Compounds comprising a cyclobutyl group

Abstract

The present application is in the field of medicinal chemistry and relates to compounds containing a cyclobutyl group, in particular to compounds of Formula I, processes for their preparation, pharmaceutical compositions containing them, and their use in the treatment of diseases, such as cancer.

Description

Technical Field

[0001] This application relates to compounds containing cyclobutyl, methods for their preparation, pharmaceutical compositions containing the compounds, and their use in treating related diseases (such as cancer). Background Technology

[0002] The androgen receptor (AR) belongs to the steroid receptor family of nuclear receptors. 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 into the cell nucleus. It binds to its associated DNA fragment, thereby stimulating the transcription of its target gene. The transcriptional activity of the androgen receptor activated by ligand binding is coordinated by co-activators. The main function of AR antagonists is to directly prevent testosterone or dihydrotestosterone from binding to the androgen receptor, blocking the effects of androgens on cells, thus exerting anti-androgenic effects and inhibiting cell growth, ultimately promoting apoptosis and playing an important role in the treatment of prostate cancer.

[0003] PROTAC (proteolysis targeting chimera) molecules are bifunctional compounds that can simultaneously bind to target proteins and E3 ubiquitin ligases. These compounds induce the target protein to be recognized by the cell's proteasome, causing its degradation and effectively reducing its concentration in cells. By introducing ligands that bind to different target proteins into PROTAC molecules, the application of PROTAC technology in the treatment of various diseases has become possible, and this technology has received widespread attention in recent years. Invention Details

[0005] On the one hand, this application relates to compounds of formula I, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0006] in, Ring A does not exist or is selected from C. 5-15 Cycloalkenyl, 5-15 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl; Ring B is selected from phenyl or 5-6-membered heteroaryl groups; Cyclic C is selected from 5-6 member heteroaryl groups; Each R 1 Independently selected from halogens, -OH, -NH2, -CN, C 1-10 Alkyl, C 1-10 alkoxy or halogenated C 1-10 Alkyl groups, namely -OH, -NH2, C 1-10 Alkyl, C 1-10alkoxy or halogenated C 1-10 The alkyl group may optionally be 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 C selected from H, halogens, deuterium, or optionally substituted with one or more substituents 1-6 Alkyl (e.g., R) f C selected from halogens, deuterium, or optionally substituted with one or more substituents 1-6 alkyl); X 6 Selected from -O-, -NH-, or -N(C 1-6 alkyl)-, said -NH- or -N(C 1-6 Alkyl group is optionally substituted with one or more substituents; Each R 2 R 3 and R 4 Each is independently selected from halogens, -OH, -NH2, -CN, and C. 1-10 Alkyl, C 1-10 alkoxy or halogenated C 1-10 Alkyl groups, namely -OH, -NH2, C 1-10 Alkyl, C 1-10 alkoxy or halogenated C 1-10 The alkyl group may optionally be 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 heteroaryl groups; Ring E is selected from C 3-10 Cycloalkyl or 3-10 membered heterocyclic alkyl; Ring F is selected from C 6-10 Aryl or 5-10 heteroaryl groups; R t Selected from hydrogen, -OH, C 1-6 Alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 3-10 The cycloalkyl or 3-10 membered heterocycloalkyl group is optionally substituted with one or more substituents.

[0007] In some implementations, ring A is absent, or is selected from C. 5-10 Cycloalkenyl, 5-10 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl.

[0008] In some implementations, ring A is absent, or is selected from C. 5-9 Cycloalkenyl, 5-9 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl.

[0009] In some implementations, ring A is absent, or is selected from C. 5-7 Cycloalkenyl, 5-9 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl.

[0010] In some implementations, ring A is absent, or is selected from C. 5-6 Cycloalkenyl, 5-10 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl.

[0011] In some implementations, ring A is absent, or is selected from C. 5-6 Cycloalkenyl, 5-9 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl.

[0012] In some implementations, ring A is absent, or is selected from C. 5-6 Cycloalkenyl, 5-9 membered heterocyclic alkenyl, phenyl or 5 membered heteroaryl.

[0013] In some implementations, ring A is absent, or is selected from C. 5-6 Cycloalkenyl, 5-9 membered heterocyclic alkenyl, phenyl, pyrroleyl, pyrazolyl, furanyl, or oxazolyl.

[0014] In some embodiments, ring A is absent, or is selected from C5-cycloalkenyl, C6-cycloalkenyl, 5-membered heterocyclic alkenyl, 6-membered heterocyclic alkenyl, 7-membered heterocyclic alkenyl, 8-membered heterocyclic alkenyl or 9-membered heterocyclic alkenyl, phenyl, pyrroleyl, pyrazolyl, furanyl or oxazolyl.

[0015] In some embodiments, ring A is absent or selected from cyclopentenyl, monocyclohexenyl, dicyclohexenyl, dihydropyrrolyl, tetrahydropyridyl, tetrahydroazapyrrolyl, azaspirooctenyl, azaspirononenyl, phenyl, pyrrolyl, pyrazolyl, furanyl, oxazolyl, or dihydrooxazinyl.

[0016] In some specific implementation schemes, ring A is selected from C. 5-10 Cycloalkenyl, 5-10 membered heterocyclic alkenyl or 5-6 membered heteroaryl.

[0017] In some specific implementation schemes, ring A is selected from C. 5-9 Cycloalkenyl, 5-9 membered heterocyclic alkenyl or 5-6 membered heteroaryl.

[0018] In some specific implementation schemes, ring A is selected from C. 5-7 Cycloalkenyl, 5-9 membered heterocyclic alkenyl or 5-6 membered heteroaryl.

[0019] In some specific implementation schemes, ring A is selected from C. 5-6Cycloalkenyl, 5-10 membered heterocyclic alkenyl or 5-6 membered heteroaryl.

[0020] In some specific implementation schemes, ring A is selected from C. 5-6 Cycloalkenyl, 5-9 membered heterocyclic alkenyl or 5-6 membered heteroaryl.

[0021] In some specific implementation schemes, ring A is selected from C. 5-6 Cycloalkenyl, 5-9 membered heterocyclic alkenyl or 5 membered heteroaryl.

[0022] In some specific implementation schemes, ring A is selected from C. 5-10 Cycloalkenyl or 5-10 membered heterocyclic alkenyl. In some specific embodiments, ring A is selected from C. 5-9 Cycloalkenyl or 5-9 membered heterocyclic alkenyl. In some specific embodiments, ring A is C. 5-8 Cycloalkenyl. In some specific embodiments, ring A is C. 5-6 Cycloalkenyl. In some embodiments, ring A is a 5-9 membered heterocyclic alkenyl group. In some embodiments, ring A is a 5-9 membered heterocyclic alkenyl group containing 1-2 heteroatoms selected from N or O. In some embodiments, ring A is a 5-8 membered heterocyclic alkenyl group containing 1-2 heteroatoms selected from N or O. In some embodiments, ring A is a 5-7 membered heterocyclic alkenyl group containing 1-2 N atoms.

[0023] In some specific embodiments, ring A is selected from cyclopentenyl, monocyclohexenyl, dicyclohexenyl, dihydropyrroleyl, tetrahydropyridyl, tetrahydroazapyryl, azaspirocyclic nonenyl, azaspirocyclic octenyl, or dihydrooxazinyl.

[0024] In some embodiments, ring A is cyclopentenyl. In some embodiments, ring A is monocyclohexenyl. In some embodiments, ring A is dicyclohexenyl. In some embodiments, ring A is dihydropyrroleyl. In some embodiments, ring A is tetrahydropyridyl. In some embodiments, ring A is tetrahydroazapyryl. In some embodiments, ring A is azaspirocyclic nonenyl. In some embodiments, ring A is azaspirocyclic octenyl. In some embodiments, ring A is dihydrooxazinyl.

[0025] In some more specific embodiments, ring A is selected from phenyl, pyrrole, pyrazolyl, furanyl, or oxazolyl.

[0026] In some more specific embodiments, ring A is selected from phenyl, pyrrole, or pyrazolyl.

[0027] In some embodiments, ring B 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 B is phenyl.

[0028] In some embodiments, the ring C is selected from a 5-membered heteroaryl group. In some embodiments, the ring C is selected from isoxazolyl or furanyl.

[0029] In some specific embodiments, the ring C is an isoxazolyl group. In some specific embodiments, the ring C is a furanyl group.

[0030] In some specific implementations, ring A is present, and when both ring A and ring B are phenyl, ring C is not oxazolyl.

[0031] In some implementation schemes, R 1 The replacement position is selected from ring A or ring B. In some embodiments, R 1 The replacement position is selected from ring A. In some embodiments, R 1 The replacement position is selected from ring B. In some embodiments, R 1 The substitution position is selected from ring C.

[0032] In some implementations, ring F is connected to L. In some implementations, ring A is connected to L. In some implementations, ring B is connected to L. In some implementations, ring C is connected to L. In some implementations, ring A is connected to segment L. Connection. In some implementations, ring B is connected to segment. Connection. In some implementations, ring C is connected to the segment. Connections. In some implementations, ring F and ring A are connected to L, and ring C is connected to the segment. connect.

[0033] In some implementations, structural fragments Selected from or In some implementations, structural fragments Selected from , , , , or In some implementations, structural fragments Selected from , , , , or In some implementations, structural fragments for In some implementations, structural fragments for In some implementations, structural fragments for .

[0034] In some implementations, structural fragments Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , or In some implementations, structural fragments Not selected In some implementations, structural fragments Not selected or .

[0035] In some implementations, structural fragments Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or In some implementations, structural fragments Not selected In some implementations, structural fragments Not selected or .

[0036] In some implementations, structural fragments Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0037] In some implementations, structural fragments for In some implementations, structural fragments for In some implementations, structural fragments for In some implementations, structural fragments for In some implementations, structural fragments for In some implementations, structural fragments for In some implementations, structural fragments for In some implementations, structural fragments for In some implementations, structural fragments for In some implementations, structural fragments for In some implementations, structural fragments for In some implementations, structural fragments for .

[0038] In some implementations, each R 1 Independently selected from halogens, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkyl groups, namely -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. In some embodiments, each R... 1 Independently selected from halogens, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 alkoxy or halogenated C 1-4 Alkyl group. In some embodiments, each R 1 Independently selected from halogens, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 alkoxy or halogenated C 1-3 Alkyl group. In some embodiments, each R 1 Independently selected from fluorine, chlorine, bromine, -OH, -NH2, or -CN. In some embodiments, each R 1 It is independently selected from fluorine, chlorine, or bromine. In some embodiments, each R... 1 It is fluorine on its own.

[0039] In some implementations, n is selected from 0, 1, or 2. In some implementations, n is selected from 0 or 1. In some specific implementations, n is 0.

[0040] In some implementations, structural fragments Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0041] In some embodiments, the L is selected from the following groups optionally substituted with one or more substituents: C 1-50 Alkylene, C 2-50 imide or C 2-50 Idemyne ​​group, the C 1-50 Alkylene, C 2-50 imide or C 2-50 One or more -CH2- groups in the ethynyl group are optionally replaced by -O-, C-. 3-15 Cycloalkyl, 3-15 membered heterocyclic alkyl, 4-15 membered heterocyclic alkenyl, C 6-15 Aryl, containing 5-15 membered heteroaryl, -NH-, -N(C 1-6 Alkyl)- or -S- substitution.

[0042] In some embodiments, the L is selected from the following groups optionally substituted with one or more substituents: C 1-30 Alkylene, C2-30 imide or C 2-30 Imyynyl group, the C 1-30 Alkylene, C 2-30 imide or C 2-30 One or more -CH2- groups in the ethynyl group are optionally replaced by -O-, C-. 3-12 Cycloalkyl, 3-12-membered heterocyclic alkyl, 4-12-membered heterocyclic alkenyl, C 6-12 Aryl, containing 5-12 membered heteroaryl, -NH-, -N(C 1-6 Alkyl)- or -S- substitution.

[0043] In some embodiments, the L is selected from the following groups optionally substituted with one or more substituents: C 1-20 Alkylene, C 2-20 imide or C 2-20 Idemyne ​​group, the C 1-20 Alkylene, C 2-20 imide or C 2-20 One or more -CH2- groups in the ethynyl group are optionally replaced by -O-, C-. 3-10 Cycloalkyl, 3-11 membered heterocyclic alkyl, 4-10 membered heterocyclic alkenyl, C 6-10 Aryl, any 5-10 heteroaryl, -NH-, -N(C 1-6 Alkyl)- or -S- substitution.

[0044] In some embodiments, the L is selected from the following groups optionally substituted with one or more substituents: C 1-15 Alkylene, C 2-15 imide or C 2-15 Imyynyl group, the C 1-15 Alkylene, C 2-15 imide or C 2-15 One or more -CH2- groups in the ethynyl group are optionally replaced by -O-, C-. 3-9 Cycloalkyl, 3-11 membered heterocyclic alkyl, 4-8 membered heterocyclic alkenyl, C 6-8 Aryl, 5-8 quinone heteroaryl, -NH-, -N(C 1-4 Alkyl)- or -S- substitution.

[0045] In some embodiments, the L is selected from the following groups optionally substituted with one or more substituents: C 1-10 Alkylene, C 2-10 imide or C 2-10 Imyynyl group, the C 1-10 Alkylene, C 2-10 imide or C 2-10 One or more -CH2- groups in the ethynyl group are optionally replaced by -O-, C-. 3-9Cycloalkyl, 3-11 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, -NH-, -N(C 1-3 Alkyl)- or -S- substitution.

[0046] In some embodiments, the L is selected from the following groups optionally substituted with one or more substituents: C 1-6 Alkylene, C 2-6 imide or C 2-6 Imyynyl group, the C 1-6 Alkylene, C 2-6 imide or C 2-6 One or more -CH2- groups in the ethynyl 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- substitution.

[0047] In some embodiments, the L is selected from the following groups optionally substituted with one or more substituents: C 1-4 Alkylene, C 2-4 imide or C 2-4 Imyynyl group, the C 1-4 Alkylene, C 2-4 imide or C 2-4 One or more (e.g., one or two, one or three, etc.) of the ethynyl group are 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-replacement. In some embodiments, the L is selected from C 1-6 Alkylene, the C 1-6 One or more -CH2- atoms in the alkylene group are optionally selected from -O-, C-. 3-10 Cycloalkyl, 4-11 membered heterocyclic alkyl, 4-10 membered heterocyclic alkenyl, -NH-, -N(C 1-3 Alkyl)- or -S-replacement, the C 1-6 The alkylene group may optionally be substituted with one or more substituents.

[0048] In some implementations, the L is selected from C. 1-6 Alkylene, the C 1-6 One or more -CH2- atoms in the alkylene group are optionally selected from -O-, C-. 3-10 Cycloalkyl, 4-11 membered heterocyclic alkyl, 5-6 membered heterocyclic alkenyl, -NH-, -N(C 1-3 Alkyl)- or -S-replacement, the C 1-6The alkylene group is optionally substituted with one or more substituents. In some embodiments, the L is selected from -(5-8 membered heterocyclic alkyl groups containing 1-2 N or O atoms)-C 1-6 Alkylene-, -(C 5-8 cycloalkyl)-C 1-6 alkylene-, -C 1-6 Alkylene (5-8 membered heterocyclic alkyl group containing 1-2 N or O atoms)-C 1-6 alkylene- or -C 1-6 Alkylene-(C 5-8 cycloalkyl)-C 1-6 Alkylene-.

[0049] In some embodiments, in the definition of L, the substituent is selected from halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 1-6 Alkylamino, diC 1-6 Alkylamino, C 3-12 Cycloalkyl or 4-12 membered heterocyclic alkyl groups. In some embodiments, in the definition of L, the substituent is selected from halogens, =O, -OH, -NH2, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 1-4 Alkylamino, diC 1-4 Alkylamino, C 3-10 Cycloalkyl or 4-10 membered heterocyclic alkyl groups. In some embodiments, in the definition of L, the substituent is selected from halogens, =O, OH, NH2, CN, C. 1-6 Alkyl or C 1-6 Alkyl group. In some embodiments, in the definition of L, the substituent is selected from =O, OH, NH2, halogen, or CN. In some embodiments, in the definition of L, the substituent is =O.

[0050] In some implementations, the L is selected from -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -Cy 3 -,in, Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. a The following groups are substituted: C 3-12Cycloalkyl, 4-12 membered heterocyclic alkyl or 4-12 membered heterocyclic alkenyl; LNK, LNK 1 and LNK 2 Each is independently selected from the bond, NH, O, S, or optionally by one or more R b The following groups are substituted: C 1-12 Alkylene, C 2-12 imidene group, C 2-12 Ethyne or C 1-12 Heteroalkylene; Each R a and R b Each is independently selected from halogens, =O, -OH, -NH2, -CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 1-6 Alkylamino, diC 1-6 Alkylamino, C 3-12 Cycloalkyl or 4-12 membered heterocyclic alkyl.

[0051] In some implementations, Cy 1 Cy 2 and Cy 3 They are not both keys. In some implementations, Cy 2 and Cy 3 As a key. In some implementations, LNK 1 and LNK 2 For key.

[0052] In some implementations, the L is selected from -Cy 1 -、-Cy 2 -、-LNK 1 -、- Cy 1 -LNK-、-Cy 1 -Cy 2 -、-LNK 1 -Cy 1 -LNK-、-LNK-Cy 2 -LNK 2 -、-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 implementations, L is -Cy 1 - In some implementations, the L is selected from -LNK. 1 - In some implementations, L is -Cy 1 -LNK-.

[0053] In some implementation schemes, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, NH, O, S, or optionally by one or more R b The following groups are substituted: C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Ethyne or C 1-10 Heteroalkylene compounds. In some embodiments, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, NH, O, S, or optionally by one or more R b The following groups are substituted: C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne or C 1-6 Heteroalkylene compounds. In some embodiments, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, NH, O, S, or optionally by one or more R b The following groups are substituted: C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Ethyne or C 1-4 Heteroalkylene compounds. In some embodiments, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, NH, O, S, or optionally by one or more R b The following groups are substituted: C 1-6 Alkylene or C 1-6Heteroalkylene compounds. In some embodiments, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, NH, O, S, or optionally by one or more R b The following groups are substituted: C 1-4 Alkylene or C 1-4 Heteroalkylene compounds. In some embodiments, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, NH, O, or optionally by one or more R b The following groups are substituted: C 1-3 Alkylene or C 1-3 Heteroalkylene compounds. In some embodiments, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, NH, O, or optionally by one or more R b The following groups are substituted: C 1-2 Alkylene or C 1-2 Heteroalkylene compounds. In some embodiments, LNK, LNK 1 and LNK 2 Each is independently selected from the following: bond, NH, O, -NHCH2-, -CH2NHCH2-, -CH2-, -CH2CH2-, -C(O)-, or -C(O)CH2-. In some embodiments, LNK, LNK 1 and LNK 2 Each is a separate key. In some implementations, LNK, LNK... 1 and LNK 2 Each is independently -CH2-.

[0054] In some implementations, Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. a The following groups are substituted: C 3-11 Cycloalkyl, 4-12-membered heterocyclic alkyl, or 4-11-membered heterocyclic alkenyl. In some embodiments, Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. a The following groups are substituted: C 4-10 Cycloalkyl, 4-11 membered heterocyclic alkyl, or 5-6 membered heterocyclic alkenyl. In some embodiments, Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. aThe following groups are substituted: C 4-9 Cycloalkyl, 4-11 membered heterocyclic alkyl, or 5-6 membered heterocyclic alkenyl. In some embodiments, Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. a The following groups are substituted: C 4-6 Cycloalkyl, C9 cycloalkyl, 4-11 membered heterocyclic alkyl or 6 membered heterocyclic alkenyl.

[0055] In some implementations, Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. a The following groups may be substituted: cyclobutyl, cyclopentyl, cyclohexyl, spironyl, azircyclobutyl, pyrrolyl, piperidinyl, tetrahydropyridyl, piperazine, monoazirspiroheptyl, monoazirspironyl, diazirspironyl, monoazirspirodecyl, diazirspirodecane, monoazirspiroundecyl, diazirspiroundecyl, octahydrocyclopentylpyrryl, diazirbicyclooctyl, or monoazirbicyclononyl.

[0056] In some specific implementation schemes, Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. a The following groups are substituted: 4-11 membered heterocyclic alkyl groups. In some specific embodiments, Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. a The following groups are substituted: 7-11 membered heterocyclic alkyl groups. In some specific embodiments, Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. a The following groups are substituted: 4-6 membered heterocyclic alkyl groups. In some embodiments, Cy 1 Cy 2 or Cy 3 Each is a separate key. In some implementations, Cy 1 Cy 2 or Cy 3 Each independently and optionally by one or more R a Substituted 6-membered heterocyclic alkyl groups.

[0057] In some specific implementation schemes, Cy 1 Cy2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. a The following groups may be substituted: cyclobutyl, cyclopentyl, cyclohexyl, spironyl, aziroxybutyl, pyrrolidinyl, piperidinyl, tetrahydropyridyl, or piperazine. In some specific embodiments, Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. a The following groups may be substituted: monoazaspiroheptyl, monoazaspirononyl, diazaspirononyl, monoazaspirodealkyl, diazaspirodealkyl, monoazaspironundecyl, diazaspironundecyl, octahydrocyclopentylpyrroleyl, diazabicyclooctyl or monoazabicyclononyl.

[0058] In some implementations, Cy 1 Cy 2 or Cy 3 Selected independently from keys, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or In some implementations, Cy 1 Cy 2 or Cy 3 Each independently In some implementations, Cy 1 Cy 2 or Cy 3 Each independently .

[0059] In some implementations, each R a and R b Each is independently selected from halogens, =O, -OH, -NH2, -CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 1-6 Alkylamino, diC 1-6 Alkylamino, C 3-10 Cycloalkyl or 4-10 membered heterocyclic alkyl. In some embodiments, each R a and R b Each is independently selected from halogens, =O, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 1-6 Alkylamino or diC 1-6 Alkylamino. In some embodiments, each R a and R b Each is independently selected from halogens, =O, -OH, -NH2, -CN, and C. 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 1-4 alkylamino, or di-C 1-4 Alkylamino.

[0060] In some implementations, each R a and R b Each is independently selected from halogens, =O, -OH, -NH2, -CN, or C. 1-3 Alkyl group. In some embodiments, each R a and R b Each is independently selected from halogens, =O, -OH, -NH2, or -CN. In some embodiments, each R... a and R b Each is independently equal to O.

[0061] In some implementations, L or -LNK 1 - is selected from -NHCH2-, -CH2NHCH2-, -CH2- or -C(O)CH2-.

[0062] In some implementations, L or -Cy 1 -Selected from , , , , , , , , , , , or .

[0063] In some implementations, L or -Cy 1 -LNK- Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0064] In some implementations, L or -Cy 1 -Cy 2 -Selected from , , , , , , , , , or .

[0065] In some implementations, L or -Cy 1 -Cy 2 -Cy 3 -Selected from , , , , , , , , or .

[0066] In some implementations, L or -LNK 1 -Cy 1 -LNK- Selected from , , , , , , , , or .

[0067] In some implementations, L or -Cy 1 -Cy 2 -LNK 2 -Selected from , , , , or .

[0068] In some implementations, L or -Cy 1 -LNK-Cy 2 -Selected from , , , , , , , , , , , , , or .

[0069] In some implementations, L or -LNK 1 -Cy 1 -Cy 2 -LNK 2 -Selected from , or .

[0070] In some implementations, L or -Cy 1 -LNK-Cy 2 -LNK 2 -for .

[0071] In some embodiments, the L is selected from the following: -NHCH2-, -CH2NHCH2-, -CH2-, -C(O)CH2-, ... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0072] In some implementations, L is selected from... , , , , , , , , , , , , , or .

[0073] In some implementations, L is In some implementations, L is... In some implementations, L is... .

[0074] In some implementations, structural fragments Selected from , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , or .

[0075] In some implementations, structural fragments Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0076] In some implementation schemes, R f C selected from H, fluorine, chlorine, bromine, deuterium, or optionally substituted with one or more substituents 1-3 Alkyl group. In some embodiments, R f Selected from H, fluorine, chlorine, bromine, deuterium or C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with one or more of the following groups: halogen, -OH, -NH2, or -CN. In some embodiments, R f Selected from H, fluorine, chlorine, bromine, deuterium or C 1-3 Alkyl group. In some embodiments, Rf Selected from H, fluorine, deuterium, or methyl. In some embodiments, R f For H.

[0077] In some implementation schemes, X 5 Selected from CH or N. In some implementations, X 5 For CH.

[0078] In some implementation schemes, X 6 Selected from -O-, -NH-, or -N(C 1-3 Alkyl)-. In some embodiments, X 6 Selected from -O- or -N(CH3)-. In some implementations, X 6 It is -O-.

[0079] In some implementations, each R 2 R 3 and R 4 Each is independently selected from halogens, -OH, -NH2, -CN, and C. 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkyl groups, namely -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. In some embodiments, each R... 2 R 3 and R 4 Each is independently selected from halogens, -OH, -NH2, -CN, and C. 1-4 Alkyl, C 1-4 alkoxy or halogenated C 1-4 alkyl.

[0080] In some implementations, each R 2 Independently selected from halogens, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 alkoxy or halogenated C 1-3 Alkyl group. In some embodiments, each R 2 Independently selected from halogens, -OH, -NH2, -CN, C 1-3 Alkyl or C 1-3 Alkyl groups. In some embodiments, each R 2 Independently selected from fluorine, chlorine, bromine, -OH, -NH2, -CN, methyl, or methoxy. In some embodiments, each R 2 Independently selected from fluorine, chlorine, bromine, -CN, or methoxy. In some embodiments, each R... 2Independently selected from -CN or methoxy. In some embodiments, each R 2 Independently selected from -CN or C 1-6 Alkoxy groups (e.g., C) 1-5 Alkoxy, C 1-4 Alkoxy or C 1-3 Alkoxy group).

[0081] In some implementations, each R 3 Each is independently selected from halogens, -OH, -NH2, -CN, and C. 1-3 Alkyl, C 1-3 alkoxy or halogenated C 1-3 Alkyl group. In some embodiments, each R 3 Each is independently selected from halogens, -OH, -NH2, -CN, or C. 1-3 Alkyl group. In some embodiments, each R 3 Selected independently from C 1-6 Alkyl, C 1-5 Alkyl or C 1-4 Alkyl (preferably C) 1-3 Alkyl group). In some embodiments, each R 3 Each is independently a methyl group.

[0082] In some implementations, each R 4 Each is independently selected from halogens, -OH, -NH2, -CN, and C. 1-3 Alkyl, C 1-3 alkoxy or halogenated C 1-3 Alkyl group. In some embodiments, each R 4 Each is independently selected from halogens, -OH, -NH2, -CN, or C. 1-3 Alkyl group. In some embodiments, each R 4 Each of the following is independently selected from fluorine, chlorine, bromine, -OH, -NH2, or -CN.

[0083] 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.

[0084] In some implementations, structural fragments for .

[0085] 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 (a 6-membered heteroaryl containing 1-2 nitrogen atoms). In some embodiments, the ring G is phenyl.

[0086] In some implementations, ring E is selected from C. 3-9 Cycloalkyl or 3-9 membered heterocyclic alkyl. In some embodiments, the ring E is selected from C. 4-9 Cycloalkyl or 4-9 membered heterocyclic alkyl. In some embodiments, the ring E is selected from C. 4-7 Cycloalkyl or 4-7 membered heterocyclic alkyl. In some embodiments, the ring E is selected from C. 4-7 cycloalkyl (e.g., C10) 4-6 cycloalkyl, C 4-5 (Cycloalkyl). In some embodiments, ring E is selected from cyclobutyl, cyclopentyl, or cyclohexyl.

[0087] In some embodiments, ring E is cyclobutyl. In some embodiments, ring E is... In some implementations, ring E is... In some implementations, the structural portion for In some implementations, the structural portion for .

[0088] In some implementations, ring F is selected from C. 6-10 Aryl or 5-7-membered heteroaryl. 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., a 6-membered heteroaryl containing 1-3 or 1-2 N atoms). In some embodiments, ring F is selected from phenyl, pyridyl, pyridinyl, 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 pyridinyl. In some embodiments, ring F is selected from... , , , or In some implementations, ring F is... In some implementations, ring F is... In some implementations, ring F is... In some implementations, ring F is... In some implementations, ring F is... .

[0089] In some implementation schemes, Selected from , , , or .

[0090] In some implementation schemes, R t Selected from hydrogen, -OH, C 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein C 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl groups are optionally substituted. In some embodiments, R t Selected from hydrogen, -OH, C 1-3 Alkyl, C 3-4 Cycloalkyl or 3-4 membered heterocycloalkyl, wherein C 1-3 Alkyl, C 3-4 Cycloalkyl or 3-4 membered heterocyclic alkyl groups are optionally substituted. In some embodiments, R t Selected from hydrogen or C 1-3 Alkyl groups (such as methyl, ethyl, propyl). In some embodiments, R t It is hydrogen.

[0091] In some embodiments, the optional substitution means optional substitution with one or more of the following groups: halogen (e.g., fluorine, chlorine, bromine or iodine), -CN, -OH or -NH2.

[0092] In some implementations, structural fragments for In some implementations, structural fragments for In some implementations, structural fragments for In some implementations, structural fragments for In some implementations, structural fragments for In some implementations, structural fragments for In some implementations, structural fragments Selected from , , , , , or In some implementations, structural fragments , , , or Selected from .

[0093] In some embodiments, the aforementioned heterocyclic alkenyl, heteroaryl, heterocyclic alkyl, or heteroalkylene group comprises one or more heteroatoms or heteroatom groups independently selected from -O-, -NH-, -N-, -S-, C=O, -C(=O)NH-, -C(=O)O-, -S(=O)-, or -S(=O)2-; in some embodiments, the aforementioned heterocyclic alkenyl, heteroaryl, heterocyclic alkyl, or heteroalkylene group comprises one or more heteroatoms or heteroatom groups independently selected from -O-, -NH-, -N-, or -S-; in some embodiments, the aforementioned heterocyclic alkenyl, heteroaryl, heterocyclic alkyl, or heteroalkylene group comprises one or more heteroatoms or heteroatom groups independently selected from -O-, -NH-, or -N-. In some embodiments, the number of said heteroatoms or heteroatom groups 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.

[0094] In some embodiments, the heteroatom in the heterocyclic alkenyl group is selected from N, NH, O, or S. In some embodiments, the heteroatom in the heterocyclic alkenyl group is selected from N, O, or S. In some specific embodiments, the heteroatom in the heterocyclic alkenyl group is selected from N or O. In some embodiments, the number of heteroatoms in the heterocyclic alkenyl group is selected from 1, 2, 3, 4, 5, or 6. In some embodiments, the number of heteroatoms in the heterocyclic alkenyl group is selected from 1, 2, 3, or 4. In some embodiments, the number of heteroatoms in the heterocyclic alkenyl group is selected from 1, 2, or 3. In some specific embodiments, the number of heteroatoms in the heterocyclic alkenyl group is selected from 1 or 2.

[0095] It should be understood that any embodiment of the compounds of this application as described above and any specific ring A, ring B, ring C, ring E, ring F, ring G, R in the compounds of this application as described above are considered to be specific to this application. 1 R 2 R 3 R 4 R t L, X 5 X 6 Any specific substituent described herein may be independently combined with other embodiments of this application and / or substituents of compounds to form embodiments of the invention not specifically described above. Furthermore, any specific ring A, ring B, ring C, ring E, ring F, ring G, or ring R mentioned in the specific embodiments and / or claims... 1 R 2 R 3 R 4 R t L, X 5 X6 Where the scope of substituents is disclosed, it should be understood that one or more substituents may be removed from that scope, and the remaining scope of substituents should also be considered as an embodiment of this application.

[0096] This application relates to compounds of formula I-1 or I-1A, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0097] Among them, rings A, B, C, F, and R 1 n, R 2 m, R 3 p, R 4 , q, X 5 X 6 L is defined as described in this application.

[0098] In some implementation schemes, the structural portion As stated in this application.

[0099] This application relates to compounds of formula I-2, formula I-2A, formula I-3, or formula I-3A, their stereoisomers, or pharmaceutically acceptable salts thereof. ,

[0100] or , Among them, rings A, B, C, F, and R 1 n, R 2 m, R 3 p, R 4 , q, X 5 The definitions of L are as described in this application; X is selected from CH or N.

[0101] In some implementations, structural fragments , The definition is as stated in this application.

[0102] In some embodiments, optionally, the compounds described in this application are not the following compounds: , , , , , .

[0103] In some embodiments, optionally, the compounds described in this application are not the following compounds:

[0104]

[0105] or .

[0106] In some embodiments, optionally, the compounds described in this application are not the following compounds: or .

[0107] In some solutions, the structural portion or Not selected , , , , or .

[0108] In some solutions, the structural portion or Not selected , , , , ,or In some solutions, the structural portion or Not selected or .

[0109] In some solutions, the structural portion or Not selected , , , , or In some solutions, the structural portion or Not selected , , ,or In some solutions, the structural portion or Not selected or .

[0110] On the other hand, this application relates to compounds of formula I' or I'', moiety, stereoisomers thereof, derivatives (specifically, Protac molecules) or pharmaceutically acceptable salts thereof. ,

[0111] Among them, ring A either does not exist or is selected from C. 5-10 Cycloalkenyl, 5-10 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl; Ring B is phenyl; The ring C is selected from isoxazolyl or furanyl; L is a linking group; optionally, L is defined as described in this application; optionally, R 1 The definitions of n are as described in this application.

[0112] In some embodiments, this application relates to the following portions, or compounds containing such portions (including Protac molecules), their stereoisomers, or pharmaceutically acceptable salts thereof:

[0113] Wherein, L is defined as described above, Y 6 For C(R) 5 ) or N, R 5 H, deuterium, tritium, C 1-3 Alkyl group, =O (preferably H); d and d' may be the same or different, and each can be 1, 2 or 3 independently.

[0114] In some embodiments, this application relates to the following portions, or compounds containing such portions (including Protac molecules), their stereoisomers, or pharmaceutically acceptable salts thereof:

[0115] Among them, L and Y 6 The definitions of Y, d, and d' are as described in this application. 5 For C(R) 5 ) or N, R 5 H, deuterium, tritium, C 1-3 Alkyl group, =O (preferably, H).

[0116] In some implementation schemes, the structural portion As stated in this application.

[0117] On the other hand, this application relates to compounds of formula I'-a or I''-a, portions thereof, stereoisomers thereof, derivatives (specifically, Protac molecules) or pharmaceutically acceptable salts thereof.

[0118] Among them, ring A either does not exist or is selected from C. 5-10 Cycloalkenyl, 5-10 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl; Ring B is phenyl; The ring C is selected from isoxazolyl or furanyl; Each R 1a Independently selected from halogens, -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, wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-12 The cycloalkyl or 4-12 membered heterocycloalkyl group 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 Alkyl COC(O)-substituted 4-10 membered heterocyclic alkyl groups; n is selected from 0, 1, 2 or 3.

[0119] In some implementations, ring A is absent or selected from C. 5-7 Cycloalkenyl, 5-9 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl.

[0120] In some implementations, ring A is absent or selected from C. 5-6 Cycloalkenyl, 5-10 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl.

[0121] In some implementations, ring A is absent or selected from C. 5-6 Cycloalkenyl, 5-9 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl.

[0122] In some implementations, ring A is absent or selected from C. 5-6 Cycloalkenyl, 5-9 membered heterocyclic alkenyl, phenyl or 5 membered heteroaryl.

[0123] In some implementations, ring A is absent or selected from C. 5-6 Cycloalkenyl, 5-9 membered heterocyclic alkenyl, phenyl, pyrroleyl, pyrazolyl, furanyl, or oxazolyl.

[0124] 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 heterocyclic alkenyl, phenyl, pyrroleyl, pyrazolyl, furanyl or oxazolyl.

[0125] In some embodiments, ring A is absent or selected from cyclopentenyl, monocyclohexenyl, dicyclohexenyl, dihydropyrrolyl, tetrahydropyridyl, tetrahydroazapyrrolyl, azaspirooctenyl, azaspirononenyl, phenyl, pyrrolyl, pyrazolyl, furanyl, oxazolyl, or dihydrooxazinyl.

[0126] In some specific implementation schemes, ring A is selected from C. 5-9 Cycloalkenyl, 5-9 membered heterocyclic alkenyl, phenyl or 5 membered heteroaryl.

[0127] In some specific implementation schemes, ring A is selected from C. 5-6 Cycloalkenyl, 5-9 membered heterocyclic alkenyl, phenyl or 5 membered heteroaryl.

[0128] In some specific implementation schemes, ring A is selected from C. 5-9 Cycloalkenyl or 5-9 membered heterocyclic alkenyl. In some specific embodiments, ring A is selected from C. 5-6 Cycloalkenyl or 5-9 membered heterocyclic alkenyl.

[0129] In some specific implementation schemes, ring A is selected from C. 5-9 Cycloalkenyl. In some specific embodiments, cycloA is selected from C. 5-6 Cycloalkenyl. In some specific embodiments, ring A is selected from 5-9 membered heterocyclic alkenyl groups.

[0130] In some specific embodiments, ring A is selected from cyclopentenyl, dihydropyrrolyl, tetrahydropyridyl, tetrahydroazapyrrolyl, azaspirocyclononenyl, azaspirocyclooctenyl, phenyl, pyrrolyl or pyrazolyl.

[0131] In some specific embodiments, ring A is selected from cyclopentenyl, dihydropyrrolyl, tetrahydropyridyl, tetrahydroazapyrrolyl, azaspirocyclic nonenyl, or azaspirocyclic octenyl.

[0132] In some specific embodiments, ring A is selected from cyclopentenyl. In some specific embodiments, ring A is selected from dihydropyrroleyl, tetrahydropyridyl, tetrahydroazapyryl, or azaspirooctene.

[0133] In some specific embodiments, ring A is selected from phenyl, pyrrole, or pyrazolyl.

[0134] In some implementations, ring A is selected from... , , , , , , , , , , , , , or .

[0135] In some specific embodiments, the ring C is an isoxazolyl group. In some specific embodiments, the ring C is a furanyl group.

[0136] In some implementation schemes, the structural portion Selected from or .

[0137] In some implementations, structural fragments Selected from , , , , or In some implementations, structural fragments Selected from , or Or, structural fragments Selected from or Or, structural fragments Selected from .

[0138] In some implementations, structural fragments Selected from , , , , or In some implementations, structural fragments Selected from , or Or, structural fragments Selected from or Or, structural fragments for .

[0139] In some implementations, structural fragments Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or In some specific implementation schemes, structural fragments Not selected or .

[0140] In some implementations, structural fragments Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , or In some implementations, each R 1a Independently selected from halogens, -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, wherein C1-4 Alkyl, C 1-4 Alkoxy, C 3-10 The cycloalkyl or 4-10 membered heterocycloalkyl group 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 Alkyl COC(O)-substituted 4-10 membered heterocyclic alkyl groups.

[0141] In some implementations, each R 1a Independently selected from halogens, -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, wherein C 1-3 Alkyl, C 1-3 Alkoxy, C 3-9 The cycloalkyl or 4-9 membered heterocycloalkyl group 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 Alkyl COC(O)-substituted 4-9 membered heterocyclic alkyl groups.

[0142] In some implementations, each R 1a Independently selected from halogens, -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, wherein C 1-3 Alkyl, C 1-3 Alkoxy, C 4-6 The cycloalkyl or 4-6 membered heterocycloalkyl group 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 Alkyl COC(O)-substituted 3-6 membered heterocyclic alkyl groups.

[0143] In some implementations, each R 1a Independently selected from halogens, -OH, -NH2, -CN, -CHO, C 1-4 Alkyl OC(O)-, C1-3 Alkyl or 4-6 membered heterocyclic alkyl, wherein the C 1-3 The alkyl group or 4-6 membered heterocyclic alkyl group 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 Alkyl OC(O)-substituted 4-6 membered heterocyclic alkyl groups.

[0144] In some implementations, each R 1a Independently selected from halogens, -OH, -CHO, (CH3)3COC(O)-, C 1-3 alkyl, cyclobutyl or piperidinyl, wherein C 1-3 The alkyl, cyclobutyl, or piperidinyl group is optionally substituted with one or more of the following groups: -OH, (CH3)3COC(O)-, or a cyclobutyl group optionally substituted with (CH3)3COC(O)-.

[0145] In some implementations, each R 1a Independently selected from F, -OH, -CHO, (CH3)3COC(O)-, -CH2OH, , , , , or .

[0146] In some implementations, n is selected from 0, 1, or 2. In some implementations, n is selected from 0 or 1. In some implementations, n is 0.

[0147] This application relates to the following compounds, portions, stereoisomers, derivatives (specifically, the Protac molecule), or pharmaceutically acceptable salts thereof. , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0148] In some embodiments, this application relates to a compound of formula I, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein ring A is C 5-10Cycloalkenyl, or 5-15 membered heterocyclic alkenyl groups containing 1-2 heteroatoms selected from N or O (e.g., C). 5-8 Cycloalkenyl, or a 5-8 membered heterocyclic alkenyl 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- atoms in the alkylene group are optionally C 5-8 Cycloalkyl groups, or 5-8 membered heterocyclic alkyl groups containing 1-3 or 1-2 N or O atoms; Each R 2 Independently -OH, -NH2, -CN, C 1-10 Alkyl, C 1-10 alkoxy or halogenated C 1-10 Alkyl; each R 3 Independent of 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 It is -O- or -NH-; ring G is phenyl or a 6-membered heteroaryl containing 1-2 N 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 or O atoms; R t It is hydrogen, -OH or C 1-6 alkyl.

[0149] In some embodiments, this application relates to compounds, their stereoisomers, or pharmaceutically acceptable salts thereof:

[0150] Among them, each R 2 Independently -NH2, -CN, C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkyl groups (e.g., -CN, C) 1-6 Alkoxy, C 1-5 Alkoxy, C 1-4 Alkoxy or C 1-3 alkoxy); Each R 3 Independently for C 1-6 Alkyl or halogenated C 1-6 Alkyl (e.g., C) 1-6 Alkyl, C1-5 Alkyl, C 1-4 Alkyl or C 1-3 alkyl); m is 1, 2 or 3 (preferably 1 or 2), and p is 0, 1, 2, 3 or 4 (preferably 2, 3 or 4). X 6 It can be -O- or -NH- (preferably -O-); R t It is hydrogen, -OH or C 1-6 Alkyl (preferably hydrogen); Ring F is C 6-10 Aryl or 6-10-membered heteroaryl (preferably phenyl or a 6-membered heteroaryl containing 1-4, 1-3 or 1-2 N atoms); L is C 1-6 Alkylene, the C 1-6 One or more -CH2- atoms in the alkylene group are optionally replaced by 5- to 7-membered heterocyclic alkyl groups containing 1-3 or 1-2 N atoms (e.g., , , Preferred , ); Ring A is C 5-9 Cycloalkenyl or 5-9 membered heterocyclic alkenyl groups containing 1-2 N atoms (preferably C) 5-7 Cycloalkenyl or 5-7 membered heterocyclic alkenyl containing one nitrogen atom.

[0151] In some embodiments, this application relates to compounds, their stereoisomers, or pharmaceutically acceptable salts thereof: Preferred , , , or

[0152] Among them, R 2 R 3 m, p, X 6 R t The definitions of rings F, L, and A are as described above, and each R... 2 They can be the same or different, each R 3 They can be the same or different; Y 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 1-3Alkyl group, =O (preferably H, deuterium, tritium); d and d' may be the same or different, each independently being 1, 2, or 3. In some preferred embodiments, the Y 1 Y 2 Y 3 and Y 4 At most three of them are N, more preferably, the Y 1 Y 2 Y 3 and Y 4 At most two of them are N.

[0153] In some implementation schemes, Y 1 For CH or N. In some implementations, Y 1 For CH. In some implementations, Y 1 Let N be the number of elements in the array.

[0154] In some implementation schemes, Y 2 For CH or N. In some implementations, Y 2 For CH. In some implementations, Y 2 Let N be the number of elements in the array.

[0155] In some implementation schemes, Y 3 For CH or N. In some implementations, Y 3 For CH. In some implementations, Y 3 Let N be the number of elements in the array.

[0156] In some implementation schemes, Y 4 It is CH or N. In some implementations, Y 4 For CH. In some implementations, Y 4 Let N be the number of elements in the array.

[0157] In some implementation schemes, Y 5 It is CH or N. In some implementations, Y 5 For CH. In some implementations, Y 5 Let N be the number of elements in the array.

[0158] In some implementation schemes, Y 6 For CH or N. In some implementations, Y 6 For CH. In some implementations, Y 6 Let N be the number of elements in the array.

[0159] On the other hand, this application relates to the use of the aforementioned compounds (e.g., formula I' or I'' or I'-a or I''-a or specific compounds), portions thereof, isomers thereof (e.g., stereoisomers), and derivatives thereof in the preparation of Protac molecules. On the other hand, this application relates to the use of the aforementioned compounds (e.g., formula I' or I'' or I'-a or I''-a or specific compounds), portions thereof, isomers thereof (e.g., stereoisomers), and derivatives thereof in constituting a part of a Protac molecule. On the other hand, this application relates to the existence of the aforementioned compounds (e.g., formula I' or I'' or I'-a or I''-a or specific compounds), portions thereof, isomers thereof (e.g., stereoisomers), and derivatives thereof in the form of Protac molecules. On the other hand, this application relates to the use of the aforementioned compounds (e.g., formula I' or I'' or I'-a or I''-a or specific compounds), portions thereof, isomers thereof (e.g., stereoisomers), and derivatives thereof for the degradation of proteins (e.g., AR), such as the degradation of the protein in the form of Protac molecules by the aforementioned compounds (e.g., formula I' or I'' or I'-a or I''-a or specific compounds), portions thereof, isomers thereof (e.g., stereoisomers), and derivatives thereof. On the other hand, this application relates to the use of the aforementioned compounds (e.g., formula I' or I'' or I'-a or I''-a or specific compounds), portions thereof, isomers thereof (e.g., stereoisomers), and derivatives thereof in the form of Protac molecules for the degradation of proteins. This application relates to the use of the aforementioned compounds (e.g., formula I' or I'' or I'-a or I''-a or specific compounds), portions thereof, isomers thereof (e.g., as preparation intermediates) in the preparation of Protac molecules. This application relates to the use of the compounds (e.g., formula I' or formula I'' or I'-a or formula I''-a or specific compounds), portions thereof, isomers thereof (e.g., stereoisomers), and derivatives thereof (e.g., as preparation intermediates) in the preparation of protein degrading agents.

[0160] This application relates to the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof: or .

[0161] This application also relates to the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof:

[0162] or .

[0163] This application also covers solutions obtained by arbitrarily combining, deleting, or changing the above-described embodiments.

[0164] On the other hand, this application relates to the above-mentioned compounds in crystalline or amorphous form, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0165] On the other hand, this application relates to a pharmaceutical composition containing the above-described compounds of this application, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0166] In some embodiments, the pharmaceutical composition contains 0.01 mg to 1000 mg (in the free form of the compound) of the above-mentioned compound, its stereoisomers, or pharmaceutically acceptable salts thereof.

[0167] In some embodiments, the pharmaceutical composition contains, in a single dose of 0.01 mg to 1000 mg (in the free form of the compound), the stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0168] In some embodiments, the 0.01 mg to 1000 mg is further selected from 0.1 mg to 1000 mg, 1 mg to 1000 mg, 10 mg to 1000 mg, 20 mg to 1000 mg, 30 mg to 1000 mg, or 31 mg to 1000 mg.

[0169] In some embodiments, the pharmaceutical composition contains 0.01 to 95% wt of the compound, its stereoisomers, or pharmaceutically acceptable salts thereof (in the free form of the compound).

[0170] In some embodiments, the 0.01~95%wt is further selected from 0.1~95%wt, 0.4~95%wt, or 1~95%wt.

[0171] In some embodiments, the pharmaceutical composition wherein the compound, its stereoisomers, or pharmaceutically acceptable salts thereof are selected from crystalline or amorphous forms of the compound, its stereoisomers, or pharmaceutically acceptable salts thereof.

[0172] In some embodiments, the target of administration of the pharmaceutical composition is selected from mammals, such as humans.

[0173] In some embodiments, the pharmaceutical composition is selected from solid pharmaceutical compositions, semi-solid pharmaceutical compositions, liquid pharmaceutical compositions, or gaseous pharmaceutical compositions.

[0174] In some embodiments, the pharmaceutical composition is selected from solid pharmaceutical compositions. In some embodiments, the pharmaceutical composition is selected from liquid pharmaceutical compositions.

[0175] In some embodiments, the pharmaceutical composition is selected from tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres, or aerosols.

[0176] In some embodiments, the solid pharmaceutical composition is selected from tablets, pills, capsules, powders, or granules.

[0177] In some embodiments, the liquid pharmaceutical composition is selected from injectable formulations.

[0178] In some embodiments, the pharmaceutical composition is selected from pharmaceutical compositions in oral or injectable form.

[0179] In some embodiments, the pharmaceutical composition is selected from pharmaceutical compositions in oral form.

[0180] In some embodiments, the pharmaceutical composition is selected from injectable pharmaceutical compositions.

[0181] In some embodiments, the pharmaceutical composition is selected from oral solid pharmaceutical compositions.

[0182] In some embodiments, the pharmaceutical composition is selected from liquid pharmaceutical compositions for injection.

[0183] In some embodiments, the pharmaceutical composition of this application further includes pharmaceutically acceptable excipients.

[0184] In some embodiments, the pharmaceutical composition may be prepared by combining the above-described compounds of this application, their stereoisomers or pharmaceutically acceptable salts thereof with suitable pharmaceutically acceptable excipients.

[0185] In some embodiments, the routes of administration of the pharmaceutical composition include, but are not limited to, oral, rectal, local, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, or intravenous.

[0186] On the other hand, this application relates to the use of the above-mentioned compounds, their stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention or treatment of conditions by degrading target proteins (such as androgen receptors, AR) that bind to target ligands.

[0187] On the other hand, this application relates to the use of the above-mentioned compounds, their stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention or treatment of conditions that are treated by binding to cerebellar proteins (CRBN) in vivo.

[0188] On the other hand, this application relates to the use of the above-mentioned compounds, their stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention or treatment of AR-related diseases.

[0189] This application relates to a method for treating or preventing conditions in mammals by degrading target proteins (such as androgen receptors, AR) that bind to target ligands, including administering a therapeutically effective amount of the aforementioned compound of this application, its stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, to a mammal (preferably a human) requiring such treatment.

[0190] This application relates to methods for treating or preventing conditions by binding to cerebellar proteins in vivo, including administering a therapeutically effective amount of the aforementioned compound of this application, its stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, to a mammal (preferably a human) in need of such treatment.

[0191] On the other hand, this application relates to a method for treating mammals with AR-related diseases, including administering a therapeutically effective amount of the above-mentioned compound of this application, its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal (preferably a human) in need of such treatment.

[0192] On the other hand, this application relates to the aforementioned compounds, their stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the prevention or treatment of conditions that are treated by degrading target proteins (such as androgen receptors, AR) that bind to target ligands.

[0193] On the other hand, this application relates to the aforementioned compounds, their stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the prevention or treatment of conditions that are treated by binding to cerebellar proteins in the body.

[0194] On the other hand, this application relates to the above-mentioned compounds, their stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the prevention or treatment of AR-related diseases.

[0195] On the other hand, this application relates to the use of the aforementioned compounds, their stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the prevention or treatment of conditions that are treated by degrading target proteins (such as androgen receptors, AR) that bind to target ligands.

[0196] On the other hand, this application relates to the use of the aforementioned compounds, their stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the prevention or treatment of conditions that are treated by binding to cerebellar proteins in vivo.

[0197] On the other hand, this application relates to the use of the above-mentioned compounds, their stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the prevention or treatment of AR-related diseases.

[0198] Furthermore, the compound, its stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, may optionally be used in combination with one or more other drugs.

[0199] Furthermore, this application relates to the use of the aforementioned compounds, their stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of one or more other drugs for the prevention or treatment of AR-related diseases.

[0200] Furthermore, this application relates to the use of the aforementioned compounds, their stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of a treatment for the prevention or treatment of AR-related diseases, wherein the compounds, their stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof are used in combination with one or more other drugs.

[0201] In another aspect, this application relates to the use of the above-mentioned compounds, their stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of a preventive or therapeutic treatment for AR-related diseases, wherein the preventive or therapeutic treatment includes use in combination with one or more other drugs.

[0202] In some specific embodiments, the aforementioned AR-related diseases are selected from conditions treated by degrading and / or inhibiting proteins (androgen receptors, AR) that bind to AR target protein ligands. In some specific embodiments, the aforementioned AR-related diseases are selected from conditions treated by binding to cerebellar proteins in vivo. In some embodiments, the aforementioned diseases or conditions are selected from cancers, such as prostate cancer.

[0203] In some specific embodiments, the conditions treated by binding to cerebellar proteins in vivo and / or by degrading target proteins bound to target ligands are selected from AR-related diseases. In some specific embodiments, the AR-related diseases are selected from cancers, such as prostate cancer.

[0204] The compounds mentioned above in this application, or the compounds described herein, include compounds of general formulas, specific compounds, or compounds of embodiments.

[0205] In this document, "one or more" refers to an integer from one to ten. For example, "one or more" means one, two, three, four, five, six, seven, eight, nine, or ten; in some embodiments, "one or more" is selected from one, two, three, four, five, or six. In some embodiments, "one or more" is selected from one, two, or three. In some embodiments, "one or more" is selected from one or two.

[0206] In some embodiments, this application includes the variables defined above and their implementation schemes, as well as any combination thereof.

[0207] Technical effect The compounds of this application have protein degradation activity against AR or its mutants and antiproliferative activity against related cells, such as degradation activity against VCaP cell AR, and / or MDA-PCA-2B cell AR (including its L702H and / or T878A mutation), 22RV1 cell AR (including its H875Y and / or ARV7 mutation), HEK293 cell AR (including its L702H mutation), and / or LNCaP cell AR (including its T878A mutation); and antiproliferative activity against VCaP cells, and / or LNCaP cells (including its T878A mutation), and / or 22RV1 cells (including its H875Y and / or ARV7 mutation), and / or MDA-PCA-2B cells (including its L702H and / or T878A mutation), and / or HEK293 cells (including its L702H mutation). Furthermore, the compounds of this application also exhibit good in vitro liver microsomal stability and in vivo pharmacokinetic properties in mammals (e.g., mice) (specifically, AUC, t). 1 / 2 (and other parameters), it can inhibit tumor growth in vivo, showing promise as a drug.

[0208] definition Unless otherwise stated, the following terms as used in this application have the following meanings. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0209] Unless otherwise specified, Used to represent Hydrogen atoms at any position of a group can be replaced by a group connected by a hyphen ("-").

[0210] The term "substitution" refers to the substitution of one or more hydrogen atoms on a specific atom by a substituent, provided that the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted; oxo substitution does not occur on aromatic groups.

[0211] The terms “optional” or “optionally” mean that the event or condition subsequently described may or may not occur, including both the occurrence and non-occurrence of said event or condition. “Optionally substituted” includes both unsubstituted and substituted forms; for example, an ethyl group “optionally” substituted with a halogen means that the ethyl group can be unsubstituted (CH2CH3), monosubstituted (e.g., CH2CH2F), polysubstituted (e.g., CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible and / or cannot be synthesized is introduced.

[0212] C in this article m-n This means that the part has an integer number of carbon atoms within a given range. For example, "C 1-6 "" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.

[0213] When any variable (such as R) appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group contains two Rs, then each R has an independent option.

[0214] When a bond cross-bonds two atoms in a ring (including monocyclic, fused, or spirocyclic rings), this bond can bond with any atom in the ring (including monocyclic, fused, or spirocyclic rings). For example, structural units. This indicates that the bonds on both sides can be connected to any two different atoms in ring A, ring B, or ring C; for example... This indicates that the bonds on both sides can be connected to any two different atoms on ring A, the middle benzene ring, or ring C; further for example... This indicates that the bonds on both sides can be connected to any two different atoms in the four rings of the system.

[0215] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine. The term "hydroxyl" refers to the -OH group. The term "amino" refers to the -NH2 group. The term "cyano" refers to the -CN group.

[0216] The term "alkyl" refers to a compound with the general formula C10. n H 2n+1The alkyl group is a hydrocarbon group. This alkyl group can be straight-chain or branched. For example, the term "C1-6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio groups has the same definition as above.

[0217] 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 "C1-6 alkylene" refers to an alkylene containing 1 to 6 carbon atoms; the term "C1-4 alkylene" refers to an alkylene containing 1 to 4 carbon atoms, including but not limited to -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-.

[0218] The term "alkenyl" refers to a divalent group formed by removing a hydrogen atom from any position of an alkenyl group. For example, the term "C2-6 alkenyl" refers to an alkenyl group containing 2 to 6 carbon atoms; the term "C2-4 alkenyl" refers to an alkenyl group containing 2 to 4 carbon atoms, including but not limited to -CH2CH=CH-, -CH2CH2CH=CH-, or -CH2CH=CHCH2-.

[0219] The term "acetylenol" refers to a divalent group formed by removing a hydrogen atom from any position of an acetylenic group. For example, the term "C2-6 acetylenol" refers to an acetylenol containing 2 to 6 carbon atoms; the term "C2-4 acetylenol" refers to an acetylenol containing 2 to 4 carbon atoms, including but not limited to... , , or .

[0220] The term "heteroalkyl" refers to a straight-chain or branched alkyl group composed of a certain number of carbon atoms and at least one heteroatom, preferably having 1 to 14 carbon atoms in the chain, more preferably 1 to 10 carbon atoms, even more preferably 1 to 6 carbon atoms, most preferably 1 to 3 carbon atoms, and preferably having 1, 2, or 3 heteroatoms selected from S, O, and N. For example, C mA heteroalkyl group is defined as an alkyl group with heteroatoms inserted into 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 heterogroup can be located at any internal position of the heteroalkyl group, including positions where the hydrocarbon group is attached to the rest of the molecule. Exemplary heteroalkyl groups include alkyl ethers, secondary and tertiary alkylamines, amides, alkyl sulfides, etc., including alkoxy, alkylthio, and alkylamino groups; unless otherwise specified, C 1-6 Heteroalkyl groups include C1, C2, C3, C4, C5, and C6 heteroalkyl groups, such as C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino.

[0221] The term "heteroalkylene" refers to a divalent group formed by removing a hydrogen atom from any position of a heteroalkyl group.

[0222] The term "alkoxy" refers to -O-alkyl.

[0223] The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one double bond. Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, etc.

[0224] The term "cycloalkenyl" refers to a non-aromatic carbon ring that is not fully saturated and may exist as a monocyclic, bicyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 4- to 16-membered, 4- to 12-membered, 4- to 10-membered, or 4- to 8-membered ring. Non-limiting examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, and cycloheptadienyl.

[0225] The term "cycloalkyl" refers to a fully saturated carbon ring that may exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 3- to 16-membered ring (e.g., a 3- to 10-membered ring, or a 5- to 8-membered ring). Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, etc.

[0226] The term "heterocyclic alkyl" refers to a fully saturated cyclic group that may exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3- to 16-membered ring, a 3- to 11-membered ring, a 3- to 10-membered ring, a 3- to 7-membered ring, a 3- to 6-membered ring, or a 3- to 5-membered ring containing 1 to 3 heteroatoms independently selected from sulfur, oxygen, and / or nitrogen (preferably 1 or 2 heteroatoms). Examples of 3-membered heterocyclic alkyl groups include, but are not limited to, ethylene oxide, cyclothioethylene, and cycloazoethylene; non-limiting examples of 4-membered heterocyclic alkyl groups include, but are not limited to, acridine, oxadiazolyl, and thiobutyl; examples of 5-membered heterocyclic alkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, imidazolyl, and tetrahydropyrazolyl; examples of 6-membered heterocyclic alkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, morpholinyl, piperazine, 1,4-thiaoxane, 1,4-dioxane, thiomorpholinyl, 1,3-dithiaalkyl, and 1,4-dithiaalkyl; and examples of 7-membered heterocyclic alkyl groups include, but are not limited to, azirheptanyl, oxeheptanyl, and thioheptanyl. Monocyclic heterocyclic alkyl groups having 5 or 6 ring atoms are preferred.

[0227] The term "spirocyclic ring" refers to a fully saturated or partially unsaturated polycyclic system in which the individual rings share a single carbon atom (called a spiro atom), including carbon rings and heterocyclic rings. Unless otherwise indicated, the spirocyclic ring is 5 to 20 rings, preferably 6 to 14 rings, and more preferably 8 to 12 rings. When the spirocyclic ring is a heterocyclic ring, one or more ring atoms in the polycyclic ring are selected from N, O, and S(O). n P(O) n (where n is 0, 1 or 2) heteroatoms (preferably 1 or 2 heteroatoms), and the remaining ring atoms are carbon atoms.

[0228] The term "spirocycloalkyl" refers to a fully saturated polycyclic aromatic hydrocarbon sharing a single carbon atom (called a spiro atom) between its rings. Unless otherwise indicated, the spirocycloalkyl group is 5 to 20 quinary members, preferably 6 to 14 quinary members, and more preferably 8 to 12 quinary members. Spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups according to the number of spiro atoms shared between the rings, preferably monospirocycloalkyl and bispirocycloalkyl, more preferably 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups include... , , and .

[0229] The term "spiroheteroalkyl" refers to a fully saturated polycyclic ring in which one or more ring atoms are selected from N, O, and S(O). n P(O) n(where n is 0, 1, or 2) heteroatoms (preferably 1 or 2 heteroatoms), with the remaining ring atoms being carbon atoms. Unless otherwise indicated, the spiroheteroalkyl group is 5 to 20 quinary, preferably 6 to 14 quinary, and more preferably 6 to 10 quinary. Spiroheterocycles are classified into monospiroheterocycles, bispiroheterocycles, or multispiroheterocycles according to the number of shared spiro atoms between rings, preferably monospiroheterocycles or bispiroheterocycles, more preferably 4-quinary / 4-quinary, 4-quinary / 5-quinary, 4-quinary / 6-quinary, 5-quinary / 5-quinary, or 5-quinary / 6-quinary monospiroheterocycles. Non-limiting examples of spiroheteroalkyl groups include , , , , or wait.

[0230] The term "heterocyclic alkenyl" includes cycloalkenyl groups in which one or more carbon atoms (e.g., 1-5, 1-4, 1-3, 1-2) are substituted with heteroatoms, specifically, for example, cycloalkenyl groups in which at most 3 carbon atoms, at most 2 carbon atoms in one embodiment, or in another embodiment, 1 carbon atom is independently substituted with O, S, S(O), or N, provided that at least one cycloalkenyl carbon-carbon double bond is retained. Cyclic groups that can exist as monocyclic, bridged, or spirocyclic groups can be 3 to 16-membered rings (e.g., 3 to 12-membered, 5 to 8-membered rings, specifically 5-, 6-, 7-, 8-, 9-, 10-, or 11-membered rings). Examples of heterocyclic alkenyl groups include, but are not limited to, dihydropyrroleyl, tetrahydropyridyl, tetrahydroazapyryl, or azaspirooctene.

[0231] The term "aryl" refers to an aromatic ring group consisting of an all-carbon monocyclic or fused polycyclic ring with a conjugated π-electron system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracene, and 1,2,3,4-tetrahydronaphthalene.

[0232] The term "heteroaryl" refers to a monocyclic or fused polycyclic system containing at least one (e.g., 1-5, 1-4, 1-3, 1-2) ring atoms selected from N, O, and S, with the remaining ring atoms being C, and having at least one aromatic ring. Preferred heteroaryls have a single 4- to 8-membered ring, particularly a 5- to 8-membered ring (e.g., 5-, 6-, 7-, or 8-membered), or multiple fused rings containing 6 to 14, particularly 6 to 10 (e.g., 6, 7, 8, 9, or 10) ring atoms. Non-limiting examples of heteroaryls include, but are not limited to, pyrroleyl, furanyl, thiopheneyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothiopheneyl, indoleyl, isoindoleyl, etc.

[0233] Unless otherwise specified, the term "heteroatom" means heteroatom or heterogroup (i.e., a group containing heteroatoms), including atoms other than carbon (C) and hydrogen (H) and groups containing such heteroatoms, such as 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)-.

[0234] The term "derivative" refers to a new compound or group of new compounds that retain the basic structure of the parent compound after one or more chemical reactions or structural evolution, but are modified only in the side chain, functional group or substituent.

[0235] The substitution or substituent substitution in the terms "substituent," "optionally substituted by one or more substituents," or "optionally substituted" includes all substituents mentioned in the context of this document, and can be, for example, the terms "halogen," "deuterium," etc., mentioned below. "-NH2", "-NH(C" 1-4 Alkyl group), -N(C) 1-4 Alkyl group 2", "-OH", "-OC" 1-4 Alkyl group, -CN, C 1-4"alkyl", "3-6 membered heterocyclic alkyl", etc., and corresponding non-limiting or exemplary groups, wherein some non-limiting examples of the "substituent" include mercapto, nitro, nitroso, cyano, azide, sulfoxide, sulfone, sulfonamide, carboxyl, aldehyde, imine, alkyl, halo-alkyl, cycloalkyl, halo-cycloalkyl, alkenyl, halo-alkenyl, cycloalkenyl, halo-cycloalkenyl, alkynyl, halo-alkynyl, cycloalkynyl, halo-cycloalkynyl, heteroalkyl, halo-heteroalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, arylalkylene, arylalkoxy, arylalkylthio, heteroaryl The substituents include heteroaryloxy, heteroarylthio, heteroarylalkylene, heteroarylalkoxy, heteroarylalkylthio, heterocyclic, heterocyclicoxy, heterocyclicthio, heterocyclicalkylene, heterocyclicalkoxy, heterocyclicalkylthio, acyl, acyloxy, carbamate group, amide group, urea group, epoxy group, ester group, and oxo, wherein the substituents are optionally substituted by one or more substituents selected from: oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, - OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclic, heterocyclic alkylene, heterocyclic oxy, heterocyclic alkyl, heterocyclic alkylalkylene, heterocyclic alkyloxy, heterocyclic alkyl, heterocyclic alkyloxy, heterocyclic alkyloxy, heteroaryl, heteroaryl alkylene, heteroaryloxy, aryl, aryl alkylene or aryloxy.

[0236] In some embodiments herein, the substituents are selected from deuterium, tritium, hydroxyl, mercapto, halogen, amino, nitro, nitroso, cyano, azide, sulfoxide, sulfone, sulfonamide, carboxyl, aldehyde, imine, C 1-12 Alkyl, Halogenated -C 1-12 Alkyl, 3-12 membered cycloalkyl, halo-3-12 membered cycloalkyl, C 2-12 alkenyl, halogenated -C 2-12 alkenyl, 3-12-membered cycloalkenyl, halo-3-12-membered cycloalkenyl, C 2-12 Alkyne group, halogenated -C 2-12 Alkynyl, 8-12 membered cycloalkynyl, halogenated-8-12 membered cycloalkynyl, C 1-12 Heteroalkyl, halogenated-C 1-12 Heteroalkyl, C 1-12 Alkoxy, C 1-12Alkylthio, 6-10 aryl, 6-10 aryloxy, 6-10 arylthio, 6-10 arylC 1-12 Alkylene, 6-10 aryl C 1-12 Alkoxy, 6-10 aryl C 1-12 Alkylthio, 5-10 heteroaryl, 5-10 heteroaryloxy, 5-10 heteroarylthio, 5-10 heteroarylalkylene, 5-10 heteroarylalkoxy, 5-10 heteroarylalkylthio, 3-12 heterocyclic, 3-12 heterocyclic oxy, 3-12 heterocyclic thio, 3-12 heterocyclic C 1-12 Alkylene, 3-12 membered heterocyclic C 1-12 Alkoxy, 3-12 membered heterocyclic C 1-12 Alkylthio, C 1-12 Acyl group, C 1-12 Acyloxy group, carbamate group, C 1-12 Amide group, urea group, epoxy group, C 2-12 The ester group and oxo group, wherein the substituent is optionally substituted by one or more substituents selected from: oxo, hydroxy, amino, nitro, halogen, cyano, C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 1-12 Alkylamino, diC 1-12 Alkylamino, halogenated C 1-12 Alkylamino, Halogenated diC 1-12 Alkylamino, carboxyl, -C(O)OC 1-12 Alkyl, -OC(O)-C 1-12 Alkyl group, -C(O)NH2, -C(O)NH-C 1-12 Alkyl, -C(O)N(C) 1-12 Alkyl)2、-NHC(O)-C 1-12 Alkyl, -C(O)-C 1-12 Alkyl, -S(O)-C 1-12 Alkyl, -S(O)2-C 1-12 Alkyl group, -S(O)2NH2, -S(O)2NH-C 1-12 Alkyl group, -S(O)2N(C) 1-12 Alkyl) 2, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12 Alkylene, 3-12 membered cycloalkyloxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group C 1-12 Alkylene, 3-12-membered heterocyclic oxy group, 3-12-membered heterocyclic alkyl group, 3-12-membered heterocyclic alkyl group C 1-12Alkylene, 3-12-membered heterocyclic alkyloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryl C 1-12 alkylene, 5-10 heteroaryloxy, 6-10 aryl, 6-10 aryl C 1-12 Alkylene or 6-10 aryloxy groups.

[0237] Unless otherwise specified, the term "heteroatom" means heteroatom or heterogroup (i.e., a group containing heteroatoms), including atoms other than carbon (C) and hydrogen (H) and groups containing such heteroatoms, such as heteroatoms including but not limited to oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), silicon (Si), germanium (Ge), aluminum (Al), and boron (B), and specific heteroatoms or heterogroups such as: -O-, -S-, -N=, =O, =S, -P(=O)-, -P(=O)2-, -P(=O)O-, -P(=O)2O-, -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, and optionally substituted -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)- or -S(=O)N(H)-. Preferably, the term "heterogeneous" means that the heteroatom or heteroatomic group (i.e., a group containing a heteroatom) is selected from oxygen, nitrogen, or sulfur.

[0238] In this application, wavy lines are used ( ) represents one of the absolute configurations of a solid center (e.g. or one, specific express or ) or one of the relative configurations (e.g. express or When the compounds described herein contain alkene double bonds or other geometrically asymmetric centers, unless otherwise specified, they include... E、Z Geometric isomers. Similarly, all tautomer forms are included within the scope of this application.

[0239] Groups or structural fragments in this application, such as -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -、-Cy 1 -Cy 2 -LNK 2 -、LNK、Cy 1 Cy 2 -Cy 1 -LNK-Cy 2 -、-Cy 1-LNK- or -LNK-Cy 2 - and its specific options, optionally read in a left-to-right order, are respectively connected to the left and right groups of the group or fragment in the general formula, for example, in L selected from -Cy 1 -LNK- when Cy 1 Selected from Following the reading order from left to right, Cy 1 The left side and the corresponding segment on the left side of the general formula Connect, right side and right side fragment Connect, and the resulting fragment is Optionally, groups or structural fragments in this application, such as -LNK, may be used. 1 -Cy 1 -LNK-Cy 2 -LNK 2 -、-Cy 1 -Cy 2 - LNK 2 -、LNK、Cy 1 Cy 2 -Cy 1 -LNK-Cy 2 -、-Cy 1 -LNK- or -LNK-Cy 2 - and its specific options, can be read from right to left, corresponding to the left and right groups of the group or fragment in the general formula, for example, L is selected from -Cy 1 -LNK- when Cy 1 Selected from Following the reading order from right to left, Cy 1 The right side corresponds to the left side of the general formula. Connect the left side to the corresponding right side segment in the general formula. The segments formed by the connection are Other groups are the same as described above.

[0240] The term “treatment” means administering the compound or formulation described in this application to improve or eliminate a disease or one or more symptoms associated with the disease, and includes: (i) suppressing the disease or disease state, i.e., curbing its development; (ii) alleviating the disease or disease state, even if the disease or disease state subsides.

[0241] The term “prevention” means administering the compound or formulation described in this application to prevent a disease or one or more symptoms associated with the disease, including: preventing the occurrence of a disease or disease state in mammals, particularly when such mammals are susceptible to the disease state but have not yet been diagnosed with the disease state.

[0242] The term "therapeutic effective amount" means (i) the amount of the compound of this application used to treat or prevent a particular disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of this application constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and this disclosure.

[0243] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0244] As pharmaceutically acceptable salts, for example, metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, and salts formed with basic or acidic amino acids may be mentioned.

[0245] The term "pharmaceutical composition" refers to a mixture of one or more compounds of this application or their salts with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compounds of this application to an organism.

[0246] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0247] The word “comprise” or “comprise” and its English variants such as comprises or comprising should be understood in an open, non-exclusive sense, meaning “including but not limited to”.

[0248] Unless the context clearly indicates otherwise, singular terms in this document encompass the plural referents, and vice versa. Similarly, unless the context clearly indicates otherwise, the word "or" in this document is intended to include "and".

[0249] Unless otherwise stated, all figures used herein to indicate the amount of components, measurements, or reaction conditions should be understood to be modified by the term "about" in all cases. When used with percentages, the term "about" may mean, for example, ±1%, preferably ±0.5%, more preferably ±0.1%.

[0250] The compounds and intermediates of this application may also exist in different tautomer forms, and all such forms are included within the scope of this application. The terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can interconvert via low-barrier transitions. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. A specific example of a proton tautomer is the imidazole moiety, where a proton can migrate between two ring nitrogens. Valence tautomers include interconversions via the recombination of some bonding electrons. Specifically, any compound of this disclosure, such as pyrazole alone or as part of a heterocyclic group, may exist in any tautomer form or a mixture of any number of two tautomers, i.e. ,or This disclosure includes all possible tautomers of the compounds disclosed herein, as a single tautomer, or any mixture of said tautomers in any proportion.

[0251] This application also includes compounds of this application that are identical to those described herein, but with one or more atoms replaced by isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.

[0252] Certain isotope-labeled compounds of this application (e.g., using...) 3 H and 14 Those labeled with C can be used in the analysis of compound and / or substrate tissue distribution. Tritiumization (i.e. 3 H) and carbon-14 (i.e. 14C) Isotopes are particularly preferred due to their ease of preparation and detectability. Positron-emitting isotopes, such as... 15 O、 13 N、 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. The isotopically labeled compounds of this application can typically be prepared by replacing the unlabeled reagent with an isotopically labeled reagent using a procedure similar to those disclosed in the schemes and / or examples below.

[0253] In addition, heavier isotopes (such as deuterium) are used. 2 H)) substitution can provide certain therapeutic advantages resulting from higher metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and may therefore be preferred in certain situations, where deuterium substitution can be partial or complete, with partial deuterium substitution referring to at least one hydrogen being replaced by at least one deuterium.

[0254] The compounds of this application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include enantiomers and diastereomers. The compounds containing asymmetric carbon atoms of this application can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized using chiral starting materials or chiral reagents.

[0255] The compounds described in this application are generally present in solid form, which may be crystalline or amorphous. The crystalline compounds of this application can be prepared using methods well-known in the art, such as recrystallization. The amorphous compounds of this application can be prepared using methods well-known in the art, such as spray drying.

[0256] The pharmaceutical compositions of this application can be prepared by combining the compounds of this application with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols.

[0257] Typical routes of administration for the compounds of this application or their pharmaceutically acceptable salts or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0258] The pharmaceutical composition of this application can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, sugar-coated pill making, grinding, emulsification, freeze drying, etc.

[0259] 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 this application to be formulated into tablets, pills, lozenges, sugar-coated tablets, capsules, liquids, gels, pastes, suspensions, etc., for oral administration to patients.

[0260] Solid oral compositions can be prepared using conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or sugar-coated formulation. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0261] The pharmaceutical composition may also be suitable for parenteral administration, such as in suitable unit dosage forms of sterile solutions, suspensions or lyophilized products.

[0262] In all methods of administration of the compounds of general formula I described herein, the daily dose is from 0.01 to 200 mg / kg body weight, in the form of single or separate doses.

[0263] The compounds of this application can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of this application.

[0264] The chemical reactions in the specific embodiments of this application are carried out in a suitable solvent, which must be suitable for the chemical changes and the reagents and materials required in this application. In order to obtain the compounds of this application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction process based on existing embodiments.

[0265] An important consideration in synthetic route planning in this field is selecting appropriate protecting groups for reactive functional groups (such as amino groups in this application). For example, see Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc. In some implementations, when L is -Cy 1 When -LNK- is used, the compound of formula I-2 of this application can be prepared by those skilled in the art of organic synthesis using the following intermediates or their salts via the following route:

[0266]

[0267]

[0268]

[0269] Among them, rings A, B, C, F, and R 1 n, R 2 m, R 3 p, R 4 , q, X 5 X 6 Cy 1 The LNK definition is as described in this application; R x Selected from leaving groups, such as halogens (fluorine, chlorine, bromine, or iodine); R p Selected from protecting groups, such as Boc.

[0270] This application uses the following abbreviations: DMSO represents dimethyl sulfoxide; DMF represents N,N-dimethylformamide; MeOH represents methanol; IBX represents 2-iodobenzoic acid; DIPEA represents N,N'-diisopropylethylamine; HATU represents 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; DCE represents dichloroethane; iPrOH represents isopropanol; Boc represents tert-butyloxycarbonyl; DC 50 Dmax represents the drug concentration at which the degradation rate reaches 50%; Dmax represents the maximum degradation rate.

[0271] For clarity, the invention is further illustrated by examples, but these examples are not intended to limit the scope of this application. All reagents used in this application are commercially available and can be used without further purification. Detailed Implementation

[0272] Example 1: Synthesis of Compound 1

[0273] Step 1: Preparation of intermediate 1b Intermediate 1a (10 g), 4-piperidinemethanol (8.97 g), DMSO (100 mL), and DIPEA (16.77 g) were added sequentially to a single-necked flask, and the mixture was heated to 90°C. oC. After the reaction was complete, 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 again with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The solution was then purified by silica gel column chromatography to obtain intermediate 1b (10.03 g). MS (ESI, [M+H)) + ) m / z 250.2 Step 2: Preparation of intermediate 1c Add intermediate 1b (2.7 g), MeOH (40 mL), water (5 mL), and sodium hydroxide (1.24 g) sequentially to a single-necked flask, and heat the mixture to 50°C. o C. After the reaction was complete, the reaction solution was cooled to room temperature. 3N dilute hydrochloric acid was added to adjust the pH to weakly acidic. The solvent was removed by vacuum distillation. Methanol was added to the concentrate to dissolve the product. The mixture was filtered, and the filtrate was collected. The solvent was removed by vacuum distillation to obtain intermediate 1c (1.82 g). MS (ESI, [MH]) - ) m / z 234.1 Step 3: Preparation of intermediate 1d Intermediate 1c (235 mg), intermediate 2d (175 mg), DMF (5 mL), DIPEA (0.562 mL), and HATU (321 mg) were added sequentially to a single-necked flask, and the mixture was reacted at room temperature. After the reaction was complete, ethyl acetate and water were added to the system for extraction. The organic phase was separated, and the 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 removed by vacuum distillation. The purified intermediate 1d (0.22 g) was obtained by silica gel column chromatography. MS (ESI, [M+H)) + ) m / z 492.1 Step 4: Preparation of intermediate 1e 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 the reaction was complete, the system was extracted with ethyl acetate and a saturated sodium bicarbonate aqueous solution. The organic phase was separated, and the aqueous phase was extracted again with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain intermediate 1e (190 mg).

[0274] Step 5: Preparation of Compound 1 Intermediate 1e (200 mg), intermediate z1 (131 mg) (synthetic route referred to Example 19 of WO2023088406), DCE / iPrOH=5 / 1 (5 mL), sodium acetate (35.4 mg), and sodium triacetoxyborohydride (268 mg) were added sequentially to a single-necked flask, and the mixture was reacted at room temperature. After the reaction was completed, the solvent was removed by vacuum distillation, and the mixture was purified by silica gel column chromatography to obtain compound 1 (128 mg).

[0275] MS(ESI, [M+H)) + ) m / z : 759.6. 1 H NMR (500 MHz, DMSO- d 6) δ 11.08 (s, 1H), 7.74 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 8.6 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.48 (d, J =9.2 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 6.96 (d, J = 8.6 Hz, 2H), 6.64 (d, J = 2.2Hz, 1H), 6.54 (dd, J = 8.6, 2.2 Hz, 1H), 4.56 (dd, J = 11.9, 5.0 Hz, 1H), 4.27(s, 1H), 4.05 (d, J = 9.1 Hz, 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, 4.3 Hz, 1H), 2.49 – 2.44 (m,1H), 2.40 (d, J = 7.1 Hz, 2H), 2.19 (dq, J = 13.8, 4.8 Hz, 1H), 1.95 – 1.79 (m,3H), 1.22 (s, 8H), 1.15 (s, 6H). Example 2: Synthesis of Compound 2

[0276] Step 1: Preparation of intermediate 2c Intermediate 2a (6 g) and DMF (30 mL) were added sequentially to a reaction flask. Sodium hydride (1.479 g) was added under ice bath conditions, and the mixture was stirred for 20 min in an ice bath. Intermediate 2b (4.47 g) was then added, and the mixture was allowed to react at room temperature. After the reaction was complete, the reaction solution was slowly poured into 300 mL of ice water to quench the reaction. The mixture was filtered to obtain a filter cake, which was then dried to obtain intermediate 2c (8.9 g). MS (ESI, [M+H)) + ) m / z : 275.42. 1 H NMR (500 MHz, DMSO- d 6) δ 7.62 (d, J = 8.6 Hz, 1H), 6.65(d, J = 9.5 Hz, 1H), 6.60 (d, J = 2.2 Hz, 1H), 6.50 (dd, J = 8.7, 2.3 Hz, 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). Step 2: Preparation of intermediate 2d Intermediate 2c (8.9 g) and dioxane hydrochloride solution (59.4 mL) were added sequentially to a single-necked flask, and the mixture was reacted at room temperature. After the reaction was complete, the solvent was removed by vacuum evaporation, and the mixture was dried under vacuum to obtain intermediate 2d (8.2 g). MS (ESI, [M+H]) + ) m / z :275.21. 1 H NMR (500 MHz, DMSO- d 6) δ 8.47 (d, J = 6.3 Hz, 3H), 7.64 (d, J = 8.6Hz, 1H), 6.63 (d, J = 2.3 Hz, 1H), 6.53 (dd, J = 8.7, 2.3 Hz, 1H), 4.31 (s, 1H), 3.90 (s, 3H), 3.06 (q, J= 6.0 Hz, 1H), 1.32 (s, 6H), 1.11 (s, 6H). Step 3: Preparation of 2g of intermediate Add intermediate 2e (2 g), intermediate 2f (1.782 g), DMF (20 mL), and potassium carbonate (5.35 g) sequentially to a single-necked flask, and heat the mixture to 110°C. o C. After the reaction was complete, 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 again with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The solution was then purified by silica gel column chromatography to give 2 g (0.72 g) of the intermediate. MS (ESI, [M+H)) + ) m / z :251.0. 1 H NMR (500 MHz, DMSO- d 6) δ 8.36 (d, J = 3.0 Hz, 1H), 7.84 (d, J = 8.9Hz, 1H), 7.31 (dd, J = 8.9, 3.1 Hz, 1H), 4.49 (t, J = 5.3 Hz, 1H), 4.02 – 3.95 (m, 2H), 3.79 (s, 3H), 3.30 – 3.24 (m, 2H), 2.86 (td, J = 12.7, 2.8 Hz, 2H), 1.81 – 1.71 (m, 2H), 1.69 – 1.56 (m, 1H), 1.25 – 1.12 (m, 2H). Step 4: Preparation of intermediates over 2 hours Referring to the preparation process of intermediate 1c in step 2 of Example 1, intermediate 2g replaced intermediate 1b, and intermediate 2h (0.86g) was prepared by reaction.

[0277] MS(ESI, [M+H)) + ) m / z : 237.23. 1 H NMR (500 MHz, DMSO- d 6) δ 8.30 (d, J = 3.0 Hz, 1H), 8.03 (d, J = 9.1 Hz, 1H), 7.75 (dd,J = 9.2, 2.9 Hz, 1H), 4.06 (dt, J = 13.4, 3.4 Hz, 2H), 3.28 (d, J = 6.2 Hz, 2H), 3.00 (td, J = 12.6, 2.6 Hz, 2H), 1.83 –1.73 (m, 2H), 1.68 (tq, J = 11.4, 3.5 Hz, 1H), 1.21 (qd, J = 12.5, 4.1 Hz, 2H). Step 5: Preparation of intermediate 2i Referring to the preparation process of intermediate 1d in step 3 of Example 1, intermediate 2h replaced intermediate 1c, and the reaction was carried out to prepare intermediate 2i (0.25g).

[0278] MS(ESI, [M+H)) + ) m / z : 493.44. 1 H NMR (500 MHz, DMSO- d 6) δ 8.33 (d, J = 2.9 Hz, 1H), 8.09 (d, J = 9.1 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.41 (dd, J = 8.9, 2.9 Hz, 1H), 6.67 (d, J = 2.2 Hz, 1H), 6.57 (dd, J = 8.7, 2.2Hz, 1H), 4.49 (t, J = 5.3 Hz, 1H), 4.37 (s, 1H), 3.99 – 3.93 (m, 3H), 3.91 (s,3H), 3.28 (t, J = 5.7 Hz, 2H), 2.85 (td, J = 12.6, 2.7 Hz, 2H), 2.69 (s, 1H), 1.74 (dd, J = 13.7, 3.6 Hz, 2H), 1.62 (dtd, J= 14.1, 7.7, 3.4 Hz, 1H), 1.23 (d, J = 8.7 Hz, 1H), 1.20 (s, 6H), 1.15 (s, 6H). Step 6: Preparation of intermediate 2j Referring to the preparation process of intermediate 1e in step 4 of Example 1, intermediate 2i replaced intermediate 1d, and intermediate 2j (210 mg) was prepared by reaction.

[0279] MS(ESI, [M+H)) + ) m / z 491.25 Step 7: Preparation of Compound 2 Following the preparation process of compound 1 in step 5 of Example 1, intermediate 2j replaced intermediate 1e, and compound 2 (160 mg) was prepared by reaction.

[0280] MS(ESI, [M+H)) + ) m / z : 760.01. 1 H NMR (500 MHz, DMSO- d 6) δ 11.08 (s, 1H), 8.34 (d, J = 3.0 Hz, 1H), 8.09 (d, J = 9.1 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.64(d, J = 8.6 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.42 (dd, J = 9.0, 2.9 Hz, 1H), 7.11(d, J = 8.3 Hz, 1H), 6.67 (d, J = 2.2 Hz, 1H), 6.57 (dd, J = 8.6, 2.2 Hz, 1H), 4.56(dd, J = 11.9, 5.0 Hz, 1H), 4.37 (s, 1H), 3.95 (dd, J = 10.7, 5.0 Hz, 3H), 3.91(s, 3H), 3.71 (s, 2H), 3.00 (t, J= 5.7 Hz, 2H), 2.94 – 2.85 (m, 2H), 2.82 –2.73 (m, 3H), 2.61 (dt, J = 17.2, 4.2 Hz, 1H), 2.47 (dd, J = 12.1, 4.4 Hz, 1H), 2.40 (d, J = 7.1 Hz, 2H), 2.19 (dq, J = 13.4, 4.6 Hz, 1H), 1.94 (d, J = 7.0 Hz, 1H), 1.84 (d, J = 13.0 Hz, 2H), 1.20 (s, 8H), 1.15 (s, 6H). Example 3: Synthesis of Compound 3

[0281] Step 1: Preparation of intermediate 3b Referring to step 3 of Example 2, intermediate 2g was prepared by replacing intermediate 2e with intermediate 3a to obtain intermediate 3b (2.5g).

[0282] MS(ESI, [M+H)) + ) m / z :251.31. 1 H NMR (500 MHz, DMSO- d 6) δ 8.62 (d, J = 2.3 Hz, 1H), 7.90 (dd, J = 9.0, 2.5 Hz, 1H), 6.85 (d, J = 9.1 Hz, 1H), 4.51 – 4.40 (m,3H), 3.78 (s, 3H), 3.27 (t, J = 5.7 Hz, 2H), 2.90 (td, J = 12.8, 2.6 Hz, 2H),1.77 – 1.62 (m, 3H), 1.09 (tdd, J = 12.7, 11.2, 4.3 Hz, 2H). Step 2: Preparation of intermediate 3c Referring to the preparation process of intermediate 1c in step 2 of Example 1, intermediate 1b was replaced by intermediate 3b, and intermediate 3c (0.86g) was prepared by reaction.

[0283] MS(ESI, [M+H)) + ) m / z : 237.31. 1 H NMR (500 MHz, DMSO- d 6) δ 8.41 (d, J = 2.3 Hz, 1H), 8.11 (dd, J = 9.6, 2.3 Hz, 1H), 7.31 (d, J = 9.6 Hz, 1H), 4.44 (d, J = 13.4Hz, 2H), 3.28 (d, J = 5.9 Hz, 2H), 3.24 – 3.17 (m, 2H), 1.86 – 1.71 (m, 3H), 1.30 – 1.16 (m, 2H). Step 3: Preparation of intermediate 3D Referring to the preparation process of intermediate 1d in step 3 of Example 1, intermediate 1c was replaced by intermediate 3c, and intermediate 3d (0.25g) was prepared by reaction.

[0284] MS(ESI, [M+H)) + ) m / z : 493.45. 1 H NMR (500 MHz, DMSO- d 6) δ 8.61 (d, J = 2.5 Hz, 1H), 7.93 (dd, J = 9.0, 2.6 Hz, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.58 (d, J = 9.3 Hz, 1H), 6.85 (d, J = 9.0 Hz, 1H), 6.64 (d, J = 2.2 Hz, 1H), 6.54 (dd, J = 8.6, 2.3 Hz,1H), 4.50 – 4.39 (m, 3H), 4.25 (s, 1H), 4.05 (d, J = 9.2 Hz, 1H), 3.91 (s, 3H), 3.27 (t, J = 5.7 Hz, 2H), 2.87 (td, J= 12.8, 2.6 Hz, 2H), 1.77 – 1.62 (m, 3H), 1.22 (s, 6H), 1.14 (s, 6H), 1.12 – 1.07 (m, 2H). Step 4: Preparation of intermediate 3e Following the preparation process of intermediate 1e in step 4 of Example 1, intermediate 1d was replaced with intermediate 3d, and the reaction yielded intermediate 3e (210 mg). MS (ESI, [M+H)) + ) m / z : 491.27.

[0285] Step 5: Preparation of Compound 3 Following the preparation procedure of compound 1 in step 5 of Example 1, intermediate 1e was replaced by intermediate 3e, and compound 3 (150 mg) was prepared by reaction. MS (ESI, [M+H)) + ) m / z : 759.90. 1 H NMR (500 MHz, DMSO- d 6) δ 11.08 (s, 1H), 8.62 (d, J = 2.5 Hz, 1H), 7.93 (dd, J = 9.0, 2.5 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.58 (d, J = 8.6 Hz, 2H), 7.11 (d, J = 8.3 Hz, 1H), 6.85 (d, J = 9.1 Hz, 1H), 6.64 (d, J = 2.2 Hz, 1H), 6.54 (dd, J = 8.7, 2.2 Hz, 1H), 4.56 (dd, J = 11.9, 5.0Hz, 1H), 4.42 (d, J = 13.0 Hz, 2H), 4.25 (s, 1H), 4.05 (d, J = 9.1 Hz, 1H), 3.91(s, 3H), 3.71 (s, 2H), 3.00 (t, J = 5.8 Hz, 2H), 2.93 (td, J= 13.1, 2.6 Hz, 2H),2.82 – 2.72 (m, 3H), 2.61 (dt, J = 17.3, 4.3 Hz, 1H), 2.47 (dd, J = 12.2, 4.4 Hz, 1H), 2.38 (d, J = 7.1 Hz, 2H), 2.19 (dq, J = 13.6, 4.8 Hz, 1H), 1.99 (t, J = 3.8Hz, 1H), 1.83 (d, J = 12.8 Hz, 2H), 1.22 (s, 6H), 1.14 (s, 8H). Example 4: Synthesis of Compound 4

[0286] Step 1: Preparation of intermediate 4b Referring to step 3 of Example 2, intermediate 2g was prepared by replacing intermediate 2e with intermediate 4a to obtain intermediate 4b (6.8 g).

[0287] MS(ESI, [M+H)) + ) m / z :266.2.

[0288] Step 2: Preparation of intermediate 4c Following the preparation process of intermediate 1c in step 2 of Example 1, intermediate 1b was replaced with intermediate 4b, and intermediate 4c (1.54 g) was prepared by reaction. MS (ESI, [MH]) - ) m / z :236.1.

[0289] Step 3: Preparation of intermediate 4d Following the preparation process of intermediate 1d in step 3 of Example 1, intermediate 1c was replaced with intermediate 4c, and intermediate 4d (0.26 g) was prepared by reaction. MS (ESI, [M+H) + ) m / z :494.1.

[0290] Step 4: Preparation of intermediate 4e Referring to the preparation process of intermediate 1e in step 4 of Example 1, intermediate 4d replaced intermediate 1d, and intermediate 4e (224 mg) was prepared by reaction.

[0291] Step 5: Preparation of Compound 4 Following the preparation process of compound 1 in step 5 of Example 1, intermediate 4e replaced intermediate 1e, and compound 4 (142 mg) was prepared by reaction.

[0292] MS(ESI, [M+H)) + ) m / z : 760.9. 1 H NMR (500 MHz, DMSO- d 6) δ 11.07 (s, 1H), 8.75 (s, 2H), 7.70 (d, J = 9.2 Hz, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 6.64 (d, J = 2.3 Hz, 1H), 6.54 (dd, J = 8.6, 2.2 Hz, 1H), 4.75 (d, J = 13.0 Hz, 2H), 4.56 (dd, J = 11.9, 5.0 Hz, 1H), 4.23 (s, 1H), 4.03 (d, J = 9.2 Hz, 1H), 3.91 (s, 3H), 3.71 (s, 2H), 2.99 (d, J = 11.1 Hz, 4H), 2.77 (tt, J = 11.8, 5.9 Hz, 3H), 2.61 (dt, J = 17.3, 4.3 Hz, 1H), 2.53 (s, 1H), 2.49 – 2.43 (m, 1H), 2.39 (d, J = 7.2 Hz, 2H), 2.19 (dq, J = 13.5, 4.9 Hz, 1H), 1.85 (d, J = 12.1 Hz, 2H), 1.22 (s, 6H), 1.13 (s, 8H). Example 5: Synthesis of Compound 5

[0293] Step 1: Preparation of intermediate 5b Following the preparation process of intermediate 1d in step 3 of Example 1, intermediate 1c was replaced with intermediate 5a, and intermediate 5b (0.56 g) was prepared by reaction. MS (ESI, [M+H) + ) m / z :415.4.

[0294] Step 2: Preparation of intermediate 5c Intermediate 5b (0.56 g), intermediate 2f (0.3 g), acetonitrile (20 mL), and potassium carbonate (0.55 g) were added sequentially to a single-necked flask, 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 again with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The purified intermediate 5c (0.48 g) was obtained by silica gel column chromatography. MS (ESI, [M+H)) + ) m / z :494.1.

[0295] Step 3: Preparation of intermediate 5d Referring to the preparation process of intermediate 1e in step 4 of Example 1, intermediate 5c replaced intermediate 1d, and intermediate 5d (425 mg) was prepared by reaction.

[0296] Step 4: Preparation of Compound 5 Following the preparation process of compound 1 in step 5 of Example 1, intermediate 5d replaced intermediate 1e, and compound 5 (98 mg) was prepared by reaction.

[0297] MS(ESI, [M+H)) + ) m / z :761.0. 1 H NMR (500 MHz, DMSO- d 6) δ 11.08 (s, 1H), 8.61 (d, J = 1.2 Hz, 1H), 8.33 (d, J = 1.5 Hz, 1H), 7.81 (d, J = 9.1 Hz, 1H), 7.64 (d, J =8.6 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.11 (d, J = 8.2 Hz, 1H), 6.66 (d, J = 2.3Hz, 1H), 6.56 (dd, J= 8.7, 2.3 Hz, 1H), 4.56 (dd, J = 11.9, 5.0 Hz, 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, 5.5 Hz, 3H), 2.61 (dt, J = 17.3, 4.4 Hz, 1H), 2.47 (dd, J = 12.2, 4.3 Hz, 1H), 2.40 (d, J = 7.1 Hz, 2H), 2.24 – 2.15 (m, 1H), 2.08 – 1.97 (m, 1H), 1.86 (d, J = 12.6 Hz, 2H), 1.17 (d, J = 26.2 Hz, 14H). Example 6: Synthesis of Compound 6

[0298] Step 1: Preparation of intermediate 6b Following the preparation process of intermediate 1b in step 1 of Example 1, intermediate 1a was replaced with intermediate 6a, and intermediate 6b (6.8 g) was prepared by reaction. MS (ESI, [M+H) + ) m / z :252.0.

[0299] Step 2: Preparation of intermediate 6c Following the preparation process of intermediate 1c in step 2 of Example 1, intermediate 1b was replaced with intermediate 6b, and intermediate 6c (2.62 g) was prepared by reaction. MS (ESI, [MH]) - ) m / z :236.1.

[0300] Step 3: Preparation of intermediate 6d Referring to the preparation process of intermediate 1d in step 3 of Example 1, intermediate 6c replaced intermediate 1c, and intermediate 6d (0.17g) was prepared by reaction.

[0301] MS(ESI, [M+H)) + ) m / z :494.1.

[0302] Step 4: Preparation of intermediate 6e Referring to the preparation process of intermediate 1e in step 4 of Example 1, intermediate 6d replaced intermediate 1d, and intermediate 6e (162 mg) was prepared by reaction.

[0303] Step 5: Preparation of Compound 6 Following the preparation process of compound 1 in step 5 of Example 1, intermediate 6e replaced intermediate 1e, and compound 6 (78 mg) was prepared by reaction.

[0304] MS(ESI, [M+H)) + ) m / z : 761.6. 1 H NMR (500 MHz, DMSO- d 6) δ 11.08 (s, 1H), 8.24 (d, J = 9.2 Hz, 1H), 7.82 (d, J = 9.5 Hz, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.58 (d, J =8.1 Hz, 1H), 7.37 (d, J = 9.7 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 6.67 (d, J = 2.2Hz, 1H), 6.57 (dd, J = 8.6, 2.2 Hz, 1H), 4.60 – 4.47 (m, 3H), 4.40 (s, 1H), 4.00 (d, J = 9.2 Hz, 1H), 3.91 (s, 3H), 3.72 (s, 2H), 3.11 – 2.97 (m, 4H), 2.77(dt, J = 17.3, 5.5 Hz, 3H), 2.61 (dt, J = 17.2, 4.2 Hz, 1H), 2.54 (d, J = 4.6 Hz, 1H), 2.47 (dd, J = 12.1, 4.2 Hz, 1H), 2.40 (d, J = 7.2 Hz, 2H), 2.19 (dq, J = 8.6, 4.5 Hz, 1H), 1.87 (d, J= 12.1 Hz, 2H), 1.20 (d, J = 34.9 Hz, 14H). Example 7 Synthesis of Compound 7

[0305] Step 1: Preparation of intermediate 7a 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 proceed to completion at room temperature. The reaction mixture was poured into water, extracted with ethyl acetate, and purified by silica gel column chromatography to obtain intermediate 7a (0.28 g).

[0306] MS (ESI) m / z [M+H] + :563.31.

[0307] Step 2: Preparation of intermediate 7b Intermediate 7a (0.28 g), DCM (10 mL), and 4M dioxane hydrochloride (5 mL) were mixed and reacted at room temperature until complete. The mixture was concentrated to obtain intermediate 7b (0.19 g) by MS (ESI). m / z [M+H] + :463.25.

[0308] Step 3: Preparation of Compound 7 Intermediate 7b (0.11 g), intermediate z5 (0.07 g) (synthetic route refers to intermediate 26f in WO2024037616), sodium acetate (0.04 g), and DCE / IPA (v:v=5:1) (5 mL) were mixed, and sodium triacetoxyborohydride (0.10 g) was added. The reaction was allowed to proceed to completion at room temperature. The reaction solution was concentrated and purified by silica gel column chromatography to obtain compound 7 (0.06 g).

[0309] MS (ESI) m / z [M+H] + :745.43. 1 H NMR (500 MHz, DMSO) δ 11.08 (s, 1H), 7.76(d, J = 8.6 Hz, 2H), 7.63 (dd, J = 15.6, 8.3 Hz, 2H), 7.52 (d, J = 9.2 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 6.99 (d, J= 8.9 Hz, 2H), 6.64 (d, J = 2.2 Hz, 1H), 6.54 (dd, J = 8.7, 2.2 Hz, 1H), 4.57 (ddd, J = 11.9, 5.0, 1.8 Hz, 1H), 4.27 (s, 1H), 4.06 (d, J = 9.2 Hz, 1H), 3.91 (s, 3H), 3.35 (s, 1H), 3.30 – 3.17 (m, 6H), 2.93(d, J = 13.0 Hz, 2H), 2.86 (dd, J = 16.0, 5.2 Hz, 1H), 2.77 (ddd, J = 17.2, 11.9,5.4 Hz, 1H), 2.66 – 2.54 (m, 5H), 2.41 (d, J = 7.3 Hz, 2H), 2.23 – 2.16 (m,1H), 1.23 (s, 6H), 1.15 (s, 6H). The following intermediates were synthesized using the same method as intermediate 7b:

[0310] Example 8: Synthesis of Compound 8

[0311] Intermediate 1e (0.1 g), intermediate z2 (0.08 g) (synthetic route referred to Example 1 of WO2024037616), sodium acetate (0.04 g), 1,2-dichloroethane (10 mL), and isopropanol (2 mL) were added sequentially to the reaction flask. The mixture was stirred at room temperature for 10 min, and then sodium triacetoxyborohydride (0.1 g) was added, and the reaction was carried out at room temperature for 1 h. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, washed with saturated brine, concentrated, and purified by silica gel column chromatography to obtain compound 8 (0.10 g). MS (ESI, [M+H)) + m / z: 745.41. 1 H NMR (500 MHz, DMSO) δ 11.09 (s, 1H),7.73 (dd, J = 14.9, 8.3 Hz, 3H), 7.64 (d, J = 8.6 Hz, 1H), 7.49 (d,J = 9.2 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 6.97 (d, J = 9.0 Hz, 2H), 6.64 (d, J = 2.2 Hz, 1H), 6.54 (dd, J = 8.7, 2.2 Hz, 1H), 4.60 (dd, J = 11.9, 5.0 Hz, 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, 3.9 Hz, 3H), 2.69 – 2.58 (m, 3H), 2.54 (d, J = 4.5 Hz, 1H), 2.20 (dq, J =13.6, 4.8 Hz, 1H), 1.93 – 1.85 (m, 2H), 1.81 (d, J = 3.8 Hz, 1H), 1.31 – 1.24(m, 2H), 1.23 (s, 6H), 1.15 (s, 6H). Example 9: Synthesis of Compound 9

[0312] Following the method described in Example 8, intermediate z2 was replaced with intermediate z3 (synthetic route referred to Example 3 of WO2024037616) to synthesize compound 9 (0.08 g). MS (ESI, [M+H) + m / z: 759.39. 1 H NMR (500 MHz, DMSO) δ 11.07 (s, 1H), 7.74 (d, J = 8.6 Hz, 2H), 7.64 (d, J = 8.6 Hz, 1H), 7.59(d, J = 8.1 Hz, 1H), 7.48 (d, J = 9.2 Hz, 1H), 7.15 (d, J = 8.2 Hz, 1H), 7.00 –6.93 (m, 2H), 6.64 (d, J= 2.3 Hz, 1H), 6.54 (dd, J = 8.7, 2.2 Hz, 1H), 4.56 (dd, J = 11.9, 5.0 Hz, 1H), 4.27 (s, 1H), 4.05 (d, J = 9.2 Hz, 1H), 3.91 (s, 3H), 3.86 (d, J = 12.9 Hz, 2H), 3.81 (s, 2H), 2.96 (t, J = 5.7 Hz, 2H), 2.89 – 2.72(m, 5H), 2.60 (dt, J = 17.3, 4.2 Hz, 1H), 2.48 (d, J = 4.3 Hz, 1H), 2.44 (d, J =6.9 Hz, 2H), 2.19 (dt, J = 13.2, 4.8 Hz, 1H), 1.99 – 1.80 (m, 3H), 1.22 (s, 8H), 1.14 (s, 6H). Example 10: Synthesis of Compound 10

[0313] Following the method described in Example 8, intermediate z2 was replaced with intermediate z4 (synthetic route referred to Example 5 of WO2024037616) to synthesize compound 10 (0.07 g). MS (ESI, [M+H) + m / z: 773.42. 1 H NMR (500 MHz, DMSO) δ 11.07 (s, 1H), 7.74 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.6 Hz, 1H), 7.54(d, J = 7.9 Hz, 1H), 7.49 (d, J = 9.2 Hz, 1H), 7.18 (d, J = 8.1 Hz, 1H), 7.01 –6.94 (m, 2H), 6.64 (d, J = 2.2 Hz, 1H), 6.54 (dd, J = 8.6, 2.2 Hz, 1H), 4.54 (dd,J = 11.9, 5.0 Hz, 1H), 4.27 (s, 1H), 4.05 (d, J = 9.2 Hz, 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, 5.1 Hz, 5H), 2.47 (dd, J = 12.3, 4.4 Hz, 1H), 2.34 (d, J = 6.8 Hz, 2H), 2.18 (dq, J = 13.6, 4.1 Hz, 1H), 1.83 (t, J = 14.6 Hz, 3H), 1.23 (s, 8H), 1.15 (s, 6H). The following compounds were synthesized using the same methods as compounds 7 and 8:

[0314] Example 27 Synthesis of Compound 27

[0315] Following the method described in Example 8, intermediate 1e was replaced by intermediate 3e, and intermediate z6 (synthetic route refers to Example 12 of WO2024037616) was replaced by intermediate z2 to synthesize compound 27 (0.15 g).

[0316] MS(ESI, [M+H)) + m / z: 759.33. 1 H NMR (500 MHz, DMSO) δ 10.87 (s, 1H),8.62 (d, J = 2.5 Hz, 1H), 7.93 (dd, J = 9.0, 2.5 Hz, 1H), 7.84 (s, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.58 (d, J = 9.3 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 6.96 (d,J = 8.1Hz, 1H), 6.85 (d, J = 9.0 Hz, 1H), 6.64 (d, J = 2.2 Hz, 1H), 6.54 (dd, J = 8.6, 2.2Hz, 1H), 4.42 (d, J = 13.2 Hz, 2H), 4.25 (s, 1H), 4.10 (dd, J = 11.8, 4.9 Hz, 1H), 4.05 (d, J = 9.2 Hz, 1H), 3.91 (s, 3H), 3.65 (s, 2H), 3.05 – 2.87 (m, 4H), 2.74 (tt, J = 12.0, 5.8 Hz, 3H), 2.57 (dt, J = 17.3, 4.2 Hz, 1H), 2.41 – 2.23 (m,3H), 2.11 (dq, J = 13.7, 4.8 Hz, 1H), 1.83 (d, J = 12.8 Hz, 2H), 1.18 (d, J = 41.6Hz, 14H). Example 28 Synthesis of Compound 28

[0317] Following the method described in Example 8, intermediate 1e was replaced by intermediate 3e, and intermediate z7 (synthetic route refers to Example 75 of WO2024037616) was replaced by intermediate z2 to synthesize compound 28 (0.11 g).

[0318] MS(ESI, [M+H)) + m / z: 774.43. 1 H NMR (500 MHz, DMSO) δ 10.50 (s, 1H),8.63 (d, J = 2.5 Hz, 1H), 8.05 (s, 1H), 7.94 (dd, J = 9.0, 2.5 Hz, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.58 (d, J = 9.3 Hz, 1H), 7.29 (d, J= 7.8 Hz, 1H), 7.06 (d, J = 8.0Hz, 1H), 6.86 (d, J = 9.0 Hz, 1H), 6.64 (d, J = 2.2 Hz, 1H), 6.54 (dd, J = 8.6, 2.2Hz, 1H), 4.43 (d, J = 13.0 Hz, 2H), 4.25 (s, 1H), 4.05 (d, J = 9.5 Hz, 1H), 3.91(s, 3H), 3.82 (t, J = 6.7 Hz, 2H), 3.12 (d, J = 6.1 Hz, 2H), 3.03 – 2.88 (m, 4H), 2.77 (t, J = 6.6 Hz, 2H), 2.69 – 2.56 (m, 4H), 2.32 (d, J = 6.6 Hz, 2H), 1.85 (t, J = 14.8 Hz, 3H), 1.23 (s, 6H), 1.14 (s, 6H), 1.13 – 1.05 (m, 2H). Compounds 29-36 were prepared by referring to Example 3 or Compound 14, or by the synthetic procedures disclosed in the prior art:

[0319] Experimental Example 1: The Degradation Effect of Compounds on Cellular AR 1.1 Assay of AR degradation activity in VCaP cells Detection was performed using the HTRF HUMAN ANDROGEN RECEPTOR DETECTION KIT (cisbio, 64ANDRPEG). A 4× Supplemented Lysis buffer was prepared using Blocking reagent stock solution (100×) and Lysis buffer stock solution (4×). A 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.

[0320] Collect healthy VCaP cells, wash with PBS, digest with trypsin, stop digestion with 1% CSS-FBS in phenol red-free DMEM complete medium, collect in centrifuge tubes, and adjust cell density to 5 × 10⁻⁶ cells / mL. 5 Cells were seeded at a density of 100 μL / well in 96-well plates and cultured overnight. Compounds were then added using a nanoparticle pipette, serially diluted 5-fold to a final concentration of 100 nM–0.032 nM, with two replicates. A control was also included. After culturing for 24 hours, 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 the cell lysate was added to a 384-well plate, along with 4 μL / well of Premixed antibody solutions. The plate was incubated at 25°C for 2 hours, and fluorescence was detected at 665 nm / 620 nm using an Envision microplate reader. Four-parameter analysis was performed, a dose-response curve was fitted, and DC was calculated. 50 And Dmax. The results are shown in Table 1.

[0321] Table 1. Compound activity against AR degradation in VCaP cells

[0322] Experimental results show that the compounds of this application (such as the compounds in the examples) have degradation activity against AR in VCaP cells.

[0323] 1.2 Assay of AR degradation activity in LNCaP(T878A) cells Detection was performed using the HTRF HUMAN ANDROGEN RECEPTOR DETECTION KIT (cisbio, 64ANDRPEG). A 4× Supplemented Lysis buffer was prepared using Blocking reagent stock solution (100×) and Lysis buffer stock solution (4×). A 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.

[0324] Collect LNCaP cells in good growth condition, wash with PBS, digest with trypsin, stop digestion with 2% CSS-FBS phenol red-free 1640 complete medium, collect in centrifuge tubes, and adjust cell density to 1×10⁻⁶. 6 Cells were seeded at a density of 100 μL / well in 96-well plates and cultured overnight. Compounds were then added using a nanoparticle pipette, serially diluted 2-fold to a final concentration of 500 nM–0.488 nM, with two replicates. A control was also included. After culturing for 24 hours, 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 the cell lysate was added to a 384-well plate, along with 4 μL / well of Premixed antibody solutions. The plate was incubated at 25°C for 2 hours, and fluorescence was detected at 665 nm / 620 nm using an Envision microplate reader. Four-parameter analysis was performed, a dose-response curve was fitted, and DC was calculated. 50 And Dmax. The experimental results are shown in Table 2.

[0325] Table 2. Compound activity against AR degradation in LNCaP(T878A) cells

[0326] The experimental results show that the compounds of this application (such as the compounds in the examples) have degradation activity against AR in LNCaP cells.

[0327] 1.3 Assay of AR degradation activity in MDA-PCA-2B (L702H\T878A) cells Detection was performed using the HTRF HUMAN ANDROGEN RECEPTOR DETECTION KIT (cisbio, 64ANDRPEG). A 4× Supplemented Lysis buffer was prepared using Blocking reagent stock solution (100×) and Lysis buffer stock solution (4×). A 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.

[0328] Collect MDA-PCA-2B cells in good growth condition, wash with PBS, digest with trypsin, add MDA-PCA-2B complete culture medium to stop digestion, collect in centrifuge tubes, and adjust cell density to 1×10⁻⁶. 6 Cells were seeded at a density of 100 μL / well in 96-well plates and cultured overnight. Compounds were then added using a nanoparticle pipette, serially diluted 5-fold to a final concentration of 5000 nM–1.6 nM, with two replicates. A control was also included. After culturing for 24 hours, 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 the cell lysate was added to a 384-well plate, along with 4 μL / well of Premixed antibody solutions. The plate was incubated at 25°C for 2 hours, and fluorescence was detected at 665 nm / 620 nm using an Envision microplate reader. Four-parameter analysis was performed, a dose-response curve was fitted, and DC was calculated. 50 And Dmax. The results are shown in Table 3.

[0329] Table 3

[0330] Experimental results show that the compounds of this application (such as the compounds in the examples) have degradation activity against AR in MDA-PCA-2B cells.

[0331] Experimental Example 2: In vitro cell proliferation inhibitory activity 2.1 Assay of VCaP cell proliferation inhibitory activity Collect healthy VCaP cells, wash with PBS, digest with trypsin, stop digestion with 5% CSS-FBS in phenol red-free DMEM complete medium, collect in centrifuge tubes, and adjust cell density to 1×10⁻⁶. 5 The compound was seeded at a concentration of 100 μL / well in 96-well plates using a nanoparticle pipette. The compound was serially diluted 2-fold to a final concentration of 1000 nM - 0.061 nM and 5000 nM - 0.305 nM, with two replicates. A control was also included. After culturing for 168 hours, the assay reagent CCK-8 (Dojindo, 10 μL / well) was added. After incubation for 7.0 hours, the absorbance was measured at 450 nm using a PerkinElmer Envision microplate reader. Four-parameter analysis was performed, a dose-response curve was fitted, and the IC50 was calculated. 50 The results are shown in Table 4.

[0332] Table 4. Inhibitory activity of compounds on LNCaP cell proliferation

[0333] The experimental results show that the compounds of this application (such as the compounds in the examples) have proliferative inhibitory activity against VCaP cells.

[0334] 2.2 Assay of LNCaP(T878A) cell proliferation inhibition activity Collect LNCaP cells in good growth condition, wash with PBS, digest with trypsin, stop digestion with 2% CSS-FBS phenol red-free 1640 complete medium, collect in centrifuge tubes, and adjust cell density to 1×10⁻⁶. 5 The compound was seeded at a concentration of 100 μL / well in 96-well plates using a nanoparticle pipette. The compound was serially diluted 2-fold to a final concentration of 1000 nM - 0.061 nM and 5000 nM - 0.305 nM, with two replicates. A control was also included. After culturing for 168 hours, the assay reagent CCK-8 (Dojindo, 10 μL / well) was added. After incubation for 2.0 hours, the absorbance was measured at 450 nm using a PerkinElmer Envision microplate reader. Four-parameter analysis was performed, a dose-response curve was fitted, and the IC50 was calculated. 50 The experimental results are shown in Table 5.

[0335] Table 5. Inhibitory activity of compounds on LNCaP(T878A) cell proliferation.

[0336] The experimental results show that the compounds of this application (such as the compounds in the examples) have proliferative inhibitory activity against LNCaP cells.

[0337] 2.322RV1(H875Y / ARV7) cell proliferation inhibitory activity assay Collect healthy 22RV1 cells, wash with PBS, digest with trypsin, stop digestion with 1640 complete medium containing 5% FBS, collect in centrifuge tubes, and adjust cell density to 5 × 10⁻⁶ cells / mL. 4 Cells were seeded at a concentration of 100 μL / well in 96-well plates, and the compound was simultaneously added using a nanoparticle pipette. The compounds were serially diluted 3-fold to a final concentration of 5000 nM–2.286 nM, with two replicates. A control was also included. After culturing for 168 hours in an incubator, CellTiter-Glo (manufacturer: Promega, 50 μL / well) was added, and the cells were incubated at room temperature for 10 min. Then, 100 μL / well was transferred to a white plate. Luminesence values ​​were detected using a PerkinElmer Envision multi-mode microplate reader. Four-parameter analysis was performed, a dose-response curve was fitted, and the IC50 was calculated. 50 The experimental results are shown in Table 6.

[0338] Table 6. Inhibitory activity of compounds on the proliferation of 22RV1(H875Y / ARV7) cells.

[0339] The experimental results show that the compounds of this application (such as the compounds in the examples) have proliferative inhibitory activity against 22RV1 cells.

[0340] 2.4 Assay of the inhibitory activity of MDA-PCA-2B (L702H\T878A) cell proliferation Collect MDA-PCA-2B cells in good growth condition, wash with PBS, digest with trypsin, add MDA-PCA-2B complete culture medium to stop digestion, collect in centrifuge tubes, and adjust cell density to 1×10⁻⁶. 5 The compound was seeded at a concentration of 100 μL / well in 96-well plates using a nanoparticle pipette, and serially diluted 3-fold to a final concentration of 5000 nM - 2.286 nM, with two replicates. A control was also included. After culturing for 168 hours, the assay reagent CCK-8 (manufacturer: Dojindo, 10 μL / well) was added, and the cells were incubated for 5 hours. The absorbance was measured at 450 nm using a PerkinElmer Envision microplate reader. Four-parameter analysis was performed, a dose-response curve was fitted, and the IC50 was calculated. 50 The experimental results are shown in Table 7.

[0341] Table 7. Inhibitory activity of compounds against the proliferation of MDA-PCA-2B (L702H\T878A) cells.

[0342] Experimental results show that the compounds of this application (such as the compounds in the examples) have proliferative inhibitory activity against MDA-PCA-2B cells.

[0343] Experimental Example 3: In vitro liver microsite stability Liver microsomal incubation samples were prepared as follows: PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / mL), test compound, and NADPH + MgCl2 solution were mixed and incubated at 37°C and 300 rpm for 1 hour. Samples at 0 hours were prepared as follows: PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / mL), and test compound. The samples were precipitated with acetonitrile solution containing an internal standard to prepare the supernatant, which was then diluted with a 1:1 (v:v) mixture of acetonitrile and water for LC / MS / MS analysis. Results are shown in Tables 8 and 9.

[0344] Table 8

[0345] Table 9

[0346] The experimental results show that the compound of this application has in vitro liver microsite stability (species: human, dog, rat or mouse).

[0347] Experimental Example 4: Mouse Pharmacokinetics ICR mice, weighing 18-22 g, were randomly divided into groups of 9 mice each after acclimatization for 3-5 days. The gavage group was given the test compound solution by gavage at a dose of 10 mg / kg (20 mg / kg or 30 mg / kg), while the intravenous injection group was given the test compound solution by intravenous injection at a dose of 1 mg / kg.

[0348] Blood samples were collected at the following time points after administration: 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 samples were collected at the following time points after administration: 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 orbital cavity to prepare plasma samples for testing.

[0349] Take 30 µL of the plasma sample and standard curve sample, add acetonitrile solution containing internal standard, and obtain the supernatant after protein precipitation. Dilute 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.

[0350] Table 10 Results of pharmacokinetic studies of the compounds in mice

[0351] Experimental results show that the compound of this application has good in vivo pharmacokinetic properties (e.g., AUC, C10). max t 1 / 2 Parameters such as F, for example, AUC > 15000 ng*h / mL for oral administration (10 mpk), C max >600ng / mL, t 1 / 2 >8h.

[0352] Experimental Example 5: Efficacy evaluation of DPTC-AR in a VCap human prostate cancer B-NDG mouse subcutaneous xenograft model VCap human prostate cancer cells were subcutaneously injected into the right axilla of SPF-grade male B-NDG mice (source: Biocytogen), 5 × 10⁶ cells / mL. 6 One tumor per animal (1:1 Matrigel mixture, inoculated). Inoculate when the average tumor volume reaches 250 mm². 3 Around the time of the experiment, the animals were divided into groups. The day of grouping was designated as day 0. Starting from day 0, the animals were administered the drug once daily by gavage (1-10 mpk), while a solvent (DMSO + PEG40) was administered as a control group. Tumor volume was measured 2-3 times per week, and the mice were weighed and the data were recorded. The general performance of the mice was observed and recorded daily. After the experiment, the tumors were removed, weighed, and photographed.

[0353] The detection indicators and calculation formulas are as follows: 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.

[0354] Relative to tumor volume, RTV = TV t / TV0; where TV0 is the tumor volume on day 0, TV t This represents the tumor volume at each measurement.

[0355] Relative tumor proliferation rate, T / C (%) = T RTV / C RTV ×100%; where T RTV For the treatment group, RTV; C RTV The solvent control group is RTV.

[0356] Tumor growth inhibition rate, TGI (%) = (1 - TW / TW0) × 100%; where TW is the tumor weight in the treatment group and TW0 is the tumor weight in the solvent control group.

[0357] Weight change rate, WCR (%) = (Wt) t -Wt0) / Wt0×100%; where Wt0 is the mouse's body weight on day 0, Wtt The mouse's weight at each measurement.

[0358] The experimental results show that the compounds in the embodiments of this application have good in vivo tumor inhibition effects (e.g., parameters such as TV, RTV, T / C (%), TGI (%), WCR (%), etc.). For example, at a dosage of 3 mpk, on day 23, the relative tumor proliferation rate (T / C) is <40%, and the tumor growth inhibition rate TGI (%) is >66%.

Claims

1. Pharmaceutical compositions of compounds of formula I, their stereoisomers, or pharmaceutically acceptable salts thereof, in, Ring A does not exist or is selected from C. 5-15 Cycloalkenyl, 5-15 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl; Ring B is selected from phenyl or 5-6-membered heteroaryl groups; Cyclic C is selected from 5-6 member heteroaryl groups; Each R 1 Independently selected from halogens, -OH, -NH2, -CN, C 1-10 Alkyl, C 1-10 alkoxy or halogenated C 1-10 Alkyl groups, namely -OH, -NH2, C 1-10 Alkyl, C 1-10 alkoxy or halogenated C 1-10 The alkyl group may optionally be 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 C selected from H, halogens, deuterium, or optionally substituted with one or more substituents 1-6 alkyl; X 6 Selected from -O-, -NH-, or -N(C 1-6 alkyl)-, said -NH- or -N(C 1-6 Alkyl group is optionally substituted with one or more substituents; Each R 2 R 3 and R 4 Each is independently selected from halogens, -OH, -NH2, -CN, and C. 1-10 Alkyl, C 1-10 alkoxy or halogenated C 1-10 Alkyl groups, namely -OH, -NH2, C 1-10 Alkyl, C 1-10 alkoxy or halogenated C 1-10 The alkyl group may optionally be 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 heteroaryl groups; Ring E is selected from C 3-10 Cycloalkyl or 3-10 membered heterocyclic alkyl; Ring F is selected from C 6-10 Aryl or 5-10 heteroaryl groups; R t Selected from hydrogen, -OH, C 1-6 Alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 3-10 The cycloalkyl or 3-10 membered heterocycloalkyl group is optionally substituted with one or more substituents; The pharmaceutical composition is selected from pharmaceutical compositions in oral or injectable form; Alternatively, the pharmaceutical composition may contain 0.01 mg to 1000 mg of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof. Alternatively, in the pharmaceutical composition, the content of the compound, its stereoisomers, or pharmaceutically acceptable salts thereof is 0.01 to 95% wt. Alternatively, the target of administration of the pharmaceutical composition may be selected from mammals, such as humans.

2. The pharmaceutical composition of claim 1, wherein, Ring A does not exist or is selected from C. 5-10 Cycloalkenyl, 5-10 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl; Alternatively, ring A does not exist, or it is selected from C. 5-9 Cycloalkenyl, 5-9 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl; Alternatively, ring A does not exist, or it is selected from C. 5-7 Cycloalkenyl, 5-9 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl; Alternatively, ring A does not exist, or it is selected from C. 5-6 Cycloalkenyl, 5-10 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl; Alternatively, ring A does not exist, or it is selected from C. 5-6 Cycloalkenyl, 5-9 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl; Alternatively, ring A does not exist, or it is selected from C. 5-6 Cycloalkenyl, 5-9 membered heterocyclic alkenyl, phenyl or 5 membered heteroaryl; Alternatively, ring A does not exist, or it is selected from C. 5-6 Cycloalkenyl, 5-9 membered heterocyclic alkenyl, phenyl, pyrrolyl, pyrazolyl, furanyl, or oxazolyl; Alternatively, ring A is absent, or is selected from C5-cycloalkenyl, C6-cycloalkenyl, 5-membered heterocyclic alkenyl, 6-membered heterocyclic alkenyl, 7-membered heterocyclic alkenyl, 8-membered heterocyclic alkenyl or 9-membered heterocyclic alkenyl, phenyl, pyrroleyl, pyrazolyl, furanyl or oxazolyl. Alternatively, ring A is absent, or is selected from cyclopentenyl, monocyclohexenyl, dicyclohexenyl, dihydropyrrolyl, tetrahydropyridyl, tetrahydroazapyrrolyl, azaspirooctenyl, azaspirononenyl, phenyl, pyrrolyl, pyrazolyl, furanyl, oxazolyl, or dihydrooxazinyl; and / or, The ring B is selected from phenyl or a 6-membered heteroaryl group; Alternatively, ring B is selected from phenyl; and / or, The ring C is selected from 5-membered heteroaryl groups; Alternatively, the ring C is selected from isoxazolyl or furanyl; Optionally, structural fragments Selected from or ; Or, structural fragments Selected from , , , , or ; Or, structural fragments Selected from , , , , or ; Or, structural fragments Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; Or, structural fragments Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; Or, structural fragments Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; Optionally, each R 1 Independently selected from halogens, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkyl groups, namely -OH, -NH2, C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 The alkyl group may optionally be substituted with one or more substituents; Or, each R 1 Independently selected from halogens, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 alkoxy or halogenated C 1-4 alkyl; Or, each R 1 Independently selected from halogens, -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 can be selected from 0 or 1.

3. The pharmaceutical composition according to claim 1 or 2, wherein, The L is selected from the following groups optionally substituted with one or more substituents: C 1-50 Alkylene, C 2-50 imide or C 2-50 Imyynyl group, the C 1-50 Alkylene, C 2-50 imide or C 2-50 One or more -CH2- groups in the ethynyl group are optionally replaced by -O-, C-. 3-15 Cycloalkyl, 3-15 membered heterocyclic alkyl, 4-15 membered heterocyclic alkenyl, C 6-15 Aryl, containing 5-15 membered heteroaryl, -NH-, -N(C 1-6 Alkyl)- or -S-replacement; Alternatively, the L is selected from the following groups optionally substituted with one or more substituents: C 1-30 Alkylene, C 2-30 imide or C 2-30 Imyynyl group, the C 1-30 Alkylene, C 2-30 imide or C 2-30 One or more -CH2- groups in the ethynyl group are optionally replaced by -O-, C-. 3-12 Cycloalkyl, 3-12-membered heterocyclic alkyl, 4-12-membered heterocyclic alkenyl, C 6-12 Aryl, containing 5-12 membered heteroaryl, -NH-, -N(C 1-6 Alkyl)- or -S-replacement; Alternatively, the L is selected from the following groups optionally substituted with one or more substituents: C 1-20 Alkylene, C 2-20 imide or C 2-20 Imyynyl group, the C 1-20 Alkylene, C 2-20 imide or C 2-20 One or more -CH2- groups in the ethynyl group are optionally replaced by -O-, C-. 3-10 Cycloalkyl, 3-11 membered heterocyclic alkyl, 4-10 membered heterocyclic alkenyl, C 6-10 Aryl, any 5-10 heteroaryl, -NH-, -N(C 1-6 Alkyl)- or -S-replacement; Alternatively, the L is selected from the following groups optionally substituted with one or more substituents: C 1-15 Alkylene, C 2-15 imide or C 2-15 Idemyne ​​group, the C 1-15 Alkylene, C 2-15 imide or C 2-15 One or more -CH2- groups in the ethynyl group are optionally replaced by -O-, C-. 3-9 Cycloalkyl, 3-11 membered heterocyclic alkyl, 4-8 membered heterocyclic alkenyl, C 6-8 Aryl, 5-8 quinone heteroaryl, -NH-, -N(C 1-4 Alkyl)- or -S-replacement; Alternatively, the L is selected from the following groups optionally substituted with one or more substituents: C 1-10 Alkylene, C 2-10 imide or C 2-10 Imyynyl group, the C 1-10 Alkylene, C 2-10 imide or C 2-10 One or more -CH2- groups in the ethynyl 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-replacement; Alternatively, the L is selected from the following groups optionally substituted with one or more substituents: C 1-6 Alkylene, C 2-6 imide or C 2-6 Imyynyl group, the C 1-6 Alkylene, C 2-6 imide or C 2-6 One or more -CH2- groups in the ethynyl 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-replacement; Alternatively, the L is selected from the following groups optionally substituted with one or more substituents: C 1-4 Alkylene, C 2-4 imide or C 2-4 Idemyne ​​group, the C 1-4 Alkylene, C 2-4 imide or C 2-4 One or more (e.g., one or two, one or three, etc.) of the ethynyl group are 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-substitution; or, the L is selected from C 1-6 Alkylene, the C 1-6 One or more -CH2- atoms in the alkylene group are optionally selected from -O-, C-. 3-10 Cycloalkyl, 4-11 membered heterocyclic alkyl, 4-10 membered heterocyclic alkenyl, -NH-, -N(C 1-3 Alkyl)- or -S-replacement, the C 1-6 The alkylene group may optionally be substituted with one or more substituents; Alternatively, the L is selected from C. 1-6 Alkylene, the C 1-6 One or more -CH2- atoms in the alkylene group are optionally selected from -O-, C-. 3-10 Cycloalkyl, 4-11 membered heterocyclic alkyl, 5-6 membered heterocyclic alkenyl, -NH-, -N(C 1-3 Alkyl)- or -S-replacement, the C 1-6 The alkylene group may optionally be substituted with one or more substituents.

4. The pharmaceutical composition of claim 1 or 2, wherein the L is selected from -LNK. 1 -Cy 1 -LNK-Cy 2 -LNK 2 -Cy 3 -,in, Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. a The following groups are substituted: C 3-12 Cycloalkyl, 4-12 membered heterocyclic alkyl, or 4-12 membered heterocyclic alkenyl; LNK, LNK 1 and LNK 2 Each is independently selected from the bond, NH, O, S, or optionally by one or more R b The following groups are substituted: C 1-12 Alkylene, C 2-12 imidene group, C 2-12 Ethyne or C 1-12 Heteroalkylene; Each R a and R b Each is independently selected from halogens, =O, -OH, -NH2, -CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 1-6 Alkylamino, diC 1-6 Alkylamino, C 3-12 Cycloalkyl or 4-12 membered heterocyclic alkyl.

5. The pharmaceutical composition of claim 4, wherein LNK, LNK 1 and LNK 2 Each is independently selected from the bond, NH, O, S, or optionally by one or more R b The following groups are substituted: C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Ethyne or C 1-10 Heteroalkylene; Or, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, NH, O, S, or optionally by one or more R b The following groups are substituted: C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne or C 1-6 Heteroalkylene; Or, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, NH, O, S, or optionally by one or more R b The following groups are substituted: C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Ethyne or C 1-4 Heteroalkylene; Or, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, NH, O, S, or optionally by one or more R b The following groups are substituted: C 1-6 Alkylene or C 1-6 Heteroalkylene; Or, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, NH, O, S, or optionally by one or more R b The following groups are substituted: C 1-4 Alkylene or C 1-4 Heteroalkylene; Or, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, NH, O, or optionally by one or more R b The following groups are substituted: C 1-3 Alkylene or C 1-3 Heteroalkylene; Or, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, NH, O, or optionally by one or more R b The following groups are substituted: C 1-2 Alkylene or C 1-2 Heteroalkylene; Or, LNK, LNK 1 and LNK 2 Each is independently selected from the following: bond, NH, O, -NHCH2-, -CH2NHCH2-, -CH2-, -CH2CH2-, -C(O)- or -C(O)CH2-; and / or Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. a The following groups are substituted: C 3-11 Cycloalkyl, 4-12 membered heterocyclic alkyl or 4-11 membered heterocyclic alkenyl; Or, Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. a The following groups are substituted: C 4-10 Cycloalkyl, 4-11 membered heterocycloalkyl or 5-6 membered heterocycloalkenyl; Or, Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. a The following groups are substituted: C 4-9 Cycloalkyl, 4-11 membered heterocycloalkyl or 5-6 membered heterocycloalkenyl; Or, Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. a The following groups are substituted: C 4-6 Cycloalkyl, C9 cycloalkyl, 4-11 membered heterocyclic alkyl or 6 membered heterocyclic alkenyl; Or, Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. a The following groups may be substituted: cyclobutyl, cyclopentyl, cyclohexyl, spironyl, azircyclobutyl, pyrrolyl, piperidinyl, tetrahydropyridyl, piperazine, monoazaspiroheptyl, monoazaspirononyl, diazaspirononyl, monoazaspirodecyl, diazaspirodecyl, monoazaspirodecyl, diazaspirodecane, monoazaspiroundecyl, diazaspiroundecyl, octahydrocyclopentylpyrryl, diazabicyclooctyl or monoazabicyclononyl; Optionally, each R a and R b Each is independently selected from halogens, =O, -OH, -NH2, -CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 1-6 Alkylamino, diC 1-6 Alkylamino, C 3-10 Cycloalkyl or 4-10 membered heterocyclic alkyl; Or, each R a and R b Each is independently selected from halogens, =O, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 1-6 Alkylamino or diC 1-6 Alkylamino; Or, each R a and R b Each is independently selected from halogens, =O, -OH, -NH2, -CN, and 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 halogens, =O, -OH, -NH2, -CN, or C. 1-3 alkyl; Or, each R a and R b Each is independently selected from halogens, =O, -OH, -NH2, or -CN; Or, each R a and R b Each is independently selected from =O.

6. The pharmaceutical composition according to any one of claims 1-5, wherein, The L is selected from the following: -NHCH2-, -CH2NHCH2-, -CH2-, -C(O)CH2-, ... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

7. The pharmaceutical composition according to any one of claims 1-6, wherein, R f C selected from H, fluorine, chlorine, bromine, deuterium, or optionally substituted with one or more substituents 1-3 alkyl; Or, R f Selected from H, fluorine, chlorine, bromine, deuterium or C 1-3 Alkyl, the C 1-3 The alkyl group may optionally be substituted with one or more of the following groups: halogen, -OH, -NH2, or -CN; Or, R f Selected from H, fluorine, chlorine, bromine, deuterium or C 1-3 alkyl; Or, R f Selected from H, fluorine, deuterium, or methyl; and / or X 5 Selected from CH or N; and / or X 6 Selected from -O-, -NH-, or -N(C 1-3 alkyl)-; or, X 6 Selected from -O- or -N(CH3)-; or, X 6 Selected from -O-.

8. The pharmaceutical composition according to any one of claims 1-7, wherein, Each R 2 R 3 and R 4 Each is independently selected from halogens, -OH, -NH2, -CN, and C. 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkyl groups, namely -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 The alkyl group may optionally be substituted with one or more substituents; Or, each R 2 R 3 and R 4 Each is independently selected from halogens, -OH, -NH2, -CN, and C. 1-4 Alkyl, C 1-4 alkoxy or halogenated C 1-4 alkyl; Or, each R 2 Independently selected from halogens, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 alkoxy or halogenated C 1-3 alkyl; Or, each R 2 Independently selected from halogens, -OH, -NH2, -CN, C 1-3 Alkyl or C 1-3 Alkoxy; Or, each R 2 It is independently selected from fluorine, chlorine, bromine, -OH, -NH2, -CN, methyl or methoxy; Or, each R 2 Independently selected from fluorine, chlorine, bromine, -CN, or methoxy; Or, each R 2 Independently selected from -CN or methoxy; and / or Each R 3 Each is independently selected from halogens, -OH, -NH2, -CN, and C. 1-3 Alkyl, C 1-3 alkoxy or halogenated C 1-3 alkyl; Or, each R 3 Each is independently selected from halogens, -OH, -NH2, -CN, or C. 1-3 alkyl; Or, each R 3 Selected independently from C 1-3 alkyl; Or, each R 3 Each and every one is independently selected from methyl; and / or Each R 4 Each is independently selected from halogens, -OH, -NH2, -CN, and C. 1-3 Alkyl, C 1-3 alkoxy or halogenated C 1-3 alkyl; Or, each R 4 Each is independently selected from halogens, -OH, -NH2, -CN, or C. 1-3 alkyl; Or, each R 4 Each of the following is independently selected from fluorine, chlorine, bromine, -OH, -NH2, or -CN; Optionally, 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.

9. The pharmaceutical composition according to any one of claims 1-8, 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. Optionally, ring E is selected from C. 3-9 Cycloalkyl or 3-9 membered heterocycloalkyl; or, the ring E is selected from C. 4-9 Cycloalkyl or 4-9 membered heterocyclic alkyl; or, the ring E is selected from C. 4-7 Cycloalkyl or 4-7 membered heterocycloalkyl; or, the ring E is selected from C 4-7 cycloalkyl; Alternatively, ring E is selected from cyclobutyl, cyclopentyl, or cyclohexyl; Alternatively, ring E is cyclobutyl; or ring E is... Or ring E is ; Optionally, where 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, pyridinyl, pyrimidinyl or pyrazinyl; or, ring F is selected from phenyl; or, ring F is selected from... , , , or .

10. The pharmaceutical composition according to any one of claims 1-9, wherein, R t Selected from hydrogen, -OH, C 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein C 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6-membered heterocycloalkyl groups may optionally be substituted; or, R t Selected from hydrogen, -OH, C 1-3 Alkyl, C 3-4 Cycloalkyl or 3-4 membered heterocycloalkyl, wherein C 1-3 Alkyl, C 3-4 Cycloalkyl or 3-4 membered heterocyclic alkyl groups may optionally be substituted; or, R t Selected from hydrogen or C 1-3 Alkyl groups (such as methyl, ethyl, propyl); or, R t Selected from hydrogen.

11. The pharmaceutical composition according to any one of claims 1-10, wherein, Structural fragments Selected from Or, structural fragments Selected from Or, structural fragments Selected from Or, structural fragments Selected from Or, structural fragments Selected from Or, structural fragments Selected from Or, structural fragments Selected from , , , , , or .

12. The pharmaceutical composition according to any one of claims 1-11, wherein, The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof is a compound of formula I-1 or I-1A, formula I-2, formula I-2A, formula I-3, or formula I-3A, its stereoisomer, or a pharmaceutically acceptable salt thereof. 、 or , X is selected from CH or N.

13. The pharmaceutical composition according to any one of claims 1-12, wherein, Ring A is C 5-10 Cycloalkenyl, or a 5-15 membered heterocyclic alkenyl 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- atoms in the alkylene group are optionally C 5-8 Cycloalkyl groups, or 5-8 membered heterocyclic alkyl groups containing 1-3 or 1-2 N or O atoms; Each R 2 Independently -OH, -NH2, -CN, C 1-10 Alkyl, C 1-10 alkoxy or halogenated C 1-10 Alkyl; each R 3 Independent of 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 It is -O- or -NH-; ring G is phenyl or a 6-membered heteroaryl containing 1-2 N 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 or O atoms; R t It is hydrogen, -OH or C 1-6 alkyl.

14. The pharmaceutical composition according to any one of claims 1-13, wherein, The compound is: ； or .

15. The pharmaceutical composition according to any one of claims 1-14, further comprising a pharmaceutically acceptable excipient.

16. Use of the pharmaceutical composition according to any one of claims 1-15 in the preparation of a medicament for the prevention or treatment of a disease by means of the degradation of a target protein that binds to a target ligand.

17. Use of the pharmaceutical composition according to any one of claims 1-15 in the preparation of a medicament for the prevention or treatment of a condition by binding to cerebellar proteins in vivo.

18. Use of the pharmaceutical composition according to any one of claims 1-15 in the preparation of a treatment for the prevention or treatment of AR-related diseases.

19. The use according to any one of claims 16-18, wherein the disease or ailment is selected from cancer.

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