-15 Alkylene, C 2-15 Alkenylene or C 2-15 One or more -CH2- in the alkynylene group are independently optionally replaced by -O-, C 3-9 Cycloalkyl, 3-11 membered heterocycloalkyl, 4-8 membered heterocycloalkenyl, C 6-8 Aryl, 5-8 membered heteroaryl, -NH-, -N(C 1-4 alkyl)- or -S-substituted; Alternatively, said L is selected from the following groups optionally substituted by one or more substituents: C 1-10 Alkylene, C 2-10 Alkenylene or C 2-10 Alkynylidene, optionally, the C 1-10 Alkylene, C 2-10 Alkenylene or C 2-10 One or more -CH2- in the alkynylene group are independently optionally replaced by -O-, C 3-9 Cycloalkyl, 3-11 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, -NH-, -N(C 1-3 alkyl)- or -S-substituted; Alternatively, said L is selected from the following groups optionally substituted by one or more substituents: C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkynylidene, optionally, the C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 One or more -CH2- in the alkynylene group are independently optionally replaced by -O-, C 3-9 Cycloalkyl, 3-11 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, -NH-, -N(C 1-3 alkyl)- or -S-substituted; Alternatively, said L is selected from the following groups optionally substituted by one or more substituents: C 1-4 Alkylene, C 2-4 Alkenylene or C 2-4 Alkynylidene, optionally, the C 1-4 Alkylene, C 2-4 Alkenylene or C 2-4 One or more (e.g., one or two, one or three, etc.) -CH2- in the alkynylene group are independently optionally replaced by -O-, C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, -NH-, -N(C 1-3 alkyl)- or -S-substituted; Alternatively, said L is selected from C optionally substituted by one or more substituents 1-10 Alkylene or C 2-10 Alkynylidene, optionally, the C 1-10 Alkylene or C 2-10 One or more -CH2- in the alkynylene group are independently optionally selected from -O-, C 3-12 Cycloalkyl, 4-12 membered heterocycloalkyl, 4-12 membered heterocycloalkenyl, -NH-, -N(C 1-6 alkyl)- or -S-substituted; Alternatively, said L is selected from C optionally substituted by one or more substituents 1-6 Alkylene or C 2-6 Alkynylidene, optionally, the C 1-6 Alkylene or C 2-6 One or more -CH2- in the alkynylene group are independently optionally selected from -O-, C 3-10 Cycloalkyl, 4-11 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl, -NH-, -N(C 1-3 alkyl)- or -S-substituted; Alternatively, said L is selected from C optionally substituted by one or more substituents 1-6 Alkylene or C 2-6 Alkynylidene, optionally, the C 1-6 Alkylene or C 2-6 One or more -CH2- in the alkynylene group are independently optionally selected from -O-, C 3-10 Cycloalkyl or 4-11 membered heterocycloalkyl, -NH-, -N(C 1-3 alkyl)- or -S-substituted; Optionally, in the definition of L, the substituent is selected from halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, (C 1-6 Alkyl)NH-, (C 1-6 Alkyl)2N-, C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl.

9. The compound according to any one of claims 1 to 8, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is selected from -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -Cy 3 -,in, Cy 1 、Cy 2 or Cy 3 are independently selected from a bond, or optionally substituted by one or more R b Substituted with the following groups: C 3-12 Cycloalkyl, 4-12 membered heterocycloalkyl or 4-12 membered heterocycloalkenyl; LNK, LNK 1 and LNK 2 are independently selected from a bond, -NH-, -O-, -S-, or optionally substituted by one or more R c Substituted with the following groups: C 1-12 Alkylene, C 2-12 Alkenylene, C 2-12 Alkynylidene or C 1-12 heteroalkylene; Each R b and R c Each independently selected from halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, (C 1-6 Alkyl)NH-, (C 1-6 Alkyl)2N-, C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl; Alternatively, L is selected from -Cy 1 -, -Cy 2 -, -LNK 1 -, -Cy 1 -LNK-, -Cy 1 -Cy 2 -, -LNK 1 -Cy 1 -LNK-, -LNK-Cy 2 -LNK 2 -, -Cy 1 -Cy 2 -LNK 2 -, -LNK 1 -Cy 1 -Cy 2 -, -Cy 1 -LNK-Cy 2 -, -LNK 1 -Cy 1 -Cy 2 -LNK 2 -, -LNK 1 -Cy 1 -LNK-Cy 2 -, -Cy 1 -LNK-Cy 2 -LNK 2 -, -Cy 1 -Cy 2 -Cy 3 - or -Cy 1 -Cy 2 -LNK 2 -Cy 3 -; Or, LNK, LNK 1 and LNK 2 are independently selected from a bond, -NH-, -O-, -S-, or optionally substituted by one or more R c Substituted with the following groups: C 1-10 Alkylene, C 2-10 Alkenylene, C 2-10 Alkynylidene or C 1-10 heteroalkylene; Or, LNK, LNK 1 and LNK 2 are independently selected from a bond, -NH-, -O-, -S-, or optionally substituted by one or more R c Substituted with the following groups: C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene or C 1-6 heteroalkylene; Or, LNK, LNK 1 and LNK 2 are independently selected from a bond, -NH-, -O-, -S-, or optionally substituted by one or more R c Substituted with the following groups: C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene or C 1-4 heteroalkylene; Or, LNK, LNK 1 and LNK 2 are independently selected from a bond, -NH-, -O-, -S-, or optionally substituted by one or more R c Substituted with the following groups: C 1-6 Alkylene, C 2-6 Alkynylidene or C 1-6 heteroalkylene; Or, LNK, LNK 1 and LNK 2 are independently selected from a bond, -NH-, -O-, -S-, or optionally substituted by one or more R c Substituted with the following groups: C 1-4 Alkylene, C 2-4 Alkynylidene or C 1-4 heteroalkylene; Or, LNK, LNK 1 and LNK 2 are independently selected from a bond, -NH-, -O-, or optionally substituted by one or more R c Substituted with the following groups: C 1-3 Alkylene, C 2-3 Alkynylidene or C 1-3 heteroalkylene; Or, LNK, LNK 1 and LNK 2 are independently selected from a bond, -NH-, -O-, or optionally substituted by one or more R c Substituted with the following groups: C 1-2 Alkylene, C2 alkynylene or C 1-2 heteroalkylene; Or, LNK, LNK 1 and LNK 2 are independently selected from a bond, -NH-, -O-, -NHCH2-, -CH2NHCH2-, -CH2-, -CH2CH2-, ethynylene, -C(O)- or -C(O)CH2-; and / or, Cy 1 、Cy 2 or Cy 3 are independently selected from a bond, or optionally substituted by one or more R b Substituted with the following groups: C 3-11 Cycloalkyl, 4-12 membered heterocycloalkyl or 4-11 membered heterocycloalkenyl; Alternatively, Cy 1 、Cy 2 or Cy 3 are independently selected from a bond, or optionally substituted by one or more R b Substituted with the following groups: C 4-10 Cycloalkyl, 4-11 membered heterocycloalkyl or 5-6 membered heterocycloalkenyl; Alternatively, Cy 1 、Cy 2 or Cy 3 are independently selected from a bond, or optionally substituted by one or more R b Substituted with the following groups: C 4-9 Cycloalkyl, 4-11 membered heterocycloalkyl or 5-6 membered heterocycloalkenyl; Alternatively, Cy 1 、Cy 2 or Cy 3 are independently selected from a bond, or optionally substituted by one or more R b Substituted with the following groups: C 4-6 Cycloalkyl, C9 cycloalkyl, 4-11 membered heterocycloalkyl or 6 membered heterocycloalkenyl; Alternatively, Cy 1 、Cy 2 or Cy 3 are independently selected from a bond, or optionally substituted by one or more R b Substituted cyclobutyl, cyclopentyl, cyclohexyl, spironanyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyridinyl, piperazinyl, monoazaspiroheptanyl, monoazaspirooctanyl, monoazaspironanyl, diazaspironanyl, monoazaspirodecanyl, diazaspirodecanyl, monoazaspiroundecyl, diazaspiroundecyl, monoazaspiroundecyl, monoazabicyclohexane, octahydrocyclopentapyrrolyl, diazabicyclooctanyl or monoazabicyclononanyl; Alternatively, Cy 1 、Cy 2 or Cy 3 are independently selected from a bond, and / or, Each R b and R c Each independently selected from halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, (C 1-6 Alkyl)NH-, (C 1-6 Alkyl)2N-, C 3-10 Cycloalkyl or 4-10 membered heterocycloalkyl; Or, each R b and R c Each independently selected from halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, (C 1-6 alkyl)NH- or (C 1-6 Alkyl)2N-; Or, each R b and R c Each independently selected from halogen, =O, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, (C 1-4 Alkyl)NH-, or (C 1-4 Alkyl)2N-; Or, each R b and R c Each independently selected from halogen, =O, -OH, -NH2, -CN or C 1-3 alkyl; Or, each R b and R c Each is independently selected from halogen, =O, -OH, -NH2 or -CN; Or, each R b and R c Each independently selected from =0; Optionally, L is selected from a bond, -NHCH2-, -CH2NHCH2-, -CH2-, -C(O)CH2-, 10. The compound according to any one of claims 1 to 9, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein X 6 Selected from bond, -O-, -S-, -N(R t )-、-C 1-4 Alkylene-, -C 2-4 Alkenylene-, -C 2-4 Alkynylidene-, -N(R t )C 1-4 Alkylene-, -OC 1-4 Alkylene-, -SC 1-4 Alkylene- or -N(R t )C(O)-; Or, X 6 Selected from bond, -O-, -S-, -N(R t )-、-C 1-3 Alkylene-, -C 2-3 Alkenylene-, -C 2-3 Alkynylidene-, -N(R t )C 1-3 Alkylene-, -OC 1-3 Alkylene-, -SC 1-3 Alkylene- or -N(R t )C(O)-; Or, X 6 Selected from bond, -O-, -S-, -N(R t )-、-C 1-3 Alkylene-, -C 2-3 Alkenylene-, -C 2-3 Alkynylidene-, -N(R t )C 1-3 Alkylene-, -OC 1-3 Alkylene- or -N(R t )C(O)-; Or, X 6 Selected from bond, -O-, -S-, -N(R t )-、-CH2-、-C2alkynylene-、-N(R t )C 1-2 Alkylene-, -OC 1-2 Alkylene- or -N(R t )C(O)-; Or, X 6 is selected from a bond, -O-, -S-, -NH-, -CH2-, -NHCH2-, -N(CH3)CH2-, -OCH2-, -OCH(CH3)- or -NHC(O)-; Or, X 6 Selected from -O-, -S-, -NH-, -C 2-4 Alkynylidene-, -NHC 1-4 Alkylene- or -OC 1-4 Alkylene-; Or, X 6 Selected from bond, -O-, -NHC 1-3 Alkylene- or -OC 1-3 Alkylene-; Or, X 6 Selected from bond, -O-, -C 2-3 Alkynylidene- or -OC 1-3 Alkylene-; Or, X 6 is selected from a bond, -O-, -ethynylene- or -OCH2-; Or, X 6 is selected from a bond, -O-, -NHCH2- or -OCH2-.

11. The compound according to any one of claims 1 to 10, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R t Selected from H or C 1-6 alkyl; Alternatively, the R t Selected from H or C 1-3 Alkyl; or, the R t Selected from H or methyl.

12. The compound according to any one of claims 1 to 11, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein each R 2 are independently selected from halogen, -CN, the following groups optionally substituted with one or more R': R v -、R v O-、R v S-、R s R v N-、R v C(O)-、R v S(O)2-、R v S(O)-、R v =N-、R v OC(O)-、R v C(O)O-、R v S(O)O-、R v OS(O)-、R v S(O)2O-、R v OS(O)2-、R s R v NC(O)-、R v C(O)NH-、R v OC(O)NH-、R v NHC(O)O-、R v S(O)NH-、R s R v NS(O)-、R v S(O)2NH-、R s R v NS(O)2-or R s R v S(O)=N-; Or, each R 2 are independently selected from halogen, -CN, the following groups optionally substituted with one or more R': R v -、R v O-、R v C(O)-、R v =N-、R v S(O)2NH- or R s R v S(O)=N-; Optionally, R s and R v are independently selected from H, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkyl C 1- 3-membered alkylene-, 3-12-membered heterocycloalkyl, 3-12-membered heterocycloalkyl C 1-3 Alkylene-, C 3-12 Cycloalkenyl, C 3-12 Cycloalkenyl C 1-3 Alkylene-, 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl C 1-3 Alkylene-, C 6-10 Aryl, C 6-10 Aryl C 1-3 Alkylene, 5-10 membered heteroaryl or 5-10 membered heteroarylC 1-3 Alkylene-; Or, R s and R v are independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl C 1-3 Alkylene-, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkylC 1-3 Alkylene-, C 3-10 Cycloalkenyl, C 3-10 Cycloalkenyl C 1-3 Alkylene-, 3-10 membered heterocycloalkenyl, 3-10 membered heterocycloalkenyl C 1-3 Alkylene-, C 6-10 Aryl, C 6-10 Aryl C 1-3 Alkylene-, 5-10 membered heteroaryl or 5-10 membered heteroarylC 1- 3-alkylene-; Or, R s are independently selected from H or C 1-6 Alkyl; or, R s are each independently selected from H; Or, R s and R v are independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-6 membered heteroaryl; Or, R s and R v are independently selected from H, C 1-4 Alkyl, C 3-4 Cycloalkyl, 4-7 membered heterocycloalkyl or 5-6 membered heteroaryl; Or, R s and R v are independently selected from H, methyl, ethyl, n-propyl, isopropyl, isobutyl, vinyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrothiophenyl, Piperidinyl, Morpholinyl, piperazinyl, 1,4-oxathiyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl, thiadiazolyl, or phenyl; Or, R s and R v are independently selected from H, methyl, ethyl, n-propyl, isopropyl, isobutyl, vinyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, pyrrolidinyl, Piperidinyl, Morpholinyl, piperazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl or thiadiazolylphenyl.

13. The compound according to any one of claims 1 to 12, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein each R 2 are independently selected from halogen, -OH, -NH2, -CN, the following groups optionally substituted by one or more substituents R': C 1-6 Alkyl, C 1-6 Alkyl O-, 4-10 membered heterocycloalkyl O-, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-10 CycloalkylNH-, 4-10 membered heterocycloalkylNH-, C 1-6 Alkyl C(O)-, C 3-10 Cycloalkyl C (O) -, 5-10 membered heterocycloalkyl C (O) -, C 1-6 Alkyl S(O)2-, H2NC(O)-, C 1-6 Alkyl NHC(O)-, (C 1-6 Alkyl) 2NC(O)-, C 2-6 Alkenyl C(O)NH-, C 1-6 Alkyl S(O)2NH-, C 3-10 Cycloalkyl-S(O)2NH-, H2NS(O)2-, (C 1-6 alkyl)2S(O)=N-, 4-12 membered heterocycloalkyl=N-, C 3-10 Cycloalkyl, 4-12 membered heterocycloalkyl or 5-10 membered heteroaryl; Or, each R 2 are independently selected from halogen, -OH, -NH2, -CN, the following groups optionally substituted by one or more substituents R': C 1-6 Alkyl, C 1-6 Alkyl O-, 4-6 membered heterocycloalkyl O-, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 CycloalkylNH-, 4-6 membered heterocycloalkylNH-, C 1-6 Alkyl C(O)-, C 3-6 Cycloalkyl C (O) -, 5-6 membered heterocycloalkyl C (O) -, C 1-6 Alkyl S(O)2-, H2NC(O)-, C 1-6 Alkyl NHC(O)-, (C 1-6 Alkyl) 2NC(O)-, C 2-6 Alkenyl C(O)NH-, C 1-6 Alkyl S(O)2NH-, C 3-6 Cycloalkyl-S(O)2NH-, H2NS(O)2-, (C 1-6 alkyl)2S(O)=N-, 4-10 membered heterocycloalkyl=N-, C 3-6 Cycloalkyl, 4-10 membered heterocycloalkyl or 5-6 membered heteroaryl; Or, each R 2 are independently selected from the following groups: halogen, C 1-4 Alkyl, C 1-4 Alkyl O-, C 1-3 Alkyl C(O)-, C 1-3 Alkyl S(O)2NH-, (C 1-3 alkyl)2S(O)=N-, 5-6 membered heterocycloalkyl=N-, C 3-4 Cycloalkyl, 4-7 membered heterocycloalkyl or 5 membered heteroaryl, the C 1- 4 alkyl, C 1-4 Alkyl O-, C 1-3 Alkyl C(O)-, C 1-3 Alkyl S(O)2NH-, (C 1-3 alkyl)2S(O)=N-, 5-6 membered heterocycloalkyl=N-, C 3-4 Cycloalkyl, 4-7 membered heterocycloalkyl or 5 membered heteroaryl are optionally substituted with one or more of the following groups: halogen, -OH, -NH2, -CN, C 1-3 Alkyl, =O or C 1-3 Alkyl S(O)2NH-; Or, each R 2 are independently selected from halogen, or the following groups optionally substituted by one or more R': C 1-6 Alkyl, C 1-6 Alkyl O-, C 1-6 Alkyl C(O)-, C 1-6 Alkyl S(O)2NH-, (C 1-6 alkyl)2S(O)=N-, 5-7 membered heterocycloalkyl=N-, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl or 5-6 membered heteroaryl; Or, each R 2 are independently selected from halogen, -OH, -NH2, -CN, the following groups optionally substituted by one or more substituents R': methyl, ethyl, n-propyl, isopropyl, isobutyl, <h2 style=";text-align:left;direction:ltr">CH3S-, CH3NH-, CH3CH2NH-, (CH3)2CHNH-, (CH3)2N-<h2 style=";text-align:left;direction:ltr"> Cyclopropyl-NH-, CH3C(O)-、CH3CH2C(O)-、(CH3)2CHC(O)-、cyclopropyl-C(O)-、cyclobutyl-C(O)-、cyclopentyl-C(O)-、 CH3S(O)2-、H2NC(O)-、CH3NHC(O)-、CH3CH2NHC(O)-、(CH3)2NC(O)-、 CH3S(O)2NH-, cyclopropyl-S(O)2NH-, H2NS(O)2-, (CH3)2S(O) ＝ N-、 Cyclopropyl, Azetidinyl, pyrrolidinyl, Piperidinyl, Morpholinyl, piperazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl, thiadiazolyl, CH3O-, CH3CH2O-, Alternatively, each R' is independently selected from halogen, -OH, -NH2, -CN, =O, or the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, C 1-6 Alkyl OC 1-6 Alkyl-, C 1-6 Alkyl O-, C 1-6 Alkyl S-, (C 1-6 Alkyl)NH-, (C 1-6 Alkyl)2N-, C 1- 6-alkyl C(O)-, C 1-6 Alkyl S(O)2-, C 1-6 Alkyl C(O)NH-, C 1-6 Alkyl S(O)2NH-, C 1-6 Alkyl S(O)NH-, (C 1-6 alkyl)2S(O)=N-、C 1-6 Alkyl NHC(O)-, C 1-6 AlkylNHS(O)2-, C 1-6 Alkyl NHS(O)-, C 1-6 Alkyl C(O)O-, C 1-6 Alkyl S(O)2O-, C 1-6 Alkyl S(O)O-, C 1-6 Alkyl OC(O)-, C 1-6 Alkyl OS(O)2-, C 1-6 Alkyl OS(O)-, C 1-6 Alkyl NHC(O)O-, C 1-6 Alkyl OC(O)NH-, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl; Alternatively, each R' is independently selected from halogen, -OH, -NH2, -CN, =O, C optionally substituted with one or more hydroxyl or halogen 1-6 Alkyl, C 1-6 Alkyl OC 1-6 Alkylene-, C 1-6 Alkyl O-, (C 1-6 Alkyl)NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl S(O)2-, C 3-6 Cycloalkyl, or 3-6 membered heterocycloalkyl optionally substituted by one or more halogens; Alternatively, each R' is independently selected from halogen, -OH, -NH2, -CN, =O, C 1-6 Alkyl, C 1-6 Alkyl O-, (C 1-6 Alkyl)NH-, C 1-6 Alkyl S(O)2NH-, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl; Alternatively, each R' is independently selected from halogen, -OH, -NH2, -CN, =O, C 1-4 Alkyl or C 1-4 Alkyl S (O) 2NH-; or, each R 'is independently selected from -F, -OH, -NH2, -CN, =O, methyl, ethyl, HOCH2-, CH3OCH2-, CH3CH2O-, (CH3) 2N-, CH3S (O) 2-, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, -Cl or CH3S(O)2NH-; Or, each R 2 Each independently selected from -F, -CN, -NH2, methyl, CH3CH2-, CH3CH(NH2)-, CH3CH(OH)-, (CH3)2C(OH)-, CH3CH2CH(OH)-, (CH3)2CHCH(OH)-, <h2 style=";text-align:left;direction:ltr">CH3S-, CH3NH-, CH3CH2NH-, (CH3)2CHNH-<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">(CH3)2N-<h2 style=";text-align:left;direction:ltr"> Cyclopropyl-NH-, CH3C(O)-、CH3CH2C(O)-、(CH3)2CHC(O)-、cyclopropyl-C(O)-、cyclobutyl-C(O)-、cyclopentyl-C(O)-、 CH3S(O)2-、H2NC(O)-、CH3NHC(O)-、CH3CH2NHC(O)-、(CH3)2NC(O)-、 CH3S(O)2NH-, cyclopropyl-S(O)2NH-, H2NS(O)2-, (CH3)2S(O)=N-, Cyclopropyl, Azetidine, Pyrrolidino, Piperidinyl, Morpholinyl, Piperazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl, thiadiazolyl, -Cl、-CHF2、-CF3、CH3O-、CHF2O-、CF3O-、CF3CH2O-、 Or, each R 2 Each independently selected from -F, CH3CH(OH)-, (CH3)2C(OH)-, -CHF2, -CF3, CH3O-, CHF2O-, CF3O-, CF3CH2O-, CH3C(O)-, CH3S(O)2NH-, (CH3)2S(O)=N-, Cyclopropyl, 14. The compound according to any one of claims 1 to 13, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein each R 3 are independently selected from halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl or 5-6 membered heteroaryl; Or, each R 3 are independently selected from halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 alkyl; Or, each R 3 are independently selected from halogen, -OH, -NH2, -CN or methyl; Or, each R 3 are independently selected from halogen; or, each R 3 are independently selected from F.

15. The compound according to any one of claims 1 to 14, its stereoisomer or pharmaceutically acceptable salt thereof, wherein each R 4 are independently selected from halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl or 5-6 membered heteroaryl; Or, each R 4 are independently selected from halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 alkyl; Or, each R 4 are independently selected from halogen, -OH, -NH2, -CN or methyl; Or, each R 4 are independently selected from halogen, -OH, -NH2 or -CN; Or, each R 4 are independently selected from halogen or -CN; Or, each R 4 are independently selected from -F, -Cl or -CN.

16. The compound according to any one of claims 1 to 15, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein m is selected from 0, 1, 2 or 3; Alternatively, m is selected from 1 or 2; Optionally, p is selected from 0, 1 or 2; or, p is selected from 0 or 1; Optionally, k is selected from 0, 1, 2 or 3; or, k is selected from 0, 1 or 2.

17. The compound according to any one of claims 1 to 16, its stereoisomer or pharmaceutically acceptable salt thereof, wherein ring G is selected from C 4-6 Cycloalkyl, 4-9 membered heterocycloalkyl, phenyl, 5-8 membered heteroaryl or 9-10 membered heterocycloalkenyl; or, ring G is selected from C 4-6 cycloalkyl, 4-9 membered heterocycloalkyl, phenyl, 5-8 membered heteroaryl, tetrahydroisoquinolinyl, tetrahydropyridopyrimidinyl, tetrahydropyridopyrazinyl, pyrrolopyrimidinyl or pyrimidopyrrolidinyl; Alternatively, the ring G is selected from phenyl, 5-6 membered heteroaryl or 9-10 membered heterocycloalkenyl; Alternatively, the ring G is selected from cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, dioxane, phenyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Alternatively, the ring G is selected from cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, dioxane, phenyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Alternatively, the ring G is selected from cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, dioxane, Alternatively, the ring G is selected from 18. The compound according to any one of claims 1 to 17, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein ring E is selected from C 6-12 Aryl or 5-10 membered heteroaryl; Alternatively, ring E is selected from phenyl or 5-6 membered heteroaryl; Alternatively, ring E is selected from phenyl or 6-membered heteroaryl; Alternatively, ring E is selected from 19. The compound according to any one of claims 1 to 18, its stereoisomer or pharmaceutically acceptable salt thereof, wherein ring F is selected from C 6-12 Aryl or 5-10 membered heteroaryl; Alternatively, ring F is selected from phenyl or 5-6 membered heteroaryl; Alternatively, ring F is selected from phenyl or 6-membered heteroaryl; Alternatively, ring F is selected from Optionally, Selected from Optionally, Selected from Optionally, Z is selected from -C-.

20. The compound according to any one of claims 1 to 19, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 are independently selected from H, =O, halogen, -OH, -NH2, -CN, C 1-6 Alkyl or C 2-6 Alkenyl, or R 5 and R 6 are linked to each other to form the following group which is optionally substituted by one or more substituents such as R": 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl; Or, R 5 and R 6 are independently selected from H, C 1-3 Alkyl or C 2-3 Alkenyl, or R 5 and R 6 are linked to each other to form the following group optionally substituted by one or more R": 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl; Or, R 5 and R 6 are independently selected from H, methyl, ethyl or vinyl, or R 5 and R 6 are linked to each other to form the following groups optionally substituted by one or more R″: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl or oxetanyl; Optionally, the R" is selected from halogen, -OH, -NH2, -CN, C 1-3 Alkyl or halogenated C 1-3 alkyl; Or, R 5 and R 6 are independently selected from H, methyl, ethyl or vinyl, or R 5 and R 6 Connected to each other to form the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl or oxetanyl; Or, R 5 and R 6 are independently selected from H or C 1-6 Alkyl, or R 5 and R 6 Connected to form the following groups: C 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl; Or, R 5 and R 6 are independently selected from H or C 1-3 Alkyl, or R 5 and R 6 Connected to form the following groups: C 3-4 Cycloalkyl or 4-membered heterocycloalkyl; or, R 5 and R 6 are independently selected from H or C 1-3 Alkyl, or R 5 and R 6 Connected to each other to form a 4-membered heterocycloalkyl group; Or, R 5 and R 6 are independently selected from methyl, or, R 5 and R 6 Connected to each other to form oxetane groups; Optionally, the structural part Selected from 21. The compound according to any one of claims 1 to 20, its stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound of formula III, its stereoisomer or pharmaceutically acceptable salt thereof is selected from the following compounds, their stereoisomers or pharmaceutically acceptable salts, Where T 1 、T 2 、T 3 、T 4 、T 5 and T 6 are independently selected from CH or N; X 7 selected from CH or N; T 7 、T 8 、T 9 and T 10 are independently selected from CH or N; Preferably, X 5 C(R f ), R f Selected from H, halogen, deuterium or C 1-3 alkyl; represents a single bond; L 1 is the key; Ring A is selected from a 5-6 membered heterocycloalkenyl group containing 1-2 N atoms or O atoms, Ring B is selected from a phenyl group or a pyridyl group, and Ring C is a 5 membered heteroaryl group containing 1-2 heteroatoms selected from N, O or S; R 1 Selected from deuterium, halogen, -OH or -NH2; n is 0 or 1; L is selected from PTM is R 2 Selected from halogen, -CHF2, -CF3, methyl, CH3O-, CHF2O-, CF3O-, CF3CH2O-, CH3CH(OH)-, (CH3)2C(OH)-, CH3CH2CH(OH)-, cyclopropyl, CH3S(O)2NH- or cyclopropyl-S(O)2NH-; m is 1; Ring G is selected from phenyl or a 5-6 membered heteroaryl group containing 1-3 N atoms; X 6 Selected from bond, -O-, -S-, -C 2-3 Alkenylene- or -C 2-3 Alkynylidene-; Ring E is selected from phenyl or a 6-membered heteroaryl group containing 1-2 N atoms; p is 0; Z is selected from -C-; R 5 and R 6 are independently selected from C 1-3 Alkyl or C 2-3 alkenyl; Ring F is selected from phenyl or a 6-membered heteroaryl group containing 1-2 N atoms; R 4 Selected from halogen or -CN; k is 0 or 1.

22. The compound according to any one of claims 1 to 21, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from:

23. A pharmaceutical composition comprising the compound according to any one of claims 1 to 22, its stereoisomer or a pharmaceutically acceptable salt thereof, and optionally further comprising a pharmaceutically acceptable excipient.

24. Use of the compound according to any one of claims 1 to 22, its stereoisomer, or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 23 in the preparation of a medicament for preventing or treating a disease; optionally, the disease is selected from a GSPT1-related disease; optionally, the disease is selected from an AR or ARv7-related disease; preferably, the disease is cancer.

25. A method for treating or preventing a mammalian disease, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 22, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23; optionally, the disease is selected from a GSPT1-related disease; optionally, the disease is selected from an AR or ARv7-related disease; preferably, the disease is cancer.

26. A compound according to any one of claims 1 to 22, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23 for use in preventing or treating a disease; optionally, the disease is selected from a GSPT1-related disease; optionally, the disease is selected from an AR or ARv7-related disease; preferably, the disease is cancer.

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