Compound containing three fused heterocyclic rings

Abstract

The present application belongs to the field of medicinal chemistry and specifically relates to a compound as shown in 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). PTM-L-CLM I

Description

Compounds containing tricyclic heterocycles

[0001] Cross-reference to related applications

[0002] This application claims priority and benefit to the following Chinese patent application filed with the China National Intellectual Property Administration, the contents of which are incorporated herein by reference in their entirety: Chinese Patent Application No. 202411595030.1, filed on November 8, 2024. Technical Field

[0003] This application belongs to the field of medicinal chemistry and relates to compounds containing tricyclic heterocycles, methods for their preparation, pharmaceutical compositions containing such compounds, and their use in the treatment of related diseases (such as cancer). Background Technology

[0004] SMARCA2 (BRM) and SMARCA4 (BRG1) are subunits containing catalytic ATPase domains and are essential for the function of SWI / SNF in interfering with histone-DNA contact, thus providing access sites for transcription factors and homologous DNA elements that promote gene activation and repression. SMARCA2 and SMARCA4 share high homology (up to 75%). SMARCA4 is frequently mutated (i.e., deleted or inactivated) in primary tumors. SMARCA2 is one of the most important essential genes in SMARCA4-mutant (deleted) cancer cell lines. This is because SMARCA4-deficient cancer cells rely entirely on SMARCA2 ATPase activity to achieve their chromatin remodeling activity for cellular functions such as cell proliferation, survival, and growth. Therefore, targeting SMARCA2 may be a promising therapeutic approach for SMARCA4-related or defective cancers (genetically synthetic lethality).

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

[0006] Small molecule therapeutic agents that target and degrade SMARCA2 will be very promising for treatment.

[0007] Invention Details

[0008] On the one hand, this application relates to compounds of formula I, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0009] PTM-L-CLM

[0010] I

[0011] in,

[0012] CLM is selected from the E3 ubiquitin ligase binding region;

[0013] L is selected from a linking group;

[0014] PTM is selected from the structural portion that binds to the protein binding sites of SMARCA2 and / or SMARCA4.

[0015] In some embodiments, the E3 ubiquitin ligase-binding moiety is selected from the cereblon E3 ubiquitin ligase-binding moiety, the VHL E3 ubiquitin ligase-binding moiety, the IAP E3 ubiquitin ligase-binding moiety, or the MDM2 E3 ubiquitin ligase-binding moiety.

[0016] In some embodiments, CLM is selected from small molecule compounds. In some embodiments, PTM is selected from small molecule compounds.

[0017] In some implementations, the CLM is covalently connected to L. In some implementations, the PTM is covalently connected to L.

[0018] On the one hand, this application relates to compounds of formula I, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0019] PTM-L-CLM

[0020] I

[0021] PTM is selected from

[0022] R 2 Each is independently selected from deuterium, halogen, -OH, -NH2, -CN, COOH, -CONH2, or optionally influenced by one or more R. 2a’ The following groups are substituted: C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, C 1-10 Alkyl NH-, (C 1-10 Alkyl)2N-, C 1-10 Alkyl C(O)-, C 1-10 Alkyl C(O)O-, C 1-10 Alkyl OC(O)-, C 1-10Alkyl C(O)NH-, C 1-10 Alkyl NHC(O)-, C 1-10 Alkyl S(O)NH-, C 1-10 Alkyl NHS(O)-, C 1-10 Alkyl S(O)2NH-, C 1-10 Alkyl NHS(O)2-, C 3-12 Cycloalkyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl or 5-12 heteroaryl groups;

[0023] Each R 2a’ Each is independently selected from deuterium, halogens, -OH, -NH2, -CN, and C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, C 1-10 Alkyl NH-, (C 1-10 Alkyl)2N-, C 3-12 Cycloalkyl or 3-12 membered heterocyclic alkyl;

[0024] m is selected from 0, 1, 2, 3, 4, 5, 6 or 7;

[0025] L 2 Selected from key, or selected from C 1-6 Alkylene or C 2-6 Idenoyl, the C 1-6 Alkylene or C 2-6 One or two methylene groups in the alkenyl group are optionally and independently replaced by -O-, -C(O)-, -C(S)-, -NH-, -S-, or -S(O)2-, wherein the C 1-6 Alkylene or C 2-6 The alkenyl group is optionally surrounded by one or more R L Replace, each R L Each is independently selected from deuterium, halogens, -CN, OH, NH2, and C. 3-12 Cycloalkyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl or 5-12 heteroaryl groups;

[0026] R 3 Selected from one or more R 3a The following groups are substituted: C 3-12 Cycloalkyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C 6- 12 Aryl or 5-12 heteroaryl groups;

[0027] Each R 3a Selected independently from deuterium, halogens, -CN, and C respectively.1-12 alkyl, halogenated or hydroxylated C 1-6 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl, 5-12 heteroaryl, 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-;

[0028] R s and R v Selected independently from H and C respectively 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 cycloalkyl, C 3-12 cycloalkyl C 1-3 alkylene-, 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkyl C 1-3 Alkylene-, C 3-12 Cycloalkenyl, C 3-12 Cycloalkenyl C 1-3 alkylene-, 3-12-membered heterocyclic alkenyl, 3-12-membered heterocyclic alkenyl C 1-3 Alkylene-, C 6-12 Aryl, C6-12 Aryl C 1-3 alkylene-, 5-12 heteroaryl, or 5-12 heteroaryl C 1-3 alkylene-;

[0029] Cyclomeric G is selected from 5-12 heteroaryl groups;

[0030] Ring E is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl or 5-12 heteroaryl groups;

[0031] Ring F is selected from non-existent, C 3-12 Cycloalkyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl or 5-12 heteroaryl groups;

[0032] Ring H is selected from non-existent, C 3-12 Cycloalkyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl or 5-12 heteroaryl groups;

[0033] L is selected from a linking group;

[0034] CLM is selected from

[0035] Indicates a single bond or a double bond;

[0036] Each R 1 The following groups are selected independently from deuterium, halogens, -OH, -NH2, -CN, or optionally substituted by 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 group, C 3-10 Cycloalkyl or 3-10 membered heterocyclic alkyl;

[0037] n is selected from 0, 1, 2, or 3;

[0038] Ring W is selected from 5-20 element rings;

[0039] X 5 Selected from C(R) f ) or N;

[0040] R f C selected from H, halogens, deuterium, or optionally substituted with one or more substituents 1-6 alkyl;

[0041] L 1 Selected from -NH-, -O-, -S-, -CONH-, or -CON(C) 1-6 alkyl)-;

[0042] Each R a Each is independently selected from deuterium, hydroxyl, halogen, amino, cyano, or C. 1-8 Alkyl group; q is selected from 0, 1, 2 or 3;

[0043] X 4 Selected from N or CH that is optionally substituted with one or more substituents.

[0044] On the one hand, this application relates to compounds of formula II, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0045] in,

[0046] Indicates a single bond or a double bond;

[0047] Ring A does not exist, or is selected from C. 3-15 Cycloalkenyl, 3-15 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl;

[0048] Ring B is selected from phenyl or 5-6-membered heteroaryl groups;

[0049] Cyclic C is selected from 5-6 member heteroaryl groups;

[0050] Each R 1 The following groups are independently selected from deuterium, halogens, -OH, -NH2, -CN, and optionally substituted by one or more substituents: C 1- 10 Alkyl, C 1-10 Alkoxy, (C 1-10 alkyl)NH-, (C 1-10 Alkyl)2N-, hydroxyl or halogenated C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Cycloalkyl or 3-10 membered heterocyclic alkyl;

[0051] n is selected from 0, 1, 2, or 3;

[0052] X 5 Selected from C(R) f ) or N;

[0053] R f C selected from H, halogens, deuterium, or optionally substituted with one or more substituents 1-6 alkyl;

[0054] L1 Selected from -NH-, -O-, -S-, -CONH-, or -CON(C) 1-6 alkyl)-;

[0055] L is selected from a linking group;

[0056] PTM is a structural portion selected from the protein-binding portion that binds to SMARCA2 and / or SMARCA4.

[0057] On the one hand, this application also relates to compounds of formula III, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0058] in,

[0059] Indicates a single bond or a double bond;

[0060] Each R 1 The following groups are independently selected from deuterium, halogens, -OH, -NH2, -CN, and optionally substituted by 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 group, C 3-10 Cycloalkyl or 3-10 membered heterocyclic alkyl;

[0061] n is selected from 0, 1, 2, or 3;

[0062] X 5 Selected from C(R) f ) or N;

[0063] R f C selected from H, halogens, deuterium, or optionally substituted with one or more substituents 1-6 alkyl;

[0064] L 1 Selected from -NH-, -O-, -S-, -CONH-, or -CON(C) 1-6 alkyl)-;

[0065] L is selected from a linking group;

[0066] R 2 Each is independently selected from deuterium, halogen, -OH, -NH2, -CN, COOH, -CONH2, or optionally influenced by one or more R. 2a’ The following groups are substituted: C 1-10 Alkyl, C2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, C 1-10 Alkyl NH-, (C 1-10 Alkyl)2N-, C 1-10 Alkyl C(O)-, C 1-10 Alkyl C(O)O-, C 1-10 Alkyl OC(O)-, C 1-10 Alkyl C(O)NH-, C 1-10 Alkyl NHC(O)-, C 1-10 Alkyl S(O)NH-, C 1-10 Alkyl NHS(O)-, C 1-10 Alkyl S(O)2NH-, C 1-10 Alkyl NHS(O)2-, C 3-12 Cycloalkyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl or 5-12 heteroaryl groups;

[0067] Each R 2a’ Each is independently selected from deuterium, halogens, -OH, -NH2, -CN, and C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, C 1-10 Alkyl NH-, (C 1-10 Alkyl)2N-, C 3-12 Cycloalkyl or 3-12 membered heterocyclic alkyl;

[0068] m is selected from 0, 1, 2, 3, 4, 5, 6 or 7;

[0069] L 2 Selected from key, or selected from C 1-6 Alkylene or C 2-6 Idenoyl, the C 1-6 Alkylene or C 2-6 One or two methylene groups in the alkenyl group are optionally and independently replaced by -O-, -C(O)-, -C(S)-, -NH-, -S-, or -S(O)2-, wherein the C 1-6 Alkylene or C 2-6 The alkenyl group is optionally surrounded by one or more R L Replace, each R L Selected from deuterium, halogens, -CN, OH, NH2, C 3-12 Cycloalkyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl or 5-12 heteroaryl groups;

[0070] R 3Selected from one or more R 3a The following groups are substituted: C 3-12 Cycloalkyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl or 5-12 heteroaryl groups;

[0071] Each R 3a Selected independently from deuterium, halogens, -CN, and C respectively. 1-12 alkyl, halogenated or hydroxylated C 1-6 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl, 5-12 heteroaryl, 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-;

[0072] R s and R v Selected independently from H and C respectively 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 cycloalkyl, C 3-12 cycloalkyl C1-3 alkylene-, 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkyl C 1-3 Alkylene-, C 3-12 Cycloalkenyl, C 3-12 Cycloalkenyl C 1-3 alkylene-, 3-12-membered heterocyclic alkenyl, 3-12-membered heterocyclic alkenyl C 1-3 Alkylene-, C 6-12 Aryl, C 6-12 Aryl C 1-3 alkylene-, 5-12 heteroaryl, or 5-12 heteroaryl C 1- 3-alkylene-;

[0073] Cyclomeric G is selected from 5-12 heteroaryl groups;

[0074] Ring E is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl or 5-12 heteroaryl groups;

[0075] Ring F is selected from non-existent, C 3-12 Cycloalkyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl or 5-12 heteroaryl groups;

[0076] Ring H is selected from non-existent, C 3-12 Cycloalkyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl or 5-12 heteroaryl groups;

[0077] Ring W is selected from 5-20 element rings.

[0078] In some embodiments, the ring W is selected from 10-15 membered heterocyclic alkenyl groups, C 6-10 Aryl or 5-7 heteroaryl compounds.

[0079] In some embodiments, the ring W is selected from 11-15 membered heterocycles. In some embodiments, the ring W is selected from non-aromatic heterocycles.

[0080] In some implementation schemes, ring W is selected from Phenyl or 6-membered heteroaryl (e.g., pyridyl), wherein ring A, ring B, and ring C are as described in this application.

[0081] In some implementations, the ring W is selected from 11-15 membered heterocyclic alkenyl groups.

[0082] In some implementation schemes, ring W is selected from Rings A, B, and C are as described in this application. In some embodiments, ring A is absent or selected from ring C. 3-12Cycloalkenyl, 3-12 membered heterocyclic alkenyl, phenyl, or 5-6 membered heteroaryl. In some embodiments, C 3-12 The cycloalkenyl group is selected from C 3-6 Cycloalkenyl. In some embodiments, the 3-12 membered heterocyclic alkenyl is selected from the 4-9 membered heterocyclic alkenyl.

[0083] In some implementations, ring A is absent, or is selected from C. 5-15 Cycloalkenyl, 5-15 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl.

[0084] In some implementations, ring A is absent, or is selected from C. 5-10 Cycloalkenyl, 5-10 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl.

[0085] In some implementations, ring A is absent, or is selected from C. 5-9 Cycloalkenyl, 5-9 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl.

[0086] In some implementations, ring A is absent, or is selected from C. 5-7 Cycloalkenyl, 5-7 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl.

[0087] In some implementations, ring A is absent, or is selected from C. 5-9 Cycloalkenyl, 5-9 membered heterocyclic alkenyl, phenyl, pyrroleyl, pyrazolyl, furanyl, or oxazolyl.

[0088] In some embodiments, ring A is absent, or is selected from C5-cycloalkenyl, C6-cycloalkenyl, C7-cycloalkenyl, C8-cycloalkenyl, C9-cycloalkenyl, 5-membered, 6-membered, 7-membered, 8-membered or 9-membered heterocyclic alkenyl, phenyl, pyrroleyl, pyrazolyl, furanyl or oxazolyl.

[0089] In some embodiments, ring A is absent, or is selected from cyclopentenyl, monocyclohexenyl, dicyclohexenyl, cycloheptenyl, dihydropyrroleyl, tetrahydropyridyl, tetrahydroaza The group can be alkyl, azirospirooctenyl, azirospirononenyl, phenyl, pyrroleyl, pyrazolyl, furanyl, oxazolyl, or dihydrooxazinyl.

[0090] In some specific implementation schemes, ring A is selected from C. 3-15 Cycloalkenyl or 3-15 membered heterocyclic alkenyl. In some specific embodiments, ring A is selected from C. 5-10 Cycloalkenyl or 5-10 membered heterocyclic alkenyl. In some specific embodiments, ring A is selected from C. 5-8 Cycloalkenyl or 5-8 membered heterocyclic alkenyl.

[0091] In some specific implementation schemes, ring A is selected from C. 5-7 Cycloalkenyl or 5-7 membered heterocyclic alkenyl.

[0092] In some embodiments, ring A is selected from C5-cyclic, C6-cyclic, C7-cyclic, 5-membered heterocyclic alkenyl groups containing one nitrogen atom, 6-membered heterocyclic alkenyl groups containing one nitrogen atom, and 7-membered heterocyclic alkenyl groups containing one nitrogen atom. In some specific embodiments, ring A is selected from... The asterisk (*) indicates that the bond with the asterisk is connected to the L group.

[0093] In some specific implementation schemes, ring A is selected from... The asterisk (*) indicates that the bond marked with an asterisk is connected to the L group on the left side of the general formula.

[0094] In some embodiments, the ring B is selected from phenyl or 6-membered heteroaryl.

[0095] In some embodiments, ring B is selected from phenyl or pyridyl. In some embodiments, ring B is phenyl.

[0096] In some embodiments, the cyclic C is selected from 5-membered heteroaryl groups.

[0097] In some embodiments, the ring C is selected from isoxazolyl, pyrazolyl, or furanyl.

[0098] In some embodiments, the ring C is selected from isoxazolyl or furanyl.

[0099] In some embodiments, ring C is an isoxazolyl group. In some embodiments, ring A is selected from C. 5-15 Cycloalkenyl or 5-15 membered heterocyclic alkenyl, wherein ring B is selected from phenyl and ring C is selected from isoxazolyl or furanyl.

[0100] In some implementations, ring A is selected from C. 5-7 Cycloalkenyl or 5-7 membered heterocyclic alkenyl, wherein ring B is selected from phenyl and ring C is isoxazolyl.

[0101] In some implementation schemes, R 1 The replacement position is selected from ring A or ring B. In some embodiments, R 1 The replacement position is selected from ring A. In some embodiments, R 1 The replacement position is selected from ring B. In some embodiments, R 1 The substitution position is selected from ring C.

[0102] In some implementations, ring A is connected to L. In some implementations, ring B is connected to L. In some implementations, ring C is connected to L. In some implementations, ring A is connected to segment L. (when L) 1Selected from key connections. In some implementations, ring B is connected to the segment. (when L) 1 Selected from key connections. In some implementations, ring C is connected to fragments. (when L) 1 (Selected from key) connection.

[0103] In some implementations, structural fragments Selected from In some implementations, structural fragments Selected from

[0104] In some implementations, structural fragments Selected from In some specific implementation schemes, structural fragments Selected from

[0105] In some implementations, structural fragments Selected from In some specific implementation schemes, structural fragments Selected from

[0106] In some implementations, structural fragments Selected from

[0107] In some implementations, structural fragments Selected from In some implementations, structural fragments Selected from

[0108] In some implementations, structural fragments Selected from

[0109] In some implementations, structural fragments Selected from In some implementations, structural fragments Selected from In some implementations, structural fragments Selected from

[0110] In some implementations, structural fragments Selected from In some implementations, structural fragments Selected from In some implementations, structural fragments Selected from

[0111] In some implementations, structural fragments Selected from The asterisk (*) indicates that the bond marked with an asterisk is connected to the L group on the left side of the general formula.

[0112] In some implementations, structural fragments by n R 1 Each can replace the others independently.

[0113] In some implementations, each R 1 The following groups are independently selected from deuterium, halogens, -OH, -NH2, -CN, and optionally substituted by one or more substituents: C 1-6 Alkyl, C 1-6 Alkoxy, (C 1-10 alkyl)NH-, (C 1-10 Alkyl group (2N-), hydroxyl group, halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl.

[0114] In some implementations, each R 1 The following groups are independently selected from deuterium, halogens, -OH, -NH2, -CN, and optionally substituted by one or more substituents: C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 alkyl.

[0115] In some implementations, each R 1 Independently selected from deuterium, halogens, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 alkoxy or halogenated C 1-4 alkyl.

[0116] In some implementations, each R 1 Independently selected from deuterium, halogens, -OH, -NH2, -CN, C 1-3 Alkyl, C1-3 alkoxy or halogenated C 1-3 Alkyl group. In some embodiments, each R 1 Independently selected from halogens, -OH, -NH2, -CN, or C. 1-3 Alkyl group. In some embodiments, each R 1 Independently selected from halogen or C 1-3 alkyl.

[0117] In some implementations, each R 1 Independently selected from fluorine, chlorine, bromine, -OH, -NH2, or -CN. In some embodiments, each R 1 It is independently selected from fluorine, chlorine, or bromine.

[0118] In some implementations, each R 1 It is independently selected from fluorine or methyl.

[0119] In some implementations, the R 1 One or more substituents are selected from: deuterium, halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-10 cycloalkyl, C 6-10 Aryl, 3-10 heterocyclic alkyl or 5-10 heteroaryl.

[0120] In some implementations, the R 1 In this context, one or more substituents are selected from: deuterium, halogen, -OH, -NH2, -CN, C. 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, C6 aryl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl.

[0121] In some implementations, n is selected from 0, 1, or 2.

[0122] In some specific implementations, n is selected from 0. In some implementations, structural fragments Selected from

[0123] In some implementation schemes, X 5 Selected from C(R) f ).

[0124] In some implementation schemes, R f C selected from H, fluorine, chlorine, bromine, deuterium, or optionally substituted with one or more substituents 1-3 alkyl.

[0125] In some implementation schemes, R f Selected from H, fluorine, chlorine, bromine, deuterium or C 1-3 Alkyl, the C 1-3 The alkyl group may optionally be substituted with one or more of the following groups: halogen, -OH, -NH2 or -CN.

[0126] In some implementation schemes, R f Selected from H, fluorine, chlorine, bromine, deuterium or C 1-3 Alkyl group. In some embodiments, R f Selected from H, fluorine, deuterium, or methyl. In some embodiments, R f Selected from H.

[0127] In some implementation schemes, X 5 Selected from CH or N.

[0128] In some implementation schemes, X 5 Selected from CH.

[0129] In some implementation schemes, Selected from In some implementation schemes, for

[0130] In some implementation schemes, the structural portion Selected from

[0131] In some implementation schemes, CLM, (when L) 1 Selected from (key time) Selected from Among them, ring A is selected from C. 5-7 Cycloalkenyl or 5-7 membered heterocyclic alkenyl.

[0132] In some implementation schemes, CLM, (when L) 1 Selected from (key time) Selected from

[0133] In some implementation schemes, CLM, (when L) 1 Selected from (key time) Selected from

[0134] In some implementation schemes, CLM, Selected from In some implementation schemes, CLM, Selected from In some implementations, the R 1 Each is independently selected from deuterium, hydroxyl, halogen, amino, cyano, or C. 1-8Alkyl group. In some embodiments, the R... 1 Each is independently selected from halogens. In some embodiments, n is selected from 0, 1, 2, or 3.

[0135] In some implementation schemes, CLM, Selected from In some implementation schemes, CLM, Selected from

[0136] In some implementations, the CLM is selected from

[0137] In some implementations, the L 1 Selected from the bond, -NH-, or -CONH-. In some embodiments, the L 1 Selected from key.

[0138] 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 imide or C 2-50 Alkyne group, optionally, the C 1-50 Alkylene, C 2-50 imide or C 2-50 One or more -CH2- groups in the ethynyl group are independently and optionally separated by -O-, C 3-15 Cycloalkyl, 3-15 membered heterocyclic alkyl, 4-15 membered heterocyclic alkenyl, C 6-15 Aryl, 5-15 quinone heteroaryl, -NH-, -N(C 1-6 Alkyl)- or -S- substitution.

[0139] 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 imide or C 2-30 Alkyne group, optionally, the C 1-30 Alkylene, C 2-30 imide or C 2-30 One or more -CH2- groups in the ethynyl group are independently and optionally separated by -O-, C 3-12 Cycloalkyl, 3-12-membered heterocyclic alkyl, 4-12-membered heterocyclic alkenyl, C 6-12 Aryl, 5-12 heteroaryl, -NH-, -N(C 1-6 Alkyl)- or -S- substitution.

[0140] 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 imide or C2-20 Alkyne group, optionally, the C 1-20 Alkylene, C 2-20 imide or C 2-20 One or more -CH2- groups in the ethynyl group are independently and optionally separated by -O-, C 3-10 Cycloalkyl, 3-11 membered heterocyclic alkyl, 4-10 membered heterocyclic alkenyl, C 6-10 Aryl, 5-10 heteroaryl, -NH-, -N(C 1-6 Alkyl)- or -S- substitution.

[0141] 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 imide or C 2-15 Alkyne group, optionally, the C 1-15 Alkylene, C 2-15 imide or C 2-15 One or more -CH2- groups in the ethynyl group are independently and optionally separated by -O-, C 3-9 Cycloalkyl, 3-11 membered heterocyclic alkyl, 4-8 membered heterocyclic alkenyl, C 6-8 Aryl, 5-8 quinone heteroaryl, -NH-, -N(C 1-4 Alkyl)- or -S- substitution.

[0142] 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 imide or C 2-10 Alkyne group, optionally, the C 1-10 Alkylene, C 2-10 imide or C 2-10 One or more -CH2- groups in the ethynyl group are independently and optionally separated 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- substitution.

[0143] 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 imide or C 2-6 Alkyne group, optionally, the C 1-6 Alkylene, C 2-6 imide or C 2-6 One or more -CH2- groups in the ethynyl group are independently and optionally separated by -O-, C 3-9Cycloalkyl, 3-11 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, -NH-, -N(C 1-3 Alkyl)- or -S- substitution.

[0144] 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 imide or C 2-4 Alkyne group, optionally, the C 1-4 Alkylene, C 2-4 imide or C 2-4 One or more (e.g., one or two, one or three, etc.) of the ethynyl group are independently and optionally separated by -O-, C 4-6 Cycloalkyl, 4-11 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, -NH-, -N(C 1-3 Alkyl)- or -S- substitution.

[0145] In some embodiments, the L is selected from C that is optionally substituted with one or more substituents. 1-10 Alkylene or C 2-10 Alkyne group, optionally, the C 1-10 Alkylene or C 2-10 One or more -CH2- groups in the ethynyl group are independently and optionally selected from -O-, C-. 3-12 Cycloalkyl, 4-12-membered heterocycloalkyl, 4-12-membered heterocycloalkenyl, 5-12-membered heteroaryl, -NH-, -N(C 1-6 Alkyl)- or -S- substitution.

[0146] In some embodiments, the L is selected from C that is optionally substituted with one or more substituents. 1-6 Alkylene or C 2-6 Alkyne group, optionally, the C 1-6 Alkylene or C 2-6 One or more -CH2- groups in the ethynyl group are independently and optionally selected from -O-, C-. 3-10 Cycloalkyl, 4-11 membered heterocycloalkyl, 5-6 membered heterocyclic alkenyl, 5-6 membered heteroaryl, -NH-, -N(C 1-3 Alkyl)- or -S- substitution.

[0147] In some embodiments, the L is selected from C that is optionally substituted with one or more substituents. 1-6 Alkylene or C 2-6 Alkyne group, optionally, the C 1-6 Alkylene or C 2-6 One or more -CH2- groups in the ethynyl group are independently and optionally selected from -O-, C-. 3-10Cycloalkyl, 4-11 membered heterocycloalkyl, 5-6 membered heteroaryl, -NH-, -N(C 1-3 Alkyl)- or -S- substitution.

[0148] In some embodiments, in the definition of L, the substituent is selected from deuterium, halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, (C 1-6 alkyl)NH-, (C 1-6 Alkyl)2N-, C 3-12 Cycloalkyl or 4-12 membered heterocyclic alkyl.

[0149] In some embodiments, in the definition of L, the substituent is selected from deuterium, halogen, =O, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, hydroxyl C 1-6 Alkyl, (C 1-4 alkyl)NH-, (C 1-4 Alkyl)2N-, C 3-10 Cycloalkyl or 4-10 membered heterocycloalkyl. In some embodiments, in the definition of L, the substituent is =O or HOCH2-.

[0150] In some embodiments, in the definition of L, the substituent is selected from =O, hydroxyl C. 1-3 Alkyl, -NH2, -CN, halogen, C 1- 3-alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, (C 1-3 alkyl)NH- or (C 1-3 Alkyl)2N-.

[0151] In some embodiments, in the definition of L, the substituent is selected from =O or hydroxyC. 1-3 alkyl.

[0152] In some implementations, the L is selected from -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -Cy 3 -,in,

[0153] Cy 1 Cy 2 or Cy 3Each is independently selected from a key, or optionally selected by one or more R keys. b The following groups are substituted: C 3-12 Cycloalkyl, 4-12 membered heterocyclic alkyl, C 6-12 Aryl, 5-12-membered heteroaryl, or 4-12-membered heterocyclic alkenyl;

[0154] LNK, LNK 1 and LNK 2 Each is independently selected from the bond, -NH-, -O-, -S-, or optionally by one or more R- bonds. c The following groups are substituted: C 1-12 Alkylene, C 2-12 imidene group, C 2-12 alkyne or C 1-12 Heteroalkylene;

[0155] Each R b and R c Each is independently selected from deuterium, halogens, =O, -OH, -NH2, -CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, (C 1-6 alkyl)NH-, (C 1-6 Alkyl)2N-, C 3-12 Cycloalkyl or 4-12 membered heterocyclic alkyl.

[0156] In some implementations, Cy 1 Cy 2 and Cy 3 They are not both keys. In some implementations, Cy 1 Cy 2 and Cy 3 As a key. In some implementations, Cy 2 and Cy 3 As a key. In some implementations, LNK 1 and LNK 2 Selected from key.

[0157] In some implementations, 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 -、-Cy1 -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 - In some implementations, the L is selected from -Cy 1 -、-Cy 2 -、-LNK 1 -、-Cy 1 -LNK-、-LNK 1 -Cy 1 -LNK- or -LNK-Cy 2 -LNK 2 -

[0158] In some implementations, the L is selected from -Cy 1 -、-Cy 2 -、-LNK 1 -、-Cy 1 -LNK-、-LNK 1 -Cy 1 -LNK-、-LNK-Cy 2 -LNK 2 -、or-Cy 1 -LNK-Cy 2 -

[0159] In some implementations, the L is selected from -LNK 1 - In some implementations, the L is selected from -Cy 1 -LNK-. In some implementations, the L is selected from -LNK-Cy. 2 -LNK 2 - In some implementations, the L is selected from -Cy1 -LNK-Cy 2 -

[0160] In some implementation schemes, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, -NH-, -O-, -S-, or optionally by one or more R- bonds. c The following groups are substituted: C 1-10 Alkylene, C 2-10 imidene group, C 2-10 alkyne or C 1-10 Heteroalkylene.

[0161] In some implementation schemes, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, -NH-, -O-, -S-, or optionally by one or more R- bonds. c The following groups are substituted: C 1-6 Alkylene, C 2-6 imidene group, C 2-6 alkyne or C 1-6 Heteroalkylene.

[0162] In some implementation schemes, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, -NH-, -O-, -S-, or optionally by one or more R- bonds. c The following groups are substituted: C 1-4 Alkylene, C 2-4 imidene group, C 2-4 alkyne or C 1-4 Heteroalkylene.

[0163] In some implementation schemes, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, -NH-, -O-, -S-, or optionally by one or more R- bonds. c The following groups are substituted: C 1-6 Alkylene, C 2-6 alkyne or C 1-6 Heteroalkylene.

[0164] In some implementation schemes, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, -NH-, -O-, -S-, or optionally by one or more R- bonds. c The following groups are substituted: C 1-4 Alkylene, C 2-4 alkyne or C 1-4 Heteroalkylene.

[0165] In some implementation schemes, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, -NH-, -O-, or optionally by one or more R c The following groups are substituted: C 1-3 Alkylene, C 2-3 alkyne or C 1-3 Heteroalkylene.

[0166] In some implementation schemes, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, -NH-, -O-, or optionally by one or more R c The following groups are substituted: C 1-2 alkylene, C2-alkynyl or C 1-2 Heteroalkylene.

[0167] In some implementation schemes, LNK, LNK 1 and LNK 2 Each group is independently selected from the following groups: bond, -NH-, -O-, -NHCH2-, -CH2NHCH2-, -CH2-, -CH2CH2-, ethynyl group, -C(O)-, or -C(O)CH2-.

[0168] In some implementation schemes, LNK, LNK 1 and LNK 2 Each is independently selected from the key, or selected from those optionally controlled by one or more R. c The following groups are substituted: C 1-6 Alkylene or C 1-6 Heteroalkylene.

[0169] In some implementation schemes, LNK, LNK 1 and LNK 2 Each is independently selected from the key, or selected from those optionally controlled by one or more R. c Replacement C 1-3 Alkylene.

[0170] In some specific implementation plans, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, or selected from -CH2-, -C(O)- or -C(O)CH2-.

[0171] In some implementations, Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. bThe following groups are substituted: C 3-11 Cycloalkyl, 4-12-membered heterocycloalkyl, 4-11-membered heterocycloalkenyl or 5-11-membered heteroaryl.

[0172] In some implementations, Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. b The following groups are substituted: C 4-10 Cycloalkyl, 4-11 membered heterocycloalkyl, 5-6 membered heterocyclic alkenyl or 5-6 membered heteroaryl.

[0173] In some implementations, Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. b The following groups are substituted: C 4-9 Cycloalkyl, 4-11 membered heterocycloalkyl, 5-6 membered heterocyclic alkenyl or 5-6 membered heteroaryl.

[0174] In some implementations, Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. b The following groups are substituted: C 4-6 Cycloalkyl, C9 cycloalkyl, 4-11 member heterocycloalkyl, 6 member heterocyclic alkenyl or 6 member heteroaryl.

[0175] In some specific implementation schemes, Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. b The following groups are substituted: C 4-6 (e.g., C4, C5, or C6) cycloalkyl, 4-9 quinary (e.g., 4, 5, 6, 7, 8, or 9) heterocycloalkyl, or 5-6 heteroaryl. In some embodiments, Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. bThe following groups may be substituted: cyclobutyl, cyclopentyl, cyclohexyl, spironyl, azircyclobutyl, pyrrolyl, piperidinyl, tetrahydropyridyl, piperazine, azirspiroheptyl, azirspiroctyl, azirspironyl, diazirspironyl, azirspirodealkyl, diazirspirodealkyl, azirspiroundecyl, diazirspiroundecyl, azirbicyclohexane, octahydrocyclopentylpyrrole, diazirbicyclooctyl, azirbicyclononyl, azirbicycloheptyl, or pyrazine.

[0176] In some specific implementation schemes, Cy 1 Cy 2 or Cy 3 Each is independently selected from the key, or selected from those optionally controlled by one or more R. b The following groups may be substituted: cyclobutyl, cyclohexyl, azircyclobutyl, piperidinyl, azircycloheptyl, azirspirononyl, or pyrazinyl.

[0177] In some implementations, Cy 1 Cy 2 or Cy 3 Selected independently from keys, Optionally, the Cy 1 Cy 2 or Cy 3 (When present) Optionally controlled by one or more R b replace.

[0178] In some implementations, Cy 1 Cy 2 or Cy 3 Selected independently from keys, Optionally, the Cy 1 Cy 2 or Cy 3 (When present) Optionally controlled by one or more R b replace.

[0179] In some implementations, Cy 1 Cy 2 or Cy 3 Selected independently from keys, Optionally, the Cy 1 Cy 2 or Cy 3 (When present) Optionally controlled by one or more R b replace.

[0180] In some implementations, Cy 1 Cy 2 or Cy 3 Selected independently from keys, Optionally, the Cy 1 Cy 2 or Cy 3 (When present) Optionally controlled by one or more R b replace.

[0181] In some implementations, Cy 1 Cy 2 or Cy 3 Each is independently selected from the key, or selected from those optionally controlled by one or more R. b The following groups are substituted: In some implementations, Cy 1 Cy 2 or Cy 3 Each independently selected from one or more R b The following groups are substituted:

[0182] In some implementations, each R b and R c Each is independently selected from deuterium, halogens, =O, -OH, -NH2, -CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, (C 1-6 alkyl)NH-, (C 1-6 Alkyl)2N-, C 3-10 Cycloalkyl or 4-10 membered heterocyclic alkyl.

[0183] In some implementations, each R b and R c Each is independently selected from deuterium, halogens, =O, -OH, -NH2, -CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, (C 1-6 alkyl)NH- or (C 1-6 Alkyl)2N-.

[0184] In some implementations, each R b and R c Each is independently selected from deuterium, halogens, =O, -OH, -NH2, -CN, and C. 1-4 Alkyl, C1-4 Alkoxy, halogenated C 1-4 Alkyl, hydroxyl C 1-6 Alkyl, (C 1-4 alkyl)NH-, or (C 1-4 Alkyl)2N-.

[0185] In some implementations, each R b and R c Each is independently selected from C-terminals that are =O or hydroxyl-substituted. 1-3 alkyl.

[0186] In some implementations, each R b and R c Each is independently selected from =O or HOCH2-.

[0187] In some implementations, L or -LNK 1 - Selected from -O-, -NHCH2-, -CH2NHCH2-, -CH2-, -CH2CH2-, ethynyl group, -C(O)- or -C(O)CH2-.

[0188] In some implementations, L or -LNK 1 - Selected from -CH2- or -C(O)CH2-. In some embodiments, the L or -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -Cy 3 - Selected from -NHCH2-, -CH2NHCH2-, -CH2-, -C(O)CH2-,

[0189] In some implementations, the L is selected from -CH2-, -C(O)CH2-,

[0190] In some implementations, L is selected from -CH2-, -C(O)CH2-*, *-C(O)CH2-, In this context, "*" indicates that L is connected to one end of the CLM, such as the ring W part.

[0191] In some implementations, the R 2 Each is independently selected from deuterium, halogen, -OH, -NH2, -CN, -COOH, -CONH2, or optionally influenced by one or more R. 2a’The following groups are substituted: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl C(O)-, C 1-6 Alkyl C(O)O-, C 1-6 Alkyl OC(O)-, C 1-6 Alkyl C(O)NH-, C 1-6 Alkyl NHC(O)-, C 1- 6alkylS(O)NH-,C 1-6 Alkyl NHS(O)-, C 1-6 Alkyl S(O)2NH-, C 1-6 Alkyl NHS(O)2-, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl, 3-8 membered heterocyclic alkenyl, C 6-10 Aryl or 5-8 heteroaryl compounds.

[0192] In some implementations, the R 2 Each is independently selected from deuterium, halogen, -OH, -NH2, -CN, or optionally influenced by one or more R. 2a’ The following groups are substituted: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl.

[0193] In some implementations, the R 2a’ Each is independently selected from deuterium, halogens, -OH, -NH2, -CN, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-8 Cycloalkyl or 3-8 membered heterocyclic alkyl.

[0194] In some implementations, the R 2a’ Each is independently selected from deuterium, halogens, -OH, -NH2, -CN, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1- 3alkylNH- or (C 1-3Alkyl)2N-.

[0195] In some implementations, the R 2a’ Each is independently selected from halogens (e.g., F or Cl) or C. 1-3 Alkyl group.

[0196] In some implementations, the R 2 Selected independently from C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with one or more of the following groups: deuterium, halogen (e.g., -F or -Cl) or C. 1-3 Alkyl groups (e.g., methoxy, ethoxy) are substituted.

[0197] In some implementations, the R 2 Each can be independently selected from -CH3, -CH2F, -CHF2, -CF3, -CH2CH3 or -CH2OCH3.

[0198] In some implementations, m is selected from 0, 1, or 2.

[0199] In some implementations, L 2 Selected from key, or selected from C 1-3 Alkylene or C 2-3 Idenoyl, the C 1-3 Alkylene or C 2-3 One or two methylene groups of the alkenyl group are optionally and independently replaced by -O-, -C(O)-, -C(S)-, -NH-, -S-, or -S(O)2-, wherein the C 1-3 Alkylene or C 2-3 The alkenyl group is optionally surrounded by one or more R L replace.

[0200] In some implementation schemes, R L Selected from deuterium, halogens, -CN, -OH, -NH2, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, C6 aryl or 5-6 membered heteroaryl.

[0201] In some implementations, L 2 Selected from bonds, -CH2-, -O-, -C(O)-, or -NH-. In some embodiments, L 2 It is a key.

[0202] In some implementation schemes, R 3 Selected from one or more R 3a The following groups are substituted: C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl, 3-8 membered heterocyclic alkenyl, C 6-10Aryl or 5-10 heteroaryl compounds.

[0203] In some implementation schemes, R 3 Selected from one or more R 3a The following groups are substituted: phenyl or 5-6 membered heteroaryl. In some embodiments, R 3 Selected from one or more R 3a Substituted phenyl groups.

[0204] In some implementation schemes, R 3a Selected independently from deuterium, halogens, -CN, and C respectively. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 3-8 Cycloalkenyl, 3-8 membered heterocyclic alkenyl, C 6-10 Aryl, 5-8 quinone heteroaryl, 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-.

[0205] In some implementation schemes, R s and R v Selected independently from H and C respectively 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-3 Alkylene-, 3-8 membered heterocyclic alkyl, 3-8 membered heterocyclic alkyl C 1-3 Alkylene-, C 3-8 Cycloalkenyl, C 3-8 Cycloalkenyl C 1-3 alkylene-, 3-8 membered heterocyclic alkenyl, 3-8 membered heterocyclic alkenyl C 1-3 Alkylene-, C 6-10 Aryl, C 6-10 Aryl C 1-3 alkylene-, 5-8 heteroaryl, or 5-8 heteroaryl C 1-3 Alkylene-.

[0206] In some implementation schemes, R s and R v Each independently selected from H or C 1-4 alkyl.

[0207] In some implementation schemes, R 3a Each is independently selected from deuterium, halogens, -OH, -CN, -NH2, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkenyl or 3-6 membered heterocyclic alkenyl.

[0208] In some implementation schemes, R 3a Each is independently selected from deuterium, halogens, -OH, -CN, -NH2, and C. 1-3 Alkyl or halogenated C 1-3 alkyl,.

[0209] In some implementation schemes, R 3a Each can be independently selected from -F, -Cl, -OH, or -CH3.

[0210] In some embodiments, ring G is selected from 5-10-membered heteroaryl groups. In some embodiments, ring G is selected from 5-6-membered heteroaryl groups. In some embodiments, ring G is selected from 6-membered heteroaryl groups. In some embodiments, ring G is selected from 6-membered heteroaryl groups containing one or two nitrogen atoms. In some embodiments, ring G is selected from pyridazinyl groups.

[0211] In some implementations, ring E is selected from C. 3-7 Cycloalkyl, 3-7 heterocyclic alkyl, 3-7 heterocyclic alkenyl, C6 aryl or 5-7 heteroaryl.

[0212] In some embodiments, ring E is selected from 5-6-membered heterocyclic alkyl or 5-6-heterocyclic alkenyl. In some embodiments, ring E is selected from 5-6-heterocyclic alkenyl. In some embodiments, ring E is selected from dihydropyrrole or tetrahydropyrazinyl. In some embodiments, ring E is selected from 2,3-dihydropyrrole or 1,2,3,4-tetrahydropyrazinyl.

[0213] In some implementations, ring F is selected from non-existent, C 3-7 Cycloalkyl, 3-7 membered heterocyclic alkyl, 3-7 membered heterocyclic alkenyl, C6 aryl, or 5-6 membered heteroaryl. In some embodiments, ring F is selected from absent or 5-6 membered heterocyclic alkyl. In some embodiments, ring F is selected from absent or pyrrolidinyl.

[0214] In some implementations, ring F is selected from C. 3-7 Cycloalkyl, 3-7-membered heterocyclic alkyl, 3-7-membered heterocyclic alkenyl, C6 aryl, or 5-6-membered heteroaryl. In some embodiments, ring F is selected from 5-6-membered heterocyclic alkyl. In some embodiments, ring F is selected from pyrrolidinyl.

[0215] In some implementations, ring H is selected from C 3-7 Cycloalkyl, 3-7-membered heterocycloalkyl, 3-7-membered heterocycloalkenyl, C6 aryl, or 5-7-membered heteroaryl. In some embodiments, the ring H is selected from C6. 4-6 Cycloalkyl or 4-6 membered heterocyclic alkyl. In some embodiments, the ring H is selected from 4-6 membered heterocyclic alkyl. In some embodiments, the ring H is selected from aziridine or piperidinyl.

[0216] In some embodiments, ring F is pyrroloalkyl and ring H is azacyclobutane or piperidinyl.

[0217] In some embodiments, ring F is selected from those that are not present, and ring H is piperidinyl.

[0218] In some implementations, ring H is connected to ring L.

[0219] In some implementations, ring G and ring E are connected in parallel ring configuration.

[0220] In some implementations, ring E and ring F are connected in a parallel ring configuration.

[0221] In some implementations, ring F and ring H are connected by a screw ring. In some implementations, when ring F is absent, ring E and ring H are connected by a screw ring.

[0222] In some implementations, ring F is absent, and rings G, E, and H are connected in parallel ring configuration.

[0223] In some implementations, ring F is absent, and ring G is connected to ring E via a parallel loop, while ring E is connected to ring H via a helical loop.

[0224] In some implementations, ring G and ring E are connected in a parallel loop configuration, and ring E and ring F are connected in a parallel loop configuration, while ring F and ring H are connected in a spiral loop configuration.

[0225] In some implementation schemes, R 2 The substitution site is ring G, ring E, ring F, or ring H. In some embodiments, R 2 The substitution site is either ring E or ring F. In some embodiments, R 2 The substitution sites are on the fused carbon atoms of ring E and ring F.

[0226] In some implementation schemes, the structural portion Selected from In some implementation schemes, the structural portion Selected from In some implementation schemes, the structural portion Selected from

[0227] In some implementation schemes, the structural portion Or PTM selected

[0228] In some implementation schemes, the structural portion Or PTM selected In some implementation schemes Or PTM selected

[0229] In some implementation schemes, the structural portion Or PTM selected

[0230] In some implementation schemes, the structural portion Or PTM selected In some implementation schemes, the structural portion Or PTM selected In some implementation schemes, the structural portion Or PTM selected

[0231] In some implementation schemes, the structural portion Or PTM selected Where k is selected from 0, 1, 2, 3, 4 or 5; or k is selected from 1, 2 or 3.

[0232] In some implementation schemes, the structural portion Or PTM selected

[0233] In some implementation schemes, the structural portion Or PTM selected

[0234] In some implementation schemes, the structural portion Or PTM selected

[0235] In some implementation schemes, the structural portion PTM is selected from

[0236] In some embodiments, the compounds of formula I, II, III, their stereoisomers, or pharmaceutically acceptable salts thereof are selected from formulas III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, or III-10, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0237] Among them, R 3 R 3a L 2 Ring G, Ring E, Ring F, Ring H, R 2 m, ring W, R 1 , n, X 5 L, L 1 The definitions of ring A, ring B, and ring C are as described in this application;

[0238] X 7 Selected from CH or N; k is selected from 0, 1, 2, 3, 4 or 5.

[0239] Other structural parts, such as As described in this application.

[0240] In some embodiments, the heterocyclic alkenyl, heteroaryl, heterocyclic, heterocyclic alkyl, or heteroalkylene group comprises one or more heteroatoms or heteroatom groups 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 heterocyclic alkenyl, heteroaryl, heterocyclic, heterocyclic alkyl, or heteroalkylene group comprises one or more heteroatoms or heteroatom groups independently selected from -O-, -NH-, -N-, or -S-; in some embodiments, the heterocyclic alkenyl, heteroaryl, heterocyclic, heterocyclic alkyl, or heteroalkylene group comprises one or more heteroatoms or heteroatom groups independently selected from -O-, -NH-, or -N-. In some embodiments, the number of heteroatoms or heterogroups is independently selected from 1, 2, 3, 4, 5 or 6; or from 1, 2, 3 or 4; or from 1, 2 or 3; or from 1 or 2.

[0241] In some embodiments, the heteroatom in the heterocyclic alkenyl group is selected from N, O, or S. In some specific embodiments, the heteroatom in the heterocyclic alkenyl group is selected from N or O. In some embodiments, the number of heteroatoms in the heterocyclic alkenyl group is selected from 1, 2, 3, 4, 5, or 6. In some embodiments, the number of heteroatoms in the heterocyclic alkenyl group is selected from 1, 2, 3, or 4. In some embodiments, the number of heteroatoms in the heterocyclic alkenyl group is selected from 1, 2, or 3. In some specific embodiments, the number of heteroatoms in the heterocyclic alkenyl group is selected from 1 or 2.

[0242] In some embodiments, the halogenation is selected from fluorinated, chlorinated, or brominated compounds. In some embodiments, the halogenation is selected from fluorinated or chlorinated compounds. In some embodiments, the halogenation is selected from fluorinated compounds.

[0243] In some implementations, 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 implementations, C 1- 6 is selected from C 1-4 C 1-3 or C 1-2 In some implementations, the C 1-4 Selected from C4, C3, C2, or C1. In some embodiments, C... 1-3 Choose from C3, C2, or C1.

[0244] In some implementations, the C 2-10 Selected from C 2-8C 2-6 C 2-5 C 2-4 C 2-3 In some implementations, the C 2-6 Selected from C 2- 4 or C 2-3 In some implementations, the C 2-4 Choose from C4, C3, or C2.

[0245] In some implementations, the C 3-6 Selected from C 3-5 C 3-4 C 4-6 C 4-5 or C 5-6 In some implementations, the C 6-10 Selected from C 6-9 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 implementations, 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 implementations, the C 3-15 Selected from C 3-12 Or C 3-10 In some implementations, the C3-12 Selected from C 3-10 In some implementations, the C 6-12 Selected from C 6-10 .

[0246] In some implementations, 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 implementations, 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, or 9-10 yuan. In some implementations, 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, and 9-10 yuan. In some implementations, the 3-15 yuan is selected from 3-12 yuan or 3-10 yuan. In some implementations, the 3-12 yuan is selected from 3-10 yuan. In some implementations, the 5-12 yuan is selected from 5-10 yuan.

[0247] It should be understood that any embodiment of the compounds of this application as described above and any specific ring A, ring B, ring C, R in the compounds of this application as described above are not necessarily related to this application. 1 X 5 L, L 1 L 2 X 6 R 2 R 3 R 4 Any specific substituent described in the embodiments and / or claims concerning rings G, E, F, H, and W can be independently combined with substituents of other embodiments and / or compounds of this application to form embodiments of the invention not specifically described above. Furthermore, any specific ring A, B, C, R... 1 X 5 L, L 1 L 2 X 6 R 2 R 3 R 4 In cases where the range of substituents for rings G, E, F, H, and W is disclosed, it should be understood that one or more substituents may be deleted from that range, and the remaining range of substituents should also be considered as an embodiment of this application.

[0248] In some implementations, PTM is selected from Among them, R 3 L 2 Rings G, E, F, H, m, and R 2 The definition is as described in this application. In some embodiments, the structural portion As defined in this application. In some embodiments of this application, unless otherwise stated, when m is not 0, the R 2 The substitution sites are independently located on one or more of the rings G, E, F, or H.

[0249] In some embodiments, the VHL E3 ubiquitin ligase binding moiety is selected from:

[0250] In some embodiments, the IAP E3 ubiquitin ligase binding moiety is selected from:

[0251] In some embodiments, the MDM2 E3 ubiquitin ligase binding moiety is selected from:

[0252] In some implementations, the CLM is selected from in R 1 , n, L 1 and X 5 The definition is as described in this application; ring W is selected from 5-20 element rings.

[0253] In some implementations, CLM or Selected from in Ring A, Ring B, Ring C, R 1 , n, L 1 and X 5 The definition is as stated in this application.

[0254] In some implementations, the CLM is selected from the following structural fragments:

[0255] Where j and j1 are independently selected from 0, 1 or 2 respectively;

[0256] R 7 Each is independently selected from hydrogen or C. 1-6 alkyl;

[0257] X 11 Selected from bonds, O, S, CH2, or NH;

[0258] The ring W is selected from 5-20 membered rings (e.g., aryl, heteroaryl, cycloalkyl, heterocyclic alkenyl, or heterocyclic alkyl);

[0259] R 1 , n, L 1 The definition is as stated in this application.

[0260] In some implementations, the R 7 Each is independently selected from hydrogen or C. 1-3 Alkyl group. In some embodiments, the R... 7 Each is independently selected from hydrogen.

[0261] In some embodiments, the heteroatoms in the heteroaryl, heterocyclic alkenyl, and heterocyclic alkyl groups are selected from nitrogen, oxygen, or sulfur, and the number of heteroatoms is optionally 1, 2, 3, 4, 5, or 6.

[0262] In some embodiments, the ring W is selected from 5-15 membered rings; in some embodiments, the ring W is selected from 5-12 membered rings; in some embodiments, the ring W is selected from 5-10 membered rings; in some embodiments, the ring W is selected from 5-7 membered rings; in some embodiments, the ring W is selected from 5-15 membered heterocyclic alkenyl groups, C 6-15 Aryl, 5-15 quinone heteroaryl, C 5-15 Cycloalkyl or 5-15-membered heterocycloalkyl; in some embodiments, the ring W is selected from 5-12-membered heterocycloalkenyl, C 6-12 Aryl, 5-12 heteroaryl, C 5-12 Cycloalkyl or 5-12-membered heterocycloalkyl; in some embodiments, the ring W is selected from 5-10-membered heterocycloalkenyl, C 6-10 Aryl, 5-10 heteroaryl, C 5-10 Cycloalkyl or 5-10-membered heterocycloalkyl; in some embodiments, the ring W is selected from 5-7-membered heterocycloalkenyl, C 6-10 Aryl, 5-7 quinone heteroaryl, C 5-7 Cycloalkyl or 5-7 membered heterocyclic alkyl. In some embodiments, the ring W is selected from C. 6-10 Aryl, 5-6 membered heteroaryl, or 5-14 membered heterocyclic alkenyl. In some embodiments, the ring W is selected from C. 6-10 Aryl, or 5-14 membered heterocyclic alkenyl. In some embodiments, ring W is selected from phenyl, or 9-14 membered heterocyclic alkenyl. In some specific embodiments, ring W is selected from phenyl, or 9-, or 12-14 membered heterocyclic alkenyl.

[0263] In some embodiments, the aforementioned 5-20 membered rings, 5-15 membered rings, 5-14 membered rings, 12-14 membered rings, 5-12 membered rings, 5-10 membered rings, 5-7 membered rings, 9 membered rings, 12 membered rings, 13 membered rings, or 14 membered rings are optionally fully saturated, partially unsaturated heterocyclic or aromatic rings, and optionally are carbon rings or heterocyclic rings existing in the form of monocyclic, bridged, fused, and / or spirocyclic forms.

[0264] In some implementations, the CLM is selected from the following structural fragments:

[0265] Among them, each R a Each is independently selected from deuterium, hydroxyl, halogen, amino, cyano, or C. 1-8 alkyl;

[0266] q is selected from 0, 1, 2, or 3;

[0267] X 4 Selected from N or CH which may be optionally substituted.

[0268] In some implementations, the CLM is selected from

[0269] In some implementations, R a Each is independently selected from deuterium, hydroxyl, halogen, amino, cyano, or C. 1-6 alkyl.

[0270] In some implementations, R a Each is independently selected from deuterium, hydroxyl, halogen, amino, cyano, or C. 1-4 alkyl.

[0271] In some implementations, R a Each is independently selected from deuterium, hydroxyl, halogen, amino, cyano, or C. 1-3 alkyl.

[0272] In some implementations, R a Each group is independently selected from deuterium, hydroxyl, halogen, amino, or cyano groups.

[0273] In some implementations, R a Each is independently selected from deuterium, halogen, or amino groups.

[0274] In some implementations, q is selected from 0, 1, or 2.

[0275] In some implementation schemes, X 4 Selected from N or CH, wherein CH is optionally substituted with the following substituents: deuterium, hydroxyl, halogen, amino, cyano, or C.1-4 alkyl.

[0276] In some implementation schemes, X 4 Selected from N. In some implementations, X 4 Selected from CH.

[0277] In some implementations, the CLM is selected from the following structural fragments:

[0278] This application relates to compounds of formula XI, structural moieties thereof, derivatives thereof (e.g., protac), stereoisomers thereof, or pharmaceutically acceptable salts thereof:

[0279] Among them, R 3 L 2 m and R 2 The definition is as described in this application;

[0280] X 2 and X 3 Each is independently selected from CH or N;

[0281] Ring J is selected from C 3-15 Cycloalkyl, 3-15 membered heterocyclic alkyl or 3-15 membered heterocyclic alkenyl;

[0282] R 2a Selected from hydrogen, deuterium, halogens, -NH2, -OH, -CN, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl OC(O)-, C 1-6 Alkyl OC(O)C 1-6 Alkyl-, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocyclic alkenyl, C 6- 10 Aryl, 5-10 heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl OC(O)-, C 1-6 Alkyl OC(O)C 1-6 Alkyl-, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocyclic alkenyl, C 6-10Aryl and 5-10 heteroaryl groups may optionally be substituted with the following groups: deuterium, halogen, -NH2, -OH, -CN, =O, -C(O)OH, -C(O)H, C 1-6 Alkyl OC(O)-, C 1-6 Alkoxy C 1-6 Alkyl- or di(C) 1-6 Alkoxy)C 1-6 alkyl.

[0283] In some implementation schemes, R 2 The replacement position is X 3 .

[0284] In some embodiments, the ring J is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, or 3-15 membered heterocyclic alkenyl. In some embodiments, the ring J is selected from C. 3-9 Cycloalkyl, 3-9 membered heterocyclic alkyl, or 3-9 membered heterocyclic alkenyl. In some embodiments, the ring J is selected from C. 4-7 Cycloalkyl or 4-7 membered heterocyclic alkyl. In some embodiments, the ring J is selected from C. 4-6 Cycloalkyl or 4-6 membered heterocyclic alkyl. In some embodiments, ring J is selected from 4-6 membered heterocyclic alkyl. In some embodiments, ring J is selected from aza-butyl or piperidinyl. In some embodiments, ring J is selected from... In some implementations, the ring J is selected from...

[0285] In some implementation schemes, R 2a The replacement position is ring J.

[0286] In some implementation schemes, R 2a Selected from hydrogen, deuterium, halogens, -NH2, -OH, -CN, =O, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl OC(O)-, C 1-4 Alkyl OC(O)C 1-4 Alkyl-, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocyclic alkenyl, C6 aryl, 5-6 membered heteroaryl, wherein C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl OC(O)-, C 1-4 Alkyl OC(O)C1-4 Alkyl-, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocyclic alkenyl, C6 aryl, and 5-6 membered heteroaryl groups may optionally be substituted with the following groups: deuterium, halogen, -NH2, -OH, -CN, =O, -C(O)OH, -C(O)H, C 1-6 Alkyl OC(O)-, C 1- 6-alkoxy C 1-6 Alkyl- or di(C) 1-6 Alkoxy)C 1-6 alkyl-.

[0287] In some implementation schemes, R 2a Selected from hydrogen, deuterium, and C 1-3 Alkyl, C 3-4 Alkyl OC(O)-, C 3-4 Alkyl OC(O)C 1-3 Alkyl-, C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl or 6 membered heteroaryl, wherein C 1-3 Alkyl, C 3-4 Alkyl OC(O)-, C 3-4 Alkyl OC(O)C 1-3 Alkyl-, C 4-6 Cycloalkyl, 4-6-membered heterocycloalkyl, or 6-membered heteroaryl groups may optionally be substituted with the following groups: -C(O)OH, -C(O)H,

[0288] In some implementation schemes, R 2a Selected from hydrogen, -CH2C(O)OH、

[0289] In some embodiments, the compound of formula XI, the structural moiety, its derivatives (e.g., protac), its stereoisomers, or pharmaceutically acceptable salts thereof are selected from compounds of formula XI-1, XI-2, XI-3, XI-4, XI-5, XI-6, XI-7, XI-8, XI-9, XI-10, or XI-11, the structural moiety, its derivatives (e.g., protac), its stereoisomers, or pharmaceutically acceptable salts thereof.

[0290] Where k is selected from 0, 1, 2, 3, 4 or 5; or k is selected from 1, 2 or 3;

[0291] R 3 R 3a R 2a m and R 2The definition is as stated in this application.

[0292] This application provides the following compounds, structural moieties, derivatives thereof (e.g., protac), or pharmaceutically acceptable salts thereof:

[0293] In some embodiments, the PTM described in this application may be selected from compounds of formula XI, structural moieties, derivatives thereof (e.g., protac), or groups formed from pharmaceutically acceptable salts thereof.

[0294] In some embodiments, the PTM described in this application may be selected from the following compounds, structural moieties, derivatives thereof (e.g., protac), or pharmaceutically acceptable salts thereof:

[0295] This application relates to compounds of formula XII, structural moieties thereof, derivatives thereof (e.g., protac), stereoisomers thereof, or pharmaceutically acceptable salts thereof:

[0296] in,

[0297] X 5 and L 1 The definition is as described in this application;

[0298] Ring B is selected from phenyl or 5-6-membered heteroaryl groups;

[0299] X 18 Selected from CH or N;

[0300] X 23 X 24 X 25 and X 26 Each is independently selected from CH2 or X 23 X 24 X 25 and X 26 One of them is selected from the bond, and the others are selected from CH2;

[0301] Each R 1b The following groups, each independently selected from deuterium, halogen, -OH, oxo, -NH2, -CN, -CHO, and optionally substituted by one or more substituents: C 1-10 Alkyl, C 1-10 Alkoxy, (C 1-10alkyl)NH-, (C 1-10 Alkyl)2N-, Halogenated C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl or C 1-10 Alkyl OC(O)-;

[0302] n is selected from 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0303] In some embodiments, ring B is selected from phenyl or 6-membered heteroaryl. In some embodiments, ring B is selected from phenyl.

[0304] In some implementation schemes, X 18 Selected from N.

[0305] In some implementation schemes, the structural portion Selected from

[0306] In some implementation schemes, X 23 X 24 X 25 and X 26 Each is independently selected from CH2. In some implementations, X 23 X 24 X 25 and X 26 One of them is selected from the bond, and the others are selected from CH2.

[0307] In some implementations, each R 1b The following groups, independently selected from deuterium, halogen, -OH, oxo, -NH2, -CN, -CHO, and optionally substituted by one or more substituents: C 1-6 Alkyl, C 1-6 Alkoxy, (C 1-6 alkyl)NH-, (C 1-6 Alkyl)2N-, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl or C 1-6 Alkyl OC(O)-.

[0308] In some implementations, each R 1b Independently selected from deuterium, halogen, -OH, oxo, -NH2, -CN, -CHO, C 1-6 Alkyl, C 3-6 cycloalkyl (such as C) 4-6), 4-6 membered heterocyclic alkyl (e.g., 5-6 membered) or C 1-6 Alkyl OC(O)-, the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl or C 1-6 Alkyl OC(O)- is optionally substituted with one or more of the following groups: halogen, -OH, -NH2, -CN, -CHO, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkylamino, diC 1-4 Alkylamino, or -COOH.

[0309] In some implementations, each R 1b Independently selected from C atoms optionally substituted with one or more deuterium, halogen, -OH, -NH2, or -CN. 1-4 alkyl.

[0310] In some implementations, each R 1b Selected from oxo, -CHO, or HOCH2-.

[0311] In some implementations, n is selected from 0 or 1.

[0312] This application relates to the following compounds, structural moieties, stereoisomers thereof, derivatives thereof (such as PROTAC), or pharmaceutically acceptable salts thereof:

[0313] In some embodiments, the CLM described in this application may be selected from compounds of formula XII, structural moieties, derivatives thereof (e.g., protac), or groups formed from pharmaceutically acceptable salts thereof.

[0314] In some embodiments, the CLM described in this application may be selected from the following compounds, structural moieties, derivatives thereof (e.g., protac), or groups formed from pharmaceutically acceptable salts thereof:

[0315] On the other hand, this application relates to the use of the aforementioned compounds (e.g., formulas I, II, III, III-1 to III-10, XI, XI-1 to XI-11, XII, or specific compounds), structural moieties, isomers (e.g., stereoisomers), and derivatives in PROTAC molecules. Furthermore, this application relates to the use of the aforementioned compounds (e.g., formulas I, II, III, III-1 to III-10, XI, XI-1 to XI-11, XII, or specific compounds), structural moieties, isomers (e.g., stereoisomers), and derivatives in constituting a part of a PROTAC molecule. Finally, this application relates to the existence of the aforementioned compounds (e.g., formulas I, II, III, III-1 to III-10, XI, XI-1 to XI-11, XII, or specific compounds), structural moieties, isomers (e.g., stereoisomers), and derivatives in the form of PROTAC molecules. On the other hand, this application relates to the use of the aforementioned compounds (e.g., formulas I, II, III, III-1 to III-10, XI, XI-1 to XI-11, XII, or specific compounds), structural portions, isomers (e.g., stereoisomers), and derivatives thereof for the degradation of proteins, for example, the use of the aforementioned compounds (e.g., formulas I, II, III, III-1 to III-10, XI, XI-1 to XI-11, XII, or specific compounds), structural portions, isomers (e.g., stereoisomers), and derivatives thereof for the degradation of the proteins in the form of PROTAC molecules. On the other hand, this application relates to the use of the aforementioned compounds (e.g., formulas I, II, III, III-1 to III-10, XI, XI-1 to XI-11, XII, or specific compounds), structural portions, isomers (e.g., stereoisomers), and derivatives thereof for the degradation of proteins in the form of PROTAC molecules. This application relates to the use of the aforementioned compounds (e.g., formulas I, II, III, III-1 to III-10, XI, XI-1 to XI-11, XII, or specific compounds), structural moieties, isomers (e.g., stereoisomers), and derivatives (e.g., as preparation intermediates) in the preparation of PROTAC molecules. This application also relates to the use of the aforementioned compounds (e.g., formulas I, II, III, III-1 to III-10, XI, XI-1 to XI-11, XII, or specific compounds), structural moieties, isomers (e.g., stereoisomers), and derivatives (e.g., as preparation intermediates) in the preparation of protein degrading agents.

[0316] A PROTAC molecule comprising the compound, structural moiety, derivative thereof, stereoisomer thereof, or pharmaceutically acceptable salt thereof described in this application.

[0317] "Derivative" refers to a new compound or group of new compounds resulting from the substitution or replacement of one or more hydrogen atoms in the basic structure of a parent compound with other groups or structural parts. In this application, derivative refers to a derived compound that retains the parent compound's structure. For example, a parent compound is derived into a PROTAC molecule, specifically a PTM-L-CLM molecule (i.e., the compound of formula I described in this application, its stereoisomer, or its pharmaceutically acceptable salt), where PTM is the protein target portion that binds to the target protein or target polypeptide (as described in this application, the portion that binds to the target protein); L is a linker group; and CLM refers to the E3 ubiquitin ligase-binding portion.

[0318] Among them, "PROTAC (proteolysis targeting chimera) molecules" are a class of bifunctional compounds capable of simultaneously binding to both the target protein and the E3 ubiquitin ligase. These compounds can induce the target protein to be recognized by the cell's proteasome, causing degradation of the protein and effectively reducing the content of the target protein in the cell. Specific examples include compounds of formula I, II, or III described in this application, their stereoisomers, or pharmaceutically acceptable salts thereof. Specifically, examples include compounds of formula I described in this application, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0319] This application also relates to the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof:

[0320] This application also covers solutions obtained by arbitrarily combining, deleting, or changing the above-described embodiments.

[0321] On the other hand, this application relates to a pharmaceutical composition comprising the compounds, structural moieties, derivatives thereof (e.g., protac), stereoisomers thereof, or pharmaceutically acceptable salts thereof described above. In some embodiments, the pharmaceutical composition of this application further includes pharmaceutically acceptable excipients.

[0322] On the other hand, this application relates to methods for treating mammalian diseases, including administering to a mammal, preferably a human, a therapeutically effective amount of the compound of this application, its structural moiety, its derivative, its stereoisomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of this disclosure.

[0323] On the other hand, this application relates to the use of the compounds of this application, their structural portions, their derivatives, their stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions of this application in the preparation of medicaments for treating diseases.

[0324] On the other hand, this application relates to the use of the compounds of this application, their structural portions, their derivatives, their stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions of this application in the treatment of diseases.

[0325] On the other hand, this application relates to compounds of this application, their structural portions, their derivatives, their stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of this application for the treatment of diseases.

[0326] In some embodiments, the disease is selected from diseases treated by binding to cerebellar proteins in vivo and / or by degrading / inhibiting target proteins that bind to target ligands.

[0327] In some implementations, the disease is selected from diseases associated with or mediated by SMARCA2 and / or SMARCA4.

[0328] In some implementations, the disease (e.g., SMARCA2 and / or SMARCA4-related or mediated diseases) is selected from cancer.

[0329] In some embodiments, the disease (e.g., SMARCA2 and / or SMARCA4-related or mediated diseases) is selected from lung cancer, such as non-small cell lung cancer. In some embodiments, the disease (e.g., SMARCA2 and / or SMARCA4-related or mediated diseases) is selected from melanoma.

[0330] On the other hand, this application relates to the use of the aforementioned compounds, structural moieties, derivatives thereof (e.g., protac), stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of medicaments for the prevention or treatment of conditions by degradation of target proteins (such as SMARCA2 and / or SMARCA4) that bind to target ligands.

[0331] On the other hand, this application relates to the use of the aforementioned compounds, structural moieties, derivatives thereof (e.g., protac), stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention or treatment of conditions by binding to cerebellar proteins in vivo.

[0332] On the other hand, this application relates to the use of the above-mentioned compounds, structural moieties, derivatives thereof (e.g., protac), stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention or treatment of diseases related to SMARCA2 and / or SMARCA4.

[0333] This application relates to methods for treating or preventing diseases in mammals by degrading target proteins (such as SMARCA2 and / or SMARCA4) that bind to target ligands, including administering a therapeutically effective amount of the aforementioned compounds, structural moieties, derivatives thereof (e.g., protac), stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, of this application to a mammal (preferably a human) requiring such treatment.

[0334] This application relates to methods for treating or preventing conditions by binding to cerebellar proteins in vivo, including administering a therapeutically effective amount of the aforementioned compound, structural moiety, derivative thereof (e.g., protac), stereoisomer thereof, or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, of this application to a mammal (preferably a human) requiring such treatment.

[0335] On the other hand, this application relates to a method of treating mammals with diseases associated with SMARCA2 and / or SMARCA4, including administering a therapeutically effective amount of the aforementioned compound, structural moiety, derivative thereof (e.g., protac), stereoisomer thereof, or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, of this application to a mammal (preferably a human) requiring such treatment.

[0336] On the other hand, this application relates to the aforementioned compounds, structural moieties, derivatives thereof (e.g., protac), stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the prevention or treatment of conditions by degrading target proteins (such as SMARCA2 and / or SMARCA4) that bind to target ligands.

[0337] On the other hand, this application relates to the aforementioned compounds, structural portions, derivatives thereof (e.g., protac), stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the prevention or treatment of conditions that are treated by binding to cerebellar proteins in vivo.

[0338] On the other hand, this application relates to the aforementioned compounds, structural portions, derivatives thereof (e.g., protac), stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the prevention or treatment of diseases associated with SMARCA2 and / or SMARCA4.

[0339] On the other hand, this application relates to the use of the above-mentioned compounds, their stereoisomers, structural moieties, their derivatives (e.g., protac), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the prevention or treatment of conditions treated by degradation of target proteins (such as SMARCA2 and / or SMARCA4) that bind to a target ligand.

[0340] On the other hand, this application relates to the use of the aforementioned compounds, structural moieties, derivatives thereof (e.g., protac), stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the prevention or treatment of conditions that are treated by binding to cerebellar proteins in vivo.

[0341] On the other hand, this application relates to the use of the above-mentioned compounds, structural moieties, derivatives thereof (e.g., protac), stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the prevention or treatment of diseases related to SMARCA2 and / or SMARCA4.

[0342] In some specific embodiments, the aforementioned SMARCA2 and / or SMARCA4-related diseases are selected from conditions treated by degrading and / or inhibiting proteins (SMARCA2 and / or SMARCA4) that bind to SMARCA2 or SMARCA4 target protein ligands; in some specific embodiments, the aforementioned SMARCA2 and / or SMARCA4-related diseases are selected from conditions treated by binding to cerebellar proteins in vivo; in some embodiments, the aforementioned diseases or conditions are selected from cancer.

[0343] In some specific embodiments, the conditions treated by binding to cerebellar proteins in vivo and / or by degrading target proteins that bind to target ligands are selected from diseases related to SMARCA2 and / or SMARCA4; in some specific embodiments, the SMARCA2 and / or SMARCA4-related diseases are selected from cancer.

[0344] In some embodiments, this application includes the variables defined above and their implementation schemes, as well as any combination thereof.

[0345] Technical effect

[0346] The compounds of this application possess one or more of the following properties: degradative activity against SMARCA2 and / or SMARCA4 proteins, or selective degradation of SMARCA2; for example, degradative activity against Hela-SM2-Hibit and / or Hela-SM4-Hibit cells; or selective degradative activity against Hela-SM2-Hibit; antiproliferative activity against cells (NCI-H838 and SK-MEL-5 cells); good in vitro stability in liver microparticles (species: human, canine, rat, or mouse); good in vivo pharmacokinetic properties in mammals (e.g., mice) (specific parameters such as AUC); and in vivo inhibition of tumor growth. These properties demonstrate promising drug development potential.

[0347] definition

[0348] Unless otherwise stated, the following terms as used in this application shall have the following meanings. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0349] In this document, "one or more" refers to an integer from one to ten. For example, "one or more" means one, two, three, four, five, six, seven, eight, nine, or ten; in some embodiments, "one or more" is selected from one, two, three, four, five, or six. In some embodiments, "one or more" is selected from one, two, or three. In some embodiments, "one or more" is selected from one or two.

[0350] Unless otherwise specified, Hydrogen atoms at any position of a group within [ ] can be replaced by a group connected by "—", for example, by an L-connected group.

[0351] The term "substitution" refers to the replacement of one or more hydrogen atoms or lone pairs of electrons on a specific atom by a substituent, provided that the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced; oxo substitution does not occur on aromatic groups. For example... Its ring A, ring B, or ring C can be n, for example, one or more R 1 Substituent substitution, wherein the R 1 It can replace any position in ring A, ring B, or ring C (under permissible conditions).

[0352] The terms “optional” or “optionally” mean that the event or condition subsequently described may or may not occur, including both the occurrence and non-occurrence of said event or condition. “Optionally substituted” includes both unsubstituted and substituted forms; for example, an ethyl group “optionally” substituted with a halogen means that the ethyl group can be unsubstituted (CH2CH3), monosubstituted (e.g., CH2CH2F), polysubstituted (e.g., CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible and / or cannot be synthesized is introduced.

[0353] C in this article m-n This means that the part has an integer number of carbon atoms within 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.

[0354] When any variable (such as R) appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group contains two Rs, then each R has an independent option.

[0355] When the number of a linking group is 0, such as -(CH2)0-, it indicates that the linking group is a covalent bond.

[0356] When one of the variables is selected from covalent bonds (i.e., the group is selected from the bond), it means that the two groups connected are directly connected. For example, when L in ALZ represents a covalent bond, it means that the structure is actually AZ.

[0357] When a bond cross-bonds two atoms in a ring (including monocyclic, fused, or spirocyclic rings), this bond can bond with any atom in the ring (including monocyclic, fused, or spirocyclic rings). For example, structural units. This indicates that the bonds on both sides can be connected to any two different atoms in ring A, ring B, or ring C; for example... This 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... This indicates that the bonds on both sides can be connected to any two different atoms in the four rings of the system.

[0358] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0359] The term "hydroxyl group" refers to the -OH group.

[0360] The term "amino" refers to the -NH2 group.

[0361] The term "cyano" refers to the -CN group.

[0362] The term "alkyl" refers to a compound with the general formula C10. n H 2n+1 The alkyl group. This alkyl group can be straight-chain or branched. For example, the term "C 1-6 "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 groups has the same definition as above.

[0363] The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one double bond. Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, etc.

[0364] The term "alkylene" refers to a divalent group formed by removing a hydrogen atom 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-.

[0365] The term "alkenyl" 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 alkenyl group containing 2 to 6 carbon atoms; the term "C" 2-4 "Alkenyl" refers to an alkenyl group containing 2 to 4 carbon atoms, including but not limited to -CH2CH=CH-, -CH2CH2CH=CH-, or -CH2CH=CHCH2-.

[0366] The term "alkynyl" 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 "Alynyl" refers to an alkynyl group containing 2 to 6 carbon atoms; the term "C" 2-4 "Alynyl group" refers to an alkynyl 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-.

[0367] The term "heteroalkyl" refers to a straight-chain or branched heteroalkyl group composed of a certain number of carbon atoms and at least one heteroatom. It preferably has 1 to 14 carbon atoms in the chain, more preferably 1 to 10 carbon atoms, even more preferably 1 to 6 carbon atoms, and most preferably 1 to 3 carbon atoms, wherein the heteroatom is preferably selected from S, O, and N heteroatoms, and the number is preferably 1, 2, or 3. The nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. The heteroatom or heteroatomic group can be located at any internal 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 alkylamines, tertiary alkylamines, amides, thioethers, etc., 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.

[0368] The term "heteroalkylene" refers to a divalent group formed by removing a hydrogen atom from any position of a heteroalkyl group.

[0369] The term "cycloalkenyl" refers to an incompletely saturated (but not completely unsaturated) aromatic carbon ring that can exist as a monocyclic, fused, bridged, and / or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 4- to 16-membered, 4- to 12-membered, 4- to 10-membered, or 4- to 8-membered ring. Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, benzocyclohexenyl, etc.

[0370] The term "cycloalkyl" refers to a fully saturated carbon ring that can exist as a monocyclic, fused, bridged, and / or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 3- to 16-membered ring (e.g., a 3- to 10-membered ring, or a 5- to 8-membered ring). 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.

[0371] The term "heterocyclic alkyl" refers to a fully saturated cyclic group that may exist as a monocyclic, fused, bridged, and / or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically 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 heterocyclic alkyl groups include, but are not limited to, ethylene oxide, cyclothioethylene, and cycloazoethylene; non-limiting examples of 4-membered heterocyclic alkyl groups include, but are not limited to, acridine, oxadiazolyl, and thiobutyl; examples of 5-membered heterocyclic alkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, imidazolyl, and tetrahydropyrazolyl; examples of 6-membered heterocyclic alkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, morpholinyl, piperazine, 1,4-thiaoxane, 1,4-dioxane, thiomorpholinyl, 1,3-dithiaalkyl, and 1,4-dithiaalkyl; and examples of 7-membered heterocyclic alkyl groups include, but are not limited to, azirheptanyl, oxeheptanyl, and thioheptanyl. Monocyclic heterocyclic alkyl groups having 5 or 6 ring atoms are preferred.

[0372] The term "spirocyclic" refers to a fully saturated or partially unsaturated polycyclic system in which the individual rings share a single carbon atom (called a spiro atom), including carbon rings and heterocyclic rings. Unless otherwise indicated, the spirocyclic ring is 5 to 20-membered, preferably 6 to 14-membered, and more preferably 8 to 12-membered. When the spirocyclic ring is a heterocyclic ring, one or more ring atoms in the polycyclic ring are selected from N, O, and S(O). n P(O) n (where n is 0, 1 or 2) heteroatoms (preferably 1 or 2 heteroatoms), and the remaining ring atoms are carbon atoms.

[0373] The term "heterocyclic alkenyl" refers to a partially unsaturated (but not fully unsaturated) heteroaromatic group that may exist as a monocyclic, fused, bridged, and / or spirocyclic ring. Unless otherwise indicated, the heterocyclic alkenyl is typically a 3-12-membered, 3-10-membered, 3-8-membered, 3-6-membered, 4-12-membered, 4-10-membered, 4-8-membered, 4-6-membered, 5-10-membered, 5-8-membered, 5-7-membered, or 5-6-membered ring containing 1 to 3 heteroatoms independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon, and / or boron, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms may optionally be oxidized (i.e., C=O, NO, and S(O)p, where p is 1 or 2). Examples of heterocyclic alkenyl groups include, but are not limited to, dihydropyrrolyl, dihydropyrazolyl, dihydroimidazolyl, dihydrofuranyl, dihydrooxazolyl, dihydroisooxazolyl, dihydrothiophenyl, dihydrothiazolyl, dihydroisothiazolyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrazinyl, dihydropyridazinyl, dihydropyridazinyl, tetrahydropyridyl, tetrahydropyrimidinyl, tetrahydropyrazinyl, tetrahydropyridazinyl, and tetrahydroazapyrazinyl. , dihydropyranyl, azacycloheptenyl, diazacycloheptenyl, oxacycloheptenyl, azaoxacycloheptenyl, azacycloheptenadiyl, diazacycloheptenadiyl, oxacycloheptenadiyl, pyridinocyclohexenyl, benzodihydropyrrole, azaspirooctene, wait.

[0374] The term "aryl" refers to an aromatic ring group consisting of an all-carbon monocyclic or fused polycyclic ring with 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, anthracene, and 1,2,3,4-tetrahydronaphthalene.

[0375] The term "heterocyclic group" refers to a fully saturated or partially unsaturated (but not fully unsaturated) heteroaromatic group, which may be a monocyclic, fused, bridged, and / or spirocyclic group containing at least one (e.g., 1-5, 1-4, 1-3, 1-2) ring atoms selected from N, O, and S, with the remaining ring atoms being C. It may be a cyclic group without double bonds or having at least one or more double bonds. Preferred heterocyclic 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. Saturated heterocyclic groups are heterocyclic alkyl groups, and partially unsaturated heterocyclic groups are heterocyclic alkenyl groups.

[0376] The term "heteroaryl" refers to an aromatic cyclic group having a conjugated electron system, which can be a monocyclic or fused polycyclic system containing at least one (e.g., 1-5, 1-4, 1-3, 1-2) ring atoms selected from N, O, and S, with the remaining ring atoms being C. Preferred heteroaryls have a single 4- to 8-membered ring, particularly a 5- to 8-membered ring (e.g., 5-, 6-, 7-, or 8-membered), or multiple fused rings containing 6 to 14, particularly 6 to 10 (e.g., 6, 7, 8, 9, or 10) ring atoms. Non-limiting examples of heteroaryls include, but are not limited to, pyrroleyl, furanyl, thiopheneyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothiopheneyl, indoleyl, isoindoleyl, etc. The term "ring" can be selected from cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl, heterocycloyl, or heteroaryl, and can exist as a monocyclic, fused, bridged, and / or spirocyclic ring. The term "carbocyclic" is a cyclic structure composed of carbon atoms, including cycloalkyl, cycloalkenyl, or aryl, and can exist as a monocyclic, fused, bridged, and / or spirocyclic ring.

[0377] The terms “substituent,” “optionally substituted with one or more substituents,” or “optionally substituted,” refer to substitution or substituent substitution, including all substituents mentioned in the context of this document, such as the terms “halogen,” “deuterium,” etc., mentioned below. "-NH2", "-NH(C" 1- 4-alkyl), "-N(C)" 1-4 Alkyl group 2", "-OH", "-OC" 1-4 Alkyl group, -CN, C 1-4 "alkyl", "3-6 membered heterocyclic alkyl", etc., and corresponding non-limiting or exemplary groups, wherein some non-limiting examples of the "substituent" include mercapto, 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, halogenated-heteroalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, arylalkylene, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroarylalkylene, heteroarylalkoxy, heteroarylalkylthio, heterocyclic, heterocyclicoxy, heterocyclicthio, heterocyclic alkylene, heterocyclic alkoxy, heterocyclic alkylthio, acyl, acyloxy, carbamate group, amide group, urea group, epoxy group, ester group The substituents, such as oxo and oxy, are optionally substituted by one or more substituents selected from: oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC( -O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclic, heterocyclic alkylene, heterocyclic oxy, heterocyclic alkyl, heterocyclic alkylalkylene, heterocyclic alkyloxy, heterocyclic alkyl, heterocyclic alkyloxy, heteroaryl, heteroaryl alkylene, heteroaryloxy, aryl, aryl alkylene or aryloxy.

[0378] In some embodiments herein, the substituents are selected from deuterium, tritium, hydroxyl, mercapto, halogen, amino, nitro, nitroso, cyano, azide, sulfoxide, sulfone, sulfonamide, carboxyl, aldehyde, imine, C 1-12 Alkyl, Halogenated -C 1-12 Alkyl, 3-12 membered cycloalkyl, halo-3-12 membered cycloalkyl, C 2-12 alkenyl, halogenated -C2-12 alkenyl, 3-12-membered cycloalkenyl, halo-3-12-membered cycloalkenyl, C 2-12 Alkyne group, halogenated -C 2-12 Alkynyl, 8-12 membered cycloalkynyl, halogenated-8-12 membered cycloalkynyl, C 1-12 Heteroalkyl, halogenated-C 1-12 Heteroalkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, 6-10 aryl, 6-10 aryloxy, 6-10 arylthio, 6-10 arylC 1-12 Alkylene, 6-10 aryl C 1-12 Alkoxy, 6-10 aryl C 1-12 Alkylthio, 5-10 heteroaryl, 5-10 heteroaryloxy, 5-10 heteroarylthio, 5-10 heteroarylalkylene, 5-10 heteroarylalkoxy, 5-10 heteroarylalkylthio, 3-12 heterocyclic, 3-12 heterocyclic oxy, 3-12 heterocyclic thio, 3-12 heterocyclic C 1-12 Alkylene, 3-12 membered heterocyclic C 1-12 Alkoxy, 3-12 membered heterocyclic C 1-12 Alkylthio, C 1-12 Acyl group, C 1-12 Acyloxy group, carbamate group, C 1-12 Amide group, urea group, epoxy group, C 2-12 The ester group and oxo group, wherein the substituent is optionally substituted by one or more substituents selected from: oxo, hydroxy, amino, nitro, halogen, cyano, C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 1-12 Alkylamino, diC 1-12 Alkylamino, halogenated C 1-12 Alkylamino, Halogenated diC 1-12 Alkylamino, carboxyl, -C(O)OC 1-12 Alkyl, -OC(O)-C 1-12 Alkyl group, -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 group, -S(O)2NH2, -S(O)2NH-C 1-12Alkyl group, -S(O)2N(C) 1-12 Alkyl) 2, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12 Alkylene, 3-12 membered cycloalkyloxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group C 1-12 Alkylene, 3-12-membered heterocyclic oxy group, 3-12-membered heterocyclic alkyl group, 3-12-membered heterocyclic alkyl group C 1-12 Alkylene, 3-12-membered heterocyclic alkyloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryl C 1-12 alkylene, 5-10 heteroaryloxy, 6-10 aryl, 6-10 aryl C 1-12 Alkylene or 6-10 aryloxy groups.

[0379] Unless otherwise specified, the term "heteroatom" means heteroatom or heterogroup (i.e., a group containing heteroatoms), including atoms other than carbon (C) and hydrogen (H) and groups containing such heteroatoms, such as heteroatoms including but not limited to oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), silicon (Si), germanium (Ge), aluminum (Al), and boron (B), and specific heteroatoms or heterogroups such as: -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 "heterogeneous" means that the heteroatom or heteroatomic group (i.e., a group containing a heteroatom) is selected from oxygen, nitrogen, or sulfur.

[0380] The term "derivative" refers to a new compound or group of new compounds that are produced through one or more chemical reactions or structural evolution, retaining the basic structure of the parent compound but changing or modifying only the side chains, functional groups or substituents.

[0381] In this application, wavy lines are used. One of the absolute configurations representing the center of a solid (e.g.) one, specific express ) or one of the relative configurations (e.g. express When the compounds described herein contain an alkene double bond or other geometrically asymmetric centers, they include E and Z geometric isomers, unless otherwise specified. Similarly, all tautomer forms are included within the scope of this application.

[0382] 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, optionally read in a left-to-right order, are respectively connected to the left and right groups of the group or fragment in the general formula, for example, in L selected from -Cy 1 -LNK- when Cy 1 Selected from Following the reading order from left to right, Cy 1 The left side and the corresponding segment on the left side of the general formula Connect, right side and right side fragment Connect, and the resulting fragment is Optionally, groups or structural fragments in this application, such as -LNK, may be used. 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 from right to left, corresponding to the left and right groups of the group or fragment in the general formula, for example, L is selected from -Cy 1 -LNK- when Cy 1 Selected from Following the reading order from right to left, Cy 1 The right side corresponds to the left side of the general formula. Connect the left side to the corresponding right side segment in the general formula. The segments formed by the connection are The other groups are the same as described above.

[0383] The term “treatment” means administering the compound or formulation described in this application to improve or eliminate a disease or one or more symptoms associated with the disease, and includes: (i) suppressing the disease or disease state, i.e., curbing its development; (ii) alleviating the disease or disease state, even if the disease or disease state subsides.

[0384] The term “prevention” means administering the compound or formulation described in this application to prevent a disease or one or more symptoms associated with the disease, including: preventing the occurrence of a disease or disease state in mammals, particularly when such mammals are susceptible to the disease state but have not yet been diagnosed with the disease state.

[0385] The term "therapeutic effective amount" means the amount of the compound of this application used to treat or prevent a particular disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of this application constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the present disclosure.

[0386] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0387] As pharmaceutically acceptable salts, for example, metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, and salts formed with basic or acidic amino acids may be mentioned.

[0388] The term "pharmaceutical composition" refers to a mixture of one or more compounds of this application or their salts with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compounds of this application to an organism.

[0389] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0390] The word “comprise” or “include” and its English variants such as comprises or comprising should be understood in an open, non-exclusive sense, meaning “including but not limited to”.

[0391] Unless the context clearly indicates otherwise, singular terms in this document encompass the plural referents, and vice versa. Similarly, unless the context clearly indicates otherwise, the word "or" in this document is intended to include "and".

[0392] Unless otherwise stated, all figures used herein to represent amounts of components, measurements, or reaction conditions should be understood to be modified by the term "about" in all cases. When used with percentages, the term "about" may mean, for example, ±1%, preferably ±0.5%, more preferably ±0.1%.

[0393] The compounds and intermediates of this application may also exist in different tautomer forms, and all such forms are included within the scope of this application. The terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can interconvert via low-barrier transitions. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. A specific example of a proton tautomer is the imidazole moiety, where a proton can migrate between two ring nitrogens. Valence tautomers include interconversions via the recombination of some bonding electrons. Specifically, any compound of this disclosure, such as pyrazole alone or as part of a heterocyclic group, may exist in the form of two tautomers or any mixture of two tautomers, i.e. or This disclosure includes all possible tautomers of the compounds disclosed herein, as a single tautomer, or any mixture of said tautomers in any proportion.

[0394] This application also includes compounds of this application that are identical to those described herein, but with one or more atoms replaced by isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this 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, etc.

[0395] Certain isotope-labeled compounds of this application (e.g., using...) 3 H and 14 Those labeled with C can be used in the analysis of compound and / or substrate tissue distribution. Tritiumization (i.e. 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Positron-emitting isotopes, such as... 15 O、 13 N、 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. The isotopically labeled compounds of this application can typically be prepared by replacing the unlabeled reagent with an isotopically labeled reagent using a procedure similar to those disclosed in the schemes and / or examples below.

[0396] The compounds of this application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include enantiomers and diastereomers. The compounds containing asymmetric carbon atoms of this application can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized using chiral starting materials or chiral reagents.

[0397] The pharmaceutical compositions of this application can be prepared by combining the compounds of this application with suitable pharmaceutically acceptable excipients.

[0398] Typical routes of administration for the compounds of this application or their pharmaceutically acceptable salts 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.

[0399] The pharmaceutical composition of this application can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, sugar-coated pill making, grinding, emulsification, freeze drying, etc.

[0400] In some implementations, the pharmaceutical composition is in oral form.

[0401] Solid oral compositions can be prepared using conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or sugar-coated formulation.

[0402] The pharmaceutical composition is also suitable for parenteral administration.

[0403] In all methods of administration of the compounds of general formula I described herein, the daily dose is from 0.001 to 2000 mg / kg body weight, in the form of single or separate doses.

[0404] The compounds of this application can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of this application.

[0405] The chemical reactions in the specific embodiments of this application are carried out in a suitable solvent, which must be suitable for the chemical changes and the reagents and materials required in this application. In order to obtain the compounds of this application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction process based on existing embodiments.

[0406] An important consideration in synthetic route planning in this field is selecting appropriate protecting groups for reactive functional groups (such as amino groups in this application). For example, see Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.

[0407] In some embodiments, the compounds of this application can be prepared by those skilled in the art of organic synthesis using the following intermediates or their salts via the following route:

[0408] Among them, ring F, ring H, and R 3a , k, R 2 m, ring A, ring B, ring C, R 1 , n, X 5 The definition of L is as described in this application. This application uses the following abbreviations:

[0409] DCM represents dichloromethane; THF represents tetrahydrofuran; TEA represents triethylamine; EA represents ethyl acetate; DMAP represents 4-dimethylaminopyridine; LiHMDS represents lithium bis(trimethylsilyl)amino; HATU represents 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; DIPEA represents N,N-diisopropylethylamine; TFA represents trifluoroacetic acid; DMSO represents dimethyl sulfoxide; PdCl2(dppf) represents 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride; MeOH represents methanol; DCE represents dichloroethane; IPA represents isopropanol; Boc represents tert-butoxycarbonyl; MeOH represents methanol; OBn represents benzyloxy.

[0410] For clarity, the invention is further illustrated by examples, but these 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 Implementation

[0411] Examples z1 and z2: Synthesis of intermediates z1 and z2

[0412] Step 1: Preparation of intermediate z1b

[0413] Z1a (100g), pyrrolidine (58g), and toluene (1L) were added sequentially to a reaction flask. A Dean-Stark apparatus was used to separate the water, and the reaction was carried out at 140°C for 5 hours until no more water was generated in the apparatus. The reaction solution was then evaporated to dryness to obtain intermediate Z1b (140g).

[0414] Step 2: Preparation of intermediate z1d

[0415] Z1C (400g) was dissolved in DCM (2L), and an aqueous solution (2L) of hydroxylamine hydrochloride (143g) was added dropwise under ice bath conditions. After the addition was complete, the mixture was moved to room temperature and allowed to react overnight. After the reaction was completed by TLC monitoring, the aqueous layer was extracted with DCM, and the organic layers were combined, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain intermediate Z1D (293g).

[0416] Step 3: Preparation of intermediate z1e

[0417] Z1b (131 g) was dissolved in THF (1300 mL), and Z1d (127 g) was slowly added under ice bath conditions. After the addition was complete, the reaction mixture was moved to room temperature and stirred for 30 min. Then, TEA (67 g) was added dropwise under ice bath conditions. After the addition was complete, the reaction mixture was moved to room temperature and reacted for 30 min. The reaction was monitored by TLC until it was complete. The reaction mixture was quenched with citric acid and extracted with EA. The organic layer was first washed with sodium bicarbonate, then washed with saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to dryness to obtain intermediate Z1e (109 g).

[0418] Step 4: Preparation of intermediate z1f

[0419] Z1e (116 g) was dissolved in ethanol (1200 mL), and then Raney nickel (116 g) was added. The reaction was carried out at room temperature for 36 h under the action of hydrogen. After the reaction was completed by TLC monitoring, the reaction solution was filtered, the filtrates were combined and evaporated to dryness to obtain intermediate Z1f (100 g).

[0420] Step 5: Preparation of intermediate z1g

[0421] Z1F (100g), di-tert-butyl dicarbonate (77g), DMAP (2.1g), and DCM (1L) were added sequentially to a reaction flask and reacted at room temperature for 2 hours. After the reaction was complete as monitored by TLC, the reaction solution was first washed with citric acid, then the organic layer was washed with sodium bicarbonate solution and saturated sodium chloride aqueous solution, respectively, and finally dried with anhydrous sodium sulfate. The filtrate was concentrated after filtration, and the crude product was purified by column chromatography to obtain intermediate Z1G (57g).

[0422] Step 6: Preparation of intermediate z1h

[0423] Z1 g (55 g) was dissolved in THF (850 mL), and LiHMDS (1 M in THF, 215 mL) was slowly added dropwise at -80 °C. After the addition was complete, the mixture was brought to room temperature and stirred for 1 h. Then, difluoromethyl trifluoromethanesulfonate (45 mL) was slowly added dropwise at -80 °C. After the addition was complete, the mixture was brought to room temperature and the reaction was allowed to proceed overnight. The reaction solution was quenched with citric acid and extracted with EA. The organic layer was first washed with sodium bicarbonate, then washed with saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to dryness to obtain intermediate Z1 h (63 g).

[0424] Step 7: Preparation of intermediate z1i

[0425] Z1h (63g), lithium hydroxide monohydrate (30g), methanol (500mL) and water (100mL) were mixed and reacted at 50℃ for 2h. The reaction solution was quenched with citric acid and extracted with EA. The organic layer was first washed with sodium bicarbonate and then with saturated sodium chloride aqueous solution. It was then dried with anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain intermediate Z1i (36g).

[0426] Step 8: Preparation of intermediate z1j

[0427] Z1i (36g), HATU (44g), DIPEA (46mL), and DCM (700mL) were mixed and reacted at room temperature for 2 hours. After the reaction was complete, the reaction solution was evaporated to dryness to obtain the crude product. 3-Amino-4-bromo-6-chloropyridazine (26g), 60wt% sodium hydride (18g), and THF (500mL) were mixed and stirred for 30 minutes. The crude product was then dissolved in THF and slowly added dropwise to the reaction flask under ice bath conditions. After the addition was complete, the reaction solution was allowed to stand at room temperature for 2 hours. After the reaction was complete, the reaction solution was quenched with citric acid and extracted with EA. The organic layer was first washed with sodium bicarbonate, then with saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate. The filtrate was filtered and evaporated to dryness to obtain intermediate Z1j (66g). MS(ESI)m / z[M+H] + :595.9.

[0428] Step 9: Preparation of intermediate z1k

[0429] z1j (65 g), TFA (300 mL), and DCM (300 mL) were mixed and reacted at room temperature for 5 h. After the reaction was complete, the reaction solution was directly evaporated to dryness to obtain intermediate z1k (92 g). MS(ESI) m / z[M+H] + 395.9.

[0430] Step 10: Preparation of intermediate z1l

[0431] Z1K (92 g), di-tert-butyl dicarbonate (18 mL), DIPEA (100 mL), and DCM (900 mL) were mixed and reacted at room temperature for 5 h. After the reaction was complete, the reaction solution was quenched with citric acid, extracted with EA, and the organic layer was washed first with sodium bicarbonate, then with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to obtain intermediate Z1L (27 g). MS(ESI) m / z[M+H] + 496.0.

[0432] Step 11: Preparation of intermediate z1m

[0433] Z1L (27g), DIPEA (28mL), and DMSO (270mL) were mixed and reacted at 80℃ for 4h. After the reaction was complete, the reaction solution was quenched with citric acid, extracted with EA, and the organic layer was first washed with sodium bicarbonate solution, then with saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to dryness to obtain intermediate Z1M (21g). MS(ESI)m / z[M+H] + 416.4.

[0434] Step 12: Separation conditions for intermediates z1n-1 and z1n-2

[0435] Instrumentation: High-performance liquid chromatography (HPLC), column: Pre-packed REGIS IC (30*250mm 10μm), mobile phase A: dichloromethane, mobile phase B: methanol, intermediates z1n-1 (8.5g) and z1n-2 (8.3g) were obtained successively.

[0436] z1n-1:MS(ESI,[M+H) + m / z: 416.4.

[0437] z1n-2:MS(ESI,[M+H) + m / z: 416.4.

[0438] Step 13: Preparation of intermediate z1o-1

[0439] Z1n-1 (4 g), 3-fluoro-2-hydroxyphenylboronic acid (4.31 g), PdCl2 (dppf) (1.4 g), potassium carbonate (3.99 g), and 1,4-dioxane / water = 4 / 1 (v:v, 40 mL) were added to a reaction flask, and the reaction was carried out at 90 °C. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with EA, and then the organic phase was dried with anhydrous sodium sulfate. After filtration, the filtrate was purified by column chromatography to obtain intermediate Z1o-1 (3.1 g). MS(ESI)m / z[M+H] + 492.2.

[0440] Step 14: Preparation of intermediate z1

[0441] Z1o-1 (2 g), THF (20 mL), and lithium borohydride (7.83 mL, 2 M in THF) were added to the reaction flask, and the reaction was carried out at room temperature. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride solution, extracted with EA, the organic phase was separated, and then dried with anhydrous sodium sulfate. The residue was then added with trifluoroacetic acid (10 mL) and triethylsilane (3 mL), and refluxed at 80 °C. After the reaction was completed, 5 mL of methanol was added for concentration, and the concentrate was purified by column chromatography to obtain product Z1 (1.4 g). MS(ESI) m / z[M+H] + 378.3.

[0442] Step 15: Preparation of intermediate z1o-2

[0443] Following the preparation conditions of z1o-1, intermediate z1o-2 (3.3 g) was obtained from z1n-2 (4 g) as the starting material. MS(ESI) m / z[M+H] + 492.5.

[0444] Step 16: Preparation of intermediate z2

[0445] Following the preparation conditions of z1, z2 (1.44 g) was obtained from z1o-2 (3.3 g) as the starting material. MS(ESI)m / z[M+H] + 378.4.

[0446] Examples z3 and z4: Synthesis of intermediates z3 and z4

[0447] By replacing compound z1a with z3a and referring to the synthesis process of intermediates z1 and z2, intermediates z3 (1.8g) and z4 (1.93g) were obtained.

[0448] Compound z3: MS(ESI) m / z[M+H] + 406.3.

[0449] Compound z4: MS(ESI) m / z[M+H] + 406.3.

[0450] Preparation Examples: Synthesis of Compounds Z6 and Z7

[0451] Step 1: Preparation of intermediate z6a

[0452] CCl4 (6750 mL), 2,3-dimethyl anisole (450 g), 2,2-azobisisobutyronitrile (18.45 g), and N-bromosuccinimide (1194 g) were added sequentially to a reaction flask. The mixture was heated to 80 °C and refluxed. After the reaction was complete as monitored by TLC, the reaction solution was filtered, the solvent was removed from the filtrate by vacuum distillation, petroleum ether was added and the mixture was stirred, filtered, and the filter cake was collected to obtain intermediate Z6a (833 g).

[0453] Steps 2 and 3: Preparation of intermediate z6c

[0454] At 0°C, a solution of intermediate z6a (69 g) and diethyl 1,3-propanone dicarboxylate (57.0 g) in DCM (350 mL) was slowly added dropwise to a mixture of tetrabutylammonium iodide (52.0 g) in sodium bicarbonate solution (1 M, 1178 mL) and DCM (500 mL) with stirring. The reaction was carried out at room temperature. After the reaction was completed, the mixture was extracted with dichloromethane. The extract was concentrated and then slurried with methyl tert-butyl ether. The mixture was filtered, and the filtrate was concentrated to obtain z6b. Then, ethanol (1000 mL) and potassium hydroxide (1 M, 1173 mL) were added to the crude product, and the reaction was carried out at 85°C. After the reaction was completed, dilute hydrochloric acid was added to adjust the pH to neutral, and the mixture was extracted with dichloromethane. The organic phase was concentrated and purified by column chromatography to obtain intermediate z6c (24 g).

[0455] Step 4: Preparation of intermediate z6d

[0456] At 0℃ and under N2 protection, a 1M, 157mL solution of potassium tert-butoxide in THF was slowly added dropwise to a 450mL solution of (methoxymethyl)triphenylphosphine chloride (49.7g) in THF. After the addition was complete, the mixture was stirred at 0℃ for 0.5h. Then, intermediate z6c (23g) was added, and the mixture was allowed to react at room temperature. After the reaction was completed, a saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic phase was separated, concentrated, and purified by column chromatography to obtain intermediate z6d (28.6g).

[0457] Step 5: Preparation of intermediate z6e

[0458] Intermediate Z6D (28.8 g), THF (200 mL), and 2M hydrochloric acid (130 mL) were added sequentially to the reaction flask, and the reaction was carried out at room temperature. After the reaction was completed, saturated sodium bicarbonate solution was added to adjust the pH to neutral, and the mixture was extracted with ethyl acetate to separate the organic phase. After concentration, intermediate Z6E (25.9 g) was obtained.

[0459] Following the method described in Preparation Example z22 or z33 of WO2023125944, perform the following steps 6 to 18:

[0460] Step 6: Preparation of intermediate z6f

[0461] Following the method described in step 6 of preparation examples z22 or z33, intermediate z6f (25.6 g) was synthesized by replacing intermediate z22f with intermediate z6e.

[0462] Step 7: Preparation of intermediate z6g

[0463] Following the method described in step 5 of preparation examples z22 or z33, intermediate z6g (14.42g) was synthesized by replacing intermediate z22e with intermediate z6g.

[0464] Steps 8-17: Preparation of intermediates z6p-1 and z6p-2

[0465] Following the method described in steps 7-15 of preparation examples z22 or z33, intermediate z6g was used instead of intermediate z22g to prepare the first peak compound z6o-1 and the last peak compound z6o-2; further following the method described in step 16 of preparation examples z22 or z33, compounds z6p-1 (2.20g) and z6p-2 (2.31g) were synthesized.

[0466] Compound z6p-1: MS (ESI, [MH]) - )m / z:327.1.

[0467] Compound z6p-2: MS (ESI, [MH]) - )m / z:327.1.

[0468] Step 18: Preparation of compound z6

[0469] Intermediate Z6p-1 (80 mg), DMSO (1.5 mL), and 2-iodobenzoic acid were added sequentially to a reaction flask, and the reaction was carried out at room temperature. After the reaction was completed, water and saturated sodium bicarbonate solution were added to quench the reaction. After extraction with ethyl acetate, the organic phase was separated and concentrated to obtain Z6 (107 mg).

[0470] MS(ESI,[M+H) + )m / z:327.1.

[0471] Step 19: Preparation of compound z7

[0472] Following the procedure in step 18, replace z6p-1 with z6p-2 to obtain z7 (105mg).

[0473] MS(ESI,[M+H) + )m / z:327.3.

[0474] Synthesis of compounds z8-1 to z12 in preparation examples z8 and z9

[0475] Following the synthetic route of intermediates z1 or z2, 3-fluoro-2-hydroxyphenylboronic acid was replaced with the following borate ester structure (starting material 1) to synthesize z8-1, z8-2, z9, z10, z11, and z12.

[0476] Example 1: Synthesis of Compound 1

[0477] Step 1: Preparation of intermediate 1a

[0478] Z5 (130 mg, synthesized according to the method of preparation example Z20 in WO2023125944), DMF (3 mL), and tert-butyl bromoacetate (47 mg) were added sequentially to the reaction flask, followed by DIPEA (45 mg). The reaction was carried out at room temperature. After the reaction was complete, water was added for dilution, and the mixture was extracted with EA to separate the organic phase. The organic phase was concentrated and purified by column chromatography to obtain intermediate 1a (103 mg).

[0479] MS(ESI)m / z[M+H] + 414.3.

[0480] Step 2: Preparation of intermediate 1b

[0481] In a reaction flask, intermediate 1a (40 mg), DCM (2 mL), and TFA (1 mL) were added sequentially, and the reaction was carried out at room temperature. After the reaction was completed, the mixture was concentrated to obtain intermediate 1b (130 mg).

[0482] MS(ESI)m / z[M+H] + 358.2.

[0483] Step 3: Preparation of Compound 1

[0484] Intermediate Z2 (56 mg), intermediate 1b (104 mg), DMF (2 mL), and DIPEA (104 μL) were added sequentially to a reaction flask, followed by HATU (68 mg). The reaction was carried out at room temperature. After the reaction was complete, the mixture was diluted with water, extracted with EA, the organic phase was separated, concentrated, and purified by column chromatography to obtain compound 1 (103 mg).

[0485] MS(ESI)m / z[M+H] + 717.3.

[0486] 1 H NMR (500MHz, DMSO) δ11.07(s,1H),7.81–7.74(m,1H),7.55(dd,J=8.0,5.5Hz,1H),7.50(t,J=4.2Hz,1H),7.2 2(d,J=6.7Hz,1H),7.21–7.15(m,2H),6.83(tt,J=8.0,5.1Hz,1H),6.18(d,J=55.8Hz,1H),4.54(ddd,J=12.0 ,5.1,2.2Hz,1H),4.42–4.25(m,2H),4.06–3.90(m,4H),3.73–3.66(m,1H),3.18(dd,J=13.1,6.0Hz,3H),3.0 4(q,J=10.7Hz,3H),2.80–2.64(m,5H),2.63–2.57(m,2H),2.17(ddt,J=20.1,14.0,5.8Hz,2H),1.23(s,2H).

[0487] Example 2: Synthesis of Compound 2

[0488] Step 1: Preparation of intermediate 2a

[0489] Z2 (130 mg), DMF (3 mL), tert-butyl bromoacetate (47 mg), and DIPEA (60 μL) were added sequentially to the reaction flask, and the reaction was carried out at room temperature. After the reaction was complete, the reaction solution was diluted with water, extracted with EA, the organic phase was separated, concentrated, and purified by column chromatography to obtain intermediate 2a (42 mg).

[0490] MS(ESI)m / z[M+H] + 492.3.

[0491] Step 2: Preparation of intermediate 2b

[0492] Intermediate 2a (40 mg), DCM (2 mL), and TFA (1 mL) were added sequentially to a reaction flask, and the reaction was carried out at room temperature. After the reaction was completed, the mixture was concentrated to obtain intermediate 2b (65 mg).

[0493] MS(ESI)m / z[M+H] + 436.5.

[0494] Step 3: Preparation of Compound 2

[0495] 2b (55 mg), z5 (24 mg), DMF (2 mL), HATU (32 mg), and DIPEA (100 μL) were added sequentially to the reaction flask, and the reaction was carried out at room temperature. After the reaction was complete, water was added for dilution, and the mixture was extracted with EA. The organic phase was separated, concentrated, and purified by column chromatography to obtain compound 2 (35 mg). MS (ESI) m / z [M+H] + 717.3.

[0496] 1 H NMR (500MHz, DMSO) δ11.06(s,1H),7.81(d,J=8.1Hz,1H),7.58(d,J=8.0Hz,1H),7.46(d,J=4.0Hz,1H),7.26–7.19(m,2H),7.17(dd,J=11 .1,8.0Hz,1H),6.81(td,J=8.0,4.9Hz,1H),6.08(s,1H),4.55(dd,J=11.9,5.0Hz,1H),3.94(dd,J=11.6,4.1Hz,1H),3.88(d,J=11.4Hz,1 H),3.73–3.59(m,5H),3.42(d,J=6.0Hz,5H),3.26–3.21(m,1H),3.15(q,J=5.9Hz,2H),3.04(t,J=5.1Hz,1H),3.01–2.96(m,1H),2.76(dd d,J=18.8,9.0,3.8Hz,1H),2.60(dt,J=17.4,4.2Hz,1H),2.46(s,1H),2.18(dq,J=14.0,4.8Hz,1H),2.01(d,J=13.9Hz,1H),1.24(s,2H).

[0497] Example 3: Synthesis of Compound 3

[0498] Step 1: Preparation of intermediate 3a

[0499] Intermediate z2 (100 mg), N-tert-butyloxycarbonyl-4-piperidinone (79 mg), sodium cyanoborohydride (33 mg), and MeOH (2 mL) were mixed and reacted at 60 °C. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with DCM. The organic phase was separated, concentrated, and purified by column chromatography to obtain compound 3a (64 mg).

[0500] MS(ESI)m / z[M+H] + 561.37.

[0501] Step 2: Preparation of intermediate 3b

[0502] In a reaction flask, intermediate 3a (64 mg) and TFA (2 mL) were added sequentially, and the reaction was carried out at room temperature. After the reaction was completed, the reaction solution was concentrated to obtain intermediate 3b (107 mg).

[0503] MS(ESI)m / z[M+H] + :461.43.

[0504] Step 3: Preparation of Compound 3

[0505] Intermediate Z7 (100 mg), intermediate 3b (107 mg), sodium acetate (38 mg), sodium triacetoxyborohydride (74 mg), and DCE:IPA = 5:1 (v:v, 2 mL) were added sequentially to a reaction flask and mixed. The mixture was reacted at room temperature. After the reaction was complete, the solvent was removed from the reaction solution by vacuum distillation, and the crude product was purified by column chromatography to give compound 3 (51 mg).

[0506] MS(ESI)m / z[M+H] + 771.4.

[0507] 1H NMR (500MHz, DMSO) δ15.73(s,1H),11.06(d,J=3.5Hz,1H),7.85(d,J=8.1Hz,1H),7.51(d,J=8.0Hz,1H),7.46(d,J=4.0Hz,1H),7.26(s,1H),7.17(dd, J=9.4,5.7Hz,2H),6.82(td,J=8.0,4.9Hz,1H),6.08(s,1H),4.53(ddd,J=1 1.9,5.1,2.9Hz,1H),3.94(d,J=11.4Hz,1H),3.89(d,J=11.4Hz,1H),3.68( dd,J=13.1,4.4Hz,1H),3.40–3.34(m,5H),3.06(s,1H),2.95(dq,J=24.9,1 2.8Hz,3H),2.77(td,J=12.2,5.9Hz,3H),2.60(dt,J=17.4,4.0Hz,1H),2.4 8–2.39(m,2H),2.18(tt,J=8.9,4.6Hz,2H),2.12–2.02(m,3H),1.98(d,J=1 4.3Hz, 4H), 1.64 (s, 1H), 1.23 (s, 2H), 1.20 (d, J = 11.1Hz, 2H), 0.96 (s, 1H).

[0508] Example 4: Synthesis of Compound 4

[0509] Step 1: Preparation of intermediate 4b

[0510] Referring to the preparation method of intermediate 3a in step 1 of Example 3, N-tert-butoxycarbonyl-4-piperidinone was replaced with 1-Boc-3-azacyclobutanone to obtain intermediate 4a.

[0511] MS(ESI)m / z[M+H] + 533.49.

[0512] Step 2: Preparation of intermediate 4c

[0513] Referring to the preparation method of intermediate 3b in step 2 of Example 3, intermediate 3a is replaced with intermediate 4a to obtain intermediate 4b.

[0514] MS(ESI)m / z[M+H] + 433.37.

[0515] Step 3: Preparation of Compound 4

[0516] Referring to the preparation method of compound 3 in step 3 of Example 3, intermediate 3b was replaced with intermediate 4b to obtain compound 4.

[0517] MS(ESI)m / z[M+H] + 743.3.

[0518] 1 H NMR (500MHz, DMSO) δ15.71(s,1H),11.05(d,J=3.3Hz,1H),7.83(d,J=8.1Hz,1H),7.51(d,J=8.0Hz,1H),7.46(d,J=4.0Hz,1H),7.24(s,1H),7.1 7(q,J=5.7Hz,2H),6.82(td,J=8.0,4.9Hz,1H),4.53(ddd,J=11.8,5.0, 2.7Hz,1H),3.92(q,J=11.5Hz,2H),3.71–3.64(m,1H),3.41–3.33(m,3H) ,3.25(d,J=5.6Hz,4H),3.14(d,J=7.0Hz,1H),3.01–2.86(m,4H),2.76(td,J=12.0,5.4Hz,2H),2.60(dq,J=17.2,4.2Hz,1H),2.45(d,J=13.7Hz ,2H),2.31(s,1H),2.18(tt,J=8.4,4.7Hz,1H),2.00(d,J=14.2Hz,3H), 1.72(s,1H),1.25(d,J=4.7Hz,1H),1.24(s,2H),1.00(d,J=12.7Hz,1H).

[0519] Example 5: Synthesis of Compound 5

[0520] Following the procedure in step 3 of Example 3, intermediate z7 was replaced with intermediate z6 to obtain compound 5 (44 mg).

[0521] MS(ESI)m / z[M+H] + 771.4.

[0522] 1H NMR (500MHz, DMSO) δ15.73(s,1H),11.06(d,J=3.5Hz,1H),7.85(d,J=8.1Hz,1H),7.51(d,J=8.0Hz,1H),7.46(d,J=4.0Hz,1H),7.26(s,1H),7.17(dd, J=9.4,5.7Hz,2H),6.82(td,J=8.0,4.9Hz,1H),6.08(s,1H),4.53(ddd,J=1 1.9,5.1,2.9Hz,1H),3.94(d,J=11.4Hz,1H),3.89(d,J=11.4Hz,1H),3.68( dd,J=13.1,4.4Hz,1H),3.40–3.34(m,5H),3.06(s,1H),2.95(dq,J=24.9,1 2.8Hz,3H),2.77(td,J=12.2,5.9Hz,3H),2.60(dt,J=17.4,4.0Hz,1H),2.4 8–2.39(m,2H),2.18(tt,J=8.9,4.6Hz,2H),2.12–2.02(m,3H),1.98(d,J=1 4.3Hz, 4H), 1.64 (s, 1H), 1.23 (s, 2H), 1.20 (d, J = 11.1Hz, 2H), 0.96 (s, 1H).

[0523] Example 6: Synthesis of Compound 6

[0524] Step 1: Preparation of intermediate 6a

[0525] Referring to step 1 of Example 3, N-tert-butoxycarbonyl-4-piperidinone was replaced with 4-(dimethoxymethyl)cyclohexane-1-one to obtain compound 6a (135 mg).

[0526] MS(ESI)m / z[M+H] + :534.3.

[0527] Step 2: Preparation of intermediate 6b

[0528] Intermediate 6a (200 mg) was mixed with an aqueous formic acid solution (v:v = 1:1, 3 mL) and reacted at 50 °C. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure. The remaining solid was added to a saturated sodium bicarbonate solution until the pH reached 8, and then extracted with DCM. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate under reduced pressure to obtain 6b (115 mg).

[0529] Step 3: Preparation of Compound 6

[0530] Referring to step 3 of Example 3, intermediate z7 was replaced with intermediate 6b, and intermediate 3b was replaced with intermediate z5 to obtain compound 6 (75 mg).

[0531] MS(ESI)m / z[M+H] + 771.4.

[0532] 1 H NMR(500MHz,DMSO)δ15.64(s,1H),11.06(s,1H),7.80(s,1H),7.51(d,J=24.8Hz,2H ),7.18(s,3H),6.83(s,1H),6.10(t,J=55.5Hz,1H),4.54(d,J=11.7Hz,1H),3.94(s, 3H),3.69(d,J=11.7Hz,1H),3.09(d,J=62.2Hz,6H),2.69(d,J=72.7Hz,6H),2.23(d, J=48.2Hz,3H),1.93(d,J=93.9Hz,5H),1.48(s,1H),1.24(s,4H),1.12–0.71(m,4H).

[0533] Example 7 Synthesis of Compound 7

[0534] Step 1: Preparation of intermediate 7a

[0535] Referring to step 3 of Example 3, intermediate z7 was replaced with 1-tert-butoxycarbonylpiperidine-4-carboxaldehyde, and intermediate 3b was replaced with intermediate z5 to obtain intermediate 7a (450 mg).

[0536] MS(ESI)m / z[M+H] + 497.4.

[0537] Step 2: Preparation of intermediate 7b

[0538] 7a (440 mg), DCM (8 mL), and 1,4-dioxane hydrochloride (4 M, 4.5 mL) were added sequentially to the reaction flask, and the reaction was carried out at room temperature. After the reaction was completed, the solvent was removed from the reaction solution under reduced pressure to obtain intermediate 7b (438 mg).

[0539] MS(ESI,[M+H) + m / z: 397.5.

[0540] Step 3: Preparation of intermediate 7c

[0541] Intermediate 7b (120 mg), DIPEA (180 μL), and DCM (2 mL) were mixed, and triphosgene (46 mg) was slowly added at 0 °C. The mixture was then allowed to react at room temperature. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with DCM. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain intermediate 7c (130 mg).

[0542] Step 4: Preparation of Compound 7

[0543] Intermediate z2 (75 mg), intermediate 7c (130 mg), DIPEA (105 μL), and DCM (2 mL) were mixed and reacted at room temperature. After the reaction was complete, a saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with DCM, and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 7 (80 mg).

[0544] MS(ESI)m / z[M+H] + 800.5.

[0545] 1 H NMR (500MHz, DMSO) δ15.70(s,1H),11.07(s,1H),7.80(d,J=8.1Hz,1H),7.51(dd,J=19.9,5.9Hz,2H),7.24(s,1H),7.18 (dd,J=11.3,7.7Hz,2H),6.83(td,J=8.0,4.9Hz,1H),6.11(t,J=55.8Hz,1H),4.54(dd,J=12.0,5.0Hz,1H),4.06–3.89(m ,6H),3.77(d,J=12.9Hz,2H),3.68(d,J=11.9Hz,1H),3.14(s,2H),3.02(d,J=11.3Hz,3H),2.75(dt,J=15.1,11.8Hz,3H ),2.69–2.52(m,6H),2.31(s,2H),2.20–2.14(m,1H),2.10(d,J=14.0Hz,1H),1.74(d,J=12.1Hz,3H),1.07–0.95(m,2H).

[0546] Example 8: Synthesis of Compound 8

[0547] Step 1: Preparation of intermediate 8a

[0548] Referring to the preparation method of intermediate 3a in step 1 of Example 3, the N-tert-butoxycarbonyl-4-piperidinone was replaced with 1-Boc-3-azacyclobutanone, and intermediate z2 was replaced with intermediate z4 to obtain intermediate 8a.

[0549] MS(ESI)m / z[M+H] + :561.52.

[0550] Step 2: Preparation of intermediate 8b

[0551] Referring to the preparation method of intermediate 3b in step 2 of Example 3, intermediate 3a is replaced with intermediate 8a to obtain intermediate 8b.

[0552] MS(ESI)m / z[M+H] + 461.43.

[0553] Step 3: Preparation of Compound 8

[0554] Referring to the preparation method of compound 3 in step 3 of Example 3, intermediate 3b was replaced with intermediate 8b to obtain compound 8.

[0555] MS(ESI)m / z[M+H] + 771.4.

[0556] 1H NMR (500MHz, DMSO) δ15.79(s,1H),11.07(d,J=3.3Hz,1H),7.82(d,J=8.1Hz,1H),7. 53(d,J=4.1Hz,1H),7.51(d,J=8.0Hz,1H),7.24(s,1H),7.21–7.14(m,2H),6.82(td ,J=8.0,5.0Hz,1H),6.15(s,1H),4.53(ddd,J=11.8,5.0,2.7Hz,1H),3.90(d,J=11. 4Hz,1H),3.67(dt,J=12.3,4.0Hz,1H),3.38(d,J=15.8Hz,5H),3.19(d,J=11.7Hz,1H ),3.11(d,J=12.1Hz,1H),2.98–2.84(m,3H),2.76(qd,J=10.5,4.2Hz,3H),2.61(q, J=4.5Hz,1H),2.59–2.52(m,1H),2.49–2.42(m,1H),2.29(s,1H),2.17(ddq,J=13.9, 9.5,5.0Hz,3H),2.04(t,J=11.3Hz,2H),1.97(d,J=8.9Hz,1H),1.73(d,J=14.1Hz,2 H),1.67(d,J=6.4Hz,2H),1.45(d,J=5.6Hz,2H),1.24(d,J=7.6Hz,2H),1.01(s,1H).

[0557] Example 9: Synthesis of Compound 9

[0558] Step 1: Preparation of intermediate 9a

[0559] Referring to the preparation method of intermediate 3a in step 1 of Example 3, intermediate z2 is replaced with intermediate z4 to obtain intermediate 9a.

[0560] MS(ESI)m / z[M+H] + 589.57.

[0561] Step 2: Preparation of intermediate 9b

[0562] Referring to the preparation method of intermediate 3b in step 2 of Example 3, intermediate 3a was replaced with intermediate 9a to obtain intermediate 9b.

[0563] MS(ESI)m / z[M+H] + 489.44.

[0564] Step 3: Preparation of Compound 9

[0565] Referring to the preparation method of compound 3 in step 3 of Example 3, intermediate 3b was replaced with intermediate 9b to obtain compound 9.

[0566] MS(ESI)m / z[M+H] + 799.4.

[0567] 1 H NMR(500MHz,DMSO)δ15.77(s,1H),11.07(d,J=3.3Hz,1H),7.81(d,J=8.2Hz, 1H),7.54(d,J=4.1Hz,1H),7.51(d,J=8.0Hz,1H),7.23(s,1H),7.21–7.13(m ,2H),6.82(td,J=8.1,5.0Hz,1H),6.16(s,1H),4.53(ddd,J=11.9,5.1,2.8H z,1H),3.89(d,J=11.4Hz,1H),3.72–3.64(m,1H),3.50–3.34(m,5H),3.26–3. 15(m,2H),3.12(d,J=12.6Hz,1H),2.94(p,J=13.3Hz,4H),2.85–2.71(m,3H) ,2.64–2.57(m,2H),2.46(dd,J=12.4,4.8Hz,1H),2.18(ddq,J=13.4,9.3,4. 7Hz,2H),2.13–2.03(m,4H),2.01(s,1H),1.94(s,1H),1.88(s,1H),1.77(s, 2H), 1.73 (s, 2H), 1.49 (s, 2H), 1.24 (d, J = 5.7Hz, 2H), 0.96 (t, J = 10.4Hz, 1H).

[0568] Example 10: Synthesis of Compound 10

[0569] Step 1: Preparation of intermediate 10a

[0570] Intermediate z1 (100 mg), N-tert-butoxycarbonyl-4-piperidinone (79 mg), sodium cyanoborohydride (33 mg), and MeOH (2 mL) were mixed and reacted at 60 °C. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with DCM. The organic phase was separated, concentrated, and purified by column chromatography to obtain compound 10a (77 mg).

[0571] MS(ESI)m / z[M+H] + 561.4.

[0572] Step 2: Preparation of intermediate 10b

[0573] Referring to step 2 of Example 3, intermediate 3a was replaced with intermediate 10a to obtain intermediate 10b (110mg).

[0574] MS(ESI)m / z[M+H] + 461.5.

[0575] Step 10: Preparation of Compound 10

[0576] Referring to step 2 of Example 3, intermediate 3b was replaced with intermediate 10b and intermediate z7 was replaced with intermediate z6 to obtain compound 10 (33 mg).

[0577] MS(ESI)m / z[M+H] + 771.4.

[0578] 1 H NMR (500MHz, DMSO) δ15.73(s,1H),11.06(d,J=3.5Hz,1H),7.85(d,J=8.1Hz,1H),7.51(d,J=8.0Hz,1H),7.46(d,J=4.0Hz,1H),7.26(s,1H),7.17(dd, J=9.4,5.7Hz,2H),6.82(td,J=8.0,4.9Hz,1H),6.08(s,1H),4.53(ddd,J=1 1.9,5.1,2.9Hz,1H),3.94(d,J=11.4Hz,1H),3.89(d,J=11.4Hz,1H),3.68( dd,J=13.1,4.4Hz,1H),3.40–3.34(m,5H),3.06(s,1H),2.95(dq,J=24.9,1 2.8Hz,3H),2.77(td,J=12.2,5.9Hz,3H),2.60(dt,J=17.4,4.0Hz,1H),2.4 8–2.39(m,2H),2.18(tt,J=8.9,4.6Hz,2H),2.12–2.02(m,3H),1.98(d,J=1 4.3Hz, 4H), 1.64 (s, 1H), 1.23 (s, 2H), 1.20 (d, J = 11.1Hz, 2H), 0.96 (s, 1H).

[0579] Example 11 Synthesis of Compound 11

[0580] Following the procedure in step 2 of Example 3, intermediate 3b was replaced with intermediate 10b to obtain compound 11 (35 mg).

[0581] MS(ESI)m / z[M+H] + 771.4.

[0582] 1 H NMR (500MHz, DMSO) δ15.73(s,1H),11.06(d,J=3.5Hz,1H),7.85(d,J=8.1Hz,1H),7.51(d,J=8.0Hz,1H),7.46(d,J=4.0Hz,1H),7.26(s,1H),7.17(dd, J=9.4,5.7Hz,2H),6.82(td,J=8.0,4.9Hz,1H),6.08(s,1H),4.53(ddd,J=1 1.9,5.1,2.9Hz,1H),3.94(d,J=11.4Hz,1H),3.89(d,J=11.4Hz,1H),3.68( dd,J=13.1,4.4Hz,1H),3.40–3.34(m,5H),3.06(s,1H),2.95(dq,J=24.9,1 2.8Hz,3H),2.77(td,J=12.2,5.9Hz,3H),2.60(dt,J=17.4,4.0Hz,1H),2.4 8–2.39(m,2H),2.18(tt,J=8.9,4.6Hz,2H),2.12–2.02(m,3H),1.98(d,J=1 4.3Hz, 4H), 1.64 (s, 1H), 1.23 (s, 2H), 1.20 (d, J = 11.1Hz, 2H), 0.96 (s, 1H).

[0583] Example 12 Synthesis of Compound 12

[0584] Step 1: Preparation of intermediate 12a

[0585] Intermediate z8-1 (100 mg), N-tert-butyloxycarbonyl-4-piperidinone (79 mg), sodium cyanoborohydride (33 mg), and MeOH (2 mL) were mixed and reacted at 60 °C. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with DCM. The organic phase was separated, concentrated, and the crude product was purified by silica gel column chromatography to obtain compound 12a (93 mg).

[0586] MS(ESI)m / z[M+H] + 543.2.

[0587] Step 2: Preparation of intermediate 12b

[0588] Referring to step 2 of Example 3, intermediate 3a was replaced with intermediate 12a to obtain intermediate 12b (100mg).

[0589] MS(ESI)m / z[M+H] + :443.1.

[0590] Step 3: Preparation of Compound 12

[0591] Following the procedure in step 3 of Example 3, intermediate 3b was replaced with intermediate 12b to obtain compound 12 (38 mg).

[0592] MS(ESI)m / z[M+H] + 753.37.

[0593] 1 H NMR (500MHz, DMSO) δ14.78(s,1H),11.07(d,J=3.5Hz,1H),8.00(d,J=7.7Hz,1H),7.51(d,J=8.0Hz,1H),7.35(s,1H),7.22(d, J=7.6Hz,2H),7.18(d,J=8.1Hz,1H),6.87(t,J=7.9Hz,2H),6.13(d,J=55.8Hz,1H),4.53(dt,J=11.9,3.9Hz,1H),3.97–3.86( m,2H),3.66(d,J=11.5Hz,1H),3.40–3.35(m,1H),3.24(s,1H),3.13(s,1H),2.97(q,J=18.2Hz,4H),2.77(ddd,J=17.4,12.0, 6.1Hz,4H),2.62(d,J=4.6Hz,1H),2.36(s,2H),2.21–2.16(m,1H),2.15–1.84(m,9H),1.63(s,2H),1.18(s,2H),0.96(s,2H).

[0594] Examples 13-16: Synthesis of compounds 13-16

[0595] Following the synthetic route of compound 12, intermediate z8-1 was replaced with z9-z12, and intermediate z7 was replaced with z6 or z7, to synthesize compounds 13-16.

[0596] Preparation Examples: Synthesis of Compounds z13, z14, and z15

[0597] Referring to steps 6-11 and 13-14 of the synthesis process of intermediate z1, the reagent difluoromethyl trifluoromethanesulfonate in step 6 of the z1 synthesis process was replaced with iodomethane to prepare intermediate z13 (530 mg).

[0598] Compound z13: MS(ESI) m / z [M+H] + 342.3.

[0599] Referring to steps 6-11 and 13-14 of the synthesis process of intermediate z1, the reagent difluoromethyl trifluoromethanesulfonate in step 6 of the z1 synthesis process was replaced with bromomethyl methyl ether to prepare intermediate z14 (770 mg).

[0600] Compound z14: MS(ESI) m / z [M+H] + 372.3.

[0601] Following steps 7-11 and 13-14 of the synthesis process for intermediate z1, intermediate z15 (1.03 g) was obtained.

[0602] Compound z15: MS(ESI) m / z [M+H] + 328.4.

[0603] Example 17: Synthesis of Compound 17

[0604] Step 1: Preparation of intermediate 17a

[0605] Intermediate z13 (100 mg), N-tert-butoxycarbonyl-4-piperidinone (70 mg), sodium cyanoborohydride (30 mg), and MeOH (2 mL) were mixed and reacted at 60 °C. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with DCM. The organic phase was separated, concentrated, and the crude product was purified by silica gel column chromatography to obtain compound 17a (88 mg).

[0606] MS(ESI)m / z[M+H] + 525.2.

[0607] Step 2: Preparation of intermediate 17b

[0608] Referring to step 2 of Example 3, intermediate 3a was replaced with intermediate 17a to obtain intermediate 17b (110mg).

[0609] MS(ESI)m / z[M+H] + 425.1.

[0610] Step 3: Preparation of Compound 17

[0611] Following the procedure in step 3 of Example 3, intermediate 3b was replaced with intermediate 17b to obtain compound 17 (40 mg).

[0612] MS(ESI)m / z[M+H] + 735.37.

[0613] 1 H NMR (500MHz, DMSO) δ11.07(d,J=3.6Hz,1H),7.77(d,J=8.2Hz,1H),7.51(d,J=7.9Hz,1H),7.37(d,J=4.1Hz,1H) ,7.25–7.10(m,2H),6.97(s,1H),6.77(td,J=8.1,5.0Hz,1H),4.53(ddd,J=11.8,5.0,2.9Hz,1H),3.90(d,J=11. 7Hz,1H),3.71–3.63(m,1H),3.46–3.34(m,5H),3.10(s,1H),3.00–2.89(m,3H),2.89–2.66(m,4H),2.64–2.58(m ,1H),2.47(t,J=6.4Hz,1H),2.33–1.77(m,11H),1.65(s,2H),1.21(d,J=20.9Hz,2H),1.11(s,3H),0.96(s,2H).

[0614] Example 18: Synthesis of Compound 18

[0615] Following the synthesis process of compound 17, compound z13 was replaced with z14 to obtain compound 18 (45 mg).

[0616] MS(ESI)m / z[M+H] + 765.39.

[0617] 1H NMR (500MHz, DMSO) δ16.12(s,1H),11.07(d,J=3.6Hz,1H),7.80(d,J=8.1Hz,1H),7.51(d,J=7.9Hz,1H),7.33(d,J=4.1Hz,1H),7.15(dd,J=18.9,9.6 Hz,2H),7.06(s,1H),6.78(td,J=8.1,4.9Hz,1H),4.53(dt,J=12.0,3.9Hz ,1H),3.94(d,J=11.4Hz,1H),3.67(d,J=11.5Hz,1H),3.59(dd,J=11.5,4. 2Hz,1H),3.37(dd,J=16.0,6.7Hz,2H),3.27(s,5H),3.09(d,J=27.2Hz,2H ),3.01–2.87(m,3H),2.86–2.68(m,5H),2.66–2.56(m,1H),2.45(s,1H),2 .35(d,J=12.7Hz,1H),2.18(tt,J=9.2,4.9Hz,1H),2.00(d,J=72.8Hz,8H) ,1.75(d,J=13.0Hz,1H),1.62(s,2H),1.18(s,2H),0.94(d,J=14.2Hz,2H).

[0618] Example 19: Synthesis of Compound 19

[0619] Following the synthesis process of compound 17, compound z13 was replaced with z15 to prepare compound 19 (43 mg).

[0620] MS(ESI)m / z[M+H] + 721.36.

[0621] 1H NMR (500MHz, DMSO) δ11.07(d,J=3.7Hz,1H),7.74(d,J=8.1Hz,1H),7.51(d,J=7. 9Hz,1H),7.29(d,J=3.9Hz,1H),7.18(d,J=8.1Hz,1H),7.14(dd,J=11.1,7.8Hz,1 H),6.94(s,1H),6.77(td,J=8.0,4.9Hz,1H),4.53(ddd,J=12.0,5.0,3.0Hz,1H), 3.73(d,J=11.4Hz,1H),3.63(tq,J=14.1,4.0Hz,2H),3.54(d,J=11.5Hz,1H),3.3 8(d,J=7.1Hz,1H),3.35(d,J=7.8Hz,1H),3.20(s,3H),2.93(dt,J=19.6,8.4Hz,3 H),2.77(td,J=12.2,6.1Hz,4H),2.60(dt,J=17.1,3.9Hz,1H),2.46(t,J=6.6Hz, 1H),2.30(s,1H),2.18(tt,J=8.8,4.7Hz,2H),2.05(d,J=37.7Hz,4H),1.96(s,2H ),1.68(t,J=12.3Hz,3H),1.25(d,J=5.0Hz,1H),1.23(s,2H),1.01–0.91(m,2H).

[0622] Example 20: Synthesis of Compound 20

[0623] Referring to step 3 of Example 3, intermediate 3b was replaced with intermediate 10b, and intermediate z7 was replaced with intermediate z16 (WO2024037616A1, compound 26a) to obtain compound 20 (42mg).

[0624] MS(ESI)m / z[M+H] + 743.33.

[0625] 1H NMR (500MHz, DMSO) δ15.77(s,1H),11.08(s,1H),7.86(d,J=8.1Hz,1H),7.60(d,J=8.0Hz,1H),7.47(d,J=4.1Hz,1H),7.34–7.23(m,2H) ,7.17(dd,J=11.1,7.9Hz,1H),6.82(td,J=8.1,5.0Hz,1H),6.08(t,J=55.8Hz,1H),4.56(dd,J=11.6,5.1Hz,1H),4.01–3.84(m,2H),3.6 7(dd,J=12.9,4.3Hz,1H),3.16(tt,J=15.3,7.7Hz,5H),3.07–2.95(m,2H),2.92–2.70(m,6H),2.60(dt,J=17.7,4.5Hz,1H),2.49–2.45 (m,1H),2.41(d,J=13.8Hz,1H),2.31(s,2H),2.19(dq,J=12.9,4.3Hz,1H),1.97(d,J=13.5Hz,4H),1.63(s,2H),1.21(d,J=21.9Hz,2H).

[0626] Example 21: Synthesis of Compound 21

[0627] Following the procedure in step 3 of Example 1, intermediate z2 was replaced with intermediate 12b to obtain compound 21 (34 mg).

[0628] MS(ESI)m / z[M+H] + 782.36.

[0629] 1H NMR (500MHz, DMSO) δ14.80(s,1H),11.08(s,1H),8.00(d,J=8.0Hz,1H),7.55(d,J=8 .0Hz,1H),7.34(d,J=4.0Hz,1H),7.25–7.15(m,3H),6.86(dd,J=8.8,4.6Hz,2H),6.1 3(d,J=55.8Hz,1H),4.55(dd,J=12.0,5.0Hz,1H),4.01(d,J=12.8Hz,1H),3.94(d,J= 11.3Hz,2H),3.88(d,J=11.4Hz,1H),3.69–3.63(m,1H),3.38(d,J=13.7Hz,1H),3.26 (d,J=9.6Hz,2H),3.15(t,J=7.6Hz,4H),3.10–3.01(m,3H),2.97(d,J=12.3Hz,1H),2 .88(d,J=13.4Hz,1H),2.77(td,J=12.0,6.0Hz,1H),2.74–2.58(m,5H),2.47(dd,J=1 2.2,4.4Hz,1H),2.41(d,J=13.8Hz,1H),2.28–2.22(m,1H),2.21–2.15(m,1H),1.97( d,J=14.0Hz,1H),1.65(d,J=35.6Hz,2H),1.20(d,J=10.6Hz,1H),1.08–1.01(m,1H).

[0630] Example 22 Synthesis of Compound 22

[0631] Step 1: Preparation of intermediate 22c

[0632] Intermediate 22a (25 g), intermediate 22b (31 g), PdCl2 (dppf) (6 g), potassium carbonate (29 g), and 1,4-dioxane:water = 4:1 (v:v, 250 mL) were mixed and reacted at 90 °C for 3 h under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with saturated ammonium chloride aqueous solution, and then extracted with EA. The organic layers were combined, washed with sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation of the filtrate. The crude product was purified by silica gel column chromatography to obtain intermediate 22c (31 mg).

[0633] MS(ESI)m / z[M+H] + 464.2.

[0634] Step 2: Preparation of intermediate 22d

[0635] Intermediate 22c (10.5 g), 4-hydroxymethylpiperidine (6.2 g), tris(dibenzylacetone)palladium (1.6 g), Ruphos (1.7 g), cesium carbonate (11.5 g), and 1,4-dioxane (150 mL) were mixed and reacted at 90 °C for 4 h under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with saturated ammonium chloride aqueous solution, and then extracted with EA. The organic layers were combined, washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation of the filtrate. The crude product was purified by silica gel column chromatography to obtain intermediate 22d (3.7 g).

[0636] MS(ESI)m / z[M+H] + 499.2.

[0637] Step 3: Preparation of intermediate 22e

[0638] Intermediate 22d (3.5 g), palladium on carbon (1.5 g), palladium hydroxide (1.5 g), and methanol (70 mL) were mixed and reacted at 40 °C for 12 h under hydrogen atmosphere. After the reaction was complete, the reaction solution was cooled to room temperature, and insoluble matter was removed by filtration. The solvent in the filtrate was removed by vacuum evaporation to obtain intermediate 22e (1.5 g).

[0639] MS(ESI)m / z[M+H] + 321.2.

[0640] Step 4: Preparation of Compound 22

[0641] Intermediate 22e (70 mg), DMSO (2 mL), and 2-iodobenzoic acid (130 mg) were reacted at room temperature. After the reaction was complete, the reaction was quenched with water and saturated sodium bicarbonate solution, extracted with ethyl acetate, and concentrated. The resulting concentrate was added to a DCE / IPA solution of intermediate 10b (100 mg), sodium acetate (75 mg), and sodium triacetoxyborohydride (65 mg) in a ratio of 5:1 (v:v, 2 mL) and reacted at room temperature. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound 22 (62 mg).

[0642] MS(ESI)m / z[M+H] + 763.37.

[0643] 1H NMR (500MHz, DMSO) δ15.78(s,1H),10.80(s,1H),7.86(d,J=8.1Hz,1H),7.48(d,J=4.0Hz,1H),7.27(s,1H),7.18(dd,J=11.1,7.9Hz,1H),7.0 6(t,J=8.7Hz,1H),6.82(td,J=8.1,5.0Hz,1H),6.73–6.66(m,2H),6.0 9(s,1H),3.94(d,J=11.4Hz,1H),3.91–3.84(m,2H),3.73–3.64(m,3H), 3.26(d,J=6.6Hz,2H),3.16(s,1H),3.05(s,1H),2.99(dd,J=12.2,4.3Hz,1H),2.75(d,J=16.4Hz,2H),2.73–2.63(m,3H),2.53(s,1H),2.41(d ,J=13.8Hz,1H),2.14(ddt,J=17.0,12.7,5.3Hz,3H),2.03–1.92(m,4H),1.75(d,J=12.6Hz,2H),1.63(s,3H),1.24(s,1H),1.20–1.11(m,4H).

[0644] Example 23 Synthesis of Compound 23

[0645] Referring to Example 22, intermediate 22a from step 1 was replaced with intermediate 23a to synthesize compound 23 (55 mg).

[0646] MS(ESI)m / z[M+H] + 781.36.

[0647] 1H NMR (500MHz, DMSO) δ15.75(s,1H),10.86(s,1H),7.85(d,J=8.1Hz,1H),7.47(d,J=4.0Hz,1H),7.26(s,1H),7.17(dd,J= 11.1,7.9Hz,1H),6.81(td,J=8.0,4.9Hz,1H),6.60(d,J=13.2Hz,2H),6.08(t,J=55.8Hz,1H),4.03(dd,J=12.6,5.2Hz, 1H),3.91(q,J=11.4Hz,2H),3.78–3.63(m,3H),3.23(s,2H),3.12(s,1H),2.98(d,J=14.8Hz,2H),2.83–2.65(m,5H),2. 40(d,J=13.9Hz,1H),2.08(ddd,J=26.1,13.0,4.3Hz,3H),2.02–1.83(m,5H),1.79–1.51(m,6H),1.14(p,J=10.7Hz,4H).

[0648] Example 24: Synthesis of Compound 24

[0649] Referring to step 3 of Example 3, intermediate 3b was replaced with intermediate 10b, and intermediate z7 was replaced with intermediate 24a (WO 2022206924A1, intermediate E) to obtain compound 24 (55 mg).

[0650] MS(ESI)m / z[M+H] + 800.39.

[0651] 1H NMR (500MHz, DMSO) δ15.77(s,1H),10.96(s,1H),7.86(d,J=8.1Hz,1H),7.47(d,J=4.0Hz,1H),7.40(d,J=8.4Hz,1H),7.31–7.2 2(m,2H),7.22–7.11(m,2H),6.81(td,J=8.0,5.0Hz,1H),6.08(t,J=55.8Hz,1H),5.09(dd,J=13.3,5.1Hz,1H),4.32(d,J=16.5H z,1H),4.20(d,J=16.6Hz,1H),3.97–3.85(m,2H),3.79–3.63(m,3H),3.30–3.21(m,2H),3.12(s,1H),2.99(d,J=15.8Hz,2H),2 .91(ddd,J=18.1,13.6,5.4Hz,1H),2.71(q,J=12.8Hz,4H),2.63–2.55(m,1H),2.38(tt,J=13.3,6.3Hz,2H),2.13(s,2H),2.04–

[0652] 1.84(m,5H),1.83–1.72(m,2H),1.61(s,3H),1.20(dd,J=25.1,13.3Hz,4H).

[0653] Test Example 1: Determination of SMARCA2 / SMARCA4 protein degradation in cells by the compound

[0654] HeLa-SMARCA2-HiBiT cells in the exponential growth phase were collected into centrifuge tubes and the cell density was adjusted to 1.25*102. 5 Cells were seeded at a density of 10 cells / mL into 384-well plates (20 μL / well). Cells were cultured in an incubator for 5 hours to ensure full adhesion. Then, compounds were added using a nanoparticle pipette to achieve a final concentration of 100 nM - 0.023 nM, with two replicates. A control was also included. After 18 hours of continuous culture in an incubator, [the cells were then]... Detection was performed using the HiBiT Lytic Detection System kit (Promega, #N3050). Remove the culture plate, allow it to equilibrate to room temperature beforehand, and add 20 μl of the solution to each well. HiBiT Lytic Reagent was used, followed by oscillation at 400 rpm for 10 minutes before detection. The plate was thoroughly agitated during detection. Detection was performed using a PerkinElmer Envision microplate reader in 384-well ultrasensitive luminescence mode. Four-parameter analysis was performed, a dose-response curve was fitted, and DC was calculated.50 The experimental results are shown in Table 1.

[0655] HeLa-SMARCA4-HiBiT cells in the exponential growth phase were collected into centrifuge tubes and the cell density was adjusted to 1.25*10⁻⁶. 5 Cells were seeded at a density of 10 cells / mL into 384-well plates (20 μL / well). Cells were cultured in an incubator for 5 hours to ensure full adhesion. Then, compounds were added using a nanoparticle pipette to achieve a final concentration of 3000 nM - 0.70 nM, with two replicates. A control was also included. After 18 hours of continuous culture in an incubator, [the cells were then]... Detection was performed using the HiBiT Lytic Detection System kit (Promega, #N3050). Remove the culture plate, allow it to equilibrate to room temperature beforehand, and add 20 μl of the solution to each well. HiBiT Lytic Reagent was used, followed by oscillation at 400 rpm for 10 minutes before detection. The plate was thoroughly agitated during detection. Detection was performed using a PerkinElmer Envision microplate reader in 384-well ultrasensitive luminescence mode. Four-parameter analysis was performed, a dose-response curve was fitted, and DC was calculated. 50 .

[0656] Table 1. Activity of compounds on SMARCA2 protein degradation in cells.

[0657] The experimental results show that the compound of this application has a degrading effect on SMARCA2 and / or SMARCA4 proteins, or selectively degrades SMARCA2.

[0658] Inhibitory effect of compound in Experiment 2 on the proliferation of NCI-H838 cells

[0659] NCI-H838 cells (SMARCA4 deficient) in good growth condition were collected into centrifuge tubes, and the cell density was adjusted to 2500 cells / mL. The cells were then seeded into 96-well plates (100 μL / well) and cultured overnight. Compounds were added using a nanoparticle pipette to achieve a final concentration of 10000 nM - 4.6 nM, with two replicates. A control was also included. After culturing for 7 days, the assay reagent CCK-8 (manufacturer: Dojin Chemical, Japan, 10 μL / well) was added. After incubation for 2 hours, the absorbance was measured at 450 nm using an Envision microplate reader. Four-parameter analysis was performed, a dose-response curve was fitted, and the IC50 was calculated. 50 The results are shown in Table 2.

[0660] The experimental results show that the compound of this application has an inhibitory effect on the proliferation of NCI-H838 cells (SMARCA4 deficient).

[0661] Inhibitory effect of compound 3 on the proliferation of SK-MEL-5 cells

[0662] SK-MEL-5 cells (SMARCA4 deficient) in the exponential growth phase were collected into centrifuge tubes, and the cell density was adjusted to 5000 cells / mL. The cells were then seeded into 96-well plates (100 μL / well). Simultaneously, a nanoparticle pipette was used to add compounds to a final concentration of 100 nM - 0.046 nM, with two replicates. A control was also included. After culturing for 7 days, the assay reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL / well) was added. After incubation for 2 hours, the absorbance was measured at 450 nm using a PerkinElmer Envision microplate reader. Four-parameter analysis was performed, a dose-response curve was fitted, and the IC50 was calculated. 50 The results are shown in Table 2.

[0663] The experimental results show that the compound of this application has an inhibitory effect on the proliferation of SK-MEL-5 cells (SMARCA4 deficient).

[0664] Table 2. Cell proliferation inhibitory activity of the compounds

[0665] Experimental Example 4: In vitro pharmacokinetics

[0666] Liver microparticles (species: human, dog, rat, or mouse) were incubated at body temperature with a mixture of PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / mL), the test compound, and NADPH + MgCl2 solution at 37°C and 300 rpm for 1 hour. Samples at 0 hours were prepared with a mixture of PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / mL), and the test compound. The samples were precipitated with acetonitrile containing an internal standard to obtain a supernatant, which was then diluted for LC / MS / MS analysis. Results are shown in Table 3.

[0667] Table 3. Hepatic microsomal metabolic stability

[0668] The experimental results show that the compound of this application is metabolically stable in liver microsomes in vitro.

Claims

1. A compound of formula I, its stereoisomers, or a pharmaceutically acceptable salt thereof, PTM-L-CLM I L is selected from a linking group; PTM is selected from R 2 are each independently selected from deuterium, halogen, -OH, -NH2, -CN, COOH, -CONH2, or the following groups optionally substituted with one or more R 2a’ substituents: C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylNH-, (C 1-10 alkyl)2N-, C 1-10 alkylC(O)-, C 1-10 alkylC(O)O-, C 1-10 alkylOC(O)-, C 1-10 alkylC(O)NH-, C 1-10 alkylNHC(O)-, C 1-10 alkylS(O)NH-, C 1-10 alkylNHS(O)-, C 1-10 alkylS(O)2NH-, C 1-10 alkylNHS(O)2-, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl, or 5-12 membered heteroaryl; Each R 2a’ Each is independently selected from deuterium, halogens, -OH, -NH2, -CN, and C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, C 1-10 Alkyl NH-, (C 1-10 Alkyl)2N-, C 3-12 Cycloalkyl or 3-12 membered heterocyclic alkyl; m is selected from 0, 1, 2, 3, 4, 5, 6 or 7; L 2 is selected from a bond, or is selected from C 1-6 alkylene or C 2-6 alkenylene, said C 1-6 alkylene or C 2-6 alkylene or C 1-6 alkylene or C 2-6 alkylene or C L alkylene or C L is selected from deuterium, halogen, -CN, OH, NH2, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl; R 3 is selected from the group consisting of optionally substituted C 3a substituted with one or more R 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl, or 5-12 membered heteroaryl; each R 3a is independently selected from deuterium, halogen, -CN, C 1-12 alkyl, halo or hydroxy substituted C 1-6 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl, 5-12 membered heteroaryl, 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 each 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 heteroaryl C 1- 3 alkylene-; Cyclomeric G is selected from 5-12 heteroaryl groups; Ring E is selected from C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl; Ring F is selected from C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl; Ring H is selected from C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl; CLM is selected from Indicates a single bond or a double bond; Each R 1 The following groups, each independently selected from deuterium, halogens, -OH, -NH2, -CN, and optionally substituted by 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 group, C 3-10 Cycloalkyl or 3-10 membered heterocyclic alkyl; n is selected from 0, 1, 2, or 3; Ring W is selected from 5-20 element rings; X 5 selected from C(R f ) or N; R f selected from H, halogen, deuterium, or C 1-6 alkyl; L 1 selected from a bond, -NH-, -0-, -S-, -CONH- or -CON(C 1-6 alkyl)-; each R is independently selected from deuterium, hydroxyl, halogen, amino, cyano, or C1-C6alkyl; a each R is independently selected from deuterium, hydroxyl, halogen, amino, cyano, or C 1-8 alkyl; q is selected from 0, 1, 2, or 3; X 4 selected from N or CH optionally substituted with one or more substituents.

2. Compounds of formula II, their stereoisomers, or pharmaceutically acceptable salts thereof, in, Indicates a single bond or a double bond; Ring A is selected from C 3-15 cycloalkenyl, or 3-15 membered heterocycloalkenyl; Ring B is selected from phenyl or 6-membered heteroaryl; Cyclic C is selected from 5-membered heteroaryl groups; Each R 1 The following groups are independently selected from deuterium, halogens, -OH, -NH2, -CN, and optionally substituted by one or more substituents: C 1- 10 Alkyl, C 1-10 Alkoxy, (C 1-10 alkyl)NH-, (C 1-10 Alkyl)2N-, hydroxyl or halogenated C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Cycloalkyl or 3-10 membered heterocyclic alkyl; n is selected from 0, 1, 2, or 3; X 5 selected from C(R f ) or N; R f selected from H, halogen, deuterium, or C 1-6 alkyl optionally substituted with one or more substituents selected from halogen, deuterium, or C L 1 selected from a bond, -NH-, -0-, -S-, -CONH- or -CON(C 1-6 alkyl)-; L is selected from a linking group; PTM is a structural portion selected from the protein-binding portion of SMARCA2 and / or SMARCA4.

3. The compound of claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, selected from compounds of formula III, their stereoisomers, or pharmaceutically acceptable salts thereof.

4. The compound of claim 1 or 3, its stereoisomers or pharmaceutically acceptable salts thereof, wherein the ring W is selected from 5-15 membered rings; Alternatively, the ring W is selected from 5-12 element rings; Alternatively, the ring W is selected from 5-10 element rings; Alternatively, the ring W is selected from 5-7 element rings; or said ring W is selected from 5-15 membered heterocyclenyl, C 6-15 aryl, 5-15 membered heteroaryl, C 5-15 cycloalkyl or 5-15 membered heterocycloalkyl; or said ring W is selected from 5-12 membered heterocycloalkenyl, C 6-12 aryl, 5-12 membered heteroaryl, C 5-12 cycloalkyl or 5-12 membered heterocycloalkyl; or said ring W is selected from 5-10 membered heterocycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl, C 5-10 cycloalkyl or 5-10 membered heterocycloalkyl; or said ring W is selected from 5-7 membered heterocycloalkenyl, C 6-10 aryl, 5-7 membered heteroaryl, C 5-7 cycloalkyl or 5-7 membered heterocycloalkyl; or said ring W is selected from C 6-10 aryl, 5-6 membered heteroaryl, or 5-14 membered heterocyclenyl; Alternatively, the ring W is selected from phenyl, or 9-membered, or 12-14-membered heterocyclic alkenyl groups; Alternatively, the ring W is selected from... wherein 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 selected from 5-6 membered heteroaryl.

5. The compound of claim 4, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is absent, or is selected from C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, phenyl, or 5-6 membered heteroaryl; or, ring A is absent, or is selected from C 5-15 cycloalkenyl, 5-15 membered heterocycloalkenyl, phenyl, or 5-6 membered heteroaryl; or, ring A is selected from C 3-15 cycloalkenyl or 3-15 membered heterocycloalkenyl; or, ring A is absent, or is selected from C 5-10 cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl, or 5-6 membered heteroaryl; or, ring A is absent, or is selected from C 5-9 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl, or 5-6 membered heteroaryl; or, ring A is absent, or is selected from C 5-7 cycloalkenyl, 5-7 membered heterocycloalkenyl, phenyl, or 5-6 membered heteroaryl; or, ring A is absent, or is selected from C 5-9 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl, pyrrolyl, pyrazolyl, furanyl, or oxazolyl; Alternatively, ring A is absent, or is selected from C5 cycloalkenyl, C6 cycloalkenyl, C7 cycloalkenyl, C8 cycloalkenyl, C9 cycloalkenyl, 5-membered, 6-membered, 7-membered, 8-membered or 9-membered heterocyclic alkenyl, phenyl, pyrroleyl, pyrazolyl, furanyl or oxazolyl. Alternatively, ring A is absent, or is selected from cyclopentenyl, monocyclohexenyl, dicyclohexenyl, cycloheptenyl, dihydropyrroleyl, tetrahydropyridyl, tetrahydroaza. The following groups are used: α-spirocyclooctenyl, α-spirocyclononenyl, phenyl, pyrroleyl, pyrazolyl, furanyl, oxazolyl, or dihydrooxazinyl. Optionally, ring B is selected from phenyl or 6-membered heteroaryl; Alternatively, ring B is selected from phenyl or pyridyl; Optionally, the ring C is selected from 5-membered heteroaryl groups; Alternatively, the ring C may be selected from isoxazolyl, pyrazolyl, or furanyl.

6. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, or a structural fragment thereof, as described in any one of claims 2, 4-5. Selected from Or, structural fragments Selected from Or, structural fragments Selected from Or, structural fragments Selected from Or, structural fragments Selected from Or, structural fragments Selected from 7. The compound of any one of claims 1-6, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein each R 1 is independently selected from deuterium, halogen, -OH, -NH2, -CN, optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, (C 1-10 alkyl)NH-, (C 1-10 alkyl)2N-, hydroxy, or 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 The following groups are independently selected from deuterium, halogens, -OH, -NH2, -CN, and optionally substituted by 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 deuterium, halogens, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 alkoxy or halogenated C 1-4 alkyl; or each R is independently selected from deuterium, halogen, -OH, -NH2, -CN, C 1 alkyl, C 1-3 alkyl, C 1-3 alkoxy, or halogenated C 1-3 alkyl; Or, each R 1 Independently selected from fluorine, chlorine, bromine, -OH, -NH2, or -CN; Optionally, the R 1 wherein one or more substituents is selected from deuterium, halogen, -OH, -NH2, -CN, C 1-3 alkyl, C 1-3 alkoxy, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl; or the R 1 group is selected from: deuterium, halogen, -OH, -NH2, -CN, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, C6aryl, 3-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; Optionally, n is selected from 0, 1, or 2.

8. The compound of any one of claims 1-7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, X 5 selected from C(R f ); or X 5 is selected from CH or N; Optionally, R f is selected from H, fluorine, chlorine, bromine, deuterium or C 1-3 alkyl; or R is selected from H, fluoro, chloro, bromo, deuterium or C f selected from H, fluoro, chloro, bromo, deuterium or C 1-3 alkyl, said C 1-3 alkyl is optionally substituted with one or more halogen, -OH, -NH2or -CN; or R is selected from H, fluoro, chloro, bromo, deuterium or C f selected from H, fluoro, chloro, bromo, deuterium or C 1-3 alkyl.

9. The compound of any one of claims 1-8, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the L 1 is selected from a bond, -NH-, or -CONH-.

10. The compound of any one of claims 1-9, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of C 1-50 alkylene, C 2-50 alkenylene, or C 2-50 alkynylene, optionally one or more -CH2- in said C 1-50 alkylene, C 2- 50 alkenylene, or C 2-50 alkynylene is independently optionally replaced with -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-; or said L is selected from the group consisting of C 1-30 alkylene, C 2-30 alkenylene or C 2-30 alkynylene, optionally 1 or more -CH2- in said C 1-30 alkylene, C 2-30 alkenylene or C 2-30 alkynylene is independently optionally replaced with -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-; or said L is selected from the group consisting of C 1-20 alkylene, C 2-20 alkenylene or C 2-20 alkynylene, optionally 1 or more -CH2- in said C 1-20 alkylene, C 2-20 alkenylene or C 2-20 alkynylene is independently optionally replaced with -O-, C 3- 10 cycloalkyl, 3-11 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl, -NH-, -N(C 1-6 alkyl)- or -S-; or said L is selected from the group consisting of C 1-15 alkylene, C 2-15 alkenylene or C 2-15 alkynylene, optionally 1 or more -CH2- in said C 1-15 alkylene, C 2-15 alkenylene or C 2-15 alkynylene is independently optionally replaced with -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-; or said L is selected from the group consisting of C 1-10 alkylene, C 2-10 alkenylene or C 2-10 alkynylene, optionally said C 1-10 alkylene, C 2-10 alkenylene or C 2-10 alkynylene, independently from one another, 1 or more -CH2- in said 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-; or said L is selected from the group consisting of C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, optionally said C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, independently of each other, 1 or more -CH2- in said 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-; or said L is selected from the group consisting of C 1-4 alkylene, C 2-4 alkenylene or C 2-4 alkynylene, optionally 1 or more (e.g., 1 or 2, 1 or 3, etc.) -CH2- of said C 1-4 alkylene, C 2-4 alkenylene or C 2-4 alkynylene is independently optionally replaced with -O-, C 4-6 cycloalkyl, 4-11 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, -NH-, -N(C 1-3 alkyl)- or -S-; or said L is selected from C 1-10 alkylene or C 2-10 alkynylene, optionally, said C 1-10 alkylene or C 2-10 alkylene or C 3-12 alkylene or C 1-6 alkylene or C or said L is selected from C 1-6 alkylene or C 2-6 alkynylene, optionally one or more -CH2- in said C 1-6 alkylene or C 2-6 alkynylene is independently optionally replaced with one or more -CH2- selected from -O-, C 3-10 cycloalkyl, 4-11 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl, 5-6 membered heteroaryl, -NH-, -N(C 1-3 alkyl)- or -S-; or said L is selected from C 1-6 alkylene or C 2-6 alkynylene, optionally one or more -CH2- in said C 1-6 alkylene or C 2-6 alkynylene is independently optionally replaced with one or more -CH2- selected from -O-, C 3-10 cycloalkyl, 4-11 membered heterocycloalkyl, 5-6 membered heteroaryl, -NH-, -N(C 1-3 alkyl)- or -S-; or, in the definition of L, the substituent is selected from deuterium, halogen, =0, -OH, -NH2, -CN, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, (C 1-6 alkyl)NH-, (C 1-6 alkyl)2N-, C 3-12 cycloalkyl or 4-12 membered heterocycloalkyl; or, in the definition of L, the substituent is selected from deuterium, halogen, =0, -OH, -NH2, -CN, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, hydroxy C 1-6 alkyl, (C 1-4 alkyl)NH-, (C 1-4 alkyl)2N-, C 3-10 cycloalkyl or 4-10 membered heterocycloalkyl; Alternatively, in the definition of L, the substituent is =O or HOCH2-; or, in the definition of L, the substituent is selected from =0, hydroxyC 1-3 alkyl, -NH2, -CN, halo, C 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkyl, (C 1-3 alkyl)NH- or (C 1-3 alkyl)2N-.

11. The compound of any one of claims 1-9, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein the L is selected from -LNK. 1 -Cy 1 -LNK-Cy 2 -LNK 2 -Cy 3 -,in, Cy 1 , Cy 2 , or Cy 3 are each independently selected from a bond, or the following groups optionally substituted with one or more R b ; C 3-12 ycloalkyl, 4-12 membered heterocycloalkyl, C 6-12 aryl, 5-12 membered heteroaryl, or 4-12 membered heterocycloalkenyl; LNK, LNK 1 and LNK 2 Each is independently selected from the bond, -NH-, -O-, -S-, or optionally by one or more R- bonds. c The following groups are substituted: C 1-12 Alkylene, C 2-12 imidene group, C 2-12 alkyne or C 1-12 Heteroalkylene; Each R b and R c Each is independently selected from deuterium, halogens, =O, -OH, -NH2, -CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, (C 1-6 alkyl)NH-, (C 1-6 Alkyl)2N-, C 3-12 Cycloalkyl or 4-12 membered heterocyclic alkyl; Optional, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, -NH-, -O-, -S-, or optionally by one or more R- bonds. c The following groups are substituted: C 1-10 Alkylene, C 2-10 imidene group, C 2-10 alkyne or C 1-10 Heteroalkylene; Or, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, -NH-, -O-, -S-, or optionally by one or more R- bonds. c The following groups are substituted: C 1-6 Alkylene, C 2-6 imidene group, C 2-6 alkyne or C 1-6 Heteroalkylene; Or, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, -NH-, -O-, -S-, or optionally by one or more R- bonds. c The following groups are substituted: C 1-4 Alkylene, C 2-4 imidene group, C 2-4 alkyne or C 1-4 Heteroalkylene; Or, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, -NH-, -O-, -S-, or optionally by one or more R- bonds. c The following groups are substituted: C 1-6 Alkylene, C 2-6 alkyne or C 1-6 Heteroalkylene; Or, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, -NH-, -O-, -S-, or optionally by one or more R- bonds. c The following groups are substituted: C 1-4 Alkylene, C 2-4 alkyne or C 1-4 Heteroalkylene; Or, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, -NH-, -O-, or optionally by one or more R c The following groups are substituted: C 1-3 Alkylene, C 2-3 alkyne or C 1-3 Heteroalkylene; Or, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, -NH-, -O-, or optionally by one or more R c The following groups are substituted: C 1-2 alkylene, C2-alkynyl or C 1-2 Heteroalkylene; Or, LNK, LNK 1 and LNK 2 Each group is independently selected from the following groups: bond, -NH-, -O-, -NHCH2-, -CH2NHCH2-, -CH2-, -CH2CH2-, ethynyl group, -C(O)-, or -C(O)CH2-. Or, LNK, LNK 1 and LNK 2 Each is independently selected from the key, or selected from those optionally controlled by one or more R. c The following groups are substituted: C 1-6 Alkylene or C 1-6 Heteroalkylene; Or, LNK, LNK 1 and LNK 2 Each is independently selected from the key, or selected from those optionally controlled by one or more R. c Replacement C 1-3 Alkylene; Or, Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. b The following groups are substituted: C 3-11 Cycloalkyl, 4-12-membered heterocycloalkyl, 4-11-membered heterocycloalkenyl or 5-11-membered heteroaryl; Or, Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. b The following groups are substituted: C 4-10 Cycloalkyl, 4-11 membered heterocycloalkyl, 5-6 membered heterocyclic alkenyl or 5-6 membered heteroaryl; Or, Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. b The following groups are substituted: C 4-9 Cycloalkyl, 4-11 membered heterocycloalkyl, 5-6 membered heterocyclic alkenyl or 5-6 membered heteroaryl; Or, Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. b The following groups are substituted: C 4-6 Cycloalkyl, C9 cycloalkyl, 4-11 membered heterocycloalkyl, 6 membered heterocyclic alkenyl or 6 membered heteroaryl; Or, Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. b The following groups may be substituted: cyclobutyl, cyclopentyl, cyclohexyl, spironyl, azircyclobutyl, pyrrolyl, piperidinyl, tetrahydropyridyl, piperazine, azirspiroheptyl, azirspiroctyl, azirspironyl, diazirspironyl, azirspirodealkyl, diazirspirodealkyl, azirspiroundecyl, diazirspiroundecyl, azirbicyclohexane, octahydrocyclopentylpyrrole, diazirbicyclooctyl, azirbicyclononyl, azirbicycloheptyl, or pyrazine; Optionally, each R b and R c Each is independently selected from deuterium, halogens, =O, -OH, -NH2, -CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, (C 1-6 alkyl)NH-, (C 1-6 Alkyl)2N-, C 3-10 Cycloalkyl or 4-10 membered heterocyclic alkyl groups; Or, each R b and R c Each is independently selected from deuterium, halogens, =O, -OH, -NH2, -CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, (C 1-6 alkyl)NH- or (C 1-6 Alkyl)2N-; Or, each R b and R c Each is independently selected from deuterium, halogens, =O, -OH, -NH2, -CN, and C. 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, hydroxyl C 1-6 Alkyl, (C 1-4 alkyl)NH-, or (C 1-4 Alkyl)2N-; Or, each R b and R c Each is independently selected from C-terminals that are =O or hydroxyl-substituted. 1-3 alkyl; Or, each R b and R c Each is independently selected from =O or HOCH2-.

12. The compound according to any one of claims 1, 3-11, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein R 2 Each is independently selected from deuterium, halogen, -OH, -NH2, -CN, -COOH, -CONH2, or optionally influenced by one or more R. 2a’ The following groups are substituted: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl C(O)-, C 1-6 Alkyl C(O)O-, C 1-6 Alkyl OC(O)-, C 1-6 Alkyl C(O)NH-, C 1-6 Alkyl NHC(O)-, C 1-6 Alkyl S(O)NH-, C 1-6 Alkyl NHS(O)-, C 1-6 Alkyl S(O)2NH-, C 1-6 Alkyl NHS(O)2-, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl, 3-8 membered heterocyclic alkenyl, C 6-10 Aryl or 5-8 quinone heteroaryl; Or, the R 2 Each is independently selected from deuterium, halogen, -OH, -NH2, -CN, or optionally influenced by one or more R. 2a’ The following groups are substituted: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; Or, the R 2a’ Each is independently selected from deuterium, halogens, -OH, -NH2, -CN, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-8 cycloalkyl or 3-8 membered heterocyclic alkyl; Optionally, the R 2a’ Each is independently selected from deuterium, halogens, -OH, -NH2, -CN, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkyl NH- or (C 1-3 Alkyl)2N-; Or, the R 2a’ Each is independently selected from halogens (e.g., F or Cl) or C. 1-3 Alkoxy; Or, the R 2 Selected independently from C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with one or more of the following groups: deuterium, halogen (e.g., -F or -Cl) or C. 1-3 Alkyl groups (e.g., methoxy, ethoxy) substitution; Or, the R 2 Each can be independently selected from -CH3, -CH2F, -CHF2, -CF3, -CH2CH3 or -CH2OCH3.

13. The compound according to any one of claims 1, 3-12, its stereoisomers, or its pharmaceutically acceptable salts, L 2 Selected from key, or selected from C 1-3 Alkylene or C 2-3 Idenoyl, the C 1-3 Alkylene or C 2-3 One or two methylene groups of the alkenyl group are optionally and independently replaced by -O-, -C(O)-, -C(S)-, -NH-, -S-, or -S(O)2-, wherein the C 1-3 Alkylene or C 2-3 The alkenyl group is optionally surrounded by one or more R L replace; Optional, R L Selected from deuterium, halogens, -CN, -OH, -NH2, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, C6 aryl or 5-6 membered heteroaryl; Or, L 2 Selected from the bond, -CH2-, -O-, -C(O)- or -NH-.

14. The compound according to any one of claims 1, 3-13, its stereoisomers, or a pharmaceutically acceptable salt thereof, R 3 Selected from one or more R 3a The following groups are substituted: C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl, 3-8 membered heterocyclic alkenyl, C 6-10 Aryl or 5-10 heteroaryl groups; Or, R 3 Selected from one or more R 3a The following groups are substituted: phenyl or 5-6 membered heteroaryl; Or, R 3 Selected from one or more R 3a Substituted phenyl; Optional, R 3a Selected independently from deuterium, halogens, -CN, and C respectively. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 3-8 Cycloalkenyl, 3-8 membered heterocyclic alkenyl, C 6-10 Aryl, 5-8 quinone heteroaryl, 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-; Optional, R s and R v Selected independently from H and C respectively 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-3 Alkylene-, 3-8 membered heterocyclic alkyl, 3-8 membered heterocyclic alkyl C 1-3 Alkylene-, C 3-8 Cycloalkenyl, C 3-8 Cycloalkenyl C 1-3 alkylene-, 3-8 membered heterocyclic alkenyl, 3-8 membered heterocyclic alkenyl C 1-3 Alkylene-, C 6-10 Aryl, C 6-10 Aryl C 1-3 alkylene-, 5-8 heteroaryl, or 5-8 heteroaryl C 1-3 alkylene-; Or, R s and R v Each independently selected from H or C 1-4 alkyl; Or, R 3a Each is independently selected from deuterium, halogens, -OH, -CN, -NH2, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkenyl or 3-6 membered heterocyclic alkenyl; Or, R 3a Each is independently selected from deuterium, halogens, -OH, -CN, -NH2, and C. 1-3 Alkyl or halogenated C 1-3 alkyl,; Or, R 3a Each can be independently selected from -F, -Cl, -OH, or -CH3.

15. The compound according to any one of claims 1, 3-14, its stereoisomers or pharmaceutically acceptable salts thereof, wherein ring G is selected from 5-10-membered heteroaryl groups; or ring G is selected from 5-6-membered heteroaryl groups; Alternatively, ring G is selected from a 6-membered heteroaryl group containing one or two nitrogen atoms; or ring G is selected from a pyridazinyl group; Optionally, ring E is selected from C. 3-7 Cycloalkyl, 3-7 heterocyclic alkyl, 3-7 heterocyclic alkenyl, C6 aryl or 5-7 heteroaryl; Alternatively, ring E is selected from 5-6 membered heterocyclic alkyl or 5-6 heterocyclic alkenyl; Alternatively, ring E is selected from dihydropyrrolidinyl or tetrahydropyrazinyl; Optionally, ring F is selected from non-existent ring C. 3-7 Cycloalkyl, 3-7-membered heterocycloalkyl, 3-7-membered heterocycloalkenyl, C6 aryl or 5-6-membered heteroaryl; Alternatively, ring F may be selected from absent or pyrrolidinyl groups; Optionally, ring H is selected from C. 3-7 Cycloalkyl, 3-7-membered heterocycloalkyl, 3-7-membered heterocycloalkenyl, C6 aryl or 5-7-membered heteroaryl; Alternatively, ring H is selected from C. 4-6 cycloalkyl or 4-6 membered heterocyclic alkyl; Alternatively, the ring H is selected from aziridine or piperidinyl; Optionally, ring G and ring E are connected in parallel ring configuration; Optionally, ring E and ring F are connected in a parallel loop configuration; Optionally, ring F and ring H are connected by a screw ring. Optionally, when ring F is absent, ring E and ring H are connected by a helical ring. Optionally, ring F does not exist, and rings G, E, and H are connected in parallel ring form; Optionally, ring F is absent, and ring G is connected to ring E via a parallel ring connection, while ring E is connected to ring H via a helical ring connection. Optionally, ring G and ring E are connected by a parallel ring, and ring E and ring F are connected by a parallel ring, while ring F and ring H are connected by a screw ring. Optional, R 2 The substitution sites are ring G, ring E, ring F, or ring H; Optional, R 2 The substitution site is either ring E or ring F; Optional, R 2 The substitution sites are on the fused carbon atoms of ring E and ring F.

16. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, PTM, or structural moiety according to any one of claims 1-15 Selected from Alternatively, PTM or structural part Selected from Or, structural parts Or PTM selected Or, structural parts Or PTM selected or, Or PTM selected Or, structural parts Or PTM selected Or, structural parts Or PTM selected Or, structural parts Or PTM selected Or, structural parts Or PTM selected Or, structural parts Or PTM selected Where k is selected from 0, 1, 2, 3, 4 or 5; or k is selected from 1, 2 or 3; Or, structural parts Or PTM selected Or, structural parts Or PTM selected Or, structural parts Or PTM selected 17. The compound of formula I, II, or III according to any one of claims 1-16, its stereoisomers, or pharmaceutically acceptable salts thereof, selected from formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, or III-10, its stereoisomers, or pharmaceutically acceptable salts thereof, in, R 3 R 3a L 2 Ring G, Ring E, Ring F, Ring H, R 2 m, ring W, R 1 , n, X 5 L, L 1 The definitions of ring A, ring B, and ring C are as described in any one of claims 1-16; X 7 Selected from CH or N; k is selected from 0, 1, 2, 3, 4 or 5.

18. The following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof:

19. Compounds of formula XI, structural moieties, derivatives thereof, stereoisomers thereof, or pharmaceutically acceptable salts thereof: X 2 and X 3 Each is independently selected from CH or N; Ring J is selected from C 3-15 Cycloalkyl, 3-15 membered heterocyclic alkyl or 3-15 membered heterocyclic alkenyl; R 2a Selected from hydrogen, deuterium, halogens, -NH2, -OH, -CN, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl OC(O)-, C 1-6 Alkyl OC(O)C 1-6 Alkyl-, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocyclic alkenyl, C 6-10 Aryl, 5-10 heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl OC(O)-, C 1-6 Alkyl OC(O)C 1-6 Alkyl-, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocyclic alkenyl, C 6-10 Aryl and 5-10 heteroaryl groups may optionally be substituted with the following groups: deuterium, halogen, -NH2, -OH, -CN, =O, -C(O)OH, -C(O)H, C 1-6 Alkyl OC(O)-, C 1-6 Alkoxy C 1-6 Alkyl- or di(C) 1-6 Alkoxy)C 1-6 alkyl.

20. The compound, structural moiety, derivative thereof, stereoisomer thereof, or pharmaceutically acceptable salt thereof as claimed in claim 19, R 2 The replacement position is X 3 ; Optionally, the ring J is selected from C. 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl or 3-15 membered heterocyclic alkenyl; Alternatively, the ring J is selected from C. 3-9 Cycloalkyl, 3-9 membered heterocyclic alkyl or 3-9 membered heterocyclic alkenyl; Alternatively, the ring J is selected from C. 4-7 cycloalkyl or 4-7 membered heterocyclic alkyl; Alternatively, the ring J is selected from C. 4-6 cycloalkyl or 4-6 membered heterocyclic alkyl; Alternatively, the ring J is selected from aziridine or piperidinyl; Optionally, the ring J is selected from... Alternatively, the ring J is selected from Optional, R 2a The substitution position is ring J; R 2a Selected from hydrogen, deuterium, halogens, -NH2, -OH, -CN, =O, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl OC(O)-, C 1-4 Alkyl OC(O)C 1-4 Alkyl-, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocyclic alkenyl, C6 aryl, 5-6 membered heteroaryl, wherein C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl OC(O)-, C 1-4 Alkyl OC(O)C 1-4 Alkyl-, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocyclic alkenyl, C6 aryl, and 5-6 membered heteroaryl groups may optionally be substituted with the following groups: deuterium, halogen, -NH2, -OH, -CN, =O, -C(O)OH, -C(O)H, C 1-6 Alkyl OC(O)-, C 1-6 Alkoxy C 1-6 Alkyl- or di(C) 1-6 Alkoxy)C 1-6 alkyl-; Or, R 2a Selected from hydrogen, deuterium, and C 1-3 Alkyl, C 3-4 Alkyl OC(O)-, C 3-4 Alkyl OC(O)C 1-3 Alkyl-, C 4-6 Cycloalkyl, 4-6-membered heterocycloalkyl or 6-membered heteroaryl, wherein C 1-3 Alkyl, C 3-4 Alkyl OC(O)-, C 3-4 Alkyl OC(O)C 1-3 Alkyl-, C 4-6 Cycloalkyl, 4-6-membered heterocycloalkyl, or 6-membered heteroaryl groups may optionally be substituted with the following groups: -C(O)OH, -C(O)H, Or, R 2a Selected from hydrogen, -CH2C(O)OH、 21. The compound, structural moiety, derivative thereof, stereoisomer thereof, or pharmaceutically acceptable salt thereof as claimed in claim 19 or 20, selected from the compounds, structural moiety, derivative thereof, stereoisomer thereof, or pharmaceutically acceptable salt thereof of XI-1, XI-2, XI-3, XI-4, XI-5, XI-6, XI-7, XI-8, XI-9, XI-10, or XI-11: in, k is selected from 0, 1, 2, 3, 4 or 5; or k is selected from 1, 2 or 3.

22. Compounds of formula XII, structural moieties, derivatives thereof, stereoisomers thereof, or pharmaceutically acceptable salts thereof: in, X 5 and L 1 The definitions are as described in this application; Ring B is selected from phenyl or 5-6-membered heteroaryl groups; X 18 Selected from CH or N; X 23 X 24 X 25 and X 26 Each is independently selected from CH2 or X 23 X 24 X 25 and X 26 One of them is selected from the bond, and the others are selected from CH2; Each R 1b The following groups, each independently selected from deuterium, halogen, -OH, oxo, -NH2, -CN, -CHO, and optionally substituted by 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 group, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl or C 1-10 Alkyl OC(O)-; n is selected from 0, 1, 2, 3, 4, 5, 6, 7, or 8.

23. The compound, structural moiety, derivative thereof, stereoisomer thereof, or pharmaceutically acceptable salt thereof as claimed in claim 22, wherein ring B is selected from phenyl or 6-membered heteroaryl; Optional, X 18 Selected from N; Optional, structural part Selected from Optional, X 23 X 24 X 25 and X 26 Each is independently selected from CH2; Or, X 23 X 24 X 25 and X 26 One of them is selected from the bond, and the others are selected from CH2; Optionally, each R 1b The following groups, independently selected from deuterium, halogen, -OH, oxo, -NH2, -CN, -CHO, and optionally substituted by one or more substituents: C 1-6 Alkyl, C 1-6 Alkoxy, (C 1-6 alkyl)NH-, (C 1-6 Alkyl)2N-, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2- 6-acetylinyl, C 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl or C 1-6 Alkyl OC(O)-; Or, each R 1b Independently selected from deuterium, halogen, -OH, oxo, -NH2, -CN, -CHO, C 1-6 Alkyl, C 3-6 cycloalkyl (such as C) 4- 6) 4-6 membered heterocyclic alkyl groups (e.g., 5-6 membered) or C 1-6 Alkyl OC(O)-, the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl or C 1- 6-alkylOC(O)- is optionally substituted with one or more of the following groups: halogen, -OH, -NH2, -CN, -CHO, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkylamino, diC 1-4 Alkylamino, or -COOH; Or, each R 1b Independently selected from C atoms optionally substituted with one or more deuterium, halogen, -OH, -NH2, or -CN. 1-4 alkyl; Or, each R 1b Selected from oxo, -CHO, or HOCH2-.

24. The use of the compound, structural moiety, derivative thereof, stereoisomer thereof or pharmaceutically acceptable salt thereof as claimed in any one of claims 19-23 in the PROTAC molecule; Alternatively, it can be used as part of the PROTAC molecule; Alternatively, it can be used for protein degradation, whereby the protein is degraded in the form of PROTAC molecules.

25. A PROTAC molecule comprising the compound, structural moiety, derivative thereof, stereoisomer thereof, or pharmaceutically acceptable salt thereof as described in any one of claims 19-23.

26. A pharmaceutical composition comprising a compound of any one of claims 1-18, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a compound of any one of claims 19-23, a structural moiety thereof, a derivative thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a PROTAC molecule of claim 25.

27. Use of the compound of any one of claims 1-18, its stereoisomers or pharmaceutically acceptable salts thereof, or the compound, structural moiety, its derivatives, its stereoisomers or pharmaceutically acceptable salts thereof, or the PROTAC molecule of claim 25, or the pharmaceutical composition of claim 26, in the preparation of a medicament for the prevention or treatment of SMARCA2 and / or SMARCA4-related diseases, optionally, wherein the SMARCA2 and / or SMARCA4-related diseases are selected from cancer.

28. A compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof, according to any one of claims 1-18, for the prevention or treatment of SMARCA2 and / or SMARCA4-related diseases; or a compound, structural moiety thereof, derivative thereof, stereoisomer thereof, or pharmaceutically acceptable salt thereof, according to any one of claims 19-23; or a PROTAC molecule according to claim 25; or a pharmaceutical composition according to claim 26, optionally wherein the SMARCA2 and / or SMARCA4-related diseases are selected from cancer.

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