Cyclohexyl group-containing compounds

Abstract

The present application relates to compounds comprising cyclohexyl groups, in particular to compounds of Formula I-AA, stereoisomers thereof, or pharmaceutically acceptable salts thereof, processes for their preparation, pharmaceutical compositions containing the compounds, and their use in the treatment of related diseases (e.g., cancer).

Description

[0001] This application is a divisional application of the following application: application date August 18, 2023; application number 202380060384.3; invention title: "Compounds containing cyclohexyl".

[0002] Cross-reference to related applications This application claims priority and benefits to the following Chinese patent application filed with the China National Intellectual Property Administration, the contents of which are incorporated herein by reference in their entirety: Chinese patent application No. 202211000005.5, filed on August 19, 2022; Chinese Patent Application No. 202310206412.X, filed on January 16, 2023; and Chinese Patent Application No. 202310996368.7, filed on August 8, 2023. Technical Field

[0003] This application relates to compounds containing cyclohexyl groups, methods for their preparation, pharmaceutical compositions containing such compounds, and their use in treating related diseases (such as cancer). Background Technology

[0004] 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.

[0005] PROTAC (proteolysis targeting chimera) molecules are bifunctional compounds that can simultaneously bind to target proteins and E3 ubiquitin ligases. These compounds induce the target protein to be recognized by the cell's proteasome, causing its degradation and effectively reducing its concentration in cells. By introducing ligands that bind to different target proteins into PROTAC molecules, the application of PROTAC technology in the treatment of various diseases has become possible, and this technology has received widespread attention in recent years. Invention Details On the one hand, this application relates to compounds of formula I-AA, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0007] 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; The ring C is selected from 5-6 membered heteroaryl groups (e.g., isoxazolyl or furanyl); Each R 1 Independently selected from halogens, -OH, -NH2, -CN, C 1-10 Alkyl (e.g., C) 1-6 Alkyl), C 1-10 Alkoxy groups (e.g., C) 1-6 alkoxy, or halogenated C 1-10 Alkyl groups (e.g., halogenated C) 1-6 Alkyl groups), namely -OH, -NH2, C 1-10 Alkyl (e.g., C) 1-6 Alkyl), C 1-10 Alkoxy groups (e.g., C) 1-6 alkoxy, or halogenated C 1-10 Alkyl groups (e.g., halogenated C) 1-6 Alkyl groups are optionally substituted with one or more substituents; n is selected from 0, 1, 2, or 3; L is selected from a linking group; X 5 Selected from CH or N; 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 (e.g., C) 1-6 Alkyl), C 1-10 Alkoxy groups (e.g., C) 1-6 alkoxy, or halogenated C 1-10 Alkyl groups (e.g., halogenated C) 1-6 Alkyl groups), namely -OH, -NH2, C 1-10 Alkyl, C 1-10 alkoxy or halogenated C 1-10 The alkyl group is optionally substituted with one or more substituents; m, p, and q are each independently selected from 0, 1, 2, 3, or 4; 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 the C 1-6 Alkyl, C 3-10 Cycloalkyl or 3-10-membered heterocycloalkyl groups may optionally be substituted.

[0008] In some implementations, ring A is absent or selected from C. 5-10 Cycloalkenyl, 5-10 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl.

[0009] In some embodiments, the ring B is selected from phenyl or 6-membered heteroaryl.

[0010] In some embodiments, the cyclic C is selected from 5-membered heteroaryl groups.

[0011] 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. In some embodiments, the ring G is phenyl.

[0012] 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. 5-7 Cycloalkyl. In some embodiments, the cycloe radical is selected from C. 4-6 Cycloalkyl. In some embodiments, ring E is cyclohexyl.

[0013] 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. In some embodiments, ring F is selected from phenyl, pyridazinyl, pyrimidinyl, or pyrazinyl.

[0014] In some implementation schemes, R t Selected from hydrogen, -OH, C 1-4 Alkyl, C3-6 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).

[0015] In some embodiments, the phrase “optionally substituted” or “optionally substituted with one or more substituents” means optional substitution with one or more of the following groups: halogen (e.g., fluorine, chlorine, bromine or iodine), CN, OH or NH2.

[0016] On the one hand, this application relates to compounds of formula I-1, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0017] in, Ring A 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 selected from phenyl; The ring C is selected from isoxazolyl or furanyl; Each R 1 Independently selected from halogens, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 alkoxy or halogenated C 1-4 alkyl; n is selected from 0, 1, 2, or 3; L is selected from a linking group; X 1 X 2 X 3 and X 4 Each is independently selected from N or CH; X 5 Selected from CH or N; X 6 Selected from -O-, -NH-, or -N(C 1-6 alkyl)-; 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; m, p, and q are each independently selected from 0, 1, 2, 3, or 4.

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

[0019] in, Ring A 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 selected from phenyl; The ring C is selected from isoxazolyl or furanyl; Each R 1 Independently selected from halogens, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 alkoxy or halogenated C 1-4 alkyl; n is selected from 0, 1, 2, or 3; L is selected from a linking group; X 1 X 2 X 3 and X 4 Each is independently selected from N or CH; X 5 Selected from CH or N; X 6 Selected from -O-, -NH-, or -N(C 1-6 alkyl)-; 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; m, p, and q are each independently selected from 0, 1, 2, 3, or 4.

[0020] 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.

[0021] 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.

[0022] 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.

[0023] In some implementations, ring A is absent or selected from C. 5-6 Cycloalkenyl, 5-9 membered heterocyclic alkenyl, phenyl or 5 membered heteroaryl.

[0024] In some implementations, ring A is absent or selected from C. 5-6 Cycloalkenyl, 5-9 membered heterocyclic alkenyl, phenyl, pyrrolyl, pyrazolyl, furanyl, or oxazolyl. In some embodiments, ring A is absent or selected from C5 cycloalkenyl, C6 cycloalkenyl, 5-, 6-, 7-, 8-, or 9-membered heterocyclic alkenyl, phenyl, pyrrolyl, pyrazolyl, furanyl, or oxazolyl.

[0025] 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.

[0026] In some embodiments, ring A is absent or selected from cyclopentenyl, dicyclohexenyl, dihydropyrrolyl, tetrahydropyridyl, tetrahydroazapyrrolyl, azaspirooctenyl, azaspirononenyl, phenyl, pyrrolyl, pyrazolyl, furanyl, oxazolyl, or dihydrooxazinyl. In some embodiments, ring A is selected from monocyclohexenyl.

[0027] In some specific implementation schemes, ring A is selected from C. 5-6 Cycloalkenyl, 5-10 membered heterocyclic alkenyl, phenyl, or 5-membered heteroaryl. In some specific embodiments, ring A is selected from C. 5-9 Cycloalkenyl, 5-9 membered heterocyclic alkenyl, phenyl or 5 membered heteroaryl.

[0028] In some specific implementation schemes, ring A is selected from C. 5-6 Cycloalkenyl, 5-9 membered heterocyclic alkenyl, phenyl or 5 membered heteroaryl.

[0029] 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. In some specific embodiments, 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.

[0030] In some specific embodiments, ring A is selected from cyclopentenyl, dihydropyrrolyl, tetrahydropyridyl, tetrahydroazapyrrolyl, azaspirocyclononenyl, azaspirocyclooctenyl, phenyl, pyrrolyl or pyrazolyl.

[0031] In some more specific embodiments, ring A is selected from cyclopentenyl, dihydropyrroleyl, tetrahydropyridyl, tetrahydroazapyryl, azaspirononenyl, or azaspirooctenyl.

[0032] In some more specific embodiments, ring A is selected from phenyl, pyrrole, or pyrazolyl.

[0033] In some specific embodiments, the ring C is an isoxazolyl group. In some specific embodiments, the ring C is a furanyl group.

[0034] In some implementations, structural fragments Selected from or .

[0035] 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 .

[0036] 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 .

[0037] In some implementations, structural fragments Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0038] In some implementations, structural fragments Selected from , , , , , , , , , , , , , , , , , , , , , , , , or In some implementations, structural fragments Selected from , , or .

[0039] In some specific implementation schemes, structural fragments Selected from , , , , , , , , , , or In some specific implementation schemes, structural fragments Selected from , ,or In some more specific implementations, structural fragments Selected from or Or, structural fragments Selected from , , , , , or Or, structural fragments Selected from , or Or, structural fragments Selected from , or .

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

[0041] In some implementations, structural fragments Selected from , , , , , , , , , , , , , , , , , , , , , , , , or In some implementations, structural fragments Selected from , , , or .

[0042] In some specific implementation schemes, structural fragments Selected from , , , , , , , , , , or In some specific implementation schemes, structural fragments Selected from , or In some more specific implementations, structural fragments Selected from or Or, structural fragments Selected from , , , , , or Or, structural fragments Selected from , or Or, structural fragments Selected from , or .

[0043] In some implementations, structural fragments Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0044] In some implementations, structural fragments Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or In some implementations, structural fragments Selected from , , , or .

[0045] In some specific implementation schemes, structural fragments Selected from , , , , , , , , , , , , or In some specific implementation schemes, structural fragments Selected from , or .

[0046] In some more specific implementation schemes, structural fragments Selected from , Or, structural fragments Selected from , , , , , or Or, structural fragments Selected from , or Or, structural fragments. Selected from , , , or .

[0047] In some implementations, 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 independently selected from fluorine.

[0048] In some implementations, n is selected from 0, 1, or 2.

[0049] In some specific implementation schemes, n is selected from 0.

[0050] In some implementations, structural fragments Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0051] In some specific implementation schemes, structural fragments Selected from , , , , , , , , , , or In some specific implementation schemes, structural fragments Selected from , , or In some more specific implementations, structural fragments Selected from or Or, structural fragments Selected from , , , , or Or, structural fragments Selected from , , or Or, structural fragments Selected from , , , or .

[0052] In some implementations, the L is selected from C. 1-30 Alkylene, C 2-30 imide or C 2-30 Idemyne ​​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, 5-12 heteroaryl, -NH-, -N(C 1-6 Alkyl)- or -S-replacement, the C 1-30 Alkylene, C2-30 imide or C 2-30 The ynyl group may optionally be substituted by one or more substituents.

[0053] In some implementations, the L is selected from 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, 3-10 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, the C 1-20 Alkylene, C 2-20 imide or C 2-20 The ynyl group may optionally be substituted by one or more substituents.

[0054] In some implementations, the L is selected from 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-. 3-8 Cycloalkyl, 3-8 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, the C 1-20 Alkylene, C 2-15 imide or C 2-15 The ynyl group may optionally be substituted by one or more substituents.

[0055] In some implementations, the L is selected from C. 1-10 Alkylene, C 2-10 imide or C 2-10 Idemyne ​​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-. 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, -NH-, -N(C 1-3 Alkyl)- or -S-replacement, the C 1-10 Alkylene, C 2-10imide or C 2-10 The ynyl group may optionally be substituted by one or more substituents.

[0056] In some implementations, the L is selected from C. 1-6 Alkylene, C 2-6 imide or C 2-6 Idemyne ​​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-. 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, -NH-, -N(C 1-3 Alkyl)- or -S-replacement, the C 1-6 Alkylene, C 2-6 imide or C 2-6 The ynyl group may optionally be substituted by one or more substituents.

[0057] In some implementations, the L is selected from 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-replacement, the C 1-4 Alkylene, C 2-4 imide or C 2-4 The ynyl group may optionally be substituted by one or more substituents.

[0058] 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, 4-10 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.

[0059] In some embodiments, in the definition of L, the substituent is selected from =O, OH, NH2, halogen, CN, C 1-6 Alkyl or C 1-6Alkyl group. In some embodiments, in the definition of L, the substituent is selected from =O, OH, NH2, halogen, or CN.

[0060] In some implementations, the L is selected from -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -,in, Cy 1 Selected from a key, or optionally by one or more R 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 Selected independently from key, C 1-12 Alkylene or C 1-12 Heteroalkylene; Cy 2 Selected from a key, or optionally by one or more R b The following groups are substituted: C 3-12 Cycloalkyl, 4-12 membered heterocyclic alkyl or 4-12 membered heterocyclic alkenyl; Each R a and R b Each is independently selected from halogens, -OH, -NH2, -CN, and C. 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 1-4 Alkylamino, diC 1-4 Alkylamino, C 3-12 Cycloalkyl or 4-12 membered heterocyclic alkyl.

[0061] In some implementations, the L is selected from -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -,in, Cy 1 Selected from a key, or optionally by one or more R a The following groups are substituted: C 3-12 Cycloalkyl or 4-12 membered heterocyclic alkyl; LNK, LNK 1 and LNK 2 Selected independently from key, C 1-12 Alkylene or C 1-12 Heteroalkylene; Cy 2 Selected from a key, or optionally by one or more Rb The following groups are substituted: C 3-12 Cycloalkyl or 4-12 membered heterocyclic alkyl; Each R a and R b Each is independently selected from halogens, -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.

[0062] In some implementations, the L is selected from -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -, where Cy 1 and Cy 2 They are not keys at the same time.

[0063] In some implementations, the L is selected from -Cy 1 -LNK-Cy 2 -LNK 2 -、-LNK 1 -Cy 1 -Cy 2 -LNK 2 -、-Cy 1 -LNK-Cy 2 -、-Cy 1 -Cy 2 -LNK 2 -、-LNK-Cy 2 -LNK 2 -、-Cy 1 -LNK-、-Cy 1 -Cy 2 -or-Cy 2 -

[0064] In some implementations, L is selected from -Cy 1 -LNK-Cy 2 -or-Cy 1 -Cy 2 -LNK 2 - In some implementations, L is selected from -Cy 1 -LNK-Cy 2 - In some implementations, L is selected from -Cy 1 -Cy 2 -LNK 2 - In some implementations, the L is selected from -Cy 1-LNK-Cy 2 -LNK 2 -

[0065] In some implementations, L or -Cy 1 -LNK-Cy 2 -Selected from-Cy 1 -、-Cy 1 -LNK-、-Cy 1 -Cy 2 -、-Cy 1 -LNK-Cy 2 -、-Cy 2 -、-LNK-Cy 2 -. In some implementations, L or -Cy 1 -LNK-Cy 2 -Selected from-Cy 1 -、-Cy 1 -Cy 2 -or-Cy 2 -. In some specific implementations, L or -Cy 1 -LNK-Cy 2 -Selected from-Cy 1 -LNK-、-Cy 1 -LNK-Cy 2 -or-LNK-Cy 2 -. In some specific implementations, L or -Cy 1 -LNK-Cy 2 -Selected from-Cy 1 -LNK-. In some specific implementations, L or -Cy 1 -LNK-Cy 2 -Selected from-Cy 1 -LNK-Cy 2 -. In some specific implementations, L or -Cy 1 -LNK-Cy 2 -Selected from -LNK-Cy 2 - In some implementations, Cy 1 Selected from one or more R a The following groups are substituted: C 3-12 Cycloalkyl or 4-12 membered heterocyclic alkyl; 2 Selected from a key, or optionally by one or more R b The following groups are substituted: C 3-12 Cycloalkyl or 4-12 membered heterocyclic alkyl.

[0066] In some implementation schemes, LNK, LNK 1 and LNK 2Selected from key. In some implementations, LNK 1 For key.

[0067] In some implementations, LNK is selected from C 1-6 Alkylene or C 1-6 Heteroalkylene, LNK 1 and LNK 2 For key.

[0068] In some implementation schemes, LNK 2 Selected from C 1-6 Alkylene or C 1-6 Heteroalkylene, LNK and LNK 1 For key.

[0069] In some implementation schemes, LNK 1 and LNK 2 Selected from key, LNK is selected from key or C 1-6 Alkylene or C 1-6 Heteroalkylene, and Cy 2 As the key, Cy 1 Selected from one or more R a The following groups are substituted: C 4-11 Cycloalkyl or 4-11 membered heterocyclic alkyl.

[0070] In some implementations, LNK is selected from C 1-6 Alkylene or C 1-6 Heteroalkylene, LNK 1 and LNK 2 For key; Cy 2 As the key, Cy 1 Selected from one or more R a The following groups are substituted: C 4-11 Cycloalkyl or 4-11 membered heterocyclic alkyl.

[0071] In some implementations, LNK is selected from C 1-6 Alkylene or C 1-6 Heteroalkylene, LNK 1 and LNK 2 For key; Cy 1 As the key, Cy 2 Selected from one or more R b The following groups are substituted: C 4-11 Cycloalkyl or 4-11 membered heterocyclic alkyl.

[0072] In some implementations, LNK is selected from C 1-6 Alkylene or C 1-6 Heteroalkylene, LNK 1and LNK 2 For key; Cy 1 Selected from one or more R a The following groups are substituted: C 4-11 Cycloalkyl or 4-11 membered heterocycloalkyl, Cy 2 Selected from one or more R b The following groups are substituted: C 4-11 Cycloalkyl or 4-11 membered heterocyclic alkyl.

[0073] In some implementations, Cy 1 As a key, or optionally by one or more R a The following groups are substituted: C 4-11 Cycloalkyl, 4-11 membered heterocyclic alkyl or 4-11 membered heterocyclic alkenyl.

[0074] In some implementations, Cy 1 As a key. In some implementations, Cy 1 Selected from one or more R a The following groups are substituted: C 6-9 Cycloalkyl, 4-11 membered heterocyclic alkyl or 4-9 membered heterocyclic alkenyl (e.g. 5-7 membered heterocyclic alkenyl).

[0075] In some implementations, Cy 1 Selected from one or more R a The following groups may be substituted: C6 cycloalkyl, C9 cycloalkyl, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered or 11-membered heterocyclic alkyl, or 6-membered heterocyclic alkenyl.

[0076] In some implementations, Cy 1 Selected from one or more R a The following groups are substituted: C6 cycloalkyl, C9 cycloalkyl, 4-membered, 6-membered, 8-11-membered heterocyclic alkyl, or 5-6-membered heterocyclic alkenyl. In some embodiments, Cy 1 Selected from one or more R a The following groups may be substituted: C6 cycloalkyl, C9 cycloalkyl, 4-membered, 6-membered, 8-11-membered heterocyclic alkyl or 6-membered heterocyclic alkenyl.

[0077] In some implementations, Cy 1 Selected from a key, or optionally by one or more R a The following groups are substituted: C 4-11 Cycloalkyl or 4-11 membered heterocyclic alkyl.

[0078] In some implementations, Cy 1 As a key. In some implementations, Cy 1Selected from one or more R a The following groups are substituted: C 6-9 Cycloalkyl or 4-11 membered heterocyclic alkyl.

[0079] In some implementations, Cy 1 Selected from one or more R a The following groups can be substituted: C6 cycloalkyl, C9 cycloalkyl, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered or 11-membered heterocyclic alkyl.

[0080] In some implementations, Cy 1 Selected from one or more R a The following groups are substituted: C6-cycloalkyl, C9-cycloalkyl, 4-membered, 6-membered, or 8-11-membered heterocyclic alkyl. In some embodiments, Cy 1 Selected from one or more R a The following groups are substituted: 4- or 5-membered heterocyclic alkyl groups. In some embodiments, Cy 1 Selected from one or more R a The following groups are substituted: 6-9 membered heterocyclic alkyl groups. In some embodiments, Cy 1 Selected from one or more R a The following groups are substituted: 6-membered, 8-membered, or 9-membered heterocyclic alkyl groups. In some specific embodiments, Cy 1 Selected from one or more R a The following groups are substituted: 6-membered heterocyclic alkyl or 9-membered heterocyclic alkyl.

[0081] In some implementations, Cy 1 Selected from one or more R a The following groups may be substituted: piperidinyl, diazaspironyl, piperazine, monoazaspironyl, cyclohexyl, spironyl, azacyclobutyl, pyrrolyl, octahydrocyclopentylpyrrolyl, azabicyclononyl, monoazaspirondecyl, diazaspirondecyl, or tetrahydropyridinyl.

[0082] In some implementations, Cy 1 Selected from one or more R a The following groups may be substituted: piperidinyl, diazaspironyl, piperazine, monoazaspironyl, cyclohexyl, spironyl, azacyclobutyl, octahydrocyclopentylpyrrolidinyl, azabicyclononyl, monoazaspirondecyl, or diazaspirondecyl. In some specific embodiments, Cy 1 Selected from one or more R a The following groups are substituted: piperidinyl, diazaspironyl, piperazineyl, or monoazaspironyl. In some specific embodiments, Cy1 Selected from one or more R a The following groups may be substituted: azirmonobutyl, pyrrolidinyl, or tetrahydropyridyl.

[0083] In some implementations, Cy 1 Selected from one or more R a The following groups are substituted: , , , , , , , , , , , , , , , , or .

[0084] In other implementations, Cy 1 Selected from one or more R a The following groups are substituted: , , , , , , , , , , , , or .

[0085] In some specific implementation schemes, Cy 1 Selected from one or more R a The following groups are substituted: , , or In some specific implementation schemes, Cy 1 Selected from one or more R a The following groups are substituted: , , or .

[0086] In some implementation schemes, LNK, LNK 1 and LNK 2Selected independently from key, C 1-6 Alkylene or C 1-6 Heteroalkylene.

[0087] In some implementation schemes, LNK, LNK 1 and LNK 2 Selected independently from key, C 1-3 Alkylene or C 1-3 Heteroalkylene.

[0088] In some implementation schemes, LNK, LNK 1 and LNK 2 Each is independently selected from the key or C. 1-4 Alkylene.

[0089] In some implementation schemes, LNK, LNK 1 and LNK 2 Each is independently selected from the key or C. 1-3 Alkylene.

[0090] In some implementation schemes, LNK, LNK 1 and LNK 2 Each is independently selected from either the -CH2- or -CH2-. In some specific embodiments, LNK is the -CH2- bond. In some specific embodiments, LNK, LNK... 1 and LNK 2 Each is independently -CH2-.

[0091] In some implementations, Cy 2 Selected from a key, or optionally by one or more R b The following groups are substituted: C 4-11 Cycloalkyl or 4-11 membered heterocyclic alkyl. In some specific embodiments, Cy 2 As a key. In some specific implementations, Cy 2 Selected from one or more R b The following groups are substituted: C 4-11 Cycloalkyl or 4-11 membered heterocyclic alkyl.

[0092] In some implementations, Cy 2 Selected from a key, or optionally by one or more R b The following groups are substituted: C 4-6 Cycloalkyl or 4-6 membered heterocyclic alkyl. In some embodiments, Cy 2 Selected from one or more R b The following groups are substituted: C 4-6 Cycloalkyl or 4-6 membered heterocyclic alkyl.

[0093] In some implementations, Cy 2Selected from a key, or optionally by one or more R b The following groups may be substituted: cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolidinyl, or piperidinyl. In some specific embodiments, Cy... 2 Selected from a key, or optionally by one or more R b The following groups may be substituted: cyclobutyl, cyclopentyl, cyclohexyl, aziridine, or piperidinyl.

[0094] In some implementations, Cy 2 Selected from key, , , , , , , , , , , , or In some specific implementation schemes, Cy 2 Selected from key, , , , , , , , , , or .

[0095] In some implementation schemes, R a and R b Each is independently selected from halogens, -OH, -NH2, -CN, and C. 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, C 1-3 alkylamino, or di-C 1-3 Alkylamino.

[0096] In some implementation schemes, R a and R b Each is independently selected from halogens, -OH, -NH2, -CN, or C. 1-3 alkyl.

[0097] In some implementation schemes, R a and R b Each is independently selected from halogens, -OH, -NH2, or -CN.

[0098] In some implementations, the structural fragment -Cy1 -LNK- Selected from , , , , , , , , , , , , , , , , , , , , , , , or .

[0099] In other implementations, the structural segment -Cy 1 -LNK- Selected from , , , , , , , , , , , , , , , , , or .

[0100] In some specific implementation schemes, the structural fragment - Cy 1 -LNK- Selected from , , , , or In some specific implementations, the structural fragment -Cy 1 -LNK- Selected from , , , , or .

[0101] In other implementations, the structural fragment -LNK-Cy 2 -Selected from the bond, -CH2-, , , , , , , , , , , , , , , , , , , or .

[0102] In some specific implementation schemes, the structural fragment -LNK-Cy 2 -Selected from the bond, -CH2-, , , , , , , , , , , , , , , or .

[0103] In some implementations, the structural fragment -Cy 1 -Cy 2 -Selected from , , , , , , , , , or .

[0104] In other implementations, the structural segment -Cy 1 -Cy 2 -Selected from , , , , , , , , or .

[0105] In some specific implementation schemes, the structural fragment - Cy 1 -Cy 2 -Selected from , , , , , , , or .

[0106] In some implementations, the structural fragment -Cy 1 -Cy 2 -LNK 2 -Selected from , , or .

[0107] In some implementations, structural fragments or -Cy 1 -Cy 2 -LNK 2 -Selected from or .

[0108] In some implementations, the structural fragment is -L- or -LNK. 1 -Cy 1 -LNK-Cy 2 -LNK 2 -Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0109] In other implementations, the structural segment is -L- or -LNK. 1 -Cy 1 -LNK-Cy 2 -LNK 2 -Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0110] In some specific implementations, the structural segment -L- or -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -Selected from , , , , , , , , , , , , , , , , , , , , , , , or , or .

[0111] In some implementations, structural fragments Selected from , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or .

[0112] In some implementations, structural fragments Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or In some implementations, structural fragments Selected from , , , , , , , , , , , , , , or .

[0113] In some implementation schemes, X 1 X 2 and X 3 Each is independently selected from N or CH, X 4 For CH. In some implementations, X 1 and X 2 Each is independently selected from N or CH, X 3 and X 4 For CH. In some implementations, X 1 and X 2 Let N and X be independent respectively. 3 and X 4 For CH. In some implementations, X 1 X 2 X 3 and X 4 For CH. In some implementations, X 1 and X 4 For CH, X 2 and X 3 For N. In some implementations, X 2 and X 3 CH and X are independent of each other. 1 and X 4 For N. In some implementations, X 1 and X 3 CH and X are independent of each other. 2 and X 4 For N. In some implementations, X2 and X 3 Each is independently selected from N or CH, X 1 and X 4 For CH. In some implementations, X 1 and X 3 Each is independently selected from N or CH, X 2 Let N, X 4 For CH.

[0114] In some implementation schemes, X 5 For CH.

[0115] 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)-.

[0116] 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, or C. 1-3 Alkyl group. In some embodiments, each R 2 Independently selected from fluorine, chlorine, bromine, -OH, -NH2, or -CN. In some embodiments, each R 2 Independently selected from fluorine, chlorine, bromine, or -CN. In some embodiments, each R... 2 It is independently selected from chlorine or -CN.

[0117] In some implementations, each R 4 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 4 Independently selected from halogens, -OH, -NH2, -CN, or C. 1-3 Alkyl group. In some embodiments, each R 4 It is independently selected from fluorine, chlorine, bromine, -OH, -NH2 or -CN.

[0118] In some implementations, m is selected from 0, 1, 2, or 3. In some implementations, m is selected from 1, 2, or 3. In some implementations, m is 2. In some implementations, q is selected from 0, 1, 2, or 3. In some implementations, q is selected from 0 or 1. In some implementations, q is 0.

[0119] In some implementations, structural fragments for .

[0120] In some implementations, each R 3 and 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 3 and R 4 Each is independently selected from halogens, -OH, -NH2, -CN, or C. 1-3 Alkyl group. In some embodiments, each R 3 and R 4 Each of the following is independently selected from fluorine, chlorine, bromine, -OH, -NH2, or -CN.

[0121] In some implementations, p and q are independently selected from 0, 1, 2, or 3. In some implementations, p and q are independently selected from 0 or 1. In some implementations, p and q are 0.

[0122] In some implementations, structural fragments Selected from , , , , , or In some implementations, structural fragments Selected from , , , , , , , , , , , , , , or Optionally, in structural fragments or be p a R3 Replacement, where p and R 3 The definition is as stated in this application.

[0123] In some implementations, structural fragments , , , or Selected from , , , , , , , , , , , , , , or Optionally, in structural fragments or be p a R 3 Replacement, where p and R 3 The definition is as stated in this application.

[0124] In some implementations, structural fragments Selected from , , , , , , , , , , , , , or Optionally, in structural fragments or be p a R 3 Replacement, where p and R 3 The definition is as stated in this application.

[0125] In some implementations, structural fragments Selected from , , , , , , , , , , , , , , or Optionally, in structural fragments or be p a R 3 Replacement, where p and R 3 The definition is as stated in this application.

[0126] In some specific implementation schemes, structural fragments Selected from , , , , Optionally, in structural fragments be p a R 3 Replacement, where p and R 3 The definition is as stated in this application.

[0127] In some specific implementation schemes, structural fragments Selected from , , , , , , or Optionally, in structural fragments or be p a R 3 Replacement, where p and R 3 The definition is as stated in this application.

[0128] In some specific implementation schemes, structural fragments Selected from , , , , or Or, structural fragments Selected from or Or, structural fragments Selected from Optionally, in structural fragments or be p a R 3 Replacement, where p and R 3 The definition is as stated in this application.

[0129] 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.

[0130] 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.

[0131] In some embodiments, the heterocyclic alkenyl group contains 1-3 (e.g., 1-2) heteroatoms selected from -O-, -NH-, -N-, or -S-. In some embodiments, the heteroaryl group contains 1-3 (e.g., 1-2) heteroatoms selected from -O-, -NH-, -N-, or -S-. In some embodiments, the heterocyclic alkyl group contains 1-3 (e.g., 1-2) heteroatoms selected from -O-, -NH-, -N-, or -S-. In some embodiments, the heteroalkylene group contains 1-3 (e.g., 1-2) heteroatoms selected from -O-, -NH-, -N-, or -S-.

[0132] It should be understood that any embodiment of the compounds of this application as described above and any specific X in the compounds of this application as described above are considered valid. 1 X 2 X 3 X 4 X 5 X 6 Rings A, B, C, E, F, G, and R 1 R 2R 3 R 4 R t Any specific substituent described in the L substituents can 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, in the specific embodiments and / or claims, any specific X... 1 X 2 X 3 X 4 X 5 X 6 Rings A, B, C, E, F, G, and R 1 R 2 R 3 R 4 R t Where the substituent range is disclosed by the L substituent, it should be understood that one or more substituents may be deleted from that range, and the remaining substituent range should also be considered as an embodiment of this application.

[0133] The compounds of formula I-AA, formula I-1, or formula I, their stereoisomers, or pharmaceutically acceptable salts thereof described in this application are selected from compounds of formula I-A1 or formula IA, their stereoisomers, or pharmaceutically acceptable salts thereof. , Among them, rings A, B, C, and R 1 n, L, X 1 X 2 X 3 X 4 X 5 X 6 R 2 R 3 R 4 m, p, q are as described in this application.

[0134] In some implementations, structural fragments , As stated in this application.

[0135] The compounds of formula I-AA, formula I-1, or formula I, their stereoisomers, or pharmaceutically acceptable salts thereof described in this application are selected from compounds of formula I-1A, I-2A, I-3A, I-4A, I-5A, I-6A, I-7A, I-8A, I-9A, I-10A, I-11A, I-12A, I-13A, I-14A, I-15A, I-16A, or I-17A, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0136] Among them, rings A, B, C, and R 1 n, R 2 m, X 1 X 2 X 3 X 5 X 6 Cy 1 Cy 2 LNK, LNK 1 LNK 2 The definitions are as described in this application; X is selected from CH or N.

[0137] The compounds of formula I-AA, I-1, I, or IA, their stereoisomers, or pharmaceutically acceptable salts thereof described in this application are selected from compounds of formula I-1A-1, I-2A-1, I-3A-1, I-4A-1, I-5A-1, I-6A-1, I-7A-1, I-8A-1, I-9A-1, I-10A-1, I-11A-1, I-12A-1, I-13A-1, I-14A-1, I-15A-1, I-16A-1, or I-17A-1, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0138] Among them, rings A, B, C, and R1 R 2 m, n, X 1 X 2 X 3 X 5 X 6 Cy 1 Cy 2 LNK, LNK 1 LNK 2 The definitions are as described in this application; X is selected from CH or N.

[0139] In some implementation schemes, X 1 and X 2 For CH, X 3 For CH. In some implementations, X 1 and X 2 Let N, X 3 For CH. In some implementations, X 2 and X 3 Let N, X 1 For CH.

[0140] In some implementation schemes, X 1 and X 2 For CH. In some implementations, X 1 and X 2 Let N be the number of elements in the array.

[0141] In some implementations, 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 .

[0142] In some implementations, structural fragments Selected from , , , , , , or Or, it is selected from , , , , , , or Or, it is selected from , , , , , , , , , , , , or .

[0143] In some implementations, structural fragments -Cy 1 -LNK-、-LNK-Cy 2 -、-Cy 1 -Cy 2 -or-Cy 1 -LNK-Cy2 -As mentioned above.

[0144] In some embodiments, optionally, the compounds described in this application are not the following compounds: , , , , , .

[0145] In some embodiments, optionally, the compounds described in this application are not the following compounds:

[0146] , .

[0147] In some solutions, the structural portion or Not selected , , , , or .

[0148] In some solutions, the structural portion or Not selected , , , , or .

[0149] In some solutions, the structural portion or Not selected , , , , or In some solutions, the structural portion or Not selected , , or .

[0150] In some implementations, structural fragments Not selected , or In some implementations, structural fragments Not selected , or In some implementations, structural fragments Not selected , , , , or .

[0151] 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.

[0152] 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 selected from phenyl; The ring C is selected from isoxazolyl or furanyl; L is selected from 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.

[0153] In some implementation schemes, the structural portion As stated in this application.

[0154] 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.

[0155] 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 selected from 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 1-4Alkoxy, 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.

[0156] 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.

[0157] 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.

[0158] 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.

[0159] In some implementations, ring A is absent or selected from C. 5-6 Cycloalkenyl, 5-9 membered heterocyclic alkenyl, phenyl or 5 membered heteroaryl.

[0160] 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.

[0161] 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.

[0162] 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.

[0163] In some specific implementation schemes, ring A is selected from C. 5-9 Cycloalkenyl, 5-9 membered heterocyclic alkenyl, phenyl or 5 membered heteroaryl.

[0164] In some specific implementation schemes, ring A is selected from C. 5-6 Cycloalkenyl, 5-9 membered heterocyclic alkenyl, phenyl or 5 membered heteroaryl.

[0165] 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.

[0166] 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.

[0167] In some specific embodiments, ring A is selected from cyclopentenyl, dihydropyrrolyl, tetrahydropyridyl, tetrahydroazapyrrolyl, azaspirocyclononenyl, azaspirocyclooctenyl, phenyl, pyrrolyl or pyrazolyl.

[0168] In some specific embodiments, ring A is selected from cyclopentenyl, dihydropyrrolyl, tetrahydropyridyl, tetrahydroazapyrrolyl, azaspirocyclic nonenyl, or azaspirocyclic octenyl.

[0169] In some specific embodiments, ring A is selected from cyclopentenyl. In some specific embodiments, ring A is selected from dihydropyrroleyl, tetrahydropyridyl, tetrahydroazapyryl, or azaspirooctene.

[0170] In some specific embodiments, ring A is selected from phenyl, pyrrole, or pyrazolyl.

[0171] In some implementations, ring A is selected from... , , , , , , , , , , , , , or .

[0172] In some specific embodiments, the ring C is an isoxazolyl group. In some specific embodiments, the ring C is a furanyl group.

[0173] In some implementation schemes, the structural portion Selected from or .

[0174] 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 .

[0175] 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 .

[0176] In some implementations, structural fragments Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0177] In some specific implementation schemes, structural fragments Selected from , , , , , , , , , , , , , , , or In some more specific implementations, structural fragments Selected from , , , , , , , , , , , , or Or, structural fragments Selected from , or .

[0178] In some implementations, structural fragments Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0179] In some specific implementation schemes, structural fragments Selected from , , , , , , , , , , , , , , , or In some more specific implementation schemes, structural fragments Selected from , , , , , , , , , , , , or Or, structural fragments Selected from , or .

[0180] 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 C 1-4 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 1-6Alkyl OC(O)-, or optionally C 1-6 Alkyl COC(O)-substituted 4-10 membered heterocyclic alkyl groups.

[0181] 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.

[0182] 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.

[0183] In some implementations, each R 1a Independently selected from halogens, -OH, -NH2, -CN, -CHO, C 1-4 Alkyl OC(O)-, C 1-3 Alkyl or 4-6 membered heterocyclic alkyl, wherein the C 1-3 The alkyl 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 1-4Alkyl OC(O)-substituted 4-6 membered heterocyclic alkyl groups.

[0184] 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)-.

[0185] In some implementations, each R 1a Independently selected from F, -OH, -CHO, (CH3)3COC(O)-, -CH2OH, , , , , or .

[0186] 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.

[0187] This application relates to the following compounds, portions thereof, stereoisomers thereof, derivatives (specifically, such as the Protac molecule), or pharmaceutically acceptable salts thereof. , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0188] 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 (e.g., stereoisomers), and derivatives thereof in the Protac molecule. 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 (e.g., stereoisomers), and derivatives thereof in constituting a part of the 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 (e.g., stereoisomers), and derivatives thereof in the form of the Protac molecule. 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 protein degradation, 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 in the form of Protac molecules. This application also 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. 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.

[0189] In some embodiments, this application relates to compounds of formula I-AA, formula I, or formula I-1, their stereoisomers, or pharmaceutically acceptable salts thereof, wherein, Ring A is selected from C 5-6 Cycloalkenyl, 5-8-membered heterocyclic alkenyl containing 1-3 heteroatoms selected from N, O, or S (e.g., 1-2 heteroatoms selected from N or O), phenyl, or 5-6-membered heteroaryl containing 1-3 heteroatoms selected from N, O, or S (e.g., 1-2 heteroatoms selected from N or O); Ring B is phenyl; The ring C is selected from isoxazolyl or furanyl; Each R 1 Independently selected from halogens, -OH, -NH2, -CN, or C. 1-3 Alkyl groups (such as methyl, ethyl, propyl); n is selected from 0 or 1; L is selected from LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -, LNK, LNK 1 and LNK 2 Each is independently selected from the key or C. 1-3 Alkylene, Cy 1 Selected from key, C 3-7 Cycloalkyl, 4-7 membered heterocyclic alkyl or 5-7 membered heterocyclic alkenyl, Cy 2 Selected from key, C 3-7 Cycloalkyl, 4-7 membered heterocyclic alkyl or 5-7 membered heterocyclic alkenyl, and Cy 1 and Cy 2 Not both are keys; X 1 X 2 X 3 and X 4 Each is independently selected from N or CH; X 5 Selected from CH or N; X 6 Selected from -O-, -NH-, or -N(C 1-6 alkyl)-; Each R 2 R 3 and R 4 Each is independently selected from halogens, -OH, -NH2, -CN, or C. 1-3 Alkyl groups (such as methyl, ethyl, propyl); m is selected from 1 or 2; p and q are each independently selected from 0 or 1.

[0190] In some embodiments, this application relates to compounds of formula I-AA, formula I, or formula I-1, their stereoisomers, or pharmaceutically acceptable salts thereof, wherein, Ring A is selected from cyclopentenyl, dihydropyrrolyl, tetrahydropyridyl, tetrahydroazapyrrolyl, azaspirooctenyl, phenyl, pyrrolyl or pyrazolyl; Ring B is phenyl; The ring C is selected from isoxazolyl or furanyl; n is 0; L is selected from either C or C. 1-3 Alkyl-linked piperidinyl, diazaspirononyl, piperazine, monoazaspirononyl, , , , , , , , , , , , , , , , Aza-heterocyclic butyl or tetrahydropyridyl; X 1 X 2 X 3 and X 4 All are CH, or X 1 X 2 X 3 and X 4 Two of them are N and the other two are CH; X 5 Selected from CH or N; X 6 Selected from -O-, -NH-, or -N(C 1-4 alkyl)-; R 2 Selected from halogens or -CN; m is 2; p and q are each 0 independently.

[0191] This application also relates to the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof: or .

[0192] In some implementations, the pharmaceutically acceptable salt is selected from maleate salts.

[0193] This application also covers solutions obtained by arbitrarily combining, deleting, or changing the above-described embodiments.

[0194] On the other hand, this application relates to a pharmaceutical composition containing the compounds described above, their stereoisomers, or pharmaceutically acceptable salts thereof, and the pharmaceutical composition of this application further includes pharmaceutically acceptable excipients.

[0195] 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.

[0196] 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 diseases 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 preparation of medicaments for the prevention or treatment of AR-related diseases.

[0198] 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.

[0199] 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.

[0200] 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.

[0201] 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.

[0202] 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.

[0203] 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.

[0204] 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.

[0205] 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.

[0206] 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.

[0207] 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 specific embodiments, the aforementioned diseases or conditions are selected from cancers, such as prostate cancer.

[0208] In some specific embodiments, the conditions treated by binding to cerebellar proteins in vivo and / or by degrading target proteins that bind to target ligands are selected from AR-related diseases; in some specific embodiments, the AR-related diseases are selected from cancers, such as prostate cancer.

[0209] 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.

[0210] In some embodiments, this application includes the variables defined above and their implementation schemes, as well as any combination thereof.

[0211] Technical effect The compounds of this application exhibit degradation activity against AR in VCaP and LNCaP cells, and also show anti-proliferative activity against both VCaP and LNCaP cells. Furthermore, the compounds of this application possess good in vitro hepatic microsomal stability and in vivo pharmacokinetic properties (specifically, parameters such as AUC) in mammals (e.g., mice), demonstrating their ability to inhibit tumor growth in vivo and showing promise as a drug.

[0212] definition Unless otherwise stated, the following terms as used in this application shall have the following meanings. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0213] 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.

[0214] 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.

[0215] 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.

[0216] 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.

[0217] 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.

[0218] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0219] The term "hydroxyl group" refers to the -OH group.

[0220] The term "amino" refers to the -NH2 group.

[0221] The term "cyano" refers to the -CN group.

[0222] The term "alkyl" refers to a compound with the general formula C10. n H 2n+1 The 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.

[0223] 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 alkyl" refers to an alkylene group containing 1 to 6 carbon atoms; the term "C1-4 alkyl" refers to an alkylene group containing 1 to 4 carbon atoms, including but not limited to -CH2-, -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2-.

[0224] 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-.

[0225] 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 .

[0226] 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 m A heteroalkyl group is defined as an alkyl group consisting of m carbon atoms and at least one heteroatom (e.g., 1-3 heteroatoms selected from S, O, and N) inserted into the chain, located between any two carbon atoms or attached to the terminal carbon atom. 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 remainder 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.

[0227] The term "heteroalkylene" refers to a divalent group formed by removing a hydrogen atom from any position of a heteroalkyl group.

[0228] The term "alkoxy" refers to -O-alkyl.

[0229] 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.

[0230] The term "cycloalkenyl" refers to an incompletely saturated non-aromatic carbon ring that can 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 include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, and cycloheptadienyl.

[0231] The term "cycloalkyl" refers to a fully saturated carbon ring that can 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.

[0232] 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.

[0233] 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.

[0234] 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 .

[0235] 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.

[0236] 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.

[0237] 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.

[0238] 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.

[0239] 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)-.

[0240] The term "derivative" refers to a new compound or group of new compounds that are produced through one or more chemical reactions or structural evolution, retaining the basic structure of the parent compound but changing or modifying only the side chains, functional groups or substituents.

[0241] The terms “substituent,” “optionally substituted with one or more substituents,” or “optionally substituted” include all substituents or substituent substitutions mentioned in the context of this document, such as 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 said "substituents" include mercapto, nitro, nitroso, cyano, azide, sulfoxide, sulfone, sulfonyl, sulfonamide, carboxyl, aldehyde, imine, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkenyl, haloalkenyl, cycloalkenyl, halocycloalkenyl, alkynyl, haloalkynyl, cycloalkynyl, halocycloalkynyl, heteroalkyl Halogenated heteroalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, arylalkylene, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroarylalkylene, heteroarylalkoxy, heteroarylalkylthio, heterocyclic, heterocyclicoxy, heterocyclicthio, heterocyclic alkylene, heterocyclic alkoxy, heterocyclic alkylthio, acyl, acyloxy, carbamate group, amide group, urea group, epoxy group, ester group and oxygen The substituents are optionally substituted by one or more substituents selected from the group consisting of: 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 alkylalkylene, heterocyclic alkyloxy, heteroaryl, heteroaryl alkylene, heteroaryloxy, aryl, aryl alkylene or aryloxy.

[0242] 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, halogenated 3-12 membered cycloalkyl, C 2-12 alkenyl, halogenated C 2-12 alkenyl, 3-12 membered cycloalkenyl, halogenated 3-12 membered cycloalkenyl, C 2-12 alkynyl, halogenated C 2-12 Alkynyl, 8-12 membered cycloalkynyl, halogenated 8-12 membered cycloalkynyl, C 1-12 Heteroalkyl, halogenated C 1-12 Heteroalkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, 6-10 aryl, 6-10 aryloxy, 6-10 arylthio, 6-10 arylC 1-12Alkylene, 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 1-12 Alkylene, 3-12-membered heterocyclic alkyloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryl C 1-12alkylene, 5-10 heteroaryloxy, 6-10 aryl, 6-10 aryl C 1-12 Alkylene or 6-10 aryloxy groups.

[0243] 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.

[0244] The term "derivative" refers to a new compound or group of new compounds that are produced through one or more chemical reactions or structural evolution, retaining the basic structure of the parent compound but changing or modifying only the side chains, functional groups or substituents.

[0245] 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.

[0246] 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-Cy 2 - 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-Cy 2 - 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.

[0247] 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.

[0248] 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.

[0249] 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.

[0250] 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.

[0251] 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.

[0252] 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.

[0253] 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.

[0254] 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”.

[0255] 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".

[0256] 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%.

[0257] The compounds and intermediates of this application may also exist in different tautomer forms, and all such forms are included within the scope of this application. The terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can interconvert via low-barrier transitions. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. A specific example of a proton tautomer is the imidazole moiety, where a proton can migrate between two ring nitrogens. Valence tautomers include interconversions via the recombination of some bonding electrons. Specifically, any compound of this disclosure, such as pyrazole alone or as part of a heterocyclic group, may exist in the form of two arbitrary tautomers or any mixture of two tautomers, i.e. ,or This disclosure includes all possible tautomers of the compounds disclosed herein, as a single tautomer or any mixture of said tautomers in any proportion.

[0258] 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.

[0259] Certain isotope-labeled compounds of this application (e.g., using...) 3 H and 14 Those labeled with C can be used in the analysis of compound and / or substrate tissue distribution. Tritiumization (i.e. 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Positron-emitting isotopes, such as... 15 O、 13 N、 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. The isotopically labeled compounds of this application can typically be prepared by replacing the unlabeled reagent with an isotopically labeled reagent using a procedure similar to those disclosed in the schemes and / or examples below.

[0260] 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.

[0261] 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.

[0262] 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.

[0263] 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.

[0264] 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.

[0265] 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.

[0266] 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.

[0267] The pharmaceutical composition may also be suitable for parenteral administration, such as in suitable unit dosage forms of sterile solutions, suspensions or lyophilized products.

[0268] 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.

[0269] 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.

[0270] 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.

[0271] 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 embodiments, the compounds of formula I of this application can be prepared by those skilled in the art of organic synthesis via the following route:

[0272]

[0273] Compound of general formula I-1 yields compound of general formula I-2 via substitution reaction; compound of general formula I-2 yields compound of general formula I-3 via deprotection reaction; then, compound of general formula I-3 yields compound of general formula I-4 via condensation reaction; compound of general formula I-4 yields compound of general formula I-5 via oxidation reaction; chlorinated aromatic carboxylic acids yield compound of general formula I-5 via hydroxyl-substituted Cy 1 The substitution reaction yields compound I-6; compound I-7 is obtained by deprotection reaction; finally, compound I-5 and compound I-7 are obtained by reductive amination reaction to yield compound I. Compounds of general formula I-3 and general formula I-10 undergo a condensation reaction to yield compound of general formula I-8, and compound of general formula I-8 undergoes a deprotection reaction to yield compound of general formula I-9; chlorinated aromatic carboxylic acids undergo a condensation reaction with Boc-protected Cy... 1 Substitution reactions yield compounds of general formula I-10; oxidation reactions yield compounds of general formula I-11; and reductive amination reactions yield compounds of general formula I from compounds of general formula I-9 and I-11.

[0274] This application uses the following abbreviations: Boc represents tert-butyloxycarbonyl; Et represents ethyl; EA represents ethyl acetate; DMSO represents dimethyl sulfoxide; DMF represents N,N-dimethylformamide; BINAP represents 1,1'-binaphthyl-2,2'-bis(diphenylphosphine); DCM represents dichloromethane; Pd2(dba)3 represents tris(dibenzylacetone)dipalladium; THF represents tetrahydrofuran; PMB represents p-methoxybenzyl; MeOH represents methanol; PE represents petroleum ether; IBX represents 2-iodobenzoic acid; DIPEA represents N,N'-diisopropylethylamine; DIBAL-H represents diisobutylaluminum hydride; NIS represents N -Iodosuccinimide; NBS represents N-bromosuccinimide; Tf represents -OSO2CF3; HATU represents 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; xantphos represents 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene; DCE represents dichloroethane; DMA or DMAC represents N,N-dimethylacetamide; AIBN represents azobisisobutyronitrile; DMAP represents 4-dimethylaminopyridine; CCl4 represents carbon tetrachloride; Ruphos represents 2-bicyclohexylphosphine-2',6'-diisopropoxybiphenyl.

[0275] 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

[0276] Synthesis of Intermediate 1 in Example 1

[0277]

[0278] Step 1: Preparation of intermediate 1b At 10°C, 1a (81g), 2,4-dimethoxybenzylamine (83g), and acetic acid (500mL) were added sequentially to the reaction flask, and the temperature was raised to 80°C. o C reaction was performed, and the reaction was monitored until it ended. Water (800 mL) was added to the reaction solution, the mixture was filtered, the filter cake was washed with water, and dried to obtain intermediate 1b (95.78 g).

[0279] MS (ESI, [MH] - ) m / z 312.02.

[0280] 1 H NMR (500 MHz, DMSO- d 6) δ 11.03 (s, 1H), 7.62 (dd, J = 8.4, 7.1 Hz, 1H), 7.29 (d, J = 7.1 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.56 (d, J = 2.4 Hz, 1H), 6.43 (dd, J = 8.4, 2.4 Hz, 1H), 4.60 (s, 2H), 3.80 (s, 3H), 3.73 (s, 3H). Step 2: Preparation of intermediate 1c At 10°C, a 2.5M lithium aluminum hydride solution in tetrahydrofuran (227 mL) was slowly added dropwise to a 1b (96.00 g) solution in tetrahydrofuran (1000 mL). The solution was then subjected to a reaction at 80°C. o C. Add 30.5 g of 15% sodium hydroxide aqueous solution and 100 mL of water to the reaction solution, filter, wash the filter cake with dichloromethane / MeOH = 1 / 1 solution, concentrate the filtrate, and separate the crude product by silica gel column chromatography to obtain intermediate 1c (55.87 g).

[0281] MS (ESI, [M+H) + ) m / z 286.01 1H NMR (500 MHz, DMSO- d 6) δ 9.28 (s, 1H), 7.24 (d, J = 8.3 Hz, 1H), 6.97(t, J = 7.7 Hz, 1H), 6.64 (d, J = 7.4 Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H), 6.55 (d, J =2.4 Hz, 1H), 6.51 (dd, J = 8.3, 2.4 Hz, 1H), 3.81 – 3.71 (m, 12H). Step 3: Preparation of intermediate 1d 48.00 g of 1 C, 350 mL of methanol, 4.8 g of palladium hydroxide, and 41.4 g of di-tert-butyl dicarbonate were added sequentially to the reaction flask. Under hydrogen protection, the mixture was heated to 25 °C. o C reaction. The reaction solution was filtered, the filtrate was concentrated, water (200 mL) and ethyl acetate were added for extraction, the mixture was washed with saturated brine and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography to obtain intermediate 1d (34.43 g).

[0282] 1 H NMR (500 MHz, DMSO- d 6) δ 7.07 (t, J = 7.7 Hz, 1H), 6.68 (ddd, J = 18.9,7.8, 2.7 Hz, 2H), 4.56 – 4.50 (m, 2H), 4.48 – 4.42 (m, 2H), 1.45 (s, 9H). Step 4: Preparation of intermediate 1e Add 1 d (35.00 g), methanol (250 mL), and 4M hydrochloric acid 1,4-dioxane solution (123 mL) sequentially to the reaction flask. o The reaction mixture was reacted at C for 3 hours. The reaction solution was concentrated, and pyridine (200 mL) and trifluoroacetic anhydride (25.20 g) were added. o The reaction mixture was stirred for 40 hours. The reaction solution was poured into a 3M hydrochloric acid aqueous solution, stirred vigorously, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain intermediate 1e (32.48 g).

[0283] MS (ESI, [MH] - ) m / z 229.99 1 H NMR (500 MHz, DMSO- d 6)δ 9.82 (d, J = 24.4 Hz, 1H), 7.16 (td, J = 7.7, 3.7 Hz, 1H), 6.81 (dd, J = 11.5, 7.5 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 4.99 (s,1H), 4.89 (s, 1H), 4.80 (s, 1H), 4.70 (s, 1H). Step 5: Preparation of intermediate 1f In a reaction flask, 1e (32.48 g), dichloromethane (300 mL), triethylamine (28.40 g), 4-dimethylaminopyridine (1.72 g), and acetic anhydride (15.78 g) were added sequentially. 25 o C reaction. After the reaction was completed, the reaction solution was poured into water, stirred vigorously, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated the filtrate, and separated the crude product by silica gel column chromatography to obtain intermediate 1f (33.82 g).

[0284] 1 H NMR (500 MHz, DMSO- d 6)δ 7.41 (td, J = 7.8, 2.3 Hz, 1H), 7.30 (t, J =8.5 Hz, 1H), 7.12 (dd, J = 7.9, 2.9 Hz, 1H), 5.09 (s, 1H), 4.90 (d, J = 12.3 Hz,2H), 4.72 (s, 1H), 2.31 (d, J = 3.4 Hz, 3H). Step 6: Preparation of 1g of intermediate Add 1f (30.00g), aluminum trichloride (29.30g), and o-dichlorobenzene (200mL) sequentially to the reaction flask, then add 150... o After reacting at C for 1 hour, the reaction solution was poured into an aqueous citric acid solution and stirred vigorously. Ethyl acetate was added for extraction, and the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by silica gel column chromatography to obtain 1 g (18.19 g) of intermediate.

[0285] 1 H NMR (500 MHz, DMSO- d 6) δ 12.38 (s, 1H), 7.94 (dd, J = 8.2, 4.7 Hz, 1H), 7.01 (dd, J = 12.7, 8.1 Hz, 1H), 5.07 (s, 1H), 4.94 (s, 1H), 4.86 (s, 1H), 4.74 (d, J = 1.6 Hz, 1H), 2.66 (d, J = 1.0 Hz, 3H). Step 7: Preparation of intermediate for 1 hour Add 1g (18.19g), sodium hydroxide (7.56g), methanol (150mL), and water (150mL) sequentially to the reaction flask. 25 o In reaction C, the reaction solution was concentrated to remove methanol, and the residue was treated with 1,4-dioxane (150 mL) and di-tert-butyl dicarbonate (15.14 g). 25 o C. Stirring reaction. After the reaction is complete, the reaction solution is poured into water, stirred vigorously, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated the filtrate, and the crude product is separated by silica gel column chromatography to obtain intermediate 1h (14.10 g).

[0286] MS (ESI, [MH] - ) m / z : 276.07 1 H NMR (500 MHz, DMSO- d 6) δ 12.36 (s, 1H), 7.89 (dd, J = 8.1, 2.9 Hz, 1H), 6.95 (t, J = 8.0 Hz, 1H), 4.62 (dt, J = 13.4, 2.2 Hz, 2H), 4.51 (dt, J =13.9, 2.3 Hz, 2H), 2.65 (s, 3H), 1.46 (s, 9H). Step 8: Preparation of intermediate 1i 1 h (14.10 g), diethyl carbonate (27.00 g), and toluene (200 mL) were added sequentially to the reaction flask, and the mixture was cooled to 0 °C. o C, after adding 60wt% sodium hydride (9.16g), heat to 120°C. oC. Stirring reaction. After the reaction was completed, the reaction solution was poured into 3M hydrochloric acid aqueous solution, stirred vigorously, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated the filtrate, and the crude product was separated by silica gel column chromatography to obtain intermediate 1i (14.96 g).

[0287] 1 H NMR (500 MHz, DMSO- d 6) δ 11.72 (d, J = 9.6 Hz, 1H), 7.82 (dd, J = 8.2, 4.7 Hz, 1H), 6.97 (t, J = 8.4 Hz, 1H), 4.63 (dt, J = 12.4, 2.1 Hz, 2H), 4.53 (dt, J = 13.7, 2.1 Hz, 2H), 4.22 (d, J = 2.5 Hz, 2H), 4.13 (q, J = 7.1 Hz, 2H), 1.46(d, J = 1.9 Hz, 9H), 1.19 (t, J = 7.1 Hz, 3H). Step 9: Preparation of intermediate 1j 1i (14.96g), 50% hydroxylamine aqueous solution (6.36g), and ethanol (150mL) were added sequentially to the reaction flask. o The reaction mixture was stirred for 3 hours. After the reaction solution was concentrated, water and ethyl acetate were added, and the layers were extracted and separated. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to obtain crude intermediate 1j (10.13 g).

[0288] MS (ESI, [MH] - ) m / z : 317.20.

[0289] 1 H NMR (500 MHz, DMSO- d 6) δ 12.59 (s, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 4.85 (dt, J = 13.5, 2.5 Hz, 2H), 4.75 (dt, J= 12.2, 2.4Hz, 2H), 4.11 (s, 2H), 1.49 (d, J = 2.1 Hz, 9H). Step 10: Preparation of intermediate 1k 10.13 g of potassium carbonate (12.55 g), 150 mL of N,N-dimethylacetamide, and 7.08 g of iodoethane were added sequentially to the reaction flask. o C. Stir the reaction mixture for 1 hour. Pour the reaction mixture into water, stir vigorously, add ethyl acetate for extraction, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate and separate by silica gel column chromatography to obtain intermediate 1k (11.22 g).

[0290] MS (ESI, [M+H) + ) m / z 347.16.

[0291] 1 H NMR (500 MHz, DMSO- d 6)δ 7.78 (d, J = 8.0 Hz, 1H), 7.39 (t, J = 7.5 Hz,1H), 4.89 – 4.82 (m, 2H), 4.75 (dd, J = 11.8, 2.8 Hz, 2H), 4.22 (d, J = 4.3 Hz, 2H), 4.13 (p, J = 7.2 Hz, 2H), 1.48 (d, J = 2.1 Hz, 9H), 1.21 – 1.17 (m, 3H). Step 11: Preparation of intermediate 1L 0 o Under C, N2 protection, acrylamide (1.32 g) was slowly added to 1 kJ (10.72 g) of tetrahydrofuran (50 mL) with stirring, followed by the dropwise addition of 1 M potassium tert-butoxide tetrahydrofuran solution (18.63 mL). The mixture was then stirred at 0°C. o The reaction mixture was stirred for 3 hours. The reaction solution was poured into an aqueous solution of ammonium chloride, stirred vigorously, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by silica gel column chromatography to obtain intermediate 1L (7.52g).

[0292] MS (ESI, [M+H) + ) m / z 372.02.

[0293] 1 H NMR (500 MHz, DMSO- d 6) δ 11.11 (s, 1H), 7.80 (dd, J = 8.1, 2.7 Hz, 1H), 7.37 (t, J = 7.9 Hz, 1H), 4.85 (dd, J = 12.2, 2.6 Hz, 2H), 4.75 (dt, J = 12.0, 2.3 Hz, 2H), 4.63 (dd, J = 12.1, 4.9 Hz, 1H), 2.78 (ddd, J = 17.3, 12.1, 5.3 Hz,1H), 2.67 – 2.51 (m, 2H), 2.20 (dq, J = 13.5, 4.7 Hz, 1H), 1.49 (d, J = 2.6 Hz, 9H). Step 12: Preparation of Intermediate 1 1 L (1.00 g), 10 mL of 4 M hydrochloric acid 1,4-dioxane solution, and 50 mL of ethyl acetate were added sequentially to the reaction flask. The reaction was carried out at 25 °C for 8 h. The reaction solution was directly filtered, and the filter cake was washed with ethyl acetate and dried to obtain intermediate 1 (0.83 g).

[0294] MS (ESI, [M+H) + ) m / z :272.11.

[0295] 1 H NMR (500 MHz, DMSO- d 6) δ 11.13 (s, 1H), 10.36 (s, 2H), 7.90 (d, J =8.1 Hz, 1H), 7.45 (d, J = 8.2 Hz, 1H), 4.81 (s, 2H), 4.70 – 4.63 (m, 3H), 2.79(ddd, J = 17.4, 12.2, 5.3 Hz, 1H), 2.62 (dt, J = 17.3, 4.0 Hz, 1H), 2.59 – 2.52(m, 1H), 2.21 (ddt, J= 13.2, 5.1, 2.5 Hz, 1H). Preparation of Intermediate 2 in Example 2

[0296]

[0297] Step 1: Preparation of intermediate 2b 2a (18 g), AIBN (0.738 g), carbon tetrachloride (500 mL), and NBS (47.8 g) were added sequentially to the reaction flask, and the temperature was raised to 60 °C. The reaction solution was cooled to room temperature, and the solvent was removed by vacuum distillation. 200 mL of dichloromethane was added to the residue. After washing with saturated brine and drying with anhydrous sodium sulfate, the solution was filtered, and the solvent was removed by vacuum distillation of the filtrate. The residue was purified by silica gel column chromatography to obtain intermediate 2b (18.7 g).

[0298] Step 2: Preparation of intermediate 2c 2b (18.7 g), benzylamine (1.78 mL), N,N-diisopropylethylamine (7.13 mL), and toluene (50 mL) were added sequentially to the reaction flask, and the temperature was raised to 50 °C. The reaction solution was cooled to room temperature, and the reaction was complete. 200 mL of ethyl acetate and 200 mL of 1M HCl ice-water solution were added to the reaction solution for extraction. The aqueous phase was collected, and the pH was adjusted to approximately 8 with sodium bicarbonate solid. Ethyl acetate was then added for extraction, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain intermediate 2c (9.6 g).

[0299] MS(ESI, [M+H)) + ) m / z :240.1.

[0300] Step 3: Preparation of intermediate 2d 2c (9.6 g), methanol (200 mL), 10% palladium on carbon (5 g), and toluene (50 mL) were added sequentially to the reaction flask. The mixture was purged with hydrogen three times and reacted at room temperature under a hydrogen atmosphere. The palladium on carbon was filtered, the filter cake was washed with methanol, the filtrate was collected, and the solvent was removed by vacuum evaporation to obtain 2d (4.5 g).

[0301] MS(ESI, [M+H)) + ) m / z : 149.9.

[0302] Step 4: Preparation of intermediate 2e 2d (4 g), tetrahydrofuran (50 mL), and trifluoroacetic anhydride (5.63 g) were added sequentially to the reaction flask, and the reaction was carried out at room temperature. The reaction was quenched by adding 200 mL of aqueous solution, followed by extraction with ethyl acetate. The organic phase was separated, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain 2e (4.58 g).

[0303] 1 H NMR (500 MHz, DMSO- d 6) δ 7.29 (t, J = 9.3 Hz, 1H), 6.98 (d, J = 8.6Hz, 1H), 6.93 – 6.86 (m, 1H), 4.97 (d, J = 21.7 Hz, 2H), 4.77 (dd, J = 21.4, 5.2Hz, 2H), 3.76 (dd, J = 3.6, 1.6 Hz, 3H). Step 5: Preparation of intermediate 2f 2e (4.6 g), dichloromethane (200 mL), and boron tribromide (1 M, 18.76 mL) were added sequentially to the reaction flask, and the reaction was carried out at room temperature. The reaction was quenched by adding 200 mL of aqueous solution to the reaction solution under ice bath. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum evaporation to obtain 2f (4.2 g). 1 H NMR (500 MHz, DMSO- d 6) δ 7.16 (t, J = 8.8 Hz, 1H), 6.87 – 6.59 (m,2H), 4.92 (d, J = 20.8 Hz, 2H), 4.72 (d, J = 19.9 Hz, 2H). Step 6: Preparation of 2g of intermediate 2f (6.5 g), dichloromethane (60 mL), triethylamine (7.8 mL), and acetic anhydride (2.94 mL) were added sequentially to the reaction flask, and the reaction was carried out at room temperature. 200 mL of dichloromethane and 300 mL of water were added to the reaction solution. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain 2 g (7 g).

[0304] 1 H NMR (500 MHz, DMSO- d6) δ 7.42 (dd, J = 10.0, 8.3 Hz, 1H), 7.17 (dd, J = 14.0, 2.1 Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H), 5.03 (d, J = 6.6 Hz, 2H), 4.83 (d, J = 6.9 Hz, 2H), 2.27 (s, 3H). Step 7: Preparation of intermediates over 2 hours 2 g (6 g) and aluminum trichloride (4.39 g) were added sequentially to the reaction flask, and the mixture was gradually heated from room temperature to 150 °C. The reaction solution was cooled to room temperature, and 500 mL of water and 100 mL of 3M hydrochloric acid aqueous solution were added to the residue. The organic phase was separated, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography after solvent removal under reduced pressure to obtain 2 h (3.78 g).

[0305] MS(ESI, [MH] - ) m / z :271.9.

[0306] Step 7: Preparation of intermediate 2j In a reaction flask, 550 mg of 2h, 5.00 mL of MeOH, and 5.00 mL of an aqueous solution of 242 mg of sodium hydroxide were added sequentially, and the reaction was carried out at room temperature. The reaction solution was concentrated to remove methanol, retaining the aqueous phase. 2i was obtained. 1,4-Dioxane (5 mL) and Boc anhydride (439 mg, 0.462 mL) were added to the system, and the reaction was carried out at room temperature. The reaction solution was extracted with 200 mL of ethyl acetate and 200 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2j (200 mg).

[0307] 1 H NMR (500 MHz, DMSO- d 6) δ 12.11 (d, J = 19.3 Hz, 1H), 7.88 (d, J = 9.5Hz, 1H), 6.74 – 6.56 (m, 1H), 4.60 – 4.50 (m, 4H), 2.63 (d, J = 6.5 Hz, 3H), 1.45 (s, 9H). Step 8: Preparation of intermediate 2k 2kJ (3.5 g), THF (300 mL), and diethyl carbonate (14.91 g, 15.29 mL) were added sequentially to the reaction flask. The temperature was lowered to approximately 0°C, and 60 wt% sodium hydroxide (5.05 g, 126 mmol) was added in portions. The reaction mixture was heated to 85°C. The reaction solution was cooled to room temperature and slowly poured into 500 mL of ice water. The solution was extracted with ethyl acetate, and the organic phase was discarded. The aqueous phase was adjusted to pH 1-2 with 3M hydrochloric acid, then extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain 2kJ (7.0 g).

[0308] MS(ESI, [MH] - ) m / z 348.3.

[0309] Step 9: Preparation of intermediate 2l 2kJ (4.4 g), hydroxylamine aqueous solution (4.16 g, 63.0 mmol), and ethanol (50 mL) were added sequentially to the reaction flask, and the reaction was carried out at 85 °C. The reaction solution was cooled to room temperature, and the residue was extracted with 200 mL of ethyl acetate and 100 mL of saturated sodium carbonate aqueous solution. The organic phase was discarded. The aqueous phase was adjusted to pH 2-3 with 1M HCl aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain 2 L (3.25 g). 1 H NMR (500 MHz, DMSO- d 6) δ 12.83 (s, 1H), 7.74 (d, J = 13.0 Hz, 1H), 7.68 (d, J = 3.5 Hz, 1H), 4.71 (d, J = 13.6 Hz, 2H), 4.66 (d, J = 11.4 Hz, 2H), 4.07 (s, 2H), 1.47 (s, 9H). Step 10: Preparation of intermediate 2m 2 L (3.14 g), potassium carbonate (1.500 g), DMA (5 mL), and iodoethane (2.308 g, 1.183 mL) were added sequentially to a reaction flask, and the mixture was heated to 80 °C. The reaction solution was cooled to room temperature, and a mixture of 100 mL ethyl acetate and 200 mL water was added. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to obtain 2 M (2.47 g).

[0310] 1 H NMR (500 MHz, DMSO- d6) δ 7.73 (d, J = 15.9 Hz, 1H), 7.69 (d, J = 3.5Hz, 1H), 4.69 (dd, J = 23.8, 12.4 Hz, 4H), 4.19 – 4.11 (m, 4H), 1.47 (s, 9H), 1.20 (t, J = 7.1 Hz, 3H). Step 11: Preparation of intermediate 2n 2M (1.5 g), THF (75 mL), and acrylamide (0.215 g) were added sequentially to the reaction flask. The mixture was cooled to approximately -15°C, and 1M potassium tert-butoxide tetrahydrofuran solution (2.60 mL) was added. The system was then heated to 0°C and reacted for 1.5 hours. The reaction mixture was quenched dropwise in 200 mL of ammonium chloride solution, extracted with ethyl acetate, and the organic phase was separated. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain 2N (0.88 g). 1 H NMR (500 MHz, DMSO- d 6) δ 11.11 (d, J = 3.4 Hz, 1H), 7.78 (d, J = 12.4Hz, 1H), 7.70 (s, 1H), 4.68 (dd, J = 29.4, 13.3 Hz, 4H), 4.58 (dd, J = 12.0, 4.9Hz, 1H), 2.79 (ddd, J = 17.3, 12.1, 5.3 Hz, 1H), 2.62 (dt, J = 17.3, 4.1 Hz, 1H), 2.56 – 2.50 (m, 1H), 2.31 – 2.14 (m, 1H), 1.47 (d, J = 1.5 Hz, 9H). Step 12: Preparation of Intermediate 2 2n (0.428 g) and dichloromethane (10.00 mL) were added sequentially to the reaction flask, followed by trifluoroacetic acid (3.29 g, 2.211 mL). The reaction was carried out at room temperature for 1 hour. 80 mL of water was added to the reaction solution, and the pH was adjusted to 7-8 with saturated sodium bicarbonate. Dichloromethane was added for extraction, and the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain intermediate 2 (0.439 g).

[0311] MS(ESI, [M+H)) + ) m / z :272.24.

[0312] 1 H NMR (500 MHz, DMSO- d 6) δ 7.81 – 7.77 (m, 1H), 7.74 (s, 1H), 4.59(dd, J = 12.1, 5.0 Hz, 1H), 4.49 (s, 2H), 4.43 (s, 2H), 2.79 (ddd, J = 17.4,12.2, 5.3 Hz, 1H), 2.62 (dt, J = 17.3, 4.0 Hz, 1H), 2.47 (dd, J = 12.4, 4.4 Hz,1H), 2.20 (ddt, J = 13.3, 5.2, 2.6 Hz, 1H). Synthesis of Intermediate 3 in Example 3

[0313]

[0314] Step 1: Preparation of intermediate 3b Intermediate 3a (25 g) was dissolved in methanol (1000 mL) and acetic acid (103 g, 99 mL, 1722 mmol), and then injected into a flow hydrogenation reactor at a pressure of 3 MPa, a temperature of 110 °C, and a flow rate of 3 mL / min. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure. The residue contained 1,4-dioxane hydrochloride solution (4 mol / L, 100 mL), and the solvent was removed under reduced pressure. The residue was then mixed with ethyl acetate, filtered, and the filter cake was collected to obtain the target intermediate 3b (28.97 g).

[0315] MS(ESI, [M+H)) + m / z: 150.0.

[0316] 1H NMR (500 MHz, DMSO-d6) δ 10.01 (s, 1H), 7.06 (t, J = 7.8 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 6.64 (d, J = 7.6 Hz, 1H), 4.01 (t, J = 4.9 Hz, 2H), 3.33 – 3.25 (m, 2H), 2.94 (t, J = 6.2 Hz, 2H). Step 2: Preparation of intermediate 3c Intermediate 3b (28.97 g) and tetrahydrofuran (300 mL) were added sequentially to a reaction flask. Trifluoroacetic anhydride (27.0 mL) was added under ice bath conditions, and the mixture was reacted at room temperature. After the reaction was complete, 500 mL of ethyl acetate and 1000 mL of water were added to the reaction solution for extraction. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The filter cake was collected to obtain the target intermediate 3c (22.67 g).

[0317] MS(ESI, [MH] - ) m / z :244.0.

[0318] 1 H NMR (500 MHz, DMSO-d6) δ 7.03 (q, J = 7.9 Hz, 1H), 6.74 – 6.68 (m,1H), 6.64 (t, J = 6.9 Hz, 1H), 4.61 (d, J = 23.5 Hz, 2H), 3.78 (td, J = 6.0,3.7 Hz, 2H), 2.84 (dt, J = 16.8, 5.9 Hz, 2H). Step 3: Preparation of intermediate 3D Intermediate 3c (22.67 g), dichloromethane (200 mL), triethylamine (28.1 g, 38.6 mL), and DMAP (0.282 g) were added sequentially to a reaction flask. Acetic anhydride (10.38 g, 9.68 mL) was added under ice bath conditions, and the mixture was allowed to return to room temperature for further reaction. After the reaction was complete, the solvent was removed from the reaction solution by vacuum distillation. The residue was extracted with 500 mL of ethyl acetate and 1000 mL of water, and the organic phases were separated. The residue was washed with saturated ammonium chloride solution and saturated brine solution, respectively, dried over anhydrous sodium sulfate, filtered, and the filtrate was further purified by vacuum distillation to obtain the target intermediate 3d (21.94 g).

[0319] 1H NMR (500 MHz, DMSO-d6) δ 7.30 (dt, J = 11.1, 7.8 Hz, 1H), 7.18 –7.11 (m, 1H), 7.05 (dt, J = 8.0, 2.2 Hz, 1H), 4.59 (s, 2H), 3.81 (q, J = 6.1Hz, 2H), 2.95 (dt, J = 10.1, 6.0 Hz, 2H), 2.33 (d, J = 9.5 Hz, 3H). Step 4: Preparation of intermediate 3e Intermediate 3d (21 g) and aluminum trichloride (14.62 g) were added sequentially to a reaction flask. Under N2 protection, the mixture was heated to 170 °C for reaction. After the reaction was completed, the reaction solution was cooled to room temperature, and the reaction was quenched with 300 mL of water. Then, dichloromethane was added for extraction. The organic phases were combined, washed with 500 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to obtain the target intermediate 3e (10.16 g).

[0320] MS(ESI, [MH] - ) m / z :286.0.

[0321] 1 H NMR (500 MHz, DMSO-d6) δ 12.76 (d, J = 8.4 Hz, 1H), 7.83 (t, J =8.8 Hz, 1H), 6.86 (dd, J = 8.3, 5.7 Hz, 1H), 4.67 (d, J = 25.1 Hz, 2H), 3.86– 3.78 (m, 2H), 2.94 (dt, J = 13.3, 5.9 Hz, 2H), 2.64 (d, J = 1.2 Hz, 3H). Step 5: Preparation of intermediate 3f Intermediate 3e (10.16 g) and methanol (100 mL) were added sequentially to a reaction flask. A solution of sodium hydroxide (4.24 g) in water (100 mL) was added dropwise under ice bath conditions, and the mixture was allowed to return to room temperature for further reaction. After the reaction was complete, the methanol was removed from the reaction solution under reduced pressure. 1,4-Dioxane (100 mL) and di-tert-butyl dicarbonate (8.49 g, 9.03 mL) were added, and the mixture was allowed to react at room temperature. After the reaction was complete, the reaction solution was extracted with 500 mL of ethyl acetate and 800 mL of water, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain the target intermediate 3f (8.96 g).

[0322] MS(ESI, [M+H)) + m / z: 292.0.

[0323] 1 H NMR (500 MHz, DMSO-d6) δ 12.72 (s, 1H), 7.76 (d, J = 8.2 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 4.41 (s, 2H), 3.55 (t, J = 5.8 Hz, 2H), 2.80 (t, J= 5.8 Hz, 2H), 2.63 (s, 3H), 1.43 (s, 9H). Step 6: Preparation of 3g of intermediate Intermediate 3f (8.76 g), diethyl carbonate (17.76 g, 18.21 mL), and toluene (90 mL) were added sequentially to a reaction flask. 60 wt% sodium hydride (6.01 g) was added in portions under ice bath conditions. The mixture was heated to 120 °C. After the reaction was complete, the reaction solution was cooled to room temperature and quenched in ice water. The pH was adjusted to 1-2 with 1 M hydrochloric acid solution, and 300 mL of ethyl acetate was added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent, yielding 3 g (12.03 g) of the target intermediate.

[0324] Step 7: Preparation of intermediate over 3 hours 3 g (9.54 g) of intermediate, 100 mL of EtOH, and 9.93 g and 9.21 mL of hydroxylamine aqueous solution were added sequentially to the reaction flask. The mixture was heated to 85 °C. After the reaction was complete, 200 mL of saturated sodium carbonate solution was added to adjust the pH to 9-10. Ethyl acetate was added for extraction, and the organic phase was separated. The organic phase was extracted twice with water, and the aqueous phases were combined. The pH of the aqueous phase was then adjusted to 3 with 1 M hydrochloric acid, and 200 mL of ethyl acetate was added for extraction. The solution was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum evaporation to obtain the target intermediate 3h (9.01 g).

[0325] MS(ESI, [MH] - ) m / z :331.0.

[0326] Step 8: Preparation of intermediate 3i Intermediate 3h (9.01 g), potassium carbonate (11.24 g), DMA (90 mL), and iodoethane (5.07 g, 2.63 mL) were added sequentially to a reaction flask. Under N2 protection, the mixture was heated to 80 °C. After the reaction was complete, the reaction solution was cooled to room temperature, and extracted with 200 mL of ethyl acetate and 1000 mL of water. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to obtain the target intermediate 3i (7.33 g).

[0327] MS(ESI, [M+H)) + m / z: 361.0.

[0328] 1 H NMR (500 MHz, DMSO-d6) δ 7.63 (d, J = 8.1 Hz, 1H), 7.21 (d, J =8.2 Hz, 1H), 4.76 (s, 2H), 4.18 (s, 2H), 4.13 (q, J = 7.1 Hz, 2H), 3.66 (t, J= 5.8 Hz, 2H), 2.93 (t, J = 5.8 Hz, 2H), 1.45 (s, 9H), 1.19 (t, J = 7.1 Hz, 3H). Step 9: Preparation of intermediate 3j Intermediate 3i (7.3 g), tetrahydrofuran (80 mL), and acrylamide (0.864 g) were added sequentially to a reaction flask. The mixture was cooled to -15°C under N2 protection, and potassium tert-butoxide tetrahydrofuran solution (1 mol / L, 11.14 mL) was added dropwise. After the addition was complete, the temperature was raised to 0°C for further reaction. After the reaction was complete, the resulting reaction mixture was added to 200 mL of saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was separated. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to obtain the target intermediate 3j (4.54 g).

[0329] MS(ESI, [MH] - ) m / z 384.3.

[0330] 1H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 7.65 (d, J = 8.1 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 4.76 (s, 2H), 4.58 (dd, J = 12.0, 5.0 Hz, 1H), 3.66(t, J = 5.8 Hz, 2H), 2.93 (t, J = 5.8 Hz, 2H), 2.77 (ddd, J = 17.3, 12.1, 5.3Hz, 1H), 2.61 (dt, J = 17.3, 4.1 Hz, 1H), 2.54 (d, J = 4.5 Hz, 1H), 2.18(dtd, J = 13.5, 5.2, 3.6 Hz, 1H), 1.45 (s, 9H). Step 10: Preparation of Intermediate 3 Intermediate 3j (300 mg) and ethyl acetate (5 mL) were added sequentially to a reaction flask, followed by 1,4-dioxane hydrochloric acid solution (4 mol / L, 3.89 mL). The mixture was reacted at room temperature. After the reaction was complete, the reaction solution was concentrated to obtain intermediate 3 (235 mg).

[0331] MS(ESI, [M+H)) + m / z: 286.10.

[0332] 1 H NMR (500 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.10 (d, J = 8.2 Hz, 1H), 4.55 (dd, J = 11.9, 5.0 Hz, 1H), 4.07 (s, 2H), 3.00(t, J = 5.7 Hz, 2H), 2.81 (t, J = 5.7 Hz, 2H), 2.78 – 2.71 (m, 1H), 2.60 (dt,J = 17.3, 4.2 Hz, 1H), 2.46 (dd, J = 12.2, 4.5 Hz, 1H), 2.18 (dq, J = 13.6, 4.9 Hz, 1H). Synthesis of Intermediate 4 in Example 4

[0333]

[0334] Step 1: Preparation of intermediate 4b Intermediate 4a was dissolved in methanol (1680 mL) and acetic acid (166 mL), and then injected into a flow hydrogenation reactor at a pressure of 3 MPa, a temperature of 110 °C, and a flow rate of 3 mL / min. After the reaction was complete, the solvent was removed by vacuum distillation. The residue contained 1,4-dioxane hydrochloride solution (4 mol / L, 200 mL). The solvent was removed by vacuum distillation, and the residue was slurried with 100 mL of ethyl acetate. After filtration, the filter cake was collected to obtain the target intermediate 4b (46.96 g).

[0335] MS(ESI, [M+H)) + m / z: 150.0.

[0336] 1 H NMR (500 MHz, DMSO-d6) δ 9.81 (s, 1H), 7.03 (t, J = 7.7 Hz, 1H), 6.78 (d, J = 7.8 Hz, 1H), 6.62 (d, J = 7.6 Hz, 1H), 4.15 (s, 2H), 3.35 (s,2H), 2.79 (s,2H). Step 2: Preparation of intermediate 4c Intermediate 4b (40 g) and tetrahydrofuran (400 mL) were added sequentially to a reaction flask. Trifluoroacetic anhydride (61.9 g, 41.0 mL) was then added under ice bath conditions, and the reaction was carried out at room temperature. After the reaction was complete, the reaction solution was extracted with 500 mL of ethyl acetate and 1000 mL of water. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent, yielding the target intermediate 4c (81 g).

[0337] MS(ESI, [MH] - ) m / z : 244.04.

[0338] Step 3: Preparation of intermediate 4d Intermediate 4c (65.3 g), dichloromethane (650 mL), triethylamine (81 g, 111 mL), and DMAP (0.813 g) were added sequentially to the reaction flask. Acetic anhydride (29.9 g, 27.9 mL) was added under ice bath conditions, and the reaction was carried out at room temperature. After the reaction was completed, the solvent was removed from the reaction solution by vacuum distillation. The residue was extracted with 500 mL of ethyl acetate and 1000 mL of water. The organic phases were separated and washed with saturated ammonium chloride solution and saturated brine solution, respectively. The residue was dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate by vacuum distillation to obtain the target intermediate 4d (55.6 g).

[0339] 1 H NMR (500 MHz, Chloroform-d) δ 7.28 (d, J = 7.9 Hz, 1H), 7.10 –7.02 (m, 1H), 7.02 – 6.95 (m, 1H), 4.79 (d, J = 27.0 Hz, 2H), 3.92 – 3.78 (m,2H), 2.82 – 2.72 (m, 2H), 2.33 (d, J = 2.0 Hz, 3H). Step 4: Preparation of intermediate 4e Intermediate 4d (30.73 g) and aluminum trichloride (21.40 g) were added sequentially to the reaction flask. Under N2 protection, the mixture was heated to 170℃ and reacted for h. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with 300 mL of water, extracted with dichloromethane, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to obtain the target intermediate 4e (16.21 g).

[0340] MS(ESI, [MH] - ) m / z : 286.0. 1 H NMR (500 MHz, DMSO-d6) δ 12.74 (d, J = 11.3 Hz, 1H), 7.82 (d, J =8.3 Hz, 1H), 6.91 (dd, J = 14.9, 8.3 Hz, 1H), 4.80 (d, J = 9.9 Hz, 2H), 3.86(dt, J = 8.2, 5.9 Hz, 2H), 2.77 (dt, J = 17.7, 6.1 Hz, 2H), 2.64 (s, 3H). Step 5: Preparation of intermediate 4f Intermediate 4e (15.7 g) and methanol (160 mL) were added sequentially to a reaction flask. A solution of sodium hydroxide (6.56 g) in water (160 mL) was added dropwise under ice bath conditions, and the mixture was allowed to return to room temperature for further reaction. After the reaction was complete, the methanol was removed from the reaction solution under reduced pressure. 1,4-Dioxane (160 mL) and di-tert-butyl dicarbonate (13.12 g, 13.96 mL) were added, and the mixture was reacted at room temperature for 1 h. After the reaction was complete, the reaction solution was extracted with 500 mL of ethyl acetate and 800 mL of water. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain the target intermediate 4f (19.83 g).

[0341] MS(ESI, [M+H))+ m / z: 292.5 1 H NMR (500 MHz, DMSO-d6) δ 12.76 (s, 1H), 7.76 (d, J = 8.3 Hz, 1H), 6.80 (d, J = 8.3 Hz, 1H), 4.52 (s, 2H), 3.57 (d, J = 1.8 Hz, 2H), 2.64 (d, J= 6.1 Hz, 5H), 1.43 (s, 9H). Step 6: Preparation of 4g of intermediate Intermediate 4f (15.92 g), diethyl carbonate (32.3 g, 33.1 mL), and toluene (200 mL) were added sequentially to the reaction flask. 60 wt% sodium hydride (10.93 g) was added in portions under ice bath conditions. The mixture was heated to 120 °C for reaction. After the reaction was complete, the reaction solution was cooled to room temperature and quenched in ice water. The pH was adjusted to 1-2 with 1 M hydrochloric acid solution, and ethyl acetate was added for extraction. The organic phases were separated, combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation of the filtrate. The residue was slurried with 100 mL of petroleum ether, filtered, and the filter cake was yielded to obtain 4 g (12 g) of the target intermediate.

[0342] 1 H NMR (500 MHz, DMSO-d6) δ 12.46 (s, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H), 5.56 (s, 1H), 4.60 (s, 2H), 3.62 (t, J = 6.0 Hz,2H), 2.83 (t, J = 5.8 Hz, 2H), 1.44 (s, 9H). Step 7: Preparation of intermediate over 4 hours 4 g (12 g) of intermediate, 120 mL of ethanol, and 12.49 g and 11.59 mL of hydroxylamine aqueous solution were added sequentially to the reaction flask. The mixture was heated to 85 °C for reaction. After the reaction was completed, 200 mL of saturated sodium bicarbonate solution was added to the reaction solution, followed by extraction with 100 mL of ethyl acetate. The organic phase was separated, and the aqueous phase was adjusted to pH 3 with 1 M hydrochloric acid. 200 mL of ethyl acetate was added, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum evaporation to obtain the target intermediate 4h (10.44 g).

[0343] MS(ESI, [MH] - ) m / z :331.0.

[0344] 1 H NMR (500 MHz, DMSO-d6) δ 12.85 (s, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 4.67 (s, 2H), 4.07 (s, 2H), 3.69 (t, J = 5.9 Hz,2H), 2.98 (t, J = 5.9 Hz, 2H), 1.44 (s, 9H). Step 8: Preparation of intermediate 4i Intermediate 4h (10.44 g), potassium carbonate (13.02 g), DMA (110 mL), and iodoethane (5.88 g, 3.05 mL) were added sequentially to a reaction flask. Under N2 protection, the mixture was heated to 80 °C for reaction. After the reaction was completed, the reaction solution was cooled to room temperature, and extracted with 200 mL of ethyl acetate and 1000 mL of water. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to obtain the target intermediate 4i (8.31 g).

[0345] MS(ESI, [M+H)) + m / z: 361.2.

[0346] Step 9: Preparation of intermediate 4j Intermediate 4i (5.5 g), tetrahydrofuran (50 mL), and acrylamide (0.759 g) were added sequentially to a reaction flask. The mixture was cooled to -15°C under N2 protection, and potassium tert-butoxide tetrahydrofuran solution (1 mol / L, 9.92 mL) was added dropwise. After the addition was complete, the temperature was raised to 0°C for further reaction. After the reaction was complete, the resulting reaction mixture was added to 200 mL of saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was separated. The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to obtain the target intermediate 4j (2.81 g).

[0347] MS(ESI, [MH] - ) m / z 384.34.

[0348] 1H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H), 4.67 (s, 2H), 4.57 (dd, J = 12.0, 5.0 Hz, 1H), 3.69(t, J = 5.9 Hz, 2H), 2.98 (t, J = 5.9 Hz, 2H), 2.77 (ddd, J = 17.3, 12.1, 5.3Hz, 1H), 2.61 (dt, J = 17.3, 4.1 Hz, 1H), 2.54 (d, J = 4.5 Hz, 1H), 2.18(dtd, J = 13.5, 5.2, 3.7 Hz, 1H), 1.44 (s, 9H). Step 10: Preparation of Intermediate 4 Intermediate 4j (850 mg) and ethyl acetate (20 mL) were added sequentially to a reaction flask, followed by a 1,4-dioxane hydrochloric acid solution (4 mol / L, 11.03 mL). The mixture was reacted at room temperature. After the reaction was complete, the reaction solution was concentrated to obtain intermediate 4 (760 mg).

[0349] MS(ESI, [M+H)) + m / z: 286.12.

[0350] 1 H NMR (500 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 4.54 (dd, J = 11.8, 5.0 Hz, 1H), 3.97 (s, 2H), 3.03(t, J = 5.8 Hz, 2H), 2.86 (t, J = 5.8 Hz, 2H), 2.76 (td, J = 12.0, 5.9 Hz,1H), 2.60 (dt, J = 17.3, 4.2 Hz, 1H), 2.46 (dd, J = 12.2, 4.4 Hz, 1H), 2.18(dq, J = 13.5, 4.8 Hz, 1H). Synthesis of Intermediate 5 in Example 5

[0351]

[0352] Step 1: Preparation of intermediate 5b 15 o At temperature C, liquid bromine (55.5 g) was added dropwise to a solution of 5a (50 g) in acetic acid (180 mL). After the addition was complete, the mixture was allowed to react at room temperature for 1 h. Methyl tert-butyl ether (800 mL) was then added dropwise to the reaction mixture, and the mixture was filtered. The filter cake was collected and dried to obtain intermediate 5b (95 g).

[0353] MS(ESI, [M+H)) + ) m / z :230.1. Step 2: Preparation of intermediate 5c 5b (80 g), glyoxal dimethyl acetal (66.9 g), triethylamine (27.3 g), anhydrous sodium sulfate (80 g), and methanol (600 mL) were added sequentially to the reaction flask, and the mixture was reacted overnight at room temperature. The reaction solution was then cooled to -15°C. o C. Add sodium borohydride (14.6 g) in portions, and allow the reaction to proceed at room temperature after the addition is complete. Concentrate the reaction solution, and add 400 mL of dichloromethane and 700 mL of water to the concentrate. Separate the organic phase, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate, and purify the concentrate by silica gel column chromatography to obtain intermediate 5c (60 g).

[0354] MS(ESI, [M+H)) + ) m / z :318.1. Step 3: Preparation of intermediate 5d 0 o Under nitrogen protection at C, 47 g of 5°C was added dropwise to 148 g of trifluoroacetic anhydride. After the addition was complete, the mixture was allowed to return to room temperature. Then, 87 g of trifluoroacetic acid was added dropwise, and the temperature was raised to 40°C. o C reaction. Add triethylsilane (68g) dropwise, and heat to 60°C. o C. Add 400 mL of ethyl acetate and 600 mL of water to the reaction solution. Separate the organic phase, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate, and purify the concentrate by silica gel column chromatography to obtain intermediate 5d (20.5 g).

[0355] 1 H NMR (500 MHz, DMSO- d 6) δ 7.46 (dd, J = 8.9, 1.7 Hz, 1H), 6.87 (d, J =8.9 Hz, 1H), 3.77 (d, J = 2.8 Hz, 3H), 3.67 (ddt,J = 14.4, 5.7, 3.4 Hz, 4H),3.22 (ddd, J = 11.9, 6.4, 4.6 Hz, 2H), 3.16 – 3.06 (m, 2H). Step 4: Preparation of intermediate 5e 0 o Under nitrogen protection at C, boron tribromide dichloromethane solution (146 mL, 1 M) was slowly added dropwise to 200 mL of dichloromethane containing 5d (20.5 g) with stirring. After the addition was complete, the mixture was moved to room temperature for reaction. After the reaction was complete, the reaction solution was slowly poured into 400 mL of ice water, stirred, filtered, and the filter cake was collected and dried to obtain 5e (18.5 g).

[0356] MS(ESI, [MH] - ) m / z : 336.1. 1 H NMR (500 MHz, DMSO- d 6) δ 9.74 (s, 1H), 7.26 (dd, J = 8.7, 1.3 Hz, 1H), 6.68 (dd, J = 8.7, 3.1 Hz, 1H), 3.73 – 3.61 (m, 4H), 3.23 – 3.13 (m, 2H), 3.12 – 3.02 (m, 2H). Step 5: Preparation of intermediate 5f 0 o Under nitrogen protection at C, acetic anhydride (5.65 g) was slowly added dropwise to 200 mL of dichloromethane containing 5e (17.0 g) and triethylamine (7.63 g) with stirring. After the addition was complete, the mixture was moved to room temperature for reaction. After the reaction was complete, the reaction solution was slowly poured into 200 mL of water to separate the organic phase. The mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 5f (19.8 g).

[0357] MS(ESI, [M+H)) + ) m / z 380.1. Step 6: Preparation of 5g of intermediate 5f (19.5 g), aluminum trichloride (18.7 g), and o-dichlorobenzene (80 mL) were added sequentially to the reaction flask, and the temperature was raised to 150°C. oC. After the reaction was complete, the reaction solution was cooled to room temperature, and 250 mL of 3N dilute hydrochloric acid was added. The mixture was then extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the concentrate was purified by silica gel column chromatography to obtain 5 g (11.2 g) of the intermediate.

[0358] MS(ESI, [MH] - ) m / z 300.0. 1 H NMR (500 MHz, DMSO- d 6) δ 12.83 (d, J = 4.8 Hz, 1H), 7.78 (dd, J = 8.1, 3.5 Hz, 1H), 6.83 (t, J = 8.3 Hz, 1H), 3.69 (ddd, J = 12.9, 9.6, 5.9 Hz, 4H), 3.11 – 3.00 (m, 4H), 2.64 (s, 3H). Step 7: Preparation of intermediates over 5 hours 5 g (9.5 g), methanol (100 mL), water (20 mL), and sodium hydroxide (1.9 g) were added sequentially to the reaction flask, and the reaction was carried out at room temperature. Then, di-tert-butyl dicarbonate (8.2 g) was added. After the reaction was complete, 200 mL of ethyl acetate and 400 mL of water were added to the reaction solution. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the concentrate was purified by silica gel column chromatography to obtain intermediate 5 h (8.5 g).

[0359] 1 H NMR (500 MHz, DMSO- d 6) δ 12.80 (s, 1H), 7.74 (d, J = 8.1 Hz, 1H), 6.79 (d, J = 8.2 Hz, 1H), 3.45 (dt, J = 11.6, 5.0 Hz, 4H), 2.92 (q, J = 5.0 Hz, 4H), 2.63 (s, 3H), 1.38 (s, 9H). Step 8: Preparation of intermediate 5i Add 8.5 g of 5 h, 16.4 g of diethyl carbonate, and 100 mL of toluene to the reaction flask in sequence. Then add 5.57 g of 60 wt% sodium hydride in portions. Heat the reaction solution to 115 °C.o C. After the reaction was complete, the reaction solution was cooled to room temperature, and 200 mL of ethyl acetate and 300 mL of water were added to the reaction solution. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the concentrate was purified by silica gel column chromatography to obtain intermediate 5i (9.0 g).

[0360] MS(ESI, [MH] - ) m / z : 330.1. Step 9: Preparation of intermediate 5j 5 μL (9.0 g), hydroxylamine aqueous solution (8.7 g), and ethanol (100 mL) were added sequentially to the reaction flask, and the reaction solution was heated to 80 °C. o C. After the reaction was complete, the reaction solution was cooled to room temperature, and 200 mL of ethyl acetate and 300 mL of water were added to the reaction solution. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the concentrate was purified by silica gel column chromatography to obtain intermediate 5j (8.5 g).

[0361] MS(ESI, [MH] - ) m / z 345.4. 1 H NMR (500 MHz, DMSO- d 6) δ 7.53 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 3.73 (q, J = 13.9, 11.5 Hz, 2H), 3.59 – 3.54 (m, 2H), 3.52 – 3.47 (m, 2H), 3.13 (t, J = 5.2 Hz, 2H), 3.07 – 2.98 (m, 2H), 1.40 (s, 9H). Step 10: Preparation of intermediate 5k Add 5g (8.5g), potassium carbonate (3.3g), iodoethane (5.1g), and DMA (70mL) sequentially to the reaction flask, and heat the reaction solution to 80°C. o C. The reaction solution was cooled to room temperature, and 200 mL of ethyl acetate and 300 mL of water were added. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the concentrate was purified by silica gel column chromatography to obtain intermediate 5k (6.5 g).

[0362] MS(ESI, [MH] - ) m / z: 373.1. 1 H NMR (500 MHz, DMSO- d 6) δ 7.56 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 4.13 (dd, J = 13.7, 6.6 Hz, 4H), 3.55 (dt, J = 28.2, 5.0 Hz, 4H), 3.17 (s,2H), 3.05 (t, J = 5.2 Hz, 2H), 1.38 (dd, J = 9.3, 4.4 Hz, 9H), 1.19 (t, J = 6.5 Hz, 3H). Step 11: Preparation of intermediate 5L -10 o Under nitrogen protection at C, sodium tert-butoxide tetrahydrofuran solution (14 mL, 1 M) was slowly added dropwise to 70 mL of 5 kJ (5.6 g) tetrahydrofuran solution with stirring. After the addition was complete, the reaction was maintained at this temperature for 30 min. Acrylamide (0.71 g) was weighed and dissolved in 5 mL of tetrahydrofuran, then added dropwise to the reaction solution, and the reaction was maintained at this temperature for 2 h. The reaction solution was slowly poured into 200 mL of saturated ammonium chloride, and 200 mL of ethyl acetate was added. The organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the concentrate was purified by silica gel column chromatography to obtain intermediate 5 L (2.5 g).

[0363] MS(ESI, [MH] - ) m / z 397.9. 1 H NMR (500 MHz, DMSO- d 6) δ 11.08 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 8.1 Hz, 1H), 4.55 (dd, J = 12.0, 4.9 Hz, 1H), 3.55 (dt, J = 31.4, 5.0Hz, 4H), 3.22 – 3.00 (m, 4H), 2.77 (ddd, J = 17.3, 12.0, 5.3 Hz, 1H), 2.60 (dt,J = 17.3, 4.1 Hz, 1H), 2.46 (dd, J = 12.2, 4.4 Hz, 1H), 2.20 – 2.12 (m, 1H), 1.38 (d, J = 6.3 Hz, 9H). Step 12: Preparation of Intermediate 5 5 L (2.5 g), ethyl acetate (30 mL), and 1,4-dioxane hydrochloride (15 mL, 4 M) were added sequentially to the reaction flask, and the reaction was carried out at room temperature. After the reaction was completed, the mixture was filtered, the filter cake was collected, and dried to obtain intermediate 5 (18.5 g).

[0364] MS(ESI, [M+H)) + ) m / z 300.2. 1 H NMR (500 MHz, DMSO- d 6) δ 11.10 (s, 1H), 9.53 (s, 2H), 7.65 (d, J =8.1 Hz, 1H), 7.27 (d, J = 8.1 Hz, 1H), 4.59 (dd, J = 12.1, 4.9 Hz, 1H), 3.43 (dd, J = 7.0, 3.3 Hz, 2H), 3.37 – 3.19 (m, 6H), 2.78 (ddd, J = 17.3, 12.1, 5.3 Hz,1H), 2.61 (dt, J = 17.3, 4.1 Hz, 1H), 2.17 (dtd, J = 13.4, 5.2, 3.6 Hz, 1H). Example 6: Synthesis of Intermediate 6

[0365]

[0366] Step 1: Preparation of intermediate 6b Carbon tetrachloride (1500 mL), 6a (100 g), 2,2-azobisisobutyronitrile (4.1 g), and N-bromosuccinimide (265 g) were added sequentially to the reaction flask, and the mixture was heated to 80 °C. oC reaction. After the reaction was complete, the mixture was filtered, the mother liquor was concentrated to dryness, petroleum ether was added to the residue and the mixture was stirred, filtered, the filter cake was collected and dried to obtain intermediate 6b (154g).

[0367] 1 H NMR (500 MHz, DMSO-d6) δ 7.36-7.33 (m, 1H), 7.09-7.04 (m, 2H), 4.78 (s, 2H), 4.76 (s, 2H), 3.87 (s, 3H). Step 2: Preparation of intermediate 6c Cycloisopropyl malonate (150 g), DMSO (500 mL), triethylamine (255 mL), and intermediate 6b (120 g) were added sequentially to a reaction flask and reacted at room temperature. After the reaction was complete, the reaction solution was poured into water, extracted with EA, and washed successively with saturated citric acid aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated brine. The solution was dried over anhydrous sodium sulfate, filtered, concentrated, dissolved in THF, heated to dissolve, and a solid precipitated at room temperature. The solid was filtered, the filter cake was collected, dried, and intermediate 6c (45 g) was obtained.

[0368] 1 H NMR (500 MHz, DMSO- d 6) δ 7.21 (t, J = 7.8 Hz, 1H), 6.83 (t, J = 7.0Hz, 2H), 3.79 (s, 3H), 3.63 (s, 2H), 3.49 (s, 2H), 1.77 (s, 6H). Step 3: Preparation of intermediate 6d At 0°C, under nitrogen protection, a lithium aluminum hydride tetrahydrofuran solution (1M, 163 mL) was slowly added dropwise to a THF (500 mL) mixture containing intermediate 6c (45 g) with stirring. The temperature was controlled below 5°C, and the mixture was reacted at 0°C for 0.5 h before being brought to room temperature. After the reaction was complete, a saturated ammonium chloride solution (200 mL) was added to quench the reaction. The mixture was extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 6d (40.5 g).

[0369] 1 H NMR (500 MHz, DMSO- d 6) δ 7.07 (t, J = 7.8 Hz, 1H), 6.74 (d, J = 7.4Hz, 1H), 6.70 (d, J= 8.1 Hz, 1H), 4.59 (t, J = 5.3 Hz, 2H), 3.73 (s, 3H), 3.34(d, J = 5.4 Hz, 4H), 2.68 (s, 2H), 2.58 (s, 2H). Step 4: Preparation of intermediate 6e At -20°C, under nitrogen protection, trifluoroacetic anhydride (122 g) was slowly added dropwise to a mixture of intermediate 6d (40.5 g) and DIPEA (76 g) in 500 mL of DCM. The mixture was stirred at -5°C for 0.5 h, then allowed to rise to room temperature. After the reaction was complete, 100 mL of water was added to quench the reaction, followed by extraction with DCM. The mixture was washed successively with 10% citric acid aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography to obtain intermediate 6e (64.2 g).

[0370] 1 H NMR (500 MHz, DMSO- d 6) δ 7.20 – 7.16 (m, 1H), 6.84 – 6.80 (m, 2H), 4.25 (s, 4H), 3.77 (s, 3H), 2.87 (s, 2H), 2.77 (s, 2H). Step 5: Preparation of intermediate 6f At room temperature and under nitrogen protection, intermediate 6e (63.4 g), benzylamine (11.51 g), DIPEA (41.6 g), and acetonitrile (500 mL) were added sequentially to a reaction flask, and the reaction was carried out overnight at room temperature. After the reaction was completed, silica gel column chromatography was performed to obtain intermediate 6f (31.5 g).

[0371] 1 H NMR (500 MHz, DMSO- d 6) δ 7.33 – 7.24 (m, 4H), 7.24 – 7.18 (m, 1H), 7.09 (t, J = 7.8 Hz, 1H), 6.78 (d, J = 7.4 Hz, 1H), 6.73 (d, J = 8.1 Hz, 1H), 3.74(s, 3H), 3.56 (s, 2H), 3.15 – 3.08 (m, 4H), 3.06 (s, 2H), 2.96 (s, 2H). Step 6: Preparation of 6g of intermediate At 0°C, a 4M solution of 1,4-dioxane hydrochloride (79 mL) was added to a 500 mL solution of intermediate 6f (25.2 g) in DCM. The reaction was allowed to proceed for 5 min, then concentrated to dryness under reduced pressure. 500 mL of DCM was added, and the mixture was cooled to -78°C. A 1M solution of boron tribromide in dichloromethane (271 mL) was slowly added dropwise. After the addition was complete, the mixture was allowed to rise to room temperature and reacted overnight. Upon completion of the reaction, the reaction solution was cooled in an ice bath, and the reaction was quenched with methanol. The pH was adjusted to neutral with saturated sodium bicarbonate solution. The mixture was extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 6 g (29.6 g) of intermediate.

[0372] MS(ESI, [M+H)) + m / z: 266.1 1 H NMR (500 MHz, DMSO- d 6) δ 9.26 (s, 1H), 7.47 – 7.31 (m, 5H), 6.94(t, J = 7.7 Hz, 1H), 6.64 (d, J = 7.3 Hz, 1H), 6.58 (d, J = 8.0 Hz, 1H), 4.42 –3.41 (m, 6H), 3.13 (s, 2H), 3.06 (s, 2H). Step 7: Preparation of intermediates over 6 hours 6 g (29.60 g) of intermediate, 10% palladium on carbon (29.6 g), and 600 mL of MeOH were added to the reaction flask in sequence. After hydrogen purging, the reaction was carried out overnight at 40 °C under hydrogen protection. After the reaction was completed, the mixture was filtered and concentrated to obtain 6 h (23.1 g) of intermediate.

[0373] MS(ESI, [M+H]+) m / z: 176.1 Step 8: Preparation of intermediate 6i At room temperature, intermediate 6h (23.5 g), THF (500 mL), and trifluoroacetic anhydride (28.4 g) were added sequentially to a reaction flask and reacted at room temperature. After the reaction was complete, 200 mL of saturated sodium bicarbonate was added to quench the reaction, followed by extraction with EA, washing with saturated brine, drying with anhydrous sodium sulfate, filtration, concentration, and silica gel column chromatography to obtain intermediate 6i (25.92 g).

[0374] MS(ESI, [MH] - m / z: 270.1 Step 9: Preparation of intermediate 6j At room temperature, intermediate 6i (23.5 g), DCM (500 mL), triethylamine (17.53 g), DMAP (1.058 g), and acetic anhydride (9.73 g) were added sequentially to a reaction flask and reacted at room temperature. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with DCM. The organic phase was collected and washed sequentially with 5% citric acid aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 6j (18.58 g).

[0375] 1 H NMR (500 MHz, DMSO- d 6) δ 7.20 (t, J = 7.7 Hz, 1H), 7.16 – 7.10 (m,1H), 6.91 (dd, J = 8.0, 0.9 Hz, 1H), 4.43 – 4.31 (m, 2H), 4.10 – 3.98 (m, 2H), 3.25 (s, 2H), 3.07 (s, 2H), 2.28 (s, 3H). Step 10: Preparation of intermediate 6k Intermediate 6j (18.4 g), aluminum trichloride (15.66 g), and o-dichlorobenzene (200 mL) were added sequentially to a reaction flask. The mixture was gradually heated from 70 °C to 150 °C. After the reaction was complete, the mixture was cooled to room temperature, and 1000 mL of EA, 60 mL of 3M hydrochloric acid, and 200 mL of water were added sequentially to dissolve the mixture. The solution was extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography to obtain intermediate 6k (15.11 g).

[0376] MS(ESI, [MH] - m / z: 312.1 1 H NMR (500 MHz, DMSO- d 6) δ 12.35 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 4.41 (d, J = 5.9 Hz, 2H), 4.10 – 4.06 (m, 2H), 3.27 (s, 2H), 3.17 (s, 2H), 2.62 (s, 3H). Step 11: Preparation of intermediate 6l At 0°C, 97 mL of 1 M sodium hydroxide aqueous solution was added to a 150 mL MeOH solution of intermediate 6K (15.11 g). The reaction was carried out at room temperature until complete. Methanol was removed by concentration, water was retained, and dioxane (150 mL) and Boc anhydride (11.58 g) were added to the residue. The reaction was carried out at room temperature until complete. The pH was adjusted to 5-6 with 10% citric acid, extracted with EA, and then washed successively with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution. The residue was dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography to obtain intermediate 6L (11.40 g).

[0377] MS(ESI, [MH] - m / z: 316.1 1 H NMR (500 MHz, DMSO- d 6) δ 12.34 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 3.81 (s, 4H), 3.18 (s, 2H), 3.06 (s, 2H), 2.61 (s, 3H), 1.38 (s, 9H). Step 12: Preparation of intermediate 6m At 0°C, sodium hydroxide (60 wt%, 6.93 g) was added in portions to a mixed solvent of intermediate 6l (11 g), diethyl carbonate (20.47 g), toluene (200 mL), and THF (100 mL). The mixture was heated to 100°C and reacted. After the reaction was complete, the reaction solution was cooled to room temperature, water was added to quench the reaction, and the mixture was extracted with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography to obtain intermediate 6m (12.62 g).

[0378] MS(ESI, [MH] - m / z: 388.2 1 H NMR (500 MHz, DMSO- d 6) δ 11.74 (s, 1H), 7.70 (d, J = 8.1 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 4.19 (s, 2H), 4.12 (q, J= 7.1 Hz, 2H), 3.82 (s, 4H), 3.19 (s, 2H), 3.08 (s, 2H), 1.38 (s, 9H), 1.18 (t, J = 7.1 Hz, 3H). Step 13: Preparation of intermediate 6n Intermediate 6m (12.5 g), hydroxylamine (5.30 g), and ethanol (200 mL) were added sequentially to a reaction flask and reacted at 85°C. After the reaction was complete, the reaction solution was cooled to room temperature, and the solvent was removed by vacuum distillation. 500 mL of EA, 200 mL of water, and 150 mL of saturated sodium carbonate aqueous solution were added to the residue, and the aqueous phase was collected. The pH of the aqueous phase was adjusted to ~4 with 1M dilute hydrochloric acid, and the aqueous phase was extracted with EA. The organic phases were combined, washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 6n (10.12 g).

[0379] 1 H NMR (500 MHz, DMSO- d 6) δ 12.86 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.1 Hz, 1H), 4.05 (s, 2H), 3.95 – 3.79 (m, 4H), 3.38 (s, 2H), 3.30 (s, 2H), 1.39 (s, 9H). Step 14: Preparation of intermediate 6o Intermediate 6n (9.6 g), potassium carbonate (11.11 g), DMA (150 mL), and iodoethane (6.27 g) were added sequentially to a reaction flask and reacted at 85°C. After the reaction was complete, the reaction solution was cooled to room temperature, 600 mL of water was added, and the mixture was extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography to obtain intermediate 6o (11.02 g).

[0380] MS(ESI, [M+H)) + m / z: 387.2 Step 15: Preparation of intermediate 6p At -5°C under nitrogen protection, a 1M, 15.52 mL solution of potassium tert-butoxide in tetrahydrofuran was slowly added dropwise to a 300 mL THF solution of intermediate 6o (10 g) and acrylamide (1.104 g) with stirring. The addition was completed after 10 minutes, and the mixture was stirred at -5°C to react. The reaction was quenched by adding 200 mL of saturated ammonium chloride solution. The mixture was extracted twice with DCM, 300 mL each time. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give intermediate 6p (4.32 g).

[0381] MS(ESI, [M+H)) + m / z: 412.2 1 H NMR (500 MHz, DMSO- d 6) δ 11.08 (s, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 4.57 (dd, J = 12.0, 4.9 Hz, 1H), 3.98 – 3.80 (m, 4H), 3.38 (s, 2H), 3.30 (s, 2H), 2.82 – 2.71 (m, 1H), 2.65 – 2.56 (m, 1H), 2.49 –2.43 (m, 1H), 2.22 – 2.14 (m, 1H), 1.39 (s, 9H). Step 16: Preparation of Intermediate 6 6p (50 mg), DCM (5.00 mL), and EA (5 mL) were added sequentially to the reaction flask. After the reaction solution was cleared, trifluoroacetic acid (1 mL) was added. The mixture was stirred at 25°C overnight. After the reaction was completed, the solution was concentrated to dryness, dissolved in DMSO, purified by reverse-phase chromatography, and lyophilized to obtain intermediate 6 (25 mg).

[0382] MS(ESI, [M+H)) + m / z: 312.2 1 H NMR (500 MHz, DMSO- d 6) δ 7.63 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.1Hz, 1H), 4.56 (dd, J = 11.9, 5.0 Hz, 1H), 3.61 (q, J= 8.2 Hz, 4H), 3.36 (s, 2H), 3.28 (s, 2H), 2.82 – 2.71 (m, 1H), 2.60 (dt, J = 17.3, 4.1 Hz, 1H), 2.49 – 2.43(m, 1H), 2.22 – 2.12 (m, 1H).

[0383] Synthesis of Intermediate 7 in Example 7

[0384]

[0385] Step 1: Preparation of compound 7b In an ice bath, 7a (33.3 g), MeOH (500 mL), iodophenyl diacetic acid (82 g, 246 mmol), and potassium hydroxide (127 g) were added sequentially to a reaction flask, and the mixture was reacted at room temperature for 3 hours. The solvent was removed from the reaction solution under reduced pressure. The residue was extracted with 500 mL of ethyl acetate and 1000 mL of sodium bicarbonate solution, and the organic phase was separated. The residue was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was dissolved in THF (500 mL), and then hydrochloric acid (6 M, 68.4 mL) was added. The reaction was carried out at room temperature. After the reaction was completed, the pH of the reaction solution was adjusted to 8 with saturated sodium bicarbonate solution, and then extracted with ethyl acetate. The residue was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain 7b (16 g).

[0386] MS(ESI, [M+H)) + ) m / z 178.9. Step 2: Preparation of compound 7c 7b (80 g) and MeOH (1000 mL) were added sequentially to the reaction flask. After dissolving, sodium borohydride (17.83 g, 471 mmol) was added, and the reaction was carried out at room temperature. After the reaction was completed, 500 mL of saturated ammonium chloride solution was added dropwise to quench the reaction mixture, and ethyl acetate was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum evaporation to obtain 7c (82 g).

[0387] 1H NMR (500 MHz, DMSO-d6) δ 7.17 (t, J = 7.8 Hz, 1H), 6.87 (d, J =7.4 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 5.34 (d, J = 6.3 Hz, 1H), 5.13 (d, J =5.0 Hz, 1H), 4.67 (t, J = 5.8 Hz, 1H), 4.06 (ddd, J = 12.0, 6.8, 5.1 Hz, 1H), 3.75 (s, 3H), 3.03 (dd, J = 15.8, 7.1 Hz, 1H), 2.43 (dd, J = 15.8, 6.5 Hz, 1H). Step 3: Preparation of compound 7d 7c (35 g), toluene (300 mL), and p-toluenesulfonic acid (66.9 g) were added sequentially to a reaction flask, and the mixture was heated to 120 °C for reaction. After the reaction was completed, the reaction solution was cooled to room temperature, and the reaction was quenched by adding 200 mL of ethyl acetate and 500 mL of water. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum evaporation to obtain 7d (35.5 g).

[0388] 1 H NMR (500 MHz, DMSO-d6) δ 7.26 – 7.22 (m, 1H), 6.93 – 6.87 (m, 2H), 3.79 (s, 3H), 3.53 (s, 2H), 3.37 (s, 2H). Step 4: Preparation of compound 7e 7d (35 g), MeOH (400 mL), and sodium borohydride (5.83 g) were added sequentially to a reaction flask and reacted at room temperature. After the reaction was completed, 500 mL of saturated ammonium chloride solution was added dropwise to quench the reaction mixture, followed by extraction with ethyl acetate, drying with anhydrous sodium sulfate, filtration, and removal of the solvent under reduced pressure to obtain 7e (18 g).

[0389] 1H NMR (500 MHz, DMSO-d6) δ 7.13 – 7.07 (m, 1H), 6.83 – 6.78 (m, 1H), 6.74 (d, J = 8.1 Hz, 1H), 4.81 (d, J = 3.8 Hz, 1H), 4.49 (tq, J = 6.5, 3.4Hz, 1H), 3.75 (s, 3H), 3.04 (dd, J = 16.1, 6.1 Hz, 1H), 2.94 (dd, J = 16.3,6.2 Hz, 1H), 2.79 – 2.61 (m, 2H). Step 5: Preparation of compound 7f 7e (60 g), dichloromethane (500 mL), triethylamine (111 g, 152 mL), and acetic anhydride (41.0 g, 38.2 mL) were added sequentially to the reaction flask, and the reaction was carried out at room temperature. After the reaction was completed, the reaction solution was washed with 500 mL of saturated ammonium chloride solution and 500 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 7f (37.2 g).

[0390] 1 H NMR (500 MHz, DMSO-d6) δ 7.22 – 7.06 (m, 1H), 6.82 (dd, J = 27.3,8.3 Hz, 2H), 5.41 (s, 1H), 3.78 (d, J = 13.2 Hz, 3H), 3.32 – 3.20 (m, 1H), 3.18 – 3.09 (m, 1H), 2.85 (dd, J = 34.6, 17.1 Hz, 2H), 1.97 (d, J = 15.3 Hz, 3H). Step 6: Preparation of 7g of compound Under ice bath conditions, boron trichloride (19.22 g, 164 mL) was slowly added dropwise to 7 g (17 g) of dichloromethane (500 mL) with stirring. After the addition was complete, the mixture was allowed to naturally rise to room temperature to react. After the reaction was complete, 160 mL of 1M HCl and 200 mL of aqueous solution were added to the reaction solution to quench the reaction, followed by extraction with dichloromethane. The organic phase was separated, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum evaporation to obtain 7 g (15 g).

[0391] MS(ESI, [MH] - ) m / z 190.9. Step 7: Preparation of compound 7h 7 g (16 g), dichloromethane (200 mL), triethylamine (9.50 g, 13.01 mL), and acetic anhydride (5.27 g, 4.91 mL) were added sequentially to the reaction flask, and the reaction was carried out at room temperature. After the reaction was completed, the reaction solution was washed with 500 mL of saturated ammonium chloride solution and 500 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 7 h (14.8 g).

[0392] MS(ESI, [MH] - ) m / z : 233.01. Step 8: Preparation of compound 7i 7h (11.6 g), dichloromethane (300 mL), and zirconium tetrachloride (46.2 g) were added sequentially to a reaction flask, and the reaction was carried out at 50 °C. After the reaction was completed, the reaction solution was cooled to room temperature, and 200 mL of 3M hydrochloric acid aqueous solution was added to the residue, followed by 100 mL of water and 100 mL of dichloromethane. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum evaporation to obtain 7i (11.4 g).

[0393] 1 H NMR (500 MHz, DMSO- d 6) δ 12.34 (s, 1H), 7.80 (d, J = 8.0 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 5.45 (tt, J = 6.3, 2.2 Hz, 1H), 3.37 – 3.33 (m, 1H), 3.19 (dd, J = 17.3, 6.3 Hz, 1H), 2.95 (dd, J = 17.9, 2.2 Hz, 1H), 2.86 (dd, J =17.3, 2.1 Hz, 1H), 2.63 (s, 3H), 1.97 (s, 3H). Step 9: Preparation of compound 7k 7i (15.4 g), ethanol (200 mL), and sodium hydroxide (2.63 g) aqueous solution (10.00 mL) were added sequentially to the reaction flask, and the reaction was carried out at room temperature. After the reaction was completed, the pH of the reaction solution was adjusted to 2-3 with 2M HCl aqueous solution, and then 100 mL of ethyl acetate and 200 mL of water were added for extraction. The mixture was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain crude intermediate 7j. Dichloroethane (200 mL), imidazole (17.90 g), and TBSCl (39.6 g) were added, and the mixture was refluxed overnight. The reaction solution was cooled to room temperature, and 100 mL of dichloromethane and 300 mL of water were added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain 7k (15.4 g).

[0394] 1 H NMR (500 MHz, DMSO- d 6) δ 12.25 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 4.64 (dq, J = 6.2, 3.2 Hz, 1H), 3.05 (ddd, J = 56.3,16.6, 6.2 Hz, 2H), 2.71 (dd, J = 17.0, 3.6 Hz, 1H), 2.61 (dd, J = 16.3, 3.5 Hz,1H), 2.51 (s, 3H), 0.78 (s, 9H), 0.00 (s, 6H). Step 10: Preparation of compound 7l 7kJ (8.4 g) and THF (300 mL) were added sequentially to the reaction flask. Diethyl carbonate (16.19 g, 16.52 mL) was added, and the temperature was lowered to approximately 0°C. 60 wt% sodium hydroxide (5.48 g, 137 mmol) was added in portions, and the reaction mixture was heated to 85°C. After the reaction was complete, the reaction solution was cooled to room temperature and slowly poured into 500 mL of ice water. The solution was extracted with 200 mL of ethyl acetate, and the organic phase was discarded. The aqueous phase was adjusted to pH 1-2 with 3M hydrochloric acid, then extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain 7 L (10 g).

[0395] MS(ESI, [MH] - m / z: 331.2. Step 11: Preparation of intermediate 7m 7 L (10 g), hydroxylamine aqueous solution (9.93 g, 9.93 mL), and ethanol (100 mL) were added sequentially to the reaction flask, and the reaction was carried out at 85 °C. After the reaction was completed, the reaction solution was cooled to room temperature, and the residue was extracted with 200 mL of ethyl acetate and 100 mL of saturated sodium carbonate aqueous solution. The organic phase was discarded. The aqueous phase was adjusted to pH 2-3 with 1M HCl aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum evaporation to obtain 7 L (11 g).

[0396] MS(ESI, [MH] - m / z: 346.2. Step 12: Preparation of intermediate 7n 7m (10 g), ethanol (150 mL), and sulfuric acid (14.40 g, 7.83 mL) were added sequentially to the reaction flask, and the reaction was carried out at 85 °C. After the reaction was completed, the reaction solution was cooled to room temperature, and 200 mL of dichloromethane and saturated sodium bicarbonate solution were added to adjust the pH to 7. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum evaporation to obtain 7n (5.8 g).

[0397] MS(ESI, [M+H)) + m / z: 261.97. 1 H NMR (500 MHz, DMSO- d 6) δ 7.65 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 8.0Hz, 1H), 5.09 (d, J = 4.0 Hz, 1H), 4.71 (dt, J = 6.4, 3.1 Hz, 1H), 4.26 – 4.12(m, 4H), 3.30 (ddd, J = 31.0, 16.5, 6.0 Hz, 2H), 2.98 (ddd, J = 31.6, 16.5, 3.0Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H). Step 13: Preparation of Intermediate 7 Compound 7n (300 mg), dichloromethane (10 mL), and Desmartin oxidant (974 mg) were added sequentially to a reaction flask, and the mixture was stirred at room temperature. After the reaction was complete, the reaction solution was quenched in a saturated sodium sulfite solution, and then extracted with 100 mL of ethyl acetate. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium bicarbonate solution and saturated brine solution, respectively, and dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent was removed from the filtrate under reduced pressure to obtain intermediate 7 (320 mg).

[0398] MS(ESI, [M+H)) + m / z: 260.0. 1 H NMR (500 MHz, DMSO-d6) δ 7.74 (d, J = 8.1 Hz, 1H), 7.38 (d, J =8.1 Hz, 1H), 4.21 (s, 2H), 4.14 (q, J = 7.1 Hz, 2H), 3.79 (s, 2H), 3.72 (s,2H), 1.19 (t, J = 7.1 Hz, 3H). Synthesis of intermediates 8 and 9 in Examples 8 and 9

[0399]

[0400] Step 1: Preparation of intermediate 8b CCl4 (6750 mL), 8a (450 g), 2,2-azobisisobutyronitrile (18.45 g), and N-bromosuccinimide (1194 g) were added sequentially to the reaction flask. The mixture was heated to 80°C. o C reaction. After the reaction was complete, the reaction solution was filtered, the solvent was removed from the filtrate by vacuum distillation, petroleum ether was added and the mixture was stirred, filtered, and the filter cake was collected to obtain intermediate 8b (833g). 1 H NMR (500 MHz, DMSO-d6) δ 7.34 (d, J = 8.1 Hz, 1H), 7.06 (ddd, J =17.8, 8.1, 1.1 Hz, 2H), 4.77 (d, J = 9.5 Hz, 4H), 3.87 (s, 3H). Step 2: Preparation of intermediate 8c 60wt% NaH (187 g), THF (2000 mL), and diethyl malonate (300 g, 284 mL) were added sequentially to the reaction flask under ice bath conditions. After stirring at room temperature for 30 min, 8b (606 g) was added, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was quenched by slowly adding a saturated ammonium chloride solution. Extraction was performed by adding 2000 mL of petroleum ether and 2000 mL of water, followed by drying with anhydrous sodium sulfate, filtration, and solvent removal by vacuum distillation of the filtrate. The intermediate 8c (262 g) was purified by silica gel column chromatography.

[0401] MS(ESI, [MH] - m / z: 291.2 1 H NMR (500 MHz, DMSO-d6) δ 7.16 (t, J = 7.8 Hz, 1H), 6.80 (dd, J =15.3, 7.8 Hz, 2H), 4.14 (q, J = 7.1 Hz, 4H), 3.77 (s, 3H), 3.48 (s, 2H), 3.38(s, 2H), 1.17 (t, J = 7.0 Hz, 6H). Step 3: Preparation of intermediate 8d 8c (130 g), DMSO (1000 mL), H2O (300 mL), and lithium chloride (42.6 g) were added to a reaction flask and stirred at 180 °C. After the reaction was complete, the reaction solution was quenched in 1000 mL of ice water, and the pH was adjusted to 2-3 with 1 M hydrochloric acid. The solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate by vacuum distillation to obtain intermediate 8d (191 g).

[0402] MS(ESI, [M+H]+) m / z: 193.05 Step 4: Preparation of intermediate 8e Add 85 g of ethanol, 1000 mL of concentrated sulfuric acid, and 44 g of concentrated sulfuric acid sequentially to a reaction flask, and heat the mixture to 70°C. o C. After the reaction was complete, the reaction solution was cooled to room temperature, the solvent was removed by vacuum distillation, and the residue was poured into ice water and neutralized with saturated sodium bicarbonate aqueous solution. Then, 1000 mL of petroleum ether was added for extraction, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation of the filtrate to give intermediate 8e (99 g). MS(ESI, [M+H]+) m / z: 221.1 1H NMR (500 MHz, DMSO-d6) δ 7.13 (t, J = 7.8 Hz, 1H), 6.81 (d, J =7.5 Hz, 1H), 6.76 (d, J = 8.2 Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 3.76 (s,3H), 3.36 – 3.31 (m, 1H), 3.20 – 3.10 (m, 2H), 3.10 – 2.96 (m, 2H), 1.20 (t,J = 7.1 Hz, 3H). Step 5: Preparation of intermediate 8f In a reaction flask under N2 protection, boron tribromide (415 g, 1657 mL) was added dropwise to a mixture of 8e (150 g) and dichloromethane (750 mL) with stirring. The reaction was carried out at 0°C. After the reaction was complete, MeOH (500 mL) was added, and the mixture was gradually brought back to room temperature with stirring. The reaction solution was then poured into a mixture of 1000 mL ice water and 1000 mL dichloromethane and stirred. The mixture was separated using a separatory funnel, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by removing the solvent under reduced pressure to obtain intermediate 8f (122 g).

[0403] 1 H NMR (500 MHz, DMSO-d6) δ 9.24 (s, 1H), 6.95 (t, J = 7.7 Hz, 1H), 6.70 – 6.60 (m, 1H), 6.62 – 6.52 (m, 1H), 4.10 (q, J = 7.1 Hz, 2H), 3.33 –3.27 (m, 1H), 3.13 – 3.01 (m, 3H), 2.96 (dd, J = 16.1, 7.1 Hz, 1H), 1.20 (t,J = 7.1 Hz, 3H). Step 6: Synthesis of 8g of intermediate In the reaction flask, 0 o Under C, N2 protection, 8f (130 g), tetrahydrofuran (2000 mL), and a 1M, 438 mL solution of lithium aluminum hydride tetrahydrofuran were added sequentially. The mixture was reacted in an ice-water bath. After the reaction was complete, 3 L of water was slowly added to quench the reaction. The pH was adjusted to 1-2 with concentrated hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to obtain 8 g (129 g) of the intermediate.

[0404] 1H NMR (500 MHz, DMSO-d6) δ 6.88 (t, J = 7.7 Hz, 1H), 6.58 (d, J =7.3 Hz, 1H), 6.52 (d, J = 7.9 Hz, 1H), 3.38 – 3.32 (m, 2H), 2.84 (ddd, J =33.5, 16.2, 8.3 Hz, 2H), 2.60 (dq, J = 13.9, 8.1, 6.6 Hz, 1H), 2.55 – 2.49(m, 3H). Step 7: Preparation of intermediates over 8 hours 8 g (120 g), 4-dimethylaminopyridine (7.14 g), dichloromethane (2000 mL), and triethylamine (177 g, 244 mL) were added sequentially to a reaction flask. Acetyl chloride (101 g, 91 mL) was slowly added dropwise at 0 °C, and the reaction was carried out at room temperature. After the reaction was completed, the reaction solution was poured into a mixed solvent of dichloromethane (1000 mL) and water (1000 mL), the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to obtain intermediate 8h (127 g).

[0405] MS(ESI, [M+H]+) m / z: 249.3 1 H NMR (500 MHz, DMSO-d6) δ 7.18 (t, J = 7.7 Hz, 1H), 7.11 (d, J =7.4 Hz, 1H), 6.88 (d, J = 7.9 Hz, 1H), 4.07 – 3.96 (m, 2H), 3.11 – 3.00 (m,1H), 2.87 (dd, J = 15.9, 7.8 Hz, 1H), 2.81 – 2.69 (m, 2H), 2.56 – 2.50 (m,1H), 2.27 (s, 3H), 2.02 (s, 3H). Step 8: Preparation of intermediate 8i 8h (91g), dichloromethane (2000mL), and zirconium tetrachloride (342g) were added sequentially to the reaction flask. The mixture was stirred overnight at 50°C under N2 protection. After the reaction was complete, the reaction solution was cooled to room temperature and poured into a mixture of 1000mL ice water and 1000mL dichloromethane. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to obtain intermediate 8i (90g).

[0406] MS(ESI, [MH]- m / z: 247.2 Step 9: Preparation of intermediate 8j 8i (95 g), ethanol (900 mL), and sodium hydroxide (77 g) H2O (800 mL) solution were added sequentially to the reaction flask under ice bath protection. The mixture was reacted at room temperature under N2 protection. After the reaction was completed, the reaction solution was diluted with 2 L ethyl acetate and 1 L water, and the pH was adjusted to 3 by slowly adding 3M hydrochloric acid. The mixture was separated, the aqueous layer was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to obtain intermediate 8j (86 g). MS(ESI, [MH] - m / z: 205.1 1 H NMR (500 MHz, DMSO-d6) δ 12.34 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 4.68 (t, J = 5.3 Hz, 1H), 3.36 (ddd, J = 7.0, 5.2,2.0 Hz, 2H), 2.98 (dd, J = 17.0, 8.2 Hz, 1H), 2.92 – 2.82 (m, 1H), 2.72 (dd,J = 16.9, 5.6 Hz, 1H), 2.61 (s, 3H), 2.61 – 2.53 (m, 2H). Step 10: Preparation of intermediate 8k 8J (37 g), 1,2-dichloroethane (700 mL), imidazole (36.6 g), and tert-butyldimethylchlorosilane (29.7 g) were added sequentially to a reaction flask, and the reaction was carried out at 75 °C. After the reaction was completed, the reaction solution was cooled to room temperature, and 1000 mL of dichloromethane and 1000 mL of water were added. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to obtain intermediate 8K (60 g).

[0407] 1 H NMR (500 MHz, DMSO- d6) δ 12.31 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 3.52 (d, J = 6.4 Hz, 2H), 2.97 (dd, J = 16.9, 8.0Hz, 1H), 2.85 (dd, J = 15.4, 7.5 Hz, 1H), 2.69 (dd, J = 16.9, 5.6 Hz, 1H), 2.64 – 2.59 (m, 1H), 2.58 (s, 3H), 2.55 (d, J = 5.6 Hz, 1H), 0.82 (s, 9H),0.00 (s, 6H). Step 11: Preparation of intermediate 8L 8 kJ (55 g), diethyl carbonate (101 g, 103 mL), and toluene (1000 mL) were added sequentially to the reaction flask. The reaction solution was cooled to 0°C, and 60 wt% sodium hydride (34.3 g, 858 mmol) was added in portions. After the addition was complete, the mixture was slowly heated to 120°C. o C. After the reaction was complete, the reaction solution was slowly poured into 2000 mL of ice water and extracted with ethyl acetate. The aqueous phase was adjusted to pH 3 with 3N hydrochloric acid, extracted with ethyl acetate, and the organic phases were combined. The solution was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain 8 L (53.6 g) of intermediate.

[0408] MS(ESI, [MH] - m / z: 345.1 1 H NMR (500 MHz, DMSO- d 6) δ 12.31 (s, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.16 (d, J = 7.9 Hz, 1H), 5.49 (s, 1H), 3.56 (d, J = 6.4 Hz, 2H), 3.04 (ddd,J = 16.0, 13.3, 8.1 Hz, 2H), 2.75 (td, J = 14.8, 13.3, 4.4 Hz, 2H), 2.71 –2.63 (m, 1H), 0.81 (s, 9H), 0.00 (s, 6H). Step 12: Preparation of intermediate 8m 8 L (51 g), hydroxylamine hydrochloride (61.4 g), sodium ethoxide (61.1 g), and ethanol (2000 mL) were added sequentially to a reaction flask. The mixture was heated to 85 °C under N2 protection. oC. After the reaction is complete, the solvent in the reaction solution is removed by vacuum, 2L of water is added, the pH is adjusted to 8-9 with saturated sodium carbonate solution, ethyl acetate is added for extraction, the aqueous phase is collected, the pH is adjusted to 6-7 with 1M hydrochloric acid, ethyl acetate is added for extraction again, the organic phase is collected, washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and the solvent in the filtrate is removed by vacuum to obtain intermediate 8m (47g).

[0409] MS(ESI, [MH] - m / z: 360.2. 1 H NMR (500 MHz, DMSO- d 6) δ 7.55 (d, J = 8.0 Hz, 1H), 7.22 (d, J =8.0 Hz, 1H), 3.97 (s, 2H), 3.57 (d, J = 6.6 Hz, 2H), 3.16 – 3.07 (m, 2H), 2.88 – 2.72 (m, 3H), 0.81 (s, 9H), 0.00 (s, 6H). Step 13 Preparation of intermediate 8n 8 mL (47 g), ethanol (1500 mL), and concentrated sulfuric acid (65.1 g, 35.4 mL) were added sequentially to a reaction flask. Under N2 protection, the mixture was heated to 85°C. o C. The reaction solution was cooled to room temperature, the solvent was removed by rotary evaporation, 1000 mL of dichloromethane was added, and saturated sodium bicarbonate aqueous solution was added dropwise for neutralization. After washing with saturated brine, the solution was dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate by vacuum evaporation to obtain intermediate 8n (43 g).

[0410] MS (ESI, [M+H) + m / z: 276.1 1 H NMR (500 MHz, DMSO-d6) δ 7.58 (d, J = 8.0 Hz, 1H), 7.27 (d, J =8.0 Hz, 1H), 4.74 (q, J = 4.9 Hz, 1H), 4.16 (s, 2H), 4.12 (t, J = 7.1 Hz, 2H), 3.43 (dd, J = 6.8, 5.3 Hz, 2H), 3.15 (ddd, J = 29.7, 16.4, 8.3 Hz, 2H), 2.93 – 2.81 (m, 2H), 2.79 – 2.70 (m, 1H), 1.19 (t, J = 7.1 Hz, 3H). Preparation of intermediates 8o-1 and 8o-2 in step 14 Preparation and resolution: 43 g of intermediate 8n was dissolved in 430 mL of dichloromethane-ethanol solution, with a concentration of approximately 100.0 mg / mL. The solution was filtered through a 0.45 μm organic filter membrane, and the filtrate was collected. Instrumentation: YMC high-performance preparative chromatograph; column: CHIRALPAK IG (Innovation 036#, 30*250 mm, S-10 μm); mobile phase A: ethanol; B: n-hexane. The initial peak yielded intermediate 8o-1 (9.057 g), and the subsequent peak yielded intermediate 8o-2 (8.833 g).

[0411] 8o-1:MS(ESI, [M+H] + m / z: 276.1. 8o-2:MS(ESI, [M+H] + m / z: 276.1. Preparation of intermediate 8 in step 15 In a reaction flask, under N2 protection, 11.93 g of 8O⁻¹, 200 mL of THF, and 3.39 g of acrylamide were added sequentially. After cooling to 0 °C, 34.7 mL of 1 M potassium tert-butoxide tetrahydrofuran solution was added, and the mixture was reacted at 0 °C. After the reaction was complete, the reaction solution was added dropwise to an ice-cold saturated ammonium chloride aqueous solution, and extracted with 1000 mL of ethyl acetate. The aqueous phase was extracted with 500 mL of ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. After filtration, the filter cake was collected to obtain 6.77 g of intermediate 8.

[0412] 1 H NMR (500 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H), 4.74 (td, J = 5.3, 2.2 Hz, 1H), 4.56 (dd, J = 2.60 (dt, J = 17.3, 4.2 Hz, 1H), 2.50 – 2.44 (m, 1H), 2.23 – 2.13 (m, 1H). Step 16 Synthesis of Intermediate 9 80-2 (12.83 g), THF (200 mL), and acrylamide (3.64 g) were added sequentially to a reaction flask. After cooling to 0°C, potassium tert-butoxide tetrahydrofuran solution (1 M, 37.3 mL) was added. The mixture was reacted at 0°C under N2 protection. After the reaction was completed, the reaction solution was added dropwise to ice-cold saturated ammonium chloride aqueous solution. Ethyl acetate was added for extraction. After extraction of the aqueous phase with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. After filtration, the filter cake was collected to obtain intermediate 9 (7.454 g).

[0413] 1 H NMR (500 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H), 4.74 (td, J = 5.3, 2.2 Hz, 1H), 4.56 (dd, J = 11.8,5.0 Hz, 1H), 3.43 (dd, J = 6.8, 5.2 Hz, 2H), 3.21 – 3.09 (m, 2H), 2.94 – 2.83(m, 2H), 2.80 – 2.71 (m, 2H), 2.60 (dt, J = 17.3, 4.2 Hz, 1H), 2.46 (dd, J =12.1, 4.5 Hz, 1H), 2.23 – 2.15 (m, 1H). Synthesis of Intermediate 10 in Example 10

[0414]

[0415] Step 1: Preparation of intermediate 10b 10a (100 g), 2,4-dimethoxybenzylamine (102 g), and acetic acid (600 mL) were added sequentially to the reaction flask. o Reaction C was completed. Water was added to the reaction solution, and the mixture was filtered. The filter cake was washed with water and dried to obtain intermediate 10b (95.7 g).

[0416] MS (ESI, [MH] - ) m / z 312.02 1 H NMR (500 MHz, DMSO- d 6) δ 11.03 (s, 1H), 7.62 (dd, J= 8.4, 7.1 Hz, 1H), 7.29 (d, J = 7.1 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.56 (d, J = 2.4 Hz, 1H), 6.43 (dd, J = 8.4, 2.4 Hz, 1H), 4.60 (s, 2H), 3.80 (s, 3H), 3.73 (s, 3H). Step 2: Preparation of intermediate 10c Intermediate 10b (130 g), potassium carbonate (97 g), iodomethane (65 mL), and N,N-dimethylformamide (1 L) were added sequentially to a reaction flask. The reaction was carried out at 80 °C until completion. After cooling to room temperature, water was added to the reaction solution, and the mixture was filtered. The filter cake was washed with water and dried to obtain intermediate 10c (126 g).

[0417] MS (ESI, [M+H) + ) m / z 327.99 1 H NMR (500 MHz, DMSO- d 6) δ 7.80 (dd, J = 8.5, 7.2 Hz, 1H), 7.48 (d, J =8.4 Hz, 1H), 7.45 – 7.39 (m, 1H), 6.91 (d, J = 8.5 Hz, 1H), 6.56 (d, J = 2.4 Hz, 1H), 6.43 (dd, J = 8.4, 2.4 Hz, 1H), 4.60 (s, 2H), 3.95 (s, 3H), 3.79 (s, 3H), 3.72 (s, 3H). Step 3: Preparation of intermediate 10d Intermediate 10c (128 g) and tetrahydrofuran (800 mL) were added sequentially to a reaction flask. Under N2 protection at 0°C, lithium aluminum hydride (89 g) was slowly added, and the temperature was raised to 80°C for the reaction to proceed. After the reaction was complete, 89 mL of water was slowly added dropwise to the reaction solution in an ice bath, followed by 267 mL of 15% NaOH aqueous solution, and then 89 mL of water. The mixture was stirred for 0.5 h, filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The filtrate was collected, the organic layer was separated, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain intermediate 10d (86.4 g).

[0418] MS (ESI, [M+H) + ) m / z 300.20 1 H NMR (500 MHz, DMSO- d 6) δ 7.26 (d, J = 8.3 Hz, 1H), 7.18 (t, J = 7.8Hz, 1H), 6.90 – 6.77 (m, 2H), 6.57 (d, J = 2.4 Hz, 1H), 6.52 (dd, J = 8.3, 2.4Hz, 1H), 3.92 (s, 2H), 3.89 – 3.80 (m, 4H), 3.78 (s, 3H), 3.76 (d, J = 3.6 Hz, 6H). Step 4: Preparation of intermediate 10e Intermediate 10d (86 g), 10% palladium / carbon (15 g), methanol (500 mL), and di-tert-butyl dicarbonate (63.3 g) were added sequentially to a reaction flask. The reaction was carried out at room temperature under a hydrogen atmosphere at 0°C until completion. The reaction solution was filtered, and the filtrate was concentrated to obtain intermediate 10e (100 g).

[0419] 1 H NMR (500 MHz, DMSO) δ 7.27 (t, J = 7.9 Hz, 1H), 6.93 – 6.86 (m, 2H), 4.60 – 4.53 (m, 2H), 4.50 – 4.43 (m, 2H), 3.80 (d, J = 1.4 Hz, 3H), 1.45 (s, 9H). Step 5: Preparation of intermediate 10f Intermediate 10e (100 g), dichloromethane (1000 mL), and trifluoroacetic acid (457 g) were added sequentially to a reaction flask and reacted at room temperature for 2 hours until the reaction was complete. The reaction solution was directly concentrated, and the concentrate was dissolved in tetrahydrofuran (1000 mL). Under an ice-water bath, trifluoroacetic anhydride (84 g) was added, and the reaction was carried out at room temperature until the reaction was complete. The reaction solution was slowly added to a saturated sodium bicarbonate solution to quench the reaction, and then extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain intermediate 10f (57.4 g).

[0420] Step 6: Preparation of 10g of intermediate Intermediate 10f (40 g) and acetonitrile (500 mL) were added sequentially to a reaction flask and dissolved. Then, N-bromosuccinimide (30.5 g) was added, and the reaction was carried out at 75°C until completion. The reaction solution was quenched with ice water, filtered, the filter cake was washed with water, and dried to obtain intermediate 10 g (60 g).

[0421] 1 H NMR (500 MHz, DMSO- d 6) δ 7.51 (dd, J = 8.7, 1.5 Hz, 1H), 6.96 (d, J =8.6 Hz, 1H), 4.95 (d, J = 29.1 Hz, 2H), 4.76 (d, J = 29.7 Hz, 2H), 3.83 (d, J = 2.4Hz, 3H). Step 7: Preparation of intermediates over 10 hours 10 g (40 g) of chloroacetyl chloride (30 mL) was added sequentially to the reaction flask. Trifluoromethanesulfonic acid (120 mL) was slowly added dropwise under an ice-water bath. The reaction was carried out at 50 °C until completion. The reaction solution was slowly added dropwise to ice water, and then extracted twice with dichloromethane. The organic phases were combined and washed twice with saturated sodium bicarbonate aqueous solution. The organic layer was separated, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target intermediate 10 h (20 g).

[0422] 1 H NMR (500 MHz, DMSO- d 6) δ 7.84 (d, J = 8.8 Hz, 1H), 5.31 (s, 1H), 5.15 (s, 1H), 5.01 (d, J= 2.4 Hz, 2H), 4.99 (s, 1H), 4.79 (s, 1H), 3.93 (d, J =19.4 Hz, 3H). Step 8: Preparation of intermediate 10i 10h (20 g) and dichloromethane (300 mL) were added sequentially to the reaction flask. Boron trichloride (149 mL) was slowly added dropwise under an ice-water bath. The reaction was carried out at room temperature until completion. The reaction solution was slowly added to ice water, and then extracted twice with dichloromethane. The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the target intermediate 10i (20 g).

[0423] MS (ESI, [M+H) + ) m / z 386.00 1 H NMR (500 MHz, DMSO- d 6) δ 11.37 (s, 1H), 7.98 (d, J = 2.5 Hz, 1H),5.18 (s, 2H),5.09 (s, 1H), 5.00 (s, 1H), 4.89 (s, 1H),4.80 (s, 1H). Step 9: Preparation of intermediate 10j 10i (19.5 g), sodium bicarbonate (12.7 g), and acetonitrile (900 mL) were added sequentially to the reaction flask, and the reaction was carried out at 80 °C until completion. Water and ethyl acetate were added, the organic layer was collected, anhydrous sodium sulfate was added and dried, filtered, and the filtrate was concentrated to obtain the target intermediate 10j (24 g).

[0424] 1 H NMR (500 MHz, DMSO- d 6) δ 7.87 (s, 1H), 5.21 (d, J = 2.4 Hz, 1H), 5.06 (s, 1H), 4.99 (d, J = 2.1 Hz, 1H), 4.97 (d, J = 3.1 Hz, 2H), 4.85 (s, 1H). Step 10: Preparation of intermediate 10k 10J (23.4 g), 10% palladium / carbon (1.4 g), sodium bicarbonate (5.61 g), and ethanol (400 mL) were added sequentially to a reaction flask. The reaction was carried out at room temperature in the presence of hydrogen until completion. The reaction solution was filtered, and the filtrate was evaporated under reduced pressure. Ethyl acetate and water were added to the residue, and the organic layer was separated. Anhydrous sodium sulfate was added and dried. The mixture was filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target intermediate 10K (12 g).

[0425] MS (ESI, [MH] - ) m / z 270.00 1 H NMR (500 MHz, DMSO- d 6) δ 7.65 (dd, J = 7.9, 2.5 Hz, 1H), 7.20 (dd, J =12.0, 7.9 Hz, 1H), 5.14 (s, 1H), 5.10 (s, 1H), 4.94 (s, 1H), 4.92 – 4.88 (m,3H). Step 11: Preparation of intermediate 10L 10kJ (11.5 g), ethoxyformylmethylenetriphenylphosphine (22.2 g), and toluene (30 mL) were added sequentially to the reaction flask. The reaction was carried out at 120 °C under N2 protection until completion. Ethyl acetate and water were added to the reaction system, the organic layer was separated, anhydrous sodium sulfate was added and dried, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target intermediate 10 L (5.3 g).

[0426] 1 H NMR (500 MHz, DMSO- d 6) δ 7.96 (d, J = 2.9 Hz, 1H), 7.60 (dd, J = 8.0,3.3 Hz, 1H), 7.33 – 7.27 (m, 1H), 5.27 (s, 1H), 5.15 (s, 1H), 5.07 (s, 1H),4.96 (s, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.81 (d, J = 1.0 Hz, 2H), 1.19 (t, J = 7.1Hz, 3H). Step 12: Preparation of intermediate 10m 10 L (5.3 g), potassium carbonate (6.4 g), and ethanol (50 mL) were added sequentially to the reaction flask, and the reaction was carried out at room temperature until completion. Ethyl acetate and water were added to the reaction system, the organic layer was separated, anhydrous sodium sulfate was added for drying, and the mixture was filtered. The filtrate was concentrated to obtain the target intermediate 10 M (4.3 g).

[0427] MS(ESI, [M+H)) + m / z: 246.10 Step 13: Preparation of intermediate 10n 10m (4.3 g), triethylamine (3.47 g), and dichloromethane (50 mL) were added sequentially to the reaction flask, followed by di-tert-butyl dicarbonate (4.11 g). The reaction was carried out at room temperature until completion. Water was added to the reaction system, the organic layer was separated, anhydrous sodium sulfate was added for drying, and the mixture was filtered. The filtrate was concentrated and purified by silica gel column chromatography to obtain the target intermediate 10n (3.7 g).

[0428] 1 H NMR (500 MHz, DMSO- d 6) δ 7.93 (s, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.23(t, J = 7.6 Hz, 1H), 4.80 (dd, J = 12.9, 2.4 Hz, 2H), 4.73 – 4.66 (m, 2H), 4.11(q, J = 7.1 Hz, 2H), 3.79 (s, 2H), 1.48 (s, 9H), 1.19 (t, J = 7.1 Hz, 3H). Step 14: Preparation of intermediate 10o 10n (3.7 g), acrylamide (0.84 g), and N,N-dimethylformamide (50 mL) were added sequentially to the reaction flask. The mixture was cooled to 0°C, and potassium tert-butoxide (8.6 mL, 1 M) was slowly added dropwise. The reaction was continued at 0°C until completion. The reaction mixture was added dropwise to an ice-cold aqueous solution of ammonium chloride, extracted with ethyl acetate, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target intermediate 10o (2.6 g).

[0429] 1 H NMR (500 MHz, DMSO- d 6) δ10.90 (s, 1H), 7.91 (s, 1H), 7.53 (dd, J=8.0, 1.9 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 4.86 – 4.77 (m, 2H), 4.69 (d, J =11.8 Hz, 2H), 4.15 (dd, J = 12.1, 5.0 Hz, 1H), 2.77 – 2.69 (m, 1H), 2.58 (dt, J =17.4, 4.0 Hz, 1H), 2.33 (qd, J = 12.5, 4.4 Hz, 1H), 2.15 – 2.07 (m, 1H), 1.48(d, J = 2.6 Hz, 9H). Step 15: Preparation of Intermediate 10 10O (2.4 g) and dioxane (15 mL) were added sequentially to the reaction flask, followed by 15 mL of hydrochloric acid-dioxane solution (4 M). The reaction was carried out at room temperature until completion. Methyl tert-butyl ether was added to the reaction system, and the mixture was filtered. The filter cake was washed with methyl tert-butyl ether, collected, and dried to obtain the target intermediate 10 (2.0 g).

[0430] MS(ESI, [M+H)) + m / z: 271.15 1 H NMR (500 MHz, DMSO- d 6) δ10.92 (s, 1H), 10.16 (s, 2H), 7.99 (s,1H), 7.61 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H), 4.75 (d, J = 5.0 Hz, 2H), 4.61 (d, J = 5.1 Hz, 2H), 4.18 (dd, J = 12.2, 4.9 Hz, 1H), 2.80 – 2.71 (m, 1H), 2.58 (dt, J = 17.3, 4.0 Hz, 1H), 2.34 (qd, J = 12.6, 4.4 Hz, 1H), 2.11 (dtd, J =13.2, 5.2, 3.4 Hz, 1H). Synthesis of Intermediate 11 in Example 11

[0431]

[0432] Step 1: Preparation of intermediate 11b Intermediate 11a and methanol (1500 mL) were added sequentially to a reaction flask. Sodium cyanoborohydride (148 g) was added at 0 °C, and the mixture was reacted at 0 °C for 10 min. Boron trifluoride diethyl ether (334 g) was added dropwise at 0 °C, and the mixture was heated to 75 °C to react. After the reaction was complete, 50 mL of saturated sodium bicarbonate solution was added to the reaction solution, and the solvent was removed by vacuum distillation. Dichloromethane and water were added for extraction, and the organic phase was separated by drying with anhydrous sodium sulfate. The mixture was filtered, and the solvent was removed by vacuum distillation of the filtrate to obtain the target intermediate 11b (102.65 g).

[0433] MS(ESI, [M+H)) + m / z: 212.2.

[0434] 1 H NMR (500 MHz, DMSO-d6) δ 7.38 (dd, J = 7.7, 1.4 Hz, 1H), 7.08 (dd,J = 16.0, 7.5 Hz, 2H), 3.74 (s, 2H), 2.89 (t, J = 5.8 Hz, 2H), 2.68 (t, J =5.8 Hz, 2H). Step 2: Preparation of intermediate 11c Intermediate 11b (100.06 g) and tetrahydrofuran (1000 mL) were added sequentially to a reaction flask. Trifluoroacetic anhydride (95 g, 63.2 mL) was then added under ice-bath conditions, and the mixture was allowed to return to room temperature for further reaction. After the reaction was complete, the reaction solution was extracted with 1000 mL of ethyl acetate and 2000 mL of water. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent, yielding the target intermediate 11c (137.6 g). 1 H NMR (500 MHz, DMSO-d6) δ 7.54 (dd, J = 7.9, 1.4 Hz, 1H), 7.26 (q,J = 7.0, 5.9 Hz, 1H), 7.23 – 7.18 (m, 1H), 4.71 (d, J = 27.7 Hz, 2H), 3.82(t, J = 6.0 Hz, 2H), 2.95 (dt, J = 13.6, 6.0 Hz, 2H). Step 3: Preparation of intermediate 11d Intermediate 11c (137.6 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (36.5 g), pinacol diborate (136 g), potassium acetate (131 g), and dioxane (1500 mL) were added sequentially to a reaction flask. Under N2 protection, the mixture was heated to 85°C for reaction. After the reaction was completed, the reaction solution was filtered, and the solvent was removed by vacuum distillation of the filtrate. Petroleum ether was added and the mixture was stirred, filtered, and 2 L of water was added to extract the filtrate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation of the filtrate to obtain the target intermediate 11d (165.4 g).

[0435] MS(ESI, [M+H)) + m / z: 356.2.

[0436] 1 H NMR (500 MHz, DMSO-d6) δ 7.59 (ddd, J = 7.4, 3.7, 1.4 Hz, 1H), 7.33 (ddd, J = 17.9, 7.6, 1.4 Hz, 1H), 7.29 – 7.22 (m, 1H), 5.03 (d, J = 38.6Hz, 2H), 3.80 (t, J = 6.2 Hz, 1H), 3.75 (t, J = 6.4 Hz, 1H), 2.94 (t, J = 6.3Hz, 2H), 1.31 (d, J = 4.3 Hz, 12H). Step 4: Preparation of intermediate 11e Intermediate 11d (165.4 g), tetrahydrofuran (1000 mL), and acetic acid (98 g, 93 mL) were added sequentially to a reaction flask. 30% hydrogen peroxide (185 g, 166 mL) was added under ice bath conditions, and the mixture was brought back to room temperature for further reaction. After the reaction was complete, the reaction solution was quenched in an ice-cold saturated sodium thiosulfate solution. The pH was adjusted to 8 with saturated sodium bicarbonate solution, and ethyl acetate was added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. The residue was slurried with 200 mL of petroleum ether / methyl tert-butyl ether, filtered, and the filter cake was collected to obtain the target intermediate 11e (85.3 g).

[0437] MS(ESI, [MH] - m / z: 244.2.

[0438] 1H NMR (500 MHz, DMSO-d6) δ 9.80 (d, J = 25.4 Hz, 1H), 7.03 (q, J =7.9 Hz, 1H), 6.71 (dd, J = 8.0, 3.1 Hz, 1H), 6.64 (t, J = 6.9 Hz, 1H), 4.61(d, J = 23.4 Hz, 2H), 3.81 – 3.75 (m, 2H), 2.84 (dt, J = 16.8, 5.9 Hz, 2H). Step 5: Preparation of intermediate 11f Intermediate 11e (30 g), acetonitrile (300 mL), potassium carbonate (33.8 g), and tert-butyl bromoacetate (26.3 g, 19.89 mL) were added sequentially to a reaction flask, and the mixture was heated to 80 °C. After the reaction was complete, the reaction solution was extracted with 500 mL of ethyl acetate and 1000 mL of water, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain the target intermediate 11f (47.4 g).

[0439] 1 H NMR (500 MHz, DMSO-d6) δ 7.18 (q, J = 8.2 Hz, 1H), 6.83 (t, J =6.9 Hz, 1H), 6.78 (dd, J = 8.3, 2.8 Hz, 1H), 4.75 – 4.66 (m, 4H), 3.83 – 3.77(m, 2H), 2.89 (dt, J = 17.6, 6.0 Hz, 2H), 1.43 – 1.41 (m, 9H). Step 6: Preparation of 11g of intermediate Intermediate 11f (47.4 g), dichloromethane (500 mL), and trifluoroacetic acid (207 g, 140 mL) were added sequentially to a reaction flask, and the mixture was reacted at room temperature for 1 h. After the reaction was complete, the solvent was removed from the reaction solution by vacuum distillation. The residue was then added to dichloromethane, and the solvent was removed by vacuum distillation to obtain the target intermediate 11 g (34.2 g).

[0440] MS(ESI, [MH] - m / z: 302.0.

[0441] 1H NMR (500 MHz, DMSO-d6) δ 13.04 (s, 1H), 7.18 (q, J = 7.9 Hz, 1H), 6.85 – 6.75 (m, 2H), 4.78 – 4.66 (m, 4H), 3.81 (q, J = 5.6 Hz, 2H), 2.88 (dt,J = 18.5, 5.9 Hz, 2H). Step 7: Preparation of intermediates 11h and 11i Intermediate 11 g (33.7 g), tetrahydrofuran (350 mL), and thionyl chloride (39.7 g) were added sequentially to a reaction flask, and the mixture was heated to 75 °C. After the reaction was complete, the reaction solution was cooled to room temperature, and the solvent was removed by vacuum distillation to obtain the target intermediate 11h. Dichloromethane (350 mL) and aluminum trichloride (39.7 g) were added to intermediate 11h, and the mixture was stirred at room temperature. After the reaction was complete, the reaction solution was quenched in 500 mL of ice water and filtered through diatomaceous earth. The filtrate was extracted with 100 mL of dichloromethane and 100 mL of water, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain the target intermediate 11i (32.5 g).

[0442] 1 H NMR (500 MHz, DMSO-d6) δ 7.50 (dd, J = 9.6, 7.9 Hz, 1H), 7.02 (dd,J = 8.0, 5.7 Hz, 1H), 4.87 (s, 2H), 4.78 (d, J = 21.1 Hz, 2H), 3.88 (td, J =5.9, 2.5 Hz, 2H), 3.02 (dt, J = 13.1, 5.8 Hz, 2H). Step 8: Preparation of intermediate 11j Intermediate 11i (32.5 g), ethoxyformylmethylenetriphenylphosphine (54.7 g), and toluene (350 mL) were added sequentially to a reaction flask. Under N2 protection, the mixture was heated to 120 °C for reaction. After the reaction was completed, the reaction solution was extracted with 300 mL of ethyl acetate and 800 mL of water. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to obtain the target intermediate 11j (19.37 g).

[0443] 1H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.47 (t, J = 8.2 Hz, 1H), 7.12 (dd, J = 8.0, 5.9 Hz, 1H), 4.99 (d, J = 22.7 Hz, 2H), 4.11 (q, J = 7.1Hz, 2H), 3.93 – 3.87 (m, 2H), 3.78 (d, J = 1.0 Hz, 2H), 3.02 (dt, J = 13.4,5.9 Hz, 2H), 1.19 (td, J = 7.1, 1.3 Hz, 3H). Step 9: Preparation of intermediate 11k Intermediate 11j, potassium carbonate (22.60 g, 164 mmol), and ethanol (200 mL) were added sequentially to a reaction flask, and the mixture was reacted at room temperature. After the reaction was complete, the reaction solution was extracted with 300 mL of ethyl acetate and 500 mL of water to separate the organic phase. The aqueous phase was extracted with ethyl acetate, and 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 the target intermediate 11k (13.12 g).

[0444] MS(ESI, [M+H)) + m / z: 260.1.

[0445] 1 H NMR (500 MHz, DMSO-d6) δ 7.81 (s, 1H), 7.32 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 7.9 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 4.05 (s, 2H), 3.73 (d, J= 1.0 Hz, 2H), 2.98 (t, J = 5.8 Hz, 2H), 2.76 (t, J = 5.7 Hz, 2H), 1.18 (t, J= 7.1 Hz, 3H). Step 10: Preparation of intermediate 11l Intermediate 11k (13.12 g), dichloromethane (130 mL), triethylamine (10.24 g, 14.10 mL), and di-tert-butyl dicarbonate (12.15 g, 12.92 mL) were added sequentially to a reaction flask, and the mixture was reacted at room temperature. After the reaction was complete, the solvent was removed from the reaction solution by vacuum distillation, and the residue was extracted with 300 mL of ethyl acetate and 500 mL of water. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to obtain the target intermediate 11k (16.32 g).

[0446] MS(ESI, [M+H)) + m / z: 360.2.

[0447] 1 H NMR (500 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.40 (d, J = 7.9 Hz, 1H), 7.06 (d, J = 7.9 Hz, 1H), 4.73 (s, 2H), 4.10 (q, J = 7.1 Hz, 2H), 3.78 – 3.75(m, 2H), 3.63 (t, J = 5.8 Hz, 2H), 2.87 (t, J = 5.8 Hz, 2H), 1.45 (s, 9H), 1.19 (t, J = 6.6 Hz, 3H). Step 11: Preparation of intermediate 11m Intermediate 11l (16.32 g), N,N-dimethylformamide (160 mL), and acrylamide (3.55 g) were added sequentially to a reaction flask. Under N2 protection, the mixture was cooled to 0°C, and then potassium tert-butoxide tetrahydrofuran solution (1 mol / L, 40.9 mL) was added. The mixture was reacted at 0°C. After the reaction was complete, the reaction solution was added dropwise to ice-cold saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phase was separated. The mixture was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The residue was slurried with 200 mL of petroleum ether / ethyl acetate, filtered, and the filter cake was collected to obtain the target intermediate 11m (14.5 g).

[0448] MS(ESI, [M+H)) + m / z: 385.1.

[0449] 1H NMR (500 MHz, DMSO-d6) δ 10.89 (s, 1H), 7.88 (s, 1H), 7.39 (d, J =8.0 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 4.73 (s, 2H), 4.12 (dd, J = 12.0, 4.9Hz, 1H), 3.63 (t, J = 5.8 Hz, 2H), 2.87 (t, J = 5.8 Hz, 2H), 2.73 (td, J =12.2, 6.0 Hz, 1H), 2.59 – 2.54 (m, 1H), 2.31 (qd, J = 12.5, 4.4 Hz, 1H), 2.10(ddt, J = 9.9, 5.2, 2.7 Hz, 1H), 1.44 (s, 9H). Step 12: Preparation of intermediate 11 Intermediate 11m (14.5 g), dichloromethane (150 mL), and 1,4-dioxane hydrochloric acid solution (4 mol / L, 141 mL) were added sequentially to a reaction flask, and the mixture was reacted at room temperature. The solvent was removed from the reaction solution by vacuum distillation, and the residue was mixed with methyl tert-butyl ether and slurryed. The mixture was filtered, and the filter cake was collected to obtain intermediate 11 (12.6 g).

[0450] MS(ESI, [M+H)) + m / z: 285.1.

[0451] 1 H NMR (500 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.87 (s, 2H), 7.93 (s,1H), 7.49 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 8.1 Hz, 1H), 4.45 (s, 2H), 4.15(dd, J = 12.1, 4.8 Hz, 1H), 3.40 (t, J = 6.1 Hz, 2H), 3.12 (t, J = 6.1 Hz,2H), 2.75 (ddd, J = 17.4, 12.3, 5.3 Hz, 1H), 2.57 (dt, J = 17.3, 4.0 Hz, 1H),2.32 (qd, J = 12.6, 4.5 Hz, 1H), 2.10 (ddt, J = 9.9, 5.2, 2.6 Hz, 1H). Synthesis of Intermediate 12 in Example 12

[0452]

[0453] Step 1: Preparation of intermediate 12a Intermediate 4c, acetonitrile (130 mL), potassium carbonate (14.09 g), and tert-butyl bromoacetate (10.94 g, 8.29 mL) were added sequentially to a reaction flask. The mixture was heated to 80 °C. After the reaction was complete, 200 mL of ethyl acetate and 500 mL of water were added for extraction. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain the target intermediate 12a (20.33 g).

[0454] 1 H NMR (500 MHz, DMSO-d6) δ 7.17 (t, J = 8.0 Hz, 1H), 6.87 (t, J =7.8 Hz, 1H), 6.76 (t, J = 8.0 Hz, 1H), 4.75 (d, J = 4.8 Hz, 2H), 4.70 (d, J =4.6 Hz, 2H), 3.84 (t, J = 6.1 Hz, 2H), 2.81 (dt, J = 16.3, 6.1 Hz, 2H), 1.41(d, J = 2.4 Hz, 9H). Step 2: Preparation of intermediate 12b Intermediate 12a (20.33 g), dichloromethane (100 mL), and trifluoroacetic acid (29.0 g, 19.61 mL) were added sequentially to a reaction flask, and the mixture was reacted at room temperature. After the reaction was complete, the solvent was removed from the reaction solution by vacuum distillation. The residue was then added to dichloromethane, and the solvent was removed by vacuum distillation to obtain the target intermediate 12b (16.2 g).

[0455] MS(ESI, [MH] - m / z: 301.9.

[0456] 1H NMR (500 MHz, DMSO-d6) δ 13.00 (s, 1H), 7.17 (t, J = 7.9 Hz, 1H), 6.87 (t, J = 8.0 Hz, 1H), 6.77 (t, J = 7.6 Hz, 1H), 4.74 (d, J = 4.7 Hz, 2H), 4.72 (d, J = 4.1 Hz, 2H), 3.84 (t, J = 6.1 Hz, 2H), 2.81 (dt, J = 16.2, 6.1Hz, 2H). Step 3: Preparation of intermediates 12c and 12d Intermediate 12b (16.2 g), tetrahydrofuran (160 mL), and thionyl chloride (30.0 g, 18.29 mL) were added sequentially to a reaction flask, and the mixture was heated to 75 °C for 2 h. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the target intermediate 12c. Trifluoromethanesulfonic acid (100 mL) was added dropwise to intermediate 12c under ice bath conditions, and the mixture was stirred at room temperature. After the reaction was complete, the reaction solution was poured into 2000 mL of ice-water solution, 500 mL of ethyl acetate was added, the organic phase was separated, the pH was adjusted to 8 with saturated sodium bicarbonate solution, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to obtain the target intermediate 12d (3.27 g).

[0457] 1 H NMR (500 MHz, DMSO-d6) δ 7.49 (d, J = 8.0 Hz, 1H), 7.08 (dd, J =13.3, 8.0 Hz, 1H), 4.89 – 4.84 (m, 4H), 3.90 (dt, J = 10.0, 6.1 Hz, 2H), 2.88(dt, J = 17.6, 6.0 Hz, 2H). Step 4: Preparation of intermediate 12e Intermediate 12d (4.59 g), ethoxyformylmethylenetriphenylphosphine (8.41 g), and toluene (100 mL) were added sequentially to a reaction flask. Under N2 protection, the mixture was heated to 130 °C for reaction. After the reaction was complete, 200 mL of ethyl acetate and 300 mL of water were added 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 filtrate was purified by silica gel column chromatography to obtain the target intermediate 12e (3.93 g).

[0458] 1H NMR (500 MHz, DMSO-d6) δ 7.92 (d, J = 2.7 Hz, 1H), 7.46 (dd, J =8.1, 3.2 Hz, 1H), 7.16 (t, J = 8.4 Hz, 1H), 4.88 (d, J = 7.3 Hz, 2H), 4.10(q, J = 7.1 Hz, 2H), 3.97 – 3.91 (m, 2H), 3.77 (d, J = 1.0 Hz, 2H), 3.09 (dt,J = 15.5, 6.0 Hz, 2H), 1.19 (td, J = 7.0, 0.8 Hz, 3H). Step 5: Preparation of intermediate 12f Intermediate 12e (3.93 g), potassium carbonate (4.36 g), and ethanol (50 mL) were added sequentially to a reaction flask, and the mixture was reacted at room temperature. After the reaction was complete, 200 mL of ethyl acetate and 300 mL of water were added for extraction, the organic phase was separated, the aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain the target intermediate 12f (2.63 g).

[0459] MS(ESI, [M+H)) + m / z: 260.1.

[0460] 1 H NMR (500 MHz, DMSO-d6) δ 7.83 (s, 1H), 7.31 (d, J = 7.9 Hz, 1H), 6.92 (d, J = 7.9 Hz, 1H), 4.09 (t, J = 7.1 Hz, 2H), 3.92 (s, 2H), 3.74 (d, J= 1.0 Hz, 2H), 3.02 (t, J = 5.9 Hz, 2H), 2.83 (t, J = 5.9 Hz, 2H), 1.18 (t, J= 7.1 Hz, 3H). Step 6: Preparation of 12g of intermediate Intermediate 12f (2.63 g), dichloromethane (30 mL), triethylamine (2.053 g, 2.83 mL), and di-tert-butyl dicarbonate (2.435 g, 2.59 mL) were added sequentially to a reaction flask, and the mixture was reacted at room temperature. After the reaction was complete, the solvent was removed from the reaction solution by vacuum distillation. The residue was extracted with 200 mL of ethyl acetate and 200 mL of water, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to obtain the target intermediate 12 g (3.53 g).

[0461] MS(ESI, [M+H)) + m / z: 360.1.

[0462] 1 H NMR (500 MHz, DMSO-d6) δ 7.88 (d, J = 1.1 Hz, 1H), 7.40 (d, J =8.0 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 4.61 (s, 2H), 4.10 (q, J = 7.1 Hz, 2H), 3.76 (d, J = 1.1 Hz, 2H), 3.66 (t, J = 5.9 Hz, 2H), 2.94 (t, J = 5.9 Hz, 2H), 1.43 (s, 9H), 1.18 (t, J = 7.1 Hz, 3H). Step 7: Preparation of intermediates over 12 hours 12 g (3.71 g) of intermediate, 12 mL of N,N-dimethylformamide, and 0.807 g of acrylamide were added sequentially to a reaction flask. Under N2 protection, the mixture was cooled to 0 °C, and then potassium tert-butoxide tetrahydrofuran solution (1 mol / L, 8.26 mL) was added. The mixture was reacted at 0 °C for 1 h. After the reaction was complete, the reaction solution was added dropwise to ice-cold saturated ammonium chloride aqueous solution, and extracted with ethyl acetate. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to obtain the target intermediate 12 h (2.57 g).

[0463] MS(ESI, [M+H)) + m / z: 385.2.

[0464] 1H NMR (500 MHz, DMSO-d6) δ 10.89 (s, 1H), 7.87 (s, 1H), 7.40 (d, J =8.0 Hz, 1H), 7.05 (d, J = 8.1 Hz, 1H), 4.61 (s, 2H), 4.11 (dd, J = 12.0, 4.9Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 2.95 (t, J = 5.9 Hz, 2H), 2.74 (ddd, J =17.3, 12.2, 5.3 Hz, 1H), 2.57 (dt, J = 17.3, 4.1 Hz, 1H), 2.35 – 2.27 (m,1H), 2.10 (dtd, J = 13.5, 5.2, 3.7 Hz, 1H), 1.43 (s, 9H). Step 8: Preparation of Intermediate 12 Intermediate 12h (2.57 g), dichloromethane (25 mL), and 1,4-dioxane hydrochloric acid solution (4 mol / L, 25.10 mL) were added sequentially to a reaction flask. The mixture was reacted at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation of the reaction solution. The residue was mixed with methyl tert-butyl ether and slurried. The mixture was filtered, and the filter cake was collected to obtain intermediate 12 (2.09 g).

[0465] MS(ESI, [M+H)) + m / z: 285.1.

[0466] 1 H NMR (500 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.72 (s, 2H), 7.94 (s,1H), 7.48 (d, J = 8.1 Hz, 1H), 7.10 (d, J = 8.2 Hz, 1H), 4.35 (d, J = 4.1 Hz,2H), 4.14 (dd, J = 12.1, 4.9 Hz, 1H), 3.38 (s, 2H), 3.18 (t, J = 6.2 Hz, 2H), 2.75 (ddd, J = 17.4, 12.3, 5.4 Hz, 1H), 2.57 (dt, J = 17.3, 4.0 Hz, 1H), 2.32(qd, J = 12.6, 4.4 Hz, 1H), 2.10 (dtd, J = 13.4, 5.2, 3.5 Hz, 1H). Synthesis of Intermediate 13 in Example 13

[0467]

[0468] Step 1: Preparation of intermediate 13a 5d (32.0 g), 10% palladium on carbon (6.1 g), and methanol (250 mL) were added sequentially to the reaction flask. The mixture was purged with hydrogen three times and reacted overnight. After the reaction was completed, diatomaceous earth was added and the mixture was filtered. The filtrate was evaporated to dryness, and 200 mL of ethyl acetate and 300 mL of water were added. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 13a (22.7 g).

[0469] MS(ESI, [M+H)) + ) m / z : 274.0. Step 2: Preparation of intermediate 13b 0 o Under nitrogen protection at temperature C, a boron tribromide dichloromethane solution (125 mL, 1 M) was slowly added dropwise to a dichloromethane solution (200 mL) containing 22.7 g of 13a. After the addition was complete, the temperature was raised to room temperature. Once the reaction was complete, the reaction mixture was slowly poured into 350 mL of ice water and stirred for 10 min. The dichloromethane was evaporated to dryness, filtered, and the filter cake was collected and dried to obtain 21.1 g of 13b.

[0470] MS(ESI, [MH] - ) m / z :258.1. 1 H NMR (500 MHz, DMSO- d 6) δ 9.39 (s, 1H), 6.93 (td, J = 7.7, 3.0 Hz, 1H), 6.71 (ddd, J = 8.1, 4.7, 1.1 Hz, 1H), 6.61 (t, J = 7.2 Hz, 1H), 3.72 – 3.57 (m, 4H), 3.07 – 2.86 (m, 4H). Step 3: Preparation of intermediate 13c Add 20.5 g of 13b, 18.5 g of tert-butyl bromoacetate, 27.3 g of potassium carbonate, and 100 mL of DMF to the reaction flask in sequence, and heat the reaction solution to 80°C. oReaction C. The reaction solution was cooled to room temperature, and 200 mL of ethyl acetate and 300 mL of water were added. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 13C (34.5 g).

[0471] MS(ESI, [MH] - ) m / z 372.1. Step 4: Preparation of intermediate 13d 13c (29.5 g), trifluoroacetic acid (90.2 g), and dichloromethane (200 mL) were added sequentially to the reaction flask, and the reaction was carried out at room temperature. After the reaction was completed, the dichloromethane was evaporated to dryness, 300 mL of water was added, the mixture was stirred for 10 min, filtered, the filter cake was collected, and dried to obtain 13d (23.5 g).

[0472] MS(ESI, [MH] - ) m / z 316.0. Step 5: Preparation of intermediate 13f 13d (21.2 g), thionyl chloride (79.5 g), and tetrahydrofuran (200 mL) were added sequentially to the reaction flask, and the reaction solution was heated to 80°C. o C. The solvent in the reaction solution was evaporated to obtain 13e, which was then added to dichloromethane (200 mL). The reaction solution was cooled to 0 °C, and trifluoromethanesulfonic acid (49.7 g) was slowly added dropwise. After the addition was complete, the mixture was allowed to return to room temperature. The reaction solution was then slowly poured into 400 mL of ice water, and dichloromethane was added. The organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the concentrate was purified by silica gel column chromatography to obtain intermediate 13f (8.8 g).

[0473] MS(ESI, [M+H)) + ) m / z :300.1.

[0474] 1 H NMR (500 MHz, DMSO- d 6) δ 7.44 (dd, J = 7.8, 1.9 Hz, 1H), 7.01 (t, J =8.4 Hz, 1H), 4.82 (d, J = 2.0 Hz, 2H), 3.73 (dq, J = 9.9, 5.8 Hz, 4H), 3.16 –3.06 (m, 4H). Step 6: Preparation of 13g of intermediate 13f (8.8 g), ethoxyformylmethylenetriphenylphosphine (14.2 g), and toluene (50 mL) were added sequentially to the reaction flask, and the reaction solution was heated to 130°C. o The reaction was carried out overnight at C. The reaction solution was cooled to room temperature, and 50 mL of ethyl acetate and 60 mL of water were added. The organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the concentrate was purified by silica gel column chromatography to obtain 13 g (6.8 g) of intermediate.

[0475] MS(ESI, [M+H)) + ) m / z 370.1 1 H NMR (500 MHz, DMSO- d 6) δ 7.92 – 7.84 (m, 1H), 7.36 (dd, J = 7.8, 3.1Hz, 1H), 7.10 (t, J = 7.9 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 3.81 – 3.70 (m, 6H), 3.30 – 3.20 (m, 2H), 3.16 – 3.06 (m, 2H), 1.19 (t, J = 7.1 Hz, 3H). Step 7: Preparation of intermediates over 13 hours Add 13g (6.8g), potassium carbonate (7.6g), and ethanol (100mL) to the reaction flask in sequence, and heat the reaction solution to 50°C. o The reaction was carried out overnight at C. The reaction solution was cooled to room temperature, and 70 mL of ethyl acetate and 150 mL of water were added. The organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the concentrate was purified by silica gel column chromatography to obtain intermediate 13h (3.8 g).

[0476] MS(ESI, [M+H)) + ) m / z : 274.2 Step 8: Preparation of intermediate 13i 13h (3.8 g), triethylamine (2.8 g), and dichloromethane (50 mL) were added sequentially to the reaction flask. Boc anhydride (3.64 g) was added with stirring, and the reaction was carried out at room temperature. 70 mL of dichloromethane and 100 mL of water were added, the organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the concentrate was purified by silica gel column chromatography to obtain intermediate 13i (3.9 g).

[0477] Step 9: Preparation of intermediate 13j 0 o Under nitrogen protection at C, a potassium tert-butoxide tetrahydrofuran solution (7.7 mL, 1 M) was slowly added dropwise to a DMF solution of 13i (3.7 g) and acrylamide (0.7 g) (30 mL). After the addition was complete, the reaction was maintained at this temperature. Once the reaction was complete, the reaction mixture was slowly poured into 100 mL of saturated ammonium chloride and stirred for 10 min. The mixture was filtered, and the filter cake was collected. The filter cake was pulped with ethyl acetate, filtered, and dried to obtain 13j (2.1 g).

[0478] MS(ESI, [MH] - ) m / z 397.0. 1 H NMR (500 MHz, DMSO- d 6) δ 10.88 (s, 1H), 7.85 (s, 1H), 7.30 (d, J =7.9 Hz, 1H), 7.05 (d, J = 7.9 Hz, 1H), 4.09 (dd, J = 11.9, 4.9 Hz, 1H), 3.52 (dt, J = 28.7, 4.3 Hz, 4H), 3.11 (d, J = 6.2 Hz, 2H), 3.02 – 2.92 (m, 2H), 2.73 (ddd, J = 17.2, 12.1, 5.3 Hz, 1H), 2.56 (dt, J = 17.3, 4.1 Hz, 1H), 2.30 (qd, J = 12.3,4.4 Hz, 1H), 2.14 – 2.04 (m, 1H), 1.40 (s, 9H). Step 10: Preparation of Intermediate 13 13j (2.1 g), 1,4-dioxane hydrochloride (10 mL), and dichloromethane (10 mL) were added sequentially to the reaction flask, and the reaction was carried out at room temperature. After the reaction was completed, the mixture was filtered, the filter cake was washed with a small amount of methyl ether, and dried to obtain intermediate 13 (1.6 g).

[0479] MS(ESI, [M+H)) + ) m / z 299.1 1 H NMR (500 MHz, DMSO- d6) δ 10.89 (s, 1H), 9.57 (s, 2H), 7.91 (s, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 4.12 (dd, J = 12.1, 4.9 Hz,1H), 3.38 (s, 2H), 3.26 (td, J = 8.1, 7.3, 3.8 Hz, 4H), 3.20 (dt, J = 8.6, 3.9Hz, 2H), 2.75 (ddd, J = 17.4, 12.3, 5.4 Hz, 1H), 2.57 (dt, J = 17.2, 4.1 Hz, 1H), 2.32 (qd, J = 12.6, 4.4 Hz, 1H), 2.09 (dq, J = 13.5, 4.7 Hz, 1H). Synthesis of Intermediate 14 in Example 14

[0480]

[0481] Step 1: Preparation of intermediate 14a Intermediate 8e (14.95 g) and THF (200 mL) were added sequentially to the reaction flask. Under N2 protection, the mixture was cooled to 0°C, and then a solution of lithium aluminum hydride tetrahydrofuran (5.67 g, 59.8 mL) was added dropwise. After the addition was complete, the mixture was reacted at 0°C for 2 h. Once the reaction was complete, the reaction solution was quenched by slow dropwise addition of water at 0°C. Anhydrous sodium sulfate was added, and the mixture was filtered. The solvent was removed from the filtrate under reduced pressure to obtain the target intermediate 14a (11.15 g).

[0482] 1H NMR (500 MHz, DMSO-d6) δ 7.08 (t, J = 7.7 Hz, 1H), 6.81 – 6.76 (m,1H), 6.71 (d, J = 8.2 Hz, 1H), 4.62 (t, J = 5.3 Hz, 1H), 3.74 (s, 3H), 3.35(dd, J = 6.8, 5.3 Hz, 2H), 2.92 (dd, J = 16.0, 8.2 Hz, 1H), 2.88 – 2.79 (m,1H), 2.65 (dd, J = 16.1, 5.7 Hz, 1H), 2.60 – 2.51 (m, 2H). Step 2: Preparation of intermediate 14b Intermediate 14a, dichloromethane (100 mL), triethylamine (18.99 g), and 4-dimethylaminopyridine (0.191 g) were added sequentially to a reaction flask. Acetic anhydride (7.03 g, 6.55 mL) was added under ice bath conditions, and the mixture was allowed to return to room temperature for 1 h. After the reaction was complete, the solvent was removed from the reaction solution by vacuum distillation. The residue was extracted with 300 mL of ethyl acetate and 500 mL of water, and the organic phases were separated. The residue was washed with saturated ammonium chloride solution and saturated brine solution, respectively, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by vacuum distillation to obtain the target intermediate 14b (12.97 g).

[0483] 1 H NMR (500 MHz, DMSO-d6) δ 7.13 – 7.09 (m, 1H), 6.80 (d, J = 7.2 Hz,1H), 6.74 (d, J = 8.0 Hz, 1H), 4.00 (d, J = 7.1 Hz, 2H), 3.75 (s, 3H), 2.99(dd, J = 15.6, 7.9 Hz, 1H), 2.92 (dd, J = 16.1, 8.1 Hz, 1H), 2.77 – 2.69 (m,1H), 2.66 (dd, J = 15.6, 6.4 Hz, 1H), 2.55 (dd, J = 16.2, 6.2 Hz, 1H), 2.02(s, 3H). Step 3: Preparation of intermediate 14c Intermediate 14b (10.15 g), N-bromosuccinimide (9.02 g), and acetonitrile (100 mL) were added sequentially to a reaction flask. The mixture was heated to 75 °C and reacted for 1 h. After the reaction was complete, 200 mL of ethyl acetate and 500 mL of water were added for extraction. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain the target intermediate 14c (14.11 g).

[0484] 1 H NMR (500 MHz, DMSO-d6) δ 7.31 (d, J = 8.7 Hz, 1H), 6.76 (d, J =8.6 Hz, 1H), 4.06 – 4.00 (m, 2H), 3.76 (s, 3H), 3.02 (ddd, J = 16.3, 14.7,8.3 Hz, 2H), 2.81 – 2.73 (m, 1H), 2.70 – 2.62 (m, 2H), 2.03 (s, 3H). Step 4: Preparation of intermediate 14d Under ice bath conditions, trifluoromethanesulfonic acid (40 mL) was slowly added dropwise to intermediate 14c (14.11 g) and chloroacetyl chloride (5.13 g, 3.61 mL) in a stirred solution. After the addition was complete, the mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction solution was poured into 500 mL of ice-water solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain the target intermediate 14d (15.23 g).

[0485] 1 H NMR (500 MHz, DMSO-d6) δ 7.67 (s, 1H), 4.99 (s, 2H), 4.07 (dd, J =6.9, 4.6 Hz, 2H), 3.86 (s, 3H), 3.28 (dd, J = 16.2, 8.2 Hz, 1H), 3.05 (dd, J = 16.9, 8.2 Hz, 1H), 2.94 (dd, J = 16.2, 6.7 Hz, 1H), 2.87 – 2.81 (m, 1H), 2.72 (dd, J = 16.9, 6.7 Hz, 1H), 2.03 (s, 3H). Step 5: Preparation of intermediate 14e Under N2 protection at -35°C, a boron trichloride dichloromethane solution (1 mol / L, 73.0 mL) was slowly added dropwise to a dichloromethane (450 mL) mixture containing intermediate 14d (15.23 g) with stirring. After the addition was complete, the mixture was stirred and reacted at -30°C. Upon completion of the reaction, the reaction solution was quenched at -30°C with 100 mL of hydrochloric acid aqueous solution (1M). After returning to room temperature, the organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain the target intermediate 14e (15.24 g).

[0486] MS(ESI, [M+H)) + m / z: 361.1.

[0487] 1 H NMR (500 MHz, DMSO-d6) δ 11.26 (s, 1H), 7.87 (s, 1H), 5.19 (s,2H), 4.05 (dd, J = 7.0, 2.5 Hz, 2H), 3.13 – 3.06 (m, 2H), 2.84 (ddd, J = 8.4,5.1, 1.8 Hz, 1H), 2.76 – 2.71 (m, 2H), 2.03 (s, 3H). Step 6: Preparation of intermediate 14f Intermediate 14e (15.24 g), acetonitrile (150 mL), and sodium carbonate (4.41 g) were added sequentially to a reaction flask, and the mixture was heated to 75 °C. After the reaction was complete, 200 mL of ethyl acetate and 500 mL of water were added for extraction, the organic phase was separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain the target intermediate 14f (13.97 g).

[0488] 1 H NMR (500 MHz, DMSO-d6) δ 7.64 (s, 1H), 4.86 (s, 2H), 4.08 (t, J =6.4 Hz, 2H), 3.20 – 3.11 (m, 2H), 2.94 – 2.90 (m, 1H), 2.85 – 2.77 (m, 2H),2.03 (s, 3H). Step 7: Preparation of 14g of intermediate Intermediate 14f (6.85 g), ethoxyformylmethylenetriphenylphosphine (11.01 g), and toluene (80 mL) were added sequentially to a reaction flask. Under N2 protection, the mixture was heated to 130 °C for reaction. After the reaction was complete, 200 mL of ethyl acetate and 300 mL of water were added 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 filtrate was purified by silica gel column chromatography to obtain 14 g (4.09 g) of the target intermediate.

[0489] 1 H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.65 (s, 1H), 4.13 – 4.08(m, 4H), 3.77 (s, 2H), 3.16 – 3.11 (m, 1H), 3.01 – 2.91 (m, 2H), 2.76 (ddd, J= 23.5, 16.3, 6.3 Hz, 2H), 2.04 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H). Step 8: Preparation of intermediates over 14 hours 14 g (1.2 g) of intermediate, 10% palladium on carbon (1.2 g), ethanol (40 mL), and dichloromethane (20 mL) were added sequentially to a reaction flask. After H2 replacement, the mixture was reacted at room temperature. After the reaction was complete, the mixture was filtered with diatomaceous earth. The pH of the filtrate was adjusted to 8 with saturated sodium bicarbonate solution, and 200 mL of ethyl acetate and 200 mL of water were added for extraction. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with 300 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum evaporation to obtain the target intermediate 14h (1.01 g).

[0490] Step 9: Preparation of intermediates 14i-1 and 14i-2 Intermediate 14h (0.98 g), potassium carbonate (1.713 g), and ethanol (15 mL) were added sequentially to a reaction flask, and the mixture was reacted at room temperature for 18 h. After the reaction was complete, 100 mL of ethyl acetate and 100 mL of water were added for extraction, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum evaporation to obtain the target intermediate 14i (0.9 g). Intermediate 14i was further separated by high performance liquid chromatography to prepare intermediates 14i-1 (0.36 g) and 14i-2 (0.42 g). The preparation conditions are as follows: Instrumentation and Preparative Column: A YMC K-prep Lab100g high-performance preparative chromatograph was used, with a CHIRALARTAmylose-SA (5μm, 30*250mm) preparative column. Mobile phase: hexane / ethanol, with isogradient elution: hexane / ethanol = 90 / 10.

[0491] The data for 14i-1 is as follows: MS(ESI, [M+H]+) m / z: 275.2.

[0492] 1 H NMR (500 MHz, DMSO-d6) δ 7.81 (s, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.11 (d, J = 7.9 Hz, 1H), 4.69 (t, J = 5.3 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 3.76 – 3.72 (m, 2H), 3.41 (ddd, J = 6.8, 5.2, 1.4 Hz, 2H), 3.12 (dd, J =16.1, 8.3 Hz, 1H), 3.05 (dd, J = 15.9, 8.2 Hz, 1H), 2.86 (dd, J = 16.2, 5.7Hz, 1H), 2.78 (dd, J = 15.9, 5.7 Hz, 1H), 2.68 (ddd, J = 13.6, 8.0, 5.8 Hz, 1H), 1.19 (t, J = 7.1 Hz, 3H). Step 10: Preparation of intermediate 14 Intermediate 14i-1 (350 mg), N,N-dimethylformamide (10 mL), and acrylamide (100 mg) were added sequentially to a reaction flask. Under N2 protection, the mixture was cooled to 0°C, and then potassium tert-butoxide tetrahydrofuran solution (1 mol / L, 1.025 mL) was added. The mixture was reacted at 0°C for 1 h. After the reaction was complete, the reaction solution was added dropwise to ice-cold saturated ammonium chloride aqueous solution. Ethyl acetate was added for extraction, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined. The mixture was then washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was purified by silica gel column chromatography to obtain intermediate 14 (0.204 g).

[0493] MS(ESI, [M+H)) + m / z: 300.1.

[0494] 1H NMR (500 MHz, DMSO-d6) δ 10.87 (s, 1H), 7.80 (s, 1H), 7.33 (d, J =7.8 Hz, 1H), 7.09 (d, J = 7.9 Hz, 1H), 4.69 (t, J = 5.2 Hz, 1H), 4.10 (dd, J = 11.9, 4.9 Hz, 1H), 3.41 (t, J = 6.1 Hz, 2H), 3.18 – 3.03 (m, 2H), 2.86 (dd,J = 16.2, 5.6 Hz, 1H), 2.81 – 2.76 (m, 1H), 2.74 – 2.63 (m, 2H), 2.56 (dt, J= 17.3, 4.2 Hz, 1H), 2.30 (qd, J = 12.2, 4.4 Hz, 1H), 2.13 – 2.06 (m, 1H). Synthesis of Intermediate 15 in Example 15

[0495]

[0496] Intermediate 14i-2 (420 mg), N,N-dimethylformamide (10 mL), and acrylamide (120 mg) were added sequentially to a reaction flask. Under N2 protection, the mixture was cooled to 0°C, and then potassium tert-butoxide (1 mol / L, 1.221 mL) was added. The mixture was reacted at 0°C. After the reaction was complete, the reaction solution was added dropwise to an ice-cold saturated ammonium chloride aqueous solution. Ethyl acetate was added for extraction, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined. The mixture was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to obtain intermediate 15 (0.237 g).

[0497] MS(ESI, [M+H)) + m / z: 300.1.

[0498] 1H NMR (500 MHz, DMSO-d6) δ 10.87 (s, 1H), 7.80 (s, 1H), 7.33 (d, J =7.8 Hz, 1H), 7.09 (d, J = 7.9 Hz, 1H), 4.69 (t, J = 5.2 Hz, 1H), 4.10 (dd, J = 11.8, 4.9 Hz, 1H), 3.41 (t, J = 6.1 Hz, 2H), 3.18 – 3.04 (m, 2H), 2.86 (dd,J = 16.2, 5.6 Hz, 1H), 2.78 (dd, J = 15.9, 5.7 Hz, 1H), 2.72 (dd, J = 11.3,6.0 Hz, 1H), 2.70 – 2.63 (m, 1H), 2.56 (dt, J = 17.3, 4.2 Hz, 1H), 2.30 (qd,J = 12.2, 4.4 Hz, 1H), 2.14 – 2.06 (m, 1H). Synthesis of Intermediate 16 in Example 16

[0499]

[0500] Step 1: Preparation of intermediate 16b 16a (60 g), potassium carbonate (1.315 g), N,N-dimethylformamide (500 mL), and iodomethane (172 g) were added sequentially to a reaction flask. Under N2 protection, the mixture was heated to 80 °C for reaction. After the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with ethyl acetate, washed with saturated sodium chloride solution, the organic layer was collected, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the target intermediate 16b (64.5 g).

[0501] MS(ESI, [M+H)) + m / z: 163.10. Step 2: Preparation of intermediate 16c Potassium hydroxide (152 g) and methanol (600 mL) were added sequentially to the reaction flask, and the mixture was stirred for 20 min in an ice bath. Intermediate 16b (40 g) was then added, and stirring continued for another 20 min. Iodophenyl diacetic acid (98 g) was added, and the mixture was reacted at room temperature for 1 h under N2 protection until the reaction was complete. The solvent was removed from the reaction solution by vacuum distillation. Ethyl acetate and saturated sodium bicarbonate solution were added to the residue to separate the organic phase. The residue was dried over anhydrous sodium sulfate, filtered, and the solvent was removed again by vacuum distillation. The concentrate was dissolved in tetrahydrofuran (600 mL), and then hydrochloric acid (82 mL, 6 M) was added. The mixture was reacted at room temperature for 0.5 h until the reaction was complete. The pH of the reaction solution was then adjusted to 8-9 with saturated sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target intermediate 16c (35.1 g).

[0502] 1 H NMR (500 MHz, Chloroform- d ) δ 7.42 – 7.31 (m, 2H), 7.08 (dd, J =7.2, 1.7 Hz, 1H), 4.51 (dd, J = 7.8, 4.7 Hz, 1H), 3.91 (s, 3H), 3.57 (dd, J =17.0, 7.8 Hz, 1H), 3.02 (s, 1H), 2.84 (dd, J = 17.0, 4.7 Hz, 1H). Step 3: Preparation of intermediate 16d Intermediate 16c (37 g) and methanol (500 mL) were added sequentially to a reaction flask, followed by sodium borohydride (8.25 g). The mixture was reacted at room temperature for 1.5 h until the reaction was complete. The reaction solution was quenched dropwise with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain intermediate 16d (50 g).

[0503] Step 4: Preparation of intermediate 16e Intermediate 16d (35 g), toluene (300 mL), and p-toluenesulfonic acid (66.9 g) were added sequentially to a reaction flask. Under N2 protection, the mixture was reacted at 120 °C until the reaction was complete. The reaction solution was cooled to room temperature, and the solvent was removed by vacuum distillation. Ethyl acetate and water were added to the residue, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined. Anhydrous sodium sulfate was added and the mixture was dried. The solution was filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target intermediate 16e (35.5 g).

[0504] 1 H NMR (500 MHz, DMSO- d 6) δ 7.26 – 7.22 (m, 1H), 6.93 – 6.87 (m, 2H), 3.79 (s, 3H), 3.53 (s, 2H), 3.37 (s, 2H). Step 5: Preparation of intermediate 16f At 0°C, intermediate 16e (35 g) and methanol (400 mL) were added sequentially to a reaction flask, followed by the addition of sodium borohydride (5.83 g) in portions. The reaction was carried out at room temperature. After the reaction was complete, saturated ammonium chloride solution was added dropwise to quench the reaction mixture. Water and ethyl acetate were then added, and the organic phase was separated. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target intermediate 16f (18 g).

[0505] 1 H NMR (500 MHz, DMSO- d 6) δ 7.10 (td, J = 7.9, 7.4, 0.9 Hz, 1H), 6.83 –6.78 (m, 1H), 6.74 (d, J = 8.1 Hz, 1H), 4.81 (d, J = 3.8 Hz, 1H), 4.49 (tq, J =6.5, 3.4 Hz, 1H), 3.75 (s, 3H), 3.04 (dd, J = 16.1, 6.1 Hz, 1H), 2.94 (dd, J =16.3, 6.2 Hz, 1H), 2.76 – 2.69 (m, 1H), 2.65 (dd, J = 16.4, 3.4 Hz, 1H). Step 6: Preparation of 16g ​​of intermediate 16f (15 g), dichloromethane (150 mL), triethylamine (27.8 g), and 4-dimethylaminopyridine (0.28 g) were added sequentially to a reaction flask. Acetic anhydride (10.2 g) was added under ice bath conditions, and the reaction was carried out at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation. Ethyl acetate and water were added to the residue, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined. The residue was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain 16 g (9.3 g) of the target intermediate.

[0506] MS(ESI, [M+H)) +m / z: 207.10 1 H NMR (500 MHz, DMSO- d 6) δ 7.22 – 7.06 (m, 1H), 6.82 (dd, J = 27.3,8.3 Hz, 2H), 5.41 (s, 1H), 3.78 (d, J = 13.2 Hz, 3H), 3.32 – 3.20 (m, 1H), 3.18– 3.09 (m, 1H), 2.85 (dd, J = 34.6, 17.1 Hz, 2H), 1.97 (d, J = 15.3 Hz, 3H). Step 7: Preparation of intermediates over 16 hours 16 g (5.6 g), N-bromosuccinimide (5.32 g), and acetonitrile (50 mL) were added sequentially to the reaction flask, and the reaction was carried out at 70 °C. After the reaction was completed, the reaction solution was cooled to room temperature, water and ethyl acetate were added, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target intermediate 16h (6.4 g).

[0507] 1 H NMR (500 MHz, DMSO- d 6) δ 7.36 (d, J = 8.6 Hz, 1H), 6.81 (d, J = 8.7Hz, 1H), 5.41 (tt, J = 6.4, 2.0 Hz, 1H), 3.77 (s, 3H), 3.31 – 3.23 (m, 2H), 2.92 (dd, J = 17.5, 2.0 Hz, 1H), 2.85 (dd, J = 17.4, 2.0 Hz, 1H), 1.97 (s, 3H). Step 8: Preparation of intermediate 16i 16h (6.3 g) and chloroacetyl chloride (7.49 g) were added sequentially to the reaction flask. Trifluoromethanesulfonic acid (60 mL) was slowly added dropwise under an ice-water bath, and the reaction was carried out at room temperature. After the reaction was completed, the reaction solution was slowly added dropwise to ice water, extracted with dichloromethane, and the organic phases were combined. The mixture was washed with saturated sodium bicarbonate aqueous solution, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target intermediate 16i (7.3 g).

[0508] 1 H NMR (500 MHz, DMSO- d 6) δ 7.71 (s, 1H), 5.46 (tq, J = 7.5, 3.4, 2.7Hz, 1H), 5.00 (s, 2H), 3.87 (d, J = 1.9 Hz, 3H), 3.57 (dd, J = 17.3, 6.2 Hz, 1H),3.39 – 3.33 (m, 1H), 3.18 (dd, J = 17.4, 2.0 Hz, 1H), 2.92 (dd, J = 18.0, 1.9 Hz,1H), 1.99 (s, 3H). Step 9: Preparation of intermediate 16j 16i (7.0 g) and dichloromethane (70 mL) were added sequentially to the reaction flask. Boron trichloride (58 mL) was slowly added dropwise under an ice-water bath, and the reaction was carried out at room temperature. After the reaction was completed, the reaction solution was slowly added dropwise to ice water, extracted with dichloromethane, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target intermediate 16j (5.0 g).

[0509] MS(ESI, [MH] - m / z: 347.00 1 H NMR (500 MHz, DMSO- d 6) δ 11.24 (s, 1H), 7.90 (s, 1H), 5.44 (tq, J =8.1, 3.5, 2.8 Hz, 1H), 5.19 (s, 2H), 3.38 (d, J = 6.3 Hz, 1H), 3.31 (t, J = 6.8Hz, 1H), 3.03 (dd, J = 17.6, 1.8 Hz, 1H), 2.92 (dd, J = 18.2, 1.9 Hz, 1H), 1.98(s, 3H). Step 10: Preparation of intermediate 16k 16kJ (4.9 g), sodium carbonate (2.99 g), and acetonitrile (120 mL) were added sequentially to the reaction flask, and the reaction was carried out at 50 °C. After the reaction was completed, water and ethyl acetate were added, the organic layer was collected, anhydrous sodium sulfate was added and dried, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target intermediate 16k (3.7 g).

[0510] 1 H NMR (500 MHz, DMSO- d 6) δ 7.69 (s, 1H), 5.51 (tt, J = 6.4, 1.9 Hz,1H), 4.88 (s, 2H), 3.49 – 3.36 (m, 2H), 3.08 (dd, J = 17.5, 1.8 Hz, 1H), 2.97(dd, J = 18.3, 1.8 Hz, 1H), 1.99 (s, 3H). Step 11: Preparation of intermediate 16l 16kJ (3.0 g), 10% palladium / carbon (0.257 g), sodium bicarbonate (0.81 g), and ethanol (90 mL) were added sequentially to a reaction flask. The reaction was carried out at room temperature in the presence of hydrogen. After the reaction was complete, the reaction solution was filtered, and the filtrate was evaporated under reduced pressure. Ethyl acetate and water were added to the residue, and the organic layer was separated. Anhydrous sodium sulfate was added and dried. The residue was filtered, and the filtrate was concentrated to give the target intermediate 16L (2.4 g).

[0511] 1 H NMR (500 MHz, DMSO- d 6) δ7.90 (d, J = 8.5 Hz, 1H), 6.95 (d, J = 8.6 Hz,1H), 5.42 (s, 1H), 3.87 (s, 2H), 3.44 (d, J = 6.3 Hz, 1H), 3.27 (dd, J = 18.6, 1.9 Hz, 1H), 3.09 (d, J = 6.5 Hz, 1H), 2.80 (dd, J = 17.6, 1.8 Hz, 1H), 1.94 (s, 3H). Step 12: Preparation of intermediate 16m 16 L (2.4 g), ethoxyformylmethylenetriphenylphosphine (5.4 g), and toluene (30 mL) were added sequentially to the reaction flask. The reaction was carried out at 120 °C under N2 protection. After the reaction was completed, ethyl acetate and water were added to the reaction system, the organic layer was separated, anhydrous sodium sulfate was added and dried, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target intermediate 16 M (0.58 g).

[0512] 1 H NMR (500 MHz, DMSO- d 6) δ 7.85 (s, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.18 (d, J = 7.9 Hz, 1H), 5.54 (tt, J = 6.3, 2.3 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 3.77 (s, 2H), 3.46 (dd, J = 17.0, 6.2 Hz, 1H), 3.40 (dd, J = 17.0, 6.4 Hz, 1H), 3.11 (dd, J = 17.1, 2.2 Hz, 1H), 3.02 (dd, J = 17.0, 2.4 Hz, 1H), 1.97(s, 3H),1.19 (t, J = 7.1 Hz, 3H). Step 13: Preparation of intermediate 16n 16m (2.4 g), potassium carbonate (0.79 g), and ethanol (30 mL) were added sequentially to the reaction flask, and the reaction was carried out at room temperature. After the reaction was completed, ethyl acetate and water were added to the reaction system, the organic layer was separated, anhydrous sodium sulfate was added and dried, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target intermediate 16n (0.42 g).

[0513] MS(ESI, [M+H)) + m / z: 261.10 1 H NMR (500 MHz, DMSO- d 6) δ 7.89 (s, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.13(d, J = 7.8 Hz, 1H), 4.96 (d, J= 4.1 Hz, 1H), 4.62 (td, J = 6.2, 2.8 Hz, 1H), 4.10(q, J = 7.1 Hz, 2H), 3.75 (d, J = 1.0 Hz, 2H), 3.24 (dd, J = 16.2, 6.1 Hz, 1H), 3.18 (dd, J = 16.0, 6.0 Hz, 1H), 2.92 (dd, J = 16.2, 3.3 Hz, 1H), 2.85 (dd, J =16.0, 3.3 Hz, 1H), 1.18 (t, J = 7.1 Hz, 3H). Step 14: Preparation of Intermediate 16 16n (90 mg), acrylamide (27 mg), and N,N-dimethylformamide (4 mL) were added sequentially to the reaction flask. The mixture was cooled to 0°C, and potassium tert-butoxide (0.28 mL, 1 M) was slowly added dropwise. The reaction was continued at 0°C. After the reaction was complete, the reaction mixture was added dropwise to an ice-cold aqueous solution of ammonium chloride. Ethyl acetate was added for extraction, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target intermediate 16 (20 mg).

[0514] 1 H NMR (500 MHz, DMSO- d 6) δ 10.88 (s, 1H), 7.80 (s, 1H), 7.35 (d, J =7.8 Hz, 1H), 7.11 (d, J = 7.9 Hz, 1H), 4.62 (tt, J = 6.8, 3.4 Hz, 1H), 4.11 (dd, J = 11.8, 4.9 Hz, 1H), 3.24 (dd, J = 16.2, 6.1 Hz, 1H), 3.17 (dd, J = 16.0, 6.0 Hz, 1H), 2.92 (dd, J = 16.2, 3.3 Hz, 1H), 2.85 (dd, J = 16.1, 3.3 Hz, 1H), 2.73 (ddd, J= 17.3, 12.0, 5.3 Hz, 1H), 2.56 (dt, J = 17.4, 4.2 Hz, 1H), 2.37 – 2.24 (m,1H), 2.10 (dq, J = 13.7, 4.7 Hz, 1H). Example 17 Synthesis of Compound 17

[0515]

[0516] Step 1: Preparation of intermediate 17b 0 o Under nitrogen protection at C, sodium hydride (60 wt%, 7.7 g) was added in portions to a DMF (100 mL) solution of 17a (20.0 g) and trans-4-BOC-aminocyclohexanol (27.7 g). The reaction was allowed to proceed at room temperature until the addition was complete. After the reaction was complete, the reaction solution was slowly poured into 400 mL of ice water and stirred for 10 min. The mixture was filtered, and the filter cake was collected and dried to obtain 17b (39.1 g).

[0517] MS(ESI, [M+H)) + ) m / z 351.1 1 H NMR (500 MHz, DMSO- d 6) δ 7.84 (d, J = 8.7 Hz, 1H), 7.37 (d, J = 2.4Hz, 1H), 7.11 (dd, J = 8.8, 2.4 Hz, 1H), 6.90 – 6.80 (m, 1H), 4.49 (ddt, J =14.2, 9.8, 4.1 Hz, 1H), 3.29 (t, J = 8.4 Hz, 1H), 2.09 – 1.99 (m, 2H), 1.87 –1.74 (m, 2H), 1.38 (s, 13H). Step 2: Preparation of intermediate 17c 17b (20.5 g) and 1,4-dioxane hydrochloride (100 mL) were added sequentially to the reaction flask and reacted at room temperature. The solvent in the reaction solution was evaporated, n-hexane was added and stirred at room temperature, filtered, and the filter cake was collected and dried to obtain 17c (18.3 g).

[0518] MS(ESI, [M+H))+ ) m / z :251.1 Step 3: Preparation of intermediate 17e 17d (10.0 g), 4-piperidinemethanol (8.1 g), DIPEA (11.2 g), and DMSO (90 mL) were added sequentially to the reaction flask. The reaction solution was then heated to 90°C. o C. After the reaction was complete, the reaction solution was poured into 300 mL of water and extracted with DCM. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 17e (12.0 g).

[0519] MS(ESI, [M+H)) + ) m / z : 252.0 1 H NMR (500 MHz, DMSO- d 6) δ 7.80 (d, J = 9.7 Hz, 1H), 7.27 (d, J = 9.7Hz, 1H), 4.58 – 4.46 (m, 3H), 3.86 (s, 3H), 3.28 (t, J = 5.6 Hz, 2H), 3.00 (td, J = 12.8, 2.6 Hz, 2H), 1.84 – 1.67 (m, 3H), 1.21 – 1.07 (m, 2H). Step 3: Preparation of intermediate 17f 17e (10.1 g), sodium hydroxide (2.4 g), methanol (100 mL), and water (10 mL) were added sequentially to the reaction flask, and the reaction was carried out at room temperature for 1 h. After the reaction was completed, the pH of the reaction solution was adjusted to 3-4 with concentrated hydrochloric acid, and the solvent was evaporated to dryness. The solution was slurried with DCM:MEOH, filtered, and the filtrate was concentrated to obtain intermediate 17f (1.2 g).

[0520] MS(ESI, [MH] - ) m / z :236.2. 1 H NMR (500 MHz, DMSO- d 6) δ 7.91 (ddd, J = 9.8, 5.4, 2.9 Hz, 1H), 7.57(d, J = 9.3 Hz, 1H), 4.51 (d, J= 13.4 Hz, 2H), 3.40 – 3.24 (m, 2H), 3.20 – 3.16(m, 2H), 3.11 (t, J = 12.8 Hz, 2H), 1.78 (t, J = 14.5 Hz, 3H), 1.29 – 1.14 (m,2H). Step 4: Preparation of 17g of intermediate 17f (1.1 g), 17c (1.1 g), HATU (2.2 g), DIPEA (1.5 g), and DMF (20 mL) were added sequentially to the reaction flask, and the reaction was carried out at room temperature. After the reaction was completed, 70 mL of ethyl acetate and 150 mL of water were added, the organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the concentrate was purified by silica gel column chromatography to obtain intermediate 17 g (1.2 g).

[0521] MS(ESI, [M+H)) + ) m / z :470.4.

[0522] 1 H NMR (500 MHz, DMSO- d 6) δ 8.63 – 8.50 (m, 1H), 7.88 – 7.71 (m, 2H), 7.43 – 7.24 (m, 2H), 7.12 (tq, J = 7.7, 4.7, 3.7 Hz, 1H), 4.50 (dtt, J = 20.4,10.3, 4.6 Hz, 4H), 3.90 – 3.76 (m, 1H), 2.97 (q, J = 13.1 Hz, 2H), 2.87 (dd, J =14.4, 6.2 Hz, 1H), 2.71 (dd, J = 14.3, 6.2 Hz, 1H), 2.07 (d, J = 13.1 Hz, 2H), 1.87 (d, J = 12.8 Hz, 2H), 1.79 – 1.67 (m, 3H), 1.61 (q, J = 12.5 Hz, 2H), 1.57 –1.44 (m, 2H), 1.20 – 1.04 (m, 2H). Step 5: Preparation of intermediates over 17 hours 17 g (0.5 g), Desmartin oxidant (1.3 g), and dichloromethane (30 mL) were added sequentially to the reaction flask, and the reaction was carried out at room temperature. After the reaction was completed, 70 mL of dichloromethane and 100 mL of water were added, the organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 17h (0.6 g).

[0523] Step 6: Preparation of Compound 17 90 mg of 17 h, 60 mg of intermediate 1, 16 mg of sodium acetate, and 20 mL of DCE / isopropanol (5:1) were added sequentially to the reaction flask. The mixture was reacted at room temperature for 30 min, followed by the addition of 24 mg of sodium cyanoborohydride, and the reaction was continued at room temperature. After the reaction was complete, the solvent in the reaction solution was evaporated to dryness, and the crude product was purified by silica gel column chromatography to obtain compound 17 (30 mg).

[0524] MS(ESI, [M+H)) + ) m / z 723.4 1 H NMR (500 MHz, DMSO- d 6) δ 11.09 (s, 1H), 8.58 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 9.5 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.41– 7.28 (m, 3H), 7.14 (dd, J = 8.7, 2.4 Hz, 1H), 4.60 (dd, J = 11.9, 5.0 Hz, 1H),4.57 – 4.46 (m, 3H), 4.16 (d, J = 2.4 Hz, 2H), 4.05 (t, J = 2.3 Hz, 2H), 3.86(tdt, J = 11.4, 8.1, 4.0 Hz, 1H), 3.11 – 3.01 (m, 2H), 2.77 (ddd, J = 17.2, 11.9,5.3 Hz, 1H), 2.69 – 2.57 (m, 3H), 2.20 (dq, J = 13.5, 4.8 Hz, 1H), 2.16 – 2.06(m, 2H), 1.91 (d,J = 13.7 Hz, 4H), 1.58 (ddt, J = 63.2, 13.6, 10.8 Hz, 5H), 1.19(d, J = 13.4 Hz, 3H). Example 18 Synthesis of Compound 18

[0525]

[0526] Intermediate 3 (70 mg), intermediate 17h (102 mg), sodium acetate (17.85 mg), 1,2-dichloroethane (5 mL), isopropanol (1 mL), and sodium cyanoborohydride (41.0 mg) were added sequentially to the reaction flask. The mixture was reacted at room temperature. After the reaction was complete, the reaction solution was neutralized with acetic acid by adding 2 mL of saturated sodium bicarbonate solution, followed by extraction with 50 mL of dichloromethane and 100 mL of water. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to give compound 18 (42 mg).

[0527] MS(ESI, [M+H)) + m / z: 737.3.

[0528] 1H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.59 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.80 (d, J = 9.5 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.34 (d, J = 9.6 Hz, 1H), 7.14 (t, J = 7.6 Hz, 2H), 4.55 (td, J = 10.9, 10.0, 4.8 Hz, 2H), 4.49 (d, J = 13.4 Hz, 2H), 3.86 (dd, J= 9.5, 5.0 Hz, 1H), 3.82 (s, 2H), 3.06 (t, J = 12.6 Hz, 2H), 2.97 (t, J = 5.7Hz, 2H), 2.76 (p, J = 6.2, 5.6 Hz, 3H), 2.60 (dt, J = 17.4, 4.3 Hz, 1H), 2.48(s, 1H), 2.44 (d, J = 7.3 Hz, 2H), 2.18 (dq, J = 13.2, 4.5 Hz, 1H), 2.13 –2.04 (m, 3H), 1.88 (t, J = 14.1 Hz, 4H), 1.64 (q, J = 12.2 Hz, 2H), 1.55 –1.47 (m, 2H), 1.15 (dd, J = 18.0, 7.8 Hz, 2H). Example 19 Synthesis of Compound 19

[0529]

[0530] Intermediate 4 (70 mg), intermediate 17h (102 mg), sodium acetate (17.85 mg), 1,2-dichloroethane (5 mL), isopropanol (1 mL), and sodium cyanoborohydride (41.0 mg) were added sequentially to the reaction flask. The mixture was reacted at room temperature. After the reaction was complete, the reaction solution was neutralized with acetic acid by adding 2 mL of saturated sodium bicarbonate solution, followed by extraction with 50 mL of dichloromethane and 100 mL of water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography to obtain compound 19 (48 mg).

[0531] MS(ESI, [M+H)) + m / z: 737.3.

[0532] 1 H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.59 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.80 (d, J = 9.5 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.34 (d, J = 9.6 Hz, 1H), 7.16 – 7.08 (m, 2H), 4.56 (dt, J = 10.5, 5.2 Hz, 2H), 4.49 (d, J = 13.1 Hz, 2H), 3.90 – 3.82 (m, 1H),3.71 (s, 2H), 3.05 (d, J = 12.6 Hz, 2H), 3.00 (t, J = 6.1 Hz, 2H), 2.76 (dt,J = 17.3, 5.6 Hz, 3H), 2.61 (dt, J = 17.5, 4.3 Hz, 1H), 2.47 (s, 1H), 2.39 (d, J = 7.2 Hz, 2H), 2.19 (dq, J = 13.3, 4.5 Hz, 1H), 2.10 (d, J = 12.0 Hz, 2H), 2.04 (s, 1H), 1.88 (t, J = 16.2 Hz, 4H), 1.64 (q, J = 12.5 Hz, 2H), 1.51(q, J = 12.0 Hz, 2H), 1.16 (d, J = 12.4 Hz, 2H). Example 20 Synthesis of Compound 20

[0533]

[0534] Step 1: Preparation of Compound 20 17h (95 mg), intermediate 5 (60 mg), sodium acetate (18 mg), and DCE / isopropanol (5:1, 20 mL) were added sequentially to the reaction flask. After reacting at room temperature for 30 min, sodium cyanoborohydride (26 mg) was added, and the reaction was continued at room temperature. The solvent in the reaction solution was evaporated to dryness, and the crude product was purified by silica gel column chromatography to obtain compound 20 (22 mg).

[0535] MS(ESI, [M+H)) + ) m / z 751.6 1 H NMR (500 MHz, DMSO- d 6) δ 11.08 (s, 1H), 8.58 (d, J = 8.2 Hz, 1H), 7.83 (dd, J = 24.4, 9.1 Hz, 2H), 7.54 (d, J = 8.0 Hz, 1H), 7.41 – 7.30 (m, 2H), 7.23 – 7.10 (m, 2H), 4.61 – 4.44 (m, 4H), 3.93 – 3.80 (m, 1H), 3.20 – 3.10(m, 2H), 3.09 – 2.98 (m, 4H), 2.77 (ddd, J = 17.2, 12.0, 5.3 Hz, 1H), 2.69 –2.65 (m, 2H), 2.65 – 2.61 (m, 2H), 2.34 (d, J = 7.0 Hz, 2H), 2.18 (dq, J = 8.8,4.3 Hz, 1H), 2.14 – 2.06 (m, 2H), 1.89 (t, J = 15.3 Hz, 5H), 1.64 (dt, J = 13.7,11.0 Hz, 2H), 1.59 – 1.45 (m, 3H), 1.17 (t, J = 11.3 Hz, 3H). Example 21 Synthesis of Compound 21

[0536]

[0537] Step 1: Preparation of Compound 21 17h (85 mg), intermediate 6 (66 mg), sodium acetate (20 mg), and DCE / isopropanol (5:1, 20 mL) were added sequentially to the reaction flask. After reacting at room temperature for 30 min, sodium cyanoborohydride (28 mg) was added, and the reaction was continued at room temperature. After the reaction was completed, the solvent in the reaction solution was evaporated, and the crude product was purified by silica gel column chromatography to obtain compound 21 (42 mg).

[0538] MS(ESI, [M+H)) + ) m / z 763.5 1 H NMR (500 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.58 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 9.6 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.32 (d, J = 9.6 Hz, 1H), 7.26 (d, J = 8.2 Hz, 1H), 7.14 (dd, J = 8.8, 2.4 Hz, 1H), 4.55 (ddd, J = 16.3, 11.2, 5.4 Hz, 2H), 4.46(d, J = 13.2 Hz, 2H), 3.91 – 3.81 (m, 1H), 2.98 (t, J = 12.5 Hz, 2H), 2.77(ddd, J = 17.2, 12.0, 5.3 Hz, 1H), 2.60 (dt, J = 17.4, 4.2 Hz, 1H), 2.32 (s,2H), 2.17 (dq, J = 13.4, 4.7 Hz, 1H), 2.10 (d, J = 11.7 Hz, 2H), 1.93 – 1.86(m, 2H), 1.84 – 1.76 (m, 2H), 1.69 – 1.59 (m, 3H), 1.58 – 1.45 (m, 3H), 1.18–1.09 (m, 3H). Example 22 Synthesis of Compound 22

[0539]

[0540] Step 1: Preparation of intermediate 22a Add 17d (10.0 g), 4-hydroxypiperidine (7.1 g), DIPEA (11.2 g), and DMSO (90 mL) to the reaction flask, and heat the reaction solution to 90°C. o The reaction proceeded for 2 hours. After the reaction was complete, the reaction solution was poured into 300 mL of water, filtered, the filter cake was collected, and dried to obtain intermediate 22a (8.2 g).

[0541] MS(ESI, [M+H))+ ) m / z 238.1 1 H NMR (500 MHz, DMSO- d 6) δ 7.80 (d, J = 9.6 Hz, 1H), 7.29 (d, J = 9.7Hz, 1H), 4.79 (d, J = 4.2 Hz, 1H), 4.16 (dt, J = 13.6, 4.8 Hz, 2H), 3.87 (s, 3H), 3.79 (tq, J = 8.2, 4.0 Hz, 1H), 3.38 (ddd, J = 13.2, 9.6, 3.3 Hz, 2H), 1.87 –1.79 (m, 2H), 1.45 – 1.35 (m, 2H). Step 2: Preparation of intermediate 22b 22a (8.3 g), sodium hydroxide (2.8 g), methanol (70 mL), and water (10 mL) were added sequentially to the reaction flask, and the reaction was carried out at room temperature. After the reaction was completed, the pH of the reaction solution was adjusted to 3-4 with concentrated hydrochloric acid, and the solvent was evaporated to dryness. The solution was slurried with DCM:MeOH, filtered, and the filtrate was concentrated to obtain intermediate 22b (1.2 g).

[0542] MS(ESI, [MH] - ) m / z :222.1 1 H NMR (500 MHz, DMSO- d 6) δ 7.80 (d, J = 9.5 Hz, 1H), 7.27 (d, J = 9.6Hz, 1H), 4.81 (s, 1H), 4.14 (dt, J = 13.5, 4.7 Hz, 2H), 3.77 (tt, J = 8.4, 3.9Hz, 1H), 3.34 – 3.30 (m, 3H), 1.82 (ddd, J = 13.1, 5.8, 3.3 Hz, 2H), 1.39 (ddt, J = 13.4, 9.1, 4.6 Hz, 2H). Step 3: Preparation of intermediate 22c 22b (1.5 g), 17c (1.3 g), HATU (3.0 g), DIPEA (2.1 g), and DMF (30 mL) were added sequentially to the reaction flask, and the reaction was carried out at room temperature. After the reaction was completed, 70 mL of ethyl acetate and 150 mL of water were added, the organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the concentrate was purified by silica gel column chromatography to obtain intermediate 22c (1.4 g).

[0543] MS(ESI, [M+H)) + ) m / z 456.3 1 H NMR (500 MHz, DMSO- d 6) δ 8.58 (d, J = 8.2 Hz, 1H), 7.83 (dd, J = 25.8,9.1 Hz, 2H), 7.41 – 7.32 (m, 2H), 7.14 (dd, J = 8.8, 2.4 Hz, 1H), 4.77 (d, J =4.2 Hz, 1H), 4.54 (tt, J = 10.3, 4.2 Hz, 1H), 4.14 (dt, J = 13.5, 4.7 Hz, 2H),3.83 (ddtd, J = 36.7, 12.6, 8.5, 8.0, 4.0 Hz, 2H), 3.35 (td, J = 9.8, 4.7 Hz,2H), 2.14 – 2.07 (m, 2H), 1.90 (dd, J = 13.1, 3.8 Hz, 2H), 1.85 – 1.77 (m, 2H), 1.69 – 1.58 (m, 2H), 1.57 – 1.46 (m, 2H), 1.39 (dtd, J = 12.9, 9.1, 3.8 Hz, 2H). Step 4: Preparation of intermediate 22d 22c (0.5 g), Desmartin oxidant (1.4 g), and dichloromethane (30 mL) were added sequentially to the reaction flask, and the reaction was carried out at room temperature for 1 h. After the reaction was completed, 70 mL of dichloromethane and 100 mL of water were added, the organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 22d (0.6 g).

[0544] Step 5: Preparation of Compound 22 Compound 22 (88 mg), intermediate 1 (69 mg), sodium acetate (25 mg), and DMA (20 mL) were added sequentially to the reaction flask. After reacting at room temperature for 30 min, sodium cyanoborohydride (31 mg) was added, and the reaction was continued at room temperature for 2 h. The solvent in the reaction solution was evaporated, and the crude product was purified by silica gel column chromatography to obtain compound 22 (32 mg).

[0545] MS(ESI, [M+H)) + ) m / z 709.3 1 H NMR (500 MHz, DMSO- d 6) δ 11.10 (s, 1H), 8.61 (d, J = 8.2 Hz, 1H), 7.84 (dd, J = 14.1, 9.1 Hz, 2H), 7.72 (d, J = 8.0 Hz, 1H), 7.43 – 7.37 (m, 2H), 7.32 (d, J = 8.2 Hz, 1H), 7.14 (dd, J = 8.8, 2.4 Hz, 1H), 4.60 (dd, J = 11.9, 5.0Hz, 1H), 4.54 (tt, J = 9.7, 4.0 Hz, 1H), 4.40 – 4.29 (m, 2H), 4.23 (s, 2H), 4.12 (s, 2H), 3.91 – 3.81 (m, 1H), 3.29 (d, J = 10.7 Hz, 2H), 2.86 (d, J = 10.1Hz, 1H), 2.77 (ddd, J = 17.2, 11.9, 5.3 Hz, 1H), 2.61 (dt, J = 17.3, 4.3 Hz, 1H), 2.21 (dq, J = 8.6, 4.5, 3.9 Hz, 1H), 2.14 – 2.08 (m, 2H), 2.08 – 2.00 (m, 2H), 1.94 – 1.85 (m, 2H), 1.72 – 1.59 (m, 3H), 1.59 – 1.45 (m, 4H). Example 23 Synthesis of Compound 23

[0546]

[0547] Step 1: Preparation of Compound 23 22d (108 mg), intermediate 5 (79 mg), sodium acetate (28 mg), and DMA (20 mL) were added sequentially to the reaction flask. After reacting at room temperature for 30 min, sodium cyanoborohydride (33 mg) was added, and the reaction was continued at room temperature. The solvent in the reaction solution was evaporated to dryness, and the crude product was purified by silica gel column chromatography to obtain compound 23 (27 mg).

[0548] MS(ESI, [M+H)) + ) m / z 737.4 1 H NMR (500 MHz, DMSO- d 6) δ 11.07 (s, 1H), 8.59 (d, J = 8.2 Hz, 1H), 7.83 (dd, J = 24.2, 9.2 Hz, 2H), 7.53 (d, J = 8.0 Hz, 1H), 7.43 – 7.30 (m, 2H), 7.23 – 7.10 (m, 2H), 4.54 (td, J = 11.0, 9.6, 5.9 Hz, 4H), 3.86 (dtd, J = 11.3,7.6, 4.1 Hz, 1H), 3.13 (t, J = 4.9 Hz, 2H), 2.98 (dt, J = 31.3, 12.8 Hz, 5H),2.82 – 2.64 (m, 5H), 2.60 (dt, J = 17.3, 4.2 Hz, 1H), 2.46 (dd, J = 12.1, 4.5 Hz, 1H), 2.18 (dq, J = 8.5, 4.4 Hz, 1H), 2.14 – 2.05 (m, 2H), 1.90 (d, J = 13.6 Hz, 2H), 1.80 (d, J = 12.2 Hz, 2H), 1.70 – 1.58 (m, 2H), 1.51 (qd, J= 12.4, 6.0 Hz, 4H). Examples 24 and 25: Synthesis of compounds 24 and 25

[0549]

[0550] Step 1: Preparation of intermediate 24b 24a (1.443 g), DMSO (10 mL), DIPEA (2.247 g, 3.08 mL), and methyl 6-chloropyridazine-3-carboxylate (1 g) were added sequentially to a reaction flask, and the mixture was reacted at 90 °C. After the reaction was complete, the mixture was poured into ice water, filtered, and the filter cake was dried to obtain 24b (2.7 g).

[0551] MS(ESI, [M+H)) + m / z: 363.16. 1 H NMR (500 MHz, DMSO- d 6) δ 7.81 (d, J = 9.6 Hz, 1H), 7.32 (d, J = 9.7Hz, 1H), 3.86 (s, 3H), 3.71 (s, 8H), 1.74 (t, J = 5.6 Hz, 4H), 1.39 (s, 9H). Step 2: Preparation of intermediate 24c 24b (2.6 g), MeOH (30 mL), and water (3 mL) were added sequentially to the reaction flask, followed by sodium hydroxide (1.43 g). The reaction was carried out at room temperature. After the reaction was completed, 6 M hydrochloric acid was added to adjust the pH to 4-5. The solvent was removed by concentration, and then approximately 100 mL of MeOH / DCM (v:v = 1 / 10) was added to the system and stirred. The solid was removed by filtration, and the mother liquor was concentrated to obtain 24c (1.9 g).

[0552] MS(ESI, [M+H)) + m / z: 349.25. Step 3: Preparation of intermediate 24d 17c (0.85 g), 24c (1.031 g), DCM (10 mL), HATU (1.68 g), and DIPEA (1.148 g, 1.551 mL) were added sequentially to the reaction flask, and the mixture was reacted at room temperature. After the reaction was complete, 100 mL of ethyl acetate was added to dilute the reaction solution, followed by washing with 100 mL of 10% citric acid aqueous solution, and then washing with 100 mL of saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 24d (1.61 g).

[0553] MS(ESI, [M+H)) + m / z: 581.28. Step 4: Preparation of intermediate 24e 24d (1.61 g), DCM (20 mL), and trifluoroacetic acid (5 mL) were added sequentially to the reaction flask, and the mixture was reacted at room temperature. After the reaction was completed, the mixture was added to 200 mL of saturated sodium bicarbonate solution, and then extracted with 200 mL of DCM. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 24e (1.3 g).

[0554] MS(ESI, [M+H)) + m / z: 481.22. 1 H NMR (500 MHz, DMSO- d 6) δ 8.59 (dd, J = 8.2, 5.4 Hz, 1H), 7.84 (dd, J =20.6, 9.1 Hz, 2H), 7.41 – 7.33 (m, 2H), 7.13 (dd, J = 8.8, 2.4 Hz, 1H), 4.53(tt, J = 9.9, 4.2 Hz, 1H), 3.85 (dtd, J = 15.2, 7.8, 3.9 Hz, 1H), 3.68 (t, J = 5.7Hz, 4H), 3.57 (s, 4H), 2.16 – 2.05 (m, 2H), 1.94 – 1.85 (m, 2H), 1.84 – 1.76(m, 3H), 1.74 – 1.44 (m, 5H). Step 5: Preparation of intermediates 24f-1 and 24f-2 24e (350 mg), 1,2-dichloroethane (10 mL), isopropanol (3 mL), intermediate 7 (208 mg), and 1 drop of acetic acid were added sequentially to the reaction flask, followed by sodium cyanoborohydride (137 mg). The mixture was reacted overnight at room temperature. After the reaction was completed, 20 mL of saturated sodium bicarbonate solution and 50 mL of water were added to the reaction solution, followed by extraction with dichloromethane. After separation of the organic phase, the solution was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the crude product. The crude product was then separated by high performance liquid chromatography to prepare intermediate 24f-1 (95 mg) of the first peak and intermediate 24f-2 (85 mg) of the second peak.

[0555] The preparation conditions are as follows: Instruments and preparation column: YMC high-pressure preparative chromatograph, preparation column model CHIRALARTCellose-SB. Mobile phase system: ethanol: dichloromethane (1:1) / n-hexane, isogradient elution ethanol: dichloromethane (1:1) / n-hexane = 50 / 50.

[0556] The 24f-1 characterization data are as follows: MS(ESI, [M+H)) + m / z: 724.30. 1 H NMR (500 MHz, DMSO- d 6) δ 8.58 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 8.7Hz, 1H), 7.79 (d, J = 9.6 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.41 – 7.32 (m, 2H), 7.27 (d, J = 8.1 Hz, 1H), 7.13 (dd, J = 8.7, 2.4 Hz, 1H), 4.54 (dq, J = 10.5, 5.8,5.1 Hz, 1H), 4.23 – 4.08 (m, 4H), 3.90 – 3.80 (m, 1H), 3.67 (t, J = 5.6 Hz,4H), 3.46 (s, 1H), 3.13 (d, J = 24.8 Hz, 5H), 2.84 (ddd, J = 31.4, 16.6, 3.1 Hz,2H), 2.16 – 2.05 (m, 2H), 1.89 (d,J = 9.9 Hz, 3H), 1.71 (t, J = 5.6 Hz, 4H),1.68 – 1.58 (m, 2H), 1.56 – 1.45 (m, 2H), 1.19 (t, J = 7.0 Hz, 3H). Step 6: Preparation of Compound 24 24f-1 (91 mg), acrylamide (8.93 mg), and THF (10 mL) were added sequentially to the reaction flask. 1 M potassium tert-butoxide tetrahydrofuran solution (0.088 mL) was added under ice bath conditions, and the mixture was reacted at 0 °C. After the reaction was complete, the reaction solution was added dropwise to a saturated ammonium chloride solution at ice water, extracted with ethyl acetate, and the organic phase was separated. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain compound 24 (17 mg).

[0557] MS(ESI, [M+H)) + m / z: 749.30. 1 H NMR (500 MHz, DMSO- d 6) δ 11.09 (s, 1H), 8.57 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 8.7 Hz, 1H), 7.79 (d, J = 9.5 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.42– 7.31 (m, 2H), 7.26 (d, J = 8.1 Hz, 1H), 7.13 (dd, J = 8.8, 2.4 Hz, 1H), 4.60 –4.49 (m, 2H), 3.85 (d, J = 10.3 Hz, 1H), 3.67 (t, J = 5.4 Hz, 4H), 3.60 (d, J = 6.1Hz, 1H), 3.06 (s, 5H), 2.89 – 2.74 (m, 3H), 2.66 – 2.55 (m, 2H), 2.18 (dd, J =13.1, 5.2 Hz, 1H), 2.10 (d, J = 11.8 Hz, 2H), 2.00 (q,J = 7.7 Hz, 1H), 1.93 –1.85 (m, 2H), 1.74 (d, J = 21.8 Hz, 4H), 1.63 (d, J = 12.4 Hz, 2H), 1.51 (d, J =12.0 Hz, 2H). Step 7: Preparation of Compound 25 24f-2 (80 mg), acrylamide (7.93 mg), and THF (10 mL) were added sequentially to the reaction flask. 1 M potassium tert-butoxide tetrahydrofuran solution (0.078 mL) was added under ice bath conditions, and the mixture was reacted at 0 °C. After the reaction was complete, the reaction solution was added dropwise to a saturated ammonium chloride solution at ice water, extracted with ethyl acetate, and the organic phase was separated. The solution was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain compound 25 (15 mg).

[0558] MS(ESI, [M+H)) + m / z: 749.52. 1 H NMR (500 MHz, DMSO- d 6) δ 11.09 (s, 1H), 8.57 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 8.7 Hz, 1H), 7.79 (d, J = 9.5 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.42– 7.31 (m, 2H), 7.26 (d, J = 8.1 Hz, 1H), 7.13 (dd, J = 8.8, 2.4 Hz, 1H), 4.60 –4.49 (m, 2H), 3.85 (d, J = 10.3 Hz, 1H), 3.67 (t, J = 5.4 Hz, 4H), 3.60 (d, J = 6.1Hz, 1H), 3.06 (s, 5H), 2.89 – 2.74 (m, 3H), 2.66 – 2.55 (m, 2H), 2.18 (dd, J =13.1, 5.2 Hz, 1H), 2.10 (d, J= 11.8 Hz, 2H), 2.00 (q, J = 7.7 Hz, 1H), 1.93 –1.85 (m, 2H), 1.74 (d, J = 21.8 Hz, 4H), 1.63 (d, J = 12.4 Hz, 2H), 1.51 (d, J =12.0 Hz, 2H). Example 26 Synthesis of Compound 26

[0559]

[0560] Step 1: Preparation of intermediate 26b 26a (5.94 g), DMSO (30 mL), DIPEA (1.23 g, 15.39 mL), and methyl 6-chloropyridazine-3-carboxylate (5 g) were added sequentially to a reaction flask, and the mixture was reacted at 90 °C. After the reaction was complete, the mixture was poured into ice water, filtered, and the filter cake was dried to obtain 26b (11.3 g).

[0561] MS(ESI, [M+H)) + m / z: 323.07.

[0562] 1 H NMR (500 MHz, DMSO- d 6) δ 7.87 (d, J = 9.6 Hz, 1H), 7.29 (d, J = 9.7Hz, 1H), 3.87 (s, 3H), 3.80 – 3.69 (m, 4H), 3.47 (dd, J = 6.3, 4.0 Hz, 4H),1.43 (s, 9H). Step 2: Preparation of intermediate 26c 11.3 g of 26b, 100 mL of MeOH, and 30 mL of water were added sequentially to the reaction flask, followed by 7.01 g of sodium hydroxide. The reaction was carried out at room temperature. After the reaction was completed, 6 M hydrochloric acid was added to adjust the pH to 4-5. The solvent was removed by concentration, and then approximately 100 mL of MeOH / DCM (v:v=1 / 10) was added to the system and stirred. The solids were removed by filtration, and the mother liquor was concentrated to obtain 9.8 g of 26c.

[0563] MS(ESI, [M+H)) +m / z: 308.99. Step 3: Preparation of intermediate 26d 17c (2.5 g), 26c (2.68 g), DCM (30 mL), HATU (4.30 g), and DIPEA (5.63 g, 7.60 mL) were added sequentially to the reaction flask, and the mixture was reacted at room temperature. After the reaction was complete, the system was diluted with 100 mL of ethyl acetate, washed with 100 mL of 10% citric acid aqueous solution, and then washed with saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 26d (3.2 g).

[0564] MS(ESI, [M+H)) + m / z: 541.21 Step 4: Preparation of intermediate 26e 26d (3.2 g), DCM (20 mL), and trifluoroacetic acid (5 mL) were added sequentially to the reaction flask, and the mixture was reacted at room temperature. After the reaction was completed, the mixture was added to 200 mL of saturated sodium bicarbonate solution, extracted with DCM, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 26e (2.56 g).

[0565] MS(ESI, [M+H)) + m / z: 441.20. 1 H NMR (500 MHz, DMSO- d 6) δ 8.62 (d, J = 8.2 Hz, 1H), 7.85 (t, J = 9.3Hz, 2H), 7.39 (d, J = 2.4 Hz, 1H), 7.34 (d, J = 9.6 Hz, 1H), 7.14 (dd, J = 8.8, 2.4Hz, 1H), 4.53 (tt, J = 10.3, 4.2 Hz, 1H), 3.86 (tdt, J = 11.8, 8.2, 4.0 Hz, 1H),3.77 – 3.61 (m, 4H), 2.99 – 2.80 (m, 4H), 2.16 – 2.05 (m, 2H), 1.95 – 1.84(m, 2H), 1.64 (qd, J = 13.1, 3.1 Hz, 2H), 1.58 – 1.45 (m, 2H). Step 5: Preparation of intermediate 26f Intermediate 8 (50 mg), Desmartin oxidant (141 mg), dichloromethane (5 mL), and DMF (1 mL) were added sequentially to the reaction flask, and the mixture was reacted at room temperature. After the reaction was complete, the reaction solution was extracted with 50 mL of water and 20 mL of ethyl acetate. The organic compounds were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to obtain the target intermediate 26f (50 mg).

[0566] MS(ESI, [M+H)) + m / z: 299.51.

[0567] Step 6: Preparation of 26g of intermediate Intermediate 26f (50 mg), 1,2-dichloroethane (6 mL), isopropanol (2 mL), intermediate 26e (88 mg), acetic acid (5.00 mg), and sodium cyanoborohydride (20.93 mg) were added sequentially to a reaction flask. The mixture was stirred at room temperature. After the reaction was complete, acetic acid was neutralized with 2 mL of saturated sodium bicarbonate solution, followed by the addition of 50 mL of dichloromethane and 100 mL of extraction solution. The organic phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain 26 g (30 mg) of compound.

[0568] MS(ESI, [M+H)) + m / z: 723.36. Step 7: Preparation of Compound 26 26 g (30 mg), maleic acid (4.81 mg), and MeOH / DCM (v:v = 1 / 10, 5 mL) were added sequentially to the reaction flask. After dissolving, the reaction solution was concentrated. The reaction solution was then slurried with 10 mL of petroleum ether and filtered to obtain 26 g (32 mg).

[0569] MS(ESI, [M+H)) + m / z: 723.43. 1 H NMR (500 MHz, DMSO- d 6) δ 11.09 (s, 1H), 8.66 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 9.4 Hz, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.66 (d, J= 8.2 Hz, 1H), 7.54– 7.42 (m, 1H), 7.39 (d, J = 2.5 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.13 (dd, J =8.9, 2.5 Hz, 1H), 6.11 (s, 2H), 4.56 (dq, J = 22.4, 6.0, 5.1 Hz, 2H), 3.93 –3.83 (m, 1H), 3.17 (s, 13H), 3.09 (s, 1H), 3.01 (d, J = 16.1 Hz, 1H), 2.90 (dd, J = 16.4, 6.1 Hz, 1H), 2.77 (td, J = 12.0, 5.8 Hz, 1H), 2.61 (d, J = 18.1 Hz, 1H),2.25 – 2.05 (m, 3H), 1.96 – 1.83 (m, 2H), 1.65 (q, J = 12.4 Hz, 2H), 1.59 –1.42 (m, 2H). Example 27 Synthesis of Compound 27

[0570]

[0571] Step 1: Preparation of intermediate 27a Intermediate 9 (50 mg), Desmartin oxidant (141 mg), dichloromethane (5 mL), and DMF (1 mL) were added sequentially to the reaction flask, and the mixture was reacted at room temperature. After the reaction was complete, the reaction solution was extracted with 50 mL of water and 20 mL of ethyl acetate. The organic compounds were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation of the filtrate to obtain the target intermediate 27a (50 mg).

[0572] MS(ESI, [M+H)) + m / z: 299.31.

[0573] Step 6: Preparation of intermediate 27b Intermediate 27a (50 mg), 1,2-dichloroethane (6 mL), isopropanol (2 mL), intermediate 26e (88 mg), acetic acid (5.00 mg), and sodium cyanoborohydride (20.93 mg) were added sequentially to a reaction flask. The mixture was stirred at room temperature. After the reaction was complete, acetic acid was neutralized with 2 mL of saturated sodium bicarbonate solution, followed by the addition of 50 mL of dichloromethane and 100 mL of extraction solution. The organic phases were separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain compound 27b (53 mg).

[0574] MS(ESI, [M+H)) + m / z: 723.42. Step 2: Preparation of Compound 27 27b (53 mg), maleic acid (8.51 mg), and MeOH / DCM (v:v = 1 / 10, 5 mL) were added sequentially to the reaction flask. After dissolving, the reaction solution was concentrated. The concentrate was slurried with 10 mL of petroleum ether and then filtered to obtain 27b (58 mg).

[0575] MS(ESI, [M+H)) + m / z: 723.52. 1 H NMR (500 MHz, DMSO- d 6) δ 11.09 (s, 1H), 8.66 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 9.4 Hz, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.54– 7.42 (m, 1H), 7.39 (d, J = 2.5 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.13 (dd, J =8.9, 2.5 Hz, 1H), 6.11 (s, 2H), 4.56 (dq, J = 22.4, 6.0, 5.1 Hz, 2H), 3.93 –3.83 (m, 1H), 3.17 (s, 13H), 3.09 (s, 1H), 3.01 (d, J = 16.1 Hz, 1H), 2.90 (dd, J= 16.4, 6.1 Hz, 1H), 2.77 (td, J = 12.0, 5.8 Hz, 1H), 2.61 (d, J = 18.1 Hz, 1H),2.25 – 2.05 (m, 3H), 1.96 – 1.83 (m, 2H), 1.65 (q, J = 12.4 Hz, 2H), 1.59 –1.42 (m, 2H). Example 28 Synthesis of Compound 28

[0576]

[0577] Step 1: Preparation of intermediate 28a Intermediate 14 (50 mg), IBX (94 mg), and dimethyl sulfoxide (5 mL) were added sequentially to the reaction flask, and the mixture was reacted at room temperature. After the reaction was completed, 100 mL of sodium bicarbonate solution was added to the reaction solution, followed by extraction with 100 mL of ethyl acetate. After organic extraction, the mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the target intermediate 28a (50 mg).

[0578] MS(ESI, [M+H)) + m / z: 298.41. Step 2: Preparation of Compound 28 Intermediate 28a (50 mg), 1,2-dichloroethane (6 mL), isopropanol (2 mL), intermediate 26e (90 mg), acetic acid (5.00 mg), and sodium cyanoborohydride (20 mg) were added sequentially to a reaction flask. The mixture was stirred at room temperature for 1 h. After the reaction was complete, the acetic acid was neutralized with 2 mL of saturated sodium bicarbonate solution, followed by extraction with 50 mL of dichloromethane and 100 mL of water. The organic phases were separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain compound 28 (72 mg).

[0579] MS(ESI, [M+H)) + m / z: 722.43. 1 H NMR (500 MHz, DMSO- d 6) δ 10.87 (d, J = 2.1 Hz, 1H), 8.61 (d, J = 8.2Hz, 1H), 7.84 (dd,J = 18.0, 8.6 Hz, 3H), 7.44 – 7.28 (m, 3H), 7.20 – 7.04 (m,2H), 4.53 (dq, J = 10.0, 5.4, 4.3 Hz, 1H), 4.11 (dd, J = 11.8, 4.9 Hz, 1H), 3.93– 3.81 (m, 1H), 3.73 (t, J = 4.8 Hz, 4H), 3.17 (ddd, J = 29.9, 16.6, 8.4 Hz, 2H), 2.98 – 2.85 (m, 2H), 2.84 – 2.67 (m, 2H), 2.65 – 2.52 (m, 5H), 2.40 (d, J = 7.4Hz, 2H), 2.31 (qd, J = 12.4, 4.4 Hz, 1H), 2.16 – 2.05 (m, 3H), 1.95 – 1.85 (m,2H), 1.72 – 1.58 (m, 2H), 1.51 (q, J = 11.8, 11.3 Hz, 2H). Example 29 Synthesis of Compound 29

[0580]

[0581] Step 1: Preparation of intermediate 29a Intermediate 15 (50 mg), IBX (94 mg), and dimethyl sulfoxide (5 mL) were added sequentially to the reaction flask, and the mixture was reacted at room temperature. After the reaction was complete, 100 mL of sodium bicarbonate solution was added to the reaction solution, followed by extraction with 100 mL of ethyl acetate. After organic extraction, the mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the target intermediate 29a (50 mg).

[0582] MS(ESI, [M+H)) + m / z: 298.35. Step 2: Preparation of Compound 29 Intermediate 29a (50 mg), 1,2-dichloroethane (6 mL), isopropanol (2 mL), intermediate 26e (90 mg), acetic acid (5.00 mg), and sodium cyanoborohydride (20 mg) were added sequentially to a reaction flask. The mixture was stirred at room temperature for 1 h. After the reaction was complete, the acetic acid was neutralized with 2 mL of saturated sodium bicarbonate solution, followed by extraction with 50 mL of dichloromethane and 100 mL of water. The organic phases were separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain compound 29 (93 mg).

[0583] MS(ESI, [M+H)) + m / z: 722.47. 1 H NMR (500 MHz, DMSO- d 6) δ 10.87 (d, J = 2.1 Hz, 1H), 8.61 (d, J = 8.2Hz, 1H), 7.84 (dd, J = 18.0, 8.6 Hz, 3H), 7.44 – 7.28 (m, 3H), 7.20 – 7.04 (m,2H), 4.53 (dq, J = 10.0, 5.4, 4.3 Hz, 1H), 4.11 (dd, J = 11.8, 4.9 Hz, 1H), 3.93– 3.81 (m, 1H), 3.73 (t, J = 4.8 Hz, 4H), 3.17 (ddd, J = 29.9, 16.6, 8.4 Hz, 2H), 2.98 – 2.85 (m, 2H), 2.84 – 2.67 (m, 2H), 2.65 – 2.52 (m, 5H), 2.40 (d, J = 7.4Hz, 2H), 2.31 (qd, J = 12.4, 4.4 Hz, 1H), 2.16 – 2.05 (m, 3H), 1.95 – 1.85 (m,2H), 1.72 – 1.58 (m, 2H), 1.51 (q, J = 11.8, 11.3 Hz, 2H). Example 30 Synthesis of Compound 30

[0584]

[0585] Step 1: Preparation of intermediate 30b 10 g of methyl 6-chloropyridazine-3-carboxylate, 26.9 g of intermediate 30a, 4.73 g of [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex, 18.43 g of sodium carbonate, 200 mL of dioxane, and 7 mL of water were added sequentially to a reaction flask. The mixture was heated to 85 °C under N2 protection. After the reaction was complete, 200 mL of ethyl acetate and 200 mL of water were added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to obtain the target intermediate 30b (8.92 g).

[0586] MS(ESI, [M+H]+) m / z: 320.0.

[0587] 1 H NMR (500 MHz, DMSO-d6) δ 8.17 (d, J = 9.0 Hz, 1H), 8.08 (d, J =8.9 Hz, 1H), 6.98 (s, 1H), 4.18 – 4.10 (m, 2H), 3.96 (s, 3H), 3.59 (t, J =5.7 Hz, 2H), 2.72 (tt, J = 6.0, 2.1 Hz, 2H), 1.44 (s, 9H). Step 2: Preparation of intermediate 30c Intermediate 30b (8.92 g), methanol (210 mL), dichloromethane (30 mL), and 10% palladium on carbon (2.23 g) were added sequentially to a reaction flask. After H2 replacement, the mixture was reacted at room temperature for 5 h. After the reaction was complete, the mixture was filtered, and the solvent was removed by vacuum distillation of the filtrate. 20 mL of dimethyl sulfoxide was added to the residue, and the mixture was filtered again. The filter cake was collected, slurried with 50 mL of water, filtered, and the filter cake was collected to obtain the target intermediate 30c (2.66 g).

[0588] MS(ESI, [M+H)) + m / z: 322.1.

[0589] 1H NMR (500 MHz, DMSO-d6) δ 8.15 (d, J = 8.7 Hz, 1H), 7.85 (d, J =8.7 Hz, 1H), 4.16 – 4.05 (m, 2H), 3.95 (s, 3H), 3.21 (ddt, J = 15.2, 11.5,5.8 Hz, 1H), 2.91 (d, J = 3.3 Hz, 2H), 1.94 – 1.88 (m, 2H), 1.67 (qd, J =12.5, 4.3 Hz, 2H), 1.42 (s, 9H). Step 3: Preparation of intermediate 30d Intermediate 30c (1.7 g), sodium hydroxide (0.423 g), methanol (20 mL), and water (1 mL) were added sequentially to a reaction flask, and the mixture was reacted at room temperature. After the reaction was complete, saturated citric acid solution was added to adjust the pH to 2-3, dichloromethane was added, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain the target intermediate 30d (1.63 g).

[0590] MS(ESI, [MH] - m / z: 306.2.

[0591] 1 H NMR (500 MHz, DMSO-d6) δ 13.75 (s, 1H), 8.12 (d, J = 8.6 Hz, 1H), 7.83 (d, J = 8.7 Hz, 1H), 4.10 (d, J = 12.9 Hz, 2H), 3.21 (tt, J = 12.0, 3.6Hz, 1H), 2.90 (s, 2H), 1.93 – 1.88 (m, 2H), 1.68 (qd, J = 12.5, 4.3 Hz, 2H), 1.42 (s, 9H). Step 4: Preparation of intermediate 30e Intermediate 30d (1.637 g), dichloromethane (30 mL), HATU (2.430 g), N,N-diisopropylethylamine (2.75 g, 3.72 mL), and intermediate 17c (1.335 g) were added sequentially to a reaction flask. The mixture was reacted at room temperature. After the reaction was complete, 200 mL of ethyl acetate and 300 mL of saturated citric acid solution were added. The organic phase was separated, washed with saturated sodium bicarbonate solution and saturated brine solution, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain the target intermediate 30e (2.52 g).

[0592] MS(ESI, [M+H)) + m / z: 540.3.

[0593] Step 5: Preparation of intermediate 30f Intermediate 30e (2.52 g), dichloromethane (30 mL), and trifluoroacetic acid (37.0 g, 25 mL) were added sequentially to a reaction flask, and the mixture was reacted at room temperature. After the reaction was complete, the solvent was removed from the reaction solution by vacuum distillation. 200 mL of dichloromethane / methanol (v:v = 9 / 1) was added to the residue, and the pH was adjusted to strongly alkaline with 20% sodium hydroxide solution. The organic phase was separated, and the aqueous phase was extracted with 100 mL of dichloromethane / methanol (v:v = 9 / 1). 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 the target intermediate 30f (1.88 g).

[0594] MS(ESI, [M+H)) + m / z: 440.3.

[0595] 1 H NMR (500 MHz, DMSO-d6) δ 9.04 (d, J = 8.1 Hz, 1H), 8.13 (d, J =8.7 Hz, 1H), 7.83 (dd, J = 31.5, 8.8 Hz, 2H), 7.40 (s, 1H), 7.15 (d, J = 9.0Hz, 1H), 4.54 (d, J = 11.6 Hz, 1H), 3.92 (q, J = 11.0, 10.4 Hz, 1H), 3.19 (d,J = 12.6 Hz, 3H), 2.81 (t, J = 12.3 Hz, 2H), 2.69 (s, 1H), 2.12 (d, J = 12.2Hz, 2H), 1.88 (dq, J = 24.6, 12.6, 12.0 Hz, 6H), 1.69 (q, J = 12.6 Hz, 2H), 1.52 (q, J = 13.6, 12.7 Hz, 2H). Step 6: Preparation of Compound 30 Intermediate 26f (60 mg), 1,2-dichloroethane (5 mL), isopropanol (1 mL), intermediate 30f (88 mg), and sodium cyanoborohydride (37.7 mg) were added sequentially to a reaction flask. The mixture was stirred at room temperature. After the reaction was complete, acetic acid was neutralized with 2 mL of saturated sodium bicarbonate solution, followed by extraction with 50 mL of dichloromethane and 100 mL of water. The organic phases were separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography to give compound 30 (77 mg).

[0596] MS(ESI, [M+H)) + m / z: 722.5.

[0597] 1 H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.03 (d, J = 8.2 Hz, 1H), 8.11 (d, J = 8.6 Hz, 1H), 7.85 (dd, J = 8.7, 5.0 Hz, 2H), 7.62 (d, J = 8.1Hz, 1H), 7.40 (d, J = 2.5 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.14 (dd, J =8.8, 2.5 Hz, 1H), 4.60 – 4.52 (m, 2H), 3.97 – 3.87 (m, 1H), 3.28 – 3.22 (m,1H), 3.22 – 3.16 (m, 1H), 3.06 (d, J = 10.5 Hz, 2H), 3.00 (t, J = 5.1 Hz,1H), 2.93 (d, J = 13.1 Hz, 2H), 2.85 (dd, J = 16.1, 4.8 Hz, 1H), 2.77 (td, J= 11.8, 5.8 Hz, 1H), 2.64 – 2.58 (m, 1H), 2.46 (s, 1H), 2.39 (d, J = 7.3 Hz, 2H), 2.20 (dq, J = 9.2, 4.3 Hz, 1H), 2.12 (d, J = 11.8 Hz, 4H), 1.94 – 1.84(m, 6H), 1.70 (q, J = 12.4 Hz, 2H), 1.53 (q, J = 11.3 Hz, 2H). Example 31 Synthesis of Compound 31

[0598]

[0599] Intermediate 27a (60 mg), 1,2-dichloroethane (5 mL), isopropanol (1 mL), intermediate 30f (88 mg), and sodium cyanoborohydride (37.7 mg) were added sequentially to a reaction flask. The mixture was stirred at room temperature. After the reaction was complete, acetic acid was neutralized with 2 mL of saturated sodium bicarbonate solution, followed by extraction with 50 mL of dichloromethane and 100 mL of water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography to give compound 31 (48 mg).

[0600] MS(ESI, [M+H)) + m / z: 722.5.

[0601] 11H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.03 (d, J = 8.2 Hz, 1H),8.11 (d, J = 8.6 Hz, 1H), 7.86 (dd, J = 8.8, 5.0 Hz, 2H), 7.62 (d, J = 8.1Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.14 (dd, J =8.6, 2.5 Hz, 1H), 4.55 (tt, J = 11.0, 5.5 Hz, 2H), 3.92 (dtd, J = 11.7, 7.7,4.1 Hz, 1H), 3.28 – 3.22 (m, 1H), 3.18 (dd, J = 16.8, 8.1 Hz, 1H), 3.06 (d, J= 10.7 Hz, 2H), 3.00 (p, J = 6.2 Hz, 1H), 2.93 (d, J = 13.0 Hz, 2H), 2.85(dd, J = 16.2, 4.8 Hz, 1H), 2.77 (ddd, J = 17.2, 11.8, 5.3 Hz, 1H), 2.61 (dt,J = 17.8, 4.5 Hz, 1H), 2.47 (s, 1H), 2.39 (d, J = 7.3 Hz, 2H), 2.20 (dq, J =8.9, 4.3 Hz, 1H), 2.12 (d, J = 12.0 Hz, 4H), 1.92 (d, J = 12.2 Hz, 5H), 1.85(d, J = 11.8 Hz, 1H), 1.70 (q, J = 11.8, 11.4 Hz, 2H), 1.53 (td, J = 13.5,6.9 Hz, 2H). Synthesis of Compound 32 in Example 32

[0602]

[0603] Intermediate 28a (50 mg), 1,2-dichloroethane (5 mL), isopropanol (1 mL), intermediate 30f (73.5 mg), and sodium cyanoborohydride (31.5 mg) were added sequentially to a reaction flask. The mixture was stirred at room temperature. After the reaction was complete, acetic acid was neutralized with 2 mL of saturated sodium bicarbonate solution, followed by extraction with 50 mL of dichloromethane and 100 mL of water. The organic phases were separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography to give compound 32 (44 mg).

[0604] MS(ESI, [M+H)) + m / z: 721.6.

[0605] 1 H NMR (500 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.04 (d, J = 8.2 Hz, 1H), 8.11 (d, J = 8.6 Hz, 1H), 7.86 (dd, J = 8.8, 5.5 Hz, 2H), 7.81 (s, 1H), 7.40(s, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.17 – 7.10 (m, 2H), 4.58 – 4.51 (m, 1H), 4.11 (dd, J = 12.0, 4.9 Hz, 1H), 3.92 (d, J = 9.3 Hz, 1H), 3.20 – 3.10 (m,2H), 3.02 (d, J = 31.3 Hz, 3H), 2.88 (d, J = 14.3 Hz, 2H), 2.81 – 2.70 (m,2H), 2.57 (d, J = 18.2 Hz, 1H), 2.42 – 2.34 (m, 2H), 2.30 (dt, J = 12.6, 6.3Hz, 1H), 2.13 (d, J = 13.3 Hz, 5H), 1.92 (d, J = 12.5 Hz, 6H), 1.70 (q, J =12.4 Hz, 2H), 1.53 (q, J = 12.1 Hz, 2H). Example 33 Synthesis of Compound 33

[0606]

[0607] Intermediate 29a (50 mg), 1,2-dichloroethane (5 mL), isopropanol (1 mL), intermediate 30f (73.5 mg), and sodium cyanoborohydride (31.5 mg) were added sequentially to a reaction flask. The mixture was stirred at room temperature. After the reaction was complete, acetic acid was neutralized with 2 mL of saturated sodium bicarbonate solution, followed by extraction with 50 mL of dichloromethane and 100 mL of water. The organic phases were separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography to give compound 33 (37 mg).

[0608] MS(ESI, [M+H)) + m / z: 721.6.

[0609] 1 H NMR (500 MHz, DMSO-d6) δ 10.88 (s, 1H), 9.03 (d, J = 8.2 Hz, 1H), 8.11 (d, J = 8.7 Hz, 1H), 7.86 (dd, J = 8.8, 5.2 Hz, 2H), 7.81 (s, 1H), 7.40(d, J = 2.4 Hz, 1H), 7.34 (d, J = 7.9 Hz, 1H), 7.17 – 7.10 (m, 2H), 4.55 (dq,J = 10.9, 6.3, 5.4 Hz, 1H), 4.11 (dd, J = 11.8, 4.9 Hz, 1H), 3.95 – 3.88 (m,1H), 3.15 (dq, J = 22.0, 7.4, 6.4 Hz, 2H), 3.02 (d, J = 30.2 Hz, 3H), 2.88(d, J = 13.2 Hz, 2H), 2.81 – 2.77 (m, 1H), 2.75 – 2.68 (m, 1H), 2.57 (d, J =18.0 Hz, 1H), 2.38 (d, J = 7.3 Hz, 2H), 2.30 (td, J = 12.3, 4.2 Hz, 1H), 2.12(d, J = 12.9 Hz, 5H), 1.92 (d, J = 12.3 Hz, 6H), 1.70 (q, J = 12.4 Hz, 2H),1.53 (q, J = 12.1 Hz, 2H). Example 34 Synthesis of Compound 34

[0610]

[0611] Step 1: Preparation of intermediate 34b 34a (3g), DCM (30 mL), and trifluoroacetic acid (5 mL) were added sequentially to the reaction flask and reacted at room temperature. After the reaction was completed, the reaction solution was concentrated to obtain 34b (2.67 g).

[0612] Step 2: Preparation of intermediate 34c 34b (2.67 g), DMSO (30 mL), DIPEA (15 mL), and methyl 6-chloropyridazine-3-carboxylate (2 g) were added sequentially to a reaction flask, and the mixture was reacted at 120 °C. After the reaction was completed, the reaction solution was diluted with ethyl acetate, extracted with saturated potassium carbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 34c (3.1 g).

[0613] MS(ESI, [M+H)) + m / z: 292.18. Step 3: Preparation of intermed...

Claims

1. A compound of formula I-AA, its stereoisomer, or a pharmaceutically acceptable salt thereof, in, Structural fragments Selected from or ; Ring A is selected from C 5-7 Cycloalkenyl or 5-8 membered heterocyclic alkenyl; Each R 1 Independently selected from fluorine, chlorine, bromine, -OH, -NH2, or -CN; n is selected from 0, 1, 2, or 3; L is selected from -Cy 1 -LNK-Cy 2 -LNK 2 -、-Cy 1 -Cy 2 -LNK 2 -、-Cy 1 -LNK-、-Cy 1 -Cy 2 -or-Cy 2 -,in, Cy 1 Selected from one or more R a The following groups are substituted: C 3-12 Cycloalkyl, 4-12 membered heterocyclic alkyl or 4-12 membered heterocyclic alkenyl; Cy 2 Selected from one or more R b The following groups are substituted: C 3-12 Cycloalkyl, 4-12 membered heterocyclic alkyl or 4-12 membered heterocyclic alkenyl; LNK and LNK 2 Selected independently from C 1-3 Alkylene; Each R a and R b Each is independently selected from halogens, -OH, -NH2, -CN, or C. 1-3 alkyl; X 5 Selected from CH or N; X 6 Selected from -O- or -N(CH3)-; Each R 2 R 3 and R 4 Each is independently selected from halogens, -OH, -NH2, -CN, or C. 1-3 alkyl; m, p, and q are each independently selected from 0, 1, 2, 3, or 4; Ring G is selected from phenyl; Ring E is selected from C 4-6 cycloalkyl; Ring F is selected from phenyl or 6-membered heteroaryl; R t Selected from hydrogen.

2. The compound of claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein, Cycle A is selected from C5 cycloalkenyl or 5-8 membered heterocyclic alkenyl; or, Cycle A is selected from cyclopentenyl, monocyclohexenyl, dicyclohexenyl, dihydropyrroleyl, tetrahydropyridyl, tetrahydroazapyryl, azaspirooctenyl, or dihydrooxazinyl.

3. The compound of claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, Structural fragments Selected from , , , , , , , , , , , , ,or ; Or, structural fragments Selected from , , , , , , , , , , , , ,or .

4. The compound of claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, n is selected from 0 or 1; Alternatively, n can be selected from 0.

5. The compound of claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein, Cy 1 Selected from one or more R a Substituted 4-11 membered heterocyclic alkyl groups; Or, Cy 1 Selected from one or more R a The following groups may be substituted: piperidinyl, diazaspirononyl, piperazine, monoazaspirononyl, cyclohexyl, spirononyl, azacyclobutyl, octahydrocyclopentylpyrryl, azabicyclononyl, monoazaspironundecyl, diazaspironundecyl, pyrrylyl, or tetrahydropyridinyl; Or, Cy 1 Selected from one or more R a The following groups are substituted: , , , , , , , , , , , , , , , , or ; Optional, LNK and LNK 2 Each is independently -CH2-; Optional, Cy 2 Selected from one or more R b Substituted 4-11 membered heterocyclic alkyl groups; Or, Cy 2 Selected from one or more R b The following groups may be substituted: cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolidinyl, or piperidinyl; Or, Cy 2 Selected from , , , , , , , , , , , or ; Or, each R a and R b Each is independently selected from halogens, -OH, -NH2, or -CN.

6. The compound of claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein... Ring E is cyclohexyl; optionally, ring F is selected from phenyl, pyridazinyl, pyrimidinyl or pyrazinyl.

7. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, as described in any one of claims 1-6, wherein, Each R 2 Independently selected from halogens, -OH, -NH2, -CN, or C. 1-3 alkyl; Optionally, each R 3 and R 4 Each is independently selected from halogens, -OH, -NH2, -CN, or C. 1-3 alkyl; Or, each R 3 and 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; Alternatively, m can be selected from 1, 2, or 3; Alternatively, m is 2; Optionally, p and q are independently selected from 0, 1, 2 or 3.

8. The compound of claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, The L is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

9. The compound of claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, Ring A is selected from C 5-6 Cycloalkenyl or 5-8 membered heterocyclic alkenyl containing 1-3 heteroatoms selected from N, O or S; Each R 1 It is independently selected from halogens, -OH, -NH2, or -CN; n is selected from 0 or 1; X 5 Selected from CH; X 6 Selected from -O-; Each R 2 R 3 and R 4 Each is independently selected from halogens, -OH, -NH2, -CN, or methyl.

10. The compound of claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein, The compound is selected from the following compounds: or 。 11. A pharmaceutical composition comprising the compound of any one of claims 1-10, its stereoisomer, or a pharmaceutically acceptable salt thereof.

12. Use of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 11, in the preparation of a medicament for the prevention or treatment of a disease by means of degradation of a target protein bound to a target ligand.

13. Use of the compound of any one of claims 1-10, its stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of claim 11 in the preparation of a treatment for the prevention or treatment of AR-related diseases.

14. The use as described in claim 12 or 13, wherein, The disease or condition is selected from cancer; or, the disease or condition is selected from prostate cancer.

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