Cyclobutyl-containing compounds

Abstract

The present application relates to the field of medicinal chemistry, relates to cyclobutyl-containing compounds, and particularly relates to compounds of formula I, a preparation method therefor, a pharmaceutical composition containing the compounds, and the use thereof in treating diseases such as cancers.

Description

Compounds containing cyclobutyl groups

[0001] Citation of Related Applications

[0002] This application claims the priority and benefits of Chinese Patent Application No. 202311073391.5 filed with the State Intellectual Property Office of the People's Republic of China on August 23, 2023, Chinese Patent Application No. 202410544791.8 filed with the State Intellectual Property Office of the People's Republic of China on April 30, 2024, and Chinese Patent Application No. 202411125992.0 filed with the State Intellectual Property Office of the People's Republic of China on August 15, 2024, the entire contents of which are hereby incorporated by reference into the text in their entirety. Technical Field

[0003] The present application relates to a compound containing a cyclobutyl group, a preparation method thereof, a pharmaceutical composition containing the compound, and its use in treating related diseases (such as cancer). Background Art

[0004] The androgen receptor (AR) belongs to the steroid receptor family of the nuclear receptor superfamily. Upon binding to androgens (such as testosterone and dihydrotestosterone), the AR is released from the heat shock protein complex, undergoes phosphorylation, forms a dimer, and translocates to the cell nucleus, where it binds to associated DNA fragments, thereby stimulating the transcription of its target genes. The transcriptional activity of the AR activated by ligand binding is coordinated by proteins called co-activators. The primary function of AR antagonists is to directly prevent testosterone or dihydrotestosterone from binding to the AR, blocking the effects of androgens on cells. This acts as an anti-androgen and inhibits cell growth, ultimately promoting cell apoptosis and achieving its crucial role in the treatment of prostate cancer.

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

[0006] Detailed Description of the Invention

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

[0008] in,

[0009] Ring A is absent or selected from C 5-15 Cycloalkenyl, 5-15 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl;

[0010] Ring B is selected from phenyl or 5-6 membered heteroaryl;

[0011] Ring C is selected from 5-6 membered heteroaryl;

[0012] Each R 1 independently selected from halogen, -OH, -NH2, -CN, C 1-10 Alkyl, C 1-10 Alkoxy or halogenated C 1-10 Alkyl, the -OH, -NH2, C 1-10 Alkyl, C 1-10 Alkoxy or halogenated C 1-10 The alkyl group is optionally substituted with one or more substituents;

[0013] n is selected from 0, 1, 2 or 3;

[0014] L is selected from a linking group;

[0015] X 5 Selected from C(R f ) or N;

[0016] R f is selected from H, halogen, deuterium or C optionally substituted by one or more substituents 1-6 Alkyl (such as R f is selected from halogen, deuterium or C optionally substituted by one or more substituents 1-6 alkyl);

[0017] X 6 Selected from -O-, -NH- or -N(C 1-6 alkyl)-, the -NH- or -N(C 1-6 alkyl)-optionally substituted with one or more substituents;

[0018] Each R 2 、R 3 and R 4 are independently selected from halogen, -OH, -NH2, -CN, C 1-10 Alkyl, C 1-10 Alkoxy or halogenated C 1-10 Alkyl, the -OH, -NH2, C 1-10 Alkyl, C 1-10 Alkoxy or halogenated C 1-10 The alkyl group is optionally substituted with one or more substituents;

[0019] m, p and q are each independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0020] Ring G is selected from C 6-10 Aryl or 5-10 membered heteroaryl;

[0021] Ring E is selected from C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl;

[0022] Ring F is selected from C 6-10 Aryl or 5-10 membered heteroaryl;

[0023] R t Selected from hydrogen, -OH, C 1-6 Alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl, the C 1-6 Alkyl, C 3-10 The cycloalkyl or 3-10 membered heterocycloalkyl is optionally substituted with one or more substituents.

[0024] In some embodiments, Ring A is absent or is selected from C 5-10 cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0025] In some embodiments, Ring A is absent or is selected from C 5-9 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0026] In some embodiments, Ring A is absent or is selected from C 5-7 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0027] In some embodiments, Ring A is absent or is selected from C 5-6 cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0028] In some embodiments, Ring A is absent or is selected from C 5-6 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0029] In some embodiments, Ring A is absent or is selected from C 5-6 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5 membered heteroaryl.

[0030] In some embodiments, Ring A is absent or is selected from C 5-6 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl, pyrrolyl, pyrazolyl, furyl, or oxazolyl.

[0031] In some embodiments, Ring A is absent or is selected from C5 cycloalkenyl, C6 cycloalkenyl, 5-membered heterocycloalkenyl, 6-membered heterocycloalkenyl, 7-membered heterocycloalkenyl, 8-membered heterocycloalkenyl, or 9-membered heterocycloalkenyl, phenyl, pyrrolyl, pyrazolyl, furanyl, or oxazolyl.

[0032] In some embodiments, Ring A is absent or is selected from cyclopentenyl, monocyclohexenyl, bicyclohexenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine 1-Hydroxy, ...

[0033] In some embodiments, Ring A is selected from C 5-10 cycloalkenyl, 5-10 membered heterocycloalkenyl or 5-6 membered heteroaryl.

[0034] In some embodiments, Ring A is selected from C 5-9 cycloalkenyl, 5-9 membered heterocycloalkenyl or 5-6 membered heteroaryl.

[0035] In some embodiments, Ring A is selected from C 5-7 cycloalkenyl, 5-9 membered heterocycloalkenyl or 5-6 membered heteroaryl.

[0036] In some embodiments, Ring A is selected from C 5-6 cycloalkenyl, 5-10 membered heterocycloalkenyl or 5-6 membered heteroaryl.

[0037] In some embodiments, Ring A is selected from C 5-6 cycloalkenyl, 5-9 membered heterocycloalkenyl or 5-6 membered heteroaryl.

[0038] In some embodiments, Ring A is selected from C 5-6 cycloalkenyl, 5-9 membered heterocycloalkenyl or 5 membered heteroaryl.

[0039] In some embodiments, Ring A is selected from C 5-10 In some embodiments, ring A is selected from C 5-9 In some embodiments, ring A is selected from C 5-8 In some embodiments, ring A is selected from C 5-6Cycloalkenyl. In some specific embodiments, Ring A is selected from a 5-9 membered heterocycloalkenyl. In some embodiments, Ring A is selected from a 5-9 membered heterocycloalkenyl containing 1-2 heteroatoms selected from N or O. In some embodiments, Ring A is selected from a 5-8 membered heterocycloalkenyl containing 1-2 heteroatoms selected from N or O. In some embodiments, Ring A is selected from a 5-7 membered heterocycloalkenyl containing 1-2 heteroatoms selected from N or O. In some embodiments, Ring A is selected from a 5-7 membered heterocycloalkenyl containing 1-2 N atoms.

[0040] In some embodiments, ring A is selected from cyclopentenyl, monocyclohexenyl, bicyclohexenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine 1-Hydroxy-1-oxazinyl, ...

[0041] In some embodiments, Ring A is cyclopentenyl. In some embodiments, Ring A is monocyclohexenyl. In some embodiments, Ring A is bicyclohexenyl. In some embodiments, Ring A is dihydropyrrolyl. In some embodiments, Ring A is tetrahydropyridinyl. In some embodiments, Ring A is tetrahydroaza In some embodiments, Ring A is an azaspirocyclononenyl. In some embodiments, Ring A is an azaspirocyclooctenyl. In some embodiments, Ring A is a dihydrooxazinyl.

[0042] In some more specific embodiments, Ring A is selected from phenyl, pyrrolyl, pyrazolyl, furanyl, or oxazolyl.

[0043] In some more specific embodiments, Ring A is selected from phenyl, pyrrolyl, or pyrazolyl.

[0044] In some embodiments, the ring B is selected from phenyl or 6-membered heteroaryl (eg, 6-membered heteroaryl containing 1-3 or 1-2 N atoms). In some embodiments, the ring B is phenyl.

[0045] In some embodiments, the ring C is selected from a 5-membered heteroaryl. In some embodiments, the ring C is selected from an isoxazolyl or furanyl.

[0046] In some embodiments, Ring C is isoxazolyl.In some embodiments, Ring C is furanyl.

[0047] In some embodiments, Ring A is present, and when Ring A and Ring B are both phenyl, Ring C is not oxazolyl.

[0048] In some embodiments, R 1 The substitution position of is selected from Ring A or Ring B. In some embodiments, R 1 The substitution position of is selected from Ring A. In some embodiments, R1 The substitution position of is selected from Ring B. In some embodiments, R 1 The substitution position is selected from ring C.

[0049] In some embodiments, Ring F is linked to L. In some embodiments, Ring A is linked to L. In some embodiments, Ring B is linked to L. In some embodiments, Ring C is linked to L. In some embodiments, Ring A is linked to Fragment In some embodiments, ring B is connected to the fragment In some embodiments, ring C is connected to the fragment In some embodiments, ring F and ring A are connected to L, and ring C is connected to fragment connect.

[0050] In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from

[0051] In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Not selected In some embodiments, the structural fragment Not selected

[0052] In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Not selected In some embodiments, the structural fragment Not selected

[0053] In some embodiments, the structural fragment Selected from

[0054] In some embodiments, the structural fragment for In some embodiments, the structural fragment for In some embodiments, the structural fragment for In some embodiments, the structural fragment for In some embodiments, the structural fragment for In some embodiments, the structural fragment for In some embodiments, the structural fragment for In some embodiments, the structural fragment for In some embodiments, the structural fragment for In some embodiments, the structural fragment for In some embodiments, the structural fragment for In some embodiments, the structural fragment for

[0055] In some embodiments, each R 1 independently selected from halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkyl, the -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkyl is optionally substituted with one or more substituents. 1 independently selected from halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy or halogenated C 1-4 In some embodiments, each R 1 independently selected from halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy or halogenated C 1-3 In some embodiments, each R1 In some embodiments, each R 1 In some embodiments, each R 1 are independently fluorine.

[0056] In some embodiments, n is selected from 0, 1, or 2. In some embodiments, n is selected from 0 or 1. In some specific embodiments, n is 0.

[0057] In some embodiments, the structural fragment Selected from

[0058] In some embodiments, the L is selected from the following groups optionally substituted with one or more substituents: C 1-50 Alkylene, C 2-50 Alkenylene or C 2-50 Alkynylidene, the C 1-50 Alkylene, C 2-50 Alkenylene or C 2-50 One or more -CH2- in the alkynylene group may be replaced by -O-, C 3-15 Cycloalkyl, 3-15 membered heterocycloalkyl, 4-15 membered heterocycloalkenyl, C 6-15 Aryl, 5-15 membered heteroaryl, -NH-, -N(C 1-6 alkyl)- or -S-substituted.

[0059] In some embodiments, the L is selected from the following groups optionally substituted with one or more substituents: C 1-30 Alkylene, C 2-30 Alkenylene or C 2-30 Alkynylidene, the C 1-30 Alkylene, C 2-30 Alkenylene or C 2-30 One or more -CH2- in the alkynylene group may be replaced by -O-, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl, 5-12 membered heteroaryl, -NH-, -N(C 1-6 alkyl)- or -S-substituted.

[0060] In some embodiments, the L is selected from the following groups optionally substituted with one or more substituents: C 1-20 Alkylene, C 2-20 Alkenylene or C 2-20 Alkynylidene, the C 1-20 Alkylene, C 2-20 Alkenylene or C 2-20One or more -CH2- in the alkynylene group may be replaced by -O-, C 3-10 Cycloalkyl, 3-11 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-10 Aryl, any 5-10 membered heteroaryl, -NH-, -N(C 1-6 alkyl)- or -S-substituted.

[0061] In some embodiments, the L is selected from the following groups optionally substituted with one or more substituents: C 1-15 Alkylene, C 2-15 Alkenylene or C 2-15 Alkynylidene, the C 1-15 Alkylene, C 2-15 Alkenylene or C 2-15 One or more -CH2- in the alkynylene group may be replaced by -O-, C 3-9 Cycloalkyl, 3-11 membered heterocycloalkyl, 4-8 membered heterocycloalkenyl, C 6-8 Aryl, 5-8 membered heteroaryl, -NH-, -N(C 1-4 alkyl)- or -S-substituted.

[0062] In some embodiments, the L is selected from the following groups optionally substituted with one or more substituents: C 1-10 Alkylene, C 2-10 Alkenylene or C 2-10 Alkynylidene, the C 1-10 Alkylene, C 2-10 Alkenylene or C 2-10 One or more -CH2- in the alkynylene group may be replaced by -O-, C 3-9 Cycloalkyl, 3-11 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, -NH-, -N(C 1-3 alkyl)- or -S-substituted.

[0063] In some embodiments, the L is selected from the following groups optionally substituted with one or more substituents: C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkynylidene, the C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 One or more -CH2- in the alkynylene group may be replaced by -O-, C 3-9 Cycloalkyl, 3-11 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, -NH-, -N(C 1-3 alkyl)- or -S-substituted.

[0064] In some embodiments, the L is selected from the following groups optionally substituted with one or more substituents: C 1-4 Alkylene, C 2-4 Alkenylene or C 2-4 Alkynylidene, the C 1-4 Alkylene, C 2-4 Alkenylene or C 2-4 One or more (e.g., one or two, one or three, etc.) -CH2- in the alkynylene group are optionally replaced by -O-, C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, -NH-, -N(C 1-3 In some embodiments, L is selected from C 1-6 Alkylene, the C 1-6 One or more -CH2- in the alkylene group is optionally selected from -O-, C 3-10 Cycloalkyl, 4-11 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, -NH-, -N(C 1-3 Alkyl)- or -S-substituted, the C 1-6 The alkylene group is optionally substituted with one or more substituents.

[0065] In some embodiments, the L is selected from C 1-6 Alkylene, the C 1-6 One or more -CH2- in the alkylene group is optionally selected from -O-, C 3-10 Cycloalkyl, 4-11 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl, -NH-, -N(C 1-3 Alkyl)- or -S-substituted, the C 1-6 Alkylene is optionally substituted with one or more substituents. In some embodiments, L is selected from -(5-8 membered heterocycloalkyl containing 1-2 N atoms or O atoms)-C 1-6 Alkylene-, -(C 5-8 Cycloalkyl)-C 1-6 Alkylene-, -C 1-6 Alkylene-(5-8 membered heterocycloalkyl containing 1-2 N atoms or O atoms)-C 1-6 Alkylene-, or -C 1-6 Alkylene-(C 5-8 Cycloalkyl)-C 1-6 Alkylene-.

[0066] In some embodiments, in the definition of L, the substituent is selected from halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl, C 1- 6 alkoxy, halogenated C 1-6 Alkyl, C 1-6Alkylamino, di-C 1-6 Alkylamino, C 3-12 In some embodiments, in the definition of L, the substituent is selected from halogen, =O, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1- 4 alkyl, C 1-4 Alkylamino, di-C 1-4 Alkylamino, C 3-10 In some embodiments, in the definition of L, the substituent is selected from halogen, =O, OH, NH2, CN, C 1-6 Alkyl or C 1-6 In some embodiments, in the definition of L, the substituent is selected from ═O, OH, NH 2 , halogen, or CN. In some embodiments, in the definition of L, the substituent is ═O.

[0067] In some embodiments, the L is selected from -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -Cy 3 -,in,

[0068] Cy 1 、Cy 2 or Cy 3 are independently selected from a bond, or optionally substituted by one or more R a Substituted with the following groups: C 3-12 Cycloalkyl, 4-12 membered heterocycloalkyl or 4-12 membered heterocycloalkenyl;

[0069] LNK, LNK 1 and LNK 2 are independently selected from a bond, NH, O, S, or optionally substituted by one or more R b Substituted with the following groups: C 1-12 Alkylene, C 2-12 Alkenylene, C 2-12 Alkynylidene or C 1-12 heteroalkylene;

[0070] Each R a and R b Each independently selected from halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 1-6 Alkylamino, di-C 1-6Alkylamino, C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl.

[0071] In some embodiments, Cy 1 、Cy 2 and Cy 3 In some embodiments, Cy 2 and Cy 3 In some embodiments, LNK 1 and LNK 2 is the key.

[0072] In some embodiments, the L is selected from -Cy 1 -、-Cy 2 -、-LNK 1 -、-Cy 1 -LNK-, -Cy 1 -Cy 2 -、-LNK 1 -Cy 1 -LNK-, -LNK-Cy 2 -LNK 2 -、-Cy 1 -Cy 2 -LNK 2 -、-LNK 1 -Cy 1 -Cy 2 -、-Cy 1 -LNK-Cy 2 -、-LNK 1 -Cy 1 -Cy 2 -LNK 2 -、-LNK 1 -Cy 1 -LNK-Cy 2 -、-Cy 1 -LNK-Cy 2 -LNK 2 -、-Cy 1 -Cy 2 -Cy 3 -or-Cy 1 -Cy 2 -LNK 2 -Cy 3 In some embodiments, L is selected from -Cy 1 -. In some embodiments, the L is selected from -LNK 1 In some embodiments, L is selected from -Cy 1 -LNK-.

[0073] In some embodiments, LNK, LNK 1 and LNK 2 are independently selected from a bond, NH, O, S, or optionally substituted by one or more R b Substituted with the following groups: C 1-10 Alkylene, C 2-10 Alkenylene, C 2-10 Alkynylidene or C 1-10 In some embodiments, LNK, LNK 1 and LNK 2 are independently selected from a bond, NH, O, S, or optionally substituted by one or more R b Substituted with the following groups: C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene or C 1-6 In some embodiments, LNK, LNK 1 and LNK 2 are independently selected from a bond, NH, O, S, or optionally substituted by one or more R b Substituted with the following groups: C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene or C 1-4 In some embodiments, LNK, LNK 1 and LNK 2 are independently selected from a bond, NH, O, S, or optionally substituted by one or more R b Substituted with the following groups: C 1-6 Alkylene or C 1-6 In some embodiments, LNK, LNK 1 and LNK 2 are independently selected from a bond, NH, O, S, or optionally substituted by one or more R b Substituted with the following groups: C 1-4 Alkylene or C 1-4 In some embodiments, LNK, LNK 1 and LNK 2 are independently selected from a bond, NH, O, or optionally substituted by one or more R b Substituted with the following groups: C 1-3 Alkylene or C 1-3 In some embodiments, LNK, LNK 1 and LNK 2 are independently selected from a bond, NH, O, or optionally substituted by one or more R b Substituted with the following groups: C 1-2Alkylene or C 1-2 In some embodiments, LNK, LNK 1 and LNK 2 are independently selected from a bond, NH, O, -NHCH2-, -CH2NHCH2-, -CH2-, -CH2CH2-, -C(O)- or -C(O)CH2-. In some embodiments, LNK, LNK 1 and LNK 2 In some embodiments, LNK, LNK 1 and LNK 2 Each independently represents -CH2-.

[0074] In some embodiments, Cy 1 、Cy 2 or Cy 3 are independently selected from a bond, or optionally substituted by one or more R a Substituted with the following groups: C 3- 11 In some embodiments, Cy is cycloalkyl, 4-12 membered heterocycloalkyl or 4-11 membered heterocycloalkenyl. 1 、Cy 2 or Cy 3 are independently selected from a bond, or optionally substituted by one or more R a Substituted with the following groups: C 4-10 In some embodiments, Cy is cycloalkyl, 4-11 membered heterocycloalkyl or 5-6 membered heterocycloalkenyl. 1 、Cy 2 or Cy 3 are independently selected from a bond, or optionally substituted by one or more R a Substituted with the following groups: C 4-9 In some embodiments, Cy is cycloalkyl, 4-11 membered heterocycloalkyl or 5-6 membered heterocycloalkenyl. 1 、Cy 2 or Cy 3 are independently selected from a bond, or optionally substituted by one or more R a Substituted with the following groups: C 4-6 Cycloalkyl, C9 cycloalkyl, 4-11 membered heterocycloalkyl or 6 membered heterocycloalkenyl.

[0075] In some embodiments, Cy 1 、Cy 2 or Cy 3 are independently selected from a bond, or optionally substituted by one or more R aSubstituted from the following groups: cyclobutyl, cyclopentyl, cyclohexyl, spironanyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyridinyl, piperazinyl, monoazaspiroheptanyl, monoazaspironanyl, diazaspironanyl, monoazaspirodecanyl, diazaspirodecane, monoazaspiroundecyl, diazaspiroundecyl, octahydrocyclopentapyrrolyl, diazabicyclooctanyl or monoazabicyclononanyl.

[0076] In some embodiments, Cy 1 、Cy 2 or Cy 3 are independently selected from a bond, or optionally substituted by one or more R a Substituted with the following groups: 4-11 membered heterocycloalkyl. In some embodiments, Cy 1 、Cy 2 or Cy 3 are independently selected from a bond, or optionally substituted by one or more R a Substituted with the following groups: 7-11 membered heterocycloalkyl. In some embodiments, Cy 1 、Cy 2 or Cy 3 are independently selected from a bond, or optionally substituted by one or more R a Substituted with the following groups: 4-6 membered heterocycloalkyl. In some embodiments, Cy 1 、Cy 2 or Cy 3 In some embodiments, Cy 1 、Cy 2 or Cy 3 are independently selected from optionally one or more R a Substituted 6-membered heterocycloalkyl.

[0077] In some embodiments, Cy 1 、Cy 2 or Cy 3 are independently selected from a bond, or optionally substituted by one or more R a In some embodiments, Cy is substituted with cyclobutyl, cyclopentyl, cyclohexyl, spirononyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyridinyl or piperazinyl. 1 、Cy 2 or Cy 3 are independently selected from a bond, or optionally substituted by one or more R a Substituted from the following groups: monoazaspiroheptyl, monoazaspironanyl, diazaspironanyl, monoazaspirodecanyl, diazaspirodecane, monoazaspiroundecyl, diazaspiroundecyl, octahydrocyclopentapyrrolyl, diazabicyclooctanyl or monoazabicyclononanyl.

[0078] In some embodiments, Cy 1 、Cy 2 or Cy 3 are independently selected from a bond, In some embodiments, Cy 1 、Cy 2 or Cy 3 Independently In some embodiments, Cy 1 、Cy 2 or Cy 3 Independently

[0079] In some embodiments, each R a and R b Each independently selected from halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 3-10 In some embodiments, each R a and R b Each independently selected from halogen, =O, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 1-6 Alkylamino or di-C 1-6 In some embodiments, each R a and R b Each independently selected from halogen, =O, -OH, -NH2, -CN, C 1-4 Alkyl, C 1- 4 Alkoxy, halogenated C 1-4 Alkyl, C 1-4 Alkylamino, or di-C 1-4 Alkylamino.

[0080] In some embodiments, each R a and R b Each independently selected from halogen, =O, -OH, -NH2, -CN or C 1-3 In some embodiments, each R a and R b Each is independently selected from halogen, =O, -OH, -NH2 or -CN. In some embodiments, each Ra and R b Each independently represents =0.

[0081] In some embodiments, L or -LNK 1 - is selected from a bond, -NHCH2-, -CH2NHCH2-, -CH2- or -C(O)CH2-.

[0082] In some embodiments, L or -Cy 1 -Selected

[0083] In some embodiments, L or -Cy 1 -LNK-Selected

[0084] In some embodiments, L or -Cy 1 -Cy 2 -Selected

[0085] In some embodiments, L or -Cy 1 -Cy 2 -Cy 3 -Selected

[0086] In some embodiments, L or -LNK 1 -Cy 1 -LNK-Selected

[0087] In some embodiments, L or -Cy 1 -Cy 2 -LNK 2 -Selected

[0088] In some embodiments, L or -Cy 1 -LNK-Cy 2 -Selected

[0089] In some embodiments, L or -LNK 1 -Cy 1 -Cy 2 -LNK 2 -Selected

[0090] In some embodiments, L or -Cy 1 -LNK-Cy 2 -LNK 2 -for

[0091] In some embodiments, L is selected from a bond, -NHCH2-, -CH2NHCH2-, -CH2-, -C(O)CH2-,

[0092] In some embodiments, the L is selected from

[0093] In some embodiments, L is In some embodiments, L is In some embodiments, L is

[0094] In some embodiments, the structural fragment Selected from

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

[0096] In some embodiments, R f is selected from H, fluorine, chlorine, bromine, deuterium or C optionally substituted by one or more substituents 1-3 In some embodiments, R f Selected from H, fluorine, chlorine, bromine, deuterium or C 1-3 Alkyl, the C 1-3 Alkyl is optionally substituted with one or more of the following groups: halogen, -OH, -NH2 or -CN. In some embodiments, R f Selected from H, fluorine, chlorine, bromine, deuterium or C 1-3 In some embodiments, R f is selected from H, fluorine, deuterium or methyl. In some embodiments, R f For H.

[0097] In some embodiments, X 5 In some embodiments, X5 For CH.

[0098] In some embodiments, X 6 Selected from -O-, -NH- or -N(C 1-3 In some embodiments, X 6 In some embodiments, X 6 It is -O-.

[0099] In some embodiments, each R 2 、R 3 and R 4 are independently selected from halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkyl, the -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkyl is optionally substituted with one or more substituents. 2 、R 3 and R 4 are independently selected from halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy or halogenated C 1-4 alkyl.

[0100] In some embodiments, each R 2 independently selected from halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy or halogenated C 1-3 In some embodiments, each R 2 independently selected from halogen, -OH, -NH2, -CN, C 1-3 Alkyl or C 1-3 In some embodiments, each R 2 In some embodiments, each R 2 In some embodiments, each R 2 In some embodiments, each R 2 Independently selected from -CN or C 1-6 Alkoxy (e.g. C 1-5 Alkoxy, C 1-4 Alkoxy or C 1-3 alkoxy).

[0101] In some embodiments, each R 3 are independently selected from halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy or halogenated C 1-3 In some embodiments, each R 3 are independently selected from halogen, -OH, -NH2, -CN or C 1-3 In some embodiments, each R 3 are independently selected from C 1-6 Alkyl, C 1-5 Alkyl or C 1-4 Alkyl (preferably C 1-3 In some embodiments, each R 3 are each independently a methyl group.

[0102] In some embodiments, each R 4 are independently selected from halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy or halogenated C 1-3 In some embodiments, each R 4 are independently selected from halogen, -OH, -NH2, -CN or C 1-3 In some embodiments, each R 4 are independently selected from fluorine, chlorine, bromine, -OH, -NH2 or -CN.

[0103] In some embodiments, m is selected from 0, 1, 2, or 3. In some embodiments, m is selected from 1, 2, or 3. In some embodiments, m is 2. In some embodiments, p is selected from 1, 2, 3, or 4. In some embodiments, p is selected from 3 or 4. In some embodiments, p is 4. In some embodiments, q is selected from 0, 1, 2, or 3. In some embodiments, q is selected from 0 or 1. In some embodiments, q is 0.

[0104] In some embodiments, the structural fragment for

[0105] In some embodiments, the ring G is selected from phenyl or 5-6 membered heteroaryl. In some embodiments, the ring G is selected from phenyl or 6 membered heteroaryl (6 membered heteroaryl containing 1-2 N atoms). In some embodiments, the ring G is phenyl.

[0106] In some embodiments, Ring E is selected from C 3-9In some embodiments, ring E is selected from C 4-9 In some embodiments, ring E is selected from C 4-7 In some embodiments, ring E is selected from C 4-7 Cycloalkyl (e.g. C 4-6 Cycloalkyl, C 4-5 In some embodiments, ring E is selected from cyclobutyl, cyclopentyl, or cyclohexyl.

[0107] In some embodiments, Ring E is cyclobutyl. In some embodiments, Ring E is In some embodiments, Ring E is In some embodiments, the moiety for In some embodiments, the moiety for

[0108] In some embodiments, Ring F is selected from C 6-10 In some embodiments, ring F is selected from phenyl or 5-6 membered heteroaryl. In some embodiments, ring F is selected from phenyl or 6 membered heteroaryl (e.g., 6 membered heteroaryl containing 1-3 or 1-2 N atoms). In some embodiments, ring F is selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl. In some specific embodiments, ring F is phenyl. In some embodiments, ring F is pyridyl. In some embodiments, ring F is pyrimidinyl. In some embodiments, ring F is pyrazinyl. In some embodiments, ring F is pyridazinyl. In some embodiments, ring F is selected from In some embodiments, Ring F is In some embodiments, Ring F is In some embodiments, Ring F is In some embodiments, Ring F is In some embodiments, Ring F is

[0109] In some embodiments, Selected from

[0110] In some embodiments, R t Selected from hydrogen, -OH, C 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-4 Alkyl, C 3-6Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted. t Selected from hydrogen, -OH, C 1-3 Alkyl, C 3-4 Cycloalkyl or 3-4 membered heterocycloalkyl, the C 1-3 Alkyl, C 3-4 Cycloalkyl or 3-4 membered heterocycloalkyl is optionally substituted. t Selected from hydrogen or C 1- 3 alkyl (such as methyl, ethyl, propyl). In some embodiments, R t For hydrogen.

[0111] In some embodiments, the optionally substituted refers to optionally substituted with one or more of the following groups: halogen (eg, fluorine, chlorine, bromine, or iodine), -CN, -OH, or -NH2.

[0112] In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment for

[0113] In some embodiments, the above-mentioned heterocycloalkenyl, heteroaryl, heterocycloalkyl or heteroalkylene group contains one or more heteroatoms or heteroatoms independently selected from -O-, -NH-, -N-, -S-, C=O, -C(=O)NH-, -C(=O)O-, -S(=O)- or -S(=O)2-; in some embodiments, the above-mentioned heterocycloalkenyl, heteroaryl, heterocycloalkyl or heteroalkylene group contains one or more heteroatoms or heteroatoms independently selected from -O-, -NH-, -N- or -S-; in some embodiments, the above-mentioned heterocycloalkenyl, heteroaryl, heterocycloalkyl or heteroalkylene group contains one or more heteroatoms or heteroatoms independently selected from -O-, -NH- or -N-. In some embodiments, the number of the heteroatoms or heteroatoms is independently selected from 1, 2, 3, 4, 5 or 6; or selected from 1, 2, 3 or 4; or selected from 1, 2 or 3; or selected from 1 or 2.

[0114] In some embodiments, the heteroatoms in the heterocycloalkenyl group are selected from N, NH, O, or S. In some embodiments, the heteroatoms in the heterocycloalkenyl group are selected from N, O, or S. In some specific embodiments, the heteroatoms in the heterocycloalkenyl group are selected from N or O. In some embodiments, the number of heteroatoms in the heterocycloalkenyl group is selected from 1, 2, 3, 4, 5, or 6. In some embodiments, the number of heteroatoms in the heterocycloalkenyl group is selected from 1, 2, 3, or 4. In some embodiments, the number of heteroatoms in the heterocycloalkenyl group is selected from 1, 2, or 3. In some specific embodiments, the number of heteroatoms in the heterocycloalkenyl group is selected from 1 or 2.

[0115] It should be understood that any embodiment of the compounds of the present application as described above and the specific rings A, B, C, E, F, G, R, and R in the compounds of the present application as described above are not limited to the embodiments of the compounds of the present application as described above. 1 、R 2 、R 3 、R 4 、R t , L, X 5 、X 6 Any specific substituent described in the substituents may be independently combined with other embodiments and / or substituents of the compounds of the present application to form embodiments of the invention not specifically described above. In addition, in the specific embodiments and / or claims, any specific ring A, ring B, ring C, ring E, ring F, ring G, R 1 、R 2 、R 3 、R 4 、R t , L, X 5 、X 6Where a range of substituents is disclosed, it is understood that one or more substituents may be deleted from the range and the remaining range of substituents is considered to be an embodiment of the present application.

[0116] The present application relates to a compound of formula I-1 or I-1A, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0117] Among them, ring A, ring B, ring C, ring F, R 1 ,n,R 2 ,m,R 3 ,p,R 4 ,q,X 5 、X 6 , L is defined as described in this application.

[0118] In some embodiments, the moiety As described in this application.

[0119] The present application relates to a compound of formula I-2, formula I-2A, formula I-3, or formula I-3A, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0120] Among them, ring A, ring B, ring C, ring F, R 1 ,n,R 2 ,m,R 3 ,p,R 4 ,q,X 5 , L is as defined in this application;

[0121] X is selected from CH or N.

[0122] In some embodiments, the structural fragment The definition of is as described in this application.

[0123] In some embodiments, optionally, the compound described herein is not the following compound:

[0124] In some embodiments, optionally, the compound described herein is not the following compound:

[0125] In some embodiments, optionally, the compound described herein is not the following compound:

[0126] In some embodiments, the structural moiety Not selected

[0127] In some embodiments, the structural moiety Not selected In some embodiments, the structural moiety Not selected

[0128] In some embodiments, the structural moiety Not selected In some embodiments, the structural moiety Not selected In some embodiments, the structural moiety Not selected

[0129] In another aspect, the present application relates to a compound of formula I' or I", a moiety, a stereoisomer, a derivative thereof (particularly a Protac molecule) or a pharmaceutically acceptable salt thereof,

[0130] wherein ring A is absent or selected from C 5-10 Cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl;

[0131] Ring B is phenyl;

[0132] Ring C is selected from isoxazolyl or furyl;

[0133] L is a linking group; optionally, L is as defined in the present application; optionally, R 1 and n are as defined in this application.

[0134] In some embodiments, the present application relates to the following moiety, or a compound comprising the moiety (including a Protac molecule), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0135] Wherein, L is defined as above, Y 6 C(R 5 ) or N, R 5 H, deuterium, tritium, C 1-3 alkyl, =0 (preferably, H); d and d' may be the same or different and are each independently 1, 2 or 3.

[0136] In some embodiments, the present application relates to the following moiety, or a compound comprising the moiety (including a Protac molecule), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0137] Among them, L, Y6 , d and d' are as defined in this application, Y 5 C(R 5 ) or N, R 5 H, deuterium, tritium, C 1-3 Alkyl, =O (preferably, H).

[0138] In some embodiments, the moiety As described in this application.

[0139] In another aspect, the present application relates to a compound of formula I'-a or I"-a, a moiety, a stereoisomer, a derivative thereof (particularly a Protac molecule) or a pharmaceutically acceptable salt thereof,

[0140] wherein ring A is absent or selected from C 5-10 Cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl;

[0141] Ring B is phenyl;

[0142] Ring C is selected from isoxazolyl or furyl;

[0143] Each R 1a independently selected from halogen, -OH, -NH2, -CN, =O, -CHO, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-6 Alkyl OC(O)-, C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl, the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl is optionally substituted with one or more of the following groups: halogen, =O, -OH, -NH2, -CN, CHO, COOH, -C 1-4 Alkyl-OH, C 1-6 Alkyl OC(O)-, or optionally C 1-6 AlkylCOC(O)-substituted 4-10 membered heterocycloalkyl;

[0144] n is selected from 0, 1, 2 or 3.

[0145] In some embodiments, Ring A is absent or selected from C 5-7 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0146] In some embodiments, Ring A is absent or selected from C 5-6 cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0147] In some embodiments, Ring A is absent or selected from C 5-6 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0148] In some embodiments, Ring A is absent or selected from C 5-6 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5 membered heteroaryl.

[0149] In some embodiments, Ring A is absent or selected from C 5-6 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl, pyrrolyl, pyrazolyl, furyl, or oxazolyl.

[0150] In some embodiments, Ring A is absent or selected from C5 cycloalkenyl, C6 cycloalkenyl, 5-membered, 6-membered, 7-membered, 8-membered, or 9-membered heterocycloalkenyl, phenyl, pyrrolyl, pyrazolyl, furanyl, or oxazolyl.

[0151] In some embodiments, Ring A is absent or selected from cyclopentenyl, monocyclohexenyl, bicyclohexenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine 1-Hydroxy, ...

[0152] In some embodiments, Ring A is selected from C 5-9 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5 membered heteroaryl.

[0153] In some embodiments, Ring A is selected from C 5-6 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5 membered heteroaryl.

[0154] In some embodiments, Ring A is selected from C 5-9 In some embodiments, ring A is selected from C 5-6 cycloalkenyl or 5-9 membered heterocycloalkenyl.

[0155] In some embodiments, Ring A is selected from C 5-9 In some embodiments, ring A is selected from C 5-6 In some embodiments, ring A is selected from 5-9 membered heterocycloalkenyl.

[0156] In some embodiments, ring A is selected from cyclopentenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine 1-amino-1-amino-2-nitro-1-oxo-1-nitro-2-oxo-1-nitro-3 ...

[0157] In some embodiments, ring A is selected from cyclopentenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine In some embodiments, ring A is selected from cyclopentenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazacyclopentenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydropyrrol ... Base or azaspirocyclooctene.

[0158] In some specific embodiments, Ring A is selected from cyclopentenyl. In some specific embodiments, Ring A is selected from dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine Base or azaspirocyclooctene.

[0159] In some embodiments, Ring A is selected from phenyl, pyrrolyl, or pyrazolyl.

[0160] In some embodiments, wherein Ring A is selected from

[0161] In some embodiments, Ring C is isoxazolyl.In some embodiments, Ring C is furanyl.

[0162] In some embodiments, the moiety Selected from

[0163] In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from Alternatively, a structural fragment Selected from Alternatively, a structural fragment Selected from

[0164] In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from Alternatively, a structural fragment Selected from Alternatively, a structural fragment for

[0165] In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Not selected

[0166] In some embodiments, the structural fragment Selected from In some embodiments, each R 1a independently selected from halogen, -OH, -NH2, -CN, -CHO, C 1-6 Alkyl OC(O)-, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-10 Cycloalkyl or 4-10 membered heterocycloalkyl, the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-10 Cycloalkyl or 4-10 membered heterocycloalkyl is optionally substituted with one or more of the following groups: halogen, =O, -OH, -NH2, -CN, -CHO, -COOH, -C 1-4 Alkyl-OH, C 1-6 Alkyl OC(O)-, or optionally C 1-6 AlkylCOC(O)-substituted 4-10 membered heterocycloalkyl.

[0167] In some embodiments, each R 1a independently selected from halogen, -OH, -NH2, -CN, -CHO, C 1-4 Alkyl OC(O)-, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-9 Cycloalkyl or 4-9 membered heterocycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-9 Cycloalkyl or 4-9 membered heterocycloalkyl is optionally substituted with one or more of the following groups: halogen, -OH, =O, -NH2, -CN, -CHO, -COOH or -C 1-4 Alkyl-OH, C 1-4 Alkyl OC(O)-, or optionally C 1-4 AlkylCOC(O)-substituted 4-9 membered heterocycloalkyl.

[0168] In some embodiments, each R 1a independently selected from halogen, -OH, -NH2, -CN, -CHO, C 1-6 Alkyl OC(O)-, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl, the C 1-3 Alkyl, C1-3 Alkoxy, C 4-6 Cycloalkyl or 4-6 membered heterocycloalkyl is optionally substituted with one or more of the following groups: halogen, -OH, =O, -NH2, -CN, -CHO, -COOH, -C 1-4 Alkyl-OH, C 1-6 Alkyl OC(O)-, or optionally C 1-6 AlkylCOC(O)-substituted 3-6 membered heterocycloalkyl.

[0169] In some embodiments, each R 1a independently selected from halogen, -OH, -NH2, -CN, -CHO, C 1-4 Alkyl OC(O)-, C 1-3 Alkyl or 4-6 membered heterocycloalkyl, the C 1-3 Alkyl or 4-6 membered heterocycloalkyl is optionally substituted with one or more of the following groups: -OH, =O, -NH2, -CN, -CHO, -COOH, C 1-4 Alkyl OC(O)-, or optionally C 1-4 AlkylOC(O)-substituted 4-6 membered heterocycloalkyl.

[0170] In some embodiments, each R 1a Independently selected from halogen, -OH, -CHO, (CH3)3COC(O)-, C 1-3 Alkyl, cyclobutyl or piperidinyl, the C 1-3 The alkyl, cyclobutyl, or piperidinyl group is optionally substituted with one or more of the following: -OH, (CH3)3COC(O)-, or cyclobutyl optionally substituted with (CH3)3COC(O)-.

[0171] In some embodiments, each R 1a Independently selected from F, -OH, -CHO, (CH3)3COC(O)-, -CH2OH,

[0172] In some embodiments, n is selected from 0, 1, or 2. In some embodiments, n is selected from 0 or 1. In some embodiments, n is 0.

[0173] The present application relates to the following compounds, moieties, stereoisomers, derivatives thereof (particularly such as Protac molecules) or pharmaceutically acceptable salts thereof,

[0174] or,

[0175] In some embodiments, the present application relates to a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Ring A is C 5- 10 Cycloalkenyl, or a 5-15 membered heterocycloalkenyl containing 1-2 heteroatoms selected from N or O (e.g. C 5-8 cycloalkenyl, or a 5-8 membered heterocycloalkenyl containing 1-2 heteroatoms selected from N or O); Ring B is phenyl; Ring C is a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N or O; n is 0; X 5 Selected from C(R f ), R f Selected from H, deuterium or C 1-6 alkyl;

[0176] L is C 1-10 Alkylene, the C 1-10 One or more -CH2- in the alkylene group is optionally replaced by C 5-8 Cycloalkyl, 5-8 membered heterocycloalkyl containing 1-3 or 1-2 N atoms or O atoms;

[0177] Each R 2 are independently -OH, -NH2, -CN, C 1-10 Alkyl, C 1-10 Alkoxy or halogenated C 1-10 Alkyl; each R 3 are independently halogen, C 1-10 Alkyl or halogenated C 1-10 Alkyl; q is 0, m is 0, 1, 2 or 3, and p is 0, 1, 2, 3 or 4; X 6 is -O-, or -NH-; Ring G is phenyl or a 6-membered heteroaryl group containing 1-2 N atoms or O atoms; Ring E is C 3-6 Cycloalkyl; Ring F is phenyl or a 6-membered heteroaryl group containing 1-3 or 1-2 N atoms or O atoms; R t is hydrogen, -OH or C 1-6 alkyl.

[0178] In some embodiments, the present application relates to the following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof:

[0179] Among them, each R 2 are independently -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkyl (e.g. -CN, C 1-6 Alkoxy, C 1-5 Alkoxy, C 1-4 Alkoxy or C 1-3alkoxy);

[0180] Each R 3 Independently C 1-6 Alkyl or halogenated C 1-6 Alkyl (e.g. C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 alkyl);

[0181] m is 1, 2 or 3 (preferably 1 or 2), and p is 0, 1, 2, 3 or 4 (preferably 2, 3 or 4);

[0182] X 6 is -O- or -NH- (preferably -O-);

[0183] R t is hydrogen, -OH or C 1-6 an alkyl group (preferably hydrogen);

[0184] Ring F is C 6-10 Aryl or 6-10 membered heteroaryl (preferably phenyl or 6-membered heteroaryl containing 1-4, 1-3 or 1-2 N atoms);

[0185] L is C 1-6 Alkylene, the C 1-6 One or more -CH2- in the alkylene group is optionally replaced by a 5-7 membered heterocycloalkyl group containing 1-3 or 1-2 N atoms (e.g. Preferred );

[0186] Ring A is C 5-9 Cycloalkenyl or 5-9 membered heterocycloalkenyl containing 1-2 N atoms (preferably C 5-7 cycloalkenyl or 5-7 membered heterocycloalkenyl containing 1 N atom).

[0187] In some embodiments, the present application relates to the following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof:

[0188] Preferred

[0189] Among them, R 2 、R 3 ,m,p,X 6 、R t , Ring F, L and Ring A are as defined above, and each R 2 They can be the same or different, each R 3 They may be the same or different; 1 、Y 2、Y 3 、Y 4 、Y 5 and Y 6 Each independently is C(R 5 ) or N, R 5 H, deuterium, tritium, C 1-3 alkyl, =O (preferably, H, deuterium, tritium); d and d' may be the same or different, and are each independently 1, 2 or 3. In some preferred embodiments, the Y 1 、Y 2 、Y 3 and Y 4 At most 3 of them are N, more preferably, the Y 1 、Y 2 、Y 3 and Y 4 At most 2 of them are N.

[0190] In some embodiments, Y 1 is CH or N. In some embodiments, Y 1 In some embodiments, Y 1 is N.

[0191] In some embodiments, Y 2 is CH or N. In some embodiments, Y 2 In some embodiments, Y 2 is N.

[0192] In some embodiments, Y 3 is CH or N. In some embodiments, Y 3 In some embodiments, Y 3 is N.

[0193] In some embodiments, Y 4 is CH or N. In some embodiments, Y 4 In some embodiments, Y 4 is N.

[0194] In some embodiments, Y 5 is CH or N. In some embodiments, Y 5 In some embodiments, Y 5 is N.

[0195] In some embodiments, Y 6 is CH or N. In some embodiments, Y 6 In some embodiments, Y 6 is N.

[0196] On the other hand, the present application relates to the use of the compound (e.g., Formula I' or Formula I" or I'-a or Formula I"-a or specific compound), part, its isomer (such as stereoisomer), and its derivative in the preparation of Protac molecules. On the other hand, the present application relates to the use of the compound (e.g., Formula I' or Formula I" or I'-a or Formula I"-a or specific compound), part, its isomer (such as stereoisomer), and its derivative for constituting a part of a Protac molecule. On the other hand, the present application relates to the compound (e.g., Formula I' or Formula I" or I'-a or Formula I"-a or specific compound), part, its isomer (such as stereoisomer), and its derivative in the form of a Protac molecule. On the other hand, the present application relates to the use of the compound (e.g., Formula I' or Formula I" or I'-a or Formula I"-a or specific compound), part, its isomer (such as stereoisomer), and its derivative for degrading proteins (e.g., AR), for example, the compound (e.g., Formula I' or Formula I" or I'-a or Formula I"-a or specific compound), part, its isomer (such as stereoisomer), and its derivative degrades the protein in the form of Protac molecules. On the other hand, the present application relates to the use of the compound (e.g., Formula I' or Formula I" or I'-a or Formula I"-a or specific compound), part, its isomer (such as stereoisomer), and its derivative in the form of Protac molecules for degrading proteins. The present application relates to the use of the compound (e.g., Formula I' or Formula I" or I'-a or Formula I"-a or specific compound), part, its isomer (such as stereoisomer), and its derivative (e.g., as a preparation intermediate) in the preparation of Protac molecules. The present application relates to the use of the compound (e.g., Formula I' or Formula I" or I'-a or Formula I"-a or specific compound), part thereof, its isomers (such as stereoisomers), and its derivatives (e.g., as preparation intermediates) in the preparation of protein degraders.

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

[0198] The present application also relates to the following compounds, their stereoisomers or pharmaceutically acceptable salts thereof:

[0199] This application also covers solutions obtained by any combination, deletion or replacement of the above embodiments.

[0200] On the other hand, the present application relates to a pharmaceutical composition, which contains the above-mentioned compound of the present application, its stereoisomer or a pharmaceutically acceptable salt thereof. Optionally, the pharmaceutical composition of the present application also includes a pharmaceutically acceptable excipient.

[0201] On the other hand, the present application relates to the use of the above-mentioned compound, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for preventing or treating a disease by degrading a target protein (such as androgen receptor, AR) bound to a targeting ligand.

[0202] On the other hand, the present application relates to the use of the above-mentioned compound, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for preventing or treating a disease that is treated by binding to cerebellar protein (CRBN) in vivo.

[0203] On the other hand, the present application relates to the use of the above-mentioned compound, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for preventing or treating AR-related diseases.

[0204] The present application relates to a method for treating or preventing a disease in a mammal by degrading a target protein (such as androgen receptor, AR) bound to a targeting ligand, comprising administering a therapeutically effective amount of the above-mentioned compound of the present application, its stereoisomer or pharmaceutically acceptable salt, or a pharmaceutical composition thereof to a mammal (preferably a human) in need of such treatment.

[0205] The present application relates to a method for treating or preventing a disease that is treated by binding to a cerebellar protein in vivo, comprising administering a therapeutically effective amount of the above-mentioned compound of the present application, its stereoisomer or pharmaceutically acceptable salt, or a pharmaceutical composition thereof to a mammal (preferably a human) in need of such treatment.

[0206] On the other hand, the present application relates to a method for treating AR-related diseases in mammals, comprising administering a therapeutically effective amount of the above-mentioned compound of the present application, its stereoisomer or pharmaceutically acceptable salt, or pharmaceutical composition thereof to a mammal (preferably a human) in need of such treatment.

[0207] On the other hand, the present application relates to the above-mentioned compound, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition for preventing or treating diseases treated by degrading the target protein (such as androgen receptor, AR) bound to the targeting ligand.

[0208] On the other hand, the present application relates to the above-mentioned compound, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition for preventing or treating a disease that is treated by binding to a cerebellar protein in vivo.

[0209] On the other hand, the present application relates to the above-mentioned compound, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition for preventing or treating AR-related diseases.

[0210] On the other hand, the present application relates to the use of the above-mentioned compound, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition in preventing or treating diseases treated by degrading target proteins (such as androgen receptor, AR) bound to targeting ligands.

[0211] On the other hand, the present application relates to the use of the above-mentioned compound, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition in preventing or treating diseases that are treated by binding to cerebellar proteins in vivo.

[0212] On the other hand, the present application relates to the use of the above-mentioned compound, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition in preventing or treating AR-related diseases.

[0213] In some embodiments, the above-mentioned AR-related diseases are selected from disorders treated by degrading and / or inhibiting proteins that bind to AR target protein ligands (androgen receptor, AR); in some embodiments, the above-mentioned AR-related diseases are selected from disorders treated by binding to cerebellar proteins in vivo; in some embodiments, the above-mentioned diseases or disorders are selected from cancer, such as prostate cancer.

[0214] In some embodiments, the above-mentioned conditions treated by binding to cerebellar proteins in vivo and / or the conditions treated by degrading target proteins bound to targeting ligands are selected from AR-related diseases; in some embodiments, the above-mentioned AR-related diseases are selected from cancers, such as prostate cancer.

[0215] As used herein, "one or more" refers to an integer from one to ten. For example, "one or more" refers to one, two, three, four, five, six, seven, eight, nine, or ten; in some embodiments, the "one or more" is selected from one, two, three, four, five, or six. In some embodiments, the "one or more" is selected from one, two, or three. In some embodiments, the "one or more" is selected from one, or two.

[0216] In some aspects, the present application comprises the above-defined variables and embodiments thereof, and any combination thereof.

[0217] Technical Effects

[0218] The compounds of the present application have protein degradation activity on AR or its mutants and anti-proliferative activity on related cells, for example, they have degradation activity on VCaP cell AR, and / or MDA-PCA-2B cell AR (including its L702H and / or T878A mutations), 22RV1 cell AR (including its H875Y and / or ARV7 mutations), HEK293 cell AR (including its L702H mutation), and / or LNCaP cell AR (including its T878A mutation); and they have anti-proliferative activity on VCaP cells, and / or LNCaP cells (including its T878A mutation), and / or 22RV1 cells (including its H875Y and / or ARV7 mutations), and / or MDA-PCA-2B cells (including its L702H and / or T878A mutations), and / or HEK293 cells (including its L702H mutation). In addition, the compounds of the present invention also have good in vitro liver microsome stability and mammalian (eg mouse) in vivo pharmacokinetic properties (specifically AUC, t 1 / 2 and other parameters), can inhibit tumor growth in vivo, showing the prospect of drug development.

[0219] definition

[0220] Unless otherwise indicated, the following terms used in this application have the following meanings. A particular term should not be construed as undefined or unclear unless specifically defined, but rather should be understood according to its ordinary meaning in the art. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0221] Unless otherwise specified, Used to indicate Any hydrogen atom in any position of the group can be replaced by a group connected by "-".

[0222] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo (i.e., =O), it means that two hydrogen atoms are replaced. Oxo does not occur on aromatic groups.

[0223] The term "optionally" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes both the occurrence of the event or situation and the non-occurrence of the event or situation. "Optionally substituted" includes unsubstituted and substituted. For example, an ethyl group is "optionally" substituted with a halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (such as CH2CH2F), polysubstituted (such as CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible and / or cannot be synthesized will be introduced.

[0224] In this article, C m-n , means that the moiety has an integer number of carbon atoms in a given range. For example, "C 1-6 ” means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0225] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. For example, if a group contains two R's, each R has an independent option.

[0226] When a bond cross-links two atoms in a ring (including a monocyclic, fused, or spirocyclic ring), the bond can be bonded to any atom in the ring (including a monocyclic, fused, or spirocyclic ring). Indicates that the bonds on both sides can be connected to any two different atoms on ring A, ring B or ring C; for example Indicates that the bonds on both sides can be connected to any two different atoms on ring A, the middle benzene ring or ring C; further, for example It means that the bonds on both sides can be connected to any two different atoms in the four rings in the system.

[0227] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine. The term "hydroxy" refers to an -OH group. The term "amino" refers to an -NH2 group. The term "cyano" refers to a -CN group.

[0228] The term "alkyl" refers to a group of the formula C n H 2n+1 The alkyl group may be straight chain or branched. For example, the term "C 1-6The term "alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio has the same definition as above.

[0229] 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 "Alkylene" refers to an alkylene group containing 1 to 6 carbon atoms; the term "C 1-4 "Alkylene" refers to an alkylene group containing 1 to 4 carbon atoms, including but not limited to -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-.

[0230] The term "alkenylene" refers to a divalent group formed by removing a hydrogen atom from any position of an alkenyl group, for example, the term "C 2-6 "Alkenylene" refers to an alkenylene group containing 2 to 6 carbon atoms; the term "C 2-4 "Alkenylene" refers to alkenylene groups containing 2 to 4 carbon atoms, including but not limited to -CH2CH=CH-, -CH2CH2CH=CH- or -CH2CH=CHCH2-.

[0231] The term "alkynylene" refers to a divalent group formed by removing a hydrogen atom from any position of an alkynyl group, for example, the term "C 2-6 "Alkyne" refers to an alkynylene group containing 2 to 6 carbon atoms; the term "C 2-4 The term "alkynylene" refers to an alkynylene group containing 2 to 4 carbon atoms, including but not limited to -C≡C-, -H2C-C≡C-, -H2C-H2C-C≡C- or -H2C-C≡C-CH2-.

[0232] The term "heteroalkyl" refers to a straight or branched chain alkyl group consisting of a certain number of carbon atoms and at least one heteroatom, preferably having 1 to 14 carbon atoms, more preferably 1 to 10 carbon atoms, even more preferably 1 to 6 carbon atoms, most preferably 1 to 3 carbon atoms in the chain, and preferably having 1, 2 or 3 heteroatoms selected from S, O and N. For example, C mHeteroalkyl refers to an alkyl group with heteroatoms inserted in the chain, consisting of m carbon atoms and at least one heteroatom (e.g., 1-3 heteroatoms selected from S, O, and N) located between any two carbon atoms. The nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. The heteroatom or heteroatom group can be located at any 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 and tertiary alkylamines, amides, sulfides, and the like, including alkoxy, alkylthio, and alkylamino groups; unless otherwise specified, C 1-6 Heteroalkyl groups include C1, C2, C3, C4, C5 and C6 heteroalkyl groups, such as C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino.

[0233] The term "heteroalkylene" refers to a divalent group formed by removing one hydrogen atom from any position of a heteroalkyl group.

[0234] The term "alkoxy" refers to an -O-alkyl group.

[0235] The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. Non-limiting examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.

[0236] The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and can exist as a monocyclic, bicyclic bridged ring, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 4 to 16-membered ring, a 4 to 12-membered ring, a 4 to 10-membered ring, or a 4 to 8-membered ring. Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, etc.

[0237] The term "cycloalkyl" refers to a fully saturated carbocyclic ring that can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically 3 to 16 membered rings (e.g., 3 to 10 membered rings, or 5 to 8 membered rings). Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, etc.

[0238] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3 to 16-membered ring, a 3-11-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 (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and / or nitrogen. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxirane, thioethane, and aziridine groups; non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl groups; examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl groups; examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl groups; examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxetanyl, and thiepanyl groups. Preferably, the heterocycloalkyl group is a monocyclic group having 5 or 6 ring atoms.

[0239] The term "spirocycle" refers to a fully saturated or partially unsaturated polycyclic ring system in which the monocyclic rings share a carbon atom (called a spiro atom), including carbocycles and heterocycles. Unless otherwise indicated, the spirocycle is 5 to 20 members, preferably 6 to 14 members, and more preferably 8 to 12 members. When the spirocycle is a heterocycle, one or more ring atoms in the polycyclic ring are selected from N, O, S(O) n 、P(O) n (wherein n is 0, 1 or 2) heteroatoms (preferably 1 or 2 heteroatoms), and the remaining ring atoms are carbon atoms.

[0240] The term "spiroalkyl" refers to a fully saturated, all-carbon polycyclic ring that shares a carbon atom (called a spiro atom) between monocyclic rings. Unless otherwise indicated, the spiroalkyl is 5 to 20 yuan, preferably 6 to 14 yuan, and more preferably 8 to 12 yuan. According to the number of spiro atoms shared between the rings, the spiroalkyl is divided into a single spiroalkyl, a double spiroalkyl or a multi-spiroalkyl, preferably a single spiroalkyl and a double spiroalkyl, more preferably a 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or a 5 yuan / 6 yuan single spiroalkyl. Non-limiting examples of spiroalkyl include

[0241] The term "spiroheterocycloalkyl" refers to a fully saturated polycyclic ring in which the monocyclic rings share a carbon atom (called a spiro atom), and one or more ring atoms in the polycyclic ring are selected from N, O, S(O) n 、P(O) n(wherein n is 0, 1 or 2) heteroatoms (preferably 1 or 2 heteroatoms), and the remaining ring atoms are carbon atoms. Unless otherwise indicated, the spiro heterocycloalkyl is 5 to 20 yuan, preferably 6 to 14 yuan, more preferably 6 to 10 yuan. According to the number of shared spiro atoms between the rings, the spiro heterocycle is divided into a monospiro heterocycle, a dispiro heterocycle or a polyspiro heterocycle, preferably a monospiro heterocycle or a dispiro heterocycle, more preferably a 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or a 5 yuan / 6 yuan monospiro heterocycle. Non-limiting examples of spiro heterocycloalkyl include wait.

[0242] The term "heterocycloalkenyl" includes cycloalkenyl groups in which one or more carbon atoms (e.g., 1-5, 1-4, 1-3, 1-2) are replaced by heteroatoms, such as cycloalkenyl groups in which up to 3 carbon atoms, in one embodiment up to 2 carbon atoms, in another embodiment 1 carbon atom are independently replaced by O, S, S(O) or N, provided that at least one cycloalkenyl carbon-carbon double bond is retained. Cyclic groups that may exist as monocyclic, bridged, or spirocyclic rings may be 3 to 16-membered rings (e.g., 3 to 12-membered, 5 to 8-membered rings, such as 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, or 11-membered rings). Examples of heterocycloalkenyl groups include, but are not limited to, dihydropyrrolyl, tetrahydropyridyl, tetrahydroazepine, pyrrolidine ... Base or azaspirocyclooctene.

[0243] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and 1,2,3,4-tetrahydronaphthalene.

[0244] The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system containing at least one (e.g., 1-5, 1-4, 1-3, 1-2) ring atom selected from N, O, S, with the remaining ring atoms being C, and having at least one aromatic ring. Preferred heteroaryl groups have single 4 to 8-membered rings, especially 5 to 8-membered rings (e.g., 5-, 6-, 7-, or 8-membered), or multiple fused rings containing 6 to 14, especially 6 to 10 (e.g., 6, 7, 8, 9, or 10) ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.

[0245] Unless otherwise specified, the term "hetero" means a heteroatom or heteroatom group (i.e., a group containing heteroatoms), including atoms other than carbon (C) and hydrogen (H) and groups containing these heteroatoms, for example, including oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), silicon (Si), germanium (Ge), aluminum (Al), boron (B), -O-, -S-, =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)-.

[0246] The term "derivative" refers to a new compound or a group of new compounds that retain the basic structure of the parent compound after one or more chemical reactions or structural evolution, and only changes or modifications are made in the side chains, functional groups or substituents.

[0247] The substitution or substituent substitution in the term "substituent", "optionally substituted with one or more substituents" or "optionally substituted" includes all substituents mentioned herein, such as the terms "halogen", "deuterium", "-NH2", "-NH(C 1-4 Alkyl)", "-N(C 1-4 Alkyl)2", "-OH", "-OC 1-4 Alkyl", "-CN", "C 1-4alkyl", "3-6 membered heterocycloalkyl", etc., and corresponding non-limiting or exemplary groups, wherein some non-limiting examples of the "substituent" include thiol, nitro, nitroso, cyano, azide, sulfoxide, sulfone, sulfonamide, carboxyl, aldehyde, imine, alkyl, halo-alkyl, cycloalkyl, halo-cycloalkyl, alkenyl, halo-alkenyl, cycloalkenyl, halo-cycloalkenyl, alkynyl, halo-alkynyl, cycloalkynyl, halo-cycloalkynyl , heteroalkyl, halo-heteroalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, arylalkylene, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroarylalkylene, heteroarylalkoxy, heteroarylalkylthio, heterocyclyl, heterocyclyloxy, heterocyclylthio, heterocyclylalkylene, heterocyclylalkoxy, heterocyclylalkylthio, acyl, acyloxy, carbamate group, amide group, urea group, epoxy group, ester group and oxo, etc., wherein the substituent is optionally substituted by one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC( -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0248] In some embodiments herein, the substituent is selected from deuterium, tritium, hydroxyl, sulfhydryl, halogen, amino, nitro, nitroso, cyano, azide, sulfoxide, sulfone, sulfone, sulfonamide, carboxyl, aldehyde, imine, C 1-12 Alkyl, halo-C 1-12 Alkyl, 3-12 membered cycloalkyl, halogenated 3-12 membered cycloalkyl, C 2-12 Alkenyl, halo-C 2-12 Alkenyl, 3-12 membered cycloalkenyl, halogenated 3-12 membered cycloalkenyl, C 2-12 Alkynyl, halo-C 2-12 Alkynyl, 8-12 membered cycloalkynyl, halogenated 8-12 membered cycloalkynyl, C 1-12 Heteroalkyl, halo-C 1-12 Heteroalkyl, C 1-12 Alkoxy, C 1-12Alkylthio, 6-10 membered aryl, 6-10 membered aryloxy, 6-10 membered arylthio, 6-10 membered arylC 1-12 Alkylene, 6-10 membered aryl C 1-12 Alkoxy, 6-10 membered aryl C 1-12 alkylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, 5-10 membered heteroarylalkylene, 5-10 membered heteroarylalkoxy, 5-10 membered heteroarylalkylthio, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, 3-12 membered heterocyclylthio, 3-12 membered heterocyclylC 1-12 Alkylene, 3-12 membered heterocyclic group C 1-12 Alkoxy, 3-12 membered heterocyclic group C 1-12 Alkylthio, C 1-12 Acyl, C 1-12 Acyloxy, carbamate group, C 1-12 Amide group, urea group, epoxy group, C 2-12 Ester group and oxo, said substituent being optionally substituted by one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, carboxyl, -C(O)OC 1-12 Alkyl, -OC(O)-C 1-12 Alkyl, -C(O)NH2, -C(O)NH-C 1-12 Alkyl, -C(O)N(C 1-12 Alkyl)2, -NHC(O)-C 1-12 Alkyl, -C(O)-C 1-12 Alkyl, -S(O)-C 1-12 Alkyl, -S(O)2-C 1-12 Alkyl, -S(O)2NH2, -S(O)2NH-C 1-12 Alkyl, -S(O)2N(C 1-12 alkyl) 2, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12 Alkylene, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group C 1-12 Alkylene, 3-12 membered heterocyclyloxy, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkylC 1-12Alkylene, 3-12 membered heterocycloalkyloxy, 5-10 membered heteroaryl, 5-10 membered heteroarylC 1-12 Alkylene, 5-10 membered heteroaryloxy, 6-10 membered aryl, 6-10 membered arylC 1-12 an alkylene group or a 6- to 10-membered aryloxy group.

[0249] Unless otherwise specified, the term "hetero" refers to a heteroatom or heteroatom group (i.e., a group containing heteroatoms), including atoms other than carbon (C) and hydrogen (H) and groups containing these heteroatoms. For example, heteroatoms include, but are not limited to, oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), silicon (Si), germanium (Ge), aluminum (Al), and boron (B). Specific heteroatoms or heteroatom groups include: -O-, -S-, -N=, =O, =S, -P(=O)-, -P(=O)2-, -P(=O)O-, -P(=O)2O-, -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, and optionally substituted -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)-, or -S(=O)N(H)-. Preferably, the term "hetero" denotes a heteroatom or a heteroatom group (ie a group containing a heteroatom) wherein the heteroatom is selected from oxygen, nitrogen or sulfur.

[0250] In this application, wavy lines are used represents one of the absolute configurations of a stereocenter (e.g. one, specific express ) or one of the relative configurations (e.g. express When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, they are intended to include both E and Z geometric isomers. Likewise, all tautomeric forms are encompassed within the scope of this application.

[0251] The groups or structural fragments in this application such as -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -、-Cy 1 -Cy 2 -LNK 2 -、LNK、Cy 1 、Cy 2 、-Cy 1 -LNK-Cy 2 -、-Cy 1 -LNK- or -LNK-Cy 2- and its specific options, optionally can be read from left to right, corresponding to the group or fragment in the general formula on the left and right groups connected, for example, when L is selected from -Cy 1 -LNK-, when Cy 1 Selected from Reading from left to right, Cy 1 The left side corresponds to the fragment on the left side of the general formula Connect, right side to right side segment The resulting fragments are Optionally, the groups or structural fragments in this application such as -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -、-Cy 1 -Cy 2 -LNK 2 -、LNK、Cy 1 、Cy 2 、-Cy 1 -LNK-Cy 2 -、-Cy 1 -LNK- or -LNK-Cy 2 - and its specific options, can be read in order from right to left, and are respectively connected to the left and right groups of the group or fragment in the general formula, for example, when L is selected from -Cy 1 -LNK-, when Cy 1 Selected from According to the reading order from right to left, Cy 1 The right side corresponds to the fragment on the left side of the general formula Connect the left side with the corresponding right side fragment in the general formula The fragments formed by the connection are Other groups are the same as described above.

[0252] The term "treating" means administering the compounds or formulations described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes: (i) inhibiting the disease or disease state, i.e., curbing its development; (ii) alleviating the disease or disease state, i.e., causing the disease or disease state to regress.

[0253] The term "prevention" means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, including preventing the occurrence of a disease or disease state in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0254] The term "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and this disclosure.

[0255] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0256] As the pharmaceutically acceptable salt, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned.

[0257] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

[0258] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0259] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0260] Unless the context clearly indicates otherwise, singular terms herein include plural referents and vice versa. Similarly, the word "or" herein is intended to include "and" unless the context clearly indicates otherwise.

[0261] Unless otherwise indicated, all numbers used herein expressing amounts of ingredients, measurements, or reaction conditions are to be understood as modified in all instances by the term "about." When used in conjunction with a percentage, the term "about" can mean, for example, ±1%, preferably ±0.5%, and more preferably ±0.1%.

[0262] The compounds and intermediates of the present application may also exist in different tautomeric forms, and all such forms are included within the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety, in which the proton can migrate between two ring nitrogens. Valence tautomers include interconversions by reorganization of some bonding electrons. For example, any compound of the present disclosure, such as pyrazole alone or as part of a heterocyclic group, may exist as any one tautomer or as a mixture of any number of two tautomers, i.e. or The present disclosure includes all possible tautomers of the disclosed compounds, either as single tautomers or as any mixture of such tautomers in any ratio.

[0263] The present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0264] Certain isotope-labeled compounds of the present application (e.g. 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as 15 O. 13 N. 11 C and 18F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0265] In addition, the use of heavier isotopes such as deuterium (i.e. 2 H)) substitution may offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium.

[0266] The compounds of the present invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the present invention containing asymmetric carbon atoms can be isolated in optically pure forms or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0267] The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

[0268] Typical routes of administration of the compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0269] The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0270] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, and the like for oral administration to a patient.

[0271] Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be prepared by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients as needed, and then granulating the mixture to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0272] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0273] In all methods of administration described herein, the compounds of formula I are administered at a dosage of 0.01 to 200 mg / kg body weight per day in single or divided doses.

[0274] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0275] The chemical reactions described in the specific embodiments of the present application are carried out in a suitable solvent that is compatible with the chemical transformations described herein and the reagents and materials required. To obtain the compounds described herein, it may sometimes be necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0276] An important consideration in synthetic route planning in this field is the selection of an appropriate protecting group for a reactive functional group (such as an amino group in this application). For example, reference can be made to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.

[0277] In some embodiments, when L is -Cy 1 -LNK-, the compound of formula I-2 of the present application can be prepared by a person skilled in the art of organic synthesis using the following intermediates or their salts through the following route:

[0278] Among them, ring A, ring B, ring C, ring F, R 1 ,n,R 2 ,m,R 3 ,p,R 4 ,q,X 5 、X6 、Cy 1 and LNK is defined as described in this application;

[0279] R x is selected from leaving groups, such as halogen (fluorine, chlorine, bromine or iodine);

[0280] R p is selected from protecting groups such as Boc.

[0281] This application uses the following abbreviations:

[0282] DMSO stands for dimethyl sulfoxide; DMF stands for N,N-dimethylformamide; MeOH stands for methanol; IBX stands for 2-iodoxybenzoic acid; DIPEA stands for N,N'-diisopropylethylamine; HATU stands for 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; DCE stands for dichloroethane; iPrOH stands for isopropyl alcohol; Boc stands for tert-butyloxycarbonyl; DC 50 It indicates the drug concentration when the degradation rate reaches 50%; Dmax indicates the maximum degradation rate.

[0283] For the sake of clarity, the present invention is further illustrated by examples, but the examples do not limit the scope of this application. All reagents used in this application are commercially available and can be used without further purification. DETAILED DESCRIPTION

[0284] Example 1 Synthesis of Compound 1

[0285] Step 1: Preparation of intermediate 1b

[0286] To a single-necked flask, intermediate 1a (10 g), 4-piperidinemethanol (8.97 g), DMSO (100 mL), and DIPEA (16.77 g) were added in sequence, and the mixture was heated to 90°C for reaction. After the reaction was completed, the reaction solution was cooled to room temperature, and ethyl acetate and water were added to the system for extraction. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The intermediate 1b (10.03 g) was purified by silica gel column chromatography. MS (ESI, [M+H] + )m / z:250.2

[0287] Step 2: Preparation of intermediate 1c

[0288] To a single-necked flask, intermediate 1b (2.7 g), MeOH (40 mL), water (5 mL), and sodium hydroxide (1.24 g) were added in sequence, and the mixture was heated to 50°C for reaction. After the reaction was completed, the reaction solution was cooled to room temperature, and 3N dilute hydrochloric acid was added to the system to adjust the pH to a weak acidic state. The solvent was evaporated under reduced pressure, and methanol was added to the concentrate to dissolve the product. The filtrate was filtered and collected, and the solvent was evaporated under reduced pressure to obtain intermediate 1c (1.82 g). MS (ESI, [MH] - )m / z:234.1

[0289] Step 3: Preparation of intermediate 1d

[0290] To a single-necked flask, intermediate 1c (235 mg), intermediate 2d (175 mg), DMF (5 mL), DIPEA (0.562 mL), and HATU (321 mg) were added sequentially, and the mixture was reacted at room temperature. After the reaction was complete, ethyl acetate and water were added to the system for extraction. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The product was purified by silica gel column chromatography to obtain intermediate 1d (0.22 g). MS (ESI, [M+H] + )m / z:492.1

[0291] Step 4: Preparation of intermediate 1e

[0292] Intermediate 1d (220 mg), DMSO (2 mL), and IBX (405 mg) were added sequentially to a single-necked flask, and the mixture was reacted at room temperature. After completion of the reaction, ethyl acetate and saturated aqueous sodium bicarbonate were added to the system for extraction. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to provide Intermediate 1e (190 mg).

[0293] Step 5: Preparation of Compound 1

[0294] To a single-necked flask were added intermediate 1e (200 mg), intermediate z1 (131 mg) (see Example 19 of WO2023088406 for the synthetic route), DCE / iPrOH = 5 / 1 (5 mL), sodium acetate (35.4 mg), and sodium triacetoxyborohydride (268 mg), and the mixture was reacted at room temperature. After completion of the reaction, the solvent was evaporated under reduced pressure, and the product was purified by silica gel column chromatography to obtain compound 1 (128 mg).

[0295] MS (ESI, [M+H] + )m / z:759.6. 1H NMR (500MHz, DMSO-d6) δ11.08(s,1H),7.74(d,J=8.5Hz,2H),7.64(d,J=8.6Hz,1H),7.58(d,J=8.1Hz,1H),7.48(d,J=9.2Hz,1H ),7.11(d,J=8.3Hz,1H),6.96(d,J=8.6Hz,2H),6.64(d,J=2.2Hz,1H),6.54(dd,J=8.6,2.2Hz,1H),4.56(dd,J=11.9,5.0Hz,1H ),4.27(s,1H),4.05(d,J=9.1Hz,1H),3.91(s,5H),3.71(s,2H),3.00(t,J=5.6Hz,2H),2.85–2.72(m,5H),2.61(dt,J=17.3,4. 3Hz,1H),2.49–2.44(m,1H),2.40(d,J=7.1Hz,2H),2.19(dq,J=13.8,4.8Hz,1H),1.95–1.79(m,3H),1.22(s,8H),1.15(s,6H).

[0296] Example 2 Synthesis of Compound 2

[0297] Step 1: Preparation of intermediate 2c

[0298] To the reaction flask, intermediate 2a (6 g) and DMF (30 mL) were added sequentially. Sodium hydride (1.479 g) was added under ice-bath conditions. The mixture was stirred for 20 min in an ice-bath. Intermediate 2b (4.47 g) was added and the mixture was reacted at room temperature. After the reaction was completed, the reaction solution was slowly poured into 300 mL of ice water to quench the reaction. The filter cake was filtered and dried to obtain intermediate 2c (8.9 g). MS (ESI, [M+H] + )m / z:275.42. 1 H NMR (500MHz, DMSO-d6) δ7.62(d,J=8.6Hz,1H),6.65(d,J=9.5Hz,1H),6.60(d,J=2.2Hz,1H),6.50(d d,J=8.7,2.3Hz,1H),4.12(s,1H),3.93(s,1H),3.89(s,3H),1.40(s,9H),1.13(s,6H),1.06(s,6H).

[0299] Step 2: Preparation of intermediate 2d

[0300] To a single-necked flask, intermediate 2c (8.9 g) and dioxane hydrochloride solution (59.4 mL) were added sequentially, and the mixture was reacted at room temperature. After the reaction was completed, the solvent was evaporated under reduced pressure and dried in vacuo to obtain intermediate 2d (8.2 g). MS (ESI, [M+H] + )m / z:275.21. 1 H NMR (500MHz, DMSO-d6) δ8.47(d,J=6.3Hz,3H),7.64(d,J=8.6Hz,1H),6.63(d,J=2.3Hz,1H),6.53( dd,J=8.7,2.3Hz,1H),4.31(s,1H),3.90(s,3H),3.06(q,J=6.0Hz,1H),1.32(s,6H),1.11(s,6H).

[0301] Step 3: Preparation of Intermediate 2g

[0302] To a single-necked flask, intermediate 2e (2 g), intermediate 2f (1.782 g), DMF (20 mL) and potassium carbonate (5.35 g) were added in sequence, and the mixture was heated to 110°C for reaction. After the reaction was completed, the reaction solution was cooled to room temperature, and ethyl acetate and water were added to the system for extraction. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The product was purified by silica gel column chromatography to obtain intermediate 2g (0.72 g). MS (ESI, [M+H] + )m / z:251.0. 1 H NMR (500MHz, DMSO-d6) δ8.36(d,J=3.0Hz,1H),7.84(d,J=8.9Hz,1H),7.31(dd,J=8.9,3.1Hz,1H),4.49(t,J=5.3Hz,1H),4.02–3. 95(m,2H),3.79(s,3H),3.30–3.24(m,2H),2.86(td,J=12.7,2.8Hz,2H),1.81–1.71(m,2H),1.69–1.56(m,1H),1.25–1.12(m,2H).

[0303] Step 4: Preparation of intermediate 2h

[0304] Referring to the preparation process of intermediate 1c in step 2 of Example 1, intermediate 2g was substituted for intermediate 1b, and intermediate 2h (0.86 g) was prepared by reaction.

[0305] MS (ESI, [M+H] + )m / z:237.23. 1H NMR (500MHz, DMSO-d6) δ8.30(d,J=3.0Hz,1H),8.03(d,J=9.1Hz,1H),7.75(dd,J=9.2,2.9Hz,1H),4.06(dt,J=13.4,3.4Hz,2H),3 .28(d,J=6.2Hz,2H),3.00(td,J=12.6,2.6Hz,2H),1.83–1.73(m,2H),1.68(tq,J=11.4,3.5Hz,1H),1.21(qd,J=12.5,4.1Hz,2H).

[0306] Step 5: Preparation of intermediate 2i

[0307] Referring to the preparation process of intermediate 1d in step 3 of Example 1, intermediate 2h was substituted for intermediate 1c, and intermediate 2i (0.25 g) was prepared by reaction.

[0308] MS (ESI, [M+H] + )m / z:493.44. 1 H NMR (500MHz, DMSO-d6) δ8.33(d,J=2.9Hz,1H),8.09(d,J=9.1Hz,1H),7.82(d,J=8. 8Hz,1H),7.64(d,J=8.6Hz,1H),7.41(dd,J=8.9,2.9Hz,1H),6.67(d,J=2.2Hz,1H), 6.57(dd,J=8.7,2.2Hz,1H),4.49(t,J=5.3Hz,1H),4.37(s,1H),3.99–3.93(m,3H),3.91(s,3H),3.28(t,J=5.7Hz,2H),2.85(td,J=12.6,2 .7Hz,2H),2.69(s,1H),1.74(dd,J=13.7,3.6Hz,2H),1.62(dtd,J=14.1,7.7,3.4Hz,1H),1.23(d,J=8.7Hz,1H),1.20(s,6H),1.15(s,6H).

[0309] Step 6: Preparation of intermediate 2j

[0310] Referring to the preparation process of intermediate 1e in step 4 of Example 1, intermediate 2i was substituted for intermediate 1d, and intermediate 2j (210 mg) was prepared by reaction.

[0311] MS (ESI, [M+H] + )m / z:491.25

[0312] Step 7: Preparation of Compound 2

[0313] Refer to the preparation process of compound 1 in step 5 of Example 1, intermediate 2j was substituted for intermediate 1e, and compound 2 (160 mg) was prepared by reaction.

[0314] MS (ESI, [M+H] + )m / z:760.01. 1 H NMR (500MHz, DMSO-d6) δ11.08(s,1H),8.34(d,J=3.0Hz,1H),8.09(d,J=9.1Hz,1H),7.83(d,J=8.8Hz,1H),7.64(d,J=8.6Hz,1H),7.58(d,J=8.2Hz,1H ),7.42(dd,J=9.0,2.9Hz,1H),7.11(d,J=8.3Hz,1H),6.67(d,J=2.2Hz,1H) ,6.57(dd,J=8.6,2.2Hz,1H),4.56(dd,J=11.9,5.0Hz,1H),4.37(s,1H),3. 95(dd,J=10.7,5.0Hz,3H),3.91(s,3H),3.71(s,2H),3.00(t,J=5.7Hz,2H ),2.94–2.85(m,2H),2.82–2.73(m,3H),2.61(dt,J=17.2,4.2Hz,1H),2.47 (dd,J=12.1,4.4Hz,1H),2.40(d,J=7.1Hz,2H),2.19(dq,J=13.4,4.6Hz,1H ),1.94(d,J=7.0Hz,1H),1.84(d,J=13.0Hz,2H),1.20(s,8H),1.15(s,6H).

[0315] Example 3 Synthesis of Compound 3

[0316] Step 1: Preparation of intermediate 3b

[0317] Referring to the preparation of intermediate 2g in step 3 of Example 2, intermediate 2e was replaced by intermediate 3a to prepare intermediate 3b (2.5g).

[0318] MS (ESI, [M+H] + )m / z:251.31. 1H NMR (500MHz, DMSO-d6) δ8.62(d,J=2.3Hz,1H),7.90(dd,J=9.0,2.5Hz,1H),6.85(d,J=9.1Hz,1H),4.51–4.40(m,3H),3. 78(s,3H),3.27(t,J=5.7Hz,2H),2.90(td,J=12.8,2.6Hz,2H),1.77–1.62(m,3H),1.09(tdd,J=12.7,11.2,4.3Hz,2H).

[0319] Step 2: Preparation of intermediate 3c

[0320] Referring to the preparation process of intermediate 1c in step 2 of Example 1, intermediate 3b was substituted for intermediate 1b, and intermediate 3c (0.86 g) was prepared by reaction.

[0321] MS (ESI, [M+H] + )m / z:237.31. 1 H NMR (500MHz, DMSO-d6) δ8.41(d,J=2.3Hz,1H),8.11(dd,J=9.6,2.3Hz,1H),7.31(d,J=9.6Hz,1H),4. 44(d,J=13.4Hz,2H),3.28(d,J=5.9Hz,2H),3.24–3.17(m,2H),1.86–1.71(m,3H),1.30–1.16(m,2H).

[0322] Step 3: Preparation of intermediate 3d

[0323] Referring to the preparation process of intermediate 1d in step 3 of Example 1, intermediate 3c was substituted for intermediate 1c, and intermediate 3d (0.25 g) was prepared by reaction.

[0324] MS (ESI, [M+H] + )m / z:493.45. 1H NMR(500MHz,DMSO-d6)δ8.61(d,J=2.5Hz,1H),7.93(dd,J=9.0,2.6Hz,1H),7.64(d,J=8.6Hz,1 H),7.58(d,J=9.3Hz,1H),6.85(d,J=9.0Hz,1H),6.64(d,J=2.2Hz,1H),6.54(dd,J=8.6,2.3Hz, 1H),4.50–4.39(m,3H),4.25(s,1H),4.05(d,J=9.2Hz,1H),3.91(s,3H),3.27(t,J=5.7Hz,2H) ,2.87(td,J=12.8,2.6Hz,2H),1.77–1.62(m,3H),1.22(s,6H),1.14(s,6H),1.12–1.07(m,2H).

[0325] Step 4: Preparation of intermediate 3e

[0326] Referring to the preparation process of intermediate 1e in step 4 of Example 1, intermediate 3d was substituted for intermediate 1d to obtain intermediate 3e (210 mg). MS (ESI, [M+H] + )m / z:491.27.

[0327] Step 5: Preparation of compound 3

[0328] Refer to the preparation process of compound 1 in step 5 of Example 1, and replace intermediate 1e with intermediate 3e to obtain compound 3 (150 mg).

[0329] MS (ESI, [M+H] + )m / z:759.90. 1H NMR (500MHz, DMSO-d6) δ11.08(s,1H),8.62(d,J=2.5Hz,1H),7.93(dd,J=9.0,2.5Hz,1H),7.64(d,J=8.5Hz,1H),7.58(d,J=8.6Hz,2H),7.11(d,J=8.3H z,1H),6.85(d,J=9.1Hz,1H),6.64(d,J=2.2Hz,1H),6.54(dd,J=8.7,2.2Hz ,1H),4.56(dd,J=11.9,5.0Hz,1H),4.42(d,J=13.0Hz,2H),4.25(s,1H),4.0 5(d,J=9.1Hz,1H),3.91(s,3H),3.71(s,2H),3.00(t,J=5.8Hz,2H),2.93(t d,J=13.1,2.6Hz,2H),2.82–2.72(m,3H),2.61(dt,J=17.3,4.3Hz,1H),2.4 7(dd,J=12.2,4.4Hz,1H),2.38(d,J=7.1Hz,2H),2.19(dq,J=13.6,4.8Hz,1 H),1.99(t,J=3.8Hz,1H),1.83(d,J=12.8Hz,2H),1.22(s,6H),1.14(s,8H).

[0330] Example 4 Synthesis of Compound 4

[0331] Step 1: Preparation of intermediate 4b

[0332] Referring to the preparation of intermediate 2g in step 3 of Example 2, intermediate 2e was replaced by intermediate 4a to prepare intermediate 4b (6.8 g).

[0333] MS (ESI, [M+H] + )m / z:266.2.

[0334] Step 2: Preparation of intermediate 4c

[0335] Referring to the preparation process of intermediate 1c in step 2 of Example 1, intermediate 4b was substituted for intermediate 1b to obtain intermediate 4c (1.54 g). MS (ESI, [MH] - )m / z:236.1.

[0336] Step 3: Preparation of intermediate 4d

[0337] Referring to the preparation process of intermediate 1d in step 3 of Example 1, intermediate 4c was substituted for intermediate 1c to obtain intermediate 4d (0.26 g). MS (ESI, [M+H] + )m / z:494.1.

[0338] Step 4: Preparation of intermediate 4e

[0339] Referring to the preparation process of intermediate 1e in step 4 of Example 1, intermediate 4d was substituted for intermediate 1d, and intermediate 4e (224 mg) was prepared by reaction.

[0340] Step 5: Preparation of compound 4

[0341] Referring to the preparation process of compound 1 in step 5 of Example 1, intermediate 4e was substituted for intermediate 1e, and compound 4 (142 mg) was prepared by reaction.

[0342] MS (ESI, [M+H] + )m / z:760.9. 1 H NMR (500MHz, DMSO-d6) δ11.07(s,1H),8.75(s,2H),7.70(d,J=9.2Hz,1H),7.64(d,J=8.6Hz,1H),7.58(d,J=8.2Hz,1H),7.11(d,J=8 .3Hz,1H),6.64(d,J=2.3Hz,1H),6.54(dd,J=8.6,2.2Hz,1H),4.75(d,J=13.0Hz,2H),4.56(dd,J=11.9,5.0Hz,1H),4.23(s,1H),4.0 3(d,J=9.2Hz,1H),3.91(s,3H),3.71(s,2H),2.99(d,J=11.1Hz,4H),2.77(tt,J=11.8,5.9Hz,3H),2.61(dt,J=17.3,4.3Hz,1H),2. 53(s,1H),2.49–2.43(m,1H),2.39(d,J=7.2Hz,2H),2.19(dq,J=13.5,4.9Hz,1H),1.85(d,J=12.1Hz,2H),1.22(s,6H),1.13(s,8H).

[0343] Example 5 Synthesis of Compound 5

[0344] Step 1: Preparation of intermediate 5b

[0345] Referring to the preparation process of intermediate 1d in step 3 of Example 1, intermediate 5a was substituted for intermediate 1c to obtain intermediate 5b (0.56 g). MS (ESI, [M+H] + )m / z:415.4.

[0346] Step 2: Preparation of intermediate 5c

[0347] To a single-necked flask, intermediate 5b (0.56 g), intermediate 2f (0.3 g), acetonitrile (20 mL) and potassium carbonate (0.55 g) were added in sequence, and the mixture was heated to 80°C for reaction. After the reaction was complete, ethyl acetate and water were added to the system for extraction. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The intermediate 5c (0.48 g) was purified by silica gel column chromatography. MS (ESI, [M+H] + )m / z:494.1.

[0348] Step 3: Preparation of intermediate 5d

[0349] Referring to the preparation process of intermediate 1e in step 4 of Example 1, intermediate 5c was substituted for intermediate 1d, and intermediate 5d (425 mg) was prepared by reaction.

[0350] Step 4: Preparation of compound 5

[0351] Refer to the preparation process of compound 1 in step 5 of Example 1, and replace intermediate 1e with intermediate 5d to obtain compound 5 (98 mg).

[0352] MS (ESI, [M+H] + )m / z:761.0. 1H NMR (500MHz, DMSO-d6) δ11.08(s,1H),8.61(d,J=1.2Hz,1H),8.33(d,J=1.5Hz,1H),7.81(d,J=9.1Hz,1H),7.64(d,J=8.6Hz,1H),7.58( d,J=8.2Hz,1H),7.11(d,J=8.2Hz,1H),6.66(d,J=2.3Hz,1H),6.56(dd,J=8.7,2.3Hz,1H),4.56(dd,J=11.9,5.0Hz,1H),4.49(d,J=13.2 Hz,2H),4.37(s,1H),3.98–3.89(m,4H),3.72(s,2H),3.08–2.97(m,4H),2.76(dt,J=16.9,5.5Hz,3H),2.61(dt,J=17.3,4.4Hz,1H),2.4 7(dd,J=12.2,4.3Hz,1H),2.40(d,J=7.1Hz,2H),2.24–2.15(m,1H),2.08–1.97(m,1H),1.86(d,J=12.6Hz,2H),1.17(d,J=26.2Hz,14H).

[0353] Example 6 Synthesis of Compound 6

[0354] Step 1: Preparation of intermediate 6b

[0355] Referring to the preparation process of intermediate 1b in step 1 of Example 1, intermediate 6a was substituted for intermediate 1a to obtain intermediate 6b (6.8 g). MS (ESI, [M+H] + )m / z:252.0.

[0356] Step 2: Preparation of intermediate 6c

[0357] Referring to the preparation process of intermediate 1c in step 2 of Example 1, intermediate 6b was substituted for intermediate 1b to obtain intermediate 6c (2.62 g). MS (ESI, [MH] - )m / z:236.1.

[0358] Step 3: Preparation of intermediate 6d

[0359] Referring to the preparation process of intermediate 1d in step 3 of Example 1, intermediate 6c was substituted for intermediate 1c, and intermediate 6d (0.17 g) was prepared by reaction.

[0360] MS (ESI, [M+H] + )m / z:494.1.

[0361] Step 4: Preparation of intermediate 6e

[0362] Referring to the preparation process of intermediate 1e in step 4 of Example 1, intermediate 6d was substituted for intermediate 1d, and intermediate 6e (162 mg) was prepared by reaction.

[0363] Step 5: Preparation of compound 6

[0364] Referring to the preparation process of compound 1 in step 5 of Example 1, intermediate 6e was substituted for intermediate 1e, and compound 6 (78 mg) was prepared by reaction.

[0365] MS (ESI, [M+H] + )m / z:761.6. 1 H NMR (500MHz, DMSO-d6) δ11.08(s,1H),8.24(d,J=9.2Hz,1H),7.82(d,J=9.5Hz,1H),7.64(d,J=8.6Hz,1H),7.58(d,J=8.1Hz,1H),7.37 (d,J=9.7Hz,1H),7.11(d,J=8.3Hz,1H),6.67(d,J=2.2Hz,1H),6.57(dd,J=8.6,2.2Hz,1H),4.60–4.47(m,3H),4.40(s,1H),4.00(d,J= 9.2Hz,1H),3.91(s,3H),3.72(s,2H),3.11–2.97(m,4H),2.77(dt,J=17.3,5.5Hz,3H),2.61(dt,J=17.2,4.2Hz,1H),2.54(d,J=4.6Hz, 1H), 2.47 (dd, J = 12.1, 4.2Hz, 1H), 2.40 (d, J = 7.2Hz, 2H), 2.19 (dq, J = 8.6, 4.5Hz, 1H), 1.87 (d, J = 12.1Hz, 2H), 1.20 (d, J = 34.9Hz, 14H).

[0366] Example 7 Synthesis of Compound 7

[0367] Step 1: Preparation of intermediate 7a

[0368] Intermediate 2d (0.20 g), 7a-1 (0.19 g), DIPEA (0.33 g), and DMF (5 mL) were mixed, and HATU (0.29 g) was added. The reaction was allowed to complete at room temperature. The reaction solution was poured into water, extracted with ethyl acetate, and purified by silica gel column chromatography to obtain Intermediate 7a (0.28 g).

[0369] MS (ESI) m / z [M+H] + :563.31.

[0370] Step 2: Preparation of intermediate 7b

[0371] Intermediate 7a (0.28 g), DCM (10 mL) and 4 M dioxane hydrochloride (5 mL) were mixed and reacted at room temperature until complete. Concentration gave Intermediate 7b (0.19 g). MS (ESI) m / z [M+H] + :463.25.

[0372] Step 3: Preparation of compound 7

[0373] Intermediate 7b (0.11 g), intermediate z5 (0.07 g) (synthesis route referenced intermediate 26f in WO2024037616), sodium acetate (0.04 g), and DCE / IPA (v:v = 5:1) (5 mL) were mixed, followed by the addition of sodium triacetoxyborohydride (0.10 g). The reaction was allowed to complete at room temperature. The reaction solution was concentrated and purified by silica gel column chromatography to afford compound 7 (0.06 g).

[0374] MS (ESI) m / z [M+H] + :745.43. 1 H NMR (500MHz, DMSO) δ11.08(s,1H),7.76(d,J=8.6Hz,2H),7.63(dd,J=15.6,8.3Hz,2H),7.52(d,J=9.2Hz,1H),7.28(d,J=8.1H z,1H),6.99(d,J=8.9Hz,2H),6.64(d,J=2.2Hz,1H),6.54(dd,J=8.7,2.2Hz,1H),4.57(ddd,J=11.9,5.0,1.8Hz,1H),4.27(s, 1H),4.06(d,J=9.2Hz,1H),3.91(s,3H),3.35(s,1H),3.30–3.17(m,6H),2.93(d,J=13.0Hz,2H),2.86(dd,J=16.0,5.2Hz,1H) ,2.77(ddd,J=17.2,11.9,5.4Hz,1H),2.66–2.54(m,5H),2.41(d,J=7.3Hz,2H),2.23–2.16(m,1H),1.23(s,6H),1.15(s,6H).

[0375] The following intermediates were synthesized by referring to the synthesis method of intermediate 7b:

[0376] Example 8 Synthesis of Compound 8

[0377] To the reaction flask, intermediate 1e (0.1 g), intermediate z2 (0.08 g) (synthesis route refers to Example 1 of WO2024037616), sodium acetate (0.04 g), 1,2-dichloroethane (10 mL), and isopropanol (2 mL) were added in sequence. The mixture was stirred at room temperature for 10 minutes, and then sodium triacetoxyborohydride (0.1 g) was added and reacted at room temperature for 1 hour. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, washed with saturated brine, concentrated, and purified by silica gel column chromatography to obtain compound 8 (0.10 g). MS (ESI, [M+H] + )m / z:745.41. 1 H NMR (500MHz, DMSO) δ11.09(s,1H),7.73(dd,J=14.9,8.3Hz,3H),7.64(d,J=8.6Hz,1H),7.49(d,J=9.2Hz,1H),7.31(d,J=8.2 Hz,1H),6.97(d,J=9.0Hz,2H),6.64(d,J=2.2Hz,1H),6.54(dd,J=8.7,2.2Hz,1H),4.60(dd,J=11.9,5.0Hz,1H),4.27(s,1H) ,4.16(s,2H),4.09–4.03(m,3H),3.91(s,5H),2.80(dddd,J=29.4,17.1,12.2,3.9Hz,3H),2.69–2.58(m,3H),2.54(d,J=4.5 Hz,1H),2.20(dq,J=13.6,4.8Hz,1H),1.93–1.85(m,2H),1.81(d,J=3.8Hz,1H),1.31–1.24(m,2H),1.23(s,6H),1.15(s,6H).

[0378] Example 9 Synthesis of Compound 9

[0379] Referring to the method described in Example 8, intermediate z3 (synthetic route refers to Example 3 of WO2024037616) was used instead of intermediate z2 to synthesize compound 9 (0.08 g). MS (ESI, [M+H] + )m / z:759.39. 1H NMR (500MHz, DMSO) δ11.07 (s, 1H), 7.74 (d, J= 8.6Hz,2H),7.64(d,J=8.6Hz,1H),7.59(d,J=8.1Hz,1H),7.48(d,J=9.2Hz,1H),7.15(d,J=8.2Hz,1H),7.00–6.93(m,2H ),6.64(d,J=2.3Hz,1H),6.54(dd,J=8.7,2.2Hz,1H),4.56(dd,J=11.9,5.0Hz,1H),4.27(s,1H),4.05(d,J=9.2Hz,1H),3 .91(s,3H),3.86(d,J=12.9Hz,2H),3.81(s,2H),2.96(t,J=5.7Hz,2H),2.89–2.72(m,5H),2.60(dt,J=17.3,4.2Hz,1H), 2.48(d,J=4.3Hz,1H),2.44(d,J=6.9Hz,2H),2.19(dt,J=13.2,4.8Hz,1H),1.99–1.80(m,3H),1.22(s,8H),1.14(s,6H).

[0380] Example 10 Synthesis of Compound 10

[0381] Referring to the method described in Example 8, intermediate z4 (synthetic route refers to Example 5 of WO2024037616) was used instead of intermediate z2 to synthesize compound 10 (0.07 g). MS (ESI, [M+H] + )m / z:773.42. 1H NMR (500MHz, DMSO) δ11.07(s,1H),7.74(d,J=8.8Hz,2H),7.65(d,J=8.6Hz,1H),7.54(d,J=7.9Hz,1H),7.49(d,J=9.2Hz,1H),7.18 (d,J=8.1Hz,1H),7.01–6.94(m,2H),6.64(d,J=2.2Hz,1H),6.54(dd,J=8.6,2.2Hz,1H),4.54(dd,J=11.9,5.0Hz,1H),4.27(s,1H), 4.05(d,J=9.2Hz,1H),3.91(s,5H),3.20–3.13(m,2H),3.09–3.01(m,2H),2.85–2.73(m,3H),2.62(ddt,J=21.6,17.5,5.1Hz,5H),2 .47(dd,J=12.3,4.4Hz,1H),2.34(d,J=6.8Hz,2H),2.18(dq,J=13.6,4.1Hz,1H),1.83(t,J=14.6Hz,3H),1.23(s,8H),1.15(s,6H).

[0382] The following compounds were synthesized by referring to the synthesis methods of compounds 7 and 8:

[0383] Example 27 Synthesis of Compound 27

[0384] Referring to the method described in Example 8, compound 27 (0.15 g) was synthesized by replacing intermediate 1e with intermediate 3e and intermediate z6 (for the synthesis route, refer to Example 12 of WO2024037616) with intermediate z2.

[0385] MS (ESI, [M+H] + )m / z:759.33. 1H NMR (500MHz, DMSO) δ10.87(s,1H),8.62(d,J=2.5Hz,1H),7.93(dd,J=9.0,2.5Hz,1H),7.84(s,1H),7.64(d,J=8.6Hz,1H), 7.58(d,J=9.3Hz,1H),7.33(d,J=8.0Hz,1H),6.96(d,J=8.1Hz,1H),6.85(d,J=9.0Hz,1H),6.64(d,J=2.2Hz,1H),6.54(dd ,J=8.6,2.2Hz,1H),4.42(d,J=13.2Hz,2H),4.25(s,1H),4.10(dd,J=11.8,4.9Hz,1H),4.05(d,J=9.2Hz,1H),3.91(s,3H) ,3.65(s,2H),3.05–2.87(m,4H),2.74(tt,J=12.0,5.8Hz,3H),2.57(dt,J=17.3,4.2Hz,1H),2.41–2.23(m,3H),2.11(dq,J =13.7,4.8Hz,1H),1.83(d,J=12.8Hz,2H),1.18(d,J=41.6Hz,14H).

[0386] Example 28 Synthesis of Compound 28

[0387] Referring to the method described in Example 8, compound 28 (0.11 g) was synthesized by replacing intermediate 1e with intermediate 3e and intermediate z7 (for the synthesis route, refer to Example 75 of WO2024037616) instead of intermediate z2.

[0388] MS (ESI, [M+H] + )m / z:774.43. 1H NMR (500MHz, DMSO) δ10.50(s,1H),8.63(d,J=2.5Hz,1H),8.05(s,1H),7.94(dd,J=9.0,2.5Hz,1H),7.64(d,J=8.6Hz,1H),7.58(d,J=9 .3Hz,1H),7.29(d,J=7.8Hz,1H),7.06(d,J=8.0Hz,1H),6.86(d,J=9.0Hz,1H),6.64(d,J=2.2Hz,1H),6.54(dd,J=8.6,2.2Hz,1H),4.4 3(d,J=13.0Hz,2H),4.25(s,1H),4.05(d,J=9.5Hz,1H),3.91(s,3H),3.82(t,J=6.7Hz,2H),3.12(d,J=6.1Hz,2H),3.03–2.88(m,4H), 2.77(t,J=6.6Hz,2H),2.69–2.56(m,4H),2.32(d,J=6.6Hz,2H),1.85(t,J=14.8Hz,3H),1.23(s,6H),1.14(s,6H),1.13–1.05(m,2H).

[0389] Compounds 29 to 36 were prepared by referring to Example 3 or compound 14 or the synthetic procedures disclosed in the prior art:

[0390] Experimental Example 1: Degradation of cellular AR by compounds

[0391] 1.1 Assay of AR degradation activity in VCaP cells

[0392] Detection was performed using the HTRF HUMAN ANDROGEN RECEPTOR DETECTION KIT (cisbio, 64ANDRPEG). 4× supplemented lysis buffer was prepared using blocking reagent stock solution (100×) and lysis buffer stock solution (4×), and 1× supplemented lysis buffer was prepared using 4× supplemented lysis buffer and ddH2O. Premixed antibody solutions were prepared using detection buffer, androgen receptor Eu cryptate antibody, and androgen receptor d2 antibody.

[0393] VCaP cells with good growth status were taken, washed with PBS, digested with trypsin, and digested with 1% CSS-FBS-free phenol red DMEM complete medium to terminate the digestion. The cells were collected into a centrifuge tube and the cell density was adjusted to 5×10 5 / mL, inoculated into 96-well plates (100μL / well), cultured overnight in a cell culture incubator, and compound loading was performed using a nanoliter pipette. Compounds were diluted 5-fold to a final concentration of 100nM-0.032nM in 2 replicates, and a control was set up at the same time. After continuing to culture in the cell culture incubator for 24 hours, the culture medium was aspirated and 40μL / well 1× Supplemented Lysis buffer was added to lyse the cells. After shaking at room temperature for 40 minutes, 16μL of cell lysate was added to a 384-well plate, and 4μL / well Premixed antibody solutions were added. The plate was placed at 25°C for 2 hours. The fluorescence value was detected at 665nm / 620nm by Envision microplate reader. Four-parameter analysis was performed, and the dose-effect curve was fitted to calculate DC. 50 The results are shown in Table 1.

[0394] Table 1 AR degradation activity of compounds in VCaP cells

[0395] The test results show that the compounds of the present application (such as the compounds in the examples) have degradation activity on AR in VCaP cells.

[0396] 1.2 Assay of AR degradation activity in LNCaP (T878A) cells

[0397] Detection was performed using the HTRF HUMAN ANDROGEN RECEPTOR DETECTION KIT (cisbio, 64ANDRPEG). 4× supplemented lysis buffer was prepared using blocking reagent stock solution (100×) and lysis buffer stock solution (4×), and 1× supplemented lysis buffer was prepared using 4× supplemented lysis buffer and ddH2O. Premixed antibody solutions were prepared using detection buffer, androgen receptor Eu cryptate antibody, and androgen receptor d2 antibody.

[0398] LNCaP cells with good growth status were taken, washed with PBS, digested with trypsin, and digested with 2% CSS-FBS phenol red-free 1640 complete medium to terminate the digestion. The cells were collected into a centrifuge tube and the cell density was adjusted to 1×10 6 Cells were plated at 100 μL / well on a 96-well plate and incubated overnight in a cell culture incubator. Compounds were added using a nanoliter pipette and diluted 2-fold to a final concentration of 500 nM-0.488 nM in duplicate wells. A control was also set up. After 24 hours of incubation in a cell culture incubator, the culture medium was aspirated and 40 μL / well of 1× Supplemented Lysis buffer was added to lyse the cells. After shaking at room temperature for 40 minutes, 16 μL of cell lysate was added to a 384-well plate. 4 μL / well of premixed antibody solutions was added and the plate was incubated at 25°C for 2 hours. Fluorescence values ​​were measured at 665 nm / 620 nm using an Envision microplate reader. Four-parameter analysis was performed, and a dose-effect curve was fitted to calculate DC. 50 The test results are shown in Table 2.

[0399] Table 2 AR degradation activity of compounds in LNCaP (T878A) cells

[0400] The test results show that the compounds of the present application (such as the example compounds) have degradation activity on LNCaP cell AR.

[0401] 1.3 Assay of AR degradation activity in MDA-PCA-2B (L702H\T878A) cells

[0402] Detection was performed using the HTRF HUMAN ANDROGEN RECEPTOR DETECTION KIT (cisbio, 64ANDRPEG). 4× supplemented lysis buffer was prepared using blocking reagent stock solution (100×) and lysis buffer stock solution (4×), and 1× supplemented lysis buffer was prepared using 4× supplemented lysis buffer and ddH2O. Premixed antibody solutions were prepared using detection buffer, androgen receptor Eu cryptate antibody, and androgen receptor d2 antibody.

[0403] MDA-PCA-2B cells with good growth status were taken, washed with PBS, digested with trypsin, and digested with MDA-PCA-2B complete medium. The cells were collected into centrifuge tubes and the cell density was adjusted to 1×10 6 / mL, inoculated into 96-well plates (100μL / well), cultured overnight in a cell culture incubator, and compound loading was performed using a nanoliter pipette. Compounds were diluted 5-fold to a final concentration of 5000nM-1.6nM, with 2 replicates, and a control was set up at the same time. After continuing to culture in the cell culture incubator for 24 hours, the culture medium was aspirated and 40μL / well 1× Supplemented Lysis buffer was added to lyse the cells. After shaking at room temperature for 40 minutes, 16μL of cell lysate was added to a 384-well plate, and 4μL / well Premixed antibody solutions were added. The plate was placed at 25°C for 2 hours. The fluorescence value was detected at 665nm / 620nm by Envision microplate reader. Four-parameter analysis was performed, and the dose-effect curve was fitted to calculate DC. 50 The results are shown in Table 3.

[0404] Table 3

[0405] The test results show that the compounds of the present application (such as the example compounds) have degradation activity on AR in MDA-PCA-2B cells.

[0406] Test Example 2: In vitro cell proliferation inhibitory activity

[0407] 2.1 VCaP cell proliferation inhibitory activity assay

[0408] VCaP cells with good growth status were taken, washed with PBS, digested with trypsin, and digested with 5% CSS-FBS-free phenol red DMEM complete medium to terminate the digestion. The cells were collected into a centrifuge tube and the cell density was adjusted to 1×10 5 Cells were plated at 100 μL / mL in a 96-well plate (100 μL / well). Compounds were added using a nanoliter pipette and diluted 2-fold to a final concentration of 1000 nM-0.061 nM, 5000 nM-0.305 nM, and two replicates. A control was also set up. Cells were cultured in a cell culture incubator for 168 hours before adding the detection reagent CCK-8 (Dojindo, 10 μL / well). After incubation in a cell culture incubator for 7.0 hours, the absorbance was measured at 450 nm using a PerkinElmer Envision microplate reader. Four-parameter analysis was performed, and a dose-effect curve was fitted to calculate the IC. 50 The results are shown in Table 4.

[0409] Table 4 Inhibitory activity of compounds on LNCaP cell proliferation

[0410] The test results show that the compounds of the present application (such as the compounds in the examples) have proliferation inhibitory activity on VCaP cells.

[0411] 2.2 LNCaP (T878A) cell proliferation inhibitory activity assay

[0412] LNCaP cells with good growth status were taken, washed with PBS, digested with trypsin, and digested with phenol red-free 1640 complete medium with 2% CSS-FBS to terminate the digestion. The cells were collected into centrifuge tubes and the cell density was adjusted to 1×10 5 Cells were plated at 100 μL / mL in a 96-well plate (100 μL / well). Compounds were added using a nanoliter pipette and diluted 2-fold to a final concentration of 1000 nM-0.061 nM, 5000 nM-0.305 nM, and two replicates. A control was also set up. Cells were cultured in a cell culture incubator for 168 hours. The detection reagent CCK-8 (manufacturer: Dojindo, 10 μL / well) was added. After incubation in a cell culture incubator for 2.0 hours, the absorbance was measured at 450 nm using a PerkinElmer Envision microplate reader. Four-parameter analysis was performed, and a dose-effect curve was fitted to calculate the IC. 50 The test results are shown in Table 5.

[0413] Table 5 Inhibitory activity of compounds on LNCaP (T878A) cell proliferation

[0414] The test results show that the compounds of the present application (such as the example compounds) have proliferation inhibitory activity on LNCaP cells.

[0415] 2.3 22RV1 (H875Y / ARV7) cell proliferation inhibitory activity assay

[0416] 22RV1 cells in good growth condition were taken, washed with PBS, digested with trypsin, and digested with 1640 complete medium containing 5% FBS. The cells were collected into centrifuge tubes and the cell density was adjusted to 5×10 4 The cells were inoculated with 100 μL / well of the 96-well plate at 500 μL / well. The compound was added using a nanoliter pipette and diluted 3-fold to a final concentration of 5000 nM-2.286 nM. Two replicates were used, and a control was set up. After 168 hours of continuous culture in a cell culture incubator, the detection reagent CellTiter-Glo (manufacturer: Promega, 50 μL / well) was added. After incubation at room temperature for 10 minutes, 100 μL / well was transferred to a white plate. Luminesence values ​​were detected using a PerkinElmer Envision multi-function microplate reader. Four-parameter analysis was performed, and the dose-effect curve was fitted to calculate the IC 50 The test results are shown in Table 6.

[0417] Table 6 Inhibitory activity of compounds on 22RV1 (H875Y / ARV7) cell proliferation

[0418] The test results show that the compounds of the present application (such as the example compounds) have proliferation inhibitory activity on 22RV1 cells.

[0419] 2.4 MDA-PCA-2B (L702H\T878A) cell proliferation inhibitory activity assay

[0420] MDA-PCA-2B cells with good growth status were taken, washed with PBS, digested with trypsin, and digested with MDA-PCA-2B complete medium. The cells were collected into centrifuge tubes and the cell density was adjusted to 1×10 5 The cells were inoculated with 100 μL / well of the 96-well plate and the compound was added using a nanoliter pipette. A three-fold serial dilution was performed to a final concentration of 5000 nM-2.286 nM, with two replicates. A control was also set up. After 168 hours of incubation in a cell culture incubator, the detection reagent CCK-8 (manufacturer: Dojindo, 10 μL / well) was added. After incubation in a cell culture incubator for 5.0 hours, the absorbance was measured at 450 nm using a PerkinElmer Envision microplate reader. Four-parameter analysis was performed, and the dose-effect curve was fitted to calculate the IC. 50 The test results are shown in Table 7.

[0421] Table 7 Inhibitory activity of compounds on MDA-PCA-2B (L702H\T878A) cell proliferation

[0422] The test results show that the compounds of the present application (such as the compounds in the examples) have proliferation inhibitory activity on MDA-PCA-2B cells.

[0423] Test Example 3 In vitro liver microstructure stability

[0424] Liver microsomal incubation samples were prepared by mixing PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / mL), the test compound, and NADPH+MgCl₂ solution and incubating at 37°C and 300 rpm for 1 hour. The 0-hour sample was prepared by mixing PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / mL), and the test compound. The sample was added to an acetonitrile solution containing an internal standard for protein precipitation, and the supernatant was prepared. The supernatant was diluted with a 1:1 (v:v) mixture of acetonitrile and water for LC / MS / MS analysis. The results are shown in Tables 8 and 9.

[0425] Table 8

[0426] Table 9

[0427] The test results show that the compounds of the present application have in vitro liver microbiota (species: human, dog, rat or mouse) stability.

[0428] Experimental Example 4 Pharmacokinetics in mice

[0429] ICR mice weighing 18-22 g were acclimated for 3-5 days and randomly divided into groups of 9. The oral administration group was given a solution of the test compound at a dose of 10 mg / kg (20 mg / kg or 30 mg / kg), and the intravenous administration group was given a solution of the test compound at a dose of 1 mg / kg by intravenous injection.

[0430] The blood was collected from the oral administration group at 15 min, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 24 h, and 48 h after administration; the blood was collected from the intravenous administration group at 0.083 min, 15 min, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 24 h, and 48 h after administration. Blood was collected from the eye sockets to prepare plasma samples for testing.

[0431] 30 μL of the plasma sample to be tested and the standard curve sample were aspirated and added to an acetonitrile solution containing the internal standard for protein precipitation. The resulting supernatant was diluted with a 1:1 (v:v) mixture of acetonitrile and water for LC / MS / MS analysis. A non-compartmental model was used for fitting. The experimental results are shown in Table 10.

[0432] Table 10 Pharmacokinetic test results of compounds in mice

[0433] The test results show that the compound of the present invention has good in vivo pharmacokinetic properties (such as AUC, C max , t 1 / 2 , F and other parameters), for example, AUC>15000ng*h / mL for oral administration (10mpk), C max >600ng / mL, t 1 / 2 >8h.

[0434] Experimental Example 5: Evaluation of the efficacy of DPTC-AR on VCap human prostate cancer subcutaneous transplant tumor model in B-NDG mice

[0435] SPF male B-NDG mice (source: Biocytogen) were subcutaneously inoculated with VCap human prostate cancer cells in the right axilla, 5×10 6 (1:1 mixed with Matrigel inoculation). When the average tumor volume reaches 250mm 3 Around 6:00 p.m., animals were divided into groups. Grouping was designated Day 0. Starting from Day 0, the animals were gavage-administered once daily (1-10 mpk). A control group (DMSO + PEG40) was also administered. Tumor volume was measured 2-3 times per week, and the mice were weighed and recorded. General performance of the mice was observed and recorded daily. At the end of the experiment, the tumors were removed, weighed, and photographed.

[0436] The detection indicators and calculation formulas are as follows:

[0437] Tumor volume, TV (mm 3 )=1 / 2×(a×b 2 ), where a is the long diameter of the tumor and b is the short diameter of the tumor.

[0438] Relative tumor volume, RTV = TV t / TV0; TV0 is the tumor volume on day 0, TV t is the tumor volume at each measurement.

[0439] Relative tumor growth rate, T / C (%) = T RTV / C RTV ×100%; where T RTV RTV for the treatment group; C RTV The vehicle control group was RTV.

[0440] Tumor growth inhibition rate, TGI (%) = (1-TW / TW0) × 100%; wherein, TW is the tumor weight of the treatment group, and TW0 is the tumor weight of the vehicle control group.

[0441] Body weight change rate, WCR (%) = (Wt t -Wt0) / Wt0×100%; where Wt0 is the weight of mice on day 0, Wt tis the weight of the mice at each measurement.

[0442] The test results show that the compounds of the examples of the present application have good in vivo tumor inhibition effects (such as parameters such as TV, RTV, T / C (%), TGI (%), WCR (%), etc.). For example, at a dose of 3 mpk, on day 23, the relative tumor proliferation rate (T / C) was <40%, and the tumor growth inhibition rate TGI (%) was >66%.

Claims

1. A compound of formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in, Ring A is absent or selected from C 5-15 Cycloalkenyl, 5-15 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; Each R 1 independently selected from halogen, -OH, -NH2, -CN, C 1-10 Alkyl, C 1-10 Alkoxy or halogenated C 1-10 Alkyl, the -OH, -NH2, C 1-10 Alkyl, C 1-10 Alkoxy or halogenated C 1-10 The alkyl group is optionally substituted with one or more substituents; n is selected from 0, 1, 2 or 3; L is selected from a linking group; X 5 Selected from C(R f ) or N; R f is selected from H, halogen, deuterium or C optionally substituted by one or more substituents 1-6 alkyl; X 6 Selected from -O-, -NH- or -N(C 1-6 alkyl)-, the -NH- or -N(C 1-6 alkyl)-optionally substituted with one or more substituents; Each R 2 , R 3 and R 4 are independently selected from halogen, -OH, -NH2, -CN, C 1-10 Alkyl, C 1-10 Alkoxy or halogenated C 1-10 Alkyl, the -OH, -NH2, C 1-10 Alkyl, C 1-10 Alkoxy or halogenated C 1-10 The alkyl group is optionally substituted with one or more substituents; m, p and q are each independently selected from 0, 1, 2, 3, 4, 5 or 6; Ring G is selected from C 6-10 Aryl or 5-10 membered heteroaryl; Ring E is selected from C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl; Ring F is selected from C 6-10 Aryl or 5-10 membered heteroaryl; R t Selected from hydrogen, -OH, C 1-6 Alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl, the C 1-6 Alkyl, C 3-10 The cycloalkyl or 3-10 membered heterocycloalkyl is optionally substituted with one or more substituents.

2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Ring A is absent or selected from C 5-10 Cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; Alternatively, ring A is absent or is selected from C 5-9 Cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; Alternatively, ring A is absent or is selected from C 5-7 Cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; Alternatively, ring A is absent or is selected from C 5-6 Cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; Alternatively, ring A is absent or is selected from C 5-6 Cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; Alternatively, ring A is absent or is selected from C 5-6 Cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5 membered heteroaryl; Alternatively, ring A is absent or is selected from C 5-6 Cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl, pyrrolyl, pyrazolyl, furanyl, or oxazolyl; Alternatively, Ring A is absent or is selected from C5 cycloalkenyl, C6 cycloalkenyl, 5-membered heterocycloalkenyl, 6-membered heterocycloalkenyl, 7-membered heterocycloalkenyl, 8-membered heterocycloalkenyl or 9-membered heterocycloalkenyl, phenyl, pyrrolyl, pyrazolyl, furanyl or oxazolyl; Alternatively, ring A is absent or is selected from cyclopentenyl, monocyclohexenyl, bicyclohexenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine 1-amino-1-nitro-2-nitro-1-yl, ... The ring B is selected from phenyl or 6-membered heteroaryl; Alternatively, the ring B is selected from phenyl; and / or, The ring C is selected from 5-membered heteroaryl; Alternatively, the ring C is selected from isoxazolyl or furanyl.

3. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Structure fragment Selected from Alternatively, the structure fragment Selected from Alternatively, the structure fragment Selected from Alternatively, the structure fragment Selected from Alternatively, the structure fragment Selected from Alternatively, the structure fragment Selected from 4. The compound according to any one of claims 1 to 3, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Each R 1 independently selected from halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkyl, the -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 The alkyl group is optionally substituted with one or more substituents; Or, each R 1 independently selected from halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy or halogenated C 1-4 alkyl; Or, each R 1 independently selected from halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy or halogenated C 1-3 alkyl; Or, each R 1 independently selected from fluorine, chlorine, bromine, -OH, -NH2 or -CN; Or, each R 1 independently selected from fluorine, chlorine or bromine; Or, each R 1 independently selected from fluorine; and / or, n is selected from 0, 1 or 2; Alternatively, n is selected from 0 or 1.

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

6. The compound according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is selected from -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -Cy 3 -,in, Cy 1 , Cy 2 or Cy 3 are independently selected from a bond, or optionally one or more R a Substituted with the following groups: C 3-12 Cycloalkyl, 4-12 membered heterocycloalkyl or 4-12 membered heterocycloalkenyl; LNK, LNK 1 and LNK 2 are independently selected from a bond, NH, O, S, or optionally substituted by one or more R b Substituted with the following groups: C 1-12 Alkylene, C 2-12 Alkenylene, C 2-12 Alkyne or C 1-12 heteroalkylene; Each R a and R b Each is independently selected from halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl.

7. The compound according to claim 6, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein LNK, LNK 1 and LNK 2 are independently selected from a bond, NH, O, S, or optionally substituted by one or more R b Substituted with the following groups: C 1-10 Alkylene, C 2-10 Alkenylene, C 2-10 Alkyne or C 1-10 heteroalkylene; Or, LNK, LNK 1 and LNK 2 are independently selected from a bond, NH, O, S, or optionally substituted by one or more R b Substituted with the following groups: C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkyne or C 1-6 heteroalkylene; Or, LNK, LNK 1 and LNK 2 are independently selected from a bond, NH, O, S, or optionally substituted by one or more R b Substituted with the following groups: C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkyne or C 1-4 heteroalkylene; Or, LNK, LNK 1 and LNK 2 are independently selected from a bond, NH, O, S, or optionally substituted by one or more R b Substituted with the following groups: C 1-6 Alkylene or C 1-6 heteroalkylene; Or, LNK, LNK 1 and LNK 2 are independently selected from a bond, NH, O, S, or optionally substituted by one or more R b Substituted with the following groups: C 1-4 Alkylene or C 1-4 heteroalkylene; Or, LNK, LNK 1 and LNK 2 are independently selected from a bond, NH, O, or optionally substituted by one or more R b Substituted with the following groups: C 1-3 Alkylene or C 1-3 heteroalkylene; Or, LNK, LNK 1 and LNK 2 are independently selected from a bond, NH, O, or optionally substituted by one or more R b Substituted with the following groups: C 1-2 Alkylene or C 1-2 heteroalkylene; Or, LNK, LNK 1 and LNK 2 are independently selected from a bond, NH, O, -NHCH2-, -CH2NHCH2-, -CH2-, -CH2CH2-, -C(O)- or -C(O)CH2-; and / or Cy 1 , Cy 2 or Cy 3 are independently selected from a bond, or optionally one or more R a Substituted with the following groups: C 3-11 Cycloalkyl, 4-12 membered heterocycloalkyl or 4-11 membered heterocycloalkenyl; Or, Cy 1 , Cy 2 or Cy 3 are independently selected from a bond, or optionally one or more R a Substituted with the following groups: C 4-10 Cycloalkyl, 4-11-membered heterocycloalkyl or 5-6-membered heterocycloalkenyl; Or, Cy 1 , Cy 2 or Cy 3 are independently selected from a bond, or optionally one or more R a Substituted with the following groups: C 4-9 Cycloalkyl, 4-11-membered heterocycloalkyl or 5-6-membered heterocycloalkenyl; Or, Cy 1 , Cy 2 or Cy 3 are independently selected from a bond, or optionally one or more R a Substituted with the following groups: C 4-6 Cycloalkyl, C9 cycloalkyl, 4-11 membered heterocycloalkyl or 6 membered heterocycloalkenyl; Or, Cy 1 , Cy 2 or Cy 3 are independently selected from a bond, or optionally one or more R a Substituted from the following groups: cyclobutyl, cyclopentyl, cyclohexyl, spironanyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyridinyl, piperazinyl, monoazaspiroheptanyl, monoazaspironanyl, diazaspironanyl, monoazaspirodecanyl, diazaspirodecane, monoazaspiroundecyl, diazaspiroundecyl, octahydrocyclopentapyrrolyl, diazabicyclooctanyl or monoazabicyclononanyl.

8. The compound according to claim 6 or 7, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Each R a and R b Each is independently selected from halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 3-10 Cycloalkyl or 4-10 membered heterocycloalkyl; Or, each R a and R b Each is independently selected from halogen, =O, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 1-6 Alkylamino or di-C 1-6 Alkylamino; Or, each R a and R b Each is independently selected from halogen, =O, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 1-4 Alkylamino, or di-C 1-4 Alkylamino; Or, each R a and R b Each is independently selected from halogen, =O, -OH, -NH2, -CN or C 1-3 alkyl; Or, each R a and R b Each is independently selected from halogen, =O, -OH, -NH2 or -CN; Or, each R a and R b Each is independently selected from =O.

9. The compound according to any one of claims 1 to 8, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The L is selected from a bond, -NHCH2-, -CH2NHCH2-, -CH2-, -C(O)CH2-, 10. The compound according to any one of claims 1 to 9, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R f is selected from H, fluorine, chlorine, bromine, deuterium or C optionally substituted by one or more substituents. 1-3 alkyl; Or, R f is selected from H, fluorine, chlorine, bromine, deuterium or C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with one or more of the following groups: halogen, -OH, -NH2, or -CN; Or, R f is selected from H, fluorine, chlorine, bromine, deuterium or C 1-3 alkyl; Or, R f is selected from H, fluorine, deuterium or methyl; and / or X 5 is selected from CH or N; and / or X 6 Selected from -O-, -NH- or -N(C 1-3 alkyl)-; or, X 6 is selected from -O- or -N(CH3)-; or, X 6 Selected from -O-.

11. The compound according to any one of claims 1 to 10, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Each R 2 , R 3 and R 4 are independently selected from halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkyl, the -OH, -NH2, -CN, C 1- 6 alkyl, C 1-6 Alkoxy or halogenated C 1-6 The alkyl group is optionally substituted with one or more substituents; Or, each R 2 , R 3 and R 4 are independently selected from halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy or halogenated C 1- 4 alkyl; Or, each R 2 independently selected from halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy or halogenated C 1-3 alkyl; Or, each R 2 independently selected from halogen, -OH, -NH2, -CN, C 1-3 Alkyl or C 1-3 Alkoxy; Or, each R 2 independently selected from fluorine, chlorine, bromine, -OH, -NH2, -CN, methyl or methoxy; Or, each R 2 are independently selected from fluorine, chlorine, bromine, -CN or methoxy; Or, each R 2 are independently selected from -CN or methoxy; and / or Each R 3 are independently selected from halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy or halogenated C 1-3 alkyl; Or, each R 3 are independently selected from halogen, -OH, -NH2, -CN or C 1-3 alkyl; Or, each R 3 are independently selected from C 1-3 alkyl; Or, each R 3 are independently selected from methyl; and / or Each R 4 are independently selected from halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy or halogenated C 1-3 alkyl; Or, each R 4 are independently selected from halogen, -OH, -NH2, -CN or C 1-3 alkyl; Or, each R 4 Each is independently selected from fluorine, chlorine, bromine, -OH, -NH2 or -CN.

12. The compound according to any one of claims 1 to 11, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: m is selected from 0, 1, 2 or 3; or, m is selected from 1, 2 or 3; or, m is selected from 2; and / or p is selected from 1, 2, 3 or 4; or, p is selected from 3 or 4; or, p is selected from 4; and / or q is selected from 0, 1, 2 or 3; or, q is selected from 0 or 1; or, q is selected from 0.

13. The compound according to any one of claims 1 to 12, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The ring G is selected from phenyl or 5-6-membered heteroaryl; or, the ring G is selected from phenyl or 6-membered heteroaryl; or, the ring G is phenyl.

14. The compound according to any one of claims 1 to 13, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Ring E is selected from C 3-9 Cycloalkyl or 3-9 membered heterocycloalkyl; or, ring E is selected from C 4-9 Cycloalkyl or 4-9 membered heterocycloalkyl; or, ring E is selected from C 4-7 Cycloalkyl or 4-7 membered heterocycloalkyl; or, ring E is selected from C 4-7 Cycloalkyl; Alternatively, Ring E is selected from cyclobutyl, cyclopentyl or cyclohexyl; Alternatively, ring E is cyclobutyl; Alternatively, ring E is Or ring E is 15. The compound according to any one of claims 1 to 14, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Ring F is selected from C 6-10 aryl or 5-7 membered heteroaryl; or, ring F is selected from phenyl or 5-6 membered heteroaryl; or, ring F is selected from phenyl or 6 membered heteroaryl; or, ring F is selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl; or, ring F is selected from phenyl; or, ring F is selected from 16. The compound according to any one of claims 1 to 15, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R t Selected from hydrogen, -OH, C 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted; or, R t Selected from hydrogen, -OH, C 1-3 Alkyl, C 3-4 Cycloalkyl or 3-4 membered heterocycloalkyl, the C 1-3 Alkyl, C 3-4 Cycloalkyl or 3-4 membered heterocycloalkyl is optionally substituted; or, R t Selected from hydrogen or C 1-3 Alkyl (such as methyl, ethyl, propyl); or, R t Selected from hydrogen.

17. The compound according to any one of claims 1 to 16, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Structure fragment Selected from Alternatively, the structure fragment Selected from Alternatively, the structure fragment Selected from Alternatively, the structure fragment Selected from Alternatively, the structure fragment Selected from Alternatively, the structure fragment Selected from Alternatively, the structure fragment Selected from 18. The compound according to any one of claims 1 to 17, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The compound, its stereoisomer or pharmaceutically acceptable salt thereof is a compound of formula I-1 or I-1A, a compound of formula I-2, formula I-2A, formula I-3, or a compound of formula I-3A, a stereoisomer or pharmaceutically acceptable salt thereof, X is selected from CH or N.

19. The compound according to any one of claims 1 to 18, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Ring A is C 5- 10 Cycloalkenyl, or a 5-15 membered heterocycloalkenyl containing 1-2 heteroatoms selected from N or O; Ring B is phenyl; Ring C is a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N or O; n is 0; X 5 Selected from C(R f ), R f Selected from H, deuterium or C 1-6 alkyl; L is C 1-10 Alkylene, the C 1-10 One or more -CH2- in the alkylene group may be replaced by C 5-8 Cycloalkyl, 5-8 membered heterocycloalkyl containing 1-3 or 1-2 N atoms or O atoms; Each R 2 are independently -OH, -NH2, -CN, C 1-10 Alkyl, C 1-10 Alkoxy or halogenated C 1-10 Alkyl; each R 3 are independently halogen, C 1-10 Alkyl or halogenated C 1-10 Alkyl; q is 0, m is 0, 1, 2 or 3, p is 0, 1, 2, 3 or 4; X 6 is -O-, or -NH-; Ring G is phenyl or a 6-membered heteroaryl group containing 1-2 N atoms or O atoms; Ring E is C 3-6 Cycloalkyl; Ring F is phenyl or a 6-membered heteroaryl group containing 1-3 or 1-2 N atoms or O atoms; R t is hydrogen, -OH or C 1-6 alkyl.

20. A compound of formula I' or I", a moiety, a stereoisomer, a derivative or a pharmaceutically acceptable salt thereof, in, Ring A is absent or selected from C 5-10 Cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; Ring B is selected from phenyl; Ring C is selected from isoxazolyl or furanyl; L is selected from a linking group.

21. A compound of formula I'-a or I"-a, a moiety, a stereoisomer, a derivative thereof, or a pharmaceutically acceptable salt thereof, in, Ring A is absent or selected from C 5-10 Cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; Ring B is selected from phenyl; Ring C is selected from isoxazolyl or furanyl; Each R 1a independently selected from halogen, -OH, -NH2, -CN, =O, -CHO, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-6 Alkyl OC(O)-, C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl, the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl is optionally substituted with one or more of the following groups: halogen, =O, -OH, -NH2, -CN, CHO, COOH, -C 1-4 Alkyl-OH, C 1-6 Alkyl OC(O)-, or optionally C 1-6 AlkylCOC(O)-substituted 4-10 membered heterocycloalkyl; n is selected from 0, 1, 2 or 3.

22. The compound according to any one of claims 1 to 19, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The compound is:

23. A pharmaceutical composition comprising a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19 and 22, or a compound, a moiety, a stereoisomer thereof, a derivative thereof, or a pharmaceutically acceptable salt thereof according to claim 20 or 21.

24. Use of a compound, a stereoisomer or a pharmaceutically acceptable salt thereof as described in any one of claims 1-19 and 22, or a compound, a portion, a stereoisomer, a derivative or a pharmaceutically acceptable salt thereof as described in claim 20 or 21, or a pharmaceutical composition as described in claim 23 in the preparation of a medicament for preventing or treating a disease treated by degrading a target protein bound to a targeting ligand.

25. Use of a compound, a stereoisomer or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 19 and 22, or a compound, a portion, a stereoisomer, a derivative or a pharmaceutically acceptable salt thereof as claimed in claim 20 or 21, or a pharmaceutical composition as claimed in claim 23 in the preparation of a medicament for preventing or treating a condition that is treated by binding to a cerebellar protein in vivo.

26. The use according to claim 24 or 25, wherein the disease or condition is selected from cancer.

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