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, such as cancer. # imgabs0 #

Description

Compounds containing cyclohexyl groups

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and the benefit of the following Chinese patent applications filed with the State Intellectual Property Office of China, the contents of which are incorporated herein by reference in their entirety:

[0003] Chinese patent application No. 202211000005.5 filed on August 19, 2022;

[0004] Chinese patent application No. 202310206412.X filed on January 16, 2023; and

[0005] Chinese patent application No. 202310996368.7 filed on August 8, 2023. Technical Field

[0006] The present application relates to a cyclohexyl-containing compound, a preparation method thereof, a pharmaceutical composition containing the compound, and its use in treating related diseases (such as cancer). Background Art

[0007] The androgen receptor (AR) belongs to the steroid receptor family of the nuclear receptor superfamily. Upon binding to androgens (such as testosterone and dihydrotestosterone), the AR is released from the heat shock protein complex, undergoes phosphorylation, forms a dimer, and translocates to the cell nucleus, where it binds to associated DNA fragments, thereby stimulating the transcription of its target genes. The transcriptional activity of the AR activated by ligand binding is coordinated by proteins called co-activators. The primary function of AR antagonists is to directly prevent testosterone or dihydrotestosterone from binding to the AR, blocking the effects of androgens on cells. This acts as an anti-androgen and inhibits cell growth, ultimately promoting cell apoptosis and achieving its crucial role in the treatment of prostate cancer.

[0008] PROTAC (proteolysis targeting chimera) molecules are a class of bifunctional compounds that can simultaneously bind to target proteins and E3 ubiquitin ligases. These compounds can induce the recognition of target proteins by the cell's proteasome, causing their degradation and effectively reducing their levels in cells. By introducing ligands that can bind to different target proteins into PROTAC molecules, PROTAC technology has become possible for the treatment of various diseases and has received widespread attention in recent years.

[0009] Detailed Description of the Invention

[0010] In one aspect, the present application relates to a compound of formula I-AA, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0011] in,

[0012] Ring A is absent or selected from C 5-15 Cycloalkenyl, 5-15 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl;

[0013] Ring B is selected from phenyl or 5-6 membered heteroaryl;

[0014] Ring C is selected from 5-6 membered heteroaryl (eg, isoxazolyl or furyl);

[0015] Each R 1 independently selected from halogen, -OH, -NH2, -CN, C 1-10 Alkyl (e.g. C 1-6 Alkyl), C 1-10 Alkoxy (e.g. C 1-6 Alkoxy), or halogenated C 1-10 Alkyl (e.g. halo-C 1-6 Alkyl), the -OH, -NH2, C 1-10 Alkyl (e.g. C 1-6 Alkyl), C 1-10 Alkoxy (e.g. C 1-6 Alkoxy), or halogenated C 1-10 Alkyl (e.g. halo-C 1-6 alkyl) is optionally substituted with one or more substituents;

[0016] n is selected from 0, 1, 2 or 3;

[0017] L is selected from a linking group;

[0018] X 5 selected from CH or N;

[0019] X 6 Selected from -O-, -NH- or -N(C 1-6 alkyl)-, the -NH- or -N(C 1-6 alkyl)-optionally substituted with one or more substituents;

[0020] Each R 2 、R 3 and R 4 are independently selected from halogen, -OH, -NH2, -CN, C 1-10 Alkyl (e.g. C 1-6 Alkyl), C 1-10 Alkoxy (e.g. C 1-6 Alkoxy), or halogenated C 1-10 Alkyl (e.g. halo-C1-6 Alkyl), the -OH, -NH2, C 1-10 Alkyl, C 1-10 Alkoxy or halogenated C 1-10 The alkyl group is optionally substituted with one or more substituents;

[0021] m, p and q are each independently selected from 0, 1, 2, 3 or 4;

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

[0023] Ring E is selected from C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl;

[0024] Ring F is selected from C 6-10 Aryl or 5-10 membered heteroaryl;

[0025] R t Selected from hydrogen, -OH, C 1-6 Alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl, the C 1-6 Alkyl, C 3-10 The cycloalkyl or 3-10 membered heterocycloalkyl group is optionally substituted.

[0026] In some embodiments, Ring A is absent or selected from C 5-10 cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0027] In some embodiments, the ring B is selected from phenyl or 6-membered heteroaryl.

[0028] In some embodiments, the ring C is selected from 5-membered heteroaryl.

[0029] 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.

[0030] In some embodiments, Ring E is selected from C 3-9 In some embodiments, ring E is selected from C 4-9 In some embodiments, ring E is selected from C 4-7 In some embodiments, ring E is selected from C 5-7 In some embodiments, ring E is selected from C 4-6 In some embodiments, Ring E is cyclohexyl.

[0031] In some embodiments, Ring F is selected from C6-10 In some embodiments, ring F is selected from phenyl or 5-6 membered heteroaryl. In some embodiments, ring F is selected from phenyl or 6 membered heteroaryl. In some embodiments, ring F is selected from phenyl, pyridazinyl, pyrimidinyl or pyrazinyl.

[0032] In some embodiments, R t Selected from hydrogen, -OH, C 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted. t Selected from hydrogen, -OH, C 1-3 Alkyl, C 3-4 Cycloalkyl or 3-4 membered heterocycloalkyl, the C 1-3 Alkyl, C 3-4 Cycloalkyl or 3-4 membered heterocycloalkyl is optionally substituted. t Selected from hydrogen or C 1-3 Alkyl (eg, methyl, ethyl, propyl).

[0033] In some embodiments, the above "optionally substituted" or "optionally substituted with one or more substituents" refers to optionally substituted with one or more of the following groups: halogen (eg, fluorine, chlorine, bromine or iodine), CN, OH or NH2.

[0034] In one aspect, the present application relates to a compound of formula I-1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0035] in,

[0036] Ring A is absent or selected from C 5-10 Cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl;

[0037] Ring B is selected from phenyl;

[0038] Ring C is selected from isoxazolyl or furyl;

[0039] Each R 1 independently selected from halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy or halogenated C 1-4 alkyl;

[0040] n is selected from 0, 1, 2 or 3;

[0041] L is selected from a linking group;

[0042] X1 、X 2 、X 3 and X 4 are independently selected from N or CH;

[0043] X 5 selected from CH or N;

[0044] X 6 Selected from -O-, -NH- or -N(C 1-6 alkyl)-;

[0045] Each R 2 、R 3 and R 4 are independently selected from halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy or halogenated C 1-4 alkyl;

[0046] m, p and q are each independently selected from 0, 1, 2, 3 or 4.

[0047] In one aspect, the present application relates to a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0048] in,

[0049] Ring A is absent or selected from C 5-10 Cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl;

[0050] Ring B is selected from phenyl;

[0051] Ring C is selected from isoxazolyl or furyl;

[0052] Each R 1 independently selected from halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy or halogenated C 1-4 alkyl;

[0053] n is selected from 0, 1, 2 or 3;

[0054] L is selected from a linking group;

[0055] X 1 、X 2 、X 3 and X 4 are independently selected from N or CH;

[0056] X 5 selected from CH or N;

[0057] X6 Selected from -O-, -NH- or -N(C 1-6 alkyl)-;

[0058] Each R 2 、R 3 and R 4 are independently selected from halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy or halogenated C 1-4 alkyl;

[0059] m, p and q are each independently selected from 0, 1, 2, 3 or 4.

[0060] In some embodiments, Ring A is absent or selected from C 5-7 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0061] In some embodiments, Ring A is absent or selected from C 5-6 cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0062] In some embodiments, Ring A is absent or selected from C 5-6 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0063] In some embodiments, Ring A is absent or selected from C 5-6 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5 membered heteroaryl.

[0064] In some embodiments, Ring A is absent or selected from C 5-6 In some embodiments, ring A is absent or selected from C5 cycloalkenyl, C6 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl, pyrrolyl, pyrazolyl, furanyl, or oxazolyl. In some embodiments, ring A is absent or selected from C5 cycloalkenyl, C6 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl, pyrrolyl, pyrazolyl, furanyl, or oxazolyl.

[0065] In some embodiments, Ring A is absent or selected from cyclopentenyl, monocyclohexenyl, bicyclohexenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine 1-Hydroxy, ...

[0066] In some embodiments, Ring A is absent or selected from cyclopentenyl, bicyclohexenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine In some embodiments, ring A is selected from monocyclohexenyl, ...

[0067] In some embodiments, Ring A is selected from C 5-6 In some embodiments, ring A is selected from C 5-9 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5 membered heteroaryl.

[0068] In some embodiments, Ring A is selected from C 5-6 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5 membered heteroaryl.

[0069] In some embodiments, Ring A is selected from C 5-9 In some embodiments, ring A is selected from C 5-6 In some embodiments, ring A is selected from C 5-9 In some embodiments, ring A is selected from C 5-6 In some embodiments, ring A is selected from 5-9 membered heterocycloalkenyl.

[0070] In some embodiments, ring A is selected from cyclopentenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine 1-amino-1-amino-2-nitro-1-oxo-1-nitro-2-oxo-1-nitro-3 ...

[0071] In some more specific embodiments, ring A is selected from cyclopentenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine azaspirocyclononenyl or azaspirocyclooctenyl.

[0072] In some more specific embodiments, Ring A is selected from phenyl, pyrrolyl, or pyrazolyl.

[0073] In some embodiments, Ring C is isoxazolyl.In some embodiments, Ring C is furanyl.

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

[0075] In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from Alternatively, a structural fragment Selected from Alternatively, a structural fragment Selected from

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

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

[0078] In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from

[0079] In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from In some more specific embodiments, the structural fragment Selected from Alternatively, a structural fragment Selected from Alternatively, a structural fragment Selected from Alternatively, a structural fragment Selected from

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

[0081] In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from

[0082] In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from In some more specific embodiments, the structural fragment Selected from Alternatively, a structural fragment Selected from Alternatively, a structural fragment Selected from Alternatively, a structural fragment Selected from In some embodiments, the structural fragment Selected from

[0083] In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from

[0084] In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from

[0085] In some more specific embodiments, the structural fragment Selected from Alternatively, a structural fragment Selected from Alternatively, a structural fragment Selected from Alternatively, a structural fragment Selected from

[0086] In some embodiments, each R 1 independently selected from halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3Alkoxy or halogenated C 1-3 In some embodiments, each R 1 In some embodiments, each R 1 In some embodiments, each R 1 are independently selected from fluorine.

[0087] In some embodiments, n is selected from 0, 1, or 2. In some embodiments, n is selected from 0 or 1.

[0088] In some specific embodiments, n is selected from 0.

[0089] In some embodiments, the structural fragment Selected from

[0090] In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from In some more specific embodiments, the structural fragment Selected from Alternatively, a structural fragment Selected from Alternatively, a structural fragment Selected from Alternatively, a structural fragment Selected from

[0091] In some embodiments, the L is selected from C 1-30 Alkylene, C 2-30 Alkenylene or C 2-30 Alkynylidene, the C 1-30 Alkylene, C 2-30 Alkenylene or C 2-30 One or more -CH2- in the alkynylene group may be replaced by -O-, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl, 5-12 membered heteroaryl, -NH-, -N(C 1-6 Alkyl)- or -S-substituted, the C 1-30 Alkylene, C 2-30 Alkenylene or C 2-30 Alkyneylene groups are optionally substituted with one or more substituents.

[0092] In some embodiments, the L is selected from C 1-20 Alkylene, C 2-20 Alkenylene or C 2-20 Alkynylidene, the C 1-20 Alkylene, C 2-20 Alkenylene or C 2-20 One or more -CH2- in the alkynylene group may be replaced by -O-, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-10 Aryl, any 5-10 membered heteroaryl, -NH-, -N(C 1-6 Alkyl)- or -S-substituted, the C 1-20 Alkylene, C 2-20 Alkenylene or C 2-20 Alkyneylene groups are optionally substituted with one or more substituents.

[0093] In some embodiments, the L is selected from C 1-15 Alkylene, C 2-15 Alkenylene or C 2-15 Alkynylidene, the C 1-15 Alkylene, C 2-15 Alkenylene or C 2-15 One or more -CH2- in the alkynylene group may be replaced by -O-, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 4-8 membered heterocycloalkenyl, C 6-8 Aryl, 5-8 membered heteroaryl, -NH-, -N(C 1-4 Alkyl)- or -S-substituted, the C 1-20 Alkylene, C 2-15 Alkenylene or C 2-15 Alkyneylene groups are optionally substituted with one or more substituents.

[0094] In some embodiments, the L is selected from C 1-10 Alkylene, C 2-10 Alkenylene or C 2-10 Alkynylidene, the C 1-10 Alkylene, C 2-10 Alkenylene or C 2-10 One or more -CH2- in the alkynylene group may be replaced by -O-, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, -NH-, -N(C 1-3 Alkyl)- or -S-substituted, the C 1-10 Alkylene, C 2-10 Alkenylene or C 2-10 Alkyneylene groups are optionally substituted with one or more substituents.

[0095] In some embodiments, the L is selected from C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkynylidene, the C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 One or more -CH2- in the alkynylene group may be replaced by -O-, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, -NH-, -N(C 1-3 Alkyl)- or -S-substituted, the C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyneylene groups are optionally substituted with one or more substituents.

[0096] In some embodiments, the L is selected from C 1-4 Alkylene, C 2-4 Alkenylene or C 2-4 Alkynylidene, the C 1-4 Alkylene, C 2-4 Alkenylene or C 2-4 One or more (e.g., one or two, one or three, etc.) -CH2- in the alkynylene group are optionally replaced by -O-, C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, -NH-, -N(C 1-3 Alkyl)- or -S-substituted, the C 1-4 Alkylene, C 2-4 Alkenylene or C 2-4 Alkyneylene groups are optionally substituted with one or more substituents.

[0097] In some embodiments, the L is selected from C 1-6 Alkylene, the C 1-6 One or more -CH2- in the alkylene group is optionally selected from -O-, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, -NH-, -N(C 1-3 Alkyl)- or -S-substituted, the C 1-6 The alkylene group is optionally substituted with one or more substituents.

[0098] In some embodiments, in the definition of L, the substituent is selected from =O, OH, NH2, halogen, CN, C 1-6 Alkyl or C 1-6 In some embodiments, in the definition of L, the substituent is selected from ═O, OH, NH 2 , halogen, or CN.

[0099] In some embodiments, the L is selected from -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -,in,

[0100] Cy 1 Selected from a bond, or optionally one or more R a Substituted with the following groups: C 3-12 Cycloalkyl, 4-12 membered heterocycloalkyl or 4-12 membered heterocycloalkenyl;

[0101] LNK, LNK 1 and LNK 2 are independently selected from a bond, C 1-12 Alkylene or C 1-12 heteroalkylene;

[0102] Cy 2 Selected from a bond, or optionally one or more R b Substituted with the following groups: C 3-12 Cycloalkyl, 4-12 membered heterocycloalkyl or 4-12 membered heterocycloalkenyl;

[0103] Each R a and R b Each independently selected from halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 1-4 Alkylamino, di-C 1-4 Alkylamino, C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl.

[0104] In some embodiments, the L is selected from -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -,in,

[0105] Cy 1 Selected from a bond, or optionally one or more R a Substituted with the following groups: C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl;

[0106] LNK, LNK 1 and LNK 2 are independently selected from a bond, C 1-12 Alkylene or C 1-12 heteroalkylene;

[0107] Cy 2Selected from a bond, or optionally one or more R b Substituted with the following groups: C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl;

[0108] Each R a and R b Each independently selected from halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 1-4 Alkylamino, or di-C 1-4 Alkylamino.

[0109] In some embodiments, the L is selected from -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -, where Cy 1 and Cy 2 Not a key at the same time.

[0110] In some embodiments, 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 -.

[0111] In some embodiments, L is selected from -Cy 1 -LNK-Cy 2 -or-Cy 1 -Cy 2 -LNK 2 In some embodiments, L is selected from -Cy 1 -LNK-Cy 2 In some embodiments, L is selected from -Cy 1 -Cy 2 -LNK 2In some embodiments, L is selected from -Cy 1 -LNK-Cy 2 -LNK 2 -.

[0112] In some embodiments, 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 embodiments, L or -Cy 1 -LNK-Cy 2 -Selected from-Cy 1 -、-Cy 1 -Cy 2 -or-Cy 2 -. In some embodiments, L or -Cy 1 -LNK-Cy 2 -Selected from-Cy 1 -LNK-, -Cy 1 -LNK-Cy 2 -or-LNK-Cy 2 -. In some embodiments, L or -Cy 1 -LNK-Cy 2 -Selected from-Cy 1 -LNK-. In some embodiments, L or -Cy 1 -LNK-Cy 2 -Selected from-Cy 1 -LNK-Cy 2 -. In some embodiments, L or -Cy 1 -LNK-Cy 2 -Selected from-LNK-Cy 2 -. In some embodiments, Cy 1 Selected from optionally one or more R a Substituted with the following groups: C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl; Cy 2 Selected from a bond, or optionally one or more R b Substituted with the following groups: C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl.

[0113] In some embodiments, LNK, LNK1 and LNK 2 In some embodiments, LNK 1 is the key.

[0114] In some embodiments, LNK is selected from C 1-6 Alkylene or C 1-6 Heteroalkylene, LNK 1 and LNK 2 is the key.

[0115] In some embodiments, LNK 2 Selected from C 1-6 Alkylene or C 1-6 Heteroalkylene, LNK and LNK 1 is the key.

[0116] In some embodiments, LNK 1 and LNK 2 Selected from the bond, LNK selected from the bond or C 1-6 Alkylene or C 1-6 Heteroalkylene, and Cy 2 is the key, Cy 1 Selected from optionally one or more R a Substituted with the following groups: C 4-11 cycloalkyl or 4-11 membered heterocycloalkyl.

[0117] In some embodiments, LNK is selected from C 1-6 Alkylene or C 1-6 Heteroalkylene, LNK 1 and LNK 2 is the key;

[0118] Cy 2 is the key, Cy 1 Selected from optionally one or more R a Substituted with the following groups: C 4-11 cycloalkyl or 4-11 membered heterocycloalkyl.

[0119] In some embodiments, LNK is selected from C 1-6 Alkylene or C 1-6 Heteroalkylene, LNK 1 and LNK 2 is the key;

[0120] Cy 1 is the key, Cy 2 Selected from optionally one or more R b Substituted with the following groups: C 4-11 cycloalkyl or 4-11 membered heterocycloalkyl.

[0121] In some embodiments, LNK is selected from C 1-6 Alkylene or C 1-6 Heteroalkylene, LNK 1 and LNK 2 is the key;

[0122] Cy 1 Selected from optionally one or more R a Substituted with the following groups: C 4-11 Cycloalkyl or 4-11 membered heterocycloalkyl, Cy 2 Selected from optionally one or more R b Substituted with the following groups: C 4-11 cycloalkyl or 4-11 membered heterocycloalkyl.

[0123] In some embodiments, Cy 1 is a bond, or optionally one or more R a Substituted with the following groups: C 4-11 cycloalkyl, 4-11 membered heterocycloalkyl or 4-11 membered heterocycloalkenyl.

[0124] In some embodiments, Cy 1 In some embodiments, Cy 1 Selected from optionally one or more R a Substituted with the following groups: C 6-9 cycloalkyl, 4-11 membered heterocycloalkyl or 4-9 membered heterocycloalkenyl (e.g., 5-7 membered heterocycloalkenyl).

[0125] In some embodiments, Cy 1 Selected from optionally one or more R a Substituted: C6 cycloalkyl, C9 cycloalkyl, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered or 11-membered heterocycloalkyl, or 6-membered heterocycloalkenyl.

[0126] In some embodiments, Cy 1 Selected from optionally one or more R a The following groups are substituted: C6 cycloalkyl, C9 cycloalkyl, 4-membered, 6-membered, 8-11-membered heterocycloalkyl or 5-6-membered heterocycloalkenyl. In some embodiments, Cy 1 Selected from optionally one or more R a Substituted: C6 cycloalkyl, C9 cycloalkyl, 4-membered, 6-membered, 8-11-membered heterocycloalkyl or 6-membered heterocycloalkenyl.

[0127] In some embodiments, Cy 1 is selected from a bond, or optionally replaced by one or more R a Substituted with the following groups: C 4-11cycloalkyl or 4-11 membered heterocycloalkyl.

[0128] In some embodiments, Cy 1 In some embodiments, Cy 1 Selected from optionally one or more R a Substituted with the following groups: C 6-9 cycloalkyl or 4-11 membered heterocycloalkyl.

[0129] In some embodiments, Cy 1 Selected from optionally one or more R a Substituted: C6 cycloalkyl, C9 cycloalkyl, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered or 11-membered heterocycloalkyl.

[0130] In some embodiments, Cy 1 Selected from optionally one or more R a The following groups are substituted: C6 cycloalkyl, C9 cycloalkyl, 4-membered, 6-membered, or 8-11-membered heterocycloalkyl. In some embodiments, Cy 1 Selected from optionally one or more R a Substituted with the following groups: 4-membered or 5-membered heterocycloalkyl. In some embodiments, Cy 1 Selected from optionally one or more R a Substituted with the following groups: 6-9 membered heterocycloalkyl. In some embodiments, Cy 1 Selected from optionally one or more R a Substituted with the following groups: 6-membered, 8-membered or 9-membered heterocycloalkyl. In some specific embodiments, Cy 1 Selected from optionally one or more R a Substituted: 6-membered heterocycloalkyl or 9-membered heterocycloalkyl.

[0131] In some embodiments, Cy 1 Selected from optionally one or more R a Substituted from the following groups: piperidinyl, diazaspironanyl, piperazinyl, monoazaspironanyl, cyclohexyl, spironanyl, azetidinyl, pyrrolidinyl, octahydrocyclopentapyrrolyl, azabicyclononanyl, monoazaspiroundecyl, diazaspiroundecyl or tetrahydropyridinyl.

[0132] In some embodiments, Cy 1 Selected from optionally one or more R asubstituted with the following groups: piperidinyl, diazaspironanyl, piperazinyl, monoazaspironanyl, cyclohexyl, spironanyl, azetidinyl, octahydrocyclopentylpyrrolyl, azabicyclononanyl, monoazaspiroundecyl or diazaspiroundecyl. In some embodiments, Cy 1 Selected from optionally one or more R a In some embodiments, Cy 1 Selected from optionally one or more R a Substituted: azetidinyl, pyrrolidinyl or tetrahydropyridinyl.

[0133] In some embodiments, Cy 1 Selected from optionally one or more R a Substituted with the following groups:

[0134] In other embodiments, Cy 1 Selected from optionally one or more R a Substituted with the following groups:

[0135] In some embodiments, Cy 1 Selected from optionally one or more R a Substituted with the following groups: In some embodiments, Cy 1 Selected from optionally one or more R a Substituted with the following groups:

[0136] In some embodiments, LNK, LNK 1 and LNK 2 are independently selected from a bond, C 1-6 Alkylene or C 1-6 Heteroalkylene.

[0137] In some embodiments, LNK, LNK 1 and LNK 2 are independently selected from a bond, C 1-3 Alkylene or C 1-3 Heteroalkylene.

[0138] In some embodiments, LNK, LNK 1 and LNK 2 are independently selected from a bond or C 1-4 Alkylene.

[0139] In some embodiments, LNK, LNK 1 and LNK 2 are independently selected from a bond or C 1-3 Alkylene.

[0140] In some embodiments, LNK, LNK 1 and LNK 2 In some embodiments, LNK is a bond. In some embodiments, LNK, LNK 1 and LNK 2 Each independently represents -CH2-.

[0141] In some embodiments, Cy 2 is selected from a bond, or optionally replaced by one or more R b Substituted with the following groups: C 4-11 In some embodiments, Cy 2 In some embodiments, Cy 2 Selected from optionally one or more R b Substituted with the following groups: C 4-11 cycloalkyl or 4-11 membered heterocycloalkyl.

[0142] In some embodiments, Cy 2 is selected from a bond, or optionally replaced by one or more R b Substituted with the following groups: C 4-6 Cycloalkyl or 4-6 membered heterocycloalkyl. In some embodiments, Cy 2 Selected from optionally one or more R b Substituted with the following groups: C 4-6 Cycloalkyl or 4-6 membered heterocycloalkyl.

[0143] In some embodiments, Cy 2 is selected from a bond, or optionally replaced by one or more R b In some embodiments, Cy is substituted with cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl or piperidinyl. 2 is selected from a bond, or optionally replaced by one or more R b Substituted from the following groups: cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl or piperidinyl.

[0144] In some embodiments, Cy 2 Select from key, In some embodiments, Cy 2 Select from key,

[0145] In some embodiments, R a and R b Each independently selected from halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, C 1-3 Alkylamino, or di-C 1-3 Alkylamino.

[0146] In some embodiments, R a and R b Each independently selected from halogen, -OH, -NH2, -CN or C 1-3 alkyl.

[0147] In some embodiments, R a and R b Each is independently selected from halogen, -OH, -NH2 or -CN.

[0148] In some embodiments, the structural fragment -Cy 1 -LNK-Selected

[0149] In other embodiments, the structural fragment -Cy 1 -LNK-Selected

[0150] In some embodiments, the structural fragment -Cy 1 -LNK-Selected In some embodiments, the structural fragment -Cy 1 -LNK-Selected

[0151] In other embodiments, the structural fragment-LNK-Cy 2 - is selected from a bond, -CH2-,

[0152] In some embodiments, the structural fragment -LNK-Cy 2 - is selected from a bond, -CH2-,

[0153] In some embodiments, the structural fragment -Cy 1 -Cy 2 -Selected

[0154] In other embodiments, the structural fragment -Cy 1 -Cy 2 -Selected

[0155] In some embodiments, the structural fragment -Cy 1 -Cy 2 -Selected

[0156] In some embodiments, the structural fragment -Cy 1 -Cy 2 -LNK 2 -Selected

[0157] In some embodiments, the structural fragment or -Cy 1 -Cy 2 -LNK 2 -Selected

[0158] In some embodiments, the structural fragment -L- or -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -Selected

[0159] In other embodiments, the structural fragment -L- or -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -Selected

[0160] In some embodiments, the structural fragment -L- or -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -Selected

[0161] In some embodiments, the structural fragment Selected from

[0162] In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from

[0163] In some embodiments, X 1 、X 2 and X 3 are independently selected from N or CH, X 4 In some embodiments, X 1 and X 2 are independently selected from N or CH, X 3 and X 4 In some embodiments, X 1 and X 2 N, X are independently 3 and X 4 In some embodiments, X 1 、X 2 、X 3 and X 4 In some embodiments, X 1 and X 4 CH, X 2 and X 3 is N. In some embodiments, X 2 and X 3 are independently CH, X 1 and X 4 is N. In some embodiments, X 1 and X 3 are independently CH, X 2 and X 4 is N. In some embodiments, X 2 and X 3 are independently selected from N or CH, X 1 and X 4 In some embodiments, X 1 and X 3 are independently selected from N or CH, X 2 N, X 4 For CH.

[0164] In some embodiments, X5 For CH.

[0165] In some embodiments, X 6 Selected from -O-, -NH- or -N(C 1-3 In some embodiments, X 6 Selected from -O- or -N(CH3)-.

[0166] In some embodiments, each R 2 independently selected from halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy or halogenated C 1-3 In some embodiments, each R 2 independently selected from halogen, -OH, -NH2, -CN or C 1-3 In some embodiments, each R 2 In some embodiments, each R 2 In some embodiments, each R 2 are independently selected from chloro or -CN.

[0167] In some embodiments, each R 4 independently selected from halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy or halogenated C 1-3 In some embodiments, each R 4 independently selected from halogen, -OH, -NH2, -CN or C 1-3 In some embodiments, each R 4 are independently selected from fluorine, chlorine, bromine, -OH, -NH2 or -CN.

[0168] In some embodiments, m is selected from 0, 1, 2, or 3. In some embodiments, m is selected from 1, 2, or 3. In some embodiments, m is 2. In some embodiments, q is selected from 0, 1, 2, or 3. In some embodiments, q is selected from 0 or 1. In some embodiments, q is 0.

[0169] In some embodiments, the structural fragment for

[0170] In some embodiments, each R 3 and R 4 are independently selected from halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3Alkoxy or halogenated C 1-3 In some embodiments, each R 3 and R 4 are independently selected from halogen, -OH, -NH2, -CN or C 1-3 In some embodiments, each R 3 and R 4 are independently selected from fluorine, chlorine, bromine, -OH, -NH2 or -CN.

[0171] In some embodiments, p and q are each independently selected from 0, 1, 2, or 3. In some embodiments, p and q are each independently selected from 0 or 1. In some embodiments, p and q are each 0.

[0172] In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from Optionally, in the structure fragment P a R 3 Substitution, where p and R 3 The definition of is as described in this application.

[0173] In some embodiments, the structural fragment Selected from Optionally, in the structure fragment P a R 3 Substitution, where p and R 3 The definition of is as described in this application.

[0174] In some embodiments, the structural fragment Selected from Optionally, in the structure fragment P a R 3 Substitution, where p and R 3 The definition of is as described in this application.

[0175] In some embodiments, the structural fragment Selected from Optionally, in the structure fragment P a R 3 Substitution, where p and R 3 The definition of is as described in this application.

[0176] In some embodiments, the structural fragment Selected from Optionally, in the structure fragment P a R 3 Substitution, where p and R 3 The definition of is as described in this application.

[0177] In some embodiments, the structural fragment Selected from Optionally, in the structure fragment P a R 3 Substitution, where p and R 3 The definition of is as described in this application.

[0178] In some embodiments, the structural fragment Selected from Alternatively, a structural fragment Selected from Alternatively, a structural fragment Selected from Optionally, in the structure fragment P a R 3 Substitution, where p and R 3 The definition of is as described in this application.

[0179] In some embodiments, the above-mentioned heterocycloalkenyl, heteroaryl, heterocycloalkyl or heteroalkylene group contains one or more heteroatoms or heteroatoms independently selected from -O-, -NH-, -N-, -S-, C=O, -C(=O)NH-, -C(=O)O-, -S(=O)- or -S(=O)2-; in some embodiments, the above-mentioned heterocycloalkenyl, heteroaryl, heterocycloalkyl or heteroalkylene group contains one or more heteroatoms or heteroatoms independently selected from -O-, -NH-, -N- or -S-; in some embodiments, the above-mentioned heterocycloalkenyl, heteroaryl, heterocycloalkyl or heteroalkylene group contains one or more heteroatoms or heteroatoms independently selected from -O-, -NH- or -N-. In some embodiments, the number of the heteroatoms or heteroatoms is independently selected from 1, 2, 3, 4, 5 or 6; or selected from 1, 2, 3 or 4; or selected from 1, 2 or 3; or selected from 1 or 2.

[0180] In some embodiments, the heteroatoms in the heterocycloalkenyl group are selected from N, NH, O, or S. In some embodiments, the heteroatoms in the heterocycloalkenyl group are selected from N, O, or S. In some specific embodiments, the heteroatoms in the heterocycloalkenyl group are selected from N or O. In some embodiments, the number of heteroatoms in the heterocycloalkenyl group is selected from 1, 2, 3, 4, 5, or 6. In some embodiments, the number of heteroatoms in the heterocycloalkenyl group is selected from 1, 2, 3, or 4. In some embodiments, the number of heteroatoms in the heterocycloalkenyl group is selected from 1, 2, or 3. In some specific embodiments, the number of heteroatoms in the heterocycloalkenyl group is selected from 1 or 2.

[0181] In some embodiments, the heterocycloalkenyl 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 heterocycloalkyl 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-.

[0182] It should be understood that any embodiment of the compounds of the present application as described above and the specific X in the compounds of the present application as described above are 1 、X 2 、X 3 、X 4 、X 5 、X 6 , Ring A, Ring B, Ring C, Ring E, Ring F, Ring G, R 1 、R 2 、R 3 、R 4 、R t Any specific substituent described for the L substituent may be independently combined with other embodiments of the present application and / or substituents of the compound to form embodiments of the present invention not specifically described above. In addition, any specific X in the specific embodiments and / or claims may be combined with other substituents of the compound to form embodiments of the present invention not specifically described above. 1 、X 2 、X 3 、X 4 、X 5 、X 6 , Ring A, Ring B, Ring C, Ring E, Ring F, Ring G, R 1 、R 2 、R 3 、R 4 、R t, L substituents When a substituent range is disclosed, it should be understood that one or more substituents can be deleted from the range, and the remaining substituent range should also be considered an embodiment of the present application.

[0183] The compound of formula I-AA, the compound of formula I-1 or the compound of formula I, their stereoisomers or pharmaceutically acceptable salts thereof are selected from the compound of formula I-A1 or the compound of formula IA, their stereoisomers or pharmaceutically acceptable salts thereof,

[0184] Among them, ring A, ring B, ring C, 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.

[0185] In some embodiments, the structural fragment As described in this application.

[0186] The compound of formula I-AA, the compound of formula I-1 or the compound of formula I described herein, a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of formula I-1A, formula I-2A, formula I-3A, formula I-4A, formula I-5A, formula I-6A, formula I-7A, formula I-8A, formula I-9A, formula I-10A, formula I-11A, formula I-12A, formula I-13A, formula I-14A, formula I-15A, formula I-16A or formula I-17A, a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0187] Among them, ring A, ring B, ring C, 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 Definitions as described in this application;

[0188] X is selected from CH or N.

[0189] The compound of formula I-AA, formula I-1, formula I, or formula IA described herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of formula I-1A-1, formula I-2A-1, formula I-3A-1, formula I-4A-1, formula I-5A-1, formula I-6A-1, formula I-7A-1, formula I-8A-1, formula I-9A-1, formula I-10A-1, formula I-11A-1, formula I-12A-1, formula I-13A-1, formula I-14A-1, formula I-15A-1, formula I-16A-1, or formula I-17A-1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0190] Among them, ring A, ring B, ring C, R 1 、R 2 ,m,n,X 1 、X 2 、X 3 、X 5 、X 6 、Cy 1 、Cy 2 、LNK、LNK 1 、LNK 2 Definitions as described in this application;

[0191] X is selected from CH or N.

[0192] In some embodiments, X 1 and X 2 CH, X 3 In some embodiments, X 1 and X 2 N, X 3 In some embodiments, X 2 and X 3 N, X 1 For CH.

[0193] In some embodiments, X 1 and X 2 In some embodiments, X 1 and X 2 is N.

[0194] In some embodiments, the structural fragment Selected from Alternatively, a structural fragment Selected from Alternatively, a structural fragment Selected from Alternatively, a structural fragment Selected from Alternatively, a structural fragment Selected from Alternatively, a structural fragment Selected from

[0195] In some embodiments, the structural fragment Selected from Alternatively, it is selected from Alternatively, it is selected from

[0196] In some embodiments, the structural fragment -Cy 1 -LNK-, -LNK-Cy 2 -、-Cy 1 -Cy 2 -or-Cy 1 -LNK-Cy 2 -As mentioned above.

[0197] In some embodiments, optionally, the compound described herein is not the following compound:

[0198] In some embodiments, optionally, the compound described herein is not the following compound:

[0199] In some embodiments, the structural moiety Not selected

[0200] In some embodiments, the structural moiety Not selected

[0201] In some embodiments, the structural moiety Not selected In some embodiments, the structural moiety Not selected

[0202] In some embodiments, the structural fragment Not selected In some embodiments, the structural fragment Not selected In some embodiments, the structural fragment Not selected

[0203] In another aspect, the present application relates to a compound of formula I' or I", a moiety, a stereoisomer, a derivative thereof (particularly a Protac molecule) or a pharmaceutically acceptable salt thereof,

[0204] wherein ring A is absent or selected from C 5-10 Cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl;

[0205] Ring B is selected from phenyl;

[0206] Ring C is selected from isoxazolyl or furyl;

[0207] L is selected from a linking group; optionally, L is as defined herein; optionally, R 1 and n are as defined in this application.

[0208] In some embodiments, the moiety As described in this application.

[0209] In another aspect, the present application relates to a compound of formula I'-a or I"-a, a moiety, a stereoisomer, a derivative thereof (particularly a Protac molecule) or a pharmaceutically acceptable salt thereof,

[0210] wherein ring A is absent or selected from C 5-10 Cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl;

[0211] Ring B is selected from phenyl;

[0212] Ring C is selected from isoxazolyl or furyl;

[0213] Each R 1a independently selected from halogen, -OH, -NH2, -CN, =O, -CHO, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-6 Alkyl OC(O)-, C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl, the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-12Cycloalkyl or 4-12 membered heterocycloalkyl is optionally substituted with one or more of the following groups: halogen, =O, -OH, -NH2, -CN, CHO, COOH, -C 1-4 Alkyl-OH, C 1-6 Alkyl OC(O)-, or optionally C 1-6 AlkylCOC(O)-substituted 4-10 membered heterocycloalkyl;

[0214] n is selected from 0, 1, 2 or 3.

[0215] In some embodiments, Ring A is absent or selected from C 5-7 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0216] In some embodiments, Ring A is absent or selected from C 5-6 cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0217] In some embodiments, Ring A is absent or selected from C 5-6 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0218] In some embodiments, Ring A is absent or selected from C 5-6 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5 membered heteroaryl.

[0219] In some embodiments, Ring A is absent or selected from C 5-6 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl, pyrrolyl, pyrazolyl, furyl, or oxazolyl.

[0220] In some embodiments, Ring A is absent or selected from C5 cycloalkenyl, C6 cycloalkenyl, 5-membered, 6-membered, 7-membered, 8-membered, or 9-membered heterocycloalkenyl, phenyl, pyrrolyl, pyrazolyl, furanyl, or oxazolyl.

[0221] In some embodiments, Ring A is absent or selected from cyclopentenyl, monocyclohexenyl, bicyclohexenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine 1-Hydroxy, ...

[0222] In some embodiments, Ring A is selected from C 5-9 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5 membered heteroaryl.

[0223] In some embodiments, Ring A is selected from C 5-6 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5 membered heteroaryl.

[0224] In some embodiments, Ring A is selected from C 5-9 In some embodiments, ring A is selected from C 5-6 cycloalkenyl or 5-9 membered heterocycloalkenyl.

[0225] In some embodiments, Ring A is selected from C 5-9 In some embodiments, ring A is selected from C 5-6 In some embodiments, ring A is selected from 5-9 membered heterocycloalkenyl.

[0226] In some embodiments, ring A is selected from cyclopentenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine 1-amino-1-amino-2-nitro-1-oxo-1-nitro-2-oxo-1-nitro-3 ...

[0227] In some embodiments, ring A is selected from cyclopentenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine In some embodiments, ring A is selected from cyclopentenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazacyclopentenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydropyrrol ... Base or azaspirocyclooctene.

[0228] In some specific embodiments, Ring A is selected from cyclopentenyl. In some specific embodiments, Ring A is selected from dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine Base or azaspirocyclooctene.

[0229] In some embodiments, Ring A is selected from phenyl, pyrrolyl, or pyrazolyl.

[0230] In some embodiments, wherein Ring A is selected from

[0231] In some embodiments, Ring C is isoxazolyl.In some embodiments, Ring C is furanyl.

[0232] In some embodiments, the moiety Selected from

[0233] In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from Alternatively, a structural fragment Selected from Alternatively, a structural fragment Selected from

[0234] In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from Alternatively, a structural fragment Selected from Alternatively, a structural fragment Selected from

[0235] In some embodiments, the structural fragment Selected from

[0236] In some embodiments, the structural fragment Selected from In some more specific embodiments, the structural fragment Selected from Alternatively, a structural fragment Selected from

[0237] In some embodiments, the structural fragment Selected from

[0238] In some embodiments, the structural fragment Selected from In some more specific embodiments, the structural fragment Selected from Alternatively, a structural fragment Selected from

[0239] In some embodiments, each R 1a independently selected from halogen, -OH, -NH2, -CN, -CHO, C 1-6 Alkyl OC(O)-, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-10 Cycloalkyl or 4-10 membered heterocycloalkyl, the C1-4 Alkyl, C 1-4 Alkoxy, C 3-10 Cycloalkyl or 4-10 membered heterocycloalkyl is optionally substituted with one or more of the following groups: halogen, =O, -OH, -NH2, -CN, CHO, COOH, -C 1-4 Alkyl-OH, C 1-6 Alkyl OC(O)-, or optionally C 1-6 AlkylCOC(O)-substituted 4-10 membered heterocycloalkyl.

[0240] In some embodiments, each R 1a independently selected from halogen, -OH, -NH2, -CN, -CHO, C 1-4 Alkyl OC(O)-, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-9 Cycloalkyl or 4-9 membered heterocycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-9 Cycloalkyl or 4-9 membered heterocycloalkyl is optionally substituted with one or more of the following groups: halogen, -OH, =O, -NH2, -CN, CHO, COOH or -C 1-4 Alkyl-OH, C 1-4 Alkyl OC(O)-, or optionally C 1-4 AlkylCOC(O)-substituted 4-9 membered heterocycloalkyl.

[0241] In some embodiments, each R 1a independently selected from halogen, -OH, -NH2, -CN, -CHO, C 1-6 Alkyl OC(O)-, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 4-6 Cycloalkyl or 4-6 membered heterocycloalkyl is optionally substituted with one or more of the following groups: halogen, -OH, =O, -NH2, -CN, CHO, COOH, -C 1-4 Alkyl-OH, C 1-6 Alkyl OC(O)-, or optionally C 1-6 AlkylCOC(O)-substituted 3-6 membered heterocycloalkyl.

[0242] In some embodiments, each R 1a independently selected from halogen, -OH, -NH2, -CN, -CHO, C 1-4 Alkyl OC(O)-, C1-3 Alkyl or 4-6 membered heterocycloalkyl, the C 1-3 Alkyl or 4-6 membered heterocycloalkyl is optionally substituted with one or more of the following groups: -OH, =O, -NH2, -CN, CHO, COOH, C 1-4 Alkyl OC(O)-, or optionally C 1-4 AlkylOC(O)-substituted 4-6 membered heterocycloalkyl.

[0243] In some embodiments, each R 1a Independently selected from halogen, -OH, -CHO, (CH3)3COC(O)-, C 1-3 Alkyl, cyclobutyl or piperidinyl, the C 1-3 The alkyl, cyclobutyl, or piperidinyl group is optionally substituted with one or more of the following: -OH, (CH3)3COC(O)-, or cyclobutyl optionally substituted with (CH3)3COC(O)-.

[0244] In some embodiments, each R 1a Independently selected from F, -OH, -CHO, (CH3)3COC(O)-, -CH2OH,

[0245] In some embodiments, n is selected from 0, 1, or 2. In some embodiments, n is selected from 0 or 1. In some embodiments, n is 0.

[0246] The present application relates to the following compounds, moieties, stereoisomers, derivatives thereof (particularly such as Protac molecules) or pharmaceutically acceptable salts thereof,

[0247] or,

[0248] On the other hand, the present application relates to the use of the compound (e.g., Formula I' or Formula I" or I'-a or Formula I"-a or specific compound), part, its isomer (such as stereoisomer), and its derivative in the Protac molecule. On the other hand, the present application relates to the use of the compound (e.g., Formula I' or Formula I" or I'-a or Formula I"-a or specific compound), part, its isomer (such as stereoisomer), and its derivative for constituting a part of the Protac molecule. On the other hand, the present application relates to the compound (e.g., Formula I' or Formula I" or I'-a or Formula I"-a or specific compound), part, its isomer (such as stereoisomer), and its derivative in the form of a Protac molecule. On the other hand, the present application relates to the use of the compound (e.g., Formula I' or Formula I" or I'-a or Formula I"-a or specific compound), part, its isomer (such as stereoisomer), and its derivative for degrading proteins, for example, the compound (e.g., Formula I' or Formula I" or I'-a or Formula I"-a or specific compound), part, its isomer (such as stereoisomer), and its derivative degrades the protein in the form of Protac molecules. On the other hand, the present application relates to the use of the compound (e.g., Formula I' or Formula I" or I'-a or Formula I"-a or specific compound), part, its isomer (such as stereoisomer), and its derivative in the form of Protac molecules for degrading proteins. The present application relates to the use of the compound (e.g., Formula I' or Formula I" or I'-a or Formula I"-a or specific compound), part, its isomer (such as stereoisomer), and its derivative (e.g., as a preparation intermediate) in the preparation of Protac molecules. The present application relates to the use of the compound (e.g., Formula I' or Formula I" or I'-a or Formula I"-a or specific compound), part thereof, its isomers (such as stereoisomers), and its derivatives (e.g., as preparation intermediates) in the preparation of protein degraders.

[0249] In some embodiments, the present application relates to a compound of formula I-AA, a compound of formula I, or a compound of formula I-1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0250] Ring A is selected from C 5-6 Cycloalkenyl, 5-8 membered heterocycloalkenyl 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);

[0251] Ring B is phenyl;

[0252] Ring C is selected from isoxazolyl or furyl;

[0253] Each R 1 independently selected from halogen, -OH, -NH2, -CN or C1-3 Alkyl (such as methyl, ethyl, propyl);

[0254] n is selected from 0 or 1;

[0255] L is selected from LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -, LNK, LNK 1 and LNK 2 are independently selected from a bond or C 1-3 Alkylene, Cy 1 Selected from bond, C 3-7 Cycloalkyl, 4-7 membered heterocycloalkyl or 5-7 membered heterocycloalkenyl, Cy 2 Selected from bond, C 3-7 Cycloalkyl, 4-7 membered heterocycloalkyl or 5-7 membered heterocycloalkenyl, and Cy 1 and Cy 2 Not a key at the same time;

[0256] X 1 、X 2 、X 3 and X 4 are independently selected from N or CH;

[0257] X 5 selected from CH or N;

[0258] X 6 Selected from -O-, -NH- or -N(C 1-6 alkyl)-;

[0259] Each R 2 、R 3 and R 4 are independently selected from halogen, -OH, -NH2, -CN or C 1-3 Alkyl (such as methyl, ethyl, propyl);

[0260] m is selected from 1 or 2;

[0261] p and q are each independently selected from 0 or 1.

[0262] In some embodiments, the present application relates to a compound of formula I-AA, a compound of formula I, or a compound of formula I-1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0263] Ring A is selected from cyclopentenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine 1-Hydroxy, ...

[0264] Ring B is phenyl;

[0265] Ring C is selected from isoxazolyl or furyl;

[0266] n is 0;

[0267] L is selected from optionally with C 1-3 Alkylene-linked piperidinyl, diazaspironanyl, piperazinyl, monoazaspironanyl, azetidinyl or tetrahydropyridinyl;

[0268] X 1 、X 2 、X 3 and X 4 All CH, or X 1 、X 2 、X 3 and X 4 Two of them are N and the other two are CH;

[0269] X 5 selected from CH or N;

[0270] X 6 Selected from -O-, -NH- or -N(C 1-4 alkyl)-;

[0271] R 2 is selected from halogen or -CN;

[0272] m is 2;

[0273] p and q are each independently 0.

[0274] The present application also relates to the following compounds, their stereoisomers or pharmaceutically acceptable salts thereof:

[0275] In some embodiments, the pharmaceutically acceptable salt is selected from maleate salts.

[0276] This application also covers solutions obtained by any combination, deletion or replacement of the above embodiments.

[0277] On the other hand, the present application relates to a pharmaceutical composition, which contains the above-mentioned compound of the present application, its stereoisomer or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition of the present application also includes a pharmaceutically acceptable excipient.

[0278] On the other hand, the present application relates to the use of the above-mentioned compound, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for preventing or treating a disease by degrading a target protein (such as androgen receptor, AR) bound to a targeting ligand.

[0279] On the other hand, the present application relates to the use of the above-mentioned compound, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for preventing or treating a disease that is treated by binding to a cerebellar protein in vivo.

[0280] On the other hand, the present application relates to the use of the above-mentioned compound, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for preventing or treating AR-related diseases.

[0281] The present application relates to a method for treating or preventing a disease in a mammal by degrading a target protein (such as androgen receptor, AR) bound to a targeting ligand, comprising administering a therapeutically effective amount of the above-mentioned compound of the present application, its stereoisomer or pharmaceutically acceptable salt, or a pharmaceutical composition thereof to a mammal (preferably a human) in need of such treatment.

[0282] The present application relates to a method for treating or preventing a disease that is treated by binding to a cerebellar protein in vivo, comprising administering a therapeutically effective amount of the above-mentioned compound of the present application, its stereoisomer or pharmaceutically acceptable salt, or a pharmaceutical composition thereof to a mammal (preferably a human) in need of such treatment.

[0283] On the other hand, the present application relates to a method for treating AR-related diseases in mammals, comprising administering a therapeutically effective amount of the above-mentioned compound of the present application, its stereoisomer or pharmaceutically acceptable salt, or pharmaceutical composition thereof to a mammal (preferably a human) in need of such treatment.

[0284] On the other hand, the present application relates to the above-mentioned compound, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition for preventing or treating diseases treated by degrading the target protein (such as androgen receptor, AR) bound to the targeting ligand.

[0285] On the other hand, the present application relates to the above-mentioned compound, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition for preventing or treating a disease that is treated by binding to a cerebellar protein in vivo.

[0286] On the other hand, the present application relates to the above-mentioned compound, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition for preventing or treating AR-related diseases.

[0287] On the other hand, the present application relates to the use of the above-mentioned compound, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition in preventing or treating diseases treated by degrading target proteins (such as androgen receptor, AR) bound to targeting ligands.

[0288] On the other hand, the present application relates to the use of the above-mentioned compound, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition in preventing or treating diseases that are treated by binding to cerebellar proteins in vivo.

[0289] On the other hand, the present application relates to the use of the above-mentioned compound, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition in preventing or treating AR-related diseases.

[0290] In some embodiments, the above-mentioned AR-related diseases are selected from disorders treated by degrading and / or inhibiting proteins that bind to AR target protein ligands (androgen receptor, AR); in some embodiments, the above-mentioned AR-related diseases are selected from disorders treated by binding to cerebellar proteins in vivo; in some embodiments, the above-mentioned diseases or disorders are selected from cancer, such as prostate cancer.

[0291] In some embodiments, the above-mentioned conditions treated by binding to cerebellar proteins in vivo and / or the conditions treated by degrading target proteins bound to targeting ligands are selected from AR-related diseases; in some embodiments, the above-mentioned AR-related diseases are selected from cancers, such as prostate cancer.

[0292] As used herein, "one or more" refers to an integer from one to ten. For example, "one or more" refers to one, two, three, four, five, six, seven, eight, nine, or ten; in some embodiments, the "one or more" is selected from one, two, three, four, five, or six. In some embodiments, the "one or more" is selected from one, two, or three. In some embodiments, the "one or more" is selected from one, or two.

[0293] In some aspects, the present application comprises the above-defined variables and embodiments thereof, and any combination thereof.

[0294] Technical Effects

[0295] The compounds of this application have AR degradation activity against VCaP and LNCaP cells and antiproliferative activity against these cells. Furthermore, the compounds of this application exhibit good in vitro liver microsomal stability and pharmacokinetic properties (specifically, parameters such as AUC) in mammals (e.g., mice), and can inhibit tumor growth in vivo, demonstrating promising drug development.

[0296] definition

[0297] Unless otherwise indicated, the following terms used in this application have the following meanings. A particular term should not be construed as undefined or unclear unless specifically defined, but rather should be understood according to its ordinary meaning in the art. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0298] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo (i.e., =O), it means that two hydrogen atoms are replaced. Oxo does not occur on aromatic groups.

[0299] The term "optionally" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes both the occurrence of the event or situation and the non-occurrence of the event or situation. "Optionally substituted" includes unsubstituted and substituted. For example, an ethyl group is "optionally" substituted with a halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (such as CH2CH2F), polysubstituted (such as CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible and / or cannot be synthesized will be introduced.

[0300] In this article, C m-n , means that the moiety has an integer number of carbon atoms in a given range. For example, "C 1-6 ” means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0301] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. For example, if a group contains two R's, each R has an independent option.

[0302] When a bond cross-links two atoms in a ring (including a monocyclic, fused, or spirocyclic ring), the bond can be bonded to any atom in the ring (including a monocyclic, fused, or spirocyclic ring). Indicates that the bonds on both sides can be connected to any two different atoms on ring A, ring B or ring C; for example Indicates that the bonds on both sides can be connected to any two different atoms on ring A, the middle benzene ring or ring C; further, for example It means that the bonds on both sides can be connected to any two different atoms in the four rings in the system.

[0303] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0304] The term "hydroxy" refers to an -OH group.

[0305] The term "amino" refers to a -NH2 group.

[0306] The term "cyano" refers to a -CN group.

[0307] The term "alkyl" refers to a group of the formula C n H 2n+1 The alkyl group may be straight-chain or branched. For example, the term "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 has the same definition as above.

[0308] The term "alkylene" refers to a divalent group formed by removing a hydrogen 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-.

[0309] The term "alkenylene" refers to a divalent group formed by removing a hydrogen atom from any position of an alkenyl group. For example, the term "C2-6 alkenyl" refers to an alkenylene group containing 2 to 6 carbon atoms; the term "C2-4 alkenyl" refers to an alkenylene group containing 2 to 4 carbon atoms, including but not limited to -CH2CH=CH-, -CH2CH2CH=CH- or -CH2CH=CHCH2-.

[0310] The term "alkynylene" refers to a divalent group formed by removing a hydrogen atom from any position of an alkynyl group. For example, the term "C2-6 alkynyl" refers to an alkynylene group containing 2 to 6 carbon atoms; the term "C2-4 alkynyl" refers to an alkynylene group containing 2 to 4 carbon atoms, including but not limited to

[0311] The term "heteroalkyl" refers to a straight or branched chain alkyl group consisting of a certain number of carbon atoms and at least one heteroatom, preferably having 1 to 14 carbon atoms, more preferably 1 to 10 carbon atoms, even more preferably 1 to 6 carbon atoms, most preferably 1 to 3 carbon atoms in the chain, and preferably having 1, 2 or 3 heteroatoms selected from S, O and N. For example, C mHeteroalkyl refers to an alkyl group with heteroatoms inserted in the chain and consisting of m carbon atoms and at least one heteroatom (e.g., 1-3 heteroatoms selected from S, O, and N) located between any two carbon atoms 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 heteroatom group can be located at any internal position of the heteroalkyl group, including the position where the hydrocarbon group is attached to the rest of the molecule; exemplary heteroalkyl groups include alkyl ethers, secondary and tertiary alkylamines, amides, sulfides, and the like, including alkoxy, alkylthio, and alkylamino groups; unless otherwise specified, C 1-6 Heteroalkyl groups include C1, C2, C3, C4, C5 and C6 heteroalkyl groups, such as C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino.

[0312] The term "heteroalkylene" refers to a divalent group formed by removing one hydrogen atom from any position of a heteroalkyl group.

[0313] The term "alkoxy" refers to an -O-alkyl group.

[0314] The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. Non-limiting examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.

[0315] The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and can exist as a monocyclic, bicyclic bridged ring or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 4 to 16-membered ring, a 4 to 12-membered ring, a 4 to 10-membered ring or a 4 to 8-membered ring. Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, etc.

[0316] The term "cycloalkyl" refers to a fully saturated carbocyclic ring that can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically 3 to 16 rings (e.g., 3 to 10 rings, or 5 to 8 rings). Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo [2.2.1] heptyl), bicyclo [2.2.2] octyl, adamantyl, etc.

[0317] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3 to 16-membered ring, a 3-11-membered ring, a 3 to 10-membered ring, a 3 to 7-membered ring, a 3 to 6-membered ring or a 3 to 5-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and / or nitrogen. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxirane, thioethane, and aziridine groups; non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl groups; examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl groups; examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl groups; examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxetanyl, and thiepanyl groups. Preferably, the heterocycloalkyl group is a monocyclic group having 5 or 6 ring atoms.

[0318] The term "spirocycle" refers to a fully saturated or partially unsaturated polycyclic ring system in which the monocyclic rings share a carbon atom (called a spiro atom), including carbocycles and heterocycles. Unless otherwise indicated, the spirocycle is 5 to 20 members, preferably 6 to 14 members, and more preferably 8 to 12 members. When the spirocycle is a heterocycle, one or more ring atoms in the polycyclic ring are selected from N, O, S(O) n 、P(O) n (wherein n is 0, 1 or 2) heteroatoms (preferably 1 or 2 heteroatoms), and the remaining ring atoms are carbon atoms.

[0319] The term "spiroalkyl" refers to a fully saturated, all-carbon polycyclic ring that shares a carbon atom (called a spiro atom) between monocyclic rings. Unless otherwise indicated, the spiroalkyl is 5 to 20 yuan, preferably 6 to 14 yuan, and more preferably 8 to 12 yuan. According to the number of spiro atoms shared between the rings, the spiroalkyl is divided into a single spiroalkyl, a double spiroalkyl or a multi-spiroalkyl, preferably a single spiroalkyl and a double spiroalkyl, more preferably a 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or a 5 yuan / 6 yuan single spiroalkyl. Non-limiting examples of spiroalkyl include

[0320] The term "spiroheterocycloalkyl" refers to a fully saturated polycyclic ring in which the monocyclic rings share a carbon atom (called a spiro atom), and one or more ring atoms in the polycyclic ring are selected from N, O, S(O) n 、P(O) n(wherein n is 0, 1 or 2) heteroatoms (preferably 1 or 2 heteroatoms), and the remaining ring atoms are carbon atoms. Unless otherwise indicated, the spiro heterocycloalkyl is 5 to 20 yuan, preferably 6 to 14 yuan, more preferably 6 to 10 yuan. According to the number of shared spiro atoms between the rings, the spiro heterocycle is divided into a monospiro heterocycle, a dispiro heterocycle or a polyspiro heterocycle, preferably a monospiro heterocycle or a dispiro heterocycle, more preferably a 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or a 5 yuan / 6 yuan monospiro heterocycle. Non-limiting examples of spiro heterocycloalkyl include wait.

[0321] The term "heterocycloalkenyl" includes cycloalkenyl groups in which one or more carbon atoms (e.g., 1-5, 1-4, 1-3, 1-2) are replaced by heteroatoms, such as cycloalkenyl groups in which up to 3 carbon atoms, in one embodiment up to 2 carbon atoms, in another embodiment 1 carbon atom are independently replaced by O, S, S(O) or N, provided that at least one cycloalkenyl carbon-carbon double bond is retained. Cyclic groups that may exist as monocyclic, bridged, or spirocyclic rings may be 3 to 16-membered rings (e.g., 3 to 12-membered, 5 to 8-membered rings, such as 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, or 11-membered rings). Examples of heterocycloalkenyl groups include, but are not limited to, dihydropyrrolyl, tetrahydropyridyl, tetrahydroazepine, pyrrolidine ... Base or azaspirocyclooctene.

[0322] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and 1,2,3,4-tetrahydronaphthalene.

[0323] The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system containing at least one (e.g., 1-5, 1-4, 1-3, 1-2) ring atom selected from N, O, S, with the remaining ring atoms being C, and having at least one aromatic ring. Preferred heteroaryl groups have single 4 to 8-membered rings, especially 5 to 8-membered rings (e.g., 5-, 6-, 7-, or 8-membered), or multiple fused rings containing 6 to 14, especially 6 to 10 (e.g., 6, 7, 8, 9, or 10) ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.

[0324] Unless otherwise specified, the term "hetero" means a heteroatom or heteroatom group (i.e., a group containing heteroatoms), including atoms other than carbon (C) and hydrogen (H) and groups containing these heteroatoms, for example, including oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), silicon (Si), germanium (Ge), aluminum (Al), boron (B), -O-, -S-, =O, =S, -P(=O)-, -P(=O)2-, -P(=O)O-, -P(=O)2O-, -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O)2-, and optionally substituted -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)- or -S(=O)N(H)-.

[0325] The term "derivative" refers to a new compound or a group of new compounds produced by one or more chemical reactions or structural evolution, retaining the basic structure of the parent compound and only undergoing changes or modifications in the side chains, functional groups or substituents.

[0326] The term "substituent", "optionally substituted with one or more substituents" or "optionally substituted" includes all substituents or substituent replacements mentioned herein, for example, the terms "halogen", "deuterium", "-NH2", "-NH(C 1-4 Alkyl)", "-N(C 1-4 Alkyl)2", "-OH", "-OC 1-4 Alkyl", "-CN", "C 1-4alkyl", "3-6 membered heterocycloalkyl", etc., and corresponding non-limiting or exemplary groups, wherein some non-limiting examples of the "substituent" include thiol, nitro, nitroso, cyano, azide, sulfoxide, sulfone, sulfonamide, carboxyl, aldehyde, imine, alkyl, 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, heterocyclyl, heterocyclyloxy, heterocyclylthio, heterocyclylalkylene, heterocyclylalkoxy, heterocyclylalkylthio, acyl, acyloxy, carbamate group, amide group, urea group, epoxy group, ester group and oxygen wherein the substituent is optionally substituted by one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(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, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0327] In some embodiments herein, the substituent is selected from deuterium, tritium, hydroxyl, sulfhydryl, halogen, amino, nitro, nitroso, cyano, azide, sulfoxide, sulfone, sulfone, sulfonamide, carboxyl, aldehyde, imine, C 1-12 Alkyl, 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, halo 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 membered aryl, 6-10 membered aryloxy, 6-10 membered arylthio, 6-10 membered arylC 1-12Alkylene, 6-10 membered aryl C 1-12 Alkoxy, 6-10 membered aryl C 1-12 alkylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, 5-10 membered heteroarylalkylene, 5-10 membered heteroarylalkoxy, 5-10 membered heteroarylalkylthio, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, 3-12 membered heterocyclylthio, 3-12 membered heterocyclylC 1-12 Alkylene, 3-12 membered heterocyclic group C 1-12 Alkoxy, 3-12 membered heterocyclic group C 1-12 Alkylthio, C 1-12 Acyl, C 1-12 Acyloxy, carbamate group, C 1-12 Amide group, urea group, epoxy group, C 2-12 Ester group and oxo, said substituent being optionally substituted by one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, carboxyl, -C(O)OC 1-12 Alkyl, -OC(O)-C 1-12 Alkyl, -C(O)NH2, -C(O)NH-C 1-12 Alkyl, -C(O)N(C 1-12 Alkyl)2, -NHC(O)-C 1-12 Alkyl, -C(O)-C 1-12 Alkyl, -S(O)-C 1-12 Alkyl, -S(O)2-C 1-12 Alkyl, -S(O)2NH2, -S(O)2NH-C 1-12 Alkyl, -S(O)2N(C 1-12 alkyl) 2, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12 Alkylene, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group C 1-12 Alkylene, 3-12 membered heterocyclyloxy, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkylC 1-12 Alkylene, 3-12 membered heterocycloalkyloxy, 5-10 membered heteroaryl, 5-10 membered heteroarylC 1-12Alkylene, 5-10 membered heteroaryloxy, 6-10 membered aryl, 6-10 membered arylC 1-12 an alkylene group or a 6- to 10-membered aryloxy group.

[0328] Unless otherwise specified, the term "hetero" refers to a heteroatom or heteroatom group (i.e., a group containing heteroatoms), including atoms other than carbon (C) and hydrogen (H) and groups containing these heteroatoms. For example, heteroatoms include, but are not limited to, oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), silicon (Si), germanium (Ge), aluminum (Al), and boron (B). Specific heteroatoms or heteroatom groups include: -O-, -S-, -N=, =O, =S, -P(=O)-, -P(=O)2-, -P(=O)O-, -P(=O)2O-, -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, and optionally substituted -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)-, or -S(=O)N(H)-. Preferably, the term "hetero" denotes a heteroatom or a heteroatom group (ie a group containing a heteroatom) wherein the heteroatom is selected from oxygen, nitrogen or sulfur.

[0329] The term "derivative" refers to a new compound or a group of new compounds produced by one or more chemical reactions or structural evolution, retaining the basic structure of the parent compound and only undergoing changes or modifications in the side chains, functional groups or substituents.

[0330] In this application, wavy lines are used represents one of the absolute configurations of a stereocenter (e.g. one, specific express ) or one of the relative configurations (e.g. express When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, they are intended to include both E and Z geometric isomers. Likewise, all tautomeric forms are encompassed within the scope of this application.

[0331] The groups or structural fragments in this application such as -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -、-Cy 1 -Cy 2 -LNK 2 -、LNK、Cy 1 、Cy 2 、-Cy 1 -LNK-Cy 2-、-Cy 1 -LNK- or -LNK-Cy 2 - and its specific options, optionally can be read from left to right, corresponding to the group or fragment in the general formula on the left and right groups connected, for example, when L is selected from -Cy 1 -LNK-Cy 2 -When Cy 1 Selected from Reading from left to right, Cy 1 The left side corresponds to the fragment on the left side of the general formula Connect, right side to right side segment The resulting fragments are Optionally, the groups or structural fragments in this application such as -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -、-Cy 1 -Cy 2 -LNK 2 -、LNK、Cy 1 、Cy 2 、-Cy 1 -LNK-Cy 2 -、-Cy 1 -LNK- or -LNK-Cy 2 - and its specific options, can be read in order from right to left, and are respectively connected to the left and right groups of the group or fragment in the general formula, for example, when L is selected from -Cy 1 -LNK-Cy 2 -When Cy 1 Selected from According to the reading order from right to left, Cy 1 The right side corresponds to the fragment on the left side of the general formula Connect the left side with the corresponding right side fragment in the general formula The fragments formed by the connection are Other groups are the same as described above.

[0332] The term "treating" means administering the compounds or formulations described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes: (i) inhibiting the disease or disease state, i.e., curbing its development; (ii) alleviating the disease or disease state, i.e., causing the disease or disease state to regress.

[0333] The term "prevention" means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, including preventing the occurrence of a disease or disease state in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0334] The term "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and this disclosure.

[0335] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0336] As the pharmaceutically acceptable salt, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned.

[0337] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

[0338] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0339] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0340] Unless the context clearly indicates otherwise, singular terms herein include plural referents and vice versa. Similarly, the word "or" herein is intended to include "and" unless the context clearly indicates otherwise.

[0341] Unless otherwise indicated, all numbers used herein expressing amounts of ingredients, measurements, or reaction conditions are to be understood as modified in all instances by the term "about." When used in conjunction with a percentage, the term "about" can mean, for example, ±1%, preferably ±0.5%, and more preferably ±0.1%.

[0342] The compounds and intermediates of the present application may also exist in different tautomeric forms, and all such forms are included within the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety, in which the proton can migrate between two ring nitrogens. Valence tautomers include interconversions by reorganization of some bonding electrons. For example, any compound of the present disclosure, such as pyrazole alone or as part of a heterocyclic group, may exist as two arbitrary tautomers or as a mixture of any number of two tautomers, i.e. or The present disclosure includes all possible tautomers of the disclosed compounds, either as single tautomers or as any mixture of said tautomers in any ratio.

[0343] The present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0344] Certain isotope-labeled compounds of the present application (e.g. 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays.3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as 15 O. 13 N. 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0345] In addition, the use of heavier isotopes such as deuterium (i.e. 2 H)) substitution may offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium.

[0346] The compounds of the present invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the present invention containing asymmetric carbon atoms can be isolated in optically pure forms or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0347] The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

[0348] Typical routes of administration of the compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0349] The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0350] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, and the like for oral administration to a patient.

[0351] Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be prepared by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients as needed, and then granulating the mixture to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0352] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0353] In all methods of administration described herein, the compounds of formula I are administered at a dosage of 0.01 to 200 mg / kg body weight per day in single or divided doses.

[0354] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0355] The chemical reactions described in the specific embodiments of the present application are carried out in a suitable solvent that is compatible with the chemical transformations described herein and the reagents and materials required. To obtain the compounds described herein, it may sometimes be necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0356] An important consideration in synthetic route planning in this field is the selection of an appropriate protecting group for a reactive functional group (such as an amino group in this application). For example, reference can be made to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.

[0357] In some embodiments, the compound of formula I of the present application can be prepared by a person skilled in the art of organic synthesis through the following route:

[0358] The compound of formula I-1 is subjected to a substitution reaction to obtain the compound of formula I-2, the compound of formula I-2 is subjected to a deprotection reaction to obtain the compound of formula I-3, and then subjected to a condensation reaction to obtain the compound of formula I-4, and the compound of formula I-4 is subjected to an oxidation reaction to obtain the compound of formula I-5; the chlorinated aromatic carboxylic acid is reacted with the hydroxyl-substituted Cy 1 The compound of general formula I-6 is obtained by substitution reaction; the compound of general formula I-7 is obtained by deprotection reaction; finally, the compound of general formula I-5 and the compound of general formula I-7 are subjected to reductive amination reaction to obtain the compound of general formula I.

[0359] The compound of general formula I-3 is reacted with the compound of general formula I-10 to obtain the compound of general formula I-8 through condensation reaction, and the compound of general formula I-8 is reacted with the deprotection group to obtain the compound of general formula I-9; the chlorinated aromatic ring carboxylic acid is reacted with the Boc-protected Cy 1 A substitution reaction is performed to obtain a compound of the general formula I-10; a compound of the general formula I-11 is obtained by an oxidation reaction; a compound of the general formula I-9 and a compound of the general formula I-11 are subjected to a reductive amination reaction to obtain a compound of the general formula I.

[0360] This application uses the following abbreviations:

[0361] 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(dibenzylideneacetone)dipalladium; THF represents tetrahydrofuran; PMB represents p-methoxybenzyl; MeOH represents methanol; PE represents petroleum ether; IBX represents 2-iodoacetylbenzoic 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'-tetramethyluronium hexafluorophosphate; xantphos represents 4,5-bisdiphenylphosphino-9,9-dimethylxanthene; DCE represents dichloroethane; DMA or DMAC represents N,N-dimethylacetamide; AIBN represents azobisisobutyronitrile; DMAP represents 4-dimethylaminopyridine; CCl4 represents carbon tetrachloride; Ruphos represents 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl.

[0362] For the sake of clarity, the present invention is further illustrated by examples, but the examples are not intended to limit the scope of this application. All reagents used in this application are commercially available and can be used without further purification. DETAILED DESCRIPTION

[0363] Example 1 Synthesis of Intermediate 1

[0364] Step 1: Preparation of intermediate 1b

[0365] At 10°C, 1a (81 g), 2,4-dimethoxybenzylamine (83 g), and acetic acid (500 mL) were added to the reaction flask in sequence. The temperature was raised to 80°C and the reaction was monitored for completion. Water (800 mL) was added to the reaction solution, which was then filtered. The filter cake was washed with water and dried to obtain intermediate 1b (95.78 g).

[0366] MS (ESI, [MH] - )m / z:312.02.

[0367] 1 H NMR (500MHz, DMSO-d6) δ11.03(s,1H),7.62(dd,J=8.4,7.1Hz,1H),7.29(d,J=7.1Hz,1H),7.22(d,J=8.4Hz,1H), 6.90(d,J=8.4Hz,1H),6.56(d,J=2.4Hz,1H),6.43(dd,J=8.4,2.4Hz,1H),4.60(s,2H),3.80(s,3H),3.73(s,3H).

[0368] Step 2: Preparation of intermediate 1c

[0369] A 2.5 M solution of lithium aluminum tetrahydride in tetrahydrofuran (227 mL) was slowly added dropwise to a solution of 1b (96.00 g) in tetrahydrofuran (1000 mL) at 10°C, and the mixture was allowed to react at 80°C. A 15% aqueous sodium hydroxide solution (30.5 g) and water (100 mL) were added to the reaction solution, which was then filtered and the filter cake was washed with a 1 / 1 solution of dichloromethane / MeOH. The filtrate was concentrated, and the crude product was purified by silica gel column chromatography to obtain intermediate 1c (55.87 g).

[0370] MS (ESI, [M+H] + )m / z:286.01

[0371] 1 H NMR(500MHz,DMSO-d6)δ9.28(s,1H),7.24(d,J=8.3Hz,1H),6.97(t,J=7.7Hz,1H),6.64(d,J=7.4Hz ,1H),6.59(d,J=8.0Hz,1H),6.55(d,J=2.4Hz,1H),6.51(dd,J=8.3,2.4Hz,1H),3.81–3.71(m,12H).

[0372] Step 3: Preparation of intermediate 1d

[0373] 1c (48.00 g), methanol (350 mL), palladium hydroxide (4.8 g), and di-tert-butyl dicarbonate (41.4 g) were added to the reaction flask in sequence and reacted at 25°C under hydrogen protection. The reaction solution was filtered, the filtrate was concentrated, and water (200 mL) and ethyl acetate were added for extraction. The product was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was separated and purified by silica gel column chromatography to obtain intermediate 1d (34.43 g).

[0374] 1 H NMR (500MHz, DMSO-d6) δ7.07(t,J=7.7Hz,1H),6.68(ddd,J=18.9,7.8,2.7Hz,2H),4.56–4.50(m,2H),4.48–4.42(m,2H),1.45(s,9H).

[0375] Step 4: Preparation of intermediate 1e

[0376] To a reaction flask, 1d (35.00 g), methanol (250 mL), and 4 M hydrochloric acid in 1,4-dioxane (123 mL) were added sequentially and allowed to react at 25°C for 3 h. The reaction solution was concentrated, and pyridine (200 mL) and trifluoroacetic anhydride (25.20 g) were added, followed by stirring at 25°C for 40 h. The reaction solution was poured into 3 M aqueous hydrochloric acid and stirred vigorously. Extraction was performed with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to afford intermediate 1e (32.48 g).

[0377] MS (ESI, [MH] - )m / z:229.99

[0378] 1 H NMR(500MHz,DMSO-d6)δ9.82(d,J=24.4Hz,1H),7.16(td,J=7.7,3.7Hz,1H),6.81(dd,J=11 .5,7.5Hz,1H),6.74(d,J=8.0Hz,1H),4.99(s,1H),4.89(s,1H),4.80(s,1H),4.70(s,1H).

[0379] Step 5: Preparation of Intermediate 1f

[0380] 1e (32.48 g), dichloromethane (300 mL), triethylamine (28.40 g), 4-dimethylaminopyridine (1.72 g), and acetic anhydride (15.78 g) were added to the reaction flask in sequence and reacted at 25°C. After the reaction, the reaction solution was poured into water and vigorously stirred. Dichloromethane was added for extraction, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was separated by silica gel column chromatography to obtain intermediate 1f (33.82 g).

[0381] 1 H NMR (500MHz, DMSO-d6) δ7.41(td,J=7.8,2.3Hz,1H),7.30(t,J=8.5Hz,1H),7.12(dd,J=7 .9,2.9Hz,1H),5.09(s,1H),4.90(d,J=12.3Hz,2H),4.72(s,1H),2.31(d,J=3.4Hz,3H).

[0382] Step 6: Preparation of Intermediate 1g

[0383] 1f (30.00 g), aluminum chloride (29.30 g), and o-dichlorobenzene (200 mL) were added to the reaction flask in sequence, and the reaction was carried out at 150°C for 1 h. The reaction solution was poured into a citric acid aqueous solution and stirred vigorously. Ethyl acetate was added for extraction, and the mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated. The crude product was separated by silica gel column chromatography to obtain intermediate 1g (18.19 g).

[0384] 1 H NMR (500MHz, DMSO-d6) δ12.38(s,1H),7.94(dd,J=8.2,4.7Hz,1H),7.01(dd,J=12.7,8.1Hz ,1H),5.07(s,1H),4.94(s,1H),4.86(s,1H),4.74(d,J=1.6Hz,1H),2.66(d,J=1.0Hz,3H).

[0385] Step 7: Preparation of Intermediate 1h

[0386] 1g (18.19g), sodium hydroxide (7.56g), methanol (150mL), and water (150mL) were added to the reaction flask in sequence and reacted at 25°C. The reaction solution was concentrated to remove methanol, and 1,4-dioxane (150mL) and di-tert-butyl dicarbonate (15.14g) were added to the residue and stirred at 25°C. After the reaction, the reaction solution was poured into water and vigorously stirred. Ethyl acetate was added for extraction, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was separated by silica gel column chromatography to obtain intermediate 1h (14.10g).

[0387] MS (ESI, [MH] - )m / z:276.07

[0388] 1 H NMR(500MHz,DMSO-d6)δ12.36(s,1H),7.89(dd,J=8.1,2.9Hz,1H),6.95(t,J=8.0Hz,1H ),4.62(dt,J=13.4,2.2Hz,2H),4.51(dt,J=13.9,2.3Hz,2H),2.65(s,3H),1.46(s,9H).

[0389] Step 8: Preparation of intermediate 1i

[0390] To the reaction flask were added 1h (14.10 g), diethyl carbonate (27.00 g), and toluene (200 mL) in sequence. The temperature was lowered to 0°C, and 60 wt% sodium hydride (9.16 g) was added. The temperature was then raised to 120°C and stirred for reaction. After the reaction, the reaction solution was poured into a 3M aqueous hydrochloric acid solution and vigorously stirred. Extraction was then added with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The crude product was separated by silica gel column chromatography to obtain intermediate 1i (14.96 g).

[0391] 1 H NMR (500MHz, DMSO-d6) δ11.72(d,J=9.6Hz,1H),7.82(dd,J=8.2,4.7Hz,1H),6.97(t,J=8.4Hz,1H),4.63(dt,J=12.4,2.1Hz, 2H), 4.53 (dt, J = 13.7, 2.1Hz, 2H), 4.22 (d, J = 2.5Hz, 2H), 4.13 (q, J = 7.1Hz, 2H), 1.46 (d, J = 1.9Hz, 9H), 1.19 (t, J = 7.1Hz, 3H).

[0392] Step 9: Preparation of Intermediate 1j

[0393] 1i (14.96 g), 50% aqueous hydroxylamine solution (6.36 g), and ethanol (150 mL) were added sequentially to the reaction flask and stirred at 85°C for 3 h. The reaction solution was concentrated, and water and ethyl acetate were added. The layers were separated by extraction, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude intermediate 1j (10.13 g).

[0394] MS (ESI, [MH] - )m / z:317.20.

[0395] 1H NMR (500MHz, DMSO-d6) δ12.59(s,1H),7.78(d,J=8.2Hz,1H),7.38(t,J=7.6Hz,1H),4.85( dt,J=13.5,2.5Hz,2H),4.75(dt,J=12.2,2.4Hz,2H),4.11(s,2H),1.49(d,J=2.1Hz,9H).

[0396] Step 10: Preparation of Intermediate 1k

[0397] 1j (10.13 g), potassium carbonate (12.55 g), N,N-dimethylacetamide (150 mL), and iodoethane (7.08 g) were added to the reaction flask in sequence and stirred at 80°C for 1 h. The reaction solution was poured into water and stirred vigorously. Ethyl acetate was added for extraction, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by silica gel column chromatography to obtain intermediate 1k (11.22 g).

[0398] MS (ESI, [M+H] + )m / z:347.16.

[0399] 1 H NMR(500MHz,DMSO-d6)δ7.78(d,J=8.0Hz,1H),7.39(t,J=7.5Hz,1H),4.89–4.82(m,2H),4.75(dd,J=11 .8,2.8Hz,2H),4.22(d,J=4.3Hz,2H),4.13(p,J=7.2Hz,2H),1.48(d,J=2.1Hz,9H),1.21–1.17(m,3H).

[0400] Step 11: Preparation of Intermediate 11

[0401] At 0°C under N2 protection, acrylamide (1.32 g) was slowly added to a stirred solution of 1k (10.72 g) in tetrahydrofuran (50 mL), followed by dropwise addition of a 1M solution of potassium tert-butoxide in tetrahydrofuran (18.63 mL). The mixture was stirred at 0°C for 3 h. The reaction solution was poured into an aqueous ammonium chloride solution and stirred vigorously. Extraction was then performed with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The crude product was separated by silica gel column chromatography to obtain intermediate 1l (7.52 g).

[0402] MS (ESI, [M+H] + )m / z:372.02.

[0403] 1H NMR (500MHz, DMSO-d6) δ11.11(s,1H),7.80(dd,J=8.1,2.7Hz,1H),7.37(t,J=7.9Hz,1H),4.85(dd,J=12.2,2.6Hz,2H),4.75(dt,J=12.0,2.3Hz ,2H),4.63(dd,J=12.1,4.9Hz,1H),2.78(ddd,J=17.3,12.1,5.3Hz,1H),2.67–2.51(m,2H),2.20(dq,J=13.5,4.7Hz,1H),1.49(d,J=2.6Hz,9H).

[0404] Step 12: Preparation of Intermediate 1

[0405] 1L (1.00 g), 4M hydrochloric acid 1,4-dioxane solution (10 mL), and ethyl acetate (50 mL) were added to the reaction flask in sequence. 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).

[0406] MS (ESI, [M+H] + )m / z:272.11.

[0407] 1 H NMR (500MHz, DMSO-d6) δ11.13(s,1H),10.36(s,2H),7.90(d,J=8.1Hz,1H),7.45(d,J=8.2Hz,1H),4.81(s,2H),4.70–4.63(m, 3H), 2.79(ddd,J=17.4,12.2,5.3Hz,1H),2.62(dt,J=17.3,4.0Hz,1H),2.59–2.52(m,1H),2.21(ddt,J=13.2,5.1,2.5Hz,1H).

[0408] Example 2 Preparation of Intermediate 2

[0409] Step 1: Preparation of intermediate 2b

[0410] 2a (18 g), AIBN (0.738 g), carbon tetrachloride (500 mL), and NBS (47.8 g) were added to the reaction flask in sequence and the temperature was raised to 60°C for reaction. The reaction solution was cooled to room temperature, and the solvent was evaporated under reduced pressure. 200 mL of dichloromethane was added to the residue. The product was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The product was purified by silica gel column chromatography to obtain intermediate 2b (18.7 g).

[0411] Step 2: Preparation of intermediate 2c

[0412] 2b (18.7 g), benzylamine (1.78 mL), N,N-diisopropylethylamine (7.13 mL), and toluene (50 mL) were added to the reaction flask in sequence, and the temperature was raised to 50°C for reaction. The reaction solution was cooled to room temperature. After the reaction was completed, 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 solid sodium bicarbonate. Ethyl acetate was added for extraction, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain intermediate 2c (9.6 g).

[0413] MS (ESI, [M+H] + )m / z:240.1.

[0414] Step 3: Preparation of intermediate 2d

[0415] To a reaction flask, 2c (9.6 g), methanol (200 mL), 10% palladium on carbon (5 g), and toluene (50 mL) were added sequentially. The atmosphere was replaced with hydrogen three times, and the mixture was reacted at room temperature under a hydrogen atmosphere. The palladium on carbon was filtered, the filter cake was rinsed with methanol, the filtrate was collected, and the solvent was evaporated under reduced pressure to give 2d (4.5 g).

[0416] MS (ESI, [M+H] + )m / z:149.9.

[0417] Step 4: Preparation of intermediate 2e

[0418] 2d (4 g), tetrahydrofuran (50 mL), and trifluoroacetic anhydride (5.63 g) were added to the reaction flask in sequence and reacted at room temperature. 200 mL of aqueous solution was added to the reaction solution to quench the reaction, followed by extraction with ethyl acetate. The organic phase was separated, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to afford 2e (4.58 g).

[0419] 1 H NMR(500MHz,DMSO-d6)δ7.29(t,J=9.3Hz,1H),6.98(d,J=8.6Hz,1H),6.93–6.86(m,1 H), 4.97 (d, J = 21.7Hz, 2H), 4.77 (dd, J = 21.4, 5.2Hz, 2H), 3.76 (dd, J = 3.6, 1.6Hz, 3H).

[0420] Step 5: Preparation of intermediate 2f

[0421] 2e (4.6 g), dichloromethane (200 mL), and boron tribromide (1 M, 18.76 mL) were added sequentially to the reaction flask and allowed to react at room temperature. The reaction was quenched by adding 200 mL of aqueous solution under an ice bath. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to yield 2f (4.2 g).

[0422] 1 H NMR (500MHz, DMSO-d6) δ7.16(t,J=8.8Hz,1H),6.87–6.59(m,2H),4.92(d,J=20.8Hz,2H),4.72(d,J=19.9Hz,2H).

[0423] Step 6: Preparation of Intermediate 2g

[0424] 2f (6.5 g), dichloromethane (60 mL), triethylamine (7.8 mL), and acetic anhydride (2.94 mL) were added to a reaction flask in sequence and allowed to react 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 evaporated under reduced pressure to yield 2g (7 g).

[0425] 1 H NMR (500MHz, DMSO-d6) δ7.42(dd,J=10.0,8.3Hz,1H),7.17(dd,J=14.0,2.1Hz,1H),7.09(d,J =8.2Hz, 1H), 5.03 (d, J = 6.6Hz, 2H), 4.83 (d, J = 6.9Hz, 2H), 2.27 (s, 3H).

[0426] Step 7: Preparation of intermediate 2h

[0427] 2g (6g) and aluminum trichloride (4.39g) were added to the reaction flask in sequence, and the mixture was gradually heated from room temperature to 150°C for reaction. The reaction solution was cooled to room temperature, and 500mL of water and 100mL of 3M hydrochloric acid aqueous solution were added to the residue. The organic phase was separated, washed with 100mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was desolvated under reduced pressure and purified by silica gel column chromatography to obtain 2h (3.78g).

[0428] MS (ESI, [MH] - )m / z:271.9.

[0429] Step 7: Preparation of intermediate 2j

[0430] To the reaction flask, 2h (550 mg), MeOH (5.00 mL), and an aqueous solution of sodium hydroxide (242 mg) (5.00 mL) were added sequentially and allowed to react at room temperature. The reaction solution was concentrated, methanol was removed, and the aqueous phase was retained. 2i was obtained. 1,4-Dioxane (5 mL) and Boc anhydride (439 mg, 0.462 mL) were added to the system and allowed to react 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).

[0431] 1 H NMR (500MHz, DMSO-d6) δ12.11(d,J=19.3Hz,1H),7.88(d,J=9.5Hz,1H),6.74–6.56(m,1H),4.60–4.50(m,4H),2.63(d,J=6.5Hz,3H),1.45(s,9H).

[0432] Step 8: Preparation of intermediate 2k

[0433] To a reaction flask, 2j (3.5 g) and THF (300 mL) were added sequentially, followed by diethyl carbonate (14.91 g, 15.29 mL). The temperature was lowered to approximately 0°C, and 60 wt% sodium hydroxide (5.05 g, 126 mmol) was added portionwise. The reaction mixture was heated to 85°C. The reaction mixture was cooled to room temperature and slowly poured into 500 mL of ice water. The mixture 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 evaporated under reduced pressure to yield 2k (7.0 g).

[0434] MS (ESI, [MH] - )m / z:348.3.

[0435] Step 9: Preparation of intermediate 21

[0436] To the reaction flask, 2k (4.4 g), aqueous hydroxylamine solution (4.16 g, 63.0 mmol), and ethanol (50 mL) were added sequentially and reacted at 85°C. The reaction mixture was cooled to room temperature, and the residue was extracted with 200 mL of ethyl acetate and 100 mL of saturated sodium carbonate solution. The organic phase was discarded. The aqueous phase was adjusted to pH 2-3 with 1 M HCl, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to yield 2l (3.25 g).

[0437] 1H NMR(500MHz,DMSO-d6)δ12.83(s,1H),7.74(d,J=13.0Hz,1H),7.68(d,J=3.5Hz ,1H),4.71(d,J=13.6Hz,2H),4.66(d,J=11.4Hz,2H),4.07(s,2H),1.47(s,9H).

[0438] Step 10: Preparation of intermediate 2m

[0439] To a reaction flask, 2l (3.14 g), potassium carbonate (1.500 g), DMA (5 mL), and iodoethane (2.308 g, 1.183 mL) were added sequentially. The mixture was heated to 80°C for reaction. The reaction mixture was cooled to room temperature and poured into a mixture of 100 mL of ethyl acetate and 200 mL of water. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure to yield 2m (2.47 g).

[0440] 1 H NMR(500MHz,DMSO-d6)δ7.73(d,J=15.9Hz,1H),7.69(d,J=3.5Hz,1H),4.69(d d,J=23.8,12.4Hz,4H),4.19–4.11(m,4H),1.47(s,9H),1.20(t,J=7.1Hz,3H).

[0441] Step 11: Preparation of intermediate 2n

[0442] 2m (1.5 g) and THF (75 mL) were added to the reaction flask in sequence, followed by acrylamide (0.215 g). The temperature was lowered to approximately -15°C, and 1 M potassium tert-butoxide tetrahydrofuran solution (2.60 mL) was added. The system was warmed to 0°C and reacted for 1.5 hours. The reaction mixture was then added dropwise to 200 mL of ammonium chloride solution for quenching. The mixture was extracted with ethyl acetate, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to afford 2n (0.88 g).

[0443] 1H NMR (500MHz, DMSO-d6) δ11.11(d,J=3.4Hz,1H),7.78(d,J=12.4Hz,1H),7.70(s,1H),4.68(dd,J=29.4,13.3Hz,4H),4.58(dd,J=12.0,4. 9Hz,1H),2.79(ddd,J=17.3,12.1,5.3Hz,1H),2.62(dt,J=17.3,4.1Hz,1H),2.56–2.50(m,1H),2.31–2.14(m,1H),1.47(d,J=1.5Hz,9H).

[0444] Step 12: Preparation of Intermediate 2

[0445] 2n (0.428 g) and dichloromethane (10.00 mL) were added to the reaction flask, followed by trifluoroacetic acid (3.29 g, 2.211 mL). The mixture was allowed to react 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. The mixture was extracted with dichloromethane. 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).

[0446] MS (ESI, [M+H] + )m / z:272.24.

[0447] 1 H NMR (500MHz, DMSO-d6) δ7.81–7.77(m,1H),7.74(s,1H),4.59(dd,J=12.1,5.0Hz,1H),4.49(s,2H),4.43(s,2H),2.79(ddd ,J=17.4,12.2,5.3Hz,1H),2.62(dt,J=17.3,4.0Hz,1H),2.47(dd,J=12.4,4.4Hz,1H),2.20(ddt,J=13.3,5.2,2.6Hz,1H).

[0448] Example 3 Synthesis of Intermediate 3

[0449] Step 1: Preparation of intermediate 3b

[0450] Intermediate 3a (25 g) was dissolved in methanol (1000 mL) and acetic acid (103 g, 99 mL, 1722 mmol) and injected into a flow hydrogenation reactor at 3 MPa, 110°C, and a flow rate of 3 mL / min. After completion of the reaction, the solvent was evaporated under reduced pressure. The residue was added with a 1,4-dioxane hydrochloride solution (4 mol / L, 100 mL) and the solvent was evaporated under reduced pressure. The residue was slurried in ethyl acetate and filtered to obtain the filter cake, yielding the desired intermediate 3b (28.97 g).

[0451] MS (ESI, [M+H] + )m / z:150.0.

[0452] 1 H NMR(500MHz,DMSO-d6)δ10.01(s,1H),7.06(t,J=7.8Hz,1H),6.76(d,J=8.0Hz,1H),6 .64(d,J=7.6Hz,1H),4.01(t,J=4.9Hz,2H),3.33–3.25(m,2H),2.94(t,J=6.2Hz,2H).

[0453] Step 2: Preparation of intermediate 3c

[0454] Intermediate 3b (28.97 g) and tetrahydrofuran (300 mL) were added to the reaction flask in sequence. Trifluoroacetic anhydride (27.0 mL) was added under ice-cooling conditions, and the mixture was reacted at room temperature. After completion of the reaction, the reaction solution was extracted with 500 mL of ethyl acetate and 1000 mL of water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The filter cake was collected by filtration to obtain the target intermediate 3c (22.67 g).

[0455] MS (ESI, [MH] - )m / z:244.0.

[0456] 1 H NMR(500MHz,DMSO-d6)δ7.03(q,J=7.9Hz,1H),6.74–6.68(m,1H),6.64(t,J=6.9Hz,1 H), 4.61 (d, J = 23.5Hz, 2H), 3.78 (td, J = 6.0, 3.7Hz, 2H), 2.84 (dt, J = 16.8, 5.9Hz, 2H).

[0457] Step 3: Preparation of intermediate 3d

[0458] Intermediate 3c (22.67 g), dichloromethane (200 mL), triethylamine (28.1 g, 38.6 mL), and DMAP (0.282 g) were added to the reaction flask in sequence. Acetic anhydride (10.38 g, 9.68 mL) was added under ice-cooling conditions, and the mixture was allowed to return to room temperature for reaction. After completion of the reaction, the solvent was removed by evaporation under reduced pressure. The residue was extracted with 500 mL of ethyl acetate and 1000 mL of water. The organic phase was separated, washed with saturated ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was then evaporated under reduced pressure to remove the solvent, yielding the target intermediate 3d (21.94 g).

[0459] 1 H NMR(500MHz,DMSO-d6)δ7.30(dt,J=11.1,7.8Hz,1H),7.18–7.11(m,1H),7.05(dt,J=8.0,2.2H z,1H),4.59(s,2H),3.81(q,J=6.1Hz,2H),2.95(dt,J=10.1,6.0Hz,2H),2.33(d,J=9.5Hz,3H).

[0460] Step 4: Preparation of intermediate 3e

[0461] Intermediate 3d (21 g) and aluminum chloride (14.62 g) were added sequentially to the reaction flask. Under N protection, the mixture was heated to 170°C for reaction. After completion of the reaction, the reaction solution was cooled to room temperature and quenched with 300 mL of water. The reaction was then extracted with dichloromethane. The organic phases were combined, washed with 500 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified on a silica gel column to obtain the target intermediate 3e (10.16 g).

[0462] MS (ESI, [MH] - )m / z:286.0.

[0463] 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

[0464] 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 in an ice bath, and the mixture was allowed to return to room temperature for reaction. After the reaction was complete, the methanol was removed by evaporation under reduced pressure, and 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, and filtered. The filtrate was then evaporated under reduced pressure to remove the solvent, yielding the target intermediate 3f (8.96 g).

[0465] MS (ESI, [M+H] + )m / z:292.0.

[0466] 1 H NMR(500MHz,DMSO-d6)δ12.72(s,1H),7.76(d,J=8.2Hz,1H),6.80(d,J=8.2Hz,1H), 4.41(s,2H),3.55(t,J=5.8Hz,2H),2.80(t,J=5.8Hz,2H),2.63(s,3H),1.43(s,9H).

[0467] Step 6: Preparation of Intermediate 3g

[0468] To a reaction flask, intermediate 3f (8.76 g), diethyl carbonate (17.76 g, 18.21 mL), and toluene (90 mL) were added sequentially. 60 wt% sodium hydroxide (6.01 g) was added portionwise in an ice bath, and the mixture was heated to 120°C for reaction. After completion of the reaction, the reaction solution was cooled to room temperature and quenched by pouring into ice water. 1 M hydrochloric acid solution was added to adjust the pH to 1-2, and extraction was performed with 300 mL of ethyl acetate. The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure to remove the solvent to obtain the target intermediate 3g (12.03 g).

[0469] Step 7: Preparation of Intermediate 3h

[0470] Intermediate 3g (9.54g), EtOH (100mL) and hydroxylamine aqueous solution (9.93g, 9.21mL) were added to the reaction flask in sequence, and the mixture was heated to 85°C. After the reaction was completed, the reaction solution was added with 200mL of saturated sodium carbonate solution to adjust the pH to 9-10, and ethyl acetate was added for extraction. The organic phase was separated and extracted twice with water. The aqueous phases were combined, and then the aqueous phase was adjusted to pH 3 with 1M hydrochloric acid. 200mL of ethyl acetate was added for extraction, and the mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to remove the solvent to obtain the target intermediate 3h (9.01g).

[0471] MS (ESI, [MH]- )m / z:331.0.

[0472] Step 8: Preparation of intermediate 3i

[0473] Intermediate 3h (9.01 g), potassium carbonate (11.24 g), DMA (90 mL), and iodoethane (5.07 g, 2.63 mL) were added to the reaction flask in sequence. Under nitrogen, the mixture was heated to 80°C for reaction. After completion of the reaction, 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 on a silica gel column to obtain the target intermediate 3i (7.33 g).

[0474] MS (ESI, [M+H] + )m / z:361.0.

[0475] 1 H NMR(500MHz,DMSO-d6)δ7.63(d,J=8.1Hz,1H),7.21(d,J=8.2Hz,1H),4.76(s,2H),4.18(s,2H),4.1 3(q,J=7.1Hz,2H),3.66(t,J=5.8Hz,2H),2.93(t,J=5.8Hz,2H),1.45(s,9H),1.19(t,J=7.1Hz,3H).

[0476] Step 9: Preparation of intermediate 3j

[0477] Intermediate 3i (7.3 g), tetrahydrofuran (80 mL), and acrylamide (0.864 g) were added to the reaction flask in sequence. The temperature was lowered 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 reaction. After the reaction was complete, the resulting reaction system was added to 200 mL of saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified on a silica gel column to obtain the target intermediate 3j (4.54 g).

[0478] MS (ESI, [MH] - )m / z:384.3.

[0479] 1H NMR (500MHz, DMSO-d6) δ11.09(s,1H),7.65(d,J=8.1Hz,1H),7.20(d,J=8.2Hz,1H),4.76(s, 2H),4.58(dd,J=12.0,5.0Hz,1H),3.66(t,J=5.8Hz,2H),2.93(t,J=5.8Hz,2H),2.77(ddd,J=17.3,12.1,5.3 Hz,1H),2.61(dt,J=17.3,4.1Hz,1H),2.54(d,J=4.5Hz,1H),2.18(dtd,J=13.5,5.2,3.6Hz,1H),1.45(s,9H).

[0480] Step 10: Preparation of Intermediate 3

[0481] Intermediate 3j (300 mg) and ethyl acetate (5 mL) were added to the reaction flask in sequence, followed by a 1,4-dioxane hydrochloride solution (4 mol / L, 3.89 mL). The mixture was reacted at room temperature. After completion of the reaction, the reaction solution was concentrated to obtain Intermediate 3 (235 mg).

[0482] MS (ESI, [M+H] + )m / z:286.10.

[0483] 1 H NMR (500MHz, DMSO-d6) δ11.08(s,1H),7.55(d,J=8.1Hz,1H),7.10(d,J=8.2Hz,1H),4.55(dd,J=11.9,5.0Hz,1H),4.07(s,2H),3.00(t,J=5. 7Hz,2H),2.81(t,J=5.7Hz,2H),2.78–2.71(m,1H),2.60(dt,J=17.3,4.2Hz,1H),2.46(dd,J=12.2,4.5Hz,1H),2.18(dq,J=13.6,4.9Hz,1H).

[0484] Example 4 Synthesis of Intermediate 4

[0485] Step 1: Preparation of intermediate 4b

[0486] Intermediate 4a was dissolved in methanol (1680 mL) and acetic acid (166 mL) and injected into a flow hydrogenation reactor at 3 MPa, 110°C, and a flow rate of 3 mL / min. After completion of the reaction, the solvent was evaporated under reduced pressure. The residue was treated with a 1,4-dioxane hydrochloride solution (4 mol / L, 200 mL) and the solvent was evaporated under reduced pressure. The residue was then slurried in 100 mL of ethyl acetate and filtered to obtain the filter cake, yielding the target intermediate 4b (46.96 g).

[0487] MS (ESI, [M+H] + )m / z:150.0.

[0488] 1 H NMR (500MHz, DMSO-d6) δ9.81(s,1H),7.03(t,J=7.7Hz,1H),6.78(d,J=7.8Hz,1H),6.62(d,J=7.6Hz,1H),4.15(s,2H),3.35(s,2H),2.79(s,2H).

[0489] Step 2: Preparation of intermediate 4c

[0490] Intermediate 4b (40 g) and tetrahydrofuran (400 mL) were added to the reaction flask in sequence. Trifluoroacetic anhydride (61.9 g, 41.0 mL) was added under ice-cooling conditions and allowed to react at room temperature. After completion of the reaction, 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, and filtered. The filtrate was evaporated under reduced pressure to remove the solvent to obtain the target intermediate 4c (81 g).

[0491] MS (ESI, [MH] - )m / z:244.04.

[0492] Step 3: Preparation of intermediate 4d

[0493] Intermediate 4c (65.3 g), dichloromethane (650 mL), triethylamine (81 g, 111 mL), and DMAP (0.813 g) were added to the reaction flask in sequence. Acetic anhydride (29.9 g, 27.9 mL) was added under ice-cooling conditions and allowed to react at room temperature. After completion of the reaction, the solvent was removed by evaporation under reduced pressure. The residue was extracted with 500 mL of ethyl acetate and 1000 mL of water. The organic phase was separated, washed with saturated ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was then evaporated under reduced pressure to remove the solvent, yielding the target intermediate 4d (55.6 g).

[0494] 1H NMR(500MHz,Chloroform-d)δ7.28(d,J=7.9Hz,1H),7.10–7.02(m,1H),7.02–6.95(m,1 H),4.79(d,J=27.0Hz,2H),3.92–3.78(m,2H),2.82–2.72(m,2H),2.33(d,J=2.0Hz,3H).

[0495] Step 4: Preparation of intermediate 4e

[0496] Intermediate 4d (30.73 g) and aluminum chloride (21.40 g) were added to the reaction flask in sequence. Under nitrogen, the mixture was heated to 170°C for 1 h. After completion of the reaction, the reaction solution was cooled to room temperature and quenched with 300 mL of water. The reaction solution was extracted with dichloromethane, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified on a silica gel column to obtain the target intermediate 4e (16.21 g).

[0497] MS (ESI, [MH] - )m / z:286.0.

[0498] 1 H NMR (500MHz, DMSO-d6) δ12.74(d,J=11.3Hz,1H),7.82(d,J=8.3Hz,1H),6.91(dd,J=14.9,8.3Hz,1 H), 4.80 (d, J = 9.9Hz, 2H), 3.86 (dt, J = 8.2, 5.9Hz, 2H), 2.77 (dt, J = 17.7, 6.1Hz, 2H), 2.64 (s, 3H).

[0499] Step 5: Preparation of intermediate 4f

[0500] 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 an ice bath, and the mixture was allowed to return to room temperature for reaction. After the reaction was complete, the methanol was removed by evaporation under reduced pressure, and 1,4-dioxane (160 mL) and di-tert-butyl dicarbonate (13.12 g, 13.96 mL) were added. The mixture was allowed to react 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, and filtered. The filtrate was then evaporated under reduced pressure to remove the solvent, yielding the target intermediate 4f (19.83 g).

[0501] MS (ESI, [M+H] + )m / z:292.5

[0502] 1H NMR(500MHz,DMSO-d6)δ12.76(s,1H),7.76(d,J=8.3Hz,1H),6.80(d,J=8.3Hz ,1H),4.52(s,2H),3.57(d,J=1.8Hz,2H),2.64(d,J=6.1Hz,5H),1.43(s,9H).

[0503] Step 6: Preparation of Intermediate 4g

[0504] The reaction flask was sequentially charged with intermediate 4f (15.92 g), diethyl carbonate (32.3 g, 33.1 mL), and toluene (200 mL). 60 wt% sodium hydroxide (10.93 g) was added in portions under ice bath conditions, and the mixture was heated to 120°C for reaction. After the reaction was completed, the reaction solution was cooled to room temperature and quenched by pouring into ice water. 1 M hydrochloric acid solution was added to adjust the pH to 1-2, and ethyl acetate was added for extraction. The organic phases were separated, combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure to remove the solvent. The residue was slurried in 100 mL of petroleum ether and filtered to obtain the filter cake of target intermediate 4g (12 g).

[0505] 1 H NMR(500MHz,DMSO-d6)δ12.46(s,1H),7.64(d,J=8.1Hz,1H),7.17(d,J=8.2Hz,1H), 5.56(s,1H),4.60(s,2H),3.62(t,J=6.0Hz,2H),2.83(t,J=5.8Hz,2H),1.44(s,9H).

[0506] Step 7: Preparation of intermediate 4h

[0507] The reaction flask was sequentially added with intermediate 4g (12g), ethanol (120mL) and hydroxylamine aqueous solution (12.49g, 11.59mL), and the mixture was heated to 85°C for reaction. After the reaction was completed, 200mL of saturated sodium bicarbonate solution was added to the reaction solution, and 100mL of ethyl acetate was added for extraction. The organic phase was separated, and the aqueous phase was adjusted to pH 3 with 1M hydrochloric acid. 200mL of ethyl acetate was added, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure to remove the solvent to obtain the target intermediate 4h (10.44g).

[0508] MS (ESI, [MH] - )m / z:331.0.

[0509] 1H NMR(500MHz,DMSO-d6)δ12.85(s,1H),7.63(d,J=8.1Hz,1H),7.21(d,J=8.2Hz,1H), 4.67(s,2H),4.07(s,2H),3.69(t,J=5.9Hz,2H),2.98(t,J=5.9Hz,2H),1.44(s,9H).

[0510] Step 8: Preparation of intermediate 4i

[0511] Intermediate 4h (10.44 g), potassium carbonate (13.02 g), DMA (110 mL), and iodoethane (5.88 g, 3.05 mL) were added to the reaction flask in sequence. 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 on a silica gel column to obtain the target intermediate 4i (8.31 g).

[0512] MS (ESI, [M+H] + )m / z:361.2.

[0513] Step 9: Preparation of intermediate 4j

[0514] Intermediate 4i (5.5 g), tetrahydrofuran (50 mL), and acrylamide (0.759 g) were added to the reaction flask in sequence. The temperature was lowered 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 reaction. After the reaction was complete, the resulting reaction system was added to 200 mL of saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified on a silica gel column to obtain the target intermediate 4j (2.81 g).

[0515] MS (ESI, [MH] - )m / z:384.34.

[0516] 1H NMR(500MHz,DMSO-d6)δ11.09(s,1H),7.64(d,J=8.2Hz,1H),7.20(d,J=8.3Hz ,1H),4.67(s,2H),4.57(dd,J=12.0,5.0Hz,1H),3.69(t,J=5.9Hz,2H),2.98( t,J=5.9Hz,2H),2.77(ddd,J=17.3,12.1,5.3Hz,1H),2.61(dt,J=17.3,4.1Hz ,1H),2.54(d,J=4.5Hz,1H),2.18(dtd,J=13.5,5.2,3.7Hz,1H),1.44(s,9H).

[0517] Step 10: Preparation of Intermediate 4

[0518] Intermediate 4j (850 mg) and ethyl acetate (20 mL) were added to the reaction flask in sequence, followed by a 1,4-dioxane hydrochloride solution (4 mol / L, 11.03 mL). The mixture was reacted at room temperature. After completion of the reaction, the reaction solution was concentrated to obtain Intermediate 4 (760 mg).

[0519] MS (ESI, [M+H] + )m / z:286.12.

[0520] 1 H NMR (500MHz, DMSO-d6) δ11.08(s,1H),7.54(d,J=8.1Hz,1H),7.05(d,J=8.2Hz,1H),4.54(dd,J=11.8,5.0Hz,1H),3.97(s,2H),3.03(t,J=5.8Hz,2 H),2.86(t,J=5.8Hz,2H),2.76(td,J=12.0,5.9Hz,1H),2.60(dt,J=17.3,4.2Hz,1H),2.46(dd,J=12.2,4.4Hz,1H),2.18(dq,J=13.5,4.8Hz,1H).

[0521] Example 5 Synthesis of Intermediate 5

[0522] Step 1: Preparation of intermediate 5b

[0523] Liquid bromine (55.5 g) was added dropwise to a solution of 5a (50 g) in acetic acid (180 mL) at 15°C. After the addition was complete, the mixture was allowed to react at room temperature for 1 h. Methyl tert-butyl ether (800 mL) was added dropwise to the reaction solution, which was then filtered. The filter cake was collected and dried to yield intermediate 5b (95 g).

[0524] MS (ESI, [M+H] + )m / z:230.1.

[0525] Step 2: Preparation of intermediate 5c

[0526] 5b (80 g), glyoxal dimethyl acetal (66.9 g), triethylamine (27.3 g), anhydrous sodium sulfate (80 g), and methanol (600 mL) were added to a reaction flask in sequence and allowed to react at room temperature overnight. The reaction solution was cooled to -15°C, and sodium borohydride (14.6 g) was added portionwise. After complete addition, the reaction was allowed to react at room temperature. The reaction solution was concentrated, and 400 mL of dichloromethane and 700 mL of water were added to the concentrate. The organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was separated and purified by silica gel column chromatography to obtain intermediate 5c (60 g).

[0527] MS (ESI, [M+H] + )m / z:318.1.

[0528] Step 3: Preparation of intermediate 5d

[0529] At 0°C, under nitrogen, 5c (47g) was added dropwise to trifluoroacetic anhydride (148g). After the addition was complete, the reaction mixture was allowed to react at room temperature. Trifluoroacetic acid (87g) was added dropwise, and the temperature was raised to 40°C. Triethylsilane (68g) was added dropwise, and the temperature was raised to 60°C. 400mL of ethyl acetate and 600mL of water were added to the reaction mixture. The organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain intermediate 5d (20.5g).

[0530] 1 H NMR(500MHz,DMSO-d6)δ7.46(dd,J=8.9,1.7Hz,1H),6.87(d,J=8.9Hz,1H),3.77(d,J=2.8Hz,3 H),3.67(ddt,J=14.4,5.7,3.4Hz,4H),3.22(ddd,J=11.9,6.4,4.6Hz,2H),3.16–3.06(m,2H).

[0531] Step 4: Preparation of intermediate 5e

[0532] At 0°C, under nitrogen, a dichloromethane solution of boron tribromide (146 mL, 1 M) was slowly added dropwise to a stirred solution of 5d (20.5 g) in dichloromethane (200 mL). After the addition was complete, the mixture was brought to room temperature for reaction. After the reaction, the reaction solution was slowly poured into 400 mL of ice water, stirred, filtered, and the filter cake was collected and dried to yield 5e (18.5 g).

[0533] MS (ESI, [MH] - )m / z:336.1.

[0534] 1 H NMR (500MHz, DMSO-d6) δ9.74(s,1H),7.26(dd,J=8.7,1.3Hz,1H),6.68(dd,J=8.7,3.1Hz,1H),3.73–3.61(m,4H),3.23–3.13(m,2H),3.12–3.02(m,2H).

[0535] Step 5: Preparation of intermediate 5f

[0536] Acetic anhydride (5.65 g) was slowly added dropwise to a mixture of 5e (17.0 g) and triethylamine (7.63 g) in 200 mL of dichloromethane at 0°C under nitrogen. After the addition was complete, the mixture was allowed to react at room temperature. After the reaction, the reaction solution was slowly poured into 200 mL of water. The organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 5f (19.8 g).

[0537] MS (ESI, [M+H] + )m / z:380.1.

[0538] Step 6: Preparation of Intermediate 5g

[0539] 5f (19.5 g), aluminum chloride (18.7 g), and o-dichlorobenzene (80 mL) were added to the reaction flask in sequence and the temperature was raised to 150°C for reaction. After the reaction, the reaction solution was cooled to room temperature, 250 mL of 3N dilute hydrochloric acid was added, and extraction was performed 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 intermediate 5g (11.2 g).

[0540] MS (ESI, [MH] - )m / z:300.0.

[0541] 1 H NMR(500MHz,DMSO-d6)δ12.83(d,J=4.8Hz,1H),7.78(dd,J=8.1,3.5Hz,1H),6.83(t ,J=8.3Hz,1H),3.69(ddd,J=12.9,9.6,5.9Hz,4H),3.11–3.00(m,4H),2.64(s,3H).

[0542] Step 7: Preparation of Intermediate 5h

[0543] 5g (9.5g), methanol (100mL), water (20mL), and sodium hydroxide (1.9g) were added to the reaction flask in sequence and allowed to react at room temperature. Di-tert-butyl dicarbonate (8.2g) was then added. After the reaction was complete, 200mL of ethyl acetate and 400mL 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 5h (8.5g).

[0544] 1 H NMR(500MHz,DMSO-d6)δ12.80(s,1H),7.74(d,J=8.1Hz,1H),6.79(d,J=8.2Hz,1H ),3.45(dt,J=11.6,5.0Hz,4H),2.92(q,J=5.0Hz,4H),2.63(s,3H),1.38(s,9H).

[0545] Step 8: Preparation of intermediate 5i

[0546] 5h (8.5 g), diethyl carbonate (16.4 g), and toluene (100 mL) were added sequentially to the reaction flask. 60 wt% sodium hydroxide (5.57 g) was added portionwise, and the reaction mixture was heated to 115°C. After the reaction was completed, the reaction mixture 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 5i (9.0 g).

[0547] MS (ESI, [MH] - )m / z:330.1.

[0548] Step 9: Preparation of intermediate 5j

[0549] 5i (9.0 g), hydroxylamine aqueous solution (8.7 g), and ethanol (100 mL) were added to the reaction flask in sequence, and the reaction mixture was heated to 80°C for reaction. After the reaction was completed, the reaction mixture was cooled to room temperature, and 200 mL of ethyl acetate and 300 mL of water were added to the reaction mixture. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the concentrate was separated and purified by silica gel column chromatography to obtain intermediate 5j (8.5 g).

[0550] MS (ESI, [MH] - )m / z:345.4.

[0551] 1H NMR (500MHz, DMSO-d6) δ7.53(d,J=8.0Hz,1H),7.12(d,J=8.0Hz,1H),3.73(q,J=13.9,11.5Hz,2 H),3.59–3.54(m,2H),3.52–3.47(m,2H),3.13(t,J=5.2Hz,2H),3.07–2.98(m,2H),1.40(s,9H).

[0552] Step 10: Preparation of Intermediate 5k

[0553] 5j (8.5 g), potassium carbonate (3.3 g), iodoethane (5.1 g), and DMA (70 mL) were added to the reaction flask in sequence, and the reaction mixture was heated to 80°C. The reaction mixture 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).

[0554] MS (ESI, [MH] - )m / z:373.1.

[0555] 1 H NMR (500MHz, DMSO-d6) δ7.56(d,J=8.0Hz,1H),7.22(d,J=8.0Hz,1H),4.13(dd,J=13.7,6.6Hz,4H),3.55(dt ,J=28.2,5.0Hz,4H),3.17(s,2H),3.05(t,J=5.2Hz,2H),1.38(dd,J=9.3,4.4Hz,9H),1.19(t,J=6.5Hz,3H).

[0556] Step 11: Preparation of Intermediate 5l

[0557] At -10°C, under nitrogen, a 1M solution of sodium tert-butoxide in tetrahydrofuran (14 mL) was slowly added dropwise to a stirred solution of 5k (5.6 g) in tetrahydrofuran (70 mL). The mixture was then incubated for 30 minutes. Acrylamide (0.71 g) was dissolved in 5 mL of tetrahydrofuran and added dropwise to the reaction mixture. The mixture was incubated for 2 hours. The reaction mixture 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, and filtered. The concentrate was purified by silica gel column chromatography to yield intermediate 5l (2.5 g).

[0558] MS (ESI, [MH] - )m / z:397.9.

[0559] 1 H NMR (500MHz, DMSO-d6) δ11.08(s,1H),7.58(d,J=8.0Hz,1H),7.21(d,J=8.1Hz,1H),4.55(dd,J=12.0,4.9Hz,1H),3.55(dt,J=31.4,5.0Hz,4H),3.22–3 .00(m,4H),2.77(ddd,J=17.3,12.0,5.3Hz,1H),2.60(dt,J=17.3,4.1Hz,1 H),2.46(dd,J=12.2,4.4Hz,1H),2.20–2.12(m,1H),1.38(d,J=6.3Hz,9H).

[0560] Step 12: Preparation of Intermediate 5

[0561] 5L (2.5 g), ethyl acetate (30 mL), and 1,4-dioxane hydrochloride (15 mL, 4 M) were added to the reaction flask in sequence and reacted at room temperature. After the reaction was completed, the filter cake was collected by filtration and dried to obtain intermediate 5 (18.5 g).

[0562] MS (ESI, [M+H] + )m / z:300.2.

[0563] 1 H NMR (500MHz, DMSO-d6) δ11.10(s,1H),9.53(s,2H),7.65(d,J=8.1Hz,1H),7.27(d,J=8.1Hz,1H),4.59(dd,J=12.1,4.9Hz,1H),3.43(dd,J= 7.0,3.3Hz,2H),3.37–3.19(m,6H),2.78(ddd,J=17.3,12.1,5.3Hz,1H),2.61(dt,J=17.3,4.1Hz,1H),2.17(dtd,J=13.4,5.2,3.6Hz,1H).

[0564] Example 6: Synthesis of Intermediate 6

[0565] Step 1: Preparation of intermediate 6b

[0566] Carbon tetrachloride (1500 mL), 6a (100 g), 2,2-azobisisobutyronitrile (4.1 g), and N-bromosuccinimide (265 g) were added to the reaction flask in sequence and heated to 80°C for reaction. After the reaction was completed, the mother liquor was filtered and concentrated to dryness. Petroleum ether was added to the residue, slurried, filtered, and the filter cake was collected and dried to obtain intermediate 6b (154 g).

[0567] 1 H NMR (500MHz, DMSO-d6) δ7.36-7.33(m,1H),7.09-7.04(m,2H),4.78(s,2H),4.76(s,2H),3.87(s,3H).

[0568] Step 2: Preparation of intermediate 6c

[0569] To a reaction flask were added cycloisopropyl malonate (150 g), DMSO (500 mL), triethylamine (255 mL), and intermediate 6b (120 g) in sequence, and the mixture was reacted at room temperature. After completion of the reaction, the reaction solution was poured into water, extracted with EA, and washed sequentially with saturated aqueous citric acid solution, saturated aqueous sodium bicarbonate solution, and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was dissolved in THF and heated to dissolve. A solid precipitated at room temperature, filtered, and the filter cake was collected and dried to obtain intermediate 6c (45 g).

[0570] 1 H NMR (500MHz, DMSO-d6) δ7.21(t,J=7.8Hz,1H),6.83(t,J=7.0Hz,2H),3.79(s,3H),3.63(s,2H),3.49(s,2H),1.77(s,6H).

[0571] Step 3: Preparation of intermediate 6d

[0572] At 0°C, under nitrogen, a 1M solution of lithium aluminum hydride in tetrahydrofuran (163 mL) was slowly added dropwise to a stirred solution of intermediate 6c (45 g) in THF (500 mL). The temperature was controlled below 5°C. The mixture was reacted at 0°C for 0.5 h and then allowed to warm to room temperature. After completion of the reaction, 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 afford intermediate 6d (40.5 g).

[0573] 1H NMR (500MHz, DMSO-d6) δ7.07(t,J=7.8Hz,1H),6.74(d,J=7.4Hz,1H),6.70(d,J=8.1Hz,1 H),4.59(t,J=5.3Hz,2H),3.73(s,3H),3.34(d,J=5.4Hz,4H),2.68(s,2H),2.58(s,2H).

[0574] Step 4: Preparation of intermediate 6e

[0575] Under nitrogen at -20°C, trifluoroacetic anhydride (122 g) was slowly added dropwise to a mixture of intermediate 6d (40.5 g) and DIPEA (76 g) in DCM (500 mL). The mixture was stirred at -5°C for 0.5 h and then allowed to warm to room temperature. After completion, 100 mL of water was added to quench the reaction, followed by extraction with DCM. The product was washed sequentially with 10% aqueous citric acid, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to afford intermediate 6e (64.2 g).

[0576] 1 H NMR (500MHz, DMSO-d6) δ7.20–7.16(m,1H),6.84–6.80(m,2H),4.25(s,4H),3.77(s,3H),2.87(s,2H),2.77(s,2H).

[0577] Step 5: Preparation of intermediate 6f

[0578] At room temperature, under nitrogen, 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 allowed to react overnight. After completion of the reaction, silica gel column chromatography afforded intermediate 6f (31.5 g).

[0579] 1 H NMR (500MHz, DMSO-d6) δ7.33–7.24(m,4H),7.24–7.18(m,1H),7.09(t,J=7.8Hz,1H),6.78(d,J=7.4H z,1H),6.73(d,J=8.1Hz,1H),3.74(s,3H),3.56(s,2H),3.15–3.08(m,4H),3.06(s,2H),2.96(s,2H).

[0580] Step 6: Preparation of Intermediate 6g

[0581] A 4M solution of 1,4-dioxane hydrochloride (79 mL) was added to a solution of intermediate 6f (25.2 g) in DCM (500 mL) at 0°C. The mixture was allowed to react for 5 min, then concentrated to dryness under reduced pressure. DCM (500 mL) was added, the temperature was lowered to -78°C, and a 1M solution of boron tribromide in dichloromethane (271 mL) was slowly added dropwise. After the addition was complete, the mixture was allowed to warm to room temperature and react overnight. After the reaction was complete, the reaction solution was cooled in an ice bath and quenched by the addition of methanol. Saturated sodium bicarbonate solution was added to adjust the pH to neutral. The mixture was extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford intermediate 6g (29.6 g).

[0582] MS (ESI, [M+H] + )m / z:266.1

[0583] 1 H NMR(500MHz,DMSO-d6)δ9.26(s,1H),7.47–7.31(m,5H),6.94(t,J=7.7Hz,1H),6.64( d,J=7.3Hz,1H),6.58(d,J=8.0Hz,1H),4.42–3.41(m,6H),3.13(s,2H),3.06(s,2H).

[0584] Step 7: Preparation of Intermediate 6h

[0585] Intermediate 6g (29.60g), palladium carbon (10%, 29.6g), and MeOH (600mL) were added to the reaction flask in sequence. After hydrogen replacement, the reaction was carried out at 40°C under hydrogen protection overnight. After the reaction was completed, the mixture was filtered and concentrated to obtain intermediate 6h (23.1g).

[0586] MS (ESI, [M+H]+) m / z: 176.1

[0587] Step 8: Preparation of intermediate 6i

[0588] 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 completion of the reaction, 200 mL of saturated sodium bicarbonate was added to quench the reaction, followed by extraction with EA, washing with saturated brine, drying over anhydrous sodium sulfate, filtration, concentration, and silica gel column chromatography to obtain intermediate 6i (25.92 g).

[0589] MS (ESI, [MH] - )m / z:270.1

[0590] Step 9: Preparation of intermediate 6j

[0591] 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 at room temperature and allowed to react. After completion of the reaction, water was added to quench the reaction, followed by extraction with DCM. The organic phase was collected and washed sequentially with 5% aqueous citric acid, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to afford Intermediate 6j (18.58 g).

[0592] 1 H NMR(500MHz,DMSO-d6)δ7.20(t,J=7.7Hz,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).

[0593] Step 10: Preparation of intermediate 6k

[0594] Intermediate 6j (18.4 g), aluminum chloride (15.66 g), and o-dichlorobenzene (200 mL) were sequentially added to a reaction flask, and the mixture was gradually heated from 70°C to 150°C for reaction. After the reaction was completed, 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 for dissolution. The mixture was extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate 6k (15.11 g).

[0595] MS (ESI, [MH] - )m / z:312.1

[0596] 1 H NMR(500MHz,DMSO-d6)δ12.35(s,1H),7.78(d,J=8.0Hz,1H),6.87(d,J=8.0Hz,1H) ,4.41(d,J=5.9Hz,2H),4.10–4.06(m,2H),3.27(s,2H),3.17(s,2H),2.62(s,3H).

[0597] Step 11: Preparation of intermediate 6l

[0598] At 0°C, aqueous sodium hydroxide solution (1 M, 97 mL) was added to a solution of intermediate 6k (15.11 g) in MeOH (150 mL) and allowed to react at room temperature. After completion of the reaction, the methanol was removed by concentration, retaining the water. Dioxane (150 mL) and Boc anhydride (11.58 g) were added to the residue and allowed to react at room temperature. The pH was adjusted to 5-6 by adding 10% citric acid, and the mixture was extracted with EA. The mixture was then washed sequentially with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography to afford intermediate 6l (11.40 g).

[0599] MS (ESI, [MH] - )m / z:316.1

[0600] 1 H NMR (500MHz, DMSO-d6) δ12.34(s,1H),7.77(d,J=8.0Hz,1H),6.85(d,J=8.0Hz,1H),3.81(s,4H),3.18(s,2H),3.06(s,2H),2.61(s,3H),1.38(s,9H).

[0601] Step 12: Preparation of intermediate 6m

[0602] At 0°C, sodium hydroxide (60 wt%, 6.93 g) was added portionwise to a mixed solvent of intermediate 6l (11 g) and diethyl carbonate (20.47 g) in toluene (200 mL) and THF (100 mL). The temperature was raised to 100°C and the reaction was allowed to proceed. After completion of the reaction, the reaction solution was cooled to room temperature and quenched with water. The mixture was extracted with EA, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and chromatographed on a silica gel column to afford intermediate 6m (12.62 g).

[0603] MS (ESI, [MH] - )m / z:388.2

[0604] 1 H NMR(500MHz,DMSO-d6)δ11.74(s,1H),7.70(d,J=8.1Hz,1H),6.87(d,J=8.1Hz,1H),4.19(s,2H), 4.12(q,J=7.1Hz,2H),3.82(s,4H),3.19(s,2H),3.08(s,2H),1.38(s,9H),1.18(t,J=7.1Hz,3H).

[0605] Step 13: Preparation of intermediate 6n

[0606] Intermediate 6m (12.5 g), hydroxylamine (5.30 g), and ethanol (200 mL) were sequentially added to a reaction flask and reacted at 85°C. After completion of the reaction, the reaction solution was cooled to room temperature and the solvent was evaporated under reduced pressure. 500 mL of EA, 200 mL of water, and 150 mL of saturated aqueous sodium carbonate were added to the residue, and the aqueous phase was collected. The pH of the aqueous phase was then adjusted to ~4 with 1 M dilute hydrochloric acid. The aqueous phase was extracted with EA, and 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).

[0607] 1 H NMR(500MHz,DMSO-d6)δ12.86(s,1H),7.62(d,J=8.0Hz,1H),7.27(d,J=8.1Hz ,1H),4.05(s,2H),3.95–3.79(m,4H),3.38(s,2H),3.30(s,2H),1.39(s,9H).

[0608] Step 14: Preparation of intermediate 6o

[0609] 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 completion of the reaction, the reaction solution was cooled to room temperature, 600 mL of water was added, and the mixture was extracted with EA. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain Intermediate 6o (11.02 g).

[0610] MS (ESI, [M+H] + )m / z:387.2

[0611] Step 15: Preparation of intermediate 6p

[0612] Under nitrogen at -5°C, a 1 M solution of potassium tert-butoxide in tetrahydrofuran (15.52 mL) was slowly added dropwise to a mixture of intermediate 6o (10 g) and acrylamide (1.104 g) in THF (300 mL). The addition was complete after 10 minutes, and the mixture was stirred at -5°C. The reaction was quenched by the addition of 200 mL of saturated ammonium chloride solution, and extracted twice with DCM (300 mL each). 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 intermediate 6p (4.32 g).

[0613] MS (ESI, [M+H] + )m / z:412.2

[0614] 1H NMR (500MHz, DMSO-d6) δ11.08(s,1H),7.64(d,J=8.1Hz,1H),7.26(d,J=8.1Hz,1H),4.57(dd,J=12.0,4.9Hz,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).

[0615] Step 16: Preparation of Intermediate 6

[0616] 6p (50 mg), DCM (5.00 mL), and EA (5 mL) were added to the reaction flask in sequence. The reaction solution became clear, and trifluoroacetic acid (1 mL) was added. The reaction was stirred at 25°C overnight. After the reaction was complete, the product was concentrated to dryness, dissolved in DMSO, purified by reverse phase chromatography, and lyophilized to obtain intermediate 6 (25 mg).

[0617] MS (ESI, [M+H] + )m / z:312.2

[0618] 1 H NMR (500MHz, DMSO-d6) δ7.63(d,J=8.0Hz,1H),7.27(d,J=8.1Hz,1H),4.56(dd,J=11.9,5.0Hz,1H),3.61(q,J=8.2Hz, 4H), 3.36 (s, 2H), 3.28 (s, 2H), 2.82–2.71 (m, 1H), 2.60 (dt, J = 17.3, 4.1Hz, 1H), 2.49–2.43 (m, 1H), 2.22–2.12 (m, 1H).

[0619] Example 7 Synthesis of Intermediate 7

[0620] Step 1: Preparation of compound 7b

[0621] 7a (33.3 g), MeOH (500 mL), iodophenyldiacetic acid (82 g, 246 mmol), and potassium hydroxide (127 g) were added sequentially to a reaction flask under an ice bath, and the mixture was reacted at room temperature for 3 hours. The reaction solution was evaporated to remove the solvent under reduced pressure, and the residue was extracted with 500 mL of ethyl acetate and 1000 mL of sodium bicarbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was dissolved in THF (500 mL), and hydrochloric acid (6 M, 68.4 mL) was added and reacted at room temperature. After the reaction, the reaction solution was adjusted to pH 8 with saturated sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain 7b (16 g).

[0622] MS (ESI, [M+H] + )m / z:178.9.

[0623] Step 2: Preparation of compound 7c

[0624] 7b (80 g) and MeOH (1000 mL) were added to a reaction flask in sequence. Sodium borohydride (17.83 g, 471 mmol) was added after the solution was dissolved and allowed to react at room temperature. After completion of the reaction, 500 mL of saturated ammonium chloride solution was added dropwise to quench the reaction mixture. Ethyl acetate was added for extraction, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain 7c (82 g).

[0625] 1 H NMR (500MHz, DMSO-d6) δ7.17(t,J=7.8Hz,1H),6.87(d,J=7.4Hz,1H),6.80(d,J=8.1Hz,1H),5.34(d,J=6.3Hz,1H),5.13(d,J=5.0Hz,1 H), 4.67 (t, J = 5.8Hz, 1H), 4.06 (ddd, J = 12.0, 6.8, 5.1Hz, 1H), 3.75 (s, 3H), 3.03 (dd, J = 15.8, 7.1Hz, 1H), 2.43 (dd, J = 15.8, 6.5Hz, 1H).

[0626] Step 3: Preparation of compound 7d

[0627] 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, the reaction solution was cooled to room temperature and quenched by the addition of 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 evaporated under reduced pressure to obtain 7d (35.5 g).

[0628] 1H NMR (500MHz, DMSO-d6) δ7.26–7.22(m,1H),6.93–6.87(m,2H),3.79(s,3H),3.53(s,2H),3.37(s,2H).

[0629] Step 4: Preparation of compound 7e

[0630] 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 completion of the reaction, 500 mL of saturated ammonium chloride solution was added dropwise to quench the reaction solution. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain 7e (18 g).

[0631] 1 H NMR (500MHz, DMSO-d6) δ7.13–7.07(m,1H),6.83–6.78(m,1H),6.74(d,J=8.1Hz,1H),4.81(d,J=3.8Hz,1H),4.49( tq,J=6.5,3.4Hz,1H),3.75(s,3H),3.04(dd,J=16.1,6.1Hz,1H),2.94(dd,J=16.3,6.2Hz,1H),2.79–2.61(m,2H).

[0632] Step 5: Preparation of compound 7f

[0633] To a reaction flask, 7e (60 g), dichloromethane (500 mL), triethylamine (111 g, 152 mL), and acetic anhydride (41.0 g, 38.2 mL) were added sequentially and allowed to react at room temperature. After completion of the reaction, 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 yield 7f (37.2 g).

[0634] 1 H NMR(500MHz,DMSO-d6)δ7.22–7.06(m,1H),6.82(dd,J=27.3,8.3Hz,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=34.6,17.1Hz,2H),1.97(d,J=15.3Hz,3H).

[0635] Step 6: Preparation of compound 7g

[0636] Boron trichloride (19.22 g, 164 mL) was slowly added dropwise to a solution of 7f (17 g) in dichloromethane (500 mL) under an ice bath. After the addition was complete, the mixture was allowed to warm to room temperature. After completion, the reaction mixture was quenched by adding 160 mL of 1M HCl and 200 mL of aqueous solution. The mixture was then extracted with dichloromethane. The organic phase was separated, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to yield 7g (15 g).

[0637] MS (ESI, [MH] - )m / z:190.9.

[0638] Step 7: Preparation of compound 7h

[0639] 7g (16g), dichloromethane (200mL), triethylamine (9.50g, 13.01mL), and acetic anhydride (5.27g, 4.91mL) were added to the reaction flask in sequence and reacted at room temperature. After the reaction, the reaction solution was washed with 500mL of saturated ammonium chloride solution and 500mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 7h (14.8g).

[0640] MS (ESI, [MH] - )m / z:233.01.

[0641] Step 8: Preparation of compound 7i

[0642] To the reaction flask, 7h (11.6 g), dichloromethane (300 mL), and zirconium tetrachloride (46.2 g) were added sequentially and reacted at 50°C. After completion of the reaction, the reaction solution was cooled to room temperature, and 200 mL of 3M aqueous hydrochloric acid 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 evaporated under reduced pressure to yield 7i (11.4 g).

[0643] 1 H NMR (500MHz, DMSO-d6) δ12.34(s,1H),7.80(d,J=8.0Hz,1H),6.91(d,J=8.0Hz,1H),5.45(tt,J=6.3,2.2Hz,1H),3.37–3.33 (m,1H),3.19(dd,J=17.3,6.3Hz,1H),2.95(dd,J=17.9,2.2Hz,1H),2.86(dd,J=17.3,2.1Hz,1H),2.63(s,3H),1.97(s,3H).

[0644] Step 9: Preparation of compound 7k

[0645] 7i (15.4 g), ethanol (200 mL), and an aqueous solution of sodium hydroxide (2.63 g) (10.00 mL) were added to the reaction flask in sequence and reacted at room temperature. After the reaction, the reaction solution was adjusted to pH 2-3 by adding 2M HCl aqueous solution, then extracted with 100 mL of ethyl acetate and 200 mL of water, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the intermediate crude product 7j. Dichloroethane (200 mL), imidazole (17.90 g), and TBSCl (39.6 g) were added and refluxed overnight. The reaction solution was cooled to room temperature, extracted with 100 mL of dichloromethane and 300 mL of water. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain 7k (15.4 g).

[0646] 1 H NMR (500MHz, DMSO-d6) δ12.25(s,1H),7.69(d,J=8.0Hz,1H),6.79(d,J=8.0Hz,1H),4.64(dq,J=6.2,3.2Hz,1H),3.05(ddd,J =56.3,16.6,6.2Hz,2H),2.71(dd,J=17.0,3.6Hz,1H),2.61(dd,J=16.3,3.5Hz,1H),2.51(s,3H),0.78(s,9H),0.00(s,6H).

[0647] Step 10: Preparation of compound 7l

[0648] To the reaction flask, 7k (8.4 g) and THF (300 mL) were added sequentially. Diethyl carbonate (16.19 g, 16.52 mL) was added and the temperature was cooled to approximately 0°C. 60 wt% sodium hydroxide (5.48 g, 137 mmol) was added portionwise and the reaction was heated to 85°C. After completion of the reaction, 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 3 M hydrochloric acid, then extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to yield 7l (10 g).

[0649] MS (ESI, [MH] - )m / z:331.2.

[0650] Step 11: Preparation of intermediate 7m

[0651] To the reaction flask were added 7l (10 g), aqueous hydroxylamine solution (9.93 g, 9.93 mL), and ethanol (100 mL) in sequence, and the mixture was reacted at 85°C. After completion of the reaction, the reaction mixture was cooled to room temperature, and the residue was extracted with 200 mL of ethyl acetate and 100 mL of saturated sodium carbonate solution. The organic phase was discarded. The aqueous phase was adjusted to pH 2-3 with 1 M HCl solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to yield 7m (11 g).

[0652] MS (ESI, [MH] - )m / z:346.2.

[0653] Step 12: Preparation of intermediate 7n

[0654] To a reaction flask, 7m (10 g), ethanol (150 mL), and sulfuric acid (14.40 g, 7.83 mL) were added sequentially and reacted at 85°C. After completion of the reaction, the reaction solution was cooled to room temperature, and the pH was adjusted to 7 by adding 200 mL of dichloromethane and saturated sodium bicarbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to yield 7n (5.8 g).

[0655] MS (ESI, [M+H] + )m / z:261.97.

[0656] 1 H NMR (500MHz, DMSO-d6) δ7.65(d,J=8.0Hz,1H),7.33(d,J=8.0Hz,1H),5.09(d,J=4.0Hz,1H),4.71(dt,J=6.4,3.1Hz,1H ),4.26–4.12(m,4H),3.30(ddd,J=31.0,16.5,6.0Hz,2H),2.98(ddd,J=31.6,16.5,3.0Hz,2H),1.22(t,J=7.1Hz,3H).

[0657] Step 13: Preparation of Intermediate 7

[0658] Compound 7n (300 mg), dichloromethane (10 mL), and Dess-Martin periodinane (974 mg) were added sequentially to the reaction flask, and the mixture was stirred at room temperature. After completion of the reaction, the reaction solution was poured into a saturated sodium sulfite solution to quench the mixture, followed by extraction with 100 mL of ethyl acetate. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with a saturated sodium bicarbonate solution and then with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent removed from the filtrate under reduced pressure to yield Intermediate 7 (320 mg).

[0659] MS (ESI, [M+H] +)m / z:260.0.

[0660] 1 H NMR(500MHz,DMSO-d6)δ7.74(d,J=8.1Hz,1H),7.38(d,J=8.1Hz,1H),4.21(s ,2H),4.14(q,J=7.1Hz,2H),3.79(s,2H),3.72(s,2H),1.19(t,J=7.1Hz,3H).

[0661] Synthesis of Intermediates 8 and 9 in Examples 8 and 9

[0662] Step 1: Preparation of intermediate 8b

[0663] CCl4 (6750 mL), 8a (450 g), 2,2-azobisisobutyronitrile (18.45 g), and N-bromosuccinimide (1194 g) were added to the reaction flask in sequence. The mixture was heated to 80°C for reaction. After completion of the reaction, the reaction mixture was filtered, the solvent was evaporated under reduced pressure, and petroleum ether was added to the filtrate for slurrying. The mixture was filtered and the filter cake was collected to obtain intermediate 8b (833 g).

[0664] 1 H NMR (500MHz, DMSO-d6) δ7.34(d,J=8.1Hz,1H),7.06(ddd,J=17.8,8.1,1.1Hz,2H),4.77(d,J=9.5Hz,4H),3.87(s,3H).

[0665] Step 2: Preparation of intermediate 8c

[0666] To the reaction flask, 60wt% NaH (187g) and THF (2000mL) were added sequentially, followed by diethyl malonate (300g, 284mL) under ice-cooling. The mixture was stirred at room temperature for 30 minutes, followed by the addition of 8b (606g), and the reaction was stirred at room temperature for 2 hours. Upon completion, the reaction mixture was slowly quenched by the addition of a saturated ammonium chloride solution. The mixture was then extracted with 2000mL of petroleum ether and 2000mL of water, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure to remove the solvent, and purified by silica gel column chromatography to afford intermediate 8c (262g).

[0667] MS (ESI, [MH] - )m / z:291.2

[0668] 1H NMR(500MHz,DMSO-d6)δ7.16(t,J=7.8Hz,1H),6.80(dd,J=15.3,7.8Hz,2H),4.1 4(q,J=7.1Hz,4H),3.77(s,3H),3.48(s,2H),3.38(s,2H),1.17(t,J=7.0Hz,6H).

[0669] Step 3: Preparation of intermediate 8d

[0670] 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 completion of the reaction, the reaction solution was poured into 1000 mL of ice water to quench, and 1 M hydrochloric acid was added to adjust the pH to 2-3. The product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure to remove the solvent to obtain intermediate 8d (191 g).

[0671] MS (ESI, [M+H]+) m / z: 193.05

[0672] Step 4: Preparation of intermediate 8e

[0673] 8d (85 g), ethanol (1000 mL), and concentrated sulfuric acid (44 g) were added sequentially to a reaction flask, and the mixture was heated to 70°C for reaction. After completion of the reaction, the reaction solution was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was poured into ice water and neutralized with saturated aqueous sodium bicarbonate. Extraction was then performed with 1000 mL of petroleum ether. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure to obtain intermediate 8e (99 g).

[0674] MS (ESI, [M+H]+) m / z: 221.1

[0675] 1 H NMR (500MHz, DMSO-d6) δ7.13(t,J=7.8Hz,1H),6.81(d,J=7.5Hz,1H),6.76(d,J=8.2Hz,1H),4.09(q,J=7 .1Hz,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=7.1Hz,3H).

[0676] Step 5: Preparation of intermediate 8f

[0677] In a reaction flask, under N2 protection, boron tribromide (415 g, 1657 mL) was added dropwise to a stirred solution of 8e (150 g) in dichloromethane (750 mL) and allowed to react at 0°C. After the reaction, MeOH (500 mL) was added and the mixture was gradually returned to room temperature with stirring. The reaction solution was poured into a mixed solvent of 1000 mL of ice water and 1000 mL of dichloromethane with stirring, separated by a separatory funnel, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was solvent-free under reduced pressure to obtain intermediate 8f (122 g).

[0678] 1 H NMR(500MHz,DMSO-d6)δ9.24(s,1H),6.95(t,J=7.7Hz,1H),6.70–6.60(m,1H),6.62–6.52(m,1H),4.10(q ,J=7.1Hz,2H),3.33–3.27(m,1H),3.13–3.01(m,3H),2.96(dd,J=16.1,7.1Hz,1H),1.20(t,J=7.1Hz,3H).

[0679] Step 6: Synthesis of Intermediate 8g

[0680] In a reaction flask at 0°C under N2 protection, 8f (130g) and tetrahydrofuran (2000mL) were added sequentially, followed by the slow dropwise addition of a 1M solution of lithium aluminum tetrahydride in tetrahydrofuran (438mL). The mixture was reacted in an ice-water bath. After completion of the reaction, 3L of water was slowly added dropwise to quench the reaction. The pH was adjusted to 1-2 with concentrated hydrochloric acid, and the reaction was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was then freed from the solvent under reduced pressure to yield intermediate 8g (129g).

[0681] 1 H NMR(500MHz,DMSO-d6)δ6.88(t,J=7.7Hz,1H),6.58(d,J=7.3Hz,1H),6.52(d,J=7.9Hz,1H), 3.38–3.32(m,2H),2.84(ddd,J=33.5,16.2,8.3Hz,2H),2.60(dq,J=13.9,8.1,6.6Hz,1H),2.55–2.49(m,3H).

[0682] Step 7: Preparation of Intermediate 8h

[0683] To the reaction flask, 8 g (120 g), 4-dimethylaminopyridine (7.14 g), dichloromethane (2000 mL), and triethylamine (177 g, 244 mL) were added sequentially. Acetyl chloride (101 g, 91 mL) was slowly added dropwise at 0°C and allowed to react at room temperature. After completion of the reaction, 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).

[0684] MS (ESI, [M+H]+) m / z: 249.3

[0685] 1 H NMR(500MHz,DMSO-d6)δ7.18(t,J=7.7Hz,1H),7.11(d,J=7.4Hz,1H),6.88(d,J=7.9Hz,1H),4.07–3.96(m,2H),3 .11–3.00(m,1H),2.87(dd,J=15.9,7.8Hz,1H),2.81–2.69(m,2H),2.56–2.50(m,1H),2.27(s,3H),2.02(s,3H).

[0686] Step 8: Preparation of intermediate 8i

[0687] 8h (91 g), dichloromethane (2000 mL), and zirconium tetrachloride (342 g) were added sequentially to the reaction flask, and the reaction was stirred at 50°C overnight under N2 protection. After completion of the reaction, the reaction solution was cooled to room temperature and poured into a mixed solvent of 1000 mL of ice water and 1000 mL of dichloromethane. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to obtain intermediate 8i (90 g).

[0688] MS (ESI, [MH] - )m / z:247.2

[0689] Step 9: Preparation of intermediate 8j

[0690] 8i (95 g) and ethanol (900 mL) were added sequentially to a reaction flask. A solution of sodium hydroxide (77 g) in H₂O (800 mL) was then added dropwise under an ice bath. The mixture was reacted at room temperature under nitrogen protection. After completion of the reaction, the reaction solution was diluted with 2 L of ethyl acetate and 1 L of water, and 3 M hydrochloric acid was slowly added to adjust the pH to 3. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated from the filtrate under reduced pressure to obtain intermediate 8j (86 g).

[0691] MS (ESI, [MH]- )m / z:205.1

[0692] 1 H NMR (500MHz, DMSO-d6) δ12.34(s,1H),7.73(d,J=8.0Hz,1H),6.84(d,J=8.0Hz,1H),4.68(t,J=5.3Hz,1H),3.36(ddd,J=7.0,5 .2,2.0Hz,2H),2.98(dd,J=17.0,8.2Hz,1H),2.92–2.82(m,1H),2.72(dd,J=16.9,5.6Hz,1H),2.61(s,3H),2.61–2.53(m,2H).

[0693] Step 10: Preparation of intermediate 8k

[0694] 8j (37 g), 1,2-dichloroethane (700 mL), imidazole (36.6 g), and tert-butyldimethylsilyl chloride (29.7 g) were added to the reaction flask in sequence and reacted at 75°C. After the reaction, 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 evaporated from the filtrate under reduced pressure to obtain intermediate 8k (60 g).

[0695] 1 H NMR (500MHz, DMSO-d6) δ12.31(s,1H),7.71(d,J=8.0Hz,1H),6.82(d,J=8.0Hz,1H),3.52(d,J=6.4Hz,2H),2.97(dd,J=16.9,8.0Hz,1H),2. 85(dd,J=15.4,7.5Hz,1H),2.69(dd,J=16.9,5.6Hz,1H),2.64–2.59(m,1H),2.58(s,3H),2.55(d,J=5.6Hz,1H),0.82(s,9H),0.00(s,6H).

[0696] Step 11: Preparation of Intermediate 81

[0697] To a reaction flask, 8k (55 g), diethyl carbonate (101 g, 103 mL), and toluene (1000 mL) were added sequentially. The reaction mixture was cooled to 0°C, and 60 wt% sodium hydride (34.3 g, 858 mmol) was added portionwise. The mixture was slowly heated to 120°C for reaction. Upon completion of the reaction, the reaction mixture 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 mixture was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by evaporation under reduced pressure to yield intermediate 8l (53.6 g).

[0698] MS (ESI, [MH] - )m / z:345.1

[0699] 1 H NMR (500MHz, DMSO-d6) δ12.31(s,1H),7.57(d,J=7.9Hz,1H),7.16(d,J=7.9Hz,1H),5.49(s,1H),3.56(d,J=6.4Hz,2H) ,3.04(ddd,J=16.0,13.3,8.1Hz,2H),2.75(td,J=14.8,13.3,4.4Hz,2H),2.71–2.63(m,1H),0.81(s,9H),0.00(s,6H).

[0700] Step 12: Preparation of Intermediate 8m

[0701] 8l (51 g), hydroxylamine hydrochloride (61.4 g), sodium ethoxide (61.1 g) and ethanol (2000 mL) were added to the reaction flask in sequence and heated to 85°C under N2 protection. After the reaction was completed, the reaction solution was solvent-freeed under reduced pressure, 2 L of water was added, and the pH was adjusted to 8-9 with saturated sodium carbonate solution. Ethyl acetate was added for extraction, and the aqueous phase was collected. 1 M hydrochloric acid was added to the aqueous phase to adjust the pH to 6-7, and ethyl acetate was added for extraction. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was solvent-freeed under reduced pressure to obtain intermediate 8m (47 g).

[0702] MS (ESI, [MH] - )m / z:360.2.

[0703] 1 H NMR(500MHz,DMSO-d6)δ7.55(d,J=8.0Hz,1H),7.22(d,J=8.0Hz,1H),3.97(s,2H),3. 57(d,J=6.6Hz,2H),3.16–3.07(m,2H),2.88–2.72(m,3H),0.81(s,9H),0.00(s,6H).

[0704] Step 13 Preparation of intermediate 8n

[0705] 8m (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 for reaction. 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 to neutralize the reaction. The reaction mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to obtain intermediate 8n (43 g).

[0706] MS (ESI, [M+H] + )m / z:276.1

[0707] 1 H NMR (500MHz, DMSO-d6) δ7.58(d,J=8.0Hz,1H),7.27(d,J=8.0Hz,1H),4.74(q,J=4.9Hz,1H),4.16(s,2H),4.12(t,J=7.1Hz,2H) ,3.43(dd,J=6.8,5.3Hz,2H),3.15(ddd,J=29.7,16.4,8.3Hz,2H),2.93–2.81(m,2H),2.79–2.70(m,1H),1.19(t,J=7.1Hz,3H).

[0708] Step 14 Preparation of Intermediates 8o-1 and 8o-2

[0709] Preparative separation: Dissolve 43 g of intermediate 8n in 430 mL of dichloromethane-ethanol solution to a concentration of approximately 100.0 mg / mL. Filter the filtrate through a 0.45 μm organic filter membrane. Instrument: YMC High-Preparative Chromatography, Column: CHIRALPAK IG (Innovation 036#, 30 x 250 mm, S-10 μm), Mobile Phase A: Ethanol, Mobile Phase B: Hexane. Intermediate 8o-1 (9.057 g) was obtained as the leading peak, and Intermediate 8o-2 (8.833 g) was obtained as the trailing peak.

[0710] 8o-1:MS(ESI,[M+H] + )m / z:276.1.

[0711] 8o-2:MS(ESI,[M+H] + )m / z:276.1.

[0712] Step 15 Preparation of Intermediate 8

[0713] In a reaction flask, 8o-1 (11.93 g), THF (200 mL), and acrylamide (3.39 g) were added in sequence under N2 protection. After cooling to 0°C, potassium tert-butoxide tetrahydrofuran solution (1 M, 34.7 mL) was added, and the mixture was reacted at 0°C. After the reaction was completed, the reaction solution was added dropwise to an ice-cold saturated aqueous ammonium chloride 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, and filtered. The filtrate was evaporated under reduced pressure to remove the solvent, filtered, and the filter cake was collected to obtain 6.77 g of intermediate 8.

[0714] 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 = 11.8, 5.0 Hz, 1H), 3.43 (dd, J = 6.8, 5.3 Hz, 2H), 3.22–3.09 (m, 2H), 2.94–2.83 (m, 2H), 2.76 (dq, J = 16.9, 6.3 Hz, 2H), 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

[0715] 8o-2 (12.83 g), THF (200 mL), and acrylamide (3.64 g) were added to the reaction flask in sequence. After cooling to 0°C, potassium tert-butoxide tetrahydrofuran solution (1 M, 37.3 mL) was added. Under N2 protection, the mixture was reacted at 0°C. After the reaction, the reaction solution was added dropwise to an ice-cold saturated aqueous ammonium chloride solution, and ethyl acetate was added for extraction. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to remove the solvent under reduced pressure, filtered, and the filter cake was collected to obtain intermediate 9 (7.454 g).

[0716] 1H NMR(500MHz,DMSO-d6)δ11.08(s,1H),7.60(d,J=8.2Hz,1H),7.25(d,J=8.1H z,1H),4.74(td,J=5.3,2.2Hz,1H),4.56(dd,J=11.8,5.0Hz,1H),3.43(dd,J =6.8,5.2Hz,2H),3.21–3.09(m,2H),2.94–2.83(m,2H),2.80–2.71(m,2H),2 .60(dt,J=17.3,4.2Hz,1H),2.46(dd,J=12.1,4.5Hz,1H),2.23–2.15(m,1H).

[0717] Example 10 Synthesis of Intermediate 10

[0718] Step 1: Preparation of intermediate 10b

[0719] 10a (100 g), 2,4-dimethoxybenzylamine (102 g), and acetic acid (600 mL) were added to the reaction flask in sequence and reacted at 80°C until completion. Water was added to the reaction solution, filtered, and the filter cake was washed with water and dried to obtain intermediate 10b (95.7 g).

[0720] MS (ESI, [MH] - )m / z:312.02

[0721] 1 H NMR (500MHz, DMSO-d6) δ11.03(s,1H),7.62(dd,J=8.4,7.1Hz,1H),7.29(d,J=7.1Hz,1H),7.22(d,J=8.4Hz,1H), 6.90(d,J=8.4Hz,1H),6.56(d,J=2.4Hz,1H),6.43(dd,J=8.4,2.4Hz,1H),4.60(s,2H),3.80(s,3H),3.73(s,3H).

[0722] Step 2: Preparation of intermediate 10c

[0723] Intermediate 10b (130 g), potassium carbonate (97 g), iodomethane (65 mL), and N,N-dimethylformamide (1 L) were added to the reaction flask in sequence and reacted at 80°C until completion. After cooling to room temperature, water was added to the reaction solution, which was filtered, and the filter cake was washed with water and dried to obtain Intermediate 10c (126 g).

[0724] MS (ESI, [M+H] + )m / z:327.99

[0725] 1 H NMR(500MHz,DMSO-d6)δ7.80(dd,J=8.5,7.2Hz,1H),7.48(d,J=8.4Hz,1H),7.45–7.39(m,1H),6.91(d,J=8.5H z,1H),6.56(d,J=2.4Hz,1H),6.43(dd,J=8.4,2.4Hz,1H),4.60(s,2H),3.95(s,3H),3.79(s,3H),3.72(s,3H).

[0726] Step 3: Preparation of Intermediate 10d

[0727] Intermediate 10c (128 g) and tetrahydrofuran (800 mL) were added sequentially to a reaction flask. Lithium aluminum hydride (89 g) was slowly added at 0°C under N2 protection, and the temperature was raised to 80°C for reaction until completion. To the reaction solution, 89 mL of water was slowly added dropwise under an ice bath, followed by 267 mL of a 15% aqueous NaOH solution and 89 mL of water. The mixture was stirred for 0.5 h and filtered through celite. The filter cake was washed with ethyl acetate, and the filtrate was collected. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to afford Intermediate 10d (86.4 g).

[0728] MS (ESI, [M+H] + )m / z:300.20

[0729] 1 H NMR (500MHz, DMSO-d6) δ7.26(d,J=8.3Hz,1H),7.18(t,J=7.8Hz,1H),6.90–6.77(m,2H),6.57(d,J=2.4H z,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=3.6Hz,6H).

[0730] Step 4: Preparation of intermediate 10e

[0731] Intermediate 10d (86 g), 10% palladium on carbon (15 g), methanol (500 mL) and di-tert-butyl dicarbonate (63.3 g) were added to the reaction flask in sequence and reacted at room temperature under a hydrogen atmosphere at 0°C. The reaction mixture was filtered and the filtrate was concentrated to obtain Intermediate 10e (100 g).

[0732] 1H NMR (500MHz, DMSO) δ7.27(t,J=7.9Hz,1H),6.93–6.86(m,2H),4.60–4.53(m,2H),4.50–4.43(m,2H),3.80(d,J=1.4Hz,3H),1.45(s,9H).

[0733] Step 5: Preparation of Intermediate 10f

[0734] The reaction flask was sequentially added with intermediate 10e (100 g), dichloromethane (1000 mL) and trifluoroacetic acid (457 g), and the reaction was completed at room temperature for 2 h. 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 completed at room temperature. The reaction solution was slowly added to a saturated sodium bicarbonate solution to quench the reaction, and then ethyl acetate was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give intermediate 10f (57.4 g).

[0735] Step 6: Preparation of intermediate 10g

[0736] Intermediate 10f (40 g) and acetonitrile (500 mL) were added to the reaction flask in sequence. After dissolution, N-bromosuccinimide (30.5 g) was added and the mixture was allowed to react at 75°C until completion. The reaction mixture was quenched with ice water, filtered, and the filter cake was washed with water and dried to obtain Intermediate 10g (60 g).

[0737] 1 H NMR (500MHz, DMSO-d6) δ7.51(dd,J=8.7,1.5Hz,1H),6.96(d,J=8.6Hz,1H),4.95(d,J=29.1Hz,2H),4.76(d,J=29.7Hz,2H),3.83(d,J=2.4Hz,3H).

[0738] Step 7: Preparation of Intermediate 10h

[0739] 10g (40g) and chloroacetyl chloride (30mL) were added to the reaction flask in sequence. Trifluoromethanesulfonic acid (120mL) was slowly added dropwise under an ice-water bath and allowed to react at 50°C until the reaction was complete. The reaction solution was slowly added dropwise to ice water and extracted twice with dichloromethane. The organic phases were combined and washed twice with saturated sodium bicarbonate aqueous solution. The organic layer 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 10h (20g).

[0740] 1H NMR (500MHz, DMSO-d6) δ7.84(d,J=8.8Hz,1H),5.31(s,1H),5.15(s,1H),5.01(d,J=2.4Hz,2H),4.99(s,1H),4.79(s,1H),3.93(d,J=19.4Hz,3H).

[0741] Step 8: Preparation of intermediate 10i

[0742] 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 and allowed to react at room temperature until the reaction was complete. The reaction solution was slowly added to ice water and extracted twice with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the target intermediate 10i (20 g).

[0743] MS (ESI, [M+H] + )m / z:386.00

[0744] 1 H NMR (500MHz, DMSO-d6) δ11.37(s,1H),7.98(d,J=2.5Hz,1H),5.18(s,2H),5.09(s,1H),5.00(s,1H),4.89(s,1H),4.80(s,1H).

[0745] Step 9: Preparation of Intermediate 10j

[0746] 10i (19.5 g), sodium bicarbonate (12.7 g), and acetonitrile (900 mL) were added to the reaction flask in sequence and reacted at 80°C until completion. Water and ethyl acetate were added, and the organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the target intermediate 10j (24 g).

[0747] 1 H NMR (500MHz, DMSO-d6) δ7.87 (s, 1H), 5.21 (d, J = 2.4Hz, 1H), 5.06 (s, 1H), 4.99 (d, J = 2.1Hz, 1H), 4.97 (d, J = 3.1Hz, 2H), 4.85 (s, 1H).

[0748] Step 10: Preparation of intermediate 10k

[0749] 10j (23.4 g), 10% palladium / carbon (1.4 g), sodium bicarbonate (5.61 g), and ethanol (400 mL) were added to the reaction flask in sequence. The reaction was allowed to proceed at room temperature in the presence of hydrogen gas 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, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography to obtain the target intermediate 10k (12 g).

[0750] MS (ESI, [MH] - )m / z:270.00

[0751] 1 H NMR (500MHz, DMSO-d6) δ7.65(dd,J=7.9,2.5Hz,1H),7.20(dd,J=12.0,7.9Hz,1H),5.14(s,1H),5.10(s,1H),4.94(s,1H),4.92–4.88(m,3H).

[0752] Step 11: Preparation of Intermediate 101

[0753] 10k (11.5 g), ethoxycarbonylmethylenetriphenylphosphine (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, and the organic layer was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography to obtain the target intermediate 10l (5.3 g).

[0754] 1 H NMR(500MHz,DMSO-d6)δ7.96(d,J=2.9Hz,1H),7.60(dd,J=8.0,3.3Hz,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=7.1Hz,2H),3.81(d,J=1.0Hz,2H),1.19(t,J=7.1Hz,3H).

[0755] Step 12: Preparation of intermediate 10m

[0756] 10l (5.3 g), potassium carbonate (6.4 g), and ethanol (50 mL) were added to the reaction flask in sequence and allowed to react at room temperature until the reaction was complete. Ethyl acetate and water were added to the reaction system, and the organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the target intermediate 10m (4.3 g).

[0757] MS (ESI, [M+H] +)m / z:246.10

[0758] Step 13: Preparation of Intermediate 10n

[0759] 10m (4.3 g), triethylamine (3.47 g), and dichloromethane (50 mL) were added to the reaction flask in sequence, followed by di-tert-butyl dicarbonate (4.11 g). The reaction was allowed to react at room temperature until completion. Water was added to the reaction system, and the organic layer was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography to obtain the target intermediate 10n (3.7 g).

[0760] 1 H NMR (500MHz, DMSO-d6) δ7.93(s,1H),7.53(d,J=7.9Hz,1H),7.23(t,J=7.6Hz,1H),4.80(dd,J=12.9,2 .4Hz,2H),4.73–4.66(m,2H),4.11(q,J=7.1Hz,2H),3.79(s,2H),1.48(s,9H),1.19(t,J=7.1Hz,3H).

[0761] Step 14: Preparation of Intermediate 10o

[0762] 10n (3.7 g), acrylamide (0.84 g), and N,N-dimethylformamide (50 mL) were added sequentially to the reaction flask, cooled to 0°C, and potassium tert-butoxide (8.6 mL, 1 M) was slowly added dropwise. The reaction was allowed to proceed at 0°C until completion. The reaction solution was added dropwise to an icy aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography to obtain the target intermediate 10o (2.6 g).

[0763] 1 H NMR (500MHz, DMSO-d6) δ10.90(s,1H),7.91(s,1H),7.53(dd,J=8.0,1.9Hz,1H),7.22(t,J=7.9Hz,1H),4.86–4.77(m,2H),4.69(d,J=11.8Hz,2H),4. 15(dd,J=12.1,5.0Hz,1H),2.77–2.69(m,1H),2.58(dt,J=17.4,4.0Hz,1H ),2.33(qd,J=12.5,4.4Hz,1H),2.15–2.07(m,1H),1.48(d,J=2.6Hz,9H).

[0764] Step 15: Preparation of Intermediate 10

[0765] 10o (2.4 g) and dioxane (15 mL) were added to the reaction flask in sequence, followed by a hydrochloric acid-dioxane solution (15 mL, 4 M). The reaction was allowed to proceed 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).

[0766] MS (ESI, [M+H] + )m / z:271.15

[0767] 1 H NMR(500MHz,DMSO-d6)δ10.92(s,1H),10.16(s,2H),7.99(s,1H),7.61(d,J =8.0Hz,1H),7.29(d,J=8.1Hz,1H),4.75(d,J=5.0Hz,2H),4.61(d,J=5.1Hz ,2H),4.18(dd,J=12.2,4.9Hz,1H),2.80–2.71(m,1H),2.58(dt,J=17.3,4. 0Hz, 1H), 2.34 (qd, J=12.6, 4.4Hz, 1H), 2.11 (dtd, J=13.2, 5.2, 3.4Hz, 1H).

[0768] Example 11 Synthesis of Intermediate 11

[0769] Step 1: Preparation of intermediate 11b

[0770] Intermediate 11a and methanol (1500 mL) were added to the reaction flask in sequence. Sodium cyanoborohydride (148 g) was added at 0°C, and the mixture was reacted at 0°C for 10 minutes. Boron trifluoride etherate (334 g) was added dropwise at 0°C, and the mixture was heated to 75°C for reaction. After the reaction was completed, 50 mL of saturated sodium bicarbonate solution was added to the reaction solution, and the solvent was removed by evaporation under reduced pressure. The solution was extracted with dichloromethane and water, and the organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was then evaporated under reduced pressure to remove the solvent to obtain the target intermediate 11b (102.65 g).

[0771] MS (ESI, [M+H] + )m / z:212.2.

[0772] 1 H NMR (500MHz, DMSO-d6) δ7.38(dd,J=7.7,1.4Hz,1H),7.08(dd,J=16.0,7.5Hz,2H),3.74(s,2H),2.89(t,J=5.8Hz,2H),2.68(t,J=5.8Hz,2H).

[0773] Step 2: Preparation of intermediate 11c

[0774] Intermediate 11b (100.06 g) and tetrahydrofuran (1000 mL) were added to the reaction flask in sequence. Trifluoroacetic anhydride (95 g, 63.2 mL) was added under ice-cooling conditions, and the mixture was returned to room temperature for reaction. After the reaction was completed, 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 to obtain the target intermediate 11c (137.6 g).

[0775] 1 H NMR(500MHz,DMSO-d6)δ7.54(dd,J=7.9,1.4Hz,1H),7.26(q,J=7.0,5.9Hz,1H),7.23–7 .18(m,1H),4.71(d,J=27.7Hz,2H),3.82(t,J=6.0Hz,2H),2.95(dt,J=13.6,6.0Hz,2H).

[0776] Step 3: Preparation of intermediate 11d

[0777] To the reaction flask were added intermediate 11c (137.6 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (36.5 g), pinacol diboron (136 g), potassium acetate (131 g), and dioxane (1500 mL). Under nitrogen protection, the mixture was heated to 85°C for reaction. After the reaction was complete, the reaction solution was filtered, and the filtrate was evaporated to remove the solvent under reduced pressure. Petroleum ether was added to the filtrate, the mixture was filtered, and the filtrate was extracted with 2 L of water. The organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated to remove the filtrate under reduced pressure to obtain the target intermediate 11d (165.4 g).

[0778] MS (ESI, [M+H] + )m / z:356.2.

[0779] 1 H NMR(500MHz,DMSO-d6)δ7.59(ddd,J=7.4,3.7,1.4Hz,1H),7.33(ddd,J=17.9,7.6,1.4Hz,1H),7.29–7.22(m,1H),5 .03(d,J=38.6Hz,2H),3.80(t,J=6.2Hz,1H),3.75(t,J=6.4Hz,1H),2.94(t,J=6.3Hz,2H),1.31(d,J=4.3Hz,12H).

[0780] Step 4: Preparation of intermediate 11e

[0781] Intermediate 11d (165.4 g), tetrahydrofuran (1000 mL), and acetic acid (98 g, 93 mL) were added to the reaction flask in sequence. 30% hydrogen peroxide (185 g, 166 mL) was added in an ice bath, and the mixture was allowed to return to room temperature for reaction. Upon completion, the reaction mixture was poured into an ice-cold saturated sodium thiosulfate solution to quench the reaction. 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, and filtered. The filtrate was evaporated to remove the solvent under reduced pressure, and the residue was slurried in 200 mL of petroleum ether / methyl tert-butyl ether, filtered, and the filter cake collected to yield the target intermediate 11e (85.3 g).

[0782] MS (ESI, [MH] - )m / z:244.2.

[0783] 1 H NMR(500MHz,DMSO-d6)δ9.80(d,J=25.4Hz,1H),7.03(q,J=7.9Hz,1H),6.71(dd,J=8.0,3.1Hz,1H ),6.64(t,J=6.9Hz,1H),4.61(d,J=23.4Hz,2H),3.81–3.75(m,2H),2.84(dt,J=16.8,5.9Hz,2H).

[0784] Step 5: Preparation of intermediate 11f

[0785] 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 for reaction. After completion of the reaction, 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 evaporated under reduced pressure to obtain the target intermediate 11f (47.4 g).

[0786] 1 H NMR(500MHz,DMSO-d6)δ7.18(q,J=8.2Hz,1H),6.83(t,J=6.9Hz,1H),6.78(dd,J=8.3,2.8Hz ,1H),4.75–4.66(m,4H),3.83–3.77(m,2H),2.89(dt,J=17.6,6.0Hz,2H),1.43–1.41(m,9H).

[0787] Step 6: Preparation of Intermediate 11g

[0788] 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 allowed to react at room temperature for 1 hour. After completion of the reaction, the solvent was evaporated under reduced pressure. Dichloromethane was added to the residue, and the solvent was evaporated under reduced pressure to obtain the target intermediate 11g (34.2 g).

[0789] MS (ESI, [MH] - )m / z:302.0.

[0790] 1 H NMR(500MHz,DMSO-d6)δ13.04(s,1H),7.18(q,J=7.9Hz,1H),6.85–6.75(m, 2H), 4.78–4.66 (m, 4H), 3.81 (q, J=5.6Hz, 2H), 2.88 (dt, J=18.5, 5.9Hz, 2H).

[0791] Step 7: Preparation of Intermediates 11h and 11i

[0792] The intermediate 11g (33.7g), tetrahydrofuran (350mL) and thionyl chloride (39.7g) were added to the reaction flask in sequence, and the mixture was heated to 75°C for reaction. After the reaction was completed, the reaction solution was cooled to room temperature and the solvent was removed by distillation under reduced pressure to obtain the target intermediate 11h. Dichloromethane (350mL) and aluminum chloride (39.7g) were added to the intermediate 11h, and the mixture was stirred at room temperature for reaction. After the reaction was completed, the reaction solution was poured into 500mL of ice water to quench and filtered through celite. The filtrate was extracted with 100mL of dichloromethane and 100mL of water, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain the target intermediate 11i (32.5g).

[0793] 1 H NMR(500MHz,DMSO-d6)δ7.50(dd,J=9.6,7.9Hz,1H),7.02(dd,J=8.0,5.7Hz,1H),4.87(s ,2H),4.78(d,J=21.1Hz,2H),3.88(td,J=5.9,2.5Hz,2H),3.02(dt,J=13.1,5.8Hz,2H).

[0794] Step 8: Preparation of intermediate 11j

[0795] Intermediate 11i (32.5 g), ethoxycarbonylmethylenetriphenylphosphine (54.7 g), and toluene (350 mL) were added sequentially to a reaction flask. Under nitrogen protection, the mixture was heated to 120°C for reaction. After completion of the reaction, 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 and filtered. The filtrate was purified on a silica gel column to obtain the target intermediate 11j (19.37 g).

[0796] 1 H NMR (500MHz, DMSO-d6) δ7.92(s,1H),7.47(t,J=8.2Hz,1H),7.12(dd,J=8.0,5.9Hz,1H),4.99(d,J=22.7Hz,2H),4.11 (q,J=7.1Hz,2H),3.93–3.87(m,2H),3.78(d,J=1.0Hz,2H),3.02(dt,J=13.4,5.9Hz,2H),1.19(td,J=7.1,1.3Hz,3H).

[0797] Step 9: Preparation of intermediate 11k

[0798] 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 completion of the reaction, the reaction solution was extracted with 300 mL of ethyl acetate and 500 mL of water. 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, and filtered. The filtrate was evaporated under reduced pressure to remove the solvent to obtain the target intermediate 11k (13.12 g).

[0799] MS (ESI, [M+H] + )m / z:260.1.

[0800] 1 H NMR(500MHz,DMSO-d6)δ7.81(s,1H),7.32(d,J=8.0Hz,1H),6.97(d,J=7.9Hz,1H),4.10(q,J=7.1Hz,2H) ,4.05(s,2H),3.73(d,J=1.0Hz,2H),2.98(t,J=5.8Hz,2H),2.76(t,J=5.7Hz,2H),1.18(t,J=7.1Hz,3H).

[0801] Step 10: Preparation of intermediate 111

[0802] 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 allowed to react at room temperature. After completion of the reaction, the solvent was evaporated under reduced pressure, 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 on a silica gel column to obtain the target intermediate 11l (16.32 g).

[0803] MS (ESI, [M+H] + )m / z:360.2.

[0804] 1 H NMR (500MHz, DMSO-d6) δ7.88 (s, 1H), 7.40 (d, J = 7.9Hz, 1H), 7.06 (d, J = 7.9Hz, 1H), 4.73 (s, 2H), 4.10 (q, J = 7. 1Hz,2H),3.78–3.75(m,2H),3.63(t,J=5.8Hz,2H),2.87(t,J=5.8Hz,2H),1.45(s,9H),1.19(t,J=6.6Hz,3H).

[0805] Step 11: Preparation of intermediate 11m

[0806] Intermediate 11l (16.32 g), N,N-dimethylformamide (160 mL), and acrylamide (3.55 g) were added to the reaction flask in sequence. Under N2 protection, the temperature was lowered to 0°C, and potassium tert-butoxide tetrahydrofuran solution (1 mol / L, 40.9 mL) was added, and the mixture was reacted at 0°C. After the reaction was completed, the reaction solution was added dropwise to an ice-cold saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by evaporation under reduced pressure. The residue was added to 200 mL of petroleum ether / ethyl acetate, slurried, filtered, and the filter cake was collected to obtain the target intermediate 11m (14.5 g).

[0807] MS (ESI, [M+H] + )m / z:385.1.

[0808] 1H NMR(500MHz,DMSO-d6)δ10.89(s,1H),7.88(s,1H),7.39(d,J=8.0Hz,1H),7.0 5(d,J=8.0Hz,1H),4.73(s,2H),4.12(dd,J=12.0,4.9Hz,1H),3.63(t,J=5.8H z,2H),2.87(t,J=5.8Hz,2H),2.73(td,J=12.2,6.0Hz,1H),2.59–2.54(m,1H) ,2.31(qd,J=12.5,4.4Hz,1H),2.10(ddt,J=9.9,5.2,2.7Hz,1H),1.44(s,9H).

[0809] Step 12: Preparation of Intermediate 11

[0810] Intermediate 11m (14.5 g), dichloromethane (150 mL), and 1,4-dioxane hydrochloride solution (4 mol / L, 141 mL) were added sequentially to a reaction flask and the mixture was reacted at room temperature. The solvent was evaporated under reduced pressure, and the residue was slurried with methyl tert-butyl ether and filtered to collect the filter cake to obtain Intermediate 11 (12.6 g).

[0811] MS (ESI, [M+H] + )m / z:285.1.

[0812] 1 H NMR(500MHz,DMSO-d6)δ10.90(s,1H),9.87(s,2H),7.93(s,1H),7.49(d,J=8.0Hz, 1H),7.10(d,J=8.1Hz,1H),4.45(s,2H),4.15(dd,J=12.1,4.8Hz,1H),3.40(t,J=6 .1Hz,2H),3.12(t,J=6.1Hz,2H),2.75(ddd,J=17.4,12.3,5.3Hz,1H),2.57(dt,J= 17.3, 4.0Hz, 1H), 2.32 (qd, J=12.6, 4.5Hz, 1H), 2.10 (ddt, J=9.9, 5.2, 2.6Hz, 1H).

[0813] Example 12 Synthesis of Intermediate 12

[0814] Step 1: Preparation of intermediate 12a

[0815] Intermediate 4c, acetonitrile (130 mL), potassium carbonate (14.09 g), and tert-butyl bromoacetate (10.94 g, 8.29 mL) were added to the reaction flask in sequence, and the mixture was heated to 80°C for reaction. After the reaction was completed, 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 combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the target intermediate 12a (20.33 g).

[0816] 1 H NMR (500MHz, DMSO-d6) δ7.17(t,J=8.0Hz,1H),6.87(t,J=7.8Hz,1H),6.76(t,J=8.0Hz,1H),4.75(d,J=4.8 Hz, 2H), 4.70 (d, J = 4.6Hz, 2H), 3.84 (t, J = 6.1Hz, 2H), 2.81 (dt, J = 16.3, 6.1Hz, 2H), 1.41 (d, J = 2.4Hz, 9H).

[0817] Step 2: Preparation of intermediate 12b

[0818] 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 allowed to react at room temperature. After completion of the reaction, the solvent was evaporated under reduced pressure. Dichloromethane was added to the residue, and the solvent was evaporated under reduced pressure to obtain the target intermediate 12b (16.2 g).

[0819] MS (ESI, [MH] - )m / z:301.9.

[0820] 1 H NMR (500MHz, DMSO-d6) δ13.00(s,1H),7.17(t,J=7.9Hz,1H),6.87(t,J=8.0Hz,1H),6.77(t,J=7.6Hz, 1H), 4.74 (d, J = 4.7Hz, 2H), 4.72 (d, J = 4.1Hz, 2H), 3.84 (t, J = 6.1Hz, 2H), 2.81 (dt, J = 16.2, 6.1Hz, 2H).

[0821] Step 3: Preparation of intermediates 12c and 12d

[0822] 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 completion of the reaction, the solvent was removed by evaporation under reduced pressure to obtain the target intermediate 12c. Trifluoromethanesulfonic acid (100 mL) was added dropwise to intermediate 12c in an ice bath, and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was poured into 2000 mL of ice-water solution, and 500 mL of ethyl acetate was added. The organic phase was separated, and saturated sodium bicarbonate solution was added to adjust the pH to 8. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified on a silica gel column to obtain the target intermediate 12d (3.27 g).

[0823] 1 H NMR(500MHz,DMSO-d6)δ7.49(d,J=8.0Hz,1H),7.08(dd,J=13.3,8.0Hz,1H),4 .89–4.84(m,4H),3.90(dt,J=10.0,6.1Hz,2H),2.88(dt,J=17.6,6.0Hz,2H).

[0824] Step 4: Preparation of intermediate 12e

[0825] Intermediate 12d (4.59 g), ethoxycarbonylmethylenetriphenylphosphine (8.41 g), and toluene (100 mL) were added to the reaction flask in sequence. Under nitrogen protection, the mixture was heated to 130°C for reaction. After completion of the reaction, 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 on a silica gel column to obtain the target intermediate 12e (3.93 g).

[0826] 1 H NMR (500MHz, DMSO-d6) δ7.92(d,J=2.7Hz,1H),7.46(dd,J=8.1,3.2Hz,1H),7.16(t,J=8.4Hz,1H),4.88(d,J=7.3Hz,2H),4 .10(q,J=7.1Hz,2H),3.97–3.91(m,2H),3.77(d,J=1.0Hz,2H),3.09(dt,J=15.5,6.0Hz,2H),1.19(td,J=7.0,0.8Hz,3H).

[0827] Step 5: Preparation of intermediate 12f

[0828] Intermediate 12e (3.93 g), potassium carbonate (4.36 g), and ethanol (50 mL) were added to the reaction flask in sequence, and the mixture was reacted at room temperature. After completion of the reaction, 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 solvent was evaporated under reduced pressure to obtain the target intermediate 12f (2.63 g).

[0829] MS (ESI, [M+H] + )m / z:260.1.

[0830] 1 H NMR(500MHz,DMSO-d6)δ7.83(s,1H),7.31(d,J=7.9Hz,1H),6.92(d,J=7.9Hz,1H),4.09(t,J=7.1Hz,2H) ,3.92(s,2H),3.74(d,J=1.0Hz,2H),3.02(t,J=5.9Hz,2H),2.83(t,J=5.9Hz,2H),1.18(t,J=7.1Hz,3H).

[0831] Step 6: Preparation of Intermediate 12g

[0832] 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 to the reaction flask in sequence and the mixture was allowed to react at room temperature. After completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was extracted with 200 mL of ethyl acetate and 200 mL of water. 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 on a silica gel column to obtain the target intermediate 12g (3.53 g).

[0833] MS (ESI, [M+H] + )m / z:360.1.

[0834] 1 H NMR (500MHz, DMSO-d6) δ7.88(d,J=1.1Hz,1H),7.40(d,J=8.0Hz,1H),7.06(d,J=8.0Hz,1H),4.61(s,2H),4.10(q,J= 7.1Hz,2H),3.76(d,J=1.1Hz,2H),3.66(t,J=5.9Hz,2H),2.94(t,J=5.9Hz,2H),1.43(s,9H),1.18(t,J=7.1Hz,3H).

[0835] Step 7: Preparation of Intermediate 12h

[0836] The intermediate 12g (3.71g), N,N-dimethylformamide (12mL), and acrylamide (0.807g) were added to the reaction flask in sequence. Under N2 protection, the temperature was lowered to 0°C and potassium tert-butoxide tetrahydrofuran solution (1moL / L, 8.26mL) was added. The mixture was reacted at 0°C for 1h. After the reaction was completed, the reaction solution was added dropwise to an ice-cold saturated aqueous ammonium chloride solution and extracted with ethyl acetate. 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 on a silica gel column to obtain the target intermediate 12h (2.57g).

[0837] MS (ESI, [M+H] + )m / z:385.2.

[0838] 1 H NMR(500MHz,DMSO-d6)δ10.89(s,1H),7.87(s,1H),7.40(d,J=8.0Hz,1H),7.05( d,J=8.1Hz,1H),4.61(s,2H),4.11(dd,J=12.0,4.9Hz,1H),3.66(t,J=6.0Hz,2H ),2.95(t,J=5.9Hz,2H),2.74(ddd,J=17.3,12.2,5.3Hz,1H),2.57(dt,J=17.3, 4.1Hz,1H),2.35–2.27(m,1H),2.10(dtd,J=13.5,5.2,3.7Hz,1H),1.43(s,9H).

[0839] Step 8: Preparation of Intermediate 12

[0840] Intermediate 12h (2.57 g), dichloromethane (25 mL), and 1,4-dioxane hydrochloride solution (4 mol / L, 25.10 mL) were added sequentially to the reaction flask and the mixture was allowed to react at room temperature. After completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was slurried with methyl tert-butyl ether and filtered to collect the filter cake to obtain Intermediate 12 (2.09 g).

[0841] MS (ESI, [M+H] + )m / z:285.1.

[0842] 1H NMR(500MHz,DMSO-d6)δ10.90(s,1H),9.72(s,2H),7.94(s,1H),7.48(d,J=8.1Hz, 1H),7.10(d,J=8.2Hz,1H),4.35(d,J=4.1Hz,2H),4.14(dd,J=12.1,4.9Hz,1H),3. 38(s,2H),3.18(t,J=6.2Hz,2H),2.75(ddd,J=17.4,12.3,5.4Hz,1H),2.57(dt,J= 17.3, 4.0Hz, 1H), 2.32 (qd, J=12.6, 4.4Hz, 1H), 2.10 (dtd, J=13.4, 5.2, 3.5Hz, 1H).

[0843] Example 13 Synthesis of Intermediate 13

[0844] Step 1: Preparation of intermediate 13a

[0845] To the reaction flask were added 5d (32.0 g), 10% palladium on carbon (6.1 g), and methanol (250 mL), followed by three hydrogen substitutions. The reaction was allowed to proceed overnight. After completion of the reaction, the mixture was filtered through Celite, the filtrate was dried, 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 afford intermediate 13a (22.7 g).

[0846] MS (ESI, [M+H] + )m / z:274.0.

[0847] Step 2: Preparation of intermediate 13b

[0848] At 0°C, under nitrogen, a dichloromethane solution of boron tribromide (125 mL, 1 M) was slowly added dropwise to a dichloromethane solution of 13a (22.7 g) (200 mL). After the addition was complete, the mixture was allowed to warm to room temperature and allowed to react. Upon completion of the reaction, the reaction mixture was slowly poured into 350 mL of ice water and stirred for 10 min. The dichloromethane was evaporated, filtered, and the filter cake was collected and dried to yield 13b (21.1 g).

[0849] MS (ESI, [MH] - )m / z:258.1.

[0850] 1H NMR(500MHz,DMSO-d6)δ9.39(s,1H),6.93(td,J=7.7,3.0Hz,1H),6.71(ddd,J=8 .1,4.7,1.1Hz,1H),6.61(t,J=7.2Hz,1H),3.72–3.57(m,4H),3.07–2.86(m,4H).

[0851] Step 3: Preparation of intermediate 13c

[0852] To the reaction flask were added 13b (20.5 g), tert-butyl bromoacetate (18.5 g), potassium carbonate (27.3 g), and DMF (100 mL) in sequence. The reaction mixture was heated to 80°C for reaction. The reaction mixture 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 afford 13c (34.5 g).

[0853] MS (ESI, [MH] - )m / z:372.1.

[0854] Step 4: Preparation of intermediate 13d

[0855] To the reaction flask were added 13c (29.5 g), trifluoroacetic acid (90.2 g), and dichloromethane (200 mL) in sequence and reacted at room temperature. After the reaction was complete, the dichloromethane was evaporated, and 300 mL of water was added. The mixture was stirred for 10 min, filtered, and the filter cake was collected and dried to afford 13d (23.5 g).

[0856] MS (ESI, [MH] - )m / z:316.0.

[0857] Step 5: Preparation of intermediate 13f

[0858] 13d (21.2 g), thionyl chloride (79.5) g, and tetrahydrofuran (200 mL) were added to the reaction flask in sequence, and the reaction solution was heated to 80°C for reaction. The reaction solution was spin-dried to obtain 13e, and dichloromethane (200 mL) was added. The reaction solution was cooled to 0°C and trifluoromethanesulfonic acid (49.7 g) was slowly added dropwise. After the addition was complete, the reaction was moved to room temperature. The reaction solution was slowly poured into 400 mL of ice water, dichloromethane was added, the organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the concentrate was separated and purified by silica gel column chromatography to obtain intermediate 13f (8.8 g).

[0859] MS (ESI, [M+H] + )m / z:300.1.

[0860] 1H NMR (500MHz, DMSO-d6) δ7.44(dd,J=7.8,1.9Hz,1H),7.01(t,J=8.4Hz,1H),4.82(d,J=2.0Hz,2H),3.73(dq,J=9.9,5.8Hz,4H),3.16–3.06(m,4H).

[0861] Step 6: Preparation of Intermediate 13g

[0862] 13f (8.8 g), ethoxycarbonylmethylenetriphenylphosphine (14.2 g), and toluene (50 mL) were added to the reaction flask in sequence, and the reaction solution was heated to 130°C and reacted overnight. 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, and filtered. The concentrate was separated and purified by silica gel column chromatography to obtain intermediate 13g (6.8 g).

[0863] MS (ESI, [M+H] + )m / z:370.1

[0864] 1 H NMR(500MHz,DMSO-d6)δ7.92–7.84(m,1H),7.36(dd,J=7.8,3.1Hz,1H),7.10(t,J=7.9Hz,1H),4.1 0(q,J=7.1Hz,2H),3.81–3.70(m,6H),3.30–3.20(m,2H),3.16–3.06(m,2H),1.19(t,J=7.1Hz,3H).

[0865] Step 7: Preparation of Intermediate 13h

[0866] To the reaction flask were added 13g (6.8g), potassium carbonate (7.6g), and ethanol (100mL) in sequence. The reaction mixture was heated to 50°C and allowed to react overnight. The reaction mixture was cooled to room temperature, and 70mL of ethyl acetate and 150mL of water were added. The organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The concentrate was separated and purified by silica gel column chromatography to obtain intermediate 13h (3.8g).

[0867] MS (ESI, [M+H] + )m / z:274.2

[0868] Step 8: Preparation of intermediate 13i

[0869] To the reaction flask were added 13h (3.8 g), triethylamine (2.8 g), and dichloromethane (50 mL) in sequence. Boc anhydride (3.64 g) was added with stirring and allowed to react at room temperature. 70 mL of dichloromethane and 100 mL of water were added, and the organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The concentrate was purified by silica gel column chromatography to afford intermediate 13i (3.9 g).

[0870] Step 9: Preparation of intermediate 13j

[0871] At 0°C, under nitrogen, a solution of potassium tert-butoxide in tetrahydrofuran (7.7 mL, 1 M) was slowly added dropwise to a solution of 13i (3.7 g) and acrylamide (0.7 g) in DMF (30 mL). After the addition was complete, the mixture was incubated for reaction. After 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 slurried with ethyl acetate, filtered, and dried to yield 13j (2.1 g).

[0872] MS (ESI, [MH] - )m / z:397.0.

[0873] 1 H NMR (500MHz, DMSO-d6) δ10.88(s,1H),7.85(s,1H),7.30(d,J=7.9Hz,1H),7.05(d ,J=7.9Hz,1H),4.09(dd,J=11.9,4.9Hz,1H),3.52(dt,J=28.7,4.3Hz,4H),3.11(d ,J=6.2Hz,2H),3.02–2.92(m,2H),2.73(ddd,J=17.2,12.1,5.3Hz,1H),2.56(dt, J=17.3,4.1Hz,1H),2.30(qd,J=12.3,4.4Hz,1H),2.14–2.04(m,1H),1.40(s,9H).

[0874] Step 10: Preparation of Intermediate 13

[0875] 13j (2.1 g), 1,4-dioxane hydrochloride (10 mL), and dichloromethane (10 mL) were added to the reaction flask in sequence and reacted at room temperature. After the reaction was completed, the mixture was filtered, and the filter cake was rinsed with a small amount of tertiary methyl ether and dried to obtain intermediate 13 (1.6 g).

[0876] MS (ESI, [M+H] + )m / z:299.1

[0877] 1H NMR(500MHz,DMSO-d6)δ10.89(s,1H),9.57(s,2H),7.91(s,1H),7.37(d,J=7.8Hz,1H ),7.11(d,J=8.0Hz,1H),4.12(dd,J=12.1,4.9Hz,1H),3.38(s,2H),3.26(td,J=8.1,7 .3,3.8Hz,4H),3.20(dt,J=8.6,3.9Hz,2H),2.75(ddd,J=17.4,12.3,5.4Hz,1H),2.5 7(dt,J=17.2,4.1Hz,1H), 2.32(qd,J=12.6,4.4Hz,1H), 2.09(dq,J=13.5,4.7Hz,1H).

[0878] Example 14 Synthesis of Intermediate 14

[0879] Step 1: Preparation of intermediate 14a

[0880] Intermediate 8e (14.95 g) and THF (200 mL) were added to the reaction flask in sequence. The mixture was cooled to 0°C under N2 protection and then added dropwise with a solution of lithium aluminum tetrahydride in tetrahydrofuran (5.67 g, 59.8 mL). The mixture was allowed to react at 0°C for 2 h. After completion of the reaction, water was slowly added dropwise at 0°C to quench the reaction. Anhydrous sodium sulfate was added, the mixture was filtered, and the solvent was evaporated from the filtrate under reduced pressure to obtain the target intermediate 14a (11.15 g).

[0881] 1 H NMR(500MHz,DMSO-d6)δ7.08(t,J=7.7Hz,1H),6.81–6.76(m,1H),6.71(d,J=8.2Hz,1H),4.62(t, J=5.3Hz,1H),3.74(s,3H),3.35(dd,J=6.8,5.3Hz,2H),2.92(dd,J=16.0,8.2Hz,1H),2.88–2.79 (m,1H),2.65(dd,J=16.1,5.7Hz,1H),2.60–2.51(m,2H).

[0882] Step 2: Preparation of intermediate 14b

[0883] Intermediate 14a, dichloromethane (100 mL), triethylamine (18.99 g), and 4-dimethylaminopyridine (0.191 g) were added to the reaction flask in sequence. Acetic anhydride (7.03 g, 6.55 mL) was added in an ice bath, and the mixture was allowed to return to room temperature and react for 1 hour. After the reaction was completed, the solvent was removed by evaporation under reduced pressure. The residue was extracted with 300 mL of ethyl acetate and 500 mL of water. The organic phase was separated, washed with saturated ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was then evaporated under reduced pressure to remove the solvent to obtain the target intermediate 14b (12.97 g).

[0884] 1 H NMR (500MHz, DMSO-d6) δ7.13–7.09(m,1H),6.80(d,J=7.2Hz,1H),6.74(d,J=8.0Hz,1H),4.00(d,J=7.1Hz,2H),3.75(s,3H),2.99(dd,J=1 5.6,7.9Hz,1H),2.92(dd,J=16.1,8.1Hz,1H),2.77–2.69(m,1H),2.66(dd,J=15.6,6.4Hz,1H),2.55(dd,J=16.2,6.2Hz,1H),2.02(s,3H).

[0885] Step 3: Preparation of intermediate 14c

[0886] Intermediate 14b (10.15 g), N-bromosuccinimide (9.02 g), and acetonitrile (100 mL) were added to a reaction flask in sequence, and the mixture was heated to 75°C for 1 h. After completion of the reaction, 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 combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the target intermediate 14c (14.11 g).

[0887] 1 H NMR(500MHz,DMSO-d6)δ7.31(d,J=8.7Hz,1H),6.76(d,J=8.6Hz,1H),4.06–4.00(m,2H),3.76( s,3H),3.02(ddd,J=16.3,14.7,8.3Hz,2H),2.81–2.73(m,1H),2.70–2.62(m,2H),2.03(s,3H).

[0888] Step 4: Preparation of Intermediate 14d

[0889] Trifluoromethanesulfonic acid (40 mL) was slowly added dropwise to a mixture of intermediate 14c (14.11 g) and chloroacetyl chloride (5.13 g, 3.61 mL) in an ice bath. After addition, the mixture was stirred at room temperature for 1 h. After completion, the reaction mixture was poured into 500 mL of ice-cold water solution and extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the target intermediate 14d (15.23 g).

[0890] 1 H NMR(500MHz,DMSO-d6)δ7.67(s,1H),4.99(s,2H),4.07(dd,J=6.9,4.6Hz,2H),3.86(s,3H),3.28(dd,J=16.2,8.2Hz,1H), 3.05(dd,J=16.9,8.2Hz,1H),2.94(dd,J=16.2,6.7Hz,1H),2.87–2.81(m,1H),2.72(dd,J=16.9,6.7Hz,1H),2.03(s,3H).

[0891] Step 5: Preparation of intermediate 14e

[0892] At -35°C, under N2 protection, a dichloromethane solution of boron trichloride (1 mol / L, 73.0 mL) was slowly added dropwise to a stirred solution of intermediate 14d (15.23 g) in dichloromethane (450 mL). After the addition was complete, the mixture was stirred at -30°C. After completion of the reaction, the reaction solution was quenched by the addition of 100 mL of 1 M aqueous hydrochloric acid at -30°C and returned to room temperature. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the target intermediate 14e (15.24 g).

[0893] MS (ESI, [M+H] + )m / z:361.1.

[0894] 1 H NMR(500MHz,DMSO-d6)δ11.26(s,1H),7.87(s,1H),5.19(s,2H),4.05(dd,J=7.0,2.5Hz,2 H),3.13–3.06(m,2H),2.84(ddd,J=8.4,5.1,1.8Hz,1H),2.76–2.71(m,2H),2.03(s,3H).

[0895] Step 6: Preparation of Intermediate 14f

[0896] Intermediate 14e (15.24 g), acetonitrile (150 mL), and sodium carbonate (4.41 g) were added to the reaction flask in sequence, and the mixture was heated to 75°C for reaction. After the reaction was completed, 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 combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the target intermediate 14f (13.97 g).

[0897] 1 H NMR (500MHz, DMSO-d6) δ7.64(s,1H),4.86(s,2H),4.08(t,J=6.4Hz,2H),3.20–3.11(m,2H),2.94–2.90(m,1H),2.85–2.77(m,2H),2.03(s,3H).

[0898] Step 7: Preparation of Intermediate 14g

[0899] Intermediate 14f (6.85 g), ethoxycarbonylmethylenetriphenylphosphine (11.01 g), and toluene (80 mL) were added to the reaction flask in sequence. Under N protection, the mixture was heated to 130°C for reaction. After completion of the reaction, 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 on a silica gel column to obtain the target intermediate 14g (4.09 g).

[0900] 1 H NMR(500MHz,DMSO-d6)δ7.90(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=23.5,16.3,6.3Hz,2H),2.04(s,3H),1.19(t,J=7.1Hz,3H).

[0901] Step 8: Preparation of Intermediate 14h

[0902] To the reaction flask were added intermediate 14g (1.2g), 10% palladium on carbon (1.2g), ethanol (40mL), and dichloromethane (20mL) in sequence. After H2 substitution, the mixture was reacted at room temperature. After completion of the reaction, the mixture was filtered through celite, and the filtrate was adjusted to pH 8 with saturated sodium bicarbonate solution. 200mL of ethyl acetate and 200mL 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 300mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the target intermediate 14h (1.01g).

[0903] Step 9: Preparation of intermediates 14i-1 and 14i-2

[0904] Intermediate 14h (0.98 g), potassium carbonate (1.713 g), and ethanol (15 mL) were added to the reaction flask in sequence, and the mixture was reacted at room temperature for 18 h. After the reaction was completed, 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 under reduced pressure to obtain the target intermediate 14i (0.9 g). Intermediate 14i was separated and prepared by high-performance liquid chromatography to obtain intermediates 14i-1 (0.36 g) and 14i-2 (0.42 g). The preparation conditions are as follows:

[0905] Instrument and preparative column: A YMC K-prep Lab100g high-pressure preparative chromatograph was used, with a preparative column model of CHIRALART Amylose-SA (5 μm, 30×250 mm). Mobile phase system: n-hexane / ethanol, isocratic elution: n-hexane / ethanol = 90 / 10.

[0906] The 14i-1 data is as follows:

[0907] MS (ESI, [M+H]+) m / z: 275.2.

[0908] 1H NMR (500MHz, DMSO-d6) δ7.81(s,1H),7.34(d,J=7.8Hz,1H),7.11(d,J=7.9Hz,1H),4.69(t ,J=5.3Hz,1H),4.10(q,J=7.1Hz,2H),3.76–3.72(m,2H),3.41(ddd,J=6.8,5.2,1.4Hz,2H ),3.12(dd,J=16.1,8.3Hz,1H),3.05(dd,J=15.9,8.2Hz,1H),2.86(dd,J=16.2,5.7Hz,1H ), 2.78 (dd, J=15.9, 5.7Hz, 1H), 2.68 (ddd, J=13.6, 8.0, 5.8Hz, 1H), 1.19 (t, J=7.1Hz, 3H).

[0909] Step 10: Preparation of Intermediate 14

[0910] Intermediate 14i-1 (350 mg), N,N-dimethylformamide (10 mL), and acrylamide (100 mg) were added to the reaction flask in sequence. Under N2 protection, the temperature was lowered to 0°C and potassium tert-butoxide tetrahydrofuran solution (1 mol / L, 1.025 mL) was added. The mixture was allowed to react at 0°C for 1 h. After completion of the reaction, the reaction solution was added dropwise to an ice-cold saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was separated, 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 filtrate was purified on a silica gel column to obtain Intermediate 14 (0.204 g).

[0911] MS (ESI, [M+H] + )m / z:300.1.

[0912] 1 H NMR (500MHz, DMSO-d6) δ10.87(s,1H),7.80(s,1H),7.33(d,J=7.8Hz,1H),7.09(d,J =7.9Hz,1H),4.69(t,J=5.2Hz,1H),4.10(dd,J=11.9,4.9Hz,1H),3.41(t,J=6.1Hz,2 H),3.18–3.03(m,2H),2.86(dd,J=16.2,5.6Hz,1H),2.81–2.76(m,1H),2.74–2.63(m ,2H),2.56(dt,J=17.3,4.2Hz,1H),2.30(qd,J=12.2,4.4Hz,1H),2.13–2.06(m,1H).

[0913] Example 15 Synthesis of Intermediate 15

[0914] To the reaction flask, intermediate 14i-2 (420 mg), N,N-dimethylformamide (10 mL), and acrylamide (120 mg) were added sequentially. Under N2 protection, the temperature was lowered to 0°C, potassium tert-butoxide (1 mol / L, 1.221 mL) was added, and the mixture was reacted at 0°C. After the reaction was completed, the reaction solution was added dropwise to an ice-cold saturated aqueous ammonium chloride solution, and ethyl acetate was added for extraction. 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 on a silica gel column to obtain intermediate 15 (0.237 g).

[0915] MS (ESI, [M+H] + )m / z:300.1.

[0916] 1 H NMR (500MHz, DMSO-d6) δ10.87(s,1H),7.80(s,1H),7.33(d,J=7.8Hz,1H),7.09(d,J=7.9Hz,1H ),4.69(t,J=5.2Hz,1H),4.10(dd,J=11.8,4.9Hz,1H),3.41(t,J=6.1Hz,2H),3.18–3.04(m,2H ),2.86(dd,J=16.2,5.6Hz,1H),2.78(dd,J=15.9,5.7Hz,1H),2.72(dd,J=11.3,6.0Hz,1H),2. 70–2.63(m,1H),2.56(dt,J=17.3,4.2Hz,1H),2.30(qd,J=12.2,4.4Hz,1H),2.14–2.06(m,1H).

[0917] Example 16 Synthesis of Intermediate 16

[0918] Step 1: Preparation of intermediate 16b

[0919] 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 completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate, and washed with saturated sodium chloride solution. The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the target intermediate 16b (64.5 g).

[0920] MS (ESI, [M+H] + )m / z:163.10.

[0921] Step 2: Preparation of intermediate 16c

[0922] Potassium hydroxide (152 g) and methanol (600 mL) were added to the reaction flask in sequence, stirred under an ice bath for 20 min, intermediate 16b (40 g) was added and stirred for 20 min, iodophenyl diacetic acid (98 g) was added, and the reaction was allowed to proceed at room temperature for 1 h under N2 protection. The reaction solution was evaporated to remove the solvent under reduced pressure, ethyl acetate and saturated sodium bicarbonate solution were added to the residue, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure; the concentrate was dissolved in tetrahydrofuran (600 mL), and hydrochloric acid (82 mL, 6 M) was added. The reaction was allowed to proceed at room temperature for 0.5 h, and the reaction was completed. The reaction solution was then adjusted to pH 8-9 with saturated sodium bicarbonate solution, extracted 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).

[0923] 1 H NMR(500MHz,Chloroform-d)δ7.42–7.31(m,2H),7.08(dd,J=7.2,1.7Hz,1H),4.51(dd,J=7.8,4 .7Hz,1H),3.91(s,3H),3.57(dd,J=17.0,7.8Hz,1H),3.02(s,1H),2.84(dd,J=17.0,4.7Hz,1H).

[0924] Step 3: Preparation of intermediate 16d

[0925] 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 allowed to react at room temperature for 1.5 h, and the reaction was complete. The reaction solution was quenched by dropwise addition of saturated ammonium chloride solution, and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to afford Intermediate 16d (50 g).

[0926] Step 4: Preparation of intermediate 16e

[0927] Intermediate 16d (35 g), toluene (300 mL), and p-toluenesulfonic acid (66.9 g) were added sequentially to the reaction flask. Under N protection, the mixture was reacted at 120°C until completion. The reaction solution was cooled to room temperature, and the solvent was evaporated under reduced pressure. Ethyl acetate and water were added to the residue, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography to obtain the target intermediate 16e (35.5 g).

[0928] 1H NMR (500MHz, DMSO-d6) δ7.26–7.22(m,1H),6.93–6.87(m,2H),3.79(s,3H),3.53(s,2H),3.37(s,2H).

[0929] Step 5: Preparation of intermediate 16f

[0930] Intermediate 16e (35 g) and methanol (400 mL) were added sequentially to a reaction flask at 0°C, followed by sodium borohydride (5.83 g) in portions, and the mixture was allowed to react at room temperature. After completion, the reaction mixture was quenched by dropwise addition of saturated ammonium chloride solution. Water and ethyl acetate were added, and the organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography to obtain the target intermediate 16f (18 g).

[0931] 1 H NMR (500MHz, DMSO-d6) δ7.10(td,J=7.9,7.4,0.9Hz,1H),6.83–6.78(m,1H),6.74(d,J=8.1Hz,1H),4.81(d,J=3.8Hz,1H),4.49(tq,J=6. 5,3.4Hz,1H),3.75(s,3H),3.04(dd,J=16.1,6.1Hz,1H),2.94(dd,J=16.3,6.2Hz,1H),2.76–2.69(m,1H),2.65(dd,J=16.4,3.4Hz,1H).

[0932] Step 6: Preparation of Intermediate 16g

[0933] To the reaction flask were added 16f (15 g), dichloromethane (150 mL), triethylamine (27.8 g), and 4-dimethylaminopyridine (0.28 g) in sequence. Acetic anhydride (10.2 g) was added under ice-cooling and the reaction was allowed to proceed at room temperature. After completion of the reaction, the solvent was evaporated under reduced pressure, ethyl acetate and water were added to the residue, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target intermediate 16 g (9.3 g).

[0934] MS (ESI, [M+H] + )m / z:207.10

[0935] 1H NMR(500MHz,DMSO-d6)δ7.22–7.06(m,1H),6.82(dd,J=27.3,8.3Hz,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=34.6,17.1Hz,2H),1.97(d,J=15.3Hz,3H).

[0936] Step 7: Preparation of Intermediate 16h

[0937] 16g (5.6g), N-bromosuccinimide (5.32g), and acetonitrile (50mL) were added to the reaction flask in sequence and reacted at 70°C. After the reaction was completed, the reaction solution was cooled to room temperature, water and ethyl acetate were added, and 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 (6.4g).

[0938] 1 H NMR(500MHz,DMSO-d6)δ7.36(d,J=8.6Hz,1H),6.81(d,J=8.7Hz,1H),5.41(tt,J=6.4,2.0Hz,1H),3.7 7(s,3H),3.31–3.23(m,2H),2.92(dd,J=17.5,2.0Hz,1H),2.85(dd,J=17.4,2.0Hz,1H),1.97(s,3H).

[0939] Step 8: Preparation of intermediate 16i

[0940] 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 allowed to react at room temperature. After completion of the reaction, the reaction solution was slowly added dropwise to ice water and extracted with dichloromethane. The organic phases were combined and washed with saturated sodium bicarbonate solution. The organic layer 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 16i (7.3 g).

[0941] 1H NMR(500MHz,DMSO-d6)δ7.71(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=17.3,6.2Hz,1H),3.39–3.33(m,1H),3.18(dd,J=17.4,2.0Hz,1H),2.92(dd,J= 18.0,1.9Hz,1H),1.99(s,3H).

[0942] Step 9: Preparation of Intermediate 16j

[0943] 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 allowed to react at room temperature. After completion of the reaction, the reaction solution was slowly added dropwise to ice water and extracted with dichloromethane. 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 16j (5.0 g).

[0944] MS (ESI, [MH] - )m / z:347.00

[0945] 1 H NMR (500MHz, DMSO-d6) δ11.24(s,1H),7.90(s,1H),5.44(tq,J=8.1,3.5,2.8Hz,1H),5.19(s,2H),3.38(d,J =6.3Hz,1H),3.31(t,J=6.8Hz,1H),3.03(dd,J=17.6,1.8Hz,1H),2.92(dd,J=18.2,1.9Hz,1H),1.98(s,3H).

[0946] Step 10: Preparation of Intermediate 16k

[0947] 16j (4.9 g), sodium carbonate (2.99 g), and acetonitrile (120 mL) were added sequentially to a reaction flask and reacted at 50°C. After completion of the reaction, water and ethyl acetate were added, and the organic layer was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography to obtain the target intermediate 16k (3.7 g).

[0948] 1H NMR(500MHz,DMSO-d6)δ7.69(s,1H),5.51(tt,J=6.4,1.9Hz,1H),4.88(s,2H),3.49– 3.36(m,2H),3.08(dd,J=17.5,1.8Hz,1H),2.97(dd,J=18.3,1.8Hz,1H),1.99(s,3H).

[0949] Step 11: Preparation of Intermediate 16l

[0950] 16k (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 and reacted at room temperature in the presence of hydrogen. After completion of the reaction, 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, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the target intermediate 16l (2.4 g).

[0951] 1 H NMR (500MHz, DMSO-d6) δ7.90(d,J=8.5Hz,1H),6.95(d,J=8.6Hz,1H),5.42(s,1H),3.87(s,2H),3.44(d,J= 6.3Hz,1H),3.27(dd,J=18.6,1.9Hz,1H),3.09(d,J=6.5Hz,1H),2.80(dd,J=17.6,1.8Hz,1H),1.94(s,3H).

[0952] Step 12: Preparation of Intermediate 16m

[0953] 16l (2.4 g), ethoxycarbonylmethylenetriphenylphosphine (5.4 g), and toluene (30 mL) were added sequentially to the reaction flask and reacted at 120°C under N2 protection. After the reaction was complete, ethyl acetate and water were added to the reaction system. The organic layer was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography to obtain the target intermediate 16m (0.58 g).

[0954] 1H NMR(500MHz,DMSO-d6)δ7.85(s,1H),7.42(d,J=7.9Hz,1H),7.18(d,J=7.9H z,1H),5.54(tt,J=6.3,2.3Hz,1H),4.10(q,J=7.1Hz,2H),3.77(s,2H),3.4 6(dd,J=17.0,6.2Hz,1H),3.40(dd,J=17.0,6.4Hz,1H),3.11(dd,J=17.1,2 .2Hz,1H),3.02(dd,J=17.0,2.4Hz,1H),1.97(s,3H),1.19(t,J=7.1Hz,3H).

[0955] Step 13: Preparation of intermediate 16n

[0956] 16m (2.4 g), potassium carbonate (0.79 g), and ethanol (30 mL) were added sequentially to the reaction flask and reacted at room temperature. After completion of the reaction, ethyl acetate and water were added to the reaction system. The organic layer was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography to obtain the target intermediate 16n (0.42 g).

[0957] MS (ESI, [M+H] + )m / z:261.10

[0958] 1 H NMR(500MHz,DMSO-d6)δ7.89(s,1H),7.36(d,J=7.8Hz,1H),7.13(d,J=7.8Hz,1H ),4.96(d,J=4.1Hz,1H),4.62(td,J=6.2,2.8Hz,1H),4.10(q,J=7.1Hz,2H),3.7 5(d,J=1.0Hz,2H),3.24(dd,J=16.2,6.1Hz,1H),3.18(dd,J=16.0,6.0Hz,1H),2 .92(dd,J=16.2,3.3Hz,1H),2.85(dd,J=16.0,3.3Hz,1H),1.18(t,J=7.1Hz,3H).

[0959] Step 14: Preparation of Intermediate 16

[0960] 16n (90 mg), acrylamide (27 mg), and N,N-dimethylformamide (4 mL) were added sequentially to the reaction flask, cooled to 0°C, and potassium tert-butoxide (0.28 mL, 1 M) was slowly added dropwise. The reaction was allowed to react at 0°C. After completion of the reaction, the reaction solution was added dropwise to an icy aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography to obtain the target intermediate 16 (20 mg).

[0961] 1 H NMR (500MHz, DMSO-d6) δ10.88(s,1H),7.80(s,1H),7.35(d,J=7.8Hz,1H),7.11(d,J=7.9Hz,1H), 4.62(tt,J=6.8,3.4Hz,1H),4.11(dd,J=11.8,4.9Hz,1H),3.24(dd,J=16.2,6.1Hz,1H),3.17(dd, J=16.0,6.0Hz,1H),2.92(dd,J=16.2,3.3Hz,1H),2.85(dd,J=16.1,3.3Hz,1H),2.73(ddd,J=17.3 ,12.0,5.3Hz,1H),2.56(dt,J=17.4,4.2Hz,1H),2.37–2.24(m,1H),2.10(dq,J=13.7,4.7Hz,1H).

[0962] Example 17 Synthesis of Compound 17

[0963] Step 1: Preparation of intermediate 17b

[0964] At 0°C, under nitrogen, sodium hydride (60 wt %, 7.7 g) was added portionwise to a solution of 17a (20.0 g) and trans-4-BOC-aminocyclohexanol (27.7 g) in DMF (100 mL). The reaction was allowed to react at room temperature. Upon completion, 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 dried to yield 17b (39.1 g).

[0965] MS (ESI, [M+H] + )m / z:351.1

[0966] 1H NMR (500MHz, DMSO-d6) δ7.84(d,J=8.7Hz,1H),7.37(d,J=2.4Hz,1H),7.11(dd,J=8.8,2.4Hz,1H),6.90–6.80(m,1 H),4.49(ddt,J=14.2,9.8,4.1Hz,1H),3.29(t,J=8.4Hz,1H),2.09–1.99(m,2H),1.87–1.74(m,2H),1.38(s,13H).

[0967] Step 2: Preparation of intermediate 17c

[0968] 17b (20.5 g) and 1,4-dioxane hydrochloride (100 mL) were added to the reaction flask in sequence and reacted at room temperature. The reaction solution was spin-dried to dryness, and n-hexane was added to slurry at room temperature. The solution was filtered, and the filter cake was collected and dried to obtain 17c (18.3 g).

[0969] MS (ESI, [M+H] + )m / z:251.1

[0970] Step 3: Preparation of intermediate 17e

[0971] To a reaction flask, 17d (10.0 g), 4-piperidinemethanol (8.1 g), DIPEA (11.2 g), and DMSO (90 mL) were added sequentially, and the reaction mixture was heated to 90°C. Upon completion, the reaction mixture was poured into 300 mL of water and extracted with DCM. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to yield intermediate 17e (12.0 g).

[0972] MS (ESI, [M+H] + )m / z:252.0

[0973] 1 H NMR(500MHz,DMSO-d6)δ7.80(d,J=9.7Hz,1H),7.27(d,J=9.7Hz,1H),4.58–4.46(m,3H),3.86(s ,3H),3.28(t,J=5.6Hz,2H),3.00(td,J=12.8,2.6Hz,2H),1.84–1.67(m,3H),1.21–1.07(m,2H).

[0974] Step 3: Preparation of intermediate 17f

[0975] To a reaction flask, 17e (10.1 g), sodium hydroxide (2.4 g), methanol (100 mL), and water (10 mL) were added sequentially and allowed to react at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was adjusted to pH 3-4 with concentrated hydrochloric acid, and the solvent was evaporated. The mixture was then slurried with DCM:MEOH, filtered, and the filtrate was concentrated to dryness to afford intermediate 17f (1.2 g).

[0976] MS (ESI, [MH] - )m / z:236.2.

[0977] 1 H NMR(500MHz,DMSO-d6)δ7.91(ddd,J=9.8,5.4,2.9Hz,1H),7.57(d,J=9.3Hz,1H),4.51(d,J=13.4Hz,2H), 3.40–3.24(m,2H),3.20–3.16(m,2H),3.11(t,J=12.8Hz,2H),1.78(t,J=14.5Hz,3H),1.29–1.14(m,2H).

[0978] Step 4: Preparation of Intermediate 17g

[0979] To a reaction flask were added 17f (1.1 g), 17c (1.1 g), HATU (2.2 g), DIPEA (1.5 g), and DMF (20 mL) in sequence and allowed to react at room temperature. Upon completion of the reaction, 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, and filtered. The concentrate was purified by silica gel column chromatography to yield intermediate 17g (1.2 g).

[0980] MS (ESI, [M+H] + )m / z:470.4.

[0981] 1H NMR (500MHz, DMSO-d6) δ8.63–8.50(m,1H),7.88–7.71(m,2H),7.43–7.24(m,2H),7.12(tq,J=7. 7,4.7,3.7Hz,1H),4.50(dtt,J=20.4,10.3,4.6Hz,4H),3.90–3.76(m,1H),2.97(q,J=13.1Hz,2 H),2.87(dd,J=14.4,6.2Hz,1H),2.71(dd,J=14.3,6.2Hz,1H),2.07(d,J=13.1Hz,2H),1.87(d, J=12.8Hz,2H),1.79–1.67(m,3H),1.61(q,J=12.5Hz,2H),1.57–1.44(m,2H),1.20–1.04(m,2H).

[0982] Step 5: Preparation of Intermediate 17h

[0983] To the reaction flask were added 17g (0.5g), Dess-Martin periodinane (1.3g), and dichloromethane (30mL) in sequence and allowed to react at room temperature. After the reaction, 70mL of dichloromethane and 100mL of water were added. The organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to afford intermediate 17h (0.6g).

[0984] Step 6: Preparation of compound 17

[0985] To the reaction flask were added 17h (90 mg), intermediate 1 (60 mg), sodium acetate (16 mg), and DCE / isopropanol (5:1, 20 mL) in sequence, and the mixture was allowed to react at room temperature for 30 min. Sodium cyanoborohydride (24 mg) was then added and allowed to react at room temperature. After completion of the reaction, the solvent was evaporated, and the crude product was purified by silica gel column chromatography to afford compound 17 (30 mg).

[0986] MS (ESI, [M+H] + )m / z:723.4

[0987] 1H NMR (500MHz, DMSO-d6) δ11.09(s,1H),8.58(d,J=8.2Hz,1H),7.85(d,J=8.8Hz,1H),7.81(d,J=9.5Hz,1H),7.72(d,J=8.1Hz,1H), 7.41–7.28(m,3H),7.14(dd,J=8.7,2.4Hz,1H),4.60(dd,J=11.9,5.0Hz,1H),4.57–4.46(m,3H),4.16(d,J=2.4Hz,2H),4.05(t,J =2.3Hz,2H),3.86(tdt,J=11.4,8.1,4.0Hz,1H),3.11–3.01(m,2H),2.77(ddd,J=17.2,11.9,5.3Hz,1H),2.69–2.57(m,3H),2.20 (dq,J=13.5,4.8Hz,1H),2.16–2.06(m,2H),1.91(d,J=13.7Hz,4H),1.58(ddt,J=63.2,13.6,10.8Hz,5H),1.19(d,J=13.4Hz,3H).

[0988] Example 18 Synthesis of Compound 18

[0989] 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 to the reaction flask in sequence, and the mixture was reacted at room temperature. After the reaction was completed, the reaction solution was neutralized with acetic acid by adding 2 mL of saturated sodium bicarbonate solution, and then extracted 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 on a silica gel column to obtain compound 18 (42 mg).

[0990] MS (ESI, [M+H] + )m / z:737.3.

[0991] 1H NMR (500MHz, DMSO-d6) δ11.09(s,1H),8.59(d,J=8.2Hz,1H),7.85(d,J=8.8Hz,1H),7.80(d,J=9.5Hz,1H),7.60(d,J=8.1Hz,1H),7.39(d,J=2.4Hz ,1H),7.34(d,J=9.6Hz,1H),7.14(t,J=7.6Hz,2H),4.55(td,J=10.9,10. 0,4.8Hz,2H),4.49(d,J=13.4Hz,2H),3.86(dd,J=9.5,5.0Hz,1H),3.82( s,2H),3.06(t,J=12.6Hz,2H),2.97(t,J=5.7Hz,2H),2.76(p,J=6.2,5.6 Hz,3H),2.60(dt,J=17.4,4.3Hz,1H),2.48(s,1H),2.44(d,J=7.3Hz,2H) ,2.18(dq,J=13.2,4.5Hz,1H),2.13–2.04(m,3H),1.88(t,J=14.1Hz,4H) ,1.64(q,J=12.2Hz,2H),1.55–1.47(m,2H),1.15(dd,J=18.0,7.8Hz,2H).

[0992] Example 19 Synthesis of Compound 19

[0993] 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 to the reaction flask in sequence, and the mixture was reacted at room temperature. After the reaction was completed, the reaction solution was neutralized with acetic acid by adding 2 mL of saturated sodium bicarbonate solution, and then extracted 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 the filtrate was purified by silica gel column to obtain compound 19 (48 mg).

[0994] MS (ESI, [M+H] + )m / z:737.3.

[0995] 1H NMR (500MHz, DMSO-d6) δ11.09(s,1H),8.59(d,J=8.1Hz,1H),7.85(d,J=8.8Hz,1H),7.80(d,J=9.5Hz,1H),7.58(d,J=8.1Hz,1H),7.39(d,J=2.4Hz ,1H),7.34(d,J=9.6Hz,1H),7.16–7.08(m,2H),4.56(dt,J=10.5,5.2Hz, 2H),4.49(d,J=13.1Hz,2H),3.90–3.82(m,1H),3.71(s,2H),3.05(d,J=1 2.6Hz,2H),3.00(t,J=6.1Hz,2H),2.76(dt,J=17.3,5.6Hz,3H),2.61(dt ,J=17.5,4.3Hz,1H),2.47(s,1H),2.39(d,J=7.2Hz,2H),2.19(dq,J=13. 3,4.5Hz,1H),2.10(d,J=12.0Hz,2H),2.04(s,1H),1.88(t,J=16.2Hz,4H ),1.64(q,J=12.5Hz,2H),1.51(q,J=12.0Hz,2H),1.16(d,J=12.4Hz,2H).

[0996] Example 20 Synthesis of Compound 20

[0997] Step 1: Preparation of compound 20

[0998] To the reaction flask were added 17h (95 mg), intermediate 5 (60 mg), sodium acetate (18 mg), and DCE / isopropanol (5:1, 20 mL) in sequence. The mixture was allowed to react at room temperature for 30 min, followed by the addition of sodium cyanoborohydride (26 mg), and the reaction was continued at room temperature. The solvent was evaporated, and the crude product was purified by silica gel column chromatography to afford compound 20 (22 mg).

[0999] MS (ESI, [M+H] + )m / z:751.6

[1000] 1H NMR (500MHz, DMSO-d6) δ11.08(s,1H),8.58(d,J=8.2Hz,1H),7.83(dd,J=24.4,9.1Hz,2H),7.54(d,J=8.0Hz,1H),7.4 1–7.30(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(d dd,J=17.2,12.0,5.3Hz,1H),2.69–2.65(m,2H),2.65–2.61(m,2H),2.34(d,J=7.0Hz,2H),2.18(dq,J=8.8,4.3Hz,1H) ,2.14–2.06(m,2H),1.89(t,J=15.3Hz,5H),1.64(dt,J=13.7,11.0Hz,2H),1.59–1.45(m,3H),1.17(t,J=11.3Hz,3H).

[1001] Example 21 Synthesis of Compound 21

[1002] Step 1: Preparation of compound 21

[1003] To the reaction flask were added 17h (85 mg), intermediate 6 (66 mg), sodium acetate (20 mg), and DCE / isopropanol (5:1, 20 mL) in sequence. The mixture was allowed to react at room temperature for 30 min, followed by the addition of sodium cyanoborohydride (28 mg). The reaction was continued at room temperature. After completion of the reaction, the solvent was evaporated, and the crude product was purified by silica gel column chromatography to afford compound 21 (42 mg).

[1004] MS (ESI, [M+H] + )m / z:763.5

[1005] 1H NMR (500MHz, DMSO-d6) δ11.08(s,1H),8.58(d,J=8.2Hz,1H),7.86(d,J=8.8Hz,1H),7.79(d,J=9.6Hz,1H),7.62(d,J=8.0Hz,1H),7.39(d,J= 2.4Hz,1H),7.32(d,J=9.6Hz,1H),7.26(d,J=8.2Hz,1H),7.14(dd,J=8.8,2.4Hz,1H),4.55(ddd,J=16.3,11.2,5.4Hz,2H),4.46(d,J=13.2H z,2H),3.91–3.81(m,1H),2.98(t,J=12.5Hz,2H),2.77(ddd,J=17.2,12.0,5.3Hz,1H),2.60(dt,J=17.4,4.2Hz,1H),2.32(s,2H),2.17(dq, J=13.4,4.7Hz,1H),2.10(d,J=11.7Hz,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).

[1006] Example 22 Synthesis of Compound 22

[1007] Step 1: Preparation of intermediate 22a

[1008] To a reaction flask, 17d (10.0 g), 4-hydroxypiperidine (7.1 g), DIPEA (11.2 g), and DMSO (90 mL) were added, and the reaction mixture was heated to 90°C for 2 h. Upon completion of the reaction, the reaction mixture was poured into 300 mL of water, filtered, and the filter cake was collected and dried to obtain intermediate 22a (8.2 g).

[1009] MS (ESI, [M+H] + )m / z:238.1

[1010] 1H NMR (500MHz, DMSO-d6) δ7.80(d,J=9.6Hz,1H),7.29(d,J=9.7Hz,1H),4.79(d,J=4.2Hz,1H),4.16(dt,J=13.6,4.8Hz,2 H),3.87(s,3H),3.79(tq,J=8.2,4.0Hz,1H),3.38(ddd,J=13.2,9.6,3.3Hz,2H),1.87–1.79(m,2H),1.45–1.35(m,2H).

[1011] Step 2: Preparation of intermediate 22b

[1012] 22a (8.3 g), sodium hydroxide (2.8 g), methanol (70 mL), and water (10 mL) were added to a reaction flask in sequence and reacted at room temperature. Upon completion of the reaction, the reaction solution was adjusted to pH 3-4 with concentrated hydrochloric acid, and the solvent was evaporated. The product was slurried with DCM:MeOH, filtered, and the filtrate was concentrated to dryness to obtain intermediate 22b (1.2 g).

[1013] MS (ESI, [MH] - )m / z:222.1

[1014] 1 H NMR(500MHz,DMSO-d6)δ7.80(d,J=9.5Hz,1H),7.27(d,J=9.6Hz,1H),4.81(s,1H),4.14(dt,J=13.5,4.7Hz,2H),3.7 7(tt,J=8.4,3.9Hz,1H),3.34–3.30(m,3H),1.82(ddd,J=13.1,5.8,3.3Hz,2H),1.39(ddt,J=13.4,9.1,4.6Hz,2H).

[1015] Step 3: Preparation of intermediate 22c

[1016] 22b (1.5 g), 17c (1.3 g), HATU (3.0 g), DIPEA (2.1 g), and DMF (30 mL) were added to a reaction flask in sequence and reacted at room temperature. After the reaction, 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, and filtered. The concentrate was purified by silica gel column chromatography to obtain intermediate 22c (1.4 g).

[1017] MS (ESI, [M+H] + )m / z:456.3

[1018] 1H NMR (500MHz, DMSO-d6) δ8.58(d,J=8.2Hz,1H),7.83(dd,J=25.8,9.1Hz,2H),7.41–7.32(m,2H),7.14(dd,J =8.8,2.4Hz,1H),4.77(d,J=4.2Hz,1H),4.54(tt,J=10.3,4.2Hz,1H),4.14(dt,J=13.5,4.7Hz,2H),3.83( ddtd,J=36.7,12.6,8.5,8.0,4.0Hz,2H),3.35(td,J=9.8,4.7Hz,2H),2.14–2.07(m,2H),1.90(dd,J=13.1 ,3.8Hz,2H),1.85–1.77(m,2H),1.69–1.58(m,2H),1.57–1.46(m,2H),1.39(dtd,J=12.9,9.1,3.8Hz,2H).

[1019] Step 4: Preparation of intermediate 22d

[1020] To the reaction flask were added 22c (0.5 g), Dess-Martin periodinane (1.4 g), and dichloromethane (30 mL) in sequence and allowed to react at room temperature for 1 h. After the reaction, 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 afford intermediate 22d (0.6 g).

[1021] Step 5: Preparation of compound 22

[1022] To the reaction flask, 22d (88 mg), intermediate 1 (69 mg), sodium acetate (25 mg), and DMA (20 mL) were added sequentially. The mixture was allowed to react at room temperature for 30 min, followed by the addition of sodium cyanoborohydride (31 mg). The reaction mixture was allowed to react at room temperature for 2 h. The solvent was evaporated, and the crude product was purified by silica gel column chromatography to afford compound 22 (32 mg).

[1023] MS (ESI, [M+H] + )m / z:709.3

[1024] 1H NMR (500MHz, DMSO-d6) δ11.10(s,1H),8.61(d,J=8.2Hz,1H),7.84(dd,J=14.1,9.1Hz,2H),7.72(d,J=8.0Hz,1H),7.43–7.37(m,2H),7.32 (d,J=8.2Hz,1H),7.14(dd,J=8.8,2.4Hz,1H),4.60(dd,J=11.9,5.0Hz,1H),4.54(tt,J=9.7,4.0Hz,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=10.7Hz,2H),2.86(d,J=10.1Hz,1H),2.77(ddd,J=17.2,11.9,5.3Hz,1H),2.61(dt,J=17.3,4. 3Hz,1H),2.21(dq,J=8.6,4.5,3.9Hz,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).

[1025] Example 23 Synthesis of Compound 23

[1026] Step 1: Preparation of compound 23

[1027] To the reaction flask were added 22d (108 mg), intermediate 5 (79 mg), sodium acetate (28 mg), and DMA (20 mL) in sequence. The mixture was allowed to react at room temperature for 30 min, followed by the addition of sodium cyanoborohydride (33 mg). The reaction mixture was evaporated to dryness, and the crude product was purified by silica gel column chromatography to afford compound 23 (27 mg).

[1028] MS (ESI, [M+H] + )m / z:737.4

[1029] 1H NMR (500MHz, DMSO-d6) δ11.07(s,1H),8.59(d,J=8.2Hz,1H),7.83(dd,J=24.2,9.2Hz,2H),7.53(d,J=8.0Hz,1H),7.43–7.30 (m,2H),7.23–7.10(m,2H),4.54(td,J=11.0,9.6,5.9Hz,4H),3.86(dtd,J=11.3,7.6,4.1Hz,1H),3.13(t,J=4.9Hz,2H),2.98 (dt,J=31.3,12.8Hz,5H),2.82–2.64(m,5H),2.60(dt,J=17.3,4.2Hz,1H),2.46(dd,J=12.1,4.5Hz,1H),2.18(dq,J=8.5,4. 4Hz,1H),2.14–2.05(m,2H),1.90(d,J=13.6Hz,2H),1.80(d,J=12.2Hz,2H),1.70–1.58(m,2H),1.51(qd,J=12.4,6.0Hz,4H).

[1030] Example 24, 25 Synthesis of Compounds 24, 25

[1031] Step 1: Preparation of intermediate 24b

[1032] 24a (1.443 g), DMSO (10 mL), DIPEA (2.247 g, 3.08 mL), and methyl 6-chloropyridazine-3-carboxylate (1 g) were added to a reaction flask in sequence and reacted at 90°C. After completion of the reaction, the mixture was poured into ice water, filtered, and the filter cake was dried to obtain 24b (2.7 g).

[1033] MS (ESI, [M+H] + )m / z:363.16.

[1034] 1 H NMR (500MHz, DMSO-d6) δ7.81(d,J=9.6Hz,1H),7.32(d,J=9.7Hz,1H),3.86(s,3H),3.71(s,8H),1.74(t,J=5.6Hz,4H),1.39(s,9H).

[1035] Step 2: Preparation of intermediate 24c

[1036] 24b (2.6 g), MeOH (30 mL), and water (3 mL) were added to a reaction flask, followed by sodium hydroxide (1.43 g) and allowed to react at room temperature. After completion of the reaction, the pH of the system was adjusted to 4-5 with 6 M hydrochloric acid, and the solvent was removed by concentration. The system was then slurried with approximately 100 mL of MeOH / DCM (v:v = 1 / 10). The solid was removed by filtration, and the mother liquor was concentrated to afford 24c (1.9 g).

[1037] MS (ESI, [M+H] + )m / z:349.25.

[1038] Step 3: Preparation of intermediate 24d

[1039] To a reaction flask were added compound 17c (0.85 g), compound 24c (1.031 g), DCM (10 mL), HATU (1.68 g), and DIPEA (1.148 g, 1.551 mL) in sequence, and the mixture was allowed to react at room temperature. After completion of the reaction, the reaction mixture was diluted with 100 mL of ethyl acetate, washed with 100 mL of 10% aqueous citric acid, and then washed with 100 mL of saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 24d (1.61 g).

[1040] MS (ESI, [M+H] + )m / z:581.28.

[1041] Step 4: Preparation of intermediate 24e

[1042] 24d (1.61 g), DCM (20 mL), and trifluoroacetic acid (5 mL) were added to a reaction flask in sequence and the mixture was reacted at room temperature. After completion of the reaction, the mixture was added to 200 mL of saturated sodium bicarbonate solution and extracted with 200 mL of DCM. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to afford 24e (1.3 g).

[1043] MS (ESI, [M+H] + )m / z:481.22.

[1044] 1H NMR(500MHz,DMSO-d6)δ8.59(dd,J=8.2,5.4Hz,1H),7.84(dd,J=20.6,9.1Hz,2H), 7.41–7.33(m,2H),7.13(dd,J=8.8,2.4Hz,1H),4.53(tt,J=9.9,4.2Hz,1H),3.85(d td, J = 15.2, 7.8, 3.9 Hz, 1H), 3.68 (t, J = 5.7 Hz, 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

[1045] To the reaction flask were added 24e (350 mg), 1,2-dichloroethane (10 mL), isopropanol (3 mL), intermediate 7 (208 mg), and 1 drop of acetic acid. Sodium cyanoborohydride (137 mg) was then added, and the mixture was allowed to react at room temperature overnight. After the reaction, 20 mL of saturated sodium bicarbonate solution and 50 mL of water were added to the reaction solution, followed by extraction with dichloromethane. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain a crude product. The crude product was then separated by HPLC to obtain the pre-peak intermediate 24f-1 (95 mg) and the post-peak intermediate 24f-2 (85 mg).

[1046] Preparation conditions are as follows: Instrument and preparative column: YMC high-pressure preparative chromatograph, preparative column model CHIRALART Cellose-SB. Mobile phase system: ethanol: dichloromethane (1:1) / n-hexane, isocratic elution: ethanol: dichloromethane (1:1) / n-hexane = 50 / 50.

[1047] 24f-1 characterization data are as follows:

[1048] MS (ESI, [M+H] + )m / z:724.30.

[1049] 1H NMR (500MHz, DMSO-d6) δ8.58(d,J=8.2Hz,1H),7.85(d,J=8.7Hz,1H),7.79(d,J=9.6Hz,1H),7.61(d,J=8.0Hz,1H),7.41 –7.32(m,2H),7.27(d,J=8.1Hz,1H),7.13(dd,J=8.7,2.4Hz,1H),4.54(dq,J=10.5,5.8,5.1Hz,1H),4.23–4.08(m,4H),3 .90–3.80(m,1H),3.67(t,J=5.6Hz,4H),3.46(s,1H),3.13(d,J=24.8Hz,5H),2.84(ddd,J=31.4,16.6,3.1Hz,2H),2.16 –2.05(m,2H),1.89(d,J=9.9Hz,3H),1.71(t,J=5.6Hz,4H),1.68–1.58(m,2H),1.56–1.45(m,2H),1.19(t,J=7.0Hz,3H).

[1050] Step 6: Preparation of compound 24

[1051] 24f-1 (91 mg), acrylamide (8.93 mg), and THF (10 mL) were added to the reaction flask in sequence. A 1 M solution of potassium tert-butoxide in tetrahydrofuran (0.088 mL) was added under ice-cooling, and the mixture was reacted at 0°C. After completion of the reaction, the reaction solution was added dropwise to a saturated aqueous solution of ammonium chloride in ice, extracted with ethyl acetate, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to afford compound 24 (17 mg).

[1052] MS (ESI, [M+H] + )m / z:749.30.

[1053] 1H NMR (500MHz, DMSO-d6) δ11.09(s,1H),8.57(d,J=8.2Hz,1H),7.85(d,J=8.7Hz,1H),7.79(d,J=9.5Hz,1H),7.62(d,J=8.1Hz,1H),7 .42–7.31(m,2H),7.26(d,J=8.1Hz,1H),7.13(dd,J=8.8,2.4Hz,1H),4.60–4.49(m,2H),3.85(d,J=10.3Hz,1H),3.67(t,J=5.4Hz, 4H), 3.60 (d, J = 6.1 Hz, 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

[1054] 24f-2 (80 mg), acrylamide (7.93 mg), and THF (10 mL) were added to the reaction flask in sequence. A 1 M solution of potassium tert-butoxide in tetrahydrofuran (0.078 mL) was added under ice-cooling, and the mixture was reacted at 0°C. After completion of the reaction, the reaction solution was added dropwise to a saturated aqueous solution of ammonium chloride in ice, extracted with ethyl acetate, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to afford compound 25 (15 mg).

[1055] MS (ESI, [M+H] + )m / z:749.52.

[1056] 1H NMR (500MHz, DMSO-d6) δ11.09(s,1H),8.57(d,J=8.2Hz,1H),7.85(d,J=8.7Hz,1H),7.79(d,J=9.5Hz,1H),7.62(d,J=8.1Hz,1H ),7.42–7.31(m,2H),7.26(d,J=8.1Hz,1H),7.13(dd,J=8.8,2.4Hz,1H),4.60–4.49(m,2H),3.85(d,J=10.3Hz,1H),3.67(t,J= 5.4Hz,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=13.1,5.2Hz,1H),2.10(d,J= 11.8Hz,2H),2.00(q,J=7.7Hz,1H),1.93–1.85(m,2H),1.74(d,J=21.8Hz,4H),1.63(d,J=12.4Hz,2H),1.51(d,J=12.0Hz,2H).

[1057] Example 26 Synthesis of Compound 26

[1058] Step 1: Preparation of intermediate 26b

[1059] 26a (5.94 g), DMSO (30 mL), DIPEA (1.23 g, 15.39 mL), and methyl 6-chloropyridazine-3-carboxylate (5 g) were added to a reaction flask in sequence and reacted at 90°C. After completion of the reaction, the mixture was poured into ice water, and the filter cake was filtered and dried to obtain 26b (11.3 g).

[1060] MS (ESI, [M+H] + )m / z:323.07.

[1061] 1 H NMR (500MHz, DMSO-d6) δ7.87(d,J=9.6Hz,1H),7.29(d,J=9.7Hz,1H),3.87(s,3H),3.80–3.69(m,4H),3.47(dd,J=6.3,4.0Hz,4H),1.43(s,9H).

[1062] Step 2: Preparation of intermediate 26c

[1063] 26b (11.3 g), MeOH (100 mL), and water (30 mL) were added to a reaction flask, followed by sodium hydroxide (7.01 g) and allowed to react at room temperature. After the reaction, 6 M hydrochloric acid was added to adjust the pH to 4-5, and the solvent was removed by concentration. Approximately 100 mL of MeOH / DCM (v:v = 1 / 10) was added to the system for slurrying. The solid was removed by filtration, and the mother liquor was concentrated to give 26c (9.8 g).

[1064] MS (ESI, [M+H] + )m / z:308.99.

[1065] Step 3: Preparation of intermediate 26d

[1066] To a reaction flask were added compound 17c (2.5 g), compound 26c (2.68 g), DCM (30 mL), HATU (4.30 g), and DIPEA (5.63 g, 7.60 mL) in sequence, and the mixture was allowed to react at room temperature. After completion of the reaction, the system was diluted with 100 mL of ethyl acetate, washed with 100 mL of 10% aqueous citric acid, and then washed with saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 26d (3.2 g).

[1067] MS (ESI, [M+H] + )m / z:541.21

[1068] Step 4: Preparation of intermediate 26e

[1069] 26d (3.2 g), DCM (20 mL), and trifluoroacetic acid (5 mL) were added sequentially to a reaction flask and the mixture was reacted at room temperature. After completion of the reaction, the mixture was added to 200 mL of saturated sodium bicarbonate solution and extracted with DCM. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to afford 26e (2.56 g).

[1070] MS (ESI, [M+H] + )m / z:441.20.

[1071] 1H NMR (500MHz, DMSO-d6) δ8.62(d,J=8.2Hz,1H),7.85(t,J=9.3Hz,2H),7.39(d,J=2.4 Hz,1H),7.34(d,J=9.6Hz,1H),7.14(dd,J=8.8,2.4Hz,1H),4.53(tt,J=10.3,4.2Hz ,1H),3.86(tdt,J=11.8,8.2,4.0Hz,1H),3.77–3.61(m,4H),2.99–2.80(m,4H),2.1 6–2.05(m,2H),1.95–1.84(m,2H),1.64(qd,J=13.1,3.1Hz,2H),1.58–1.45(m,2H).

[1072] Step 5: Preparation of intermediate 26f

[1073] Intermediate 8 (50 mg), Dess-Martin periodinane (141 mg), dichloromethane (5 mL), and DMF (1 mL) were added to the reaction flask in sequence, and the mixture was reacted at room temperature. After completion of the reaction, the reaction solution was extracted with 50 mL of water and 20 mL of ethyl acetate. The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure to remove the solvent to obtain the target intermediate 26f (50 mg).

[1074] MS (ESI, [M+H] + )m / z:299.51.

[1075] Step 6: Preparation of Intermediate 26g

[1076] 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 to the reaction flask in sequence, and the mixture was stirred at room temperature. After the reaction was completed, the reaction solution was neutralized with 2 mL of saturated sodium bicarbonate solution to remove the acetic acid. 50 mL of dichloromethane and 100 mL of extraction were added. 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, concentrated, and purified on a silica gel column to obtain compound 26g (30 mg).

[1077] MS (ESI, [M+H] + )m / z:723.36.

[1078] Step 7: Preparation of compound 26

[1079] 26 g (30 mg), maleic acid (4.81 mg), and MeOH / DCM (v:v = 1 / 10, 5 mL) were added to the reaction flask in sequence, and the reaction solution was concentrated. The reaction solution was slurried with 10 mL of petroleum ether and filtered to obtain 26 (32 mg).

[1080] MS (ESI, [M+H] + )m / z:723.43.

[1081] 1 H NMR (500MHz, DMSO-d6) δ11.09(s,1H),8.66(d,J=8.2Hz,1H),7.93(d,J=9.4Hz,1H),7.86(d,J=8.7Hz,1H),7.66(d,J=8.2Hz,1 H),7.54–7.42(m,1H),7.39(d,J=2.5Hz,1H),7.30(d,J=8.1Hz,1H),7.13(dd,J=8.9,2.5Hz,1H),6.11(s,2H),4.56(dq,J=22.4 ,6.0,5.1Hz,2H),3.93–3.83(m,1H),3.17(s,13H),3.09(s,1H),3.01(d,J=16.1Hz,1H),2.90(dd,J=16.4,6.1Hz,1H),2.77(td ,J=12.0,5.8Hz,1H),2.61(d,J=18.1Hz,1H),2.25–2.05(m,3H),1.96–1.83(m,2H),1.65(q,J=12.4Hz,2H),1.59–1.42(m,2H).

[1082] Example 27 Synthesis of Compound 27

[1083] Step 1: Preparation of intermediate 27a

[1084] Intermediate 9 (50 mg), Dess-Martin periodinane (141 mg), dichloromethane (5 mL), and DMF (1 mL) were added to the reaction flask in sequence, and the mixture was reacted at room temperature. After completion of the reaction, the reaction solution was extracted with 50 mL of water and 20 mL of ethyl acetate. The organic residues were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure to remove the solvent to obtain the target intermediate 27a (50 mg).

[1085] MS (ESI, [M+H] + )m / z:299.31.

[1086] Step 6: Preparation of intermediate 27b

[1087] 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 to the reaction flask in sequence, and the mixture was stirred at room temperature. After the reaction was completed, the reaction solution was neutralized with 2 mL of saturated sodium bicarbonate solution to remove the acetic acid. 50 mL of dichloromethane and 100 mL of extraction were added. 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, concentrated, and purified on a silica gel column to obtain compound 27b (53 mg).

[1088] MS (ESI, [M+H] + )m / z:723.42.

[1089] Step 2: Preparation of compound 27

[1090] 27b (53 mg), maleic acid (8.51 mg) and MeOH / DCM (v:v = 1 / 10, 5 mL) were added to the reaction flask in sequence, and the reaction solution was concentrated. The concentrate was slurried with 10 mL of petroleum ether and filtered to obtain 27 (58 mg).

[1091] MS (ESI, [M+H] + )m / z:723.52.

[1092] 1 H NMR (500MHz, DMSO-d6) δ11.09(s,1H),8.66(d,J=8.2Hz,1H),7.93(d,J=9.4Hz,1H),7.86(d,J=8.7Hz,1H),7.66(d,J=8.2Hz,1 H),7.54–7.42(m,1H),7.39(d,J=2.5Hz,1H),7.30(d,J=8.1Hz,1H),7.13(dd,J=8.9,2.5Hz,1H),6.11(s,2H),4.56(dq,J=22.4 ,6.0,5.1Hz,2H),3.93–3.83(m,1H),3.17(s,13H),3.09(s,1H),3.01(d,J=16.1Hz,1H),2.90(dd,J=16.4,6.1Hz,1H),2.77(td ,J=12.0,5.8Hz,1H),2.61(d,J=18.1Hz,1H),2.25–2.05(m,3H),1.96–1.83(m,2H),1.65(q,J=12.4Hz,2H),1.59–1.42(m,2H).

[1093] Example 28 Synthesis of Compound 28

[1094] Step 1: Preparation of intermediate 28a

[1095] Intermediate 14 (50 mg), IBX (94 mg), and dimethyl sulfoxide (5 mL) were added to the reaction flask in sequence, 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, and 100 mL of ethyl acetate was added for extraction. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the target intermediate 28a (50 mg).

[1096] MS (ESI, [M+H] + )m / z:298.41.

[1097] Step 2: Preparation of compound 28

[1098] 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 to the reaction flask in sequence, and the mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was neutralized with 2 mL of saturated sodium bicarbonate solution to remove the acetic acid, and then extracted 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, concentrated, and purified on a silica gel column to obtain compound 28 (72 mg).

[1099] MS (ESI, [M+H] + )m / z:722.43.

[1100] 1H NMR(500MHz,DMSO-d6)δ10.87(d,J=2.1Hz,1H),8.61(d,J=8.2Hz,1H),7.84(dd,J=18.0,8.6Hz,3H),7.44–7.28(m,3H), 7.20–7.04(m,2H),4.53(dq,J=10.0,5.4,4.3Hz,1H),4.11(dd,J=11.8,4.9Hz,1H),3.93–3.81(m,1H),3.73(t,J=4.8Hz ,4H),3.17(ddd,J=29.9,16.6,8.4Hz,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,2 H),2.31(qd,J=12.4,4.4Hz,1H),2.16–2.05(m,3H),1.95–1.85(m,2H),1.72–1.58(m,2H),1.51(q,J=11.8,11.3Hz,2H).

[1101] Example 29 Synthesis of Compound 29

[1102] Step 1: Preparation of intermediate 29a

[1103] Intermediate 15 (50 mg), IBX (94 mg), and dimethyl sulfoxide (5 mL) were added to the reaction flask in sequence, and the mixture was reacted at room temperature. After completion of the reaction, 100 mL of sodium bicarbonate solution was added to the reaction solution, and 100 mL of ethyl acetate was added for extraction. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the target intermediate 29a (50 mg).

[1104] MS (ESI, [M+H] + )m / z:298.35.

[1105] Step 2: Preparation of compound 29

[1106] 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 to the reaction flask in sequence, and the mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was neutralized with 2 mL of saturated sodium bicarbonate solution to remove the acetic acid, and then extracted 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, concentrated, and purified on a silica gel column to obtain compound 29 (93 mg).

[1107] MS (ESI, [M+H] + )m / z:722.47.

[1108] 1 H NMR(500MHz,DMSO-d6)δ10.87(d,J=2.1Hz,1H),8.61(d,J=8.2Hz,1H),7.84(dd,J=18.0,8.6Hz,3H),7.44–7.28(m,3H), 7.20–7.04(m,2H),4.53(dq,J=10.0,5.4,4.3Hz,1H),4.11(dd,J=11.8,4.9Hz,1H),3.93–3.81(m,1H),3.73(t,J=4.8Hz ,4H),3.17(ddd,J=29.9,16.6,8.4Hz,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,2 H),2.31(qd,J=12.4,4.4Hz,1H),2.16–2.05(m,3H),1.95–1.85(m,2H),1.72–1.58(m,2H),1.51(q,J=11.8,11.3Hz,2H).

[1109] Example 30 Synthesis of Compound 30

[1110] Step 1: Preparation of intermediate 30b

[1111] Methyl 6-chloropyridazine-3-carboxylate (10 g), intermediate 30a (26.9 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (4.73 g), sodium carbonate (18.43 g), dioxane (200 mL), and water (7 mL) were added to the reaction flask in sequence. Under nitrogen protection, the mixture was heated to 85°C for reaction. 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 on a silica gel column to obtain the target intermediate 30b (8.92 g).

[1112] MS (ESI, [M+H]+) m / z: 320.0.

[1113] 1H NMR(500MHz,DMSO-d6)δ8.17(d,J=9.0Hz,1H),8.08(d,J=8.9Hz,1H),6.98(s,1H),4.18–4 .10(m,2H),3.96(s,3H),3.59(t,J=5.7Hz,2H),2.72(tt,J=6.0,2.1Hz,2H),1.44(s,9H).

[1114] Step 2: Preparation of intermediate 30c

[1115] Intermediate 30b (8.92 g), methanol (210 mL), dichloromethane (30 mL), and 10% palladium on carbon (2.23 g) were added to the reaction flask in this order. After H2 substitution, the mixture was reacted at room temperature for 5 h. After completion of the reaction, the mixture was filtered, and the solvent was removed from the filtrate by vacuum distillation. 20 mL of dimethyl sulfoxide was added to the residue, and the filter cake was collected. The filter cake was slurried with 50 mL of water and filtered to obtain the desired intermediate 30c (2.66 g).

[1116] MS (ESI, [M+H] + )m / z:322.1.

[1117] 1 H NMR(500MHz,DMSO-d6)δ8.15(d,J=8.7Hz,1H),7.85(d,J=8.7Hz,1H),4.16–4.05(m,2H),3.95(s,3H),3.21(ddt ,J=15.2,11.5,5.8Hz,1H),2.91(d,J=3.3Hz,2H),1.94–1.88(m,2H),1.67(qd,J=12.5,4.3Hz,2H),1.42(s,9H).

[1118] Step 3: Preparation of intermediate 30d

[1119] Intermediate 30c (1.7 g), sodium hydroxide (0.423 g), methanol (20 mL), and water (1 mL) were added to the reaction flask in sequence and the mixture was allowed to react at room temperature. After completion of the reaction, saturated citric acid solution was added to adjust the pH to 2-3. Dichloromethane was added, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the target intermediate 30d (1.63 g).

[1120] MS (ESI, [MH] - )m / z:306.2.

[1121] 1H NMR (500MHz, DMSO-d6) δ13.75(s,1H),8.12(d,J=8.6Hz,1H),7.83(d,J=8.7Hz,1H),4.10(d,J=12.9Hz,2H) ,3.21(tt,J=12.0,3.6Hz,1H),2.90(s,2H),1.93–1.88(m,2H),1.68(qd,J=12.5,4.3Hz,2H),1.42(s,9H).

[1122] Step 4: Preparation of intermediate 30e

[1123] 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 to a reaction flask in this order, and the mixture was allowed to react at room temperature. After completion of the reaction, 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, respectively, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the target intermediate 30e (2.52 g).

[1124] MS (ESI, [M+H] + )m / z:540.3.

[1125] Step 5: Preparation of intermediate 30f

[1126] 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 allowed to react at room temperature. After completion of the reaction, the solvent was removed by evaporation under reduced pressure. 200 mL of dichloromethane / methanol (v:v = 9 / 1) was added to the residue, and the pH was adjusted to a strongly alkaline state 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 evaporation under reduced pressure to obtain the target intermediate 30f (1.88 g).

[1127] MS (ESI, [M+H] + )m / z:440.3.

[1128] 1H NMR (500MHz, DMSO-d6) δ9.04(d,J=8.1Hz,1H),8.13(d,J=8.7Hz,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=11.6Hz,1H),3.92(q,J=11.0,10.4H z,1H),3.19(d,J=12.6Hz,3H),2.81(t,J=12.3Hz,2H),2.69(s,1H),2.12(d,J=12.2Hz,2H) ,1.88(dq,J=24.6,12.6,12.0Hz,6H),1.69(q,J=12.6Hz,2H),1.52(q,J=13.6,12.7Hz,2H).

[1129] Step 6: Preparation of compound 30

[1130] Intermediate 26f (60 mg), 1,2-dichloroethane (5 mL), isopropanol (1 mL), intermediate 30f (88 mg), and sodium cyanoborohydride (37.7 mg) were added to the reaction flask in sequence, and the mixture was stirred at room temperature. After the reaction was completed, the reaction solution was neutralized with acetic acid by adding 2 mL of saturated sodium bicarbonate solution, and then extracted 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 the filtrate was purified on a silica gel column to obtain compound 30 (77 mg).

[1131] MS (ESI, [M+H] + )m / z:722.5.

[1132] 1H NMR (500MHz, DMSO-d6) δ11.09(s,1H),9.03(d,J=8.2Hz,1H),8.11(d,J=8.6Hz,1H),7.85(dd,J=8.7,5.0Hz,2H),7.62(d,J=8.1Hz,1H),7.40(d,J=2 .5Hz,1H),7.28(d,J=8.1Hz,1H),7.14(dd,J=8.8,2.5Hz,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 =10.5Hz,2H),3.00(t,J=5.1Hz,1H),2.93(d,J=13.1Hz,2H),2.85(dd,J= 16.1,4.8Hz,1H),2.77(td,J=11.8,5.8Hz,1H),2.64–2.58(m,1H),2.46(s ,1H),2.39(d,J=7.3Hz,2H),2.20(dq,J=9.2,4.3Hz,1H),2.12(d,J=11.8H z,4H),1.94–1.84(m,6H),1.70(q,J=12.4Hz,2H),1.53(q,J=11.3Hz,2H).

[1133] Example 31 Synthesis of Compound 31

[1134] To the reaction flask were added intermediate 27a (60 mg), 1,2-dichloroethane (5 mL), isopropanol (1 mL), intermediate 30f (88 mg), and sodium cyanoborohydride (37.7 mg) in sequence, and the mixture was stirred at room temperature. After the reaction was completed, the reaction solution was neutralized with acetic acid by adding 2 mL of saturated sodium bicarbonate solution, and then extracted 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 the filtrate was purified on a silica gel column to obtain compound 31 (48 mg).

[1135] MS (ESI, [M+H] + )m / z:722.5.

[1136] 1H NMR(500MHz,DMSO-d6)δ11.09(s,1H),9.03(d,J=8.2Hz,1H),8.11(d,J=8.6Hz,1H),7 .86(dd,J=8.8,5.0Hz,2H),7.62(d,J=8.1Hz,1H),7.40(d,J=2.4Hz,1H),7.28(d,J=8. 1Hz,1H),7.14(dd,J=8.6,2.5Hz,1H),4.55(tt,J=11.0,5.5Hz,2H),3.92(dtd,J=11.7 ,7.7,4.1Hz,1H),3.28–3.22(m,1H),3.18(dd,J=16.8,8.1Hz,1H),3.06(d,J=10.7Hz, 2H),3.00(p,J=6.2Hz,1H),2.93(d,J=13.0Hz,2H),2.85(dd,J=16.2,4.8Hz,1H),2.77 (ddd,J=17.2,11.8,5.3Hz,1H),2.61(dt,J=17.8,4.5Hz,1H),2.47(s,1H),2.39(d,J= 7.3Hz,2H),2.20(dq,J=8.9,4.3Hz,1H),2.12(d,J=12.0Hz,4H),1.92(d,J=12.2Hz,5H ),1.85(d,J=11.8Hz,1H),1.70(q,J=11.8,11.4Hz,2H),1.53(td,J=13.5,6.9Hz,2H).

[1137] Example 32 Synthesis of Compound 32

[1138] To the reaction flask were added intermediate 28a (50 mg), 1,2-dichloroethane (5 mL), isopropanol (1 mL), intermediate 30f (73.5 mg), and sodium cyanoborohydride (31.5 mg), and the mixture was stirred at room temperature. After the reaction was completed, the reaction solution was neutralized with acetic acid by adding 2 mL of saturated sodium bicarbonate solution, and then extracted 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 the filtrate was purified on a silica gel column to obtain compound 32 (44 mg).

[1139] MS (ESI, [M+H] + )m / z:721.6.

[1140] 1H NMR (500MHz, DMSO-d6) δ10.89(s,1H),9.04(d,J=8.2Hz,1H),8.11(d,J=8.6Hz,1H),7.86(dd,J=8.8 ,5.5Hz,2H),7.81(s,1H),7.40(s,1H),7.34(d,J=7.8Hz,1H),7.17–7.10(m,2H),4.58–4.51(m,1H), 4.11(dd,J=12.0,4.9Hz,1H),3.92(d,J=9.3Hz,1H),3.20–3.10(m,2H),3.02 (d,J=31.3Hz,3H),2.88(d,J=14.3Hz,2H),2.81–2.70(m,2H),2.57(d,J=18. 2Hz,1H),2.42–2.34(m,2H),2.30(dt,J=12.6,6.3Hz,1H),2.13(d,J=13.3Hz ,5H),1.92(d,J=12.5Hz,6H),1.70(q,J=12.4Hz,2H),1.53(q,J=12.1Hz,2H).

[1141] Example 33 Synthesis of Compound 33

[1142] To the reaction flask were added intermediate 29a (50 mg), 1,2-dichloroethane (5 mL), isopropanol (1 mL), intermediate 30f (73.5 mg), and sodium cyanoborohydride (31.5 mg), and the mixture was stirred at room temperature. After the reaction was completed, the reaction solution was neutralized with acetic acid by adding 2 mL of saturated sodium bicarbonate solution, and then extracted 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 the filtrate was purified on a silica gel column to obtain compound 33 (37 mg).

[1143] MS (ESI, [M+H] + )m / z:721.6.

[1144] 1H NMR (500MHz, DMSO-d6) δ10.88(s,1H),9.03(d,J=8.2Hz,1H),8.11(d,J=8.7Hz,1H),7.86(dd,J=8.8,5.2Hz,2H),7.81(s,1H),7.40(d,J=2.4H z,1H),7.34(d,J=7.9Hz,1H),7.17–7.10(m,2H),4.55(dq,J=10.9,6.3,5.4Hz,1H),4.11(dd,J=11.8,4.9Hz,1H),3.95–3.88(m,1H),3.15(dq, J=22.0,7.4,6.4Hz,2H),3.02(d,J=30.2Hz,3H),2.88(d,J=13.2Hz,2H),2.81–2.77(m,1H),2.75–2.68(m,1H),2.57(d,J=18.0Hz,1H),2.38( d,J=7.3Hz,2H),2.30(td,J=12.3,4.2Hz,1H),2.12(d,J=12.9Hz,5H),1.92(d,J=12.3Hz,6H),1.70(q,J=12.4Hz,2H),1.53(q,J=12.1Hz,2H).

[1145] Example 34 Synthesis of Compound 34

[1146] Step 1: Preparation of intermediate 34b

[1147] 34a (3 g), DCM (30 mL) and trifluoroacetic acid (5 mL) were added to the reaction flask in sequence and reacted at room temperature. After the reaction, the reaction solution was concentrated to obtain 34b (2.67 g).

[1148] Step 2: Preparation of intermediate 34c

[1149] 34b (2.67 g), DMSO (30 mL), DIPEA (15 mL), and methyl 6-chloropyridazine-3-carboxylate (2 g) were added to a reaction flask in sequence, and the mixture was reacted at 120°C. After the reaction, the reaction mixture was diluted with ethyl acetate and extracted with saturated potassium carbonate solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to afford 34c (3.1 g).

[1150] MS (ESI, [M+H] + )m / z:292.18.

[1151] Step 3: Preparation of Intermediate 34d

[1152] To a reaction flask were added 34c (3 g), MeOH (100 mL), and water (30 mL), followed by sodium hydroxide (2.88 g), and the reaction was allowed to react at room temperature. After completion of the reaction, 6 M hydrochloric acid was added to adjust the pH to 4-5. The solvent was removed by concentration, and the system was slurried with MeOH / DCM. The solid was removed by filtration, and the mother liquor was concentrated to afford 34d (3.1 g).

[1153] MS (ESI, [M+H] + )m / z:278.14.

[1154] Step 4: Preparation of intermediate 34e

[1155] A mixture of 17c (1 g), 34d (1.48 g), DCM (10 mL), HATU (1.58 g), and DIPEA (2.43 mL) was added sequentially to a reaction flask and reacted at room temperature. After completion of the reaction, the reaction mixture was diluted with 100 mL of ethyl acetate and extracted with 10% aqueous citric acid (100 mL), followed by extraction with saturated sodium bicarbonate solution (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to afford 34e (1.1 g).

[1156] MS (ESI, [M+H] + )m / z:510.21.

[1157] 1 H NMR (500MHz, DMSO-d6) δ8.56(d,J=8.2Hz,1H),7.85(d,J=8.7Hz,1H),7.79(d,J=9.5Hz,1H),7.38(d,J= 2.4Hz,1H),7.33(d,J=9.6Hz,1H),7.13(dd,J=8.8,2.4Hz,1H),4.57–4.50(m,1H),4.45(t,J=5.3Hz,1H) ,3.85(ddd,J=11.3,6.6,2.9Hz,1H),3.72–3.66(m,2H),3.60(dd,J=6.8,4.4Hz,2H),3.38(t,J=5.8Hz, 2H), 2.36 (p, J = 7.4Hz, 1H), 2.14–2.07 (m, 2H), 1.92–1.82 (m, 4H), 1.67–1.60 (m, 4H), 1.57–1.48 (m, 6H).

[1158] Step 5: Preparation of intermediate 34f

[1159] To a reaction flask were added 34e (600 mg), DCM (10 mL), and Dess-Martin periodinane (926 mg) in this order, and the mixture was reacted at room temperature. After completion of the reaction, the reaction mixture was quenched with saturated sodium thiosulfate solution and sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was separated. The collected organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to afford 34f (490 mg).

[1160] 1 H NMR (500MHz, DMSO-d6) δ9.71(d,J=1.6Hz,1H),8.57(d,J=8.2Hz,1H),7.85(d,J=8.7Hz,1H),7.80(d,J=9.6H z,1H),7.38(d,J=2.4Hz,1H),7.35(d,J=9.7Hz,1H),7.13(dd,J=8.8,2.4Hz,1H),4.57–4.50(m,1H),3.86(d td,J=11.3,7.5,4.0Hz,1H),3.73–3.67(m,2H),3.65–3.59(m,2H),3.23(dtd,J=9.3,7.6,6.1Hz,1H),2.14– 2.07(m,2H),2.04–1.97(m,4H),1.92–1.87(m,2H),1.71–1.59(m,4H),1.51(ddt,J=12.8,10.7,4.0Hz,4H).

[1161] Step 6: Preparation of Intermediate 34g

[1162] Intermediate 34f (111 mg), 1,2-dichloroethane (6 mL), isopropanol (2 mL), Intermediate 1 (70 mg), sodium acetate (17 mg), and sodium cyanoborohydride (27 mg) were added to the reaction flask in sequence, and the mixture was stirred at room temperature. After the reaction was completed, the reaction solution was neutralized with acetic acid by adding 2 mL of saturated sodium bicarbonate solution, and then extracted with 50 mL of dichloromethane and 100 mL of water. The organic phase was 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 on a silica gel column to obtain compound 34g (40 mg).

[1163] MS (ESI, [M+H] + )m / z:763.18.

[1164] Step 7: Preparation of compound 34

[1165] 34 g (40 mg), maleic acid (6 mg), and MeOH / DCM (1 / 10, 5 mL) were added to the reaction flask in sequence, and the reaction solution was concentrated and slurried with petroleum ether and filtered to obtain compound 34 (43 mg).

[1166] MS (ESI, [M+H] + )m / z:763.58.

[1167] 1 H NMR (500MHz, DMSO-d6) δ11.12(s,1H),8.56(d,J=8.2Hz,1H),7.87(dd,J=13.6,8.4Hz,2H),7.81(d,J=9 .5Hz,1H),7.43(d,J=8.2Hz,1H),7.41–7.31(m,2H),7.13(dd,J=8.8,2.5Hz,1H),6.07(s,2H),5.02–4. 32(m,6H),3.86(tdt,J=11.6,8.1,3.8Hz,1H),3.73(t,J=5.3Hz,2H),3.69–3.62(m,2H),3.32(s,2H),2 .78(dtd,J=18.5,13.4,12.8,6.7Hz,2H),2.63(dt,J=17.2,4.1Hz,1H),2.58–2.53(m,1H),2.21(dq,J= 13.5,4.6Hz,1H),2.18–2.02(m,4H),1.96–1.85(m,2H),1.61(dddd,J=71.5,36.0,12.6,7.2Hz,10H).

[1168] Example 35 Synthesis of Compound 35

[1169] Step 1: Preparation of intermediate 35a

[1170] Intermediate 3 (70 mg), Intermediate 34f (111 mg), sodium acetate (17.85 mg), 1,2-dichloroethane (5 mL), isopropanol (1 mL), and sodium cyanoborohydride (27.3 mg) were added to the reaction flask in sequence, and the mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was neutralized with 2 mL of saturated sodium bicarbonate solution to remove the acetic acid, and then extracted with 50 mL of dichloromethane and 100 mL of water. The organic phase was separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified on a silica gel column to obtain Intermediate 35a (92 mg).

[1171] MS (ESI, [M+H] +)m / z:777.5.

[1172] Step 2: Preparation of compound 35

[1173] Intermediate 35a (92 mg), dichloromethane (10 mL), methanol (5 mL), and maleic acid (15.11 mg) were added to the reaction flask in sequence and the mixture was reacted at room temperature. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was slurried with petroleum ether and filtered to collect the filter cake to obtain compound 35 (63 mg).

[1174] MS (ESI, [M+H] + )m / z:777.5.

[1175] 1 H NMR (500MHz, DMSO-d6) δ11.10(s,1H),9.97(s,1H),8.56(d,J=8.2Hz,1H),7.86(d,J=8.8Hz,1H),7.81(d,J=9.4Hz,1H),7.77(d,J =8.2Hz,1H),7.40–7.34(m,2H),7.28(d,J=8.2Hz,1H),7.13(dd,J=8.8,2.4Hz,1H),6.08(s,2H),4.61(dd,J=12.2,5.0Hz,2H),4. 54(dq,J=10.5,5.4Hz,2H),3.88–3.83(m,1H),3.73(t,J=5.4Hz,2H),3.64(t,J=5.3Hz,2H),3.23(s,6H),2.88(q,J=8.0Hz,1H),2 .82–2.75(m,1H),2.62(dt,J=17.5,4.1Hz,1H),2.54(d,J=16.2Hz,1H),2.21–2.09(m,5H),1.94–1.87(m,2H),1.73–1.51(m,10H).

[1176] Example 36 Synthesis of Compound 36

[1177] Step 1: Preparation of intermediate 36a

[1178] Intermediate 4 (70 mg), Intermediate 34f (111 mg), sodium acetate (17.85 mg), 1,2-dichloroethane (5 mL), isopropanol (1 mL), and sodium cyanoborohydride (27.3 mg) were added to the reaction flask in sequence, and the mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was neutralized with 2 mL of saturated sodium bicarbonate solution to remove the acetic acid. The mixture was then extracted with 50 mL of dichloromethane and 100 mL of water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified on a silica gel column to obtain the target intermediate 36a (97 mg).

[1179] MS (ESI, [M+H] + )m / z:777.5.

[1180] Step 2: Preparation of compound 36

[1181] Intermediate 36a (97 mg), dichloromethane (10 mL), methanol (5 mL), and maleic acid (15.93 mg) were added to the reaction flask in sequence and the mixture was reacted at room temperature. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was slurried in petroleum ether and filtered to collect the filter cake to obtain compound 36 (100 mg).

[1182] MS (ESI, [M+H] + )m / z:777.5.

[1183] 1 H NMR (500MHz, DMSO-d6) δ11.10(s,1H),9.94(s,1H),8.55(d,J=8.2Hz,1H),7.86(d,J=8.7Hz,1H),7.81(d,J=9.6Hz,1H),7.76(d,J =8.2Hz,1H),7.42–7.33(m,2H),7.24(d,J=8.3Hz,1H),7.13(dd,J=8.8,2.4Hz,1H),6.09(s,2H),4.68–4.36(m,4H),3.86(dtd,J= 11.5,7.6,4.0Hz,1H),3.76–3.70(m,2H),3.65–3.60(m,2H),3.18(d,J=5.7Hz,6H),2.80(ddt,J=17.3,12.1,6.8Hz,2H),2.62(dt ,J=17.5,4.1Hz,1H),2.55(d,J=13.0Hz,1H),2.23–2.07(m,5H),1.94–1.86(m,2H),1.60(dddd,J=58.7,33.4,13.0,7.2Hz,10H).

[1184] Example 37 Synthesis of Compound 37

[1185] Step 1: Preparation of intermediate 37a

[1186] Intermediate 34f (106 mg), 1,2-dichloroethane (6 mL), isopropanol (2 mL), intermediate 5 (70 mg), sodium acetate (17 mg), and sodium cyanoborohydride (26 mg) were added to the reaction flask in sequence, and the mixture was stirred at room temperature. After the reaction was completed, the reaction solution was neutralized with acetic acid by adding 2 mL of saturated sodium bicarbonate solution, and then extracted 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, concentrated, and purified on a silica gel column to obtain compound 37a (70 mg).

[1187] MS (ESI, [M+H] + )m / z:791.23.

[1188] Step 7: Preparation of compound 37

[1189] 37a (70 mg), maleic acid (10 mg), and MeOH / DCM (1 / 10, 5 mL) were added to the reaction flask in sequence, and the reaction solution was concentrated and slurried with petroleum ether and filtered to obtain compound 37 (73 mg).

[1190] MS (ESI, [M+H] + )m / z:791.35.

[1191] 1 H NMR (500MHz, DMSO-d6) δ11.09(s,1H),9.67(s,1H),8.55(d,J=8.2Hz,1H),7.83(dd,J=25.1,9.1Hz,2H),7. 67(d,J=8.0Hz,1H),7.45–7.33(m,2H),7.29(d,J=8.1Hz,1H),7.13(dd,J=8.7,2.5Hz,1H),6.10(s,2H),4. 68–4.46(m,2H),3.89–3.80(m,1H),3.66(dt,J=47.6,5.3Hz,7H),3.52–3.31(m,7H),2.79(ddd,J=17.0,11 .6,5.2Hz,2H),2.67–2.58(m,1H),2.56(m,1H),2.22–2.04(m,5H),1.95–1.83(m,2H),1.73–1.44(m,10H).

[1192] Example 38 Synthesis of Compound 38

[1193] Step 1: Preparation of intermediate 38b

[1194] 38a (50 g), diethyl carbonate (216.9 g), and toluene (500 mL) were added to the reaction flask in sequence. The reaction mixture was cooled to 0°C and 60 wt% sodium hydride (44.06 g) was added portionwise. The mixture was first heated to 70°C for about 10 minutes and then heated to 120°C for 5 hours. The reaction mixture was cooled to room temperature and slowly poured into stirred ice water. The mixture was extracted with ethyl acetate and the organic phase was discarded. The aqueous phase was adjusted to pH 3 with 3N hydrochloric acid and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to afford intermediate 38b (55 g).

[1195] 1 H NMR (500MHz, DMSO-d6) δ12.52(s,1H),7.83(dd,J=7.8,1.7Hz,1H),7.65(ddd,J=8.6,7.2,1.7Hz,1H),7.43–7.32(m,2H),5.61(s,1H).

[1196] Step 2: Preparation of intermediate 38c

[1197] Intermediate 38b (55 g), methanol (500 mL), hydroxylamine hydrochloride (63.5 g), and sodium ethoxide (80.8 g) were added to a reaction flask in sequence. The mixture was heated to 80°C and allowed to react overnight. The reaction solution was cooled to room temperature, adjusted to pH 5 with 3N hydrochloric acid, and concentrated. 2 L of water was added, and the reaction flask was cooled in an ice-water bath while adjusting the pH to 3 with 3N hydrochloric acid. The mixture was stirred for 30 minutes and filtered. The filter cake was collected and dried to yield Intermediate 38c (54.5 g).

[1198] 1 H NMR(500MHz,DMSO-d6)δ12.90(s,1H),7.86(dt,J=7.9,1.0Hz,1H),7.74(d,J=8.4Hz, 1H), 7.66 (ddd, J=8.3, 7.0, 1.2Hz, 1H), 7.40 (td, J=7.4, 7.0, 0.9Hz, 1H), 4.11 (s, 2H).

[1199] Step 3: Preparation of intermediate 38d

[1200] Intermediate 38c (54 g), ethanol (400 mL), and sulfuric acid (106 g) were added sequentially to a reaction flask, and the mixture was heated to 90°C for 2 h. The reaction solution was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was diluted with 1 L of ethyl acetate and 1 L of water. Saturated sodium bicarbonate solution was added to adjust the pH to 7. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to afford Intermediate 38d (62 g).

[1201] MS (ESI, [M+H] + )m / z:206.1.

[1202] Step 4: Preparation of intermediate 38e

[1203] Intermediate 38d (30 g) and sulfuric acid (200 mL) were added sequentially to the reaction flask. A mixed solution of nitric acid (11.05 g) and sulfuric acid (4 mL) was slowly added under an ice bath. After the addition was complete, the temperature was slowly warmed to room temperature and the reaction was allowed to react for 1 h. The reaction solution was slowly poured into 2 L of ice water and extracted with ethyl acetate. The organic phase was collected and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was separated and purified by silica gel column chromatography to obtain Intermediate 38e (29.3 g).

[1204] MS (ESI, [M+H] + )m / z:251.1.

[1205] Step 5: Preparation of intermediate 38f

[1206] Intermediate 38e (29 g), ethanol (300 mL), and stannous chloride dihydrate (130.76 g) were added sequentially to the reaction flask, and the mixture was stirred at room temperature for 4 h. The reaction solution was concentrated, and dichloromethane (1 L) and water (0.5 L) were added to the residue. Saturated sodium bicarbonate solution was slowly added under an ice bath to adjust the pH to 9-10. The organic phase of the filtrate was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was separated and purified by silica gel column chromatography to obtain intermediate 38f (24.3 g).

[1207] MS (ESI, [MH] - )m / z:219.1.

[1208] Step 6: Preparation of Intermediate 38g

[1209] Intermediate 38f (24 g) and DCM (200 mL) were added sequentially to a reaction flask. NBS (21.34 g) was added at 0°C, and the mixture was reacted at room temperature for 1 h. The reaction solution was added with 500 mL of DCM and 500 mL of water. The organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain Intermediate 38g (22.4 g).

[1210] MS (ESI, [M+H] + )m / z:299.2.

[1211] 1 H NMR (500MHz, DMSO-d6) δ7.52(d,J=8.9Hz,1H),7.17(d,J=8.9Hz,1H),4.87(s,2H),4.19–4.11(m,4H),1.20(t,J=7.1Hz,3H).

[1212] Step 7: Preparation of Intermediate 38h

[1213] Intermediate 38g (30.0g), ethoxyethylene borate (24.83g), cesium carbonate (94.25g), palladium acetate (2.16g), Ruphos (9.00g), and 1,4-dioxane (500mL) were added to the reaction flask and stirred at 100°C. After the reaction was completed, water (1000mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography to obtain intermediate 38h (14.50g).

[1214] MS (ESI, [M+H] + )m / z:291.11.

[1215] Step 8: Preparation of intermediate 38j

[1216] Intermediate 38i (20 g), MeOH (500 mL), trimethyl orthoformate (61.99 g), and p-toluenesulfonic acid (2.01 g) were added to a reaction flask and stirred at room temperature overnight. After confirming the completion of the reaction, saturated NaHCO3 solution (100 mL) was added to the reaction solution. The reaction solution was rotary evaporated, and water (200 mL) was added to the residue. The solution was extracted with DCM. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain intermediate 38j (21.65 g), which was directly used for the next reaction.

[1217] Step 9: Preparation of intermediate 38k

[1218] Intermediate 38h (7.5 g), intermediate 38j (16.84 g), acetonitrile (150 mL), iodine (656 mg), and triethylsilane (6.01 g) were added to a reaction flask and stirred at room temperature overnight. After the reaction, sodium thiosulfate solution (100 mL) was added to the reaction solution, and the reaction solution was rotary evaporated. Water (200 mL) was added to the residue and extracted with DCM. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography to obtain intermediate 38k (5.05 g).

[1219] MS (ESI, [M+H]+) m / z: 446.16.

[1220] Step 10: Preparation of Intermediate 38l

[1221] Intermediate 38k (5.00 g) and DCM (100 mL) were added to the reaction flask, and a 1,4-dioxane hydrochloride solution (4 M, 4.21 mL) was added dropwise with stirring. The mixture was stirred at room temperature for 1 hour. After the reaction, 200 mL of water was added to the reaction solution, and the mixture was shaken and allowed to stand to separate. The aqueous layer was extracted with DCM, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography to obtain intermediate 38l (1.35 g).

[1222] MS (ESI, [M+H]+) m / z: 400.15.

[1223] Step 11: Preparation of Intermediate 38m

[1224] Intermediate 38l (1.30 g), acrylamide (254 mg) and anhydrous THF (30 mL) were added to a reaction flask, and a THF solution of potassium tert-butoxide (4.88 mL, 4.88 mmol) was slowly added dropwise at -5°C. The reaction was allowed to complete at room temperature. After the reaction was completed, the reaction solution was added dropwise to a stirring mixture of saturated NH4Cl solution (100 mL) and ethyl acetate (50 mL). The mixture was shaken and allowed to stand for stratification. The aqueous layer was extracted with EA (50 mL). The combined organic ...

Claims

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

2. The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound of formula I-AA is selected from the compound of formula I-1, in, Ring A is absent or selected from C 5-10 Cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; Ring B is selected from phenyl; Ring C is selected from isoxazolyl or furyl; Each R 1 independently selected from halogen, -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 are 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 are independently selected from halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy or halogenated C 1-4 alkyl; m, p and q are independently selected from 0, 1, 2, 3 or 4.

3. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Ring A is absent or selected from C 5-7 5- to 10-membered cycloalkenyl, 5- to 10-membered heterocycloalkenyl, phenyl, or 5- to 6-membered heteroaryl; Alternatively, Ring A is absent or selected from C 5-6 5- to 9-membered cycloalkenyl, 5- to 9-membered heterocycloalkenyl, phenyl or 5- to 6-membered heteroaryl; Alternatively, ring A is absent or selected from cyclopentenyl, monocyclohexenyl, bicyclohexenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine 1-Hydroxy, ...

4. The compound according to any one of claims 1 to 3, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Structural fragments Selected from Alternatively, a structural fragment Selected from Alternatively, a structural fragment Selected from Alternatively, a structural fragment Selected from 5. The compound according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Each R 1 independently selected from halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy or halogenated C 1-3 alkyl; Or, each R 1 are independently selected from fluorine, chlorine, bromine, -OH, -NH2 or -CN.

6. The compound according to any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The L is selected from C 1-30 Alkylene, C 2-30 Alkenylene or C 2-30 Alkynylidene, the C 1-30 Alkylene, C 2-30 Alkenylene or C 2-30 One or more -CH2- in the alkynylene group are optionally replaced by -O-, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl, 5-12 membered heteroaryl, -NH-, -N(C 1-6 Alkyl)- or -S-substituted, the C 1-30 Alkylene, C 2-30 Alkenylene or C 2-30 Alkyne is optionally substituted with one or more substituents; Alternatively, the L is selected from -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -、-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 -,in, Cy 1 Selected from a bond, or optionally one or more R a Substituted with the following groups: C 3-12 Cycloalkyl, 4-12 membered heterocycloalkyl or 4-12 membered heterocycloalkenyl; LNK, LNK 1 and LNK 2 are independently selected from a bond, C 1-12 Alkylene or C 1-12 heteroalkylene; Cy 2 Selected from a bond, or optionally one or more R b Substituted with the following groups: C 3-12 Cycloalkyl, 4-12 membered heterocycloalkyl, or 4-12 membered heterocycloalkenyl; Each R a and R b Each independently selected from halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 1-4 Alkylamino, di-C 1-4 Alkylamino, C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl.

7. The compound according to claim 6, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein Cy 1 is selected from a bond, or optionally replaced by one or more R a Substituted with the following groups: C 4-11 Cycloalkyl, 4-11 membered heterocycloalkyl or 4-11 membered heterocycloalkenyl; Alternatively, Cy 1 Selected from optionally one or more R a substituted piperidinyl, diazaspironanyl, piperazinyl, monoazaspironanyl, cyclohexyl, spironanyl, azetidinyl, octahydrocyclopentylpyrrolyl, azabicyclononanyl, monoazaspiroundecyl, diazaspiroundecyl, pyrrolidinyl, or tetrahydropyridinyl; Alternatively, Cy 1 Selected from optionally one or more R a Substituted with the following groups:

8. The compound according to claim 6, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein Cy 2 is selected from a bond, or optionally replaced by one or more R b Substituted with the following groups: C 4-11 Cycloalkyl or 4-11 membered heterocycloalkyl; Alternatively, Cy 2 is selected from a bond, or optionally replaced by one or more R b substituted cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl or piperidinyl; Alternatively, Cy 2 Select from key, 9. The compound according to claim 6, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein Structural fragment -L- or -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -Selected 10. The compound according to any one of claims 1 to 9, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Structural fragments Selected from 11. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Structural fragments Selected from 12. The compound according to any one of claims 1 to 11, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I-AA or the compound of formula I-1 is selected from the compound of formula I, formula I-A1, or formula IA, Alternatively, wherein the compound of formula I-AA or the compound of formula I-1 is selected from a compound of formula I-1A, formula I-2A, formula I-3A, formula I-4A, formula I-5A, formula I-6A, formula I-7A, formula I-8A, formula I-9A, formula I-10A, formula I-11A, formula I-12A, formula I-13A, formula I-14A, formula I-15A, formula I-16A or formula I-17A, in, X is selected from CH or N; Alternatively, the compound of formula I-AA or the compound of formula I-1 is selected from the group consisting of compounds of formula I-1A-1, formula I-2A-1, formula I-3A-1, formula I-4A-1, formula I-5A-1, formula I-6A-1, formula I-7A-1, formula I-8A-1, formula I-9A-1, formula I-10A-1, formula I-11A-1, formula I-12A-1, formula I-13A-1, formula I-14A-1, formula I-15A-1, formula I-16A-1, or formula I-17A-1 wherein X is selected from CH or N.

13. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from C 5-6 Cycloalkenyl, 5-8 membered heterocycloalkenyl 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; Ring C is selected from isoxazolyl or furyl; Each R 1 independently selected from halogen, -OH, -NH2, -CN or C 1-3 Alkyl (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 are independently selected from a bond or C 1-3 Alkylene, Cy 1 Selected from bond, C 3-7 Cycloalkyl, 4-7 membered heterocycloalkyl or 5-7 membered heterocycloalkenyl, Cy 2 Selected from bond, C 3-7 Cycloalkyl, 4-7 membered heterocycloalkyl or 5-7 membered hetero Cycloalkenyl, and Cy 1 and Cy 2 Not a key at the same time; X 1 、X 2 、X 3 and X 4 are 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 are independently selected from halogen, -OH, -NH2, -CN or C 1-3 Alkyl (such as methyl, ethyl, propyl); m is selected from 1 or 2; p and q are each independently selected from 0 or 1.

14. The compound according to any one of claims 1 to 13, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from the following compounds:

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

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

17. The compound, moiety, stereoisomer, derivative or pharmaceutically acceptable salt thereof according to claim 15 or 16, wherein: The compound is selected from:

18. Use of the compound, portion, isomer, derivative or pharmaceutically acceptable salt thereof according to any one of claims 15 to 17 in a Protac molecule; or for constituting a portion of a Protac molecule; or for degrading androgen receptor (AR), wherein the compound exists in the form of a Protac molecule.

19. A pharmaceutical composition comprising a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, or a compound, a moiety, an isomer thereof, a derivative thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 15 to 17.

20. Use of a compound according to any one of claims 1 to 14, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a compound, a portion, an isomer thereof, a derivative thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 15 to 17, or a pharmaceutical composition according to claim 19 in the preparation of a medicament for preventing or treating a disease that is treated by degrading a target protein bound to a targeting ligand.

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